EA043045B1 - HETEROAROMATIC COMPOUNDS AS VANIN INHIBITORS - Google Patents

Description

Prerequisites for the creation of the invention

1. Field of technology.

The invention relates to novel vanin-inhibiting compounds, to pharmaceutical compositions containing them, and to their use as medicines.

2. General information.

Vanine enzyme isoforms 1 and 2 are single-domain extracellular pantetheinases that catalyze the cleavage of pantethine and pantetheine into pantothenic acid and cystamine, and, respectively, cysteamine (Martin, Immunogenetics, (2001 May-June) vol. 53, no. 4, pp. 296-306) . Cysteamine generation has been associated with increased tissue oxidative stress as a result of reduced glutathione levels, a condition common to many pathological conditions including IBD (Xavier, Nature. 2011 Jun 15;474(7351):307-17), cancer (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, p. 20310).

Increased vanin-1 activity in the intestinal epithelium promoted tissue damage and inflammation by reducing resistance to oxidative stress in mouse models (Naquet, Biochem Soc Trans. 2014 Aug; 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,

c. 2817-27); (Pouyet, Inflammatory bowel diseases, (Jan. 2010) vol. 16, no. 1, pp. 96-104). Homozygous mice knocked out for VNN1 (KO) do not have significant levels of cysteamine in the blood and tissues and demonstrate glutathione-mediated tissue resistance to oxidative stress (Berruyer, The Journal of experimental medicine, (2006 Dec. 25) vol. 203, no. 13, pp. 2817-27). In addition, these mice are protected from intestinal injury in models of TNBS, DSS, and schistosome-induced colitis (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). Given that rodents lack vanin-2, their only source of cysteamine is vanin-1, so the protective phenotype of the VNN1 KO mouse is attributed to a lack of cysteamine.

In humans, vanin-1 was upregulated in the intestinal epithelium in tissue biopsies from patients with UC and CD, and a functional polymorphism in the regulatory region of the VNN1 gene, which led to increased expression of VNN1, was associated with increased susceptibility to IBD (P = 0.0003 heterozygous versus wild type) (Gensollen, Inflammatory bowel diseases (Oct. 2013) vol. 19, no. 11, pp. 2315-25).

In addition, upregulation of vanin-1 activity in skin and blood has been 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, c 3326-3335), and elevated vanin-1 levels have been observed in chronic juvenile idiopathic thrombocytopenia (Zhang, Blood, (2011 Apr. 28) vol. 117, no. 17, c. 4569-79), Psoriasis and Atopic Dermatitis (Jansen, The Journal of investigative dermatology, (Sept. 2009) vol.129, no.9, pp. 2167-74).

Increased vanin-1 expression and activity are also present and serve as biomarkers for pancreatic cancer associated with newly diagnosed diabetes (Kang, Cancer Letters (New York, NY, United States) (2016), 373(2), 241-250 ) and is also correlated with poor prognosis and treatment response in colorectal cancer (Chai, American journal of translational research, (2016) vol. 8, no. 10, pp. 4455-4463).

WO2014048547, WO2018011681 and WO2016193844 describe vanin inhibitors for the treatment of a number of diseases such as Crohn's disease and ulcerative colitis.

The problem solved by the present invention is to create new compounds that act as inhibitors of vanin enzymes, preferably as inhibitors of the vanin-1 enzyme.

Surprisingly, the compounds according to the present invention have been found to have potent vanin-1 inhibitory activity, preferably exhibiting inhibition of VNN-1 IC ₅₀ [nM] < 100, more preferably IC ₅₀ [nM] < 10, particularly preferably IC ₅₀ [ nM] < 1.

Preference is given to drugs with a long residence time in the body, as they remain effective for a longer period of time and therefore can be used at lower doses. Surprisingly, the compounds according to the present invention show a favorable mean retention time (MRT).

Moreover, the compounds of the present invention exhibit additional properties favorable to their pharmacokinetic and pharmacological profile, such as good solubility and good metabolic stability. In addition, the compounds according to the present invention exhibit good chemical stability.

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Detailed description of the invention

Surprisingly, it was found that the above problem can be solved using the compounds of formula I in accordance with the present invention.

Therefore, the present invention relates to a compound of formula I o

in which n means 1 or 2;

m means 1, 2 or 3;

R ¹ and R ² are independently selected from the group consisting of H, C _1-4 -alkyl, 6-10 membered aryl substituted with R ² ' ¹ , and pyrimidine, where R ² ' ¹ is selected from the group consisting of H, F, Cl, -CN;

R ³ means NR ³¹ R ³² or

R ³ means a group of formula R ³ ' ^a or R ³ ' ^b

R ^3b in which X means CH ₂ or O;

R ³ ' ¹ is selected from the group consisting of C ₁ _ ₄ -alkyl-CO-, pyrimidine, C ₃ _ ₅ -cycloalkyl-CO-, substituted by R ³ ' ¹ ' ¹ and R ³ ' ¹ '²;

where R ³ ' ¹ ' ¹ , R ³ ' ¹ ' ² are independently selected from the group consisting of H, CH ₃ , F and -CN;

R ³ ' ² means C _1-4 -alkyl;

R ⁴ means hydrogen or C _1-4 -alkyl or

R ³ and R ⁴ together form a 4-6 membered heterocycle containing one oxygen atom;

or its pharmaceutically acceptable salt’

Preferred Embodiments

In another embodiment of the present invention, m means 1 or 2'

In another embodiment of the present invention, m means 1 '

In another embodiment of the present invention, m means 2'

In another embodiment of the present invention, m means 3 '

In another embodiment of the present invention, n means 1 '

In another embodiment of the present invention, n is 2'

In another embodiment of the present invention, R ¹ means H or methyl'

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

In another embodiment of the present invention, R ¹ means methyl'

In another embodiment of the present invention, R ² is methyl, ethyl, pyrimidine, or phenyl substituted with R ² ' ¹ , where R ² ' ¹ is selected from the group consisting of H, F, Cl and -CN'

In another embodiment of the present invention, R ² means methyl or phenyl substituted with R ^2'1 '

In another embodiment of the present invention R ² means methyl, ethyl, pyrimidine or phenyl'

In another embodiment of the present invention, R ² means methyl or ethyl'

In another embodiment of the present invention, R ² means methyl'

In another embodiment of the present invention, R ² means ethyl'

In another embodiment of the present invention, R ² means pyrimidine'

In another embodiment of the present invention, R ² means phenyl, substituted by R ^2'1 '

In another embodiment of the present invention, R ² ' ¹ means H, F, Cl or CN'

In another embodiment of the present invention, R ² ' ¹ means H'

In another embodiment of the present invention, R ² ' ¹ means F'

In another embodiment of the present invention, R ² ' ¹ means Cl'

In another embodiment of the present invention, R ² ' ¹ means CN'

In another embodiment of the present invention

R ³ means NR ³ '1R ³ ' ² or

R ³ means a group of formula R ³ ' ^a

- 2 043045 in which X means CH2 or O;

R ³ ' ¹ is -COCH3, pyrimidine, C3-4-cycloalkyl-CO— substituted with R ³ · ¹ · ¹ and R ³ · ¹ · ² ; where R ^{3 1 1} and r ^{3 1 2} are independently H, CH3, F or -CN;

R ³ ' ² means CH ₃ ·

In another embodiment of the present invention, R ³ means NR ³ '1R ³ ' ² ·

In another embodiment of the present invention, R ³ means a group of formula R ^{3 a}

In another embodiment of the present invention, R ³ means a group of formula R ³ ' ^b o

_R 3.b

In another embodiment of the present invention, X is CH2·

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

In another embodiment of the present invention, R ³ ' ¹ means -COCH ₃ , pyrimidine, 3 1 1 3 1 2 3 1 1 3 1 2

C ₃ _ ₄ -cycloalkyl-CO- substituted with R and R , where R and R are independently H, -CH ₃ , F or -CN·

In another embodiment of the present invention R ³ ' ¹ means C1-4-alkyl-COB another embodiment of the present invention R ³ ' ¹ means -COCH3·

In another embodiment of the present invention, R ³ ' ¹ means pyrimidine·

In another embodiment of the present invention, R ³ ' ¹ is C ₃ _ ₄ -cycloalkyl-COB. In another embodiment of the present invention, R ³ ' ¹ is cyclopropyl-CO- substituted by R ^{3 1 1} and R ³ ' ¹ '2 .

In another embodiment of the present invention, R ³ ' ¹ is cyclobutyl-CO- substituted with R ^{3 1 1} and R ³ ' ¹ '2 .

In another embodiment of the present invention, R ³ ' ¹ ' ¹ and R ³ ' ¹ ' ² are independently H, CH ₃ , F or -CN·

In another embodiment of the present invention, R ³ ' ¹ ' ¹ means H·

In another embodiment of the present invention, R ³ ' ¹ ' ² means H·

In another embodiment of the present invention, R ³ ' ¹ ' ¹ and R ³ ' ¹ ' ² are H·

In another embodiment of the present invention, R ³ ' ² means CH ₃ ·

In another embodiment of the present invention, R ⁴ means hydrogen·

In another embodiment of the present invention, R ³ and R ⁴ together form a 6-membered heterocycle containing one oxygen atom

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

in which n means 1 or 2;

m means 1, 2 or 3;

R ¹ means H or methyl;

R ² is methyl, ethyl, pyrimidine or phenyl substituted with R ² ' ¹ , where R ² ' ¹ is selected from the group consisting of H, F, Cl and -CN;

R ³ means NR ³ '1R ³ ' ² or

R ³ means a group of formula R ^{3 a} ,

in which X means CH ₂ or O;

3'1 3'1'1 3'1'2

R is -COCH ₃ , pyrimidine or C _3-4 -cycloalkyl-CO- substituted with R and R ;

where R ³ · ¹ · ¹ and R ³ · ¹ · ² independently of each other mean H, CH ₃ , F or -CN;

R ^3'2 means CH ₃ ;

R ⁴ means hydrogen or

R ³ and R ⁴ together form a 6-membered heterocycle containing one oxygen atom;

or a pharmaceutically acceptable salt thereof

- 3 043045

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

in which n means 1 or 2;

m means 1;

R ¹ means methyl;

R ² is methyl or phenyl substituted with R ² ' ¹ , where R ² ' ¹ is selected from the group consisting of H, F, Cl and -CN;

R ³ means NR ³ '1R ³ ' ² or

R ³ means a group of formula R ^{3 a} ,

in which X means CH ₂ or O;

R ³ ' ¹ means -COCH ₃ , pyrimidine, C ₃ _ ₄ -cycloalkyl-CO-, substituted by R ³ ' ¹ ' ¹ and R ³ ' ¹ '²;

where R ³ ' ¹ ' ¹ and R ³ ' ¹ ' ² independently of each other mean H, CH ₃ , F or -CN;

R ^3'2 means CH ₃ ;

R ⁴ means hydrogen or

R ³ and R ⁴ together form a 6-membered heterocycle containing one oxygen atom;

or its pharmaceutically acceptable salt

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

in which n means 1 or 2;

m means 2;

R ¹ means H or methyl;

R ² means methyl, ethyl, pyrimidine or phenyl;

R ³ means NR ³¹ R ³² or

R ³ means a group of formula R ^{3 a}

in which X means CH ₂ or O;

3'1 3'1'1 3'1'2

R is -COCH ₃ , pyrimidine or C ₃ _ ₄ -cycloalkyl-CO- substituted with R and R ;

where R ³ ' ¹ ' ¹ and r ³ ' ¹ ' ² independently of each other mean H, CH ₃ , F or -CN;

R ^3'2 means CH ₃ ;

R ⁴ means hydrogen or

R ³ and R ⁴ together form a 6-membered heterocycle containing one oxygen atom;

or its pharmaceutically acceptable salt

Another preferred embodiment of the present invention are the above compounds of formula I selected from the group consisting of examples , 11'10, 4'4, 11'9, 7'4, 4'3, 7Ί, 8'3, 11'6, 10 and 9'3'

- 4 043045

or a pharmaceutically acceptable salt thereof.

- 5 043045

Another preferred embodiment of the present invention are the above compounds of formula I selected from the group consisting of examples 6, 9.1, 8.2, 5.3, 2.1, 7.2, 5.2, 4.1, 4.4, 7.4, 4.3, 7.1, 8.3, 10 and 9.3 .

