WO2023051749A1 - Aak1 inhibitor and use thereof - Google Patents

Aak1 inhibitor and use thereof Download PDF

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WO2023051749A1
WO2023051749A1 PCT/CN2022/122990 CN2022122990W WO2023051749A1 WO 2023051749 A1 WO2023051749 A1 WO 2023051749A1 CN 2022122990 W CN2022122990 W CN 2022122990W WO 2023051749 A1 WO2023051749 A1 WO 2023051749A1
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substituted
alkyl
halogen
unsubstituted
cycloalkyl
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PCT/CN2022/122990
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French (fr)
Chinese (zh)
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张学军
李金平
臧杨
贾一民
刘礼飞
李杨
张博
程智逵
赵心
杨辉
杨俊�
李莉娥
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武汉人福创新药物研发中心有限公司
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Publication of WO2023051749A1 publication Critical patent/WO2023051749A1/en

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Definitions

  • the invention belongs to the field of medicinal chemistry. Specifically, the invention relates to a compound capable of inhibiting annexin-associated kinase 1 (AAK1), its preparation method, composition and its use in the preparation of medicines.
  • AAK1 annexin-associated kinase 1
  • Adapter protein-associated kinase 1 (AAK1), also known as AP-2-associated kinase 1, is a serine/threonine protein kinase that belongs to the Ark1/Prk1 family.
  • the precursor mRNA of AAK1 can produce different splicing variants, expressing the long form of AAK1 of 960 amino acids and the short form of AAK1 of 863 amino acids, and the long form of AAK1 is highly expressed in brain and heart tissues.
  • the C-terminus of AKK1 contains clathrin-binding domains (CBD1 and CBD2), which can interact with clathrin and stimulate the kinase activity of AAK1 (Henderson et al., Mol Biol Cell, 2007).
  • AAK1 can regulate clathrin-mediated endocytosis by binding to the AP-2 adapter protein complex.
  • Clathrin-mediated endocytosis is the main pathway for transferring proteins on the cell surface to endosomes or lysosomes for recycling or degradation (Traub, Nat Rev Mol Cell Biol, 2009).
  • the AP-2 complex is an adapter factor for clathrin and consists of four proteins, including the ⁇ subunit, ⁇ 2 subunit, ⁇ 2 subunit, and ⁇ 2 subunit. Among them, the ⁇ 2 subunit, also known as AP2M1, is located in the core part of the AP-2 complex and mediates the interaction between the transported body (cargo) and clathrin-coated pits.
  • the C-terminus of AP2M1 binds to the tyrosine-based endocytic sorting YXX ⁇ motif at the cytoplasmic end of the transporter, facilitating recruitment of the transporter to clathrin-coated pits (Royle et al., J Biol Chem, 2002) .
  • AAK1 can phosphorylate threonine 156 of AP2M1, induce its conformational change, and promote the combination of AP2M1 and YXX ⁇ motif, thereby enhancing endocytosis (Jackson et al., J Cell Biol, 2003).
  • AAK1 knockout mice have significantly reduced response to persistent pain in the phase II phase of the formalin model, and significantly alleviated mechanical hyperalgesia caused by SNL (spinal nerve ligation).
  • LP-935509 a small molecule inhibitor of AAK1
  • can significantly attenuate the pain response in the phase II phase of formalin mouse model, mechanical hyperalgesia induced by mouse SNL, mouse CCI (sciatic nerve ligation) model and streptourea Mycin induces pain responses in a mouse model of diabetic neuropathy (Kostich et al., J Pharmacol Exp Ther, 2016).
  • AAK1 gene was identified as a possible Parkinson's disease susceptibility gene in a genome-wide association study (GWAS) of familial Parkinson's cases (Latourelle et al., BMC Med Genet, 2009).
  • GWAS genome-wide association study
  • AAK1 activity may be beneficial for schizophrenia, cognitive deficit, Parkinson's disease, bipolar disorder and Alzheimer's disease. sdisease) and other diseases have potential therapeutic effects.
  • viruses There are many ways for viruses to enter cells, such as endocytosis and membrane fusion. Most viruses use endocytosis as the main entry method, and clathrin-mediated is the main endocytic pathway. Vesicular stomatitis virus (VSV), influenza virus (IAV), and Congo hemorrhagic fever virus (CCHFV) all enter cells through clathrin-dependent pathways. Studies have found that the infection process of various viruses depends on AAK1, such as vesicular stomatitis virus (VSV), rabies virus (RABV), hepatitis C virus (HCV), etc.
  • AAK1 such as vesicular stomatitis virus (VSV), rabies virus (RABV), hepatitis C virus (HCV), etc.
  • the invention aims to provide an AAK1 receptor antagonist, which can be used to prepare medicines for treating Alzheimer's disease, bipolar disorder, pain, Parkinson's disease and schizophrenia.
  • the present invention proposes a compound represented by formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug:
  • Ring A is selected from
  • R 1 is selected from -H, hydroxyl, amino, cyano, C 1 -C 6 alkyl unsubstituted or substituted by R 12 , C 3 -C 6 cycloalkyl unsubstituted or substituted by R 12 , halogen or
  • the substitution of R 12 may be one or more substitutions, and the R 12 each independently selected from the following substituents: hydroxyl, amino, cyano, halogen, C 1 -C 6 alkyl or -O-(C 1 -C 6 alkyl); when there are multiple substituents, the The substituents are the same or different;
  • R 11 is selected from unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted -OC 1 -C 6 alkyl, unsubstituted or substituted 4-8 membered hetero Cycloalkyl, or -NR x R y ; in the C 1 -C 6 alkyl substituted by R 111 or the 4-8 membered heterocycloalkyl substituted by R 111 , the substitution of R 111 may be One or more substitutions, the R 111 are each independently selected from the following substituents: hydroxyl, amino, cyano, halogen, C 1 -C 6 alkyl or -O-(C 1 -C 6 alkyl); When there are multiple substituents, the substituents are the same or different;
  • R x and R y are each independently a C 1 -C 6 alkyl group substituted by 1-5 identical or different R z or R x and R y together with the N to which they are attached form an N-containing heterocyclic group, said R z are each independently selected from -H, halogen, C 1 -C 6 alkyl, -O-(C 1 -C 6 alkyl) or C 3 -C 6 cycloalkyl; when there are multiple substituents, The substituents are the same or different;
  • R 2 is selected from -H, hydroxyl, amino, cyano, C 1 -C 6 alkyl unsubstituted or substituted by R 21 ; in the C 1 -C 6 alkyl substituted by R 21 , the The substitution of R 21 may be one or more substitutions, and each of the R 21s is independently selected from the following substituents: hydroxyl, amino, cyano, halogen, C 1 -C 6 alkyl or -O-(C 1 -C 6 alkyl); when there are multiple substituents, the substituents are the same or different;
  • Ring B selected from where "*" means the same as and "**” indicates connection with ring A;
  • R 3 and R 4 are each independently selected from -H, -SF 5 , hydroxyl, amino, cyano, C 1 -C 6 alkyl unsubstituted or substituted by R 31 , C 3 unsubstituted or substituted by R 31 -C 6 cycloalkyl, halogen or
  • the substitution of R 31 may be one or more substitutions, and the R 31 each independently selected from the following substituents: hydroxyl, amino, cyano, halogen, C 1 -C 6 alkyl or -O-(C 1 -C 6 alkyl); when there are multiple substituents, the The substituents are the same or different;
  • R 32 is selected from -H, unsubstituted or substituted by R 321 C 1 -C 6 alkyl, or, unsubstituted or substituted by R 321 C 3 -C 6 cycloalkyl; said substituted by R 321 In C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl substituted by R 31 , the substitution of R 321 may be one or more substitutions, and each of the R 321 is independently selected from the following substituents : hydroxyl, amino, cyano, halogen, C 1 -C 6 alkyl or -O-(C 1 -C 6 alkyl); when there are multiple substituents, the substituents are the same or different;
  • R 5 is selected from -H, cyano, C 1 -C 6 alkyl substituted by 1-5 identical or different halogens, C 3 -C 6 cycloalkyl substituted by 1-5 identical or different halogens , C 3 -C 6 cycloalkyl or C 1 -C 6 alkyl;
  • R is selected from hydroxyl, amino, cyano, Unsubstituted or substituted by R 61 C 1 -C 6 alkyl, halogen or unsubstituted or substituted by R 61 C 3 -C 6 cycloalkyl; said C 1 -C 6 alkyl substituted by R 61 Or in the C 3 -C 6 cycloalkyl group substituted by R 61 , the R 61 substitution can be one or more substitutions, and each of the R 61 is independently selected from the following substituents: hydroxyl, amino, cyano , halogen, C 1 -C 6 alkyl substituted by 1-6 identical or different halogens, -O-(C 1 -C 6 alkyl) substituted by 1-6 identical or different halogens, C 1 -C 6 alkyl or -O-(C 1 -C 6 alkyl); when there are multiple substituents, the substituents are the same or different.
  • Ring A is selected from
  • R 1 is selected from -H, hydroxyl, amino, cyano, C 1 -C 6 alkyl unsubstituted or substituted by R 12 , C 3 -C 6 cycloalkyl unsubstituted or substituted by R 12 , halogen or
  • the substitution of R 12 may be one or more substitutions, each of the R 12 Independently selected from the following substituents: hydroxyl, amino, cyano, halogen, C 1 -C 6 alkyl or -O-(C 1 -C 6 alkyl); when there are multiple substituents, the substituent same or different basis;
  • R 11 is selected from C 1 -C 6 alkyl unsubstituted or substituted by R 111 , 4-8 membered heterocycloalkyl unsubstituted or substituted by R 111 , or -NR x R y ;
  • the R 111 substitution may be one or more substitutions, and each of the R 111 is independently selected from the following Substituent: hydroxyl, amino, cyano, halogen, C 1 -C 6 alkyl or -O-(C 1 -C 6 alkyl); when there are multiple substituents, the substituents are the same or different;
  • R x and R y are each independently C 1 -C 6 alkyl substituted by 1 to 5 identical or different R z , each of which R z is independently selected from -H, halogen, -O-(C 1 -C 6 alkyl) or C 3 -C 6 cycloalkyl; when there are multiple substituents, the substituents are the same or different;
  • R 2 is selected from -H, hydroxyl, amino, cyano, C 1 -C 6 alkyl unsubstituted or substituted by R 21 ; in the C 1 -C 6 alkyl substituted by R 21 , the The substitution of R 21 may be one or more substitutions, and each of the R 21s is independently selected from the following substituents: hydroxyl, amino, cyano, halogen, C 1 -C 6 alkyl or -O-(C 1 -C 6 alkyl); when there are multiple substituents, the substituents are the same or different;
  • Ring B selected from where "*" means the same as and "**” indicates connection with ring A;
  • R 3 and R 4 are each independently selected from -H, -SF 5 , hydroxyl, amino, cyano, C 1 -C 6 alkyl unsubstituted or substituted by R 31 , C 3 unsubstituted or substituted by R 31 -C 6 cycloalkyl, halogen or
  • the substitution of R 31 may be one or more substitutions, and the R 31 each independently selected from the following substituents: hydroxyl, amino, cyano, halogen, C 1 -C 6 alkyl or -O-(C 1 -C 6 alkyl); when there are multiple substituents, the The substituents are the same or different;
  • R 32 is selected from -H, unsubstituted or substituted by R 321 C 1 -C 6 alkyl, or, unsubstituted or substituted by R 321 C 3 -C 6 cycloalkyl; said substituted by R 321 In C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl substituted by R 31 , the substitution of R 321 may be one or more substitutions, and each of the R 321 is independently selected from the following substituents : hydroxyl, amino, cyano, halogen, C 1 -C 6 alkyl or -O-(C 1 -C 6 alkyl); when there are multiple substituents, the substituents are the same or different;
  • R 5 is selected from -H, cyano, C 1 -C 6 alkyl substituted by 1-5 identical or different halogens, C 3 -C 6 cycloalkyl substituted by 1-5 identical or different halogens , C 3 -C 6 cycloalkyl or C 1 -C 6 alkyl;
  • R is selected from hydroxyl, amino, cyano, Unsubstituted or substituted by R 61 C 1 -C 6 alkyl, halogen or unsubstituted or substituted by R 61 C 3 -C 6 cycloalkyl; said C 1 -C 6 alkyl substituted by R 61 Or in a C 3 -C 6 cycloalkyl group substituted by R 61 , the substitution of R 61 may be one or more substitutions, and each of the R 61s is independently selected from the following substituents: hydroxyl, amino, cyano, Halogen, C 1 -C 6 alkyl substituted by 1-6 identical or different halogens, -O-(C 1 -C 6 alkyl) substituted by 1-6 identical or different halogens, C 1 -C 6 Alkyl or -O-(C 1 -C 6 alkyl); when there are multiple substituents, the substituents are the same or different.
  • the compound represented by formula I its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug is:
  • Ring A is selected from
  • R 1 is selected from -H, hydroxyl, amino, cyano, C 1 -C 6 alkyl unsubstituted or substituted by R 12 , C 3 -C 6 cycloalkyl unsubstituted or substituted by R 12 , halogen or
  • the substitution of R 12 may be one or more substitutions, and the R 12 each independently selected from the following substituents: hydroxyl, amino, cyano, halogen, C 1 -C 6 alkyl or -O-(C 1 -C 6 alkyl); when there are multiple substituents, the The substituents are the same or different;
  • R 11 is selected from C 1 -C 6 alkyl unsubstituted or substituted by R 111 , 4-8 membered heterocycloalkyl unsubstituted or substituted by R 111 , or -NR x R y ;
  • the R 111 substitution may be one or more substitutions, and each of the R 111 is independently selected from The following substituents: hydroxyl, amino, cyano, halogen, C 1 -C 6 alkyl or -O-(C 1 -C 6 alkyl); when there are multiple substituents, the substituents are the same or different ;
  • R x and R y are each independently C 1 -C 6 alkyl substituted by 1 to 5 identical or different R z , each of which R z is independently selected from -H, halogen, -O-(C 1 -C 6 alkyl) or C 3 -C 6 cycloalkyl; when there are multiple substituents, the substituents are the same or different;
  • R 2 is selected from -H, hydroxyl, amino, cyano, C 1 -C 6 alkyl unsubstituted or substituted by R 21 ; in the C 1 -C 6 alkyl substituted by R 21 , the The substitution of R 21 may be one or more substitutions, and each of the R 21s is independently selected from the following substituents: hydroxyl, amino, cyano, halogen, C 1 -C 6 alkyl or -O-(C 1 -C 6 alkyl); when there are multiple substituents, the substituents are the same or different;
  • Ring B selected from where "*" means the same as and "**” indicates connection with ring A;
  • R 3 and R 4 are each independently selected from -H, -SF 5 , hydroxyl, amino, cyano, C 1 -C 6 alkyl unsubstituted or substituted by R 31 , C 3 unsubstituted or substituted by R 31 -C 6 cycloalkyl, halogen or
  • the substitution of R 31 may be one or more substitutions, each of the R 31 Independently selected from the following substituents: hydroxyl, amino, cyano, halogen, C 1 -C 6 alkyl or -O-(C 1 -C 6 alkyl); when there are multiple substituents, the substituent same or different basis;
  • R 32 is selected from -H, unsubstituted or substituted by R 331 C 1 -C 6 alkyl, or, unsubstituted or substituted by R 321 C 3 -C 6 cycloalkyl; said substituted by R 321 In C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl substituted by R 31 , the substitution of R 321 may be one or more substitutions, and each of the R 321 is independently selected from the following substituents: Hydroxy, amino, cyano, halogen, C 1 -C 6 alkyl or -O-(C 1 -C 6 alkyl); when there are multiple substituents, the substituents are the same or different;
  • R 5 is selected from -H, cyano, C 1 -C 6 alkyl substituted by 1-5 identical or different halogens, C 3 -C 6 cycloalkyl substituted by 1-5 identical or different halogens , halogen, C 3 -C 6 cycloalkyl or C 1 -C 6 alkyl;
  • R is selected from hydroxyl, amino, cyano, Unsubstituted or substituted by R 61 C 1 -C 6 alkyl, halogen or unsubstituted or substituted by R 61 C 3 -C 6 cycloalkyl; said C 1 -C 6 alkyl substituted by R 61 Or in a C 3 -C 6 cycloalkyl group substituted by R 61 , the substitution of R 61 may be one or more substitutions, and each of the R 61s is independently selected from the following substituents: hydroxyl, amino, cyano, Halogen, C 1 -C 6 alkyl or -O-(C 1 -C 6 alkyl); when there are multiple substituents, the substituents are the same or different.
  • the compound represented by formula II, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug is:
  • ring A, ring B, R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are as defined above.
  • the compound represented by formula III, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug is:
  • the compound represented by formula IV its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug is:
  • R 3 , R 4 and R 6 are as defined above.
  • the compound shown in formula IV' its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug is:
  • R 3 , R 4 and R 6 are as defined above.
  • the compound represented by formula IV its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug is:
  • R 3 , R 4 and R 6 are as defined above.
  • the compound represented by formula V its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug is:
  • Ring C is C 3 -C 6 cycloalkyl which is unsubstituted or substituted by R 61 .
  • the compound represented by formula VI its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug is:
  • X 1 , X 2 , X 3 , and X 4 are independently C or N;
  • X 1 and X 2 are different, when X 1 is N, X 3 is N, when X 2 is N, X 4 is N.
  • Ring B is selected from
  • Ring A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • R2 is -H.
  • R1 is -H.
  • R 1 is C 1 -C 6 alkyl unsubstituted or substituted by R 12
  • said C 1 -C 6 alkyl is methyl, ethyl, n-propyl or isopropyl.
  • R 1 when R 1 is an unsubstituted or substituted C 1 -C 6 alkyl group, said C 1 -C 6 alkyl group is methyl.
  • R 1 is C 1 -C 6 alkyl substituted by R 12
  • said R 12 is halogen
  • halogen when R12 is halogen, said halogen is F or Cl.
  • halogen when R12 is halogen, said halogen is F.
  • R 1 is C 1 -C 6 alkyl substituted by R 12
  • said R 12 is substituted by 1, 2 or 3.
  • R 1 is a C 1 -C 6 alkyl group substituted by R 12
  • the number of R 12 substitutions is 2.
  • R is
  • R 11 when R 11 is unsubstituted or substituted by R 111 -OC 1 -C 6 alkyl, the -OC 1 -C 6 alkyl is -O-methyl, -O -ethyl, -O-n-propyl or -O-isopropyl.
  • R 11 is -NR x R y .
  • R x and R y are C 1 -C 6 alkyl substituted by 1-5 identical or different R z , said C 1 -C 6 alkyl is methane radical, ethyl, n-propyl or isopropyl.
  • R x and R y are C 1 -C 6 alkyl substituted by 1-5 identical or different R z , said C 1 -C 6 alkyl is methane base.
  • R x and R y are C 1 -C 6 alkyl substituted by 1-5 same or different R z , R z is substituted with 1, 2 or 3.
  • R x and R y are C 1 -C 6 alkyl substituted by 1-5 same or different R z , the R z is substituted with 1, 2 or 3.
  • Rz is -H.
  • R 11 is a 4-8 membered heterocycloalkyl group that is unsubstituted or substituted by R 111
  • the 4-8 membered heterocycloalkyl group is azetidinyl, nitrogen Heterocyclopentyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, morpholinyl, pyrrolidinyl, morpholinyl or piperazinyl.
  • R 11 is a 4-8 membered heterocycloalkyl group that is unsubstituted or substituted by R 111
  • the 4-8 membered heterocycloalkane is azacyclopentyl
  • R4 is -H.
  • R3 is -H.
  • R3 when R3 is halogen, said halogen is F or Cl.
  • R 3 is -SF 5 .
  • R 3 is
  • R 32 is a C 1 -C 6 alkyl group that is unsubstituted or substituted by R 321
  • the C 1 -C 6 alkyl group is methyl, ethyl, n-propyl or Isopropyl.
  • R 32 is a C 1 -C 6 alkyl group that is unsubstituted or substituted by R 321 , the C 1 -C 6 alkyl group is methyl.
  • R 3 is a C 1 -C 6 alkyl unsubstituted or substituted by R 31 , the C 1 -C 6 alkyl is methyl, ethyl, n-propyl or isopropyl.
  • R 3 is a C 1 -C 6 alkyl group that is unsubstituted or substituted by R 31 , the C 1 -C 6 alkyl group is methyl or ethyl.
  • R 3 is C 1 -C 6 alkyl substituted by R 31 , said R 31 is halogen.
  • halogen when R31 is halogen, said halogen is F or Cl.
  • halogen when R31 is halogen, said halogen is F.
  • R 3 is C 1 -C 6 alkyl substituted by R 31 , the halogen substitution is 1, 2 or 3.
  • R 3 is a C 3 -C 6 cycloalkyl group that is unsubstituted or substituted by R 31
  • the C 3 -C 6 cycloalkyl group is cyclopropyl
  • R 5 is a C 1 -C 6 alkyl group
  • the C 1 -C 6 alkyl group is methyl, ethyl, n-propyl or isopropyl.
  • R 5 is C 1 -C 6 alkyl
  • said C 1 -C 6 alkyl is methyl
  • R 5 is C 3 -C 6 cycloalkyl
  • said C 3 -C 6 cycloalkyl is cyclopropyl
  • R 6 is
  • R 6 when R 6 is C 1 -C 6 alkyl unsubstituted or substituted by R 61 , said C 1 -C 6 alkyl is methyl, ethyl, n-propyl or isopropyl.
  • R 6 when R 6 is C 1 -C 6 alkyl unsubstituted or substituted by R 61 , said C 1 -C 6 alkyl is isopropyl.
  • R 6 when R 6 is C 1 -C 6 alkyl substituted by R 61 , said R 61 is halogen.
  • R 61 when R 61 is halogen, said halogen is F or Cl.
  • R 61 when R 61 is halogen, said halogen is F.
  • R 6 is C 1 -C 6 alkyl substituted by R 61
  • the number of R 61 substitutions is 6.
  • R 6 is a C 3 -C 6 cycloalkyl group that is unsubstituted or substituted by R 61
  • the C 3 -C 6 cycloalkyl group is cyclopropyl or cyclobutyl .
  • R 6 when R 6 is C 3 -C 6 cycloalkyl substituted by R 61 , said R 61 is halogen.
  • R 6 is a C 3 -C 6 cycloalkyl group substituted by R 61
  • the substitution of R 61 is 1, 2 or 3.
  • R 6 when R 6 is C 3 -C 6 cycloalkyl substituted by R 61 , said R 61 is C 1 -C 6 substituted by 1-6 identical or different halogens alkyl.
  • R 61 is C 1 -C 6 alkyl substituted by 1-6 identical or different halogens
  • the halogen substitutions are 1, 2 or 3.
  • R 61 is C 1 -C 6 alkyl substituted by 1-6 identical or different halogens
  • the number of said halogens is 3.
  • R 61 is C 1 -C 6 alkyl substituted by 1-6 identical or different halogens
  • said halogen is F or Cl.
  • R 61 is C 1 -C 6 alkyl substituted by 1-6 identical or different halogens
  • said halogen is F
  • R 6 is a C 3 -C 6 cycloalkyl group substituted by R 61
  • the number of R 61 substitutions is 2.
  • R 1 is selected from -H, In an optional embodiment of the present invention, R 1 is -H,
  • R is
  • R2 is -H.
  • R 3 is selected from -H, -Cl, methyl, -SF 5 ,
  • R 3 is selected from -H, -SF 5 ,
  • R 3 is selected from -H, -SF 5 ,
  • R4 is -H.
  • R 5 is selected from methyl or cyclopropyl.
  • R 5 is methyl
  • R is selected from isopropyl, cyclopropyl,
  • R is selected from isopropyl
  • R is selected from cyclobutyl, cyclopentyl,
  • Ring A is and ring B is , R 1 is hydroxyl or and R 11 is -NR x R y or
  • R 5 is C 3 -C 6 cycloalkyl, cyano or C 3 -C 6 cycloalkyl substituted by 1-5 identical or different halogens.
  • Ring A when Ring A is and ring B is When, R 6 is hydroxyl, amino, cyano, C 1 -C 6 alkyl substituted by R 61 , halogen or C 3 -C 6 cycloalkyl unsubstituted or substituted by R 61 .
  • the compound represented by formula I its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug is selected from any of the following compounds :
  • the present invention proposes a pharmaceutical composition, which includes a therapeutically effective dose of the above compound, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically An acceptable salt or prodrug and a pharmaceutically acceptable carrier, diluent or excipient.
  • the pharmaceutical composition of the present invention may include a therapeutically effective dose of the above compound, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt Or prodrugs and pharmaceutically acceptable pharmaceutical carriers, diluents or excipients are mixed to prepare pharmaceutical preparations, which are suitable for oral or parenteral administration.
  • Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal and oral routes.
  • the formulation can be administered by any route, for example, by infusion or bolus injection, by absorption through the epithelium or mucocutaneous (eg, oral mucosa or rectum, etc.).
  • Administration can be systemic or local.
  • formulations for oral administration include solid or liquid dosage forms, specifically, tablets, pills, granules, powders, capsules, syrups, emulsions, suspensions and the like.
  • the formulations can be prepared by methods known in the art, and contain carriers, diluents or excipients commonly used in the field of pharmaceutical formulations.
  • the present invention proposes the above-mentioned compound, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug or the above-mentioned pharmaceutical composition in the preparation of Use in drugs for treating diseases related to AAK1.
  • the above-mentioned compound or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug or the use of the above-mentioned pharmaceutical composition in the preparation of medicine can be used for treating related diseases such as Alzheimer's disease, bipolar disorder, pain, Parkinson's disease or schizophrenia.
  • the present invention proposes the above-mentioned compound, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug or the above-mentioned pharmaceutical composition, for Treating or preventing AAK1-related diseases, such as treating Alzheimer's disease, bipolar disorder, pain, Parkinson's disease or schizophrenia and other related diseases.
  • the present invention proposes a method for treating or preventing AAK1-related diseases.
  • the method includes administering to the patient a pharmaceutically acceptable dose of the above-mentioned compound, which tautomorphically Constructs, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs or the above pharmaceutical compositions.
  • pharmaceutically acceptable salt refers to pharmaceutically acceptable salts of non-toxic acids or bases, including salts of inorganic acids and bases, organic acids and bases.
  • composition means a mixture of one or more compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof with other chemical components such as a physiologically/pharmaceutically acceptable carrier and excipients.
  • the purpose of a pharmaceutical composition is to facilitate the administration of a compound to an organism.
  • excipient refers to a pharmaceutically acceptable inert ingredient.
  • examples of categories of the term “excipient” include, but are not limited to, binders, disintegrants, lubricants, glidants, stabilizers, fillers, diluents, and the like. Excipients can enhance the handling characteristics of a pharmaceutical formulation, ie make the formulation more suitable for direct compression by increasing flow and/or cohesiveness.
  • prodrug refers to a compound of the invention that can be converted to biological activity under physiological conditions or by solvolysis.
  • the prodrugs of the present invention are prepared by modifying functional groups in the compounds which can be removed routinely or in vivo to yield the parent compound.
  • Prodrugs include compounds formed by linking a hydroxyl or amino group in the compound of the present invention to any group. When the prodrug of the compound of the present invention is administered to a mammalian individual, the prodrug is split to form free hydroxyl, free of amino.
  • stereoisomer refers to isomers resulting from differences in the arrangement of atoms in a molecule in space, including cis-trans isomers, enantiomers, diastereoisomers and conformers.
  • tautomer refers to isomers of functional groups resulting from the rapid movement of an atom in a molecule between two positions.
  • the compounds of the present invention may exhibit tautomerism.
  • Tautomeric compounds can exist in two or more interconvertible species.
  • Prototropic tautomers result from the migration of a covalently bonded hydrogen atom between two atoms.
  • Tautomers generally exist in equilibrium and attempts to isolate a single tautomer usually result in a mixture whose physicochemical properties are consistent with the mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule.
  • the keto form predominates
  • the enol form predominates.
  • the present invention encompasses all tautomeric forms of the compounds.
  • Certain compounds of the invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are included within the scope of the present invention.
  • the compounds of the invention may exist in particular geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, D-isomers, L-isomers, and racemic and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention within.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
  • Optically active (R)- and (S)-isomers as well as D- and L-isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliary agents, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide pure desired enantiomer.
  • a diastereomeric salt is formed with an appropriate optically active acid or base, and then step by step known in the art Resolution of diastereomers by crystallization or chromatography followed by recovery of the pure enantiomers.
  • the separation of enantiomers and diastereomers is usually accomplished by the use of chromatography using chiral stationary phases, optionally in combination with chemical derivatization methods (e.g. amines to amino groups formate).
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compounds.
  • compounds may be labeled with radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C). All changes in isotopic composition of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
  • the term "effective amount” or “therapeutically effective amount” refers to a non-toxic but sufficient amount of the drug or agent to achieve the desired effect.
  • the "effective amount” of one active substance in the composition refers to the amount needed to achieve the desired effect when used in combination with another active substance in the composition.
  • the determination of the effective amount varies from person to person, depending on the age and general condition of the recipient, and also depends on the specific active substance. The appropriate effective amount in each case can be determined by those skilled in the art according to routine experiments.
  • active ingredient refers to a chemical entity that is effective in treating the disorder, disease or condition of interest.
  • substituted refers to the replacement of any one or more hydrogen atoms on a specified atom with a substituent, including deuterium and hydrogen variants, as long as the valence of the specified atom is normal and the substituted compound is stable .
  • Keto substitution does not occur on aromatic groups.
  • optionally substituted means that it may or may not be substituted, and unless otherwise specified, the type and number of substituents may be arbitrary on a chemically realizable basis.
  • C 1 -C 6 alkyl is understood to mean a straight-chain or branched saturated monovalent hydrocarbon radical having 1, 2, 3, 4, 5 or 6 carbon atoms.
  • the alkyl group is for example methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl Base, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl
  • -O-(C 1 -C 6 alkyl) is to be understood as meaning that an alkyl group is attached to the rest of the molecule via an oxygen atom, wherein "C 1 -C 6 alkyl” has the above definition. Such as -O-(methyl), -O-(ethyl).
  • C 3 -C 6 cycloalkyl is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3 to 6 carbon atoms, including fused or bridged polycyclic ring systems. Such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
  • 4-8 membered heterocycloalkyl refers to a monocyclic ring having a total of 4, 5, 6, 7 or 8 ring atoms and containing one or two identical or different ring heteroatoms or heteroatom-containing groups Saturated heterocyclic ring, the ring heteroatom or heteroatom-containing group is selected from: N, NH, O, S, SO and SO 2 , and the heterocycloalkyl group can pass through any carbon atom or (if present) nitrogen Atoms are connected to the rest of the molecule.
  • the heterocycloalkyl group can be a 4-membered ring, such as azetidinyl, oxetanyl or thietanyl; or a 5-membered ring, such as tetrahydrofuranyl, 1,3-dioxo Pentyl, thiolanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, 1,1-dioxothiolanyl, 1,2-oxazolidinyl, 1,3-oxo oxazolidinyl or 1,3-thiazolidinyl; or a 6-membered ring, such as tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, Piperazinyl, 1,3-dioxanyl, 1,4-dioxanyl or 1,2-oxazepinyl
  • halo or halogen refers to fluoro, chloro, bromo and iodo.
  • the present invention has at least one of the following technical effects:
  • AAK1 inhibitors with novel structure, excellent pharmacokinetic properties, and good efficacy or druggability, which can be used to effectively treat diseases and diseases related to AAK1;
  • the compound of the present invention can be used to treat related diseases such as Alzheimer's disease, bipolar disorder, pain, Parkinson's disease or schizophrenia;
  • the compound of the present invention has a strong affinity for AAK1.
  • the structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS).
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • the unit of NMR shift is 10 -6 (ppm).
  • the solvents determined by NMR are deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is tetramethylsilane (TMS).
  • M molar concentration, such as 1M hydrochloric acid means 1mol/L hydrochloric acid solution
  • IC 50 half inhibitory concentration, which refers to the concentration at which half of the maximum inhibitory effect is achieved.
  • the synthetic route of target compound 1 is as follows:
  • Step 1 Synthesis of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2,4-dimethylpentanoic acid
  • Step 4 Synthesis of 2-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine
  • Step 5 Synthesis of (S)-1-((6-bromo-2-(difluoromethyl)pyridin-3-yl)oxo)-2,4-dimethylpentane-2-amine
  • Embodiment 1 the preparation of target compound I-1
  • the synthetic route of target compound 1-1 is as follows:
  • Step 1 Synthesis of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine
  • Embodiment 2 the preparation of target compound 1-2
  • the first step N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)pyrrolidin-1-methanol Amide synthesis
  • Embodiment 3 the preparation of target compound 1-3
  • the first step the synthesis of diethyl 2-(cyclopropylmethyl)-2-methylmalonate
  • the second step the synthesis of 2-(cyclopropylmethyl)-3-ethoxy-2-methyl-3-oxyethylene propionic acid
  • the third step the synthesis of ethyl 3-amino-2-(cyclopropylmethyl)-2-methyl-3-oxypropylene propyl ester
  • the fourth step the synthesis of ethyl 2-amino-3-cyclopropyl-2-methylpropyl ester
  • Step 7 Synthesis of 1-((6-bromo-2-(difluoromethyl)pyridin-3-yl)oxo)-3-cyclopropyl-2-methylpropane-2-amine
  • Step 8 1-((2',6-bis(difluoromethyl)-[2,4'-bipyridyl]-5-yl)oxo)-3-cyclopropyl-2-methylpropane Synthesis of -2-amine
  • the crude product was prepared by reverse phase (chromatographic column: Waters Xbridge 150 ⁇ 25mm ⁇ 5 ⁇ m; mobile phase: [water (0.225% ammonia water)-acetonitrile]; B%: 34%-64%, 9min) to separate and obtain 1-((2' ,6-bis(difluoromethyl)-[2,4'-bipyridyl]-5-yl)oxo)-3-cyclopropyl-2-methylpropane-2-amine (100mg, 12.2% yield Rate)
  • Step 10 (S)-1-((2',6-bis(difluoromethyl)-[2,4'-bipyridyl]-5-yl)oxo)-3-cyclopropyl-2 -Preparation of methylpropane-2-amine (I-3)
  • Embodiment 4 the preparation of target compound 1-4
  • Step 1 Synthesis of 2',6-bis(difluoromethyl)-5-fluoro-2,4'-bipyridine
  • the second step the synthesis of diethyl 2-((3,3-difluorocyclobutyl)methyl)-2-methylmalonate
  • the third step the synthesis of 2-((3,3-difluorocyclobutyl)methyl)-3-ethoxy-2-methyl-3-oxopropionic acid
  • Step 4 Synthesis of ethyl 3-amino-2-((3,3-difluorocyclobutyl)methyl)-2-methyl-3-oxopropionate
  • Step 5 Synthesis of ethyl 2-amino-3-(3,3-difluorocyclobutyl)-2-methylpropionate
  • the seventh step (S)-1-((2',6-bis(difluoromethyl)-[2,4'-bipyridyl]-5-yl)oxo)-3-(3,3- Synthesis of Difluorocyclobutyl)-2-methylpropan-2-amine (I-4)
  • the crude product was prepared by reverse phase (chromatographic column: Phenomenex Synergi C18 150 ⁇ 25mm ⁇ 10 ⁇ m; mobile phase: [water (0.225% formic acid)-acetonitrile]; B%: 16%-46%, 2min) to separate a yellow solid, and then through SFC (Chromatographic column: DAICEL CHIRALPAK AD (250mm ⁇ 30mm, 10 ⁇ m); Mobile phase: [0.1% ammonia/ethanol]; B%: 20%-20%, 3.9min) separated to obtain: yellow solid (S)-1-( (2',6-bis(difluoromethyl)-[2,4'-bipyridyl]-5-yl)oxo)-3-(3,3-difluorocyclobutyl)-2-methyl Propan-2-amine (I-4) (43.6 mg, yield 27.8%).
  • Embodiment 5 the preparation of target compound 1-6
  • Step 1 Synthesis of 1-fluoro-4-nitro-2-(pentafluoro- ⁇ 6 -mercapto)benzene
  • the second step the synthesis of 4-nitro-2-(pentafluoro- ⁇ 6 -mercapto)phenol
  • the third step the synthesis of 1-methoxy-4-nitro-2-(pentafluoro- ⁇ 6 -mercapto)benzene
  • Step 4 Synthesis of 4-methoxy-3-(pentafluoro- ⁇ 6 -mercapto)aniline
  • Step 5 Synthesis of 4-bromo-1-methoxy-2-(pentafluoro- ⁇ 6 -mercapto)benzene
  • Step 6 Synthesis of 2-(difluoromethyl)-4-[4-methoxy-3-(pentafluoro- ⁇ 6 -mercapto)phenyl]pyridine
  • Step 7 Synthesis of 4-[2-(difluoromethyl)pyridin-4-yl]-2-(pentafluoro- ⁇ 6 -mercapto)phenol
  • reaction solution was poured into ice water (10.0 mL), then extracted with ethyl acetate (10.0 mL ⁇ 3), the organic phase was washed with brine (25.0 mL) and dried over anhydrous sodium sulfate, filtered and concentrated get crude.
  • the separation method was as follows: chromatographic column: Waters Xbridge 150 ⁇ 25mm ⁇ 5 ⁇ m; mobile phase: [water (ammonia v/v)-acetonitrile]; B%: 53%-83 %, 9min), to obtain (2S)-1-(4-[2-(difluoromethyl)pyridin-4-yl]-2-(pentafluoro- ⁇ 6 -mercapto)phenoxy)-2,4 -Dimethylpentan-2-amine (I-6) (4.97 mg, yield 19.5%).
  • Embodiment 6 the preparation of target compound 1-12
  • the synthetic route of target compound I-12 is as follows:
  • the first step the synthesis of 3-bromo-2-(bromomethyl)-6-chloropyridine
  • the second step the synthesis of 2-(azidomethyl)-3-bromo-6-chloropyridine
  • the third step the synthesis of (3-bromo-6-chloropyridin-2-yl)methanamine
  • the fourth step the synthesis of N-((3-bromo-6-chloropyridin-2-yl)methyl)formamide
  • Embodiment 7 the preparation of target compound I-18
  • the synthetic route of target compound 1-18 is as follows:
  • the third step Synthesis of tert-butyl (4S)-4-isobutyl-4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-sulfone
  • the fourth step the synthesis of 2-(difluoromethyl)-4-(4-methoxyphenyl)pyridine
  • the fifth step the synthesis of 2-(difluoromethyl)-4-(3-iodo-4-methoxyphenyl)pyridine
  • the sixth step 4-(2-(difluoromethyl)pyridin-4-yl)-2-iodophenol
  • reaction solution was poured into a saturated sodium bicarbonate solution (60.0 mL), extracted with dichloromethane, the organic phase was concentrated and dried to obtain a crude product, which was separated by column chromatography (petroleum ether: ethyl acetate 10:1 to 3: 1) 4-(2-(difluoromethyl)pyridin-4-yl)-2-iodophenol (1.31 g, 45.1% yield) was obtained as a white solid.
  • the seventh step tert-butyl (S)-(1-(4-(2-(difluoromethyl)pyridin-4-yl)-2-iodophenoxy)-2,4-dimethylpentane -2-yl) carbamate synthesis
  • Trifluoroacetic acid (1.68 g, 14.7 mmol) was added to a dichloromethane solution (1.00 mL) of alk-2-yl)aminomethyl esters (120 mg, 214 ⁇ mol), and the reaction solution was stirred at 25° C. for 0.5 hours.
  • the crude product was prepared by reverse phase (chromatographic column: Phenomenex Synergi C18 150 ⁇ 25mm ⁇ 10 ⁇ m; mobile phase: [water (0.225% formic acid)-acetonitrile]; B%: 16%-46%, 10min) to obtain yellow solid (S)-1 -(4-(2-(Difluoromethyl)pyridin-4-yl)-2-(prop-1-yn-1-yl)phenoxy)-2,4-dimethylpentane-2- Amine ⁇ formate (I-18) (40.0 mg, 43.5% yield).
  • Embodiment 8 the preparation of target compound I-21
  • the second step the synthesis of 5-chloro-8-(2-(difluoromethyl)pyridin-4-yl)imidazo[1,2-a]pyridine
  • reaction solution was concentrated to remove tetrahydrofuran, then water (5.00mL) and ethyl acetate (8.00mL) were added to dissolve, the organic phase was separated, the aqueous phase was extracted with ethyl acetate (8.00mL ⁇ 3), the organic phases were combined, organic The phase was washed with brine (20.0 mL) and dried over anhydrous sodium sulfate, then concentrated by filtration to give the crude product.
  • the organic phase was washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product.
  • the separation method was: chromatographic column: Waters Xbridge 150 ⁇ 25mm ⁇ 5 ⁇ m; mobile phase : [water(ammonia hydroxide v/v)-ACN]; B%: 32%-62%, 9min, to obtain off-white solid (S)-1-((8-(2-(difluoromethyl)pyridine- 4-yl)imidazo[1,2-a]pyridin-5-yl)oxo)-2,4-dimethylpentan-2-amine (2.65 mg, 3.05% yield).
  • Embodiment 9 the preparation of target compound I-24
  • the first step tert-butyl (S)-(1-((2'-(difluoromethyl)-2-oxoylidene-2H-[1,4'-bipyridyl]-4-yl)oxo )-2,4-dimethylpentan-2-yl) carbamate synthesis
  • the third step 4-(((S)-2-amino-2,4-dimethylpentyl)oxo)-1-(2-(difluoromethyl)pyridin-4-yl)piperidine- Synthesis of 2-keto (I-24)
  • Embodiment 10 the preparation of target compound I-25
  • the synthetic route of target compound 1-25 is as follows:
  • the first step the synthesis of 8-(2-(difluoromethyl)pyridin-4-yl)-5-methoxyquinoline
  • the reaction solution was concentrated, then water (10.0 mL) and ethyl acetate (10.0 mL) were added, the organic phase was separated, the aqueous phase was extracted with ethyl acetate (20.0 mL ⁇ 3), the organic phases were combined, and the organic phase was washed with saturated After washing with brine (30.0 mL) and drying over anhydrous sodium sulfate, the crude product was obtained by filtration and concentration. Adjust the pH to 7-9 with saturated sodium bicarbonate solution, then extract with ethyl acetate (10.0ml ⁇ 3), combine the organic layers, wash the organic phase with saturated brine (10.0mL), dry over anhydrous sodium sulfate, and concentrate to obtain Crude.
  • the second step the synthesis of 8-(2-(difluoromethyl)pyridin-4-yl)quinoline-5-ol
  • reaction solution was poured into water (10.0 mL) at 25° C., the pH of the reaction solution was adjusted to 9 with saturated sodium bicarbonate solution, and then dichloromethane (25.0 mL ⁇ 3) After extraction, the organic phase was washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product.
  • reaction solution was poured into water, then extracted with ethyl acetate (15.0 mL ⁇ 3), the organic phase was washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product.
  • Embodiment 11 Preparation of target compound I-27
  • the first step the synthesis of N-methyl-2-nitropyridin-3-amine
  • the second step the synthesis of 4-bromo-N-methyl-2-nitropyridin-3-amine
  • the third step the synthesis of 4-bromo-N3-methylpyridine-2,3-diamine
  • the fifth step 1-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-dihydro-2H- Synthesis of imidazo[4,5-b]pyridin-2-one
  • the seventh step (S)-7-(5-((2-amino-2,4-dimethylpentyl)oxo)-6-(difluoromethyl)pyridin-2-yl)-1- Synthesis of Methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (I-27)
  • Embodiment 12 the preparation of target compound I-29
  • the first step the synthesis of (1-fluorocyclopropyl)methanol
  • the second step the synthesis of (1-fluorocyclopropyl) methyl methanesulfonate
  • the third step the synthesis of 2-((1-fluorocyclopropyl)methyl)diethyl malonate
  • reaction solution was lowered to room temperature, diluted with water (100mL), extracted with ethyl acetate (100mL ⁇ 3), the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain Diethyl 2-((1-fluorocyclopropyl)methyl)-2-methylmalonate (2.90 g, crude) as a yellow oil.
  • Step 5 Synthesis of 3-ethoxy-2-((1-fluorocyclopropyl)methyl)-2-methyl-3-oxopropionic acid
  • Step 6 Synthesis of ethyl 3-amino-2-((1-fluorocyclopropyl)methyl)-2-methyl-3-oxopropionate
  • Step 7 Synthesis of ethyl 2-amino-3-(1-fluorocyclopropyl)-2-methylpropionate
  • Ethyl 3-amino-2-((1-fluorocyclopropyl)methyl)-2-methyl-3-oxopropanoic acid ethyl ester (1.20 g, 5.52 mmol) was dissolved in toluene (12.0 mL), Diacetoxyiodobenzene (1.78g, 5.52mmol) was added, the reaction solution was heated to 45°C for 2 hours, then 4M dilute hydrochloric acid (4.60mL) was added, and the reaction was continued at 45°C for 12 hours.
  • reaction solution was lowered to room temperature, separated, the water phase was adjusted to pH 10-11 by adding 1M sodium hydroxide, extracted with ethyl acetate (20mL ⁇ 3), the organic phases were combined, and washed with saturated sodium chloride solution , dried over anhydrous sodium sulfate, filtered, and concentrated to give ethyl 2-amino-3-(1-fluorocyclopropyl)-2-methylpropionate (0.58 g, crude product) as a yellow oil.
  • Step 8 Synthesis of 2-amino-3-(1-fluorocyclopropyl)-2-methylpropan-1-ol
  • Step 9 (S)-1-((2',6-bis(difluoromethyl)-[2,4'-bipyridyl]-5-yl)oxo)-3-(1-fluorocyclo Propyl)-2-methylpropan-2-amine (I-29)
  • Embodiment 13 the preparation of target compound I-34, I-35
  • the second step the synthesis of 5-chloro-8-(2-(difluoromethyl)pyridin-4-yl)imidazo[1,2-a]pyridine (3)
  • the third step 1-(3,3-difluorocyclobutyl)-3-((8-(2-(difluoromethyl)pyridin-4-yl)imidazo[1,2-a]pyridine- Synthesis of 5-yl)oxo)-2-methylpropan-2-amine
  • the purification method was: chromatographic column: 3_Phenomenex Luna C18 75 ⁇ 30mm ⁇ 3 ⁇ m; mobile phase: [water(HCl)-ACN]; B%: 3%-23%, 8min , after purification afforded 1-(3,3-difluorocyclobutyl)-3-((8-(2-(difluoromethyl)pyridin-4-yl)imidazo[1,2-a]pyridine- 5-yl)oxo)-2-methylpropan-2-amine (100 mg, 39.3% yield).
  • Embodiment 14 Preparation of target compound I-36
  • the first step the synthesis of 3-bromo-6-chloro-2-hydrazinopyridine
  • reaction solution was concentrated to remove ethanol, then diluted with water (30 mL), extracted with ethyl acetate (20 mL ⁇ 3), combined organic phases, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated
  • the second step the synthesis of 8-bromo-5-chloro-[1,2,4]triazolo[4,3-a]pyridine
  • the third step the synthesis of 5-chloro-8-(2-(difluoromethyl)pyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridine
  • the purification method was: chromatographic column: Phenomenex C18 75 ⁇ 30mm ⁇ 3 ⁇ m; mobile phase: [water(FA)-ACN]; B%: 30%-60%, 7min, Purification afforded (S)-1-((3-chloro-8-(2-(difluoromethyl)pyridin-4-yl)imidazo[1,2-a]pyridin-5-yl)oxo) - 2,4-Dimethylpentane-2-amine formate (15.4 mg, yield 7.56%).
  • Embodiment 15 Preparation of Target Compound I-37
  • the first step Synthesis of 5-chloro-8-(2-(difluoromethyl)pyridin-4-yl)-2-methylimidazo[1,2-a]pyridine
  • Embodiment 16 Preparation of target compound I-38
  • the first step Synthesis of 6-chloro-2'-(difluoromethyl)-[3,4'-bipyridyl]-2-amine
  • the second step the synthesis of 5-chloro-8-(2-(difluoromethyl)pyridin-4-yl)-3-methylimidazo[1,2-a]pyridine
  • 6-chloro-2'-(difluoromethyl)-[3,4'-bipyridine]-2-amine 400mg, 1.56mmol
  • 2-bromo-1,1-dimethoxy Pyridine p-toluenesulfonate 432mg, 1.72mmol
  • propane 372mg, 2.03mmol
  • n-butanol 5.00mL
  • Embodiment 17 Preparation of target compound I-39
  • Embodiment 18 Preparation of target compound I-40
  • the first step 4-(5-chloroimidazo[1,2-a]pyridin-8-yl)pyridin-2-amine
  • the crude product was purified by beating (ethyl acetate, 25°C) to obtain methyl (4-(5-chloroimidazo[1,2-a]pyridin-8-yl)pyridin-2-yl)aminomethyl ester (108mg, yield rate 54.0%).
  • the separation method was: chromatographic column: 3_Phenomenex Luna C18 75 ⁇ 30mm ⁇ 3 ⁇ m; mobile phase: [water(HCl)-ACN]; B%: 0%-21%, 8min , after purification to give (S)-methyl(4-(5-((2-amino-2,4-dimethylpentyl)oxo)imidazo[1,2-a]pyridin-8-yl) Pyridin-2-yl)aminomethyl ester hydrochloride (10.0 mg, yield 7.46%).
  • Embodiment 19 Preparation of target compound I-41
  • the crude product was prepared by reverse phase (chromatographic column: Phenomenex luna C18 150 ⁇ 25mm ⁇ 10 ⁇ m; mobile phase: [water (0.225% formic acid)-acetonitrile]; B%: 15%-45%, 10min) to obtain (S)-1- ((2-(Difluoromethyl)-8-(2-(difluoromethyl)pyridin-4-yl)imidazo[1,2-a]pyridin-5-yl)oxo)-2,4 -Dimethylpentan-2-amine (I-41) (27.0 mg, 15.8% yield)
  • Test Example 1 AAK1 Kinase Binding Assay Based on TR-FRET (Time-Resolved Fluorescence Resonance Energy Transfer)
  • test compound (the control compound 1 prepared in the previous example and compounds I-1 ⁇ I-41, RI-4, RI-29) in DMSO and prepare a 10mM mother solution, and dilute it to the highest point of the concentration gradient with DMSO 100-fold, followed by 3-fold serial dilution until reaching 8 concentration gradients.
  • AAK1 Recombinant Human Protein (Invitrogen, A30967) and LanthaScreen TM Eu-anti-GST Antibody (Invitrogen, PV5594) were prepared into a 2 ⁇ kinase/Antibody mixture, added to a 384-well plate (16 ⁇ l/well) and pipetted evenly. Equilibrate at room temperature for 15 minutes. Add 4 ⁇ l of 4 ⁇ Kinase Tracer 222 (Invitrogen, PV6121) to each well, and pipette evenly. Incubate at room temperature for 1h.
  • % binding rate (ER high signal control - ER sample ) / (ER high signal control - ER low signal control ) ⁇ 100, use GraphPad 8.0 to fit the curve and calculate the IC 50 value.
  • Tables a, b, c, and d below indicate the range of IC 50 values of the compounds, that is, a ⁇ 10nM, 10 ⁇ b ⁇ 50nM, 50nM ⁇ c ⁇ 500nM, 500nM ⁇ d.
  • the stability test of human hepatocytes was tested by co-incubating the compound with human hepatocytes.
  • the frozen hepatocytes were taken out from the liquid nitrogen, thawed in a water bath at 37°C, and the hepatocyte thawing medium was added, mixed gently and then centrifuged at 500 rpm for 3 minutes. Discard the supernatant, add 10 times the volume of KHB buffer (Krebs-Henseleit buffer, Sigma, Cat#K3753-10X1L) and 5.6g/L HEPES to resuspend the cells, mix gently and centrifuge at 500rpm for 3 minutes. Discard the supernatant and determine the viability and yield of hepatocytes.
  • KHB buffer Krebs-Henseleit buffer
  • test compound control compound 1 or one of compounds I-1 to I-41, RI-4, RI-29 prepared in the previous example
  • DMSO solution DMSO solution to 990 ⁇ L KHB buffer, centrifuge at 5594g for 15 minutes, Add 50 ⁇ L/well to the wells designated at different time points.
  • the plasma protein binding rate of the compounds was detected by equilibrium dialysis (HTDialysis, HTD 96b).
  • the compounds to be tested (the control compound 1 prepared in the previous example and compounds I-1 ⁇ I-41, R-I-4, R-I-29) were prepared as 0.5mM stock solutions with DMSO, and then buffered with 0.05M sodium phosphate solution diluted 25 times as the working solution. Take a blank 96-well plate, preload each well with 380 ⁇ L plasma, then add 20 ⁇ L/well working solution to the plasma and mix well, the final concentration of the compound is 1 ⁇ M, and each well contains 0.2% DMSO.
