Compounds that Inhibit Necroptosis and Their Preparation Methods

A compound as shown in general formula I, or a pharmaceutically acceptable salt thereof, its stereoisomer or its tautomer, or a prodrug:

• wherein,
• Z1, Z2, and Z3 are independently N, C(R);
• R is independently H, halogen, —OH, —CN, —COOH, C1-C6 alkyl, —C0-C6 alkylene alkoxy, C1-C6 alkyl-, C1-C6 halogenated alkyl, C1-C6 alkoxy, C1-C6 halogenated alkoxy, C2-C10 alkoxyl-alkyl, C2-C10 halogenated alkoxyl-alkyl, C1-C6 hydroxyalkyl, —C0-C6 alkylene, —S—C1-C6 alkyl-, —C0-C6 alkylene, —C6-C10 aryl, —C0-C6 alkylene-X—C6-C10 aryl, —C0-C6 alkylene-5-10-membered heteroaryl, —C0-C6 alkoxy-X-5-10-membered heteroaryl, —C0-C6 alkylene-3-10-membered non-aromatic heterocyclyl (wherein, the heteroatoms are independently one or more of sulfur, oxygen, NH, or NRg), —C0-C6 alkylene, —C3-C10 cycloalkyl, —C0-C6 alkylene, —C3-C10 cycloalkenyl, —C0-C6 alkylene-CORc, —C0-C6 alkylene-CO2, C1-C6 alkyl, —C0-C6 alkylene-CONRaRb, —C0-C6 alkylene-SO2NRaRb, —C0-C6 alkylene-S(O)2Rc, SF5, —C0-C6 alkylene-NRaRb, —C0-C6 alkylene-NHC(O)Rc, —C0-C6 alkylene-NHC(O)C(O)NRaRb, —C0-C6 alkoxy-NHC(O)C(O)ORa, —C0-C6 alkylene-NHC(O)NRaRb, —C0-C6 alkylene-P(O)Me2, —C0-C6 alkylene-P(O)(OMe)2, —C0-C6 alkylene, C3-C6 cycloalkyloxy, —C0-C6 alkylene, C1-C6 alkoxy, —C0-C6 alkylene, C1-C6 halogenated alkoxy, —C0-C6 alkylene, —C≡C—R2, —O—C1-C6 alkylene, —C≡C—R2, —S—C1-C6 alkylene, —C≡C—R2, and —C0-C6 alkylene-C(Ra)═C(Rb)—R2;
• R can be unsubstituted or substituted by 1 to 4 Rf;
• when R is connected to a nitrogen atom, R is not a halogen;
• R is specifically selected from the following groups:
• X can be O, S, SO, S(O)2, NH, C(O), CH2, CF2, CH(CH3), CH(OH), or N(CH3);
• R1 and R1a are independently of H, C1-C6 alkyl or —C0-C3 alkylene-C3-C6 cycloalkyl;
• R2 is hydrogen, C1-C10 alkyl, —C0-C6 alkylene-C6-C10 aryl, —C0-C6 alkylene-5-10-membered heteroaryl, —C0-C6 alkylene-3-10-membered non-aromatic heterocyclyl (wherein, the heteroatoms are independent one or more of sulfur, oxygen, NH, or NRg), —C0-C6 alkylene-C3-C10 cycloalkyl, or —C0-C6 alkylene-C1-C10 alkoxy;
• R2 can be independently unsubstituted or substituted by 1 to 4 Rf;
• Rf, at each occurrence, is independently halogen, —OH, carbonyl, —CN, —COOH, C1-C6 alkyl, —C0-C6 alkylene alkoxy, C1-C6 alkyl, C1-C6 halogenated alkyl, C1-C6 alkoxy, C1-C6 halogenated alkoxy, C2-C10 alkoxyl-alkyl, C2-C10 halogenated alkoxyl-alkyl, C1-C6 hydroxyalkyl, —C0-C6 alkylene-S—C1-C6 alkyl, —SF5, —C0-C6 alkylene-CORc, —C0-C6 alkylene-CO2C1-C6 alkyl, —C0-C6 alkylene-CONRaRb, —C0-C6 alkylene-SO2NRaRb, —C0-C6 alkylene-S(O)2R, —C0-C6 alkylene-NRaRb, —C0-C6 alkylene-C(O)NRaRb, —C0-C6 alkylene-NHC(O)Rc, —C0-C6 alkylene-NHC(O)C(O)NRaRb, —C0-C6 alkylene-NHC(O)C(O)ORa, —C0-C6 alkylene-NHC(O)NRaRb, —C0-C6 alkylene-P(O)Me2, —C0-C6 alkylene-P(O)(OMe)2. Two neighboring Rf or two Rf connected to the same carbon atom together form a 3- to 8-membered ring or a 4- to 8-membered heterocyclic ring, which may contain heteroatoms such as sulfur, oxygen, NH, or NRg;
• Ra and Rb are independent hydrogen, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C6-C10 aryl, or substituted or unsubstituted C3-C10 heteroaryl respectively;
