BR102016018778A2 - N - [(PYRIMIDINYLAMINO) PROPANIL] - AND N- (PIRAZINYLAMINO) PROPANIL] - Google Patents

Abstract

The present invention relates to novel n - [(pyrimidinylamino) propanyl] - and n - [(pyrazinylamino) propanyl] arylcarboxamide derivatives and processes for their preparation.

Description

(54) Title: NOVAS N - [(PYRIMIDINYLAMINO) PROPANIL] - E N- (PIRAZINILAMINO)

PROPANIL] AR ILCARBOXAMI DAS (51) Int. Cl .: C07D 207/30; C07D 239/28; C07C 233/36; C07C 237/14; A61K 31/4192; (...) (73) Owner (s): BOEHRINGER INGELHEIM INTERNATIONAL GMBH (72) Inventor (s): DORIS RIETHER (74) Attorney (s): FLÁVIA SALIM LOPES (57) Abstract: The present invention relates to new derivatives of N - [(pyrimidinylamino) propanyl] - and N - [(pyrazinylamino) -propanyl] arylcarboxamide and processes for preparing these.

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NEW N - [(PYRIMIDINYLAMINE) PROPANIL] - EN (PIRAZINYLAMINE) PROPANIL] ARYLCARBOXAMIDES FIELD OF INVENTION [001] The present invention relates to new N '- [(pyrimidinylamino) propanyl derivatives] - and ^ - [(pyrazinylamino) propanyl] arylcarboxamide, processes for preparing these, containing pharmaceutical compositions and their use in therapy, particularly in the treatment or prevention of conditions having an association with the orexin receptor subtype 1.

BACKGROUND OF THE INVENTION [002] Orexins are hypothalamic neuropeptides that play an important role in the regulation of many physiological behaviors, such as arousal, insomnia (Wakefullness), appetite, food intake, cognition, motivated behaviors, reward, mood and stress. Orexin, also referred to as hypocretin 1, is a peptide composed of 33 amino acids and orexin B, also referred to as hypocretin 2, is a peptide composed of 28 amino acids. Both are derived from a common precursor peptide referred to as pre-pro-orexin [Sakurai et al., Cell, 1998 Feb 20; 92 (4): 573-85, and De Lecea et al., Proc. Nat. Acad. Sci., 1998 Jan 06; 95 (1): 322-7). The orexins bind to two orphan receptors coupled to protein G, the type 1 orexin receptor (OX1R) and the type 2 orexin receptor (OX2R), which are widely distributed in the central nervous system and peripheral organs, such as adrenal glands, gonads, and intestine. Considering orexin A binds predominantly to OX1R, orexin B is able to bind to both OX1R and OX2R.

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2/70 [003] Orexins are involved in the regulation of a wide range of behaviors, including, for example, the regulation of emotion and reward, cognition, impulse control, regulation of autonomic and neuroendocrine functions, excitation, vigilance and states of sonoinsônia (Muschamp et al., Proc. Natl. Acad. Sci. USA 2014 Apr 22; 111 (16): E1648-55; for a recent review, see Sakurai, Nat. Rev. Neurosci, 2014; Nov; 15 (11 ): 719-31; Chen et al., Med. Res. Rev., 2015; Jan; 35 (1): 152-97; Gotter et al., Pharmacol. Rev., 2012, 64: 389-420 and many more).

[004] Double antagonism of OX1R and OX2R by small molecules is clinically effective in the treatment of insomnia, for which the drug suvorexanthus, [[(7 #) - 4- (5-chloro-1,3benzoxazol-2-yl) - 7-methyl-1,4-diazepan-1-yl] [5-methyl-2- (2HI, 2,3-triazol-2-yl) phenyl] methanone] has been granted marketing authorization (Kishi et al., PLoS One, 2015; 10 (8): e0136910). The sleep-inducing effects of double orexin receptor antagonists are predominantly mediated through OX2R (Bonaventure et al.,

J. Pharmacol. Exp. Ther., March 2015, 352, 3, 590-601), while the other physiological states, such as emotion and reward, cognition, impulse control, regulation of autonomic and neuroendocrine functions, arousal and surveillance are largely mediated via OX1R.

[005] Due to their sleep-inducing effects, the dual OX1R and OX2R antagonists are not suitable for the treatment of impulse-related disorders deficits in control as seen in addictions such as substance use disorders, personality disorders such as Disorder

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3/70 borderline personality, eating disorders such as binge eating disorder or attention deficit hyperactivity disorder. Therefore, it is desirable to provide a selective OX1R antagonist for the treatment of impulse control deficits.

[006] Orexin receptor antagonists of various structural classes are reviewed in Roecker et al. (J. Med. Chem. 2015, 59, 504-530). WO03 / 051872, WO2013 / 187466, WO2016 / 034882 and Bioorganic & Medicinal Chemistry 2015, 23, 1260-1275 describe orexin receptor antagonists.

DETAILED DESCRIPTION OF THE INVENTION [007] The present invention provides new derivatives of N '- [(pyrimidinylamino) propanyl] - and ^ - [(pyrazinylamino) propanyl] arylcarboxamide that unexpectedly are highly potent OX1R antagonists (assay A) still characterized by

1) high selectivity over the OX2 receptor (assay

B),

2) a highly stable medium in microsomes in liver human (test C), and 3) little or no MDCK (canine kidney of Madin-Darby) in efflux (test D).

[008] The compounds of the present invention are superior to those disclosed in the prior art in terms of combining the following key pharmacodynamic and pharmacokinetic parameters:

1) potency as OX1R antagonists,

2) selectivity over the OX2 receiver,

3) stability in human liver microsomes, and

4) MDCK efflux.

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4/70 [009] The compounds of the present invention are, however, encompassed by the formula I of WO03 / 051872, differ structurally from those explicitly disclosed in this, in which:

1) they contain a portion of the central N-ethyl (propan-2-yl) amino group in place of N-methyl-ethylamino, NH-ethylamino, or NH- (propan-2-yl) amino portion, and

2) the left side portion consists of a phenyl, pyridyl, pyrimidyl or pyrazyl group additionally substituted with a heteroaryl group instead of a thiazolyl group additionally substituted with a phenyl group. These structural differences unexpectedly result in greater potency, higher selectivity through OX2R and improved stability in human liver microsomes than the structurally closest example explicitly disclosed in WO03 / 051872.

[0010] The compounds of the present invention differ structurally from those described in WO2013 / 187466, in that they contain a (5-trifluoromethyl-pyrimidin-2-yl) -amino or (5-trifluoromethyl-pyrazin-2-yl) -amino instead of a Het1-Het2 fraction, where Het2 is phenyl or pyridyl. These structural differences unexpectedly result in higher selectivity through OX2R and improved stability in human liver microsomes.

[0011] The compounds of the present invention differ structurally from Examples 46, 70, 73, and 91 in WO2016 / 034882 (state of the art), in that they contain a central portion of N-ethyl- (propan-2-yl) ) amino replacing the N-ethyl- [butan-2-yl] amino or N-methyl [butan-2-yl] amino portion. These structural differences

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5/70 unexpectedly results in a higher concentration of the following key Pharma-codinamic and pharmacokinetic parameters:

1) potency as OX1R antagonists,

2) selectivity over the OX2 receiver,

3) stability in human liver microsomes, and

4) MDCK efflux.

[0012] Due to their high potency at OX1R and selectivity over OX2R, the compounds of the present invention are both expected to be effective in in vivo models and to have a sufficient window between efficacy and undesirable effects, such as drowsiness and sleep.

[0013] Due to the superior combination of key pharmacodynamic compounds and pharmacokinetic parameters (# 1-4) of the present invention they are expected to demonstrate adequate brain exposure and have a downward shape in in vivo clearance and thus a longer duration of action and greater tolerability. Therefore, the compounds of the present invention should be more viable for human use.

GENERAL DEFINITIONS [0014] The terms not specifically defined here should be given the meaning that would be given to them by a person skilled in the art in the light of description and context.

Stereochemistry:

[0015] Unless specifically indicated, throughout the report and the appended claims, a given chemical formula or name must encompass all stereo, optical and geometric tautomers and isomers (e.g., enantiomers, diastereoisomers, E / Z isomers etc.) ) and their racemates, as well as mixtures in different proportions

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6/70 of the separate enantiomers, mixtures of diastereoisomers, or mixtures of any of the above forms in which such isomers and enantiomers exist, as well as their salts, including pharmaceutically acceptable salts thereof.

Salts:

[0016] The phrase pharmaceutically acceptable is used here to refer to those compounds, materials, compositions, and / or dosage forms that, within the scope of appropriate medical judgment, are suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problem or complication, and compatible with a reasonable benefit / risk ratio.

[0017] As used herein, pharmaceutically acceptable salts refer to derivatives of the disclosed compounds, wherein the original compound forms a salt with Examples of acids for acids forming a pharmaceutically acceptable salt with a precursor compound containing a basic portion include mineral acids or organic such as benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gentisic acid, hydrobromic acid, hydrochloric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, 4-methylbenzenesulfonic acid, phosphoric, salicylic acid, succinic acid, sulfuric acid or tartaric acid.

[0018] The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic unit by methods

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7/70 conventional chemicals. Generally, these salts can be prepared by reacting the free acid or base forms of these compounds with an appropriate sufficient amount of the base or acid in water or in an organic diluent, such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, or a mixture of them.

[0019] Salts of acids other than those mentioned above, which are useful for example for the purification or isolation of the compounds of the present invention (e.g., trifluoroacetate salts) also comprise a part of the invention.

BIOLOGICAL TESTS

Abbreviations:

IP1 D-myo-inositol-1-phosphate

IP3 D-myo-inositol-1,4,5-triphosphate

4- (2-hydroxyethyl) -1HEPES piperazinoethanesulfonic acid HBSS Hanks' Balanced Salt Solution

BSA Bovine serum albumin

DMSO Dimethylsulfoxide

CHO Chinese hamster ovary [0020] Activation of the orexin receptors expressed in cell lines results in an increased concentration of intracellular IP3. IP1, a metabolite downstream of IP3, accumulates in cells following activation of the receptor and is stable in the presence of LiCl. Using homogeneous time resolved fluorescence technology with Lumi4-Tb cryptate (commercially available from Cisbio Bioassay.) And a suitable fluorescence plate reader. This functional response is detectable and quantifiable, as

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8/70 described in Trinquet et al. Anal. Biochem. 2006, 358, 126135, Degorce et al. Curr. Chem. Genomics 2009, 3, 22-32. This technique is used to characterize the pharmacological modification of orexin receptors.

[0021] The biological activity of the compounds is determined by the following methods:

A. OX1R potency in vitro assay: OX1R IP1 [0022] IP1 measurements are performed on CHO-K1 cells stably expressing the total human orexin 1 receptor length and the aequorin photoprotein. The cells are cultured in a Ham F12 nutrient mixture medium with 10% fetal calf serum, in a 37 ° C bath, 95% humidity and a 5% CO ₂ incubator. The mass of CHO-K1 / hOx1 cells is expanded to larger numbers of cells. The cells are obtained as cells frozen in cryovials and stored until used at -150 ° C. The viability of the cells after thawing is> 90%. In preparation for the test, 24 hours before the test, the cells are thawed at 37 ° C and immediately diluted with cell culture medium. After centrifugation, the cell pellet is resuspended in medium and then distributed on assay plates with a density of 10,000 cells / 25 µl per well. The plates are incubated for one hour at room temperature to reduce edge effects before being incubated for 24 hours at 37 ° C / 5% CO2. The compounds are prepared by an 8-point serial dilution in DMSO and a final dilution step in assay buffer (HBSS with 20 mM HEPES, 0.1% BSA and 50 mM LiCl, pH 7.4) to ensure a final DMSO concentration of 1% in the assay.