  • the 96-well plate was vortexed at 600 rpm for 10 minutes, centrifuged at 5594g for 15 minutes (Thermo Multifuge ⁇ 3R), and 50 ⁇ L of the supernatant was transferred to a new 96-well plate , and the sample was mixed with 50 ⁇ L ultrapure water for LC-MS/MS analysis.
  • % binding rate 100 ⁇ ([supply side concentration] 5h- [receiving side concentration] 5h )/[supply side concentration] 5h .
  • % free fraction 100 - % bound
  • Human liver cancer cells HepG2 were cultured in MEM medium containing 10% FBS, and seeded in a 96-well plate at a density of 10000/well and 100 ⁇ L/well when the cells were in good growth state. Place in a 37°C, 5% CO2 incubator overnight.
  • test compound one of the control compound 1 or compound I-1 ⁇ I-41, RI-4, RI-29 prepared in the previous example
  • DMSO DMSO
  • the 96-well plate was taken out of the incubator, and equilibrated at room temperature for 30 min.
  • IC50 values were calculated using Graphpad 8 software.
  • the experimental results show that, compared with the control compound 1, the compound of the present invention has lower ability to inhibit the proliferation of HepG2 and less toxicity at the cellular level.
  • Test Example 5 Rat pharmacokinetic test
  • Rat pharmacokinetics test each group adopts 3 male SD rats, 180-240g, fasted overnight, oral gavage administration (comparison compound 1 or compound I-1 ⁇ I-41 prepared in the previous embodiment , R-I-4, R-I-29 one) 10mg/kg. Blood was collected before dosing and at 15, 30 minutes and 1, 2, 4, 8, 24 hours after dosing. Blood samples were centrifuged at 8000 rpm at 4°C for 6 minutes, plasma was collected and stored at -20°C.

Abstract

The present invention relates to an AAK1 inhibitor and the use thereof. Specifically, the present invention relates to a compound as represented by formula I, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, a preparation method therefor and the use thereof in the preparation of a drug.

Description

AAK1抑制剂及其用途AAK1 inhibitors and uses thereof
优先权信息priority information
本申请请求2021年09月30日和2022年03月01日向中国国家知识产权局提交的、专利申请号为202111162430X、2022101940945的专利申请的优先权和权益，并且通过参照将其全文并入此处。This application claims the priority and rights of the patent application numbers 202111162430X, 2022101940945 filed with the State Intellectual Property Office of China on September 30, 2021 and March 1, 2022, and is hereby incorporated by reference in its entirety .
技术领域technical field
本发明属于医药化学领域，具体的，本发明涉及可抑制连接蛋白相关激酶1(AAK1)的化合物、其制备方法、组合物以及其在制备药物中的用途。The invention belongs to the field of medicinal chemistry. Specifically, the invention relates to a compound capable of inhibiting annexin-associated kinase 1 (AAK1), its preparation method, composition and its use in the preparation of medicines.
背景技术Background technique
接头蛋白相关激酶1(AP2 associated kinase 1,AAK1)，又称AP-2相关激酶1，是一种丝氨酸/苏氨酸蛋白激酶，属于Ark1/Prk1家族成员。AAK1的前体mRNA可产生不同的剪接变体，表达960个氨基酸的长型AAK1和863个氨基酸的短型AAK1，其中长型AAK1在脑和心脏组织中高表达。AKK1的C端包含网格蛋白结合结构域(CBD1和CBD2)，可与网格蛋白相互作用，刺激AAK1的激酶活性(Henderson et al.,Mol Biol Cell,2007)。AAK1可通过与AP-2接头蛋白复合体结合，调控网格蛋白介导的内吞过程。网格蛋白介导的内吞，是将细胞表面的蛋白转移到内体或溶酶体进行再循环或降解的主要途径(Traub,Nat Rev Mol Cell Biol,2009)。AP-2复合体是网格蛋白的衔接因子，由四种蛋白质组成，包括α亚基、β2亚基、μ2亚基和σ2亚基。其中μ2亚基，又称AP2M1，定位于AP-2复合体的核心部分，介导被转运体(cargo)与网格蛋白包被小窝的相互作用。AP2M1的C端与被转运体胞质端基于酪氨酸的内吞分选YXXφ基序结合，帮助被转运体募集到网格蛋白包被小窝(Royle et al.,J Biol Chem,2002)。而AAK1可磷酸化AP2M1的苏氨酸156，诱导其构象产生变化，促进AP2M1与YXXφ基序的结合，从而增强内吞作用(Jackson et al.,J Cell Biol,2003)。Adapter protein-associated kinase 1 (AAK1), also known as AP-2-associated kinase 1, is a serine/threonine protein kinase that belongs to the Ark1/Prk1 family. The precursor mRNA of AAK1 can produce different splicing variants, expressing the long form of AAK1 of 960 amino acids and the short form of AAK1 of 863 amino acids, and the long form of AAK1 is highly expressed in brain and heart tissues. The C-terminus of AKK1 contains clathrin-binding domains (CBD1 and CBD2), which can interact with clathrin and stimulate the kinase activity of AAK1 (Henderson et al., Mol Biol Cell, 2007). AAK1 can regulate clathrin-mediated endocytosis by binding to the AP-2 adapter protein complex. Clathrin-mediated endocytosis is the main pathway for transferring proteins on the cell surface to endosomes or lysosomes for recycling or degradation (Traub, Nat Rev Mol Cell Biol, 2009). The AP-2 complex is an adapter factor for clathrin and consists of four proteins, including the α subunit, β2 subunit, μ2 subunit, and σ2 subunit. Among them, the μ2 subunit, also known as AP2M1, is located in the core part of the AP-2 complex and mediates the interaction between the transported body (cargo) and clathrin-coated pits. The C-terminus of AP2M1 binds to the tyrosine-based endocytic sorting YXXφ motif at the cytoplasmic end of the transporter, facilitating recruitment of the transporter to clathrin-coated pits (Royle et al., J Biol Chem, 2002) . AAK1 can phosphorylate threonine 156 of AP2M1, induce its conformational change, and promote the combination of AP2M1 and YXXφ motif, thereby enhancing endocytosis (Jackson et al., J Cell Biol, 2003).
研究表明，AAK1基因敲除的小鼠，在福尔马林模型的II期时相中对持续性疼痛的反应显著降低，显著减轻SNL(脊神经结扎)引起的机械痛觉超敏。AAK1小分子抑制剂LP-935509，可显著减轻福尔马林小鼠模型的II期时相中的疼痛反应、小鼠SNL引起的机械痛觉超敏、小鼠CCI(坐骨神经结扎)模型和链脲霉素诱导小鼠糖尿病神经病变模型中的疼 痛反应(Kostich et al.,J Pharmacol Exp Ther,2016)。这些研究结果表明，抑制AAK1的活性可能对疼痛具有潜在的治疗作用。Studies have shown that AAK1 knockout mice have significantly reduced response to persistent pain in the phase II phase of the formalin model, and significantly alleviated mechanical hyperalgesia caused by SNL (spinal nerve ligation). LP-935509, a small molecule inhibitor of AAK1, can significantly attenuate the pain response in the phase II phase of formalin mouse model, mechanical hyperalgesia induced by mouse SNL, mouse CCI (sciatic nerve ligation) model and streptourea Mycin induces pain responses in a mouse model of diabetic neuropathy (Kostich et al., J Pharmacol Exp Ther, 2016). These findings suggest that inhibiting the activity of AAK1 may have potential therapeutic effects on pain.
一项meta分析的结果显示，AAK1基因在家族性帕金森病例的全基因组关联研究(GWAS)中被鉴定为可能的帕金森病易感基因(Latourelle et al.,BMC Med Genet,2009)。这些研究进展表明，抑制AAK1的活性可能对精神分裂症(schizophrenia)、认知缺陷(cognitive deficit)、帕金森病(Parkinson's disease)、双相情感障碍(bipolardisorder)和阿尔茨海默病(Alzheimer’sdisease)等疾病具有潜在疗效。The results of a meta-analysis showed that the AAK1 gene was identified as a possible Parkinson's disease susceptibility gene in a genome-wide association study (GWAS) of familial Parkinson's cases (Latourelle et al., BMC Med Genet, 2009). These research advances suggest that inhibition of AAK1 activity may be beneficial for schizophrenia, cognitive deficit, Parkinson's disease, bipolar disorder and Alzheimer's disease. sdisease) and other diseases have potential therapeutic effects.
病毒进入细胞有内吞和膜融合等多种方式，大多数病毒以内吞作为主要的进入方式，其中由网格蛋白介导的为主要内吞途径。水疱性口炎病毒(VSV)，流感病毒(IAV)，刚果出血热病毒(CCHFV)等都是通过网格蛋白依赖的途径进入细胞。研究发现，多种病毒的感染过程都依赖AAK1，如水疱性口炎病毒(VSV)，狂犬病毒(RABV)，丙型肝炎病毒(HCV)等(Luo et al.,Life(Basel),2020；Wang et al.,Viruses,2019；Neveu et al.,J Virol,2015)。这些结果显示，抑制AAK1的活性可能对病毒感染相关疾病有潜在的疗效。There are many ways for viruses to enter cells, such as endocytosis and membrane fusion. Most viruses use endocytosis as the main entry method, and clathrin-mediated is the main endocytic pathway. Vesicular stomatitis virus (VSV), influenza virus (IAV), and Congo hemorrhagic fever virus (CCHFV) all enter cells through clathrin-dependent pathways. Studies have found that the infection process of various viruses depends on AAK1, such as vesicular stomatitis virus (VSV), rabies virus (RABV), hepatitis C virus (HCV), etc. (Luo et al., Life (Basel), 2020; Wang et al., Viruses, 2019; Neveu et al., J Virol, 2015). These results suggest that inhibition of AAK1 activity may have potential therapeutic effects on viral infection-associated diseases.
发明内容Contents of the invention
本发明旨在提出一种AAK1受体拮抗剂，可用于制备治疗阿尔茨海默症、双相情感障碍、疼痛、帕金森病和精神分裂症的药物。The invention aims to provide an AAK1 receptor antagonist, which can be used to prepare medicines for treating Alzheimer's disease, bipolar disorder, pain, Parkinson's disease and schizophrenia.
在本发明的第一方面，本发明提出了式I所示化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药：In the first aspect of the present invention, the present invention proposes a compound represented by formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug:
Figure PCTCN2022122990-appb-000001
Figure PCTCN2022122990-appb-000001
其中，in,
环A选自
Figure PCTCN2022122990-appb-000002
Ring A is selected from
Figure PCTCN2022122990-appb-000002
R 1选自-H、羟基、氨基、氰基、未取代或被R 12取代的C 1-C 6烷基、未取代或被R 12取代 的C 3-C 6环烷基、卤素或
Figure PCTCN2022122990-appb-000003
所述的被R 12取代的C 1-C 6烷基或被R 12取代的C 3-C 6环烷基中，所述的R 12取代可以是一个或多个取代，所述的R 12各自独立地选自下列取代基：羟基、氨基、氰基、卤素、C 1-C 6烷基或-O-(C 1-C 6烷基)；当取代基为多个时，所述的取代基相同或不同； R 1 is selected from -H, hydroxyl, amino, cyano, C 1 -C 6 alkyl unsubstituted or substituted by R 12 , C 3 -C 6 cycloalkyl unsubstituted or substituted by R 12 , halogen or
Figure PCTCN2022122990-appb-000003
In the C 1 -C 6 alkyl substituted by R 12 or the C 3 -C 6 cycloalkyl substituted by R 12 , the substitution of R 12 may be one or more substitutions, and the R 12 each independently selected from the following substituents: hydroxyl, amino, cyano, halogen, C 1 -C 6 alkyl or -O-(C 1 -C 6 alkyl); when there are multiple substituents, the The substituents are the same or different;
R 11选自未取代或被R 111取代的C 1-C 6烷基、未取代或被R 111取代的-O-C 1-C 6烷基、未取代或被R 111取代的4-8元杂环烷基、或-NR xR y；所述的被R 111取代的C 1-C 6烷基或被R 111取代的4-8元杂环烷基中，所述的R 111取代可以是一个或多个取代，所述的R 111各自独立地选自下列取代基：羟基、氨基、氰基、卤素、C 1-C 6烷基或-O-(C 1-C 6烷基)；当取代基为多个时，所述的取代基相同或不同； R 11 is selected from unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted -OC 1 -C 6 alkyl, unsubstituted or substituted 4-8 membered hetero Cycloalkyl, or -NR x R y ; in the C 1 -C 6 alkyl substituted by R 111 or the 4-8 membered heterocycloalkyl substituted by R 111 , the substitution of R 111 may be One or more substitutions, the R 111 are each independently selected from the following substituents: hydroxyl, amino, cyano, halogen, C 1 -C 6 alkyl or -O-(C 1 -C 6 alkyl); When there are multiple substituents, the substituents are the same or different;
R x和R y各自独立地为被1-5个相同或不同的R z取代的C 1-C 6烷基或R x和R y连同其所连接的N形成含N杂环基，所述R z各自独立地选自-H、卤素、C 1-C 6烷基、-O-(C 1-C 6烷基)或C 3-C 6环烷基；当取代基为多个时，所述的取代基相同或不同； R x and R y are each independently a C 1 -C 6 alkyl group substituted by 1-5 identical or different R z or R x and R y together with the N to which they are attached form an N-containing heterocyclic group, said R z are each independently selected from -H, halogen, C 1 -C 6 alkyl, -O-(C 1 -C 6 alkyl) or C 3 -C 6 cycloalkyl; when there are multiple substituents, The substituents are the same or different;
R 2选自-H、羟基、氨基、氰基、未取代或被R 21取代的C 1-C 6烷基；所述的被R 21取代的C 1-C 6烷基中，所述的R 21取代可以是一个或多个取代，所述的R 21各自独立地选自下列取代基：羟基、氨基、氰基、卤素、C 1-C 6烷基或-O-(C 1-C 6烷基)；当取代基为多个时，所述的取代基相同或不同； R 2 is selected from -H, hydroxyl, amino, cyano, C 1 -C 6 alkyl unsubstituted or substituted by R 21 ; in the C 1 -C 6 alkyl substituted by R 21 , the The substitution of R 21 may be one or more substitutions, and each of the R 21s is independently selected from the following substituents: hydroxyl, amino, cyano, halogen, C 1 -C 6 alkyl or -O-(C 1 -C 6 alkyl); when there are multiple substituents, the substituents are the same or different;
环B选自
Figure PCTCN2022122990-appb-000004
Figure PCTCN2022122990-appb-000005
Figure PCTCN2022122990-appb-000006
其中“*”表示与
Figure PCTCN2022122990-appb-000007
连接且“**”表示与环A连接； Ring B selected from
Figure PCTCN2022122990-appb-000004
Figure PCTCN2022122990-appb-000005
Figure PCTCN2022122990-appb-000006
where "*" means the same as
Figure PCTCN2022122990-appb-000007
and "**" indicates connection with ring A;
R 3和R 4各自独立地选自-H、-SF 5、羟基、氨基、氰基、未取代或被R 31取代的C 1-C 6烷基、未取代或被R 31取代的C 3-C 6环烷基、卤素或
Figure PCTCN2022122990-appb-000008
所述的被R 31取代的C 1-C 6烷基或被R 31取代的C 3-C 6环烷基中，所述的R 31取代可以是一个或多个取代，所述的R 31各自独立地选自下列取代基：羟基、氨基、氰基、卤素、C 1-C 6烷基或-O-(C 1-C 6烷基)；当 取代基为多个时，所述的取代基相同或不同； R 3 and R 4 are each independently selected from -H, -SF 5 , hydroxyl, amino, cyano, C 1 -C 6 alkyl unsubstituted or substituted by R 31 , C 3 unsubstituted or substituted by R 31 -C 6 cycloalkyl, halogen or
Figure PCTCN2022122990-appb-000008
In the C 1 -C 6 alkyl substituted by R 31 or the C 3 -C 6 cycloalkyl substituted by R 31 , the substitution of R 31 may be one or more substitutions, and the R 31 each independently selected from the following substituents: hydroxyl, amino, cyano, halogen, C 1 -C 6 alkyl or -O-(C 1 -C 6 alkyl); when there are multiple substituents, the The substituents are the same or different;
R 32选自-H、未取代或被R 321取代的C 1-C 6烷基、或、未取代或被R 321取代的C 3-C 6环烷基；所述的被R 321取代的C 1-C 6烷基或被R 31取代的C 3-C 6环烷基中，所述的R 321取代可以是一个或多个取代，所述的R 321各自独立地选自下列取代基：羟基、氨基、氰基、卤素、C 1-C 6烷基或-O-(C 1-C 6烷基)；当取代基为多个时，所述的取代基相同或不同； R 32 is selected from -H, unsubstituted or substituted by R 321 C 1 -C 6 alkyl, or, unsubstituted or substituted by R 321 C 3 -C 6 cycloalkyl; said substituted by R 321 In C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl substituted by R 31 , the substitution of R 321 may be one or more substitutions, and each of the R 321 is independently selected from the following substituents : hydroxyl, amino, cyano, halogen, C 1 -C 6 alkyl or -O-(C 1 -C 6 alkyl); when there are multiple substituents, the substituents are the same or different;
R 5选自-H、氰基、被1-5个相同或不同的卤素取代的C 1-C 6烷基、被1-5个相同或不同的卤素取代的C 3-C 6环烷基、C 3-C 6环烷基或C 1-C 6烷基； R 5 is selected from -H, cyano, C 1 -C 6 alkyl substituted by 1-5 identical or different halogens, C 3 -C 6 cycloalkyl substituted by 1-5 identical or different halogens , C 3 -C 6 cycloalkyl or C 1 -C 6 alkyl;
R 6选自羟基、氨基、氰基、
Figure PCTCN2022122990-appb-000009
未取代或被R 61取代的C 1-C 6烷基、卤素或未取代或被R 61取代的C 3-C 6环烷基；所述的被R 61取代的C 1-C 6烷基或被R 61取代的C 3-C 6环烷基中，所述的R 61取代可以是一个或多个取代，所述的R 61各自独立地选自下列取代基：羟基、氨基、氰基、卤素、被1-6个相同或不同卤素取代的C 1-C 6烷基、被1-6个相同或不同卤素取代的-O-(C 1-C 6烷基)、C 1-C 6烷基或-O-(C 1-C 6烷基)；当取代基为多个时，所述的取代基相同或不同。 R is selected from hydroxyl, amino, cyano,
Figure PCTCN2022122990-appb-000009
Unsubstituted or substituted by R 61 C 1 -C 6 alkyl, halogen or unsubstituted or substituted by R 61 C 3 -C 6 cycloalkyl; said C 1 -C 6 alkyl substituted by R 61 Or in the C 3 -C 6 cycloalkyl group substituted by R 61 , the R 61 substitution can be one or more substitutions, and each of the R 61 is independently selected from the following substituents: hydroxyl, amino, cyano , halogen, C 1 -C 6 alkyl substituted by 1-6 identical or different halogens, -O-(C 1 -C 6 alkyl) substituted by 1-6 identical or different halogens, C 1 -C 6 alkyl or -O-(C 1 -C 6 alkyl); when there are multiple substituents, the substituents are the same or different.
在本发明一任选实施方案中，为式I所示化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药：In an optional embodiment of the present invention, it is a compound represented by formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug:
Figure PCTCN2022122990-appb-000010
Figure PCTCN2022122990-appb-000010
其中，in,
环A选自
Figure PCTCN2022122990-appb-000011
Ring A is selected from
Figure PCTCN2022122990-appb-000011
R 1选自-H、羟基、氨基、氰基、未取代或被R 12取代的C 1-C 6烷基、未取代或被R 12取代的C 3-C 6环烷基、卤素或
Figure PCTCN2022122990-appb-000012
所述的被R 12取代的C 1-C 6烷基或被R 12取代的C 3-C 6环烷基中，所述的R 12取代可以是一个或多个取代，述的R 12各自独立地选自下列取代基：羟基、氨基、氰基、卤素、C 1-C 6烷基或-O-(C 1-C 6烷基)；当取代基为多个时，所述的取代 基相同或不同； R 1 is selected from -H, hydroxyl, amino, cyano, C 1 -C 6 alkyl unsubstituted or substituted by R 12 , C 3 -C 6 cycloalkyl unsubstituted or substituted by R 12 , halogen or
Figure PCTCN2022122990-appb-000012
In the C 1 -C 6 alkyl substituted by R 12 or the C 3 -C 6 cycloalkyl substituted by R 12 , the substitution of R 12 may be one or more substitutions, each of the R 12 Independently selected from the following substituents: hydroxyl, amino, cyano, halogen, C 1 -C 6 alkyl or -O-(C 1 -C 6 alkyl); when there are multiple substituents, the substituent same or different basis;
R 11选自未取代或被R 111取代的C 1-C 6烷基、未取代或被R 111取代的4-8元杂环烷基、或、-NR xR y；所述的被R 111取代的C 1-C 6烷基或被R 111取代的4-8元杂环烷基中，所述的R 111取代可以是一个或多个取代，述的R 111各自独立地选自下列取代基：羟基、氨基、氰基、卤素、C 1-C 6烷基或-O-(C 1-C 6烷基)；当取代基为多个时，所述的取代基相同或不同； R 11 is selected from C 1 -C 6 alkyl unsubstituted or substituted by R 111 , 4-8 membered heterocycloalkyl unsubstituted or substituted by R 111 , or -NR x R y ; In the C 1 -C 6 alkyl substituted by 111 or the 4-8 membered heterocycloalkyl substituted by R 111 , the R 111 substitution may be one or more substitutions, and each of the R 111 is independently selected from the following Substituent: hydroxyl, amino, cyano, halogen, C 1 -C 6 alkyl or -O-(C 1 -C 6 alkyl); when there are multiple substituents, the substituents are the same or different;
R x和R y各自独立地为被1-5个相同或不同的R z取代的C 1-C 6烷基，所述R z各自独立地选自-H、卤素、-O-(C 1-C 6烷基)或C 3-C 6环烷基；当取代基为多个时，所述的取代基相同或不同； R x and R y are each independently C 1 -C 6 alkyl substituted by 1 to 5 identical or different R z , each of which R z is independently selected from -H, halogen, -O-(C 1 -C 6 alkyl) or C 3 -C 6 cycloalkyl; when there are multiple substituents, the substituents are the same or different;
R 2选自-H、羟基、氨基、氰基、未取代或被R 21取代的C 1-C 6烷基；所述的被R 21取代的C 1-C 6烷基中，所述的R 21取代可以是一个或多个取代，所述的R 21各自独立地选自下列取代基：羟基、氨基、氰基、卤素、C 1-C 6烷基或-O-(C 1-C 6烷基)；当取代基为多个时，所述的取代基相同或不同； R 2 is selected from -H, hydroxyl, amino, cyano, C 1 -C 6 alkyl unsubstituted or substituted by R 21 ; in the C 1 -C 6 alkyl substituted by R 21 , the The substitution of R 21 may be one or more substitutions, and each of the R 21s is independently selected from the following substituents: hydroxyl, amino, cyano, halogen, C 1 -C 6 alkyl or -O-(C 1 -C 6 alkyl); when there are multiple substituents, the substituents are the same or different;
环B选自
Figure PCTCN2022122990-appb-000013
Figure PCTCN2022122990-appb-000014
其中“*”表示与
Figure PCTCN2022122990-appb-000015
连接且“**”表示与环A连接； Ring B selected from
Figure PCTCN2022122990-appb-000013
Figure PCTCN2022122990-appb-000014
where "*" means the same as
Figure PCTCN2022122990-appb-000015
and "**" indicates connection with ring A;
R 3和R 4各自独立地选自-H、-SF 5、羟基、氨基、氰基、未取代或被R 31取代的C 1-C 6烷基、未取代或被R 31取代的C 3-C 6环烷基、卤素或
Figure PCTCN2022122990-appb-000016
所述的被R 31取代的C 1-C 6烷基或被R 31取代的C 3-C 6环烷基中，所述的R 31取代可以是一个或多个取代，所述的R 31各自独立地选自下列取代基：羟基、氨基、氰基、卤素、C 1-C 6烷基或-O-(C 1-C 6烷基)；当取代基为多个时，所述的取代基相同或不同； R 3 and R 4 are each independently selected from -H, -SF 5 , hydroxyl, amino, cyano, C 1 -C 6 alkyl unsubstituted or substituted by R 31 , C 3 unsubstituted or substituted by R 31 -C 6 cycloalkyl, halogen or
Figure PCTCN2022122990-appb-000016
In the C 1 -C 6 alkyl substituted by R 31 or the C 3 -C 6 cycloalkyl substituted by R 31 , the substitution of R 31 may be one or more substitutions, and the R 31 each independently selected from the following substituents: hydroxyl, amino, cyano, halogen, C 1 -C 6 alkyl or -O-(C 1 -C 6 alkyl); when there are multiple substituents, the The substituents are the same or different;
R 32选自-H、未取代或被R 321取代的C 1-C 6烷基、或、未取代或被R 321取代的C 3-C 6环烷基；所述的被R 321取代的C 1-C 6烷基或被R 31取代的C 3-C 6环烷基中，所述的R 321取代可以是一个或多个取代，所述的R 321各自独立地选自下列取代基：羟基、氨基、氰基、卤素、C 1-C 6烷基或-O-(C 1-C 6烷基)；当取代基为多个时，所述的取代基相同或不同； R 32 is selected from -H, unsubstituted or substituted by R 321 C 1 -C 6 alkyl, or, unsubstituted or substituted by R 321 C 3 -C 6 cycloalkyl; said substituted by R 321 In C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl substituted by R 31 , the substitution of R 321 may be one or more substitutions, and each of the R 321 is independently selected from the following substituents : hydroxyl, amino, cyano, halogen, C 1 -C 6 alkyl or -O-(C 1 -C 6 alkyl); when there are multiple substituents, the substituents are the same or different;
R 5选自-H、氰基、被1-5个相同或不同的卤素取代的C 1-C 6烷基、被1-5个相同或不同的 卤素取代的C 3-C 6环烷基、C 3-C 6环烷基或C 1-C 6烷基； R 5 is selected from -H, cyano, C 1 -C 6 alkyl substituted by 1-5 identical or different halogens, C 3 -C 6 cycloalkyl substituted by 1-5 identical or different halogens , C 3 -C 6 cycloalkyl or C 1 -C 6 alkyl;
R 6选自羟基、氨基、氰基、
Figure PCTCN2022122990-appb-000017
未取代或被R 61取代的C 1-C 6烷基、卤素或未取代或被R 61取代的C 3-C 6环烷基；所述的被R 61取代的C 1-C 6烷基或被R 61取代的C 3-C 6环烷基中，所述的R 61取代可以是一个或多个取代，述的R 61各自独立地选自下列取代基：羟基、氨基、氰基、卤素、被1-6个相同或不同卤素取代的C 1-C 6烷基、被1-6个相同或不同卤素取代的-O-(C 1-C 6烷基)、C 1-C 6烷基或-O-(C 1-C 6烷基)；当取代基为多个时，所述的取代基相同或不同。 R is selected from hydroxyl, amino, cyano,
Figure PCTCN2022122990-appb-000017
Unsubstituted or substituted by R 61 C 1 -C 6 alkyl, halogen or unsubstituted or substituted by R 61 C 3 -C 6 cycloalkyl; said C 1 -C 6 alkyl substituted by R 61 Or in a C 3 -C 6 cycloalkyl group substituted by R 61 , the substitution of R 61 may be one or more substitutions, and each of the R 61s is independently selected from the following substituents: hydroxyl, amino, cyano, Halogen, C 1 -C 6 alkyl substituted by 1-6 identical or different halogens, -O-(C 1 -C 6 alkyl) substituted by 1-6 identical or different halogens, C 1 -C 6 Alkyl or -O-(C 1 -C 6 alkyl); when there are multiple substituents, the substituents are the same or different.
在本发明一任选实施方案中，式I所示化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药为：In an optional embodiment of the present invention, the compound represented by formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug is:
Figure PCTCN2022122990-appb-000018
Figure PCTCN2022122990-appb-000018
其中，in,
环A选自
Figure PCTCN2022122990-appb-000019
Ring A is selected from
Figure PCTCN2022122990-appb-000019
R 1选自-H、羟基、氨基、氰基、未取代或被R 12取代的C 1-C 6烷基、未取代或被R 12取代的C 3-C 6环烷基、卤素或
Figure PCTCN2022122990-appb-000020
所述的被R 12取代的C 1-C 6烷基或被R 12取代的C 3-C 6环烷基中，所述的R 12取代可以是一个或多个取代，所述的R 12各自独立地选自下列取代基：羟基、氨基、氰基、卤素、C 1-C 6烷基或-O-(C 1-C 6烷基)；当取代基为多个时，所述的取代基相同或不同； R 1 is selected from -H, hydroxyl, amino, cyano, C 1 -C 6 alkyl unsubstituted or substituted by R 12 , C 3 -C 6 cycloalkyl unsubstituted or substituted by R 12 , halogen or
Figure PCTCN2022122990-appb-000020
In the C 1 -C 6 alkyl substituted by R 12 or the C 3 -C 6 cycloalkyl substituted by R 12 , the substitution of R 12 may be one or more substitutions, and the R 12 each independently selected from the following substituents: hydroxyl, amino, cyano, halogen, C 1 -C 6 alkyl or -O-(C 1 -C 6 alkyl); when there are multiple substituents, the The substituents are the same or different;
R 11选自未取代或被R 111取代的C 1-C 6烷基、未取代或被R 111取代的4-8元杂环烷基、或、-NR xR y；所述的被R 111取代的C 1-C 6烷基或被R 111取代的4-8元杂环烷基中，所述的R 111取代可以是一个或多个取代，所述的R 111各自独立地选自下列取代基：羟基、氨基、氰基、卤素、C 1-C 6烷基或-O-(C 1-C 6烷基)；当取代基为多个时，所述的取代基相同或不同； R 11 is selected from C 1 -C 6 alkyl unsubstituted or substituted by R 111 , 4-8 membered heterocycloalkyl unsubstituted or substituted by R 111 , or -NR x R y ; In the C 1 -C 6 alkyl substituted by 111 or the 4-8 membered heterocycloalkyl substituted by R 111 , the R 111 substitution may be one or more substitutions, and each of the R 111 is independently selected from The following substituents: hydroxyl, amino, cyano, halogen, C 1 -C 6 alkyl or -O-(C 1 -C 6 alkyl); when there are multiple substituents, the substituents are the same or different ;
R x和R y各自独立地为被1-5个相同或不同的R z取代的C 1-C 6烷基，所述R z各自独立地 选自-H、卤素、-O-(C 1-C 6烷基)或C 3-C 6环烷基；当取代基为多个时，所述的取代基相同或不同； R x and R y are each independently C 1 -C 6 alkyl substituted by 1 to 5 identical or different R z , each of which R z is independently selected from -H, halogen, -O-(C 1 -C 6 alkyl) or C 3 -C 6 cycloalkyl; when there are multiple substituents, the substituents are the same or different;
R 2选自-H、羟基、氨基、氰基、未取代或被R 21取代的C 1-C 6烷基；所述的被R 21取代的C 1-C 6烷基中，所述的R 21取代可以是一个或多个取代，所述的R 21各自独立地选自下列取代基：羟基、氨基、氰基、卤素、C 1-C 6烷基或-O-(C 1-C 6烷基)；当取代基为多个时，所述的取代基相同或不同； R 2 is selected from -H, hydroxyl, amino, cyano, C 1 -C 6 alkyl unsubstituted or substituted by R 21 ; in the C 1 -C 6 alkyl substituted by R 21 , the The substitution of R 21 may be one or more substitutions, and each of the R 21s is independently selected from the following substituents: hydroxyl, amino, cyano, halogen, C 1 -C 6 alkyl or -O-(C 1 -C 6 alkyl); when there are multiple substituents, the substituents are the same or different;
环B选自
Figure PCTCN2022122990-appb-000021
Figure PCTCN2022122990-appb-000022
其中“*”表示与
Figure PCTCN2022122990-appb-000023
连接且“**”表示与环A连接； Ring B selected from
Figure PCTCN2022122990-appb-000021
Figure PCTCN2022122990-appb-000022
where "*" means the same as
Figure PCTCN2022122990-appb-000023
and "**" indicates connection with ring A;
R 3和R 4各自独立地选自-H、-SF 5、羟基、氨基、氰基、未取代或被R 31取代的C 1-C 6烷基、未取代或被R 31取代的C 3-C 6环烷基、卤素或
Figure PCTCN2022122990-appb-000024
所述的被R 31取代的C 1-C 6烷基或被R 31取代的C 3-C 6环烷基中，所述的R 31取代可以是一个或多个取代，述的R 31各自独立地选自下列取代基：羟基、氨基、氰基、卤素、C 1-C 6烷基或-O-(C 1-C 6烷基)；当取代基为多个时，所述的取代基相同或不同； R 3 and R 4 are each independently selected from -H, -SF 5 , hydroxyl, amino, cyano, C 1 -C 6 alkyl unsubstituted or substituted by R 31 , C 3 unsubstituted or substituted by R 31 -C 6 cycloalkyl, halogen or
Figure PCTCN2022122990-appb-000024
In the C 1 -C 6 alkyl substituted by R 31 or the C 3 -C 6 cycloalkyl substituted by R 31 , the substitution of R 31 may be one or more substitutions, each of the R 31 Independently selected from the following substituents: hydroxyl, amino, cyano, halogen, C 1 -C 6 alkyl or -O-(C 1 -C 6 alkyl); when there are multiple substituents, the substituent same or different basis;
R 32选自-H、未取代或被R 331取代的C 1-C 6烷基、或、未取代或被R 321取代的C 3-C 6环烷基；所述的被R 321取代的C 1-C 6烷基或被R 31取代的C 3-C 6环烷基中，所述的R 321取代可以是一个或多个取代，述的R 321各自独立地选自下列取代基：羟基、氨基、氰基、卤素、C 1-C 6烷基或-O-(C 1-C 6烷基)；当取代基为多个时，所述的取代基相同或不同； R 32 is selected from -H, unsubstituted or substituted by R 331 C 1 -C 6 alkyl, or, unsubstituted or substituted by R 321 C 3 -C 6 cycloalkyl; said substituted by R 321 In C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl substituted by R 31 , the substitution of R 321 may be one or more substitutions, and each of the R 321 is independently selected from the following substituents: Hydroxy, amino, cyano, halogen, C 1 -C 6 alkyl or -O-(C 1 -C 6 alkyl); when there are multiple substituents, the substituents are the same or different;
R 5选自-H、氰基、被1-5个相同或不同的卤素取代的C 1-C 6烷基、被1-5个相同或不同的卤素取代的C 3-C 6环烷基、卤素、C 3-C 6环烷基或C 1-C 6烷基； R 5 is selected from -H, cyano, C 1 -C 6 alkyl substituted by 1-5 identical or different halogens, C 3 -C 6 cycloalkyl substituted by 1-5 identical or different halogens , halogen, C 3 -C 6 cycloalkyl or C 1 -C 6 alkyl;
R 6选自羟基、氨基、氰基、
Figure PCTCN2022122990-appb-000025
未取代或被R 61取代的C 1-C 6烷基、卤素或未取代或被R 61取代的C 3-C 6环烷基；所述的被R 61取代的C 1-C 6烷基或被R 61取代的C 3-C 6环烷基中，所述的R 61取代可以是一个或多个取代，述的R 61各自独立地选自下列取代基：羟基、氨基、氰基、卤素、C 1-C 6烷基或-O-(C 1-C 6烷基)；当取代基为多个时，所述的取代基相同或不同。 R is selected from hydroxyl, amino, cyano,
Figure PCTCN2022122990-appb-000025
Unsubstituted or substituted by R 61 C 1 -C 6 alkyl, halogen or unsubstituted or substituted by R 61 C 3 -C 6 cycloalkyl; said C 1 -C 6 alkyl substituted by R 61 Or in a C 3 -C 6 cycloalkyl group substituted by R 61 , the substitution of R 61 may be one or more substitutions, and each of the R 61s is independently selected from the following substituents: hydroxyl, amino, cyano, Halogen, C 1 -C 6 alkyl or -O-(C 1 -C 6 alkyl); when there are multiple substituents, the substituents are the same or different.
在本发明一任选实施方案中，如式II所示化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药为：In an optional embodiment of the present invention, the compound represented by formula II, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug is:
Figure PCTCN2022122990-appb-000026
Figure PCTCN2022122990-appb-000026
其中，环A、环B、R 1、R 2、R 3、R 4、R 5、R 6的定义如前文所述。 Wherein, ring A, ring B, R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are as defined above.
在本发明一任选实施方案中，如式III所示化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药为：In an optional embodiment of the present invention, the compound represented by formula III, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug is:
Figure PCTCN2022122990-appb-000027
Figure PCTCN2022122990-appb-000027
其中，当环A和环B相同时，R 1和R 3不同，环A、环B、R 1、R 3、R 5、R 6的定义如前文所述。 Wherein, when ring A and ring B are the same, R 1 and R 3 are different, and ring A, ring B, R 1 , R 3 , R 5 , and R 6 are as defined above.
在本发明一任选实施方案中，如式IV所示化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药为：In an optional embodiment of the present invention, the compound represented by formula IV, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug is:
Figure PCTCN2022122990-appb-000028
Figure PCTCN2022122990-appb-000028
其中，R 3、R 4和R 6的定义如前文所述。 Wherein, R 3 , R 4 and R 6 are as defined above.
在本发明一任选实施方案中，如式IV’所示化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药为：In an optional embodiment of the present invention, the compound shown in formula IV', its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug is:
Figure PCTCN2022122990-appb-000029
Figure PCTCN2022122990-appb-000029
其中，R 3、R 4和R 6的定义如前文所述。 Wherein, R 3 , R 4 and R 6 are as defined above.
在本发明一任选实施方案中，如式IV”所示化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药为：In an optional embodiment of the present invention, the compound represented by formula IV", its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug is:
Figure PCTCN2022122990-appb-000030
Figure PCTCN2022122990-appb-000030
其中，R 3、R 4和R 6的定义如前文所述。 Wherein, R 3 , R 4 and R 6 are as defined above.
在本发明一任选实施方案中，如式V所示化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药为：In an optional embodiment of the present invention, the compound represented by formula V, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug is:
Figure PCTCN2022122990-appb-000031
Figure PCTCN2022122990-appb-000031
其中，环C为未取代或被R 61取代的C 3-C 6环烷基。 Wherein, Ring C is C 3 -C 6 cycloalkyl which is unsubstituted or substituted by R 61 .
在本发明一任选实施方案中，如式VI所示化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药为：In an optional embodiment of the present invention, the compound represented by formula VI, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug is:
Figure PCTCN2022122990-appb-000032
Figure PCTCN2022122990-appb-000032
其中，X 1、X 2、X 3、X 4分别独立地为C或N； Wherein, X 1 , X 2 , X 3 , and X 4 are independently C or N;
且X 1和X 2不同，当X 1为N时，X 3为N，当X 2为N时，X 4为N。 And X 1 and X 2 are different, when X 1 is N, X 3 is N, when X 2 is N, X 4 is N.
在本发明一任选实施方案中，环B选自
Figure PCTCN2022122990-appb-000033
Figure PCTCN2022122990-appb-000034
In an optional embodiment of the present invention, Ring B is selected from
Figure PCTCN2022122990-appb-000033
Figure PCTCN2022122990-appb-000034
在本发明一任选实施方案中，环A为
Figure PCTCN2022122990-appb-000035
In an optional embodiment of the present invention, Ring A is
Figure PCTCN2022122990-appb-000035
在本发明一任选实施方案中，R 2为-H。 In an optional embodiment of the invention, R2 is -H.
在本发明一任选实施方案中，R 1为-H。 In an optional embodiment of the invention, R1 is -H.
在本发明一任选实施方案中，当R 1为未取代或被R 12取代的C 1-C 6烷基时，所述C 1-C 6烷基为甲基、乙基、正丙基或异丙基。 In an optional embodiment of the present invention, when R 1 is C 1 -C 6 alkyl unsubstituted or substituted by R 12 , said C 1 -C 6 alkyl is methyl, ethyl, n-propyl or isopropyl.
在本发明一任选实施方案中，当R 1为未取代或被R 12取代的C 1-C 6烷基时，所述C 1-C 6烷基为甲基。 In an optional embodiment of the present invention, when R 1 is an unsubstituted or substituted C 1 -C 6 alkyl group, said C 1 -C 6 alkyl group is methyl.
在本发明一任选实施方案中，当R 1为被R 12取代的C 1-C 6烷基时，所述R 12为卤素。 In an optional embodiment of the present invention, when R 1 is C 1 -C 6 alkyl substituted by R 12 , said R 12 is halogen.
在本发明一任选实施方案中，当R 12为卤素时，所述卤素为F或Cl。 In an optional embodiment of the present invention, when R12 is halogen, said halogen is F or Cl.
在本发明一任选实施方案中，当R 12为卤素时，所述卤素为F。 In an optional embodiment of the present invention, when R12 is halogen, said halogen is F.
在本发明一任选实施方案中，当R 1为被R 12取代的C 1-C 6烷基时，所述R 12取代为1个、2个或3个。 In an optional embodiment of the present invention, when R 1 is C 1 -C 6 alkyl substituted by R 12 , said R 12 is substituted by 1, 2 or 3.
在本发明一任选实施方案中，当R 1为被R 12取代的C 1-C 6烷基时，所述R 12取代为2个。 In an optional embodiment of the present invention, when R 1 is a C 1 -C 6 alkyl group substituted by R 12 , the number of R 12 substitutions is 2.
在本发明一任选实施方案中，R 1为
Figure PCTCN2022122990-appb-000036
In an optional embodiment of the present invention, R is
Figure PCTCN2022122990-appb-000036
在本发明一任选实施方案中，R 11为未取代或被R 111取代的-O-C 1-C 6烷基时，所述-O-C 1-C 6烷基为-O-甲基、-O-乙基、-O-正丙基或-O-异丙基。 In an optional embodiment of the present invention, when R 11 is unsubstituted or substituted by R 111 -OC 1 -C 6 alkyl, the -OC 1 -C 6 alkyl is -O-methyl, -O -ethyl, -O-n-propyl or -O-isopropyl.
在本发明一任选实施方案中，R 11为-NR xR y。 In an optional embodiment of the invention, R 11 is -NR x R y .
在本发明一任选实施方案中，当R x和R y为被1-5个相同或不同的R z取代的C 1-C 6烷基时，所述C 1-C 6烷基为甲基、乙基、正丙基或异丙基。 In an optional embodiment of the present invention, when R x and R y are C 1 -C 6 alkyl substituted by 1-5 identical or different R z , said C 1 -C 6 alkyl is methane radical, ethyl, n-propyl or isopropyl.
在本发明一任选实施方案中，当R x和R y为被1-5个相同或不同的R z取代的C 1-C 6烷基时，所述C 1-C 6烷基为甲基。 In an optional embodiment of the present invention, when R x and R y are C 1 -C 6 alkyl substituted by 1-5 identical or different R z , said C 1 -C 6 alkyl is methane base.
在本发明一任选实施方案中，当R x和R y为被1-5个相同或不同的R z取代的C 1-C 6烷基时，所R z取代为1个、2个或3个。 In an optional embodiment of the present invention, when R x and R y are C 1 -C 6 alkyl substituted by 1-5 same or different R z , R z is substituted with 1, 2 or 3.
在本发明一任选实施方案中，当R x和R y为被1-5个相同或不同的R z取代的C 1-C 6烷基时，所R z取代为1个，2个或3个。 In an optional embodiment of the present invention, when R x and R y are C 1 -C 6 alkyl substituted by 1-5 same or different R z , the R z is substituted with 1, 2 or 3.
在本发明一任选实施方案中，R z为-H。 In an optional embodiment of the invention, Rz is -H.
在本发明一任选实施方案中，当R x和R y连同其所连接的N形成含N杂环基时，所述N 杂环基为
Figure PCTCN2022122990-appb-000037
In an optional embodiment of the present invention, when R x and R y together with the N to which they are attached form an N-containing heterocyclic group, the N heterocyclic group is
Figure PCTCN2022122990-appb-000037
在本发明一任选实施方案中，当R 11为未取代或被R 111取代的4-8元杂环烷基时，所述4-8元杂环烷基为氮杂环丁基、氮杂环戊基、氧杂环丁基、吡咯烷基、四氢呋喃基、吡唑烷基、咪唑烷基、噁唑烷基、吗啉基、吡咯烷基、吗啉基或哌嗪基。 In an optional embodiment of the present invention, when R 11 is a 4-8 membered heterocycloalkyl group that is unsubstituted or substituted by R 111 , the 4-8 membered heterocycloalkyl group is azetidinyl, nitrogen Heterocyclopentyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, morpholinyl, pyrrolidinyl, morpholinyl or piperazinyl.
在本发明一任选实施方案中，当R 11为未取代或被R 111取代的4-8元杂环烷基时，所述4-8元杂环烷为氮杂环戊基。 In an optional embodiment of the present invention, when R 11 is a 4-8 membered heterocycloalkyl group that is unsubstituted or substituted by R 111 , the 4-8 membered heterocycloalkane is azacyclopentyl.
在本发明一任选实施方案中，R 4为-H。 In an optional embodiment of the invention, R4 is -H.
在本发明一任选实施方案中，R 3为-H。 In an optional embodiment of the invention, R3 is -H.
在本发明一任选实施方案中，当R 3为卤素时，所述卤素为F或Cl。 In an optional embodiment of the present invention, when R3 is halogen, said halogen is F or Cl.
在本发明一任选实施方案中，R 3为-SF 5。 In an optional embodiment of the invention, R 3 is -SF 5 .
在本发明一任选实施方案中，R 3为
Figure PCTCN2022122990-appb-000038
In an optional embodiment of the present invention, R 3 is
Figure PCTCN2022122990-appb-000038
在本发明一任选实施方案中，当R 32未取代或被R 321取代的C 1-C 6烷基时，所述C 1-C 6烷基为甲基、乙基、正丙基或异丙基。 In an optional embodiment of the present invention, when R 32 is a C 1 -C 6 alkyl group that is unsubstituted or substituted by R 321 , the C 1 -C 6 alkyl group is methyl, ethyl, n-propyl or Isopropyl.
在本发明一任选实施方案中，当R 32未取代或被R 321取代的C 1-C 6烷基时，所述C 1-C 6烷基为甲基。 In an optional embodiment of the present invention, when R 32 is a C 1 -C 6 alkyl group that is unsubstituted or substituted by R 321 , the C 1 -C 6 alkyl group is methyl.
在本发明一任选实施方案中，当R 3为未取代或被R 31取代的C 1-C 6烷基时，所述C 1-C 6烷基为甲基、乙基、正丙基或异丙基。 In an optional embodiment of the present invention, when R 3 is a C 1 -C 6 alkyl unsubstituted or substituted by R 31 , the C 1 -C 6 alkyl is methyl, ethyl, n-propyl or isopropyl.
在本发明一任选实施方案中，当R 3为未取代或被R 31取代的C 1-C 6烷基时，所述C 1-C 6烷基为甲基或乙基。 In an optional embodiment of the present invention, when R 3 is a C 1 -C 6 alkyl group that is unsubstituted or substituted by R 31 , the C 1 -C 6 alkyl group is methyl or ethyl.
在本发明一任选实施方案中，当R 3为被R 31取代的C 1-C 6烷基时，所述R 31为卤素。 In an optional embodiment of the present invention, when R 3 is C 1 -C 6 alkyl substituted by R 31 , said R 31 is halogen.
在本发明一任选实施方案中，当R 31为卤素时，所述卤素为F或Cl。 In an optional embodiment of the present invention, when R31 is halogen, said halogen is F or Cl.
在本发明一任选实施方案中，当R 31为卤素时，所述卤素为F。 In an optional embodiment of the invention, when R31 is halogen, said halogen is F.
在本发明一任选实施方案中，当R 3为被R 31取代的C 1-C 6烷基时，所述卤素取代为1个、2个或3个。 In an optional embodiment of the present invention, when R 3 is C 1 -C 6 alkyl substituted by R 31 , the halogen substitution is 1, 2 or 3.
在本发明一任选实施方案中，当R 3为未取代或被R 31取代的C 3-C 6环烷基时，所述C 3-C 6环烷基为环丙基。 In an optional embodiment of the present invention, when R 3 is a C 3 -C 6 cycloalkyl group that is unsubstituted or substituted by R 31 , the C 3 -C 6 cycloalkyl group is cyclopropyl.
在本发明一任选实施方案中，当R 5为C 1-C 6烷基时，所述C 1-C 6烷基为甲基、乙基、正丙基或异丙基。 In an optional embodiment of the present invention, when R 5 is a C 1 -C 6 alkyl group, the C 1 -C 6 alkyl group is methyl, ethyl, n-propyl or isopropyl.
在本发明一任选实施方案中，当R 5为C 1-C 6烷基时，所述C 1-C 6烷基为甲基。 In an optional embodiment of the present invention, when R 5 is C 1 -C 6 alkyl, said C 1 -C 6 alkyl is methyl.
在本发明一任选实施方案中，当R 5为C 3-C 6环烷基时，所述C 3-C 6环烷基为环丙基。 In an optional embodiment of the present invention, when R 5 is C 3 -C 6 cycloalkyl, said C 3 -C 6 cycloalkyl is cyclopropyl.
在本发明一任选实施方案中，R 6为
Figure PCTCN2022122990-appb-000039
In an optional embodiment of the present invention, R 6 is
Figure PCTCN2022122990-appb-000039
在本发明一任选实施方案中，当R 6为未取代或被R 61取代的C 1-C 6烷基时，所述C 1-C 6烷基为甲基、乙基、正丙基或异丙基。 In an optional embodiment of the present invention, when R 6 is C 1 -C 6 alkyl unsubstituted or substituted by R 61 , said C 1 -C 6 alkyl is methyl, ethyl, n-propyl or isopropyl.
在本发明一任选实施方案中，当R 6为未取代或被R 61取代的C 1-C 6烷基时，所述C 1-C 6烷基为异丙基。 In an optional embodiment of the present invention, when R 6 is C 1 -C 6 alkyl unsubstituted or substituted by R 61 , said C 1 -C 6 alkyl is isopropyl.
在本发明一任选实施方案中，当R 6为被R 61取代的C 1-C 6烷基时，所述R 61为卤素。 In an optional embodiment of the present invention, when R 6 is C 1 -C 6 alkyl substituted by R 61 , said R 61 is halogen.
在本发明一任选实施方案中，当R 61为卤素时，所述卤素为F或Cl。 In an optional embodiment of the present invention, when R 61 is halogen, said halogen is F or Cl.
在本发明一任选实施方案中，当R 61为卤素时，所述卤素为F。 In an optional embodiment of the present invention, when R 61 is halogen, said halogen is F.
在本发明一任选实施方案中，当R 6为被R 61取代的C 1-C 6烷基时，所述R 61取代为6个。 In an optional embodiment of the present invention, when R 6 is C 1 -C 6 alkyl substituted by R 61 , the number of R 61 substitutions is 6.
在本发明一任选实施方案中，当R 6为未取代或被R 61取代的C 3-C 6环烷基时，所述C 3-C 6环烷基为环丙基或环丁基。 In an optional embodiment of the present invention, when R 6 is a C 3 -C 6 cycloalkyl group that is unsubstituted or substituted by R 61 , the C 3 -C 6 cycloalkyl group is cyclopropyl or cyclobutyl .
在本发明一任选实施方案中，当R 6为被R 61取代的C 3-C 6环烷基时，所述R 61为卤素。 In an optional embodiment of the present invention, when R 6 is C 3 -C 6 cycloalkyl substituted by R 61 , said R 61 is halogen.
在本发明一任选实施方案中，当R 6为被R 61取代的C 3-C 6环烷基时，所述R 61取代为1个、2个或3个。 In an optional embodiment of the present invention, when R 6 is a C 3 -C 6 cycloalkyl group substituted by R 61 , the substitution of R 61 is 1, 2 or 3.
在本发明一任选实施方案中，当R 6为被R 61取代的C 3-C 6环烷基时，所述R 61为被1-6个相同或不同卤素取代的C 1-C 6烷基。 In an optional embodiment of the present invention, when R 6 is C 3 -C 6 cycloalkyl substituted by R 61 , said R 61 is C 1 -C 6 substituted by 1-6 identical or different halogens alkyl.
在本发明一任选实施方案中，当R 61为被1-6个相同或不同卤素取代的C 1-C 6烷基时，所述卤素取代为1个、2个或3个。 In an optional embodiment of the present invention, when R 61 is C 1 -C 6 alkyl substituted by 1-6 identical or different halogens, the halogen substitutions are 1, 2 or 3.
在本发明一任选实施方案中，当R 61为被1-6个相同或不同卤素取代的C 1-C 6烷基时，所述卤素取代为3个。 In an optional embodiment of the present invention, when R 61 is C 1 -C 6 alkyl substituted by 1-6 identical or different halogens, the number of said halogens is 3.
