BR102016020905A2 - REPLACED HETEROARIS PIRAZOLIL AND ITS USE AS MEDICINAL PRODUCTS - Google Patents

Abstract

The invention relates to novel substituted heteroaryls of formula 1 or formula 1. wherein a is n or ch, where r 2 is selected from the group consisting of -C 1-3 alkyl, -C 1-3 haloalkyl, f, br, cl, wherein y is selected from -o- or -ch 2 - and wherein r3 is as defined in claim 1, and the pharmaceutically acceptable salts thereof, are the use of those compounds mentioned above for the treatment of diseases such as asthma, dpoc, allergic rhinitis, allergic dermatitis, lupus erythematosus, lupus nephritis and rheumatoid arthritis.

Description

(54) Title: HETEROARIS PIRAZOLILSUBSTITUADOS AND THEIR USE AS MEDICINES (51) Int. Cl .: C07D 471/04; C07D 401/14; C07D 407/14; C07D 487/04; A61P 29/00; (...) (73) Holder (s): BOEHRINGER INGELHEIM INTERNATIONAL GMBH (72) Inventor (s): MATTHIAS HOFFMANN; GEORG DAHMANN; CHRISTIAN GNAMM; JOHN SCOTT; CLIVE MCCARTHY; DANIEL FANDRICK (74) Attorney (s): FLÁVIA SALIM LOPES (57) Abstract: Is the invention related to new substituted heteroaris of formula 1 or formula 1? where A is N or CH, where R2 is selected from the group consisting of -Cl-3alkyl, -Cl-3-haloalkyl, F, Br, Cl, where Y is selected from -O- or -CH2-, and wherein R3 is defined as in claim 1, and the pharmaceutically acceptable salts thereof, for the use of those compounds mentioned above for the treatment of diseases such as, for example, asthma, COPD, allergic rhinitis, allergic dermatitis, lupus erythematosus, lupus nephritis and rheumatoid arthritis.

1/176

PIRAZOLIL-SUBSTITUTED HETEROARIS AND ITS USE AS

MEDICINES [001] The invention relates to substituted heteroaris of formula 1

or formula 1 '

where A is N or CH, where Y is -O- or -CH ₂ -, where R ³ is an ortho-position or a meta-position substituent on the pyrazolyl ring of formula 1 and is selected from the group consisting of in -Ci-6-linear or branched alkyl, -Ci-6-haloalkyl, -C3-6-cycloalkyl, -Ci-4-alkylene-C3-6cycloalkyl, a five or six membered monocyclic heterocycle with 1, 2 or 3 heteroatoms, each selected

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2/176 regardless of O, S or N, a 9 to 10 membered bicyclic heterocycle with 1, 2 or 3 heteroatoms, each independently selected from O, S or N, where R ³ is optionally substituted by one, two, three or four substituents, each independently of the other, selected from the group consisting of halogen (F), -C1-3-alkyl, oxo, -CN, where R ² is selected from the group consisting of -C1- 3-alkyl, -C1-3-haloalkyl, F, Br, Cl, and the pharmaceutically acceptable salts of the compounds mentioned above.

1. Basics of the invention

1.1 SYK Inhibitors [002] The present invention describes compounds that inhibit the protein kinase SYK (spleen tyrosine kinase), its preparation and formulation and its use for the preparation of a medicament.

[003] SYK is an intracellular tyrosine kinase that has an important mediating function in signal transduction of different receptors in B cells, mast cells, monocytes, macrophages, neutrophils, T cells, dendritic cells and epithelial cells. Receptors in which SYK plays an important role in signal transduction include, for example, receptors for IgE (FceRI) and IgG (FcyR1) in mast cells and B cells, the B cell receptor (BCR) and the T cell receptor ( TCR) in B and T cells, the ICAM1 receptor (ICAM1R) in respiratory tract epithelial cells, the DAP12 receptor in natural killer cells, dendritic cells and osteoclasts, the dectin 1 receptor in a subpopulation of T-helper cells (cells Th-17) as well

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3/176 as integrin receptors for β1, β2 and β3 integrins in neutrophils, monocytes and macrophages (Wong et al; Expert Opin. Investig. Drugs (2004) 13 (7), 743-762; Ulanova et al; Expert Opion. Ther. Target (2005) 9 (5); 901-921; Wang et al; J. Immunol. (2006) 177, 6,859-6,870; Leib und Gut-Landmann et al; Nature Immunology (2007) 8, 630-638; Slack et al, European J. Immunol. (2007) 37, 1,600-1,612). Molecular processes are best described for FceRI signal transduction. In mast cells, the binding of IgE to FceRI causes the cross-linking of IgE receptors and the recruitment and activation of Lyn (a tyrosine kinase of the Src family). Lyn activates phosphorylates the so-called ITAM motifs, which are present in many of the receptors listed above and thus generates binding sites for the SH2 domain of SYK. As a result of binding to the ITAM motif, SYK is activated and then phosphorylates various substrates that are necessary for the release of allergic and inflammatory mediators, such as histamine and B-hexosamidase (bHA), as well as for the synthesis of lipid mediators. such as prostaglandins and leukotrienes.

[004] In view of its central function in different signal transduction pathways, SYK has been discussed as a therapeutic target for different diseases such as, for example, allergic rhinitis, asthma, autoimmune diseases, rheumatoid arthritis, osteopenia, osteoporosis, COPD and several leukemias and lymphomas (Wong et al.; Expert Opin. Investig. Drugs (2004) 13 (7), 743-762; Ulanova et al; Expert Opion. Ther. Target (2005) 9 (5); 901-921 ; Sigh and Masuda. Annual Reports in Medicinal Chemistry (2007) Vol. 42; 379-391; Bajpai et al; Expert Opin. Investig. Drugs (2008) Vol. 15 (5); 641-659;

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Masuda and Schmitz; PPT (2008) Vol. 21; 461-467; Riccaboni et al, Drug Discovery Today (2010) Vol. 00 (0); 517-530; Efremov and Luarenti, Expert Opin. Investig. Drugs. (2011) 20 (5): 623-36).

[005] Allergic rhinitis and asthma are diseases associated with allergic reactions and inflammatory processes and that involve different types of cells, such as mast cells, eosinophils, T cells and dendritic cells. After exposure to allergens, the high-affinity immunoglobulin receptors for IgE (FceRI) and IgG (FcyR1) are activated and induce the release of pro-inflammatory and bronchoconstrictor mediators. An inhibitor of SYK kinase activity must therefore be able to inhibit these steps.

[006] Rheumatoid arthritis (RA) is an autoimmune disease in which the bones and ligament structures surrounding the joints are progressively destroyed. In the pathophysiology of RA, B cells play a significant role, as demonstrated, for example, by the therapeutic use of rituximab, a B-cell depleting antibody. In addition to the function of SYK in BCR signal transduction (which, after being stimulated also induces the release of pro-inflammatory mediators), SYK also plays an important role in the maturation and proliferation of B cells (Cheng et al. Nature (1995) 378, 303-306, Cornall et al, PNAS (2000) 97 ( 4), 1,713-1,718). An inhibitor of SYK kinase activity may therefore offer a therapeutic option for the treatment of autoimmune diseases, such as RA and diseases with an increased proliferation of B cells, such as B cell lymphomas.

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5/176 [007] Chronic obstructive pulmonary disease (COPD) is characterized by successive deterioration of lung function and chronic inflammation of the airways, which is initiated and produced by harmful substances of all types and contributes to the maintenance of the course of disease. At a cellular level, in COPD there is, in particular, a multiplication of T lymphocytes, neutrophils, granulocytes and macrophages. In particular, there is an increase in the number of CD8 positive lymphocytes, which is directly connected to the deficit in lung function. Another characteristic of COPD is acute deterioration of lung function (exacerbations), characterized by viral infections (for example, Rhinovirus), or bacterial infections (for example, Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis).

[008] In view of the pro-inflammatory function of SYK in macrophages, T cells and neutrophils, as described above (see: Wong et al .; Expert Opin. Investig. Drugs (2004) 13 (7), 743-762; and references therein), an inhibitor of SYK kinase activity could be a new therapeutic approach for the treatment of inflammatory processes that support COPD. It has also been shown that SYK in epithelial cells of the respiratory tract is involved in ICAM1R-mediated uptake and subsequent replication of the rhinovirus, and that a si-RNA against SYK blocks these steps (Wang et al; J. Immunol. (2006) 177, 6,859-6,870; Lau et al; J. Immunol. (2008) 180, 870-880). Thus, an inhibitor of SYK kinase activity could also be used therapeutically in exacerbations caused by rhinovirus.

[009] Several studies suggest that SYK is involved in the malignant transformation of lymphocytes (summarized in Sigh and

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Masuda, Annual Reports in Medicinal Chemistry (2007) Vol. 42; 379-391). A TEL-SYK fusion protein with a constitutive activity of SYK transformed B cells of a patient with myelodysplastic syndrome, an ITK-SYK constitutively active fusion protein was isolated from patients with peripheral T cell lymphomas (PTCL). In addition, constitutively active SYK was found in patients' B-cell lymphoma cells, especially in acute B-cell lymphoblastic leukemia (B-ALL), follicular lymphoma (FL), large diffuse B-cell lymphoma (DLBCL), lymphomas of mantle cell and non-Hodgkin B-cell lymphomas (NHLs), as well as in acute myeloid leukemia (AML). Based on these data, it appears that SYK is a proto-oncogene in hematopoietic cells and represents a potential target for the treatment of certain leukemias and lymphomas.

[010] Idiopathic thrombocytopenic purpura (ITP) is an autoimmune disease in which IgG autoantibodies against antigens present on platelets bind and destroy platelets. ITP patients have an accelerated clearance of platelets coated with circulating IgG by means of macrophages in the spleen and liver. In view of the SYK FcyR-mediated proinflammatory function in macrophages, a SYK inhibitor is considered to have a therapeutic benefit in FcyR-mediated cytopenias such as, for example, ITP. In fact, the SYK inhibitor R788 (R406) increased platelet counts in an open, single-center study in patients with ITP (Podolanczuk et al .; Blood (2009) 113, 3,154-3,169).

[011] Bullous pemphigoid is characterized by the presence of specific immunoglobulin G (IgG) autoantibodies

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7/176 for BP230 (BPAgl) and BP180 (BPAg2) bullous pemphigoid antigens. Pemphigus vulgaris (Venugopal et al. Dermatol. Clin. 2011; 29: 373-80) is a chronic skin disease that forms blisters with skin lesions that rarely itch but are often painful. Pemphigus vulgaris is an autoimmune disease caused by IgG autoantibodies directed against desmoglein 1 and desmoglein 3 that result in the loss of cohesion between keratinocytes in the epidermis. It is characterized by extensive flabby blisters and mucocutaneous erosions. In both diseases, IgG autoantibodies bind to the Fc gamma receptor (FcRy) and activate FcRy and downstream signaling via SYK kinase. Thus, an inhibitor of SYK kinase activity that blocks downstream FcRy signaling could be used therapeutically to treat patients with bullous pemphigoid and pemphigus vulgaris.

[012] Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that can affect basically any organ in the body. It is characterized by multisystemic microvascular inflammation and the presence of autoantibodies. FcyR-deficient mice are protected from various aspects of SLE in preclinical models related to the disease, suggesting that a SYK inhibitor may have a therapeutic benefit in SLE in view of the FcyR-mediated pro-inflammatory function of SYK in various cells .

1.2 Established technique [013] 1,6-Naphthyridines are known as SYK inhibitors. For example, US Patent Number US 3,928,367, US 4,017,500, US 4,115,395 and US 4,260,759 describe 5-amino1,6-naphthyridines with an antifungal activity , and

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8/176 antibacterial. In addition, WO 9918077 describes 5piperazinyl-1,6-naphthyridines as serotonin antagonists. In addition, U.S. Patent 7,321,041 describes substituted 1,6-naphthyridines as SYK inhibitors; however, these 1,6-naphthyridines have a completely different substitution pattern from the compounds according to the invention. In addition, WO 2011092128 discloses 1,6naphthyridines which are substituted at positions 5 and 7.

[014] In WO 2012/167733, WO 2012/167423 and WO 2012/123312, other naphthyridine derivatives, for example, pyrido [3,4-b] pyrazines, which were also substituted in positions 5 and 7, were disclosed as SYK inhibitors.

[015] Additionally, WO 01/83485 discloses substituted imidazopyrimidines and triazolopyrimidines as SYK inhibitors, while WO 2008/113469 discloses substituted triazolopyrimidines imidazo and GSK 3β inhibitors.

[016] Quinolones are also known as SYK inhibitors. For example, WO 2006038041 and WO 2013014060 disclose quinoline compounds that are substituted at positions 5 and 7, however, the substitution pattern - in particular at position 7 - is completely different from those of the compounds of formula 1 of the present invention.

[017] Additionally, also PCT / EP2015055228, PCT / EP2015055237 and PCT / EP2015055242 have been deposited (not yet published). Here, several pyrazolyl-substituted heteroaris are also disclosed which are all unsubstituted at the 3-position of the compounds.

[018] In addition, WO 2015017610 also reveals pyrazolyl-substituted heteroaris that have all, modifications

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9/176 plants compared to the compounds of the present invention.

[019] In addition, Thoma et al “Orally Bioavailabe Inhibitors of SYK With Activity in a Rat PK / PD Model, Bioorganic & Medicinal Chemistry Letters (2015) http://dx.doi.org/10.1016/j-bmcl.2015.08037 (article in print) was published online, in which SYK inhibitors with similar benzo- and pyrido-thiazole / isothiazole structures are disclosed. However, the most promising compound, N ° 5, with satisfactory SYK inhibitory capabilities, has not been further investigated as a result of the fact that N ° 5 compound also inhibits Aurora B (AURB), which severely impaired selectivity for SYK of the compound

No. 5.

[020] Consequently, it was the aim of the present invention to provide effective SYK inhibitors with excellent SYK inhibitory capabilities, and which also exhibit sufficient selectivity for SYK.

[021] Surprisingly, it has now been found that the compounds of formulas 1 and 1 'of the present invention are particularly well suited for the treatment of respiratory complaints, allergic diseases, osteoporosis, gastrointestinal diseases, autoimmune diseases, inflammatory diseases and diseases of the peripheral nervous system or central, particularly for the treatment of asthma, allergic rhinitis, rheumatoid arthritis, allergic dermatitis, lupus erythematosus (SLE) and COPD, in particular because all of these compounds of the present invention exhibit the following desired capabilities at the same time:

- high SYK inhibition (reflected by low IC50 values with respect to SYK inhibition (IC50 value <10

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10/176 nmol in the SYK and EC50 inhibition assay <150 nmol in the CD63 assay)).

- excellent selectivity for SYK, which means very low inhibition of other kinases such as Aurora B (reflected by high IC50 values in relation to AURB inhibition), FLT3 (reflected by high IC50 values in relation to inhibition of FLT3), GSK3p (reflected by high IC50 values with respect to GSK3p inhibition) etc.

- good metabolic stability, which can be measured by a low percentage of Qh in human hepatocytes (% Qh <20).

2. DESCRIPTION OF THE INVENTION [022] The present invention relates to a compound of formula 1,

where A is N or CH, where Y is -0- or CH ₂ , where R ³ is an ortho-position or meta-position substituent on the pyrazolyl ring of formula 1 and is selected from the group consisting of - Straight or branched C 1-6 alkyl, -Ci-6-haloalkyl, -C3-6-cycloalkyl, -Ci-4-alkylene-C3-6cycloalkyl, a five or six membered monocyclic heterocycle with 1, 2 or 3 hetero atoms, each selected

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11/176 regardless of 0, S or N, a 9 to 10 membered bicyclic heterocycle with 1, 2 or 3 heteroatoms, each independently selected from 0, S or N, where R ³ is optionally substituted by one, two, three or four substituents, each independently of the other, selected from the group consisting of halogen (F), -Ci-3-alkyl, oxo, -CN, where R ² is selected from the group consisting of -C1- 3alkyl, -Ci-3-haloalkyl, F, Br, Cl, and the pharmaceutically acceptable salts of the compounds mentioned above.

[023] In a preferred embodiment, the invention relates to compounds of formula 1 '

wherein A, Y, R ² and R ³ are defined as mentioned above, and the pharmaceutically acceptable salts of the compounds mentioned above.

[024] In an additional preferred embodiment, the invention relates to compounds of formula 1 or formula 1 ', where A is N or CH, where Y is -0- or CH ₂ , where R ³ is a substituent in the ortho-position or the meta-position of the formula 1 pyrazolyl ring and is selected

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12/176 of the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, -Ci-6-fluoralkyl, cyclopropyl, cyclobutyl, cyclopentyl, -Ci-2-alkylene-C3- 6cyclopropyl, -C1-2-alkylene-C3-6-cyclobutyl, -C1-2-alkyleneC3-6-cyclopentyl, a five- or six-membered monocyclic heterocycle with 1 oxygen atom, a 9 to 10-membered bicyclic heterocycle with 1 or 2 heteroatoms, each independently selected from O, S or N, where R ³ is optionally substituted by one, two, three or four substituents, each independently from the other, selected from the group consisting of F, Cl, Br, methyl, ethyl, -CN, where R ² is selected from the group consisting of methyl, ethyl, isopropyl, -CF3, F, Br, Cl, and the pharmaceutically acceptable salts of the compounds mentioned above.

[025] In another preferred embodiment, the invention relates to the aforementioned compounds of formula 1 or formula 1 ', where A is N or CH, where Y is -O- or -CH2-, where R ³ is an ortho-position or meta-position substituent on the formula 1 pyrazolyl ring and is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, - (CH2) 2 -CF3, -CH2-CH2F, cyclopropyl, cyclobutyl, cyclopentyl, -methylene-C3-6cyclopropyl, tetrahydrofuranyl, tetrahydropyranyl, hexahydrofuropiranyl, where R ³ is optionally substituted by one, two, three or four substituents, each, regardless of one

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13/176 other, selected from the group consisting of F, Cl, Br, methyl, ethyl, -CN, wherein R ² is selected from the group consisting of methyl and F, and the pharmaceutically acceptable salts of the compounds mentioned above.

[026] In another preferred embodiment, the invention relates to the aforementioned compounds of formula 1 or formula 1 ', wherein R ² is methyl, and the pharmaceutically acceptable salts of the compounds mentioned above.

[027] In an additional preferred embodiment, the invention relates to the aforementioned compounds of formula 1 or formula 1 ', wherein R ² is F, and the pharmaceutically acceptable salts of the compounds mentioned above.

[028] In an additional preferred embodiment, the invention relates to the aforementioned compounds of formula 1 or formula 1 ', wherein R ³ is a meta-position substituent on the pyrazolyl ring of formula 1, and the pharmaceutically acceptable salts of the compounds mentioned previously.

[029] In another preferred embodiment, the invention relates to the aforementioned compounds of formula 1 or formula 1 ', wherein R ³ is an ortho-position substituent on the pyrazolyl ring of formula 1, and the pharmaceutically acceptable salts of the compounds previously mentioned.

[030] In an additional preferred embodiment, the invention relates to the aforementioned compounds of formula

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14/176 or formula 1 ', where R ³ is replaced by one, two, three or four substituents, each independently of the other, selected from the group consisting of F, methyl and CN, and the pharmaceutically acceptable salts of the compounds mentioned above.

[031] In another preferred embodiment, the invention relates to the aforementioned compounds of formula 1 or formula 1 ', where A is N or CH, where Y is -CH ₂ -, where R ³ is a substituent in ortho-position or meta-position of the formula 1 pyrazolyl ring and is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, - (CH ₂ ) 2-CF ₃ , -CH ₂ -CH ₂ F, where R ³ is optionally substituted by one, two, three or four substituents, each independently of the other, selected from the group consisting of F, methyl and -CN, and the pharmaceutically acceptable salts of the compounds mentioned above.

[032] In a particularly preferred embodiment, the invention relates to the aforementioned compound of formula 1 or formula 1 ', which is selected from the group consisting of:

O

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15/176 and the pharmaceutically acceptable salts of the compounds mentioned above.

[033] In an additional preferred embodiment, the invention relates to the aforementioned compounds of formula 1 or formula 1 ', where A is N or CH, where Y is -0- or CH ₂ , where R ³ is an ortho-position or meta-position substituent on the formula 1 pyrazolyl ring and is selected from the group consisting of isopropyl, isobutyl and t-butyl, where R ³ is not further substituted, and the pharmaceutically acceptable salts of the compounds mentioned previously.

[034] In another particularly preferred embodiment, the invention relates to the aforementioned compound of formula 1 or formula 1 ', which is selected from the group consisting of:

-N

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16/176 and the pharmaceutically acceptable salts of the aforementioned compound.

[035] In another particularly preferred embodiment, the invention relates to the aforementioned compound composed of formula 1 or formula 1 ', which is:

and the pharmaceutically acceptable salts of the aforementioned compound.

[036] In another particularly preferred embodiment, the invention relates to the aforementioned compound of formula 1 or formula 1 ', which is:

and the pharmaceutically acceptable salts of the aforementioned compound.

[037] In another particularly preferred embodiment, the invention relates to the aforementioned compound of formula 1 or formula 1 ', which is:

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17/176

and the pharmaceutically acceptable salts of the aforementioned compound.

[038] In another particularly preferred embodiment, the invention relates to the aforementioned compound of formula 1 or formula 1 ', which is:

and the pharmaceutically acceptable salts of the aforementioned compound.

[039] In another particularly preferred embodiment, the invention relates to the aforementioned compound of formula 1 or formula 1 ', which is:

and the pharmaceutically acceptable salts of the compound

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18/176 mentioned earlier.

[040] In another particularly preferred embodiment, the invention relates to the aforementioned compound of formula 1 or formula 1 ', which is:

and the pharmaceutically acceptable salts of the aforementioned compound.

[041] In another particularly preferred embodiment, the invention relates to the aforementioned compound of formula 1 or formula 1 ', which is:

and the pharmaceutically acceptable salts of the aforementioned compound.

[042] In another particularly preferred embodiment, the invention relates to the aforementioned compound of formula 1 or formula 1 ', in which:

where A is N or CH,

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19/176 where Y is -CH ₂ -, where R ³ is an ortho-position or meta-position substituent on the pyrazolyl ring of formula 1 and is selected from the group consisting of:

cyclopropyl, cyclobutyl, cyclopentyl, -methylene-C3-6cyclopropyl, tetrahydrofuranyl, tetrahydropyranyl, hexahydrofuropiranyl, where R ³ is optionally substituted by one, two, three or four substituents, each, independently of the other, selected from the group consisting of F, methyl and -CN, and the pharmaceutically acceptable salts of the compounds mentioned above.

[043] In another particularly preferred embodiment, the invention relates to the aforementioned compound of formula 1 or formula 1 ', which is selected from the group consisting of:

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20/176

and the pharmaceutically acceptable salts of the compounds mentioned above.

[044] In another particularly preferred embodiment, the invention relates to the aforementioned compound of formula 1 or formula 1 ', which is:

and the pharmaceutically acceptable salts of the compounds mentioned above.

[045] In another particularly preferred embodiment, the invention relates to the aforementioned compound of formula 1 or formula 1 ', which is:

and the pharmaceutically acceptable salts of the compounds

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21/176 mentioned earlier.

[046] In another particularly preferred embodiment, the invention relates to the aforementioned compound of formula 1 or formula 1 ', which is:

and the pharmaceutically acceptable salts of the compounds mentioned above.

[047] In another particularly preferred embodiment, the invention relates to the aforementioned compound of formula 1 or formula 1 ', which is:

and the pharmaceutically acceptable salts of the compounds mentioned above.

[048] In another particularly preferred embodiment, the invention relates to the aforementioned compound of formula 1 or formula 1 ', which is:

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22/176, ο —Ν

Ν and the pharmaceutically acceptable salts of the compounds mentioned above.

[049] In another particularly preferred embodiment, the invention relates to the aforementioned compound of formula 1 or formula 1 ', which is:

and the pharmaceutically acceptable salts of the compounds mentioned above.

[050] In another particularly preferred embodiment, the invention relates to the aforementioned compound of formula 1 or formula 1 ', which is:

and the pharmaceutically acceptable salts of the compounds

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23/176 mentioned earlier.

[051] In another particularly preferred embodiment, the invention relates to the aforementioned compound of formula 1 or formula 1 ', which is:

and the pharmaceutically acceptable salts of the compounds mentioned above.

[052] In an additional preferred embodiment, the invention relates to the compounds mentioned above for the treatment of a disease that can be treated by inhibiting the SYK enzyme.

[053] In another preferred embodiment, the invention relates to the compounds mentioned above for the treatment of a disease selected from the group consisting of allergic rhinitis, asthma, COPD, adult respiratory distress syndrome, bronchitis, B-cell lymphoma, dermatitis and contact dermatitis, allergic dermatitis, allergic rhinoconjunctivitis, rheumatoid arthritis, antiphospholipid syndrome, Berger's disease, Evans syndrome, ulcerative colitis, antibody-based allergic glomerulonephritis, granulocytopenia, Goodpasture syndrome, hepatitis, Henoch-Schonlein purpura hypersensitivity, immunohemolytic anemia, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura,

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24/176 Kawasaki syndrome, allergic conjunctivitis, lupus erythematosus, lupus nephritis, capsule cell lymphoma, neutropenia, unfamiliar lateral sclerosis, arteriosclerosis, Crohn's disease, multiple sclerosis, myasthenia gravis, osteoporosis, osteolytic diseases, osteopenia, psoriasis , Sjogren's syndrome, scleroderma, T-cell lymphoma, urticaria / angioedema, Wegener's granulomatosis, celiac disease, Waldenstrom's macroglobulinemia, systemic sclerosis (SSc), malaria and dengue.

[054] In an additional preferred embodiment, the invention relates to the compounds mentioned above for the treatment of a disease selected from the group consisting of asthma, COPD, allergic rhinitis, adult respiratory distress syndrome, bronchitis, allergic dermatitis, dermatitis of contact, idiopathic thrombocytopenic purpura, rheumatoid arthritis, lupus erythematosus, lupus nephritis, systemic sclerosis (SSc) and allergic rhinoconjunctivitis.

[055] In another preferred embodiment, the invention relates to the aforementioned compound for the treatment of a disease selected from the group consisting of asthma, COPD, allergic rhinitis, idiopathic thrombocytopenic purpura, allergic dermatitis, lupus erythematosus, lupus nephritis and rheumatoid arthritis .

[056] In an additional preferred embodiment, the invention relates to pharmaceutical formulations that contain one or more of the aforementioned compounds and a pharmaceutically acceptable excipient.

[057] In another preferred embodiment, the invention relates to pharmaceutical formulations that contain one or

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25/176 more of the aforementioned compounds in combination with an active substance selected from the group consisting of anticholinergics, betamimetics, corticosteroids, PDE4 inhibitors, EGFR inhibitors, LTD4 antagonists, CCR3 inhibitors, iNOS inhibitors, CRTH2 antagonists, triple kinase inhibitors against PDGFR, FGFR and VEGFR, HMG-CoA reductase inhibitors and NSAIDs.

[058] In another preferred embodiment, the invention relates to an intermediate compound selected from the group consisting of formula 7

PG,, 0

Hal in formula 8

Hal in formula 11

R ', 3

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26/176 where R ² is F or methyl, where Y is -0- or CH ₂ , and where R ³ is defined as in one of claims 1 to 3 and where Hal is Cl or Br, and where PG is a protecting group selected from the group consisting of benzyl, 1-phenylethyl, 1- (4-methoxyphenyl) ethyl.

[059] In another preferred embodiment, the invention relates to an intermediate compound selected from the group consisting of:

3. TERMS AND DEFINITIONS USED [060] Unless otherwise stated, all substituents are independent of each other. If, for example, a number of C1-6-alkyl groups are possible substituents in a group, in the case of three substituents, for example, C1-6-alkyl could represent, independently of each other, a methyl, an n-propyl and tert-butyl.

[061] Within the scope of this request, in the definition of possible substituents, these can also be presented in the form of a structural formula. An asterisk (*) in the structural formula of the substituent must be understood as being the point of attachment to the rest of the molecule. Beyond

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27/176 In addition, the atom of the substituent after the point of attachment is understood to be the atom in position number 1. Thus, for example, the groups N-piperidinyl (I), 4piperidinyl (II), 2-tolyl (III ), 3-tolyl (IV) and 4-tolyl (V) are represented as follows:

[062] If there is no asterisk (*) in the structural formula of the substituent, each hydrogen atom can be removed in the substituent and the valence thus released by serving as a binding site for the rest of a molecule. So, for example, VI

VI can represent 2-tolyl, 3-tolyl, 4-tolyl and benzyl.

[063] Alternatively to * within the scope of that application, Xi is also understood to be the point of attachment of the group R ¹ to the structure of formula 1, and X2 to be the point of attachment of the group R ² to the structure of formula 1.

[064] The term C1-6-alkyl (including those that are part of other groups) means branched and unbranched alkyl groups with 1 to 6 carbon atoms and the term C1-3 alkyl means branched and unbranched alkyl groups with 1 to 3 carbon atoms. C1-4-alkyl therefore represents branched and unbranched alkyl groups with 1 to 4 carbon atoms. Alkyl groups having 1 to 4 carbon atoms are preferred. Examples of these include: methyl, ethyl, n-propyl, iso-propyl, n-butyl, isoPetition 870170059664, of 17/08/2017, p. 35/185

28/176 butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, neopentyl or hexyl. The abbreviations Me, Et, n-Pr, i-Pr, n-Bu, iBu, t-Bu etc., can also be optionally used for the groups mentioned above. Unless otherwise stated, the definitions propyl, butyl, pentyl and hexyl include all possible isomeric forms of the groups in question. Thus, for example, propyl includes n-propyl and iso-propyl, butyl includes iso-butyl, sec-butyl and tert-butyl etc.

[065] The term Cx-g-alkylene ”(including those that are part of other groups) means branched and unbranched alkylene groups with 1 to 6 carbon atoms and the term C1-4 alkylene” means branched and non-alkylene groups branched with 1 to 4 carbon atoms. Alkylene groups having 1 to 4 carbon atoms are preferred. Examples of these include: methylene, ethylene, propylene, 1methylene, dimethylethylene, dimethylpropylene, butylene, 1-methylpropylene, 1,11,2-dimethylethylene, pentylene, 1,12,2-dimethylpropylene, 1,2dimethylpropylene, 1,3-dimethylpropylene or hexylene. Unless otherwise stated, the definitions propylene, butylene, pentylene and hexylene include all possible isomeric forms of the groups in question with the same number of carbons. Thus, for example, propyl also includes 1-methylethylene and butylene includes 1-methylpropylene, 1,1-dimethylethylene, 1,2-dimethylethylene.

[066] If the carbon chain is replaced by a group that, together with one or two carbon atoms in the alkylene chain, forms a carbocyclic ring with 3, 5 or 6 carbon atoms, this includes, inter alia, the following examples of

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29/176 rings:

[067] The term C2-6-alkenyl (including those that are part of other groups) means branched and unbranched alkenyl groups with 2 to 6 carbon atoms and the term C2-4-alkenyl means branched and unbranched alkenyl groups 2 to 4 carbon atoms, as long as they have at least one double bond. Alkenyl groups having 2 to 4 carbon atoms are preferred. Examples include: ethylene or vinyl, propenyl, butenyl, pentenyl or hexenyl. Unless otherwise stated, the definitions propenyl, butenyl, pentenyl and hexenyl include all possible isomeric forms of the groups in question. Thus, for example, propenyl includes propenyl and 2-propenyl, butenyl includes 1-, 2- and 3-butenyl, 1-methyl-1-propenyl, 1-methyl-2propenyl, etc.

[068] The term C2-6-alkenylene (including those that are part of other groups) means branched and unbranched alkenylene groups with 2 to 6 carbon atoms and the term C2-4-alkenylene means branched and unbranched alkylene groups with 2 to 4 carbon atoms. Alkenylene groups having 2 to 4 carbon atoms are preferred. Examples of these include: ethylene, propenylene, 1-methylethylene, butenylene, 1-methylpropenylene, dimethylethylene, 1,2-dimethylethylene, pentenylene, 1,1dimethylpropenylene, dimethylpropenylene, 1,2dimethylpropenylene, 1,3-dimethylpropenylene or hexenylene. Unless otherwise stated, the definitions

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30/176 propenylene, butenylene, pentenylene and hexenylene include all possible isomeric forms of the groups in question with the same number of carbons. Thus, for example, propenyl also includes 1-methylethylene and butenylene includes 1-methylpropenylene, 1,1-dimethylethylene, 1,2dimethylethylene.

[069] The term aryl (including those that are part of other groups) means aromatic ring systems with 6 or 10 carbon atoms. Examples include: phenyl or naphthyl, the preferred aryl group being phenyl. Unless stated differently, the aromatic groups can be replaced by one or more groups selected from methyl, ethyl, iso-propyl, tert-butyl, hydroxy, fluorine, chlorine, bromine and iodine.

