Pyrimidine formamide compound and application thereof

Abstract

To provide pyrimidine formamide compounds having potent Vanin-1 inhibitory activity and uses thereof.SOLUTION: The present invention provides a pyrimidine formamide compound represented by formula (I), or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, a mixture form thereof, or a pharmaceutically acceptable salt thereof. The compound can be used as a Vanin enzyme inhibitor, and can be used for treating various diseases including Crohn's disease and ulcerative colitis.SELECTED DRAWING: None

Description

Detailed Description of the Invention

[0001] This application claims priority to Chinese patent application No. 2020110207210, filed on September 25, 2020, and Chinese patent application No. 2021110954656, filed on September 17, 2021. This application cites the above-mentioned Chinese patent applications in their entirety.

[0002] [Technical field] The present invention relates to pyrimidine formamide compounds and their uses. [Background technology] Vanin-1 (vascular non-inflammatory molecule-1) is an exonuclease with ubiquitinase activity that mainly catalyzes the hydrolysis of pantetheine to produce pantothenic acid (VB5) and mercaptoethylamine. Coenzyme A (CoA) synthesized by VB5 regulates biotransformations such as fatty acid synthesis and oxidation, and energy metabolism, and the reversible reaction between mercaptoethylamine and cystamine is an important sensor of oxidative stress. More and more studies have shown that deficiency or reduced levels of mercaptoethylamine can enhance γ-GCS activity, leading to increased endogenous GSH storage in tissues, which can prevent or eliminate tissue inflammation. Studies have found that Vanin-1 mRNA is highly expressed in human colon, duodenum, endometrium, liver, kidney, gallbladder, and small intestine. In UC (ulcerative colitis) patients, Vanin-1 expression is high, diffuse, and limited to the brush border. Furthermore, the expression level of Vanin-1 in the colon remained significantly higher than that of the control group during the clinical quiescent phase of UC. - / - The survival rate of Vanin-1 mice treated with 90% cystamine was significantly higher than that of the model control group, and there was no significant weight loss. - / -The mice died within 5 days, indicating that cystamine completely reversed the protective effect of Vanin-1 deficiency against colitis. Histopathological analysis of mice also showed that inhibition or knockout of Vanin-1 could significantly ameliorate the lesions in mouse colon (Berruyer C,et al., Vanin-1- / -mice exhibit a glutathione mediated tissue resistance to oxidative stress. Mol. Cell Biol. 2004;24: 7214-7224;Berruyer C,et al. Vanin-1 licenses inflammatory mediator production by gut epithelial cells and controls colitis by antagonizing peroxisome proliferator-activated receptorγactivity. J. Exp. Med. 2006;203: 2817-2827).

[0003] Furthermore, Vanin-1 is believed to play a regulatory role in cardiovascular and oncological diseases. Studies have demonstrated that Vanin-1 regulates smooth muscle cell activation in vitro and the development of neointimal hyperplasia in response to carotid artery ligation in vivo. Polymorphisms in the VNN1 gene are associated with blood pressure and HDL levels. In SF-1 transgenic mice, Vanin-1 deficiency prevents the mice from developing adrenal cortical tumors, indicating a role for Vanin-1 in certain cancers. Studies in inflammatory diseases have shown that Vanin-1 is highly upregulated in psoriatic skin lesions compared to normal individuals. Gene expression of VNN1 is also upregulated in whole blood of pediatric immune thrombocytopenia (ITP) patients, where overexpression of VNN1 is associated with the progression of chronic ITP. Furthermore, elevated Vanin-1 has been detected in the urine of patients with various renal disorders, including systemic lupus erythematosus, nephrotoxicant-induced nephropathy, and type 2 diabetes. (Rommelaere S, et al. PPARalpha regulates the production of serum Vanin-1 by liver. FEBS Lett.2013 Nov 15;587(22):3742-8).

[0004] [Summary of the invention] The technical problem to be solved by the present invention is to overcome the lack of Vanin enzyme-based therapeutic agents in the prior art, and provide pyrimidine formamide compounds and their uses. The pyrimidine formamide compounds provided by the present invention are compounds with Vanin enzyme inhibitory activity, have strong Vanin-1 inhibitory activity, and can be used to treat various diseases, including Crohn's disease and ulcerative colitis.

[0005] The present invention solves the above technical problems through the following technical solutions. The present invention provides a pyrimidine formamide compound represented by formula I, or a tautomer, mesomeric, racemic, enantiomer, diastereomer, or mixture thereof, or a pharma- ceutically acceptable salt thereof.

[0006] [ka]

[0007] where n is 0, 1, 2, or 3; R 1 are independently halogen, C1-C6 alkyl, one or more R 1a is a C1-C6 alkyl substituted with Z 1 is -(CR 6a R 6b )-or-(NR 6c )- and Z 2 is a connecting bond, or Z 1 is a connecting bond, and Z 2 is -(CR 7a R 7b )-and Z 3is a linking bond or -(CR 8a R 8b )-and R a are independently H, R 6a , R 6b , R 7a and R 7b are independently H, halogen or C1-C6 alkyl; R 6c are independently H or C1-C4 alkyl; R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 8a and R 8b are independently H, halogen, C1-C6 alkyl, one or more R 1c C1-C6 alkyl substituted with -(NR 9a R 9b ) or -(NR 10a )-(C=O)-R 10b and Or R 4a and R 4b , or R 4a and R 5a , or R 4a and R 8a together with the carbon to which they are attached form ring B, and ring B is selected from the group consisting of 4- to 7-membered cycloalkyl, 4- to 7-membered heterocycloalkyl, one or more R 1d or one or more R 1e wherein said 4- to 7-membered heterocycloalkyl and one or more R 1e In the 4- to 7-membered heterocycloalkyl substituted by, the heteroatom is N, O or S, and the number of heteroatoms is 1 or 2; R 1a , R 1c , R 1d and R 1eare independently halogen, C1-C4 alkyl, or C1-C4 alkyl substituted with one or more halogens; R 9a , R 9b , R 10a and R 10b are independently H, C1-C4 alkyl or one or C1-C4 alkyl substituted with multiple halogens; A is phenyl or 6-membered heteroaryl, in which the heteroatom is N and the number of heteroatoms is 1 or 2;

[0008] [ka] represents a single bond or a double bond.

[0009] In some preferred embodiments of the present invention, the specific groups in the pyrimidine formamide compound represented by formula I, or in the form of a tautomer, mesomeric, racemic, enantiomer, diastereomer, or mixture thereof, or a pharma- ceutically acceptable salt thereof, are as defined below, and groups not mentioned are as described in any embodiment of this application (hereinafter referred to as "some embodiments"), and n is 0 or 1.

[0010] In some embodiments, Z 1 is -(CR 6a R 6b )- and Z 2 is a connecting bond. In some embodiments, R 6a and R 6b are independently H or halogen.

[0011] In some embodiments, R 7a and R 7b are independently H, i.e., Z 2 is -(CH2)-. In some embodiments, Z 3 is -(CR 8a R 8b )-.

[0012] In some embodiments, R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 8a and R 8b are independently H, C1-C6 alkyl, -(NR 9a R 9b ) or -(NR 10a )-(C=O)-R 10b It is.

[0013] In some embodiments, R 3a and R 3b are independently H. In some embodiments, R 5a and R 5b are independently H.

[0014] In some embodiments, R 4a and R 4b are independently H, C1-C6 alkyl, -(NR 9a R 9b ) or -(NR 10a )-(C=O)-R 10b It is.

[0015] In some embodiments, R 4a are independently C1-C6 alkyl, -(NR 9a R 9b ) or -(NR 10a )-(C=O)-R 10b and R 4b are independently H or C1-C6 alkyl.

[0016] In some embodiments, R 4a and R 4b , or R 4a and R 5a , or R 4a and R 8a form ring B together with the carbon to which they are attached, For example, ring B can be a 4- to 7-membered cycloalkyl, a 4- to 7-membered heterocycloalkyl, one or more R 1d and is a 4- to 7-membered heterocycloalkyl substituted by:

[0017] In some embodiments, R 8a and R 8b are independently H, i.e., Z 3 is -(CH2)-. In some embodiments, R 1a , R 1c , R 1d and R 1e are independently halogen or C1 to C4 alkyl.

[0018] In some embodiments, R 1a are independently halogen, for example, F. In some embodiments, R 1e is independently C1 to C4 alkyl.

[0019] In some embodiments, R 9a , R 9b , R 10a and R 10b is independently C1-C4 alkyl or C1-C4 alkyl substituted with one or more halogens.

[0020] In some embodiments, A is a 6-membered heteroaryl, for example, pyridyl. In some embodiments,

[0021] [ka] is a single bond.

[0022] In some embodiments,

[0023] [ka] teeth,

[0024] [ka] or a mixture thereof, for example

[0025] [ka] It is.

[0026] In some embodiments, n is 0 or 1, R 1 are independently halogen, C1-C6 alkyl, one or more R 1a is a C1-C6 alkyl substituted with Z 1 is -(CR 6a R 6b )-or-(NR 6c )- and Z 2 is a connecting bond, or Z 1 is a connecting bond, and Z 2 is -(CR 7a R 7b )-and Z 3 is -(CR 8a R 8b )-and R a are independently H, R 6a , R 6b , R 7a and R 7bare independently H or halogen; R 6c are independently H or C1-C4 alkyl; R 3a , R 3b , R 5a , R 5b , R 8a and R 8b are independently H, R 4a and R 4b are independently H, C1-C6 alkyl, -(NR 9a R 9b ) or -(NR 10a )-(C=O)-R 10b and Or R 4a and R 4b , or R 4a and R 5a , or R 4a and R 8a together with the carbon to which they are attached form ring B, and ring B is selected from the group consisting of 4- to 7-membered cycloalkyl, 4- to 7-membered heterocycloalkyl, one or more R 1d or one or more R 1e is a 4- to 7-membered heterocycloalkyl substituted with R 1a , R 1d and R 1e are independently halogen or C1-C4 alkyl, R 9a , R 9b , R 10a and R 10b are independently C1-C4 alkyl or C1-C4 alkyl substituted with one or more halogens; A is phenyl or 6-membered heteroaryl;

[0027] [ka] represents a single bond or a double bond.

[0028] In some embodiments, n is 0 or 1, R 1 are independently halogen, C1-C6 alkyl, one or more R 1a is a C1-C6 alkyl substituted with Z 1 is -(CR 6a R 6b )-or-(NR 6c )- and Z 2 is a connecting bond, or Z 1 is a connecting bond, and Z 2 is -(CR 7a R 7b )-and Z 3 is -(CR 8a R 8b )-and R a are independently H, R 6a and R 6b are independently H or halogen; R 7a and R 7b are independently H, R 1a are independently halogen; R 6c are independently H or C1-C4 alkyl; R 3a , R 3b , R 5a , R 5b , R 8a and R 8b are independently H, R 4a are independently C1-C6 alkyl, -(NR 9a R 9b ) or -(NR 10a )-(C=O)-R 10b and R 4b are independently H or C1-C6 alkyl; Or R 4a and R 4b , or R 4a and R 5a , or R 4a and R 8atogether with the carbon to which they are attached form ring B, and ring B is a 4- to 7-membered cycloalkyl, a 4- to 7-membered heterocycloalkyl, or one or more R 1e is a 4- to 7-membered heterocycloalkyl substituted with R 1e are independently C1-C4 alkyl; R 9a , R 9b , R 10a and R 10b are independently C1-C4 alkyl or C1-C4 alkyl substituted with one or more halogens; A is a 6-membered heteroaryl, for example, pyridyl;

[0029] [ka] is a single bond.

[0030] In some embodiments, R 1 When is halogen, said halogen is fluorine, chlorine or bromine, for example fluorine or chlorine, also for example fluorine.

