WO2020211836A1 - 苯甲烯哌啶衍生物及其制备方法、中间体和用途 - Google Patents

苯甲烯哌啶衍生物及其制备方法、中间体和用途 Download PDF

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WO2020211836A1
WO2020211836A1 PCT/CN2020/085294 CN2020085294W WO2020211836A1 WO 2020211836 A1 WO2020211836 A1 WO 2020211836A1 CN 2020085294 W CN2020085294 W CN 2020085294W WO 2020211836 A1 WO2020211836 A1 WO 2020211836A1
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methyl
chloro
piperidin
ylidene
compound
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PCT/CN2020/085294
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French (fr)
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孟庆华
王小虎
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北京酷瓴生物技术有限公司
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/70—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D471/04—Ortho-condensed systems

Definitions

  • This application belongs to the field of medical technology, and relates to benzene piperidine derivatives with ROR ⁇ t inhibitory activity.
  • Autoimmune diseases are mainly caused by the disorder of the immune system, especially the dysfunction of T cells, which causes the immune system to recognize abnormally and attack its own tissues or antigens.
  • Other inflammatory diseases such as allergic diseases, are mainly caused by the overreaction of the immune system to foreign antigens.
  • IL-17 cells especially Th17 cells
  • psoriasis commonly known as cowhide Moss
  • multiple sclerosis etc.
  • Th17 cells also have important pathological effects in some allergic diseases, especially neutrophil-enriched asthma (Chang et al., 2017).
  • IL-17 and Th17 cells expressing IL-17 are enriched in the tumor tissues of a variety of cancer patients (these cancers include colon cancer, lung cancer, liver cancer, breast cancer, ovarian cancer, pancreatic cancer, prostate cancer Cancer, melanoma, etc.) and may have tumor-promoting or anti-tumor effects under different conditions (Asadzadeh et al., 2017). Therefore, some inhibitors or agonists against IL-17 or Th17 cells will not only be possible to treat the above-mentioned autoimmune diseases or allergic diseases, but also be used in the clinical treatment of cancer.
  • Th17 cells are the third type of helper CD4-positive T cells after Th1 and Th2 cells discovered by Professor Dong Chen and Professor Weaver in 2005.
  • Th17 cells mainly express interleukin ((IL))-17 and IL-17F (Harrington et al., 2005; Park et al., 2005), among which IL-17 is considered to be the most important effector cytokine of Th17 cells.
  • IL-17 interleukin
  • Th17 cells can directly or indirectly recruit immune cells such as neutrophils and macrophages by secreting chemokines and cytokines to resist infection by extracellular bacteria and fungi, and by regulating the mucosal barrier Integrity has an important function in the body's mucosal immunity.
  • Abnormal and persistent Th17 cell activation can cause persistent inflammation in related tissues and organs, causing a variety of autoimmune diseases and affecting the disease progression of a variety of tumors (Asadzadeh et al., 2017).
  • Th17 cells are mainly controlled by a key primary transcription factor ROR ⁇ t, which directly regulates the expression of cytokines including IL-17 and IL-17F by binding to the sites of Th17 cell-related genes (Ivanov et al., 2006; Yang et al., 2008).
  • ROR ⁇ t also known as ROR ⁇ 2, is one of the two spliced forms of orphan receptor ROR ⁇ , ROR ⁇ 1 and ROR ⁇ 2.
  • ROR ⁇ 1 is expressed in muscle, liver, kidney and thymus tissues, while ROR ⁇ t is mainly expressed in immune cells. .
  • benzene piperidine derivatives can target ROR ⁇ t, inhibit the activity of ROR ⁇ t, the differentiation and development of Th17 cells and the expression of IL-17, and can be used to treat related autoimmune diseases, inflammatory diseases or cancers.
  • One or more embodiments of the application provide a compound of formula (I)
  • R 1 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, halogen or cyano; the C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy are each Independently optionally optionally substituted by one or more selected from C1-C6 alkyl, C1-C6 haloalkyl, cyano, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C7 alicyclic hydrocarbon group and 3- 7-membered heterocycloalkyl group substitution;
  • Each R 2 is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, halogen or cyano; the C1-C6 alkyl, C1-C6 haloalkyl are each independently optionally One or more selected from C1-C6 alkyl, C1-C6 haloalkyl, cyano, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C7 alicyclic hydrocarbon group and 3-7 membered heterocycloalkyl The group substitution;
  • R 3 is C1-C6 alkyl, C1-C6 alkoxy, C3-C7 alicyclic hydrocarbon group, 3-7 membered heteroatom-containing alicyclic hydrocarbon group, C5-C10 aryl group or 5-10 membered heteroaryl group, wherein The C1-C6 alkyl group, C1-C6 alkoxy group, C3-C7 alicyclic hydrocarbon group, 3-7 membered heteroatom-containing alicyclic hydrocarbon group, C5-C10 aryl group, 5-10 membered heteroaryl group are each independently Optionally by one or more selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, cyano, acyl, carboxy, hydroxy, C1-C6 alkoxy, C1-C6 haloalkoxy, carbonyl, C3 -C7 alicyclic hydrocarbon group, 3-7 membered heterocycloalkyl group, sulfonyl group,
  • R 4 is C1-C6 alkyl, C1-C6 alkoxy, C3-C7 alicyclic hydrocarbon group, 3-7 membered heteroatom-containing alicyclic hydrocarbon group, C5-C10 aryl group or 5-10 membered heteroaryl group, wherein The C1-C6 alkyl group, C1-C6 alkoxy group, C3-C7 alicyclic hydrocarbon group, 3-7 membered heteroatom-containing alicyclic hydrocarbon group, C5-C10 aryl group, 5-10 membered heteroaryl group are each independently Optionally by one or more selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, amino, cyano, acyl, carboxy, hydroxy, C1-C6 alkoxy, C1-C6 haloalkoxy, carbonyl , C3-C7 alicyclic hydrocarbon group, 3-7 membered heterocycloalkyl, sulfonyl optional
  • n 0, 1 or 2;
  • p is 0 or 1;
  • One or more embodiments of the present application provide a compound containing formula (I) or a stereoisomer, enantiomer or tautomer of the compound or a mixture thereof, or a pharmaceutically acceptable salt thereof, Pharmaceutical compositions of solvates or prodrugs.
  • One or more embodiments of the present application provide a compound of formula (I) or a stereoisomer, enantiomer or tautomer of the compound or a mixture thereof, or a pharmaceutically acceptable salt and solvent thereof
  • the pharmaceutical composition is used for the prevention and/or treatment of diseases.
  • One or more embodiments of the present application provide a compound of formula (I) or a stereoisomer, enantiomer or tautomer of the compound or a mixture thereof, or a pharmaceutically acceptable salt and solvent thereof
  • the pharmaceutical composition is used in the preparation of ROR ⁇ t receptor inhibitors.
  • One or more embodiments of the present application provide a compound of formula (I) or a stereoisomer, enantiomer or tautomer of the compound or a mixture thereof, or a pharmaceutically acceptable salt and solvent thereof
  • the pharmaceutical composition is used to prevent and/or treat diseases related to abnormal activation of ROR ⁇ t receptor.
  • One or more embodiments of the present application provide a compound of formula (I) or a stereoisomer, enantiomer or tautomer of the compound or a mixture thereof, or a pharmaceutically acceptable salt and solvent thereof
  • Compounds or prodrugs, or containing compounds of formula (I) or stereoisomers, enantiomers or tautomers of the compounds or mixtures thereof, or pharmaceutically acceptable salts, solvates or prodrugs thereof The use of the pharmaceutical composition in inhibiting ROR ⁇ t receptor.
  • One or more embodiments of the present application provide a compound of formula (I) or a stereoisomer, enantiomer or tautomer of the compound or a mixture thereof, or a pharmaceutically acceptable salt and solvent thereof
  • Compounds or prodrugs, or containing compounds of formula (I) or stereoisomers, enantiomers or tautomers of the compounds or mixtures thereof, or pharmaceutically acceptable salts, solvates or prodrugs thereof The pharmaceutical composition for use as a medicine.
  • One or more embodiments of the present application provide a compound of formula (I) or a stereoisomer, enantiomer or tautomer of the compound or a mixture thereof, or a pharmaceutically acceptable salt and solvent thereof
  • Compounds or prodrugs, or containing compounds of formula (I) or stereoisomers, enantiomers or tautomers of the compounds or mixtures thereof, or pharmaceutically acceptable salts, solvates or prodrugs thereof A pharmaceutical composition for the preparation of RORyt receptor inhibitors.
  • One or more embodiments of the present application provide a compound of formula (I) or a stereoisomer, enantiomer or tautomer of the compound or a mixture thereof, or a pharmaceutically acceptable salt and solvent thereof
  • Compounds or prodrugs, or containing compounds of formula (I) or stereoisomers, enantiomers or tautomers of the compounds or mixtures thereof, or pharmaceutically acceptable salts, solvates or prodrugs thereof A pharmaceutical composition for preventing and/or treating diseases related to abnormal activation of RORyt receptor.
  • One or more embodiments of the present application provide a compound of formula (I) or a stereoisomer, enantiomer or tautomer of the compound or a mixture thereof, or a pharmaceutically acceptable salt and solvent thereof
  • Compounds or prodrugs, or containing compounds of formula (I) or stereoisomers, enantiomers or tautomers of the compounds or mixtures thereof, or pharmaceutically acceptable salts, solvates or prodrugs thereof A pharmaceutical composition for inhibiting the RORyt receptor.
  • One or more embodiments of the present application provide a method for preventing and/or treating a disease, the method comprising providing a compound of formula (I) or a stereoisomer or enantiomer of the compound to an individual in need thereof Or a tautomer or a mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a compound of formula (I) or a stereoisomer, enantiomer or tautomer of the compound A structure or a mixture thereof, or a pharmaceutical composition of a pharmaceutically acceptable salt, solvate or prodrug thereof.
  • One or more embodiments of the present application provide a method for preventing and/or treating diseases associated with abnormal activation of RORyt receptors, the method comprising providing a compound of formula (I) or a stereoisomer of the compound to an individual in need thereof Isomers, enantiomers or tautomers or mixtures thereof, or pharmaceutically acceptable salts, solvates or prodrugs thereof, or compounds containing formula (I) or stereoisomers or enantiomers of the compounds Isomers or tautomers or mixtures thereof, or pharmaceutical compositions of pharmaceutically acceptable salts, solvates or prodrugs thereof.
  • One or more embodiments of the present application provide a method of inhibiting RORyt receptor, the method comprising providing a compound of formula (I) or a stereoisomer, enantiomer or mutuality of the compound to an individual in need thereof Tautomers or mixtures thereof, or pharmaceutically acceptable salts, solvates or prodrugs thereof, or containing compounds of formula (I) or stereoisomers, enantiomers or tautomers of the compounds Or a mixture thereof, or a pharmaceutical composition of a pharmaceutically acceptable salt, solvate or prodrug thereof.
  • FIG. 1 Example 4 In the experimental autoimmune encephalomyelitis (EAE) test in mice, after administering compound 31 at 10 mg/kg body weight of mice, the immunization days of mice versus clinical scores.
  • EAE experimental autoimmune encephalomyelitis
  • FIG. 1 Example 4 In the experimental autoimmune encephalomyelitis (EAE) test in mice, after administering compound 31 at 30 mg/kg body weight of mice, the immunization days of mice versus clinical scores.
  • EAE experimental autoimmune encephalomyelitis
  • FIG. 3 Example 4 In the experimental autoimmune encephalomyelitis (EAE) test in mice, after administering compound 31 at 100 mg/kg body weight of mice, the immunization days of mice versus clinical scores.
  • EAE experimental autoimmune encephalomyelitis
  • One or more embodiments of the application provide a compound of formula (I)
  • R 1 is hydrogen, C1-C6 alkyl, C3-C7 alicyclic hydrocarbon group, C1-C6 haloalkyl, C1-C6 alkoxy, halogen or cyano; the C1-C6 alkyl group, C3-C7 alicyclic hydrocarbon group , C1-C6 haloalkyl, C1-C6 alkoxy, each independently optionally selected from C1-C6 alkyl, C1-C6 haloalkyl, cyano, C1-C6 alkoxy, C1 -C6 haloalkoxy, C3-C7 alicyclic hydrocarbon group, 3-7 membered heterocycloalkyl group substitution;
  • Each R 2 is independently C1-C6 alkyl, C1-C6 haloalkyl, C3-C7 alicyclic hydrocarbon group, C1-C6 alkoxy, halogen, or cyano; the C1-C6 alkyl group, C3-C7 alicyclic hydrocarbon group , C1-C6 haloalkyl, each independently optionally selected from C1-C6 alkyl, C1-C6 haloalkyl, cyano, C1-C6 alkoxy, C1-C6 haloalkoxy, C3 -C7 alicyclic hydrocarbon group, 3-7 membered heterocycloalkyl group substitution;
  • R 3 is C1-C6 alkyl, C1-C6 alkoxy, C3-C7 alicyclic hydrocarbon group, 3-7 membered heteroatom-containing alicyclic hydrocarbon group, C5-C10 aryl group or 5-10 membered heteroaryl group, wherein The C1-C6 alkyl group, C1-C6 alkoxy group, C3-C7 alicyclic hydrocarbon group, 3-7 membered heteroatom-containing alicyclic hydrocarbon group, C5-C10 aryl group, 5-10 membered heteroaryl group are each independently Optionally by one or more selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, cyano, acyl, carboxy, hydroxy, C1-C6 alkoxy, C1-C6 haloalkoxy, carbonyl, C3 -C7 alicyclic hydrocarbon group, 3-7 membered heterocycloalkyl group, sulfonyl group,
  • R 4 is C1-C6 alkyl, C1-C6 alkoxy, C3-C7 alicyclic hydrocarbon group, 3-7 membered heteroatom-containing alicyclic hydrocarbon group, C5-C10 aryl group or 5-10 membered heteroaryl group, wherein The C1-C6 alkyl group, C1-C6 alkoxy group, C3-C7 alicyclic hydrocarbon group, 3-7 membered heteroatom-containing alicyclic hydrocarbon group, C5-C10 aryl group, 5-10 membered heteroaryl group are each independently Optionally by one or more selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, amino, cyano, acyl, carboxy, hydroxy, C1-C6 alkoxy, C1-C6 haloalkoxy, carbonyl , C3-C7 alicyclic hydrocarbon group, 3-7 membered heterocycloalkyl, sulfonyl optional
  • n 0, 1 or 23;
  • p is 0 or 1;
  • X is
  • R 1 is hydrogen, C1-C6 alkyl, C3-C7 alicyclic hydrocarbon group, C1-C6 haloalkyl, C1-C6 alkoxy or halogen. In one or more embodiments of this application, R 1 is hydrogen, C1-C6 alkyl or halogen. In one or more embodiments of the present application, R 1 is methyl or Cl.
  • each R 2 is independently a C1-C6 alkyl group, a C3-C7 alicyclic hydrocarbon group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group or a halogen. In one or more embodiments of the present application, each R 2 is independently halogen. In one or more embodiments of the present application, each R 2 is independently F and Cl. In one or more embodiments of the present application, when m is 1 or 2, at least one R 2 is located at the para position of R 1 .
  • R 4 is a C3-C7 alicyclic hydrocarbon group, a 3-7 membered heteroatom-containing alicyclic hydrocarbon group, a C5-C10 aryl group or a 5-10 membered heteroaryl group; the C3 -C7 alicyclic hydrocarbon group, 3-7 member heteroatom-containing alicyclic hydrocarbon group, C5-C10 aryl group or 5-10 member heteroaryl group are each independently optionally selected from halogen, C1-C6 alkyl , C1-C6 haloalkyl, amino, cyano, acyl, carboxyl, hydroxyl, C1-C6 alkoxy, C1-C6 haloalkoxy, carbonyl, C3-C7 alicyclic hydrocarbon group, 3-7 membered heteroatom-containing lipid Cycloalkyl and sulfonyl groups optionally substituted with C1-C3 alkyl groups are substituted.
  • R 4 is a 3-7 membered heteroatom-containing alicyclic hydrocarbon group, C5-C10 aryl group or 5-10 membered heteroaryl group, and the 3-7 membered heteroatom-containing Alicyclic hydrocarbon group, C5-C10 aryl group or 5-10 membered heteroaryl group is optionally selected by one or more selected from halogen, C1-C6 alkyl, cyano, C1-C6 alkoxy, carbonyl, C3-C7 fat Cycloalkyl and sulfonyl groups optionally substituted with C1-C3 alkyl groups are substituted.
  • R 4 is optionally substituted by one or more of F, Cl, C1-C3 alkyl and cyano C5-C10 aryl or 5-10 membered heteroaryl.
  • R 4 is preferably R 4 is optionally substituted by one or more of F, Cl, C1-C3 alkyl and cyano C5-C10 aryl or 5-10 membered heteroaryl.
  • R 4 is
  • R 3 is C1-C6 alkyl, C1-C6 alkoxy, C3-C7 cycloalkyl, 3-7 membered heterocycloalkyl, or 5-10 membered heteroaryl ;
  • the C1-C6 alkyl group, C1-C6 alkoxy group, C3-C7 alicyclic hydrocarbon group, 3-7 membered heterocycloalkyl group or 5-10 membered heteroaryl group is optionally halogenated, C1-C6 haloalkyl , C1-C6 alkoxy, C1-C6 haloalkoxy, or C1-C6 alkyl substituted.
  • R 3 is C1-C4 alkyl, C3-C6 cycloalkyl, 3-7 membered heterocycloalkyl or 5-6 membered heteroaryl; the C1-C4 alkyl Group, C3-C6 cycloalkyl, 3-7 membered heterocycloalkyl, or 5-6 membered heteroaryl group is optionally fluorine, C1-C3 fluoroalkyl, C1-C6 alkoxy, C1-C3 fluoro Alkoxy or C1-C6 alkyl substitution.
  • R 3 is
  • R 1 is C1-C6 alkyl
  • R 2 is halogen
  • R 3 is C1-C6 alkyl or C3-C7 alicyclic hydrocarbon group optionally substituted by halogen
  • X is
  • R 4 is a C5-C10 aryl group or a 5-10 membered heteroaryl group optionally substituted by one or more of halogen, C1-C6 alkyl and cyano
  • m is 1
  • p is 0 or 1.
  • R 1 is methyl;
  • R 2 is Cl or F;
  • R 3 is isopropyl, cyclopropyl, cyclopentyl or ring optionally substituted with one or more F Hexyl;
  • X is R 4 is phenyl, pyridyl or optionally substituted by one or more of F, methyl and cyano m is 1;
  • p is 0 or 1;
  • R 1 is methyl;
  • R 2 is Cl or F;
  • R 3 is isopropyl, cyclopropyl, cyclopentyl or ring optionally substituted with one or two F Hexyl;
  • X is R 4 is pyridyl optionally substituted by one F, methyl and cyano or m is 1;
  • p is 0 or 1.
  • the structure of the compound of formula (I) is:
  • R 1 , R 2 and R 3 are as defined above.
  • One or more embodiments of the present application provide the following compounds or their stereoisomers, enantiomers or tautomers or mixtures thereof, or pharmaceutically acceptable salts, solvates or prodrugs thereof, The structure is shown in Table 1:
  • the compound of formula (I) can be prepared by the steps shown in Scheme A or Scheme B:
  • the reduction in step ii) is performed in THF.
  • the alkaline conditions in step v) are generated by NaH.
  • the Wittig reaction in step v) is performed in DMSO.
  • R 1 , R 2 , and m are as defined in formula (I) above.
  • R 1 , R 2 and m are as defined in formula (I) above.
  • the compound of formula (IG) or its salt (such as hydrochloride or trifluoroacetate) is subjected to condensation reaction with R 3 COR 5 to obtain the compound of formula (IH);
  • R 1 , R 2 , R 3 , m and p are as defined in formula (I) above.
  • R 1 , R 2 , R 3 , m and p are as defined in formula (I) above.
  • the compound of formula (II) is reacted with the R 4 COR 6 , R 4 NCO and R 4 SO 2 Cl 2 compound to carry out a transesterification reaction, addition reaction or condensation reaction to obtain a compound of formula (I);
  • R 5 is a group commonly used in the field of amino transesterification reactions, such as hydroxyl , Halogens such as chlorine, methoxy, ethoxy, etc.
  • R 1 , R 2 and m are as defined in formula (I) above; the compound of formula (IF) is prepared according to the method of step 1 of Scheme A.
  • step 1 of this scheme the compound of formula (I-J) can also be prepared using the following scheme:
  • the intermediate compound of formula (I-M) is coupled with the intermediate compound of formula (I-N) to obtain the intermediate compound of formula (I-J);
  • R 1 , R 2 and m are as defined in formula (I); intermediate compounds of formula (IM) and intermediate compounds of formula (IN) can be prepared using methods conventionally used in the art, such as the middle of formula (IM) The body compound and the intermediate compound of formula (IN) can be prepared by the above reaction scheme.
  • R 1 , R 2 , R 4 , X and m are as defined in the above formula (I);
  • R 5 is selected from hydroxyl, halogen (e.g. chlorine), alkoxy (e.g. methoxy, ethoxy) .
  • R 1 , R 2 , X and m are as defined in formula (I).
  • the compound of formula (IL) or its salt (such as hydrochloride or trifluoroacetate) is subjected to condensation reaction with R 3 COR 5 to obtain the compound of formula (I);
  • R 1 -R 3 , X, m and p are as defined in formula (I).
  • a compound of formula (I-F), a compound of formula (I-G), and a compound of formula (I-H) are respectively provided
  • R 1 -R 3 , m and p are as defined in formula (I).
  • R 1 -R 3 , m and p are as defined in formula (I).
  • the compound of formula (I-I) includes, but is not limited to, the following compounds:
  • a compound of formula (I-J) and a compound of formula (I-K) are also provided respectively
  • R 1 , R 2 , X and m are as defined in formula (I).
  • R 1 , R 2 , X and m are as defined in formula (I).
  • One or more embodiments of the present application also provide a pharmaceutical composition, which comprises a compound of formula (I) or a stereoisomer, enantiomer or tautomer or a mixture thereof, or a pharmaceutical composition thereof Accepted salts, solvates or prodrugs, and one or more pharmaceutically acceptable excipients and/or carriers.
  • One or more embodiments of the present application also provide a compound of formula (I) or a stereoisomer, enantiomer or tautomer or a mixture thereof, or a pharmaceutically acceptable salt, solvate or Prodrugs, or pharmaceutical compositions containing a compound of formula (I) or its stereoisomers, enantiomers or tautomers or mixtures thereof, or pharmaceutically acceptable salts, solvates or prodrugs thereof Use as a medicine, or use in the treatment of diseases.
  • One or more embodiments of the present application also provide a compound of formula (I) or a stereoisomer, enantiomer or tautomer or a mixture thereof, or a pharmaceutically acceptable salt, solvate or Prodrugs, or pharmaceutical compositions containing a compound of formula (I) or its stereoisomers, enantiomers or tautomers or mixtures thereof, or pharmaceutically acceptable salts, solvates or prodrugs thereof Use in the preparation of ROR ⁇ t receptor inhibitors.
  • One or more embodiments of the present application also provide a compound of formula (I) or a stereoisomer, enantiomer or tautomer or a mixture thereof, or a pharmaceutically acceptable salt, solvate or Prodrugs, or pharmaceutical compositions containing a compound of formula (I) or its stereoisomers, enantiomers or tautomers or mixtures thereof, or pharmaceutically acceptable salts, solvates or prodrugs thereof Use in the preparation of a medicine for preventing and/or treating diseases related to abnormal activation of ROR ⁇ t receptor.
  • the above-mentioned diseases related to abnormal activation of ROR ⁇ t receptors include autoimmune diseases, allergic diseases and cancer.
  • the above-mentioned diseases associated with abnormal activation of ROR ⁇ t receptors include Psoriasis, Psoriatic Arthritis, Rheumatoid Arthritis, and Ankylosing Spondylitis (Ankylosing Spondylitis), Multiple Sclerosis, Sjogren's Syndrome, Dry Eye Syndrome, Graft-versus-host Disease, Inflammatory Bowel Disease (Inflammatory Bowel Disease), Chronic Obstructive Pulmonary Disease, Asthma, Autoimmune Uveitis, Autoimmune Hepatitis, Autoimmune Thyroid Disease ), autoimmune nephritis (Autoimmune Nephritis), atopic dermatitis (Dermatitis), prostatitis (Begign Prostatic Hyperplasia) and prostate cancer (castration-resistant prostate cancer).
  • One or more embodiments of the present application also provide a compound of formula (I) or a stereoisomer, enantiomer or tautomer or a mixture thereof, or a pharmaceutically acceptable salt, solvate or Prodrugs, or pharmaceutical compositions containing a compound of formula (I) or its stereoisomers, enantiomers or tautomers or mixtures thereof, or pharmaceutically acceptable salts, solvates or prodrugs thereof Use in inhibiting ROR ⁇ t receptor.
  • the compound of formula (I) of the present application or its stereoisomers, enantiomers or tautomers or mixtures thereof, or pharmaceutically acceptable salts or solvates thereof
  • the prodrug can effectively inhibit the ROR ⁇ t protein receptor, thereby regulating the differentiation of Th17 cells and inhibiting the production of IL-17. Therefore, the compound of formula (I) of the present application can be used as a preferred therapeutic drug for treating diseases related to abnormal activation of ROR ⁇ t receptor receptor.
  • the term "compound” includes all stereoisomers, geometric isomers, and tautomers.
  • the "compounds” described herein may be asymmetric, for example, have one or more stereoisomers. Unless otherwise specified, all stereoisomers include, for example, individual enantiomers and diastereomers or other stereoisomeric forms or mixtures thereof.
  • the compounds containing asymmetric carbon atoms herein can be isolated in optically pure form or in racemic form. The optically active pure form can be resolved from the racemic mixture or synthesized by using chiral starting materials or chiral reagents.
  • the "compounds” described herein also include geometric isomeric forms.
  • Geometric isomeric forms refer to compounds in which the substituents on the double bond or ring have different cis and trans isomers without chirality.
  • the "compounds" described herein also include tautomeric forms.
  • the tautomeric form can be derived from the exchange of a single bond with an adjacent double bond accompanied by the migration of a proton.
  • the compounds herein, whether they are intermediates or compounds of formula (I), can also be isotopically labeled by replacing one or more atoms with atoms having different atomic masses or mass numbers.
  • Such isotopically-labeled (ie, radiolabeled) compounds are considered to be within the scope of this document.
  • isotopes in the compounds herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, each of which has the same number of protons but different mass numbers.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • amino refers to -NH 2 .
  • cyano refers to -CN.
  • nitro refers to -NO 2 .
  • hydroxyl refers to -OH.
  • the “mercapto” group refers to the "-SH” group.
  • the “isocyanato” group refers to the "-NCO” group.
  • the "thiocyanato” group refers to the "-CNS” group.
  • the “isothiocyanato” group refers to the "-NCS” group.
  • CA to CB or “CA-CB” refers to the number of carbon atoms in an alkyl, alkenyl or alkynyl group, or the number of carbon atoms in an aryl or heteroaryl group, where "A” and “B” are integers . That is, the alkyl group, alkenyl group, alkynyl group, aryl group, and heteroaryl group may contain "A” to "B” carbon atoms.
  • C1 to C4 alkyl or “C1-C4 alkyl” group refers to all alkyl groups having 1 to 4 carbons, namely CH 3 -, CH 3 CH 2 -, CH 3 CH 2 CH 2 -, (CH 3 ) 2 CH-, CH 3 CH 2 CH 2 CH 2 -, CH 3 CH 2 CH(CH 3 )- and (CH 3 ) 3 C-.
  • alkyl refers to a linear or branched saturated hydrocarbon group composed of carbon atoms and hydrogen atoms, such as a C1-C20 alkyl group, preferably a C1-C6 alkyl group.
  • C1-C20 alkyl refers to an alkyl group having 1 to 20 carbon atoms, for example, having 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 Carbon atoms, 8 carbon atoms, 9 carbon atoms, 10 carbon atoms, 11 carbon atoms, 12 carbon atoms, 13 carbon atoms, 14 carbon atoms, 15 carbon atoms, 16 carbon atoms, 17 An alkyl group of 6 carbon atoms, 18 carbon atoms, 19 carbon atoms, or 20 carbon atoms.
  • alkyl groups include, but are not limited to, methyl, ethyl, propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, sec-butyl or tert-butyl), pentyl (Including n-pentyl, isopentyl, neopentyl), hexyl (for example, n-hexyl) and the like.
  • the alkyl group may be unsubstituted or substituted by one or more substituents, including but not limited to alkyl, alkoxy, cyano, hydroxy, carbonyl, carboxy, aryl, heteroaryl, Amino, halogen, sulfonyl, sulfinyl, phosphono, etc.
  • Alkenyl refers to a hydrocarbon group containing one or more double bonds in a straight or branched hydrocarbon chain. Alkenyl groups can be unsubstituted or substituted. Alkenyl groups can have 1 to 20 carbon atoms, and whenever appearing herein, a numerical range such as “1 to 20" refers to each integer in the given range; for example, "1 to 20 carbon atoms” means that Contains 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms, 10 carbon atoms , 11 carbon atoms, 12 carbon atoms, 13 carbon atoms, 14 carbon atoms, 15 carbon atoms, 16 carbon atoms, 17 carbon atoms, 18 carbon atoms, 19 carbon atoms or 20 carbon atoms ⁇ alkenyl.
  • Alkynyl refers to a hydrocarbon group containing one or more triple bonds in a straight or branched hydrocarbon chain.
  • the alkynyl group can be unsubstituted or substituted.
  • An alkynyl group can have 1 to 20 carbon atoms, and whenever it appears herein, a numerical range such as “1 to 20” refers to each integer in the given range; for example, "1 to 20 carbon atoms” means that Contains 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms, 10 carbon atoms , 11 carbon atoms, 12 carbon atoms, 13 carbon atoms, 14 carbon atoms, 15 carbon atoms, 16 carbon atoms, 17 carbon atoms, 18 carbon atoms, 19 carbon atoms or 20 carbon atoms ⁇ alkynyl.
  • alicyclic alkyl refers to saturated (ie, “alicyclic alkyl") or unsaturated carbon atoms (e.g., 3, 4, 5, 6, 7, 8, 9 or 10 A single ring, fused ring, spiro ring or bridged ring consisting of carbon atoms) and hydrogen atoms.
  • examples of the alicyclic hydrocarbon group include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, spiro[3.4]octyl, bicyclo[1.1.1]pentyl , Bicyclo[3.1.0] hexane group.
  • the alicyclic hydrocarbon group includes alicyclic alkyl (cycloalkyl).
  • heteroatom-containing alicyclic hydrocarbon group refers to saturated (heterocycloalkyl) or unsaturated non-aromatic ones containing one or more (for example, 1, 2, 3, or 4) heteroatoms Monocyclic, fused, bridged and spiro rings. Wherein the heteroatom is typically N, O, S or SO 2
  • the heteroatom-containing alicyclic hydrocarbon group can be a 3- to 10-membered (for example, containing 3, 4, 5, 6, 7, 8, 9, or 10 ring atoms) monocyclic or bicyclic or Three rings.
  • heteroatom-containing alicyclic hydrocarbon groups include, but are not limited to, piperazinyl, morpholinyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl and the like.
  • the heteroatom-containing alicyclic hydrocarbon group may be unsubstituted or substituted by one or more substituents, including but not limited to halogen, alkyl, haloalkyl, amino, cyano, hydroxyl, alkoxy , Halogenated alkoxy groups, carbonyl groups, alicyclic hydrocarbon groups, heteroatom-containing alicyclic hydrocarbon groups, sulfonyl groups optionally substituted by C1-C3 alkyl groups, aryl groups and heteroaryl groups.
  • substituents including but not limited to halogen, alkyl, haloalkyl, amino, cyano, hydroxyl, alkoxy , Halogenated alkoxy groups, carbonyl groups, alicyclic hydrocarbon groups, heteroatom-containing alicyclic hydrocarbon groups, sulfonyl groups optionally substituted by C1-C3 alkyl groups, aryl groups and heteroaryl groups.
  • heteroatom-containing alicyclic hydrocarbon group when substituted by a carbonyl group, it may be 2-oxo-1,2-dihydropyridyl Or "3-oxo-1,2-dihydropyridazinyl
  • the heteroatom-containing alicyclic hydrocarbon group includes a heterocycloalkyl group.
  • aryl refers to an all-carbon monocyclic or all-carbon fused ring with a fully conjugated ⁇ -electron system, usually having 5-14 carbon atoms, for example, 6, 10, 12, 14 carbons atom.
  • the aryl group may be unsubstituted or substituted by one or more substituents including but not limited to alkyl, alkoxy, cyano, hydroxy, carboxy, aryl, aralkyl, amine, Halogen, sulfonyl, sulfinyl, phosphono.
  • unsubstituted aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl.
  • heteroaryl refers to a monocyclic or condensed ring having 6-12 ring atoms (for example, 6, 10, 12, 14 ring atoms), which contains 1-4 (for example, 1, 2, 3 or 4) heteroatoms selected from N, O, S, the rest of the ring atoms are C, and have a fully conjugated ⁇ -electron system, including but not limited to pyrrolyl, furyl, thiophene Group, imidazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolinyl, isoquinolinyl, triazolyl, benzimidazole, benzene And triazole and so on.
  • Heteroaryl groups can be unsubstituted or substituted, and the substituents include but are not limited to alkyl, alkoxy, cyano, hydroxyl, carbonyl, carboxy, aryl, aralkyl, amine, halogen, sulfonyl, Sulfinyl, phosphono.
  • the heteroaryl group when substituted by a hydroxyl group, it can be piperidin-2-ol Pyridazin-3-ol
  • Alkoxy refers to the formula -OR, where R is an alkyl group as defined herein.
  • Non-limiting examples of alkoxy groups are methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, isobutoxy, sec-butoxy , Tert-Butoxy.
  • the alkoxy group may be substituted or unsubstituted.
  • acyl refers to a hydrogen, alkyl, alkenyl, alkynyl or aryl group as a substituent attached through a carbonyl group. Examples include formyl, acetyl, propionyl, benzoyl and acryloyl.
  • the acyl group can be substituted or unsubstituted.
  • Haloalkyl refers to an alkyl group in which one or more hydrogen atoms are replaced by halogen (e.g., monohaloalkyl, dihaloalkyl, and trihaloalkyl). Such groups include, but are not limited to, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1-chloro-2-fluoromethyl, and 2-fluoroisobutyl.
  • halogen e.g., monohaloalkyl, dihaloalkyl, and trihaloalkyl.
  • Such groups include, but are not limited to, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1-chloro-2-fluoromethyl, and 2-fluoroisobutyl.
  • the haloalkyl group can be substituted or unsubstituted.
  • Haloalkoxy refers to an alkoxy group in which one or more hydrogen atoms are replaced by halogen (e.g., monohaloalkoxy, dihaloalkoxy, and trihaloalkoxy).
  • halogen e.g., monohaloalkoxy, dihaloalkoxy, and trihaloalkoxy.
  • groups include, but are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 1-chloro-2-fluoromethoxy, and 2-fluoroisobutoxy.
  • the halogenated alkoxy group can be substituted or unsubstituted.
  • Arylthio refers to RS-, where R is an aryl group, such as but not limited to phenyl.
  • the arylthio group may be substituted or unsubstituted.
  • the thiocarbonyl group may be substituted or unsubstituted.
  • trihalomethanesulfonyl refers to the "X 3 CSO 2 -" group, where each X is a halogen.
  • Trihalo methane sulfonamido refers to a "X 3 CS (O) 2 N (R A) -" group, wherein each X is a halogen, and R A is hydrogen, an alkyl group, an alkenyl group, Alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclic, aralkyl, (heteroaryl)alkyl, or (heteroalicyclic)alkyl.
  • the “sulfanyl” group refers to the "-SR" group, in which R can be an alkyl group (the “sulfanyl” in this case is an “alkylsulfanyl”), alkenyl, alkynyl, cycloalkyl, ring Alkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclic, aralkyl, (heteroaryl)alkyl, or (heteroalicyclic)alkyl.
  • the hydrocarbylthio group may be substituted or unsubstituted.
  • the sulfinyl group can be substituted or unsubstituted.
  • the "sulfonyl” group refers to a "SO 2 R" group, wherein R has the same definition as R in the hydrocarbylthio group.
  • the sulfonyl group may be substituted or unsubstituted.
  • DMSO dimethyl sulfoxide
  • the C-acylamino group may be substituted or unsubstituted.
  • the N-acylamino group may be substituted or unsubstituted.
  • -S- sulfonamido refers to a group “-SO 2 N (R A R B)" group, wherein R A and R B is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, , Cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclic, aralkyl, (heteroaryl)alkyl, or (heteroalicyclic)alkyl.
  • the S-sulfonylamino group may be substituted or unsubstituted.
  • N-sulfonamido group refers to "RSO 2 N (R A) -" group, wherein R A and R may be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl Group, cycloalkynyl, aryl, heteroaryl, heteroalicyclic, aralkyl, (heteroaryl)alkyl, or (heteroalicyclic)alkyl.
  • the N-sulfonylamino group may be substituted or unsubstituted.
  • the O-carbamoyl group may be substituted or unsubstituted.
  • the N-carbamoyl group can be substituted or unsubstituted.
  • the O-thiocarbamoyl group may be substituted or unsubstituted.
  • the N-thiocarbamoyl group may be substituted or unsubstituted.
  • the "optionally substituted” or “substituted” groups can be individually and independently substituted by one or more groups selected from the following: alkyl, alkenyl, alkyne Group, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclic, aralkyl, heteroaralkyl, (heteroalicyclic) alkyl, hydroxyl, alkoxy, Aryloxy, acyl, mercapto, alkylthio, arylthio, cyano, halogen, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thioamino Formyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, carboxyl, isocyanato, thiocyanato, is
  • covalent bond refers to the interaction between atoms through shared electron pairs.
  • treatment means any treatment of diseases in mammals, including: (1) preventing diseases, even if the symptoms of clinical diseases do not develop; (2) inhibiting diseases, that is, preventing the development of clinical symptoms; (3) reducing diseases, Even if the clinical symptoms subsided.
  • pharmaceutical composition refers to a combination of one or more of the compounds herein and a carrier, excipient or adjuvant generally accepted in the art, for example, for the delivery of a biologically active compound to an organism (such as a human) preparation.
  • a carrier, excipient or adjuvant generally accepted in the art, for example, for the delivery of a biologically active compound to an organism (such as a human) preparation.
  • the purpose of the pharmaceutical composition is to facilitate the administration and delivery of the organism.
  • pharmaceutically acceptable excipient and/or carrier refers to substances that are co-administered with the active ingredient and facilitate the administration of the active ingredient, including But not limited to any glidants, sweeteners, diluents, preservatives, fuels/colorants, flavor enhancers, surface active agents that are acceptable for use in humans or animals (such as livestock) approved by the State Food and Drug Administration Agents, wetting agents, dispersing agents, disintegrating agents, suspending agents, stabilizers, isotonic agents, solvents or emulsifiers. Examples include, but are not limited to, calcium carbonate, calcium phosphate, various sugars and various starches, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.
  • composition described herein can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, solutions, suppositories, injections, inhalations Agents, gels, microspheres and aerosols.
  • the pharmaceutical composition described herein can be manufactured by methods well known in the art, such as conventional mixing method, dissolution method, granulation method, sugar-coated pill method, grinding method, emulsification method, freeze-drying method, etc.
  • the administration routes of the compounds described herein or their pharmaceutically acceptable salts or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, transmucosal, enteral administration, or topical, transdermal, inhalation, parenteral, Sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.
  • the preferred route of administration is oral, intravenous, intramuscular and diseased organs (such as eyes, prostate, etc.) injection.
  • the pharmaceutical composition can be formulated by mixing the active compound with a pharmaceutically acceptable carrier well known in the art.
  • the compounds herein can be formulated into tablets, pills, lozenges, sugar-coated agents, capsules, liquids, gels, slurries, suspensions, etc., for oral administration to patients.
  • a pharmaceutical composition for oral administration a tablet can be obtained by combining the active ingredient with one or more solid carriers, granulating the resulting mixture if necessary, and adding a small amount if necessary Excipients are processed into mixtures or granules to form tablets or tablet cores.
  • the tablet core can be combined with a coating material that is optionally suitable for enteric dissolution, and processed into a coating preparation form that is more conducive to absorption by organisms (such as humans).
  • pharmaceutically acceptable salt refers to a salt of a compound that does not produce significant irritation to the administered organism and does not destroy the biological activity and properties of the compound.
  • the salt is an acid addition salt of the compound.
  • Pharmaceutical salts can be obtained by reacting compounds with inorganic acids such as hydrohalic acid (for example, hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid, and phosphoric acid.
  • Pharmaceutical salts can be obtained by reacting compounds with organic acids such as aliphatic or aromatic carboxylic acids or sulfonic acids, such as formic acid, acetic acid, succinic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, smoke Acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid or naphthalenesulfonic acid.
  • organic acids such as aliphatic or aromatic carboxylic acids or sulfonic acids, such as formic acid, acetic acid, succinic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, smoke Acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid or naphthalenesulfonic acid.
  • Pharmaceutical salts can also be obtained by reacting compounds with bases to form salts, such as ammonium salts, alkali metal salts such as sodium or potassium salts, alkaline earth metal salts such as calcium or magnesium salts, such as dicyclohexylamine, N- Methyl-D-glucosamine, tris(hydroxymethyl) methylamine, C 1 -C 7 alkylamine, cyclohexylamine, triethanolamine, ethylenediamine and organic base salts such as arginine and lysine Amino acid salt of amino acid.
  • salts such as ammonium salts, alkali metal salts such as sodium or potassium salts, alkaline earth metal salts such as calcium or magnesium salts, such as dicyclohexylamine, N- Methyl-D-glucosamine, tris(hydroxymethyl) methylamine, C 1 -C 7 alkylamine, cyclohexylamine, triethanolamine, ethylenediamine and organic base salts
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or/and liquid mass spectrometry (LC-MS).
  • NMR nuclear magnetic resonance
  • LC-MS liquid mass spectrometry
  • the NMR shift ( ⁇ ) is given in units of 10 -6 (ppm).
  • the measurement of NMR is performed with ZKNJ BIXI-1 (Wuhan Zhongke Oxford Spectroscopy Technology Co., Ltd.) 300MHz, BRUKER AVANCE III 400MHz, Bruker Avance Neo 400MHz or JEOL 400MHz nuclear magnetometer.
  • the liquid-mass spectrometry (LC-MS) measurement was performed with Waters H-class UPLC-SQD2, Agilent 1260/6120 or Agilent 1100.
  • the solvent for NMR measurement is deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), and the internal standard is tetramethylsilane (TMS).
  • a suspension of sodium hydride (44mg, 60% purity) in dimethyl sulfoxide (5mL) was stirred at 80°C for 1 hour, then cooled to 5°C, and bromine (5-chloro-2-methyl-3-nitro Benzyl)triphenylphosphorane (527mg, 1.0mmol), stirred for 10 minutes, then added tert-butyl 4-oxopiperidine-1-carboxylate (200mg, 1.0mmol), stirred for 1 hour at room temperature, and reacted The solution was slowly warmed to 80°C and stirred overnight. The reaction was quenched slowly with water and extracted with ether.
  • 6-methylnicotinic acid (82mg, 0.6mmol) was dissolved in thionyl chloride (3mL), heated to 50°C, and stirred for 1 hour. Cool to room temperature and concentrate to obtain crude 6-methylnicotinoyl chloride, which was used directly in the next step.
  • 5-fluoro-6-methylnicotinic acid 54mg, 0.35mmol
  • 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate 159mg , 0.42mmol
  • N,N-diisopropylethylamine 0.2mL, 1.1mmol
  • 3-cyanobenzoic acid (104mg, 0.71mmol) was dissolved in thionyl chloride (4mL), and the reaction solution was stirred at 50°C for 6 hours under nitrogen protection. Concentrate to remove the solvent. The concentrated residue was dissolved in N,N-dimethylformamide (8 mL). Then add (4-(3-amino-5-chloro-2-methylbenzylidene) piperidin-1-yl) (cyclopentyl) ketone (100mg, 0.30mmol) and triethylamine (0.2 mL, 1.4mmol). Under the protection of nitrogen, the reaction mixture was stirred at 25°C for 1 hour.
  • Methyl 5-cyanonicotinate 50mg, 0.31mmol
  • (4-(3-amino-5-chloro-2-methylbenzylidene)piperidin-1-yl)(cyclopentyl)methanone 103mg, 0.31mmol
  • toluene 5mL
  • the reaction solution was cooled to 0°C and stirred under the protection of nitrogen, and then trimethylaluminum (0.31mL, 0.62mmol) solution was added.
  • the reaction mixture was stirred at 80°C for 3 hours.
  • the reaction was quenched with ammonium chloride solution and extracted with dichloromethane (20 mL ⁇ 3).
  • 6-Oxy-1,6-dihydropyridazine-4-carboxylic acid (1.0g, 7.1mmol) and potassium carbonate (4.9g, 35.4mmol) dissolved in N,N-dimethylformamide (30mL), nitrogen Under protection, iodomethane (5.2mL, 71.1mmol) was added to the reaction solution.
  • the reaction mixture was stirred at 50°C for 2 hours. Concentrate to remove the solvent N,N-dimethylformamide. Water was added to the concentrated residue and extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered.
  • Methyl 1-methyl-6-oxo-1,6-dihydropyridazine-4-carboxylate (414 mg, 2.5 mmol) was dissolved in methanol (20 mL), and then 40% sodium hydroxide solution (5 mL) was added. The reaction mixture was stirred at room temperature for 1 hour, and then adjusted to pH 3 with 1N hydrochloric acid solution. After concentration to remove methanol, water was added, and extraction was performed with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered.
  • reaction solution was concentrated, and the concentrated residue was purified by preparative high performance liquid chromatography to obtain N-(5-chloro-3-((1-(cyclopentylcarbonyl)piperidin-4-ylidene)methyl)-2-toluene (Yl)-4-cyanobenzamide 5mg, purity 95%, yield 4%, white solid.
  • Methyl 3-cyano-5-methoxybenzoate (83mg, 0.430mmol) and (4-(3-amino-5-chloro-2-methylbenzylidene)piperidin-1-yl) (ring Amyl) ketone (143 mg, 0.429 mmol) was dissolved in toluene (10 mL), and under the protection of nitrogen, a toluene solution of trimethyl aluminum (0.4 mL, 0.800 mmol) was slowly added at 0°C. The reaction solution was stirred at 80°C for 1 hour, and then cooled to room temperature. The reaction was quenched by adding 1mol/L hydrochloric acid at 0°C.
  • 1 H NMR 400MHz, DMSO-d 6 ): ⁇ 13.46 (s, 1H), 8.15 (d, 1H), 7.27 (s, 1H), 3.88 (s, 3H).
  • Methyl 6-oxy-1,6-dihydropyridazine-4-carboxylate (167mg, 1.1mmol), cyclopropylboronic acid (209mg, 2.4mmol), copper acetate (197mg, 1.1mmol), bipyridine (169mg, 1.1mmol) and sodium carbonate (260mg, 2.5mmol) were dissolved in 1,2-dichloroethane (15mL), and the reaction solution was stirred at 70°C overnight under nitrogen protection.
  • Methyl 3-cyano-2-fluorobenzoate 50mg, 0.28mmol
  • (4-(3-amino-5-chloro-2-methylbenzylidene)piperidin-1-yl) (cyclopentyl ) Methyl ketone dissolved in toluene (5mL), stirred at 0°C under nitrogen protection, and then added trimethylaluminum toluene solution (0.28mL, 0.56mmol) to the reaction solution.
  • the reaction mixture was stirred at 80°C for 3 hours. It was quenched with saturated ammonium chloride solution and extracted with dichloromethane (20 mL ⁇ 3).
  • Methyl 6-methoxypyridazine-4-carboxylate (crude product obtained in the previous step, 0.519mmol) and (4-(3-amino-5-chloro-2-methylbenzylidene)piperidin-1-yl ) (Cyclopentyl) ketone (150 mg, 0.450 mmol) was dissolved in 10 mL of toluene, and a toluene solution of trimethyl aluminum (0.6 mL, 1.20 mmol) was slowly added dropwise to it under nitrogen protection at 0°C. The reaction mixture was stirred at 80°C for 2 hours. After adding 10 mL of water to dilute the reaction solution, add 3 mL of 1 mol/L hydrochloric acid.
  • 6-cyano-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid methyl ester 50mg, 0.26mmol
  • (4-(3-amino-5-chloro-2-methyl Benzylidene) piperidin-1-yl) (cyclopentyl) ketone 87mg, 0.26mmol
  • toluene 5mL
  • trimethylaluminum 0.26mL, 0.52 mmol
  • Methyl 2-chlorothiazole-5-carboxylate 500mg, 2.8mmol
  • cyclopropyl acid 1.2g, 14mmol
  • [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride 228mg, 0.28mmol
  • potassium carbonate 1.16g, 8.4mmol
  • Methyl 2-cyclopropylthiazole-5-carboxylate 60mg, 0.33mmol
  • Methyl ketone 109 mg, 0.33 mmol
  • 5 mL of anhydrous toluene stirred at 0°C under nitrogen protection, and a toluene solution of trimethyl aluminum (0.33 mL, 0.66 mmol) was added to the reaction solution.
  • the reaction mixture was stirred at 80°C for 3 hours. It was quenched with ammonium chloride solution and extracted with dichloromethane (20 mL ⁇ 3).
  • Methyl 3-methoxybenzoate 50mg, 0.3mmol
  • (4-(3-amino-5-chloro-2-methylbenzylidene)piperidin-1-yl)(cyclopentyl)methanone 79mg, 0.237mmol
  • toluene 10mL
  • a toluene solution of trimethylaluminum 0.3mL, 0.6mmol
  • the reaction mixture was stirred at 80°C for 3 hours.
  • the reaction was quenched with ammonium chloride solution, and extracted with dichloromethane (20 mL ⁇ 3).
  • N-(5-chloro-2-methyl-3-(piperidin-4-ylidenemethyl)phenyl)-3-cyanobenzamide hydrochloride (0.30mmol), tetrahydro-2H-pyridine Pyran-4-carboxylic acid (39mg, 0.30mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (114mg, 0.3mmol) )
  • N,N-dimethylformamide (3mL) was dissolved in N,N-dimethylformamide (3mL), and triethylamine (0.3mL) was added to the reaction solution.
  • the reaction mixture was stirred at 40°C for 2 hours under the protection of nitrogen.
  • N-(5-Chloro-2-methyl-3-(piperidin-4-ylidenemethyl)phenyl)-3-cyanobenzamide hydrochloride (0.22mmol), cyclopropylacetic acid (0.5 mL, 0.55mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (92mg, 0.24mmol) dissolved in N,N- Dimethylformamide (3mL), triethylamine (0.3mL) was added to the reaction solution. The reaction mixture was stirred at 40°C for 2 hours under the protection of nitrogen.
  • N-(5-chloro-2-methyl-3-(piperidin-4-ylidenemethyl)phenyl-3-cyanobenzamide 50mg, 0.14mmol
  • 3,3-difluorocyclopenta Carboxylic acid 42mg, 0.28mmol
  • 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate 53mg, 0.14mmol
  • N , N-Dimethylformamide (3mL) add triethylamine (0.1mL) to the reaction solution.
  • the reaction mixture was stirred at room temperature under nitrogen protection for 2 hours.
  • reaction solution was concentrated, and the concentrated residue was purified by preparative high performance liquid chromatography N-(5-chloro-3-((1-(3,3-difluorocyclopentylcarbonyl)piperidin-4-ylidene)methyl)-2-tolyl)-3-cyanobenzyl Amide 20mg, purity 95%, yield 29%, white solid.
  • N-(5-Chloro-2-methyl-3-(piperidin-4-ylidenemethyl)phenyl)-3-cyanobenzamide (50mg, 0.14mmol), bicyclo[3.1.0] Hexane-3-carboxylic acid (35mg, 0.28mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (53mg, 0.14mmol) )
  • N,N-dimethylformamide (3mL) N,N-dimethylformamide (3mL)
  • triethylamine 0.1mL
  • reaction solution was concentrated, and the concentrated residue was purified by preparative high performance liquid chromatography to obtain white solid N-(3-((1-(Bicyclo[3.1.0]hexane-3-carbonyl)piperidin-4-ylidene) Methyl)-5-chloro-2-tolyl-3-cyanobenzamide 20mg, purity 95%, yield 30%.
  • N-(5-Chloro-2-methyl-3-(piperidin-4-ylidenemethyl)phenyl)-3-cyanobenzamide 70mg, 0.19mmol
  • 3,3-difluoro ring Butyl formic acid 51mg, 0.38mmol
  • 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate 80mg, 0.21mmol
  • N,N-dimethylformamide 3mL
  • triethylamine 0.1mL
  • reaction solution was concentrated, and the concentrated residue was purified by preparative high performance liquid chromatography to obtain N-(5-chloro-3-((1-(3,3-difluorocyclobutylcarbonyl)piperidin-4-ylidene)methyl 2-methylphenyl)-3-cyanobenzamide 35mg, purity 95%, yield 38%, white solid.
  • N-(5-chloro-2-methyl-3-(piperidin-4-ylidenemethyl)phenyl)-3-cyanobenzamide 60mg, 0.16mmol
  • 2-(bicyclo[1.1 .1]Pentan-1-yl)acetic acid 40mg, 0.32mmol
  • triethylamine 0.1mL
  • the reaction mixture was added with 2-(7- Nitrobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (61 mg, 0.16 mmol).
  • the reaction mixture was stirred at 50°C for 1.5 hours under nitrogen protection.
  • reaction solution was concentrated, and the concentrated residue was purified by preparative high performance liquid chromatography to obtain N-(3-((1-(2-(bicyclo[1.1.1]pentane-1-yl)acetyl)piperidine-4 -Ylidene)methyl)-5-chloro-2-tolyl)-3-cyanobenzamide 30mg, purity 95%, yield 39%, white solid.
  • Methyl 6-cyano-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxylate (300mg, 1.56mmol) and 4-(3-amino-5-chloro-2-methyl Tert-butyl benzyl)piperidine-1-carboxylate (525 mg, 1.56 mmol) was dissolved in toluene (10 mL), and stirred at 0°C under nitrogen protection. Then added trimethylaluminum toluene solution (1.56 mL, 3.12 mmol). The reaction solution was stirred at 80°C for 3 hours. The reaction was quenched with ammonium chloride solution and extracted with dichloromethane (20 mL ⁇ 5). The organic phases were combined and concentrated.
  • N-(5-Chloro-2-methyl-3-(piperidin-4-ylidenemethyl)phenyl)-6-cyano-1-methyl-2-oxo-1,2-dihydropyridine -4-carboxamide (100mg, 0.27mmol), 2-(bicyclo[1.1.1]pentan-1-yl)acetic acid (60mg, 0.54mmol), 2-(7-azobenzotriazole) -N,N,N',N'-tetramethylurea hexafluorophosphate (308mg, 0.81mmol) and triethylamine (0.22mL, 0.81mmol) dissolved in N,N-dimethylformamide (3mL) , Stir at room temperature overnight.
  • reaction solution was purified by preparative high performance liquid chromatography to obtain N-(3-((1-(2-(bicyclo[1.1.1]pentan-1-yl)acetyl)piperidine-4- Subunit) methyl)-5-chloro-2-tolyl)-6-cyano-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxamide 36mg, purity 95%, yield The rate is 26%, white solid.
  • reaction solution was purified by preparative high performance liquid chromatography to obtain N-(5-chloro-3-((1-(4,4-difluorocyclohexylcarbonyl)piperidin-4-ylidene)methyl) -2-tolyl)-6-cyano-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxamide 5 mg, purity 94%, yield 7%, white solid.
  • N-(5-Chloro-2-methyl-3-(piperidin-4-ylidenemethyl)phenyl)-3-cyanobenzamide 60mg, 0.16mmol
  • 4,4-difluoro ring Hexylformic acid 53mg, 0.32mmol
  • triethylamine 0.1mL
  • 2-(7-azobenzotriazole)-N was added to the reaction solution ,N,N',N'-Tetramethylurea hexafluorophosphate (61mg, 0.16mmol).
  • the reaction mixture was stirred at 50°C for 1 hour under nitrogen protection.
  • reaction solution was concentrated, and the concentrated residue was purified by preparative high performance liquid chromatography to obtain N-(5-chloro-3-((1-(4,4-difluorocyclohexylcarbonyl)piperidin-4-ylidene)methyl )-2-Tolyl)-3-cyanobenzamide 20mg, purity 95%, yield 24%, white solid.
  • N-(5-Chloro-2-methyl-3-(piperidin-4-ylidenemethyl)phenyl)-3-cyanobenzamide (150mg, 0.41mmol), potassium carbonate (171mg, 1.23mmol) ) was dissolved in acetonitrile (12 mL), and thiophene-2-carbonyl chloride (180 mg, 1.23 mmol) was added to the reaction solution. The reaction mixture was stirred overnight at room temperature under nitrogen protection. Water was added to the reaction solution and extracted with ethyl acetate. The organic phases were combined and concentrated.
  • N-(5-Chloro-2-methyl-3-(piperidin-4-ylidenemethyl)phenyl)-6-cyano-1-methyl-2-oxo-1,2-dihydropyridine -4-carboxamide (110mg, 0.27mmol), 2-cyclobutylacetic acid (0.03mL, 0.33mmol), 2-(7-azobenzotriazole)-N,N,N',N'- Tetramethylurea hexafluorophosphate (188mg, 0.50mmol) and triethylamine (0.12mL, 0.81mmol) were dissolved in N,N-dimethylformamide (3mL) and stirred at room temperature overnight.
  • reaction solution was purified by preparative high performance liquid chromatography to obtain N-(5-chloro-3-((1-(2-cyclobutylacetyl)piperidin-4-ylidene)methyl)-2 -Tolyl)-6-cyano-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxamide 12 mg, purity 95%, yield 9%, white solid.
  • Methyl 5-cyanonicotinate (100mg, 0.62mmol) and tert-butyl 4-(3-amino-5-chloro-2-methylbenzylidene)piperidine-1-carboxylate (207mg, 0.62mmol) are dissolved in 10mL of toluene, stirred at 0°C under nitrogen protection, and then added a toluene solution of trimethylaluminum (0.62mL, 1.24mmol). The reaction mixture was stirred at 80°C for 3 hours. The reaction was quenched with ammonium chloride solution and extracted with dichloromethane (20 mL ⁇ 3).
  • N-(5-Chloro-2-methyl-3-(piperidin-4-ylidenemethyl)phenyl)-5-cyanonicotinamide (110mg, 0.237mmol), 2-cyclopropylacetic acid (24mg ,0.240mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (108mg, 0.284mmol) and N,N-diiso Propylethylamine (0.2mL) was dissolved in N,N-dimethylformamide (6mL) and stirred at room temperature for 2 hours. The reaction solution was concentrated.
  • N-(5-Chloro-2-methyl-3-(piperidin-4-ylidenemethyl)phenyl)-6-cyano-1-methyl-2-oxo-1,2-dihydropyridine -4-carboxamide 80mg crude product, 0.2mmol
  • 2-cyclopropylacetic acid 24mg, 0.24mmol
  • 2-(7-azobenzotriazole)-N,N,N',N'- Tetramethylurea hexafluorophosphate 137mg, 0.36mmol
  • triethylamine 0.1mL, 0.6mmol
  • reaction solution was concentrated, and the concentrated residue was purified by preparative high performance liquid chromatography to obtain N-(5-chloro-2-methyl-3-((1-(3,3,3-trifluoropropionyl)piperidine-4) -Subunit)methyl)phenyl)-6-cyano-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxamide 60mg, purity 95%, yield 47%, white solid.
  • N-(5-Chloro-2-methyl-3-(piperidin-4-ylidenemethyl)phenyl)-6-cyano-1-methyl-2-oxo-1,2-dihydropyridine -4-formamide hydrochloride (100mg, 0.25mmol), tetrahydrofuran-3-carboxylic acid (58mg, 0.5mmol), triethylamine (0.2mL) dissolved in N,N-dimethylformamide (3mL), 0
  • 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (96mg, 0.25mmol) at°C. The reaction solution was stirred at room temperature for 1.5 hours.
  • N-(5-Chloro-2-methyl-3-(piperidin-4-ylidenemethyl)phenyl)-6-cyano-1-methyl-2-oxo-1,2-dihydropyridine -4-carboxamide hydrochloride (100mg, 0.25mmol), 3,3-dimethylcyclobutyl carboxylic acid (32mg, 0.25mmol) and triethylamine (77mg, 0.76mmol) dissolved in N,N-dimethyl Methyl formamide (5 mL), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (144mg, 0.38mmol) was added at 0°C.
  • N-(5-Chloro-2-methyl-3-(piperidin-4-ylidenemethyl)phenyl)-6-cyano-1-methyl-2-oxo-1,2-dihydropyridine -4-carboxamide hydrochloride 100mg, 0.25mmol
  • 1-fluorocyclopentyl carboxylic acid 33mg, 0.25mmol, 1eq
  • triethylamine 77mg, 0.76mmol
  • 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate 144mg, 0.38mmol, 1.5eq
  • N-(5-Chloro-2-methyl-3-(piperidin-4-ylidenemethyl)phenyl)-6-cyano-1-methyl-2-oxo-1,2-dihydropyridine -4-formamide hydrochloride 100mg, 0.25mmol
  • 3,3-difluorocyclopentyl carboxylic acid 38mg, 0.25mmol, 1eq
  • triethylamine 77mg, 0.76mmol
  • N, N-di Methylformamide 5 mL
  • 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate 144mg, 0.38mmol
  • N-(5-Chloro-2-methyl-3-(piperidin-4-methylene)phenyl)-6-cyano-1-methyl-2-oxo-1,2-dihydropyridine -4-formamide hydrochloride 100mg, 0.25mmol
  • triethylamine 0.1mL
  • isobutyryl chloride 0.03mL, 0.3mmol
  • N-(5-Chloro-2-methyl-3-(piperidin-4-methylene)phenyl)-6-cyano-1-methyl-2-oxo-1,2-dihydropyridine -4-formamide hydrochloride 100mg, 0.25mmol
  • potassium carbonate 17.3mg, 1.25mmol
  • 3-methylbutyryl chloride 60mg, 0.5mmol was added at 0°C.
  • the reaction solution was stirred at 0°C for half an hour.
  • reaction solution was concentrated, and the concentrated residue was purified by preparative high performance liquid chromatography to obtain N-(5-chloro-2-methyl-3-((1-(3-methylbutyryl)piperidine-4-methylene) )Phenyl)-6-cyano-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxamide 60mg, purity 95%, yield 50%, white solid.
  • 2-fluoro-2-methylpropionic acid (30mg, 0.28mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate ( 106mg, 0.28mmol) and triethylamine (70mg, 0.69mmol) were dissolved in dichloromethane (2mL) and stirred at room temperature for 10 minutes. Then add N-(5-chloro-2-methyl-3-(piperidine-4-methylene)phenyl)-6-cyano-1-methyl-2-oxo-1,2-di Hydropyridine-4-carboxamide hydrochloride (100 mg, 0.23 mmol) was stirred at room temperature for one hour.
  • reaction solution was concentrated, and the concentrated residue was purified by preparative high performance liquid chromatography to obtain N-(5-chloro-3-((1-(cyclobutylcarbonyl)piperidin-4-ylidene)methyl)-2-methyl (Phenyl)-6-cyano-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxamide 88 mg, purity 95%, yield 73%, white solid.
  • Ethyl 5-cyano-2-hydroxy-6-methylnicotinate (2g, 9.7mmol) was dissolved in phosphorus oxychloride (15mL), and stirred at 106°C overnight. After the completion of the reaction, it was concentrated to remove phosphorus oxychloride, and the concentrated residue was diluted with water and extracted with dichloromethane (20 mL ⁇ 4). The organic phases were combined, concentrated, and dried in vacuo to obtain crude 2-chloro-5-cyano-6-methylnicotinic acid ethyl ester as a red oil.
  • Ethyl 2-chloro-5-cyano-6-methylnicotinate (2.79g, 12.5mmol) was dissolved in methanol (50mL), ammonium formate (12g, 18.8mmol) and Pd/C (1g) were added to the reaction solution .
  • the reaction mixture was stirred at room temperature for 3 hours.
  • the reaction solution was filtered, and the filtrate was concentrated.
  • the concentrated residue was diluted with water and extracted with dichloromethane (50 mL ⁇ 3).
  • N-(5-Chloro-2-methyl-3-(piperidin-4-ylidenemethyl)phenyl)-5-cyano-6-methylnicotinamide 38mg, 0.29mmol
  • 1-fluoro Cyclopentyl carboxylic acid 38mg, 0.29mmol
  • 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate 109mg, 0.29mmol
  • Dissolve in N,N-dimethylformamide (3mL) add triethylamine (0.1mL, 0.78mmol) at 0°C. The reaction solution was stirred at room temperature for 2.5 hours.
  • N-(5-chloro-2-methyl-3-(piperidine-4-methylene)phenyl)-5-cyano-6-methylnicotinamide 100mg, 0.26mmol
  • triethylamine 0.1 mL
  • dichloromethane 5 mL
  • isobutyryl chloride 0.03 mL, 0.31 mmol
  • reaction mixture was concentrated, and the concentrated residue was purified by preparative high performance liquid chromatography to obtain N-(5-chloro-3-((1-isobutyrylpiperidin-4-ylidene)methyl)-2-tolyl) -5-cyano-6-methylnicotinamide 39mg, purity 95%, yield 33%, white solid.
  • 4,4-Difluoropiperidine hydrochloride (88mg, 0.56mmol) was dissolved in dichloromethane (1mL), and triethylamine (70mg, 0.70mmol) was added.
  • Triphosgene (166mg, 0.56mmol) was added at 0°C under nitrogen protection, and stirred for 20 minutes.
  • N-(5-chloro-2-methyl-3-(piperidin-4-ylidenemethyl)phenyl)-6-cyano-1-methyl-2-oxo-1,2-dihydro Pyridine-4-carboxamide hydrochloride 120 mg, 0.28 mmol was dissolved in dichloromethane (1 mL), and triethylamine (71 mg, 0.70 mmol) was added. Then, this mixed solution was added dropwise to the previous reaction solution at 0°C and stirred at room temperature for 3 hours. The reaction was quenched with water and extracted with dichloromethane (10 mL ⁇ 3). The organic phases were combined, dried over anhydrous sodium sulfate and concentrated.
  • N-(5-Chloro-2-methyl-3-(piperidin-4-ylidenemethyl)phenyl)-3-cyanobenzamide hydrochloride (100mg, 0.249mmol) and triphosgene (37mg, 0.125mmol) was dissolved in dichloromethane (12mL). Under nitrogen protection, triethylamine (0.2mL, 1.42mmol) was slowly added to the reaction solution at 0°C, followed by stirring for 30 minutes. Then 3,3-difluoropyrrole hydrochloride (36 mg, 0.251 mmol) was added, and the mixture was stirred at room temperature for 1 hour.
  • N-(5-Chloro-2-methyl-3-(piperidin-4-ylidenemethyl)phenyl)-3-cyanobenzamide 60mg, 0.16mmol
  • isopropoxy acid chloride 39mg ,0.32mmol
  • triethylamine 0.1mL
  • reaction solution was concentrated, and the concentrated residue was purified by preparative high performance liquid chromatography to obtain 4-(5-chloro-3-(3-cyanobenzamide)-2-methylbenzylidene)piperidine-1-carboxylic acid isoform Propyl ester 30mg, purity 95%, yield 42%, white solid.
  • reaction solution was concentrated, and the concentrated residue was purified by preparative high performance liquid chromatography to obtain 1-(5-chloro-3-((1-(cyclopentylcarbonyl)piperidin-4-ylidene)methyl)-2-toluene Yl)-3-(pyridin-2-yl)urea 25mg, purity 95%, yield 19%, off-white solid.
  • 6-cyano-1-ethyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid methyl ester (366mg, 1.78mmol) was dissolved in toluene (20mL), under nitrogen protection, slowly added three A toluene solution of methyl aluminum (2.4 mL, 4.80 mmol). Then tert-butyl 4-(3-amino-5-chloro-2-methylbenzylidene) piperidine-1-carboxylate (598 mg, 1.78 mmol) was added, and the reaction solution was stirred at 80°C for 4 hours, and then cooled At room temperature, hydrochloric acid (15mL, 1mol/L) was added to quench the reaction.
  • N-(5-Chloro-2-methyl-3-(piperidin-4-ylidenemethyl)phenyl)-5-cyano-6-methylnicotinamide 100mg, 0.26mmol
  • 2-ring Propyl acetic acid 52mg, 0.52mmol
  • 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate 109mg, 0.286mmol
  • N,N-dimethylformamide (3mL) triethylamine (0.1mL) was added to the reaction solution.
  • the reaction mixture was stirred at 50°C for 1 hour under the protection of nitrogen.
  • reaction solution was concentrated, and the concentrated residue was purified by silica gel column chromatography (100% ethyl acetate) to obtain N-(5-chloro-3-((1-(2-cyclopropaneacetyl)piperidin-4-ylidene group) )Methyl)-2-methylphenyl)-5-cyano-6-methylnicotinamide 80mg, purity 95%, yield 66%, white solid.
  • reaction solution was concentrated, and the concentrated residue was purified by silica gel column chromatography (100% ethyl acetate) to obtain N-(5-chloro-3-((1-(2-cyclobutylacetyl)piperidine-4-ylidene) (Yl)methyl)-2-methylphenyl)-5-cyano-6-methylnicotinamide 70mg, purity 95%, yield 56%, white solid.
  • reaction solution was concentrated, and the concentrated residue was purified by preparative high performance liquid chromatography to obtain N-(5-chloro-3-((1-(4,4-difluorocyclohexylcarbonyl)piperidin-4-ylidene)methyl )-2-Methylphenyl)-5-cyano-6-methylnicotinamide 60mg, purity 95%, yield 44%, white solid.
  • Methyl 2-chloro-6-methoxyisonicotinate (209mg, 1.04mmol) and sodium iodide (476mg, 3.18mmol) were dissolved in thionyl chloride (8mL) and added to the reaction solution under nitrogen protection at 0°C Trimethylchlorosilane (0.4 mL, 3.16 mmol) was added dropwise. The reaction mixture was stirred at 80°C for 4 hours and then cooled to room temperature. The reaction was quenched with 10 mL of water. The organic phase was washed with saturated sodium thiosulfate, dried over anhydrous sodium sulfate, and concentrated.
  • 6-Chloro-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid methyl ester (57mg, 0.284mmol) and (4-(3-amino-5-chloro-2-methyl Benzyl)piperidin-1-yl)(cyclopentyl)methanone (94mg, 0.282mmol) was dissolved in toluene (10mL), and under nitrogen protection, slowly added trimethylaluminum (0.3mL, 0.600mmol). The reaction solution was stirred at 80°C overnight, and then cooled to room temperature. The reaction was quenched with hydrochloric acid (1mol/L, 5mL). Extract with ethyl acetate (10 mL ⁇ 2).
  • 1 HNMR 400MHz, DMSO-d 6 ): ⁇ 13.47 (brs, 1H), 8.16-8.15 (m, 1H), 7.27 (d, 1H), 3.88 (s, 3H).
  • Methyl 6-oxy-1,6-dihydropyridazine-4-carboxylate 45mg, 0.292mmol
  • (4-(3-amino-5-chloro-2-methylbenzylidene)piperidine-1- (Cyclopentyl) ketone 98mg, 0.294mmol
  • toluene 10mL
  • trimethylaluminum toluene solution 0.600mmol
  • Methyl 2-cyano-6-methoxyisonicotinate 50mg mg, 0.262mmol
  • (4-(3-amino-5-chloro-2-methylbenzylidene)piperidin-1-yl) (Cyclopentyl) ketone 87mg, 0.261mmol
  • toluene 5mL
  • trimethylaluminum toluene solution 0.2mL, 0.400mmol
  • Methyl 2-cyano-6-methoxyisonicotinate (4.9g, 25.6mmol) and sodium iodide (12.0g, 80.0mmol) were dissolved in acetonitrile (100mL), under nitrogen protection, slowly add trimethyl at 0°C Chlorosilane (10 mL, 78.9 mmol). The reaction mixture was stirred at 80°C for 4 hours and then cooled to room temperature. Water (100 mL) was added, the organic phase was separated, dried over anhydrous sodium sulfate, and concentrated.
  • Methyl 6-cyano-2-oxo-1,2-dihydropyridine-4-carboxylate (42mg, 0.237mmol) and (4-(3-amino-5-chloro-2-methylbenzylidene)piperidine Pyridin-1-yl)(cyclopentyl)methanone (79mg, 0.237mmol) was dissolved in toluene (10mL), and under nitrogen protection, the trimethylaluminum toluene solution (0.2mL, 0.400mmol) was slowly added at 0°C. The reaction mixture was stirred at 80°C for 3 hours and then cooled to room temperature.
  • hexamethyldisilazane lithium salt (1M, 11mL) was added dropwise to a suspension of bromomethyltriphenylphosphine bromide (4.8g, 11mmol) in tetrahydrofuran (11mL) under argon. After stirring for 15 minutes, tert-butyl 4-oxopiperidine-1-carboxylate (1.99 g, 10 mmol) was added at -15°C. After the reaction solution was stirred at room temperature for 2 hours, it was quenched with water, extracted with ethyl acetate (30 mL ⁇ 3), and the organic phase was washed with saturated brine, then dried with anhydrous sodium sulfate and concentrated.
  • reaction solution was cooled to zero degree, the reaction was quenched with potassium sodium tartrate solution, and extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The concentrated residue was purified by preparative high performance liquid chromatography to obtain 6-cyano-N-(5-fluoro-3-((1-isobutyrylpiperidin-4-ylidene)methyl)-2-methylbenzene (Yl)-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxamide 66 mg, purity 95%, yield 43%, white solid.

