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 Selected from H, by R 1.1 and R 1.3 Substituted phenyl, R 1.2 and R 1.5 substituted 5-6 membered heteroaryl containing 1 to 3 heteroatoms selected from S, N and O, replaced by R 1.4 a substituted 5-6 membered heterocyclic group containing 1 or 2 heteroatoms selected from S, N and O;

[0018] in

[0019] R 1.1 Selected from H, –CN, Br, Cl, F, C 1-4 Alkyl, C 3-5 Cycloalkyl, optionally C 1-3 Alkyl-substituted 5-membered heteroaryl, CF3, F3C-CH2, HF2C-, H2N-S(O)2-, H3C-NH-S(O)2-, (H3C)2N-S(O)2-, H3C-NH-CO-, C 1-4 Alkyl-O-, H3C-O-CO-, H2N-, (H3C)2N-, H2N-CO-, and H3C-CO-NH-;

[0020] R 1.2 Selected from H, –CN, Br, Cl, F, C 1-4 Alkyl, C 3-5 Cycloalkyl, CF3, F3C-CH2, HF2C-, H2N-S(O)2-, H3C-NH-S(O)2-, (H3C)2N-S(O)2-, H3C-NH-CO-, C 1-4 -alkyl-O-, H3C-O-CO-, H2N-, (H3C)2N-, H2N-CO- and H3C-CO-NH-;

[0021] Among them, 1.1 and R 1.2In the definition of , the alkyl group is optionally substituted by 1 to 3 F atoms;

[0022] R 1.3 Selected from H, Cl, F, CN, C 1-4 Alkyl and C 1-4 Alkyl-O-;

[0023] R 1.4 is selected from H, -CN, Br, Cl, F, and C optionally substituted by 1 to 3 F atoms 1-4 alkyl;

[0024] R 1.5 H or C 1-4 alkyl;

[0025] R 2 and R 3 are independently selected from H and C 1-3 alkyl;

[0026] or

[0027] R 2 and R 3 Together they form a 3- to 6-membered carbocyclic ring, a 4- to 6-membered heterocyclic ring containing 1 O atom or 1 N atom, or a 5- to 9-membered heteroaryl group containing 1 to 2 N atoms;

[0028] R 4 Represents R 4.1 R 4.2 N- or NC-;

[0029] or

[0030] R 4 Expression R 4.a Group

[0031]

[0032] Wherein X represents CH2 or O;

[0033] R 4.1 Selected from C 1-4 Alkyl-CO-, 6-membered heteroaryl containing 1 to 2 nitrogen atoms, R 4.1.1 and R 4.1.2 Substituted C 3-5 Cycloalkyl-CO-, optionally substituted by 1 to 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-,

[0034] in

[0035] R4.1.1 , R 4.1.2 are independently selected from H, -CH3, F and -CN;

[0036] R 4.2 Indicates H or C 1-3 alkyl;

[0037] R 5 represents H or methyl;

[0038] or

[0039] R 4 and R 5 together form a 4-6 membered heterocyclic group containing 1 to 2 heteroatoms selected from N and O,

[0040] or a pharmaceutically acceptable salt thereof.

[0041] Preferred Implementation

[0042] In another embodiment of the present invention, R 1 Indicates H.

[0043] In another embodiment of the present invention, R 1 Indicates that R 1.1 and R 1.3 Substituted phenyl.

[0044] In another embodiment of the present invention, R 1 It represents pyridyl.

[0045] In another embodiment of the present invention, R 1 Indicates that R 1.2 and R 1.5 Substituted 5-6 membered heteroaryl containing 1 to 3 heteroatoms selected from S, N and O.

[0046] In another embodiment of the present invention, R 1 Indicates that R 1.4 Substituted 5-6 membered heterocyclic group containing 1 or 2 heteroatoms selected from S, N and O.

[0047] In another embodiment of the present invention, R 1 Selected independently from each other by R 1.2 Substituted pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl, thienyl and pyridinyl.

[0048] In another embodiment of the present invention, R 1 Indicates that R 1.5 Substituted pyrazolyl.

[0049] In another embodiment of the present invention,

[0050] R 1 is selected from H, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl, thienyl, 1.1 and R 1.3 Substituted phenyl, R 1.2 Substituted pyridyl and R 1.5 Substituted pyrazolyl.

[0051] In another embodiment of the present invention,

[0052] R 1.1 A 5-membered heteroaryl group selected from H, -CN, Cl, F, CF3, HF2C-, H2N-S(O)2-, H3C-NH-S(O)2-, (H3C)2N-S(O)2-, H3C-NH-CO-, H3C-O-CO-, H2N-CO-, H3C-CO-NH-, and CF3, F3C-CH2 or HF2C-substituted with 1 to 3 heteroatoms selected from N and O;

[0053] R 1.2 is selected from the group consisting of H, -CN, methyl, Br, Cl, F, H3C-O-, CF3, H2N- and (H3C)2N-;

[0054] R 1.3 Indicates H or F;

[0055] R 1.4 represents H or F3C-CH2-;

[0056] and

[0057] R 1.5 It represents H, methyl or butyl.

[0058] In another embodiment of the present invention,

[0059] R 1.1 is selected from H, –CN, Cl, F, CF3, HF2C-, H2N-S(O)2-, H3C-NH-S(O)2-, (H3C)2N-S(O)2-, H3C-NH-CO-, H3C-O-CO-, H2N-CO-, H3C-CO-NH- and oxadiazolyl substituted with F3C-CH2-;

[0060] In another embodiment of the present invention,

[0061] R 1.2 is selected from H, -CN, methyl, Br, Cl, F, H3C-O-, CF3, H2N- and (H3C)2N-, preferably H;

[0062] In another embodiment of the present invention, R 1.3Indicates H or F;

[0063] In another embodiment of the present invention, R 1.4 represents H or F3C-CH2-;

[0064] In another embodiment of the present invention, R 1.5 It represents H, methyl or butyl.

[0065] In another embodiment of the present invention, R 2 Indicates H or C 1-2 alkyl.

[0066] In another embodiment of the present invention, R 2 Indicates H.

[0067] In another embodiment of the present invention, R 2 Represents methyl.

[0068] In another embodiment of the present invention, R 2 It represents ethyl.

[0069] In another embodiment of the present invention, R 3 Indicates H or C 1-2 alkyl.

[0070] In another embodiment of the present invention, R 3 Indicates H.

[0071] In another embodiment of the present invention, R 3 Represents methyl.

[0072] In another embodiment of the present invention, R 3 It represents ethyl.

[0073] In another embodiment of the present invention, R 2 and R 3 Indicates H.

[0074] In another embodiment of the present invention, R 2 and R 3 Represents methyl.

[0075] In another embodiment of the present invention, R 2 represents methyl and R 3 Indicates H.

[0076] In another embodiment of the present invention,

[0077] R 2 and R 3 Together they form C 3-4 Cycloalkyl or 8- to 9-membered heteroaryl containing 1 to 2 N atoms.

[0078] In another embodiment of the present invention, R 2 and R 3 Together they form a cyclopropyl group.

[0079] In another embodiment of the present invention, R 2 and R 3 Together they form a cyclobutyl group.

[0080] In another embodiment of the present invention, R 2 and R 3 Together they form an 8- to 9-membered heteroaryl group selected from the group consisting of formulae (a) to (c):

[0081]

[0082] In another embodiment of the present invention, R 4 Represents R 4.1 R 4.2 N or NC-.

[0083] In another embodiment of the present invention, R 4 Represents R 4.1 R 4.2 N.

[0084] In another embodiment of the present invention, R 4 Indicates NC-.

[0085] In another embodiment of the present invention, R 4 Expression R 4.a The group.

[0086]

[0087] In another embodiment of the present invention,

[0088] R 4.1 Selected from C 1-4 Alkyl-CO-, pyrimidinyl, R 4.1.1 and R 4.1.2 Substituted C 3-4 Cycloalkyl-CO-,

[0089] in

[0090] R 4.1.1 , R 4.1.2 are independently selected from H, -CH3, F and -CN;

[0091] and

[0092] R 4.2 It represents H or methyl.

[0093] In another embodiment of the present invention, R4.1 Represents C 1-4 Alkyl –CO-.

[0094] In another embodiment of the present invention, R 4.1 Represents H3C–CO-.

[0095] In another embodiment of the present invention, R 4.2 Indicates H.

[0096] In another embodiment of the present invention, R 4.2 Represents methyl.

[0097] In another embodiment of the present invention, R 4.1 represents H3C–CO- and R 4.2 Represents methyl.

[0098] In another embodiment of the present invention, R 4.1 Represents a pyrimidinyl group.

[0099] 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-.

[0100] In another embodiment of the present invention, R 4.1.1 is selected from H, CH3, F and –CN;

[0101] In another embodiment of the present invention, R 4.1.1 Indicates H.

[0102] In another embodiment of the present invention, R 4.1.2 Indicates H or F;

[0103] In another embodiment of the present invention, R 4.1.2 Indicates H.

[0104] In another embodiment of the present invention, R 5 It represents H or methyl.

[0105] In another embodiment of the present invention, R 5 Indicates H.

[0106] In another embodiment of the present invention, R 5 Represents methyl.

[0107] In another embodiment of the present invention, R 4 Represents R 4.1 R 4.2 N, R 4.1 Represents C 1-4Alkyl –CO-, and R 5 Indicates H.