[070] The term aryl-C1-6-alkylene (including those that are part of other groups) means branched and unbranched alkylene groups with 1 to 6 carbon atoms, which are replaced by an aromatic ring system with 6 or 10 carbon atoms. Examples include: benzyl, 1- or 2-phenylethyl or 1- or 2-naphthylethyl. Unless otherwise stated, aromatic groups may be substituted by one or more groups selected from methyl, ethyl, isopropyl, tert-butyl, hydroxy, fluorine, chlorine, bromine and iodine.

[071] The term heteroaryl-C1-6-alkylene (including those that are part of other groups) means - although already included under aryl-C1-6-alkylene - branched and unbranched alkylene groups with 1 to 6 carbon atoms , which are replaced by a heteroaryl.

[072] If not specifically defined differently, such a heteroaryl includes aromatic groups

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31/176 five or six membered heterocyclic or 5-10 membered bicyclic heteroaryl rings that can contain one, two, three or four heteroatoms selected from oxygen, sulfur and nitrogen, and contain so many conjugated double bonds that an aromatic system is formed. The following are examples of aromatic heterocyclic groups of five or six members or bicyclic heteroaryl rings:

[073] Unless stated differently, these heteroaris can be replaced by one or more groups selected from methyl, ethyl, iso-propyl, tert-butyl, hydroxy, fluorine, chlorine, bromine and iodine.

[074] The following will show examples of heteroarylCi-6-alkylenes:

[075] 0 are part branched C1-6-haloalkyl (including those from other groups) means alkyl and unbranched groups with 1 to 6 carbon atoms, which are replaced by one or more halogen atoms. The term C1-4-alkyl means branched and non-branched alkyl groups

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32/176 branched with 1 to 4 carbon atoms, which are replaced by one or more halogen atoms. Alkyl groups having 1 to 4 carbon atoms are preferred. Examples include: CF3, CHF2, CH2F, CH2CF3.

[076] The term C3-7-cycloalkyl (including those that are part of other groups) means cyclic alkyl groups with 3 to 7 carbon atoms, if not specifically defined differently. Examples include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Unless otherwise stated, cyclic alkyl groups may be replaced by one or more groups selected from methyl, ethyl, iso-propyl, tert-butyl, hydroxy, fluorine, chlorine, bromine and iodine.

[077] If not specifically defined differently, the term C3-io-cycloalkyl also means monocyclic alkyl groups with 3 to 7 carbon atoms and also bicyclic alkyl groups with 7 to 10 carbon atoms, or monocyclic alkyl groups that are in bridge by at least one C1-3-carbon bridge.

[078] The term heterocyclic rings or heterocycle means, unless otherwise stated, five, six or seven membered, saturated, partially saturated or unsaturated heterocyclic rings, which may contain one, two or three heteroatoms selected from oxygen, sulfur and nitrogen, while the ring can be attached to the molecule through a carbon atom or through a nitrogen atom, if one exists. Although included by the term heterocyclic rings or heterocycles, the term saturated heterocyclic ring refers to five, six or seven-membered saturated rings. Examples include:

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1 [079] Although included by the term heterocyclic rings or heterocyclic group, the term partially saturated heterocyclic group refers to the five, six or seven-membered partially saturated rings that contain one or two double bonds, without so many double bonds being produced that a system aromatic is formed, unless specifically defined differently. Examples include:

[080] Although included by the term heterocyclic rings or heterocycles, the term aromatic heterocyclic rings, unsaturated or heteroaryl heterocyclic group refers to the 5- or 6-membered heterocyclic aromatic groups or 5-10 membered bicyclic heteroaryl rings that can contain one, two, three or four heteroatoms selected from oxygen, sulfur and nitrogen, and contain so many conjugated double bonds that an aromatic system is formed, unless not specifically defined differently. Examples of five- or six-membered heterocyclic aromatic groups include:

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Γ ¹ Γ 7 [081] Unless otherwise mentioned, a heterocyclic ring (or heterocycle) can be provided with a keto group. Examples include:

[082] Although covered by the term cycloalkyl, the term bicyclic cycloalkyls generally represents eight-, nine- or ten-membered bicyclic carbon rings. Examples include:

T? Γ 3 P '1 [083] Although already included by the term heterocycle, the term bicyclic heterocycles generally represents eight, nine or ten membered bicyclic rings that may contain one or more heteroatoms, preferably 1-4, more preferably 1-3, still more preferably 1-2, particularly a heteroatom, selected from oxygen, sulfur and nitrogen, unless not specifically defined differently. The ring may be attached to the molecule by means of a ring carbon atom or by means of a ring nitrogen atom, if one exists. Examples include:

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ΗΝ

[084] Although already included by the term aryl, the term bicyclic aryl represents a 5-10 membered bicyclic aryl ring that contains enough conjugated double bonds to form an aromatic system. An example of a bicyclic aryl is naphthyl.

[085] Although already included under heteroaryl, the term bicyclic heteroaryl represents a 5-10 membered bicyclic heteroaryl ring, which may contain one, two, three or four heteroatoms selected from oxygen, sulfur and nitrogen, and contains sufficient conjugated double bonds form an aromatic system, unless specifically defined differently.

[086] Although included by the term bicyclic cycloalkyls or bicyclic aryl, the term fused cycloalkyl or fused aryl represents bicyclic rings in which the bridge that separates the rings represents a direct simple bond. The following are examples of a fused bicyclic cycloalkyl:

[087] Although included by the term bicyclic heterocycles or bicyclic heteroaris, the term fused bicyclic heterocycles of fused bicyclic heteroaris represents 5-10 membered bicyclic hetero rings containing one, two, three or four selected hetero atoms

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36/176 between oxygen, sulfur and nitrogen, and where the bridge that separates the rings represents a direct simple bond. The fused bicyclic heteroaris, moreover, contain enough conjugated double bonds to form an aromatic system. Examples include pyrrolizine, indole, indolizine, isoindole, indazole, purine, quinoline, isoquinoline, benzimidazole, benzofuran, benzopyran, benzothiazole, benzothiazole, benzoisothiazole, pyridopyrimidine, pteridine, pyrimidopyrimidine,

[088] Halogen within the scope of the present invention represents fluorine, chlorine, bromine or iodine. Unless otherwise stated, fluorine, chlorine and bromine are considered to be preferred halogens.

[089] Compounds of general formulas 1 or 1 'may have acidic groups, mainly carboxyl groups, and / or basic groups such as, for example, amino functions. Compounds of general formulas 1 or 1 'can therefore be present as internal salts, such as salts with pharmaceutically usable inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, sulfonic acid or organic acids (such as, for example, maleic acid, fumaric acid, citric acid, tartaric acid or acetic acid) or as salts with pharmaceutically usable acids such as alkali metal or alkaline earth metal hydroxides or carbonates, zinc hydroxides or

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37/176 ammonium or organic amines such as, for example, diethylamine, triethylamine, triethanolamine, inter alia.

[090] As previously mentioned, the compounds of formulas 1 or 1 'can be converted to the salts thereof, particularly for pharmacological use, to the physiologically and pharmacologically acceptable salts thereof. These salts can be present, on the one hand, as physiologically and pharmacologically acceptable acid addition salts of the compounds of formula 1 with inorganic or organic acids. On the other hand, the compound of formulas 1 or 1 ', when R is hydrogen, can be converted by reaction with inorganic bases into physiologically and pharmacologically acceptable salts with alkali or alkaline earth metal cations as a counterion. Acid addition salts can be prepared, for example, by using hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or acid maleic. It is also possible to use mixtures of the acids mentioned above. To prepare the alkali and alkaline earth metal salts of the compounds of formulas 1 or 1 'in which R represents hydrogen, it is preferable to use the alkali and alkaline earth metal hydroxides and hydrides, of which the alkali metal hydroxides and hydrides, particularly sodium and potassium, are preferred, while sodium and potassium hydroxides are particularly preferred.

[091] Compounds of general formulas 1 or 1 'can optionally be converted to their salts, particularly for pharmacological use, to the addition salts

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38/176 of pharmacologically acceptable acid with an inorganic or organic acid. Examples of suitable acids for this purpose include succinic acid, hydrobromic acid, acetic acid, fumaric acid, maleic acid, methanesulfonic acid, lactic acid, phosphoric acid, hydrochloric acid, sulfuric acid, tartaric acid or citric acid. It is also possible to use mixtures of the acids mentioned above.

[092] The invention relates to the compounds of formula 1 or 1 'in question, optionally in the form of individual optical isomers, mixtures of the individual enantiomers or racemates, in the form of tautomers, as well as in the form of free bases or in addition salts corresponding acids with pharmacologically acceptable acids such as acid addition salts with hydroalic acids - for example, hydrochloric or hydrobromic acid - or organic acids - such as, for example, oxalic, fumaric, diglycolic or methanesulfonic acid.

[093] The compounds of formula 1 or 1 'according to the invention can optionally be present as racemates, but can also be obtained as pure enantiomers, that is, in the (R) or (S) form. Compounds with the specific stereochemistry of formula 1 'are preferred.

[094] The invention relates to the compounds in question, optionally in the form of individual optical isomers, diastereomers, mixtures of diastereomers, mixtures of individual enantiomers or racemates, in the form of tautomers, as well as in the form of free bases or addition salts corresponding acid acids with pharmacologically acceptable acids - such as, for example, salts of

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39/176 addition of acid with hydroalic acids - for example, hydrochloric or hydrobromic acid - or organic acids - such as, for example, oxalic, fumaric, diglycolic or methanesulfonic acid.

[095] The invention relates to the respective compounds of formulas 1 or 1 'in the form of the pharmacologically acceptable salts thereof. These pharmacologically acceptable salts of the compounds of formulas 1 or 1 'may also be present in the form of their respective hydrates (for example, monohydrates, dihydrates, etc.), as well as in the form of their respective solvates.

[096] The term hydrate of the compound according to formulas 1 or 1 'means, for the purposes of the invention, a crystalline salt of the compound according to formulas 1 or 1', which contain water of crystallization.

[097] The term solvate of the compound according to formulas 1 or 1 'means, for the purposes of the invention, a crystalline salt of the compound according to formulas 1 or 1', which contains solvent molecules (for example, ethanol , methanol, etc.) in the crystal network.

[098] Those skilled in the art will be familiar with standardized methods of obtaining hydrates and solvates (for example, recrystallization by the corresponding solvent or by water).

4. PREPARATION METHODS [099] The Examples according to the invention were prepared as shown in Schemes 1, 2 or 3.

Layout 1

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A is N, CH, Y is 0, ch ₂ , Hal is Br or Cl, Hal ¹  is Cl, F,

with X being -B (OH) ₂ ,-pinacolic ester of boronic acid,

PG is a protecting group (for example, benzyl, 1-phenylethyl, 1- (4-methoxyphenyl) ethyl) and

R ² and R ³ are as defined hereinbefore.

Layout 2

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Hal is Br or Cl, with X being -B (OH) ₂ , pinacolic ester of boronic acid,

PG is a protecting group (for example, benzyl, 1-phenylethyl, 1- (4-methoxyphenyl) ethyl) and R ² and R ³ are as defined hereinbefore.

Layout 3

Hal is Br or Cl,

PG is a protecting group (for example, benzyl, 1-phenylethyl, 1- (4-methoxyphenyl) ethyl) and R ² and R ³ are as defined hereinbefore.

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4Τ / Υ16

4.1 Starting materials of formulas 2, 3, 4, 5 and 6

4.1.1 Synthesis of compounds of formula 2 from Schemes 1, 2 and 3 [100] Synthesis of (R) -4 - [(R) -1-hydroxyethyl] -1 - [(S) -1- (4methoxyphenyl ) -ethyl] -pyrrolidin-2-one (2.1) for Examples 1, 2, 4-12, 14, 15, 17, 19 and (R) -4 - [(S) -1-hydroxyethyl] - [( S) 1- (4-methoxyphenyl) -ethyl] -pyrrolidin-2-one (2.2) for Examples 13, 16, 18, 20, 21, 22.

Step 1: Synthesis of (1'R, 3R / S) -1- (1'- (4methoxyphenylethyl) -5-oxo-3-pyrrolidine carboxylic (mixture of diastereoisomers)

O.

[101] A suspension of 100 g of (R) -1- (4-methoxy-phenyl) ethylamine and 95 g of itaconic acid in 0.5 liter of methyl2-pyrrolidinone was heated to 80 ° C for 1 hour. The solution was stirred for another 4 hours at 120 ° C. The reaction mixture was cooled to 25 ° C and poured into 1.5 liters of demineralized water. The precipitate was filtered, washed with demineralized water and dried at 50 ° C.

[102] Yield: 195 g (quantitative yield) of solid as a mixture of diastereoisomers [103] Analysis (method G): R _t : 2.6 min and 2.7 min, (M + H) ⁺ :

264.

Step 2: Synthesis of (R / S) -N-methoxy-5-oxo-1 - [(S) -1- (4methoxyphenyl) -ethyl] -pyrrolidine-3-carboxamide as a mixture of diastereoisomers

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[104] Two hundred and sixty g of 1,1'-carbonyldiimidazole (CDI) was added to a solution of 285 g acid (l'R, 3R / S) -l- (l '- (4-methoxyphenylethyl) -5 -oxo-3-pyrrolidine carboxylic (mixture of diastereoisomers) in 2 liters of methyltetrahydrofuran at 20 ° C. The suspension was stirred at 20 ° C for 80 minutes. Two hundred and thirty-five ml of ethildiisopropylamine (DIPEA) and 130 g of hydrochloride of N, 0-dimethylhydroxylamine were added. The suspension was stirred for 3 hours at 20 ° C. Upon cooling, 850 ml of 4 M hydrochloric acid were added. The organic phase was separated and washed twice with 500 ml of 1 N hydrochloric acid. The aqueous phase was extracted again twice with 500 ml of ethyl acetate The combined organic phases were dried over sodium sulfate After filtration, the solvent was evaporated under reduced pressure.

[105] Yield: 271 g (82% of theory) of (R / S) -Nmethoxy-5-oxo-1 - [(S) -1- (4-methoxyphenyl) -ethyl] -pyrrolidine-3carboxamide (mixture of diastereoisomers) as an oil.

[106] Analysis (method H): R _t : 11.1 min (% of area 41) and 13.8 min (% of area 59), (M + H) ⁺ : 307.

Step 3: Synthesis of (R / S) -4-Acetyl-1 - [(S) -1- (4methoxyphenyl) -ethyl] -pyrrolidine-2-one as a mixture of diastereoisomers

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[107] Five hundred and thirty ml of a 3 M solution of methylmagnesium bromide in diethyl ether were added slowly to a chilled solution of 271 g of (R / S) -Nmetoxy-5-oxo-l - [(S) - 1- (4-methoxyphenyl) -ethyl] -pyrrolidine-3carboxamide (mixture of diastereoisomers) in 1.4 liters of 2-methyltetrahydrofuran so that the temperature is kept below 0 ° C. After complete addition, the temperature was maintained for 75 minutes at 0 ° C and then heated to 20 ° C. The suspension was stirred for 16 hours at 20 ° C. Upon cooling, 650 ml of 4 M hydrochloric acid was added. The organic phase was separated and washed with 500 ml saturated sodium carbonate solution and 500 ml saturated brine. The organic phase was dried over sodium sulfate. After filtration, the solvent was evaporated under reduced pressure.

[108] Yield: 188 g (81% of theory) of (R / S) -4Acetyl-1 - [(S) -1- (4-methoxyphenyl) -ethyl] -pyrrolidine-one (mixture of diastereoisomers) as a oil.

[109] Analysis (method H): R _t : 7.4 min and 9.6 min, (M + H) ⁺ :

262.

Step 4: Crystallization of (R) -4-Acetyl-l- [(S) -1- (4methoxyphenyl) -ethyl] -pyrrolidine-2-one under conditions of base-induced epimerization

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[110] One hundred and three g of a mixture of diastereoisomers (R / S) -4-acetyl-1 - [(S) -1- (4-methoxyphenyl) -ethyl] -pyrrolidine2-one were dissolved in 155 ml of 1 -butanol at 25 ° C. Eighteen ml of benzyltrimethylammonium hydroxide (40% methanol solution) was added. The solution was stirred for 30 minutes at 25 ° C. The solution was cooled to 0 ° C. The precipitation started. The suspension was stirred for 15 minutes at 0 ° C. One hundred ml of n-heptane was added slowly and the suspension was stirred for 30 minutes at 0 ° C. The addition of 100 ml portions of n-heptane was repeated 4 times with subsequent stirring of the suspension at 0 ° C for 30 minutes. The precipitate was isolated, washed with n-heptane and dried at 50 ° C.

[111] Yield: 77.1 g of a beige solid (75% of theory) with a diastereomeric purity of approximately 95: 5 (method H).

[112] For further purification, the crude product was dissolved in 310 ml of 2-methyl-2-butanol at 40 ° C (temperature <50 ° C). The solution was slowly cooled to 0 ° C. The precipitation started. At 0 ° C, 385 ml of n-heptane was added and the suspension was stirred for 1 hour. The precipitate was filtered, washed with n-heptane and dried at 50 ° C.

[113] Yield: 68.7 g (67% of theory) of a colorless solid with a diastereomeric purity of> 99: 1.

[114] Analysis (method H): R _t : 6.8 min, (M + H) ⁺ : 262.

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Step 4: Crystallization of (R) -4-Acetyl-1 - [(S) -1- (4methoxyphenyl) -ethyl] -pyrrolidine-2-one under conditions of base-induced epimerization [115] 13.2 g of a mixture of (R / S) -4-acetyl-1 - [(S) -1- (4-methoxyphenyl) -ethyl] -pyrrolidine2-one diastereoisomers were dissolved in 18 ml of 1-butanol at 25 ° C. The solution was cooled to 3 ° C and treated with 100 mg (R) 4-Acetyl-1- [(S) -1- (4-methoxyphenyl) -ethyl] -pyrrolidine-2-one.

The resulting mixture was stirred for 15 min at 3 ° C, when then 2.3 ml of benzyltrimethylammonium hydroxide (40% methanol solution) was added. The solution was stirred for 30 minutes at 3 ° C. Sixty-four ml of n-heptane was added slowly over 1 h at 0 to 3 ° C and the suspension was stirred for 60 minutes at 0 ° C. The precipitate was isolated, washed with n-heptane and dried at 30 ° C.

[116] Yield: 10.6 g of a beige solid (80% of theory) with a diastereomeric purity of approximately 98: 2 (method H).

[117] Analysis (method H): R _t : 6.8 min, (M + H) ⁺ : 262.

Step 5: Synthesis of (R) -4 - [(R) -1-hydroxyethyl] -1- [(S) 1- (4-methoxyphenyl) -ethyl] -pyrrolidin-one 2.1

OH

2.1

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47/176 [118] 94.6 mg of dichloro (pentamethylcyclopentadienyl) -iridium (III) and 105 mg of (S, S) N- (p-toluenesulfonyl) -1,2-diphenylethylendiamine [(R, R) TsDPEN] were dissolved in 20 ml of acetonitrile and subsequently loaded into a 50 g slurry of (R) -4acetyl-1 - [(S) -1- (4-methoxyphenyl) -ethyl] -pyrrolidine-2-one and 65 g of sodium formate in 500 ml of water at 25 ° C. The sludge was heated to 60 ° C and stirred at that temperature while sparging with nitrogen for 3 h. The reaction was diluted to 60 ° C with 500 ml of isopropyl acetate and subsequently cooled to room temperature. The layers were separated, and the organic portion was washed twice with 300 ml of water. The organic portion was concentrated to an oily solid. The residual material was crystallized three times from ethyl acetate and hexanes, followed by drying in a vacuum oven with a stream of nitrogen at 30 ° C.

[119] 25.4 g of a beige solid with a diastereomeric purity of> 99: 1.

Step 5: Synthesis of (R) -4 - [(S) -1-hydroxyethyl] -1 - [(S) 1- (4-methoxyphenyl) -ethyl] -pyrrolidin-one (2.2)

2 ^ 2 [120] 9.46 mg of dichloro (pentamethylcyclopentadienyl) -iridium (III) and 10.52 mg of (R, R) -N- (p-toluenesulfonyl) -1,2-diphenylethylendiamine [(R , R) -TsDPEN] were dissolved in 1 ml of acetonitrile and subsequently loaded into a slurry of 5 g of (R) -4acetyl-1 - [(S) -1- (4-methoxyphenyl) -ethyl] -pyrrolidine-2 -one and

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6.5 g of sodium formate in 50 ml of water at 25 ° C. The sludge was heated to 60 ° C and stirred at that temperature while sparging with nitrogen for 3 h. The reaction was diluted to 60 ° C with 50 ml of isopropyl acetate and subsequently cooled to room temperature. The layers were separated, and the organic portion was washed with 20 ml of water. The organic portion was concentrated to an oil. The oil was dissolved in 8 ml of isopropyl acetate at reflux. The solution was cooled to room temperature, where crystallization occurred. The mixture was diluted dropwise with 10 ml of heptane at room temperature. The mixture was stirred for 30 minutes. The solids were collected by filtration, washed with a 20% volume solution of isopropyl acetate in heptane and dried in a vacuum oven with a nitrogen stream at 55 ° C. 3.82 g of a beige solid with a 99: 1 diastereomeric purity.

[121] Analysis (method I): R _t : 12.9 min, (M + H) ⁺ : 264.

Synthesis of [(IS) -1 - [(3R) -1 - [(IS) -1- (4-methoxyphenyl) ethyl] -5-oxo-pyrrolidin-3-yl] ethyl] 4-methylbenzenesulfonate (2.3) for Examples 13, 16, 18, 20, 21, 22 [122] To a mixture of (R) -4 - [(S) -1-hydroxyethyl] -1 - [(S) 1- (4-methoxyphenyl) - ethyl] -pyrrolidin-2-one 2.2 (20.0 g), p-toluenesulfonyl chloride (21.67 g) and N, Ndimethylpyridin-4-amine (0.92 g) were added 42 ml of

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49/176 pyridine and dichloromethane (42 ml / DCM). The resulting mixture was stirred at 34 ° C for 18 h under an argon atmosphere. The reaction mixture was diluted with isopropyl acetate and washed with water and 2M aqueous HCl. The combined organic phases were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was taken up in isopropyl acetate and n-heptane. The precipitate was filtered off, washed with n-heptane / isopropyl acetate to provide [(IS) -1 - [(3R) -1 - [(IS) -1- (4-methoxyphenyl) ethyl] -5oxo-pyrrolidin -3-yl] ethyl] 4-methylbenzenesulfonate (2.3) (19.83 g) as a solid.

[123] Analysis: HPLC-MS: R _t = 0.680 min (method J), M + H =

418.

Synthesis of 5- (1-hydroxy-ethyl) -3- (4-methoxy-benzyl) oxazolidin-2-one (2.4) for Example 3

[124] Step 1: To the (R) -2-hydroxy-succinic acid (10 g) was added under cooling trifluoroacetic acid anhydride (25 ml) and the mixture is stirred at room temperature. After 4 h, the solution was concentrated in vacuo, to which benzyl alcohol was added and the mixture was stirred

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50/176 overnight. The solution was concentrated in vacuo (3 mbar, 60 ° C) and the residual oil (28 g) was used without further purification in the next step.

[125] Analyze: HPLC-MS: Rt = 0.99 min (method E), M + H = 225. [126] Step 2: The product of previous step (23 g) was dissolved in toluene (350 ml) and triethylamine (16 ml), and

diphenylphosphoryl azide (24.5 ml) was added. The mixture was stirred at reflux for 3 h, and then partially concentrated and extracted with water (250 ml) and EtOAc (250 ml). The phases were separated and the aqueous phase was extracted twice with EtOAc (100 ml). The combined organic phases were washed with saturated NaHCO3, dried over MgSO4 and concentrated. The residual was purified by means of SiO2 (cyclohexane / EtOAc 1: 2) to provide 7.4 g of a white solid.

[127] Analysis: HPLC-MS: Rt = 0.95 min (method E), M + H =

222.

[128] Step 3: To the benzyl ester of (R) -2-oxooxazolidine-5-carboxylic acid (1.5 g) in acetonitrile (20 ml) were added Cs2CO3 (3.31 g) and, after 10 min, 1bromomethyl -4-methoxy-benzene (1.86 g) and the mixture was stirred for 14 h at 45 ° C. Water (20 ml) and DCM (60 ml) were added, and the mixture stirred for 10 min. Then, the phases were separated, the organic phase concentrated and the product purified by means of preparative HPLC to provide benzyl ester of (R) -3- (4-methoxy-benzyl) -2-oxo-oxazolidine-5-carboxylic acid (349 mg) as a white solid.

[129] Analysis: HPLC-MS: Rt = 0.85 min (X018_S03), M + H = 342.

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51/176 [130] Step 4: To the benzyl ester of (R) -3- (4-methoxy-benzyl) -2-oxo-oxazolidine-5-carboxylic acid (345 mg) in

2.5 ml water and dioxane (2.5 ml), 0.485 ml of LiOH (2.5 N) was added and the mixture stirred at room temperature for

1.5 h. Acetonitrile (10 ml), water (20 ml) and 1 M aqueous HCl (1.2 ml) were added and the product lyophilized to provide a white solid (310 mg) which was used without further purification in the next step.

[131] Analysis: HPLC-MS: Rt = 0.52 min (X018_S01), M + H = 252.

[132] Step 5: (R) -3- (4-Methoxy-benzyl) -2-oxooxazolidine-5-carboxylic acid (310 mg) and dimethylhydroxylamine * HCl (210 mg) in DMF (5 ml) at 0 ° C hydroxybenzotriazole (140 mg), N-methylmorpholine (300 pl) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide x HCl (200 mg) were added, and the mixture was stirred for 3.5 h. iPrOAc (50 ml) and a 10% citric acid solution, 20 ml) were added, and the phases were separated. The aqueous phase was extracted twice with iPrOAc (20 ml) and the combined organic phases were washed with aqueous NaHCO3 (5%, 20 ml). The dry organic phase was concentrated and purified by means of preparative HPLC to provide methoxy-methyl-amide of (R) 3- (4-methoxy-benzyl) -2-oxo-oxazolidine-5-carboxylic acid (147 mg) colorless oil.

[133] Analysis: HPLC-MS: Rt = 0.60 min (X018_S03), M + H = 295.

[134] Step 6: To the (R / S) -3- (4-methoxy-benzyl) -2-oxo-oxazolidine-5-carboxylic acid methoxy-methyl amide (145 mg) in 2 ml of THF was added bromide methylmagnesium (1.4 N, 490 pl) under cooling over 20 min at -10 ° C and at

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52/176 mixture was stirred for 30 min. To this mixture were added 1N aqueous KHSO4 (160 μΐ, NaBH ₄ (56 mg) and EtOH (300 pl) at -1 ° C, and the mixture stirred for 30 min. Dichloromethane (20 ml) and water (15 ml) were added, and the phases were separated and the aqueous phase extracted once with DCM The combined organic phases were concentrated and purified by means of preparative HPLC (water / acetonitrile / NH ₃ ) to provide 5- (1-hydroxy-ethyl) -3 (4-methoxy-benzyl) -oxazolidin-2-one (90 mg) 2,4 as a colorless oil containing all 4 stereoisomers in a comparable amount.

[135] Analysis: HPLC-MS: R _t = 0.42 min (X011_S03), M + H = 250.

[136] Chiral HPLC: Chirlapak AS-H 4.6 x 250 mm, 5 pm 4 ml / min, scCCh / Isopropanol, 20 mM NH3, 20% in 10 min, 150 bar. R _t = 2.577 min (product a), R _t = 2.986 min (product b), Rt = 3.362 min (product c), R _t = 3.655 min (product d).

4.1.2 Synthesis of pyrazoles with formulas .3 ^and â.

4.1.2.1 Synthesis of halogenated pyrazoles 2

Synthesis of 4-bromo-1-tert-butyl-pyrazole (3.1) for

Examples 3, 13, 15

Step 1: Synthesis of 1-tert-butyl-pyrazole

[137] To a stirred mixture of 34.48 g of 1,1,3,3tetramethoxy-propane and 26,20 g of tert-butylhydrazine hydrochloride in 230 ml of ethanol was added 40.0 ml of concentrated hydrochloric acid dropwise 50 ° C, and then the mixture was stirred at reflux for 2 h. The reaction mixture was diluted with water. The solvent was almost removed

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53/176 by distillation and the aqueous residue extracted with diethyl ether. The combined aqueous phases were basified with IN sodium hydroxide solution and extracted with diethyl ether. The combined organic phases were washed with saturated brine, dried over sodium sulfate, filtered and concentrated in vacuo to generate 21.90 g of 1-tert-butylpyrazole as an oil.

[138] Analysis: HPLC-MS: R _t = 0.412 min (method A), M + H =

125.

Step 2: Synthesis of 4-bromo-l-tert-butyl-pyrazole

Br

3.1 [139] To a mixture of 21.9 g of 1-tert-butyl-pyrazole in 150 ml of DCM was added 31.5 g of N-bromosuccinimide in portions between 0 and 10 ° C. The resulting mixture was stirred for 30 min. The reaction mixture was allowed to reach room temperature. The precipitate was removed by filtration and washed with DCM. The combined organic extracts were washed with water and saturated brine, dried over magnesium sulfate, filtered and concentrated in vacuo to generate 34.0 g of 4-bromo-1-tert-butyl-pyrazole as an oil.

[140] Analysis: HPLC-MS: Rt = 1.35 min (method B), M + H = 203/205.

Synthesis of 4-bromo-1- (2,2,5,5-tetramethyltetrahydrofuran-3-yl) -1H-pyrazole (3,2) for Examples 14,

3.2

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54/176 [141] To a mixture of 1- (2,2,5,5-tetramethyltetrahydrofuran-3-yl) -1H-pyrazole (900 mg) in 15 ml DCM was added N-bromosuccinimide (830 mg) in room temperature. The resulting mixture was stirred for 2 h. To the reaction mixture, 15 ml of saturated brine were then added. The organic phase was dried over Na2SO4, filtered and concentrated in vacuo to generate 1.26 g of 3.2 as an oil which subsequently crystallized.

[142] Analysis: HPLC-MS: R _t = 0.601 min (method X018_S03), M + H = 273/275.

Synthesis of 2- (bromo-pyrazol-1-yl) -2-methylpropionitrile (3.3) for Example 17

3 = 3 [143] Step 1: The acid (4 g) was dissolved in methanol (40 ml) and thionyl chloride (4.5 ml) was added at 10 ° C. The mixture was stirred overnight at room temperature, then evaporated and dissolved in DCM. The organic phase was extracted with aqueous sodium bicarbonate, dried over MgSCu and, after filtration, concentrated in vacuo to generate 4 g of methyl ester for step 2.

[144] Analysis: MS: M + H = 247/249, Rt = 1.121 min (method Z001_005).

[145] Step 2: The methyl ester (1 g) was dissolved in methanol (4 ml) containing 10% NH3. Calcium g chloride medium was added and the mixture stirred for 20 h at room temperature. The mixture was concentrated and distributed between isopropyl acetate (50 ml) and water (20 ml). The aqueous phase

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55/176 was extracted again with isopropyl acetate (20 ml) and the combined organic phases dried and concentrated in vacuo to generate 830 mg of amide.

[146] Analysis: MS: M + H = 232/234, R _t = 0.705 min (method Z018_S04).

[147] Step 3: The amide (336 mg) was dissolved in 400 μΐ of POCI3 and stirred at 90 ° C for 1.5 h. The reaction mixture was poured into water and the pH was adjusted to 7-8 by the addition of aqueous NaHCCb. The aqueous phase was extracted 3x with DCM and the organic phases were concentrated in vacuo to generate 284 mg of 3.3.

[148] Analysis: MS: M + H = 214, R _t = 0.58 min (method

X011_S03).

Synthesis of 4-bromo-1- (3,3-difluoro-cyclopentyl) -1Hpyazole 3.4 for Examples 7, 22

[149] Step 1: 4-bromopyrazole (12 g) and 2-cyclopenten1-one (7.1 g) were suspended in acetonitrile (100 ml). Then, scandium trifluoromethanesulfonate (0.5 g) was added (slightly exothermic) and the mixture was stirred at room temperature overnight and 2 h at 40 ° C. The mixture was concentrated and the yellow oil was purified by silica gel (2 kg of SiO2, cyclohexane cyclohexane: ethyl acetate 7: 3 gradient) to generate 16.8 g of ketone.

[150] Analysis: MS: M + H = 229/231, Rt = 0.622 min (method X018 S03).

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56/176 [151] Step 2: The ketone (5 g) was dissolved in dichloromethane (80 ml) and [bis (2 methoxyethyl) amino] sulfur trifluoride (45 ml, 50% in THF) was added in portions at 30 ° Ç. The mixture was poured into aqueous sodium bicarbonate solution and extracted with dichloromethane. The organic phase was washed with brine, dried over Na ₂ SO4 and, after filtration, concentrated to 40 mbar to generate 3.67 g of 3.4.