Abstract

公开了苯甲烯哌啶衍生物及其制备方法、中间体和用途。具体而言，本文涉及式(I)的化合物及其制备方法、用于制备式(I)化合物的中间体，及式(I)化合物在治疗和/或预防与RORγt异常激活相关的疾病中的用途。式(I)化合物可抑制RORγt蛋白受体，调控Th17细胞的分化，抑制IL-17的产生，故而可用作与RORγt异常激活相关的疾病的治疗药物。

Description

苯甲烯哌啶衍生物及其制备方法、中间体和用途 技术领域
本申请属于医药技术领域，涉及具有RORγt抑制活性的苯甲烯哌啶衍生物。
背景技术
自身免疫性疾病主要是由于免疫系统的失调，特别是T细胞的功能紊乱，导致免疫系统异常识别、攻击自身组织或抗原造成的。其它一些炎症性疾病，譬如过敏性疾病，主要是由于免疫系统对外来抗原的过度反应造成的。过去10多年来的研究表明，表达IL-17的细胞，特别是Th17细胞的过度反应能导致多种人类自身免疫性疾病，其中包括类风湿关节炎、强直性脊柱炎、银屑病(俗称牛皮藓)、多发性硬化症等(Dong,2014)。此外，有研究表明，Th17细胞在一些过敏性疾病中，特别是中性粒细胞富集型哮喘，也具有重要的病理作用(Chang et al.,2017)。有意思的是，研究还发现IL-17和表达IL-17的Th17细胞在多种癌症病人的肿瘤组织里富集(这些癌症包括结肠癌、肺癌、肝癌、乳腺癌、卵巢癌、胰腺癌、前列腺癌、黑色素瘤等)并可能在不同的条件下具有促进肿瘤或抗肿瘤等的作用(Asadzadeh et al.,2017)。因此，针对IL-17或Th17细胞的一些抑制剂或激动剂将不仅有可能用于治疗上述自身免疫性疾病或过敏性疾病，还可用于癌症的临床治疗。
Th17细胞是由董晨教授和Weaver教授等人在2005年发现的继Th1和Th2细胞之后的第三类辅助性CD4阳性T细胞。Th17细胞主要表达白细胞介素((IL))-17和IL-17F(Harrington et al.,2005；Park et al.,2005)，其中IL-17被认为是Th17细胞最主要的效应细胞因子。在正常情况下，Th17细胞能够通过分泌趋化因子和细胞因子以直接或间接的方式招募中性粒细胞、巨噬细胞等免疫细胞，抵御胞外细菌和真菌的感染，并通过调控黏膜屏障的完整性，在人体的粘膜免疫中具有重要的功能。而异常的、持续性的Th17细胞激活，则能导致相关组织和器官发生持续性的炎症反应，造成多种自身免疫性疾病并影响多种肿瘤的疾病进程(Asadzadeh et al.,2017)。
Th17细胞的分化和发育主要受一个关键的首要转录因子RORγt控制，RORγt主要通过结合到Th17细胞相关基因的位点直接调控包括IL-17和IL-17F等细胞因子的表达(Ivanov et al.,2006；Yang et al.,2008)。RORγt，也称为RORγ2，是孤儿受体RORγ的两个拼接体形式RORγ1和RORγ2之一，其中RORγ1在肌肉组合、肝脏、肾脏和胸腺组织中有一定的表达，而RORγt主要在免疫细胞中表达。研究发现，RORγt的基因缺陷，或者用小分子阻断RORγt的功能，能够导致Th17细胞的发育受阻和IL-17的表达缺陷，并对多种小鼠自身免疫性疾病模型产生抗性(不敏感)，这些疾病包括小鼠实验性自身免疫性脑脊髓炎(EAE)、关节炎、银屑样皮肤炎症等(Lai and Dong,2016)。近年来，已经有多个针对IL-17和IL-17受体的单克隆药物在多种人类自身免疫性疾病的临床实验中表现出良好的治疗效果，并且被欧、美、日等国家和地区批准用于治疗中度到重度银屑病、银屑样关节病、强直性脊柱炎等慢性炎症(Lai and Dong,2016)。但是，由于单克隆抗体药物价格高昂，市场 上急需价格低廉、疗效显著且能惠及大众病人的替代药物，因此，IL-17上游的关键转录因子RORγt也成为了治疗Th17相关疾病的一个重要热门药物靶点。
发明内容
本申请的一个或多个实施方案提供了苯甲烯哌啶衍生物。该苯甲烯哌啶衍生物可靶向RORγt，抑制RORγt的活性以及Th17细胞的分化发育和IL-17的表达，可用于治疗相关的自身免疫性疾病、炎症性疾病或癌症。
本申请的一个或多个实施方案提供了式(I)的化合物
Figure PCTCN2020085294-appb-000001
其中
X为
Figure PCTCN2020085294-appb-000002
R 1为氢、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、卤素或氰基；所述C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基各自独立地任选地被一个或多个选自C1-C6烷基、C1-C6卤代烷基、氰基、C1-C6烷氧基、C1-C6卤代烷氧基、C3-C7脂环烃基和3-7元杂环烷基的基团取代；
各个R 2独立地为C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、卤素或氰基；所述C1-C6烷基、C1-C6卤代烷基各自独立地任选地被一个或多个选自C1-C6烷基、C1-C6卤代烷基、氰基、C1-C6烷氧基、C1-C6卤代烷氧基、C3-C7脂环烃基和3-7元杂环烷基的基团取代；
R 3为C1-C6烷基、C1-C6烷氧基、C3-C7脂环烃基、3-7元含杂原子的脂环烃基、C5-C10芳基或5-10元杂芳基，其中所述C1-C6烷基、C1-C6烷氧基、C3-C7脂环烃基、3-7元含杂原子的脂环烃基、C5-C10芳基、5-10元杂芳基各自独立地任选地被一个或多个选自卤素、C1-C6烷基、C1-C6卤代烷基、氰基、酰基、羧基、羟基、C1-C6烷氧基、C1-C6卤代烷氧基、羰基、C3-C7脂环烃基、3-7元杂环烷基、磺酰基、C5-C10芳基和5-10元杂芳基的基团取代；
R 4为C1-C6烷基、C1-C6烷氧基、C3-C7脂环烃基、3-7元含杂原子的脂环烃基、C5-C10芳基或5-10元杂芳基，其中所述C1-C6烷基、C1-C6烷氧基、C3-C7脂环烃基、3-7元含杂原子的脂环烃基、C5-C10芳基、5-10元杂芳基各自独立地任选地被一个或多个选自卤素、C1-C6烷基、C1-C6卤代烷基、氨基、氰基、酰基、羧基、羟基、C1-C6烷氧基、C1-C6卤代烷氧基、羰基、C3-C7脂环烃基、3-7元杂环烷基、任选被C1-C3烷基取代的磺酰基、C5-C10芳基和5-10元杂芳基的基团取代；
m为0、1或2；
p为0或1；
或其立体异构体、对映异构体或互变异构体或其混合物，或其药物可接受的盐、溶剂化物或前药。
本申请的一个或多个实施方案提供了含有式(I)的化合物或该化合物的立体异构体、对映异构体或互变异构体或其混合物，或其药物可接受的盐、溶剂化物或前药的药物组合物。
本申请的一个或多个实施方案提供了式(I)的化合物或该化合物的立体异构体、对映异构体或互变异构体或其混合物，或其药物可接受的盐、溶剂化物或前药，或包含式(I)的化合物或该化合物的立体异构体、对映异构体或互变异构体或其混合物，或其药物可接受的盐、溶剂化物或前药的药物组合物用于预防和/或治疗疾病的用途。
本申请的一个或多个实施方案提供了式(I)的化合物或该化合物的立体异构体、对映异构体或互变异构体或其混合物，或其药物可接受的盐、溶剂化物或前药，或包含式(I)的化合物或该化合物的立体异构体、对映异构体或互变异构体或其混合物，或其药物可接受的盐、溶剂化物或前药的药物组合物用于制备RORγt受体抑制剂中的用途。
本申请的一个或多个实施方案提供了式(I)的化合物或该化合物的立体异构体、对映异构体或互变异构体或其混合物，或其药物可接受的盐、溶剂化物或前药，或包含式(I)的化合物或该化合物的立体异构体、对映异构体或互变异构体或其混合物，或其药物可接受的盐、溶剂化物或前药的药物组合物用于预防和/或治疗与RORγt受体异常激活相关疾病的用途。
本申请的一个或多个实施方案提供了式(I)的化合物或该化合物的立体异构体、对映异构体或互变异构体或其混合物，或其药物可接受的盐、溶剂化物或前药，或包含式(I)的化合物或该化合物的立体异构体、对映异构体或互变异构体或其混合物，或其药物可接受的盐、溶剂化物或前药的药物组合物在抑制RORγt受体中的用途。
本申请的一个或多个实施方案提供了式(I)的化合物或该化合物的立体异构体、对映异构体或互变异构体或其混合物，或其药物可接受的盐、溶剂化物或前药，或包含式(I)的化合物或该化合物的立体异构体、对映异构体或互变异构体或其混合物，或其药物可接受的盐、溶剂化物或前药的药物组合物，其用作药物。
本申请的一个或多个实施方案提供了式(I)的化合物或该化合物的立体异构体、对映异构体或互变异构体或其混合物，或其药物可接受的盐、溶剂化物或前药，或包含式(I)的化合物或该化合物的立体异构体、对映异构体或互变异构体或其混合物，或其药物可接受的盐、溶剂化物或前药的药物组合物，其用于制备RORyt受体抑制剂。
本申请的一个或多个实施方案提供了式(I)的化合物或该化合物的立体异构体、对映异构体或互变异构体或其混合物，或其药物可接受的盐、溶剂化物或前药，或包含式(I)的化合物或该化合物的立体异构体、对映异构体或互变异构体或其混合物，或其药物可接受的盐、溶剂化物或前药的药物组合物，其用于预防和/或治疗与RORyt受体异常激活相关疾病。
本申请的一个或多个实施方案提供了式(I)的化合物或该化合物的立体异构体、对映异构体或互变异构体或其混合物，或其药物可接受的盐、溶剂化物或前药，或包含式(I)的化合物或该化合物的立体异构体、对映异构体或互变异构体或其混合物，或其药物可接受的盐、溶剂化物或前药的药物组合物，其用于抑制RORyt受体。
本申请的一个或多个实施方案提供了预防和/或治疗疾病的方法，该方法包括向有此需要的个体提供式(I)的化合物或该化合物的立体异构体、对映异构体或互变异构体或其混合物，或其药物可接受的盐、溶剂化物或前药，或包含式(I)的化合物或该化合物的立体异构体、对映异构体或互变异构体或其混合物，或其药物可接受的盐、溶剂化物或前药的药物组合物。
本申请的一个或多个实施方案提供了预防和/或治疗与RORyt受体异常激活相关疾病的方法，该方法包括向有此需要的个体提供式(I)的化合物或该化合物的立体异构体、对映异构体或互变异构体或其混合物，或其药物可接受的盐、溶剂化物或前药，或包含式(I)的化合物或该化合物的立体异构体、对映异构体或互变异构体或其混合物，或其药物可接受的盐、溶剂化物或前药的药物组合物。
本申请的一个或多个实施方案提供了抑制RORyt受体的方法，该方法包括向有此需要的个体提供式(I)的化合物或该化合物的立体异构体、对映异构体或互变异构体或其混合物，或其药物可接受的盐、溶剂化物或前药，或包含式(I)的化合物或该化合物的立体异构体、对映异构体或互变异构体或其混合物，或其药物可接受的盐、溶剂化物或前药的药物组合物。
附图说明
图1：实施例4小鼠实验性自身免疫性脑脊髓炎(EAE)试验中，以10mg/kg小鼠体重施用化合物31后，小鼠的免疫接种天数对临床评分图。
图2：实施例4小鼠实验性自身免疫性脑脊髓炎(EAE)试验中，以30mg/kg小鼠体重施用化合物31后，小鼠的免疫接种天数对临床评分图。
图3：实施例4小鼠实验性自身免疫性脑脊髓炎(EAE)试验中，以100mg/kg小鼠体重施用化合物31后，小鼠的免疫接种天数对临床评分图。
具体实施方式
本申请的一个或多个实施方案提供了式(I)的化合物
Figure PCTCN2020085294-appb-000003
其中
X为
Figure PCTCN2020085294-appb-000004
R 1为氢、C1-C6烷基、C3-C7脂环烃基、C1-C6卤代烷基、C1-C6烷氧基、卤素或氰基；所述C1-C6烷基、C3-C7脂环烃基、C1-C6卤代烷基、C1-C6烷氧基、各自独立地任选地被一个或多个选自C1-C6烷基、C1-C6卤代烷基、氰基、C1-C6烷氧基、C1-C6卤代烷氧基、C3-C7脂环烃基、3-7元杂环烷基的基团取代；
各个R 2独立地为C1-C6烷基C1-C6卤代烷基、C3-C7脂环烃基、C1-C6烷氧基、卤素或氰基；所述C1-C6烷基、C3-C7脂环烃基、C1-C6卤代烷基、各自独立地任选地被一个或多个选自C1-C6烷基、C1-C6卤代烷基、氰基、C1-C6烷氧基、C1-C6卤代烷氧基、C3-C7脂环烃基、3-7元杂环烷基的基团取代；
R 3为C1-C6烷基、C1-C6烷氧基、C3-C7脂环烃基、3-7元含杂原子的脂环烃基、C5-C10芳基或5-10元杂芳基，其中所述C1-C6烷基、C1-C6烷氧基、C3-C7脂环烃基、3-7元含杂原子的脂环烃基、C5-C10芳基、5-10元杂芳基各自独立地任选地被一个或多个选自卤素、C1-C6烷基、C1-C6卤代烷基、氰基、酰基、羧基、羟基、C1-C6烷氧基、C1-C6卤代烷氧基、羰基、C3-C7脂环烃基、3-7元杂环烷基、磺酰基、C5-C10芳基和5-10元杂芳基的基团取代；
R 4为C1-C6烷基、C1-C6烷氧基、C3-C7脂环烃基、3-7元含杂原子的脂环烃基、C5-C10芳基或5-10元杂芳基，其中所述C1-C6烷基、C1-C6烷氧基、C3-C7脂环烃基、3-7元含杂原子的脂环烃基、C5-C10芳基、5-10元杂芳基各自独立地任选地被一个或多个选自卤素、C1-C6烷基、C1-C6卤代烷基、氨基、氰基、酰基、羧基、羟基、C1-C6烷氧基、C1-C6卤代烷氧基、羰基、C3-C7脂环烃基、3-7元杂环烷基、任选被C1-C3烷基取代的磺酰基、C5-C10芳基和5-10元杂芳基的基团取代；
m为0、1或23；
p为0或1；
或其立体异构体、对映异构体或互变异构体或其混合物，或其药物可接受的盐、溶剂化物或前药。
本申请的一个或多个实施方案中，X为
Figure PCTCN2020085294-appb-000005
本申请的一个或多个实施方案中，R 1为氢、C1-C6烷基、C3-C7脂环烃基、C1-C6卤代烷基、C1-C6烷氧基或卤素。本申请的一个或多个实施方案中，R 1为氢、C1-C6烷基或 卤素。本申请的一个或多个实施方案中，R 1为甲基或Cl。
本申请的一个或多个实施方案中，各个R 2独立地为C1-C6烷基、C3-C7脂环烃基、C1-C6卤代烷基、C1-C6烷氧基或卤素。本申请的一个或多个实施方案中，各个R 2独立地为卤素。本申请的一个或多个实施方案中，各个R 2独立地为F和Cl。本申请的一个或多个实施方案中，当m为1或2时，至少一个R 2位于R 1的对位。
本申请的一个或多个实施方案中，R 4为C3-C7脂环烃基、3-7元含杂原子的脂环烃基、C5-C10芳基或5-10元杂芳基；所述C3-C7脂环烃基、3-7元含杂原子的脂环烃基、C5-C10芳基或5-10元杂芳基各自独立地任选被一个或多个选自卤素、C1-C6烷基、C1-C6卤代烷基、氨基、氰基、酰基、羧基、羟基、C1-C6烷氧基、C1-C6卤代烷氧基、羰基、C3-C7脂环烃基、3-7元含杂原子的脂环烃基和任选被C1-C3烷基取代的磺酰基的基团取代。
本申请的一个或多个实施方案中，R 4为3-7元含杂原子的脂环烃基、C5-C10芳基或5-10元杂芳基，所述3-7元含杂原子的脂环烃基、C5-C10芳基或5-10元杂芳基任选被一个或多个选自卤素、C1-C6烷基、氰基、C1-C6烷氧基、羰基、C3-C7脂环烃基和任选被C1-C3烷基取代的磺酰基的基团取代。
本申请的一个或多个实施方案中，R 4为任选被F、Cl、C1-C3烷基和氰基中的一个或多个基团取代的
Figure PCTCN2020085294-appb-000006
C5-C10芳基或5-10元杂芳基。
本申请的一个或多个实施方案中，R 4为优选地R 4为任选被F、Cl、C1-C3烷基和氰基中的一个或多个基团取代的
Figure PCTCN2020085294-appb-000007
C5-C10芳基或5-10元杂芳基。
本申请的一个或多个实施方案中，R 4为
Figure PCTCN2020085294-appb-000008
Figure PCTCN2020085294-appb-000009
本申请的一个或多个实施方案中，R 3为C1-C6烷基、C1-C6烷氧基、C3-C7环烷基、3-7元杂环烷基或5-10元杂芳基；所述C1-C6烷基、C1-C6烷氧基、C3-C7脂环烃基、3-7元杂环烷基或5-10元杂芳基任选地被卤素、C1-C6卤代烷基、C1-C6烷氧基、C1-C6卤代烷氧基、或C1-C6烷基取代。
本申请的一个或多个实施方案中，R 3为C1-C4烷基、C3-C6环烷基、3-7元杂环烷基或5-6元杂芳基；所述C1-C4烷基、C3-C6环烷基、3-7元杂环烷基或5-6元杂芳基任选被氟、C1-C3氟代烷基、C1-C6烷氧基、C1-C3氟代烷氧基、或C1-C6烷基取代。
本申请的一个或多个实施方案中，R 3为
Figure PCTCN2020085294-appb-000010
Figure PCTCN2020085294-appb-000011
本申请的一个或多个实施方案中，R 1为C1-C6烷基；R 2为卤素；R 3为任选被卤素取代的C1-C6烷基或C3-C7脂环烃基；X为
Figure PCTCN2020085294-appb-000012
R 4为任选被卤素、C1-C6烷基和氰基中的一个或多个基团取代的C5-C10芳基或5-10元杂芳基；m为1；p为0或1。
本申请的一个或多个实施方案中，R 1为甲基；R 2为Cl或F；R 3为任选被一个或多个F取代的异丙基、环丙基、环戊基或环己基；X为
Figure PCTCN2020085294-appb-000013
R 4为任选被F、甲基和氰基中的一个或多个基团取代的苯基、吡啶基或
Figure PCTCN2020085294-appb-000014
m为1；p为0或1；
本申请的一个或多个实施方案中，R 1为甲基；R 2为Cl或F；R 3为任选被一个或两个F取代的异丙基、环丙基、环戊基或环己基；X为
Figure PCTCN2020085294-appb-000015
R 4为任选被一个F、甲基和氰基取代的吡啶基或
Figure PCTCN2020085294-appb-000016
m为1；p为0或1。
在本申请的一个或多个实施方案中，式(I)化合物的结构为：
Figure PCTCN2020085294-appb-000017
其中X、R 1、R 2和R 3如上文所定义。
本申请的一个或多个实施方案提供了如下化合物或其立体异构体、对映异构体或互变异构体或其混合物，或其药物可接受的盐、溶剂化物或前药，它们的结构如表1中所示：
化合物1
N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-6-甲基烟酰胺
化合物2
N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-5-氟-6-甲基烟酰胺
化合物3
N-(5-氯-3((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-3-氰基苯甲酰胺
化合物4
N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-2-甲基异烟酰胺
化合物5
N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-5-氰基烟酰胺
化合物6
N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-1-甲基-6-氧-1,6-二氢哒嗪-4-酰胺
化合物7
N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-4-氰基苯甲酰胺
化合物8
N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-3-氰基-5-羟基苯甲酰胺
化合物9
N-(5-氯3-((1-(环戊基羰基)哌啶-4-亚基)甲基-2-甲苯基)-1-乙基-6-氧-1,6-二氢哒嗪-4-甲酰胺
化合物10
N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-1-环丙基-6-氧-1,6-二氢哒嗪-4-甲酰胺
化合物11
N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)咪唑[1,2-a]吡啶-7-甲酰胺
化合物12
N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-[1,2,4]三唑[1,5-a]吡啶-7-甲酰胺
化合物13
N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-2-环丙基嘧啶-5-甲酰胺
化合物14
N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-5-氰基-2-氟苯甲酰胺
化合物15
N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-3-氰基-2-氟苯甲酰胺
化合物16
N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-3-(甲磺酰基)苯甲酰胺
化合物17
N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-6-甲氧基哒嗪-4-甲酰胺
化合物18
N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-6-氰基-1-甲基-2-氧-1,2-二氢吡啶-4-甲酰胺
化合物19
N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-2-环丙基噻唑-5-甲酰胺
化合物20
N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-1-环丙基-1H-吡唑-4-甲酰胺
化合物21
N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-3-甲氧基苯甲酰胺
化合物22
N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-3-甲氧基环丁基酰胺
化合物23
N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-3-苯基丙酰胺
化合物24
N-(5-氯-2-甲基-3-((1-(四氢-2H-吡喃-4-羰基)哌啶-4-亚基)甲基)苯基)3-氰基苯甲酰胺
化合物25
N-(5-氯-3-((1-(2-环丙基乙酰)哌啶-4-亚基)甲基)-2-甲苯基)-3-氰基苯甲酰胺
化合物26
N-(5-氯-3-((1-(3,3-二氟环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-3-氰基苯甲酰胺
化合物27
N-(3-((1-(二环[3.1.0]正己烷-3-羰基)哌啶-4-亚基)甲基)-5-氯-2-甲苯基)-3-氰基苯甲酰胺
化合物28
N-(5-氯-3-((1-(3,3-二氟环丁基羰基)哌啶-4-亚基)甲基-2-甲苯基)-3-氰基苯甲酰胺
化合物29
N-(3-((1-(2-(二环[1.1.1]戊烷-1-基)乙酰基)哌啶-4-亚基)甲基)-5-氯-2-甲苯基)-3-氰基苯甲酰胺
化合物30
N-(3-((1-(2-(二环[1.1.1]戊烷-1-基)乙酰基)哌啶-4-亚基)甲基)-5-氯-2-甲苯基)-6-氰基-1-甲基-2-氧-1,2-二氢吡啶-4-甲酰胺
化合物31
N-(5-氯-3-((1-(4,4-二氟环己基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-6-氰基-1-甲基-2-氧-1,2-二氢吡啶-4-甲酰胺
化合物32
N-(5-氯-3-((1-(4,4-二氟环己基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-3-氰基苯甲酰胺
化合物33
N-(5-氯-2-甲基-3-((1-(噻吩-2-羰基)哌啶-4-亚基)甲基)苯基)-3-氰基苯甲酰胺
化合物34
N-(5-氯-3-((1-(2-环丁基乙酰基)哌啶-4-亚基)甲基)-2-甲苯基)-6-氰基-1-甲基-2-氧-1,2-二氢吡啶-4-甲酰胺
化合物35
N-(5-氯-3-((1-(2-环丙基乙酰基)哌啶-4-亚基)甲基)-2-甲苯基)-5-氰基烟酰胺
化合物36
N-(5-氯-3-((1-(2-环丙基乙酰基)哌啶-4-亚基)甲基)-2-甲苯基)-6-氰基-1-甲基-2-氧-1,2-二氢吡啶-4-甲酰胺
化合物37
5-氯-N-(5-氯-3-((1-(2-环丙基乙酰基)哌啶-4-亚基)甲基)-2-甲苯基)-6-甲基烟酰胺
化合物38
N-(5-氯-2-甲基-3-((1-(3,3,3-三氟丙酰基)哌啶-4-亚基)甲基)苯基)-6-氰基-1-甲基-2-氧代-1,2-二氢吡啶-4-甲酰胺
化合物39
N-(5-氯-2-甲基-3-((1-(四氢呋喃-3-羰基)哌啶-4-亚基)甲基)苯基)-6-氰基-1-甲基-2-氧-1,2-二氢吡啶-4-甲酰胺
化合物40
N-(5-氯-3-((1-(3,3-二甲基环丁基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-6-氰基-1-甲基-2-氧-1,2-二氢吡啶-4-甲酰胺
化合物41
N-(5-氯-3-((1-(1-氟代环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-6-氰基-1-甲基-2-氧-1,2-二氢吡啶-4-甲酰胺
化合物42
N-(5-氯-3-((1-(3,3-二氟环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-6-氰基-1-甲基-2-氧-1,2-二氢吡啶-4-甲酰胺
化合物43
(R)-N-(5-氯-3-((1-(3,3-二氟环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-6-氰基-1-甲基-2-氧-1,2-二氢吡啶-4-甲酰胺
化合物44
(S)-N-(5-氯-3-((1-(3,3-二氟环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-6-氰基-1-甲基-2-氧-1,2-二氢吡啶-4-甲酰胺
化合物45
N-(5-氯-2-甲基-3-((1-(四氢呋喃-2-羰基)哌啶-4-亚基)甲基)-2-甲苯基)-6-氰基-1-甲基-2-氧-1,2-二氢吡啶-4-甲酰胺
化合物46
N-(5-氯-3-((1-异丁酰基哌啶-4-亚基)甲基)-2-甲苯基)-6-氰基-1-甲基-2-氧代-1,2-二氢吡 啶-4-甲酰胺
化合物47
N-(5-氯-2-甲基-3-((1-(3-甲基丁酰基)哌啶-4-亚基)苯基)-6-氰基-1-甲基-2-氧代-1,2-二氢吡啶-4-甲酰胺
化合物48
N-(5-氯-3-((1-(2-氟-2-甲基丙酰基)哌啶-4-亚基)甲基)-2-甲苯基)-6-氰基-1-甲基-2-氧代-1,2-二氢吡啶-4-甲酰胺
化合物49
N-(5-氯-3-((1-(环丁基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-6-氰基-1-甲基-2-氧代-1,2-二氢吡啶-4-甲酰胺
化合物50
N-(5-氯-3-((1-(1-氟环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-5-氰基-6-甲基烟酰胺
化合物51
(R)-N-(5-氯-3-((1-(3,3-二氟环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-5-氰基-6-甲基烟酰胺
化合物52
(S)-N-(5-氯-3-((1-(3,3-二氟环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-5-氰基-6-甲基烟酰胺
化合物53
N-(5-氯-3-((1-异丁酰基哌啶-4-亚基)甲基)-2-甲苯基)-5-氰基-6-甲基烟酰胺
化合物54
N-(5-氯-3-(1-(4,4-二氟哌啶-1-羰基)哌啶-4-亚基)甲基)-2-甲苯基)-6-氰基-1-甲基-2-氧-1,2-二氢吡啶-4-甲酰胺
化合物55
N-(5-氯-3-((1-(3,3-二氟四氢吡咯-1-羰基)哌啶-4-亚基)甲基)-2-甲苯基)-3-氰基苯甲酰胺
化合物56
N-(5-氯-2-甲基-3-((1-(四氢吡咯-1-羰基)哌啶-4-亚基)甲基)苯基)-3-氰基苯甲酰胺
化合物57
4-(5-氯-3-(3-氰基苯甲酰胺)-2-甲基亚苄基)哌啶-1-甲酸异丙酯
化合物58
N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-3-氰基苯磺酰胺
化合物59
1-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-3-(吡啶-2-基)脲
化合物60
N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-6-氰基-1-乙基-2-氧代-1,2-二 氢吡啶-4-甲酰胺
化合物61
N-(5-氯-3-((1-(2-环丙基乙酰基)哌啶-4-亚基)甲基)-2-甲苯基)-6-氰基-1-乙基-2-氧代-1,2-二氢吡啶-4-甲酰胺
化合物62
N-(5-氯-3-((1-(2-环丁基乙酰基)哌啶-4-亚基)甲基)-2-甲苯基)-6-氰基-1-乙基-2-氧代-1,2-二氢吡啶-4-甲酰胺
化合物63
N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-5-氰基-6-甲基烟酰胺
化合物64
N-(5-氯-3-((1-(2-环丙烷乙酰基)哌啶-4-亚基)甲基)-2-甲苯基)-5-氰基-6-甲基烟酰胺
化合物65
N-(5-氯-3-((1-(2-环丁基乙酰基)哌啶-4-亚基)甲基)-2-甲苯基)-5-氰基-6-甲基烟酰胺
化合物66
N-(5-氯-3-((1-(4,4-二氟环己基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-5-氰基-6-甲基烟酰胺
化合物67
6-氯-N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-1-甲基-2-氧-1,2-二氢吡啶-4-甲酰胺
化合物68
N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-6-氧-1,6-二氢哒嗪-4-甲酰胺
化合物69
N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-2-氰基-6-甲氧基烟酰胺
化合物70
N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-6-氰基-2-氧-1,2-二氢吡啶-4-甲酰胺
化合物71
3-氰基-N-(3-(1-(环戊基羰基)哌啶-4-亚基)甲基)-5-氟-2-甲苯基)苯甲酰胺
化合物72
N-(2-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)苯基)-3-氰基苯甲酰胺
化合物73
3-氰基-N-(3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)苯甲酰胺
化合物74
6-氰基-N-(3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-5-氟-2-甲苯基)-1-甲基-2-氧-1,2-二氢吡啶-4-甲酰胺
化合物75
6-氰基-N-(3-((1-(2-环丙基乙酰基)哌啶-4-亚基)甲基)-5-氟-2-甲苯基)-1-甲基-2-氧-1,2-二氢吡啶-4-甲酰胺
化合物76
6-氰基-N-(5-氟-3-((1-异丁酰基哌啶-4-亚基)甲基)-2-甲苯基)-1-甲基-2-氧代-1,2-二氢吡啶-4-甲酰胺
化合物77
(R)-6-氰基-N-(3-((1-(3,3-二氟环戊基羰基)哌啶-4-亚基)甲基)-5-氟-2-甲苯基)-1-甲基-2-氧-1,2-二氢吡啶-4-甲酰胺
化合物78
5-氯-N-(3-((1-(2-环丙基乙酰基)哌啶-4-亚基)甲基)-5-氟-2-甲苯基)-6-甲基烟酰胺
化合物79
5-氰基-N-(3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-5-氟-2-甲苯基)-6-甲基烟酰胺
化合物80
5-氰基-N-(3-((1-(2-环丙基乙酰基)哌啶-4-亚基)甲基)-5-氟-2-甲苯基)-6-甲基烟酰胺
化合物81
5-氰基-N-(5-氟-3-((1-异丁酰基哌啶-4-亚基)甲基)-2-甲苯基)-6-甲基烟酰胺
化合物82
(R)-5-氰基-N-(3-((1-(3,3-二氟环戊基羰基)哌啶-4-亚基)甲基)-5-氟-2-甲苯基)-6-甲基烟酰胺
表1本申请式(I)化合物中典型化合物的编号和结构为：
Figure PCTCN2020085294-appb-000018
Figure PCTCN2020085294-appb-000019
Figure PCTCN2020085294-appb-000020
Figure PCTCN2020085294-appb-000021
合成
本申请的一个或多个实施方案中，式(I)的化合物可由方案A或方案B所示步骤制备：
方案A
步骤1
Figure PCTCN2020085294-appb-000022
i)将取代的式(I-A)的化合物用混酸硝化得到式(I-B)的化合物，其中所述混酸为浓硝酸和浓硫酸的混合；
ii)用硼烷还原式(I-B)的化合物，得到式(I-C)的化合物；
iii)使式(I-C)的化合物和四溴化碳、三苯基膦进行取代反应得到式(I-D)的化合物；
iv)使式(I-D)的化合物与三苯基膦进行加成反应得到叶立德试剂式(I-E)的化合物；
v)在碱性条件下，使式(I-E)的化合物与4-氧哌啶-1-甲酸叔丁酯进行Wittig反应，得到式(I-F)的化合物。
在一个或多个实施方案中，步骤ii)中所述还原在THF中进行。
在一个或多个实施方案中，步骤v)中所述碱性条件由NaH产生。
在一个或多个实施方案中，步骤v)中所述Wittig反应在DMSO中进行。
其中R 1、R 2、和m如上文的式(I)中所定义。
步骤2
Figure PCTCN2020085294-appb-000023
将式(I-F)的化合物脱除保护基，得到式(I-G)的化合物或其盐；
其中R 1、R 2和m如上文的式(I)中所定义。
步骤3
Figure PCTCN2020085294-appb-000024
将式(I-G)的化合物或其盐(如盐酸盐或者三氟乙酸盐)与R 3COR 5进行缩合反应得到式(I-H)的化合物；
其中R 1、R 2、R 3、m和p如上文的式(I)中所定义。
步骤4
Figure PCTCN2020085294-appb-000025
用铁粉还原式(I-H)的化合物得到式(I-I)的化合物；
其中R 1、R 2、R 3、m和p如上文的式(I)中所定义。
步骤5
Figure PCTCN2020085294-appb-000026
将式(I-I)化合物分别与R 4COR 6、R 4NCO和R 4SO 2Cl 2化合物进行氨酯交换反应、加成反应或缩合反应，得到式(I)化合物；
其中：X、R 1、R 2、R 3、R 4、m和p如上文的式(I)中所定义；R 5为本领域进行氨酯交换反应时所常规使用的基团，例如羟基、卤素如氯、甲氧基、乙氧基等。
方案B
步骤1
Figure PCTCN2020085294-appb-000027
用铁粉对式(I-F)的化合物进行还原，得到式(I-J)的化合物；
其中：R 1、R 2和m如上文的式(I)中所定义；式(I-F)的化合物按照方案A步骤1的方法制备。
在本方案步骤1中，式(I-J)的化合物还可以使用如下方案制备：
Figure PCTCN2020085294-appb-000028
使式(I-M)中间体化合物与式(I-N)中间体化合物进行偶联反应，得到式(I-J)中间体化合物；
其中：R 1、R 2和m如式(I)中所定义；式(I-M)中间体化合物和式(I-N)中间体化合物可使用本领域常规使用的方法制得，如式(I-M)中间体化合物和式(I-N)中间体化合物可通过上示反应方案制备。
步骤2
Figure PCTCN2020085294-appb-000029
将式(I-J)的化合物与R 4COR 6进行反应，得到式(I-K)的化合物；
其中：R 1、R 2、R 4、X和m如上文的式(I)中所定义；R 5选自羟基、卤素(例如氯)、烷氧基(例如甲氧基、乙氧基)。
步骤3
Figure PCTCN2020085294-appb-000030
将式(I-K)的化合物脱除Boc保护，得到式(I-L)的化合物或其盐；
其中：R 1、R 2、X和m如式(I)中所定义。
步骤4
Figure PCTCN2020085294-appb-000031
将式(I-L)的化合物或其盐(如盐酸盐或三氟乙酸盐)与R 3COR 5进行缩合反应，得到式(I)化合物；
其中：R 1-R 3、X、m和p如式(I)中所定义。
上述合成方案只是列举了本申请中部分化合物的制备方法，按照本领域的公知技术，技术人员在上述合成方案的基础上，采用类似的方法也可以合成本申请的化合物。
中间体
本申请的一个或多个实施方案中，还分别提供式(I-F)的化合物、式(I-G)的化合物、式(I-H)的化合物
Figure PCTCN2020085294-appb-000032
其中：R 1-R 3、m和p如式(I)中所定义。
本申请的一个或多个实施方案中，提供式(I-I)的中间体化合物，
Figure PCTCN2020085294-appb-000033
其中：R 1-R 3、m和p如式(I)中所定义。
在一些实施方案中，所述式(I-I)化合物包括，但不限于如下化合物:
本申请的一个或多个实施方案中，还分别提供式(I-J)的化合物和式(I-K)的化合物
Figure PCTCN2020085294-appb-000034
其中：R 1、R 2、X和m如式(I)中所定义。
本申请的一个或多个实施方案中，还提供式(I-L)的化合物
Figure PCTCN2020085294-appb-000035
其中：R 1、R 2、X和m如式(I)中所定义。
本申请的一个或多个实施方案还提供了药物组合物，其包含式(I)的化合物或其立体异构体、对映异构体或互变异构体或其混合物，或其药物可接受的盐、溶剂化物或前药，以及一种或多种药物可接受的赋形剂和/或载体。
本申请的一个或多个实施方案还提供了式(I)化合物或其立体异构体、对映异构体或互变异构体或其混合物，或其药物可接受的盐、溶剂化物或前药，或包含式(I)的化合物或其立体异构体、对映异构体或互变异构体或其混合物，或其药物可接受的盐、溶剂化物或前药的药物组合物作为药品使用的用途，或治疗疾病的用途。
本申请的一个或多个实施方案还提供了式(I)化合物或其立体异构体、对映异构体或互变异构体或其混合物，或其药物可接受的盐、溶剂化物或前药，或包含式(I)的化合物或其立体异构体、对映异构体或互变异构体或其混合物，或其药物可接受的盐、溶剂化物或前药的药物组合物在制备RORγt受体抑制剂中的用途。
本申请的一个或多个实施方案还提供了式(I)化合物或其立体异构体、对映异构体或互变异构体或其混合物，或其药物可接受的盐、溶剂化物或前药，或包含式(I)的化合物或其立体异构体、对映异构体或互变异构体或其混合物，或其药物可接受的盐、溶剂化物或前药的药物组合物在制备用于预防和/或治疗与RORγt受体异常激活相关的疾病的药物中的用途。
本申请的一个或多个实施方案中，上述与RORγt受体异常激活相关的疾病包括自身免疫性疾病、过敏性疾病和癌症。
本申请的一个或多个实施方案中，上述与RORγt受体异常激活相关的疾病包括屑病(Psoriasis)、银屑样关节炎(Psoriatic Arthritis)、类风湿关节炎(Rheumatoid Arthritis)、强直脊柱炎(Ankylosing Spondylitis)、多发性硬化症(Multiple Sclerosis)、干燥综合症(Sjogren’s syndrome)、干眼综合症(Dry Eye Syndrome)、移植物抗宿主病(Graft-versus-host disease)、炎 症性肠病(Inflammatory Bowel Disease)、慢阻肺(Chronic Obstructive Pulmonary Disease)、哮喘(Asthma)、自身免疫性葡萄膜炎(Autoimmune Uveitis)、自身免疫性肝炎(Autoimmune Hepatitis)、自身免疫性甲状腺炎(Autoimmune Thyroid Disease)、自身免疫性肾炎(Autoimmune Nephritis)、特应性皮肤炎(Atopic Dermatitis)、前列腺炎(Begign Prostatic Hyperplasia)和前列腺癌(castration-resistant prostate cancer)。
本申请的一个或多个实施方案还提供了式(I)化合物或其立体异构体、对映异构体或互变异构体或其混合物，或其药物可接受的盐、溶剂化物或前药，或包含式(I)的化合物或其立体异构体、对映异构体或互变异构体或其混合物，或其药物可接受的盐、溶剂化物或前药的药物组合物在抑制RORγt受体中的用途。
后文中将结合具体实施方式进一步说明，本申请式(I)的化合物或其立体异构体、对映异构体或互变异构体或其混合物，或其药物可接受的盐、溶剂化物或前药可有效抑制RORγt蛋白受体，从而调控Th17细胞的分化，抑制IL-17的产生。因此本申请式(I)的化合物可作为治疗RORγt受体受体异常激活相关类疾病的优选治疗药物。
定义
如在说明书和所附的权利要求书中所使用的，除非有相反的特定说明，否则本申请的术语具有如下表示的意义：
术语“化合物”，包括所有立体异构体，几何异构体，互变异构体。本文中所述的“化合物”，可以是不对称的，例如，具有一个或多个立体异构体。除非另有说明，所有立体异构体都包括，如单独的对映异构体和非对映异构体或其他立体异构体形式或它们的混合物。本文中含有不对称碳原子的化合物，可以以光学活性纯的形式或外消旋体形式被分离出来。光学活性纯的形式可以从外消旋混合物拆分，或通过使用手性原料或手性试剂合成。本文所述的“化合物”，还包括几何异构形式，几何异构形式指化合物在双键或环上的取代基有不同的顺反异构而不具手性的形式。本文所述的“化合物”，还包括互变异构体形式。互变异构体形式可来源于一个单键与相邻的双键交换并一起伴随一个质子的迁移。
本文的化合物，无论是中间体或式(I)化合物，均还可以通过使其中的一个或多个原子被具有不同的原子质量或质量数的原子替代而被同位素标记。此类经同位素标记的(即，放射性标记的)化合物被视为处于在本文的范围内。本文的化合物中的同位素的实例包括氢、碳、氮、氧、磷、硫、氟、氯和碘的同位素，各同位素间分别具有相同的质子数，但质量数不同。
术语“卤素”是指氟、氯、溴或碘。
术语“氨基”指-NH 2。
术语“氰基”，是指-CN。
术语“硝基”指-NO 2。
术语“羟基”，是指-OH。
术语“羧基”，是指-COOH。
“巯基”基团是指“-SH”基团。
“羰基”基团是指C＝O基团。
“异氰酸基”基团是指“-NCO”基团。
“硫氰酸基”基团是指“-CNS”基团。
“异硫氰酸基”基团是指“-NCS”基团。
“CA至CB”或“CA-CB”是指烷基、烯基或炔基中的碳原子数，或芳基、杂芳基中的碳原子数，其中“A”和“B”是整数。即，烷基、烯基、炔基、芳基、杂芳基可包含“A”至“B”个碳原子。因此，例如，“C1至C4烷基”或“C1-C4烷基”基团是指具有1至4个碳的所有烷基，即CH 3-、CH 3CH 2-、CH 3CH 2CH 2-、(CH 3) 2CH-、CH 3CH 2CH 2CH 2-、CH 3CH 2CH(CH 3)-和(CH 3) 3C-。
术语“烷基”，指由碳原子和氢原子组成的直链或支链的饱和烃基团，如C1-C20烷基，优选为C1-C6烷基。C1-C20烷基指具有1至20个碳原子的烷基，例如具有1个碳原子、2个碳原子、3个碳原子、4个碳原子、5个碳原子、6个碳原子、7个碳原子、8个碳原子、9个碳原子、10个碳原子、11个碳原子、12个碳原子、13个碳原子、14个碳原子、15个碳原子、16个碳原子、17个碳原子、18个碳原子、19个碳原子或20个碳原子的烷基。烷基的实例包括但不限于甲基、乙基、丙基(包括正丙基和异丙基)、丁基(包括正丁基、异丁基、仲丁基或叔丁基)、戊基(包括正戊基、异戊基、新戊基)、己基(例如正己基)等。所述烷基可以是非取代的或被一个或多个取代基所取代，所述取代基包括但不限于烷基、烷氧基、氰基、羟基、羰基、羧基、芳基、杂芳基、胺基、卤素、磺酰基、亚磺酰基、膦酰基等。
“烯基”是指在直链或支链烃链中包含一个或多个双键的烃基。烯基可为未取代的或取代的。烯基可具有1至20个碳原子，每当在本文出现时，诸如“1至20”的数值范围是指给定范围中的各个整数；例如，“1至20个碳原子”是指可包含1个碳原子、2个碳原子、3个碳原子、4个碳原子、5个碳原子、6个碳原子、7个碳原子、8个碳原子、9个碳原子、10个碳原子、11个碳原子、12个碳原子、13个碳原子、14个碳原子、15个碳原子、16个碳原子、17个碳原子、18个碳原子、19个碳原子或20个碳原子的烯基。
“炔基”是指在直链或支链烃链中包含一个或多个叁键的烃基。炔基可为未取代的或取代的。炔基可具有1至20个碳原子，每当在本文出现时，诸如“1至20”的数值范围是指给定范围中的各个整数；例如，“1至20个碳原子”是指可包含1个碳原子、2个碳原子、3个碳原子、4个碳原子、5个碳原子、6个碳原子、7个碳原子、8个碳原子、9个碳原子、10个碳原子、11个碳原子、12个碳原子、13个碳原子、14个碳原子、15个碳原子、16个碳原子、17个碳原子、18个碳原子、19个碳原子或20个碳原子的炔基。
术语“脂环烃基”，指饱和(即“脂环烷基”)或不饱和的由碳原子(例如，3个、4个、5个、6个、7个、8个、9个或10个碳原子)和氢原子组成的单环、稠环、螺环或桥环。所述脂环烃基的实例包括但不限于，环丙基、环丁基、环戊基、环戊烯基、环己基、螺[3.4]辛烷基、二环[1.1.1]戊烷基、二环[3.1.0]己烷基。脂环烃基包括脂环烷基(环烷基)。
术语“含杂原子的脂环烃基”，指饱和(杂环烷基)或不饱和的非芳香性的含一个或多个(例如，1个、2个、3个或4个)杂原子的单环、稠合、桥环和螺环。其中所述杂原子典型的为N、O、S或SO 2
Figure PCTCN2020085294-appb-000036
含杂原子的脂环烃基可为3元至10元(例如，包含3个、4个、5个、6个、7个、8个、9个或10个环原子)的单环或双环或三环。含杂原子的脂环烃基的实例包括但不限于哌嗪基、吗啉基、哌啶基、吡咯烷基、四氢呋喃基、四氢-2H-吡喃基等。含杂原子的脂环烃基可以是非取代的，也可以被一个或多个取代基所取代，所述取代基包括但不限于卤素、烷基、卤代烷基、氨基、氰基、羟基、烷氧基、卤代烷氧基、羰基、脂环烃基、含杂原子的脂环烃基、任选由C1-C3烷基取代的磺酰基、芳基和杂芳基等。例如，当含杂原子的脂环烃基被羰基取代时，其可以为2-氧代-1,2-二氢吡啶基
Figure PCTCN2020085294-appb-000037
或“3-氧代-1,2-二氢哒嗪基
Figure PCTCN2020085294-appb-000038
含杂原子的脂环烃基包括杂环烷基。
术语“芳基”，指具有完全共轭的π电子体系的全碳单环或全碳稠合环，通常具有5-14个碳原子，例如，6个、10个、12个、14个碳原子。芳基可以是非取代的，或被一个或多个取代基所取代，所述取代基包括但不限于烷基、烷氧基、氰基、羟基、羧基、芳基、芳烷基、胺基、卤素、磺酰基、亚磺酰基、膦酰基。非取代的芳基实例包括但不限于苯基、萘基和蒽基。
术语“杂芳基”，是指具有6-12个环原子(例如，6个、10个、12个、14个环原子)的单环或稠合环，其中含有1-4个(例如，1个、2个、3个或4个)选自N、O、S的杂原子，其余环原子为C，且具有完全共轭π-电子体系，包括但不限于吡咯基、呋喃基、噻吩基、咪唑基、噁唑基，异噁唑基、吡唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、喹啉基、异喹啉基、三唑基、苯并咪唑、苯并三唑等。杂芳基可以是非取代的或取代的，所述取代基包括但不限于烷基、烷氧基、氰基、羟基、羰基、羧基、芳基、芳烷基、胺基、卤素、磺酰基、亚磺酰基、膦酰基。例如，当杂芳基被羟基取代时，其可以为哌啶-2-醇
Figure PCTCN2020085294-appb-000039
或哒嗪-3-醇
Figure PCTCN2020085294-appb-000040
“烷氧基”是指式-OR，其中R为本文定义的烷基。烷氧基的非限制性列举为甲氧基、乙氧基、正丙氧基、1-甲基乙氧基(异丙氧基)、正丁氧基、异丁氧基、仲丁氧基、叔丁氧基。烷氧基可为取代的或未取代的。
“酰基”是指通过羰基连接的作为取代基的氢、烷基、烯基、炔基或芳基。实例包括甲酰基、乙酰基、丙酰基、苯甲酰基和丙烯酰基。酰基可为取代的或未取代的。
“卤代烷基”是指其中一个或多个氢原子被卤素取代(例如，单卤代烷基、二卤代烷基和三卤代烷基)的烷基。这类基团包括但不限于氯甲基、氟甲基、二氟甲基、三氟甲基、1-氯-2-氟甲基和2-氟异丁基。卤代烷基可为取代的或未取代的。
“卤代烷氧基”是指其中一个或多个氢原子被卤素(例如，单卤代烷氧基、二卤代烷氧基和三卤代烷氧基)取代的烷氧基。这类基团包括但不限于氯甲氧基、氟甲氧基、二氟甲氧基、三氟甲氧基、1-氯-2-氟甲氧基和2-氟异丁氧基。卤代烷氧基可为取代的或未取代的。
“芳硫基”是指RS-，其中R为芳基，例如但不限于苯基。芳硫基可为取代的或未取代的。
“硫代羰基”基团是指“-C(＝S)R”基团，其中R与关于O-羧基中的R的定义相同。硫代羰基可为取代的或未取代的。
“三卤代甲烷磺酰基”基团是指“X 3CSO 2-“基团，其中各个X为卤素。
“三卤代甲烷亚磺酰氨基”基团是指“X 3CS(O) 2N(R A)-”基团，其中各个X为卤素，且R A为氢、烷基、烯基、炔基、环烷基、环烯基、环炔基、芳基、杂芳基、杂脂环基、芳烷基、(杂芳基)烷基或(杂脂环基)烷基。
“烃硫基”基团是指“-SR”基团，其中R可为烷基(此时的“烃硫基”为“烷硫基”)、烯基、炔基、环烷基、环烯基、环炔基、芳基、杂芳基、杂脂环基、芳烷基、(杂芳基)烷基或(杂脂环基)烷基。烃硫基可为取代的或未取代的。
“亚磺酰基”基团是指“-S(＝O)-R”基团，其中R与烃硫基中的R定义相同。亚磺酰基可为取代的或未取代的。
“磺酰基”基团是指“SO 2R”基团，其中R与烃硫基中的R的定义相同。磺酰基可为取代的或未取代的。
“DMSO”指二甲基亚砜。
“C-酰氨基”基团是指“-C(＝O)N(R AR B)”基团，其中R A和R B可独立地为氢、烷基、烯基、炔基、环烷基、环烯基、环炔基、芳基、杂芳基、杂脂环基、芳烷基、(杂芳基)烷基或(杂脂环基)烷基。C-酰氨基可为取代的或未取代的。
“N-酰氨基”基团是指“RC(＝O)N(R A)-”基团，其中R和R A可独立地为氢、烷基、烯基、炔基、环烷基、环烯基、环炔基、芳基、杂芳基、杂脂环基、芳烷基、(杂芳基)烷基或(杂脂环基)烷基。N-酰氨基可为取代的或未取代的。