Another preferred embodiment of the present invention are the above compounds of formula I selected from the group consisting of examples 13.1, 13.3, 11.10, 11.9 and 11.6.

Another preferred embodiment of the present invention is the compound of Example 6.

Another preferred embodiment of the present invention is the compound of Example 9.1

Another preferred embodiment of the present invention is the compound of Example 8.2.

Another preferred embodiment of the present invention is the compound of Example 5.3.

Another preferred embodiment of the present invention is the compound of Example 2.1.

Another preferred embodiment of the present invention is the compound of Example 7.2.

Another preferred embodiment of the present invention is the compound of Example 13.3.

Another preferred embodiment of the present invention is the compound of Example 5.2.

Another preferred embodiment of the present invention is the compound of Example 13.1.

Another preferred embodiment of the present invention is the compound of Example 4.1.

Another preferred embodiment of the present invention is the compound of Example 11.10.

Another preferred embodiment of the present invention is the compound of Example 4.4.

Another preferred embodiment of the present invention is the compound of Example 11.9.

Another preferred embodiment of the present invention is the compound of Example 7.4.

Another preferred embodiment of the present invention is the compound of Example 4.3.

Another preferred embodiment of the present invention is the compound of Example 7.1.

Another preferred embodiment of the present invention is the compound of Example 8.3.

Another preferred embodiment of the present invention is the compound of Example 11.6.

Another preferred embodiment of the present invention is the compound of Example 10.

Another preferred embodiment of the present invention is the compound of Example 9.3.

Another preferred embodiment of the present invention are pharmaceutically acceptable salts of the above compounds of formula I selected from the group consisting of examples 6, 9.1, 8.2, 5.3, 2.1, 7.2, 13.3, 5.2, 13.1, 4.1, 11.10, 4.4, 11.9, 7.4, 4.3, 7.1, 8.3, 11.6, 10 and 9.3.

Another preferred embodiment of the present invention are pharmaceutically acceptable salts of the above compounds of formula I selected from the group consisting of examples 6, 9.1, 8.2, 5.3, 2.1, 7.2, 5.2, 4.1, 4.4, 7.4, 4.3, 7.1, 8.3, 10 and 9.3.

Another preferred embodiment of the present invention are pharmaceutically acceptable salts of the above compounds of formula I, selected from the group consisting of examples 13.1, 13.3, 11.10, 11.9 and 11.6.

Another preferred embodiment of the present invention are pharmaceutically acceptable salts of the compound of Example 6.

Another preferred embodiment of the present invention are pharmaceutically acceptable salts of the compound of example 9.1

Another preferred embodiment of the present invention are pharmaceutically acceptable salts of the compound of example 8.2.

Another preferred embodiment of the present invention are pharmaceutically acceptable salts of the compound of example 5.3.

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Another preferred embodiment of the present invention are pharmaceutically acceptable salts of the compound of example 2.1.

Another preferred embodiment of the present invention are pharmaceutically acceptable salts of the compound of example 7.2.

Another preferred embodiment of the present invention are pharmaceutically acceptable salts of the compound of example 13.3.

Another preferred embodiment of the present invention are pharmaceutically acceptable salts of the compound of example 5.2.

Another preferred embodiment of the present invention are pharmaceutically acceptable salts of the compound of example 13.1.

Another preferred embodiment of the present invention are pharmaceutically acceptable salts of the compound of example 4.1.

Another preferred embodiment of the present invention are pharmaceutically acceptable salts of the compound of example 11.10.

Another preferred embodiment of the present invention are pharmaceutically acceptable salts of the compound of example 4.4.

Another preferred embodiment of the present invention are pharmaceutically acceptable salts of the compound of example 11.9.

Another preferred embodiment of the present invention are pharmaceutically acceptable salts of the compound of example 7.4.

Another preferred embodiment of the present invention are pharmaceutically acceptable salts of the compound of example 4.3.

Another preferred embodiment of the present invention are pharmaceutically acceptable salts of the compound of example 7.1.

Another preferred embodiment of the present invention are pharmaceutically acceptable salts of the compound of example 8.3.

Another preferred embodiment of the present invention are pharmaceutically acceptable salts of the compound of example 11.6.

Another preferred embodiment of the present invention are pharmaceutically acceptable salts of the compound of Example 10.

Another preferred embodiment of the present invention are pharmaceutically acceptable salts of the compound of example 9.3.

Another preferred embodiment of the present invention are compounds of formula I selected from the group consisting of examples listed in table. A or their pharmaceutically acceptable salts.

Table A

Racemates

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- 8 043045

Another preferred embodiment of the present invention are compounds of formula I selected from the group consisting of the examples shown in table. B or their pharmaceutically acceptable salts.

- 9 043045

Table B

- 10 043045

Another embodiment of the present invention are compounds of formula IA or pharmaceutically acceptable salts thereof.

O

IA

Another embodiment of the present invention are compounds of formula IB or pharmaceutically acceptable salts thereof.

O

IB

Another embodiment of the present invention are compounds of formula IC or pharmaceutically acceptable salts thereof.

O

IC

Another embodiment of the present invention are compounds of formula ID or pharmaceutically acceptable salts thereof.

O

ID

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

Another embodiment of the present invention is a pharmaceutical composition comprising 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.

Another embodiment of the present invention is a compound of formula I or a pharmaceutically acceptable salt thereof for use as a drug.

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

- 11 043045 or vanin-2, especially vanin-1, including but not limited to the treatment and/or prevention of inflammatory diseases, preferably inflammatory bowel diseases.

Another 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, colon cancer, and pancreatic cancer associated with newly diagnosed diabetes.

Another 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), chronic obstructive pulmonary disease or atopic dermatitis, preferably Crohn's disease, ulcerative colitis , systemic sclerosis, non-alcoholic steatohepatitis (NASH) or atopic dermatitis, especially from Crohn's disease or ulcerative colitis.

Another 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.

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

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

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

In another embodiment, a method is provided for treating a disease selected from Crohn's disease, ulcerative colitis, Crohn's disease, ulcerative colitis, 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, colon cancer, and pancreatic cancer associated with newly diagnosed diabetes, comprising administering to a patient a therapeutically effective amount a compound according to the first embodiment or any of its associated embodiments or a pharmaceutically acceptable salt thereof.

In another embodiment, provide a method for obtaining a compound in accordance with the first embodiment or any of the associated embodiment of the methods presented in this application below.

In an additional 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 an additional 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 relates to methods for treating or preventing the above diseases and conditions, the method comprising administering an effective amount of a compound of general formula 1 to a human.

The actual pharmaceutically effective amount or therapeutic dosage will generally depend on factors known to those skilled in the art, such as the age and weight of the patient, the route of administration, and the severity of the disease. In any case, the compounds will be administered in dosages and in such a way that a pharmaceutically effective amount can be delivered depending on the individual condition of the patient.

Another embodiment of the present invention is a pharmaceutical composition comprising, 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 cyclooxygenase enzyme inhibitors, tumor necrosis factor (TNF) receptor antagonists, IL12/23 antagonists and IL23, α4β7 integrin blocking antibodies, non-selective and selective JAK kinase inhibitors and methotrexate, and combinations of two or three active substances.

Definitions.

Terms not specifically defined in this application should be given the meanings to be given to them by a person skilled in the art in light of the disclosure and context. However, as they

- 12 043045 are used in the description, unless otherwise indicated, the following terms have the meanings indicated and the following conventions are observed.

In the groups, radicals or fragments defined below, the number of carbon atoms is often indicated before the group, for example, C ₁ . ₆ -alkyl means an alkyl group or a radical having from 1 to 6 carbon atoms. Usually in groups such as HO, H2N, (O)S, (O)2S, CN (cyano), HOOC, F3C, or the like, a qualified specialist can see the point (s) of attachment of the radical to the molecule by free valences of itself groups. For combined groups containing two or more subgroups, the last named subgroup is the point of attachment of the radical, for example, substituent aryl-C _1-3 -alkyl means an aryl group that is linked to C ₁ . ₃ -alkyl group, the last of which is connected to the core or to the group to which the substituent is attached.

In the event that a compound according to the present invention is presented in the form of a chemical name and in the form of a formula, then in the event of any inconsistency, the formula shall prevail.

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

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

DAyun * ² P o where the carboxy group is attached to the third carbon atom of the propyl group. The terms 1-methylpropyl, 2,2-dimethylpropyl or cyclopropylmethyl group are the following groups:

CH ₃ 1 ³

I _sn, \ ³ \ * ¹ 2 ³ n ₃ s sn ₃

An asterisk may be used in subformulas to indicate a bond that is linked to the parent molecule as defined.

As used herein, the term "substituted" means that any one or more hydrogen atoms on said atom are replaced by those selected from the named group, provided that the normal valence of said atom is not exceeded, and that the substitution results in a stable compound.

Unless otherwise stated, throughout the specification and the appended claims, a given chemical formula or name shall encompass tautomers and all stereo, optical, and geometric isomers (e.g., enantiomers, diastereomers, E/Z isomers, etc.) and their racemates, also mixtures in various proportions of individual enantiomers, mixtures of diastereomers or mixtures of any of the above forms, where such isomers and enantiomers exist, as well as salts, including their pharmaceutically acceptable salts and their solvates, such as, for example, hydrates, including solvates of free compounds or solvates of the salt of the compound.

Generally, substantially pure stereoisomers can be prepared according to synthetic principles known to those skilled in the art, eg, separation of appropriate mixtures, using pure stereochemically starting materials, and/or by stereoselective synthesis. It is known in the art how to prepare optically active forms, eg by resolution of racemic forms or by synthesis, eg starting from optically active starting materials and/or using chiral reagents.

Enantiomerically pure compounds in accordance with the present invention or intermediates can be obtained using asymmetric synthesis, for example, by obtaining and subsequent separation of the corresponding diastereomeric compounds or intermediates, which can be separated by known methods (for example, chromatographic separation or crystallization) and/or using chiral reagents such as chiral starting materials, chiral catalysts, or chiral auxiliaries.

In addition, the person skilled in the art knows how to obtain enantiomerically pure compounds from the 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 resolving agent, for example by diastereomeric salt formation of the racemic compound with optically active acids or bases, followed by separation of the salts and isolation of the desired compound from the salt; or by derivatization of the corresponding racemic compounds with optically active chiral auxiliary reagents, followed by separation of the diastereomers and removal of the chiral auxiliary group; or by kinetic resolution of the racemate (eg, by enzymatic resolution); enantioselective crystallization from a conglomerate of enantiomorphic crystals under suitable conditions; or (fractional) crystallization from a suitable solvent in the presence of an optically active chiral auxiliary.

Used in this application, the expression pharmaceutically acceptable refers to those compounds, substances, compositions and / or dosage forms, which from a medical point of view

- 13 043045 are suitable for use in contact with human and animal tissues without undue toxicity, irritation, allergic response or other impairment or complication, and are commensurate with a reasonable benefit/risk ratio.

Used in this application, the term pharmaceutically acceptable salts refers to derivatives of the disclosed compounds in which the parent compound is modified by obtaining its acidic or basic salts. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acid residues such as carboxylic acids; etc.

For example, such salts include 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 acid, phosphoric acid, salicylic acid, succinic acid, sulfuric acid and tartaric acid.

Other pharmaceutically acceptable salts may be formed with ammonia, L-arginine, calcium, 2,2'-iminobisethanol, L-lysine, magnesium, N-methyl-O-glucamine, potassium, sodium, and tris-(hydroxymethyl)-aminomethane cations.

Pharmaceutically acceptable salts in accordance with the present invention can be synthesized from the parent compound, which contains a basic or acidic moiety, by conventional chemical methods. Typically, such salts can be prepared by reacting the free acidic or basic forms of these compounds with a sufficient amount of the appropriate base or acid in water or in an organic diluent such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile, or a mixture thereof.

Salts of acids other than those mentioned above, which are, for example, suitable for purifying or isolating the compounds of the present invention (eg trifluoroacetate salts) are also part of the invention.