[0031] In some embodiments, R 1 But one or more R 1a When it is a C1-C6 alkyl substituted by, the number of the substituents is 1, 2, 3, 4 or 5, for example, 1, 2 or 3, for example, trifluoromethyl.

[0032] In some embodiments, R 1 is C1-C6 alkyl, one or more R 1a When the C1-C6 alkyl is a C1-C6 alkyl substituted with one or more R 1aThe C1-C6 alkyl (e.g., methyl, ethyl, propyl, butyl, pentyl or hexyl) in the C1-C6 alkyl substituted by is independently C1-C4 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl), for example, methyl.

[0033] In some embodiments, R 6a , R 6b , R 7a and R 7b When is independently a halogen, the halogen is independently fluorine, chlorine or bromine, for example fluorine or chlorine, also for example fluorine.

[0034] In some embodiments, R 6a , R 6b , R 7a and R 7b are independently C1-C6 alkyl, the C1-C6 alkyl (e.g., methyl, ethyl, propyl, butyl, pentyl or hexyl) is independently C1-C4 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl), for example, methyl.

[0035] In some embodiments, R 6c is independently C1-C4 alkyl, said C1-C4 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example, methyl.

[0036] In some embodiments, R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 8a and R 8bWhen is independently a halogen, the halogen is independently fluorine, chlorine or bromine, for example fluorine or chlorine, also for example fluorine.

[0037] In some embodiments, R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 8a and R 8b are independently C1 to C6 alkyl, one or more R 1c When the C1-C6 alkyl is a C1-C6 alkyl substituted with one or more R 1c The C1-C6 alkyl (e.g., methyl, ethyl, propyl, butyl, pentyl or hexyl) in the C1-C6 alkyl substituted by is independently C1-C4 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl), for example, methyl or ethyl.

[0038] In some embodiments, Ring B is a 4- to 7-membered cycloalkyl, one or more R 1d When the 4- to 7-membered cycloalkyl is substituted by R 1d The 4- to 7-membered cycloalkyl substituted by is independently cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, and is, for example, cyclopentyl.

[0039] In some embodiments, Ring B is a 4- to 7-membered heterocycloalkyl, or one or more R 1e When the 4- to 7-membered heterocycloalkyl is substituted by R 1eThe 4- to 7-membered heterocycloalkyl in the 4- to 7-membered heterocycloalkyl substituted by is independently tetrahydrofuranyl, tetrahydro-2H-pyranyl, pyrrolidinyl, for example, R 4a and R 4b form ring B together with the carbon to which they are attached, ring B is

[0040] [ka] and R 4a and R 5a , or R 4a and R 8a form ring B together with the carbon to which they are attached, ring B is

[0041] [ka] It is.

[0042] In some embodiments, R 1a , R 1c , R 1d and R 1e is independently halogen or C1-C4 alkyl substituted with one or more halogens, the halogen in said halogen and C1-C4 alkyl substituted with one or more halogens may be independently fluorine, chlorine or bromine, for example, fluorine or chlorine, and for example, fluorine.

[0043] In some embodiments, R 1a , R 1c , R 1d and R 1e wherein the C1-C4 alkyl in the C1-C4 alkyl or C1-C4 alkyl substituted by one or more halogens is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example, methyl or ethyl.

[0044] In some embodiments, R 9a , R 9b , R 10a and R 10b is independently C1-C4 alkyl, said C1-C4 alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example, methyl or ethyl.

[0045] In some embodiments, R 9a , R 9b , R 10a and R 10b is C1-C4 alkyl independently substituted with one or more halogens, in said C1-C4 alkyl substituted with one or more halogens, said C1-C4 alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example, methyl or ethyl.

[0046] In some embodiments, R 9a , R 9b , R 10a and R 10b is C1-C4 alkyl independently substituted with one or more halogens, the halogens are independently fluorine, chlorine or bromine, for example, fluorine, and for example, the C1-C4 alkyl substituted with one or more halogens is trifluoromethyl.

[0047] In some embodiments, When A is a 6-membered heteroaryl, said 6-membered heteroaryl is pyridyl, pyrazinyl or pyrimidinyl, said pyridyl being

[0048] [ka] wherein said pyrazinyl is

[0049] [ka] wherein said pyrimidinyl is

[0050] [ka] a may be A and

[0051] [ka] Represents the connection position of.

[0052] In some embodiments, R 1 is independently F, methyl or trifluoromethyl. In some embodiments, Z 1 is -(CH2)-, -(CF2)-, -(NH)- or -(N(CH3))-.

[0053] In some embodiments, R 4a and R 4b are independently H, ethyl, dimethylamino,

[0054] [ka] For example, R 4a and R 4b are independently ethyl, or R 4a is H and R 4b is dimethylamino,

[0055] [ka] It is.

[0056] In some embodiments, R4a and R 4b form ring B together with the carbon to which they are attached, e.g.

[0057] [ka] It is.

[0058] In some embodiments, R 4a and R 5a , or R 4a and R 8a form ring B together with the carbon to which they are attached, e.g.

[0059] [ka] It is.

[0060] In some embodiments,

[0061] [ka] teeth,

[0062] [ka] For example,

[0063] [ka] It is.

[0064] In some embodiments,

[0065] [ka] is phenyl,

[0066] [ka] For example,

[0067] [ka] (a represents the position of the fusion)

[0068] In some embodiments,

[0069] [ka] teeth,

[0070] [ka] For example,

[0071] [ka] It is.

[0072] In some embodiments,

[0073] [ka] teeth,

[0074] [ka] For example,

[0075] [ka] It is.

[0076] In some embodiments,

[0077] [ka] teeth,

[0078] [ka] For example,

[0079] [ka] It is.

[0080] In some preferred embodiments of the present invention, the pyrimidine formamide compound of formula I has any of the following structures:

[0081] [ka] TIFF2025038060000035.tif91168

[0082] In some preferred embodiments of the present invention, the pyrimidine formamide compound of formula I has any of the following structures: Compound with retention time of 8.483 minutes under the following conditions

[0083] [ka] : Separation by chiral chromatography, Chromatography column: CHIRALPAK AD-H, 250×4.6mm, 5um, Column temperature: 35℃, Flow rate: 0.4mL / min, Wavelength: 254nm, Gradient: A: n-hexane, B: isopropanol, A:B=1:4, Run time: 50min;

[0084] Compound with retention time of 13.580 minutes under the following conditions

[0085] [ka] : Separation by chiral chromatography, chromatographic column: CHIRALPAK AD-H, 250×4.6 mm, 5 um, column temperature: 35° C., flow rate: 0.4 mL / min, wavelength: 254 nm, gradient: A: n-hexane, B: isopropanol, A:B=1:4, run time: 50 min. Those skilled in the art should understand that the absolute configuration of the compound is only distinguished by retention time, and the absolute configuration corresponding to different retention times is subject to actual conditions.

[0086] In the present invention, the pyrimidineformamide compound represented by formula I or its pharma- ceutically acceptable salt can have one or more chiral carbon atoms, and can be separated to obtain optically pure isomers, such as pure enantiomers, or racemates, or mixed isomers.Pure single isomers can be obtained by separation methods in the art, such as salt formation by chiral crystallization, or chiral preparative column separation.

[0087] In the present invention, when stereoisomers exist in the pyrimidineformamide compound represented by formula I or its pharma- ceutical acceptable salt, they may exist in the form of a single stereoisomer or a mixture thereof (e.g., racemate). The term "stereoisomer" refers to a cis-trans isomer or an optical isomer. These stereoisomers can be separated, purified and concentrated by asymmetric synthesis or chiral separation methods (including but not limited to thin layer chromatography, rotary chromatography, column chromatography, gas chromatography, high pressure liquid chromatography, etc.), and can also be obtained by chiral resolution by bonding (e.g., chemical bonding) or salt formation (e.g., physical bonding) with other chiral compounds. The term "single stereoisomer" refers to the mass content of one stereoisomer of the compound of the present invention relative to all stereoisomers of the compound being 95% or more.

[0088] Therefore, throughout the specification, a person skilled in the art can select groups or substituents in the pyrimidine formamide compound represented by formula I, or its tautomer, mesomeric, racemic, enantiomer, diastereomer, or mixture form thereof, or its pharma- ceutically acceptable salt, to provide a stable pyrimidine formamide compound represented by formula I, or its tautomer, mesomeric, racemic, enantiomer, diastereomer, or mixture form thereof, or its pharma- ceutically acceptable salt, including, but not limited to, the compounds described in the examples of the present invention.

[0089] The pyrimidine formamide compound represented by formula I according to the present invention, or its tautomer, mesomeric, racemic, enantiomer, diastereomer, or mixture form thereof, or its pharma- ceutically acceptable salt, can be synthesized by a method including a method similar to a method known in the chemical art, and the procedure and conditions can refer to the procedure and conditions of a similar reaction in the art, and can be synthesized in particular according to the description in the present specification. Starting materials are generally available from commercial sources such as Aldrich, or can be easily prepared using methods known to those skilled in the art (available from SciFinder, Reaxys online database).

[0090] In the present invention, the pyrimidineformamide compound represented by the formula I, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture form thereof, or its pharma- ceutically acceptable salt, which is further produced by peripheral modification of the pyrimidineformamide compound represented by the formula I, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture form thereof, or its pharma- ceutically acceptable salt, in a manner conventional in the art, to obtain another pyrimidineformamide compound represented by the formula I, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture form thereof, or its pharma- ceutically acceptable salt.

[0091] In general, the compounds of the present invention can be prepared by the methods described herein, and unless otherwise indicated, the substituents are as defined in Formula I. Examples are used to further explain the invention.

[0092] The raw materials or reagents required for the preparation of the compounds of formula I are either commercially available or prepared by synthetic methods known in the art. The compounds of the present invention, either as free bases or as acid addition salts thereof, can be prepared by the methods described in the experimental section below. The term pharmaceutically acceptable salts refers to pharmaceutically acceptable salts as defined herein, which possess all the pharmacological activity of the parent compound. The pharmaceutically acceptable salts can be prepared by adding an acid corresponding to the appropriate organic solvent of the organic base, and following conventional methods to prepare the pharmaceutically acceptable salts.

[0093] Examples of salt formation include salt formation with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, and salt formation with organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, muconic acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, tartaric acid, p-toluenesulfonic acid, or trimethylacetic acid.

[0094] The pyrimidineformamide compounds of formula I can have one or more chiral carbon atoms, and therefore can be separated to obtain optically pure isomers, such as pure enantiomers, or racemates, or mixed isomers. Pure single isomers can be obtained by separation methods in the art, such as salt formation by chiral crystallization, or chiral preparative column separation.

[0095] The chemicals used in the synthetic pathways described in the present invention include solvents, reagents, catalysts, and protecting groups, deprotecting groups, and the protecting groups include tert-butoxycarbonyl (Boc). The above methods may further include previous or subsequent steps as specifically described herein, and the target compound may be obtained by adding or removing the appropriate protecting group. Furthermore, the various synthetic steps may be performed alternately or sequentially to obtain the final target compound.

[0096] The present invention provides a pharmaceutical composition comprising the pyrimidine formamide compound represented by the above formula I, or its tautomer, mesomeric, racemic, enantiomer, diastereomer, or mixture form thereof, or its pharmaceutically acceptable salt, and (one or more) pharmaceutically acceptable auxiliary (e.g., pharmaceutically acceptable carrier, diluent, solvent or other excipient). The amount of the pyrimidine formamide compound represented by the above formula I, or its tautomer, mesomeric, racemic, enantiomer, diastereomer, or mixture form thereof, or its pharmaceutically acceptable salt, may be a therapeutically effective amount.

