Heteroaromatic compounds as VANIN inhibitors

Abstract

The present invention includes compounds of formula I which are useful for treating diseases associated with Vanin, and relates to methods of preparing these compounds, pharmaceutical formulations containing these compounds, and methods of using them.

Description

Technical Field

[0001] The present invention relates to novel compounds for inhibiting Vanin, pharmaceutical compositions containing the compounds and uses thereof as medicines. Background Art

[0002] Vanin enzyme subtype 1 and subtype 2 are single-domain extracellular pantetheinases that catalyze the cleavage of pantethine and pantetheine into pantothenic acid and cystamine and cysteamine, respectively (Martin, Immunogenetics, (2001 May-Jun) Vol. 53, No. 4, pp. 296-306). Cysteamine production is associated with increased tissue oxidative stress caused by decreased glutathione levels, which is a characteristic of many pathological conditions, including IBD (Xavier, Nature. 2011 Jun 15; 474(7351): 307-17), cancer (Sosa, Ageing research reviews, (2013 Jan) Vol. 12, No. 1, pp. 376-90) and diabetes (Lipinski, Journal of diabetes and its complications, (2001 Jul-Aug) Vol. 15, No. 4, pp. 203-10).

[0003] In murine models, increased Vanin-1 activity in intestinal epithelial cells may promote tissue damage and inflammation by reducing resistance to oxidative stress (Naquet, Biochem Soc Trans. 2014Aug; 42(4): 1094-100); (Berruyer, Molecular and cellular biology, (2004Aug) Vol. 24, No. 16, pp. 7214-24); (Berruyer, The Journal of experimental medicine, (2006Dec 25) Vol. 203, No. 13, pp. 2817-27); (Pouyet, Inflammatory bowel diseases, (2010Jan) Vol. 16, No. 1, pp. 96-104). Homozygous VNN1 knockout (KO) mice lack significant levels of cysteamine in the blood and tissues and exhibit 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 damage in TNBS, DSS and schistosomiasis-induced colitis models (Berruyer, The Journal of experimental medicine, (2006 Dec 25) Vol. 203, No. 13, pp. 2817-27; Pouyet, Inflammatory bowel diseases, (2010 Jan) Vol. 16, No. 1, pp. 96-104; Martin, The Journal of clinical investigation, (2004 Feb) Vol. 113, No. 4, pp. 591-7). Given that rodents lack Vanin-2 and their sole source of cysteamine is Vanin-1, the protective phenotype of VNN1 KO mice is attributed to the lack of cysteamine.

[0004] In humans, upregulation of Vanin-1 was observed in intestinal epithelial cells of tissue biopsies from UC and CD patients, and functional polymorphisms in the regulatory region of the VNN1 gene that resulted in increased VNN1 expression were associated with increased susceptibility to IBD (P = 0.0003 for heterozygotes compared with wild type) (Gensollen, Inflammatory bowel diseases, (2013 Oct) Vol. 19, No. 11, pp. 2315-25).

[0005] In addition, upregulation of Vanin-1 activity in the skin and blood is associated with the occurrence and severity of fibrosis in patients with systemic sclerosis (Kavian, Journal of immunology (Baltimore, Md.: 1950), (20161015) Vol. 197, No. 8, pp. 3326-3335), while increased Vanin-1 levels are observed in chronic juvenile idiopathic thrombocytopenia (Zhang, Blood, (2011Apr 28) Vol. 117, No. 17, pp. 4569-79), psoriasis and atopic dermatitis (Jansen, The Journal of investigative dermatology, (2009Sep) Vol. 129, No. 9, pp. 2167-74).

[0006] There is also an increase in Vanin-1 expression and activity, and it serves as a biomarker for new-onset diabetes associated with pancreatic cancer (Kang, Cancer Letters (New York, NY, United States) (2016), 373 (2), 241-250), and is also associated with poor prognosis and treatment response in colorectal cancer (Chai, American journal of translational research, (2016) Vol. 8, No. 10, pp. 4455-4463).

[0007] WO2018011681 and WO2016193844 disclose Vanin inhibitors for use in treating a range of diseases such as Crohn's disease and ulcerative colitis.

[0008] The problem to be solved by the present invention is to provide novel compounds as Vanin enzyme inhibitors, preferably as Vanin-1 enzyme inhibitors.

[0009] Surprisingly, it was found that the compounds of the present invention have potent Vanin-1 inhibitory activity, preferably showing an inhibitory effect on VNN-1 of IC 50 [nM]<100, preferably IC 50 [nM]<10, IC is particularly preferred 50 [nM]<1.

[0010] Drugs that have a longer residence time in the body are preferred because they remain effective for a longer period of time and can therefore be used in lower doses. Surprisingly, the compounds of the present invention demonstrate advantageous mean residence times (MRT).

[0011] Furthermore, the compounds of the present invention also exhibit further capabilities that are favorable to their pharmacokinetic and pharmacological characteristics, such as good solubility and good metabolic stability. DETAILED DESCRIPTION OF THE INVENTION

[0013] Surprisingly, it has been found that the compounds of the formula I according to the invention solve the abovementioned problems.

[0014] Therefore, the present invention relates to a compound of formula I or a pharmaceutically acceptable salt thereof,

[0015]

[0016] in

[0017] R 1 Indicates that R 1.1 and R 1.2 Substituted naphthyl or R 1.1 and R 1.2 substituted 8-10 membered heteroaryl containing 1 to 3 heteroatoms selected from S, N and O,

[0018] R 1.1 Selected from H, C 1-4 Alkyl, C 1-2 Alkyl-O-, CF3, C 3-5 Cycloalkyl, H2N-, Br, Cl and F;

[0019] R 1.2 Selected from H, C 1-4 Alkyl, CF3, H2N-, Br, Cl and F;

[0020] Among them, 1.1 and R 1.2 In the definition of

[0021] R 2 and R 3 are independently selected from H and methyl,

[0022] R 4 Represents R 4.1 R 4.2 N- or NC;

[0023] or

[0024] R 4 Expression R 4.a Group

[0025]

[0026] in,

[0027] X represents CH2 or O;

[0028] R 4.1 Selected from C 1-4 Alkyl-CO-, 6-membered heteroaryl containing 1-2 nitrogen atoms, R 4.1.1 and R 4.1.2 Substituted C 3-5 Cycloalkyl-CO-, optionally substituted by 1-2 halogen atoms, C 1-4 alkyl- or CH3-O-substituted phenyl-CO-, and optionally C 1-4 Alkyl- or CH3-O-substituted 5-6 membered heteroaryl-CO-,

[0029] in

[0030] R 4.1.1 , R 4.1.2 are independently selected from H, -CH3, F and -CN;

[0031] R 4.2 Indicates H or C 1-3 alkyl,

[0032] R 5 It represents H or methyl.

[0033] Preferred Implementation

[0034] In another embodiment of the present invention, R 1 Represents naphthyl, R 1.1 and R 1.2 substituted 8-10 membered heteroaryl containing 1 to 3 heteroatoms selected from N and S, or R 1.1 and R 1.2 A substituted 8-10 membered heteroaryl group containing 1 to 3 heteroatoms selected from N and O, or a pharmaceutically acceptable salt thereof.

[0035] In another embodiment of the present invention, R 1 It represents naphthyl.

[0036] In another embodiment of the present invention, R 1 Indicates that R 1.1 and R 1.2 Substituted 8-10 membered heteroaryl containing 1 to 3 heteroatoms selected from N and S.

[0037] In another embodiment of the present invention, R 1 Indicates that R 1.1 and R 1.2 Substituted 8-10 membered heteroaryl containing 1 to 3 heteroatoms selected from N and O.

[0038] In another embodiment of the present invention, R 1 By R 1.1 and R1.2 substituted, and selected from the substituent R 1.a To R 1.p :

[0039]

[0040] In another embodiment of the present invention, R 1 By R 1.1 and R 1.2 substituted, and selected from the substituent R 1.a , R 1.d , R 1.e , R 1.g , R 1.i , R 1.h , R 1.m and R 1.p .

[0041] In another embodiment of the present invention, R 1.1 Selected from H, methyl, H2N-, Br, Cl and F.

[0042] In another embodiment of the present invention, R 1.2 is selected from H, methyl and Cl.

[0043] In another embodiment of the present invention, R 1.1 and R 1.2 It's H.

[0044] In another embodiment of the present invention, R 1.1 Indicates H.

[0045] In another embodiment of the present invention, R 1.2 Indicates H.

[0046] In another embodiment of the present invention, R 2 represents H, and R 3 Represents methyl.

[0047] In another embodiment of the present invention, R 2 and R 3 Indicates H.

[0048] In another embodiment of the present invention, R 4 Represents R 4.1 R 4.2 N.

[0049] In another embodiment of the present invention, R 4 Indicates -CN.

[0050] In another embodiment of the present invention, R 4 Expression R 4.a Groups:

[0051]

[0052] in

[0053] X represents CH2 or O.

[0054] In another embodiment of the invention, X represents O.

[0055] In another embodiment of the invention, X represents CH2.

[0056] In another embodiment of the present invention,

[0057] R 4.1 Selected from C 1-4 -alkyl-CO-, R 4.1.1 and R 4.1.2 Substituted C 3-4 Cycloalkyl-CO-;

[0058] in

[0059] R 4.1.1 , R 4.1.2 are independently selected from H, CH3, F and -CN; and

[0060] R 4.2 It represents a methyl or ethyl group.

[0061] In another embodiment of the present invention,

[0062] R 4.1 Selected from CH3-CO- or R 4.1.1 and R 4.1.2 Substituted C 3-4 Cycloalkyl-CO-,

[0063] in

[0064] R 4.1.1 , R 4.1.2 are independently selected from H, -CH3, F and -CN; and

[0065] R 4.2 Represents methyl.

[0066] In another embodiment of the present invention, R 4.1 It stands for CH3-CO-.

[0067] In another embodiment of the present invention, R 4.1 Indicates that R 4.1.1 and R 4.1.2 Substituted C 3-4 Cycloalkyl-CO-.

[0068] In another embodiment of the present invention, R4.1.1 and R 4.1.2 Indicates H.

[0069] In another embodiment of the present invention, R 4.1.1 and R 4.1.2 Indicates F.

[0070] In another embodiment of the present invention, R 4.1.1 represents CH3, F or -CN; and R 4.1.2 Indicates H.

[0071] In another embodiment of the present invention, R 5 Indicates H.

[0072] In another embodiment of the present invention, R 5 Represents methyl.

[0073] A preferred embodiment of the present invention is a compound of formula I or a pharmaceutically acceptable salt thereof,

[0074] in

[0075] R 1 Indicates that R 1.1 and R 1.2 Substituted naphthyl or R 1.1 and R 1.2 substituted 8-10 membered heteroaryl containing 1 to 3 heteroatoms selected from S, N and O,

[0076] R 1.1 Selected from H, C 1-4 Alkyl, CF3, H2N-, Br, Cl and F;

[0077] R 1.2 Selected from H, C 1-4 Alkyl, CF3, H2N-, Br, Cl and F;

[0078] R 2 and R 3 are independently selected from H and methyl,

[0079] R 4 Represents R 4.1 R 4.2 N- or NC;

[0080] or

[0081] R 4 Expression R 4.a Group

[0082]

[0083] in

[0084] X represents CH2 or O;

[0085] R 4.1 Selected from C 1-4 Alkyl-CO-, R 4.1.1 and R 4.1.2 Substituted C 3-4 Cycloalkyl-CO-;

[0086] in

[0087] R 4.1.1 , R 4.1.2 are independently selected from H, CH3, F and -CN;

[0088] R 4.2 represents a methyl or ethyl group;

[0089] R 5 It represents H or methyl.

[0090] Another preferred embodiment of the present invention is a compound of formula I or a pharmaceutically acceptable salt thereof, wherein

[0091] R 1 Represents naphthyl or R 1.1 and R 1.2 substituted 8-10 membered heteroaryl containing 1 to 3 heteroatoms selected from S, N and O,

[0092] R 1.1 is selected from the group consisting of H, methyl, H2N-, Br, Cl and F;

[0093] R 1.2 is selected from H, methyl and Cl;

[0094] R 2 and R 3 independently of each other represent H or methyl;

[0095] R 4 Represents R 4.1 R 4.2 N- or NC-;

[0096] or R 4 Expression R 4.a Group

[0097]

[0098] in

[0099] X represents CH2 or O;

[0100] R 4.1 Selected from C 1-4 Alkyl-CO, R 4.1.1 and R 4.1.2 Substituted C3-4 Cycloalkyl-CO-,

[0101] in

[0102] R 4.1.1 , R 4.1.2 are independently selected from H, -CH3, F and -CN;

[0103] R 4.2 represents a methyl group;

[0104] R 5 It represents H or methyl.

[0105] R 1 , R 2 , R 3 , R 4 , R 5 , R 1.1 , R 1.2 , R 4.1 , R 4.2 , R 4.1.1 , R 4.1.2 , R 4.a Any and every one of the definitions of and X can be combined with each other.

[0106] Another preferred embodiment of the present invention is a compound of formula I above selected from Examples 2.1, 3.1, 4.1, 5.2, 5.3, 5.4, 5.7, 5.13, 5.14, 5.22, 5.24, 5.38 and 5.40:

[0107]

[0108]

[0109]

[0110] or a pharmaceutically acceptable salt thereof.