• Ra and Rb can form a 3- to 8-membered ring or a 4- to 8-membered heterocyclic ring when connected to a nitrogen or carbon atom, which may contain heteroatoms such as sulfur, oxygen, NH, or NRg;
• the said 3- to 8-membered ring or 4- to 8-membered heterocyclic ring can be substituted by one or multiple Re;
• Rc is independently H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 halogenated alkyl, C3-C10 cycloalkenyl, C1-C6 alkoxy, C1-C6 cycloalkyloxy, C0-C6 alkylene hydroxyl, C6-C10 aryl, 5- to 10-membered heteroaryl, 3- to 10-membered non-aromatic heterocyclyl, —C0-C6 alkylene CF3, —C1-C6 alkylene CN, —C1-C6 alkylene-C1-C6 alkoxy, C1-C6 alkylene NRaRb, C1-C6 alkylene NRbC(O)Ra, C1-C6 alkylene NRS(O)2Ra, C1-C6 alkylene carboxyl, —C1-C6 alkylene CO2, C1-C6 alkyl, C1-C6 alkylene CORa, —C0-C6 alkylene CONRaRb;
• wherein, the said C6-C10 aryl, 5- to 10-membered heteroaryl, 3- to 10-membered non-aromatic heterocyclyl, C3-C6 cycloalkyl, or C3-C10 cycloalkenyl is each independently unsubstituted or substituted by one or two substituents independently selected from the following:
• halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C4 alkoxy, C0-C6 alkylene NRaRb, —C0-C6 alkylene CN, —C0-C6 alkylene OH;
• Rg is C1-C10 alkyl, C1-C10 heteroalkyl, C3-C10 cycloalkyl, C6-C10 aryl, or C3-C10 heteroaryl;
• X1, X2, X3, X4, and X5 are independently selected from C, CR, N, and NR, provided that the rules of valence bonding are conformed;
• is selected from the following:
• the said 3- to 10-membered non-aromatic heterocyclyl can also have the bicyclic or spiral ring structures as follows:
• L1 is structured as follows:
• Ring A is a substituted or unsubstituted benzene ring, a 5- to 6-membered heteroaromatic ring, or a 5- to 6-membered non-aromatic heterocyclic ring;
• Ring A can be furan, thiophene, isoxazole, oxazole, thiazole, oxadiazole, pyrrole, pyrazole, imidazole, triazole, or tetrazole;
• preferably, Ring A is structured as follows:
• Ring A can be substituted by one or two halogens, —CN, C1-C6 alkyl, or C1-C6 halogenated alkyl;
• Ring B is a substituted or unsubstituted 5- to 7-membered heterocyclic ring containing nitrogen atom;
• Ring C is a substituted or unsubstituted benzene ring, or a 5- to 6-membered heteroaromatic ring;
• Y1 and Y2 are independent carbon atoms or nitrogen atoms;
• preferably,
• is structured as follows:
• Rd is independently selected from H, halogen, C1-C6 alkyl, or C1-C6 halogenated alkyl;
• Re is H, C1-C6 alkyl, or C1-C6 halogenated alkyl;
• L2 is O, NRg, CRaRb, or a chemical bond;
• L3 is C0-C6 alkylene, C2-C6 alkenylene, C3-C6 cycloalkyl, benzene ring, 5- to 6-membered heteroaromatic ring, or 5- to 6-membered non-aromatic heterocyclic ring;
• L3 can be substituted by 1 to 3 R5;
• R5 is independently H, halogen, —OH, —CN, carbonyl, C1-C6 alkyl, C1-C6 halogenated alkyl, C1-C6 alkoxy, or C1-C6 halogenated alkoxy;
• Ring D is C3-C6 cycloalkyl, phenyl, naphthyl, C3-C6 cycloalkyl and phenyl, 5- to 6-membered heteroaryl, or 5- to 6-membered non-aromatic heterocyclyl;
• R10 is independently selected from halogen, CN, C1-C6 alkyl, C1-C6 halogenated alkyl, OC1-C6 alkyl, or C3-C6 cycloalkyl;
• n is 0, 1, 2, or 3.