[0097] The present invention also provides the use of the pyrimidine formamide compound represented by formula I, or its tautomer, mesomeric, racemic, enantiomer, diastereomer, or mixture form thereof, or its pharma- ceutically acceptable salt, in the manufacture of Vanin-1 inhibitors. In the use, the Vanin-1 inhibitors can be used in mammalian organisms, and can also be used outside the organism, mainly for experimental purposes, for example, as standard or control samples to provide comparison, or prepared into kits according to conventional methods in the art to provide rapid detection of Vanin-1 inhibitory effects. The term "vanin-1 (enzyme) inhibitors" as used herein refers to compounds that bind to vanin-1 (enzyme) and reduce the enzymatic activity produced thereby.

[0098] The present invention also relates to a method for the preparation of a medicament comprising the use of a pyrimidine formamide compound represented by formula I or a tautomer, mesomeric, racemic, enantiomer, diastereomer, or provides the use of a mixture form thereof or a pharma- ceutical acceptable salt thereof, the medicament being for use in the prevention and / or treatment of a disease associated with Vanin-1, or the medicament being for use in the prevention and / or treatment of one or more of autoimmune diseases, inflammatory diseases, allergic diseases, metabolic diseases, infectious diseases, fibrotic diseases, cardiovascular diseases, respiratory diseases, kidney diseases, skin diseases, liver diseases, digestive diseases, oral diseases, and hematopoietic diseases, or for example, a medicament for treating Crohn's disease, inflammatory bowel disease, and ulcerative colitis. The Vanin-1 associated disease may include one or more of autoimmune diseases, inflammatory diseases, allergic diseases, metabolic diseases, infectious diseases, fibrotic diseases, cardiovascular diseases, respiratory diseases, kidney diseases, skin diseases, liver diseases, digestive diseases, oral diseases, and hematopoietic diseases, or for example, inflammatory bowel disease, ulcerative colitis, Crohn's disease, colorectal cancer, and gastritis.

[0099] Another aspect of the present invention relates to a method for preventing and / or treating diseases associated with Vanin-1, comprising administering to a patient a therapeutically effective dose of a pyrimidine formamide compound of formula I, or a tautomer, mesomeric, racemic, enantiomer, diastereomer, or mixture thereof, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for example treating diseases or conditions mediated by or associated with the inhibition of Vanin-1 enzyme, such as one or more of autoimmune diseases, inflammatory diseases, allergic diseases, metabolic diseases, infectious diseases, fibrotic diseases, cardiovascular diseases, respiratory diseases, renal diseases, skin diseases, liver diseases, digestive diseases, oral diseases, and hematopoietic diseases, or for example inflammatory bowel diseases, ulcerative colitis, Crohn's disease, colorectal cancer, and gastritis.

[0100] Another aspect of the present invention relates to a method for preventing and / or treating one or more of autoimmune diseases, inflammatory diseases, allergic diseases, metabolic diseases, infectious diseases, fibrotic diseases, cardiovascular diseases, respiratory diseases, renal diseases, skin diseases, liver diseases, digestive diseases, oral diseases and hematopoietic diseases (e.g., inflammatory bowel disease, ulcerative colitis, Crohn's disease, colorectal cancer and gastritis), which comprises administering to a patient a therapeutically effective amount of the pyrimidine formamide compound represented by formula I, or a tautomer, mesomeric, racemic, enantiomer, diastereomer or mixture thereof, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0101] Another aspect of the present invention relates to a pharmaceutical agent for inhibiting Vanin-1, comprising a pyrimidine formamide compound represented by the above formula I, or a tautomer, mesomeric, racemic, enantiomer, diastereomer, or mixture thereof, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition containing the same.

[0102] The compounds of the invention can be administered locally or systemically, for example for enteral administration, such as rectal or oral administration, or for parenteral administration to mammals, particularly humans. The compounds of the invention can also be administered parenterally, for example by injection or infusion, intravenously, intraarterially, intraosseously, intramuscularly, intracerebrally, extraventricularly, intrasynovially, intrasternally, intrathecally, intralesionally, intracranially, intratumorally, intradermally and subcutaneously.

[0103] The effective amount of the compound, pharmaceutical composition or drug according to the present invention is determined according to the species of mammal, body weight, age, individual condition, individual pharmacokinetic parameters, the disease to be treated and the administration method. The effective amount of the compound, pharmaceutical composition or drug according to the present invention can be easily determined by routine experimentation, and the most effective and convenient route of administration and the most suitable formulation can also be determined by routine experimentation.

[0104] Said pharmaceutical excipient may be an excipient widely used in the field of pharmaceutical manufacturing. The excipient is mainly used to provide a safe, stable and functional pharmaceutical composition, and can also provide a way to allow the subject to dissolve the active ingredient at a desired rate after administration, or to promote effective absorption of the active ingredient after administration of the composition to the subject. The pharmaceutical excipients may be inert fillers or may serve a specific function, such as stabilizing the overall pH of the composition or preventing degradation of the active ingredients of the composition. The pharmaceutical excipients may include one or more of the following: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrants, lubricants, anti-adherents, glidants, wetting agents, gelling agents, absorption retarders, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavoring agents, and sweeteners.

[0105] Substances that can be used as pharma- ceutically acceptable excipients include ion exchangers, aluminum, aluminum stearate, lecithin, serum proteins such as human serum albumin, phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, buffer substances such as salts, or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, lanolin, sugars such as lactose, glucose, sucrose, starches such as corn starch and potato starch, sodium carboxymethylcellulose, ethylcellulose, and and cellulose and its derivatives such as cellulose acetate, powdered gums, malt, gelatin, talc, excipients such as cocoa butter and suppository waxes, oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, soybean oil, glycols such as propylene glycol and polyethylene glycol, esters such as ethyl oleate, ethyl laurate, agar, buffer solutions such as magnesium hydroxide and aluminum hydroxide, alginic acid, pyrogen-free water, isotonic salts, Ringer's solution, ethanol, phosphate buffer solutions, and other non-toxic suitable lubricants such as sodium lauryl sulfate, magnesium stearate, colorants, release agents, coating agents, sweeteners, flavorings and fragrances, preservatives and antioxidants.

[0106] The pharmaceutical compositions of the present invention can be manufactured according to the present disclosure using any method known to one skilled in the art, for example, conventional mixing, dissolving, granulating, emulsifying, grinding, encapsulating, entrapping or lyophilizing processes.

[0107] Pharmaceutical dosage forms of the compounds of the present invention can be provided as immediate release, controlled release, sustained release or targeted drug release systems. Common dosage forms include, for example, solutions and suspensions, (micro)emulsions, ointments, gels and patches, liposomes, tablets, dragees, soft or hard shell capsules, suppositories, ovules, implants, amorphous or crystalline powders, aerosols and lyophilized formulations. Depending on the route of administration used, special devices may be required to administer or administer the drug, such as syringes and needles, inhalers, pumps, injection pens, applicators or special flasks. Pharmaceutical dosage forms often consist of a drug, excipients, and a container / closure system. One or more excipients (also called inactive ingredients) can be added to the compounds of the present invention to improve or facilitate the manufacture, stability, administration and safety of the drug, as well as to provide a desired drug release curve method. Thus, the type of excipients added to the drug is determined by various factors, such as the physical and chemical properties of the drug, the route of administration, and the manufacturing process. Pharmaceutically acceptable excipients exist in the art and include those listed in various pharmacopoeias (US Pharmacopeia, USP, Japanese Pharmacopoeia, Jp, European Pharmacopoeia, EP and British pharmacopoeia, BP, the US Food and Drug Administration (www.fda.gov) Center for Drug Evaluation and Research, (CEDR) publications such as the Inactive Ingredient Guide (1996), Ash and Ash's Handbook of Pharmaceutical Excipients (Handbook of Pharmaceutical Excipients), and other publications such as the Inactive Ingredient Guide (1996) ... (See e.g., R.A.C. Additives, 2002, SIR (Synapse Information Resources, Inc., Endicott NY)).

[0108] Pharmaceutical dosage forms of the compounds of the present invention may be prepared by any method known in the art, for example by conventional mixing, sieving, dissolving, melting, granulating, dragee-making, tabletting, suspending, extruding, spray-drying, grinding, emulsifying, (nano / micro)encapsulating, entrapping or lyophilizing processes.

[0109] The pharmaceutical composition of the present invention can be administered locally or systemically, for example, for enteral administration such as rectal or oral administration, or for parenteral administration to mammals (especially humans), and can contain a therapeutically effective amount of the compound according to the present invention or its pharma- ceutical acceptable active ingredient, together with a pharma- ceutical acceptable excipient such as a pharma- ceutical acceptable carrier. The therapeutically effective amount of the active ingredient is as defined above and below in this specification, and the compound of the present invention can be prepared into various dosage forms depending on the species of mammal, body weight, age, individual condition, individual pharmacokinetic parameters, disease to be treated, and administration method, and in the case of enteral administration, for example, oral administration.

[0110] The pharmaceutical compositions and dosage forms may contain one or more compounds of the present invention as an active ingredient, or one or more pharma- ceutically acceptable salts thereof. The pharma- ceutically acceptable carriers may be solid or liquid. Solid preparations include powders, tablets, pills, troches, capsules, cachets, suppositories, and dispersible granules. The solid carrier may also be one or more of a diluent, flavoring, solubilizer, lubricant, suspending agent, binder, preservative, tablet disintegrating agent, or encapsulating material. In powders, the carrier is usually a finely divided solid, which is in admixture with the finely divided active ingredient. In tablets, the active ingredient is usually mixed with a carrier having the necessary binding capacity in suitable proportions and compacted into the desired shape and size. Suitable carriers include, but are not limited to, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The formulation of the active compound may include an encapsulating material as a carrier, with or without a carrier, providing a capsule in which the active ingredient is surrounded by a carrier to which it is bound.

[0111] Other forms suitable for oral administration include liquid form preparations, including emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions, or solid form preparations intended to be converted to liquid form preparations immediately before use. Emulsions can be prepared with solutions such as aqueous propylene glycol solutions, or can contain emulsifiers such as lecithin, sorbitan monooleate, or gum labia. Aqueous solutions can be prepared by dissolving the active ingredient in water and adding suitable colorants, flavors, stabilizers, and thickeners. Aqueous suspensions can be prepared by dispersing finely divided active ingredients in water with binders such as natural or synthetic gums, resins, methylcellulose, carboxymethylcellulose, and other commonly used suspending agents. Solid preparations include solutions, suspensions, and emulsions, and contain colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, and the like in addition to the active ingredient.

[0112] Exemplary combinations for rectal administration include suppositories containing suitable nonirritating excipients, such as, for example, cocoa butter, synthetic glycerides, or polyethylene glycols, which are solid at ordinary temperatures but can melt and / or dissolve in the rectal cavity to release the drug.

[0113] A therapeutically effective dose can be estimated initially using various methods known in the art. Initial dosages for animal studies can be based on effective concentrations established in cell culture assays. Suitable dosage ranges for human individuals can be determined, for example, using data obtained from animal studies and cell culture assays. In certain embodiments, the compounds of the invention can be prepared as pharmaceutical agents for oral administration.

[0114] An effective or therapeutically effective amount or dose of a drug (e.g., a compound of the invention) refers to that amount of drug or compound that results in amelioration of symptoms or a prolongation of survival in an individual. Toxicity and therapeutic efficacy of the molecules can be measured by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., LD50 (the dose that is lethal to 50% of the population) and ED 50 The dose ratio between toxic and therapeutic effects is the therapeutic index, and the LD 50 / ED 50 It is preferred that the agent exhibit a high therapeutic index.