The term halogen generally means 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, alone or in combination with another radical means 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 -, H ₃ C-CH (CH ₃ ) -, H ₃ C-CH ₂ -CH ₂ -CH ₂ -, H ₃ C-CH ₂ CH (CH ₃ ) -, H ₃ C-CH (CH ₃ ) -CH ₂ -, H ₃ C-C (CH ₃ ) ₂ -, H ₃ C-CH ₂ -CH ₂ -CH ₂ -CH ₂ -, H ₃ C-CH ₂ -CH ₂ -CH (CH ₃ ) -, H ₃ C-CH ₂ CH (CH3) - CH2-, H3C-CH(CH3)-CH2-CH2-, H3C-CH2-C(CH3)2-, H3C-C(CH3)2-CH2-, H3C-CH(CH3)-CH(CH3)- and H3C-CH2-CH(CH2CH3)-.

The term C _3-n -cycloalkyl, where n is an integer from 4 to n, alone or in combination with another radical means a cyclic, saturated, straight 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, alone or in combination with another radical, means a mono-, bi- or tricyclic ring structure of 3-14 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 encompasses fused, bridged and spirocyclic systems.

The term aryl, as used herein, alone or in combination with another radical, means a carbocyclic aromatic monocyclic group containing 6 carbon atoms, which is optionally further fused to 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 means 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, where none of the heteroatoms are part of an aromatic ring. The term heterocyclyl or heterocycle includes all possible isomeric forms.

- 14 043045

Thus, the term heterocyclyl or heterocycle includes the following exemplary structures, which are not depicted as radicals because each form is optionally attached via a covalent bond to any atom, as long as the appropriate valences are maintained:

The term heteroaryl means 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, where at least one of heteroatoms is included in the aromatic ring. The term heteroaryl includes all possible isomeric forms.

Thus, the term heteroaryl includes the following exemplary structures, which are not depicted as radicals, since each form is optionally attached via a covalent bond to any atom, as long as the corresponding valences are retained:

- 15 043045

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

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

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

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

ace Acetyl ACN Acetonitrile water. water Vp Benzyl In and Butyl Vos t/2el?-butyloxy carbon yl °C degree Celsius cat. Catalyst BC Crohn's disease CONC. concentrated SooN Cyclohexane d day(s) DBU 1,8-Diazabicyclo(5.4.0)undec-7-ene DXM dichloromethane DMAP 4-A ^g , A ^g -dimethylaminopyridine DMA Dimethylacetamide DME 1,2-dimethoxyethane DMF A,A-dimethylformamide DMSO Dimethyl sulfoxide DIPE Diisopropyl ether DIPEA ΛζΑ-diisopropylethylamine dppf 1.1 ^g -bis(diphenylphosphino)ferrocene EDC 1 -Ethyl-3 - (3 - dimethylaminopropyl) carbodiimide

- 16 043045

ERI Electrospray ionization ERI-MS Mass spectrometry with electrospray ionization Et Ethyl _Et2O diethyl ether EtOAc ethyl acetate EtOH ethanol Etc. Example h. watch) HATU N,N,N',N'-tetramethyl-O-(7azabenzotriazol-1-yl)uronium hexafluorophosphate vezhkh High Performance Liquid Chromatography HWB analysis Human Whole Blood Analysis i iso vzk inflammatory bowel disease PS intermediate connection IP Ac Isopropyl acetate l liter zhh Liquid chromatography LiHMDS lithium bis(trimethylsilyl)amide Me Methyl Meon methanol min. minutes µl microliter ml milliliter HCSD Medium pressure liquid chromatography MS Mass spectrometry NBS A-bromo-succinimide NMP A-methylpyrrolidone NF Normal phase n.a. not available RE Petroleum ether PBS Phosphate buffered saline Ph Phenyl Rg Propil Rug pyridine rac Racemic FU (FU) retention factor OF reversed phase By (HPLC) Retention time (HPLC) CT Room temperature (approx. 20 °C) us. Saturated SKFS Supercritical Fluid Chromatography TBAF Tetrabutylammonium fluoride TVME shresh-butyl methyl ether TBTU Benzotriazolyl-tetramethyluronium tetrafluoroborate tBu tert-butyl TEA Triethylamine pace. Temperature tert Tertiary Tf Triflat TFU Trifluoroacetic acid THF T tetrahydrofuran those Thin layer chromatography on SiO ₂ Ts i-tosyl TsOH and-toluenesulfonic acid YAK Ulcerative colitis UV Ultraviolet VNN-1 Vanin-1 VNN-2 Vanin-2

The features and advantages of the present invention will become apparent from the following detailed examples, which illustrate the basics of the invention by way of example without limiting its scope.

Preparation of Compounds According to the Invention

General synthesis methods.

Compounds in accordance with the present invention and their intermediates can be obtained using synthetic methods that are known to the person skilled in the art and described in the literature on organic synthesis. Preferably, the compounds are obtained

- 17 043045 similar to the preparation methods described in more detail below, in particular as described in the experimental part. In some cases, the order of the reaction steps may be changed. Can also be used variants of reaction methods that are known to the person skilled in the art, but are not described in detail in this application.

General methods for obtaining compounds in accordance with the invention will become apparent to a person skilled in the art, having studied the following schemes. Starting materials can be obtained by methods that are described in the literature or in this application, or can be obtained in a similar or similar way. Any functional groups in the starting materials or intermediates can be protected using conventional protecting groups. These protecting groups can be cleaved off again at a suitable stage in the reaction sequence using methods known to the person skilled in the art.

Compounds in accordance with the present invention are obtained by the synthetic methods described below, in which substituents of the general formulas have the meanings indicated above. These methods are intended to illustrate the invention without limiting its subject matter and the scope of the compounds claimed by these examples. If the preparation of the starting compounds is not described, then they are commercially available or can be obtained similarly to known compounds or methods described in this application. Substances described in the literature are prepared according to published synthetic methods.

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 vinylboronic acid palladium-catalyzed boronic acid ester (e.g., tetrakis(triphenylphosphine)palladium) to form pyridine B. Cyclization to partially saturated bicycle C is achieved using strong acids (e.g., H2SO4 or HCl). The heterocycle C ester is hydrolyzed (eg with aq. HCl) followed by amide coupling (eg TBTU or HATU as coupling reagent) to give a compound of general formula (I).

Compounds of formula II can be prepared as shown in Schemes II-a and II-b below.

Scheme II-a

In Scheme II-a, pyridine A is treated with a suitable allylboronic acid/palladium-catalyzed boronic acid ester (e.g., tetrakis(triphenylphosphine)palladium) to form pyridine B. Cyclization to partially saturated bicycle C is carried out using strong acids (e.g., H ₂ SO ₄ or HCl). The heterocycle C ester is hydrolysed (eg with aq. HCl) followed by amide coupling (eg TBTU or HATU as coupling reagent) to give a compound of general formula (II).

Scheme II-b

In Scheme II-b, pyridine A is treated with a suitable propargyl alcohol catalyzed by palladium and copper (e.g., tetrakis(triphenylphosphine)palladium and CuI)) to form pyridine B. After

- 18 043045 catalytic hydrogenation (eg Pd/C in the presence of H2) of a triple bond with pyridine C cyclization to a partially saturated bicycle E is carried out using strong acids (eg H ₂ SO ₄ or HCl). Alternatively, the cyclization can be carried out using a two-step mechanism in which a leaving group (eg chloride by treating the substrate with thionyl chloride) is established to the cyclization conditions (pyridine D). The heterocycle ester E is hydrolysed (eg with aq. HCl) followed by amide coupling (eg TBTU or HATU as coupling reagent) to give a compound of general formula (II).

Compounds of formula III can be prepared as shown in Schemes III-a and III-b below.

Scheme III-a

In Scheme III-a, pyridine A is treated with a suitable homopropargyl alcohol in palladium catalysis (e.g., tetrakis(triphenylphosphine)palladium) to give pyridine B. After catalytic hydrogenation of the triple bond (e.g., Pd/C in the presence of H ₂ ) to give pyridine C, cyclization to partially saturated bicycle D is carried out using strong acids (eg H2SO4 or HCl). The heterocycle ester D is hydrolyzed (eg with aq. HCl) followed by amide coupling (eg TBTU or HATU as coupling reagent) to give a compound of general formula (III).

Scheme III-b

In Scheme III-b, bicycle A is carbonylated using CO and MeOH in the presence of a Pd catalyst system (eg 1,1'-bis-(diphenylphosphino)ferrocene and Pd(OAc) ₂ ). The ester of heterocycle B is hydrolyzed (eg with aq. HCl) followed by amide coupling (eg TBTU or HATU as coupling reagent) to give a compound of general formula (III).

Synthesis examples

The following examples are intended to illustrate the present invention without limiting it. The terms ambient temperature and room temperature are used interchangeably and refer to a temperature of about 20°C.

Preparation of initial compounds.

Intermediate I.

Intermediate I.1 (general method). Methyl 6-amino-5-(2-methylprop-1-en-1-yl)pyridine3-carboxylate

To a mixture of 1.6 g (6.93 mmol) of methyl 6-amino-5-bromopyridine-3-carboxylate, 13.9 ml (27.7 mmol; 2 mol/l) of Na ₂ CO ₃ solution and 30 ml of dioxane are added 1, 89 g (10.4 mmol) of 4,4,5,5-tetramethyl-2-(2methylprop-1-en-1-yl)-1,3,2-dioxaborolane and the mixture is purged with argon. Then, 800 mg (0.69 mmol) of tetrakis(triphenylphosphine)palladium are added, and the reaction mixture is stirred at 120°C for 40 min. After cooling to RT, the reaction mixture was diluted with EtOAc and extracted with sat. aq. a solution of NaHCO ₃ and water (1:1), the organic layer is dried over Na ₂ SO ₄ , filtered and the solvent is removed in vacuo. The remaining crude product is purified by column chromatography (silica gel; CyH/EtOAc 1/1).

C11H14N2O2 (M = 206.2 g/mol)

ERI-MS: 207 [M+H] ⁺

By (HPLC): 0.69 min (Method A)

The following compounds are prepared according to the general procedure (Intermediate I.1) described above.

- 19 043045

PS starting material Structure EI-MS HPLC retention time (method) [min] 1.2 o- o=/ 221 [M+H] ⁺ 0.90 (V)

Intermediate II.

Intermediate II.1 (general method). Methyl 2,2-dimethyl-1Н,2Н,3Н-pyrrolo[2,3b]pyridine-5-carboxylate

A mixture of 1.36 g (6.27 mmol) methyl 6-amino-5-(2-methylprop-1-en-1-yl)pyridine-3-carboxylate (1.1) in 10 ml (142.7 mmol) conc. H ₂ SO ₄ stirred at RT for 20 min. The mixture was poured onto ice water, made basic with NaOH (4 mol/l) and extracted with DCM. The combined organic layers are dried over Na ₂ O ₄ and concentrated in vacuo to give the product.

CuH ₁₄ N ₂ O2

ERI-MS:

By (HPLC):

(M = 206.2 g/mol)

207 [M+H] ⁺

0.62 min (method A)

The following compounds are prepared according to the general procedure (Intermediate II.1) described above.

starting material

221 [M+H] ⁺

HPLC retention time (method) [min]

Intermediate III.

Intermediate III.1 (general method). 2,2-Dimethyl-1Н,2Н,3Н-pyrrolo[2,3-b]pyridine-5carboxylic acid

A mixture of 1.51 g (7.32 mmol) of intermediate II.1 in 10 ml of HCl (conc. 6 mol/l) was stirred at 100°C for 35 min. The reaction mixture is then cooled to RT, the precipitate is filtered off and dried to give the product.

C10H12N2O2* HCl (M = 228.7 g/mol)

ERI-MS: 193 [M+N] ⁺

By (HPLC): 0.54 min (Method A)

The following compounds are prepared according to the general procedure (intermediate III.1) described above.

PS starting material Structure Reaction conditions EI-MS HPLC retention time (method) [min] III.2 II.2 O on 'n 80°C 4.5 hours 207 [M+H] ⁺ 0.43 (V) sh.z XIX. 1 /XV HCI\ ⁿ 90°C 2 hours evaporation to obtain a crude product 221 [M+H] ⁺ 0.65 (A) III.4 XXVI O HCI n 75 °C 4 hours 193 [M+H] ⁺ 0.14 (V)

- 20 043045

Intermediate IV.

