Oxadiazole amide c-Myc inhibitor as well as preparation method and application thereof

Abstract

The invention provides a novel c-Myc inhibitor which can be used for preventing and / or treating c-Myc related or mediated diseases, such as tumors and the like.

Description

Technical Field

[0001] The present invention relates to c-Myc inhibitors and their preparation methods and uses. The inhibitors and pharmaceutical compositions containing the same can be used for preventing and / or treating c-Myc-related diseases or disorders. Background Art

[0002] The transcription factor c-Myc is a major regulator of normal gene expression, regulating biological processes such as normal cell proliferation, cell cycle, differentiation, metabolism, apoptosis, and angiogenesis (Nat Rev Cancer. 2008 Dec; 8(12): 976-90.). However, c-Myc also plays a key role in tumorigenesis, maintenance, and drug resistance. Due to gene amplification, translocation, mRNA upregulation, and abnormal protein stability, c-Myc protein is dysregulated in 70% of tumors (Cell. 2012 Mar 30; 149(1): 22-35.). The c-Myc protein itself has poor stability and only has a stable conformation after binding to Max. After forming the c-Myc-Max complex, it binds to DNA-Ebox to initiate downstream gene transcription (Mol Cancer. 2021 Jan 4; 20(1): 3.). Silencing c-Myc expression in various tumor models leads to tumor growth arrest or regression (Science. 2002 Jul 5; 297(5578): 102-4., Cancer Res. 65, 4471–4474.). Therefore, targeting dysregulated c-Myc protein has broad therapeutic effects (Cold Spring Harb Perspect Med. 2014 Oct 1; 4(10): a014266.).

[0003] However, c-Myc is an intrinsically disordered protein (IDP) without a stable protein conformation and lacks a defined pocket, and has always been considered a "difficult drug target". For the drug development for treating c-Myc-related diseases, there are currently various development strategies, such as directly targeting the c-Myc-Max interaction in the c-Myc pathway, inhibiting the interaction between the c-Myc-Max complex and DNA, and indirectly regulating the upstream and downstream pathways of c-Myc. Over the years, although researchers have discovered multiple small molecule compounds that directly bind to c-Myc and inhibit c-Myc-Max dimerization and / or the formation of the c-Myc-Max-DNA complex, most of them have weak binding ability to c-Myc, low inhibitory activity on c-Myc-driven tumor cell proliferation, and poor druggability and pharmacokinetic properties, further limiting their in vivo applications (J. Am. Chem. Soc. 2023, 145, 3259-3269). Therefore, there is an urgent need to discover small molecule c-Myc inhibitors with better activity and druggability. Summary of the Invention

[0004] The present invention provides a novel c-Myc inhibitor, which can be used for preventing and / or treating c-Myc related or mediated diseases, such as tumors.

[0005] According to one aspect of the present invention, the present invention provides a compound shown in the following (I) or a pharmaceutically acceptable salt or deuterated compound thereof:

[0006]

[0007] Wherein,

[0008] X and Y are independently selected from N, CR 7 ;

[0009] R 1 is selected from -OR 8 , -C(O)OR 8 , -C(O)N(R 8 )R 9 , -C(O)R 8 , -S(O) 2 N(R 8 )R 9 , -N(R 8 )R 9 , -N(R 8 )C(O)R 9 , -N(R 8 )S(O) 2 R 9 , -B(OH) 2 , -S(O) 2 R 8 , -P(O)(R 8 )R 9 ;

[0010] R 2 and R 3 are independently selected from H, halogen, -CN, -NO 2 , -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)N(R 8 )R 9 , -N(R 8 )R 9 , -N(R 8 )C(O)R 9 , -N(R 8 )S(O) 2 R 9 , -S(O) 2 R 8 , -P(O)(R8 )R 9 、C 1-4 a straight-chain or branched-chain alkyl group, C 2-4 a straight-chain or branched-chain alkenyl group, C 2-4 a straight-chain or branched-chain alkynyl group, C 3-7 a cycloalkyl group, a 3- to 7-membered heterocycloalkyl group containing 1 to 3 ring heteroatoms independently selected from N, O, and S and connected to the proximal ring through C or N, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl groups are optionally substituted by one or more groups independently selected from F, Cl, Br, -OH, -CN, -NH 2 、C 1-4 a straight-chain or branched-chain alkyl group, optionally substituted by one or more groups independently selected from F, Cl, Br, OH, CN, NH 2 、C 1-4 a straight-chain or branched-chain alkyl group, C 1-4 a straight-chain or branched-chain alkoxy group-substituted C 3-7 a cycloalkyl group, a 3- to 7-membered heterocycloalkyl group containing 1 to 3 ring heteroatoms independently selected from N, O, and S, and R 2 and R 3 are not simultaneously halogen;

[0011] R 4 、R 5 and R 6 are independently selected from H, C 1-4 a straight-chain or branched-chain alkyl group, C 3-7 a cycloalkyl group, a 3- to 7-membered heterocycloalkyl group containing 1 to 3 ring heteroatoms independently selected from N, O, and S and connected to the proximal carbon atom through C or N, wherein the alkyl, cycloalkyl, and heterocycloalkyl groups are optionally substituted by one or more groups independently selected from F, Cl, Br, -OH, -CN, -NH 2 、C 1-4 a straight-chain or branched-chain alkyl group, C 1-4 a straight-chain or branched-chain alkoxy group;

[0012] Or, R 5 and R 6 together with the carbon atom to which they are commonly attached form C=O, a 3- to 7-membered cycloalkyl group, a 3- to 7-membered heterocycloalkyl group containing 1 to 3 ring heteroatoms independently selected from N, O, and S, wherein the cycloalkyl and heterocycloalkyl groups are optionally substituted by one or more groups independently selected from F, Cl, Br, OH, CN, NH 2 、-C(O)R 8 、C 1-4 a straight-chain or branched-chain alkyl group, C 1-4 a straight-chain or branched-chain alkoxy group;

[0013] Ring A is selected from phenyl, 5- to 11-membered heteroaryl having 1 to 3 ring heteroatoms independently selected from N, O, and S and connected to the proximal carbon atom through C or N, C 3-7 cycloalkyl, C 3-7 cycloalkenyl, 3- to 7-membered heterocycloalkyl having 1 to 3 ring heteroatoms independently selected from N, O, and S and connected to the proximal carbon atom through C or N, C 5-9 bridged cycloalkyl, 5- to 9-membered heterobridged cycloalkyl having 1 to 3 ring heteroatoms independently selected from N, O, and S and connected to the proximal carbon atom through C or N, and bicyclic formed by the fusion of any two of the phenyl, heteroaryl, cycloalkyl, cycloalkenyl, and heterocycloalkyl;

[0014] m is 0, 1, 2, 3, 4, or 5;

[0015] R 7 is independently selected from H, F, Cl, Br, -CN, -NO 2 , C 1-4 linear or branched alkyl, C 2-4 linear or branched alkenyl, C 2-4 linear or branched alkynyl, C 3-7 cycloalkyl, 3- to 7-membered heterocycloalkyl having 1 to 3 ring heteroatoms independently selected from N, O, and S and connected to the proximal group through C or N, 5- to 11-membered heteroaryl having 1 to 3 ring heteroatoms independently selected from N, O, and S and connected to the proximal group through C or N, phenyl, -OR 8 , -C(O)R 8 , -C(O)OR 8 , -C(O)N(R 8 )R 9 , -S(O) 2 R 8 , -S(O) 2 N(R 8 )R 9 , -N(R 8 )R 9 , -N(R 8 )C(O)R 9 , -N(R 8 )S(O) 2 R 9 , -P(O)(R 8 )R 9 , and the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, and phenyl are optionally substituted with one or more independently selected from F, Cl, Br, -OH, -CN, -NH 2 , C 1-4 linear or branched alkyl, C 2-4 linear or branched alkenyl, C2-4 a straight-chain or branched alkynyl, C 1-4 a straight-chain or branched alkoxy, C 3-7 a cycloalkyl, a substituted group of a 3- to 7-membered heterocycloalkyl containing 1 to 3 ring heteroatoms independently selected from N, O, S, and substituted by a group linked to the proximal group through C or N;

[0016] R 8 and R 9 are independently selected from H, -OH, -NH 2 , C 1-4 a straight-chain or branched alkyl, C 2-4 a straight-chain or branched alkenyl, C 2-4 a straight-chain or branched alkynyl, C 3-7 a cycloalkyl, a 3- to 7-membered heterocycloalkyl containing 1 to 3 ring heteroatoms independently selected from N, O, S, P and substituted by a group linked to the proximal group through C or N, C 5-9 a bridged cycloalkyl, a 5- to 9-membered heterobridged cycloalkyl containing 1 to 3 ring heteroatoms independently selected from N, O, S and substituted by a group linked to the proximal group through C or N, a phenyl, a 5- to 11-membered heteroaryl containing 1 to 3 ring heteroatoms independently selected from N, O, S and substituted by a group linked to the proximal group through C or N, a spiro ring linked to the proximal group through C on any one of the rings of the spiro ring, the spiro ring being composed of a 3- to 7-membered heteroalkane ring containing 1 to 3 ring heteroatoms independently selected from N, O, S and a 3- to 7-membered alkane ring, and the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, bridged cycloalkyl, heterobridged cycloalkyl, phenyl, heteroaryl, spiro ring are optionally substituted by one or more groups independently selected from F, Cl, Br, OH, CN, NH 2 , =O, C optionally substituted by one or more groups independently selected from F, Cl, Br, OH, CN, NH 2 a straight-chain or branched alkyl, C optionally substituted by one or more groups independently selected from F, Cl, Br, OH, CN, NH 1-4 a straight-chain or branched alkoxy, C optionally substituted by one or more groups independently selected from F, Cl, Br, OH, CN, NH 2 a straight-chain or branched alkyl, C optionally substituted by one or more groups independently selected from F, Cl, Br, OH, CN, NH 1-4 a straight-chain or branched alkoxy, C optionally substituted by one or more groups independently selected from F, Cl, Br, OH, CN, NH 2 a straight-chain or branched alkyl, C optionally substituted by one or more groups independently selected from F, Cl, Br, OH, CN, NH 3-7 a cycloalkyl, a substituted group of a 3- to 7-membered heterocycloalkyl containing 1 to 3 ring heteroatoms independently selected from N, O, S and substituted by a group optionally substituted by one or more groups independently selected from F, Cl, Br, OH, CN, NH 2 ;

[0017] When R 8 and R 9 are linked to the same atom, R 8 and R 9Together with the atoms to which it is commonly attached, it can form a 3- to 7-membered heterocycloalkyl containing 1 to 3 ring heteroatoms independently selected from N, O, and S. The heterocycloalkyl is optionally substituted by one or more substituents independently selected from F, Cl, Br, -OH, -CN, -NH 2 、C 1-4 a straight-chain or branched-chain alkyl, C 2-4 a straight-chain or branched-chain alkenyl, C 2-4 a straight-chain or branched-chain alkynyl, C 1-4 a straight-chain or branched-chain alkoxy, and the alkyl, alkenyl, alkynyl, and alkoxy are optionally substituted by one or more substituents independently selected from F, Cl, Br, -OH, -CN, -NH 2 、C 1-4 a straight-chain or branched-chain alkyl, C 2-4 a straight-chain or branched-chain alkenyl, C 2-4 a straight-chain or branched-chain alkynyl, C 1-4 a straight-chain or branched-chain alkoxy group.

[0018] In a preferred embodiment, in the compound of formula (I),

[0019] X and Y are independently selected from N, CR 7 ;

[0020] R 1 is selected from -OH, -OCH 3 、-C(O)OCH 3 、-C(O)NH 2 、-COOH、-NH 2 、-N(H)C(O)CH 3 、-N(H)S(O) 2 CH 3 、-B(OH) 2 、-S(O) 2 CH 3 、-P(O)(CH 3 ) 2 、-OCH 2 CH 2 OH、-C(O)N(H)CH 2 CH 2 OH、-C(O)N(H)CH 2 CH 2 NH 2 ;

[0021] R 2 and R 3 are independently selected from F, Cl, Br, I, -CN, -CH 3 、-CF 3 、-OCF 3 、-C(O)CH3 、 -S(O) 2 CH 3 、 -P(O)(CH 3 ) 2 、 -C(O)OCH 3 、 -C(O)NH 2 、 ethynyl, cyclopropyl, oxetanyl, and R 2 and R 3 are not both halogen at the same time;

[0022] R 4 、 R 5 and R 6 are independently selected from H, -CH 3 、 -CH 2 CF 3 、 cyclopropyl;

[0023] Or, R 5 and R 6 together with the carbon atom to which they are commonly attached form C=O, cyclopropyl, oxetanyl;

[0024] Ring A is selected from phenyl, a 5 - 11 - membered heteroaryl containing 1 - 3 ring heteroatoms independently selected from N, O, S and connected to the proximal carbon atom through C, C 3-7 cycloalkyl, C 3-7 cycloalkenyl, a 3 - 7 - membered heterocycloalkyl containing 1 - 3 ring heteroatoms independently selected from N, O, S and connected to the proximal carbon atom through C, C 5-9 bridged cycloalkyl, a 5 - 9 - membered heterobridged cycloalkyl containing 1 - 3 ring heteroatoms independently selected from N, O, S and connected to the proximal carbon atom through C, and a bicyclic formed by the fusion of any two of the phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl;

[0025] m is 1 or 2;

[0026] R 7 is independently selected from H, F, Cl, Br, -CN, C 1-4 linear or branched alkyl, C 3-7 cycloalkyl, a 3 - 7 - membered heterocycloalkyl containing 1 - 3 ring heteroatoms independently selected from N, O, S and connected to the proximal group through C or N, -OR 8 、 -C(O)R 8 、 -S(O) 2 R 8 、 -N(R 8 )R 9 、 -N(R 8 )C(O)R 9 、 -P(O)(R 8 )R9 The alkyl, cycloalkyl, or heterocycloalkyl is optionally substituted by one or more substituents independently selected from F, Cl, Br, C 1-4 a straight-chain or branched-chain alkyl group;

[0027] R 8 and R 9 are independently selected from H, C 1-4 a straight-chain or branched-chain alkyl, C 3-7 a cycloalkyl, a 3- to 7-membered heterocycloalkyl containing 1 to 3 ring heteroatoms independently selected from N, O, S and linked to the proximal group through C, C 5-9 a bridged cycloalkyl, a 5- to 9-membered heterobridged cycloalkyl containing 1 to 3 ring heteroatoms independently selected from N, O, S and linked to the proximal group through C, a phenyl, a 5- to 11-membered heteroaryl containing 1 to 3 ring heteroatoms independently selected from N, O, S and linked to the proximal group through C, a spiro ring linked to the proximal group through C on any one of the spiro rings, the spiro ring being composed of a 3- to 7-membered heteroalkane ring containing 1 to 3 ring heteroatoms independently selected from N, O, S and a 3- to 7-membered alkane ring, and the alkyl, cycloalkyl, heterocycloalkyl, bridged cycloalkyl, heterobridged cycloalkyl, phenyl, heteroaryl, spiro ring are optionally substituted by one or more substituents independently selected from F, Cl, Br, a C 1-4 a straight-chain or branched-chain alkyl optionally substituted by one or more substituents independently selected from F, Cl, Br, a C 1-4 a straight-chain or branched-chain alkoxy group;

[0028] In a further preferred embodiment, in the compound of formula (I),

[0029] X and Y are independently selected from N, CH;

[0030] R 1 is selected from -OH, -OCH 3 , -C(O)OCH 3 , -C(O)NH 2 , -COOH, -NH 2 , -N(H)C(O)CH 3 , -N(H)S(O) 2 CH 3 , -B(OH) 2 , -S(O) 2 CH 3 , -P(O)(CH 3 ) 2 , -OCH 2 CH 2 OH;

[0031] R2 and R 3 are independently selected from F, Cl, Br, I, -CN, -CH 3 , -CF 3 , -OCF 3 , -C(O)CH 3 , -S(O) 2 CH 3 , -P(O)(CH 3 ) 2 , -C(O)OCH 3 , -C(O)NH 2 , and R 2 and R 3 are not both halogen at the same time;

[0032] R 4 , R 5 and R 6 are independently selected from H, -CH 3 ;

[0033] The A ring is selected from phenyl, a 5-6 membered heteroaryl containing 1-3 ring heteroatoms independently selected from N, O, S and connected to the proximal carbon atom through C; preferably, the A ring is selected from phenyl, pyridyl;

[0034] m is 1 or 2;

[0035] R 7 is independently selected from F, Cl, Br, -CN, C 1-4 a straight-chain or branched-chain alkyl, C 1-4 a straight-chain or branched-chain alkoxy, cyclohexyloxy, cyclobutyloxy, phenoxy, and the alkyl, alkoxy, cyclohexyloxy, cyclobutyloxy, phenoxy are optionally substituted by one or more substituents independently selected from F, Cl, Br, C 1-4 a straight-chain or branched-chain alkyl.