“S-磺酰氨基”基团是指“-SO 2N(R AR B)”基团，其中R A和R B可独立地为氢、烷基、烯基、炔基、环烷基、环烯基、环炔基、芳基、杂芳基、杂脂环基、芳烷基、(杂芳基)烷基或(杂 脂环基)烷基。S-磺酰氨基可为取代的或未取代的。
“N-磺酰氨基”基团是指“RSO 2N(R A)-“基团，其中R和R A可独立地为氢、烷基、烯基、炔基、环烷基、环烯基、环炔基、芳基、杂芳基、杂脂环基、芳烷基、(杂芳基)烷基或(杂脂环基)烷基。N-磺酰氨基可为取代的或未取代的。
“O-氨基甲酰基”基团是指“-OC(＝O)N(R AR B)”基团，其中R A和R B可独立地为氢、烷基、烯基、炔基、环烷基、环烯基、环炔基、芳基、杂芳基、杂脂环基、芳烷基、(杂芳基)烷基或(杂脂环基)烷基。O-氨基甲酰基可为取代的或未取代的。
“N-氨基甲酰基”基团是指“ROC(＝O)N(R A)-“基团，其中R和R A可独立地为氢、烷基、烯基、炔基、环烷基、环烯基、环炔基、芳基、杂芳基、杂脂环基、芳烷基、(杂芳基)烷基或(杂脂环基)烷基。N-氨基甲酰基可为取代的或未取代的。
“O-硫代氨基甲酰基”基团是指“-OC(＝S)-N(R AR B)”基团，其中R A和R B可独立地为氢、烷基、烯基、炔基、环烷基、环烯基、环炔基、芳基、杂芳基、杂脂环基、芳烷基、(杂芳基)烷基或(杂脂环基)烷基。O-硫代氨基甲酰基可为取代的或未取代的。
“N-硫代氨基甲酰基”基团是指“ROC(＝S)N(R A)-“基团，其中R和R A可独立地为氢、烷基、烯基、炔基、环烷基、环烯基、环炔基、芳基、杂芳基、杂脂环基、芳烷基、(杂芳基)烷基或(杂脂环基)烷基。N-硫代氨基甲酰基可为取代的或未取代的。
术语“任选”，指存在或不存在的情况。
当基团被描述为“任选取代的”时，则基团可为未取代的或被一个或多个所示的取代基取代。相似地，当基团被描述为“未取代的或取代的”时，如果是取代的，则取代基可选自一种或多种所示的取代基。如果没有指出取代基，则是所述的“任选取代的”或“取代的”基团可单独和独立地被选自以下的一种或多种基团取代：烷基、烯基、炔基、环烷基、环烯基、环炔基、芳基、杂芳基、杂脂环基、芳烷基、杂芳烷基、(杂脂环基)烷基、羟基、烷氧基、芳氧基、酰基、巯基、烷硫基、芳硫基、氰基、卤素、硫代羰基、O-氨基甲酰基、N-氨基甲酰基、O-硫代氨基甲酰基、N-硫代氨基甲酰基、C-酰氨基、N-酰氨基、S-磺酰氨基、N-磺酰氨基、羧基、异氰酸基、硫氰酸基、异硫氰酸基、硝基、甲硅烷基、烃硫基、亚磺酰基、磺酰基、卤代烷基、卤代烷氧基、三卤代甲烷磺酰基、三卤代甲烷亚磺酰氨基和氨基。
术语“共价键”，指原子间通过共用电子对所形成的相互作用。
术语“治疗”意味着对哺乳动物体内疾病的任何治疗，包括：(1)防止疾病，即使临床疾病的症状不发展；(2)抑制疾病，即阻止临床症状的发展；(3)减轻疾病，即使临床症状的消退。
术语“药物组合物”，指一种或多种本文的化合物与在本领域中通常可接受的例如用于将生物活性化合物输送至有机体(例如人)的载体、赋形剂或辅料所组成的制剂。例如，药 物组合物的目的是有利于有机体的给药输送。
术语“药学上可接受的赋形剂和/或载体”或“药物可接受的赋形剂和/或载体”，指与活性成分共同给药的、且有利于活性成分给药的物质，包括但不限于国家食品药品监督管理局许可的可接受用于人或动物(例如家畜)的任何助流剂、增甜剂、稀释剂、防腐剂、燃料/着色剂、矫味增强剂、表面活性剂、润湿剂、分散剂、崩解剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。例如包括但不限于碳酸钙、磷酸钙、各种糖和各类淀粉、纤维素衍生物、明胶、植物油和聚乙二醇。
本文所述的药物组合物，可配制成固态、半固态、液态或气态制剂，如片剂、丸剂、胶囊剂、粉剂、颗粒剂、膏剂、乳剂、悬浮剂、溶液剂、栓剂、注射剂、吸入剂、凝胶剂、微球及气溶胶等。
本文所述的药物组合物，可以采用本领域熟知的方法制造，如常规的混合法、溶解法、制粒法、制糖衣药丸法、磨细法、乳化法、冷冻干燥法等。
本文所述的化合物或其药学上可接受的盐或其药物组合物的给药途径，包括但不限于口服、直肠、透黏膜、经肠给药，或者局部、经皮、吸入、肠胃外、舌下、阴道内、鼻内、眼内、腹膜内、肌内、皮下、静脉内给药。优选的给药途径是口服、静脉内、肌肉和病变器官(如眼睛，前列腺等)内注射给药。
对于口服给药，可以通过将活性化合物与本领域熟知的药学上可接受的载体混合，来配制该药物组合物。可以将本文的化合物配制成片剂、丸剂、锭剂、糖衣剂、胶囊剂、液体、凝胶剂、浆剂、悬浮剂等，以用于对患者的口服给药。例如，用于口服给药的药物组合物，可采用如下方式获得片剂：将活性成分与一种或多种固体载体合并，如果需要将所得混合物制粒，并且如果需要的话，可加入少量的赋型剂加工成混合物或颗粒，以形成片剂或片芯。片芯可与任选适合肠溶的包衣材料结合，加工成更有利于有机体(例如人)吸收的包衣制剂形式。
术语“药学上可接受的盐”是指对所施用的生物体不产生显著刺激并且不破坏化合物的生物活性和性质的化合物的盐。在一些实施方案中，所述盐为化合物的酸加成盐。能通过使化合物与无机酸反应获得药物盐，所述无机酸例如氢卤酸(例如，氢氯酸或氢溴酸)、硫酸、硝酸和磷酸。能通过使化合物与有机酸反应获得药物盐，所述有机酸例如脂肪族或芳香族的羧酸或磺酸，例如甲酸、乙酸、琥珀酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、烟酸、甲烷磺酸、乙烷磺酸、对甲苯磺酸、水杨酸或萘磺酸。还能通过使化合物与碱反应以形成盐来获得药物盐，例如铵盐、诸如钠盐或钾盐的碱金属盐、诸如钙盐或镁盐的碱土金属盐、诸如二环己基胺、N-甲基-D-葡糖胺、三(羟基甲基)甲基胺、C 1-C 7烷基胺、环己基胺、三乙醇胺、乙二胺的有机碱盐和与诸如精氨酸和赖氨酸的氨基酸的盐。
除非另外规定，本申请中使用的术语和短语及其变型，特别是在所附的权利要求中应被解释为开放式的而非限定。作为前述的实例，术语“包括”应被理解为是指“包括而不限于”同义并且为包括式或开放式，并且不排除附加、未列举的元素或方法步骤；术语“具有”应 被解释“具有至少”。
以下结合具体实施例，对本文的技术方案做进一步的描述。给出的实施例仅用于解释目的，而不是限制本文，在不背离本文的精神和范围的情况下，可以对本文作出各种改变。
本文提供的目标化合物制备方法中，化合物的结构是通过核磁共振(NMR)或/和液质联用(LC-MS)来确定的。NMR位移(δ)以10 -6(ppm)的单位给出。NMR的测定用ZKNJ BIXI-1(武汉中科牛津波谱技术有限公司)300MHz、BRUKER AVANCE III 400MHz、Bruker Avance Neo 400MHz或者JEOL 400MHz核磁仪进行。液质联用(LC-MS)的测定用Waters H-class UPLC-SQD2、Agilent 1260/6120或者Agilent 1100进行。NMR测定溶剂为氘代二甲基亚砜(DMSO-d 6)，氘代氯仿(CDCl 3)，氘代甲醇(CD 3OD)，内标为四甲基硅烷(TMS)。
此外，凡涉及易氧化或易水解的原料的所有操作都在氮气保护下进行。除非另有说明，本文使用的原料都是市售原料，无需进一步纯化可以直接使用。
制备实施例
5-氯-2-甲基-3-硝基苯甲醇
Figure PCTCN2020085294-appb-000041
5-氯-2-甲基-3-硝基苯甲酸(4.6g,21.0mmol)溶于无水四氢呋喃(50mL)，氮气保护下，反应液冷却到0℃，然后缓慢滴加硼烷的四氢呋喃溶液(27.4mL,27.4mmol)，反应液缓慢升温至室温，然后室温搅拌过夜。0℃下，用10％盐酸(28.2mL)将反应缓慢淬灭，反应液加水稀释，用乙酸乙酯萃取。合并有机层，分别用饱和碳酸氢钠水溶液和食盐水洗，浓缩除去溶剂得到粗品。粗品用硅胶柱柱层析纯化(石油醚/乙酸乙酯＝5/1～3/1，体积比)得到5-氯-2-甲基-3-硝基苯甲醇3.7g，产率87％，白色固体。 1H-NMR(400MHz,DMSO-d 6)：δ7.89(s,1H),7.72(s,1H),5.57(s,1H),4.58(s,2H),2.24(s,3H)。
1-溴甲基-5-氯-2-甲基-3-硝基苯
Figure PCTCN2020085294-appb-000042
5-氯-2-甲基-3-硝基苯甲醇(1.8g,9.0mmol)溶于二氯甲烷(20mL)，反应液冷却到0℃，加入三苯基磷(2.6g,9.9mmol)，然后缓慢滴加四溴化碳(3.3g,9.9mmol)的二氯甲烷(5mL)溶液。室温搅拌过夜。浓缩除去溶剂得到粗品。粗品用硅胶柱柱层析纯化(石油醚/乙酸乙酯＝20/1～10/1，体积比)得到1-溴甲基-5-氯-2-甲基-3-硝基苯2.1g，产率64％，白色固体。 1H NMR(400MHz,DMSO-d 6)：δ8.01(s,1H),7.93(s,1H),4.83(s,2H),2.45(s,3H)。
溴(5-氯-2-甲基-3-硝基苄基)三苯基磷烷
Figure PCTCN2020085294-appb-000043
1-溴甲基-5-氯-2-甲基-3-硝基苯(265mg,1.0mmol)溶于甲苯(5mL)，加入三苯基磷(289mg,1.1mmol)，然后80℃搅拌6小时。反应液冷却到室温，过滤收集沉淀固体，甲苯洗，固体真空干燥。得到溴(5-氯-2-甲基-3-硝基苄基)三苯基磷烷481mg，产率91％，白色固体。1H NMR(400MHz,DMSO-d6)：δ8.04(s,1H),7.98-7.69(m,15H),7.27(s,1H),5.30(d,2H),1.64(s,3H)。
叔丁基4-(5-氯-2-甲基-3-硝基亚苄基)哌啶-1-羧酸酯
Figure PCTCN2020085294-appb-000044
氢化钠(44mg,60％纯度)的二甲基亚砜(5mL)悬浮液在80℃下搅拌1小时后，冷却至5℃，加入溴(5-氯-2-甲基-3-硝基苄基)三苯基磷烷(527mg,1.0mmol)，搅拌10分钟，然后加入叔丁基4-氧代哌啶-1-羧酸酯(200mg,1.0mmol)，室温再搅拌1小时，反应液缓慢升温至80℃并搅拌过夜。用水缓慢淬灭反应，乙醚萃取。合并有机层，食盐水洗，无水硫酸钠干燥、过滤、浓缩，粗品用硅胶柱柱层析纯化(石油醚/乙酸乙酯＝20/1～5/1，体积比)得到叔丁基4-(5-氯-2-甲基-3-硝基亚苄基)哌啶-1-羧酸酯218mg，产率60％，无色油状物。 1H-NMR(300MHz,CDCl 3)：δ7.70(s,1H),7.27(s,1H),6.24(s,1H),3.54(t,2H),3.39(t,2H),2.37(t,2H),2.35(s,3H),2.19(t,2H),1.48(s,9H)。
4-(5-氯-2-甲基-3-硝基亚苄基)哌啶盐酸盐
Figure PCTCN2020085294-appb-000045
将叔丁基4-(5-氯-2-甲基-3-硝基亚苄基)哌啶-1-羧酸酯(218mg,0.59mmol)溶于盐酸/乙酸乙酯(2mL)中，室温搅拌过夜，过滤，乙酸乙酯洗，固体真空干燥。得到4-(5-氯-2-甲基-3-硝基亚苄基)哌啶盐酸盐82mg，产率45％，白色固体。 1H NMR(300MHz,DMSO-d 6)δ9.16(s,2H),7.95(s,1H),7.54(s,1H),6.44(s,1H),3.18-3.13(m,2H),3.07-3.04(m,2H),3.60-3.56(m,2H),2.38-2.34(m,2H),2.26(s,3H)。
(4-(5-氯-2-甲基-3-硝基亚苄基)哌啶-1-基)(环戊基)甲酮
Figure PCTCN2020085294-appb-000046
0℃下，向4-(5-氯-2-甲基-3-硝基亚苄基)哌啶盐酸盐(3.0g,9.8mmol)的二氯甲烷(200mL)悬浮液中缓慢滴加环戊基酰氯(1.4mL,11.8mmol)和三乙胺(4.1mL,29.4mmol)，室温搅拌10分钟。将水加入反应液中，分层，用二氯甲烷萃取，合并有机层，饱和食盐水洗，无水硫酸钠干燥，浓缩除去溶剂得到粗品。粗品用硅胶柱柱层析纯化(石油醚/乙酸乙酯＝5/1，体积比)得到(4-(5-氯-2-甲基-3-硝基亚苄基)哌啶-1-基)(环戊基)甲酮3.4g，产率96％，棕色油状物。 1H-NMR(300MHz,DMSO-d 6)：δ7.92(s,1H),7.46(s,1H),6.37(s,1H),3.58-3.45(m,4H),3.02(m,1H),2.39-2.08(m,4H),2.26(s,3H),1.78-1.54(m,8H)。
(4-(3-氨基-5-氯-2-甲基亚苄基)哌啶-1-基)(环戊基)甲酮
Figure PCTCN2020085294-appb-000047
将(4-(5-氯-2-甲基-3-硝基亚苄基)哌啶-1-基)(环戊基)甲酮(3.1g,8.5mmol)溶于乙醇/水(80mL/40mL)中，室温下加入三水合乙酸钠(2.3g,17.1mmol)、乙酸(9mL)和铁粉(1.9g,34.2mmol)，然后升温至85℃，并搅拌1小时。反应液冷却至0℃，加1N盐酸稀释，用乙酸乙酯萃取，合并有机层，饱和食盐水洗，浓缩除去溶剂得到粗品。粗品用硅胶柱柱层析纯化(二氯甲烷/甲醇＝50/1，体积比)得到(4-(3-氨基-5-氯-2-甲基亚苄基)哌啶-1-基)(环戊基)甲酮2.3g，产率81％，黄色固体。 1H NMR(300MHz,DMSO-d 6)：δ7.06(s,1H),6.79(s,1H),6.31(s,1H),3.62-3.50(m,2H),3.49-3.37(m,2H),3.06-2.91(m,1H),2.37-2.00(m,4H),2.06(s,3H),1.82-1.41(m,8H)。
6-甲基烟酰氯
Figure PCTCN2020085294-appb-000048
氮气保护下将6-甲基烟酸(82mg,0.6mmol)溶于氯化亚砜(3mL)中，升温至50℃，并搅拌1小时。冷却至室温，浓缩，得到6-甲基烟酰氯粗品，直接用于下一步。
N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-6-甲基烟酰胺(化合物1)
Figure PCTCN2020085294-appb-000049
(4-(3-氨基-5-氯-2-甲基亚苄基)哌啶-1-基)(环戊基)甲酮(100mg,0.3mmol)和6-甲基烟酰氯化物(上一步得到的粗产品)溶于无水N,N-二甲基甲酰胺(2mL)，加入三乙胺(0.2mL,1.5mmol)。氮气保护下，反应液室温搅拌1.5小时。反应液倾倒入水中，用二氯甲烷萃取。合并有机层，浓缩得到粗产品，用制备型高效液相色谱纯化得到N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-6-甲基烟酰胺21mg，产率15％，白色固体。 1H NMR(400MHz,DMSO-d 6)δ10.12(s,1H),9.01(d,1H),8.20(dd,1H),7.43(d,1H),7.38(dd,1H),7.06(d,1H),6.38(s,1H),3.55-3.61(m,2H),3.44-3.49(m,2H),3.00-3.04(m,1H),2.56(s,3H),2.28-2.37(m,2H),2.12-2.22(m,2H),2.10(s,3H),1.49-1.79(m,8H)。MS计算值：451.2，MS实测值：452.0([M+H] +)。
N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-5-氟-6-甲基烟酰胺(化合物2)
Figure PCTCN2020085294-appb-000050
5-氟-6-甲基烟酸(54mg,0.35mmol)、2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(159mg,0.42mmol)和N,N-二异丙基乙胺(0.2mL,1.1mmol)溶于N,N-二甲基甲酰胺(8mL)，氮气保护下室温搅拌30分钟。然后加入(4-(3-氨基-5-氯-2-甲基亚苄基)哌啶-1-基)(环戊基)甲酮(115mg，0.35mmol)，反应液升温至50℃，氮气保护下搅拌过夜。浓缩得到粗产品，用制备型高效液相色谱纯化得到N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)—5-氟-6-甲基烟酰胺20mg，产率12％，灰白色固体。 1H NMR(400MHz,DMSO-d 6)δ10.23(s,1H),8.89(s,1H),8.10(dd,1H),7.44(s,1H),6.99(s,1H),6.37(s,1H),3.61-3.55(m,2H),3.61-3.55(m,2H),3.07-2.95(m,1H),2.53(d,3H),2.38-2.10(m,4H),2.10(s,3H),1.82-1.49(m,8H)。MS计算值：469.2，MS实测值：470.2([M+H] +)。
N-(5-氯-3((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-3-氰基苯甲酰胺(化合物3)
Figure PCTCN2020085294-appb-000051
3-氰基苯甲酸(104mg,0.71mmol)溶于氯化亚砜(4mL)，氮气保护下，反应液在50℃下搅拌6小时。浓缩除去溶剂。将浓缩剩余物溶解于N,N-二甲基甲酰胺(8mL)中。然后向其中加入(4-(3-氨基-5-氯-2-甲基亚苄基)哌啶-1-基)(环戊基)甲酮(100mg,0.30mmol)和三乙胺(0.2mL,1.4mmol)。氮气保护下，反应混合液在25℃搅拌1小时。浓缩得到粗产品，用制备型高效液相色谱纯化得到N-(5-氯-3((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-3-氰基苯甲酰胺20mg，产率14％，白色固体。 1H NMR(400MHz,DMSO-d 6)δ10.22(s,1H),8.40(s,1H),8.26(d,1H),8.10(d,1H),7.77(t,1H),7.38(d,1H),7.07(d,1H),6.38(s,1H),3.60-3.57(m,2H),3.50-3.45(m,2H),3.05-2.98(m,1H),2.38-2.11(m,4H),2.11(s,3H),1.80-1.51(m,8H)。MS计算值461.2，MS实测值：462.2([M+H] +)。
2-甲基异烟酸酰氯
Figure PCTCN2020085294-appb-000052
2-甲基异烟酸(206mg,1.5mmol)溶于氯化亚砜(2mL)，氮气保护下，室温搅拌1小时。反应液浓缩得到2-甲基异烟酸酰氯粗品，直接用于下一步反应。
N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-2-甲基异烟酰胺(化合物4)
Figure PCTCN2020085294-appb-000053
(4-(3-氨基-5-氯-2-甲基亚苄基)哌啶-1-基)(环戊基)甲酮(100mg,0.3mmol)和2-甲基异烟酸酰氯(粗品)溶于N,N-二甲基甲酰胺(5mL)，反应液中加入三乙胺(243mg，2.4mmol)。反应混合液氮气保护下室温搅拌1小时。水淬灭反应，二氯甲烷萃取，合并有机相并浓缩，浓缩剩余物用制备型高效液相色谱纯化得到N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-2-甲基异烟酰胺8mg，纯度95％，产率6％，类白色固体。 1H NMR(400MHz,DMSO-d 6):δ10.24(s,1H),8.65(d,1H),7.74(s,1H),7.66(d,1H),7.36(d,1H),7.08(d,1H),6.38(s,1H),3.61-3.56(m,2H),3.50-3.44(m,2H),3.03-2.97(m,1H),2.58(s,3H),2.38-2.12(m,4H),2.09(s,3H),1.81-1.51(m,8H)。MS计算值:451.2，MS实测值:452.1([M+H] +)。
N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-5-氰基烟酰胺(化合物5)
Figure PCTCN2020085294-appb-000054
5-氰基烟酸甲酯(50mg,0.31mmol)和(4-(3-氨基-5-氯-2-甲基亚苄基)哌啶-1-基)(环戊基)甲酮(103mg,0.31mmol)溶于甲苯(5mL)，氮气保护下，反应液冷却到0℃搅拌，然后加入三甲基铝(0.31mL,0.62mmol)溶液。反应混合液80℃搅拌3小时。氯化铵溶液淬灭反应，二氯甲烷萃取(20mL×3)。有机相合并，浓缩，浓缩剩余物用制备型高效液相色谱纯化得到白色固体N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-5-氰基烟酰胺72mg，纯度94％，产率47％。 1H NMR(400MHz,DMSO-d 6)δ10.32(s,1H),9.33(s,1H),9.23(s,1H),8.79(s,1H),7.41(s,1H),7.06(s,1H),6.36(s,1H),3.59-3.46(m,4H),3.05-2.97(m,1H),2.38-2.12(m,4H),2.12(s,3H),1.76-1.53(m,8H)。MS计算值：462.1，MS实测值：463.3([M+H] +)。
1-甲基-6-氧-1,6-二氢哒嗪-4-羧酸甲酯
Figure PCTCN2020085294-appb-000055
6-氧-1,6-二氢哒嗪-4-羧酸(1.0g,7.1mmol)和碳酸钾(4.9g,35.4mmol)溶于N,N-二甲基甲酰胺(30mL)，氮气保护下，向反应液中加入碘甲烷(5.2mL,71.1mmol)。反应混合液在50℃搅拌2小时。浓缩除去溶剂N,N-二甲基甲酰胺。水加入到浓缩剩余物中，用乙酸乙酯萃取。合并有机层，饱和食盐水洗，无水硫酸钠干燥，过滤。滤液浓缩后，用硅胶柱柱层析纯化(二氯甲烷/甲醇＝40/1,体积比)得到1-甲基-6-氧-1,6-二氢哒嗪-4-羧酸甲酯1.0g，产率83％，黄色固体。 1H NMR(400MHz,CDCl 3)：δ8.20(s,1H),7.49(s,1H),3.96(s,3H),3.82(s,3H)。
1-甲基-6-氧-1,6-二氢哒嗪-4-羧酸
Figure PCTCN2020085294-appb-000056
1-甲基-6-氧-1,6-二氢哒嗪-4-羧酸甲酯(414mg,2.5mmol)溶于甲醇(20mL)，然后加入40％的氢氧化钠溶液(5mL)。反应混合液室温搅拌1小时，然后用1N的盐酸溶液调解pH值至3。浓缩除去甲醇后，加入水，用乙酸乙酯萃取。合并有机层，饱和食盐水洗，无水 硫酸钠干燥，过滤。滤液浓缩后得到1-甲基-6-氧-1,6-二氢哒嗪-4-羧酸220mg，产率58％，淡黄色固体。 1H NMR(400MHz,DMSO-d 6)：δ14.14(br,1H),8.17(s,1H),7.28(s,1H),3.68(s,3H)。
N-(5-氯-3((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-1-甲基-6-氧-1,6-二氢哒嗪-4-酰胺(化合物6)
Figure PCTCN2020085294-appb-000057
1-甲基-6-氧-1,6-二氢哒嗪-4-羧酸(120mg,0.78mmol)和N,N-二甲基甲酰胺(0.1mL)溶于氯化亚砜(4mL)，氮气保护下，反应液室温搅拌20分钟。浓缩除去二氯亚砜，浓缩剩余物溶于N,N-二甲基甲酰胺(10mL)。然后加入(4-(3-氨基-5-氯-2-甲基亚苄基)哌啶-1-基)(环戊基)甲酮(125mg,0.38mmol)和三乙胺(0.2mL)。氮气保护下，反应混合液25℃搅拌1小时。浓缩得到粗产品，用制备型高效液相色谱纯化得到N-(5-氯-3((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-1-甲基-6-氧-1,6-二氢哒嗪-4-酰胺30mg，产率17％，白色固体。1H NMR(400MHz,DMSO-d6)δ10.33(s,1H),8.22(s,1H),7.45(d,1H),7.38(d,1H),7.08(d,1H),6.37(s,1H),3.71(s,3H),3.61-3.55(m,2H),3.48-3.42(m,2H),3.05-2.97(m,1H),2.37-2.12(m,4H),2.09(s,3H),1.79-1.51(m,8H)。MS计算值：468.2，MS实测值：469.0([M+H] +)。
4-氰基苯甲酰氯
Figure PCTCN2020085294-appb-000058
4-氰基苯甲酸(132mg,0.9mmol)溶于氯化亚砜(3mL)，然后加入一滴无水N,N-二甲基甲酰胺。反应液在氮气保护下室温搅拌2小时。反应液浓缩得到4-氰基苯甲酰氯粗品，不纯化直接用于下一步反应。
N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-4-氰基苯甲酰胺(化合物7)
Figure PCTCN2020085294-appb-000059
(4-(3-氨基-5-氯-2-甲基亚苄基)哌啶-1-基)(环戊基)甲酮(100mg,0.3mmol)，4-氰基苯甲酰氯(粗品,0.9mmol)溶于无水N,N-二甲基甲酰胺(3mL)，然后加入三乙胺(0.5mL)。反应 混合液在氮气保护下30℃搅拌过夜。反应液浓缩，浓缩剩余物用制备型高效液相色谱纯化得到N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-4-氰基苯甲酰胺5mg，纯度95％，产率4％，白色固体。 1H NMR(400MHz,DMSO-d 6)δ10.27(s,1H),8.12(d,2H),8.05(d,2H),7.38(d,1H),7.07(d,1H),6.38(s,1H),3.56-3.61(m,2H),3.44-3.50(m,2H),2.99-3.04(m,1H),2.13-2.37(m,4H),2.10(s,3H),1.49-1.79(m,8H)。MS计算值:461.2，MS实测值:462.0([M-H] +)。
3-溴-5-甲氧基苯甲酸甲酯
Figure PCTCN2020085294-appb-000060
3-溴-5-羟基苯甲酸(401mg,1.85mmol)，碘甲烷(1.0mL,13.7mmol)和碳酸钾(767mg,5.55mmol)溶于N,N-二甲基甲酰胺(15mL)，氮气保护下50℃搅拌过夜。反应液浓缩，浓缩剩余物用硅胶柱柱层析(石油醚/乙酸乙酯＝20/1，体积比)纯化得到3-溴-5-甲氧基苯甲酸甲酯385mg，产率85％，无色油状物。 1H NMR(400MHz,CDCl 3)δ7.76(s,1H),7.49(s,1H),7.24(d,1H),3.92(s,3H),3.84(s,3H)。
3-氰基-5-甲氧基苯甲酸甲酯
Figure PCTCN2020085294-appb-000061
3-溴-5-甲氧基苯甲酸甲酯(380mg,1.55mmol)，氰化锌(218mg,1.86mmol)和四(三苯基膦)钯(179mg,0.155mmol)溶于N,N-二甲基甲酰胺(20mL)，氮气保护下90℃搅拌过夜。反应液浓缩，浓缩剩余物用硅胶柱柱层析(石油醚/乙酸乙酯＝20/1，体积比)纯化得到3-氰基-5-甲氧基苯甲酸甲酯260mg，产率87％，白色固体。 1H NMR(400MHz,CDCl 3)δ7.91(s,1H),7.78(d,1H),7.33(d,1H),3.96(s,3H),3.89(s,3H)。
N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-3-氰基-5-甲氧基苯甲酰胺(化合物8’)
Figure PCTCN2020085294-appb-000062
3-氰基-5-甲氧基苯甲酸甲酯(83mg,0.430mmol)和(4-(3-氨基-5-氯-2-甲基亚苄基)哌 啶-1-基)(环戊基)甲酮(143mg,0.429mmol)溶于甲苯(10mL)，氮气保护下，0℃缓慢加入三甲基铝(0.4mL,0.800mmol)甲苯溶液。反应液80℃搅拌1小时，然后冷却到室温。0℃加入1mol/L的盐酸淬灭反应。每次10mL乙酸乙酯萃取两次。合并有机相，无水硫酸钠干燥后浓缩。浓缩剩余物用硅胶柱柱层析(石油醚/乙酸乙酯＝3/1，体积比)纯化得到N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-3-氰基-5-甲氧基苯甲酰胺121mg，产率57％，白色固体。 1H NMR(400MHz,DMSO-d 6)δ10.16(s,1H),7.96(s,1H),7.80(s,1H),7.70(s,1H),7.36(d,1H),7.07(d,1H),6.37(s,1H),3.90(s,3H),3.59-3.57(m,2H),3.49-3.46(m,2H),3.05-2.97(m,1H),2.39-2.36(m,1H),2.32-2.28(m,1H),2.24-2.20(m,1H),2.15-2.12(m,1H),2.10(s,3H),1.77-1.51(m,8H)。
N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-3-氰基-5-羟基苯甲酰胺(化合物8)
Figure PCTCN2020085294-appb-000063
N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-3-氰基-5-甲氧基苯甲酰胺(40mg,0.0813mmol)和四丁基碘化铵(33mg,0.0893mmol)溶于二氯甲烷(5mL)，氮气保护下-78℃缓慢加入三溴化硼二氯甲烷溶液(0.3mL,0.300mmol)。反应液-78℃搅拌1小时，然后室温继续搅拌2小时。0℃加入盐酸(4mL,1mol/L)淬灭反应。每次10mL二氯甲烷萃取两次。合并有机相，无水硫酸钠干燥后浓缩。浓缩剩余物用硅胶柱柱层析(石油醚/乙酸乙酯＝3/1，体积比)纯化得到N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-3-氰基-5-羟基苯甲酰胺4mg，产率10％，白色固体。 1H NMR(400MHz,DMSO-d 6)δ10.61(s,1H),10.10(s,1H),7.83(s,1H),7.64(s,1H),7.36(d,2H),7.06(s,1H),6.37(s,1H),3.59-3.57(m,2H),3.49-3.46(m,2H),3.06-2.97(m,1H),2.39-2.12(m,4H),2.10(s,3H),1.77-1.53(m,8H)。MS计算值:477.2，MS实测值:478.1([M+H] +)。
6-氧-1,6-二氢哒嗪-4-甲酸甲酯
Figure PCTCN2020085294-appb-000064
6-氧-1,6-二氢哒嗪-4-甲酸(1.0g,7.1mmol)溶于甲醇(20mL)，反应液冷却到0℃，氮气保护下加入二氯亚砜(3mL)。反应混合液50℃搅拌2小时，然后真空浓缩。浓缩剩余物用硅胶柱柱层析纯化(二氯甲烷/甲醇＝100/1，体积比)得到6-氧-1,6-二氢哒嗪-4-甲酸甲酯760mg，产率69％，淡黄色固体。 1H NMR(400MHz,DMSO-d 6)：δ13.46(s,1H),8.15(d,1H),7.27(s,1H),3.88(s,3H)。
1-乙基-6-氧-1,6-二氢哒嗪-4-甲酸甲酯
Figure PCTCN2020085294-appb-000065
6-氧-1,6-二氢哒嗪-4-甲酸甲酯(97mg,0.63mmol)、碘乙烷(0.1mL,1.2mmol)和碳酸钾(174mg,1.3mmol)溶于N,N-二甲基甲酰胺(10mL)，反应液氮气保护下，50℃搅拌过夜。反应液浓缩除去溶剂，浓缩剩余物用硅胶柱柱层析纯化(二氯甲烷/甲醇＝100/1，体积比)得到1-乙基-6-氧-1,6-二氢哒嗪-4-甲酸甲酯71mg，产率62％，淡黄色固体。 1H NMR(400MHz,CDCl 3)：δ8.21(d,1H),7.46(d,1H),4.24(q,2H),3.96(s,3H),1.39(t,2H)。
N-(5-氯3-((1-(环戊基羰基)哌啶-4-亚基)甲基-2-甲苯基)-1-乙基-6-氧-1,6-二氢哒嗪-4-甲酰胺(化合物9)
Figure PCTCN2020085294-appb-000066
1-乙基-6-氧-1,6-二氢哒嗪-4-甲酸甲酯(70mg,0.39mmol)和(4-(3-氨基-5-氯-2-甲基亚苄基)哌啶-1-基)(环戊基)甲酮(128mg,0.38mmol)溶于甲苯(10mL)，反应液冷却到0℃，氮气保护下缓慢加入三甲基铝(0.4mL,0.80mmol)。反应混合液80℃搅拌2小时。加入10mL水稀释反应液，然后再加入1N的盐酸(3mL)。混合液用乙酸乙酯(10mL×3)萃取。合并有机相，无水硫酸钠干燥，浓缩。浓缩剩余物用制备型高效液相色谱纯化得到N-(5-氯3-((1-(环戊基羰基)哌啶-4-亚基)甲基-2-甲苯基)-1-乙基-6-氧-1,6-二氢哒嗪-4-甲酰胺30mg，纯度95％，产率16％，白色固体。 1H NMR(400MHz,DMSO-d 6)δ10.29(s,1H),8.24(d,1H),7.43(s,1H),7.38(s,1H),7.07(d,1H),6.36(s,1H),4.14(q,2H),3.58(m,2H),3.47(m,2H),3.03-2.97(m,1H),2.37-2.08(m,4H),2.10(s,3H),1.77-1.53(m,8H),1.29(t,3H)。MS计算值：482.2，MS实测值：483.3([M+H] +)。
1-环丙基-6-氧-1,6-二氢哒嗪-4-甲酸甲酯
Figure PCTCN2020085294-appb-000067
6-氧-1,6-二氢哒嗪-4-甲酸甲酯(167mg,1.1mmol)、环丙基硼酸(209mg,2.4mmol)、醋酸铜(197mg,1.1mmol)、联吡啶(169mg,1.1mmol)和碳酸钠(260mg,2.5mmol)溶于1,2-二氯乙烷(15mL)，反应液氮气保护下，70℃搅拌过夜。反应液浓缩除去溶剂，浓缩剩余物用硅胶柱柱层析纯化(石油醚/乙酸乙酯＝50/1，体积比)得到1-环丙基-6-氧-1,6-二氢哒嗪-4-甲酸甲酯110mg，产率52％，淡黄色固体。 1H NMR(400MHz,CDCl 3)：δ8.16(d,1H),7.46(d,1H),4.19(m,1H),3.95(s,3H),1.19-1.15(m,2H),1.07-1.02(m,2H)。
N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-1-环丙基-6-氧-1,6-二氢哒嗪-4-甲酰胺(化合物10)
Figure PCTCN2020085294-appb-000068
1-环丙基-6-氧-1,6-二氢哒嗪-4-甲酸甲酯(70mg,0.36mmol)和(4-(3-氨基-5-氯-2-甲基亚苄基)哌啶-1-基)(环戊基)甲酮(120mg,0.36mmol)溶于甲苯，(10mL)反应液冷却到0℃，氮气保护下缓慢加入三甲基铝(0.4mL,0.80mmol)。反应混合液80℃搅拌2小时。加入5mL水稀释反应液，然后加入3mL 1N的盐酸。混合液用乙酸乙酯(10mL×3)萃取。合并有机相，无水硫酸钠干燥，然后浓缩。浓缩剩余物用制备型高效液相色谱纯化得到N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基-2-甲苯基)-1-环丙基-6-氧-1,6-二氢哒嗪-4-甲酰胺40mg，纯度95％，产率22％，白色固体。 1H NMR(400MHz,DMSO-d 6)δ10.28(s,1H),8.19(s,1H),7.42(s,1H),7.38(s,1H),7.07(s,1H),6.36(s,1H),4.09-4.08(m,1H),3.58(m,2H),3.46(m,2H),3.05-2.97(m,1H),2.37-2.09(m,4H),2.09(s,3H),1.77-1.53(m,8H),1.03-1.01(m,4H)。MS计算值：494.2，MS实测值：495.2([M+H] +)。
N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)咪唑[1,2-a]吡啶-7-甲酰胺(化合物11)
Figure PCTCN2020085294-appb-000069
咪唑[1,2-a]吡啶-7-甲酸甲酯(50mg,0.28mmol)和(4-(3-氨基-5-氯-2-甲基亚苄基)哌啶-1-基)(环戊基)甲酮(95mg,0.28mmol)溶于甲苯(5mL)，反应液氮气保护下，0℃搅拌，然后加入三甲基铝(0.29mL,0.56mmol)。反应混合液80℃搅拌3小时。反应完成后，氯化铵溶液淬灭反应，乙酸乙酯(20mL×3)。合并有机相，浓缩，浓缩剩余物用制备型高效液相色谱纯化得到N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-咪唑[1,2-a]吡啶-7-甲酰胺24mg，纯度94％，产率17％，白色固体。 1H NMR(400MHz,DMSO-d 6)δ10.50(s,1H),8.96(d,1H),8.47(s,1H),8.41(s,1H),8.22(s,1H),7.81(d,1H),7.41(s,1H),7.10(s,1H),6.39(s,1H),3.59-3.48(m,4H),3.03-2.96(m,1H),2.38-2.13(m,4H),2.13(s,3H),1.77-1.53(m,8H)。MS计算值：476.2，MS实测值：477.0([M+H] +)。
[1,2,4]三唑[1,5-a]吡啶-7-甲酸甲酯
Figure PCTCN2020085294-appb-000070
7-溴-[1,2,4]三唑[1,5-a]吡啶(200mg,1.0mmol)溶于甲醇(10mL)中，然后加入[1,1’-双(二苯基膦基)二茂铁]二氯化钯(82mg,0.10mmol)和三乙胺(0.42mL,3.0mmol)。反应混合液氮气保护下，100℃搅拌过夜。反应液冷却到室温，用硅胶柱柱层析纯化(石油醚/乙酸乙酯＝3/1，体积比)得到[1,2,4]三唑[1,5-a]吡啶-7-甲酸甲酯150mg，产率85％，白色固体。 1H NMR(400MHz,DMSO-d 6)：δ9.10(d,1H),8.70(s,1H),8.38(s,1H),7.60(dd,1H),3.95(s,3H)。
N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-[1,2,4]三唑[1,5-a]吡啶-7-甲酰胺(化合物12)
Figure PCTCN2020085294-appb-000071
[1,2,4]三唑[1,5-a]吡啶-7-甲酸甲酯(50mg,0.28mmol)和(4-(3-氨基-5-氯-2-甲基亚苄基)哌啶-1-基)(环戊基)甲酮(94mg,0.28mmol)溶于甲苯(5mL)，氮气保护下，0℃搅拌，然后加入三甲基铝(0.28mL,0.56mmol)。反应混合液80℃搅拌3小时。氯化铵溶液淬灭反应，二氯甲烷(20mL×3)萃取。合并有机相，用制备型高效液相色谱纯化得到N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-[1,2,4]三唑[1,5-a]吡啶-7-甲酰胺73.8mg，纯度95％，产率55％，白色固体。 1H NMR(400MHz,DMSO-d 6)δ10.34(s,1H),9.11(d,1H),8.67(s,1H),8.49(s,1H),7.65(d,1H),7.42(s,1H),7.09(s,1H),6.39(s,1H),3.59-3.47(m,4H),3.05-2.98(m,1H),2.38-2.09(m,4H),2.14(s,3H),1.77-1.53(m,8H)。MS计算值：477.1，MS实测值：478.0([M+H] +)。
2-环丙基嘧啶-5-甲酸乙酯
Figure PCTCN2020085294-appb-000072
2-氯嘧啶-5-甲酸乙酯(300mg,1.6mmol)、环丙基硼酸(690mg,8.0mmol)、[1,1’-双(二苯基膦基)二茂铁]二氯化钯(130mg,0.16mmol)和碳酸钾(662mg,4.8mmol)溶于1,4-二氧六环(20mL)，反应液氮气保护下，90℃搅拌14小时。反应完成后，过滤。滤液用水稀 释，乙酸乙酯(50mL×3)萃取。有机相合并，浓缩，用硅胶柱柱层析纯化(石油醚/乙酸乙酯＝20/1，体积比)得到黄色油状2-环丙基嘧啶-5-甲酸乙酯50mg，产率16％。 1H NMR(400MHz,DMSO-d 6)δ9.05(s,2H),4.35(q,2H),2.34-2.28(m,1H),1.33(t,3H),1.18-1.15(m,2H),1.12-1.09(m,2H)。
N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-2-环丙基嘧啶-5-甲酰胺(化合物13)
Figure PCTCN2020085294-appb-000073
2-环丙基嘧啶-5-甲酸乙酯(50mg,0.26mmol)和(4-(3-氨基-5-氯-2-甲基亚苄基)哌啶-1-基)(环戊基)甲酮(86mg,0.26mmol)，溶于甲苯(5mL)，反应液氮气保护下，冷却到0℃搅拌，然后加入三甲基铝(0.26mL,0.52mmol)溶液。反应混合液80℃搅拌3小时。氯化铵溶液淬灭反应，二氯甲烷(20mL×3)萃取。合并有机相，浓缩，用制备型高效液相色谱纯化得到N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-2-环丙基嘧啶-5-甲酰胺21.8mg，纯度95％，产率17％，白色固体。 1H NMR(400MHz,DMSO-d 6)δ10.18(s,1H),9.09(s,2H),7.40(s,1H),7.06(s,1H),6.37(s,1H),3.58-3.46(m,4H),3.03-2.99(m,1H),2.37-2.10(m,5H),2.10(s,3H),1.75-1.52(m,8H),1.23-1.09(m,4H)。MS计算值：478.2，MS实测值：479.0([M+H] +)。
N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-5-氰基-2-氟苯甲酰胺(化合物14)
Figure PCTCN2020085294-appb-000074
(4-(3-氨基-5-氯-2-甲基亚苄基)哌啶-1-基)(环戊基)甲酮(100mg,0.30mmol)和5-氰基-2-氟苯甲酸甲酯(65mg,0.40mmol)，溶于无水甲苯(5mL)中，冷却到0℃，向反应液中加入三甲基铝甲苯溶液(0.3ml,0.60mmol)。反应混合液氮气保护下，80℃搅拌4小时，然后冷却到0℃，用水淬灭反应，用乙酸乙酯萃取。合并有机相，饱和食盐水洗，浓缩。浓缩剩余物用制备型高效液相色谱纯化得到N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-5-氰基-2-氟苯甲酰胺39mg，纯度95％，产率27％，白色固体。 1H NMR(400MHz,DMSO-d 6)δ10.22(s,1H),8.29(d,1H),8.15-8.11(m,1H),7.64(t,1H),7.49(d,1H),7.06(d,1H),6.37(s,1H),3.61-3.57(m,2H),3.50-3.44(m,2H),3.03-2.99(m,1H),2.38-2.13(m,4H), 2.13(s,3H),1.78-1.48(m,8H)。MS计算值：479.2，MS实测值：480.3([M+H] +)。
3-氰基-2-氟苯甲酸甲酯
Figure PCTCN2020085294-appb-000075
3-溴-2-氟苯甲腈(2.0g,10.0mmol)溶于甲醇(100mL)中，反应液置于300mL的密封压力瓶中，然后加入[1,1’-双(二苯基膦基)二茂铁]二氯化钯(82mg,0.10mmol)和三乙胺(2.8mL,20.0mmol)。反应混合液用一氧化碳(60psi)加压，100℃搅拌过夜。反应冷却，用硅胶柱柱层析纯化(石油醚/乙酸乙酯＝40/1,体积比)得到3-氰基-2-氟苯甲酸甲酯1.6g，产率89％，白色固体。 1H NMR(300MHz,DMSO-d 6)δ8.23-8.17(m,2H),7.53(t,1H),3.88(s,3H)。
N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-3-氰基-2-氟苯甲酰胺(化合物15)
Figure PCTCN2020085294-appb-000076
3-氰基-2-氟苯甲酸甲酯(50mg,0.28mmol)和(4-(3-氨基-5-氯-2-甲基亚苄基)哌啶-1-基)(环戊基)甲酮，溶于甲苯(5mL)，氮气保护下，0℃搅拌，然后反应液中加入三甲基铝甲苯溶液(0.28mL,0.56mmol)。反应混合液80℃搅拌3小时。饱和氯化铵溶液淬灭，用二氯甲烷(20mL×3)萃取。合并有机相，浓缩，浓缩剩余物用制备型高效液相色谱纯化得到N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-3-氰基-2-氟苯甲酰胺15mg，纯度99％，产率11％，白色固体。 1H NMR(400MHz,DMSO-d 6)δ10.22(s,1H),8.15-8.07(m,2H),7.57(t,1H),7.51(s,1H),7.07(s,1H),6.37(s,1H),3.60-3.55(m,2H),3.50-3.44(m,2H),3.05-2.97(m,1H),2.37-2.13(m,4H),2.14(s,3H),1.79-1.50(m,8H)。MS计算值：479.1，MS实测值：480.2([M+H] +)。
3-(甲磺酰基)苯甲酰氯
Figure PCTCN2020085294-appb-000077
3-(甲磺酰基)苯甲酸(300mg,1.5mmol)溶于二氯亚砜(3mL)中，反应液氮气保护下，室温搅拌1小时。反应液浓缩后得到3-(甲磺酰基)苯甲酰氯粗品，没有经过进一步纯化直接用于下一步反应。
N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-3-(甲磺酰基)苯甲酰胺(化合物16)
Figure PCTCN2020085294-appb-000078
(4-(3-氨基-5-氯-2-甲基亚苄基)哌啶-1-基)(环戊基)甲酮(100mg,0.30mmol)，3-(甲磺酰基)苯甲酰氯化物(上一步得到的粗品)溶于无水N,N-二甲基甲酰胺(5mL)，向反应液中加入三乙胺(243mg,2.4mmol)。反应混合液氮气保护下，室温搅拌1小时。反应液用水稀释后，二氯甲烷萃取。合并有机相，浓缩，剩余物用制备型高效液相色谱纯化得到灰白色固体N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-3-(甲磺酰基)苯甲酰胺27mg，纯度95％，产率18％，类白色固体。 1H NMR(400MHz,DMSO-d 6)δ10.34(s,1H),8.49(s,1H),8.30(d,1H),8.16(d,1H),7.84(t,1H),7.36(s,1H),7.08(d,1H),6.38(s,1H),3.60-3.50(m,2H),3.49-3.44(m,2H),3.30(s,3H),3.03-2.99(m,1H),2.37-2.11(m,4H),2.11(s,3H),1.78-1.51(m,8H)。MS计算值：514.2，MS实测值：515.0([M+H] +)。
6-甲氧基哒嗪-4-甲酸
Figure PCTCN2020085294-appb-000079
氢化钠(480mg,12.0mmol)溶于10mL甲醇中，氮气保护下，缓慢加入到0℃下的6-氯哒嗪-4-甲酸甲酯(345mg,2.00mmol)的甲醇(10mL)溶液中。反应混合液50℃搅拌三小时。然后，冷却到室温。用1mol/L的盐酸调节pH到3。反应液浓缩，浓缩剩余物用制备型高效液相色谱纯化得到6-甲氧基哒嗪-4-甲酸80mg，产率24％，类白色固体。 1H NMR(400MHz,DMSO-d 6)δ14.15(br,1H),9.20(d,1H),7.50(d,1H),4.09(s,3H)。
6-甲氧基哒嗪-4-甲酸
Figure PCTCN2020085294-appb-000080
6-甲氧基哒嗪-4-甲酸(80mg,0.52mmol)溶于7mL甲醇/四氢呋喃溶液(体积比＝1/6)中，氮气保护下，0℃向此反应液中加入三甲基硅基重氮甲烷(0.5mL,1.00mmol)。反应混合液0℃搅拌2小时，浓缩。浓缩剩余物没有进一步纯化直接用于下一步反应。
N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-6-甲氧基哒嗪-4-甲酰胺(化合物17)
Figure PCTCN2020085294-appb-000081
6-甲氧基哒嗪-4-甲酸甲酯(上一步得到的粗品,0.519mmol)和(4-(3-氨基-5-氯-2-甲基亚苄基)哌啶-1-基)(环戊基)甲酮(150mg,0.450mmol)溶于10mL甲苯中，氮气保护下，0℃向其中缓慢滴加三甲基铝(0.6mL,1.20mmol)的甲苯溶液。反应混合液80℃搅拌2小时。加入10mL水稀释反应液后，再加入3mL 1mol/L盐酸。混合液用乙酸乙酯(10mL×3)萃取。合并有机相，无水硫酸钠干燥，过滤并浓缩。浓缩剩余物用制备型高效液相色谱纯化得到N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-6-甲氧基哒嗪-4-甲酰胺80mg，纯度95％，产率40％，类白色固体。 1H NMR(400MHz,DMSO-d 6)δ10.38(s,1H),9.28(d,1H),7.64(d,1H),7.41(d,1H),7.08(d,1H),6.37(s,1H),4.10(s,3H),3.58-3.57(m,2H),3.48-3.46(m,2H),3.03-2.97(m,1H),2.39-2.10(m,4H),2.11(s,3H),1.77-1.51(m,8H)。MS计算值:468.2，MS实测值:469.2([M+H] +)。
3,5-二氯-1-甲基吡嗪-2(1H)-酮
Figure PCTCN2020085294-appb-000082
2-(甲氨基)-乙腈(10g,93.9mmol)溶于氯苯(80mL)，室温条件下逐滴加入草酰氯(27mL,320mmol)，反应混合液缓慢升温到90℃，搅拌5小时。浓缩除去溶剂，浓缩剩余物用硅胶柱柱层析纯化(石油醚/乙酸乙酯＝10/1，体积比)得到3,5-二氯-1-甲基吡嗪-2(1H)-酮12.7g，粗品，产率75％，深棕色油状物。
5-氯-3-(二乙胺基)-1-甲基吡嗪-2(1H)-酮
Figure PCTCN2020085294-appb-000083
3,5-二氯-1-甲基吡嗪-2(1H)-酮(800mg,4.5mmol)溶于1,4-二氧六环(5mL)，向反应液中加入二乙胺(1mL,9.0mmol)。反应混合液50℃搅拌2小时。反应完成后，浓缩除去溶剂，浓缩剩余物溶于二氯甲烷，水洗。有机层浓缩，用硅胶柱柱层析纯化(石油醚/乙酸乙酯＝7/1，体积比)得到5-氯-3-(二乙胺基)-1-甲基吡嗪-2(1H)-酮560mg，产率58％，黄色固体。 1H NMR(400MHz,DMSO-d 6)δ7.06(s,1H),3.66(q,4H),3.31(s,3H),1.13(t,6H)。
