WO2022063333A1 - 一种嘧啶甲酰胺类化合物及其应用 - Google Patents

一种嘧啶甲酰胺类化合物及其应用 Download PDF

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WO2022063333A1
WO2022063333A1 PCT/CN2021/128344 CN2021128344W WO2022063333A1 WO 2022063333 A1 WO2022063333 A1 WO 2022063333A1 CN 2021128344 W CN2021128344 W CN 2021128344W WO 2022063333 A1 WO2022063333 A1 WO 2022063333A1
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independently
alkyl
substituted
halogen
butyl
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French (fr)
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姚元山
栾林波
陈永凯
王朝东
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上海美悦生物科技发展有限公司
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Priority to US18/028,213 priority Critical patent/US20240083873A1/en
Publication of WO2022063333A1 publication Critical patent/WO2022063333A1/zh

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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
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Definitions

  • the present invention relates to a pyrimidine carboxamide compound and its application.
  • Vanin-1 vascular non-inflammatory molecule-1
  • vascular non-inflammatory molecule-1 is an exonuclease with ubiquitidase activity, which mainly catalyzes the hydrolysis of pantothenic mercaptoethylamine to produce pantothenic acid (VB5) and mercaptoethylamine.
  • Coenzyme A (CoA) synthesized from VB5 regulates biotransformations such as fatty acid synthesis and oxidation and energy metabolism, and the reversible reaction between cysteamine and cystamine is an important sensor of oxidative stress.
  • a growing number of studies have found that lack or reduced levels of cysteamine lead to enhanced ⁇ -GCS activity, resulting in elevated endogenous GSH reserves in tissues, which can prevent or eliminate tissue inflammation.
  • Vanin-1 is highly expressed in human colon, duodenum, endometrium, liver, kidney, gallbladder and small intestine.
  • UC ulcerative colitis
  • Vanin-1 is highly expressed, diffuse, and limited to brush borders.
  • the expression level of Vanin-1 in the colon was still significantly higher than that of the control.
  • the survival rate of mice after Vanin-1 knockout was significantly higher than that of the model control group, and there was no obvious weight loss.
  • Vanin-1 -/- mice treated with cystamine died within 5 days, indicating that cystamine completely reversed the protective effect of Vanin-1 deficiency on colitis.
  • histopathological analysis of mice revealed that inhibition or knockout of Vanin-1 significantly ameliorated 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 receptor gamma activity. J. Exp. Med. 2006; 203: 2817-2827).
  • Vanin-1 is also believed to play a regulatory role in cardiovascular and tumor diseases. It has been demonstrated that Vanin-1 regulates the activation of smooth muscle cells in vitro and the occurrence of neointimal hyperplasia in response to carotid artery ligation in vivo. Polymorphisms of the VNN1 gene were associated with blood pressure and HDL levels. In SF-1 transgenic mice, Vanin-1 deletion prevented the mice from developing neoplasia of the adrenal cortex, suggesting a role for Vanin-1 in certain cancers. Studies in inflammatory diseases have found that Vanin-1 is highly upregulated in skin lesions of psoriasis compared to normal individuals.
  • VNN1 Gene expression of VNN1 was also upregulated in whole blood from patients with childhood immune thrombocytopenia (ITP), where overexpression of VNN1 was associated with the progression of chronic ITP.
  • ITP immune thrombocytopenia
  • VNN1 Gene expression of VNN1 was also upregulated in whole blood from patients with childhood immune thrombocytopenia (ITP), where overexpression of VNN1 was associated with the progression of chronic ITP.
  • elevated Vanin-1 has been detected in the urine of patients with a variety of renal disorders, including systemic lupus erythematosus, nephrotoxicant-induced kidney damage, 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).
  • 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 to provide a pyrimidine carboxamide compound and its application.
  • the pyrimidinecarboxamide compounds provided by the present invention are compounds with Vanin enzyme inhibitory activity; have strong Vanin-1 inhibitory activity; they can be used to treat various conditions, including Crohn's disease and ulcerative colitis.
  • the present invention solves the above-mentioned technical problems through the following technical solutions.
  • the present invention provides a pyrimidinecarboxamide compound as shown in formula I, or its tautomer, meso, racemate, enantiomer, diastereomer, or in the form of a mixture or a pharmaceutically acceptable salt thereof;
  • n 0, 1, 2 or 3;
  • R 1 is independently halogen, C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted with one or more R 1a ;
  • Z 1 is -(CR 6a R 6b )- or -(NR 6c )-, Z 2 is a connecting bond; or, Z 1 is a connecting bond, Z 2 is -(CR 7a R 7b )-;
  • Z 3 is a connecting bond or -(CR 8a R 8b )-;
  • Ra is independently H
  • R 6a , R 6b , R 7a and R 7b are independently H, halogen or C 1 -C 6 alkyl
  • R 6c is independently H or C 1 -C 4 alkyl
  • Ring B is 4-7 membered cycloalkyl, 4-7 membered heterocyclic Cycloalkyl, 4-7 membered cycloalkyl substituted with one or more R 1d , or 4-7 membered heterocycloalkyl substituted with one or more R 1e ; the 4-7 membered heterocycloalkyl and in the 4-7-membered heterocycloalkyl group in the 4-7-membered heterocycloalkyl group substituted by one or more R 1e , 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 alkyl or C 1 -C 4 alkyl substituted with one or more halogens;
  • R 9a , R 9b , R 10a and R 10b are independently H, C 1 -C 4 alkyl or C 1 -C 4 alkyl substituted with 1 or more halogen;
  • A is phenyl or 6-membered heteroaryl; in the 6-membered heteroaryl, the heteroatom is N, and the number of heteroatoms is 1 or 2;
  • the pyrimidinecarboxamides shown in formula I, or their tautomers, mesomers, racemates, enantiomers, non- Certain groups in the enantiomers, or their mixtures or their pharmaceutically acceptable salts are defined as follows, and the unmentioned groups are the same as those described in any scheme of this application (hereinafter referred to as "in a certain scheme”). ”), n is 0 or 1.
  • Z 1 is -(CR 6a R 6b )-, and Z 2 is a connecting bond.
  • R 6a and R 6b are independently H or halogen.
  • R 7a and R 7b are independently H; that is, Z 2 is -(CH 2 )-.
  • Z 3 is -(CR 8a R 8b )-.
  • R 3a and R 3b are independently H.
  • R 5a and R 5b are independently H.
  • R 4b is independently H or C 1 -C 6 alkyl.
  • 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 bound form Ring B;
  • Ring B is 4-7 membered cycloalkyl, 4-7 membered heterocycloalkyl, 4-7 membered heterocycloalkyl substituted with one or more R 1d .
  • R 8a and R 8b are independently H; that is, Z 3 is -(CH 2 )-.
  • R 1a , R 1c , R 1d and R 1e are independently halogen or C 1 -C 4 alkyl.
  • R 1a is independently halogen; eg, F.
  • R 1e is independently C 1 -C 4 alkyl.
  • R 9a , R 9b , R 10a and R 10b are independently C 1 -C 4 alkyl or C 1 -C 4 alkyl substituted with one or more halogens.
  • A is a 6-membered heteroaryl; eg, pyridyl.
  • n 0 or 1
  • R 1 is independently halogen, C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted with one or more R 1a ;
  • Z 1 is -(CR 6a R 6b )- or -(NR 6c )-, Z 2 is a connecting bond; or Z 1 is a connecting bond, Z 2 is -(CR 7a R 7b )-;
  • Z 3 is -(CR 8a R 8b )-;
  • Ra is independently H
  • R 6a , R 6b , R 7a and R 7b are independently H or halogen
  • R 6c is independently H or C 1 -C 4 alkyl
  • R 3a , R 3b , R 5a , R 5b , R 8a and R 8b are independently H;
  • Ring B is 4-7 membered cycloalkyl, 4-7 membered heterocyclic cycloalkyl, 4-7 membered cycloalkyl substituted with one or more R 1d or 4-7 membered heterocycloalkyl substituted with one or more R 1e ;
  • R 1a , R 1d and R 1e are independently halogen or C 1 -C 4 alkyl
  • R 9a , R 9b , R 10a and R 10b are independently C 1 -C 4 alkyl or C 1 -C 4 alkyl substituted with 1 or more halogen;
  • A is phenyl or 6-membered heteroaryl
  • n 0 or 1
  • R 1 is independently halogen, C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted with one or more R 1a ;
  • Z 1 is -(CR 6a R 6b )- or -(NR 6c )-, Z 2 is a connecting bond; or, Z 1 is a connecting bond, Z 2 is -(CR 7a R 7b )-;
  • Z 3 is -(CR 8a R 8b )-;
  • Ra is independently H
  • R 6a and R 6b are independently H or halogen; R 7a and R 7b are independently H;
  • R 1a is independently halogen
  • R 6c is independently H or C 1 -C 4 alkyl
  • R 3a , R 3b , R 5a , R 5b , R 8a and R 8b are independently H;
  • R 4b is independently H or C 1 -C 6 alkyl
  • Ring B is 4-7 membered cycloalkyl, 4-7 membered heterocyclic cycloalkyl, or 4-7 membered heterocycloalkyl substituted with one or more R 1e ;
  • R 1e is independently C 1 -C 4 alkyl
  • R 9a , R 9b , R 10a and R 10b are independently C 1 -C 4 alkyl or C 1 -C 4 alkyl substituted with 1 or more halogen;
  • A is a 6-membered heteroaryl; for example, pyridyl;
  • R 1 is halogen
  • the halogen is fluorine, chlorine or bromine; such as fluorine or chlorine; another example is fluorine.
  • R 1 is C 1 -C 6 alkyl substituted by one or more R 1a , the number of said substituents is 1, 2, 3, 4 or 5; for example, 1, 2 or 3; For example trifluoromethyl.
  • R 1 is C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted by one or more R 1a
  • said C 1 -C 6 alkyl and C 1 -C 6 alkyl substituted by one or more R 1a C 1 -C 6 alkyl (eg methyl, ethyl, propyl, butyl, pentyl or hexyl) in C 1 -C 6 alkyl is independently C 1 -C 4 alkyl (eg methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl); eg methyl.
  • R 6a , R 6b , R 7a and R 7b are independently halogen
  • the halogen is independently fluorine, chlorine or bromine; such as fluorine or chlorine; another example is fluorine.
  • R 6a , R 6b , R 7a and R 7b are independently C 1 -C 6 alkyl
  • said C 1 -C 6 alkyl eg methyl, ethyl, propyl, butyl, pentyl or hexyl
  • said C 1 -C 6 alkyl is independently a C1 - C4 alkyl group (eg methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl); eg methyl.
  • R 6c is independently a C 1 -C 4 alkyl group
  • the C 1 -C 4 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; eg methyl.
  • R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 8a and R 8b are independently halogen
  • said halogen is independently fluorine, chlorine or bromine; such as fluorine or chlorine; another example fluorine.
  • R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 8a and R 8b are independently C 1 -C 6 alkyl, C 1 -C 6 alkane substituted with one or more R 1c
  • the C 1 -C 6 alkyl group such as methyl, ethyl, propyl, butyl, pentyl or hexyl
  • C1 - C4 alkyl eg methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl
  • methyl or ethyl for example methyl or ethyl.
  • ring B is a 4-7 membered cycloalkyl, a 4-7 membered cycloalkyl substituted by one or more R 1d , the 4-7 membered cycloalkyl and a 4-7 membered cycloalkyl substituted by one or more R 1d
  • the 4-7 membered cycloalkyl in the 4-7 membered cycloalkyl is independently cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; another example is cyclopentyl.
  • Ring B is a 4-7-membered heterocycloalkyl, or a 4-7-membered heterocycloalkyl substituted by one or more R 1e , the 4-7-membered heterocycloalkyl and the The 4-7-membered heterocycloalkyl in the 4-7-membered heterocycloalkyl substituted by R 1e is independently tetrahydrofuranyl, tetrahydro-2H-pyranyl, pyrrolidinyl; for example, when R 4a and R 4b are combined with When the carbons to which they are bonded together form Ring B, Ring B is When R 4a and R 5a , or, R 4a and R 8a together with the carbon to which they are bound form Ring B, Ring B is
  • R 1a , R 1c , R 1d and R 1e are independently halogen or C 1 -C 4 alkyl substituted with one or more halogens
  • Halogen in C4 alkyl can independently be fluorine, chlorine or bromine; such as fluorine or chlorine; another example is fluorine.
  • R 1a , R 1c , R 1d and R 1e are independently C 1 -C 4 alkyl or C 1 -C 4 alkyl in C 1 -C 4 alkyl substituted by one or more halogens
  • C 1 -C 4 alkyl is independently Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; eg methyl or ethyl.
  • R 9a , R 9b , R 10a and R 10b are independently C 1 -C 4 alkyl
  • the C 1 -C 4 alkyl is independently methyl, ethyl, n-propyl, isopropyl , n-butyl, isobutyl, sec-butyl or tert-butyl; for example methyl or ethyl.
  • R 9a , R 9b , R 10a and R 10b are independently C 1 -C 4 alkyl substituted with 1 or more halogens
  • the C 1 -C 4 alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; for example, methyl or ethyl.
  • R 9a , R 9b , R 10a and R 10b are independently C 1 -C 4 alkyl substituted with one or more halogens
  • the halogens are independently fluorine, chlorine or bromine; such as fluorine; another example
  • the C 1 -C 4 alkyl substituted with one or more halogens is trifluoromethyl.
  • the 6-membered heteroaryl group is pyridyl, pyrazinyl or pyrimidinyl; the pyridyl can be The pyrazinyl group can be The pyrimidine group can be a means A and connection location.
  • R1 is independently F , methyl or trifluoromethyl.
  • Z 1 is -(CH 2 )-, -(CF 2 )-, -(NH)- or -(N(CH 3 ))-.
  • R 4a and R 4b are independently H, ethyl, dimethylamino,
  • R 4a and R 4b are independently ethyl, or R 4a is H, R 4b is dimethylamino,
  • R 4a and R 4b together with the carbon to which they are bonded form Ring B; e.g.
  • R 4a and R 5a or, R 4a and R 8a together with the carbon to which they are bound form Ring B; for example:
  • the pyrimidinecarboxamide compound shown in formula I is any of the following structures:
  • the pyrimidinecarboxamide compound shown in formula I is any of the following structures:
  • the pyrimidinecarboxamides shown in formula I or their pharmaceutically acceptable salts may have one or more chiral carbon atoms, so optically pure isomers can be isolated, such as pure Enantiomers, or racemates, or mixed isomers. Pure single isomers can be obtained by separation methods in the art, such as chiral crystallization into salts, or chiral preparative column separation.
  • pyrimidinecarboxamides shown in formula I or their pharmaceutically acceptable salts have stereoisomers, they can be used as single stereoisomers or their mixtures (such as elimination vortex) in the form of.
  • stereoisomer refers to a cis-trans isomer or an optical isomer.
  • stereoisomers can be separated, purified and enriched by asymmetric synthesis methods or chiral separation methods (including but not limited to thin layer chromatography, spin chromatography, column chromatography, gas chromatography, high pressure liquid chromatography, etc.) It can be obtained by chiral resolution by forming bonds with other chiral compounds (chemical bonding, etc.) or forming salts (physical bonding, etc.).
  • single stereoisomer means that the mass content of one stereoisomer of the compound of the present invention relative to all stereoisomers of the compound is not less than 95%.
  • the pyrimidinecarboxamide compounds represented by formula I of the present invention can be synthesized by methods including those analogous to those well known in the chemical art, the steps and conditions of which may be referred to those of analogous reactions in the art, especially synthesized according to the description herein.
  • Starting materials are typically from commercial sources such as Aldrich or can be readily prepared using methods well known to those skilled in the art (obtained via SciFinder, Reaxys online database).
  • the pyrimidinecarboxamides shown in formula I can also be prepared by the described pyrimidinecarboxamide compounds shown in formula I, or its tautomer, meso, racem Rotomers, enantiomers, diastereomers, or their mixtures or their pharmaceutically acceptable salts, using conventional methods in the art, through peripheral modification to obtain other described compounds as shown in formula I Pyrimidinecarboxamides, or tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof or pharmaceutically acceptable salts thereof.