[0115] An effective amount or therapeutically effective amount is that amount of a compound or pharmaceutical composition that elicits the biological or medical response in a tissue, system, animal or human that is desired by a researcher, veterinarian, physician or other clinician. The dosage is preferably administered with little or no toxicity ED. 50 The circulating concentration range includes: 100 mg / kg / day, ...

[0116] Dosage and interval can be adjusted individually to provide plasma levels of the active moiety sufficient to obtain the desired effect, i.e., the minimal effective concentration (MEC). The MEC for each compound varies but can be estimated, for example, from in vitro data and animal studies. The dosage required to achieve the MEC depends on individual characteristics and the route of administration. In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to the plasma concentration.

[0117] The amount of drug or composition administered will depend on a variety of factors, including the sex, age, and weight of the individual being treated, the severity of the condition, the manner of administration, and the judgment of the prescribing physician. The composition of the present invention can be provided in a packing or dispensing device, if necessary, containing one or more unit dosage forms (including active ingredient). For example, the packing or dispensing device can contain metal or plastic foil (such as foam packing) or glass and rubber stopper, such as vial. The packing or dispensing device can be accompanied by instructions for use. Also, compositions of the compound of the present invention formulated in a compatible pharmaceutical carrier can be prepared and placed in an appropriate container, and can be labeled for the treatment of a specific disease.

[0118] Unless otherwise defined, all technical and scientific terms used herein have standard meanings within the art to which the claimed subject matter belongs. In the event that there are a plurality of definitions for a term, those set forth herein prevail.

[0119] Group Definition As used herein, the following definitions shall apply unless otherwise stated. For purposes of this invention, the chemical elements are consistent with the CAS Periodic Table of the Elements and the "Handbook of Chemistry and Physics", 75th Edition, 1994. General principles of organic chemistry are also described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito:1999, and "March's Advanced Organic Chemistry" by Michael B. Smith and Jerry March, John Wiley & Sons, Inc. Sons, New York: 2007, the entire contents of which are incorporated herein by reference.

[0120] In this specification, groups and substituents thereof may be selected by one skilled in the art to provide stable structural moieties and compounds. Where a substituent is depicted in a conventional chemical formula written from left to right, the substituent also includes the chemically equivalent substituent that would result if the structural formula were written from right to left.

[0121] Certain chemical groups defined herein are preceded by a shorthand symbol indicating the total number of carbon atoms present in that group. For example, C1-C6 alkyl refers to an alkyl, as defined below, having a total of 1, 2, 3, 4, 5 or 6 carbon atoms. The total number of carbon atoms in the shorthand symbol does not include carbons that may be present in substituents of said group.

[0122] In this specification, the numerical ranges defined for substituents, for example, 0 to 4, 1 to 4, 1 to 3, etc., represent integers within the ranges; for example, 1 to 6 is 1, 2, 3, 4, 5, 6. In addition to the above, as used in the specification and claims of this application, unless specifically stated otherwise, the following terms have the meanings indicated below.

[0123] The term "comprises" is an open-ended definition, i.e. includes the subject matter specified in the present invention but does not exclude other aspects. The term "substituted" refers to the replacement of any one or more hydrogen atoms at a particular atom with a substituent, including deuterium and hydrogen variants, provided that the particular valence state is normal and the compound is stable after substitution.

[0124] In general, the term "substituted" refers to one or more hydrogen atoms in a given structure being replaced with a specific substituent. Furthermore, when the substituent is replaced with one or more of the aforementioned substituents, the aforementioned substituents are independent of each other, i.e., the aforementioned one or more substituents may be different from each other or may be the same. Unless otherwise stated, a substituent may be replaced at each substitutable position of the substituent. When multiple positions of a given structural formula may be replaced with one or more substituents selected from a specific group, the substituent may be replaced at each position in the same or different manner.

[0125] In various parts of this specification, the substituents of the compounds disclosed herein are disclosed according to radical types or ranges. In particular, the present invention includes each independent subcombination of each member of these radical types and ranges. For example, the terms "C1-C6 alkyl" or "C 1-6"Alkyl" specifically refers to any of the independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, etc. C5 alkyl and C6 alkyl. 1-4 "Alkyl" is specifically disclosed separately. "C4 alkyl" refers to substituted methyl, ethyl, C3 alkyl (i.e., propyl, including n-propyl and isopropyl), and C4 alkyl (i.e., butyl, including n-butyl, isobutyl, sec-butyl, and tert-butyl).

[0126] The term "halogen" is selected from F, Cl, Br or I and particularly refers to F or Cl. In this application, the term "alkyl" as a group or part of another group refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 12 carbon atoms, preferably a straight or branched chain alkyl group containing 1 to 6 carbon atoms. n H 2n+1 The term "C1-C6 alkyl" refers to an alkyl moiety having 1, 2, 3, 4, 5, or 6 carbon atoms. In some embodiments, the "alkyl" refers to a C1-C6 alkyl. In some embodiments, the "alkyl" refers to a C1-C4 alkyl.

[0127] Non-limiting examples of lower alkyls containing 1 to 6 carbon atoms include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2 These include 1-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like. Non-limiting examples containing 1 to 12 carbon atoms include the lower alkyl examples containing 1 to 6 carbon atoms listed above, as well as 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-quinyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and the various branched chain isomers.

[0128] In this application, unless otherwise defined as a group or part of another group, the term "cycloalkyl" refers to a saturated monocyclic, polycyclic or bridged carbocyclic substituent composed only of carbon and hydrogen atoms and may be attached to the remainder of the molecule by a single bond through any suitable carbon atom, or in the case of polycyclic, may be a fused or spiro-bonded (i.e., two geminal hydrogens at a carbon atom are replaced by alkylene) bridged or spiro ring system. The cycloalkyl substituent may be attached to the core molecule through any suitable carbon atom. In some embodiments, a ring having 3 to 10 carbon atoms is a C3 to C4 ring. 10 In some embodiments, C3-C6 cycloalkyl includes cyclopropyl (C3), cyclobutyl (C4), cyclopentyl (C5), and cyclohexyl (C6). 10Illustrative examples of cycloalkyl include cycloheptyl (C7), cyclooctyl (C8), cyclononyl (C9), and cyclodecyl (C10), along with the above C3-C6 cycloalkyls. 10 ) are included.

[0129] In this application, the term "heterocycloalkyl" as a group or part of another group refers to a stable 3- to 7-membered saturated cyclic group consisting of 2 to 6 carbon atoms and 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur. Exemplary 3-membered heterocyclyl groups include, but are not limited to, aziridinyl, oxiranyl, and thiacyclopropanyl, or stereoisomers thereof, and the like; exemplary 4-membered heterocyclyl groups include, but are not limited to, azetidinyl, epoxypropanyl, thietanyl, or isomers and stereoisomers thereof, and the like; exemplary 5-membered heterocyclyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, imidazolidinyl, pyrazolidinyl, dioxolanyl, oxathiofuranyl, dithiofuranyl, or isomers and stereoisomers thereof, and the like. Exemplary 6-membered heterocyclyl groups include, but are not limited to, piperidinyl, tetrahydropyranyl, thianyl, morpholinyl, thiomorpholinyl, dithianyl, dioxanyl, piperazinyl, triazinyl, or isomers and stereoisomers thereof, and exemplary 7-membered heterocyclyl groups include, but are not limited to, azepanyl, oxepanyl, thiepanyl, and diazepanyl, or isomers and stereoisomers thereof. In some embodiments, a "heterocycloalkyl" is a C2-C5 heterocycloalkyl, where the heteroatom is selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, or 3.

[0130] As used herein, as a group or part of another group, the term "heteroaryl" refers to an aromatic ring system having carbon atoms and one to three heteroatoms, where each heteroatom is independently "4-16 membered heteroaryl" refers to a group of 4-16 membered mono- or bicyclic 4n+2 aromatic ring systems (e.g., having 6 or 10 shared p electrons in a cyclic arrangement) having one or more nitrogen atoms selected from nitrogen, oxygen and sulfur. In heteroaryls containing one or more nitrogen atoms, the point of attachment may be at a carbon or nitrogen atom, where valence permits.

[0131] In some embodiments, the heteroaryl has one or more heteroatoms selected from N, O, and S, and is a 4- to 6-membered heteroaryl having 1 to 3 heteroatoms, preferably a 5- to 6-membered heteroaryl.

[0132] Exemplary 5-membered heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, furanyl, oxatriazolyl, or tetrazolyl, etc. Exemplary 6-membered heteroaryl groups include, but are not limited to, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl, or tetrazinyl, etc.

[0133] As used herein, the terms "moiety," "structural moiety," "chemical moiety," "group," and "chemical group" refer to specific fragments or functional groups in a molecule. A chemical moiety is generally recognized as a chemical entity embedded in or attached to a molecule.

[0134] If a recited substituent does not indicate through which atom it is attached to a compound contained in a general formula but not specifically mentioned, such substituent may be attached through any of the atoms. Combinations of substituents and / or variables thereof are permissible only if such combinations result in stable compounds.

[0135] In various parts of the present invention, linking substituents are described. If the structure clearly requires a linking group, the Markush variable listed for that group should be understood as the linking group. For example, if the structure requires a linking group and "alkyl" or "aryl" is listed as the Markush group definition for this variable, then "alkyl" or "aryl" should be understood to represent the linked alkylene or arylene group, respectively.

[0136] In some specific structures, when an alkyl group is explicitly depicted as a linking group, said alkyl group represents a linked alkylene group, e.g., the C1-C6 alkyl of "halo-C1-C6 alkyl" is to be understood as C1-C6 alkylene.

[0137] The term "alkylene" refers to a saturated divalent hydrocarbon group obtained by removing two hydrogen atoms from a saturated straight or branched chain hydrocarbon. Examples of alkylene groups include methylene (-CH-), ethylene {including -CHCH- or -CH(CH)-}, isopropylidene {including -CH(CH)CH- or -C(CH)-}, and the like.

[0138] Unless otherwise defined, all technical and scientific terms used herein have standard meanings within the art to which the claimed subject matter belongs. In the event that there are a plurality of definitions for a term, those set forth herein prevail.

[0139] Unless otherwise defined, singular forms such as "a" and "an" as used herein should be understood to include plural referents. Also, the term "comprises" is an open rather than closed limitation, i.e., includes the subject matter specified in the present invention but does not exclude other aspects.

[0140] Unless otherwise defined, the present invention employs conventional methods of mass spectrometry and elemental analysis, and each step and condition may refer to conventional operating steps and conditions in the art. Unless otherwise defined, this invention uses standard nomenclature and standard laboratory procedures and techniques of analytical chemistry, organic synthetic chemistry, and optics. In some cases, standard techniques are used for chemical syntheses, chemical analyses, and performance testing of light emitting devices.

[0141] Unless otherwise defined, the description method "independently ..." used in the present invention should be understood in a broad sense, and each described individual is independent of each other, and may be the same or different specific groups independently. More specifically, the description method "independently ..." refers to specific options represented by the same symbol in different groups not affecting each other, and also represents that specific options represented by the same symbol in the same group not affecting each other.

[0142] Those skilled in the art will recognize, in accordance with conventions used in the art, the " " used in the structural formulas of groups described in this application.

[0143] [ka] " indicates that the corresponding group is connected to other fragments and groups within the compound through this site.

[0144] "Pharmaceutically acceptable" refers to the conditions under which a substance may be used in the manufacture of a pharmaceutical composition, including conditions that are generally safe, non-toxic, and non-biologically and otherwise undesirable, and that are acceptable for veterinary and human medicine.

