CN115872927A - AAK1 inhibitors and uses thereof - Google Patents
AAK1 inhibitors and uses thereof Download PDFInfo
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- CN115872927A CN115872927A CN202211211185.1A CN202211211185A CN115872927A CN 115872927 A CN115872927 A CN 115872927A CN 202211211185 A CN202211211185 A CN 202211211185A CN 115872927 A CN115872927 A CN 115872927A
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Abstract
The invention provides an AAK1 inhibitor and application thereof, and particularly relates to a compound shown as a formula I, a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof, a preparation method of the compound and application of the compound in preparing medicines
Description
Technical Field
The invention belongs to the field of medicinal chemistry, and particularly relates to a compound capable of inhibiting connexin-associated kinase 1 (AAK 1), a preparation method and a composition thereof, and application of the compound in preparation of medicines.
Background
The adaptor protein related kinase 1 (AP 2 associated kinase 1, AAK1), also called AP-2 related kinase 1, is a serine/threonine protein kinase, and belongs to the Ark1/Prk family member. The precursor mRNA of AAK1 can produce different splice variants, expressing a 960 amino acid long form of AAK1 and a 863 amino acid short form of AAK1, with the long form of AAK1 highly expressed in brain and heart tissue. The C-terminus of AKK1 contains clathrin-binding domains (CBD 1 and CBD 2) that interact with clathrin, stimulating kinase activity of AAK1 (Henderson et al, mol Biol Cell, 2007). AAK1 can regulate and control clathrin-mediated endocytosis process by combining with AP-2 linker protein complex. Clathrin-mediated endocytosis is the major component of protein transfer from the cell surface to endosomes or lysosomes for recycling or degradationPathway (Trub, nat Rev Mol Cell Biol, 2009). The AP-2 complex is an engagement factor for clathrin, and is composed of four proteins, including an α subunit, a β 2 subunit, a μ 2 subunit, and a σ 2 subunit. Among them, the μ 2 subunit, also known as AP2M1, is localized to the core of the AP-2 complex, mediating the interaction of the transporter (cargo) with clathrin-coated pits. C-terminal of AP2M1 was sorted from tyrosine-based endocytosis of the cytoplasmic end of the transporter
Motif binding helps recruit the transported body to clathrin-coated pits (Royle et al, J Biol Chem, 2002). AAK1 can phosphorylate threonine 156 of AP2M1, induce the conformational change of the threonine, and promote AP2M1 and->
Motif binding, thereby enhancing endocytosis (Jackson et al, J Cell Biol, 2003).
Research shows that AAK1 gene knockout mice have a significantly reduced response to persistent pain in phase II of the formalin model, and significantly reduce SNL (spinal nerve ligation) -induced mechanical allodynia. The AAK1 small molecule inhibitor LP-935509 can significantly reduce pain response in phase II time phase of the formalin Lin Xiao mouse model, mechanical allodynia caused by mouse SNL, mouse CCI (sciatic nerve ligation) model and streptozotocin-induced pain response in the mouse diabetic neuropathy model (Kostich et al, J Pharmacol Exp Ther, 2016). These findings suggest that inhibition of AAK1 activity may have a potential therapeutic effect on pain.
One meta analysis showed that the AAK1 gene was identified as a possible parkinson susceptibility gene in Genome Wide Association Studies (GWAS) in familial parkinson cases (lathourelle et al, BMC Med Genet, 2009). These research advances suggest that inhibiting the activity of AAK1 may have potential therapeutic effects on diseases such as schizophrenia (schizophrenia), cognitive deficits (cognitive deficits), parkinson's disease, bipolar disorder (bipolardisorder) and Alzheimer's disease.
The viruses enter cells in various modes such as endocytosis, membrane fusion and the like, most of the viruses take endocytosis as a main entering mode, and clathrin mediated is a main endocytosis path. Vesicular Stomatitis Virus (VSV), influenza virus (IAV), congo hemorrhagic fever virus (CCHFV), and the like, enter cells through clathrin-dependent pathways. It has been found that the infection process of many 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 nevu et al, J Virol, 2015. These results show that inhibition of the activity of AAK1 may have potential therapeutic effects on diseases associated with viral infections.
Disclosure of Invention
The invention aims to provide an AAK1 receptor antagonist which can be used for preparing medicines for treating Alzheimer's disease, bipolar disorder, pain, parkinson's disease and schizophrenia.
In a first aspect of the invention, the invention provides a compound of formula I, a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt, or a prodrug thereof:
wherein the content of the first and second substances,
ring A is selected from
R 1 Selected from-H, hydroxy, amino, cyano, unsubstituted or substituted by R 12 Substituted C 1 -C 6 Alkyl, unsubstituted or substituted by R 12 Substituted C 3 -C 6 Cycloalkyl, halogen or
The quilt R 12 Substituted C 1 -C 6 Alkyl or by R 12 Substituted C 3 -C 6 In the cycloalkyl group, the R is 12 The substitution may be oneOr a plurality of substitutions, said R 12 Each independently selected from the following substituents: hydroxy, amino, cyano, halogen, C 1 -C 6 Alkyl or-O- (C) 1 -C 6 Alkyl groups); when the number of the substituents is plural, the substituents may be the same or different;
R 11 selected from unsubstituted or substituted by R 111 Substituted C 1 -C 6 Alkyl, unsubstituted or substituted by R 111 substituted-O-C 1 -C 6 Alkyl, unsubstituted or substituted by R 111 Substituted 4-8 membered heterocycloalkyl, or-NR x R y (ii) a The quilt R 111 Substituted C 1 -C 6 Alkyl or by R 111 In substituted 4-8 membered heterocycloalkyl, said R 111 The substitution may be one or more, and R is 111 Each independently selected from the following substituents: hydroxy, amino, cyano, halogen, C 1 -C 6 Alkyl or-O- (C) 1 -C 6 Alkyl groups); when the number of the substituents is plural, the substituents may be the same or different;
R x and R y Each independently by 1 to 5R which may be the same or different z Substituted C 1 -C 6 Alkyl or R x And R y Together with the N to which it is attached form an N-containing heterocyclic group, said R z Each independently selected from-H, halogen, C 1 -C 6 Alkyl, -O- (C) 1 -C 6 Alkyl) or C 3 -C 6 A cycloalkyl group; when the substituent is plural, the substituents are the same or different;
R 2 selected from-H, hydroxy, amino, cyano, unsubstituted or substituted by R 21 Substituted C 1 -C 6 An alkyl group; the quilt R 21 Substituted C 1 -C 6 In the alkyl group, the R is 21 The substitution may be one or more, and R is 21 Each independently selected from the following substituents: hydroxy, amino, cyano, halogen, C 1 -C 6 Alkyl or-O- (C) 1 -C 6 Alkyl groups); when the number of the substituents is plural, the substituents may be the same or different;
ring B is selected from
/>
Wherein "+" denotes a combination with +>
And ". Star" indicates a connection to ring a;
R 3 and R 4 Each independently selected from-H, -SF 5 Hydroxy, amino, cyano, unsubstituted or substituted by R 31 Substituted C 1 -C 6 Alkyl, unsubstituted or substituted by R 31 Substituted C 3 -C 6 Cycloalkyl, halogen or
The quilt R 31 Substituted C 1 -C 6 Alkyl or by R 31 Substituted C 3 -C 6 In the cycloalkyl group, the R is 31 The substitution may be one or more, and R is 31 Each independently selected from the following substituents: hydroxy, amino, cyano, halogen, C 1 -C 6 Alkyl or-O- (C) 1 -C 6 Alkyl groups); when the number of the substituents is plural, the substituents may be the same or different;
R 32 selected from-H, unsubstituted or substituted by R 321 Substituted C 1 -C 6 Alkyl, or, unsubstituted or substituted by R 321 Substituted C 3 -C 6 A cycloalkyl group; the quilt R 321 Substituted C 1 -C 6 Alkyl or by R 31 Substituted C 3 -C 6 In the cycloalkyl group, the R is 321 The substitution may be one or more, and R is 321 Each independently selected from the following substituents: hydroxy, amino, cyano, halogen, C 1 -C 6 Alkyl or-O- (C) 1 -C 6 Alkyl groups); when the number of the substituents is plural, the substituents may be the same or different;
R 5 selected from-H, cyano, C substituted by 1-5 same or different halogens 1 -C 6 Alkyl, C substituted by 1-5 identical or different halogens 3 -C 6 Cycloalkyl radical, C 3 -C 6 Cycloalkyl or C 1 -C 6 An alkyl group;
R 6 selected from hydroxy, amino, cyano,
Unsubstituted or substituted by R 61 Substituted C 1 -C 6 Alkyl, halogen or unsubstituted or substituted by R 61 Substituted C 3 -C 6 A cycloalkyl group; the quilt R 61 Substituted C 1 -C 6 Alkyl or by R 61 Substituted C 3 -C 6 In the cycloalkyl group, the R is 61 The substitution may be one or more, and R is 61 Each independently selected from the following substituents: hydroxy, amino, cyano, halogen, C substituted by 1 to 6 identical or different halogens 1 -C 6 Alkyl, -O- (C) substituted by 1-6 identical or different halogens 1 -C 6 Alkyl group), C 1 -C 6 Alkyl or-O- (C) 1 -C 6 Alkyl groups); when the substituent is plural, the substituents may be the same or different.
In an optional embodiment of the invention is a compound of formula I, a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt, or a prodrug thereof:
wherein the content of the first and second substances,
ring A is selected from
R 1 Selected from-H, hydroxy, amino, cyanoRadicals, unsubstituted or substituted by R 12 Substituted C 1 -C 6 Alkyl, unsubstituted or substituted by R 12 Substituted C 3 -C 6 Cycloalkyl, halogen or
The quilt R 12 Substituted C 1 -C 6 Alkyl or by R 12 Substituted C 3 -C 6 In the cycloalkyl group, said R 12 The substitution may be one or more, and R is as defined above 12 Each independently selected from the following substituents: hydroxy, amino, cyano, halogen, C 1 -C 6 Alkyl or-O- (C) 1 -C 6 Alkyl groups); when the substituent is plural, the substituents are the same or different;
R 11 selected from unsubstituted or substituted by R 111 Substituted C 1 -C 6 Alkyl, unsubstituted or substituted by R 111 Substituted 4-8 membered heterocycloalkyl, or-NR x R y (ii) a The quilt R 111 Substituted C 1 -C 6 Alkyl or by R 111 In substituted 4-8 membered heterocycloalkyl, said R 111 The substitution may be one or more, and R is as defined above 111 Each independently selected from the following substituents: hydroxy, amino, cyano, halogen, C 1 -C 6 Alkyl or-O- (C) 1 -C 6 Alkyl groups); when the substituent is plural, the substituents are the same or different;
R x and R y Each independently of the other is represented by 1 to 5 identical or different R z Substituted C 1 -C 6 Alkyl radical, said R z Each independently selected from-H, halogen, -O- (C) 1 -C 6 Alkyl) or C 3 -C 6 A cycloalkyl group; when the substituent is plural, the substituents are the same or different;
R 2 selected from-H, hydroxy, amino, cyano, unsubstituted or substituted by R 21 Substituted C 1 -C 6 An alkyl group; the quilt R 21 Substituted C 1 -C 6 In the alkyl group, said R 21 The substitution may be one or more, such thatR is as described 21 Each independently selected from the following substituents: hydroxy, amino, cyano, halogen, C 1 -C 6 Alkyl or-O- (C) 1 -C 6 Alkyl groups); when the number of the substituents is plural, the substituents may be the same or different;
ring B is selected from
Wherein "X" means and->
And "+" indicates attachment to ring a;
R 3 and R 4 Each independently selected from-H, -SF 5 Hydroxy, amino, cyano, unsubstituted or substituted by R 31 Substituted C 1 -C 6 Alkyl, unsubstituted or substituted by R 31 Substituted C 3 -C 6 Cycloalkyl, halogen or
The quilt R 31 Substituted C 1 -C 6 Alkyl or by R 31 Substituted C 3 -C 6 In the cycloalkyl group, the R is 31 The substitution may be one or more, and R is 31 Each independently selected from the following substituents: hydroxy, amino, cyano, halogen, C 1 -C 6 Alkyl or-O- (C) 1 -C 6 Alkyl groups); when the number of the substituents is plural, the substituents may be the same or different;
R 32 selected from-H, unsubstituted or substituted by R 321 Substituted C 1 -C 6 Alkyl, or, unsubstituted or substituted by R 321 Substituted C 3 -C 6 A cycloalkyl group; the quilt R 321 Substituted C 1 -C 6 Alkyl or by R 31 Substituted C 3 -C 6 In the cycloalkyl group, the R is 321 The substitution may be one or more, and R is 321 Each independently selected from the following substituents: hydroxy, amino, cyano, halogen, C 1 -C 6 Alkyl or-O- (C) 1 -C 6 Alkyl groups); when the number of the substituents is plural, the substituents may be the same or different;
R 5 selected from-H, cyano, C substituted by 1-5 same or different halogens 1 -C 6 Alkyl, C substituted by 1-5 identical or different halogens 3 -C 6 Cycloalkyl radical, C 3 -C 6 Cycloalkyl or C 1 -C 6 An alkyl group;
R 6 selected from hydroxy, amino, cyano,
Unsubstituted or substituted by R 61 Substituted C 1 -C 6 Alkyl, halogen or unsubstituted or substituted by R 61 Substituted C 3 -C 6 A cycloalkyl group; the quilt R 61 Substituted C 1 -C 6 Alkyl or by R 61 Substituted C 3 -C 6 In the cycloalkyl group, the R is 61 The substitution may be one or more, and R is as defined above 61 Each independently selected from the following substituents: hydroxy, amino, cyano, halogen, C substituted by 1 to 6 identical or different halogens 1 -C 6 Alkyl, -O- (C) substituted by 1-6 identical or different halogens 1 -C 6 Alkyl group), C 1 -C 6 Alkyl or-O- (C) 1 -C 6 Alkyl); when the substituent is plural, the substituents may be the same or different.
In an optional embodiment of the invention, the compound of formula I, tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof is:
wherein the content of the first and second substances,
ring A is selected from
R 1 Selected from-H, hydroxy, amino, cyano, unsubstituted or substituted by R 12 Substituted C 1 -C 6 Alkyl, unsubstituted or substituted by R 12 Substituted C 3 -C 6 Cycloalkyl, halogen or
The quilt R 12 Substituted C 1 -C 6 Alkyl or by R 12 Substituted C 3 -C 6 In the cycloalkyl group, the R is 12 The substitution may be one or more, and R is 12 Each independently selected from the following substituents: hydroxy, amino, cyano, halogen, C 1 -C 6 Alkyl or-O- (C) 1 -C 6 Alkyl groups); when the number of the substituents is plural, the substituents may be the same or different;
R 11 selected from unsubstituted or substituted by R 111 Substituted C 1 -C 6 Alkyl, unsubstituted or substituted by R 111 Substituted 4-8 membered heterocycloalkyl, or-NR x R y (ii) a The quilt R 111 Substituted C 1 -C 6 Alkyl or by R 111 In substituted 4-8 membered heterocycloalkyl, said R 111 The substitution may be one or more, and R is 111 Each independently selected from the following substituents: hydroxy, amino, cyano, halogen, C 1 -C 6 Alkyl or-O- (C) 1 -C 6 Alkyl groups); when the substituent is plural, the substituents are the same or different;
R x and R y Each independently by 1 to 5R which may be the same or different z Substituted C 1 -C 6 Alkyl radical, said R z Each independently selected from-H, halogen, -O- (C) 1 -C 6 Alkyl) or C 3 -C 6 A cycloalkyl group; when the substituent is plural, the substituents are the same or different;
R 2 selected from-H, hydroxy, amino, cyano, unsubstituted or substituted by R 21 Substituted C 1 -C 6 An alkyl group; the quilt R 21 Substituted C 1 -C 6 In the alkyl group, said R 21 The substitution may be one or more, and R is 21 Each independently selected from the following substituents: hydroxy, amino, cyano, halogen, C 1 -C 6 Alkyl or-O- (C) 1 -C 6 Alkyl groups); when the number of the substituents is plural, the substituents may be the same or different;
ring B is selected from
Wherein "X" means and->
And ". Star" indicates a connection to ring a;
R 3 and R 4 Each independently selected from-H, -SF 5 Hydroxy, amino, cyano, unsubstituted or substituted by R 31 Substituted C 1 -C 6 Alkyl, unsubstituted or substituted by R 31 Substituted C 3 -C 6 Cycloalkyl, halogen or
The quilt R 31 Substituted C 1 -C 6 Alkyl or by R 31 Substituted C 3 -C 6 In the cycloalkyl group, the R is 31 The substitution may be one or more, and R is as defined above 31 Each independently selected from the following substituents: hydroxy, amino, cyano, halogen, C 1 -C 6 Alkyl or-O- (C) 1 -C 6 Alkyl); when the number of the substituents is plural, the substituents may be the same or different;
R 32 selected from-H, unsubstituted or substituted by R 331 Substituted C 1 -C 6 Alkyl, or, unsubstituted or substituted by R 321 Substituted C 3 -C 6 A cycloalkyl group; the quilt R 321 Substituted C 1 -C 6 Alkyl or by R 31 Substituted C 3 -C 6 In the cycloalkyl group, the R is 321 The substitution may be one or more, and R is as defined above 321 Each independently selected from the following substituents: hydroxy, amino, cyano, halogen, C 1 -C 6 Alkyl or-O- (C) 1 -C 6 Alkyl); when the number of the substituents is plural, the substituents may be the same or different;
R 5 selected from-H, cyano, C substituted by 1-5 same or different halogens 1 -C 6 Alkyl, C substituted by 1 to 5 identical or different halogens 3 -C 6 Cycloalkyl, halogen, C 3 -C 6 Cycloalkyl or C 1 -C 6 An alkyl group;
R 6 selected from hydroxy, amino, cyano,
Unsubstituted or substituted by R 61 Substituted C 1 -C 6 Alkyl, halogen or unsubstituted or substituted by R 61 Substituted C 3 -C 6 A cycloalkyl group; the quilt R 61 Substituted C 1 -C 6 Alkyl or by R 61 Substituted C 3 -C 6 In the cycloalkyl group, the R is 61 The substitution may be one or more, and R is 61 Each independently selected from the following substituents: hydroxy, amino, cyano, halogen, C 1 -C 6 Alkyl or-O- (C) 1 -C 6 Alkyl groups); when the substituent is plural, the substituents may be the same or different.
In an optional embodiment of the invention, the compound of formula II, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug is:
wherein, ring A, ring B, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 As defined above.
In an optional embodiment of the invention, the compound of formula III, tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs thereof is:
wherein, when ring A and ring B are the same, R is 1 And R 3 In contrast, ring A, ring B, R 1 、R 3 、R 5 、R 6 As defined above.
In an optional embodiment of the invention, the compound of formula IV, tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof is:
wherein R is 3 、R 4 And R 6 As defined above.
In an optional embodiment of the present invention, the compound of formula IV', its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug is:
wherein R is 3 、R 4 And R 6 As defined above.
In an optional embodiment of the present invention, the compound of formula IV ", its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, is:
wherein R is 3 、R 4 And R 6 As defined above.
In an optional embodiment of the present invention, the compound of formula V, its tautomers, its stereoisomers, its hydrates, its solvates, its pharmaceutically acceptable salts or its prodrugs are:
wherein ring C is unsubstituted or substituted by R 61 Substituted C 3 -C 6 A cycloalkyl group.
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:
wherein, X 1 、X 2 、X 3 、X 4 Each independently is C or N;
and X 1 And X 2 In a different way, when X 1 When is N, X 3 Is N, when X 2 When is N, X 4 Is N.
In an optional embodiment of the invention, ring B is selected from
In an optional embodiment of the invention, ring A is
In an optional embodiment of the invention, R 2 is-H.
In an optional embodiment of the invention, R 1 is-H.
In an optional embodiment of the invention, when R 1 Is unsubstituted or substituted by R 12 Substituted C 1 -C 6 When alkyl, said C 1 -C 6 Alkyl is methyl, ethyl, n-propyl or isopropyl.
In an optional embodiment of the invention, when R 1 Is unsubstituted or substituted by R 12 Substituted C 1 -C 6 When alkyl, said C 1 -C 6 The alkyl group is a methyl group.
In an optional embodiment of the invention, when R 1 Is represented by R 12 Substituted C 1 -C 6 When it is alkyl, said R 12 Is halogen.
In an optional embodiment of the invention, when R 12 When halogen is present, the halogen is F or Cl.
In an optional embodiment of the invention, when R 12 When halogen, the halogen is F.
In an optional embodiment of the invention, when R 1 Is as a quilt R 12 Substituted C 1 -C 6 When it is alkyl, said R 12 The substitutions are 1,2 or 3.