[0036] In a further preferred embodiment, the present invention provides a compound shown in the following (II) or a pharmaceutically acceptable salt or deuterated compound thereof:

[0037]

[0038] R 1 is selected from -OH, -OCH 3 , -C(O)OCH 3 , -C(O)NH 2 , -COOH, -NH 2 , -N(H)C(O)CH 3 , -N(H)S(O) 2 CH 3 , -B(OH) 2, -S(O) 2 CH 3 , -P(O)(CH 3 ) 2 , -OCH 2 CH 2 OH;

[0039] R 2 and R 3 are independently selected from F, Cl, Br, I, -CN, -CH 3 , -CF 3 , -OCF 3 , -C(O)CH 3 , -S(O) 2 CH 3 , -P(O)(CH 3 ) 2 , -C(O)OCH 3 , -C(O)NH 2 , and R 2 and R 3 are not simultaneously halogen;

[0040] R 7 is cyclohexyloxy, which is optionally substituted by one or more substituents independently selected from F, Cl, Br.

[0041] In a further preferred embodiment, in the compound of formula (II),

[0042] R 1 is selected from -OH, -C(O)OCH 3 , -COOH, -S(O) 2 CH 3 , -OCH 2 CH 2 OH;

[0043] R 2 is selected from F, Cl, Br, I, -CN, -CH 3 , -CF 3 , -OCF 3 , -C(O)CH 3 , -S(O) 2 CH 3 , -P(O)(CH 3 ) 2 , -C(O)OCH 3 , -C(O)NH 2 ;

[0044] R 3 is -CH 3 ;

[0045] R 7 is cyclohexyloxy or

[0046] In a further preferred embodiment, the present invention provides a compound shown in the following (III) or a pharmaceutically acceptable salt or deuterated compound thereof:

[0047]

[0048] R 1 is selected from -OH, -OCH 3 , -C(O)OCH 3 , -C(O)NH 2 , -COOH, -NH 2 , -N(H)C(O)CH 3 , -N(H)S(O) 2 CH 3 , -B(OH) 2 , -S(O) 2 CH 3 , -P(O)(CH 3 ) 2 , -OCH 2 CH 2 OH;

[0049] R 2 and R 3 are independently selected from F, Cl, Br, I, -CN, -CH 3 , -CF 3 , -OCF 3 , -C(O)CH 3 , -S(O) 2 CH 3 , -P(O)(CH 3 ) 2 , -C(O)OCH 3 , -C(O)NH 2 , and, R 2 and R 3 are not simultaneously halogen;

[0050] R 7 is cyclohexyloxy, and the cyclohexyloxy is optionally substituted by one or more substituents independently selected from F, Cl, Br.

[0051] In a further preferred embodiment, in the compound of formula (III),

[0052] R 1 is selected from -OH, -C(O)OCH 3 , -COOH, -S(O) 2CH 3 、 -OCH 2 CH 2 OH;

[0053] R 2 is selected from F, Cl, Br, I, -CN, -CH 3 , -CF 3 , -OCF 3 , -C(O)CH 3 , -S(O) 2 CH 3 , -P(O)(CH 3 ) 2 , -C(O)OCH 3 , -C(O)NH 2 ;

[0054] R 3 is -CH 3 ;

[0055] R 7 is cyclohexyloxy or

[0056] In a more preferred embodiment, the compound of formula (I) of the present invention is selected from the following compounds or their pharmaceutically acceptable salts, deuterated compounds:

[0057]

[0058]

[0059]

[0060]

[0061] In the present invention, although the substituents are disclosed in groups or ranges, the groups or ranges of the present invention specifically refer to each specific group covered by them. For example, the term "C1-4 alkyl" specifically refers to methyl (i.e., C1 alkyl), ethyl (i.e., C2 alkyl), propyl (i.e., C3 alkyl), butyl (i.e., C4 alkyl) disclosed independently. The same applies to "C1-4 straight-chain or branched-chain alkyl", "C2-4 straight-chain or branched-chain alkenyl", "C2-4 straight-chain or branched-chain alkynyl", "C1-4 straight-chain or branched-chain alkoxy", etc.

[0062] In the present invention, "halogen" specifically refers to fluorine, chlorine, bromine, iodine disclosed independently.

[0063] In the present invention, "C3-7 cycloalkyl" or "3-7 membered cycloalkyl" specifically refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl disclosed independently.

[0064] In the present invention, "a 3- to 7-membered heterocycloalkyl containing 1 to 3 ring heteroatoms independently selected from N, O, and S" specifically refers to those independently disclosed, such as but not limited to ethylene oxide, thiirane, aziridine, oxetane, N-azetidine, α-lactam ring, β-lactam ring, β-lactone, tetrahydrofuran, thiolane, pyrrolidine, pyrroline, dioxolane, oxazolidine, oxazoline, isoxazolidine, thiazolidine, isothiazolidine, thiazoline, imidazolidine, imidazoline, pyrazolidine, pyrazoline, tetrahydropyran, dihydropyran, pyran, piperidine, 1,4-dioxane, morpholine, piperazine, 1,4-oxazepane, 1,4-thiazepane, azepane, cyclohexene oxide, thiepane, etc.

[0065] In the present invention, "a 5- to 6-membered heteroaryl containing 1 to 3 ring heteroatoms independently selected from N, O, and S" specifically refers to those independently disclosed, such as but not limited to furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, oxadiazole, thiadiazole, pyridine, pyrimidine, pyridazine, pyrazine, triazine, etc.

[0066] In the present invention, "a 5- to 11-membered heteroaryl containing 1 to 3 ring heteroatoms independently selected from N, O, and S" in addition to the above, specifically refers to those independently disclosed, such as but not limited to benzazetidine, benzoyl-β-lactam ring, benzoyl-β-lactone, benzodioxole, benzofuran, benzothiophene, indole, indazole, isoindazole, benzimidazole, benzothiazole, benzisothiazole, benzoxazole, benzisoxazole, benzotriazole, benzoxadiazole, benzothiadiazole, benzodioxane, benzomorpholine, benzopiperidine, benzopyran, benzopyrone, benzopyridine, benzopyrimidine, benzotriazine, benzazepanone, benzazepanone, pyridoazetidine, pyrido-β-lactam ring, pyrido-β-lactone, pyridodioxole, pyridofuran, pyridothiophene, pyridopyrrole, pyridopyrazole, pyridoimidazole, pyridothiazole, pyridoisothiazole, pyridooxazole, pyridoisoxazole, pyridotriazole, pyridooxadiazole, pyridothiadiazole, pyridodioxane, pyridomorpholine, pyridopiperidine, pyridopyran, pyridopyridine, pyridopyrimidine, pyridotriazine, pyridoazepanone, furanopyrrole, thiazolopyrimidine, etc.

[0067] In the present invention, "C 5-9 bridged cycloalkyl" includes but is not limited to bicyclo[1.1.1]pentane, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.1.1]heptane, bicyclo[4.1.1]octane, bicyclo[4.2.1]nonane, bicyclo[3.2.2]nonane, etc.

[0068] In the present invention, "5- to 9-membered hetero-bridged cycloalkyl containing 1 to 3 ring heteroatoms independently selected from N, O, and S" includes but is not limited to 2-oxabicyclo[2.2.2]octane, 2-oxabicyclo[2.1.1]hexane, 1-azabicyclo[2.2.1]heptane, 2-azabicyclo[2.2.1]heptane, 7-azabicyclo[2.2.1]heptane, 3,6-diazabicyclo[3.2.2]nonane, 3,6-diazabicyclo[3.1.1]heptane, 3-aza-6-oxabicyclo[3.1.1]heptane, 3-oxa-6-azabicyclo[3.1.1]heptane, 3,8-diazabicyclo[3.2.1]octane, 3-oxa-8-azabicyclo[3.2.1]octane, 3-aza-8-oxabicyclo[3.2.1]octane, 2-oxa-5-azabicyclo[2.2.1]heptane, 2,5-diazabicyclo[2.2.1]heptane, 2-oxa-5-azabicyclo[2.2.2]octane, 2,5-diazabicyclo[2.2.2]octane, and the like.

[0069] The compounds of the present invention may be asymmetric, for example, having one or more stereocenters. All stereoisomers, such as enantiomers and diastereomers, are included within the scope of the present invention unless otherwise specified. In the present invention, compounds containing asymmetrically substituted carbon atoms may be isolated in any optically active form or racemic form. Various methods for preparing optically active forms are known in the art, for example, by resolution of racemic mixtures or by stereoselective synthesis.

[0070] The present invention also includes pharmaceutically acceptable salts of the compounds. The compounds of the present invention can be prepared into pharmaceutically acceptable salts by reacting with non-toxic inorganic or organic acids. Inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid, nitric acid, bisulfate, boric acid, hemisulfuric acid, etc.; organic acids such as formic acid, acetic acid, propionic acid, butyric acid, valeric acid, hexanoic acid, heptanoic acid, undecanoic acid, palmitic acid, stearic acid, oleic acid, oxalic acid, malonic acid, adipic acid, lactic acid, malic acid, maleic acid, hippuric acid, tartaric acid, citric acid, succinic acid, ascorbic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, benzoic acid, camphoric acid, camphorsulfonic acid, citric acid, fumaric acid, gluconic acid, galacturonic acid, dodecylsulfuric acid, and various amino acids, etc. The compounds of the present invention can also be prepared into pharmaceutically acceptable salts by reacting with non-toxic organic bases. Organic bases such as trimethylamine, triethylamine, N-ethyldiisopropylamine, pyridine, quinoline, piperidine, imidazole, picoline, dimethylaminopyridine, dimethylaniline, N-methylmorpholine, 1,5-diazabicyclo[4.3.0]nonene-5, 1,8-diazabicyclo[5.4.0]undecene-7, 1,4-diazabicyclo[2.2.2]octane, etc. The compounds of the present invention can also form salts of alkali metals such as sodium, potassium, lithium, cesium, magnesium, calcium, ammonium salts, etc.

[0071] The present invention also includes hydrates and solvates of the compound.

[0072] The present invention also includes all forms of the compound in which its atoms are various isotopes. Isotopes include all atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include deuterium.

[0073] The present invention also includes prodrugs of the compound. A "prodrug" refers to a compound obtained by structurally modifying the compound, which is inactive or has less activity in vitro in a patient, but releases the compound in the patient's body through enzymatic or non-enzymatic conversion to exert its drug effect.

[0074] Those skilled in the art can understand that the compounds of the present invention can be prepared by various methods disclosed in the literature. The reaction can be carried out in a suitable solvent to prepare the compounds of the present invention. Those skilled in the field of organic synthesis can easily select a suitable solvent that basically does not react with the reactants, intermediates or products. The reaction can be carried out in one solvent or a mixture of one or more solvents. The reaction can be carried out at a suitable temperature to prepare the compounds of the present invention, for example, between the freezing temperature and the boiling temperature of the solvent. The methods for preparing the compounds of the present invention involve protecting and deprotecting various chemical groups. Those skilled in the field of organic synthesis can easily determine whether it is necessary to protect and deprotect the chemical groups and select a suitable protecting group. Any method known in the art can be used to monitor the reaction for preparing the compounds of the present invention, such as nuclear magnetic resonance spectroscopy, infrared spectroscopy, mass spectrometry, chromatography, etc.

[0075] The present invention provides a method for preparing a compound of formula (I) as follows:

[0076] Method I:

[0077]

[0078] The definitions of the groups in each formula are as described above.

[0079] Among them, the synthesis reaction of I-2 can be carried out in a solvent in the presence of a base. The solvent can be selected from ethanol, methanol, tetrahydrofuran, dioxane, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, water, etc. or any mixture thereof; the base can be selected from triethylamine, N,N-diisopropylethylamine, DBU, pyridine, DMAP, N-methylmorpholine, etc.

[0080] Among them, the synthesis reaction of I-3 can be carried out in a solvent in the presence of a base. The solvent can be selected from dichloromethane, ethyl acetate, dioxane, tetrahydrofuran, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, pyridine, etc. or any mixture thereof; the base can be selected from triethylamine, N,N-diisopropylethylamine, DBU, pyridine, DMAP, N-methylmorpholine, etc.

[0081] Among them, the synthesis reaction of the compound of formula (I) can be carried out in the presence or absence of a catalyst and in the presence or absence of a solvent. The solvent can be selected from ethanol, methanol, tetrahydrofuran, dioxane, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, etc. or any mixture thereof; the catalyst can be selected from trimethylaluminum, sodium ethoxide, potassium tert-butoxide, n-butyllithium, ethylmagnesium bromide, sodium bis(trimethylsilyl)amide, etc.

[0082] Method II:

[0083]

[0084] The definitions of the groups in each formula are as described above.

[0085] Among them, the synthesis reaction of I-4 can be carried out in a solvent in the presence of a catalyst. The solvent can be selected from ethanol, methanol, tetrahydrofuran, ethyl acetate, dioxane, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, water, etc. or any mixture thereof; the catalyst can be selected from sodium hydroxide, lithium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sulfuric acid, hydrochloric acid, phosphoric acid, acetic acid, etc.