[0111] Another preferred embodiment of the invention is a compound of formula I above selected from Examples 2.1, 3.1, 4.1, 5.2, 5.3, 5.4, 5.7, 5.13, 5.14, 5.22, 5.24, 5.38 and 5.40.

[0112] Another preferred embodiment of the invention is the compound of Example 2.1.

[0113] Another preferred embodiment of the invention is the compound of Example 3.1.

[0114] Another preferred embodiment of the invention is the compound of Example 4.1.

[0115] Another preferred embodiment of the invention is the compound of Example 5.2.

[0116] Another preferred embodiment of the invention is the compound of Example 5.3.

[0117] Another preferred embodiment of the invention is the compound of Example 5.4.

[0118] Another preferred embodiment of the invention is the compound of Example 5.7.

[0119] Another preferred embodiment of the invention is the compound of Example 5.13.

[0120] Another preferred embodiment of the invention is the compound of Example 5.14.

[0121] Another preferred embodiment of the invention is the compound of Example 5.22.

[0122] Another preferred embodiment of the invention is the compound of Example 5.24.

[0123] Another preferred embodiment of the invention is the compound of Example 5.38.

[0124] Another preferred embodiment of the invention is the compound of Example 5.40.

[0125] Another preferred embodiment of the invention is a pharmaceutically acceptable salt of a compound of formula I as above, wherein the compound of formula I is selected from Examples 2.1, 3.1, 4.1, 5.2, 5.3, 5.4, 5.7, 5.13, 5.14, 5.22, 5.24, 5.38 and 5.40.

[0126] Another preferred embodiment of the present invention is a pharmaceutically acceptable salt of the compound of Example 2.1.

[0127] Another preferred embodiment of the present invention is a pharmaceutically acceptable salt of the compound of Example 3.1.

[0128] Another preferred embodiment of the present invention is a pharmaceutically acceptable salt of the compound of Example 4.1.

[0129] Another preferred embodiment of the present invention is a pharmaceutically acceptable salt of the compound of Example 5.2.

[0130] Another preferred embodiment of the present invention is a pharmaceutically acceptable salt of the compound of Example 5.3.

[0131] Another preferred embodiment of the present invention is a pharmaceutically acceptable salt of the compound of Example 5.4.

[0132] Another preferred embodiment of the present invention is a pharmaceutically acceptable salt of the compound of Example 5.7.

[0133] Another preferred embodiment of the present invention is a pharmaceutically acceptable salt of the compound of Example 5.13.

[0134] Another preferred embodiment of the present invention is a pharmaceutically acceptable salt of the compound of Example 5.14.

[0135] Another preferred embodiment of the present invention is a pharmaceutically acceptable salt of the compound of Example 5.22.

[0136] Another preferred embodiment of the present invention is a pharmaceutically acceptable salt of the compound of Example 5.24.

[0137] Another preferred embodiment of the present invention is a pharmaceutically acceptable salt of the compound of Example 5.38.

[0138] Another preferred embodiment of the present invention is a pharmaceutically acceptable salt of the compound of Example 5.40.

[0139] Another embodiment of the 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.

[0140] Another embodiment of the invention is a compound of formula I or a pharmaceutically acceptable salt thereof for use as a medicament.

[0141] In addition, the present invention relates to the use of the compound of general formula I for treating patients with Crohn's disease, ulcerative colitis, atopic dermatitis, systemic sclerosis, non-alcoholic steatohepatitis (NASH), psoriasis, chronic kidney disease, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, rheumatoid arthritis, scleroderma, asthma, allergic rhinitis, allergic eczema, juvenile rheumatoid arthritis, juvenile idiopathic arthritis, graft-versus-host disease, psoriatic arthritis, hyperlipidemia, colorectal cancer or pancreatic cancer-related newly-onset diabetes.

[0142] A pharmaceutical composition further comprising, in addition to the compound of formula I, a pharmaceutically active compound selected from an immunomodulator, an anti-inflammatory agent or a chemotherapeutic agent.

[0143] In addition, the present invention relates to the use of compounds of general formula I for treating and / or preventing diseases and / or conditions associated with or regulated by Vanin-1 or Vanin-2 (especially Vanin-1), including but not limited to the treatment and / or prevention of inflammatory diseases (preferably inflammatory bowel disease).

[0144] Another embodiment of the invention is the use of a compound of formula I for treating a patient suffering from Crohn's disease, ulcerative colitis, atopic dermatitis, systemic sclerosis, nonalcoholic steatohepatitis (NASH), psoriasis, chronic kidney disease, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, rheumatoid arthritis, scleroderma, asthma, allergic rhinitis, allergic eczema, juvenile rheumatoid arthritis, juvenile idiopathic arthritis, graft-versus-host disease, psoriatic arthritis, hyperlipidemia, colorectal cancer or pancreatic cancer associated new onset diabetes.

[0145] Another embodiment of the invention is the use of a compound of formula I for treating patients suffering from Crohn's disease, ulcerative colitis, systemic sclerosis, nonalcoholic steatohepatitis (NASH), chronic obstructive pulmonary disease or atopic dermatitis, preferably Crohn's disease, ulcerative colitis, systemic sclerosis, nonalcoholic steatohepatitis (NASH) or atopic dermatitis, particularly preferably Crohn's disease or ulcerative colitis.

[0146] Another embodiment of the invention is the use of a compound of formula I for treating patients with moderate to severe Crohn's disease.

[0147] Another embodiment of the invention is the use of a compound of formula I for treating patients suffering from ulcerative colitis.

[0148] Another embodiment of the invention is the use of a compound of formula I for treating a patient suffering from atopic dermatitis.

[0149] Another embodiment of the invention is the use of a compound of formula I for treating NASH patients.

[0150] In another embodiment, provided is a method for treating a disease selected from Crohn's disease, ulcerative colitis, atopic dermatitis, systemic sclerosis, nonalcoholic steatohepatitis (NASH), psoriasis, chronic kidney disease, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, rheumatoid arthritis, scleroderma, asthma, allergic rhinitis, allergic eczema, juvenile rheumatoid arthritis, juvenile idiopathic arthritis, graft-versus-host disease, psoriatic arthritis, hyperlipidemia, colorectal cancer or pancreatic cancer-associated new-onset diabetes, which comprises administering to the patient a therapeutically effective amount of a compound according to any one of the first embodiment or its related embodiments, or a pharmaceutically acceptable salt thereof.

[0151] In another embodiment, there is provided a method for preparing a compound according to the first embodiment or any one of its related embodiments by the method described below.

[0152] In another aspect, the present invention relates to compounds of general formula I for use in the treatment and / or prevention of the above mentioned diseases and disorders.

[0153] In another aspect, the present invention relates to the use of compounds of general formula I for the preparation of medicaments for the treatment and / or prevention of the above-mentioned diseases and disorders.

[0154] In another aspect, the present invention relates to a method for treating or preventing the above-mentioned diseases and disorders, which method comprises administering an effective amount of a compound of formula I to a human.

[0155] The actual pharmaceutically effective amount or therapeutic dose generally depends 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, based on the patient's unique condition, the compound is administered in a dosage and manner that enables the delivery of a pharmaceutically effective amount.

[0156] Another embodiment of the invention is a pharmaceutical composition comprising, in addition to the compound of formula I, a pharmaceutically active compound selected from immunomodulators, anti-inflammatory agents or chemotherapeutic agents. Examples of such drugs include, but are not limited to, cyclophosphamide, mycophenolate mofetil (MMF), hydroxychloroquine, glucocorticoids, corticosteroids, immunosuppressants, NSAIDs, non-specific and COX-2 specific cyclooxygenase inhibitors, tumor necrosis factor receptor (TNF) receptor antagonists, IL-12 / 23 and IL-23 antagonists, α4β7 integrin blocking antibodies, non-selective and selective JAK kinase inhibitors and methotrexate, as well as combinations of two or three active substances.

[0157] definition

[0158] Terms not specifically defined herein should be given the meanings that would be given to them by a person skilled in the art according to the disclosure and context of this article. However, as used in the specification, unless otherwise specified, the following terms have the indicated meanings and comply with the following conventions.

[0159] In the groups, radicals or moieties defined below, the number of carbon atoms is usually specified before the group, e.g. 1-6 Alkyl refers to an alkyl group or free radical having 1 to 6 carbon atoms. In general, in groups such as HO, H2N, (O)S, (O)2S, CN (cyano), HOOC, F3C, etc., one skilled in the art can see the free radical attachment point of the molecule from the free valence of the group itself. For a combined group containing two or more subunits, the last named subunit is the free radical attachment point, for example, the substituent "aryl-C 1-3 "Alkyl" refers to a C 1-3 The alkyl group is combined with the aryl group, the C 1-3 The alkyl group is bound to the core or group to which the substituent is attached.

[0160] Where compounds of the present invention are described in terms of both a chemical name and a structural formula, the structural formula shall prevail if there is any discrepancy.

[0161] The numbering of substituent atoms begins with the atom closest to the core or group to which the substituent is attached.

[0162] For example, the term "3-carboxypropyl" represents the following substituents:

[0163]

[0164] The carboxyl group is attached to the third carbon atom of the propyl group. The term "1-methylpropyl-", "2,2-dimethylpropyl-" or "cyclopropylmethyl-" groups represent the following groups:

[0165]

[0166] Asterisks may be used in subformulae to indicate bonds to the defined core molecule.

[0167] As used herein, the term "substituted" refers to the selection of one or more hydrogen atoms on a designated atom by a designated group, provided that the normal valency of the designated atom is not exceeded and that the substitution results in a stable compound.

[0168] Unless otherwise indicated throughout the specification and appended claims, a given chemical formula or name shall include tautomers and all stereoisomers, optical isomers and geometric isomers (e.g., enantiomers, diastereomers, E / Z isomers, etc.) and racemates thereof, as well as mixtures of individual enantiomers, mixtures of diastereomers, or mixtures in varying proportions in any of the foregoing forms in which such isomers and enantiomers exist, and salts thereof (including pharmaceutically acceptable salts) and solvates thereof (e.g., hydrates, including solvates of the free compound or of a salt of the compound).

[0169] In general, substantially pure stereoisomers can be obtained according to synthetic principles known to those skilled in the art, for example by separation of the corresponding mixtures, by use of stereochemically pure starting materials and / or by stereoselective synthesis. It is known in the art how to prepare optically active forms, for example by resolution of racemic forms or by synthesis, for example starting from optically active starting materials and / or by using chiral reagents.

[0170] Enantiomerically pure compounds or intermediates of the invention may be prepared by asymmetric synthesis, for example by preparation and subsequent separation of appropriate diastereomeric compounds or intermediates, which may be separated by known methods (e.g. by chromatographic separation or crystallization) and / or by using chiral reagents (e.g. chiral starting materials, chiral catalysts or chiral auxiliary agents).

[0171] Furthermore, the person skilled in the art knows how to prepare enantiomerically pure compounds from the corresponding racemic mixtures, for example by chromatographic separation of the corresponding racemic mixtures on a chiral stationary phase; or by resolution of the racemic mixtures by using suitable resolving agents, for example by formation of diastereomeric salts of the racemic compounds with an optically active acid or base, subsequent resolution of the salts and liberation of the desired compounds from the salts; or by derivatization of the corresponding racemic compounds with an optically active chiral auxiliary, subsequent separation of the diastereomers and removal of the chiral auxiliary group; or by kinetic resolution of the racemates (for example by enzymes); by enantioselective crystallization under suitable conditions from a mass of enantiomeric crystals; or by (fractional) crystallization from a suitable solvent in the presence of an optically active chiral auxiliary.

[0172] As used herein, the phrase "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with human tissues without excessive toxicity, irritation, allergic response, or other problem or complication, and are commensurate with a reasonable benefit / risk ratio.

[0173] As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds in which the parent compound is modified by preparing acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.

[0174] For example, such salts include those derived from benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gentisic, hydrobromic, hydrochloric, maleic, malic, malonic, mandelic, methanesulfonic, 4-methylbenzenesulfonic, phosphoric, salicylic, succinic, sulfuric, and tartaric acids.

[0175] Other pharmaceutically acceptable salts may be formed using cations derived from ammonia, L-arginine, calcium, 2,2'-iminobisethanol, L-lysine, magnesium, N-methyl-D-glucamine, potassium, sodium, and tris(hydroxymethyl)-aminomethane.

[0176] Pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing alkaline or acidic moieties. Typically, such salts can be prepared by reacting the free acid or base forms of these compounds with a sufficient amount of a suitable base or acid in water or an organic diluent such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile or a mixture thereof.

[0177] For example, salts of acids other than the above acids (eg, trifluoroacetate) used for purification or isolation of the compounds of the present invention also form part of the present invention.

[0178] The term halogen generally refers to fluorine, chlorine, bromine and iodine.