6-氰基-1-甲基-2-氧-1,2-二氢吡啶-4-甲酸甲酯
Figure PCTCN2020085294-appb-000084
5-氯-3-(二乙胺基)-1-甲基吡嗪-2(1H)-酮(300mg,1.4mmol)和丙烯酸甲酯(0.4mL,4.2mmol)溶于15mL甲苯，反应液氮气保护下，80℃搅拌过夜。反应完成后，浓缩除去溶剂，浓缩剩余物用硅胶柱柱层析纯化(石油醚/乙酸乙酯＝3/1，体积比)得到6-氰基-1-甲基-2-氧-1,2-二氢吡啶-4-甲酸甲酯110mg，产率41％，白色固体。 1H NMR(400MHz,DMSO-d 6)δ7.35(d,1H),7.20(d,1H),3.87(s,3H),3.57(s,3H)。
N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-6-氰基-1-甲基-2-氧-1,2-二氢吡啶-4-甲酰胺(化合物18)
Figure PCTCN2020085294-appb-000085
6-氰基-1-甲基-2-氧-1,2-二氢吡啶-4-甲酸甲酯(50mg,0.26mmol)和(4-(3-氨基-5-氯-2-甲基亚苄基)哌啶-1-基)(环戊基)甲酮(87mg,0.26mmol)溶于甲苯(5mL)，氮气保护下，0℃搅拌，然后加入三甲基铝(0.26mL,0.52mmol)的甲苯溶液。反应混合液80℃搅拌3小时。氯化铵溶液淬灭反应，用二氯甲烷(20mL×3)萃取。合并有机相，浓缩，浓缩剩余物用制备型高效液相色谱纯化得到N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-6-氰基-1-甲基-2-氧-1,2-二氢吡啶-4-甲酰胺56mg，纯度95％，产率44％，白色固体。 1H NMR(400MHz,DMSO-d 6)δ10.28(s,1H),7.40(s,1H),7.35(s,1H),7.32(s,1H),7.08(s,1H),6.37(s,1H),3.59(s,3H),3.59-3.41(m,4H),3.04-2.97(m,1H),2.40-2.04(m,4H),2.07(s,3H),1.75-1.52(m,8H)。MS计算值:492.2，MS实测值:493.2([M+H] +)。
2-环丙基噻唑-5-甲酸甲酯
Figure PCTCN2020085294-appb-000086
2-氯噻唑-5-甲酸甲酯(500mg,2.8mmol)，环丙基酸(1.2g,14mmol)，[1,1'-双(二苯基膦基)二茂铁]二氯化钯(228mg,0.28mmol)和碳酸钾(1.16g,8.4mmol)溶于1,4-二氧六环(30mL)，氮气保护下，90℃搅拌14小时。浓缩除去溶剂，水稀释，二氯甲烷(20mL×3)萃取。合并有机相，浓缩，浓缩剩余物用硅胶柱柱层析纯化(石油醚/乙酸乙酯＝3/1，体积比) 得到2-环丙基噻唑-5-甲酸甲酯180mg，产率35％，黄色油状物。 1H NMR(400MHz,DMSO-d 6)δ8.23(s,1H),3.82(s,3H),2.51(m,1H),1.22-1.06(m,4H)。
N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-2-环丙基噻唑-5-甲酰胺(化合物19)
Figure PCTCN2020085294-appb-000087
2-环丙基噻唑-5-甲酸甲酯(60mg,0.33mmol)，(4-(3-氨基-5-氯-2-甲基亚苄基)哌啶-1-基)(环戊基)甲酮(109mg,0.33mmol)溶于5mL的无水甲苯，氮气保护下，0℃搅拌，反应液中加入三甲基铝(0.33mL,0.66mmol)的甲苯溶液。反应混合液80℃搅拌3小时。氯化铵溶液淬灭，二氯甲烷(20mL×3)萃取。合并有机层后，浓缩，浓缩剩余物用制备型高效液相色谱纯化得到N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-2-环丙基噻唑-5-甲酰胺35mg，纯度95％，产率22％，白色固体。 1H NMR(400MHz,DMSO-d 6)δ10.09(s,1H),8.35(s,1H),7.31(s,1H),7.05(s,1H),6.36(s,1H),3.59-3.55(m,2H),3.47-3.45(m,2H),3.01-2.97(m,1H),2.40-2.08(m,5H),2.07(s,3H),1.76-1.53(m,8H),1.21-1.16(m,2H),1.06-1.02(m,2H)。MS计算值:483.1，MS实测值:484.2([M+H] +)。
1-环丙基-1氢-吡唑-4-甲酸甲酯
Figure PCTCN2020085294-appb-000088
1氢-吡唑-4-甲酸甲酯(252mg,2.00mmol)，环丙基酸(378mg,4.40mmol)，醋酸铜(363mg,2.00mmol)，2,2’-联吡啶(312mg,2.00mmol)和碳酸钠(488mg,4.60mmol)溶于二氯乙烷(20mL)，反应液氮气保护下，70℃搅拌过夜。浓缩除去溶剂，浓缩剩余物用硅胶柱柱层析纯化(二氯甲烷/甲醇＝100/1，体积比)得到1-环丙基-1氢-吡唑-4-甲酸甲酯100mg，产率36％，无色油状物。 1H NMR(400MHz,CDCl 3)δ7.94(s,1H),7.87(s,1H),3.82(s,3H),3.63(m,1H),1.17-1.12(m,2H),1.10-1.04(m,2H)。
N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-1-环丙基-1H-吡唑-4-甲酰胺(化合物20)
Figure PCTCN2020085294-appb-000089
1-环丙基-1H-吡唑-4-甲酸甲酯(60mg,0.361mmol)和(4-(3-氨基-5-氯-2-甲基亚苄基)哌啶-1-基)(环戊基)甲酮(120mg,0.360mmol)溶于10mL甲苯，氮气保护下，0℃向反应液 中缓慢加入三甲基铝(0.4mL,0.800mmol)。反应混合液80℃搅拌2小时。加入10mL水稀释反应液，再加入3mL 1mol/L的盐酸。乙酸乙酯(10mL×3)萃取。合并有机相，无水硫酸钠干燥，浓缩。浓缩剩余物用制备型高效液相色谱纯化得到N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-1-环丙基-1H-吡唑-4-甲酰胺12mg，纯度95％，产率7％，白色固体。 1H NMR(400MHz,DMSO-d 6)δ9.53(s,1H),8.38(s,1H),7.96(s,1H),7.32(s,1H),7.02(s,1H),6.36(s,1H),3.84-3.78(m,1H),3.61-3.55(m,2H),3.50-3.42(m,2H),3.05-2.97(m,1H),2.40-2.10(m,4H),2.08(s,3H),1.77-1.53(m,8H),1.09-1.05(m,2H),1.03-0.98(m,2H)。MS计算值:466.2，MS实测值:467.2([M+H] +)。
N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-3-甲氧基苯甲酰胺(化合物21)
Figure PCTCN2020085294-appb-000090
3-甲氧基苯甲酸甲酯(50mg,0.3mmol)和(4-(3-氨基-5-氯-2-甲基亚苄基)哌啶-1-基)(环戊基)甲酮(79mg,0.237mmol)溶于甲苯(10mL)，氮气保护下，0℃搅拌，向反应液中缓慢加入三甲基铝(0.3mL,0.6mmol)的甲苯溶液。反应混合液80℃搅拌3小时。氯化铵溶液淬灭反应，二氯甲烷(20mL×3)萃取。合并有机相，浓缩，浓缩剩余物用制备型高效液相色谱纯化得到N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-3-甲氧基苯甲酰胺11mg，纯度95％，产率8％，白色固体。 1H NMR(400MHz,DMSO-d 6)δ9.96(s,1H),7.56(d,1H),7.50(d,1H),7.46-7.42(m,1H),7.34(d,1H),7.18-7.15(m,1H),7.05(s,1H),6.37(s,1H),3.83(s,3H),3.58-3.55(m,2H),3.48-3.44(m,2H),3.03-2.99(m,1H),2.37-2.09(m,4H),2.08(s,3H),1.76-1.51(m,8H)。MS计算值:466.2，MS实测值:467.0([M+H] +)。
N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-3-甲氧基环丁基酰胺(化合物22)
Figure PCTCN2020085294-appb-000091
3-甲氧基环丁基甲酸(101mg,0.78mmol)溶于氯化亚砜(4mL)，氮气保护下，反应液50℃下搅拌2小时。浓缩除去氯化亚砜，剩余物溶解到6mL N,N-二甲基甲酰胺。然后加入(4-(3-氨基-5-氯-2-甲基亚苄基)哌啶-1-基)(环戊基)甲酮(129mg,0.39mmol)和三乙胺(0.2mL,1.43mmol)。氮气保护下，反应混合溶液25℃下搅拌1小时。浓缩得到粗产品，用制备型高效液相色谱纯化得到N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-3-甲氧基丁烷 酰胺20mg，纯度95％，产率12％，白色固体。 1H NMR(400MHz,DMSO-d 6)δ9.37(s,1H),7.39(s,1H),6.94(d,1H),6.33(s,1H),3.79(p,1H),3.60-3.54(m,2H),3.46-3.40(m,2H),3.13(s,3H),3.04-2.94(m,1H),2.85-2.76(m,1H),2.43-2.34(m,3H),2.28-2.26(t,1H),2.18(t,1H),2.14-1.98(m,6H),1.78-1.46(m,8H)。MS计算值：444.2，MS实测值：445.2([M+H] +)。
N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-3-苯基丙酰胺(化合物23)
Figure PCTCN2020085294-appb-000092
3-苯基丙酸(100mg,0.67mmol)溶于氯化亚砜(4mL)，反应液50℃搅拌2小时。浓缩除去溶剂，真空干燥。残留物溶于N,N-二甲基甲酰胺(8mL)，然后加入(4-(3-氨基-5-氯-2-甲基亚苄基)哌啶-1-基)(环戊基)甲酮(100mg,0.30mmol)和三乙胺(0.13mL,0.90mmol)。反应混合液室温搅拌过夜。反应完全后，浓缩除去溶剂，剩余物用制备型高效液相色谱纯化得到N-(5-氯-3((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-3-苯基丙酰胺14mg，纯度95％，产率10％，白色固体。 1H NMR(400MHz,DMSO-d 6)δ9.39(s,1H),7.35-7.24(m,5H),7.21-7.17(m,1H),6.93(s,1H),6.31(s,1H),3.54-3.58(m,2H),3.41-3.47(m,2H),2.98-3.03(m,1H),2.92(t,2H),2.67(t,2H),2.09-2.34(m,4H),1.96(s,3H),1.79-1.71(m,2H),1.67-1.23(m,6H)。MS计算值：464.2，MS实测值：465.2([M+H] +)。
叔丁基4-(3-氨基-5-氯-2-甲基亚苄基)哌啶-1-羧酸酯
Figure PCTCN2020085294-appb-000093
叔丁基4-(-5-氯-2-甲基-3-硝基亚苄基)哌啶-1-羧酸酯(900mg,2.5mmol)、醋酸钠(407mg,5.0mmol)和醋酸(2mL)溶解于乙醇/水(40mL/20mL)，向反应液中加入铁粉(556mg,9.9mmol)。反应混合液80℃搅拌1小时。反应液倒入水中，用乙酸乙酯萃取。合并有机相，浓缩，浓缩剩余物用硅胶柱柱层析纯化(石油醚/乙酸乙酯＝8/1，体积比)得到叔丁基4-(3-氨基-5-氯-2-甲基亚苄基)哌啶-1-羧酸酯650mg，产率78％，黄色油状物。 1H NMR(400MHz,DMSO-d 6)：δ6.56(d,1H),6.26(d,1H),6.25(s,1H),5.14(s,2H),3.41(t,2H),3.28(t,2H),2.25(t,2H),2.09(t,2H),1.89(s,3H),1.40(s,9H)。
4-(5-氯-3-(3-氰基苯甲酰胺)-2-甲基亚苄基)哌啶-1-羧酸叔丁酯
Figure PCTCN2020085294-appb-000094
4-(3-氨基-5-氯-2-甲基亚苄基)哌啶-1-羧酸叔丁酯(100mg,0.30mmol)和3-氰基苯甲酸甲酯(48mg,0.30mmol)溶于无水甲苯(2mL)，降温到0℃，氮气保护下，反应液中加入三甲基铝(0.3mL,2M,0.60mmol)甲苯溶液。反应混合液氮气保护下，80℃搅拌3小时。反应液中加入饱和氯化铵溶液，乙酸乙酯萃取。合并有机相，浓缩，浓缩剩余物用硅胶柱柱层析纯化(石油醚/乙酸乙酯＝2/1，体积比)得到4-(5-氯-3-(3-氰基苯甲酰胺)-2-甲基亚苄基)哌啶-1-羧酸叔丁酯140mg，产率100％，白色固体。 1H NMR(400MHz,DMSO-d 6)δ10.21(s,1H),8.40(s,1H),8.26(d,1H),8.09(d,1H),7.77(t,1H),7.37(d,1H),7.06(d,1H),6.37(s,1H),3.44(t,2H),3.33(t,2H),2.31(t,2H),2.17(d,2H),2.10(s,3H),1.41(s,9H)。
N-(5-氯-2-甲基-3-(哌啶-4-亚基甲基)苯基)-3-氰基苯甲酰胺盐酸盐
Figure PCTCN2020085294-appb-000095
4-(5-氯-3-(3-氰基苯甲酰胺)-2-甲基亚苄基)哌啶-1-羧酸酯(140mg,0.30mmol)溶于乙酸乙酯(2mL)，反应液中加入乙酸乙酯/盐酸溶液(2mL)。反应混合液室温搅拌1小时。反应混合液浓缩得到N-(5-氯-2-甲基-3-(哌啶-4-亚基甲基)苯基)-3-氰基苯甲酰胺盐酸盐，没有经过进一步纯化直接用于下一步反应。
N-(5-氯-2-甲基-3-((1-(四氢-2H-吡喃-4-羰基)哌啶-4-亚基)甲基)苯基)3-氰基苯甲酰胺(化合物24)
Figure PCTCN2020085294-appb-000096
N-(5-氯-2-甲基-3-(哌啶-4-亚基甲基)苯基)-3-氰基苯甲酰胺盐酸盐(0.30mmol)、四氢-2H-吡喃-4-羧酸(39mg,0.30mmol)和2-(7-偶氮苯并三氮唑)-N,N,N’,N’-四甲基脲六氟磷酸酯(114mg,0.3mmol)溶于N,N-二甲基甲酰胺(3mL)，反应液中加入三乙胺(0.3mL)。反应混合液氮气保护下，40℃搅拌2小时。反应液浓缩，浓缩剩余物用制备液相色谱法得到N-(5-氯-2-甲基-3-((1-(四氢-2H-吡喃-4-羰基)哌啶-4-亚基)甲基)苯基)3-氰基苯甲酰胺27mg， 纯度95％，产率20％，白色固体。 1H NMR(400MHz,DMSO-d 6)δ10.24(s,1H),8.41(s,1H),8.27(d,1H),8.16(d,1H),7.78(t,1H),7.39(d,1H),7.08(d,1H),6.39(s,1H),3.84-3.86(m,2H),3.36-3.62(m,6H),2.90-2.95(m,1H)2.14-2.40(m,4H),2.12(s,3H),1.53-1.66(m,4H)。MS计算值：477.2，MS实测值：478.2([M+H] +)。
N-(5-氯-3-((1-(2-环丙基乙酰)哌啶-4-亚基)甲基)-2-甲苯基)-3-氰基苯甲酰胺(化合物25)
Figure PCTCN2020085294-appb-000097
N-(5-氯-2-甲基-3-(哌啶-4-亚基甲基)苯基)-3-氰基苯甲酰胺盐酸盐(0.22mmol)、环丙基乙酸(0.5mL,0.55mmol)和2-(7-偶氮苯并三氮唑)-N,N,N’,N’-四甲基脲六氟磷酸酯(92mg,0.24mmol)溶于N,N-二甲基甲酰胺(3mL)，反应液中加入三乙胺(0.3mL)。反应混合液氮气保护下，40℃搅拌2小时。反应液浓缩，浓缩剩余物用制备液相色谱法得到N-(5-氯-3-((1-(2-环丙基乙酰)哌啶-4-亚基)甲基)-2-甲苯基)-3-氰基苯甲酰胺21mg，纯度95％，产率21％,白色固体。 1H NMR(400MHz,DMSO-d 6)δ10.21(s,1H),8.40(s,1H),8.26(d,1H),8.09(d,1H),7.77(t,1H),7.38(d,1H),7.07(d,1H),6.38(s,1H),3.51-3.58(m,2H),3.40-3.47(m,2H),2.13-2.39(m,6H),2.10(s,3H),0.96(m,1H),0.43-0.47(m,2H),0.12(t,2H)。MS计算值：447.2，MS实测值：448.0([M+H] +)。
N-(5-氯-3-((1-(3,3-二氟环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-3-氰基苯甲酰胺(化合物26)
Figure PCTCN2020085294-appb-000098
N-(5-氯-2-甲基-3-(哌啶-4-亚基甲基)苯基-3-氰基苯甲酰胺(50mg,0.14mmol)、3,3-二氟环戊基甲酸(42mg,0.28mmol)和2-(7-偶氮苯并三氮唑)-N,N,N’,N’-四甲基脲六氟磷酸酯(53mg,0.14mmol)溶于N,N-二甲基甲酰胺(3mL)，反应液中加入三乙胺(0.1mL)。反应混合液氮气保护下室温搅拌2小时。反应液浓缩，浓缩剩余物用制备型高效液相色谱纯化得到N-(5-氯-3-((1-(3,3-二氟环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-3-氰基苯甲酰胺20mg，纯度95％，产率29％，白色固体。 1H NMR(400MHz,DMSO-d 6)δ10.22(s,1H),8.40(s,1H), 8.26(d,1H),8.09(d,1H),7.77(t,1H),7.38(s,1H),7.06(s,1H),6.39(s,1H),3.48-3.60(m,4H),3.31-3.40(m,1H),2.01-2.39(m,9H),2.11(s,3H),1.80(m,1H)。MS计算值：497.2，MS实测值：498.0([M+H] +)。
N-(3-((1-(二环[3.1.0]己烷-3-羰基)哌啶-4-亚基)甲基)-5-氯-2-甲苯基-3-氰基苯甲酰胺(化合物27)
Figure PCTCN2020085294-appb-000099
N-(5-氯-2-甲基-3-(哌啶-4-亚基甲基)苯基)-3-氰基苯甲酰胺(50mg,0.14mmol)、二环[3.1.0]己烷-3-甲酸(35mg,0.28mmol)和2-(7-偶氮苯并三氮唑)-N,N,N’,N’-四甲基脲六氟磷酸酯(53mg,0.14mmol)溶于N,N-二甲基甲酰胺(3mL)，反应液中加入三乙胺(0.1mL)。反应混合液氮气保护下，室温搅拌2小时。反应液浓缩，浓缩剩余物用制备型高效液相色谱纯化得到白色固体N-(3-((1-(二环[3.1.0]己烷-3-羰基)哌啶-4-亚基)甲基)-5-氯-2-甲苯基-3-氰基苯甲酰胺20mg，纯度95％，产率30％。 1H NMR(400MHz,DMSO-d 6)δ10.19(s,1H),8.40(s,1H),8.26(d,1H),8.09(d,1H),7.77(t,1H),7.38(s,1H),7.06(s,1H),6.37(s,1H),3.52(s,2H),3.41(s,2H),3.29-3.31(m,1H),2.10-2.36(m,6H),2.10(s,3H),1.89(d,2H),1.23(s,2H),0.21-0.33(m,2H)。MS计算值：473.2，MS实测值：474.0([M+H] +)。
N-(5-氯-3-((1-(3,3-二氟环丁基羰基)哌啶-4-亚基)甲基-2-甲苯基)-3-氰基苯甲酰胺(化合物28)
Figure PCTCN2020085294-appb-000100
N-(5-氯-2-甲基-3-(哌啶-4-亚基甲基)苯基)-3-氰基苯甲酰胺(70mg,0.19mmol)、3,3-二氟环丁基甲酸(51mg,0.38mmol)和2-(7-偶氮苯并三氮唑)-N,N,N’,N’-四甲基脲六氟磷酸酯(80mg,0.21mmol)溶于N,N-二甲基甲酰胺(3mL)，反应液中加入三乙胺(0.1mL)。反应混合液氮气保护下，40℃搅拌1小时。反应液浓缩，浓缩剩余物用制备型高效液相色谱纯化得到N-(5-氯-3-((1-(3,3-二氟环丁基羰基)哌啶-4-亚基)甲基-2-甲苯基)-3-氰基苯甲酰胺35mg，纯度95％，产率38％，白色固体。 1H NMR(400MHz,DMSO-d 6)δ10.19(s,1H),8.40(s, 1H),8.26(d,1H),8.08(d,1H),7.77(t,1H),7.38(s,1H),7.06(s,1H),6.39(s,1H),3.26-3.59(m,5H),2.75-2.85(m,4H),2.17-2.36(m,4H),2.11(s,3H)。MS计算值：483.2，MS实测值：484.2([M+H] +)。
N-(3-((1-(2-(二环[1.1.1]戊烷-1-基)乙酰基)哌啶-4-亚基)甲基)-5-氯-2-甲苯基)-3-氰基苯甲酰胺(化合物29)
Figure PCTCN2020085294-appb-000101
N-(5-氯-2-甲基-3-(哌啶-4-亚基甲基)苯基)-3-氰基苯甲酰胺(60mg,0.16mmol)，2-(二环[1.1.1]戊烷-1-基)乙酸(40mg,0.32mmol)和三乙胺(0.1mL)溶于N,N-二甲基甲酰胺(3mL)，反应液中加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(61mg,0.16mmol)。反应混合液氮气保护下50℃搅拌1.5个小时。反应液浓缩，浓缩剩余物用制备型高效液相色谱纯化得到N-(3-((1-(2-(二环[1.1.1]戊烷-1-基)乙酰基)哌啶-4-亚基)甲基)-5-氯-2-甲苯基)-3-氰基苯甲酰胺30mg，纯度95％，产率39％，白色固体。 1H NMR(400MHz,DMSO-d 6)δ10.19(s,1H),8.40(s,1H),8.26(d,1H),8.09(d,1H),7.77(t,1H),7.38(d,1H),7.07(s,1H),6.38(s,1H),3.57-3.53(m,2H),3.46-3.42(m,2H),2.56(d,2H),2.46(d,1H),2.38-2.12(m,4H),2.11(s,3H),1.74(d,6H)。MS计算值:473.2，MS实测值:474.1([M+H] +)。
4-(5-氯-3-(6-氰基-1-甲基-2-氧-1,2-二氢吡啶-4-酰胺)-2-甲基亚苄基)哌啶-1-甲酸叔丁酯
Figure PCTCN2020085294-appb-000102
6-氰基-1-甲基-2-氧-1,2-二氢吡啶-4-甲酸甲酯(300mg,1.56mmol)和4-(3-氨基-5-氯-2-甲基亚苄基)哌啶-1-甲酸叔丁酯(525mg,1.56mmol)溶于甲苯(10mL)，氮气保护下，0℃搅拌。然后加入三甲基铝甲苯溶液(1.56mL,3.12mmol)。反应液80℃搅拌3小时。氯化铵溶液淬灭反应，二氯甲烷萃取(20mL×5)。合并有机相并浓缩，浓缩剩余物用硅胶柱柱层析(石油醚/乙酸乙酯＝2/1，体积比)纯化得到4-(5-氯-3-(6-氰基-1-甲基-2-氧-1,2-二氢吡啶-4-酰胺)-2-甲基亚苄基)哌啶-1-甲酸叔丁酯620mg，产率80％，白色固体。 1H NMR(400MHz,DMSO-d 6)δ10.27(s,1H),7.40(d,1H),7.34(d,1H),7.32(s,1H),7.07(s,1H),6.35(s,1H),3.60(s,3H),3.43-3.41(m,2H),3.34-3.32(m,2H),3.32-3.29(m,2H),3.16-3.13(m,2H),2.07(s,3H),1.41(s,9H)。
N-(5-氯-2-甲基-3-(哌啶-4-亚基甲基)苯基)-6-氰基-1-甲基-2-氧-1,2-二氢吡啶-4-甲酰胺
Figure PCTCN2020085294-appb-000103
4-(5-氯-3-(6-氰基-1-甲基-2-氧-1,2-二氢吡啶-4-羧酰胺)-2-甲基亚苄基)哌啶-1-甲酸叔丁酯(620mg,1.25mmol)溶于二氯甲烷(4mL)，反应液中加入三氟乙酸(6mL)。反应混合液室温搅拌过夜。浓缩除去溶剂，浓缩剩余物用水稀释，碳酸氢钠溶液中和，二氯甲烷萃取(20mL×5)。合并有机相并浓缩，真空干燥得到N-(5-氯-2-甲基-3-(哌啶-4-亚基甲基)苯基)-6-氰基-1-甲基-2-氧-1,2-二氢吡啶-4-甲酰胺粗品600mg，黄色固体。 1H NMR(400MHz,DMSO-d 6)δ10.27(s,1H),7.48(s,1H),7.41(s,1H),7.31(s,1H),6.90(s,1H),6.20(s,1H),3.58(s,3H),3.41-3.39(m,1H),3.28-3.26(m,1H),2.77-2.75(m,1H),2.67-2.64(m,1H),2.25-2.16(m,2H),2.08-2.03(m,2H),2.06(s,3H)。
N-(3-((1-(2-(二环[1.1.1]戊烷-1-基)乙酰基)哌啶-4-亚基)甲基)-5-氯-2-甲苯基)-6-氰基-1-甲基-2-氧-1,2-二氢吡啶-4-甲酰胺(化合物30)
Figure PCTCN2020085294-appb-000104
N-(5-氯-2-甲基-3-(哌啶-4-亚基甲基)苯基)-6-氰基-1-甲基-2-氧-1,2-二氢吡啶-4-甲酰胺(100mg,0.27mmol)，2-(二环[1.1.1]戊烷-1-基)乙酸(60mg,0.54mmol)，2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(308mg,0.81mmol)和三乙胺(0.22mL,0.81mmol)溶于N,N-二甲基甲酰胺(3mL)，室温搅拌过夜。反应完成后，反应液用制备型高效液相色谱纯化得到N-(3-((1-(2-(二环[1.1.1]戊烷-1-基)乙酰基)哌啶-4-亚基)甲基)-5-氯-2-甲苯基)-6-氰基-1-甲基-2-氧-1,2-二氢吡啶-4-甲酰胺36mg，纯度95％，产率26％，白色固体。 1H NMR(400MHz,DMSO-d 6)δ10.25(s,1H),7.39(d,1H),7.35(d,1H),7.32(d,1H),7.08-7.06(s,1H),6.36(s,1H),3.59(s,3H),3.56-3.54(m,1H),3.52-3.49(m,1H),3.45-3.42(m,1H),3.40-3.36(m,1H),2.55(d,2H),2.46(d,1H),2.37-2.35(m,1H),2.30-2.27(m,1H),2.21-2.18(m,1H),2.13-2.10(m,1H),2.07(s,3H),1.74-1.72(m,6H)。MS计算值:504.2，MS实测值:505.0([M+H] +)。
N-(5-氯-3-((1-(4,4-二氟环己基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-6-氰基-1-甲基-2-氧-1,2-二氢吡啶-4-甲酰胺(化合物31)
Figure PCTCN2020085294-appb-000105
N-(5-氯-2-甲基-3-(哌啶-4-亚基甲基)苯基)-6-氰基-1-甲基-2-氧-1,2-二氢吡啶-4-甲酰胺(50mg,0.135mmol),4,4-二氟环己基甲酸(44mg,0.27mmol)，2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(154mg,0.40mmol)和三乙胺(0.11mL,0.40mmol)溶于N,N-二甲基甲酰胺(3mL)，室温搅拌过夜。反应完成后，反应液用制备型高效液相色谱纯化得到N-(5-氯-3-((1-(4,4-二氟环己基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-6-氰基-1-甲基-2-氧-1,2-二氢吡啶-4-甲酰胺5mg，纯度94％，产率7％，白色固体。 1H NMR(400MHz,DMSO-d 6)δ10.26(s,1H),7.39(s,1H),7.35(s,1H),7.32(s,1H),7.09(d,1H),6.37(s,1H),3.64-3.44(m,4H),3.60(s,3H),2.86-2.79(m,1H),2.40-2.12(m,4H),2.06(s,3H),2.04-2.02(m,2H),1.95-1.83(m,2H),1.76-1.73(m,2H),1.63-1.54(m,2H)。MS计算值:542.2，MS实测值:543.0([M+H] +)。
N-(5-氯-3-((1-(4,4-二氟环己基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-3-氰基苯甲酰胺(化合物32)
Figure PCTCN2020085294-appb-000106
N-(5-氯-2-甲基-3-(哌啶-4-亚基甲基)苯基)-3-氰基苯甲酰胺(60mg,0.16mmol)，4,4-二氟环己基甲酸(53mg,0.32mmol)和三乙胺(0.1mL)溶于N,N-二甲基甲酰胺(3mL)，反应液中加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(61mg,0.16mmol)。反应混合液氮气保护下50℃搅拌1小时。反应液浓缩，浓缩剩余物用制备型高效液相色谱纯化得到N-(5-氯-3-((1-(4,4-二氟环己基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-3-氰基苯甲酰胺20mg，纯度95％，产率24％，白色固体。 1H NMR(400MHz,DMSO-d 6)δ10.21(s,1H),8.40(s,1H),8.26(d,1H),8.09(d,1H),7.77(t,1H),7.38(s,1H),7.08(d,1H),6.39(s,1H),3.63-3.47(m,4H),2.82-2.89(m,1H),2.41-2.16(m,4H),2.11(s,3H),2.00-2.06(m,2H), 1.83-1.95(m,2H),1.73-1.76(m,2H),1.57-1.64(m,2H)。MS计算值:511.2，MS实测值:512.1([M+H] +)。
N-(5-氯-2-甲基-3-((1-(噻吩-2-羰基)哌啶-4-亚基)甲基)苯基)-3-氰基苯甲酰胺(化合物33)
Figure PCTCN2020085294-appb-000107
N-(5-氯-2-甲基-3-(哌啶-4-亚基甲基)苯基)-3-氰基苯甲酰胺(150mg,0.41mmol)，碳酸钾(171mg,1.23mmol)溶于乙腈(12mL)，反应液中加入噻吩-2-羰基氯(180mg,1.23mmol)。反应混合液氮气保护下，室温搅拌过夜。反应液中加入水，乙酸乙酯萃取。合并有机相并浓缩，浓缩剩余物用制备型高效液相色谱纯化得到N-(5-氯-2-甲基-3-((1-(噻吩-2-羰基)哌啶-4-亚基)甲基)苯基)-3-氰基苯甲酰胺80mg，纯度95％，产率39％，白色固体。 1H NMR(400MHz,DMSO-d 6)δ10.20(s,1H),8.40(s,1H),8.26(d,1H),8.09(dt,1H),7.75-7.79(m,2H),7.44(dd,1H),7.39(d,1H),7.12-7.14(m,1H),7.09(d,1H),6.42(s,1H),3.74(t,2H),3.63(t,2H),2.45(t,2H),2.30(t,2H),2.12(s,3H)。MS计算值:475.1，MS实测值:476.0([M+H] +)。
N-(5-氯-3-((1-(2-环丁基乙酰基)哌啶-4-亚基)甲基)-2-甲苯基)-6-氰基-1-甲基-2-氧-1,2-二氢吡啶-4-甲酰胺(化合物34)
Figure PCTCN2020085294-appb-000108
N-(5-氯-2-甲基-3-(哌啶-4-亚基甲基)苯基)-6-氰基-1-甲基-2-氧-1,2-二氢吡啶-4-甲酰胺(110mg,0.27mmol)，2-环丁基乙酸(0.03mL,0.33mmol)，2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(188mg,0.50mmol)和三乙胺(0.12mL,0.81mmol)溶于N,N-二甲基甲酰胺(3mL)，室温搅拌过夜。反应完成后，反应液用制备型高效液相色谱纯化得到N-(5-氯-3-((1-(2-环丁基乙酰基)哌啶-4-亚基)甲基)-2-甲苯基)-6-氰基-1-甲基-2-氧-1,2-二氢吡啶-4-甲酰胺12mg，纯度95％，产率9％，白色固体。 1H NMR(400MHz,DMSO-d 6)δ10.25(s,1H),7.39(d,1H),7.34(d,1H),7.32(d,1H),7.06(d,1H),6.35(s,1H),3.59(s,3H),3.54-3.50(m,2H),3.44-3.36(m,2H),2.66-2.56(m,1H),2.46-2.45(m,2H),2.36-2.08(m,4H),2.07(s,3H),2.05-1.97(m,2H),1.85-1.77(m,2H),1.67-1.61(m,2H)。MS计算值:492.2，MS实测值:493.0([M+H] +)。
4-(5-氯-3-(5-氰基烟酰胺)-2-甲基亚苄基)哌啶-1-甲酸叔丁酯
Figure PCTCN2020085294-appb-000109
5-氰烟酸甲酯(100mg,0.62mmol)和4-(3-氨基-5-氯-2-甲基亚苄基)哌啶-1-甲酸叔丁酯(207mg,0.62mmol)溶于10mL甲苯，氮气保护下0℃搅拌，然后加入三甲基铝(0.62mL,1.24mmol)的甲苯溶液。反应混合液80℃搅拌3小时。氯化铵溶液淬灭反应，用二氯甲烷(20mL×3)萃取。合并有机相并浓缩，浓缩剩余物用硅胶柱柱层析(石油醚/乙酸乙酯＝2/1，体积比)纯化得到4-(5-氯-3-(5-c氰基烟酰胺)-2-甲基亚苄基)哌啶-1-甲酸叔丁酯120mg，产率42％，白色固体。
N-(5-氯-2-甲基-3-(哌啶-4-亚基甲基)苯基)-5-氰基烟酰胺
Figure PCTCN2020085294-appb-000110
4-(5-氯-3-(5-氰基烟酰胺)-2-甲基亚苄基)哌啶-1-甲酸叔丁酯(120mg,0.258mmol)溶于二氯甲烷(8mL)，缓慢的加入三氟乙酸(2mL)。反应混合液室温搅拌2小时，然后浓缩。浓缩剩余物没纯化直接用于下一步反应。
N-(5-氯-3-((1-(2-环丙基乙酰基)哌啶-4-亚基)甲基)-2-甲苯基)-5-氰基烟酰胺(化合物35)
Figure PCTCN2020085294-appb-000111
N-(5-氯-2-甲基-3-(哌啶-4-亚基甲基)苯基)-5-氰基烟酰胺(110mg,0.237mmol)，2-环丙基乙酸(24mg,0.240mmol)，2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(108mg,0.284mmol)和N,N-二异丙基乙胺(0.2mL)溶于N,N-二甲基甲酰胺(6mL)，室温搅拌2小时。反应液浓缩。浓缩剩余物中加入水(10mL)，用乙酸乙酯(20mL×3)萃取。合并有机相，无水硫酸钠干燥后浓缩。浓缩剩余物用制备型高效液相色谱纯化得到N-(5-氯-3-((1-(2-环丙基乙酰基)哌啶-4-亚基)甲基)-2-甲苯基)-5-氰基烟酰胺16mg，纯度95％，产率15％，白色固体。 1H NMR(400MHz,DMSO-d 6)δ10.33(s,1H),9.33(d,1H),9.23(d,1H),8.79(t, 1H),7.41(d,1H),7.07(d,1H),6.38(s,1H),3.59-3.51(m,2H),3.47-3.40(m,2H),2.38-2.11(m,6H),2.12(s,3H),0.97(m,1H),0.46-0.43(m,2H),0.13-0.11(m,2H)。MS计算值:428.2，MS实测值:449.0([M+H] +)。
N-(5-氯-3-((1-(2-环丙基乙酰基)哌啶-4-亚基)甲基)-2-甲苯基)-6-氰基-1-甲基-2-氧-1,2-二氢吡啶-4-甲酰胺(化合物36)
Figure PCTCN2020085294-appb-000112
N-(5-氯-2-甲基-3-(哌啶-4-亚基甲基)苯基)-6-氰基-1-甲基-2-氧-1,2-二氢吡啶-4-甲酰胺(80mg粗品,0.2mmol)，2-环丙基乙酸(24mg,0.24mmol)，2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(137mg,0.36mmol)和三乙胺(0.1mL,0.6mmol)溶于N,N-二甲基甲酰胺(2mL)，反应液室温搅拌过夜。反应完成后，混合物用制备型高效液相色谱纯化得到N-(5-氯-3-((1-(2-环丙基乙酰基)哌啶-4-亚基)甲基)-2-甲苯基)-6-氰基-1-甲基-2-氧-1,2-二氢吡啶-4-甲酰胺2mg，纯度90％，产率2.3％，白色固体。 1H NMR(400MHz,DMSO-d 6)δ10.25(s,1H),7.39(s,1H),7.35(s,1H),7.31(s,1H),7.06(s,1H),6.36(s,1H),3.61(s,3H),3.59-3.51(m,2H),3.44-3.40(m,2H),2.38-2.11(m,6H),2.07(s,3H),0.97(m,1H),0.46-0.43(m,2H),0.13-0.09(m,2H)。MS计算值:478.2，MS实测值:479.0.
4-(5-氯-3-(5-氯-6-甲基烟酰胺)-2-甲基亚苄基)哌啶-1-甲酸叔丁酯
Figure PCTCN2020085294-appb-000113
4-(3-氨基-5-氯-2-甲基亚苄基)哌啶-1-甲酸叔丁酯(100mg,0.3mmol)，5-氯-6-甲基烟酸甲酯(61mg,0.33mmol)溶于无水甲苯(10mL)，氮气保护下，0℃向反应液中加入三甲基铝(0.3mL,2M,0.6mmol)的甲苯溶液。反应混合液氮气保护下，80℃搅拌3小时。氯化铵溶液淬灭反应后，乙酸乙酯萃取。合并有机相并浓缩，浓缩剩余物用硅胶柱柱层析(石油醚/乙酸乙酯＝2/1，体积比)纯化得到4-(5-氯-3-(5-氯-6-甲基烟酰胺)-2-甲基亚苄基)哌啶-1-甲酸叔丁酯100mg，产率69％，无色油状物。MS计算值:489.2，MS实测值:490.1([M+H] +)。
5-氯-N-(5-氯-2-甲氨基-3-(哌啶-4-亚基甲基)苯基)-6-甲基烟酰胺盐酸盐
Figure PCTCN2020085294-appb-000114
4-(5-氯-3-(5-氯-6-甲基烟酰胺)-2-甲基亚苄基)哌啶-1-甲酸叔丁酯(100mg,0.2mmol)溶于乙酸乙酯(4mL)，反应液中加入乙酸乙酯盐酸气溶液(2mL)。反应混合液室温搅拌30分钟。反应浓缩得到5-氯-N-(5-氯-2-甲氨基-3-(哌啶-4-亚基甲基)苯基)-6-甲基烟酰胺盐酸盐，白色固体，没有进一步纯化直接用于下一步反应。
5-氯-N-(5-氯-3-((1-(2-环丙基乙酰基)哌啶-4-亚基)甲基)-2-甲苯基)-6-甲基烟酰胺(化合物37)
Figure PCTCN2020085294-appb-000115
5-氯-N-(5-氯-2-甲氨基-3-(哌啶-4-亚基甲基)苯基)-6-甲基烟酰胺盐酸盐(粗品,0.21mmol)，2-环丙基乙酸(0.05mL,0.525mmol)，三乙胺(0.3mL)溶于N,N-二甲基甲酰胺(3mL)，反应液中加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(88mg,0.23mmol)。反应混合液氮气保护下，40℃搅拌3小时。反应液浓缩，浓缩剩余物用硅胶柱柱层析(石油醚/乙酸乙酯＝1/2，体积比)纯化得到5-氯-N-(5-氯-3-((1-(2-环丙基乙酰基)哌啶-4-亚基)甲基)-2-甲苯基)-6-甲基烟酰胺90mg，纯度93％，产率87％，白色固体。 1H NMR(400MHz,DMSO-d 6)δ10.20(s,1H),8.95(d,1H),8.35(d,1H),7.37(d,1H),7.06(d,1H),6.37(s,1H),3.51-3.58(m,2H),3.40-3.47(m,2H),2.64(s,3H),2.36-2.13(m,6H),2.10(s,3H),0.90-1.10(m,1H),0.42-0.48(m,2H),0.12(t,2H)。MS计算值:471.2，MS实测值:472.0([M+H] +)。
N-(5-氯-2-甲基-3-((1-(3,3,3-三氟丙酰基)哌啶-4-亚基)甲基)苯基)-6-氰基-1-甲基-2-氧代-1,2-二氢吡啶-4-甲酰胺(化合物38)
Figure PCTCN2020085294-appb-000116
N-(5-氯-2-甲基-3-(哌啶-4-亚基甲基)苯基)-6-氰基-1-甲基-2-氧-1,2-二氢吡啶-4-甲酰胺盐酸盐(100mg,0.25mmol)，3,3,3,-三氟丙酸(64mg,0.5mmol)，三乙胺(0.3mL)溶于N,N- 二甲基甲酰胺(3mL)，0℃加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(96mg,0.25mmol)。反应液室温搅拌1.5小时。反应液浓缩，浓缩剩余物用制备型高效液相色谱纯化得到N-(5-氯-2-甲基-3-((1-(3,3,3-三氟丙酰基)哌啶-4-亚基)甲基)苯基)-6-氰基-1-甲基-2-氧代-1,2-二氢吡啶-4-甲酰胺60mg，纯度95％，产率47％，白色固体。 1H NMR(400MHz,DMSO-d 6)δ10.29(s,1H),7.40(s,1H),7.35(s,1H),7.33(s,1H),7.08(s,1H),6.38(s,1H),3.64-3.76(m,2H),3.60(s,3H),3.60-3.44(m,4H),2.41-2.14(m,4H),2.08(s,3H)。MS计算值:506.1，MS实测值:507.2([M+H] +)。
N-(5-氯-2-甲基-3-((1-(四氢呋喃-3-羰基)哌啶-4-亚基)甲基)苯基)-6-氰基-1-甲基-2-氧-1,2-二氢吡啶-4-甲酰胺(化合物39)
Figure PCTCN2020085294-appb-000117
N-(5-氯-2-甲基-3-(哌啶-4-亚基甲基)苯基)-6-氰基-1-甲基-2-氧-1,2-二氢吡啶-4-甲酰胺盐酸盐(100mg,0.25mmol)，四氢呋喃-3-甲酸(58mg,0.5mmol)，三乙胺(0.2mL)溶于N,N-二甲基甲酰胺(3mL)，0℃加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(96mg,0.25mmol)。反应液室温搅拌1.5小时。反应液浓缩，浓缩剩余物用制备型高效液相色谱纯化得到N-(5-氯-2-甲基-3-((1-(四氢呋喃-3-羰基)哌啶-4-亚基)甲基)苯基)-6-氰基-1-甲基-2-氧-1,2-二氢吡啶-4-甲酰胺55mg，纯度95％，产率44％，白色固体。 1H NMR(400MHz,DMSO-d 6)δ10.29(s,1H),7.40(s,1H),7.35(s,1H),7.32(s,1H),7.08(m,1H),6.37(s,1H),3.86-3.93(m,1H),3.66-3.73(m,3H),3.60(s,3H),3.55-3.60(m,2H),3.46-3.50(m,2H),3.58-3.43(m,1H),2.36-2.12(m,4H),2.08(s,3H),2.00-2.04(m,2H)。MS计算值:494.2，MS实测值:495.2([M+H] +)。
N-(5-氯-3-((1-(3,3-二甲基环丁基羰基)哌啶-4-亚基)甲基)-2-甲基苯基)-6-氰基-1-甲基-2-氧-1,2-二氢吡啶-4-甲酰胺(化合物40)
Figure PCTCN2020085294-appb-000118
N-(5-氯-2-甲基-3-(哌啶-4-亚基甲基)苯基)-6-氰基-1-甲基-2-氧-1,2-二氢吡啶-4-甲酰胺盐酸盐(100mg,0.25mmol)，3,3-二甲基环丁基甲酸(32mg,0.25mmol)和三乙胺(77mg,0.76mmol)溶于N,N-二甲基甲酰胺(5mL)，0℃加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲 基脲六氟磷酸酯(144mg,0.38mmol)。反应混合液室温搅拌过夜。水淬灭反应，乙酸乙酯萃取。合并有机相并浓缩，浓缩剩余物用制备型高效液相色谱纯化得到N-(5-氯-3-((1-(3,3-二甲基环丁基羰基)哌啶-4-亚基)甲基)-2-甲基苯基)-6-氰基-1-甲基-2-氧-1,2-二氢吡啶-4-甲酰胺61mg，纯度95％，产率48％，白色固体。 1H NMR(400MHz,DMSO-d 6)δ10.26(s,1H),7.39(s,1H),7.34(s,1H),7.32(s,1H),7.06(s,1H),6.35(s,1H),3.59(s,3H),3.55-3.53(m,1H),3.44-3.39(m,2H),3.30-3.27(m,2H),2.32-2.27(m,2H),2.17-2.12(m,2H),2.09(s,3H),1.98-1.93(m,2H),1.91-1.86(m,2H),1.15(d,3H),1.01(s,3H)。MS计算值:506.2，MS实测值:507.3([M+H] +)。
N-(5-氯-3-((1-(1-氟代环戊基羰基)哌啶-4-亚基)甲基)-2-甲基苯基)-6-氰基-1-甲基-2-氧-1,2-二氢吡啶-4-甲酰胺(化合物41)
Figure PCTCN2020085294-appb-000119
N-(5-氯-2-甲基-3-(哌啶-4-亚基甲基)苯基)-6-氰基-1-甲基-2-氧-1,2-二氢吡啶-4-甲酰胺盐酸盐(100mg,0.25mmol)，1-氟代环戊基甲酸(33mg,0.25mmol,1eq)和三乙胺(77mg,0.76mmol)溶于N,N-二甲基甲酰胺(5mL)，0℃加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(144mg,0.38mmol,1.5eq)。反应混合液室温搅拌过夜。水淬灭反应，乙酸乙酯萃取。合并有机相并浓缩，浓缩剩余物用制备型高效液相色谱纯化得到N-(5-氯-3-((1-(1-氟代环戊基羰基)哌啶-4-亚基)甲基)-2-甲基苯基)-6-氰基-1-甲基-2-氧-1,2-二氢吡啶-4-甲酰胺58mg，纯度95％，产率45％，白色固体。 1H NMR(400MHz,DMSO-d 6)δ10.26(s,1H),7.39(s,1H),7.35(s,1H),7.32(s,1H),7.068(s,1H),6.37(s,1H),3.79-3.66(m,1H),3.64-3.54(m,5H),3.53-3.43(m,1H),2.43-2.33(m,2H),2.32-2.14(m,4H),2.08(s,3H),2.05-1.93(m,2H),1.78-1.61(m,4H)。MS计算值:510.2，MS实测值:511.2([M+H] +)。
N-(5-氯-3-((1-(3,3-二氟环戊基羰基)哌啶-4-亚基)甲基)-2-甲基苯基)-6-氰基-1-甲基-2-氧-1,2-二氢吡啶-4-甲酰胺(化合物42)
Figure PCTCN2020085294-appb-000120
N-(5-氯-2-甲基-3-(哌啶-4-亚基甲基)苯基)-6-氰基-1-甲基-2-氧-1,2-二氢吡啶-4-甲酰胺 盐酸盐(100mg,0.25mmol)，3,3-二氟环戊基甲酸(38mg,0.25mmol,1eq)和三乙胺(77mg,0.76mmol)溶于N,N-二甲基甲酰胺(5mL)，0℃加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(144mg,0.38mmol)。反应混合液室温搅拌过夜。水淬灭反应，乙酸乙酯萃取。合并有机相并浓缩，浓缩剩余物用制备型高效液相色谱纯化得到N-(5-氯-3-((1-(3,3-二氟环戊基羰基)哌啶-4-亚基)甲基)-2-甲基苯基)-6-氰基-1-甲基-2-氧-1,2-二氢吡啶-4-甲酰胺55mg，纯度95％，产率42％，白色固体。 1H NMR(400MHz,DMSO-d 6)δ10.26(s,1H),7.39(s,1H),7.35(s,1H),7.32(s,1H),7.08(s,1H),6.37(s,1H),3.59-3.58(m,5H),3.52-3.43(m,2H),3.42-3.35(m,1H),2.45-2.35(m,2H),2.34-2.25(m,2H),2.25-2.19(m,1H),2.17-2.09(m,2H),2.08(s,3H),2.05-1.94(m,2H),1.86-1.72(m,1H)。MS计算值:528.2，MS实测值:529.1([M+H] +)。
(R)-N-(5-氯-3-((1-(3,3-二氟环戊基羰基)哌啶-4-亚基)甲基)-2-甲基苯基)-6-氰基-1-甲基-2-氧代-1,2-二氢吡啶-4-甲酰胺(化合物43)
Figure PCTCN2020085294-appb-000121
(R)-3,3-二氟环戊基甲酸(125mg,0.83mmol)和2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(315mg,0.83mmol)溶于二氯甲烷(5mL)，加入三乙胺(209mg,2.07mmol)并搅拌10分钟。.然后加入N-(5-氯-2-甲基-3-(4-哌啶-亚甲基)苯基)-6-氰基-1-甲基-2-氧代-1，2-二氢吡啶-4-甲酰胺盐酸盐(300mg,0.69mmol)。反应液室温搅拌1小时。反应液倒入水里，二氯甲烷萃取。合并有机相，无水硫酸钠干燥，过滤并浓缩。浓缩剩余物用制备型高效液相色谱纯化得到(R)-N-(5-氯-3-((1-(3,3-二氟环戊基羰基)哌啶-4-亚基)甲基)-2-甲基苯基)-6-氰基-1-甲基-2-氧代-1,2-二氢吡啶-4-甲酰胺201mg,纯度95％,产率55％，白色固体。1H NMR(400MHz,DMSO-d6)δ10.27(s,1H),7.40(d,1H),7.35(d,1H),7.32(s,1H),7.07(t,1H),6.37(s,1H),3.60(s,3H),3.59-3.60(m,2H),3.47(s,1H),3.35-3.42(m,1H),2.36-2.42(m,2H),2.26-2.31(m,2H),2.22-2.23(m,1H),2.13-2.18(m,2H),1.99-2.06(m,2H),1.80-1.82(m,1H)。MS计算值:528.2，MS实测值:529.2([M+H]+)