In an optional embodiment of the invention, when R 1 Is as a quilt R 12 Substituted C 1 -C 6 When it is alkyl, said R 12 The number of substitutions is 2.
In an optional embodiment of the invention, R 1 Is composed of
In an optional embodiment of the invention, R 11 Is unsubstituted or substituted by R 111 substituted-O-C 1 -C 6 When alkyl, said-O-C 1 -C 6 Alkyl is-O-methyl, -O-ethyl, -O-n-propyl or-O-isopropyl.
In an optional embodiment of the invention, R 11 is-NR x R y 。
In an optional embodiment of the invention, when R x And R y Is represented by 1-5 identical or different R z Substituted C 1 -C 6 When alkyl, said C 1 -C 6 Alkyl is methyl, ethyl, n-propyl or isopropyl.
In an optional embodiment of the invention, when R x And R y Is represented by 1-5 identical or different R z Substituted C 1 -C 6 When alkyl, said C 1 -C 6 Alkyl is methyl.
In an optional embodiment of the invention, when R x And R y Is represented by 1-5 identical or different R z Substituted C 1 -C 6 When alkyl, R is substituted z Substitutions are 1,2 or 3.
In an optional embodiment of the invention, when R x And R y Is represented by 1-5 identical or different R z Substituted C 1 -C 6 When alkyl, R is substituted z Substitutions are 1,2 or 3.
In an optional embodiment of the invention, R z is-H.
In an optional embodiment of the invention, when R x And R y Together with the N to which it is attached form an N-containing heterocyclyl, the N-heterocyclyl is
In an optional embodiment of the invention, when R 11 Is unsubstituted or substituted by R 111 Substituted 4-8 membered heterocycloalkyl, said 4-8 membered heterocycloalkyl is azetidinyl, azepinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, morpholinyl, pyrrolidinyl, morpholinyl, or piperazinyl.
In an optional embodiment of the invention, when R 11 Is unsubstituted or substituted by R 111 When substituted with a 4-8 membered heterocycloalkyl group, the 4-8 membered heterocycloalkyl is an azacyclopentyl group.
In an optional embodiment of the invention, R 4 is-H.
In an optional embodiment of the invention, R 3 is-H.
In an optional embodiment of the invention, when R 3 When halogen is present, the halogen is F or Cl.
In an optional embodiment of the invention, R 3 is-SF 5 。
In an optional embodiment of the invention, R 3 Is composed of
In an optional embodiment of the invention, when R 32 Unsubstituted or substituted by R 321 Substituted C 1 -C 6 When alkyl, said C 1 -C 6 Alkyl is methyl, ethyl, n-propyl or isopropyl.
In an optional embodiment of the invention, when R 32 Unsubstituted or substituted by R 321 Substituted C 1 -C 6 When alkyl, said C 1 -C 6 The alkyl group is a methyl group.
In an optional embodiment of the invention, when R 3 Is unsubstituted or substituted by R 31 Substituted C 1 -C 6 When alkyl, said C 1 -C 6 Alkyl is methyl, ethyl, n-propyl or isopropyl.
In an optional embodiment of the invention, when R 3 Is unsubstituted or substituted by R 31 Substituted C 1 -C 6 When alkyl, said C 1 -C 6 Alkyl is methyl or ethyl.
In an optional embodiment of the invention, when R 3 Is as a quilt R 31 Substituted C 1 -C 6 When it is alkyl, said R 31 Is halogen.
In an optional embodiment of the invention, when R 31 When halogen is used, the halogen is F or Cl.
In an optional embodiment of the invention, when R 31 When halogen, the halogen is F.
In an optional embodiment of the inventionIn when R is 3 Is represented by R 31 Substituted C 1 -C 6 In the case of alkyl, the halogen is substituted by 1,2 or 3.
In an optional embodiment of the invention, when R 3 Is unsubstituted or substituted by R 31 Substituted C 3 -C 6 When a cycloalkyl group is present, C is 3 -C 6 Cycloalkyl is cyclopropyl.
In an optional embodiment of the invention, when R 5 Is C 1 -C 6 When alkyl, said C 1 -C 6 Alkyl is methyl, ethyl, n-propyl or isopropyl.
In an optional embodiment of the invention, when R 5 Is C 1 -C 6 When alkyl, said C 1 -C 6 The alkyl group is a methyl group.
In an optional embodiment of the invention, when R 5 Is C 3 -C 6 When a cycloalkyl group is said C 3 -C 6 Cycloalkyl is cyclopropyl.
In an optional embodiment of the invention, R 6 Is composed of
In an optional embodiment of the invention, when R 6 Is unsubstituted or substituted by R 61 Substituted C 1 -C 6 When alkyl, said C 1 -C 6 Alkyl is methyl, ethyl, n-propyl or isopropyl.
In an optional embodiment of the invention, when R 6 Is unsubstituted or substituted by R 61 Substituted C 1 -C 6 When alkyl, said C 1 -C 6 The alkyl group is an isopropyl group.
In an optional embodiment of the invention, when R 6 Is as a quilt R 61 Substituted C 1 -C 6 When it is alkyl, said R 61 Is halogen.
In an optional embodiment of the invention, when R 61 When halogen is used, the halogen is F or Cl.
In an optional embodiment of the inventionIn the table, when R is 61 When halogen, the halogen is F.
In an optional embodiment of the invention, when R 6 Is as a quilt R 61 Substituted C 1 -C 6 When alkyl, said R 61 The number of substitutions is 6.
In an optional embodiment of the invention, when R 6 Is unsubstituted or substituted by R 61 Substituted C 3 -C 6 When a cycloalkyl group is present, C is 3 -C 6 Cycloalkyl is cyclopropyl or cyclobutyl.
In an optional embodiment of the invention, when R 6 Is as a quilt R 61 Substituted C 3 -C 6 When a cycloalkyl group is present, said R 61 Is a halogen.
In an optional embodiment of the invention, when R 6 Is as a quilt R 61 Substituted C 3 -C 6 When cycloalkyl is present, said R 61 Substitutions are 1,2 or 3.
In an optional embodiment of the invention, when R 6 Is as a quilt R 61 Substituted C 3 -C 6 When cycloalkyl is present, said R 61 Is C substituted by 1 to 6 identical or different halogens 1 -C 6 An alkyl group.
In an optional embodiment of the invention, when R 61 Is C substituted by 1 to 6 identical or different halogens 1 -C 6 In the case of alkyl, the halogen is substituted by 1,2 or 3.
In an optional embodiment of the invention, when R 61 Is C substituted by 1 to 6 identical or different halogens 1 -C 6 In the case of alkyl, the halogen is substituted by 3.
In an optional embodiment of the invention, when R 61 Is C substituted by 1 to 6 identical or different halogens 1 -C 6 When alkyl, the halogen is F or Cl.
In an optional embodiment of the invention, when R 61 Is C substituted by 1 to 6 identical or different halogens 1 -C 6 When alkyl, the halogen is F.
In an optional embodiment of the invention, when R 6 Is as a quilt R 61 Substituted C 3 -C 6 When cycloalkyl is present, said R 61 The number of substitutions is 2.
In an optional embodiment of the invention, R 1 Selected from the group consisting of-H,
In an optional embodiment of the invention, R 1 is-H,
In an optional embodiment of the invention, R 1 Is composed of
In an optional embodiment of the invention, R 2 is-H.
In an optional embodiment of the invention, R 3 Selected from-H, -Cl, methyl, -SF 5 、
In an optional embodiment of the invention, R 3 Selected from-H, -SF 5 、
In an optional embodiment of the invention, R 3 Selected from-H, -SF 5 、
In an optional embodiment of the invention, R 4 is-H.
In an optional embodiment of the invention, R 5 Selected from methyl or cyclopropyl.
In the present inventionIn an optional embodiment, R 5 Is methyl.
In an optional embodiment of the invention, R 6 Selected from isopropyl, cyclopropyl,
In an optional embodiment of the invention, R 6 Selected from isopropyl group,
In an optional embodiment of the invention, R 6 Selected from cyclobutyl, cyclopentyl,
In an optional embodiment of the invention, when ring A is
And ring B is
When R is 1 Is hydroxy or->
And R is 11 is-NR x R y Or->
In an optional embodiment of the invention, when ring A is
And ring B is
When R is 3 is-SF 5 Hydroxy, amino and/or are present in>
In an optional embodiment of the invention, when ring A is
And ring B is
When R is 5 Is C 3 -C 6 Cycloalkyl, cyano or C substituted by 1 to 5 identical or different halogens 3 -C 6 A cycloalkyl group.
In an optional embodiment of the invention, when ring A is
And ring B is
When R is 6 Is hydroxy, amino, cyano, or>
By R 61 Substituted C 1 -C 6 Alkyl, halogen or unsubstituted or substituted by R 61 Substituted C 3 -C 6 A cycloalkyl group.
In an optional embodiment of the invention, the compound of formula I, tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof is selected from any one of the following compounds:
in a second aspect of the present invention, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of the above compound, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, and a pharmaceutically acceptable carrier, diluent or excipient.
According to a specific embodiment of the present invention, the pharmaceutical composition of the present invention may be prepared into a pharmaceutical formulation suitable for oral or parenteral administration by mixing a therapeutically effective amount of the above-mentioned compound, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, and a pharmaceutically acceptable carrier, diluent or excipient. Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, and oral routes. The formulations may be administered by any route, for example by infusion or bolus injection, by a route of absorption through epithelial or cutaneous mucosa (e.g. oral mucosa or rectum, etc.). Administration may be systemic or local. Examples of the formulation for oral administration include solid or liquid dosage forms, specifically, tablets, pills, granules, powders, capsules, syrups, emulsions, suspensions and the like. The formulations may be prepared by methods known in the art and include carriers, diluents or excipients conventionally used in the art of pharmaceutical formulation.
In a third aspect of the present invention, the present invention provides the use of the above compound, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or the above pharmaceutical composition for the preparation of a medicament for the treatment of AAK 1-related diseases.
According to a specific embodiment of the present invention, the use of the above compound or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or the above pharmaceutical composition for the preparation of a medicament for the treatment of alzheimer's disease, bipolar disorder, pain, parkinson's disease, schizophrenia or related diseases.
Terms and definitions
Unless otherwise indicated, the terms and definitions used in the present application, including in the specification and claims of the present application, are as follows.
It will be understood by those skilled in the art that, according to the convention used in the art, in the structural formulae of the present application,
for delineating chemical bonds, which are the points at which moieties or substituents are attached to a core structure or a backbone structure.
The term "pharmaceutically acceptable salts" refers to pharmaceutically acceptable salts of non-toxic acids or bases, including salts of inorganic acids and bases, organic acids and bases.
The term "pharmaceutical composition" denotes a mixture of one or more of the compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof with other chemical components, such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate the administration of the compound to an organism.
The term "adjuvant" refers to a pharmaceutically acceptable inert ingredient. Examples of classes of the term "excipient" include, without limitation, binders, disintegrants, lubricants, glidants, stabilizers, fillers, diluents, and the like. Excipients enhance the handling characteristics of the pharmaceutical formulation, i.e., make the formulation more amenable to direct compression by increasing flowability and/or adhesiveness.
The term "prodrug" refers to a compound of the invention that can be converted to a biologically active compound under physiological conditions or by solvolysis. Prodrugs of the invention are prepared by modifying functional groups in the compounds, which modifications may be routinely made or removed in vivo to provide the parent compound. Prodrugs include compounds of the present invention wherein a hydroxy or amino group is attached to any group that, when administered to a mammalian subject, cleaves to form a free hydroxy or a free amino group, respectively.
The term "stereoisomer" refers to isomers resulting from the different arrangement of atoms in a molecule, including cis-trans isomers, enantiomers, diastereomers, and conformers.
The term "tautomer" refers to an isomer of a functional group resulting from the rapid movement of an atom in two positions in a molecule. The compounds of the invention may exhibit tautomerism. Tautomeric compounds may 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 often 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; whereas in phenol the enol type predominates. The present invention encompasses all tautomeric forms of the compounds.
Certain compounds of the present invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are all included within the scope of the present invention.
The illustrations of mesomeric, ambiscientific and scientific or enantiomerically pure compounds herein are from Maehr, J.chem.Ed.1985, 62. Unless otherwise indicated, the absolute configuration of a stereocenter is indicated by wedge bonds and dashed bonds. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, they include E, Z geometric isomers, unless otherwise specified. Likewise, all tautomeric forms are included within the scope of the invention.
The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-) -and (+) -enantiomers, (R) -and (S) -enantiomers, diastereomers, D-isomers, L-isomers, as well as racemic and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. 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 of the enantiomers of a compound of the invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl), diastereomeric salts are formed with an appropriate optically active acid or base, followed by resolution of the diastereomers by fractional crystallization or chromatography, as is well known in the art, and the pure enantiomers are recovered. Furthermore, separation of enantiomers and diastereomers is typically accomplished by using chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (e.g., carbamate formation from amines).
The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compound may be labeled with a radioisotope, such as tritium ( 3 H) Iodine-125 ( 125 I) Or C-14 ( 14 C) .1. The All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.
The term "effective amount" or "therapeutically effective amount" with respect to a drug or pharmacologically active agent refers to a sufficient amount of the drug or agent that is non-toxic but achieves the desired effect. For oral dosage forms of the invention, an "effective amount" of one active agent in a composition is the amount required to achieve the desired effect when combined with another active agent in the composition. The determination of an effective amount varies from person to person, depending on the age and general condition of the recipient and also on the particular active substance, and an appropriate effective amount in a case may be determined by a person skilled in the art in the light of routine tests.
The terms "active ingredient," "therapeutic agent," "active substance," or "active agent" refer to a chemical entity that is effective in treating a target disorder, disease, or condition.
The term "substituted" means that any one or more hydrogen atoms on a particular atom is replaced with a substituent, including deuterium and hydrogen variants, so long as the valency of the particular atom is normal and the substituted compound is stable. When the substituent is keto (i.e = O), it means that two hydrogen atoms are substituted. The keto substitution does not occur on an aromatic group. The term "optionally substituted" means that it may or may not be substituted, and unless otherwise specified, the kind and number of substituents may be arbitrary on the basis of chemical realizability.
Prefix "C u- C v "means that the following groups have from u to v carbon atoms. For example, "C 1- C 6 Alkyl "means that the alkyl has 1 to 6 carbon atoms.
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-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 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, or the like or isomers thereof. In particular, the radicals have 1,2 or 3 carbon atoms ("C) 1 -C 3 Alkyl), such as methyl, ethyl, n-propyl or isopropyl.
The term "-O- (C) 1 -C 6 Alkyl) "is understood to mean that the alkyl radical is bonded to the rest of the molecule via an oxygen atom, where" C "is 1 -C 6 Alkyl "has the above definition. Such as-O- (methyl), -O- (ethyl).
The term "C 3 -C 6 Cycloalkyl radicalsIt 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.
The term "4-8 membered heterocycloalkyl" refers to a monocyclic saturated heterocyclic 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 selected from: n, NH, O, S, SO and SO 2 The heterocycloalkyl group may be attached to the rest of the molecule through any carbon atom or, if present, nitrogen atom. The heterocycloalkyl group may be a 4-membered ring, such as azetidinyl, oxetanyl or thietanyl; or a 5-membered ring, such as tetrahydrofuranyl, 1,3-dioxolanyl, thiacyclopentyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, 1,1-dioxothiacyclopentyl, 1,2-oxazolidinyl, 1,3-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-oxazacyclohexyl.
The term "halo" or "halogen" is fluorine, chlorine, bromine and iodine.
The terms "optional" or "optionally" mean 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.
In addition, it should be noted that, unless otherwise explicitly indicated, the description of "… … independently" as used in the present invention is to be understood broadly to mean that the individual entities described are independent of each other and may be independently the same or different specific groups. In more detail, the description "… … independently" can mean that the specific options expressed between the same symbols do not affect each other in different groups, or that the specific options expressed between the same symbols do not affect each other in the same groups.
Has the beneficial effects that:
according to the embodiment of the invention, the invention has at least one of the following technical effects:
1) Provides an AAK1 inhibitor with novel structure, excellent pharmacokinetic property and good drug effect or pharmaceutical performance, which can be used for effectively treating AAK1 related diseases and symptoms;
2) The compounds of the invention are useful in the treatment of Alzheimer's disease, bipolar disorder, pain, parkinson's disease, schizophrenia and related diseases;
3) The compound has stronger AAK1 affinity.
Additional aspects and advantages of the invention will be set forth in part in the description which follows and, in part, will be obvious from the description, or may be learned by practice of the invention.
Detailed Description
The scheme of the invention will be explained with reference to the examples. It will be appreciated by those skilled in the art that the following examples are illustrative of the invention only and should not be taken as limiting the scope of the invention. The examples, where specific techniques or conditions are not indicated, are to be construed according to the techniques or conditions described in the literature in the art or according to the product specifications. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available.
Unless otherwise specified, the compounds of the present invention are structurally defined by Nuclear Magnetic Resonance (NMR) and/or Mass Spectrometry (MS). NMR shift in units of 10 -6 (ppm). Solvents for NMR measurement are deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol and the like, and internal standard is Tetramethylsilane (TMS).
The abbreviations of the present invention are defined as follows:
m: molar concentration, e.g. 1M hydrochloric acid for 1mol/L hydrochloric acid solution
LC-MS: liquid chromatography-mass spectrometry
DMSO, DMSO: dimethyl sulfoxide
IC 50 : the median inhibitory concentration refers to the concentration at which half of the maximal inhibitory effect is achieved.
Comparative example 1: preparation of control Compound 1
(S) -1- ((2 ', 6-bis (difluoromethyl) - [2,4' -bipyridinyl ] -5-yl) oxo) -2,4-dimethylpentan-2-amine (control Compound 1).
The synthetic route for the target compound 1 is shown below:
the first step is as follows: synthesis of (S) -2- ((((9H-fluoren-9-yl) methoxy) carbonyl) amino) -2,4-dimethylpentanoic acid
To a solution of (S) -2-amino-2,4-dimethylpentanoic acid (8.00g, 55.1mmol) and sodium hydroxide (2.64g, 66.1mmol) in water (40.0 mL) and acetone (40.0 mL) at room temperature was added in portions (9H-fluoren-9-yl) methyl (2,5-dioxopyrrolidin-1-yl) carbonate (18.5g, 55.1mmol), and the reaction was stirred at room temperature overnight. After completion of the reaction, the pH was adjusted to 2 with 2N hydrochloric acid, sufficiently stirred and extracted with ethyl acetate (200 mL), the organic phase was dried over anhydrous sodium sulfate and concentrated by filtration to give a crude product which was purified by column chromatography (silica gel, ethyl acetate: petroleum ether =10:1 to 3:1) to give (S) -2- ((((9H-fluoren-9-yl) methoxy) carbonyl) amino) -2,4-dimethylpentanoic acid (10.0g, 27.2mmol, yield 49.4%) as a colorless oil.
The second step is that: synthesis of (S) - (9H-fluoren-9-yl) methyl (1-hydroxy-2,4-dimethylpentan-2-yl) aminomethyl ester
Isobutyl chloroformate (3.27g, 23.9 mmol) was added dropwise at 0 ℃ to a solution of (S) -2- ((((9H-fluoren-9-yl) methoxy) carbonyl) amino) -2,4-dimethylpentanoic acid (8.00g, 21.7 mmol) and N, N-diisopropylethylamine (3.38g, 26.1 mmol) in tetrahydrofuran (80.0 mL), the reaction was stirred at 0 ℃ for 0.5 hour, sodium borohydride (1.65g, 43.5 mmol) was added, and the reaction was heated to 25 ℃ and stirred for 0.5 hour. After completion of the reaction, the reaction solution was quenched by dropwise addition of dilute hydrochloric acid and extracted with ethyl acetate (200 mL), the organic phase was dried over anhydrous sodium sulfate and concentrated by filtration to give a crude product, which was purified by column chromatography (silica gel, ethyl acetate: petroleum ether =10, 1 to 5:1) to give (S) - (9H-fluoren-9-yl) methyl (1-hydroxy-2,4-dimethylpentan-2-yl) aminomethyl ester (6.50g, 18.3mmol,84.4% yield) as a colorless oil.
The third step: synthesis of (S) -2-amino-2,4-dimethylpentan-1-ol
To (S) - (9H-fluoren-9-yl) methyl (1-hydroxy-2,4-dimethylpentan-2-yl) aminomethyl ester (5.10 g,14.4 mmol) in dichloromethane (50.0 mL) was added diethylamine (3.17g, 43.2 mmol) at room temperature, and the reaction was stirred at room temperature for 2 hours. After completion of the reaction, the reaction solution was concentrated to give (S) -2-amino-2,4-dimethylpentan-1-ol (3.50 g, crude) as a yellow solid.