  • the compounds of the present invention can be prepared by the methods described in the present invention, wherein the substituents are as defined in formula I unless otherwise specified.
  • the following reaction schemes and examples serve to further illustrate the content of the present invention.
  • the necessary starting materials or reagents for the preparation of compounds such as those of formula I are either commercially available or prepared by synthetic methods known in the art.
  • Compounds of the invention can be prepared as free bases or as acid salts thereof as described in the experimental section below.
  • the term pharmaceutically acceptable salt refers to a pharmaceutically acceptable salt as defined herein, and which possesses all of the pharmaceutically activity of the parent compound.
  • Pharmaceutically acceptable salts can be prepared by treating the organic base in a suitable organic solvent with the corresponding acid according to conventional methods.
  • salt formation examples include: salt formation with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; and salts formed 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 , mucofuroic acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, tartaric acid, p-toluenesulfonic acid or trimethylacetic acid.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid
  • the pyrimidinecarboxamides shown in formula I may have one or more chiral carbon atoms, and thus can be separated into optically pure isomers, such as pure enantiomers, or racemates, or mixed isomeric isomers. Construct. Pure single isomers can be obtained by separation methods in the art, such as chiral crystallization into salts, or chiral preparative column separation.
  • the chemicals used in the synthetic route described in this patent include solvents, reagents, catalysts, and protecting groups, deprotecting groups, and protecting groups including tert-butoxycarbonyl (Boc).
  • the above methods may additionally include steps before or after the steps specifically described herein, where appropriate protecting groups may be added or removed to obtain the target compound. Additionally, various synthetic steps can be performed alternately or sequentially to obtain the final target product.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the above-mentioned pyrimidinecarboxamide compound represented by formula I, or its tautomer, meso, racemate and enantiomer , diastereomers, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and, (one or more) pharmaceutically acceptable excipients (eg, and pharmaceutically acceptable carriers, diluents, vehicles, or other excipients) agent).
  • Said pyrimidinecarboxamide compound as shown in formula I, or its tautomer, meso, racemate, enantiomer, diastereomer, or its mixture form or a pharmaceutically acceptable salt thereof may be used in a therapeutically effective amount.
  • the present invention also provides a described pyrimidinecarboxamide compound shown in formula I, or its tautomer, meso, racemate, enantiomer, diastereomer Use of the isomer, or a mixture thereof or a pharmaceutically acceptable salt thereof, in the preparation of a Vanin-1 inhibitor.
  • the Vanin-1 inhibitor can be used in mammalian organisms; it can also be used in vitro, mainly for experimental purposes, such as: providing comparison as a standard sample or a control sample, or according to the routine in the art Methods A kit was prepared to provide rapid detection of the inhibitory effect of Vanin-1.
  • the term "inhibitor of vanin-1 (enzyme)" as used herein refers to a compound that binds vanin-1 (enzyme) and reduces the enzymatic activity produced.
  • the present invention also provides a described pyrimidinecarboxamide compound shown in formula I, or its tautomer, meso, racemate, enantiomer, diastereomer
  • the medicament can be used for the prevention and/or treatment of diseases related to Vanin-1, or the medicament can be
  • autoimmune diseases inflammatory diseases, allergic diseases, metabolic diseases, infection-based diseases, fibrotic diseases, cardiovascular diseases, respiratory diseases, renal diseases, dermatological diseases, liver diseases
  • inflammatory diseases inflammatory diseases, allergic diseases, metabolic diseases, infection-based diseases, fibrotic diseases, cardiovascular diseases, respiratory diseases, renal diseases, dermatological diseases, liver diseases
  • fibrotic diseases cardiovascular diseases
  • respiratory diseases renal diseases
  • dermatological diseases liver diseases
  • liver diseases One or more of disease, gastrointestinal disease, oral disease, and hematopoietic disease
  • another example is a drug for Crohn's disease, inflammatory bowel disease, and ulcerative colitis.
  • the diseases associated with Vanin-1 may include autoimmune diseases, inflammatory diseases, allergic diseases, metabolic diseases, infection-based diseases, fibrotic diseases, cardiovascular diseases, respiratory diseases, renal diseases, skin diseases one or more of medical disease, liver disease, gastrointestinal disease, oral disease, and hematopoietic disease; another example is inflammatory bowel disease, ulcerative colitis, Crohn's disease, colorectal cancer, and gastritis.
  • Another aspect of the present invention relates to a method for preventing and/or treating a Vanin-1-related disease, comprising administering to a patient a therapeutically effective dose of the pyrimidinecarboxamides shown in formula I, or their interaction A mutator, meso, racemate, enantiomer, diastereomer, or a mixture thereof or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same.
  • a disease or disorder mediated by, or otherwise associated with, inhibition of vanin-1 enzyme is treated.
  • autoimmune diseases for example, autoimmune diseases, inflammatory diseases, allergic diseases, metabolic diseases, infection-based diseases, fibrotic diseases, cardiovascular diseases, respiratory diseases, renal diseases, dermatological diseases, liver diseases, gastrointestinal diseases, oral diseases
  • disease and hematopoietic disease eg, inflammatory bowel disease, ulcerative colitis, Crohn's disease, colorectal cancer, and gastritis.
  • Another aspect of the invention relates to a treatment for preventing and/or treating autoimmune diseases, inflammatory diseases, allergic diseases, metabolic diseases, infection-based diseases, fibrotic diseases, cardiovascular diseases, respiratory diseases, renal diseases , a method for one or more of dermatological disease, liver disease, gastrointestinal disease, oral disease, and hematopoietic disease (eg, inflammatory bowel disease, ulcerative colitis, Crohn's disease, colorectal cancer, and gastritis), It comprises administering to a patient a therapeutically effective dose of the pyrimidinecarboxamides shown in formula I, or their tautomers, mesomers, racemates, enantiomers, non-pairs An enantiomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
  • autoimmune diseases e.g, inflammatory bowel disease, ulcerative colitis, Crohn's disease, colorectal cancer, and gastritis
  • Another aspect of the present invention relates to a medicament for inhibiting Vanin-1, which comprises the pyrimidinecarboxamides shown in formula I, or their tautomers, mesomers, racemates Rotors, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same.
  • the compounds of the present invention may be administered topically or systemically, eg, for enteral administration, such as rectal or oral administration, or for parenteral administration to mammals, especially humans.
  • the compounds of the invention may also be administered parenterally, eg, by inhalation, injection or infusion, such as by intravenous, intraarterial, intraosseous, intramuscular, intracerebral, extraventricular, intrasynovial, intrasternal, intrathecal Intra, intralesional, intracranial, intratumoral, intradermal and subcutaneous injection or infusion.
  • the effective amount of the compound, pharmaceutical composition or medicament of the present invention depends on the species, body weight, age, individual condition, individual pharmacokinetic parameters, disease to be treated and mode of administration of the mammal.
  • An effective amount of a compound, pharmaceutical composition or medicament of the present invention can be readily determined by routine experimentation, as can the most effective and convenient route of administration and the most appropriate formulation.
  • the pharmaceutical excipients can be those widely used in the field of pharmaceutical production. Excipients are mainly used to provide a safe, stable and functional pharmaceutical composition, and can also provide a method to enable the subject to dissolve the active ingredient at a desired rate after administration, or to promote the activity of the subject after the composition is administered. The ingredients are effectively absorbed.
  • the pharmaceutical excipients can be inert fillers, or provide some function, such as stabilizing the overall pH of the composition or preventing degradation of the active ingredients of the composition.
  • Described pharmaceutical adjuvants may include one or more of the following adjuvants: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrating agents, lubricants, anti-sticking agents Agents, glidants, wetting agents, gelling agents, absorption delaying agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavors and sweeteners.
  • adjuvants may include one or more of the following adjuvants: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrating agents, lubricants, anti-sticking agents Agents, glidants, wetting agents, gelling agents, absorption delaying agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavors and sweeten
  • Substances that can be used as pharmaceutically acceptable excipients include, but are not limited to, ion exchangers, aluminum, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphate, glycine, sorbic acid, sorbic acid Potassium acid, partial glyceride mixture of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon, magnesium trisilicate, polyethylene Pyrrolidones, polyacrylates, waxes, polyethylene-polyoxypropylene-blocking polymers, lanolin, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as carboxymethyl Sodium cellulose, ethyl cellulose and cellulose acetate; gum powder; malt; gelatin; talc; adjuvants
  • compositions of the present invention can be prepared in light of the disclosure using any method known to those skilled in the art. For example, conventional mixing, dissolving, granulating, emulsifying, attenuating, encapsulating, entrapping or lyophilizing processes.
  • Pharmaceutical dosage forms of the compounds of the present invention may be provided in immediate release, controlled release, sustained release or targeted drug release systems.
  • common dosage forms include solutions and suspensions, (micro)emulsions, ointments, gels and patches, liposomes, tablets, dragees, soft or hard shell capsules, suppositories, ovules, implants, amorphous Or crystalline powder, aerosol and lyophilized preparations.
  • special devices may be required to administer or administer the drug, such as syringes and needles, inhalers, pumps, injection pens, applicators, or special flasks.
  • a pharmaceutical dosage form often consists of a drug, an excipient, and a container/closure system.
  • excipients also known as inactive ingredients
  • excipients may be added to the compounds of the present invention to improve or facilitate the manufacture, stability, administration and safety of the drug and may provide for the desired drug release Curve method.
  • the type of excipients added to the drug may depend on various factors, such as the physical and chemical properties of the drug, the route of administration, and the steps of preparation.
  • Pharmaceutically acceptable excipients exist in the art and include those listed in various pharmacopeias. (See US Pharmacopeia (USP), Japanese Pharmacopoeia (JP), European Pharmacopoeia (EP), and British Pharmacopoeia (BP); the US Food and Drug Administration (the US Food and Drug).
  • Pharmaceutical dosage forms of the compounds of this invention can be manufactured by any of the methods well known in the art, such as by conventional mixing, sieving, dissolving, melting, granulating, dragee-making, tableting, suspending, extrusion, spray drying, Milling, emulsification, (nano/micro) encapsulation, encapsulation or lyophilization processes.
  • compositions of the present invention may be administered topically or systemically, for example, for enteral administration, such as rectal or oral administration, or for parenteral administration to mammals, especially humans, and include those according to the present invention.
  • enteral administration such as rectal or oral administration
  • parenteral administration to mammals, especially humans, and include those according to the present invention.
  • the therapeutically effective amount of the active ingredient is as defined above and below, and depends on the species of mammal, body weight, age, individual condition, individual pharmacokinetic parameters, the disease to be treated and the mode of administration.
  • enteral administration such as oral administration
  • the compounds of the present invention can be formulated into a wide variety of dosage forms.
  • compositions and dosage forms may contain, as an active ingredient, one or more compounds of the present invention or one or more pharmaceutically acceptable salts thereof.
  • Pharmaceutically acceptable carriers can be solid or liquid. Solid form preparations include powders, tablets, pills, lozenges, capsules, cachets, suppositories and dispersible granules.
  • a solid carrier can also be one or more substances that act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
  • the carrier is usually a finely divided solid which is in admixture with the finely divided active component.
  • the active component is usually mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired.
  • 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 can include as carrier an encapsulating material providing a capsule in which the active component, with or without carriers, is surrounded by a carrier in association with it.
  • liquid form preparations including emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions, or solid form preparations which are intended to be converted shortly before use to liquid form preparations.
  • Emulsions can be prepared in solutions, such as aqueous propylene glycol, or can contain emulsifying agents, such as lecithin, sorbitan monooleate, or acacia.
  • Aqueous solutions can be prepared by dissolving the active component in water and adding suitable colorants, fragrances, stabilizers and thickening agents.
  • Aqueous suspensions can be prepared by dispersing the finely divided active ingredient in water with binders such as natural or synthetic gums, resins, methyl cellulose, carboxymethyl cellulose, and other conventional suspending agents.
  • Solid form preparations include solutions, suspensions and emulsions, and may contain, in addition to the active ingredient, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers Wait.
  • Exemplary combinations for rectal administration include suppositories, which may contain, for example, suitable non-irritating excipients such as cocoa butter, synthetic glycerides, or polyethylene glycols, which are solid at ordinary temperatures, but in the rectal cavity Melt and/or dissolve to release drug.
  • suitable non-irritating excipients such as cocoa butter, synthetic glycerides, or polyethylene glycols, which are solid at ordinary temperatures, but in the rectal cavity Melt and/or dissolve to release drug.
  • a therapeutically effective dose can first be estimated using various methods well known in the art. Initial doses for animal studies can be based on effective concentrations established in cell culture assays. Dosage ranges suitable for human subjects can be determined, for example, using data obtained from animal studies and cell culture assays. In certain embodiments, the compounds of the present invention can be prepared as medicaments for oral administration.
  • an effective or therapeutically effective amount or dose of an agent refers to the amount of the agent or compound that results in an improvement in symptoms or prolonged survival in an individual.
  • Toxicity and therapeutic efficacy of the molecule can be determined in cell cultures or experimental animals by standard medical procedures, for example by measuring the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). dose).
  • the dose ratio of toxic to therapeutic effects is the therapeutic index and can be expressed as LD50 / ED50 . Agents that exhibit high therapeutic indices are preferred.
  • An effective or therapeutically effective amount is the amount of a compound or pharmaceutical composition that will elicit a biological or medical response in a tissue, system, animal or human being sought by a researcher, veterinarian, physician or other clinician.
  • the dosage lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity.
  • the dosage may vary within this range depending upon the dosage form employed and/or the route of administration employed.
  • the correct formulation, route of administration, dosage and dosing interval should be selected according to methods known in the art, taking into account the particularities of the individual situation.
  • MEC minimal effective concentration
  • the amount of the agent or composition administered may depend on various factors, including the sex, age and weight of the individual being treated, the severity of the affliction, the mode of administration and the judgment of the prescribing physician.
  • compositions of the present invention can be presented in a pack or dispenser device containing one or more unit dosage forms containing the active ingredient, as required.
  • the package or device may comprise metal or plastic foil (eg, blister packs) or glass and rubber stoppers, as in vials.
  • the pack or dispenser device may be accompanied by instructions for use.
  • Compositions comprising a compound of the invention formulated in a compatible pharmaceutical carrier can also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
  • C1-C6 alkyl refers to an alkyl group as defined below having a total of 1, 2, 3, 4, 5 or 6 carbon atoms.
  • the total number of carbon atoms in the abbreviated notation does not include carbons that may be present in the substituents of the stated groups.
  • substituted means that any one or more hydrogen atoms on a specified atom are replaced by a substituent, including deuterium and hydrogen variants, as long as the valence of the specified atom is normal and the substituted compound is stable .
  • substituted means that one or more hydrogen atoms in a given structure have been replaced with a specified substituent.
  • the substituents are independent of each other, that is, the one or more substituents may be different from each other or the same of.
  • a substituent group may be substituted at various substitutable positions of the substituted group. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, the substituents can be substituted identically or differently at each position.
  • the substituents of the compounds disclosed in the present invention are disclosed in terms of group type or scope. Specifically, the present invention includes each and every independent subcombination of each member of these group species and ranges.
  • the term " C1 - C6 alkyl” or " C1-6 alkyl” specifically refers to the independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl and C6 alkanes
  • C 1-4 alkyl specifically refers to independently disclosed methyl, ethyl, C 3 alkyl (ie propyl, including n-propyl and isopropyl ), C 4 alkyl (ie butyl, including n-butyl, isobutyl, sec-butyl and tert-butyl).
  • halogen is selected from F, Cl, Br or I, especially F or Cl.
  • 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 containing 1 Alkyl groups of up to 6 carbon atoms are straight or branched.
  • General formula C n H 2n+1 .
  • C1 - C6 alkyl means that the alkyl moiety contains 1, 2, 3, 4, 5 or 6 carbon atoms.
  • the "alkyl” refers to a C1 - C6 alkyl group.
  • said “alkyl” refers to C1 - C4 alkyl.