在本发明一任选实施方案中，当R 61为被1-6个相同或不同卤素取代的C 1-C 6烷基时，所述卤素为F或Cl。 In an optional embodiment of the present invention, when R 61 is C 1 -C 6 alkyl substituted by 1-6 identical or different halogens, said halogen is F or Cl.
在本发明一任选实施方案中，当R 61为被1-6个相同或不同卤素取代的C 1-C 6烷基时，所 述卤素为F。 In an optional embodiment of the present invention, when R 61 is C 1 -C 6 alkyl substituted by 1-6 identical or different halogens, said halogen is F.
在本发明一任选实施方案中，当R 6为被R 61取代的C 3-C 6环烷基时，所述R 61取代为2个。 In an optional embodiment of the present invention, when R 6 is a C 3 -C 6 cycloalkyl group substituted by R 61 , the number of R 61 substitutions is 2.
在本发明一任选实施方案中，R 1选自-H、
Figure PCTCN2022122990-appb-000040
在本发明一任选实施方案中，R 1为-H、
Figure PCTCN2022122990-appb-000041
In an optional embodiment of the present invention, R 1 is selected from -H,
Figure PCTCN2022122990-appb-000040
In an optional embodiment of the present invention, R 1 is -H,
Figure PCTCN2022122990-appb-000041
在本发明一任选实施方案中，R 1为
Figure PCTCN2022122990-appb-000042
In an optional embodiment of the present invention, R is
Figure PCTCN2022122990-appb-000042
在本发明一任选实施方案中，R 2为-H。 In an optional embodiment of the invention, R2 is -H.
在本发明一任选实施方案中，R 3选自-H、-Cl、甲基、-SF 5、
Figure PCTCN2022122990-appb-000043
Figure PCTCN2022122990-appb-000044
In an optional embodiment of the present invention, R 3 is selected from -H, -Cl, methyl, -SF 5 ,
Figure PCTCN2022122990-appb-000043
Figure PCTCN2022122990-appb-000044
在本发明一任选实施方案中，R 3选自-H、-SF 5、
Figure PCTCN2022122990-appb-000045
In an optional embodiment of the present invention, R 3 is selected from -H, -SF 5 ,
Figure PCTCN2022122990-appb-000045
在本发明一任选实施方案中，R 3选自-H、-SF 5、
Figure PCTCN2022122990-appb-000046
In an optional embodiment of the present invention, R 3 is selected from -H, -SF 5 ,
Figure PCTCN2022122990-appb-000046
在本发明一任选实施方案中，R 4为-H。 In an optional embodiment of the invention, R4 is -H.
在本发明一任选实施方案中，R 5选自甲基或环丙基。 In an optional embodiment of the invention, R 5 is selected from methyl or cyclopropyl.
在本发明一任选实施方案中，R 5为甲基。 In an optional embodiment of the invention, R 5 is methyl.
在本发明一任选实施方案中，R 6选自异丙基、环丙基、
Figure PCTCN2022122990-appb-000047
In an optional embodiment of the present invention, R is selected from isopropyl, cyclopropyl,
Figure PCTCN2022122990-appb-000047
在本发明一任选实施方案中，R 6选自异丙基、
Figure PCTCN2022122990-appb-000048
In an optional embodiment of the present invention, R is selected from isopropyl,
Figure PCTCN2022122990-appb-000048
在本发明一任选实施方案中，R 6选自环丁基、环戊基、
Figure PCTCN2022122990-appb-000049
In an optional embodiment of the present invention, R is selected from cyclobutyl, cyclopentyl,
Figure PCTCN2022122990-appb-000049
在本发明一任选实施方案中，当环A为
Figure PCTCN2022122990-appb-000050
且环B为
Figure PCTCN2022122990-appb-000051
时，R 1为羟基或
Figure PCTCN2022122990-appb-000052
且R 11为-NR xR y或
Figure PCTCN2022122990-appb-000053
In an optional embodiment of the present invention, when Ring A is
Figure PCTCN2022122990-appb-000050
and ring B is
Figure PCTCN2022122990-appb-000051
, R 1 is hydroxyl or
Figure PCTCN2022122990-appb-000052
and R 11 is -NR x R y or
Figure PCTCN2022122990-appb-000053
在本发明一任选实施方案中，当环A为
Figure PCTCN2022122990-appb-000054
且环B为
Figure PCTCN2022122990-appb-000055
时，R 3为-SF 5、羟基、氨基、
Figure PCTCN2022122990-appb-000056
In an optional embodiment of the present invention, when ring A is
Figure PCTCN2022122990-appb-000054
and ring B is
Figure PCTCN2022122990-appb-000055
When, R 3 is -SF 5 , hydroxyl, amino,
Figure PCTCN2022122990-appb-000056
在本发明一任选实施方案中，当环A为
Figure PCTCN2022122990-appb-000057
且环B为
Figure PCTCN2022122990-appb-000058
时，R 5为C 3-C 6环烷基、氰基或被1-5个相同或不同的卤素取代的C 3-C 6环烷基。 In an optional embodiment of the present invention, when ring A is
Figure PCTCN2022122990-appb-000057
and ring B is
Figure PCTCN2022122990-appb-000058
When, R 5 is C 3 -C 6 cycloalkyl, cyano or C 3 -C 6 cycloalkyl substituted by 1-5 identical or different halogens.
在本发明一任选实施方案中，当环A为
Figure PCTCN2022122990-appb-000059
且环B为
Figure PCTCN2022122990-appb-000060
时，R 6为羟基、氨基、氰基、
Figure PCTCN2022122990-appb-000061
被R 61取代的C 1-C 6烷基、卤素或未取代或被R 61取代的C 3-C 6环烷基。 In an optional embodiment of the present invention, when Ring A is
Figure PCTCN2022122990-appb-000059
and ring B is
Figure PCTCN2022122990-appb-000060
When, R 6 is hydroxyl, amino, cyano,
Figure PCTCN2022122990-appb-000061
C 1 -C 6 alkyl substituted by R 61 , halogen or C 3 -C 6 cycloalkyl unsubstituted or substituted by R 61 .
在本发明一任选实施方案中，式I所示的化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药选自下列任一化合物：In an optional embodiment of the present invention, the compound represented by formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug is selected from any of the following compounds :
Figure PCTCN2022122990-appb-000062
Figure PCTCN2022122990-appb-000062
Figure PCTCN2022122990-appb-000063
Figure PCTCN2022122990-appb-000063
Figure PCTCN2022122990-appb-000064
Figure PCTCN2022122990-appb-000064
Figure PCTCN2022122990-appb-000065
Figure PCTCN2022122990-appb-000065
本发明的第二方面，本发明提出了一种药物组合物，所述药物组合物包括治疗有效剂量的上述化合物，其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药以及药学上可接受的药用载体、稀释剂或赋形剂。In the second aspect of the present invention, the present invention proposes a pharmaceutical composition, which includes a therapeutically effective dose of the above compound, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically An acceptable salt or prodrug and a pharmaceutically acceptable carrier, diluent or excipient.
根据本发明的具体实施例，可以将本发明的所述药物组合物包括治疗有效剂量的上述化合物，其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药以及药学上可接受的药用载体、稀释剂或赋形剂混合制备成药物制剂，以适合于经口或胃肠外给药。给药方法包括，但不限于皮内、肌内、腹膜内、静脉内、皮下、鼻内和经口途径。所述制剂可以通过任何途径施用，例如通过输注或推注，通过经上皮或皮肤粘膜(例如口腔粘膜或直肠等)吸收的途径施用。给药可以是全身的或局部的。经口施用制剂的实例包括固体或液体剂型，具体而言，包括片剂、丸剂、粒剂、粉剂、胶囊剂、糖浆、乳剂、混悬剂等。所述制剂可通过本领域已知的方法制备，且包含药物制剂领域常规使用的载体、稀释剂或赋形剂。According to specific embodiments of the present invention, the pharmaceutical composition of the present invention may include a therapeutically effective dose of the above compound, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt Or prodrugs and pharmaceutically acceptable pharmaceutical carriers, diluents or excipients are mixed to prepare pharmaceutical preparations, which are suitable for oral or parenteral administration. Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal and oral routes. The formulation can be administered by any route, for example, by infusion or bolus injection, by absorption through the epithelium or mucocutaneous (eg, oral mucosa or rectum, etc.). Administration can be systemic or local. Examples of formulations for oral administration include solid or liquid dosage forms, specifically, tablets, pills, granules, powders, capsules, syrups, emulsions, suspensions and the like. The formulations can be prepared by methods known in the art, and contain carriers, diluents or excipients commonly used in the field of pharmaceutical formulations.
本发明的第三方面，本发明提出了上述化合物，其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药或上述药物组合物在制备用于治疗与AAK1相关疾病药物中的用途。In the third aspect of the present invention, the present invention proposes the above-mentioned compound, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug or the above-mentioned pharmaceutical composition in the preparation of Use in drugs for treating diseases related to AAK1.
根据本发明的具体实施例，上述化合物或其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药或上述药物组合物在制备药物中的用途，所述药物可用于治疗阿尔茨海默症、双相情感障碍、疼痛、帕金森病或精神分裂症等相关疾病。According to a specific embodiment of the present invention, the above-mentioned compound or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug or the use of the above-mentioned pharmaceutical composition in the preparation of medicine, The medicament can be used for treating related diseases such as Alzheimer's disease, bipolar disorder, pain, Parkinson's disease or schizophrenia.
在本发明的第四方面，本发明提出了上述化合物，其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药或上述药物组合物，用于治疗或预防AAK1相关疾病，如治疗阿尔茨海默症、双相情感障碍、疼痛、帕金森病或精神分裂症等相关疾病。In the fourth aspect of the present invention, the present invention proposes the above-mentioned compound, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug or the above-mentioned pharmaceutical composition, for Treating or preventing AAK1-related diseases, such as treating Alzheimer's disease, bipolar disorder, pain, Parkinson's disease or schizophrenia and other related diseases.
在本发明的第五方面，本发明提出了一种治疗或预防AAK1相关疾病的方法，根据本发明的实施例，所述方法包括给与患者药学上可接受剂量的上述化合物，其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药或上述药物组合物。In the fifth aspect of the present invention, the present invention proposes a method for treating or preventing AAK1-related diseases. According to an embodiment of the present invention, the method includes administering to the patient a pharmaceutically acceptable dose of the above-mentioned compound, which tautomorphically Constructs, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs or the above pharmaceutical compositions.
术语和定义Terms and Definitions
除非另有说明，用于本发明申请，包括本申请说明书和权利要求书中记载的术语和定义如下。Unless otherwise stated, the terms and definitions used in the present application, including the description and claims of the present application, are as follows.
本领域技术人员可以理解，根据本领域中使用的惯例，在本申请的结构式中，
Figure PCTCN2022122990-appb-000066
用于描绘化学键，所述化学键为部分或取代基与核心结构或骨架结构相连的点。 Those skilled in the art can understand that, according to the convention used in this field, in the structural formula of the present application,
Figure PCTCN2022122990-appb-000066
Used to depict a chemical bond, which is the point at which a moiety or substituent is attached to a core or backbone structure.
术语“药学上可接受的盐”是指药学上可接受的无毒酸或碱的盐，包括无机酸和碱、有机酸和碱的盐。The term "pharmaceutically acceptable salt" refers to pharmaceutically acceptable salts of non-toxic acids or bases, including salts of inorganic acids and bases, organic acids and bases.
术语“药物组合物”表示一种或多种文本所述化合物或其生理学/药学上可接受的盐或前体药物与其它化学组分的混合物，其它组分例如生理学/药学上可接受的载体和赋形剂。药物组合物的目的是促进化合物对生物体的给药。The term "pharmaceutical composition" means a mixture of one or more compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof with other chemical components such as a physiologically/pharmaceutically acceptable carrier and excipients. The purpose of a pharmaceutical composition is to facilitate the administration of a compound to an organism.
术语“辅料”是指可药用惰性成分。术语“赋形剂”的种类实例非限制性地包括粘合剂、崩解剂、润滑剂、助流剂、稳定剂、填充剂和稀释剂等。赋形剂能增强药物制剂的操作特性，即通过增加流动性和/或粘着性使制剂更适于直接压缩。The term "excipient" refers to a pharmaceutically acceptable inert ingredient. Examples of categories of the term "excipient" include, but are not limited to, binders, disintegrants, lubricants, glidants, stabilizers, fillers, diluents, and the like. Excipients can enhance the handling characteristics of a pharmaceutical formulation, ie make the formulation more suitable for direct compression by increasing flow and/or cohesiveness.
术语“前药”是指可以在生理条件下或者通过溶剂解转化为具有生物活性的本发明化合物。本发明的前药通过修饰在该化合物中的功能基团来制备，该修饰可以按常规的操作或者在体内被除去，而得到母体化合物。前药包括本发明化合物中的一个羟基或者氨基连接到任何基团上所形成的化合物，当本发明化合物的前药被施予哺乳动物个体时，前药被割裂而分别形成游离的羟基、游离的氨基。The term "prodrug" refers to a compound of the invention that can be converted to biological activity under physiological conditions or by solvolysis. The prodrugs of the present invention are prepared by modifying functional groups in the compounds which can be removed routinely or in vivo to yield the parent compound. Prodrugs include compounds formed by linking a hydroxyl or amino group in the compound of the present invention to any group. When the prodrug of the compound of the present invention is administered to a mammalian individual, the prodrug is split to form free hydroxyl, free of amino.
术语“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体，包括顺反异构体、对映异构体、非对应异构体和构象异构体。The term "stereoisomer" refers to isomers resulting from differences in the arrangement of atoms in a molecule in space, including cis-trans isomers, enantiomers, diastereoisomers and conformers.
术语“互变异构体”是指因分子中某一原子在两个位置迅速移动而产生的官能团异构体。本发明化合物可表现出互变异构现象。互变异构的化合物可以存在两种或多种可相互转化的种类。质子移变互变异构体来自两个原子之间共价键合的氢原子的迁移。互变异构体一般以平衡形式存在，尝试分离单一互变异构体时通常产生一种混合物，其理化性质与化合物的混合物是一致的。平衡的位置取决于分子内的化学特性。例如，在很多脂族醛和酮如乙醛中，酮型占优势；而在酚中，烯醇型占优势。本发明包含化合物的所有互变异构形式。The term "tautomer" refers to isomers of functional groups resulting from the rapid movement of an atom in a molecule between two positions. The compounds of the present invention may exhibit tautomerism. Tautomeric compounds can exist in two or more interconvertible species. Prototropic tautomers result from the migration of a covalently bonded hydrogen atom between two atoms. Tautomers generally exist in equilibrium and attempts to isolate a single tautomer usually result in a mixture whose physicochemical properties are consistent with the mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form predominates; in phenols, the enol form predominates. The present invention encompasses all tautomeric forms of the compounds.
本发明的某些化合物可以具有不对称碳原子(光学中心)或双键。外消旋体、非对映异构体、几何异构体和单个的异构体都包括在本发明的范围之内。Certain compounds of the invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are included within the scope of the present invention.
本文中消旋体、ambiscalemic and scalemic或者对映体纯的化合物的图示法来自Maehr,J.Chem.Ed.1985,62:114-120。除非另有说明，用楔形键和虚线键表示一个立体中心的绝对 构型。当本文所述化合物含有烯属双键或其它几何不对称中心，除非另有规定，它们包括E、Z几何异构体。同样地，所有的互变异构形式均包括在本发明的范围之内。The graphic representation of racemic, ambiscalemic and scalemic or enantiomerically pure compounds herein is from Maehr, J. Chem. Ed. 1985, 62:114-120. Unless otherwise stated, the absolute configuration of a stereocenter is indicated by wedge-shaped bonds and dashed-line bonds. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, unless otherwise specified, they include E, Z geometric isomers. Likewise, all tautomeric forms are included within the scope of the invention.
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对对映体、(R)-和(S)-对映体、非对映异构体、D-异构体、L-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。The compounds of the invention may exist in particular geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, D-isomers, L-isomers, and racemic and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention within. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D-和L-异构体。如果想得到本发明某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的分步结晶法或色谱法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。Optically active (R)- and (S)-isomers as well as D- and L-isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliary agents, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as amino group) or an acidic functional group (such as carboxyl group), a diastereomeric salt is formed with an appropriate optically active acid or base, and then step by step known in the art Resolution of diastereomers by crystallization or chromatography followed by recovery of the pure enantiomers. Furthermore, the separation of enantiomers and diastereomers is usually accomplished by the use of chromatography using chiral stationary phases, optionally in combination with chemical derivatization methods (e.g. amines to amino groups formate).
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚( 3H)，碘-125( 125I)或C-14( 14C)。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。 The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compounds. For example, compounds may be labeled with radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C). All changes in isotopic composition of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
针对药物或药理学活性剂而言，术语“有效量”或“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。对于本发明中的口服剂型，组合物中一种活性物质的“有效量”是指与该组合物中另一种活性物质联用时为了达到预期效果所需要的用量。有效量的确定因人而异，取决于受体的年龄和一般情况，也取决于具体的活性物质，个案中合适的有效量可以由本领域技术人员根据常规试验确定。For a drug or a pharmacologically active agent, the term "effective amount" or "therapeutically effective amount" refers to a non-toxic but sufficient amount of the drug or agent to achieve the desired effect. For the oral dosage forms in the present invention, the "effective amount" of one active substance in the composition refers to the amount needed to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount varies from person to person, depending on the age and general condition of the recipient, and also depends on the specific active substance. The appropriate effective amount in each case can be determined by those skilled in the art according to routine experiments.
术语“活性成分”、“治疗剂”，“活性物质”或“活性剂”是指一种化学实体，它可以有效地治疗目标紊乱、疾病或病症。The terms "active ingredient", "therapeutic agent", "active substance" or "active agent" refer to a chemical entity that is effective in treating the disorder, disease or condition of interest.
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为酮基(即＝O)时，意味着两个氢原子被取代。酮取代不会发生在芳香基上。术语“任选被取代的”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。The term "substituted" refers to the replacement of any one or more hydrogen atoms on a specified atom with a substituent, including deuterium and hydrogen variants, as long as the valence of the specified atom is normal and the substituted compound is stable . When a substituent is keto (ie =0), it means that two hydrogen atoms are replaced. Keto substitution does not occur on aromatic groups. The term "optionally substituted" means that it may or may not be substituted, and unless otherwise specified, the type and number of substituents may be arbitrary on a chemically realizable basis.
前缀“C u-C v”表示接下来的基团具有从u至v个碳原子。例如，“C 1-C 6烷基”表示该烷基具有1至6个碳原子。 The prefix "Cu - Cv " indicates that the following group has from u to v carbon atoms. For example, "C 1- C 6 alkyl" means that the alkyl has 1 to 6 carbon atoms.
术语“C 1-C 6烷基”应理解为表示具有1、2、3、4、5或6个碳原子的直链或支链饱和一价烃基。所述烷基是例如甲基、乙基、丙基、丁基、戊基、己基、异丙基、异丁基、仲丁基、叔丁基、异戊基、2-甲基丁基、1-甲基丁基、1-乙基丙基、1,2-二甲基丙基、新戊基、1,1-二甲基丙基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、2-乙基丁基、1-乙基丁基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、2,3-二甲基丁基、1,3-二甲基丁基或1,2-二甲基丁基等或它们的异构体。特别地，所述基团具有1、2或3个碳原子(“C 1-C 3烷基”)，例如甲基、乙基、正丙基或异丙基。 The term "C 1 -C 6 alkyl" is understood to mean a straight-chain or branched saturated monovalent hydrocarbon radical having 1, 2, 3, 4, 5 or 6 carbon atoms. The alkyl group is for example methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl Base, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, etc. or their isomers. In particular, said groups have 1, 2 or 3 carbon atoms (“C 1 -C 3 alkyl”), for example methyl, ethyl, n-propyl or isopropyl.
术语“-O-(C 1-C 6烷基)”应理解为烷基基团通过氧原子与分子其余部分相连，其中“C 1-C 6烷基”具有上述定义。如-O-(甲基)、-O-(乙基)。 The term "-O-(C 1 -C 6 alkyl)" is to be understood as meaning that an alkyl group is attached to the rest of the molecule via an oxygen atom, wherein "C 1 -C 6 alkyl" has the above definition. Such as -O-(methyl), -O-(ethyl).
术语“C 3-C 6环烷基”应理解为表示饱和的一价单环或双环烃环，其具有3～6个碳原子，包括稠合或桥接的多环系统。如环丙基、环丁基、环戊基、环己基。 The term "C 3 -C 6 cycloalkyl" is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3 to 6 carbon atoms, including fused or bridged polycyclic ring systems. Such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
术语“4-8元杂环烷基”是指总共具有4、5、6、7或8个环原子且包含一个或两个相同或不同的环杂原子或含杂原子的基团的单环饱和杂环，所述环杂原子或含杂原子的基团选自：N、NH、O、S、SO和SO 2，所述杂环烷基可通过任何一个碳原子或(如果存在)氮原子与分子的其余部分连接。所述杂环烷基可为4元环，例如氮杂环丁烷基、氧杂环丁烷基或硫杂环丁烷基；或者为5元环，例如四氢呋喃基、1,3-二氧戊环基、硫杂环戊基、吡咯烷基、咪唑烷基、吡唑烷基、1,1-二氧代硫杂环戊基、1,2-噁唑烷基、1,3-噁唑烷基或1,3-噻唑烷基；或者为6元环，例如四氢吡喃基、四氢噻喃基、哌啶基、吗啉基、二噻烷基、硫代吗啉基、哌嗪基、1,3-二氧杂环己基、1,4-二氧杂环己基或1,2-氧氮杂环己基。 The term "4-8 membered heterocycloalkyl" refers to a monocyclic ring having a total of 4, 5, 6, 7 or 8 ring atoms and containing one or two identical or different ring heteroatoms or heteroatom-containing groups Saturated heterocyclic ring, the ring heteroatom or heteroatom-containing group is selected from: N, NH, O, S, SO and SO 2 , and the heterocycloalkyl group can pass through any carbon atom or (if present) nitrogen Atoms are connected to the rest of the molecule. The heterocycloalkyl group can be a 4-membered ring, such as azetidinyl, oxetanyl or thietanyl; or a 5-membered ring, such as tetrahydrofuranyl, 1,3-dioxo Pentyl, thiolanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, 1,1-dioxothiolanyl, 1,2-oxazolidinyl, 1,3-oxo oxazolidinyl or 1,3-thiazolidinyl; or a 6-membered ring, such as tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, Piperazinyl, 1,3-dioxanyl, 1,4-dioxanyl or 1,2-oxazepinyl.
术语“卤代基”或“卤素”为氟、氯、溴和碘。The term "halo" or "halogen" refers to fluoro, chloro, bromo and iodo.
术语“任选”或“任选地”意思是随后所述的事件或情形可发生或可不发生，且所述描述包括其中所述事件或情形发生的情况以及其中所述事件或情形不发生的情况。The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not Condition.
另外，需要说明的是，除非以其他方式明确指出，在本发明中所采用的描述方式“……独立地”应作广义理解，是指所描述的各个个体之间是相互独立的，可以独立地为相同或不同的具体基团。更详细地，描述方式“……独立地”既可以是指在不同基团中，相同符合之间所表达的具体选项之间互相不影响，也可以表示在相同的基团中，相同符号之间所表达的具体选项之间互相不影响。In addition, it should be noted that, unless otherwise clearly stated, the description method "...independently" used in the present invention should be understood in a broad sense, which means that the described individuals are independent of each other and can be independently are the same or different specific groups. In more detail, the description "...independently" can mean that in different groups, the specific options expressed between the same symbols do not affect each other, or it can mean that in the same group, the same symbol The specific options expressed between them do not affect each other.
有益效果：Beneficial effect:
根据本发明的实施例，本发明至少具有如下技术效果至少之一：According to the embodiments of the present invention, the present invention has at least one of the following technical effects:
1)提供了结构新颖、药代动力学性质优良、药效或成药性好的AAK1抑制剂，可以用于有效治疗AAK1相关的疾病、病症；1) Provide AAK1 inhibitors with novel structure, excellent pharmacokinetic properties, and good efficacy or druggability, which can be used to effectively treat diseases and diseases related to AAK1;
2)本发明化合物可用于治疗阿尔茨海默症、双相情感障碍、疼痛、帕金森病或精神分裂症等相关疾病；2) The compound of the present invention can be used to treat related diseases such as Alzheimer's disease, bipolar disorder, pain, Parkinson's disease or schizophrenia;
3)本发明化合物具有较强的AAK1亲和力。3) The compound of the present invention has a strong affinity for AAK1.
本发明的附加方面和优点将在下面的描述中部分给出，部分将从下面的描述中变得明显，或通过本发明的实践了解到。Additional aspects and advantages of the invention will be set forth in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention.
具体实施方式Detailed ways
下面将结合实施例对本发明的方案进行解释。本领域技术人员将会理解，下面的实施例仅用于说明本发明，而不应视为限定本发明的范围。实施例中未注明具体技术或条件的，按照本领域内的文献所描述的技术或条件或者按照产品说明书进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。The solutions of the present invention will be explained below in conjunction with examples. Those skilled in the art will understand that the following examples are only for illustrating the present invention and should not be considered as limiting the scope of the present invention. If no specific technique or condition is indicated in the examples, it shall be carried out according to the technique or condition described in the literature in this field or according to the product specification. The reagents or instruments used were not indicated by the manufacturer, and they were all commercially available conventional products.
如无特别说明，本发明的化合物均是通过核磁共振(NMR)和/或质谱(MS)来确定其结构的。NMR位移的单位为10 -6(ppm)。NMR测定的溶剂为氘代二甲基亚砜、氘代氯仿、氘代甲醇等，内标为四甲基硅烷(TMS)。 Unless otherwise specified, the structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS). The unit of NMR shift is 10 -6 (ppm). The solvents determined by NMR are deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is tetramethylsilane (TMS).
本发明的缩写定义如下：The abbreviations of the present invention are defined as follows:
M：摩尔浓度，如1M盐酸表示1mol/L盐酸溶液M: molar concentration, such as 1M hydrochloric acid means 1mol/L hydrochloric acid solution
LC-MS：液质联用色谱LC-MS: liquid chromatography-mass chromatography
DMSO：二甲基亚砜DMSO: dimethyl sulfoxide
IC 50：半数抑制浓度，指达到最大抑制效果一半时的浓度。 IC 50 : half inhibitory concentration, which refers to the concentration at which half of the maximum inhibitory effect is achieved.
对照例1：对照化合物1的制备Comparative Example 1: Preparation of Comparative Compound 1
(S)-1-((2',6-二(二氟甲基)-[2,4'-联吡啶]-5-基)氧代)-2,4-二甲基戊烷-2-胺(对照化合物1)。(S)-1-((2',6-bis(difluoromethyl)-[2,4'-bipyridyl]-5-yl)oxo)-2,4-dimethylpentane-2 - Amine (comparative compound 1).
Figure PCTCN2022122990-appb-000067
Figure PCTCN2022122990-appb-000067
目标化合物1的合成路线如下所示：The synthetic route of target compound 1 is as follows:
Figure PCTCN2022122990-appb-000068
Figure PCTCN2022122990-appb-000068
第一步：(S)-2-((((9H-芴-9-基)甲氧基)羰基)氨基)-2,4-二甲基戊酸的合成Step 1: Synthesis of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2,4-dimethylpentanoic acid
Figure PCTCN2022122990-appb-000069
Figure PCTCN2022122990-appb-000069
在室温下，向(S)-2-氨基-2,4-二甲基戊酸(8.00g,55.1mmol)和氢氧化钠(2.64g,66.1mmol)的水(40.0mL)和丙酮(40.0mL)溶液中分批加入(9H-芴-9-基)甲基(2,5-二氧亚基吡咯烷-1-基)碳酸盐(18.5g,55.1mmol)，反应液在室温下搅拌过夜。反应完成后，用2N盐酸调节pH至2，充分搅拌后用乙酸乙酯(200mL)萃取，有机相用无水硫酸钠干燥后过滤浓缩得到粗品，粗品通过柱层析(硅胶，乙酸乙酯：石油醚＝10:1到3:1)纯化得到无色油状物(S)-2-((((9H-芴-9-基)甲氧基)羰基)氨基)-2,4-二甲基戊酸(10.0g,27.2mmol,收率49.4％)。Add (S)-2-amino-2,4-dimethylvaleric acid (8.00 g, 55.1 mmol) and sodium hydroxide (2.64 g, 66.1 mmol) to water (40.0 mL) and acetone (40.0 mL) solution was added in batches to (9H-fluoren-9-yl)methyl(2,5-dioxylidenepyrrolidin-1-yl)carbonate (18.5g, 55.1mmol), and the reaction solution was Stir overnight. After the reaction was completed, the pH was adjusted to 2 with 2N hydrochloric acid, extracted with ethyl acetate (200 mL) after stirring well, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product, which was passed through column chromatography (silica gel, ethyl acetate: Petroleum ether = 10:1 to 3:1) to obtain colorless oil (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2,4-dimethyl Givaleric acid (10.0 g, 27.2 mmol, yield 49.4%).
第二步：(S)-(9H-芴-9-基)甲基(1-羟基-2,4-二甲基戊烷-2-基)氨基甲酯的合成The second step: Synthesis of (S)-(9H-fluoren-9-yl)methyl(1-hydroxy-2,4-dimethylpentan-2-yl)aminomethyl ester
Figure PCTCN2022122990-appb-000070
Figure PCTCN2022122990-appb-000070
在0℃下向(S)-2-((((9H-芴-9-基)甲氧基)羰基)氨基)-2,4-二甲基戊酸(8.00g,21.7mmol)和N,N-二异丙基乙胺(3.38g,26.1mmol)的四氢呋喃(80.0mL)溶液中滴加氯甲酸异丁酯(3.27g,23.9mmol)，反应液在0℃搅拌0.5小时后加入硼氢化钠(1.65g,43.5mmol)，反应液升温至25℃搅拌0.5小时。反应完成后，向反应液中滴加稀盐酸淬灭后用乙酸乙酯(200mL)萃取，有机相用无水硫酸钠干燥后过滤浓缩得到粗品，粗品通过柱层析(硅胶，乙酸乙酯：石 油醚＝10:1到5:1)纯化得到无色油状物(S)-(9H-芴-9-基)甲基(1-羟基-2,4-二甲基戊烷-2-基)氨基甲酯(6.50g,18.3mmol,84.4％收率)。(S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2,4-dimethylpentanoic acid (8.00g, 21.7mmol) and N , N-diisopropylethylamine (3.38g, 26.1mmol) in tetrahydrofuran (80.0mL) was added dropwise isobutyl chloroformate (3.27g, 23.9mmol), and the reaction solution was stirred at 0°C for 0.5 hours before adding boron Sodium hydride (1.65g, 43.5mmol), the temperature of the reaction solution was raised to 25°C and stirred for 0.5 hours. After the reaction was completed, dilute hydrochloric acid was added dropwise to the reaction solution to quench it and then extracted with ethyl acetate (200 mL). The organic phase was dried over anhydrous sodium sulfate and then concentrated by filtration to obtain the crude product. The crude product was passed through column chromatography (silica gel, ethyl acetate: Petroleum ether = 10:1 to 5:1) Purification gave (S)-(9H-fluoren-9-yl)methyl(1-hydroxy-2,4-dimethylpentan-2-yl) as a colorless oil ) carbamate (6.50 g, 18.3 mmol, 84.4% yield).
第三步：(S)-2-氨基-2,4-二甲基戊烷-1-醇的合成The third step: the synthesis of (S)-2-amino-2,4-dimethylpentan-1-ol
Figure PCTCN2022122990-appb-000071
Figure PCTCN2022122990-appb-000071
在室温下，向(S)-(9H-芴-9-基)甲基(1-羟基-2,4-二甲基戊烷-2-基)氨基甲酯(5.10g,14.4mmol)的二氯甲烷(50.0mL)中加入二乙基胺(3.17g,43.2mmol)，反应液在室温下搅拌2小时。反应完成后，将反应液浓缩得到黄色固体(S)-2-氨基-2,4-二甲基戊烷-1-醇(3.50g,粗品)。To (S)-(9H-fluoren-9-yl)methyl(1-hydroxy-2,4-dimethylpentan-2-yl)aminomethyl ester (5.10g, 14.4mmol) at room temperature Diethylamine (3.17 g, 43.2 mmol) was added to dichloromethane (50.0 mL), and the reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated to obtain (S)-2-amino-2,4-dimethylpentan-1-ol (3.50 g, crude product) as a yellow solid.
第四步：2-(二氟甲基)-4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)吡啶的合成Step 4: Synthesis of 2-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine
Figure PCTCN2022122990-appb-000072
Figure PCTCN2022122990-appb-000072
在室温下，向4-溴-2-(二氟甲基)吡啶(1.80g,8.65mmol)，双联嚬哪醇硼酸酯(2.75g,10.8mmol)和乙酸钾(2.12g,21.6mmol)的1,4-二氧六环(20.0mL)溶液中加入1,1-双(二苯基磷)二茂铁氯化钯(633mg,865μmol)反应液在80℃搅拌过夜。反应完成后，将反应液冷却至室温，加水(50.0mL)稀释后用乙酸乙酯(50.0mL)萃取,有机相用无水硫酸钠干燥后过滤浓缩得到粗品化合物2-(二氟甲基)-4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)吡啶(2.50g,粗品)。At room temperature, add 4-bromo-2-(difluoromethyl)pyridine (1.80g, 8.65mmol), bisanalyl borate (2.75g, 10.8mmol) and potassium acetate (2.12g, 21.6mmol ) in 1,4-dioxane (20.0 mL) was added 1,1-bis(diphenylphosphino)ferrocenepalladium chloride (633 mg, 865 μmol) and the reaction solution was stirred overnight at 80°C. After the reaction was completed, the reaction solution was cooled to room temperature, diluted with water (50.0 mL) and extracted with ethyl acetate (50.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain crude compound 2-(difluoromethyl) - 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (2.50 g, crude).
第五步：(S)-1-((6-溴-2-(二氟甲基)吡啶-3-基)氧代)-2,4-二甲基戊烷-2-胺的合成Step 5: Synthesis of (S)-1-((6-bromo-2-(difluoromethyl)pyridin-3-yl)oxo)-2,4-dimethylpentane-2-amine
Figure PCTCN2022122990-appb-000073
Figure PCTCN2022122990-appb-000073
在室温下，向(S)-2-氨基-2,4-二甲基戊烷-1-醇(1.16g,8.85mmol)的四氢呋喃(12.0mL)溶液中加入叔丁醇钾(1.19g,10.6mmol)，搅拌0.5小时后，分批加入6-溴-2-(二氟甲基)-3-氟吡啶(2.00g,8.85mmol)，反应也升温至80℃搅拌12小时。反应完成后，加入1N盐酸调节反应液pH至2，混合液用乙酸乙酯(20.0mL)萃取，水相加入1M氢氧化钠水溶液调节pH至12后用乙酸乙酯(25.0mL)萃取，有机相用无水硫酸钠干燥后过滤浓缩得到粗品化合物(S)-1-((6-溴-2-(二氟甲基)吡啶-3-基)氧代)-2,4-二甲基戊烷-2-胺(690mg,粗品)。To a solution of (S)-2-amino-2,4-dimethylpentan-1-ol (1.16 g, 8.85 mmol) in tetrahydrofuran (12.0 mL) was added potassium tert-butoxide (1.19 g, 10.6mmol), after stirring for 0.5 hours, 6-bromo-2-(difluoromethyl)-3-fluoropyridine (2.00g, 8.85mmol) was added in batches, and the reaction was also heated to 80°C and stirred for 12 hours. After the reaction was completed, 1N hydrochloric acid was added to adjust the pH of the reaction solution to 2, and the mixed solution was extracted with ethyl acetate (20.0 mL), and the aqueous phase was extracted with ethyl acetate (25.0 mL) after adding 1M aqueous sodium hydroxide solution to adjust the pH to 12. The phase was dried over anhydrous sodium sulfate and concentrated by filtration to obtain the crude compound (S)-1-((6-bromo-2-(difluoromethyl)pyridin-3-yl)oxo)-2,4-dimethyl Pentan-2-amine (690 mg, crude).
1H NMR(400MHz,CHLOROFORM-d)δppm 7.53(d,J＝8.78Hz,1H)7.21(d,J＝8.66Hz,1H)6.53-6.91(m,1H)3.78(d,J＝1.51Hz,2H)1.61-1.88(m,4H)1.48(t,J＝5.27Hz,2H)1.23(s,3H)0.98(dd,J＝8.53,6.65Hz,7H). 1 H NMR (400MHz, CHLOROFORM-d) δppm 7.53 (d, J = 8.78Hz, 1H) 7.21 (d, J = 8.66Hz, 1H) 6.53-6.91 (m, 1H) 3.78 (d, J = 1.51Hz, 2H)1.61-1.88(m,4H)1.48(t,J=5.27Hz,2H)1.23(s,3H)0.98(dd,J=8.53,6.65Hz,7H).
LC-MS,M/Z:337.1[M+H] +. LC-MS, M/Z:337.1[M+H] + .
第六步：(S)-1-((2',6-二(二氟甲基)-[2,4'-联吡啶]-5-基)氧代)-2,4-二甲基戊烷-2-胺(7)的合成Step 6: (S)-1-((2',6-bis(difluoromethyl)-[2,4'-bipyridyl]-5-yl)oxo)-2,4-dimethyl Synthesis of Pentane-2-amine (7)
Figure PCTCN2022122990-appb-000074
Figure PCTCN2022122990-appb-000074
在室温下，向(S)-1-((6-溴-2-(二氟甲基)吡啶-3-基)氧代)-2,4-二甲基戊烷-2-胺(600mg,1.78mmol)，2-(二氟甲基)-4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)吡啶(615.39mg,3.56mmol)和磷酸钾(1.51g,7.12mmol)的四氢呋喃(12.0mL)溶液中加入氯(2-二环己基膦基-2,4,6-三异丙基-1,1-联苯基)[2-(2-氨基-1,1-联苯)]钯(II)(140mg,177μmol)，反应液在80℃搅拌12小时。反应完成后，将反应液过滤浓缩得到粗品，粗品通过反相高效液相色谱法进行分离，分离方法为：色谱柱:Waters Xbridge C18 150×50mm×10μm；流动相:[水(碳酸氢铵)-乙腈]；B％:40％-70％,11min]，得到黄色固体化合物(S)-1-((2',6-二(二氟甲基)-[2,4'-联吡啶]-5-基)氧代)-2,4-二甲基戊烷-2-胺(314mg,776μmol,收率43.6％)。At room temperature, to (S)-1-((6-bromo-2-(difluoromethyl)pyridin-3-yl)oxo)-2,4-dimethylpentan-2-amine (600mg , 1.78mmol), 2-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (615.39mg, 3.56mmol) and potassium phosphate (1.51g, 7.12mmol) in tetrahydrofuran (12.0mL) solution was added chlorine (2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl )[2-(2-Amino-1,1-biphenyl)]palladium(II) (140mg, 177μmol), and the reaction solution was stirred at 80°C for 12 hours. After the reaction was completed, the reaction solution was filtered and concentrated to obtain the crude product, which was separated by reverse-phase high-performance liquid chromatography, and the separation method was: chromatographic column: Waters Xbridge C18 150 × 50mm × 10 μm; mobile phase: [water (ammonium bicarbonate) -acetonitrile]; B%:40%-70%, 11min], obtain yellow solid compound (S)-1-((2',6-bis(difluoromethyl)-[2,4'-bipyridine] -5-yl)oxo)-2,4-dimethylpentan-2-amine (314 mg, 776 μmol, yield 43.6%).
1H NMR(400MHz,CDCl 3)δ8.79(d,1H),8.40(d,1H),8.33(s,1H)8.22(br d,1H),7.81(d,1H),6.89-7.47(m,2H)3.89(s,2H)1.81(dt,1H),1.57(br s,2H)1.39(dd,2H),1.12(s,3H)0.93(t,6H). 1 H NMR (400MHz, CDCl 3 )δ8.79(d,1H),8.40(d,1H),8.33(s,1H),8.22(br d,1H),7.81(d,1H),6.89-7.47( m,2H)3.89(s,2H)1.81(dt,1H),1.57(br s,2H)1.39(dd,2H),1.12(s,3H)0.93(t,6H).
LC-MS,M/Z:386.1[M+H] +。 LC-MS, M/Z: 386.1 [M+H] + .
实施例1：目标化合物I-1的制备Embodiment 1: the preparation of target compound I-1
(S)-3-(5-((2-氨基-2,4-二甲代戊基)氧代)-6-(二氟甲基)-[2,4'-联吡啶]-2'-基)-1,1-二甲基脲(目标化合物I-1)(S)-3-(5-((2-Amino-2,4-dimethylpentyl)oxo)-6-(difluoromethyl)-[2,4'-bipyridine]-2' -yl)-1,1-dimethylurea (target compound I-1)
Figure PCTCN2022122990-appb-000075
Figure PCTCN2022122990-appb-000075
目标化合物I-1的合成路线如下所示：The synthetic route of target compound 1-1 is as follows:
Figure PCTCN2022122990-appb-000076
Figure PCTCN2022122990-appb-000076
第一步：4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)吡啶-2-胺的合成Step 1: Synthesis of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine
Figure PCTCN2022122990-appb-000077
Figure PCTCN2022122990-appb-000077
将4-溴吡啶-2-胺(3.00g,17.3mmol)和4,4,4',4',5,5,5',5'-八甲基-2,2'-联(1,3,2-二噁硼戊环)(5.28g,20.8mmol)溶解在1,4-二氧六环(30.0mL)中，再把1,1-双(二苯基磷)二茂铁氯化钯(1.27g,1.73mmol)和醋酸钾(3.39g,34.7mmol)加到反应液中，置换氮气3次，在80℃下反应12小时。将反应液降至25℃后加入水(60.0mL)，然后用二氯甲烷(30.0mL×3)萃取，用饱和食盐水(30.0mL)洗涤有机相，硫酸钠干燥，浓缩得到粗品，粗品用石油醚：甲基叔丁基醚＝2:1(30ml)打浆20分钟，过滤后干燥，得到棕色固体4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)吡啶-2-胺(3.45g，产率89.8％)。4-bromopyridin-2-amine (3.00g, 17.3mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-linked (1, 3,2-dioxaborolane) (5.28g, 20.8mmol) was dissolved in 1,4-dioxane (30.0mL), and then 1,1-bis(diphenylphosphine)ferrocene chloride Palladium chloride (1.27g, 1.73mmol) and potassium acetate (3.39g, 34.7mmol) were added to the reaction solution, nitrogen was replaced 3 times, and the reaction was carried out at 80°C for 12 hours. After the reaction solution was lowered to 25°C, water (60.0 mL) was added, then extracted with dichloromethane (30.0 mL×3), the organic phase was washed with saturated brine (30.0 mL), dried over sodium sulfate, and concentrated to obtain a crude product, which was used for Petroleum ether: methyl tert-butyl ether = 2:1 (30ml) Slurry for 20 minutes, filter and dry to obtain brown solid 4-(4,4,5,5-tetramethyl-1,3,2-diox Boropentan-2-yl)pyridin-2-amine (3.45 g, 89.8% yield).
LC-MS,M/Z(ESI):221.2[M+H] +。 LC-MS, M/Z (ESI): 221.2 [M+H] + .
第二步：1,1-二甲基-3-(4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)吡啶-2-基)脲的合成The second step: 1,1-dimethyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2- base) urea synthesis
Figure PCTCN2022122990-appb-000078
Figure PCTCN2022122990-appb-000078
将4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)吡啶-2-胺(300mg,1.36mmol)和三乙胺(414mg,4.09mmol)溶解在二氯甲烷(12.0mL)和四氢呋喃(4.00mL)中，缓慢滴加氯甲酸苄酯(427mg,2.73mmol)，25℃反应12小时后，再加入二甲胺盐酸盐(167mg,2.04mmol)，25℃继续反应4小时。向反应液加入水(20.0mL)，然后用乙酸乙酯(20.0mL×3)萃取，用饱和食盐水(20.0mL)洗涤有机相，硫酸钠干燥，浓缩得到粗品，为棕色油状物1,1-二甲基-3-(4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)吡啶-2-基)脲(280mg，产率70.5％)。4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (300mg, 1.36mmol) and triethylamine (414mg, 4.09mmol) was dissolved in dichloromethane (12.0mL) and tetrahydrofuran (4.00mL), and benzyl chloroformate (427mg, 2.73mmol) was slowly added dropwise, and after reacting for 12 hours at 25°C, dimethylamine hydrochloride ( 167mg, 2.04mmol), the reaction was continued at 25°C for 4 hours. Water (20.0 mL) was added to the reaction solution, then extracted with ethyl acetate (20.0 mL×3), the organic phase was washed with saturated brine (20.0 mL), dried over sodium sulfate, and concentrated to obtain the crude product as a brown oil 1,1 -Dimethyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)urea (280mg, yield rate of 70.5%).
LC-MS,M/Z(ESI):292.0[M+H] +。 LC-MS, M/Z (ESI): 292.0 [M+H] + .
第三步：(S)-3-(5-((2-氨基-2,4-二甲代戊基)氧代)-6-(二氟甲基)-[2,4'-联吡啶]-2'-基)-1,1-二甲基脲(I-1)的合成The third step: (S)-3-(5-((2-amino-2,4-dimethylpentyl)oxo)-6-(difluoromethyl)-[2,4'-bipyridine Synthesis of ]-2'-yl)-1,1-dimethylurea (I-1)
Figure PCTCN2022122990-appb-000079
Figure PCTCN2022122990-appb-000079
将1,1-二甲基-3-(4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)吡啶-2-基)脲(256mg,890μmol)和(S)-1-((6-溴-2-(二氟甲基)吡啶-3-基)氧)-2,4-二甲基戊烷-2-胺(200mg,593μmol)溶解在四氢呋喃(4.00mL)中，再把二氯双[二叔丁基-(4-二甲基氨基苯基)膦]钯(II)(21.0mg,29.7μmol)和磷酸钾(378mg,1.78mmol)加到反应液中，置换氮气3次，在70℃下反应12小时。将反应液降至25℃后加入水(10.0mL)，然后用乙酸乙酯(10.0mL×3)萃取，用饱和食盐水(10.0mL)洗涤有机相，硫酸钠干燥，浓缩得到粗品，然后通过反相高效液相色谱法进行分离，分离方法为(色谱柱：Waters Xbridge 150×25mm×5μm；流动相：A＝水+氨水(0.05％)，B＝乙腈；梯度：35％-65％，9分钟)，然后冻干得到黑色胶状化合物(S)-3-(5-((2-氨基-2,4-二甲代戊基)氧代)-6-(二氟甲基)-[2,4'-联吡啶]-2'-基)-1,1-二甲基脲(I-1)(8.90mg，产率3.36％)。1,1-Dimethyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)urea (256mg, 890μmol) and (S)-1-((6-bromo-2-(difluoromethyl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine (200mg ,593μmol) was dissolved in tetrahydrofuran (4.00mL), then dichlorobis[di-tert-butyl-(4-dimethylaminophenyl)phosphine] palladium (II) (21.0mg, 29.7μmol) and potassium phosphate ( 378mg, 1.78mmol) was added to the reaction solution, nitrogen was replaced 3 times, and the reaction was carried out at 70°C for 12 hours. After the reaction solution was lowered to 25°C, water (10.0 mL) was added, and then extracted with ethyl acetate (10.0 mL×3), the organic phase was washed with saturated brine (10.0 mL), dried over sodium sulfate, concentrated to obtain a crude product, and passed through Reversed-phase high-performance liquid chromatography is separated, and separation method is (chromatographic column: Waters Xbridge 150 * 25mm * 5 μ m; Mobile phase: A=water+ammonia (0.05%), B=acetonitrile; Gradient: 35%-65%, 9 minutes), and then lyophilized to obtain a black gum compound (S)-3-(5-((2-amino-2,4-dimethylpentyl)oxo)-6-(difluoromethyl)- [2,4'-bipyridyl]-2'-yl)-1,1-dimethylurea (I-1) (8.90 mg, yield 3.36%).
1H NMR(400MHz,CDCl 3)δ8.60(s,1H),8.27(d,1H),7.97(d,1H),7.68(d,1H),7.35(br d,2H),6.69-7.01(m,1H),3.80-3.88(m,2H),3.09(s,6H),2.01(s,1H),1.78-1.86(m,2H),1.46-1.57(m,2H),1.26(s,3H),0.99(dd,6H). 1 H NMR (400MHz, CDCl 3 )δ8.60(s,1H),8.27(d,1H),7.97(d,1H),7.68(d,1H),7.35(br d,2H),6.69-7.01 (m,1H),3.80-3.88(m,2H),3.09(s,6H),2.01(s,1H),1.78-1.86(m,2H),1.46-1.57(m,2H),1.26(s ,3H),0.99(dd,6H).
LC-MS,M/Z(ESI):422.1[M+H] +。 LC-MS, M/Z (ESI): 422.1 [M+H] + .
实施例2：目标化合物I-2的制备Embodiment 2: the preparation of target compound 1-2
(S)-N-(5-((2-氨基-2,4-二甲代戊基)氧代)-6-(二氟甲基)-[2,4'-联吡啶]-2'-基)吡咯烷-1-甲酰胺(目标化合物I-2)(S)-N-(5-((2-Amino-2,4-dimethylpentyl)oxo)-6-(difluoromethyl)-[2,4'-bipyridine]-2' -yl) pyrrolidine-1-carboxamide (target compound I-2)
Figure PCTCN2022122990-appb-000080
Figure PCTCN2022122990-appb-000080
目标化合物I-2的合成路线如下所示：The synthetic route of target compound 1-2 is as follows:
Figure PCTCN2022122990-appb-000081
Figure PCTCN2022122990-appb-000081
第一步：N-(4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)吡啶-2-基)吡咯烷-1-甲酰胺的合成The first step: N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)pyrrolidin-1-methanol Amide synthesis
Figure PCTCN2022122990-appb-000082
Figure PCTCN2022122990-appb-000082
将4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)吡啶-2-胺(1.00g,4.54mmol)和三乙胺(1.38g,13.6mmol)溶解在二氯甲烷(20.0mL)和四氢呋喃(10.0mL)中，缓慢滴加氯甲酸苄酯(1.42g,9.09mmol)，25℃反应12小时后，再加入吡咯烷(1.62g,22.7mmol)，25℃继续反应4小时。向反应液降至加入水(50.0mL)，然后用乙酸乙酯(30.0mL×3)萃取，用饱和食盐水(30.0mL)洗涤有机相，硫酸钠干燥，浓缩得到粗品，为棕色油状物N-(4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)吡啶-2-基)吡咯烷-1-甲酰胺(1.25g，产率86.8％)。4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (1.00g, 4.54mmol) and triethylamine (1.38 g, 13.6mmol) was dissolved in dichloromethane (20.0mL) and tetrahydrofuran (10.0mL), and benzyl chloroformate (1.42g, 9.09mmol) was slowly added dropwise. After reacting for 12 hours at 25°C, pyrrolidine (1.62 g, 22.7mmol), the reaction was continued at 25°C for 4 hours. Water (50.0 mL) was added to the reaction solution, then extracted with ethyl acetate (30.0 mL×3), the organic phase was washed with saturated brine (30.0 mL), dried over sodium sulfate, and concentrated to give the crude product as a brown oil. -(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)pyrrolidine-1-carboxamide (1.25g, Yield 86.8%).
LC-MS,M/Z(ESI):318.1[M+H] +。 LC-MS, M/Z (ESI): 318.1 [M+H] + .