[0179] The term "C 1-n "alkyl" (wherein n is an integer selected from 2, 3, 4, 5 or 6, preferably 4 or 6) means an acyclic, saturated, branched or straight-chain hydrocarbon radical having 1 to n C atoms. For example, the term C 1-5 Alkyl groups include free radicals H3C-, H3C-CH2-, H3C-CH2-CH2-, H3C-CH(CH3)-, H3C-CH2-CH2-CH2-, H3C-CH2-CH(CH3)-, H3C-CH(CH3)-CH2-, H3C-C(CH3)2-, H3C-CH2-CH2-CH2-CH2-, H3C-CH2-CH2-CH(CH3)-, H3C-CH2-CH(CH3)-, H3C-CH2-CH(CH3)-, H3C-CH2-CH(CH3)-CH2-, H3C-CH(CH3)-CH2-, H3C-CH2-CH2-CH(CH3)-, H3C-CH2-CH(CH3)-CH2-, H3C-CH(CH3)-CH2-, H3C-CH2-C(CH3)2-, H3C-C(CH3)2-CH2-, H3C-CH(CH3)-CH(CH3)- and H3C-CH2-CH(CH2CH3)-.

[0180] The term "C 3-n "Cycloalkyl" (wherein n is an integer from 4 to n) means a cyclic, saturated, unbranched hydrocarbon radical having 3 to n C atoms. For example, the term C 3-7 Cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

[0181] The term "carbocyclyl" or "carbocycle" used alone or in combination with another free radical refers to a monocyclic, bicyclic or tricyclic structure consisting of 3 to 14 carbon atoms. The term "carbocyclyl" or "carbocycle" refers to fully saturated ring systems and aromatic ring systems as well as partially saturated ring systems. The term "carbocyclyl" or "carbocycle" includes fused rings, bridged rings and spiro ring systems.

[0182]

[0183] The term "aryl" used herein, alone or in combination with another free radical, refers to a carbocyclic monocyclic aromatic group containing 6 carbon atoms, which is optionally fused to another five-membered or six-membered carbocyclic group that is optionally aromatic, saturated or unsaturated. Aryl includes, but is not limited to, phenyl, dihydroindenyl, indenyl, naphthyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl and dihydronaphthyl.

[0184] The term "heterocyclyl" or "heterocycle" refers to a saturated or unsaturated monocyclic or polycyclic ring system, including one or more rings selected from N, O or S(O) r(where r = 0, 1 or 2) is an aromatic ring system containing 3 to 14 ring atoms, wherein no heteroatom is part of an aromatic ring. The term "heterocyclyl" or "heterocycle" is intended to include all possible isomeric forms.

[0185] Thus, the term "heterocyclyl" or "heterocycle" includes the following exemplary structures, which are not depicted as free radicals because each form may be optionally attached to any atom by a covalent bond as long as the appropriate valence is maintained:

[0186]

[0187]

[0188] The term "heteroaryl" refers to a monocyclic or polycyclic ring system containing one or more rings selected from N, O or S(O) r (where r = 0, 1 or 2), consisting of 5 to 14 ring atoms, wherein at least one heteroatom is part of an aromatic ring. The term "heteroaryl" is intended to include all possible isomeric forms.

[0189] Thus, the term "heteroaryl" includes the following exemplary structures, which are not depicted as free radicals because each form may be optionally attached to any atom via a covalent bond as long as the appropriate valence is maintained:

[0190]

[0191]

[0192] Many of the terms given above may be used repeatedly in the formulae or group definitions and have in each case one of the meanings given above and independently of one another.

[0193] Suitable formulations for administering compounds of Formula I are readily apparent to those of ordinary skill in the art and include, for example, tablets, pills, capsules, suppositories, lozenges, troches, solutions, syrups, elixirs, sachets, injections, inhalants, powders, and the like, with tablets being preferred.

[0194] For example, suitable tablets can be obtained by mixing one or more compounds of Formula I with known excipients (eg, inert diluents, carriers, disintegrants, adjuvants, surfactants, binders and / or lubricants).

[0195] For purposes of this invention, a therapeutically effective amount is that amount of a substance that is capable of eliminating disease symptoms or alleviating such symptoms, or prolonging the survival of the patient being treated.

[0196] List of abbreviations

[0197]

[0198]

[0199] Preparation of the compounds of the present invention

[0200] General Synthesis Methods

[0201] The compounds of the present invention and their intermediates can be obtained using synthetic methods known to those skilled in the art and described in the literature on organic synthesis. Preferably, the compounds are obtained in a manner similar to the preparation methods explained more fully below, especially in a manner similar to that described in the experimental section. In some cases, the order in which the reaction steps are carried out may be different. Variants of the reaction methods known to those skilled in the art but not described in detail herein may also be used.

[0202] The general process for preparing the compounds of the invention will become apparent to those skilled in the art who study the following routes. The starting materials may be prepared by methods described in the literature or herein, or in a similar or analogous manner. Any functional groups in the starting materials or intermediates may be protected using conventional protecting groups. These protecting groups may be cleaved again at the appropriate stage of the reaction sequence using methods familiar to those skilled in the art.

[0203] The compounds of the invention are prepared by the following synthetic methods, wherein the substituents of the general formula have the above meanings. These methods are intended to illustrate the invention without limiting the scope of its subject matter and the claimed compounds to these examples. If the preparation of the starting compound is not described, it is a commercial product or can be prepared analogously to the known compounds or methods described herein. The substances described in the literature are prepared according to published synthetic methods.

[0204] Compounds of formula (I) can be prepared as shown in Scheme I below.

[0205] Route I:

[0206]

[0207] In route I, pyridine A is treated with an appropriate primary amine at elevated temperature to give pyridine B. Next an amide coupling with an appropriate heterocycle (eg TBTU or HATU as coupling agent) gives compounds of general formula (I).

[0208] Alternatively, the compound of formula (I) can also be prepared as shown in the following Scheme II.

[0209] Route II:

[0210]

[0211] In Scheme II, an acid chloride A (Y=Cl) is treated with an appropriate heterocycle to generate a pyridine B. The leaving group in pyridine B can be displaced using an appropriate primary amine at elevated temperature to provide compounds of general formula (I).

[0212] The amines used in the previously described reactions can be obtained using methods known to those skilled in the art, as shown in the following Scheme III:

[0213] Route III:

[0214]

[0215] In Scheme III, amine A is acylated with an appropriate acylating agent to give amide B, which can be further deprotected (eg, using HCl or TFA when PG=BOC) to give the desired amine C.

[0216] Further options for generating these desired amines are shown below in Scheme IV:

[0217] Route IV:

[0218]

[0219] In route IV, nitrile A is treated with an alkylating agent to give nitrile B, which is then deprotected (eg, using HCl or TFA when PG=BOC) to give amine C.

[0220] Compounds of formula (II) can be prepared as shown in Scheme V below.

[0221] Route V:

[0222]

[0223] In Scheme V, ketone or aldehyde A is reacted with a suitable auxiliary to produce compound B. The imine is reduced or further alkylated with a suitable alkylating agent (i.e., Grignard reagent) to produce intermediate C or E, respectively. After deprotection of amine D (i.e., with strong acid), compound II is then obtained as shown in Schemes I and II.

[0224] Synthesis Example

[0225] The following examples are intended to illustrate the invention without limiting it.The terms "ambient temperature" and "room temperature" are used interchangeably and designate a temperature of about 20°C, such as 19 to 24°C.

[0226] Preparation of starting compounds

[0227] Embodiment 1

[0228] Example I.1 (General approach)

[0229] 6-[({imidazo[1,2-a]pyridin-3-yl}methyl)amino]pyridine-3-carboxylic acid methyl ester

[0230]

[0231] A mixture of 0.60 g (3.84 mmol) of methyl 6-fluoropyridine-3-carboxylate, 0.56 g (3.84 mmol) of {imidazo[1,2-a]pyridin-3-yl}methylamine (CAS No. 160771-89-1), 2.63 mL (15.4 mmol) of DIPEA and 6 mL of DMSO was stirred at 120° C. for 6 h. The mixture was diluted with EtOAc and washed with a mixture of saturated aqueous NaHCO3 and water (1 / 1). The organic layer was dried and the solvent was removed in vacuo.

[0232] The crude product was purified by HPLC (ACN / H2O / NH4OH).

[0233] C 15 H 14 N4O2 (M=282.3g / mol)

[0234] ESI-MS: 283[M+H] +

[0235] R t (HPLC): 0.79min (Method C)

[0236] Example II

[0237] Example II.1

[0238] 6-[({imidazo[1,2-a]pyridin-3-yl}methyl)amino]pyridine-3-carboxylic acid

[0239]

[0240] A mixture of 0.42 g (1.47 mmol) of methyl 6-[({imidazo[1,2-a]pyridin-3-yl}methyl)amino]pyridine-3-carboxylate (Example 1.1) and 5 mL of HCl (6 mol / L) was stirred at 90° C. for 4 h. After cooling to room temperature, the solvent was removed in vacuo to give the product.

[0241] C 14 H 12 N4O2*HCl (M=304.7g / mol)

[0242] ESI-MS: 269[M+H] +

[0243] R t (HPLC): 0.10min (Method A)

[0244] Example III

[0245] Example III.1 (General route)

[0246] 3-[(3S)-Pyrrolidin-3-yl]-1,3-oxazolidin-2-one hydrochloride

[0247]

[0248] A mixture of 2.00 g (10.7 mmol) (3S)-3-aminopyrrolidine-1-carboxylic acid tert-butyl ester in 0.5 mL DCM and 4 mL NaOH (50%) was cooled to 0 ° C. A 0.5 mL DCM solution of 1.38 g (9.66 mmol) 2-chloroethylcarbonochloridate was added dropwise, and the reaction mixture was stirred for 1 h at 0 ° C. 3.48 g (5.37 mmol) tetrabutylammonium hydroxide (40% MeOH solution) was added, and the mixture was stirred at room temperature overnight. The mixture was quenched with H2O and extracted with DCM. The combined organic layers were dried on a phase separation column, and the solvent was removed in vacuo.

[0249] The crude product was purified by column chromatography (silica gel; CyH / EtOAc) and the solvent was removed in vacuo.

[0250] C 12 H 20 N2O4 (M=256.3g / mol)

[0251] ESI-MS: 201[M-tBU+H] +

[0252] R t (HPLC): 0.82min (Method C)

[0253] The above product was added to 2.5 mL of dioxane, 5 mL (20.0 mmol) of HCl in dioxane (4 mol / L) and some MeOH, and the mixture was stirred at room temperature overnight. The solvent was removed in vacuo to obtain the product.

[0254] C7H 12 N2O2*HCl (M=192.6g / mol)

[0255] ESI-MS: 157[M+H] +

[0256] R t (HPLC): 0.17min (Method C)

[0257] The following compounds were prepared according to the general procedure described above (Example III.1):

[0258]

[0259] Example IV

[0260] Example IV.1 (General route)

[0261] N-[(3S)-1-(6-Fluoropyridine-3-carbonyl)pyrrolidin-3-yl]-N-methylacetamide

[0262]

[0263] To a solution of 4.00 g (22.4 mmol) of N-methyl-N-[(3S)-pyrrolidin-3-yl]acetamide hydrochloride and 14.8 mL (106.6 mmol) of TEA in 30 mL of DCM was added dropwise 3.40 g (21.3 mmol) of 2-fluoropyridine-5-carbonyl chloride (CAS No. 65352-94-5) dissolved in 5 mL of DCM at 0° C. After stirring at 0° C. for 10 min, the reaction mixture was filtered and purified by column chromatography (silica gel; DCM / MeOH, 98 / 2-85 / 15).

[0264] C 13 H 16 FN3O2 (M=265.3g / mol)

[0265] ESI-MS: 266[M+H] +

[0266] R t (HPLC): 0.63min (Method A)

[0267] Example V

[0268] Example V.1 (General Approach)

[0269] {Thieno[3,2-c]pyridin-7-yl}methanamine

[0270]

[0271] A mixture of 600 mg (3.08 mmol) 4-chlorothieno[3,2-c]pyridine-7-carbonitrile, 500 mg Pd / c (10%) and 25 mL NH3 in MeOH was hydrogenated at room temperature and 3 bar H2 pressure for 20 h. The reaction mixture was filtered and the solvent was removed in vacuo. The crude product was dissolved in DMF and purified by HPLC (ACN / H2O / NH4OH) to give the product.

[0272] C8H8N2S (M=164.2g / mol)

[0273] ESI-MS: 165[M+H] +

[0274] R t (HPLC): 0.62min (Method C)

[0275] Example VI

[0276] Example VI.1 (General Approach)

[0277] N-Methyl-N-[(3S)-pyrrolidin-3-yl]cyclobutanecarboxamide hydrochloride

[0278]

[0279] 0.86mL (4.99mmol) DIPEA is added to 5mL THF solution of 1.00g (4.99mmol) (S)-tert-butyl-3-(methylamino) pyrrolidine-1-carboxylic acid tert-butyl ester, and 0.59g (4.99mmol) cyclobutanecarbonyl chloride is added dropwise. After stirring overnight at room temperature, the mixture is filtered, cleaned with 10mL THF, and the filtrate is concentrated in a vacuum. Residue is stirred for 2h at room temperature in 50mL ethanolic hydrochloric acid solution (1.25M). The mixture is concentrated by evaporation, and residue is dissolved in 30mL isopropanol. The mixture is concentrated by evaporation.