[152] Analysis: MS: M + H = 251/253, R _t = 0.848 min (method X018_S03).

[153] The following halogens were commercially available:

- 4-bromo-1- (3,3,3-trifluorpropyl) -1H-pyrazole 3.5 for Example 12

4-Chloro-1- (2-fluoro-ethyl) -H-pyrazole 3.6 for

Example 11

- 4-Bromo-3-tert-butyl-1H-pyrazole 3.7 for Example 4

4.1.3 Synthesis of compounds of formula 4 (Schemes 1 and

2)

Synthesis of 1-tert-butyl-4- (4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl) pyrazole (4.1) for Examples 3, 13, 15

[154] To a stirred mixture of 4-bromo-1-tert-butylpyrazole 3.1 (50 g) in 230 ml of THF was added dropwise 2.5 M N-butyllithium (100 ml, hexane) under an argon atmosphere below -60 ° C, and then the mixture was stirred at that

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57/176 temperature for 5 min, before adding 2-isopropoxy4,4,5,5-tetramethyl-1,3,2-dioxaborolane (52 ml) dropwise below -60 ° C. The reaction mixture was allowed to reach room temperature. The mixture was cooled with an ice bath and diluted with aqueous phosphate buffer and water and neutralized with 2M aqueous hydrochloric acid. The organic solvent was distilled off and the residue was extracted with DCM. The combined organic extracts were washed with saturated brine, dried over sodium sulfate, filtered and concentrated in vacuo to generate 1-tert-butyl4 - (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- ii) pyrazole (44.26 g) as a solid.

[155] Analysis: HPLC-MS: R _t = 0.904 min (method F), M + H =

251.

Boronic synthesis (4.2) of 3-tert-butyl-1H-pyrazol-4-yl-4 acid for Example 4

[156] Step 1: 4-bromo-3-tert-butyl-1H-pyrazole 3.7 (580 mg) was dissolved in dichloromethane (20 ml) and triethylamine (477 μΐ) and di-tert-butyldicarbonate (623 mg) at temperature environment for 48 h. The mixture was extracted with water and the organic phase separated and concentrated to generate 833 mg as a colorless oil.

[157] Analysis: HPLC-MS: R _t = 0.80 min (X012_S01), M + H = 249.

[158] Step 2: 4-Bromo-3 acid tert-butyl ester Petition 870170059664, of 17/08/2017, p. 65/185

58/176 tert-butyl-pyrazol-1-carboxylic (369 mg) was dissolved in THF (6 ml) and cooled to -78 ° C. n-BuLi (837 pl, 1.6 M) was added and the mixture stirred for 20 min. Then, 2 methoxy-4,4,4,4-tetramethyl-1,3,2-dioxaborolane (239 pl) was added and the mixture was allowed to warm up to room temperature overnight. Water and DCM were added to the reaction mixture and the organic phase was separated. The aqueous phase was purified by means of preparative HPLC to provide 39 mg of 4.2.

[159] Analysis: HPLC-MS: Rt = 0.47 min (X012_S01), M + H = 169.

[160] The following boronic acids and boronic esters were commercially available:

- 1- (Cyclopropylmethyl) -4- (4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl) -1H-pyrazole 4.4 for Examples 6, 8

- 1-Cyclopropyl-4- (4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl) -1H-pyrazole 4.5 for Examples 5, 20

- pinacolic ester of 1-isopropyl-1H-pyrazole-4boronic acid 4.6 for Examples 2, 18

- 1-Cyclobutyl-4- (4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl) -1H-pyrazole 4.8 for Examples 1, 21

- 4- (4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) -1Hpyazole 4.9 for Examples 9, 10

- Isobutyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl) -1H-pyrazole 4.10 for Example 19

4.1.4 Synthesis of compounds of formula 5

Synthesis of (3R, 3aS, 7aR) - (hexahydrofuro [3,2-b] pyran-3yl) toluene-4-sulfonic acid ester (5.1) for Example 10

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59/176

[161] (3R, 3aR, 7aR) -Hexahydrofuro [3,2-b] pyran-3-ol (300 mg) was dissolved in dichloromethane (3 ml) and pyridine (0.445 g). P-Toluene sulfonic acid chloride (0.524 g) and DMAP (15 mg) were added, and the mixture stirred for 68 h at room temperature. Then, water (20 ml) and dichloromethane (20 ml) were added and stirring continued for 15 min. The phases were separated and the organic phase concentrated. Purification was achieved via flash chromatography on silica gel (cyclohexane - + cyclohexane / ethyl acetate 1: 1) to provide 5.1 (0.451 g) as a colorless oil.

[162] Analysis: HPLC-MS: Rt = 0.52 min (X012_S01), M + H = 299.

[163] The following tosylate was commercially available:

(S) -2,2-Dimethyltetrahydro-2H-pyran-4-yl 4methylbenzenesulfonate 5.2 for Example 9

4.1.5 Synthesis of Heterocyclic 6 from Schemes 1, 2 and 3

Synthesis of 6-bromo-2,3-dimethyl-2H-indazol-4-ol (6.1) for Examples 8-11, 13, 16-22

[164] Step 1: 1-Bromo-3,5-difluorbenzene (100 g) was dissolved in THF (600 ml) and cooled to -78 ° C. LDA (300 ml, 2 N in heptane / THF / ethylbenzene) was added over 20 min and the mixture stirred for 1 h. This mixture was

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60/176 added via transfer cannula to acetic anhydride (250 ml, cooled to -78 ° C) within 30 min. Then, the mixture was heated to -30 ° C, THF was removed in vacuum and dichloromethane (300 ml) was added. The mixture was basified with saturated sodium bicarbonate solution and extracted 3x with dichloromethane (300 ml). The organic phase was washed with saturated ammonium chloride solution and saturated brine, dried and concentrated at 100 mbar / 50 ° C in vacuum. The residue was distilled by vacuum fractionation at 30 to 10 mbar / 70-100 ° C to generate 57.8 g and 74.7 g (80% content) of the desired product.

[165] Analysis: HPLC-MS: Rt = 0.974 min (Z018_S04), M + H = 235.

[166] Step 2: To 1- (4-bromo-2,6-difluoro-phenyl) ethanone (22.05 g) dissolved in THF (80 ml) was added hydrazine hydrate (10 ml) at room temperature and mixture was stirred overnight. Water (50 ml) and 2-Me-THF (70 ml) were added and the organic phase was dried and concentrated in vacuo. The crude product was dissolved in acetonitrile (70 ml) at 80 ° C and cooled to room temperature for 2 days. The precipitate was filtered and washed with acetonitrile and dried under vacuum for 45 min at 45 ° C to provide 15.6 g of white needles.

[167] Analysis: HPLC-MS: Rt = 0.58 min (X011_S03), M + H = 229/231.

[168] Step 3: The indazole (32 g) from the previous step was suspended in dichloromethane (400 ml) and trimethyloxonium tetrafluorborate (26.75 g) was added and the mixture stirred for 24 h at room temperature. Saturated sodium bicarbonate (150 ml) was added and the mixture was basified

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61/176 to ο pH 9 with sodium carbonate (10 ml). The precipitate was removed by filtration, the phases separated and the aqueous phase extracted with iPrOAc. The combined organic phases were dried and concentrated in vacuum to generate 33.1 g of raw material which was dissolved in methyl tert-butyl ether (100 ml) and heated to reflux and cooled to room temperature. The precipitate was removed by filtration after 2 days to generate 6.1 (22.4 g) as light yellow crystals.

[169] Analysis: HPLC-MS: R _t = 0.673 min (X018_S02), M + H = 243/245.

Synthesis of 4,6-Dichloro-2,3-dimethyl-2H-pyrazolo [4,3clpyridine (6.2) for Examples 3, 4, 15

[170] Step 1: To a solution of 2,4,6-trichloro-pyridine (5.00 g) in tetrahydrofuran (anhydrous, 50.00 ml) at -78 ° C under an atmosphere of nitrogen was added n-butyl lithium (2.5 M in hexane) (10.96 ml) dropwise. The mixture was stirred at -78 ° C and then piperidine-1-carbaldehyde (3.04 ml) was added dropwise. The reaction was stirred at -78 ° C for 1 h. The reaction mixture was quenched with saturated aqueous NH4Cl (50 ml). The mixture was extracted with TBME (3 x 40 ml) and the organic phase washed successively with 1 M HCl (75 ml) and saturated ammonium carbonate (75 ml). The organic phase was dried (Na2SC> 4) and concentrated, and the residue

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62/176 purified by Biotage Isolera FCC (SiO2: 50 g) eluting with 10-50% TBME in cyclohexane to generate 2.94 g of product as a yellow solid.

[171] Analysis: HPLC-MS: Rt = 1.27 min (method P).

[172] ¹ H-RNM (DMSO, 250 MHz) δ 8.07 (1H, s), 10.28 (1H,

s).

[173] Step 2: Methylmagnesium bromide (3 M in diethyl ether, 3.83 ml) was added dropwise and a stirred solution of 2,4,6-trichloro-pyridine-3-carbaldehyde (2.20 g ) in tetrahydrofuran (anhydrous, 44 ml) at -78 ° C under a nitrogen atmosphere. The reaction was stirred at -78 ° C for 30 min and then allowed to warm to room temperature. The reaction was quenched with NH4Cl (25 ml) and neutralized to pH 7-8 with 1M HCl. The aqueous phase was extracted with EtOAc (3 x 50 ml), the combined dry organic phase (Na2SO4) and concentrated. The crude material was purified by Biotage Isolera (SiO2; 50 g) eluting in 100% EtOAc in cyclohexane to generate 1.39 g (58.7%) as a colorless oil.

[174] Analysis: HPLC-MS: Rt = 1.19 min (method P), M + H = 226/228. [175] ¹ H-RNM (CDCl3, 500 MHz) δ 1.64 (3H, d, J = 6.9 Hz), 2.67 (1H, d, J = 9.2 Hz), 5.51 (1H, d, J = 6.9 Hz), 7.33 (1H, s). [176] Step 3: The one solution agitated by 1- (2,4,6- trichloro- pyridin-3-yl) -ethanol ( 2.57 g) in dichloromethane

(51.4 ml) N-methyl morpholino-N-oxide (1.994 g) was added. The reaction was stirred at room temperature for 10 min, and then tetra-n-propylammonium perrutenate (TPAP) (135.6 mg) was added and stirring continued for 7 days. The mixture was filtered through celite and the filtrate concentrated and

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63/176 purified by Biotage Isolera FCC (SiO2; 25 g) eluting with 7: 1 cyclohexane-EtOAc to generate 1.74 g as a colorless oil.

[177] Analysis: HPLC-MS: Rt = 1.27 min (method P), M + H = 224/226.

[178] ¹ H-RNM (CDCl3, 500 MHz) δ 2.59 (3H, s), 7.38 (1H,

s).

[179] Step 4: To a solution of 1- (2,4,6-trichloropyridin-3-yl) -ethanone (1.75 g in ethanol, absolute) (8.75 ml) was added hydrazine hydrate (0 , 76 ml). The reaction was stirred at room temperature over the weekend (40 h). The solvent was evaporated and water (10 ml) added. The aqueous phase was extracted with DCM (3 x 10 ml), the combined organic phases were dried (Na2SO4) and concentrated. The crude material was purified by Biotage Isolera FCC (SiO2; 50 g) eluting EtOAc in 10-30% cyclohexane to generate 0.74 g of product as an off-white solid.

[180] Analysis: HPLC-MS: Rt = 1.15 min (method P), M + H = 202/204.

[181] ¹ H-RNM (DMSO, 500 MHz) δ 2.64 (3H, s), 7.64 (1H, s).

[182] Step 5: To a solution of 4,6-dichloro-3-methyl-1Hpyrazolo [4,3-c] pyridine (550.00 mg) in dioxane (11.00 ml) under an atmosphere of nitrogen was added trimethyloxonium tetrafluorborate (563.70 mg). The reaction was stirred at room temperature for 1 h. NaHCO3 (10 ml) was added and the mixture extracted with DCM (3 x 10 ml). The combined organics were dried (Na2SO4), concentrated and the crude residue purified by Biotage Isolera FCC (SiO2; 10

g) 50/50 EtOAc / cyclohexane) to generate 380 mg of 6.2 (64.6%) as a white solid.

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64/176 [183] Analysis: HPLC-MS: R _t = 216/218.

[184] iH-RNM (CDCl ₃ , 500 MHz S), 7.39 (1H, s).

1.16 min (method P), M + H = δ 2.84 (3H, s), 4.10 (3H,

Synthesis of 6-bromo-3-fluoro-2-methyl-2H-indazol-4-ol (6.3) for Examples 1, 2, 5-7, 12, 14

6.3 [185] Step 1: Twenty-five g of 6-bromo-4-methoxy-1Hindazole (commercially available from JW-Pharmlab) were suspended in 400 ml of dichloromethane and 20 g of trimethyloxonium tetrafluorborate were added and the mixture stirred for 4 h at room temperature. The reaction mixture was diluted with water (300 ml), filtered through cellulose and diatomaceous earth and the organic phase was extracted with semi-saturated aqueous sodium bicarbonate. The organic phase was dried and concentrated in vacuo to generate 24.6 g.

[186] Analysis: HPLC-MS: R _t = 0.938 min (Z018_S04), M + H = 241/243.

[187] ¹ H-RNM (DMSO, 400 MHz) δ 3.90 (3H, s), 4.10 (3H, s), 6.51 (1H, s), 7.38 (1H, s), 8.37 (1H, s).

[188] Step 2: The indazole (5 g) from the previous step was dissolved in 70 ml of THF and cooled to -78 ° C. LDA (13.5 ml, 2 M in THF) was added slowly and the mixture stirred for 30 min, and then N-fluorbenzenesulfonimide (9.16 g) was added. After 30 min, the reaction mixture was allowed to warm up, and then water and dichloromethane were added and the organic phase was separated and concentrated. 0

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65/176 residue was dissolved in DMF / water / TFA and purified by means of preparative HPLC to generate 2.95 g.

[189] Analysis: HPLC-MS: R _t = 0.56 min (X012_S01), M + H = 259/261.

[190] ¹ H-RNM (DMSO, 400 MHz) δ 3.90 (3H, s), 3.94 (3H,

s), 6.49 (IH, s), 7.26 (IH, s).

[191] Step 3: 2-Fluorindazole (2.9 g) from the previous step was dissolved in DCM (10 ml) and boron tribromide (3.24 ml) and the mixture was heated under reflux overnight, and then water was added and the mixture was basified with 1 N NaOH. The aqueous phase was separated, acidified with 4 N HCl and the precipitate was filtered off and dried at 60 ° C for 2 h under vacuum to generate 6.3 (2, 4 g).

[192] Analysis: HPLC-MS: R _t = 0.41 min (X012_S01), M + H = 245/246.

[193] ¹ H-RNM (DMSO, 400 MHz) δ 3.92 (3H, s), 6.34 (IH,

s), 7.08 (IH, s), 10.80 (IH, s

Synthesis of 6-bromo-2,3-dimethyl-2H-indazol-4-ol (6.4) for Examples 13, 16, 18 20-22

6.4 [194] Step 1: Bromo-2,6-difluoro-benzaldehyde (200 g) was dissolved in 1 liter of methanol, and CS2CO3 (300 g) was added under cooling at 10 ° C and stirring continued at 30 ° C overnight. The mixture was acidified until

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66/176 pH 6 with aqueous HCl and the formed precipitate filtered. The precipitate was suspended in EtOH / water 3: 1 (800 ml) and dissolved in heat and cooled to room temperature for 2 days. The precipitate (91 g) was collected and purified by means of SiO2 (MPLC, cyclohexan / ethyl acetate 9: 1) to generate 65.5 g of product. The mother liquor was concentrated and extracted with DCM and also purified by means of SiO2 (MPLC, cyclohexan / ethyl acetate 9: 1) to generate 2 9.4 g of product.

[195] Analysis: HPLC-MS: Rt = 0.987 min (Z018_S04).

[196] ¹ H-RNM (DMSO, 400 MHz) δ 3.91 (3H, s), 7.25-7.33 (2H, m), 10.23 (1H, s).

[197] Step 2: 4-Bromo-2-fluoro-6-methoxy-benzaldehyde (65.5 g) was dissolved in THF (250 ml) and methylmagnesium bromide (220 ml, 1.4 N in toluene / THF) it was added at 0 ° C and stirred for 48 h at room temperature. More methylmagnesium bromide (60 ml, 1.4 N in toluene / THF) was added and stirring was continued for 4 h. The mixture was concentrated, suspended in DCM and water (50 ml) and HCl (4N, 20 ml) was added under cooling on ice. A precipitate was removed by filtration, the phases were separated and the aqueous phase was extracted twice with DCM. The organic phases were dried and concentrated to generate 70 g of product.

[198] = 231/233 [199] (3H, s), (2H, m).

[200]

Analysis: HPLC-MS: Rt = 0.950 min (Z018_S04), M + H ^{+ 1} H-RNM (DMSO, 400 MHz) δ 1.37-1.38 (3H, d), 3.82

4.95-4.96 (1H, d), 5.10-5.13 (1H, dt), 7.02-7.06

Step 3: 1- (4-Bromo-2-fluoro-6-methoxy-phenyl) ethanol

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67/176 (90 g) was dissolved in DCM (500 ml) and tetrapropylammonium perrutenate (0.6 g, TPAP) and N-methyl morpholine N-oxide (42 g, NMO) and the mixture stirred for 3 h at room temperature . More TPAP (0.5 g) and NMO (10 g) were added and the mixture stirred for 3 h, then diluted with DCM and water and the organic phase was separated. 2,4,6-trimercaptotriazine resin (9 g, 0.5 mmol / g) was added to the organic phase and stirred for 30 min, dried with Na2SO4, filtered through cellulose and diatomaceous earth and concentrated in vacuum to generate 100 g (70% content) of product, which was used in the next step without further purification.

[201] Analysis: HPLC-MS: Rt = 0.993 min (Z018_S04), M + H + = 247/249.

[202] ¹ H-RNM (DMSO, 400 MHz) δ 2.45 (3H, s), 3.87 (3H, s), 7.22-7.23 (2H, m).

[203] Step 4: One hundred g of product (70% content) from the previous step were suspended in ethylene glycol and hydrazine hydrate (200 ml) and the mixture was stirred at 100 ° C for 4 h, and then at 70 ° C for 48 h. The mixture was poured over ice water and extracted 3x with DCM. The combined organic phases were dried (Na2SO4) to provide 85 g of product as a yellow solid, which was used in the next step without further purification.

[204] Analysis: HPLC-MS: Rt = 0.940 min (Z018_S04), M + H ⁺ = 241/243.

[205] Step 5: Fifty g of product from the previous step was dissolved in DCM (200 ml) and trimethyl-oxonium tetrafluorborate (30 g) was added in portions at 0 ° C and stirred overnight at room temperature. To the mixture, aqueous NaHCO3 was added and the pH adjusted to 9

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68/176 with Na ₂ CO3. The mixture was then extracted 3x with DCM and twice with ethyl acetate, the organic phases were dried and the residue purified by means of SiO ₂ (MPLC, 2.5 kg, cyclohexane / ethyl acetate 4: 1) and the fractions combined to generate 18 g of product.

[206] Analysis: HPLC-MS: R _t = 0.944 min (Z018_S04), M + H + = 255/257.

[207] ¹ H-RNM (DMSO, 400 MHz) δ 2.66 (3H, s), 3.89 (3H,

s), 3.96 (3H, s), 6.40 (1H, s), 7.26 (1H, s).

[208] Step 6: To 6-bromo-4-methoxy-2,3-dimethyl-2Hindazole (2.3 g) in DCM (20 ml), boron tribromide (25 ml, 1 M in DCM) was added and the The mixture was stirred for 2 h at 40 ° C. The mixture was concentrated and extracted with water and DCM. The precipitate was collected and dried to provide 1.62 g of

6.4.

[209] Analysis: HPLC-MS: R _t = 0.761 min (Z018_S04), M + H ⁺ = 241/243.

[210] ¹ H-RNM (DMSO, 400 MHz) δ 2.67 (3H, s), 3.94 (3H,

s), 6.28 (1H, s), 7.08 (1H, s), 10.40 (1H, s).

4.2 Synthesis of intermediates 7, £ and 9_ from schemes 1 and 2

Synthesis of ((R) -4 - [(R) -1- (6-bromo-2,3-dimethyl-2Hindazol-4-yloxy) -ethyl] -1 - [(S) -1- (4-methoxy -phenyl) -ethyl] pyrrolidin-2-one (7.1) for Examples 8-11, 13, 16-22

6.1

OH

2.1

7.1

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69/176 [211] 6.1 (32.8 g) was dissolved in DMA (400 ml), and then 2.1 (39 g) was added and the mixture was heated to 80 ° C. potassium tert-butylate (25 g) was added and the mixture stirred for 20 min at 80 ° C and subsequently cooled to room temperature. Aqueous NH ₄ C1 (100 ml) and water (200 ml) were added. The mixture was then extracted 3x with i-PrOAc (300 ml) and the combined organic phases were dried over Mg ₂ SO4 and evaporated under reduced pressure to generate 75.1 g (88% time) of product, of which 12 g were purified by means of preparative HPLC to generate 10.0 g of 7.1.

[212] Analysis: HPLC-MS: R _t = 0.597 min (X016_S01), M + H = 486/484.

[213]! H-RNM (DMSO, 400 MHz) δ 1.16 (3H, d, J = 6.1 Hz),

1.41 (3H, d, J = 7.2 Hz) ι, 2, 33 -2.39 (1H, m), 2.44 (3H, s) , 2.73 (1H, s), 2.78-2.82 (1H, m) ι, 2.89 (1H, s) , 3, li 3 (1H :, d, J = 5.1 Hz), 3.49 (1H, t, J = 9.2 Hz), 3.64 (3H, s) , 3.93 (3H, s), 4.60-4.66 (1H, m), 5, 18-5.23 (1H, q , J = 7.2 Hz), 6.37 (1H, s), 6.57-6.60 (2H 7 m), 7.09-7.11 (2H, m), 7.21 (1H, d, J = 1.2 Hz).

[214] Alternatively, 7.1 has been summarized as follows:

[215] 6-Bromo-2,3-dimethyl-2H-indazol-4-ol 6.4 (10.5 g), potassium carbonate (16.8 g) and 2.3 (18.6 g) were suspended

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70/176 in anhydrous DMF and stirred for 2ha70 ° C overnight at 50 ° C. An additional 2.3 (5 g) and potassium carbonate (5 g) were added and the mixture was stirred for 3 h at 70 ° C. The mixture was concentrated, water and DCM were added and the aqueous phase was extracted 3x with DCM (250 ml). The organic phase was washed with KHSO4 and dried (Na2S04) and concentrated. The mixture was purified by means of SiO2 (DCM: MeOH 9: 1) to generate 12.7 g of 7.1.

[216] Analysis: HPLC-MS: R _t = 1.029 min (Z018_S04), M + H = 486/488.

[217] i-H-RNM (DMSO, 400 MHz) δ 1.16 (3H, d, J = 6.1 Hz),

1.41 (3H, d, J = 7.2 Hz) i, 2, 33 -2.39 (1H, m), 2.44 (3H, s) , 2.73 (1H, s), 2.78-2.82 (1H, m) i, 2.89 (1H, s) , 3, li 3 (1H :, d, J = 5.1 Hz), 3.49 (1H, t, J = 9.2 Hz), 3.64 (3H, s) , 3.93 (3H, s), 4.60-4.66 (1H, m), 5, 18-5.23 (1H, q , J = 7.2 Hz), 6.37 (1H, s), 6.57-6.60 (2H z m), 7.09-7.11 (2H, m), 7.21 (1H, d, J = 1.2 Hz).

Synthesis of (R) -4 - [(R) -1- (6-Chloro-2,3-dimethyl-2Hpyrazolo [4,3-c] pyridin-4-yloxy) -ethyl] -1 - [(S) -1- (4-methoxyphenyl) -ethyl] -pyrrolidin-2-one (7.2) for Examples 3, 4,

[218] 2.1 (3.2 g) was dissolved in THF (50 ml) and NaH (1.08 g, 60% dispersion in mineral oil) was added and

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71/176 the mixture was stirred for 5 min, then 6.2 (2.5 g) was added and stirring continued at 50 ° C for 3 h. After cooling, aqueous NH ₄ C1 (50 ml) was added and the mixture extracted 2x with iPrOAc and the combined organic phases dried (MgSCu) and concentrated. The product was purified by means of preparative HPLC to generate 7.2 (3.65 g) as a white solid.

[219] Analysis: HPLC-MS: R _t = 0.60 min (X012_S01), M + H = 443.

[220] ^ -RNM (DMSO, 400 MHz) δ 1.22 (3H, d, J = 6.2 Hz),

1.40 (3H, d, J = 7.2 Hz), , 2.37-2.43 (1H, m), 2.45 (3H, s) , 2.51- 2.56 (1H, m), 2.64- 2.72 (1H, m), 2.76- -2.80 (1H, m), 3.53 (1H, t, J = 9.3 Hz), 3.62 (3H, s), 3.96 (3H, s), 5 , 16- 5.18 (1H, q, J = 7.2 Hz), 5.33-5.35 (1H, m), 6.47-6.49 (2H, m), 7 , 01- 7.03 (3H, m).

Synthesis of (1R, 4R) -4 - [(R) -1- (6-bromo-3-fluor-2-methyl2H-indazol-4-yloxy) -ethyl] -1- [1- (4-methoxy- phenyl) -ethyl] pyrrolidin-2-one (7.3) for Examples 1, 2, 5-7, 12, 14 ψετ

N,

-THE

H

2.3

7.3 [221] 2.4 g of 6.3 were dissolved in DMF (20 ml), potassium carbonate (5.41 g) and 2.3 (6.13 g) was added and the mixture stirred at 70 ° C overnight . The mixture was concentrated in vaccum, water was added and the mixture was extracted 3x with DCM. The organic phase was separated to generate 5.5 g (80% content) of product 7.3, which was used without

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72/176 further purification in the next step.

[222] Analysis: HPLC-MS: R _t = 0.61 min (X012_S01), M + H =

490/492.

Synthesis of (R) -5 - [(R) -1- (6-Chloro-2,3-dimethyl-2Hpyrazolo [4,3-c] pyridin-4-yloxy) -ethyl] -3- (4-methoxy -benzyl) oxazolidin-2-one (7.4) for Example 3

7.4

2.4

7.5

L223J A 6.2 (75 mg) and NaH (32 mg) 2.4 (90 mg) dissolved in dimethylacetamide (DMA; 2 ml) were added and the solution was stirred for 5 h. The mixture was purified by means of preparative HPLC (water / acetonitrile / NH3) to provide 7.4 (38 mg) and 7.5 (46 mg) as white solids (7.4 and 7.5 as a mixture of enantiomers).

[224] Analysis of 7.4: HPLC-MS: R _t = 0.83 min (X018_S03), M + H = 431.

[225] Analysis of 7.5: HPLC-MS: R _t = 0.87 min (X018_S03), M + H = 431.

Synthesis of (R) -4 - [(R) -1- (6-bromo-2,3-dimethyl-2Hindazol-4-yloxy) -ethyl] -pyrrolidin-2-one (8.1) for Examples 8, 13 , 18, 19, 20

Br 'Br

7.1

3.1

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73/176 [226] A mixture of 7.1 (2.3 g) in TFA (40 ml) and anisole (5 ml) was stirred at 80 ° C for 15 h and 8 h at room temperature. The reaction mixture was concentrated, diluted with acetonitrile (8 ml), basified with 25% NH ₃ and diluted with water and separated by means of preparative HPLC. The yellow oil was dissolved in tert-butyl methyl ether and a white precipitate formed, which was collected after 3 days to generate

8.1 (1.35 g).

[227] Analysis: HPLC-MS: R _t = 0.45 min (X012_S01), M + H = 352/354.

[228] i-H-RNM (DMSO, 400 MHz) δ 1.28 (3H, d, J = 6.1 Hz),

2.15-2.35 (2H, m), 2.63 (3H, s), 2.72-2.82 (1H, m), 3.07- 3.11 (1H, m), 3.37 (1H, t, J = 8.9 Hz), 3.95 (3H, s) , 4.63- 4.69 (1H, m), 6.45 (1H, s), 7.23 (1H, d, J = 1.0 Hz) , 7.55

(1H, s).

Synthesis of (R) -4 - [(R) -1- (6-chloro-2,3-dimethyl-2Hpyrazolo [4,3-c] pyridin-4-yloxy) -ethyl] -pyrrolidin-2-one ( 8.2) for Examples 4, 15

O

7.1

3.1 [229] 7.2 (2.4 g, 85% content) was stirred in TFA (20 ml) at 80 ° C for 4 h, and then it was concentrated. The residual was dissolved in iPrOAc and saturated aqueous NaHCCb (30 ml), and water (20 ml) was added. The precipitate was collected, washed with water, iPrOAc and light petroleum to provide 890 mg of

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74/176 a white solid 8.2.

[230] Analyze: HPLC-MS: Rt = 0.48 min (X012_S02 ), M + H = 309. [231] ¹ H-RNM (CDCI3, 500 MHz) δ 1.41 (3H, d, J = 6.3 Hz), 2.43-2.57 (2H, m), 2.86 (1H , ddd, J = 14,1, 8,3, 6.0 Hz), 3.32 (1H, dd, J = 9.6, 6.4 Hz), 3.55 (1H, t, J = 9.1 Hz), 4.00 (3H, s), 5.59 (1H, m), 5.72 (1H, s), 7.03 (1H, s) .

Synthesis of (R) -4 - [(R) -1- (6-bromo-3-fluor-2-methyl-2Hindazol-4-yloxy) -ethyl] -pyrrolidin-2-one (8.3) for Examples 1 , 2, 5, 6

[232] A mixture of 7.3 (2.8 g) in 10 ml TFA was stirred at 80 ° C for 2 h. The reaction mixture was poured into water, basified with NaOH (4 N) and extracted with DCM. The organic phase was concentrated and purified by means of SiO2 and the desired fractions were combined to generate 8.3 (0.868 g).

[233] Analysis: HPLC-MS: R _t = 0.46 min (X012_S02), M + H = 357/359.

4.1.6. Synthesis of boronic acids and boronic esters 9 and 12 from Schemes 1 and 2

Synthesis of (R) -4 - {(R) -1- [2,3-dimethyl-6- (4,4,5,5tetramethyl- [1,3,2] dioxaborolan-2-yl) -2H-indazole -4-yloxy] ethyl} -l - [(S) -1- (4-methoxy-phenyl) -ethyl] -pyrrolidin-2-one (9.1) for Examples 11, 16, 17, 22

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[234] 7.1 (50 mg), bis- (pinacolate) -diboro (31 mg), tetrakis (triphenylphosphine palladium (0) (24 mg) and potassium acetate (30 mg) were suspended in dioxane (2 ml) and the mixture stirred at 100 ° C for 1.5 h The mixture was diluted with DCM (20 ml) and water (20 ml) and the organic phase was separated and concentrated to generate 9.1 (84 mg, 50% content) as a oil, which was used in the next step without further purification.

[235] Analysis: HPLC-MS: R _t = 0.41 (acid) + 0.61 (ester, 9.1) min (X016_S01), M + H = 452 and 534.

Synthesis of (R) -4 - {(R) -1- [3-fluorine-2-methyl-6- (4,4,5,5tetramethyl- [1,3,2] dioxaborolan-2-yl) -2H -indazol-4-yloxy] ethyl} -pyrrolidin-2-one (12.1) for Examples 12, 14

[236] 8.3 (400 mg), bis- (pinacolato) -diboro (342 mg) and potassium acetate (330 mg) were suspended in dioxane (5 ml) and degassed with nitrogen for 5 min.

[237] (2-Dicyclohexylphosphino-2 ', 4', 6'-triisopropyl1,1'-biphenyl) [2 - (2-amino-1,1'-biphenyl)] palladium (II)

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76/176 methanesulfonate (95 mg) was added and the mixture stirred at 75 ° C overnight, and then filtered through Agilent StratoSpheres PL-Thiol MP SPE using MeOH as the eluent and concentrated to generate 12.1 (400 mg) as an oil, which was used without further purification.

[238] Analysis: HPLC-MS: R _t = 0.51 min M + H: 404 (method X012_S01).

4.3 Synthesis of formula ± patent examples using formulas 8-11

Synthesis of (R) -4 - {(R) -1- [6- (1-Cyclobutyl-1H-pyrazol-4yl) -3-fluor-2-methyl-2H-indaz-ol-4-yloxy] -ethyl } -pyrrolidin2-one (Example 1)

[23 9] To 8.3 (70 mg) in dioxane (1 ml) and 2 M aqueous Na2CO3 (295 μΐ) borolane 4.8 (48.7 mg) and 1.1'bis (diphenylphosphine) ferrocenodichloropalladium (II) (A) (A ), 7.2 mg) and the mixture was stirred for 45 min at 70 ° C. The mixture was filtered through Agilent StratoSpheres PL-Thiol MP SPE using MeOH as the eluent and purified by means of preparative HPLC to generate, after lyophilization, 43 mg of Example

1.