[0108] Another embodiment of the invention is a compound of formula I, wherein

[0109] in

[0110] R 1 Selected from H, by R 1.1 and R 1.3 Substituted phenyl, R 1.2 and R 1.5 substituted 5-6 membered heteroaryl containing 1 to 3 heteroatoms selected from S, N and O, replaced by R 1.4 a substituted 5-6 membered heterocyclic group containing 1 or 2 heteroatoms selected from S, N and O;

[0111] in

[0112] R 1.1 Selected from H, –CN, Br, Cl, F, C 1-4 Alkyl, CF3, F3C-CH2, HF2C-, H2N-S(O)2-, H3C-NH-S(O)2-, (H3C)2N-S(O)2-, H3C-NH-CO-, H3C-O-, H3C-O-CO-, H2N-, (H3C)2N-, H2N-CO-, H3C-CO-NH- and 5-membered heteroaryl containing 1 to 3 heteroatoms selected from N and O which is optionally substituted with CF3, F3C-CH2 or HF2C-;

[0113] R 1.2 Selected from H, –CN, Br, Cl, F, C 1-4 Alkyl, CF3, F3C-CH2, HF2C-, H2N-S(O)2-, H3C-NH-S(O)2-, (H3C)2N-S(O)2-, H3C-NH-CO-, H3C-O-, H3C-O-CO-, H2N-, (H3C)2N-, H2N-CO- and H3C-CO-NH-;

[0114] R 1.3 Indicates H or F;

[0115] R 1.4 Selected from H, –CN, Br, Cl, F, C 1-4 Alkyl, CF3, F3C-CH2, HF2C-, H2N-S(O)2-, H3C-NH-S(O)2-, (H3C)2N-S(O)2-, H3C-NH-CO-, H3C-O-, H3C-O-CO-, H2N-, (H3C)2N-, H2N-CO- and H3C-CO-NH-;

[0116] R 1.5 H or C 1-4 alkyl,

[0117] R 2 and R 3 are independently selected from H and C 1-3 alkyl,

[0118] or

[0119] R 2 and R 3 Together they form a 3-6 membered carbocyclic ring or a 5-9 membered heteroaryl group containing 1 to 2 N atoms;

[0120] R 4 Represents R 4.1 R 4.2 N- or NC-;

[0121] or

[0122] R 4 Expression R 4.a Group

[0123]

[0124] in

[0125] X represents CH2 or O;

[0126] R 4.1 Selected from C 1-4 Alkyl-CO-, 6-membered heteroaryl containing 1 to 2 nitrogen atoms, R 4.1.1 and R 4.1.2 Substituted C 3-4 Cycloalkyl-CO-,

[0127] in

[0128] R 4.1.1 , R 4.1.2 are independently selected from H, -CH3, F and -CN;

[0129] R 4.2 represents H or methyl,

[0130] R 5 represents H or methyl;

[0131] or

[0132] R 4 and R 5 Together they form a 5-6 membered heterocyclic group containing 1 to 2 heteroatoms selected from N and O.

[0133] Another embodiment of the present invention is a compound of formula I or a pharmaceutically acceptable salt thereof, wherein

[0134] R 1 is selected from H, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl, thienyl, 1.1 and R 1.3 Substituted phenyl, R 1.2 Substituted pyridyl and R 1.5 Substituted pyrazolyl;

[0135] in

[0136] R 1.1 is selected from H, -CN, Cl, F, CF3, HF2C-, H2N-S(O)2-, H3C-NH-S(O)2-, (H3C)2N-S(O)2-, H3C-NH-CO-, H3C-O-CO-, H2N-CO-, H3C-CO-NH- and oxadiazolyl optionally substituted with CF3, F3C-CH2 and HF2C-;

[0137] R 1.2 is selected from the group consisting of H, -CN, methyl, Br, Cl, F, H3C-O-, CF3, H2N- and (H3C)2N-;

[0138] R 1.3 Indicates H or F;

[0139] R 1.4 represents H or F3C-CH2-;

[0140] R 1.5 represents H, methyl or butyl;

[0141] R 2 and R 3 are independently selected from H and C 1-2 alkyl,

[0142] or

[0143] R 2 and R 3 Together they form C 3-4 Cycloalkyl or 8- to 9-membered heteroaryl containing 1 to 2 N atoms;

[0144] R 4 Represents R 4.1 R 4.2 N- or NC-;

[0145] or R 4 Expression R 4 . a Group

[0146]

[0147] in

[0148] X represents CH2 or O;

[0149] R 4.1 Selected from C 1-4 Alkyl-CO-, pyrimidinyl, R 4.1.1 and R 4.1.2 Substituted C 3-4 Cycloalkyl-CO-,

[0150] in

[0151] R 4.1.1 , R 4.1.2 are independently selected from H, -CH3, F and -CN;

[0152] R 4.2 represents H or methyl;

[0153] R 5 represents H or methyl;

[0154] or

[0155] R 4 and R 5 Together they form an oxalyl group.

[0156] R 1 , R 2 , R 3 , R 4 , R 5 , R 4.1 , R 4 .. 2 , R 4.1.1 , R 4.1.2 , R 1.1 , R 1.2 , R 1.3 , R 1.4 , R 1.5 Any and every one of the definitions of and X can be combined with each other.

[0157] In a preferred embodiment of the invention, the compound of formula I is selected from Examples 1.11, 1.28, 1.44, 2.2, 2.3, 3.2, 4.1, 4.3, 7.1, 9.3, 9.4 and 9.6,

[0158]

[0159] *The stereochemistry of chiral centers was not determined for enantiomerically and diastereomerically pure compounds.

[0160] or a pharmaceutically acceptable salt thereof.

[0161] Another preferred embodiment of the invention are compounds of formula I above, selected from Examples 1.11, 1.28, 1.44, 2.2, 2.3, 3.2, 4.1, 4.3, 7.1, 9.3, 9.4 and 9.6.

[0162] Another preferred embodiment of the invention is a compound of formula I above, which is selected from Examples 1.11, 1.28, 1.44, 2.2, 2.3, 4.1, 7.1, 9.3, 9.4 and 9.6.

[0163] Another preferred embodiment of the invention is the compound of Example 1.11.

[0164] Another preferred embodiment of the invention is the compound of Example 1.28.

[0165] Another preferred embodiment of the invention is the compound of Example 1.44.

[0166] Another preferred embodiment of the invention is the compound of Example 2.2.

[0167] Another preferred embodiment of the invention is the compound of Example 2.3.

[0168] Another preferred embodiment of the invention is the compound of Example 3.2.

[0169] Another preferred embodiment of the invention is the compound of Example 4.1.

[0170] Another preferred embodiment of the invention is the compound of Example 4.3.

[0171] Another preferred embodiment of the invention is the compound of Example 7.1.

[0172] Another preferred embodiment of the invention is the compound of Example 9.3.

[0173] Another preferred embodiment of the invention is the compound of Example 9.4.

[0174] Another preferred embodiment of the invention is the compound of Example 9.6.

[0175] Another preferred embodiment of the invention is a pharmaceutically acceptable salt of a compound of formula I as defined above, wherein the compound of formula I is selected from Examples 1.11, 1.28, 1.44, 2.2, 2.3, 3.2, 4.1, 4.3, 7.1, 9.3, 9.4 and 9.6.

[0176] Another preferred embodiment of the present invention is a pharmaceutically acceptable salt of a compound of formula I as defined above, wherein the compound of formula I is selected from Examples 1.11, 1.28, 1.44, 2.2, 2.3, 4.1, 7.1, 9.3, 9.4 and 9.6.

[0177] Another preferred embodiment of the present invention is a pharmaceutically acceptable salt of the compound of Example 1.11.

[0178] Another preferred embodiment of the present invention is a pharmaceutically acceptable salt of the compound of Example 1.28.

[0179] Another preferred embodiment of the present invention is a pharmaceutically acceptable salt of the compound of Example 1.44.

[0180] Another preferred embodiment of the present invention is a pharmaceutically acceptable salt of the compound of Example 2.2.

[0181] Another preferred embodiment of the present invention is a pharmaceutically acceptable salt of the compound of Example 2.3.

[0182] Another preferred embodiment of the present invention is a pharmaceutically acceptable salt of the compound of Example 4.1.

[0183] Another preferred embodiment of the present invention is a pharmaceutically acceptable salt of the compound of Example 7.1.

[0184] Another preferred embodiment of the present invention is a pharmaceutically acceptable salt of the compound of Example 9.3.

[0185] Another preferred embodiment of the present invention is a pharmaceutically acceptable salt of the compound of Example 9.4.

[0186] Another preferred embodiment of the present invention is a pharmaceutically acceptable salt of the compound of Example 9.6.

[0187] 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.

[0188] Another embodiment of the invention is a compound of formula I or a pharmaceutically acceptable salt thereof for use as a medicament.

[0189] 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.

[0190] 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).

[0191] 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.

[0192] 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.

[0193] Another embodiment of the invention is the use of a compound of formula I for treating patients with moderate to severe Crohn's disease.

[0194] Another embodiment of the invention is the use of a compound of formula I for treating patients suffering from ulcerative colitis.

[0195] Another embodiment of the invention is the use of a compound of formula I for treating a patient suffering from atopic dermatitis.

[0196] Another embodiment of the invention is the use of a compound of formula I for treating NASH patients.

[0197] 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.

[0198] 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.

[0199] 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.

[0200] 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.

[0201] 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.

[0202] 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.

[0203] 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.

[0204] Another embodiment of the invention is a compound of formula IA or a pharmaceutically acceptable salt thereof.

[0205]

[0206] Another embodiment of the present invention is a compound of formula IB or a pharmaceutically acceptable salt thereof.

[0207]

[0208] Another embodiment of the present invention is a compound of formula IC or a pharmaceutically acceptable salt thereof.

[0209] definition

[0210] 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.

[0211] 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 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.

[0212] 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.

[0213] The numbering of substituent atoms begins with the atom closest to the core or group to which the substituent is attached.

[0214] For example, the term "3-carboxypropyl" represents the following substituents:

[0215]

[0216] 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:

[0217]

[0218] Asterisks may be used in subformulae to indicate bonds to the defined core molecule.

[0219] 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.

[0220] 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).

[0221] 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.

[0222] 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).

[0223] 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.

[0224] 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.

[0225] 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.

[0226] 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.

[0227] 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.

[0228] 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.

[0229] 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.

[0230] The term halogen generally refers to fluorine, chlorine, bromine and iodine.

[0231] 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)-.

[0232] 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.

[0233] 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.

[0234]

[0235] 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.

[0236] 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.

[0237] 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:

[0238]

[0239]

[0240]

[0241] 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.

[0242] 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:

[0243]

[0244]

[0245] 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.

[0246] 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.

[0247] 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).

[0248] 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.

[0249] The features and advantages of the present invention will be apparent from the following detailed examples, which are provided by way of example to illustrate the basic principles of the present invention without limiting the scope thereof:

[0250] Preparation of the compounds of the present invention

[0251] General Synthesis Methods

[0252] 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.

[0253] 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.

[0254] 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.

[0255] Compounds of formula (I) can be prepared as shown in Scheme I below.

[0256] Route I:

[0257]

[0258] 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).

[0259] Alternatively, the compound of formula (I) can also be prepared as shown in the following Scheme II.