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9/70 [0023] On the day of the assay, the cells on the plate were washed twice with 60 μL of assay buffer (20 μl of buffer remained in the wells after washing), followed by the addition of 5 μl per well of compounds diluted in assay buffer. After 15 minutes of incubation at room temperature, 5 μl per well of Orexin A peptide (final concentration: 0.5 nM, and / or 50 nM) dissolved in assay buffer is added to the assay plate. The assay plate is incubated for 60 minutes at 37 ° C. Then, 5 μl per well of an antiIPl-cryptate Tb solution and 5 μl per well of the IP1-D2 dilution are added and the plate is incubated for another 60 minutes, protected from light, at room temperature. Emissions at 615 nm and 665 nm (excitation wavelength: 320 nm) are measured using an EnVision reader (PerkinElmer). The ratio between the emission at 665 nm and 615 is calculated by the reader.

[0024] Adjustment of four 8-point parametric non-linear curves and determination of IC ₅₀ values and Hill slopes are performed using regular analysis software, for example, AssayExplorer (Accelrys). In order to establish a parameter independent of the agonist concentration, Kb values are calculated using the following equation: IC ₅₀ / ((2+ (A / EC ₅₀ ) ⁿ ) ^{1 / n} -1) (with A = agonist concentration, EC ₅₀ = EC ₅₀ agonist, n = Hill slopes agonist) (see P. Leff, IG Dougall, Trends Pharmacol. Sci., 1993, 14 (4), 110-112).

B. OX2R power in vitro test: OX2R IP1 [0025] IP1 measurements are performed on CHO-K1 cells stably expressing the total length of the

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10/70 human orexin 2 and the aequorin photoprotein. The cells are cultured in a nutrient mixture of Ham F12 with 10% fetal calf serum, in a bath at 37 ° C, 95% humidity and a 5% CO ₂ incubator. The mass of CHO-K1 / hOx2 cells is expanded to larger numbers of cells. The cells are obtained as cells frozen in cryovials and stored until used at -150 ° C. The viability of the cells after thawing is> 90%. In preparation for the test, 24 hours before the test, the cells are thawed at 37 ° C and immediately diluted with cell culture medium. After centrifugation, the cell pellet is resuspended in the medium and then distributed on assay plates with a density of 5000 cells / 25 pl per well. The plates are incubated for one hour at room temperature to reduce edge effects before being incubated for 24 hours at 37 ° C / 5% CO2. The compounds are prepared by an 8-point serial dilution in DMSO and a final dilution step in assay buffer (HBSS with 20 mM HEPES, 0.1% BSA and 50 mM LiCl, pH 7.4) to ensure a final DMSO concentration of 1% in the assay.

[0026] On the day of the assay, the cells on the plate were washed twice with 60 µl of assay buffer (20 µl of buffer remained in the wells after washing), followed by the addition of 5 µl per well of compounds diluted in assay buffer. . After 15 minutes of incubation at room temperature, 5 µl per well of Orexin A peptide (final concentration: 0.5 nM) dissolved in assay buffer is added to the assay plate. The assay plate is incubated for 60 minutes at 37 ° C. Then 5 pl per

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11/70 well of anti-IPl-cryptate Tb solution and 5 μΐ per well of IP1-D2 dilution are added to all wells of the plate and the plate is incubated for another 60 minutes, protected from light, at room temperature. Emissions at 615 nm and 665 nm (excitation wavelength: 320 nm) are measured using a reader

EnVision (PerkinElmer). The ratio between the emission at 665 nm and 615 is calculated by the reader.

[0027] Four 8-point parametric non-linear curve adjustment and determination of IC ₅₀ values and Hill slopes are performed using regular analysis software, for example, AssayExplorer (Accelrys). In order to establish a parameter independent of the agonist concentration, Kb values are calculated using the following equation: IC50 / ((2+ (A / EC50) ⁿ ) ^{1 / n} -1) (with A agonist, EC50 = EC50 agonist, n = agonist) (see P. Leff, IG Dougall, Trends Pharmacol. Sci., 1993, 14 (4), 110-112).

[0028] The Kb values of Assay A (OX1R) and Assay B (OX2R) can then provide a selectivity ratio that is independent of the concentration (Orexin A) of the agonist.

C. Evaluation of metabolic stability in human liver microsomes (human MST) [0029] The metabolic stability of the compounds according to the invention can be investigated as follows:

[0030] The metabolic degradation of the test compound is tested at 37 ° C with aggregated human liver microsomes. The final incubation volume of 100 μl per time point contains TRIS buffer pH 7.6 at room temperature (0.1 M), MgCl ₂ (5 mM), microsomal protein (1 mg / mL) and the slope concentration compound Hill

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12/70 test at a final concentration of 1 μΜ. After a short pre-incubation period at 37 ° C, the reactions are initiated by the addition of dinucleotide phosphate adenine bethanicotinamide, reduced form (NADPH, 1 mM), and finished by transferring an aliquot in solvent after the different points of time. After centrifugation (10,000 g, 5 minutes), an aliquot of the supernatant is assayed by LCMS / MS for the amount of original compound. The half-life (T1 / 2) is determined by the slope of the semi-log graph of the concentration-time profile.

D. Evaluation of efflux of canine kidney cells in Madin-Darby (MDCK) transfected with the human MDR1 gene [0031] Apparent permeability coefficients (PE) of the compounds through the MDCK-MDR1 cell monolayers are measured (pH 7.4 , 37 ° C) towards apical-to-basal (AB) and basal-to-apical (BA) transport. AB permeability (PEAB) represents the absorption of drug from blood in the brain and efflux of BA permeability drug (PEBA) from the brain back into the bloodstream via passive permeability, as well as active transport mechanisms mediated by efflux and absorption of transporters that are expressed on MDCK-MDR1 cells, predominantly by overexpressed human MDR1 P-gp. The compounds are assigned to permeability / absorption classes by comparing AB permeabilities with the AB permeabilities of reference compounds known in in vitro permeability and human oral absorption. The identical or similar permeabilities in both directions of transport indicate passive permeation, points of vector permeability for mechanisms

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Additional 13/70 active transport. PEBA greater than PEAB indicates active efflux involvement mediated by MDR1 Pgp. Active transport is saturable depending on concentration.

[0032] The MDCK-MDR1 cells (1-2 x 10 and 5 cells / 1 cm ² in area) were seeded in filter inserts (Costar polycarbonate or PET filters, 0.4 pm pore size) and cultured (DMEM ) for 7 days. Subsequently, MDR1 expression is driven by culturing the cells with 5 mM sodium butyrate in complete medium for 2 days. The compounds are dissolved in the appropriate solvent (such as DMSO, 1 -20 mM stock solutions). The stock solutions are diluted with HTP-4 buffer (128.13 mM NaCl, 5.36 mM KCl, 1 mM MgSO ₄ , 1.8 mM CaCl ₂ , 4.17 mM NaHCO ₃ , 1, 19 mM Na ₂ HPO ₄ x 7H ₂ O, 0.41 mM NaH ₂ PO ₄ xH ₂ O, 15 mM HEPES, 20 mM glucose, 0.25% BSA, pH 7.4) to prepare the transport solutions (0.1-300 pM of the compound, final DMSO <= 0.5%). The transport solution (TL) is applied to the side of the apical or basolateral donor for the measurement of permeability AB or BA (repetitions of 3 filters), respectively. The side of the recipient contains the same plug as the side of the donor. Samples are collected at the beginning and at the end of the donor experiment and at various intervals up to 2 hours also from the side of the receiver for the measurement of concentration by HPLC-MS / MS or scintillation counting. Volumes of the sampled receiver are replaced with fresh receiver solution.

Biological data

Comparison of tests A and B with the tests described in WO03 / 051872

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Table 1: In vitro potencies of the document compounds

W003 / 051872 as reported in this report as determined in tests A, B, C, and D (described above)

Structure of Example 6 in W003 / 051872 F sfY Ύ 1 ¹ Data as described in W003 / 051872 (pages 16-18) 0X1R pKb = 6.4 to 7.4 matches for Kb = 400 to 40 nM 0X2 R pKb <6.6 up to 7.4 matches to Kb > 250 to 40 nM 0X2RKb / 0X1R Kb = no described Data as determined in Tests A and B (concentration of 0.5 nM Orexin A) Test A: 0X1R Kb = 3 0 nM Test B: 0X2R Kb = 101 nM 0X2RKb / 0X1R Kb = 3.4 Data as determined in Tests C and D Test C: Human MST ti / 2 = 8 min Test D: Reason for MDCK efflux (BA / AB) = 0.8

Comparison of tests A and B with the tests described in WO2013 / 187466 [0033] The tests described in WO2013 / 187466 differ from tests A and B in:

• Technology and reading: fluorescence measurement of

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15/70 intracellular Ca ²⁺ changes (WO2013 / 187466) instead of the IP1 luminescence measurement (assays A and B).

· Cell lines that overexpress Ox1R Ox2R and used for the assays described in WO2013 / 187466 are of different origin as the cell lines used for assays A and B.

· Use of modified orexin A (2 substituted amino acids) as agonist instead of orexin A.

· 300 pM agonist concentration used for the OX1R assay and 3 nM for the OX2R assay (EC75 versus EC100; according to Okumura T. et al., Biochemical and Biophysical Research Communications, 2001) (WO2013 / 187466). The IC 50 values that have been reported are dependent on the concentration of the agonist. Selectivity ratios calculated from these IC50 values cannot be compared with the selectivity ratios calculated from the agonist concentration independent of Kb values obtained from assay A and B.

[0034] Due to these differences between the tests, a direct comparison has to be established. Therefore, examples 69, 70 (the most selective) and 5 (one of the most potent) described in WO2013 / 187466 are tested in tests A and B, in order to be directly compared with the compounds of the present invention (see Table 2 ).

Table 2a: In vitro potencies of WO2013 / 187466 compounds as reported in this versus as determined in assays A and B (described above)

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Structure As described in WO2013 / 187466 As determined in Tests A and B the OX1R Kb OX2R Kb OX1R OX2R IC50 OX2R [nM] [nM] (0.5 OX2R Example # in WO2013 / 187466 IC50 IC50 / OX1R (Orexin A concentrates nM Orexin A Kb / OX1R [nM] [nM] IC50 traction concentrate Kb used) traction) n N ^ N O Ãjà ^F 1.6 1896 1185 2.25 (0.5 nM) 98 43 Example 69 N ^ N ψ hkXl · Ό ^: 1.1 452 411 1.10 (0.5 nM) 0.72 29 26 40 F Example 70 (50 nM) iTN N ^ N ο 1 AU N = \ 1.78 ç 0.5 76 152 (0.5 nM) 0.94 28 16 30 F Example 5 (50 nM)

Table 2b: Stability in human liver microsomes and the efflux ratios of MDCK compounds WO2013 / 187466, as determined in tests C and D (described above)

Example # in WO2013 / 187466 Data determined as in Test C: t _1/2 Human MST [min] Data like determined in Test D: MDCK efflux ratio (BA / AB)

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Example 69 23 1.3 Example 70 16 0.8 Example 5 30 3.1

Table 3a: In vitro potencies of compounds structurally closest to the prior art (Example

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Structure

As described in WO2016 / 034882 (Table 1, Table 2, Table 3, pages 177-180)

Example # in WO2016 / 034882

OX1R

OX2R

OX2R

IC50 /

OX1R

IC50

V

O

N

H

N ^ ^ N.