  • Lower alkyl containing 1 to 6 carbon atoms non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl base, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methyl Butyl, 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, etc.
  • Non-limiting examples containing 1 to 12 carbon atoms include the above-mentioned examples of lower alkyl groups containing 1 to 6 carbon atoms, 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-di Methylhexyl, 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-
  • cycloalkyl as part of a group or other group, unless otherwise specified, means a saturated monocyclic, polycyclic or bridged carbocyclic substituted consisting solely of carbon and hydrogen atoms is attached to the rest of the molecule by a single bond via any suitable carbon atom; when polycyclic, it may be a copular or spiro (i.e., two geminal hydrogens on a carbon atom are linked by an alkylene substituted) bridged ring system or spiro ring system. Cycloalkyl substituents can be attached to the central molecule through any suitable carbon atom. In some embodiments, rings having 3-10 carbon atoms may be represented as C3 - C10 cycloalkyl.
  • the C 3 -C 6 cycloalkyl group includes cyclopropyl (C 3 ), cyclobutyl (C 4 ), cyclopentyl (C 5 ), and cyclohexyl (C 6 ).
  • examples of C 3 -C 10 cycloalkyl groups include the above-mentioned C 3 -C 6 cycloalkyl groups together with cycloheptyl (C 7 ), cyclooctyl (C 8 ), cyclononyl ( C 9 ) and cyclodecyl (C 10 ).
  • heterocycloalkyl as a group or part of another group means a stable compound consisting of 2-6 carbon atoms and 1-4 heteroatoms selected from nitrogen, oxygen and sulfur 3- to 7-membered saturated cyclic group.
  • Exemplary 3-membered heterocyclyl groups include, but are not limited to, aziridyl, oxiranyl, and thiirane groups, or stereoisomers thereof; exemplary 4-membered heterocyclyl groups Including, but not limited to, azetidinyl, propylene oxide, thietane, or isomers and stereoisomers thereof; exemplary 5-membered heterocyclyl groups include, but are not Limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, imidazolidinyl, pyrazolidinyl, dioxolanyl, oxygen Heterothiofuranyl, dithiofuranyl, or isomers and stereoisomers thereof.
  • Exemplary 6-membered heterocyclyl groups include, but are not limited to, piperidinyl, tetrahydropyranyl, cyclopentyl sulfide, morpholinyl, thiomorpholinyl, dithianyl, dioxanyl , piperazinyl, triazinyl, or isomers and stereoisomers thereof;
  • exemplary 7-membered heterocyclyl groups include, but are not limited to, azepanyl, oxepane radicals, thiepanyl, and diazepanyl, or isomers and stereoisomers thereof.
  • heterocycloalkyl is C 2 -C 5 heterocycloalkyl, wherein the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3 indivual.
  • heteroaryl as part of a group or other group means having carbon atoms and 1-3 heteroatoms (wherein each heteroatom is independently provided in the aromatic ring system) Groups (" 4-16 membered heteroaryl”).
  • heteroaryl groups containing one or more nitrogen atoms the point of attachment can be a carbon or nitrogen atom, as valence allows.
  • the heteroaryl group is one or more heteroatoms selected from N, O and S, and a 4-6 membered heteroaryl group with 1 to 3 heteroatoms, preferably It is a 5-6-membered heteroaryl group.
  • Exemplary 5-membered heteroaryl groups include, but are not limited to: pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl , oxadiazolyl, thiadiazolyl, furyl, oxtriazolyl or tetrazolyl.
  • Exemplary 6-membered heteroaryl groups include, but are not limited to, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl, or tetrazinyl.
  • moiety refers to a specific fragment or functional group in a molecule.
  • a chemical moiety is usually thought of as a chemical entity embedded or attached to a molecule.
  • linking substituents are described.
  • the Markush variables listed for that group should be understood to be the linking group.
  • the Markush group definition for that variable recites “alkyl” or “aryl”, it should be understood that the “alkyl” or “aryl” respectively represents the linking An alkylene group or an arylene group.
  • alkyl group when an alkyl group is clearly represented as a linking group, the alkyl group represents the alkylene group to which it is attached, eg, the group "halo-C 1 -C 6 alkane
  • a C 1 -C 6 alkyl group in "radical” should be understood as a C 1 -C 6 alkylene group.
  • alkylene refers to a saturated divalent hydrocarbyl group obtained by removing two hydrogen atoms from a saturated straight or branched chain hydrocarbyl group.
  • alkylene groups include methylene ( -CH2- ), ethylene ⁇ including -CH2CH2- or -CH( CH3 )- ⁇ , isopropylidene ⁇ including -CH( CH3 ) )CH 2 -or -C(CH 3 ) 2 - ⁇ and so on.
  • each step and condition may refer to the conventional operation steps and conditions in the art.
  • the present invention employs standard nomenclature and standard laboratory procedures and techniques of analytical chemistry, synthetic organic chemistry, and optics. In some cases, standard techniques are used for chemical synthesis, chemical analysis, and performance testing of light-emitting devices.
  • the description mode "...independently” used in the present invention should be understood in a broad sense, meaning that the described individuals are independent of each other and may be independent of each other. are the same or different specific groups.
  • the description mode "...independently” can either mean that in different groups, the specific options expressed between the same symbols do not affect each other; it can also mean that in the same group, the same symbols are The specific options expressed between them do not affect each other.
  • “Pharmaceutically acceptable” means that which can be used in the preparation of pharmaceutical combinations, is generally safe and non-toxic, and is not biologically and otherwise undesirable, and includes both for veterinary and human pharmaceutical use acceptable situation.
  • excipient refers to a pharmaceutically acceptable chemical substance, such as an agent known to those of ordinary skill in the art of pharmacy to aid in the administration of pharmaceuticals. It is a compound that can be used to prepare a pharmaceutical composition that is generally safe, non-toxic, and biologically or otherwise undesirable, including excipients that are pharmaceutically acceptable for veterinary and human use. Common excipients include binders, surfactants, diluents, disintegrants and lubricants.
  • treatment effective amount refers to an amount of a compound used that, when administered to a subject to treat a disease state, is sufficient to effect such treatment of the disease state.
  • the “administratively effective 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, the judgment of the attending medical or veterinarian, and the like.
  • mammal refers to a human or any mammal such as a primate, farm animal, pet animal or laboratory animal. Examples of such animals are monkeys, cows, sheep, horses, pigs, dogs, cats, rabbits, mice and rats and the like. Mammals are preferred to humans.
  • the reagents and raw materials used in the present invention are all commercially available.
  • a pyrimidine carboxamide compound is provided, which can be used as a Vanin enzyme, especially a Vanin-1 inhibitor; it can be used for the preparation of prevention and/or treatment of Crohn's disease, ulcerative colon inflammation and inflammatory bowel disease.
  • the crude product 2-1d was dissolved in 500 mL of methanol, and 200 mL of 4N HCl/MeOH was added slowly. The reaction was carried out at room temperature for 2h. After the reaction was completed, the reaction solution was concentrated to obtain an oily substance, which was added with ethyl acetate and stirred. After filtration, compound 2-1e was obtained as a red solid powder (300 g, ee value 92%, purity 99%).
  • Compound A is It is prepared by referring to the method of Example 142 in CN109476645A.
  • Preparation method Accurately weigh the required compound, add a certain volume of DMSO in proportion, vortex and mix to dissolve completely, then add Solutol and PBS in sequence according to the above proportion, and mix well.