[0260] Route II:

[0261]

[0262] In Scheme II, the acid chloride A (Y=Cl) is treated with an appropriate heterocycle to give the pyridine B. Alternatively, the carboxylic acid (Y=OH) is treated with an appropriate heterocycle in the presence of a coupling agent such as TBTU or HATU to give the pyridine B. The leaving group (LG) in the pyridine B can be displaced with an appropriate primary amine at elevated temperature to give compounds of general formula (I).

[0263] The heterocyclic 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:

[0264] Route III:

[0265]

[0266] 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.

[0267] Further options for generating these desired amines are shown below in Scheme IV:

[0268] Route IV:

[0269]

[0270] In route IV, nitrile A is treated with an alkylating agent under basic conditions to give nitrile B, which is subsequently deprotected (eg, using HCl or TFA when PG=BOC) to give amine C.

[0271] Compounds of formula (II) can be prepared as shown in Scheme V below.

[0272] Route V:

[0273]

[0274] In route V, ketone or aldehyde A is reacted with a suitable auxiliary (e.g., alkylsulfenamide) to form compound B. Reduction of the imine with a borohydride reagent affords intermediate C. After deprotection (e.g., with HCl) to afford amine D, compounds of formula (II) are obtained.

[0275] Experimental Section

[0276] The features and advantages of the present invention will become apparent from the following detailed examples which are presented to illustrate the basic principles of the invention by way of example without limiting the scope thereof.

[0277] The terms "ambient temperature" and "room temperature" are used interchangeably and designate a temperature of about 20°C, such as 19 to 24°C.

[0278] Abbreviations:

[0279]

[0280]

[0281] Preparation of starting compounds

[0282] Embodiment 1

[0283] Example I.1

[0284] N-[(3S)-1-(6-Fluoropyridine-3-carbonyl)pyrrolidin-3-yl]-N-methylacetamide

[0285]

[0286] 4.00 g (22.38 mmol) of N-methyl-N-[(3S)-pyrrolidin-3-yl]acetamide (CAS No. 1215264-39-3) and 14.83 mL (106.55 mmol) of TEA were diluted with 30 mL of DCM and cooled in an ice bath. 3.40 g (21.31 mmol) of 2-fluoropyridine-5-carbonyl chloride (CAS No. 65352-94-5) dissolved in 5 mL of DCM were added to the mixture. The reaction mixture was stirred at 0 ° C for 10 min. The precipitate was filtered and the filtrate was purified by column chromatography (silica gel; DCM / MeOH) to obtain the product.

[0287] C 13 H 16 FN3O2 (M=265.28g / mol)

[0288] ESI-MS: 266[M+H] +

[0289] R t (HPLC): 0.63min (Method A)

[0290] Example II

[0291] Example II.1

[0292] (3S)-1-(6-Fluoropyridine-3-carbonyl)-N-methylpyrrolidin-3-amine hydrochloride

[0293]

[0294] 1.00 g (7.09 mmol) 6-fluoronicotinic acid (CAS No. 403-45-2), 1.56 g (7.80 mmol) (S)-3-(N-BOC-N-methylamino)pyrrolidine (CAS No. 169750-01-0), 2.62 g (8.15 mmol) TBTU and 1.84 mL (10.63 mmol) DIPEA were diluted with 7 mL DMF and stirred at room temperature. The reaction mixture was treated with water and saturated NaHCO and the aqueous layer was extracted 3 times with EtOAc. The combined organic phases were dried over MgSO, filtered and concentrated in vacuo.

[0295] The crude product was diluted with 20 mL of 1,4-dioxane, and 10 mL of hydrogen chloride (4N in 1,4-dioxane) was added, and the reaction mixture was stirred at room temperature for 3 h. The solvent was evaporated under reduced pressure to obtain the product.

[0296] C 11 H 14 FN3O*HCl (M=259.71g / mol)

[0297] ESI-MS: 224[M+H] +

[0298] R t (HPLC): 0.60min (Method C)

[0299] Example III

[0300] Example III.1

[0301] N-[(3S)-1-(6-Fluoropyridine-3-carbonyl)pyrrolidin-3-yl]-N-methylcyclopropane-carboxamide

[0302]

[0303] 50 mg (0.58 mmol) cyclopropanecarboxylic acid (CAS No. 1759-53-1), 181 mg (0.70 mmol) N-[(3S)-1-(6-fluoropyridine-3-carbonyl)pyrrolidin-3-yl]-N-methylcyclopropane-carboxamide (Example II.1), 214 mg (0.67 mmol) TBTU and 0.30 mL (1.74 mmol) DIPEA were diluted with 4 mL DMF and stirred at room temperature for 2 h. The reaction mixture was filtered through a microplate syringe filter and purified by HPLC (ACN / H2O / NH4OH) to obtain the product.

[0304] C 15 H 18 FN3O2 (M=291.32)

[0305] ESI-MS: 292[M+H] +

[0306] R t (HPLC) 0.71min (Method C)

[0307] The following compounds were prepared according to the general procedure described above (Example III):

[0308]

[0309] Example IV

[0310] Example IV.1

[0311] 6-{[(Pyridin-3-yl)methyl]amino}pyridine-3-carboxylic acid methyl ester

[0312]

[0313] A mixture of 500 mg (3.22 mmol) of methyl 6-fluoronicotinate (CAS No. 1427-06-1), 349 mg (3.22 mmol) of 3-pyridinemethylamine (CAS No. 3731-52-0) and 2.21 mL (12.89 mmol) of DIPEA in 5 mL of DMSO was stirred at 120 ° C. for 6 h, then filtered through a microplate syringe filter and purified by HPLC (ACN / H2O / NH4OH) to give the product.

[0314] C 13 H 13 N3O2 (M=243.26)

[0315] ESI-MS: 244[M+H] +

[0316] R t (HPLC) 0.74min (Method C)

[0317] Example V

[0318] Example V.1

[0319] 6-{[(Pyridin-3-yl)methyl]amino}pyridine-3-carboxylic acid hydrochloride

[0320]

[0321] 1.6 g (6.58 mmol) of methyl 6-{[(pyridin-3-yl)methyl]amino}pyridine-3-carboxylate (Example Iv.1) and 30.0 mL (180 mmol) of 6N hydrogen chloride were stirred at 95°C for 3 h. The solvent was evaporated under reduced pressure. The residue was co-evaporated once with 30 mL of toluene and once with 40 mL of ACN, and then 30 mL of ACN was added. The solid was filtered, washed with 30 mL of ACN, and dried under reduced pressure at 50°C for 3 h to obtain the product.

[0322] C 12 H 11 N3O2*HCl (M=265.70)

[0323] ESI-MS: 230[M+H] +

[0324] R t (HPLC) 0.15min (Method C)

[0325] Example VI

[0326] Example V.1

[0327] N-Methyl-N-[(3S)-pyrrolidin-3-yl]cyclobutanecarboxamide hydrochloride

[0328]

[0329] A mixture of 1.00 g (4.22 mmol) of (3S)-3-(methylamino)pyrrolidine-1-carboxylic acid tert-butyl ester hydrochloride (CAS No. 1004538-30-0) and 2.94 mL (21.12 mmol) of TEA in 25 mL of DCM was cooled in an ice bath, and 0.53 mL (4.65 mmol) of cyclobutanecarbonyl chloride (CAS No. 5006-22-4) was added dropwise over 10 min. The precipitate was filtered. The filtrate was diluted with DCM, washed with NH4Cl saturated aqueous solution, then washed with NaHCO3 saturated aqueous solution and brine, dried with Na2SO4, and concentrated in vacuo to obtain the BOC protected product.

[0330] C 15 H 20 N2O2 (M=282.38g / mol)

[0331] ESI-MS: 227[M-tBu+H] +

[0332] R t (HPLC): 0.94min (Method C)

[0333] The above product was dissolved in 3 mL of MeOH and 3 mL (12.00 mmol) of 4N hydrogen chloride in 1,4-dioxane was added. The reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuo to obtain the product.

[0334] C 10 H 18 N2O*HCl (M=218.72g / mol)

[0335] ESI-MS: 183[M+H] +

[0336] R t (HPLC): 0.68min (Method C)

[0337] The following compounds were prepared according to the general procedure described above (Example VI.1):

[0338]

[0339] Example VII

[0340] Example VII.1

[0341] 6-{[(4-Chlorophenyl)methyl]amino}pyridine-3-carboxylic acid

[0342]

[0343] A mixture of 400 mg (2.58 mmol) of methyl 6-fluoronicotinate (CAS No. 1427-06-1), 627 μL (5.16 mmol) of 4-chlorobenzylamine (CAS No. 104-86-9), and 2.21 mL (10 mmol) of DIPEA in 3 mL of DMSO was stirred at 120° C. for 2 h. After the reaction was complete, the mixture was diluted with MeOH (2 mL), filtered through a microplate syringe filter, and purified by HPLC to obtain the desired product.

[0344] C 14 H 13 ClN2O2 (M=276.72g / mol)

[0345] ESI-MS: 277[M+H] +

[0346] R t (HPLC): 0.81min (Method C)

[0347] The above product was diluted with 4 mL of hydrogen chloride solution (1:1 concentrated HCl / H2O) and stirred at 100°C for 2 h, and the solvent was removed in vacuo to obtain the product.

[0348] C 13 H 11 ClN2O2 (M=262.69g / mol)

[0349] ESI-MS: 263[M+H] +

[0350] R t (HPLC): 0.73min (Method A)

[0351] The following compounds were prepared according to the general procedure described above (Example VII.1):

[0352]

[0353] Example VIII

[0354] Example VIII.1

[0355] 3,3-Difluoro-N-methyl-N-[(3S)-pyrrolidin-3-yl]cyclobutane-1-carboxamide hydrochloride

[0356]

[0357] 1.99 g (5.24 mmol) HATU was added to a mixture containing 1.00 g (4.99 mmol) (3S)-3-(methylamino)pyrrolidine-1-carboxylic acid tert-butyl ester (CAS No. 147081-59-2), 0.75 g (5.24 mmol) 3,3-difluorocyclobutanecarboxylic acid (CAS No. 107496-54-8) and 1.72 mL (9.99 mmol) DIPEA dissolved in 10 mL THF. The reaction mixture was stirred overnight at room temperature, then concentrated in vacuo and the residue was taken up with EtOAc. The organic phase was washed with citric acid (20%) and a saturated aqueous solution of NaHCO3, dried over Na2SO4 and the solvent was evaporated under reduced pressure. The crude material was treated with 50 mL hydrogen chloride (1.25 M in EtOH) and the reaction mixture was stirred at room temperature for 2 h. The mixture was evaporated in vacuo and the residue was co-evaporated with isopropanol to obtain the product.