[0280] C 10 H 18 N2O*HCl (M=218.7g / mol)

[0281] ESI-MS: 183[M+H] +

[0282] R t (HPLC): 0.96min (Method B)

[0283] Example VII

[0284] Example VII.1 (General route)

[0285] (R)-2-Methyl-N-[(1Z)-(1-methyl-1H-indazol-4-yl)methylene]propane-2-sulfenamide

[0286]

[0287] A solution of a mixture of 1.50 g (9.37 mmol) 1-methyl-1H-indazole-4-carbaldehyde, 1.36 g (11.2 mmol) (R)-2-methylpropane-2-sulfenamide, 5.55 mL (18.7 mmol) tetrakis(propan-2-yloxy)titanium and 20 mL THF was stirred at 70° C. for 1 h.

[0288] After being cooled to room temperature, dilute the mixture with 50mL NaCl saturated solution. Remove the resulting precipitate by diatomite filtration, and clean with EtOAc. Separate the organic layer, and clean with NaCl saturated solution. Then dry the organic layer on phase separation column, and remove the solvent in a vacuum to obtain product.

[0289] C 13 H 17 N3OS (M=263.4g / mol)

[0290] ESI-MS: 264[M+H] +

[0291] R t (HPLC): 0.92min (Method C)

[0292] The following compounds were prepared according to the general procedure described above (Example VII.1):

[0293]

[0294] Example VIII

[0295] Example VIII.1 (General route)

[0296] (R)-2-Methyl-N-[(1S)-1-(1-methyl-1H-indazol-4-yl)ethyl]propane-2-sulfenamide

[0297] (R)-2-Methyl-N-[(1R)-1-(1-methyl-1H-indazol-4-yl)ethyl]propane-2-sulfenamide

[0298]

[0299] To a mixture of 2.46 g (9.34 mmol) (R)-2-methyl-N-[(1Z)-(1-methyl-1H-indazol-4-yl)methylene]propane-2-sulfenamide in 25 mL DCM was added dropwise 6.23 mL (18.5 mmol) bromo(methyl)magnesium (3 mol / L) at -50°C and the mixture was stirred at -50°C for 1 h and overnight at room temperature. Additional 6.23 mL (18.5 mmol) bromo(methyl)magnesium (3 mol / L) was added dropwise at room temperature and stirred for 1 h. The mixture was then diluted with 50 mL saturated NH4Cl solution and extracted twice with DCM. The organic layer was washed with saturated NaCl solution, dried and the solvent removed in vacuo.

[0300] The crude product was purified by HPLC (ACN / H2O / NH4OH) to obtain the product. The organic solvent was removed in vacuo, and the remaining solution was diluted with a saturated solution of NaCl and extracted twice with methyl-THF. The combined organic layers were dried with Na2SO4, filtered and the solvent was removed in vacuo to obtain the product.

[0301] Product A:

[0302] C 14 H 21 N3OS (M=279.4g / mol)

[0303] ESI-MS: 280[M+H] +

[0304] R t (HPLC): 0.87min (Method A)

[0305] Product B:

[0306] C 14 H 21 N3OS (M=279.4g / mol)

[0307] ESI-MS: 280[M+H] +

[0308] R t (HPLC): 0.90min (Method A)

[0309] The following compounds were prepared according to the general procedure described above (Example VIII.1):

[0310]

[0311]

[0312] Example IX

[0313] Example IX.1 (General Approach)

[0314] (1S)-1-(1-Methyl-1H-indazol-4-yl)ethane-1-amine hydrochloride

[0315]

[0316] To a mixture of 1.52 g (5.43 mmol) of (R)-2-methyl-N-[(1S)-1-(1-methyl-1H-indazol-4-yl)ethyl]propane-2-sulfenamide in 15 mL of THF was added 5 mL of HCl (4 mol / L in dioxane) at 0° C. The reaction mixture was stirred until it reached room temperature, and the resulting precipitate was filtered off and dried in vacuo to give the product.

[0317] C 10 H 13 N3*HCl (M=211.7g / mol)

[0318] ESI-MS: 176[M+H] +

[0319] R t (HPLC): 0.59min (Method A)

[0320] The following compounds were prepared according to the general procedure described above (Example IX.1):

[0321]

[0322]

[0323] Example X

[0324] Example X.1 (General Approach)

[0325] (1S)-1-(1H-Indazol-5-yl)ethane-1-amine hydrochloride

[0326]

[0327] To a mixture of 0.44 g (1.67 mmol) of (S)-N-[(1E)-1-(1H-indazol-5-yl)ethylidene]-2-methylpropane-2-sulfenamide (Example VII.2) in 7 mL of THF and 0.10 mL of H2O was added 0.19 g (5.00 mmol) of sodium borohydride at -50°C. The reaction mixture was stirred for 1.25 h without an ice bath. The mixture was diluted with a saturated solution of NH4Cl and extracted twice with EtOAc. The organic layer was then dried on a phase separation column and the solvent was removed in vacuo to give the product. The crude product was purified by HPLC (ACN / H2O / NH4OH).

[0328] C 13 H 19 N3OS (M=265.4g / mol)

[0329] ESI-MS: 266[M+H] +

[0330] R t (HPLC): 0.83min (Method C)

[0331] The above product was added to 2 mL THF and 2 mL HCl (4 mol / L in dioxane), and the mixture was stirred at room temperature for 45 min. The solvent was removed in vacuo to obtain the product.

[0332] C9H 11 N3*HCl (M=197.7g / mol)

[0333] ESI-MS: 145[M+H] +

[0334] R t (HPLC): 0.62min (Method C)

[0335] Example XI

[0336] Example XI.1 (General Approach)

[0337] tert-Butyl N-[(1S)-1-[(2-amino-4-chlorophenyl)carbamoyl]ethyl]carbamate

[0338]

[0339] To a mixture of 25.0 g (132 mmol) (2S)-2-{[(tert-butoxy)carbonyl]amino}propionic acid and 18.8 g (132 mmol) 4-chlorobenzene-1,2-diamine in 50 mL THF was added dropwise 30.0 g (145 mmol) DCC and 60 mL THF solution under ice-cold conditions. The reaction mixture was stirred at room temperature overnight. The precipitate was filtered out and washed with THF. The filtrate was concentrated to dryness in vacuo. The crude product was treated with a mixture of Et2O / PE (1 / 1) and the resulting precipitate was filtered out. The solid was dried in vacuo at 40°C to obtain the product.

[0340] C 14 H 20 ClN3O3 (M=313.8g / mol)

[0341] Rf(TLC): 0.3(CyH / EtOAc 1 / 1)

[0342] Example XII

[0343] Example XII.1 (General Approach)

[0344] tert-Butyl N-[(1S)-1-(5-chloro-1H-1,3-benzodiazol-2-yl)ethyl]carbamate

[0345]

[0346] A mixture of 525 mg (1.67 mmol) of tert-butyl N-[(1S)-1-[(2-amino-4-chlorophenyl)carbamoyl]ethyl]carbamate and 5 mL of HOAc was stirred at 40° C. for 3 h. The mixture was poured onto ice and the precipitate was filtered off. The filtrate was concentrated in vacuo and treated with Et2O. The precipitate was filtered off and the filtrate was concentrated in vacuo to dryness.

[0347] C 14 H 18 ClN3O2 (M=295.8g / mol)

[0348] Rf(TLC): 0.35(Et2O / PE 2 / 1)

[0349] Example XIII

[0350] Example XIII.1 (General route)

[0351] (1S)-1-(5-Chloro-1H-1,3-benzodiazol-2-yl)ethane-1-amine hydrochloride

[0352]

[0353] To a mixture of 1.03 g (3.48 mmol) of tert-butyl N-[(1S)-1-(5-chloro-1H-1,3-benzodiazol-2-yl)ethyl]carbamate in 10 mL of EtOH was added 20 mL of concentrated HCl and the mixture was stirred at 80 ° C for 2 h. The solvent was removed in vacuo and the residue was treated with EtOH. The precipitate was filtered off, washed with Et2O, and dried in vacuo at 40 ° C to give a blue powder.

[0354] Example XIV

[0355] Example XIV.1 (General Approach)

[0356] tert-Butyl N-[(1S)-1-(5-chloro-6-fluoro-1H-1,3-benzodiazol-2-yl)ethyl]carbamate

[0357]

[0358] Under ice-cold conditions, 4.54g (22.0mmol) of DCC dissolved in 50mL THF was added dropwise to a mixture of 3.78g (20.0mmol) (2S)-2-{[(-tert-butoxy)carbonyl]amino}propionic acid and 3.21g (20.0mmol) 4-chloro-5-fluorobenzene-1,2-diamine in 30mL THF, and the reaction mixture was stirred at room temperature to continue over the weekend. The resulting precipitate was filtered out, washed with THF, and the filtrate was concentrated to dryness in vacuo. The residue was dissolved in 70mL HOAc, and the mixture was stirred at 55°C for 4h. The solvent was removed in vacuo, the crude product was dissolved in DCM, and washed with H2O and NaHCO3 solution (5%). The organic layer was dried with Na2SO4, and the solvent was removed in vacuo. The crude product was purified by column chromatography (silica gel; DCM / EtOH; 1-3% EtOH) and ground twice with DIPE. The solid was filtered out and dried to obtain the product.

[0359] C 14 H 17 ClFN3O2 (M=313.8g / mol)

[0360] Rf(TLC): 0.4(PE / EtOAc 7 / 3)

[0361] Example XV

[0362] Example XV.1 (General Approach)

[0363] (1S)-1-(5-Chloro-6-fluoro-1H-1,3-benzodiazol-2-yl)ethane-1-amine hydrochloride

[0364]

[0365] A mixture of 2.60 g (8.29 mmol) of tert-butyl N-[(1S)-1-(5-chloro-6-fluoro-1H-1,3-benzodiazol-2-yl)ethyl]carbamate and 70 mL of HCl in EtOH was stirred for 1 h at 50° C. After cooling, the resulting precipitate was filtered off, washed with cold EtOH and Et2O and dried.

[0366] C9H9ClFN3*HCl (M=250.1g / mol)

[0367] Rf(TLC): 0.3(DCM / EtOH 9 / 1)

[0368] Example XVI

[0369] Example XVI.1 (General Approach)

[0370] (S)-2-Methyl-N-[(1E)-1-(2-methyl-2H-indazol-4-yl)ethylidene]propane-2-sulfenamide

[0371]

[0372] A mixture of 0.30 g (1.72 mmol) of 1-(2-methyl-2H-indazol-4-yl)ethan-1-one, 0.31 g (2.58 mmol) of (S)-2-methylpropane-2-sulfenamide, 1.72 mL (3.44 mmol) of tetraethoxytitanium (2 mol / L) and 5 mL of THF was stirred at 80° C. overnight.

[0373] After cooling to room temperature, the mixture was diluted with 50 mL of a saturated solution of NaCl and 100 mL of DCM. The resulting precipitate was filtered off and the layers were separated. The organic layer was dried and the solvent was removed in vacuo to obtain a crude product.

[0374] C 14 H 19 N3OS (M=277.4g / mol)

[0375] ESI-MS: 278[M+H] +

[0376] R t (HPLC): 0.87min (Method C)

[0377] The following compounds were prepared according to the general procedure described above (Example XVI.1):

[0378]

[0379] Example XVII

[0380] Example XVII.1 (General Approach)

[0381] (S)-2-Methyl-N-[(1S)-1-(2-methyl-2H-indazol-4-yl)ethyl]propane-2-sulfenamide

[0382] (S)-2-Methyl-N-[(1R)-1-(2-methyl-2H-indazol-4-yl)ethyl]propane-2-sulfenamide

[0383]

[0384] To a mixture of 0.48 g (1.73 mmol) of (S)-2-methyl-N-[(1E)-1-(2-methyl-2H-indazol-4-yl)ethylidene]propane-2-sulfenamide and 5 mL of THF was added 0.5 mL of H2O, and the mixture was cooled to -50° C. Then 0.20 g (5.18 mmol) of sodium borate was added, and the mixture was allowed to reach room temperature.

[0385] The reaction mixture was washed with a mixture of NaHCO 3 saturated solution and H 2 O (1:1). The organic layer was dried and the crude product was purified by HPLC (ACN / H 2 O / NH 4 OH).

[0386] Product A:

[0387] C 14 H 21 N3OS (M=279.4g / mol)

[0388] ESI-MS: 280[M+H] +

[0389] R t (HPLC): 0.83min (Method C)

[0390] Product B:

[0391] C 14 H 21 N3OS (M=279.4g / mol)

[0392] ESI-MS: 280[M+H] +

[0393] R t (HPLC): 0.79min (Method C)

[0394] The following compounds were prepared according to the general procedure described above (Example XVII.1):

[0395]

[0396] Example XVIII

[0397] Example XVIII.1 (General Approach)

[0398] (S)-N-[(1E)-1-(4-amino-3-nitrophenyl)ethylidene]-2-methylpropane-2-sulfenamide

[0399]

[0400] A mixture of 400 mg (2.00 mmol) of 1-(4-amino-3-nitrophenyl)ethan-1-one, 296 mg (2.44 mmol) of (S)-2-methylpropane-2-sulfenamide, 2.22 mL of tetraethoxytitanium (2 mol / L) and 8 mL of THF was stirred at 80° C. overnight.

[0401] After cooling to room temperature, the mixture was diluted with 50 mL of a saturated solution of NaCl and a mixture of H2O (1 / 1). The resulting precipitate was filtered out, washed with EtOAc, and the layers were separated. The organic layer was dried over Na2SO4, filtered, and prepared for column chromatography. The crude product was purified by column chromatography (silica gel; DCM / EtOH, 2-20% MeOH).

