EA043969B1 - SUBSTITUTED XANTHINE DERIVATIVES - Google Patents

Description

Field of technology to which the invention relates

The present invention relates to substituted xanthine derivatives, pharmaceutical compositions containing them, and their use for therapy, especially for the treatment or prevention of conditions associated with TRPC5-containing ion channels.

Prerequisites for creating the invention

There are many ion channel proteins that mediate ion flow across cell membranes. Proper expression and function of ion channel proteins is essential for maintaining cellular function and intracellular communication. Numerous diseases result from improper regulation of membrane potential or improper calcium transport. Given the central importance of ion channels in modulating membrane potential and ion flux in cells, the identification of agents that can stimulate or inhibit specific ion channels is of great interest as research tools and as possible therapeutic agents.

Cation channels, such as transient receptor potential (TRP) cation channel subfamily C member 5 (TRPC5), modulate the flux of calcium and sodium ions across cell membranes. The influx of sodium and calcium leads to cell depolarization. This increases the likelihood that voltage-gated ion channels will reach the threshold required for activation. As a result, activation of nonselective cation channels can increase electrical excitability and increase the frequency of voltage-gated events. Voltage-gated events include, but are not limited to, neuronal action potentials, cardiac action potentials, smooth muscle contraction, cardiac muscle contraction, and skeletal muscle contraction.

Calcium influx caused by activation of nonselective cation channels such as TRPC5 also alters the concentration of free intracellular calcium. Calcium is a ubiquitous second messenger within the cell, and changes in intracellular calcium levels have profound effects on signal transduction and gene expression. Thus, activation of nonselective cation channels such as TRPC5 can lead to changes in gene expression and cellular phenotype. Gene expression events include, but are not limited to, the production of mRNAs encoding cell surface receptors, ion channels, and kinases. These changes in gene expression can lead to increased excitability in that cell.

Homomeric TRPC5 ion channels are signal transduction-gated Ca ²⁺ -permeable channels that are predominantly expressed in neurons. TRPC5 forms homomultimeric structures such as tetramers (i.e., TRPC5 homomultimers) and heteromultimeric structures such as tetramers (i.e., TRPC5-TRPC1 heteromultimers). Unless explicitly stated otherwise, when the term TRPC5 is used herein, for example, when identifying a TRPC5 modulator such as a TRPC5 antagonist, the term TRPC5 is used in a general sense to include either one or both of a TRPC5 homomultimer or heteromultimer (e.g., TRPC5-TPRC1 heteromultimer or TRPC5-TRPC4). Examples of TRPC5 in the literature include the following: Nature 2008 Jan. 3; 451 (7174):6972; Mol Pharmacol. 2008 Jan; 73 (1):42-9; J Biol Chem. 2007 Nov. 16; 282(46):33868-78; Biochem Biophys Res Commun. 2008 Jan. eleven; 365 (2):239-45; J Biol Chem. 2006 Nov. 3; 281(44):33487-96; Eur J Pharmacol. 2005 Mar. 14; 510(3):217-22; J Biol Chem. 2006 Feb. 24; 281 (8):4977-82; Biochem Soc Trans. February 2007; 35 (Pt.l):101-4; Handb Exp Pharmacol. 2007; (179):109-23; J Biol Chem. 2005 Mar. 25; 280 (12): 109971006; J Physiol. 2006 Jan. 15; 570(Pt 2):219-35; and Nat Neurosci. (2003) 6:837-45.

Modulation of the function of TRPC5 proteins provides a means of modulating calcium homeostasis, sodium homeostasis, membrane polarization, and/or intracellular calcium levels, and compounds that can modulate TRPC5 function are useful in many aspects, including, but not limited to, maintaining calcium homeostasis, modulating levels intracellular calcium, modulation of membrane polarization and treatment or prevention of diseases, disorders or conditions associated with calcium and/or sodium homeostasis or dyshomeostasis.

Compounds that inhibit TRPC5-containing ion channels are useful, for example, for treating conditions such as neuropsychiatric disorder, neurodegenerative disorder, nephropathy and epilepsy by modulating the activity of the transient receptor potential subfamily C member 5 (TRPC5) cation channel that may exist in homomultimeric form, as well as in heteromultimeric form with other ion channels such as TRPC1 or TRPC3 (i.e. TRPC5-TRPC1 and TRPC1-TRPC3-TRPC5). WO 2014/143799 discloses xanthine derivatives that inhibit TRPC5. They modulate TRPC5 function by inhibiting TRPC5-mediated ion flow or by inhibiting TRPC5-mediated inward current, outward current, or both.

- 1 043969

Detailed Description of the Invention

The present invention provides new substituted xanthine derivatives of formula I

R ³

I in which R ¹ represents ethyl, isopropyl, isobutyl, cyclobutyl; R ² represents

R ³ represents hydrogen, fluorine, C ₁ -C ₃ alkyl, optionally substituted with one or more fluorine atoms;

R ⁴ represents hydrogen or fluorine;

R ⁵ represents

- 2 043969 or their physiologically acceptable salts.

In another embodiment, compounds of general formula I are provided, wherein

R ¹ represents ethyl, isopropyl, isobutyl, cyclobutyl;

R ² represents

R ³ represents hydrogen, fluorine, methyl, ethyl, -CF ₃ ;

R ⁴ represents hydrogen or fluorine;

R ⁵ represents

or physiologically acceptable salts thereof.

The compounds of the present invention are potent TRPC5 inhibitors. They differ from the structurally most closely related compounds disclosed in WO 2014/143799 in that the C8 position of the xanthine in the compounds of the present invention is replaced by a 3-pyridyl group rather than a phenyl group.

The compounds of the present invention modulate TRPC5 function by inhibiting TRPC5-mediated ion flow or by inhibiting TRPC5-mediated inward current, outward current, or both. They, in comparison with connections of the nearest prior art in WO

- 3 043969

2014/143799, are characterized by higher activity in relation to TRPC5 inhibition.

Thus, the present invention provides compounds for use in the treatment of a TRPC5-mediated disorder.

Moreover, the present invention provides methods for treating a TRPC5-mediated disorder in a human subject, comprising administering to the subject a compound or composition of a compound of the present invention or a pharmaceutically acceptable salt thereof.

In one aspect, the invention provides a method of treating a condition in which reduced TRPC5 activity may reduce the severity of the condition by administering a TRPC5 antagonist, such as a compound as described herein, that inhibits TRPC5-mediated current and/or TRPC5-mediated ion flow . Disclosed herein are compounds that are TRPC5 antagonists having a measured IC ₅₀ for TRPC5 inhibition of 5 nmol/L or less. In certain embodiments, compounds described herein that are TRPC5 antagonists inhibit one or both of the influent and effluent TRPC5-mediated currents with an IC ₅₀ value of 5 nmol/L or less. In certain embodiments, the compounds described herein inhibit at least 95% of TRPC5-mediated current or TRPC5-mediated ion flow when administered at a concentration of 1 micromol/L or less.

In another aspect, compounds described herein that are TRPC5 antagonists can be used to inhibit TRPC5 function, eg, TRPC5-mediated current and/or TRPC5-mediated ion flow. In some embodiments, the compounds described herein can be used to inhibit TRPC5-mediated current in vitro, for example, in cells in culture. In other embodiments, the compounds described herein can be used to inhibit TRPC5-mediated current in vivo. In certain embodiments, the compounds described herein inhibit both inward and outward TRPC5-mediated current.

Definitions

Terms not specifically defined in the present invention are to be given the meanings given to them by one skilled in the art in light of the disclosure and context.

The terms antagonist and inhibitor are used interchangeably to refer to an agent that reduces or inhibits a biological activity, for example, inhibits the activity of an ion channel such as TRPC5. The TRPC5 ion channels described in the present invention include homomultimeric and heteromultimeric structures (eg, homomultimeric TRPC5 and heteromeric TRPC5-TRPC1 or TRPC5-TRPC4). TRPC5 antagonists include inhibitors having any combination of structural and/or functional properties disclosed in the present invention.

An effective amount of, for example, a TRPC5 antagonist, with respect to methods of inhibition or treatment, refers to the amount of antagonist in a formulation that, when administered as part of a desired dosage regimen, results in the desired clinical or functional outcome. Without being limited by any theory, an effective amount of a TRPC5 antagonist for use in the methods of the present invention includes an amount of a TRPC5 antagonist effective to attenuate one or more TRPC5 channel functions in vitro or in vivo. Typical functions include, but are not limited to, membrane polarization (eg, an antagonist can stimulate cell hyperpolarization), ion flux, cell ion concentration, outward current, and inward current. Compounds that antagonize TRPC5 function include compounds that antagonize the functional activity of TRPC5 in vitro or in vivo. When a particular functional activity is observed exceptionally readily in an in vitro assay, then the ability of a compound to inhibit TRPC5 function in that in vitro assay serves as reasonable evidence of the activity of that compound. In certain embodiments, an effective amount is an amount sufficient to inhibit TRPC5-mediated current and/or an amount sufficient to inhibit TRPC5-mediated ion flow.

TRPC5 antagonists for use in the methods of the present invention can be characterized according to their activity or lack of activity on one or more other ion channels. When other ion channels are mentioned, inhibition of the function of such other ion channels is defined in a similar manner. For example, inhibition of an ion channel or ion channel activity means that the antagonist inhibits one or more functional activities of another ion channel. Such functions include specific ion channel-mediated current, ion flux, or membrane polarization.

The terms compound and agent are used interchangeably to refer to the inhibitors/antagonists of the invention.

The compounds described in the present invention may be asymmetric (eg, having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended to be covered by the claimed invention unless otherwise stated. The compounds of the present invention, which contain asymmetrically substituted carbon atoms, can be isolated in op.

- 4 043969 biologically active or racemic form. Methods by which optically active forms are prepared from optically active starting materials are known in the art, such as the resolution of racemic mixtures or stereoselective synthesis.

Separation of racemic mixtures of compounds can be accomplished by any of numerous methods known in the art. An example method involves fractional recrystallization using a chiral resolving acid, which is an optically active salt-forming organic acid. Suitable resolving agents for fractional recrystallization methods are, for example, optically active acids such as the D- and L-forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or various optically active camphorsulfonic acids such as β camphorsulfonic acid acid. Other resolving agents suitable for fractional crystallization methods include stereoisomerically pure forms of α-methylbenzylamine (e.g., S- and R-forms, or diastereomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine and 1,2 -diaminocyclohexane.

Separation of racemic mixtures can also be accomplished by eluting on a column packed with an optically active resolving agent (eg dinitrobenzoylphenylglycine). A suitable composition of the elution solvent can be determined by one skilled in the art. The compounds of the invention also include tautomeric forms, such as keto-enol tautomers.

Unless specifically stated otherwise, throughout the specification and appended claims, this chemical formula or title is intended to include tautomers and all stereo, optical and geometric isomers (e.g., enantiomers, diastereoisomers, E/Z isomers) and racemates thereof, as well as mixtures in varying proportions of individual enantiomers, a mixture of diastereoisomers, or a mixture of any of the above forms, where such isomers and enantiomers exist.

The compounds of the invention may also include all isotopes of atoms found in intermediate compounds or final compounds. For example, a compound of the invention may be labeled with radioactive isotopes such as, for example, tritium ( ^3H ) or carbon-14 ( ^14C ). It is intended that all isotopic variants, radioactive or not, are within the scope of the present invention.

As used herein, the expression pharmaceutically acceptable salts refers to derivatives of the disclosed compounds where the parent compound forms a salt with an acid or base.

Examples of acids forming a pharmaceutically acceptable salt with the parent compound containing the basic moiety include mineral or organic acids 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, 4methylbenzenesulfonic acid, phosphoric acid, salicylic acid, succinic acid, sulfuric acid or tartaric acid. Also included are salts of amino acids, such as arginate, and salts of organic acids, such as glucuronic or galacturonic acids (see, for example, Berge et al., Pharmaceutical Salts, Journal of Pharmaceutical Science, 1977, 66, 1-19).

Examples of cations and bases that form a pharmaceutically acceptable salt with the parent compound containing an acid moiety include Na ⁺ , K ⁺ , Ca ²⁺ , Mg ²⁺ , NH ₄ ⁺ , L-arginine, 2,2'iminobisathanol, L-lysine, N-methyl-D-glucamine or tris(hydroxymethyl)-aminomethane.

Neutral forms of the compound of the invention are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the usual manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but in other respects the salts are equivalent to the parent form for purposes of the present invention

The terms TRPC5, TRPC5 protein, and TRPC5 channel are used interchangeably throughout the application. Unless expressly stated otherwise, the term TRPC5 includes homomultimeric structures (eg, homomultimeric TRPC5) and heteromultimeric structures (eg, heteromultimeric TRPC5-TRPC1).

Biological tests

The biological activity of the compounds was determined using the following methods.

Assay A: Determination of TRPC5 inhibition.

Patch clamp experiments provide the opportunity to record currents flowing through the TRPC5 channel in a cell line. In normal voltage clamp recordings on a whole cell, a glass electrode is brought into contact with an individual cell and a high resistance (gigaohm) region of the cell membrane is created. The membrane is then pierced to achieve a whole cell configuration, which makes it possible to monitor the voltage across the cell membrane and measure the currents flowing through the membrane using an amplifier attached to the electrode, resulting in

- 5 043969 less cytoplasm with a solution from a pipette. The perfusion system allows control of the extracellular solution, including the addition of blockers and current activators. The current can be activated by adding 1.4 µM free Ca ²⁺ to the pipetting solution (intracellular), and 80 µM LaCl ₃ to the extracellular solution.

TRPC5 cells were induced for 20–48 h, removed from growth plates, and replated at low density (to achieve good physical separation of individual cells) onto glass coverslips for measurement. In some cases, cells were grown at low density overnight on glass coverslips. Patch clamp recordings were performed in whole cell mode with a holding potential of -40 mV. Every 5 seconds, a voltage ramp was applied from 120 to +100 mV for 400 ms. Evoked currents were quantified at −80 mV and +80 mV. The internal solution consisted of 140 mM cesium aspartate, 10 mM HEDTA, 2 mM CaCl ₂ , 2.27 mM MgCl ₂ and 10 mM HEPES, pH 7.2, with 1,400 nM calculated free Ca ²⁺ . The external solution consisted of 150 mM NaCl, 4.5 mM 15 KCl, 1 mM _MgCl2 , 2 mM _CaCl2 , 10 mM HEPES, 10 mM glucose, 1 mM EGTA, pH 7.4. After addition of LaCl ₃ , TRPC5 current was induced only in TRPC5-expressing cells and not in parental HEK293 TREx cells. Removing the LaCh stimulus causes most of the current to flow away. Potential blockers were tested for their ability to block both inward and outward currents in the constant presence of LaCl ₃ .

The IC5o of the compounds of the invention was assessed by testing the compound at a concentration of 500 nM. If the compound at 500 nM showed no blocking, the IC ₅₀ was estimated to be >1 µM. Compounds blocking 50% or more of the current at 500 nM were retested at multiple concentrations and % blocking was determined using standard equations to accurately determine the IC ₅₀ using a 5/6 point concentration-response experiment.

Biological data.

Table 1

In vitro efficiencies of prior art compounds WO2014/143799 determined in assay A (described above)

TRPC5 inhibition assay A

Example 441 in

WO2014/143799

Example 465 in

WO2014/143799

Structure

324 nM

The compounds of the present invention unexpectedly showed significantly higher activity in inhibiting TRPC5 when measured in the same assay (Assay A) than the prior art compounds (Examples #441 and #465 in WO2014/143799).

The compounds of the present invention are structurally different from examples 441 and 465 in WO 2014/143799, i.e. compounds of the prior art, in that the C8-position of xanthine in the compounds claimed in the present invention is replaced by 3-pyridyl, and not by a phenyl group, as in Examples 441 and 465 of WO 2014/143799. Moreover, the heteroaryl group in the compounds claimed herein is replaced by a cycloalkyl-O group rather than a methoxy group as in Examples 441 and 465 of WO 2014/143799. These structural differences unexpectedly lead to markedly increased activity in TRPC5 inhibition (Tables 1 and 2).

These results demonstrate that the compounds of the present invention are surprisingly superior to the structurally most similar example disclosed in WO2014/143799 (prior art compounds) in inhibiting TRPC5. Thus, the compounds of the present invention are more suitable for medical use.