The fourth step: synthesis of 2- (difluoromethyl) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine
To a solution of 4-bromo-2- (difluoromethyl) pyridine (1.80g, 8.65mmol), bis-pinacolinate borate (2.75g, 10.8 mmol) and potassium acetate (2.12g, 21.6 mmol) in 1,4-dioxane (20.0 mL) was added 1,1-bis (diphenylphosphino) ferrocene palladium chloride (633mg, 865. Mu. Mol) at room temperature, and the mixture was stirred at 80 ℃ overnight. After the reaction was completed, the reaction solution was cooled to room temperature, diluted with water (50.0 mL), extracted with ethyl acetate (50.0 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a crude compound, 2- (difluoromethyl) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine (2.50 g, crude).
The fifth step: synthesis of (S) -1- ((6-bromo-2- (difluoromethyl) pyridin-3-yl) oxo) -2,4-dimethylpentan-2-amine
To a solution of (S) -2-amino-2,4-dimethylpentan-1-ol (1.169g, 8.85mmol) in tetrahydrofuran (12.0 mL) was added potassium tert-butoxide (1.19g, 10.6 mmol) at room temperature, stirred for 0.5 h, then 6-bromo-2- (difluoromethyl) -3-fluoropyridine (2.00g, 8.85mmol) was added in portions, and the reaction was also warmed to 80 ℃ and stirred for 12 h. After completion of the reaction, 1N hydrochloric acid was added to adjust the pH of the reaction solution to 2, the mixture was extracted with ethyl acetate (20.0 mL), the aqueous phase was adjusted to pH 12 with 1M aqueous sodium hydroxide solution and extracted with ethyl acetate (25.0 mL), and the organic phase was dried over anhydrous sodium sulfate and then filtered and concentrated to give crude compound (S) -1- ((6-bromo-2- (difluoromethyl) pyridin-3-yl) oxo) -2,4-dimethylpentane-2-amine (690 mg, crude).
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] + .
And a sixth step: synthesis of (S) -1- ((2 ', 6-bis (difluoromethyl) - [2,4' -bipyridine ] -5-yl) oxo) -2,4-dimethylpentan-2-amine (7)
To a solution of (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 (12.0 mL) was added chlorine (2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl) [2- (2-amino-1,1-biphenyl) ] palladium (II) (140mg, 177. Mu. Mol) at room temperature, and the reaction was stirred at 80 ℃ for 12 hours. After the reaction is finished, filtering and concentrating the reaction liquid to obtain a crude product, and separating the crude product by using a reversed-phase high performance liquid chromatography, wherein the separation method comprises the following steps: chromatography column Waters Xbridge C18X 50mm X10 μm; mobile phase [ water (ammonium bicarbonate) -acetonitrile ]; b% 40% -70%,11min ] to obtain yellow solid compound (S) -1- ((2 ', 6-bis (difluoromethyl) - [2,4' -bipyridyl ] -5-yl) oxo) -2,4-dimethylpentane-2-amine (314mg, 776 μmol, yield 43.6%).
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] + 。
Example 1: preparation of target Compound I-1
(S) -3- (5- ((2-amino-2,4-dimethylpentyl) oxo) -6- (difluoromethyl) - [2,4 '-bipyridine ] -2' -yl) -1,1-dimethylurea (object compound I-1)
The synthetic route of the target compound I-1 is shown as follows:
the first step is as follows: synthesis of 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2-amine
4-bromopyridin-2-amine (3.00g, 17.3mmol) and 4,4,4',4',5,5,5',5' -octamethyl-2,2 ' -bis (1,3,2-dioxaborolan) (5.28g, 20.8mmol) were dissolved in 1,4-dioxane (30.0 mL), and 1,1-bis (diphenylphosphino) ferrocene 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 reacted at 80 ℃ for 12 hours. The reaction was cooled to 25 ℃ and water (60.0 mL) was added, followed by extraction with dichloromethane (30.0 mL. Times.3), the organic phase was washed with saturated brine (30.0 mL), dried over sodium sulfate, and concentrated to give crude product which was purified by petroleum ether: methyl tert-butyl ether =2:1 (30 ml) was slurried for 20 minutes, filtered and dried to give 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2-amine as a brown solid (3.45 g, 89.8% yield).
LC-MS,M/Z(ESI):221.2[M+H] + 。
The second step is that: synthesis of 1,1-dimethyl-3- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2-yl) urea
4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2-amine (300mg, 1.36mmol) and triethylamine (414mg, 4.09mmol) were dissolved in dichloromethane (12.0 mL) and tetrahydrofuran (4.00 mL), benzyl chloroformate (427mg, 2.73mmol) was slowly added dropwise, after 12 hours of reaction at 25 deg.C, dimethylamine hydrochloride (167mg, 2.04mmol) was added and the reaction was continued for 4 hours at 25 deg.C. Water (20.0 mL) was added to the reaction solution, followed by extraction with ethyl acetate (20.0 mL × 3), and the organic phase was washed with saturated brine (20.0 mL), dried over sodium sulfate, and concentrated to give a 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 (280 mg, 70.5% yield).
LC-MS,M/Z(ESI):292.0[M+H] + 。
The third step: synthesis of (S) -3- (5- ((2-amino-2,4-dimethylpentyl) oxo) -6- (difluoromethyl) - [2,4 '-bipyridine ] -2' -yl) -1,1-dimethylurea (I-1)
1,1-dimethyl-3- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2-yl) urea (256 mg, 890. Mu. Mol) and (S) -1- ((6-bromo-2- (difluoromethyl) pyridin-3-yl) oxy) -2,4-dimethylpentan-2-amine (200mg, 593. Mu. Mol) were dissolved in tetrahydrofuran (4.00 mL), and dichlorobis [ di-t-butyl- (4-dimethylaminophenyl) phosphine ] palladium (II) (21.0mg, 29.7. Mu. Mol) and potassium phosphate (378mg, 1.78mmol) were added to the reaction solution, nitrogen was replaced 3 times, and the reaction was carried out at 70 ℃ for 12 hours. The reaction solution was cooled to 25 ℃ and then water (10.0 mL) was added, followed by extraction with ethyl acetate (10.0 mL × 3), the organic phase was washed with saturated brine (10.0 mL), dried over sodium sulfate, concentrated to give a crude product, which was then separated by reverse phase high performance liquid chromatography by (column: waters Xbridge150 × 25mm × 5 μm; mobile phase: a = water + ammonia (0.05%), B = acetonitrile; gradient: 35% -65%,9 min), and then lyophilized to give black gum compound (S) -3- (5- ((2-amino-2,4-dimethylpentyl) oxo) -6- (difluoromethyl) - [2,4 '-bipyridine ] -2' -yl) -1,1-dimethylurea (I-1) (8.90 mg, 3.36% yield).
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] + 。
Example 2: preparation of target Compound I-2
(S) -N- (5- ((2-amino-2,4-dimethylpentyl) oxo) -6- (difluoromethyl) - [2,4 '-bipyridinyl ] -2' -yl) pyrrolidine-1-carboxamide (object Compound I-2)
The synthetic route of the target compound I-2 is shown as follows:
the first step is as follows: synthesis of N- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2-yl) pyrrolidine-1-carboxamide
4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2-amine (1.00g, 4.54mmol) and triethylamine (1.38g, 13.6 mmol) were dissolved in dichloromethane (20.0 mL) and tetrahydrofuran (10.0 mL), benzyl chloroformate (1.42g, 9.09mmol) was slowly added dropwise, and after 12 hours of reaction at 25 deg.C, pyrrolidine (1.62g, 22.7 mmol) was added and the reaction continued for 4 hours at 25 deg.C. The reaction was cooled down to water (50.0 mL), 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 crude product as a brown oil N- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2-yl) pyrrolidine-1-carboxamide (1.25 g, 86.8% yield).
LC-MS,M/Z(ESI):318.1[M+H] + 。
The second step is that: (S) -N- (5- ((2-amino-2,4-dimethylpentyl) oxo) -6- (difluoromethyl) - [2,4 '-bipyridinyl ] -2' -yl) pyrrolidine-1-carboxamide (object Compound I-2)
N- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2-yl) pyrrolidine-1-carboxamide (166mg, 522. Mu. Mol) and (S) -1- ((6-bromo-2- (difluoromethyl) pyridin-3-yl) oxy) -2,4-dimethylpentan-2-amine (117mg, 348. Mu. Mol) were dissolved in tetrahydrofuran (2.00 mL), and dichlorobis [ di-tert-butyl- (4-dimethylaminophenyl) phosphine ] palladium (II) (12.3 mg, 17.4. Mu. Mol) and potassium phosphate (222mg, 1.04mmol) were added to the reaction solution, nitrogen was replaced 3 times, and reacted at 70 ℃ for 12 hours. The reaction solution was cooled to 25 ℃ and then water (10.0 mL) was added, followed by extraction with ethyl acetate (10.0 mL × 3), the organic phase was washed with saturated brine (10.0 mL), dried over sodium sulfate, concentrated to give a crude product, which was then separated by reverse phase high performance liquid chromatography by (column: waters Xbridge150 × 25mm × 5 μm; mobile phase: a = water + ammonia (0.05%), B = acetonitrile; gradient: 36% -66%,9 min), and then lyophilized to give yellow gum compound (S) -N- (5- ((2-amino-2,4-dimethylpentyl) oxo) -6- (difluoromethyl) - [2,4 '-bipyridine ] -2' -yl) pyrrolidine-1-carboxamide (I-2) (8.94 mg, yield 5.71%).
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] + 。
Example 3: preparation of object Compound I-3
(S) -1- ((2 ', 6-bis (difluoromethyl) - [2,4' -bipyridine ] -5-yl) oxo) -3-cyclopropyl-2-methylpropan-2-amine (target compound I-3)
The synthetic route of the target compound I-3 is shown as follows:
the first step is as follows: synthesis of diethyl 2- (cyclopropylmethyl) -2-methylmalonate
To a solution of diethyl 2-methylpropanediester (20.0 g, 114mmol) bromomethylcyclopropane (15.5 g, 114mmol) in ethanol (150 mL) was added sodium ethoxide (58.6 g, 172mmol) at room temperature, and the reaction solution was stirred at 65 ℃ for 3 hours. After the reaction, the crude product is obtained by concentration. Dilute with water and ethyl acetate. Extraction with ethyl acetate and concentration gave diethyl 2- (cyclopropylmethyl) -2-methylmalonate as a yellow oil (25.0 g, 95.4% yield).
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)
The second step is that: synthesis of 2- (cyclopropylmethyl) -3-ethoxy-2-methyl-3-oxoylidenepropionic acid
To a solution of diethyl 2- (cyclopropylmethyl) -2-methylmalonate (24.0 g, 105mmol) in ethanol (150 mL) was added a solution of potassium hydroxide (7.08g, 126mmol) in water (30.0 mL) at room temperature, and the reaction was stirred at 25 ℃ for 48 hours. After the reaction, the mixture was concentrated, diluted with water, and extracted with ethyl acetate to remove impurities. The pH was adjusted to 3 with dilute hydrochloric acid, extracted with ethyl acetate, and concentrated to give 2- (cyclopropylmethyl) -3-ethoxy-2-methyl-3-oxoylidenepropionic acid as a yellow oily liquid (15.8g, 75.1% yield)
The third step: synthesis of ethyl 3-amino-2- (cyclopropylmethyl) -2-methyl-3-oxopropylidene ester
To a solution of 2- (cyclopropylmethyl) -3-ethoxy-2-methyl-3-oxoylidenepropionic acid (2.50g, 12.5 mmol), ammonium chloride (1.67g, 31.2mmol) and triethylamine (3.79g, 37.46mmol) in dimethylformamide (20.0 mL) was added 2- (7-azobenzotriazol) -N, N, N-tetramethyluronium hexafluorophosphate (5.22g, 13.73mmol) at room temperature, and the reaction mixture was stirred at 25 ℃ for 2 hours. After the reaction was complete, it was diluted with water, extracted with ethyl acetate, the organic phase was washed three times with water, dried over sodium sulfate, filtered and concentrated to give yellow oleyl 3-amino-2- (cyclopropylmethyl) -2-methyl-3-oxoylidene-propyl ester (6.0 g, crude).
The fourth step: synthesis of ethyl 2-amino-3-cyclopropyl-2-methylpropyl ester
Iodobenzene acetate (12.6 g,39.1 mmol) was added to a mixture of ethyl 3-amino-2- (cyclopropylmethyl) -2-methyl-3-oxoylidene-propyl ester (6.00g, 30.1 mmol) in acetonitrile (40 mL) and water (15 mL) at room temperature, and the reaction mixture was stirred at 25 ℃ for 12 hours. After the reaction, the mixture was concentrated, acidified to pH 2 with 1mol of hydrochloric acid, and extracted with ethyl acetate to remove impurities. Adjusting pH to 10 with 1mol sodium hydroxide, extracting with ethyl acetate, and concentrating to obtain ethyl 2-amino-3-cyclopropyl-2-methylpropyl ester as yellow oily liquid (680mg, 13.2% yield)
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)
The fifth step: synthesis of 2-amino-3-cyclopropyl-2-methylpropan-1-ol
To ethyl 2-amino-3-cyclopropyl-2-methylpropyl ester (650mg, 3.80mmol) in tetrahydrofuran (10.0 mL) at zero degrees was added in portions lithium aluminum hydride (216mg, 5.69mmol), and the reaction was stirred at 0 degrees for 0.5 hour. After the reaction, the mixture was diluted with anhydrous tetrahydrofuran in a nitrogen atmosphere. Quenched at zero with 0.2mL of 2 molar sodium hydroxide. Filtration and concentration gave 2-amino-3-cyclopropyl-2-methylpropan-1-ol as a yellow oily liquid (450mg, 91.8% yield).
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)
And a sixth step: synthesis of 6-bromo-2- (difluoromethyl) -3-fluoropyridine
To a solution of 6-bromo-3-fluoro-pyridine-2-carbaldehyde (3.00g, 14.7 mmol) in dichloromethane (60.0 mL) at-20 deg.C was added diethylaminosulfur trifluoride (5.22g, 32.3 mmol), and the reaction mixture was stirred at 25 deg.C for 3 hours. After the reaction was completed, the reaction solution was slowly poured into an ice-water solution of sodium hydrogencarbonate. Extraction with dichloromethane and concentration gave 6-bromo-2- (difluoromethyl) -3-fluoropyridine (8) (3.05g, 91.8% yield) as a yellow solid
LC-MS,M/Z(ESI):226.0[M+H] +
The seventh step: synthesis of 1- ((6-bromo-2- (difluoromethyl) pyridin-3-yl) oxo) -3-cyclopropyl-2-methylpropan-2-amine
To a solution of 6-bromo-2- (difluoromethyl) -3-fluoropyridine (800mg, 3.54mmol), 2-amino-3-cyclopropyl-2-methylpropan-1-ol (411mg, 3.19mmol) in tetrahydrofuran (10 mL) was added potassium tert-butoxide (6.40mmol, 2eq) at room temperature, and the reaction was stirred at 70 ℃ for 2 hours. After the reaction, water was added to dilute the mixture, and the mixture was extracted with ethyl acetate. Concentration and isolation of the crude product by reverse phase chromatography (basic) gave 1- ((6-bromo-2- (difluoromethyl) pyridin-3-yl) oxo) -3-cyclopropyl-2-methylpropan-2-amine as a white solid (600mg, 45.5% yield).
LC-MS,M/Z(ESI):335.0[M+H] +
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)
Eighth step: synthesis of 1- ((2 ', 6-bis (difluoromethyl) - [2,4' -bipyridin ] -5-yl) oxo) -3-cyclopropyl-2-methylpropan-2-amine
To a mixture of 1- ((6-bromo-2- (difluoromethyl) pyridin-3-yl) oxo) -3-cyclopropyl-2-methylpropan-2-amine (300mg, 895 μmol), 2- (difluoromethyl) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine (319mg, 1.25mmol), potassium carbonate (371mg, 2.69mmol) in dioxane (3.00 mL) and water (1.00 mL) was added dichlorobis [ di-tert-butyl- (4-dimethylaminophenyl) phosphine ] palladium (II) (63.3mg, 89.5 μmol) at room temperature, and the reaction was stirred at 80 ℃ for 2 hours. After the reaction, water was added to dilute the mixture, and the mixture was extracted with ethyl acetate. Concentrating to obtain crude product. The crude product was isolated by reverse phase preparation (column: waters Xbridge 150X 25mm X5 μm; mobile phase: [ water (0.225% ammonia) -acetonitrile ]; B%:34% -64%,9 min) to give 1- ((2 ', 6-bis (difluoromethyl) - [2,4' -bipyridinyl ] -5-yl) oxo) -3-cyclopropyl-2-methylpropan-2-amine (100mg, 12.2% yield)
LC-MS,M/Z(ESI):383.9[M+H] +
The tenth step: preparation of (S) -1- ((2 ', 6-bis (difluoromethyl) - [2,4' -bipyridin ] -5-yl) oxo) -3-cyclopropyl-2-methylpropan-2-amine (I-3)
The crude product was resolved by SFC (column: daicel ChiralPak IG (250X 30mm,10 μm), mobile phase: [ carbon dioxide (0.1% ammonia) -methanol ]; B%:20% -20%,4.6 min) to give (S) -1- ((2 ', 6-bis (difluoromethyl) - [2,4' -bipyridin ] -5-yl) oxo) -3-cyclopropyl-2-methylpropan-2-amine (I-3) as a white solid
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)。
Example 4: preparation of target Compound I-4
(S) -1- ((2 ', 6-bis (difluoromethyl) - [2,4' -bipyridine ] -5-yl) oxo) -3- (3,3-difluorocyclobutyl) -2-methylpropan-2-amine
The synthetic route of the target compound I-4 is shown as follows:
the first step is as follows: synthesis of 2', 6-bis (difluoromethyl) -5-fluoro-2,4' -bipyridine
6-bromo-2- (difluoromethyl) -3-fluoro-pyridine (500mg, 2.21mmol) and 2- (difluoromethyl) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine (846mg, 3.32mmol) were dissolved in tetrahydrofuran (20.0 mL) and water (5.00 mL) at room temperature, followed by potassium phosphate (939mg, 4.42mmol) and [2- (2-aminophenyl) phenyl ] -chloro-palladium; dicyclohexyl- [3- (2,4,6-triisopropylphenyl) phenyl ] phosphane (87.0mg, 111. Mu. Mol), nitrogen was replaced 3 times, and the mixture was stirred at 80 ℃ for 12 hours, the reaction was diluted with water (20.0 mL), and then extracted with ethyl acetate (10.0 mL. Times.3), and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate, followed by filtration and concentration to give a crude product. The crude product was purified by column chromatography (silica, petroleum ether: ethyl acetate =8:1 to 3:1) to give 2', 6-bis (difluoromethyl) -5-fluoro-2,4' -bipyridine as a yellow solid (400 mg, yield 65.9%).
LC-MS,M/Z(ESI):275.1[M+H] +
The second step is that: synthesis of diethyl 2- ((3,3-difluorocyclobutyl) methyl) -2-methylmalonate
Diethyl 2-methylmalonate (2.00g, 11.5 mmol) and 3- (bromomethyl) -1,1-difluoro-cyclobutane (2.15g, 11.6 mmol) were added to sodium ethoxide (7.81g, 23.0mmol,20 w/w) at room temperature, then the reaction was stirred at 65 ℃ for six hours under nitrogen protection, after completion of the reaction, the reaction was concentrated, then diluted with water at 0 ℃, 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 diethyl 2- ((3,3-difluorocyclobutyl) methyl) -2-methylmalonate as a yellow oil (1.90 g, yield 59.5%).
The third step: synthesis of 2- ((3,3-difluorocyclobutyl) methyl) -3-ethoxy-2-methyl-3-oxopropanoic acid
Diethyl 2- ((3,3-difluorocyclobutyl) methyl) -2-methylmalonate (1.90g, 6.83mmol) was dissolved in ethanol (10.0 mL) and water (5.00 mL) at room temperature, potassium hydroxide (460mg, 8.19mmol) was added, the reaction solution was stirred at 65 ℃ for 12 hours, after completion of the reaction, water (20.00 mL) was added to the reaction solution, followed by extraction with ethyl acetate (10.0 mL × 2), then the PH of the aqueous phase was adjusted to 3 with 1M aqueous hydrochloric acid, followed by extraction with ethyl acetate (10.0 mL × 3), and after the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate, then filtered, and concentrated to give 2- ((3,3-difluorocyclobutyl) methyl) -3-ethoxy-2-methyl-3-oxopropanoic acid as a yellow oil (700 mg, 41.0%) in yield.