[0358] C 10 H 16 F2N2O2*HCl (M=254.70g / mol)

[0359] ESI-MS: 219[M+H] +

[0360] R t (HPLC): 0.45min (Method B)

[0361] Example IX

[0362] Example IX.1.A and Example IX.1.B

[0363] (3R)-3-Cyano-3-methylpyrrolidine-1-carboxylic acid tert-butyl ester

[0364] (3S)-3-Cyano-3-methylpyrrolidine-1-carboxylic acid tert-butyl ester

[0365]

[0366] At -78 ° C, 15.1 mL (15.1 mmol) of LiHMDS was added to a mixture of 2.70 g (13.8 mmol) of tert-butyl 3-cyanopyrrolidine-1-carboxylate (CAS No. 122684-34-8) 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 at room temperature for 30 min. The mixture was poured into a mixture of 100 mL of saturated aqueous NH4Cl 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. By chiral SFC ( The crude product was purified by Cellulose-SC_20x250mm_5μm; scCO2 / 2-propanol+20mM NH3 95:5) to give two enantiomers. The absolute stereochemistry of the chiral centers of the enantiomerically pure compounds was not determined.

[0367] Product IX.1.A (first elution):

[0368] C 11 H 18 N2O2 (M=210.27g / mol)

[0369] Rt(HPLC): 2.58min(Method F)

[0370] Product IX.1.B (secondary elution):

[0371] C 11 H 18 N2O2 (M=210.27g / mol)

[0372] Rt(HPLC): 3.65min(Method F)

[0373] Example X

[0374] Example X.1

[0375] (3S or 3R)-3-Methylpyrrolidine-3-carbonitrile hydrochloride

[0376]

[0377] To a mixture of 1.25 g (5.95 mmol) or pure enantiomer 3-cyano-methylpyrrolidine-1-carboxylic acid tert-butyl ester (Example IX.1.A) in 10 mL 1,4-dioxane was added 2.97 mL (11.9 mmol) HCl (4M in 1,4-dioxane) and the mixture was stirred at room temperature overnight. The resulting precipitate was filtered off, washed with 1,4-dioxane and dried in the open air.

[0378] C6H 10 N2*HCl (M=146.62g / mol)

[0379] ESI-MS: 111[M+H] +

[0380] R f (TLC): 0.3(SiO2,DCM / MeOH / NH3 9 / 1 / 0.1)

[0381] The following compounds were prepared according to the general procedure described above (Example X.1):

[0382]

[0383] *The stereochemistry of the chiral centers was not determined for the enantiomerically pure compounds.

[0384] Example XI

[0385] Example XI.1

[0386] 6-[(2-Phenylpropan-2-yl)amino]pyridine-3-carboxylic acid

[0387]

[0388] 100 mg (0.71 mmol) of 6-fluoropyridine-3-carboxylic acid (CAS No. 403-45-2) and 383 mg (2.83 mmol) of cumylamine (CAS No. 585-32-0) were diluted with 2 mL of NMP and stirred at 150° C. for 12 h. The reaction mixture was acidified with 4N aqueous hydrogen chloride solution and purified by HPLC to obtain the product.

[0389] C 15 H 16 N2O2 (M=256.30g / mol)

[0390] ESI-MS: 257[M+H] +

[0391] R t (HPLC): 0.71min (Method A)

[0392] The following compounds were prepared according to the general procedure described above (Example XI1):

[0393]

[0394]

[0395] Example XII

[0396] Example XII.1

[0397] (3'S)-[1,3'-Bispyrrolidino]-2-one hydrochloride

[0398]

[0399] 2.00 g (10.74 mmol) of (3S)-3-aminopyrrolidine-1-carboxylic acid tert-butyl ester (CAS No. 147081-44-5) was diluted with 20 mL of DCM and 4 mL of sodium hydroxide (50% aqueous solution) and cooled to 0°C. 1.09 mL (9.66 mmol) of 4-chlorobutyryl chloride (CAS No. 4635-59-0) was dissolved in 10 mL of DCM and added dropwise to the reaction mixture. The reaction mixture was stirred at 0°C for 1 h. 3.48 g (5.37 mmol) of TBAOH (40% MeOH solution) was added to the mixture. The reaction mixture was stirred at room temperature overnight, diluted with water, and the aqueous layer was extracted 3 times with DCM. The combined organic phases were dried over PTK and evaporated under reduced pressure. The crude product was purified by column chromatography (silica gel; cyclohexane / EtOAc, 15%-100%) to obtain the desired intermediate.

[0400] C 13 H 22 N2O3 (M=254.33g / mol)

[0401] ESI-MS: 255[M+H] +

[0402] R t (HPLC): 0.83min (Method C)

[0403] The above intermediate was dissolved with 2.5 mL of 1,4-dioxane and 5.0 mL (20 mmol) of hydrogen chloride (4N in 1,4-dioxane) was added. Some MeOH was also added to dissolve the reaction mixture, which was then stirred at room temperature overnight and concentrated to dryness in vacuo to obtain the product.

[0404] 8H 14 N2O*HCl (M=190.67g / mol)

[0405] ESI-MS: 155[M+H] +

[0406] R t (HPLC): 0.27min (Method C)

[0407] The following compounds were prepared according to the general procedure described above (Example XII.1):

[0408]

[0409] Example XIII

[0410] Example XIII.1

[0411] (3S)-3-(1-Methylcyclobutaneamido)pyrrolidine-1-carboxylic acid tert-butyl ester

[0412]

[0413] 0.55g (4.83mmol) 1-methylcyclobutane-1-carboxylic acid (CAS No.147081-44-5) was diluted with 7.5mL DMF, and 2.08mL (12.08mmol) DIPEA and 1.94g (6.04mmol) TBTU were added. After stirring at room temperature for 30min, 0.75g (4.03mmol) (3S)-3-aminopyrrolidine-1-carboxylic acid tert-butyl ester (CAS No.147081-44-5) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc, and the NaHCO aqueous solution was washed once, and the NH4Cl saturated aqueous solution was washed once, and the salt solution was washed twice. Na2SO4 was used for drying the organic phase, and the solvent was evaporated under reduced pressure to obtain the product.

[0414] C 15 H 26 N2O3 (M=282.38g / mol)

[0415] ESI-MS: 183[M+H-BOC] +

[0416] R t (HPLC): 0.92min (Method C)

[0417] Example XIV

[0418] Example XIV.1

[0419] N,1-Dimethyl-N-[(3S)-pyrrolidin-3-yl]cyclobutane-1-carboxamide hydrochloride

[0420]

[0421] 1.37 g (4.85 mmol) of (3S)-3-(1-methylcyclobutaneamide)pyrrolidine-1-carboxylic acid tert-butyl ester (Example XIII.1) was diluted with 10 mL of THF and 0.44 mL (7.03 mmol) of methyl iodide was added. The mixture was cooled to -10 ° C and stirred at -10 ° C for a short time. After adding 0.33 g (8.31 mmol) of sodium hydride, the reaction mixture was stirred at room temperature overnight. NaHCO3 aqueous solution and EtOAc were added, and the biphasic mixture was vigorously stirred for a short time and then separated. The aqueous phase was extracted twice with EtOAc. The combined organic phases were dried over PTK and evaporated. The crude material was purified by HPLC to obtain the desired intermediate.

[0422] C 16 H 28N2O3 (M=296.41g / mol)

[0423] ESI-MS: 297[M+H] +

[0424] R t (HPLC): 0.98min (Method A)

[0425] The above intermediate was dissolved with 4.00 mL MeOH and 4.00 mL (16 mmol) hydrogen chloride (4N in 1,4-dioxane) and stirred at room temperature over the weekend. The reaction mixture was concentrated to dryness in vacuo to give the product.

[0426] C 11 H 20 N2O*HCl (M=232.75g / mol)

[0427] ESI-MS: 197[M+H] +

[0428] R t (HPLC): 0.57min (Method A)

[0429] Example XV

[0430] Example XV.1

[0431] (3S)-1-(6-Fluoropyridine-3-carbonyl)-N-methylpyrrolidin-3-amine trifluoroacetic acid

[0432]

[0433] 2.26 g (14.17 mmol) 6-fluoropyridine-3-carbonyl chloride (CAS No. 65352-94-5) was added dropwise to an ice-cold mixture of 2.84 g (14.17 mmol) N-methyl-N-[(3S)-pyrrolidin-3-yl] tert-butyl carbamate (CAS No. 169750-01-0) and 9.86 mL (70.83 mmol) TEA in 70 mL DCM. The reaction mixture was stirred at 0° C. for 10 min. The precipitate was filtered and the filtrate was purified by column chromatography (silica gel; DCM / MeOH) to obtain the BOC-protected product.

[0434] C 16 H 22 FN3O3 (M=323.36g / mol)

[0435] ESI-MS: 324[M+H] +

[0436] R t(HPLC): 0.89min (Method C)

[0437] The above intermediate was dissolved in 25 mL of DCM, then 5 mL of TFA was added and stirred at room temperature overnight. The reaction mixture was evaporated under reduced pressure to obtain the product.

[0438] C 11 H 14 FN3O*C2HF3O2 (M=337.27g / mol)

[0439] ESI-MS: 224[M+H] +

[0440] R t (HPLC): 0.61min (Method C)

[0441] Example XVI

[0442] Example XVI.1

[0443] N-[(3S)-1-(6-Fluoropyridine-3-carbonyl)pyrrolidin-3-yl]-N,1-dimethylcyclobutane-1-carboxamide

[0444]

[0445] 1.1 g (3.26 mmol) of (3S)-1-(6-fluoropyridine-3-carbonyl)-N-methylpyrrolidin-3-amine trifluoroacetic acid (Example XV.1), 0.45 g (3.91 mmol) of 1-methylcyclobutane-1-carboxylic acid (CAS No. 32936-76-8) and 2.79 mL (16.30 mmol) of DIPEA were diluted with 10 mL of DMF and 1.86 g (4.89 mmol) of HATU were added. The reaction mixture was stirred at room temperature for 10 min, then diluted with DCM, washed once with a saturated solution of NaHCO, once with a saturated solution of NH4Cl and once with brine. The organic phase was dried over Na2SO4 and concentrated to dryness in vacuo. The crude product was purified by column chromatography (silica gel, DCM / MeOH, 1%-10%) to obtain the product.