- 6 043969

table 2

In vitro efficacies of the compounds of the present invention determined in Assay A (described above)

Example Structure TRPC5 inhibition assay A 1 I O <0.032 nM 2 o o _n j II νъ ζ/~θ ο^ν^ν ^-ν У-^ 0.095 nM 3 Cl R j II v—\ ζ/“θ o^n^n n 0.099 nM 4 I o R <0.1 nM 5 o R o o T <0.1 nM 6 oh oh <0.1 nM 7 '8 ^ΗθΧ ^^ ^Ν ιΓ'ΠκΛΛ l j II v h ⁰ ; ^N 0.104 nM 8 °/-О a L —ά '' I O^Sl^N Vn 0.106 nM

- 7 043969

9 β ho^^n ^x v ⁿ v/=\ _η j II ν—\ // ^- ° ο ^λ ν ^λ ν / ^- ν 0.130 nM 10 CI in /=\ j L —ά // ^- ° o^n^n _f In i fX CJ F 0.150 hM eleven ^035?°^ 0.163 hM 12 I ''Lee o^N'-'N fJ-N Vy F 0.171 hM 13 C , “'^'L^ngV ⁰ . o^N^N ^-n 0.174 hM 14 Br B ho^^n ^x S- ⁿ ^/=\ _l 7 II />—v. y ^- o o^n^n 0.178 hM

-8043969

15 В o^n^n _f Jn Уу' F 0.184 hM 16 In ΗΟ^^Ν ιΓ ^Ν κ/ ⁼ \ η ο^ν^ν Vn in ⁰ 0.190 hM 17 Cl in j II //—\ /^° 0.199 hM 18 'p, “ΑΪ4Χ _C A ₍ ^A N ^-N 0.207 hM 19 β _HO ^^ ^N Ar'Ch, LL no^n^n ^-n 0.236 hM 20 ⁰ r^O ^ho ^iY^<h ₀ ^S/-NN 0.246 hM

-9043969

- 10043969

26 I O <0.32 nM 27 0.402 nM 28 o ^ν ^=' 0.917 nM 29 'in ho^^n LgLLLL-p j II v—<x /?“θ ο^ν^ν χ-Ν 0.403 nM thirty I o ^y ·^ in σ° 0.426 nM 31 I O o ) \_ V 0.431 nM

32 β /=\ ϊ II )β // ^-0 O^N^N 0.460ηΜ 33 IN ο^ν^-ν /“ν У-. 0.477 ηΜ 34 β i 1 '>“Λ /)-° ο^ν^ν y _N 0.485ηΜ 35 LL Ο^ β ο ο τ 0.531 ηΜ 36 CI in ΗΟ^^Ν^γΝ/^ _η 1 II ν—ζ/ο^ν^ν ^-ν V>. 0.551 ηΜ 37 2''Ό J II 4>---//“θ O^Sr^N 2~Ν 0.603ηΜ

- 12043969

38 Br IN l LL —B '' B 0.613 hM 39 Ο °) F u^Br^sC ο^ν^ν У^ 0.628 hM 40 Cl in ΗΟ^^Ν |Γ ^Ν \/ ⁼ \r> j II //—B // B Ο^Ν^Ν ^V N 0.643 hM 41 V u^VgVDD o^n^n 2~1 0.688 hM 42 oh da j II //—s\ //~θ O^Sr^N /-N 0.713 hM 43 B T' ^N V^ ⁼ Vn 1 IL v—//4 O^N^N F ^F 0.732 hM

- 13 043969

44 V j II "—\ "-° o^n^n 0.743 hM 45 B ^ΗΟ ^^ ^Ν iT ^N '^/ ⁼ Vn j II '/—ζ?”θ o^n^n 0.750 hM 46 :t· IN j L '/—v °. o^n^n 0.812 hM 47 B ^HO ^^ ^N iT ^N ^V ⁼ Vn l L \ ^z ' 4 o^n^n F ^F 0.859 hM 48 Cl B HO^^N ^> V ^N v/=\ j II '/—v θ o^n^n 0.873 hM 49 o o HO^^N^Sr/^ _n l !L v—//4 O^Sl^N 1.007 hM

- 14043969

50 ts o^n^n ^-n 1.163 nM 51 IN j II //—//~θ try n n 1.360 hM 52 I ^but hVyaCH O^^-N ^N 1.582 hM 53 Cl 4 oS ^a n 1.587 hM 54 I o F sl° 1.601 hM 55 in ^HO ^^ ^N iT ^N ^V ⁼ V^ A. L\ '/ θ θ4 ^Λ Ν 2.162 hM

- 15 043969

56 8 j II \ ^z /° o^n^n 2.643 hM 57 ¥ j II v—\\ //“O o^n^n ^V N 2.663 hM 58 F F-Cj ⁰ ) JL ''—''°. 3.668 hM 59 'Ts 'Ύϊ'ΗΧ o^n^n 1.727 hM 60 Q C>\ Ηθ'' ^χ ^Ν'\-Ν/=\ o^n^n Vn 2.094 hM 61 Q°? ho^^^ ⁿ ^V ⁿ < /=\ _l j. IL ^/“A /)-° O^Sl^N /~N 2.426 hM 62 '8 ^HO ^^ ^N iT ^N ^V ⁼ Vo j II />— o^n^n >-n 3.369 hM 63 8 A L\'' 4 o^n^n 3.155 hM 64 ° g£У ^Р ΗΟ^^^Ν ^χ ν ^Ν ν/ ⁼ \ j II -7—//4 0<Sj^N 2.715 hM

- 16043969

Application for treatment / method of application

The present invention provides compounds that are useful for treating a disease, disorder and condition in which inhibition of the activity of the transient receptor potential cation channel TRPC5 provides a therapeutic effect. This includes, but is not limited to, the treatment and/or prevention of psychiatric, neurological or neurodegenerative conditions, pain, seizures, non-neuronal conditions and malignancy.

Psychiatric disorders include disorders associated with dysregulated emotional processing (eg, borderline personality disorder or depressive disorders such as major depression, major depressive disorder, psychiatric depression, dysthymia and postpartum depression, and bipolar disorders), anxiety disorders, and fear-related disorders. (eg, post-traumatic stress disorder, panic disorder, agoraphobia, social phobias, generalized anxiety disorder, panic disorder, social anxiety disorder, obsessive-compulsive disorder and separation anxiety), memory disorders (eg, Alzheimer's disease, amnesia, aphasia, traumatic brain injury, brain tumor, chronic fatigue syndrome, Creutzfeldt-Jakob disease, dissociative amnesia, fugue amnesia, Huntington's disease, learning disabilities, sleep disorders, multiple personality disorder, pain, post-traumatic stress disorder, schizophrenia, sports injuries, stroke and Wernicke-Korsakoff syndrome) , disorders associated with impaired impulse control and addiction.

Neurological or neurodegenerative conditions include, for example, Alzheimer's disease (AD), Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), and other brain disorders caused by trauma or other damage, including aging.

Pain disorders include nociceptive pain, inflammatory pain, cancer-related pain, and neuropathic pain (eg, cancer-related pain, osteoarthritic pain, rheumatoid arthritis pain, postherpetic neuralgia, pain due to burns, and other features) . The pain can be chronic or acute.

Seizures can be caused by excitotoxicity of various origins. Typically, excessive generation of electrical impulses by neurons can cause seizure activity. Compounds that reduce hyperexcitability of relevant neuronal populations have significant potential for reducing seizure activity. Compounds of the invention that inhibit TRPC5 may reduce hyperexcitability and therefore reduce seizure activity.

Non-neuronal conditions include nephropathy, proteinuric kidney disease, liver diseases such as liver dyslipidemia associated with cholestasis, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD) [WO2018/146485], pruritus, disorders associated with cardiac dysfunction. vascular system or vascular permeability (eg, pulmonary arterial hypertension, acute respiratory distress syndrome (ARDS), maladaptive cardiac remodeling, disorders associated with maladaptive blood pressure control such as hypertension or hypotension, and other medical conditions such as diabetes mellitus, insulin resistance, metabolic syndrome and obesity It is suggested that use for the treatment of non-neuronal conditions may also extend to use for cosmetic weight loss (WO2018/146485).

Another aspect of the invention relates to pharmaceutical compositions for use in a human patient containing an effective amount of a compound (or a pharmaceutically acceptable salt thereof) described herein, and one or more pharmaceutically acceptable excipient(s). The invention also provides for the use of the compounds described herein in the manufacture of a medicament or pharmaceutical composition for treating or reducing the symptoms of any of the diseases or conditions described herein. The compounds described in the present invention can be used to treat a particular disease or condition, and they can be formulated for administration by a route suitable for the particular disease or condition.

A useful daily dose of the compounds of the present invention may vary from 0.1 to 2000 mg.

The actual pharmaceutically effective amount or therapeutic dose will depend on factors known to those skilled in the art, such as the age and weight of the patient, the route of administration, and the severity of the disease. In any case, the drug substance should be administered in a dose and in a manner that will deliver a pharmaceutically effective amount appropriate to the patient's condition.

- 17 043969

Pharmaceutical compositions

Suitable compositions for administering the compounds of the present invention will be apparent to those skilled in the art and include, for example, tablets, pellets, capsules, suppositories, lozenges, trochets, solutions, syrups, elixirs, sachets, injection solutions, inhalants and powders. The content of pharmaceutically active compound(s) may vary in the range from 0.1 to 95 wt.%, preferably from 5.0 to 90 wt.%, based on the weight of the composition as a whole.

Suitable tablets can be prepared, for example, by mixing the compound of the present invention with known excipients, for example, inert diluents, carriers, disintegrants, adjuvants, surfactants, binders and/or lubricants, and compressing the resulting mixture into tablets.

Combination therapy

The compounds of the present invention can be used alone or in combination with other active pharmaceutical ingredients. In particular, the compounds of the present invention may be combined with other treatment options known for use in the art in connection with the treatment of any of the indications the treatment of which is the focus of the present invention.

Among such active pharmaceutical ingredients or treatment options considered suitable for combination with the compounds and treatment in accordance with the present invention are antidepressants, mood stabilizers, typical and atypical antipsychotics, anxiolytics, antiepileptic drugs, hypnotics, cognitive enhancers, stimulants, additional psychotropic drugs, anti-inflammatory drugs, analgesics, chemotherapeutic agents, and active pharmaceutical ingredients that are used or potentially useful for the treatment of metabolic disorders, liver diseases and kidney diseases, the latter active pharmaceutical ingredients also including potential TRPC3 and/or TRPC6 inhibitors.

Experimental section List of abbreviations:

ACN Acetonitrile conc. concentrated d day(s)

DCM dichloromethane

DIPEA N-ethyldiisopropylamine

DMAP 4-dimethylaminopyridine

DMF N,N-dimethylformamide

DMSO dimethyl sulfoxide

EtOAc ethyl acetate g gram h hour(s)

BUT Ac acetic acid

HPLC high performance liquid chromatography

MeOH methanol min minute(s) mg milligram ml milliliter

And. normal

k.t. room temperature

RT hold time

SKFH supercritical fluid chromatography

THF tetrahydrofuran

TFA trifluoroacetic acid µl microliter

- 18 043969

HPLC methods:

Method name:A

Column: XBridge VEN C18_ 2.1 x 30 mm, 1.7 µm

Column supplier: Waters

Gradient/Solvent Time [min] % Sol. [H ₂ O, 0.1% TFA] % Sol. [ACN] Flow [ml/min] Temp [°C] 0.00 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 name: B

Column: XBridge VEN Phenyl, 2.1 x 30 mm, 1.7 µm

Column supplier: Waters

Gradient/Solvent Time [min] % Sol. [H ₂ O, 0.1% NH ₃ ] % Sol. [Acetonitrile] Flow [ml/min] Temp [°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: C

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

Column supplier: Waters

Gradient/Solvent Time [min] % Sol. [H ₂ O, 0.1% NH ₃ ] % Sol. [ACN] Flow [ml/min] Temp [°C] 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:D

Column: XBridge VEN C18, 2.1 x 30 mm, 1.7 µm

Column supplier: Waters

Gradient/Solvent Time [min] % Sol. [H ₂ O, 0.1% NH ₃ ] % Sol. [ACN] Flow [ml/min] Temp [°C] 0.00 95 5 1.3 60

- 19 043969

Gradient/Solvent Time [min] % Sol. [H ₂ O, 0.1% NH ₃ ] % Sol. [ACN] Flow [ml/min] Temp [°C] 0.02 95 5 1.3 60 E00 0 100 1.3 60 EY 0 100 1.3 60

Method name: E

Column: XBridge VEN C18_2.1 x 30 mm_2.5 µm

Column supplier: Waters

Gradient/Solvent Time [min] % Sol. [H ₂ O, 0.1% NH ₃ ] % Sol. [ACN] Flow [ml/min] Temp [°C] 0.00 50 50 1.3 60 0.02 50 50 1.3 60 1.00 0 100 1.3 60 1.10 0 100 1.3 60

Method name:F

Column: Sunfire C18_3.0 x 30 mm_2.5 µm

Column supplier: Waters

Gradient/Solvent Time [min] % Sol. [H ₂ O, 0.1% TFA (v/v)] % Sol. [ACN] Flow [ml/min] Temp [°C] 0.0 95.0 5.0 1.5 60.0 1.3 0.0 100.0 1.5 60.0 1.5 0.0 100.0 1.5 60.0

Method name: G

Column: XBridge VEN C18_2.1 x 30 mm_2.5 µm

Column supplier: Waters

Gradient/Solvent Time [min] % Sol. [H ₂ O, 0.1% NH ₃ ] % Sol. [ACN] Flow [ml/min] Temp [°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:N

Column: XBridge VEN C18_2.1 x 30 mm_L7 µm

Column supplier: Waters

- 20 043969

Gradient/Solvent Time [min] % Sol. [H ₂ O, 0.1% NH ₃ ] % Sol. [ACN] Flow [ml/min] Temp [°C] 0.00 50 50 1.3 60 0.02 50 50 1.3 60 1.00 0 100 1.3 60 1.10 0 100 1.3 60

Method name:

Column:

Column supplier:

I

Lux® Cellulose_3 4.6 x 250 mm_5 µm

Phenomenex

Gradient/Solvent Time [min] % Sol. [ _scCO2 ] % Sol. [MeOH 20 mM NH ₃ ] Flow [ml/min] Temp [°C] Back Pressure (psi) 0.0 90.0 10.0 4.0 40.0 2175.0 10.0 90.0 10.0 4.0 40.0 2175.0

Method name:

Column:

Column supplier:

J

Chiralpak® 1A_4.6 x 250 mm_5 microns

Daicel

Gradient/Solvent Time [min] % Sol. [ _scCO2 ] % Sol. [MeOH 20 mM NH ₃ ] Flow [ml/min] Temp [°C] Back Pressure (psi) 0.0 85.0 15.0 4.0 40.0 2175.0 10.0 85.0 15.0 4.0 40.0 2175.0

Method name:

Column:

Column supplier:

TO

Lux® Amylose-2_4.6 x 250 mm_5 µm

Phenomenex

Gradient/Solvent Time [min] % Sol. [ _scCO2 ] % Sol. [MEON 20 mM NH ₃ ] Flow [ml/min] Temp [°C] Back Pressure (psi) 0.0 95.0 5.0 4.0 40.0 2175.0 10.0 95.0 5.0 4.0 40.0 2175.0

NMR method: NMR spectra were recorded on a Bruker AVANCE IIIHD 400 MHz instrument using TopSpin 3.2 p16 software. Chemical shifts are given in parts per million (ppm) in δ units, downfield from the internal standard, trimethylsilane. The selected data are presented as follows: chemical shift (multiplicity, interaction constants (J), number of hydrogen atoms).

The following abbreviations are used: s (singlet), d (doublet), t (triplet), q (quartet), spt (septet), m (multiplet), br (broad).

Intermediate connections.

Intermediate 1.1

The reaction was carried out in an argon atmosphere and in a dried glass container. Sodium [metal] (4.50 g, 196 mmol) was added piecemeal to dry propan-2-ol (150 mL). The mixture was stirred for 2 hours and heated to 95°C. After the sodium had completely dissolved, isopropyl urea (10.0 g, 97.9 mmol) and cyanoacetic acid ethyl ester (10.4 mL, 97.9 mmol) were added and the mixture was stirred overnight at 95°C. The mixture was cooled and H2O (40.0 ml) was added and the pH was adjusted to 6 with conc. HCl. Stirring was continued under ice-cooling under N2 for 12 hours. The resulting precipitate was filtered and dried to obtain 7.33 g of product.

MS (ESI+): (M+H) ⁺ 170.

HPLC: RT=0.23 min, Method F.

- 21 043969

Intermediate connection 1.2

The reaction was carried out in an argon atmosphere and in a dried glass container. Sodium (metal) (20.9 g, 908 mmol) was added piecemeal to dry ethanol (600 ml). The mixture was stirred for 3 days and heated to 60°C. After the sodium had completely dissolved, ethyl urea (40.0 g, 454 mmol) and ethyl 2-cyanoacetate (48.3 mL, 454 mmol) were added and the mixture was stirred for 4 days at reflux. The mixture was concentrated in vacuo, H2O (200 ml) was added and the pH was adjusted to 7 with conc. HCl. Stirring was continued under ice cooling for 30 minutes. The resulting precipitate was filtered off, washed with H ₂ O and dried to obtain 48.59 g of product.

MS (ESI ⁺ ): (M+H) ⁺ 156.

HPLC: RT=1.18 min, Method B.

Intermediate connection 1.3

The reaction was carried out under a nitrogen atmosphere and in a dried glass container. Sodium (metal) (0.6 g, 26.3 mmol) was added piecemeal to dry propan-2-ol (20 ml). The mixture was stirred for 1 hour at 60°C. EtOH (5 mL, 60.7 mmol) was then added and the mixture was stirred for 30 min at 60°C. Once the sodium had completely dissolved, cyclobutylurea (1.5 g, 13.1 mmol) and ethyl 2cyanoacetate (1.4 mL, 13.1 mmol) were added and the mixture was stirred overnight at reflux. The mixture was concentrated in vacuo, H ₂ O (5.0 ml) was added and the pH was adjusted to 7 with conc. HCl. Stirring was continued under ice-cooling under N2 for 45 minutes. The resulting precipitate was filtered and dried to obtain 1.61 g of product.

MS (ESI ⁺ ): (M+H) ⁺ 182.

HPLC: RT=0.31 min, Method F.

Intermediate 2.1

To a mixture of intermediate 1.1 (1.00 g, 5.91 mmol) in HCl (1 mol/L, 16.5 mL, 16.5 mmol), NaNO2 (571 mg, 8.28 mmol) in H2O (6.00 mL) was added dropwise. NaOH (4 N, approximately 4 ml) was added until the solution reached pH 9. The resulting precipitate was filtered off, washed with MeOH and tert-butyl methyl ether and dried to obtain 0.79 g of product.

MS (ESI+): (M+H) ⁺ 199.

HPLC: RT=0.24 min, Method F.

- 22 043969

Intermediate connection 2.2

To a mixture of intermediate 1.2 (48.6 g, 0.304 mol) in HCl (1 mol/L, 800 ml, 800 mmol), NaNO ₂ (29.3 g, 0.425 mol) in H ₂ O (280 ml) was added dropwise. The mixture was stirred overnight at room temperature. The mixture was then made alkaline with NaOH (60%, approximately 15 ml). The resulting precipitate was filtered off, washed with MeOH and tert-butyl methyl ether and dried to obtain 43.8 g of product.

MS (ESI ⁺ ): (M+H) ⁺ 185.

HPLC: RT=0.09 min, Method B.

Intermediate connection 2.3

To a mixture of intermediate 1.3 (2.31 g, 0.013 mol) in HCl (1 mol/L, 16.5 ml, 16.5 mmol), NaNO ₂ (1.23 g, 0.018 mol) in H ₂ O (6 ml) was added dropwise. The mixture was then neutralized with NaOH (4N). The resulting precipitate was filtered off, washed with H ₂ O and tert-butyl methyl ether and dried to obtain 2.27 g of product.