  • the vehicle used in the intravenous (iv) administration group and the oral (po) administration group was the same vehicle.
  • the intravenous dose is 1mpk and the oral dose is 2mpk.

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Abstract

本发明公开了一种嘧啶甲酰胺类化合物及其应用。本发明提供了一种如式（I）所示的嘧啶甲酰胺类化合物、或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其药学上可接受的盐；其可以用作Vanin酶抑制剂；其可用于制备用于治疗多种病状，包括克罗恩氏病及溃疡性结肠炎等的药物。

Description

一种嘧啶甲酰胺类化合物及其应用
本申请要求申请日为2020年9月25日的中国专利申请2020110207210的优先权和申请日为2021年9月17日的中国专利申请2021110954656的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明涉及一种嘧啶甲酰胺类化合物及其应用。
背景技术
Vanin-1(血管非炎性分子-1)是一种具有泛肽酶活性的外切酶，主要催化泛酰巯基乙胺的水解而产生泛酸(pantothenic acid，VB5)和巯基乙胺。由VB5合成而来的辅酶A(CoA)调节脂肪酸合成和氧化以及能力代谢等生物转化，而巯基乙胺和胱胺之间的可逆反应是氧化应激的重要传感器。越来越多的研究发现，巯基乙胺的缺乏或水平降低导致γ-GCS活性增强，引起组织中内源性GSH储备升高，从而可以预防或消除组织炎症。研究发现，Vanin-1的mRNA在人结肠、十二指肠、子宫内膜、肝、肾、胆囊和小肠中高表达。在UC(溃疡性结肠炎)患者中，Vanin-1高表达且弥漫，而且仅限于笔刷边界。另外，在UC的临床静止期，结肠中Vanin-1的表达水平仍显著高于对照品。在TNBS模型实验中，小鼠Vanin-1敲除(Vanin-1 -/-)后生存率明显高于模型对照组，并且未表现明显体重降低。而且，90％经胱胺处理的Vanin-1 -/-小鼠在5天内死亡，说明胱胺完全逆转Vanin-1的缺乏对结肠炎的保护作用。此外，对小鼠组织病理学分析发现，对Vanin-1的抑制或敲除能显著改善小鼠结肠的病变(Berruyer C,等人Vanin-1-/-mice exhibit a glutathione mediated tissue resistance to oxidative stress.Mol.Cell Biol.2004；24:7214-7224；Berruyer C,等人Vanin-1licenses inflammatory mediator production by gut epithelial cells and controls colitis by antagonizing peroxisome proliferator-activated receptorγactivity.J.Exp.Med.2006；203:2817-2827)。
另外，Vanin-1也被认为在心血管疾病和肿瘤疾病中起调节作用。有研究证明，Vanin-1在体外调节平滑肌细胞的活化，并在体内调节响应于颈动脉结扎的新内膜增生的发生。VNN1基因的多态性与血压和HDL水平相关。在SF-1转基因小鼠中，Vanin-1缺失防止小鼠发展为肾上腺皮质的瘤形成，表明了Vanin-1在某些癌症中的作用。在炎症性疾病方面的研究发现，与正常个体相比，在牛皮癣的皮肤损伤中，Vanin-1高度上调。在患有儿童免疫血小板减少症(ITP)的患者的全血中，VNN1的基因表达也上调，其中VNN1的过表达与慢性ITP的进展相关。另外，在患有多种肾脏病症的患者尿液中已检测到Vanin-1升高，所述肾脏病症包括系统性红斑狼疮、肾脏毒物(nephrotoxicant)-诱导的肾损伤 和2型糖尿病(Rommelaere S,等人PPARalpha regulates the production of serum Vanin-1 by liver.FEBS Lett.2013 Nov 15；587(22):3742-8)。
发明内容
本发明所要解决的技术问题是为了克服现有技术中基于Vanin酶的治疗剂缺乏的问题；而提供了一种嘧啶甲酰胺类化合物及其应用。本发明提供的嘧啶甲酰胺类化合物为具有Vanin酶抑制活性的化合物；具有较强的Vanin-1抑制剂活性；其可以用于治疗多种病状，包括克罗恩氏病及溃疡性结肠炎。
本发明是通过下述技术方案来解决上述技术问题的。
本发明提供了一种如式I所示的嘧啶甲酰胺类化合物、或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其药学上可接受的盐；
Figure PCTCN2021128344-appb-000001
其中，n为0、1、2或3；
R 1独立地为卤素、C 1-C 6烷基、被一个或多个R 1a取代的C 1-C 6烷基；
Z 1为-(CR 6aR 6b)-或-(NR 6c)-，Z 2为连接键；或，Z 1为连接键，Z 2为-(CR 7aR 7b)-；
Z 3为连接键或-(CR 8aR 8b)-；
R a独立地为H；
R 6a、R 6b、R 7a和R 7b独立地为H、卤素或C 1-C 6烷基；
R 6c独立地为H或C 1-C 4烷基；
R 3a、R 3b、R 4a、R 4b、R 5a、R 5b、R 8a和R 8b独立地为H、卤素、C 1-C 6烷基、被一个或多个R 1c取代的C 1-C 6烷基、-(NR 9aR 9b)或-(NR 10a)-(C＝O)-R 10b；
或者，R 4a和R 4b、或、R 4a和R 5a、或、R 4a和R 8a与它们键合的碳一起形成环B；环B为4-7元环烷基、4-7元杂环烷基、被一个或多个R 1d取代的4-7元环烷基或被一个或多个R 1e取代的4-7元杂环烷基；所述的4-7元杂环烷基和被一个或多个R 1e取代的4-7元杂环烷基里的4-7元杂环烷基中，杂原子为N、O或S，杂原子个数为1或2个；
R 1a、R 1c、R 1d和R 1e独立地为卤素、C 1-C 4烷基或被一个或多个卤素取代的C 1-C 4烷基；
R 9a、R 9b、R 10a和R 10b独立地为H、C 1-C 4烷基或被1个或多个卤素取代的C 1-C 4烷基；
A为苯基或6-元杂芳基；所述的6-元杂芳基中，杂原子为N，杂原子个数为1或2个；
Figure PCTCN2021128344-appb-000002
表示单键或双键。
在本发明某些优选实施方案中，所述的如式I所示的嘧啶甲酰胺类化合物、或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其药学上可接受的盐中的某些基团如下定义，未提及的基团同本申请任一方案所述(以下简称为“在某一方案中”)，n为0或1。
在某一方案中，
Z 1为-(CR 6aR 6b)-，Z 2为连接键。
在某一方案中，
R 6a和R 6b独立地为H或卤素。
在某一方案中，
R 7a和R 7b独立地为H；即Z 2为-(CH 2)-。
在某一方案中，
Z 3为-(CR 8aR 8b)-。
在某一方案中，
R 3a、R 3b、R 4a、R 4b、R 5a、R 5b、R 8a和R 8b独立地为H、C 1-C 6烷基、-(NR 9aR 9b)或-(NR 10a)-(C＝O)-R 10b。
在某一方案中，
R 3a和R 3b独立地为H。
在某一方案中，
R 5a和R 5b独立地为H。
在某一方案中，
R 4a和R 4b独立地为H、C 1-C 6烷基、-(NR 9aR 9b)或-(NR 10a)-(C＝O)-R 10b。
在某一方案中，
R 4a独立地为C 1-C 6烷基、-(NR 9aR 9b)或-(NR 10a)-(C＝O)-R 10b；
R 4b独立地为H或C 1-C 6烷基。
在某一方案中，
R 4a和R 4b、或、R 4a和R 5a、或、R 4a和R 8a与它们键合的碳一起形成环B；
例如，环B为4-7元环烷基、4-7元杂环烷基、被一个或多个R 1d取代的4-7元杂环烷基。
在某一方案中，
R 8a和R 8b独立地为H；即Z 3为-(CH 2)-。
在某一方案中，
R 1a、R 1c、R 1d和R 1e独立地为卤素或C 1-C 4烷基。
在某一方案中，
R 1a独立地为卤素；例如F。
在某一方案中，
R 1e独立地为C 1-C 4烷基。
在某一方案中，
R 9a、R 9b、R 10a和R 10b独立地为C 1-C 4烷基或被1个或多个卤素取代的C 1-C 4烷基。
在某一方案中，
A为6-元杂芳基；例如吡啶基。
在某一方案中，
Figure PCTCN2021128344-appb-000003
表示单键。
在某一方案中，
Figure PCTCN2021128344-appb-000004
为
Figure PCTCN2021128344-appb-000005
或其混合物；例如
Figure PCTCN2021128344-appb-000006
在某一方案中，
n为0或1；
R 1独立地为卤素、C 1-C 6烷基、被一个或多个R 1a取代的C 1-C 6烷基；
Z 1为-(CR 6aR 6b)-或-(NR 6c)-，Z 2为连接键；或Z 1为连接键，Z 2为-(CR 7aR 7b)-；
Z 3为-(CR 8aR 8b)-；
R a独立地为H；
R 6a、R 6b、R 7a和R 7b独立地为H或卤素；
R 6c独立地为H或C 1-C 4烷基；
R 3a、R 3b、R 5a、R 5b、R 8a和R 8b独立地为H；
R 4a和R 4b独立地为H、C 1-C 6烷基、-(NR 9aR 9b)或-(NR 10a)-(C＝O)-R 10b；
或者，R 4a和R 4b、或、R 4a和R 5a、或、R 4a和R 8a与它们键合的碳一起形成环B；环B为4-7元环烷基、4-7元杂环烷基、被一个或多个R 1d取代的4-7元环烷基或被一个或多个R 1e取代的4-7元杂环烷基；
R 1a、R 1d和R 1e独立地为卤素或C 1-C 4烷基；
R 9a、R 9b、R 10a和R 10b独立地为C 1-C 4烷基或被1个或多个卤素取代的C 1-C 4烷基；
A为苯基或6元杂芳基；
Figure PCTCN2021128344-appb-000007
表示单键或双键。
在某一方案中，
n为0或1；
R 1独立地为卤素、C 1-C 6烷基、被一个或多个R 1a取代的C 1-C 6烷基；
Z 1为-(CR 6aR 6b)-或-(NR 6c)-，Z 2为连接键；或，Z 1为连接键，Z 2为-(CR 7aR 7b)-；
Z 3为-(CR 8aR 8b)-；
R a独立地为H；
R 6a和R 6b独立地为H或卤素；R 7a和R 7b独立地为H；
R 1a独立地为卤素；
R 6c独立地为H或C 1-C 4烷基；
R 3a、R 3b、R 5a、R 5b、R 8a和R 8b独立地为H；
R 4a独立地为C 1-C 6烷基、-(NR 9aR 9b)或-(NR 10a)-(C＝O)-R 10b；
R 4b独立地为H或C 1-C 6烷基；
或者，R 4a和R 4b、或、R 4a和R 5a、或、R 4a和R 8a与它们键合的碳一起形成环B；环B为4-7元环烷基、4-7元杂环烷基、或被一个或多个R 1e取代的4-7元杂环烷基；
R 1e独立地为C 1-C 4烷基；
R 9a、R 9b、R 10a和R 10b独立地为C 1-C 4烷基或被1个或多个卤素取代的C 1-C 4烷基；
A为6元杂芳基；例如吡啶基；
Figure PCTCN2021128344-appb-000008
表示单键。
在某一方案中，
当R 1为卤素时，所述的卤素为氟、氯或溴；例如氟或氯；又例如氟。
在某一方案中，
当R 1为被一个或多个R 1a取代的C 1-C 6烷基时，所述的取代基的个数为1、2、3、4或5个；例如1、2或3个；例如三氟甲基。
在某一方案中，
当R 1为C 1-C 6烷基、被一个或多个R 1a取代的C 1-C 6烷基时，所述的C 1-C 6烷基和被一个或多个R 1a取代的C 1-C 6烷基里的C 1-C 6烷基(例如甲基、乙基、丙基、丁基、戊基或己基)独立地为C 1～C 4烷基(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基)；例如甲基。
在某一方案中，
当R 6a、R 6b、R 7a和R 7b独立地为卤素时，所述的卤素独立地为氟、氯或溴；例如氟或氯；又例如氟。
在某一方案中，
当R 6a、R 6b、R 7a和R 7b独立地为C 1-C 6烷基时，所述的C 1-C 6烷基(例如甲基、乙基、丙基、丁基、戊基或己基)独立地为C 1～C 4烷基(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁 基或叔丁基)；例如甲基。
在某一方案中，
当R 6c独立地为C 1-C 4烷基时，所述的C 1～C 4烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；例如甲基。
在某一方案中，
当R 3a、R 3b、R 4a、R 4b、R 5a、R 5b、R 8a和R 8b独立地为卤素时，所述的卤素独立地为氟、氯或溴；例如氟或氯；又例如氟。
在某一方案中，
当R 3a、R 3b、R 4a、R 4b、R 5a、R 5b、R 8a和R 8b独立地为C 1-C 6烷基、被一个或多个R 1c取代的C 1-C 6烷基时，所述的C 1-C 6烷基和被一个或多个R 1c取代的C 1-C 6烷基里的C 1-C 6烷基(例如甲基、乙基、丙基、丁基、戊基或己基)独立地为C 1～C 4烷基(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基)；例如甲基或乙基。
在某一方案中，
当环B为4-7元环烷基、被一个或多个R 1d取代的4-7元环烷基时，所述的4-7元环烷基和被一个或多个R 1d取代的4-7元环烷基里的4-7元环烷基独立地为环丁基、环戊基、环己基或环庚基；又例如环戊基。
在某一方案中，
当环B为4-7元杂环烷基、或被一个或多个R 1e取代的4-7元杂环烷基时，所述的4-7元杂环烷基和被一个或多个R 1e取代的4-7元杂环烷基里的4-7元杂环烷基独立地为四氢呋喃基、四氢-2H-吡喃基、吡咯烷基；例如，当R 4a和R 4b与它们键合的碳一起形成环B时，环B为
Figure PCTCN2021128344-appb-000009
Figure PCTCN2021128344-appb-000010
当R 4a和R 5a、或、R 4a和R 8a与它们键合的碳一起形成环B时，环B为
Figure PCTCN2021128344-appb-000011
Figure PCTCN2021128344-appb-000012
在某一方案中，
当R 1a、R 1c、R 1d和R 1e独立地为卤素或被一个或多个卤素取代的C 1-C 4烷基时，所述的卤素和被一个或多个卤素取代的C 1-C 4烷基里的卤素可独立地为氟、氯或溴；例如氟或氯；又例如氟。
在某一方案中，
当R 1a、R 1c、R 1d和R 1e独立地为C 1-C 4烷基或被一个或多个卤素取代的C 1-C 4烷基里的C 1～C 4烷 基独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；例如甲基或乙基。
在某一方案中，
当R 9a、R 9b、R 10a和R 10b独立地为C 1-C 4烷基时，所述的C 1～C 4烷基独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；例如甲基或乙基。
在某一方案中，
当R 9a、R 9b、R 10a和R 10b独立地为被1个或多个卤素取代的C 1-C 4烷基时，所述的被1个或多个卤素取代的C 1～C 4烷基中，所述C 1～C 4烷基独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；例如甲基或乙基。
在某一方案中，
当R 9a、R 9b、R 10a和R 10b独立地为被1个或多个卤素取代的C 1-C 4烷基时，所述卤素独立地为氟、氯或溴；例如氟；再例如所述被1个或多个卤素取代的C 1-C 4烷基为三氟甲基。
在某一方案中，
当A为6-元杂芳基时，所述6-元杂芳基为吡啶基、吡嗪基或嘧啶基；所述的吡啶基可为
Figure PCTCN2021128344-appb-000013
Figure PCTCN2021128344-appb-000014
所述吡嗪基可为
Figure PCTCN2021128344-appb-000015
所述嘧啶基可为
Figure PCTCN2021128344-appb-000016
a表示A与
Figure PCTCN2021128344-appb-000017
连接位置。
在某一方案中，
R 1独立地为F、甲基或三氟甲基。
在某一方案中，
Z 1为-(CH 2)-、-(CF 2)-、-(NH)-或-(N(CH 3))-。
在某一方案中，
R 4a和R 4b独立地为H、乙基、二甲氨基、
Figure PCTCN2021128344-appb-000018
例如R 4a和R 4b独立地为乙基，或R 4a为H、R 4b为二甲氨基、
Figure PCTCN2021128344-appb-000019
在某一方案中，
R 4a和R 4b与它们键合的碳一起形成环B；例如
Figure PCTCN2021128344-appb-000020
在某一方案中，
R 4a和R 5a、或、R 4a和R 8a与它们键合的碳一起形成环B；例如：
Figure PCTCN2021128344-appb-000021
在某一方案中，
Figure PCTCN2021128344-appb-000022
为
Figure PCTCN2021128344-appb-000023
例如
Figure PCTCN2021128344-appb-000024
在某一方案中，
Figure PCTCN2021128344-appb-000025
为苯基、
Figure PCTCN2021128344-appb-000026
Figure PCTCN2021128344-appb-000027
例如
Figure PCTCN2021128344-appb-000028
(a表示稠合的位置)
在某一方案中，
Figure PCTCN2021128344-appb-000029
为
Figure PCTCN2021128344-appb-000030
Figure PCTCN2021128344-appb-000031
例如
Figure PCTCN2021128344-appb-000032
