[1,2,4]Triazolo[4,3-a]quinoxaline derivative, method for preparing same, and pharmaceutical composition for preventing or treating BET protein-related diseases, containing same as active ingredient

A preparation method of the compound represented by formula 1 comprising the following steps, as shown in reaction formula 1 below:

• preparing the compound represented by formula 4 by reacting the compound represented by formula 2 with the compound represented by formula 3 (step 1);
• and
• preparing the compound represented by formula 1 by reacting the compound represented by formula 4 prepared in step 1 above with the compound represented by formula 5 (step 2):
• wherein,
• R1 is C1-20 straight or branched alkyl nonsubstituted or substituted with one or more halogens, or C6-20 aryl;
• R2 is hydrogen, C1-20 straight or branched alkyl, or C1-20 straight or branched alkoxy;
• R3 is hydrogen, nitro, halogen, nonsubstituted or substituted C1-20 straight or branched alkyl, nonsubstituted or substituted C1-20 straight or branched alkoxy, 5-10 membered heteroaryl nonsubstituted or substituted with one or more methyl groups containing one or more heteroatoms selected from the group consisting of N, O and S,
• which forms 6 membered cycloalkyl containing one or more heteroatoms selected from the group consisting of S and O along with R4,
• wherein, the substituted C1-20 straight or branched alkyl and the substituted C1-20 straight or branched alkoxy can be independently substituted with one or more substituents selected from the group consisting of halogen, C1-3 straight or branched alkoxy, 5-10 membered heterocycloalkyl containing one or more heteroatoms selected from the group consisting of N, O and S, and C6-10 aryl nonsubstituted or substituted with one or more nitro groups,
• A1 is hydrogen, or C1-20 straight or branched alkyl,
• B1 and B2 are independently hydrogen, C1-20 straight or branched alkyl, diC1-3 straight or branched alkylamino C1-3 straight or branched alkyl, or C6-10 aryl, and B1 and B2 are linked to each other to form 5-10 membered heterocycloalkyl nonsubstituted or substituted with one or more benzyl groups containing one or more heteroatoms selected from the group consisting of N, O and S,
• C1 is hydrogen, C1-20 straight or branched alkyl, or C1-20 straight or branched alkoxy,
• D1 and D2 are independently hydrogen, hydroxy, C1-20 straight or branched alkyl saturated or containing one or more carbon≡carbon unsaturated bonds, C1-20 straight or branched alkyl nonsubstituted or substituted with one or more cyano groups, or C1-20 straight or branched alkylsulfonyl,
• E1 is C1-20 straight or branched alkyl, or C6-10 aryl C1-5 straight or branched alkyl,
• F1 is C1-20 straight or branched alkyl, or C6-10 aryl,
• G1 is C1-20 straight or branched alkyl, or C6-10 aryl;
• R4 is hydrogen, hydroxy, halogen, nitro, C1-20 straight or branched alkyl nonsubstituted or substituted with one or more ═S groups, C1-20 straight or branched alkylsulfanyl nonsubstituted or substituted with one or more oxo (═O) groups, C1-20 straight or branched alkylsulfonyl, 5-10 membered heterocycloalkyloxy nonsubstituted or substituted with one or more C1-5 straight or branched alkoxycarbonyl containing one or more heteroatoms selected from the group consisting of N, O and S, nonsubstituted or substituted 5-10 membered heteroaryl containing one or more heteroatoms selected from the group consisting of N, O and S, nonsubstituted or substituted C1-20 straight or branched alkoxy,
• wherein, the substituted 5-10 membered heteroaryl can be substituted with one or more substituents selected from the group consisting of C1-3 straight or branched alkyl, C1-3 straight or branched alkoxy and C1-3 straight or branched alkoxy C1-3 straight or branched alkyl,