The fourth step: synthesis of ethyl 3-amino-2- ((3,3-difluorocyclobutyl) methyl) -2-methyl-3-oxopropanoate
At room temperature, 2- ((3,3-difluorocyclobutyl) methyl) -3-ethoxy-2-methyl-3-oxopropanoic acid (700mg, 2.80mmol), ammonium chloride (449mg, 8.39mmol) were dissolved in N, N-dimethylformamide (7.00 mL), O- (7-azabenzotriazole-1-yl) -N, N' -tetramethyluronium hexafluorophosphate (1.60g, 4.20mmol) and N, N-diisopropylethylamine (1.81g, 13.99mmol) were added, the reaction solution was stirred at 25 ℃ for 5 hours, after completion of the reaction, diluted with water (20.00 mL), followed by extraction with ethyl acetate (10.0 mL × 3), the organic phase was washed with 0.1M aqueous hydrochloric acid solution 2 times, then with saturated saline and dried over sodium sulfate, then filtered anhydrous, and concentrated to give crude 3-amino-2- ((3,3-difluorocyclobutyl) methyl) -2-methyl-3-oxopropanoic acid as a yellow oil (1.00 g).
The fifth step: synthesis of ethyl 2-amino-3- (3,3-difluorocyclobutyl) -2-methylpropionate
Ethyl 3-amino-2- ((3,3-difluorocyclobutyl) methyl) -2-methyl-3-oxopropanoate (1.00g, 4.01mmol) was dissolved in acetonitrile (70.0 mL) and water (5.00 mL) at room temperature, then [ phenyl- (2,2,2-trifluoroacetyl) oxo- λ 3-iodoalkyl ]2,2,2-trifluoroacetate (2.07g, 4.81mmol) was added, the reaction was stirred at 25 ℃ for 12 hours, after completion of the reaction, the pH of the aqueous phase was adjusted to 11 with 1M aqueous sodium hydroxide solution, extraction was then carried out with ethyl acetate (20.0 mL. Times.3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to give ethyl 2-amino-3- (3,3-difluorocyclobutyl) -2-methylpropionate (831 mg, crude product) as a yellow oil.
And a sixth step: synthesis of 2-amino-3- (3,3-difluorocyclobutyl) -2-methylpropan-1-ol
Ethyl 2-amino-3- (3,3-difluorocyclobutyl) -2-methylpropanoate (831mg, 4.01mmol) was dissolved in tetrahydrofuran (10.0 mL) at 0 deg.C, lithium aluminum hydride (228mg, 6.02mmol) was added in portions, the reaction mixture was stirred at 0 deg.C for 0.5 hour, after completion of the reaction, the reaction was quenched with 1M aqueous sodium hydroxide solution at 0 deg.C, then diluted with tetrahydrofuran (30.0 mL), dried over anhydrous sodium sulfate, then filtered, and concentrated to give 2-amino-3- (3,3-difluorocyclobutyl) -2-methylpropan-1-ol as a yellow oil (600 mg, crude product).
The seventh step: synthesis of (S) -1- ((2 ', 6-bis (difluoromethyl) - [2,4' -bipyridin ] -5-yl) oxo) -3- (3,3-difluorocyclobutyl) -2-methylpropan-2-amine (I-4)
2- (difluoromethyl) -6- [2- (difluoromethyl) -4-pyridyl ] -3-fluoro-pyridine (400mg, 1.46mmol), 2-amino-3- (3,3-difluorocyclobutyl) -2-methyl-propan-1-ol (523mg, 2.92mmol) were dissolved in tetrahydrofuran (8.00 mL) at room temperature, a potassium tert-butoxide (1M, 3.65mL) solution was added thereto, the reaction mixture was stirred at 70 ℃ for 4 hours, after completion of the reaction, it was diluted with water (20.00 mL), followed by extraction with ethyl acetate (10.00 mL. Times.3), and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate, followed by filtration and concentration to give a crude product. The crude product was separated by reverse phase preparation (column: phenomenex Synergi C18X 25mm X10 μm; mobile phase: water (0.225% formic acid) -acetonitrile; B%:16% -46%,2 min) to give a yellow solid, which was separated by SFC (column: DAICEL CHIRALPAK AD (250 mm X30mm, 10 μm); mobile phase: 0.1% ammonia/ethanol; B%:20% -20%,3.9 min) to give: yellow solid (S) -1- ((2 ', 6-bis (difluoromethyl) - [2,4' -bipyridine ] -5-yl) oxo) -3- (3,3-difluorocyclobutyl) -2-methylpropan-2-amine (I-4) (43.6 mg, yield 27.8%).
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] + 。
Yellow solid (R) -1- ((2 ', 6-bis (difluoromethyl) - [2,4' -bipyridine ] -5-yl) oxo) -3- (3,3-difluorocyclobutyl) -2-methylpropan-2-amine (R-I-4) (45.0 mg, 28.1% yield).
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] +
Example 5: preparation of target Compound I-6
(2S) -1- (4- [2- (difluoromethyl) pyridin-4-yl)]-2- (pentafluoro- λ) 6 -mercapto) phenoxy) -2,4-dimethylpentan-2-amine (target compound I-6).
The synthetic route of the target compound I-6 is shown below:
the first step is as follows: 1-fluoro-4-nitro-2- (pentafluoro-lambda-ethyl) ketone 6 Synthesis of (mercapto) benzene
Reacting 1-fluoro-2- (pentafluoro-lambda-methyl) 6 Mercapto) benzene (2.50g, 11.3 mmol) was dissolved in concentrated sulfuric acid (25.0 mL), concentrated nitric acid (780 mg,12.3 mmol) was slowly added dropwise under ice-bath conditions, and the reaction solution was stirred at 25 ℃ for 3 hours after completion of the addition. After completion of the reaction, the reaction solution was slowly poured into crushed ice, followed by extraction with ethyl acetate (50.0 mL. Times.3), and the organic layers were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated to give 1-fluoro-4-nitro-2- (pentafluoro-. Lamda.) - 6 Mercapto) benzene (3.00 g, crude).
1 H NMR(400MHz,CDCl 3 )δ8.82-8.66(m,1H),8.46(td,1H),7.45(t,1H)。
The second step: 4-Nitro-2- (pentafluoro-lambda) 6 Synthesis of (mercapto) phenols
Reacting 1-fluoro-4-nitro-2- (pentafluoro-lambda-ethyl) 6 -mercapto) benzene (600mg, 2.26mmol) was dissolved in N, N-dimethylformamide (12.0 mL), potassium carbonate (625mg, 4.53mmol) was added to the solution, and after reaction at 25 ℃ for 30 minutes, the reaction solution was cooled to 0 ℃ and methyl iodide (642mg, 4.53mmol) was added dropwise, and finally the reaction solution was stirred at 25 ℃ for 12 hours. After the reaction is completed, the reaction solution is poured into crushed ice, and thenExtraction was performed with ethyl acetate (30.0 mL. Times.3), and the organic layers were combined, washed with saturated brine (50.0 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. Purifying the crude product by column chromatography (silica, petroleum ether: ethyl acetate = 5:1-3:1) to obtain 4-nitro-2- (pentafluoro-lambda) 6 Mercapto) phenol (442 mg, yield 69.9%).
1 H NMR(400MHz,DMSO)δ8.48(d,1H),8.34(dd,1H),7.28(d,1H)。
The third step: 1-methoxy-4-nitro-2- (pentafluoro-lambda) 6 Synthesis of (mercapto) benzene
Reacting 4-nitro-2- (pentafluoro-lambda-methyl) benzene with an alcohol 6 After (600mg, 2.26mmol) of-mercapto) phenol was dissolved in N, N-dimethylformamide (6.00 mL), potassium carbonate (625mg, 4.53mmol) was added thereto, nitrogen gas was substituted 3 times, and the reaction mixture was stirred at 25 ℃ for 0.5 hour. Methyl iodide (642mg, 4.53mmol) was then added dropwise at 0 ℃ and after completion of the addition, the reaction mixture was stirred at 25 ℃ for 12 hours. After completion of the reaction, the reaction solution was poured into ice water (30.0 mL), followed by extraction with ethyl acetate (20.0 mL. Times.3), and the organic phase was washed with brine (40.0 mL) and dried over anhydrous sodium sulfate, followed by filtration and concentration to give a crude product. Purifying the crude product by column chromatography (silica, petroleum ether: ethyl acetate = 5:1-3:1) to obtain 1-methoxy-4-nitro-2- (pentafluoro-lambda) 6 Mercapto-benzene (442 mg, 69.9% yield)
1 H NMR(400MHz,DMSO)δ8.59-8.40(m,2H),7.58(d,1H),4.07(s,3H)。
The fourth step: 4-methoxy-3- (pentafluoro-lambda) 6 Synthesis of (mercapto) anilines
1-methoxy-4-nitro-2- (pentafluoro-lambda) 6 -mercapto) benzene (440mg, 1.58mmol) was dissolved in ethanol (10.0 mL), palladium on carbon (10%, 44.0 mg) was added to the solution under nitrogen, and then nitrogen was usedThe reaction was carried out 3 times by gas exchange and carried out under hydrogen (50 PSI) at 30 ℃ for 15 hours. After the reaction is completed, the reaction solution is filtered by diatomite, the filtrate is concentrated to obtain a crude product, and the crude product is purified by column chromatography (silicon dioxide, petroleum ether: ethyl acetate = 8:1-6:1) to obtain 4-methoxy-3- (pentafluoro-lambda-f) 6 Mercapto) aniline (338 mg, yield 86.0%).
The fifth step: 4-bromo-1-methoxy-2- (pentafluoro-lambda) 6 Synthesis of (mercapto) benzene
Reacting 4-methoxy-3- (pentafluoro-lambda) 6 Mercapto) aniline (338mg, 1.36mmol) was dissolved in acetonitrile (4.00 mL), copper bromide (303mg, 1.36mmol) and tert-butyl nitrite (363mg, 3.53mmol) were added at 0 ℃ and the reaction mixture was stirred at 25 ℃ for 0.5 hour. After completion of the reaction, the reaction solution was poured into ice water (10.0 mL), followed by extraction with ethyl acetate (10.0 mL. Times.3), the organic phase was washed with brine (25.0 mL) and dried over anhydrous sodium sulfate, and then concentrated by filtration to give the crude product. Purifying the crude product by column chromatography (silica, petroleum ether: ethyl acetate = 5:1-3:1) to obtain 4-bromo-1-methoxy-2- (pentafluoro-lambda) 6 Mercapto) benzene (374 mg, yield 88.0%).
1 H NMR(400MHz,DMSO)δ7.96(d,1H),7.84(dd,1H),7.35(d,1H),3.93(s,3H)。
And a sixth step: 2- (difluoromethyl) -4- [ 4-methoxy-3- (pentafluoro- λ) 6 -mercapto) phenyl]Synthesis of pyridine
Reacting 4-bromo-1-methoxy-2- (pentafluoro-lambda) 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) were dissolved in tetrahydrofuran (5.00 mL) and water (1.00 mL), then chlorine (2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl) was added [2- (2-amino-1,1-biphenyl)]Palladium (93.9 mg, 119. Mu. Mol), nitrogenThe displacement was carried out three times, followed by stirring at 70 ℃ for 16 hours. After completion of the reaction, concentration under reduced pressure, extraction with water (10.0 mL) and then ethyl acetate (10.0 mL. Times.3), washing of the organic phase with brine (20.0 mL) and drying over anhydrous sodium sulfate, and concentration by filtration gave a crude product. The crude product was purified by column chromatography (silica, petroleum ether: ethyl acetate =5:1 to 3:1) to give 2- (difluoromethyl) -4- [ 4-methoxy-3- (pentafluoro- λ) 6 -mercapto) phenyl]Pyridine (280 mg, yield 55.0%).
LCMS,M/Z(ESI):261.9[M+H] +
The seventh step: 4- [2- (difluoromethyl) pyridin-4-yl]-2- (pentafluoro- λ) 6 Synthesis of (mercapto) phenols
Reacting 2- (difluoromethyl) -4- [ 4-methoxy-3- (pentafluoro-lambda-methyl) 6 -mercapto) phenyl]Pyridine (374 mg, 1.19mmol) was dissolved in glacial acetic acid (2.00 mL), aqueous hydrogen bromide (19mL, 40% percent purity) was added, and the reaction solution was stirred at 100 ℃ for 48 hours. After completion of the reaction, the reaction solution was poured into ice water (10.0 mL), followed by extraction with ethyl acetate (10.0 mL. Times.3), and the organic phase was washed with brine (25.0 mL) and dried over anhydrous sodium sulfate, followed by filtration and concentration to give a crude product. The crude product was purified by column chromatography (silica, petroleum ether: ethyl acetate =3:1 to 1:1) to give 4- [2- (difluoromethyl) pyridin-4-yl as a yellow solid]-2- (pentafluoro- λ) 6 Mercapto) phenol (117 mg, yield 61.7%).
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)。
Eighth step: n- [ (2S) -1- (4- [2- (difluoromethyl) pyridin-4-yl)]-2- (pentafluoro- λ) 6 -mercapto) phenoxy) -2,4-dimethylpentan-2-yl]Synthesis of tert-butyl carbamate
Reacting 4- [2- (difluoromethyl) pyridin-4-yl]-2- (penta)Fluorine-lambda 6 Mercapto) phenol (117mg, 336. Mu. Mol) and (S) -4-isobutyl-4-methyl-1,2,3-oxathiazolidine-3-carboxylic acid tert-butyl ester 2,2-dioxo (148mg, 505. Mu. Mol) were dissolved in N, N-dimethylformamide (2.00 mL), followed by addition of potassium carbonate (93.1mg, 674. Mu. Mol), and the reaction solution was stirred at 100 ℃ for 15 hours. After completion of the reaction, the reaction solution was poured into ice water (10.0 mL), followed by extraction with ethyl acetate (10.0 mL. Times.3), and the organic phase was washed with brine (25.0 mL) and dried over anhydrous sodium sulfate, followed by filtration and concentration to give a crude product. The crude product was purified by column chromatography (silica, petroleum ether: ethyl acetate =3:1 to 2:1) to give N- [ (2S) -1- (4- [2- (difluoromethyl) pyridin-4-yl) as a colorless oil]-2- (pentafluoro- λ) 6 -mercapto) phenoxy) -2,4-dimethylpentan-2-yl]Tert-butyl carbamate (30.0 mg, 5.32% yield).
LCMS,M/Z(ESI):561.0[M+H] +
The ninth step: (2S) -1- (4- [2- (difluoromethyl) pyridin-4-yl)]-2- (pentafluoro- λ) 6 Synthesis of (mercapto) -phenoxy) -2,4-dimethylpentan-2-amine (I-6)
Reacting N- [ (2S) -1- (4- [2- (difluoromethyl) pyridin-4-yl)]-2- (pentafluoro- λ) 6 -mercapto) phenoxy) -2,4-dimethylpentan-2-yl]Tert-butyl carbamate (30.0 mg, 53.5. Mu. Mol) was dissolved in ethyl acetate (2.00 mL), ethyl acetate hydrochloride (4M, 80.28. Mu.L) was then added, and the reaction mixture was stirred at 25 ℃ for 2 hours. After completion of the reaction, the pH was adjusted to 7 with a saturated sodium bicarbonate solution, followed by extraction with ethyl acetate (10.0 mL. Times.3), washing of the organic phase with brine (25.0 mL) and drying over anhydrous sodium sulfate, and concentration by filtration to give the crude product. The crude product is separated and purified by a reversed phase high performance liquid chromatography, and the separation method comprises the following steps: chromatography column Waters Xbridge 150X 25mm X5 μm; mobile phase of [ water (ammonia water v/v) -acetonitrile](ii) a B% is 53-83%, 9 min), obtaining (2S) -1- (4- [2- (difluoromethyl) pyridine-4-yl)]-2- (pentafluoro- λ) 6 -mercapto) phenoxy) -2,4-dimethylpentan-2-amine (I-6) (4.97 mg, 19.5% yield).
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)。
Example 6: preparation of target Compound I-12
(S) -1- ((8- (2- (difluoromethyl) pyridin-4-yl) imidazo [1,5-a ] pyridin-5-yl) oxo) -2,4-dimethylpentan-2-amine (I-12)
The synthetic route of the target compound I-12 is shown as follows:
the first step is as follows: synthesis of 3-bromo-2- (bromomethyl) -6-chloropyridine
3-bromo-6-chloro-2-methylpyridine (10.0g, 48.4mmol) was dissolved in 1,2-dichloroethane (100 mL), N-bromosuccinimide (9.48g, 53.3mmol) and azobisbutyronitrile (795mg, 4.84mmol) were further added, and the reaction solution was stirred at 70 ℃ for 2 hours. After completion of the reaction, the reaction solution was cooled to room temperature, water (100 mL) was added, extraction was performed with methylene chloride (100 mL. Times.3), the organic phases were combined, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give 3-bromo-2- (bromomethyl) -6-chloropyridine (13.0 g, crude product) as a yellow oil.
LC-MS,M/Z(ESI):285.9[M+H] + 。
The second step is that: synthesis of 2- (azidomethyl) -3-bromo-6-chloropyridine
3-bromo-2- (bromomethyl) -6-chloropyridine (12.0 g, 42.1mmol) was dissolved in N, N-dimethylformamide (60.0 mL), sodium azide (3.28g, 50.5 mmol) was added in portions, and the reaction solution was stirred at 25 ℃ for 2 hours under a nitrogen atmosphere. After the reaction was completed, water (100 mL) was added for dilution, extraction was performed with ethyl acetate (100 mL. Times.3), and the organic phases were combined, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to give 2- (azidomethyl) -3-bromo-6-chloropyridine (10.0 g, crude) as a yellow oil.
The third step: synthesis of (3-bromo-6-chloropyridin-2-yl) methylamine
2- (azidomethyl) -3-bromo-6-chloropyridine (10.0g, 40.4mmol) was dissolved in tetrahydrofuran (100 mL) and water (20.0 mL), and triphenylphosphine (21.2g, 80.8mmol) was slowly added and stirred at 50 ℃ for 2 hours. After the reaction was completed, it was diluted with water (100 mL), extracted with ethyl acetate (100 mL. Times.3), and the organic phases were combined, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to give (3-bromo-6-chloropyridin-2-yl) methylamine (6.30 g, crude) as a yellow oil.
LC-MS,M/Z(ESI):222.9[M+H] + 。
The fourth step: synthesis of N- ((3-bromo-6-chloropyridin-2-yl) methyl) formamide
(3-bromo-6-chloropyridin-2-yl) methylamine (6.00g, 27.1 mmol) was dissolved in formic acid (60.0 mL) and stirred at 100 ℃ for 12 h. After the reaction was completed, the reaction solution was concentrated to obtain N- ((3-bromo-6-chloropyridin-2-yl) methyl) formamide (6.50 g, crude) as a brown oil.
The fifth step: synthesis of 8-bromo-5-chloroimidazo [1,5-a ] pyridine
N- ((3-bromo-6-chloropyridin-2-yl) methyl) formamide (6.50g, 26.1mmol) was dissolved in toluene (65.0 mL), phosphorus oxychloride (11.9 g,78.2 mmol) was added slowly, and the mixture was stirred at 100 ℃ for 2 hours. After the reaction was completed, the reaction solution was concentrated and separated by a chromatography column (petroleum ether: ethyl acetate =10:1 to 5:1) to obtain 8-bromo-5-chloroimidazo [1,5-a ] pyridine (2.53 g, yield 41.9%) as a yellow solid.
1 H NMR(400MHz,CDCl 3 )δ8.37(s,1H),7.65(s,1H),6.94(d,1H),6.56(d,1H)。
LC-MS,M/Z(ESI):232.9[M+H] + 。
And a sixth step: synthesis of 5-chloro-8- (2- (difluoromethyl) pyridin-4-yl) imidazo [1,5-a ] pyridine
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) were dissolved in tetrahydrofuran (10.0 mL) and water (2.00 mL), and dichlorobis [ di-tert-butyl- (4-dimethylaminophenyl) phosphine ] palladium (II) (84.9mg, 108. Mu. Mol) and potassium phosphate (917mg, 4.32mmol) were added, nitrogen replaced 3 times, and stirring was carried out at 80 ℃ for 4 hours. After the reaction was completed, it was diluted with water (20.0 mL), extracted with ethyl acetate (20.0 mL. Times.3), the organic phase was concentrated, and separated by chromatography column (petroleum ether: ethyl acetate =5:1 to 2:1) to give 5-chloro-8- (2- (difluoromethyl) pyridin-4-yl) imidazo [1,5-a ] pyridine (7) (300 mg, yield 49.7%) as a yellow solid.