Intermediate IV.1 (general method). 1-[(1E)-1-Bromoprop-1-en-2-yl1-4-fluorobenzene

10.0 g (73.4 mmol) of 1-fluoro-4-(prop-1-en-2-yl)benzene is dissolved in 100 ml of DCM and cooled to 0°C. Then 3.96 ml (77.1 mmol) of bromine is added dropwise at 0-5°C and the reaction mixture is stirred at 0°C until the color of the solution is stable. The reaction mixture was allowed to warm to RT and stirring was continued for 1 h. 150 ml of aq. A solution of Na ₂ S ₂ O ₃ (1 mol/l) and the organic layer are separated, dried and the solvent is removed in vacuo. 50 ml of 2-methylpropan-2-ol and 9.89 g (88.1 mmol) of KOtBu are added to the crude intermediate in several portions (caution: exothermic reaction). Finally, the reaction mixture is stirred at 70° C. for 5 minutes. The mixture is cooled to RT, diluted with H ₂ O and DCM, and the layers are separated. The organic layer is dried and the solvents are removed in vacuo. The remaining residue is purified by vacuum distillation (0.03 mbar) to obtain the product.

C ₉ H ₈ BrF

EI-MS:

By (HPLC):

(M = 215.1 g/mol) 214/216 [M*] ⁺ 1.16 min (method I)

The following compounds are prepared according to the general procedure (intermediate IV.1) described above.

PS starting material Structure EI-MS HPLC retention time (method) [min] IV.2 XIV F 214/216 [M*] ⁺ 1.14 (A)

Intermediate V.

Intermediate connection V.1 (general method). 1-[(1E)-1-Bromoprop-1-en-2-yl]-4-chlorobenzene

To a mixture of 30 ml (0.21 mol) of 1-chloro-4-(prop-1-en-2-yl)benzene in 100 ml of chlorobenzene was added 40.7 g (229 mmol) of N-bromosuccinimide and 1.71 g ( 10.4 mmol) of 2,2'-azobis-(isobutyronitrile) and the mixture was stirred at 132° C. for 20 minutes. After cooling, the reaction mixture is filtered, the precipitate is washed once with DCM and the solvent is removed in vacuo. The crude product is purified by column chromatography (silica gel; PE/DCM, 9/1) to give two products.

Product A

C ₉ H ₈ BrC1 (M = 231.5 g/mol) ERI-MS: 230/232 [M+H] ⁺ Fu (TLC) 0.45 (RE/DXM 9/1) Product B C ₉ H ₈ BrC1 (M = 231.5 g/mol) ERI-MS: 230/232 [M+H] ⁺ Fu (TLC) 0.59 (RE/DXM 9/1)

The following compounds are prepared according to the general procedure (Intermediate V.1) described above.

- 21 043045

PS starting material Structure Reaction conditions EI-MS HPLC retention time (method) [min] V.2.A ¥ I am from 130°C 20 minutes 196/198 [M+H] ⁺ 1.05 (A) V.2.B ¥ I am from 130°C 20 minutes 196/198 [M+H] ⁺ 1.13 (A) V.3.A XIV. 2 from 130°C 20 minutes 230/232 [M+H] ⁺ 1.11 (A) V.3.B XIV. 2 ¥CI 130°C 20 minutes 230/232 [M+H] ⁺ 1.19 (A)

Intermediate VI.

Intermediate VI.1 (general method). 2-[(1E)-2-(4-Fluorophenyl)prop-1-en-1-yl]-4,4,5,5tetramethyl-1,3,2-dioxaborolane

Mixture of 10.0 g (46.5 mmol) of intermediate IV.1, 17.9 g (69.7 mmol) 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3 ,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane and 11.9 g (121 mmol) of potassium acetate in 100 ml of dioxane are purged with argon. Then 3.80 g of a complex (4.65 mmol) of [1,H-bis-(diphenylphosphino)ferrocene]dichloropalladium(II) with DCM (1:1) was added and the mixture was stirred at 90° C. for 1 hour. After cooling to RT, the reaction mixture was diluted with EtOAc and washed with a mixture of sat. aq. a solution of NaHCO ₃ and water (1:1), the organic layer is dried over Na ₂ SO ₄ , filtered and the solvent is removed in vacuo. The crude product is purified by column chromatography (silica gel; CyH/EtOAc) to give the product.

C15H20BFO2 (М = 262.1 g/mol)

ERI-MS: 263 [M+H] ⁺

Wu (HPLC): 1.24 min (method A)

The following compounds are prepared according to the general procedure (intermediate VI.1) described above.

PS starting material Structure Reaction conditions ERI-MS HPLC retention time (method) [min] VI.2 V.2.B O -co 4 100°C 1.5 hours 245 [M+H] ⁺ 1.20 (A) VI. 3 IV. 2. 1 F 90°C 2 hours 263 [M+H] ⁺ 1.25 (A) VI. 4 V.3.A Cl 120°C 20 minutes 279 [M+H] ⁺ 1.21 (A) VI. 5 VI.B 0 i /~o 120°C 1 hour 279/81 [M+H] ⁺ 1.26 (A)

Intermediate VII.

Intermediate VII.1 (general method). Methyl 6-amino-5-[(1E)-2-(4-fluorophenyl)prop-1en-1-yl]pyridine-3-carboxylate

To 0.60 g (2.61 mmol) of methyl 6-amino-5-bromopyridine-3-carboxylate in 5.23 ml (10.5 mmol; 2 mol/l) of Na2CO3 solution and 10 ml of dioxane is added 0.69 g (2.61 mmol) intermediate connection

- 22 043045

VI.1, and the resulting mixture is purged with argon. Then, 302 mg (0.26 mmol) of tetrakis(triphenylphosphine)palladium(0) was added, and the reaction mixture was stirred at 120°С for 40 min. After cooling to RT, the reaction mixture was diluted with EtOAc and washed with sat. aq. a solution of NaHCO ₃ and water (1:1), the organic layer is dried over Na ₂ SO ₄ , filtered, and the solvent is removed in vacuo. The remaining crude product was purified by column chromatography (silica gel; CyH/EtOAc 1/1) to give the product.

C ₁₆ H ₁₅ FN2O2 (M = 286.3 g/mol)

ERI-MS: 287 [M+H] ⁺

By (HPLC): 0.81 min (method A)

The following compounds are prepared according to the general procedure (Intermediate VII.1) described above.

PS starting material Structure Reaction conditions ERI-MS HPLC retention time (method) [min] VII.2 VI. 2 o - o \u003d / \ ^z ) \u003d / A __ / I vy 120°C 30 min 269 [M+H] ⁺ 0.81 (A) VII. 3 VI. 3 ΛΑ Oh 120°C 30 min 287 [M+H] ⁺ 0.82 (A) VII.4 VI. 4 Λ J ¹ η ₂ ν ν 120°C 40 min 303/05 [M+N] ⁺ 0.83 (A) VII. 5 VI. 5 ο- ο=/ (y ο 120°C 60 min 303 [M+H] ⁺ 0.86 (A)

Intermediate VIII.

Intermediate VIII.1 (general method). Methyl 2-(4-fluorophenyl)-2-methyl-1Н,2Н,3Нpyrrolo[2,3-b]pyridine-5-carboxylate

A mixture of 4.50 g (14.15 mmol) of intermediate VII.1 and 30 ml (428 mmol) of conc. H ₂ SO ₄ stirred at RT for 80 min. The mixture was poured into ice water, made slightly alkaline with NaOH (6 mol/l) and extracted with DCM. The combined organic layers are dried over Na ₂ SO ₄ and the solvent is removed in vacuo. The remaining solid is triturated with diethyl ether.

Ci ₆ H ₁₅ C1N ₂ O2 (M = 286.3 g / mol)

ERI-MS: 287 [M+H] ⁺

By (HPLC): 0.77 min (method I)

The following compounds are prepared according to the general procedure (intermediate VIII.1) described above.

- 23 043045

Intermediate IX.

Intermediate IX.1 (general method). Methyl (2R)-2-(4-fluorophenyl)-2-methyl-1H,2H,3Hpyrrolo[2,3-b]pyridine-5-carboxylate and methyl (2S)-2-(4-fluorophenyl)-2- methyl 1Н,2Н,3Н-pyrrolo[2,3b]pyridine-5-carboxylate

350 mg (1.21 mmol) of intermediate VIII.1 are separated by SCPC (method E for preparative scale).

Product IX.1.A (first elution):

Ci ₆ Hi ₅ FN ₂ O2

ERI-MS:

By (HPLC):

(M = 286.3 g/mol)

287 [M+H] ⁺

2.57 min (Method E)

Product IX. 1.B (second elution): Ci ₆ Hi ₅ FN ₂ O2 (M = 286.3 g/mol)

By (HPLC): 3.88 min (Method E)

The following compounds are prepared according to the general procedure (intermediate

IX.1) described above.

PS starting material Structure HPLC retention time (method) [min] IX.2.A VIII. 5 o JL J। J Г hn^ _n ^ Cl 2.72(F) IX.2.B VIII. 5 O- Q O 4.50(F) IX.FA VIII. 4 ABOUT |j T hn-^·^ Cl 2.13(D) IX.3.B VIII. 4 ABOUT Cl 9.82(D) IX.4.A VIII. 3 o T J hn^ _n <^ 3.16(C) IX.4.B VIII. 3 - O 3.36(S)

Intermediate X.

Intermediate X.1.A (general method). (2R)-2-(4-Fluorophenyl)-2-methyl1Н,2Н,3Н-pyrrolo[2,3-b]pyridine-5-carboxylic acid hydrochloride

980 mg (3.42 mmol) of intermediate IX.I.A in 15 ml of HCl (6 mol/l) was stirred at 90° C. for 3 hours. The reaction mixture was concentrated in vacuo, 20 ml of isopropanol was added and concentrated again in vacuo. The remaining product is triturated with DIPE.

Ci ₅ H ₁₃ FN ₂ O2*HC1

ERI-MS:

By (HPLC):

(M = 308.7 g/mol)

273 [M+H] ⁺

6.87 min (Method G)

The following compounds are prepared according to the general procedure (Intermediate X.1) described above.

- 24 043045

PS starting material Structure Reaction conditions ERI-MS HPLC retention time (method) [min] X.1.B IX. 1.B o D J hn^ _n A HCl 90 °C 3 hours 273 [M+H] ⁺ 3.35 (G) X.2 VIII. 2 o o =( o/z ό 80°C 1.5 hours 255 [M+H] ⁺ 0.68 (A) H.Z.A IX.4.A ABOUT /° 0 I 90°C 1 hour 273 [M+H] ⁺ 0.69 (A) h.z.v IX.4.B n J HCl F 90°C 1 hour 273 [M+H] ⁺ 0.69 (A) X.4.A IX.2.A O Π J hn^ _n <^ on 90°C 1 hour 289/91 [M+H] ⁺ 0.75 (A) X.5.A IX.3.A δ O ⁸ 90°C 1 hour 289/91 [M+H] ⁺ 0.74 (A) X.5.B IX.3.B η J ην-Ά^ Cl on 90°C 1 hour 289/91 [M+H] ⁺ 0.75 (A) X.6 VIII. 5 ο / ⁼ \ ΧΑϊΆ/όη ^α Α Λ J ν—y HCI 80 °C 2 h Purification by HPLC (ACN/H2O/TFA) 289/91 [M+H] ⁺ 0.76 (A)

Intermediate XI.

Intermediate XI.1 (general method). N-[(3S)-1-[2-(4-Chlorophenyl)-2-methyl-1H,2H,3Hpyrrolo[2,3-b]pyridine-5-carbonyl]pyrrolidin-3-yl]-N-methylacetamide

To a mixture of 48 mg (0.19 mmol) of intermediate X.2 and 43.8 mg (0.25 mmol) of intermediate XVI in 2 ml of DMF and mmol) HATU, and the reaction mixture is stirred for 20 min at RT. The reaction mixture was purified by HPLC (ACN/H2O/NH4OH).

C22H26N4O2

ERI-MS:

By (HPLC):

(M = 378.5 g/mol)

379 [M+H] ⁺

0.82 min (method B)

The following compounds are prepared according to the general procedure (Intermediate XI.1) described above.

starting materials

HPLC retention time (method)

- 25 043045

Intermediate compound XII.

Intermediate XII.1 (general method).

(3S) 1-{2,2-Dimethyl-1H,2H,3H-pyrrolo[2,3-b]pyridine-5-carbonyl}-N-methylpyrrolidin-3-amine; trifluoroacetic acid

To a mixture of 350 mg (1.53 mmol) of intermediate III.1 and 540 mg (2.30 mmol) of intermediate XVI in 6 ml of DMF and 920 μl (5.36 mmol) of DIPEA was added 870 mg (2.30 mmol) HATU, and the reaction mixture is stirred for several minutes. The mixture was purified by HPLC (ACN/H2O/NH ₄ OH).