[0145] The term "excipient" refers to a pharma- ceutically acceptable chemical, e.g., a reagent to aid in the administration of a drug, known to those skilled in the art of pharmacy. It is a compound that may be used in the preparation of a pharmaceutical composition, and includes excipients that are generally safe, non-toxic, and biologically or otherwise undesirable and are acceptable for veterinary and human medicines. Common excipients include binders, surfactants, diluents, disintegrants, and lubricants.

[0146] The term "effective therapeutic amount" refers to the amount of a compound used that, when administered to a subject for treating a disease state, is sufficient to treat the disease state. An "effective therapeutic amount" will vary depending on the compound, the disease state being treated, the severity of the disease being treated, the age and relative health of the subject, the route and mode of administration, and the judgment of the attending physician or veterinarian.

[0147] The term mammal refers to a human or any mammal, such as, for example, a primate, farm animal, pet or laboratory animal. Examples of such animals include monkeys, cows, sheep, horses, pigs, dogs, cats, rabbits, mice and rats. The mammal is preferably a human.

[0148] The above preferred conditions can be combined in any manner to obtain each preferred embodiment of the present invention, without violating the ordinary skill in the art. The reagents and materials used in the present invention are commercially available.

[0149] The positive effect of the present invention is to provide pyrimidine formamide compounds which can be used as Vanin enzyme, particularly Vanin-1, inhibitors for the prevention and / or treatment of Crohn's disease, ulcerative colitis, and inflammatory bowel disease. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0150] The present invention will be further described below by way of examples, but the present invention is not limited to the scope of the examples. In the following examples, experimental methods for which no specific conditions are described were selected according to conventional methods and conditions or product instructions.

[0151] Example 1 Synthesis of Compound 1

[0152] [ka]

[0153] Step 1 Sodium acetate (129 mg) and hydroxylamine hydrochloride (322 mg) were added in sequence to a solution of compound 1a (250 mg) in a mixed solvent of ethanol / water (v / v=4:1, 5 mL). The resulting reaction solution was heated to 94° C. and stirred for 2 hours. The reaction was completed. After cooling, water (50 mL) was added, and the mixture was extracted with ethyl acetate (100 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the crude product of compound 1b (257 mg).

[0154] Step 2 Zinc powder (339 mg) was added in batches to a solution of compound 1b (257 mg) in acetic acid (5 mL). The resulting reaction solution was heated to 70° C. and stirred for 2 hours. The reaction was completed. It was cooled, filtered through diatomaceous earth, and the filtrate was concentrated and adjusted to pH 9 with aqueous NaOH (10%), extracted with ethyl acetate (20 mL×4), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give crude compound 1c (100 mg).

[0155] Step 3 Under conditions of -10°C and nitrogen gas protection, T3P (propylphosphonic anhydride) (254.00 g) was slowly added dropwise to a solution of compound 1d (25.40 g), compound 1e (31.00 g) and triethylamine (61.00 g) in acetonitrile (250 mL). After the addition was completed, the reaction system was maintained at -5°C and reacted for 3 hours. The reaction was completed. 300 mL of water was added to the reaction solution to quench the reaction, and the organic solvent was removed by concentration. The residue was stirred at 5°C for 1 hour to precipitate a solid, filtered, and the cake was washed with water (100 mL x 1) and dried to obtain compound 1f (42.00 g), with a yield of 93%.

[0156] 1 H NMR (400 MHz, CDCl3) δ 8.80 (s, 2H), 3.81-3.57 (m, 7H), 3.36 (s, 1H), 1.93 (td, J = 14.58, 7.25 Hz, 2H), 1.66 (t, J = 5.35 Hz, 2H), 1.58 (dd, J = 11.10, 4.64 Hz, 2H).

[0157] Step 4 A solution of compound 1f (168 mg), compound 1c (100 mg) and potassium carbonate (99 mg) in a mixed solvent of isopropanol / water (v / v=99:1, 2 mL) was heated to 85° C. and stirred for 4 hours. The reaction was completed. It was cooled, filtered, the cake was rinsed with isopropanol (10 mL×2), concentrated, and the residue was purified on a silica gel column (methanol / dichloromethane=0-100%) to obtain compound 1 (26 mg).

[0158] 1 H NMR (400 MHz, MeOH-d4) δ 8.60 (s, 2H), 8.44 (s, 1H), 8.36 (d, J = 3.89 Hz, 1H), 7.37 (d, J = 4.86 Hz, 1H), 5.75 (t, J = 6.75 Hz, 1H), 3.66 (ddd, J = 19.18, 16.47, 5.76 Hz, 6H), 3.54 (d, J = 22.28 Hz, 2H), 3.16-3.09 (m, 1H), 2.98 (dd, J = 16.74, 8.39 Hz, 1H), 2.71-2.57 (m, 1H), 2.05 (dd, J = 12.89, 8.02 Hz, 1H), 1.93 (dd, J = 15.51, 7.35 Hz, 2H), 1.73-1.51 (m, 4H). LCMS (ESI), [M+H] + = 380.2

[0159] Example 2 Synthesis of Compound 2, Compound 2-1, and Compound 2-2

[0160] [ka]

[0161] Step 1 Sodium acetate (740 mg) and hydroxylamine hydrochloride (630 mg) were added in sequence to a solution of compound 2a (500 mg) in ethanol / water (v / v=4:1, 10 mL) mixed solvent, and the resulting reaction solution was heated to 94° C. and stirred for 2 hours. The reaction was completed. After cooling, water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product of compound 2b (500 mg).

[0162] Step 2 Zinc powder (421 mg) was added in batches to a solution of compound 2b (320 mg) in acetic acid (6 mL), and the resulting reaction solution was heated to 70° C. and stirred for 2 hours. The reaction was completed. It was cooled, filtered, and concentrated. The residue was adjusted to pH 9 with aqueous NaOH (10%), extracted with ethyl acetate (20 mL×4), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give crude compound 2c (100 mg).

[0163] Step 3 According to the method of Example 1, compound 2 (66 mg) was obtained from compound 1f (168 mg) and compound 2c (100 mg).

[0164] 1 H NMR (400 MHz MeOH-d4)δ8.58 (s, 2H), 8.35 (d, J = 4.69 Hz, 1H), 7.78-7.70 (m, 1H),7.27-7.18 (m, 1H), 5.71 (t, J = 7.15 Hz, 1H), 3.80-3.59 (m, 6H), 3.54 (d, J = 20.77 Hz, 2H),3.13 (ddd, J = 16.55, 9.14, 3.68 Hz, 1H),3.00 (td, J = 16.84, 8.51 Hz, 1H), 2.67 (ddd, J = 16.06, 8.24, 3.91 Hz, 1H), 2.14-1.99 (m, 1H), 1.93 (dd, J = 16.94, 7.33 Hz, 2H),1.72-1.51 (m, 4H). LCMS (ESI), [M+H] + = 380.3 Compound 2 was subjected to chiral resolution to give two enantiomers, 2-1 (retention time: 8.483 min) and 2-2 (retention time: 13.580 min).

[0165] The chromatographic conditions are as shown below. Chromatography column: CHIRALPAK AD-H (5um, 4.6×250mm) Flow rate: 0.4mL / min Wavelength: 254nm Column temperature: 35℃ Mobile phase: A: n-hexane, B: isopropanol, A:B=1:4 Run Time: 50 minutes

[0166] Example 3 Synthesis of Compound 7

[0167] [ka]

[0168] Step 1 Compound 7a (200 mg, 1.27 mmol), compound 1e (187 mg, 1.33 mmol), and acetonitrile (3 mL) were added to a 25 mL three-neck flask. The reaction mixture was cooled to -10°C, and T3P (350 mg, 0.4 mol) was slowly added dropwise. Next, triethylamine (260 mg, 5.54 mmol) was dissolved in acetonitrile (5 mL) and added to the reaction solution, and the reaction system was kept at -5°C and stirred for 3 hours. After the reaction was completed, water (30 mL) was added to the reaction mixture to quench the reaction. The mixture was concentrated, cooled to 5°C, and stirred for 1 hour. After filtration, the cake was washed with 100 mL of water to obtain 200 mg of a white solid, which was compound 7c, and the yield was 56%.

[0169] Step 2 Compound 7c (200 mg, 0.71 mmol), compound 7d (100 mg, 0.75 mol) and isopropanol / water (V / V=99:1, 5 mL) were added sequentially to a 10 mL three-neck flask, followed by potassium carbonate (489 mg, 3.55 mmol). The reaction mixture was heated to 85° C. and stirred at reflux for 4 hours. After completion of the reaction, the reaction was cooled to 45° C., 5 mL of acetone was added and stirred for 1 hour. It was filtered and the cake was washed with 20 mL of acetone. The filtrate was concentrated to 3 mL, and 4 mL of isopropanol was added to concentrate to 2 mL, then cooled to 0° C. and stirred for 1 hour. It was filtered to obtain 100 mg of an off-white solid, which was compound 7, with a yield of 38%.

[0170] LCMS m / z(ESI): 379 [M+1]. 1 H NMR (400 MHz, DMSO-D6):δ11.36 (s, 1H), 10.02 (s, 1H), 8.68 (d, J=1.6H Z , 2H), 8.22 (m, 2H),7.85 (s, 1H), 7.02-7.05 (m, 1H), 3.54-3.70 (m, 7H), 3.33-3.38 (m, 1H), 1.81 (s, 2H),1.46-1.56 (m, 4H).

[0171] Example 4 Synthesis of Compound 8

[0172] [ka]

[0173] Step 1 Compound 8a (200 mg, 1.27 mmol), compound 1e (187 mg, 1.33 mmol), and acetonitrile (3 mL) were added to a 25 mL three-neck flask, cooled to -10°C, and T3P (350 mg, 0.4 mol) was slowly added dropwise. Triethylamine (260 mg, 5.54 mmol) was dissolved in acetonitrile (5 mL) and added to the reaction solution, and the reaction system was kept at -5°C and stirred for 3 hours. After completion of the reaction, water (30 mL) was added to the reaction mixture to quench the reaction. The mixture was concentrated, cooled to 5°C, and stirred for 1 hour. After filtration, the cake was washed with water (100 mL) to obtain 200 mg of a white solid, which was compound 8c, and the yield was 56%.

[0174] Step 2 Compound 8c (90 mg, 0.32 mmol), compound 8d (50 mg, 0.34 mol) and isopropanol / water (v / v=99:1, 5 mL) were added sequentially to a 10 mL three-neck flask, followed by potassium carbonate (220 mg, 1.6 mmol). The reaction mixture was heated to 85° C. and stirred at reflux for 4 hours. After completion of the reaction, the reaction mixture was cooled to 45° C., acetone (5 mL) was added and stirred for 1 hour. It was filtered and the cake was washed with acetone (20 mL). The filtrate was concentrated to 3 mL and isopropanol (4 ml) was added and concentrated to 2 mL. It was cooled to 0° C. and stirred for 1 hour. It was filtered to give 40 mg of an off-white solid, which was compound 8, with a yield of 32%.

[0175] LCMS m / z(ESI): 393 [M+1]. 1 H NMR (400 MHz, DMSO-D6):δ10.11 (s, 1H ), 8.68 (d, J=1.6H Z, 2H), 8.22 (m, 2H), 7.94(m, 1H), 7.02-7.05 (m, 1H), 5.75(s, 1H), 3.61(s, 3H), 3.54-3.70 (m, 6H), 3.33-3.38 (m, 2H), 1.81 (s, 2H), 1.46-1.56 (m, 5H).