第二步：(S)-N-(5-((2-氨基-2,4-二甲代戊基)氧代)-6-(二氟甲基)-[2,4'-联吡啶]-2'-基)吡咯烷-1-甲酰胺(目标化合物I-2)The second step: (S)-N-(5-((2-amino-2,4-dimethylpentyl)oxo)-6-(difluoromethyl)-[2,4'-bipyridine ]-2'-yl)pyrrolidine-1-carboxamide (target compound I-2)
Figure PCTCN2022122990-appb-000083
Figure PCTCN2022122990-appb-000083
将N-(4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)吡啶-2-基)吡咯烷-1-甲酰胺(166mg,522μmol)和(S)-1-((6-溴-2-(二氟甲基)吡啶-3-基)氧)-2,4-二甲基戊烷-2-胺(117mg,348μmol)溶解在四氢呋喃(2.00mL)中，再将二氯双[二叔丁基-(4-二甲基氨基苯基)膦]钯(II)(12.3mg,17.4μmol)和磷酸钾(222mg,1.04mmol)加到反应液中，置换氮气3次，在70℃下反应12小时。将反应液降至25℃后加入水(10.0mL)，然后用乙酸乙酯(10.0mL×3)萃取，用饱和食盐水(10.0mL)洗涤有机相，硫酸钠干燥，浓缩得到粗品，然后通过反相高效液相色谱法进行分离，分离方法为(色谱柱：Waters Xbridge 150×25mm×5μm；流动相：A＝水+氨水(0.05％)，B＝乙腈；梯度：36％-66％，9分钟)，然后冻干得到黄色胶状化合物(S)-N-(5-((2-氨基-2,4-二甲代戊基)氧代)-6-(二氟甲基)-[2,4'-联吡啶]-2'-基)吡咯烷-1-甲酰胺(I-2)(8.94mg，产率 5.71％)。N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)pyrrolidine-1-carboxamide (166mg , 522μmol) and (S)-1-((6-bromo-2-(difluoromethyl)pyridin-3-yl)oxy)-2,4-dimethylpentane-2-amine (117mg, 348μmol ) was dissolved in tetrahydrofuran (2.00mL), and dichlorobis[di-tert-butyl-(4-dimethylaminophenyl)phosphine] palladium (II) (12.3mg, 17.4μmol) and potassium phosphate (222mg, 1.04 mmol) was added to the reaction solution, nitrogen was replaced three times, and the reaction was carried out at 70° C. for 12 hours. After the reaction solution was lowered to 25°C, water (10.0 mL) was added, and then extracted with ethyl acetate (10.0 mL×3), the organic phase was washed with saturated brine (10.0 mL), dried over sodium sulfate, concentrated to obtain a crude product, and passed through Reversed-phase high-performance liquid chromatography is separated, and separation method is (chromatographic column: Waters Xbridge 150 * 25mm * 5 μ m; Mobile phase: A=water+ammonia (0.05%), B=acetonitrile; Gradient: 36%-66%, 9 minutes), and then lyophilized to obtain yellow gum compound (S)-N-(5-((2-amino-2,4-dimethylpentyl)oxo)-6-(difluoromethyl)- [2,4'-bipyridyl]-2'-yl)pyrrolidine-1-carboxamide (I-2) (8.94 mg, yield 5.71%).
1H NMR(400MHz,CDCl 3)δ8.65(s,1H),8.26(d,1H),7.97(d,1H),7.67(d,1H),7.34(d,1H),7.18(br s,1H),6.69-7.00(m,1H),3.81-3.89(m,2H),3.52(br s,4H),1.99-2.05(m,4H),1.74-1.85(m,1H),1.47-1.58(m,2H),1.27(s,3H),0.99(dd,6H). 1 H NMR (400MHz, CDCl 3 )δ8.65(s,1H),8.26(d,1H),7.97(d,1H),7.67(d,1H),7.34(d,1H),7.18(br s ,1H),6.69-7.00(m,1H),3.81-3.89(m,2H),3.52(br s,4H),1.99-2.05(m,4H),1.74-1.85(m,1H),1.47- 1.58(m,2H),1.27(s,3H),0.99(dd,6H).
LC-MS,M/Z(ESI):448.2[M+H] +。 LC-MS, M/Z (ESI): 448.2 [M+H] + .
实施例3：目标化合物I-3的制备Embodiment 3: the preparation of target compound 1-3
(S)-1-((2',6-二(二氟甲基)-[2,4'-联吡啶]-5-基)氧代)-3-环丙基-2-甲基丙烷-2-胺(目标化合物I-3)(S)-1-((2',6-bis(difluoromethyl)-[2,4'-bipyridyl]-5-yl)oxo)-3-cyclopropyl-2-methylpropane -2-amine (target compound I-3)
Figure PCTCN2022122990-appb-000084
Figure PCTCN2022122990-appb-000084
目标化合物I-3合成路线如下所示：The synthetic route of target compound 1-3 is as follows:
Figure PCTCN2022122990-appb-000085
Figure PCTCN2022122990-appb-000085
第一步：二乙基2-(环丙基甲基)-2-甲基丙二酸酯的合成The first step: the synthesis of diethyl 2-(cyclopropylmethyl)-2-methylmalonate
Figure PCTCN2022122990-appb-000086
Figure PCTCN2022122990-appb-000086
在室温下，向二乙基2-甲基丙二酯(20.0g,114mmol)溴甲基环丙烷(15.5g,114mmol)的乙醇(150mL)溶液加入乙醇钠(58.6g,172mmol)，反应液在65℃下搅拌3小时。反应结束后，浓缩得到粗品。用水和乙酸乙酯稀释。乙酸乙酯萃取，浓缩得到黄色的油二乙基2-(环丙基甲基)-2-甲基丙二酸酯(25.0g,收率95.4％)。At room temperature, sodium ethoxide (58.6 g, 172 mmol) was added to a solution of diethyl 2-methylpropylene glycol (20.0 g, 114 mmol) bromomethylcyclopropane (15.5 g, 114 mmol) in ethanol (150 mL), and the reaction solution Stir at 65°C for 3 hours. After the reaction was completed, it was concentrated to obtain a crude product. Dilute with water and ethyl acetate. Extracted with ethyl acetate and concentrated to give yellow oil diethyl 2-(cyclopropylmethyl)-2-methylmalonate (25.0 g, yield 95.4%).
1H NMR(400MHz,CDCl 3)δ4.31-4.18(m,2H),1.93-1.78(m,2H),1.33-1.26(m,3H),0.75-0.62(m,1H),0.53-0.40(m,2H),0.13-0.05(m,2H) 1 H NMR (400MHz, CDCl 3 )δ4.31-4.18(m,2H),1.93-1.78(m,2H),1.33-1.26(m,3H),0.75-0.62(m,1H),0.53-0.40 (m,2H),0.13-0.05(m,2H)
第二步：2-(环丙基甲基)-3-乙氧基-2-甲基-3-氧亚基丙酸的合成The second step: the synthesis of 2-(cyclopropylmethyl)-3-ethoxy-2-methyl-3-oxyethylene propionic acid
Figure PCTCN2022122990-appb-000087
Figure PCTCN2022122990-appb-000087
在室温下，向二乙基2-(环丙基甲基)-2-甲基丙二酸酯(24.0g,105mmol)的乙醇溶液(150mL)加入氢氧化钾(7.08g,126mmol)的水(30.0mL)溶液，反应液在25度下搅拌48小时。反应结束后，浓缩，加水稀释，用乙酸乙酯萃取除去杂质。用稀盐酸调节pH到3，乙酸乙酯萃取，浓缩得到黄色的油状液体2-(环丙基甲基)-3-乙氧基-2-甲基-3-氧亚基丙酸(15.8g,75.1％收率)To a solution of diethyl 2-(cyclopropylmethyl)-2-methylmalonate (24.0 g, 105 mmol) in ethanol (150 mL) was added potassium hydroxide (7.08 g, 126 mmol) in water at room temperature (30.0 mL) solution, and the reaction solution was stirred at 25 degrees for 48 hours. After the reaction, it was concentrated, diluted with water, and extracted with ethyl acetate to remove impurities. Adjust the pH to 3 with dilute hydrochloric acid, extract with ethyl acetate, and concentrate to obtain a yellow oily liquid 2-(cyclopropylmethyl)-3-ethoxy-2-methyl-3-oxyethylenepropionic acid (15.8g ,75.1% yield)
第三步：乙基3-氨基-2-(环丙基甲基)-2-甲基-3-氧亚基丙酯的合成The third step: the synthesis of ethyl 3-amino-2-(cyclopropylmethyl)-2-methyl-3-oxypropylene propyl ester
Figure PCTCN2022122990-appb-000088
Figure PCTCN2022122990-appb-000088
在室温下，向2-(环丙基甲基)-3-乙氧基-2-甲基-3-氧亚基丙酸(2.50g,12.5mmol)，氯化铵(1.67g,31.2mmol)和三乙胺(3.79g,37.46mmol)的二甲基甲酰胺(20.0mL)溶液中加入2-(7-偶氮苯并三氮唑)-N,N,N,N-四甲基脲六氟磷酸酯(5.22g,13.73mmol),反应液在25度下搅拌2小时。反应结束后，加水稀释，乙酸乙酯萃取，有机相水洗三次，硫酸钠干燥，过滤浓缩得到黄的的油乙基3-氨基-2-(环丙基甲基)-2-甲基-3-氧亚基-丙酯(6.0g,粗品)。At room temperature, add 2-(cyclopropylmethyl)-3-ethoxy-2-methyl-3-oxopropionic acid (2.50g, 12.5mmol), ammonium chloride (1.67g, 31.2mmol ) and triethylamine (3.79g, 37.46mmol) in dimethylformamide (20.0mL) solution was added 2-(7-azobenzotriazole)-N,N,N,N-tetramethyl Urea hexafluorophosphate (5.22g, 13.73mmol), and the reaction solution was stirred at 25°C for 2 hours. After the reaction, dilute with water, extract with ethyl acetate, wash the organic phase three times with water, dry over sodium sulfate, filter and concentrate to obtain yellow oily ethyl 3-amino-2-(cyclopropylmethyl)-2-methyl-3 -Oxylidene-propyl ester (6.0 g, crude).
第四步：乙基2-氨基-3-环丙基-2-甲基丙酯的合成The fourth step: the synthesis of ethyl 2-amino-3-cyclopropyl-2-methylpropyl ester
Figure PCTCN2022122990-appb-000089
Figure PCTCN2022122990-appb-000089
在室温下，向乙基3-氨基-2-(环丙基甲基)-2-甲基-3-氧亚基-丙酯6.00g,30.1mmol)的乙腈(40mL)和水(15mL)的混合液中加入醋酸碘苯(12.6g,39.1mmol)，将反应液在25度下搅拌12小时。反应结束后，浓缩，加1摩尔盐酸酸化至PH为2，乙酸乙酯萃取去去除杂质。用1摩尔氢氧化钠调节pH为10，乙酸乙酯萃取，浓缩得到黄色油状液体乙基2-氨基-3- 环丙基-2-甲基丙酯(680mg,13.2％收率)Ethyl 3-amino-2-(cyclopropylmethyl)-2-methyl-3-oxylidene-propyl ester 6.00 g, 30.1 mmol) in acetonitrile (40 mL) and water (15 mL) at room temperature Add iodobenzene acetate (12.6 g, 39.1 mmol) to the mixed solution, and stir the reaction solution at 25 degrees for 12 hours. After the reaction, concentrate, add 1 mole of hydrochloric acid to acidify to pH 2, and extract with ethyl acetate to remove impurities. Adjust the pH to 10 with 1 mole of sodium hydroxide, extract with ethyl acetate, and concentrate to obtain ethyl 2-amino-3-cyclopropyl-2-methylpropyl ester (680mg, 13.2% yield) as a yellow oily liquid
1H NMR(400MHz,CDCl3)δ4.11-3.99(m,2H),1.65-1.59(m,1H),1.33(mz,1H),1.23(s,3H),1.19-1.13(m,3H),0.57-0.46(m,1H),0.40-0.26(m,2H),0.04-0.14(m,2H) 1 H NMR (400MHz, CDCl3) δ4.11-3.99 (m, 2H), 1.65-1.59 (m, 1H), 1.33 (mz, 1H), 1.23 (s, 3H), 1.19-1.13 (m, 3H) ,0.57-0.46(m,1H),0.40-0.26(m,2H),0.04-0.14(m,2H)
第五步：2-氨基-3-环丙基-2-甲基丙烷-1-醇的合成Step 5: Synthesis of 2-amino-3-cyclopropyl-2-methylpropan-1-ol
Figure PCTCN2022122990-appb-000090
Figure PCTCN2022122990-appb-000090
在零度下，向乙基2-氨基-3-环丙基-2-甲基丙酯(650mg,3.80mmol)的四氢呋喃(10.0mL)分批次加入四氢铝锂(216mg,5.69mmol)，将反应液在0度下搅拌0.5小时。反应结束后，在氮气氛围下，无水四氢呋喃稀释。在零度用0.2mL 2摩尔氢氧化钠淬灭。过滤浓缩得到黄色油状液体2-氨基-3-环丙基-2-甲基丙烷-1-醇(450mg,91.8％收率)。To ethyl 2-amino-3-cyclopropyl-2-methylpropyl ester (650 mg, 3.80 mmol) in tetrahydrofuran (10.0 mL) was added lithium aluminum tetrahydride (216 mg, 5.69 mmol) in portions at zero degrees, The reaction solution was stirred at 0 degrees for 0.5 hours. After the reaction was completed, it was diluted with anhydrous tetrahydrofuran under nitrogen atmosphere. Quench with 0.2 mL of 2M NaOH at zero degrees. Filtration and concentration gave yellow oily liquid 2-amino-3-cyclopropyl-2-methylpropan-1-ol (450 mg, 91.8% yield).
1H NMR(400MHz,CDCl 3)δ3.44-3.29(m,2H),1.37-1.27(m,2H),1.14(s,3H),0.78-0.62(m,1H),0.56-0.44(m,2H),0.16-0.04(m,2H) 1 H NMR (400MHz, CDCl 3 ) δ3.44-3.29(m,2H),1.37-1.27(m,2H),1.14(s,3H),0.78-0.62(m,1H),0.56-0.44(m ,2H),0.16-0.04(m,2H)
第六步：6-溴-2-(二氟甲基)-3-氟吡啶的合成Step 6: Synthesis of 6-bromo-2-(difluoromethyl)-3-fluoropyridine
Figure PCTCN2022122990-appb-000091
Figure PCTCN2022122990-appb-000091
在-20度下，向6-溴-3-氟-吡啶-2-甲醛(3.00g,14.7mmol)的二氯甲烷(60.0mL)溶液加入二乙胺基三氟化硫(5.22g,32.3mmol)，反应液在25度下搅拌3小时。反应结束后，将反应液缓慢的倒入碳酸氢钠的冰水溶液中。二氯甲烷萃取，浓缩得到黄色固体6-溴-2-(二氟甲基)-3-氟吡啶(8)(3.05g,91.8％收率)To a solution of 6-bromo-3-fluoro-pyridine-2-carbaldehyde (3.00 g, 14.7 mmol) in dichloromethane (60.0 mL) was added diethylaminosulfur trifluoride (5.22 mmol), the reaction solution was stirred at 25 degrees for 3 hours. After the reaction was completed, the reaction solution was slowly poured into an ice solution of sodium bicarbonate. Extracted with dichloromethane, concentrated to give yellow solid 6-bromo-2-(difluoromethyl)-3-fluoropyridine (8) (3.05g, 91.8% yield)
LC-MS,M/Z(ESI):226.0[M+H] + LC-MS, M/Z(ESI):226.0[M+H] +
第七步：1-((6-溴-2-(二氟甲基)吡啶-3-基)氧代)-3-环丙基-2-甲基丙烷-2-胺的合成Step 7: Synthesis of 1-((6-bromo-2-(difluoromethyl)pyridin-3-yl)oxo)-3-cyclopropyl-2-methylpropane-2-amine
Figure PCTCN2022122990-appb-000092
Figure PCTCN2022122990-appb-000092
在室温下，向6-溴-2-(二氟甲基)-3-氟吡啶(800mg,3.54mmol)，2-氨基-3-环丙基-2-甲基丙烷-1-醇(411mg,3.19mmol)的四氢呋喃(10mL)溶液加入叔丁醇钾(6.40mmol,2eq)，反应液在70度下搅拌2小时。反应结束后，加水稀释，乙酸乙酯萃取。浓缩，粗品通过反相色谱(碱性)分离得到白的固体1-((6-溴-2-(二氟甲基)吡啶-3-基)氧代)-3-环丙基-2-甲基丙烷-2-胺(600mg,45.5％收率)。At room temperature, add 6-bromo-2-(difluoromethyl)-3-fluoropyridine (800mg, 3.54mmol), 2-amino-3-cyclopropyl-2-methylpropan-1-ol (411mg , 3.19mmol) in tetrahydrofuran (10mL) was added potassium tert-butoxide (6.40mmol, 2eq), and the reaction solution was stirred at 70°C for 2 hours. After the reaction, it was diluted with water and extracted with ethyl acetate. Concentrated and the crude product was isolated by reverse phase chromatography (basic) to give 1-((6-bromo-2-(difluoromethyl)pyridin-3-yl)oxo)-3-cyclopropyl-2-yl as a white solid Methylpropan-2-amine (600 mg, 45.5% yield).
LC-MS,M/Z(ESI):335.0[M+H] + LC-MS, M/Z(ESI):335.0[M+H] +
1H NMR(400MHz,DMSO-d6)δ7.79-7.72(m,1H),7.66-7.64(m,1H),7.28-6.97(m,1H),3.86(s,2H),1.65(s,2H),1.42-1.25(m,2H),1.08(s,3H),0.80-0.67(m,1H),0.41-0.26(m,2H),0.02-0.01(m,2H) 1 H NMR(400MHz,DMSO-d6)δ7.79-7.72(m,1H),7.66-7.64(m,1H),7.28-6.97(m,1H),3.86(s,2H),1.65(s, 2H),1.42-1.25(m,2H),1.08(s,3H),0.80-0.67(m,1H),0.41-0.26(m,2H),0.02-0.01(m,2H)
第八步：1-((2',6-二(二氟甲基)-[2,4'-联吡啶]-5-基)氧代)-3-环丙基-2-甲基丙烷-2-胺的合成Step 8: 1-((2',6-bis(difluoromethyl)-[2,4'-bipyridyl]-5-yl)oxo)-3-cyclopropyl-2-methylpropane Synthesis of -2-amine
Figure PCTCN2022122990-appb-000093
Figure PCTCN2022122990-appb-000093
在室温下，向1-((6-溴-2-(二氟甲基)吡啶-3-基)氧代)-3-环丙基-2-甲基丙烷-2-胺(300mg,895μmol)，2-(二氟甲基)-4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)吡啶(319mg,1.25mmol)，碳酸钾(371mg,2.69mmol)的二氧六环(3.00mL)和水(1.00mL)的混合液中加入二氯双[二叔丁基-(4-二甲基氨基苯基)膦]钯(II)(63.3mg,89.5μmol)，将反应液在80度下搅拌2小时。反应结束后，加水稀释，乙酸乙酯萃取。浓缩得到粗品。粗品经反相制备(色谱柱:Waters Xbridge 150×25mm×5μm；流动相:[水(0.225％氨水)-乙腈]；B％:34％-64％,9min)分离得到1-((2',6-二(二氟甲基)-[2,4'-联吡啶]-5-基)氧代)-3-环丙基-2-甲基丙烷-2-胺(100mg,12.2％收率)At room temperature, to 1-((6-bromo-2-(difluoromethyl)pyridin-3-yl)oxo)-3-cyclopropyl-2-methylpropane-2-amine (300mg, 895μmol ), 2-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (319mg, 1.25mmol), Add dichlorobis[di-tert-butyl-(4-dimethylaminophenyl)phosphine]palladium to a mixture of potassium carbonate (371mg, 2.69mmol) in dioxane (3.00mL) and water (1.00mL) (II) (63.3 mg, 89.5 μmol), the reaction solution was stirred at 80 degrees for 2 hours. After the reaction, it was diluted with water and extracted with ethyl acetate. Concentration gave the crude product. The crude product was prepared by reverse phase (chromatographic column: Waters Xbridge 150 × 25mm × 5 μm; mobile phase: [water (0.225% ammonia water)-acetonitrile]; B%: 34%-64%, 9min) to separate and obtain 1-((2' ,6-bis(difluoromethyl)-[2,4'-bipyridyl]-5-yl)oxo)-3-cyclopropyl-2-methylpropane-2-amine (100mg, 12.2% yield Rate)
LC-MS,M/Z(ESI):383.9[M+H] + LC-MS, M/Z(ESI):383.9[M+H] +
第十步：(S)-1-((2',6-二(二氟甲基)-[2,4'-联吡啶]-5-基)氧代)-3-环丙基-2-甲基丙烷-2-胺(I-3)的制备Step 10: (S)-1-((2',6-bis(difluoromethyl)-[2,4'-bipyridyl]-5-yl)oxo)-3-cyclopropyl-2 -Preparation of methylpropane-2-amine (I-3)
Figure PCTCN2022122990-appb-000094
Figure PCTCN2022122990-appb-000094
粗品经SFC拆分(色谱柱:Daicel ChiralPak IG(250×30mm,10μm)；移动相:[二氧化碳(0.1％氨水)-甲醇]；B％:20％-20％,4.6min)得到白的固体(S)-1-((2',6-二(二氟甲基)-[2,4'-联吡啶]-5-基)氧代)-3-环丙基-2-甲基丙烷-2-胺(I-3)The crude product was separated by SFC (chromatographic column: Daicel ChiralPak IG (250×30mm, 10 μm); mobile phase: [carbon dioxide (0.1% ammonia water)-methanol]; B%: 20%-20%, 4.6min) to obtain a white solid (S)-1-((2',6-bis(difluoromethyl)-[2,4'-bipyridyl]-5-yl)oxo)-3-cyclopropyl-2-methylpropane -2-amine (I-3)
1H NMR(400MHz,CDCl 3)δ8.77-8.71(m,1H),8.24-8.18(m,1H),8.06-8.01(m,1H),7.96-7.94(m,1H),7.44(d,1H),7.00-6.56(m,2H),4.02-3.98(m,1H),3.96-3.92(m,1H),3.83-3.83(m,1H),1.57-1.47(m,2H),1.33(s,3H),0.79-0.69(m,1H),0.54-0.46(m,2H),0.14-0.08(m,2H)。 1 H NMR (400MHz, CDCl 3 )δ8.77-8.71(m,1H),8.24-8.18(m,1H),8.06-8.01(m,1H),7.96-7.94(m,1H),7.44(d ,1H),7.00-6.56(m,2H),4.02-3.98(m,1H),3.96-3.92(m,1H),3.83-3.83(m,1H),1.57-1.47(m,2H),1.33 (s, 3H), 0.79-0.69 (m, 1H), 0.54-0.46 (m, 2H), 0.14-0.08 (m, 2H).
实施例4：目标化合物I-4的制备Embodiment 4: the preparation of target compound 1-4
(S)-1-((2',6-二(二氟甲基)-[2,4'-联吡啶]-5-基)氧代)-3-(3,3-二氟环丁基)-2-甲基丙烷-2-胺(S)-1-((2',6-bis(difluoromethyl)-[2,4'-bipyridyl]-5-yl)oxo)-3-(3,3-difluorocyclobutane base)-2-methylpropan-2-amine
Figure PCTCN2022122990-appb-000095
Figure PCTCN2022122990-appb-000095
目标化合物I-4合成路线如下所示：The synthetic route of target compound 1-4 is as follows:
Figure PCTCN2022122990-appb-000096
Figure PCTCN2022122990-appb-000096
第一步：2',6-二(二氟甲基)-5-氟-2,4'-联吡啶的合成Step 1: Synthesis of 2',6-bis(difluoromethyl)-5-fluoro-2,4'-bipyridine
Figure PCTCN2022122990-appb-000097
Figure PCTCN2022122990-appb-000097
在室温下，将6-溴-2-(二氟甲基)-3-氟-吡啶(500mg,2.21mmol)和2-(二氟甲基)-4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)吡啶(846mg,3.32mmol)溶于四氢呋喃(20.0mL)和水(5.00mL)中，再加入磷酸钾(939mg,4.42mmol)和[2-(2-氨基苯基)苯基]-氯-钯；二环己基-[3-(2,4,6-三异丙基苯基)苯基]磷烷(87.0mg,111μmol)，置换氮气3次，在80℃搅拌12小时，反应完成用水(20.0mL)稀释，之后用乙酸乙酯(10.0mL×3)萃取，有机相用饱和食盐水洗涤和无水 硫酸钠干燥后，然后过滤，浓缩得到粗品。粗品经柱层析(二氧化硅，石油醚：乙酸乙酯＝8:1到3:1)纯化得到黄色固体2',6-二(二氟甲基)-5-氟-2,4'-联吡啶(400mg，收率65.9％)。At room temperature, mix 6-bromo-2-(difluoromethyl)-3-fluoro-pyridine (500 mg, 2.21 mmol) and 2-(difluoromethyl)-4-(4,4,5,5- Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (846mg, 3.32mmol) was dissolved in tetrahydrofuran (20.0mL) and water (5.00mL), and potassium phosphate (939mg, 4.42 mmol) and [2-(2-aminophenyl)phenyl]-chloro-palladium; dicyclohexyl-[3-(2,4,6-triisopropylphenyl)phenyl]phosphine (87.0mg , 111 μmol), replaced nitrogen 3 times, stirred at 80°C for 12 hours, diluted with water (20.0mL) after the reaction was completed, extracted with ethyl acetate (10.0mL×3), the organic phase was washed with saturated brine and anhydrous sodium sulfate After drying, it was then filtered and concentrated to give the crude product. The crude product was purified by column chromatography (silica, petroleum ether: ethyl acetate = 8:1 to 3:1) to give yellow solid 2',6-bis(difluoromethyl)-5-fluoro-2,4' - Bipyridine (400 mg, yield 65.9%).
LC-MS,M/Z(ESI):275.1[M+H] + LC-MS, M/Z(ESI):275.1[M+H] +
第二步：2-((3,3-二氟环丁基)甲基)-2-甲基丙二酸二乙酯的合成
Figure PCTCN2022122990-appb-000098
The second step: the synthesis of diethyl 2-((3,3-difluorocyclobutyl)methyl)-2-methylmalonate
Figure PCTCN2022122990-appb-000098
在室温下，将2-甲基丙二酸二乙酯(2.00g,11.5mmol)和3-(溴甲基)-1,1-二氟-环丁烷(2.15g,11.6mmol)加入到乙醇钠(7.81g,23.0mmol,20％w/w)中，然后在氮气保护下，反应液在65℃下搅拌六个小时，反应完成后，浓缩反应液，然后在0℃下，用水稀释，之后用乙酸乙酯萃取，有机相用饱和食盐水洗涤和无水硫酸钠干燥后，然后过滤，浓缩得到黄色油状物2-((3,3-二氟环丁基)甲基)-2-甲基丙二酸二乙酯(1.90g，收率59.5％)。At room temperature, diethyl 2-methylmalonate (2.00 g, 11.5 mmol) and 3-(bromomethyl)-1,1-difluoro-cyclobutane (2.15 g, 11.6 mmol) were added to Sodium ethoxide (7.81g, 23.0mmol, 20% w/w), and then under the protection of nitrogen, the reaction solution was stirred at 65°C for six hours. After the reaction was completed, the reaction solution was concentrated, and then diluted with water at 0°C , then extracted with ethyl acetate, the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate, then filtered and concentrated to give yellow oil 2-((3,3-difluorocyclobutyl)methyl)-2 - Diethyl methylmalonate (1.90 g, yield 59.5%).
第三步：2-((3,3-二氟环丁基)甲基)-3-乙氧基-2-甲基-3-氧代丙酸的合成The third step: the synthesis of 2-((3,3-difluorocyclobutyl)methyl)-3-ethoxy-2-methyl-3-oxopropionic acid
Figure PCTCN2022122990-appb-000099
Figure PCTCN2022122990-appb-000099
在室温下，将2-((3,3-二氟环丁基)甲基)-2-甲基丙二酸二乙酯(1.90g,6.83mmol)溶于乙醇(10.0mL)和水(5.00mL)中，再加入氢氧化钾(460mg,8.19mmol)，反应液在65℃下搅拌12小时，反应完成后，向反应液中加入水(20.00mL)，之后用乙酸乙酯(10.0mL×2)萃取，然后用1M盐酸水溶液将水相的PH调节至3，之后用乙酸乙酯(10.0mL×3)萃取，有机相用饱和食盐水洗涤和无水硫酸钠干燥后，然后过滤，浓缩得到黄色油状物2-((3,3-二氟环丁基)甲基)-3-乙氧基-2-甲基-3-氧代丙酸(700mg，产率41.0％)。Diethyl 2-((3,3-difluorocyclobutyl)methyl)-2-methylmalonate (1.90 g, 6.83 mmol) was dissolved in ethanol (10.0 mL) and water ( 5.00mL), potassium hydroxide (460mg, 8.19mmol) was added, and the reaction solution was stirred at 65°C for 12 hours. After the reaction was completed, water (20.00mL) was added to the reaction solution, and then ethyl acetate (10.0mL ×2) extraction, and then adjust the pH of the aqueous phase to 3 with 1M hydrochloric acid aqueous solution, then extract with ethyl acetate (10.0mL×3), the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate, and then filtered, Concentration gave 2-((3,3-difluorocyclobutyl)methyl)-3-ethoxy-2-methyl-3-oxopropanoic acid (700 mg, yield 41.0%) as a yellow oil.
第四步：3-氨基-2-((3,3-二氟环丁基)甲基)-2-甲基-3-氧代丙酸乙酯的合成Step 4: Synthesis of ethyl 3-amino-2-((3,3-difluorocyclobutyl)methyl)-2-methyl-3-oxopropionate
Figure PCTCN2022122990-appb-000100
Figure PCTCN2022122990-appb-000100
在室温下，将2-((3,3-二氟环丁基)甲基)-3-乙氧基-2-甲基-3-氧代丙酸(700mg,2.80mmol)，氯化铵(449mg,8.39mmol)溶于N,N-二甲基甲酰胺(7.00mL)中,再加入O-(7-氮杂苯并三氮唑-1-基)-N,N,N’,N’-四甲基脲六氟磷酸酯(1.60g,4.20mmol)和N,N-二异丙基乙胺(1.81g,13.99mmol)，反应液在25℃下搅拌5小时，反应完成后，用水(20.00mL)稀释，之后用乙酸乙酯(10.0mL×3)萃取，有机相先用0.1M的盐酸水溶液洗涤2次，然后再用饱和食盐水洗涤和无水硫酸钠干燥后，然后过滤，浓缩得到黄色油状物3-氨基-2-((3,3-二氟环丁基)甲 基)-2-甲基-3-氧代丙酸乙酯(1.00g，粗品)。At room temperature, 2-((3,3-difluorocyclobutyl)methyl)-3-ethoxy-2-methyl-3-oxopropionic acid (700mg, 2.80mmol), ammonium chloride (449mg, 8.39mmol) was dissolved in N,N-dimethylformamide (7.00mL), and O-(7-azabenzotriazol-1-yl)-N,N,N' was added, N'-tetramethyluronium hexafluorophosphate (1.60g, 4.20mmol) and N,N-diisopropylethylamine (1.81g, 13.99mmol), the reaction solution was stirred at 25°C for 5 hours, after the reaction was completed , diluted with water (20.00mL), then extracted with ethyl acetate (10.0mL×3), the organic phase was first washed twice with 0.1M aqueous hydrochloric acid solution, then washed with saturated brine and dried over anhydrous sodium sulfate, then Filtration and concentration afforded ethyl 3-amino-2-((3,3-difluorocyclobutyl)methyl)-2-methyl-3-oxopropanoate (1.00 g, crude) as a yellow oil.
第五步：2-氨基-3-(3,3-二氟环丁基)-2-甲基丙酸乙酯的合成Step 5: Synthesis of ethyl 2-amino-3-(3,3-difluorocyclobutyl)-2-methylpropionate
Figure PCTCN2022122990-appb-000101
Figure PCTCN2022122990-appb-000101
在室温下，将3-氨基-2-((3,3-二氟环丁基)甲基)-2-甲基-3-氧代丙酸乙酯(1.00g,4.01mmol)溶于乙腈(70.0mL)和水(5.00mL)中，再加入[苯基-(2,2,2-三氟乙酰基)氧代-λ3-碘烷基]2,2,2-三氟醋酸盐(2.07g,4.81mmol)，反应液在25℃下搅拌12小时，反应完成后，用1M氢氧化钠水溶液将水相的PH调节至11，再用乙酸乙酯(20.0mL×3)萃取，有机相用饱和食盐水洗涤后，再用无水硫酸钠干燥后，然后过滤，浓缩得到黄色油状物2-氨基-3-(3,3-二氟环丁基)-2-甲基丙酸乙酯(831mg，粗品)。Dissolve ethyl 3-amino-2-((3,3-difluorocyclobutyl)methyl)-2-methyl-3-oxopropanoate (1.00 g, 4.01 mmol) in acetonitrile at room temperature (70.0mL) and water (5.00mL), then add [phenyl-(2,2,2-trifluoroacetyl) oxo-λ3-iodoalkyl] 2,2,2-trifluoroacetate (2.07g, 4.81mmol), the reaction solution was stirred at 25°C for 12 hours, after the reaction was completed, the pH of the aqueous phase was adjusted to 11 with 1M aqueous sodium hydroxide solution, and then extracted with ethyl acetate (20.0mL×3), The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 2-amino-3-(3,3-difluorocyclobutyl)-2-methylpropionic acid as a yellow oil Ethyl ester (831 mg, crude).
第六步：2-氨基-3-(3,3-二氟环丁基)-2-甲基丙烷-1-醇的合成Step 6: Synthesis of 2-amino-3-(3,3-difluorocyclobutyl)-2-methylpropan-1-ol
Figure PCTCN2022122990-appb-000102
Figure PCTCN2022122990-appb-000102
在0℃下，将2-氨基-3-(3,3-二氟环丁基)-2-甲基丙酸乙酯(831mg,4.01mmol)溶于四氢呋喃(10.0mL)中，再分批加入四氢铝锂(228mg,6.02mmol)，反应液在0℃下搅拌0.5小时，反应完成后，在0℃下用1M氢氧化钠水溶液淬灭反应，然后用四氢呋喃(30.0mL)稀释，再用无水硫酸钠干燥后，然后过滤，浓缩得到黄色油状物2-氨基-3-(3,3-二氟环丁基)-2-甲基丙烷-1-醇(600mg，粗品)。Dissolve ethyl 2-amino-3-(3,3-difluorocyclobutyl)-2-methylpropionate (831mg, 4.01mmol) in tetrahydrofuran (10.0mL) at 0°C, and Lithium aluminum tetrahydride (228mg, 6.02mmol) was added, and the reaction solution was stirred at 0°C for 0.5 hours. After the reaction was completed, the reaction was quenched with 1M aqueous sodium hydroxide solution at 0°C, then diluted with tetrahydrofuran (30.0mL), and then After drying over anhydrous sodium sulfate, then filtration and concentration gave 2-amino-3-(3,3-difluorocyclobutyl)-2-methylpropan-1-ol (600 mg, crude) as a yellow oil.
第七步：(S)-1-((2',6-二(二氟甲基)-[2,4'-联吡啶]-5-基)氧代)-3-(3,3-二氟环丁基)-2-甲基丙烷-2-胺(I-4)的合成The seventh step: (S)-1-((2',6-bis(difluoromethyl)-[2,4'-bipyridyl]-5-yl)oxo)-3-(3,3- Synthesis of Difluorocyclobutyl)-2-methylpropan-2-amine (I-4)
Figure PCTCN2022122990-appb-000103
Figure PCTCN2022122990-appb-000103
在室温下，将2-(二氟甲基)-6-[2-(二氟甲基)-4-吡啶基]-3-氟-吡啶(400mg,1.46mmol)，2-氨基-3-(3,3-二氟环丁基)-2-甲基-丙烷-1-醇(523mg,2.92mmol)溶于四氢呋喃(8.00mL)中，再加入叔丁醇钾(1M,3.65mL)溶液，反应液在70℃下搅拌4小时，反应完成后，用水(20.00mL)稀释，之后用乙酸乙酯(10.00mL×3)萃取，有机相用饱和食盐水洗涤和无水硫酸钠干燥后，然后过滤，浓缩得粗品。粗品经反相制备(色谱柱:Phenomenex Synergi C18150×25mm×10μm；流动相:[水(0.225％甲酸)-乙腈]；B％:16％-46％,2min)分离得到黄色固体，再经过SFC(色谱柱：DAICEL CHIRALPAK AD(250mm×30mm,10μm)；流动相:[0.1％ 氨/乙醇]；B％:20％-20％,3.9min)分离得到：黄色固体(S)-1-((2',6-二(二氟甲基)-[2,4'-联吡啶]-5-基)氧代)-3-(3,3-二氟环丁基)-2-甲基丙烷-2-胺(I-4)(43.6mg，收率27.8％)。At room temperature, 2-(difluoromethyl)-6-[2-(difluoromethyl)-4-pyridyl]-3-fluoro-pyridine (400 mg, 1.46 mmol), 2-amino-3- (3,3-Difluorocyclobutyl)-2-methyl-propan-1-ol (523mg, 2.92mmol) was dissolved in tetrahydrofuran (8.00mL), and potassium tert-butoxide (1M, 3.65mL) solution was added , the reaction solution was stirred at 70° C. for 4 hours. After the reaction was completed, it was diluted with water (20.00 mL), then extracted with ethyl acetate (10.00 mL×3), and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. It was then filtered and concentrated to obtain the crude product. The crude product was prepared by reverse phase (chromatographic column: Phenomenex Synergi C18 150×25mm×10 μm; mobile phase: [water (0.225% formic acid)-acetonitrile]; B%: 16%-46%, 2min) to separate a yellow solid, and then through SFC (Chromatographic column: DAICEL CHIRALPAK AD (250mm × 30mm, 10μm); Mobile phase: [0.1% ammonia/ethanol]; B%: 20%-20%, 3.9min) separated to obtain: yellow solid (S)-1-( (2',6-bis(difluoromethyl)-[2,4'-bipyridyl]-5-yl)oxo)-3-(3,3-difluorocyclobutyl)-2-methyl Propan-2-amine (I-4) (43.6 mg, yield 27.8%).
1H NMR(400MHz，DMSO-d 6)δ8.78(d,1H),8.40(d,1H),8.32(s,1H),8.21(d,1H,),7.80(d,1H),6.9-7.4(m,2H),3.87(s,2H),2.6-2.7(m,2H),2.2-2.3(m,3H),1.70(d,2H),1.23(s,1H),1.08(s,3H)。 1 H NMR (400MHz, DMSO-d 6 )δ8.78(d,1H),8.40(d,1H),8.32(s,1H),8.21(d,1H,),7.80(d,1H),6.9 -7.4(m,2H),3.87(s,2H),2.6-2.7(m,2H),2.2-2.3(m,3H),1.70(d,2H),1.23(s,1H),1.08(s ,3H).
LC-MS,M/Z(ESI):434.2[M+H] +。 LC-MS, M/Z (ESI): 434.2 [M+H] + .
Figure PCTCN2022122990-appb-000104
Figure PCTCN2022122990-appb-000104
黄色固体(R)-1-((2',6-二(二氟甲基)-[2,4'-联吡啶]-5-基)氧代)-3-(3,3-二氟环丁基)-2-甲基丙烷-2-胺(R-I-4)(45.0mg，产率28.1％)。Yellow solid (R)-1-((2',6-bis(difluoromethyl)-[2,4'-bipyridyl]-5-yl)oxo)-3-(3,3-difluoro Cyclobutyl)-2-methylpropan-2-amine (R-I-4) (45.0 mg, 28.1% yield).
1H NMR(400MHz，DMSO-d 6)δ8.80(d,1H),8.43(d,1H),8.33(s,1H),8.23(d,1H),7.84(d,1H),6.9-7.5(m,2H),4.03(d,2H),2.6-2.8(m,2H),2.2-2.3(m,3H),1.83(br t,2H),1.20(s,3H)。 1 H NMR (400MHz, DMSO-d 6 )δ8.80(d,1H),8.43(d,1H),8.33(s,1H),8.23(d,1H),7.84(d,1H),6.9- 7.5 (m, 2H), 4.03 (d, 2H), 2.6-2.8 (m, 2H), 2.2-2.3 (m, 3H), 1.83 (br t, 2H), 1.20 (s, 3H).
LC-MS,M/Z(ESI):434.2[M+H] + LC-MS, M/Z(ESI):434.2[M+H] +
实施例5：目标化合物I-6的制备Embodiment 5: the preparation of target compound 1-6
(2S)-1-(4-[2-(二氟甲基)吡啶-4-基]-2-(五氟-λ6-巯基)苯氧基)-2,4-二甲基戊烷-2-胺(目标化合物I-6)。(2S)-1-(4-[2-(Difluoromethyl)pyridin-4-yl]-2-(pentafluoro-λ6-mercapto)phenoxy)-2,4-dimethylpentane- 2-Amine (target compound 1-6).
Figure PCTCN2022122990-appb-000105
Figure PCTCN2022122990-appb-000105
目标化合物I-6的合成路线如下所示：The synthetic route of target compound 1-6 is as follows:
Figure PCTCN2022122990-appb-000106
Figure PCTCN2022122990-appb-000106
第一步：1-氟-4-硝基-2-(五氟-λ 6-巯基)苯的合成 Step 1: Synthesis of 1-fluoro-4-nitro-2-(pentafluoro-λ 6 -mercapto)benzene
Figure PCTCN2022122990-appb-000107
Figure PCTCN2022122990-appb-000107
将1-氟-2-(五氟-λ 6-巯基)苯(2.50g,11.3mmol)溶于浓硫酸(25.0mL)中，然后在冰浴条件下慢慢滴加浓硝酸(780mg,12.3mmol)，滴加完成后反应液在25℃条件下搅拌3小时。反应完成后，将反应液慢慢倒入碎冰，然后用乙酸乙酯(50.0mL×3)萃取，合并有机层，用饱和食盐水(100mL)洗涤有机相，有机相用无水硫酸钠干燥，浓缩得到1-氟-4-硝基-2-(五氟-λ 6-巯基)苯(3.00g，粗品)。 Dissolve 1-fluoro-2-(pentafluoro-λ 6 -mercapto)benzene (2.50g, 11.3mmol) in concentrated sulfuric acid (25.0mL), then slowly add concentrated nitric acid (780mg, 12.3 mmol), after the dropwise addition, the reaction solution was stirred at 25°C for 3 hours. After the reaction was completed, the reaction solution was slowly poured into crushed ice, then extracted with ethyl acetate (50.0 mL×3), the organic layers were combined, and the organic phase was washed with saturated brine (100 mL), and the organic phase was dried over anhydrous sodium sulfate , concentrated to give 1-fluoro-4-nitro-2-(pentafluoro-λ 6 -mercapto)benzene (3.00 g, crude product).
1H NMR(400MHz,CDCl 3)δ8.82-8.66(m,1H),8.46(td,1H),7.45(t,1H)。 1 H NMR (400 MHz, CDCl 3 ) δ 8.82-8.66 (m, 1H), 8.46 (td, 1H), 7.45 (t, 1H).
第二步：4-硝基-2-(五氟-λ 6-巯基)苯酚的合成 The second step: the synthesis of 4-nitro-2-(pentafluoro-λ 6 -mercapto)phenol
Figure PCTCN2022122990-appb-000108
Figure PCTCN2022122990-appb-000108
把1-氟-4-硝基-2-(五氟-λ 6-巯基)苯(600mg,2.26mmol)溶解在N,N-二甲基甲酰胺(12.0mL)中，将碳酸钾(625mg,4.53mmol)加入到该溶液中，在25℃下反应30分钟后，将反应液降温至0℃，然后滴加碘甲烷(642mg,4.53mmol)，最后反应液在25度搅拌12小时。反应完成后，将反应液倒入碎冰，然后用乙酸乙酯(30.0mL×3)萃取，合并有机层，用饱和食盐水(50.0mL)，洗涤有机相，无水硫酸钠干燥，浓缩得到粗品。粗品经柱层析(二氧化硅，石油醚：乙酸乙酯＝5:1到3:1)纯化后得到4-硝基-2-(五氟-λ 6-巯基)苯酚(442mg,收率69.9％)。 Dissolve 1-fluoro-4-nitro-2-(pentafluoro-λ 6 -mercapto)benzene (600mg, 2.26mmol) in N,N-dimethylformamide (12.0mL), potassium carbonate (625mg , 4.53mmol) was added to the solution, and after reacting at 25°C for 30 minutes, the reaction solution was cooled to 0°C, then methyl iodide (642mg, 4.53mmol) was added dropwise, and finally the reaction solution was stirred at 25°C for 12 hours. After the reaction was completed, the reaction solution was poured into crushed ice, then extracted with ethyl acetate (30.0 mL×3), the organic layers were combined, washed with saturated brine (50.0 mL), dried over anhydrous sodium sulfate, and concentrated to obtain Crude. The crude product was purified by column chromatography (silica, petroleum ether: ethyl acetate = 5:1 to 3:1) to obtain 4-nitro-2-(pentafluoro-λ 6 -mercapto)phenol (442mg, yield 69.9%).
1H NMR(400MHz,DMSO)δ8.48(d,1H),8.34(dd,1H),7.28(d,1H)。 1 H NMR (400 MHz, DMSO) δ 8.48 (d, 1H), 8.34 (dd, 1H), 7.28 (d, 1H).
第三步：1-甲氧基-4-硝基-2-(五氟-λ 6-巯基)苯的合成 The third step: the synthesis of 1-methoxy-4-nitro-2-(pentafluoro-λ 6 -mercapto)benzene
Figure PCTCN2022122990-appb-000109
Figure PCTCN2022122990-appb-000109
把4-硝基-2-(五氟-λ 6-巯基)苯酚(600mg,2.26mmol)溶解在N,N-二甲基甲酰胺(6.00mL)中，然后加入碳酸钾(625mg,4.53mmol)，氮气置换3次，反应液在25℃下搅拌0.5小时。然后在0℃滴加碘甲烷(642mg,4.53mmol)，滴加完毕后，反应液在25℃下搅拌12小时。反应完成后，将反应液倒入到冰水(30.0mL)中，然后用乙酸乙酯(20.0mL×3)萃取，有机相用盐水(40.0mL)洗涤和无水硫酸钠干燥后，过滤浓缩得到粗品。粗品经柱层析(二氧化硅，石油醚：乙酸乙酯＝5:1到3:1)纯化后得到1-甲氧基-4-硝基-2-(五氟-λ 6-巯基)苯(442mg,收率69.9％) Dissolve 4-nitro-2-(pentafluoro-λ 6 -mercapto)phenol (600mg, 2.26mmol) in N,N-dimethylformamide (6.00mL), then add potassium carbonate (625mg, 4.53mmol ), nitrogen replacement 3 times, and the reaction solution was stirred at 25°C for 0.5 hours. Then methyl iodide (642mg, 4.53mmol) was added dropwise at 0°C. After the dropwise addition, the reaction solution was stirred at 25°C for 12 hours. After the reaction was complete, the reaction solution was poured into ice water (30.0 mL), then extracted with ethyl acetate (20.0 mL×3), the organic phase was washed with brine (40.0 mL) and dried over anhydrous sodium sulfate, filtered and concentrated get crude. The crude product was purified by column chromatography (silica, petroleum ether: ethyl acetate = 5:1 to 3:1) to obtain 1-methoxy-4-nitro-2-(pentafluoro-λ 6 -mercapto) Benzene (442mg, yield 69.9%)
1H NMR(400MHz,DMSO)δ8.59-8.40(m,2H),7.58(d,1H),4.07(s,3H)。 1 H NMR (400 MHz, DMSO) δ 8.59-8.40 (m, 2H), 7.58 (d, 1H), 4.07 (s, 3H).
第四步：4-甲氧基-3-(五氟-λ 6-巯基)苯胺的合成 Step 4: Synthesis of 4-methoxy-3-(pentafluoro-λ 6 -mercapto)aniline
Figure PCTCN2022122990-appb-000110
Figure PCTCN2022122990-appb-000110
将1-甲氧基-4-硝基-2-(五氟-λ 6-巯基)苯(440mg,1.58mmol)溶解在乙醇(10.0mL)中，在氮气保护下，将钯碳(10％,44.0mg)加入到该溶液中，然后用氮气置换3次，在氢气(50PSI)和30℃下反应15小时。反应完成后，将反应液用硅藻土过滤，滤液浓缩后得到粗品，粗品经柱层析(二氧化硅，石油醚：乙酸乙酯＝8:1到6:1)纯化后得到4-甲氧基-3-(五氟-λ 6-巯基)苯胺(338mg,收率86.0％)。 1-Methoxy-4-nitro-2-(pentafluoro-λ 6 -mercapto)benzene (440mg, 1.58mmol) was dissolved in ethanol (10.0mL), and palladium carbon (10% , 44.0mg) was added to the solution, then replaced with nitrogen three times, and reacted under hydrogen (50PSI) at 30°C for 15 hours. After the reaction was completed, the reaction solution was filtered with diatomaceous earth, and the filtrate was concentrated to obtain a crude product, which was purified by column chromatography (silica, petroleum ether: ethyl acetate = 8:1 to 6:1) to obtain 4-formaldehyde Oxy-3-(pentafluoro-λ 6 -mercapto)aniline (338 mg, yield 86.0%).
第五步：4-溴-1-甲氧基-2-(五氟-λ 6-巯基)苯的合成 Step 5: Synthesis of 4-bromo-1-methoxy-2-(pentafluoro-λ 6 -mercapto)benzene
Figure PCTCN2022122990-appb-000111
Figure PCTCN2022122990-appb-000111
将4-甲氧基-3-(五氟-λ 6-巯基)苯胺(338mg,1.36mmol)溶于乙腈(4.00mL)中，在0℃下，加入溴化铜(303mg,1.36mmol)和亚硝酸叔丁酯(363mg,3.53mmol)，反应液在25℃下搅拌0.5小时。反应完成后，将反应液倒入到冰水(10.0mL)中，然后用乙酸乙酯(10.0mL×3)萃取，有机相用盐水(25.0mL)洗涤和无水硫酸钠干燥后，过滤浓缩得到粗品。粗品经柱层析(二氧化硅，石油醚：乙酸乙酯＝5:1到3:1)纯化后得到4-溴-1-甲氧基-2-(五氟-λ 6-巯基)苯(374mg,收率88.0％)。 4-Methoxy-3-(pentafluoro-λ 6 -mercapto)aniline (338mg, 1.36mmol) was dissolved in acetonitrile (4.00mL), at 0°C, copper bromide (303mg, 1.36mmol) was added and Tert-butyl nitrite (363mg, 3.53mmol), the reaction solution was stirred at 25°C for 0.5 hours. After the reaction was complete, the reaction solution was poured into ice water (10.0 mL), then extracted with ethyl acetate (10.0 mL×3), the organic phase was washed with brine (25.0 mL) and dried over anhydrous sodium sulfate, filtered and concentrated get crude. The crude product was purified by column chromatography (silica, petroleum ether: ethyl acetate = 5:1 to 3:1) to obtain 4-bromo-1-methoxy-2-(pentafluoro-λ 6 -mercapto)benzene (374mg, yield 88.0%).
1H NMR(400MHz,DMSO)δ7.96(d,1H),7.84(dd,1H),7.35(d,1H),3.93(s,3H)。 1 H NMR (400 MHz, DMSO) δ 7.96 (d, 1H), 7.84 (dd, 1H), 7.35 (d, 1H), 3.93 (s, 3H).
第六步：2-(二氟甲基)-4-[4-甲氧基-3-(五氟-λ 6-巯基)苯基]吡啶的合成 Step 6: Synthesis of 2-(difluoromethyl)-4-[4-methoxy-3-(pentafluoro-λ 6 -mercapto)phenyl]pyridine
Figure PCTCN2022122990-appb-000112
Figure PCTCN2022122990-appb-000112
将4-溴-1-甲氧基-2-(五氟-λ 6-巯基)苯(374mg,1.19mmol)和2-(二氟甲基)-4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)吡啶(609mg,2.39mmol)，磷酸钾(760mg,3.58mmol)溶于四氢呋喃(5.00mL)和水(1.00mL)中，然后加入氯(2-二环己基膦基-2,4,6-三异丙基-1,1-联苯基)[2-(2-氨基-1,1-联苯)]钯(93.9mg,119μmol)，氮气置换三次，然后再70℃下搅拌16小时。反应完成后，减压浓缩，用水(10.0mL)，然后用乙酸乙酯(10.0mL×3)萃取，有机相用盐水(20.0mL)洗涤和无水硫酸钠干燥后，过滤浓缩得到粗品。粗品经柱层析(二氧化硅，石油醚：乙酸乙酯＝5:1到3:1)纯化后得到2-(二氟甲基)-4-[4-甲氧基-3-(五氟-λ 6-巯基)苯基]吡啶(280mg,收率55.0％)。 4-Bromo-1-methoxy-2-(pentafluoro-λ 6 -mercapto)benzene (374mg, 1.19mmol) and 2-(difluoromethyl)-4-(4,4,5,5- Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (609mg, 2.39mmol), potassium phosphate (760mg, 3.58mmol) dissolved in tetrahydrofuran (5.00mL) and water (1.00mL) , and then added chloro(2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)[2-(2-amino-1,1-biphenyl)]palladium ( 93.9mg, 119μmol), replaced with nitrogen three times, and then stirred at 70°C for 16 hours. After the reaction was complete, it was concentrated under reduced pressure, extracted with water (10.0 mL) and then ethyl acetate (10.0 mL×3), the organic phase was washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by column chromatography (silica, petroleum ether: ethyl acetate = 5:1 to 3:1) to obtain 2-(difluoromethyl)-4-[4-methoxy-3-(penta Fluoro-λ 6 -mercapto)phenyl]pyridine (280 mg, yield 55.0%).