MS (ESI ⁺ ): (M+H) ⁺ 211.

HPLC: RT=0.30 min, Method F.

Intermediate 3.1

A mixture of intermediate 2.1 (8.04 g, 40.6 mmol), Pd/C (10%, 1.9 g), MeOH (120 ml), H ₂ O (80 ml) and HCl solution (4 mol/L, 11.2 ml, 44.6 mmol ) were hydrogenated at room temperature. and pressure H ₂ 50 psi. inch for 4 hours. The mixture was filtered, MeOH was evaporated, ACN was added and lyophilized to obtain 3.04 g of product.

MS (ESI+): (M+H) ⁺ 185.

HPLC: RT=0.01 min, Method D.

Intermediate 3.2

A mixture of intermediate 2.2 (43.3 g, 235 mmol), Pd/C (10%, 4.95 g), MeOH (400 ml), H2O (300 ml) and HCl solution (1 mol/L, 259 ml, 259 mmol) was hydrogenated at k.t. and pressure H ₂ 50 psi. inch for 1 day. The mixture was filtered, MeOH was evaporated, ACN was added and lyophilized to obtain 47.2 g of product.

- 23 043969

MS (ESI ⁺ ): (M+H) ⁺ 169/171.

HPLC: RT=0.08/0.1 min, Method B.

Intermediate 3.3

A mixture of intermediate 2.2 (31.0 g, 109 mmol), Pd/C (10%, 3.0 g), MeOH (270 ml), H ₂ O (207 ml) and HCl solution (1 mol/L, 185 ml, 185 mmol ) were hydrogenated at room temperature. and pressure H ₂ 50 psi. inch for 1.5 d (temperature increased to 50°C). The mixture was filtered, MeOH was evaporated and lyophilized. The residue was dissolved in H ₂ O (390 ml) and NaHCO ₃ was added until the pH reached 6-7. The resulting precipitate was filtered off, washed with cold H2O and t-butyl methyl ether and dried to obtain 15.6 g of product.

MS (ESI ⁺ ): (M+H) ⁺ 171.

HPLC: RT=0.14 min, Method F.

Intermediate 3.4

A mixture of intermediate 2.3 (1.0 g, 4.76 mmol), Pd/C (10%, 115 mg), MeOH (15 ml), H2O (7.5 ml) and HCl solution (1 mol/L, 5.23 ml, 5.23 mmol) was hydrogenated at k.t. and pressure H ₂ 50 psi. inch for 4 hours. The mixture was filtered and the mixture was concentrated in vacuo. The crude product was purified by chromatography to obtain 1.24 g of product.

MS (ESI ⁺ ): (M+H) ⁺ 197.

HPLC: RT=0.15 min, Method F.

Intermediate 4.1

To a mixture of intermediate 3.1 (0.4 g, 1.8 mmol) in DMF (1.00 ml) and DMSO (1.00 ml) was added 6-chloro-2-methylpyridin-3-carbaldehyde (282 mg, 1.8 mmol) and the mixture was stirred for 45 min at 100°C in a microwave oven. The mixture was cooled to room temperature, H ₂ O was added, and the resulting precipitate was filtered and dried to obtain 0.41 g of product.

MS (ESI ⁺ ): (M+H) ⁺ 319.

HPLC: RT=0.70 min, Method F.

Intermediate connection 4.2

.

Intermediate 4.2 was prepared by analogy with the preparation of intermediate

- 24 043969

4.1 using intermediate 3.2 and 6-chloro-2-methylpyridine-3-carbaldehyde.

MS (ESI ⁺ ): (M+H) ⁺ 306.

HPLC: RT=0.54 min, Method C.

Intermediate connection 4.3

To a mixture of intermediate 3.3 (2.0 g, 10.6 mmol) in (diethoxymethoxy)ethane (16.5 ml) was added formic acid (0.535 ml, 12.2 mmol) and the mixture was stirred overnight at 150°C. The mixture was cooled in an ice bath, the resulting precipitate was filtered off, washed with t-butyl methyl ether and dried to obtain 1.93 g of product.

MS (ESI ⁺ ): (M+H) ⁺ 181.

HPLC: RT=0.27 min, Method F.

Intermediate connection 4.4

To a mixture of intermediate 3.2 (0.8 g, 3.1 mmol) in DMF (4.00 ml, 49.2 mmol) and DMSO (4.00 ml, 56.3 mmol) was added 6-chloro-2-(trifluoromethyl)pyridine-3-carbaldehyde (649 mg, 3.1 mmol), and the mixture was stirred for 45 min at 100°C in a microwave oven. H2O was added, the resulting precipitate was filtered and dried to obtain 1.10 g of product.

MS (ESI ⁺ ): (M+H) ⁺ 360.

HPLC: RT=0.68 min, Method F.

Intermediate connection 4.6

To a mixture of intermediate 3.4 (300 mg, 1.03 mmol) in DMF (1 ml, 12.3 mmol) and DMSO (1 ml, 14.1 mmol) was added 6-chloro-2-methylpyridine-3-carbaldehyde (160.5 mg, 1.03 mmol), and the mixture was stirred for 45 minutes at 100°C in a microwave oven. H2O was added, the resulting precipitate was filtered and dried to obtain 0.31 g of product.

MS (ESI ⁺ ): (M+H) ⁺ 332/334.

HPLC: RT=0.75 min, Method F.

Intermediate connection 4.8

Formic acid (3.08 ml, 70.4 mmol), and the mixture was stirred overnight at 150°C. The mixture was cooled, H ₂ O was added and the resulting precipitate was filtered, washed with H ₂ O and dried to obtain 5.83 g of product.

MS (ESI+): (M+H) ⁺ 153.1.

- 25 043969

HPLC: RT=0.10 min, Method D.

Intermediate connection 4.10

To a mixture of intermediate 3.2 (2.0 g, 8.23 mmol) in H ₂ O (104 ml) was added benzaldehyde (1.67 ml, 16.46 mmol) and the mixture was stirred for 1 h at room temperature. The resulting precipitate was filtered off, washed with water and dried to obtain 2.27 g of product.

MS (ESI ⁺ ): (M+H) ⁺ 259/260.

HPLC: RT=0.41 min, Method D.

Intermediate connection 4.11

Formic acid (170.6 μL, 4.52 mmol) was added to a mixture of intermediate 23.1 (594 mg, 1.62 mmol) in (diethoxymethoxy)ethane (17.47 mL, 105 mmol) and the mixture was stirred for 30 min at reflux. The mixture was cooled, H ₂ O was added and the resulting precipitate was filtered and dried to obtain 241 mg of product.

MS (ESI ⁺ ): (M+H) ⁺ 271/272.

HPLC: RT=0.39 min, Method D.

Intermediate connection 4.12

To a mixture of intermediate 3.2 (1.0 g, 4.84 mmol) in DMF (10 mL, 123 mmol) and DMSO (10 mL, 141 mmol) was added 6-chloropyridine-3-carbaldehyde (685 mg, 4.84 mmol) and the mixture was stirred for 45 minutes at 100°C in a microwave oven. H2O was added, the resulting precipitate was filtered off, washed with H2O and dried to obtain 1.0 g of product.

MS (ESI+): (M+H) ⁺ 292/294.

HPLC: RT=0.57 min, Method C.

Intermediate connection 4.13

.

Intermediate 4.13 was prepared in a similar manner to the preparation of intermediate 4.12 using intermediate 3.2 and 6-fluoro-2-methylpyridinium-3-carbaldehyde.

MS (ESI ⁺ ): (M+H) ⁺ 290/291.

HPLC: RT=0.52 min, Method F.

- 26 043969

Intermediate connection 5.1

To a mixture of intermediate 4.1 (405 mg, 1.27 mmol) in DMF (3.00 ml), THF (3 ml) and DMSO (3 ml) was added DIPEA (0.262 ml, 1.52 mmol) and 1-(bromomethyl)-4-fluorobenzene ( 0.157 ml, 1.27 mmol), and the mixture was stirred for 2.5 h at 80°C. The mixture was acidified using TFA and purified by chromatography to obtain 508 mg of product.

MS (ESI ⁺ ): (M+H) ⁺ 427.

HPLC: RT=0.88 min, Method F.

Intermediate connection 5.2

To a mixture of intermediate 4.1 (1.5 g, 4.47 mmol) in DMF (15.0 ml), DIPEA (0.923 ml, 5.37 mmol) and (bromomethyl)benzene (0.53 ml, 4.47 mmol) were added and the mixture was stirred for 1 h at 80° WITH. H ₂ O was added and extracted with EtOAc. The combined organic layers were dried and concentrated in vacuo to give 1.54 g of product.

MS (ESI ⁺ ): (M+H) ⁺ 411/413.

HPLC: RT=0.9 min, Method F.

Intermediate connection 5.3

.

Intermediate 5.3 was prepared in a similar manner to the preparation of intermediate 5.1 using intermediate 4.2 and 1-(bromomethyl)-4-chlorobenzene.

MS (ESI ⁺ ): (M+H) ⁺ 430.

HPLC: RT=0.85 min, Method F.

- 27 043969

Intermediate connection 5.4

To a mixture of intermediate 4.2 (1.0 g, 3.27 mmol) in DMF (10.0 mL), DIPEA (0.675 mL, 3.93 mmol) and 1-(bromomethyl)-4-fluorobenzene (0.404 mL, 3.27 mmol) were added and the mixture was stirred for 4 hours at 80°C. The mixture was cooled, filtered and the filtrate was purified by chromatography to give 0.67 g of product.

MS (ESI+): (M+H) ⁺ 414/416.

HPLC: RT=0.79 min, Method F.

Intermediate connection 5.5

To a mixture of intermediate 4.3 (150 mg, 0.83 mmol) in THF (0.53 mL) and DMSO (0.53 mL) was added DIPEA (0.29 mL, 1.67 mmol) and the mixture was stirred for 5 min at 80°C. (Bromomethyl)benzene (0.99 mL, 0.83 mmol) was then added and the mixture was stirred for 1 hour at 80°C. H ₂ O was added and extracted with EtOAc. The combined organic layers were dried, concentrated in vacuo and purified by chromatography to give 85.0 mg of product.

MS (ESI ⁺ ): (M+H) ⁺ 271/272.

HPLC: RT=0.4 min, Method G.

Intermediate connection 5.6

To a mixture of intermediate 4.4 (0.2 g, 0.56 mmol) in DMF (4.0 mL), DIPEA (0.115 mL, 0.67 mmol) and 1-(bromomethyl)-4-chlorobenzene (114 mg, 0.56 mmol) were added and the mixture was stirred for 2.5 hours at 80°C. The reaction mixture was filtered and purified by chromatography to obtain 226 mg of product.

MS (ESI ⁺ ): (M+H) ⁺ 484.

HPLC: RT=0.95 min, Method F.

- 28 043969

Intermediate connection 5.7

.

Intermediate 5.7 was prepared in a similar manner to the preparation of intermediate 5.6 using intermediate 4.4 and (bromomethyl)benzene.

MS (ESI+): (M+H) ⁺ 450 HPLC: RT=0.87 min, Method F.

Intermediate connection 5.9

To a mixture of intermediate 13.1 (90 mg, 0.347 mmol) in DMF (1.0 ml), DIPEA (0.119 ml, 0.695 mmol) and 1-(bromomethyl)-4-fluorobenzene (0.043 ml, 0.347 mmol) were added and the mixture was stirred for 1 hour at room temperature. H2O was added and the resulting precipitate was filtered and dried to obtain 104 mg of product.

MC (ESI ⁺ ): (M+H) ⁺ 367/369.

HPLC: RT=0.74 min, Method F.

Intermediate connection 5.10 o

5.10.

Intermediate 5.10 was prepared by analogy with the preparation of intermediate

5.6 using intermediate 4.2 and 1-bromo-4-(bromomethyl)benzene.

MC (ESI ⁺ ): (M+H) ⁺ 476.

HPLC: RT=0.88 min, Method F.

Intermediate connection 5.11

F

F ^F

5.11.

Intermediate 5.11 was prepared by analogy with the preparation of intermediate

5.6 using intermediate 4.4 and 1-(bromomethyl)-4-fluorobenzene.

- 29 043969

MS (ESI ⁺ ): (M+H) ⁺ 468.

HPLC: RT=0.90 min, Method F.

Intermediate connection 5.12

5.12

To a mixture of intermediate 4.6 (308 mg, 0.93 mmol) in DMF (5.0 ml), DIPEA (0.192 ml, 1.11 mmol) and (bromomethyl)benzene (110.3 μl, 0.93 mmol) were added and the mixture was stirred for 2 h at 80° WITH. The reaction mixture was purified by chromatography to obtain 282 mg of product.

MS (ESI ⁺ ): (M+H) ⁺ 422/424.

HPLC: RT=0.96 min, Method F.

Intermediate connection 5.14

n

5.14

To a mixture of intermediate 13.2 (6.1 g, 13.2 mmol) in DMF (35 ml), THF (35 ml) and DMSO (35 ml) was added DIPEA (6.8 ml, 39.6 mmol) and (bromomethyl)benzene (1.67 ml, 14.5 mmol ), and the mixture was stirred for 45 min at room temperature. The mixture was filtered, concentrated in vacuo and purified by chromatography to give 1.70 g of product.

MS (ESI ⁺ ): (M+H) ⁺ 321.

HPLC: RT=0.56 min, Method F.

Intermediate connection 5.15

5.15

To a mixture of intermediate 4.2 (1.0 g, 3.27 mmol) in DMF (10.0 ml), DIPEA (0.675 ml, 3.93 mmol) and (bromomethyl)benzene (388.5 μl, 3.27 mmol) were added and the mixture was stirred for 4 h at 80° WITH. The reaction mixture was cooled, filtered and purified by chromatography to obtain 684 mg of product.

MS (ESI ⁺ ): (M+H) ⁺ 396/398.

HPLC: RT=0.78 min, Method F.

- 30 043969

Intermediate connection 5.17

To a mixture of intermediate 4.3 (540 mg, 3 mmol) in DMSO (2 ml) and THF (2 ml) was added DIPEA (1.03 ml, 6 mmol) and [2-(chloromethoxy)ethyl]trimethylsilane (0.53 ml, 3 mmol) , and the mixture was stirred for 1 hour at room temperature. to obtain a crude product which was used without further purification.

MS (ESI ⁺ ): (M+H) ⁺ 311.

HPLC: RT=0.54 min, Method D.

Intermediate connection 5.18

To a mixture of intermediate 4.12 (350 mg, 1.2 mmol) in DMF (3 mL, 37 mmol) was added DIPEA (247.7 μL, 1.44 mmol) and 1-(bromomethyl)-4-chlorobenzene (246.6 mg, 1.2 mmol), and the mixture stirred overnight at 80°C. The reaction mixture was filtered and purified by chromatography to obtain 148 mg of product.

MS (ESI+): (M+H) ⁺ 416/418.

HPLC: RT=0.85 min, Method F.

Intermediate connection 5.19

To a mixture of intermediate 4.13 (426 mg, 1.47 mmol) in DMF (5 mL, 61.5 mmol) was added DIPEA (304 μL, 1.77 mmol) and 1-(bromomethyl)-4-fluorobenzene (193 μL, 1.47 mmol), and the mixture stirred for 1 hour at 80°C. The reaction mixture was filtered, H ₂ O was added and extracted with EtOAc. The combined organic layers were dried and concentrated in vacuo. The crude product was purified by chromatography to obtain 344 mg of product.

MS (ESI ⁺ ): (M+H) ⁺ 398/400.

HPLC: RT=0.73 min, Method F.

- 31 043969

Intermediate connection 5.20

To a mixture of intermediate 22.1 (23.5 mg, 0.05 mmol) in THF (413 µl, 5.2 mmol) and

DMSO (413 µl, 5.8 mmol) was added to DIPEA (9.5 µl, 0.06 mmol) and 1-(bromomethyl)-4-chlorobenzene (15.4 mg, 0.075 mmol) and the mixture was stirred at 50°C. The mixture was cooled and used without further purification.

MS (ESI+): (M+H) ⁺ 594.

HPLC: RT=0.9 min, Method D.

Intermediate connection 5.21

.

Intermediate 4.12 (300 mg, 1.03 mmol) was dissolved in DMF (1 ml), THF (1 ml) and DMSO (1 ml). DIPEA (581 μl, 3.4 mmol) was added and the mixture was stirred for 5 min at 80°C. Intermediate 24.1 (217 mg, 1.03 mmol) was then added and the mixture was stirred for 1.5 h at 80°C. The reaction mixture was acidified with TFA, filtered, purified by chromatography and lyophilized to give 61.1 mg of product.

MS (ESI ⁺ ): (M+H) ⁺ 422.

HPLC: RT=0.91 min, Method F.

Intermediate connection 5.23

To a mixture of intermediate 13.1 (611 mg, 2.36 mmol) in DMF (5.75 mL), DIPEA (1.22 mL, 7.08 mmol) and 1-(bromomethyl)-4-chlorobenzene (484.6 mg, 2.36 mmol) were added and the mixture was stirred for 1 hour at room temperature The mixture was purified by chromatography to obtain 850 mg of product.

MS (ESI ⁺ ): (M+H) ⁺ 385.

HPLC: RT=0.57 min, Method G.

- 32 043969

Intermediate connection 5.24

To a mixture of intermediate 4.12 (150 mg, 0.514 mmol) in DMF (3 mL), DIPEA (106 μL, 0.617 mmol) and 1-(bromomethyl)-4-fluorobenzene (63.5 μL, 0.514 mmol) were added and the mixture was stirred for nights at 80°C. The mixture was cooled, filtered and purified by chromatography to obtain 54.0 mg of product.

MS (ESI+): (M+H) ⁺ 400/402.

HPLC: RT=0.79 min, Method F.

Intermediate connection 5.25

To a mixture of intermediate 22.1 (42.3 mg, 0.09 mmol) in THF (744 µl, 9.27 mmol) and

DMSO (740 µl, 10.4 mmol) was added to DIPEA (17 µl, 0.10 mmol) and 1-(bromomethyl)-4-chloro-2fluorobenzene (18.3 µl, 0.135 mmol) and the mixture was stirred overnight at 50°C. The mixture was cooled and used without further purification.