[240] Analysis: HPLC-MS: R _t = 0.68 min (001_CA02), M + H = 398.

[241] ¹ H-RNM (DMSO, 400 MHz) δ 1.31 (3H, d, J = 6.1 Hz),

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1.78-1.85 (2H, m), 2.17-2.32 (2H, m) , 2.38-2.44 (3H, m), 2.75-2.77 (1H, m), 3.09-3.13 (1H, m), 3.37 (1H, t, J = 9.0 Hz), 3.92 (3H, s), 4.73-4.85 (2H, m) , 6.66 (1H, s), 7.18

(1H, s), 7.53 (1H, s), 7.96 (1H, s), 8.33 (1H, s).

[242] The following examples were synthesized analogously to Example 1, using the following palladium catalyst systems:

A) 1,1'-Bis (diphenylphosphino) ferrocenodichloropalladium (II) or

B) Dicyclohexyl- [2- (2,4,6-triisopropylphenyl) phenyl] phosphane [2- (2-aminophenyl) phenyl] -methylsulfonyloxy-palladium

Example Formula 8 Acid / ester boronic (which matches to formula 4) Rendered ment Analyze Catali- sador Example 2 8.3 3 9 mg HPLC-MS: (R) -4 - {(R) -1- [3- (51%) R _t = 0.64 min fluorine- 1-isopropyl-4- THE) (001_CA02) M + H = 386 6- (1-isopropyl-1H- (4,4,5,5- pyrazol-4-yl) -2- tetramethyl-1,3,2- methyl- dioxaborolan-2- 2H-indazol-4-yloxy] - il) pyrazole 4.6 ethyl} -pyrrolidin-2- ona Example 4 8.2 3-tert- 15 mg HPLC-MS: (R) -4- {(R) -1- [6- (3- butyl-1H-pyrazole- (32%) R _t = 46 min tert-Butyl-1H- 4-il-4-boronic B) (X012_S01) M + H = 397 pyrazol-4-yl) - 4.2 ¹ H-RNM (DMSO, 400 2,3-dimethyl-2H- MHz) δ 1.30 (9H, s), pyrazole [4,3- 1.36 (3H, d, J = 6.2

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c] pyridin-4-yloxy] - Hz), 2.22-2.35 (2H, ethyl} -pyrrolidin-2- m), 2.65 (3H, s), ona 2.75-2.84 (1H, m), 3.12-3.17 (1H, m), 3.40 (2H, t, J = 9.0 Hz), 3.98 (3H, s), 5.66-5.71 (1H, m), 6.59 (1H, s), 7.42 (1H, s), 7.53 (1H, s) Example 5 8.3 44 mg HPLC-MS: (R) -4 - {(R) -1- [6- (1- 1-Cyclopropyl-4- (58%) R _t = 0.62 min Cycloprop-yl-1H- (4,4,5,5- THE) (001_CA02), M + H = 384 pyrazol-4-yl) -3- tetramethyl- fluorine-2-methyl-2H- [1,3,2] dioxaborol indazol-4-yloxy] - an-2-yl) -1H- ethyl} -pyrrolidin-2- pyrazole 4.5 ona Example 6 8.3 4 7 mg HPLC-MS: (R) -4 - {(R) -1- [6- (1- 1- (Cyclopropyl- (60%) R _t = 0.66 min Cycloprop-ylmethyl-1H- methyl) -4- THE) (001_CA02), M + H = 398 pyrazol-4-yl) -3- (4,4,5,5- fluorine-2-methyl-2H- tetramethyl-1,3,2- indazol-4-yloxy] - dioxaborolan-2- ethyl} -pyrrolidin-2- il) -1H-pyrazole ona 4.4 Example 8 8.1 1- (Cyclopropyl- 22 mg HPLC-MS: (R) -4 - {(R) -1- [6- (1- methyl) -4- (40%) R _t = 0.55 min Cyclopropylmethyl-1H- (4,4,5,5-tetra- THE) (X011_S03), M + H = 395 pyrazol-4-yl) -2,3- methyl-1,3,2- dimethyl-2H-indazole-4- dioxaborolan-2-

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iloxy] -ethyl} - pyrrolidin-2-one il) -1H-pyrazole 4.4 8.1 12 0 mg HPLC-MS: (47%) R _t = 0.51 min THE) (X018_S01), M + H = 396 ¹ H-RNM (DMSO, 400 MHz) δ 1.32 (3H, d, J = 6.0 Hz), 1.56 (9H, s), 2.20-2.38 (2H, m), 2.63 (3H, s), 2.75-2.85 (1H, m), Example 13 3.12-3.16 (1H, m), (R) -4 - {(R) -1- [6- (1- 3.40 (1H, t, J = 9.1 tert-Butyl-lH- 1-tert-butyl-4- Hz), 3.94 (3H, s), pyrazol-4-yl) -2,3- (4,4,5,5- 4.75-4.80 (1H, m), dimethyl-2H-indazole-4- tetramethyl-1,3,2- 6.59 (1H, s), 7.57 iloxy] -ethyl} - dioxaborolan-2- (1H, s), 7.89 (1H, pyrrolidin-2-one il) pyrazole 4.1 s), 8.26 (1H, s) 63 0 mg HPLC-MS: (60%) R _t = 0.48 min (X012_S01), Example 15 M + H = 397 (R) -4 - {(R) -1- [6- (1- ¹ H-RNM (MeOD, 500 tert-Butyl-1H- MHz) δ 1.47 (3H, d, pyrazol-4-yl) -2,3- J = 6.3 Hz), 1.63 (9H, dimethyl-2H- 1-tert-butyl-4- s), 2.54 (2H, dd, J = pyrazole [4,3- (4,4,5,5- 8.2, 5.1 Hz), 2.70 c] pyridin-4-yloxy] - tetramethyl-1,3,2- (3H, s), 2.88-2.99 ethyl} -pyrrolidin-2- dioxaborolan-2- (1H, m), 3.36 (1H, ona 8.2 il) pyrazole 4.1 THE) dd, J = 10.1, 5.8

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Hz), 3.59 (1H, dd, J = 10.0, 8.7 Hz), 4.00 (3H, s), 5.72 (1H, p, J = 6.2 Hz), 7.16 (1H, s), 8.18 (1H, s) Example 18 (R) -4- {(R) -1- [6- (1- Isopropyl-1H-pyrazole- 4-yl) -2,3-dimethyl-2H- indazol-4-yloxy] - ethyl} -pyrrolidin-2- ona 8.1 1-Isopropyl-4- (4,4,5,5-tetra- methyl-1,3,2- dioxoborolan-2- il) pyrazole 4.6 43 0 mg (99%) HPLC-MS: R _t = 0.52 min (X018_S03), M + H = 382 ¹ H-RNM (DMSO, 400 MHz) δ 1.32 (3H, d, J = 6.1 Hz), 1.46 (6H, d, J = 6.7 Hz), 2,192.37 (2H, m), 2.63 (3H, s), 2.75-2.85 (1H, m), 3.11-3, 15 (1H, m), 3.40 (1H, t, J = 9.1 Hz), 3.95 (3H, s), 4.47-4.53 (1H, m), 4.74-4 , 80 (1H, m), 6.59 (1H, s), 7.20 (1H, s), 7.58 (1H, s), 7.89 (1H, s), 8.23 (1H, s) B) Example 19 (R) -4 - {(R) -1- [6- (1- Isobutyl-1H-pyrazole- 4-yl) -2,3-dimethyl-2H- indazol-4-yloxy] - ethyl} -pyrrolidin-2- ona 8.1 1-Isobutyl-4- (4,4,5,5- tetramethyl-1,3,2- dioxaborolan-2- il) -1H-pyrazole 4.10 242 mg (98%) HPLC-MS: R _t = 0.43 min (X017_S01), M + H = 396 B)

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Example 20 (R) -4 - {(R) -1- [6- (1- 8.1 1-Cyclopropyl-4 - 23 mg (35%) HPLC-MS: Rt = 0.58 min Cyclopropyl-1H- pyrazol-4-yl) -2,3- dimethyl-2H-indazole-4 - iloxy] -ethyl} - pyrrolidin-2-one (4,4,5,5- tetramethyl- [1,3,2] dioxaborol an-2-yl) -1H- pyrazole 4.5 THE) (003_CA04), M + H = 381 Example 21 8.1 14 5 mg HPLC-MS: (R) -4 - {(R) -1- [6- (1- 1-Cyclobuil-4 - (65%) R _t = 0.57 min Cyclobutyl-1H- (4,4,5,5- (X018_S03), M + H = 394 pyrazol-4-yl) -2,3- tetramethyl- dimethyl-2H-indazole-4 - [1,3,2] dioxaborol iloxy] -ethyl} - an-2-yl) -1H- pyrrolidin-2-one pyrazole 4.8

Example 13 was alternatively synthesized using the following synthesis procedure

[243]

Stage

1:

Isopropyl chloride complex

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82/176 magnesium / lithium chloride (1.3 M in THF, 28.4 ml, 37 mmol) was loaded into a solution of 4-bromo-1- (tert-butyl) -1Hpyrazole (5.0 g, 25 mmol) in anhydrous THF (25 ml) under argon at room temperature. Anhydrous dioxane (3.3 g, 37 mmol) was charged to the reaction, and the reaction was stirred at 45 ° C for 4 h. The resulting mixture was cooled to room temperature and charged to an anhydrous solution of acetic anhydride (7.5 g, 73 mmol) in THF (25 ml) at -20 ° C. The resulting mixture was warmed to room temperature and concentrated to a residue. The mixture was dissolved in methyl t-butyl ether (50 ml) and washed with water (25 ml). The organic portion was concentrated to provide crude 1- (1- (tert-butyl) -1H-pyrazol-4yl) ethan-1-one as an oil (7.6 g, 36% by weight) and 67% yield. Crystallization from a mixture of methyl t-butyl ether and heptane provided analytically pure material of 1- (1- (tert-Butyl) -1H-pyrazol-4-yl) ethan-1-one. ¹ H-RNM (500 MHz, CDCl3) δ = 7.96 (s, 1H), 7.86 (s, 1H), 2.37 (s, 3H), 1.55 (s, 9H).

[244] Step 2: Degassed 1,4-Dioxane (10 ml) was loaded into a mixture of palladium acetate (51 mg, 0.23 mmol), tri-t-butylphosphonium tetrafluorborate (128 mg, 0.44 mmol), lithium t-butoxide (1.47 g, 18 mmol), 3-iodo1,5-dimethyl-1H-pyrazol-4-carboxylic acid (1.0 g, 3.7 mmol, Organic Letters (2015) , 17 (12), 2,964-2,967) and 1- (1-tbutyl) -1H-pyrazol-4-yl) ethan-1-one (0.68 g, 4.1 mmol) at room temperature under argon. The stirred mixture was heated to 80 ° C over approximately 15 min and stirred at that temperature for 30 min. The reaction was cooled to room temperature and diluted with trifluoroacetic acid (30 ml) and acetonitrile (15 ml). The mixture

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83/176 was stirred at 78 ° C for 10 h. The reaction was cooled to room temperature and concentrated to a solid residue. The residue was dissolved in a mixture of isopropyl acetate and water. The pH of the aqueous layer was adjusted to pH approximately 10 with 3M NaOH. The layers were separated, and the organic portion was washed twice with water. The organic portion was concentrated to a solid (1.92 g). The solid was dissolved in hot n-propanol (7 ml) and cooled to room temperature, where crystallization occurred. The mixture was diluted with water (10 ml) dropwise and stirred for 30 min. The solids were collected by filtration and washed with a 20% volume solution of n-propanol in water. The solids were dried in a vacuum oven at 50 ° C with a stream of nitrogen to provide 6- (1- (tert-butyl) 1H-pyrazol-4-yl) -2,3-dimethylpyran [4,3-c ] pyrazole-4 (2H) -one as a solid in approximately 94% by weight of purity (49% yield). ¹ H-RNM (CDCl3, 400 MHz), δ = 7.96 (s, 1H), 7.83 (s, 1H), 6.61 (s, 1H), 3.8 9 (s, 3H), 2.66 (s, 3H), 1.62 (s, 9H).

[245] Step 3: Dimethyl methylphosphonate (1.2 g, 10 mmol) was added dropwise to an anhydrous lithium diisopropyl amide slurry (2.0 M, 4.6 ml, 9.2 mmol) in THF (15 ml) at - 78 ° C under argon. After stirring for 50 min, an anhydrous slurry of 6- (1- (tert-butyl) -1H-pyrazol-4-yl) -2,3dimethylpyran [4,3-c] pyrazol-4 (2H) -one (0 , 89 g, 3.11 mmol) in THF (10 ml) was charged to the phosphonate solution lithium above at -78 ° C. The reaction mixture was stirred at -78 ° C for 1 h and allowed to warm to room temperature over 1 h. The reaction was quenched with methanol (3 ml) and stirred for 1 h. 3 M aqueous HCl (4 ml) was loaded

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84/176 to the reaction, and the reaction was stirred overnight at room temperature. The reaction was diluted with water (15 ml) and concentrated in vacuo to remove organic solvents. The resulting slurry was diluted with isopropyl acetate and water. The pH of the aqueous layer was adjusted to 3-4 with 3M HCl. The layers were separated, and the aqueous portion was extracted back with isopropyl acetate. The combined organic layers were concentrated to a solid in vacuo. The solid was dissolved in hot n-propanol (6 ml), cooled to room temperature and diluted with water (35 ml) dropwise with stirring. The mixture was stirred for 1 h at room temperature. The solids were collected by filtration, washed with water and dried in a vacuum oven at 50 ° C with a stream of nitrogen to provide 6- (1- (tercbutyl) -1H-pyrazol-4-yl) -2,3- dimethyl-2H-indazol-4-ol (760 mg, 84% by weight, 72% yield). ¹ H-RNM (DMSO-d6, 400 MHz), δ = 9.86 (s, 1H), 8.11 (s, 1H), 7.75 (s, 1H), 7.11 (s, 1H) , 6.41 (s, 1H), 3.94 (s, 3H), 2.67 (s, 3H), 1.55 (s, 9H).

[246] Step 4: A mixture of potassium carbonate (610 mg, 4.4 mmol), (S) -1 - ((R) -1 - ((S) -1- (4-methoxyphenyl) ethyl) -5oxopyrrolidin- 3-yl) ethyl 4-methylbenzenesulfonate (810 mg, 1.9 mmol), and 6- (1- (tert-butyl) -1H-pyrazol-4-yl) -2,3dimethyl-2H-indazol-4-ol (418 mg, 1.5 mmol) in anhydrous dimethyl formamide (1.5 ml) was stirred under nitrogen at 70 ° C for 18 h. More (S) -1 - ((R) -1 - ((S) -1- (4-methoxyphenyl) ethyl) -5oxopyrrolidin-3-yl) ethyl 4-methylbenzenesulfonate (0.280 mg, 0.66 mmol) was loaded to the reaction, and the reaction was stirred at 70 ° C for 20 h. The reaction was diluted with isopropyl acetate and water. The layers were separated, and the organic portion was washed twice. The organic portion was concentrated to a

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85/176 oily solid. Purification by chromatography on silica gel (methanol in ethyl acetate) gave the desired product (R) 4 - ((R) -1 - ((6- (1- (tert-butyl) -1H-pyrazol-4-yl ) -2,3-dimethyl2H-indazol-4-yl) oxy) ethyl) -1 - ((S) -1- (4methoxyphenyl) ethyl) pyrrolidin-2-one (10.5) as a foam in approximately 90% purity (769 mg, 89%). ¹ H-RNM (CDCl ₃ ,

500 MHz), δ = 7.77 (s, 1H), 7.72 (s, 1H), 7.24 (s, 1H), 7 , 15 (d, J = 8 74 Hz, 2H), 6.23 (d, J = 8.54 Hz, 2H) , 6.26 (s, 1H) , 5.46 (q, J = 7.41 Hz, 1H), 4.50-4.56 (m, 1H) , 3.97 (s, 3H) , 3.69 (s, 3H) , 3.48 (t , J = 9.0 Hz, 1H), 2, 93-3.0 (m,

1H), 2.62-2.80 (m, 2H), 2.55-2.62 (m, 1H), 2.48 (s, 3H), 1.64 (s, 9H), 1.50 (d, J = 7.4 Hz, 3H), 1.31 (d, J = 6.3 Hz, 3H).

[247] Step 5: A solution of (R) -4 - ((R) -1 - ((6- (1- (tercbutyl) -1H-pyrazol-4-yl) -2,3-dimethyl-2H- indazol-4yl) oxy) ethyl) -1 - ((S) -1- (4-methoxyphenyl) ethyl) pyrrolidin-2-one (585 mg, 1.1 mmol) in trifluoroacetic acid (3 ml) and anisole (1 , 5 ml) was stirred at 75 ° C under nitrogen for 18 h. The reaction was cooled to room temperature and diluted with isopropyl acetate and water. The aqueous pH portion was adjusted to 6 with 3M aqueous NaOH. The layers were separated and the organic portion was concentrated to an oil. Purification by chromatography on silica gel (EtOH in EtOAc) provided example 13 as a foam (420 mg, 94%).

Synthesis of (R) -5 - {(R) -1- [6- (1-tert-butyl-1H-pyrazol-4yl) -2,3-dimethyl-2H-pyrazolo [4,3-c] pyridin- 4-yloxy] -ethyl} oxazolidin-2-one (Example 3)

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[248]

Step 1: A 4.1 (46 mg) and dicyclohexyl- [2- (2,4,6triisopropylphenyl) phenyl] phosphane [2- (2-aminophenyl) phenyl] methylsulfonyloxy-palladium (15 mg) were added 7.4 (38 mg), dissolved in dioxane (1 ml) and MeOH (0.2 ml) and aqueous Na ₂ CÜ3 2 (0.175 ml), and the mixture was heated for 50 min at 90 ° C. Then, MeOH (10 ml) was added and the mixture was filtered through Agilent StratoSpheres PL-Thiol MP SPE and concentrated. The residual was dissolved in DCM (20 ml) and extracted with water (20 ml) and the aqueous phase extracted with DCM (10 ml). The combined organic phases were dried and concentrated to generate 10.1 (74 mg), which was used without further purification for the next step.

[249] Analysis: HPLC-MS: R _t = 0.86 min (X018_S03), M + H = 519.

[250] Step 2: At 10.1 (74 mg) trifluoroacetic acid (2.956 g) was added and the mixture was stirred for 30 h at 75 ° C. The mixture was then concentrated and purified by means of preparative HPLC (water / acetonitrile / NH ₃ ) to provide a white solid, which was then separated by means of Chiral SFC (Knauer Eurocel 01; scCO ₂ 80% / MeOH 20% + 20 mM NH3; 120 bar BPR; 40 ° C to provide Example 3 (13 mg) as a white solid.

[251] Analysis: HPLC-MS: R _t = 0.92 min (V011_S01), M + H = 399.

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Synthesis of (R) -4 - ((R) -1- {6- [1 - ((R) -2,2-dimethyltetrahydro-pyran-4-yl) -1H-pyrazol-4-yl] -2, 3-dimethyl-2Hindazol-4-yloxy} -ethyl) -pyrrolidin-2-one (Example 9)

[252] Step 1: A 7.1 (200 mg), 4- (4,4,5,5-Tetramethyl [1,3,2] dioxaborolan-2-yl) -1H-pyrazole 4.9 (120 mg), Dicyclohexyl- [2 - (2,4,6-tripropylphenyl) phenyl] phosphane [2 (2-aminophenyl) phenyl] -methylsulfonyloxy-palladium (40 mg) was added dioxane (3 ml) and 2 M aqueous Na ₂ CO3 (0.7 ml) and the mixture was stirred for 2 h at 90 ° C. The mixture was diluted with DCM (50 ml) and water (30 ml). After phase separation, the aqueous phase was extracted 2x with DCM (25 ml). The combined organic phases were dried (MgSCu) and purified by means of preparative HPLC to provide 11.1 as a yellow oil (137 mg).

[253] Analysis: HPLC-MS: R _t = 0.44 min (X012_S01), M + H = 474.

[254] Step 2: At 5.2 (61 mg) and Cs ₂ CO3 (93 mg) 11.1 (68 mg) dissolved in DMF (1 ml) was added and the suspension was heated to 70 ° C for 3 h. Another 5.2 (45 mg) and Cs ₂ CO3 (93 mg) were added, and stirring continued for 5 h at 70 ° C, and then another 5.2 (45 mg) and Cs ₂ CO3 (93 mg) were added, and stirring continued at 80 ° C for 10 h and 3 days at room temperature. The mixture was diluted with DCM (20 ml) and water (20 ml) and the phases were separated. The aqueous phase was extracted with DCM (20 ml) and the organic phases combined

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88/176 were dried, concentrated and purified by means of preparative HPLC to provide 10.2 (57 mg) as a colorless oil.

[255] Analyze: HPLC-MS: Rt = 0.65 min (X012_S01), M + H = 586. [256] Step 3: THE 10.2 (57 mg) was added acid trifluoroacetic (2 ml) and the mixture was agitated by 3 h

80 ° C. The mixture was concentrated and purified by means of preparative HPLC to provide Example 9 (23.7 mg).

[257] Analysis: HPLC-MS: R _t = 0.90 min (003_CA03), M + H = 452.

Synthesis of 4- (l- {6 - [(R) - (3S, 3aR, 7aR) -1 (Hexahydrofuro [3,2-b] pyran-3-yl) -ΙΗ-pyrazol-yl] -2,3dimethyl -2H-indazol-4-yloxy} -ethyl) -pyrrolidin-2-one (Example

10)

W.3

Example 10 [258] Step 1: A 5.1 (64 mg) and CS2CO3 (93 mg) 11.1 (68 mg) dissolved in DMF (1 ml) was added and the suspension was heated to 70 ° C for 3 h. Another 5.1 (45 mg) and CS2CO3 (93 mg) were added, and stirring continued for 5 h at 70 ° C, and then another 5.1 (45 mg) and CS2CO3 (93 mg) were added, and stirring continued at 80 ° C for 10 h and 3 days at room temperature and 3 h at 100 ° C. The mixture was diluted with DCM (20 ml) and water (20 ml) and the phases were separated. The aqueous phase was extracted with DCM (20 ml) and the phases

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The combined organic 89/176 were dried, concentrated and purified by means of preparative HPLC to provide 10.3 (42 mg) as a colorless oil.

[259] Analysis: HPLC-MS: R _t = 0.64 min (X012_S01), M + H = 600.

[260] Step 2: At 10.3 (41 mg) trifluoroacetic acid (2 ml) was added and the mixture was stirred for 3 h at 80 ° C. The mixture was concentrated and purified by means of preparative HPLC to provide Example 10 (17.1 mg).

[261] Analysis: HPLC-MS: R _t = 0.88 min (003_CA03), M + H = 466.

Synthesis of (R) -4 - ((R) -l- {6- [1- (2-fluoro-ethyl) -1Hpyazol-4-yl] -2,3-dimethyl-2H-indazol-4-yloxy} -ethyl) -

Step 2

[262] A 9.1 (150 mg), 3.6 (35 mg) and Dicyclohexyl- [2 (2,4,6-triisopropylphenyl) phenyl] phosphane [2- (2aminophenyl) phenyl] -methylsulfonyloxy-palladium (17 mg) in dioxane (1 ml) and 2 M aqueous Na2CC> 3 (3 94 μΐ) were heated for 3 h at 100 ° C. Water was added, and the aqueous phase was extracted 3x with DCM and the combined organic phases concentrated, dissolved in MeOH and filtered through Agilent StratoSpheres PL-Thiol MP SPE and concentrated to provide 10.4, which was used without further purification for

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90/176 the next step.

[263] Analysis: HPLC-MS: Rt = 0.53 min (X011_S03), M + H = 520.

[264] Step 2: At 10.4 (107 mg) trifluoroacetic acid (1.5 ml) was added and heated for 2.5 h at 70 ° C. To the mixture, water and saturated aqueous NaHCO3 were added, and the aqueous phase was extracted 2x with DCM. The combined organic phases were concentrated and purified by means of preparative HPLC to provide Example 11 (12 mg) as a white solid.

[265] Analysis: HPLC-MS: Rt = 0.41 min (X011_S03), M + H = 386.

[266] ¹ H-RNM (DMSO, 400 MHz) δ 1.32 (3H, d, J = 6.0 Hz),

2.19-2.37 (2H, m), 2.63 (3H, s), 2.75-2.84 (1H, m), 3,113.15 (1H, m), 3.40 (1H, t, J = 9.1 Hz), 3.94 (3H, s), 4.40 (1H, t, J = 4.7 Hz), 4.47 (1H, t, J = 4.7 Hz) , 4.73-4.78 (2H, m), 4.86 (1H, t, J = 4.7 Hz), 6.56 (1H, s), 7.20 (1H, s), 7, 56 (1H, s), 7.96 (1H, s), 8.23 (1H, s).

[267] The following Examples were synthesized analogously to Example 11 using intermediate 9.1 and one of the following palladium catalyst systems:

A) 1,1'-Bis (diphenylphosphino) ferrocenodichloropalladium (II) or

B) Dicyclohexyl- [2- (2,4,6-triisopropylphenyl) phenyl] phosphane [2- (2-aminophenyl) phenyl] -methylsulfonyloxy-palladium

Example Bromide (which stands for formula 3) Yield Analyze A) or B) Example 16 4-bromo-1- 2 7 mg HPLC-MS:

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(R) -4 - ((R) -1- {2,3-dimethyl-6 - [1- (2,2,5,5- tetramethyl- tetrahydro- furan-3-yl) -1H- pyrazol-4-yl] - 2H-indazole-4- iloxy} -ethyl) - pyrrolidin-2-one (2,2,5,5- tetramethyl- tetrahydro- furan-3-il) - 1H-pyrazole 3.2 (41%) (two phases) Rt = 0.70 min (003_CA04), M + H = 466 1H-RNM (DMSO, 400 MHz) δ 0.77 (3H, d, J = 1.1 Hz), 1.27 (3H, s), 1.33 (3H, d, J = 6.0 Hz), 1.37 (6H, s), 2.20-2.38 (3H, m), 2.64 (3H, s), 2.76-2.85 (2H, m), 3.11 - 3.15 (1H, m), 3.38-3.42 (1H, m), 3.95 (3H, s), 4.74-4.81 (2H, m), 6.66 (1H, s), 7.24 (1H, s), 7.56 (1H, s), 7.97 (1H, s), 8.34 (1H, d, J = 4.0 Hz) B) Example 17 2- (4- {2,3- dimethyl-4 - [(R) - 1 - ((R) -5-oxo- pyrrolidin-3- il) -ethoxy] -2H- indazol-6-il} - pyrazol-1-yl) -2- methyl- propionitrile 2 - (4-bromo- pyrazole-1- il) -2-methyl- propionitrile 3.3 6 mg (9%) (two phases) HPLC-MS: Rt = 0.41 min (X012_S01), M + H = 407 THE) Example 22 4-bromo-1- 80 mg (35%) HPLC-MS:

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(R) -4 - ((R) -1- {6- (3,3-diflúor- B) Rt = 0.592 min [1- (3,3-Diflúor- cyclopentyl) - (X018_ _S03), M + H = cyclopentyl) -1H- 1H-pyrazole 444 pyrazol-4-yl] - 3.4 2,3-dimethyl-2H- indazole-4- iloxy} -ethyl) - pyrrolidin-2-one

Synthesis of (R) -4 - ((R) -1- {3-fluoro-2-methyl-6- [1- (3,3,3trifluoro-propyl) -1H-pyrazol-4-yl] -2H- indazol-4-yloxy} ethyl) -pyrrolidin-2-one (Example 12) [268] A mixture of 12.1 (40 mg), 3.5 (19 mg) and 1,1'bis (diphenylphosphino) ferrocenodichloropalladium (II) (2 , 9 mg) in dioxane (1 ml) and 2 M aqueous Na2CO3 (119 μΐ) was heated overnight to 45 ° C. The mixture was diluted with MeOH and filtered through Agilent StratoSpheres PL-Thiol MP SPE, concentrated and purified by means of preparative HPLC to provide Example 12 (8 mg).

[269] Analysis: HPLC-MS: Rt = 0.48 min (X011_S03), M + H = 440.

[270] ¹ H-RNM (DMSO, 400 MHz) δ 1.31 (3H, d, J = 6.1 Hz),

2.17-2.32 (2H, m), 2.71-2.81 (1H, m), 2.85-2.98 (2H, m),

3.09-3.13 (1H, m), 3.37 (1H, t, J = 901 Hz), 3.92 (3H, d, J = 1.2 Hz), 4.39 (2H, t , J = 6.9 Hz), 4.70-4.76 (1H, m), 6.63 (1H, s), 7.17 (1H, s), 7.53 (1H, s), 8 .00 (1H, s), 8.32 (1H,

s).

The following Example 14 was synthesized in a similar way to Example 12.

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Example Bromide (which stands for formula 3) Yield Analyze Example 14 4-bromo-1- 22 mg HPLC-MS: (R) -4 - ((R) -l- {3- (2,2,5,5- (24%) Rt = 0.54 min fluorine-2-methyl-6- [1- tetramethyl- (X011_S03), (2,2,5,5- tetrahydro- M + H = 470 tetramethyl- furan-3-yl) -1H- tetrahydro-furan-3 - pyrazole il) -lH-pyrazole-4 - 3.2 yl] -2H-indazol-4- iloxy} -ethyl) - pyrrolidin-2-one

4.5 Analytical methods [271] The example compounds prepared according to the synthesis schemes described above were characterized by the following chromatographic methods and / or MRI spectroscopy.

4.5.1 Chromatographic methods (HPLC-MS methods) Method A:

Column: Xbridge BEH C18, 2.1 x 30 mm, 1.7 pm Supplier Waters column: Time to % of the sun. % of the sun. in Flow Temp. gradient/ of [H ₂ 0, [Acetonitrile] [ml / min] [° C] solvent [min] nh _3.0 ,%] 0.00 99 1 1.3 60 0.02 99 1 1.3 60 1.00 0 100 1.3 60 1.10 0 100 1.3 60

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Method Β:

Column: Sunfire C18, 3 x 30 mm, 2.5 pm Supplier Waters column: Time to % gives % of the sun. Flow Temp. gradient / solvent Sun. in in [ml / min] [° C] [min] [H ₂ 0, TFA [Methanol] 0.1%] 0.0 95 5 1.8 60 0.25 95 5 1.8 60 1.70 0 100 1.8 60 1.75 0 100 2.5 60 1.90 0 100 2.5 60

Method Ε:

Column: Sunfire Cl8, 2.1 x 20 mm, 2 5 pm Supplier Waters column: Time to % of the sun. % of the sun. Flow Temp. gradient / solvent of [H ₂ 0, in [ml / min] [° C] [min] TFA [Methanol] 0.10%] 0.00 99 1 1.3 60 0.15 99 1 1.3 60 1.10 0 100 1.3 60 1.25 0 100 1.3 60

Method F:

Column: XBridge C18, 3 x 30 mm, 2.5 pm Provider Waters column:

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Time to % of the sun. in % of the sun. in Flow Temp. gradient/ [H2O, NH3 [Acetonitrile] [ml / min] [° C] solvent 0.1%] [min] 0.00 97 3 2.2 60 0.20 97 3 2.2 60 1.20 0 100 2.2 60 1.25 0 100 3 60 1.40 0 100 3 60

Method H:

Eluent A: Hexane

Eluent B: 2-Propanol

Time [min] % of A % of B Flow rate [ml / min] 00.00 90 10 1.0 20.00 90 10 1.0

[272] The stationary phase used was a Chiralpak AD-H (Daicel), 5 μm; dimension: 150 x 4.6 mm, (column temperature: constant at 10 ° C).

[273] DAD detection 225 nm.

Method I:

Eluent A: Hexane

Eluent B: 2-Propanol

Time [min] % of A % of B Flow rate [ml / min] 00.00 90 10 1.0 25.00 90 10 1.0

[274] The stationary phase used was a Chiralpak AD-H (Daicel), 5 μm; dimension: 150 x 4.6 mm, (column temperature: constant at 10 ° C).

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96/176 [275] DAD detection 225 nm.