LCMS,M/Z(ESI):261.9[M+H] + LCMS,M/Z(ESI):261.9[M+H] +
第七步：4-[2-(二氟甲基)吡啶-4-基]-2-(五氟-λ 6-巯基)苯酚的合成 Step 7: Synthesis of 4-[2-(difluoromethyl)pyridin-4-yl]-2-(pentafluoro-λ 6 -mercapto)phenol
Figure PCTCN2022122990-appb-000113
Figure PCTCN2022122990-appb-000113
将2-(二氟甲基)-4-[4-甲氧基-3-(五氟-λ 6-巯基)苯基]吡啶(374mg,1.19mmol)溶于冰醋酸(2.00mL)中，加入溴化氢水溶液(19mL,40％purity)，反应液在100℃下搅拌48小时。反应完成后，将反应液倒入到冰水(10.0mL)中，然后用乙酸乙酯(10.0mL×3)萃取，有机相用盐水(25.0mL)洗涤和无水硫酸钠干燥后，过滤浓缩得到粗品。粗品经柱层析(二氧化硅，石油醚：乙酸乙酯＝3:1到1:1)纯化后得到黄色固体4-[2-(二氟甲基)吡啶-4-基]-2-(五氟-λ 6-巯基)苯酚(117mg,收率61.7％)。 2-(Difluoromethyl)-4-[4-methoxy-3-(pentafluoro-λ 6 -mercapto)phenyl]pyridine (374 mg, 1.19 mmol) was dissolved in glacial acetic acid (2.00 mL), Hydrogen bromide aqueous solution (19 mL, 40% purity) was added, and the reaction solution was stirred at 100° C. for 48 hours. After the reaction was complete, the reaction solution was poured into ice water (10.0 mL), then extracted with ethyl acetate (10.0 mL×3), the organic phase was washed with brine (25.0 mL) and dried over anhydrous sodium sulfate, filtered and concentrated get crude. The crude product was purified by column chromatography (silica, petroleum ether: ethyl acetate = 3:1 to 1:1) to obtain a yellow solid 4-[2-(difluoromethyl)pyridin-4-yl]-2- (Pentafluoro-λ 6 -mercapto)phenol (117 mg, yield 61.7%).
1H NMR(400MHz,DMSO)δ8.69(d,1H),8.10(d,1H),7.94(br s,2H),7.85(br d,1H),7.18(br d,1H),7.14-6.83(m,1H)。 1 H NMR (400MHz,DMSO)δ8.69(d,1H),8.10(d,1H),7.94(br s,2H),7.85(br d,1H),7.18(br d,1H),7.14- 6.83 (m, 1H).
第八步：N-[(2S)-1-(4-[2-(二氟甲基)吡啶-4-基]-2-(五氟-λ 6-巯基)苯氧基)-2,4-二甲基戊烷-2-基]氨基甲酸叔丁酯的合成 The eighth step: N-[(2S)-1-(4-[2-(difluoromethyl)pyridin-4-yl]-2-(pentafluoro-λ 6 -mercapto)phenoxy)-2, Synthesis of tert-butyl 4-dimethylpentan-2-yl]carbamate
Figure PCTCN2022122990-appb-000114
Figure PCTCN2022122990-appb-000114
将4-[2-(二氟甲基)吡啶-4-基]-2-(五氟-λ 6-巯基)苯酚(117mg,336μmol)和(S)-4-异丁基-4- 甲基-1,2,3-氧杂噻唑烷-3-甲酸叔丁酯2,2-二氧代(148mg,505μmol)溶于N,N-二甲基甲酰胺(2.00mL)中，然后加入碳酸钾(93.1mg,674μmol),反应液在100℃搅拌15小时。反应完成后，将反应液倒入到冰水(10.0mL)中，然后用乙酸乙酯(10.0mL×3)萃取，有机相用盐水(25.0mL)洗涤和无水硫酸钠干燥后，过滤浓缩得到粗品。粗品经柱层析(二氧化硅，石油醚：乙酸乙酯＝3:1到2:1)纯化后得到无色油状物N-[(2S)-1-(4-[2-(二氟甲基)吡啶-4-基]-2-(五氟-λ 6-巯基)苯氧基)-2,4-二甲基戊烷-2-基]氨基甲酸叔丁酯(30.0mg,产率5.32％)。 4-[2-(Difluoromethyl)pyridin-4-yl]-2-(pentafluoro-λ 6 -mercapto)phenol (117 mg, 336 μmol) and (S)-4-isobutyl-4-methyl tert-butyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxo (148mg, 505μmol) was dissolved in N,N-dimethylformamide (2.00mL), then added Potassium carbonate (93.1mg, 674μmol), and the reaction solution was stirred at 100°C for 15 hours. After the reaction was complete, the reaction solution was poured into ice water (10.0 mL), then extracted with ethyl acetate (10.0 mL×3), the organic phase was washed with brine (25.0 mL) and dried over anhydrous sodium sulfate, filtered and concentrated get crude. The crude product was purified by column chromatography (silica, petroleum ether: ethyl acetate = 3:1 to 2:1) to give colorless oil N-[(2S)-1-(4-[2-(difluoro Methyl)pyridin-4-yl]-2-(pentafluoro-λ 6 -mercapto)phenoxy)-2,4-dimethylpentan-2-yl]carbamate tert-butyl ester (30.0mg, yield rate 5.32%).
LCMS,M/Z(ESI):561.0[M+H] + LCMS,M/Z(ESI):561.0[M+H] +
第九步：(2S)-1-(4-[2-(二氟甲基)吡啶-4-基]-2-(五氟-λ 6-巯基)苯氧基)-2,4-二甲基戊烷-2-胺(I-6)的合成 The ninth step: (2S)-1-(4-[2-(difluoromethyl)pyridin-4-yl]-2-(pentafluoro-λ 6 -mercapto)phenoxy)-2,4-di Synthesis of Methylpentan-2-amine (I-6)
Figure PCTCN2022122990-appb-000115
Figure PCTCN2022122990-appb-000115
将N-[(2S)-1-(4-[2-(二氟甲基)吡啶-4-基]-2-(五氟-λ 6-巯基)苯氧基)-2,4-二甲基戊烷-2-基]氨基甲酸叔丁酯(30.0mg,53.5μmol)溶于乙酸乙酯(2.00mL)中，然后加入盐酸乙酸乙酯(4M,80.28μL),反应液在25℃搅拌2小时。反应完成后，用饱和碳酸氢钠溶液将pH调至7，然后用乙酸乙酯(10.0mL×3)萃取，有机相用盐水(25.0mL)洗涤和无水硫酸钠干燥后，过滤浓缩得到粗品。粗品经反相高效液相色谱法进行分离纯化，分离方法为：色谱柱:Waters Xbridge 150×25mm×5μm；流动相:[水(氨水v/v)-乙腈]；B％:53％-83％,9min)，得到(2S)-1-(4-[2-(二氟甲基)吡啶-4-基]-2-(五氟-λ 6-巯基)苯氧基)-2,4-二甲基戊烷-2-胺(I-6)(4.97mg，收率19.5％)。 N-[(2S)-1-(4-[2-(Difluoromethyl)pyridin-4-yl]-2-(pentafluoro-λ 6 -mercapto)phenoxy)-2,4-di Methylpentan-2-yl] tert-butyl carbamate (30.0mg, 53.5μmol) was dissolved in ethyl acetate (2.00mL), then ethyl acetate hydrochloride (4M, 80.28μL) was added, and the reaction solution was heated at 25°C Stir for 2 hours. After the reaction was completed, the pH was adjusted to 7 with saturated sodium bicarbonate solution, then extracted with ethyl acetate (10.0 mL×3), the organic phase was washed with brine (25.0 mL) and dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product . The crude product was separated and purified by reverse-phase high-performance liquid chromatography. The separation method was as follows: chromatographic column: Waters Xbridge 150×25mm×5 μm; mobile phase: [water (ammonia v/v)-acetonitrile]; B%: 53%-83 %, 9min), to obtain (2S)-1-(4-[2-(difluoromethyl)pyridin-4-yl]-2-(pentafluoro-λ 6 -mercapto)phenoxy)-2,4 -Dimethylpentan-2-amine (I-6) (4.97 mg, yield 19.5%).
1H NMR(400MHz,CDCl 3)δ8.72(d,1H),8.04(d,1H),7.81-7.76(m,2H),7.57(d,1H),7.19(d,1H),6.71(t,1H),4.11-4.01(m,2H),1.86-1.76(m,1H),1.72-1.60(m,2H),1.40(s,3H),1.00(dd,6H)。 1 H NMR (400MHz, CDCl 3 )δ8.72(d,1H),8.04(d,1H),7.81-7.76(m,2H),7.57(d,1H),7.19(d,1H),6.71( t,1H), 4.11-4.01(m,2H), 1.86-1.76(m,1H), 1.72-1.60(m,2H), 1.40(s,3H), 1.00(dd,6H).
实施例6：目标化合物I-12的制备Embodiment 6: the preparation of target compound 1-12
(S)-1-((8-(2-(二氟甲基)吡啶-4-基)咪唑并[1,5-a]吡啶-5-基)氧代)-2,4-二甲基戊烷-2-胺(I-12)(S)-1-((8-(2-(Difluoromethyl)pyridin-4-yl)imidazo[1,5-a]pyridin-5-yl)oxo)-2,4-dimethyl Nylpentan-2-amine (I-12)
Figure PCTCN2022122990-appb-000116
Figure PCTCN2022122990-appb-000116
目标化合物I-12合成路线如下所示：The synthetic route of target compound I-12 is as follows:
Figure PCTCN2022122990-appb-000117
Figure PCTCN2022122990-appb-000117
第一步：3-溴-2-(溴甲基)-6-氯吡啶的合成The first step: the synthesis of 3-bromo-2-(bromomethyl)-6-chloropyridine
Figure PCTCN2022122990-appb-000118
Figure PCTCN2022122990-appb-000118
将3-溴-6-氯-2-甲基吡啶(10.0g,48.4mmol)溶于1,2-二氯乙烷(100mL)中，再加入N-溴代丁二酰亚胺(9.48g,53.3mmol)和偶氮二乙丁腈(795mg,4.84mmol)，将反应液在70℃下搅拌2小时。反应结束后，将反应液降至室温，加入水(100mL)，用二氯甲烷(100mL×3)萃取，合并有机相，用饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，浓缩滤液得到黄色油状物3-溴-2-(溴甲基)-6-氯吡啶(13.0g,粗品)。3-Bromo-6-chloro-2-methylpyridine (10.0g, 48.4mmol) was dissolved in 1,2-dichloroethane (100mL), and N-bromosuccinimide (9.48g , 53.3mmol) and azobisethylbutyronitrile (795mg, 4.84mmol), the reaction solution was stirred at 70°C for 2 hours. After the reaction, the reaction solution was lowered to room temperature, added water (100mL), extracted with dichloromethane (100mL×3), combined the organic phases, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated 3-Bromo-2-(bromomethyl)-6-chloropyridine (13.0 g, crude) was obtained as a yellow oil.
LC-MS,M/Z(ESI):285.9[M+H] +。 LC-MS, M/Z (ESI): 285.9 [M+H] + .
第二步：2-(叠氮甲基)-3-溴-6-氯吡啶的合成The second step: the synthesis of 2-(azidomethyl)-3-bromo-6-chloropyridine
Figure PCTCN2022122990-appb-000119
Figure PCTCN2022122990-appb-000119
将3-溴-2-(溴甲基)-6-氯吡啶(12.0g,42.1mmol)溶于N,N-二甲基甲酰胺(60.0mL)中，再分批加入叠氮钠(3.28g,50.5mmol)，将反应液在氮气氛围下25℃搅拌2小时。反应结束后，加水(100mL)稀释，用乙酸乙酯(100mL×3)萃取，合并有机相，用饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，浓缩得到黄色油状物2-(叠氮甲基)-3-溴-6-氯吡啶(10.0g,粗品)。Dissolve 3-bromo-2-(bromomethyl)-6-chloropyridine (12.0g, 42.1mmol) in N,N-dimethylformamide (60.0mL), then add sodium azide (3.28 g, 50.5 mmol), and the reaction solution was stirred at 25°C for 2 hours under a nitrogen atmosphere. After the reaction, add water (100mL) to dilute, extract with ethyl acetate (100mL×3), combine the organic phases, wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, and concentrate to obtain yellow oil 2-( Nitromethyl)-3-bromo-6-chloropyridine (10.0 g, crude).
第三步：(3-溴-6-氯吡啶-2-基)甲胺的合成The third step: the synthesis of (3-bromo-6-chloropyridin-2-yl)methanamine
Figure PCTCN2022122990-appb-000120
Figure PCTCN2022122990-appb-000120
将2-(叠氮甲基)-3-溴-6-氯吡啶(10.0g,40.4mmol)溶于四氢呋喃(100mL)和水(20.0mL)，再缓慢加入三苯基膦(21.2g,80.8mmol)，并在50℃下搅拌2小时。反应结束后，加水(100mL)稀释，用乙酸乙酯(100mL×3)萃取，合并有机相，用饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，浓缩得到黄色油状物(3-溴-6-氯吡啶-2-基)甲胺(6.30g，粗品)。2-(azidomethyl)-3-bromo-6-chloropyridine (10.0g, 40.4mmol) was dissolved in tetrahydrofuran (100mL) and water (20.0mL), and triphenylphosphine (21.2g, 80.8 mmol), and stirred at 50°C for 2 hours. After the reaction, dilute with water (100 mL), extract with ethyl acetate (100 mL×3), combine the organic phases, wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, and concentrate to obtain a yellow oil (3-bromo -6-chloropyridin-2-yl)methanamine (6.30 g, crude).
LC-MS,M/Z(ESI):222.9[M+H] +。 LC-MS, M/Z (ESI): 222.9 [M+H] + .
第四步：N-((3-溴-6-氯吡啶-2-基)甲基)甲酰胺的合成The fourth step: the synthesis of N-((3-bromo-6-chloropyridin-2-yl)methyl)formamide
Figure PCTCN2022122990-appb-000121
Figure PCTCN2022122990-appb-000121
将(3-溴-6-氯吡啶-2-基)甲胺(6.00g,27.1mmol)溶于甲酸(60.0mL)中，并在100℃下搅拌12小时。反应结束后，将反应液浓缩，得到棕色油状物N-((3-溴-6-氯吡啶-2-基)甲基)甲酰胺(6.50g，粗品)。(3-Bromo-6-chloropyridin-2-yl)methanamine (6.00 g, 27.1 mmol) was dissolved in formic acid (60.0 mL) and stirred at 100° C. for 12 hours. After the reaction, the reaction solution was concentrated to obtain N-((3-bromo-6-chloropyridin-2-yl)methyl)formamide (6.50 g, crude product) as a brown oil.
第五步：8-溴-5-氯咪唑并[1,5-a]吡啶的合成Step 5: Synthesis of 8-bromo-5-chloroimidazo[1,5-a]pyridine
Figure PCTCN2022122990-appb-000122
Figure PCTCN2022122990-appb-000122
将N-((3-溴-6-氯吡啶-2-基)甲基)甲酰胺(6.50g,26.1mmol)溶于甲苯(65.0mL)，缓慢加入三氯氧磷(11.9g,78.2mmol)，并在100℃下搅拌2小时。反应结束后，将反应液浓缩，经层析柱分离(石油醚：乙酸乙酯＝10:1到5:1)得到黄色固体8-溴-5-氯咪唑并[1,5-a]吡啶(2.53g，收率41.9％)。Dissolve N-((3-bromo-6-chloropyridin-2-yl)methyl)formamide (6.50g, 26.1mmol) in toluene (65.0mL), slowly add phosphorus oxychloride (11.9g, 78.2mmol ), and stirred at 100°C for 2 hours. After the reaction, the reaction solution was concentrated and separated by column chromatography (petroleum ether: ethyl acetate = 10:1 to 5:1) to obtain a yellow solid 8-bromo-5-chloroimidazo[1,5-a]pyridine (2.53 g, yield 41.9%).
1H NMR(400MHz,CDCl 3)δ8.37(s,1H),7.65(s,1H),6.94(d,1H),6.56(d,1H)。 1 H NMR (400 MHz, CDCl 3 ) δ 8.37 (s, 1H), 7.65 (s, 1H), 6.94 (d, 1H), 6.56 (d, 1H).
LC-MS,M/Z(ESI):232.9[M+H] +。 LC-MS, M/Z (ESI): 232.9 [M+H] + .
第六步：5-氯-8-(2-(二氟甲基)吡啶-4-基)咪唑并[1,5-a]吡啶的合成Step 6: Synthesis of 5-chloro-8-(2-(difluoromethyl)pyridin-4-yl)imidazo[1,5-a]pyridine
Figure PCTCN2022122990-appb-000123
Figure PCTCN2022122990-appb-000123
将8-溴-5-氯咪唑并[1,5-a]吡啶(500mg,2.16mmol)和2-(二氟甲基)-4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)吡啶(826mg,3.24mmol)溶于四氢呋喃(10.0mL)和水(2.00mL)，再加入二氯双[二叔丁基-(4-二甲基氨基苯基)膦]钯(II)(84.9mg,108μmol)和磷酸钾(917mg,4.32mmol)，置换氮气3次，在80℃下搅拌4小时。反应结束后，用水(20.0mL)稀释，用乙酸乙酯(20.0mL×3)萃取，有机相经浓缩，经层析柱分离(石油醚：乙酸乙酯＝5:1到2:1)得到黄色固体5-氯-8-(2-(二氟甲基)吡啶-4-基)咪唑并[1,5-a]吡啶(7)(300mg,收率49.7％)。Mix 8-bromo-5-chloroimidazo[1,5-a]pyridine (500mg, 2.16mmol) and 2-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1 , 3,2-dioxaborolan-2-yl)pyridine (826mg, 3.24mmol) was dissolved in tetrahydrofuran (10.0mL) and water (2.00mL), then dichlorobis[di-tert-butyl-(4- Dimethylaminophenyl)phosphine]palladium(II) (84.9mg, 108μmol) and potassium phosphate (917mg, 4.32mmol) were replaced with nitrogen three times, and stirred at 80°C for 4 hours. After the reaction, it was diluted with water (20.0 mL), extracted with ethyl acetate (20.0 mL×3), the organic phase was concentrated, and separated by column chromatography (petroleum ether: ethyl acetate = 5:1 to 2:1) to obtain Yellow solid 5-chloro-8-(2-(difluoromethyl)pyridin-4-yl)imidazo[1,5-a]pyridine (7) (300 mg, yield 49.7%).
1H NMR(400MHz,CDCl 3)δ8.80(d,1H),8.46(s,1H),7.92(s,1H),7.72(br d,1H),7.70(s,1H),6.89-6.92(m,1H),6.59-6.87(m,2H)。 1 H NMR (400MHz, CDCl 3 )δ8.80(d,1H),8.46(s,1H),7.92(s,1H),7.72(br d,1H),7.70(s,1H),6.89-6.92 (m,1H),6.59-6.87(m,2H).
LC-MS,M/Z(ESI):280.0[M+H] +。 LC-MS, M/Z (ESI): 280.0 [M+H] + .
第七步：(S)-1-((8-(2-(二氟甲基)吡啶-4-基)咪唑并[1,5-a]吡啶-5-基)氧代)-2,4-二甲基戊烷-2- 胺(I-12)的合成The seventh step: (S)-1-((8-(2-(difluoromethyl)pyridin-4-yl)imidazo[1,5-a]pyridin-5-yl)oxo)-2, Synthesis of 4-Dimethylpentan-2-amine (I-12)
Figure PCTCN2022122990-appb-000124
Figure PCTCN2022122990-appb-000124
将5-氯-8-(2-(二氟甲基)吡啶-4-基)咪唑并[1,5-a]吡啶(100mg,357μmol)和(S)-2-氨基-2,4-二甲基戊烷-1-醇(46.9mg,357μmol)溶于四氢呋喃溶液(2.00mL)，再加入叔丁醇钾的四氢呋喃溶液(1M,0.893mL)，将反应液在70℃下搅拌1小时。反应结束后，用水稀释，乙酸乙酯萃取，浓缩，粗品经层析柱分离(二氯甲烷：甲醇＝10:1)得到黄色固体(S)-1-((8-(2-(二氟甲基)吡啶-4-基)咪唑并[1,5-a]吡啶-5-基)氧代)-2,4-二甲基戊烷-2-胺(I-12)(25.5mg,18.5％收率)。5-Chloro-8-(2-(difluoromethyl)pyridin-4-yl)imidazo[1,5-a]pyridine (100mg, 357μmol) and (S)-2-amino-2,4- Dimethylpentan-1-ol (46.9mg, 357μmol) was dissolved in tetrahydrofuran solution (2.00mL), then potassium tert-butoxide in tetrahydrofuran solution (1M, 0.893mL) was added, and the reaction solution was stirred at 70°C for 1 hour . After the reaction was completed, it was diluted with water, extracted with ethyl acetate, concentrated, and the crude product was separated by column chromatography (dichloromethane:methanol=10:1) to obtain a yellow solid (S)-1-((8-(2-(difluoro Methyl)pyridin-4-yl)imidazo[1,5-a]pyridin-5-yl)oxo)-2,4-dimethylpentane-2-amine (I-12) (25.5mg, 18.5% yield).
1H NMR(400MHz,DMSO-d 6)δ8.77(d,1H),8.63(s,1H),7.96(s,1H),7.92(d,1H),7.65(s,1H),7.30(d,1H),6.90-7.19(m,1H),6.27(d,1H),4.06(s,2H),1.83(td,2H),1.39-1.50(m,2H),1.18(s,3H),0.94(dd,6H)。 1 H NMR (400MHz,DMSO-d 6 )δ8.77(d,1H),8.63(s,1H),7.96(s,1H),7.92(d,1H),7.65(s,1H),7.30( d,1H),6.90-7.19(m,1H),6.27(d,1H),4.06(s,2H),1.83(td,2H),1.39-1.50(m,2H),1.18(s,3H) ,0.94(dd,6H).
LC-MS,M/Z(ESI):375.1[M+H] +。 LC-MS, M/Z (ESI): 375.1 [M+H] + .
实施例7：目标化合物I-18的制备Embodiment 7: the preparation of target compound I-18
(S)-1-(4-(2-(二氟甲基)吡啶-4-基)-2-(丙-1-炔-1-基)苯氧基)-2,4-二甲基戊烷-2-胺(I-18)(S)-1-(4-(2-(difluoromethyl)pyridin-4-yl)-2-(prop-1-yn-1-yl)phenoxy)-2,4-dimethyl Pentane-2-amine (I-18)
Figure PCTCN2022122990-appb-000125
Figure PCTCN2022122990-appb-000125
目标化合物I-18合成路线如下所示：The synthetic route of target compound 1-18 is as follows:
Figure PCTCN2022122990-appb-000126
Figure PCTCN2022122990-appb-000126
第一步：(S)-(1-羟基-2,4-二甲基戊烷-2-基)氨基甲酸叔丁酯的合成The first step: Synthesis of (S)-(1-hydroxy-2,4-dimethylpentan-2-yl) tert-butyl carbamate
Figure PCTCN2022122990-appb-000127
Figure PCTCN2022122990-appb-000127
在室温下，向(2S)-2-氨基-2,4-二甲基-戊烷-1-醇(3.07g,23.4mmol)的二氯甲烷(40.0mL)加入碳酸二叔丁酯(5.62g,25.7mmol)，将反应液在25℃下搅拌0.5小时。反应结束后，直接旋蒸浓缩得到粗品。粗品经过层析柱分离(石油醚：乙酸乙酯20:1到5:1)得到黄色油状液体(S)-(1-羟基-2,4-二甲基戊烷-2-基)氨基甲酸叔丁酯(5.02g,92.4％收率)。To (2S)-2-amino-2,4-dimethyl-pentan-1-ol (3.07 g, 23.4 mmol) in dichloromethane (40.0 mL) was added di-tert-butyl carbonate (5.62 g, 25.7mmol), the reaction solution was stirred at 25°C for 0.5 hours. After the reaction was completed, the crude product was directly concentrated by rotary evaporation. The crude product was separated by column chromatography (petroleum ether: ethyl acetate 20:1 to 5:1) to obtain yellow oily liquid (S)-(1-hydroxy-2,4-dimethylpentan-2-yl)carbamic acid tert-Butyl ester (5.02 g, 92.4% yield).
第二步：叔丁基(4S)-4-异丁基-4-甲基-1,2,3-氧杂噻唑烷-3-甲酸基酯2-亚砜的合成The second step: Synthesis of tert-butyl (4S)-4-isobutyl-4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2-sulfoxide
Figure PCTCN2022122990-appb-000128
Figure PCTCN2022122990-appb-000128
在-10℃下，向(S)-(1-羟基-2,4-二甲基戊烷-2-基)氨基甲酯(600mg,2.59mmol)，三乙胺(787mg,7.78mmol)，咪唑(388mg,5.71mmol)的二氯甲烷(22.0mL)缓慢滴加二氯亚砜(432mg,3.63mmol)的二氯甲烷(3.00mL)溶液，将反应液在10℃下搅拌3小时。反应结束后，加水稀释，二氯甲烷萃取，有机相干燥浓缩得到黄色油状液体叔丁基(4S)-4-异丁基-4-甲基-1,2,3-氧杂噻唑烷-3-甲酸基酯2-亚砜(660mg,91.7％收率)。At -10°C, to (S)-(1-hydroxy-2,4-dimethylpentan-2-yl)aminomethyl ester (600mg, 2.59mmol), triethylamine (787mg, 7.78mmol), A solution of imidazole (388mg, 5.71mmol) in dichloromethane (22.0mL) was slowly added dropwise to a solution of thionyl chloride (432mg, 3.63mmol) in dichloromethane (3.00mL), and the reaction solution was stirred at 10°C for 3 hours. After the reaction, dilute with water, extract with dichloromethane, dry and concentrate the organic phase to obtain yellow oily liquid tert-butyl (4S)-4-isobutyl-4-methyl-1,2,3-oxathiazolidine-3 -Formyl ester 2-sulfoxide (660 mg, 91.7% yield).
第三步：叔丁基(4S)-4-异丁基-4-甲基-1,2,3-氧杂噻唑烷-3-甲酸基酯2，2-砜的合成The third step: Synthesis of tert-butyl (4S)-4-isobutyl-4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-sulfone
Figure PCTCN2022122990-appb-000129
Figure PCTCN2022122990-appb-000129
在10℃下，向叔丁基(4S)-4-异丁基-4-甲基-1,2,3-氧杂噻唑烷-3-甲酸基酯2-亚砜(650mg,2.34mmol)的乙腈(12.0mL)和水(2.00mL)溶液分批次加入三氯化钌(24.3mg,117μmol)和高碘酸钠(651mg,3.05mmol)，将反应液在25℃下搅拌4小时。反应结束后加入亚硫酸钠水溶液淬灭反应，有机相浓缩，乙酸乙酯萃取，有机相经干燥浓缩得到粗品，粗品经过柱层析层析柱分离(石油醚：乙酸乙酯1:0到30:1)得到(400mg,58.2％收率)。At 10°C, tert-butyl (4S)-4-isobutyl-4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2-sulfoxide (650mg, 2.34mmol) Ruthenium trichloride (24.3 mg, 117 μmol) and sodium periodate (651 mg, 3.05 mmol) were added to a solution of acetonitrile (12.0 mL) and water (2.00 mL) in batches, and the reaction solution was stirred at 25°C for 4 hours. Add sodium sulfite aqueous solution after the reaction to quench the reaction, concentrate the organic phase, extract with ethyl acetate, dry and concentrate the organic phase to obtain the crude product, and the crude product is separated by column chromatography (petroleum ether: ethyl acetate 1:0 to 30:1 ) to give (400 mg, 58.2% yield).
第四步：2-(二氟甲基)-4-(4-甲氧苯基)吡啶的合成The fourth step: the synthesis of 2-(difluoromethyl)-4-(4-methoxyphenyl)pyridine
Figure PCTCN2022122990-appb-000130
Figure PCTCN2022122990-appb-000130
在室温下，向2-(4-甲氧苯基)-4,4,5,5-四甲基-1,3,2-二噁硼戊环(2.97g,12.7mmol)，4-溴-2-(二氟甲基)吡啶(2.40g,11.5mmol)，二三苯基膦二氯化钯(323mg,461μmol)，碳酸钾(3.19g,23.1mmol)在二氧六环(20.0mL)溶液加入水(3.00mL)，将反应液体在氮气氛围下90℃搅拌12小时。反应结束后，加水稀释，乙酸乙酯萃取，有机相浓缩得到粗品黄色油状液体 2-(二氟甲基)-4-(4-甲氧苯基)吡啶(2.61g,76.7％收率)。At room temperature, to 2-(4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.97g, 12.7mmol), 4-bromo -2-(Difluoromethyl)pyridine (2.40g, 11.5mmol), ditriphenylphosphine palladium dichloride (323mg, 461μmol), potassium carbonate (3.19g, 23.1mmol) in dioxane (20.0mL ) solution was added water (3.00 mL), and the reaction liquid was stirred at 90° C. for 12 hours under a nitrogen atmosphere. After the reaction, it was diluted with water, extracted with ethyl acetate, and the organic phase was concentrated to obtain the crude yellow oily liquid 2-(difluoromethyl)-4-(4-methoxyphenyl)pyridine (2.61g, 76.7% yield).
LC-MS,M/Z(ESI):236.0[M+H] +。 LC-MS, M/Z (ESI): 236.0 [M+H] + .
第五步：2-(二氟甲基)-4-(3-碘-4-甲氧苯基)吡啶的合成The fifth step: the synthesis of 2-(difluoromethyl)-4-(3-iodo-4-methoxyphenyl)pyridine
Figure PCTCN2022122990-appb-000131
Figure PCTCN2022122990-appb-000131
在室温下，向2-(二氟甲基)-4-(4-甲氧苯基)吡啶(2.00g,8.50mmol)，单质碘(2.37g,9.35mmol)的乙腈(20.0mL)溶液中加入选择性氟试剂(3.31g,9.35mmol)，将反应液在25℃下搅拌16小时。反应结束后，加入亚硫酸钠水溶液淬灭反应，乙酸乙酯萃取，有机相浓缩得到黄色油状液体2-(二氟甲基)-4-(3-碘-4-甲氧苯基)吡啶(3.00g,97.7％收率)。At room temperature, add 2-(difluoromethyl)-4-(4-methoxyphenyl)pyridine (2.00g, 8.50mmol), elemental iodine (2.37g, 9.35mmol) in acetonitrile (20.0mL) solution A selective fluorine reagent (3.31 g, 9.35 mmol) was added, and the reaction solution was stirred at 25° C. for 16 hours. After the reaction was completed, aqueous sodium sulfite was added to quench the reaction, extracted with ethyl acetate, and the organic phase was concentrated to obtain a yellow oily liquid 2-(difluoromethyl)-4-(3-iodo-4-methoxyphenyl)pyridine (3.00g , 97.7% yield).
LC-MS,M/Z(ESI):361.8[M+H] +。 LC-MS, M/Z (ESI): 361.8 [M+H] + .
第六步：4-(2-(二氟甲基)吡啶-4-基)-2-碘苯酚The sixth step: 4-(2-(difluoromethyl)pyridin-4-yl)-2-iodophenol
Figure PCTCN2022122990-appb-000132
Figure PCTCN2022122990-appb-000132
在0℃下，向2-(二氟甲基)-4-(3-碘-4-甲氧苯基)吡啶(3.00g,8.31mmol)的二氯甲烷(30.0mL)加入三溴化硼(4.16g,16.6mmol)，将反应液在25℃下搅拌12小时。反应结束后，将反应液倒入到饱和碳酸氢钠溶液中(60.0mL)，二氯甲烷萃取，有机相浓缩干燥得到粗品，层析柱分离(石油醚：乙酸乙酯10:1到3:1)得到白的固体4-(2-(二氟甲基)吡啶-4-基)-2-碘苯酚(1.31g,45.1％收率)。To 2-(difluoromethyl)-4-(3-iodo-4-methoxyphenyl)pyridine (3.00 g, 8.31 mmol) in dichloromethane (30.0 mL) was added boron tribromide at 0°C (4.16g, 16.6mmol), the reaction solution was stirred at 25°C for 12 hours. After the reaction, the reaction solution was poured into a saturated sodium bicarbonate solution (60.0 mL), extracted with dichloromethane, the organic phase was concentrated and dried to obtain a crude product, which was separated by column chromatography (petroleum ether: ethyl acetate 10:1 to 3: 1) 4-(2-(difluoromethyl)pyridin-4-yl)-2-iodophenol (1.31 g, 45.1% yield) was obtained as a white solid.
LC-MS,M/Z(ESI):348.1[M+H] +。 LC-MS, M/Z (ESI): 348.1 [M+H] + .
第七步：叔丁基(S)-(1-(4-(2-(二氟甲基)吡啶-4-基)-2-碘苯氧基)-2,4-二甲基戊烷-2-基)氨基甲酸酯的合成The seventh step: tert-butyl (S)-(1-(4-(2-(difluoromethyl)pyridin-4-yl)-2-iodophenoxy)-2,4-dimethylpentane -2-yl) carbamate synthesis
Figure PCTCN2022122990-appb-000133
Figure PCTCN2022122990-appb-000133
在室温下，将叔丁基(4S)-4-异丁基-4-甲基-2,2-二氧亚基-氧杂噻唑烷-3-甲酸基酯(120mg,409μmol)，4-(2-(二氟甲基)吡啶-4-基)-2-碘苯酚(141mg,409μmol)的二甲基甲酰胺溶液(2.00mL)加入碳酸钾(169mg,1.23mmol)，将反应液在90℃下搅拌3小时。反应结束后，将反应液倒入水中(20.0mL)，乙酸乙酯萃取，有机相浓缩干燥得到粗品，层析板分离(石油醚：乙酸乙酯＝3:1)得到白的固体叔丁基(S)-(1-(4-(2-(二氟甲基)吡啶-4-基)-2-碘苯氧基)-2,4-二甲 基戊烷-2-基)氨基甲酯(120mg,52.4％收率)。At room temperature, tert-butyl (4S)-4-isobutyl-4-methyl-2,2-dioxylidene-oxathiazolidine-3-carboxylate (120 mg, 409 μmol), 4- (2-(Difluoromethyl)pyridin-4-yl)-2-iodophenol (141mg, 409μmol) in dimethylformamide solution (2.00mL) was added potassium carbonate (169mg, 1.23mmol), and the reaction solution was Stir at 90°C for 3 hours. After the reaction, the reaction solution was poured into water (20.0 mL), extracted with ethyl acetate, the organic phase was concentrated and dried to obtain the crude product, which was separated by chromatography (petroleum ether: ethyl acetate = 3:1) to obtain a white solid tert-butyl (S)-(1-(4-(2-(difluoromethyl)pyridin-4-yl)-2-iodophenoxy)-2,4-dimethylpentan-2-yl)aminomethyl Ester (120 mg, 52.4% yield).
LC-MS,M/Z(ESI):561.3[M+H] +。 LC-MS, M/Z (ESI): 561.3 [M+H] + .
第八步：(S)-1-(4-(2-(二氟甲基)吡啶-4-基)-2-碘苯氧基)-2,4-二甲基戊烷-2-胺的合成The eighth step: (S)-1-(4-(2-(difluoromethyl)pyridin-4-yl)-2-iodophenoxy)-2,4-dimethylpentane-2-amine Synthesis
Figure PCTCN2022122990-appb-000134
Figure PCTCN2022122990-appb-000134
在室温下，向叔丁基(S)-(1-(4-(2-(二氟甲基)吡啶-4-基)-2-碘苯氧基)-2,4-二甲基戊烷-2-基)氨基甲酯(120mg,214μmol)的二氯甲烷溶液(1.00mL)加入三氟乙酸(1.68g,14.7mmol)，将反应液在25℃下搅拌0.5小时。反应结束后，直接旋蒸浓缩得到黄色油状液体(S)-1-(4-(2-(二氟甲基)吡啶-4-基)-2-碘苯氧基)-2,4-二甲基戊烷-2-胺(100mg,crude,TFA)。At room temperature, to tert-butyl (S)-(1-(4-(2-(difluoromethyl)pyridin-4-yl)-2-iodophenoxy)-2,4-dimethylpentane Trifluoroacetic acid (1.68 g, 14.7 mmol) was added to a dichloromethane solution (1.00 mL) of alk-2-yl)aminomethyl esters (120 mg, 214 μmol), and the reaction solution was stirred at 25° C. for 0.5 hours. After the reaction was completed, direct rotary evaporation concentrated to obtain yellow oily liquid (S)-1-(4-(2-(difluoromethyl)pyridin-4-yl)-2-iodophenoxy)-2,4-di Methylpentan-2-amine (100 mg, crude, TFA).
LC-MS,M/Z(ESI):461.2[M+H] +。 LC-MS, M/Z (ESI): 461.2 [M+H] + .
第九步：(S)-1-(4-(2-(二氟甲基)吡啶-4-基)-2-(丙-1-炔-1-基)苯氧基)-2,4-二甲基戊烷-2-胺(I-18)的合成The ninth step: (S)-1-(4-(2-(difluoromethyl)pyridin-4-yl)-2-(prop-1-yn-1-yl)phenoxy)-2,4 -Synthesis of dimethylpentane-2-amine (I-18)
Figure PCTCN2022122990-appb-000135
Figure PCTCN2022122990-appb-000135
在室温下，将(S)-1-(4-(2-(二氟甲基)吡啶-4-基)-2-碘苯氧基)-2,4-二甲基戊烷-2-胺(100mg,217μmol)，丙炔(1.00M,4.00mL)，碘化亚铜(16.5mg,86.9μmol)，三乙胺(329mg,3.26mmol)，的四氢呋喃溶液(1.00mL)在氮气氛围下置换三次，并在40℃下搅拌1小时。溶液结束后直接过滤，滤液进浓缩得到粗品。粗品经反相制备(色谱柱:Phenomenex Synergi C18150×25mm×10μm；流动相:[水(0.225％甲酸)-乙腈]；B％:16％-46％,10min)得到黄色固体(S)-1-(4-(2-(二氟甲基)吡啶-4-基)-2-(丙-1-炔-1-基)苯氧基)-2,4-二甲基戊烷-2-胺·甲酸盐(I-18)(40.0mg,43.5％收率)。At room temperature, (S)-1-(4-(2-(difluoromethyl)pyridin-4-yl)-2-iodophenoxy)-2,4-dimethylpentane-2- Amine (100mg, 217μmol), propyne (1.00M, 4.00mL), cuprous iodide (16.5mg, 86.9μmol), triethylamine (329mg, 3.26mmol), THF solution (1.00mL) under nitrogen atmosphere Replace three times and stir at 40°C for 1 hour. After the solution was finished, it was directly filtered, and the filtrate was concentrated to obtain the crude product. The crude product was prepared by reverse phase (chromatographic column: Phenomenex Synergi C18 150×25mm×10 μm; mobile phase: [water (0.225% formic acid)-acetonitrile]; B%: 16%-46%, 10min) to obtain yellow solid (S)-1 -(4-(2-(Difluoromethyl)pyridin-4-yl)-2-(prop-1-yn-1-yl)phenoxy)-2,4-dimethylpentane-2- Amine · formate (I-18) (40.0 mg, 43.5% yield).
1H NMR(400MHz,CHLOROFORM-d)δ8.63(d,1H),8.44(s,1H),7.74(s,1H),7.65(d,1H),7.49(d,2H),7.00(d,1H),6.83-6.53(m,4H),4.22(d,1H),4.10(d,1H),2.10(s,3H),1.93-1.76(m,3H),1.54(s,3H),1.00(dd,6H)1H NMR(400MHz,CHLOROFORM-d)δ8.63(d,1H),8.44(s,1H),7.74(s,1H),7.65(d,1H),7.49(d,2H),7.00(d, 1H),6.83-6.53(m,4H),4.22(d,1H),4.10(d,1H),2.10(s,3H),1.93-1.76(m,3H),1.54(s,3H),1.00 (dd,6H)
LC-MS,M/Z(ESI):373.2[M+H] +。 LC-MS, M/Z (ESI): 373.2 [M+H] + .
实施例8：目标化合物I-21的制备Embodiment 8: the preparation of target compound I-21
(S)-1-((8-(2-(二氟甲基)吡啶-4-基)咪唑并[1,2-a]吡啶-5-基)氧代)-2,4-二甲基戊烷-2-胺(目标 化合物I-21)。(S)-1-((8-(2-(Difluoromethyl)pyridin-4-yl)imidazo[1,2-a]pyridin-5-yl)oxo)-2,4-dimethyl ylpentan-2-amine (target compound I-21).
Figure PCTCN2022122990-appb-000136
Figure PCTCN2022122990-appb-000136
目标化合物I-21的合成路线如下所示：The synthetic route of target compound I-21 is as follows:
Figure PCTCN2022122990-appb-000137
Figure PCTCN2022122990-appb-000137
第一步：8-溴-5-氯咪唑并[1,2-a]吡啶的合成Step 1: Synthesis of 8-bromo-5-chloroimidazo[1,2-a]pyridine
Figure PCTCN2022122990-appb-000138
Figure PCTCN2022122990-appb-000138
将3-溴-6-氯吡啶-2-胺(0.5g,2.41mmol)溶于乙醇(5.00mL)中，再加入2-氯乙醛(946mg,4.82mmol)，反应液在50℃条件下搅拌16小时。反应完成后，将反应液浓缩，然后加水(8.00mL)溶解，用饱和碳酸氢钠溶液调pH至7～9，再用乙酸乙酯(10.0ml×3)萃取，合并有机层，用饱和食盐水(10.0mL)洗涤有机相，无水硫酸钠干燥，浓缩得到粗品。粗品经柱层析(硅胶，乙酸乙酯：石油醚＝5:1到2:1)纯化后得到淡黄色固体化合物8-溴-5-氯咪唑并[1,2-a]吡啶(450mg,产率80.6％)。Dissolve 3-bromo-6-chloropyridin-2-amine (0.5g, 2.41mmol) in ethanol (5.00mL), then add 2-chloroacetaldehyde (946mg, 4.82mmol), and the reaction solution was heated at 50°C Stir for 16 hours. After the reaction is complete, concentrate the reaction solution, add water (8.00mL) to dissolve, adjust the pH to 7-9 with saturated sodium bicarbonate solution, then extract with ethyl acetate (10.0ml×3), combine the organic layers, and wash with saturated salt The organic phase was washed with water (10.0 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by column chromatography (silica gel, ethyl acetate:petroleum ether=5:1 to 2:1) to obtain light yellow solid compound 8-bromo-5-chloroimidazo[1,2-a]pyridine (450mg, Yield 80.6%).
LC-MS,M/Z(ESI):232.9[M+H] + LC-MS, M/Z(ESI):232.9[M+H] +
第二步：5-氯-8-(2-(二氟甲基)吡啶-4-基)咪唑并[1,2-a]吡啶的合成The second step: the synthesis of 5-chloro-8-(2-(difluoromethyl)pyridin-4-yl)imidazo[1,2-a]pyridine
Figure PCTCN2022122990-appb-000139
Figure PCTCN2022122990-appb-000139
将8-溴-5-氯咪唑并[1,2-a]吡啶(200mg,864μmol)和2-(二氟甲基)-4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)吡啶(441mg,1.73mmol)溶于四氢呋喃(8.00mL)和水(2.00mL)溶液中，再加入磷酸钾(550mg,2.59mmol)和[2-(2-氨基苯基)苯基]-氯-钯；二环己基-[3-(2,4,6-三异丙基苯基)苯基]磷烷(68.0mg,86.4μmol)，然后用氮气置换3次，在75℃下反应16小时。反应完成后，将反应液浓缩除去四氢呋喃，然后加水(5.00mL)和乙酸乙酯(8.00mL)溶解，分离 有机相，水相用乙酸乙酯(8.00mL×3)萃取，合并有机相，有机相用盐水(20.0mL)洗涤和无水硫酸钠干燥后，过滤浓缩得到粗品。粗品经柱层析(硅胶，乙酸乙酯：石油醚＝5:1到3:1)纯化后黄色油状物5-氯-8-(2-(二氟甲基)吡啶-4-基)咪唑并[1,2-a]吡啶(211mg,产率43.57％)。8-Bromo-5-chloroimidazo[1,2-a]pyridine (200 mg, 864 μmol) and 2-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl)pyridine (441mg, 1.73mmol) was dissolved in tetrahydrofuran (8.00mL) and water (2.00mL) solution, then potassium phosphate (550mg, 2.59mmol) and [2 -(2-Aminophenyl)phenyl]-chloro-palladium; Dicyclohexyl-[3-(2,4,6-triisopropylphenyl)phenyl]phosphine (68.0 mg, 86.4 μmol), Then, it replaced with nitrogen 3 times, and reacted at 75 degreeC for 16 hours. After the reaction was completed, the reaction solution was concentrated to remove tetrahydrofuran, then water (5.00mL) and ethyl acetate (8.00mL) were added to dissolve, the organic phase was separated, the aqueous phase was extracted with ethyl acetate (8.00mL×3), the organic phases were combined, organic The phase was washed with brine (20.0 mL) and dried over anhydrous sodium sulfate, then concentrated by filtration to give the crude product. The crude product was purified by column chromatography (silica gel, ethyl acetate:petroleum ether=5:1 to 3:1) and the yellow oil 5-chloro-8-(2-(difluoromethyl)pyridin-4-yl)imidazole Ac[1,2-a]pyridine (211 mg, yield 43.57%).
LC-MS,M/Z(ESI):280.0[M+H] + LC-MS, M/Z(ESI):280.0[M+H] +
第三步：(S)-1-((8-(2-(二氟甲基)吡啶-4-基)咪唑并[1,2-a]吡啶-5-基)氧代)-2,4-二甲基戊烷-2-胺(I-21)The third step: (S)-1-((8-(2-(difluoromethyl)pyridin-4-yl)imidazo[1,2-a]pyridin-5-yl)oxo)-2, 4-Dimethylpentan-2-amine (I-21)
Figure PCTCN2022122990-appb-000140
Figure PCTCN2022122990-appb-000140
将5-氯-8-(2-(二氟甲基)吡啶-4-基)咪唑并[1,2-a]吡啶(130mg,232μmol)和(S)-2-氨基-2,4-二甲基戊烷-1-醇(45.7mg,348μmol)溶于四氢呋喃(4.00mL)中，再加入叔丁醇钾溶液(1.00M,278μL)，反应在70℃下搅拌2小时。反应完成后，将反应液倒入到水中，然后用乙酸乙酯萃取，有机相用盐水(20.0mL)洗涤和无水硫酸钠干燥后，过滤浓缩得到粗品。将粗品经层析硅胶板(硅胶，乙酸乙酯：石油醚＝1:1)和反相高效液相色谱法进行分离纯化，分离方法为：色谱柱:Waters Xbridge 150×25mm×5μm；流动相:[water(ammonia hydroxide v/v)-ACN]；B％:32％-62％,9min，得到类白色固体(S)-1-((8-(2-(二氟甲基)吡啶-4-基)咪唑并[1,2-a]吡啶-5-基)氧代)-2,4-二甲基戊烷-2-胺(2.65mg,产率3.05％)。5-Chloro-8-(2-(difluoromethyl)pyridin-4-yl)imidazo[1,2-a]pyridine (130mg, 232μmol) and (S)-2-amino-2,4- Dimethylpentan-1-ol (45.7 mg, 348 μmol) was dissolved in tetrahydrofuran (4.00 mL), and potassium tert-butoxide solution (1.00 M, 278 μL) was added, and the reaction was stirred at 70° C. for 2 hours. After the reaction was completed, the reaction solution was poured into water, and then extracted with ethyl acetate. The organic phase was washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was separated and purified by chromatographic silica gel plate (silica gel, ethyl acetate:petroleum ether=1:1) and reversed-phase high-performance liquid chromatography. The separation method was: chromatographic column: Waters Xbridge 150×25mm×5 μm; mobile phase : [water(ammonia hydroxide v/v)-ACN]; B%: 32%-62%, 9min, to obtain off-white solid (S)-1-((8-(2-(difluoromethyl)pyridine- 4-yl)imidazo[1,2-a]pyridin-5-yl)oxo)-2,4-dimethylpentan-2-amine (2.65 mg, 3.05% yield).
1H NMR(400MHz，CDCl 3)δ8.73(d,1H),8.34-8.19(m,2H),7.76(d,2H),7.55(d,1H),6.72(t,1H),6.22(d,1H),4.09(s,2H),1.86(td,3H),1.60(t,2H),1.35(s,3H),1.02(dd,6H)。 1 H NMR (400MHz, CDCl 3 )δ8.73(d,1H),8.34-8.19(m,2H),7.76(d,2H),7.55(d,1H),6.72(t,1H),6.22( d,1H), 4.09(s,2H), 1.86(td,3H), 1.60(t,2H), 1.35(s,3H), 1.02(dd,6H).
LC-MS,M/Z(ESI):375.2[M+H] +。 LC-MS, M/Z (ESI): 375.2 [M+H] + .
实施例9：目标化合物I-24的制备Embodiment 9: the preparation of target compound I-24
4-(((S)-2-氨基-2,4-二甲代戊基)氧代)-1-(2-(二氟甲基)吡啶-4-基)哌啶-2-酮(I-24)4-(((S)-2-amino-2,4-dimethylpentyl)oxo)-1-(2-(difluoromethyl)pyridin-4-yl)piperidin-2-one ( I-24)
Figure PCTCN2022122990-appb-000141
Figure PCTCN2022122990-appb-000141
目标化合物I-24合成路线如下所示：The synthetic route of target compound I-24 is as follows:
Figure PCTCN2022122990-appb-000142
Figure PCTCN2022122990-appb-000142
第一步：叔丁基(S)-(1-((2'-(二氟甲基)-2-氧亚基-2H-[1,4'-联吡啶]-4-基)氧代)-2,4-二甲基戊烷-2-基)氨基甲酸酯的合成The first step: tert-butyl (S)-(1-((2'-(difluoromethyl)-2-oxoylidene-2H-[1,4'-bipyridyl]-4-yl)oxo )-2,4-dimethylpentan-2-yl) carbamate synthesis
Figure PCTCN2022122990-appb-000143
Figure PCTCN2022122990-appb-000143
在室温下，向1-[2-(二氟甲基)-4-吡啶基]-4-羟基-吡啶-2-酮(300mg,1.26mmol)和叔丁基(S)-4-异丁基-4-甲基-氧杂噻唑烷2,2-二氧化砜(267mg,1.39mmol)的N,N二甲基甲酰胺(6.00mL)溶液中加入碳酸钾(435mg,3.15mmol)，将反应液在100℃下搅拌3小时。反应结束后加水(10mL)稀释，乙酸乙酯萃取(20.0mL×3)有机相经无水硫酸钠干燥，过滤，浓缩得到黄色的油状液体叔丁基(S)-(1-((2'-(二氟甲基)-2-氧亚基-2H-[1,4'-联吡啶]-4-基)氧代)-2,4-二甲基戊烷-2-基)氨基甲酸酯(290mg,51.0％收率)。At room temperature, 1-[2-(difluoromethyl)-4-pyridyl]-4-hydroxy-pyridin-2-one (300 mg, 1.26 mmol) and tert-butyl (S)-4-isobutyl Add potassium carbonate (435mg, 3.15mmol) to a solution of 2,2-dioxide sulfone (267mg, 1.39mmol) in N,N dimethylformamide (6.00mL) The reaction solution was stirred at 100°C for 3 hours. After the reaction was completed, it was diluted with water (10mL), extracted with ethyl acetate (20.0mL×3), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain yellow oily liquid tert-butyl (S)-(1-((2' -(Difluoromethyl)-2-oxyylidene-2H-[1,4'-bipyridyl]-4-yl)oxo)-2,4-dimethylpentan-2-yl)aminomethyl Ester (290 mg, 51.0% yield).
LC-MS,M/Z(ESI):452.2[M+H] +。 LC-MS, M/Z (ESI): 452.2 [M+H] + .
第二步：叔丁基((2S)-1-((1-(2-(二氟甲基)吡啶-4-基)-2-氧亚基哌啶-4-基)氧代)-2,4-二甲基戊烷-2-基)氨基甲酸酯的合成The second step: tert-butyl ((2S)-1-((1-(2-(difluoromethyl)pyridin-4-yl)-2-oxyethylenepiperidin-4-yl)oxo)- Synthesis of 2,4-Dimethylpentan-2-yl)carbamate
Figure PCTCN2022122990-appb-000144
Figure PCTCN2022122990-appb-000144
将叔丁基(S)-(1-((2'-(二氟甲基)-2-氧亚基-2H-[1,4'-联吡啶]-4-基)氧代)-2,4-二甲基戊烷-2-基)氨基甲酸酯(250mg,553μmol)溶于甲醇(6.00mL)，再加入钯碳(100mg)，将反应液里在25℃下氢气氛围下(50Psi)反应16小时。反应结束后，加入甲醇稀释(15.0mL)，硅藻土过滤，浓缩得到黄色的油状液体叔丁基((2S)-1-((1-(2-(二氟甲基)吡啶-4-基)-2-氧亚基哌啶-4-基)氧代)-2,4-二甲基戊烷-2-基)氨基甲酸酯(300mg,粗品)。Tert-butyl (S)-(1-((2'-(difluoromethyl)-2-oxoylidene-2H-[1,4'-bipyridyl]-4-yl)oxo)-2 , 4-dimethylpentan-2-yl) carbamate (250mg, 553μmol) was dissolved in methanol (6.00mL), then palladium carbon (100mg) was added, and the reaction solution was placed in a hydrogen atmosphere at 25°C ( 50Psi) for 16 hours. After the reaction, add methanol to dilute (15.0mL), filter through celite, and concentrate to obtain yellow oily liquid tert-butyl ((2S)-1-((1-(2-(difluoromethyl)pyridine-4- yl)-2-oxylidenepiperidin-4-yl)oxo)-2,4-dimethylpentan-2-yl)carbamate (300 mg, crude).