MS (ESI ⁺ ): (M+H) ⁺ 614.

HPLC: RT=0.92 min, Method D.

Intermediate connection 5.26

To a mixture of intermediate 22.1 (42.3 mg, 0.09 mmol) in THF (744 μL, 9.27 mmol) and DMSO (740 μL, 10.4 mmol) was added DIPEA (17 μL, 0.10 mmol) and 1-(bromomethyl)-4(trifluoromethyl) benzene (20.9 µl, 0.135 mmol), and the mixture was stirred overnight at 50°C. The mixture was cooled and used without further purification.

MS (ESI ⁺ ): (M+H) ⁺ 628.

HPLC: RT=0.92 min, Method D.

- 33 043969

Intermediate connection 5.27

To a mixture of intermediate 22.1 (42.3 mg, 0.09 mmol) in THF (744 μL, 9.27 mmol) and DMSO (740 μL, 10.4 mmol) was added DIPEA (17 μL, 0.10 mmol) and 1-(bromomethyl)-4-methylbenzene ( 25 mg, 0.135 mmol), and the mixture was stirred overnight at 50°C. The mixture was cooled and used without further purification.

MS (ESI ⁺ ): (M+H) ⁺ 574.

HPLC: RT=0.91 min, Method D.

Intermediate connection 5.28

DIPEA (17 μL, 0.10 mmol) and 4-(bromomethyl)-1,2- difluorobenzene (28 mg, 0.135 mmol) and the mixture was stirred overnight at 50°C. The mixture was cooled and used without further purification.

MS (ESI+): (M+H) ⁺ 596.

HPLC: RT=0.88 min, Method D.

Intermediate connection 5.29

To a mixture of intermediate 22.1 (74 mg, 0.102 mmol) in THF (1 mL, 12.5 mmol) and DMSO (1 mL, 14.1 mmol) was added DIPEA (81 μL, 0.47 mmol) and intermediate 24.2 (63 mg, 0.24 mmol) , and the mixture was stirred for 45 minutes at 50°C and overnight at 90°C. Additional DIPEA and intermediate 24.2 and ACN (2 ml) were added and the mixture was stirred for 4 hours at 90°C. The mixture was cooled, filtered and purified by chromatography to obtain 13.0 mg of product.

MS (ESI ⁺ ): (M+H) ⁺ 656.

HPLC: RT=0.97 min, Method A.

- 34 043969

Intermediate connection 5.30

To a mixture of intermediate 4.3 (400 mg, 2.22 mmol) in THF (1.42 mL) and DMSO (1.42 mL) was added DIPEA (274 μL, 4.44 mmol) and after 5 min at 80°C, 1-(bromomethyl)-4fluorobenzene was added (274 μl, 2.22 mmol), and the mixture was stirred for 1 h at 80°C. H ₂ O was added and extracted with EtOAc. The combined organic layers were dried, concentrated in vacuo and purified by chromatography to give 268 mg of product.

MS (ESI ⁺ ): (M+H) ⁺ 289.

HPLC: RT=0.59 min, Method F.

Intermediate connection 5.31

To a mixture of intermediate 4.12 (150 mg, 0.514 mmol) in DMF (3 mL, 37 mmol), DIPEA (106 μL, 0.617 mmol) and (bromomethyl)benzene (61 μL, 0.514 mmol) were added and the mixture was stirred overnight at 80°C. The mixture was cooled, filtered and purified by chromatography to obtain 57.0 mg of product.

MS (ESI+): (M+H) ⁺ 382/384.

HPLC: RT=0.78 min, Method F.

Intermediate 6.1

To a mixture of intermediate 5.1 (0.51 g, 1.19 mmol) in anhydrous DMF (2 ml) was added K ₂ CO ₃ (0.328 g, 2.38 mmol) and 2-(3-bromopropoxy)tetrahydro-2H-pyran (0.302 ml, 1.78 mmol ), and the mixture was stirred for 1 hour at 80°C. H ₂ O was added and extracted with EtOAc. The combined organic layers were dried, concentrated in vacuo and the crude product was purified by chromatography to give 556 mg of product.

MS (ESI ⁺ ): (M+H) ⁺ 570.

HPLC: RT=0.83 min, Method D.

Intermediate 6.2

.

Intermediate 6.2 was prepared by analogy with the preparation of intermediate

- 35 043969

6.1, using intermediate connection 5.2. MS (ESI ⁺ ): (M+H) ⁺ 553/554 HPLC: RT=0.82 min, Method G.

Intermediate connection 6.3

To a mixture of intermediate 5.3 (0.39 g, 0.91 mmol) in anhydrous DMF (2 ml) was added K ₂ CO ₃ (0.252 g, 1.82 mmol) and 2-(3-bromopropoxy)tetrahydro-2H-pyran (0.232 ml, 1.37 mmol ), and the mixture was stirred for 2 hours at 50°C. H ₂ O was added and extracted with EtOAc. The combined organic layers were dried, concentrated in vacuo and the crude product was purified by chromatography to give 438 mg of product.

MC (ESI+): (M+H) ⁺ 572.

HPLC: RT=1.38 min, Method C.

Intermediate connection 6.4

.

Intermediate 6.4 was prepared in a similar manner to the preparation of intermediate 6.1 using intermediate 5.4. MS (ESI ⁺ ): (M+H) ⁺ 556/558 HPLC: RT=0.77 min, Method D.

Intermediate 6.5

6.5.

Intermediate 6.5 was prepared in a similar manner to the preparation of intermediate 6.1 using intermediate 5.5.

MC (ESI ⁺ ): (M+H) ⁺ 413/414.

HPLC: RT=0.63 min, Method G.

Intermediate 6.6

Cl

Cl.

Intermediate 6.6 was prepared in a similar manner to the preparation of intermediate 6.3 using intermediate 5.6.

MS (ESI ⁺ ): (M+H) ⁺ 626.

- 36 043969

HPLC: RT=1.45 min, Method C.

Intermediate 6.7

ci

6.7.

Intermediate 6.7 was prepared by analogy with the preparation of intermediate

6.3, using intermediate connection 5.7.

MS (ESI ⁺ ): (M+H) ⁺ 592.

HPLC: RT=1.38 min, Method C.

Intermediate connection 6.9

.

Intermediate 6.9 was prepared in a similar manner to the preparation of intermediate 6.3 using intermediate 5.9.

MS (ESI ⁺ ): (M+n) ⁺ 5 10/511.

HPLC: RT=0.73 min, Method G.

Intermediate connection 6.10

6.10.

Intermediate 6.10 was prepared in a similar manner to the preparation of intermediate 6.3 using intermediate 5.10.

MS (ESI ⁺ ): (M+h) ⁺ 618.

HPLC: RT=0.83 min, Method D.

Intermediate connection 6.11

To a mixture of intermediate 5.11 (192 mg, 0.41 mmol) in anhydrous DMF (2 ml) was added K ₂ CO ₃ (114 mg, 0.82 mmol) and 2-(3-bromopropoxy)tetrahydro-2H-pyran (0.105 ml, 0.62 mmol ), and the mixture was stirred for 2 hours at 50°C. H ₂ O was added and extracted with EtOAc. The combined organic layers were dried, concentrated in vacuo and purified by chromatography to give 207 mg of product.

MS (ESI+): (M+H) ⁺ 610.

HPLC: RT=1.40 min, Method C.

- 37 043969

Intermediate connection 6.12

To a mixture of intermediate 5.12 (282 mg, 0.67 mmol) in anhydrous DMF (3 ml) was added K ₂ CO ₃ (277.2 mg, 2.01 mmol) and 2-(3-bromopropoxy)tetrahydro-2H-pyran (170.4 μl, 1.00 mmol ), and the mixture was stirred for 2 hours at 80°C. H ₂ O was added and extracted with EtOAc. The combined organic layers were dried, concentrated in vacuo and purified by chromatography to give 321 mg of product.

MS (ESI+): (M+H) ⁺ 564/566.

HPLC: RT=0.84 min, Method F.

Intermediate connection 6.14

To a mixture of intermediate 19.1 (700 mg, 1.86 mmol) in THF (7.73 ml), DMSO (7.78 ml) and DMF (7.84 ml) was added K2CO3 (769 mg, 0.006 mol) and 2-(3-bromopropoxy)tetrahydro-2H -pyran (0.42 ml, 2.78 mmol) and the mixture was stirred for 1 hour at 100°C. The mixture was cooled, diluted with ACN and purified by chromatography to give 811 mg of product.

MS (ESI ⁺ ): (M+H-THP) ⁺ 437.

HPLC: RT=0.84 min, Method G.

Intermediate connection 6.15

To a mixture of intermediate 19.2 (660 mg, 2.16 mmol) in anhydrous DMF (5 ml) was added K2CO3 (0.9 g, 6.48 mmol) and 2-(3-bromopropoxy)tetrahydro-2H-pyran (0.55 ml, 3.24 mmol), and the mixture was stirred for 2 hours at 80°C. H ₂ O was added and extracted with EtOAc. The combined organic layers were dried, concentrated in vacuo and the crude product was purified by chromatography and lyophilized to give 767 mg of product.

MS (ESI ⁺ ): (M+H) ⁺ 427/428.

HPLC: RT=0.97 min, Method F.

Intermediate connection 6.16

.

Intermediate 6.16 was prepared in a similar manner to the preparation of intermediate 6.11 using intermediate 5.15.

MS (ESI ⁺ ): (M+H) ⁺ 538/540.

HPLC: RT=1.06 min, Method F.

- 38 043969

Intermediate connection 6.18

K2CO3 (1244 mg, 9 mol) and 2-(3bromopropoxy)tetrahydro-2H-pyran (764 μL, 4.5 mmol) were added to the reaction mixture of intermediate 5.17 and the mixture was stirred overnight at 90°C. The mixture was cooled and purified by chromatography to obtain 920 mg of product.

MS (ESI+): (M+H-THP) ⁺ 369.

HPLC: RT=0.75 min, Method D.

Intermediate connection 6.19

To a mixture of intermediate 11.5 (0.63 g, 2.08 mmol) in DMF (10 ml) was added K2CO3 (0.86 g, 6.23 mmol) and 2-(3-bromopropoxy)tetrahydro-2H-pyran (0.53 ml, 3.12 mmol), and the mixture stirred for 2 hours at 80°C. H ₂ O was added and extracted with EtOAc. The combined organic layers were dried and concentrated in vacuo. The crude product was purified by chromatography and lyophilized to obtain 414 mg of product.

MS (ESI ⁺ ): (M+H) ⁺ 447/449.

HPLC: RT=0.73 min, Method G.

Intermediate 6.20

To a mixture of intermediate 5.18 (148 mg, 0.356 mmol) in anhydrous DMF (1 ml) was added K2CO3 (98.3 mg, 0.711 mmol) and 2-(3-bromopropoxy)tetrahydro-2H-pyran (90.4 µl, 0.533 mmol), and the mixture was stirred for 2 hours at 50°C. H ₂ O was added and extracted with EtOAc. The combined organic layers were dried and concentrated in vacuo. The crude product was purified by chromatography and lyophilized to obtain 174 mg of product.

MS (ESI ⁺ ): (M+H) ⁺ 558/560.

HPLC: RT=1.38 min, Method C.

Intermediate 6.21

6.21 •

Intermediate 6.21 was prepared in a similar manner to the preparation of intermediate 6.19 using intermediate 5.19.

- 39 043969

MS (ESI ⁺ ): (M+H) ⁺ 540/541. HPLC: RT=0.69 min, Method D. Intermediate 6.22

To a mixture of intermediate 5.21 (61 mg, 0.145 mmol) in DMF (2 ml) was added K2CO3 (40 mg, 0.29 mmol) and 2-(3-bromopropoxy)tetrahydro-2H-pyran (36.8 μl, 0.217 mmol), and the mixture stirred for 2 hours at 50°C. H ₂ O was added and extracted with EtOAc. The combined organic layers were dried and concentrated in vacuo. The crude product was purified by chromatography and lyophilized to obtain 66 mg of product.

MS (ESI ⁺ ): (M+H) ⁺ 564.

HPLC: RT=1.17 min, Method F.

Intermediate connection 6.24

To a mixture of intermediate 5.23 (900 mg, 2.35 mmol) in DMF (3.81 mL) was added K2CO3 (0.97 g, 7.04 mmol) and 2-(3-bromopropoxy)tetrahydro-2H-pyran (0.60 mL, 3.52 mmol), and the mixture stirred for 1 hour at 110°C. The mixture was cooled, filtered, diluted with ACN and purified by chromatography to give 1.15 g of product.

MS (ESI ⁺ ): (M+H-THP) ⁺ 527.

HPLC: RT=0.79 min, Method G.

Intermediate 6.25

To a mixture of intermediate 5.24 (54 mg, 0.135 mmol) in DMF (1 ml) was added K2CO3 (37 mg, 0.270 mmol) and 2-(3-bromopropoxy)tetrahydro-2H-pyran (34.3 μl, 0.203 mmol), and the mixture stirred for 2 hours at 50°C. H ₂ O was added and extracted with EtOAc. The combined organic layers were dried and concentrated in vacuo. The crude product was purified by chromatography and lyophilized to obtain 55.0 mg of product.

MS (ESI ⁺ ): (M+H-THP) ⁺ 542/544.

HPLC: RT=1.32 min, Method C.

Intermediate 6.26

- 40 043969

To a mixture of intermediate 5.30 (268 mg, 0.928 mmol) in DMF (3 ml) was added K2CO3 (567 mg, 1.856 mmol) and 2-(3-bromopropoxy)tetrahydro-2H-pyran (0.24 ml, 1.392 mmol), and the mixture stirred for 1 hour at 80°C. H2O was added and extracted with EtOAc. The combined organic layers were dried, concentrated in vacuo and the crude product was purified by chromatography to give 345 mg of product.

MS (ESI ⁺ ): (M+H) ⁺ 431 HPLC: RT=0.91 min, Method F.

Intermediate 6.27

.

Intermediate 6.27 was prepared in a similar manner to the preparation of intermediate 6.25 using intermediate 5.31.

MC (ESI ⁺ ): (M+H-THP) ⁺ 524/526.

HPLC: RT=1.31 min, Method C.

Intermediate connection 7.1

To a mixture of intermediate 6.1 (50 mg, 0.088 mmol) in dioxane (1 ml) was added 2methylcyclobutan-1-ol (0.5 ml) and sodium hydride (55%, 7.7 mg, 0.175 mmol). The mixture was stirred for 6 hours at 100°C. H ₂ O was added and extracted with EtOAc. The combined organic layers were dried and concentrated in vacuo and the resulting crude product was used without further purification.

HPLC: RT=1.36 min, Method F.

Intermediate connection 7.2

Intermediate 6.2 (70 mg, 0.127 mmol) was added to a mixture of cyclohexanol (26.7 µl, 0.254 mmol) and sodium hydride (11.1 mg, 0.254 mmol) in DMF (0.5 ml) and the reaction mixture was stirred for 1 h at 50°C . H2O was added and extracted with DCM. The combined organic layers were dried and concentrated in vacuo and the resulting crude product was used without further purification.

MS (ESI+): (M+H) ⁺ 616/617.

HPLC: RT=0.75 min, Method E.

Intermediate connection 7.3

- 41 043969

To a mixture of sodium hydride (55%, 7.6 mg, 0.18 mmol) in 2-methylcyclobutan-1-ol (0.5 ml) was added intermediate 6.3 (50 mg, 0.09 mmol) and the mixture was stirred for 1.5 h at 100°C. H ₂ O was added and extracted with EtOAc. The combined organic layers were dried and concentrated in vacuo and used without further purification.

MS (ESI+): (M+H) ⁺ 622.

HPLC: RT=1.65 min, Method C.

Intermediate connection 7.4

•

Intermediate 7.4 was prepared in a similar manner to the preparation of intermediate 7.1 using intermediate 6.1 and cyclopentanol.

MS (ESI ⁺ ): (M+H) ⁺ 621.

HPLC: RT=1.36 min, Method F.

Intermediate 7.5

.

Intermediate 7.5 was prepared in a similar manner to the preparation of intermediate 7.1 using intermediate 6.1 and 3-methylcyclobutan-1-ol.

HPLC: RT=1.35 min, Method F.

Intermediate connection 7.6

To a mixture of intermediate 6.2 (70 mg, 0.13 mmol) in DMF (0.5 ml) was added spiro[3.3]heptan-1-ol (28.5 mg, 0.25 mmol) and sodium hydride (55%, 11.1 mg, 0.25 mmol). The mixture was stirred for 1 hour at 50°C. H ₂ O was added and extracted with DCM. The combined organic layers were dried and concentrated in vacuo and the crude product was used without further purification.

MS (ESI ⁺ ): (M+H) ⁺ 628/629.

HPLC: RT=0.8 min, Method E.

Intermediate connection 7.7

- 42 043969

To a mixture of intermediate 6.4 (135 mg, 0.24 mmol) in dioxane (1 ml) was added bicyclo[2.2.1]heptan-2-ol (0.5 ml, 4.28 mmol) and sodium hydride (55%, 21.2 mg, 0.49 mmol) . The mixture was stirred for 3 hours at 110°C. H ₂ O was added and extracted with EtOAc. The combined organic layers were dried and concentrated in vacuo. The crude product was purified by chromatography to obtain 117 mg of product.

MS (ESI+): (M+H) ⁺ 632.

HPLC: RT=0.98 min, Method G.

Intermediate connection 7.8

Intermediate 6.2 (100 mg, 0.18 mmol) was added to a mixture of cyclopentanol (1 ml) and sodium hydride (55%, 15.8 mg, 0.36 mmol) in DMF (1 ml) and the reaction mixture was stirred for 1.5 h at 110°C . H ₂ O was added and extracted with EtOAc. The combined organic layers were dried and concentrated in vacuo and used without further purification.

HPLC: RT=0.98 min, Method D.

Intermediate connection 7.9

•

Intermediate 7.9 was prepared in a similar manner to the preparation of intermediate 7.3 using intermediate 6.6.

MS (ESI ⁺ ): (M+H) ⁺ 676.

HPLC: RT=1.65 min, Method C.