N ^CF 3

Example 70

Table 1 e: not reported

Table 1 and

2: not reported

Table 3:

Table 3:

Table

3:

PIC50 = 8.8

PIC50 = 5.3> 3125 corresponds to IC50 = 1.6 nM corresponds to IC50> 5000 nM

Table 1 and

2: not reported

Table 1 and

2: not reported

N, „N N O

H

N ^ N

X

Example 73

Table 3:

³ PIC50 = 8.8 corresponds to IC50 = 1.6 nM

Table 3:

PIC50 <6.0 corresponds to IC50> 1000 nM

Table

3:

> 625

Y ' ^N -, v

CF,

Example 91

Table 1 and

2: not reported

Table 1 and

2: not reported

Table 3:

ICP50 = 7.6 corresponds to IC50 = 25 nM

Table 3:

ICP50 <5.1 corresponds to IC50 = 7950 nM

Table

3:

318

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Table 3b: In vitro potencies of compounds structurally closest to the prior art (Example 46, 70, 73 and 91) in WO2016 / 034882, as determined in tests A and B (described above)

Example # in WO2016 / 034882 OX1R Kb [nM] (used concentration of Orexin A) OX2R Kb [nM] (concentration of 0.5 nM Orexin A) OX2R Kb / OX1R Kb Example 46 1.17 (0.5 nM) 1.56 (50 nM) 372 318 238 Example 70 0.135 (50 nM) 42.7 316 Example 73 0.390 (0.5 nM) 0.309 (50 nM) 148 379 479 Example 91 3.63 (0.5 nM) 313 86

Table 3c: Stability in human liver microsomes and the efflux ratios of MDCK compounds WO2016 / 034882, as determined in tests C and D (described above)

Example # in WO2016 / 034882 Data determined as in Test C: t _1/2 Human MST [min] Data as determined in Test D: MDCK efflux ratio (BA / AB) Example 46 32 0.7 Example 70 20 0.7 Example 73 11 0.7 Example 91 > 130 0.6

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Compounds of the present invention [0035] Table 4a lists data on OX1R and OX2R potencies and Table 4b lists data on stability in human liver microsomes and MDCK efflux of the compounds of the present invention. These data demonstrate that the compounds of the present invention are superior to those of the prior art in the combination of potency, selectivity, stability in human liver microsomes and MDCK efflux:

[0036] The compounds of the present invention are more potent, more selective and more stable in human liver microsomes than the more structurally similar example, Example 6, described in WO03 / 051872.

[0037] The compounds of the present invention are more selective about OX2R than the preferred examples, Examples 5, 69 and 70, described in WO2013 / 187466. In addition, they are more stable in human liver microsomes.

[0038] The compounds of the present invention are superior to the most structurally similar examples to those described in WO2016 / 034882, in at least one of the following criteria: potency, selectivity or stability in human liver microsomes, that is, more potent and more stable in human liver microsomes than Example 46, more potent and more selective than Example 91, and more stable in human liver microsomes than Examples 70 and 73.

Table 4a: Biological data of the compounds of the present invention

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Example Structure Assay A OX1R Kb [nM] (50 nM concentration of Orexin A) Assay B OX2R Kb [nM] (concentration of 0.5 nM Orexin A) OX2RKb / OX1R Kb 1 / n, N oy% x _: 0.048 19.4 404 2 _V x _v , ^F F ^F 0.188 64.5 343 3 Q _o C ^ AÀAa ^N ^ X _< F FF 0.015 6.27 418 4 ÇN ^N OI _f X..XJ ^N ^ X _< F ^F FF 0.096 46.9 489 5 Ό- rf V '·' N ^ í> \ LfX JN ^ l F F ^F 0.083 35.3 425 6 Ό ΧγΧ n ^ X <f _F F 0.091 53.1 584

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Example Structure Assay A OX1R Kb [nM] (50 nM concentration of Orexin A) Assay B OX2R Kb [nM] (concentration of 0.5 nM Orexin A) OX2RKb / OX1R Kb 7 Ό · No. cX ..... 'ϊΧ. F ^F 0.141 33.4 237 8 Ό · ϊ O | O \ Ιχ ,; N 0.292 33.4 114 9 -ο- Αα T p 0.106 32.9 310 10 Ό · ^N O _H iAAAAA '^'Ύ; FF 1.12 1060 949 11 r X Λ X .n. Ai n - a \; O ^ V ^F f; 0.014 19.3 1379 12 O- Ια Λ / Lx <V n ^z ^ ^/ A ^ A \ χϊ N ^ Jkp 1 r 0.614 129 210

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Example Structure Assay A OX1R Kb [nM] (50 nM concentration of Orexin A) Assay B OX2R Kb [nM] (concentration of 0.5 nM Orexin A) OX2RKb / OX1R Kb 13 fk kk, k ^N ^ k _< F ^F FF 0.0925 62.0 670 14 LL _ / LL J oJ ~ \ ° ^ \ / ⁼ \ 0.138 44.0 319 15 NOI φΎΛχ _the FF 0.0397 22.9 577 16 kzJ / L Jk À z ^N ^ / N, ίΐ ^ Ί Ν ^^> | _F ^^ k ^^ \ < ^F F ^F 0.0947 76.8 811 17 1 .zK .k / N. N, n ^N < 0.0216 54.0 2500 18 ÇN ^N O. _N kk k ^N ^ \ _<: f FF 0.0512 18.0 352

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Example Structure Assay A OX1R Kb [nM] (50 nM concentration of Orexin A) Assay B OX2R Kb [nM] (concentration of 0.5 nM Orexin A) OX2RKb / OX1R Kb 19 ΛΛλαΛ) F ^F 0.120 12.5 104 20 , k Jk xk / N \ / N, n U- 'N''N k ^{N. : N} Ef 0.566 68.0 120 21 l \ ^> N k N ^ kr F F 0.363 55.9 154 22 ^X N ^X kk k ^^ \ < ^F 0.0202 7.37 366 23 LL , Λ> LL 0.558 222 398 24 ÇN ^N O 1 ^F ^ Y '' ^J k ^ - ' ^N V ^? '''N kk k ⁿ ^ y ^f 0.0141 10.0 709

Table 4b: Stability in hepatic microsomes

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25/70 humans and the MDCK efflux ratios of the compounds of the present invention

Examples Assay C ti / 2 Human MST> 12 0 min 1, 5, 6, 8, 10, 11, 13, 15, 17, 18, 19, 21, 22, 23 ti / 2 Human MST = 43 - 100 2, 3, 4, 7, 9, 12, 14, 16, min 20, 24 Essay D 1, 2, 3, 4, 5, 6, 7, 9, 12, Efflux ratio MDCK 13, 14 , 15, 16, 17, 18, 19, (BA / AB) <3 20, 21, 21 Efflux ratio MDCK 8, 10, 11, 22, 23, 24 (BA / AB) = 3-5

TREATMENT USE / METHOD OF USE [0039] The present invention is directed to compounds that are useful in the treatment of a disease, disorder and condition in which the OX1R antagonism is of therapeutic benefit, including, but not limited to, treatment and / or prevention of psychiatric and neurological diseases associated with deficits in impulse control. Such impulse control deficits are seen in addictions, including substance use disorders; personality disorders, such as borderline personality disorder; disorders such as binge eating disorder; or attention deficit hyperactivity disorder. In accordance with another aspect of the invention, the compounds of the present invention are useful in the treatment of OX1R-related pathophysiological disorders in arousal / insomnia, appetite / food intake,

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26/70 cognition, motivated / reward behaviors, mood and stress.

[0040] In view of their pharmacological effect, the compounds of the present invention are suitable for use in the treatment of a disease or condition selected from the list consisting of:

(1) treating or preventing substance abuse / addiction / recurrence or addiction, as well as preventing relapse (including, but not limited to, drugs such as cocaine, opiates, such as morphine, barbiturates, benzodiazepines, amphetamines, nicotine / tobacco and other psychostimulants), alcoholism and alcohol-related disorders, drug abuse or addiction or relapse, tolerance to narcotics or withdrawal from narcotics, (2) eating disorders such as binge eating, bulimia nervosa, anorexia nervosa, other specific food or eating disorders, obesity, overweight, cachexia, appetite / taste disorders, vomiting, nausea, Prader-Willi-Syndrome, hyperphagia, appetite / taste disorders, (3) attention deficit hyperactivity disorder, conduct disorders , attention problems and related disorders, sleep disorders, anxiety disorders, such as generalized anxiety disorder, panic disorder, phobias, stomach disorder posttraumatic stress, schizophrenia, Alzheimer's disease, Parkinson's disease, Huntington's disease and Gilles de la Tourette syndrome, restless legs syndrome, dementia, dyskinesia, severe mental retardation, diseases

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27/70 neurodegenerative disorders, including nosological entities such as disinhibition-dementia-parkinsonism-amyotrophy complex, pale-dot-nigral degeneration, (4) cognitive dysfunction in psychiatric or neurological disease, cognitive difficulties associated with schizophrenia, Alzheimer's disease and other disorders neurological and psychiatric disorders, (5) mood disorders, bipolar disorder, mania, depression, manic depression, borderline personality disorder, antisocial personality disorder, aggression, such as impulsive aggression, suicidal tendencies, frontotemporal dementia, obsessive-compulsive disorder , delirium, affective disorder / neurosis, depressive disorder / neurosis, anxiety neurosis, dysthymic disorder, (6) sexual disorder, sexual dysfunction, psychosexual disorder, (7) impulse control disorders, such as pathological gambling, trichotillomania, intermittent explosive disorder , kleptomania, pyromania, compulsive shopping, internet addiction, compul are sexual, (8) sleep disorders such as narcolepsy, time zone, sleep apnea, insomnia, parasomnia, disturbed circadian and biological rhythms, sleep disorders associated with psychiatric and neurological disorders, (9) treatment, prevention and control of relapse impulsivity and / or impulse control deficits and / or behavioral disinhibition in any psychiatric and / or neurological condition, (10) personality disorders, such as

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28/70 borderline personality, antisocial personality disorder, paranoid personality disorder, schizoid and schizoid personality disorder, histrionic personality disorder, narcissistic personality disorder, elusive personality disorder, dependent personality disorder, other specific personality disorders and non-specific, (11) neurological diseases, such as cerebral edema and angioedema, cerebral dementia, such as, for example, Parkinson's disease and Alzheimer's disease, senile dementia; multiple sclerosis, epilepsy, temporal lobe epilepsy, drug-resistant epilepsy, seizure disorders, stroke, myasthenia gravis, brain and meningeal infections such as encephalomyelitis, meningitis, HIV, as well as schizophrenia, delusional disorders, autism, affective disorders and tic disorders.

[0041] The applicable daily dose of compounds of the present invention can vary between 0.1 and 2000 mg.

[0042] The pharmaceutically effective amount or effective therapeutic dose will depend on factors known to those skilled in the art, such as the age and weight of the patient, route of administration and the severity of the disease. In any case, the drug substance is to be administered in a dose and in a way that allows a pharmaceutically effective amount to be administered, which is appropriate for the patient's condition.