Method J:

Column: Sunfire C18, 2.1 x 30 mm, 2.5 pm Supplier Waters column: Time to % of the sun. % of the sun. in Flow Temp. gradient/ of [H ₂ 0, [Acetonitrile] [ml / min] [° C] solvent [min] 0.1% TFA] 0.0 99 1 1.5 60 0.02 99 1 1.5 60 1.00 0 100 1.5 60 1.10 0 100 1.5 60

Method X018 S03

Column: Sunfire C18, 3.0 x 30 mm, 2.5 pm Supplier Waters column: Time to % of the sun. % of the sun. in Flow Temp. gradient/ of [H ₂ 0, [Acetonitrile] [ml / min] [° C] solvent [min] 0.1% TFA] 0.0 95 5 1.5 60 1.3 0 100 1.5 60 1.5 0 100 1.5 60

SOI X018 Method

Column: Sunfire C18, 2.1 x 30 mm, 2.5 pm Supplier Waters column: Time to % of the sun. % of the sun. in Flow Temp. gradient/ of [H ₂ 0, [Acetonitrile] [ml / min] [° C] solvent 0.1% TFA] [min]

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0.0 99 1 1.5 60 0.02 99 1 1.5 60 1.00 0 100 1.5 60 1.10 0 100 1.5 60

Method X011 S03

Column: Xbridge BEH C18, 2.1 x 30 mm, 1.7 pm Supplier Waters column: Time to % of the sun. % of the sun. in Flow Temp. gradient/ of [H ₂ O, [Acetonitrile] [ml / min] [° C] solvent [min] nh _3.0 ,%] 0.00 95 5 1.3 60 0.02 95 5 1.3 60 1.00 0 100 1.3 60 1.10 0 100 1.3 60

SOI X012 Method

Name of method: X012S01 Name of X012S01 method: Column: Xbridge BEH C18, 2.1 x 30 mm, 1.7 pm Supplier Waters column: Time to % of the sun. % of the sun. in Flow Temp. gradient/ of [H ₂ 0, [Acetonitrile] [ml / min] [° C] solvent [min] 0.1% TFA] 0.0 99 1 1.6 60 0.02 99 1 1.6 60

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1.00 0 100 1.6 60 1.10 0 100 1.6 60

Method X012 S02

Name of method: X012S02 Column: Xbridge BEH C18, 2.1 x 30 mm, 1.7 pm Supplier Waters column: Time to % of the sun. % of the sun. in Flow Temp. gradient/ of [H ₂ O, [Acetonitrile] [ml / min] [° C] solvent [min] 0.1% TFA] 0.0 99 1 1.3 60 0.02 99 1 1.3 60 1.00 0 100 1.3 60 1.10 0 100 1.3 60

SOI X016 Method

Name of method: X016S01 Column: Xbridge BEH Fenil, 2.1 x 30 mm, 1.7 pm Name of method: X016S01 Supplier column: Waters Time to gradient/ solvent [min] % of the sun. [H ₂ 0, 0.1% TFA] % of the sun. in [Acetonitrile] Flow [ml / min] Temp. [° C] 0.0 99 1 1.6 60 0.02 99 1 1.6 60 1.00 0 100 1.6 60

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1.10 0 100 1.6 60

Method X017 S01

Column: Zorbax Stable Bond C18, 2.1 x 30 mm, 1.8 pm Supplier column: Waters Time to % gives % of the sun. in Flow Temp. gradient / solvent [min] Sun. in [H2O, TFA 0.1%] [Acetonitrile] [ml / min] [° C] 0.0 99 1 1.6 60 0.02 99 1 1.6 60 1.00 0 100 1.6 60 1.10 0 100 1.6 60

Method P:

[276] Column: Supelco Ascentis Express (2.1 x 30 mm, 2.7 pm column) [277] Flow rate: 1 ml / min [278] Solvent A: 0.1% formic acid / water [279] Solvent B: 0.1% formic acid / acetonitrile [280] Injection volume: 3 pl [281] Column temperature: 40 ° C [282] UV detection wavelength: 215 nm [283] Eluent: 0 to 1 , 5 minutes, constant gradient from solvent A 95% + solvent B 5% to solvent B 100%; 1.5 to

1.6 minutes, 100% solvent B; 1.60 to 1.61 minutes, constant gradient from solvent B 100% to solvent A 95% + solvent

B 5%; 1.61 to 2.00 minutes, solvent A 95% + solvent B 5%.

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100/176 [284] MS detection using Waters LCT Premier, Micro QT, ZQ or Shimadzu LCMS2010EV [285] UV detection using Waters 2996 photodiode array, Waters 2998 photodiode array, UV Waters 2487 or Shimadzu SPD-M20A PDA.

Method 001 CA02

Column: SunFire C18, 3.0 x 30 mm , 2.5 pm Supplier Waters column: Description: Waters Acquity, QDa Detector Time to % of the sun. in Flow Temp. [° C] gradient / solvent [Acetonitrile [ml / min] [min] 0.08% TFA] 0.0 5.0 1.5 40.0 1.3 100.0 1.5 40.0 1.5 100.0 1.5 40.0 1.6 5.0 1.5 40.0

Method 003 CA03

Device Agilent 1100 with DAD, Auto-injector CTC and Description: MS Waters detector Column: Sunfire C18, 3.0 x 30 mm, 3.5 pm Supplier Waters column: Description: Time to % of the sun. % of the sun. in Flow Temp. gradient/ of [H ₂ 0 [Acetonitrile] [ml / min] [° C] solvent [min] 0.1% TFA] 0.0 98.0 2.0 2.0 60.0 0.3 98.0 2.0 2.0 60.0 1.5 0.0 100.0 2.0 60.0

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1.6 0.0 100.0 2.0 60.0

Method 003 CAO4

Description of device: Agilent 1100 with DAD, Auto-injector CTC and Detector MS Waters Column: XBridge C18, 3.0 x 30 mm, 2.5 pm Supplier column: Waters Time to gradient / solvent [min] % of the sun. [H ₂ O NH ₄ 0H 0.1%] % of the sun. in [Acetonitrile] Flow [ml / min] Temp. [° C] 0.0 98.0 2.0 2.0 60.0 1.2 0.0 100.0 2.0 60.0 1.4 0.0 100.0 2.0 60.0

Method Z001 005

Column: XBridge C18, 3 x 30 mm, 2.5 pm Supplier Waters column: Time to % of the sun. % of the sun. Flow Temp. gradient/ of [H ₂ 0, in [ml / min] [° C] solvent [min] 0.1% TFA] [Methanol] 0.0 95 5 1.9 60 0.20 95 5 1.9 60 1.55 0 100 1.9 60 1.60 0 100 2.4 60 1.80 0 100 2.4 60

Method Z018 S03

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Column: Sunfire, 3 x 30 mm , 2.5 pm Supplier Waters column: Time to % of the sun. % of the sun. in Flow Temp. gradient/ of [H ₂ O, [Acetonitrile] [ml / min] [° C] solvent [min] 0.1% TFA] 0.0 95 5 1.9 60 0.20 95 5 1.9 60 1.55 0 100 1.9 60 1.60 0 100 2.4 60 1.80 0 100 2.4 60

Method Z018 S04

Column: Sunfire, 3 x 30 mm , 2.5 pm Supplier Waters column: Time to % of the sun. % of the sun. in Flow Temp. gradient/ of [H ₂ 0, [Acetonitrile] [ml / min] [° C] solvent [min] 0.1% TFA] 0.00 97 3 2.2 60 0.20 97 3 2.2 60 1.20 0 100 2.2 60 1.25 0 100 3 60 1.40 0 100 3 60

Method Z011 SOI

Column: XBridge C18, 4.6 x 30 mm, 3.5 pm Supplier column: Waters Time to gradient / solvent % gives Sun. in % gives Sun. in Flow [ml / min] Temp. [° C]

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[min] [h ₂ o, nh ₃ 0.1%] [ACN] 0.0 97 3 5 60 0.2 97 3 5 60 1.6 0 100 5 60 1.7 0 100 5 60

Method X018 S02

Name of method: Column: Sunfire C18, 2.1 x 30 mm, 2.5 pm Supplier Waters column: Time to % of the sun. % of the sun. in Flow Temp. gradient/ of [H ₂ 0, [Acetonitrile] [ml / min] [° C] solvent [min] 0.1% TFA] 0.0 99 1 1.3 60 0.02 99 1 1.3 60 1.00 0 100 1.3 60 Name of method: 1.10 0 100 1.3 60

Method G:

Eluent A: Water / KH2PO4 0.2% pH = 3 Eluent B: Acetonitrile

Time [min] % of A % of B Flow rate [ml / min] 0.00 80 20 1.50 5.00 20 80 1.50 8.00 20 80 1.50

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104/176 [286] The stationary phase used was Inertsil C8-3 (GL Sciences), 5 μm; dimension: 100 x 4.0 mm (column temperature: constant at 30 ° C). UV detection 220 nm.

4.5.2 MRI spectroscopy

Bruker DRX 500 MHz RNM configuration [287] High-performance digital RNM spectrometer, 2-channel microbay console and Windows XP host workstation running Topspin version 1.3.

[288] Equipped with:

- Magneto Oxford Instruments 11.74 Tesla (proton resonance frequency of 500 MHz)

- B-VT 3000 temperature controller

- GRASP II gradient spectroscopy accessory for rapid acquisition of 2D pulse sequences

- Deuterium lock switch for gradient shim

- 5 mm wide band inverted double resonance probe with automated fine adjustment and compatibility (BBI ATMA). It allows the observation of ¹ H with pulsation / decoupling of cores in the frequency range 15N and 31P with a ² H lock and shielded coils of gradient.

Bruker DPX 400 MHz RNM configuration [289] High performance two-channel digital RNM spectrometer console from a 400 MHz Bruker bay and Windows XP host workstation running XwinRNM version 3.5.

[290] Equipped with:

- Magneto Oxford Instruments 9.39 Tesla (400 MHz proton resonance frequency)

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- Variable temperature control unit B-VT

3300

- Switchable four-core probe (QNP) for observation of ¹ H, ¹³ C, ¹⁹ F and ³¹ P with ² H lock

Configuration of the 500 MHz RNM Bruker [291] High performance digital RNM spectrometer, one bay and 2 channel console and Linux host workstation running Topspin version 2.1 PL6.

[292] Equipped with:

- Magneto Bruker-Biospin AVANCE III 500A 11.75 Tesla (proton resonance frequency of 500 MHz)

- B-VT 3000 temperature controller

- 5 mm “Multinuclear Broad Band Fluorine Observe” (BBFO) probe with digital adjustment that covers the ¹⁵ N and ³¹ P range, in addition to ¹⁹ F, with ¹ H decoupling.

Bruker DPX 400 MHz RNM configuration [293] High-performance digital RNM spectrometer, 2-channel microbay console and Linux host workstation running Topspin version 2.1 PL6 [294] Equipped with:

- Magneto Bruker-Biospin AVANCE III DPX400C 9.40 Tesla (proton resonance frequency 400 MHz)

- Variable temperature control unit B-VT

3200

- 5 mm “Multinuclear Broad Band Fluorine Observe” (BBFO) probe with digital adjustment that covers the range of ¹⁵ N and ³¹ P, in addition to ¹⁹ F, with ¹ H decoupling

5. EXAMPLES [295] The following Examples were prepared analogously to the synthetic methods described above. Those

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106/176 compounds are suitable as SYK inhibitors and have IC50 values with respect to SYK inhibition of less than 10 nmol in the SYK inhibition assay and EC50 values less than 150 nmol in the CD63 assay. In addition, these compounds exhibit very good selectivity for SYK, which means that - while SYK is effectively inhibited - other kinases such as Aurora B (AURB), FLT3, GSK3p etc. they are not or are almost not inhibited (additional kinases that should not be effectively inhibited are RET, FLT4 RPS6KA3, STK22D and EPHA2). Consequently, unwanted side effects of these effective SYK inhibitors of the invention are minimized.

[296] AURB phosphorylates Ser10 and Ser28 in histone H3, a crucial event in mitosis and cell proliferation. Inhibition of AURB, therefore, has the potential to block cell proliferation, and could compromise tissues that exhibit elevated cell turnover, for example, the intestine or bone marrow. It is, therefore, desirable to avoid parallel AURB inhibition of an effective SYK inhibitor to enhance the overall clinical safety profile of the compound. Consequently, all example compounds exhibit IC 50 values with respect to Aurora B inhibition of more than 10,000 nmol and the IC 50 (aurB) / IC 50 (syk) ratios of all example compounds are preferably greater than 10,000. even greater than 15,000.

[297] FLT3 is a receptor tyrosine kinase. When an FLT3 ligand binds to the receptor, the receptor's intrinsic tyrosine kinase activity is activated which, in turn, phosphorylates and activates signal transduction molecules (for example, SHC) which in turn propagates the signal in the cell.

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Signaling through FLT3 participates in cell survival, proliferation and differentiation and is important for the development of lymphocytes (B cell and T cell). It is, therefore, desired to avoid inhibition of parallel FLT3 of an effective SYK inhibitor to enhance the overall clinical safety profile of the compound. Consequently, all of the example compounds of the present invention exhibit IC 50 values with respect to FLT3 inhibition of more than 1,000 nmol.

[298] Glycogen synthase kinase 3-beta (GSK33) is a proline-directed serine threonine kinase that is prominent in the intracellular TGF-β and Wnt signaling pathways. GSK3p facilitates several intracellular signaling pathways, including activation of the catenin-β complex. In adults, GSK3e is involved in cell proliferation and energy metabolism, while in neonates it is involved in neuronal cell development and body pattern formation. It is therefore desired to avoid the inhibition of parallel GSK3e of an effective SYK inhibitor to enhance the overall clinical safety profile of the compound. Consequently, all of the example compounds of the invention exhibit IC 50 values with respect to GSK3e inhibition of more than 5,000 nmol, preferably more than 10,000 nmol.

[299] IC50 values with respect to SYK inhibition, with respect to Aurora B and FLT3 inhibition for each of the individual example substances are shown in Table 1 below and have been determined experimentally as follows:

5.1 Recombinant human SYK kinase inhibition test [300] SYK (amino acids 342-635) was

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108/176 expressed as a fusion protein with an N-terminated GST tag, affinity purified and deep frozen to a concentration of approximately 50 100 μΜ in storage buffer (25 mM HEPES pH 7.5; 25 mM MgCl2 ; 5 mM MnCl2; 50 mM KCl; 0.2% BSA; 0.01% CHAPS; 100 μM NaaVO ^ · 0.5 mM DTT, 10% glycerol) at -80 ° C until use.

[301] The catalytic activity of the GSTSYK fusion protein kinase was determined using the “Kinase Glo® Luminescence” kinase test (Promega; V6712). In this homogeneous test, the amount of ATP remaining after the kinase reaction is quantified by a luciferin-luciferase reaction that uses luminescence. The luminescence signal obtained correlates with the amount of ATP still present and, therefore, it inversely correlates with the kinase activity.

Method [302] The test compounds were dissolved in 100% DMSO at a concentration of 10 mM and diluted in DMSO to a concentration of 1 mM. Serial dilution is done in 100% DMSO. All other dilutions of the substances were performed with test buffer (25 mM HEPES pH 7.5; 25 mM MgCl2; 5 mM MnCl2; 50 mM KCl; 0.2% HSA; 0.01% CHAPS; 100 μM Na3VO4; 0.5 mM DTT). The dilution steps and the concentration range were adapted according to the need. 7 μ aliquots! these dilutions were transferred to a 384-well Optiplate (Perkin Elmer, # 6007290). GSTSYK was diluted to 12 nM in the test buffer and 5 μl of that dilution was used in the kinase test (final concentration of SYK = 4 nM in a total volume of 15 μ ^. After incubation

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109/176 15 minutes at room temperature, 3 μΐ of a mixture of 750 nM ATP and 100 μ9 ^ 1 of poly (L-glutamic acid: Ltirosine 4: 1), Fluka # 81357) in test buffer were added to each well and incubation was continued for another 60 minutes at room temperature.

[303] Positive controls are reaction mixtures that do not contain test substance; Negative controls (reaction blanks) are reaction mixtures that do not contain kinase.

[304] After 60 minutes, 10 μ1 of Kinase-Glo® solution (Promega, Cat. # V6712) (heated to room temperature) was added to each well and incubation was continued for another 15 minutes. The plates were read on an Envision luminescence reader (Perkin-Elmer).

Data evaluation and calculation:

[305] The reader output file is a csv file that contains the well number and the relative light units (RLU) measured. For data evaluation and calculation, the negative control measurement was set to 100% of the control and the positive control measurement was set to 0% of the control. Based on these values, the% value for the measurement of each substance concentration was calculated using an “Assay Explorer” software (Accelrys). Normally, the calculated% control values are between 0% and 100%, but can also occur outside these limits in individual cases based on the variability or characteristics of the compound. The IC50 values were calculated from the% control values using the “Assay Explorer” software. Calculation: [y = (a / (1+ (x / c) ^A b) + d], a = low value, d = high value; x =

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110/176 concentration M; c = IC 50 of M; b = hill; y =% of control.

[306] Satisfactory inhibitory capacities for SYK are represented by an IC50 value (syk) measured by this test of <10 nmol.

5.2 CD63 assay (cell assay for inhibition of

SYK) [307] SYK is essential for FceR1-mediated activation and degranulation of mast cells and basophils. In this assay, IgE aroused against dinitrophenol (DNP) is incubated in whole blood where it binds to FceR1 in basophils. Subsequently, the DNP antigen is added, which binds to IgE bound to FctR1, resulting in degranulation of SYK-dependent basophils. CD63 normally resides in the intracellular granule membrane within basophils which, upon degranulation, are then expressed on the surface where it can be detected by flow cytometry. The surface expression of CD63 correlates extremely well with the release of histamine by basophils. The CD63 trial was previously validated as a clinical biomarker of engagement with the target in the Fostamatinib SYK program (Braselmann et al., J. Pharm. Exp. Therap. 319: 998-1.008, 2006).

Method:

[308] Heparinized whole blood is mixed gently (vortex mixer) and 100 pl per test divided into aliquots on a 96-well plate. Anti-DNP (1 mg / ml) is diluted 1: 100 with PBS / 0.1% HSA to 10 pg / ml (final concentration: 1 pg / ml). DNP / BSA pre-diluted (5 mg / ml) to a concentration of 60 ng / ml with washing solution.

[3 09] Compounds: 1 mM solutions; 100 μΜ; 10 μΜ; 1 μΜ and 0.1 μΜ are prepared with 100% DMSO. 1: 100 dilutions

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111/176 with PBS / HSA 0.1% to generate concentrations of 10 μΜ; 1 μΜ; 0.1 μΜ; 0.01 μΜ; 0.001 μM (final concentration: 1,000; 100; 10; 1; 0.1 nM).

[310] The reagents are provided by the Basotest® kit.

[311] Incubate 10 μΐ of 10 μg / ml anti-DNP and 10 μΐ of compound with 100 μΐ of whole blood in a water bath preheated to 37 ° C. After 30 minutes, 20 μΐ of stimulation buffer is added to the whole blood samples and swirled gently. Incubate the samples for 10 min at 37 ° C in a water bath. One hundred μl of DNP / BSA is added per test to the whole blood. Add 100 μl of the wash solution to an additional test tube as a negative control. Add 100 μl of DNP / BSA (final 30 ng / ml) to the compound tubes. All tubes are mixed again. The samples are incubated for 20 min at 37 ° C in a water bath.

[312] Stop degranulation by incubating samples on ice for 5 min. Add 20 μl of staining reagent to each tube. Swirl and incubate the tubes for 20 min in an ice bath, covered to prevent exposure to light. The whole blood samples are lysed and fixed with 2 ml of preheated lysis solution (room temperature) 1 x. Swirl and incubate for 10 min at room temperature. Centrifuge the cells (5 min, 250 x g, 4 ° C).

Discard the supernatant.

[313] Add 3 ml of washing solution to the tubes. Centrifuge the tubes (5 min, 250 x g, 4 ° C). Aspirate the supernatant. Add 200 μl of washing solution to the cell pellet, swirl. Incubate the tubes in a covered ice bath until analysis.

[314] Cells are analyzed by flow cytometry

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112/176 using blue-green excitation light (488 nm argon ion laser). Acquire data by using fluorescence triggering in the FL2 (PE) channel to surround basophilic granulocytes that express high amounts of IgE. This live lock reduces the amount of data and saves memory capacity. Acquire at least 500 basophils per sample.

Data evaluation and calculation:

[315] For evaluation and data calculation, the measurement of the negative control (unstimulated blood) was set to 100% of the control and the measurement of the positive control (DNP / anti-blood stimulated with DNP) was set to 0% of the control . Based on these values, the% value for the measurement of each substance concentration was calculated, an adapted concentration-effect curve and an EC50 value calculated using GraphPad Prism version 6.01 for Windows. The EC50 value was calculated using a non-linear adjustment (log (inhibitor) vs. response - variable slope). Normally, the calculated% control values are between 0% and 100%, but can also occur outside these limits in individual cases based on the variability or characteristics of the compound.

[316] Satisfactory CD63 inhibitory capacities are represented by an EC50 value measured by this test of <150 nmol.

5.3 Recombinant human Aurora B kinase test [317] Aurora B (amino acids 1-344, clone number DU1773, molecular weight 40.2 kDa, “University of Dundee”) was expressed as a fusion protein with a His tag. N terminal, affinity purified and

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113/176 deep frozen at a concentration of approximately 0.25 - 0.5 mg / ml in storage buffer (50 mM Tris-HCl pH 8; 25 mM Na-B-glycerophosphate; 0.1 mM EGTA; 150 mM NaCl; 0.03% Brij-35; 1 mM DTT and 10% glycerol) at -80 ° C until use.

[318] Aurora B kinase protein activity was determined using the “ADP Glo® Luminescence” kinase test (Promega; V9103X). In this homogeneous test, the amount of ADP remaining after the kinase reaction is quantified by a luciferin-luciferase reaction that uses luminescence. The luminescence signal obtained correlates with the amount of ADP still present and, therefore, correlates with the activity of the protein kinase.

Method [319] The test compounds were dissolved in 100% DMSO at a concentration of 10 mM and diluted in DMSO to a concentration of 5 mM. Serial dilution is done in 1:10 steps in 100% DMSO. All other dilutions of the substances were performed with test buffer (50 mM Hepes, pH 7.5, 10 mM MgCl2, 1 mM EGTA, 60 pM Ultra Pure ATP, Brij35 0.01%, BSA 0.1 %, 5 mM B-glycerophosphate) until a concentration was reached that was 2.5 times above the final test concentration (final concentration of compounds: 50 pM to 0.005 nM). 4 pl aliquots of these dilutions were transferred to a 384-well Optiplate (Perkin Elmer, # 6007290). His-Aurora B was diluted to 125 nM in the test buffer and 4 pl of that dilution was used in the kinase test (final Aurora B concentration = 50 nM in a total volume of 10 pl). After 15 minutes incubation at room temperature 2 pl of 250 pM substrate

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114/176 ([LRRLSLGLRRLSLGLRRLSLGLRRLSLG]; University of Dundee) in test buffer was added to each well and incubation was continued for another 60 minutes at room temperature.

[320] Positive controls are reaction mixtures that do not contain test substance; Negative controls (reaction blanks) are reaction mixtures that do not contain kinase.

[321] After 60 minutes, 10 μΐ of ADP-Glo® solution (ADP-Glo Reagent # V912B Promega) (warmed to room temperature) was added to each well and incubation was continued for another 40 minutes. Next, 20 μl of kinase detection mixture (Detection Buffer # V913B Promega; Kinase Detection Substrate # V914B Promega) was added and incubated for 40 minutes at room temperature. The plates were read on an Envision luminescence reader (Perkin-Elmer).

Data evaluation and calculation:

[322] The reader output file is a csv file that contains the well number and the measured RLU. For data evaluation and calculation, the negative control measurement was set to 0% of the control and the positive control measurement was set to 100% of the control. Based on these values, the% value for the measurement of each substance concentration can be calculated using an “Assay Explorer” software (for example, Accelrys). Normally, the calculated% control values are between 0% and 100%, but can also occur outside these limits in individual cases based on the variability or characteristics of the compound. IC50 values were calculated from the% control values by

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115/176 use of the “Assay Explorer” software. Calculation: [y = (ad) / (1+ (x / c) Ab) + d], a = low value, d = high value; x = concentration M; c = IC50 M; b = hill; y =% of control.

[323] The compounds of the present invention are SYK inhibitors and should not affect other kinases such as, for example, AURB, which is generally reflected by a higher IC50 (AURB) value, preferably> 10,000 nmol and, more preferably, of> 15,000 nmol, particularly preferably> 20,000 nmol and by an IC50 (aurb) / IC50 (syk) ratio> 10,000, more preferably> 15,000, particularly preferable> 20,000.

5.4 FLT3 kinase test [324] Recombinant human FLT3 (amino acids 564-958, Molecular weight 48.6 kDa, Invitrogen # PR4666C) was expressed with a histidine tag, purified by affinity and deep frozen at a concentration of approximately 0. 35 mg / ml in storage buffer (50 mM Tris (pH 7.5), 100 mM NaCl, 0.05 mM EDTA, 0.05% NP-40, 2 mM DTT and 50% glycerol) at -80 ° C until use. The activity of the FLT3 kinase protein was determined using the “ADP Glo® Luminescence” kinase test (Promega; V9103X). In this homogeneous test, the amount of ADP remaining after the kinase reaction is quantified by a luciferin-luciferase reaction that uses luminescence. The luminescence signal obtained correlates with the amount of ADP still present and, therefore, correlates with the activity of the protein kinase.

Method [325] The test compounds were dissolved in 100% DMSO at a concentration of 10 mM and diluted in DMSO to a concentration of 5 mM. Serial dilution is done in stages of

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1:10 in 100% DMSO. All other dilutions of the substances were performed with test buffer (50 mM Hepes, pH 7.5, 10 mM MgCl2, 1 mM EGTA, Brij35 0.01%, BSA 0.1%) until a concentration that was 2.5 times above the final test concentration (final concentration of compounds: 50 μΜ to 0.005 nM). 4 μΐ aliquots of these dilutions were transferred to a 384-well Optiplate (Perkin Elmer, # 6007290). The FLT3 enzyme was diluted to 5 nM in the test buffer and 4 μl of that dilution was used in the kinase test (final concentration of FLT3 = 2 nM in a total volume of 10 μ ^. After 60 minutes incubation at room temperature, 2 μl of a mixture of 2.5 mg / ml of substrate (Poli-Glu / Tyr; Sigma # P0275) and 2.5 mM of Ultra Pure ATP (Promega # V915B) in test buffer were added to each well and the incubation was continued for another 90 minutes at room temperature.

[326] Positive controls are reaction mixtures that do not contain test substance; Negative controls (reaction blanks) are reaction mixtures that do not contain kinase.

[327] After 90 minutes, 10 μl of ADP-Glo® solution (ADP-Glo Reagent # V912B Promega) (warmed to room temperature) was added to each well and incubation was continued for another 60 minutes. Next, 20 μl of kinase detection mixture (Detection Buffer # V913B Promega; Kinase Detection Substrate # V914B Promega) was added and incubated for 40 minutes at room temperature. The plates were read on an Envision luminescence reader (Perkin-Elmer).

Data evaluation and calculation:

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117/176 [328] The reader output file is a csv file that contains the well number and the measured RLU. For data evaluation and calculation, the negative control measurement was set to 0% of the control and the positive control measurement was set to 100% of the control. Based on these values, the% value for the measurement of each substance concentration can be calculated using an “Assay Explorer” software (for example, Accelrys). Normally, the calculated% control values are between 0% and 100%, but can also occur outside these limits in individual cases based on the variability or characteristics of the compound. The IC50 values were calculated from the% control values using the “Assay Explorer” software. Calculation: [y = (ad) / (1+ (x / c) Ab) + d], a = low value, d = high value; x = concentrate M; c = IC50 M; b = hill; y =% of control.

[329] The compounds of the present invention are SYK inhibitors and should not affect other kinases such as, for example, FLT3, which is generally reflected by a higher IC50 (FLT3) value, preferably> 1000 nmol.

5.5 GSK3 kinase test 6 [330] GSK3-beta inhibition is measured in an ADP-Glo kinase assay, Adapted, # V9103X, Promega.

[331] Human GSK3p (expressed and purified from SF21 cells) is obtained from "University Dundee" -Scotland (Dr. James Hastie - "Dept. of Biochemistry", 51.05 KDa, # 899) in 50 mM Tris (pH 7, 5); 150 mM NaCl; 0.1 mM EGTA, 270 mM sucrose, 0.1% B-mercaptoethanol, 1 mM benzamidine, 0.2 mM PMSF).

[332] The enzyme is diluted to 0.63 mg / ml (12.34 pM),

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118/176 stored in aliquots at -80 ° C.

Method:

[333] Assay buffer (50 mM Hepes, pH 7.5, 10 mM Hepes

MgCl2, 1 mM EGTA, Brij35 0.01%, BSA 0.1%) is prepared from stock solutions, which are stored at 4 ° C. All buffers and reagents are equilibrated to room temperature. Enzyme and ATP are diluted immediately before use.

[334] Test compounds are dissolved in DMSO to a concentration of 10 mM and stored at -20 ° C.

[335] Serial dilutions of 10 mM of compound stocks are pre-prepared in DMSO with a dilution factor of 6. Compound stocks are used for serial dilution with 1: 2 predilution, which results in a final concentration of 50 μΜ test start or other useful predilution factors. The final DMSO concentration is 1%.

[336] Serial dilutions (8 concentrations) are transferred to assay buffer at 1:40 dilution.

[337] Four μl of these compound buffer dilutions are added to a 384-well Optiplate (384-well plates, white Optiplate, flat bottom, # 6007290, Perkin Elmer).

[338] Positive and negative controls contain DMSO also diluted 1:40 in assay buffer, 4 μl / well.

[339] His-GSK3-beta is diluted in assay buffer to a concentration 2.5 times above the final concentration (final = 2 nM), Four μl / well is added to compound predilutions and high values. Assay buffer without enzyme is added to the negative controls.

[340] No substrate is needed, because of the

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119/176 autophosphorylation in the enzyme.

[341] Optiplates are centrifuged (short spin), gently shaken, covered with a lid and incubated at room temperature for 60 min.

[342] ATP (Ultra Pure ATP, 10 mM # V915B, Promega) is diluted in assay buffer to a concentration 5 times above the final concentration (final = 7 μΜ), 2 μl / well is added to the compound and enzyme mixture , also up to high and low values.

[343] Optiplates are centrifuged (short spin), shaken gently, covered as a lid and incubated at room temperature for 90 min.

[344] Ten μl ADP-Glo Reagent (Promega ADP-Glo Reagent # V912B) is added to all wells to peel off unused ATP. The plates are mixed by gentle shaking, incubation time 60 min, covered with a lid.

[345] Twenty μ! of Kinase Detection Reagent (Promega Kinase Detection Substrate # V914B Promega dissolved in Promega Kinase Detection Buffer # V913B) are added to all wells to convert ADP to ATP, which was produced during the kinase reaction. The plates are mixed by gentle shaking, incubation time 40 min, sealed with a top seal, protected from light.

[346] The plates were read on an Envision luminescence reader (Perkin-Elmer).

Data evaluation and calculation:

[347] The reader output file is a csv file that contains the well number and the measured RLU. For evaluation and data calculation, the measurement of the negative control was established as 0% of the control and the measurement of the control

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120/176 positive was established as 100% of the control. Based on these values, the% value for the measurement of each substance concentration can be calculated using an “Assay Explorer” software (for example, Accelrys). Normally, the calculated% control values are between 0% and 100%, but can also occur outside these limits in individual cases based on the variability or characteristics of the compound. The IC50 values were calculated from the% control values using the “Assay Explorer” software. Calculation: [y = (ad) / (1+ (x / c) Ab) + d], a = low value, d = high value; x = concentration M; c = IC50 M; b = hill; y =% of control.

[348] The compounds of the present invention are SYK inhibitors and should not affect other kinases, for example, GSK3p, which is generally reflected by a higher IC50 (gsk3P) value, preferably> 5,000 nmol and, more preferably, > 10,000 nmol.

5.6 Microsomal stability test of human liver [349] In addition, it is desirable that a SYK inhibitor that is sufficiently SYK-specific as described above has some metabolic stability, as measured, for example, in the presence of human liver microsomes, which corresponds to Qh <23%, where Qh is the percentage of hepatic blood flow (stability is better the lower the Qh value). If the Qh value for the SYK inhibitor in question is very high (greater than 23%), it will be difficult to achieve an adequate plasma level of the corresponding SYK inhibitor in the patient to be treated.

Method:

[350] Metabolic degradation to a SYK inhibitor

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121/176 specific is performed at 37 ° C with pool of human liver microsomes (human liver microsomes are commercially available as “BD UltraPool ™” from Corning Life Sciences, Fogostraat 12, 1060 LJ Amsterdam, Netherlands).

The final incubation volume of 100 pl per time point contains TRIS buffer pH 7.6 at room temperature (0.1 M), magnesium chloride (5 mM), microsomal protein (1 mg / ml) and the test compound at a final concentration of 1 μΜ.