Intermediate connection 7.11

Intermediate 6.4 (70 mg, 0.126 mmol) was added to a mixture of 2,2-dimethylcyclobutan-1-ol (0.5 mL) and sodium hydride (55%, 11 mg, 0.252 mmol) and the reaction mixture was stirred for 2 h at .T. H ₂ O was added and extracted with DCM. The combined organic layers were dried and concentrated in vacuo and the crude product was used without further purification.

MC (ESI ⁺ ): (M+H) ⁺ 620/621.

HPLC: RT=0.97 min, Method D.

- 43 043969

Intermediate connection 7.12

To a mixture of sodium hydride (55%, 13.3 mg, 0.30 mmol) in 2-methylcyclobutan-1-ol (0.5 ml) was added intermediate 6.7 (90 mg, 0.15 mmol) and the mixture was stirred for 1.5 h at 100°C. H ₂ O was added and extracted with EtOAc. The combined organic layers were dried, concentrated in vacuo and the crude product was purified by chromatography to give 33.0 mg of product.

MC (ESI ⁺ ): (M+H) ⁺ 642.

HPLC: RT=1.62 min, Method C.

Intermediate connection 7.14

Vg

7.14 •

Intermediate 7.14 was prepared by analogy with the preparation of intermediate

7.11, using intermediate connection 6.10.

MC (ESI ⁺ ): (M+H) ⁺ 668.

HPLC: RT=0.99 min, Method D.

Intermediate connection 7.15

To a mixture of sodium hydride (55%, 12.9 mg, 0.30 mmol) in 2-methylcyclobutan-1-ol (0.3 ml) was added intermediate 6.11 (90 mg, 0.15 mmol) and the mixture was stirred for 2 h at 100°C. H ₂ O was added and extracted with EtOAc. The combined organic layers were dried, concentrated in vacuo and the resulting crude product was purified by chromatography to give 69.7 mg of product.

MS (ESI+): (M+H) ⁺ 660.

HPLC: RT=1.61 min, Method C.

Intermediate connection 7.17

To a mixture of cyclobutanol (44.2 μl, 0.567 mmol) and sodium hydride (24.8 mg, 0.567 mmol) in DMF (1

- 44043969 ml) intermediate 6.12 (160 mg, 0.284 mmol) was added and the reaction mixture was stirred for 4.5 h at 50°C. H ₂ O was added and extracted with EtOAc. The combined organic layers were dried and concentrated in vacuo and the resulting crude product was used without further purification.

MS (ESI+): (M+H) ⁺ 600/601.

HPLC: RT=0.99 min, Method G.

Intermediate connection 7.18

To a mixture of sodium hydride (55%, 12.2 mg, 0.28 mmol) in 3-methylcyclobutan-1-ol (0.3 ml) was added intermediate 6.3 (80 mg, 0.14 mmol) and the mixture was stirred for 2 h at 100°C. H ₂ O was added and extracted with EtOAc. The combined organic layers were dried and concentrated in vacuo and the resulting crude product was used without further purification.

MS (ESI+): (M+H) ⁺ 622.

HPLC: RT=1.64 min, Method C.

Intermediate 7.20

.

Intermediate 7.20 was prepared in a similar manner to the preparation of intermediate 7.11 using intermediate 6.4 and 3-methylcyclobutan-1-ol.

MS (ESI+): (M+H) ⁺ 606/607.

HPLC: RT=0.93 min, Method D.

Intermediate connection 7.21

To a mixture of sodium hydride (55%, 14.2 mg, 0.33 mmol) in 2-methylcyclobutan-1-ol (0.5 ml) was added intermediate 6.2 (100 mg, 0.16 mmol) and the mixture was stirred for 2 h at room temperature. H ₂ O was added and extracted with DCM. The combined organic layers were dried and concentrated in vacuo and the resulting crude product was used without further purification.

MS (ESI ⁺ ): (M+H) ⁺ 602/603.

HPLC: RT=1.68 min, Method C.

- 45 043969

Intermediate connection 7.22

To a mixture of intermediate 15.2 (230 mg, 0.42 mmol) in THF (2.5 ml), 3methylcyclobutan-1-ol (72 mg) and sodium hydride (60%, 33.5 mg, 0.84 mmol) were added and the reaction mixture was stirred for 1 h at room temperature, 30 min at 40°C and 1.5 h at 60°C. The mixture was cooled and used without further purification.

MS (ESI ⁺ ): (M+H) ⁺ 616.

HPLC: RT=0.75 min, Method G.

Intermediate connection 7.23

To a mixture of intermediate 6.3 (60 mg, 0.11 mmol) in dioxane (0.5 ml) was added trans-2methylcyclopentan-1-ol (1 ml) and sodium hydride (55%, 9.2 mg, 0.21 mmol). The mixture was stirred for 1.5 h at 100°C. H ₂ O was added and extracted with EtOAc. The combined organic layers were dried and concentrated in vacuo to give 13.1 mg of product as a racemic mixture.

MS (ESI+): (M+H) ⁺ 636.

HPLC: RT=0.76 min, Method H.

Intermediate connection 7.24

Intermediate 6.2 (70 mg, 0.13 mmol) was added to a mixture of cyclopent-3-en-1-ol (21.3 mg, 0.25 mmol) and sodium hydride (11.1 mg, 0.25 mmol) in DMF (0.5 mL) and the reaction mixture was stirred for 1 hour at 50°C. H ₂ O was added and extracted with DCM. The combined organic layers were dried and concentrated in vacuo and used without further purification.

MS (ESI ⁺ ): (M+H) ⁺ 600/601.

HPLC: RT=0.64 min, Method E.

Intermediate 7.25

To a mixture of sodium hydride (55%, 11.6 mg, 0.266 mmol) in cyclopentanol (0.5 ml) was added intermediate

- 46 043969 exact compound 6.3 (76 mg, 0.133 mmol) and the mixture was stirred for 1.5 h at 100°C. H2O was added and extracted with EtOAc. The combined organic layers were dried, concentrated in vacuo and purified by chromatography to give 26.2 mg of product.

MS (ESI+): (M+H) ⁺ 622.

HPLC: RT=1.64 min, Method C.

Intermediate 7.26

•

Intermediate 7.26 was prepared in a similar manner to the preparation of intermediate 7.21 using intermediate 6.4 and 3,3-dimethylcyclobutan-1-ol.

MS (ESI+): (M+H) ⁺ 620/621.

HPLC: RT=0.96 min, Method D.

Intermediate connection 7.27

The reaction was carried out in an argon atmosphere.

Mixture of intermediate 6.1 (74 mg, 0.13 mmol), 5-(di-tert-butylphosphanyl)-1',3',5'triphenyl-GN-1,4'-bipyrazole (3.3 mg, 0.006 mmol), tris( (1E,4E)-1,5-diphenylpenta-1,4-dien-3one)dipalladium (4.8 mg, 0.005 mmol), CS ₂ CO ₃ (42.3 mg, 0.13 mmol) and 3,3-difluorocyclobutan-1-ol (300 µl) in anhydrous dioxane (2 ml, 22.7 mmol) was stirred for 45 min at 100°C in a microwave oven. The mixture was filtered, concentrated in vacuo, and the resulting crude product was purified by chromatography and lyophilized to give 53.0 mg of product.

MS (ESI+): (M+H) ⁺ 462/463.

HPLC: RT=0.9 min, Method G.

Intermediate connection 7.28

Sodium hydride (55%, 7.9 mg, 0.18 mmol) was added to a mixture of intermediate 6.4 (50 mg, 0.09 mmol) in cyclohexanol (0.5 mL, 4.8 mmol) and dioxane (1 mL, 11.3 mmol) and the reaction mixture was stirred for 1 hour at 110°C. H ₂ O was added and extracted with EtOAc. The combined organic layers were dried and concentrated in vacuo and the resulting crude product was used without further purification.

MC (ESI+): (M+H) ⁺ 620.

HPLC: RT=0.95 min, Method F.

- 47 043969

Intermediate connection 7.29

To a mixture of sodium hydride (55%, 11.4 mg, 0.26 mmol) in 2,2-dimethylcyclobutan-1-ol (0.5 ml) was added intermediate 6.16 (70 mg, 0.13 mmol) and the mixture was stirred for 1 h at 50° WITH. H ₂ O was added and extracted with DCM. The combined organic layers were dried, concentrated in vacuo and the resulting crude product was used without further purification.

MC (ESI ⁺ ): (M+H) ⁺ 602/603.

HPLC: RT=1.32 min, Method F.

Intermediate connection 7.30

To a mixture of sodium hydride (55%, 11.4 mg, 0.26 mmol) in 3,3-dimethylcyclobutan-1-ol (0.5 ml) was added intermediate 6.16 (70 mg, 0.13 mmol) and the mixture was stirred for 1 h at room temperature. T. Additional sodium hydride was added and the mixture was stirred for 1 hour at 50°C. H2O was added and extracted with DCM. The combined organic layers were dried, concentrated in vacuo and the resulting crude product was used without further purification.

MC (ESI+): (M+H) ⁺ 602/603.

HPLC: RT=1.29 min, Method F.

Intermediate connection 7.31

.

Intermediate 7.31 was prepared in a similar manner to the preparation of intermediate 7.21 using intermediate 6.1. MS (ESI ⁺ ): (M+H) ⁺ 606 HPLC: RT=0.85 min, Method D.

Intermediate 7.32

To a mixture of intermediate 6.16 (83 mg, 0.15 mmol) in dioxane (0.5 ml, 5.67 mmol) was added 3-methylcyclobutan-1-ol (0.5 ml) and sodium hydride (55%, 13.5 mg, 0.31 mmol), and the reaction mixture stirred for 2 hours at 100°C. H2O was added and extracted with EtOAc. The combined organic layers were dried and concentrated in vacuo and used without further purification.

- 48 043969

MC (ESI ⁺ ): (M+H) ⁺ 588.

HPLC: RT=0.93 min, Method D.

Intermediate connection 7.34

.

Intermediate 7.34 was prepared in a similar manner to the preparation of intermediate 7.6 using intermediate 6.4 and 4-(trifluoromethyl)cyclohexan-1-ol.

MS (ESI ⁺ ): (M+H) ⁺ 688/689.

HPLC: RT=0.94 min, Method G.

Intermediate 7.35

To a mixture of sodium hydride (55%, 12.7 mg, 0.29 mmol) in cyclobutanol (1.5 ml) was added intermediate 6.3 (83 mg, 0.145 mmol) and the mixture was stirred overnight at 100°C. H ₂ O was added and extracted with EtOAc. The combined organic layers were dried, concentrated in vacuo and the resulting crude product was used without further purification.

MS (ESI+): (M+H) ⁺ 622.

HPLC: RT=1.64 min, Method C.

Intermediate 7.36

To a mixture of intermediate 15.2 (230 mg, 0.42 mmol) in THF (2.52 mL, 31.4 mmol), cyclopentanol (72 mg, 0.84 mmol) and sodium hydride (60%, 33.5 mg, 0.84 mmol) were added and the reaction mixture was stirred for 1 hour at room temperature, 30 minutes at 40°C and 1.5 hours at 60°C. The mixture was cooled and used without further purification.

MS (ESI+): (M+H) ⁺ 616.

HPLC: RT=0.75 min, Method E.

Intermediate 7.37

To a mixture of intermediate 6.20 (57 mg, 0.102 mmol) in dioxane (0.3 ml, 3.40 mmol) was added 2-methylcyclobutan-1-ol (0.2 ml) and sodium hydride (55%, 8.9 mg, 0.204 mmol), and the reaction

- 49 043969 the mixture was stirred for 2 hours at room temperature. and 1 hour at 40°C. H ₂ O was added and extracted with DCM. The combined organic layers were dried, concentrated and the resulting crude product was used without further purification.

MS (ESI ⁺ ): (M+H) ⁺ 608/610.

HPLC: RT=1.62 min, Method C.

Intermediate 7.38

To a mixture of sodium hydride (55%, 9.3 mg, 0.214 mmol) in 2-methylcyclobutan-1-ol (0.3 ml) and DMF (0.3 ml) was added intermediate 6.4 (70 mg, 0.107 mmol) and the mixture was stirred for 1 h at room temperature and 2 hours at 50°C. H ₂ O was added and extracted with DCM. The combined organic layers were dried, concentrated in vacuo and the resulting crude product was used without further purification.

MS (ESI+): (M+H) ⁺ 606/607.

HPLC: RT=1.6 min, Method C.

Intermediate 7.39

To a mixture of intermediate 15.2 (230 mg, 0.42 mmol) in THF (2.52 mL, 31.4 mmol), cyclobutanol (60.4 mg, 0.84 mmol) and sodium hydride (60%, 33.5 mg, 0.84 mmol) were added and the reaction mixture was stirred for 1 hour at room temperature, 30 minutes at 40°C and 1.5 hours at 60°C. The mixture was cooled and the resulting crude product was used without further purification.

MS (ESI ⁺ ): (M+H) ⁺ 602.

HPLC: RT=0.69 min, Method E.

Intermediate 7.40

The reaction was carried out in an argon atmosphere.

Mixture of intermediate 6.2 (70 mg, 0.127 mmol), 5-(di-tert-butylphosphanyl)-1',3',5'triphenyl-1H-1,4'-bipyrazole (3.21 mg, 0.006 mmol), tris( (1E,4E)-1,5-diphenylpenta-1,4-dien-3one)dipalladium (4.64 mg, 0.005 mmol), CS2CO3 (41.3 mg, 0.127 mmol) and 3,3-difluorocyclobutan-1-ol (250 mg ) in anhydrous dioxane (2 ml, 22.7 mmol) was stirred for 45 min at 100°C in a microwave oven. The mixture was filtered, concentrated in vacuo, purified by chromatography and lyophilized to give 61 mg of product.

MS (ESI ⁺ ): (M+H) ⁺ 624/625.

HPLC: RT=0.9 min, Method G.

- 50 043969

Intermediate connection 7.41

To a mixture of sodium hydride (55%, 11 mg, 0.252 mmol) in cyclopentanol (0.5 ml) was added intermediate 6.4 (70 mg, 0.126 mmol) and the mixture was stirred for 2 h at room temperature. H ₂ O was added and extracted with DCM. The combined organic layers were dried, concentrated and the resulting crude product was used without further purification.

MS (ESI ⁺ ): (M+H) ⁺ 606/607.

HPLC: RT=0.93 min, Method D.

Intermediate 7.42

To a mixture of intermediate 6.4 (50 mg, 0.09 mmol) in dioxane (1 ml, 11.3 mmol) was added cyclopent-3-en-1-ol (0.5 ml) and sodium hydride (55%, 7.85 mg, 0.18 mmol), and the reaction mixture was stirred for 1 hour at 110°C. H2O was added and extracted with EtOAc. The combined organic layers were dried, concentrated and the resulting crude product was used without further purification.

MS (ESI+): (M+H) ⁺ 604.

HPLC: RT=0.88 min, Method G.

Intermediate 7.43

A mixture of intermediate 6.21 (80 mg, 0.126 mmol) and 3,3-difluorocyclobutan-1-ol (27.2 mg, 0.252 mmol) in anhydrous THF (0.5 ml, 6.2 mmol) was cooled to 0°, then 2-methylpropan2-olate was added potassium (28.3 mg, 0.252 mmol), and the reaction mixture was stirred for 1 hour while cooling. H2O was added and extracted with DCM. The combined organic layers were dried, concentrated and the resulting crude product was used without further purification.

MC (ESI ⁺ ): (M+H) ⁺ 628/629.

HPLC: RT=0.78 min, Method D.

Intermediate 7.45

To a mixture of intermediate 6.22 (66 mg, 0.12 mmol) in dioxane (1 ml) was added cyclobe

- 51 043969 tanol (0.5 ml) and sodium hydride (55%, 10.3 mg, 0.24 mmol), and the reaction mixture was stirred for 4.5 hours at 110°C. H2O was added and extracted with EtOAc. The combined organic layers were dried, concentrated and the resulting crude product was used without further purification.

HPLC: RT=1.30 min, Method F.

Intermediate 7.47

.

Intermediate 7.47 was prepared in a similar manner to the preparation of intermediate 7.41 using intermediate 6.4 and cyclobutanol.

MC (ESI ⁺ ): (M+H) ⁺ 606.

HPLC: RT=0.9 min, Method D.

Intermediate 7.48

To a mixture of intermediate 6.25 (55 mg, 0.101 mmol) in dioxane (0.3 ml), 2methylcyclobutan-1-ol (0.2 ml) and sodium hydride (55%, 8.86 mg, 0.203 mmol) were added and the reaction mixture was stirred for 1 h at 40°C. H ₂ O was added and extracted with DCM. The combined organic layers were dried, concentrated and the resulting crude product was used without further purification.

MS (ESI+): (M+H) ⁺ 592/593.

HPLC: RT=1.56 min, Method C.

Intermediate 7.49

To a mixture of intermediate 6.16 (83 mg, 0.154 mmol) in dioxane (0.5 ml), cyclobutanol (2.0 ml) and sodium hydride (55%, 13.5 mg, 0.309 mmol) were added and the reaction mixture was stirred for 2 h at 100°C . H2O was added and extracted with EtOAc. The combined organic layers were dried, concentrated and the resulting crude product was used without further purification.

MS (ESI ⁺ ): (M+H) ⁺ 574.

HPLC: RT=0.89 min, Method D.

- 52 043969

Intermediate 7.50

To a mixture of intermediate 6.4 (70 mg, 0.126 mmol) in DMF (1 ml) was added cisbicyclo[3.1.0]hexan-3-ol (61.8 mg, 0.629 mmol) and sodium hydride (55%, 11 mg, 0.252 mmol) , and the reaction mixture was stirred for 1 hour at 50°C. Additional sodium hydride and (1R,5S)-bicyclo[3.1.0]hexan-3-ol were added and the mixture was stirred for 1 hour at 50°C. H ₂ O was added and extracted with DCM. The combined organic layers were dried, concentrated and the resulting crude product was used without further purification.

MS (ESI ⁺ ): (M+H) ⁺ 618/619.

HPLC: RT=0.94 min, Method G.

Intermediate connection 7.51

To a mixture of sodium hydride (55%, 13.8 mg, 0.316 mmol) in 2-methylcyclobutan-1-ol (0.5 ml) was added intermediate 6.16 (85 mg, 0.158 mmol) and the mixture was stirred for 1.5 h at 100°C. H2O was added and extracted with EtOAc. The combined organic layers were dried, concentrated and the resulting crude product was used without further purification.