C20H30N4O3 (M = 374.4 g/mol)

ERI-MS: 375 [M+N] ⁺

By (HPLC): 0.92 min (method B)

The above intermediate was dissolved in 5 ml DCM, 1 ml TFA was added and the mixture was stirred at RT for 2 h. After that, all volatiles were removed in vacuo.

C ₁₅ H ₂₂ N ₄ O * C ₂ HF ₃ O ₂ (M - 388.4 g / mol)

ERI-MS: 275 [M+N] ⁺

By (HPLC): 0.72 min (method B)

The following compounds are prepared according to the general procedure (intermediate XII.1) described above.

PS starting materials Structure ERIMS HPLC retention time (method) [min] XII.2 III.2 o Uv° \ hci Η ABOUT 1 U C^-βΝΗ About ^F> Y^OH F 289 [M+H] ⁺ 0.75 (V)

Intermediate XIII.

Intermediate XIII.1 (general method). 3-[(3S)-pyrrolidin-3-yl]-1,3oxazolidin-2-one hydrochloride

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

The crude product is purified by column chromatography (silica gel; CyH/EtOAc) and solvent. The combined organic layers are dried over a phase separator cartridge and the solvent is removed in vacuo.

Ci ₂ H ₂ oN ₂ 04

ERI-MS:

By (HPLC):

(M = 256.3 g/mol)

201 [M-tBU+H] ⁺

0.82 min (method B)

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

C ₇ H ₁₂ N2O2 * HC1 (M = 192.6 g / mol)

ERI-MS: 157 [M+H] ⁺

By (HPLC): 0.17 min (method B)

The following compounds are prepared according to the general procedure (intermediate XIII.1) described above.

PS starting materials Structure ERI-MS HPLC retention time (method) [min] t/?eot-butyl CI XIII.2 (33)-3-aminopyrrolidine-1- G 155 [M+H] ⁺ 0.27 (V) carboxylate \CI \___/HCI

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Intermediate XIV.

Intermediate XIV.1 (general method). 1-Fluoro-3-(prop-1-en-2-yl)benzene

A mixture of 16.1 g (39.8 mmol) of iodine(methyl)triphenylphosphane in 130 ml of THF is cooled with an ice bath. Then, 4.47 g (39.8 mmol) of potassium 2-methylpropan-2-olate are added while cooling with ice, and the reaction mixture is stirred for 1 hour. Then a solution of 5.00 g (36.2 mmol) of 1-(3fluorophenyl)ethane-1 is added -one in 20 ml THF during ice-cooling and the mixture was stirred at RT for 1 h. The mixture was quenched with sat. aq. NH4Cl solution, and the layers are separated. The organic layer is dried and the solvent is removed in vacuo.

50 ml of PE are added and the mixture is stirred. The resulting oil is separated and the PE layer is dried over Na ₂ SO ₄ , filtered and the solvent is removed in vacuo to obtain the product.

The following compounds are prepared according to the general procedure (intermediate

C ₉ H ₉ F

EI-MS:

By (HPLC):

(M = 136.2 g/mol)

136 [M*] ⁺

1.09 min (method A)

Compound XV. N-Methyl-N-[(3S)-pyrrolidin-3-yl]pyrimidin-2 hydrochloride Amine intermediate

g (6.29 mmol) 2-bromopyrimidine, 1.51 g (7.55 mmol) tert-butyl (3S)-3 °C for 2 hours. The solvent is removed in vacuo and the crude product A is purified by column chromatography (silica gel; DCM/MeOH).

C14H22N4O2

ERI-MS:

By (HPLC):

(M = 278.3 g/mol)

279 [M+H] ⁺

0.87 min (method A)

10 ml of MeOH and 4 ml of HCl in dioxane (4 mol/l) were added to the above product and the mixture was stirred overnight at RT. Solvents are removed in vacuo to give the final product.

C ₉ Hi ₄ N ₄ *HC1

ERI-MS:

By (HPLC):

(M = 214.7 g/mol)

179 [M+H] ⁺

0.15 min (method A)

Intermediate XVI. N-methyl-N-[(3S)-pyrrolidin-3-yl]acetamide hydrochloride

A mixture of 2.5 g (11.0 mmol) tert-butyl (3S)-3-acetamidopyrrolidine-1-carboxylate and 1 ml (15.9 mmol) iodomethane in 25 ml THF is cooled to -10°C. Then 0.75 g (18.8 mmol) NaH (60%) is added and the mixture is stirred overnight at RT. The reaction mixture was quenched with H ₂ O and EtOAc and stirred vigorously for 5 minutes. The layers are separated and the H ₂ O layer is extracted with EtOAc. The combined organic layers are dried over a phase separator cartridge and concentrated in vacuo. The residue is taken up in 10 ml of HCl in dioxane and stirred at RT. The resulting precipitate is filtered off, washed with dioxane and dried in vacuo to give the product.

C ₇ H ₁₄ N ₂ O * HC1

ERI-MS:

By (HPLC):

(M = 178.7 g/mol)

143 [M+H] ⁺

0.29 min (method B)

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Intermediate XVII.

Intermediate XVII.1 (general method). Methyl 6-amino-5-(4-hydroxy-4-methylpent-1yn-1-yl)pyridine-3-carboxylate

0.84 ml of (6.06 mmol) TEA, 33.0 mg (0.17 mmol) Cu(I)I and 0.20 g (0.17 mmol) tetrakis(triphenylphosphine)palladium(0) and the reaction mixture was stirred at 80 °C for 1 h. After cooling to RT, the reaction mixture is diluted with EtOAc and washed with a mixture of sat. aq. NH ₄ Cl solution and ammonia (9:1), the organic layer is dried over a phase separator cartridge and the solvent is removed in vacuo. The remaining crude product was purified by column chromatography (silica gel; CyH/EtOAc 9/1) to give the product.

C13H16N2O3

ERI-MS:

By (HPLC):

(M = 248.2 g/mol)

249 [M+H] ⁺

0.67 min (method A)

The following compounds are prepared according to the general procedure (Intermediate XVII.1) described above.

ps starting material Structure Reaction conditions ERIMS HPLC retention time (method) [min] XVII.2 ΛΑ—( \=/ o T °/=\ W /°o \ 80 °C 1.5 h Purification by HPLC (ACN/H2O/N H ₄ OH) 283 [M+H] ⁺ 0.87 (V) XVII. 3 I p ^{0 n} ° Jk / JU ⁰ Η ₂ Ν Ν 80 °C 1.5 h Purification by HPLC (ACN/H2O/N H ₄ OH) 297 [M+H] ⁺ 0.92 (V) XVII.4 N'^N X \Ο/ ¹ 80°C 35 min 299 [M+H] ⁺ 0.68 (A)

Intermediate XVIII.

Intermediate methylpentyl)pyridine-3-carboxylate

XVIII.1 (general method). Methyl 6-amino-5-(4-hydroxy-4-

A mixture of 0.40 g (1.61 mmol) of intermediate XVII.1, 40.0 mg of Pd/C (10%) and 10 ml of MeOH is hydrogenated at RT and 3 bar H ₂ for 1 h. The mixture is filtered and the solvent is removed in vacuo to receive the product.

c ₁₃ h ₂₀ n ₂ o ₃

ERI-MS:

By (HPLC):

(M = 252.3 g/mol)

253 [M+H] ⁺

0.63 min (method A)

The following compounds are prepared according to the general procedure (intermediate compound XVIII.1) described above.

PS starting material Structure Reaction conditions ERI-MS HPLC retention time (method) [min] XVIII.2 XVII. 2 0 O but η ₂ ν kg Purification by HPLC (ACN/H ₂ O/NH ₄ O H) 287 [M+H] ⁺ 0.85 (V) XVIII. 3 XVII. 3 ^S XO \ Z > ^z O / ⁰ 0' \ Purification by HPLC (ACN/H ₂ O/NH ₄ O H) 301 [M+N] ⁺ 0.88 (V) XVIII.4 XVII. 4 Pd(II)OH, EUN CT, during the night 303 [M+H] ⁺ 0.58 (A)

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Intermediate XIX. Methyl-7-ethyl-7-methyl-5,6,7,8-tetrahydro-1,8-naphthyridine-3carboxylate

A mixture of 500 mg (1.98 mmol) of intermediate XVIII.1 and 5 ml of conc. H ₂ SO ₄ stirred at RT. The reaction mixture was poured onto ice and carefully basified using aq. NaOH (conc. 4 mol/l). The aqueous phase is extracted twice with DCM. The organic layers are combined, dried over Na ₂ SO ₄ , filtered and the solvent removed in vacuo. The crude product is purified by HPLC (ASZHN ₂ O/TFA).

Ci ₃ H ₁₈ N ₂ O ₂

ERI-MS:

By (HPLC):

(M = 234.2 g/mol)

235 [M+H] ⁺

0.71 min (method A)

Intermediate XX. Methyl 6-amino-5-(3-chloro-3-phenylpropyl)pyridine-3-carboxylate

To a solution of 0.12 g (0.43 mmol) of XVIII.2 in ml of trichloromethane was added 93.7 μl (1.29 mmol) of thionyl chloride and the mixture was stirred at 60° C. overnight. The solvent is removed in vacuo to give the crude product.

C ₁₆ H ₁₇ C1N ₂ O ₂

ERI-MS:

By (HPLC):

(M = 304.7 g/mol) 305/307 [M+H] ⁺ 0.81 min (method A)

Intermediate XXI. Intermediate XXI.1 (general method). 7-Phenyl5,6,7,8-tetrahydro-1,8-naphthyridine-3-carboxylic acid

A mixture of 0.13 g (0.43 mmol) of intermediate XX in 1 ml of HCl (6 mol/l) was stirred at 100° C. for 1.5 hours. The solvent was removed in vacuo to give the crude product.

C1 ₅ H ₁₄ N ₂ O ₂ (M = 254.2 g/mol)

ERI-MS: 255 [M+N] ⁺

By (HPLC): 0.70 min (Method A)

The following compounds are prepared according to the general procedure (Intermediate XXI.1) described above.

PS starting material Structure Reaction conditions ERI-MS HPLC retention time [min] (method) XXI. 2 XXII. 1 O Λ G / s N ⁿ HCI 100°С 1.5 hours 269 [M+H] ⁺ 0.74 (A) XXI. 3 XVIII. 4 O And 1 I G Τι he A 7 / N N 'n HCI 120°С 1.5 hours 271 [M+H] ⁺ 0.48 (A) XXI. 4 XVIII. 1 ABOUT A 100 °C 16 h Purification by HPLC 221 [M+H] ⁺ 0.66 (N)

Intermediate XXII. Methyl 7-methyl-7-phenyl-5,6,7,8-tetrahydro-1,8-naphthyridine-3-carboxylate

To a solution of 0.10 g (0.33 mmol) of exemplary compound XVIII.3 in 1 ml of trichloromethane was added 72.6 μl (1.00 mmol) of thionyl chloride and the mixture was stirred at 60° C. overnight. An additional 73 μl (1.00 mmol) of thionyl chloride is added and the mixture is stirred at 60° C. for 3 hours. The solvent is removed in vacuo and the crude product is purified by HPLC (ACN/H ₂ O/TFA).

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C17H18N2O2

ERI-MS:

By (HPLC):

(M = 282.3 g/mol)

283 [M+H] ⁺

0.82 min (method A)

Intermediate XXIII. N-Methyl-N-[(3S)-pyrrolidin-3-yl]cyclobutanecarboxamide

To a mixture of 1.00 g (4.22 mmol) of tert-butyl-(3S)-3-(methylamino)pyrrolidine-1-carboxylate hydrochloride and 2.94 ml (21.1 mmol) of TEA in 25 ml of DCM was added dropwise with ice-cooling 0.53 ml (4.65 mmol) of cyclobutanecarbonyl chloride , and the mixture was stirred at 0° C. for 10 minutes. The solids are then filtered off and the filtrate is washed once with us. NH4Cl solution, 1 time with us. NaHCO3 solution and 1 time with us. NaCl solution. The organic layer is dried over Na ₂ SO ₄ and the solvent is removed in vacuo.