[0086] Among them, the synthesis reaction of the compound of formula (I) can be carried out in a solvent in the presence of a catalyst and a base. The solvent can be selected from dichloromethane, ethyl acetate, tetrahydrofuran, dioxane, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, etc. or any mixture thereof; the catalyst can be selected from EDCI, CDI, DCC, DIC, HATU, HBTU, BOP, PyBOP, TCFH, MTM, T3P, etc., and the base can be selected from DIPEA, TEA, HOBT, MNI, DBU, etc.

[0087] The compounds of the present invention can inhibit c-Myc. Therefore, according to another aspect of the present invention, the present invention provides a method for inhibiting c-Myc.

[0088] According to another aspect of the present invention, the present invention provides a method for preventing and / or treating c-Myc-related or mediated diseases, wherein an individual in need is administered a prophylactically and / or therapeutically effective amount of the compound of the present invention or a pharmaceutical composition containing the compound of the present invention.

[0089] c-Myc related or mediated diseases include any diseases directly and / or indirectly related to the expression and / or activity of c-Myc, e.g., diseases that can be prevented and / or treated by inhibiting c-Myc. For example, c-Myc related diseases include tumors selected from: lung cancer, breast cancer, liver cancer, pancreatic cancer, colorectal cancer, melanoma, bladder cancer, prostate cancer, gastric cancer, esophageal cancer, ovarian cancer, head and neck cancer, urothelial cancer, endometrial cancer, thyroid cancer, kidney cancer, nasopharyngeal cancer, glioma, osteosarcoma, lymphoma, hematological tumors, etc.

[0090] According to another aspect of the present invention, the present invention provides the use of the compounds of the present invention in the preparation of c-Myc inhibitors.

[0091] According to another aspect of the present invention, the present invention provides the use of the compounds of the present invention in the preparation of a medicament for preventing and / or treating c-Myc related or mediated diseases.

[0092] When using the compounds of the present invention to prevent and / or treat c-Myc related or mediated diseases, the compounds of the present invention can be administered in the form of a pharmaceutical composition. Therefore, according to another aspect of the present invention, the present invention provides a pharmaceutical composition comprising the compounds of the present invention and a pharmaceutically acceptable carrier.

[0093] Those skilled in the art can understand that the pharmaceutical compositions of the present invention can be prepared by various methods disclosed in the literature. The compounds or pharmaceutical compositions of the present invention can be administered by a variety of routes, depending on the need for local or systemic treatment and the area to be treated. For example, it can be administered orally, parenterally (e.g., intravenous, arterial, subcutaneous, intraperitoneal, intramuscular injection or infusion), intracranially such as intrathecally or intraventricularly, transdermally, ophthalmically, nasally, vaginally, rectally, by inhalation or insufflation of powder or aerosol into the lungs.

[0094] For oral administration, the pharmaceutical compositions of the present invention are usually provided in the form of tablets, capsules or solutions. Tablets may contain the compounds of the present invention and pharmaceutically acceptable carriers. The carriers include but are not limited to diluents, disintegrants, binders, lubricants, colorants or preservatives. Capsules include hard capsules and soft capsules. For parenteral administration, the pharmaceutical compositions of the present invention can be administered by intravenous injection, intramuscular injection or subcutaneous injection. It is usually provided as a sterile aqueous solution or suspension or lyophilized powder, and the appropriate pH and isotonicity are adjusted.

[0095] The effective amount of the compounds of the present invention can be determined according to the specific use of the treatment, the mode of administration, and the condition of the individual in need, such as the patient. Those skilled in the art are capable of determining the effective amount of the compounds of the present invention. Typical dosage ranges are, for example, 1 μg to 1000 mg / kg / day.

[0096] When preventing and / or treating c-Myc-related or mediated diseases, the compounds of the present invention can be used in combination with one or more other drugs. Detailed implementation manners

[0097] The present invention will be further described below in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and not to limit the scope of the present invention. In addition, it should be understood that after reading the content described in the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the present invention.

[0098] Preparation Example 1. Synthesis of common intermediate common int-1

[0099]

[0100] Synthesis of N,4-dihydroxy-3,5-dimethylbenzamidine (2):

[0101] Dissolve 3,5-dimethyl-4-hydroxybenzonitrile (400.0 mg, 2.72 mmol), hydroxylamine hydrochloride (571.4 mg, 8.22 mmol), and N,N-diisopropylethylamine (1.1 g, 8.51 mmol) in ethanol (30 mL), heat to 80 °C and react for 3 hours. After the reaction solution is cooled, it is concentrated under reduced pressure. The concentrated solution is diluted with water (100 mL) and extracted with ethyl acetate (100 mL × 2). The combined organic phases are washed with saturated sodium chloride aqueous solution (200 mL × 4), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a white solid (400.0 mg). LC-MS: [M-H] － : 179.1.

[0102] Synthesis of ethyl 3-(4-hydroxy-3,5-dimethylphenyl)-1,2,4-oxadiazole-5-carboxylate (common int-1):

[0103] Dissolve compound N,4-dihydroxy-3,5-dimethylbenzamidine (200.0 mg, 1.11 mmol) in pyridine (2 ml), dropwise add ethyl oxalyl chloride (197.5 mg, 1.45 mmol) at 0 °C, stir and react at this temperature for 0.5 hour, then heat to 60 °C and continue to react for 3 hours. After the reaction solution is cooled, it is concentrated under reduced pressure. The concentrated solution is diluted with water (50 mL) and extracted with ethyl acetate (50 mL × 2). The combined organic phases are washed with saturated sodium chloride aqueous solution (100 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a yellow solid (150.0 mg). LC-MS: [M-H] － : 261.1.

[0104] Preparation Example 2. Synthesis of Common Intermediate common int-2

[0105]

[0106] Synthesis of 3-bromo-4-hydroxy-5-(trifluoromethyl)benzonitrile (2):

[0107] Dissolve 4-hydroxy-3-(trifluoromethyl)benzonitrile (3.0 g, 16.03 mmol) and N-bromosuccinimide (4.3 g, 24.16 mmol) in acetonitrile (50 mL), and heat the solution to 80 °C and react for 2 hours. After the reaction solution is cooled, it is concentrated, diluted with water (100 mL), and extracted with ethyl acetate (100 mL × 3). The combined organic phases are washed with saturated sodium chloride aqueous solution (100 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude white solid. The crude product is purified by silica gel column chromatography (0 - 20% ethyl acetate / petroleum ether) to obtain a white solid (4.1 g). LC-MS: [M-H] - : 264.3, 266.3.

[0108] Synthesis of 3-bromo-4-((4-methoxybenzyl)oxy)-5-(trifluoromethyl)benzonitrile (3):

[0109] Dissolve 3-bromo-4-hydroxy-5-(trifluoromethyl)benzonitrile (4.1 g, 15.41 mmol), 4-methoxybenzyl chloride (3.2 g, 20.43 mmol), tetrabutylammonium iodide (1.1 g, 2.98 mmol), and potassium carbonate (5.4 g, 39.07 mmol) in acetone (50 mL), and react at room temperature for 1 hour. After the reaction solution is concentrated, it is diluted with water (300 mL), and extracted with ethyl acetate (300 mL × 2). The combined organic phases are washed with saturated brine (500 mL × 6), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude white solid. The crude product is purified by silica gel column chromatography (0 - 10% ethyl acetate / petroleum ether) to obtain a yellow solid (3.2 g). 1 H NMR (400 MHz, DMSO-d6) δ 8.67 (s, 1H), 8.35 (s, 1H), 7.45 (d, J = 8.4 Hz, 2H), 7.00 (d, J = 8.4 Hz, 2H), 5.07 (s, 2H), 3.78 (s, 3H).

[0110] Synthesis of 4-((4-methoxybenzyl)oxy)-3-methyl-5-(trifluoromethyl)benzonitrile (4):

[0111] The compound 3-bromo-4-((4-methoxybenzyl)oxy)-5-(trifluoromethyl)benzonitrile (1.0 g, 2.59 mmol), trimethylcyclotriboroxane (0.6 g, 4.78 mmol), chloro(2-(dicyclohexylphosphino)-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.2 g, 0.26 mmol), and potassium carbonate (1.1 g, 7.96 mmol) were placed in 1,4-dioxane (15 mL) and water (1.5 mL), and the temperature was raised to 100 °C for reaction for 3 hours. After the reaction solution was cooled, it was diluted with water (100 mL) and extracted with ethyl acetate (100 mL × 2). The combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (0 - 12% ethyl acetate / petroleum ether) to obtain a yellow solid (350.0 mg). 1 H NMR(400MHz,DMSO-d 6 )δ8.12–8.10(m,2H),7.42(d,J=8.4Hz,2H),6.99(d,J=8.4Hz,2H),4.93(s,2H),3.78(s,3H),2.43(s,3H).

[0112] Synthesis of N-hydroxy-4-((4-methoxybenzyl)oxy)-3-methyl-5-(trifluoromethyl)benzamidine (5):

[0113] The compound 4-((4-methoxybenzyl)oxy)-3-methyl-5-(trifluoromethyl)benzonitrile (320.0 mg, 1.00 mmol), hydroxylamine hydrochloride (208.0 mg, 2.99 mmol), and N,N-diisopropylethylamine (385.0 mg, 2.98 mmol) were dissolved in ethanol (4 ml), and the temperature was raised to 80 °C for reaction for 2 hours. After the reaction solution was cooled, it was diluted with water (60 mL) and extracted with ethyl acetate (60 mL × 2). The combined organic phases were washed with saturated brine (120 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude white solid (300.0 mg), which was directly used in the next step. LC-MS: [M + H] + : 355.1.

[0114] Synthesis of ethyl 3-(4-((4-methoxybenzyl)oxy)-3-methyl-5-(trifluoromethyl)phenyl)-1,2,4-oxadiazole-5-carboxylate (common int-2):

[0115] Dissolve the compound N-hydroxy-4-((4-methoxybenzyl)oxy)-3-methyl-5-(trifluoromethyl)benzamidine (300.0 mg, 0.85 mmol) in pyridine (3 mL). After cooling in an ice bath, slowly add ethyl oxalyl chloride (149.8 mg, 1.10 mmol), and then raise the temperature to 60 °C and stir the reaction for 4 hours. After the reaction solution is cooled, it is concentrated under reduced pressure. The residue is diluted with water (80 mL) and extracted with ethyl acetate (80 mL × 2). The combined organic phases are washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product is purified by silica gel column chromatography (0 - 30% ethyl acetate / petroleum ether) to obtain a white solid (250.0 mg). LC-MS: [M+H] + : 437.3.

[0116] Preparation Example 3. Synthesis of common intermediate common int-3

[0117]

[0118] (Z)-3-Chloro-N’,4-dihydroxy-5-methylbenzamidine (2) synthesis:

[0119] Dissolve the compound 3-chloro-4-hydroxy-5-methylbenzonitrile (300.0 mg, 1.79 mmol) and hydroxylamine hydrochloride (248.1 mg, 3.57 mmol) in ethanol (5 mL), add N,N-diisopropylethylamine (696.6 mg, 5.39 mmol), and raise the temperature of the reaction solution to 80 °C and react for 16 hours. After the reaction is completed, concentrate the reaction solution to dryness, pour it into an aqueous solution (30 mL), and then extract with ethyl acetate (40 mL × 3). The combined organic phases are dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain a crude brown solid (220.7 mg). LC-MS: [M+H] + : 201.1, 203.1.

[0120] Ethyl 3-(3-chloro-4-hydroxy-5-methylphenyl)-1,2,4-oxadiazole-5-carboxylate (common int-3) synthesis:

[0121] Dissolve the compound (Z)-3-chloro-N',4-dihydroxy-5-methylbenzamidine (220.7 mg, 1.10 mmol) in pyridine (1 mL), slowly add ethyl oxalyl chloride (166.6 mg, 1.22 mmol) dropwise, and then heat the reaction system to 60 °C and stir for 2 hours. After the reaction is completed, concentrate the reaction solution to dryness, pour it into an aqueous solution (10 mL), then extract with ethyl acetate (10 mL × 3). Combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate to dryness, and purify by a chromatography column (petroleum ether:ethyl acetate = 10:1) to obtain a white solid (270.0 mg). LC-MS: [M+H] + : 283.3, 285.3.

[0122] Preparation Example 4. Synthesis of common intermediate common int-4

[0123]

[0124] Synthesis of N,4-dihydroxy-3-methylbenzamidine (2):

[0125] Dissolve the compound 4-hydroxy-3-methylbenzonitrile (4.2 g, 31.54 mmol) and hydroxylamine hydrochloride (4.4 g, 63.32 mmol) in ethanol (60 mL), add N,N-diisopropylethylamine (12.2 g, 94.39 mmol), and heat the reaction solution to 80 °C and react for 16 hours. After the reaction is completed, concentrate the reaction solution to dryness, pour it into an aqueous solution (30 mL), then extract with ethyl acetate (40 mL × 3). Combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate to dryness, and obtain a crude brown solid (4.5 g). LC-MS: [M+H] + : 167.1.

[0126] Synthesis of ethyl 3-(4-hydroxy-3-methylphenyl)-1,2,4-oxadiazole-5-carboxylate (3):

[0127] Dissolve the compound N,4-dihydroxy-3-methylbenzamidine (4.5 g, 27.08 mmol) in pyridine (25 mL), slowly add ethyl oxalyl chloride (4.1 g, 30.03 mmol) dropwise, and then heat the reaction system to 60 °C and stir for 2 hours. After the reaction is completed, concentrate the reaction solution to dryness, pour it into an aqueous solution (30 mL), then extract with ethyl acetate (40 mL × 3). Combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate to dryness, and purify by a chromatography column (petroleum ether:ethyl acetate = 10:1) to obtain a white solid (1.5 g). LC-MS: [M+H] + : 249.3. Synthesis of methyl 3-(4-hydroxy-3-iodo-5-methylphenyl)-1,2,4-oxadiazole-5-carboxylate (common int-4):

[0128] Ethyl 3-(4-hydroxy-3-methylphenyl)-1,2,4-oxadiazole-5-carboxylate (1.5 g, 6.04 mmol) and sodium acetate (545.5 mg, 6.65 mmol) were dissolved in methanol (15 mL), and iodine (1.7 g, 6.70 mmol) was added. The reaction mixture was reacted at 80 °C for 2 hours. After the reaction was completed, an aqueous solution of sodium thiosulfate (10 mL) was poured into the reaction mixture, and water (10 mL) and ethyl acetate (20 mL × 3) were added for extraction. The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and purified by a chromatography column (petroleum ether:ethyl acetate = 10:1) to obtain a white solid (700.0 mg). LC-MS: [M+H] + : 361.0.

