WO2023051749A1 - Inhibiteur d'aak1 et son utilisation - Google Patents

Inhibiteur d'aak1 et son utilisation 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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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/fr

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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.

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Abstract

La présente invention concerne un inhibiteur D'AAK1 et son utilisation. En particulier, la présente invention concerne un composé représenté par la formule I, un tautomère, un stéréoisomère, un hydrate, un solvate, un sel pharmaceutiquement acceptable ou un promédicament de celui-ci ; son procédé de préparation et son utilisation dans la préparation d'un médicament.
PCT/CN2022/122990 2021-09-30 2022-09-30 Inhibiteur d'aak1 et son utilisation WO2023051749A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106458994A (zh) * 2014-04-02 2017-02-22 百时美施贵宝公司 联芳激酶抑制剂
CN108290843A (zh) * 2015-10-01 2018-07-17 百时美施贵宝公司 联芳基激酶抑制剂

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106458994A (zh) * 2014-04-02 2017-02-22 百时美施贵宝公司 联芳激酶抑制剂
CN108290843A (zh) * 2015-10-01 2018-07-17 百时美施贵宝公司 联芳基激酶抑制剂

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