The residue is then added to 3 ml MeOH before 3 ml (12.0 mmol) HCl in dioxane (4 mol/l) is added. The mixture is stirred overnight at RT. The solvent is removed in vacuo to give the crude product.

C ₁₀ H ₁₈ N ₂ O * HC1

ERI-MS:

By (HPLC):

(M = 218.7 g/mol)

183 [M+H] ⁺

0.67 min (method B)

Intermediate XXIV. tert-Butyl (3S)-3-(N-methylcyclopropanamido)pyrrolidine-1carboxylate

A mixture of 0.38 ml (4.77 mmol) cyclopropanecarboxylic acid, 1.00 g (4.99 mmol) tert-butyl (3S)-3-(methylamino)pyrrolidine-1-carboxylate, 1.69 g (5.25 mmol) TBTU and 2.06 ml (11.9 mmol ) DIPEA in 10 ml DMF is stirred overnight at RT. The solvent is removed in vacuo. The residue is diluted with 20 ml of us. NaHCO ₃ solution and extracted with EtOAc. The combined organic layers are dried over MgSO ₄ , filtered and the solvent removed in vacuo to give the product.

C14H24N2O3

ERI-MS:

By (HPLC):

(M = 268.3 g/mol)

269 [M+H] ⁺

0.51 min (method A)

Intermediate XXV. N-Methyl-N-[(3S)-pyrrolidin-3-yl]cyclopropanecarboxamide hydrochloride

A mixture of 1.27 g of intermediate XXIV, 10 ml (40.0 mmol) HCl in dioxane (4 mol/l) and 10 ml of dioxane was stirred overnight at RT. The solvent is removed in vacuo to give the product.

C ₉ H ₁₆ N ₂ O * HC1

ERI-MS:

By (HPLC):

(M = 204.7 g/mol)

169 [M+H] ⁺

0.58 min (method B)

Intermediate XXVI. Methyl 5H,6H,7H,8H,9H-pyriddo[2,3-b]azepine-3-carboxylate

To 2 ml of methanol and 2 ml of DMF add 0.20 g (0.88 mmol) of 3-bromo-5H,6H,7H,8H,9H-pyrido[2,3b]azepine, 0.02 g (44.0 μmol) of 1,1'- bis-(diphenylphosphino)ferrocene, 0.01 g (44.0 µmol) Pd(OAc) ₂ and 0.25 ml TEA (1.76 mmol). After degassing, the reaction mixture is purged with CO (5 bar) and stirred at 80° C. for 18 hours. After cooling to RT, the mixture is filtered and the solvent is removed in vacuo. The crude product is purified by HPLC (ACN/H2O/NH3).

C11H14N2O2

ERI-MS:

Wu (HPLC):

(M = 206.2 g/mol)

207 [M+H] ⁺

0.85 min (method B)

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Obtaining final compounds

Example 1

Example 1.1 (general way). X-[(38)-1-{2,2-Dimethyl-1H,2H,3H-pyrrolo[2,3-b]pyridine-5carbonyl}pyrrolidin-3-yl]-N-methylacetamide

To a mixture of 33.0 mg (0.14 mmol) of intermediate III. 1 and 38.7 mg (0.22 mmol) of intermediate XVI in 1 ml of DMF are added 74.0 μl (0.43 mmol) of DIPEA and 82.3 mg (0.22 mmol) of HATU, and the reaction mixture is stirred for several minutes. The mixture was purified by HPLC (ACN/H ₂ O/NH ₄ OH) to give the product.

C17H24N4O2 (М = 316.4 g/mol)

ERI-MS: 317[M+H] ⁺

By (HPLC): 0.71 min (Method B)

The following compounds are prepared according to the general procedure (example 1.1) described above.

Example 2

Example 2.1 (general way). X-[(38)-1-(2,2-Dimethyl-1H,2H,3H-pyrrolo[2,3-b]pyridine-5carbonyl} pyrrolidin-3-yl]-N-methylcyclobutanecarboxamide o

To a mixture of 50.0 mg (0.13 mmol) of intermediate XII. 1 and 19.3 mg (0.19 mmol) of cyclobutanecarboxylic acid in 1 ml (119 mmol) of DMF and 77.0 μl (0.45 mmol) of DIPEA are added with 73.4 mg (0.19 mmol) of HATU and the reaction mixture is stirred at RT at within 30 min. The mixture was purified by HPLC (ACN/H ₂ O/NH4OH) to give the product.

C17H ₂₄ N ₄ O2 (М = 356.5 g/mol)

ERI-MS: 357 [M+H] ⁺

By (HPLC): 0.89 min (Method B)

The following compounds are prepared according to the general procedure (example 2.1) described above.

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Example 3 N-[(3S)-1-{2,2-Dimethyl-1H,2H,3H-pyrrolo[2,3-b]pyridine-5-carbonyl}pyrrolidin-3yl]-M-methylpyrimidine-2- amine

A mixture of 50.0 mg (0.13 mmol) of intermediate XII.1 and 22.5 mg (0.14 mmol) of 2-bromopyrimidine in 111 µl (0.64 mmol) of DIPEA and 1.5 ml (18.4 mmol) of DMF was stirred overnight at 120°C. The mixture was purified by HPLC (ACN/H2O/NH4OH) to give the product.

C ₁₇ H ₂₄ N ₄ O ₂ (M = 352.4 g/mol)

ERI-MS: 353 [M+N] ⁺

By (HPLC): 0.83 min (method B)

Example 4

Example 4.1 (general method). 3-[(3S)-1-[(2R)-2-(3-Fluorophenyl)-2-methyl-1H,2H,3H-pyrrolo[2,3b]pyridine-5-carbonyl]pyrrolidin-3-yl] -1,3-oxazolidin-2-one

To a mixture of 45.0 mg (0.15 mmol) of intermediate X.3.A and 33.7 mg (0.18 mmol) of intermediate XIII.1 in 2 ml (30.6 mmol) of DMF and 149 µl (0.87 mmol) of DIPEA was added 83.1 mg (0.22 mmol) HATU, and the reaction mixture is stirred for several minutes. The mixture was purified by HPLC (ACN/H2O/NH4OH) to give the product.

C ₂₂ H ₂₃ FN ₄ O ₃ (M = 410.4 g/mol)

ERI-MS: 411[M+H] ⁺

By (HPLC): 0.70 min (Method A)

The following compounds were prepared according to the general procedure (Example 4.1) described in

Example 5

Example 5.1 (general method). 2-[(2R)-2-(4-Fluorophenyl)-2-methyl-1H,2H,3H-pyrrolo[2,3-b]pyridine-5-carbonyl]-8-oxa-2-azaspiro[4.5]decane

To a mixture of 40.0 mg (0.13 mmol) of intermediate X.1.A and 27.6 mg (0.16 mmol) of 8-oxa-2-azaspiro[4.5]decane hydrochloride in 1.5 ml (22.9 mmol) of DMF and 66.4 μl (0.39 mmol) of DIPEA 73.9 mg (0.19 mmol) of HATU are added and the reaction mixture is stirred for 2 min. The mixture was purified by HPLC (ACN/H2O/NH4OH) to give the product.

C ₂₃ H ₂₆ FN ₃ O ₂ (M = 395.4 g/mol)

ERI-MS: 396 [M+N] ⁺

By (HPLC): 0.89 min (method B)

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

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Example 6 N-[(3S)-1-[(2R)-2-(4-Fluorophenyl)-2-methyl-1H,2H,3H-pyrrolo[2,3-b]pyridine-5-carbonyl]pyrrolidine -3 -yl]-N-methylacetamide

To a mixture of 1.65 g (5.34 mmol) of intermediate X.1.A and 1.15 g (6.41 mmol) of intermediate XVI in 3.65 ml (21.4 mmol) of DIPEA and 20 ml of DMF was added 1.80 g (5.61 mmol) of TBTU, and the reaction the mixture is stirred at RT for 10 min. the reaction mixture is diluted with aq. NaHCO ₃ solution and extracted with EtOAc. The combined organic layers are dried and the solvent is removed in vacuo. The crude product is purified by column chromatography (silica gel; EtOAc/MeOH 4/1) and the solvents are removed in vacuo. The residue is triturated with DIPE, the solid is filtered off, washed with DIPE and dried at 50° C. under vacuum to give the product.

C22H25FN4O2 (М = 396.5 g/mol)

ERI-MS: 397 [M+N] ⁺

By (HPLC): 3.19 min (method K)

Example 7

Example 7.1 (general method). (3'S)-1'-[2-(3-Chlorophenyl)-2-methyl-1H,2H,3H-pyrrolo[2,3-b]pyridine-5carbonyl] - [1,3'-bipyrrolidine] -2- He

61.4 mg (0.16 mmol) HATU, and the reaction mixture is stirred for several minutes. The mixture was purified by HPLC (ACN/H2O/NH4OH) to give the product.

C ₂₃ H ₂ 5C1N ₄ O2 (M = 424.9 g/mol)

ERI-MS: 425 [M+N] ⁺

By (HPLC): 0.74 min (Method A)

The following compounds are prepared according to the general procedure (example 7.1) described above.

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starting materials

Reaction conditions

ERIMS

413 [M+N]

413 [M+N]

427 [M+N]

HPLC retention time (method) [min]

Example 8

Example 8.1 (general method). N-(3S)-1-[2-(4-Chlorophenyl)-2-methyl-1H,2H,3H-pyrrolo[2,3-b]pyridine5-carbonyl]pyrrolidin-3-yl]-N-methylacetamide

To a mixture of 100 mg (0.31 mmol) of intermediate X.6 and 65.6 mg (0.46 mmol) of N-methyl-N[(3S)-pyrrolidin-3-yl]acetamide in 3 ml (45.9 mmol) of DMF and 315 µl (1.85 mmol) of DIPEA are added with 175 mg (0.46 mmol) of HATU and the reaction mixture is stirred for 20 min. The mixture was purified by HPLC (ACN/H2O/NH4OH) to give the product.

C ₂₂ H ₂ 5C1N ₄ O2 (M = 412.9 g/mol)

ERI-MS:

413 [M+N]

By (HPLC):

0.87 min (method B)

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

PS starting materials Structure Reaction conditions ERIMS HPLC retention time (method) [min] 8.2 X.4.A XIII. 1 O. U U° fi J hn-^ _n ^ CT 427 [M+H] ⁺ 0.88 (V) 8.3 X.4.A XIII.2 about xL CT 1 hour 425 [M+Hf 0.87 (V)

Example 9

Examples 9.1 and 9.2 (general method). N[(3S)-1-[(2R)-2-(4-Chlorophenyl)-2-methyl-1H,2H,3H-pyrrolo[2.3b]pyridine-5-carbonyl]pyrrolidin-3-yl]-N -methylacetamide and N-[(3S)-1-[(2S)-2-(4-chlorophenyl)-2-methyl1H,2H,3H-pyrrolo[2,3-b]pyridine-5-carbonyl]pyrrolidine-3 -yl]-N-methylacetamide

160 mg (0.39 mmol) of example 8.1 are separated (method K).

Product 9.1 (first elution):

C ₂ 2H2 ₅ C1N ₄ O2

ERI-MS:

to its diastereoisomers using chiral SCPC

Wu (HPLC):

(M = 412.9 g/mol)

413 [M+H]+

4.58 min (method K)

Product 9.2 (second elution):

C ₂ 2H2 ₅ C1N ₄ O2

ERI-MS:

Wu (HPLC):

(M = 412.9 g/mol)

413 [M+H]+

5.08 min (method K)

The following compounds are prepared according to the general procedure (Example 9.1) described above.

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PS starting material Structure ERI-MS HPLC retention time (method) [min] 9.3 XI. 1 ⁰ 379 [M+H] ⁺ 3.51 (K) 9.4 XI. 1 oadAL 379 [M+H] ⁺ 3.99 (K)

Example 10 N-[(3S)-1-[(2R)-2-(4-cyanophenyl)-2-methyl-1H,2H,3H-pyrrolo[2,3-b]pyridine-5carbonyl]pyrrolidine-3 -yl]-N-methylacetamide

56.0 mg (0.14 mmol) of the compound of example 9.1 and 31.9 mg (0.27 mmol) of zinc dicarbonitrile are dissolved in 2 ml of DMF and purged with argon. Then add 10.0 mg (0.014 mmol) of [2-(2aminoethyl)phenyl](chloro)palladium; dicyclohexyl[2',4',6'-tris-(propan-2-yl)-[1,1'-biphenyl]-2-yl]phosphane and the reaction mixture was stirred at 130° C. for 20 minutes. The mixture was purified by HPLC (ACN/H2O/NH4OH) to give the product.