[0176] Example 5 Synthesis of Compound 13

[0177] [ka]

[0178] Step 1 Compound 13a (200 mg, 1.27 mmol), compound 13b (168 mg, 1.33 mmol), and acetonitrile (3 mL) were added to a 25 mL three-neck flask, cooled to -10°C, and T3P (350 mg, 0.4 mol) was slowly added dropwise. Triethylamine (260 mg, 5.54 mmol) was dissolved in acetonitrile (5 mL) and added to the reaction solution, and the reaction system was kept at -5°C and stirred for 3 hours. After completion of the reaction, water (30 mL) was added to the reaction mixture to quench the reaction. The mixture was concentrated, cooled to 5°C, and stirred for 1 hour. After filtration, the cake was washed with water (100 mL) to obtain 70 mg of a white solid, which was compound 13c, and the yield was 20%.

[0179] Step 2 Compound 13c (70 mg, 0.26 mmol), compound 13d (41 mg, 0.28 mol) and isopropanol / water (V / V=99:1, 5 mL) were added sequentially to a 10 mL three-neck flask, followed by potassium carbonate (180 mg, 1.3 mmol). The reaction mixture was heated to 85° C. and stirred at reflux for 4 hours. After completion of the reaction, the reaction mixture was cooled to 45° C., acetone (5 mL) was added and stirred for 1 hour. It was filtered and the cake was washed with acetone (5 mL). The filtrate was concentrated to 3 mL, isopropanol (4 ml) was added and concentrated to 3 mL, cooled to 0° C. and stirred for 1 hour. It was filtered to give 30 mg of an off-white solid, which was compound 13, with a yield of 30%.

[0180] LCMS m / z(ESI): 366 [M+1]. 1 H NMR (400 MHz, DMSO-D6)δ8.56(s, 2H), 8.37-8.38(d, J=2.8 Hz, 1H), 8.11-8.13 (d, J=2.8 Hz, 1H), 7.58-7.59 (m, 1H), 7.13-7.14(m, 1H), 5.56-5.62 (m, 1H), 3.54-3.65(m, 2H), 3.49(s, 1H), 3.27-3.31 (m, 1H), 2.85-3.04 (m, 2H), 2.53-2.55(s, 1H), 1.98-2.46(m, 1H), 1.68-1.70 (m, 2H), 1.33-1.42 (m, 4H), 0.76-0.85(m, 6H).

[0181] Example 6 Synthesis of Compound 16

[0182] [ka]

[0183] Step 1 Compound 16a (150 mg, 0.42 mmol), compound 16b (114 mg, 0.46 mmol), and acetonitrile (2 mL) were added to a 25 mL three-neck flask, cooled to -10°C, and T3P (350 mg, 0.4 mol) was slowly added dropwise. Triethylamine (181 mg, 1.8 mmol) was dissolved in acetonitrile (5 mL) and added to the reaction solution, and the reaction system was kept at -5°C and stirred for 3 hours. After completion of the reaction, water (30 mL) was added to the reaction mixture to quench the reaction. The mixture was concentrated, cooled to 5°C, and stirred for 1 hour. After filtration, the cake was washed with water (100 mL) to obtain 160 mg of a white solid, which was compound 16c, with a yield of 63%.

[0184] Step 2 Compound 16c (160 mg, 0.62 mmol), compound 16d (85 mg, 0.64 mol) and isopropanol / water (v / v=99:1, 10 mL) were added sequentially to a 10 mL three-neck flask, followed by potassium carbonate (0.41 g, 3.2 mmol). The reaction mixture was heated to 85° C. and stirred at reflux for 4 hours. After completion of the reaction, the reaction mixture was cooled to 45° C., acetone (5 mL) was added and stirred for 1 hour. It was filtered and the cake was washed with acetone (2 mL). The filtrate was concentrated to 3 mL and isopropanol (4 ml) was added and concentrated to 3 mL. It was cooled to 0° C. and stirred for 1 hour. It was filtered to obtain 155 mg of an off-white solid, which was compound 16, with a yield of 71%.

[0185] LCMS m / z(ESI): 352.1 [M+1]. 1 H NMR (400 MHz, DMSO-D6)δ8.59 (s, 2H), 8.37 (d, J = 7.54 Hz, 1H), 8.15 (d, J = 7.54 Hz, 1H), 7.64~7.56 (m, 1H), 7.17-7.14 (m, 1H), 5.69-5.53 (m, 1H), 3.76-3.63 (m, 4H), 3.55-3.46 (m, 5H), 2.94-2.79 (m, 4H), 2.03-1.97 (m, 1H).

[0186] Example 7 Synthesis of Compound 17

[0187] [ka]

[0188] Step 1 Compound 17a (150 mg, 0.42 mmol), compound 17b (134 mg, 0.46 mmol), and acetonitrile (2 mL) were added to a 25 mL three-neck flask, cooled to -10°C, and T3P (350 mg, 0.4 mol) was slowly added dropwise. Triethylamine (181 mg, 1.8 mmol) was dissolved in acetonitrile (5 mL) and added to the reaction solution, and the reaction system was kept at -5°C and stirred for 3 hours. After completion of the reaction, water (30 mL) was added to the reaction mixture to quench the reaction. The mixture was concentrated, cooled to 5°C, and stirred for 1 hour. After filtration, the cake was washed with water (100 mL) to obtain 40 mg of a white solid, which was compound 17c, and the yield was 33%.

[0189] Step 2 Compound 17c (40 mg, 0.14 mmol), compound 17d (16 mg, 0.145 mol) and isopropanol / water (v / v=99:1, 3.9 mL) were added sequentially to a 10 mL three-neck flask, followed by potassium carbonate (96.6 mg, 0.7 mmol). The reaction mixture was heated to 85° C. and stirred at reflux for 4 hours. After completion of the reaction, the reaction solution was extracted with ethyl acetate (10 mL×3), and the organic phases were combined and dried over anhydrous sodium sulfate. The crude product was obtained by filtration and concentration, and purified by reverse phase column chromatography to obtain 25 mg of an off-white solid, which was compound 17, with a yield of 25%.

[0190] LCMS m / z(ESI): 381.1 [M+1]. 1H NMR (400 MHz, DMSO-d6):δ8.59 (s, 2H), 8.37 (d, J = 7.54 Hz, 1H), 8.15 (d, J =7.54 Hz, 1H), 7.64~7.56 (m, 1H), 7.17-7.14 (m, 1H), 5.69-5.53 (m, 1H), 4.25 (s, 1H), 3.67-3.51 (m, 4H), 3.04-2.91 (m, 4H), 2.86(s, 1H), 2.58-2.56 (m, 1H), 2.08-1.94 (m, 6H).

[0191] Example 8 Synthesis of Compound 19

[0192] [ka]

[0193] Step 1 Compound 19a (150 mg, 0.42 mmol), compound 1e (154 mg, 0.46 mmol), and acetonitrile (2 mL) were added to a 25 mL three-neck flask, cooled to -10°C, and T3P (350 mg, 0.4 mol) was slowly added dropwise. Triethylamine (181 mg, 1.8 mmol) was dissolved in acetonitrile (5 mL) and added to the reaction solution, and the reaction system was kept at -5°C and stirred for 3 hours. After completion of the reaction, water (30 mL) was added to the reaction mixture to quench the reaction. The mixture was concentrated, cooled to 5°C, and stirred for 1 hour. After filtration, the cake was washed with water (100 mL) to obtain 60 mg of a white solid, which was compound 19c, and the yield was 33%.

[0194] Step 2 Compound 19c (60 mg, 0.21 mmol), compound 19d (24 mg, 0.22 mol) and isopropanol / water (v / v=99:1, 3.9 mL) were added sequentially to a 10 mL three-neck flask, followed by potassium carbonate (152 mg, 1.1 mmol). The reaction mixture was heated to 85° C. and stirred at reflux for 4 hours. After completion of the reaction, the reaction solution was extracted with ethyl acetate (10 mL×3), and the organic phases were combined and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate gave the crude product, which was purified by reverse phase column chromatography to give 16 mg of an off-white solid, which was compound 19, with a yield of 15%.

[0195] LCMS m / z(ESI): 394.1 [M+1]. 1 H NMR (400 MHz, DMSO-d6):δ8.57 (s, 2H), 8.09 (d, J=7.54 Hz, 1H), 7.49(d, J= 8.0 Hz, 1H), 7.02-7.00 (d, J=8.0 Hz, 1H), 5.60-5.53 (m, 1H), 3.86-3.53 (m, 8H), 2.96-2.85 (m, 2H), 2.43 (s, 3H), 2.00-1.95 (m, 1H), 1.82-1.79 (m, 2H), 1.56-1.47 (m, 5H).

[0196] Example 9 Synthesis of Compound 23

[0197] [ka]

[0198] Step 1 Compound 23a (150 mg, 0.42 mmol), compound 1e (154 mg, 0.46 mmol), and acetonitrile (2 mL) were added to a 25 mL three-neck flask, cooled to -10°C, and T3P (350 mg, 0.4 mol) was slowly added dropwise. Triethylamine (181 mg, 1.8 mmol) was dissolved in acetonitrile (5 mL) and added to the reaction solution, and the reaction system was kept at -5°C and stirred for 3 hours. After completion of the reaction, water (30 mL) was added to the reaction mixture to quench the reaction. The mixture was concentrated, cooled to 5°C, and stirred for 1 hour. After filtration, the cake was washed with water (100 mL) to obtain 60 mg of a white solid, which was compound 23c, and the yield was 33%.

[0199] Step 2 Compound 23c (60 mg, 0.21 mmol), compound 23d (26 mg, 0.22 mol) and isopropanol / water (v / v=99:1, 3.9 mL) were added sequentially to a 10 mL three-neck flask, followed by potassium carbonate (152 mg, 1.1 mmol). The reaction mixture was heated to 85° C. and stirred at reflux for 4 hours. After completion of the reaction, the reaction mixture was cooled to 45° C., acetone (5 mL) was added, and stirred for 1 hour. It was filtered and the cake was washed with acetone (2 mL). The filtrate was concentrated to 3 mL, and isopropanol (4 mL) was added and concentrated to 3 mL. It was cooled to 0° C. and stirred for 1 hour. It was filtered to obtain 12 mg of an off-white solid, which was compound 23, with a yield of 12%.

[0200] LCMS m / z(ESI): 458.1 [M+1]. 1H NMR (400 MHz, CD3OD): δ 8.59 (s, 2H), 8.45 (d, J = 2.1 Hz, 1H), 7.86-7.84 (m, 1H), 5.70 (t, J = 7.9 Hz, 1H), 3.75 (s, 1H), 3.54 (d, J = 19.3 Hz, 4H), 3.12-2.88 (m, 4H), 2.73-2.53 (m, 2H), 2.11 (dd, J = 13.1, 8.5 Hz, 2H), 1.98-1.90 (m, 4H), 1.66 (d, J = 8.4 Hz, 3H).

[0201] Example 10 Synthesis of Compound 21

[0202] [ka]

[0203] Compound 23 (50 mg, 0.10 mmol), methylboronic acid (12 mg, 0.22 mmol), potassium phosphate (60 mg, 0.3 mmol), Pd(dppf)2Cl2 (16 mg, 0.02 mmol) were added to 2 ml of 1,4-dioxane and 0.5 ml of water and stirred at 100 °C for 3 h. After completion of the reaction, the reaction mixture was extracted with dichloromethane (10 ml x 3). The organic phases were combined, dried and concentrated to give 70 mg of crude product, which was purified by column chromatography (DCM:CH3OH = 20:1) to give compound 21 (30 mg, yield was 65%).

[0204] LCMS m / z(ESI): 394.2 [M+1]. 1H NMR (400 MHz, DMSO-d6) δ 8.57 (s, 2H), 8.22 (s, 1H), 8.10 (d, J = 8.4 Hz, 1H), 7.40 (s, 1H), 5.58 (q, J = 8.3 Hz, 1H), 3.69- 3.45 (m, 7H), 2.89 (dd, J = 31.4, 8.2 Hz, 2H), 2.24 (s, 3H), 1.98 (dd, J = 12.2, 8.4 Hz, 2H), 1.80 (d, J = 7.4 Hz, 2H), 1.51 (d, J = 33.8 Hz, 4H).

