Tetrahydrocyclopentapyrazole compound, preparation method thereof and application of tetrahydrocyclopentapyrazole compound in medicine

Abstract

The invention relates to a tetrahydrocyclopentapyrazole compound which simultaneously has RIPK1 inhibitory activity, free radical scavenging capacity and lipid peroxidation resistance, and application of the tetrahydrocyclopentapyrazole compound in preparation of drugs for treating or preventing RIPK1-mediated diseases or diseases caused by programmed necrosis of cells. Specifically, the invention relates to a compound as shown in a general formula, and pharmaceutically acceptable salt or stereoisomer thereof.

Description

Technical Field

[0001] This invention relates to a tetrahydrocyclopentapyrazole compound having receptor-interacting protein kinase 1 (RIPK1) inhibitory activity, and its use in the preparation of medicaments for the treatment or prevention of RIPK1-mediated diseases. Specifically, it relates to compounds of the general formula, their tautomers, or pharmaceutically acceptable combinations thereof. Background Technology

[0002] Receptor-interacting protein kinase 1 (RIPK1) is a key signaling protein in the TNF receptor signaling pathway. It possesses an N-terminal (N-terminal) kinase domain, a C-terminal (C-terminal) death domain, and an intermediate domain of the receptor-interacting protein homotypic interacting motif (RHIM), allowing it to bind to other RHIM-containing proteins. The C-terminal death domain mediates homodimerization and heterodimerization with other death-domain-containing proteins (such as FADD, TNFR1, and Fas), while the N-terminal kinase domain mediates autophosphorylation of the trans-terminal domain to promote its own activation. RIPK1 drives apoptosis and programmed necrosis through two distinct mechanisms: apoptosis is mediated by caspases, while in the absence of apoptotic conditions, RIPK1 and its downstream molecules RIPK3 and MLKL activate the programmed necrosis pathway.

[0003] The crucial role of RIPK1 in driving cell death and inflammation, the established safety profile of inhibiting human RIPK1 kinase activity, and the existence of a unique kinase regulatory allosteric pocket are the main factors contributing to RIPK1's prominence as a therapeutic target. Therefore, RIPK1 has gradually become one of the effective targets for the treatment of various diseases, including autoimmune diseases, inflammation, and neurodegenerative diseases. Several RIPK1 inhibitors have demonstrated their efficacy and safety in preclinical models and clinical trials. Among them, Necrostatin-1s (Nec-1s) was the first small-molecule RIPK1 kinase inhibitor developed. AbbVie's ABBV-668 and Sanofi's SAR443122 are both in Phase II clinical trials for ulcerative colitis, Vitalilon's SIR1-365 is registered for systemic inflammation in clinical trials, while Sanofi's brain penetrant SAR443820 is registered for amyotrophic lateral sclerosis (ALS) and multiple sclerosis in clinical trials.

[0004] Stroke is an acute cerebrovascular disease, classified into ischemic stroke and hemorrhagic stroke based on the sudden rupture or blockage of a blood vessel in the brain, preventing blood flow. Ischemic stroke accounts for 60%–70% of all strokes. Stroke is characterized by high incidence, high mortality, and high disability rates. The pathological process of ischemic stroke includes excitotoxicity, oxidative stress, and inflammatory responses. The therapeutic mechanism of the marketed drug edaravone is to exert an antioxidant effect through free radical scavenging, thereby providing neuroprotection. After ischemic stroke, apoptosis occurring in the penumbra (around the ischemic core) of the brain is salvageable, and RIPK1 is a key component of the necroptotic signaling pathway. Furthermore, since TNFR2 has a protective effect in the central nervous system, and RIPK1 kinase does not trigger signaling through TNFR2, RIPK1 is a safer target for the treatment of central nervous system diseases compared to TNF inhibitors.

[0005] Currently developed small-molecule inhibitors of RIPK1 kinase activity mainly focus on peripheral inflammation treatment, but they suffer from drawbacks such as insufficient specificity, poor inhibitory activity, and poor blood-brain barrier penetration. Therefore, we are developing small-molecule compounds that simultaneously possess RIPK1 inhibitory activity, antioxidant capacity, and high blood-brain barrier penetration to treat ischemic stroke through antioxidant action and blocking of programmed cell death, in order to meet the huge market demand. Summary of the Invention

[0006] This invention provides compounds of formula (I), pharmaceutically acceptable salts or stereoisomers thereof:

[0007]

[0008] in:

[0009] X 1a Selected from CR 1a Or N;

[0010] X 1b Selected from CR 1b Or N;

[0011] X 1c Selected from CR 1c Or N;

[0012] X 1d Selected from CR 1d Or N;

[0013] X 1e Selected from CR 1e Or N;

[0014] R 1a R 1b R1c R 1d R 1e When present, they are independently selected from: H, halogens, C. 1-6 Alkyl or cyano groups;

[0015] X 2a X 2b X 2c Each is independently selected from: CH or N;

[0016] X 3a Selected from CR 3a Or N;

[0017] X 3b Selected from CR 3b Or N;

[0018] X 3c Selected from CR 3c Or N;

[0019] X 3d Selected from CR 3d Or N;

[0020] X 3e Selected from CR 3e ;

[0021] R 3a R 3b R 3c When present, they are each independently selected from: H, halogens, or C. 1-6 alkyl;

[0022] R 3d and R 3e One of the selections The other is selected from H, halogen, or C. 1-6 alkyl;

[0023] L1 is selected from single bonds, C 1-6 alkylene, or

[0024] L2 is selected from single bond, C 6-10 Alpha-aryl;

[0025] R4 is selected from: H, or C 1-6 alkyl.