[0446] C 17 H 22 FN3O2 (M=319.37g / mol)

[0447] ESI-MS: 320[M+H] +

[0448] R t (HPLC): 0.80min (Method C)

[0449] Example XVII

[0450] Example XVII.1

[0451] N-Methyl-N-[(3S)-pyrrolidin-3-yl]pyrimidin-2-amine hydrochloride

[0452]

[0453] 1.00 g (6.29 mmol) 2-bromopyrimidine (CAS No. 4595-60-2), 1.51 g (7.55 mmol) (3S)-tert-butyl 3-(methylamino)pyrrolidine-1-carboxylate (CAS No. 147081-59-2) and 3.81 mL (22.01 mmol) DIPEA were diluted with 10 mL DMF and stirred for 2 h at 120° C. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, DCM / MeOH, 0%-4%) to give the BOC-protected product.

[0454] C 14 H 22 N4O2 (M=278.35g / mol)

[0455] ESI-MS: 279[M+H] +

[0456] R t (HPLC): 0.87min (Method A)

[0457] The above intermediate was dissolved in 10 mL of MeOH, then 4 mL of HCl (4N in 1,4-dioxane) was added and stirred at room temperature overnight. The reaction mixture was evaporated under reduced pressure to obtain the product.

[0458] C9H 14 FN4*HCl (M=214.70g / mol)

[0459] ESI-MS: 179[M+H] +

[0460] R t (HPLC): 0.15min (Method A)

[0461] Example XVIII

[0462] Example XVIII.1

[0463] (3S)-3-(N-Methyl-1-cyanocyclopropionamido)pyrrolidine-1-carboxylic acid tert-butyl ester

[0464]

[0465] 150 mg (1.35 mmol) 1-cyanocyclopropane-1-carboxylic acid (CAS No. 6914-79-0), 300 mg (1.5 mmol) (3S)-3-(methylamino) pyrrolidine-1-carboxylic acid tert-butyl ester (CAS No. 147081-59-2), 500 mg (1.56 mmol) TBTU and 0.6 mL (3.47 mmol) DIPEA were diluted with 4 mL DMF and stirred at room temperature for 2 h. The reaction mixture was filtered through a microplate syringe filter and purified by HPLC to obtain the product.

[0466] C 15 H 23 N3O3 (M=293.36g / mol)

[0467] ESI-MS: 294[M+H] +

[0468] R t (HPLC): 0.90min (Method C)

[0469] Example XIX

[0470] Example XIX.1

[0471] 1-(Pyrimidin-5-yl)cyclopropane-1-amine trifluoroacetate

[0472]

[0473] 1-(Pyrimidin-5-yl)cyclopropane-1-amine trifluoroacetate was prepared according to the procedure described in WO 2016193844.

[0474] Example XX

[0475] Example XX.1

[0476] 6-({5H,6H,7H-cyclopenta[b]pyridin-5-yl}amino)pyridine-3-carboxylic acid methyl ester

[0477]

[0478] 0.37 g (2.41 mmol) of 6-fluoropyridine-3-carboxylic acid methyl ester (CAS No. 1427-06-1), 0.50 g (2.41 mmol) of 5H, 6H, 7H-cyclopentadien [b] pyridine-5-amine dihydrochloride (CAS No. 1187930-17-1), 2.48 mL (14.49 mmol) of DIPEA and 5 mL of DMSO were stirred at 120 ° C for 1 h. The reaction mixture was diluted with EtOAc and washed twice with NaHCO3 aqueous solution. The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo to obtain the product.

[0479] C 15 H 15 N3O2 (M=269.30g / mol)

[0480] ESI-MS: 270[M+H] +

[0481] R t (HPLC): 0.54min (Method A)

[0482] Example XXI

[0483] Example XXI.1.A and Example XXI.1.B 6-{[(5S)-5H,6H,7H-cyclopenta[b]pyridin-5-yl] Amino}pyridine-3-carboxylic acid methyl ester

[0484] 6-{[(5R)-5H,6H,7H-cyclopenta[b]pyridin-5-yl]amino}pyridine-3-carboxylic acid methyl ester

[0485]

[0486] By chiral SFC ( Amylose-2 2.1×250 mm_5 μm; scCO2 / MeOH+20 mM NH3 75:25) was used to purify 0.65 g (2.41 mmol) of methyl 6-({5H,6H,7H-cyclopenta[b]pyridin-5-yl}amino)pyridine-3-carboxylate to give two enantiomers. The absolute stereochemistry of the chiral centers of the enantiomerically pure compounds was not determined.

[0487] Product XXI.1.A (first elution):

[0488] C 15 H 15 N3O2 (M=269.30g / mol)

[0489] Rt(HPLC): 2.32min(Method H)

[0490] Product XXI.1.B (secondary elution):

[0491] C 15 H 15 N3O2 (M=269.30g / mol)

[0492] Rt(HPLC): 3.31min(Method H)

[0493] Example XXII

[0494] Example XXII.1

[0495] 6-{[5H,6H,7H-cyclopenta[b]pyridin-5-yl]amino}pyridine-3-carboxylic acid hydrochloride

[0496]

[0497] 30.0 mg (0.11 mmol) of methyl 6-{[5H,6H,7H-cyclopenta[b]pyridin-5-yl]amino}pyridine-3-carboxylate (Example XXI.1.A) in 1 mL of 6N hydrogen chloride was stirred for 1 h at 80° C. The reaction mixture was evaporated under reduced pressure to give the product.

[0498] C 14 H 13 N3O2*HCl (M=291.73g / mol)

[0499] ESI-MS: 256[M+H] +

[0500] R t (HPLC): 0.09min (Method A)

[0501] The following compounds were prepared according to the general procedure described above (Example XXII 1):

[0502]

[0503] * and **: The stereochemistry of the chiral centers was not determined for the enantiomerically pure compounds.

[0504] Example XXIII

[0505] Example XXIII.1

[0506] 6-{[(1S)-1-phenylethyl]amino}pyridine-3-carboxylic acid

[0507]

[0508] A solution of 250 mg (1.77 mmol) of 6-fluoropyridine-3-carboxylic acid (CAS No. 403-45-2), 429 mg (3.54 mmol) of (1S)-1-phenylethane-1-amine (CAS No. 2627-86-3) and 980 mg (7.09 mmol) of potassium carbonate in 2 mL of DMSO was stirred overnight at 150° C. The reaction mixture was filtered through a microplate syringe filter and purified by HPLC to obtain the product.

[0509] C 14 H 14 N2O2 (M=242.27g / mol)

[0510] ESI-MS: 243[M+H] +

[0511] R t(HPLC): 0.71min (Method I)

[0512] The following compounds were prepared according to the general procedure described above (Example XXIII.1):

[0513]

[0514] Example XXIV

[0515] Example XXIV.1

[0516] 3-[(1E)-1-{[(S)-2-methylpropane-2-sulfinyl]imino}ethyl]benzene-1-sulfonamide

[0517]

[0518] 0.20g (1.00mmol) 3-acetylbenzene-1-sulfonamide (CAS No.35203-88-4), 0.49g (4.02mmol) (S)-2-methylpropane-2-sulfinamide (CAS No.146374-27-8) and 1.95mL (10.04mmol) titanium (IV) isopropoxide 2mL THF solution was stirred overnight at 80 ℃. The reaction mixture was cooled and diluted with 10mL salt solution and 20mL water. The precipitate was filtered through diatomite and washed with EtOAc. The organic phase was separated and washed with salt solution, dried with Na2SO4, and concentrated to dryness in a vacuum.

[0519] C 12 H 18 N2O3S2 (M=302.42g / mol)

[0520] ESI-MS: 303[M+H] +

[0521] R t (HPLC): 0.68min (Method C)

[0522] The following compounds were prepared according to the general procedure described above (Example XXIV.1):

[0523]

[0524]

[0525] Example XXV

[0526] Example XXV.1

[0527] 3-[(1S)-1-Aminoethyl]benzene-1-sulfonamide hydrochloride

[0528]

[0529] 0.57 g (0.94 mmol) of 3-[(1E)-1-{[(S)-2-methylpropane-2-sulfinyl]imino}ethyl]benzene-1-sulfonamide (Example XXIV.1) was dissolved in 5 mL of THF, 0.1 mL of water was added, and the mixture was cooled to -50°C. 0.11 g (2.83 mmol) of sodium borohydride was added to the cooled mixture. The reaction mixture was warmed to room temperature and diluted with a saturated aqueous solution of ammonium chloride, the organic phase was separated, dried and evaporated to give the protected product.

[0530] C 12 H 20 N2O3S2 (M=304.43g / mol)

[0531] ESI-MS: 305[M+H] +

[0532] R t (HPLC): 0.71min (Method C)

[0533] The above intermediate was dissolved in 10 mL of THF and cooled to 0° C. The reaction mixture was treated with 2.0 mL (8.00 mmol) of hydrogen chloride (4N in 1,4-dioxane) and warmed to room temperature. The precipitate was filtered to obtain the product.

[0534] 8H 12 N2O2S*HCl (M=236.72g / mol)

[0535] ESI-MS: 201[M+H] +

[0536] R t (HPLC): 0.28min (Method C)

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

[0538]

[0539] Example XXVI

[0540] Example XXVI.1

[0541] 1-[5-(Trifluoromethyl)pyridin-3-yl]cyclopropane-1-amine trifluoroacetate

[0542]

[0543] 688mg (4.00mmol) 5-(trifluoromethyl)pyridine-3-carbonitrile (CAS No.951624-83-2) was diluted with 30mL ether. 1.37mL (4.67mmol) Ti(iPrO)4 was added dropwise at room temperature. 2.95mL (8.84mmol) ethylmagnesium bromide (3M in ether) was added to the reaction mixture and the temperature was maintained between 15°C and 20°C. The mixture was stirred at room temperature for 30min and then treated with 1.26mL (9.97mmol) boron trifluoride etherate under temperature control (18°C-22°C). The reaction mixture was stirred at room temperature, cooled, and 20mL 2N sodium hydroxide was added. Stir at room temperature for 2h. The reaction mixture was filtered through diatomaceous earth and washed with ether. The organic phase was separated and the aqueous phase was extracted twice with ether. The combined organic phase was evaporated. The residue was absorbed with ACN / water and purified by HPLC to obtain the product.