• wherein, the substituted C1-20 straight or branched alkoxy can be substituted with one or more substituents selected from the group consisting of halogen, cyano, C1-3 straight or branched alkoxy, nonsubstituted or substituted 5-10 membered heterocycloalkyl containing one or more heteroatoms selected from the group consisting of N, O and S, and nonsubstituted or substituted C6-10 aryl,
• wherein, the substituted 5-10 membered heterocycloalkyl and the substituted C6-10 aryl can be independently substituted with one or more substituents selected from the group consisting of cyano,
• C1-5 straight or branched alkoxycarbonyl, and 5-8 membered heteroaryl nonsubstituted or substituted with one or more N groups,
• A3 is hydrogen, or C1-20 straight or branched alkyl,
• B3 and B4 are independently hydrogen, C1-20 straight or branched alkyl, diC1-3 straight or branched alkylamino C1-3 straight or branched alkyl, nonsubstituted or substituted C6-10 aryl, nonsubstituted or substituted C6-10 aryl C1-3 straight or branched alkyl, and B3 and B4 are linked to each other to form 5-10 membered heterocycloalkyl nonsubstituted or substituted with one or more benzyl groups containing one or more heteroatoms selected from the group consisting of N, O and S,
• wherein, the substituted C6-10 aryl can be substituted with one or more substituents selected from the group consisting of amine, halogen, C1-5 straight or branched alkyl and C1-5 straight or branched alkoxy,
• C3, C4 and C5 are independently hydrogen, amine, halogen, C1-20 straight or branched alkyl, or C1-20 straight or branched alkoxy,
• D3 and D4 are independently hydrogen, hydroxy, C1-20 straight or branched alkyl saturated or containing one or more carbon≡carbon unsaturated bonds, C1-20 straight or branched alkyl nonsubstituted or substituted with one or more cyano groups, or C1-20 straight or branched alkylsulfonyl nonsubstituted or substituted with one or more halogens, and D3 and D4 are linked to each other to form 5-10 membered heteroaryl containing one or more heteroatoms selected from the group consisting of N, O and S, or 5-10 membered heterocycloalkyl fused with 5 membered heteroaryl nonsubstituted or substituted with one or more methyl groups or containing one S group and one or more heteroatoms selected from the group consisting of N, O and S,
• E3 is C1-20 straight or branched alkyl, or C6-10 aryl C1-5 straight or branched alkyl,
• F3 is C1-20 straight or branched alkyl, or C6-10 aryl,
• G3 is C1-20 straight or branched alkyl, or C6-10 aryl,
• H3 is C6-10 aryl, 5-10 membered heterocycloalkyl containing one or more heteroatoms selected from the group consisting of N, O and S, or 5-10 membered heteroaryl nonsubstituted or substituted with one or more methyl groups containing one or more heteroatoms selected from the group consisting of N, O and S,
• I3 is diC1-3 straight or branched alkylamino;
• R5 is hydrogen, halogen, C1-20 straight or branched alkyl nonsubstituted or substituted with one or more halogens, or C1-20 straight or branched alkoxy;
• R6 is
• B5 and B6 are independently hydrogen, C1-20 straight or branched alkyl, C6-10 aryl C1-3 straight or branched alkyl, or 5-10 membered heteroaryl C1-3 straight or branched alkyl containing one or more heteroatoms selected from the group consisting of N, O and S,
• D5 and D6 are independently hydrogen, hydroxy, C1-20 straight or branched alkyl saturated or containing one or more carbon≡carbon unsaturated bonds, C1-20 straight or branched alkyl nonsubstituted or substituted with one or more cyano groups, or C1-20 straight or branched alkylsulfonyl nonsubstituted or substituted with one or more halogens,