(S)-N-(5-氯-3-((1-(3,3-二氟环戊基羰基)哌啶-4-亚基)甲基)-2-甲基苯基)-6-氰基-1-甲基-2-氧代-1,2-二氢吡啶-4-甲酰胺(化合物44)
Figure PCTCN2020085294-appb-000122
(S)-3,3-二氟环戊基甲酸(125mg,0.83mmol)和2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(315mg,0.83mmol)溶于二氯甲烷(5mL)，加入三乙胺(209mg,2.07mmol)室温搅拌10分钟。然后加入N-(5-氯-2-甲基-3-(4-哌啶-亚甲基)苯基)-6-氰基-1-甲基-2-氧代-1，2-二氢吡啶-4-甲酰胺盐酸盐(300mg,0.69mmol)。反应液室温搅拌1小时。反应液倒入水里，二氯甲烷萃取。合并有机相，无水硫酸钠干燥，过滤并浓缩。浓缩剩余物用制备型高效液相色谱纯化得到(S)-N-(5-氯-3-((1-(3,3-二氟环戊基羰基)哌啶-4-亚基)甲基)-2-甲基苯基)-6-氰基-1-甲基-2-氧代-1,2-二氢吡啶-4-甲酰胺237mg，纯度95％，产率65％，白色固体。1H NMR(400MHz,DMSO-d6)δ10.27(s,1H),7.40(d,1H),7.35(d,1H),7.32(s,1H),7.08(t,1H),6.37(s,1H),3.60(s,3H),3.56-3.59(m,2H),3.47(s,1H),3.35-3.42(m,1H),2.36-2.42(m,2H),2.26-2.31(m,2H),2.22-2.23(m,1H),2.13-2.18(m,2H),1.97-2.05(m,2H),1.75-1.84(m,1H)。MS计算值:528.2，MS实测值:529.2([M+H]+)
N-(5-氯-2-甲基-3-((1-(四氢呋喃-2-羰基)哌啶-4-亚基)甲基)-2-甲基苯基)-6-氰基-1-甲基-2-氧-1,2-二氢吡啶-4-甲酰胺(化合物45)
Figure PCTCN2020085294-appb-000123
N-(5-氯-2-甲基-3-(哌啶-4-亚基甲基)苯基)-6-氰基-1-甲基-2-氧-1,2-二氢吡啶-4-甲酰胺盐酸盐(100mg,0.25mmol)，四氢呋喃-2-甲酸(29mg,0.25mmol)和三乙胺(77mg,0.76mmol)溶于N,N-二甲基甲酰胺(5mL)，0℃加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(144mg,0.38mmol)。反应混合液室温搅拌过夜。水淬灭反应，乙酸乙酯萃取。合并有机相并浓缩，浓缩剩余物用制备型高效液相色谱纯化得到N-(5-氯-2-甲基-3-((1-(四氢呋喃-2-羰基)哌啶-4-亚基)甲基)-2-甲基苯基)-6-氰基-1-甲基-2-氧-1,2-二氢吡啶-4-甲酰胺50mg，纯度95％，产率40％，白色固体。 1H NMR(400MHz,DMSO-d 6)δ10.26(s,1H),7.39(s,1H),7.35(s,1H),7.32(s,1H),7.07(s,1H),6.36(s,1H),4.73-4.65(m,1H),3.82-3.69(m,2H),3.65-3.55(m,4H),3.54-3.45(m,2H),2.44-3.35(m,1H),2.41-2.35(m,1H),2.34-2.27(m,1H),2.26-2.18(s,1H),2.17-2.10(m,1H)，2.07(s,3H),2.05-1.93(m,2H),1.91-1.75(m,2H)。MS计算值:494.2，MS实测值:495.2([M+H] +)。
N-(5-氯-3-((1-异丁酰基哌啶-4-亚基)甲基)-2-甲基苯基)-6-氰基-1-甲基-2-氧代-1,2-二氢吡啶-4-甲酰胺(化合物46)
Figure PCTCN2020085294-appb-000124
N-(5-氯-2-甲基-3-(哌啶-4-亚甲基)苯基)-6-氰基-1-甲基-2-氧代-1,2-二氢吡啶-4-甲酰胺盐酸盐(100mg,0.25mmol),三乙胺(0.1mL)溶于二氯甲烷(5mL)，0℃加入异丁酰氯(0.03mL,0.3mmol)。反应液0℃搅拌半小时。反应混合液浓缩，浓缩剩余物用制备型高效液相色谱纯化得到N-(5-氯-3-((1-异丁酰基哌啶-4-亚基)甲基)-2-甲基苯基)-6-氰基-1-甲基-2-氧代-1,2-二氢吡啶-4-甲酰胺35mg,纯度95％,产率30％，白色固体。 1H NMR(400MHz,DMSO-d 6)δ10.26(s,1H),7.39(d,1H),7.35(d,1H),7.32(d,1H),7.08(s,1H),6.37(s,1H),3.60(s,3H),3.56-3.60(m,2H),3.44-3.48(m,2H),2.87-2.93(m,1H),2.12-2.39(m,4H),2.08(s,3H),1.01(d,6H)。MS计算值:466.2，MS实测值:467.2([M+H] +)。
N-(5-氯-2-甲基-3-((1-(3-甲基丁酰基)哌啶-4-亚甲基)苯基)-6-氰基-1-甲基-2-氧代-1,2-二氢吡啶-4-甲酰胺(化合物47)
Figure PCTCN2020085294-appb-000125
N-(5-氯-2-甲基-3-(哌啶-4-亚甲基)苯基)-6-氰基-1-甲基-2-氧代-1,2-二氢吡啶-4-甲酰胺盐酸盐(100mg,0.25mmol)，碳酸钾(173mg,1.25mmol)溶于乙腈(5mL)，0℃加3-甲基丁酰氯(60mg,0.5mmol)。反应液0℃搅拌半小时。反应液浓缩，浓缩剩余物用制备型高效液相色谱纯化得到N-(5-氯-2-甲基-3-((1-(3-甲基丁酰基)哌啶-4-亚甲基)苯基)-6-氰基-1-甲基-2-氧代-1,2-二氢吡啶-4-甲酰胺60mg，纯度95％，产率50％，白色固体。 1H NMR(400MHz,DMSO-d 6)δ10.25(s,1H),7.39(d,1H),7.35(d,1H),7.32(s,1H),7.07(s,1H),6.36(s,1H),3.60(s,3H),3.55-3.56(m,2H),3.43-3.45(m,2H),2.35-2.37(m,1H),2.28-2.27(m,1H),2.20-2.25(m,3H),2.11-2.13(m,1H),2.08(s,3H),1.96-2.04(m,1H),0.91(t,6H)。MS计算值:480.2，MS实测值:481.2([M+H] +)。
N-(5-氯-3-((1-(2-氟-2-甲基丙酰基)哌啶-4-亚基)甲基)-2-甲基苯基)-6-氰基-1-甲基-2-氧代-1,2-二氢吡啶-4-甲酰胺(化合物48)
Figure PCTCN2020085294-appb-000126
2-氟-2-甲基丙酸(30mg,0.28mmol)，2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(106mg,0.28mmol)和三乙胺(70mg,0.69mmol)溶于二氯甲烷(2mL)，室温搅拌10分钟。然后加入N-(5-氯-2-甲基-3-(哌啶-4-亚甲基)苯基)-6-氰基-1-甲基-2-氧代-1,2-二氢吡啶-4-甲酰胺盐酸盐(100mg,0.23mmol)，室温搅拌一小时。反应液倒入水里，二氯甲烷萃取。合并有机相，无水硫酸钠干燥，过滤并浓缩。浓缩剩余物用制备型高效液相色谱纯化得N-(5-氯-3-((1-(2-氟-2-甲基丙酰基)哌啶-4-亚基)甲基)-2-甲基苯基)-6-氰基-1-甲基-2-氧代-1,2-二氢吡啶-4-甲酰胺17mg，纯度95％，产率15％，白色固体。 1H NMR(400MHz,DMSO-d6)δ10.25(s,1H),7.39(d,1H),7.35(d,1H),7.32(s,1H),7.08(d,1H),6.37(s,1H),3.71-3.77(m,2H),3.60(s,3H),3.42-3.60(m,2H),2.39(s,2H),2.22(s,2H),2.08(s,3H),1.59(s,3H),1.53(s,3H)。MS计算值:484.2，MS实测值:485.2([M+H] +)。
N-(5-氯-3-((1-(环丁基羰基)哌啶-4-亚基)甲基)-2-甲基苯基)-6-氰基-1-甲基-2-氧代-1,2-二氢吡啶-4-甲酰胺(化合物49)
Figure PCTCN2020085294-appb-000127
N-(5-氯-2-甲基-3-(哌啶-4-亚甲基)苯基)-6-氰基-1-甲基-2-氧代-1,2-二氢吡啶-4-甲酰胺盐酸盐(100mg,0.25mmol)，环丁基甲酸(25mg,0.25mmol)，三乙胺(0.14mL,1mmol)溶于二氯甲烷(5mL)，0℃加2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(95mg,0.25mmol)。混合反应液室温搅拌一小时。反应液浓缩，浓缩剩余物用制备型高效液相色谱纯化得到N-(5-氯-3-((1-(环丁基羰基)哌啶-4-亚基)甲基)-2-甲基苯基)-6-氰基-1-甲基-2-氧代-1,2-二氢吡啶-4-甲酰胺88mg，纯度95％，产率73％，白色固体。 1H NMR(400MHz,DMSO-d 6)δ10.25(s,1H),7.39(s,1H),7.35(s,1H),7.32(s,1H),7.06(s,1H),6.35(s,1H),3.60(s,3H),3.54-3.56(m,1H),3.28-3.41(m,4H),2.29-2.32(m,2H),2.07-2.16(m,6H),2.07(s,3H),1.85-1.96(m,1H),1.74-1.76(m,1H)。MS计算值:478.2，MS实测值:479.3([M+H] +)。
5-氰基-2-羟基-6-甲基烟酸乙酯
Figure PCTCN2020085294-appb-000128
(E)-3-氨基-2-烯腈(8.2g,100mmol)和2-(乙氧基亚甲基)丙二酸二乙酯(21.6g,100 mmol)置于圆底烧瓶中，150℃搅拌2小时，室温静置过夜。反应液过滤。滤出的沉淀物用冰甲醇洗涤得到5-氰基-2-羟基-6-甲基烟酸乙酯6.4g，产率31％，黄色固体。
2-氯-5-氰基-6-甲基烟酸乙酯
Figure PCTCN2020085294-appb-000129
5-氰基-2-羟基-6-甲基烟酸乙酯(2g,9.7mmol)溶于三氯氧磷(15mL)，106℃搅拌过夜。反应完成后，浓缩除去三氯氧磷，浓缩剩余物用水稀释，二氯甲烷萃取(20mL×4)。合并有机相并浓缩，真空干燥得到2-氯-5-氰基-6-甲基烟酸乙酯粗品，红色油状物。
5-氰基-6-甲基烟酸乙酯
Figure PCTCN2020085294-appb-000130
2-氯-5-氰基-6-甲基烟酸乙酯(2.79g,12.5mmol)溶于甲醇(50mL)，反应液中加入甲酸铵(12g,18.8mmol)和Pd/C(1g)。反应混合液室温搅拌3小时。反应液过滤，滤液浓缩。浓缩剩余物用水稀释，二氯甲烷萃取(50mL×3)。合并有机相并浓缩，浓缩剩余物用硅胶柱柱层析纯化(石油醚/乙酸乙酯＝5/1，体积比)得5-氰基-6-甲基烟酸乙酯2g，产率84％，白色固体。
4-(5-氯-3-(5-氰基-6-甲基烟酰胺)-2-甲基亚苄基)哌啶-1-甲酸叔丁酯
Figure PCTCN2020085294-appb-000131
4-(3-氨基-5-氯-2-甲基亚苄基)哌啶-1-甲酸叔丁酯(780mg,2.32mmol)，5-氰基-6-甲基烟酸乙酯(485mg,2.55mmol)溶于无水甲苯(20mL)，0℃氮气保护下加入三甲基铝(2.3mL,2M/toluene,4.64mmol)。反应混合液80℃搅拌3小时。氯化铵溶液淬灭反应，乙酸乙酯萃取(20mL×3)。合并有机相并浓缩，浓缩剩余物用柱层析硅胶(石油醚/乙酸乙酯＝2/1，体积比)纯化得到4-(5-氯-3-(5-氰基-6-甲基烟酰胺)-2-甲基亚苄基)哌啶-1-甲酸叔丁酯580mg，产率53％，白色固体。MS计算值:480.2，MS实测值:481.2([M+H] +)。
N-(5-氯-2-甲基-3-(哌啶-4-亚基甲基)苯基)-5-氰基-6-甲基烟酰胺
Figure PCTCN2020085294-appb-000132
4-(5-氯-3-(5-氰基-6-甲基烟酰胺)-2-甲基亚苄基)哌啶-1-甲酸叔丁酯(580mg,1.21mmol)溶于二氯甲烷(6mL)，然后加入三氟乙酸(3mL)。反应液室温搅拌1小时。反应混合液浓缩，浓缩剩余物溶于水中。碳酸钠溶液调到pH大于9后，乙酸乙酯萃取。合并有机相并浓缩得到N-(5-氯-2-甲基-3-(哌啶-4-亚基甲基)苯基)-5-氰基-6-甲基烟酰胺440mg，产率96％，白色固体。
N-(5-氯-3-((1-(1-氟环戊基羰基)哌啶-4-亚基)甲基)-2-甲基苯基)-5-氰基-6-甲基烟酰胺(化合物50)
Figure PCTCN2020085294-appb-000133
N-(5-氯-2-甲基-3-(哌啶-4-亚基甲基)苯基)-5-氰基-6-甲基烟酰胺(38mg,0.29mmol)，1-氟代环戊基甲酸(38mg,0.29mmol)，2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(109mg,0.29mmol)溶于N,N-二甲基甲酰胺(3mL)，0℃加入三乙胺(0.1mL,0.78mmol)。反应液室温搅拌2.5小时。加入水淬灭反应，乙酸乙酯萃取。合并有机相并浓缩，浓缩剩余物用硅胶柱柱层析(石油醚/乙酸乙酯＝1/1，体积比)纯化得N-(5-氯-3-((1-(1-氟环戊基羰基)哌啶-4-亚基)甲基)-2-甲基苯基)-5-氰基-6-甲基烟酰胺30mg，纯度95％，产率23％，白色固体。 1H NMR(400MHz,DMSO-d 6)δ10.25(s,1H),9.20(s,1H),8.72(s,1H),7.40(s,1H),7.08(s,1H),6.39(s,1H),3.70-3.60(m,4H),2.77(s,3H),2.39(s,2H),2.17-2.30(m,4H),2.12(s,3H),1.98-2.07(m,2H),1.65-1.73(m,4H)。MS计算值:494.2，MS实测值:495.2([M+H] +)。
(R)-N-(5-氯-3-((1-(3,3-二氟环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-5-氰基-6-甲基烟酰胺(化合物51)
Figure PCTCN2020085294-appb-000134
N-(5-氯-2-甲基-3-(哌啶-4-亚甲基)苯基)-5-氰基-6-甲基烟酰胺(200mg,0.53mmol),3， 3-二氟环戊基甲酸(80mg,0.53mmol),三乙胺(0.2mL,1.59mmol)溶于N,N-二甲基甲酰胺(3mL)，0℃加2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(200mg,0.53mmol)。反应液室温搅拌1.5小时。反应液浓缩，浓缩剩余物用柱层层析硅胶(石油醚/乙酸乙酯＝1/1，体积比)纯化得到白色固体。白色固体手性拆分(色谱柱：AD-H-Hex(250mm*4.6mm 5um)；流动相：EtOH/DEA＝50/50(v/v)；流速：1mL/min；检测波长：UV 230nm；柱温：30℃))得到((R)-N-(5-氯-3-((1-(3,3-二氟环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-5-氰基-6-甲基烟酰胺23mg,纯度95％,产率8％，白色固体。 1H NMR(400MHz,DMSO-d 6)δ10.30(s,1H),9.20(d,1H),8.72(d,1H),7.40(d,1H),7.06(d,1H),6.39(s,1H),3.59(s,2H),3.48(s,2H),3.33-3.42(m,1H),2.77(s,3H),2.20-2.43(m,5H),2.13-2.16(m,2H),2.12(s,3H),1.99-2.08(m,2H),1.76-1.85(m,1H)。MS计算值:512.2，MS实测值:513.2([M+H] +)。
(S)-N-(5-氯-3-((1-(3,3-二氟环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-5-氰基-6-甲基烟酰胺(化合物52)
Figure PCTCN2020085294-appb-000135
操作步骤同实施例KLS1228，手性拆分得到(S)-N-(5-氯-3-((1-(3,3-二氟环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-5-氰基-6-甲基烟酰胺33mg,纯度95％,产率12％，白色固体。 1H NMR(400MHz,DMSO-d 6)δ10.33(s,1H),9.21(d,1H),8.72(d,1H),7.41(d,1H),7.05(d,1H),6.38(s,1H),3.59(s,2H),3.48(s,2H),3.33-3.42(m,1H),2.77(s,3H),2.20-2.43(m,5H),2.13-2.16(m,2H),2.11(s,3H),1.99-2.08(m,2H),1.75-1.85(m,1H)。MS计算值:512.2，MS实测值:513.2([M+H] +)。
N-(5-氯-3-((1-异丁酰基哌啶-4-亚基)甲基)-2-甲苯基)-5-氰基-6-甲基烟酰胺(化合物53)
Figure PCTCN2020085294-appb-000136
N-(5-氯-2-甲基-3-(哌啶-4-亚甲基)苯基)-5-氰基-6-甲基烟酰胺(100mg,0.26mmol),三乙胺(0.1mL)溶于二氯甲烷(5mL)，0℃加异丁酰氯(0.03mL,0.31mmol)。反应液0℃搅拌半小时。反应混合液浓缩，浓缩剩余物用制备型高效液相色谱纯化得到N-(5-氯-3-((1-异丁酰基哌啶-4-亚基)甲基)-2-甲苯基)-5-氰基-6-甲基烟酰胺39mg,纯度95％,产率33％，白色固体。 1H NMR(400MHz,DMSO-d 6)δ10.26(s,1H),9.20(d,1H),8.72(d,1H),7.40(d, 1H),7.07(s,1H),6.38(s,1H),3.58(s,2H),3.47(s,2H),2.88-2.94(m,1H),2.77(s,3H),2.11-2.40(m,4H),2.12(s,3H),1.02(d,6H)。MS计算值:450.2，MS实测值:451.2([M+H] +)。
N-(5-氯-3-(1-(4,4-二氟哌啶-1-羰基)哌啶-4-亚基)甲基)-2-甲苯基)-6-氰基-1-甲基-2-氧-1,2-二氢吡啶-4-甲酰胺(化合物54)
Figure PCTCN2020085294-appb-000137
4,4-二氟哌啶盐酸盐(88mg,0.56mmol)溶于二氯甲烷(1mL)，加入三乙胺(70mg,0.70mmol)。氮气保护下0℃加入三光气(166mg,0.56mmol)，搅拌20分钟。然后N-(5-氯-2-甲基-3-(哌啶-4-亚基甲基)苯基)-6-氰基-1-甲基-2-氧-1,2-二氢吡啶-4-甲酰胺盐酸盐(120mg,0.28mmol)溶于二氯甲烷(1mL)，加入三乙胺(71mg,0.70mmol)。接着0℃将此混合液逐滴加入到之前的反应液中，室温搅拌3小时。用水淬灭反应，二氯甲烷萃取(10mL×3)。合并有机相无水硫酸钠干燥并浓缩，浓缩剩余物用制备型高效液相色谱纯化得到N-(5-氯-3-(1-(4,4-二氟哌啶-1-羰基)哌啶-4-亚基)甲基)-2-甲苯基)-6-氰基-1-甲基-2-氧-1,2-二氢吡啶-4-甲酰胺12mg，纯度95％，产率8％，白色固体。 1H NMR(400MHz,DMSO-d 6)δ10.25(s,1H),7.39(d,1H),7.34(d,1H),7.32(s,1H),7.06(d,1H),6.34(s,1H),3.60(s,3H),3.25-3.28(m,5H),3.18(t,2H),2.36(t,2H),2.20(t,2H),2.07(s,3H),1.94-2.01(m,5H)。MS计算值:543.2，MS实测值:544.2([M+H] +)
N-(5-氯-3-((1-(3,3-二氟吡咯-1-羰基)哌啶-4-亚基)甲基)-2-甲苯基)-3-氰基苯甲酰胺(化合物55)
Figure PCTCN2020085294-appb-000138
N-(5-氯2-甲基-3-(哌啶-4-亚基甲基)苯基)-3-氰基苯甲酰胺盐酸盐(100mg,0.249mmol)和三光气(37mg,0.125mmol)溶于二氯甲烷(12mL)，氮气保护下，0℃向反应液中缓慢加入三乙胺(0.2mL,1.42mmol)，接着搅拌30分钟。然后加入3,3-二氟吡咯盐酸盐(36mg,0.251mmol)，室温搅拌1小时。反应液浓缩，浓缩剩余物用制备型高效液相色谱纯化得到N-(5-氯-3-((1-(3,3-二氟吡咯-1-羰基)哌啶-4-亚基)甲基)-2-甲苯基)-3-氰基苯甲酰胺25mg， 纯度95％，产率20％，白色固体。 1H NMR(400MHz,DMSO-d 6)δ10.20(s,1H),8.40(s,1H),8.26(d,1H),8.09(d,1H),7.77(t,1H),7.38(d,1H),7.06(d,1H),6.36(s,1H),3.71(t,2H),3.54(t,2H),3.32-3.30(m,2H),3.21-3.18(m,2H),2.38-2.32(m,4H),2.22(t,2H),2.11(s,3H)。MS计算值:498.2，MS实测值:498.9([M+H] +)。
N-(5-氯-2-甲基-3-((1-(四氢吡咯-1-羰基)哌啶-4-亚基)甲基)苯基)-3-氰基苯甲酰胺(化合物56)
Figure PCTCN2020085294-appb-000139
N-(5-氯-2-甲基-3-(哌啶-4-亚基甲基)苯基)-3-氰基苯甲酰胺(60mg,0.16mmol)和四氢吡咯-1-酰氯(43mg,0.32mmol)溶于无水N,N-二甲基甲酰胺(3mL)，反应液中加入三乙胺(0.1mL)。氮气保护下，反应混合液室温搅拌1小时。反应液中加入水，用乙酸乙酯萃取。合并有机相，浓缩，浓缩剩余物用柱层析硅胶纯化得到N-(5-氯-2-甲基-3-((1-(四氢吡咯-1-羰基)哌啶-4-亚基)甲基)苯基)-3-氰基苯甲酰胺25mg，纯度95％，产率34％，白色固体。
1H NMR(400MHz,DMSO-d 6)δ10.19(s,1H),8.40(s,1H),8.26(d,1H),8.09(d,1H),7.77(t,1H),7.37(s,1H),7.06(s,1H),6.34(s,1H),3.28-3.31(m,6H),3.16(s,2H),2.36(s,2H),2.21(s,2H),2.11(s,3H),1.75(s,4H)。MS计算值：462.2，MS实测值：463.2([M+H] +)。
4-(5-氯-3-(3-氰基苯甲酰胺)-2-甲基亚苄基)哌啶-1-甲酸异丙酯(化合物57)
Figure PCTCN2020085294-appb-000140
N-(5-氯-2-甲基-3-(哌啶-4-亚基甲基)苯基)-3-氰基苯甲酰胺(60mg,0.16mmol)，异丙氧基酰氯(39mg,0.32mmol)溶于无水N,N-二甲基甲酰胺(3mL)，反应液中加入三乙胺(0.1mL)。反应混合液氮气保护下，0℃搅拌1小时。反应液浓缩，浓缩剩余物用制备型高效液相色谱纯化得到4-(5-氯-3-(3-氰基苯甲酰胺)-2-甲基亚苄基)哌啶-1-甲酸异丙酯30mg，纯度95％，产率42％，白色固体。 1H NMR(400MHz,DMSO-d 6)δ10.19(s,1H),8.40(s,1H),8.26(d,1H),8.08(d,1H),7.77(t,1H),7.37(s,1H),7.06(s,1H),6.37(s,1H),4.79(m,1H),3.48(s,2H),3.36(s,2H),2.33(s,2H),2.18(s,2H),2.10(s,3H),1.20(d,6H)。MS计算值：451.2，MS实测值：452.0([M+H] +)。
N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-3-氰基苯磺酰胺(化合物58)
Figure PCTCN2020085294-appb-000141
3-氰基苯磺酰氯(73mg,0.362mmol)和(4-(3-氨基-5-氯-2-甲基亚苄基)哌啶-1-基)(环戊基)甲酮(73mg,0.219mmol)溶于吡啶(6mL)，氮气保护下，室温搅拌过夜。用盐酸(10mL,1mol/L)洗两次。有机相用无水硫酸钠干燥并浓缩。浓缩剩余物用制备型高效液相色谱纯化得到N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-3-氰基苯磺酰胺31mg，纯度95％，产率28％，白色固体。 1H NMR(400MHz,DMSO-d 6)δ10.09(s,1H),8.18(d,1H),8.02(s,1H),7.95(s,1H),7.84-7.80(m,1H),7.03(s,1H),6.89(s,1H),6.23(s,1H),3.58-3.55(m,2H),3.45-3.42(m,2H),3.06-2.95(m,1H),2.32-2.21(m,2H),2.08-1.98(m,2H),1.78(s,3H),1.77-1.53(m,8H)。MS计算值:497.2，MS实测值:498.1([M+H] +)。
1-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-3-(吡啶-2-基)脲(化合物59)
Figure PCTCN2020085294-appb-000142
(4-(3-氨基-5-氯-2-甲基亚苄基)哌啶-1-基)(环戊基)甲酮(99mg,0.297mmol)和三乙胺(0.3mL,2.13mmol)溶于二氯甲烷(6mL)，反应液中加入三光气(44mg,0.148mmol)。反应混合液氮气保护下0℃搅拌30分钟。然后加入吡啶-2-胺(28mg,0.298mmol)，反应液0℃继续搅拌2小时。反应液浓缩，浓缩剩余物用制备型高效液相色谱纯化得到1-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-3-(吡啶-2-基)脲25mg，纯度95％，产率19％，类白色固体。 1H NMR(400MHz,DMSO-d 6)δ11.23(br,1H),9.92(s,1H),8.28(d,1H),8.12(s,1H),7.78(t,1H),7.27(d,1H),7.03(t,1H),6.83(s,1H),6.37(s,1H),3.60-3.57(m,2H),3.49-3.46(m,2H),3.05-2.96(m,1H),2.37-2.07(m,4H),2.21(s,3H),1.77-1.52(m,8H)。MS计算值:452.2，MS实测值:453.1([M+H] +)。
6-氰基-1-乙基-2-氧代-1,2-二氢吡啶-4-甲酸甲酯
Figure PCTCN2020085294-appb-000143
6-氰基-2-氧代-1,2-二氢吡啶-4-甲酸甲酯(1.0g,5.65mmol)，碘乙烷(2.5mL,31.2mmol)和碳酸钾(2.3g,16.6mmol)溶于N,N-二甲基甲酰胺(30mL)，氮气保护下50℃搅拌过夜。反应液浓缩。浓缩剩余物溶于乙醇水溶液(20mL,体积比＝1：1)。分离出有机相，水相用乙酸乙酯萃取(10mL×2)。合并有机相，无水硫酸钠干燥，浓缩。浓缩剩余物用硅胶柱柱层析纯化(石油醚/乙酸乙酯＝50/1-10/1，体积比)得到6-氰基-1-乙基-2-氧代-1,2-二氢吡啶-4-甲酸甲酯200mg，产率17％，灰白色固体。 1H NMR(400MHz,DMSO-d 6):δ7.38(d,1H),7.21(d,1H),4.11(q,2H),3.87(s,3H),1.27(t,3H)。
N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲基苯基)-6-氰基-1-乙基-2-氧代-1,2-二氢吡啶-4-甲酰胺(化合物60)
Figure PCTCN2020085294-appb-000144
(4-(3-氨基-5-氯-2-甲基亚苄基)哌啶-1-基)(环戊基)甲酮(98mg,0.294mmol)溶于甲苯(10mL)，氮气保护下，0℃缓慢加入三甲基铝(0.4mL,0.800mmol)甲苯溶液。然后加入6-氰基-1-乙基-2-氧代-1,2-二氢吡啶-4-甲酸甲酯(60mg,0.293mmol)。反应液80℃搅拌4小时，然后冷却到室温。加入盐酸(10mL,1mol/L)淬灭反应。用乙酸乙酯萃取(10mL×2)。合并有机相，无水硫酸钠干燥后浓缩。浓缩剩余物用制备型高效液相色谱纯化得到N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲基苯基)-6-氰基-1-乙基-2-氧代-1,2-二氢吡啶-4-甲酰胺60mg，纯度95％，产率40％，白色固体。 1H NMR(400MHz,DMSO-d 6):δ10.26(d,1H),7.43(d,1H),7.35(d,1H),7.32(d,1H),7.07(dd,1H),6.36(s,1H),4.13(q,2H),3.59-3.53(m,2H),3.48-3.44(m,2H),3.05-2.97(m,1H),2.38-2.10(m,4H),2.08(s,3H),1.77-1.51(m,8H),1.29(t,3H)。MS计算值:506.2，MS实测值:507.2([M+H] +)。
4-(5-氯-3-(6-氰基-1-乙基-2-氧代-1,2-二氢吡啶-4-羧基酰胺)-2-甲基亚苄基)哌啶-1-甲酸叔丁酯
Figure PCTCN2020085294-appb-000145
6-氰基-1-乙基-2-氧代-1,2-二氢吡啶-4-甲酸甲酯(366mg,1.78mmol)溶于甲苯(20mL)， 氮气保护下，0℃缓慢加入三甲基铝(2.4mL,4.80mmol)甲苯溶液。然后加入叔丁基4-(3-氨基-5-氯-2-甲基亚苄基)哌啶-1-甲酸叔丁酯(598mg,1.78mmol)，反应液80℃搅拌4小时，然后冷却到室温，加入盐酸(15mL,1mol/L)淬灭反应。用乙酸乙酯萃取(20mL×3)。合并有机相，无水硫酸钠干燥后浓缩。浓缩剩余物用硅胶柱柱层析纯化(石油醚/乙酸乙酯＝3/1，体积比)得4-(5-氯-3-(6-氰基-1-乙基-2-氧代-1,2-二氢吡啶-4-羧基酰胺)-2-甲基亚苄基)哌啶-1-甲酸叔丁酯347mg，产率38％，白色固体。 1H NMR(400MHz,DMSO-d 6):δ10.24(s,1H),7.42(d,1H),7.35(d,1H),7.32(d,1H),7.07(d,1H),6.35(s,1H),4.13(q,2H),3.46-3.40(m,2H),3.34-3.31(m,2H),2.35-2.28(m,2H),2.16-2.13(m,2H),2.07(s,3H),1.41(s,9H),1.29(t,3H)。
N-(5-氯-2-甲基-3-(哌啶-4-亚基甲基)苯基)-1-乙基-6-氧代-1,6-二氢哒嗪-4-甲酰胺
Figure PCTCN2020085294-appb-000146
4-(5-氯-3-(6-氰基-1-乙基-2-氧代-1,2-二氢吡啶-4-羧基酰胺)-2-甲基亚苄基)哌啶-1-甲酸叔丁酯(347mg,0.682mmol)溶于三氟乙酸二氯甲烷(20mL,体积比＝1/4)溶液，室温搅拌3小时。反应液浓缩，浓缩剩余物直接用于下一步反应。
N-(5-氯-3-((1-(2-环丙基乙酰基)哌啶-4-亚基)甲基)-2-甲基苯基)-6-氰基-1-乙基-2-氧代-1,2-二氢吡啶-4-甲酰胺(化合物61)
Figure PCTCN2020085294-appb-000147
2-环丙基乙酸(22mg,0.220mmol)，2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(100mg,0.263mmol)和N,N-二异丙基乙胺(0.2mL,1.11mmol)溶于N,N-二甲基甲酰胺(6mL)，反应液氮气保护下室温搅拌30分钟。然后加入N-(5-氯-2-甲基-3-(哌啶-4-亚基甲基)苯基)-6-氰基-1-乙基-2-氧代-1,2-二氢吡啶-4-甲酰胺(粗品,0.216mmol)，反应混合液50℃搅拌2小时。反应液浓缩，浓缩剩余物溶于乙醇水溶液(20mL,体积比＝1：1)。分出有机相，无水硫酸钠干燥，浓缩。浓缩剩余物用制备型高效液相色谱纯化得到N-(5-氯-3-((1-(2-环丙基乙酰基)哌啶-4-亚基)甲基)-2-甲基苯基)-6-氰基-1-乙基-2-氧代-1,2-二氢吡啶-4-甲酰胺40mg，纯度95％，产率38％，白色固体。 1H NMR(400MHz,d6-DMSO):δ10.24(s,1H),7.42(s,1H),7.35(d,1H),7.32(d,1H),7.07(s,1H),6.36(s,1H),4.13(q,2H),3.56-3.52(m,2H),3.45-3.41(m,2H),2.38-2.34(m,1H),2.32-2.26(m,3H),2.24-2.18(m,1H),2.14-2.10(m,1H),2.08(s,3H),1.29(t,3H),0.98-0.96(m,1H),0.46-0.43(m,2H),0.13-0.11(m, 2H)。MS计算值:492.2，MS实测值:493.0([M+H] +)。
N-(5-氯-3-((1-(2-环丁基乙酰基)哌啶-4-亚基)甲基)-2-甲基苯基)-6-氰基-1-乙基-2-氧代-1,2-二氢吡啶-4-甲酰胺(化合物62)
Figure PCTCN2020085294-appb-000148
2-环丁基乙酸(105mg,0.920mmol)，2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(409mg,1.08mmol)和N,N-二异丙基乙胺(0.7mL,3.97mmol溶于N,N-二甲基甲酰胺(8mL)，反应液氮气保护下室温搅拌30分钟。然后加入N-(5-氯-2-甲基-3-(哌啶-4-亚基甲基)苯基)-6-氰基-1-乙基-2-氧代-1,2-二氢吡啶-4-甲酰胺(粗品,0.444mmol)，反应混合液50℃搅拌2小时。反应液浓缩，浓缩剩余物溶于乙醇水溶液。分出有机相，无水硫酸钠干燥，浓缩。浓缩剩余物用制备型高效液相色谱纯化得到N-(5-氯-3-((1-(2-环丁基乙酰基)哌啶-4-亚基)甲基)-2-甲基苯基)-6-氰基-1-乙基-2-氧代-1,2-二氢吡啶-4-甲酰胺70mg，纯度95％，产率31％，白色固体。 1H NMR(400MHz,DMSO-d 6):δ10.24(s,1H),7.43(d,1H),7.35(d,1H),7.32(d,1H),7.07(d,1H),6.36(s,1H),4.13(q,2H),3.53-3.51(m,2H),3.44-3.39(m,2H),2.65-2.55(m,1H),2.46(d,2H),2.40-2.35(m,1H),2.30-2.25(m,1H),2.26-2.18(m,1H),2.13-2.08(m,1H),2.07(s,3H),2.08-2.02(m,2H),1.85-1.75(m,2H),1.70-1.60(m,2H),1.29(t,3H)。MS计算值:506.2，MS实测值:507.0([M+H] +)。
N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲基苯基)-5-氰基-6-甲基烟酰胺(化合物63)
Figure PCTCN2020085294-appb-000149
5-氰基-6-甲基烟酸乙酯(68mg,0.36mmol)和(4-(3-氨基-5-氯-2-甲基亚苄基)哌啶-1-基)(环戊基)甲酮(120mg,0.36mmol)溶于甲苯(5mL)，氮气保护下，0℃搅拌。然后加入三甲基铝(0.40mL,0.72mmol)。反应混合液80℃搅拌3小时。氯化铵溶液淬灭反应，用乙酸乙酯萃取(20mL×3)。合并有机相并浓缩，浓缩剩余物用制备型高效液相色谱纯化得到N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲基苯基)-5-氰基-6-甲基烟酰胺103mg，纯度95％，产率60％，黄色固体。 1H NMR(400MHz,DMSO-d 6):δ10.28(s,1H),9.20(s,1H),8.73(s,1H),7.40(s,1H),7.08(d,1H),6.38(s,1H),3.59-3.57(m,2H),3.48-3.45(m,2H),3.05-2.97(m,1H),2.77(s,3H),2.38-2.10(m,4H),2.07(s,3H),1.76-1.51(m,8H)。MS计算值:476.2，MS实测值:477.0([M+H] +)。
N-(5-氯-3-((1-(2-环丙烷乙酰基)哌啶-4-亚基)甲基)-2-甲基苯基)-5-氰基-6-甲基烟酰胺(化合物64)
Figure PCTCN2020085294-appb-000150
N-(5-氯-2-甲基-3-(哌啶-4-亚基甲基)苯基)-5-氰基-6-甲基烟酰胺(100mg,0.26mmol)，2-环丙基乙酸(52mg,0.52mmol)，2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(109mg,0.286mmol)溶于N,N-二甲基甲酰胺(3mL)，反应液中加入三乙胺(0.1mL)。反应混合液氮气保护下，50℃搅拌1小时。反应液浓缩，浓缩剩余物用硅胶柱柱层析纯化(100％乙酸乙酯)得N-(5-氯-3-((1-(2-环丙烷乙酰基)哌啶-4-亚基)甲基)-2-甲基苯基)-5-氰基-6-甲基烟酰胺80mg，纯度95％，产率66％，白色固体。 1H NMR(400MHz,DMSO-d 6):δ10.27(s,1H),9.20(d,1H),8.72(d,1H),7.40(d,1H),7.07(s,1H),6.38(s,1H),3.53-3.57(m,2H),3.41-3.46(m,2H),2.77(s,3H),3.36-3.38(m,1H),2.72-2.32(m,2H),2.72-2.32(m,1H),2.21-2.23(m,1H),2.13-2.15(m,1H),2.11(s,3H),0.94-0.97(m,1H),0.44-0.47(m,2H),0.12(t,2H)。MS计算值:462.2，MS实测值:463.2([M+H] +)。
N-(5-氯-3-((1-(2-环丁基乙酰基)哌啶-4-亚基)甲基)-2-甲基苯基)-5-氰基-6-甲基烟酰胺(化合物65)
Figure PCTCN2020085294-appb-000151
N-(5-氯-2-甲基-3-(哌啶-4-亚基甲基)苯基)-5-氰基-6-甲基烟酰胺(100mg,0.26mmol)，2-环丁基乙酸(59mg,0.52mmol)，2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(109mg,0.286mmol)溶于N,N-二甲基甲酰胺(3mL)，反应液中加入三乙胺(0.1mL)。反应混合液氮气保护下，50℃搅拌1小时。反应液浓缩，浓缩剩余物用硅胶柱柱层析纯化(100％乙酸乙酯)得N-(5-氯-3-((1-(2-环丁基乙酰基)哌啶-4-亚基)甲基)-2-甲基苯基)-5-氰基-6-甲基烟酰胺70mg，纯度95％，产率56％，白色固体。 1H NMR(400MHz,DMSO-d 6):δ10.27(s,1H),9.20(s,1H),8.72(s,1H),7.40(s,1H),7.07(s,1H),6.37(s,1H),3.50-3.56(m,2H),3.39-3.40(m,2H),2.77(s,3H),2.57-2.62(m,1H),2.45-2.50(m,2H),2.36-2.34(m,1H),2.26-2.29(m,1H),2.21-2.23(m,1H),2.11-2.15(m,1H),2.11(s,3H),2.02-2.05(m,2H),1.77-1.83(m,2H),1.62-1.68(m,2H)。MS计算值:476.2，MS实测值:477.2([M+H] +)。
N-(5-氯-3-((1-(4,4-二氟环己基羰基)哌啶-4-亚基)甲基)-2-甲基苯基)-5-氰基-6-甲基烟酰胺(化合物66)
Figure PCTCN2020085294-appb-000152
N-(5-氯-2-甲基-3-(哌啶-4-亚基甲基)苯基)-5-氰基-6-甲基烟酰胺(100mg,0.26mmol)，4,4-二氟环己基甲酸(85mg,0.52mmol)，2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(296mg,0.78mmol)溶于N,N-二甲基甲酰胺(2mL)，反应液中加入三乙胺(0.1mL,0.78mmol)。反应混合液室温搅拌过夜。反应液浓缩，浓缩剩余物用制备型高效液相色谱纯化得到N-(5-氯-3-((1-(4,4-二氟环己基羰基)哌啶-4-亚基)甲基)-2-甲基苯基)-5-氰基-6-甲基烟酰胺60mg，纯度95％，产率44％，白色固体。 1H NMR(400MHz,DMSO-d 6):δ10.27(s,1H),9.20(s,1H),8.72(s,1H),7.40(s,1H),7.09(d,1H),6.39(s,1H),3.64-3.60(m,1H),3.60-3.54(m,1H),3.54-3.50(m,1H),3.48-3.42(m,1H),2.89-2.80(m,1H),2.77(s,3H),2.41-2.39(m,1H),2.32-2.30(m,1H),2.25-2.24(m,1H),2.15-2.13(m,1H),2.11(s,3H),2.08-1.70(m,6H),1.63-1.54(m,2H)。MS计算值:526.1，MS实测值:527.2([M+H] +)。
2-氯-6-甲氧基异烟酸
Figure PCTCN2020085294-appb-000153
2,6-二氯异烟酸(2.0g,10.4mmol)溶于甲醇(20mL)，0℃缓慢加入浓度为33％的氢氧化钠溶液(9.0g,75.0mmol)。反应液70℃搅拌3小时，然后冷却到室温。用盐酸(1mol/L)调节pH到3。沉淀物滤出，用盐酸(1mol/L)洗，干燥，得到2-氯-6-甲氧基异烟酸1.7g，产率81％，白色固体。 1HNMR(400MHz,DMSO-d 6):δ13.86(br s,1H),7.40(d,1H),7.19(d,1H),3.90(s,3H)。
2-氯-6-甲氧基异烟酸甲酯
Figure PCTCN2020085294-appb-000154
2-氯-6-甲氧基异烟酸(1.7g,9.09mmol)溶于甲醇(20mL)，0℃缓慢加入氯化亚砜(4.0mL,55.0mmol)。反应液氮气保护下50C搅拌4小时后浓缩。浓缩剩余物用硅胶柱柱层析纯化(二氯甲烷/甲醇＝100/1，体积比)得到2-氯-6-甲氧基异烟酸甲酯1.3g，产率72％，白色固体。 1HNMR(400MHz,DMSO-d 6):δ7.43(s,1H),7.21(s,1H),3.91(s,3H),3.86(s,3H)。
6-氯-2-氧-1,2-二氢吡啶-4-甲酸甲酯
Figure PCTCN2020085294-appb-000155
2-氯-6-甲氧基异烟酸甲酯(209mg,1.04mmol)和碘化钠(476mg,3.18mmol)溶于氯化亚砜(8mL)，氮气保护下，0℃向反应液中逐滴加入三甲基氯硅烷(0.4mL,3.16mmol)。反应混合液80℃搅拌4小时，然后冷却到室温。10mL水淬灭反应。有机相用饱和硫代硫酸钠洗，无水硫酸钠干燥，浓缩。浓缩剩余物用硅胶柱柱层析纯化(二氯甲烷/甲醇＝100/1，体积比)得到6-氯-2-氧-1,2-二氢吡啶-4-甲酸甲酯150mg，产率77％，白色固体。 1HNMR(400MHz,DMSO-d 6):δ12.07(s,1H),7.29(s,1H),7.03(s,1H),3.87(s,3H)。
6-氯-1-甲基-2-氧-1,2-二氢吡啶-4-甲酸甲酯
Figure PCTCN2020085294-appb-000156
6-氯-2-氧-1,2-二氢吡啶-4-甲酸甲酯(140mg,0.749mmol)，碘化钠(0.2mL,2.73mmol)和碳酸钾(310mg,2.24mmol)溶于N,N-二甲基甲酰胺(10mL)，氮气保护下50℃搅拌过夜。反应液浓缩。浓缩剩余物用硅胶柱柱层析纯化(二氯甲烷/甲醇＝100/1，体积比)得到6-氯-1-甲基-2-氧-1,2-二氢吡啶-4-甲酸甲酯64mg，产率43％，白色固体。
6-氯-N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-1-甲基-2-氧-1,2-二氢吡啶-4-甲酰胺(化合物67)
Figure PCTCN2020085294-appb-000157
6-氯-1-甲基-2-氧-1,2-二氢吡啶-4-甲酸甲酯(57mg,0.284mmol)和(4-(3-氨基-5-氯-2-甲基亚苄基)哌啶-1-基)(环戊基)甲酮(94mg,0.282mmol)溶于甲苯(10mL)，氮气保护下，0℃缓慢向反应液中加入三甲基铝(0.3mL,0.600mmol)。反应液80℃搅拌过夜，然后冷却到室温。用盐酸(1mol/L,5mL)淬灭反应。用乙酸乙酯(10mL×2)萃取。合并有机相，无水硫酸钠干燥，浓缩。浓缩剩余物用制备型高效液相色谱纯化得到6-氯-N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-1-甲基-2-氧-1,2-二氢吡啶-4-甲酰胺50mg，纯度95％，产率35％，白色固体。 1HNMR(400MHz,DMSO-d 6):δ10.19(d,1H),7.33(d,1H),7.07(d,1H),6.98(d,1H),6.84(d,1H),6.36(s,1H),3.61(s,3H),3.58-3.56(m,2H),3.48-3.44(m,2H),3.05-2.95(m,1H),2.38-2.11(m,4H),2.07(s,3H),1.77-1.51(m,8H)。MS计算值:501.2，MS实测值:502.2([M+H] +)。
6-氧-1,6-二氢哒嗪-4-甲酸甲酯
Figure PCTCN2020085294-appb-000158
6-氧-1,6-二氢哒嗪-4-甲酸(209mg,1.49mmol)溶于甲醇(10mL)，0℃缓慢加入氯化亚砜(2.0mL)。反应液氮气保护下，50℃搅拌5小时，然后浓缩。浓缩剩余物用柱层析硅胶纯化(石油醚/乙酸乙酯＝10/1，体积比)得到6-氧-1,6-二氢哒嗪-4-甲酸甲酯172mg，产率75％，灰白色固体。 1HNMR(400MHz,DMSO-d 6):δ13.47(brs,1H),8.16-8.15(m,1H),7.27(d,1H),3.88(s,3H)。
N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-6-氧-1,6-二氢哒嗪-4-甲酰胺(化合物68)
Figure PCTCN2020085294-appb-000159
6-氧-1,6-二氢哒嗪-4-甲酸甲酯(45mg,0.292mmol)和(4-(3-氨基-5-氯-2-甲基亚苄基)哌啶-1-基)(环戊基)甲酮(98mg,0.294mmol)溶于甲苯(10mL)，氮气保护下，0℃缓慢加入三甲基铝甲苯溶液(0.3mL,0.600mmol)。反应混合液80℃搅拌4小时，然后冷却到室温。用盐酸(1mol/L,4mL)淬灭反应，用乙酸乙酯(10mL×2)萃取。合并有机相，无水硫酸钠干燥，浓缩。浓缩剩余物用制备型高效液相色谱纯化得到N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-6-氧-1,6-二氢哒嗪-4-甲酰胺15mg，纯度95％，产率11％，白色固体。 1HNMR(400MHz,DMSO-d 6):δ13.35(brs,1H),10.29(brs,1H),8.18(d,1H),7.39(d,1H),7.37(d,1H),7.10(d,1H),6.36(s,1H),3.61(s,3H),3.59-3.57(m,2H),3.48-3.44(m,2H),3.05-2.97(m,1H),2.38-2.11(m,4H),2.10(s,3H),1.77-1.51(m,8H)。MS计算值:454.2，MS实测值:455.2([M+H] +)。
2-氰基-6-甲氧基异烟酸甲酯
Figure PCTCN2020085294-appb-000160
2-氯-6-甲氧基异烟酸甲酯(8.5g,42.3mmol)和氰化锌(6.0g,51.1mmol)和四(三苯基膦)钯(4.9g,4.24mmol)溶于N,N-二甲基甲酰胺(200mL)，氮气保护下，90℃搅拌过夜。反应液浓缩，浓缩剩余物用硅胶柱柱层析纯化(石油醚/乙酸乙酯＝50/1，体积比)得到2-氰基-6- 甲氧基异烟酸甲酯6.0g，产率74％，白色固体。 1HNMR(400MHz,CDCl 3):δ7.99(s,1H),7.55(s,1H),3.96(s,3H),3.91(s,3H)。
N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-2-氰基-6-甲氧基异烟酰胺(化合物69)
Figure PCTCN2020085294-appb-000161
2-氰基-6-甲氧基异烟酸甲酯(50mg mg,0.262mmol)和(4-(3-氨基-5-氯-2-甲基亚苄基)哌啶-1-基)(环戊基)甲酮(87mg,0.261mmol)溶于甲苯(5mL)，氮气保护下，0℃缓慢加入三甲基铝甲苯溶液(0.2mL,0.400mmol)。反应混合液80℃搅拌3小时，然后冷却到室温。用盐酸(1mol/L,3mL)淬灭反应，用乙酸乙酯(10mL×2)萃取。合并有机相，无水硫酸钠干燥，浓缩。浓缩剩余物用制备型高效液相色谱纯化得到N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-2-氰基-6-甲氧基异烟酰胺40mg，纯度95％，产率31％，白色固体。 1HNMR(400MHz,DMSO-d 6):δ10.35(s,1H),8.07(s,1H),7.65(s,1H),7.39(d,1H),7.09(d,1H),6.37(s,1H),3.98(s,3H),3.60-3.56(m,2H),3.48-3.44(m,2H),3.05-2.97(m,1H),2.38-2.11(m,4H),2.10(s,3H),1.77-1.51(m,8H)。MS计算值:492.2，MS实测值:493.0([M+H] +)。
6-氰基-2-氧-1,2-二氢吡啶-4-甲酸甲酯
Figure PCTCN2020085294-appb-000162