[0026] In some embodiments of the present invention, the compound structure represented by formula (I) above is as shown in formula (IA) or (IB):

[0027]

[0028] in:

[0029] X1a Selected from CR 1a Or N;

[0030] X 1b Selected from CR 1b Or N;

[0031] X 1c Selected from CR 1c Or N;

[0032] X 1d Selected from CR 1d Or N;

[0033] X 1e Selected from CR 1e Or N;

[0034] R 1a R 1b R 1c R 1d R 1e When present, they are independently selected from: H, halogens, C. 1-6 Alkyl or cyano groups;

[0035] X 2a X 2b X 2c Each is independently selected from: CH or N;

[0036] X 3a Selected from CR 3a Or N;

[0037] X 3b Selected from CR 3b Or N;

[0038] X 3c Selected from CR 3c Or N;

[0039] X 3d Selected from CR 3d Or N;

[0040] X 3e Selected from CR 3e ;

[0041] R 3a R 3b R 3c When present, they are each independently selected from: H, halogens, or C. 1-6 alkyl;

[0042] R 3d and R 3e One of the selections The other is selected from H, halogen, or C. 1-6 alkyl;

[0043] L1 is selected from single bonds, C 1-6 alkylene, or

[0044] L2 is selected from single bond, C 6-10 Alpha-aryl;

[0045] R4 is selected from: H, or C 1-6 alkyl.

[0046] In some embodiments of the present invention, the compound represented by formula (I), (IA), or (IB), its pharmaceutically acceptable salt, or stereoisomer, wherein,

[0047] X 1a Selected from CR 1a ;

[0048] X 1b Selected from CR 1b ;

[0049] X 1c Selected from CR 1c ;

[0050] X 1d Selected from CR 1d ;

[0051] X 1e Selected from CR 1e ;

[0052] R 1a R 1b R 1c R 1d R 1e Each is independently selected from: H, halogen, C 1-6 Alkyl or cyano groups;

[0053] Other groups are as defined in this invention.

[0054] In some embodiments of the present invention, the compound represented by formula (I), (IA), or (IB), its pharmaceutically acceptable salt, or stereoisomer, wherein,

[0055] X 1a Selected from CR 1a ;

[0056] X 1b Selected from CR 1b ;

[0057] X 1c Selected from CR 1c ;

[0058] X 1dSelected from CR 1d ;

[0059] X 1e Selected from CR 1e ;

[0060] R 1a R 1c R 1e Each is independently selected from H;

[0061] R 1b R 1d Each is independently selected from: H, halogen, C 1-6 Alkyl or cyano groups;

[0062] Other groups are as defined in this invention.

[0063] In some embodiments of the present invention, the compound represented by formula (I), (IA), or (IB), its pharmaceutically acceptable salt, or stereoisomer, wherein,

[0064] X 1a Selected from CR 1a ;

[0065] X 1b Selected from N;

[0066] X 1c Selected from CR 1c ;

[0067] X 1d Selected from CR 1d ;

[0068] X 1e Selected from CR 1e ;

[0069] R 1a R 1c R 1d R 1e Each is independently selected from: H, halogen, C 1-6 Alkyl or cyano groups;

[0070] Other groups are as defined in this invention.

[0071] In some embodiments of the present invention, the compound represented by formula (I), (IA), or (IB), its pharmaceutically acceptable salt, or stereoisomer, wherein,

[0072] X 1a Selected from CR 1a ;

[0073] X 1b Selected from N;

[0074] X 1c Selected from CR 1c ;

[0075] X 1d Selected from CR 1d ;

[0076] X 1e Selected from CR 1e ;

[0077] R 1a R 1c R 1e Each is independently selected from H;

[0078] R 1d Selected from: H, halogens, C 1-6 Alkyl or cyano groups;

[0079] Other groups are as defined in this invention.

[0080] In some embodiments of the present invention, the compound represented by formula (I), (IA), or (IB), its pharmaceutically acceptable salt, or stereoisomer, wherein X 2a X 2b Each is independently selected from: N; X 2c Selected from: CH; other groups are as defined in this invention.

[0081] In some embodiments of the present invention, the compound represented by formula (I), (IA), or (IB), its pharmaceutically acceptable salt, or stereoisomer, wherein X 2a X 2b X 2c Each group is independently selected from: N; other groups are as defined in this invention.

[0082] In some embodiments of the present invention, the compound represented by formula (I), (IA), or (IB), its pharmaceutically acceptable salt, or stereoisomer, wherein,

[0083] X 3a Selected from CR 3a ;

[0084] X 3b Selected from CR 3b ;

[0085] X 3c Selected from CR 3c ;

[0086] X 3d Selected from CR 3d ;

[0087] X 3e Selected from CR 3e ;

[0088] R 3a R 3b R 3c R 3e Each is independently selected from: H, halogen, or C. 1-6 alkyl;

[0089] R 3d Selected from

[0090] Other groups are as defined in this invention.

[0091] In some embodiments of the present invention, the compound represented by formula (I), (IA), or (IB), its pharmaceutically acceptable salt, or stereoisomer, wherein,

[0092] X 3a Selected from CR 3a ;

[0093] X 3b Selected from CR 3b ;

[0094] X 3c Selected from CR 3c ;

[0095] X 3d Selected from CR 3d ;

[0096] X 3e Selected from CR 3e ;

[0097] R 3a R 3b R 3c R 3d Each is independently selected from: H, halogen, or C. 1-6 alkyl;

[0098] R 3e Selected from

[0099] Other groups are as defined in this invention.