MS (ESI ⁺ ): (M+H) ⁺ 588.

HPLC: RT=0.94 min, Method D.

Intermediate connection 7.52

To a mixture of intermediate 6.16 (83 mg, 0.154 mmol) in dioxane (0.5 ml), cyclopentanol (0.5 ml) and sodium hydride (55%, 13.5 mg, 0.309 mmol) were added and the reaction mixture was stirred for 6 h at 100°C . H ₂ O was added and extracted with EtOAc. The combined organic layers were dried, concentrated and the resulting crude product was used without further purification.

MS (ESI+): (M+H) ⁺ 588.

HPLC: RT=0.93 min, Method D.

Intermediate 7.53

To a mixture of intermediate 6.27 (54 mg, 0.067 mmol) in dioxane (0.3 ml) was added 2methylcyclobutan-1-ol (0.2 ml) and sodium hydride (55%, 5.9 mg, 0.134 mmol), and the reaction mixture was

- 53 043969 stirred for 2 hours at room temperature. and for 1 hour at 40°C. H ₂ O was added and extracted with DCM. The combined organic layers were dried, concentrated in vacuo and the resulting crude product was used without further purification.

MS (ESI+): (M+H) ⁺ 574/575.

HPLC: RT=1.56 min, Method C.

Intermediate connection 8.1 o

XX ^nh ₂

8.1

To mixture 2.1 (2.5 g, 12.62 mmol) in NaOH (1 mol/l, 30 ml, 30 mmol) was added hydrazine hydrate (1.16 ml, 23.34 mmol) and cooled to 0°C. Raney nickel was then added and the mixture was stirred for 1 hour at 0°C. The mixture was cooled, acidified to pH 7-8 using conc. HCl, the resulting precipitate was filtered off, washed with H ₂ O (50 ml) and t-butyl methyl ether (50 ml) and dried to obtain 2.15 g of product.

MS (ESI ⁺ ): (M+H) ⁺ 185.

HPLC: RT=0.15 min, Method F.

Intermediate connection 9.1

XX

Cl<s

9.1

After stirring a mixture of cyclobutanol (0.31 ml, 3.8 mmol) and sodium hydride (91.2 mg, 3.8 mmol) for 5 min in DMF (2 ml, 25 mmol), 2-chloro-6-fluoropyridine (250 mg, 1.9 mmol) was added. and the mixture was stirred for 1 hour at room temperature. H2O was added and extracted with DCM. The combined organic layers were dried and concentrated in vacuo. The crude product was purified by chromatography to obtain 245 mg of product.

MS (ESI ⁺ ): (M+H) ⁺ 184/186.

HPLC: RT=0.69 min, Method F.

Intermediate connection 9.2

9.2

The reaction was carried out in an argon atmosphere.

To a mixture of Pd(OAc) ₂ (118 mg, 0.526 mmol) and {[1,1'-binaphthalene]-2-yl}di-tert-butyl)phosphane (210 mg, 0.526 mmol) in anhydrous dioxane (20 ml, 227 mmol) 2-bromo-3-fluoro-6-methylpyridine (1.0 g, 5.263 mmol), cyclobutanol (821 µl, 10.526 mmol) and CS ₂ CO ₃ (1.715 g, 5.263 mmol) were added after 5 min. The reaction mixture was stirred for 45 min at 140°C in a microwave oven. The mixture was filtered, concentrated in vacuo and purified by chromatography to give 270 mg of product.

MS (ESI ⁺ ): (M+H) ⁺ 182/183.

HPLC: RT=0.72 min, Method G.

Intermediate connection 9.3

- 54 043969

After stirring a mixture of 3-methylcyclobutan-1-ol (0.25 ml, 2.7 mmol) and sodium hydride (55%, 236 mg, 5.4 mmol) for 10 min in DMF (5 ml, 61.5 mmol), 2-fluoro-6- methylpyridine (300 mg, 2.7 mmol) and the mixture was stirred for 1 h at room temperature. H ₂ O was added and extracted with diethyl ether. The combined organic layers were dried and concentrated and the resulting crude product was used without further purification.

MS (ESI ⁺ ): (M+H) ⁺ 178/179.

HPLC: RT=0.54 min, Method F.

Intermediate connection 9.4

To a mixture of 6-fluoro-3-iodo-2-methylpyridine (237 mg, 1.0 mmol) and 3-methylcyclobutan-1-ol (103 mg, 1.2 mmol) in THF (2 ml, 25 mmol) was added (tert-butoxy) potassium (224 mg, 2.0 mmol) at 0°C. The mixture was stirred for 15 minutes at 0°C. H ₂ O was added and extracted with EtOAc. The combined organic layers were dried and concentrated in vacuo to give 250 mg of product.

HPLC: RT=1.407/1.724 min, cis/trans, Method K.

Intermediate 9.5

After stirring a mixture of cyclobutanol (1.05 ml, 13.5 mmol) and sodium hydride (55%, 1178 mg, 27 mmol) for 10 min in DMF (10 ml, 123 mmol), 2-fluoro-6-methylpyridine (1.5 g, 13.5 mmol), and the mixture was stirred for 1 hour at room temperature. Additional sodium hydride was added and the mixture was stirred for 1 hour at 50°C. H ₂ O was added and extracted with diethyl ether. The combined organic layers were dried, concentrated and the resulting crude product was used without further purification.

MS (ESI ⁺ ): (M+H) ⁺ 164.

HPLC: RT=0.38 min, Method F.

Intermediate connection 9.6

To a mixture of cyclobutanol (8.14 ml, 104.4 mmol) in

THF (25.1 ml, 313.2 mmol), sodium hydride (60%, 835.2 mg, 20.8 mmol) was added and the mixture was stirred for 20 min at 60°C. 2chloro-5-iodopyridine (5.0 g, 20.8 mmol) was then added and the mixture was stirred overnight at 60°C. The mixture was cooled, filtered and concentrated in vacuo. The crude product was purified by chromatography to obtain 2.60 g of product.

MS (ESI+): (M+H) ⁺ 276.

HPLC: RT=0.76 min, Method D.

Intermediate connection 9.7

To a mixture of 5-bromo-2-chloro-4-(trifluoromethyl)pyridine (521 mg, 2.0 mmol) and cyclobutanol (313.2 μl,

- 55043969 mmol) in THF (2.4 ml, 30 mmol), potassium 2-methylpropan-2-olate (247 mg, 2.2 mmol) was added and the mixture was stirred for 20 min at room temperature. H ₂ O was added and extracted with DCM. The combined organic layers were dried and concentrated in vacuo to give 845 mg of product.

MS (ESI+): (M+H) ⁺ 297.

HPLC: RT=1.22 min, Method G.

Intermediate connection 9.8

9.8

Sodium hydride (379 mg, 8.69 mmol) was added to a mixture of 2,6-difluoropyridine (1.0 g, 8.69 mmol) and cyclobutanol (627 mg, 8.69 mmol) in DMF (8 mL) and the mixture was stirred overnight at room temperature. . H ₂ O was added and extracted with EtOAc. The combined organic layers were dried and concentrated in vacuo. The crude product was purified by chromatography to obtain 1.0 g of product.

MS (ESI ⁺ ): (M+H) ⁺ 116.

HPLC: RT=0.58 min, Method F.

Intermediate connection 10.1 χχ

10.1

The reaction was carried out in an argon atmosphere.

To a mixture of intermediate 9.1 (1.52 g, 8.28 mmol), potassium ethyl trifluoroboronide (2.25 g, 16.57 mmol) and K ₂ CO ₃ (3.43 g, 24.85 mmol) in a mixture of toluene/H ₂ O (10/1, 12 ml) Pd(OAc) ₂ (93 mg, 0.41 mmol) and X-Phos, and the mixture was stirred for 10 h at 140°C. The mixture was filtered, concentrated in vacuo and purified by chromatography to give 885 mg of product.

MS (ESI ⁺ ): (M+H) ⁺ 178/179.

HPLC: RT=0.54 min, Method F.

Intermediate connection 11.1

Bg XX ' ό

11.1

To a mixture of intermediate 10.1 (905 mg, 5.11 mmol) in anhydrous DMF (10 mL, 122.9 mmol) was added 1-bromopyrrolidine-2,5-dione (909 mg, 5.11 mmol) and the mixture was stirred for 2.5 h at room temperature. T. Na ₂ S ₂ O ₃ solution (10%) was added and extracted with DCM. The combined organic layers were dried and concentrated in vacuo. The crude product was purified by chromatography to obtain 905 mg of product.

MS (ESI ⁺ ): (M+H) ⁺ 256/258.

HPLC: RT=1.25 min, Method F.

Intermediate connection 11.2

To a mixture of intermediate 9.2 (220 mg, 1.21 mmol) in anhydrous DMF (3 ml, 36.9

- 56043969 mmol) 1-bromopyrrolidine-2,5-dione (259 mg, 1.46 mmol) was added and the mixture was stirred for 2 hours at 60°C. Na ₂ S ₂ O ₃ solution (10%) was added and extracted with DCM. The combined organic layers were dried and concentrated in vacuo. The crude product was purified by chromatography to obtain 116 mg of product.

HPLC: RT=0.85 min, Method G.

Intermediate connection 11.3

The reaction was carried out in an argon atmosphere.

To a mixture of intermediate 9.3 (478 mg, 2.7 mmol) in anhydrous THF (30 mL, 374 mmol) was added 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione (1.16 g, 4.05 mmol), and the mixture stirred overnight at room temperature. A Na ₂ S ₂ O ₃ solution was added, THF was evaporated and extracted with DCM. The combined organic layers were dried and concentrated in vacuo. The crude product was purified by chromatography to obtain 498 mg of product.

MS (ESI+): (M+H) ⁺ 256/258.

HPLC: RT=1.21 min, Method F.

Intermediate connection 11.4

The reaction was carried out in an argon atmosphere.

To a mixture of intermediate 9.5 (2.59 g, 13.5 mmol) in anhydrous THF (100 ml, 1247 mmol) was added 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione (5.78 g, 20.2 mmol), and the mixture stirred overnight at room temperature. A Na ₂ S ₂ O ₃ solution was added, THF was evaporated and extracted with DCM. The combined organic layers were dried and concentrated in vacuo. The crude product was purified by chromatography to obtain 2.27 g of product.

MS (ESI+): (M+H) ⁺ 242/244.

HPLC: RT=1.14 min, Method F.

Intermediate connection 11.5

To a mixture of intermediate 4.11 (722 mg, 2.23 mmol) in anhydrous THF (25 ml) was added 1-chloropyrrolidine-2,5-dione (0.33 g, 2.45 mmol) and the mixture was stirred overnight at 60°C. The mixture was concentrated in vacuo, H ₂ O was added and the resulting precipitate was filtered and dried to give 633 mg of product.

MS (ESI+): (M+H) ⁺ 305/307.

HPLC: RT=0.7 min, Method G.

Intermediate connection 11.6

To a mixture of intermediate 9.8 (300 mg, 1.79 mmol) in DCM (5 ml) was added 1 bromopyrrolidine-2,5-dione (319 mg, 1.79 mmol) and the mixture was stirred for 1 h at 50°C. Additional 1-bromopyrrolidine-2,5-dione and DMF (1 ml) were added and the mixture was stirred overnight at 50°C and for 3 days at room temperature. The mixture was concentrated in vacuo and purified by chromatography to give 389 mg of product as a 70/30 (11.6.1/11.6.2) mixture of regioisomers.

- 57 043969

MS (ESI ⁺ ): (M+H) ⁺ 246.

HPLC: RT=1.09 min, Method F.

Intermediate connection 12.1

The reaction was carried out in an argon atmosphere.

K ₂ CO ₃ (61 mg, 0.44 mmol), tricyclohexylphosphane (25 mg, 0.088 mmol), Pd(OAc) ₂ (10 mg, 0.044 mmol) and CuI (126 mg, 0.66 mmol), and the mixture was stirred overnight at 130°C. MeOH was added, filtered and concentrated in vacuo. H ₂ O was added and extracted with DCM. The combined organic layers were dried and concentrated in vacuo. The crude product was purified by chromatography to obtain 44.0 mg of product.

MS (ESI+): (M+H) ⁺ 588/589.

HPLC: RT=0.95 min, Method G.

Intermediate connection 12.2

The reaction was carried out in an argon atmosphere.

To a mixture of intermediate 6.15 (100 mg, 0.234 mmol) and intermediate 11.3 (60.1 mg, 0.234 mmol) in anhydrous THF (200 µl, 2.49 mmol) and anhydrous DMF (400 µl, 4.92 mmol) was added K2CO3 (65 mg, 0.469 mmol), tricyclohexylphosphane (26 mg, 0.094 mmol), Pd(OAc) ₂ (10.5 mg, 0.047 mmol) and CuI (134 mg, 0.703 mmol), and the mixture was stirred for 2 d at 130°C. H ₂ O was added and extracted with EtOAc. The combined organic layers were dried and concentrated in vacuo. The crude product was purified by chromatography and lyophilized to obtain 35.0 mg of product.

MS (ESI ⁺ ): (M+H) ⁺ 602.

HPLC: RT=1.32 min, Method F.

Intermediate connection 12.3

The reaction was carried out in an argon atmosphere.

K ₂ CO ₃ (173 mg, 1.254 mmol), tricyclohexylphosphane (70 mg, 0.251 mmol), Pd(OAc) ₂ (28 mg, 0.125 mmol) and CuI (358 mg, 1.88 mmol), and the mixture was stirred overnight at 125°C. The mixture was cooled and purified on a silica gel column and further purified by chromatography to obtain 57.0 mg of product.

MS (ESI+): (M+H) ⁺ 588.

HPLC: RT=0.92 min, Method D.

- 58 043969

Intermediate connection 12.4

The reaction was carried out in an argon atmosphere.

K2CO3 (143 mg, 1.03 mmol), tricyclohexylphosphane (58 mg, 0.206 mmol), Pd(OAc) ₂ (23 mg, 0.103 mmol) and CuI (295 mg, 1.55 mmol), and the mixture was stirred overnight at 130°C. H ₂ O was added and the mixture was made basic with NH 3 and extracted with EtOAc. The combined organic layers were dried and concentrated in vacuo. The crude product was purified by chromatography to obtain 121 mg of product.

MS (ESI ⁺ ): (M+H) ⁺ 589/590.

HPLC: RT=0.8 min, Method F.

Intermediate connection 12.5

The reaction was carried out in an argon atmosphere.

K ₂ CO ₃ (428 mg, 3.09 mmol), tricyclohexylphosphane (162 mg, 0.62 mmol), Pd(OAc) ₂ (69 mg, 0.309 mmol) and CuI (884 mg, 4.64 mmol), and the mixture was stirred for 4 h at 180°C. H ₂ O was added and extracted with DCM. The combined organic layers were dried and concentrated in vacuo. The crude product was purified by chromatography to obtain 221 mg of product.

MS (ESI+): (M+H) ⁺ 600.

HPLC: RT=0.99 min, Method D.

Intermediate connection 12.6

12.6

The reaction was carried out in an argon atmosphere.

K2CO3 (51.4 mg, 0.372 mmol), tricyclohexylphosphane (20.9 mg, 0.074 mmol), Pd(OAc) ₂ (8.3 mg, 0.037 mmol) and CuI (106 mg, 0.558 mmol), and the mixture was stirred overnight at 130°C. The mixture was filtered, washed with ACN and DMF, and purified by chromatography to obtain 42.3 mg of product.

MS (ESI ⁺ ): (M+H) ⁺ 596.

- 59 043969

Intermediate connection 13.1

To a mixture of intermediate 4.3 (230 mg, 1.277 mmol) in HOAc (5 ml) was added sodium acetate (209.5 mg, 2.553 mmol) and the mixture was heated to 50°C. To this mixture was added a solution of dibromine (131 μl, 2.553 mmol) in HOAc (5 ml), and the reaction mixture was stirred for 1 hour at 50°C. Water was added, the resulting precipitate was filtered, washed with water and dried to obtain 90.0 mg of product.

MS (ESI ⁺ ): (M+H) ⁺ 261/262.

HPLC: RT=0.37 min, Method F.

Intermediate connection 13.2

To a mixture of intermediate 4.8 (7.42 g, 35.74 mmol) in H ₂ O (35.4 ml, 1.97 mol) was added dibrome (2.75 ml, 53.62 mmol) and the mixture was stirred overnight at 100°C in a closed vessel. The mixture was cooled, H ₂ O (200 ml) was added and the resulting precipitate was filtered, washed with H ₂ O and t-butyl methyl ether and dried to give 3.05 g of product.

MS (ESI+): (M+H) ⁺ 232.

HPLC: RT=0.24 min, Method F.

Intermediate connection 14.1

The reaction was carried out in an argon atmosphere.

Mixture of intermediate 11.2 (76 mg, 0.292 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3, 2-dioxaborolane (80.2 mg), potassium acetate (86.1 mg, 0.877 mmol) and complex 1,G-bis(diphenylphosphino)ferrocene-palladium(P) dichloride - dichloromethane (7.2 mg, 0.009 mmol) in dioxane (1 ml) were stirred overnight at 50°C. The mixture was filtered and concentrated in vacuo. H ₂ O was added and extracted with DCM. The combined organic layers were filtered through a silica gel column, dried and concentrated in vacuo to give 85.0 mg of product.

MC (ESI ⁺ ): (M+H) ⁺ 308/309.

HPLC: RT=0.94 min, Method G.

Intermediate connection 15.1

The reaction was carried out in an argon atmosphere.

To a mixture of intermediate 6.9 (112 mg, 0.22 mmol) and intermediate 14.1

- 60 043969 (104 mg, 0.22 mmol) in THF (2 ml, 25 mmol) was added K3PO4 (1 mol/l, 0.44 ml, 0.44 mmol) and after 5 min dicyclohexyl[2',4',6'- tris(propan-2-yl)-[1,1'-biphenyl]-2-yl]phosphane {2'-amino[1,1'-biphenyl]-2-yl}palladium yl methanesulfonate (18.6 mg, 0.022 mmol), and the reaction mixture was stirred for 5 hours at 100°C. The mixture was filtered, washed with MeOH and concentrated in vacuo. The crude product was purified by chromatography to obtain 35 mg of product.