2-氰基-6-甲氧基异烟酸甲酯(4.9g,25.6mmol)和碘化钠(12.0g,80.0mmol)溶于乙腈(100mL)，氮气保护下，0℃缓慢加入三甲基氯硅烷(10mL,78.9mmol)。反应混合液80℃搅拌4小时，然后冷却到室温。加入水(100mL)，分出有机相，无水硫酸钠干燥，浓缩。浓缩剩余物用硅胶柱柱层析纯化(二氯甲烷/甲醇＝100/1，体积比)得到6-氰基-2-氧-1,2-二氢吡啶-4-甲酸甲酯3.0g，产率67％，白色固体。 1HNMR(400MHz,DMSO-d 6):δ12.42(brs,1H),7.80(s,1H),7.34(s,1H),3.90(s,3H)。
N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-6-氰基-2-氧-1,2-二氢吡啶-4-甲酰胺(化合物70)
Figure PCTCN2020085294-appb-000163
6-氰基-2-氧-1,2-二氢吡啶-4-甲酸甲酯(42mg,0.237mmol)和(4-(3-氨基-5-氯-2-甲基亚苄基)哌啶-1-基)(环戊基)甲酮(79mg,0.237mmol)溶于甲苯(10mL)，氮气保护下，0℃缓慢加入三甲基铝甲苯溶液(0.2mL,0.400mmol)。反应混合液80℃搅拌3小时，然后冷却到室温。用盐酸(1mol/L,3mL)淬灭反应，用乙酸乙酯(10mL×2)萃取。合并有机相，无水硫酸钠干燥，浓缩。浓缩剩余物用制备型高效液相色谱纯化得到N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-6-氰基-2-氧-1,2-二氢吡啶-4-甲酰胺10mg，纯度95％，产率9％，白色固体。 1HNMR(400MHz,DMSO-d 6):δ10.26(brs,1H),7.78(s,1H),7.37(s,2H),7.08(d,1H),6.37(s,1H),3.60-3.57(m,2H),3.47-3.42(m,2H),3.05-2.97(m,1H),2.38-2.11(m,4H),2.09(s,3H),1.77-1.51(m,8H)。MS计算值:478.2，MS实测值:479.2([M+H] +)。
4-(溴亚甲基)哌啶-1-甲酸叔丁酯
Figure PCTCN2020085294-appb-000164
在-15℃，氩气状态下将六甲基二硅氮烷锂盐(1M,11mL)滴加入溴甲基三苯基膦溴盐(4.8g,11mmol)的四氢呋喃(11mL)悬浮液中。搅拌15分钟后，在-15℃下加入4-氧代哌啶-1-甲酸叔丁酯(1.99g,10mmol)。该反应液在室温下搅拌2小时后，用水进行淬灭，用乙酸乙酯(30mL×3)进行萃取，有机相用饱和食盐水进行洗涤，然后用无水硫酸钠干燥、浓缩。通过硅胶柱柱层析纯化(乙酸乙酯:石油醚＝1:50至1:10)得到无色油状4-(溴亚甲基)哌啶-1-甲酸叔丁酯1.6g,产率59％。 1H NMR(400MHz,CDCl 3)δ5.99(t,1H),3.46-3.36(m,4H),2.41-2.35(m,2H),2.27-2.19(m,2H),1.46(s,9H)。
5-氟-2-甲基-3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊基-2-基)苯胺
Figure PCTCN2020085294-appb-000165
在氩气保护下向3-溴-5-氟-2-甲基苯胺(1g,4.9mmol)，联硼酸频那醇酯(1.5g,6mmol)和醋酸钾(735mg,7.5mmol)在二氧六环(30mL)的溶液中加入[1,1'-双(二苯基膦基)二茂铁]二氯化钯(220mg,0.3mmol)。该反应液在100℃下搅拌过夜后过滤掉固体杂质，通过硅胶 柱柱层析纯化(乙酸乙酯:石油醚＝1:20→1:5)得到黄色固体5-氟-2-甲基-3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊基-2-基)苯胺1.07g,产率87％。LC-MS:252.0[M+H +]
4-(3-氨基-5-氟-2-甲基亚苄基)哌啶-1-甲酸叔丁酯
Figure PCTCN2020085294-appb-000166
在氩气保护下向5-氟-2-甲基-3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊基-2-基)苯胺(126mg,0.5mmol)，4-(溴亚甲基)哌啶-1-甲酸叔丁酯(165mg,0.6mmol)和饱和碳酸钠溶液(100μL)的二氧六环(10mL)溶液中加入[1,1'-双(二苯基膦基)二茂铁]二氯化钯(37mg,0.05mmol)。该反应液在90℃搅拌过夜后滤掉固体杂质，减压浓缩。产生的混合物通过制备薄层色谱(乙酸乙酯:石油醚＝1:4)纯化得到无色油状4-(3-氨基-5-氟-2-甲基亚苄基)哌啶-1-甲酸叔丁酯80mg,产率50％。LC-MS:265.1[M- tBu+H +]
4-(3-(3-氰基苯甲酰氨基)-5-氟-2-甲基亚苄基)哌啶-1-甲酸叔丁酯
Figure PCTCN2020085294-appb-000167
向4-(3-氨基-5-氟-2-甲基亚苄基)哌啶-1-甲酸叔丁酯(80mg,0.25mmol)，3-氰基苯甲酸(44mg,0.3mmol)和2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(143mg,0.375mmol)在二氯甲烷(4mL)的溶液中加入二异丙基乙基胺(124μL,0.75mmol)。该反应液在室温下搅拌过夜后直接减压浓缩通过制备薄层色谱(乙酸乙酯:石油醚＝1:4)纯化得到白色固体4-(3-(3-氰基苯甲酰氨基)-5-氟-2-甲基亚苄基)哌啶-1-甲酸叔丁酯99mg,产率88％。LC-MS:394.2[M- tBu+H +]
3-氰基-N-(5-氟-2-甲基-3-(哌啶-4-亚基甲基)苯基)苯甲酰胺三氟乙酸盐
Figure PCTCN2020085294-appb-000168
将三氟乙酸(1mL)加入到4-(3-(3-氰基苯甲酰氨基)-5-氟-2-甲基亚苄基)哌啶-1-甲酸叔丁酯的二氯甲烷(5mL)的溶液中室温下搅拌4小时。混合液直接通过减压浓缩得到无色油状3-氰基-N-(5-氟-2-甲基-3-(哌啶-4-亚基甲基)苯基)苯甲酰胺三氟乙酸盐的粗产品(100mg)。LC-MS:350.2[M+H +]
3-氰基-N-(3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-5-氟-2-甲基苯基)苯甲酰胺(化合物71)
Figure PCTCN2020085294-appb-000169
将环戊基甲酰氯(63μL,0.52mmol)加入3-氰基-N-(5-氟-2-甲基-3-(哌啶-4-亚基甲基)苯基)苯甲酰胺三氟乙酸盐(100mg)和三乙胺(109μL,0.78mmol)在二氯甲烷(5mL)的溶液中。该反应液在室温下搅拌2小时后直接浓缩通过制备薄层色谱(乙酸乙酯:石油醚＝1:2)纯化得到淡黄色固体3-氰基-N-(3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-5-氟-2-甲基苯基)苯甲酰胺35.1mg,产率30％。 1H NMR(400MHz,CD 3OD)δ8.32(s,1H),8.25(d,1H),7.96(d,1H),7.73(t,1H),7.11(dd,1H),6.88-6.80(m,1H),6.42(s,1H),3.70(dd,2H),3.57(dd,J＝11.3,5.3Hz,2H),3.16-3.03(m,1H),2.49-2.23(m,4H),2.16(s,3H),1.91-1.57(m,8H)。LC-MS:446.2[M+H +]
3-溴-2-氯-苯胺
Figure PCTCN2020085294-appb-000170
将1-溴-2-氯-3-硝基苯(1g,4.23mmol)，铁粉(1.2g,21.5mmol)和氯化铵(228mg,4.3mmol)加入乙醇和水(3mL/1.5mL)中。该混合液在60℃下搅拌2小时。将反应液过滤掉固体，残液减压浓缩后溶于乙酸乙酯中，用水和盐水分别洗涤，有机相用无水硫酸钠干燥后浓缩得到褐色油状3-溴-2-氯-苯胺0.824g,产率93％。LC-MS:205.9[M+H +]
2-氯-3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊基-2-基)苯胺
Figure PCTCN2020085294-appb-000171
在氩气保护下向3-溴-2-氯苯胺(0.5g,2.4mmol)，联硼酸频那醇酯(0.62g,2.4mmol)和醋酸钾(470mg,4.8mmol)在二氧六环(10mL)的溶液中加入[1,1'-双(二苯基膦基)二茂铁]二氯化钯(88mg,0.12mmol)。该反应液在100℃下搅拌过夜后过滤掉固体杂质，通过硅胶柱柱层析纯化(乙酸乙酯:石油醚＝1:20→1:5)得到白色固体2-氯-3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊基-2-基)苯胺0.48g,产率79％。LC-MS:254.1[M+H +]
4-(3-氨基-2-氯亚苄基)哌啶-1-甲酸叔丁酯
Figure PCTCN2020085294-appb-000172
在氩气保护下向2-氯-3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊基-2-基)苯胺(202mg,0.8mmol)，4-(溴亚甲基)哌啶-1-甲酸叔丁酯(264mg,0.96mmol)和饱和碳酸钾溶液(150μL)的二氧六环(10mL)溶液中加入[1,1'-双(二苯基膦基)二茂铁]二氯化钯(59mg,0.08mmol)。该反应液在90℃搅拌过夜后滤掉固体杂质，减压浓缩。产生的混合物通过制备薄层色谱(乙酸乙酯:石油醚＝1:4)纯化得到白色固体4-(3-氨基-2-氯亚苄基)哌啶-1-甲酸叔丁酯150mg,产率58％。LC-MS:267.1[M- tBu+H +]
4-(2-氯-3-(3-氰基苯甲酰氨基)亚苄基)哌啶-1-甲酸叔丁酯
Figure PCTCN2020085294-appb-000173
向4-(3-氨基-2-氯亚苄基)哌啶-1-甲酸叔丁酯(150mg,0.47mmol)，3-氰基苯甲酸(82mg,0.56mmol)和2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(268mg,0.71mmol)在二氯甲烷(8mL)的溶液中加入二异丙基乙基胺(233μL,1.41mmol)。该反应液在室温下搅拌过夜后直接减压浓缩通过制备薄层色谱(乙酸乙酯:石油醚＝1:4)纯化得到白色固体4-(2-氯-3-(3-氰基苯甲酰氨基)亚苄基)哌啶-1-甲酸叔丁酯91mg,产率43％。LC-MS:396.1[M- tBu+H +]
N-(2-氯-3-(哌啶-4-亚基甲基)苯基)-3-氰基苯甲酰胺三氟乙酸盐
Figure PCTCN2020085294-appb-000174
将三氟乙酸(1mL)加入到4-(2-氯-3-(3-氰基苯甲酰氨基)亚苄基)哌啶-1-甲酸叔丁酯的二氯甲烷(5mL)的溶液中室温下搅拌4小时。混合液直接通过减压浓缩得到无色油状N-(2-氯-3-(哌啶-4-亚基甲基)苯基)-3-氰基苯甲酰胺三氟乙酸盐的粗产品93mg。LC-MS:352.1[M+H +]
N-(2-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)苯基)-3-氰基苯甲酰胺(化合物72)
Figure PCTCN2020085294-appb-000175
将环戊基甲酰氯(73μL,0.6mmol)加入N-(2-氯-3-(哌啶-4-亚基甲基)苯基)-3-氰基苯甲酰胺三氟乙酸盐(93mg)和二异丙基乙基胺(100mg,0.78mmol)在二氯甲烷(10mL)的溶液中。该反应液在室温下搅拌2小时后直接浓缩通过制备薄层色谱(乙酸乙酯:石油醚＝1:2)纯化得到淡黄色固体N-(2-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)苯基)-3-氰基苯甲酰胺 24mg,产率27％。 1H NMR(400MHz,CD 3OD)δ8.34-8.22(m,2H),7.95(d,1H),7.71(t,1H),7.63(d,1H),7.32(t,1H),7.19(d,1H),6.43(s,1H),3.73-3.63(m,2H),3.55(d,2H),3.14-3.00(m,1H),2.38(tt,4H),1.95-1.53(m,8H)。LC-MS:448.2[M+H +]
2-甲基-3-硝基苄醇
Figure PCTCN2020085294-appb-000176
在室温下向2-甲基-3-硝基苯甲酸甲酯(1.95g,10mmol)的四氢呋喃(10mL)溶液中加入硼氢化钠(1.52g,40mmol)。混合液回流3小时后加入甲醇(5mL)继续回流4小时后室温搅拌过夜。加入水(20mL)淬灭，用乙酸乙酯(30mL×3)萃取，用饱和食盐水洗涤后浓缩得到黄色固体2-甲基-3-硝基苄醇1.4g,产率84％。
2-甲基-3-硝基苄溴
Figure PCTCN2020085294-appb-000177
在0℃下将三溴化磷(1.88mL,20mmol)的二氯甲烷溶液(20mL)滴加入到2-甲基-3-硝基苄醇(1.4g,8.38mmol)的二氯甲烷(15mL)溶液中。将该反应液恢复至室温搅拌3小时后在0℃下用水淬灭该反应，用二氯甲烷(30mL×3)进行萃取，用饱和碳酸钾溶液洗涤，饱和食盐水洗涤，用无水硫酸钠干燥后减压浓缩得到黄色油状2-甲基-3-硝基苄溴1.6g,产率83％。
(2-甲基-3-硝基苄基)三苯基溴化鏻
Figure PCTCN2020085294-appb-000178
在氩气下将2-甲基-3-硝基苄溴(900mg,3.9mmol)和三苯基膦(1g,3.9mmol)溶于甲苯(15mL)中。该混合液在110℃下搅拌4小时后冷却至0℃，过滤后得白色固体(2-甲基-3-硝基苄基)三苯基溴化鏻1.7g,产率89％。LC-MS:412.2[M+H +]
4-(2-甲基-3-硝基亚苄基)哌啶-1-甲酸叔丁酯
Figure PCTCN2020085294-appb-000179
在-15℃氩气保护下将六甲基二硅氮烷锂盐(1M,1.1mL)加入(2-甲基-3-硝基苄基)三苯基溴化鏻(491mg,1mmol)的四氢呋喃(3mL)中。搅拌15分钟后，在-15℃氩气保护下将4-氧代哌啶-1-羧酸叔丁酯(199mg,1mmol)的四氢呋喃溶液加入该反应液，恢复至室温继续 搅拌2小时，用水淬灭该反应，用乙酸乙酯(30mL×3)进行萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，通过硅胶柱柱层析纯化(乙酸乙酯:石油醚＝1:50→1:10)得到无色油状4-(2-甲基-3-硝基亚苄基)哌啶-1-甲酸叔丁酯70mg，产率21％。LC-MS:277.1[M- tBu+H +]
4-(2-甲基-3-氨基亚苄基)哌啶-1-甲酸叔丁酯
Figure PCTCN2020085294-appb-000180
将4-(2-甲基-3-硝基亚苄基)哌啶-1-甲酸叔丁酯(70mg,0.21mmol),铁粉(59mg,1.05mmol)和氯化铵(11mg,0.21mmol)加入乙醇和水(3mL/0.5mL)中，然后在60℃搅拌4小时。将反应液过滤掉固体后减压浓缩，通过制备薄层色谱(乙酸乙酯:石油醚＝1:4)纯化得到黄色油状4-(2-甲基-3-氨基亚苄基)哌啶-1-甲酸叔丁酯50mg，产率79％。
4-(3-(3-氰基苯甲酰氨基)-2-甲基亚苄基)哌啶-1-甲酸叔丁酯
Figure PCTCN2020085294-appb-000181
向4-(2-甲基-3-氨基亚苄基)哌啶-1-甲酸叔丁酯(50mg,0.17mmol),3-氰基苯甲酸(29mg,0.2mmol)和2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(97mg,0.26mmol)的二氯甲烷(4mL)溶液中加入二异丙基乙基胺(84μL,0.51mmol)。该反应混合液在室温下搅拌过夜。该反应液通过制备薄层色谱(乙酸乙酯:石油醚＝1:2.5)纯化得到白色固体4-(3-(3-氰基苯甲酰氨基)-2-甲基亚苄基)哌啶-1-甲酸叔丁酯67mg,产率91％。LC-MS:376.1[M- tBu+H +]
3-氰基-N-(2-甲基-3-(哌啶-4-亚基甲基)苯基)苯甲酰胺三氟乙酸盐
Figure PCTCN2020085294-appb-000182
向4-(3-(3-氰基苯甲酰氨基)-2-甲基亚苄基)哌啶-1-甲酸叔丁酯(67mg,0.16mmol)的二氯甲烷(5mL)溶液中加入三氟乙酸(1mL)，该反应液在室温下搅拌4小时后直接减压浓缩得到无色油状3-氰基-N-(2-甲基-3-(哌啶-4-亚基甲基)苯基)苯甲酰胺三氟乙酸盐的粗产品70mg。LC-MS:332.2[M+H +]
3-氰基-N-(3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲基苯基)苯甲酰胺(化合物73)
Figure PCTCN2020085294-appb-000183
向3-氰基-N-(2-甲基-3-(哌啶-4-亚基甲基)苯基)苯甲酰胺三氟乙酸盐和二异丙基乙基胺的二氯甲烷溶液中加入环戊基甲酰氯，该反应液在室温下搅拌2小时后减压浓缩，通过制备薄层色谱(乙酸乙酯:石油醚＝1:2)纯化得到黄色色固体3-氰基-N-(3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲基苯基)苯甲酰胺67mg,产率39％。 1H NMR(400MHz,CD 3OD)δ8.37-8.22(m,2H),7.94(d,1H),7.71(t,1H),7.2-7.16(m,2H),7.07(d,1H),6.43(s,1H),3.61(ddd,4H),3.17-3.00(m,1H),2.49-2.22(m,4H),2.18(s,3H),1.89-1.57(m,-8H)。LC-MS:428.2[M+H +]
6-氰基-N-(3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-5-氟-2-甲基苯基)-1-甲基-2-氧-1,2-二氢吡啶-4-甲酰胺(化合物74)
Figure PCTCN2020085294-appb-000184
(4-(3-氨基-5-氟-2-甲基亚苄基)哌啶-1-基)(环戊基)甲酮(100mg,0.32mmol)和6-氰基-1-甲基-2-氧-1,2-二氢吡啶-4-甲酸甲酯(62mg,0.32mmol)溶于甲苯(10mL)，0℃逐滴加入三甲基铝(0.4mL,2M,0.62mmol)。反应混合液80℃搅拌2小时。然后0℃加入水，二氯甲烷萃取。有机相饱和食盐水洗，无水硫酸钠干燥并浓缩。浓缩剩余物用制备型高效液相色谱纯化得到6-氰基-N-(3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-5-氟-2-甲基苯基)-1-甲基-2-氧-1,2-二氢吡啶-4-甲酰胺91mg，纯度95％，产率60％，白色固体。 1H NMR(400MHz,DMSO-d 6):δ10.25(s,1H),7.40(s,1H),7.33(s,1H),7.14(dd,1H),6.91-6.87(m,1H),6.38(s,1H),3.60-3.57(m,5H),3.48-3.44(m,2H),3.03-2.97(m,1H),2.37-2.14(m,4H),2.33-2.32(s,1H),2.06(s,3H),1.79-1.53(m,8H)。MS计算值:476.2，MS实测值:477.1([M+H] +)。
6-氰基-N-(3-((1-(2-环丙基乙酰基)哌啶-4-亚基)甲基)-5-氟-2-甲基苯基)-1-甲基-2-氧-1,2-二氢吡啶-4-甲酰胺(化合物75)
Figure PCTCN2020085294-appb-000185
1-(4-(3-氨基-5-氟-2-甲基亚苄基)哌啶-1-基)-2-环丙基乙酮(100mg,0.33mmol)和6-氰基-1-甲基-2-氧-1,2-二氢吡啶-4-甲酸甲酯(64mg,0.33mmol)溶于甲苯(10mL)，0℃逐滴加入三甲基铝(0.4mL,2M,0.66mmol)。反应混合液80℃搅拌2小时。然后0℃加入水，二氯甲烷萃取。有机相饱和食盐水洗，无水硫酸钠干燥并浓缩。浓缩剩余物用制备型高效液相色谱纯化得到6-氰基-N-(3-((1-(2-环丙基乙酰基)哌啶-4-亚基)甲基)-5-氟-2-甲基苯基)-1-甲基-2-氧-1,2-二氢吡啶-4-甲酰胺46mg，纯度95％，产率30％，白色固体。 1H NMR(400MHz,DMSO-d 6):δ10.25(s,1H),9.20(s,1H),7.40(s,1H),7.14(dd,1H),6.88(dd,1H),3.60-3.51(m,3H),3.46-3.41(m,2H),2.43(t,2H),2.36-2.15(m,3H),2.08(t,1H),2.06(t,3H),1.89(s,3H),0.97-0.96(m,1H),0.14-0.11(m,2H),0.01(t,2H)。 19F NMR(376MHz,DMSO-d6)δ-117.3(d,1F)。MS计算值:462.2，MS实测值:463.1([M+H] +)。
1-(4-(5-氟-2-甲基-3-硝基亚苄基)哌啶-1-基)-2-甲基丙烷-1-酮
Figure PCTCN2020085294-appb-000186
4-(5-氟-2-甲基-3-硝基亚苄基)哌啶盐酸盐(500mg,1.75mmol)溶于二氯甲烷(10mL)，加入三乙胺(530mg,5.25mmol)。然后0℃氮气保护下滴加异丁酰氯(223mg,2.1mmol)。混合反应液室温搅拌3小时。反应液浓缩，浓缩剩余物用柱层层析硅胶(石油醚/乙酸乙酯＝3/2，体积比)纯化得到1-(4-(5-氟-2-甲基-3-硝基亚苄基)哌啶-1-基)-2-甲基丙烷-1-酮550mg，产率98％，黄色油状。MS计算值:320.2，MS实测值:321.0([M+H] +)。
1-(4-(3-氨基-5-氟-2-甲基亚苄基)哌啶-1-基)-2-甲基丙烷-1-酮
Figure PCTCN2020085294-appb-000187
1-(4-(5-氟-2-甲基-3-硝基亚苄基)哌啶-1-基)-2-甲基丙烷-1-酮(550mg,1.72mmol)溶于乙醇(10mL)和水(5mL)，室温下加入醋酸钠(282mg,3.44mmol),醋酸(1mL)和铁粉(385mg,6.88mmol)。反应混合液85℃搅拌1小时。反应液冷却至0℃，碳酸钠溶液淬灭，乙酸乙酯萃取。合并有机相，饱和食盐水洗并浓缩。浓缩剩余物用柱层层析硅胶(石油醚/乙酸乙酯＝1/1，体积比)纯化得到1-(4-(3-氨基-5-氟-2-甲基亚苄基)哌啶-1-基)-2-甲基丙烷-1-酮490mg，产率98％，黄色油状。MS计算值:290.2，MS实测值:291.1([M+H] +)。
6-氰基-N-(5-氟-3-((1-异丁酰基哌啶-4-亚基)甲基)-2-甲基苯基)-1-甲基-2-氧代-1,2-二氢吡啶-4-甲酰胺(化合物76)
Figure PCTCN2020085294-appb-000188
1-(4-(3-氨基-5-氟-2-甲基亚苄基)哌啶-1-基)-2-甲基丙烷-1-酮(100mg,0.34mmol)和6-氰基-1-甲基-2-氧代-1,2-二氢吡啶-4-羧酸盐(71mg,0.37mmol)溶于甲苯(2mL)，0℃氮气保护下慢慢滴加三甲基铝(0.34mL,2M in toluene,0.68mmol)。反应液85℃搅拌4小时。反应液冷却至零度，酒石酸钾钠溶液淬灭反应，乙酸乙酯萃取。合并有机相,饱和食盐水洗，无水硫酸钠干燥，过滤并浓缩。浓缩剩余物用制备型高效液相色谱纯化得到6-氰基-N-(5-氟-3-((1-异丁酰基哌啶-4-亚基)甲基)-2-甲基苯基)-1-甲基-2-氧代-1,2-二氢吡啶-4-甲酰胺66mg，纯度95％，产率43％，白色固体。 1H NMR(400MHz,DMSO-d6)δ10.25(s,1H),7.40(d,1H),7.32(d,1H),7.15(dd,1H),6.89(t,1H),6.38(s,1H),3.60(s,3H),3.58-3.60(m,2H),3.46(m,2H),2.87-2.95(m,1H),2.14-2.38(m,4H),2.07(s,3H),1.01(t,6H)。MS计算值:450.2，MS实测值:451.2([M+H] +)。
(R)-6-氰基-N-(3-((1-(3,3-二氟环戊基羰基)哌啶-4-亚基)甲基)-5-氟-2-甲基苯基)-1-甲基-2-氧-1,2-二氢吡啶-4-甲酰胺(化合物77)
Figure PCTCN2020085294-appb-000189
(R)-3,3-二氟环戊基羧酸(126mg,0.84mmol)，三乙胺(212mg,2.1mmol)和2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(319mg,0.84mmol)溶于二氯甲烷(4mL)室温搅拌10分钟。然后加入6-氰基-N-(5－氟－2－甲基－3－(哌啶-4-亚甲基)苯基)-1-甲基-2-氧代-1，2-二氢吡啶-4-甲酰胺盐酸盐(290mg,0.70mmol)，反应液室温搅拌1小时。反应液倒入水里，二氯甲烷萃取。合并有机相，无水硫酸钠干燥，过滤并浓缩。浓缩剩余物用制备型高效液相色谱纯化得到(R)-6-氰基-N-(3-((1-(3,3-二氟环戊基羰基)哌啶-4-亚基)甲基)-5-氟-2-甲基苯基)-1-甲基-2-氧-1,2-二氢吡啶-4-甲酰胺189mg，纯度95％，产率53％，白色固体。 1H NMR(400MHz,DMSO-d6)δ7.40(s,1H),7.33(s,1H),7.15(dd,1H),6.89(t,1H),6.39(s,1H),3.60(s,3H),3.57-3.60(m,2H),3.47(t,2H),3.35-3.42(m,1H),2.36-2.42(m,2H),2.28-2.34(m,2H),2.21-2.26(m,2H),2.14-2.16(m,1H),2.06(s,3H),1.99-2.03(m,2H),1.80-1.82(m,1H)。 19F NMR(376MHz,DMSO-d6)δ-89.26～-88.52(m,1F),-91.86～-91.08 (m,1F),-117.39～-117.25(m,1F)。MS计算值:512.2，MS实测值:513.2([M+H] +)。
(5-氟-2-甲基-3-硝基苯基)甲醇
Figure PCTCN2020085294-appb-000190
5-氟-2-甲基-3-硝基苯甲酸(2.0g,10mmol)溶于四氢呋喃(20mL)，氮气保护下，0℃逐滴加入硼烷四氢呋喃溶液(13.0mL,13mmol)。反应混合液室温搅拌过夜。0℃逐滴加入甲醇淬灭反应。然后混合液浓缩。浓缩剩余物用水稀释，二氯甲烷萃取。有机相碳酸氢钠洗，饱和食盐水洗，无水硫酸钠干燥并浓缩。浓缩剩余物用硅胶柱柱层析纯化(石油醚/乙酸乙酯＝5/1到1/1，体积比)得到(5-氟-2-甲基-3-硝基苯基)甲醇0.8g，产率45％，白色固体。 1H NMR(300MHz,DMSO-d 6):δ7.72(dd,2H),7.55(dd,2H),5.58(t,1H),4.58(d,2H),2.22(s,3H)。
1-(溴甲基)-5-氟-2-甲基-3-硝基苯
Figure PCTCN2020085294-appb-000191
(5-氟-2-甲基-3-硝基苯基)甲醇(7.2g,38.9mmol)溶于二氯甲烷(100mL)，0℃加入三苯基膦(16.3g,62.2mmol)。然后0℃逐滴加入四溴化碳(20.6g,62.2mmol)的二氯甲烷溶液(50mL)。反应混合液室温搅拌过夜。反应液浓缩，浓缩剩余物用硅胶柱柱层析纯化(石油醚/乙酸乙酯＝100/1到50/1，体积比)得到1-(溴甲基)-5-氟-2-甲基-3-硝基苯7.3g，产率71％，棕色油状物。 1H NMR(400MHz,DMSO-d 6):δ7.50(dd,1H),7.32(dd,1H),4.49(s,2H),2.48(s,3H)
(5-氟-2-甲基-3-硝基苄基)溴三苯基膦
Figure PCTCN2020085294-appb-000192
1-(溴甲基)-5-氟-2-甲基-3-硝基苯(600mg,2.4mmol)溶于甲苯(10mL)，室温加入三苯基膦(760mg,2.9mmol)。反应液80℃搅拌6小时。然后冷却到室温。过滤收集沉淀固体并用甲苯洗涤。滤饼减压干燥得到(5-氟-2-甲基-3-硝基苄基)溴三苯基膦1.1g，产率91％，白色固体。 1H NMR(400MHz,DMSO-d 6):δ7.98-7.92(m,4H),7.80-7.69(m,12H),7.11(d,2H),5.32-5.27(m,2H),1.59(s,3H)。
4-(5-氟-2-甲基-3-硝基亚苄基)哌啶-1-甲酸叔丁酯
Figure PCTCN2020085294-appb-000193
钠氢(96mg,2.4mmol)和二甲基亚砜(10mL)的悬浮液加热到80℃搅拌1小时。然后将混合液冷却至5℃，加入(5-氟-2-甲基-3-硝基苄基)溴三苯基膦(1.1g,2.2mmol)。继续搅拌10分钟，然后5℃加入4-氧代哌啶-1-甲酸叔丁酯(0.44g,2.2mmol)。反应混合液升温到80℃，搅拌过夜。0℃加入水并用乙酸乙酯萃取。有机相饱和食盐水洗，无水硫酸钠干燥并浓缩。浓缩剩余物用硅胶柱柱层析纯化(石油醚/乙酸乙酯＝20/1，体积比)得到4-(5-氟-2-甲基-3-硝基亚苄基)哌啶-1-甲酸叔丁酯375mg，产率49％，无色油状物。 1H NMR(400MHz,DMSO-d 6):δ7.76(s,1H),7.32(s,1H),6.38(s,1H),3.44(t,2H),3.32(m,2H),3.32(t,2H),2.25(s,3H),2.14(t,2H),1.41(s,9H)。
4-(5-氟-2-甲基-3-硝基亚苄基)哌啶盐酸盐
Figure PCTCN2020085294-appb-000194
4-(5-氟-2-甲基-3-硝基亚苄基)哌啶-1-甲酸叔丁酯(375mg,1.1mmol)溶于盐酸乙酸乙酯溶液(6mL)，室温搅拌2小时。反应液浓缩。粗产品不进一步纯化直接用于下一步反应。
2-环丙基-1-(4-(5-氟-2-甲基-3-硝基亚苄基)哌啶-1-基)乙酮
Figure PCTCN2020085294-appb-000195
2-环丙基乙酸(0.9mL,9.6mmol)，2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(5.47g,14.4mmol)和三乙胺(7.6mL,14.4mL)溶于N,N-二甲基甲酰胺(30mL)，室温搅拌1小时。然后加入4-(5-氟-2-甲基-3-硝基亚苄基)哌啶盐酸盐(1.38g,4.8mmol)。反应混合液室温搅拌过夜。反应液浓缩。浓缩剩余物水稀释，二氯甲烷萃取。有机相饱和食盐水洗，无水硫酸钠干燥并浓缩。浓缩剩余物用硅胶柱柱层析纯化(石油醚/乙酸乙酯＝10/1到3/1，体积比)得到2-环丙基-1-(4-(5-氟-2-甲基-3-硝基亚苄基)哌啶-1-基)乙酮1.52g，产率96％，棕色油状物。 1H NMR(400MHz,CDCl 3):δ7.46(d,1H),7.04(d,1H),6.30(d,1H),3.74(t,1H),3.61-3.56(m,2H),3.43-3.38(t,1H),2.45-2.41(m,2H),2.36-2.30(m,5H),2.26-2.20(m,2H),1.18-1.01(m,1H),0.62-0.56(m,2H),0.22-0.16(m,2H)。
1-(4-(3-氨基-5-氟-2-甲基亚苄基)哌啶-1-基)-2-环丙基乙酮
Figure PCTCN2020085294-appb-000196
2-环丙基-1-(4-(5-氟-2-甲基-3-硝基亚苄基)哌啶-1-基)乙酮(1.52g,1.0mmol)，铁粉(1.03g,18.4mmol)，醋酸钠(0.76g,9.2mmol)和醋酸溶于乙醇水溶液(50mL,v/v＝2/1)，80℃搅拌2小时。然后将所得混合物通过硅藻土过滤。滤饼用甲醇和二氯甲烷洗涤。滤液浓缩。浓缩剩余物加水稀释，二氯甲烷萃取。有机相饱和食盐水洗，无水硫酸钠干燥并浓缩。浓缩剩余物用硅胶柱柱层析纯化(二氯甲烷/甲醇＝100/1，体积比)得到1-(4-(3-氨基-5-氟-2-甲基亚苄基)哌啶-1-基)-2-环丙基乙酮1.36mg，产率98％，棕色油状物。 1H NMR(400MHz,DMSO-d 6):δ6.35-6.29(m,2H),6.06(dd,1H),5.17(s,2H),3.57-3.49(m,2H),3.45-3.37(m,3H),2.34-2.27(m,4H),2.24-1.93(m,2H),1.91(d,3H),0.49-0.43(m,2H),0.14-0.10(m,2H)。
5-氯-N-(3-((1-(2-环丙基乙酰基)哌啶-4-亚基)甲基)-5-氟-2-甲基苯基)-6-甲基烟酰胺(化合物78)
Figure PCTCN2020085294-appb-000197
1-(4-(3-氨基-5-氟-2-甲基亚苄基)哌啶-1-基)-2-环丙基乙酮(100mg,0.33mmol)和5-氯-6-甲基烟酸甲酯(62mg,0.33mmol)溶于甲苯(10mL)，0℃逐滴加入三甲基铝(0.4mL,2M,0.66mmol)。反应混合液80℃搅拌2小时。0℃加入水淬灭反应，二氯甲烷萃取。有机相饱和食盐水洗，无水硫酸钠干燥并浓缩。浓缩剩余物用制备型高效液相色谱纯化得到5-氯-N-(3-((1-(2-环丙基乙酰基)哌啶-4-亚基)甲基)-5-氟-2-甲基苯基)-6-甲基烟酰胺75mg，纯度95％，产率50％，白色固体。 1H NMR(400MHz,DMSO-d 6):δ10.20(s,1H),8.95(s,1H),8.36(s,1H),7.17(dd,1H),6.87(dd,1H),6.39(s,1H),3.57-3.51(m,2H),3.47-3.40(m,2H),2.64(s,3H),2.37(t,1H),2.32-2.27(m,3H),2.23(t,1H),2.16(t,1H),2.09(s,3H),1.02-0.99(m,1H),0.46-0.44(m,2H),0.12(t,2H)。MS计算值:455.2，MS实测值:456.1([M+H] +)。
5-氰基-N-(3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-5-氟-2-甲基苯基)-6-甲基烟酰胺(化合物79)
Figure PCTCN2020085294-appb-000198
(4-(3-氨基-5-氟-2-甲基亚苄基)哌啶-1-基)(环戊基)甲酮(100mg,0.32mmol)和5-氰基-6-甲基烟酸甲酯(61mg,0.32mmol)溶于甲苯(10mL)，0℃逐滴加入三甲基铝(0.4mL,2M,0.62mmol)。反应混合液80℃搅拌2小时。然后0℃加入水，二氯甲烷萃取。有机相饱和食盐水洗，无水硫酸钠干燥并浓缩。浓缩剩余物用制备型高效液相色谱纯化得到5-氰基-N-(3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-5-氟-2-甲基苯基)-6-甲基烟酰胺43.8mg，纯度95％，产率30％，白色固体。 1H NMR(400MHz,DMSO-d 6):δ10.25(s,1H),9.20(s,1H),8.72(s,1H),7.20(dd,1H),6.91-6.87(m,1H),6.39(s,1H),3.60-3.56(m,2H),3.49-3.45(m,2H),3.06-2.97(m,1H),2.77(s,3H),2.37-2.36(m,1H),2.33-2.30(m,1H),2.30-2.23(m,1H),2.15-2.08(m,1H),1.77(s,3H),1.77-1.23(m,8H)。MS计算值:460.2，MS实测值:461.3([M+H] +)483.3([M+Na] +)。
5-氰基-N-(3-((1-(2-环丙基乙酰基)哌啶-4-亚基)甲基)-5-氟-2-甲基苯基)-6-甲基烟酰胺(化合物80)
Figure PCTCN2020085294-appb-000199
1-(4-(3-氨基-5-氟-2-甲基亚苄基)哌啶-1-基)-2-环丙基乙酮(100mg,0.33mmol)和5-氯-6-甲基烟酸甲酯(63mg,0.33mmol)溶于甲苯(10mL)，0℃逐滴加入三甲基铝(0.4mL,2M,0.66mmol)。反应混合液80℃搅拌2小时。然后0℃加入水，二氯甲烷萃取。有机相饱和食盐水洗，无水硫酸钠干燥并浓缩。浓缩剩余物用制备型高效液相色谱纯化得到5-氰基-N-(3-((1-(2-环丙基乙酰基)哌啶-4-亚基)甲基)-5-氟-2-甲基苯基)-6-甲基烟酰胺51mg，纯度95％，产率34％，白色固体。 1H NMR(400MHz,DMSO-d 6):δ10.25(s,1H),9.20(s,1H),8.72(s,1H),7.20(dd,1H),6.87(dd,1H),6.39(s,1H),3.57-3.51(m,2H),3.46-3.40(m,2H),2.77(s,3H),2.42(t,1H),2.37-2.33(m,3H),2.30-2.23(m,1H),2.17-1.91(m,1H),2.09(s,3H),0.97-0.95(m,1H),0.45-0.44(m,2H),0.13-0.01(m,2H)。MS计算值:446.2，MS实测值:447.2([M+H] +)。
5-氰基-N-(5-氟-3-((1-异丁酰基哌啶-4-亚基)甲基)-2-甲基苯基)-6-甲基烟酰胺(化合物81)
Figure PCTCN2020085294-appb-000200
1-(4-(3-氨基-5-氟-2-甲基亚苄基)哌啶-1-基)-2-甲基丙烷-1-酮(100mg,0.34mmol)和5-氰基-6-甲基烟酸乙酯(70mg,0.37mmol)溶于甲苯(2mL)，0℃氮气保护下慢慢滴加三甲基铝(0.34mL,2M in toluene,0.68mmol)。反应液80℃搅拌4小时。反应液冷却至零度，酒石酸钾钠溶液淬灭反应，乙酸乙酯萃取。合并有机相,饱和食盐水洗，无水硫酸钠干燥，过滤并浓缩。浓缩剩余物用制备型高效液相色谱纯化得到5-氰基-N-(5-氟-3-((1-异丁酰基哌啶-4-亚基)甲基)-2-甲基苯基)-6-甲基烟酰胺111mg，纯度95％，产率74％，白色固体。 1H NMR(400MHz,DMSO-d6)δ10.21(s,1H),9.20(d,1H),8.73(d,1H),7.20(dd,1H),6.88(t,1H),6.39(s,1H),3.58(s,2H),3.47(s,2H),2.83-2.97(m,1H),2.77(s,3H),2.15-2.39(m,4H),2.10(s,3H),1.01(t,6H)。MS计算值:434.2，MS实测值:435.2([M+H] +)。
(R)-5-氰基-N-(3-((1-(3,3-二氟环戊基羰基)哌啶-4-亚基)甲基)-5-氟-2-甲基苯基)-6-甲基烟酰胺(化合物82)
Figure PCTCN2020085294-appb-000201
(R)-3,3-二氟环戊基羧酸(90mg,0.6mmol)、三乙胺(152mg,1.5mmol)和2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(228mg,0.6mmol)溶于二氯甲烷(4mL)室温搅拌10分钟。然后加入5-氰基-N-(5-氟-2-甲基-3-(哌啶-4-亚甲基)苯基)-6-甲基烟酰胺盐酸盐(200mg,0.5mmol)。反应液室温搅拌1小时。反应液倒入水里，二氯甲烷萃取。合并有机相，无水硫酸钠干燥，过滤并浓缩。浓缩剩余物用制备型高效液相色谱纯化得到(R)-5-氰基-N-(3-((1-(3,3-二氟环戊基羰基)哌啶-4-亚基)甲基)-5-氟-2-甲基苯基)-6-甲基烟酰胺118mg，纯度95％，产率48％白色固体。 1H NMR(400MHz,DMSO-d6)δ10.23(d,1H),9.20(d,1H),8.72(d,1H),7.18-7.22(m,1H),6.86-6.90(m,1H),6.40(s,1H),3.59(t,2H),3.48(t,2H),3.33-3.42(m,1H),2.77(s,3H),2.38-2.44(m,2H),2.30-2.37(m,2H),2.21-2.28(m,2H),2.15-2.18(m,1H),2.10(s,3H),1.97-2.06(m,2H),1.75-1.85(m,1H)。MS计算值:496.2，MS实测值:497.2([M+H] +)。
测试实施例
实施例1人源RORγt(hRORγt)放射性配体结合分析
通过测定受试化合物和[26,27-3H]25-羟基-胆固醇(Perkin Elmer NET674250UC)在重组人源RORγt-LBD蛋白上的配体结合位点之间的竞争来评估RORγt反向激动剂在无细胞体 系中的活性。在此放射性配体竞争性结合试验中使用的蛋白质是N-6xHis-GST-RORγt-LBD(GenBank号P51449，氨基酸265-518)。
实验方法：
测定在含有150mM NaCl、5mM MgCl 2、10％甘油、2mM CHAPS、0.5mMβ-辛基吡喃葡萄糖苷、5mM DTT和50mM HEPES缓冲液(pH7.4)的96孔SPA板中进行。将待测试的化合物在DMSO中溶解，并用相同的溶剂制备化合物的半对数(3.162×)连续稀释液。将2μL DMSO溶液与28μL 8.6nM[26,27-3H]25-羟基-胆固醇和50μL 12nM RORγt LBD混合。将板以700rpm摇动20分钟，并在室温下放置10分钟，之后加入40μL Poly-Lys YSi SPA珠(多聚赖氨酸YSi SPA，每孔50μg，PerkinElmer)。将板振荡器上孵育20分钟，然后在室温下不搅拌放置10分钟，在Microbeta(PerkinElmer)上读取SPA的氚β辐射强度。用DMSO对照获得的高信号和10μM TO901317(Sigma)对RORγt观察到的最低信号计算抑制百分比值。从剂量-反应曲线上的拐点浓度拟合计算出IC 50值。
表2所测定的化合物的hRORγt蛋白结合活性
化合物编号 IC 50(nM) 化合物编号 IC 50(nM)
1 6.9 2 4.9
3 3.2 4 8.0
5 3.3 6 12.0
7 6.4 8 4.6
9 3.4 10 5.5
11 5.6 12 4.0
13 4.0 14 3.8
15 2.8 16 4.9
17 10.6 18 12.8
19 6.6 20 7.7
21 3.3 22 28.9
23 2.3 24 16.3
25 4.3 26 5.1
27 4.2 28 5.1
29 3.1 30 11.4
31 30.6 32 9.0
33 5.7 34 8.7
35 13.8 36 11.6
37 7.5 38 43.9
39 43.1 40 6.0
41 4.0 42 8.3
43 22.3 44 11.5
45 60.4 46 22.9
47 15.5 48 11.1
49 14.0 50 4.4
51 11.5 52 9.1
53 8.2 54 22.9
55 7.1 56 7.2
57 4.1 58 4.4
59 5.7 60 6.5
61 15.5 62 7.2
63 4.8 64 9.8
65 7.5 66 8.8
67 5.6 68 5.9
69 2.6 70 9.4
71 7.0 72 5.5
73 4.9 74 9.0
75 29.7 76 23.9
77 15.5 78 21.4
79 5.2 80 15.6
81 11.7 82 11.0
实施例2在Jurkat细胞中的活性测定：
使用分泌性Nanoluc荧光素酶在Jurkat细胞(ATCC)中测定人体全长RORγt蛋白的转录活性。使用KpnI和HindIII限制性位点，将5个重复的RORγt应答元件(RORE)AAAGTAGGTCA插入无启动子的质粒pNL1.3[secNluc](Promega)中。人体全长RORγt的表达质粒购自于Genecopoeia。
实验方法：
使用LTX lipofectamine和Plus试剂(Life Technologies)，在OptiMEM培养基中用10μg RORγt质粒和25μg报道质粒转染3000万个Jurkat细胞。在37℃，5％CO 2孵育箱子中5小时后，收集转染细胞，并重悬于含有10％活性炭处理的FBS的无酚红RPMI培养基中，分配到384孔组织培养板(每孔30,000个细胞)。将测试的化合物在DMSO中溶解，并用相同的溶剂制备化合物的半对数(3.162×)连续稀释液。将待测试的化合物加入到384孔组织培养板中的转染细胞(DMSO的最终浓度为0.1％)，并将培养板放置在37℃下的5％CO 2培养箱中孵育40-44小时。取上清液测定NanoGlo(Promega)的荧光素酶活性。基于完全抑制(10μM TO317)和未抑制(DMSO)对照计算抑制百分比值，使用四参数非线性拟合模型将值相对于测试化合物的浓度回归以得到IC 50值。
表3所测定的化合物的Jurkat RORγt蛋白在Jurkat细胞的转录活性
化合物编号 IC 50(nM) 化合物编号 IC 50(nM)
1 57.3 2 25.6
3 18.7 4 95.0
5 12.6 6 66.8
7 119.6 8 20.8
9 89.4 10 123.1
11 105.5 12 60.7
13 63.7 14 27.3
15 47.2 16 77.5
17 177.6 18 22.2
19 598.6 20 202.3
21 94.2 22 503.8
23 209.7 24 215.7
25 117.3 26 43.0
27 45.1 28 137.7
29 47.1 30 17.2
31 83.7 32 85.8
33 89.6 34 21.5
35 87.3 36 55.4
37 67.7 38 193.0
39 179.1 40 24.6
41 22.7 42 36.0
43 29.1 44 26.4
45 181.7 46 33.3
47 21.1 48 41.5
49 24.9 50 24.2
51 22.6 52 21.0
53 14.0 54 131.6
55 241.1 56 76.7
57 49.8 58 86.9
59 193.3 60 19.1
61 77.0 62 28.5
63 17.4 64 15.6
65 14.8 66 34.5
67 156.1 68 61.9
69 15.5 70 388.1
71 40.3 72 46.7
73 52.0 74 29.5
75 171.0 76 63.0
77 36.6 78 187.8
79 15.6 80 86.3
81 46.6 82 27.9
实施例3 Th17细胞的体外分化抑制实验
实验方法：
1)初始CD4+T细胞的分离和Th17细胞的分化实验。Th17细胞的分化条件参照现有技术文章(Xu et al.,J Biol Chem.2011；286(26):22707-10.2011)，取若干只6-10周大的野生型C57BL/6小鼠，以CO 2窒息法处死，采集小鼠的脾脏和外周淋巴结组织，置于含1％血清的 无菌1×PBS的溶液中，以滤纸覆盖碾磨的方式制备单细胞悬浮液，然后通过利用美天妮公司的磁珠分选试剂分选CD4阳性T细胞。这些富集的CD4阳性T细胞随后被用针对CD62L、CD44、CD25的流式荧光抗体进行表面染色标记，并利用流式细胞仪分选CD4 +CD25 -CD62L hiCD44 lo的初始T细胞。Th17细胞的体外分化是在48孔板的细胞培养板里进行，在培养的前一天，通过每孔添加200μl的1×PBS溶液，其中含anti-CD3(8ng/ml，1×PBS)和anti-CD28抗体(8ng/ml，1×PBS)，对细胞培养板进行封闭。Th17细胞的培养条件为每个培养孔添加0.78ml RPMI1640完全细胞培养液，其中包含0.4×10 6个初始T细胞、1ng/ml TGF-β、10ng/ml IL-6、6.25ng/ml IL-23、10ng/ml IL-1β。随后把铺好细胞的48孔培养板置于37℃冰的CO 2培养箱，培养3-4天后，经过在培养液中加入PMA(Phorbol 12-Myristate 13-Acetate)(50ng/ml)、INOMYCIN(500ng/ml)、BD GlogiStop TM(1:1000稀释)的试剂，继续在37℃刺激4-5小时后，然后收集细胞并对IL-17和IL-17F的表达利用BD Cytofix/Cytoperm TMPlus固定染色试剂盒进行胞内流式荧光抗体染色，最后利用BD公司的LSRFortessa仪器和FlowJo软件进行分析染色结果。
2)小分子抑制实验：小分子化合物(即本文的化合物)被首先溶于DMSO中，储备液浓度为50mM，避光冻存于-80℃冰箱中。待使用前，用DMSO稀释成1000×的使用液浓度，再利用RPMI1640完全培养液稀释成10×的使用液浓度，随后取十分之一的体积在分化开始前加入Th17细胞的培养体系中。
其中本步实验所使用的RPMI1640完全培养液配方为：500ml RPMI1640培养液、56ml胎牛血清(FBS)、5ml青霉素-链霉素双抗溶液(100×)、0.5mlβ-巯基乙醇。本步实验所使用的1×PBS配方通过索莱宝公司的10×PBS(P1022)以灭菌水稀释而成，所述10×PBS的具体成分为：1000ml水含：8g NaCl、0.2g KCl、1.44g Na 2HPO 4和0.24g KH 2PO 4，pH7.2-7.4。
表4所测定的化合物的Th17细胞体外分化抑制活性
Figure PCTCN2020085294-appb-000202
Figure PCTCN2020085294-appb-000203
实施例4小鼠实验性自身免疫性脑脊髓炎(EAE)试验：
实验方法：
动物：7-9周，17-20g雌性C57BL/6小鼠。
动物免疫：在实验的首日，将MOG35-55冻干粉溶于生理盐水中，浓度为2mg/ml，然后与4mg/ml的完全弗氏佐剂(CFA)等体积混合均匀，得到乳剂。将实验动物用2％-3％异氟烷和氧的混合气体吸入麻醉后，背部剃毛后，皮下3点注射共100μL所述乳剂：一个点在两肩中点，另外两个点位于下背部中线两侧，以诱导小鼠实验性自身免疫性脑脊髓炎(EAE)。免疫后(第0天)和免疫后48小时，小鼠腹腔注射百日咳毒素(将200ng百日咳毒素溶解到200μL PBS中)。
动物给药和临床观察：动物免疫当天视为第0天。从第1天开始，连续灌胃给药25天，每天对小鼠进行临床观察和临床评分。
临床评分按照Hooke Laboratories的临床症状评分标准(Lawrence，MA，USA)：
0分：正常老鼠，无明显疾病表现
1分：尾巴无力或后肢虚弱无力
2分：尾巴无力同时后肢虚弱无力
3分：后肢完全瘫痪
4分：后肢完全瘫痪同时前肢部分瘫痪
5分：濒死状态；小鼠实验性自身免疫性脑脊髓炎(EAE)致死；人道主义处死
在小鼠实验性自身免疫性脑脊髓炎(EAE)研究中，化合物18、31、46和64以10、30或者100mg/kg的剂量，每天给药两次(B.I.D)进行测试。小鼠实验性自身免疫性脑脊髓炎(EAE)实验结果显示化合物18、31、46和64能够降低临床评分。其中针对化合物31的具体实验结果请见附图1-3所示。