[0544] C9H9N2F3*C2H1O2F3 (M=316.20g / mol)

[0545] ESI-MS: 203[M+H] +

[0546] R t (HPLC): 0.49min (Method J)

[0547] Example XXVII

[0548] Example XXVII.1

[0549] tert-Butyl N-[(2E)-2-[(dimethylamino)methylene]-3-oxocyclopentyl]carbamate

[0550]

[0551] A mixture of 2.00 g of tert-butyl N-(3-oxocyclopentyl)carbamate (CAS No. 847416-99-3) in 20 mL of N,N-dimethylformamide dimethyl acetal was stirred at 80° C. for 12 h. The reaction mixture was evaporated under reduced pressure. The residue was purified by column chromatography (silica gel, PE / EtOAc, 15%-50%) to obtain the desired product.

[0552] C 13 H 22 N2O3 (M=254.33g / mol)

[0553] R f (TLC): 0.50 (silica gel; DCM / MeOH (10:1))

[0554] Example XXVIII

[0555] Example XXVIII.1

[0556] tert-Butyl N-{1H,4H,5H,6H-cyclopenta[c]pyrazol-4-yl}carbamate

[0557]

[0558] 0.30 g (9.36 mmol) of hydrazine hydrate was added to a stirred solution of 1.00 g (3.93 mmol) of tert-butyl N-[(2E)-2-[(dimethylamino)methylene]-3-oxocyclopentyl]carbamate (Example XXVII.1) in 12.5 mL of MeOH. The resulting mixture was heated at 80 ° C for 2 h. After the reaction was complete, the mixture was evaporated and dried, then diluted with water and EtOAc. The organic layer was separated and Na was used SO and dried and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, hexane / EtOAc, 20%-30%) to obtain the product.

[0559] C 11 H 17 N3O2 (M=223.27g / mol)

[0560] R f (TLC): 0.30 (silica gel; DCM / MeOH (10:1))

[0561] Example XXIX

[0562] Example XXIX.1.A and Example XXIX.1.B

[0563] tert-Butyl N-[(4S)-1H,4H,5H,6H-cyclopenta[c]pyrazol-4-yl]carbamate

[0564] tert-Butyl N-[(4R)-1H,4H,5H,6H-cyclopenta[c]pyrazol-4-yl]carbamate

[0565]

[0566] By chiral SFC ( Cellulose-4_21.2x250mm_5μm; scCO2 / MeOH+20mM NH3 85:15) was used to purify 1.50 g (0.01 mol) of tert-butyl N-{1H,4H,5H,6H-cyclopenta[c]pyrazol-4-yl}carbamate (Example XXVIII.1) to give two enantiomers. The absolute stereochemistry of the chiral centers of the enantiomerically pure compounds was not determined.

[0567] Product XXIX.1.A (first elution):

[0568] C 11 H 17 N3O2 (M=223.27g / mol)

[0569] Rt(HPLC): 2.37min(Method K)

[0570] Product XXIX.1.B (secondary elution):

[0571] C 11 H 17 N3O2 (M=223.27g / mol)

[0572] Rt(HPLC): 3.07min(Method K)

[0573] Example XXX

[0574] Example XXX.1

[0575] 3-[1-({5-[(3S)-3-(N-methylacetylamino)pyrrolidine-1-carbonyl]pyridin-2-yl}amino)ethyl]benzene Methyl formate

[0576]

[0577] A mixture of 100 mg (0.38 mmol) of N-[(3S)-1-(6-fluoropyridine-3-carbonyl)pyrrolidin-3-yl]-N-methylacetamide (Example 1.1), 100 mg (0.56 mmol) of methyl 3-(1-aminoethyl)benzoate (CAS No. 153994-69-5) and 0.39 mL (2.26 mmol) of DIPEA in 1.5 mL of DMSO was stirred overnight at 120° C. The reaction mixture was purified by HPLC to give the product.

[0578] C 23 H 28 N4O4 (M=424.49g / mol)

[0579] ESI-MS: 425[M+H] +

[0580] R t (HPLC): 0.84min (Method C)

[0581] Example XXXI

[0582] Example XXXI.1

[0583] 3-[1-({5-[(3S)-3-(N-methylacetylamino)pyrrolidine-1-carbonyl]pyridin-2-yl}amino)ethyl]benzene Formic acid

[0584]

[0585] A mixture of 42.0 mg (0.10 mmol) of methyl 3-[1-({5-[(3S)-3-(N-methylacetylamino)pyrrolidine-1-carbonyl]pyridin-2-yl}amino)ethyl]benzoate (Example XXX.1) and 0.15 mL (0.30 mmol) of lithium hydroxide (2N aqueous solution) in 1 mL of THF was stirred at 70° C. for 1 h. The reaction mixture was concentrated under reduced pressure to give the product.

[0586] C 22 H 26 N4O4 (M = 410.47 g / mol)

[0587] The following compounds were prepared according to the general procedure described above (Example XXXI.1):

[0588]

[0589] Example XXXII

[0590] Example XXXII.1

[0591] 3-Acetyl-N,N-dimethylbenzamide

[0592]

[0593] 1.34 mL (2.68 mmol) of dimethylamine solution (2NTHF solution) and 0.40 g (2.44 mmol) of 3-acetylbenzoic acid (CAS No. 586-42-5) were diluted with DMF (3.0 mL), and then 1.46 mL (8.53 mmol) of DIPEA was added, and the mixture was stirred at room temperature for 2 minutes. 1.39 g (3.66 mmol) of HATU was added to the reaction mixture, and stirred at room temperature for 2 h. A saturated aqueous solution of NaHCO3 was added to the mixture, and the aqueous phase was extracted twice with DCM. The organic phases were combined, dried over PTK and concentrated in vacuo. The residue was dissolved with minimal MeOH, filtered through a microplate syringe filter, and purified by HPLC to obtain the product.

[0594] C 11 H 13 NO2 (M=191.23g / mol)

[0595] ESI-MS: 192[M+H] +

[0596] R t (HPLC): 0.67min (Method C)

[0597] Example XXXIII

[0598] Example XXXIII.1

[0599] tert-Butyl N-[(tert-Butoxy)carbonyl]-N-(prop-2-yn-1-yl)carbamate

[0600]

[0601] 25.0 g (113 mmol) of tert-butyl N-[(tert-butoxy)carbonyl]carbamate (CAS No. 51779-32-9) was diluted with 100 mL of DMF and treated with 35.0 g (253 mmol) of K2CO3. The mixture was cooled to 0°C and 14.0 mL (130 mmol) of 3-bromoprop-1-yne (80% toluene solution; CAS No. 106-96-7) was added dropwise. The reaction mixture was stirred at room temperature for 2 h and some additional 3-bromoprop-1-yne was added to complete the reaction. After stirring at room temperature for 1 h, the reaction mixture was diluted with DCM and the organic phase was washed once with a saturated aqueous solution of NaHCO3 and once with brine. The organic phase was concentrated under reduced pressure and the residue was purified by MPLC (SiO2; DCM / MeOH 99:1) to obtain the product.

[0602] C 13 H 21 NO4 (M=255.31g / mol)

[0603] R f (TLC): 0.82(SiO2,DCM / MeOH 95:05)

[0604] Example XXXIV

[0605] Example XXXIV.1

[0606] tert-Butyl N-[(tert-Butoxy)carbonyl]-N-(4-cyclopropyl-4-oxobut-2-yn-1-yl)carbamate

[0607]

[0608] Under an inert argon atmosphere, 15.2 g (59.5 mmol) of tert-butyl N-[(tert-butoxy)carbonyl]-N-(prop-2-yn-1-yl)carbamate (Example XXXIII.1) was diluted with THF (200 mL) and cooled to -78°C. 45.0 mL (70.0 mmol) of n-butyllithium (1.60 M in n-hexane) was added dropwise. The reaction mixture was stirred at -78°C for 30 min. The solution was then slowly transferred to a precooled (-78°C) THF solution (50 mL) containing 7.00 g (50.0 mmol) of N-methoxy-N-methylcyclopropanecarboxamide (CAS No. 147356-78-3). The reaction mixture was slowly heated to 0°C and stirred at this temperature for 3 h. The solution was then acidified with 2N hydrogen chloride at 0°C and diluted with EtOAc. The organic phase was separated, washed once with brine, dried over Na2SO4 and concentrated under reduced pressure to give the product.

[0609] C 17 H 25 NO5 (M = 323.38 g / mol)

[0610] Example XXXV

[0611] Example XXXV.1

[0612] 1-(3-Cyclopropyl-1-methyl-1H-pyrazol-5-yl)methanamine hydrochloride

[0613]

[0614] 21.0g (52.0mmol) N-[(tert-butoxy) carbonyl]-N-(4-cyclopropyl-4-oxobut-2-yn-1-yl) tert-butyl carbamate (Example XXXIV.1) and 2.87g (62.3mmol) methylhydrazine were diluted with 100mL EtOH and stirred in microwaves for 12min at 130°C. The solvent was evaporated in a vacuum and the residue was purified by MPLC (silica gel, eluent: DCM / MeOH). The BOC protected product was diluted with EtOH (20mL) and treated with 155mL (155mmol) 1N hydrogen chloride in ether. The reaction mixture was stirred at room temperature overnight. The precipitate was filtered, cleaned with ether, and dried in vacuo to obtain the product.

[0615] 8H 13 N3*HCl (M=187.67g / mol)

[0616] ESI-MS: 152[M+H] +

[0617] R t (HPLC): 0.32min (Method C)

[0618] The following compounds were prepared according to the general procedure described above (Example XXXV1):

[0619]

[0620] Example XXXXI

[0621] Example XXXXI.1

[0622] tert-Butyl N-(6-methyl-2-oxohept-3-yn-1-yl)carbamate

[0623]

[0624] A 50 mL THF solution of 1.50 g (6.74 mmol) of tert-butyl N-{[methoxy(methyl)carbamoyl]-methyl}carbamate (CAS No. 121505-93-9) was cooled to -70 ° C, and 2.00 mL (6.00 mmol) of chloromethyl magnesium solution (3.0 M THF solution) was added dropwise. The suspension was stirred at -70 ° C for 90 min. In a separate flask, a THF (50 mL) solution of 0.79 mL (6.74 mmol) of 4-methylpent-yne (CAS No. 7154-75-8) was prepared, cooled to -70 ° C, and then 7.60 mL (12.16 mmol) of n-butyllithium solution (1.60 M n-hexane solution) was slowly added. The clear solution was stirred at -70 ° C for 90 min, and then slowly transferred to the previous mixture at -70 ° C. The white suspension was further stirred for 1 h at this temperature, and then warmed to room temperature. The resulting clear solution was cooled again using an ice bath, treated with 17 mL of 1N hydrochloric acid and allowed to warm to room temperature. The aqueous phase was extracted with EtOAc, and the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give the product.

