EA045542B1 - HETEROAROMATIC COMPOUNDS AS VANINE INHIBITORS - Google Patents

Description

Prerequisites for creating the invention

1. Field of technology to which the invention relates

The present invention relates to new compounds that inhibit vanin, pharmaceutical compositions that contain them, and their use as drugs.

2. State of the art

Vanine enzyme isoforms 1 and 2 are single-domain extracellular panthetheinases that catalyze the cleavage of pantethine and panthetheine into pantothenic acid and cystamine and cysteamine, respectively (Martin, Immunogenetics, (May-June, 2001) vol. 53, no. 4, pp. 296 -306). Cysteamine formation is associated with increased oxidation in tissue stress resulting from decreased glutathione levels, a condition that characterizes many pathological conditions, including IBD (Xavier, Nature, June 2011 15;474 (7351):307-17), malignancy (Sosa , Ageing research reviews, (Jan. 2013) Vol. 12, No. 1, pp. 376-90) and diabetes (Lipinski, Journal of diabetes and its complications, (July-Aug. 2001) Vol. 15, No. 4 , pp. 203-10).

Increased vanin-1 activity in the intestinal epithelium has been implicated in promoting tissue damage and inflammation by reducing resistance to oxidative stress in mouse models (Naquet, Biochem Soc Trans Aug 2014;42(4):1094-100); (Berruyer, Molecular and cellular biology, (Aug. 2004) Vol. 24, No. 16, pp. 7214-24); (Berruyer, The Journal of experimental medicine, (25 Dec. 2006) Vol. 203, No. 13, pp. 2817-27); (Pouyet, Inflammatory bowel diseases, (Jan. 2010) Vol. 16, No. 1, pp. 96-104). Homozygous VNN1 knockout (KO) mice lack sufficient levels of cysteamine in the blood and tissues and exhibit glutathione-mediated tissue resistance to oxidative stress (Berruyer, The Journal of Experimental Medicine, (Dec. 25, 2006) Vol. 203, No. 13, pp. 2817-27). Additionally, these mice are protected from intestinal injury in TNBS, DSS and Schistosoma-induced colitis models (Berruyer, The Journal of experimental medicine, (25 Dec 2006) Vol. 203, No. 13, pp. 2817-27; Pouyet, Inflammatory bowel diseases, (Jan 2010) Vol. 16, No. 1, pp. 96-104; Martin, The Journal of clinical investigation, (Feb. 2004) Vol. 113, No. 4, pp. 591-7). These rodents lack vanin-2 and their only source of cysteamine is vanin-1, hence the protective phenotype of the VNN1 KO mouse is promoted by the absence of cysteamine.

In humans, there is upregulation of vanin-1 in the intestinal epithelium in tissue biopsies from UC and CD patients and a functional polymorphism in the regulatory region of the VNN1 gene, leading to increased expression of VNN1 which is associated with increased IBD sensitivity (P=0.0003 heterozygous vs. wild type). type) (Gensollen, Inflammatory Bowel Diseases, (Oct 2013) Vol. 19, No. 11, pp. 2315-25).

Additionally, upregulation of Vanin-1 activity in skin and blood is associated with the development and severity of fibrosis in patients with systemic sclerosis (Kavian, Journal of immunology (Baltimore, Md.: 1950), (20161015) Vol. 197, No. 8, cc. 3326 -3335), and increased levels of Vanin-1 are observed in chronic juvenile idiopathic thrombocytopenia (Zhang, Blood, (28 Apr. 2011) Vol. 117, No. 17, pp. 4569-79), psoriasis and atopic dermatitis (Jansen, The Journal of investigative dermatology, (Sept. 2009) Vol. 129, No. 9, cc. 2167-74). Increased Vanin-1 expression and activity are also present and serve as biomarkers for pancreatic cancer associated with new-onset diabetes (Kang, Cancer Letters (New York, NY, United States) (2016), 373(2), 241-250 ) and also correlates with poor prognosis and response to treatment for colorectal cancer (Chai, American journal of translational research, (2016) Vol. 8, No. 10, pp. 4455-4463).

WO 2018011681 and WO 2016193844 describe vanin inhibitors for the treatment of a number of diseases, such as Crohn's disease and ulcerative colitis.

An object achieved by the present invention is to provide new compounds that act as an inhibitor of vanin enzymes, preferably as an inhibitor of the vanin-1 enzyme.

Surprisingly, it has been found that the compounds of the present invention have effective Vanin-1 inhibitory activity, preferably exhibiting VNN-1 inhibition IC ₅₀ [nM] < 100, more preferably IC ₅₀ [nM] < 10, especially preferably IC ₅₀ [nM ] < 1.

Medicines with a long retention time in the body are preferred because they remain effective for a longer period of time and therefore can be used in lower doses. Surprisingly, the compounds of the present invention exhibit favorable mean retention time (MRT). In addition, the compounds of the present invention exhibit additional properties that are favorable to their pharmacokinetic and pharmacological profile, for example, good solubility and good metabolic stability.

Detailed Description of the Invention

Surprisingly, it has been found that the problem mentioned above is solved by the compounds of formula I according to the present invention.

Thus, the present invention relates to a compound of formula I

- 1 045542

I where R ¹ is naphthalenyl substituted with R ¹ ' ¹ and R ¹ ' ² or 8-10 membered heteroaryl containing 1-3 heteroatoms selected from the group consisting of S, N and O, substituted with R ¹ ' ¹ and

R ¹ ' ¹ is selected from the group consisting of H, C1_4alkyl, C1_2alkyl-O-, CF3, C3_5cycloalkyl, H2N-, Br, Cl and F; R ¹ ' ² is selected from the group consisting of H, C1_ ₄ alkyl, CF ₃ , H ₂ N-, Br, Cl and F;

where in the definition of R ¹ · ¹ and R ¹ ' ² the specified alkyl is optionally substituted with 1-3 F atoms;

R ² and R ³ are independently selected from the group consisting of H and methyl,

R ⁴ is R ⁴¹ R ⁴ ' ² N- or NC; or

R ⁴ represents a group of the formula R ⁴ ' ^a

R ^{4 and} where X represents CH ₂ or O;

R ⁴ ' ¹ is selected from the group consisting of CH3-CO-, C3_4cycloalkyl-CO-, substituted R ⁴ ' ¹ ' ¹ and R ⁴ ' ¹ ' ² , where R ⁴ ' ¹ ' ¹ , R ⁴ ' ¹ ' ² are independently each other from each other selected from the group consisting of H, -CH3, F, and -CN;

R ⁴ ' ² represents H or C ₁ _ ₃ alkyl, R ⁵ represents H or methyl; or a pharmaceutically acceptable salt thereof

Preferred Embodiments

In another embodiment of the present invention, R ¹ is naphthalenyl, an 8-10 membered heteroaryl containing 1-3 heteroatoms selected from the group consisting of N and S, substituted with R and R, or

8-10 membered heteroaryl containing 1-3 heteroatoms selected from the group consisting of N and O, substituted with R ¹ ' ¹ and R ¹ ' ² , or a pharmaceutically acceptable salt thereof

In another embodiment of the present invention, R ¹ is naphthalenyl'

In another embodiment of the present invention, R ¹ is

8-10 membered heteroaryl containing 1-3 heteroatoms selected from the group consisting of N and S, substituted with R ¹ ' ¹ and R ¹ ' ² '

In another embodiment of the present invention, R ¹ is

8-10 membered heteroaryl containing 1-3 heteroatoms selected from the group consisting of N and O, substituted with R ¹ ' ¹ and R ¹ ' ² '

In another embodiment of the present invention, R ¹ is substituted with R ¹ ' ¹ and R ¹ ' ² and is selected from the group consisting of R ¹ ' ^a - R ¹ ' ^P '

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In another embodiment of the present invention, R ¹ is substituted with R ¹ ' ¹ and R ¹ ' ² and is selected from the group consisting of R ^k;l , R ^kd , R ^1.e , R ^kg , R ¹ ' ¹ , R ^Lh , R ^km and R ¹ · ^р ·

In another embodiment of the present invention, R ^{1 1} is selected from the group consisting of H, methyl, H ₂ N-, Br, Cl and F·

In another embodiment of the present invention, R ¹ ' ² is selected from the group consisting of H, methyl and Cl.

In another embodiment of the present invention, R ¹ ' ¹ and R ¹ ' ² are H·

In another embodiment of the present invention, R ¹ ' ¹ is H'

In another embodiment of the present invention, R ^' is H'

In another embodiment of the present invention, R ² is H, and R ³ is

- 3 045542 is methyl.

In another embodiment of the present invention, R ² and R ³ are H.

In another embodiment of the present invention, R ⁴ is R^'R^N.

In another embodiment of the present invention, R ⁴ represents -CN.

In another embodiment of the present invention ^{, R4} is a group of the formula R^

where X represents CH ₂ or O.

In another embodiment of the present invention, X is O.

In another embodiment of the present invention, X is CH ₂ .

In another embodiment of the present invention

R ⁴⁴ is selected from the group consisting of CH3-CO-, C _3-4 cycloalkyl-CO-, substituted R ⁴¹¹ and R ⁴¹² ;

where R ⁴⁴⁴ , R ⁴⁴ ' ² are independently selected from the group consisting of H, CH ₃ , F and -CN; and R ⁴ ' ² is methyl or ethyl.

In another embodiment of the present invention

R ⁴⁴ is CH3-CO- or C _3-4 cycloalkyl-CO-, substituted by R ⁴⁴⁴ and R ⁴¹² , where R ⁴⁴⁴ , R ^44.2 are independently selected from the group consisting of H, -CH ₃ , F and -CN ; and R ^{4 2} represents methyl.

In another embodiment of the present invention, R ⁴⁴ is CH3-CO-.

In another embodiment of the present invention _, R ⁴⁴ is C _{3_4} cycloalkylCO- substituted with R ⁴⁴⁴ and R ⁴⁴ . ² .

In another embodiment of the present invention, R ⁴⁴⁴ and R ⁴¹² are H.

In another embodiment of the present invention, R ⁴⁴⁴ and R ⁴¹² are F.

In another embodiment of the present invention, R ⁴⁴⁴ is CH ₃ , F or -CN and

R ^44.2 is H.

In another embodiment of the present invention, R ⁵ is H.

In another embodiment of the present invention, R ⁵ is methyl.

A preferred embodiment of the present invention is a compound of formula I wherein R ¹ is naphthalenyl substituted with R ¹⁴ and R ¹² or

8-10 membered heteroaryl containing 1-3 heteroatoms selected from the group consisting of S, N and O, substituted with R ^1.1 and

R ¹ ' ¹ is selected from the group consisting of H, C1_4alkyl, CF3, H2N-, Br, Cl and F; R ¹² is selected from the group consisting of H, C1-4alkyl, CF ₃ , H ₂ N-, Br, Cl and F;

R ² and R ³ are independently selected from the group consisting of H and methyl,

R ⁴ is R ⁴ V ² N- or NC; or

R ⁴ represents a group of the formula R ⁴ ' ^a

where X represents CH ₂ or O;

R ⁴⁴ is selected from the group consisting of CH3-CO-, C _3-4 cycloalkyl-CO-, substituted R ^{41 1} and R ⁴¹² ;

where R ⁴⁴⁴ , R ⁴¹² are independently selected from the group consisting of H, CH ₃ , F and -CN;

R ^4.2 is methyl or ethyl; R ⁵ represents H or methyl; or a pharmaceutically acceptable salt thereof.

A preferred embodiment of the present invention is a compound of formula I

R ¹ represents naphthalenyl or

8-10 membered heteroaryl containing 1-3 heteroatoms selected from the group consisting of S, N and O, substituted with R ^1.1 and

R ^1.1 is selected from the group consisting of H, methyl, H ₂ N-, Br, Cl and F;

R ^1.2 is selected from the group consisting of H, methyl and Cl;

R ² and R ³ are independently H or methyl;

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R ⁴ is R ⁴ '1R ⁴ ' ² N- or NC-; or R ⁴ represents a group of the formula R ⁰ ъ r ⁴ and where X represents CH ₂ or O;

R ⁴ ' ¹ is selected from the group consisting of CH3-CO-, C _{3_4} cycloalkyl-CO-, substituted R ^{4 ' 1} _' ¹ and R ⁴ ' ¹ ' ² , where R ⁴ ' ¹ ' ¹ , R ⁴ ' ¹ ' ² are independently selected from the group consisting of H, -CH3, F and -CN;

R ^4'2 represents methyl;

R ⁵ represents H or methyl;

or a pharmaceutically acceptable salt thereof

Any and each of the definitions of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ¹ ' ¹ , R ¹ ' ² , R ⁴ ' ¹ , R ⁴ ' ² , R ⁴ ' ¹ ' ¹ , R ⁴ ' ¹ ' ² , R ⁴ ' ^a and X can be combined with each other.

A further preferred embodiment of the present invention are the above compounds of formula I selected from the group consisting of examples 2'1, 3'1, 4'1, 5'2, 5'3, 5'4, 5'7, 5'13, 5'14, 5'22, 5'24, 5'38 and 5-40;

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or a pharmaceutically acceptable salt thereof.

A further preferred embodiment of the present invention are the above compounds of formula I selected from the group consisting of examples 2.1, 3.1, 4.1, 5.2, 5.3, 5.4, 5.7, 5.13, 5.14, 5.22, 5.24, 5.38 and 5.40.

Further preferred option of the present inventions represents connections from example 2.1. Further preferred option present inventions is yourself connections from example 3.1 Further preferred option present inventions is yourself connections from example 4.1. Further preferred option present invention represents connections from example 5.2. Further preferred option present inventions is yourself connections from example 5.3. Further preferred option present inventions is yourself connections from example 5.4. Further preferred option present inventions is yourself connections from example 5.7. Further preferred option present inventions is yourself connections from example 5.13. Further preferred option present inventions is yourself connections from Example 5.14. Further preferred option present inventions is yourself connections from Example 5.22. Further preferred option present inventions is yourself connections from Example 5.24. Further preferred option present inventions is yourself connections from Example 5.38. Further preferred option present inventions is yourself connections

from Example 5.40.

A further preferred embodiment of the present invention are pharmaceutically acceptable salts of the above-described compounds of Formula I selected from the group consisting of Examples 2.1, 3.1, 4.1, 5.2, 5.3, 5.4, 5.7, 5.13, 5.14, 5.22, 5.24, 5.38 and 5.40.

A further preferred embodiment of the present invention are the pharmaceutically acceptable salts of the compound of Example 2.1. A further preferred embodiment of the present invention are pharmaceutically acceptable salts of the compound from Example 3.1. A further preferred embodiment of the present invention are pharmaceutically acceptable salts of the compound from Example 4.1.