[0100] In some embodiments of the present invention, the compound represented by formula (I), (IA), or (IB), its pharmaceutically acceptable salt, or stereoisomer, wherein,

[0101] X 3a Selected from CR 3a ;

[0102] X 3b Selected from CR 3b ;

[0103] X 3c Selected from N;

[0104] X 3d Selected from CR 3d ;

[0105] X 3e Selected from CR 3e ;

[0106] R 3a R 3b R 3e Each is independently selected from: H, halogen, or C. 1-6 alkyl;

[0107] R 3d Selected from

[0108] Other groups are as defined in this invention.

[0109] In some embodiments of the present invention, the compound represented by formula (I), (IA), or (IB), its pharmaceutically acceptable salt, or stereoisomer, wherein,

[0110] X 3a Selected from CR 3a ;

[0111] X 3b Selected from CR 3b ;

[0112] X 3c Selected from N;

[0113] X 3d Selected from CR 3d ;

[0114] X 3e Selected from CR 3e ;

[0115] R 3a R 3b R 3d Each is independently selected from: H, halogen, or C. 1-6 alkyl;

[0116] R 3e Selected from

[0117] Other groups are as defined in this invention.

[0118] In some embodiments of the present invention, the compound represented by formula (I), (IA), or (IB), its pharmaceutically acceptable salt, or stereoisomer, wherein,

[0119] X3a Selected from N;

[0120] X 3b Selected from N;

[0121] X 3c Selected from CR 3c ;

[0122] X 3d Selected from CR 3d ;

[0123] X 3e Selected from CR 3e ;

[0124] R 3c R 3e Each is independently selected from: H, halogen, or C. 1-6 alkyl;

[0125] R 3d Selected from

[0126] Other groups are as defined in this invention.

[0127] In some embodiments of the present invention, the compound represented by formula (I), (IA), or (IB), its pharmaceutically acceptable salt, or stereoisomer, wherein,

[0128] X 3a Selected from N;

[0129] X 3b Selected from N;

[0130] X 3c Selected from CR 3c ;

[0131] X 3d Selected from CR 3d ;

[0132] X 3e Selected from CR 3e ;

[0133] R 3c R 3d Each is independently selected from: H, halogen, or C. 1-6 alkyl;

[0134] R 3e Selected from

[0135] Other groups are as defined in this invention.

[0136] In some embodiments of the present invention, the compound represented by formula (I), (IA), or (IB), its pharmaceutically acceptable salt, or stereoisomer, wherein,

[0137] X 3a Selected from N;

[0138] X 3b Selected from CR 3b ;

[0139] X 3c Selected from N;

[0140] X 3d Selected from CR 3d ;

[0141] X 3e Selected from CR 3e ;

[0142] R 3b R 3e Each is independently selected from: H, halogen, or C. 1-6 alkyl;

[0143] R 3d Selected from

[0144] Other groups are as defined in this invention.

[0145] In some embodiments of the present invention, the compound represented by formula (I), (IA), or (IB), its pharmaceutically acceptable salt, or stereoisomer, wherein,

[0146] X 3a Selected from N;

[0147] X 3b Selected from CR 3b ;

[0148] X 3c Selected from N;

[0149] X 3d Selected from CR 3d ;

[0150] X 3e Selected from CR 3e ;

[0151] R 3b R 3d Each is independently selected from: H, halogen, or C. 1-6 alkyl;

[0152] R 3e Selected from

[0153] Other groups are as defined in this invention.

[0154] In some embodiments of the present invention, the compound represented by formula (I), (IA), or (IB), its pharmaceutically acceptable salt, or stereoisomer, wherein,

[0155] X 3a Selected from CR 3a ;

[0156] X 3b Selected from N;

[0157] X 3c Selected from CR 3c ;

[0158] X 3d Selected from N;

[0159] X 3e Selected from CR 3e ;

[0160] R 3a R 3c Each is independently selected from: H, halogen, or C. 1-6 alkyl;

[0161] R 3e Selected from

[0162] Other groups are as defined in this invention.

[0163] In some embodiments of the present invention, the compound represented by formula (I), (IA), or (IB), its pharmaceutically acceptable salt, or stereoisomer, wherein,

[0164] L1 is selected from single bond, -CH2-, -(CH2)2-, -(CH2)3-, or

[0165] L2 is selected from single bonds and phenylene;

[0166] Other groups are as defined in this invention.

[0167] In some embodiments of the present invention, the compound represented by formula (I), (IA), or (IB), its pharmaceutically acceptable salt, or stereoisomer, wherein,

[0168] L1 is selected from a single bond;

[0169] L2 is selected from single bonds;

[0170] Other groups are as defined in this invention.

[0171] In some embodiments of the present invention, the compound represented by formula (I), (IA), or (IB), its pharmaceutically acceptable salt, or stereoisomer, wherein,

[0172] L1 is selected from a single bond;

[0173] L2 is selected from phenylene;

[0174] Other groups are as defined in this invention.

[0175] In some embodiments of the present invention, the compound represented by formula (I), (IA), or (IB), its pharmaceutically acceptable salt, or stereoisomer, wherein,

[0176] L1 is selected from a single bond;

[0177] L2 is selected from

[0178] Other groups are as defined in this invention.

[0179] In some embodiments of the present invention, the compound represented by formula (I), (IA), or (IB), its pharmaceutically acceptable salt, or stereoisomer, wherein,

[0180] L1 is selected from

[0181] L2 is selected from phenylene;

[0182] Other groups are as defined in this invention.