LC-MS,M/Z(ESI):456.3[M+H] +。 LC-MS, M/Z (ESI): 456.3 [M+H] + .
第三步：4-(((S)-2-氨基-2,4-二甲代戊基)氧代)-1-(2-(二氟甲基)吡啶-4-基)哌啶-2-酮(I-24) 的合成The third step: 4-(((S)-2-amino-2,4-dimethylpentyl)oxo)-1-(2-(difluoromethyl)pyridin-4-yl)piperidine- Synthesis of 2-keto (I-24)
Figure PCTCN2022122990-appb-000145
Figure PCTCN2022122990-appb-000145
在室温下，向叔丁基((2S)-1-((1-(2-(二氟甲基)吡啶-4-基)-2-氧亚基哌啶-4-基)氧代)-2,4-二甲基戊烷-2-基)氨基甲酸酯(300mg,658μmol)的二氯甲烷(1.00mL)加入三氟乙酸(1.54g,13.5mmol)，将反应液在25℃下搅拌0.5小时，反应结束后直接浓缩粗品，粗品经反相制备(色谱柱:Phenomenex Synergi C18 150×25mm×10μm；流动相:[水(0.225％甲酸)-乙腈]；B％:7％-37％,10min)纯化得到黄色固体4-(((S)-2-氨基-2,4-二甲代戊基)氧代)-1-(2-(二氟甲基)吡啶-4-基)哌啶-2-酮(I-24)(20.0mg,收率7.19％)。At room temperature, to tert-butyl ((2S)-1-((1-(2-(difluoromethyl)pyridin-4-yl)-2-oxoylidenepiperidin-4-yl)oxo) -2,4-Dimethylpentan-2-yl)carbamate (300mg, 658μmol) in dichloromethane (1.00mL) was added trifluoroacetic acid (1.54g, 13.5mmol), and the reaction solution was heated at 25°C Stir under down for 0.5 hour, directly concentrate crude product after reaction finishes, and crude product is prepared through reversed phase (chromatographic column: Phenomenex Synergi C18 150 * 25mm * 10 μ m; Mobile phase: [water (0.225% formic acid)-acetonitrile]; B%: 7%- 37%, 10min) was purified to give yellow solid 4-(((S)-2-amino-2,4-dimethylpentyl)oxo)-1-(2-(difluoromethyl)pyridine-4- base) piperidin-2-one (I-24) (20.0 mg, yield 7.19%).
1H NMR(400MHz,CDCl 3)δ8.59(d,1H),7.78-7.62(m,4H),7.43(d,1H),6.60(t,1H),4.29-4.18(m,1H),3.90(s,1H),3.64-3.44(m,3H),2.88(d,1H),2.68-2.58(m,1H),2.20-2.00(m,2H),1.60-1.56(m,2H),1.40-1.34(m,1H),1.25(s,3H),0.95-0.85(m,6H)。 1 H NMR (400MHz, CDCl 3 )δ8.59(d,1H),7.78-7.62(m,4H),7.43(d,1H),6.60(t,1H),4.29-4.18(m,1H), 3.90(s,1H),3.64-3.44(m,3H),2.88(d,1H),2.68-2.58(m,1H),2.20-2.00(m,2H),1.60-1.56(m,2H), 1.40-1.34 (m, 1H), 1.25 (s, 3H), 0.95-0.85 (m, 6H).
LC-MS,M/Z(ESI):356.2[M+H] +。 LC-MS, M/Z (ESI): 356.2 [M+H] + .
实施例10：目标化合物I-25的制备Embodiment 10: the preparation of target compound I-25
(S)-1-((8-(2-(二氟甲基)吡啶-4-基)喹啉-5-基)氧代)-2,4-二甲基戊烷-2-胺(目标化合物I-25)。(S)-1-((8-(2-(difluoromethyl)pyridin-4-yl)quinolin-5-yl)oxo)-2,4-dimethylpentane-2-amine ( Target compound I-25).
Figure PCTCN2022122990-appb-000146
Figure PCTCN2022122990-appb-000146
目标化合物I-25的合成路线如下所示：The synthetic route of target compound 1-25 is as follows:
Figure PCTCN2022122990-appb-000147
Figure PCTCN2022122990-appb-000147
第一步：8-(2-(二氟甲基)吡啶-4-基)-5-甲氧基喹啉的合成The first step: the synthesis of 8-(2-(difluoromethyl)pyridin-4-yl)-5-methoxyquinoline
Figure PCTCN2022122990-appb-000148
Figure PCTCN2022122990-appb-000148
将8-溴-5-甲氧基喹啉(500mg,2.10mmol)和2-(二氟甲基)-4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)吡啶(1.07g,4.20mmol)溶于四氢呋喃(10.0mL)中，再加入氯(2-二环己基膦基-2,4,6-三异丙基-1,1-联苯基)[2-(2-氨基-1,1-联苯)]钯(II)(165mg,210μmol)和磷酸钾(1.34g,6.30mmol)，然后用氮气置换三次，反应液在75℃条件下搅拌16小时。反应完成后，将反应液浓缩，然后加水(10.0mL)和乙酸乙酯(10.0mL)，分离有机相，水相用乙酸乙酯(20.0mL×3)萃取，合并有机相，有机相用饱和食盐水(30.0mL)洗涤和无水硫酸钠干燥后，过滤浓缩得到粗品。用饱和碳酸氢钠溶液调pH至7～9，再用乙酸乙酯(10.0ml×3)萃取，合并有机层，用饱和食盐水(10.0mL)洗涤有机相，无水硫酸钠干燥，浓缩得到粗品。粗品经柱层析(硅胶，乙酸乙酯：石油醚＝5:1到3:1)纯化后得到8-(2-(二氟甲基)吡啶-4-基)-5-甲氧基喹啉(490mg,产率78.4％)。8-Bromo-5-methoxyquinoline (500mg, 2.10mmol) and 2-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-di Oxaborolan-2-yl)pyridine (1.07g, 4.20mmol) was dissolved in tetrahydrofuran (10.0mL), and then chloro(2-dicyclohexylphosphino-2,4,6-triisopropyl-1 ,1-biphenyl)[2-(2-amino-1,1-biphenyl)]palladium (II) (165mg, 210μmol) and potassium phosphate (1.34g, 6.30mmol), then replaced three times with nitrogen, the reaction The solution was stirred at 75°C for 16 hours. After the reaction was completed, the reaction solution was concentrated, then water (10.0 mL) and ethyl acetate (10.0 mL) were added, the organic phase was separated, the aqueous phase was extracted with ethyl acetate (20.0 mL×3), the organic phases were combined, and the organic phase was washed with saturated After washing with brine (30.0 mL) and drying over anhydrous sodium sulfate, the crude product was obtained by filtration and concentration. Adjust the pH to 7-9 with saturated sodium bicarbonate solution, then extract with ethyl acetate (10.0ml×3), combine the organic layers, wash the organic phase with saturated brine (10.0mL), dry over anhydrous sodium sulfate, and concentrate to obtain Crude. The crude product was purified by column chromatography (silica gel, ethyl acetate:petroleum ether=5:1 to 3:1) to obtain 8-(2-(difluoromethyl)pyridin-4-yl)-5-methoxyquin morphine (490mg, yield 78.4%).
LC-MS,M/Z(ESI):287.1[M+H] + LC-MS, M/Z(ESI):287.1[M+H] +
第二步：8-(2-(二氟甲基)吡啶-4-基)喹啉-5-酚的合成The second step: the synthesis of 8-(2-(difluoromethyl)pyridin-4-yl)quinoline-5-ol
Figure PCTCN2022122990-appb-000149
Figure PCTCN2022122990-appb-000149
将8-(2-(二氟甲基)吡啶-4-基)-5-甲氧基喹啉(490mg,1.71mmol)溶于二氯甲烷(5.00mL)溶液中，在0℃条件下，将三溴化硼(1.29g,5.13mmol)加入到该溶液中，然后用氮气置换3次，在25℃下反应12小时。反应完成后，在25℃条件下，将反应液倒入到水(10.0mL)中，用饱和的碳酸氢钠溶液将反应液的pH调至9，然后用二氯甲烷(25.0mL×3)萃取，有机相用盐水洗涤和无水硫酸钠干燥后，过滤浓缩得到粗品。粗品经层析硅胶(乙酸乙酯：石油醚＝3：1)纯化后得8-(2-(二氟甲基)吡啶-4-基)喹啉-5-酚(160mg,产率31.42％)。8-(2-(Difluoromethyl)pyridin-4-yl)-5-methoxyquinoline (490mg, 1.71mmol) was dissolved in dichloromethane (5.00mL) solution, at 0°C, Boron tribromide (1.29 g, 5.13 mmol) was added to the solution, and then replaced with nitrogen three times, and reacted at 25° C. for 12 hours. After the reaction was completed, the reaction solution was poured into water (10.0 mL) at 25° C., the pH of the reaction solution was adjusted to 9 with saturated sodium bicarbonate solution, and then dichloromethane (25.0 mL×3) After extraction, the organic phase was washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by chromatography on silica gel (ethyl acetate:petroleum ether=3:1) to give 8-(2-(difluoromethyl)pyridin-4-yl)quinoline-5-ol (160mg, yield 31.42% ).
LC-MS,M/Z(ESI):273.0[M+H] + LC-MS, M/Z(ESI):273.0[M+H] +
第三步：(S)-(1-((8-(2-(二氟甲基)吡啶-4-基)喹啉-5-基)氧代)-2,4-二甲基戊烷-2-基)氨基甲酸叔丁酯的合成The third step: (S)-(1-((8-(2-(difluoromethyl)pyridin-4-yl)quinolin-5-yl)oxo)-2,4-dimethylpentane Synthesis of -2-yl) tert-butyl carbamate
Figure PCTCN2022122990-appb-000150
Figure PCTCN2022122990-appb-000150
将8-(2-(二氟甲基)吡啶-4-基)喹啉-5-酚(100mg,367μmol)和(S)-4-异丁基-4-甲基-1,2,3-氧杂噻唑烷-3-甲酸基酯2,2-二氧代(129mg,441μmol)溶于N,N-二甲基甲酰胺溶液中(2.00mL)，将碳酸钾(102mg,735μmol)加入到该反应液中，反应在25℃下搅拌3小时。反应完成后，将反应液倒入到水中，然后用乙酸乙酯(15.0mL×3)萃取，有机相用盐水(20.0mL)洗涤和无水硫酸钠干燥后，过滤浓缩得到粗品。将粗品经层析硅胶板(硅胶，乙酸乙酯：石油醚＝3:1)纯化得到白色固体(S)-(1-((8-(2-(二氟甲基)吡啶-4-基)喹啉-5-基)氧代)-2,4-二甲基戊烷-2-基)氨基甲酸叔丁酯(80.0mg,159μmol,产率43.1％)。8-(2-(Difluoromethyl)pyridin-4-yl)quinolin-5-ol (100mg, 367μmol) and (S)-4-isobutyl-4-methyl-1,2,3 -Oxathiazolidine-3-carboxylate 2,2-dioxo (129 mg, 441 μmol) was dissolved in N,N-dimethylformamide solution (2.00 mL), potassium carbonate (102 mg, 735 μmol) was added To this reaction solution, the reaction was stirred at 25°C for 3 hours. After the reaction was complete, the reaction solution was poured into water, then extracted with ethyl acetate (15.0 mL×3), the organic phase was washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by silica gel plate chromatography (silica gel, ethyl acetate:petroleum ether=3:1) to obtain white solid (S)-(1-((8-(2-(difluoromethyl)pyridin-4-yl )quinolin-5-yl)oxo)-2,4-dimethylpentan-2-yl)tert-butyl carbamate (80.0 mg, 159 μmol, 43.1% yield).
LC-MS,M/Z(ESI):486.2[M+H] + LC-MS, M/Z(ESI):486.2[M+H] +
第四步：(S)-1-((8-(2-(二氟甲基)吡啶-4-基)喹啉-5-基)氧代)-2,4-二甲基戊烷-2-胺(I-25)的合成The fourth step: (S)-1-((8-(2-(difluoromethyl)pyridin-4-yl)quinolin-5-yl)oxo)-2,4-dimethylpentane- Synthesis of 2-amine (I-25)
Figure PCTCN2022122990-appb-000151
Figure PCTCN2022122990-appb-000151
把(1-((8-(2-(二氟甲基)吡啶-4-基)喹啉-5-基)氧代)-2,4-二甲基戊烷-2-基)氨基甲酸叔丁酯(73.0mg,150μmol,)溶解在1,4-二氧六环(2.00mL)中，加入盐酸/1,4-二氧六环溶液(4M,376μL)，反应在25摄氏度下搅拌8小时。反应完成后，用饱和的碳酸氢钠溶液将pH调至7～9，然后用乙酸乙酯(10.0mL×3)萃取，有机相用盐水(20.0mL)洗涤和无水硫酸钠干燥后，过滤浓缩得到(S)-1-((8-(2-(二氟甲基)吡啶-4-基)喹啉-5-基)氧代)-2,4-二甲基戊烷-2-胺(46.4mg，产率90.6％)。(1-((8-(2-(difluoromethyl)pyridin-4-yl)quinolin-5-yl)oxo)-2,4-dimethylpentan-2-yl)carbamic acid Tert-butyl ester (73.0 mg, 150 μmol,) was dissolved in 1,4-dioxane (2.00 mL), hydrochloric acid/1,4-dioxane solution (4M, 376 μL) was added, and the reaction was stirred at 25 °C 8 hours. After the reaction was completed, the pH was adjusted to 7-9 with saturated sodium bicarbonate solution, then extracted with ethyl acetate (10.0 mL×3), the organic phase was washed with brine (20.0 mL), dried over anhydrous sodium sulfate, and filtered Concentration gave (S)-1-((8-(2-(difluoromethyl)pyridin-4-yl)quinolin-5-yl)oxo)-2,4-dimethylpentane-2- Amine (46.4 mg, 90.6% yield).
1H NMR(400MHz,CDCl 3)δ8.97(dd,1H),8.75-8.66(m,2H),7.99(s,1H),7.80(d,1H),7.71(d,1H),7.50(dd,1H),6.97(d,1H),6.74(t,1H),3.98(s,2H),1.90-1.85(m,1H),1.62(t,2H),1.35(s,3H),1.02(dd,6H)。 1 H NMR (400MHz, CDCl 3 )δ8.97(dd,1H),8.75-8.66(m,2H),7.99(s,1H),7.80(d,1H),7.71(d,1H),7.50( dd,1H),6.97(d,1H),6.74(t,1H),3.98(s,2H),1.90-1.85(m,1H),1.62(t,2H),1.35(s,3H),1.02 (dd,6H).
LC-MS,M/Z(ESI):386.1[M+H] + LC-MS, M/Z(ESI):386.1[M+H] +
实施例11：目标化合物I-27的制备Embodiment 11: Preparation of target compound I-27
(S)-7-(5-((2-氨基-2,4-二甲代戊基)氧代)-6-(二氟甲基)吡啶-2-基)-1-甲基-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮(目标化合物I-27)(S)-7-(5-((2-amino-2,4-dimethylpentyl)oxo)-6-(difluoromethyl)pyridin-2-yl)-1-methyl-1 ,3-Dihydro-2H-imidazo[4,5-b]pyridin-2-one (target compound I-27)
Figure PCTCN2022122990-appb-000152
Figure PCTCN2022122990-appb-000152
目标化合物I-27的合成路线如下所示：The synthetic route of target compound 1-27 is as follows:
Figure PCTCN2022122990-appb-000153
Figure PCTCN2022122990-appb-000153
第一步：N-甲基-2-硝基吡啶-3-胺的合成The first step: the synthesis of N-methyl-2-nitropyridin-3-amine
Figure PCTCN2022122990-appb-000154
Figure PCTCN2022122990-appb-000154
将3-氟-2-硝基-吡啶(9.00g,63.3mmol)溶解在四氢呋喃(90.0mL)中，在氮气保护下依次加入碳酸铯(82.5g,253mmol)，甲胺盐酸盐(17.1g,253mmol)加完后，室温反应2小时。将反应液用水(100mL)淬灭，再用乙酸乙酯(450mL)萃取，用饱和食盐水(300mL)洗涤有机相，硫酸钠干燥，浓缩得到粗品黄色固体化合物N-甲基-2-硝基吡啶-3-胺(11.0g，粗品)。Dissolve 3-fluoro-2-nitro-pyridine (9.00g, 63.3mmol) in tetrahydrofuran (90.0mL), add cesium carbonate (82.5g, 253mmol) and methylamine hydrochloride (17.1g , 253mmol) After the addition was completed, the reaction was carried out at room temperature for 2 hours. The reaction solution was quenched with water (100 mL), extracted with ethyl acetate (450 mL), washed the organic phase with saturated brine (300 mL), dried over sodium sulfate, and concentrated to obtain the crude yellow solid compound N-methyl-2-nitro Pyridin-3-amine (11.0 g, crude).
1H NMR(400MHz,CDCl 3)δ7.84(dd,1H),7.77-7.56(m,1H),7.41(dd,1H),7.27(dd,1H),2.98(s,3H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.84 (dd, 1H), 7.77-7.56 (m, 1H), 7.41 (dd, 1H), 7.27 (dd, 1H), 2.98 (s, 3H).
第二步：4-溴-N-甲基-2-硝基吡啶-3-胺的合成The second step: the synthesis of 4-bromo-N-methyl-2-nitropyridin-3-amine
Figure PCTCN2022122990-appb-000155
Figure PCTCN2022122990-appb-000155
将N-甲基-2-硝基吡啶-3-胺(10.0g,65.3mmol)溶解在醋酸(100mL)中，加入醋酸钾(6.41g,65.3mmol)，在室温下反应1小时，然后缓慢滴加溴素(10.4g,65.3mmol)，搅拌2小时，过滤，洗涤，将滤饼浓缩，得到黄色固体化合物4-溴-N-甲基-2-硝基吡啶-3-胺(11.2g，粗品)。Dissolve N-methyl-2-nitropyridin-3-amine (10.0g, 65.3mmol) in acetic acid (100mL), add potassium acetate (6.41g, 65.3mmol), react at room temperature for 1 hour, then slowly Bromine (10.4g, 65.3mmol) was added dropwise, stirred for 2 hours, filtered, washed, and the filter cake was concentrated to obtain a yellow solid compound 4-bromo-N-methyl-2-nitropyridin-3-amine (11.2g ,Crude).
LC-MS,M/Z:234.0[M+H] +。 LC-MS, M/Z: 234.0 [M+H] + .
第三步：4-溴-N3-甲基吡啶-2,3-二胺的合成The third step: the synthesis of 4-bromo-N3-methylpyridine-2,3-diamine
Figure PCTCN2022122990-appb-000156
Figure PCTCN2022122990-appb-000156
将4-溴-N-甲基-2-硝基吡啶-3-胺(10.0g,49.2mmol)溶解在乙醇(100mL)中，加二氯化锡(33.3g,147mmol)，然后在氮气保护下70℃搅拌反应2小时。将反应液过滤，并用乙醇洗涤，将滤饼浓缩，浓缩得到粗品棕色油状物化合物4-溴-N3-甲基吡啶-2,3-二胺(4.00g，粗品)。Dissolve 4-bromo-N-methyl-2-nitropyridin-3-amine (10.0g, 49.2mmol) in ethanol (100mL), add tin dichloride (33.3g, 147mmol), and then The reaction was stirred at 70°C for 2 hours. The reaction liquid was filtered and washed with ethanol, and the filter cake was concentrated to obtain a crude brown oil compound 4-bromo-N3-methylpyridine-2,3-diamine (4.00 g, crude product).
LC-MS,M/Z:174.1[M+H] +。 LC-MS, M/Z: 174.1 [M+H] + .
第四步：7-溴-1-甲基-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮的合成Step 4: Synthesis of 7-bromo-1-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one
Figure PCTCN2022122990-appb-000157
Figure PCTCN2022122990-appb-000157
将4-溴-N3-甲基吡啶-2,3-二胺(3.00g,14.8mmol)溶解在四氢呋喃(30.0mL)中，加1,1-羰基二咪唑(4.82g,29.7mmol)，然后在氮气保护下80℃搅拌反应8小时。将反应液过滤，用乙酸乙酯洗涤，将滤饼浓缩，用乙酸乙酯打浆纯化，得到灰白色固体化合物7-溴-1-甲基-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮(2.20g，产率64.9％)。Dissolve 4-bromo-N3-methylpyridine-2,3-diamine (3.00g, 14.8mmol) in tetrahydrofuran (30.0mL), add 1,1-carbonyldiimidazole (4.82g, 29.7mmol), then The reaction was stirred at 80° C. for 8 hours under the protection of nitrogen. The reaction solution was filtered, washed with ethyl acetate, the filter cake was concentrated, and purified by beating with ethyl acetate to obtain off-white solid compound 7-bromo-1-methyl-1,3-dihydro-2H-imidazo[4, 5-b] Pyridin-2-one (2.20 g, 64.9% yield).
1H NMR(400MHz,DMSO-d 6)δ11.79(br s,1H),7.39(d,1H),7.22(d,1H),3.27(s,3H)。 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.79 (br s, 1H), 7.39 (d, 1H), 7.22 (d, 1H), 3.27 (s, 3H).
LC-MS,M/Z:230.0[M+H] +。 LC-MS, M/Z: 230.0 [M+H] + .
第五步：1-甲基-7-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮的合成The fifth step: 1-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-dihydro-2H- Synthesis of imidazo[4,5-b]pyridin-2-one
Figure PCTCN2022122990-appb-000158
Figure PCTCN2022122990-appb-000158
将7-溴-1-甲基-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮(1.10g,4.82mmol)溶解在N,N-二甲基甲酰胺(50.0mL)中，氮气保护下加入双联嚬哪醇硼酸酯(1.47g,5.79mmol)，[1,1-双(二苯基膦)二茂铁]二氯化钯二氯甲烷(196mg,241μmol)，醋酸钾(946mg,9.65mmol)，100℃反应12小时。趁热过滤，然后用乙酸乙酯洗涤，硫酸钠干燥，浓缩得到粗品，得到棕色油状化合物1-甲基-7-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮(1.00g，粗品)。7-Bromo-1-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (1.10 g, 4.82 mmol) was dissolved in N,N-dimethylformaldehyde Amide (50.0mL), under the protection of nitrogen, add bis-analcohol borate (1.47g, 5.79mmol), [1,1-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane (196mg, 241μmol), potassium acetate (946mg, 9.65mmol), react at 100°C for 12 hours. Filtration while hot, then washed with ethyl acetate, dried over sodium sulfate, and concentrated to give the crude product, the compound 1-methyl-7-(4,4,5,5-tetramethyl-1,3,2-di Oxaborolan-2-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (1.00 g, crude).
LC-MS,M/Z(ESI):276.1[M+H] +。 LC-MS, M/Z (ESI): 276.1 [M+H] + .
第六步：7-(6-(二氟甲基)-5-氟吡啶-2-基)-1-甲基-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮的合成The sixth step: 7-(6-(difluoromethyl)-5-fluoropyridin-2-yl)-1-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridine Synthesis of -2-one
Figure PCTCN2022122990-appb-000159
Figure PCTCN2022122990-appb-000159
将1-甲基-7-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮(1.00g,3.63mmol)溶解在N,N-二甲基甲酰胺(10.0ml)中，氮气保护下加入6-溴-2-(二氟甲基)-3-氟-吡啶(410mg,1.82mmol)，磷酸钾(1.16g,5.45mmol)，[1,1-双(二苯基膦)二茂铁]二氯化钯二氯甲烷(74.2mg,90.8μmol)，90℃反应12小时。加入水(20.0mL)，然后用乙酸乙酯(60.0mL)萃取，饱和食盐水(60.0mL)洗涤，硫酸钠干燥，浓缩得到粗品，粗品经用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝10:1-2:1)得到黄色固体化合物7-(6-(二氟甲基)-5-氟吡啶-2-基)-1-甲基-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮(100mg，产率9.35％)。1-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-dihydro-2H-imidazo[ 4,5-b]pyridin-2-one (1.00g, 3.63mmol) was dissolved in N,N-dimethylformamide (10.0ml), and 6-bromo-2-(difluoromethyl )-3-fluoro-pyridine (410mg, 1.82mmol), potassium phosphate (1.16g, 5.45mmol), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane (74.2mg ,90.8μmol), reacted at 90°C for 12 hours. Water (20.0 mL) was added, then extracted with ethyl acetate (60.0 mL), washed with saturated brine (60.0 mL), dried over sodium sulfate, and concentrated to obtain a crude product, which was separated and purified with a silica gel column (petroleum ether: ethyl acetate ( V/V)=10:1-2:1) to obtain yellow solid compound 7-(6-(difluoromethyl)-5-fluoropyridin-2-yl)-1-methyl-1,3-dihydro -2H-imidazo[4,5-b]pyridin-2-one (100 mg, yield 9.35%).
1H NMR(400MHz,DMSO-d 6)δ11.76(br s,1H),8.41(dd,1H),8.12-7.97(m,2H),7.58(d,1H),7.34(s,1H),7.23-7.18(m,1H),7.07(s,1H),3.34(br s,3H)。 1 H NMR (400MHz,DMSO-d 6 )δ11.76(br s,1H),8.41(dd,1H),8.12-7.97(m,2H),7.58(d,1H),7.34(s,1H) , 7.23-7.18 (m, 1H), 7.07 (s, 1H), 3.34 (br s, 3H).
LC-MS,M/Z(ESI):294.8[M+H] +。 LC-MS, M/Z (ESI): 294.8 [M+H] + .
第七步：(S)-7-(5-((2-氨基-2,4-二甲代戊基)氧代)-6-(二氟甲基)吡啶-2-基)-1-甲基-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮(I-27)的合成The seventh step: (S)-7-(5-((2-amino-2,4-dimethylpentyl)oxo)-6-(difluoromethyl)pyridin-2-yl)-1- Synthesis of Methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (I-27)
Figure PCTCN2022122990-appb-000160
Figure PCTCN2022122990-appb-000160
将7-(6-(二氟甲基)-5-氟吡啶-2-基)-1-甲基-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮(100mg,339μmol)溶解在四氢呋喃(1.00ml)中，氮气保护下加入(2S)-2-氨基-2,4-二甲基-戊烷-1-醇(44.6mg,339μmol)，叔丁醇钾(1.16g,5.45mmol)在70℃反应2小时。加入碳酸氢钠饱和溶液调节pH至8，用乙酸乙酯(15.0mL)萃取，饱和食盐水(15.0mL)洗涤，无水硫酸钠干燥，过滤，浓缩，用色谱柱Waters Xbridge 150×25mm×5μm；流动相：A＝水+0.225体积％氨水(99％)，B＝乙腈；梯度：25％-58％，9min纯化，得到产品白色固体化合物(S)-7-(5-((2-氨基-2,4-二甲代戊基)氧代)-6-(二氟甲基)吡啶-2-基)-1-甲基-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮(I-27)(120mg，产率9.35％)。7-(6-(Difluoromethyl)-5-fluoropyridin-2-yl)-1-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridine-2- Ketone (100mg, 339μmol) was dissolved in tetrahydrofuran (1.00ml), and (2S)-2-amino-2,4-dimethyl-pentan-1-ol (44.6mg, 339μmol) was added under nitrogen protection, tert-butyl Potassium alcoholate (1.16g, 5.45mmol) was reacted at 70°C for 2 hours. Add saturated sodium bicarbonate solution to adjust the pH to 8, extract with ethyl acetate (15.0mL), wash with saturated brine (15.0mL), dry over anhydrous sodium sulfate, filter, concentrate, and use a chromatographic column Waters Xbridge 150×25mm×5μm Mobile phase: A=water+0.225% by volume ammoniacal liquor (99%), B=acetonitrile; Gradient: 25%-58%, 9min is purified, obtains product white solid compound (S)-7-(5-((2- Amino-2,4-dimethylpentyl)oxo)-6-(difluoromethyl)pyridin-2-yl)-1-methyl-1,3-dihydro-2H-imidazo[4, 5-b] Pyridin-2-one (I-27) (120 mg, 9.35% yield).
1H NMR(400MHz,DMSO-d 6)δ8.31(d,1H),8.02(d,1H),7.73(d,1H),7.54(d,1H),7.18(t, 1H),3.83(s,2H),2.52(br d,3H),1.85-1.74(m,1H),1.42-1.33(m,2H),1.11(s,3H),0.92(t,6H)。 1 H NMR (400MHz,DMSO-d 6 )δ8.31(d,1H),8.02(d,1H),7.73(d,1H),7.54(d,1H),7.18(t,1H),3.83( s, 2H), 2.52 (br d, 3H), 1.85-1.74 (m, 1H), 1.42-1.33 (m, 2H), 1.11 (s, 3H), 0.92 (t, 6H).
LC-MS,M/Z(ESI):406.1[M+H] +。 LC-MS, M/Z (ESI): 406.1 [M+H] + .
实施例12：目标化合物I-29的制备Embodiment 12: the preparation of target compound I-29
(S)-1-((2',6-二(二氟甲基)-[2,4'-联吡啶]-5-基)氧代)-3-(1-氟环丙基)-2-甲基丙烷-2-胺(I-29)(S)-1-((2',6-bis(difluoromethyl)-[2,4'-bipyridyl]-5-yl)oxo)-3-(1-fluorocyclopropyl)- 2-Methylpropan-2-amine (I-29)
(R)-1-((2',6-二(二氟甲基)-[2,4'-联吡啶]-5-基)氧代)-3-(1-氟环丙基)-2-甲基丙烷-2-胺(R-I-29)(R)-1-((2',6-bis(difluoromethyl)-[2,4'-bipyridyl]-5-yl)oxo)-3-(1-fluorocyclopropyl)- 2-Methylpropane-2-amine (R-I-29)
Figure PCTCN2022122990-appb-000161
Figure PCTCN2022122990-appb-000161
目标化合物I-29合成路线如下所示：The synthetic route of target compound I-29 is as follows:
Figure PCTCN2022122990-appb-000162
Figure PCTCN2022122990-appb-000162
第一步：(1-氟环丙基)甲醇的合成The first step: the synthesis of (1-fluorocyclopropyl)methanol
Figure PCTCN2022122990-appb-000163
Figure PCTCN2022122990-appb-000163
将1-氟环丙基甲酸(8.00g,76.9mmol)溶于四氢呋喃(80.0mL)中，将反应液降至0℃，分批加入氢化铝锂(3.21g,84.5mmol)，加入完毕后，升温至30℃反应2小时。反应结束后，将反应液降至0℃，在氮气保护下，缓慢滴加水(3.50mL)淬灭，再加入无水硫酸钠干燥15分钟，过滤，滤液直接用于下一步。1-Fluorocyclopropanecarboxylic acid (8.00g, 76.9mmol) was dissolved in tetrahydrofuran (80.0mL), the reaction solution was lowered to 0°C, and lithium aluminum hydride (3.21g, 84.5mmol) was added in batches. After the addition was complete, The temperature was raised to 30° C. for 2 hours. After the reaction, the reaction solution was lowered to 0° C., and quenched by slowly adding water (3.50 mL) dropwise under nitrogen protection, then adding anhydrous sodium sulfate to dry for 15 minutes, and filtering. The filtrate was directly used in the next step.
第二步：(1-氟环丙基)甲基甲磺酸酯的合成The second step: the synthesis of (1-fluorocyclopropyl) methyl methanesulfonate
Figure PCTCN2022122990-appb-000164
Figure PCTCN2022122990-appb-000164
将(1-氟环丙基)甲醇的四氢呋喃溶液降至0℃，加入三乙胺(16.0g,144mmol)和甲基磺酸 酐(15.1g,86.6mmol)，将反应液在氮气氛围下25℃搅拌2小时。反应结束后，将反应液降至室温，加水(100mL)稀释，用乙酸乙酯(100mL×3)萃取，合并有机相，用饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，浓缩得到黄色油状物(1-氟环丙基)甲基甲磺酸酯(4.20g,粗品)。The tetrahydrofuran solution of (1-fluorocyclopropyl)methanol was lowered to 0°C, triethylamine (16.0g, 144mmol) and methanesulfonic anhydride (15.1g, 86.6mmol) were added, and the reaction solution was heated at 25°C under a nitrogen atmosphere Stir for 2 hours. After the reaction, the reaction solution was lowered to room temperature, diluted with water (100mL), extracted with ethyl acetate (100mL×3), the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain Yellow oil (1-fluorocyclopropyl)methyl mesylate (4.20 g, crude).
1H NMR(400MHz,CDCl 3)δ4.37-4.59(m,2H),3.11(s,3H),1.24(dt,2H),0.87(q,2H)。 1 H NMR (400 MHz, CDCl 3 ) δ 4.37-4.59 (m, 2H), 3.11 (s, 3H), 1.24 (dt, 2H), 0.87 (q, 2H).
第三步：2-((1-氟环丙基)甲基)丙二酸二乙酯的合成The third step: the synthesis of 2-((1-fluorocyclopropyl)methyl)diethyl malonate
Figure PCTCN2022122990-appb-000165
Figure PCTCN2022122990-appb-000165
将丙二酸二乙酯(4.00g,25.0mmol)溶于四氢呋喃(40.0mL)中，降至0℃后，分批加氢化钠(1.90g,50.0mmol)，在0℃下搅拌1小时，再加入(1-氟环丙基)甲基甲磺酸酯(5.00g，30.0mmol)和碘化钾(8.30g，50.0mmol)，并将反应液加热至70℃反应12小时。反应结束后，将反应液降至室温，加水(100mL)稀释，用乙酸乙酯(100mL×3)萃取，合并有机相，用饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，浓缩得粗品，将层析柱(二氧化硅，石油醚：乙酸乙酯＝20:1到10:1)纯化后得到黄色油状物2-((1-氟环丙基)甲基)丙二酸二乙酯(3.20g，收率：55.2％)。Dissolve diethyl malonate (4.00g, 25.0mmol) in tetrahydrofuran (40.0mL), and after cooling down to 0°C, add sodium hydride (1.90g, 50.0mmol) in batches, and stir at 0°C for 1 hour , and then added (1-fluorocyclopropyl) methyl methanesulfonate (5.00 g, 30.0 mmol) and potassium iodide (8.30 g, 50.0 mmol), and heated the reaction solution to 70° C. for 12 hours. After the reaction, the reaction liquid was lowered to room temperature, diluted with water (100 mL), extracted with ethyl acetate (100 mL×3), combined organic phases, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain The crude product was purified by chromatographic column (silica, petroleum ether: ethyl acetate = 20:1 to 10:1) to obtain yellow oil 2-((1-fluorocyclopropyl)methyl)malonate di Ethyl ester (3.20 g, yield: 55.2%).
1H NMR(400MHz,CDCl 3)δ4.18-4.25(m,4H)，3.75(t,1H)，2.33-2.45(m,2H)，1.26-1.31(m,6H)，0.97-1.06(m,2H)，0.54-0.63(m,2H)。 1 H NMR (400MHz, CDCl 3 ) δ4.18-4.25 (m, 4H), 3.75 (t, 1H), 2.33-2.45 (m, 2H), 1.26-1.31 (m, 6H), 0.97-1.06 (m ,2H), 0.54-0.63 (m,2H).
第四步：2-((1-氟环丙基)甲基)-2-甲基丙二酸二乙酯的合成Step 4: Synthesis of 2-((1-fluorocyclopropyl)methyl)-2-methylmalonate diethyl
Figure PCTCN2022122990-appb-000166
Figure PCTCN2022122990-appb-000166
将2-((1-氟环丙基)甲基)丙二酸二乙酯(3.00g,12.5mmol)溶于四氢呋喃(30.0mL)中，降至0℃后，分批加入氢化钠(1.03mg,25.8mmol)，在0℃下搅拌1小时，再加入碘甲烷(5.30g，38.7mmol)，并将反应液加热至70℃反应12小时。反应结束后，将反应液降至室温，加水(100mL)稀释，用乙酸乙酯(100mL×3)萃取，合并有机相，用饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，浓缩得到黄色油状物2-((1-氟环丙基)甲基)-2-甲基丙二酸二乙酯(2.90g，粗品)。Diethyl 2-((1-fluorocyclopropyl)methyl)malonate (3.00g, 12.5mmol) was dissolved in tetrahydrofuran (30.0mL), and after cooling down to 0°C, sodium hydride (1.03 mg, 25.8mmol), stirred at 0°C for 1 hour, then added iodomethane (5.30g, 38.7mmol), and heated the reaction solution to 70°C for 12 hours. After the reaction, the reaction solution was lowered to room temperature, diluted with water (100mL), extracted with ethyl acetate (100mL×3), the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain Diethyl 2-((1-fluorocyclopropyl)methyl)-2-methylmalonate (2.90 g, crude) as a yellow oil.
1H NMR(400MHz,CDCl 3)δ4.16-4.21(m,4H)，2.39-2.52(m,2H)，1.60(s,3H)，1.23-1.27(m,6H)，0.96-1.05(m,2H)，0.52-0.60(m,2H)。 1 H NMR (400MHz, CDCl 3 ) δ4.16-4.21 (m, 4H), 2.39-2.52 (m, 2H), 1.60 (s, 3H), 1.23-1.27 (m, 6H), 0.96-1.05 (m ,2H), 0.52-0.60 (m,2H).
第五步：3-乙氧基-2-((1-氟环丙基)甲基)-2-甲基-3-氧代丙酸的合成Step 5: Synthesis of 3-ethoxy-2-((1-fluorocyclopropyl)methyl)-2-methyl-3-oxopropionic acid
Figure PCTCN2022122990-appb-000167
Figure PCTCN2022122990-appb-000167
将2-((1-氟环丙基)甲基)-2-甲基丙二酸二乙酯(2.40g,9.75mmol)溶于四氢呋喃(24.0mL)和水(8.00mL)中，加入氢氧化钾(656mg,11.7mmol)，将反应液加热至65℃反应12小时。反应结束后，将反应液降至室温，加1M稀盐酸调节pH至3～4，用乙酸乙酯(20mL×3)萃取，合并有机相，用饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，浓缩浓缩得粗品，将层析柱(二氧化硅，石油醚：乙酸乙酯＝5:1到2:1)纯化后得到黄色油状物3-乙氧基-2-((1-氟环丙基)甲基)-2-甲基-3-氧代丙酸(1.56g，收率：73.2％)。Diethyl 2-((1-fluorocyclopropyl)methyl)-2-methylmalonate (2.40 g, 9.75 mmol) was dissolved in tetrahydrofuran (24.0 mL) and water (8.00 mL), and hydrogen Potassium oxide (656mg, 11.7mmol), the reaction solution was heated to 65°C for 12 hours. After the reaction, the reaction solution was lowered to room temperature, added 1M dilute hydrochloric acid to adjust the pH to 3-4, extracted with ethyl acetate (20mL×3), combined the organic phases, washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate , filtered, and concentrated to obtain a crude product, which was purified by a chromatographic column (silica, petroleum ether: ethyl acetate = 5:1 to 2:1) to obtain a yellow oil 3-ethoxy-2-((1- Fluorocyclopropyl)methyl)-2-methyl-3-oxopropanoic acid (1.56 g, yield: 73.2%).
1H NMR(400MHz,DMSO-d 6)δ12.88(br s,1H)，4.09(dq,2H)，2.38-2.47(m,1H)，2.19-2.31(m,1H)，1.46(s,3H)，1.14-1.18(m,3H)，0.88-0.98(m,2H)，0.54-0.71(m,2H)。 1 H NMR (400MHz,DMSO-d 6 )δ12.88(br s,1H), 4.09(dq,2H), 2.38-2.47(m,1H), 2.19-2.31(m,1H), 1.46(s, 3H), 1.14-1.18 (m, 3H), 0.88-0.98 (m, 2H), 0.54-0.71 (m, 2H).
第六步：3-氨基-2-((1-氟环丙基)甲基)-2-甲基-3-氧代丙酸乙酯的合成Step 6: Synthesis of ethyl 3-amino-2-((1-fluorocyclopropyl)methyl)-2-methyl-3-oxopropionate
Figure PCTCN2022122990-appb-000168
Figure PCTCN2022122990-appb-000168
将3-乙氧基-2-((1-氟环丙基)甲基)-2-甲基-3-氧代丙酸(1.50g,6.87mmol)和三乙胺(765mg,7.56mmol)溶于四氢呋喃(15.0mL)中，将反应液降至-10℃后缓慢滴加氯甲酸异丁酯(938mg,6.87mmol)，反应1小时后在加入氨水(2.19g,20.6mmol)并0℃下反应2小时。反应结束后，向反应液中加水(20.0mL)，用乙酸乙酯(20mL×3)萃取，合并有机相，用饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，浓缩浓缩得到黄色油状物3-氨基-2-((1-氟环丙基)甲基)-2-甲基-3-氧代丙酸乙酯(1.23g，粗品)。3-Ethoxy-2-((1-fluorocyclopropyl)methyl)-2-methyl-3-oxopropionic acid (1.50g, 6.87mmol) and triethylamine (765mg, 7.56mmol) Dissolve in tetrahydrofuran (15.0mL), drop the reaction solution down to -10°C, and slowly add isobutyl chloroformate (938mg, 6.87mmol) dropwise. After reacting for 1 hour, add ammonia (2.19g, 20.6mmol) and cool at 0°C The reaction was carried out for 2 hours. After the reaction, add water (20.0 mL) to the reaction solution, extract with ethyl acetate (20 mL×3), combine the organic phases, wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, concentrate and concentrate to obtain a yellow oil Ethyl 3-amino-2-((1-fluorocyclopropyl)methyl)-2-methyl-3-oxopropanoate (1.23 g, crude).
1H NMR(400MHz,DMSO-d 6)δ7.11-7.27(m,2H)，3.98-4.15(m,2H)，3.25-3.39(m,1H)，2.10-2.26(m,1H)，1.45(s,3H)，1.12-1.18(m,3H)，0.88-1.03(m,2H)，0.61-0.72(m,1H)，0.48-0.59(m,1H)。 1 H NMR (400MHz, DMSO-d 6 ) δ7.11-7.27 (m, 2H), 3.98-4.15 (m, 2H), 3.25-3.39 (m, 1H), 2.10-2.26 (m, 1H), 1.45 (s, 3H), 1.12-1.18 (m, 3H), 0.88-1.03 (m, 2H), 0.61-0.72 (m, 1H), 0.48-0.59 (m, 1H).
第七步：2-氨基-3-(1-氟环丙基)-2-甲基丙酸乙酯的合成Step 7: Synthesis of ethyl 2-amino-3-(1-fluorocyclopropyl)-2-methylpropionate
Figure PCTCN2022122990-appb-000169
Figure PCTCN2022122990-appb-000169
将乙基3-氨基-2-((1-氟环丙基)甲基)-2-甲基-3-氧代丙酸乙酯(1.20g,5.52mmol)溶于甲苯(12.0mL)，加入二乙酰氧基碘苯(1.78g,5.52mmol)，将反应液加热至45℃反应2小时，再加入4M稀盐酸(4.60mL)，在45℃下继续反应12小时。反应结束后，将反应液降至室温，分液，水相加1M氢氧化钠调节pH至10～11，用乙酸乙酯(20mL×3)萃取，合并有机 相，用饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，浓缩浓缩得到黄色油状物2-氨基-3-(1-氟环丙基)-2-甲基丙酸乙酯(0.58g，粗品)。Ethyl 3-amino-2-((1-fluorocyclopropyl)methyl)-2-methyl-3-oxopropanoic acid ethyl ester (1.20 g, 5.52 mmol) was dissolved in toluene (12.0 mL), Diacetoxyiodobenzene (1.78g, 5.52mmol) was added, the reaction solution was heated to 45°C for 2 hours, then 4M dilute hydrochloric acid (4.60mL) was added, and the reaction was continued at 45°C for 12 hours. After the reaction, the reaction solution was lowered to room temperature, separated, the water phase was adjusted to pH 10-11 by adding 1M sodium hydroxide, extracted with ethyl acetate (20mL×3), the organic phases were combined, and washed with saturated sodium chloride solution , dried over anhydrous sodium sulfate, filtered, and concentrated to give ethyl 2-amino-3-(1-fluorocyclopropyl)-2-methylpropionate (0.58 g, crude product) as a yellow oil.
1H NMR(400MHz,DMSO)δ4.01-4.12(m,2H)，2.09-2.20(m,1H)，1.96-2.04(m,1H)，1.92(br d,2H)，1.27(s,3H)，1.18(t,3H)，0.87-0.95(m,2H)，0.52-0.68(m,2H)。 1 H NMR (400MHz,DMSO)δ4.01-4.12(m,2H), 2.09-2.20(m,1H), 1.96-2.04(m,1H), 1.92(br d,2H), 1.27(s,3H ), 1.18(t,3H), 0.87-0.95(m,2H), 0.52-0.68(m,2H).
第八步：2-氨基-3-(1-氟环丙基)-2-甲基丙烷-1-醇的合成Step 8: Synthesis of 2-amino-3-(1-fluorocyclopropyl)-2-methylpropan-1-ol
Figure PCTCN2022122990-appb-000170
Figure PCTCN2022122990-appb-000170
将2-氨基-3-(1-氟环丙基)-2-甲基丙酸乙酯(580mg,3.07mmol)溶于四氢呋喃(10.0mL)中，将反应液降至0℃，分批加入氢化铝锂(233mg,6.13mmol)，加入完毕后，升温至25℃反应2小时。反应结束后，将反应液降至0℃，在氮气保护下，缓慢滴加水(3.50mL)淬灭，再加入无水硫酸钠干燥15分钟，过滤，浓缩浓缩得到黄色油状物2-氨基-3-(1-氟环丙基)-2-甲基丙烷-1-醇(0.35g，粗品)。Dissolve ethyl 2-amino-3-(1-fluorocyclopropyl)-2-methylpropionate (580mg, 3.07mmol) in tetrahydrofuran (10.0mL), lower the reaction solution to 0°C, and add in batches After the addition of lithium aluminum hydride (233 mg, 6.13 mmol), the temperature was raised to 25° C. for 2 hours. After the reaction was completed, the reaction solution was lowered to 0°C. Under the protection of nitrogen, water (3.50 mL) was slowly added dropwise to quench, then anhydrous sodium sulfate was added to dry for 15 minutes, filtered, concentrated and concentrated to obtain yellow oil 2-amino-3 -(1-fluorocyclopropyl)-2-methylpropan-1-ol (0.35 g, crude).
第九步：(S)-1-((2',6-二(二氟甲基)-[2,4'-联吡啶]-5-基)氧代)-3-(1-氟环丙基)-2-甲基丙烷-2-胺(I-29)Step 9: (S)-1-((2',6-bis(difluoromethyl)-[2,4'-bipyridyl]-5-yl)oxo)-3-(1-fluorocyclo Propyl)-2-methylpropan-2-amine (I-29)
(R)-1-((2',6-二(二氟甲基)-[2,4'-联吡啶]-5-基)氧代)-3-(1-氟环丙基)-2-甲基丙烷-2-胺(R-I-29)(R)-1-((2',6-bis(difluoromethyl)-[2,4'-bipyridyl]-5-yl)oxo)-3-(1-fluorocyclopropyl)- 2-Methylpropane-2-amine (R-I-29)
Figure PCTCN2022122990-appb-000171
Figure PCTCN2022122990-appb-000171
将2',6-二(二氟甲基)-5-氟-2,4'-联吡啶(558mg,2.04μmol)和2-氨基-3-(1-氟环丙基)-2-甲基丙烷-1-醇(300mg,2.04μmol)溶于四氢呋喃(10.0mL)，再加入1M叔丁醇钾的四氢呋喃溶液(8.15mL)，反应液在70℃下搅拌1小时。反应结束后，反应结束后，向反应液中加水(20.0mL)，用乙酸乙酯(20mL×3)萃取，合并有机相，用饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，浓缩浓缩得到粗品，经将层析柱(二氧化硅，乙酸乙酯：甲醇＝50:1到20:1)和手性柱拆分(色谱柱:Daicel ChiralPak IG(250×30mm,10μm)；流动相:[0.1％氨水-甲醇]；B％:30％-30％,3.6min)得到白色固体(S)-1-((2',6-二(二氟甲基)-[2,4'-联吡啶]-5-基)氧代)-3-(1-氟环丙基)-2-甲基丙烷-2-胺(I-29)(99.4mg，收率：19.1％)和黄色固体(R)-1-((2',6-二(二氟甲基)-[2,4'-联吡啶]-5-基)氧代)-3-(1-氟环丙基)-2-甲基丙烷-2-胺(R-I-29)(112mg，收率：21.5％)。2',6-bis(difluoromethyl)-5-fluoro-2,4'-bipyridine (558 mg, 2.04 μmol) and 2-amino-3-(1-fluorocyclopropyl)-2-methanol Propan-1-ol (300 mg, 2.04 μmol) was dissolved in tetrahydrofuran (10.0 mL), and 1 M potassium tert-butoxide in tetrahydrofuran (8.15 mL) was added, and the reaction solution was stirred at 70° C. for 1 hour. After the reaction is over, add water (20.0 mL) to the reaction solution, extract with ethyl acetate (20 mL×3), combine the organic phases, wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, and concentrate Concentrate to obtain the crude product, which is resolved through a chromatographic column (silica, ethyl acetate:methanol=50:1 to 20:1) and a chiral column (chromatographic column: Daicel ChiralPak IG (250×30mm, 10 μm); mobile Phase: [0.1% ammonia water-methanol]; B%: 30%-30%, 3.6min) to obtain white solid (S)-1-((2',6-bis(difluoromethyl)-[2,4 '-bipyridyl]-5-yl)oxo)-3-(1-fluorocyclopropyl)-2-methylpropane-2-amine (I-29) (99.4 mg, yield: 19.1%) and Yellow solid (R)-1-((2',6-bis(difluoromethyl)-[2,4'-bipyridyl]-5-yl)oxo)-3-(1-fluorocyclopropyl )-2-methylpropan-2-amine (R-I-29) (112 mg, yield: 21.5%).
1H NMR(400MHz,DMSO-d 6)δ8.79(d,1H)，8.40(d,1H)，8.32(s,1H)，8.21(d,1H)，7.82(d,1H)，6.89-7.41(m,2H)，3.98-4.07(m,2H)，1.90-2.08(m,2H)，1.72(br s,2H)，1.24(s,3H)，0.93(br d,2H)，0.54-0.66(m,2H)。 1 H NMR (400MHz, DMSO-d 6 )δ8.79(d,1H), 8.40(d,1H), 8.32(s,1H), 8.21(d,1H), 7.82(d,1H), 6.89- 7.41(m,2H), 3.98-4.07(m,2H), 1.90-2.08(m,2H), 1.72(br s,2H), 1.24(s,3H), 0.93(br d,2H), 0.54- 0.66(m,2H).
1H NMR(400MHz,DMSO-d 6)δ8.79(d,1H),8.40(d,1H),8.32(s,1H),8.22(br d,1H),7.83(d,1H),6.89-7.44(m,2H),3.99-4.12(m,2H),2.53-2.64(m,2H),1.91-2.12(m,2H),1.26(s,3H),0.94(br d,2H),0.55-0.69(m,2H)。 1 H NMR (400MHz,DMSO-d 6 )δ8.79(d,1H),8.40(d,1H),8.32(s,1H),8.22(br d,1H),7.83(d,1H),6.89 -7.44(m,2H),3.99-4.12(m,2H),2.53-2.64(m,2H),1.91-2.12(m,2H),1.26(s,3H),0.94(br d,2H), 0.55-0.69 (m,2H).
LC-MS,M/Z(ESI):402.2[M+H] +。 LC-MS, M/Z (ESI): 402.2 [M+H] + .