PHARMACEUTICAL COMPOSITIONS [0043] Preparations suitable for administration of the compounds of the present invention will be apparent to those of ordinary skill in the art and include, for example,

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29/70 example, tablets, pills, capsules, suppositories, tablets, lozenges, solutions, syrups, elixirs, sachets, injectables, inhalable powders, etc. The content of the pharmaceutically active compound (s) may vary in the range of 0.1 to 95% by weight, preferably 5.0-90% by weight of the composition as a whole.

[0044] Suitable tablets can be obtained, for example, by mixing a compound of the present invention with known excipients, for example, inert diluents, vehicles, disintegrants, adjuvants, surfactants, binders and / or lubricants and compressing the resulting mixture to form pills.

COMBINATION THERAPY [0045] Compounds according to the present invention can be combined with other treatment options

known for be used in the art in connection with one treatment in any of indications that O treatment it is in the focus of this invention. [0046] In between such options treatments that are

considered suitable for combination with the treatment according to the present invention are the following:

- Antidepressants,

- mood stabilizers,

- Antipsychotics,

- Anxiolytics,

- antiepileptic drugs,

- Sleeping agents,

- Cognitive stimulator,

- Stimulants,

- Non-stimulating medication for

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30/70 attention deficit,

- Additional psychoactive drugs.

EXPERIMENTAL SECTION Abbreviation lists

RT ambient temperature

Ionization mass spectrometry ESI-MS electrospray APCI Chemical pressure ionization atmospheric aq. aqueous MS Mass spectrometry MeOH methanol EtOH ethanol AND THE Ethyl acetate DMF N, N-dimethylformamide DCM dichloromethane DMA dimethylacetamide TEA triethylamine THF tetrahydrofuran dppf 1,1'-bis (diphenylphosphanyl) ferrocene DIPEA N, N-diisopropylethylamine HATU 1- [bis (dimethylamino) methylene] -1H- 1,2,3-triazolo [4,5-b] pyridinium 3 - hexafluorophosphate oxide DBU 1,8-Diazabiciclo [5.4.0] undec-7-eno DAY D diisopropyl azodicarboxylate Rt Retention time H hour (s) min minutes sat. saturated

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ACN acetonitrile

TFA Trifluoroacetic acid

High performance liquid chromatography

HPLC performance

High performance liquid chromatography

HPLC-MS performance-2-chloro-4,5CIP dihydro-1,3-dimethyl-1H-imidazole hexafluorophosphate mass spectrometry

HPLC methods:

Method Name: A

Column: Venusil XBP-C18, 2.1x50mm, 5pm

Spine Supplier: Agela Technologies

Gradient / Solvent % Sun [H2O, % Sun [ACN, Flow Temperature Time [min] 0.0375% 0.018% [mL / min] [° C] TFA] TFA] 0.00 90 10 0.8 50 0.40 90 10 0.8 50 3.40 0 100 0.8 50 3.85 0 100 0.8 50 3.86 90 10 0.8 50 4.50 90 10 0.8 50

Method Name: B

Column: Sunfire C18, 2.1 x 30 mm, 2.5 pm

Column Supplier: Waters

Gradient / Solvent Time [min] % Sun [H2O, 0.1% TFA] % Sun [ACN] Flow [mL / min] Temp [° C] 0.00 99 1 1.5 60

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

Method Name: C

Column: Chromolith Flash RP-18e 25-2mm

Spine Supplier: Merck

Gradient / Solvent % Sun % Sun Flow Temp [° C] Time [min] [H2O, [ACN, [mL / min] 0.0375% 0.018% TFA] TFA] 0.00 95 5 1.5 40 0.70 5 95 1.5 40 1.15 5 95 1.5 40 1.16 95 5 1.5 40 1.60 5 95 1.5 40

Method Name: D

Column: XBridge BEH Fenil, 2.1 x 30 mm, 1.7 pm

Column Supplier: Waters

Gradient / Solvent % Sun % Sun Flow Temp Time [min] [H2O, 0.1% NH3] [Acetonitrile] [mL / min] [° C] 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

Method Name: E

Column: XBridge C18, 4.6 x 30 mm, 3.5 pm

Column Supplier: Waters

Gradient / Solvent % Sol [H2O, % Sun Flow Temp [° C] Time [min] 0.1% NH3] [ACN] [mL / min]

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0.00 97 3 5 60 0.02 97 3 5 60 1.60 0 100 5 60 1.70 0 100 5 60

Method Name: F

Column: Sunfire C18, 2.1 x 30 mm, 2.5 pm

Column Supplier: Waters

Gradient / Solvent % Sun % Sun Flow Temp [° C] Time [min] [H ₂ O, 0.1% TFA] [ACN] [mL / min] 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

Method Name: G

Column: XBridge C18, 3 x 30 mm, 2.5 pm

Column Supplier: Waters

Gradient / Solvent % Sun % Sun Flow Temp Time [min] [H ₂ O, 0.1% NH3] [ACN] [mL / min] [° C] 0.00 97 3 2.2 60 0.02 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 Name: H

Column: Xselect CSH, 2.5 pm, 4.6 x 50 mm

Column Supplier: Waters

Gradient / Solvent % Sun % Sun Flow Temp Time [min] [90% H ₂ O + [90% ACN + [mL / min] [° C]

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10% ACN + 10% h ₂ o + 0.1% HCOOH] 0.1% HCOOH] 0.00 100 0 1.4 RT 4.00 0 100 1.4 RT 5.30 0 100 1.4 RT 5.50 100 0 1.4 RT 6.00 100 0 1.4 RT

Method Name: I

Column: Xselect CSH Fenil- Hexil, 2.5 pm, 4.6 x 50 mm

Column Supplier: Waters

Gradient / Solvent % Sun % Sun Flow Temp Time [min] [90% H2O + [90% ACN + [mL / min] [° C] 10% ACN + 10% h ₂ o + 0.1% HCOOH] 0.1% HCOOH] 0.00 100 0 1.4 RT 4.00 0 100 1.4 RT 5.30 0 100 1.4 RT 5.50 100 0 1.4 RT 6.00 100 0 1.4 RT

Method Name: J

Column: Sunfire C18, 3.0 x 30 mm, 2.5 pm

Column Supplier: Waters

Gradient / Solvent Time [min] % Sol [h ₂ o, 0.1% TFA] % Sun [ACN] Flow [mL / min] Temp [° C] 0.00 95 5 1.5 60 1.30 0 100 1.5 60 1.50 0 100 1.5 60

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Method Name: K

Column: BEH C18, 1.7 pm, 2.1 x 50 mm

Column Supplier: Waters

Gradient / Solvent % Sun % Sun Flow Temp Time [min] [90% H2O + [90% ACN + [mL / min] [° C] 10% ACN + 5 10% H2O] nM NH ₄ HCO ₃ ] 0.00 100 0 0.7 35 1.20 0 100 0.7 35 1.45 0 100 0.7 35 1.55 100 0 0.7 35 1.75 100 0 0.7 35

Method Name: L

Column: CSH C18, 1.7 pm, 2.1 x 50 mm

Column Supplier: Waters

Gradient / Solvent % Sun % Sun Flow Temp [° C] Time [min] [90% H ₂ O + [90% ACN [mL / min] 10% ACN + + 10% H2O] 0.1% HCOOH] 0.00 100 0 0.7 35 1.20 0 100 0.7 35 1.45 0 100 0.7 35 1.55 100 0 0.7 35 1.75 100 0 0.7 35

Method Name: M

Column: Atlantis T3, 3.0 pm 2.1 x 50 mm

Column Supplier: Waters

Gradient / Solvent % Sol [90% H ₂ O % Sun Flow Temp Time [min] + 10% ACN + [90% ACN + [mL / min] [° C] 0.1% HCOOH] 10% H2O]

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0.00 100 0 0.7 35 2.40 0 100 0.7 35 2.70 0 100 0.7 35 2.80 100 0 0.7 35 3.00 100 0 0.7 35

Method Name: N

Column: Synergi Hydro RP100A, 2.5 pm, 3 x 50 mm

Spine Supplier: Phenomenex

Gradient / Solvent % Sun % Sun Flow Temp Time [min] [90% H ₂ O + [90% ACN + [mL / min] [° C] 10% ACN + 5 10% H ₂ O] mM NH ₄ COOH] 0.00 100 0 1.2 RT 4.00 0 100 1.2 RT 5.30 0 100 1.2 RT 5.50 100 0 1.2 RT 6.00 100 0 1.2 RT

Method Name: O

Column: HSS C18, 1.8 pm, 2.1 x 50 mm

Column Supplier: Waters

Gradient / Solvent Time [min] % Sol [90% H2O + 10% ACN + 0.1% CF ₃ COOH] % Sun [90% ACN + 10% H2O] Flow [mL / min] Temp [° C] 0.00 100 0 0.7 35 1.20 0 100 0.7 35 1.45 0 100 0.7 35 1.55 100 0 0.7 35 1.75 100 0 0.7 35

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Method Name: P

Column: BEH C18 1.7 pm 2.1 x 50 mm

Column Supplier: Waters

Gradient / Solvent % Sol [90% H2O % Sun Flow Temp Time [min] + 10% ACN + 5 [90% ACN + [mL / min] [° C] mM of NH ₄ COOH] 10% H ₂ O] 0.00 100 0 0.7 35 1.20 0 100 0.7 35 1.45 0 100 0.7 35 1.55 100 0 0.7 35 1.75 100 0 0.7 35

Method Name: Q

Column: Venusil XBP-C18, 2.1 x 50 mm, 5 pm

Spine Supplier: Agilent

Gradient / Solvent % Sun % Sun Flow Temp [° C] Time [min] [H2O, 0.0375% [ACN, [mL / min] TFA] 0.018% TFA] 0.00 90 10 1.0 50 2.00 20 80 1.0 50 2.48 20 80 1.0 50 2.50 90 10 1.0 50 3.00 90 10 1.0 50

Method Name: R

Column: Luna-C18 5pm, 2.0 * 50mm

Spine Supplier: Phenomenex

Gradient / Solvent Time [min] % Sol [H2O, 0.0375% TFA] % Sol [ACN, 0.018% TFA] Flow [mL / min] Temp [° C] 0.00 99 1 0.8 40 0.40 99 1 0.8 40 3.40 0 100 0.8 40

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3.85 0 100 0.8 40 3.86 99 1 0.8 40 4.50 99 1 0.8 40

Method Name: S

Column: XBridge C18 2.5pm, 3.0 * 30mm

Column Supplier: Waters

Gradient / Solvent Time [min] % Sun [Water 0.1% NH ₃ ] % Sun [Acetonitrile] Flow [mL / min] Temp [° C] 0.00 95 5 1.5 60 1.30 0 100 1.5 60 1.50 0 100 1.5 60 1.60 95 5 1.5 60

Method Name: T

Column: Atlantis dC18 5pm 4.6 x 50 mm

Column Supplier: Waters

Gradient / Solvent % Sun % Sun Flow Temp Time [min] [90% H ₂ O + 10% [90% ACN + [mL / min] [° C] ACN + 0.05% 10% H ₂ O] CF ₃ COOH] 0.00 100 0 1.3 35 0.70 100 0 1.3 35 4.50 0 100 1.3 35 5.80 0 100 1.3 35 6.00 100 0 1.3 35

Method Name: U

Column: Sunfire, 3 x 30 mm, 2.5 pm

Column Supplier: Waters

Gradient / Solvent Time [min] % Sol [H2O, 0.1% TFA] % Sun [ACN] Flow [mL / min] Temp [° C] 0.00 97 3 2.2 60

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0.02 97 3 2.2 60 1.00 0 100 2.2 60 1.25 0 100 3 60 1.40 0 100 3 60

[0047] Traces of HPLC and NMR of the examples and some advanced intermediates are of greater complexity due to the fact that these compounds exist in an equilibrium of various rotameric forms. In the case of multiple peaks in the HPLC spectrum, the retention time of the main peak is reported.