[0183] In some embodiments of the present invention, the compound represented by formula (I), (IA), or (IB), its pharmaceutically acceptable salt, or stereoisomer, wherein,

[0184] L1 is selected from -CH2-, -(CH2)2-, or -(CH2)3-;

[0185] L2 is selected from phenylene;

[0186] Other groups are as defined in this invention.

[0187] In some embodiments of the present invention, the compound represented by formula (I), (IA), or (IB), its pharmaceutically acceptable salt, or stereoisomer, wherein,

[0188] L1 is selected from -CH2-, -(CH2)2-, or -(CH2)3-;

[0189] L2 is selected from

[0190] Other groups are as defined in this invention.

[0191] In some embodiments of the present invention, the compound represented by formula (I), (IA), or (IB), its pharmaceutically acceptable salt, or stereoisomer, wherein,

[0192] R 1a R 1b R 1c R 1d R 1e Each is independently selected from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, or cyano;

[0193] R 3a R 3b R 3c When present, each is independently selected from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, or isopropyl;

[0194] R 3d and R 3e One of the selections The other is selected from H, F, Cl, Br, I, methyl, ethyl, n-propyl, or isopropyl;

[0195] R4 is selected from: H, methyl, ethyl, n-propyl, or isopropyl;

[0196] Other groups are as defined in this invention.

[0197] In other embodiments of the invention, the invention provides compounds of formula (II), pharmaceutically acceptable salts of which, or stereoisomers, are provided:

[0198]

[0199] in:

[0200] X 1b Selected from CR 1b Or N;

[0201] X 1d Selected from CR 1d Or N;

[0202] R 1b R 1d When present, they are independently selected from: H, halogens, C. 1-6 Alkyl or cyano groups;

[0203] X 2c Each is independently selected from: CH or N;

[0204] R 3d and R 3e One of the selections The other is selected from H, halogen, or C. 1-6 alkyl;

[0205] L1 is selected from single bonds, C 1-6 alkylene, or

[0206] L2 is selected from single bond, C 6-10 Alpha-aryl;

[0207] R4 is selected from: H, or C 1-6 alkyl.

[0208] In some embodiments of the present invention, the compound structure represented by formula (II) above is as shown in formula (IIA) or (IIB):

[0209]

[0210] in:

[0211] X 1b Selected from CR 1b Or N;

[0212] X 1d Selected from CR 1d Or N;

[0213] R 1b R 1d When present, they are independently selected from: H, halogens, C. 1-6 Alkyl or cyano groups;

[0214] X 2c Each is independently selected from: CH or N;

[0215] R 3d and R 3e One of the selections The other is selected from H, halogen, or C. 1-6 alkyl;

[0216] L1 is selected from single bonds, C 1-6 alkylene, or

[0217] L2 is selected from single bond, C 6-10 Alpha-aryl;

[0218] R4 is selected from: H, or C 1-6 alkyl.

[0219] In some embodiments of the present invention, the compounds represented by formulas (II), (IIA), or (IIB) above, their pharmaceutically acceptable salts or stereoisomers, wherein,

[0220] X 1b Selected from CR 1b ;

[0221] X 1d Selected from CR 1d ;

[0222] R 1b R 1d Each is independently selected from: H, halogen, C 1-6 Alkyl or cyano groups;

[0223] Other groups are as defined in this invention.

[0224] In some embodiments of the present invention, the compounds represented by formulas (II), (IIA), or (IIB) above, their pharmaceutically acceptable salts or stereoisomers, wherein,

[0225] X 1b Selected from N;

[0226] X 1d Selected from CR 1d ;

[0227] R 1d Selected from: H, halogens, C 1-6 Alkyl or cyano groups;

[0228] Other groups are as defined in this invention.

[0229] In some embodiments of the present invention, the compound represented by formula (II), (IIA), or (IIB) above, its pharmaceutically acceptable salt or stereoisomer, wherein X 2c Selected from CH; other groups are as defined in this invention.

[0230] In some embodiments of the present invention, the compound represented by formula (II), (IIA), or (IIB) above, its pharmaceutically acceptable salt or stereoisomer, wherein X 2c Selected from N; other groups are as defined in this invention.

[0231] In some embodiments of the present invention, the compounds represented by formulas (II), (IIA), or (IIB) above, their pharmaceutically acceptable salts or stereoisomers, wherein,

[0232] R 3d Selected from

[0233] R 3e Selected from H, halogen, or C 1-6 alkyl;

[0234] Other groups are as defined in this invention.

[0235] In some embodiments of the present invention, the compounds represented by formulas (II), (IIA), or (IIB) above, their pharmaceutically acceptable salts or stereoisomers, wherein,

[0236] R 3e Selected from

[0237] R 3d Selected from H, halogen, or C 1-6 alkyl;

[0238] Other groups are as defined in this invention.

[0239] In some embodiments of the present invention, the compounds represented by formulas (II), (IIA), or (IIB) above, their pharmaceutically acceptable salts or stereoisomers, wherein,

[0240] L1 is selected from a single bond;

[0241] L2 is selected from single bonds;

[0242] Other groups are as defined in this invention.

[0243] In some embodiments of the present invention, the compounds represented by formulas (II), (IIA), or (IIB) above, their pharmaceutically acceptable salts or stereoisomers, wherein,

[0244] L1 is selected from a single bond;

[0245] L2 is selected from phenylene;

[0246] Other groups are as defined in this invention.