[0129] Preparation Example 5. Synthesis of common intermediate common int-5

[0130]

[0131] Synthesis of 6-((4,4-difluorocyclohexyl)oxy)nicotinonitrile (2):

[0132] 60% Sodium hydride (1.2 g, 30.00 mmol) was dissolved in N,N-dimethylformamide (10 mL), and nitrogen was displaced three times. 4,4-Difluorocyclohexan-1-ol (3.5 g, 25.71 mmol) was dissolved in N,N-dimethylformamide (10 mL), and the above solution was added at 0 °C. After returning to room temperature, the mixture was stirred for 1 hour. 6-Fluoro-3-pyridinecarbonitrile (3.0 g, 24.57 mmol) was dissolved in N,N-dimethylformamide (10 mL), and the solution was added to the reaction mixture at 0 °C and stirred for 1 hour. Monitored by LCMS, the raw materials disappeared and the product was the main peak. The reaction was quenched by adding saturated ammonium chloride (40 mL), and the organic phase was collected. The aqueous phase was extracted with ethyl acetate (50 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and rotary evaporated to obtain a crude product, which was purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain a white solid (2.5 g). LC-MS: [M+H] + : 239.1.

[0133] Synthesis of (6-((4,4-difluorocyclohexyl)oxy)pyridin-3-yl)methanamine (common int-5):

[0134] Dissolve 6-((4,4-difluorocyclohexyl)oxy)nicotinonitrile (2.5 g, 10.49 mmol) in tetrahydrofuran (10 mL), displace nitrogen three times, add 1 M borane tetrahydrofuran solution (21 mL, 21.00 mmol) at 0 °C, warm to 65 °C and stir for 3 hours. Monitor by LCMS, and the product is the main peak. Quench with methanol (10 mL), rotary evaporate the reaction solution to obtain the crude product, and obtain a yellow oil (883.0 mg) through a silica gel column (methylene chloride:methanol = 10:1). LC-MS: [M+H] + : 243.1.

[0135] Example 1. Synthesis of compound DP001

[0136]

[0137] Synthesis of 3-(4-hydroxy-3,5-dimethylphenyl)-N-(4-phenoxybenzyl)-1,2,4-oxadiazole-5-carboxamide (DP001):

[0138] Dissolve ethyl 3-(4-hydroxy-3,5-dimethylphenyl)-1,2,4-oxadiazole-5-carboxylate (130.0 mg, 0.50 mmol) and (4-phenoxyphenyl)methanamine (148.0 mg, 0.74 mmol) in ethanol (2 mL), heat to 80 °C and react for 16 hours. After the reaction solution is cooled and concentrated, the crude product is purified by preparative liquid chromatography to obtain a white solid (10.8 mg). 1 H NMR (400 MHz, DMSO-d6) δ 9.94 (t, J = 6.0 Hz, 1H), 9.04 (s, 1H), 7.65 (s, 2H), 7.40–7.36 (m, 4H), 7.13 (t, J = 7.2 Hz, 1H), 7.02–6.95 (m, 4H), 4.47 (d, J = 6.0 Hz, 2H), 2.24 (s, 6H); LC-MS: [M+H] + : 416.1.

[0139] Example 2. Synthesis of compound DP002

[0140]

[0141] Synthesis of 3-(4-((4-methoxybenzyl)oxy)-3-methyl-5-(trifluoromethyl)phenyl)-N-(4-phenoxybenz)-1,2,4-oxadiazole-5-carboxamide (2):

[0142] Ethyl 3-(4-((4-methoxybenzyl)oxy)-3-methyl-5-(trifluoromethyl)phenyl)-1,2,4-oxadiazole-5-carboxylate (100.0 mg, 0.23 mmol) and (4-phenoxyphenyl)methanamine (45.5 mg, 0.23 mmol) were dissolved in ethanol (1 mL), and the reaction was carried out at 80 °C for 1 hour at room temperature. After cooling, the reaction solution was concentrated to obtain a white solid (130.0 mg), which was directly used for the next reaction. LC-MS: [M+H] + : 590.1.

[0143] Synthesis of 3-(4-hydroxy-3-methyl-5-(trifluoromethyl)phenyl)-N-(4-phenoxybenzyl)-1,2,4-oxadiazole-5-carboxamide (DP002):

[0144] To a solution of 3-(4-((4-methoxybenzyl)oxy)-3-methyl-5-(trifluoromethyl)phenyl)-N-(4-phenoxybenzyl)-1,2,4-oxadiazole-5-carboxamide (130.0 mg, 0.22 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (0.3 mL), and the reaction was carried out at room temperature for 1 hour. The reaction solution was directly concentrated to obtain a crude product, which was purified by preparative high performance liquid chromatography to obtain a white solid (34.0 mg). 1 1H NMR (400 MHz, MeOD) δ 8.11–8.08 (d, J = 13.2 Hz, 2H), 7.41–7.30 (m, 4H), 7.11–7.09 (m, 1H), 6.99–6.91 (m, 4H), 4.57 (s, 2H), 2.35 (s, 3H); LC-MS: [M-H] - : 468.3.

[0145] Example 3. Synthesis of compound DP003

[0146]

[0147] Synthesis of N-(4-(cyclohexyloxy)benzyl)-3-(4-hydroxy-3,5-dimethylphenyl)-1,2,4-oxadiazole-5-carboxamide (DP003):

[0148] Ethyl 3-(4-hydroxy-3,5-dimethylphenyl)-1,2,4-oxadiazole-5-carboxylate (100.0 mg, 0.38 mmol) and (4-(cyclohexyloxy)phenyl)methanamine (87.0 mg, 0.42 mmol) were dissolved in ethanol (1 mL), and the temperature was raised to 80 °C for 2 hours. After cooling, the reaction solution was concentrated to obtain a crude product, which was purified by preparative high performance liquid chromatography to obtain (32.4 mg). 11H NMR (400 MHz, DMSO-d6) δ 9.86 (t, J = 6.0 Hz, 1H), 9.03 (s, 1H), 7.65 (s, 2H), 7.25 (d, J = 8.4 Hz, 2H), 6.89 (d, J = 8.4 Hz, 2H), 4.39 (d, J = 6.0 Hz, 2H), 4.34–4.27 (m, 1H), 2.24 (s, 6H), 1.91–1.88 (m, 2H), 1.73–1.65 (m, 2H), 1.55–1.48 (m, 1H), 1.45–1.25 (m, 5H). LC-MS: [M-H] - : 420.3。

[0149] Example 4. Synthesis of Compound DP004

[0150]

[0151] Synthesis of N-(4-(cyclohexyloxy)benzyl)-3-(4-((4-methoxybenzyl)oxy)-3-methyl-5-(trifluoromethyl)phenyl)-1,2,4-oxadiazole-5-carboxamide (2):

[0152] Ethyl 3-(4-((4-methoxybenzyl)oxy)-3-methyl-5-(trifluoromethyl)phenyl)-1,2,4-oxadiazole-5-carboxylate (100.0 mg, 0.23 mmol) and (4-(cyclohexyloxy)phenyl)methanamine (47.0 mg, 0.23 mmol) were dissolved in ethanol (1 mL), and the mixture was heated to 80 °C and stirred for 16 h. After cooling, the reaction solution was concentrated to obtain a white solid (120.0 mg), which was directly used in the next step. LC-MS: [M+H] + : 596.1。

[0153] Synthesis of N-(4-(cyclohexyloxy)benzyl)-3-(4-hydroxy-3-methyl-5-(trifluoromethyl)phenyl)-1,2,4-oxadiazole-5-carboxamide (DP004):

[0154] Trifluoroacetic acid (0.3 mL) was added to a solution of N-(4-(cyclohexyloxy)benzyl)-3-(4-((4-methoxybenzyl)oxy)-3-methyl-5-(trifluoromethyl)phenyl)-1,2,4-oxadiazole-5-carboxamide (110.0 mg, 0.18 mmol) in dichloromethane (1 mL), and the mixture was stirred at room temperature for 1 h. The crude product obtained by concentrating the reaction solution was purified by preparative high performance liquid chromatography to obtain (30.0 mg). 11H NMR (400 MHz, MeOD) δ 8.11–8.08 (m, 2H), 7.28 (d, J = 8.4, 6 Hz, 2H), 6.88 (d, J = 8.4, 6 Hz, 2H), 4.51 (s, 2H), 4.34–4.23 (m, 1H), 2.35 (s, 3H), 1.99–1.91 (m, 2H), 1.82–1.74 (m, 2H), 1.61–1.29 (m, 6H); LC-MS: [M-H] - : 474.4。

[0155] Example 5. Synthesis of Compound DP005

[0156]

[0157] Synthesis of methyl 3-(3-cyano-4-hydroxy-5-methylphenyl)-1,2,4-oxadiazole-5-carboxylate (1):

[0158] Dissolve methyl 3-(4-hydroxy-3-iodo-5-methylphenyl)-1,2,4-oxadiazole-5-carboxylate (200.0 mg, 0.56 mmol) and zinc cyanide (98.3 mg, 0.84 mmol) in N,N-dimethylformamide (2 mL), and add tetrakis(triphenylphosphine)palladium (69.0 mg, 0.06 mmol). React the reaction solution at 80 °C for 2 hours. After the reaction is completed, extract the reaction solution with saturated brine (10 mL) and ethyl acetate (20 mL × 3). Combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate to dryness. Purify by column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain a white solid (100.0 mg). LC-MS: [M+H] + : 260.3。

[0159] Synthesis of 3-(3-cyano-4-hydroxy-5-methylphenyl)-N-(4-(cyclohexyloxy)benzyl)-1,2,4-oxadiazole-5-carboxamide (DP005):

[0160] Dissolve methyl 3-(3-cyano-4-hydroxy-5-methylphenyl)-1,2,4-oxadiazole-5-carboxylate (85.0 mg, 0.33 mmol) and (4-(cyclohexyloxy)phenyl)methanamine (67.0 mg, 0.34 mmol) in ethanol (3 mL), and add trimethylaluminum (71.3 mg, 0.99 mmol). React the reaction solution at 85 °C for 16 hours. After the reaction is completed, concentrate the reaction solution, add water (10 mL) and ethyl acetate (20 mL × 3) for extraction. Combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate to dryness. Purify by preparative separation to obtain a white solid (8.6 mg). 11H NMR (400 MHz, DMSO) δ 9.90 (t, J = 6.2 Hz, 1H), 8.05 (d, J = 3.1 Hz, 2H), 7.25 (d, J = 8.5 Hz, 2H), 6.89 (d, J = 8.6 Hz, 2H), 4.40 (d, J = 6.2 Hz, 2H), 4.34–4.27 (m, 1H), 2.30 (s, 3H), 1.93–1.87 (m, 2H), 1.73–1.66 (m, 2H), 1.50–1.24 (m, 6H); LC-MS: [M-H] - : 431.1。

[0161] Example 6. Synthesis of Compound DP006

[0162]

[0163] Synthesis of 4-(tetrahydro-2H-pyran-4-yloxy)benzonitrile (2):

[0164] Dissolve compound tetrahydro-2H-pyran-4-ol (847.7 mg, 8.30 mmol) and 60% sodium hydride (496.0 mg, 12.40 mmol) in N,N-dimethylformamide (10 mL). After reacting for 30 minutes, add 4-fluorobenzonitrile (1 g, 8.26 mmol), and then stir the reaction system at room temperature for 2 hours. After the reaction is completed, concentrate the reaction solution, add water (10 mL) and extract with ethyl acetate (20 mL × 3). Combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate to dryness. Purify by column chromatography (petroleum ether:ethyl acetate = 15:1) to obtain a white solid (1.5 g). LC-MS: [M+H] + : 204.3。

[0165] (4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)methanamine (3) synthesis:

[0166] Dissolve compound 4-(tetrahydro-2H-pyran-4-yloxy)benzonitrile (500.0 mg, 2.46 mmol) in tetrahydrofuran (3 mL). Slowly add 1 M borane in tetrahydrofuran solution (4.92 mL, 4.92 mmol) dropwise at 0 °C, and then raise the reaction system to 80 °C and stir for 2 hours. After the reaction is completed, quench with methanol solution (10 mL), dry over anhydrous sodium sulfate, filter, and concentrate to dryness. Purify by column chromatography (dichloromethane:methanol = 10:1) to obtain a transparent liquid (220.0 mg). LC-MS: [M+H] + : 208.3。

[0167] Synthesis of 3-(4-((4-Methoxybenzyl)oxy)-3-methyl-5-(trifluoromethyl)phenyl)-N-(4-((tetrahydro-2H-pyran-4-yl)oxy)benzyl)-1,2,4-oxadiazole-5-carboxamide (4):

[0168] Dissolve (4-((Tetrahydro-2H-pyran-4-yl)oxy)phenyl)methanamine (60.0 mg, 0.29 mmol) in ethanol (3 mL), and add ethyl 3-(4-((4-methoxybenzyl)oxy)-3-methyl-5-(trifluoromethyl)phenyl)-1,2,4-oxadiazole-5-carboxylate (126.0 mg, 0.29 mmol). Heat the reaction mixture to 90 °C and react for 3 hours. After the reaction is completed, concentrate the reaction mixture to dryness by rotary evaporation, add water (10 mL) and extract with ethyl acetate (20 mL × 3). Combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate to dryness. Purify by column chromatography (dichloromethane:methanol = 20:1) to obtain a yellow solid (80.0 mg). LC-MS: [M+H] + : 598.2.

[0169] Synthesis of 3-(4-Hydroxy-3-methyl-5-(trifluoromethyl)phenyl)-N-(4-((tetrahydro-2H-pyran-4-yl)oxy)benzyl)-1,2,4-oxadiazole-5-carboxamide (DP006):

[0170] Dissolve 3-(4-((4-Methoxybenzyl)oxy)-3-methyl-5-(trifluoromethyl)phenyl)-N-(4-((tetrahydro-2H-pyran-4-yl)oxy)benzyl)-1,2,4-oxadiazole-5-carboxamide (80.0 mg, 0.13 mmol) in dichloromethane (1.5 mL), and add trifluoroacetic acid (1 mL). React the reaction mixture at room temperature for 1 hour. After the reaction is completed, concentrate the reaction mixture to dryness and purify by preparative separation to obtain a white solid (30.3 mg). 1 H NMR (400 MHz, DMSO) δ 9.93 (t, J = 6.4 Hz, 1H), 8.07 (s, 1H), 8.02 (s, 1H), 7.27 (d, J = 8.8 Hz, 2H), 6.95 (d, J = 8.4 Hz, 2H), 4.58–4.51 (m, 1H), 4.41 (d, J = 6.4 Hz, 2H), 3.86–3.80 (m, 2H), 3.50–3.43 (m, 2H), 2.35 (s, 3H), 1.97–1.91 (m, 2H), 1.60–1.51 (m, 2H); LC-MS: [M-H] - : 476.0.