Preparation of Intermediates

Acid Intermediates:

Acid Name Structure Reference / Source TO 1 Acid 2- [1,2,3] triazole-2yl-benzoic FF N _{x X} N NO J ^ OH WO2008 / 143856, page 30, Compound B-1 A-2 3-Fluoro-2 [1,2,3] triazole-2yl-benzoic acid ΓΛ N _{x X} N NO F, X. / X jj OH WO2011 / 50198, Page 47, Intermediate 5 A-3 4-fluoro-2 [1,2,3] triazole-2yl-benzoic acid FF N _{x X} N NO X ° O „ WO2011 / 50200, Page 54, Intermediate 16

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Acid

Name

Structure

Reference / Source

A-4

3-chloro-2 [1,2,3] triazole-2yl-benzoic acid

A-5

5-fluoro-2 [1,2,3] triazole-2yl-benzoic acid

A-6

5-cyano-2 [1,2,3] triazole-2yl-benzoic acid

A-7

4-fluoro-2pyrimidin-2-ylbenzoic acid

A-8

2-Fluoro-6 [1,2,3] triazole-2yl-benzoic acid

FF

O

WO2013 / 68935 E-23 in Table 6,

OH

P.

V

OH

F

FF

V

O

N

OH

FF

WO2011 / 50198, Pages 45-46, Intermediate 1

WO2012 / 85852 Page 50, Intermediate

WO2011 / 50200, page 95, intermediate 85

WO2012 / 145581, intermediate 12, pages 49-50

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Acid Name Structure Reference / Source 3-Fluoro-2- acid ^ N O WO2011 / 50200, A-9 pyrimidin-2-il- Fx page 78, benzoic Ύ OH Intermediate 52 ⁿ L AN O A-10 5-fluoro-2pyrimidin-2-ylbenzoic acid (f k ..... OH WO2011 / 50200, pages 54-57, Intermediate 17 F ζ THE 2-Fluoro-6- acid N ^ f ^N O WO2011 / 50198 A1, A-11 pyrimidin-2-il- II page 52, benzoic V X Oh Intermediate 14 ‘F A-12 6-Methyl-3 [1,2,3] triazole-2yl-pyridine-2-carboxylic acid r O sl N Y Af O 0 oH WO2012 / 89606, Page 44, Intermediate D40 A-13 6-Methyl-3pyrazol-1-ylpyridine-2-carboxylic acid Q Λτ O 0 OH WO2010 / 122151, Page 47, Intermediate D37 Commercially 1 available from A-14 2-Methyl-4-phenyl-pyrimidine5-carboxylic acid An- OH ^ O Fluorochemical catalog number 322095, CDM number: MFCD02682072

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Acid Name Structure Reference / Source A-15 3-Phenylpyridine-2-carboxylic acid Commercially available from Fluorochemical Catalog Number 065974, CDM Number: MFCD04114112 A-16 4-Phenylpyrimidine-5carboxylic acid OH Commercially available from Emolecules catalog number 45773153, CDM number: MFCD09835877 A-17 3-Phenylpyrazine-2-carboxylic acid OH Commercially available from Fluorochemical Catalog Number 079153, CDM Number: MFCD02181157

3,5-Difluor-2- [1,2,3] triazol-2-yl-benzoic acid A-18:

A-18.4 [0048] Step 1: A mixture of A-18.1 (9.80 g, 0.55 mmol) in water (70 mL) and H ₂ SO ₄ (25.0 mL, 0.48 mol) is cooled at 0 ° C. Then, NaNO ₂ (4.8 g, 69 mmol) in H ₂ O (20 mL) is added dropwise and the reaction mixture is stirred for 1.5 h. To this mixture, Kl (45.0 g, 0.27 mol) in H ₂ O (40 ml) is added slowly. The reaction mixture is heated to RT and then heated to 90 ° C for 90 min. The mixture is allowed to cool to RT and Na ₂ S ₂ O ₃ (aq. Solution) is added until the color disappears. The precipitate is filtered and then taken up in NaOH (4 M aq. Solution). The mixture is filtered, the filtrate is acidified with HCl (4 M aq. Solution) and the precipitate is

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/3 / 70 filtered off, washed with water and dried to provide 9.0 g of A-18.2. ESI-MS: 285 [M + H] ⁺ ; HPLC (Rt):

0.71 min (Method C).

[0049] Step 2: A mixture of A-45.2, (3.50 g, 11.1 mmol), A-18.3 (1.56 g, 22.2 mmol), Cul (0.18 g, 0.89 mmol),

A-18.4 (0.70 mL, 4.44 mmol) and K ₂ CO ₃ (3.46 g, 23.9 mmol) in

DMF (10 mL) is cooled to 100 ° C by microwave during

1.5 h. The mixture is poured into water and extracted with EA. The organic phase is washed with water. The combined aqueous phases are acidified with HCl (0.5 M aq. Solution) and extracted with EA. The organic phase is washed with brine, dried and concentrated to provide the crude product which is purified by means of HPLC-MS (using a solvent gradient H ₂ 0 + 0.075% TFA, with 5-35% ACN) to provide 1.3 g of A-18. ESI-MS: 226 [M + H] ⁺ ; HPLC (Rt): 1.88 min (Method A).

4-Fluor-2- (5-methyl- [1,3,4] oxadiazol-2-yl) benzoic acid A-19:

[0050] Step 1: To a mixture of A-19.1 (2.00 g, 8.42 mmol) in dry DCM (50 mL) is added A-19.2 (0.83 g, 10.1 mmol) and stirred at RT for 1 h. Another portion of A19.2 (0.83 g, 10.1 mmol) is added and the reaction is stirred overnight. MeOH (5.0 mL) is added and the solvent is

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44/70 reduced to half the volume. The precipitate is filtered to obtain 0.5 g of A-19.3. The filtrate is concentrated and purified by flash column chromatography on silica gel (using a solvent gradient from 100% DCM to 95% DCM and 5% MeOH) to provide another 1.10 g of A-19.3. ESI-MS: 275 [M + H] +; HPLC (Rt): 0.11 min (Method D).

[0051] Step 2: To a mixture of A-19.3 (1.57 g, 5.71 mmol) in DCM (50 mL) is added A-19.4 (2.70 g, 11.3 mmol) and the mixture is busy at night. In ₂ CO ₃ (2M aq.) Is added, the organic phase is extracted with Na2CO3 (2M aq.), The combined organic phases are washed with saline, dried and concentrated to provide 0.80 g of A -19.5. ESI-MS: 257.3 [M + H] +; HPLC (Rt): 0.47 min (Method D).

[0052] Step 3: To a mixture of A-19.5 (0.80 g, 3.10 mmol), dry MeOH (10 mL) and TEA (1.08 mL, 7.46 mmol) is added Pd (dppf) Cl ₂ * DCM (152 mg, 0.19 mmol). The reaction is stirred at 70 ° C under a pressure of carbon monoxide (3 bar - 300 KPa) for 4 h. The mixture is filtered, concentrated and purified by HPLC-MS (using a solvent gradient of H2O / ACN with NH4OH) to

provide 0.55 g of A-19.6 (Rt): 0.88 min (method E). . ESI-MS : 237.1 [M + H] ⁺ ; HPLC [0053] Step 4: A mixture of A-19.6 (0.55 g, 2.31 mmol), MeOH (4.0 mL) and NaOH (4M of solution aq., 2.88 mL, 11.5 mmol) is stirred at RT during 30 min The mixture is

concentrated and acidified with HCl (4M aq. solution) to pH 2 and extracted with EA, the organic phase is dried and concentrated to provide 0.40 g of A-19. ESI-MS: 223.4 [M + H] ⁺ ; HPLC (Rt): 0.10 min (Method D).

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Α5 / 70

3,4-Difluor-2- [1,2,3] triazol-2-yl-benzoic acid A-20

[0054] A mixture of A-20.1 (9.00 g, 36.1 mmol), A20.2 (5.25 g, 72.1 mmol), Cul (0.70 g, 3.61 mmol) and K ₂ CO ₃ (11.3 g, 77.6 mmol) in DMF (100 ml) is heated to 120 ° C for 16 h. The mixture is acidified with HCl (0.5M aq. Solution) to pH 2. The mixture is extracted with EA, the organic phase is washed with brine, dried and concentrated to provide the crude product which is purified by prep HPLC. HPLC-MS (using a solvent gradient H ₂ 0 + 0.075% TFA, with 5-35% ACN) to provide 3.00 g of A-20. ESI-MS: 248 [M + Na] ⁺ ; HPLC (Rt): 0.45 min (Method B).

5-Fluoro-2- [1,2,3] triazol-2-yl-nicotinic acid A-21:

H

A-21.3

[0055] Step 1: A mixture of A-21.1 (2.00 g, 11.0 mmol), A-21.2 (3.88 g, 17.1 mmol), Cul (0.13 g, 0.68 mmol ), A-21.3 (0.15 mL, 1.03 mmol) and K ₂ CO ₃ (2.36 g, 17.1 mmol) in

Dry DMF (10 mL) is heated to 120 ° C by microwave

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46/70 for 40 min. The mixture is poured into water and extracted with Et ₂ O. The aqueous phase is acidified with HCl (4M aq. Solution) and extracted with EA. The combined organic phases are dried and concentrated to provide the crude product, which is purified by silica gel flash column chromatography (using a solvent gradient of 100% EA to EA / MeOH = 9/1) to obtain 3 , 6 g of A-21.4. APCI +/-: 365 [M + H] ⁺ ; HPLC (Rt): 1.10 min (Method N).

[0056] Step 2: For A-21.4 (3.60 g, 7.87 mmol) in anhydrous EtOH (36 mL) A-21.5 (0.86 mL,

11.8 mmol). The mixture is heated to reflux overnight, then concentrated. The crude product is purified by flash column chromatography on silica gel. The compound thus obtained is taken up in DCM and washed with NaHCO3 (sat. Solution). The organic phase is dried and concentrated to provide 2.30 g of A-21.6. ES + / -: 395 [M + H] +; HPLC (Rt): 1.23 min (Method P).

[0057] Step 3: For A-21.6 (2.0 g, 5.0 mmol) dissolved in EtOH (25 mL) TEA (1.4 mL, 10 mmol) and palladium on carbon (10%, 0, 20 g, 1.88 mmol). The reaction is stirred overnight under a hydrogen atmosphere (2 bar = 200 kPa). The mixture is filtered through a pad of Celite and concentrated. The residue is dissolved in DCM and washed with citric acid (sat. Aq. Solution). The organic phase is dried and concentrated to obtain 1.4 g of A-21.7. ES + / -: 237 [M + H] +; HPLC (Rt): 0.88 min (Method P).