[0402] C 12 H 17 N3O3S (M=283.4g / mol)

[0403] ESI-MS: 284[M+H] +

[0404] R t (HPLC): 0.88min (Method C)

[0405] Example XIX

[0406] Example XIX.1 (General Approach)

[0407] (S)-N-[(1S)-1-(4-amino-3-nitrophenyl)ethyl]-2-methylpropane-2-sulfenamide

[0408]

[0409] To a mixture of 565 mg (2.00 mmol) of (S)-N-[(1E)-1-(4-amino-3-nitrophenyl)ethylidene]-2-methylpropane-2-sulfenamide in 11 mL of THF was added 0.20 mL of H2O, and the mixture was cooled to -50° C. Then 227 mg (5.98 mmol) of sodium borate was added, and the mixture was allowed to reach room temperature.

[0410] The reaction mixture was washed twice with saturated NH4Cl solution. The organic layer was dried over Na2SO4, filtered, and the solvent was removed in vacuo to give the crude product.

[0411] C 12 H 19 N3O3S (M=285.4g / mol)

[0412] ESI-MS: 286[M+H] +

[0413] R t (HPLC): 0.85min (Method C)

[0414] Example XX

[0415] Example XX.1 (General Approach)

[0416] (S)-N-[(1S)-1-(3,4-Diaminophenyl)ethyl]-2-methylpropane-2-sulfenamide

[0417]

[0418] A mixture of 581 mg (2.00 mmol) of (S)-N-[(1S)-1-(4-amino-3-nitrophenyl)ethyl]-2-methylpropane-2-sulfenamide, 58.1 mg of Pd / C and 10 mL of THF was stirred at room temperature under 3 bar H2 pressure overnight. The solvent was evaporated to give a crude product.

[0419] C 12 H 21 N3OS (M=255.4g / mol)

[0420] ESI-MS: 256[M+H] +

[0421] R t (HPLC): 0.70min (Method C)

[0422] Example XXI

[0423] Example XXI.1 (General Approach)

[0424] (1S)-1-(1H-1,3-Benzadiazole-6-yl)ethane-1-amine hydrochloride

[0425]

[0426] A mixture of 75.0 mg (0.29 mmol) of (S)-N-[(1S)-1-(3,4-diaminophenyl)ethyl]-2-methylpropane-2-sulfinamide and 1 mL of trimethoxymethane was stirred at reflux for 30 min. The reaction mixture was diluted with a mixture of saturated NaHCO3 solution and H2O (1 / 1) and extracted twice with EtOAc. The organic layer was dried over Na2SO4, filtered, and the solvent was removed in vacuo.

[0427] C 13 H 19 N3OS (M=265.4g / mol)

[0428] ESI-MS: 266[M+H] +

[0429] R t (HPLC): 0.75min (Method C)

[0430] The remaining product was dissolved in 2 mL of THF and 0.5 mL of HCl (4 mol / L in dioxane) was added at 0° C. The reaction mixture was allowed to reach room temperature and the solvent was removed in vacuo to give the product.

[0431] C9H 11 N3*HCl (M=197.7g / mol)

[0432] ESI-MS: 162[M+H] +

[0433] R t (HPLC): 0.10min (Method A)

[0434] Example XXII

[0435] Example XXII.1 (General Approach)

[0436] (R)-N-[(1E)-(1H-indazol-4-yl)methylene]-2-methylpropane-2-sulfenamide

[0437]

[0438] In the mixture of (R)-2-methylpropane-2-sulfinamide and 5mL DCM, add 869mg (5.45mmol) dry copper sulfate (2+), then add 438mg (3.00mmol) 1H-indazole-4-carboxaldehyde, and the mixture is stirred at room temperature overnight.Add extra dry copper sulfate (2+), and the mixture is stirred at room temperature 1 day.Desolventize in vacuum, and by column chromatography (silica gel; CyH / EtOAc) purification crude product to obtain product.

[0439] C12 H 15 N3OS (M=249.3g / mol)

[0440] ESI-MS: 250[M+H] +

[0441] R t (HPLC): 0.87min (Method B)

[0442] Example XXIII

[0443] Example XXIII.1 (General Approach)

[0444] (R)-N-[(1S)-1-(1H-indazol-4-yl)ethyl]-2-methylpropane-2-sulfenamide

[0445] (R)-N-[(1R)-1-(1H-indazol-4-yl)ethyl]-2-methylpropane-2-sulfenamide

[0446]

[0447] To a mixture of 220 mg (0.88 mmol) (R)-N-[(1E)-(1H-indazol-4-yl)methylene]-2-methylpropane-2-sulfinamide in 10 mL DCM was added 618 μL (1.85 mmol) bromo(methyl)magnesium (3 mol / LEt2O solution) dropwise at -48°C, and the mixture was stirred for 4 h. After reaching room temperature, the solvent was removed in vacuo. The crude product was dissolved in DMF and purified by HPLC (ACN / H2O / NH4OH) to obtain 2 products.

[0448] Product A:

[0449] C 13 H 19 N3OS (M=265.4g / mol)

[0450] ESI-MS: 266[M+H] +

[0451] R t (HPLC): 0.76min (Method C)

[0452] Product B:

[0453] C 13 H 19 N3OS (M=265.4g / mol)

[0454] ESI-MS: 266[M+H] +

[0455] R t(HPLC): 0.80min (Method C)

[0456] Example XXIV

[0457] Example XXIV.1 (General Approach)

[0458] (1S)-1-(1H-indazol-4-yl)ethan-1-amine

[0459]

[0460] A mixture of 90.0 mg (0.34 mmol) of (R)-N-[(1S)-1-(1H-indazol-4-yl)ethyl]-2-methylpropane-2-sulfenamide and 5 mL of HCl in MeOH was stirred at room temperature overnight. The solvent was removed in vacuo to give the product.

[0461] C9H 11 N3 (M=161.2g / mol)

[0462] ESI-MS: 145[M-NH2] +

[0463] R t (HPLC): 0.38min (Method B)

[0464] Example XXV

[0465] Example XXV.1 (General Approach)

[0466] (S)-2-Methyl-N-[(1E)-1-(2-methyl-2H-indazol-5-yl)ethylidene]propane-2-sulfenamide

[0467]

[0468] To a mixture of 70.0 mg (0.40 mmol) 1-(2-methyl-2H-indazol-5-yl)ethane-1-one (CAS: 1159511-28-0) and 2 mL THF was added 53.6 mg (0.44 mmol) (S)-2-methylpropane-2-sulfinamide and 0.39 mL (1.61 mmol) tetraethoxytitanium (85%) and the reaction mixture was stirred at 80° C. overnight. An additional 0.55 equivalents of (S)-2-methylpropane-2-sulfinamide was added and the mixture was stirred at 80° C. for 4 h and at room temperature over the weekend. The reaction mixture was poured into a dilute NaCl solution, EtOAc was added and stirred for 5 min. The resulting precipitate was then filtered off and the layers separated. The H2O layer was extracted with EtOAc, the combined organic layers were dried on a phase separation column, and the solvent was removed in vacuo to give the product.

[0469] C 14 H 19N3OS (M=277.4g / mol)

[0470] ESI-MS: 278[M+H] +

[0471] R t (HPLC): 0.85min (Method C)

[0472] Example XXVI

[0473] Example XXVI.1 (General Approach)

[0474] (1S)-1-(2-Methyl-2H-indazol-5-yl)ethane-1-amine hydrochloride

[0475]

[0476] To a mixture of 0.13 g (0.45 mmol) of (S)-2-methyl-N-[(1E)-1-(2-methyl-2H-indazol-5-yl)ethylidene]propane-2-sulfenamide, 5 mL of THF and 0.10 mL of H2O was added 51.8 mg (1.36 mmol) of sodium borohydride at -50°C. The reaction mixture was stirred for 1 h without an ice bath. The mixture was diluted with saturated NH4Cl solution and extracted twice with EtOAc. The organic layer was then dried on a phase separation column and the solvent removed in vacuo.

[0477] C 14 H 21 N3OS (M=279.4g / mol)

[0478] ESI-MS: 280[M+H] +

[0479] R t (HPLC): 0.83min (Method C)

[0480] To the above product was added 1 mL of THF and 2 mL of HCl (4 mol / L in dioxane) solution, and the mixture was stirred at room temperature for 15 min. The solvent was removed in vacuo to obtain the product.

[0481] C 10 H 13 N3*HCl (M=211.7g / mol)

[0482] ESI-MS: 159[M+H] +

[0483] R t (HPLC): 0.66min (Method C)

[0484] Example XXVI

[0485] Example XXVI.1 (General Approach)

[0486] (3S)-3-(N-Methylcyclopropanecarboxamido)pyrrolidine-1-carboxylic acid tert-butyl ester

[0487]

[0488] At 0°C, 0.50 g (4.78 mmol) of cyclopropanecarbonyl chloride dissolved in 3 mL of DCM was added dropwise to a solution of 0.96 g (4.78 mmol) of (3S)-3-(methylamino)pyrrolidine-1-carboxylic acid tert-butyl ester and 3.33 mL (23.9 mmol) of TEA in 10 mL of DCM. After stirring for 10 min at 0°C, the reaction mixture was filtered and diluted with DCM. The organic layer was washed with a mixture of a saturated solution of NaHCO and water (1 / 1). Washed with a saturated solution of NH4Cl and washed with a saturated solution of NaCl. The combined organic layers were dried with Na2SO4, filtered, and the solvent was removed in vacuo to obtain the product.

[0489] C 14 H 24 N2O3 (M=268.4g / mol)

[0490] ESI-MS: 270[M+H] +

[0491] R t (HPLC): 0.52min (Method A)

[0492] Example XXVII

[0493] Example XXVII.1 (General Approach)

[0494] N-Methyl-N-[(3S)-pyrrolidin-3-yl]cyclopropanecarboxamide hydrochloride

[0495]

[0496] A mixture of 0.99 g (3.69 mmol) of tert-butyl (3S)-3-(N-methylcyclopropanecarboxamido)pyrrolidine-1-carboxylate and 5 mL (20.0 mmol) of HCl (4 mol / L in dioxane) was stirred at room temperature for 1 h. The solvent was removed in vacuo to give the product.

[0497] C9H 16 N2O*HCl (M=204.7g / mol)

[0498] ESI-MS: 169[M+H] +

[0499] Rt (HPLC): 0.57min (Method C)

[0500] Example XXVIII

[0501] Example XXVIII.1 (General Approach)

[0502] (1S)-1-{1H-pyrrolo[2,3-b]pyridin-5-yl}ethan-1-amine hydrochloride

[0503]

[0504] A mixture of 1.20 g (4.52 mmol) of (S)-2-methyl-N-[(1S)-1-{1H-pyrrolo[2,3-b]pyridin-5-yl}ethyl]propane-2-sulfenamide, 5 mL of HCl in dioxane and 10 mL of THF was stirred at room temperature for 30 min. The resulting precipitate was filtered off and dried in vacuo to obtain the product.

[0505] C9H 11 N3*HCl (M=197.7g / mol)

[0506] ESI-MS: 162[M+H] +

[0507] R t (HPLC): 0.09min (Method A)

[0508] Example XXIX

[0509] Example XXIX.1 (General Approach)

[0510] 6-{[(1S)-1-{1H-pyrrolo[2,3-b]pyridin-5-yl}ethyl]amino}pyridine-3-carboxylic acid methyl ester

[0511]

[0512] A mixture of 0.85 g (4.30 mmol) of 1S-1-{1H-pyrrolo[2,3-b]pyridin-5-yl}ethan-1-amine hydrochloride, 0.67 g (4.30 mmol) of methyl 6-fluoropyridine-3-carboxylate, 3.68 mL (22.0 mmol) of DIPEA and 5 mL of DMSO was stirred at 0°C to 120°C for 2 h.

[0513] The crude was purified by HPLC (ACN / H2O / NH4OH) to give the product.

[0514] C 16 H 16 N4O2 (M=296.3g / mol)

[0515] ESI-MS: 297[M+H] +

[0516] R t (HPLC): 0.84min (Method C)

[0517] Example XXX

[0518] Example XXX.1 (General Approach)

[0519] 6-{[(1S)-1-{1H-pyrrolo[2,3-b]pyridin-5-yl}ethyl]amino}pyridine-3-carboxylic acid hydrochloride

[0520]

[0521] A mixture of 0.15 g (0.51 mmol) of methyl 6-{[(1S)-1-{1H-pyrrolo[2,3-b]pyridin-5-yl}ethyl]amino}pyridine-3-carboxylate and 3 mL of half-concentrated HCl was stirred at 90° C. for 4 h. The solvent was removed in vacuo at room temperature to give the product.