在某一方案中，
Figure PCTCN2021128344-appb-000033
为
Figure PCTCN2021128344-appb-000034
Figure PCTCN2021128344-appb-000035
Figure PCTCN2021128344-appb-000036
例如
Figure PCTCN2021128344-appb-000037
在某一方案中，
Figure PCTCN2021128344-appb-000038
为
Figure PCTCN2021128344-appb-000039
Figure PCTCN2021128344-appb-000040
Figure PCTCN2021128344-appb-000041
例如
Figure PCTCN2021128344-appb-000042
在本发明某些优选实施方案中，所述的如式I所示的嘧啶甲酰胺类化合物为如下任一结构：
Figure PCTCN2021128344-appb-000043
Figure PCTCN2021128344-appb-000044
在本发明某些优选实施方案中，所述的如式I所示的嘧啶甲酰胺类化合物为如下任一结构：
在下述条件下保留时间为8.483min的化合物
Figure PCTCN2021128344-appb-000045
Figure PCTCN2021128344-appb-000046
手性色谱拆分，色谱柱:CHIRALPAK AD-H,250x 4.6mm，5um；柱温:35℃；流速:0.4mL/min；波长:254nm；梯度:A:正己烷，B:异丙醇，A:B＝1:4；运行时间：50min；
在下述条件下保留时间为13.580min的化合物
Figure PCTCN2021128344-appb-000047
Figure PCTCN2021128344-appb-000048
手性色谱拆分，色谱柱:CHIRALPAK AD-H,250x 4.6mm，5um；柱温:35℃；流速:0.4mL/min；波长:254nm；梯度:A:正己烷，B:异丙醇，A:B＝1:4；运行时间：50min。本领域技术人员应当理解，该化合物的绝对构型只是采用保留时间进行区分，不同保留时间对应的绝对构型以实际为准。
本发明中，所述的如式I所示的嘧啶甲酰胺类化合物或其药学上可接受的盐可具有一个或多个手性碳原子，因此可以分离得到光学纯度异构体，例如纯的对映异构体，或者外消旋体，或者混合异构体。可以通过本领域的分离方法来获得纯的单一异构体，如手性结晶成盐，或者手性制备柱分离得到。
本发明中，所述的如式I所示的嘧啶甲酰胺类化合物或其药学上可接受的盐如存在立体异构体，则可以以单一的立体异构体或它们的混合物(例如外消旋体)的形式存在。术语“立体异构体”是指顺反异构体或旋光异构体。这些立体异构体可以通过不对称合成方法或手性分离法(包括但不限于薄层色谱、旋转色谱、柱色谱、气相色谱、高压液相色谱等)分离、纯化及富集，还可以通过与其它手性化合物成键(化学结合等)或成盐(物理结合等)等方式进行手性拆分获得。术语“单一的立体异构体”是指本发明化合物的一种立体异构体相对于该化合物的所有立体异构体的质量含量不低于95％。
由此，在本说明书通篇中，本领域技术人员可对所述的如式I所示的嘧啶甲酰胺类化合物、或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其药学上可接受的盐中所述基团及其取代基进行选择，以提供稳定的如式I所示的嘧啶甲酰胺类化合物、或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或药学上可接受的盐，包括但不限于本发明的实施例中所述的化合物。
本发明所述的如式I所示的嘧啶甲酰胺类化合物、或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其药学上可接受的盐可通过包括与化学领域公知方法相似的方法合成，其步骤和条件可参考本领域类似反应的步骤和条件，特别是根据本文说明进行合成。起始原料通常是来自商业来源，例如Aldrich或可使用本领域技术人员公知的方法(通过SciFinder、Reaxys联机数据库得到)容易地制备。
本发明中，所述的如式I所示的嘧啶甲酰胺类化合物、或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其药学上可接受的盐，也可以通过已制备得到的所述的如式I所示的嘧啶甲酰胺类化合物、或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其药学上可接受的盐，采用本领域常规方法，经外周修饰进而得到其他所述的如式I所示的嘧啶甲酰胺类化合物、或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其药学上可接受的盐。
一般地，本发明的化合物可以通过本发明所描述的方法制备得到，除非有进一步的说明，其中取代基的定义如式I所示。下面的反应方案和实施例用于进一步举例说明本发明的内容。
用于制备如式I中化合物的必要原料或试剂可以商购获得，或者通过本领域已知的合成方法制备。如下实验部分所描述的方法，可以制备游离碱或者其加酸所成盐的本发明的化合物。术语药学上可接受的盐指的是本文所定义的药学上可接受的盐，并且具有母体化合物所有的药学活性。药学上可接受的盐可以通过在有机碱的合适的有机溶剂中加入相应的酸，根据常规方法处理来制备药学上可接受的盐。
成盐实例包括：与无机酸成盐，如盐酸、氢溴酸、硫酸、硝酸、磷酸；和有机酸所形成的盐，如醋酸、苯磺酸、苯甲酸、樟脑磺酸、柃檬酸、乙磺酸、富马酸、葡庚糖酸、谷氨酸、乙醇酸、羟基萘甲酸、2-羟基乙磺酸、乳酸、马来酸、苹果酸、丙二酸、扁桃酸、甲磺酸、黏糠酸、2-萘磺酸、丙酸、水杨酸、琥珀酸、酒石酸、对甲苯磺酸或三甲基乙酸。
如式I所示的嘧啶甲酰胺类化合物可能具有一个或多个手性碳原子，因此可以分离得到光学纯度异构体，例如纯的对映异构体，或者外消旋体，或者混合异构体。可以通过本领域的分离方法来获得纯的单一异构体，如手性结晶成盐，或者手性制备柱分离得到。
本专利所述的合成路线中所用的化学品，包括溶剂，试剂，催化剂以及保护基团，脱保护基团，保护基团包括叔丁氧基羰基(Boc)。上述方法还可以另外包括在本文具体描述的步骤之前或之后的步骤，可以添加或除去合适的保护基团，以得到目标化合物。另外，各种合成步骤可以交替或顺次的进行以得到最终的目标产物。
本发明提供了一种药物组合物，其包含如上所述的式I所示的嘧啶甲酰胺类化合物、或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其药学上可接受的盐，和，(一种或多种)药用辅料(例如和可药用载体、稀释剂、媒介物或其它赋形剂)。所述的如式I所示的嘧啶甲酰胺类化合物、或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其药学上可接受的盐的用量可为治疗有效量。
本发明还提供了一种所述的如式I所示的嘧啶甲酰胺类化合物、或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其药学上可接受的盐在制备Vanin-1抑制剂中的应用。在所述的应用中，所述的Vanin-1抑制剂可用于哺乳动物生物体内；也可用于生物体外，主要作为实验用途，例如：作为标准样或对照样提供比对，或按照本领域常规方法制成试剂盒，为Vanin-1的抑制效果提供快速检测。如本文使用的术语“vanin-1(酶)的抑制剂”指结合vanin-1(酶)和降低产生的酶活性的化合物。
本发明还提供了一种所述的如式I所示的嘧啶甲酰胺类化合物、或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其药学上可接受的盐在制备药物中的应用； 所述的药物可为用于预防和/或治疗与Vanin-1有关的疾病，或者，所述的药物可为用于预防和/或治疗自身免疫疾病、炎性疾病、变态反应性疾病、代谢疾病、基于感染的疾病、纤维变性疾病、心血管疾病、呼吸系统疾病、肾疾病、皮肤病学疾病、肝脏疾病、胃肠疾病、口腔疾病和造血疾病中的一种或多种；又例如克罗恩氏病、炎性肠病及溃疡性结肠炎的药物。所述的与Vanin-1有关的疾病可包括自身免疫疾病、炎性疾病、变态反应性疾病、代谢疾病、基于感染的疾病、纤维变性疾病、心血管疾病、呼吸系统疾病、肾疾病、皮肤病学疾病、肝脏疾病、胃肠疾病、口腔疾病和造血疾病中的一种或多种；又例如炎性肠病、溃疡性结肠炎、克隆氏病、结肠直肠癌和胃炎。
本发明的另一方面涉及一种预防和/或治疗Vanin-1有关的疾病的方法，其包括向患者施用治疗有效剂量的所述的如式I所示的嘧啶甲酰胺类化合物、或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其药学上可接受的盐或包含其的药物组合物。例如治疗vanin-1酶的抑制介导的或另外地与vanin-1酶的抑制相关的疾病或病症。例如自身免疫疾病、炎性疾病、变态反应性疾病、代谢疾病、基于感染的疾病、纤维变性疾病、心血管疾病、呼吸系统疾病、肾疾病、皮肤病学疾病、肝脏疾病、胃肠疾病、口腔疾病和造血疾病中的一种或多种；又例如炎性肠病、溃疡性结肠炎、克隆氏病、结肠直肠癌和胃炎。
本发明的另一方面涉及一种治疗预防和/或治疗自身免疫疾病、炎性疾病、变态反应性疾病、代谢疾病、基于感染的疾病、纤维变性疾病、心血管疾病、呼吸系统疾病、肾疾病、皮肤病学疾病、肝脏疾病、胃肠疾病、口腔疾病和造血疾病中的一种或多种(例如炎性肠病、溃疡性结肠炎、克隆氏病、结肠直肠癌和胃炎)的方法，其包括向患者施用治疗有效剂量的所述的如式I所示的嘧啶甲酰胺类化合物、或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其药学上可接受的盐或包含其的药物组合物。
本发明的另一方面涉及一种用于抑制Vanin-1的药物，其包括所述的如式I所示的嘧啶甲酰胺类化合物、或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其药学上可接受的盐或包含其的药物组合物。
本发明的化合物可以用局部或全身给药，例如，用于肠内给药，比如直肠或口服用药，或用于肠胃外给药至哺乳动物(尤其指人)。本发明的化合物也可在肠胃外给药，例如，通过吸入式、注射或输液、如通过静脉内、动脉内、骨内、肌内、大脑内、脑室外、滑膜内、胸骨内、鞘内、病灶内、颅内、肿瘤内、皮内和皮下注射或输入。
本发明所述化合物、药物组合物或药物的有效量取决于哺乳动物的种类、体重、年龄、个体状况、个体药代动力学参数、待治疗的疾病和给药方式。
本发明所述化合物、药物组合物或药物的有效量可通过常规实验容易的测定，最有效和方便的给药途径以及最适当的制剂也可通过常规实验测定。
所述的药用辅料可为药物生产领域中广泛采用的那些辅料。辅料主要用于提供一个安全、稳定和功能性的药物组合物，还可以提供方法，使受试者接受给药后活性成分以所期望速率溶出，或促进受试者接受组合物给药后活性成分得到有效吸收。所述的药用辅料可以是惰性填充剂，或者提供某种功能，例如稳定该组合物的整体pH值或防止组合物活性成分的降解。所述的药用辅料可以包括下列辅料中的一种或多种：粘合剂、助悬剂、乳化剂、稀释剂、填充剂、成粒剂、胶粘剂、崩解剂、润滑剂、抗粘着剂、助流剂、润湿剂、胶凝剂、吸收延迟剂、溶解抑制剂、增强剂、吸附剂、缓冲剂、螯合剂、防腐剂、着色剂、矫味剂和甜味剂。
可作为药学上可接受辅料的物质包括，但并不限于，离子交换剂，铝，硬脂酸铝，卵磷脂，血清蛋白，如人血清蛋白，缓冲物质如磷酸盐，甘氨酸，山梨酸，山梨酸钾，饱和植物脂肪酸的部分甘油酯混合物，水，盐或电解质，如硫酸鱼精蛋白，磷酸氢二钠，磷酸氢钾，氯化钠，锌盐，胶体硅，三硅酸镁，聚乙烯吡咯烷酮，聚丙烯酸脂，蜡，聚乙烯-聚氧丙烯-阻断聚合体，羊毛脂，糖，如乳糖，葡萄糖和蔗糖；淀粉如玉米淀粉和土豆淀粉；纤维素和它的衍生物如羧甲基纤维素钠，乙基纤维素和乙酸纤维素；树胶粉；麦芽；明胶；滑石粉；辅料如可可豆脂和栓剂蜡状物；油如花生油，棉子油，红花油，麻油，橄榄油，玉米油和豆油；二醇类化合物，如丙二醇和聚乙二醇；酯类如乙基油酸酯和乙基月桂酸酯；琼脂；缓冲剂如氢氧化镁和氢氧化铝；海藻酸；无热原的水；等渗盐；林格(氏)溶液；乙醇，磷酸缓冲溶液，和其他无毒的合适的润滑剂如月桂硫酸钠和硬脂酸镁，着色剂，释放剂，包衣衣料，甜味剂，调味剂和香料，防腐剂和抗氧化剂。
本发明的药物组合物可根据公开的内容使用本领域技术人员已知的任何方法来制备。例如，常规混合、溶解、造粒、乳化、磨细、包封、包埋或冻干工艺。
本发明的化合物的医药剂型可以以速释、控释、缓释或靶药物释放系统形式提供。例如，常用剂型包括溶液和悬浮液、(微)乳液、软膏、凝胶和贴片、脂质体、片剂、糖衣药丸、软壳或硬壳胶囊、栓剂、胚珠、植入物、非晶形或结晶粉末、气溶胶和冻干制剂。视所用的给药途径而定，可能需要特殊装置来施用或给予药物，例如注射器和针、吸入器、泵、注射笔、涂药器或专用瓶(Specialflask)。药物剂型常常由药物、赋形剂和容器/密封系统组成。可将一种或多种赋形剂(又称为非活性成分)添加到本发明的化合物中来改善或促进药物的制造、稳定性、给药和安全性，并且可提供获得所需药物释放曲线的方法。因此，添加到药物中的赋形剂类型可视各种因素而定，例如药物的物理和化学特性、给药途径和制备步骤。在该领域中存在药用赋形剂并且包括各种药典中所列的那些。(参见美国药典(U.S.Pharmacopeia,USP)、日本药典(Japanese Pharmacopoeia,JP)、欧洲药典(European Pharmacopoeia,EP)和英国药典(British pharmacopoeia,BP)；美国食品与药品管理局(the U.S.Food and Drug Administration,www.fda.gov)药物评价与研究中心(Centerfor Drug Evaluation and Research,CEDR)出版物，例如《非活性组分指南》(Inactive Ingredient Guide,1996)；Ash和Ash编写的《药物添加剂手册》 (Hand book of Pharmaceutical Additives,2002,联合信息资源公司(Synapse Information Resources,Inc.,Endicott NY；etc.)。
本发明化合物的药物剂型可通过本领域中熟知的任一种方法来制造，例如通过常规混合、筛分、溶解、熔化、造粒、制造糖衣药丸、压片、悬浮、挤压、喷雾干燥、研磨、乳化、(纳米/微米级)囊封、包理或冻干工艺。
本发明的药物组合物可以用局部或全身给药，例如，用于肠内给药，比如直肠或口服用药，或用于肠胃外给药至哺乳动物(尤其指人)，并且包括根据本发明的化合物或其药学上可接受的盐作为活性成分的治疗有效量，连同药学上可接受的赋形剂，如药学上可接受的载体。活性成份的治疗有效量如上下文所定义，并且取决于哺乳动物的种类、体重、年龄、个体状况、个体药代动力学参数、待治疗的疾病和给药方式对于肠内给药，如口服药，本发明化合物可以配制成广泛的多种剂型。
所述药物组合物和剂型可以包含一种或多种本发明的化合物或其一种或多种药学上可接受的盐作为活性组分。药学上可接受的载体可以是固体或液体。固体的形式的制剂包括粉剂、片剂、丸剂、锭剂、胶囊剂、扁嚢剂、栓剂和可分散的颗粒剂。固体载体可以还是作为稀释剂、调味剂、增溶剂、润滑剂、悬浮剂、粘合剂、防腐剂、片剂崩解剂或者包封材料的一种或多种物质。在粉剂中，载体通常是细碎的固体，其是与细碎的活性组分的混合物。在片剂中，活性组分通常与具有必要粘合能力的载体以合适的比例混合并按照所需的形状和尺寸压实。合适的载体包括但不限于碳酸镁、硬脂酸镁、滑石、糖、乳糖、果胶、糊精，淀粉、明胶、甲基纤维素、羧甲基纤维素钠、低熔点蜡，可可脂等。活性化合物的制剂可以包括作为载体的包封材料，提供胶囊，其中有或没有载体的活性组分被与其结合的载体包围。
适于口服给药的其它形式包括液体形式制剂，包括乳液、糖浆剂、酏剂、水溶液、水性悬浊液、或意图在使用前不久转化成液体形式制剂的固体形式制剂。乳液可以在溶液中制备，例如丙二醇水溶液中，或者可以含有乳化剂，如卵磷脂、脱水山梨糖醇单油酸酯或阿拉伯胶。水溶液可以通过将活性组分溶解在水中并加入合适的着色剂、香料、稳定剂和增稠剂来制备。水性混悬液可以通过将细小颗粒的活性成分用粘合剂如天然或合成胶、树脂、甲基纤维素、羧甲基纤维素和其它常用的悬浮剂分散在水中制备。固体形式的制剂包括溶液剂、混悬剂和乳液，除了活性组分外，还可以含有着色剂、香料、稳定剂、缓冲剂、人造和天然甜味剂、分散剂、增稠剂、增溶剂等。
用于直肠给药的示例性组合包括栓剂，其可以包含例如适合的非刺激性赋形剂，例如可可脂、合成甘油酯或聚乙二醇，其在常温下是固体，但是在直肠腔中融化和/或溶解以释放药物。
治疗有效剂量可首先使用本领域中熟知的各种方法来估算。用于动物研究的初始剂量可基于细胞培养测定中所确立的有效浓度。适合于人个体的剂量范围例如可使用从动物研究和细胞培养测定所获得的数据来确定。在某些实施方案中，可以将本发明的化合物制备为用于口服的药剂。
药剂(例如本发明的化合物)的有效量或治疗有效量或剂量指的是引起个体症状改善或存活延长的药剂或化合物的量。所述分子的毒性和治疗功效可在细胞培养物或实验动物中通过标准医药程序来测定，例如通过测LD 50(使群体50％致死的剂量)和ED 50(对群体的50％治疗有效的剂量)。毒性作用与治疗作用的剂量比是治疗指数，可表示为LD 50/ED 50。优选显示高治疗指数的药剂。
有效量或治疗有效量是将会引发研究人员、兽医、医生或其它临床医生所探求的组织、系统、动物或人类的生物或医学反应的化合物或医药组合物的量。剂量优选在包括极小毒性或无毒性的ED 50的循环浓度的范围内。剂量可在这个范围内变化，视所用的剂型和/或所用的给药途径而定。应根据本领域中已知的方法，考虑个体状况的特殊性来选择正确的制剂、给药途径、剂量和给药间隔时间。
剂量和间隔时间可个别地加以调整以提供足以获得所需效果的活性部分的血浆水平；即最小有效浓度(minimal effective concentration，MEC)。各化合物的MEC将有所不同，但可以例如从体外(invitro)数据和动物实验估算。获得MEC所必需的剂量将视个体特征和给药途径而定。在局部给药或选择性摄取的情况下，药物的有效局部浓度可能与血浆浓度无关。
所施予的药剂或组合物的量可视各种因素而定，包括所治疗个体的性别、年龄和体重、病痛的严重性、给药方式和处方医师的判断。
在需要时，本发明的组合物可以用含有一个或一个以上单位剂型(含有活性成分)的包装或分配装置提供。举例来说，所述包装或装置可包含金属或塑料箔(如发泡包装)或玻璃和橡皮塞，如在小瓶中。所述包装或分配装置可附有用药说明书。也可以制备包含在相容性医药载体中配制的本发明化合物的组合物，将其置于适当容器中，并且加上用于治疗指定病状的标签。
除非另有规定，本文使用的所有技术术语和科学术语具有要求保护主题所属领域的标准含义。倘若对于某术语存在多个定义，则以本文定义为准。
基团定义