[0058] Step 4: To a mixture of A-21.7 (0.85 g, 2.52 mmol) in water (5.0 mL) and THF (15 mL) is added LiOH monohydrate (0.32 g, 7 , 60 mmol) and the mixture is stirred

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47/70 at RT overnight. The mixture is concentrated and the aqueous phase is acidified with HCl (4M aq. Solution) and extracted with DCM. The organic phase is dried and concentrated to obtain 0.6 g of A-21. ES + / -: 209 [M + H] ⁺ ; HPLC (Rt): 0.61 min (Method 0).

Alternative route to the A-21:

[0059] Step 1: A mixture of A-21.1 (15.0 g, 81.0 mmol), A-21.8 (11.0 g, 0.16 mol), Cul (0.94 g, 4.90 mmol ) and Cs ₂ CO ₃ (53.0 g, 0.16 mol) in 1,4-dioxane (60 ml) and H ₂ 0 (0.50 ml) is heated to 100 ° C by microwave for 10 min . The mixture is poured into water and extracted with EA. The organic phase is washed with water and the aqueous phase is acidified with HCl (5M aq. Solution) and extracted with EA. The combined organic phases are washed with saline, dried and concentrated to obtain 12 g of a mixture of A-21.9 and A-21.10.

[0060] Step 2: The mixture of A-21.9 and A-21.10 (4.0 g,

6.5 mmol) is dissolved in MeOH (50 mL) and A-21.11 is added dropwise to the mixture cooled to 0 ° C. The reaction is stirred at RT overnight. The mixture is cooled instantly with acetic acid and the product is extracted with EA. The organic phase is washed with water and brine, dried and concentrated. The crude product is purified by preparative HPLC (using a solvent gradient of H ₂ O / CAN with NH4HCO3), to obtain 2.6 g of A-21.12 as a

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43/70 single isomer. ESI-MS: 223 [M + H] ⁺ ; HPLC (Rt): 0.77 min (method P). The hydrolysis of A-21.12 is carried out in analogy with the conversion of A-21.7 to A-21.

2 - (5-Methyl- [1,2,4] oxadiazol-3-yl) -benzoic acid A-22

O

Br

A-22.1 A-22.2 A-22.3 A-22 4 A-22 [0061] Step 1: A mixture of NH ₂ 0H.HC1 (28.6 g, 0.41 mol) and K ₂ CO ₃ (56.9 g, 0.41 mol) in EtOH (500 mL) is stirred at 25 ° C for 30 min. A-22.1 (30.0 g, 0.17 mol) is

added and the reaction mixture is heated to 70 ° C for 12 h. After filtration, the mixture is concentrated and the residue is purified by flash chromatography on a silica gel column (using petroleum ether / EA = 5: 1 to 2: 1) to obtain 25 g of

A-22.2.

[0062] Step 2: To a mixture of A-22.2 (18.0 g, 0.08 mol) in ACN (200 mL) is added acetic anhydride (10.3 g, 0.10 mol) and TEA (16, 9 g, 0.17 mol). The mixture is stirred at 120 ° C for 48 h. The mixture is concentrated in vacuo and the residue is purified by flash chromatography on a silica gel column (using petroleum ether / EA = 1/0 to 10/1), to obtain 9.0 g of A-22.3. ESI-MS: 239/241 [M + H] ⁺ ; HPLC (Rt): 1.43 min (Method Q).

[0063] Step 3: To a mixture of A-22.3 (9.00 g, 0.04 mol) and TEA (11.5 g, 0.11 mol) in MeOH (200 ml) was added Pd (dppf) C1 ₂ * DCM (1.00 g, 1.20 mmol). The mixture is stirred at 50 ° C under an atmosphere of carbon monoxide (50 psi 344.74 kPa) for 16 h. The mixture is concentrated and the

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49/70 residue is purified by flash chromatography on a silica gel column (using petroleum ether / EA = 1/0 to 5/1) to obtain 4.0 g of A-22.4. ESI-MS: 219 [M + H] ⁺ ; HPLC (Rt): 1.28 min (Method Q).

[0064] Step 4: To a mixture of A-22.4 (4.00 g, 0.02 mol) in MeOH (40 ml) and H ₂ 0 (4.0 ml) is added NaOH (1.47 g, 0.04 mol) at 25 ° C under a nitrogen atmosphere. The mixture is stirred at 70 ° C for 4 h and is then concentrated. 0 residue is taken up in H ₂ 0, acidified with HC1 (4M solution aq.) To pH 3 and the precipitate is filtered to give 2.2 g of A-22 as an HC1 salt. ESI-MS: 205 [M + H] ⁺ ; HPLC (Rt): 2.13 min (Method R).

Synthesis of amine intermediates

N- [(2S) -2- (ethylamino) propyl] -5 (trifluormethyl) pyrimidin-2-amine hydrochloride B-1:

[0065] Step 1: A mixture of B-1.11 (5.0 g, 66 mmol), B-1.12 (6.8 mL, 66 mmol) in anhydrous THF (180 mL) is stirred at RT for 1 h. Sodium triacetoxyborohydride (44.6 g, 0.20 mol) is added at 0 ° C and the mixture is stirred at RT

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50/70 for 30 min. B-1.13 (11.0 ml, 0.20 mol) in THF (20 ml) is added dropwise within 10 min at 0 ° C and the mixture is stirred at RT overnight. Additional B-1.13 (10 mL) is added and stirred at RT for 3 h. The precipitate is filtered and washed with THF and DCM. NaHCO3 (sat. Aq. Solution, 200 mL) and solid NaHCO3 are added until the gas formation is complete. The aqueous phase is extracted with DCM, dried and concentrated to provide 12 g of B-1.14. ESI-MS: 194 [M + H] +; HPLC (Rt): 1.13 min (Method E).

[0066] Step 2: To a mixture of B-1.14 (3.47 g, 18.0 mmol) in MeOH (4.9 ml) is added Pd / C (350 mg). The mixture is stirred at RT for 16 h under an atmosphere of hydrogen (3 bar - 300 KPa). The mixture is filtered through a pad of celite and the solvent is evaporated to obtain 2.7 g of B-1.15. ESI-MS: 130 [M + H] +; HPLC (Rt): 0.27 min (Method P).

[0067] Step 3: B-1.15 (3.15 g, 22.6 mmol) and di-tert-butyldicarbonate (5.42 g, 24.8 mmol) are dissolved in THF (100 mL). With stirring DIPEA (10.0 mL, 58.4 mmol) is added in portions and the mixture is stirred at RT for 3 h. The mixture is concentrated and the residue is dissolved in DCM. The mixture is washed with H ₂ O, NaOH (1 N aq.), HCl (1 N aq.) And NaCl (sat. Aq.). The organic phase is dried and concentrated. The crude product is purified by flash column chromatography on silica gel (using a solvent gradient of 100% cyclohexane to 60% cyclohexane and 40% EA) to provide 4.5 g of B1.16. ESI-MS: 204 [M + H] +; HPLC (Rt): 0.92 min (Method P).

[0068] Step 4: To a mixture of B-1.16 (4.50 g, 22.1 mmol), B-1.17 (5.00 g, 34.0 mmol) and PPh ₃ (8.90 g, 33, 9

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51/70 mmol) in dry THF (80 mL) DIAD (6.00 mL, 33.2 mmol) is added dropwise at 0 ° C and under an atmosphere of nitrogen. The mixture is stirred at RT for 16 h. The solvent is concentrated, the residue is treated with H ₂ O and extracted with EA. The organic layer is separated, dried and concentrated. The residue is purified by flash chromatography on a silica gel column (using a 70/30/1 n-hexane / EA / MeOH solvent mixture respectively) to obtain 4.4 g of B-1.18. ESIMS: 333 [M + H] +; HPLC (Rt): 1.25 min (Method P).

[0069] Step 5: MeNH ₂ (33% in EtOH, 20 mL) is added to B-1.18 (1.20 g, 3.61 mmol) in RT. The mixture is stirred for 20 h. Then, cooled in ice-water and the solid is filtered and washed with cold EtOH. The solvent is evaporated and the residue is treated with cold citric acid (10% aq. Solution). The mixture is extracted with EA. The organic layer is separated. The aqueous phase is treated with NH4OH and extracted with EA. The organic layer is separated, dried and concentrated to provide 650 mg of B-1.19. ESI-MS: 203 [M + H] +; HPLC (Rt): 0.65 min (Method P).

[0070] Step 6: To a stirred mixture of B-1.19 (1.88 g, 9.29 mmol) and DIPEA (2.50 mL, 14.6 mmol) in NMP (20 mL) is added at room temperature under an atmosphere of nitrogen B-1.20 (2.20 g, 12.1 mmol). The mixture is stirred in the microwave at 100 ° C for 30 min. The mixture is poured into H2O and extracted with EA. The organic phase is separated, washed with citric acid (10% aq. Solution) and H ₂ O. The organic layer is dried and concentrated. The residue is purified by flash chromatography on a silica gel column (using a solvent mixture of n-hexane / EA 80/20) to obtain 2.7 g of B-1.21. ESI-MS: 349 [M + H] ⁺ ; HPLC (Rt): 1.34 min (Method

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52/70

Ρ) · [0071] Step 7: HCl (4 M in dioxane, 40 mL) is added to a stirred mixture of B-1.21 (5.50 g, 15.8 mmol) in dioxane (10 mL) at RT and at mixture is stirred for 2h. The solvent is evaporated. The residue is treated with EA and the solid is filtered to provide 3.5 g of Bl. ESI-MS: 249 [M + H] ⁺ ; HPLC (Rt): 0.63 min (Method P).

N - [(2S) -2- (ethylamino) propyl] -5 (trifluormethyl) pyrazin-2-amine hydrochloride B-2:

[0072] Step 1: To a stirred mixture of B-1.8 (1.00 g,

4.90 mmol) and DIPEA (1.4 mL, 8.0 mmol) in NMP (8.0 mL) is added at room temperature under an atmosphere of nitrogen, Bl.9 (0.8 mL, 6.4 mmol ). The reaction is heated to 100 ° C in a microwave for 30 min. The reaction is poured into water and extracted with EA. The organic layer is separated, washed with citric acid (10% aq. Solution) and water. The organic layer is dried and concentrated. The residue is purified by flash chromatography on a silica gel column (using CH / EA 80/20 as eluent). After evaporation 1.0 g of Bl. 10 is obtained. ES +/-: 349 [M + H] ⁺ ; HPLC (Rt): 1.36 min (Method P).

[0073] Step 2: HCl (4 M in dioxane, 20 mL) is added to a mixture of Bl. 10 (1.50 g, 4.30 mmol) in dioxane (5.0 mL) at 0 ° C and then stirred at RT overnight. The solvent is removed and the residue is treated with Et ₂ O

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53/70 to provide 830 mg of B-1. ES +/-: 249 [M + H] +; HPLC (Rt): 0.67 min (Method P).

N - [(2S) -2 (ethylamino) propyl] carbamate tert-butyl hydrochloride B-3

[0074] Step 1: Di-tert-butyldicarbonate (1.50 g, 6.87 mmol) in THF (10 mL) is added dropwise to a stirred mixture of B-3.1 (1.32 g, 6.86 mmol) in THF (20 mL) at RT. After 16h, the solvent is evaporated and the residue is purified by flash chromatography on a silica gel column (using a solvent mixture of n-hexane / EA / MeOH 80/20/1), to obtain

1.7 g of B-3.2. ES +/-: 293 [M + H] ⁺ ; HPLC (Rt): 1.31 min (Method P).