A further preferred embodiment of the present invention are pharmaceutically acceptable salts of the compound from Example 5.2. A further preferred embodiment of the present invention are pharmaceutically acceptable salts of the compound from Example 5.3. A further preferred embodiment of the present invention are pharmaceutically acceptable salts of the compound from Example 5.4. A further preferred embodiment of the present invention are pharmaceutically acceptable salts of the compound from Example 5.7. A further preferred embodiment of the present invention are pharmaceutically acceptable salts of the compound from Example 5.13. A further preferred embodiment of the present invention are pharmaceutically acceptable salts of the compound from Example 5.14. A further preferred embodiment of the present invention are pharmaceutically acceptable salts of the compound from Example 5.22. A further preferred embodiment of the present invention are pharmaceutically acceptable salts of the compound from Example 5.24. A further preferred embodiment of the present invention are pharmaceutically acceptable salts of the compound from Example 5.38. A further preferred embodiment of the present invention are pharmaceutically acceptable salts of the compound from Example 5.40.

A further embodiment of the present invention is a pharmaceutical composition containing a therapeutically effective amount of at least one compound of formula I or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

A further embodiment of the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof for use as a drug

Furthermore, the present invention relates to the use of a compound of general formula I for the treatment of a patient suffering from Crohn's disease, ulcerative colitis, atopic dermatitis, systemic sclerosis, non-alcoholic steatohepatitis (NASH), psoriasis, chronic kidney disease, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis , rheumatoid arthritis, scleroderma, asthma, allergic rhinitis, allergic eczema, juvenile rheumatoid arthritis, juvenile idiopathic arthritis, graft-versus-host disease, psoriatic arthritis, hyperlipidemia, colorectal cancer or pancreatic cancer associated with first diagnosed diabetes.

A pharmaceutical composition containing, in addition to a compound of formula I, a pharmaceutically active compound selected from the group consisting of an immunomodulatory agent, an anti-inflammatory agent or a chemotherapeutic agent.

In addition, the present invention relates to the use of a compound of general formula I for the treatment and/or prevention of a disease and/or condition associated with or modulated by vanin-1 or vanin-2, in particular vanin-1, including, but not limited to, treating and/or preventing inflammatory diseases, preferably inflammatory bowel diseases.

A further embodiment of the present invention is the use of a compound of formula I for the treatment of a patient suffering from Crohn's disease, ulcerative colitis, atopic dermatitis, systemic sclerosis, non-alcoholic steatohepatitis (NASH), psoriasis, chronic kidney disease, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, rheumatoid arthritis, scleroderma, asthma, allergic rhinitis, allergic eczema, juvenile rheumatoid arthritis, juvenile idiopathic arthritis, graft-versus-host disease, psoriatic arthritis, hyperlipidemia, colorectal cancer or pancreatic cancer associated with first diagnosed diabetes. A further embodiment of the present The invention is the use of a compound of formula I for the treatment of a patient suffering from Crohn's disease, ulcerative colitis, systemic sclerosis, non-alcoholic steatohepatitis (NASH), chronic obstructive pulmonary disease or atopic dermatitis, preferably Crohn's disease, ulcerative colitis, systemic sclerosis, non-alcoholic steatohepatitis (NASH ) or atopic dermatitis, especially preferably Crohn's disease or ulcerative colitis. A further embodiment of the present invention is the use of a compound of formula I for the treatment of a patient suffering from moderate to severe Crohn's disease.

A further embodiment of the present invention is the use of a compound of formula I for the treatment of a patient suffering from ulcerative colitis.

A further embodiment of the present invention is the use of a compound of formula I for the treatment of a patient suffering from atopic dermatitis.

A further embodiment of the present invention is the use of a compound of formula I for the treatment of a patient suffering from NASH.

In a further embodiment, a method of treating a disease selected

- 7 045542 from Crohn's disease, ulcerative colitis, atopic dermatitis, systemic sclerosis, non-alcoholic steatohepatitis (NASH), psoriasis, chronic kidney disease, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, rheumatoid arthritis, scleroderma, asthma, allergic rhinitis, allergic eczema, juvenile rheumatoid arthritis, juvenile idiopathic arthritis, graft-versus-host disease, psoriatic arthritis, hyperlipidemia, colorectal cancer, or pancreatic cancer associated with first diagnosed diabetes, comprising administering to the patient a therapeutically effective amount of a compound in accordance with the first embodiment or any of its related embodiments or a pharmaceutically acceptable salt thereof. In a further embodiment, a method for producing a compound according to the first embodiment or any of its related embodiments using the methods presented in the present invention below is provided.

In a further aspect, the present invention relates to a compound of general formula 1 for use in the treatment and/or prevention of the above diseases and conditions.

In a further aspect, the present invention relates to the use of a compound of general formula 1 for the preparation of a medicament for the treatment and/or prevention of the above diseases and conditions. In a further aspect, the present invention provides methods for treating or preventing the above diseases and conditions, wherein the method includes administering to a human an effective amount of a compound of general formula 1. The actual pharmaceutically effective amount or therapeutic dosage will generally depend on factors known to those skilled in the art, such as such as the age and weight of the patient, the route of administration and the severity of the disease. In any case, the compounds will be administered in dosages and in a manner that will provide a pharmaceutically effective amount based on the unique condition of the patient.

A further embodiment of the present invention is a pharmaceutical composition containing, in addition to a compound of formula I, a pharmaceutically active compound selected from the group consisting of an immunomodulatory agent, an anti-inflammatory agent, or a chemotherapeutic agent. Examples of such agents include, but are not limited to, cyclophosphamide, mycophenolate (MMF), hydroxychloroquine, glucocorticoids, corticosteroids, immunosuppressants, NSAIDs, non-specific and specific COX-2 specific cyclooxygenase enzyme inhibitors, tumor necrosis factor (TNF) receptor antagonists, IL12 antagonists /23 and IL23, antibodies blocking α4β7 integrin, non-selective and selective JAK kinase inhibitor and methotrexate, as well as combinations of two and three active substances.

Definitions

Terms not specifically defined herein are to be understood as intended by one skilled in the art, taking into account the disclosure and context. However, as used in the specification, unless specifically stated otherwise, the following terms have the meanings indicated and the following conventions apply to them.

In groups, radicals or components defined below, the number of carbon atoms is often indicated before the group, for example, C _1-6 αlkyl refers to an alkyl group or radical having from 1 to 6 carbon atoms. In general, in groups such as HO, H ₂ N, (O)S, (O) ₂ S, CN (cyano), HOOC, F ₃ C or others, one skilled in the art can see the point(s) addition of a radical to a molecule from various free valences of the group itself. For combination groups containing two or more subgroups, the last named subgroup represents the point of addition of the radical, for example, the substituent aryl-C _1-3 alkyl denotes an aryl group that is bonded to a C _1-3 alkyl group, the latter of which is bonded to the core or a group to which a substituent is attached.

In case the compound of the present invention is presented in the form of a chemical name and in the form of a formula, in case of any conflict, the formula will prevail.

The numbering of the substituent atoms begins with the atom that is closest to the nucleus or to the group to which the substituent is attached.

For example, the term 3-carboxypropyl group represents the following substituent:

* ² p o

where the carboxy group is attached to the third carbon atom of the propyl group. Terms 1methylpropyl, 2,2-dimethylpropyl or cyclopropylmethyl group represents the following groups:

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An asterisk can be used in subformulas to indicate the bond that attaches to the core of the molecule as specified.

The term substituted, as used in the present invention, means that any one or more hydrogens on a specified atom are replaced by a group selected from the specified groups, provided that the normal valency of the specified atom is not exceeded and that the substitution results in a stable compound.

Unless specifically stated otherwise, for the entire specification and appended claims, the chemical formula or title presented will cover tautomers and all stereo, optical and geometric isomers thereof (e.g., enantiomers, diastereomers, E/Z isomers, etc.) and racemates, and also mixtures in varying proportions of separated enantiomers, mixtures of diastereomers, or mixtures of any of the above forms, where such isomers and enantiomers exist, as well as salts, including pharmaceutically acceptable salts thereof and solvates thereof, such as, for example, hydrates, including solvates of the free compounds or solvates of salts of compounds.

In general, substantially pure stereoisomers can be prepared according to synthetic principles known to one skilled in the art, for example, by resolving appropriate mixtures, by using stereochemically pure starting materials, and/or by stereoselective synthesis. It is known in the art to prepare optically active forms, for example by resolution of racemic forms or by synthesis, for example using optically pure substances as starting materials and/or by using chiral reagents.

Enantiomerically pure compounds of the present invention or intermediates can be prepared by asymmetric synthesis, for example, by preparing and subsequently resolving suitable diastereomeric compounds or intermediates, which can be separated using known methods (for example, by chromatographic separation or crystallization) and/or by using chiral reagents such as chiral starting materials, chiral catalysts or chiral auxiliaries. In addition, one skilled in the art will know how to prepare enantiomerically pure compounds from appropriate racemic mixtures, for example, by chromatographic separation of the appropriate racemic mixtures on chiral stationary phases; or by separating the racemic mixture using a suitable separating agent, for example by forming a diastereomeric salt of the racemic compound with optically active acids or bases, then separating the salts and releasing the desired compound from the salt; or by derivatization of the corresponding racemic compounds with optically active chiral auxiliary elements, subsequent separation of the diastereomers and removal of the chiral auxiliary group; or by kinetic resolution of the racemate (eg, by enzymatic resolution); by enantioselective crystallization from a conglomerate of enantiomorphic crystals under suitable conditions; or by (fractionated) crystallization from a suitable solvent in the presence of an optically active chiral auxiliary.

The phrase pharmaceutically acceptable is used herein to refer to those compounds, materials, compositions, and/or dosage forms that, to the extent of their intended medical use, are suitable for use in contact with human tissue without causing excessive toxicity, irritation, allergic response, or other problem or complication, and in proportion to a reasonable benefit/risk ratio.

As used in the present invention, a pharmaceutically acceptable salt refers to derivatives of the disclosed compounds wherein the parent compound is modified by forming an acid, preferably strong acid, or alkaline salt thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of alkali residues such as amines; alkaline or organic salts of acid residues such as carboxylic acids; and others.

For example, such salts include the salts of benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gentisic acid, hydrobromic acid, hydrochloric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, 4-methyl- benzenesulfonic acid, phosphoric acid, salicylic acid, succinic acid, sulfuric acid and tartaric acid.

Other pharmaceutically acceptable salts can be formed with cations such as ammonia, L-arginine, calcium, 2,2'-iminobisethanol, L-lysine, magnesium, N-methyl-D-glucamine, potassium, sodium and tris(hydroxymethyl)- aminomethane The pharmaceutically acceptable salts of the present invention can be synthesized from a starting compound that contains an alkaline or acidic component using conventional chemical methods. In general, such salts can be prepared by reacting the free acid or free base form of these compounds with a sufficient amount of a suitable base or acid in water or an organic diluent such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, or a mixture thereof.

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Salts of other acids other than those mentioned above in this invention, for example, suitable for the purification or isolation of the compounds according to the present invention (for example, trifluoroacetate salts), also form part of the invention.

The term halogen usually refers to fluorine, chlorine, bromine and iodine.

The term C _1-n alkyl, where n is an integer selected from 2, 3, 4, 5 or 6, preferably 4 or 6, either alone or in combination with another radical, is an acyclic, saturated, branched or linear hydrocarbon radical with 1-n C atoms. For example, the term C _1-5 alkyl covers the radicals H ₃ C-, H ₃ C-CH ₂ -, H ₃ C-CH ₂ -CH ₂ -, H3C-SCHCH3)-, H ₃ C -CH ₂ -CH ₂ -CH ₂ -, H ₃ CCH ₂ -CH(CH ₃ )-, H ₃ C-CH(CH ₃ )-CH ₂ -, H ₃ C-C(CH ₃ ) ₂ -, N ₃ C-CH ₂ -CH ₂ -CH ₂ -CH ₂ -, H ₃ C-CH ₂ -CH ₂ -CH(CH ₃ )-, H ₃ CCH ₂ -CH(CH ₃ )-CH ₂ -, H ₃ C-CH(CH ₃ )-CH ₂ -CH ₂ -, H ₃ C-CH ₂ -C(CH ₃ ) ₂ -, n ₃ s-s(cn ₃ ) ₂ -sn ₂ -, n ₃ s-sn (CH ₃ )CH(CH3)- and H ₃ C-CH ₂ -CH(CH ₂ CH ₃ )-.

The term C _3-n cycloalkyl, where n is an integer from 4 to n, either alone or in combination with another radical, is a cyclic, saturated, straight-chain hydrocarbon radical with 3-n C atoms. For example, the term C _3-7 cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

The term carbocyclyl or carbocycle, as used either alone or in combination with another radical, denotes a mono-, bi- or tricyclic ring structure consisting of 3-14 14 carbon atoms. The term carbocyclyl or carbocycle refers to fully saturated and aromatic ring systems and partially saturated ring systems. The term carbocyclyl or carbocycle covers conjugated, bridged and spirocyclic systems.

The term aryl, as used in the present invention, either alone or in combination with another radical, is a carbocyclic aromatic monocyclic group containing 6 carbon atoms, which is optionally further conjugated with a second five- or six-membered, carbocyclic group, which is optionally aromatic , saturated or unsaturated. Aryl includes, but is not limited to, phenyl, indanyl, indenyl, naphthyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl and dihydronaphthyl.

The term heterocyclyl or heterocycle refers to saturated or unsaturated mono- or polycyclic ring systems, including an aromatic ring system, containing one or more heteroatoms selected from N, O or S(O)r, where r = 0, 1 or 2, consisting of 3 -14 ring atoms, none of the heteroatoms are part of an aromatic ring. The term heterocyclyl or heterocycle covers all possible isomeric forms.

Thus, the term heterocyclyl or heterocycle includes the following illustrative structures, which are not represented as either radicals or each form, which is optionally attached by a covalent bond to any atom as long as suitable valencies are maintained:

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The term heteroaryl refers to mono- or polycyclic ring systems containing one or more heteroatoms selected from N, O or S(O)r, where r = 0, 1 or 2, consisting of 5-14 ring atoms, in which at least one of the heteroatoms is part of an aromatic ring. The term heteroaryl covers all possible isomeric forms. Thus, the term heteroaryl includes the following illustrative structures, which are not represented as radicals and each form is optionally attached by a covalent bond to any atom as long as suitable valencies are maintained:

Many of the terms presented above may be used repeatedly in the definition of a formula or group, and in each case have one of the meanings given above, independently of each other.

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Suitable preparations for administering the compounds of formula 1 will be apparent to those skilled in the art and include, for example, tablets, pills, capsules, suppositories, lozenges, lozenges, solutions, syrups, elixirs, sachets, injectables, inhalants and powders , etc., preferably tablets.

Suitable tablets can be prepared, for example, by mixing one or more compounds according to formula I with known excipients, for example, inert diluents, carriers, disintegrants, adjuvants, surfactants, binders and/or lubricants.

By therapeutically effective amount for the purposes of the present invention is meant an amount of a substance that is capable of eliminating or alleviating the symptoms of a disease, or which prolongs the survival of the treated patient.