[0171] Example 7. Synthesis of Compound DP007

[0172]

[0173] Synthesis of 3-(3-chloro-4-hydroxy-5-methylphenyl)-N-(4-phenoxybenzyl)-1,2,4-oxadiazole-5-carboxamide (DP007):

[0174] Ethyl 3-(3-chloro-4-hydroxy-5-methylphenyl)-1,2,4-oxadiazole-5-carboxylate (80.0 mg, 0.28 mmol) was dissolved in ethanol (3 mL), and (4-phenoxyphenyl)methanamine (56.0 mg, 0.28 mmol) was added. The reaction mixture was reacted at 80 °C for 2 hours. After the reaction was completed, the reaction mixture was concentrated, water (10 mL) and ethyl acetate (20 mL × 3) were added for extraction. The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and purified by preparative separation to obtain a white solid (64.3 mg). 1 H NMR (400 MHz, DMSO) δ 9.97 (t, J = 6.0 Hz, 1H), 7.85 (d, J = 2.0 Hz, 1H), 7.78 (d, J = 1.6 Hz, 1H), 7.40–7.36 (m, 4H), 7.13 (t, J = 7.2 Hz, 1H), 7.01–6.97 (m, 4H), 4.48 (d, J = 6.4 Hz, 2H), 2.29 (s, 3H); LC-MS: [M+H] + : 436.0, 438.0.

[0175] Example 8. Synthesis of Compounds DP008, DP009, and DP010

[0176]

[0177] Synthesis of N-(4-(cyclohexyloxy)benzyl)-3-(4-hydroxy-3-iodo-5-methylphenyl)-1,2,4-oxadiazole-5-carboxamide (DP009):

[0178] (4-(Cyclohexyloxy)phenyl)methanamine (137.6 mg, 0.67 mmol) was dissolved in ethanol (3 mL), and methyl 3-(4-hydroxy-3-iodo-5-methylphenyl)-1,2,4-oxadiazole-5-carboxylate (248.5 mg, 0.69 mmol) was added. The reaction mixture was stirred at 80 °C for 2 hours. After the reaction was completed, the reaction mixture was concentrated. The crude product was purified by preparative separation to obtain a white solid (230.0 mg). 11H NMR (400 MHz, DMSO) δ 9.90 (t, J = 6.0 Hz, 1H), 8.21 (d, J = 2.0 Hz, 1H), 7.80 (d, J = 1.2 Hz, 1H), 7.25 (d, J = 8.4 Hz, 2H), 6.89 (d, J = 8.4 Hz, 2H), 4.40 (d, J = 6.0 Hz, 2H), 4.30 (td, J = 8.4, 3.6 Hz, 1H), 2.31 (s, 3H), 1.91–1.88 (d, J = 9.2 Hz, 2H), 1.74–1.63 (m, 2H), 1.56–1.47 (m, 1H), 1.43–1.24 (m, 5H); LC-MS: [M-H] - : 532.3。

[0179] Synthesis of methyl 5-(5-((4-(cyclohexyloxy)benzyl)carbamoyl)-1,2,4-oxadiazol-3-yl)-2-hydroxy-3-methylbenzoate (DP010):

[0180] Dissolve (N-(4-(cyclohexyloxy)benzyl)-3-(4-hydroxy-3-iodo-5-methylphenyl)-1,2,4-oxadiazole-5-carboxamide (202.7 mg, 0.38 mmol) in acetonitrile (5 mL), add triethylamine (38.5 mg, 0.38 mmol), palladium acetate (4.3 mg, 0.019 mmol), 1,1'-bis(diphenylphosphino)ferrocene (21.1 mg, 0.038 mmol) and methanol (1 mL). After the reaction system is purged with carbon monoxide gas three times, it is heated to 70 °C and reacted for 16 hours. After the reaction is completed, the reaction solution is concentrated, diluted with water (10 mL), and extracted with ethyl acetate (20 mL × 3). The combined organic phases are dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The crude product is separated by preparative separation to obtain a white solid (140.0 mg). 1 1H NMR (400 MHz, CDCl 3 ) δ 11.38 (s, 1H), 8.42 (d, J = 2.0 Hz, 1H), 8.03 (d, J = 1.2 Hz, 1H), 7.37 (t, J = 5.2 Hz, 1H), 7.28 (d, J = 8.4 Hz, 2H), 6.91 (d, J = 8.4 Hz, 2H), 4.61 (d, J = 5.6 Hz, 2H), 4.28–4.22 (m, 1H), 3.98 (s, 3H), 2.32 (s, 3H), 2.01–1.94 (m, 2H), 1.84–1.77 (m, 2H), 1.61–1.50 (m, 3H), 1.41–1.29 (m, 3H). LC-MS: [M+H] + : 466.1。

[0181] Synthesis of 3-(3-carbamoyl-4-hydroxy-5-methylphenyl)-N-(4-(cyclohexyloxy)benzyl)-1,2,4-oxadiazole-5-carboxamide (DP008):

[0182] Methyl 5-(5-((4-(cyclohexyloxy)benzyl)carbamoyl)-1,2,4-oxadiazol-3-yl)-2-hydroxy-3-methylbenzoate (107.1 mg, 0.23 mmol) was added to ammonia in methanol (5 mL). The reaction mixture was heated to 70 °C and stirred for 16 h. After completion of the reaction, the reaction mixture was concentrated, then diluted with aqueous sodium carbonate solution (10 mL), and extracted with ethyl acetate (20 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated by preparative chromatography to obtain a white solid (4.0 mg). 1 1H NMR (400 MHz, DMSO) δ 14.24 (s, 1H), 9.95 (t, J = 6.0 Hz, 1H), 8.90 (s, 1H), 8.52 (d, J = 1.6 Hz, 1H), 8.16 (s, 1H), 8.04 (s, 1H), 7.33 (d, J = 8.8 Hz, 2H), 6.96 (d, J = 8.4 Hz, 2H), 4.48 (d, J = 6.0 Hz, 2H), 4.40–4.34 (m, 1H), 2.30 (s, 3H), 1.99–1.93 (m, 2H), 1.79–1.72 (m, 2H), 1.61–1.55 (m, 1H), 1.50–1.32 (m, 5H); LC-MS: [M-H] - : 449.4

[0183] Example 9. Synthesis of Compounds DP011 and DP012

[0184]

[0185] Synthesis of 3-(3-chloro-4-hydroxy-5-methylphenyl)-N-(4-(cyclohexyloxy)benzyl)-1,2,4-oxadiazole-5-carboxamide (DP011):

[0186] Ethyl 3-(3-chloro-4-hydroxy-5-methylphenyl)-1,2,4-oxadiazole-5-carboxylate (178.1 mg, 0.63 mmol) and (4-(cyclohexyloxy)phenyl)methanamine (195.0 mg, 0.95 mmol) were dissolved in ethanol (2.0 mL). The reaction system was stirred at 80 °C for 24 h under nitrogen protection. After completion of the reaction, the reaction mixture was concentrated to obtain a crude product. The crude product was separated by preparative chromatography to obtain a white solid (130.0 mg). 11H NMR (400 MHz, MeOD) δ 7.90 (d, J = 1.6 Hz, 1H), 7.82–7.78 (m, 1H), 7.28 (d, J = 8.8 Hz, 2H), 6.88 (d, J = 8.8 Hz, 2H), 4.51 (s, 2H), 4.33–4.23 (m, 1H), 2.31 (s, 3H), 2.00–1.90 (m, 2H), 1.83–1.72 (m, 2H), 1.62–1.26 (m, 6H); LC-MS: [M-H] - : 440.3, 442.3.

[0187] Synthesis of 2-chloro-4-(5-((4-(cyclohexyloxy)benzyl)carbamoyl)-1,2,4-oxadiazol-3-yl)-6-methylphenyl trifluoromethanesulfonate (1):

[0188] Dissolve compound 3-(3-chloro-4-hydroxy-5-methylphenyl)-N-(4-(cyclohexyloxy)benzyl)-1,2,4-oxadiazole-5-carboxamide (115.0 mg, 0.26 mmol) in dichloromethane (2.0 mL), and slowly add triethylamine (52.6 mg, 0.52 mmol). Cool the system to 0 °C, and slowly add trifluoroacetic anhydride (60.9 mg, 0.29 mmol). Remove the ice bath and stir the reaction at room temperature for 2 h. After the reaction is complete, add 10% sodium carbonate solution (10.0 mL) to quench the reaction, extract with ethyl acetate (20 mL × 3), combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate to obtain the crude product. Purify by column chromatography (dichloromethane:methanol = 20:1) to obtain a white solid (100.0 mg). LC-MS: [M-H] - : 572.2, 574.1.

[0189] Synthesis of methyl 2-chloro-4-(5-((4-(cyclohexyloxy)benzyl)carbamoyl)-1,2,4-oxadiazol-3-yl)-6-methylbenzoate (DP012):

[0190] 2-Chloro-4-(5-((4-(cyclohexyloxy)benzyl)carbamoyl)-1,2,4-oxadiazol-3-yl)-6-methylphenyl trifluoromethanesulfonate (97.6 mg, 0.17 mmol), triethylamine (49.6 mg, 0.49 mmol), palladium(II) acetate (9.4 mg, 0.042 mmol) and 1,1'-bis(diphenylphosphino)ferrocene (10.0 mg, 0.018 mmol) were dissolved in a mixed solution of methanol and N,N-dimethylformamide (2.1 mL, methanol:N,N-dimethylformamide = 20:1). The reaction system was stirred at 80 °C for 12 h under a carbon monoxide atmosphere (8 atm). After the reaction was complete, the reaction solution was concentrated to obtain a crude product. The crude product was separated by preparative chromatography to obtain a white solid (30.0 mg). 1 H NMR(400MHz,CDCl 3 )δ7.98(s,1H),7.87(s,1H),7.33(s,1H),7.30–7.28(m,2H),6.91(dd,J=8.8,2.0Hz,2H),4.61(d,J=4.0Hz,2H),4.25(s,1H),3.98(s,3H),2.40(s,3H),2.05–1.94(m,2H),1.82–1.80(m,2H),1.55–1.46(m,2H),1.43–1.25(m,4H);LC-MS:[M-H] - :482.2,484.2。

[0191] Example 10. Synthesis of Compound DP013

[0192]

[0193] Synthesis of 3-bromo-5-chloro-4-hydroxybenzonitrile (2):

[0194] 3-Chloro-4-hydroxybenzonitrile (2.5 g, 16.28 mmol) was dissolved in acetonitrile (15 mL), and N-bromosuccinimide (2.9 g, 16.29 mmol) was added portionwise at 0 °C. The mixture was stirred at room temperature for 16 h. LCMS was used to monitor the reaction until the raw material was completely reacted. After adding water (60 mL) to the reaction solution, a solid precipitated. The solid was filtered and dried to obtain the product (3.0 g). LC-MS:[M-H] - :229.7,231.7。

[0195] Synthesis of 3-chloro-5-cyclopropyl-4-hydroxybenzonitrile (3):

[0196] Dissolve 3-bromo-5-chloro-4-hydroxybenzonitrile (1.5 g, 6.45 mmol), cyclopropylboronic acid (799.7 mg, 9.31 mmol), tricyclohexylphosphine (300.0 mg, 1.07 mmol), potassium phosphate (4.1 g, 19.32 mmol) and palladium(II) acetate (139.2 mg, 0.62 mmol) in toluene (10 mL) and water (1 mL). Replace the gas with nitrogen three times, then heat to 100 °C and stir the reaction for 6 hours. After rotary evaporation of the reaction solution, add water (50 mL) to dilute it, and extract with ethyl acetate (50 mL × 3). Combine the organic phases, wash with saturated brine (50 mL), dry over anhydrous sodium sulfate, filter and concentrate to obtain the crude product. Purify by silica gel column chromatography (petroleum ether:ethyl acetate = 0 - 7%) to obtain a yellow solid (72.0 mg). LC-MS: [M-H] - : 191.9.

[0197] Synthesis of 3-chloro-5-cyclopropyl-N,4-dihydroxybenzamidine (4):

[0198] Dissolve hydroxylamine hydrochloride (129.3 mg, 1.86 mmol) and N,N-diisopropylethylamine (240.4 mg, 1.86 mmol) in ethanol (2 mL), stir for 1 hour, and add 3-chloro-5-cyclopropyl-4-hydroxybenzonitrile (71.6 mg, 0.37 mmol) to the above solution in batches. Then heat to 80 °C and stir for 12 hours. Monitor by LCMS until the raw materials have reacted completely. After vacuum concentration of the reaction solution, add water (20 mL) to dilute it, and extract with ethyl acetate (30 mL × 3). Combine the organic phases, dry over anhydrous sodium sulfate, filter and concentrate to obtain the crude product. Purify by column chromatography (ethyl acetate / petroleum ether = 10 - 36%) to obtain a white solid (61.2 mg). LC-MS: [M+H] + : 226.9, 228.9.

[0199] Synthesis of ethyl 3-(3-chloro-5-cyclopropyl-4-hydroxyphenyl)-1,2,4-oxadiazole-5-carboxylate (5):

[0200] Dissolve compound 3-chloro-5-cyclopropyl-N,4-dihydroxybenzamidine (61.2 mg, 0.27 mmol) and N,N-diisopropylethylamine (68.5 mg, 0.53 mmol) in tetrahydrofuran (2 mL). After cooling to 0 °C in an ice bath, add compound ethyl oxalyl chloride (54.6 mg, 0.40 mmol) dropwise to the above solution. Then raise the temperature to 60 °C and stir for 2 hours. When LCMS monitors that the raw materials have reacted completely, dilute the reaction solution with water (20 mL) and extract with ethyl acetate (30 mL×3). Combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate to obtain the crude product. Purify by column chromatography (ethyl acetate / petroleum ether = 0 - 16%) to obtain a white solid (32.0 mg). LC-MS: [M+H] + : 309.0, 311.0.

[0201] Synthesis of 3-(3-chloro-5-cyclopropyl-4-hydroxyphenyl)-N-(4-(cyclohexyloxy)benzyl)-1,2,4-oxadiazole-5-carboxamide (DP013):

[0202] Dissolve compound ethyl 3-(3-chloro-5-cyclopropyl-4-hydroxyphenyl)-1,2,4-oxadiazole-5-carboxylate (26.9 mg, 0.087 mmol) and 4-(cyclohexyloxy)phenyl)methanamine (20.5 mg, 0.10 mmol) in ethanol (1 mL), raise the temperature to 80 °C and stir for 12 hours. When LCMS monitors that the raw materials have reacted completely, directly concentrate the reaction solution to obtain the crude product. Purify by preparative chromatography to obtain a yellow solid (9.3 mg). 1 H NMR (400 MHz, DMSO) δ 9.88 (t, J = 5.8 Hz, 1H), 7.81 (s, 1H), 7.39 (s, 1H), 7.25 (d, J = 8.6 Hz, 2H), 6.89 (d, J = 8.6 Hz, 2H), 4.40 (d, J = 5.8 Hz, 2H), 4.35–4.25 (m, 1H), 2.20–2.10 (m, 1H), 1.95–1.85 (m, 2H), 1.74–1.65 (m, 2H), 1.56–1.49 (m, 1H), 1.45–1.25 (m, 5H), 1.05–0.95 (m, 2H), 0.70–0.60 (m, 2H); LC-MS: [M-H] - : 466.4, 468.4.