MC (ESI ⁺ ): (M+H) ⁺ 610/611.

HPLC: RT=1.26 min, Method F.

Intermediate connection 15.2

The reaction was carried out in an argon atmosphere.

To a mixture of intermediate 6.14 (810 mg, 1.56 mmol) in dioxane (34.4 ml, 390 mmol) was added a complex of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) with dichloromethane (1:1, 255 mg, 0.31 mmol) and after 5 min (6-fluoro-2-methylpyridin-3-yl)boronic acid (314 mg, 2.03 mmol) and CS ₂ CO ₃ (2 mol/l, 1.56 ml, 3.12 mmol) were added, and the mixture stirred for 3 hours at 100°C. The mixture was cooled, filtered and washed with a mixture of MeOH/ACN (1/1). Thiol polymer (1 g) was added and the mixture was again filtered and washed with MeOH/ACN (1/1). The crude product was purified by chromatography to obtain 700 mg of product.

MS (ESI+): (M+H) ⁺ 550.

HPLC: RT=0.83 min, Method G.

Intermediate connection 15.3

The reaction was carried out in an argon atmosphere.

To a mixture of intermediate 6.19 (100 mg, 0.22 mmol) and intermediate 14.1 (82 mg, 0.17 mmol) in THF (2 ml, 25 mmol) was added K3PO4 (0.5 mol/l, 0.9 ml, 0.45 mmol) and after 5 min, methanesulfonate (2-dicyclohexylphosphino-2',4',6'-triisopropyl)-1,1'-biphenyl)[2(2'-amino-1,1'-biphenyl)]palladium(II) (18.9 mg) was added , 0.022 mmol), and the reaction mixture was stirred for 5 h at 100°C. The mixture was filtered, washed with MeOH and concentrated in vacuo. The crude product was purified by chromatography to obtain 58.0 mg of product.

MS (ESI ⁺ ): (M+H) ⁺ 592/593.

HPLC: RT=0.9 min, Method G.

Intermediate connection 16.1

To a mixture of 3-sulfamoylbenzoic acid (70.1 mg, 0.348 mmol) and DMAP (4.4 mg, 0.036 mmol) in DMF (0.5 ml), 2-methylcyclobutan-1-ol (30 mg, 0.348 mmol) and DCC (86.5 mg, 0.415 mmol) and the mixture was stirred for 1 hour. H ₂ O was added and the mixture was extracted with DCM. The combined organic layers were dried, concentrated in vacuo and purified by chromatography to give 21.0 mg of product as a mixture of diastereomers.

- 61 043969

MS (ESI ⁺ ): (M+H) ⁺ 268/269.

HPLC: RT=0.53/0.54 min, Method D.

Intermediate connection 19.1

A mixture of intermediate 5.14 (1.7 g, 5.29 mmol) in DMF (22 ml, 270 mmol) was heated to 50°C. Sodium hydride (60%, 211.8 mg, 5.29 mmol) was then added and stirred for 30 min at 50°C. Additional DMF (7.3 mL, 90 mmol) and 2-iodobutane (3.05 mL, 26.5 mmol) were added and the mixture was stirred for 3 h at 80°C. The mixture was cooled and purified by chromatography to obtain 700.0 mg of product.

MS (ESI ⁺ ): (M+H) ⁺ 379.

HPLC: RT=0.63 min, Method G.

Intermediate connection 19.2

A mixture of intermediate 21.1 (2 g, 8.26 mmol) in DMF (45 ml, 553 mmol) was heated to 50°C. Sodium hydride (55%, 360.3 mg, 8.23 mmol) was then added and stirred for 1 hour at 50°C. 2-iodopropane (4.13 mL, 41.28 mmol) was added and the mixture was stirred for 1 hour at 80°C. The mixture was cooled, purified by chromatography and lyophilized to give 661 mg of product.

MS (ESI ⁺ ): (M+H) ⁺ 285/286.

HPLC: RT=0.65 min, Method F.

Intermediate connection 20.1

To a mixture of 2-amino-9-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6,9-dihydro-1Hpurin-6-one (60 g, 211.8 mmol) in DMSO (160 ml, 2.25 mol), (bromomethyl)benzene (30.2 ml, 254.2 mmol) was added dropwise, and the mixture was stirred for 4 h at 50°C. The mixture was cooled and HCl (4 mol/L, 122 mL, 487.2 mmol) was added dropwise and the mixture was stirred for 2 hours at 70°C. The mixture was cooled, filtered, washed with MeOH and dried to obtain 41.8 g of product.

MS (ESI ⁺ ): (M+H) ⁺ 242.

HPLC: RT=0.28 min, Method D.

- 62 043969

Intermediate connection 21.1

To a mixture of intermediate 20.1 (1.41 g, 5.86 mmol) in AcOH (40 ml), NaNO ₂ (404 mg, 5.86 mmol) in H ₂ O (5 ml) was added dropwise at 50°C, and the mixture was stirred for 3 h at 50°C. Additional NaNO ₂ (404 mg, 5.86 mmol) in H ₂ O (5 ml) was added and the mixture was stirred overnight at 70°C. The mixture was cooled, made basic with NaHCO ₃ solution and extracted with DCM. The combined organic layers were dried and concentrated in vacuo. The crude product was purified by chromatography and lyophilized to give 1.13 g of product.

MS (ESI ⁺ ): (M+H) ⁺ 242.

HPLC: RT=0.32 min, Method A.

Intermediate connection 22.1

To a mixture of intermediate 12.5 (220 mg, 0.367 mmol) in THF (3.03 mL, 37.8 mmol) was added tetrabutylammonium fluoride (1 mol/L, 651 mg, 0.734 mmol) and the mixture was stirred overnight at 80°C. The mixture was cooled and used without further purification.

MS (ESI+): (M+H) ⁺ 386.

HPLC: RT=0.62 min, Method D.

Intermediate connection 23.1

A mixture of intermediate 4.10 (0.89 g, 1.72 mmol), Raney nickel (60 mg) and NaOH (1 N, 60 ml, 1.5 mol) was hydrogenated at room temperature. and pressure H ₂ 50 psi. inch for 2 days. The mixture was filtered and acidified with HCl. The resulting precipitate was filtered off, washed with water and dried to obtain 62.0 mg of product.

MS (ESI ⁺ ): (M+H) ⁺ 261/262.

HPLC: RT=0.34 min, Method D.

Intermediate connection 24.1

To a mixture of (4-cyclopropylphenyl)methanol (646 mg, 4.36 mmol) in DCM (5 mL) was added tribromophosphamide (286.8 μL, 3.05 mmol) and THF (1 mL), and the mixture was stirred for 30 min at room temperature. Additional tribromophosphamide was added and the mixture was made basic with saturated NaHCO ₃ solution under ice cooling and extracted with DCM. The combined organic layers were dried and concentrated in vacuo to give 744 mg of product.

HPLC: RT=0.69 min, Method F.

- 63 043969

Intermediate connection 24.2

Tribromophosphamide (355.3 μL, 2.88 mmol) was added to a mixture of {4-[2-(trimethylsilyl)ethynyl]phenyl}methanol (772.4 mg, 3.78 mmol) in chloroform (3 mL) under ice cooling. The mixture was stirred overnight at room temperature. H ₂ O was added and extracted with DCM. The combined organic layers were dried and concentrated in vacuo. The crude product was purified by chromatography to obtain 150.0 mg of product.

HPLC: RT=1.20 min, Method F.

Intermediate connection 25.1

25.1

To a mixture of intermediate 5.29 (13 mg, 0.02 mmol) in MeOH (1 ml) and THF (1 ml) was added K ₂ CO ₃ (5.5 mg) and the mixture was stirred for 2 h at room temperature. and used without further purification in the next step.

MS (ESI+): (M+H) ⁺ 584.

HPLC: RT=0.81 min, Method A.

Intermediate connection 26.1

The reaction was carried out in an argon atmosphere.

A mixture of intermediate 9.6 (1.375 g, 5.00 mmol), tris(dibenzylideneacetone)dipalladium(0) (45.8 mg, 0.05 mmol) and triphenylphosphane (1.31 g, 5.00 mmol) in xylene (3.37 ml, 28.5 mmol) was stirred for 4.5 h when heated under reflux. The mixture was cooled, EtOAc (100 ml) was added and refluxed. The mixture was cooled again and the resulting precipitate was filtered, washed with EtOAc and dried to obtain 2.20 g of product.

MS (ESI ⁺ ): (M+H) ⁺ 410.

HPLC: RT=0.58 min, Method A.

Intermediate connection 27.1

The reaction was carried out in an argon atmosphere.

To a mixture of intermediate 26.1 (633 mg, 0.88 mmol) and Pd(OAc) ₂ (40 mg, 0.18 mmol) in DMF (2.5 ml) was added a solution of intermediate 6.9 (450 mg, 0.88 mmol) and K ₂ CO ₃ (366 mg, 2.65 mmol) in DMF (3 ml), and the mixture was stirred for 3 days at 120°C. The mixture was cooled, filtered

- 64 043969 was poured through a celite pack, washed with DCM/MeOH (95/5), concentrated in vacuo and purified by chromatography to give 27.0 mg of product.

MS (ESI+): (M+H) ⁺ 578.

HPLC: RT=0.87 min, Method D.

Examples

Example 1

Toluene-4-sulfonic acid hydrate (20.7 mg, 0.11 mmol) was added to a mixture of intermediate 7.1 (54.0 mg, 0.09 mmol) in MeOH (1.0 mL) and THF (1.0 mL). The mixture was stirred for 1 hour at room temperature. The mixture was concentrated in vacuo and purified by chromatography to give 29.5 mg of product.

MS (ESI ⁺ ): (M+H) ⁺ 536.

HPLC: RT=0.84 min, Method F.

Example 2

Toluene-4-sulfonic acid hydrate (0.06 g, 0.32 mmol) was added to a mixture of intermediate 7.2 (39.0 mg, 0.06 mmol) in MeOH (2.0 mL). The mixture was stirred for 1 hour at room temperature. The mixture was purified by chromatography to obtain 23.0 mg of product.

MS (ESI ⁺ ): (M+H) ⁺ 533.

HPLC: RT=0.88 min, Method G.

¹ H NMR (DMSO-d ₆ ) δ 7.64 (d, J=8.4 Hz, 1H), 7.22-7.24 (m, 3H), 6.87-6.90 (m, 2H), 6.68 (d, J=8.4 Hz, 1H ), 5.41 (s, 2H), 5.01-5.15 (m, 2H), 4.42 (t, J=5.3 Hz, 1H), 3.94-3.97 (m, 2H), 3.43-3.48 (m, 2H), 2.05 ( s, 3H), 1.91-1.99 (m, 2H), 1.69-1.75 (m, 4H), 1.24-1.56 (m, 12H).

Example 3

Example 3 was prepared in a similar manner to Example 1 using intermediate 7.3.

MC (ESI ⁺ ): (M+H) ⁺ 539/541 (Cl isotope pattern).

RT=1.44 min, Method C.

- 65 043969

Example 4

Example 4 was prepared by analogy with example 1 using the intermediate

7.4.

MC (ESI+): (M+H) ⁺ 536.

RT=0.83 min, Method F.

1H NMR (DMSO) δ 7.63 (d, J=8.5 Hz, 1H), 7.04-7.09 (m, 2H), 6.93-6.95 (m, 2H), 6.69 (d, J=8.5 Hz, 1H), 5.38- 5.41 (m, 3H), 5.06-5.15 (m, 1H), 4.42 (t, J=5.3 Hz, 1H), 3.94-3.97 (m, 2H), 3.42-3.48 (m, 2H), 2.07 (s, 3H), 1.91-2.00 (m, 2H), 1.57-1.76 (m, 8H), 1.51 (d, J=6.8 Hz, 6H).

Example 5

Example 5 was prepared in a similar manner to Example 1 using 7.5. MS (ESI ⁺ ): (M+H) ⁺ 536 RT=0.83 min, Method F.

Example 6 intermediate connection

Example 6 was prepared according to 7.6.

MS (ESI ⁺ ): (M+H) ⁺ 545.

RT=0.59 min, Method E.

Example 7

Example 7 was obtained from

b analogies for obtaining example 1 using an intermediate compound

analogies to obtaining example 1 using an intermediate

- 66 043969

7.7.

MS (ESI ⁺ ): (M+H) ⁺ 548.

RT=0.84 min, Method G.

Example 8

12.1.

Example 8 was prepared by analogy with example 2 using the intermediate

MS (ESI ⁺ ): (M+H) ⁺ 505.

RT=0.8 min, Method G.

Example 9

Example 9 was prepared by analogy with example 1 using the intermediate

7.8.

MS (ESI ⁺ ): (M+H) ⁺ 518.

RT=0.85 min, Method D.

^1H NMR (DMSO-06) δ 7.64 (d, J=8.5 Hz, 1H), 7.22-7.24 (m, 3H), 6.86-6.89 (m, 2H), 6.68 (d, J=8.5 Hz, 1H) , 5.38-5.41 (m, 3H), 5.06-5.15 (m, 1H), 4.42 (t, J=5.3 Hz, 1H), 3.94-3.97 (m, 2H), 3.42-3.48 (m, 2H), 2.04 (s, 3H), 1.91-2.00 (m, 2H), 1.57-1.76 (m, 8H), 1.51 (d, J=7.0 Hz, 6H).

Example 10

Example 10 was prepared by analogy with example 1 using the intermediate

7.9.

MS (ESI ⁺ ): (M+H) ⁺ 593/595 (Cl isotope pattern).

RT=1.47 min, Method C.

- 67 043969

Example 11

analogies to obtaining example 2 using an intermediate

Example 11 was obtained from 7.11.

MS (ESI ⁺ ): (M+H) ⁺ 537.

RT=0.84 min, Method D.

Example 12

analogies to obtaining example 1 using an intermediate

Example 12 was prepared according to 7.12.

MS (ESI ⁺ ): (M+H) ⁺ 559.

RT=1.41 min, Method C.

Example 13

Toluene-4-sulfonic acid hydrate (0.055 g, 0.29 mmol) was added to a mixture of intermediate 15.1 (35.0 mg, 0.06 mmol) in MeOH (2.0 mL). The mixture was stirred for 1 hour at room temperature. The mixture was purified by chromatography to obtain 27.0 mg of product.

MS (ESI+): (M+H) ⁺ 527.

HPLC: RT=0.78 min, Method G.

Example 14

- 68 043969

Toluene-4-sulfonic acid hydrate (35 mg, 0.182 mmol) was added to a mixture of intermediate 7.14 (97 mg, 0.146 mmol) in MeOH (1.0 mL) and THF (1.0 mL). The mixture was stirred for 1.5 h at room temperature. The mixture was concentrated in vacuo and purified by chromatography to give 42.2 mg of product.

MS (ESI+): (M+H) ⁺ 583/585 (Br isotope pattern).

HPLC: RT=0.86 min, Method D.

Example 15

Toluene-4-sulfonic acid hydrate (25 mg, 0.13 mmol) was added to a mixture of intermediate 7.15 (70 mg, 0.11 mmol) in MeOH (1.0 mL) and THF (1.0 mL). The mixture was stirred for 4 hours at room temperature. The mixture was concentrated in vacuo and purified by chromatography to obtain 45.4 mg of product.

MC (ESI ⁺ ): (M+H) ⁺ 577.

HPLC: RT=1.42 min, Method C.

Example 16

Toluene-4-sulfonic acid hydrate (0.27 g, 1.42 mmol) was added to a mixture of intermediate 7.17 (170 mg, 0.28 mmol) in MeOH (2.0 mL). The mixture was stirred for 1 hour at room temperature. The mixture was purified by chromatography and lyophilized to obtain 123 mg of product.

MC (ESI ⁺ ): (M+H) ⁺ 517.

RT=0.85 min, Method G.

Example 17

Example 17 was prepared in a similar manner to Example 15 using intermediate 7.18.

MC (ESI ⁺ ): (M+H) ⁺ 539/541 (Cl isotope pattern).

RT=0.84 min, Method C.

- 69 043969

Example 18

Example 18 yielded 7.20.

MC (ESI ⁺ ): (M+H) ⁺ 523.

RT=0.8 min, Method D.

Example 19

analogies with receiving example

16, using an intermediate connection

Toluene-4-sulfonic acid hydrate (0.155 g, 0.81 mmol) was added to a mixture of intermediate 7.21 (98 mg, 0.16 mmol) in THF (1.0 mL). The mixture was stirred for 1 hour at room temperature. The mixture was purified by chromatography and lyophilized to obtain 55.0 mg of product.

MC (ESI+): (M+H) ⁺ 519.

HPLC: RT=1.48 min, Method C.

Example 20

To a mixture of intermediate 7.22 (crude, 259 mg, 0.42 mmol) in ACN (1 ml) was added toluene-4-sulfonic acid hydrate (240 mg, 1.26 mmol) and MeOH (5 ml, 0.125 mol) and the mixture was stirred for 30 min at room temperature The mixture was purified by chromatography to obtain 170 mg of product.

MS (ESI ⁺ ): (M+H) ⁺ 533.

RT=0.88 min, Method G.

- 70 043969

Example 21

Toluene-4-sulfonic acid hydrate (5 mg, 0.03 mmol) was added to a mixture of intermediate 7.23 (13 mg, 0.02 mmol) in MeOH (0.5 mL) and THF (0.5 mL). The mixture was stirred for 1.5 h at room temperature. The mixture was concentrated in vacuo and purified by chromatography to give 9.4 mg of product as a racemic mixture.

MS (ESI ⁺ ): (M+H) ⁺ 553/555 (Cl isotope pattern).

RT=0.88 min, Method D.

Example 22

By analogy with the preparation of Example 16, using the intermediate compound Example 22, we obtained 7.24.

MS (ESI ⁺ ): (M+H) ⁺ 517.

RT=0.41 min, Method E.

Example 23

Toluene-4-sulfonic acid hydrate (10 mg, 0.05 mmol) was added to a mixture of intermediate 7.25 (26 mg, 0.04 mmol) in MeOH (1 mL) and THF (1 mL). The mixture was stirred for 0.5 h at room temperature. The mixture was concentrated in vacuo and purified by chromatography to give 14.5 mg of product.