[351] After a short pre-incubation period at 37 ° C, the reaction is initiated by adding beta-nicotinamide adenine dinucleotide phosphate in its reduced form (NADPH, 1 mM) and terminated by transferring an aliquot in solvent after points different time frames. Additionally, NADPH-independent degradation is monitored in incubations without NADPH terminated at the last point of time.

[352] The extinct (finished) incubations are then pelleted by centrifugation (10,000 g, 5 min).

[353] An aliquot of the supernatant is tested by LCMS / MS for the remaining amount of parent compound. The half-life (t1 / 2 INVITRO) is determined by the slope of the semi-log graph of the concentration-time profile.

Data evaluation and calculation:

[354] Intrinsic clearance (CL_INTRINSIC) is calculated by considering the amount of protein in the incubation:

CL_INTRINSIC ^ l / min / mg of protein] = (Ln 2 / (t1 / 2 INVITRO [min] * protein content [mg / ml])) * 1,000 [355] The protein content [mg / ml] has been determined with the “Bicinchoninic Acid Kit” by Sigma Aldrich (commercially available).

[356] Scaling intrinsic clearance (CL_UP_INT)

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122/176 higher is calculated considering the weight of the liver [g of liver / kg of body weight] and the microsomal recovery [mg of protein / g of liver]:

CL_UP_INT [ml / min / kg] = 0.001 * CL_INTRINSIC * liver weight * microsomal recovery with microsomal recovery = 45 mg protein / g liver with liver weight = 25.7 g liver / kg body weight [357] The percentage hepatic blood flow (% Qh) is finally calculated considering the blood flow of the human liver Q [ml / min / kg]:

% Qh [%] = ((Q * CL_UP_INT) / (Q + CL_UP_INT) / Q) * 100 with hepatic blood flow (Q) = 20.7 ml / min / kg.

5.7 Human hepatocyte stability test [358] A more comprehensive way to measure the metabolic stability of a compound of the present invention than microsomal stability (section 5.6) is the human hepatocyte stability test as described below. Here, metabolic degradation for the compound in question is carried out in a suspension of human hepatocytes.

[359] Human hepatocytes (typically cryopreserved) are incubated in an appropriate buffer system (eg, Dulbecco-modified Eagle's medium plus 3.5 pg of glucagon / 500 ml, 2.5 mg of insulin / 500 ml and 3, 75 mg / 500 ml of hydrocortisone) containing 5% serum.

[360] After a pre-incubation (typically) of 30 min in an incubator (37 ° C, CO2 10%), 5 pl of the solution of the compound to be tested (80 μΜ; 2 mM in diluted DMSO stock solution 1:25 with medium) are added in 3 95 μΤ of suspension

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123/176 hepatocytes (cell density is in the range of 0.25-5 Mio cells / ml, typically 1 Mio cell / ml; the final concentration of the compound in question is 1 μΜ, the final DMSO concentration is 0 , 05%).

[361] The cells are incubated for six hours (incubator, orbital shaker) and samples (25 μ!) Are taken at 0, 0.5, 1, 2, 4 and 6 hours. The samples are transferred in acetonitrile and pelleted by centrifugation (5 min). The supernatant is transferred to a new 96-well deep plate, evaporated under nitrogen and resuspended.

[362] The decline of the compound to be tested is analyzed by HPLC-MS / MS.

Data evaluation and calculation:

[363] CLint is calculated as follows:

CL_INTRINSIC = Dose / AUC = (C0 / CD) / (AUD + clast / k) x

1,000 / 60

C0: initial concentration at incubation [μΜ],

CD: cell density of vital cells [10 ⁶ cells / ml],

AUD: area under the data [μΜ x h], clast: concentration of the last data point [μΜ], k: slope of the regression line for the decline of the compound in question [h-1].

[364] The calculated in vitro intrinsic liver clearance can be scaled to in vivo intrinsic liver clearance and used to predict hepatic blood clearance in vivo (CL) by using a liver model (well-agitated model).

CL_INTRINSIC_INVIVO [ml / min / kg] = (CL_INTRINSIC [pl / min / 10 ⁶ cells] x liver cellularity [10 ⁶ cells / g liver]

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124/176 x liver factor [g / kg body weight]) / 1,000 CL [ml / min / kg] = CL_INTRINSIC_INVIVO [ml / min / kg] x liver blood flow [ml / min / kg] / (CL_INTRINSIC_INVIVO [ml / min / kg] + hepatic blood flow [ml / min / kg])

Qh [%] = CL [ml / min / kg] / hepatic blood flow [ml / min / kg])

Hepatic, human cellularity: 120 x 10 ⁶ cells / g of liver

Hepatic, human factor: 25.7 g / kg body weight, Human blood flow: 21 ml / (min x kg) [365] A satisfactory human hepatocyte stability for a compound in question as measured by this assay is represented by a Qh <20% (where stability is better the lower the Qh value).

Table 1: Example compounds and their properties with respect to SYK inhibition, selectivity for SYK and metabolic stability (as determined experimentally).

Ex. Structure Value of Value of Value of Value of Stability Proportion No. IC50 of EC50's IC50 of IC50 of in in rehearsal of hepatocytes selected inhibition CD63 inhibition inhibition humans life of of SYK, (chapter from AURB from FLT3 (chapter IC50 (AURB) / (chapter 5.2) [nM] (chapter (chapter 5.7) HEPhu IC50 (SYK) 5.1) [nM] 5.3) [nM] 5.4) [nM] [% of Qh]

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1 Chiral 1 41 34800 2230 10 34800 F -N O 7 Ό ^ -N B 2 Chiral 1.3 45 31141 2834 <4 23955 K ° F -N Ι \ oL N ^s Λ 'XX * O 3 V · o, _r Chiral 2 51 31461 1340 7 15731 the '^x> -N N \ j ^ X Ό 4 Chiral 2.2 64 65200 7410 10 29636 z ° <A * -N 1 ^ <^ χ. V

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5 Chiral 3.3 52 50000 3990 <4 15152 F -N \ Ç N O 2 C ^N K 6 Chiral 2.6 42 34100 3730 6 13115 d F THE -N NS X / N M 7 Chiral 1.3 53 26200 2440 <4 20154 .0 N — Ç F X "O N ί ^ Ί Ά X vj — F 1 F

Petition 870170059664, of 08/17/2017, p. 134/185 m / ns

8 Chiral 1.4 47 21112 2071 5 15080 O / * 1 z pr ν> 9 0. Chiral 1, 1 52 23341 1840 6 21219 5 N -N ΊΛν , x J V 10 O, Chiral 3.3 65 34030 2015 9 10312 5 -N çp / ^N %2 H

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11 Chiral 1.5 65 31200 3480 4 20800 —N ’ \ —Σ N IM ^J o- Ό ^ι X < F 12 , 0 Chiral 2.9 67 29600 5030 <4 10207 X F oX -N jT \ -dL XS χ % / ~ N λ- F F 13 O. Chiral 0.9 58 35984 5219 3 39982 - ⁿ x jT XS Xvi ^ X. C ⁿ

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17 Chiral 2.9 92 50000 11295 4 17241 z 1 ~ z II 18 Chiral 1.1 95 20155 4673 <4 18323 B THE / b + Ax -N C ^N A 19 .0 Chiral 1.8 107 23782 4954 7 13212 oX -N v Ά z ~ b

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20 Chiral 2.5 134 34831 3316 <4 13932 z ° N - -N Also }> 21 Chiral 1.2 76 17330 2210 7 14442 N - í 1 z Xb H 22 B Chiral 1.2 67 13448 1948 3 11207 V -N b ^N V CX F

Table 2: Compounds of the closest structurally established technique (as disclosed in WO 15017610) and their properties in relation to SYK inhibition, selectivity for SYK and metabolic stability (as determined experimentally).

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Compound of the technique Structure Value of Value of EC50's Value of Value of Establllda from in Proportion in estab. IC50 of rehearsal of IC50 of IC50 of hepatocyte selectively inhibition of CD63 Inhibition Inhibition s humans dade SYK (chapter from AURB from FLT3 (chapter ICsO (ADRB) / (chapter 5.2) [nM] (chapter (chapter 5.7) IC50 (SYK) 5.1) [nM] 5.3) [nM] 5.4) [nM] HEPhu [% of Qh] Example Chiral 0.2 77 162 43 31 810 5.20 on N L 0 3 page 506 i 0 from WO 15017610 ç X Example Chiral 1.9 42 1692 384 7 891 3A.02, at page 196 X from WO \ / T | 7 15017610 \\ N Example Chiral 0.1 20 37 25 17 370 6.09 on H // page 559 from WO X 15017610 0 / lô ⁴ V

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Example Chiral 0.8 29 771 307 5 964 3B.22 in page 219 5 from WO 15017610 \ T * Example Chiral 10.3 483 > 50000 6677 <4 > 4850 6.60 at page 587 N— from WO 15017610 ^z ò 2 —- Z >.

[366] Exemplary compounds of the present invention ^Nos 1 to 22 (see Table 1) were synthesized in accordance with Chapter 4 and then the sample compounds were subjected to various tests as described in Chapter 5 in order to to determine:

- the ability to inhibit SYK (low IC50 value means good SYK inhibition, at particular IC50 values of <10 nmol in the SYK inhibition assay and ECso values of <150 nmol in the CD63 assay mean inhibitory properties of Satisfactory SYK)

- selectivity for SYK, which means a very low inhibition of other kinases such as:

a) Aurora B (good selectivity for SYK is reflected by high ICso values with respect to AURB inhibition; ICso (aurb)> 10,000 or a ratio of ICso (aurb) / ICso <syk)> 10,000 nmol is desired and means a good selectivity for SYK),

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b) FLT3 (good selectivity for SYK is reflected by high IC50 values with respect to inhibition of FLT3, IC50 (flt3)> 1,000 nmol is desired and means good selectivity for SYK),

- metabolic stability which can, for example, be measured by the percentage of Qh in human hepatocytes (% Qh <20 means sufficient metabolic stability for a SYK inhibitor to be developed as a medicine).

[367] The closest structurally established technique compounds as disclosed in WO 15017610 have also been synthesized and subjected to the same tests, as described in Chapter 5, in order to determine the properties of these structurally established technique compounds closest to capacity from inhibition of SYK, CD63 potency, to selectivity for SYK and metabolic stability and to compare them with the example compounds of the present invention.

[368] While example 5.20 on page 506 of WO 15017610, example 3A.02 on page 196 of WO 15017610, example 6.09 on page 559 of WO 15017610 and example 3B.22 on page 219 of WO 15017610 have IC50 values (SYK ) acceptable with an IC50 (SYK) <10 nmol in the SYK inhibition assay and with an EC50 <150 nmol in the CD63 assay, all those compounds of the established technique do not exhibit satisfactory selectivity for SYK over AURB. The IC50 (aurb) of these compounds of the established technique are, with 162 nmol, 1,692 nmol, 37 nmol and 771 nmol, significantly lower than the IC50 (AURB) of the example compounds of the invention, which all have an IC50 ( AURB)> 10,000 nmol (most of them

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135/176 also has an IC50 (aurb)> 15,000 nmol). The same is true for the IC5o (aurb) / IC5o (syk) proportions, which are, for the examples of the established technique 5.20, 3A.02, 6.09 and 3B.22, with 810, 891, 370 and 964, significantly smaller than 10,000. The example compounds of the present invention, however, have IC 50 (aurb) / IC 50 (syk) ratios of> 10,000, very often even> 15,000.

[369] In addition, example 5.20 on page 506 of WO 15017610, example 3A.02 on page 196 of WO 15017610, example 6.09 on page 559 of WO 15017610 and example 3B.22 on page 219 of WO 15017610, all of them do not exhibit satisfactory selectivity for SYK over FLT3.

[370] The IC50 (flt3) of the example compounds of the established technique 5.20 on page 506 of WO 15017610, example 3A.02 on page 196 of WO 15017610, example 6.09 on page 559 of WO 15017610 and example 3B.22 on page 219 of WO 15017610 is, at 43 nmol, 384 nmol, 25 nmol and 307 nmol, significantly less than the IC50 (flt3) of the example compounds of the invention which, all, have an IC50 (flt3)> 1,000 nmol (most

their own an IC50 (flt3) still> 2. 000 nmol). [371] In contrast to that, O technique compound established 6.60 on page 587 of WO 15017610 seems to have, with IC50 (aurb) > 50,000 nmol and with IC5o (flt3) = 6677 nmol, at least

less with respect to absolute measurements, a sufficient selectivity for SYK, however, for that compound of the established technique 6.60 (on page 587 of WO 15017610), the inhibitory capacity of SYK is not sufficient with an IC50 (syk) of 10.3 nmol (IC5o (syk) greater than 10 nmol) and with an EC5o (syk) in the CD63 assay of 483 nmol (EC50 in the CD63 assay is greater than 150 nmol).

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136/176 [372] Consequently, only the compounds of the present invention have at the same time:

a) excellent SYK inhibitory capacity (IC50 (syk) <10 nmol, EC50 <150 nmol)

b) good selectivity for SYK (IC50 (aurb)> 10,000 nmol, and IC50 (AURB) / IC50 (SYK)> 10000 and IC50 (FLT3)> 1,000 nmol)) and

c) sufficient metabolic stability (% of Qh <20 in human hepatocytes), which are all properties that are very significant for the use of a SYK inhibitor as a drug in order to treat SYK-related diseases.

6. INDICATIONS [373] As noted, compounds of formula 1 or 1 'are characterized by their range of applications in the therapeutic field. Particular mention should be made of those applications for which the compounds of formula 1 or 1 'according to the invention are preferably used on the basis of their pharmaceutical activity as SYK inhibitors. Examples include respiratory complaints, allergic diseases, osteoporosis, gastrointestinal diseases or complaints, immune or autoimmune diseases, allergic diseases, inflammatory diseases, for example, inflammatory diseases of the joints, skin and eyes, and diseases of the peripheral or central nervous system.

[374] Particular mention should be made of the prevention and treatment of diseases of the respiratory and pulmonary tract that are accompanied by increased mucus production, inflammation and / or obstructive airway diseases. Examples of these include asthma, pediatric asthma, ARDS (adult respiratory distress syndrome), acute, allergic or

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137/176 chronic, autoimmune hemolytic anemia, chronic obstructive bronchitis (COPD) (including treatment of rhinovirus-induced exacerbations), coughs, allergic rhinitis or sinusitis, allergic rhinoconjunctivitis, rhinitis or chronic sinusitis, alveolitis, farmer's lung, hyperactive airways , infectious bronchitis or pneumonitis, bronchiectasis, pulmonary arterial hypertension, pulmonary fibrosis, bronchial edema, pulmonary edema, interstitial pneumonia or pneumonia triggered by various causes, such as aspiration, inhalation of toxic gases or bronchitis, pneumonia or interstitial pneumonia triggered by insufficiency cardiac, radiation, chemotherapy, cystic fibrosis or mucoviscidosis, alpha 1 antitrypsin deficiency.

[375] The compounds according to the invention are also preferably suitable for the treatment of allergic diseases such as, for example, allergic rhinitis, allergic rhinoconjunctivitis, allergic conjunctivitis, and contact dermatitis, urticaria / angioedema and allergic dermatitis.

[376] Mention should preferably also be made of the treatment of inflammatory diseases of the gastrointestinal tract. Examples of these are Crohn's disease and ulcerative colitis.

[377] The compounds according to the invention are also preferably suitable for the treatment of inflammatory diseases of the joints, blood vessels and kidney, or inflammatory diseases of the skin and eyes. Examples of these are rheumatoid arthritis, antibody-based glomerulonephritis, psoriasis, Kawasaki syndrome, celiac disease

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138/176 (sprue), arteriosclerosis and Wegener's granulomatosis, osteoarthritis, systemic scleroderma, ankylosing spondylitis.

[3 78] The compounds according to the invention are also preferably suitable for the treatment of autoimmune diseases. Examples of these are hepatitis (autoimmune based), lupus erythematosus, lupus nephritis, systemic lupus, systemic lupus erythematosus, discoid lupus, cutaneous lupus erythematosus (acute, subacute, chronic), antiphospholipid syndrome, Berger disease, Evans syndrome, immune anemia -hemolytic, ITP (idiopathic thrombocytopenic purpura; adult, neonatal and pediatric), myasthenia gravis, Sjogren's syndrome, scleroderma, bullous pemphigoid and pemphigus vulgaris.

[379] The compounds according to the invention are also preferably suitable for the treatment of B-cell lymphomas, for example, chronic lymphocytic leukemia and non-Hodgkin's lymphomas, Waldenstrom's macroglobulinemia (Clinicai Cancer Research (2015), 21 (11) , 2,538-2,545) or T cell lymphomas.

[380] The compounds according to the invention are also preferably suitable for the treatment of graft-versus-host disease.

[381] Mention should also be made preferably of prevention and treatment of diseases of the peripheral or central nervous system. Examples of these are acute and chronic multiple sclerosis or unfamiliar lateral sclerosis.

[382] Mention should also be made preferably of treatment for systemic sclerosis (SSc). Pamuk Omer Nuri; Can Guray; Ayvaz Suleyman; Karaca Turan; Demirtas Selim;

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Pamuk Gulsum E; Tsokos George, Clinicai and Experimental Rheumatology (2015); ISSN: 0392-856X.

[383] Mention should preferably also be made of the treatment of infectious diseases. Examples of these are malaria (Abstracts, “Joint 41st Great Lakes and 46th Central Regional Meeting of the American Chemical Society, GrandRapids, MI, United States, May 27-30 (2015), JGLCRM-283; WO 2014100113) and dengue (Journal of Biological Chemistry, Volume: 290, Number: 28, Pages: 17.306-17.320).

[384] Mention should also be made preferably of prevention and treatment of osteoporotic diseases such as osteopenia associated with the disease, osteoporosis and osteolytic diseases.

[385] The present invention relates particularly preferably to the use of compounds of formula 1 for the preparation of a pharmaceutical composition for the treatment of diseases selected from asthma, COPD, allergic rhinitis, adult respiratory distress syndrome, bronchitis, allergic dermatitis, dermatitis contact, ITP, rheumatoid arthritis, systemic lupus erythematosus, lupus nephritis and allergic rhinoconjunctivitis.

[386] More preferably, the compounds of formula 1 can be used for the treatment of a disease selected from asthma, allergic rhinitis, rheumatoid arthritis, systemic lupus erythematosus, lupus nephritis, allergic dermatitis and COPD.

7. COMBINATIONS [387] The compounds of formula 1 or 1 'can be used by themselves or in conjunction with other active substances of formula 1 or 1' according to the invention. The

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140/176 compounds of formula 1 or 1 'can also optionally be used in conjunction with other pharmacologically active substances. Preferably, the active substances used herein can be selected, for example, from betamimetics, anticholinergics, corticosteroids, PDE4 inhibitors, LTD4 antagonists, EGFR inhibitors, MRP4 inhibitors, dopamine agonists, H1 antihistamines, H1 antagonists. PAF, iNos inhibitors, HMG-CoA reductase inhibitors (statins), PI3 kinase inhibitors, CCR3 antagonists, CCR2 antagonists, CCR1 antagonists, IKK2 inhibitors, A2a agonists, alpha-4-integrin inhibitors, CRTH2 antagonists, histamine 1, combined H1 / H3 antagonists, p38 kinase inhibitors, methylxanthines, ENaC inhibitors, CXCR1 antagonists, CXCR2 antagonists, ICE inhibitors, LTB4 antagonists, 5-LO antagonists, FLAP antagonists. LTB4 antagonists; chromoglycine, dissociated glucocorticoid mimetics, immunosuppressive agents, cytostatics, non-steroidal anti-inflammatory drugs (NSAIDs), chloroquine, hydroxychloroquine, anti-TNF antibodies, anti-GM-CSF antibodies, anti-CD46 antibodies, anti-IL-1 antibodies, antibodies anti-IL-2, anti-IL-4 antibodies, anti-IL-5 antibodies, antiIL6 antibodies, anti-IL6 receptor antibodies, anti-IL-13 antibodies, anti-IL-18 antibodies, anti-CD30 L antibodies, anti-Ox40L antibodies, anti-IL-4 / IL-13 antibodies, anti-IL23 antibodies (p19), anti-IL-12 / IL-23 antibodies (p40), anti-CD3 antibodies, anti-CD4 antibodies, anti antibodies -CD154, antibodies to CD89, anti-IL-2 / CD25 antibodies, anti-CD22 antibodies, anti-interferon antibodies, anti-ICOS antibodies, anti-ICOS antibodies, anti-CD20 antibodies,

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141/176 anti-CD40 antibodies, anti-BAFF / BLyS antibodies, anti-CD18 antibodies, anti-CD62L antibodies, anti-CD147 antibodies, anti-integrin antibodies, antibodies that interfere with LFA-1, modulators of the IL- 36, M- CSF / c-fms antagonists, CTLA-4 fusions, mTor modulators, Toll-like 7 receptor inhibitors (TLR7 inhibitor), Toll-like 9 receptor inhibitors (TLR9 inhibitors), co-stimulating modulators cells, such as CTLA4 fusions, JAK inhibitors, IRF modulators, CX3 chemokine receptor antagonists (CX3CR1 antagonists), IRAK inhibitors (in particular IRAK1 and IRAK4 inhibitors), sphingosine-1 modulators -phosphate (modulators of the S1P pathway), triple kinase inhibitors against PDGFR, FGFR and VEGFR eg Nintedanib, [388] or double or triple combinations of these such as combinations of one, two or three compounds selected from among :

- SYK inhibitors of formula 1 or 1 ', betamimetics, corticosteroids, EGFR inhibitors and PDE4 antagonists,

- SYK inhibitors of formula 1 or 1 ', anticholinergics, betamimetics, corticosteroids, EGFR inhibitors and PDE4 antagonists,

- inhibitors of formula SYK 1 or 1 ', inhibitors PDE4, corticosteroids and inhibitors in EGFR, - inhibitors of formula SYK 1 or 1 ', inhibitors EGFR and inhibitors of PDE4, - inhibitors of formula SYK 1 or 1 ', and inhibitors

EGFR,

- SYK inhibitors of formula 1, betamimetics and anticholinergics

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- anticholinergic inhibitors, PDE4 inhibitors,

- anticholinergic, betamimetic SYK inhibitors, formula 1 or 1 ', corticosteroids and formula 1 or 1', corticosteroids, betamimetic SYK, iNOS inhibitors and HMG-CoA reductase inhibitors.

[389] Combinations of three active substances, each taken from one of the categories of compounds mentioned above, are also an object of the invention.

[390] Suitable betamimetics used are preferably compounds selected from arformoterol, carmoterol, formoterol, indacaterol, salmeterol, albuterol, bambuterol, bitolterol, broxaterol, carbuterol, clenbuterol, phenoterol, hexoprenaline, ibuterol, isoetholine, isoprenaline, orosalbuterol, milosol, toluene, methanol , meluadrine, metaproterenol, pirbuterol, procaterol, reproterol, rimiterol, ritodrine, salmefamol, soterenol, sulfonterol, terbutaline, thiaramide, tolubuterol, zinterol,

6-hydroxy-8- {1-hydroxy-2- [2- (4-methoxy-phenyl) -1,1-dimethylethylamino] -ethyl} -4'-benzo [1,4] oxazin-3-one; 8- {2- [2 - (2,4difluoro-phenyl) -1,1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6hydroxy-4'-benzo [1,4] oxazine-3-one; 8- {2- [2- (3,5-difluorophenyl) -1,1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4'benzo [1,4] oxazin-3-one; 8- {2- [2- (4-ethoxy-phenyl) -1,1dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4'benzo [1,4] oxazine-3-one; 8- {2- [2- (4-fluoro-phenyl) -1,1dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4'benzo [1,4] oxazin-3-one; N- (5- {2- [3- (4,4-diethyl-2-oxo-4'benzo [d] [1,3] oxazine-1-yl) -1,1-dimethyl-propylamino] -1hydroxy -ethyl} -2-hydroxy-phenyl) -methanesulfonamide; N- (5- {2Petition 870170059664, of 17/08/2017, p. 150/185

143/176 [3- (4,4-diethyl-6-fluor-2-oxo-4'-benzo [d] [1,3] oxazin-1-yl) 1,1-dimethyl-propylamino] -hydroxy- ethyl} -2-hydroxy-phenyl) methanesulfonamide; N- (5- {2- [3- (4,4-diethyl-6-methoxy-2-oxo4'-benzo [d] [1,3] oxazine-1-yl) -1,1-dimethyl-propylamino ] -1hydroxy-ethyl} -2-hydroxy-phenyl) -methanesulfonamide; N- (5- {2 [1,1-dimethyl-3- (2-oxo-4,4-dipropyl-4'-benzo [d] [1,3] oxazin1-yl) -propylamino] -1-hydroxy -ethyl} -2-hydroxy-phenyl) methanesulfonamide; 8- {2- [1,1-dimethyl-3- (2-oxo-2,3-dihydrobenzoimidazol-1-yl) -propylamino] -1-hydroxy-ethyl} -6-hydroxy4'-benzo [1,4 ] oxazine-3-one; 8- {2- [1,1-dimethyl-3- (6-methyl-2oxo-2,3-dihydro-benzoimidazol-1-yl) -propylamino] -1-hydroxyethyl} -6-hydroxy-4'-benzo [1.4] oxazine-3-one; 8- {2- [1,1dimethyl-3- (2-oxo-5-trifluormethyl-2,3-dihydro-benzoimidazol1-yl) -propylamino] -1-hydroxy-ethyl} -6-hydroxy-4'benzo [ 1.4] oxazine-3-one; 8- {2- [1,1-dimethyl-3- (3-methyl-2oxo-2,3-dihydro-benzoimidazol-1-yl) -propylamino] -1-hydroxyethyl} -6-hydroxy-4'-benzo [1.4] oxazine-3-one; N- [2-hydroxy-5 ((1R) -1-hydroxy-2- {2- [4- (2-hydroxy-2-phenyl-ethylamino) phenyl] -ethylamino} -ethyl) -phenyl] -formamide; 8-hydroxy-5 ((1R) -1-hydroxy-2- {2- [4- (6-methoxy-biphenyl-3-ylamino) phenyl] -ethylamino} -ethyl) -1H-quinoline-2-one; 8-hydroxy-5 [(1R) -1-hydroxy-2- (6-phenethylaminohexylamino) -ethyl] -1Hquinoline-2-one; 5 - [(1R) -2- (2- {4- [4- (2-amino-2-methylpropoxy) -phenylamino] -phenyl} -ethylamino) -1-hydroxy-ethyl] -8hydroxy-1H-quinoline- 2-one; [3- (4- {6 - [(2R) -2-hydroxy-2- (4-hydroxy-3-hydroxymethyl-phenyl) -ethylamino] -hexyloxy} -butyl) 5-methyl-phenyl] -urea; 4 - ((1R) -2- {6- [2- (2,6-dichlorobenzyloxy) -ethoxy] -hexylamino} -1-hydroxy-ethyl) -2hydroxymethyl-phenol; 3- (4- {6 - [(2R) -2-hydroxy-2- (4-hydroxy-3hydroxymethyl-phenyl) -ethylamino] -hexyloxy} -butyl) Petition 870170059664, of 17/08/2017, p. 151/185

144/176 benzenesulfonamide; 3- (3- {7 - [(2R) -2-hydroxy-2- (4-hydroxy3-hydroxymethyl-phenyl) -ethylamino] -heptiloxy} -propyl) benzenesulfonamide; 4 - ((1R) -2- {6- [4- (3Ciclopentanesulfonyl-phenyl) -butoxy] -hexylamino} -1-hydroxyethyl) -2-hydroxymethyl-phenol, 4- (2- {6- [2- ( 2,6-dichlorobenzyloxy) -ethoxy] -hexylamino} -1-hydroxy-ethyl) -2hydroxymethyl-phenol; Vilanterol; N-1-adamantanyl-2- {3 - [(2R) 2 - ({(2R) -2-hydroxy-2- [4-hydroxy-3 (hydroxymethyl) phenyl] ethyl} amino) propyl] phenyl} acetamide; 2 (3- {2- [2-hydroxy-3-methanesulfonylamino-phenyl) -ethylamino] propyl} -phenyl) -N- [4- (4-hydroxy-phenyl) -2-vinyl-penta-2,4dienyl] -acetamide; (1R) -5- {2- [6- (2,2-difluoro-2-phenylethoxy) -hexylamino] -1-hydroxy-ethyl} -8-hydroxy-1H-quinoline2-one; (R, S) -4- (2 - {[6- (2,2-difluor-4-phenylbutoxy) hexyl] amino} -1-hydroxy-ethyl) -2 (hydroxymethyl) phenol; (R, S) -4- (2 - {[6- (2,2-difluor-2-phenylethoxy) hexyl] amino} -1-hydroxy-ethyl) -2 (hydroxymethyl) phenol; (R, S) -4- (2 - {[4,4-difluoro-6- (4phenylbutoxy) hexyl] amino} -1-hydroxy-ethyl) -2 (hydroxymethyl) phenol; (R, S) -4- (2 - {[6- (4,4-difluor-4-phenylbutoxy) hexyl] amino} -1-hydroxy-ethyl) -2 (hydroxymethyl) phenol; (R, S) -5- (2 - {[6- (2,2-difluor-2-phenylethoxy) hexyl] amino} -1-hydroxy-ethyl) -8-hydroxyquinoline2 (1H) -one; (R, S) - [2 - ({6- [2,2-difluoro-2- (3methylphenyl) ethoxy] hexyl} amino) -1-hydroxyethyl] -2 (hydroxymethyl) phenol; 4- (1R) -2 - {[6- (2,2-difluoro-2-phenylethoxy) hexyl] amino} -1-hydroxyethyl) -2 (hydroxymethyl) phenol; (R, S) -2- (hydroxymethyl) -4- (1-hydroxy-2 {[4,4,5,5] -tetrafluor-6- (3-phenylpropoxy) hexyl] amino} ethyl) phenol; (R, S) - [5- (2 - {[6- (2,2-diflúor-2Petição 870170059664, of 8/17/2017, page 152/185

145/176 phenylethoxy) hexyl] amino} -1-hydroxy-ethyl) -2hydroxyphenyl] formamide; (R, S) -4- [2 - ({6- [2- (3-bromophenyl) 2,2-difluorethoxy] hexyl} amino) -1-hydroxyethyl] -2 (hydroxymethyl) phenol; (R, S) -N- [3- (1,1-difluoro-2 - {[6 - ({2hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) hexyl] oxy} ethyl) phenyl] -urea; 3- [3- (1,1-diflúor2 - {[6 - ({2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) hexyl] oxy} ethyl) phenyl] imidazolidine- 2,4-dione; (R, S) -4- [2 - ({6- [2,2-difluoro-2- (3methoxyphenyl) ethoxy] hexyl} amino) -1-hydroxyethyl] -2 (hydroxymethyl) phenol; 5 - ((1R) -2 - {[6- (2,2-difluoro-2-phenylethoxy) hexyl] amino} -1-hydroxyethyl) -8-hydroxyquinoline2 (1H) -one; 4 - ((1R) -2 - {[4,4-difluoro-6- (4phenylbutoxy) hexyl] amino} -1-hydroxy-ethyl) -2 (hydroxymethyl) phenol; (R, S) -4- (2 - {[6- (3,3-difluor-3-phenylpropoxy) hexyl] amino} -1-hydroxy-ethyl) -2 (hydroxymethyl) phenol; (R, S) - (2 - {[6- (2,2-difluoro-2-phenylethoxy) -4,4-difluorohexyl] amino} -1-hydroxyethyl) -2 (hydroxymethyl) phenol; (R, S) -4- (2 - {[6- (2,2-difluor-3-phenylpropoxy) hexyl] amino} -1-hydroxyethyl) -2 (hydroxymethyl) phenol; 3- [2- (3-chlorphenyl) -ethoxy] -N- (2-ethylamino-ethyl) -N- {2- [2- (4-hydroxy-2-oxo-2,3-dihydrobenzothiazol-7-yl) - ethylamino] -ethyl} -propionamide; N- (2-ethylamino-ethyl) -N- {2- [2- (4-hydroxy-2-oxo-2,3-dihydrobenzothiazol-7-yl) -ethylamino] -ethyl} -3- (2-naphthalen-1 -ethyloxy) -propionamide; 7- [2- (2- {3- [2- (2-chlorphenyl) ethylamino] -propylsulfanyl} -ethylamino) -1-hydroxy-ethyl] -4-hydroxy-3H-benzothiazole-2-one, optionally in the form of racemates , enantiomers, diastereomers and, optionally, in the form of acid addition salts pharmacologically

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146/176 acceptable solvates or hydrates thereof.

[391] According to the invention, the acid addition salts of betamimetics are preferably selected from the hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrocarbonate, hydrocarbonate, hydrocarbonate hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate, preferably the hydrochloride, hydrobromide, hydrosulfate, hydrophosphate, hydrofumarate and hydromethanesulfonate salts. Of the acid addition salts mentioned above, the salts of hydrochloric acid, methanesulfonic acid, benzoic acid and acetic acid are particularly preferred according to the invention.