List of abbreviations. _________________________________________________

ACN acetonitrile Alox aluminium oxide Drive. water °C degrees Celsius SuN cyclohexane conc. concentrated DCC Ν,Ν'-dicyclohexylmethanediimine DXM dichloromethane DIPE diisopropyl ether DIPEA N,N-diisopropylethylamine DMF N,N-dimethyl formamide DMSO dimethyl sulfoxide ERI-MS electrospray ionization of mass spectrometry Et20 diethyl ether EtOAc ethyl acetate etc example eq equivalent h hour HATU Hexafluorophosphate X,X,T\G,GG-tetramethyl-O-(7- azabenzotriazol-1-yl)uranium NS1 hydrochloric acid HNO3 Nitric acid SPLA acetic acid HPLC high performance liquid chromatography LiHMDS lithium bis(trimethylsilyl)amide MeOH methanol NaHOPS bicarbonate of soda min minute ml milliliter Pd/C palladium on activated carbon Pd(dppf)C12 [1,1'- Bis(diphenylphosphino)ferrocene]dichloropalladium(P) RE petroleum ether CT room temperature (approx. 20 °C) us. saturated TEA triethylamine TFU trifluoroacetic acid THF tetrahydrofuran TSHH thin layer chromatography on SiO2

Preparation of compounds in accordance with the invention.

General methods of synthesis.

The compounds of the present invention and their intermediates may

- 13 045542 be obtained using synthetic methods that are known to a qualified specialist in the art and described in the literature of organic synthesis. Preferably, the compounds are prepared similarly to the preparation methods described in more detail later in the present invention, especially as described in the experimental section. In some cases, the order of the reaction steps may be changed. Variants of reaction methods that are known to one skilled in the art, but not described in detail in the present invention, can also be used.

The general processes for preparing the compounds of the invention will be apparent to one skilled in the art upon examination of the following schemes. The starting materials can be prepared using methods that are described in the literature or in the present invention, or can be prepared in a similar or similar manner. Any functional groups in the starting materials or intermediates can be protected using conventional protecting groups. These protecting groups can be removed again at a suitable stage within the reaction sequence using methods familiar to one skilled in the art.

The compounds of the invention were prepared using the synthetic methods described later in the present invention, in which the substituents of the general formulas have the meanings specified in the present invention above. These methods are intended to illustrate the invention, without limiting its objects and scope of the claimed compounds to these examples. If the preparation of the starting compounds is not described, they can be obtained commercially or prepared similarly to known compounds or methods described in the present invention. Substances described in the literature are prepared according to published synthetic methods.

The compounds of formula (I) can be prepared as shown in Scheme I below.

Scheme I:

In Scheme I, pyridine A is treated with a suitable primary amine at elevated temperature to produce pyridine B. Amide coupling (e.g. TBTU or HATU as a coupling reagent) with a suitable heterocycle as a next step produces a compound of general formula (I) .

Alternatively, the compounds of formula (I) can be prepared as shown in Scheme II below. Scheme II:

In Scheme II, acid chloride (Y = Cl) A is treated with a suitable heterocycle to produce pyridine B. The leaving group in pyridine B can be replaced by a suitable primary amine using elevated temperature, providing a compound of general formula (I).

The amines used in the above reactions can be prepared using methods known to one skilled in the art, as illustrated in Scheme III below.

Scheme III:

A B C

In Scheme III, amine A is acylated with a suitable acylating reagent to produce amide B, which can then be deprotected (e.g. HCl or TFA for PG = BOC) to produce the desired amine C.

A further possibility for preparing these desired amines is presented in Scheme IV below.

- 14 045542

Scheme IV:

AB C

In Scheme IV, nitrile A is treated with an alkylating agent to produce nitrile B and then deprotected (e.g. HCl or TFA for PG = BOC) to produce amine C.

The compounds of formula (II) can be prepared as shown in Scheme V.

Scheme V:

In Scheme V, ketone or aldehyde A is reacted with a suitable auxiliary to produce compound B. This imine is either reduced or then alkylated with a suitable alkylating reagent, i.e. a Grignard reagent, to produce intermediates C or E, respectively. After deprotection of amine D (i.e. with strong acids), compounds II are then prepared as shown in Schemes I and II.

Examples of synthesis.

The following Examples are intended to illustrate the present invention without limiting it. The terms ambient temperature and room temperature are used interchangeably and indicate a temperature of approximately 20°C, for example, in the range of 19 to 24°C.

Preparation of starting compounds

Example I

Example I.1 (general path).

Methyl 6-[({imidazo[1,2-a]pyridin-3-yl}methyl)amino]pyridine-3-carboxylate

Mixture of 0.60 g (3.84 mmol) methyl 6-fluoropyridin-3-carboxylate, 0.56 g (3.84 mmol) {imidazo[1,2a]pyridin-3-yl}methanamine (CAS No. 160771-89 -1), 2.63 ml (15.4 mmol) DIPEA and 6 ml DMSO were stirred at 120°C for 6 hours. The mixture was diluted with EtOAc and washed with sat. NaHCO ₃ solution and water (1/1). The organic layer was dried and the solvent was removed in vacuo.

The crude product was purified by HPLC (ACN/H2O/NH4OH).

C15H14N4O2 (M = 282.3 g/mol).

ERI-MS: 283 [M+H]+.

- 15 045542

Rt (HPLC): 0.79 min (method C).

Example II.

Example II.1.

6-[({Imidazo[1,2-a]pyridin-3-yl}methyl)amino]pyridine-3-carboxylic acid

A mixture of 0.42 g (1.47 mmol) methyl 6-[({imidazo[1,2-a]pyridin-3-yl}methyl)amino]pyridine-3carboxylate (Example I.1) and 5 ml of HCl ( 6 mol/L) was stirred at 90°C for 4 hours. After cooling to RT, the solvent was removed in vacuo to obtain the product. C ₁₄ H ₁₂ N ₄ O ₂ -HCl (M = 304.7 g/mol)

ERI-MS: 269 [M+H] ⁺ .

Rt (HPLC): 0.10 min (method A).

Example III

Example III.1 (general path).

- [(3 8)-Pyrrolidin-3-yl]-1,3-oxazolidin-2-one hydrochloride

A mixture of 2.00 g (10.7 mmol) tert-butyl (38)-3-aminopyrrolidine-1-carboxylate in 0.5 ml DCM and 4 ml NaOH (50%) was cooled to 0°C. A solution of 1.38 g (9.66 mmol) of 2-chloroethyl carbonochloridate in 0.5 ml of DCM was added dropwise and the reaction mixture was stirred at 0° for 1 hour. 3.48 g (5.37 mmol) of tetrabutyl ammonium hydroxide ( 40% in MeOH) and the mixture was stirred overnight at RT. The mixture was quenched with H ₂ O and extracted with DCM. The combined organic layers were dried over a phase separation cartridge and the solvent was removed in vacuo.

The crude product was purified by column chromatography (silica gel; CyH/EtOAc) and the solvents were removed in vacuo.

C ₁₂ H ₂₀ N ₂ O ₄ (M = 256.3 g/mol).

ERI-MS: 201 [M-tBU+H]+.

R _t (HPLC): 0.82 min (method C).

The above product was added to 2.5 ml of dioxane, 5 ml (20.0 mmol) HCl in dioxane (4 mol/l) and a small amount of MeOH and the mixture was stirred overnight at RT. The solvent was removed in vacuo to give the product.

C ₇ H ₁₂ N ₂ O ₂ -HCl (M = 192.6 g/mol).

ERI-MS: 157 [M+H] ⁺ .

Rt (HPLC): 0.17 min (method C).

The following compounds were prepared according to the general procedure (Example III.1) described above:

Etc. Starting materials Structure ERIMS HPLC Rt [min] (method) III. 2 νη ₂ O G' O ABOUT \___/HCI 155 [M+N] + 0.27 (C)

Example IV.

Example IV.1 (general path).

N-[(3S)-1-(6-Fluoropyridin-3-carbonyl)pyrrolidin-3-yl]-N-methylacetamide

To 4.00 g (22.4 mmol) N-methyl-N-[(3S)-pyrrolidin-3-yl]acetamide hydrochloride and 14.8 ml (106.6

- 16 045542 mmol) TEA in 30 ml of DCM, 3.40 g (21.3 mmol) of 2-fluoropyridine-5-carbonyl chloride (CAS No. 65352-94-5), dissolved in 5 ml of DCM, was added dropwise at 0° C. After stirring for 10 min at 0°C, the reaction mixture was filtered and purified by column chromatography (silica gel; DCM/MeOH, 98/2-85/15).

C13H16FN3O2 (M = 265.3 g/mol).

ERI-MS: 266 [M+H] ⁺ .

R _t (HPLC): 0.63 min (method A).

Example V

Example V.1 (general path).

{Thieno[3,2-c]pyridin-7-yl}methanamine

N—λ Ν ^- λ

Cl—C ρ--=Ν ft __

Ι\ / \ ^ΝΗ 2

A mixture of 600 mg (3.08 mmol) 4-chlorothieno[3,2-c]pyridine-7-carbonitrile, 500 mg Pd/C (10%) and 25 ml NH ₃ in MeOH was hydrogenated at RT and H ₂ pressure 3 bar for 20 hours. The reaction mixture was filtered and the solvent was removed in vacuo. The crude product was dissolved in DMF and purified by HPLC (ACN/H ₂ O/NH ₄ OH) to give the product.

C ₈ H ₈ N ₂ S (M = 164.2 g/mol).

ERI-MS: 165 [M+H] ⁺ .

Rt (HPLC): 0.62 min (method C).

Example VI.

Example VI.1 (general path).

N-methyl-N-[(3S)-pyrrolidin-3-yl]cyclobutanecarboxamide hydrochloride

To 1.00 g (4.99 mmol) (S)-tert-butyl-3-(methylamino)pyrrolidine-1-carboxylate in 5 ml THF was added 0.86 ml (4.99 mmol) DIPEA and dropwise 0. 59 g (4.99 mmol) cyclobutanecarbonyl chloride. After stirring overnight at RT, the mixture was filtered, washed with 10 ml THF and the filtrate was concentrated in vacuo. The residue was stirred in 50 ml ethanol HCl (1.25 M) for 2 h at RT. The mixture was concentrated by evaporation and the residue was dissolved in 30 ml of isopropanol. The mixture was concentrated by evaporation.

C _w H18N2O-HCl (M = 218.7 g/mol).

ERI-MS: 183 [M+H] ⁺ .

Rt (HPLC): 0.96 min (method B).

Example VII.

Example VII.1 (general path).

(R)-2-Methyl-N-[(1Z)-(1-methyl-1H-indazol-4-yl)methylidene]propane-2-sulfinamide

A mixture of 1.50 g (9.37 mmol) 1-methyl-1H-indazole-4-carbaldehyde, 1.36 g (11.2 mmol) (R)-2methylpropane-2-sulfinamide, 5.55 ml (18. 7 mmol) tetrakis(propan-2-yloxy)titanium and 20 ml THF were stirred at 70°C for 1 h.

After cooling to RT, the mixture was diluted with 50 ml of sat. NaCl solution.

The resulting precipitate was filtered through celite and washed with EtOAc. The organic layer was separated and washed with our help. NaCl solution. The organic layer was then dried over a phase separation cartridge and the solvents were removed in vacuo to yield the product.

C ₁₃ H ₁₇ N ₃ OS (M = 263.4 g/mol).

ERI-MS: 264 [M+H] ⁺ .

Rt (HPLC): 0.92 min (method C).

The following compounds were prepared according to the general procedure (Example VII.1) described above:

- 17 045542

Example VIII.

Example VIII.1 (general path).

(R)-2-Methyl-N-[( 1S)-1-(1 -methyl-1 H-indazol-4-yl)ethyl]propane-2-sulfinamide.

(R)-2-Methyl-N-[( 1R)-1-(1 -methyl-1 H-indazol-4-yl)ethyl]propane-2-sulfinamide

To a mixture of 2.46 g (9.34 mmol) (R)-2-methyl-N-[(1Z)-(1-methyl-1H-indazol-4-yl)methylidene]propan-2sulfinamide in 25 ml of DCM was added dropwise 6.23 ml (18.5 mmol) bromo(methyl)magnesium (3 mol/l) at -50°C and the mixture was stirred for 1 hour at -50°C and overnight at RT. Additionally, 6.23 ml (18.5 mmol) bromine(methyl)magnesium (3 mol/l) was added dropwise at RT and stirred for 1 hour. The mixture was then diluted with 50 ml sat.

NH ₄ Cl solution and extracted 2x with DCM. The organic layer was washed with our help. NaCl solution, dried and the solvent was removed in vacuo.

The crude product was purified by HPLC (ACN/H2O/NH4OH) to give the products. The organic solvent was removed in vacuo and the remaining solution was diluted with our help. NaCl solution and extracted 2x with Methyl-THF.

The combined organic layer was dried over Na ₂ SO ₄ , filtered and the solvent was removed in vacuo to give the product.

Product A:

C14H21N3OS (M = 279.4 g/mol).

ERI-MS: 280 [M+H]+.

Rt (HPLC): 0.87 min (method A).

Product B:

C ₁₄ H ₂₁ N ₃ OS (M = 279.4 g/mol).

ERI-MS: 280 [M+H ^]+ .

Rt (HPLC): 0.90 min (method A).

The following compounds were prepared according to the general procedure (Example VIII.1) described above:

- 18 045542

Etc. Starting material Structure Reaction conditions ERIMS HPLC Rt [min] (method) VIII. 2. A S\/^N ⁸ A ^'Ζ^ Ei τζ \ 280 [Μ+Η] ⁺ 2.82 (I) VIII. 2. B \\ ^==<11 V ^N / J6 τζ \ _\^ ^=o 280 [M+N] ⁺ 3.41 (I) VIII. 3. A °A N ABOUT /N ο / \\ / ......ί / Λ τζ / \ ^.ζ ⁴ ζ 280 [M+N] ⁺ 0.86 (C) VIII. 3. in Ά nА ο - ^χ ζ _χ III1H··/ \ / ζτ \/ / Un-ω / ' Ο 280 [M+N] ⁺ 0.89 (C)

Example IX.

Example IX.1 (general path).

(1S)-1-(1-Methyl-1H-indazol-4-yl)ethane-1-amine hydrochloride

To a mixture of 1.52 g (5.43 mmol) (R)-2-methyl-N-[(1S)-1-(1-methyl-1H-indazol-4-yl)ethyl]propan-2sulfinamide in 15 ml of THF was added 5 ml HCl (4 mol/l in dioxane) at 0°C. The reaction mixture was stirred until RT was reached and the resulting precipitate was filtered and dried in vacuo to give the product.

C ₁₀ H ₁₃ N ₃ -HCl (M = 211.7 g/mol).

ERI-MS: 176 [M+H]+.

Rt (HPLC): 0.59 min (method A).