[0205] Example 10 Synthesis of Compound 24

[0206] [ka]

[0207] Step 1 Compound 24a (150 mg, 0.42 mmol), compound 24b (134 mg, 0.46 mmol), and acetonitrile (2 mL) were added to a 25 mL three-neck flask, cooled to -10°C, and T3P (350 mg, 0.4 mol) was slowly added dropwise. Triethylamine (181 mg, 1.8 mmol) was dissolved in acetonitrile (5 mL) and added to the reaction solution, and the reaction system was kept at -5°C and stirred for 3 hours. After completion of the reaction, water (30 mL) was added to the reaction mixture to quench the reaction. The mixture was concentrated, cooled to 5°C, and stirred for 1 hour. After filtration, the cake was washed with water (100 mL) to obtain 20 mg of a white solid, which was compound 24c, with a yield of 16%.

[0208] Step 2 Compound 24c (20 mg, 0.14 mmol), compound 24d (8 mg, 0.145 mol) and isopropanol / water (V / V=99:1, 1.9 mL) were added sequentially to a 10 mL three-neck flask, followed by potassium carbonate (0.14 g, 0.98 mmol). The reaction mixture was heated to 85° C. and stirred at reflux for 4 hours. After completion of the reaction, the reaction solution was extracted with ethyl acetate (10 mL×3), and the organic phases were combined and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate gave the crude product, which was purified by reverse phase column chromatography to give 8 mg of an off-white solid, which was compound 24, with a yield of 35%.

[0209] LCMS m / z(ESI): 353.1 [M+1]. 1 H NMR (400 MHz, DMSO-D6):δ8.56 (s, 1H), 8.38 (d, J = 4.8 Hz, 1H), 8.33-8.28 (m, 1H), 7.68 (s, 1H), 7.19-7.14 (m, 1H), 5.60 (d, J = 8.1 Hz, 1H), 4.23 (d, J = 7.6 Hz, 1H), 3.60 (s, 2H), 2.83 (d, J = 26.4 Hz, 4H), 2.36 (ddd, J = 15.3, 7.7, 3.6 Hz, 2H), 2.21-2.09 (m, 6H), 2.04-1.97 (m, 2H).

[0210] Example 11 Synthesis of Compound 26

[0211] [ka]

[0212] Step 1 Compound 26a (150 mg, 0.41 mmol), compound 26b (134 mg, 0.45 mmol), and acetonitrile (2 mL) were added to a 25 mL three-neck flask, cooled to -10°C, and T3P (350 mg, 0.4 mol) was slowly added dropwise. Triethylamine (181 mg, 1.8 mmol) was dissolved in acetonitrile (5 mL) and added to the reaction solution, and the reaction system was kept at -5°C and stirred for 3 hours. After completion of the reaction, water (30 mL) was added to the reaction mixture to quench the reaction. The mixture was concentrated, cooled to 5°C, and stirred for 1 hour. After filtration, the cake was washed with water (100 mL) to obtain 40 mg of a white solid, which was compound 26c, and the yield was 33%.

[0213] Step 2 Compound 26c (40 mg, 0.14 mmol), compound 26d (16 mg, 0.145 mol) and isopropanol / water (V / V=99:1, 3.9 mL) were added sequentially to a 10 mL three-neck flask, followed by potassium carbonate (99.6 mg, 0.7 mmol). The reaction mixture was heated to 85° C. and stirred at reflux for 4 hours. After completion of the reaction, the reaction mixture was cooled to 45° C., acetone (5 mL) was added, and stirred for 1 hour. It was filtered and the cake was washed with acetone (2 mL). The filtrate was concentrated to 3 mL, and isopropanol (4 ml) was added, concentrated to 3 mL, cooled to 0° C. and stirred for 1 hour. It was filtered to obtain 36 mg of a grey solid, which was compound 26, with a yield of 57%.

[0214] LCMS: [M+1] = 395.1, RT = 0.62 min 1 H NMR (400 MHz, DMSO-D6)δ ppm 8.55-8.65 (m, 2H), 8.38 (d, J = 7.54 Hz, 1H),8.17 (d, J = 7.54 Hz, 1H), 7.71-7.69 (m, 1H), 7.58-7.56 (m, 1H) 5.69-5.53 (m, 1H), 4.25 (s, 1H), 3.76-3.53 (m, 4H), 2.94-2.79 (m, 6H), 2.34-2.24 (m, 2H), 2.03-1.97 (m, 2H), 1.34 (d, J = 6.13 Hz, 2H),1.24 (d, J = 5.82 Hz, 3H).

[0215] Biological Test Evaluation 1. Vanin-1 recombinase activity inhibition experiment A predetermined amount of compound was accurately weighed and prepared using DMSO and reaction buffer (50 mM Tris base, 50 mM KCl, 1.6 mM cysteamine, 0.005% Brij35, pH 8.0, prepared upon use) to give a compound working solution with a maximum concentration of 10,000 nM, which was then diluted 4-fold to give 10 compound working solutions with different concentrations.

[0216] For the activity inhibition reaction of recombinant human Vanin-1 (Biolab, JN0618), first 2.5 μL of compound working solution was mixed with 5 μL of recombinant human Vanin-1 protein, and incubated at room temperature for 15 min, then 2.5 μL of Pantetheine 7-amino-4-trifluoromethylcoumarin substrate was added, so that the final concentration of recombinant human Vanin-1 was 62.5 pM and the final concentration of the substrate 7-amino-4-trifluoromethylcoumarin was 45 μM in a 10 μL reaction system. The reaction was performed in a 384-well plate (PerkinElmer, 6007280), the final concentration of DMSO was 1%, and the excitation light was set to 405 nm and the emission light to 505 nm in a microplate reader, and the kinetic reading was performed at 25 °C for 1 h. The raw data at 30 min was collected for data processing and analysis, and the concentration-effect curve was fitted with GraphPad Prism 8 software, and the IC of compound concentration was calculated. 50 The data is shown in Table 1 below.

[0217] [Table 1]

[0218] Compound A is

[0219] [ka] and was prepared by reference to the method of Example 142 of CN109476645A.

[0220] 2. Pharmacokinetic evaluation in mice Purpose of the test: To detect the pharmacokinetic parameters of the compounds of the present invention in C57BL6 mice.

[0221] Experimental scheme: The solvent used in the experiment was DMSO:Solutol:PBS=5%:25%:70% (v / v / v). Preparation method: Accurately weigh the required compound, add a predetermined amount of DMSO in proportion, mix with vortex until completely dissolved, then add Solutol and PBS sequentially according to the above proportion and mix evenly. In the experiment, the solvent used in the intravenous (iv) administration group and the oral (po) administration group was the same solvent. The intravenous dose was 1mpk, and the oral dose was 2mpk. Experimental blood collection time points: IV group: 0.083, 0.25, 0.5, 1, 2, 4, 7, 24 hours; PO group: 0.25, 0.5, 1, 2, 4, 7, 24 hours, 200uL of whole blood was collected from the jugular vein at each time point, anticoagulated with EDTA-K2, and immediately centrifuged at 4000rpm×5 minutes at 4℃, the supernatant was taken, and the sample was stored in a -80℃ freezer. Plasma sample processing: Precipitation with ACN / MeOH (1:1, v / v) precipitant containing internal standards, centrifugation at 14000 rpm for 5 min, and the supernatant was taken and analyzed by LC-MS / MS (AB Triple Quard 5500) to obtain blood drug concentrations. The calculations were performed using the non-compartmental model of Winnolin 8.1 version. The results are shown in Table 2.

[0222] [Table 2]

[0223] Conclusion: Both compounds 2-1 and 17 showed high bioavailability in mice at the given doses of 76.4% and 61.4%, respectively, indicating that the compounds of the present invention have excellent pharmacokinetic properties.

Claims

1. A pyrimidine formamide compound represented by formula I, or a tautomer, mesomeric, racemic, enantiomer, diastereomer, or mixture thereof, or a pharma- ceutically acceptable salt thereof. 【Chemistry 1】 (wherein n is 0, 1, 2, or 3; R １ are independently halogen, C １ ~C ６ alkyl, one or more R １ａ C substituted with １ ~C ６ is alkyl, Z １ is -(CR ６ａ R ６ｂ )-or-(NR ６ｃ )-, and Z ２ is a connecting bond, or Z １ is a connecting bond, Z ２ is -(CR ７ａ R ７ｂ ) - and Z ３ is a connecting bond or -(CR ８ａ R ８ｂ ) - and R ａ are independently H; R ６ａ , R ６ｂ , R ７ａ and R ７ｂ are independently H, halogen or C １ ~C ６ is alkyl, R ６ｃ are independently H or C １ ~C ４ is alkyl, R ３ａ , R ３ｂ , R ４ａ , R ４ｂ , R ５ａ , R ５ｂ , R ８ａ and R ８ｂ are independently H, halogen, C １ ~C ６ alkyl, one or more R １ｃ C substituted with １ ~C ６ Alkyl, -(NR ９ａ R ９ｂ ) or -(NR １０ａ )-(C=O)-R １０ｂ and Or, R ４ａ and R ４ｂ , or R ４ａ and R ５ａ , or R ４ａ and R ８ａ together with the carbon to which they are attached form ring B, and ring B is selected from the group consisting of 4- to 7-membered cycloalkyl, 4- to 7-membered heterocycloalkyl, one or more R １ｄ or one or more R １ｅ and one or more R １ｅ In the 4- to 7-membered heterocycloalkyl substituted by, the heteroatom is N, O or S, and the number of heteroatoms is 1 or 2; R １ａ , R １ｃ , R １ｄ and R １ｅ are independently halogen, C １ ~C ４ C substituted with alkyl or one or more halogens １ ~C ４ is alkyl, R ９ａ , R ９ｂ , R １０ａ and R １０ｂ are independently H, C １ ~C ４ C substituted with alkyl or one or more halogens １ ~C ４ is alkyl, A is phenyl or 6-membered heteroaryl, in which the heteroatom is N and the number of heteroatoms is 1 or 2; 【Chemistry 2】 represents a single bond or a double bond.

2. n is 0 or 1; And / or Z １ is -(CR ６ａ R ６ｂ )-, and Z ２ is a connecting bond, And / or Z ３ is -(CR ８ａ R ８ｂ ) - and And / or R ６ａ and R ６ｂ are independently H or halogen; And / or R ７ａ and R ７ｂ are independently H; And / or R ３ａ and R ３ｂ are independently H; And / or R ４ａ and R ４ｂ are independently H, C １ ~C ６ Alkyl, -(NR ９ａ R ９ｂ ) or -(NR １０ａ )-(C=O)-R １０ｂ and And / or R ５ａ and R ５ｂ are independently H; and / or Ring B is selected from the group consisting of 4- to 7-membered cycloalkyl, 4- to 7-membered heterocycloalkyl, one or more R １ｄ is a 4- to 7-membered heterocycloalkyl substituted by And / or R ８ａ and R ８ｂ are independently H; And / or R １ａ , R １ｃ , R １ｄ and R １ｅ are independently halogen or C １ ~C ４ is alkyl, And / or R ９ａ , R ９ｂ , R １０ａ and R １０ｂ is independently C １ ~C ４ C substituted with alkyl or one or more halogens １ ~C ４ is alkyl, and / or A is a 6-membered heteroaryl; and / or 【Chemistry 3】 represents a single bond, and / or 【Chemistry 4】 teeth, 【Chemistry 5】 2. The pyrimidine formamide compound of formula I according to claim 1, characterized in that it is a pyrimidine formamide compound of formula I according to claim 1, or a mixture thereof, or a tautomer, mesomeric, racemic, enantiomer, diastereomer, or mixture thereof, or a pharma- ceutically acceptable salt thereof.