[392] The anticholinergics used are preferably compounds selected from:

tiotropium salts, particularly the bromide salt, oxytropium salts, particularly the bromide salt, salts of

flutrope, particularly the salt in bromide, salts in ipratropium, particularly the salt in bromide, salts in aclidinium, particularly the salt in bromide, salts in glycopyrronium, particularly the salt of bromide, salts in

tropium, particularly the chloride salt, tolterodine, (3R) -1-phenethyl-3- (9H-xanthene-9-carbonyloxy) -1azoniabicyclo [2.2.2] octan salts; 2,2-diphenyl-propionic acid tropenolic ester metobromide; 2,2-diphenyl-propionic acid scopinic ester metobromide; scopinic ester metobromide of 2-fluorine-2,2diphenyl-acetic acid; 2-fluoro-2,2-diphenyl-acetic acid tropenolic ester metobromide; ester metobromide

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147/176 tropenolic acid 3,3 ', 4,4'-tetrafluoro-benzyl; scopinic ester metobromide of 3.3 ', 4.4' tetrafluoro-benzyl acid; 4,4'-difluoro-benzyl acid tropenolic ester metobromide; 4,4'-difluoro-benzyl acid scopinic ester metobromide; 3,3'-difluoro-benzyl acid tropenolic ester metobromide; 3,3'-difluoro-benzyl acid scopinic ester metobromide; 9-hydroxy-fluorene-9-carboxylic acid tropenolic ester metobromide; 9-fluoro-fluoro-9-carboxylic acid tropenolic ester metobromide; 9-hydroxy-fluorene-9-carboxylic acid scopinic ester metobromide; 9 fluoro-fluorene-9-carboxylic acid scopinic ester metobromide; 9-methyl-fluorene-9-carboxylic acid tropenolic ester metobromide; 9-methyl-fluoro-9-carboxylic acid scopinic ester metobromide; benzyl acid cyclopropyltropinic ester metobromide; 2,2-diphenyl-propionic acid cyclopropyltropinic ester metobromide; 9-hydroxy-xanthene-9-carboxylic acid cyclopropyltropinic ester metobromide; 9-methyl-fluorene-9-carboxylic acid cyclopropyltropinic ester metobromide;

methylxanthene-9-carboxylic acid cyclopropyltropinic ester metobromide; 9-hydroxy-fluorene-9-carboxylic acid cyclopropyltropinic ester metobromide; 4,4'-difluoro-benzyl acid methyl ester cyclopropyltropinic ester metobromide; 9-hydroxy-xanthene-9-carboxylic acid tropenolic ester metobromide; 9-hydroxy-xanthene-9-carboxylic acid scopinic ester metobromide; 9-methyl-xanthene-9-carboxylic acid tropenolic ester metobromide;

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148/176 9-methyl-xanthene-9-carboxylic acid scopinic ester metobromide; 9-ethyl-xanthene-9-carboxylic acid tropenolic ester metobromide; 9-difluormethyl-xanthene-9-carboxylic acid tropenolic ester metobromide; 9-hydroxymethyl-xanthene-9-carboxylic acid scopinic ester metobromide;

3- [2- (3-Chloro-phenyl) -ethoxy] -N- (2-diethylamino-ethyl) -N {2- [2- (4-hydroxy-2-oxo-2,3-dihydro-benzothiazole- 7-yl) ethylamino] -ethyl} -propionamide;

N- (2-diethylamino-ethyl) -N- {2- [2- (4-hydroxy-2-oxo-2,3dihydro-benzothiazol-7-yl) -ethylamino] -ethyl} -3- (2-naphthalen -1yl-ethoxy) -propionamide;

7- [2- (2- {3- [2- (2-chloro-phenyl) -ethylamino] propylsulfanyl} -ethylamino) -1-hydroxy-ethyl] -4-hydroxy-3'-benzothiazole-2-one and Darotrope ;

optionally in the form of the solvates or hydrates thereof.

[393] In the salts mentioned above, the tiotropium, oxytrope, flutrope, ipratropium, glycopyrronium, aclidinium and triospium cations are the pharmacologically active ingredients. As anions, the salts mentioned above may preferably contain chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate or ptoluenesulfonate, while chloride, bromide, iodide, sulfate , methanesulfonate or p-toluenesulfonate are preferred as counterions. Of all salts, chlorides, bromides, iodides and methanesulfonate are particularly preferred.

[394] Of particular importance is tiotropium bromide. In the case of tiotropium bromide, the combinations

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149/176 pharmaceuticals according to the invention preferably contain it in the form of crystalline tiotropium bromide monohydrate, which is known as WO 02/30928. If tiotropium bromide is used in anhydrous form in the pharmaceutical combinations according to the invention, it is preferable to use anhydrous crystalline tiotropium bromide, which is known as

WO 03/000265.

[395] Corticosteroids used here are preferably compounds selected from:

beclomethasone, betamethasone, budesonide, butixocort, ciclesonide, deflazacort, dexamethasone, flunisolide, prednisolone, fluticasone, prednisone, loteprednola, rofleponide, etiprednol, mometasone, triamcinolone, tipredan; Pregna-1,4-diene-3,20-dione, 6-fluoro-11-hydroxy16,17 - [(1-methylethylidene) bis (oxy)] - 21 - [[4 [(nitrooxy) methyl] benzoyl] oxide ] -, (6-alpha, 11-beta, 16-alpha) (9CI); 16,17-butylidenedioxy-6,9-difluoro-11-hydroxy-17 (methylthio) androst-4-en-3-one; (S) -6,9-Difluoro-17 - [(2-furanylcarbonyl) oxy] -11-hydroxy-16methyl-3-oxo-androsta-1,4-dien-17-carbothione fluoromethyl ester; (S) -fluormethyl 6,9-difluoro-17 - [(2-furanylcarbonyl) oxy] -11-hydroxy-16methyl-3-oxo-androsta-1,4-diene-17-carbothionate; cyanomethyl ester of 6-alpha, 9-alpha-difluoro-11-beta-hydroxy-16alpha-methyl-3-oxo-17-alpha- (2,2,3,3tetramethylcyclopropylcarbonyl) oxide-androsta-1,4-diene Beta-carboxylic acid, each optionally in the form of racemates, enantiomers or diastereomers thereof and optionally in the form of salts and derivatives, solvates and / or hydrates thereof.

[396] Particularly preferably, the steroid is

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150/176 selected from budesonide, fluticasone, mometasone, ciclesonide and (S) -fluormethyl 6,9-difluoro-17 - [(2-furanylcarbonyl) oxide] -11-hydroxy-16-methyl-3-oxo-androsta1,4-diene -17-carbothionate, optionally in the form of racemates, enantiomers or diastereomers thereof and optionally in the form of salts and derivatives, solvates and / or hydrates thereof.

[397] Any reference to steroids includes a reference to any of the salts or derivatives, hydrates or solvates thereof that may exist. Examples of possible steroid salts and derivatives may be: alkali metal salts such as sodium or potassium salts, sulfobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogen phosphates, palmitates, pivalates or furoates thereof.

[398] PDE4 inhibitors that can be used are preferably compounds selected from enprofilin, theophylline, roflumilast, ariflo (cilomilast), tofimilast, pumafentrin, lirimilast, apremilast, arophylline, atizoram, oglemilast, tetomilast; 5 - [(N- (2,5-dichloro-3-pyridinyl) carboxamide] -8-methoxy-quinoline (D-4418); 5- [N- (3,5dichloro-1-oxide-4-pyridinyl) - carboxamide] -8-methoxy-2 (trifluormethyl) -quinoline (D-4396 (Sch-351591)); N- (3,5-dichloropyrid-4-yl) amide - [1- (4-fluorbenzyl) - 5-hydroxy-indol-3-yl] glyoxylic (AWD-12-281 (GW-842470)); 9 [(2-fluorophenyl) methyl] -N-methyl-2- (trifluoromethyl) -9H-purin-6amine (NCS- 613); 4 - [(2R) -2- [3- (cyclopentyloxy) -4methoxyphenyl] -2-phenylethyl] -pyridine (CDP-840); N - [(3R) 3,4,6,7-tetrahydro- 9-methyl-4-oxo-1-phenylpyrrolo [3,2,1jk] [1,4] benzodiazepin-yl] -4-pyridinecarboxamide (PDPetition 870170059664, from 17/08/2017, p. 158/185

151/176

168787); 4- [6,7-diethoxy-2,3-bis (hydroxymethyl) -1naphthalenyl] -1- (2-methoxyethyl) -2 (1H) -pyridinone (T-440); 2 [4- [6,7-diethoxy-2,3-bis (hydroxymethyl) -1-naphthalenyl] -2-pyridinyl] -4- (3-pyridinyl) -1 (2H) -phthalazinone (T-2585); (3 (3-cyclopenyloxy-4-methoxybenzyl) -6-ethylamino-8-isopropyl3H-purine (V-11294A); beta- [3- (cyclopentyloxy) -4methoxyphenyl] -1,3-dihydro-1,3-dioxo -2H-Isoindol-2-propanamide (CDC-801); Imidazo [1,5-a] pyrido [3,2-e] pyrazine-6 (5H) -one, 9-ethyl-2-methoxy-7-methyl -5-propyl (D-22888); 5- [3 (cyclopentyloxy) -4-methoxyphenyl] -3 - [(3-methylphenyl) methyl] -, (3S, 5S) -2-piperidinone (HT-0712); 4- [1- [3,4bis (difluoromethoxy) phenyl] -2- (3-methyl-1-oxide-4pyridinyl) ethyl] -alpha, alpha-bis (trifluormethyl) -Benzenemethanol (L-826141); N- ( 3,5-dichloro-1-oxo-pyridin-4-yl) -4difluormethoxy-3-cyclopropylmethoxybenzamide; (-) p [(4aR *, 106S *) - 9-ethoxy-1,2,3,4,4a, 10b-hexahydro-8-methoxy-2 [399] methylbenzo [s] [1,6] naphthyridin-6-yl] -N, Ndiisopropylbenzamide; (R) - (+) - 1- (4-brombenzil) -4- [(3cyclopentyloxy) -4-methoxyphenyl] -2-pyrrolidon; 3 (cyclopentyloxy-4-methoxyphenyl) -1- (4-N '- [N-2-cyano-S-methylisothioureido] benzyl) -2-pyrrolidon; cis [4-cyano-4- (3 [400] cyclopentyloxy-4-methoxyphenyl) cyclohexan-1-carboxylic]; 2-carbomethoxy-4-cyano-4- (3-cyclopropylmethoxy4-diflu oromethoxyphenyl) cyclohexan-1-one; cis [4-cyano-4- (3cyclopropylmethoxy-4-difluormethoxyphenyl) cyclohexan-1-ol]; (R) - (+) - ethyl [4- (3-cyclopentyloxy-4-methoxyphenyl) pyrrolidin2-yliden] acetate; (S) - (-) - ethyl [4- (3-cyclopentyloxy-4methoxyphenyl) pyrrolidin-2-yliden] acetate; 9-cyclopentyl-5,6dihydro-7-ethyl-3- (2-thienyl) -9H-pyrazolo [3,4-c] -1,2,4triazolo [4,3-a] pyridine; 9-Cyclopentyl-5,6-dihydro-7-ethyl-3 Petition 870170059664, of 17/08/2017, p. 159/185

152/176 (tert-butyl) -9H-pyrazolo [3,4-c] -1,2,4-triazolo [4,3a] pyridine, optionally in the form of racemates, enantiomers or diastereomers and, optionally, in the form of pharmacologically acceptable acid addition salts, solvates and / or hydrates thereof.

[402] By acid addition salts with pharmacologically acceptable acids with which the PDE4 inhibitors mentioned above may be in a position to form, mean, for example, salts selected from the hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate salts , hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrobenzoate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate, preferably hydrochloride, hydrobromide, hydrosulfate, hydrophosphate and hydrophosphate.

[403] LTD4 antagonists that can be used are preferably compounds selected from montelukast, pranlukast, zafirlukast; (E) -8- [2- [4- [4- (4 fluorophenyl) butoxy] phenyl] ethenyl] -2- (1H-tetrazol-5-yl) -4H-1benzopyran-4-one (MEN-91507); 4- [6-acetyl-3- [3- (4acetyl-3-hydroxy-2-propylphenylthio) propoxy] -2-propylphenoxy] butyric acid (MN-001); 1 - ((((R) - (3- (2- (6,7-difluor-2quinolinyl) ethenyl) phenyl) -3- (2- (2-hydroxy-2propyl) phenyl) thio) methylcyclopropane-acetic acid; 1 ((((1 (R) -3 (3- (2- (2,3-dichlortiene [3,2-b] pyridin-5-yl) - (E) ethenyl) phenyl) -3- (2- ( 1-hydroxy-1-methylethyl) phenyl) propyl) thio) methyl) cyclopropane acetic acid [2 - [[2- (4-tert-butylPetition 870170059664, 08/17/2017, page 160/185

153/176

2-thiazolyl) -5-benzofuranyl] oxymethyl] phenyl] acetic, optionally in the form of racemates, enantiomers or diastereomers, optionally in the form of pharmacologically acceptable acid addition salts and, optionally, in the form of salts and derivatives, solvates and / or hydrates of these.

[404] By acid addition salts with pharmacologically acceptable acids which LTD4 antagonists may be able to form mean, for example, salts selected from the hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate salts , hydroacetate, hydrobenzoate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate, preferably hydrochloride, hydrobromide, hydrosulfate, hydrophosphate, hydrofumarate and hydromethanesulfonate. By salts or derivatives which LTD4 antagonists may be able to form mean, for example: alkali metal salts such as sodium or potassium salts, alkaline earth metal salts, sulfobenzoates, phosphates, isonicotinates, acetates, propionates , dihydrogen phosphates, palmitates, pivalates or furoates.

[405] The EGFR inhibitors used are preferably compounds selected from 4 - [(3-chloro-4fluorfenyl) amino] -6 - {[4- (morpholino-4-yl) -1-oxo-2-butene-1yl] amino} -7-cyclopropylmethoxy-quinazoline, 4 - [(3-chloro-4fluorfenyl) amino] -6 - {[4- (N, N-diethylamino) -1-oxo-2-butene-1yl] amino} -7 -cyclopropylmethoxy-quinazoline, 4 - [(3-chloro-4fluorfenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-butene1-yl] amino} -7-cyclopropylmethoxy-quinazoline , 4 - [(R) - (1Petition 870170059664, of 8/17/2017, page 161/185

154/176 phenyl-ethyl) amino] -6 - {[4- (morpholino-4-yl) -1-oxo-butene-1yl] amino} -7-cyclopentyloxy-quinazoline, 4 - [(3-chloro-4fluor -phenyl) amino] -6 - {[4 - ((R) -6-methyl-2-oxo-morpholino-4yl) -1-oxo-2-butene-1-yl] amino} -7-cyclopropylmethoxyquinazoline, 4 - [(3-chloro-4-fluoro-phenyl) amino] -6 - {[4 - ((R) -6methyl-2-oxo-morpholino-4-yl) -1-oxo-2-butene-1- il] amino} -7 [(S) - (tetrahydrofuran-3-yl) oxy] -quinazoline, 4 - [(3-chloro-4fluorophenyl) amino] -6 - {[4 - ((R) -2 -methoxymethyl-6-oxomorpholin-4-yl) -1-oxo-2-butene-1-yl] amino} -7cyclopropylmethoxy-quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6- [2 - (((S) -6-methyl-2-oxo-morpholino-4-yl) ethoxy] -7-methoxy-quinazoline, 4 - [((3-chloro-4fluorfenyl) amino] -6 - ({4- [N - (2-methoxy-ethyl) -N-methyl-amino] 1-oxo-2-butene-1-yl} amino) -7-cyclopropylmethoxy-quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1oxo-2-butene-1-yl] amino} -7-cyclopentyloxy-quinazoline, 4 [(R) - (1-phenyl-ethyl) amino] - 6 - {[4- (N, N-bis- (2-methoxy-ethyl) amino) -1-oxo-2-butene-1-yl] amino} -7-cyclopropylmethoxyquinazoline, 4 - [(R) - ( 1-phenyl- ethyl) amino] -6 - ({4- [N- (2methoxy-ethyl) -N-ethyl-amino] -1-oxo-2-butene-1-yl} amino) -7cyclopropylmethoxy-quinazoline, 4 - [( R) - (1-phenyl-ethyl) amino] 6 - ({4- [N- (2-methoxy-ethyl) -N-methyl-amino] -1-oxo-2-butene-1yl} amino) -7 -cyclopropylmethoxy-quinazoline, 4 - [(R) - (1-phenylethyl) amino] -6 - ({4- [N- (tetrahydropyran-4-yl) -N-methyl-amino] 1-oxo-2-butene -1-yl} amino) -7-cyclopropylmethoxy-quinazoline, 4 - [(R) - (1-phenyl-ethyl) amino] -6 - ({4- [N- (2-methoxy-ethyl) -Nmethyl- amino] -1-oxo-2-butene-1-yl} amino) -7cyclopropylmethoxy-quinazoline, 4 - [(R) - (1-phenyl-ethyl) amino] 6 - ({4- [N- (tetrahydropyran- 4-yl) -N-methyl-amino] -1-oxo-2butene-1-yl} amino) -7-cyclopropylmethoxy-quinazoline, 4- [(3Petition 870170059664, of 17/08/2017, p. 162/185

155/176 chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2butene-1-yl] amino} -7 - ((R) -tetrahydrofuran-3- yloxy) quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, Ndimethylamino) -1-oxo-2-butene-1-yl] amino} -7 - (( S) tetrahydrofuran-3-yloxy) -quinazoline, 4 - [(3-chloro-4fluorfenyl) amino] -6 - ({4- [N- (2-methoxy-ethyl) -N-methyl-amino] 1-oxo -2-butene-1-yl} amino) -7-cyclopentyloxy-quinazoline, 4 [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N-cyclopropyl-N-methylamino) -1- oxo-2-butene-1-yl] amino} -7-cyclopentyloxyquinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, Ndimethylamino) -1-oxo-2- butene-1-yl] amino} -7 - [(R) (tetrahydrofuran-2-yl) methoxy] -quinazoline, 4 - [(3-chloro-4fluorfenyl) amino] -6 - {[4- (N, N - dimethylamino) -1-oxo-2-butene1-yl] amino} -7 - [(S) - (tetrahydrofuran-2-yl) methoxy] quinazoline, 4 - [(3-ethynyl-phenyl) amino] -6, 7-bis- (2-methoxyethoxy) -quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -7- [3 (morpholino-4-yl) -propyloxy] -6 - [(vinylcarbonyl) amino] quinazoline, 4 - [(R) - (1-phenyl-ethyl) amino] -6- (4-hydroxyphenyl) -7H-pyrrole [2,3-d] p irimidine, 3-cyano-4 - [(3-chloro-4fluorfenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-butene-yl] amino} -7-ethoxy- quinoline, 4 - {[3-chloro-4- (3-fluorobenzyloxy) -phenyl] amino} -6- (5 - {[(2-methanesulfonylethyl) amino] methyl} -furan-2-yl) quinazoline, 4- [(R) - (1-phenylethyl) amino] -6 - {[4 - ((R) -6-methyl-2-oxo-morpholino-4-yl) -1-oxo2-butene-1-yl] amino } -7-methoxy-quinazoline, 4 - [(3-chloro-4fluorfenyl) amino] -6 - {[4- (morpholino-4-yl) -1-oxo-2-butene-1yl] -amino} -7 - [(tetrahydrofuran-2-yl) methoxy] -quinazoline, 4 [(3-chloro-4-fluorophenyl) amino] -6 - ({4- [N, N-bis- (2-methoxyethyl) -amino] - 1-oxo-2-butene-1-yl} amino) -7 [(tetrahydrofuran-2-yl) methoxy] -quinazoline, 4- [(3-ethynylPetition 870170059664, from 08/17/2017, p. 163/185

156/176 phenyl) amino] -6 - {[4- (5.5-dimethyl-2-oxo-morpholino-4-yl) -1oxo-2-butene-1-yl] amino} -quinazoline, 4 - [(3 -chloro-4-fluorophenyl) amino] -6- [2- (2.2-dimethyl-6-oxo-morpholino-4-yl) ethoxy] -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluorophenyl ) amino] -6- [2- (2.2-dimethyl-6-oxo-morpholino-4-yl) ethoxy] -7 - [(R) - (tetrahydrofuran-2-yl) methoxy] -quinazoline, 4 [(3 -chloro-4-fluoro-phenyl) amino] -7- [2- (2.2-dimethyl-6-oxomorpholino-4-yl) -ethoxy] -6 - [(S) - (tetrahydrofuran-2yl) methoxy] -quinazoline , 4 - [(3-chloro-4-fluoro-phenyl) amino] -6 {2- [4- (2-oxo-morpholino-4-yl) -piperidine-1-yl] -ethoxy} -7methoxy-quinazoline , 4 - [(3-chloro-4-fluoro-phenyl) amino] -6- [1 (tert-butyloxycarbonyl) -piperidine-4-yloxy] -7-methoxyquinazoline, 4- [(3-chloro-4-fluorine -phenyl) amino] -6- (trans-4amino-cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4- [(3-chloro-4-fluoro-phenyl) amino] -6- (trans-4-methanesulfonylaminocyclohexan- 1-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) amino] -6- (tetrahydropyran-3-yloxy) -7-methoxyquinazoline, 4 - [(3-chloro-4- fluorine-phenyl) amino] -6- (1-methylpiperidin a-4-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4fluoro-phenyl) amino] -6- {1 - [(morpholino-4-yl) carbonyl] piperidine-4-yloxy} - 7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) amino] -6- {1 - [(methoxymethyl) carbonyl] -piperidine4-yloxy} -7-methoxy-quinazoline, 4 - [(3- chloro-4-fluorophenyl) amino] -6- (piperidine-3-yloxy) -7-methoxy-quinazoline,

4 - [(3-chloro-4-fluoro-phenyl) amino] -6- [1- (2-acetylamino-ethyl) piperidine-4-yloxy] -7-methoxy-quinazoline, 4 - [(3-chloro- 4-fluoro-phenyl) amino] -6- (tetrahydropyran-4-yloxy) -7-ethoxyquinazoline, 4 - [(3-chloro-4-fluoro-phenyl) amino] -6 - ((S) tetrahydrofuran-3-yloxy) -7-hydroxy-quinazoline, 4- [(3-chloro-4-fluoro-phenyl) amino] -6- (tetrahydropyran-4-yloxy) -7Petition 870170059664, from 17/08/2017, p. 164/185

157/176 (2-methoxy-ethoxy) -quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6- {trans-4 - [(dimethylamino) sulfonylamino] cyclohexan-1-yloxy} -7- methoxy-quinazoline, 4 - [(3-chloro-4fluor-phenyl) amino] -6- {trans-4 - [(morpholino-4yl) carbonylamino] -cyclohexan-1-yloxy} -7-methoxy-quinazoline, 4- [(3-chloro-4-fluoro-phenyl) amino] -6- {trans-4 - [(morpholino-4yl) sulfonylamino] -cyclohexan-1-yloxy} -7-methoxy-quinazoline, 4 - [(3- chloro-4-fluoro-phenyl) amino] -6- (tetrahydropyran-4yloxy) -7- (2-acetylamino-ethoxy) -quinazoline, 4 - [(3-chloro-4fluoro-phenyl) amino] -6- (tetrahydropyran -4-yloxy) -7- (2-methanesulfonylamino-ethoxy) -quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) amino] -6- {1 - [(piperidine-1-yl) carbonyl] piperidine-4- iloxy} -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) amino] -6- (1-aminocarbonylmethyl-piperidine-4yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro- 4-fluorophenyl) amino] -6- (cis-4- {N - [(tetrahydropyran-4-yl) carbonyl] N-methyl-amino} -cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4 [( 3-chloro-4-fluoro-phenyl) amino] -6- (cis-4- {N - [(morpholino-4yl) carbonyl] -N-methyl 1-amino} -cyclohexan-1-yloxy) -7-methoxyquinazolin; 4- {2- [4- (3-chloro-4-fluoro-phenylamino) -7-methoxyquinazolin-6-yloxy] -ethyl} -6-methyl-morpholino-2-one, 4- {4- [4 ( 3-chloro-2-fluoro-phenylamino) -7-methoxy-quinazolin-6-yloxy] cyclohexyl} -1-methyl-piperazine-2-one, 4 - [(3-chloro-4-fluorophenyl) amino] -6 - (cis-4- {N - [(morpholino-4-yl) sulfonyl] -Nmethyl-amino} -cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4 [(3-chloro-4-fluoro-phenyl ) amino] -6- (trans-4ethanesulfonylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) amino] -6- (1-methanesulfonylpiperidine-4- yloxy) -7-ethoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) amino] -6- (1-methanesulfonyl-piperidine-4Petition 870170059664, of 17/08/2017, p. 165/185

158/176 yloxy) -7- (2-methoxy-ethoxy) -quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6- [1- (2-methoxy-acetyl) -piperidine-4- yloxy] -7 (2-methoxy-ethoxy) -quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6- (cis-4-acetylamino-cyclohexan-1-yloxy) -7methoxy-quinazoline, 4 - [(3-ethynyl-phenyl) amino] -6- [1- (tert-butyloxycarbonyl) -piperidine-4-yloxy] -7-methoxy-quinazoline, 4 - [(3-ethynyl-phenyl) amino] -6- ( tetrahydropyran-4-yloxy] -7methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) amino] -6 (cis-4- {N - [(piperidine-1-yl) carbonyl] -N- methyl-amino} cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4fluoro-phenyl) amino] -6- (cis-4- {N - [(4-methyl-piperazine- 1il) carbonyl] -N-methyl-amino} -cyclohexan-1-yloxy) -7-methoxyquinazoline, 4 - [(3-chloro-4-fluoro-phenyl) amino] -6- {cis-4 [(morpholino- 4-yl) carbonylamino] -cyclohexan-1-yloxy} -methoxyquinazoline, 4 - [(3-chloro-4-fluoro-phenyl) amino] -6- {1- [2- (2oxopyrrolidin-1-yl) ethyl] -piperidine-4-yloxy} -7-methoxyquinazoline, 4- [(3-chloro-4-fluoro-phenyl) amino] -6- {1 [(morpholino-4-yl) carbonyl] -piperidine-4-yloxy} -7- (2-method) xiethoxy) -quinazoline, 4 - [(3-ethynyl-phenyl) amino] -6- (1-acetylpiperidine-4-yloxy) -7-methoxy-quinazoline, 4 - [(3-ethynylphenyl) amino] -6- ( 1-methyl-piperidine-4-yloxy) -7-methoxyquinazoline, 4 - [(3-ethinyl-phenyl) amino] -6- (1-methanesulfonyl-piperidine-4-yloxy) -7-methoxy-quinazoline, 4 - [( 3-chloro-4-fluoro-phenyl) amino] -6- (1-methyl-piperidine-4yloxy) -7 (2-methoxy-ethoxy) -quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6- (1-isopropyloxycarbonyl-piperidine-4-yloxy) 7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) amino] -6 (cis-4-methylamino-cyclohexan-1-yloxy ) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) amino] -6- {cis-4- [N- (2-methoxyacetyl) -N-methyl-amino] -cyclohexan- 1-ilóxi} -7-metóxiPetição 870170059664, of 08/17/2017, p. 166/185

159/176 quinazoline, 4 - [(3-ethynyl-phenyl) amino] -6- (piperidine-4yloxy) -7-methoxy-quinazoline, 4 - [((3-ethynyl-phenyl) amino] -6 [1- ( 2-methoxy-acetyl) -piperidine-4-yloxy] -7-methoxyquinazoline, 4 - [(3-ethynyl-phenyl) amino] -6- {1 - [(morpholino-4yl) carbonyl] -piperidine-4-yloxy } -7-methoxy-quinazoline, 4 [(3-chloro-4-fluoro-phenyl) amino] -6- {1 - [(cis-2,6-dimethylmorpholine-4-yl) carbonyl] -piperidine-4- iloxy} -7-methoxyquinazoline, 4 - [(3-chloro-4-fluoro-phenyl) amino] - 6- {1 - [(2methyl-morpholino-4-yl) carbonyl] -piperidine-4-yloxy} -7methoxy -quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) amino] -6- {1 [(S, S) - (2-oxa-5-aza-bicyclo [2,2,1] hept- 5-yl) carbonyl] piperidine-4-yloxy} -7-methoxy-quinazoline, 4 - [(3-chloro-4fluoro-phenyl) amino] -6- {1 - [(N-methyl-N-2-methoxyethylamino ) carbonyl] -piperidine-4-yloxy} -7-methoxy-quinazoline,

4 - [(3-chloro-4-fluoro-phenyl) amino] -6- (1-ethyl-piperidine-4yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] - 6- {1 - [(2-methoxyethyl) carbonyl] -piperidine-4yloxy} -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6- {1 - [(3-methoxypropyl -amino) -carbonyl] piperidine-4-yloxy} -7-methoxy-quinazoline, 4 - [(3-chloro-4fluoro-phenyl) amino] -6- [cis-4- (N-methanesulfonyl-N-methylamino) -cyclohexan-1-yloxy] -7-methoxy-quinazoline, 4- [(3-chloro-4-fluoro-phenyl) amino] -6- [cis-4- (N-acetyl-N-methylamino) -cyclohexan-1- yloxy] -7-methoxy-quinazoline, 4- [(3-chloro-4-fluoro-phenyl) amino] -6- (trans-4-methylaminocyclohexan-1-yloxy) -7-methoxy-quinazoline, 4 - [(3- chloro-4-fluoro-phenyl) amino] -6- [trans-4- (N-methanesulfonyl-N-methylamino) -cyclohexan-1-yloxy] -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl ) amino] -6- (trans-4-dimethylaminocyclohexan-1-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4Petition 870170059664, from 17/08/2017, p. 167/185

160/176 fluoro-phenyl) amino] -6- (trans-4- {N - [(morpholino-4yl) carbonyl] -N-methyl-amino} -cyclohexan-1-yloxy) -7-methoxyquinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino] -6- [2- (2.2dimethyl-6-oxo-morpholino-4-yl) -ethoxy] -7 - [(S) (tetrahydrofuran-2-yl) methoxy] -quinazoline, 4 - [(3-chloro-4fluoro-phenyl) amino] -6- (1-methanesulfonyl-piperidine-4yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6- (1-cyano-piperidine-4-yloxy) -7-methoxyquinazoline, 3-cyano-4 - [(3-chlor-4-fluorophenyl) amino] -6 - {[4 (N, N- dimethylamino) -1-oxo-2-butene-1-yl] amino} -7-ethoxyquinoline, [4- [(3-chloro-4-fluoro-phenyl) amino] -6 - {[4 (homomorpholino-4- yl) -1-oxo-2-butene-1-yl] amino} -7 - [(S) (tetrahydrofuran-3-yl) oxy] -quinazoline, 4 - [(3-chloro-4fluorophenyl) amino] -7- (2- {4 - [(S) - (2-oxo-tetrahydrofuran-5yl) carbonyl] -piperazine-1-yl} -ethoxy) -6 [(vinylcarbonyl) amino] -quinazoline, 4- [( 3-chloro-4-fluorophenyl) amino] -7- [2 - ((S) -6-methyl-2-oxo-morpholino-4-yl) ethoxy] -6 - [(vinylcarbonyl) amino] -quinazoline, 4 - [((3-chloro-4-fluoro-phenyl) amino] -7- [4 - ((R) -6-methyl-2-oxo-morpholino- 4-yl) butyloxy] -6 - [(vinylcarbonyl) amino] -quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) amino] -7- [4 - ((S) -6-methyl-2-oxomorpholine -4-yl) -butyloxy] -6 - [(vinylcarbonyl) amino] quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) amino] -7- (2- {4 - [(S) (2 -oxo-tetrahydrofuran-5-yl) carbonyl] -piperazine-1-yl} ethoxy) -6 - [(vinylcarbonyl) amino] -quinazoline, 4 - [(3-chloro-4fluorophenyl) amino] -7- [ 2 - ((S) -6-methyl-2-oxo-morpholino-4-yl) ethoxy] -6 - [(vinylcarbonyl) amino] -quinazoline, 4 - [(3-chloro-4fluorophenyl) amino] - 7- [4 - ((R) -6-methyl-2-oxo-morpholino-4-yl) butyloxy] -6 - [(vinylcarbonyl) amino] -quinazoline, 4 - [(3chloro-4-fluoro-phenyl) amino] -7- [4 - ((S) -6-methyl-2-oxoPetition 870170059664, of 8/17/2017, p. 168/185

161/176 morpholino-4-yl) -butyloxy] -6 - [(vinylcarbonyl) amino] quinazoline, cetuximab, trastuzumab, panitumumab (= ABX-EGF), ICR-62 Mab, gefitinib, pelitinib, canertinib and erlotinib, optionally na form of the racemates, enantiomers or diastereomers thereof, optionally in the form of the pharmacologically acceptable acid addition salts thereof, the solvates and / or hydrates thereof.