[0625] C 13 H 21 NO3 (M = 239.31 g / mol)

[0626] Rf(SiO2;DCM / MeOH 95:05)0.82

[0627] Example XXXXII

[0628] Example XXXXII.1

[0629] 1-[3-(2-Methylpropyl)-1H-pyrazol-5-yl]methanamine hydrochloride

[0630]

[0631] 0.55 g (2.17 mmol) of tert-butyl N-{[3-(2-methylpropyl)-1H-pyrazol-5-yl]methyl}carbamate (Example XXXV.2) was suspended in 10 mL of water, cooled in an ice bath and treated with 5 mL of concentrated hydrogen chloride. The reaction mixture was stirred at room temperature for 3 h. After the reaction was complete, the solution was lyophilized to obtain the given product.

[0632] 8H 15 N3*HCl (M=189.69g / mol)

[0633] ESI-MS: 154[M+H] +

[0634] Preparation of final compounds

[0635] Example 1

[0636] Example 1.1 (General approach)

[0637] N-[(3S)-1-(6-{[(3-cyanophenyl)methyl]amino}pyridine-3-carbonyl)pyrrolidin-3-yl]-N-methyl Acetamide

[0638]

[0639] A mixture of 100 mg (0.19 mmol) of N-[(3S)-1-(6-fluoropyridine-3-carbonyl)pyrrolidin-3-yl]-N-methylacetamide (Example 1.1), 50 mg (0.38 mmol) of 3-aminomethylbenzonitrile (CAS No. 10406-24-3) and 0.16 mL (0.95 mmol) of DIPEA in 1 mL of DMSO was stirred overnight at 120° C. The reaction mixture was diluted with MeOH, filtered through a microplate syringe filter, and purified by preparative HPLC to give the product.

[0640] C 21 H 23 N5O2 (M=377.44)

[0641] ESI-MS: 378[M+H] +

[0642] R t (HPLC) 0.77min (Method A)

[0643] The following compounds were prepared according to the general procedure described above (Example 1.1):

[0644]

[0645]

[0646]

[0647]

[0648]

[0649]

[0650] *The stereochemistry of chiral centers was not determined for enantiomerically and diastereomerically pure compounds.

[0651] Example 2

[0652] Example 2.1 (General Approach)

[0653] N-methyl-N-[(3S)-1-{6-[(2-phenylpropan-2-yl)amino]pyridine-3-carbonyl}pyrrolidin-3-yl] cyclopentyl Propane formamide

[0654]

[0655] A mixture of 70 mg (0.24 mmol) of N-[(3S)-1-(6-fluoropyridine-3-carbonyl)pyrrolidin-3-yl]-N-methylcyclopropanecarboxamide (Example III.1) and 0.14 mL (0.96 mmol) of cumylamine (CAS No. 585-32-0) in 2 mL of NMP was stirred in a microwave at 190° C. for 24 h. Subsequently, it was filtered through a microplate syringe filter and purified by HPLC to obtain the product.

[0656] C 24 H 30 N4O2 (M=406.52)

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

[0658] R t (HPLC) 0.75min (Method A)

[0659] The following compounds were prepared according to the general procedure described above (Example 2.1):

[0660]

[0661] Example 3

[0662] Example 3.1 (General Approach)

[0663] N-methyl-N-[(3S)-1-(6-{[(pyridin-3-yl)methyl]amino}pyridine-3-carbonyl)pyrrolidin-3-yl] cyclopentyl Butanecarboxamide

[0664]

[0665] To a mixture of 26.6 mg (0.10 mmol) 6-{[(pyridin-3-yl)methyl]amino}pyridine-3-carboxylic acid hydrochloride (Example V.1), 21.9 mg (0.10 mmol) N-methyl-N-[(3S)-pyrrolidin-3-yl]cyclobutanecarboxamide hydrochloride (Example VI.1) and 56.8 μL (0.33 mmol) DIPEA in 1 mL DMF was added 41.8 mg (0.11 mmol) HATU. The reaction mixture was stirred at room temperature overnight, filtered through a microplate syringe filter, and purified by HPLC to give the product.

[0666] C 22 H 27 N5O2 (M=393.48)

[0667] ESI-MS: 394[M+H] +

[0668] R t (HPLC) 0.50min(method D)

[0669] The following compounds were prepared according to the general procedure described above (Example 3.1):

[0670]

[0671] *The stereochemistry of chiral centers was not determined for enantiomerically and diastereomerically pure compounds.

[0672] Example 4

[0673] Example 4.1 (General Approach)

[0674] N-[(3S)-1-(6-{[(4-chlorophenyl)methyl]amino}pyridine-3-carbonyl)pyrrolidin-3-yl]-N-methylethyl Amide

[0675]

[0676] To a mixture of 1.25 g (4.76 mmol) 6-{[(4-chlorophenyl)methyl]amino}pyridine-3-carboxylic acid (Example VII.1), 1.02 g (5.71 mmol) N-methyl-N-[(3S)-pyrrolidin-3-yl]acetamide hydrochloride (CAS No. 1215264-39-3) and 3.25 mL (19.03 mmol) DIPEA in 10 mL DMF was added 1.60 g (5.00 mmol) TBTU. The reaction mixture was stirred at room temperature for 10 min and purified by HPLC to give the product.

[0677] C 20 H23 ClN4O2 (M=386.88)

[0678] ESI-MS: 387[M+H] +

[0679] R t (HPLC) 0.88min (Method C)

[0680] The following compounds were prepared according to the general procedure described above (Example 4.1):

[0681]

[0682] Example 5

[0683] Example 5.1.A and Example 5.1.B

[0684] N-Methyl-N-[(3S)-1-(6-{[(1R)-1-(1,3-thiazol-2-yl)ethyl]amino}pyridine-3-carbonyl]pyridine [3-pyridin-1-yl]acetamide

[0685] N-Methyl-N-[(3S)-1-(6-{[(1S)-1-(1,3-thiazol-2-yl)ethyl]amino}pyridine-3-carbonyl)pyridine [3-pyridin-1-yl]acetamide

[0686]

[0687] 26.5 mg (0.10 mmol) of N-[(3S)-1-(6-fluoropyridine-3-carbonyl)pyrrolidin-3-yl]-N-methylacetamide (Example I.1) was dissolved in 1 mL of DMSO, and 51.6 μL (0.30 mmol) of DIPEA and 15.4 mg (0.12 mmol) of 1-thiazol-2-yl-ethylamine (CAS No. 432047-36-4) were added. The reaction mixture was stirred at 100° C. overnight and at 120° C. for another 24 h. More 1-thiazol-2-yl-ethylamine (15.4 mg, 0.12 mmol) was added and the conversion was complete at 120° C. for 24 h. The reaction mixture was filtered through a microplate syringe filter and purified by HPLC. The reaction mixture was purified by chiral SFC ( The separated racemic product was purified by Cellulose-SB_10X250mm; 5μL; scCO2 / IPA+20mM NH3 80:20) to obtain the enantiomerically pure product. The absolute stereochemistry of the chiral centers of the enantiomerically and diastereomerically pure compounds was not determined.

[0688] Product 5.1.A (first elution):

[0689] C 18 H 23 N5O2S (M=373.47)

[0690] ESI-MS: 374[M+H] +

[0691] R t (Chiral HPLC) 2.99 min (Method E)

[0692] Product 5.1.B (secondary elution):

[0693] C 18 H 23 N5O2S (M=373.47)

[0694] ESI-MS: 374[M+H] +

[0695] R t (Chiral HPLC) 3.49 min (Method E)

[0696] Example 6

[0697] Example 6.1.A and Example 6.1.B

[0698] N-Methyl-N-[(3S)-1-(6-{[(1S)-1-(pyridin-3-yl)ethyl]amino}pyridine-3-carbonyl)pyrrolidine- 3-Methyl]acetamide

[0699] N-Methyl-N-[(3S)-1-(6-{[(1R)-1-(pyridin-3-yl)ethyl]amino}pyridine-3-carbonyl)pyrrolidine- 3-Methyl]acetamide

[0700]

[0701] 300 mg (1.13 mmol) of N-[(3S)-1-(6-fluoropyridine-3-carbonyl)pyrrolidin-3-yl]-N-methylacetamide (Example I.1), 276 mg (2.26 mmol) of 1-pyridin-3-ylethylamine (CAS No. 56129-55-6) and 0.97 mL (10.00 mmol) of DIPEA were dissolved in 2.5 mL of DMSO and stirred overnight at 120 ° C. The reaction mixture was poured into an aqueous solution of NaHCO3 and the aqueous phase was extracted twice with DCM. The combined organic phases were dried over PTK and concentrated to dryness in vacuo. The residue was dissolved in MeOH, filtered and purified by HPLC. The product was purified by chiral SFC ( The racemic product was purified by eluting with Amylose-SA_10X250mm; 5μL; scCO2 / IPA+20mM NH3 65:35) to obtain enantiomerically pure product. The absolute stereochemistry of the chiral centers of the enantiomerically and diastereomerically pure compounds was not determined.

[0702] Product 6.1.A (first elution)

[0703] C 20 H 25N5O2 (M=367.45)

[0704] ESI-MS: 368[M+H] +

[0705] R t (HPLC) 0.69min (Method C)

[0706] R t (Chiral SFC) 5.57 min (Method L)

[0707] Product 6.1.B (secondary elution)

[0708] C 20 H 25 N5O2 (M=367.45)

[0709] ESI-MS: 368[M+H] +

[0710] R t (HPLC) 0.69min (Method C)

[0711] R t (Chiral SFC) 5.84 min (Method L)

[0712] Example 7

[0713] Example 7.1 (General Approach)

[0714] N-Methyl-N-[(3S)-1-(6-{[(pyridin-3-yl)methyl]amino}pyridine-3-carbonyl)pyrrolidin-3-yl]ethyl Amide

[0715]

[0716] 0.47 g (1.77 mmol) of 6-{[(pyridin-3-yl)methyl]amino}pyridine-3-carboxylic acid hydrochloride (Example V.1), 0.47 g (2.65 mmol) of N-methyl-N-(S)-pyrrolidin-3-yl-acetamide hydrochloride (CAS No. 1215264-39-3) and 1.21 mL (7.08 mmol) of DIPEA were dissolved in 5 mL of DMF and 1.01 g (2.65 mmol) of HATU were added. The reaction mixture was stirred at room temperature for 10 min, poured into an aqueous NaHCO solution and the aqueous phase was extracted twice with DCM. The combined organic phases were dried over PTK and concentrated to dryness in vacuo. The residue was purified by column chromatography (silica gel, DCM / MeOH, 2% to 20%) to give the product.