3. A pyrimidine formamide compound represented by formula I according to claim 1, or a tautomer, mesomeric, racemic, enantiomer, diastereomer, or mixture thereof, or a pharma- ceutically acceptable salt thereof, characterized in that the compound is represented by the following protocol 1 or protocol 2: Protocol 1: n is 0 or 1; R １ are independently halogen, C １ ~C ６ alkyl, one or more R １ａ C substituted with １ ~C ６ is alkyl, Z １ is -(CR ６ａ R ６ｂ )-or-(NR ６ｃ )-, and Z ２ is a connecting bond, or Z １ is a connecting bond, Z ２ is -(CR ７ａ R ７ｂ ) - and Z ３ is -(CR ８ａ R ８ｂ ) - and R ａ are independently H; R ６ａ , R ６ｂ , R ７ａ and R ７ｂ are independently H or halogen; R ６ｃ are independently H or C １ ~C ４ is alkyl, R ３ａ , R ３ｂ , R ５ａ , R ５ｂ , R ８ａ and R ８ｂ are independently H; R ４ａ and R ４ｂ are independently H; C １ ~C ６ Alkyl, -(NR ９ａ R ９ｂ ) or -(NR １０ａ )-(C=O)-R １０ｂ and Or, R ４ａ and R ４ｂ , or R ４ａ and R ５ａ , or R ４ａ and R ８ａ together with the carbon to which they are attached form ring B, and ring B is selected from the group consisting of 4- to 7-membered cycloalkyl, 4- to 7-membered heterocycloalkyl, one or more R １ｄ or one or more R １ｅ is a 4- to 7-membered heterocycloalkyl substituted by R １ａ , R １ｄ and R １ｅ are independently halogen or C １ ~C ４ is alkyl, R ９ａ , R ９ｂ , R １０ａ and R １０ｂ is independently C １ ~C ４ C substituted with alkyl or one or more halogens １ ~C ４ is alkyl, A is phenyl or 6-membered heteroaryl; Protocol 2: n is 0 or 1; R １ are independently halogen, C １ ~C ６ alkyl, one or more R １ａ C substituted with １ ~C ６ is alkyl, Z １ is -(CR ６ａ R ６ｂ )-or-(NR ６ｃ )-, and Z ２ is a connecting bond, or Z １ is a connecting bond, Z ２ is -(CR ７ａ R ７ｂ ) - and Z ３ is -(CR ８ａ R ８ｂ ) - and R ａ are independently H; R ６ａ and R ６ｂ are independently H or halogen; R ７ａ and R ７ｂ are independently H; R １ａ are independently halogen; R ６ｃ are independently H or C １ ~C ４ is alkyl, R ３ａ , R ３ｂ , R ５ａ , R ５ｂ , R ８ａ and R ８ｂ are independently H; R ４ａ is independently C １ ~C ６ Alkyl, -(NR ９ａ R ９ｂ ) or -(NR １０ａ )-(C=O)-R １０ｂ and R ４ｂ are independently H or C １ ~C ６ is alkyl, Or, R ４ａ and R ４ｂ , or R ４ａ and R ５ａ , or R ４ａ and R ８ａ together with the carbon to which they are attached form ring B, and ring B is a 4- to 7-membered cycloalkyl, a 4- to 7-membered heterocycloalkyl, or one or more R １ｅ is a 4- to 7-membered heterocycloalkyl substituted by R １ｅ is independently C １ ~C ４ is alkyl, R ９ａ , R ９ｂ , R １０ａ and R １０ｂ is independently C １ ~C ４ C substituted with alkyl or one or more halogens １ ~C ４ is alkyl, A is a 6-membered heteroaryl; 【Chemistry 6】 represents a single bond, or a tautomer, mesomeric, racemic, enantiomer, diastereomer, or mixture thereof, or a pharma- ceutically acceptable salt thereof.

4. R １ is a halogen, said halogen is fluorine, chlorine or bromine, for example fluorine or chlorine, also for example fluorine; And / or R １ is one or more R １ａ C substituted with １ ~C ６ When it is alkyl, the number of said substituents is 1, 2, 3, 4 or 5, for example 1, 2 or 3; And / or R １ But, C １ ~C ６ alkyl, one or more R １ａ C substituted with １ ~C ６ When it is alkyl, １ ~C ６ Alkyl and one or more R １ａ C substituted with １ ~C ６ C in alkyl １ ~C ６ alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example, methyl; And / or R ６ａ , R ６ｂ , R ７ａ and R ７ｂ is independently a halogen, the halogen is independently fluorine, chlorine or bromine, e.g., fluorine or chlorine; And / or R ６ａ , R ６ｂ , R ７ａ and R ７ｂ But independently, C １ ~C ６ When it is alkyl, １ ~C ６ alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example, methyl; And / or R ６ｃ is independently C １ ~C ４ When it is alkyl, １ ~C ４ alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example, methyl; And / or R ３ａ , R ３ｂ , R ４ａ , R ４ｂ , R ５ａ , R ５ｂ , R ８ａ and R ８ｂ is independently a halogen, the halogen is independently fluorine, chlorine or bromine, e.g., fluorine or chlorine; And / or R ３ａ , R ３ｂ , R ４ａ , R ４ｂ , R ５ａ , R ５ｂ , R ８ａ and R ８ｂ But independently, C １ ~C ６ alkyl, one or more R １ｃ C substituted with １ ~C ６ When it is alkyl, １ ~C ６ Alkyl and one or more R １ｃ C substituted with １ ~C ６ C in alkyl １ ~C ６ alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example, methyl or ethyl; and / or Ring B is 4- to 7-membered cycloalkyl, one or more R １ｄ When the 4- to 7-membered cycloalkyl is substituted by R １ｄ the 4- to 7-membered cycloalkyl substituted by is independently cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, for example cyclopentyl; and / or Ring B is a 4- to 7-membered heterocycloalkyl, or one or more R １ｅ When the heterocycloalkyl is a 4- to 7-membered heterocycloalkyl substituted by R １ｅ The 4- to 7-membered heterocycloalkyl in the 4- to 7-membered heterocycloalkyl substituted by is independently tetrahydrofuranyl, tetrahydro-2H-pyranyl, pyrrolidinyl, for example, R ４ａ and R ４ｂ form ring B together with the carbon to which they are attached, ring B is 【Chemistry 7】 and R ４ａ and R ５ａ , or R ４ａ and R ８ａ form ring B together with the carbon to which they are attached, ring B is 【Chemistry 8】 and And / or R １ａ , R １ｃ , R １ｄ and R １ｅ are independently halogen or one or more C substituted with a number of halogens １ ~C ４ When it is alkyl, it is C substituted with one or more halogens. １ ~C ４ Halogen in alkyl is independently fluorine, chlorine or bromine, e.g., fluorine or chlorine; And / or R １ａ , R １ｃ , R １ｄ and R １ｅ is independently C １ ~C ４ C substituted with alkyl or one or more halogens １ ~C ４ When it is alkyl, １ ~C ４ alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example, methyl or ethyl; And / or R ９ａ , R ９ｂ , R １０ａ and R １０ｂ But independently, C １ ~C ４ When it is alkyl, １ ~C ４ alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example, methyl or ethyl; And / or R ９ａ , R ９ｂ , R １０ａ and R １０ｂ C independently substituted with one or more halogens １ ~C ４ When it is alkyl, it is C substituted by one or more halogens. １ ~C ４ In the alkyl, １ ~C ４ alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example, methyl or ethyl; And / or R ９ａ , R ９ｂ , R １０ａ and R １０ｂ C independently substituted with one or more halogens １ ~C ４ When alkyl, the halogen is independently fluorine, chlorine or bromine, e.g., fluorine, and for example, C substituted with one or more halogens. １ ~C ４ Alkyl is trifluoromethyl; and / or when A is a 6-membered heteroaryl, said 6-membered heteroaryl is pyridyl, pyrazinyl or pyrimidinyl, said pyridyl being 【Chemistry 9】 wherein said pyrazinyl is 【Chemistry 10】 wherein said pyrimidinyl is 【Chemistry 11】 a may be A and 【Chemistry 12】 The pyrimidine formamide compound of formula I according to claim 1, characterized in that:

5. R １ are independently F, methyl or trifluoromethyl, for example: 【Chemistry 13】 is phenyl, 【Chemistry 14】 and And / or Z １ is a single bond, -(CH ２ ) -, -(CF ２ )-, -(NH)- or -(N(CH ３ ))--, for example, 【Chemistry 15】 teeth, 【Chemistry 16】 and And / or R ４ａ and R ４ｂ are independently H; ethyl, dimethylamino, 【Chemistry 17】 and And / or ring B is 【Chemistry 18】 and and / or 【Chemistry 19】 teeth, 【Chemistry 20】 For example, 【Chemistry 21】 2. The pyrimidine formamide compound of formula I according to claim 1, characterized in that:

6. The pyrimidine formamide compound of formula I according to claim 1, characterized in that the pyrimidine formamide compound of formula I is any one of the following structures: 【Chemical 22】 【change】

7. The pyrimidine formamide compound of formula I according to claim 1, characterized in that the pyrimidine formamide compound of formula I is any one of the following structures: Compound with retention time of 8.483 minutes under the following conditions 【Chemistry 23】 : Separation by chiral chromatography, chromatographic column: CHIRALPAK AD-H, 250×4.6 mm, 5 um, column temperature: 35° C., flow rate: 0.4 mL / min, wavelength: 254 nm, gradient: A: n-hexane, B: isopropanol, A:B=1:4, run time: 50 min; Compound with retention time of 13.580 minutes under the following conditions 【Chemistry 24】 : Separation by chiral chromatography, Chromatography column: CHIRALPAK AD-H, 250×4.6 mm, 5 um, Column temperature: 35° C., Flow rate: 0.4 mL / min, Wavelength: 254 nm, Gradient: A: n-hexane, B: isopropanol, A:B=1:4, Run time: 50 min.

8. A pharmaceutical composition comprising a pyrimidine formamide compound of formula I according to any one of claims 1 to 7, or a tautomer, mesomeric, racemic, enantiomer, diastereomer, or mixture thereof, or a pharma- ceutically acceptable salt thereof, and a pharma-ceutically acceptable auxiliary.

9. Use of a pyrimidine formamide compound of formula I according to any one of claims 1 to 7, or a tautomer, mesomeric, racemic, enantiomer, diastereomer, or mixture thereof, or a pharma- ceutically acceptable salt thereof, in the manufacture of a Vanin-1 inhibitor.

10. Use of a pyrimidine formamide compound of formula I according to any one of claims 1 to 7, or a tautomer, mesomeric, racemic, enantiomer, diastereomer, or mixture thereof, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament, comprising: The medicament can be used for the prevention and / or treatment of a disease associated with Vanin-1, or the medicament can be used for the prevention and / or treatment of one or more of autoimmune diseases, inflammatory diseases, allergic diseases, metabolic diseases, infectious diseases, fibrotic diseases, cardiovascular diseases, respiratory diseases, kidney diseases, skin diseases, liver diseases, digestive diseases, oral diseases, and hematopoietic diseases, such as Crohn's disease, ulcerative colitis and inflammatory bowel disease, and gastritis; The Vanin-1 associated disease may include one or more of an autoimmune disease, an inflammatory disease, an allergic disease, a metabolic disease, an infectious disease, a fibrotic disease, a cardiovascular disease, a respiratory disease, a kidney disease, a skin disease, a liver disease, a digestive disease, an oral disease, and a hematopoietic disease.

Images