[406] By acid addition salts with pharmacologically acceptable acids which EGFR inhibitors may be able to form mean, for example, salts selected from the hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate salts , hydroacetate, hydrobenzoate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate, preferably hydrochloride, hydrobromide, hydrosulfate, hydrophosphate, hydrofumarate and hydromethanesulfonate.

[407] Examples of dopamine agonists that can be used preferably include compounds selected from bromocriptine, cabergoline, alpha-dihydroergocriptine, lisuride, pergolide, pramipexole, roxindol, ropinirole, talipexole, terguride and viozan. Any reference to the dopamine agonists mentioned above within the scope of the present invention includes a reference to any of the pharmacologically acceptable acid addition salts and, optionally, hydrates thereof that may exist. By the physiologically acceptable acid addition salts that can be formed by the dopamine agonists mentioned above, they mean, for example, pharmaceutically acceptable salts

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162/176 which are selected from the salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid and maleic acid.

[408] Examples of H1 antihistamines preferably include compounds selected from epinastine, cetirizine, azelastine, fexofenadine, levocabastine, loratadine, mizolastine, ketotifen, emedastine, dimetinden, clemastine, bamipine, dimexamine, chloramenamine, phenoxamine promethazine, ebastine, olopatadine, desloratidine and meclozine. Any reference to the H1 antihistamines mentioned above within the scope of the present invention includes a reference to any of the pharmacologically acceptable acid addition salts that may exist.

[409] Examples of PAF antagonists preferably include compounds selected from lexipafant, 4- (2-chlorophenyl) -9-methyl-2- [3 (4-morpholinyl) -3-propanon-1-yl] -6Hthene- [3,2 -f] -triazolo [4,3-a] [1,4] diazepines, 6- (2-chlorophenyl) -8,9-dihydro-1-methyl-8 - [(4-morpholinyl) carbonyl] 4H, 7H-cycle -penta- [4,5] thieno- [3,2-f] [1,2,4] triazolo [4,3a] [1,4] diazepines. Any reference to the PAF antagonists mentioned above includes, within the scope of the present invention, a reference to any of the pharmacologically acceptable acid addition salts thereof that may exist.

[410] Examples of non-steroidal anti-inflammatory drugs (NSAIDs) preferably include compounds

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163/176 selected from Aceclofenac, Acemetacin, Acetylsalicylate, Alclofenac, Alminoprofen, Amfenac, Ampiroxicam, Antolmetinguacil, Anirolac, Antrafenina, Azapropazon, Benorilat, Bermoprofen, Bindarit, Bromfenaco, Butlatan, Bucloxacon, , Carprofen, magnesium choline trisalicylate, Celecoxib, Cinmetacin, Cinnoxicam, Clidanac, Clobuzarit, Deboxamet, Dexibuprofen, Dexcetoprofen, Diclofenac, Diflunisal, Droxicam, Eltenac, Enfenaminaure, Etersalofac, Ettersalat, Ettersalat, Etterol, Etodol, Etodol Fenoprofen, Fentiazac, Fepradinol, Feprazon, Flobufen, Floctafenin, Flufenaminaure, Flufenisal, Flunoxaprofen, Flurbiprofen, Flurbiprofenaxetil, Furofenac, Furprofen, Glucametacacin, Ibufenac, Ibuprofen, Induprofen, Ibuprofen, Induprofen, Induprofen, Induprofen Lonazolac, Lornoxicam, Loxoprofene, Lumiracoxib, Meclofenaminaure , Meclofen, Mefenaminaure, Meloxicam, Mesalazin, Miroprofen, Mofezolac, Nabumeton, Naproxen, Nifluminaure, Olsalazin, Oxaprozin, Oxipinac, Oxyphenbutazon, Parecoxib, Phenilbutazon, Pelubiprofen, Pyrubprofen, Pyrobenzene, Pyrobenzene, Pyrobenzene, Pyrophenone , Protizininsaure, Rofecoxib, Romazarit, Salicylamid, Salicylsaure, Salmistein, Salnacedin, Salsalat, Sulindac, Sudoxicam, Suprofen, Talniflumat, Tenidap, Tenosal, Tenoxicam, Tepoxalin, Tiaprofensaure, Taramidin, Taramidin, Taramid, Taramid, Taramid, Taramid, Taramid, Taramid, Taramidinam , Valdecoxib, Ximoprofeno, Zaltoprofeno und Zoliprofeno.

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164/176 [411] Used MRP4 inhibitors are preferably compounds selected from N-acetyl-dinitrophenylcysteine, cGMP, cholate, diclofenac, dehydroepiandrosterone

3-glucuronide, dehydroepiandrosterone 3-sulfate, dilazep, dinitrophenyl-s-glutathione, estradiol 17-beta-glucuronide, estradiol 3,17-disulfate, estradiol 3-glucuronide, estradiol 3 sulfate, estrone sulfate, flurbiprofen, folate, N5-formyl-tetrahydrofolate, glycocholate, glycolitocholic acid sulfate, ibuprofen, indomethacin, indoprofen, ketoprofen, lithocholic acid sulfate, methotrexate, ((E) -3- [[[3- [2- (7-chloro-2quinolinyl acid ) ethenyl] phenyl] - [[3-dimethylamino) -3oxopropyl] thio] methyl] thio] -propanoic, alpha-naphthyl-beta-Dglucuronide, nitrobenzyl mercaptopurine riboside, probenecid, sildenafil, sulfinpyrazone, tauroquenodesoxycholate, taurochenodoxycholate, taurochydesoxycholate, taurochydesoxycholate, taurochydexoxate,

taurolithocolato, sulfate in taurolitocholic acid, topotecan, trequinsin and zaprinast, dipyridamole, optionally on form From racemates, enantiomers, diastereomers and the salts addition of acid pharmacologically acceptable and hydrates of these.

[412] Examples of JAK inhibitors preferably include compounds selected from Tofacitinib and Ruxolitinib.

[413] Examples of immunosuppressive agents preferably include compounds selected from mycophenolate mofetil, mycophenolic acid, azathioprine, cyclosporine, tacrolimus, pimecrolimus, abetimus, gusperimus and leflunomide.

[414] An example of a cytostatic is cyclophosphamide.

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165/176 [415] The invention relates more preferably to the use of MRP4 inhibitors for the preparation of a pharmaceutical composition for the treatment of respiratory complaints, containing SYK inhibitors of formula 1 or 1 'and inhibitors of MRP4 according to MRP4 inhibitors preferably being selected from dehydroepiandrosterone 3-sulfate, flurbiprofen 3,17-disulfate, indomethacin, indoprofen, estradiol, taurocholate, optionally in the form of racemates, enantiomers, diastereomers and pharmacologically acceptable acid addition salts and hydrates of these. The separation of enantiomers from racemates can be carried out using methods known in the art (for example, chiral chromatography, etc.).

[416] By acid addition salts with pharmacologically acceptable acids mean, for example, salts selected from the salts of hydrochlorides, hydrobromides, hydroiodides, hydrosulfates, hydromethanesulfonates, hydronitrates, hydroacetates, hydrofumarates, hydrosuccinates, hydrophosphates, hydromaleates, hydrocrylates, hydrochlorides, hydrochlorides, hydrochlorides, hydro-hydrobenzoates, hydrotartrates, hydrobenzoates, toluenesulfonates, preferably salts of hydrochlorides, hydrobromides, hydrosulfates, hydrophosphates, hydrofumarates and hydromethanesulfonates.

[417] The invention also relates to pharmaceutical preparations that contain a triple combination of SYK inhibitors of formula 1 or 1 ', MRP4 inhibitors and other active substance according to the invention, such as an anticholinergic, an inhibitor of PDE4, a

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166/176 steroid, an LTD4 antagonist or a beta mimetic, and its preparation and use for the treatment of respiratory complaints.

[418] Compounds that can be used as iNOS inhibitors are compounds selected from: S- (2aminoethyl) isothiourea, aminoguanidine, 2aminomethylpyridine, 5,6-dihydro-6-methyl-4H-1,3-thiazine-2amine (= AMT ), L-canavanine, 2-iminopiperidine, Sisopropylisothiouréia, S-methylisothiouréia, Setilisothiouréia, S-methyltiocitrulina, S-etiltiocitrulina, L-NA (N-nitro-L-arginina), L-NAME (N ”-nitro-L- argininamethyl ester), L-NMMA (NG-monomethyl-L-arginine), L-NIO (N ”iminoethyl-L-ornithine), L-NIL (N” -iminoethyl-lysine), (1Htetrazol-5-yl) - (S) -6- acetimidoylamino-2aminohexanoic acid amide (SC-51) (J. Med. Chem. 2002, 45, 1.6861.689), N - [[3- (aminomethyl) phenyl] methyl] -etanimidamide (= 1400W), (S) -4- (2-acetimidoylamino-ethylsulfanyl) -2amino-butyric acid (GW274150) (Bioorg. Med. Chem. Lett. 2000,

10, 597-600), 2- [2- (4-methoxy-pyridin-2-yl) -ethyl] -3Himidazo [4,5-b] pyridine (BYK191023) (Mol. Pharmacol. 2006,

69, 328-337), 2 - ((R) -3-amino-1-phenyl-propoxy) -4-chloro-5fluorbenzonitrile (WO 01/62704), 2 - ((1R, 3S) -3-amino- 4-hydroxy-1-thiazol-5-yl-butylsulfanyl) -6-trifluormethylnicotinonitrile (WO 2004/041794), 2 - ((1R, 3S) -3-amino-4-hydroxy-1-thiazol-5-yl-butylsulfanyl) -4 -chloro-benzonitrile (WO 2004/041794), 2 - ((1R, 3S) -3-amino-4-hydroxy-1-thiazol-5yl-butylsulfanyl) -5-chloro-benzonitrile (WO 2004/041794), ( 2S, 4R) -2-amino-4- (2-chloro-5-trifluormethyl-phenylsulfanyl) 4-thiazol-5-yl-butan-1-ol (WO 2004/041794), 2 - ((1R.3S) -3amino-4-hydroxy-1-thiazol-5-yl-butylsulfanyl) -5-chloroPetition 870170059664, of 8/17/2017, p. 174/185

167/176 nicotinonitrile (WO 2004/041794), 4 - ((S) -3-amino-4-hydroxy-1-phenyl-butylsulfanyl) -6-methoxy-nicotinonitrile (WO

02/090332), substituted 3-phenyl-3,4-dihydro-1-isoquinolinamine such as (1S, 5S, 6R) -7-chloro-5-methyl2-aza-bicyclo [4.1.0] hept- 2-en-3-ylamine (ONO-1714) (Biochem. Biophys. Res. Commun. 2000, 270, 663-667), (4R, 5R) -5-ethyl-4-methyl-thiazolidin-2-ylidenoamine ( Bioorg. Med. Chem. 2004, 12, 4,101), (4R, 5R) -5-ethyl-4-methylselenazolidin-2-ylidenoamine (Bioorg. Med. Chem. Lett. 2005, 15, 1,361), 4-aminotetrahydrobiopterine ( Curr. Drug Metabol. 2002, 3, 119-121), (E) -3- (4-chlorophenyl) -N- (1- {2-oxo-2- [4 (6-trifluoromethyl-pyrimidin-4-yloxy ) -piperidine-1-yl] ethylcarbamoyl} -2-pyridin-2-yl-ethyl) -acrylamide (FR260330) (Eur. J. Pharmacol. 2005, 509, 71-76), 3- (2,4-difluorophenyl ) -6- [2- (4-imidazol-1-ylmethyl-phenoxy) -ethoxy] -2-phenylpyridine (PPA250) (J. Pharmaco Exp. Ther. 2002, 303, 52-57),

3- {[(benzo [1,3] dioxol-5-ylmethyl) -carbamoyl] -methyl} -4- (2imidazol-1-yl-pyrimidin-4-yl) -piperazine-1-carboxylate (BBS-1) (Drugs Future 2004, 29, 45-52), (R) -1- (2-imidazol-1-yl-6-methylpyrimidin-) (2-benzo [1,3] dioxol5-yl-ethyl) -amide 4-yl) -pyrrolidine-2-carboxylic (BBS-2) (Drugs

Future 2004, 29, 45-52) and pharmaceutical salts, prodrugs or solvates thereof.

[419] Examples of iNOS inhibitors within the scope of the present invention may also include antisense oligonucleotides, particularly those antisense oligonucleotides that bind to the nucleic acids that encode iNOS. For example, WO 01/52902 describes antisense oligonucleotides, particularly antisense oligonucleotides that bind to the nucleic acids encoding iNOS, for

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168/176 modulation of iNOS expression. INOS antisense oligonucleotides, as described particularly in WO 01/52902, can therefore also be combined with the PDE4 inhibitors of the present invention because of their similar effect to iNOS inhibitors.

[420] Suitable HMG-CoA reductase inhibitors (also called statins) that can preferably be used in double or triple combinations with the compounds of formula 1 are selected from Atorvastatins, Cerivastatin, Flurvastatin, Lovastatin, Pitavastatin, Pravastatin, Rosuvastatin, Simvastatin, optionally in the form of their pharmaceutically available salts of addition of acid, prodrugs, solvates or hydrates thereof.

8. FORMULATIONS [421] The compounds of formula 1 or 1 'according to the invention also have the properties necessary for the manufacture of suitable pharmaceutical dosage forms. Such properties include, for example, properties relevant to sufficient bioavailability of the active ingredient, in particular, sufficiently high solubilities of these, for example, a solubility that is> 2 pg / ml measured in aqueous solution at pH 6.8.

[422] Suitable forms for administration are, for example, tablets, capsules, solutions, syrups, emulsions or inhalable powders or aerosols. The content of the pharmaceutically effective compound (s) in each case should be in the range of 0.1 to 90% by weight, preferably 0.5 to 50% by weight of the total composition, that is, in amounts that are sufficient to obtain the dosage range specified here below.

[423] Preparations can be administered orally

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169/176 in the form of a tablet, as a powder, as a powder in a capsule (for example, a hard gelatin capsule), as a solution or suspension. When administered by inhalation, the active substance combination can be given as a powder, as an aqueous or aqueous-ethanolic solution or as a propellant gas formulation.

[424] Preferably, therefore, pharmaceutical formulations are characterized by the content of one or more compounds of formula 1 or 1 'according to the preferred embodiments above.

[425] It is particularly preferable that compounds of formula 1 or 1 'are administered orally, and it is also particularly preferable that they are administered once or twice a day. Suitable tablets can be obtained, for example, by mixing the active substance (s) with known excipients, for example, inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as, eg corn starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc and / or release delay agents, eg carboxymethylcellulose, cellulose acetate phthalate or polyvinyl acetate. The tablets can also comprise several layers.

[426] Coated tablets can therefore be prepared by coating cores produced analogously to tablets with substances normally used for tablet coatings, for example, collidone or shellac, gum arabic, talc, titanium dioxide or sugar. To obtain delayed release or avoid

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170/176 incompatibilities, the core can also consist of several layers. Similarly, the tablet coating may consist of several layers to obtain delayed release, possibly using the excipients mentioned above for the tablets.

[427] Syrups containing the active substances or combinations thereof according to the invention may additionally contain a sweetener such as saccharin, cyclamate, glycerol or sugar and a flavor enhancer, for example, a flavoring such as, for example, vanillin or orange extract. They can also contain suspension aids or thickeners such as, for example, sodium carboxymethylcellulose, wetting agents such as products of condensation of fatty alcohols with ethylene oxide, or preservatives such as, for example, hydroxybenzoates.

[428] Capsules containing one or more active substances or combinations of active substances can, for example, be prepared by mixing the active substances with inert carriers such as, for example, lactose or sorbitol and their packaging in gelatin capsules. Suitable suppositories can be made, for example, by mixing with carriers provided for this purpose, for example, neutral fats or polyethylene glycol or its derivatives.

[429] Excipients that can be used include, for example, water, pharmaceutically acceptable organic solvents such as, for example, paraffins (for example, petroleum fractions), vegetable oils (for example, peanut or sesame oil), mono or alcohols polyfunctional (for example, ethanol or glycerol), carriers such as, for example,

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171/176 natural mineral powders (for example, kaolin, clays, talc, chalk), synthetic mineral powders (for example, salicylic acid and highly dispersed silicates), sugars (for example, cane sugar, lactose and glucose), emulsifiers ( eg lignin, spent sulphite liquor, methyl cellulose, starch and polyvinylpyrrolidone) and lubricants (eg magnesium stearate, talc, stearic acid and sodium lauryl sulphate).

[430] For oral administration, the tablets may, of course, contain, in addition to the carriers mentioned above, additives such as, for example, sodium citrate, calcium carbonate and calcium diphosphate, together with various additives with, for example, starch, preferably potato starch, gelatin and the like. In addition, lubricants, such as magnesium stearate, sodium lauryl sulfate and talc, can be used at the same time for the tablet production process. In the case of aqueous suspensions, the active substances can be combined with various flavor enhancers or colorants, in addition to the excipients mentioned above.

[431] Furthermore, it is preferred that the compounds of formula 1 or 1 'are administered by inhalation, particularly preferably if they are administered once or twice a day. For this purpose, compounds of formula 1 or 1 'must become available in forms suitable for inhalation. Inhalable preparations include inhalable powders, metered-dose aerosols containing propellant or inhalable propellant-free solutions, which are optionally present mixed with conventional physiologically acceptable excipients.

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172/176 [432] Within the scope of the present invention, the term "propellant-free inhalable solutions" also includes ready-to-use sterile concentrates or inhalable solutions. The preparations that can be used according to the invention are described in more detail in the following part of the specification.

Inhalable powders [433] If the active substances of formula 1 or 1 'are present mixed with physiologically acceptable excipients, the following physiologically acceptable excipients can be used to prepare the inhalable powders according to the invention: monosaccharides (for example, glucose or arabinose ), disaccharides (for example, lactose, sucrose, maltose), oligo and polysaccharides (for example, dextran), polyalcohols (for example, sorbitol, mannitol, xylitol), salts (for example, sodium chloride, calcium carbonate) or mixtures of these excipients between them. Preferably, mono- or disaccharides are used, while the use of lactose or glucose is preferred, particularly, exclusively, in the form of their hydrates. Purposes of the invention, but not. For the excipient lactose is particularly preferred, while lactose monohydrate is the more particularly preferred.

[434] Methods of preparing inhalable powders according to the invention by grinding and micronizing and, finally, by mixing the components together, are known by the established technique.

Inhalable aerosols containing propellant [435] Inhalable aerosols containing propellant that

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173/176 can be used according to the invention may contain the compounds of formula 1 or 1 'dissolved in the propellant gas or in dispersed form. Propellant gases that can be used to prepare aerosols for inhalation according to the invention are known by the established art. Suitable propellant gases are selected from hydrocarbons such as, for example, n-propane, n-butane or isobutane, and halohydrocarbons, for example, preferably fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane. The propellant gases mentioned above can be used alone or in mixtures thereof. Particularly preferred propellant gases are fluorinated alkane derivatives selected from TG134a (1,1,1,2-tetrafluoroethane), TG227 (1,1,1,2,3,3,3 heptafluorpropane) and mixtures thereof. Propellant-driven inhalation aerosols used within the scope of use according to the invention may also contain other ingredients, for example, co-solvents, stabilizers, surfactants, antioxidants, lubricants and pH adjusters. All of these ingredients are known in the art.

Propellant-free inhalable solutions [436] The compounds of formula 1 or 1 'according to the invention are preferably used to prepare inhalable solutions and propellant-free inhalable suspensions. Solvents used for this purpose include aqueous or alcoholic solutions, preferably ethanolic solutions. The solvent can be just water or a mixture of water and ethanol. The solutions or suspensions are adjusted to a pH of 2 to 7, preferably 2 to 5, with the use of suitable acids.

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174/176

The pH can be adjusted using acids selected from inorganic or organic acids. Examples of particularly suitable inorganic acids include hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and / or phosphoric acid. Examples of particularly suitable organic acids include ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid and / or propionic acid etc. Preferred inorganic acids are hydrochloric and sulfuric acids. It is also possible to use acids that have already formed an acid addition salt with one of the active substances. Of organic acids, ascorbic acid, fumaric acid and citric acid are preferred. If desired, mixtures of the above acids can also be used, particularly in the case of acids that have other properties, in addition to their acidifying qualities, for example, as flavorings, antioxidants or complexing agents, for example, citric acid or ascorbic acid, for example. According to the invention, it is particularly preferred to use hydrochloric acid to adjust the pH.

[437] Co-solvents and / or other excipients can be added to the propellant-free inhalable solutions used for the purpose according to the invention. Preferred co-solvents are those containing hydroxyl groups or other polar groups, for example, alcohols - particularly isopropyl alcohol, glycols - particularly propylene glycol, polyethylene glycol, polypropylene glycol, glycol ether, glycerol, polyoxyethylene alcohols and polyoxyethylene fatty acid esters. The terms excipients and additives in this context mean any substance

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175/176 pharmacologically acceptable which is not an active substance, but which can be formulated with the active substance or substances in the pharmacologically suitable solvent in order to enhance the qualitative properties of the active substance formulation. Preferably, these substances have no pharmacological effect or, in connection with the desired therapy, no appreciable pharmacological effect or, at least, no undesirable pharmacological effect. Excipients and additives include, for example, surfactants such as, for example, soy lecithin, oleic acid, sorbitan esters, for example, polysorbates, polyvinylpyrrolidone, other stabilizers, complexing agents, antioxidants and / or preservatives that guarantee or prolong the validity of the finished pharmaceutical formulation, flavorings, vitamins and / or other additives known in the art. Additives also include pharmacologically acceptable salts, such as sodium chloride, as isotonic agents. Preferred excipients include antioxidants such as ascorbic acid, as long as it has not already been used to adjust pH, vitamin A, vitamin E, tocopherols and similar vitamins or provitamins that occur in the human body. Preservatives can be used to protect the formulation from contamination with pathogens. Suitable preservatives are those that are known in the art, particularly pyridinium cetyl chloride, benzalkonium chloride or benzoic acid or benzoates, for example, sodium benzoate, in the concentration known by the established technique.

[438] For the forms of treatment described above, ready-to-use packaging for medicine is provided

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176/176 for the treatment of respiratory complaints, containing a description on the packaging that includes, for example, the words respiratory disease, COPD or asthma, together with an imidazolylpyrimidine according to formula 1 or 1 'and one or more combination partners selected from those described above.

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1/16

Claims (16)

1. A compound characterized by having the formula where A is N or OH, where Y is -0- or CH ₂ , where R ³ is an ortho-position or a meta-position substituent on the pyrazolyl ring of formula 1 and it is selected from the group consisting of -O- -C ₆ straight or branched--C 6 haloalkyl, _ ₃ -C ₆ -cycloalkyl, -Ci_ ₄ -alkylene-C ₃ _ ₆ cycloalkyl, a monocyclic five- or six members with one, two or three hetero atoms, each independently selected from 0, S or N, a 9 to 10 membered bicyclic heterocycle with 1, 2 or 3 hetero atoms, each independently selected from 0, S or N, where R ³ is optionally substituted by one, two, three or four substituents, each, independently of one another, selected from the group consisting of halogen (F), -Ci- ₃ -alkyl, oxo, -0N, where R ² is selected from the group consisting of -Ci_ ₃ alkyl, -Ci_ ₃ -haloalkyl, F, Br, Cl, and the pharmaceutically acceptable salts of the compounds Petition 870160050561, of 09/09/2016, p. 186/202 2/16 mentioned earlier. A compound characterized by having the formula 1 of claim 1, wherein A, Y, R ² and R ³ are defined as in claim 1, and the pharmaceutically acceptable salts of the compounds mentioned above. A compound characterized by having the formula 1 'of claim 1 or formula 1' of claim 2: where A is N or CH, where Y is -0- or CH ₂ , where R ³ is an ortho-position or a meta-position substituent on the pyrazolyl ring of formula 1 'and is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, -Ci- _6- fluoralkyl, cyclopropyl, cyclobutyl, cyclopentyl, -Ci-2-alkylene-C ₃ _ ₆ cyclopropyl, -Ci-2- C _3-4 alkylene- _6- cyclobutyl, -Ci_ ₂ -C ₃ alkylene - _6- cyclopentyl, a five or six membered monocyclic heterocycle with 1 oxygen atom, a 9 to 10 membered bicyclic heterocycle with 1 or 2 heteroatoms, each Petition 870160050561, of 09/09/2016, p. 187/202 3/16 one independently selected from O, S or N, where R is optionally substituted by one, two, three or four substituents, each independently of the other, selected from the group consisting of F, Cl, Br, methyl, ethyl, -CN, on what R ² is selected of group consisting of methyl, ethyl, isopropyl, -CF ₃ , F, Br, Cl, and the pharmaceutically acceptable salts of the compounds previously mentioned. 4. Featured compound for having formula 1 or The formula 1 'from any of the claims 1 to 3, in what : in that A is N or OH, in that Y is -O- or -CH ₂ -, in ₃ that R ³ is a substituent in ortho position or in target position of the pyrazolyl ring of formula 1 and is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, - (CH ₂ ) ₂ -CF ₃ , -CH ₂ -CH ₂ F, cyclopropyl, cyclobutyl, cyclopentyl, -methylene-C _3-6 cyclopropyl, tetrahydrofuranyl, tetrahydropyranyl, hexahydrofuropiranyl, where R is optionally substituted by one, two, three or four substituents, each, independently of each other, selected from the group consisting of F, Ol, Br, methyl, ethyl, -CN, where R is selected from the group consisting of methyl and F, and the pharmaceutically acceptable salts of the compounds mentioned above. 5. Compound characterized by having formula 1 or Petition 870160050561, of 09/09/2016, p. 188/202 The formula 1 'of any one of claims 1 to 4, wherein R is methyl, and the pharmaceutically acceptable salts of the compounds mentioned above. A compound characterized by having formula 1 or formula 1 'of any one of claims 1 to 4, wherein r ² and F, and the pharmaceutically acceptable salts of the compounds mentioned above. A compound characterized by having formula 1 or formula 1 'of at least one of claims 1 to 6, wherein: R is a meta-position substituent on the pyrazolyl ring of formula 1, and the pharmaceutically acceptable salts of the compounds mentioned above. A compound characterized by having formula 1 or formula 1 'of at least one of claims 1 to 6, wherein: R is an ortho-substituent of the pyrazolyl ring of formula 1, and the pharmaceutically acceptable salts of the compounds mentioned above. A compound characterized by having formula 1 or formula 1 'of at least one of claims 1 to 8, wherein: ₃ R is substituted by one, two, three or four substituents, each independently of the other, selected from the group consisting of F, methyl and -CN, and the pharmaceutically acceptable salts of the compounds Petition 870160050561, of 09/09/2016, p. 189/202 5/16 mentioned earlier. 10. Featured compound for having formula 1 or the formula 1 'of at least one of the claims 1 to 6, in that A is N or CH, in that Y is -CH ₂ -, in that R ³ is a substituent in ortho position or in target position of the pyrazolyl ring of formula V and is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, - (CH ₂ ) ₂ -CF ₃ , -CH ₂ -CH ₂ F, where R ³ is optionally substituted by one, two, three or four substituents, each independently of the other, selected from the group consisting of F, methyl and CN, and the pharmaceutically acceptable salts of the compounds mentioned previously. A compound characterized by having formula 1 or formula 1 'of at least one of claims 1 to 6, which is selected from the group consisting of and the pharmaceutically acceptable salts of the compounds mentioned above. 12. Compound characterized by having formula 1 or Petition 870160050561, of 09/09/2016, p. 190/202 The formula 1 'of at least one of claims 1 to 6, wherein A is N or CH, where Y is -0- or CH ₂ , R ³ is an ortho-position or full-position substituent on the pyrazolyl ring of formula 1 and is selected from the group consisting of isopropyl, isobutyl and t-butyl, where R ³ is not further substituted, and the pharmaceutically acceptable salts of the compounds previously mentioned. A compound characterized by having formula 1 or formula 1 'of claim 12, which is selected from the group consisting of: and the pharmaceutically acceptable salts of the compounds mentioned above. Compound characterized by having formula 1 or formula 1 'of claim 13, which is: Petition 870160050561, of 09/09/2016, p. 191/202 7/16 and the pharmaceutically acceptable salts of the aforementioned compound. A compound characterized by having formula 1 or formula 1 'of claim 13, which is: and the pharmaceutically acceptable salts of the aforementioned compound. A compound characterized by having formula 1 or formula 1 of claim 13, which is: and the pharmaceutically acceptable salts of the compound Petition 870160050561, of 09/09/2016, p. 192/202 8/16 mentioned earlier. A compound characterized by having formula 1 or formula 1 'of claim 13, which is: and the pharmaceutically acceptable salts of the aforementioned compound. A compound characterized by having formula 1 or formula 1 'of claim 13, which is: and the pharmaceutically acceptable salts of the aforementioned compound. A compound characterized by having formula 1 or formula 1 'of claim 13, which is: Petition 870160050561, of 09/09/2016, p. 193/202 9/16 ο, and the pharmaceutically acceptable salts of the aforementioned compound. A compound characterized by having formula 1 or formula 1 'of claim 13, which is: and the pharmaceutically acceptable salts of the aforementioned compound. 21. A compound characterized by having formula 1 or formula 1 'of any one of claims 1 to 6: where A is N or CH, where Y is -CH ₂ -, where R ³ is an ortho-position or meta-position substituent on the pyrazolyl ring of formula 1 and is selected from the group consisting of cyclopropyl, cyclobutyl , cyclopentyl, -methylene-C ₃ -6-cyclopropyl, tetrahydrofuranyl, tetrahydropyranyl, hexahydrofuropiranyl, where R ³ is optionally substituted by one, two, Petition 870160050561, of 09/09/2016, p. 194/202 10/16 three or four substituents, each independently of the other, selected from the group consisting of F, methyl and CN, and the pharmaceutically acceptable salts of the compounds mentioned above. 22. A compound characterized by having formula 1 or formula 1 'of claim 21, which is selected from the group consisting of: 23. A compound characterized by having formula 1 or formula 1 'of claim 22, which is: Petition 870160050561, of 09/09/2016, p. 195/202 11/16 and the pharmaceutically acceptable salts of the compounds mentioned above. 24. A compound characterized by having formula 1 or formula 1 'of claim 22, which is: and the pharmaceutically acceptable salts of the compounds mentioned above. 25. A compound characterized by having formula 1 or formula 1 'of claim 22, which is: and the pharmaceutically acceptable salts of the compounds mentioned above. 26. A compound characterized by having formula 1 or Petition 870160050561, of 09/09/2016, p. 196/202 12/16 formula 1 'of claim 22, which is: and the pharmaceutically acceptable salts of the compounds mentioned above. 27. A compound characterized by having formula 1 or formula 1 'of claim 22, which is: and the pharmaceutically acceptable salts of the compounds mentioned above. 28. A compound characterized by having formula 1 or formula 1 'of claim 22, which is: Petition 870160050561, of 09/09/2016, p. 197/202 13/16 and the pharmaceutically acceptable salts of the compounds mentioned above. 29. A compound characterized by having formula 1 or formula 1 'of claim 22, which is: and the pharmaceutically acceptable salts of the compounds mentioned above. A compound characterized by having formula 1 or formula 1 'of claim 23, which is: and the pharmaceutically acceptable salts of the compounds mentioned above. 31. Intermediate compound characterized by being selected from the group consisting of formula 7 Petition 870160050561, of 09/09/2016, p. 198/202 14/16 where R ² is F or methyl, where Y is -0- or CH ₂ , Petition 870160050561, of 09/09/2016, p. 199/202 15/16 and where R ³ is defined as in one of claims 1 to 3 and where Hal is Cl or Br, and where PG is a protecting group selected from the group consisting of benzyl, 1-phenylethyl, 1- (4methoxyphenyl) ethyl. 32. Intermediate compound characterized by being selected from the group consisting of 33. Formulations contain one or more claims 1 to 30 acceptable. pharmaceuticals, characterized by compounds according to one and a pharmaceutically excipient 34. Pharmaceutical formulations, characterized in that they contain one or more compounds according to one of claims 1 to 30, in combination with an active substance selected from anticholinergics, from the group consisting of betamimetics, corticosteroids, PDE4 inhibitors, EGFR inhibitors, antagonists of LTD4, CCR3 inhibitors, iNOS inhibitors, CRTH2 antagonists, triple kinase inhibitors against PDGFR, FGFR Petition 870160050561, of 09/09/2016, p. 200/202 16/16 and VEGFR, HMG-CoA reductase inhibitors and NSAIDs. Petition 870160050561, of 09/09/2016, p. 201/202 1/1