[0075] Step 2: B-3.2 (900 mg, 3.08 mmol) is dissolved in MeOH (50 mL). Pd / C (120 mg, 0.11 mmol) is added and the mixture is stirred under an atmosphere of hydrogen (3 bar = 300 kPa) overnight. The mixture is filtered through celite and the solution is concentrated to provide 500 mg of B-3. ES +/-: 203 [Μ + H] ⁺ ; HPLC (Rt): 0.58 min (Method P).

N- [(2S) -1-aminopropan-2-yl] -W-ethyl-3-fluor-2 (pyrimidin-2-yl) benzamide C-1:

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54/70

C-1.3 C-1.4

C-1.4

C-1.7 C-1.6

F

C-1.9

C-1 [0076] Step 1: A mixture of C-1.2 (10 g, 67 mmol) in

DCM (30 ml) is added dropwise to a stirred mixture of Cl.l (5.0 g, 67 mmol) and TEA (19.0 ml, 0.13 mol) in DCM (70 ml). The mixture is stirred at RT overnight, then NH ₄ C1 (sat. Aq. Solution) is added and the aqueous phase is extracted with DCM. The organic phase is dried and concentrated to provide 10 g of C-1.3. ESI-MS: 189 [M + H] ⁺ ; HPLC (Rt): 0.84 min (Method P).

[0077] Step 2: To a mixture of A-9 (2.49 g, 11.4 mmol) in dry DMF (40 mL) under a nitrogen atmosphere is added DIPEA (5.8 mL, 34 mmol) and HATU (5.7 g, 15 mmol) and the mixture is stirred for 10 min. C-1.3 is added (2.4 g, 13 mmol) and the mixture is stirred at RT for 16 h. The mixture is treated with water and the aqueous phase was extracted with EA. The organic phase is separated, washed with NaHCO ₃ (sat. Aq. Solution) and citric acid (5% aq. Solution), dried and concentrated. The residue is purified by flash chromatography

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55/70 column on silica gel (using n-hexane / EA 50/50) to obtain 2.7 g of C-1.4. ESI-MS: 389 [M + H] +; HPLC (Rt):

1.30 min (Method P).

[0078] Step 3: NaH (330 mg, 60% suspension in mineral oil, 8.24 mmol) is added to a stirred mixture of C-1.4 (2.14 g, 5.49 mmol) and C-1.5 ( 883 pL, 11.0 mmol) in dry DMF (3 mL) at 0 ° C under a nitrogen atmosphere. The mixture is stirred at 0 ° C for 2h. Water is added and the aqueous phase was extracted with Et ₂ O. The organic layer is dried and concentrated to obtain 2.3 g of C-1.6. ESI-MS: 418 [M + H] ⁺ ; HPLC (Rt): 1.50 min (Method P).

[007 9] Step 4: TBAF (765 mg, 0.86 mL, 0.86 mmol) is added to a stirred mixture of C-1.6 (200 mg, 0.43 mmol) in THF (5.0 mL), under stirring at 0 ° C. The mixture is stirred at 0 ° C for 30 min, concentrated and the residue purified by flash column chromatography on silica gel (using a solvent gradient of 100% DCM to 97% DCM / 3% MeOH) to obtain 130 mg of C-1.7. ESI-MS: 304 [M + H] ⁺ ; HPLC (Rt): 0.68 min (Method P).

[0080] Step 5: methanesulfonyl chloride (30.0 pL, 0.39 mmol) is added to a stirred mixture of C-1.7 (100 mg, 0.33 mmol) and DIPEA (70.0 pL, 0.41 mmol) in dry DCM at 10 ° C. After 2 hours, the reaction is treated with water. The organic phase is separated, dried and concentrated under reduced pressure without heating. To the residue are added C-1.8 (70.0 mg, 0.38 mmol) and DMF at room temperature with stirring. After 1 h, the reaction is poured into water and extracted with EA. The organic layer is separated, dried and concentrated. The residue is purified by flash column chromatography on silica gel (using n-hexane / EA / MeOH 50/50/1), to obtain 75 mg

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50/70 of C-1.9. ESI-MS: 433 [Μ + H] ⁺ ; HPLC (Rt): 3.71 min (Method

N).

[0081] Step 6: N ₂ H ₄ xH ₂ 0 (30.0 pL, 0.60 mmol) is added to a mixture of C-1.9 (60.0 mg, 0.14 mmol) in

EtOH (3.0 mL) at RT. The mixture is stirred for 20 h. The mixture is poured into ice-water and the solid is filtered and washed with cold EtOH. The solvent is evaporated and the residue is treated with cold citric acid (10% aq. Solution). The mixture is extracted with EA. The organic phase is separated, the aqueous phase is treated with NH ₄ 0H and extracted with EA. The organic layer is separated, dried and concentrated to obtain 30 mg of Cl. ES +/-: 303 [Μ + H] ⁺ ; HPLC (Rt): 0.58 min (Method P).

Alternative route to C-l from C-l.7

[0082] Step 1: To a stirred mixture of C-l.7 (100 mg,

0.33 mmol) and DBU (100 pL, 0.67 mmol) in dry THF (4.0 mL) in RT under a nitrogen atmosphere Cl.10 (90.0 pL, 0.42 mmol) is added. After 16 h, the mixture is concentrated and the residue is purified by flash column chromatography on silica gel (using n-hexane / EA / MeOH 80/20/1), to obtain 80 mg of Cl-11. ESI-MS: 329 [Μ + H] ⁺ ; HPLC (Rt): 0.94 min (Method P).

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57/70 [0083] Step 2: PPh ₃ (160 mg, 0.61 mmol) is added to a stirred mixture of Cl.ll (80.0 mg, 0.24 mmol) in THF (5.0 mL) and water (0.24 mL) at RT under a nitrogen atmosphere. After 16 h, the mixture is concentrated and the residue is treated with HCl (1M aq. Solution) and the aqueous phase is washed with EA. The aqueous phase is treated with NH ₄ 0H (aq. Solution) until pH 10-11 and extracted with DCM. The organic layer is separated, dried and concentrated to provide 65 mg of ΟΙ. ES +/-: 303 [M + H] ⁺ ; HPLC (Rt): 0.58 min (Method P).

N- [(2S) -1-aminopropan-2-yl] -N-ethyl-3-fluor-2- (2H-1,2,3triazole-2-i1) benzamide C-2:

O

C-2 C-2.4 [0084] Step 1: To a mixture of B-1.14 (10.0 g, 0.05 mol) and C-2.1 (7.60 g, 0.05 mol) in THF (150 mL ) PPh ₃ (13.6 g, 0.05 mol) is added. Then, DIAD (8.80 g, 0.05 mol) is added dropwise at 0 ° C. The mixture is stirred at RT for 12 h. The reaction mixture is concentrated and the residue is purified by flash chromatography on a silica gel column (using petroleum ether / EA 20/1 to 10/1) to obtain 10 g of C-2.2.

[0085] Step 2: To a mixture of C-2.2 (2.00 g, 0.01

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58/70 mol) in MeOH (30 ml) Pd / C (1.0 g) is added. The mixture is stirred at 20 ° C for 12 h under an atmosphere of hydrogen (50 psi = 344.74 KPa). The mixture is filtered and the filtrate is concentrated to obtain 800 mg of C-2.3.

[0086] Step 3: To a mixture of C-2.3 (2.50 g, 9.30 mmol) in dry ACN (50 mL) is added A-2 (2.30 g, 11.0 mmol), DIPEA ( 4.8 ml, 28 mmol) and CIP (3.1 g, 11 mmol) and the mixture is stirred at RT for 2 h. Another portion of A-2 (200 mg) and CIP (500 mg) is added and the reaction is stirred for an additional 2 h. Then, another portion of DIPEA (1.5 mL) and CIP (300 mg) is added and the reaction is stirred for 2 h. Water (70 ml) is added to the reaction mixture and is stirred for 1 h. The precipitate is filtered and dried. The mother liquor is extracted with EA, dried and concentrated. The residue is purified by prep. (using a solvent gradient of H2O / ACN with NH4OH) and combined with the dry solid to produce 3.4 g of C-2.4. ESI pos. + Business (Loop-Inj.) [M + H] +: 422; HPLC (Rt): 0.97 min (Method G).

[0087] Step 5: To a mixture of C-2.4 (3.4 g, 8.0 mmol) in EtOH (100 mL) is added to RT N2H4xH2O (1.2 mL, 20 mmol) and the reaction is stirred for at night. Another portion of N2H4xH2O (0.50 mL) is added and the reaction is stirred at 60 ° C for 2 h. The solid is filtered. The solvent is evaporated and the residue is dissolved in EA and extracted with HCl (1 M aq. Solution). The acidic aqueous layer is washed with EA, then the pH is adjusted with NH ₄ OH (25% aq. Solution) until pH = 10. The aqueous phase is extracted with EA, dried and concentrated to obtain 2.1 g of C-2. ESI pos. + Business (LoopInj.) [M + H] ⁺ : 292 [M + H] +; HPLC (Rt): 0.70 min (Method

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U).

Amides

N-Ethyl-2-fluor-6-iodo-N- [(S) -l-methyl-2- (5trifluormethyl-pyridin-2-yloxy) -ethyl] -benzamide D-l

[0088] Dl.l (150 mg, 0.56 mmol) is dissolved in dry DCM (3.0 ml). With stirring oxalyl chloride (846 mg, 1.13 mmol) and a drop of DMF are added and the mixture is stirred for 2 h. The mixture is concentrated and the residue is taken up in dry DCM (3.0 ml). The resulting mixture is added dropwise to a mixture of Bl (145 mg, 0.51 mmol) and DIPEA (390 µL, 2.30 mmol) in DCM (4.0 mL) at 0 ° C. The cold bath is removed and the mixture is stirred for 2 h. The crude product is diluted with DCM and washed with NH ₄ C1 (sat. Solution), KHCO ₃ (aq. Solution) and water. The organic phase is dried and concentrated. The residue is purified by flash column chromatography (using a solvent gradient of 100% cyclohexane to cyclohexane / EA 65/35) to obtain 160 mg of compound D1. ESI-MS: 497 [M + H] ⁺ ; HPLC (Rt): 1.21 min (Method P).

Preparation of the compounds of the present invention

Example 1:

[0089] CIP (76 mg, 0.27 mmol) is added to a

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60/70 stirred mixture of A-1 (48 mg, 0.25 mmol), B-1 (60 mg, 0.21 mmol) and DIPEA (109 μΏ, 0.63 mmol) in dry ACN (2.0 mL ) to RT. After 16 h, the reaction is treated with ACN / water and purified by preparative LCMS (using a H2O / ACN solvent gradient with NH4OH) to obtain 50 mg of the compound of Example 1. MS-ESI: 420 [M + Na] +; HPLC (Rt): 1.02 min (Method G).

[0090] The following examples are prepared in analogy to the process described above using the corresponding acid (see Acid Intermediates) and amine (see Amine Intermediates), as described above. For Example 4, isolation and purification are adapted: The crude product is concentrated and the residue is taken up in EA and washed with citric acid (10% aq. Solution), Na2CO3 (sat. Aq. Solution) and water, dried and focused. The residue is purified by flash column chromatography on silica gel (cyclohexane using cyclohexane / EA 4/6).