[0522] C 15 H 14 N4O2*HCl (M=318.8g / mol)

[0523] ESI-MS: 283[M+H] +

[0524] R t (HPLC): 0.56min (Method A)

[0525] Example XXXI

[0526] Example XXXI.1 (General Approach)

[0527] 5-[(3S)-3-(Methylamino)pyrrolidine-1-carbonyl]-N-[(1S)-1-{1H-pyrrolo[2,3-b]pyridine-5- 1-[4-[(2 ...((2-((-(methoxy}ethyl]pyridin-2-amine trifluoroacetate

[0528]

[0529] To a mixture of 0.32 g (1.00 mmol) 6-{[(1S)-1-{1H-pyrrolo[2,3-b]pyridin-5-yl}ethyl]amino}pyridine-3-carboxylic acid hydrochloride, 0.29 g (1.21 mmol) N-methyl-N-[(3S)-pyrrolidin-3-yl]carbamic acid tert-butyl ester hydrochloride, 1.72 mL (10.0 mmol) DIPEA and 3 mL DMF was added 0.46 g (1.21 mmol) HATU, and the mixture was stirred for several minutes. The reaction mixture was diluted with MeOH, filtered and purified by HPLC (ACN / H2O / NH4OH).

[0530] C 25 H 32N6O3 (M=464.6g / mol)

[0531] ESI-MS: 465[M+H] +

[0532] R t (HPLC): 0.92min (Method C)

[0533] The above product was dissolved in 10 mL of DCM, and 2.5 mL of TFA was added. The mixture was stirred at room temperature for 1 h.

[0534] C 20 H 24 N6O*C2HF3O2(M=478.5g / mol)

[0535] ESI-MS: 365[M+H] +

[0536] R t (HPLC): 0.73min (Method C)

[0537] The following compounds were prepared according to the general procedure described above (Example XXXI.1):

[0538]

[0539] Example XXXII

[0540] Example XXXII.1 (General Approach)

[0541] (3S)-3-(1-Methylcyclobutaneamido)pyrrolidine-1-carboxylic acid tert-butyl ester

[0542]

[0543] A mixture of 0.55 g (4.83 mmol) 1-methylcyclobutane-1-carboxylic acid, 2.08 mL (12.1 mmol) DIPEA, 1.94 g (6.04 mmol) and 7.5 mL DMF was stirred at room temperature for 30 min. 0.75 g (4.03 mmol) (3S)-tert-butyl 3-aminopyrrolidine-1-carboxylate was then added and the mixture was stirred at room temperature overnight.

[0544] The reaction mixture was diluted with EtOAc and washed with half-concentrated NaHCO3 solution, once with NH4Cl solution, and twice with half-concentrated NaCl solution. The combined organic layers were dried over Na2SO4, filtered, and the solvent was removed in vacuo to give a crude product.

[0545] C 15 H 26N2O3 (M=282.4g / mol)

[0546] ESI-MS: 183[M+H-BOC] +

[0547] R t (HPLC): 0.92min (Method C)

[0548] Example XXXIII

[0549] Example XXXIII.1 (General Approach)

[0550] N,1-Dimethyl-N-[(3S)-pyrrolidin-3-yl]cyclobutane-1-carboxamide hydrochloride

[0551]

[0552] 0.44mL (7.03mmol) iodomethane was added to a mixture of 1.37g (4.85mmol) (3S)-3-(1-methylcyclobutaneamide) pyrrolidine-1-carboxylic acid tert-butyl ester and 10mL THF, and the mixture was cooled to -10°C. Then 0.33g (8.31mmol) sodium hydride (60%) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with NaHCO3 semi-concentrated solution and EtOAc, and stirred vigorously. The layers were separated and the H2O layer was extracted 2 times with EtOAc. The combined organic layers were dried on a phase separation column and the solvent was removed in vacuo. The crude product was purified by HPLC (ACN / H2O / NH4OH) to obtain an intermediate.

[0553] C 16 H 28 N2O3 (M=296.4g / mol)

[0554] ESI-MS: 241[M+H-tert-butyl] +

[0555] R t (HPLC): 0.98min (Method A)

[0556] To the above product was added 4 mL MeOH and 4 mL HCl (4 mol / L in dioxane) and the mixture was stirred at room temperature over the weekend. The solvent was removed in vacuo to give the product.

[0557] C 11 H 20 N2O*HCl (M=232.8g / mol)

[0558] ESI-MS: 197[M+H] +

[0559] R t (HPLC): 0.57min (Method A)

[0560] Example XXXIV

[0561] Example XXXIV.1 (General Approach)

[0562] 6-{[(1-Benzothiophen-3-yl)methyl]amino}pyridine-3-carboxylic acid methyl ester

[0563]

[0564] To a mixture of 0.78 g (5.00 mmol) of methyl 6-fluoropyridine-3-carboxylate and 10 mL of DMSO was added 2.58 mL (15.0 mmol) of DIPEA and 1.00 g (5.00 mmol) of 1-(1-benzothiophen-3-yl)methylamine hydrochloride, and the mixture was stirred overnight at 100° C. The reaction mixture was filtered and purified by HPLC (ACN / H2O / NH4OH). The fractions were combined, the organic solvent was removed in vacuo, the resulting precipitate was filtered out, washed with H2O, and dried in air to give a white solid.

[0565] C 16 H 14 N2O2S (M=298.4g / mol)

[0566] ESI-MS: 299[M+H] +

[0567] R t (HPLC): 1.00min (Method C)

[0568] Example XXXV

[0569] Example XXXV.1 (General Approach)

[0570] 6-{[(1-Benzothiophen-3-yl)methyl]amino}pyridine-3-carboxylic acid

[0571]

[0572] At 90°C, a mixture of 1.10 g (3.69 mmol) of 6-{[(1-benzothiophene-3-yl)methyl]amino}pyridine-3-carboxylic acid methyl ester and 10 mL of HCl (4 mol / L) was stirred for 1 h. A precipitate was produced, and the reaction mixture was diluted with 50 mL of THF and stirred for 2 h at 90°C. 10 mL of concentrated HCl was then added and the mixture was stirred for 5 h at 90°C. The solvent was removed in vacuo, and the residue was treated with toluene twice, also removing toluene in vacuo. The remaining yellow oil was dissolved in MeOH and purified by HPLC (ACN / H2O / HCOOH).

[0573] C 15 H 12 N2O2S (M=284.3g / mol)

[0574] ESI-MS: 285[M+H] +

[0575] R t (HPLC): 0.56min (Method C)

[0576] Example XXXVI

[0577] Example XXXVI.1 (General Approach)

[0578] (3S)-1-(6-Fluoropyridine-3-carbonyl)-N-methylpyrrolidin-3-amine trifluoroacetate

[0579]

[0580] To a solution of 2.84 g (14.2 mmol) of tert-butyl N-methyl-N-[(3S)-pyrrolidin-3-yl]carbamate and 9.86 mL (70.8 mmol) of TEA in 40 mL of DCM was added dropwise 2.26 g (14.2 mmol) of 2-fluoropyridine-5-carbonyl chloride (CAS No. 65352-94-5) dissolved in 30 mL of DCM at 0° C. After stirring at 0° C. for 10 min, the reaction mixture was filtered and purified by column chromatography (silica gel; DCM / MeOH, 99 / 1-90 / 10).

[0581] C 16 H 22 FN3O3 (M=323.4g / mol)

[0582] ESI-MS: 268[M+H-tert-butyl] +

[0583] R t (HPLC): 0.89min (Method C)

[0584] The above product was added to 25 mL DCM and 5 mL TFA solution and the mixture was stirred at room temperature over the weekend. The solvent was removed in vacuo to give the product.

[0585] C 11 H 14 FN3O*C2HF3O2 (M=337.3g / mol)

[0586] ESI-MS: 224[M+H] +

[0587] R t (HPLC): 0.61min (Method C)

[0588] Example XXXVII

[0589] Example XXXVII.1 (General Approach)

[0590] N-[(3S)-1-(6-Fluoropyridine-3-carbonyl)pyrrolidin-3-yl]-N-methylcyclopropanecarboxamide

[0591]

[0592] To a solution of 2.40 g (7.12 mmol) of (3S)-1-(6-fluoropyridine-3-carbonyl-N-methylpyrrolidin-3-amine trifluoroacetate and 10 mL of DCM in 40 mL of DCM was added dropwise 0.82 g (7.83 mmol) of cyclopropanecarbonyl chloride dissolved in 10 mL of DCM at 0°C. After stirring at 0°C for 10 min, the reaction mixture was washed with a mixture of saturated NaHCO3 solution and H2O (1 / 1), and with a saturated NaCl solution. The organic layer was dried over Na2SO4, filtered, and the solvent was removed in vacuo. The crude product was purified by HPLC (DCM / MeOH 99 / 1-90 / 10) to give the product.

[0593] C 15 H 18 FN3O2 (M=291.3g / mol)

[0594] ESI-MS: 292[M+H] +

[0595] R t (HPLC): 0.72min (Method A)

[0596] Example XXVIII

[0597] Example XXXVIII.1 (General Approach)

[0598] (3S)-3-Cyano-3-methylpyrrolidine-1-carboxylic acid tert-butyl ester

[0599] (3R)-3-Cyano-3-methylpyrrolidine-1-carboxylic acid tert-butyl ester

[0600]

[0601] The reaction was carried out under an Ar atmosphere. At -78 ° C, 15.1 mL (15.1 mmol) of LiHMDS was added to a mixture of 2.70 g (13.8 mmol) 3-cyanopyrrolidine-1-carboxylic acid tert-butyl ester and 40 mL of THF. After stirring at -78 ° C for 30 min, 1.28 mL (20.6 mmol) of iodomethane was added dropwise. The reaction mixture was stirred at -78 ° C for 30 min and stirred at room temperature for 30 min. The mixture was poured into a mixture of 100 mL of NH4Cl saturated aqueous solution and water (1: 1) and extracted twice with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and the solvent was evaporated. The crude product was purified by chiral SFC (method G).

[0602] *or**: The absolute stereochemistry of the chiral center was not determined for the enantiomerically pure compound.

[0603] Product A (first elution):

[0604] C 11 H 18 N2O2 (M=210.3g / mol)

[0605] Rt(HPLC): 2.58min(Method J)

[0606] Product B (secondary elution):

[0607] C 11 H 18 N2O2 (M=210.3g / mol)

[0608] Rt(HPLC): 3.65min(Method J)

[0609] Example XXXIX

[0610] Example XXXIX.1 (General Approach)

[0611] (3S)-3-Methylpyrrolidine-3-carbonitrile hydrochloride

[0612]

[0613] To a mixture of 1.25 g (5.95 mmol) of 3-cyano-methylpyrrolidine-1-carboxylic acid tert-butyl ester (Example XIII.1.A) in 10 mL of dioxane was added 2.97 mL (11.9 mmol) of HCl (4 M in dioxane), and the mixture was stirred at room temperature overnight. The resulting precipitate was filtered off, washed with dioxane, and dried in air.

[0614] C6H 10 N2*HCl (M=146.6g / mol)

[0615] ESI-MS: 111[M+H] +

[0616] R f (TLC): 0.3(SiO2,DCM / MeOH / NH3 9 / 1 / 0.1)

[0617] Example XXXX

[0618] Example XXXX.1 (General Approach)

[0619] 6-[({imidazo[1,5-a]pyridin-1-yl}methyl)amino]pyridine-3-carboxylic acid

[0620]

[0621] A mixture of 250 mg (1.77 mmol) of 6-fluoropyridine-3-carboxylic acid, 651 mg (3.54 mmol) of 1-{imidazo[1,5-a]pyridin-1-yl}methanamine hydrochloride, 980 mg (7.09 mmol) of potassium carbonate and 2 mL of DMSO was stirred at 150° C. overnight.

[0622] The reaction mixture was filtered and purified by HPLC (ACN / H2O / HCOOH).

[0623] C 14 H 12 N4O2 (M=268.3g / mol)

[0624] ESI-MS: 269[M+H] +

[0625] R t (HPLC): 0.3min (Method H)

[0626] The following compounds were prepared according to the general procedure described above (Example XXXX.1):

[0627]

[0628] Example XXXXI

[0629] Example XXXXI.1

[0630] N-(3-Cyano-4-methyl-2-nitrophenyl)acetamide

[0631]

[0632] To 65.0 g (XXX mmol) 5-amino-2-methylbenzonitrile was added 85 mL acetic anhydride (solution formed; exothermic reaction). Upon cooling, the product crystallized. Diethyl ether was added to the reaction mixture, the precipitate was filtered off and washed with diethyl ether to obtain a wet intermediate.

[0633] At -30 ° C, 85.0 g of the wet intermediate was added in batches to 300 mL of fuming HNO3. The reaction mixture was stirred for 5 min and then poured into ice water. The resulting precipitate was filtered off and washed with H2O. The solid was dried in air overnight and then recrystallized from EtOH.

[0634] C 10 H9N3O3 (M=219.2g / mol)

[0635] Example XXXXII

[0636] Example XXXXII.1

[0637] 2,6-Dimethyl-1H-1,3-benzodiazole-7-carbonitrile

[0638]

[0639] A mixture of 22 g (0.1 mol) N-(3-cyano-4-methyl-2-nitrophenyl)acetamide, 2 g Pd / C (10%) and 800 mL MeOH was treated with 5 bar H2 pressure at room temperature for X h. The mixture was filtered and the solvent was removed in vacuo to obtain the intermediate.

[0640] 18 g (0.10 mol) of the intermediate and 400 mL of MeOH (solution) were heated and HCl gas was bubbled into the reaction at reflux for 30 min. After cooling to room temperature, the resulting white precipitate was filtered off and washed with Et2O.