[0717] C 19 H 23 N5O2 (M=353.42)

[0718] ESI-MS: 354[M+H] +

[0719] R t (HPLC) 0.68min (Method C)

[0720] Example 8

[0721] Example 8.1 (General Approach)

[0722] N,1-Dimethyl-N-[(3S)-1-(6-{[2-(pyridin-3-yl)propan-2-yl]amino}pyridine-3-carbonyl)pyridine [3-pyridin-1-yl]cyclobutane-1-carboxamide

[0723]

[0724] 26.0 mg (0.10 mmol) of 6-{[2-(pyridin-3-yl)propan-2-yl]amino}pyridine-3-carboxylic acid (Example VII.2) and 35.3 mg (0.15 mmol) of N,1-dimethyl-N-[(3S)-pyrrolidin-3-yl]cyclobutane-1-carboxamide hydrochloride (Example XIV.1) were diluted with 1 mL of DMF, and 60.5 μL (0.35 mmol) of DIPEA were added. The reaction mixture was treated with 57.6 mg (0.15 mmol) of HATU. After stirring at room temperature for 10 min, the reaction mixture was quenched with MeOH, filtered through a microplate syringe filter, and purified by HPLC to obtain the product.

[0725] C 25 H 33 N5O2 (M=435.56)

[0726] ESI-MS: 436[M+H] +

[0727] R t (HPLC) 0.86min (Method C)

[0728] The following compounds were prepared according to the general procedure described above (Example 8.1):

[0729]

[0730]

[0731]

[0732] * and **: The stereochemistry of the chiral centers was not determined for enantiomerically and diastereomerically pure compounds.

[0733] Example 9

[0734] Example 9.1 (General Approach)

[0735] N-methyl-N-[(3S)-1-(6-{[(1S)-1-[6-(trifluoromethyl)pyridin-3-yl]ethyl]amino}pyridine-3-yl] [(2-( ...

[0736]

[0737] 50.0 mg (0.19 mmol) of N-[(3S)-1-(6-fluoropyridine-3-carbonyl)pyrrolidin-3-yl]-N-methylacetamide (Example I.1) and 107.5 mg (0.57 mmol) of (1S)-1-[6-(trifluoromethyl)pyridin-3-yl]ethane-1-amine (CAS No. 1071435-52-5) were diluted with 1 mL of NMP and stirred overnight at 130° C. After cooling, the reaction mixture was filtered through a microplate syringe filter and purified by HPLC to give the product.

[0738] C 21 H 24 F3N5O2 (M=435.44)

[0739] ESI-MS: 436[M+H] +

[0740] R t (HPLC) 0.71min (Method A)

[0741] The following compounds were prepared according to the general procedure described above (Example 9.1):

[0742]

[0743]

[0744] Example 10

[0745] Example 10.1

[0746] 3-[1-({5-[(3S)-3-(N-methylacetylamino)pyrrolidine-1-carbonyl]pyridin-2-yl}amino)ethyl]benzene Formamide

[0747]

[0748] 40.0 mg (0.10 mmol) of 3-[1-({5-[(3S)-3-(N-methylacetylamino)pyrrolidine-1-carbonyl]pyridin-2-yl}amino)ethyl]benzoic acid (Example XXXI.1) and 20.0 mg (0.10 mmol) of CDI were dissolved in DMF, stirred at room temperature for 1 h, then cooled with an ice bath, and 0.19 mL (0.10 mmol) of concentrated ammonia was added dropwise. The reaction mixture was heated to room temperature and stirred for 1 h, and then purified by HPLC (ACN / water / NH4OH) to obtain the product.

[0749] C 22 H 27 N5O3 (M=409.48)

[0750] ESI-MS: 410[M+H] +

[0751] R t (HPLC) 0.69min (Method C)

[0752] Embodiment 11

[0753] Example 11.1

[0754] N-[(3S)-1-(6-{[(1S)-1-(6-cyanopyridin-3-yl)ethyl]amino}pyridine-3-carbonyl)pyrrolidine- 3-Methyl]-N-methylacetamide

[0755]

[0756] A mixture of 30.0 mg (0.07 mmol) of N-[(3S)-1-(6-{[(1S)-1-(6-chloropyridin-3-yl)ethyl]-amino}pyridine-3-carbonyl)pyrrolidin-3-yl]-N-methylacetamide (Example 1.11), 5.2 mg (0.04 mmol) of zinc cyanide, 3.4 mg (0.01 mmol) of tris(dibenzylideneacetone)dipalladium(0) and 4.1 mg (0.01 mmol) of 1,1′-bis(diphenylphosphino)ferrocene in 2 mL of DMF was stirred at 100° C. overnight. To achieve complete conversion, more zinc cyanide (10 mg, 0.08 mmol), more tris(benzylideneacetone)dipalladium(0) (3.4 mg, 0.01 mmol) and more 1,1'-bis(diphenylphosphino)-ferrocene (4.1 mg, 0.01 mmol) were added and further stirred for 3 h at 120° C. The reaction mixture was diluted with ACN, filtered through a microplate syringe filter and purified by HPLC to give the product.

[0757] C 21 H 24 N6O2 (M=392.45)

[0758] ESI-MS: 393[M+H] +

[0759] R t (HPLC) 0.64min (Method A)

[0760] HPLC analysis method

[0761] Method A

[0762]

[0763] Analytical column: Sunfire (Waters) 2.5 μm; 3.0 x 30 mm; column temperature: 60 °C

[0764] Method B

[0765]

[0766] Analytical column: Stable Bond (Agilent) 1.8 μm; 3.0 x 30 mm; column temperature: 60 °C

[0767] Method C

[0768]

[0769] Analytical column: XBridge C18 (Waters) 2.5 μm; 3.0 x 30 mm; column temperature: 60 °C

[0770] Method D

[0771]

[0772] Preparative column: XBridge (Waters) C18_3.0x30mm_2.5μm

[0773] Method E

[0774]

[0775] Cellulose SB_4.6x250mm_5μm(YMC)

[0776] Method F

[0777]

[0778] Cellulose SC_4.6x250mm_5μm(YMC)

[0779] Method G

[0780]

[0781] Amylose SA_4.6x250mm_5μm(YMC)

[0782] Method H

[0783]

[0784] Amylose-2_4.6x250mm_5μm(Phenomenex)

[0785] Method I

[0786]

[0787] Analytical column: Sunfire C18 (Waters) 2.5 μm; 3.0 x 30 mm; column temperature: 60 °C

[0788] Method J

[0789]

[0790] Preparative column: XBridge (Waters) C18_3.0x30mm_2.5μm

[0791] Method K

[0792]

[0793] Amylose-4_4.6x250mm_5μm(Phenomenex)

[0794] Method L

[0795]

[0796] IB_4.6x250mm_5μm(Daicel)

[0797] Method M

[0798]

[0799] Preparative column: XBridge C18 (Waters) 3.5 μm; 4.6 x 50 mm; column temperature: 40 °C

[0800] Method N

[0801]

[0802] Analytical column: Xbridge (Waters) 2.5 μm; 3.0 x 30 mm; column temperature: 60 °C

[0803] Method O

[0804]

[0805] Analytical column: Xbridge (Waters) 3.5 μm; 4.6 x 30 mm; column temperature: 60 °C

[0806] Method P

[0807]

[0808] Preparative column: Sunfire (Waters) C18_3.0x30mm_2.5μm

[0809] Description of biological properties

[0810] Vanin-1 enzymatic assay

[0811] 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.

[0812] 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).

[0813] 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.

[0814] 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.

[0815] 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).

[0816] Synthesis of tool inhibitor BI-1:

[0817]

[0818]

[0819] 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.

[0820] 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).

[0821] C9H 17 NO4S (M=235.3g / mol)

[0822] ESI-MS: 258[M+Na] +

[0823] R f (TLC, silica gel) 0.4 (PE / EtOAc 3 / 1)

[0824] 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).

[0825] C9H 17NO5S (M=251.3g / mol)

[0826] ESI-MS: 252[M+H] +

[0827] R f (TLC, silica gel) 0.55 (PE / EtOAc 3 / 1)

[0828] 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.

[0829] The residue was purified by column chromatography (silica gel, 0-5% MeOH / CH2Cl2).

[0830] C 16 H 23 IN2O5 (M=450.3g / mol)

[0831] ESI-MS: 451[M+H] +

[0832] 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.

[0833] 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).

[0834] 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.

[0835] C 10 H 12 N2O3 (M=208.2g / mol)

[0836] ESI-MS: 209[M+H] +

[0837] Rt(HPLC): 0.60min(Method A)

[0838] 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.

[0839] The volatiles were removed in vacuo and the residue was purified by column chromatography (Biotage KP-Nh cartridge, 0-10% MeOH / EtOAc).

[0840] C 17 H 24 N4O3 (M=332.4g / mol)

[0841] ESI-MS: 333[M+H] +

[0842] Rt(HPLC): 0.63min(Method A)

[0843] 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.

[0844] Table I. Biological properties of the present invention

[0845]

[0846]

Claims

1. A compound selected from the following or a pharmaceutically acceptable salt thereof: *The stereochemistry of chiral centers was not determined for enantiomerically and diastereomerically pure compounds.

2. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound according to claim 1 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

3. Use of a compound according to claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating patients with Crohn's disease, ulcerative colitis, atopic dermatitis, systemic sclerosis, nonalcoholic steatohepatitis, psoriasis, chronic kidney disease, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, rheumatoid arthritis, asthma, allergic rhinitis, allergic eczema, juvenile idiopathic arthritis, graft-versus-host disease, psoriatic arthritis, hyperlipidemia, colorectal cancer or pancreatic cancer-related new-onset diabetes.

4. The use according to claim 3, wherein the medicament is a medicament for treating patients suffering from scleroderma or juvenile rheumatoid arthritis.

Images