除非另外说明，应当应用本文所使用的下列定义。出于本发明的目的，化学元素与元素周期表CAS版，和《化学和物理手册》，第75版，1994一致。此外，有机化学一般原理可参考"Organic Chemistry",Thomas Sorrell,University Science Books,Sausalito:1999,和"March's Advanced Organic Chemistry”by Michael B.Smith and Jerry March,John Wiley&Sons,New York:2007中的描述，其全部内容通过引用并入本文。
在本说明书中，可由本领域技术人员选择基团及其取代基以提供稳定的结构部分和化合物。当通过从左向右书写的常规化学式描述取代基时，该取代基也同样包括从右向左书写结构式时所得到的在化学上等同的取代基。
在本文中定义的某些化学基团前面通过简化符号来表示该基团中存在的碳原子总数。例如，C1-C6烷基是指具有总共1、2、3、4、5或6个碳原子的如下文所定义的烷基。简化符号中的碳原子总 数不包括可能存在于所述基团的取代基中的碳。
在本文中，取代基中定义的数值范围如0至4、1-4、1至3等表明该范围内的整数，如1-6为1、2、3、4、5、6。
除前述以外，当用于本申请的说明书及权利要求书中时，除非另外特别指明，否则以下术语具有如下所示的含义。
术语“包括”为开放式表达，即包括本发明所指明的内容，但并不排除其他方面的内容。
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。
一般而言，术语“取代的”表示所给结构中的一个或多个氢原子被具体取代基所取代。进一步地，当该基团被1个以上所述取代基取代时，所述取代基之间是相互独立，即，所述的1个以上的取代基可以是互不相同的，也可以是相同的。除非其他方面表明，一个取代基团可以在被取代基团的各个可取代的位置进行取代。当所给出的结构式中不只一个位置能被选自具体基团的一个或多个取代基所取代，那么取代基可以相同或不同地在各个位置取代。
在本说明书的各部分，本发明公开化合物的取代基按照基团种类或范围公开。特别指出，本发明包括这些基团种类和范围的各个成员的每一个独立的次级组合。例如，术语“C 1～C 6烷基”或“C 1- 6烷基”特别指独立公开的甲基、乙基、C 3烷基、C 4烷基、C 5烷基和C 6烷基；“C 1- 4烷基”特指独立公开的甲基、乙基、C 3烷基(即丙基，包括正丙基和异丙基)、C 4烷基(即丁基，包括正丁基、异丁基、仲丁基和叔丁基)。
术语“卤素”选自于F，Cl，Br或I，尤其指F或Cl。
在本申请中，作为基团或是其它基团的一部分，术语“烷基”是指饱和脂肪族烃基团，其为包含1至12个碳原子的直链或支链基团，优选含有1至6个碳原子的烷基直链或支链的。通式C nH 2n+1。术语“C 1-C 6烷基”是指烷基部分包含1，2，3，4，5或6个碳原子。在某一实施方案中，所述的“烷基”是指C 1-C 6烷基。在某一实施方案中，所述的“烷基”是指C 1-C 4烷基。
含有1至6个碳原子的低级烷基，非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1，1-二甲基丙基、1，2-二甲基丙基、2，2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1，1，2-三甲基丙基、1，1-二甲基丁基、1，2-二甲基丁基、2，2-二甲基丁基、1，3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2，3-二甲基丁基等。含有1至12个碳原子的非限制性实例包括上述含有1至6个碳原子的低级烷基的实例，以及2，4-二甲基戊基、2，2-二甲基戊基、3，3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2，3-二甲基己基、2，4-二甲基己基、2，5-二甲基己基、2，2-二甲基己基、3，3-二甲基己基、4，4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基 -3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2，2-二乙基戊基、正奎基、3，3-二乙基己基、2，2-二乙基己基，及其各种支链异构体等。
在本申请中，作为基团或是其它基团的一部分，除非另有规定，术语“环烷基”意指仅由碳原子和氢原子组成的饱和的单环、多环或者桥接碳环取代基，且其可经由任何适宜的碳原子通过单键与分子的其余部分连接；当为多环时，可为并环连接或螺环连接(即，碳原子上的两个偕氢被亚烷基取代)的桥环体系或螺环体系。环烷基取代基可以经任何适宜的碳原子连接在中心分子上。在一些实施例中，具有3-10个碳原子的环可以表示为C 3-C 10环烷基。在一些实施例中，C 3～C 6的环烷基包括环丙基(C 3)、环丁基(C 4)、环戊基(C 5)及环己基(C 6)。在一些实施例中，C 3～C 10的环烷基的实例包括上述C 3～C 6环烷基基团连同环庚基(C 7)、环辛基(C 8)、环壬基(C 9)及环癸基(C 10)。
在本申请中，作为基团或是其它基团的一部分，术语“杂环烷基”意指由2-6个碳原子以及1-4个选自氮、氧和硫的杂原子组成的稳定的3元至7元饱和环状基团。示例性3-元杂环基基团包括但不限于，氮杂环丙基、环氧乙烷基以及硫杂环丙烷基，或者其立体异构体；示例性4-元杂环基基团包括但不限于，氮杂环丁烷基，环氧丙烷基，硫杂环丁烷基，或者其同分异构体和立体异构体；示例性5-元杂环基基团包括但不限于，四氢呋喃基，四氢噻吩基，吡咯烷基，噻唑烷基，异噻唑烷基，噁唑烷基，异噁唑烷基，咪唑烷基，吡唑烷基，二氧戊环基，氧杂硫呋喃基，二硫呋喃基，或者其同分异构体和立体异构体。示例性6-元杂环基基团包括但不限于，哌啶基，四氢吡喃基，硫化环戊烷基，吗啉基，硫代吗啉基，二噻烷基，二噁烷基，哌嗪基，三嗪烷基，或者其同分异构体和立体异构体；示例性7-元杂环基基团包括但不限于，氮杂环庚烷基，氧杂环庚烷基，硫杂环庚烷基，以及二氮杂环庚基，或者其同分异构体和立体异构体。在某一方案中，“杂环烷基”为C 2～C 5杂环烷基，其中杂原子选自N、O和S中的一种或多种，杂原子数为1、2或3个。
在本申请中，作为基团或是其它基团的一部分，术语“杂芳基”是指具有碳原子以及提供在该芳香族环系统中的1-3个杂原子(其中每个杂原子独立地选自氮、氧以及硫)的4-16元单环的或二环的4n+2芳香族环系统(例如，在循环阵列中具有6或10个共享的p电子)的基团(“4-16元杂芳基”)。在包含一个或多个氮原子的杂芳基基团中，连接点可以是碳或氮原子，只要化合价允许。
在一些实施例中，所述的杂芳基为杂原子选自N、O和S中的一种或多种，杂原子数为1～3个的4-6元杂芳基，较佳地为5-6元杂芳基。
示例性5元杂芳基基团包括但不限于：吡咯基、呋喃基、噻吩基、咪唑基、吡唑基、噁唑基、异噁唑基、噻唑基、异噻唑基、三氮唑基、噁二唑基、噻二唑基、呋喃基、噁三唑基或四唑基。示例性6元杂芳基基团包括但不限于：吡啶基、吡嗪基、哒嗪基、嘧啶基、三嗪基或四嗪基。
本文所用术语“部分”、“结构部分”、“化学部分”、“基团”、“化学基团”是指分子中的特定片段或官能团。化学部分通常被认为是嵌入或附加到分子上的化学实体。
当所列举的取代基中没有指明其通过哪一个原子连接到化学结构通式中包括但未具体提及的化合物时，这种取代基可以通过其任何原子相键合。取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
在本发明的各部分，描述了连接取代基。当该结构清楚地需要连接基团时，针对该基团所列举的马库什变量应理解为连接基团。例如，如果该结构需要连接基团并且针对该变量的马库什基团定义列举了“烷基”或“芳基”，则应该理解，该“烷基”或“芳基”分别代表连接的亚烷基基团或亚芳基基团。
在一些具体的结构中，当烷基基团清楚地表示为连接基团时，则该烷基基团代表连接的亚烷基基团，例如，基团“卤代-C 1～C 6烷基”中的C 1-C 6烷基应当理解为C 1～C 6亚烷基。
术语“亚烷基”表示从饱和的直链或支链烃基中去掉两个氢原子所得到的饱和的二价烃基基团。亚烷基基团的实例包括亚甲基(-CH 2-)，亚乙基{包括-CH 2CH 2-或-CH(CH 3)-}，亚异丙基{包括-CH(CH 3)CH 2-或-C(CH 3) 2-}等等。
除非另有规定，本文使用的所有技术术语和科学术语具有要求保护主题所属领域的标准含义。倘若对于某术语存在多个定义，则以本文定义为准。
应该理解，在本发明中使用的单数形式，如“一种”，包括复数指代，除非另有规定。此外，术语“包括”是开放性限定并非封闭式，即包括本发明所指明的内容，但并不排除其他方面的内容。
除非另有说明，本发明采用质谱、元素分析的传统方法，各步骤和条件可参照本领域常规的操作步骤和条件。
除非另有指明，本发明采用分析化学、有机合成化学和光学的标准命名及标准实验室步骤和技术。在某些情况下，标准技术被用于化学合成、化学分析、发光器件性能检测。
另外，需要说明的是，除非以其他方式明确指出，在本发明中所采用的描述方式“…独立地为”应做广义理解，是指所描述的各个个体之间是相互独立的，可以独立地为相同或不同的具体基团。更详细地，描述方式“…独立地为”既可以是指在不同基团中，相同符号之间所表达的具体选项之间互相不影响；也可以表示在相同的基团中，相同符号之间所表达的具体选项之间互相不影响。
本领域技术人员可以理解，根据本领域中使用的惯例，本申请描述基团的结构式中所使用的
Figure PCTCN2021128344-appb-000049
是指，相应的基团通过该位点与化合物中的其它片段、基团进行连接。
“药学上可接受的”是指可用于制备药物组合的情形，通常是安全的和无毒的，且非生物学以及其它方面所不期望，并且包括对于兽用和用于人的药物用途的可接受的情形。
术语“赋形剂”是指药学上可接受的化学物质，例如药学领域的普通技术人员已知的用于帮助给予药用的试剂。它是可以用于制备药物组分的化合物，通常是安全的、无毒的，且是生物学或者其它方面所不可期望的，其包括对于兽用和人用药物可接受的赋形剂。通常的赋形剂包括粘合剂、表面活性 剂、稀释剂、崩解剂和润滑剂。
术语“有效治理量”是指当给予受试者来治疗疾病状态时足以实现疾病状态的这种治理的所用化合物的量。“有效治理量”将根据化合物、所治疗的疾病状态、所治疗疾病的严重程度、受试者的年龄和相对健康、给药途径和方式、主治医疗或兽医的判断等而变化。
术语哺乳动物是指人或任何哺乳动物，如灵长类动物、农场动物、宠物动物或者实验动物。这些动物的实例有猴、母牛、羊、马、猪、狗、猫、兔、小鼠和大鼠等。哺乳动物优选于人。
在不违背本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于：提供了一种嘧啶甲酰胺类化合物，可以用作Vanin酶、特别是Vanin-1抑制剂；其可用于制备预防和/或治疗克罗恩氏病、溃疡性结肠炎及炎性肠病。
具体实施方式
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。
实施例1 化合物1的合成
Figure PCTCN2021128344-appb-000050
第一步
向化合物1a(250mg)的乙醇/水(v/v＝4:1，5mL)混合溶剂的溶液中依次加入醋酸钠(129mg)和盐酸羟胺(322mg)。将所得反应液加热至94℃并搅拌2h。反应结束。冷却，加入水(50mL)，乙酸乙酯萃取(100mL x 3)，合并有机相，无水硫酸钠干燥，过滤，滤液浓缩得化合物1b粗品(257mg)。
第二步
向化合物1b(257mg)的醋酸(5mL)溶液中分批加入锌粉(339mg)。将所得反应液加热至70℃并搅拌2小时。反应结束。冷却，硅藻土过滤，滤液浓缩，用NaOH水溶液(10％)调节pH到9，乙酸乙酯萃取(20mL x 4)，合并有机相，无水硫酸钠干燥，过滤，浓缩得化合物1c粗品(100mg)。
第三步
在-10℃和氮气保护的条件下，向化合物1d(25.40g)，化合物1e(31.00g)和三乙胺(61.00g)的乙腈(250mL)溶液中缓慢滴加T 3P(丙基磷酸酐)(254.00g)。滴加完毕后，维持体系在-5℃反应3h。反应结束。向反应液中加入300mL水淬灭反应，浓缩除去有机溶剂，残留物在5℃搅拌1h，有固体析出，过滤，滤饼用水(100mL x 1)洗涤，干燥，得化合物1f(42.00g)，收率93％。
1H NMR(400MHz,CDCl 3)δ8.80(s,2H),3.81-3.57(m,7H),3.36(s,1H),1.93(td,J＝14.58,7.25Hz,2H),1.66(t,J＝5.35Hz,2H),1.58(dd,J＝11.10,4.64Hz,2H).
第四步
将化合物1f(168mg)，化合物1c(100mg)和碳酸钾(99mg)的异丙醇/水(v/v＝99:1，2mL)混合溶剂溶液加热至85℃并继续搅拌4h。反应结束。冷却，过滤，滤饼用异丙醇(10mL x 2)淋洗，浓缩，残留物经硅胶柱(甲醇/二氯甲烷＝0-100％)纯化得到化合物1(26mg)。
1H NMR(400MHz,MeOH-d4)δ8.60(s,2H),8.44(s,1H),8.36(d,J＝3.89Hz,1H),7.37(d,J＝4.86Hz,1H),5.75(t,J＝6.75Hz,1H),3.66(ddd,J＝19.18,16.47,5.76Hz,6H),3.54(d,J＝22.28Hz,2H),3.16-3.09(m,1H),2.98(dd,J＝16.74,8.39Hz,1H),2.71-2.57(m,1H),2.05(dd,J＝12.89,8.02Hz,1H),1.93(dd,J＝15.51,7.35Hz,2H),1.73-1.51(m,4H).
LCMS(ESI)，[M+H] +＝380.2
实施例2 化合物2和化合物2-1和化合物2-2的合成
Figure PCTCN2021128344-appb-000051
第一步
向化合物2a(500mg)的乙醇/水(v/v＝4:1，10mL)混合溶剂溶液中依次加入醋酸钠(740mg)和盐酸羟胺(630mg)，所得反应液加热至94℃并继续搅拌2h。反应结束。冷却，向反应液中加入水(50mL)，乙酸乙酯萃取(30mL x 3)，合并有机相，无水硫酸钠干燥，过滤，浓缩得到化合物2b粗品(500mg)。
第二步
向化合物2b(320mg)的醋酸(6mL)溶液中分批加入锌粉(421mg)，所得反应液加热至70℃并继续搅拌2小时。反应结束。冷却，过滤，浓缩。残留物用NaOH水溶液(10％)调节pH值到9，乙酸乙酯萃取(20mL x 4)，合并有机相，无水硫酸钠干燥，过滤，浓缩，得到化合物2c(100mg)粗品。
第三步
按照实施例1的方法由化合物1f(168mg)和化合物2c(100mg)得到化合物2(66mg)。
1H NMR(400MHz,MeOH-d4)δ8.58(s,2H),8.35(d,J＝4.69Hz,1H),7.78-7.70(m,1H),7.27-7.18(m,1H),5.71(t,J＝7.15Hz,1H),3.80-3.59(m,6H),3.54(d,J＝20.77Hz,2H),3.13(ddd,J＝16.55,9.14,3.68Hz,1H),3.00(td,J＝16.84,8.51Hz,1H),2.67(ddd,J＝16.06,8.24,3.91Hz,1H),2.14-1.99(m,1H),1.93(dd,J＝16.94,7.33Hz,2H),1.72-1.51(m,4H).
LCMS(ESI)，[M+H] +＝380.3
化合物2经手性拆分得到两个对映异构体2-1(保留时间为8.483min)和2-2(保留时间为13.580min)
色谱条件如下：
色谱柱：CHIRALPAK AD-H(5um，4.6*250mm)
流速：0.4mL/min
波长：254nm
柱温：35℃
流动相：A:正己烷，B:异丙醇，A:B＝1:4
运行时间：50min。
化合物2-1的制备方法：
Figure PCTCN2021128344-appb-000052
化合物2-1f的制备：
将2-氯嘧啶-5-羧酸(284g，1.78mol)和8-氧杂-2-氮杂螺[4.5]癸烷(310g，1.78mol)溶于二氯甲烷中，冷却到-10℃，慢慢滴加T 3P(625g,1.78mol)，加入完后，在该温度下继续反应2小时。LCMS检测反应完成后，加入水，搅拌，有固体析出，过滤，干燥得到化合物2-1f(350g,纯度98％)。
第一步：化合物2-1c的制备
将化合物2-1b(385g，3.18mol)和钛酸四乙酯(905g，3.97mol)溶于甲苯(3L)，搅拌加热至110℃，回流；向上述反应液中滴加化合物2-1a(352g，2.65mol)的甲苯溶液(500mL)。滴加结束后，继续加热回流1小时。反应完成后，停止反应，冷却至室温，浓缩除去甲苯，剩余物加水淬灭，加乙酸乙酯提取产物，反应液用硅藻土过滤，去掉固体不溶物。将滤液分液，收集有机相，无水硫酸钠干燥，浓缩除去溶剂；剩余物用少量MTBE溶解，加入石油醚搅拌，有固体析出，过滤，滤液浓缩得到化合物2-1c(500g，收率：80％)。
第二步：化合物2-1d的制备
将化合物2-1c(500g，2.1mol)溶于3000mL的THF中，冷却到-60℃，然后慢慢滴加L-三仲丁基硼氢化锂(2510mL，2.51mol)。滴加完成后，在-60℃下搅拌。反应完成后，慢慢加入100mL水淬灭反应。用乙酸乙酯萃取(500mL×3)，合并有机相，用饱和氯化钠溶液洗涤(200mL)，干燥。减压蒸馏除去溶剂，粗产物2-1d直接用于下一步。
第三步：化合物2-1e的制备
将粗产物2-1d溶于500mL甲醇中，慢慢加入200mL 4N HCl/MeOH。在室温下反应2h。反应完成后，浓缩反应液得到油状物，加入乙酸乙酯搅拌，过滤后得到化合物2-1e，为红色固体粉末(300g，ee值92％，纯度99％)。
第四步：化合物2-1的制备
将化合物2-1e(284g，1.375mol)、化合物2-1f(350g，1.25mol)和K 2CO 3(862.5g，6.25mol)溶解在异丙醇中，加热回流过夜。反应完成后，冷却到室温。将反应体系减压蒸馏除去溶剂，加入二氯甲烷，搅拌，过滤。将滤液溶于2N HCl中，水相用1N NaOH调节到pH为8～9。用二氯甲烷萃取，干燥浓缩，得到化合物2-1。
1H NMR(400MHz,CD 3OD)δ8.58(s,2H),8.37(d,J＝5.1Hz,1H),7.77(s,1H),7.26(d,J＝2.5Hz,1H),5.72(t,J＝7.7Hz,1H),4.53(s,2H),3.80–3.58(m,7H),3.54(d,J＝18.8Hz,2H),3.15(ddd,J＝16.9,9.2,3.7Hz,1H),3.02(dt,J＝16.8,8.5Hz,1H),2.68(dq,J＝12.8,4.4Hz,1H),2.14–2.02(m,1H),1.93(q,J＝8.1Hz,2H),1.67(d,J＝5.8Hz,2H),1.59(d,J＝5.7Hz,2H).