MS (ESI+): (M+H) ⁺ 539/541 (Cl isotope pattern).

RT= 1.42 min, Method C.

- 71 043969

Example 24

Example 24 was prepared by analogy with the preparation of example 7.26.

MS (ESI ⁺ ): (M+H) ⁺ 537.

RT=0.82 min, Method D.

Example 25

Example 25 was prepared by analogy with the preparation of example

16 using intermediate connection

16 using intermediate connection

7.27.

MC (ESI ⁺ ): (M+H) ⁺ 559.

RT=1.08 min, Method F.

1H NMR (DMSO-d6) δ 7.72 (d, J=8.5 Hz, 1H), 7.05-7.09 (m, 2H), 6.92-6.96 (m, 2H), 6.81 (d, J=8.5 Hz, 1H), 5.39 (s, 2H), 5.05-5.20 (m, 2H), 4.42 (t, J=5.3 Hz, 1H), 3.94-3.98 (m, 2H), 3.43-3.48 (m, 2H), 3.11-3.21( m, 2H), 2.66-2.80 (m, 2H), 2.06 (s, 3H), 1.69-1.76 (m, 2H), 1.51 (d, J=6.9 Hz, 6H).

Example 26

Example 26 was prepared in a similar manner to Example 16 using intermediate 12.2. MC (ESI+): (M+H) ⁺ 519 RT =1.13 min, Method F

Example 27

- 72 043969

Toluene-4-sulfonic acid hydrate (100 mg, 0.53 mmol) was added to a mixture of intermediate 12.3 (155 mg, 0.26 mmol) in MeOH (1.5 mL).

The mixture was stirred for 3 hours at room temperature. The mixture was concentrated in vacuo and purified by chromatography. Cis/trans isomers were separated by SCPC (see example 28 for another isomer).

MS (ESI+): (M+H) ⁺ 505.

RT=4.428 min, Method J

Example 28

Toluene-4-sulfonic acid hydrate (100 mg, 0.53 mmol) was added to a mixture of intermediate 12.3 (155 mg, 0.26 mmol) in MeOH (1.5 mL). The mixture was stirred for 3 hours at room temperature. The mixture was concentrated in vacuo and purified by chromatography. Cis/trans isomers were separated by SCPC (see example 27 for another isomer).

MS (ESI ⁺ ): (M+H) ⁺ 505.

RT=5.005 min, Method J.

Example 29

Toluene-4-sulfonic acid hydrate (21 mg, 0.11 mmol) was added to a mixture of intermediate 7.28 (55 mg, 0.09 mmol) in MeOH (1.0 mL) and THF (1.0 mL). The mixture was stirred for 1 hour at room temperature. The mixture was concentrated in vacuo and purified by chromatography to give 34.3 mg of product.

MS (ESI ⁺ ): (M+H) ⁺ 537.

HPLC: RT=0.82 min, Method D.

Example 30

Toluene-4-sulfonic acid hydrate (182 mg, 0.96 mmol) was added to a mixture of intermediate 12.4 (121 mg, 0.19 mmol) in MeOH (3.0 mL). The mixture was stirred for 1 hour at room temperature. The mixture was concentrated in vacuo, purified by chromatography and lyophilized to give 95.0 mg of product.

MS (ESI ⁺ ): (M+H) ⁺ 505.

HPLC: RT=1.08 min, Method F.

¹ H NMR (DMSO-d6) δ 7.66 (d, J=8.5 Hz, 1H), 7.21-7.25 (m, 3H), 6.86-6.89 (m, 2H), 6.70 (d, J=8.5 Hz, 1H) , 5.41 (s, 2H), 5.05-5.19 (m, 2H), 4.42 (t, J=5.3 Hz, 1H), 3.94-3.97 (m, 2H), 3.42-3.48 (m, 2H), 2.36-2.45 (m,

- 73 043969

2H), 2.01-2.12 (m, 5H), 1.61-1.83 (m, 4H), 1.51 (d, J=7.0 Hz, 6H).

Example 31

analogies to obtain example 30 using an intermediate

Example 31 was prepared from 7.29.

MS (ESI ⁺ ): (M+H) ⁺ 519.

RT=0.85 min, Method D.

Example 32

analogies to obtain example 30 using an intermediate

Example 32 was obtained at 7.30.

MS (ESI+): (M+H) ⁺ 519.

RT=0.83 min, Method D.

Example 33

Example 33 was prepared in a similar manner to Example 29 using intermediate 7.31.

MS (ESI ⁺ ): (M+H) ⁺ 523.

RT=0.73 min, Method D.

1H NMR (DMSO-d6) δ 7.65 (d, J=8.5 Hz, 1H), 7.04-7.09 (m, 2H), 6.92-6.95 (m, 2H), 6.71 (d, J=8.4 Hz, 1H), 5.39 (s, 2H), 5.05-5.19 (m, 2H), 4.41-4.43 (m, 1H), 3.94-3.97 (m, 2H), 3.42-3.48 (m, 2H), 2.36-2.45 (m, 2H ), 2.01-2.12 (m, 5H), 1.61-1.83 (m, 4H), 1.51 (d, J=7.0 Hz, 6H).

- 74 043969

Example 34

7.32.

7.34.

7.35.

Example 34 was prepared in a similar manner to Example 29 using the intermediate

MS (ESI+): (M+H) ⁺ 505.

RT=0.79 min, Method D.

Example 35

analogies to obtain example 30 using an intermediate

Example 35 was obtained from

MS (ESI ⁺ ): (M+H) ⁺ 605.

RT=0.72 min, Method D.

Example 36

Example 36 was obtained from

analogies to obtain example 29 using an intermediate

MS (ESI ⁺ ): (M+H) ⁺ 525/527 (Cl isotope pattern).

RT= 1.35 min, Method C.

- 75 043969

Example 37

Example 37 was prepared in a similar manner to Example 30 using intermediate 7.36.

MS (ESI ⁺ ): (M+H) ⁺ 533.

RT=0.88 min, Method G

Example 38

To a mixture of intermediate 22.1 (40 mg, 0.085 mmol) in THF (704 µl) and DMSO (697 µl) was added DIPEA (16.1 µl, 0.094 mmol) and 1-bromo-4-(bromomethyl)benzene (32 mg, 0.128 mmol ). The mixture was stirred for 1.5 h at 50°C. Additional DIPEA was added and the mixture was stirred for 45 minutes at 90°C. Additional 1-bromo-4(bromomethyl)benzene was then added and the mixture was stirred for 1 hour at 90°C. The mixture was cooled and purified by chromatography to obtain 8.0 mg of product.

MS (ESI+): (M+H) ⁺ 555/557 (Br isotope pattern).

HPLC: RT=0.78 min, Method D.

Example 39

Example 39 was prepared in a similar manner to Example 30 using intermediate 15.3.

MS (ESI ⁺ ): (M+H) ⁺ 509.

RT=0.77 min, Method G.

- 76 043969

Example 40

Toluene-4-sulfonic acid hydrate (182 mg, 0.96 mmol) was added to a mixture of intermediate 7.37 (62 mg, 0.102 mmol) in THF (1.0 mL). The mixture was stirred for 1 hour at room temperature. The mixture was concentrated in vacuo, purified by chromatography and lyophilized to give 40.0 mg of product.

MS (ESI+): (M+H) ⁺ 526/528 (Cl isotope pattern).

HPLC: RT=1.4 min, Method C.

Example 41

F

Example 41 was prepared in a similar manner to Example 40 using intermediate 7.38.

MS (ESI ⁺ ): (M+H) ⁺ 523.

RT=1.37 min, Method C.

Example 42

To a mixture of intermediate 7.39 (253 mg, 0.42 mmol) in ACN (1 mL), MeOH (5 mL) and toluene-4-sulfonic acid hydrate (240 mg, 1.26 mmol) were added and the mixture was stirred for 30 min at room temperature. T. The mixture was purified by chromatography to obtain 181 mg of product.

MS (ESI ⁺ ): (M+H) ⁺ 519.

RT=0.84 min, Method G.

- 77 043969

Example 43

Example 43 was prepared in a similar manner to Example 30 using intermediate 7.40.

MS (ESI+): (M+H) ⁺ 541.

RT=1.07 min, Method F.

¹ H NMR (DMSO-d ₆ ) δ 7.73 (d, J=8.5 Hz, 1H), 7.21-7.25 (m, 3H), 6.87-6.89 (m, 2H), 6.80 (d, J=8.2 Hz, 1H ), 5.41 (s, 2H), 5.05-5.19 (m, 2H), 4.43 (t, J=5.0 Hz, 1H), 3.94-3.98 (m, 2H), 3.43-3.48 (m, 2H), 3.11- 3.21(m, 2H), 2.66-2.80 (m, 2H), 2.06 (s, 3H), 1.69-1.76 (m, 2H), 1.51 (d, J=6.9 Hz, 6H).

Example 44

Example 44 was prepared from 7.41. MS (ESI ⁺ ): (M+H) ⁺ 523. RT=0.79 min, Method D. Example 45 Example 45 was prepared from 7.42. MS (ESI ⁺ ): (M+H) ⁺ 521. RT=0.74 min, Method D. F Q o\ 44 analogies to obtain example 30 using an intermediate F Q o\ -.....'β> p V 45 analogies to obtain example 29 using an intermediate

- 78 043969

Example 46

To a mixture of intermediate 22.1 (40 mg, 0.085 mmol) in THF (704 μL) and DMSO (697 μL) was added DIPEA (16.1 μL, 0.094 mmol) and 4-(trifluoromethylthio)benzyl chloride (29 mg, 0.128 mmol). The mixture was stirred for 1.5 h at 50°C. Additional DIPEA was added and the mixture was stirred for 1.5 hours at 90°C. Additional 4(trifluoromethylthio)benzyl chloride was then added and the mixture was stirred for 1 hour at 90°C. The mixture was cooled and purified by chromatography to obtain 7.0 mg of product.

MS (ESI ⁺ ): (M+H) ⁺ 577.

HPLC: RT=0.83 min, Method D.

Example 47

Example 47 was prepared in a similar manner to Example 30 using intermediate 7.43.

MS (ESI ⁺ ): (M+H) ⁺ 545.

RT=0.67 min, Method D.

Example 48

Toluene-4-sulfonic acid hydrate (28.5 mg, 0.15 mmol) and MeOH (0.5 mL) were added to the crude reaction mixture of intermediate 5.20 (29.7 mg, 0.05 mmol). The mixture was stirred overnight at room temperature. The mixture was purified by chromatography to obtain 18.3 mg of product.

MS (ESI ⁺ ): (M+H) ⁺ 511/513 (Cl isotope pattern).

HPLC: RT=0.76 min, Method D.

- 79 043969

Example 49

7.45.

Example 49 was obtained from

MS (ESI+): (M+H) ⁺ 517.

RT=1.11 min, Method F.

Example 50

Example 50 was obtained by

7.47.

MS (ESI ⁺ ): (M+H) ⁺ 509.

RT=0.75 min, Method D.

Example 51

analogies to obtain example 29 using an intermediate

analogies to obtain example 30 using an intermediate but

Example 51 was prepared in a similar manner to Example 40 using intermediate 6.25.

MS (ESI ⁺ ): (M+H) ⁺ 509.

RT=1.34 min, Method C.

- 80 043969

Example 52

To a mixture of intermediate 7.49 (88 mg, 0.153 mmol) in MeOH (1 mL) and THF (1 mL) was added toluene-4-sulfonic acid hydrate (36.5 mg, 0.192 mmol) and the mixture was stirred for 1 h at room temperature. T. The mixture was purified by chromatography to obtain 69.1 mg of product.

MS (ESI ⁺ ): (M+H) ⁺ 491.

RT=0.74 min, Method D.

Example 53

Toluene-4-sulfonic acid hydrate (171.2 mg, 0.90 mmol) and MeOH (2 mL) were added to the reaction mixture of intermediate 5.25. The mixture was stirred for 1 hour at room temperature. The mixture was purified by chromatography to obtain 41.0 mg of product.

MS (ESI+): (M+H) ⁺ 529/531 (Cl isotope pattern).

HPLC: RT=0.78 min, Method D.

Example 54

Example 54 was prepared in a similar manner to Example 53 using intermediate 5.26.

MS (ESI ⁺ ): (M+H) ⁺ 545.

RT=0.79 min, Method D.

- 81 043969

Example 55

Example 55 was prepared in a similar manner to Example 53 using intermediate 5.27.

MS (ESI+): (M+H) ⁺ 491.

RT=0.77 min, Method D.

Example 56

F

Example 56 was prepared in a similar manner to Example 53 using intermediate 5.28.

MC (ESI ⁺ ): (M+H) ⁺ 513.

RT=0.74 min, Method D.

Example 57

Toluene-4sulfonic acid hydrate (11.3 mg, 0.06 mmol) and MeOH (2 mL) were added to the crude reaction mixture of intermediate 25.1. The mixture was stirred for 1 hour at room temperature. The mixture was purified by chromatography to give 5.8 µt.

MC (ESI ⁺ ): (M+H) ⁺ 501.

HPLC: RT=0.70 min, Method A.

- 82 043969

Example 58

To a mixture of intermediate 22.1 (40 mg, 0.085 mmol) in THF (704 µl) and DMSO (697 µl) was added DIPEA (16.1 µl, 0.094 mmol) and 1-(bromomethyl)-3,5-difluorobenzene (26.5 mg, 0.128 mmol). The mixture was stirred for 1.5 h at 50°C. Additional DIPEA was added and the mixture was stirred for 2 hours at 90°C. Additional 1-(bromomethyl)-3,5difluorobenzene was then added and the mixture was stirred for 1 hour at 90°C. The mixture was cooled and purified by chromatography to obtain 15.0 mg of product.

MS (ESI ⁺ ): (M+H) ⁺ 513.

HPLC: RT=0.74 min, Method D.

Example 59

analogies to obtaining example 53 using an intermediate

Example 59 was obtained at 7.50.

MS (ESI ⁺ ): (M+H) ⁺ 535.

RT=1.09 min, Method F.

Example 60

To a mixture of intermediate 7.51 (92 mg, 0.157 mmol) in MeOH (1 mL) and THF (1 mL) was added toluene-4-sulfonic acid hydrate (37.2 mg, 0.196 mmol) and the mixture was stirred for 1.5 h at room temperature. T. The mixture was purified by chromatography to obtain 43.0 mg of product.

MS (ESI+): (M+H) ⁺ 505.

RT=0.8 min, Method D.

- 83 043969

Example 61

Example 61 was prepared in a similar manner to Example 54 using intermediate 7.52.

MS (ESI+): (M+H) ⁺ 505.

RT=0.78 min, Method D.

Example 62

F

To a mixture of intermediate 12.6.1 (42 mg, 0.071 mmol) in MeOH (1 ml) and THF (1 ml) was added toluene-4-sulfonic acid hydrate (12.2 mg, 0.071 mmol) and the mixture was stirred for 1 h at k.t. The mixture was purified by chromatography to obtain 13.7 mg of product.

MS (ESI ⁺ ): (M+H) ⁺ 513.

RT=0.74 min, Method G.

Example 63

To a mixture of intermediate 7.53 (38 mg, 0.066 mmol) in THF (1 ml) was added toluene-4-sulfonic acid hydrate (63 mg, 0.331 mmol) and the mixture was stirred for 1 h at room temperature. The mixture was purified by chromatography and lyophilized to obtain 27.0 mg of product.

MS (ESI ⁺ ): (M+H) ⁺ 491.

RT=1.33 min, Method C.

Example 64

Example 64 was prepared in a similar manner to Example 53 using intermediate 27.1.

-

Claims (3)

MS (ESI ⁺ ): (M+H) ⁺ 495. RT=0.73 min, Method D. CLAIM 1. Compound of formula I R ³ represents hydrogen, fluorine, C ₁ -C ₃ alkyl, optionally substituted with one or more fluorine atoms; R ⁴ represents hydrogen or fluorine; R ⁵ represents - 85 043969 2. The connection according to claim 1, where R ¹ represents ethyl, isopropyl, isobutyl, cyclobutyl; R ² represents R ³ represents hydrogen, fluorine, methyl, ethyl, -CF ₃ ; R ⁴ represents hydrogen or fluorine; R ⁵ represents - 86 043969 3. The connection according to claim 1 or 2, in which it is and/or represents or present4. A compound according to claim 1, 2 or 3, namely a compound selected from the group consisting of - 87 043969 - 88 043969 - 89 043969 - 90 043969 - 91 043969 - 92 043969 -93043969 - 94 043969 - 95 043969 - 96 043969 5. Connection according to claim 4, namely 6. Connection according to claim 4, namely 7. Connection according to claim 4, namely 8. Connection according to claim 4, namely '7 ₀ <S^N I Γ ^Ν \ Μ j L *—\\ ^/° O^N^N / ^- N Q Ηθ^^Ν^^Ν/=\ \ L '>~L ν θ / ^- N 'B ^HO ^^ ^N j II V— \\ and ° o^n^n >N Q θ/ J II V—S\ //“O o^n^n ^and s A> ^{F h} o^^ ⁿ ArVv^Vn j II Ά o^n^nn B ^NoL *E |T ^N iO-0 ₀ ^- _n 4-kE ^m O^y V - 97 043969 9. The connection according to claim 4, namely 10. The connection according to claim 4, namely G 11. The connection according to claim 4, namely 12. A pharmaceutically acceptable salt of the compound according to any one of claims 1 to 11. 13. Use of a compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt according to claim 12 as a medicament for the treatment of conditions associated with transient receptor potential subfamily C member 5 (TCPC5)-containing ion channels. 14. A pharmaceutical composition containing an effective amount of a compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt according to claim 12 and a pharmaceutically acceptable excipient. 15. A method of treating a cation channel transient receptor potential subfamily C member 5 (TCPC5)-mediated disorder in a subject, comprising administering to the subject an effective amount of a compound of any one of claims 1 to 11 or a pharmaceutically acceptable salt of claim 12. Eurasian Patent Organization, EAPO Russia, 109012, Moscow, Maly Cherkassky lane, 2