The following compounds were prepared according to the general procedure (Example IX.1) described above:

- 19 045542

_etc Starting material Structure Reaction conditions ERIms HPLC Rt [min] (method) IX. 2 θ^'ΝΗ /''ПШ n^ ⁿ / H _? N—f ) Z^ ^N HCI 176 [M+N] + 0.58(A) IX. 3 1 ^{H2N \} .> the precipitate was filtered off as a product 176 [M+N] + 0.67 (C) --N HCI IX. 4 ώ-ζ \ O* ¹ \ -- III....../ § the precipitate was filtered off as a product 159 [M+НNH3] ⁺ 0.90 (C) IX. 5 /ABOUT 1 ΗΝ.χ —J ^H 2 ^N ^^ - HCI the precipitate was filtered off as a product 176 [M+N] + 0.65 (C) IX. 6 ^hn HCI \ the precipitate was filtered off as a product 159 [M+N] + 0.70 (C)

Example X.

Example X.1 (general path).

(1S)-1-(1H-Indazol-5-yl)ethane-1-amine hydrochloride

HCI

To a mixture of 0.44 g (1.67 mmol) (S)-N-[(1E)-1-(1H-indazol-5-yl)ethylidene]-2-methylpropane-2sulfinamide (Example VII.2) in 7 ml THF and 0.10 ml H ₂ O, 0.19 g (5.00 mmol) sodium borohydride was added at -50°C. The reaction mixture was stirred for 1.25 hours without an ice bath. The mixture was diluted with our help.

- 20 045542

NH ₄ Cl solution and extracted 2x with EtOAc. The organic layer was then dried over a phase separation cartridge and the solvents were removed in vacuo. The crude product was purified by HPLC (ACN/H2O/NH4OH).

C ₁₃ H ₁₉ N ₃ OS (M = 265.4 g/mol).

ERI-MS: 266 [M+H]+.

R _t (HPLC): 0.83 min (method C).

To the above product were added 2 ml THF and 2 ml HCl (4 mol/L) and stirred for 45 min at RT. The solvents were removed in vacuo to obtain the product.

C9HnN ₃ -HCl (M = 197.7 g/mol).

ERI-MS: 145 [M+H] ⁺ .

Rt (HPLC): 0.62 min (method C).

Example XI.

Example XI.1 (general path).

tert-Butyl N-[(1S)-1-[(2-amino-4-chlorophenyl)carbamoyl]ethyl]carbamate dioxane) and a mixture of pere-

To a mixture of 25.0 g (132 mmol) (2B)-2-{[(tert-butoxy)carbonyl]amino}propanoic acid and 18.8 g (132 mmol) 4-chlorobenzene-1,2-diamine in 50 ml THF was added dropwise to a solution of 30.0 g (145 mmol) DCC and 60 ml THF while cooling on ice. The reaction mixture was stirred at RT overnight. The precipitate was filtered off and washed with THF. The filtrate was concentrated in vacuo to dryness. The crude product was treated with a mixture of Et ₂ O/PE (1/1) and the resulting precipitate was filtered. The solid was dried at 40°C in vacuo to give the product.

C ₁₄ H ₂₀ ClN ₃ O ₃ (M = 313.8 g/mol).

Rf (TSH): 0.3 (CyH/EtOAc 1/1).

Example XII.

Example XII.1 (general path).

tert-Butyl N-[(1S)-1-(5-chloro-1H-1,3-benzodiazol-2-yl)ethyl]carbamate

A mixture of 525 mg (1.67 mmol) tert-butyl N-[(1S)-l-[(2-amino-4-chlorophenyl)carbamoyl]ethyl]carbamate and 5 ml HOAc was stirred at 40°C for 3 hours. The mixture was poured into ice and the precipitate was filtered off. The filtrate was concentrated in vacuo and treated with Et ₂ O. The precipitate was filtered off and the filtrate was concentrated to dryness in vacuo. C ₁₄ H ₁₈ ClN ₃ O ₂ (M = 295.8 g/mol).

Rf (TSH): 0.35 (Et ₂ O/PE 2/1).

Example XIII.

Example XIII.1 (general path).

(1S)-1-(5-Chloro-1H-1,3-benzodiazol-2-yl)ethan-1-amine hydrochloride

To a mixture of 1.03 g (3.48 mmol) tert-butyl N-[(1S)-1-(5-chloro-1H-1,3-benzodiazol-2-yl)ethyl]carbamate in

- 21 045542 ml EtOH added 20 ml conc. HCl and the mixture was stirred at 80°C for 2 hours. Solvents were removed in vacuo and the residue was treated with EtOH. The precipitate was filtered off, washed with Et ₂ O and dried at 40°C in vacuo to give the product as a blue powder.

Example XIV.

Example XIV.1 (general path).

tert-Butyl N-[(1S)-1 -(5-chloro-6-fluoro-1H-1,3-benzodiazol-2-yl)ethyl]carbamate

To a mixture of 3.78 g (20.0 mmol) (2S)-2-{[(tert-butoxy)carbonyl]amino}propanoic acid and 3.21 g (20.0 mmol) 4-chloro-5-fluorobenzene- 1,2-diamine in 30 mL THF, 4.54 g (22.0 mmol) of DCC dissolved in 50 mL THF was added dropwise while cooling on ice, and the reaction mixture was stirred at RT over the weekend. The resulting precipitate was filtered off, washed with THF, and the filtrate was concentrated to dryness in vacuo. The residue was dissolved in 70 ml of HOAc and the mixture was stirred at 55°C for 4 hours. The solvent was removed in vacuo and the crude product was dissolved in DCM and washed with H2O and NaHCO ₃ solution (5%). The organic layer was dried over Na ₂ SO ₄ and the solvent was removed in vacuo. The crude product was purified by column chromatography (silica gel; DCM/EtOH; 1-3% EtOH) and triturated 2x with DIPE. The solid was filtered and dried to give the product.

C14H17CWN3O2 (M = 313.8 g/mol).

Rf (TSH): 0.4 (PE/EtOAc 7/3).

Example XV.

Example XV.1 (general path).

(1S)-1-(5-Chloro-6-fluoro-1H-1,3-benzodiazol-2-yl)ethan-1-amine hydrochloride

F

A mixture of 2.60 g (8.29 mmol) tert-butyl N-[(1S)-1-(5-chloro-6-fluoro-1H-1,3-benzodiazol-2yl)ethyl]carbamate and 70 ml HCl in EtOH was stirred at 50°C for 1 hour. After cooling, the resulting precipitate was filtered, washed with cold EtOH and Et ₂ O and dried.

C9H9ClFN3-HCl (M = 250.1 g/mol).

Rf (TSH): 0.3 (DCM/EtOH 9/1).

Example XVI.

Example XVI.1 (general path).

(S)-2-Methyl-N-[(1E)-1-(2-methyl-2H-indazol-4-yl)ethylidene]propane-2-sulfinamide

A mixture of 0.30 g (1.72 mmol) 1-(2-methyl-2H-indazol-4-yl)ethan-1-one, 0.31 g (2.58 mmol) (S)-2methylpropan-2- sulfinamide, 1.72 ml (3.44 mmol) tetraethoxytitanium (2 mol/l) and 5 ml THF were stirred at 80°C overnight.

After cooling to RT, the mixture was diluted with 50 ml of sat. NaCl solution and 100 ml DCM. The resulting precipitate was filtered off and the layers were separated.

The organic layer was dried and the solvents were removed in vacuo to obtain the crude product.

C ₁₄ H ₁₉ N ₃ OS (M = 277.4 g/mol).

ERI-MS: 278 [M+H]+.

- 22 045542

Rt (HPLC): 0.87 min (method C).

The following compounds were prepared according to the general procedure (Example XVI.1) described above:

Etc. Starting materials Structure ERI -MS HPLC Rt [min] (method) XVI. 2 G o CN t% ^:O θ 1 ¹¹ \ 263 [M+ N] ⁺ 0.78(A)

Example XVII.

Example XVII.1 (general path).

(S)-2-Methyl-N-[(1S)-1-(2-methyl-2H-indazol-4-yl)ethyl]nponan-2-sulfinamide.

(S)-2-Methyl-N-[(1R)-1-(2-methyl-2H-indazol-4-yl)ethyl]propane-2-sulfinamide

To a mixture of 0.48 g (1.73 mmol) (S)-2-methyl-N-[(1E)-1-(2-methyl-2H-indazol-4-yl)ethylidene]npropane-2sulfinamide and 5 ml THF was added to 0.5 ml H2O and the mixture was cooled to -50°C. 0.20 g (5.18 mmol) of sodium borohydride was then added and the mixture was allowed to return to RT.

The reaction mixture was washed with a mixture of us. solution of NaHCO ₃ and H ₂ O (1/1). The organic layer was dried and the crude product was purified by HPLC (ACN/H2O/NH4OH)

Product A:

C14H21N3OS (M = 279.4 g/mol).

ERI-MS: 280 [M+H]+.

Rt (HPLC): 0.83 min (method C).

Product B:

C14H21N3OS (M = 279.4 g/mol).

ERI-MS: 280 [M+H] ⁺ .

Rt (HPLC): 0.79 min (method C).

The following compounds were prepared according to the general procedure (Example XVII.1) described above:

Etc. Starting material Structure ERI-MS HPLC Rt [min] (method) XVII. 2. A O I ⁴ n^nh θ n V \ 266 [M+N] ⁺ 0.69(A) XVII. 2. IN θ ζ / ^{0 :} R II......... 266 [M+N] ⁺ 0.66(A)

Example XVIII.

Example XVIII. 1 (common path).

(S)-N-[(1E)-1-(4-Amino-3-nitrophenyl)ethylidene]-2-methylpropane-2-sulfinamide

A mixture of 400 mg (2.00 mmol) 1-(4-amino-3-nitrophenyl)ethan-1-one, 296 mg (2.44 mmol) (S)-2methylpropan-2-sulfinamide, 2.22 ml tetraethoxytitanium ( 2 mol/L) and 8 ml THF were stirred at 80°C overnight.

- 23 045542

After cooling to RT, the mixture was diluted with 50 ml of us mixture. solution of NaCl and H ₂ O (1/1). The resulting precipitate was filtered off, washed with EtOAc and the layers were separated. The organic layer was dried over Na ₂ SO ₄ , filtered and prepared for column chromatography. The crude product was purified by column chromatography (silica gel, DCM/MeOH, 2-20% MeOH).

C12H17N3O3S (M = 283.4 g/mol).

ERI-MS: 284 [M+H]+.

Rt (HPLC): 0.88 min (method C).

Example XIX.

Example XIX.1 (general path).

(S)-N-[(1S)-1-(4-Amino-3-nitrophenyl)ethyl]-2-methylpropane-2-sulfinamide

To a mixture of 565 mg (2.00 mmol) (S)-N-[(1E)-1-(4-amino-3-nitrophenyl)ethylidene]-2-methylpropane-2sulfinamide in 11 ml THF was added 0.20 ml H2O and the mixture was cooled to -50°C. 227 mg (5.98 mmol) sodium borohydride was then added and the mixture was allowed to return to RT.

The reaction mixture was washed 2x. NH ₄ Cl solution. The organic layer was dried over Na ₂ SO ₄ , filtered and the solvent was removed in vacuo to give the crude product.

C12H19N3O3S (M = 285.4 g/mol).

ERI-MS: 286 [M+H]+.

Rt (HPLC): 0.85 min (method C).

Example XX.

Example XX.1 (general path).

(S)-N-[(1S)-1-(3,4-Diaminophenyl)ethyl]-2-methylpropane-2-sulfinamide

A mixture of 581 mg (2.00 mmol) (S)-N-[(1S)-1-(4-amino-3-nitrophenyl)ethyl]-2methylpropan-2 sulfinamide, 58.1 mg Pd/C and 10 ml THF was stirred at CT overnight at a pressure of H ₂ 3 bar.

The solvent was evaporated to obtain the crude product.

C ₁₂ H ₂₁ N ₃ OS (M = 255.4 g/mol).

ERI-MS: 256 [M+H]+.

R _t (HPLC): 0.70 min (method C).

Example XXI.

Example XXI.1 (general path).

(1S)-1-(1H-1,3-Benzodiazol-6-yl)ethan-1-amine hydrochloride

A mixture of 75.0 mg (0.29 mmol) (S)-N-[(1S)-1-(3,4-diaminophenyl)ethyl]-2-methylpropane-2-sulfinamide and 1 ml trimethoxymethane was stirred in a reflux flask. refrigerator for 30 minutes. The reaction mixture was diluted using a mixture of us. solution of NaHCO ₃ and H ₂ O (1/1) and extracted 2x with EtOAc.

The organic layer was dried over Na ₂ SO ₄ , filtered and the solvent was removed in vacuo.

C ₁₃ H ₁₉ N ₃ OS (M = 265.4 g/mol).

ERI-MS: 266 [M+H]+.

- 24 045542

Rt (HPLC): 0.75 min (method C).

The remaining product was dissolved in 2 ml THF and 0.5 ml HCl (4 mol/l in dioxane) was added at 0°C. The reaction mixture was allowed to return to RT and the solvents were removed in vacuo to give the product.

C9H11N3-HQ (M = 197.7 g/mol).

ERI-MS: 162 [M+H]+.

Rt (HPLC): 0.10 min (method A).

Example XXII.

Example XXII.1 (general path).

(R)-N-[(1E)-(1H-Indazol-4-yl)methylidene]-2-methylpropane-2-sulfinamide

A mixture of 330 mg (2.72 mmol) (R)-2-methylpropane-2-sulfinamide and 5 ml DCM was added to 869 mg (5.45 mmol), dried with copper (2+) sulfate and then 438 mg (3. 00 mmol) 1H-indazole-4carbaldehyde and the mixture was stirred at RT overnight. Additionally, anhydrous copper(2+) sulfate was added and the mixture was stirred at RT for 1 d. The solvent was removed in vacuo and the crude product was purified by column chromatography (silica gel; CyH/EtOAc) to give the product.

C ₁₂ H ₁₅ N ₃ OS (M = 249.3 g/mol).

ERI-MS: 250 [M+H] ⁺ .

R _t (HPLC): 0.87 min (method B).

Example XXIII.

Example XXIII.1 (general path).

(R)-N-[(1S)-1-(1H-indazol-4-yl)ethyl]-2-methylpropane-2-sulfinamide.

(R)-N-[(1R)-1-(1H-indazol-4-yl)ethyl]-2-methylpropane-2-sulfinamide

Х°Х°

I II

I ⁺ ► I + y Y Z? At Z?

618 μl of (1, 85 mmol) brom(methyl)magnesium (3 mol/l in Et ₂ O) at -48°C and the mixture was stirred for 4 hours. Once RT was reached, the solvents were removed in vacuo.

The crude product was dissolved in DMF and purified by HPLC (ACN/H2O/NH4OH) to give 2 products.

Product A:

C ₁₃ H ₁₉ N ₃ OS (M = 265.4 g/mol).

ERI-MS: 266 [M+H] ⁺ .

R _t (HPLC): 0.76 min (method C).

Product B:

C ₁₃ H ₁₉ N ₃ OS (M = 265.4 g/mol).

ERI-MS: 266 [M+H] ⁺ .

R _t (HPLC): 0.80 min (method C).

Example XXIV.

Example XXIV.1 (general path).