化合物2-1通过与上述手性化合物的制备方法的比较测定确定了绝对的立体化学构型。
实施例3 化合物7的合成
Figure PCTCN2021128344-appb-000053
第一步
将化合物7a(200mg,1.27mmol)，化合物1e(187mg,1.33mmol)，乙腈(3mL)加入到25mL三口瓶中。将反应混合物降温至-10℃，缓慢的滴加T 3P(350mg,0.4mol)。然后将三乙胺(260mg,5.54mmol)溶于乙腈(5mL)加入反应液中，体系保持-5℃，搅拌3h。反应结束后，向反应混合物中加入水(30mL)淬灭反应。浓缩，降温至5℃，搅拌1h。过滤，滤饼用水洗100mL，得到白色固体200mg，为化合物7c，收率56％。
第二步
将化合物7c(200mg，0.71mmol)，化合物7d(100mg，0.75mol)和异丙醇/水(V/V＝99:1，5mL)依次加入到10mL三口瓶中，然后再加入碳酸钾(489mg，3.55mmol)。将反应混合物加热至85℃，回流搅拌4h。反应结束后，将体系降温至45℃，加入5mL丙酮搅拌1h。过滤，滤饼用20mL丙酮洗。滤液浓缩至3mL，再加入4ml异丙醇浓缩至2mL，然后降温至0℃，搅拌1h。过滤，得到类白色固体100mg，为化合物7，收率38％。
LCMS m/z(ESI):379[M+1]。
1H NMR(400MHz,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)。
实施例4 化合物8的合成
Figure PCTCN2021128344-appb-000054
第一步
将化合物8a(200mg,1.27mmol)，化合物1e(187mg,1.33mmol)，乙腈(3mL)加入到25mL三口瓶中，降温至-10℃，缓慢的滴加T 3P(350mg,0.4mol)。将三乙胺(260mg,5.54mmol)溶于乙腈(5mL)加入反应液中，体系保持-5℃，搅拌3h。反应结束后，向反应混合物中加入水(30mL)淬灭反应。浓缩，降温至5℃，搅拌1h。过滤，滤饼用水洗(100mL)，得到白色固体200mg，为化合物8c，收率56％。
第二步
将化合物8c(90mg，0.32mmol)，化合物8d(50mg，0.34mol)和异丙醇/水(v/v＝99:1，5mL)依次加入到10mL三口瓶中，然后再加入碳酸钾(220mg，1.6mmol)。将反应混合物加热至85℃，回流搅拌4h。反应结束后，将反应混合物降温至45℃，加入丙酮(5mL)搅拌1h。过滤，滤饼用丙酮(20mL)洗。将滤液浓缩至3mL，再加入异丙醇(4ml)浓缩至2mL。降温至0℃，搅拌1h。过滤，得到类白色固体40mg，为化合物8，收率32％。
LCMS m/z(ESI):393[M+1]。
1H NMR(400MHz,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)。
实施例5 化合物13的合成
Figure PCTCN2021128344-appb-000055
第一步
将化合物13a(200mg,1.27mmol)，化合物13b(168mg,1.33mmol)，乙腈(3mL)加入到25mL三口瓶中，降温至-10℃，缓慢的滴加T 3P(350mg,0.4mol)。将三乙胺(260mg,5.54mmol)溶于乙腈(5mL)加入反应液中，体系保持-5℃，搅拌3h。反应结束后，向反应混合物中加入水(30mL)进行淬灭反应。浓缩，降温至5℃，搅拌1h。过滤，滤饼用水洗(100mL)，得到白色固体70mg，为化合物13c，收率20％。
第二步
将化合物13c(70mg，0.26mmol),化合物13d(41mg，0.28mol)和异丙醇/水(V/V＝99:1，5mL)依次加入到10mL三口瓶中，然后再加入碳酸钾(180mg，1.3mmol)。将反应混合物加热至85℃，回流搅拌4h。反应结束后，将反应混合物降温至45℃，加入丙酮(5mL)搅拌1h。过滤，滤饼用丙酮(5mL)洗。将滤液浓缩至3mL，再加入异丙醇(4ml)浓缩至3mL，降温至0℃，搅拌1h。过滤，得到类白色固体30mg，为化合物13，收率30％。
LCMS m/z(ESI):366[M+1]。
1H NMR(400MHz,DMSO-D6)δ8.56(s,2H),8.37-8.38(d,J＝2.8Hz,1H),8.11-8.13(d,J＝2.8Hz,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)。
实施例6 化合物16的合成
Figure PCTCN2021128344-appb-000056
第一步
将化合物16a(150mg,0.42mmol)，化合物16b(114mg,0.46mmol)，乙腈(2mL)加入到25mL三口瓶中，降温-10℃，缓慢的滴加T 3P(350mg,0.4mol)。将三乙胺(181mg,1.8mmol)溶于乙腈(5mL)加入反应液中，体系保持-5℃，搅拌3h。反应结束后，向反应混合物中加入水(30mL)淬灭反应。浓缩，降温至5℃，搅拌1h。过滤，滤饼用水洗(100mL)，得到白色固体160mg，为化合物16c，收率63％。
第二步
将化合物16c(160mg，0.62mmol),化合物16d(85mg，0.64mol)和异丙醇/水(v/v＝99:1，10mL)依次加入到10mL三口瓶中，然后加入碳酸钾(0.41g，3.2mmol)。将反应混合物加热至85℃，回流搅拌4h。反应结束后，将反应混合物降温至45℃，加入丙酮(5mL)搅拌1h。过滤，滤饼用丙酮(2mL)洗。滤液浓缩至3mL，再加入异丙醇(4ml)浓缩至3mL。降温至0℃，搅拌1h。过滤，得到类白色固体155mg，为化合物16，收率71％。
LCMS m/z(ESI):352.1[M+1]。
1H NMR(400MHz,DMSO-D6)δ8.59(s,2H),8.37(d,J＝7.54Hz,1H),8.15(d,J＝7.54Hz,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)。
实施例7 化合物17的合成
Figure PCTCN2021128344-appb-000057
第一步
将化合物17a(150mg,0.42mmol)，化合物17b(134mg,0.46mmol)，乙腈(2mL)加入到25mL三口瓶中,降温-10℃，缓慢的滴加T 3P(350mg,0.4mol)。将三乙胺(181mg,1.8mmol)溶于乙腈(5mL)加入反应液中，体系保持-5℃，搅拌3h。反应结束后，向反应混合物中加入水(30mL)淬灭反应。浓缩，降温至5℃，搅拌1h。过滤，滤饼用水洗(100mL)，得到白色固体40mg，为化 合物17c，收率33％。
第二步
将化合物17c(40mg，0.14mmol),化合物17d(16mg，0.145mol)和异丙醇/水(v/v＝99:1，3.9mL)依次加入到10mL三口瓶中，然后加入碳酸钾(96.6mg，0.7mmol)。将反应混合物加热至85℃，回流搅拌4h。反应结束后，反应液用乙酸乙酯萃取(10mL×3)，合并有机相，用无水硫酸钠干燥。过滤，浓缩得到粗品，经反相柱层析，得到类白色固体25mg，为化合物17，收率25％。
LCMS m/z(ESI):381.1[M+1]。
1H NMR(400MHz,DMSO-d6)：δ8.59(s,2H),8.37(d,J＝7.54Hz,1H),8.15(d,J＝7.54Hz,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)。
实施例8 化合物19的合成
Figure PCTCN2021128344-appb-000058
第一步
将化合物19a(150mg,0.42mmol)，化合物1e(154mg,0.46mmol)，乙腈(2mL)加入到25mL三口瓶中，降温至-10℃，缓慢的滴加T 3P(350mg,0.4mol)。将三乙胺(181mg,1.8mmol)溶于乙腈(5mL)加入反应液中，体系保持-5℃，搅拌3h。反应结束后，向反应混合物中加入水(30mL)淬灭反应。浓缩，降温至5℃，搅拌1h。过滤，滤饼用水洗(100mL)，得到白色固体60mg，为化合物19c，收率33％。
第二步
将化合物19c(60mg，0.21mmol),化合物19d(24mg，0.22mol)和异丙醇/水(v/v＝99:1，3.9mL)依次加入到10mL三口瓶中，然后加入碳酸钾(152mg，1.1mmol)。将反应混合物加热至85℃，回流搅拌4h。反应结束后，将反应液用乙酸乙酯萃取(10mL×3)，合并有机相，用无水硫酸钠干燥。过滤，滤液浓缩得到粗品，经反相柱层析得到类白色固体16mg，为化合物19，收率15％。
LCMS m/z(ESI):394.1[M+1]。
1H NMR(400MHz,DMSO-d6)：δ8.57(s,2H),8.09(d,J＝7.54Hz,1H),7.49(d,J＝8.0Hz,1H),7.02-7.00(d,J＝8.0Hz,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)。
实施例9 化合物23的合成
Figure PCTCN2021128344-appb-000059
第一步
将化合物23a(150mg,0.42mmol)，化合物1e(154mg,0.46mmol)，乙腈(2mL)加入到25mL三口瓶中，降温至-10℃，缓慢的滴加T 3P(350mg,0.4mol)。将三乙胺(181mg,1.8mmol)溶于乙腈(5mL)加入反应液中，体系保持-5℃，搅拌3h。反应结束后，向反应混合物中加入水(30mL)淬灭反应。浓缩，降温至5℃，搅拌1h。过滤，滤饼用水洗(100mL)，得到白色固体60mg，为化合物23c，收率33％。
第二步
将化合物23c(60mg，0.21mmol),化合物23d(26mg，0.22mol)和异丙醇/水(v/v＝99:1，3.9mL)依次加入到10mL三口瓶中，然后加入碳酸钾(152mg，1.1mmol)。将反应混合物加热至85℃，回流搅拌4h。反应结束后，将反应混合物降温至45℃，加入丙酮(5mL)，搅拌1h。过滤，滤饼用丙酮(2mL)洗。将滤液浓缩至3mL，再加入异丙醇(4mL)浓缩至3mL。降温至0℃，搅拌1h。过滤，得到类白色固体12mg，为化合物23，收率12％。
LCMS m/z(ESI):458.1[M+1]。
1H NMR(400MHz,CD 3OD)：δ8.59(s,2H),8.45(d,J＝2.1Hz,1H),7.86-7.84(m,1H),5.70(t,J＝7.9Hz,1H),3.75(s,1H),3.54(d,J＝19.3Hz,4H),3.12-2.88(m,4H),2.73-2.53(m,2H),2.11(dd,J＝13.1,8.5Hz,2H),1.98-1.90(m,4H),1.66(d,J＝8.4Hz,3H)。
实施例10 化合物21的合成
Figure PCTCN2021128344-appb-000060
将化合物23(50mg,0.10mmol)，甲基硼酸(12mg,0.22mmol)，磷酸钾
(60mg,0.3mmol)，Pd(dppf) 2Cl 2(16mg,0.02mmol)加入到2ml 1,4-二氧六环和0.5ml水中，100摄氏度下搅拌3h。反应完全后，将反应混合物用二氯甲烷萃取(10ml×3。合并有机相，干燥，浓缩后得到粗品70mg，经柱层析(DCM：CH3OH＝20:1)得到化合物21(30mg,收率65％)。
LCMS m/z(ESI):394.2[M+1]。
1H NMR(400MHz,DMSO-d6)δ8.57(s,2H),8.22(s,1H),8.10(d,J＝8.4Hz,1H),7.40(s,1H),5.58 (q,J＝8.3Hz,1H),3.69-3.45(m,7H),2.89(dd,J＝31.4,8.2Hz,2H),2.24(s,3H),1.98(dd,J＝12.2,8.4Hz,2H),1.80(d,J＝7.4Hz,2H),1.51(d,J＝33.8Hz,4H)。
实施例10 化合物24的合成
Figure PCTCN2021128344-appb-000061
第一步
将化合物24a(150mg,0.42mmol)，化合物24b(134mg,0.46mmol)，乙腈(2mL)加入到25mL三口瓶中，降温至-10℃，缓慢的滴加T 3P(350mg,0.4mol)。将三乙胺(181mg,1.8mmol)溶于乙腈(5mL)加入反应液中，体系保持-5℃，搅拌3h。反应结束后，向反应混合物中加入水(30mL)淬灭反应。浓缩，降温至5℃，搅拌1h。过滤，滤饼用水洗(100mL)，得到白色固体20mg，为化合物24c，收率16％。
第二步
将化合物24c(20mg，0.14mmol),化合物24d(8mg，0.145mol)和异丙醇/水(V/V＝99:1，1.9mL)依次加入到10mL三口瓶中，然后加入碳酸钾(0.14g，0.98mmol)。将反应混合物加热至85℃，回流搅拌4h。反应结束后，将反应液用乙酸乙酯萃取(10mL×3)，合并有机相，用无水硫酸钠干燥。过滤，将滤液浓缩得到粗品，经反相柱层析得到类白色固体8mg，为化合物24，收率35％。
LCMS m/z(ESI):353.1[M+1]。
1H NMR(400MHz,DMSO-D6)：δ8.56(s,1H),8.38(d,J＝4.8Hz,1H),8.33-8.28(m,1H),7.68(s,1H),7.19-7.14(m,1H),5.60(d,J＝8.1Hz,1H),4.23(d,J＝7.6Hz,1H),3.60(s,2H),2.83(d,J＝26.4Hz,4H),2.36(ddd,J＝15.3,7.7,3.6Hz,2H),2.21-2.09(m,6H),2.04-1.97(m,2H)。
实施例11 化合物26的合成
Figure PCTCN2021128344-appb-000062
第一步
将化合物26a(150mg,0.41mmol)，化合物26b(134mg,0.45mmol)，乙腈(2mL)加入到25mL三口瓶中，降温至-10℃，缓慢的滴加T3P(350mg,0.4mol)。将三乙胺(181mg,1.8mmol)溶于乙腈(5mL)加入反应液中，体系保持-5℃，搅拌3h。反应结束后，向反应混合物中加入水(30mL) 淬灭反应。浓缩，降温至5℃，搅拌1h。过滤，滤饼用水洗(100mL)，得到白色固体40mg，为化合物26c，收率33％。
第二步
将化合物26c(40mg，0.14mmol),化合物26d(16mg，0.145mol)和异丙醇/水(V/V＝99:1，3.9mL)依次加入到10mL三口瓶中，然后加入碳酸钾(99.6mg，0.7mmol)。将反应混合物加热至85℃，回流搅拌4h。反应结束后，将反应混合物降温至45℃，加入丙酮(5mL)，搅拌1h。过滤，滤饼用丙酮(2mL)洗。将滤液浓缩至3mL，再加入异丙醇(4ml)浓缩至3mL，降温至0℃搅拌1h。过滤，得到灰色固体36mg，为化合物26，收率57％。
LCMS:[M+1]＝395.1,RT＝0.62min
1H NMR(400MHz,DMSO-D6)δppm 8.55-8.65(m,2H),8.38(d,J＝7.54Hz,1H),8.17(d,J＝7.54Hz,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＝6.13Hz,2H),1.24(d,J＝5.82Hz,3H)
生物测试评价
1.Vanin-1重组酶活性抑制实验
精确称取一定质量的化合物，用DMSO以及反应缓冲液(50mM Tris base，50mM KCl，1.6mM半胱胺，0.005％Brij 35,pH 8.0，现配现用)配置化合物，使化合物的最高浓度为10000nM,按4倍梯度稀释，配制成10个不同浓度的化合物工作液；
对于重组人Vanin-1(百奥莱博，JN0618)活性抑制反应，先将2.5μL的化合物工作液和5μL重组人Vanin-1蛋白混合，室温孵育15min后，加入2.5μL的Pantetheine 7-amino-4-trifluoromethylcoumarin底物，使10μL反应体系中，重组人Vanin-1的终浓度为62.5pM,底物Pantetheine 7-amino-4-trifluoromethylcoumarin的终浓度为45μM,反应在384孔板(PerkinElmer，6007280)中进行，DMSO的终浓度为1％在酶标仪上设定激发光为405nm、发射光为505nm，25℃动力学读数1小时。收集第30分钟的原始数据进行数据处理和分析，再用GraphPad Prism 8软件拟合浓度-效应曲线，并计算化合物浓度的IC 50。数据如下表-1所示。
表-1
实施例 IC 50(nM)
化合物2 8.9
化合物2-1 2.4
化合物13 4.2
化合物17 0.6
化合物19 2.9
化合物23 1.7
化合物21 6.9
化合物26 2.0
化合物A 11.25
化合物A为
Figure PCTCN2021128344-appb-000063
参考CN109476645A中实施例142的方法制备得到。
2.小鼠体内药代动力学评价
实验目的：
检测本发明化合物在C57BL6小鼠体内的药代动力学参数
实验方案：