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] + 。
The seventh step: synthesis of (S) -1- ((8- (2- (difluoromethyl) pyridin-4-yl) imidazo [1,5-a ] pyridin-5-yl) oxo) -2,4-dimethylpentan-2-amine (I-12)
5-chloro-8- (2- (difluoromethyl) pyridin-4-yl) imidazo [1,5-a ] pyridine (100mg, 357. Mu. Mol) and (S) -2-amino-2,4-dimethylpentan-1-ol (46.9mg, 357. Mu. Mol) were dissolved in tetrahydrofuran solution (2.00 mL), a solution of potassium t-butoxide in tetrahydrofuran (1M, 0.893 mL) was added, and the reaction was stirred at 70 ℃ 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 chromatography column (dichloromethane: methanol = 10).
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] + 。
Example 7: preparation of target Compound I-18
(S) -1- (4- (2- (difluoromethyl) pyridin-4-yl) -2- (prop-1-yn-1-yl) phenoxy) -2,4-dimethylpentan-2-amine (I-18)
The synthesis route of the target compound I-18 is shown as follows:
the first step is as follows: synthesis of (S) - (1-hydroxy-2,4-dimethylpentan-2-yl) carbamic acid tert-butyl ester
To (2S) -2-amino-2,4-dimethyl-pentan-1-ol (3.07g, 23.4 mmol) in dichloromethane (40.0 mL) at room temperature was added di-tert-butyl carbonate (5.62g, 25.7 mmol) and the reaction was stirred at 25 ℃ for 0.5 h. After the reaction is finished, directly carrying out rotary evaporation and concentration to obtain a crude product. The crude product was subjected to column chromatography (petroleum ether: ethyl acetate 20:1 to 5:1) to give (S) - (1-hydroxy-2,4-dimethylpentan-2-yl) carbamic acid tert-butyl ester as a yellow oily liquid (5.02g, 92.4% yield).
The second step: synthesis of tert-butyl (4S) -4-isobutyl-4-methyl-1,2,3-oxathiazolidine-3-carboxylic acid ester 2-sulfoxide
A solution of thionyl chloride (432mg, 3.63mmol) in dichloromethane (3.00 mL) was slowly added dropwise to (S) - (1-hydroxy-2,4-dimethylpentan-2-yl) aminomethyl ester (600mg, 2.59mmol), triethylamine (787 mg, 7.78mmol), and imidazole (388mg, 5.71mmol) in dichloromethane (22.0 mL) at-10 ℃ and the reaction mixture was stirred at 10 ℃ for 3 hours. After the reaction, water was added to dilute the reaction mixture, followed by extraction with dichloromethane and organic phase drying and concentration to obtain tert-butyl (4S) -4-isobutyl-4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2-sulfoxide as a yellow oily liquid (660mg, 91.7% yield).
The third step: synthesis of tert-butyl (4S) -4-isobutyl-4-methyl-1,2,3-oxathiazolidine-3-carboxylic acid ester 2,2-sulfone
To a solution of tert-butyl (4S) -4-isobutyl-4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2-sulfoxide (650mg, 2.34mmol) in acetonitrile (12.0 mL) and water (2.00 mL) at 10 ℃ were added ruthenium trichloride (24.3mg, 117. Mu. Mol) and sodium periodate (651mg, 3.05mmol) in portions, and the reaction mixture was stirred at 25 ℃ for 4 hours. After the reaction, sodium sulfite aqueous solution was added to quench the reaction, the organic phase was concentrated, extracted with ethyl acetate, and the organic phase was dried and concentrated to give a crude product, which was separated by column chromatography (petroleum ether: ethyl acetate 1:0 to 30) to give (400mg, 58.2% yield.
The fourth step: synthesis of 2- (difluoromethyl) -4- (4-methoxyphenyl) pyridine
To a solution of 2- (4-methoxyphenyl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolan (2.97g, 12.7mmol), 4-bromo-2- (difluoromethyl) pyridine (2.40g, 11.5mmol), palladium bistriphenylphosphine dichloride (323mg, 461 μmol), potassium carbonate (3.19g, 23.1mmol) in dioxane (20.0 mL) was added water (3.00 mL) at room temperature, and the reaction liquid was stirred at 90 ℃ for 12 hours under nitrogen atmosphere. After the reaction was complete, it was diluted with water, extracted with ethyl acetate and the organic phase was concentrated to give crude 2- (difluoromethyl) -4- (4-methoxyphenyl) pyridine as a yellow oily liquid (2.61g, 76.7% yield).
LC-MS,M/Z(ESI):236.0[M+H] + 。
The fifth step: synthesis of 2- (difluoromethyl) -4- (3-iodo-4-methoxyphenyl) pyridine
To a solution of 2- (difluoromethyl) -4- (4-methoxyphenyl) pyridine (2.00g, 8.50mmol) and elemental iodine (2.37g, 9.35mmol) in acetonitrile (20.0 mL) was added a selective fluorine reagent (3.31g, 9.35mmol) at room temperature, and the reaction mixture was stirred at 25 ℃ for 16 hours. After the reaction was completed, sodium sulfite aqueous solution was added to quench the reaction, ethyl acetate was extracted, and the organic phase was concentrated to obtain 2- (difluoromethyl) -4- (3-iodo-4-methoxyphenyl) pyridine (3.00g, 97.7% yield) as a yellow oily liquid.
LC-MS,M/Z(ESI):361.8[M+H] + 。
And a sixth step: 4- (2- (difluoromethyl) pyridin-4-yl) -2-iodophenol
Boron tribromide (4.16g, 16.6 mmol) was added to 2- (difluoromethyl) -4- (3-iodo-4-methoxyphenyl) pyridine (3.00g, 8.31mmol) in dichloromethane (30.0 mL) at 0 ℃ and the reaction mixture was stirred at 25 ℃ for 12 hours. After the reaction was completed, the reaction solution was poured into a saturated sodium bicarbonate solution (60.0 mL), extracted with dichloromethane, and the organic phase was concentrated and dried to give a crude product, which was subjected to column chromatography (petroleum ether: ethyl acetate 10, 1 to 3:1) to give 4- (2- (difluoromethyl) pyridin-4-yl) -2-iodophenol (1.31g, 45.1% yield) as a white solid.
LC-MS,M/Z(ESI):348.1[M+H] + 。
The seventh step: synthesis of tert-butyl (S) - (1- (4- (2- (difluoromethyl) pyridin-4-yl) -2-iodophenoxy) -2,4-dimethylpentan-2-yl) carbamate
A solution of tert-butyl (4S) -4-isobutyl-4-methyl-2,2-dioxolidene-oxathiazolidine-3-carboxylate (120mg, 409. Mu. Mol), 4- (2- (difluoromethyl) pyridin-4-yl) -2-iodophenol (141mg, 409. Mu. Mol) in dimethylformamide (2.00 mL) was added to potassium carbonate (1699 mg, 1.23mmol) at room temperature, and the reaction mixture was stirred at 90 ℃ for 3 hours. After the reaction was completed, the reaction solution was poured into water (20.0 mL), extracted with ethyl acetate, the organic phase was concentrated and dried to give a crude product, and the crude product was isolated by chromatography plate (petroleum ether: ethyl acetate = 3:1) to give tert-butyl (S) - (1- (4- (2- (difluoromethyl) pyridin-4-yl) -2-iodophenoxy) -2,4-dimethylpentan-2-yl) aminomethyl ester as a white solid (120mg, 52.4% yield).
LC-MS,M/Z(ESI):561.3[M+H] + 。
Eighth step: synthesis of (S) -1- (4- (2- (difluoromethyl) pyridin-4-yl) -2-iodophenoxy) -2,4-dimethylpentan-2-amine
Trifluoroacetic acid (1.68g, 14.7 mmol) was added to a solution of tert-butyl (S) - (1- (4- (2- (difluoromethyl) pyridin-4-yl) -2-iodophenoxy) -2,4-dimethylpentan-2-yl) aminomethyl ester (120mg, 214. Mu. Mol) in dichloromethane (1.00 mL) at room temperature, and the reaction was stirred at 25 ℃ for 0.5 hour. After the reaction was complete, it was directly concentrated by rotary evaporation to give (S) -1- (4- (2- (difluoromethyl) pyridin-4-yl) -2-iodophenoxy) -2,4-dimethylpentan-2-amine (100mg, crede, TFA) as a yellow oily liquid.
LC-MS,M/Z(ESI):461.2[M+H] + 。
The ninth step: synthesis of (S) -1- (4- (2- (difluoromethyl) pyridin-4-yl) -2- (prop-1-yn-1-yl) phenoxy) -2,4-dimethylpentan-2-amine (I-18)
A solution of (S) -1- (4- (2- (difluoromethyl) pyridin-4-yl) -2-iodophenoxy) -2,4-dimethylpentan-2-amine (100mg, 217. Mu. Mol), propyne (1.00M, 4.00mL), cuprous iodide (16.5mg, 86.9. Mu. Mol), triethylamine (329mg, 3.26mmol), in tetrahydrofuran (1.00 mL) was replaced three times at room temperature under a nitrogen atmosphere and stirred at 40 ℃ for 1 hour. Directly filtering after the solution is finished, and concentrating the filtrate to obtain a crude product. The crude product was prepared in reverse phase (column: phenomenex Synergi C18X 25mm X10 μm; mobile phase: [ water (0.225% formic acid) -acetonitrile ]; B%:16% -46%,10 min) to give (S) -1- (4- (2- (difluoromethyl) pyridin-4-yl) -2- (prop-1-yn-1-yl) phenoxy) -2,4-dimethylpentan-2-amine formate (I-18) (40.0mg, 43.5% yield) as a yellow solid.
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] + 。
Example 8: preparation of target Compound I-21
(S) -1- ((8- (2- (difluoromethyl) pyridin-4-yl) imidazo [1,2-a ] pyridin-5-yl) oxo) -2,4-dimethylpentan-2-amine (target compound I-21).
The synthetic route of the target compound I-21 is shown below:
the first step is as follows: synthesis of 8-bromo-5-chloroimidazo [1,2-a ] pyridine
3-bromo-6-chloropyridin-2-amine (0.5g, 2.41mmol) was dissolved in ethanol (5.00 mL), 2-chloroacetaldehyde (946 mg, 4.82mmol) was added, and the reaction mixture was stirred at 50 ℃ for 16 hours. After completion of the reaction, the reaction mixture was concentrated, then dissolved in water (8.00 mL), adjusted to pH 7-9 with a saturated sodium bicarbonate solution, extracted with ethyl acetate (10.0 mL. Times.3), the organic layers were combined, the organic phase was washed with a saturated saline solution (10.0 mL), dried over anhydrous sodium sulfate, and concentrated to give a crude product. The crude product was purified by column chromatography (silica gel, ethyl acetate: petroleum ether =5:1 to 2:1) to give 8-bromo-5-chloroimidazo [1,2-a ] pyridine as a pale yellow solid (450 mg, 80.6% yield).
LC-MS,M/Z(ESI):232.9[M+H] +
The second step is that: synthesis of 5-chloro-8- (2- (difluoromethyl) pyridin-4-yl) imidazo [1,2-a ] pyridine
8-bromo-5-chloroimidazo [1,2-a ] pyridine (200mg, 864 μmol) and 2- (difluoromethyl) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine (441mg, 1.73mmol) were dissolved in a solution of tetrahydrofuran (8.00 mL) and water (2.00 mL), followed by addition of potassium phosphate (550mg, 2.59mmol) and [2- (2-aminophenyl) phenyl ] -chloro-palladium; dicyclohexyl- [3- (2,4,6-triisopropylphenyl) phenyl ] phosphane (68.0 mg, 86.4. Mu. Mol), which was then replaced with nitrogen gas 3 times, reacted at 75 ℃ for 16 hours. After completion of the reaction, the reaction mixture was concentrated to remove tetrahydrofuran, and then dissolved in water (5.00 mL) and ethyl acetate (8.00 mL), the organic phase was separated, the aqueous phase was extracted with ethyl acetate (8.00 mL. Times.3), the organic phases were combined, washed with brine (20.0 mL) and dried over anhydrous sodium sulfate, and 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) followed by 5-chloro-8- (2- (difluoromethyl) pyridin-4-yl) imidazo [1,2-a ] pyridine as a yellow oil (211 mg, 43.57% yield).
LC-MS,M/Z(ESI):280.0[M+H] +
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)
5-chloro-8- (2- (difluoromethyl) pyridin-4-yl) imidazo [1,2-a ] pyridine (130mg, 232. Mu. Mol) and (S) -2-amino-2,4-dimethylpentan-1-ol (45.7 mg, 348. Mu. Mol) were dissolved in tetrahydrofuran (4.00 mL), followed by addition of potassium tert-butoxide solution (1.00M, 278. Mu.L) and the reaction stirred at 70 ℃ for 2 hours. After completion of the reaction, the reaction solution was poured into water, followed by extraction with ethyl acetate, and the organic phase was washed with brine (20.0 mL) and dried over anhydrous sodium sulfate, and then concentrated by filtration to give a crude product. Separating and purifying the crude product by silica gel chromatography plate (silica gel, ethyl acetate: petroleum ether = 1:1) and reversed phase high performance liquid chromatography, the separation method comprises: chromatography column Waters Xbridge 150X 25mm X5 μm; mobile phase [ water (ammonium hydroxide v/v) -ACN ]; and B% is 32% -62%, and the white solid (S) -1- ((8- (2- (difluoromethyl) pyridine-4-yl) imidazo [1,2-a ] pyridine-5-yl) oxo) -2,4-dimethylpentan-2-amine (2.65 mg, 3.05% yield) is obtained after 9 min.
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] + 。
Example 9: preparation of target Compound I-24
4- (((S) -2-amino-2,4-dimethylpentyl) oxo) -1- (2- (difluoromethyl) pyridin-4-yl) piperidin-2-one (I-24)
The synthetic route of the target compound I-24 is shown as follows:
the first step is as follows: synthesis of tert-butyl (S) - (1- ((2 '- (difluoromethyl) -2-oxoidene-2H- [1,4' -bipyridine ] -4-yl) oxo) -2,4-dimethylpentan-2-yl) carbamate
To a solution of 1- [2- (difluoromethyl) -4-pyridyl ] -4-hydroxy-pyridin-2-one (300mg, 1.26mmol) and tert-butyl (S) -4-isobutyl-4-methyl-oxathiazolidine 2,2-sulfone dioxide (267mg, 1.39mmol) in N, N dimethylformamide (6.00 mL) at room temperature was added potassium carbonate (435mg, 3.15mmol), and the reaction mixture was stirred at 100 ℃ for 3 hours. After the reaction was completed, water (10 mL) was added to dilute the reaction solution, and the organic phase was extracted with ethyl acetate (20.0 mL. Times.3), dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl (S) - (1- ((2 '- (difluoromethyl) -2-oxoylidene-2H- [1,4' -bipyridin ] -4-yl) oxo) -2,4-dimethylpentan-2-yl) carbamate as a yellow oily liquid (290mg, 51.0% yield).
LC-MS,M/Z(ESI):452.2[M+H] + 。
The second step is that: synthesis of tert-butyl ((2S) -1- ((1- (2- (difluoromethyl) pyridin-4-yl) -2-oxidenidopiperidin-4-yl) oxo) -2,4-dimethylpentan-2-yl) carbamate
Tert-butyl (S) - (1- ((2 '- (difluoromethyl) -2-oxoidene-2H- [1,4' -bipyridin ] -4-yl) oxo) -2,4-dimethylpentan-2-yl) carbamate (250mg, 553. Mu. Mol) was dissolved in methanol (6.00 mL), palladium on charcoal (100 mg) was added, and the reaction solution was reacted at 25 ℃ under a hydrogen atmosphere (50 Psi) for 16 hours. After the reaction was completed, it was diluted with methanol (15.0 mL), filtered through celite, and concentrated to give t-butyl ((2S) -1- ((1- (2- (difluoromethyl) pyridin-4-yl) -2-oxoylidenepiperidin-4-yl) oxo) -2,4-dimethylpentan-2-yl) carbamate as a yellow oily liquid (300 mg, crude).
LC-MS,M/Z(ESI):456.3[M+H] + 。
The third step: synthesis of 4- (((S) -2-amino-2,4-dimethylpentyl) oxo) -1- (2- (difluoromethyl) pyridin-4-yl) piperidin-2-one (I-24)
Trifluoroacetic acid (1.54g, 13.5 mmol) was added to t-butyl ((2S) -1- ((1- (2- (difluoromethyl) pyridin-4-yl) -2-oxoylidenepiperidin-4-yl) oxo) -2,4-dimethylpentan-2-yl) carbamate (300mg, 658. Mu. Mol) in dichloromethane (1.00 mL) at room temperature, the reaction was stirred at 25 ℃ for 0.5 hour, the crude product was directly concentrated after the completion of the reaction, and the crude product was prepared by reverse phase (column: phenomenex Synergi C18X 25mm X10. Mu.m; mobile phase: [ water (0.225% formic acid) -acetonitrile ]; B%:7% -37%,10 min) and purified to give 4- (((S) -2-amino-2,4-dimethylpentyl) oxo) -1- (2- (difluoromethyl) pyridin-4-yl) piperidin-2-one (I-24) (yield 20.0mg, 7.19%).
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] + 。
Example 10: preparation of target Compound I-25
(S) -1- ((8- (2- (difluoromethyl) pyridin-4-yl) quinolin-5-yl) oxo) -2,4-dimethylpentan-2-amine (target compound I-25).
The synthetic route of the target compound I-25 is shown below:
the first step is as follows: synthesis of 8- (2- (difluoromethyl) pyridin-4-yl) -5-methoxyquinoline
8-bromo-5-methoxyquinoline (500mg, 2.10 mmol) and 2- (difluoromethyl) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine (1.07g, 4.20 mmol) were dissolved in tetrahydrofuran (10.0 mL), and then chlorine (2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl) [2- (2-amino-1,1-biphenyl) ] palladium (II) (165mg, 210. Mu. Mol) and potassium phosphate (1.34g, 6.30mmol) were added thereto, followed by substitution with nitrogen gas three times, and the reaction solution was stirred at 75 ℃ for 16 hours. After completion of the reaction, 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. Times.3), the organic phases were combined, the organic phase was washed with a saturated saline solution (30.0 mL) and dried over anhydrous sodium sulfate, and filtered and concentrated to give a crude product. The pH was adjusted to 7 to 9 with a saturated sodium bicarbonate solution, followed by extraction with ethyl acetate (10.0 mL. Times.3), and the organic layers were combined, washed with a saturated saline solution (10.0 mL), dried over anhydrous sodium sulfate, and concentrated to give a crude product. The crude product was purified by column chromatography (silica gel, ethyl acetate: petroleum ether =5:1 to 3:1) to give 8- (2- (difluoromethyl) pyridin-4-yl) -5-methoxyquinoline (490 mg, 78.4% yield).
LC-MS,M/Z(ESI):287.1[M+H] +
The second step is that: synthesis of 8- (2- (difluoromethyl) pyridin-4-yl) quinolin-5-ol
8- (2- (difluoromethyl) pyridin-4-yl) -5-methoxyquinoline (490mg, 1.71mmol) was dissolved in a dichloromethane (5.00 mL) solution, and boron tribromide (1.29g, 5.13mmol) was added to the solution at 0 ℃ and then replaced with nitrogen gas 3 times, and reacted at 25 ℃ for 12 hours. After completion of the reaction, the reaction solution was poured into water (10.0 mL) at 25 ℃, the pH of the reaction solution was adjusted to 9 with a saturated sodium bicarbonate solution, and then extracted with dichloromethane (25.0 mL. Times.3), and the organic phase was washed with brine and dried over anhydrous sodium sulfate, and then concentrated by filtration to give 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) quinolin-5-ol (160 mg, 31.42% yield).
LC-MS,M/Z(ESI):273.0[M+H] +
The third step: synthesis of tert-butyl (S) - (1- ((8- (2- (difluoromethyl) pyridin-4-yl) quinolin-5-yl) oxo) -2,4-dimethylpentan-2-yl) carbamate
8- (2- (difluoromethyl) pyridin-4-yl) quinolin-5-ol (100mg, 367. Mu. Mol) and (S) -4-isobutyl-4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxo (129mg, 441. Mu. Mol) were dissolved in a solution of N, N-dimethylformamide (2.00 mL), potassium carbonate (102mg, 735. Mu. Mol) was added to the reaction solution, and the reaction was stirred at 25 ℃ for 3 hours. After completion of the reaction, the reaction solution was poured into water, followed by extraction with ethyl acetate (15.0 mL. Times.3), the organic phase was washed with brine (20.0 mL) and dried over anhydrous sodium sulfate, and then concentrated by filtration to give the crude product. The crude product was purified on a silica gel chromatography plate (silica gel, ethyl acetate: petroleum ether = 3:1) to give (S) - (1- ((8- (2- (difluoromethyl) pyridin-4-yl) quinolin-5-yl) oxo) -2,4-dimethylpentan-2-yl) carbamic acid tert-butyl ester as a white solid (80.0 mg,159 μmol, 43.1% yield).