(1S)-1-(1H-Indazol-4-yl)ethan-1-amine

- 25 045542

A mixture of 90.0 mg (0.34 mmol) (R)-N-[(1S)-1-(1H-indazol-4-yl)ethyl]-2-methylpropan-2-sulfinamide and 5 ml HCl in MeOH was stirred with CT scan overnight. Solvents were removed in vacuo to give the product.

C ₉ HnN ₃ (M = 161.2 g/mol).

ERI-MS: 145 [M-NH ₂ ] ⁺ .

Rt (HPLC): 0.38 min (method B).

Example XXV.

Example XXV.1 (general path).

(S)-2-Methyl-N-[(1E)-1-(2-methyl-2H-inαzol-5-yl)ethylidene]propαn-2-sulfinαmide

To a mixture of 70.0 mg (0.40 mmol) 1-(2-methyl-2H-indazol-5-yl)ethan-1-one (CAS: 1159511-28-0) and 2 ml THF was added 53.6 mg (0.44 mmol) (S)-2-methylpropane-2-sulfinamide and 0.39 ml (1.61 mmol) tetraethoxytitanium (85%) and the reaction mixture was stirred at 80°C overnight. An additional 0.55 equiv was added. (S)-2-methylpronan-2-sulfinamide and the mixture was stirred at 80°C for 4 hours and at RT over the weekend. The reaction mixture was poured into a diluted NaCl solution, EtOAc was added and stirred for 5 minutes. Then the resulting precipitate was filtered and the layers were separated. The H ₂ O layer was extracted with EtOAc, the combined organic layers were dried over a phase separation cartridge and the solvent was removed in vacuo to give the product.

C ₁₄ H ₁₉ N ₃ OS (M = 277.4 g/mol).

ERI-MS: 278 [M+H] ⁺ .

R _t (HPLC): 0.85 min (method C).

Example XXVI.

Example XXVI.1 (general path).

(1S)-1 -(2-Methyl-2H-indazol-5-yl)ethane-1-amine hydrochloride

To a mixture of 0.13 g (0.45 mmol) (S)-2-methyl-N-[(1E)-1-(2-methyl-2H-indazol-5-yl)ethylidene]propan-2sulfinamide, 5 ml THF and 0.10 ml H ₂ O were added to 51.8 mg (1.36 mmol) of sodium borohydride at - 50°C. The reaction mixture was stirred for 1 hour without an ice bath.

The mixture was diluted with our help. NH4Cl solution and extracted 2x with EtOAc.

The organic layer was then dried over a phase separation cartridge and the solvents were removed in vacuo.

C ₁₄ H ₂₁ N ₃ OS (M = 279.4 g/mol).

ERI-MS: 280 [M+H] ⁺ .

Rt (HPLC): 0.83 min (method C).

To the above product were added 1 ml THF and 2 ml HCl (4 mol/L in dioxane) and the mixture was stirred at RT for 15 minutes. Solvents were removed in vacuo to give the product.

C ₁₀ H ₁₃ N ₃ -HCl (M = 211.7 g/mol).

ERI-MS: 159 [M+H] ⁺ .

R _t (HPLC): 0.66 min (method C).

Example XXVI.

Example XXVI.1 (general path).

tert-Butyl (3S)-3-(N-methylcyclonepropanamido)pyrrolidine-1-carboxylate

0.50 g (4.78 mmol) cyclopropanecarbonyl chloride dissolved in 3 ml DCM at 0°C. After stirring for 10 min at 0°C, the reaction mixture was filtered and diluted with DCM. The organic layer was washed with a mixture of us. NaHCO ₃ solution and water (1/1), washed with us. NH ₄ Cl solution and with the help of us. NaCl solution. The organic layer was dried over Na ₂ SO ₄ , filtered and the solvent was removed in vacuo to give the product.

C14H24N2O3 (M = 268.4 g/mol).

- 26 045542

ERI-MS: 270 [M+H]+.

Rt (HPLC): 0.52 min (method A).

Example XXVII.

Example XXVII.1 (general path).

N-Methyl-N-[(3S)-nirrolidin-3-yl]cyclopronanecarboxamide hydrochloride

A mixture of 0.99 g (3.69 mmol) tert-butyl (3S)-3-(N-methylcyclopropanamido)pyrrolidine-1-carboxylate and 5 ml (20.0 mmol) HCl (4 mol/L in dioxane) was stirred at RT in for 1 hour. Solvents were removed in vacuo to give the product.

C ₉ H ₁₆ N ₂ O-HCl (M = 204.7 g/mol).

ERI-MS: 169 [M+H] ⁺ .

Rt (HPLC): 0.57 min (method C).

Example XXVIII.

Example XXVIII.1 (general path).

(1S)-1-{1H-Pyrrolo[2,3-b]pyridin-5-yl} ethan-1-amine hydrochloride

A mixture of 1.20 g (4.52 mmol) (S)-2-methyl-N-[(1S)-1-{1H-pyrrolo[2,3-b]niridin-5-yl}ethyl]propan-2sulfinamide , 5 ml HCl in dioxane and 10 ml THF were stirred at RT for 30 min. The resulting precipitate was filtered and dried in vacuo to obtain the product.

C9H ₁₁ N ₃ -HCl (M = 197.7 g/mol).

ERI-MS: 162 [M+H] ⁺ .

Rt (HPLC): 0.09 min (method A).

Example XXIX.

Example XXIX.1 (general path).

Methyl 6-{[(1S)-l-{1H-pyrrolo[2,3-b]pyridin-5-yl}ethyl]amino}pyridine-3-carboxylate

A mixture of 0.85 g (4.30 mmol) (1S)-1-{1H-pyrrolo[2,3-b]pyridin-5-yl}ethan-1-amine hydrochloride, 0.67 g (4.30 mmol ) methyl 6-fluoropyridine-3-carboxylate, 3.68 (22.0 mmol) DIPEA and 5 ml DMSO were stirred at 0°C120°C for 2 hours.

The reaction mixture was purified by HPLC (ACN/H ₂ O/NH ₄ OH) to give the product.

C ₁₆ H ₁₆ N ₄ O ₂ (M = 296.3 g/mol).

ERI-MS: 297 [M+H] ⁺ .

Rt (HPLC): 0.84 min (method C).

Example XXX.

Example XXX.1 (general path).

6-{[(1S)-1-{1H-pyrrolo[2,3-b]pyridin-5-yl}ethyl]amino}pyridine-3-carboxylic acid hydrochloride

A mixture of 0.15 g (0.51 mmol) methyl 6-{[(1S)-1-{1H-pyrrolo[2,3-b]pyridin-5-yl}ethyl]amino}pyridine 3-carboxylate and 3 ml of semi conc. HCl was stirred at 90°C for 4 hours. The solvent was removed in vacuo at RT to obtain the product.

- 27 045542

C ₁₅ H ₁₄ N ₄ O ₂ -HCl (M = 318.8 g/mol).

ERI-MS: 283 [M+H]+.

Rt (HPLC): 0.56 min (method A).

Example XXXI.

Example XXXI.1 (general path).

5-[(3S)-3 -(Methylamino)pyrrolidin-1-carbonyl]-N-[(1S)-1-{1 H-pyrrolo[2,3-b]pyridin-5 yl}ethyl]pyridin-2 -trifluoroacetic acid amine

hydrochloride 6-{[(1S)-1-{1 H-pyrrolo[2,3-b]pyridine-5K mixture

0.32 g (1.00 mmol) yl}ethyl]amino}pyridine-3-carboxylic acid, 0.29 g (1.21 mmol) tert-butyl N-methylN-[(3S)-πyrrolidine-3-hydrochloride yl]carbamate, 1.72 ml (10.0 mmol) DIPEA and 3 ml DMF, 0.46 g (1.21 mmol) HATU was added and the mixture was stirred for several minutes. The reaction mixture was diluted with MeOH, filtered and purified by HPLC (ACN/H2O/NH4OH). C ₂₅ H ₃₂ N ₆ O ₃ (M = 464.6 g/mol)

ERI-MS: 465 [M+H] ⁺ .

R _t (HPLC): 0.92 min (method C).

The above product was dissolved in 10 ml of DCM and 2.5 ml of TFA was added.

The mixture was stirred at RT for 1 hour.

C20H24N60-C2HF3O2 (M = 478.5 g/mol).

ERI-MS: 365 [M+H] ⁺ .

R _t (HPLC): 0.73 min (method C).

The following compounds were prepared according to the general procedure (Example XXXI.1) described above:

Etc. Starting materials Structure Reaction conditions ERIMS HPLC Rt [min] (method) XXXI. 2 II. 1 o A ¹ - / \ HCI Z’ ό o=/ o h 1. CT scan, 10 min; 2. ct, overnight, evaporation 351 [M+N ] ⁺ 0.61 (C)

Example XXXII.

Example XXXII.1 (general path).

tert-Butyl (3 S)-3-(1-methylcyclobutanamido)pyrrolidine-1-carboxylate

A mixture of 0.55 g (4.83 mmol) 1-methylcyclobutane-1-carboxylic acid, 2.08 ml (12.1 mmol) DIPEA, 1.94 g (6.04 mmol) and 7.5 ml DMF was stirred at RT in for 30 minutes. Then 0.75 g (4.03 mmol) tert-butyl (3S)-3-aminopyrrolidine-1-carboxylate was added and the mixture was stirred at RT overnight. The reaction mixture was diluted with EtOAc, washed with semiconc. NaHCO ₃ solution, 1x using us. NH4Cl solution and 2x using semi-s. NaCl solution. Organic layer

- 28 045542 dried over Na ₂ SO ₄ and the solvents were removed in vacuo to give the crude product.

C15H26N2O3 (M = 282.4 g/mol).

ERI-MS: 183 [M+N-VOS] ⁺ .

Rt (HPLC): 0.92 min (method C).

Example XXXIII.

Example XXXIII.1 (general path).

N, 1-Dimethyl-N-[(3S)-pyrrolidin-3-yl]cyclobutan-1-carboxamide hydrochloride

To a mixture of 1.37 g (4.85 mmol) tert-butyl (3S)-3-(1-methylcyclobutanamido)pyrrolidine-1-carboxylate and 10 ml THF, 0.44 ml (7.03 mmol) iodomethane was added and the mixture was cooled to - 10°C. Then 0.33 g (8.31 mmol) sodium hydride (60%) was added and the mixture was stirred at RT overnight. The reaction mixture was diluted with semiconc. solution of NaHCO ₃ and EtOAc and stirred vigorously. The layers were separated and the H2O layer was extracted 2x with EtOAc. The combined organic layers were dried over a phase separation cartridge and the solvents were removed in vacuo. The crude product was purified by HPLC (ACN/H2O/NH4OH) to give the intermediate.

C ₁₆ H ₂₈ N ₂ O ₃ (M = 296.4 g/mol).

ERI-MS: 241 [M+N-tert-butyl] ⁺ '

R _t (HPLC): 0.98 min (method A).

4 ml MeOH and 4 ml HCl (4 mol/L in dioxane) were added to the above product and the mixture was stirred at RT over the weekend. Solvents were removed in vacuo to give the product.

C ₁₁ H ₂₀ N ₂ O-HCl (M = 232.8 g/mol).

ERI-MS: 197 [M+H] ⁺ .

R _t (HPLC): 0.57 min (method A).

Example XXXIV.

Example XXXIV.1 (general path).

Methyl 6-{[(1-benzothiophen-3-yl)methyl]amino} pyridine-3-carboxylate

To a mixture of 0.78 g (5.00 mmol) methyl 6-fluoropyridine-3-carboxylate and 10 ml DMSO was added 2.58 ml (15.0 mmol) DIPEA and 1.00 g hydrochloride (5.00 mmol) 1- (1-benzothiophen-3-yl)methanamine and the mixture was stirred at 100°C overnight. The reaction mixture was filtered and purified by HPLC (ACN/H ₂ O/NH ₄ OH). The fractions were combined, the organic solvent was removed in vacuo, and the resulting precipitate was filtered, washed with H2O and air dried to give a white solid.

C16H14N2O2S (M = 298.4 g/mol).

ERI-MS: 299 [M+H]+.

Rt (HPLC): 1.00 min (method C).

Example XXXV.

Example XXXV.1 (general path).

6-{[(1-Benzothiophen-3-yl)methyl] amino} pyridine-3-carboxylic acid

A mixture of 1.10 g (3.69 mmol) methyl 6-{[(1-benzothiophen-3-yl)methyl]amino}pyridine-3-carboxylate and 10 ml HCl (4 mol/l) was stirred at 90°C in for 1 hour.

A precipitate formed and the reaction mixture was diluted with 50 ml of THF and stirred at 90°C for 2 hours. Then 10 ml of conc. HCl and the mixture was stirred at 90°C for 5 hours. Solvents were removed in vacuo and the residue was treated 2x with toluene, which was also removed in vacuo.

The remaining yellow oil was dissolved in MeOH and purified by HPLC (ACN/H2O/HCOOH).

- 29 045542

C ₁₅ H ₁₂ N ₂ O ₂ S (M = 284.3 g/mol).

ERI-MS: 285 [M+H] ⁺ .

Rt (HPLC): 0.56 min (method C).

Example XXXVI.

Example XXXVI. 1 (general pathway) (3S)-1-(6-Fluoropyridin-3-carbonyl)-N-methylpyrrolidin-3-amine trifluoroacetic acid

To 2.84 g (14.2 mmol) tert-butyl N-methyl-N-[(3S)-pyrrolidin-3-yl]carbamate and 9.86 ml (70.8 mmol) TEA in 40 ml DCM dropwise 2.26 g (14.2 mmol) of 2-fluoropyridine-5-carbonyl chloride (CAS No. 65352-94-5) dissolved in 30 ml of DCM was added at 0°C. After stirring for 10 min at 0°C, the reaction mixture was filtered and purified by column chromatography (silica gel;

DXM/MeOH, 99/1-90/10).

C ₁₆ H ₂₂ FN ₃ O ₃ (M = 323.4 g/mol).

ERI-MS: 268 [M+N-tert-butyl] ⁺ .

Rt (HPLC): 0.89 min (method C).

25 ml of DCM and 5 ml of TFA were added to the above product and the mixture was stirred at RT over the weekend. Solvents were removed in vacuo to give the product.

C _u Hi4FN ₃ O-C2HF ₃ O2 (M = 337.3 g/mol)

ERI-MS: 224 [M+H] ⁺ .

Rt (HPLC): 0.61 min (method C).

Example XXXVII.

Example XXXVII.1 (general path).

N-[(3S)-1-(6-Fluoropyridin-3-carbonyl)pyrrolidin-3-yl]-N-methylcyclopropanecarboxamide

To 2.40 g (7.12 mmol) (3S)-1-(6-fluoropyridine-3-carbonyl)-N-methylpyrrolidin-3-amine trifluoroacetic acid and 4.95 ml (35.6 mmol) TEA in 40 ml DCM, 0.82 g (7.83 mmol) of cyclopropanecarbonyl chloride dissolved in 10 ml DCM was added dropwise at 0°C. After stirring for 10 min at 0°C, the reaction mixture was washed with a mixture of sat. solution of NaHCO ₃ and water (1/1) and sat. NaCl solution. The organic layer was dried over Na ₂ SO ₄ , filtered and the solvent was removed in vacuo. The crude product was purified by column chromatography (DCM/MeOH 99/1-90/10) to give the product.