[0247] In some embodiments of the present invention, the compounds represented by formulas (II), (IIA), or (IIB) above, their pharmaceutically acceptable salts or stereoisomers, wherein,

[0248] L1 is selected from a single bond;

[0249] L2 is selected from

[0250] Other groups are as defined in this invention.

[0251] In some embodiments of the present invention, the compounds represented by formulas (II), (IIA), or (IIB) above, their pharmaceutically acceptable salts or stereoisomers, wherein,

[0252] L1 is selected from

[0253] L2 is selected from phenylene;

[0254] Other groups are as defined in this invention.

[0255] In some embodiments of the present invention, the compounds represented by formulas (II), (IIA), or (IIB) above, their pharmaceutically acceptable salts or stereoisomers, wherein,

[0256] L1 is selected from -CH2-, -(CH2)2-, or -(CH2)3-;

[0257] L2 is selected from phenylene;

[0258] Other groups are as defined in this invention.

[0259] In some embodiments of the present invention, the compounds represented by formulas (II), (IIA), or (IIB) above, their pharmaceutically acceptable salts or stereoisomers, wherein,

[0260] L1 is selected from -CH2-, -(CH2)2-, or -(CH2)3-;

[0261] L2 is selected from

[0262] Other groups are as defined in this invention.

[0263] In some embodiments of the present invention, the compounds represented by formulas (II), (IIA), or (IIB) above, their pharmaceutically acceptable salts or stereoisomers, wherein,

[0264] R 1b R 1d Each is independently selected from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, or cyano;

[0265] R 3d and R 3e One of the selections The other is selected from H, F, Cl, Br, I, methyl, ethyl, n-propyl, or isopropyl;

[0266] R4 is selected from: H, methyl, ethyl, n-propyl, or isopropyl;

[0267] Other groups are as defined in this invention.

[0268] In some embodiments of the present invention, the compounds represented by formulas (II), (IIA), or (IIB) above, their pharmaceutically acceptable salts or stereoisomers, wherein,

[0269] X 1b Selected from CR 1b ;

[0270] X 1d Selected from CR 1d Or N;

[0271] R 1b R 1d When present, each is independently selected from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, or cyano;

[0272] X 2c Each is independently selected from: CH or N;

[0273] R 3e Selected from R 3d Selected from H, H, F, Cl, Br, I, methyl, ethyl, n-propyl, or isopropyl;

[0274] L1 is selected from single bonds, or

[0275] L2 is selected from single bond,

[0276] R4 is selected from: H, methyl, ethyl, n-propyl, or isopropyl.

[0277] In other embodiments of the invention, the invention provides compounds of formula (III), pharmaceutically acceptable salts of which, or stereoisomers, are provided:

[0278]

[0279] in:

[0280] X 1b Selected from CR 1b Or N;

[0281] X 1d Selected from CR 1d Or N;

[0282] R 1b R 1d When present, they are independently selected from: H, halogens, C. 1-6 Alkyl or cyano groups;

[0283] X 2c Each is independently selected from: CH or N;

[0284] X 3a Selected from CR 3a Or N;

[0285] X 3b Selected from CR 3b Or N;

[0286] X 3c Selected from CR 3c Or N;

[0287] X 3dSelected from CR 3d Or N;

[0288] R 3a R 3b R 3c R 3d Each is independently selected from: H, halogen, or C. 1-6 alkyl;

[0289] R 3e Selected from

[0290] L1 is selected from single bonds, C 1-6 alkylene, or L2 is selected from single bond, C 6-10 Alpha-aryl;

[0291] R4 is selected from: H, or C 1-6 alkyl.

[0292] In some embodiments of the present invention, the compound structure represented by formula (III) above is as shown in formula (IIIA) or (IIIB):

[0293]

[0294] in:

[0295] X 1b Selected from CR 1b Or N;

[0296] X 1d Selected from CR 1d Or N;

[0297] R 1b R 1d When present, they are independently selected from: H, halogens, C. 1-6 Alkyl or cyano groups;

[0298] X 2c Each is independently selected from: CH or N;

[0299] X 3a Selected from CR 3a Or N;

[0300] X 3b Selected from CR 3b Or N;

[0301] X 3c Selected from CR 3c Or N;

[0302] X 3d Selected from CR 3d Or N;

[0303] R 3a R 3b R 3c R 3d Each is independently selected from: H, halogen, or C. 1-6 alkyl;

[0304] R 3e Selected from

[0305] L1 is selected from single bonds, C 1-6 alkylene, or

[0306] L2 is selected from single bond, C 6-10 Alpha-aryl;

[0307] R4 is selected from: H, or C 1-6 alkyl.

[0308] In some embodiments of the present invention, the compounds represented by formulas (III), (IIIA), or (IIIB) above, their pharmaceutically acceptable salts, or stereoisomers, wherein,

[0309] X 1b Selected from CR 1b ;

[0310] X 1d Selected from CR 1d ;

[0311] R 1b R 1d Each is independently selected from: H, halogen, C 1-6 Alkyl or cyano groups;

[0312] Other groups are as defined in this invention.

[0313] In some embodiments of the present invention, the compounds represented by formulas (III), (IIIA), or (IIIB) above, their pharmaceutically acceptable salts, or stereoisomers, wherein,

[0314] X 1b Selected from N;

[0315] X 1d Selected from CR 1d ;

[0316] R 1d Selected from: H, halogens, C 1-6 Alkyl or cyano groups;

[0317] Other groups are as defined in this invention.

[0318] In some embodiments of the present invention, the compounds represented by formulas (III), (IIIA), or (IIIB) above, their pharmaceutically acceptable salts or stereoisomers, wherein X 2c Selected from CH; other groups are as defined in this invention.