LC-MS,M/Z(ESI):486.2[M+H] +
The fourth step: synthesis of (S) -1- ((8- (2- (difluoromethyl) pyridin-4-yl) quinolin-5-yl) oxo) -2,4-dimethylpentan-2-amine (I-25)
Tert-butyl (1- ((8- (2- (difluoromethyl) pyridin-4-yl) quinolin-5-yl) oxo) -2,4-dimethylpentan-2-yl) carbamate (73.0 mg, 150. Mu. Mol.) was dissolved in 1,4-dioxane (2.00 mL), hydrochloric acid/1,4-dioxane solution (4M, 376. Mu.L) was added, and the reaction was stirred at 25 ℃ for 8 hours. After completion of the reaction, the pH was adjusted to 7 to 9 with a saturated sodium bicarbonate solution, followed by extraction with ethyl acetate (10.0 mL. Times.3), washing of the organic phase with brine (20.0 mL) and drying over anhydrous sodium sulfate, filtration and concentration to give (S) -1- ((8- (2- (difluoromethyl) pyridin-4-yl) quinolin-5-yl) oxo) -2,4-dimethylpentan-2-amine (46.4 mg, 90.6% yield).
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] +
Example 11: preparation of target Compound 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)
The synthetic route for the target compound I-27 is shown below:
the first step is as follows: synthesis of N-methyl-2-nitropyridine-3-amine
3-fluoro-2-nitro-pyridine (9.00g, 63.3 mmol) was dissolved in tetrahydrofuran (90.0 mL), and cesium carbonate (82.5g, 253mmol) and methylamine hydrochloride (17.1g, 253mmol) were added in this order under nitrogen protection, followed by reaction at room temperature for 2 hours. The reaction was quenched with water (100 mL), extracted with ethyl acetate (450 mL), and the organic phase was washed with saturated brine (300 mL), dried over sodium sulfate, and concentrated to give the crude N-methyl-2-nitropyridin-3-amine compound as a yellow solid (11.0 g, crude).
1 H 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)。
The second step is that: synthesis of 4-bromo-N-methyl-2-nitropyridine-3-amine
N-methyl-2-nitropyridin-3-amine (10.0 g,65.3 mmol) was dissolved in acetic acid (100 mL), potassium acetate (6.41g, 65.3 mmol) was added and reacted at room temperature for 1 hour, then bromine (10.4 g,65.3 mmol) was slowly added dropwise, stirred for 2 hours, filtered, washed and the filter cake was concentrated to give 4-bromo-N-methyl-2-nitropyridin-3-amine as a yellow solid (11.2 g, crude).
LC-MS,M/Z:234.0[M+H] + 。
The third step: synthesis of 4-bromo-N3-methylpyridine-2,3-diamine
4-bromo-N-methyl-2-nitropyridin-3-amine (10.0 g,49.2 mmol) was dissolved in ethanol (100 mL), tin dichloride (33.3 g, 147mmol) was added, and the reaction was stirred at 70 ℃ for 2 hours under nitrogen. The reaction was filtered and washed with ethanol, the filter cake was concentrated to give the crude brown oil compound 4-bromo-N3-methylpyridine-2,3-diamine (4.00 g, crude).
LC-MS,M/Z:174.1[M+H] + 。
The fourth step: synthesis of 7-bromo-1-methyl-1,3-dihydro-2H-imidazo [4,5-b ] pyridin-2-one
4-bromo-N3-methylpyridine-2,3-diamine (3.00g, 14.8mmol) was dissolved in tetrahydrofuran (30.0 mL), 1,1-carbonyldiimidazole (4.82g, 29.7 mmol) was added, and the reaction was stirred at 80 ℃ for 8 hours under nitrogen. The reaction was filtered, washed with ethyl acetate, the filter cake was concentrated and purified by slurrying with ethyl acetate to give 7-bromo-1-methyl-1,3-dihydro-2H-imidazo [4,5-b ] pyridin-2-one as an off-white solid (2.20 g, 64.9% yield).
1 H NMR(400MHz,DMSO-d 6 )δ11.79(br s,1H),7.39(d,1H),7.22(d,1H),3.27(s,3H)。
LC-MS,M/Z:230.0[M+H] + 。
The fifth step: synthesis of 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
7-bromo-1-methyl-1,3-dihydro-2H-imidazo [4,5-b ] pyridin-2-one (1.10 g, 4.82mmol) was dissolved in N, N-dimethylformamide (50.0 mL), and bis pinacolborate (1.47g, 5.79mmol), [1,1-bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane (196mg, 241. Mu. Mol), potassium acetate (946mg, 9.65mmol) was added under nitrogen protection and reacted at 100 ℃ for 12 hours. Filtered while hot, then washed with ethyl acetate, dried over sodium sulfate, and concentrated to give the crude product as a brown oil, 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 (1.00 g, crude).
LC-MS,M/Z(ESI):276.1[M+H] + 。
And a sixth step: synthesis of 7- (6- (difluoromethyl) -5-fluoropyridin-2-yl) -1-methyl-1,3-dihydro-2H-imidazo [4,5-b ] pyridin-2-one
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 (10.0 ml), 6-bromo-2- (difluoromethyl) -3-fluoro-pyridine (410mg, 1.82mmol), potassium phosphate (1.1lg, 5.45mmol), [1,1-bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane (74.2mg, 90.8. Mu. Mol) was added under nitrogen protection, and reacted at 90 ℃ for 12 hours. Water (20.0 mL) was added, followed by extraction with ethyl acetate (60.0 mL), washing with saturated brine (60.0 mL), drying over sodium sulfate, and concentration to give a crude product, which was purified by separation with a silica gel column (petroleum ether: ethyl acetate (V/V) = 10-2:1) to give 7- (6- (difluoromethyl) -5-fluoropyridin-2-yl) -1-methyl-1,3-dihydro-2H-imidazo [4,5-b ] pyridin-2-one (100 mg, 9.35% yield) as a yellow solid.
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] + 。
The seventh step: synthesis of (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)
7- (6- (difluoromethyl) -5-fluoropyridin-2-yl) -1-methyl-1,3-dihydro-2H-imidazo [4,5-b ] pyridin-2-one (100mg, 339. Mu. Mol) was dissolved in tetrahydrofuran (1.00 ml) and (2S) -2-amino-2,4-dimethyl-pentan-1-ol (44.6 mg, 339. Mu. Mol), potassium tert-butoxide (1.1lg, 5.45mmol) was added under nitrogen for 2 hours at 70 ℃. Adding saturated sodium bicarbonate solution to adjust pH to 8, extracting with ethyl acetate (15.0 mL), washing with saturated brine (15.0 mL), drying over anhydrous sodium sulfate, filtering, concentrating, and purifying with chromatographic column Waters Xbridge 150X 25mm X5 μm; mobile phase: a = water +0.225 vol% ammonia (99%), B = acetonitrile; gradient: 25% -58% and purified at 9min to obtain the product (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) as a white solid (120 mg, 9.35% yield).
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] + 。
Example 12: preparation of object Compound I-29
(S) -1- ((2 ', 6-bis (difluoromethyl) - [2,4' -bipyridine ] -5-yl) oxo) -3- (1-fluorocyclopropyl) -2-methylpropan-2-amine (I-29)
(R) -1- ((2 ', 6-bis (difluoromethyl) - [2,4' -bipyridine ] -5-yl) oxo) -3- (1-fluorocyclopropyl) -2-methylpropan-2-amine (R-I-29)
The synthesis route of the target compound I-29 is shown as follows:
the first step is as follows: synthesis of (1-fluorocyclopropyl) methanol
1-fluorocyclopropylformic acid (8.00g, 76.9 mmol) was dissolved in tetrahydrofuran (80.0 mL), the reaction solution was cooled to 0 ℃, lithium aluminum hydride (3.21g, 84.5 mmol) was added in portions, and after the addition was completed, the temperature was raised to 30 ℃ to react for 2 hours. After the reaction, the reaction solution was cooled to 0 ℃ and quenched by slowly dropping water (3.50 mL) under nitrogen, followed by addition of anhydrous sodium sulfate, drying for 15 minutes, and filtration, and the filtrate was used in the next step directly.
The second step is that: synthesis of (1-fluorocyclopropyl) methyl methanesulfonate
A tetrahydrofuran solution of (1-fluorocyclopropyl) methanol was cooled to 0 ℃ and triethylamine (16.0 g, 144mmol) and methanesulfonic anhydride (15.1g, 86.6 mmol) were added to stir the reaction mixture at 25 ℃ for 2 hours under a nitrogen atmosphere. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with water (100 mL), extracted with ethyl acetate (100 mL. Times.3), and the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to give (1-fluorocyclopropyl) methylmethanesulfonate ester (4.20 g, crude) as a yellow oil.
1 H NMR(400MHz,CDCl 3 )δ4.37-4.59(m,2H),3.11(s,3H),1.24(dt,2H),0.87(q,2H)。
The third step: synthesis of diethyl 2- ((1-fluorocyclopropyl) methyl) malonate
Diethyl malonate (4.00g, 25.0 mmol) was dissolved in tetrahydrofuran (40.0 mL), and after cooling to 0 deg.C, sodium hydride (1.90g, 50.0 mmol) was added in portions, and stirring was performed at 0 deg.C for 1 hour, followed by addition of (1-fluorocyclopropyl) methyl methanesulfonate (5.00g, 30.0 mmol) and potassium iodide (8.30g, 50.0 mmol), and the reaction solution was heated to 70 deg.C for 12 hours. After the reaction was completed, the reaction solution was cooled to room temperature, diluted with water (100 mL), extracted with ethyl acetate (100 mL × 3), and the organic phases were combined, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was purified by a chromatography column (silica, petroleum ether: ethyl acetate =20 to 10) to obtain diethyl 2- ((1-fluorocyclopropyl) methyl) malonate (3.20 g, yield: 55.2%) as a yellow oil.
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)。
The fourth step: synthesis of 2- ((1-fluorocyclopropyl) methyl) -2-methyl diethyl malonate
Diethyl 2- ((1-fluorocyclopropyl) methyl) malonate (3.00g, 12.5 mmol) was dissolved in tetrahydrofuran (30.0 mL), cooled to 0 ℃, sodium hydride (1.03mg, 25.8mmol) was added in portions, stirred at 0 ℃ for 1 hour, iodomethane (5.30g, 38.7 mmol) was added, and the reaction solution was heated to 70 ℃ for reaction for 12 hours. After the reaction was completed, the reaction solution was cooled to room temperature, diluted with water (100 mL), extracted with ethyl acetate (100 mL × 3), and the organic phases were combined, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to give 2- ((1-fluorocyclopropyl) methyl) -2-methylmalonic acid diethyl ester (2.90 g, crude product) as a yellow oil.
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)。
The fifth step: synthesis of 3-ethoxy-2- ((1-fluorocyclopropyl) methyl) -2-methyl-3-oxopropanoic acid
Diethyl 2- ((1-fluorocyclopropyl) methyl) -2-methylmalonate (2.40g, 9.75mmol) was dissolved in tetrahydrofuran (24.0 mL) and water (8.00 mL), potassium hydroxide (656 mg,11.7 mmol) was added, and the reaction solution was heated to 65 ℃ for 12 hours. After the reaction was completed, the reaction solution was cooled to room temperature, 1M diluted hydrochloric acid was added to adjust pH to 3 to 4, and extracted with ethyl acetate (20 mL × 3), the organic phases were combined, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated to obtain a crude product, and the crude product was purified by a chromatography column (silica, petroleum ether: ethyl acetate =5:1 to 2:1) to obtain 3-ethoxy-2- ((1-fluorocyclopropyl) methyl) -2-methyl-3-oxopropanoic acid (1.56 g, yield: 73.2%) as a yellow oily substance.
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)。
And a sixth step: synthesis of ethyl 3-amino-2- ((1-fluorocyclopropyl) methyl) -2-methyl-3-oxopropanoate
3-ethoxy-2- ((1-fluorocyclopropyl) methyl) -2-methyl-3-oxopropanoic acid (1.50g, 6.87mmol) and triethylamine (765mg, 7.56mmol) were dissolved in tetrahydrofuran (15.0 mL), the reaction mixture was cooled to-10 ℃ and isobutyl chloroformate (938mg, 6.87mmol) was slowly added dropwise, and after 1 hour of reaction, ammonia (2.19g, 20.6mmol) was added and the reaction was carried out at 0 ℃ for 2 hours. After completion of the reaction, water (20.0 mL) was added to the reaction solution, extracted with ethyl acetate (20 mL × 3), and the organic phases were combined, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated to give ethyl 3-amino-2- ((1-fluorocyclopropyl) methyl) -2-methyl-3-oxopropanoate as a yellow oil (1.23 g, crude product).
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)。
The seventh step: synthesis of ethyl 2-amino-3- (1-fluorocyclopropyl) -2-methylpropionate
Ethyl 3-amino-2- ((1-fluorocyclopropyl) methyl) -2-methyl-3-oxopropanoate (1.20g, 5.52mmol) was dissolved in toluene (12.0 mL), diacetoxyiodobenzene (1.78g, 5.52mmol) was added, the reaction mixture was heated to 45 ℃ for reaction for 2 hours, 4M diluted hydrochloric acid (4.60 mL) was added, and the reaction was continued at 45 ℃ for 12 hours. After the reaction was completed, the reaction solution was cooled to room temperature, liquid was separated, the pH of the aqueous phase was adjusted to 10 to 11 with 1M sodium hydroxide, extracted with ethyl acetate (20 mL × 3), and the organic phases were combined, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated and concentrated to obtain a yellow oily ethyl 2-amino-3- (1-fluorocyclopropyl) -2-methylpropionate (0.58 g, crude product).
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)。
Eighth step: synthesis of 2-amino-3- (1-fluorocyclopropyl) -2-methylpropan-1-ol
Ethyl 2-amino-3- (1-fluorocyclopropyl) -2-methylpropionate (580mg, 3.07mmol) was dissolved in tetrahydrofuran (10.0 mL), the reaction mixture was cooled to 0 ℃ and lithium aluminum hydride (233mg, 6.13mmol) was added in portions, and after the addition was completed, the temperature was raised to 25 ℃ to react for 2 hours. After the reaction, the reaction solution was cooled to 0 ℃, quenched by slowly dropping water (3.50 mL) under nitrogen, dried for 15 minutes by adding anhydrous sodium sulfate, filtered, concentrated to obtain a yellow oily 2-amino-3- (1-fluorocyclopropyl) -2-methylpropan-1-ol (0.35 g, crude product).
The ninth step: (S) -1- ((2 ', 6-bis (difluoromethyl) - [2,4' -bipyridine ] -5-yl) oxo) -3- (1-fluorocyclopropyl) -2-methylpropan-2-amine (I-29)
(R) -1- ((2 ', 6-bis (difluoromethyl) - [2,4' -bipyridine ] -5-yl) oxo) -3- (1-fluorocyclopropyl) -2-methylpropan-2-amine (R-I-29)
2', 6-bis (difluoromethyl) -5-fluoro-2,4' -bipyridine (558mg, 2.04. Mu. Mol) and 2-amino-3- (1-fluorocyclopropyl) -2-methylpropan-1-ol (300mg, 2.04. Mu. Mol) were dissolved in tetrahydrofuran (10.0 mL), and a 1M solution of potassium tert-butoxide in tetrahydrofuran (8.15 mL) was added to stir the reaction at 70 ℃ for 1 hour. After the reaction was completed, water (20.0 mL) was added to the reaction solution, extracted with ethyl acetate (20 mL × 3), the organic phases were combined, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product, which was resolved through a chromatography column (silica, ethyl acetate: methanol =50:1 to 20) and a chiral column (chromatography column: daicel ChiralPak IG (250 × 30mm,10 μm); mobile phase: [0.1% ammonia-methanol ]; B%:30% -30%,3.6 min) to give (S) -1- ((2 ', 6-bis (difluoromethyl) - [2,4' -bipyridinyl ] -5-yl) oxo) -3- (1-fluorocyclopropyl) -2-methylpropan-2-amine (I-29) (99.4 mg, yield: 19.1%) and (R) -1- ((2 ', 6-bis (difluoromethyl) - [ 3262 zxft 3238' -bipyridinyl ] -5-yl) oxo) -3- (1-fluorocyclopropyl) -2-methylpropan-amine (I-29) (99.4 mg, yield: 19.1%) as a white solid and (R) -1- ((2 ', 6-bis (difluoromethyl) - [ 3262 zxft) - [ 5' -bipyridinyl) -2-oxo) -2-propyl) -2-amino (I-1) (yield: 112mg, 21 mg).
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)。
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] + 。
Example 13: preparation of object Compounds I-34, I-35
(S) -1- (3,3-difluorocyclobutyl) -3- ((8- (2- (difluoromethyl) pyridin-4-yl) imidazo [1,2-a ] pyridin-5-yl) oxo) -2-methylpropan-2-amine (I-34)
(R) -1- (3,3-difluorocyclobutyl) -3- ((8- (2- (difluoromethyl) pyridin-4-yl) imidazo [1,2-a ] pyridin-5-yl) oxo) -2-methylpropan-2-amine (I-35)
The synthetic routes of the target compounds I-34 and I-35 are shown as follows:
the first step is as follows: synthesis of 8-bromo-5-chloroimidazo [1,2-a ] pyridine
3-bromo-6-chloropyridin-2-amine (1.00g, 4.82mmol) was dissolved in ethanol (10.0 mL), and then 2-chloroacetaldehyde (1.89g, 9.64mmol) and sodium bicarbonate (810mg, 9.64mmol) were added, and the reaction was stirred at 50 ℃ for 16 hours under nitrogen. After completion of the reaction, the solvent was removed by concentration under reduced pressure, dissolved in water (20.0 mL), adjusted to pH 7 to 9 with 1M hydrochloric acid, then extracted with ethyl acetate (15.0 mL. Times.3), the organic phase was washed with a saturated sodium chloride solution (40.0 mL) and dried over anhydrous sodium sulfate, and then filtered and concentrated to give a crude product. The crude product was purified by column chromatography (silica gel, petroleum ether: ethyl acetate =5:1 to 2:1) to give 8-bromo-5-chloroimidazo [1,2-a ] pyridine (655mg, 2.64mmol, 54.7% yield).
LCMS,M/Z(ESI):233.1[M+2H] +
The second step: synthesis of 5-chloro-8- (2- (difluoromethyl) pyridin-4-yl) imidazo [1,2-a ] pyridine (3)
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 (3970 mg, 1.56mmol), potassium carbonate (430mg, 3.11mmol) were dissolved in 1,4-dioxane (4.00 mL) and water (1.00 mL), followed by dichloro bis [ di-tert-butyl- (4-dimethylaminophenyl) phosphine ] palladium (II) (110mg, 156. Mu. Mol), nitrogen substitution three times, and the reaction stirred at 80 ℃ for 2 hours. After completion of the reaction, the solvent was removed by concentration under reduced pressure, diluted with water (20.0 mL), extracted with ethyl acetate (15.0 mL. Times.3), the organic phase was washed with a saturated sodium chloride solution (40.0 mL) and dried over anhydrous sodium sulfate, and then concentrated by filtration to give a crude product. The crude product was purified by column chromatography (silica gel, petroleum ether: ethyl acetate =5:1 to 3:1) to give 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] +
The third step: synthesis of 1- (3,3-difluorocyclobutyl) -3- ((8- (2- (difluoromethyl) pyridin-4-yl) imidazo [1,2-a ] pyridin-5-yl) oxo) -2-methylpropan-2-amine
5-chloro-8- (2- (difluoromethyl) pyridin-4-yl) imidazo [1,2-a ] pyridine (160mg, 572. Mu. Mol) and 2-amino-3- (3,3-difluorocyclobutyl) -2-methylpropan-1-ol (154mg, 858. Mu. Mol) were dissolved in tetrahydrofuran (3.00 mL), followed by addition of a potassium tert-butoxide solution (1.00M, 2.29mL) and stirring of the reaction solution at 50 ℃ for 1 hour. After completion of the reaction, it was quenched with water (10.0 mL), then extracted with ethyl acetate (10.0 mL. Times.3), the organic phase was washed with saturated sodium chloride solution (20.0 mL) and dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. The crude product is separated and purified by a reversed phase high performance liquid chromatography, and the purification method comprises the following steps: chromatographic column 3 \ u Phenomenex Luna C18X 30mm X3 μm; mobile phase [ water (HCl) -ACN ]; and B% is 3% -23%, and the product is purified for 8min to obtain 1- (3,3-difluorocyclobutyl) -3- ((8- (2- (difluoromethyl) pyridin-4-yl) imidazo [1,2-a ] pyridin-5-yl) oxo) -2-methylpropan-2-amine (100 mg, yield 39.3%).