[0091] For some examples, the reaction times are adapted: 4h for Example 7; 1h for Example 9; 2 h at 60 ° C for Example 16:

Example Structure ESI-MS [M + H] + HPLC (Rt) [min] Method HPLC N _{x X} N NO. I II H 2 438 0.83 s

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Example Structure ESI-MS [M + H] + HPLC (Rt) [min] Method HPLC 4 FF N _{x X} N NO. R / LXX / N _{x /} N _{x F} ^^^ X ^N ^ X ^ ^F 456 3.19 H 5 N FF X / N NO. XF \ / N. / N. kk k ⁿ F F k 438 1.02 G 8 N FF X / N NO. / L A. xX / ^ / N. 1 NX XX X n ^ X ^ / F ΐ ^{f / f} N 445 0.77 s 9 N FF < _X N NO. zX / X xX / ^ / N. 1 N ^ || ⁿ k ⁿ F cn ₃ k 435 1.04 G 10 FF N _{x X} N NO. xXxX X \ / N. .N. k ^N <F k 439 0.71 s

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Example Structure ESI-MS [M + H] + HPLC (Rt) [min] Method HPLC 12 N 0. χΥ / Y Y. / H. _Z N _X i Y ^ n Y Y> NYN ^ Y ^ F 1 kF 434 0.81 s 20 M k ⁿ ^ v ^{f F} F 431 0.79 s 21 ⁰ | _H Y> NYN ^ Y ^ F ^F F 431 1.02 G

Example Structure ESI pos. + Business (LoopInj.) [M + H] + HPLC (Rt) Method HPLC / ΓΛ N _{x X} N N 0 I H 7 <Ύ N ^NN 438 1.07 G T k ^N - Y fF

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[0092] Α-4 (61 mg, 0.27 mmol) is dissolved in dry DMF (2 ml). HATU (112 mg, 0.30 mmol) and DIPEA (127 pL, 0.74 mmol) are added and the mixture is stirred for 10 min. Then, Bl (70 mg, 0.25 mmol) is added and the reaction is stirred at RT for 3 h. The mixture is purified by preparative LCMS (using a solvent gradient of H ₂ O / ACN with NH 4 OH). After concentration, the residue is extracted with DCM. The organic phase is dried and concentrated to provide 70 mg of the compound of Example 3. MS-ESI: 454 [M + Na] ⁺ ; HPLC (Rt): 3.52 min (Method H).

[0093] The following examples are prepared in analogy to the process described above using the corresponding acid (see Acid Intermediates) and amine (see Amine Intermediates), as described above, adjusting the reaction time: overnight to Example 14, 19:

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^F Α-18

Cl — Η

Β-1

ΓΊ \

[0094] Α-18 (640 mg, 2.8 mmol), Β-1 (809 mg, 2.84 mmol), CIP (1.0 g, 3.7 mmol) and DIPEA (1.5 mL, 8 , 5 mmol) are mixed in dry ACN (3 mL) and the mixture is stirred at RT overnight. The mixture is concentrated and the residue is taken up with EA and washed with citric acid (10% aq. Solution), Na ₂ CO ₃ (aq. Solution) and with brine, dried and concentrated. The residue is purified by flash column chromatography on silica gel (using a cyclohexane to cyclohexane / EA 2/3 solvent gradient) to obtain 802 mg of Example 6. MS-ESI: 456 [M + Na] ⁺ ; HPLC (Rt): 4.40 min

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65/50 (Method N).

Example 11:

F

F [0095] To a stirred mixture of C-1 (1.0 g, 3.3 mmol) in NMP (15 mL), 11.1 (700 mg, 3.8 mmol) and DIPEA (0.70 mL,

4.1 mmol) are added at room temperature under a nitrogen atmosphere. The reaction is heated to 100 ° C for 1 h. After cooling, the reaction is poured into water and extracted with EA. The organic layer is separated, washed with citric acid (10% aq. Solution), dried and concentrated. The residue is purified by flash column chromatography on silica gel (using DCM / MeOH 97/3 as eluant) to obtain 1.3 g of Example 11. ESI-MS: 471 [M + Na] ⁺ ; HPLC (Rt): 3.16 min (Method H).

Example 13:

Example 13 [0096] To a mixture of Dl (160 mg, 0.29 mmol), Cul (2.80 mg, 0.01 mmol), Pd (PPh ₃ ) ₄ (17 mg, 0.01 mmol) and CsF (66 mg, 0.44 mmol) in dry DME (2.0 mL), under a nitrogen atmosphere 13.1 (92 pL, 0.29 mmol) is added. The reaction is heated to 120 ° C by microwave for 2 h. Then, at 130 ° C for 30 min. After cooling, the

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00/70 mixture is poured into water and extracted with Et ₂ O (2x). The organic layer is dried and concentrated to obtain the crude product, which is purified by means of preparative LCMS (using a solvent gradient of H ₂ O / ACN with NH ₄ OH) to obtain 28 mg of Example 13. ESI-MS : 471 [M + Na] ⁺ ; HPLC (Rt): 3.54 min (Method H).

Example 15:

[0097] Step 1: 15.1 (1.50 g, 5.64 mmol) is dissolved in DCM (8.3 mL). Then, oxalyl chloride (5.6 ml, 11.3 mmol) is added followed by a drop of DMF and the mixture is stirred at RT for 1 h. The solvent is removed under reduced pressure. The residue is mixed with DCM (8 ml) and added at 0 ° C, to a mixture of B-3 (1.04 g, 5.13 mmol) and DIPEA (3.9 ml, 22.6 mmol) in DCM (8 mL). The mixture is stirred for 12 h at 20 ° C. Water is added and the organic layer is washed with NH ₄ C1 (sat. Aq. Solution), KHCO ₃ (sat. Aq. Solution) and water. The organic phase is dried and concentrated. The residue is purified by flash column chromatography (using a 100% solvent gradient

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67/70 cyclohexane to cyclohexane / EA 8/2) to obtain 0.91 g of 15.2. ESI-MS: 451 [M + H] +; HPLC (Rt): 1.17 min (Method

P).

[0098] Step 2: 15.2 (914 mg, 1.93 mmol), 15.3 (980 pL,

3.0 9 mmol), CuI (36.7 mg, 0.19 mmol) CsF (589 mg, 3.88 mmol) and Pd (PPh ₃ ) ₄ are dissolved in dry DMF (7.0 mL) and the mixture is stirred in a microwave at 130 ° C for 15 min. water is added and the product is extracted with EA. The organic phase is dried and concentrated. The crude product is purified by flash column chromatography on silica gel (using a gradient solvent of cyclohexane / EA 30/70 to 100% EA) to obtain 477 mg of 15.4. ESI-MS: 403 [M + H] +; HPLC (Rt): 1.02 min (Method P).

[0099] Step 3: To a mixture of 15.4 (477 mg, 1.19 mmol) in MeOH (6.0 mL) HCl (4 M aq. Solution, 7.41 mL, 2 9.6 mmol) is added at 0 ° C. The mixture is stirred at RT for 1 h. The solvent is evaporated and the residue is purified by HPLC-MS prep. (using a H ₂ O / ACN solvent gradient with NH ₄ OH) to obtain 333 mg of 15.5. ESI-MS: 303 [M + H] +; HPLC (Rt): 2.98 min (Method N).

[00100] Step 4: To a mixture of 15.5 (45.0 mg, 0.15 mmol) in dry DMF (1.0 mL), DIPEA (77.3 pL, 0.45 mmol) is added. After 20 min, 15.6 (32.6 mg, 0.18 mmol) is added and the mixture is stirred at 70 ° C for 1.5 h. EA is added and the organic layer is washed with water, dried and concentrated. The residue is purified by flash chromatography on a silica gel column (using a 10/90 cyclohexane / EA solvent mixture) to obtain 34 mg of Example 15. ESIMS: 471 [M + Na] ⁺ ; HPLC (Rt): 3.21 min (Method H).

Example 17:

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Example 17 [00101] To a mixture of A-14 (135 mg, 0.63 mmol), Bl (150 mg, 0.53 mmol) and DIPEA (273 pL, 1.60 mmol) in dry ACN (2.0 ml) CIP (191 mg, 0.68 mmol) is added and the mixture is stirred at room temperature for 2 days. ACN / H ₂ O is added and the mixture is purified by prep HPLC. HPLC-MS (using a solvent gradient of H ₂ O / ACN with NH ₄ OH) to provide 133 mg of Example 17. ESI-MS: 445 [M + Na] ⁺ ; HPLC (Rt): 1.04 min (Method G).

Example 18:

A-2 B-1

[00102] Thionyl chloride (0.28 mL, 3.86 mmol) is added to a stirred mixture of A-2 (800 mg, 3.86 mmol) in toluene (6.0 mL). A drop of DMF is added and the mixture is heated to 60 ° C for 2 h. The solvent is evaporated. The residue is dissolved in dry DCM (10 ml) and then a mixture of Bl (1.00 g, 3.50 mmol) and TEA (1.5 ml, 11 mmol) in DCM is added dropwise to 0 ° C. The reaction mixture is heated to RT. Water is added and the organic layer is dried and concentrated. The crude product is purified by flash chromatography on a silica gel column (using a solvent mixture of ethyl acetate / nhexane / MeOH 90/10/1), to obtain 1.2 g of Example 18. ESIPetition 870160043843, from 15/08 / 2016, p. 72/81

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MS: 438 [Μ + Na] ⁺ ; HPLC (Rt): 4.32 min (Method T).

Example 22:

[00103] CIP (55 mg, 0.20 mmol) is added to a stirred mixture of Al (40 mg, 0.14 mmol), B-2 (35 mg, 0.19 mmol) and DIPEA (80 pL, 0 , 47 mmol) in dry DMA (2.0 mL) at RT. After 16 h, the reaction is treated with water and extracted with EA. The organic layer is separated and washed with NaHCO ₃ (5% aq. Solution). The organic layer is separated, dried and concentrated. The residue is purified by flash column chromatography on silica gel (using DCM / MeOH 100/2 as eluant) to obtain 35 mg of Example 22. ES +/-: 420 [M + H] ⁺ ; HPLC (Rt): 4.28 min (Method N).

[00104] The following examples are prepared in analogy to the process described above using the corresponding acid (see Acid Intermediates) and amine (see Amine Intermediates), as described above.

Example Structure ESI-MS [M + H] ⁺ HPLC (Rt) [min] Method HPLC 23 H, C Οχ /> N γ 0 CH, II 1 H 453 3.26 H \ / F N / 1 ^F F

Example 24:

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[00105] To a mixture of C-2 (30.0 mg, 0.08 mmol) and

DIPEA (35.0 pL, 0.21 mmol) in DMF (4.0 mL) is added 24.1 (18.0 mg, 0.10 mmol) under an atmosphere of nitrogen. The reaction mixture is heated in a microwave at 90 ° C for 30 min. After cooling the reaction mixture, water is added and the mixture is extracted with DCM, the combined organic phases are washed with NH ₄ C1 (sat. Aq. Solution), dried and concentrated. The crude product is purified by means of preparative LCMS (using a solvent gradient of H ₂ O / ACN with HCOOH) to obtain 10 mg of Example 24. ESI-MS: 438 [M + H] ⁺ ; HPLC (Rt): 4.42 min (Method N).

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1/6

Claims (6)

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