[0641] C 10 H9N3 (M=171.2g / mol)

[0642] Rf(TLC): 0.55(DCM / MeOH 9 / 1)

[0643] Example XXXXIII

[0644] Example XXXXIII.1

[0645] 1-(2,6-Dimethyl-1H-1,3-benzodiazol-7-yl)methanamine

[0646]

[0647] A mixture of 2.80 g (16.4 mmol) 2,6-dimethyl-1H-1,3-benzodiazole-7-carbonitrile, 1.00 g Raney nickel and 50 mL NH3 in MeOH was stirred at 50°C and 3 bar H2 pressure for X h. The reaction mixture was filtered and the solvent was removed in vacuo. The remaining crude product was triturated with Et2O and the product was filtered out as a white solid.

[0648] C 10 H 13 N3 (M=175.2g / mol)

[0649] Rf(TLC): 0.12(DCM / MeOH / NH3 9 / 1 / 0.1)

[0650] Preparation of final compounds

[0651] Example 1

[0652] Example 1.1 (General approach)

[0653] 3-[(3S)-1-{6-[({imidazo[1,2-a]pyridin-3-yl}methyl)amino]pyridine-3-carbonyl}pyrrolidine- 3-yl]-1,3-oxazolidin-2-one

[0654] To a mixture of 50.0 mg (0.16 mmol) of 6-[({imidazo[1,2-a]pyridin-3-yl}methyl)amino]pyridine-3-carboxylic acid hydrochloride (Example II.1) and 37.9 mg (0.20 mmol) of 3-[(3S)-pyrrolidin-3-yl]-1,3-oxazolidin-2-one hydrochloride (Example III.1) in 2 mL of DMF and 168 μL (0.98 mmol) of DIPEA was added 93.6 mg (0.25 mmol) of HATU, and the reaction mixture was stirred at room temperature for 10 min.

[0655] The crude was purified by HPLC (ACN / H2O / NH4OH) to give the product.

[0656] C 21 H 22 N6O3 (M=406.4g / mol)

[0657] ESI-MS: 407[M+H] +

[0658] R t (HPLC): 0.67min (Method C)

[0659] The following compounds were prepared according to the general procedure described above (Example 1.1):

[0660]

[0661]

[0662]

[0663] *The stereochemistry of chiral centers was not determined for enantiomerically and diastereomerically pure compounds.

[0664] Example 2

[0665] Example 2.1 (General Approach)

[0666] N-[(3S)-1-(6-{[(5-chloro-1H-indazol-3-yl)methyl]amino}pyridine-3-carbonyl)pyrrolidin-3-yl]-N-methylacetamide

[0667]

[0668] To a mixture of 26.5 mg (0.10 mmol) of N-[(3S)-1-(6-fluoropyridine-3-carbonyl)pyrrolidin-3-yl]-N-methylacetamide in 1 mL of DMSO was added 51.6 μL (0.30 mmol) of DIPEA and 21.8 mg (0.12 mmol) of (5-chloro-1H-indazol-3-yl)methanamine, and the reaction mixture was stirred overnight at 100° C. The crude product was purified by HPLC (ACN / H2O / TFA) to give the product.

[0669] C 21 H 23 ClN6O2 (M=426.9g / mol)

[0670] ESI-MS: 427[M+H] +

[0671] R t (HPLC): 0.44min (Method G)

[0672] The following compounds were prepared according to the general procedure described above (Example 2.1):

[0673]

[0674]

[0675] Example 3

[0676] Example 3.1 (General Approach)

[0677] N-[(3S)-1-(6-{[(1-benzothiophen-3-yl)methyl]amino}pyridine-3-carbonyl)pyrrolidin-3-yl]-N-methylacetamide

[0678]

[0679] To a mixture of 250 mg (0.94 mmol) of N-[(3S)-1-(6-fluoropyridine-3-carbonyl)pyrrolidin-3-yl]-N-methylacetamide in 10 mL of DMSO was added 486 μL (0.28 mmol) of DIPEA and 226 mg (0.11 mmol) of 1-(1-1-benzothiophen-3-yl)methylamine hydrochloride, and the reaction mixture was stirred overnight at 100° C. The mixture was filtered and purified by HPLC (ACN / H2O / NH4OH). After freezing, the product was repurified by column chromatography (silica gel; DCM / MeOH, 7 / 3). The solvent was removed in vacuo, and the remaining product was dissolved in dioxane and lyophilized.

[0680] C 22 H 24 N4O2S (M=408.5g / mol)

[0681] ESI-MS: 409[M+H] +

[0682] R t (HPLC): 0.86min (Method C)

[0683] Example 4

[0684] Example 4.1 (General Approach)

[0685] N-[(3S)-1-{6-[({imidazo[1,2-a]pyridin-3-yl}methyl)amino]pyridine-3-carbonyl}pyrrolidine- 3-Methyl]-N-methylcyclobutanecarboxamide

[0686]

[0687] To a mixture of 0.15 g (0.49 mmol) 6-[({imidazo 1,2-a]pyridin-3-yl}methyl)amino]pyridine-3-carboxylic acid hydrochloride, 0.16 g (0.74 mmol) N-methyl-N-[(3S)-pyrrolidin-3-yl]cyclobutanecarboxamide hydrochloride, 0.84 mL (0.49 mmol) DIPEA in 3 mL DMF was added 0.28 g (0.74 mmol) HATU, and the reaction mixture was stirred at room temperature for 5 minutes. The mixture was purified by HPLC (ACN / H2O / NH4OH). The organic solvent was removed in vacuo, and the remaining solution was diluted with a saturated solution of NaHCO3 and extracted twice with DCM. The combined organic layers were dried on a phase separation column and the solvent was removed in vacuo. The remaining crude product was purified by column chromatography (silica gel; DCM / EtOH, 98 / 2-80 / 20). The solvent was removed in vacuo to obtain the product.

[0688] C 24 H 28 N6O2 (M=432.5g / mol)

[0689] ESI-MS: 433[M+H] +

[0690] R t (HPLC): 0.78min (Method C)

[0691] Example 5

[0692] Example 5.1 (General Approach)

[0693] N-methyl-N-[(3S)-1-{6-[({thieno[3,2-c]pyridin-7-yl}methyl)amino]pyridine-3-carbonyl} Pyrrolidin-3-yl]acetamide

[0694]

[0695] To a mixture of 30.0 mg (0.11 mmol) of N-[(3S)-1-(6-fluoropyridine-3-carbonyl)pyrrolidin-3-yl]-N-methylacetamide in 1 mL of DMSO, 58.3 μL (0.34 mmol) of DIPEA and 20.4 mg (0.12 mmol) of 1-{thieno[3,2-c]pyridin-7-yl}methanamine were added, and the reaction mixture was stirred overnight at 120° C. The mixture was filtered and purified by HPLC (ACN / H2O / NH4OH) to give the product.

[0696] C 21 H 23 N5O2S (M=409.5g / mol)

[0697] ESI-MS: 410[M+H]+

[0698] R t (HPLC): 0.45min (Method D)

[0699] The following compounds were prepared according to the general procedure described above (Example 5.1):

[0700]

[0701]

[0702]

[0703]

[0704]

[0705]

[0706] Example 6

[0707] Example 6.1 (General Approach)

[0708] N-Methyl-N-[(3S)-1-(6-{[(6-methyl-1H-indazol-4-yl)methyl]amino}pyridine-3-carbonyl)pyrrole 3-Alkyl]acetamide

[0709]

[0710] The reaction was carried out under Ar atmosphere.

[0711] A mixture of 50.0 mg (0.11 mmol) of N-[(3S)-1-(6-{[(6-bromo-1H-indazol-4-yl)methyl]amino}pyridine-3-carbonyl)pyrrolidin-3-yl]-N-methylacetamide, 22.1 μL (0.16 mmol) of trimethyl-1,3,5,2,4,6-trioxatriborinane, 0.11 mL of Na2CO3 solution (2 mol / L) and 5 mL of dioxane was degassed and purged with argon. Then 4.33 mg (0.01 mmol) of Pd(dppf)Cl2 was added, and the reaction mixture was stirred at 100°C for 2 h.

[0712] The solvent was removed in vacuo, and the crude product was dissolved in EtOAc and filtered. The filtrate was washed with a saturated solution of NaCl, dried over Na2SO4, and the solvent was removed in vacuo. The crude product was dissolved in DMF and purified by HPLC (ACN / H2O / NH4OH) to obtain the product.

[0713] C 22 H26 N6O2 (M=406.5g / mol)

[0714] ESI-MS: 407[M+H] +

[0715] R t (HPLC): 0.48min (Method D)

[0716] Example 7

[0717] Example 7.1 (General Approach)

[0718] N-[(3S)-1-(6-{[(1S)-1-(1H-indazol-4-yl)ethyl]amino}pyridine-3-carbonyl)pyrrolidine-3- -3-yl]-N-methylacetamide

[0719]

[0720] A mixture of 50.0 mg (0.19 mmol) of N-[(3S)-1-(6-fluoropyridine-3-carbonyl)pyrrolidin-3-yl]-N-methylacetamide, 33.4 mg (0.21 mmol) of (1S)-1-(1H-indazol-4-yl)ethan-1-amine, 113 μL (1.00 mmol) of DIPEA and 2 mL of NMP was stirred in a sealed vial at 110° C. for 15 h. The mixture was filtered and purified twice by HPLC (ACN / H2O / NH4OH) to give the product.

[0721] C 22 H 26 N6O2 (M=406.5g / mol)

[0722] ESI-MS: 407[M+H] +

[0723] R t (HPLC): 0.47min (Method E)

[0724] Example 8

[0725] Example 8.1 (General Approach)

[0726] 3-[(3S)-1-(6-{[(1-benzothiophen-3-yl)methyl]amino}pyridine-3-carbonyl)pyrrolidin-3-yl]-1, 3-Oxazolidin-2-one

[0727]

[0728] To a mixture of 28.4 mg (0.10 mmol) of 6-{[(1-benzothiophen-3-yl)methyl]amino}pyridine-3-carboxylic acid, 19.3 mg (0.10 mmol) of 3-[(3S)-pyrrolidin-3-yl]-1,3-oxazolidin-2-one hydrochloride, 41.8 mg (0.11 mmol) of HATU and 1 mL of DMF was added 56.8 μL (0.33 mmol) of DIPEA, and the reaction mixture was stirred at room temperature overnight.

[0729] The mixture was filtered through Al2O3, washed with 0.5 mL DMF, and purified by HPLC (ACN / H2O / NH4OH) to give the product.

[0730] C 22 H 22 N4O3S (M=422.5g / mol)

[0731] ESI-MS: 423[M+H] +

[0732] R t (HPLC): 0.66min (Method D)

[0733] The following compounds were prepared according to the general procedure described above (Example 8.1):

[0734]

[0735] Example 9

[0736] Example 9.1 (General Approach)

[0737] N-[(3S)-1-(6-{[(1-benzothiophen-3-yl)methyl]amino}pyridine-3-carbonyl)pyrrolidin-3-yl]-N- Methylcyclobutanecarboxamide

[0738]

[0739] To a mixture of 28.4 mg (0.10 mmol) of 6-{[(1-benzothiophen-3-yl)methyl]amino}pyridine-3-carboxylic acid, 21.9 mg (0.10 mmol) of N-methyl-N-[(3S)-pyrrolidin-3-yl]cyclobutanecarboxamide hydrochloride, 56.8 μL (0.33 mmol) of DIPEA and 1 mL of DMF was added 41.8 mg (0.11 mmol) of HATU, and the reaction mixture was stirred at room temperature overnight.

[0740] The mixture was filtered through Al2O3, washed with 0.5 mL DMF, and purified by HPLC (ACN / H2O / TFA) to give the product.

[0741] C 22 H22 N4O3S (M=448.6g / mol)

[0742] ESI-MS: 449[M+H] +

[0743] R t (HPLC): 0.59min (Method F)

[0744] The following compounds were prepared according to the general procedure described above (Example 9.1):

[0745]

[0746] *The stereochemistry of chiral centers was not determined for enantiomerically and diastereomerically pure compounds.

[0747] HPLC analysis method

[0748] Method A

[0749]

[0750] Analytical column: Sunfire (Waters) 2.5 μm; 3.0 x 30 mm; column temperature: 60 °C

[0751] Method B

[0752]

[0753] Analytical column: Stable Bond (Agilent) 1.8 μm; 3.0 x 30 mm; column temperature: 60 °C

[0754] Method C

[0755]

[0756] Analytical column: XBridge C18 (Waters) 2.5 μm; 3.0 x 30 mm; column temperature: 60 °C

[0757] Method D

[0758]

[0759] Preparative column: XBridge (Waters) C18_3.0x 30mm_2.5μm

[0760] Method E

[0761]

[0762] XBridge C18_3.0x 30mm_2.5μm(Waters)

[0763] Method F

[0764]

[0765] Preparative column: Sunfire (Waters) C18_3.0x 30mm_2.5μm

[0766] Method G

[0767]

[0768] Preparative column: Sunfire (Waters) C18_3.0x 30mm_2.5μm

[0769] Method H

[0770]

[0771] Sunfire C18_3.0x 30mm_2.5μm(Waters)

[0772] Method I

[0773]

[0774] Cellulose SC_4.6x 250mm_5μm(Agilent)

[0775] Method J

[0776]

[0777] Cellulose SC_4.6x 250mm_5μm(YMC)

[0778] Description of biological properties

[0779] Vanin-1 enzymatic assay

[0780] The test compound is dissolved in 100% DMSO at a concentration of 10 mM and diluted in DMSO to a concentration of 5 mM in a first step, followed by serial dilutions in 100% DMSO. The dilution factor and the number of dilution steps can vary as required. Typically eight different concentrations of 1:5 dilutions are prepared, with further intermediate dilutions of the substance in assay buffer to give a final DMSO concentration of 1% in the assay.