LCMS,M/Z(ESI):423.2[M+H] +
The fourth step: (S) -1- (3,3-difluorocyclobutyl) -3- ((8- (2- (difluoromethyl) pyridin-4-yl) imidazo [1,2-a ] pyridin-5-yl) oxo) -2-methylpropan-2-amine (I-34)
Preparation of (R) -1- (3,3-difluorocyclobutyl) -3- ((8- (2- (difluoromethyl) pyridin-4-yl) imidazo [1,2-a ] pyridin-5-yl) oxo) -2-methylpropan-2-amine (I-35)
Racemic 1- (3,3-difluorocyclobutyl) -3- ((8- (2- (difluoromethyl) pyridin-4-yl) imidazo [1,2-a)]Pyridine-5-yl) oxo) -2-methylpropane-2-amine (100mg, 225 μmol) was resolved by normal phase chiral chromatography column, the resolution method was: column DAICEL CHIRALPAK IG (250 mm × 30mm,10 μm); mobile phase [0.1% 3 H 2 O MEOH](ii) a 45 to 45 percent of B percent and 5.1min to obtain (S) -1- (3,3-difluorocyclobutyl) -3- ((8- (2- (difluoromethyl) pyridine-4-yl) imidazo [1,2-a)]Pyridin-5-yl) oxo) -2-methylpropan-2-amine (7.82 mg, yield 15.3%)
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)。
The remaining components were collected to give (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).
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)。
Example 14: preparation of target Compound I-36
(S) -1- ((8- (2- (difluoromethyl) pyridin-4-yl) - [1,2,4] triazolo [4,3-a ] pyridin-5-yl) oxo) -2,4-dimethylpentan-2-amineformate (I-36)
The synthesis route of the target compound I-36 is shown as follows:
the first step is as follows: synthesis of 3-bromo-6-chloro-2-hydrazinopyridine
3-bromo-2,6-dichloropyridine (2.00g, 8.81mmol) was dissolved in ethanol (20.0 mL), hydrazine hydrate (2.06g, 35.0 mmol) was added, and the reaction mixture was stirred at 80 ℃ for 12 hours. After the reaction was completed, the reaction solution was concentrated to remove ethanol, and then diluted with water (30 mL), extracted with ethyl acetate (20 mL. Times.3), the organic phases were combined, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product, which was purified by a chromatography column (silica, petroleum ether: ethyl acetate =5:1 to 1:1) to give 3-bromo-6-chloro-2-hydrazinopyridine (1.40 g, yield: 71.4%).
1 H NMR(400MHz,DMSO)δ7.84(s,1H),7.72(d,1H),6.57(d,1H),4.28(s,2H)。
LC-MS,M/Z(ESI):222.0[M+H] +
The second step is that: synthesis of 8-bromo-5-chloro- [1,2,4] triazolo [4,3-a ] pyridine
3-bromo-6-chloro-2-hydrazinopyridine (1.20g, 5.39mmol) was dissolved in trimethyl orthoformate (10.0 mL), and the reaction solution was stirred at 100 ℃ for 3 hours. After the reaction was completed, the reaction solution was concentrated to obtain a crude product, which was purified by a column chromatography (silica, petroleum ether: ethyl acetate =2:1 to 1:1) to give 8-bromo-5-chloro- [1,2,4] triazolo [4,3-a ] pyridine (0.52 g, yield: 41.6%).
1 H NMR(400MHz,CDCl 3 )δ9.03(s,1H),7.53(d,1H),6.84(d,1H)。
LC-MS,M/Z(ESI):234.0[M+H] +
The third step: synthesis of 5-chloro-8- (2- (difluoromethyl) pyridin-4-yl) - [1,2,4] triazolo [4,3-a ] pyridine
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 (461mg, 1.81mmol) were dissolved in dioxane (9.00 mL) and water (2.00 mL), potassium carbonate (499g, 3.62mmol) and (2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl) [2- (2-amino-1,1-biphenyl) ] palladium (II) (64.0mg, 90.3. Mu. Mol) were added, nitrogen was replaced 3 times, and the reaction solution was stirred at 80 ℃ for 1 hour. After the reaction was completed, the reaction solution was cooled to room temperature, diluted with water (20.0 mL), extracted with ethyl acetate (20.0 mL. Times.3), the organic phases were combined, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product, which was purified by a column chromatography (silica, petroleum ether: ethyl acetate =3:1 to 1:1) to give 5-chloro-8- (2- (difluoromethyl) pyridin-4-yl) - [1,2,4] triazolo [4,3-a ] pyridine (300 mg, yield: 59.2%).
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] +
The fourth step: (S) -1- ((8- (2- (difluoromethyl) pyridin-4-yl) - [1,2,4] triazolo [4,3-a ] pyridin-5-yl) oxo) -2,4-dimethylpentan-2-amineformate (I-36)
5-chloro-8- (2- (difluoromethyl) pyridin-4-yl) - [1,2,4] triazolo [4,3-a ] pyridine (150mg, 534. Mu. Mol) and (S) -2-amino-2,4-dimethylpentan-1-ol (119mg, 907. Mu. Mol) were dissolved in tetrahydrofuran (3.00 mL), followed by addition of a potassium tert-butoxide solution (1.00M, 1.60mL) and the reaction stirred at 50 ℃ for 1 minute. After the reaction was completed, water (10.0 mL) was added for dilution, followed by extraction with ethyl acetate (10.0 mL. Times.3), the organic phase was washed with saturated sodium chloride solution (40.0 mL) and dried over anhydrous sodium sulfate, and then filtered and concentrated to give a crude product, which was separated and purified by reversed-phase high-performance liquid chromatography by the following purification method: a chromatographic column, phenomenex C18 is 75mm multiplied by 30mm multiplied by 3 mu m; mobile phase [ water (FA) -ACN ]; and B% is 30% -60%, and the product is purified for 7min to obtain (S) -1- ((3-chloro-8- (2- (difluoromethyl) pyridine-4-yl) imidazo [1,2-a ] pyridine-5-yl) oxo) -2,4-dimethylpentane-2-amineformate (15.4 mg, yield 7.56%).
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] +
Example 15: preparation of target Compound 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)
The synthesis route of the target compound I-37 is shown as follows:
the first step is as follows: synthesis of 5-chloro-8- (2- (difluoromethyl) pyridin-4-yl) -2-methylimidazo [1,2-a ] pyridine
To a solution of 6-chloro-2 '- (difluoromethyl) - [3,4' -bipyridin ] -2-amine (400mg, 1.56mmol), 1-bromo-2,2-dimethoxy-propane (371mg, 2.03mmol) in n-butanol (5.00 mL) at room temperature was added pyridine p-toluenesulfonate (470mg, 1.87mmol), and the reaction mixture was stirred at 120 ℃ for 10 hours. After the reaction was completed, the reaction mixture was directly concentrated. To obtain a crude product. The crude product was separated by column chromatography (petroleum ether: ethyl acetate 5:1 to 2:1) to give 5-chloro-8- [2- (difluoromethyl) -4-pyridinyl ] -2-methyl-imidazo [1,2-a ] pyridine (300 mg, crude).
LC-MS,M/Z(ESI):294.1[M+H] +
The second step is that: synthesis of (S) -1- ((8- (2- (difluoromethyl) pyridin-4-yl) -2-methylimidazo [1,2-a ] pyridin-5-yl) oxo) -2,4-dimethylpentan-2-amine (I-37)
To a solution of 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 (4.00 mL) at room temperature was added a solution of potassium tert-butoxide in tetrahydrofuran (1M, 1.53mL), and the reaction was stirred at 50 ℃ for 1 hour. After the reaction, water was added to dilute the reaction solution, followed by extraction with ethyl acetate. The organic phase is concentrated by drying. The crude product was isolated by chromatography plate (dichloromethane: methanol =10 1) and prepared by reverse phase (column: phenomenex luna C18 x 25mm x 10 μm; mobile phase: [ water (0.225% formic acid) -acetonitrile ]; B%:1% -27%,10 min.) mobile phase: [ water (0.225% formic acid) -acetonitrile ]; b%:1% -27%,10 min) to give (S) -1- ((8- (2- (difluoromethyl) pyridin-4-yl) -2-methylimidazo [1,2-a ] pyridin-5-yl) oxo) -2,4-dimethylpentan-2-amine (I-37) (26.6 mg,6.57% yield).
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] +
Example 16: preparation of target Compound 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)
The synthesis route of the target compound I-38 is shown as follows:
the first step is as follows: synthesis of 6-chloro-2 '- (difluoromethyl) - [3,4' -bipyridine ] -2-amine
To a solution of 3-bromo-6-chloro-pyridin-2-amine (850mg, 4.10mmol), 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-dimethylaminophenyl) phosphine ] palladium (87.0mg, 123. Mu. Mol) was dissolved in dioxane (10.0 mL) and water (2.00 mL) at room temperature, nitrogen was replaced three times, and the reaction solution was stirred at 80 ℃ for 1 hour. After the reaction, water was added to dilute the reaction mixture, ethyl acetate was used for extraction, and the organic phase was dried and concentrated to give a crude product, which was separated by a column chromatography (petroleum ether: ethyl acetate 5:1 to 1:1) to give 6-chloro-2 '- (difluoromethyl) - [3,4' -bipyridine ] -2-amine (2) (950mg, 90.7% yield).
LC-MS,M/Z(ESI):257.0[M+H] +
The second step is that: synthesis of 5-chloro-8- (2- (difluoromethyl) pyridin-4-yl) -3-methylimidazo [1,2-a ] pyridine
6-chloro-2 '- (difluoromethyl) - [3,4' -bipyridin ] -2-amine (400mg, 1.56mmol), 2-bromo-1,1-dimethoxy-propane (372mg, 2.03mmol) in n-butanol (5.00 mL) was added pyridine p-toluenesulfonate (432mg, 1.72mmol) at room temperature, and the reaction was stirred at 120 ℃ for 10 hours. Directly concentrating after the reaction is finished to obtain a crude product. The crude product was separated by column chromatography (petroleum ether: ethyl acetate 5:1 to 1:1) to give 5-chloro-8- (2- (difluoromethyl) pyridin-4-yl) -3-methylimidazo [1,2-a ] pyridine (3) (300mg, 65.3% yield).
LC-MS,M/Z(ESI):294.1[M+H] +
The third step: synthesis of (S) -1- ((8- (2- (difluoromethyl) pyridin-4-yl) -3-methylimidazo [1,2-a ] pyridin-5-yl) oxo) -2,4-dimethylpentan-2-amine (I-38)
A solution of 5-chloro-8- (2- (difluoromethyl) pyridin-4-yl) -3-methylimidazo [1,2-a ] pyridine (200mg, 681. Mu. Mol), (2S) -2-amino-2,4-dimethyl-pentan-1-ol (98.3mg, 749. Mu. Mol) in tetrahydrofuran (3.00 mL) was added to a solution of potassium tert-butoxide in tetrahydrofuran (1M, 1.36mL) at room temperature, and the reaction was stirred at 50 ℃ for 1 hour. After the reaction is finished, water is added for dilution, ethyl acetate is used for extraction, and an organic phase is dried and concentrated. The crude was isolated by chromatography plate (dichloromethane: methanol =10: 1) and prepared on reverse phase (column: phenomenex synergy C18 × 25mm × 10 μm; mobile phase: [ water (0.225% formic acid) -acetonitrile ]; B%:1% -27%,10 min) to give (S) -1- ((8- (2- (difluoromethyl) pyridin-4-yl) -3-methylimidazo [1,2-a ] pyridin-5-yl) oxo) -2,4-dimethylpentan-2-amine (I-38) (10.0mg, 3.31% yield).
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] +
Example 17: preparation of target Compound 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).
The synthetic route of the target compound I-39 is shown below:
the first step is as follows: 3,5-dichloro-8- (2- (difluoromethyl) pyridin-4-yl) imidazo [1,2-a ] pyridine
5-chloro-8- (2- (difluoromethyl) pyridin-4-yl) imidazo [1,2-a ] pyridine (300mg, 1.07mmol) was dissolved in acetonitrile (5.00 mL), N-chlorosuccinimide (215mg, 1.61mmol) was added, and the reaction was stirred at 65 ℃ for 12 hours. After completion of the reaction, the solvent was removed by concentration under reduced pressure, water (10.0 mL) was added, the pH was adjusted to 7 to 9 with a sodium hydrogencarbonate solution, followed by extraction with ethyl acetate (20.0 mL. Times.3), the organic phase was washed with a saturated sodium chloride solution (40.0 mL) and dried over anhydrous sodium sulfate, and concentration by filtration gave 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] +
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)
3,5-dichloro-8- (2- (difluoromethyl) pyridin-4-yl) imidazo [1,2-a ] pyridine (190mg, 605 μmol) and (S) -2-amino-2,4-dimethylpentan-1-ol (119mg, 907 μmol) were dissolved in tetrahydrofuran (3.00 mL) and then potassium tert-butoxide solution (1.00M, 2.42mL) was added and the reaction was stirred at 25 ℃ for 30min. After the reaction is finished, the solvent is removed by concentration under reduced pressure, water (15.0 mL) is added for dilution, then ethyl acetate (15.0 mL multiplied by 3) is used for extraction, an organic phase is washed by saturated sodium chloride solution (40.0 mL) and dried by anhydrous sodium sulfate, filtration and concentration are carried out to obtain a crude product, and the crude product is separated and purified by a reverse phase high performance liquid chromatography, wherein the purification method comprises the following steps: chromatographic column 3 \ u Phenomenex Luna C18X 30mm X3 μm; mobile phase [ water (HCl) -ACN ]; 18% -38% of the total weight of the mixture, and 8min of the total weight of the mixture to obtain (S) -1- ((3-chloro-8- (2- (difluoromethyl) pyridine-4-yl) imidazo [1,2-a ] pyridine-5-yl) oxo) -2,4-dimethylpentane-2-amine hydrochloride (40.0 mg, yield 15.9%).
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)。
Example 18: preparation of target Compound 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).
The synthetic route of the target compound I-40 is shown below:
the first step is as follows: 4- (5-Chloroimidazo [1,2-a ] pyridin-8-yl) pyridin-2-amine
8-bromo-5-chloroimidazo [1,2-a ] pyridine (500mg, 2.16mmol), 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2-amine (570mg, 2.59mmol) and potassium carbonate (597mg, 4.32mmol) were dissolved in dioxane (5.00 mL) and water (1.00 mL), followed by dichloro bis [ di-tert-butyl- (4-dimethylaminophenyl) phosphine ] palladium (II) (152mg, 216. Mu. Mol), nitrogen substitution three times, and the reaction stirred at 90 ℃ for 12 hours. After completion of the reaction, the solvent was removed by concentration under reduced pressure, diluted with water (20.0 mL), extracted with ethyl acetate (20.0 mL. Times.3), the organic phase was washed with a saturated sodium chloride solution (40.0 mL) and dried over anhydrous sodium sulfate, and then concentrated by filtration to give the crude product. The crude product was purified by column chromatography (silica gel, petroleum ether: ethyl acetate =0:1 to dichloromethane: methanol = 10) to give 4- (5-chloroimidazo [1,2-a ] pyridin-8-yl) pyridin-2-amine as a brown oil (178 mg, 23.6% yield).
LCMS,M/Z(ESI):245.0[M+H] +
The second step is that: methyl (4- (5-chloroimidazo [1,2-a ] pyridin-8-yl) pyridin-2-yl) aminomethyl ester
4- (5-Chloroimidazo [1,2-a ] pyridin-8-yl) pyridin-2-amine (145mg, 593. Mu. Mol) was dissolved in methanol (5.00 mL), followed by dropwise addition of di-tert-butyl dicarbonate (155mg, 711. Mu. Mol) at 0 ℃ and stirring of the reaction solution at 25 ℃ for 10 hours. After the reaction is completed, the solvent is removed by concentration under reduced pressure to obtain a crude product. The crude product was purified by slurrying (ethyl acetate, 25 ℃) to give methyl (4- (5-chloroimidazo [1,2-a ] pyridin-8-yl) pyridin-2-yl) aminomethyl ester (108 mg, 54.0% yield).
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] +
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)
(4- (5-Chloroimidazo [1,2-a ] pyridin-8-yl) pyridin-2-yl) aminomethyl ester (100mg, 330. Mu. Mol), (S) -2-amino-2,4-dimethylpentan-1-ol (65.0 mg, 495. Mu. Mol) was dissolved in tetrahydrofuran (2.00 mL), followed by addition of a potassium t-butoxide solution (1.00M, 1.32mL), and the reaction was reacted at 50 ℃ for 2 hours. After completion of the reaction, it was quenched with water (20.0 mL), then extracted with ethyl acetate (25.0 mL. Times.3), the organic phase was washed with saturated sodium chloride solution (60.0 mL) and dried over anhydrous sodium sulfate, and then concentrated by filtration to give the crude product. The crude product is separated and purified by a reversed phase high performance liquid chromatography, and the separation method comprises the following steps: chromatographic column 3 \ u Phenomenex Luna C18X 30mm X3 μm; mobile phase [ water (HCl) -ACN ]; and B%:0% -21%,8min, purifying to obtain (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%).
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] +
Example 19: preparation of target Compound I-41
(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)
Preparation of target Compound I-41
The first step is as follows: synthesis of tert-butyl (S) - (1- ((2-amino-2 '- (difluoromethyl) - [3,4' -bipyridin ] -6-yl) oxo) -2,4-dimethylpentan-2-yl) carbamate
A solution of (2S) -2-amino-2,4-dimethyl-pentan-1-ol (200mg, 1.53mmol) and 6-chloro-3- [2- (difluoromethyl) -4-pyridinyl ] pyridin-2-amine (300mg, 1.17mmol) in tetrahydrofuran (5.00 mL) was added to a solution of potassium tert-butoxide in tetrahydrofuran (1M, 2.93mL) at room temperature and the reaction was stirred at 70 ℃ for 16 hours. After the reaction was completed, ethyl acetate was diluted with water and extracted, and the organic phase was dried and concentrated to give a crude product, which was dissolved in a dichloromethane solution (3.00 mL), di-tert-butyl dicarbonate (374 mg) was added and stirred for 4 hours. After the reaction is finished. Concentrating to obtain crude product. The crude product was isolated by chromatography plate (petroleum ether: ethyl acetate = 1:1) to give tert-butyl (S) - (1- ((2-amino-2 '- (difluoromethyl) - [3,4' -bipyridin ] -6-yl) oxo) -2,4-dimethylpentan-2-yl) carbamate (180mg, 34.1% yield).
LC-MS,M/Z(ESI):451.1[M+H] +
The second step is that: synthesis of (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)
A solution of 3-bromo-1,1-difluoro-propan-2-one (82.5mg, 476. Mu. Mol) and tert-butyl (S) - (1- ((2-amino-2 '- (difluoromethyl) - [3,4' -bipyridinyl ] -6-yl) oxo) -2,4-dimethylpentan-2-yl) aminomethyl ester (179mg, 397. Mu. Mol) in n-propanol (2.00 mL) was exchanged three times under nitrogen at room temperature, and the reaction was stirred at 100 ℃ for 10 hours. After the reaction, the crude product is obtained by concentration. The crude product was prepared in reverse phase (column: phenomenex luna C18X 25mm X10 μm; mobile phase: [ water (0.225% formic acid) -acetonitrile ]; B%:15% -45%,10 min) to give (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) (27.0mg, 15.8% yield)
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] +
Test example 1: TR-FRET (time resolved fluorescence resonance energy transfer) -based AAK1 kinase binding assay
Test compounds (control Compound 1 and Compounds I-1 to I-41, R-I-4, R-I-29 prepared in the previous examples) were dissolved in DMSO and prepared as a 10mM stock solution, diluted 100-fold with DMSO to the highest point of the concentration gradient, and then serially diluted 3-fold until 8 concentration gradients were reached. 5 Xkinase buffer A (Invitrogen, PV 3189) was treated with ddH 2 The dilution with O was 5-fold to 1 Xkinase buffer A, and the serial compound dilutions were re-diluted with 1 Xkinase buffer A to 4-fold final concentration and added to 384-well plates (4. Mu.l/well). AAK1 Recombinant Human Protein (Invitrogen, A30967) and LanthaScreen were combined TM Eu-anti-GST Antibody (Invitrogen, PV 5594) was prepared as a 2 Xkinase/Antibody mixture, which was added to 384 well plates (16. Mu.l/well) and pipetted uniformly. Equilibrate for 15min at room temperature. Mu.l of 4 XKinase Tracer 222 (Invitrogen, PV 6121) was added to each well and blotted well. Incubate at room temperature for 1h. And (3) reading the 384-pore plate in a multifunctional microplate reader, setting the excitation wavelength as 332nm, setting the absorption wavelength as 650nm and 620nm channels, and recording the ratio of fluorescence signals (ER value) of 665nm and 620 nm. Calculating the binding rate of each hole according to the formula: % binding rate = (ER) High signal contrast -ER Sample (I) )/(ER High signal contrast -ER Low signal contrast ) X100, fitting curves with GraphPad 8.0 and calculating IC 50 The value is obtained. The following tables a, b, c, d represent the compounds IC 50 The value range, i.e. a is less than or equal to 10nM, 10<b≤50nM、50nM<c≤500nM、500nM<d。
TABLE 1 test Compounds AAK1 kinase binding Activity
The result shows that the compound of the invention has stronger affinity of AAK 1.