C ₂₃ H ₂₅ N ₅ O2 (M = 403.4 g/mol)

ERI-MS: 404 [M+N] ⁺

By (HPLC): 0.8 min (method B)

Example 11.

Example 11.1 (general method). 2-(7,7-Dimethyl-5,6,7,8-tetrahydro-1,8-naphthyridine-3-carbonyl)-8oxa-2-azaspiro[4.5]decane

HCI

To a mixture of 50.0 mg (0.21 mmol) of intermediate III.2 and 43.9 mg (0.25 mmol) of 8-oxa-2-azaspiro[4.5]decane hydrochloride in 2 ml (30.6 mmol) of DMF and 106 µl (0.25 mmol) 62 mmol) DIPEA 118 mg (0.31 mmol) HATU are added and the reaction mixture is stirred for 10 minutes. The mixture was purified by HPLC (ACN/H2O/NH4OH) to give the product.

C19H ₂₇ N ₃ O ₂ (M - 329.4 g/mol)

ERI-MS: 330 [M+N] ⁺

By (HPLC): 0.85 min (method B)

The following compounds are prepared according to the general procedure (example 11.1) described above.

PS starting materials Structure ERI-MS HPLC retention time (method) [min] 11.2 III.2 HN-D.. HCI 316 [M+H] ⁺ 0.79 (V)

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11.3 III.2 XV n 367 [M+H] ⁺ 0.88 (V) 11.4 XII. 2 O n 385 [M+H] ⁺ 0.92 (V) 11.5 III.2 XIII. 1 345 [M+H] ⁺ 0.75 (V) 11.6 III.2 XVI Oh oh 'n 331 [M+H] ⁺ 0.76 (V) 11.7 XII. 2 n 382 [M+H] ⁺ 0.82 (V) 11.8 III.2 XIII.2 ABOUT 343 [M+H] ⁺ 0.77 (V) 11.9 XII. 2 "A/ S° A A J / N N H : 357 [M+H] ⁺ 0.82 (V) 11.10 XII. 2 ABOUT 2 ⁰ / __ IZ^N / NN ' N 371 [M+H] ⁺ 0.85 (V) 11.11 XII. 2 - 407 ¹ [M+H] ⁺ 0.86 (V) 11.12 ^t III. 3 XVI °\ ⁿ 345 [M+H] ⁺ 0.80 (V)

^t Reaction time 60 min. at CT

Example 12.

Example 12.1 (general method). N-Methyl-N-[(3S)-1-(7-phenyl-5,6,7,8-tetrahydro-1,8-naphthyridine-3carbonyl)pyrrolidin-3-yl]acetamide

To a mixture of 48.0 mg (0.17 mmol) of intermediate XXI.1 and 35.4 mg (0.20 mmol) of intermediate XVI in 1 ml of DMF and 0.17 ml (0.99 mmol) of DIPEA was added 69.1 mg (0.18 mmol) of HATU, and the reaction mixture was stirred at RT for 10 min. The mixture was purified by HPLC (ACN/H2O/NH4OH) to give the product.

C ₂₂ H ₂₆ N ₄ O ₂ (M = 378.4 g/mol)

ERI-MS: 379 [M+N] ⁺

By (HPLC): 0.85 min (method B)

The following compounds are prepared according to the general procedure (example 12.1) described above.

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PS starting materials Structure ERIMS HPLC retention time (method) [min] 12.2 XXI. 2 XVI ABOUT Z z' \ zM / ° % 393 [M+H] ⁺ 0.73 (A) 12.3 III. 4 XVI ABOUT Soa' n 317 [M+H] ⁺ 0.45 (L) 12.4 XXI. 4 XVI O. ABOUT Αν 1 n 345 [M+H] ⁺ 0.80 (V) 12.5 XXI. 4 XIII. 2 O 357 [M+H] ⁺ 0.81 (V) 12.6 XXI. 4 XXV X ° \ W 371 [M+H] ⁺ 0.87 (V) 12.7 XXI. 4 XIII. 1 o _v O SS—o 359 [M+H] ⁺ 0.80 (V)

Example 13

Examples 13.1 and 13.2 (general method). N-Methyl-N-[(3S)-1-[(7R)-7-methyl-7-(pyrimidin-5-yl)-5,6,7,8tetrahydro-1,8-naphthyridine-3-carbonyl] pyrrolidin-3-yl] cyclobutanecarboxamide and N-methyl-N-[(3S)-1 [(7S)-7-methyl-7-(pyrimidin-5-yl)-5,6,7,8-tetrahydro-1 ,8-naphthyridine-3-carbonyl]pyrrolidin-3-yl]cyclobutanecarboxamide

50.0 mg (0.12 mmol) of intermediate XI.2 was purified with chiral SCPC (method K).

Example 13.1 (first elution):

C ₂₄ H ₃₀ N ₆ O ₂

ERI-MS:

Wu (HPLC):

Example 13.2 (second elution):

C ₂₄ HzoHb0 ₂

ERI-MS:

(M = 434.5 g/mol)

435 [M+H]+

4.52 min (method K) (M = 434.5 g/mol)

435 [M+H]+

5.09 min (method K)

By (HPLC):

The following compounds are prepared according to the general procedure (examples 13.1 and 13.2) described above.

PS starting material Structure ERI-MS HPLC retention time (method) [min] 13.3 XI.3 A / k g ⁴ ~ H 421 [M+H] ⁺ 2.98(J) 13.4 XI.3 421 [M+H] ⁺ 3.76(J)

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Analytical HPLC methods. Method A.

Gradient/ Thinner Time [min] % Sol. [water 0.1% TFA (v/v)] % Sol. [Acetonitrile] Flow [ml/min] Temp [°C] 0.0 97.0 3.0 2.2 60.0 0.2 97.0 3.0 2.2 60.0 1.2 0.0 100.0 2.2 60.0 1.25 0.0 100.0 3.0 60.0 1.4 0.0 100.0 3.0 60.0

Column: Sunfire C18_3.0x30 mm_2.5 µm.

Method B.

Gradient/ Thinner Time [min] % Sol. [water 0.1% _NH3 ] % Sol. [acetonitrile] Flow [ml/min] Temp [°C] 0.0 97.0 3.0 2.2 60.0 0.2 97.0 3.0 2.2 60.0 1.2 0.0 100.0 2.2 60.0 1.25 0.0 100.0 3.0 60.0 1.4 0.0 100.0 3.0 60.0

Column: XBridge C18_3.0x30 mm_2.5 µm.

Method C.

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

Column: Lux® Cellulose-4_4.6x250 mm_5 µm.

For the preparative scale: Lux® Cellulose -4_21.2x250 mm_5 µm; flow 60 ml/min.

Method D

Gradient/ Thinner Time [min] % Sol. [ _scCO2 ] % Sol. [IPA 20 mM NH ₃ ] Flow [ml/min] Temp [°C] Back pressure [psi] inch] 0.0 70.0 30.0 4.0 40.0 2175.0 10.0 70.0 30.0 4.0 40.0 2175.0

Column: Lux® Amylose-2_4.6x250 mm_5 µm.

For the preparative scale: Lux® Amylose-2_21.2x250 mm_5 µm; flow 60 ml/min.

Method E.

Gradient/ Thinner Time [min] % Sol. [ _scCO2 ] % Sol. [IPA 20 mM NH ₃ ] Flow [ml/min] Temp [°C] Back pressure [psi] inch] 0.0 80.0 20.0 4.0 40.0 2175.0 10.0 80.0 20.0 4.0 40.0 2175.0

Column: CHIRAL ART® Amylose SA_4.6x250 mm_5 µm. For preparative ART® Amylose SA_20x250 mm_5 µm; flow 80 ml/min.

Method F

scales: CHIRAL

Gradient/ Thinner Time [min] % Sol. [ _scCO2 ] % Sol. [IPA 20 mM NH ₃ ] Flow [ml/min] Temp [°C] Back pressure [psi] inch] 0.0 75.0 25.0 4.0 40.0 2175.0 10.0 75.0 25.0 4.0 40.0 2175.0

Column: CHIRAL ART® Amylose SA_4.6x250 mm_5 µm. For preparative ART® Amylose SA_20x250 mm_5 µm; flow 60 ml/min.

scales: CHIRAL

- 38 043045

Method G

Gradient/ Thinner Time [min] % Sol. [ _scCO2 ] % Sol. [MEON 20 mM NH ₃ ] Flow [ml/min] Temp [°C] Back pressure [psi] inch] 0.0 60.0 40.0 4.0 40.0 2175.0 10.0 60.0 40.0 4.0 40.0 2175.0

Column: CHIRAL ART® Amylose SA_4.6x250 mm_5 µm. Method N.

Gradient/ Thinner Time [min] % Sol. [water 0.1% FA (V/V)] % Sol. [Acetonitrile] Flow [ml/min] Temp [°C] 0.0 97.0 3.0 2.2 60.0 0.2 97.0 3.0 2.2 60.0 1.2 0.0 100.0 2.2 60.0 1.25 0.0 100.0 3.0 60.0 1.4 0.0 100.0 3.0 60.0

Column: Sunfire C18_3.0x30 mm_2.5 µm.

Method I

Gradient/ Thinner Time [min] % Sol. [Water 0.1% TFA (v/v)] % Sol. [Acetonitrile] Flow [ml/min] Temp [°C] 0.0 97.0 3.0 2.2 60.0 0.2 97.0 3.0 2.2 60.0 1.2 0.0 100.0 2.2 60.0 1.25 0.0 100.0 3.0 60.0 1.4 0.0 100.0 3.0 60.0

Column: Zorbax StableBond C18_3.0 x 30 mm_1.8 µm.

Method J

Gradient/ Thinner Time [min] % Sol. [ _scCO2 ] % Sol. [IPA 20 mM NH ₃ ] Flow [ml/min] Temp [°C] Back pressure [psi] inch] 0.0 85.0 15.0 4.0 40.0 2175.0 10.0 85.0 15.0 4.0 40.0 2175.0

Column: Lux® Cellulose-3 4.6x250 mm 5 µm.

For preparative scale: Lux® Cellulose-3_10x250 mm_5 µm; flow 10 ml/min. Method K.

Gradient/ Thinner Time [min] % Sol. [scCO2] % Sol. [MEON 20 mM NH3] Flow [ml/min] Temp [°C] Back pressure [psi] inch] 0.0 75.0 25.0 4.0 40.0 2175.0 10.0 75.0 25.0 4.0 40.0 2175.0

Column: CHIRAL ART® Cellulose SB 4.6x250 mm 5 µm.

For preparative scale: CHIRAL ART® Cellulose-SB_20x250 mm_5 µm; flow 60 ml/min.

Method L

Gradient/Solvent Time [min] % Sol. [water 0.1% _NH3 ] %solv. [Acetonitrile] Flow [ml/min] Temp [°C] 0.0 95.0 5.0 1.5 60.0 1.3 0.0 100.0 1.5 60.0 1.5 0.0 100.0 1.5 60.0 1.6 95.0 5.0 1.5 60.0

Column: XBridge C18_3.0x30 mm_2.5 µm.

- 39 043045

Description of biological properties.

Enzymatic analysis of vanin-1.

Test compounds are dissolved in 100% DMSO at a concentration of 10 mM and diluted in DMSO to a concentration of 5 mM in the first step, followed by serial dilution steps in 100% DMSO. The multiplicity of dilution and the number of stages of dilution may vary depending on the needs. Typically 8 different concentrations are prepared at a 1:5 dilution, further dilutions of the intermediates are made with assay buffer resulting in a 1% final concentration of DMSO in the assay.

0.1 nM FLAG labeled vanin-1 (AA 22-493, T26I, manufactured internally) and test compounds are incubated at room temperature for 20 min in assay buffer (1 mM DTT, 0.0025% Brij-35, 50 mM HEPES, pH 7.5). Add D-pantethine (Sigma, Cat. No. P2125-5G) to assay buffer (final concentration 3 μM) and incubate for an additional 30 min at room temperature. The total assay volume is usually 40 µl, but can be adjusted according to needs. The reaction is stopped by adding an equal volume of stop solution as reaction mixture until reaching 100 nM HD-pantothenic acid (as internal standard) and 1% TFA. The assay plates are centrifuged for 2 min and pantothenic acid production is determined by 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 12 µl C18 cartridge (Agilent Cat. No. G9205A).