C15H18FN3O2 (M = 291.3 g/mol).

ERI-MS: 292 [M+H]+.

R (HPLC): 0.72 min (method A).

Example XXXVIII.

Example XXXVIII.1 (general route) tert-Butyl (38)-3-cyano-3-methylpyrrolidine-1-carboxylate.

tert-Butyl (3R)-3-cyano-3-methylpyrrolidine-1-carboxylate

The reaction was carried out in an Ar atmosphere. 2.70 g (13.8 mmol) tert-butyp 3cyanopyrrolidine-1-carboxylate and 40 ml THF and 15.1 ml (15.1 mmol) LiHMDS were added to the mixture at -78°C. After stirring for 30 minutes at -78°C, 1.28 ml (20.6 mmol) of iodomethane was added dropwise. The reaction mixture was stirred for 30 min at -78°C and 30 min at RT. The mixture was poured into 100 ml of the mixture. aq. NH4C1 solution and water (1:1) and extracted 2x with EtOAc.

The organic layer was washed with brine, dried over MgSO ₄ , filtered and the solvent was evaporated. The crude product was purified by chiral SFC (Method G).

* or ** The absolute stereochemistry at the chiral center of enantiomerically pure compounds was not determined.

Product A (first elution):

C11H18N2O2 (M = 210.3 g/mol), R _t (HPLC): 2.58 min (method J). Product B (second elution): C11H18N2O2 (M = 210.3 g/mol), Rt (HPLC): 3.65 min (method J). Example XXXIX.

Example XXXIX.1 (general path).

(3S)-3-Methylpyrrolidine-3-carbonitrile hydrochloride

To a mixture of 1.25 g (5.95 mmol) tert-butyl 3-cyano-3-methylpyrrolidine-1-carboxylate (Example XIII.1.A) in 10 ml dioxane was added 2.97 ml (11.9 mmol) HCl (4 M in dioxane) and the mixture was stirred overnight at RT. The resulting precipitate was filtered off, washed with dioxane and dried in air.

C6H _w N2-HCl (M = 146.6 g/mol).

ERI-MS: 111 [M+H]+.

R _f (TSH): 0.3 (S1O2, DCM/MeOH/NH3 9/1/0.1).

Example XXXX.

Example XXXX.1 (general path).

6-[({Imidazo[1,5-a]pyridin-1-yl}methyl)amino]pyridine-3-carboxylic acid

A mixture of 250 mg (1.77 mmol) 6-fluoropyridin-3-carboxylic acid, 651 mg (3.54 mmol) 1-{imidazo[1,5-a]pyridin-1-yl}methanamine hydrochloride, 980 mg (7 .09 mmol) potassium carbonate and 2 ml DMSO were stirred at 150°C overnight. The reaction mixture was filtered and purified by HPLC (ACN/H2O/HCOOH).

C ₁₄ H ₁₂ N ₄ O ₂ (M = 268.3 g/mol).

ERI-MS: 269 [M+H] ⁺ .

Rt (HPLC): 0.3 min (method H).

The following compounds were prepared according to the general procedure (Example XXXX.1) described above:

Etc. Starting materials Structure ERIMS HPLC Rt [min] (method) xxxx. 2 ABOUT nm T Oh o=/ o ζ Λ 269 [Μ+Η ] ⁺ 0.23 (N)

Example XXXXI.

Example XXXXI.1.

N-(3-Cyano-4-methyl-2-nitrophenyl)acetamide

- 31 045542

85 ml of acetic anhydride was added to 65.0 g (XXX mmol) of 5-amino-2-methylbenzonitrile (a solution was formed; exothermic reaction). Upon cooling, the product crystallized. Ether was added to the reaction mixture, the precipitate was filtered off and washed with ether to obtain a wet intermediate. 85.0 g of the wet intermediate was added in portions to 300 ml of fuming HNO ₃ at -30°C. The reaction mixture was stirred for 5 minutes and then the reaction mixture was poured into ice water. The resulting precipitate was filtered and washed with H ₂ O. The solid was air dried overnight and then recrystallized from EtOH. C10H9N3O3 (M = 219.2 g/mol)

Example XXXXII.

Example XXXXII.1.

2,6-Dimethyl-1H-1,3-benzodiazole-7-carbonitrile

A mixture of 22 g (0.1 mol) N-(3-cyano-4-methyl-2-nitrophenyl)acetamide, 2 g Pd/C (10%) and 800 ml MeOH was treated under 5 bar H ₂ at RT for X hours. The mixture was filtered and the solvent was removed in vacuo to give the intermediate.

g (0.10 mol) of the intermediate and 400 ml of MeOH were heated (solution) and HCl gas was bubbled into the reaction flask for 30 minutes under reflux. After cooling to RT, the resulting white precipitate was filtered and washed with Et ₂ O.

C ₁₀ H ₉ N ₃ (M = 171.2 g/mol).

Rf (TSH): 0.55 (DCM/MeOH 9/1).

Example XXXXIII.

Example XXXXIII.1.

1-(2,6-Dimethyl-1H-1,3-benzodiazol-7-yl)methanamine

A mixture of 2.80 g (16.4 mmol) 2,6-dimethyl-1H-1,3-benzodiazole-7-carbonitrile, 1.00 g Raney nickel and 50 ml NH ₃ in MeOH was stirred at 50°C and pressure H _2-3 bar for X hours. The reaction mixture was filtered and the solvent was removed in vacuo. The remaining crude product was triturated with Et ₂ O and the product was filtered as a white solid.

C ₁₀ H ₁₃ N ₃ (M = 175.2 g/mol).

Rf (TSH): 0.12 (DCM/MeOH/NH ₃ 9/1/0.1).

Obtaining final connections.

Example 1.

Example 1.1 (general path).

3-[(3S)-1-{6-[({Imidazo[1,2-a]pyridin-3-yl}methyl)amino]pyridin-3-carbonyl}pyrrolidin-3-yl]1,3-oxazolidine -2-he

To a mixture of 50.0 mg (0.16 mmol) 6-[({imidazo[1,2-a]pyridin-3yl}methyl)amino]pyridine-3-carboxylic acid hydrochloride (example II.1) and 37, 9 mg (0.20 mmol) 3-[(3S)pyrrolidin-3-yl]-1,3-oxazolidin-2-one hydrochloride (example III.1) in 2 ml DMF and 168 μl (0.98 mmol ) DIPEA, 93.6 mg (0.25 mmol) HATU was added and the reaction mixture was stirred at RT for 10 min. The mixture was purified by HPLC (ACN/H ₂ O/NH ₄ OH) to give the product.

- 32 045542

C21H22N6O3 (M = 406.4 g/mol).

ERI-MS: 407 [M+H]+.

Rt (HPLC): 0.67 min (method C).

The following compounds were prepared according to the general procedure (Example 1.1) described above:

Etc. Starting materials Structure Reaction conditions ERIMS HPLC Rt [min] (method) 1.2 XXX. 1 XXV II. 1 5 ° //g ιΤ ^{Ν Ν} \ to 0 ⁿ 433 [Μ+Η Г 0.81 (C) 1.3 o % N XXX 1.1 p o / 11 ^{Ν Ν} \ to IJ ⁿ ην-^ν^ 458 [Μ+Η G 0.80 (C) 1.4 ABOUT XXX 1.1 I ° ХУдУо \ к 0 ^Н ην-^ν^ 447 [Μ+Η k 0.85 (C) 1.5 ABOUT XXX 1.1 1 ° ^..d. ХХке\к I] ^н HNY^ 447 [Μ+Η k 0.67(A) 1.6 ABOUT F XXX 1.1 2 ⁰ XI IJ n F hn-^ _n ^ 483 [Μ+Η k 0.84 (C) 1.7 o d Ν XXX 1.1 Z^ ιχ. °\ Z^ Kommersant ZZ III...../ Su Λ Ζ 458 [Μ+Η k 0.63 (A) 1.8 XXX. 1 XXX III. 1 at °\ O II....../ Su Λ ζ 461 [Μ+Η k 0.87 (C)

- 33 045542

- 34 045542 * The stereochemistry in the chiral center of the enantiomerically and diastereomerically pure compound was not determined.

Example 2.

Example 2.1 (general path).

N-[(3S)-1-(6-{ [(5-Chloro-1 N-indazol-3 -yl)methyl]amino} pyridin-3-carbonyl)pyrrolidin-3 -yl] -N methyl acetamide

51.6 μl (0. 30 mmol) DIPEA and 21.8 mg (0.12 mmol) (5-chloro1H-indazol-3-yl)methanamine and the reaction mixture was stirred overnight at 100°C.

The mixture was filtered and purified by HPLC (ACN/H ₂ O/TFA) to give the product.

C ₂₁ H ₂₃ ClN ₆ O ₂ (M = 426.9 g/mol).

ERI-MS: 427 [M+H]+.

Rt (HPLC): 0.44 min (method G).

The following compounds were prepared according to the general procedure (Example 2.1) described above:

Etc Starting materials Structure Reaction conditions ERIMS HPLC Rt [min] (method) 2.2 IV. 1 /--\ ° z=\ HN—(/ A—/ ^N=/ 0 417 [M+N] + 0.54(F) 2.3 IV. 1 Cl·XjTT^ ^NH2 vr j z Z^XK 100 °C, 1.5 d 443 [M+N] + 0.56(F) 2.4 IV. 1 /—NH ^N Cv S g !G/ s Ο. 4 N 120 °C overnight 410 [M+N] + 0.60 (V) 2.5 IV. 1 Cl T Z Ο ζ=η ΗΝ^^Γ HN \ J Λ ¹ — ο=/ kJ ' 406 [M+N] + 0.44(G)

- 35 045542

Example 3.

Example 3.1 (general path).

N-[(3S)-1-(6-{[(1-Benzothiophen-3-yl)methyl]amino}pyridin-3-carbonyl)pyrrolidin-3-yl]-N methylacetamide

To a mixture of 250 mg (0.94 mmol) N-[(3S)-1-(6-fluoropyridin-3-carbonyl)pyrrolidin-3-yl]-Nmethylacetamide in 10 ml DMSO was added 486 μl (0.28 mmol) DIPEA and 226 mg (0.11 mmol) of 1-(1-benzothiophen-3-yl)methanamine hydrochloride and the reaction mixture was stirred overnight at 100°C. The mixture was filtered and purified by HPLC (ACN/H ₂ O/NH ₄ OH). After freeze-drying, the product was re-purified by column chromatography (silica gel; DCM/MeOH, 7/3). Solvents were removed in vacuo and the remaining product was dissolved in dioxane and lyophilized.

C ₂₂ H ₂₄ N ₄ O ₂ S (M = 408.5 g/mol).

ERI-MS: 409 [M+H]+.

Rt (HPLC): 0.86 min (method C).

Example 4.

Example 4.1 (general path).

N-[(3S)-1-{6-[({Imidazo[1.2-a]pyridin-3-yl}methyl)amino]pyridin-3-carbonyl}pyrrolidin-3-yl]N-methylcyclobutanecarboxamide

To a mixture of 0.15 g (0.49 mmol) 6-[({imidazo[1,2-a]pyridin-3-yl}methyl)amino]pyridine3-carboxylic acid hydrochloride, 0.16 g (0.74 mmol ) N-methyl-N-[(3S)-pyrrolidin-3yl]cyclobutanecarboxamide hydrochloride, 0.84 ml (0.49 mmol) DIPEA in 3 ml DMF, 0.28 g (0.74 mmol) HATU was added and the reaction mixture was stirred with CT scan for 5 minutes. The mixture was purified by HPLC (ACN/H ₂ O/NH ₄ OH). The organic solvent was removed in vacuo and the remaining solution was diluted with our help. NaHCO ₃ solution and extracted 2x with DCM. The organic layer was dried over the phase separation cartridge and the solvent was removed in vacuo. The remaining solid was purified by column chromatography (silica gel; DCM/MeOH, 98/2-80/20). Solvents were removed in vacuo to obtain the product.

C24H28N6O2 (M = 432.5 g/mol).

ERI-MS: 433 [M+H] ⁺ .

Rt (HPLC): 0.78 min (method C).

Example 5.

Example 5.1 (general path).

N-Methyl-N-[(3S)-1-{6-[({thieno[3,2-c]pyridin-7-yl}methyl)amino]pyridin-3carbonyl}pyrrolidin-3-yl]acetamide

58.3 μl (0. 34 mmol) DIPEA and 20.4 mg (0.12 mmol) 1{thieno[3,2-c]pyridin-7-yl}methanamine and the reaction

- 36 045542 the mixture was stirred overnight at 120°C.

The mixture was filtered and purified by HPLC (ACN/H2O/NH4OH) to give the product.

C ₂₁ H ₂₃ N ₅ O ₂ S (M = 409.5 g/mol).

ERI-MS: 410 [M+H]+.

R _t (HPLC): 0.45 min (method D).