[0203] Example 11. Synthesis of compound DP014

[0204]

[0205] Synthesis of ethyl 3-(4-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-3-chloro-5-methylphenyl)-1,2,4-oxadiazole-5-carboxylate (1):

[0206] Ethyl 3-(3-chloro-4-hydroxy-5-methylphenyl)-1,2,4-oxadiazole-5-carboxylate (299.6 mg, 1.06 mmol) and potassium carbonate (293.0 mg, 2.12 mmol) were dissolved in N,N-dimethylformamide (5 mL), and (2-bromoethoxy)(tert-butyl)dimethylsilane (380.4 mg, 1.59 mmol) was added. The reaction mixture was stirred at room temperature for 16 h. After the reaction was complete, the reaction mixture was diluted with water (30 mL), then extracted with ethyl acetate (40 mL×3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain a white solid (65.0 mg). LC-MS: [M+H] + : 441.1, 443.1.

[0207] Synthesis of 3-(4-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-3-chloro-5-methylphenyl)-N-(4-(cyclohexyloxy)benzyl)-1,2,4-oxadiazole-5-carboxamide (2):

[0208] Ethyl 3-(4-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-3-chloro-5-methylphenyl)-1,2,4-oxadiazole-5-carboxylate (61.7 mg, 0.14 mmol) and (4-(cyclohexyloxy)phenyl)methanamine (28.7 mg, 0.14 mmol) were dissolved in ethanol (3 mL), and the mixture was heated to 80 °C and stirred for 2 h. After the reaction mixture was cooled to room temperature, it was concentrated to dryness. The obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain a white solid (50.0 mg). LC-MS: [M+H] + : 600.3, 602.3.

[0209] Synthesis of 3-(3-chloro-4-(2-hydroxyethoxy)-5-methylphenyl)-N-(4-(cyclohexyloxy)benzyl)-1,2,4-oxadiazole-5-carboxamide (DP014):

[0210] Dissolve 3-(4-(2-((tert-Butyldimethylsilyl)oxy)ethoxy)-3-chloro-5-methylphenyl)-N-(4-(cyclohexyloxy)benzyl)-1,2,4-oxadiazole-5-carboxamide (45.0 mg, 0.075 mmol) in tetrahydrofuran (3 mL), add pyridinium hydrofluoride (1.5 mL), and stir the reaction at room temperature for 8 hours. After the reaction is complete, quench the reaction mixture with water and extract with ethyl acetate (20 mL × 3). Combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate to dryness. The crude product is separated by preparative chromatography to obtain a white solid (12.7 mg). 1 H NMR (400 MHz, DMSO) δ 9.93 (s, 1H), 7.90 (d, J = 12.4 Hz, 2H), 7.26 (d, J = 7.6 Hz, 2H), 6.90 (d, J = 7.6 Hz, 2H), 4.93 (t, J = 5.2 Hz, 1H), 4.41 (d, J = 4.4 Hz, 2H), 4.30 (s, 1H), 4.02 (t, J = 4.4 Hz, 2H), 3.74 (d, J = 4.8 Hz, 2H), 2.39 (s, 3H), 1.88 (s, 2H), 1.72–1.65 (m, 2H), 1.57–1.48 (m, 1H), 1.42–1.23 (m, 5H); LC-MS: [M+H] + : 486.2, 488.2.

[0211] Example 12. Synthesis of Compound DP015

[0212]

[0213] Synthesis of 2-chloro-4-(5-((4-(cyclohexyloxy)benzyl)carbamoyl)-1,2,4-oxadiazol-3-yl)-6-methylbenzoic acid (DP015):

[0214] Dissolve 2-chloro-4-(5-((4-(cyclohexyloxy)benzyl)carbamoyl)-1,2,4-oxadiazol-3-yl)-6-methylphenyl trifluoromethanesulfonate (100.0 mg, 0.17 mmol), triethylamine (44.1 mg, 0.44 mmol), palladium acetate (5.9 mg, 0.026 mmol), 1,3-bis(diphenylphosphino)propane (10.8 mg, 0.026 mmol), and water (235.0 mg, 13.06 mmol) in acetonitrile solution (1.6 mL). Stir the reaction system under a carbon monoxide atmosphere (5 atm) at 80 °C for 4 hours. After the reaction is complete, concentrate to obtain the crude product. Separate by preparative chromatography to obtain a white solid (11.5 mg). 11H NMR (400 MHz, DMSO) δ 14.00 (s, 1H), 9.96 (t, J = 6.4 Hz, 1H), 7.95 (s, 2H), 7.26 (d, J = 8.4 Hz, 2H), 6.90 (d, J = 8.4 Hz, 2H), 4.41 (d, J = 6.4 Hz, 2H), 4.35–4.25 (m, 1H), 2.40 (s, 3H), 1.92–1.88 (m, 2H), 1.76–1.63 (m, 2H), 1.57–1.48 (m, 1H), 1.46–1.23 (m, 5H); LC-MS: [M-H] - : 468.2, 470.2。

[0215] Example 13. Synthesis of Compound DP016

[0216]

[0217] Synthesis of 3-chloro-4-iodo-5-methylbenzonitrile (2):

[0218] Dissolve compound 4-amino-3-chloro-5-methylbenzonitrile (1.0 g, 6.00 mmol) in water (5 mL) and hydrochloric acid (3.3 mL). Slowly add sodium nitrite (0.46 g, 6.67 mmol) dissolved in water (2.5 mL) under an ice bath, and stir for 30 minutes under an ice bath (R1). Dissolve potassium iodide (1.2 g, 7.23 mmol) in water (2.5 mL) and ethyl acetate (5 mL) (R2). Under an ice bath, slowly add R1 dropwise to R2 and stir for 30 minutes. Extract with ethyl acetate (10 mL × 3), wash the organic phase with 5% aqueous sodium thiosulfate solution (15 mL) and saturated sodium chloride (15 mL), dry, and evaporate to dryness to obtain a white solid (1.5 g). 1 1H NMR (400 MHz, CDCl 3 ) δ 7.53 (d, J = 1.2 Hz, 1H), 7.36 (d, J = 1.2 Hz, 1H), 2.57 (s, 3H).

[0219] Synthesis of 3-chloro-5-methyl-4-(methylsulfonyl)benzonitrile (3):

[0220] Dissolve 3-chloro-4-iodo-5-methylbenzonitrile (300.0 mg, 1.08 mmol), sodium methylsulfinate (220.7 mg, 2.16 mmol) and copper(I) iodide (205.9 mg, 1.08 mmol) in dimethyl sulfoxide (5 mL). Under nitrogen protection, react at 110 °C for 18 hours. Cool the reaction solution, dilute with ethyl acetate (15 mL), wash with water (10 mL × 3), dry the organic phase, evaporate to dryness, and prepare the crude product on a silica gel plate (petroleum ether:ethyl acetate = 2:1) to obtain a white solid (70.0 mg). 1 H NMR(400MHz,CDCl 3 )δ7.71(d,J=1.2Hz,1H),7.53(d,J=1.2Hz,1H),3.32(s,3H),2.81(s,3H).

[0221] Synthesis of 3-chloro-N-hydroxy-5-methyl-4-(methylsulfonyl)benzamidine (4):

[0222] Dissolve hydroxylamine hydrochloride (36.3 mg, 0.52 mmol) in ethanol (2 mL). Dropwise add N,N-diisopropylethylamine (67.5 mg, 0.52 mmol) at room temperature and stir for 0.5 hour. Add compound 3-chloro-5-methyl-4-(methylsulfonyl)benzonitrile (60.0 mg, 0.26 mmol) at room temperature. Under nitrogen protection, react at 80 °C for 2 hours. Evaporate the reaction solution to dryness, dilute the crude product with ethyl acetate (10 mL), wash with water (5 mL × 3), dry the organic phase, and evaporate to dryness to obtain a white solid (55.0 mg). LC-MS: [M+H] + :263.0,265.0.

[0223] Synthesis of ethyl 3-(3-chloro-5-methyl-4-(methylsulfonyl)phenyl)-1,2,4-oxadiazole-5-carboxylate (5):

[0224] Dissolve compound 3-chloro-N-hydroxy-5-methyl-4-(methylsulfonyl)benzamidine (55.0 mg, 0.21 mmol) in pyridine (2 mL). Dropwise add ethyl oxalyl chloride (57.2, 0.42 mmol) at room temperature. Under nitrogen protection, react at 60 °C for 2 hours. Evaporate the reaction solution to dryness, dilute with ethyl acetate (8 mL), wash with water (5 mL × 3), dry the organic phase, and evaporate to dryness to obtain a white solid (60.0 mg). LC-MS: [M+H] + :345.0,347.0.

[0225] Synthesis of 3-(3-chloro-5-methyl-4-(methylsulfonyl)phenyl)-N-((6-((4,4-difluorocyclohexyl)oxy)pyridin-3-yl)methyl)-1,2,4-oxadiazole-5-carboxamide (DP016):

[0226] Ethyl 3-(3-chloro-5-methyl-4-(methylsulfonyl)phenyl)-1,2,4-oxadiazole-5-carboxylate (70.0 mg, 0.20 mmol) and (6-((4,4-difluorocyclohexyl)oxy)pyridin-3-yl)methanamine (59.0 mg, 0.24 mmol) were dissolved in ethanol (4 mL). Under nitrogen protection, the reaction was carried out at 85 °C for 18 hours. The reaction solution was concentrated by rotary evaporation, and the crude product was purified by reverse-phase preparation (ammonium bicarbonate) to obtain a white solid (11.4 mg). 1 H NMR (400 MHz, MeOD) δ 8.21 (s, 1H), 8.17 (d, J = 2.0 Hz, 1H), 8.08 (s, 1H), 7.74 (dd, J = 8.8, 2.4 Hz, 1H), 6.79 (d, J = 8.8 Hz, 1H), 5.18 (s, 1H), 4.54 (s, 2H), 3.37 (s, 3H), 2.82 (s, 3H), 2.12–1.92 (m, 8H); LC-MS: [M+H] + : 541.2, 543.2.

[0227] Example 14. Synthesis of compound DP017

[0228]

[0229] Synthesis of 3-(3-chloro-4-hydroxy-5-methylphenyl)-N-((6-((4,4-difluorocyclohexyl)oxy)pyridin-3-yl)methyl)-1,2,4-oxadiazole-5-carboxamide (1):

[0230] Ethyl 3-(3-chloro-4-hydroxy-5-methylphenyl)-1,2,4-oxadiazole-5-carboxylate (280.0 mg, 0.99 mmol) and (6-((4,4-difluorocyclohexyl)oxy)pyridin-3-yl)methanamine (287.8 mg, 1.19 mmol) were dissolved in ethanol (5 mL), and the temperature was raised to 80 °C and stirred for 12 hours. LCMS monitored that the raw materials had reacted completely and the product was the main peak. The reaction solution was concentrated by rotary evaporation, water (20 mL) was added for dissolution, and the aqueous phase was extracted with ethyl acetate (40 mL × 3). The combined organic phases were washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated by rotary evaporation to obtain the crude product, and purified by silica gel column (petroleum ether:ethyl acetate = 5:1) to obtain a yellow solid (340.0 mg). LC-MS: [M+H] + : 479.1, 481.1.

[0231] Synthesis of 2-chloro-4-(5-(((6-((4,4-difluorocyclohexyl)oxy)pyridin-3-yl)methyl)carbamoyl)-1,2,4-oxadiazol-3-yl)-6-methylphenyl trifluoromethanesulfonate (2):

[0232] Dissolve compound 3-(3-chloro-4-hydroxy-5-methylphenyl)-N-((6-((4,4-difluorocyclohexyl)oxy)pyridin-3-yl)methyl)-1,2,4-oxadiazole-5-carboxamide (290.0 mg, 0.606 mmol) and triethylamine (122.6 mg, 1.21 mmol) in dichloromethane (6 mL), cool to 0 °C, slowly add trifluoromethanesulfonic anhydride (256.3 mg, 0.91 mmol), and stir at room temperature for 2 hours. Monitor the product by LCMS, and the main peak is the product peak. Add water (20 mL) to dilute the reaction solution, collect the organic phase, extract the aqueous phase with dichloromethane (20 mL × 3), combine the organic phases, wash once with saturated brine (50 mL), dry over anhydrous sodium sulfate, and evaporate to dryness to obtain the crude product. Purify by silica gel column (petroleum ether:ethyl acetate = 5:1) to obtain a yellow solid (340.0 mg). LC-MS: [M+H] + : 611.1, 613.1

[0233] Synthesis of methyl 2-chloro-4-(5-(((6-((4,4-difluorocyclohexyl)oxy)pyridin-3-yl)methyl)carbamoyl)-1,2,4-oxadiazol-3-yl)-6-methylbenzoate (DP017):

[0234] Dissolve compound 2-chloro-4-(5-(((6-((4,4-difluorocyclohexyl)oxy)pyridin-3-yl)methyl)carbamoyl)-1,2,4-oxadiazol-3-yl)-6-methylphenyl trifluoromethanesulfonate (60.0 mg, 0.098 mmol), palladium(II) acetate (5.3 mg, 0.024 mmol), 1,1'-bis(diphenylphosphino)ferrocene (5.4 mg, 0.0097 mmol), and triethylamine (27.8 mg, 0.27 mmol) in methanol (1.5 mL) and N,N-dimethylformamide (0.1 mL). Charge carbon monoxide (8 atm) into the autoclave, heat to 80 °C, and react for 18 hours. Monitor the main peak by LCMS, which is the product peak. Add water (10 mL) to dilute the reaction solution, extract the aqueous phase with ethyl acetate (20 mL × 3), combine the organic phases, wash once with saturated brine (40 mL), dry over anhydrous sodium sulfate, and evaporate to dryness to obtain the crude product. Purify by preparative method to obtain a white solid (3.1 mg). 11H NMR (400 MHz, DMSO) δ 8.15 (d, J = 2.4 Hz, 1H), 7.97 (s, 1H), 7.87 (s, 1H), 7.64 (dd, J = 8.4, 2.4 Hz, 1H), 7.36 (t, J = 6.0, 1H), 6.74 (d, J = 8.4 Hz, 1H), 5.28–5.18 (m, 1H), 4.61 (d, J = 6.0 Hz, 2H), 3.98 (s, 3H), 2.40 (s, 3H), 2.17–1.92 (m, 8H). LC-MS: [M+H] + : 521.1, 523.1。

[0235] Example 15. Synthesis of Compound DP018

[0236]

[0237] Synthesis of 2-chloro-4-(5-(((6-((4,4-difluorocyclohexyl)oxy)pyridin-3-yl)methyl)carbamoyl)-1,2,4-oxadiazol-3-yl)-6-methylbenzoic acid (DP018):

[0238] Dissolve compound 2-chloro-4-(5-(((6-((4,4-difluorocyclohexyl)oxy)pyridin-3-yl)methyl)carbamoyl)-1,2,4-oxadiazol-3-yl)-6-methylphenyl trifluoromethanesulfonate (100.0 mg, 0.16 mmol), palladium acetate (5.6 mg, 0.025 mmol), triethylamine (46.4 mg, 0.46 mmol) and 1,3-bis(diphenylphosphino)propane (10.3 mg, 0.025 mmol) in acetonitrile (3 mL) and water (0.35 mL). Charge carbon monoxide (8 atm) into the autoclave, heat to 80 °C, and react for 18 hours. The main peak in LCMS monitoring is the product peak. Add water (10 mL) to dilute the reaction solution, extract the aqueous phase with ethyl acetate (20 mL × 3), combine the organic phases, wash once with saturated brine (50 mL), dry over anhydrous sodium sulfate, and evaporate to dryness to obtain the crude product, which is purified by preparation to obtain a white solid (14.4 mg). 1 1H NMR (400 MHz, DMSO) δ 9.99 (t, J = 6.0 Hz, 1H), 8.15 (s, 1H), 7.90 (s, 2H), 7.72 (d, J = 8.4 Hz, 1H), 6.81 (d, J = 8.8 Hz, 1H), 5.23–5.13 (s, 1H), 4.43 (d, J = 6.0 Hz, 2H), 2.38 (s, 3H), 2.07–1.89 (m, 6H), 1.86–1.76 (m, 2H). LC-MS: [M+H] + : 507.1, 509.2。

[0239] Example 16. Synthesis of Compound DP019

[0240]

[0241] Synthesis of 4-bromo-3-methyl-5-(trifluoromethyl)aniline (2):

[0242] Dissolve 3-methyl-5-(trifluoromethyl)aniline (2.0 g, 11.42 mmol) and N-bromosuccinimide (2.03 g, 11.41 mmol) in N,N-dimethylformamide (35 mL), and stir the reaction at room temperature for 4 hours. After the reaction is completed, add water (50 mL), extract with ethyl acetate three times (60 mL×3), combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate to obtain the crude product. Separate by column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain a yellow solid (2.9 g). LC-MS: [M+H] + : 254.1, 256.1.