The values given in table. I, obtained as a result of measurements of one or more samples. In the case of multiple measurements, geometric mean values are given.

Human Whole Blood Analysis: Pantetheinase (vanine) converts pantetheine to pantothenic acid and cysteamine. Accordingly, in the described protocol, vanin activity is quantified by the formation of pantothenic acid after pantetheine supplementation via pantethine. The assay is useful for identifying vanin inhibitors. Stock solutions of compounds were dissolved in DMSO at 10 mM. Further dilutions were made in RPMI 1640 medium (Gibco, #A-10491-01) and final assay concentrations were 0.032-500 nM.

Human blood was drawn into a blood bag (1% heparin, 50 IU/ml). Blood was placed into the cavities of 96-well plates at 290 μl and mixed with 10 μl of compound or drug base solution (30 s at 1400 rpm on a shaker). The 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, with the exception of some empty wells where only 10 ml were injected substrate buffer (1 mM DTT, 0.0025% Brij-35, 50 mM HEPES, pH 7.5). The samples were shaken thoroughly (30 s, 1400 rpm) and the reaction was allowed to proceed at room temperature, 250 rpm and for 5 minutes. The reaction was stopped by adding the experimental vanin inhibitor in excess (BI-1 total conc. 10 μM). The plate was centrifuged at 4°C, 665 G for 10 min. Plasma samples (100 µl) were then transferred to another 96-well plate and proteins were precipitated (5 min on ice) by adding 100 µl of ice precipitation solution (1 µM labeled pantothenic acid (di-β-alanine-13C6,15N2 calcium salt, Sigma, #705837) in acetonitrile). After that, the plate was centrifuged (4°C, 3220 G, 10 min) and the supernatants (50 μl) were collected in another 96-well plate and mixed (10 s, 1400 rpm) with 150 μl of glacial formic acid (0.1% , Carl Roth GmbH+Co.KG, #CP03.1). The formation of pantothenic acid is detected using RapidFire mass spectrometry. A TripleQuad 6500+ (ABSciex, Germany) was equipped with an LC-1290 system, a RapidFire autosampler (Agilent, Germany), and a 12 µl C18 type C cartridge (Agilent P/N G9526-80000). Mobile phase A consisted of 0.09% formic acid and 0.01% trifluoroacetic acid in water and mobile phase B of 0.09% formic acid and 0.01% trifluoroacetic acid in acetonitrile/methanol/water = 47.5/47 .5/5.

Synthesis of experimental inhibitor BI-1.

To 70 ml of MeOH are added 5.40 g (28.8 mmol) of ketone 1 (the synthesis is described in Angew. Chem. Int. Ed. 2010, 49, 6856) and 12.9 g (34.6 mmol) of CeCl ₃ x7 H ₂ O The reaction mixture is cooled to -15° C. before 2.18 g (57.7 mmol) of NaBH ₄ are added in portions. The reaction mixture is stirred for 3 hours at 0°C. The reaction is quenched by adding saturated aq. NH ₄ Cl solution and extracted with EtOAc. The organic layers are combined, dried over Na ₂ SO ₄ and the solvent is removed in vacuo.

- 40 043045

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

C ₉ H ₁₇ NO ₄ S (M = 235.3 g/mol)

IERI-MS: 258 [M+Na] ⁺

Fu (TLC, silica gel) 0.4 (PE/EtOAc 3/1)

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

C9H17NO5S (Μ - 251.3 g/mol)

ERI-MS: 252 [M+N] ⁺

Fu (TLC, silica gel) 0.55 (PE/EtOAc 3/1)

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

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

C16H23IN2O5 (М = 450.3 g/mol)

ERI-MS: 451 [M+N] ⁺

5.00 g (11.1 mmol) of the above product are added to 50 ml of MeOH and 10 ml of CH ₂ Cl ₂ . To this is added 50 ml of 4 M HCl in dioxane. After 3 hours, the volatiles are removed in vacuo and the residue is 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 are added to 100 ml of dioxane and the mixture is thoroughly degassed. The reaction mixture is stirred at 90° C. under argon for 4 hours. The solids are filtered through a Celite® plug and evaporated. The residue was purified by column chromatography (silica gel, 0-5% MeOH/CH2C12).

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

C10H12N2O3 (M = 208.2 g/mol)

ERI-MS: 209 [M+N] ⁺

By (HPLC): 0.60 min (Method A)

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

Volatiles are removed in vacuo and the residue is purified by column chromatography (Biotage KP-Nh cartridge, 0-10% MeOH/EtOAc).

C17H24N4O3 (Μ - 332.4 g/mol)

ERI-MS: 333 [M+N] ⁺

By (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 the principles of the invention by way of example.

- 41 043045

Table I

Biological properties of representatives in accordance with the present invention

PS Structure VNN 1 1C ₅₀ (nM) HWB 1С ₅₀ (nM) 1.1 oh oh LA 2.5 1.2 1.5 11.5 1.3 1.6 1.4 >aupo 4.9 1.5 o>co\) 10.4 2.1 At 0.9 2.5

- 42 043045

- 43 043045

4.3 / 0.1 1.4 4.4 O 0.1 2.1 5.1 0.4 3.6 5.2 “P LA ^Z O / ° L Vo 0.1 1.5 5.3 xrcVA 0.1 1.5 5.4 / 87.1

-44043045

5.5 ° ΛΑ 0.2 17.2 5.6 about χΛο 0.6 10.3 6 ° °v 0.2 1.9 7.1 O _h O f_ GL^ CI 0.1 7.2 Cl 0.1 2.0 7.3 dhhla / 18.9 424.0

- 45 043045

7.4 O. oh oh CI 0.1 1.9 8.1 ° V CHELSLSG' ην^ _ν <^ 0.2 4.3 8.2 LA \=o 0.1 2.6 8.3 0.1 3.8 9.1 about ό I Va to / about 0.1 3.0 9.2 wA / 1.4 9.3 O % Ow^ 0.2 2.1

- 46 043045

9.4 / 25.9 10 °V- Oha 0.2 11.1 O Va Η 1.7 11.2 0.3 4.5 11.3 xoW Η 0.2 2.9 11.4 tCoW" Η 6' 1 0.9 11.4 11.5 o ° y _o -oY^ ' Η 4.3

- 47 043045

11.6 Oh oh 0.5 12.6 11.7 AoWt n 4.9 11.8 0.7 5.2 11.9 n 0.7 3.5 11.10 oh oh n 0.6 10.6 11.11 n 0.5 6.9 11.12 0.5 5.7

- 48 043045

12.1 Οχ about GL/LL 20.3 12.2 Oh oh 0.3 8.2 12.3 QX _f 0.4 12.4 About Οσ\> Η 2.5 12.5 o _h o \\__ / Η 1.5 12.6 ABOUT. /\ 0 / n 2.7 12.7 AoW 1.4 13.1 ⁵ H 0.2 13.2 / 23.5 13.3 Οχ/ΐΛ * Η 0.3 13.4 ο AtUi • Η / 11.5

CLAIM

Claims (14)

1. A compound of formula I or a pharmaceutically acceptable salt thereof in which n means 1 or 2; m means 1, 2 or 3; - 49 043045 R ¹ and R ² are independently selected from the group consisting of H, Ci-4-alkyl, 6-10 membered aryl substituted with R ² ' ¹ , and pyrimidine, where R ² ' ¹ is selected from the group consisting of H , F, Cl, -CN; R ³ means NR ^3.1 R ³ ' ² or R ³ means a group of formula R ³ ' ^a or R ³ ' ^b in which X means CH2 or O; R ³ ' ¹ is selected from the group consisting of C _1-4 -alkyl-CO-, pyrimidine, C _3-5 -cycloalkyl-CO-, substituted by R ³ ' ¹ ' ¹ and R ³ ' ¹ '²; where R ³ ' ¹ ' ¹ and R ³ ' ¹ ' ² are independently selected from the group consisting of H, -CH ₃ , F and -CN; R ³ ' ² means C _1-4 -alkyl; R ⁴ means hydrogen or C _1-4 -alkyl or R ³ and R ⁴ together form a 4-6-membered heterocycle containing one oxygen atom' 2' A compound according to PD, where m means 1, or a pharmaceutically acceptable salt thereof 3' A compound according to SDA, where m means 2, or a pharmaceutically acceptable salt thereof 4' A compound according to one of SPD-3, where R ¹ means H or methyl, or a pharmaceutically acceptable salt thereof' 5' The compound according to one of SPD-4, where R ² means methyl, ethyl, pyrimidine or phenyl, substituted by R ² ' ¹ , where R ² ' ¹ is selected from the group consisting of H, F, Cl and -CN, or its pharmaceutically acceptable salt' 6' A compound according to one of SPD-5, where R ³ means NR ³ ' ¹ R ³ ' ² or R ³ means a group of formula R ³ ' ^a in which X means CH ₂ or O; R ³ ' ¹ means -COCH ₃ , pyrimidine, C _3-4 -cycloalkyl-CO-, substituted by R ³ ' ¹ ' ¹ and R ³ ' ¹ '²; where R ³ ' ¹ ' ¹ and R ³ ' ¹ ' ² independently of each other mean H, CH ₃ , F or -CN; R ^3'2 is CH ₃ or a pharmaceutically acceptable salt thereof 7' The compound according to one of RPD-5, where R ³ and R ⁴ together form a 6-membered heterocycle containing one oxygen atom, or a pharmaceutically acceptable salt thereof 8' A compound according to one of SPD-6, where R ⁴ means hydrogen, or a pharmaceutically acceptable salt thereof' 9' Connection according to PD, where n means 1 or 2; m means 1; R ¹ means methyl, R ² is methyl or phenyl substituted with R ² ' ¹ , where R ² ' ¹ is selected from the group consisting of H, F, Cl and -CN; R ³ means NR ³ ' ¹ R ³ ' or R ³ means a group of formula R ³ ' ^a in which X means CH ₂ or O; R ³ ' ¹ means -COCH ₃ , pyrimidine, C _3-4 -cycloalkyl-CO-, substituted by R ³ ' ¹ ' ¹ and R ³ ' ¹ '²; where R ³ ' ¹ ' ¹ and R ³ ' ¹ ' ² independently of each other mean H, -CH ₃ , F or -CN; R ^3'2 is CH3; R ⁴ means hydrogen or R ³ and R ⁴ together form a 6-membered heterocycle containing one oxygen atom; or its pharmaceutically acceptable salt’ 10' Connection according to PD, where n means 1 or 2; m means 2; R ¹ means H or methyl; - 50 043045 R ² means methyl, ethyl, pyrimidine or phenyl; R ³ means NR ³ '1R ^{3 2} or R ³ means a group of formula R ^{3 a} in which X means CH ₂ or O; R ³ ' ¹ means -COCH ₃ , pyrimidine C _3-4 -cycloalkyl-CO-, substituted by R ³ · ¹ · ¹ and R ³ ' ¹ '²; where R ³ ' ¹ ' ¹ and R ³ · ¹ · ² independently of each other mean H, CH ₃ , F or -CN; R ³ ' ² means CH ₃ ; R ⁴ means hydrogen or R ³ and R ⁴ together form a 6-membered heterocycle containing one oxygen atom, or a pharmaceutically acceptable salt thereof. 11 A compound of formula I according to claim 1, 9 or 10, selected from the group consisting of examples 6, 9 1, 8'2, 5'3, 2'1, 7'2, 13 3, 5 2, 13 1, 4 1, 11.10, 4 4, 11 9, 7 4, 4 3, 7 1, 8 3, 11 6, 10 and 9 3 - 51 043045 or a pharmaceutically acceptable salt thereof. 12. A pharmaceutical composition containing a therapeutically effective amount of at least one compound of formula I according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. 13. The use of a compound according to one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, as a drug for the treatment and/or prevention of a disease and/or condition associated with or modulated by vanin-1 or vanin-2. 14. Use of a compound according to 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 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, colon cancer, and pancreatic cancer associated with newly diagnosed diabetes.