实施例13：目标化合物I-34、I-35的制备Embodiment 13: the preparation of target compound I-34, I-35
(S)-1-(3,3-二氟环丁基)-3-((8-(2-(二氟甲基)吡啶-4-基)咪唑并[1,2-a]吡啶-5-基)氧代)-2-甲基丙烷-2-胺(I-34)(S)-1-(3,3-difluorocyclobutyl)-3-((8-(2-(difluoromethyl)pyridin-4-yl)imidazo[1,2-a]pyridine- 5-yl)oxo)-2-methylpropan-2-amine (I-34)
(R)-1-(3,3-二氟环丁基)-3-((8-(2-(二氟甲基)吡啶-4-基)咪唑并[1,2-a]吡啶-5-基)氧代)-2-甲基丙烷-2-胺(I-35)(R)-1-(3,3-difluorocyclobutyl)-3-((8-(2-(difluoromethyl)pyridin-4-yl)imidazo[1,2-a]pyridine- 5-yl)oxo)-2-methylpropan-2-amine (I-35)
Figure PCTCN2022122990-appb-000172
Figure PCTCN2022122990-appb-000172
目标化合物I-34、I-35的合成路线如下所示：The synthetic route of target compound I-34, I-35 is as follows:
Figure PCTCN2022122990-appb-000173
Figure PCTCN2022122990-appb-000173
第一步：8-溴-5-氯咪唑并[1,2-a]吡啶的合成Step 1: Synthesis of 8-bromo-5-chloroimidazo[1,2-a]pyridine
Figure PCTCN2022122990-appb-000174
Figure PCTCN2022122990-appb-000174
将3-溴-6-氯吡啶-2-胺(1.00g,4.82mmol)溶于乙醇(10.0mL)中，然后加入2-氯乙醛(1.89g,9.64mmol)和碳酸氢钠(810mg,9.64mmol)，氮气保护下，反应液在50℃搅拌16小时。反应完成后，减压浓缩除去溶剂，加水(20.0mL)溶解，用1M盐酸调pH为7～9，然后用乙酸乙酯(15.0mL×3)萃取，有机相用饱和氯化钠溶液(40.0mL)洗涤和无水硫酸钠干燥后，过滤 浓缩得到粗品。粗品经柱层析(硅胶，石油醚：乙酸乙酯＝5:1至2:1)纯化后得到8-溴-5-氯咪唑并[1,2-a]吡啶(655mg,2.64mmol，产率54.7％)。Dissolve 3-bromo-6-chloropyridin-2-amine (1.00g, 4.82mmol) in ethanol (10.0mL), then add 2-chloroacetaldehyde (1.89g, 9.64mmol) and sodium bicarbonate (810mg, 9.64 mmol), under the protection of nitrogen, the reaction solution was stirred at 50° C. for 16 hours. After the reaction is complete, concentrate under reduced pressure to remove the solvent, add water (20.0 mL) to dissolve, adjust the pH to 7-9 with 1M hydrochloric acid, then extract with ethyl acetate (15.0 mL×3), and use saturated sodium chloride solution (40.0 mL) for the organic phase mL) was washed and dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product. The crude product was purified by column chromatography (silica gel, petroleum ether: ethyl acetate = 5:1 to 2:1) to obtain 8-bromo-5-chloroimidazo[1,2-a]pyridine (655mg, 2.64mmol, yield rate 54.7%).
LCMS,M/Z(ESI):233.1[M+2H] + LCMS,M/Z(ESI):233.1[M+2H] +
第二步：5-氯-8-(2-(二氟甲基)吡啶-4-基)咪唑并[1,2-a]吡啶(3)的合成The second step: the synthesis of 5-chloro-8-(2-(difluoromethyl)pyridin-4-yl)imidazo[1,2-a]pyridine (3)
Figure PCTCN2022122990-appb-000175
Figure PCTCN2022122990-appb-000175
将8-溴-5-氯咪唑并[1,2-a]吡啶(360mg,1.56mmol)，2-(二氟甲基)-4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)吡啶(397mg,1.56mmol)，碳酸钾(430mg,3.11mmol)溶于1，4-二氧六环(4.00mL)和水(1.00mL)，然后加入二氯双[二叔丁基-(4-二甲基氨基苯基)膦]钯(II)(110mg,156μmol)，氮气置换三次，反应在80℃搅拌2小时。反应完成后，减压浓缩除去溶剂，加水(20.0mL)稀释，用乙酸乙酯(15.0mL×3)萃取，有机相用饱和氯化钠溶液(40.0mL)洗涤和无水硫酸钠干燥后，过滤浓缩得到粗品。粗品经柱层析(硅胶，石油醚：乙酸乙酯＝5:1至3:1)纯化后得到5-氯-8-(2-(二氟甲基)吡啶-4-基)咪唑并[1,2-a]吡啶(245mg，产率55.4％)。8-Bromo-5-chloroimidazo[1,2-a]pyridine (360mg, 1.56mmol), 2-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1 , 3,2-dioxaborolan-2-yl)pyridine (397mg, 1.56mmol), potassium carbonate (430mg, 3.11mmol) dissolved in 1,4-dioxane (4.00mL) and water (1.00mL ), then dichlorobis[di-tert-butyl-(4-dimethylaminophenyl)phosphine]palladium(II) (110mg, 156μmol) was added, nitrogen was replaced three times, and the reaction was stirred at 80°C for 2 hours. After the reaction was completed, the solvent was concentrated under reduced pressure to remove the solvent, diluted with water (20.0 mL), extracted with ethyl acetate (15.0 mL×3), and the organic phase was washed with saturated sodium chloride solution (40.0 mL) and dried over anhydrous sodium sulfate. Concentrate by filtration to obtain the crude product. The crude product was purified by column chromatography (silica gel, petroleum ether: ethyl acetate = 5:1 to 3:1) to obtain 5-chloro-8-(2-(difluoromethyl)pyridin-4-yl)imidazo[ 1,2-a]pyridine (245 mg, 55.4% yield).
LCMS,M/Z(ESI):280.0[M+H] + LCMS,M/Z(ESI):280.0[M+H] +
第三步：1-(3,3-二氟环丁基)-3-((8-(2-(二氟甲基)吡啶-4-基)咪唑并[1,2-a]吡啶-5-基)氧代)-2-甲基丙烷-2-胺的合成The third step: 1-(3,3-difluorocyclobutyl)-3-((8-(2-(difluoromethyl)pyridin-4-yl)imidazo[1,2-a]pyridine- Synthesis of 5-yl)oxo)-2-methylpropan-2-amine
Figure PCTCN2022122990-appb-000176
Figure PCTCN2022122990-appb-000176
将5-氯-8-(2-(二氟甲基)吡啶-4-基)咪唑并[1,2-a]吡啶(160mg,572μmol)和2-氨基-3-(3,3-二氟环丁基)-2-甲基丙烷-1-醇(154mg,858μmol)溶于四氢呋喃(3.00mL)中，然后加入叔丁醇钾溶液(1.00M,2.29mL)，反应液在50℃搅拌1小时。反应完成后，加水(10.0mL)淬灭，然后用乙酸乙酯(10.0mL×3)萃取，有机相用饱和氯化钠溶液(20.0mL)洗涤和无水硫酸钠干燥后，过滤浓缩得到粗品。粗品经反相高效液相色谱法分离纯化，纯化方法为：色谱柱:3_Phenomenex Luna C18 75×30mm×3μm；流动相:[water(HCl)-ACN]；B％:3％-23％,8min，纯化后得到1-(3,3-二氟环丁基)-3-((8-(2-(二氟甲基)吡啶-4-基)咪唑并[1,2-a]吡啶-5-基)氧代)-2-甲基丙烷-2-胺(100mg，产率39.3％)。5-Chloro-8-(2-(difluoromethyl)pyridin-4-yl)imidazo[1,2-a]pyridine (160 mg, 572 μmol) and 2-amino-3-(3,3-di Fluorocyclobutyl)-2-methylpropan-1-ol (154mg, 858μmol) was dissolved in tetrahydrofuran (3.00mL), then potassium tert-butoxide solution (1.00M, 2.29mL) was added, and the reaction solution was stirred at 50°C 1 hour. After the reaction was complete, add water (10.0 mL) to quench, then extract with ethyl acetate (10.0 mL×3), the organic phase was washed with saturated sodium chloride solution (20.0 mL) and dried over anhydrous sodium sulfate, then filtered and concentrated to obtain the crude product . The crude product was separated and purified by reverse-phase high-performance liquid chromatography. The purification method was: chromatographic column: 3_Phenomenex Luna C18 75×30mm×3 μm; mobile phase: [water(HCl)-ACN]; B%: 3%-23%, 8min , after purification afforded 1-(3,3-difluorocyclobutyl)-3-((8-(2-(difluoromethyl)pyridin-4-yl)imidazo[1,2-a]pyridine- 5-yl)oxo)-2-methylpropan-2-amine (100 mg, 39.3% yield).
LCMS,M/Z(ESI):423.2[M+H] + LCMS,M/Z(ESI):423.2[M+H] +
第四步：(S)-1-(3,3-二氟环丁基)-3-((8-(2-(二氟甲基)吡啶-4-基)咪唑并[1,2-a]吡啶-5-基)氧代)-2-甲基丙烷-2-胺(I-34)The fourth step: (S)-1-(3,3-difluorocyclobutyl)-3-((8-(2-(difluoromethyl)pyridin-4-yl)imidazo[1,2- a] pyridin-5-yl) oxo) -2-methylpropane-2-amine (I-34)
(R)-1-(3,3-二氟环丁基)-3-((8-(2-(二氟甲基)吡啶-4-基)咪唑并[1,2-a]吡啶-5-基)氧代)-2-甲基丙烷-2-胺(I-35)的制备(R)-1-(3,3-difluorocyclobutyl)-3-((8-(2-(difluoromethyl)pyridin-4-yl)imidazo[1,2-a]pyridine- Preparation of 5-yl)oxo)-2-methylpropane-2-amine (I-35)
Figure PCTCN2022122990-appb-000177
Figure PCTCN2022122990-appb-000177
将消旋体1-(3,3-二氟环丁基)-3-((8-(2-(二氟甲基)吡啶-4-基)咪唑并[1,2-a]吡啶-5-基)氧代)-2-甲基丙烷-2-胺(100mg,225μmol)经正相手性色谱柱拆分，拆分方法为：色谱柱:DAICEL CHIRALPAK IG(250mm×30mm,10μm)；流动相:[0.1％NH 3H 2O MEOH]；B％:45％-45％,5.1min，得到(S)-1-(3,3-二氟环丁基)-3-((8-(2-(二氟甲基)吡啶-4-基)咪唑并[1,2-a]吡啶-5-基)氧代)-2-甲基丙烷-2-胺(7.82mg，产率15.3％) The racemate 1-(3,3-difluorocyclobutyl)-3-((8-(2-(difluoromethyl)pyridin-4-yl)imidazo[1,2-a]pyridine- 5-yl)oxo)-2-methylpropane-2-amine (100mg, 225μmol) was resolved by a normal-phase chiral chromatographic column, and the resolution method was: chromatographic column: DAICEL CHIRALPAK IG (250mm×30mm, 10μm); Mobile phase: [0.1% NH 3 H 2 O MEOH]; B%: 45%-45%, 5.1min, to obtain (S)-1-(3,3-difluorocyclobutyl)-3-((8 -(2-(Difluoromethyl)pyridin-4-yl)imidazo[1,2-a]pyridin-5-yl)oxo)-2-methylpropane-2-amine (7.82 mg, yield 15.3%)
1H NMR(400MHz,CDCl 3)δ＝8.74(d,1H),8.32-8.21(m,2H),7.75(d,2H),7.56(d,1H),6.73(t,1H),6.22(d,1H),4.03(s,2H),2.85-2.70(m,2H),2.44-2.19(m,3H),1.88(br d,2H),1.30(s,3H)。 1 H NMR (400MHz, CDCl 3 ) δ=8.74(d,1H),8.32-8.21(m,2H),7.75(d,2H),7.56(d,1H),6.73(t,1H),6.22( d, 1H), 4.03 (s, 2H), 2.85-2.70 (m, 2H), 2.44-2.19 (m, 3H), 1.88 (br d, 2H), 1.30 (s, 3H).
收集剩余组分得(R)-1-(3,3-二氟环丁基)-3-((8-(2-(二氟甲基)吡啶-4-基)咪唑并[1,2-a]吡啶-5-基)氧代)-2-甲基丙烷-2-胺(7.94mg，产率15.6％)。Collect the remaining components to obtain (R)-1-(3,3-difluorocyclobutyl)-3-((8-(2-(difluoromethyl)pyridin-4-yl)imidazo[1,2 -a] pyridin-5-yl)oxo)-2-methylpropan-2-amine (7.94 mg, 15.6% yield).
1H NMR(400MHz,CDCl 3)δ＝8.74(d,1H),8.30-8.23(m,2H),7.74(d,2H),7.55(d,1H),6.88-6.57(m,1H),6.22(d,1H),4.03(s,2H),2.77(ddt,2H),2.45-2.18(m,3H),1.88(d,2H),1.30(s,3H)。 1 H NMR (400MHz, CDCl 3 )δ=8.74(d,1H),8.30-8.23(m,2H),7.74(d,2H),7.55(d,1H),6.88-6.57(m,1H), 6.22 (d, 1H), 4.03 (s, 2H), 2.77 (ddt, 2H), 2.45-2.18 (m, 3H), 1.88 (d, 2H), 1.30 (s, 3H).
实施例14：目标化合物I-36的制备Embodiment 14: Preparation of target compound I-36
(S)-1-((8-(2-(二氟甲基)吡啶-4-基)-[1,2,4]三唑并[4,3-a]吡啶-5-基)氧代)-2,4-二甲基戊烷-2-胺甲酸盐(I-36)(S)-1-((8-(2-(Difluoromethyl)pyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-5-yl)oxy On behalf of) -2,4-dimethylpentane-2-amine formate (I-36)
Figure PCTCN2022122990-appb-000178
Figure PCTCN2022122990-appb-000178
目标化合物I-36合成路线如下所示：The synthetic route of target compound I-36 is as follows:
Figure PCTCN2022122990-appb-000179
Figure PCTCN2022122990-appb-000179
第一步：3-溴-6-氯-2-肼基吡啶的合成The first step: the synthesis of 3-bromo-6-chloro-2-hydrazinopyridine
Figure PCTCN2022122990-appb-000180
Figure PCTCN2022122990-appb-000180
将3-溴-2,6-二氯吡啶(2.00g,8.81mmol)溶于乙醇(20.0mL)中，再加入水合肼(2.06g,35.0mmol)，将反应液在80℃下搅拌12小时。反应结束后，将反应液浓缩除去乙醇，再加水(30mL)稀释，用乙酸乙酯(20mL×3)萃取，合并有机相，用饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，浓缩得到粗品，粗品经层析柱(二氧化硅，石油醚：乙酸乙酯＝5:1到1:1)纯化得到3-溴-6-氯-2-肼基吡啶(1.40g,收率：71.4％)。Dissolve 3-bromo-2,6-dichloropyridine (2.00g, 8.81mmol) in ethanol (20.0mL), then add hydrazine hydrate (2.06g, 35.0mmol), and stir the reaction solution at 80°C for 12 hours . After the reaction, the reaction solution was concentrated to remove ethanol, then diluted with water (30 mL), extracted with ethyl acetate (20 mL×3), combined organic phases, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated The crude product was obtained, and the crude product was purified by column chromatography (silica, petroleum ether: ethyl acetate = 5:1 to 1:1) to obtain 3-bromo-6-chloro-2-hydrazinopyridine (1.40g, yield: 71.4%).
1H NMR(400MHz,DMSO)δ7.84(s,1H),7.72(d,1H),6.57(d,1H),4.28(s,2H)。 1 H NMR (400 MHz, DMSO) δ 7.84 (s, 1H), 7.72 (d, 1H), 6.57 (d, 1H), 4.28 (s, 2H).
LC-MS,M/Z(ESI):222.0[M+H] + LC-MS, M/Z(ESI):222.0[M+H] +
第二步：8-溴-5-氯-[1,2,4]三唑并[4,3-a]吡啶的合成The second step: the synthesis of 8-bromo-5-chloro-[1,2,4]triazolo[4,3-a]pyridine
Figure PCTCN2022122990-appb-000181
Figure PCTCN2022122990-appb-000181
将3-溴-6-氯-2-肼基吡啶(1.20g,5.39mmol)溶于原甲酸三甲酯(10.0mL)中，将反应液在100℃搅拌3小时。反应结束后，将反应液浓缩得粗品，粗品经层析柱(二氧化硅，石油醚：乙酸乙酯＝2:1到1:1)纯化得到8-溴-5-氯-[1,2,4]三唑并[4,3-a]吡啶(0.52g,收率：41.6％)。3-Bromo-6-chloro-2-hydrazinopyridine (1.20 g, 5.39 mmol) was dissolved in trimethyl orthoformate (10.0 mL), and the reaction solution was stirred at 100° C. for 3 hours. After the reaction was completed, the reaction solution was concentrated to obtain a crude product, which was purified by a chromatographic column (silica, petroleum ether: ethyl acetate = 2:1 to 1:1) to obtain 8-bromo-5-chloro-[1,2 ,4] Triazolo[4,3-a]pyridine (0.52 g, yield: 41.6%).
1H NMR(400MHz,CDCl 3)δ9.03(s,1H),7.53(d,1H),6.84(d,1H)。 1 H NMR (400 MHz, CDCl 3 ) δ 9.03 (s, 1H), 7.53 (d, 1H), 6.84 (d, 1H).
LC-MS,M/Z(ESI):234.0[M+H] + LC-MS, M/Z(ESI):234.0[M+H] +
第三步：5-氯-8-(2-(二氟甲基)吡啶-4-基)-[1,2,4]三唑并[4,3-a]吡啶的合成The third step: the synthesis of 5-chloro-8-(2-(difluoromethyl)pyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridine
Figure PCTCN2022122990-appb-000182
Figure PCTCN2022122990-appb-000182
将8-溴-5-氯-[1,2,4]三唑并[4,3-a]吡啶(420mg,1.81mmol)和2-(二氟甲基)-4-(4,4,5,5-四甲 基-1,3,2-二噁硼戊环-2-基)吡啶(461mg,1.81mmol)溶于二氧六环(9.00mL)和水(2.00mL)中，再加入碳酸钾(499g,3.62mmol)和(2-二环己基膦基-2,4,6-三异丙基-1,1-联苯基)[2-(2-氨基-1,1-联苯)]钯(II)(64.0mg,90.3μmol)，置换氮气3次，反应液在80℃下搅拌1小时。反应结束后，反应结束后，将反应液降至室温，加水(20.0mL)稀释，用乙酸乙酯(20.0mL×3)萃取，合并有机相，用饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，浓缩得粗品，粗品经层析柱(二氧化硅，石油醚：乙酸乙酯＝3:1到1:1)纯化得到5-氯-8-(2-(二氟甲基)吡啶-4-基)-[1,2,4]三唑并[4,3-a]吡啶(300mg，收率：59.2％)。8-Bromo-5-chloro-[1,2,4]triazolo[4,3-a]pyridine (420mg, 1.81mmol) and 2-(difluoromethyl)-4-(4,4, 5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (461 mg, 1.81 mmol) was dissolved in dioxane (9.00 mL) and water (2.00 mL), and then Add potassium carbonate (499g, 3.62mmol) and (2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)[2-(2-amino-1,1- Biphenyl)] palladium (II) (64.0 mg, 90.3 μmol), nitrogen was replaced 3 times, and the reaction solution was stirred at 80° C. for 1 hour. After the reaction was over, the reaction liquid was lowered to room temperature, diluted with water (20.0 mL), extracted with ethyl acetate (20.0 mL×3), the organic phases were combined, washed with saturated sodium chloride solution, anhydrous sodium sulfate Dry, filter, and concentrate to obtain a crude product, which is purified by chromatography column (silica, petroleum ether: ethyl acetate = 3:1 to 1:1) to obtain 5-chloro-8-(2-(difluoromethyl) Pyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridine (300 mg, yield: 59.2%).
1H NMR(400MHz,CDCl 3)δ9.10(s,1H),8.84(d,1H),8.39(d,1H),8.29(s,1H),7.66(d,1H),7.12(d,1H),6.60-6.91(m,1H)。 1 H NMR (400MHz, CDCl 3 )δ9.10(s,1H),8.84(d,1H),8.39(d,1H),8.29(s,1H),7.66(d,1H),7.12(d, 1H), 6.60-6.91 (m, 1H).
LC-MS,M/Z(ESI):281.0[M+H] + LC-MS, M/Z(ESI):281.0[M+H] +
第四步：(S)-1-((8-(2-(二氟甲基)吡啶-4-基)-[1,2,4]三唑并[4,3-a]吡啶-5-基)氧代)-2,4-二甲基戊烷-2-胺甲酸盐(I-36)The fourth step: (S)-1-((8-(2-(difluoromethyl)pyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridine-5 -yl)oxo)-2,4-dimethylpentane-2-amine formate (I-36)
Figure PCTCN2022122990-appb-000183
Figure PCTCN2022122990-appb-000183
将5-氯-8-(2-(二氟甲基)吡啶-4-基)-[1,2,4]三唑并[4,3-a]吡啶(150mg,534μmol)和(S)-2-氨基-2,4-二甲基戊烷-1-醇(119mg,907μmol)溶于四氢呋喃(3.00mL)中，然后加入叔丁醇钾溶液(1.00M,1.60mL)，反应液在50℃搅拌1分钟。反应完成后，加水(10.0mL)稀释，然后用乙酸乙酯(10.0mL×3)萃取，有机相用饱和氯化钠溶液(40.0mL)洗涤和无水硫酸钠干燥后，过滤浓缩得到粗品，粗品经反相高效液相色谱法分离纯化，纯化方法为：色谱柱:Phenomenex C18 75×30mm×3μm；流动相:[water(FA)-ACN]；B％:30％-60％,7min，纯化后得到(S)-1-((3-氯-8-(2-(二氟甲基)吡啶-4-基)咪唑并[1,2-a]吡啶-5-基)氧代)-2,4-二甲基戊烷-2-胺甲酸盐(15.4mg,产率7.56％)。5-Chloro-8-(2-(difluoromethyl)pyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridine (150mg, 534μmol) and (S) -2-Amino-2,4-dimethylpentan-1-ol (119mg, 907μmol) was dissolved in tetrahydrofuran (3.00mL), then potassium tert-butoxide solution (1.00M, 1.60mL) was added, and the reaction solution was Stir at 50°C for 1 minute. After the reaction was completed, it was diluted with water (10.0 mL), then extracted with ethyl acetate (10.0 mL×3), the organic phase was washed with saturated sodium chloride solution (40.0 mL) and dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was separated and purified by reverse-phase high-performance liquid chromatography. The purification method was: chromatographic column: Phenomenex C18 75×30mm×3 μm; mobile phase: [water(FA)-ACN]; B%: 30%-60%, 7min, Purification afforded (S)-1-((3-chloro-8-(2-(difluoromethyl)pyridin-4-yl)imidazo[1,2-a]pyridin-5-yl)oxo) - 2,4-Dimethylpentane-2-amine formate (15.4 mg, yield 7.56%).
1H NMR(400MHz,CDCl3)δ9.62(s,1H),8.72(d,1H),8.21(s,1H),8.14(br d,1H),7.66(d,1H),6.56-6.93(m,1H),6.24(d,1H),5.97(s,1H),3.94(d,1H),3.64(d,1H),1.76-1.91(m,3H),1.23-1.36(m,2H),0.97(d,3H),0.94(d,3H),0.85(br d,1H)。 1 H NMR (400MHz, CDCl3) δ9.62(s,1H),8.72(d,1H),8.21(s,1H),8.14(br d,1H),7.66(d,1H),6.56-6.93( m,1H),6.24(d,1H),5.97(s,1H),3.94(d,1H),3.64(d,1H),1.76-1.91(m,3H),1.23-1.36(m,2H) ,0.97(d,3H),0.94(d,3H),0.85(br d,1H).
LC-MS,M/Z(ESI):376.3[M+H] + LC-MS, M/Z(ESI):376.3[M+H] +
实施例15：目标化合物I-37的制备Embodiment 15: Preparation of Target Compound I-37
(S)-1-((8-(2-(二氟甲基)吡啶-4-基)-2-甲基咪唑并[1,2-a]吡啶-5-基)氧代)-2,4-二甲基戊烷-2- 胺(I-37)(S)-1-((8-(2-(Difluoromethyl)pyridin-4-yl)-2-methylimidazo[1,2-a]pyridin-5-yl)oxo)-2 ,4-Dimethylpentan-2-amine (I-37)
Figure PCTCN2022122990-appb-000184
Figure PCTCN2022122990-appb-000184
目标化合物I-37合成路线如下所示：The synthetic route of target compound I-37 is as follows:
Figure PCTCN2022122990-appb-000185
Figure PCTCN2022122990-appb-000185
第一步：5-氯-8-(2-(二氟甲基)吡啶-4-基)-2-甲基咪唑并[1,2-a]吡啶的合成The first step: Synthesis of 5-chloro-8-(2-(difluoromethyl)pyridin-4-yl)-2-methylimidazo[1,2-a]pyridine
Figure PCTCN2022122990-appb-000186
Figure PCTCN2022122990-appb-000186
在室温下，向6-氯-2'-(二氟甲基)-[3,4'-联吡啶]-2-胺(400mg,1.56mmol)，1-溴-2,2-二甲氧基-丙烷(371mg,2.03mmol)的正丁醇(5.00mL)溶液中加入对甲苯磺酸吡啶(470mg,1.87mmol)，将反应液在120℃下搅拌10小时。反应结束后，直接浓缩。得到粗品。粗品经层析柱分离(石油醚：乙酸乙酯5:1到2:1)得到5-氯-8-[2-(二氟甲基)-4-吡啶基]-2-甲基-咪唑并[1,2-a]吡啶(300mg,粗品)。At room temperature, to 6-chloro-2'-(difluoromethyl)-[3,4'-bipyridine]-2-amine (400mg, 1.56mmol), 1-bromo-2,2-dimethoxy Pyridine p-toluenesulfonate (470 mg, 1.87 mmol) was added to a solution of propane (371 mg, 2.03 mmol) in n-butanol (5.00 mL), and the reaction solution was stirred at 120° C. for 10 hours. After the reaction was completed, it was directly concentrated. get crude. The crude product was separated by column chromatography (petroleum ether: ethyl acetate 5:1 to 2:1) to obtain 5-chloro-8-[2-(difluoromethyl)-4-pyridyl]-2-methyl-imidazole And[1,2-a]pyridine (300 mg, crude product).
LC-MS,M/Z(ESI):294.1[M+H] + LC-MS, M/Z(ESI):294.1[M+H] +
第二步：(S)-1-((8-(2-(二氟甲基)吡啶-4-基)-2-甲基咪唑并[1,2-a]吡啶-5-基)氧代)-2,4-二甲基戊烷-2-胺(I-37)的合成The second step: (S)-1-((8-(2-(difluoromethyl)pyridin-4-yl)-2-methylimidazo[1,2-a]pyridin-5-yl)oxy Synthesis of )-2,4-dimethylpentan-2-amine (I-37)
Figure PCTCN2022122990-appb-000187
Figure PCTCN2022122990-appb-000187
在室温下，向5-氯-8-[2-(二氟甲基)-4-吡啶基]-2-甲基-咪唑并[1,2-a]吡啶(300mg,1.02mmol)和(2S)-2-氨基-2,4-二甲基-戊烷-1-醇(147mg,1.12mmol)的四氢呋喃溶液(4.00mL)加入叔丁醇钾的四氢呋喃溶液(1M,1.53mL)，将反应液在50℃下搅拌1小时。反应结束后，加水稀释，乙酸乙酯萃取。有机相经干燥浓缩。粗品经过层析板分离(二氯甲烷：甲醇＝10:1)，粗 品经反相制备(色谱柱:Phenomenex luna C18 150×25mm×10μm；移动相:[水(0.225％甲酸)-乙腈]；B％:1％-27％,10min)移动相:[水(0.225％甲酸)-乙腈]；B％:1％-27％,10min)得到(S)-1-((8-(2-(二氟甲基)吡啶-4-基)-2-甲基咪唑并[1,2-a]吡啶-5-基)氧代)-2,4-二甲基戊烷-2-胺(I-37)(26.6mg,6.57％收率)。At room temperature, 5-chloro-8-[2-(difluoromethyl)-4-pyridyl]-2-methyl-imidazo[1,2-a]pyridine (300mg, 1.02mmol) and ( 2S)-2-Amino-2,4-dimethyl-pentan-1-ol (147mg, 1.12mmol) in tetrahydrofuran (4.00mL) was added to potassium tert-butoxide in tetrahydrofuran (1M, 1.53mL), and The reaction solution was stirred at 50°C for 1 hour. After the reaction, it was diluted with water and extracted with ethyl acetate. The organic phase is concentrated by drying. The crude product was separated by chromatographic plate (dichloromethane:methanol=10:1), and the crude product was prepared by reverse phase (chromatographic column: Phenomenex luna C18 150×25mm×10 μm; mobile phase: [water (0.225% formic acid)-acetonitrile]; B%: 1%-27%, 10min) mobile phase: [water (0.225% formic acid)-acetonitrile]; B%: 1%-27%, 10min) obtains (S)-1-((8-(2- (Difluoromethyl)pyridin-4-yl)-2-methylimidazo[1,2-a]pyridin-5-yl)oxo)-2,4-dimethylpentane-2-amine ( 1-37) (26.6 mg, 6.57% yield).
1H NMR(400MHz,CDCl 3)δ8.68(d,1H),8.42(s,1H),8.18(s,1H),8.16(d,1H),7.82(s,1H),7.36(d,1H),6.71(t,1H),6.06(d,1H),4.20(m,2H),2.51(s,3H),1.84-1.64(m,3H),1.39(s,3H),0.95(dd,6H)。 1 H NMR (400MHz, CDCl 3 )δ8.68(d,1H),8.42(s,1H),8.18(s,1H),8.16(d,1H),7.82(s,1H),7.36(d, 1H),6.71(t,1H),6.06(d,1H),4.20(m,2H),2.51(s,3H),1.84-1.64(m,3H),1.39(s,3H),0.95(dd ,6H).
LC-MS,M/Z(ESI):389.2[M+H] + LC-MS, M/Z(ESI):389.2[M+H] +
实施例16：目标化合物I-38的制备Embodiment 16: Preparation of target compound I-38
(S)-1-((8-(2-(二氟甲基)吡啶-4-基)-3-甲基咪唑并[1,2-a]吡啶-5-基)氧代)-2,4-二甲基戊烷-2-胺(I-38)(S)-1-((8-(2-(Difluoromethyl)pyridin-4-yl)-3-methylimidazo[1,2-a]pyridin-5-yl)oxo)-2 ,4-Dimethylpentan-2-amine (I-38)
Figure PCTCN2022122990-appb-000188
Figure PCTCN2022122990-appb-000188
目标化合物I-38合成路线如下所示：The synthetic route of target compound I-38 is as follows:
Figure PCTCN2022122990-appb-000189
Figure PCTCN2022122990-appb-000189
第一步：6-氯-2'-(二氟甲基)-[3,4'-联吡啶]-2-胺的合成The first step: Synthesis of 6-chloro-2'-(difluoromethyl)-[3,4'-bipyridyl]-2-amine
Figure PCTCN2022122990-appb-000190
Figure PCTCN2022122990-appb-000190
在室温下，向3-溴-6-氯-吡啶-2-胺(850mg,4.10mmol)，2-(二氟甲基)-4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)吡啶(1.25g,4.92mmol)，碳酸钾(1.13g,8.19mmol)，二氯双[二叔丁基-(4-二甲基氨基苯基)膦]钯(87.0mg,123μmol)溶解在二氧六环(10.0mL)和水(2.00mL)溶 液中氮气置换三次，将反应液在80℃下搅拌1小时。反应结束后，加水稀释，乙酸乙酯萃取，有机相经干燥浓缩得到粗品，粗品经层析柱分离(石油醚：乙酸乙酯5:1到1:1)得到6-氯-2'-(二氟甲基)-[3,4'-联吡啶]-2-胺(2)(950mg,90.7％收率)。At room temperature, to 3-bromo-6-chloro-pyridin-2-amine (850 mg, 4.10 mmol), 2-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1 , 3,2-dioxaborolan-2-yl)pyridine (1.25g, 4.92mmol), potassium carbonate (1.13g, 8.19mmol), dichlorobis[di-tert-butyl-(4-dimethylamino Phenyl)phosphine]palladium (87.0mg, 123μmol) was dissolved in dioxane (10.0mL) and water (2.00mL) and replaced with nitrogen three times, and the reaction solution was stirred at 80°C for 1 hour. After the reaction, it was diluted with water, extracted with ethyl acetate, and the organic phase was dried and concentrated to obtain a crude product, which was separated by column chromatography (petroleum ether: ethyl acetate 5:1 to 1:1) to obtain 6-chloro-2'-( Difluoromethyl)-[3,4'-bipyridyl]-2-amine (2) (950 mg, 90.7% yield).
LC-MS,M/Z(ESI):257.0[M+H] + LC-MS, M/Z(ESI):257.0[M+H] +
第二步：5-氯-8-(2-(二氟甲基)吡啶-4-基)-3-甲基咪唑并[1,2-a]吡啶的合成The second step: the synthesis of 5-chloro-8-(2-(difluoromethyl)pyridin-4-yl)-3-methylimidazo[1,2-a]pyridine
Figure PCTCN2022122990-appb-000191
Figure PCTCN2022122990-appb-000191
在室温下，将6-氯-2'-(二氟甲基)-[3,4'-联吡啶]-2-胺(400mg,1.56mmol)，2-溴-1,1-二甲氧基-丙烷(372mg,2.03mmol)的正丁醇(5.00mL)溶液加入对甲苯磺酸吡啶(432mg,1.72mmol)，将反应液在120℃下搅拌10小时。反应结束后直接浓缩得到粗品。粗品经层析柱分离(石油醚：乙酸乙酯5:1到1:1)得到5-氯-8-(2-(二氟甲基)吡啶-4-基)-3-甲基咪唑并[1,2-a]吡啶(3)(300mg,65.3％收率)。At room temperature, 6-chloro-2'-(difluoromethyl)-[3,4'-bipyridine]-2-amine (400mg, 1.56mmol), 2-bromo-1,1-dimethoxy Pyridine p-toluenesulfonate (432mg, 1.72mmol) was added to a solution of propane (372mg, 2.03mmol) in n-butanol (5.00mL), and the reaction solution was stirred at 120°C for 10 hours. Concentrate directly after the reaction to obtain the crude product. The crude product was separated by column chromatography (petroleum ether: ethyl acetate 5:1 to 1:1) to obtain 5-chloro-8-(2-(difluoromethyl)pyridin-4-yl)-3-methylimidazo [1,2-a]pyridine (3) (300 mg, 65.3% yield).
LC-MS,M/Z(ESI):294.1[M+H] + LC-MS, M/Z(ESI):294.1[M+H] +
第三步：(S)-1-((8-(2-(二氟甲基)吡啶-4-基)-3-甲基咪唑并[1,2-a]吡啶-5-基)氧代)-2,4-二甲基戊烷-2-胺(I-38)的合成The third step: (S)-1-((8-(2-(difluoromethyl)pyridin-4-yl)-3-methylimidazo[1,2-a]pyridin-5-yl)oxy Synthesis of )-2,4-dimethylpentan-2-amine (I-38)
Figure PCTCN2022122990-appb-000192
Figure PCTCN2022122990-appb-000192
在室温下，将5-氯-8-(2-(二氟甲基)吡啶-4-基)-3-甲基咪唑并[1,2-a]吡啶(200mg,681μmol)，(2S)-2-氨基-2,4-二甲基-戊烷-1-醇(98.3mg,749μmol)的四氢呋喃溶液(3.00mL)加入叔丁醇钾的四氢呋喃溶液(1M,1.36mL)，将反应液在50℃下搅拌1小时。反应结束后，加水稀释，乙酸乙酯萃取，有机相经干燥浓缩。粗品经过层析板分离(二氯甲烷：甲醇＝10:1)，粗品经反相制备(色谱柱:Phenomenex Synergi C18 150×25mm×10μm；流动相:[水(0.225％甲酸)-乙腈]；B％:1％-27％,10min)得到(S)-1-((8-(2-(二氟甲基)吡啶-4-基)-3-甲基咪唑并[1,2-a]吡啶-5-基)氧代)-2,4-二甲基戊烷-2-胺(I-38)(10.0mg,3.31％收率)。At room temperature, 5-chloro-8-(2-(difluoromethyl)pyridin-4-yl)-3-methylimidazo[1,2-a]pyridine (200 mg, 681 μmol), (2S) -2-Amino-2,4-dimethyl-pentan-1-ol (98.3mg, 749μmol) in tetrahydrofuran (3.00mL) was added to potassium tert-butoxide in tetrahydrofuran (1M, 1.36mL), and the reaction solution Stir at 50°C for 1 hour. After the reaction, it was diluted with water, extracted with ethyl acetate, and the organic phase was dried and concentrated. The crude product was separated by chromatographic plate (dichloromethane:methanol=10:1), and the crude product was prepared by reverse phase (chromatographic column: Phenomenex Synergi C18 150×25mm×10 μm; mobile phase: [water (0.225% formic acid)-acetonitrile]; B%: 1%-27%, 10min) to obtain (S)-1-((8-(2-(difluoromethyl)pyridin-4-yl)-3-methylimidazo[1,2-a ]pyridin-5-yl)oxo)-2,4-dimethylpentan-2-amine (I-38) (10.0 mg, 3.31% yield).
1H NMR(400MHz,CDCl 3)δ8.72(d,1H),8.15(s,2H),7.37(d,2H),7.34(s,2H),6.72(t,1H),6.12(d,1H),4.11-4.02(m,2H),3.78-3.69(m,1H),2.83(s,3H),1.85-1.81(m,1H),1.59(d,2H),1.37(s,3H),1.25(t,1H),1.02(t,6H)。 1 H NMR (400MHz, CDCl 3 )δ8.72(d,1H),8.15(s,2H),7.37(d,2H),7.34(s,2H),6.72(t,1H),6.12(d, 1H),4.11-4.02(m,2H),3.78-3.69(m,1H),2.83(s,3H),1.85-1.81(m,1H),1.59(d,2H),1.37(s,3H) , 1.25(t,1H), 1.02(t,6H).
LC-MS,M/Z(ESI):389.2[M+H] + LC-MS, M/Z(ESI):389.2[M+H] +
实施例17：目标化合物I-39的制备Embodiment 17: Preparation of target compound I-39
(S)-1-((3-氯-8-(2-(二氟甲基)吡啶-4-基)咪唑并[1,2-a]吡啶-5-基)氧代)-2,4-二甲基戊烷-2-胺盐酸盐(I-39)。(S)-1-((3-chloro-8-(2-(difluoromethyl)pyridin-4-yl)imidazo[1,2-a]pyridin-5-yl)oxo)-2, 4-Dimethylpentan-2-amine hydrochloride (I-39).
Figure PCTCN2022122990-appb-000193
Figure PCTCN2022122990-appb-000193
目标化合物I-39的合成路线如下所示：The synthetic route of target compound I-39 is as follows:
Figure PCTCN2022122990-appb-000194
Figure PCTCN2022122990-appb-000194
第一步：3,5-二氯-8-(2-(二氟甲基)吡啶-4-基)咪唑并[1,2-a]吡啶The first step: 3,5-dichloro-8-(2-(difluoromethyl)pyridin-4-yl)imidazo[1,2-a]pyridine
Figure PCTCN2022122990-appb-000195
Figure PCTCN2022122990-appb-000195
将5-氯-8-(2-(二氟甲基)吡啶-4-基)咪唑并[1,2-a]吡啶(300mg,1.07mmol)溶于乙腈(5.00mL)中，然后加入N-氯代丁二酰亚胺(215mg,1.61mmol)，反应液在65℃下搅拌12小时。反应完成后，减压浓缩除去溶剂，加水(10.0mL)，然后用碳酸氢钠溶液调pH为7～9，然后用乙酸乙酯(20.0mL×3)萃取，有机相用饱和氯化钠溶液(40.0mL)洗涤和无水硫酸钠干燥后，过滤浓缩得到3,5-二氯-8-(2-(二氟甲基)吡啶-4-基)咪唑并[1,2-a]吡啶(247mg,产率67.6％)。5-Chloro-8-(2-(difluoromethyl)pyridin-4-yl)imidazo[1,2-a]pyridine (300 mg, 1.07 mmol) was dissolved in acetonitrile (5.00 mL), and N - Chlorosuccinimide (215mg, 1.61mmol), the reaction solution was stirred at 65°C for 12 hours. After the reaction is complete, concentrate under reduced pressure to remove the solvent, add water (10.0 mL), then adjust the pH to 7-9 with sodium bicarbonate solution, then extract with ethyl acetate (20.0 mL×3), and use saturated sodium chloride solution for the organic phase (40.0 mL) washed and dried over anhydrous sodium sulfate, filtered and concentrated to give 3,5-dichloro-8-(2-(difluoromethyl)pyridin-4-yl)imidazo[1,2-a]pyridine (247 mg, yield 67.6%).
LC-MS,M/Z(ESI):313.9[M+H] + LC-MS, M/Z(ESI):313.9[M+H] +
第二步：(S)-1-((3-氯-8-(2-(二氟甲基)吡啶-4-基)咪唑并[1,2-a]吡啶-5-基)氧代)-2,4-二甲基戊烷-2-胺盐酸(I-39)The second step: (S)-1-((3-chloro-8-(2-(difluoromethyl)pyridin-4-yl)imidazo[1,2-a]pyridin-5-yl)oxo )-2,4-dimethylpentan-2-amine hydrochloride (I-39)
Figure PCTCN2022122990-appb-000196
Figure PCTCN2022122990-appb-000196
将3,5-二氯-8-(2-(二氟甲基)吡啶-4-基)咪唑并[1,2-a]吡啶(190mg,605μmol)和(S)-2-氨基 -2,4-二甲基戊烷-1-醇(119mg,907μmol)溶于四氢呋喃(3.00mL)中，然后加入叔丁醇钾溶液(1.00M,2.42mL)，反应液在25℃搅拌30分钟。反应完成后，减压浓缩除去溶剂，加水(15.0mL)稀释，然后用乙酸乙酯(15.0mL×3)萃取，有机相用饱和氯化钠溶液(40.0mL)洗涤和无水硫酸钠干燥后，过滤浓缩得到粗品，粗品经反相高效液相色谱法分离纯化，纯化方法为：色谱柱:3_Phenomenex Luna C18 75×30mm×3μm；流动相:[water(HCl)-ACN]；B％:18％-38％,8min，得(S)-1-((3-氯-8-(2-(二氟甲基)吡啶-4-基)咪唑并[1,2-a]吡啶-5-基)氧代)-2,4-二甲基戊烷-2-胺盐酸盐(40.0mg,产率15.9％)。3,5-dichloro-8-(2-(difluoromethyl)pyridin-4-yl)imidazo[1,2-a]pyridine (190mg, 605μmol) and (S)-2-amino-2 , 4-Dimethylpentan-1-ol (119mg, 907μmol) was dissolved in tetrahydrofuran (3.00mL), then potassium tert-butoxide solution (1.00M, 2.42mL) was added, and the reaction solution was stirred at 25°C for 30 minutes. After the reaction was completed, the solvent was concentrated under reduced pressure, diluted with water (15.0 mL), then extracted with ethyl acetate (15.0 mL×3), and the organic phase was washed with saturated sodium chloride solution (40.0 mL) and dried over anhydrous sodium sulfate. , filtered and concentrated to obtain the crude product, the crude product was separated and purified by reverse-phase high-performance liquid chromatography, and the purification method was: chromatographic column: 3_Phenomenex Luna C18 75 × 30mm × 3 μm; mobile phase: [water (HCl)-ACN]; B%: 18 %-38%, 8min, to get (S)-1-((3-chloro-8-(2-(difluoromethyl)pyridin-4-yl)imidazo[1,2-a]pyridine-5- (yl)oxo)-2,4-dimethylpentan-2-amine hydrochloride (40.0 mg, yield 15.9%).
1H NMR(400MHz,DMSO-d6)δ＝8.77(d,1H),8.63-8.52(m,2H),8.51(s,1H),8.25(d,1H),7.96(d,1H),7.03(t,1H),6.74(d,1H),4.59-4.42(m,2H),1.98-1.81(m,2H),1.79-1.70(m,1H),1.50(s,3H),0.96(dd,6H)。 1 H NMR (400MHz, DMSO-d6) δ=8.77(d,1H),8.63-8.52(m,2H),8.51(s,1H),8.25(d,1H),7.96(d,1H),7.03 (t,1H),6.74(d,1H),4.59-4.42(m,2H),1.98-1.81(m,2H),1.79-1.70(m,1H),1.50(s,3H),0.96(dd ,6H).
实施例18：目标化合物I-40的制备Embodiment 18: Preparation of target compound I-40
(S)-1-((3-氯-8-(2-(二氟甲基)吡啶-4-基)咪唑并[1,2-a]吡啶-5-基)氧代)-2,4-二甲基戊烷-2-胺盐酸I-40)。(S)-1-((3-chloro-8-(2-(difluoromethyl)pyridin-4-yl)imidazo[1,2-a]pyridin-5-yl)oxo)-2, 4-Dimethylpentan-2-amine hydrochloride I-40).
目标化合物I-40的合成路线如下所示：The synthetic route of target compound I-40 is as follows:
Figure PCTCN2022122990-appb-000197
Figure PCTCN2022122990-appb-000197
第一步：4-(5-氯咪唑并[1,2-a]吡啶-8-基)吡啶-2-胺The first step: 4-(5-chloroimidazo[1,2-a]pyridin-8-yl)pyridin-2-amine
Figure PCTCN2022122990-appb-000198
Figure PCTCN2022122990-appb-000198
将8-溴-5-氯咪唑并[1,2-a]吡啶(500mg,2.16mmol)，4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)吡啶-2-胺(570mg,2.59mmol)和碳酸钾(597mg,4.32mmol)溶于二氧六环(5.00mL)和水(1.00mL)中，然后加入二氯双[二叔丁基-(4-二甲基氨基苯基)膦]钯(II)(152mg,216μmol)，氮气置换三次，反应在90℃下搅拌12小时。反应完成后，减压浓缩除去溶剂，加水(20.0 mL)稀释，然后用乙酸乙酯(20.0mL×3)萃取，有机相用饱和氯化钠溶液(40.0mL)洗涤和无水硫酸钠干燥后，过滤浓缩得到粗品。粗品经柱层析(硅胶，石油醚：乙酸乙酯＝0：1至二氯甲烷：甲醇＝10：1)纯化后得到棕色油状物4-(5-氯咪唑并[1,2-a]吡啶-8-基)吡啶-2-胺(178mg,产率23.6％)。8-Bromo-5-chloroimidazo[1,2-a]pyridine (500mg, 2.16mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol Cyclo-2-yl)pyridin-2-amine (570 mg, 2.59 mmol) and potassium carbonate (597 mg, 4.32 mmol) were dissolved in dioxane (5.00 mL) and water (1.00 mL), then dichlorobis[ Di-tert-butyl-(4-dimethylaminophenyl)phosphine]palladium(II) (152 mg, 216 μmol) was replaced with nitrogen three times, and the reaction was stirred at 90° C. for 12 hours. After the reaction was complete, the solvent was concentrated under reduced pressure to remove the solvent, diluted with water (20.0 mL), then extracted with ethyl acetate (20.0 mL×3), and the organic phase was washed with saturated sodium chloride solution (40.0 mL) and dried over anhydrous sodium sulfate. , filtered and concentrated to obtain the crude product. The crude product was purified by column chromatography (silica gel, petroleum ether: ethyl acetate = 0:1 to dichloromethane: methanol = 10:1) to obtain brown oil 4-(5-chloroimidazo[1,2-a] Pyridin-8-yl)pyridin-2-amine (178 mg, 23.6% yield).
LCMS,M/Z(ESI):245.0[M+H] + LCMS,M/Z(ESI):245.0[M+H] +
第二步：甲基(4-(5-氯咪唑并[1,2-a]吡啶-8-基)吡啶-2-基)氨基甲酯The second step: Methyl (4-(5-chloroimidazo[1,2-a]pyridin-8-yl)pyridin-2-yl)aminomethyl ester
Figure PCTCN2022122990-appb-000199
Figure PCTCN2022122990-appb-000199
将4-(5-氯咪唑并[1,2-a]吡啶-8-基)吡啶-2-胺(145mg,593μmol)溶于甲醇(5.00mL)中，然后在0℃滴加二碳酸二叔丁酯(155mg,711μmol)，反应液在25度下搅拌10小时。反应完成后，减压浓缩除去溶剂得到粗品。粗品经打浆纯化(乙酸乙酯，25℃)得到甲基(4-(5-氯咪唑并[1,2-a]吡啶-8-基)吡啶-2-基)氨基甲酯(108mg,产率54.0％)。Dissolve 4-(5-chloroimidazo[1,2-a]pyridin-8-yl)pyridin-2-amine (145mg, 593μmol) in methanol (5.00mL), then add dicarbonate dicarbonate dropwise at 0°C Tert-butyl ester (155mg, 711μmol), the reaction solution was stirred at 25°C for 10 hours. After the reaction was completed, the solvent was removed by concentration under reduced pressure to obtain a crude product. The crude product was purified by beating (ethyl acetate, 25°C) to obtain methyl (4-(5-chloroimidazo[1,2-a]pyridin-8-yl)pyridin-2-yl)aminomethyl ester (108mg, yield rate 54.0%).
1H NMR(400MHz,DMSO-d6)δ＝10.28(s,1H),8.58(s,1H),8.38(d,1H),8.17(d,1H),7.84(s,1H),7.78(dd,1H),7.66(d,1H),7.36(d,1H),3.70(s,3H)。 1 H NMR (400MHz, DMSO-d6) δ=10.28(s,1H),8.58(s,1H),8.38(d,1H),8.17(d,1H),7.84(s,1H),7.78(dd ,1H), 7.66(d,1H), 7.36(d,1H), 3.70(s,3H).
LC-MS,M/Z(ESI):303.1[M+H] + LC-MS, M/Z(ESI):303.1[M+H] +
第三步：(S)-甲基(4-(5-((2-氨基-2,4-二甲代戊基)氧代)咪唑并[1,2-a]吡啶-8-基)吡啶-2-基)氨基甲酯盐酸盐(I-40)The third step: (S)-methyl(4-(5-((2-amino-2,4-dimethylpentyl)oxo)imidazo[1,2-a]pyridin-8-yl) Pyridin-2-yl)aminomethyl ester hydrochloride (I-40)
Figure PCTCN2022122990-appb-000200
Figure PCTCN2022122990-appb-000200
将(4-(5-氯咪唑并[1,2-a]吡啶-8-基)吡啶-2-基)氨基甲酯(100mg,330μmol)，(S)-2-氨基-2,4-二甲基戊烷-1-醇(65.0mg,495μmol)溶于四氢呋喃(2.00mL)，然后加入叔丁醇钾溶液(1.00M,1.32mL)，反应液在50℃下反应2小时。反应完成后，加水(20.0mL)淬灭，然后用乙酸乙酯(25.0mL×3)萃取，有机相用饱和氯化钠溶液(60.0mL)洗涤和无水硫酸钠干燥后，过滤浓缩得到粗品。粗品经反相高效液相色谱法分离纯化，分离方法为：色谱柱:3_Phenomenex Luna C18 75×30mm×3μm；流动相:[water(HCl)-ACN]；B％:0％-21％,8min，纯化后得(S)-甲基(4-(5-((2-氨基-2,4-二甲代戊基)氧代)咪唑并[1,2-a]吡啶-8-基)吡啶-2-基)氨基甲酯盐酸盐(10.0 mg,产率7.46％)。(4-(5-chloroimidazo[1,2-a]pyridin-8-yl)pyridin-2-yl)aminomethyl ester (100mg, 330μmol), (S)-2-amino-2,4- Dimethylpentan-1-ol (65.0mg, 495μmol) was dissolved in tetrahydrofuran (2.00mL), then potassium tert-butoxide solution (1.00M, 1.32mL) was added, and the reaction solution was reacted at 50°C for 2 hours. After the reaction was completed, it was quenched by adding water (20.0 mL), then extracted with ethyl acetate (25.0 mL×3), the organic phase was washed with saturated sodium chloride solution (60.0 mL) and dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product . The crude product was separated and purified by reverse-phase high-performance liquid chromatography. The separation method was: chromatographic column: 3_Phenomenex Luna C18 75×30mm×3 μm; mobile phase: [water(HCl)-ACN]; B%: 0%-21%, 8min , after purification to give (S)-methyl(4-(5-((2-amino-2,4-dimethylpentyl)oxo)imidazo[1,2-a]pyridin-8-yl) Pyridin-2-yl)aminomethyl ester hydrochloride (10.0 mg, yield 7.46%).