[0243] Synthesis of 2-bromo-5-iodo-1-methyl-3-(trifluoromethyl)benzene (3):

[0244] Dissolve 4-bromo-3-methyl-5-(trifluoromethyl)aniline (1.7 g, 6.69 mmol) in 6N hydrochloric acid (10 mL), add sodium nitrite (923.0 mg, 13.38 mmol), and stir the reaction at 0 °C for 2 hours. Add potassium iodide (2.22 g, 13.37 mmol) to the reaction solution. Stir the reaction system at 0 °C under nitrogen protection for 2 hours. After the reaction is complete, add an aqueous solution (10.0 mL) to quench the reaction, extract with ethyl acetate three times (20 mL×3), combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate to obtain the crude product. Separate by column chromatography (petroleum ether:ethyl acetate = 8:1) to obtain a yellow solid (1.9 g). LC-MS: [M+H] + : 364.9, 366.9.

[0245] Synthesis of 4-bromo-3-methyl-5-(trifluoromethyl)benzonitrile (4):

[0246] Dissolve 2-bromo-5-iodo-1-methyl-3-(trifluoromethyl)benzene (300.0 mg, 0.82 mmol), zinc cyanide (57.6 mg, 0.49 mmol), and tetrakis(triphenylphosphine)palladium (47.0 mg, 0.041 mmol) in N,N-dimethylformamide (5 mL). Stir the reaction system at 85 °C under nitrogen protection for 10 hours. After the reaction is complete, add aqueous solution (10.0 mL) to quench the reaction, extract with ethyl acetate three times (30 mL × 3), combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate to obtain the crude product. Purify by column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain a yellow solid (120.0 mg). LC-MS: [M+H] + : 264.0, 266.0.

[0247] Synthesis of 4-bromo-N-hydroxy-3-methyl-5-(trifluoromethyl)benzimidamide (5):

[0248] Dissolve 4-bromo-3-methyl-5-(trifluoromethyl)benzonitrile (120.0 mg, 0.45 mmol) in ethanol (5 mL), add N,N-diisopropylethylamine (292.0 mg, 2.26 mmol), and hydroxylamine hydrochloride (157.0 mg, 2.26 mmol). Stir the reaction system at 80 °C for 10 hours. After the reaction is complete, add aqueous solution (10.0 mL) to quench the reaction, extract with ethyl acetate three times (20 mL × 3), combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate to obtain a white solid (120.0 mg). LC-MS: [M+H] + : 297.1, 299.1.

[0249] Synthesis of ethyl 3-(4-bromo-3-methyl-5-(trifluoromethyl)phenyl)-1,2,4-oxadiazole-5-carboxylate (6):

[0250] Dissolve 4-bromo-N-hydroxy-3-methyl-5-(trifluoromethyl)benzimidamide (100.0 mg, 0.34 mmol) in pyridine (2.0 mL), add ethyl oxalyl chloride (45.0 mg, 0.33 mmol). Stir the reaction system at 60 °C for 1 hour. After the reaction is complete, add aqueous solution (10.0 mL) to quench the reaction, extract with ethyl acetate three times (20 mL × 3), combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate to obtain the crude product. Purify by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain a white solid (120.0 mg). LC-MS: [M+H] + : 379.1, 381.1.

[0251] Synthesis of 3-(4-bromo-3-methyl-5-(trifluoromethyl)phenyl)-N-((6-((4,4-difluorocyclohexyl)oxy)pyridin-3-yl)methyl)-1,2,4-oxadiazole-5-carboxamide (7):

[0252] Ethyl 3-(4-bromo-3-methyl-5-(trifluoromethyl)phenyl)-1,2,4-oxadiazole-5-carboxylate (120.0 mg, 0.32 mmol) and (6-((4,4-difluorocyclohexyl)oxy)pyridin-3-yl)methanamine (114.0 mg, 0.47 mmol) were dissolved in ethanol (5 mL), and the reaction was carried out at 85 °C for 5 hours. The reaction solution was separated by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain a white solid (85.0 mg). LC-MS: [M+H] + : 575.2, 577.2.

[0253] Synthesis of methyl 4-(5-(((6-((4,4-difluorocyclohexyl)oxy)pyridin-3-yl)methyl)carbamoyl)-1,2,4-oxadiazol-3-yl)-2-methyl-6-(trifluoromethyl)benzoate (DP019):

[0254] 3-(4-bromo-3-methyl-5-(trifluoromethyl)phenyl)-N-((6-((4,4-difluorocyclohexyl)oxy)pyridin-3-yl)methyl)-1,2,4-oxadiazole-5-carboxamide (50.0 mg, 0.087 mmol), palladium acetate (4.7 mg, 0.021 mmol), 1,1'-bis(diphenylphosphino)ferrocene (4.8 mg, 0.0087 mmol), triethylamine (25.3 mg, 0.25 mmol), and N,N-dimethylformamide (0.1 mL) were dissolved in methanol (2 mL), and the reaction was carried out at 80 °C for 18 hours under carbon monoxide (8 atm). The reaction solution was prepared by reverse-phase formic acid to obtain a white solid (1.8 mg). 1 H NMR (400 MHz, MeOD) δ 8.30 (d, J = 5.2 Hz, 2H), 8.17 (d, J = 2.0 Hz, 1H), 7.74 (dd, J = 8.8, 2.4 Hz, 1H), 6.79 (d, J = 8.8 Hz, 1H), 5.17 (s, 1H), 4.54 (s, 2H), 3.95 (s, 3H), 2.45 (s, 3H), 2.13–1.89 (m, 8H). LC-MS: [M+H] + : 555.3.

[0255] Example 17. According to the synthetic routes of Methods I and II and the preparation methods of Examples 1-16, the following compounds were prepared:

[0256]

[0257]

[0258]

[0259] Activity Test Example 1. Luciferase Reporter Gene Activity Test:

[0260] 1. 293T cells cultured in T25 (purchased from Kober Biologics) were digested with 1 mL of 0.05% trypsin until the cells detached, 1 mL of complete medium (DMEM + 10% FBS + 1% P / S) was added to terminate the digestion, centrifuged at 1000 rpm for 3 min, and the supernatant was discarded;

[0261] 2. Seeding cells in 6-well plates: Resuspend the cells and count them, adjust the cell density to 5×10 5 cells / mL, add 2 mL of cell suspension to each well of the 6-well plate, which contains 1×10 6 cells, and culture in a carbon dioxide incubator for 6 h until the cells adhered to the plate;

[0262] 3. Transfection: Mix 16 μL of transfection reagent + 4 μg of Ebox-Lucifersae plasmid, let it stand at room temperature for 15 min, then drop it into the wells of the 6-well plate, and continue to culture in a carbon dioxide incubator for 18 h;

[0263] 4. Preparation of the compound to be tested: Dilute the compound to be tested 2-fold with a multi-channel pipette to the 9th concentration, that is, dilute from 500 μM to 1.95 μM, and transfer 10 μL to each well of the 96-well cell plate in turn, with three replicates set;

[0264] 5. Digest with 1 mL of 0.05% trypsin until the cells detach, add 1 mL of complete medium to terminate the digestion, centrifuge at 1000 rpm for 3 min, and discard the supernatant; Resuspend the cells and count them, adjust the cell density to 3.3×10 5 cells / mL, add 100 μL of cell suspension to each well of the above 96-well plate, and let it stand and culture in a carbon dioxide incubator for 24 h;

[0265] 6. Discard all the medium, add 100 μL of lysis buffer to each well, and lyse on ice for 5 min; Take 20 μL and transfer it to a white 96-well microplate, add 100 μL of substrate, and detect the luciferase luminescence value; Take another 20 μL of lysis buffer and transfer it to a black 96-well microplate, add 20 μL of CTG2.0, and detect the cell viability;

[0266] 7. Normalize the luciferase luminescence values using the multiple relationship of cell viability. Normalization process: Take the average value A of all the original cell viability data treated with the same compound. Divide the original cell viability data B of each well by the average value to obtain the relative cell viability value of the corresponding well. Then divide the luciferase luminescence value C of each well by the relative cell viability value of the corresponding well to obtain the normalized value L = A * C / B;

[0267] Then, for the normalized value L of the luciferase luminescence value at each concentration, use GraphPad Prism software to fit the normalized value L of the luciferase luminescence value with the corresponding concentration to obtain the concentration-response curve and IC 50 value. Activity test example 2. HL-60 cell proliferation inhibition activity test

[0268] 1. Prepare complete medium (RPMI-1640 + 10% FBS + 1% P / S) to resuscitate HL60 cells (purchased from Hefei Prisun). Passage about two generations and select a cell line with good growth status. Collect cells in the logarithmic growth phase and count them. Adjust the cells to an appropriate concentration, and inoculate the cell suspension into a 96-well plate, adding 135 μL of cell suspension to each well, with a seeding density of 2500 cells / well;

[0269] 2. Prepare a stock solution of the test compound (Cpd) with DMSO. Use DMSO to serially dilute it 2-fold starting from the highest concentration of 15 mM to obtain 9 concentration gradients;

[0270] 3. Dilute the test compound 30-fold with complete medium. Take 15 μL each and add it to the 96-well cell plate containing 135 μL of cells. Add a culture medium without cells (containing 0.33% DMSO) to the Min control well, and add a 15 μL DMSO-cell culture medium mixture (final DMSO concentration is 0.33%) to the Max control. Incubate in a carbon dioxide incubator at 37 °C, 5%, and relative humidity above 90% for 6 days;

[0271] 4. Add 50 μL / well of CellTiter Glo to end the reaction, incubate at room temperature in the dark for 30 min, gently shake, and then detect on Paradigm to read the fluorescence value RLU per well. The cell proliferation inhibition rate (Inhibition Rate) data is processed using the following formula:

[0272] Inhibition Rate (Inh%) = 100 - (RLUCpd - RLUMin) / (RLUMax - RLUMin) * 100%;

[0273] 5. Calculate the inhibition rate corresponding to compounds at different concentrations in EXCEL, and then fit the inhibition rate curve using GraphPad Prism software and calculate the IC 50 value.

[0274] Activity Test Example 3. Proliferation Inhibition Activity Test of MDA-MB-231 Cells

[0275] 1. Prepare complete medium (L-15 + 10% FBS + 1% P / S) to resuscitate MDA-MB-231 cells (purchased from Hefei Prisegen). After passing two generations, select a cell line with good growth status, digest, centrifuge to collect cells in the logarithmic growth phase and count. Resuspend the cells to an appropriate concentration, and inoculate the cell suspension into a 96-well plate. Add 100 μL of cell suspension to each well, and the seeding density is 2000 cells / well. Place the culture plate in an incubator at 37°C, relative humidity 100%, and 5% CO 2 for 24 hours. The next day, add 35 μL of fresh medium to each well of the cell plate;

[0276] 2. Prepare a stock solution of the compound to be tested (Cpd) with DMSO, and gradually dilute it 3-fold with DMSO starting from the highest concentration of 10 mM to obtain 9 concentration gradients;

[0277] 3. Dilute the compound to be tested 10-fold with the medium, and take 15 μL each and add it to a 96-well cell plate containing 135 μL of cells. Add a culture medium without cells (containing 1% DMSO) to the Min control well, and add a 15 μL DMSO-cell culture medium mixture (final DMSO concentration is 1%) to the Max control. Incubate in a carbon dioxide incubator at 37°C, 5%, and relative humidity above 90% for 6 days;

[0278] 4. Add 50 μL / well of CellTiter Glo to end the reaction, incubate at room temperature in the dark for 30 min, gently shake, and then detect on Paradigm to read the luminescence value, the fluorescence value RLU per well. The data of the cell proliferation inhibition rate (Inhibition Rate) is processed using the following formula:

[0279] Inhibition Rate (Inh%) = 100 - (RLUCpd - RLUMin) / (RLUMax - RLUMin) * 100%;

[0280] 5. Calculate the inhibition rate corresponding to compounds at different concentrations in EXCEL, and then fit the inhibition rate curve using GraphPad Prism software and calculate the IC 50 value.