实验使用溶媒为：DMSO：Solutol：PBS＝5％：25％：70％(v/v/v)。配制方法：准确称量所需化合物，按比例加入一定体积的DMSO，涡旋混匀完全溶解后，按上述比例依次加入Solutol和PBS，混匀即可。实验中静脉(iv)给药组和口服(po)给药组所使用的溶媒为相同溶媒。静脉剂量为1mpk，口服剂量为2mpk。实验采血时间点：IV组：0.083，0.25，0.5，1，2，4，7，24h。PO组：0.25，0.5，1，2，4，7，24h每个时间点颈静脉采集全血200uL，EDTA-K2抗凝，立即在4000rpm*5min，4℃条件下离心，取上清，样品冻存于-80℃冰箱。血浆样品的处理：经含内标的ACN/MeOH(1:1，v/v)沉淀剂沉淀后，14000rpm离心5min，取上清进LC-MS/MS(AB Triple Quard 5500)分析，获得血药浓度，并通过Winnolin 8.1版本的非房室模型进行参数计算。结果见表2：
表-2
Figure PCTCN2021128344-appb-000064
注：-为数据无法计算
结论：
在所给剂量下化合物2-1和17在小鼠体内均表现出较高的生物利用度，分别为76.4％和61.4％，显示了本发明化合物具有优良的药代动力学性质。

Claims (10)

  1. 一种如式I所示的嘧啶甲酰胺类化合物、或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其药学上可接受的盐；
    Figure PCTCN2021128344-appb-100001
    其中，n为0、1、2或3；
    R 1独立地为卤素、C 1-C 6烷基、被一个或多个R 1a取代的C 1-C 6烷基；
    Z 1为-(CR 6aR 6b)-或-(NR 6c)-，Z 2为连接键；或，Z 1为连接键，Z 2为-(CR 7aR 7b)-；
    Z 3为连接键或-(CR 8aR 8b)-；
    R a独立地为H；
    R 6a、R 6b、R 7a和R 7b独立地为H、卤素或C 1-C 6烷基；
    R 6c独立地为H或C 1-C 4烷基；
    R 3a、R 3b、R 4a、R 4b、R 5a、R 5b、R 8a和R 8b独立地为H、卤素、C 1-C 6烷基、被一个或多个R 1c取代的C 1-C 6烷基、-(NR 9aR 9b)或-(NR 10a)-(C＝O)-R 10b；
    或者，R 4a和R 4b、或、R 4a和R 5a、或、R 4a和R 8a与它们键合的碳一起形成环B；环B为4-7元环烷基、4-7元杂环烷基、被一个或多个R 1d取代的4-7元环烷基或被一个或多个R 1e取代的4-7元杂环烷基；所述的4-7元杂环烷基和被一个或多个R 1e取代的4-7元杂环烷基里的4-7元杂环烷基中，杂原子为N、O或S，杂原子个数为1或2个；
    R 1a、R 1c、R 1d和R 1e独立地为卤素、C 1-C 4烷基或被一个或多个卤素取代的C 1-C 4烷基；
    R 9a、R 9b、R 10a和R 10b独立地为H、C 1-C 4烷基或被1个或多个卤素取代的C 1-C 4烷基；
    A为苯基或6-元杂芳基；所述的6-元杂芳基中，杂原子为N，杂原子个数为1或2个；
    Figure PCTCN2021128344-appb-100002
    表示单键或双键。
  2. 如权利要求1所述的如式I所示的嘧啶甲酰胺类化合物、或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其药学上可接受的盐，其特征在于，
    n为0或1；
    和/或，Z 1为-(CR 6aR 6b)-，Z 2为连接键；
    和/或，Z 3为-(CR 8aR 8b)-；
    和/或，R 6a和R 6b独立地为H或卤素；
    和/或，R 7a和R 7b独立地为H；
    和/或，R 3a和R 3b独立地为H；
    和/或，R 4a和R 4b独立地为H、C 1-C 6烷基、-(NR 9aR 9b)或-(NR 10a)-(C＝O)-R 10b；
    和/或，R 5a和R 5b独立地为H；
    和/或，环B为4-7元环烷基、4-7元杂环烷基、被一个或多个R 1d取代的4-7元杂环烷基；
    和/或，R 8a和R 8b独立地为H；
    和/或，R 1a、R 1c、R 1d和R 1e独立地为卤素或C 1-C 4烷基；
    和/或，R 9a、R 9b、R 10a和R 10b独立地为C 1-C 4烷基或被1个或多个卤素取代的C 1-C 4烷基；
    和/或，A为6-元杂芳基；
    和/或，
    Figure PCTCN2021128344-appb-100003
    表示单键；
    和/或，
    Figure PCTCN2021128344-appb-100004
    为
    Figure PCTCN2021128344-appb-100005
    或其混合物。
  3. 如权利要求1所述的如式I所示的嘧啶甲酰胺类化合物、或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其药学上可接受的盐，其特征在于，其为如下方案1、方案2；
    方案1：
    n为0或1；
    R 1独立地为卤素、C 1-C 6烷基、被一个或多个R 1a取代的C 1-C 6烷基；
    Z 1为-(CR 6aR 6b)-或-(NR 6c)-，Z 2为连接键；或，Z 1为连接键，Z 2为-(CR 7aR 7b)-；
    Z 3为-(CR 8aR 8b)-；
    R a独立地为H；
    R 6a、R 6b、R 7a和R 7b独立地为H或卤素；
    R 6c独立地为H或C 1-C 4烷基；
    R 3a、R 3b、R 5a、R 5b、R 8a和R 8b独立地为H；
    R 4a和R 4b独立地为H、C 1-C 6烷基、-(NR 9aR 9b)或-(NR 10a)-(C＝O)-R 10b；
    或者，R 4a和R 4b、或、R 4a和R 5a、或、R 4a和R 8a与它们键合的碳一起形成环B；环B为4-7元环烷基、4-7元杂环烷基、被一个或多个R 1d取代的4-7元环烷基或被一个或多个R 1e取代的4-7元杂环烷基；
    R 1a、R 1d和R 1e独立地为卤素或C 1-C 4烷基；
    R 9a、R 9b、R 10a和R 10b独立地为C 1-C 4烷基或被1个或多个卤素取代的C 1-C 4烷基；
    A为苯基或6元杂芳基；
    方案2：
    n为0或1；
    R 1独立地为卤素、C 1-C 6烷基、被一个或多个R 1a取代的C 1-C 6烷基；
    Z 1为-(CR 6aR 6b)-或-(NR 6c)-，Z 2为连接键；或，Z 1为连接键，Z 2为-(CR 7aR 7b)-；
    Z 3为-(CR 8aR 8b)-；
    R a独立地为H；
    R 6a和R 6b独立地为H或卤素；R 7a和R 7b独立地为H；
    R 1a独立地为卤素；
    R 6c独立地为H或C 1-C 4烷基；
    R 3a、R 3b、R 5a、R 5b、R 8a和R 8b独立地为H；
    R 4a独立地为C 1-C 6烷基、-(NR 9aR 9b)或-(NR 10a)-(C＝O)-R 10b；
    R 4b独立地为H或C 1-C 6烷基；
    或者，R 4a和R 4b、或、R 4a和R 5a、或、R 4a和R 8a与它们键合的碳一起形成环B；环B为4-7元环烷基、4-7元杂环烷基、或被一个或多个R 1e取代的4-7元杂环烷基；
    R 1e独立地为C 1-C 4烷基；
    R 9a、R 9b、R 10a和R 10b独立地为C 1-C 4烷基或被1个或多个卤素取代的C 1-C 4烷基；
    A为6元杂芳基；
    Figure PCTCN2021128344-appb-100006
    表示单键。
  4. 如权利要求1所述的如式I所示的嘧啶甲酰胺类化合物、或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其药学上可接受的盐，其特征在于，
    当R 1为卤素时，所述的卤素为氟、氯或溴；例如氟或氯；又例如氟；
    和/或，当R 1为被一个或多个R 1a取代的C 1-C 6烷基时，所述的取代基的个数为1、2、3、4或5个；例如1、2或3个；
    和/或，当R 1为C 1-C 6烷基、被一个或多个R 1a取代的C 1-C 6烷基时，所述的C 1-C 6烷基和被一个或多个R 1a取代的C 1-C 6烷基里的C 1-C 6烷基独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；例如甲基；
    和/或，当R 6a、R 6b、R 7a和R 7b独立地为卤素时，所述的卤素独立地为氟、氯或溴；例如氟或氯；
    和/或，当R 6a、R 6b、R 7a和R 7b独立地为C 1-C 6烷基时，所述的C 1-C 6烷基独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；例如甲基；
    和/或，当R 6c独立地为C 1-C 4烷基时，所述的C 1-C 4烷基独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；例如甲基；
    和/或，当R 3a、R 3b、R 4a、R 4b、R 5a、R 5b、R 8a和R 8b独立地为卤素时，所述的卤素独立地为氟、 氯或溴；例如氟或氯；
    和/或，当R 3a、R 3b、R 4a、R 4b、R 5a、R 5b、R 8a和R 8b独立地为C 1-C 6烷基、被一个或多个R 1c取代的C 1-C 6烷基时，所述的C 1-C 6烷基和被一个或多个R 1c取代的C 1-C 6烷基里的C 1-C 6烷基独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；例如甲基或乙基；
    和/或，当环B为4-7元环烷基、被一个或多个R 1d取代的4-7元环烷基时，所述的4-7元环烷基和被一个或多个R 1d取代的4-7元环烷基里的4-7元环烷基独立地为环丁基、环戊基、环己基或环庚基；例如环戊基；
    和/或，当环B为4-7元杂环烷基、或被一个或多个R 1e取代的4-7元杂环烷基时，所述的4-7元杂环烷基和被一个或多个R 1e取代的4-7元杂环烷基里的4-7元杂环烷基独立地为四氢呋喃基、四氢-2H-吡喃基、吡咯烷基；例如，当R 4a和R 4b与它们键合的碳一起形成环B时，环B为
    Figure PCTCN2021128344-appb-100007
    Figure PCTCN2021128344-appb-100008
    当R 4a和R 5a、或、R 4a和R 8a与它们键合的碳一起形成环B时，环B为
    Figure PCTCN2021128344-appb-100009
    和/或，当R 1a、R 1c、R 1d和R 1e独立地为卤素或被一个或多个卤素取代的C 1-C 4烷基时，所述的卤素和被一个或多个卤素取代的C 1-C 4烷基里的卤素独立地为氟、氯或溴；例如氟或氯；
    和/或，当R 1a、R 1c、R 1d和R 1e独立地为C 1-C 4烷基或被一个或多个卤素取代的C 1-C 4烷基里的C 1～C 4烷基独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；例如甲基或乙基；
    和/或，当R 9a、R 9b、R 10a和R 10b独立地为C 1-C 4烷基时，所述的C 1～C 4烷基独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；例如甲基或乙基；
    和/或，当R 9a、R 9b、R 10a和R 10b独立地为被1个或多个卤素取代的C 1-C 4烷基时，所述的被1个或多个卤素取代的C 1～C 4烷基中，所述C 1～C 4烷基独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；例如甲基或乙基；
    和/或，当R 9a、R 9b、R 10a和R 10b独立地为被1个或多个卤素取代的C 1-C 4烷基时，所述卤素独立地为氟、氯或溴；例如氟；再例如所述被1个或多个卤素取代的C 1-C 4烷基为三氟甲基；
    和/或，当A为6-元杂芳基时，所述6-元杂芳基为吡啶基、吡嗪基或嘧啶基；所述的吡啶基可为
    Figure PCTCN2021128344-appb-100010
    所述吡嗪基可为
    Figure PCTCN2021128344-appb-100011
    所述嘧啶基可为
    Figure PCTCN2021128344-appb-100012
    a表示A与
    Figure PCTCN2021128344-appb-100013
    连接位置。
  5. 如权利要求1所述的如式I所示的嘧啶甲酰胺类化合物、或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其药学上可接受的盐，其特征在于，
    R 1独立地为F、甲基或三氟甲基；例如
    Figure PCTCN2021128344-appb-100014
    为苯基、
    Figure PCTCN2021128344-appb-100015
    Figure PCTCN2021128344-appb-100016
    和/或，Z 1为单键、-(CH 2)-、-(CF 2)-、-(NH)-或-(N(CH 3))-；例如
    Figure PCTCN2021128344-appb-100017
    为
    Figure PCTCN2021128344-appb-100018
    Figure PCTCN2021128344-appb-100019
    和/或，R 4a和R 4b独立地为H、乙基、二甲氨基、
    Figure PCTCN2021128344-appb-100020
    和/或，环B为
    Figure PCTCN2021128344-appb-100021
    和/或，
    Figure PCTCN2021128344-appb-100022
    为
    Figure PCTCN2021128344-appb-100023
    例如
    Figure PCTCN2021128344-appb-100024
    Figure PCTCN2021128344-appb-100025
  6. 如权利要求1所述的如式I所示的嘧啶甲酰胺类化合物、或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其药学上可接受的盐，其特征在于，所述的如式I所示的嘧啶甲酰胺类化合物为如下任一结构：
    Figure PCTCN2021128344-appb-100026
    Figure PCTCN2021128344-appb-100027
  7. 如权利要求1所述的如式I所示的嘧啶甲酰胺类化合物、或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其药学上可接受的盐，其特征在于，
    所述的如式I所示的嘧啶甲酰胺类化合物为如下任一结构：
    在下述条件下保留时间为8.483min的化合物
    Figure PCTCN2021128344-appb-100028
    手性色谱拆分，色谱柱:CHIRALPAK AD-H,250x 4.6mm，5um；柱温:35℃；流速:0.4mL/min；波长:254nm；梯度:A:正己烷，B:异丙醇，A:B＝1:4；运行时间：50min；
    在下述条件下保留时间为13.580min的化合物
    Figure PCTCN2021128344-appb-100029
    手性色谱拆分，色谱柱:CHIRALPAK AD-H,250x 4.6mm，5um；柱温:35℃；流速:0.4mL/min；波长:254nm；梯度:A:正己烷，B:异丙醇，A:B＝1:4；运行时间：50min。
  8. 一种药物组合物，其包含如权利要求1-7中任一项所述的式I所示的嘧啶甲酰胺类化合物、或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其药学上可接受的盐，和药用辅料。
  9. 一种如权利要求1-7中任一项所述的如式I所示的嘧啶甲酰胺类化合物、或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其药学上可接受的盐在制备Vanin-1抑制剂中的应用。
  10. 一种如权利要求1-7中任一项所述的如式I所示的嘧啶甲酰胺类化合物、或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其药学上可接受的盐在制备药物中的应用；
    所述的药物可为用于预防和/或治疗与Vanin-1有关的疾病，或者，所述的药物可为用于预防和/或治疗自身免疫疾病、炎性疾病、变态反应性疾病、代谢疾病、基于感染的疾病、纤维变性疾病、心血管疾病、呼吸系统疾病、肾疾病、皮肤病学疾病、肝脏疾病、胃肠疾病、口腔疾病和造血疾病中的一种或多种；例如克罗恩氏病、溃疡性结肠炎及炎性肠病、胃炎；
    所述的与Vanin-1有关的疾病可包括自身免疫疾病、炎性疾病、变态反应性疾病、代谢疾病、基于感染的疾病、纤维变性疾病、心血管疾病、呼吸系统疾病、肾疾病、皮肤病学疾病、肝脏疾病、胃肠疾病、口腔疾病和造血疾病中的一种或多种。
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