1H NMR(400MHz,DMSO-d6)δ＝10.66(brs,1H),9.04(d,1H),8.83(br s,2H),8.45(d,1H),8.26(s,1H),8.20(s,1H),8.10(d,1H),7.47(br d,1H),7.18(d,1H),4.69-4.57(m,2H),3.71(s,3H),1.95-1.81(m,2H),1.78-1.70(m,1H),1.48(s,3H),1.06-0.85(m,6H)。 1 H NMR (400MHz, DMSO-d6) δ = 10.66 (brs, 1H), 9.04 (d, 1H), 8.83 (br s, 2H), 8.45 (d, 1H), 8.26 (s, 1H), 8.20 ( s,1H),8.10(d,1H),7.47(br d,1H),7.18(d,1H),4.69-4.57(m,2H),3.71(s,3H),1.95-1.81(m,2H ), 1.78-1.70(m,1H), 1.48(s,3H), 1.06-0.85(m,6H).
LCMS,M/Z(ESI):398.2[M+H] + LCMS,M/Z(ESI):398.2[M+H] +
实施例19：目标化合物I-41的制备Embodiment 19: Preparation of target compound I-41
(S)-1-((2-(二氟甲基)-8-(2-(二氟甲基)吡啶-4-基)咪唑并[1,2-a]吡啶-5-基)氧代)-2,4-二甲基戊烷-2-胺(I-41)(S)-1-((2-(difluoromethyl)-8-(2-(difluoromethyl)pyridin-4-yl)imidazo[1,2-a]pyridin-5-yl)oxy Substitute)-2,4-dimethylpentan-2-amine (I-41)
Figure PCTCN2022122990-appb-000201
Figure PCTCN2022122990-appb-000201
目标化合物I-41的制备Preparation of target compound I-41
Figure PCTCN2022122990-appb-000202
Figure PCTCN2022122990-appb-000202
第一步：(S)-(1-((2-氨基-2'-(二氟甲基)-[3,4'-联吡啶]-6-基)氧代)-2,4-二甲基戊烷-2-基)氨基甲酸叔丁酯的合成The first step: (S)-(1-((2-amino-2'-(difluoromethyl)-[3,4'-bipyridyl]-6-yl)oxo)-2,4-di Synthesis of tert-butyl methylpentan-2-yl)carbamate
Figure PCTCN2022122990-appb-000203
Figure PCTCN2022122990-appb-000203
在室温下将(2S)-2-氨基-2,4-二甲基-戊烷-1-醇(200mg,1.53mmol)和6-氯-3-[2-(二氟甲基)-4-吡啶基]吡啶-2-胺(300mg,1.17mmol)的四氢呋喃溶液(5.00mL)加入叔丁醇钾四氢呋喃溶液(1M,2.93mL)，将反应液在70℃下搅拌16小时。反应结束后，加水稀释乙酸乙酯萃取，有机相经干燥浓缩得到粗品，粗品溶解在二氯甲烷溶液中(3.00mL)，加入二碳酸二叔丁酯(374mg)并搅拌4小时。反应结束后。浓缩得到粗品。粗品经过层析板分离(石油醚：乙酸乙酯＝1:1)得到(S)-(1-((2-氨基-2'-(二氟甲基)-[3,4'-联吡啶]-6-基)氧代)-2,4-二甲基戊烷-2- 基)氨基甲酸叔丁酯(180mg,34.1％收率)。(2S)-2-Amino-2,4-dimethyl-pentan-1-ol (200 mg, 1.53 mmol) and 6-chloro-3-[2-(difluoromethyl)-4 -Pyridyl]pyridin-2-amine (300mg, 1.17mmol) in tetrahydrofuran (5.00mL) was added to potassium tert-butoxide in tetrahydrofuran (1M, 2.93mL), and the reaction solution was stirred at 70°C for 16 hours. After the reaction was completed, dilute ethyl acetate with water and extract. The organic phase was dried and concentrated to obtain a crude product. The crude product was dissolved in dichloromethane solution (3.00 mL), and di-tert-butyl dicarbonate (374 mg) was added and stirred for 4 hours. After the reaction is over. Concentration gave the crude product. The crude product was separated by chromatography (petroleum ether: ethyl acetate = 1:1) to obtain (S)-(1-((2-amino-2'-(difluoromethyl)-[3,4'-bipyridine ]-6-yl)oxo)-2,4-dimethylpentan-2-yl)carbamate tert-butyl ester (180 mg, 34.1% yield).
LC-MS,M/Z(ESI):451.1[M+H] + LC-MS, M/Z(ESI):451.1[M+H] +
第二步：(S)-1-((2-(二氟甲基)-8-(2-(二氟甲基)吡啶-4-基)咪唑并[1,2-a]吡啶-5-基)氧代)-2,4-二甲基戊烷-2-胺(I-41)的合成The second step: (S)-1-((2-(difluoromethyl)-8-(2-(difluoromethyl)pyridin-4-yl)imidazo[1,2-a]pyridine-5 Synthesis of -yl)oxo)-2,4-dimethylpentan-2-amine (I-41)
Figure PCTCN2022122990-appb-000204
Figure PCTCN2022122990-appb-000204
在室温下，向3-溴-1,1-二氟-丙烷-2-酮(82.5mg,476μmol)和叔-丁基(S)-(1-((2-氨基-2'-(二氟甲基)-[3,4'-联吡啶]-6-基)氧代)-2,4-二甲基戊烷-2-基)氨基甲酯(179mg,397μmol)的正丙醇(2.00mL)溶液在氮气下置换三次，并将反应液在100℃下搅拌10小时。反应结束后，浓缩得到粗品。粗品经反相制备(色谱柱:Phenomenex luna C18 150×25mm×10μm；流动相:[水(0.225％甲酸)-乙腈]；B％:15％-45％,10min)得到(S)-1-((2-(二氟甲基)-8-(2-(二氟甲基)吡啶-4-基)咪唑并[1,2-a]吡啶-5-基)氧代)-2,4-二甲基戊烷-2-胺(I-41)(27.0mg,15.8％收率)Add 3-bromo-1,1-difluoro-propan-2-one (82.5 mg, 476 μmol) and tert-butyl (S)-(1-((2-amino-2'-(di Fluoromethyl)-[3,4'-bipyridyl]-6-yl)oxo)-2,4-dimethylpentan-2-yl)aminomethyl ester (179mg, 397μmol) in n-propanol ( 2.00 mL) solution was replaced under nitrogen three times, and the reaction solution was stirred at 100° C. for 10 hours. After the reaction was completed, it was concentrated to obtain a crude product. The crude product was prepared by reverse phase (chromatographic column: Phenomenex luna C18 150×25mm×10 μm; mobile phase: [water (0.225% formic acid)-acetonitrile]; B%: 15%-45%, 10min) to obtain (S)-1- ((2-(Difluoromethyl)-8-(2-(difluoromethyl)pyridin-4-yl)imidazo[1,2-a]pyridin-5-yl)oxo)-2,4 -Dimethylpentan-2-amine (I-41) (27.0 mg, 15.8% yield)
1H NMR(400MHz,CDCl 3)δ8.69(d,1H),8.40(s,1H),8.19(s,2H),7.53(d,1H),7.08-6.54(m,2H),6.16(d,1H),4.18(s,2H),1.88-1.75(m,1H),1.71-1.62(m,2H),1.40(s,3H),1.03(dd,6H)。 1 H NMR (400MHz, CDCl 3 )δ8.69(d,1H),8.40(s,1H),8.19(s,2H),7.53(d,1H),7.08-6.54(m,2H),6.16( d,1H), 4.18(s,2H), 1.88-1.75(m,1H), 1.71-1.62(m,2H), 1.40(s,3H), 1.03(dd,6H).
LC-MS,M/Z(ESI):425.1[M+H] + LC-MS, M/Z(ESI):425.1[M+H] +
Figure PCTCN2022122990-appb-000205
Figure PCTCN2022122990-appb-000205
Figure PCTCN2022122990-appb-000206
Figure PCTCN2022122990-appb-000206
Figure PCTCN2022122990-appb-000207
Figure PCTCN2022122990-appb-000207
Figure PCTCN2022122990-appb-000208
Figure PCTCN2022122990-appb-000208
Figure PCTCN2022122990-appb-000209
Figure PCTCN2022122990-appb-000209
测试例1：基于TR-FRET(时间分辨荧光共振能量转移)的AAK1激酶结合试验Test Example 1: AAK1 Kinase Binding Assay Based on TR-FRET (Time-Resolved Fluorescence Resonance Energy Transfer)
将测试化合物(前面实施例所制备的对照化合物1与化合物I-1～I-41、R-I-4、R-I-29)分别溶解于DMSO并配制成10mM的母液，用DMSO稀释至浓度梯度最高点的100倍，随后3倍连续稀释直至达到8个浓度梯度。把5×kinase buffer A(Invitrogen,PV3189)用ddH 2O稀释5倍为1×kinase buffer A，将系列化合物稀释溶液用1×kinase buffer A再稀释至4倍终浓度，加入384孔板中(4μl/孔)。将AAK1Recombinant Human Protein(Invitrogen,A30967)与LanthaScreen TMEu-anti-GST Antibody(Invitrogen,PV5594)配制成2×kinase/Antibody混合液，加入384孔板中(16μl/孔)并吹打均匀。室温平衡15min。每孔再加入4μl的4×Kinase Tracer 222(Invitrogen,PV6121)，吹打均匀。室温孵育1h。将384孔板放入多功能酶标仪中进行读数，激发波长设为332nm，吸收波长设650nm和620nm两个通道，记录665nm与620nm的荧光信号比值(ER值)。按公式计算每孔的结合率：％结合率＝(ER 高信号对照-ER 样品)/(ER 高信号对照-ER 低信号对照)×100，用GraphPad 8.0拟合曲线并计算IC 50值。下表a、b、c、d表示化合物IC 50值范围，即a≤10nM、10<b≤50nM、50nM<c≤500nM、500nM<d。 Dissolve the test compound (the control compound 1 prepared in the previous example and compounds I-1～I-41, RI-4, RI-29) in DMSO and prepare a 10mM mother solution, and dilute it to the highest point of the concentration gradient with DMSO 100-fold, followed by 3-fold serial dilution until reaching 8 concentration gradients. Dilute 5×kinase buffer A (Invitrogen, PV3189) 5 times with ddH 2 O to 1×kinase buffer A, then dilute the serial compound dilution solution with 1×kinase buffer A to a final concentration of 4 times, and add it to a 384-well plate ( 4 μl/well). AAK1 Recombinant Human Protein (Invitrogen, A30967) and LanthaScreen TM Eu-anti-GST Antibody (Invitrogen, PV5594) were prepared into a 2×kinase/Antibody mixture, added to a 384-well plate (16 μl/well) and pipetted evenly. Equilibrate at room temperature for 15 minutes. Add 4 μl of 4×Kinase Tracer 222 (Invitrogen, PV6121) to each well, and pipette evenly. Incubate at room temperature for 1h. Put the 384-well plate into a multifunctional microplate reader for reading, set the excitation wavelength to 332nm, set the absorption wavelength to two channels of 650nm and 620nm, and record the fluorescence signal ratio (ER value) at 665nm and 620nm. Calculate the binding rate of each well according to the formula: % binding rate = (ER high signal control - ER sample ) / (ER high signal control - ER low signal control ) × 100, use GraphPad 8.0 to fit the curve and calculate the IC 50 value. Tables a, b, c, and d below indicate the range of IC 50 values of the compounds, that is, a≤10nM, 10<b≤50nM, 50nM<c≤500nM, 500nM<d.
表1测试化合物AAK1激酶结合活性Table 1 Test compound AAK1 kinase binding activity
化合物编号Compound number IC 50(nM) IC 50 (nM)
I-1I-1 aa
I-2I-2 aa
I-3I-3 aa
I-4I-4 aa
I-5I-5 aa
I-6I-6 aa
I-7I-7 aa
I-8I-8 aa
I-9I-9 aa
I-10I-10 aa
I-11I-11 aa
I-12I-12 aa
I-13I-13 aa
I-14I-14 bb
I-15I-15 bb
I-16I-16 aa
I-17I-17 aa
I-18I-18 bb
I-19I-19 aa
I-20I-20 aa
I-21I-21 aa
I-22I-22 bb
I-23I-23 bb
I-24I-24 bb
I-25I-25 aa
I-26I-26 cc
I-27I-27 bb
I-28I-28 aa
I-29I-29 aa
I-30I-30 aa
I-31I-31 aa
I-32I-32 aa
I-33I-33 aa
结果表明，本发明化合物的AAK1的亲和力较强。The result shows that the affinity of AAK1 of the compound of the present invention is relatively strong.
测试例2：人肝细胞稳定性试验Test Example 2: Human Hepatocyte Stability Test
人肝细胞稳定性试验采用化合物与人肝细胞共孵育进行检测。从液氮中取出冻存的肝细胞，37℃水浴融化后加入肝细胞解冻培养基，轻柔混匀后500rpm离心3分钟。弃上清，加入10倍体积的KHB缓冲液(Krebs-Henseleit buffer,Sigma,Cat#K3753-10X1L)和5.6g/L HEPES重悬细胞，轻柔混匀后500rpm离心3分钟。弃上清，确定肝细胞活力和产量。计数后，调整细胞密度至2×10 6cells/mL，冰上放置待用。将10μL的200μM待测化合物(前面实施例所制备的对照化合物1或化合物I-1～I-41、R-I-4、R-I-29之一)DMSO溶液加入990μL KHB缓冲液，5594g离心15分钟，以50μL/孔将加到指定不同时间点的孔中。以50μL/孔将肝细胞悬液加到计划孵育15、30、60、120分钟的孔中，放入37℃培养箱孵育相应的时间后，分别加入100μL/孔含内标的乙腈溶液终止反应。以100μL/孔将含内标的乙腈溶液，加到含有化合物KHB溶液的孔中，混匀并加入50μL/孔肝细胞悬液，设为0分钟对照孔。所有孔均终止反应后，深孔板涡旋振动10分钟(600rpm/min)。超声2分钟，再5594g离心1分钟，每孔取出50μL上清1:1加入纯化水后进行LC-MS/MS检测，获得每个时间点化合物峰面积与内标峰面积比值，将15、30、60、120分钟时化合物的峰面积比值与0min时的峰面积比值进行比较，计算每个时间点化合物的剩余百分比，使用Graphpad 8软件计算T1/2。 The stability test of human hepatocytes was tested by co-incubating the compound with human hepatocytes. The frozen hepatocytes were taken out from the liquid nitrogen, thawed in a water bath at 37°C, and the hepatocyte thawing medium was added, mixed gently and then centrifuged at 500 rpm for 3 minutes. Discard the supernatant, add 10 times the volume of KHB buffer (Krebs-Henseleit buffer, Sigma, Cat#K3753-10X1L) and 5.6g/L HEPES to resuspend the cells, mix gently and centrifuge at 500rpm for 3 minutes. Discard the supernatant and determine the viability and yield of hepatocytes. After counting, adjust the cell density to 2×10 6 cells/mL, and place on ice until use. Add 10 μL of 200 μM test compound (control compound 1 or one of compounds I-1 to I-41, RI-4, RI-29 prepared in the previous example) DMSO solution to 990 μL KHB buffer, centrifuge at 5594g for 15 minutes, Add 50 μL/well to the wells designated at different time points. Add 50 μL/well of the hepatic cell suspension to the wells planned to incubate for 15, 30, 60, and 120 minutes, put them in a 37°C incubator and incubate for the corresponding time, then add 100 μL/well of acetonitrile solution containing internal standard to terminate the reaction. Add 100 μL/well of the acetonitrile solution containing the internal standard to the wells containing the compound KHB solution, mix well and add 50 μL/well of the hepatic cell suspension, and set it as the 0-minute control well. After the reaction was terminated in all wells, the deep-well plate was vortexed for 10 minutes (600 rpm/min). Sonicate for 2 minutes, then centrifuge at 5594g for 1 minute, take out 50 μL of supernatant from each well and add purified water at 1:1 for LC-MS/MS detection, obtain the ratio of the peak area of the compound at each time point to the peak area of the internal standard, and divide 15, 30 Compare the peak area ratios of the compounds at , 60, and 120 minutes with the peak area ratios at 0 min, calculate the remaining percentage of the compound at each time point, and use Graphpad 8 software to calculate T1/2.
表2测试化合物在人肝细胞中的稳定性参数
Figure PCTCN2022122990-appb-000210
Table 2 Stability parameters of test compounds in human hepatocytes
Figure PCTCN2022122990-appb-000210
结果表明，本发明化合物在人肝细胞中有较好的代谢稳定性。The results show that the compound of the present invention has better metabolic stability in human hepatocytes.
测试例3：化合物血浆蛋白结合率Test Example 3: Compound Plasma Protein Binding Rate
采用平衡透析法(HTDialysis，HTD 96b)检测化合物的血浆蛋白结合率。用DMSO将待测化合物(前面实施例所制备的对照化合物1与化合物I-1～I-41、R-I-4、R-I-29)分别配制为0.5mM的储备液，再用0.05M磷酸钠缓冲液稀释25倍为工作液。取空白96孔板，每孔预装入380μL血浆，随后在血浆中加入20μL/孔工作液并混匀，化合物终浓度为1μM，每孔含有0.2％DMSO。The plasma protein binding rate of the compounds was detected by equilibrium dialysis (HTDialysis, HTD 96b). The compounds to be tested (the control compound 1 prepared in the previous example and compounds I-1～I-41, R-I-4, R-I-29) were prepared as 0.5mM stock solutions with DMSO, and then buffered with 0.05M sodium phosphate solution diluted 25 times as the working solution. Take a blank 96-well plate, preload each well with 380 μL plasma, then add 20 μL/well working solution to the plasma and mix well, the final concentration of the compound is 1 μM, and each well contains 0.2% DMSO.
分别加入100μL 0.05M磷酸钠缓冲液至各透析小室(HTD 96b)的接收侧，再加入100μL含有化合物的血浆到供给侧。盖好塑料盖后，放置于37℃中摇晃孵育5小时。Add 100 μL of 0.05M sodium phosphate buffer solution to the receiving side of each dialysis chamber (HTD 96b), and then add 100 μL of plasma containing the compound to the supply side. After covering the plastic cover, place it at 37°C and incubate with shaking for 5 hours.
孵育结束后，从透析小室的供给侧和接受侧各取25μL样品，置于空白96孔板中，并在供给侧样品中各加入等体积的血浆，在接受侧样品中各加入等体积的0.05M磷酸钠缓冲液，混合均匀。每孔加入200μL含有内标的乙腈溶液后，将96孔板以600rpm的速度涡旋振荡10分钟，5594g离心15分钟(Thermo Multifuge×3R)后，取50μL上清液转移至新的96孔板中，并将样品与50μL超纯水混合后进行LC-MS/MS分析。After the incubation, 25 μL samples were taken from the supply side and the receiving side of the dialysis chamber, placed in a blank 96-well plate, and an equal volume of plasma was added to the supply side samples, and an equal volume of 0.05 μL was added to the receiving side samples. M sodium phosphate buffer, mix well. After adding 200 μL of acetonitrile solution containing internal standard to each well, the 96-well plate was vortexed at 600 rpm for 10 minutes, centrifuged at 5594g for 15 minutes (Thermo Multifuge×3R), and 50 μL of the supernatant was transferred to a new 96-well plate , and the sample was mixed with 50 μL ultrapure water for LC-MS/MS analysis.
使用以下公式对血浆蛋白结合率及游离分数进行计算：％结合率＝100×([供给侧浓度] 5h-[接收侧浓度] 5h)/[供给侧浓度] 5h。％游离分数＝100-％结合率 The plasma protein binding rate and free fraction were calculated using the following formula: % binding rate=100×([supply side concentration] 5h- [receiving side concentration] 5h )/[supply side concentration] 5h . % free fraction = 100 - % bound
表3测试化合物在血浆中的游离分数Table 3 Test compound free fraction in plasma
Figure PCTCN2022122990-appb-000211
Figure PCTCN2022122990-appb-000211
实验结果表明，本发明化合物在各种属血浆中游离药物的比率均较高，成药性好。Experimental results show that the compound of the present invention has high ratios of free drugs in plasma of various species and good druggability.
测试例4：化合物对人肝癌细胞毒性评价Test Example 4: Toxicity Evaluation of Compounds on Human Liver Cancer Cells
人肝癌细胞HepG2在含10％FBS的MEM培养基中培养，在细胞生长状态良好时，按照10000/孔，100μL/孔密度接种于96孔板。放入37℃，5％CO2培养箱过夜。Human liver cancer cells HepG2 were cultured in MEM medium containing 10% FBS, and seeded in a 96-well plate at a density of 10000/well and 100 μL/well when the cells were in good growth state. Place in a 37°C, 5% CO2 incubator overnight.
每孔加入梯度稀释的待测化合物(前面实施例所制备的对照化合物1或化合物I-1～I-41、R-I-4、R-I-29之一)或DMSO，另设置不接种细胞加入培养基的孔作为空白对照。放入37℃，5％CO2培养箱培养72小时后，根据
Figure PCTCN2022122990-appb-000212
Cell Viability Assay试剂盒(Promega,Cat.No.G9243)说明书，将96孔板从培养箱取出，室温平衡30min。平衡结束后，按100μL/孔加入室温的CellTiter-Glo试剂，在摇床上震荡5min，室温孵育10min后在多功能酶标仪 上读取luminescence信号，并计算细胞活性抑制率： Add serially diluted test compound (one of the control compound 1 or compound I-1~I-41, RI-4, RI-29 prepared in the previous example) or DMSO to each well, and add culture medium without seeding cells Wells served as blank controls. After 72 hours in a 37°C, 5% CO2 incubator, according to
Figure PCTCN2022122990-appb-000212
Cell Viability Assay Kit (Promega, Cat. No. G9243) instructions, the 96-well plate was taken out of the incubator, and equilibrated at room temperature for 30 min. After equilibration, add CellTiter-Glo reagent at room temperature at 100 μL/well, shake on a shaker for 5 minutes, incubate at room temperature for 10 minutes, read the luminescence signal on a multi-functional microplate reader, and calculate the cell activity inhibition rate:
细胞活性抑制率＝(DMSO组-测试化合物)/(DMSO组-空白对照组)×100％Cell activity inhibition rate=(DMSO group-test compound)/(DMSO group-blank control group)×100%
采用Graphpad 8软件计算IC 50值。 IC50 values were calculated using Graphpad 8 software.
表4测试化合物对HepG2细胞的毒性The toxicity of table 4 test compound to HepG2 cell
化合物编号Compound number IC 50(μM) IC50 (μM)
对照化合物1Control compound 1 8.58.5
I-3I-3 32.332.3
I-4I-4 26.426.4
I-11I-11 43.343.3
I-21I-21 54.354.3
实验结果表明，本发明化合物相对于对照化合物1，抑制HepG2增殖的能力更低，细胞水平上的毒性更小。The experimental results show that, compared with the control compound 1, the compound of the present invention has lower ability to inhibit the proliferation of HepG2 and less toxicity at the cellular level.
测试例5：大鼠药代动力学试验Test Example 5: Rat pharmacokinetic test
大鼠药代动力学试验，每组采用雄性SD大鼠3只，180-240g，禁食过夜，口服灌胃给药(前面实施例所制备的对照化合物1或化合物I-1～I-41、R-I-4、R-I-29之一)10mg/kg。在给药前和在给药后15、30分钟以及1、2、4、8、24小时采血。血液样品8000转/分钟4℃离心6分钟，收集血浆，于-20℃保存。取各时间点血浆，加入3-5倍量含内标的乙腈溶液混合，涡旋混合1分钟，13000转/分钟4℃离心10分钟，取上清液加入3倍量水混合，取适量混合液进行LC-MS/MS分析。主要药代动力学参数用WinNonlin 7.0软件非房室模型分析。Rat pharmacokinetics test, each group adopts 3 male SD rats, 180-240g, fasted overnight, oral gavage administration (comparison compound 1 or compound I-1～I-41 prepared in the previous embodiment , R-I-4, R-I-29 one) 10mg/kg. Blood was collected before dosing and at 15, 30 minutes and 1, 2, 4, 8, 24 hours after dosing. Blood samples were centrifuged at 8000 rpm at 4°C for 6 minutes, plasma was collected and stored at -20°C. Take the plasma at each time point, add 3-5 times the amount of acetonitrile solution containing the internal standard and mix, vortex for 1 minute, centrifuge at 13000 rpm at 4°C for 10 minutes, take the supernatant and add 3 times the amount of water to mix, and take an appropriate amount of the mixture LC-MS/MS analysis was performed. The main pharmacokinetic parameters were analyzed by WinNonlin 7.0 software non-compartmental model.
表5大鼠药代动力学试验结果Table 5 rat pharmacokinetic test results
Figure PCTCN2022122990-appb-000213
Figure PCTCN2022122990-appb-000213
实验结果表明，本发明化合物在大鼠上口服暴露量和Cmax均较高，成药性好。Experimental results show that the compound of the present invention has higher oral exposure and Cmax on rats, and good druggability.

Claims (26)

  1. 式I所示化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药：Compounds represented by formula I, tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs thereof:
    Figure PCTCN2022122990-appb-100001
    Figure PCTCN2022122990-appb-100001
    其中，in,
    环A选自
    Figure PCTCN2022122990-appb-100002
    Ring A is selected from
    Figure PCTCN2022122990-appb-100002
    R 1选自-H、羟基、氨基、氰基、未取代或被R 12取代的C 1-C 6烷基、未取代或被R 12取代的C 3-C 6环烷基、卤素或
    Figure PCTCN2022122990-appb-100003
    所述的被R 12取代的C 1-C 6烷基或被R 12取代的C 3-C 6环烷基中，所述的R 12取代可以是一个或多个取代，所述的R 12各自独立地选自下列取代基：羟基、氨基、氰基、卤素、C 1-C 6烷基或-O-(C 1-C 6烷基)；当取代基为多个时，所述的取代基相同或不同；     R 1 is selected from -H, hydroxyl, amino, cyano, C 1 -C 6 alkyl unsubstituted or substituted by R 12 , C 3 -C 6 cycloalkyl unsubstituted or substituted by R 12 , halogen or
    Figure PCTCN2022122990-appb-100003
    In the C 1 -C 6 alkyl substituted by R 12 or the C 3 -C 6 cycloalkyl substituted by R 12 , the substitution of R 12 may be one or more substitutions, and the R 12 each independently selected from the following substituents: hydroxyl, amino, cyano, halogen, C 1 -C 6 alkyl or -O-(C 1 -C 6 alkyl); when there are multiple substituents, the The substituents are the same or different;
    R 11选自未取代或被R 111取代的C 1-C 6烷基、未取代或被R 111取代的-O-C 1-C 6烷基、未取代或被R 111取代的4-8元杂环烷基、或-NR xR y；所述的被R 111取代的C 1-C 6烷基或被R 111取代的4-8元杂环烷基中，所述的R 111取代可以是一个或多个取代，所述的R 111各自独立地选自下列取代基：羟基、氨基、氰基、卤素、C 1-C 6烷基或-O-(C 1-C 6烷基)；当取代基为多个时，所述的取代基相同或不同； R 11 is selected from unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted -OC 1 -C 6 alkyl, unsubstituted or substituted 4-8 membered hetero Cycloalkyl, or -NR x R y ; in the C 1 -C 6 alkyl substituted by R 111 or the 4-8 membered heterocycloalkyl substituted by R 111 , the substitution of R 111 may be One or more substitutions, the R 111 are each independently selected from the following substituents: hydroxyl, amino, cyano, halogen, C 1 -C 6 alkyl or -O-(C 1 -C 6 alkyl); When there are multiple substituents, the substituents are the same or different;
    R x和R y各自独立地为被1-5个相同或不同的R z取代的C 1-C 6烷基或R x和R y连同其所连接的N形成含N杂环基，所述R z各自独立地选自-H、卤素、C 1-C 6烷基、-O-(C 1-C 6烷基)或C 3-C 6环烷基；当取代基为多个时，所述的取代基相同或不同； R x and R y are each independently a C 1 -C 6 alkyl group substituted by 1-5 identical or different R z or R x and R y together with the N to which they are attached form an N-containing heterocyclic group, said R z are each independently selected from -H, halogen, C 1 -C 6 alkyl, -O-(C 1 -C 6 alkyl) or C 3 -C 6 cycloalkyl; when there are multiple substituents, The substituents are the same or different;
    R 2选自-H、羟基、氨基、氰基、未取代或被R 21取代的C 1-C 6烷基；所述的被R 21取代的C 1-C 6烷基中，所述的R 21取代可以是一个或多个取代，所述的R 21各自独立地选自下列取代基：羟基、氨基、氰基、卤素、C 1-C 6烷基或-O-(C 1-C 6烷基)；当取代基为多个时，所 述的取代基相同或不同； R 2 is selected from -H, hydroxyl, amino, cyano, C 1 -C 6 alkyl unsubstituted or substituted by R 21 ; in the C 1 -C 6 alkyl substituted by R 21 , the The substitution of R 21 may be one or more substitutions, and each of the R 21s is independently selected from the following substituents: hydroxyl, amino, cyano, halogen, C 1 -C 6 alkyl or -O-(C 1 -C 6 alkyl); when there are multiple substituents, the substituents are the same or different;
    环B选自
    Figure PCTCN2022122990-appb-100004
    Figure PCTCN2022122990-appb-100005
    Figure PCTCN2022122990-appb-100006
    其中“*”表示与
    Figure PCTCN2022122990-appb-100007
    连接且“**”表示与环A连接；     Ring B selected from
    Figure PCTCN2022122990-appb-100004
    Figure PCTCN2022122990-appb-100005
    Figure PCTCN2022122990-appb-100006
    where "*" means the same as
    Figure PCTCN2022122990-appb-100007
    and "**" indicates connection with ring A;
    R 3和R 4各自独立地选自-H、-SF 5、羟基、氨基、氰基、未取代或被R 31取代的C 1-C 6烷基、未取代或被R 31取代的C 3-C 6环烷基、卤素或
    Figure PCTCN2022122990-appb-100008
    所述的被R 31取代的C 1-C 6烷基或被R 31取代的C 3-C 6环烷基中，所述的R 31取代可以是一个或多个取代，所述的R 31各自独立地选自下列取代基：羟基、氨基、氰基、卤素、C 1-C 6烷基或-O-(C 1-C 6烷基)；当取代基为多个时，所述的取代基相同或不同；     R 3 and R 4 are each independently selected from -H, -SF 5 , hydroxyl, amino, cyano, C 1 -C 6 alkyl unsubstituted or substituted by R 31 , C 3 unsubstituted or substituted by R 31 -C 6 cycloalkyl, halogen or
    Figure PCTCN2022122990-appb-100008
    In the C 1 -C 6 alkyl substituted by R 31 or the C 3 -C 6 cycloalkyl substituted by R 31 , the substitution of R 31 may be one or more substitutions, and the R 31 each independently selected from the following substituents: hydroxyl, amino, cyano, halogen, C 1 -C 6 alkyl or -O-(C 1 -C 6 alkyl); when there are multiple substituents, the The substituents are the same or different;
    R 32选自-H、未取代或被R 321取代的C 1-C 6烷基、或、未取代或被R 321取代的C 3-C 6环烷基；所述的被R 321取代的C 1-C 6烷基或被R 31取代的C 3-C 6环烷基中，所述的R 321取代可以是一个或多个取代，所述的R 321各自独立地选自下列取代基：羟基、氨基、氰基、卤素、C 1-C 6烷基或-O-(C 1-C 6烷基)；当取代基为多个时，所述的取代基相同或不同； R 32 is selected from -H, unsubstituted or substituted by R 321 C 1 -C 6 alkyl, or, unsubstituted or substituted by R 321 C 3 -C 6 cycloalkyl; said substituted by R 321 In C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl substituted by R 31 , the substitution of R 321 may be one or more substitutions, and each of the R 321 is independently selected from the following substituents : hydroxyl, amino, cyano, halogen, C 1 -C 6 alkyl or -O-(C 1 -C 6 alkyl); when there are multiple substituents, the substituents are the same or different;
    R 5选自-H、氰基、被1-5个相同或不同的卤素取代的C 1-C 6烷基、被1-5个相同或不同的卤素取代的C 3-C 6环烷基、C 3-C 6环烷基或C 1-C 6烷基； R 5 is selected from -H, cyano, C 1 -C 6 alkyl substituted by 1-5 identical or different halogens, C 3 -C 6 cycloalkyl substituted by 1-5 identical or different halogens , C 3 -C 6 cycloalkyl or C 1 -C 6 alkyl;
    R 6选自羟基、氨基、氰基、
    Figure PCTCN2022122990-appb-100009
    未取代或被R 61取代的C 1-C 6烷基、卤素或未取代或被R 61取代的C 3-C 6环烷基；所述的被R 61取代的C 1-C 6烷基或被R 61取代的C 3-C 6环烷基中，所述的R 61取代可以是一个或多个取代，所述的R 61各自独立地选自下列取代基：羟基、氨基、氰基、卤素、被1-6个相同或不同卤素取代的C 1-C 6烷基、被1-6个相同或不同卤素取代的-O-(C 1-C 6烷基)、C 1-C 6烷基或-O-(C 1-C 6烷基)；当取代基为多个时，所述的取代基相同或不同。     R is selected from hydroxyl, amino, cyano,
    Figure PCTCN2022122990-appb-100009
    Unsubstituted or substituted by R 61 C 1 -C 6 alkyl, halogen or unsubstituted or substituted by R 61 C 3 -C 6 cycloalkyl; said C 1 -C 6 alkyl substituted by R 61 Or in the C 3 -C 6 cycloalkyl group substituted by R 61 , the R 61 substitution can be one or more substitutions, and each of the R 61 is independently selected from the following substituents: hydroxyl, amino, cyano , halogen, C 1 -C 6 alkyl substituted by 1-6 identical or different halogens, -O-(C 1 -C 6 alkyl) substituted by 1-6 identical or different halogens, C 1 -C 6 alkyl or -O-(C 1 -C 6 alkyl); when there are multiple substituents, the substituents are the same or different.
  2. 根据权利要求1所述的化合物，其为式II所示化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药：The compound according to claim 1, which is a compound shown in formula II, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug:
    Figure PCTCN2022122990-appb-100010
    Figure PCTCN2022122990-appb-100010
  3. 根据权利要求1所述的化合物，其为式III所示化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药:The compound according to claim 1, which is a compound shown in formula III, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug:
    Figure PCTCN2022122990-appb-100011
    Figure PCTCN2022122990-appb-100011
    其中，当环A和环B相同时，R 1和R 3不同。 Wherein, when ring A and ring B are the same, R 1 and R 3 are different.
  4. 根据权利要求1所述的化合物，其为式IV所示化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药:The compound according to claim 1, which is a compound shown in formula IV, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug:
    Figure PCTCN2022122990-appb-100012
    Figure PCTCN2022122990-appb-100012
  5. 根据权利要求1所述的化合物，其为式V所示化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药:The compound according to claim 1, which is a compound shown in formula V, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug:
    Figure PCTCN2022122990-appb-100013
    Figure PCTCN2022122990-appb-100013
    其中，环C为未取代或被R 61取代的C 3-C 6环烷基。 Wherein, Ring C is C 3 -C 6 cycloalkyl which is unsubstituted or substituted by R 61 .
  6. 根据权利要求1所述的化合物，其为式VI所示化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药:The compound according to claim 1, which is a compound shown in formula VI, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug:
    Figure PCTCN2022122990-appb-100014
    Figure PCTCN2022122990-appb-100014
    其中，X 1、X 2、X 3、X 4分别独立地为C或N； Wherein, X 1 , X 2 , X 3 , and X 4 are independently C or N;
    且X 1和X 2不同，当X 1为N时，X 3为N，当X 2为N时，X 4为N。 And X 1 and X 2 are different, when X 1 is N, X 3 is N, when X 2 is N, X 4 is N.
  7. 根据权利要求1-5中任一项所述的化合物，其特征在于，The compound according to any one of claims 1-5, characterized in that,
    环B选自
    Figure PCTCN2022122990-appb-100015
    Ring B selected from
    Figure PCTCN2022122990-appb-100015
  8. 根据权利要求1-6中任一项所述的化合物，其特征在于，The compound according to any one of claims 1-6, characterized in that,
    R 2为-H； R2 is -H;
    和/或，R 1为-H； And/or, R 1 is -H;
    和/或，当R 1为未取代或被R 12取代的C 1-C 6烷基时，所述C 1-C 6烷基为甲基、乙基、正丙基或异丙基； And/or, when R 1 is C 1 -C 6 alkyl unsubstituted or substituted by R 12 , said C 1 -C 6 alkyl is methyl, ethyl, n-propyl or isopropyl;
    和/或，当R 1为被R 12取代的C 1-C 6烷基时，所述R 12为卤素； And/or, when R 1 is C 1 -C 6 alkyl substituted by R 12 , said R 12 is halogen;
    和/或，当R 12为卤素时，所述卤素为F或Cl； And/or, when R 12 is halogen, said halogen is F or Cl;
    和/或，当R 1为被R 12取代的C 1-C 6烷基时，所述R 12取代为1个、2个或3个； And/or, when R 1 is C 1 -C 6 alkyl substituted by R 12 , said R 12 is substituted by 1, 2 or 3;
    和/或，R 1为
    Figure PCTCN2022122990-appb-100016
    and/or, R1 is
    Figure PCTCN2022122990-appb-100016
    和/或，R 11为未取代或被R 111取代的-O-C 1-C 6烷基时，所述-O-C 1-C 6烷基为-O-甲基、-O-乙基、-O-正丙基或-O-异丙基； And/or, when R 11 is unsubstituted or substituted by R 111 -OC 1 -C 6 alkyl, the -OC 1 -C 6 alkyl is -O-methyl, -O-ethyl, -O -n-propyl or -O-isopropyl;
    和/或，R 11为-NR xR y； And/or, R 11 is -NR x R y ;
    和/或，当R x和R y为被1-5个相同或不同的R z取代的C 1-C 6烷基时，所述C 1-C 6烷基为甲基、乙基、正丙基或异丙基； And/or, when R x and R y are C 1 -C 6 alkyl substituted by 1-5 same or different R z , said C 1 -C 6 alkyl is methyl, ethyl, normal Propyl or isopropyl;
    和/或，当R x和R y为被1-5个相同或不同的R z取代的C 1-C 6烷基时，所R z取代为1个、2个或3个； And/or, when R x and R y are C 1 -C 6 alkyl substituted by 1-5 same or different R z , the R z is substituted by 1, 2 or 3;
    和/或，R z为-H； And/or, R z is -H;
    和/或，当R x和R y连同其所连接的N形成含N杂环基时，所述N杂环基为
    Figure PCTCN2022122990-appb-100017
    And/or, when R x and R y , together with the N to which they are attached, form an N-containing heterocyclic group, the N heterocyclic group is
    Figure PCTCN2022122990-appb-100017
    和/或，当R 11为未取代或被R 111取代的4-8元杂环烷基时，所述4-8元杂环烷基为氮杂环丁基、氮杂环戊基、氧杂环丁基、吡咯烷基、四氢呋喃基、吡唑烷基、咪唑烷基、噁唑烷基、吗啉基、吡咯烷基、吗啉基或哌嗪基。 And/or, when R 11 is a 4-8 membered heterocycloalkyl group that is unsubstituted or substituted by R 111 , the 4-8 membered heterocycloalkyl group is azetidinyl, azacyclopentyl, oxygen Heterocyclobutyl, pyrrolidinyl, tetrahydrofuranyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, morpholinyl, pyrrolidinyl, morpholinyl or piperazinyl.
  9. 根据权利要求1-6中任一项所述的化合物，其特征在于，The compound according to any one of claims 1-6, characterized in that,
    R 4为-H； R4 is -H;
    和/或，R 3为-H； And/or, R 3 is -H;
    和/或，R 3为-SF 5； And/or, R 3 is -SF 5 ;
    和/或，R 3为卤素时，所述卤素为F或Cl； And/or, when R 3 is a halogen, the halogen is F or Cl;
    和/或，R 3为
    Figure PCTCN2022122990-appb-100018
    and/or, R3 is
    Figure PCTCN2022122990-appb-100018
    和/或，当R 32为未取代或被R 321取代的C 1-C 6烷基时，所述C 1-C 6烷基为甲基、乙基、正丙基或异丙基； And/or, when R 32 is C 1 -C 6 alkyl unsubstituted or substituted by R 321 , the C 1 -C 6 alkyl is methyl, ethyl, n-propyl or isopropyl;
    和/或，当R 3为未取代或被R 31取代的C 1-C 6烷基时，所述C 1-C 6烷基为甲基、乙基、正丙基或异丙基； And/or, when R 3 is C 1 -C 6 alkyl unsubstituted or substituted by R 31 , the C 1 -C 6 alkyl is methyl, ethyl, n-propyl or isopropyl;
    和/或，当R 3为被R 31取代的C 1-C 6烷基时，所述R 31为卤素； And/or, when R 3 is C 1 -C 6 alkyl substituted by R 31 , said R 31 is halogen;
    和/或，当R 31为卤素时，所述卤素为F或Cl； And/or, when R 31 is halogen, said halogen is F or Cl;
    和/或，当R 3为被R 31取代的C 1-C 6烷基时，所述卤素取代为1个、2个或3个； And/or, when R 3 is C 1 -C 6 alkyl substituted by R 31 , the halogen substitution is 1, 2 or 3;
    和/或，当R 3为未取代或被R 31取代的C 3-C 6环烷基时，所述C 3-C 6环烷基为环丙基。 And/or, when R 3 is a C 3 -C 6 cycloalkyl group that is unsubstituted or substituted by R 31 , the C 3 -C 6 cycloalkyl group is cyclopropyl.
  10. 根据权利要求1-6中任一项所述的化合物，其特征在于，The compound according to any one of claims 1-6, characterized in that,
    当R 5为C 1-C 6烷基时，所述C 1-C 6烷基为甲基、乙基、正丙基或异丙基； When R 5 is C 1 -C 6 alkyl, said C 1 -C 6 alkyl is methyl, ethyl, n-propyl or isopropyl;
    和/或，当R 5为C 3-C 6环烷基时，所述C 3-C 6环烷基为环丙基。 And/or, when R 5 is C 3 -C 6 cycloalkyl, said C 3 -C 6 cycloalkyl is cyclopropyl.
  11. 根据权利要求1-6中任一项所述的化合物，其特征在于，The compound according to any one of claims 1-6, characterized in that,
    R 6为
    Figure PCTCN2022122990-appb-100019
     R6 is
    Figure PCTCN2022122990-appb-100019
    和/或，当R 6为未取代或被R 61取代的C 1-C 6烷基时，所述C 1-C 6烷基为甲基、乙基、正丙基或异丙基； And/or, when R 6 is C 1 -C 6 alkyl unsubstituted or substituted by R 61 , the C 1 -C 6 alkyl is methyl, ethyl, n-propyl or isopropyl;
    和/或，当R 6为被R 61取代的C 1-C 6烷基时，所述R 61为卤素； And/or, when R 6 is C 1 -C 6 alkyl substituted by R 61 , said R 61 is halogen;
    和/或，当R 61为卤素时，所述卤素为F或Cl； And/or, when R 61 is halogen, said halogen is F or Cl;
    和/或，当R 6为被R 61取代的C 1-C 6烷基时，所述R 61取代为6个； And/or, when R 6 is C 1 -C 6 alkyl substituted by R 61 , the R 61 is substituted to 6;
    和/或，当R 6为未取代或被R 61取代的C 3-C 6环烷基时，所述C 3-C 6环烷基为环丙基或环丁基； And/or, when R 6 is a C 3 -C 6 cycloalkyl group that is unsubstituted or substituted by R 61 , the C 3 -C 6 cycloalkyl group is cyclopropyl or cyclobutyl;
    和/或，当R 6为被R 61取代的C 3-C 6环烷基时，所述R 61为卤素； And/or, when R 6 is C 3 -C 6 cycloalkyl substituted by R 61 , said R 61 is halogen;
    和/或，当R 6为被R 61取代的C 3-C 6环烷基时，所述R 61取代为1个、2个或3个。 And/or, when R 6 is a C 3 -C 6 cycloalkyl group substituted by R 61 , said R 61 is substituted by 1, 2 or 3.
  12. 根据权利要求1-6任一项所述的化合物，其特征在于，The compound according to any one of claims 1-6, characterized in that,
    当R 6为未取代或被R 61取代的C 3-C 6环烷基时，所述C 3-C 6环烷基为环戊基； When R 6 is a C 3 -C 6 cycloalkyl group that is unsubstituted or substituted by R 61 , the C 3 -C 6 cycloalkyl group is cyclopentyl;
    和/或，当R 6为被R 61取代的C 3-C 6环烷基时，所述R 61为被1-6个相同或不同卤素取代的C 1-C 6烷基； And/or, when R 6 is C 3 -C 6 cycloalkyl substituted by R 61 , said R 61 is C 1 -C 6 alkyl substituted by 1-6 identical or different halogens;
    和/或，当R 6为被R 61取代的C 3-C 6环烷基时，所述R 61取代为1个、2个或3个； And/or, when R 6 is a C 3 -C 6 cycloalkyl group substituted by R 61 , said R 61 is substituted by 1, 2 or 3;
    和/或，当R 61为被1-6个相同或不同卤素取代的C 1-C 6烷基时，所述卤素取代为1个、2个或3个； And/or, when R 61 is C 1 -C 6 alkyl substituted by 1-6 identical or different halogens, the halogens are substituted by 1, 2 or 3;
    和/或，当R 61为被1-6个相同或不同卤素取代的C 1-C 6烷基时，所述卤素为F或Cl。 And/or, when R 61 is C 1 -C 6 alkyl substituted by 1-6 identical or different halogens, said halogen is F or Cl.
  13. 根据权利要求1-6中任一项所述的化合物，其特征在于，The compound according to any one of claims 1-6, characterized in that,
    R 1选自-H、
    Figure PCTCN2022122990-appb-100020
    R 1 is selected from -H,
    Figure PCTCN2022122990-appb-100020
    和/或，R 2为-H； And/or, R 2 is -H;
    和/或，R 3选自-H、-Cl、甲基、-SF 5、
    Figure PCTCN2022122990-appb-100021
    And/or, R 3 is selected from -H, -Cl, methyl, -SF 5 ,
    Figure PCTCN2022122990-appb-100021
    和/或，R 4为-H； And/or, R 4 is -H;
    和/或，R 5选自甲基或环丙基； And/or, R is selected from methyl or cyclopropyl;
    和/或，R 6选自异丙基、环丙基、
    Figure PCTCN2022122990-appb-100022
    And/or, R 6 is selected from isopropyl, cyclopropyl,
    Figure PCTCN2022122990-appb-100022
  14. 根据权利要求1-6中任一项所述的化合物，其特征在于，The compound according to any one of claims 1-6, characterized in that,
    R 6选自环丁基、环戊基、
    Figure PCTCN2022122990-appb-100023
     R is selected from cyclobutyl, cyclopentyl,
    Figure PCTCN2022122990-appb-100023
  15. 根据权利要求1-6中任一项所述的化合物，其特征在于，The compound according to any one of claims 1-6, characterized in that,
    当环A为
    Figure PCTCN2022122990-appb-100024
    且环B为
    Figure PCTCN2022122990-appb-100025
    时，R 1为羟基或
    Figure PCTCN2022122990-appb-100026
    且R 11为-NR xR y或
    Figure PCTCN2022122990-appb-100027
    When ring A is
    Figure PCTCN2022122990-appb-100024
    and ring B is
    Figure PCTCN2022122990-appb-100025
    , R 1 is hydroxyl or
    Figure PCTCN2022122990-appb-100026
    and R 11 is -NR x R y or
    Figure PCTCN2022122990-appb-100027
  16. 根据权利要求1-6中任一项所述的化合物，其特征在于，The compound according to any one of claims 1-6, characterized in that,
    当环A为
    Figure PCTCN2022122990-appb-100028
    且环B为
    Figure PCTCN2022122990-appb-100029
    时，R 3为-SF 5、羟基、氨基、
    Figure PCTCN2022122990-appb-100030
    When ring A is
    Figure PCTCN2022122990-appb-100028
    and ring B is
    Figure PCTCN2022122990-appb-100029
    When, R 3 is -SF 5 , hydroxyl, amino,
    Figure PCTCN2022122990-appb-100030
  17. 根据权利要求1-6中任一项所述的化合物，其特征在于，The compound according to any one of claims 1-6, characterized in that,
    当环A为
    Figure PCTCN2022122990-appb-100031
    且环B为
    Figure PCTCN2022122990-appb-100032
    时，R 5为C 3-C 6环烷基、氰基或被1-5个相同或不同的卤素取代的C 3-C 6环烷基。     When ring A is
    Figure PCTCN2022122990-appb-100031
    and ring B is
    Figure PCTCN2022122990-appb-100032
    When, R 5 is C 3 -C 6 cycloalkyl, cyano or C 3 -C 6 cycloalkyl substituted by 1-5 identical or different halogens.
  18. 根据权利要求1-6中任一项所述的化合物，其特征在于，The compound according to any one of claims 1-6, characterized in that,
    当环A为
    Figure PCTCN2022122990-appb-100033
    且环B为
    Figure PCTCN2022122990-appb-100034
    时，R 6为羟基、氨基、氰基、
    Figure PCTCN2022122990-appb-100035
    被R 61取代的C 1-C 6烷基、卤素或未取代或被R 61取代的C 3-C 6环烷基。     When ring A is
    Figure PCTCN2022122990-appb-100033
    and ring B is
    Figure PCTCN2022122990-appb-100034
    When, R 6 is hydroxyl, amino, cyano,
    Figure PCTCN2022122990-appb-100035
    C 1 -C 6 alkyl substituted by R 61 , halogen or C 3 -C 6 cycloalkyl unsubstituted or substituted by R 61 .
  19. 根据权利要求1所述的化合物，其特征在于，其选自下列任一化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药：The compound according to claim 1, characterized in that it is selected from any of the following compounds, their tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs:
    Figure PCTCN2022122990-appb-100036
    Figure PCTCN2022122990-appb-100036
    Figure PCTCN2022122990-appb-100037
    Figure PCTCN2022122990-appb-100037
    Figure PCTCN2022122990-appb-100038
    Figure PCTCN2022122990-appb-100038
    Figure PCTCN2022122990-appb-100039
    Figure PCTCN2022122990-appb-100039
  20. 一种药物组合物，其特征在于，其包含如权利要求1-19中任一项所述的的化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，和药学上可接受的赋形剂。A pharmaceutical composition, characterized in that it comprises the compound according to any one of claims 1-19, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, and pharmaceutically acceptable excipients.
  21. 根据权利要求1-19中任一项所述的化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，或如权利要求20所述的药物组合物在制备用于治疗AAK1相关疾病药物中的用途。The compound according to any one of claims 1-19, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or as described in claim 20 Use of the pharmaceutical composition of the invention in the preparation of medicines for treating AAK1-related diseases.
  22. 根据权利要求21所述的用途，其特征在于，所述AAK1相关疾病为阿尔茨海默症、双相情感障碍、疼痛、帕金森病或精神分裂症。The use according to claim 21, characterized in that the AAK1-related disease is Alzheimer's disease, bipolar disorder, pain, Parkinson's disease or schizophrenia.
  23. 权利要求1-19中任一项所述的化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，或如权利要求20所述的药物组合物，用于治疗或预防AAK1相关疾病。The compound according to any one of claims 1-19, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or the compound according to claim 20 A pharmaceutical composition for treating or preventing AAK1-related diseases.
  24. 权利要求1-19中任一项所述的化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，或如权利要求20所述的药物组合物，用于治疗或预防阿尔茨海默症、双相情感障碍、疼痛、帕金森病或精神分裂症。The compound according to any one of claims 1-19, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or the compound according to claim 20 A pharmaceutical composition for treating or preventing Alzheimer's disease, bipolar disorder, pain, Parkinson's disease or schizophrenia.
  25. 一种治疗或预防AAK1相关疾病的方法，其特征在于，给与患者药学上可接受剂量的权利要求1-19中任一项所述的化合物、其互变异构体、立体异构体、水合物、 溶剂化物、药学上可接受的盐或前药，或如权利要求20所述的药物组合物。A method for treating or preventing AAK1-related diseases, characterized in that the compound, its tautomers, stereoisomers, Hydrate, solvate, pharmaceutically acceptable salt or prodrug, or the pharmaceutical composition as claimed in claim 20.
  26. 根据权利要求25所述的方法，其特征在于，所述AAK1相关疾病为阿尔茨海默症、双相情感障碍、疼痛、帕金森病或精神分裂症。The method according to claim 25, wherein the AAK1-related disease is Alzheimer's disease, bipolar disorder, pain, Parkinson's disease or schizophrenia.
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106458994A (en) * 2014-04-02 2017-02-22 百时美施贵宝公司 Biaryl kinase inhibitors
CN108290843A (en) * 2015-10-01 2018-07-17 百时美施贵宝公司 Biaryl based kinase inhibitors

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106458994A (en) * 2014-04-02 2017-02-22 百时美施贵宝公司 Biaryl kinase inhibitors
CN108290843A (en) * 2015-10-01 2018-07-17 百时美施贵宝公司 Biaryl based kinase inhibitors

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