Claims (18)

  1. 式(I)的化合物
    Figure PCTCN2020085294-appb-100001
    其中
    X为
    Figure PCTCN2020085294-appb-100002
    R 1为氢、C1-C6烷基、C3-C7脂环烃基、C1-C6卤代烷基、C1-C6烷氧基、卤素或氰基；所述C1-C6烷基、C3-C7脂环烃基、C1-C6卤代烷基、C1-C6烷氧基各自独立地任选地被一个或多个选自C1-C6烷基、C1-C6卤代烷基、氰基、C1-C6烷氧基、C1-C6卤代烷氧基、C3-C7脂环烃基和3-7元杂环烷基的基团取代；
    各个R 2独立地为C1-C6烷基、C3-C7脂环烃基、C1-C6卤代烷基、C1-C6烷氧基、卤素或氰基；所述C1-C6烷基、C3-C7脂环烃基、C1-C6卤代烷基各自独立地任选地被一个或多个选自C1-C6烷基、C1-C6卤代烷基、氰基、C1-C6烷氧基、C1-C6卤代烷氧基、C3-C7脂环烃基和3-7元杂环烷基的基团取代；
    R 3为C1-C6烷基、C1-C6烷氧基、C3-C7脂环烃基、3-7元含杂原子的脂环烃基、C5-C10芳基或5-10元杂芳基，其中所述C1-C6烷基、C1-C6烷氧基、C3-C7脂环烃基、3-7元含杂原子的脂环烃基、C5-C10芳基、5-10元杂芳基各自独立地任选地被一个或多个选自卤素、C1-C6烷基、C1-C6卤代烷基、氰基、酰基、羧基、羟基、C1-C6烷氧基、C1-C6卤代烷氧基、羰基、C3-C7脂环烃基、3-7元杂环烷基、磺酰基、C5-C10芳基和5-10元杂芳基的基团取代；
    R 4为C1-C6烷基、C1-C6烷氧基、C3-C7脂环烃基、3-7元含杂原子的脂环烃基、C5-C10芳基或5-10元杂芳基，其中所述C1-C6烷基、C1-C6烷氧基、C3-C7脂环烃基、3-7元含杂原子的脂环烃基、C5-C10芳基、5-10元杂芳基各自独立地任选地被一个或多个选自卤素、C1-C6烷基、C1-C6卤代烷基、氨基、氰基、酰基、羧基、羟基、C1-C6烷氧基、C1-C6卤代烷氧基、羰基、C3-C7脂环烃基、3-7元杂环烷基、任选被C1-C3烷基取代的磺酰基、C5-C10芳基和5-10元杂芳基的基团取代；
    m为0、1或2；
    p为0或1；
    或其立体异构体、对映异构体或互变异构体或其混合物，或其药物可接受的盐、溶剂化物或前药。
  2. 根据权利要求1所述的化合物或其立体异构体、对映异构体或互变异构体或其混合 物，或其药物可接受的盐、溶剂化物或前药，其中X为
    Figure PCTCN2020085294-appb-100003
  3. 根据权利要求1所述的化合物或其立体异构体、对映异构体或互变异构体或其混合物，或其药物可接受的盐、溶剂化物或前药，其中R 1为氢、C1-C6烷基、C3-C7脂环烃基、C1-C6卤代烷基、C1-C6烷氧基或卤素；优选地为氢、C1-C6烷基或卤素；更优选地为甲基或Cl。
  4. 根据权利要求1所述的化合物或其立体异构体、对映异构体或互变异构体或其混合物，或其药物可接受的盐、溶剂化物或前药，其中各个所述R 2独立地为C1-C6烷基、C3-C7脂环烃基、C1-C6卤代烷基、C1-C6烷氧基或卤素；优选地为卤素；更优选地为F和Cl；优选地，当m为1或2时，至少一个R 2位于R 1的对位。
  5. 根据权利要求1所述的化合物或其立体异构体、对映异构体或互变异构体或其混合物，或其药物可接受的盐、溶剂化物或前药，其中所述R 4为C3-C7脂环烃基、3-7元含杂原子的脂环烃基、C5-C10芳基或5-10元杂芳基；所述C3-C7脂环烃基、3-7元含杂原子的脂环烃基、C5-C10芳基或5-10元杂芳基各自独立地任选被一个或多个选自卤素、C1-C6烷基、C1-C6卤代烷基、氨基、氰基、酰基、羧基、羟基、C1-C6烷氧基、C1-C6卤代烷氧基、羰基、C3-C7脂环烃基、3-7元含杂原子的脂环烃基和任选被C1-C3烷基取代的磺酰基的基团取代。
  6. 根据权利要求5所述的化合物或其立体异构体、对映异构体或互变异构体或其混合物，或其药物可接受的盐、溶剂化物或前药，其中所述R 4为3-7元含杂原子的脂环烃基、C5-C10芳基或5-10元杂芳基，所述3-7元含杂原子的脂环烃基、C5-C10芳基或5-10元杂芳基任选被一个或多个选自卤素、C1-C6烷基、氰基、C1-C6烷氧基、羰基、C3-C7脂环烃基和任选被C1-C3烷基取代的磺酰基的基团取代。
  7. 根据权利要求5所述的化合物或其立体异构体、对映异构体或互变异构体或其混合物，或其药物可接受的盐、溶剂化物或前药，其中R 4为任选被F、Cl、C1-C3烷基和氰基中的一个或多个基团取代的
    Figure PCTCN2020085294-appb-100004
    C5-C10芳基或5-10元杂芳基；优选地R 4为任选被F、Cl、C1-C3烷基和氰基中的一个或多个基团取代的
    Figure PCTCN2020085294-appb-100005
    Figure PCTCN2020085294-appb-100006
    C5-C10芳基或5-10元杂芳基。
  8. 根据权利要求5所述的化合物或其立体异构体、对映异构体或互变异构体或其混合物，或其药物可接受的盐、溶剂化物或前药，其中R 4为
    Figure PCTCN2020085294-appb-100007
    Figure PCTCN2020085294-appb-100008
  9. 根据权利要求1所述的化合物或其立体异构体、对映异构体或互变异构体或其混合物，或其药物可接受的盐、溶剂化物或前药，其中所述R 3为C1-C6烷基、C1-C6烷氧基、C3-C7环烷基、3-7元杂环烷基或5-10元杂芳基；所述C1-C6烷基、C1-C6烷氧基、C3-C7脂环烃基、3-7元杂环烷基或5-10元杂芳基任选地被卤素、C1-C6卤代烷基、C1-C6烷氧基、C1-C6卤代烷氧基、或C1-C6烷基取代。
  10. 根据权利要求9所述的化合物或其立体异构体、对映异构体或互变异构体或其混合物，或其药物可接受的盐、溶剂化物或前药，其中所述R 3为C1-C4烷基、C3-C6环烷基、3-7元杂环烷基或5-6元杂芳基；所述C1-C4烷基、C3-C6环烷基、3-7元杂环烷基或5-6元杂芳基任选被氟、C1-C3氟代烷基、C1-C6烷氧基、C1-C3氟代烷氧基、或C1-C6烷基取代。
  11. 根据权利要求9所述的化合物或其立体异构体、对映异构体或互变异构体或其混合物，或其药物可接受的盐、溶剂化物或前药，其中所述R 3为
    Figure PCTCN2020085294-appb-100009
    Figure PCTCN2020085294-appb-100010
  12. 根据权利要求1所述的化合物或其立体异构体、对映异构体或互变异构体或其混合物，或其药物可接受的盐、溶剂化物或前药，其中
    R 1为C1-C6烷基；R 2为卤素；R 3为任选被卤素取代的C1-C6烷基或C3-C7脂环烃基；X为
    Figure PCTCN2020085294-appb-100011
    R 4为任选被卤素、C1-C6烷基和氰基中的一个或多个基团取代的C5-C10芳基或5-10元杂芳基；m为1；p为0或1；
    优选地，R 1为甲基；R 2为Cl或F；R 3为任选被一个或多个F取代的异丙基、环丙基、环戊基或环己基；X为
    Figure PCTCN2020085294-appb-100012
    R 4为任选被F、甲基和氰基中的一个或多个基团取代的苯 基、吡啶基或
    Figure PCTCN2020085294-appb-100013
    m为1；p为0或1；
    优选地，R 1为甲基；R 2为Cl或F；R 3为任选被一个或两个F取代的异丙基、环丙基、环戊基或环己基；X为
    Figure PCTCN2020085294-appb-100014
    R 4为任选被一个F、甲基和氰基取代的吡啶基或
    Figure PCTCN2020085294-appb-100015
    m为1；p为0或1。
  13. 化合物或其立体异构体、对映异构体或互变异构体或其混合物，或其药物可接受的盐、溶剂化物或前药，所述化合物为：
    化合物1
    N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-6-甲基烟酰胺
    化合物2
    N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-5-氟-6-甲基烟酰胺
    化合物3
    N-(5-氯-3((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-3-氰基苯甲酰胺
    化合物4
    N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-2-甲基异烟酰胺
    化合物5
    N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-5-氰基烟酰胺
    化合物6
    N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-1-甲基-6-氧-1,6-二氢哒嗪-4-酰胺
    化合物7
    N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-4-氰基苯甲酰胺
    化合物8
    N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-3-氰基-5-羟基苯甲酰胺
    化合物9
    N-(5-氯3-((1-(环戊基羰基)哌啶-4-亚基)甲基-2-甲苯基)-1-乙基-6-氧-1,6-二氢哒嗪-4-甲酰胺
    化合物10
    N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-1-环丙基-6-氧-1,6-二氢哒嗪-4-甲酰胺
    化合物11
    N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)咪唑[1,2-a]吡啶-7-甲酰胺
    化合物12
    N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-[1,2,4]三唑[1,5-a]吡啶-7-甲酰胺
    化合物13
    N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-2-环丙基嘧啶-5-甲酰胺
    化合物14
    N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-5-氰基-2-氟苯甲酰胺
    化合物15
    N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-3-氰基-2-氟苯甲酰胺
    化合物16
    N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-3-(甲磺酰基)苯甲酰胺
    化合物17
    N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-6-甲氧基哒嗪-4-甲酰胺
    化合物18
    N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-6-氰基-1-甲基-2-氧-1,2-二氢吡啶-4-甲酰胺
    化合物19
    N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-2-环丙基噻唑-5-甲酰胺
    化合物20
    N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-1-环丙基-1H-吡唑-4-甲酰胺
    化合物21
    N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-3-甲氧基苯甲酰胺
    化合物22
    N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-3-甲氧基环丁基酰胺
    化合物23
    N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-3-苯基丙酰胺
    化合物24
    N-(5-氯-2-甲基-3-((1-(四氢-2H-吡喃-4-羰基)哌啶-4-亚基)甲基)苯基)3-氰基苯甲酰胺
    化合物25
    N-(5-氯-3-((1-(2-环丙基乙酰)哌啶-4-亚基)甲基)-2-甲苯基)-3-氰基苯甲酰胺
    化合物26
    N-(5-氯-3-((1-(3,3-二氟环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-3-氰基苯甲酰胺
    化合物27
    N-(3-((1-(二环[3.1.0]正己烷-3-羰基)哌啶-4-亚基)甲基)-5-氯-2-甲苯基)-3-氰基苯甲酰胺
    化合物28
    N-(5-氯-3-((1-(3,3-二氟环丁基羰基)哌啶-4-亚基)甲基-2-甲苯基)-3-氰基苯甲酰胺
    化合物29
    N-(3-((1-(2-(二环[1.1.1]戊烷-1-基)乙酰基)哌啶-4-亚基)甲基)-5-氯-2-甲苯基)-3-氰基苯甲酰胺
    化合物30
    N-(3-((1-(2-(二环[1.1.1]戊烷-1-基)乙酰基)哌啶-4-亚基)甲基)-5-氯-2-甲苯基)-6-氰基-1-甲基-2-氧-1,2-二氢吡啶-4-甲酰胺
    化合物31
    N-(5-氯-3-((1-(4,4-二氟环己基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-6-氰基-1-甲基-2-氧-1,2-二氢吡啶-4-甲酰胺
    化合物32
    N-(5-氯-3-((1-(4,4-二氟环己基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-3-氰基苯甲酰胺
    化合物33
    N-(5-氯-2-甲基-3-((1-(噻吩-2-羰基)哌啶-4-亚基)甲基)苯基)-3-氰基苯甲酰胺
    化合物34
    N-(5-氯-3-((1-(2-环丁基乙酰基)哌啶-4-亚基)甲基)-2-甲苯基)-6-氰基-1-甲基-2-氧-1,2-二氢吡啶-4-甲酰胺
    化合物35
    N-(5-氯-3-((1-(2-环丙基乙酰基)哌啶-4-亚基)甲基)-2-甲苯基)-5-氰基烟酰胺
    化合物36
    N-(5-氯-3-((1-(2-环丙基乙酰基)哌啶-4-亚基)甲基)-2-甲苯基)-6-氰基-1-甲基-2-氧-1,2-二氢吡啶-4-甲酰胺
    化合物37
    5-氯-N-(5-氯-3-((1-(2-环丙基乙酰基)哌啶-4-亚基)甲基)-2-甲苯基)-6-甲基烟酰胺
    化合物38
    N-(5-氯-2-甲基-3-((1-(3,3,3-三氟丙酰基)哌啶-4-亚基)甲基)苯基)-6-氰基-1-甲基-2-氧代-1,2-二氢吡啶-4-甲酰胺
    化合物39
    N-(5-氯-2-甲基-3-((1-(四氢呋喃-3-羰基)哌啶-4-亚基)甲基)苯基)-6-氰基-1-甲基-2-氧-1,2-二氢吡啶-4-甲酰胺
    化合物40
    N-(5-氯-3-((1-(3,3-二甲基环丁基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-6-氰基-1-甲基-2-氧-1,2-二氢吡啶-4-甲酰胺
    化合物41
    N-(5-氯-3-((1-(1-氟代环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-6-氰基-1-甲基-2-氧 -1,2-二氢吡啶-4-甲酰胺
    化合物42
    N-(5-氯-3-((1-(3,3-二氟环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-6-氰基-1-甲基-2-氧-1,2-二氢吡啶-4-甲酰胺
    化合物43
    (R)-N-(5-氯-3-((1-(3,3-二氟环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-6-氰基-1-甲基-2-氧-1,2-二氢吡啶-4-甲酰胺
    化合物44
    (S)-N-(5-氯-3-((1-(3,3-二氟环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-6-氰基-1-甲基-2-氧-1,2-二氢吡啶-4-甲酰胺
    化合物45
    N-(5-氯-2-甲基-3-((1-(四氢呋喃-2-羰基)哌啶-4-亚基)甲基)-2-甲苯基)-6-氰基-1-甲基-2-氧-1,2-二氢吡啶-4-甲酰胺
    化合物46
    N-(5-氯-3-((1-异丁酰基哌啶-4-亚基)甲基)-2-甲苯基)-6-氰基-1-甲基-2-氧代-1,2-二氢吡啶-4-甲酰胺
    化合物47
    N-(5-氯-2-甲基-3-((1-(3-甲基丁酰基)哌啶-4-亚基)苯基)-6-氰基-1-甲基-2-氧代-1,2-二氢吡啶-4-甲酰胺
    化合物48
    N-(5-氯-3-((1-(2-氟-2-甲基丙酰基)哌啶-4-亚基)甲基)-2-甲苯基)-6-氰基-1-甲基-2-氧代-1,2-二氢吡啶-4-甲酰胺
    化合物49
    N-(5-氯-3-((1-(环丁基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-6-氰基-1-甲基-2-氧代-1,2-二氢吡啶-4-甲酰胺
    化合物50
    N-(5-氯-3-((1-(1-氟环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-5-氰基-6-甲基烟酰胺
    化合物51
    (R)-N-(5-氯-3-((1-(3,3-二氟环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-5-氰基-6-甲基烟酰胺
    化合物52
    (S)-N-(5-氯-3-((1-(3,3-二氟环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-5-氰基-6-甲基烟酰胺
    化合物53
    N-(5-氯-3-((1-异丁酰基哌啶-4-亚基)甲基)-2-甲苯基)-5-氰基-6-甲基烟酰胺
    化合物54
    N-(5-氯-3-(1-(4,4-二氟哌啶-1-羰基)哌啶-4-亚基)甲基)-2-甲苯基)-6-氰基-1-甲基-2-氧-1,2-二氢吡啶-4-甲酰胺
    化合物55
    N-(5-氯-3-((1-(3,3-二氟四氢吡咯-1-羰基)哌啶-4-亚基)甲基)-2-甲苯基)-3-氰基苯甲酰胺
    化合物56
    N-(5-氯-2-甲基-3-((1-(四氢吡咯-1-羰基)哌啶-4-亚基)甲基)苯基)-3-氰基苯甲酰胺
    化合物57
    4-(5-氯-3-(3-氰基苯甲酰胺)-2-甲基亚苄基)哌啶-1-甲酸异丙酯
    化合物58
    N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-3-氰基苯磺酰胺
    化合物59
    1-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-3-(吡啶-2-基)脲
    化合物60
    N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-6-氰基-1-乙基-2-氧代-1,2-二氢吡啶-4-甲酰胺
    化合物61
    N-(5-氯-3-((1-(2-环丙基乙酰基)哌啶-4-亚基)甲基)-2-甲苯基)-6-氰基-1-乙基-2-氧代-1,2-二氢吡啶-4-甲酰胺
    化合物62
    N-(5-氯-3-((1-(2-环丁基乙酰基)哌啶-4-亚基)甲基)-2-甲苯基)-6-氰基-1-乙基-2-氧代-1,2-二氢吡啶-4-甲酰胺
    化合物63
    N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-5-氰基-6-甲基烟酰胺
    化合物64
    N-(5-氯-3-((1-(2-环丙烷乙酰基)哌啶-4-亚基)甲基)-2-甲苯基)-5-氰基-6-甲基烟酰胺
    化合物65
    N-(5-氯-3-((1-(2-环丁基乙酰基)哌啶-4-亚基)甲基)-2-甲苯基)-5-氰基-6-甲基烟酰胺
    化合物66
    N-(5-氯-3-((1-(4,4-二氟环己基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-5-氰基-6-甲基烟酰胺
    化合物67
    6-氯-N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-1-甲基-2-氧-1,2-二氢吡啶-4-甲酰胺
    化合物68
    N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-6-氧-1,6-二氢哒嗪-4-甲酰胺
    化合物69
    N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-2-氰基-6-甲氧基烟酰胺
    化合物70
    N-(5-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)-6-氰基-2-氧-1,2-二氢吡啶-4-甲酰胺
    化合物71
    3-氰基-N-(3-(1-(环戊基羰基)哌啶-4-亚基)甲基)-5-氟-2-甲苯基)苯甲酰胺
    化合物72
    N-(2-氯-3-((1-(环戊基羰基)哌啶-4-亚基)甲基)苯基)-3-氰基苯甲酰胺
    化合物73
    3-氰基-N-(3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-2-甲苯基)苯甲酰胺
    化合物74
    6-氰基-N-(3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-5-氟-2-甲苯基)-1-甲基-2-氧-1,2-二氢吡啶-4-甲酰胺
    化合物75
    6-氰基-N-(3-((1-(2-环丙基乙酰基)哌啶-4-亚基)甲基)-5-氟-2-甲苯基)-1-甲基-2-氧-1,2-二氢吡啶-4-甲酰胺
    化合物76
    6-氰基-N-(5-氟-3-((1-异丁酰基哌啶-4-亚基)甲基)-2-甲苯基)-1-甲基-2-氧代-1,2-二氢吡啶-4-甲酰胺
    化合物77
    (R)-6-氰基-N-(3-((1-(3,3-二氟环戊基羰基)哌啶-4-亚基)甲基)-5-氟-2-甲苯基)-1-甲基-2-氧-1,2-二氢吡啶-4-甲酰胺
    化合物78
    5-氯-N-(3-((1-(2-环丙基乙酰基)哌啶-4-亚基)甲基)-5-氟-2-甲苯基)-6-甲基烟酰胺
    化合物79
    5-氰基-N-(3-((1-(环戊基羰基)哌啶-4-亚基)甲基)-5-氟-2-甲苯基)-6-甲基烟酰胺
    化合物80
    5-氰基-N-(3-((1-(2-环丙基乙酰基)哌啶-4-亚基)甲基)-5-氟-2-甲苯基)-6-甲基烟酰胺
    化合物81
    5-氰基-N-(5-氟-3-((1-异丁酰基哌啶-4-亚基)甲基)-2-甲苯基)-6-甲基烟酰胺
    化合物82
    (R)-5-氰基-N-(3-((1-(3,3-二氟环戊基羰基)哌啶-4-亚基)甲基)-5-氟-2-甲苯基)-6-甲基烟酰胺。
  14. 药物组合物，其包含权利要求1-13中任一项所述的化合物或其立体异构体、对映异构体或互变异构体或其混合物，或其药物可接受的盐、溶剂化物或前药，以及一种或多种药物可接受的赋形剂和/或载体。
  15. 权利要求1-13中任一项所述的化合物或其立体异构体、对映异构体或互变异构体或其混合物，或其药物可接受的盐、溶剂化物或前药或权利要求14所述的药物组合物在制备RORγt受体抑制剂中的用途。
  16. 权利要求1-13中任一项所述的化合物或其立体异构体、对映异构体或互变异构体或其混合物，或其药物可接受的盐、溶剂化物或前药或权利要求14所述的药物组合物在制备用于治疗与RORγt受体异常激活相关的疾病的药物中的用途。
  17. 根据权利要求16所述的用途，其中所述与RORγt受体异常激活相关的疾病包括自身免疫性疾病、过敏性疾病和癌症；
    优选地，所述与RORγt受体异常激活相关的疾病包括银屑病、银屑样关节炎、类风湿关节炎、强直脊柱炎、多发性硬化症、干燥综合症、干眼综合症、移植物抗宿主病、炎症性肠病、慢阻肺、哮喘、自身免疫性葡萄膜炎、自身免疫性肝炎、自身免疫性甲状腺炎、自身免疫性肾炎、特应性皮肤炎、前列腺炎和前列腺癌。
  18. 权利要求1-13中任一项所述的式(I)化合物或其立体异构体、对映异构体或互变异构体或其混合物，或其药物可接受的盐、溶剂化物或前药或权利要求14所述的药物组合物在抑制RORγt受体中的用途。
PCT/CN2020/085294 2019-04-19 2020-04-17 苯甲烯哌啶衍生物及其制备方法、中间体和用途 WO2020211836A1 (zh)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023217989A1 (en) 2022-05-12 2023-11-16 Syngenta Crop Protection Ag Alkoxy heteroaryl- carboxamide or thioamide compounds