[0319] In some embodiments of the present invention, the compounds represented by formulas (III), (IIIA), or (IIIB) above, their pharmaceutically acceptable salts or stereoisomers, wherein X 2c Selected from N; other groups are as defined in this invention.

[0320] In some embodiments of the present invention, the compounds represented by formulas (III), (IIIA), or (IIIB) above, their pharmaceutically acceptable salts, or stereoisomers, wherein,

[0321] X 3a Selected from CR 3a ;

[0322] X 3b Selected from CR 3b ;

[0323] X 3c Selected from CR 3c ;

[0324] X 3d Selected from CR 3d ;

[0325] R 3a R 3b R 3c R 3d Each is independently selected from: H, halogen, or C. 1-6 alkyl;

[0326] Other groups are as defined in this invention.

[0327] In some embodiments of the present invention, the compounds represented by formulas (III), (IIIA), or (IIIB) above, their pharmaceutically acceptable salts, or stereoisomers, wherein,

[0328] X 3a Selected from CR 3a ;

[0329] X 3b Selected from CR 3b ;

[0330] X 3c Selected from N;

[0331] X 3d Selected from CR 3d ;

[0332] R 3a R 3b R 3d Each is independently selected from: H, halogen, or C. 1-6 alkyl;

[0333] Other groups are as defined in this invention.

[0334] In some embodiments of the present invention, the compounds represented by formulas (III), (IIIA), or (IIIB) above, their pharmaceutically acceptable salts, or stereoisomers, wherein,

[0335] X 3a Selected from N;

[0336] X 3b Selected from CR 3b ;

[0337] X 3c Selected from N;

[0338] X 3d Selected from CR 3d ;

[0339] R 3b R 3d Each is independently selected from: H, halogen, or C. 1-6 alkyl;

[0340] Other groups are as defined in this invention.

[0341] In some embodiments of the present invention, the compounds represented by formulas (III), (IIIA), or (IIIB) above, their pharmaceutically acceptable salts, or stereoisomers, wherein,

[0342] X 3a Selected from N;

[0343] X 3b Selected from N;

[0344] X 3c Selected from CR 3c ;

[0345] X 3d Selected from CR 3d ;

[0346] R 3c R 3d Each is independently selected from: H, halogen, or C. 1-6 alkyl;

[0347] Other groups are as defined in this invention.

[0348] In some embodiments of the present invention, the compounds represented by formulas (III), (IIIA), or (IIIB) above, their pharmaceutically acceptable salts, or stereoisomers, wherein,

[0349] X 3a Selected from CR 3a ;

[0350] X 3b Selected from N;

[0351] X 3c Selected from CR 3c ;

[0352] X 3d Selected from N;

[0353] R 3a R 3c Each is independently selected from: H, halogen, or C. 1-6 alkyl;

[0354] Other groups are as defined in this invention.

[0355] In some embodiments of the present invention, the compounds represented by formulas (III), (IIIA), or (IIIB) above, their pharmaceutically acceptable salts, or stereoisomers, wherein,

[0356] L1 is selected from a single bond;

[0357] L2 is selected from single bonds;

[0358] Other groups are as defined in this invention.

[0359] In some embodiments of the present invention, the compounds represented by formulas (III), (IIIA), or (IIIB) above, their pharmaceutically acceptable salts, or stereoisomers, wherein,

[0360] L1 is selected from a single bond;

[0361] L2 is selected from phenylene;

[0362] Other groups are as defined in this invention.

[0363] In some embodiments of the present invention, the compounds represented by formulas (III), (IIIA), or (IIIB) above, their pharmaceutically acceptable salts, or stereoisomers, wherein,

[0364] L1 is selected from a single bond;

[0365] L2 is selected from

[0366] Other groups are as defined in this invention.

[0367] In some embodiments of the present invention, the compounds represented by formulas (III), (IIIA), or (IIIB) above, their pharmaceutically acceptable salts, or stereoisomers, wherein,

[0368] L1 is selected from

[0369] L2 is selected from phenylene;

[0370] Other groups are as defined in this invention.

[0371] In some embodiments of the present invention, the compounds represented by formulas (III), (IIIA), or (IIIB) above, their pharmaceutically acceptable salts, or stereoisomers, wherein,

[0372] L1 is selected from -CH2-, -(CH2)2-, or -(CH2)3-;

[0373] L2 is selected from phenylene;

[0374] Other groups are as defined in this invention.

[0375] In some embodiments of the present invention, the compounds represented by formulas (III), (IIIA), or (IIIB) above, their pharmaceutically acceptable salts, or stereoisomers, wherein,

[0376] L1 is selected from -CH2-, -(CH2)2-, or -(CH2)3-;

[0377] L2 is selected from

[0378] Other groups are as defined in this invention.

[0379] In some embodiments of the present invention, the compounds represented by formulas (III), (IIIA), or (IIIB) above, their pharmaceutically acceptable salts, or stereoisomers, wherein,

[0380] R 1b R 1d Each is independently selected from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, or cyano;

[0381] R 3a R 3b R 3c R 3d Each is independently selected from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, or isopropyl;

[0382] R 3e Selected from

[0383] R4 is selected from: H, methyl, ethyl, n-propyl, or isopropyl;

[0384] Other groups are as defined in this invention.