The following compounds were prepared according to the general procedure (Example 5.1) described above:

Etc. Starting materials Structure Reaction conditions ERI-MS HPLC Rt [min] (method) 5.2 IV. 1 IX. 1 A o =/ O ........./ X 421 [M+N] ⁺ 0.79 (C) 5.3 IV. 1 Όθ νη ₂ NH ^X N' 393 [M+N] ⁺ 0.71 (C) 5.4 IV. 1 CM u Ύί /X/ < \..αύ Z Z—' o^/ o 0 Z-----w 100 °C, overnight, 24 h 100 °C 433 [M+N] ⁺ 0.47(D) 5.5 IV. 1 cm CO A Z ° ° / \ fl N \ / ^HN >< II J 1 У* HI h Br ON °C, overnight 471 [M+N] ⁺ 0.52(D)

- 37 045542

- 38 045542

5.13 IV. 1 vo %IH ₂ HCI < Ύ η ° о W Ol H 120 °C, 4 h 120 °C, overnight 393 [M+N] ⁺ 0.56 (N) 5.14 IV. 1 tv τ z Z^\^—X I of IZ ^z O / ° 9 120°C overnight, Additional 0.75 eq. amine, 120 °C overnight 393 [M+N] ⁺ 0.75 (C) 5.15 IV. 1 XIII. 1 100 °C, 2 d 441 [M+N] ⁺ 0.54(D) 5.16 IV. 1 tv ΞΕ z = l—nh A AL /A ^NH o 100 °C, overnight 392 [M+N] ⁺ 0.53(D) 5.17 IV. 1 *zi J ° ^z 1 11 z jO CT T 100 °C, overnight 392 [M+N] ⁺ 0.51(D) 5.18 IV. 1 ² HN—ll 7 ' JJL KGN YuN 1EN h ₂ n ^==N HN \ brA.V UJV-r H 408 [M+N] ⁺ 0.66 (C)

-39045542

5.19 IV. 1 yun <\/ 1 Χ.ιιιι Ζ U \° ο ζ^ C.P. double purification by HPLC 393 [M+N] ⁺ 0.43(D) 5.20 IV. 1 XV. 1 ο -π Z _vV ζ 100 °C, 2 d 459 [M+N] ⁺ 0.56(D) 5.21 IV. 1 I th Z \— ² o 0 - 120 °C, 5 h 398 [M+N] ⁺ 0.79 (C) 5.22 IV. 1 N—NH Г ίμη ₂ Ν—ΝΗ ΐ Μ η Ο CAJ Οχ Η double purification by HPLC 393 [M+N] ⁺ 0.71 (C) 5.23 IV. 1 NH, ........./ y=N HN Ίθ /—\ ° 0CK ^Ν ς) ^Ο< 0^\ 100 °C, 2 d 407 [M+N] ⁺ 0.45(D) 5.24 IV. 1 ζ ν5 Ο ^{ζ ζ} Ο /=° 404 [M+N] ⁺ 0.55(A) 5.25 IV. 1 ΙΧ.2 \ /A J/ ΙΖ 4. 421 [M+N] ⁺ 0.79 (C)

-40045542

5.26 IV. 1 HCI ppp, HCI Y, V. 1 100 °C, 2 d 404 [M+N] ⁺ 0.46(D) 5.27 IV. 1 IX.3 \i°A / f ίί η N \ / n'! JI 1 i >—\ LJ| h 120 °C, Weekends 421 [M+N] ⁺ 0.75 (C) 5.28 IV. 1 CM T z ^z hn- ⁿ 100 °C, Weekends 397 [M+N] ⁺ 0.76 (C) 5.29 IV. 1 H ₂ N~_ HCI ° 0 /^N/ ( Λ J Oy 394 [M+N] ⁺ 0.67 (C) 5.30 IV. 1 HCI hch ₂ n— /=\ HN—ft AC /7 N—. °<^Ν _χ 100 °C, 2 d 404 [M+N] ⁺ 0.54(D) 5.31 IV. 1 CM T z ^x w / \ ⁰ HN—ft y-G |£ % / N=/ N-— double 1 HPLC purification 410 [M+N] ⁺ 0.54 (E)

-41 045542

5.32 IV. 1 Ν /HCI A o =/ O ΛΑ - double purification by HPLC 421 [M+N] ⁺ 0.78 (C) 5.33 IV. 1 he ⁰⁼ ( f XVa a ⁰ nh ₂ ^ho /k o HN— f| I/N=/N—. AiA-NH / \ 100 °C, overnight 392 [M+N] ⁺ 0.59(D) 5.34 IV. 1 nh ₂ HCI GDxDMN o---N ^HCI 1 <Tr ^{: ;} : M 100 °C, 2 d 409 [M+N] ⁺ 0.42(D) 5.35 IV. 1 \ N—> = νΛΪ ! YjA Aici 7 o =/ w ZI linwZ dG z 412 [M+N] ⁺ 0.75 (C) 5.36 IV. 1 XXI. 1 7 A mm../ Xki\ ^z 120 °C 4 +3 eq. DIPEA,1 20 °C overnight, + 1 eq. amine, 120 °C overnight 407 [M+N] ⁺ 0.69 (C) 5.37 IV. 1 IX.6 ъ ZI Him../a 421 [M+N] ⁺ 0.78 (C) 5.38 IV. 1 XXVI. 1 ° o - ^H 100 °C overnight, additional 421 [M+N] ⁺ 0.75 (C)

- 42 045542

Example 6.

Example 6.1 (general path).

N-Methyl-N-[(3 S)-1 -(6- {[(6-methyl-1 N-indazol-4-yl)methyl]amino} pyridin-3-carbonyl)pyrrolidin3-yl]acetamide

The reaction was carried out in an Ar atmosphere.

A mixture of 50.0 mg (0.11 mmol) N-[(3S)-1-(6-{[(6-bromo-1H-indazol-4-yl)methyl]αmino}pyridin-3carbonyl)pyrrolidine-3- yl]-N-methylacetamide, 22.1 μl (0.16 mmol) trimethyl-1,3,5,2,4,6trioxatriborinane, 0.11 ml Na ₂ CO ₃ solution (2 mol/l) and 5 ml dioxane were degassed and purged with argon. Then 4.33 mg (0.01 mmol) Pd(dppf)Cl ₂ was added and the reaction mixture was stirred at 100°C for 2 hours.

Solvents were removed in vacuo and the crude product was dissolved in EtOAc and filtered. The filtrate was washed with our help. NaCl solution, dried over Na ₂ SO ₄ and the solvent was removed in vacuo. The crude product was dissolved in DMF and purified by HPLC (ACN/H2O/NH4OH) to give the product.

C22H2 ₆ N ₆ O2 (M = 406.5 g/mol).

ERI-MS: 407 [M+H]+.

Rt (HPLC): 0.48 min (method D).

Example 7.

Example 7.1 (general path).

N-[(3S)-1-(6-{[(1S)-1-(1 H-Indazol-4-yl)ethyl]amino}pyridin-3-carbonyl)pyrrolidin-3-yl]-N methyl acetamide

Mixture of 50.0 mg (0.19 mmol) N-[(3S)-1-(6-fluoropyridin-3-carbonyl)pyrrolidin-3-yl]-Nmethylacetamide, 33.4 mg (0.21 mmol) (1S )-1-(1H-indazol-4-yl)ethan-1-amine, 113 μl (1.00 mmol) DIPEA and 2 ml NMP were stirred at 110°C for 15 h in a closed vial. Fil reaction mixture

- 43 045542 etched and purified 2x by HPLC (ACN/H ₂ O/NH ₄ OH) to obtain the product.

C22H26N6O2 (M = 406.5 g/mol).

ERI-MS: 407 [M+H]+.

Rt (HPLC): 0.47 min (method E).

Example 8.

Example 8.1 (general path).

3-[(3 S)-1 -(6-{[(1-Benzothiophen-3-yl)methyl]amino)pyridin-3-carbonyl)pyrrolidin-3-yl]-1,3oxazolidin-2-one

To a mixture of 28.4 mg (0.10 mmol) 6-{[(1-benzothiophen-3-yl)methyl]amino}pyridine-3-carboxylic acid, 19.3 mg (0.10 mmol) 3-[ hydrochloride (38)-pyrrolidin-3-yl]-1,3-oxazolidin-2-one, 41.8 mg (0.11 mmol) HATU and 1 ml DMF was added to 56.8 μl (0.33 mmol) DIPEA and the reaction the mixture was stirred at RT overnight.

The mixture was filtered through Al ₂ O ₃ , washed with 0.5 ml DMF and purified by HPLC (ACN/H2O/NH4OH) to give the product.

C ₂₂ H ₂₂ N ₄ O ₃ S (M = 422.5 g/mol).

ERI-MS: 423 [M+H] ⁺ .

Rt (HPLC): 0.66 min (method D).

The following compounds were prepared according to the general procedure (Example 8.1) described above:

Etc. Starting materials Structure Reaction conditions ERIMS HPLC Rt [min] (method) 8.2 XXXV. 1 III. 2 b Z—. сО С/У 421 [M+N] ⁺ 0.67(D)

Example 9.

Example 9.1 (general path).

N-[(3S)-1-(6-{[(1-Benzothiophen-3-yl)methyl]amino}pyridin-3-carbonyl)pyrrolidin-3-yl]-Nmethylcyclobutanecarboxamide

To a mixture of 28.4 mg (0.10 mmol) 6-{[(1-benzothiophen-3-yl)methyl]amino}pyridine-3-carboxylic acid, 21.9 mg (0.10 mmol) N-methyl hydrochloride -N-[(3S)-nirrolidin-3-yl]cyclobutanecarboxamide, 56.8 µl (0.33 mmol) DIPEA and 1 ml

DMF was added to 41.8 mg (0.11 mmol) HATU and the reaction mixture was stirred at RT overnight.

The mixture was filtered through Al ₂ O ₃ , washed with 0.5 ml DMF and purified by HPLC (ACN/H ₂ O/TFA) to give the product.

C ₂₂ H ₂₂ N ₄ O ₃ S (M = 448.6 g/mol).

ERI-MS: 449 [M+H] ⁺ .

Rt (HPLC): 0.59 min (method F).

- 44 045542

The following compounds were prepared according to the general procedure (Example 9.1) described above:

Etc. Starting materials Structure Reaction conditions ERI-MS HPLC Rt [min] (method) 9.2 XXXV. 1 XXXIX. 1 n 377 [m+n] ⁺ 0.55(F)

* The stereochemistry at the chiral center of the enantiomerically and diastereomerically pure compound was not determined.

Analytical HPLC methods.

Method A.

time (min) Vol.% water (incl. 0.1% TFA) Vol.% ACN Flow [ml/min] 0.00 97 3 2.2 0.20 97 3 2.2 1.20 0 100 2.2 1.25 0 100 h,o 1.40 0 100 3.0

Analytical column: Sunfire (Waters) 2.5 µm; 3.0x30 mm; column temperature: 60°C. Method B

time (min) Vol.% water (incl. 0.1% TFA) Vol.% ACN Flow [ml/min] 0.00 97 3 2.2 0.20 97 3 2.2 1.20 0 100 2.2 1.25 0 100 h,o 1.40 0 100 3.0

Analytical column: Stable Bond (Agilent) 1.8 µm; 3.0x30mm; column temperature: 60°C.

Method C.________________________________________________________________________________

time (min) Vol.% water (incl. 0.1%NH ₄ OH) Vol.% ACN Flow [ml/min] 0.00 97 3 2.2 0.20 97 3 2.2 1.20 0 100 2.2 1.25 0 100 3 1.40 0 100 3

Analytical column: XBridge C18 (Waters) 2.5 µm; 3.0x30 mm; column temperature: 60°C. Method D

Gradient/solvent Time [min] % sol. [Water 0.1% NH3] % sol. [Acetonitrile] Flow [ml/min] Gemi [°C] 0.0 95.0 5.0 1.5 60.0 1.3 oh oh 100.0 1.5 60.0 1.5 oh oh 100.0 1.5 60.0 1.6 95.0 5.0 1.5 60.0

Preparative column: XBridge (Waters) C18_3.0x30 mm_2.5 µm.

Method E._________________________________________________

Gradient/solvent Time [min] % sol. [Water 0.1% NH3] % sol. [Acetonitrile] Flow [ml/min] Temp [°C] oh oh 95.0 5.0 1.5 60.0 1.3 oh oh 100.0 1.5 60.0 1.5 oh oh 100.0 1.5 60.0 1.6 95.0 5.0 1.5 60.0

XBridge C18_3.0x30 mm_2.5 µm (Waters).

- 45 045542

Method F

Gradient/solvent Time [min] % sol. [Water 0.1% TFA (v/v)] % sol. [Acetonitrile 0.08% TFA (v/v)] Flow [ml/min] Temp [°C] 0.0 95.0 5.0 1.5 60.0 1.3 oh oh 100.0 1.5 60.0 1.5 oh oh 100.0 1.5 60.0 1.6 95.0 5.0 1.5 60.0

Preparative column: Sunfire (Waters) C18_3.0x30 mm_2.5 µm.

Method G. _______________________

Gradient/solvent Time [min] % sol. [Water 0.1% TFA (v/v)] % sol. [Acetonitrile 0.08% TFA (v/v)] Flow [ml/min] Temp [°C] oh oh 95.0 5.0 1.5 60.0 1.3 oh oh 100.0 1.5 60.0 1.5 oh oh 100.0 1.5 60.0 1.6 95.0 5.0 1.5 60.0

Preparative column: Sunfire (Waters) C18_3.0x30 mm_2.5 µm.

Method N.

Gradient/solvent Time [min] % sol. [Water 0.1% FA (v/v)] % sol. [Acetonitrile] Flow [ml/min] Temp [°C] 0.0 97.0 h,o 2.2 60.0 0.2 97.0 h,o 2.2 60.0 1.2 oh oh 100.0 2.2 60.0 1.25 oh oh 100.0 h,o 60.0 1.4 oh oh 100.0 3.0 60.0

Sunfire C18_3.0x30 mm_2.5 microns (Waters).

Method I.

Gradient/solvent Time [min] % sol. [scCO2] % sol. [IPA 20 mM NH3] Flow [ml/min] Temp [°C] Back pressure [psi] inch] oh oh 75.0 25.0 4.0 40.0 2175.0 10.0 75.0 25.0 4.0 40.0 2175.0

CHIRAL ART® Cellulose SC_4.6x250 mm_5 µm (Agilent). Method J.

Gradient/solvent Time [min] % sol. [scCO2] % sol. [IPA 20 mM NH3] Flow [ml/min] Temp [°C] Back pressure [psi] inch] oh oh 95.0 5.0 4.0 40.0 2175.0 10.0 95.0 5.0 4.0 40.0 2175.0

CHIRAL ART® Cellulose SC_4.6x250 mm_5 µm (YMC).

Description of biological properties.

Enzymatic study of vanin-1.

The test compounds were dissolved in 100% DMSO at a concentration of 10 mM and in the first step diluted in DMSO to a concentration of 5 mM, after which serial dilution steps were carried out in 100% DMSO. The dilution ratio and the number of dilution steps can be changed according to needs. Typically 8 different concentrations were prepared by 1:5 dilutions and further intermediate dilutions were made with assay buffer resulting in a final DMSO concentration of 1% in the assay.

0.1 nM FLAG-tagged vanin-1 (AA 22-493, T26I, produced in-house) and test compounds were incubated at room temperature for 20 min in assay buffer (1 mM DTT, 0.0025% Brij-35, 50 mM HEPES, pH 7.5). D-pantethine (Sigma, cat. no. P2125-5G) in assay buffer (final concentration 3 μM) was added and incubated for an additional 30 min at room temperature. The total volume analyzed was typically 40 µl, but this may be corrected

- 46 045542 customized according to your needs. The reaction was stopped by adding an equal volume of stop solution as a reaction mixture to reach 100 nM HD-pantothenic acid (as internal standard) and 1% TFA. The assay plates were centrifuged for 2 min and the formation of pantothenic acid was detected using RapidFire Mass spectrometry (mobile phase A: 0.1% formic acid and 0.01% trifluoroacetic acid in water; mobile phase B: 47.5% acetonitrile, 47 .5% methanol, 0.1% formic acid and 0.01% trifluoroacetic acid in water) using a C18, 12 µl cartridge (Agilent cat. no. G9205A).

The values presented in table. I are the results of measurements of one or more samples. In case of multiple measurements, geometric mean values are presented.

Human Whole Blood Study: Pantthetheinase (vanine) converts panthetheine to pantothenic acid and cysteamine. Therefore, in the described protocol, vanine activity is quantified by the formation of pantothenic acid after pantethine supplementation via pantethine. The study is applicable to the identification of vanine inhibitor. Stock solutions of compounds were dissolved in DMSO at 10 mM. Further dilutions were carried out in RPMI 1640 medium (Gibco, no. A10491-01) and the final concentrations in the study were 0.032 nM - 500 nM.