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1738801A (zh) * 2003-01-16 2006-02-22 阿斯利康(瑞典)有限公司 二芳基亚甲基哌啶衍生物、其制备及其用途
WO2013029338A1 (en) * 2011-09-01 2013-03-07 Glaxo Group Limited Novel compounds
CN106660999A (zh) * 2014-05-28 2017-05-10 葛兰素史密斯克莱知识产权发展有限公司 新化合物
CN109476653A (zh) * 2016-07-13 2019-03-15 利奥制药有限公司 类视黄醇相关孤儿受体γ的杂芳族调节剂

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TW548271B (en) * 1996-12-20 2003-08-21 Astra Pharma Inc Novel piperidine derivatives having an exocyclic double bond with analgesic effects
AU2056700A (en) * 1998-12-18 2000-07-03 Du Pont Pharmaceuticals Company 2-substituted-4-nitrogen heterocycles as modulators of chemokine receptor activity

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1738801A (zh) * 2003-01-16 2006-02-22 阿斯利康(瑞典)有限公司 二芳基亚甲基哌啶衍生物、其制备及其用途
WO2013029338A1 (en) * 2011-09-01 2013-03-07 Glaxo Group Limited Novel compounds
CN106660999A (zh) * 2014-05-28 2017-05-10 葛兰素史密斯克莱知识产权发展有限公司 新化合物
CN109476653A (zh) * 2016-07-13 2019-03-15 利奥制药有限公司 类视黄醇相关孤儿受体γ的杂芳族调节剂

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023217989A1 (en) 2022-05-12 2023-11-16 Syngenta Crop Protection Ag Alkoxy heteroaryl- carboxamide or thioamide compounds

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