[0385] In some embodiments of the present invention, compounds, pharmaceutically acceptable salts or stereoisomers thereof are provided as follows:

[0386]

[0387]

[0388]

[0389] In another aspect of the invention, the invention provides pharmaceutically acceptable salts of the aforementioned compounds. The compounds of the invention are capable of forming acid addition salts and / or base addition salts. The acid addition salts can be formed with inorganic and organic acids, wherein the inorganic acids include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; and the organic acids include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, etc.

[0390] This invention also provides a pharmaceutical composition comprising any of the above-described compounds or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. The pharmaceutical composition can be formulated into various pharmaceutically acceptable dosage forms, such as tablets, capsules, oral liquids, granules, injections, or various sustained-release formulations. The pharmaceutical composition can be administered orally or parenterally (e.g., intravenously, subcutaneously, or topically). The dosage can be appropriately adjusted according to the patient's age, sex, and disease type, generally with a daily dose of approximately 1-200 mg.

[0391] The above-mentioned compounds, their pharmaceutically acceptable salts, stereoisomers, or pharmaceutical compositions provided by this invention simultaneously possess RIPK1 inhibitory activity, free radical scavenging ability, and anti-lipid peroxidation ability.

[0392] This invention also provides the use of the above-mentioned compounds, their pharmaceutically acceptable salts, stereoisomers, or pharmaceutical compositions for the treatment and / or prevention of diseases in patients, and the use of the above-mentioned compounds, their pharmaceutically acceptable salts or stereoisomers, or pharmaceutical compositions in the preparation of medicaments. This invention further provides the use of the above-mentioned compounds, their pharmaceutically acceptable salts, stereoisomers, or pharmaceutical compositions in the preparation of medicaments, wherein the medicament is for the treatment or prevention of diseases mediated by receptor-interacting protein kinase 1 (RIPK1) or diseases caused by programmed cell death. The receptor-interacting protein kinase 1 (RIPK1)... 1. RIPK1-mediated diseases or diseases caused by programmed cell death include those that are easily regulated at least in part through programmed necrosis, apoptosis, or the production of inflammatory cytokines; for example: inflammatory bowel disease (including Crohn's disease and ulcerative colitis), psoriasis, retinal detachment, retinal degeneration, retinitis pigmentosa, macular degeneration, age-related macular degeneration, pancreatitis, arthritis (including rheumatoid arthritis, spondyloarthritis, gout), juvenile idiopathic arthritis (generalized juvenile idiopathic arthritis). Arthritis (Sojia), psoriatic arthritis, lupus, systemic lupus erythematosus (SLE), Sjögren's syndrome, systemic scleroderma, antiphospholipid syndrome (APS), vasculitis, osteoarthritis, liver damage / liver disease (non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), autoimmune hepatitis, autoimmune hepatobiliary diseases, primary sclerosing cholangitis (PSC), acetaminophen poisoning, liver poisoning), non-alcoholic fatty liver disease (NAFLD), kidney damage / kidney injury (kidney Inflammation, kidney transplantation, surgery, administration of nephrotoxic drugs such as cisplatin, acute kidney injury (AKI), celiac disease, autoimmune idiopathic thrombocytopenic purpura (ITP), transplant rejection (rejection of transplanted organs, tissues, and cells), reperfusion injury of solid organs, sepsis, systemic inflammatory response syndrome (SIRS), cerebrovascular accident (CVA, stroke), myocardial infarction (MI), atherosclerosis, Huntington's disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS). Progressive supranuclear palsy (PSP), neonatal brain injury, hypoxic-ischemic brain injury, ischemic brain injury, traumatic brain injury, allergic diseases (including asthma and atopic dermatitis), peripheral nerve injury, burns, multiple sclerosis, type 1 diabetes, type 2 diabetes, obesity, Wegener's granulomatosis, pulmonary sarcoidosis, Behcet's disease, interleukin-1 converting enzyme (ICE, also known as caspase-1)-associated fever syndrome, chronic obstructive pulmonary disease (COPD), cigarette smoke-induced damage, cystic fibrosis.Tumor necrosis factor receptor-associated cyclic syndrome (TRAPS), neoplastic tumors, periodontitis, NEMO-mutations (mutations in the NF-κ-B basal regulator gene (also known as IKKγ or IKKG)), especially NEMO-deficiency syndrome, HOIL-1 deficiency (also known as RBCK1), heme-oxidized IRP2 ubiquitin ligase-1 deficiency, linear ubiquitin chain assembly complex (LUBAC) deficiency syndrome, blood and solid organ malignancies. Sexually transmitted tumors, bacterial and viral infections (such as influenza, staphylococcal and mycobacterial (tuberculosis)), lysosomal storage diseases (especially Gaucher disease, and including GM2 ganglioside storage disease, α-mannoside storage disease, aspartate glucosamineuria, cholesterol ester storage disease, chronic aminohexosidase A deficiency, cystinosis, Danon disease, Fabry disease, Fabry disease, fucoside storage disease, galactosylsialic acid storage disease, GM1 ganglioside storage disease, mucoliposomalemia, infantile swimming disease, etc. Sialic acid storage disease, juvenile aminohexosidase A deficiency, Krabby's disease, lysosomal acid lipase deficiency, metachromatic leukodystrophy, mucopolysaccharidosis, multiple sulfatase deficiencies, Niemann-Pick disease, neuronal ceroid lipofuscin deposition disease, Pompey's disease, osteogenesis imperfecta condensans, Sandhof's disease, Schindler's disease, sialic acid storage disease, familial amaurotic idiocy and Wollman's disease, Stephen Johnson's syndrome, toxic epidermal necrolysis, glaucoma, spinal cord injury. Myeloid injury, fibrosis, complement-mediated cytotoxicity, cancers (including pancreatic cancer, pancreatic ductal adenocarcinoma, hepatocellular carcinoma, mesothelioma, melanoma, metastatic tumors, breast cancer, non-small cell lung cancer (NSCLC)), radiation-induced necrosis, ischemic kidney damage, ocular ischemia, cerebral hemorrhage, subarachnoid hemorrhage, acute liver failure and radiation protection / relief, auditory disorders such as noise-induced hearing loss and ototoxicity-related drugs (such as cisplatin) or for treating cells in vitro to preserve viability and function.