• E5 is C1-20 straight or branched alkyl saturated or containing one or more carbon≡carbon unsaturated bonds, C1-20 straight or branched alkoxy saturated or containing one or more carbon═carbon unsaturated bonds, C3-10 cycloalkyloxy, C3-10 cycloalkyl C1-3 straight or branched alkyl, C3-10 cycloalkyl, C6-10 aryloxy, C6-10 aryl C1-3 straight or branched alkoxy, C1-20 straight or branched alkylsulfanyl, nonsubstituted or substituted C6-10 aryl, diC1-3 straight or branched alkylamino, 5-10 membered heterocycloalkyl containing one or more heteroatoms selected from the group consisting of N, O and S, or nonsubstituted or substituted 5-10 membered heteroaryl containing one or more N groups,
• wherein, the substituted C1-20 straight or branched alkyl can be substituted with one or more substituents selected from the group consisting of hydroxy, halogen, C1-3 straight or branched alkoxy, C1-3 straight or branched alkylcarbonyloxy, C1-3 straight or branched alkoxycarbonyl, hydroxycarbonyl, C6-10 aryl nonsubstituted or substituted with one or more hydroxyl groups, 5-10 membered heteroaryl containing one or more heteroatoms selected from the group consisting of N, O and S, and
• T1 and T2 are independently hydrogen, C1-5 straight or branched alkyl, C1-5 straight or branched alkoxycarbonyl, C1-5 straight or branched alkylcarbonyl nonsubstituted or substituted with one or more halogens or hydroxyl groups, and T1 and T2 are linked to each other to form heterocycloalkyl nonsubstituted or substituted with one or more hydroxyl groups or C1-3 straight or branched alkyl groups containing one S group and one or more heteroatoms selected from the group consisting of N, O and S,
• wherein, the substituted C6-10 aryl and the substituted 5-10 membered heteroaryl can be independently substituted with one or more substituents selected from the group consisting of halogen, nitro, C1-5 straight or branched alkyl and C1-5 straight or branched alkoxy,
• F5 is C1-20 straight or branched alkyl, C3-10 cycloalkyl, or C6-10 aryl nonsubstituted or substituted with one or more halogens, and
• G5 is C1-20 straight or branched alkyl;
• M is C1-20 straight or branched alkylene;
• and
• X is —NH—.

A preparation method of the compound represented by formula 1 comprising the following steps, as shown in reaction formula 2 below:

• preparing the compound represented by formula 8 by reacting the compound represented by formula 7 with the compound represented by formula 5 (step 1);
• preparing the compound represented by formula 9 by reacting the compound represented by formula 8 prepared in step 1 above with hydrazine hydrate (step 2);
• and
• preparing the compound represented by formula 1 by reacting the compound represented by formula 9 prepared in step 2 above with the compound represented by formula 3 (step 3):
• wherein,
• R1 is C1-20 straight or branched alkyl nonsubstituted or substituted with one or more halogens, or C6-20 aryl;
• R2 is hydrogen, C1-20 straight or branched alkyl, or C1-20 straight or branched alkoxy;
• R3 is hydrogen, nitro, halogen, nonsubstituted or substituted C1-20 straight or branched alkyl, nonsubstituted or substituted C1-20 straight or branched alkoxy, 5-10 membered heteroaryl nonsubstituted or substituted with one or more methyl groups containing one or more heteroatoms selected from the group consisting of N, O and S,
• which forms 6 membered cycloalkyl containing one or more heteroatoms selected from the group consisting of S and O along with R4,
• wherein, the substituted C1-20 straight or branched alkyl and the substituted C1-20 straight or branched alkoxy can be independently substituted with one or more substituents selected from the group consisting of halogen, C1-3 straight or branched alkoxy, 5-10 membered heterocycloalkyl containing one or more heteroatoms selected from the group consisting of N, O and S, and C6-10 aryl nonsubstituted or substituted with one or more nitro groups,
• A1 is hydrogen, or C1-20 straight or branched alkyl,