[0781] 0.1 nM FLAG-tagged Vanin-1 (AA 22-493, T26I, produced in-house) and test compounds were incubated in assay buffer (1 mM DTT, 0.0025% Brij-35, 50 mM HEPES, pH 7.5) at room temperature for 20 min. D-pantethine (Sigma, catalog number P2125-5G) in assay buffer was added (final concentration 3 μM) and incubated for another 30 min at room temperature. The total assay volume was typically 40 μl, but can be adjusted as needed. The reaction was terminated by adding an equal volume of stop solution as the reaction mixture to achieve 100 nM HD-pantothenic acid (as internal standard) and 1% TFA. The assay plate was centrifuged for 2 minutes and the formation of pantothenic acid was detected by RapidFire mass spectrometry using a C18, 12 μL column (Agilent catalog number G9205A) (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).

[0782] The values ​​given in Table I are the results of measurements on one or more samples. If multiple measurements were made, the geometric mean is given.

[0783] Human whole blood assay: Pantethine (vanin) converts pantethine to pantothenic acid and cysteamine. Therefore, in the described protocol, vanin activity is quantitatively determined by the formation of pantothenic acid after pantethine supplementation with pantethine. This assay is suitable for identifying vanin inhibitors. Compound stocks are dissolved in DMSO at 10 mM. Further dilutions are performed in RPMI 1640 medium (Gibco, #A-10491-01) with a final concentration of 0.032 nM–500 nM in this assay.

[0784] Human blood was drawn into a blood bag (1% heparin, 50 I.E. / mL). The blood was aliquoted into 96 deep-well plates in 290 μL and mixed with 10 μL of compound solution or vehicle (centrifuged on a shaker at 1400 rpm for 30 seconds). Then equilibrated at room temperature and 250 rpm for 30 min. The assay was started by adding 10 μL of substrate solution (20 μM pantetheine in 1 mM DTT, 0.0025% Brij-35, 50 mM HEPES, pH 7.5) to each well, except for some blank wells to which only 10 mL of substrate buffer (1 mM DTT, 0.0025% Brij-35, 50 mM HEPES, pH 7.5) was added. The samples were shaken thoroughly (30 seconds, 1400 rpm) and reacted at room temperature and 250 rpm for 5 min. The reaction was terminated by adding an excess of vanin tool inhibitor (total concentration of BI-1 10 μM). The plate was centrifuged at 4°C, 665G for 10 min. The plasma sample (100 μL) was then transferred to another 96-deep well plate and the protein was precipitated by adding 100 μL of ice-cold precipitation solution (1 μM labeled pantothenic acid (di-β-alanine-13C6,15N2 calcium salt, Sigma, #705837)) in acetonitrile (5 min on ice). The plate was then centrifuged (4°C, 3220G, 10 min), and the supernatant (50 μL) was collected in another 96-deep well plate and mixed with 150 μL of ice-cold formic acid (0.1%, Carl Roth GmbH + Co. KG, #CP03.1) (10 sec, 1400 rpm). The formation of pantothenic acid was detected by RapidFire mass spectrometry. TripleQuad 6500+ (ABSciex, Germany) was equipped with LC-1290 system, RapidFire autosampler (Agilent, Germany) and C-type C18 column 12 μL (Agilent catalog number G9526-80000). Mobile phase A consisted of 0.09% formic acid and 0.01% trifluoroacetic acid in water, and mobile phase B consisted of 0.09% formic acid and 0.01% trifluoroacetic acid in acetonitrile / methanol / water (=47.5 / 47.5 / 5).

[0785] Synthesis of tool inhibitor BI-1:

[0786]

[0787] 5.40 g (28.8 mmol) of ketone 1 (synthesis described in Angew. Chem. Int. Ed. 2010, 49, 6856) and 12.9 g (34.6 mmol) of CeCl3*7H2O were added to 70 mL of MeOH. The reaction mixture was cooled to -15 °C and then 2.18 g (57.7 mmol) of NaBH4 was added in portions. The reaction mixture was stirred at 0 °C for 3 h. The reaction was quenched by adding saturated aqueous NH4Cl solution and extracted with EtOAc. The organic layers were combined, dried over Na2SO4, and the solvent was removed in vacuo.

[0788] A stirred solution of 6.29 g (52.8 mmol) of thionyl chloride in 50 mL of acetonitrile was cooled to -50 ° C, and a solution of 4 g (21.1 mmol) of the above product in ACN was added dropwise. After the addition was complete, 258 mg (2.11 mmol) of DMAP was added at once. The mixture was stirred for 15 min, keeping the temperature below -40 ° C, and then 8.36 g (106 mmol) of dry pyridine was added, keeping the external temperature at -40 ° C. Stirring was continued for 1 h. EtOAc was added, stirred for 5 min, a suspension (pyridinium salt) appeared, filtered and washed with EtOAc. 12 mL of saturated Na2HPO4 was slowly added to the filtrate. The resulting solution was stirred for 40 minutes. The two layers were separated. The organic layer was washed with 10 mL of 1 M NaHSO4 aqueous solution, dried with Na2SO4 and concentrated under reduced pressure. The crude compound was purified by column chromatography (silica gel, hexane solution containing 8% EtOAc).

[0789] C9H 17 NO4S (M=235.3g / mol)

[0790] ESI-MS: 258[M+Na] +

[0791] R f (TLC, silica gel) 0.4 (PE / EtOAc 3 / 1)

[0792] 1.36g (0.006mol) NaIO4 10mL H2O solution was added to 10,000mL EtOAc solution of 1.00g (0.004mol) of the above product, and then 44mg (0.2mmol) RuCl3 was added, and the mixture was stirred for 12h at 0 to 15°C. The mixture was quenched with H2O (20mL) and extracted with EtOAc. The organic phase was then washed with saline (20mL), dried with Na2SO4, filtered and concentrated to dryness. The residue was purified by column chromatography (silica gel, PE / EtOAc=10:1 to 3:1).

[0793] C9H 17NO5S (M=251.3g / mol)

[0794] ESI-MS: 252[M+H] +

[0795] R f (TLC, silica gel) 0.55 (PE / EtOAc 3 / 1)

[0796] 4.00 g (14.3 mmol) of 5-hydroxy-6-iodopyridine-3-carboxylic acid methyl ester was added to 40 mL of DMF. 602 mg (15.1 mmol) of sodium hydride was added thereto. After the gas was released, 5.40 g (21.5 mmol) was added and the reaction mixture was stirred at 75 ° C for 1.5 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc and rinsed with water. The organic matter was dried, filtered and evaporated.

[0797] The residue was purified by column chromatography (silica gel, 0-5% MeOH / CH2Cl2).

[0798] C 16 H 23 IN2O5 (M=450.3g / mol)

[0799] ESI-MS: 451[M+H] +

[0800] 5.00 g (11.1 mmol) of the above product was added to 50 mL MeOH and 10 mL CH2Cl2. To this was added 50 mL 4M HCl in dioxane. After 3 h, the volatiles were removed in vacuo and the residue was used without further purification.

[0801] 3.28 g (9.37 mmol) of the above product, 105 mg (0.47 mmol) of Pd(OAc)2, 0.33 g (0.56 mmol) of 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.33 g; 0.56 mmol; 6.00 mol%) and 9.16 g (28.1 mmol) of cesium carbonate were added to 100 mL of dioxane and the mixture was thoroughly degassed. The reaction mixture was stirred at 90°C under argon for 4 h. The solid was filtered through a short column and evaporated. The residue was purified by column chromatography (silica gel, 0-5% MeOH / CH2Cl2).

[0802] 1.50 g (6.75 mmol) of the above product was added to 5 mL MeOH and 70 mL water. 323 mg (13.5 mmol) LiOH was added and the reaction mixture was stirred at 50 °C for 1 h. The reaction was filtered and the MeOH was removed in vacuo. The aqueous layer was neutralized with 1 M HCl. The solid was filtered, dried and used without further purification.

[0803] C 10 H 12 N2O3 (M=208.2g / mol)

[0804] ESI-MS: 209[M+H] +

[0805] Rt(HPLC): 0.60min(Method A)

[0806] 915 mg (4.39 mmol) of the above product was dissolved in 20 mL of DMF. 0.86 g (4.83 mmol) of intermediate XVI and 1.84 mL (13.2 mmol) of TEA were added thereto, followed by 1.84 g (4.83 mmol) of HATU. The reaction mixture was stirred at room temperature for 16 h.

[0807] The volatiles were removed in vacuo and the residue was purified by column chromatography (Biotage KP-Nh cartridge, 0-10% MeOH / EtOAc).

[0808] C 17 H 24 N4O3 (M=332.4g / mol)

[0809] ESI-MS: 333[M+H] +

[0810] Rt(HPLC): 0.63min(Method A)

[0811] Other features and advantages of the present invention will become apparent from the following more detailed examples, which illustrate by way of example the principles of the invention.

[0812] Table I. Biological properties of the present invention

[0813]

[0814]

[0815]

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof, in R 1 Indicates that R 1.1 and R 1.2 Substituted naphthyl or R 1.1 and R 1.2 substituted 8-10 membered heteroaryl containing 1 to 3 heteroatoms selected from S, N and O, R 1.1 Selected from H, C 1-4 Alkyl, C 1-2 Alkyl-O-, CF3, C 3-5 Cycloalkyl, H2N-, Br, Cl and F; R 1.2 Selected from H, C 1-4 Alkyl, CF3, H2N-, Br, Cl and F; Among them, 1.1 and R 1.2 In the definition of R 2 and R 3 are independently selected from H and methyl, R 4 Represents R 4.1 R 4.2 N- or NC; or R 4 Expression R 4.a Group in, X represents CH2 or O; R 4.1 Selected from C 1-4 Alkyl-CO-, 6-membered heteroaryl containing 1-2 N atoms, and R 4.1.1 and R 4.1.2 Substituted C 3-5 Cycloalkyl-CO-, in R 4.1.1 , R 4.1.2 are independently selected from H, -CH3, F and -CN; R 4.2 Indicates H or C 1-3 alkyl, R 5 represents H or methyl; or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 Represents naphthyl, replaced by R 1.1 and R 1.2 substituted 8-10 membered heteroaryl containing 1 to 3 heteroatoms selected from N and S, or R 1.1 and R 1.2 Substituted 8-10 membered heteroaryl containing 1 to 3 heteroatoms selected from N and O.

3. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, R 1.1 Selected from H, methyl, H2N-, Br, Cl and F.

4. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R 1.2 is selected from H, methyl and Cl.

5. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R 2 represents H, and R 3 Represents methyl.

6. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 Indicates H.

7. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R 4 Represents R 4.1 R 4.2 N.

8. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R 4.1 Selected from CH3-CO-, R 4.1.1 and R 4.1.2 Substituted C 3-4 Cycloalkyl-CO-, in R 4.1.1 , R 4.1.2 are independently selected from H, -CH3, F and -CN; R 4.2 Represents methyl.

9. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R 5 Indicates H.

10. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 Represents naphthyl or R 1.1 and R 1.2 substituted 8-10 membered heteroaryl containing 1 to 3 heteroatoms selected from S, N and O, R 1.1 is selected from the group consisting of H, methyl, H2N-, Br, Cl and F; R 1.2 is selected from H, methyl and Cl; R 2 and R 3 independently of each other represent H or methyl; R 4 Represents R 4.1 R 4.2 N- or NC-; or R 4 Expression R 4.a Group in X represents CH2 or O; R 4.1 Selected from C 1-4 Alkyl-CO, R 4.1.1 and R 4.1.2 Substituted C 3-4 Cycloalkyl-CO-, in R 4.1.1 , R 4.1.2 are independently selected from H, -CH3, F and -CN; R 4.2 represents a methyl group; R 5 It represents H or methyl.

11. A compound of formula I according to claim 1 or 10, or a pharmaceutically acceptable salt thereof, selected from embodiments 2.1, 3.1, 4.1, 5.2, 5.3, 5.4, 5.7, 5.13, 5.14, 5.22, 5.24, 5.38 and 5.40:

12. A pharmaceutical composition comprising 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. Use of the compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof in the preparation of a VANIN-1 enzyme inhibitor.

14. Use of a compound according to any one of claims 1 to 11 in the preparation of a medicament for treating a patient suffering from Crohn's disease, ulcerative colitis, atopic dermatitis, systemic sclerosis, non-alcoholic steatohepatitis (NASH), psoriasis, chronic kidney disease, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, rheumatoid arthritis, scleroderma, asthma, allergic rhinitis, allergic eczema, juvenile rheumatoid arthritis, juvenile idiopathic arthritis, graft-versus-host disease, psoriatic arthritis, hyperlipidemia, colorectal cancer or pancreatic cancer-related new-onset diabetes.

15. A pharmaceutical composition further comprising, in addition to the compound of any one of claims 1 to 11, a pharmaceutically active compound selected from an immunomodulator, an anti-inflammatory drug or a chemotherapeutic drug.

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