Human blood was collected in a blood bag (1% heparin, 50 IU/ml). Blood aliquots were added to the cavities of 96 deep well plates in an amount of 290 μl and mixed with 10 μl of compound solution or vehicle (30 s at 1400 rpm on a shaker). Equilibration was carried out at room temperature, 250 rpm and for 30 min. The assay was started by adding 10 μl of substrate solution (20 μM pantethine in 1 mM DTT, 0.0025% Brij-35, 50 mM HEPES, pH 7.5) to each well, except for some blank wells which received 10 ml of substrate buffer (1 mM DTT, 0.0025% Brij-35, 50 mM HEPES, pH 7.5) only. The samples were shaken vigorously (30 s, 1400 rpm) and the reaction was allowed to proceed at room temperature, 250 rpm, for 5 min. The reaction was stopped by adding the instrumental inhibitor vanine in excess (BI-1 total concentration 10 μM). The plate was centrifuged at 4°C, 665 G for 10 minutes. Blood plasma samples (100 μl) were then transferred to another 96 deep well plate and proteins were precipitated (5 min on ice) by adding 100 μl of ice-cold precipitating solution (1 μM labeled pantothenic acid (di-β-alanine-13C6,15K2 calcium salt , Sigma, no. 705837) in acetonitrile). After this, the plate was centrifuged (4°C, 3220 G, 10 min) and the supernatants (50 μl) were collected in another 96 deep well plate and mixed (10 s, 1400 rpm) with 150 μl glacial formic acid (0. 1%, Carl Roth GmbH+Co.KG, No. CP03.1). The formation of pantothenic acid was detected using RapidFire Mass Spectrometry. TripleQuad 6500+ (ABSciex, Germany) was equipped with an LC-1290 system, a RapidFire autosampler (Agilent, Germany) and a 12 µL Type C C18 cartridge (Agilent cat. no. G9526-80000). Mobile phase A consisted of 0.09% formic acid and 0.01% trifluoroacetic acid in water and mobile phase B consisted of 0.09% formic acid and 0.01% trifluoroacetic acid in acetonitrile/methanol/water = 47.5/47 .5/5.

Synthesis of instrumental inhibitor BI-1: o

To 70 ml of MeOH, 5.40 g (28.8 mmol) of ketone 1 (synthesis is described in Angew. Chem. Int. Ed. 2010, 49, 6856) and 12.9 g (34.6 mmol) CeCl ₃ -7H were added ₂ O. The reaction mixture was cooled to -15°C, then 2.18 g (57.7 mmol) NaBH ₄ was added in portions. The reaction mixture was stirred for 3 hours at 0°C. The reaction was quenched by adding saturated aq. NH ₄ Cl solution and extracted with EtOAc. The organic layers were combined, dried over Na ₂ SO ₄ and the solvent was removed in vacuo.

A stirred solution of 6.29 g (52.8 mmol) of thionyl chloride in 50 ml of acetonitrile was cooled to 50°C and a solution of 4 g (21.1 mmol) in ACN of the above product was added dropwise. After addition was complete, 258 mg (2.11 mmol) DMAP was added in one portion. The mixture was stirred for 15 minutes while maintaining the temperature below -40°C, and then 8.36 g (106 mmol) of anhydrous pyridine was added while maintaining the external temperature at -40°C. Stirring was continued for 1 hour. EtOAc was added, stirred for 5 minutes, a suspension (pyridine salt) appeared, which was filtered and washed with EtOAc. 12 ml of saturated Na ₂ HPO ₄ was added slowly to the filtrate. The resulting solution was stirred for 40 minutes. The two layers were separated. The organic layer was washed with 10 ml of 1M NaHSO ₄ aq., dried over Na ₂ SO ₄ and concentrated under reduced pressure. The crude compound was purified by column chromatography (silica gel, 8% EtOAc in hexane).

C ₉ H ₁₇ NO ₄ S (M = 235.3 g/mol).

ERI-MS: 258 [M+Na]+.

Rf (TSH, silica gel) 0.4 (PE/EtOAc 3/1).

To a solution of 1.00 g (0.004 mol) of the above product in 10.000 ml EtOAc was added 1.36 g (0.006 mol) NaIO ₄ in 10 ml H2O. Then 44 mg (0.2 mmol) RuCl ₃ was added and the mixture was stirred at 0-15°C for 12 hours. The mixture was quenched with H ₂ O (20 ml) and extracted with EtOAc. The organic phase was then washed with brine (20 ml), dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by column chromatography (silica gel, PE/EtOAc=10:1-3:1).

C9H17NO5S (M = 251.3 g/mol).

ERI-MS: 252 [M+H] ⁺ .

Rf (TSH, silica gel) 0.55 (PE/EtOAc 3/1).

4.00 g (14.3 mmol) methyl 5-hydroxy-6-iodopyridine-3-carboxylate was added to 40 ml DMF. To this mixture was added 602 mg (15.1 mmol) sodium hydride. After gas evolution, 5.40 g (21.5 mmol) was added and the reaction mixture was stirred at 75°C for 1.5 hours. After cooling to RT, the reaction mixture was diluted with EtOAc and washed with water. The organic components were dried, filtered, and evaporated.

The residue was purified by column chromatography (silica gel, 0-5%MeOH/CH ₂ Cl ₂ ).

C ₁₆ H ₂₃ IN ₂ O ₅ (M = 450.3 g/mol).

ERI-MS: 451 [M+H] ⁺ .

5.00 g (11.1 mmol) of the above product was added to 50 ml MeOH and 10 ml CH2Cl2. To this mixture was added 50 ml of 4 M HCl in dioxane. After 3 h, the volatile components were removed in vacuo and the residue was used without further purification.

3.28 g (9.37 mmol) of the above product, 105 mg (0.47 mmol) Pd(OAc) ₂ , 0.33 g (0.56 mmol), 9,9-dimethyl-4,5-bis( diphenylphosphino)xanthene (0.33 g; 0.56 mmol; 6.00 mol%) and 9.16 g (28.1 mmol) of cesium carbonate were added to 100 ml of dioxane and the mixture was thoroughly degassed. The reaction mixture was stirred at 90°C under argon for 4 hours. The solids were filtered through a Celite® plug and evaporated. The residue was purified by column chromatography (silica gel, 05% MeOH/CH2Cl2).

50 g (6.75 mmol) of the above product was added to 5 ml MeOH and 70 ml water. To this mixture was added 323 mg (13.5 mmol) LiOH and the reaction mixture was stirred at 50°C for 1 hour. The reaction was filtered and MeOH was removed in vacuo. The aqueous layer was neutralized with 1 M HCl. The solids were filtered and allowed to dry and used without further purification.

C10H12N2O3 (M = 208.2 g/mol).

ERI-MS: 209 [M+H] ⁺ .

Rt (HPLC): 0.60 min (method A).

915 mg (4.39 mmol) of the above product were dissolved in 20 ml of DMF. To this mixture were added 0.86 g (4.83 mmol) of intermediate XVI and 1.84 ml (13.2 mmol) TEA), followed by 1.84 g (4.83 mmol) HATU. The reaction mixture was stirred at RT for 16 hours.

Volatile components were removed in vacuo and the residue was purified by column chromatography (Biotage KP-Nh cartridge, 0-10% MeOH/EtOAc).

C17H2 ₄ N ₄ O3 (M = 332.4 g/mol).

ERI-MS: 333 [M+H] ⁺ .

R _t (HPLC): 0.63 min (method A).

Other features and advantages of the present invention will become apparent from the following more detailed examples, which illustrate, by way of example, the spirit of the invention.

- 48 045542

Biological properties of typical representatives according to the present invention

Example VNN1 IC50 (nM) HWB IC50 (nM) 1.13 0.15 3.03 1.14 0.18 2.59 1.15 0.19 4.82 1.16 0.20 2.78 1.17 0.83 10.43 1.18 0.41 3.67 1.19 0.30 3.78 2.1 0.23 5.03 2.2 0.14 2.3 0.21 2.4 0.29 1.39 2.5 0.67

Example VNN1 IC50 (nM) HWB IC50 (nM) 2.6 2.05 3.1 0.41 7.21 4.1 0.10 1.63 5.1 0.04 1.17 5.2 0.07 1.68 5.3 0.09 11.25 5.4 0.12 1.59 5.5 0.13 5.6 0.13 2.10 5.7 0.14 4.49 5.8 0.16 1.71 5.9 0.18 10.33

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Claims (15)

49 045542 5.10 0.18 1.41 5.23 1.43 4.10 5.36 0.22 4.86 5.11 0.21 5.24 1.23 3.88 5.37 0.24 5.12 0.23 3.91 5.25 1.43 5.38 0.36 1.37 5.13 0.28 1.71 5.26 1.62 5.39 0.29 26.22 5.14 0.36 1.69 5.27 2.25 5.40 0.54 1.06 5.15 0.60 7.52 5.28 2.65 6.1 0.14 5.16 0.62 4.39 5.29 2.74 7.1 0.33 7.66 5.17 0.64 5.30 3.02 8.1 0.20 5.18 0.69 5.31 4.62 8.2 0.21 5.19 0.75 3.69 5.32 9.06 9.1 0.26 5.20 0.76 5.33 9.33 9.2 1.14 5.21 0.79 3.40 5.34 9.43 5.22 0.82 3.35 5.35 0.12 1.39 CLAIM 1. A compound of formula I or a pharmaceutically acceptable salt thereof where R ¹ is naphthalenyl substituted with R ¹ ' ¹ and R ¹ ' ² or 8-10-membered heteroaryl containing 1-3 heteroatoms selected from the group consisting of S, N and O, substituted with R ¹ ' ¹ and R ¹ '²; R ¹ ' ¹ is selected from the group consisting of H, C1. ₄ alkyl, C ₁ . ₂ alkyl-O-, CF ₃ , C ₃ . ₅ cycloalkyl, H ₂ N-, Br, Cl and F; R ¹ ' ² is selected from the group consisting of H, C ₁ . ₄ alkyl, CF ₃ , H ₂ N-, Br, Cl and F; where in the definition of R ¹ ' ¹ and R ¹ ' ² the specified alkyl is optionally substituted with 1-3 F atoms; R ² and R ³ are independently selected from the group consisting of H and methyl, R ⁴ is R ⁴ ' ¹ R ⁴ ' ² N- or NC; or R ⁴ represents a group of the formula R ⁴ ' ^a R ^4a where X represents CH ₂ or O; R ⁴ ' ¹ is selected from the group consisting of CH3-CO-, C3.4cycloalkyl-CO-, substituted R ⁴ ' ¹ ' ¹ and R ⁴ ' ¹ ' ² , where R ⁴ ' ¹ ' ¹ , R ⁴ ' ¹ ' ² independently selected from the group consisting of H, -CH3, F, and -CN; R ⁴ ' ² represents H or C ₁ . ₃ alkyl, - 50 045542 R ⁵ represents H or methyl; or a pharmaceutically acceptable salt thereof. 2. The connection according to claim 1, where R ¹ represents naphthalenyl, 8-10 membered heteroaryl containing 1-3 heteroatoms selected from the group consisting of N and S, substituted with R ¹ ' ¹ and R ¹ ' ² , or An 8-10 membered heteroaryl containing 1-3 heteroatoms selected from the group consisting of N and O, substituted with R ¹ ' ¹ and R ¹ ' ² , or a pharmaceutically acceptable salt thereof. 3. Connection according to claim 1 or 2, where R ¹ ' ¹ is selected from the group consisting of H, methyl, H2N-, Br, Cl and F; or a pharmaceutically acceptable salt thereof. 4. Connection according to one or more claims 1-3, where R ¹ ' ² is selected from the group consisting of H, methyl and Cl; or a pharmaceutically acceptable salt thereof. 5. Connection according to one or more claims 1-4, where R ² represents H, and R ³ represents methyl; or a pharmaceutically acceptable salt thereof. 6. Connection according to one or more claims 1-4, where R ² and R ³ represent H; or a pharmaceutically acceptable salt thereof. 7. Connection according to one or more claims 1-4, where R ⁴ is R ⁴ '1R ⁴ ' ² N; or a pharmaceutically acceptable salt thereof. 8. Connection according to one or more claims 1-7, where R ⁴ ' ¹ is selected from the group consisting of CH3-CO-, C _{3_4} cycloalkyl-CO-, substituted R ⁴ ' ₁ ^{' 1} and R ⁴ ' ¹ ' ² , where R ⁴ ' ¹ ' ¹ , R ⁴ ' ¹ ' ² are independently selected from the group consisting of H, -CH ₃ , F and -CN; R ⁴ ' ² represents methyl; or a pharmaceutically acceptable salt thereof. 9. Connection according to one or more claims 1-8, where R ⁵ represents H; or a pharmaceutically acceptable salt thereof. 10. Connection according to claim 1, where R ¹ represents naphthalenyl or 8-10-membered heteroaryl containing 1-3 heteroatoms selected from the group consisting of S, N and O, substituted with R ¹ ' ¹ and R ¹ '²; R ¹ ' ¹ is selected from the group consisting of H, methyl, H2N-, Br, Cl and F; R ¹ ' ² is selected from the group consisting of H, methyl and Cl; R ² and R ³ are independently H or methyl; R ⁴ is R ⁴ '1R ⁴ ' ² N- or NC-; or R ⁴ represents a group of the formula R ⁴ ' ^a R ⁴ “where X represents CH ₂ or O; R ⁴ ' ¹ is selected from the group consisting of CH3-CO-, C3.4cycloalkyl-CO-, substituted R ⁴ ' ¹ ' ¹ and R ⁴ ' ¹ ' ² , where R ⁴ ' ¹ ' ¹ , R ⁴ ' ¹ ' ² independently selected from the group consisting of H, -CH3, F and -CN; R ^4'2 represents methyl; R ⁵ represents H or methyl; or a pharmaceutically acceptable salt thereof. 11. A compound of formula I according to claim 1 or 10, selected from the group consisting of: - 51 045542 - 52 045542 or a pharmaceutically acceptable salt thereof. 12. Pharmaceutical composition containing a therapeutically effective amount of at least one compound of formula I according to one of the following. 1-11 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients. 13. Use of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11 as a medicinal product. 14. Use of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11 for the treatment of a patient suffering from Crohn's disease, ulcerative colitis, atopic dermatitis, systemic sclerosis, non-alcoholic steatohepatitis (NASH), psoriasis, chronic kidney disease, chronic obstructive disease lungs, idiopathic pulmonary fibrosis, rheumatoid arthritis, scleroderma, asthma, allergic rhinitis, allergic eczema, juvenile rheumatoid arthritis, juvenile idiopathic arthritis, graft-versus-host disease, psoriatic arthritis, hyperlipidemia, colorectal cancer or pancreatic cancer associated with new diagnosed diabetes. 15. A pharmaceutical composition containing a compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11 and a pharmaceutically active compound selected from the group consisting of an immunomodulatory agent, an anti-inflammatory agent or a chemotherapeutic agent. Eurasian Patent Organization, EAPO Russia, 109012, Moscow, Maly Cherkassky lane, 2