• B1 and B2 are independently hydrogen, C1-20 straight or branched alkyl, diC1-3 straight or branched alkylamino C1-3 straight or branched alkyl, or C6-10 aryl, and B1 and B2 are linked to each other to form 5-10 membered heterocycloalkyl nonsubstituted or substituted with one or more benzyl groups containing one or more heteroatoms selected from the group consisting of N, O and S,
• C1 is hydrogen, C1-20 straight or branched alkyl, or C1-20 straight or branched alkoxy,
• D1 and D2 are independently hydrogen, hydroxy, C1-20 straight or branched alkyl saturated or containing one or more carbon≡carbon unsaturated bonds, C1-20 straight or branched alkyl nonsubstituted or substituted with one or more cyano groups, or C1-20 straight or branched alkylsulfonyl,
• E1 is C1-20 straight or branched alkyl, or C6-10 aryl C1-5 straight or branched alkyl,
• F1 is C1-20 straight or branched alkyl, or C6-10 aryl,
• G1 is C1-20 straight or branched alkyl, or C6-10 aryl;
• R4 is hydrogen, hydroxy, halogen, nitro, C1-20 straight or branched alkyl nonsubstituted or substituted with one or more ═S groups, C1-20 straight or branched alkylsulfanyl nonsubstituted or substituted with one or more oxo (═O) groups, C1-20 straight or branched alkylsulfonyl, 5-10 membered heterocycloalkyloxy nonsubstituted or substituted with one or more C1-5 straight or branched alkoxycarbonyl containing one or more heteroatoms selected from the group consisting of N, O and S, nonsubstituted or substituted 5-10 membered heteroaryl containing one or more heteroatoms selected from the group consisting of N, O and S, nonsubstituted or substituted C1-20 straight or branched alkoxy,
• wherein, the substituted 5-10 membered heteroaryl can be substituted with one or more substituents selected from the group consisting of C1-3 straight or branched alkyl, C1-3 straight or branched alkoxy and C1-3 straight or branched alkoxy C1-3 straight or branched alkyl,
• wherein, the substituted C1-20 straight or branched alkoxy can be substituted with one or more substituents selected from the group consisting of halogen, cyano, C1-3 straight or branched alkoxy, nonsubstituted or substituted 5-10 membered heterocycloalkyl containing one or more heteroatoms selected from the group consisting of N, O and S, and nonsubstituted or substituted C6-10 aryl,
• wherein, the substituted 5-10 membered heterocycloalkyl and the substituted C6-10 aryl can be independently substituted with one or more substituents selected from the group consisting of cyano,
• C1-5 straight or branched alkoxycarbonyl, and 5-8 membered heteroaryl nonsubstituted or substituted with one or more N groups,
• A3 is hydrogen, or C1-20 straight or branched alkyl,
• B3 and B4 are independently hydrogen, C1-20 straight or branched alkyl, diC1-3 straight or branched alkylamino C1-3 straight or branched alkyl, nonsubstituted or substituted C6-10 aryl, nonsubstituted or substituted C6-10 aryl C1-3 straight or branched alkyl, and B3 and B4 are linked to each other to form 5-10 membered heterocycloalkyl nonsubstituted or substituted with one or more benzyl groups containing one or more heteroatoms selected from the group consisting of N, O and S,
• wherein, the substituted C6-10 aryl can be substituted with one or more substituents selected from the group consisting of amine, halogen, C1-5 straight or branched alkyl and C1-5 straight or branched alkoxy,
• C3, C4 and C5 are independently hydrogen, amine, halogen, C1-20 straight or branched alkyl, or C1-20 straight or branched alkoxy,
• D3 and D4 are independently hydrogen, hydroxy, C1-20 straight or branched alkyl saturated or containing one or more carbon≡carbon unsaturated bonds, C1-20 straight or branched alkyl nonsubstituted or substituted with one or more cyano groups, or C1-20 straight or branched alkylsulfonyl nonsubstituted or substituted with one or more halogens, and D3 and D4 are linked to each other to form 5-10 membered heteroaryl containing one or more heteroatoms selected from the group consisting of N, O and S, or 5-10 membered heterocycloalkyl fused with 5 membered heteroaryl nonsubstituted or substituted with one or more methyl groups or containing one S group and one or more heteroatoms selected from the group consisting of N, O and S,