Test example 2: human hepatocyte stability assay
The human hepatocyte stability test adopts the compound and the human hepatocyte to be incubated together for detection. And (3) taking out the frozen hepatocytes from the liquid nitrogen, thawing in water bath at 37 ℃, adding a hepatocyte thawing culture medium, gently mixing uniformly, and centrifuging at 500rpm for 3 minutes. The supernatant was discarded, 10 volumes of KHB buffer (Krebs-Henseleit buffer, sigma, cat # K3753-10X 1L) and 5.6g/LHEPES were added to resuspend the cells, gently mixed, and centrifuged at 500rpm for 3 minutes. The supernatant was discarded and the hepatocyte viability and yield were determined. After counting, cell density was adjusted to 2X 10 6 cells/mL, placed on ice for use. mu.L of a 200. Mu.M DMSO solution of the test compound (control compound 1 or one of compounds I-1 to I-41, R-I-4, and R-I-29 prepared in the previous example) was added to 990. Mu.LKHB buffer, and centrifuged at 5594g for 15 minutes to add 50. Mu.L/well to wells at the indicated different time points. The hepatocyte suspension was added to the wells planned for 15, 30, 60, 120 minutes of incubation at 50. Mu.L/well, and after incubation in an incubator at 37 ℃ for a corresponding time, 100. Mu.L/well of acetonitrile containing the internal standard was added to stop the reaction. Acetonitrile solution containing internal standard was added to wells containing KHB compound solution at 100 μ L/well, mixed well and added 50 μ L/well hepatocyte suspension as 0min control wells. After all wells had stopped the reaction, the deep-well plate was vortexed for 10 minutes (600 rpm/min). Performing ultrasonic treatment for 2 minutes, centrifuging for 1 minute at 5594g, taking out 50 mu L of supernatant 1:1 from each hole, adding purified water, performing LC-MS/MS detection to obtain peak area ratio of the compound at each time point to peak area ratio of the internal standard, comparing the peak area ratio of the compound at 15, 30, 60 and 120 minutes with the peak area ratio at 0min, and calculating the peak area ratio of the compound at each time pointThe remaining percentage, T1/2 was calculated using Graphpad 8 software.
Table 2 stability parameters of test compounds in human hepatocytes
The results show that the compound of the invention has better metabolic stability in human liver cells.
Test example 3: compound plasma protein binding rate
Plasma protein binding rates of compounds were measured using equilibrium dialysis (HTDialysis, HTD 96 b). Test compounds (control compound 1 prepared in the previous example and compounds I-1 to I-41, R-I-4, and R-I-29) were prepared as 0.5mM stock solutions in DMSO, respectively, and then diluted 25-fold with 0.05M sodium phosphate buffer solution to prepare working solutions. Blank 96-well plates were preloaded with 380. Mu.L of plasma per well, followed by 20. Mu.L/well of working solution to plasma and mixed well, with a final concentration of 1. Mu.M compound containing 0.2% DMSO per well.
mu.L of 0.05M sodium phosphate buffer was added to the receiving side of each dialysis chamber (HTD 96 b), and 100. Mu.L of compound-containing plasma was added to the supplying side. After covering with a plastic cover, the cells were incubated at 37 ℃ for 5 hours with shaking.
After the completion of the incubation, 25. Mu.L of each of the samples from the supply side and the receiving side of the dialysis chamber was placed in a blank 96-well plate, and an equal volume of plasma was added to each of the samples on the supply side, and an equal volume of 0.05M sodium phosphate buffer was added to each of the samples on the receiving side, followed by uniform mixing. After adding 200. Mu.L of acetonitrile solution containing an internal standard per well, the 96-well plate was vortexed at 600rpm for 10 minutes, and after centrifugation at 5594g for 15 minutes (Thermo Multifuge. Times.3R), 50. Mu.L of the supernatant was transferred to a new 96-well plate, and the sample was mixed with 50. Mu.L of ultrapure water for LC-MS/MS analysis.
Plasma protein binding and free fraction were calculated using the following formulas: % binding =100 × ([ supply side concentration ]] 5h - [ receiver side concentration] 5h ) /[ supply side concentration] 5h . % free fraction =100-% binding rate
Table 3 free fraction of test compound in plasma
| Compound number | Human (%) | Rat (%) | Mouse (%) | Dog (%) |
| Control Compound 1 | 8.7 | 8.9 | 3.8 | 4.2 |
| I-3 | 11.1 | 10.0 | 7.0 | 3.8 |
| I-11 | 23.3 | 21.3 | 14.9 | 19.5 |
| I-21 | 19.3 | 18.5 | 12.8 | 12.9 |
The experimental result shows that the compound has higher free drug ratio in various blood plasma and good drug forming property.
Test example 4: evaluation of toxicity of compound on human liver cancer cell
Human hepatoma cells HepG2 were cultured in MEM medium containing 10% FBS, and when the cell growth state was good, they were seeded in a 96-well plate at a density of 10000/well and 100. Mu.L/well. Put into a CO2 incubator at 37 ℃ C. And 5% overnight.
A gradient of test compound (control compound 1 or one of compounds I-1 to I-41, R-I-4, R-I-29 prepared in the previous example) or DMSO was added to each well, and a blank was set up in wells into which no cells were added to the medium. Placing in a 37 ℃ C, 5% CO2 incubator for 72 hours, and culturing
Cell Viability Assay kit (Promega, cat. No. g9243) instructions, 96-well plates were removed from the incubator and equilibrated at room temperature for 30min. After the balance is finished, adding room temperature CellTiter-Glo reagent according to 100 mu L/hole, shaking for 5min on a shaking table, incubating for 10min at room temperature, reading a luminescence signal on a multifunctional microplate reader, and calculating the cell activity inhibition rate:
cell activity inhibition rate = (DMSO group-test compound)/(DMSO group-blank control group) × 100%
IC50 values were calculated using Graphpad 8 software.
TABLE 4 toxicity of the test compounds on HepG2 cells
The experimental results show that the compounds of the invention have lower ability to inhibit HepG2 proliferation and lower toxicity at the cellular level, relative to the control compound 1.
Test example 5: pharmacokinetic testing of rats
Rat pharmacokinetic experiments were carried out using 3 male SD rats per group at 180-240g, fasted overnight, orally gavaged (control Compound 1 or one of Compounds I-1 to I-41, R-I-4, R-I-29 prepared in the previous example) at 10mg/kg. Blood was collected before dosing and at 15, 30 minutes and 1,2,4, 8, 24 hours post-dosing. Blood samples were centrifuged at 8000 rpm for 6 minutes at 4 ℃ and plasma was collected and stored at-20 ℃. And (3) adding 3-5 times of acetonitrile solution containing an internal standard into the plasma at each time point, mixing, carrying out vortex mixing for 1 minute, centrifuging at 4 ℃ for 10 minutes at 13000 rpm, taking supernatant, adding 3 times of water, mixing, and taking a proper amount of mixed solution to carry out LC-MS/MS analysis. The major pharmacokinetic parameters were analyzed using WinNonlin 7.0 software, a non-compartmental model.
TABLE 5 results of pharmacokinetic experiments on rat
Experimental results show that the compound has high oral exposure and Cmax on rats and good drug-forming property.
Claims (22)
1. A compound of formula I, tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs thereof:
wherein the content of the first and second substances,
ring A is selected from
R 1 Selected from-H, hydroxy, amino, cyano,Unsubstituted or substituted by R 12 Substituted C 1 -C 6 Alkyl, unsubstituted or substituted by R 12 Substituted C 3 -C 6 Cycloalkyl, halogen or
The quilt R 12 Substituted C 1 -C 6 Alkyl or by R 12 Substituted C 3 -C 6 In the cycloalkyl group, said R 12 The substitution may be one or more, and R is 12 Each independently selected from the following substituents: hydroxy, amino, cyano, halogen, C 1 -C 6 Alkyl or-O- (C) 1 -C 6 Alkyl groups); when the substituent is plural, the substituents are the same or different;
R 11 selected from unsubstituted or substituted by R 111 Substituted C 1 -C 6 Alkyl, unsubstituted or substituted by R 111 substituted-O-C 1 -C 6 Alkyl, unsubstituted or substituted by R 111 Substituted 4-8 membered heterocycloalkyl, or-NR x R y (ii) a The quilt R 111 Substituted C 1 -C 6 Alkyl or by R 111 In substituted 4-8 membered heterocycloalkyl, said R 111 The substitution may be one or more, and R is 111 Each independently selected from the following substituents: hydroxy, amino, cyano, halogen, C 1 -C 6 Alkyl or-O- (C) 1 -C 6 Alkyl groups); when the number of the substituents is plural, the substituents may be the same or different;
R x and R y Each independently by 1 to 5R which may be the same or different z Substituted C 1 -C 6 Alkyl or R x And R y Together with the N to which it is attached form an N-containing heterocyclic group, said R z Each independently selected from-H, halogen, C 1 -C 6 Alkyl, -O- (C) 1 -C 6 Alkyl) or C 3 -C 6 A cycloalkyl group; when the number of the substituents is plural, the substituents may be the same or different;
R 2 selected from-H, hydroxy, amino, cyano, unsubstituted or substituted by R 21 Substituted C 1 -C 6 An alkyl group; the quilt R 21 Substituted C 1 -C 6 In the alkyl group, the R is 21 The substitution may be one or more, and R is 21 Each independently selected from the following substituents: hydroxy, amino, cyano, halogen, C 1 -C 6 Alkyl or-O- (C) 1 -C 6 Alkyl groups); when the number of the substituents is plural, the substituents may be the same or different;
ring B is selected from
/>
Wherein "X" means and->
And ". Star" indicates a connection to ring a;
R 3 and R 4 Each independently selected from-H, -SF 5 Hydroxy, amino, cyano, unsubstituted or substituted by R 31 Substituted C 1 -C 6 Alkyl, unsubstituted or substituted by R 31 Substituted C 3 -C 6 Cycloalkyl, halogen or
The quilt R 31 Substituted C 1 -C 6 Alkyl or by R 31 Substituted C 3 -C 6 In the cycloalkyl group, the R is 31 The substitution may be one or more, and R is 31 Each independently selected from the following substituents: hydroxy, amino, cyano, halogen, C 1 -C 6 Alkyl or-O- (C) 1 -C 6 Alkyl); when the number of the substituents is plural, the substituents may be the same or different;
R 32 selected from-H, unsubstituted or substituted by R 321 Substituted C 1 -C 6 Alkyl, or, unsubstituted or substituted by R 321 Substituted C 3 -C 6 A cycloalkyl group; the quilt R 321 Substituted C 1 -C 6 Alkyl or by R 31 Substituted C 3 -C 6 In the cycloalkyl group, the R is 321 The substitution can be one or more, and R is 321 Each independently selected from the following substituents: hydroxy, amino, cyano, halogen, C 1 -C 6 Alkyl or-O- (C) 1 -C 6 Alkyl groups); when the number of the substituents is plural, the substituents may be the same or different;
R 5 selected from the group consisting of-H, cyano, C substituted by 1 to 5 identical or different halogens 1 -C 6 Alkyl, C substituted by 1-5 identical or different halogens 3 -C 6 Cycloalkyl radical, C 3 -C 6 Cycloalkyl or C 1 -C 6 An alkyl group;
R 6 selected from hydroxy, amino, cyano,
Unsubstituted or substituted by R 61 Substituted C 1 -C 6 Alkyl, halogen or unsubstituted or substituted by R 61 Substituted C 3 -C 6 A cycloalkyl group; the quilt R 61 Substituted C 1 -C 6 Alkyl or by R 61 Substituted C 3 -C 6 In the cycloalkyl group, the R is 61 The substitution may be one or more, and R is 61 Each independently selected from the following substituents: hydroxy, amino, cyano, halogen, C substituted by 1 to 6 identical or different halogens 1 -C 6 Alkyl, -O- (C) substituted by 1-6 identical or different halogens 1 -C 6 Alkyl group), C 1 -C 6 Alkyl or-O- (C) 1 -C 6 Alkyl groups); when the substituent is plural, the substituents may be the same or different.
2. The compound of claim 1, which is a compound of formula II, a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt, or a prodrug thereof:
3. the compound of claim 1, which is a compound of formula III, a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt, or a prodrug thereof:
wherein, when ring A and ring B are the same, R 1 And R 3 Different.
4. The compound of claim 1, which is a compound of formula IV, a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt, or a prodrug thereof:
5. the compound of claim 1, which is a compound of formula V, a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt, or a prodrug thereof:
wherein ring C is unsubstituted or substituted by R 61 Substituted C 3 -C 6 A cycloalkyl group.
6. The compound of claim 1, which is a compound of formula VI, a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt, or a prodrug thereof:
wherein, X 1 、X 2 、X 3 、X 4 Each independently is C or N;
and X 1 And X 2 In a different way, when X 1 When is N, X 3 Is N, when X 2 When is N, X 4 Is N.
7. The compound according to any one of claims 1 to 5,
ring B is selected from
8. The compound of any one of claims 1-6,
R 2 is-H;
and/or, R 1 is-H;
and/or when R 1 Is unsubstituted or substituted by R 12 Substituted C 1 -C 6 When alkyl, said C 1 -C 6 Alkyl is methyl, ethyl, n-propyl or isopropyl;
and/or when R 1 Is as a quilt R 12 Substituted C 1 -C 6 When it is alkyl, said R 12 Is halogen;
and/or when R 12 When is halogen, the halogen is F or Cl;
and/or when R 1 Is as a quilt R 12 Substituted C 1 -C 6 When it is alkyl, said R 12 Substitutions are 1,2 or 3;
and/or, R 1 Is composed of
And/or, R 11 Is unsubstituted or substituted by R 111 substituted-O-C 1 -C 6 When alkyl, said-O-C 1 -C 6 Alkyl is-O-methyl, -O-ethyl, -O-n-propyl or-O-isopropyl;
and/or, R 11 is-NR x R y ；
And/or when R x And R y Is represented by 1-5 identical or different R z Substituted C 1 -C 6 When alkyl, said C 1 -C 6 Alkyl is methyl, ethyl, n-propyl or isopropyl;
and/or when R x And R y Is represented by 1-5 identical or different R z Substituted C 1 -C 6 When alkyl, R is substituted z Substitution is 1,2 or 3;
and/or, R z is-H;
and/or when R x And R y When taken together with the N to which it is attached to form an N-containing heterocyclyl, the N-heterocyclyl is
And/or when R 11 Is unsubstituted or substituted by R 111 When substituted with a 4-8 membered heterocycloalkyl group, the 4-8 membered heterocycloalkyl group is azetidinyl, azetyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, morpholinyl, pyrrolidinyl, morpholinyl, or piperazinyl.
9. The compound according to any one of claims 1 to 6,
R 4 is-H;
and/or, R 3 is-H;
and/or, R 3 is-SF 5 ；
And/or, R 3 When is halogen, the halogen is F or Cl;
and/or, R 3 Is composed of
And/or when R 32 Is unsubstituted or substituted by R 321 Substituted C 1 -C 6 When alkyl, said C 1 -C 6 Alkyl is methyl, ethyl, n-propyl or isopropyl;
and/or when R 3 Is unsubstituted or substituted by R 31 Substituted C 1 -C 6 When alkyl, said C 1 -C 6 Alkyl is methyl, ethyl, n-propyl or isopropyl;
and/or when R 3 Is as a quilt R 31 Substituted C 1 -C 6 When it is alkyl, said R 31 Is halogen;
and/or when R 31 When is halogen, the halogen is F or Cl;
and/or when R 3 Is represented by R 31 Substituted C 1 -C 6 When alkyl, the halogen is substituted by 1,2 or 3;
and/or when R 3 Is unsubstituted or substituted by R 31 Substituted C 3 -C 6 When a cycloalkyl group is present, C is 3 -C 6 Cycloalkyl is cyclopropyl.
10. The compound according to any one of claims 1 to 6,
when R is 5 Is C 1 -C 6 When alkyl, said C 1 -C 6 Alkyl is methyl, ethyl, n-propyl or isopropyl;
and/or when R 5 Is C 3 -C 6 When a cycloalkyl group is present, C is 3 -C 6 Cycloalkyl is cyclopropyl.
11. The compound according to any one of claims 1 to 6,
R 6 is composed of
And/or when R 6 Is unsubstituted or substituted by R 61 Substituted C 1 -C 6 When alkyl, said C 1 -C 6 Alkyl is methyl, ethyl, n-propyl or isopropyl;
and/or when R 6 Is as a quilt R 61 Substituted C 1 -C 6 When alkyl, said R 61 Is halogen;
and/or when R 61 When is halogen, the halogen is F or Cl;
and/or when R 6 Is as a quilt R 61 Substituted C 1 -C 6 When it is alkyl, said R 61 The number of the substitution is 6;
and/or when R 6 Is unsubstituted or substituted by R 61 Substituted C 3 -C 6 When a cycloalkyl group is present, C is 3 -C 6 Cycloalkyl is cyclopropyl or cyclobutyl;
and/or when R 6 Is as a quilt R 61 Substituted C 3 -C 6 When cycloalkyl is present, said R 61 Is halogen;
and/or when R 6 Is represented by R 61 Substituted C 3 -C 6 When a cycloalkyl group is present, said R 61 The substitutions are 1,2 or 3.
12. The compound according to any one of claims 1 to 6,
when R is 6 Is unsubstituted or substituted by R 61 Substituted C 3 -C 6 When a cycloalkyl group is present, C is 3 -C 6 Cycloalkyl is cyclopentyl;
and/or when R 6 Is as a quilt R 61 Substituted C 3 -C 6 When cycloalkyl is present, said R 61 Is C substituted by 1 to 6 identical or different halogens 1 -C 6 An alkyl group;
and/or when R 6 Is represented by R 61 Substituted C 3 -C 6 When cycloalkyl is present, said R 61 Substitutions are 1,2 or3, the number of the cells is 3;
and/or when R 61 Is C substituted by 1 to 6 identical or different halogens 1 -C 6 When alkyl, the halogen is substituted by 1,2 or 3;
and/or when R 61 Is C substituted by 1 to 6 identical or different halogens 1 -C 6 When alkyl, the halogen is F or Cl.
13. The compound of any one of claims 1-6,
R 1 is selected from-H,
And/or, R 2 is-H;
and/or, R 3 Selected from-H, -Cl, methyl, -SF 5 、
And/or, R 4 is-H;
and/or, R 5 Selected from methyl or cyclopropyl;
and/or, R 6 Selected from isopropyl, cyclopropyl,
14. The compound according to any one of claims 1 to 6,
R 6 selected from cyclobutyl, cyclopentyl,
15. The compound according to any one of claims 1 to 6,
when ring A is
And ring B is->
When R is 1 Is hydroxy or->
And R is 11 is-NR x R y Or->
16. The compound of any one of claims 1-6,
when ring A is
And ring B is->
When R is 3 is-SF 5 Hydroxy, amino and/or are present in the animal or human>
/>
17. The compound of any one of claims 1-6,
when ring A is
And ring B is->
When R is 5 Is C 3 -C 6 Cycloalkyl, cyano or C substituted by 1 to 5 identical or different halogens 3 -C 6 A cycloalkyl group.
18. The compound according to any one of claims 1 to 6,
when ring A is
And ring B is->
When R is 6 Is hydroxy, amino, cyano, or>
By R 61 Substituted C 1 -C 6 Alkyl, halogen or unsubstituted or substituted by R 61 Substituted C 3 -C 6 A cycloalkyl group.
19. The compound according to claim 1, characterized in that it is selected from any one of the following compounds, tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs thereof:
20. a pharmaceutical composition comprising a compound of any one of claims 1-19, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, or prodrug thereof, and a pharmaceutically acceptable excipient.
21. Use of a compound of any one of claims 1-19, a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt, or a prodrug thereof, or a pharmaceutical composition of claim 20, in the manufacture of a medicament for the treatment of an AAK 1-associated disease.
22. Use according to claim 21, characterized in that the AAK1 related disease is alzheimer's disease, bipolar disorder, pain, parkinson's disease or schizophrenia.
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