[0281] Activity test examples 1-3 show that the compounds obtained in the present invention can inhibit the transcriptional activity of c-Myc and inhibit the proliferation of related tumor cells driven by c-Myc. The specific results are shown in Table 1 below:

[0282] Table 1: IC of the compound on the transcriptional inhibitory activity of c-Myc protein and the proliferation inhibitory activity on HL-60 cells and MDA-MB-231 cells 50 value

[0283]

[0284]

[0285] The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiments. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims

1. A compound as shown below (I) or a pharmaceutically acceptable salt or deuterated substance thereof: in, X and Y are independently selected from N and CR7; R1 is selected from -OR8, -C(O)OR8, -C(O)N(R8)R9, -C(O)R8, -S(O)2N(R8)R9, -N(R8)R9, -N(R8)C(O)R9, -N(R8)S(O)2R9, -B(OH)2, -S(O)2R8, -P(O)(R8)R9; R2 and R3 are independently selected from H, halogen, -CN, -NO2, -OR8, -C(O)R8, -C(O)OR8, -C(O)N(R8)R9, -N(R8)R9, -N(R8)C(O)R9, -N(R8)S(O)2R9, -S(O)2R8, -P(O)(R8)R9, C 1-4 Straight or branched alkyl, C 2-4 Straight or branched alkenyl, C 2-4 Straight-chain or branched alkynyl, C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl containing 1-3 ring heteroatoms independently selected from N, O, S connected to the proximal ring through C or N, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl is optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight or branched alkyl, optionally substituted by one or more independently selected from F, Cl, Br, OH, CN, NH2, C 1-4 Straight or branched alkyl, C 1-4 C substituted with a straight-chain or branched alkoxy group 3-7 substituted by a cycloalkyl group or a 3-7 membered heterocycloalkyl group containing 1-3 ring heteroatoms independently selected from N, O, and S, and R2 and R3 are not halogen at the same time; R4, R5 and R6 are independently selected from H, C 1-4 Straight or branched alkyl, C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl containing 1-3 ring heteroatoms independently selected from N, O, S, connected to the proximal carbon atom through C or N, wherein the alkyl, cycloalkyl, heterocycloalkyl is optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight or branched alkyl, C 1-4 Substituted by a straight-chain or branched alkoxy substituent group; Alternatively, R5 and R6 together with the carbon atom to which they are commonly attached form C=O, a 3-7 membered cycloalkyl, a 3-7 membered heterocycloalkyl containing 1-3 ring heteroatoms independently selected from N, O, S, wherein the cycloalkyl and heterocycloalkyl are optionally substituted by one or more independently selected from F, Cl, Br, OH, CN, NH2, -C(O)R8, C 1-4 Straight or branched alkyl, C 1-4 Substituted by a straight-chain or branched alkoxy substituent group; A ring is selected from phenyl, 5-11 membered heteroaryl containing 1-3 ring heteroatoms independently selected from N, O, S, C 3-7 Cycloalkyl, C 3-7 Cycloalkenyl, 3-7 membered heterocycloalkyl containing 1-3 ring heteroatoms independently selected from N, O, S, C 5-9 A bridged cycloalkyl group, a 5-9 membered heterobridged cycloalkyl group containing 1-3 ring heteroatoms independently selected from N, O, and S and connected to the proximal carbon atom via C or N, and a bicyclic ring formed by condensing any two of the phenyl, heteroaryl, cycloalkyl, cycloalkenyl, and heterocycloalkyl groups; m is 0, 1, 2, 3, 4 or 5; R7 is independently selected from H, F, Cl, Br, -CN, -NO2, C 1-4 Straight or branched alkyl, C 2-4 Straight or branched alkenyl, C 2-4 Straight-chain or branched alkynyl, C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl containing 1-3 ring heteroatoms independently selected from N, O, and S and connected to the proximal group through C or N, 5-11 membered heteroaryl containing 1-3 ring heteroatoms independently selected from N, O, and S and connected to the proximal group through C or N, phenyl, -OR8, -C(O)R8, -C(O)OR8, -C(O)N(R8)R9, -S(O)2R8, -S(O)2N(R8)R9, -N(R8)R9, -N(R8)C(O)R9, -N(R8)S(O)2R9, -P(O)(R8)R9, the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, phenyl are optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight or branched alkyl, C 2-4 Straight or branched alkenyl, C 2-4 Straight-chain or branched alkynyl, C 1-4 Straight chain or branched alkoxy, C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl containing 1-3 ring heteroatoms independently selected from N, O, S, connected to the proximal group through C or N; R8 and R9 are independently selected from H, -OH, -NH2, C 1-4 Straight or branched alkyl, C 2-4 Straight or branched alkenyl, C 2-4 Straight-chain or branched alkynyl, C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl containing 1-3 ring heteroatoms independently selected from N, O, S, P, connected to the proximal group through C or N, C 5-9 a 5- to 9-membered hetero-bridged cycloalkyl group containing 1 to 3 ring heteroatoms independently selected from N, O, and S and connected to the proximal group through C or N, a 5- to 11-membered heteroaryl group containing 1 to 3 ring heteroatoms independently selected from N, O, and S and connected to the proximal group through C or N, a spirocycle connected to the proximal group through C on any one ring of the spirocycle, the spirocycle consisting of a 3- to 7-membered heteroalkyl ring containing 1 to 3 ring heteroatoms independently selected from N, O, and S and a 3- to 7-membered alkane ring, the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, bridged cycloalkyl, heterobridged cycloalkyl, phenyl, heteroaryl, spirocycle optionally substituted with one or more independently selected from F, Cl, Br, OH, CN, NH2, =O, C optionally substituted with one or more independently selected from F, Cl, Br, OH, CN, NH2 1-4 Straight or branched alkyl, C optionally substituted by one or more groups independently selected from F, Cl, Br, OH, CN, NH2 1-4 Straight or branched alkoxy, C optionally substituted by one or more groups independently selected from F, Cl, Br, OH, CN, NH2 3-7 Cycloalkyl, substituted by a 3-7 membered heterocycloalkyl group containing 1-3 ring heteroatoms independently selected from N, O, S, optionally substituted by one or more groups independently selected from F, Cl, Br, OH, CN, NH2; When R8 and R9 are attached to the same atom, R8 and R9 together with the atom to which they are attached may form a 3-7 membered heterocycloalkyl containing 1-3 ring heteroatoms independently selected from N, O, S, which heterocycloalkyl is optionally substituted with one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight or branched alkyl, C 2-4 Straight or branched alkenyl, C 2-4 Straight-chain or branched alkynyl, C 1-4 The alkyl, alkenyl, alkynyl, alkoxyl group is optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight or branched alkyl, C 2-4 Straight or branched alkenyl, C 2-4 Straight-chain or branched alkynyl, C 1-4 The radical is substituted by a straight-chain or branched alkoxy radical.

2. The compound according to claim 1 or its pharmaceutically acceptable salt or deuterated substance, characterized in that: in, X and Y are independently selected from N and CR7; R1 is selected from -OH, -OCH3, -C(O)OCH3, -C(O)NH2, -COOH, -NH2, -N(H)C(O)CH3, -N(H)S(O)2CH3, -B(OH)2, -S(O)2CH3, -P(O)(CH3)2, -OCH2CH2OH, -C(O)N(H)CH2CH2OH, -C(O)N(H)CH2CH2NH2; R2 and R3 are independently selected from F, Cl, Br, I, -CN, -CH3, -CF3, -OCF3, -C(O)CH3, -S(O)2CH3, -P(O)(CH3)2, -C(O)OCH3, -C(O)NH2, ethynyl, cyclopropyl, oxetanyl, and R2 and R3 are not halogen at the same time; R4, R5 and R6 are independently selected from H, -CH3, -CH2CF3, cyclopropyl; Alternatively, R5 and R6 together with the carbon atom to which they are commonly attached form C=O, cyclopropyl, or oxetanyl; A ring is selected from phenyl, 5-11 membered heteroaryl containing 1-3 ring heteroatoms independently selected from N, O, S, C 3-7 Cycloalkyl, C 3-7 Cycloalkenyl, 3-7 membered heterocycloalkyl containing 1-3 ring heteroatoms independently selected from N, O, S, C 5-9 A bridged cycloalkyl group, a 5-9 membered heterobridged cycloalkyl group containing 1-3 ring heteroatoms independently selected from N, O, and S and connected to the proximal carbon atom via C, and a bicyclic ring formed by condensing any two of the phenyl, heteroaryl, cycloalkyl, cycloalkenyl, and heterocycloalkyl groups; m is 1 or 2; R7 is independently selected from H, F, Cl, Br, -CN, C 1-4 Straight or branched alkyl, C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl containing 1-3 ring heteroatoms independently selected from N, O, S connected to the proximal group through C or N, -OR8, -C(O)R8, -S(O)2R8, -N(R8)R9, -N(R8)C(O)R9, -P(O)(R8)R9, wherein the alkyl, cycloalkyl, heterocycloalkyl is optionally substituted by one or more independently selected from F, Cl, Br, C 1-4 Substituted by a straight-chain or branched alkyl substituent group; R8 and R9 are independently selected from H, C 1-4 Straight or branched alkyl, C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl containing 1-3 ring heteroatoms independently selected from N, O, S, C 5-9 a 5- to 9-membered hetero-bridged cycloalkyl group containing 1 to 3 ring heteroatoms independently selected from N, O, and S, a phenyl group, a 5- to 11-membered heteroaryl group containing 1 to 3 ring heteroatoms independently selected from N, O, and S, a spirocyclic ring connected to the proximal group through C on any one of the spirocyclic rings, the spirocyclic ring consisting of a 3- to 7-membered heteroalkyl ring containing 1 to 3 ring heteroatoms independently selected from N, O, and S and a 3- to 7-membered alkane ring, the alkyl, cycloalkyl, heterocycloalkyl, bridged cycloalkyl, heterobridged cycloalkyl, phenyl, heteroaryl, spirocyclic ring optionally substituted with one or more independently selected from F, Cl, Br, C optionally substituted with one or more independently selected from F, Cl, Br 1-4 Straight or branched alkyl, C optionally substituted by one or more groups independently selected from F, Cl, Br 1-4 The radical may be substituted by a straight-chain or branched alkoxy radical.

3. The compound according to claim 1 or its pharmaceutically acceptable salt or deuterated substance, characterized in that: in, X and Y are independently selected from N and CH; R1 is selected from -OH, -OCH3, -C(O)OCH3, -C(O)NH2, -COOH, -NH2, -N(H)C(O)CH3, -N(H)S(O)2CH3, -B(OH)2, -S(O)2CH3, -P(O)(CH3)2, -OCH2CH2OH; R2 and R3 are independently selected from F, Cl, Br, I, -CN, -CH3, -CF3, -OCF3, -C(O)CH3, -S(O)2CH3, -P(O)(CH3)2, -C(O)OCH3, -C(O)NH2, and R2 and R3 are not halogen at the same time; R4, R5 and R6 are independently selected from H, -CH3; Ring A is selected from phenyl, 5-6 membered heteroaryl containing 1-3 ring heteroatoms independently selected from N, O, S connected to the proximal carbon atom via C; preferably, ring A is selected from phenyl, pyridyl; m is 1 or 2; R7 is independently selected from F, Cl, Br, -CN, C 1-4 Straight or branched alkyl, C 1-4 Straight or branched alkoxy, cyclohexyloxy, cyclobutyloxy, phenoxy, wherein the alkyl, alkoxy, cyclohexyloxy, cyclobutyloxy, phenoxy is optionally substituted by one or more independently selected from F, Cl, Br, C 1-4 The radical is substituted by a straight-chain or branched alkyl radical.

4. The compound according to claim 1 or its pharmaceutically acceptable salt or deuterated substance, characterized in that: The compound has the structure shown below (II): in, R1 is selected from -OH, -OCH3, -C(O)OCH3, -C(O)NH2, -COOH, -NH2, -N(H)C(O)CH3, -N(H)S(O)2CH3, -B(OH)2, -S(O)2CH3, -P(O)(CH3) 2、 -OCH2CH2OH; R2 and R3 are independently selected from F, Cl, Br, I, -CN, -CH3, -CF3, -OCF3, -C(O)CH3, -S(O)2CH3, -P(O)(CH3)2, -C(O)OCH3, -C(O)NH2, and R2 and R3 are not halogen at the same time; R7 is cyclohexyloxy, which is optionally substituted by one or more substituents independently selected from F, Cl, and Br; Preferably, R1 is selected from -OH, -C(O)OCH3, -COOH, -S(O)2CH3, -OCH2CH2OH; R2 is selected from F, Cl, Br, I, -CN, -CH3, -CF3, -OCF3, -C(O)CH3, -S(O)2CH3, -P(O)(CH3)2, -C(O)OCH3, -C(O)NH2; R3 is -CH3; R7 is cyclohexyloxy or Alternatively, the compound has the structure shown below (III): R1 is selected from -OH, -OCH3, -C(O)OCH3, -C(O)NH2, -COOH, -NH2, -N(H)C(O)CH3, -N(H)S(O)2CH3, -B(OH)2, -S(O)2CH3, -P(O)(CH3) 2、 -OCH2CH2OH; R2 and R3 are independently selected from F, Cl, Br, I, -CN, -CH3, -CF3, -OCF3, -C(O)CH3, -S(O)2CH3, -P(O)(CH3)2, -C(O)OCH3, -C(O)NH2, and R2 and R3 are not halogen at the same time; R7 is cyclohexyloxy, which is optionally substituted by one or more substituents independently selected from F, Cl, and Br; Preferably, R1 is selected from -OH, -C(O)OCH3, -COOH, -S(O)2CH3, -OCH2CH2OH; R2 is selected from F, Cl, Br, I, -CN, -CH3, -CF3, -OCF3, -C(O)CH3, -S(O)2CH3, -P(O)(CH3)2, -C(O)OCH3, -C(O)NH2; R3 is -CH3; R7 is cyclohexyloxy or 5. The compound according to claim 1 or its pharmaceutically acceptable salt or deuterated substance, characterized in that: The compound is selected from:

6. A pharmaceutical composition, characterized in that The pharmaceutical composition contains the compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt or deuterated substance thereof, and a pharmaceutically acceptable carrier.

7. A method for inhibiting c-Myc, characterized in that: Use the compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt or deuterated substance thereof.

8. Use of the compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt or deuterated substance thereof, or the pharmaceutical composition according to claim 6 in the preparation of a c-Myc inhibitor.

9. A method for preventing and / or treating a c-Myc-related or -mediated disease, wherein: A preventive and / or therapeutically effective amount of the compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt or deuterated substance thereof, or the pharmaceutical composition according to claim 6 is administered to an individual in need thereof. Preferably, the c-Myc-related or -mediated disease is a tumor. More preferably, the tumor is selected from lung cancer, breast cancer, liver cancer, pancreatic cancer, colorectal cancer, melanoma, bladder cancer, prostate cancer, gastric cancer, esophageal cancer, ovarian cancer, head and neck cancer, urothelial carcinoma, endometrial cancer, thyroid cancer, renal cancer, nasopharyngeal carcinoma, glioma, osteosarcoma, lymphoma, hematologic malignancy, etc.

10. Use of the compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt or deuterated substance thereof, or the pharmaceutical composition according to claim 6 in the preparation of a medicament for preventing and / or treating a c-Myc-related or mediated disease. Preferably, the c-Myc-related or -mediated disease is a tumor. More preferably, the tumor is selected from lung cancer, breast cancer, liver cancer, pancreatic cancer, colorectal cancer, melanoma, bladder cancer, prostate cancer, gastric cancer, esophageal cancer, ovarian cancer, head and neck cancer, urothelial carcinoma, endometrial cancer, thyroid cancer, renal cancer, nasopharyngeal carcinoma, glioma, osteosarcoma, lymphoma, hematologic malignancy, etc.

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