• E3 is C1-20 straight or branched alkyl, or C6-10 aryl C1-5 straight or branched alkyl,
• F3 is C1-20 straight or branched alkyl, or C6-10 aryl,
• G3 is C1-20 straight or branched alkyl, or C6-10 aryl,
• H3 is C6-10 aryl, 5-10 membered heterocycloalkyl containing one or more heteroatoms selected from the group consisting of N, O and S, or 5-10 membered heteroaryl nonsubstituted or substituted with one or more methyl groups containing one or more heteroatoms selected from the group consisting of N, O and S,
• I3 is diC1-3 straight or branched alkylamino;
• R5 is hydrogen, halogen, C1-20 straight or branched alkyl nonsubstituted or substituted with one or more halogens, or C1-20 straight or branched alkoxy;
• R6 is
• B5 and B6 are independently hydrogen, C1-20 straight or branched alkyl, C6-10 aryl C1-3 straight or branched alkyl, or 5-10 membered heteroaryl C1-3 straight or branched alkyl containing one or more heteroatoms selected from the group consisting of N, O and S,
• D5 and D6 are independently hydrogen, hydroxy, C1-20 straight or branched alkyl saturated or containing one or more carbon≡carbon unsaturated bonds, C1-20 straight or branched alkyl nonsubstituted or substituted with one or more cyano groups, or C1-20 straight or branched alkylsulfonyl nonsubstituted or substituted with one or more halogens,
• E5 is C1-20 straight or branched alkyl saturated or containing one or more carbon≡carbon unsaturated bonds, C1-20 straight or branched alkoxy saturated or containing one or more carbon═carbon unsaturated bonds, C3-10 cycloalkyloxy, C3-10 cycloalkyl C1-3 straight or branched alkyl, C3-10 cycloalkyl, C6-10 aryloxy, C6-10 aryl C1-3 straight or branched alkoxy, C1-20 straight or branched alkylsulfanyl, nonsubstituted or substituted C6-10 aryl, diC1-3 straight or branched alkylamino, 5-10 membered heterocycloalkyl containing one or more heteroatoms selected from the group consisting of N, O and S, or nonsubstituted or substituted 5-10 membered heteroaryl containing one or more N groups,
• wherein, the substituted C1-20 straight or branched alkyl can be substituted with one or more substituents selected from the group consisting of hydroxy, halogen, C1-3 straight or branched alkoxy, C1-3 straight or branched alkylcarbonyloxy, C1-3 straight or branched alkoxycarbonyl, hydroxycarbonyl, C6-10 aryl nonsubstituted or substituted with one or more hydroxyl groups, 5-10 membered heteroaryl containing one or more heteroatoms selected from the group consisting of N, O and S, and
• T1 and T2 are independently hydrogen, C1-5 straight or branched alkyl, C1-5 straight or branched alkoxycarbonyl, C1-5 straight or branched alkylcarbonyl nonsubstituted or substituted with one or more halogens or hydroxyl groups, and T1 and T2 are linked to each other to form heterocycloalkyl nonsubstituted or substituted with one or more hydroxyl groups or C1-3 straight or branched alkyl groups containing one S group and one or more heteroatoms selected from the group consisting of N, O and S,
• wherein, the substituted C6-10 aryl and the substituted 5-10 membered heteroaryl can be independently substituted with one or more substituents selected from the group consisting of halogen, nitro, C1-5 straight or branched alkyl and C1-5 straight or branched alkoxy,
• F5 is C1-20 straight or branched alkyl, C3-10 cycloalkyl, or C6-10 aryl nonsubstituted or substituted with one or more halogens,
• G5 is C1-20 straight or branched alkyl;
• M is C1-20 straight or branched alkylene;
• and
• X is —NH—.