[0393] Definitions and Explanations

[0394] Unless otherwise stated, the following terms and phrases as used herein are intended to have the following meanings. A particular term or phrase should not be considered uncertain or unclear unless specifically defined, but should be understood in its ordinary sense. When a trade name appears herein, it is intended to refer to the corresponding product or its active ingredient.

[0395] The term "pharmaceutically acceptable" as used in this invention refers to compounds, compositions, and / or dosage forms that, within the limits of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0396] The term "pharmaceutically acceptable salt" as used in this invention refers to salts of the compounds of this invention, prepared by reacting compounds with specific substituents discovered in this invention with relatively non-toxic acids or bases. When the compounds of this invention contain relatively basic functional groups, acid addition salts can be obtained by contacting a sufficient amount of acid with the neutral form of such compounds in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, organic acid salts; salts of amino acids (such as arginine), and salts of organic acids such as glucuronic acid. Certain specific compounds of this invention contain basic functional groups and can therefore be converted into any acid addition salt.

[0397] Some compounds of this invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers, and single isomers are all included within the scope of this invention.

[0398] The compounds of this invention contain one or more asymmetric centers (also referred to as chiral centers), such as chiral carbon or chiral -SO- moieties. The stereochemistry of the chiral carbon center present in the compounds of this invention is generally represented by the compound name and / or chemical structure shown herein. The compounds of this invention containing one or more chiral centers may exist as racemic mixtures, diastereomeric mixtures, enantiomer-enriched mixtures, diastereomeric-enriched mixtures, or as individual stereoisomers, either enantiomerically or diastereomeric in pure form. For example: Carbon atoms marked with an asterisk (*) are chiral carbon atoms, which may exist as a single enantiomer (R) or (S) or be rich in one enantiomer, or as a racemic mixture.

[0399] The compounds of this invention can exist in specific geometric or stereoisomeric forms. This invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)- isomers, (L)- isomers, and racemic mixtures thereof, as well as other mixtures, such as mixtures enriched with enantiomers or diastereomers, all of which are within the scope of this invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of this invention.

[0400] Unless otherwise stated, the term "enantiomer" refers to stereoisomers that are mirror images of each other.

[0401] Unless otherwise stated, the term "geometric isomer" arises from the fact that double bonds or single bonds of cyclic carbon atoms cannot rotate freely.

[0402] Unless otherwise stated, the term "diastereomer" refers to a stereoisomer of a molecule having two or more chiral centers and being in a non-mirror relationship with each other.

[0403] Unless otherwise stated, "(D)" or "(+)" indicates right-handed rotation, "(L)" or "(-)" indicates left-handed rotation, and "(DL)" or "(±)" indicates racemic rotation.

[0404] Unless otherwise specified, use wedge-shaped solid line keys. and wedge-shaped dashed key The absolute configuration of the center of a solid is represented by a straight solid line key. and straight dashed key The relative configuration of the center of a solid is indicated by a wavy line. Indicates wedge-shaped solid line key or wedge-shaped dashed key Or use wavy lines Indicates a straight solid line key and straight dashed key

[0405] The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing acid radicals or bases by conventional chemical methods. Generally, the salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture thereof.

[0406] The term "pharmaceutically acceptable carrier" refers to any formulation or carrier medium that can deliver an effective amount of the active substance of the present invention without interfering with the biological activity of the active substance and without toxic side effects on the host or patient, including but not limited to: adhesives, fillers, lubricants, disintegrants, wetting agents, dispersants, solubilizers, suspending agents, etc.

[0407] This invention is intended to include all isotopes of atoms present in the compounds of this invention. Isotopes include atoms with the same number of atoms but different mass numbers. As a general example and without limitation, isotopes of hydrogen include deuterium and tritium. Isotopes of carbon include... 13 C and 14 C. The isotope-labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by methods similar to those described herein, using a suitable isotope-labeling reagent instead of an additional unlabeled reagent.

[0408] Unless otherwise specified, the term "alkyl" is used to denote a straight-chain or branched saturated hydrocarbon group, which may be monosubstituted (e.g., -CH2F) or polysubstituted (e.g., -CF3), and may be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methine). For example, C1-C6 indicates 1 to 6 carbons, C 1-6Selected from C1, C2, C3, C4, C5, and C6; examples of alkyl groups include methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, s-butyl, t-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl, 1-ethylpropyl), hexyl (e.g., n-hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, and 2-ethylbutyl), etc. Understandably, the term "alkylene" refers to a residue that has lost one hydrogen atom from an alkyl group. Examples of C1-C6 alkylene groups include, but are not limited to, -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -CH2CH(CH3)-CH2-, etc. It is important to note that when an alkylene group (e.g., methylene) appears at the end of a straight or branched chain or at the end of a substituent, it includes "CH2=", where the hydrogen atom can be replaced by one or two halogen atoms (e.g., fluorine atoms).

[0409] Unless otherwise specified, the term "halogen" on its own or as part of another substituent means a fluorine, chlorine, bromine or iodine atom.

[0410] Unless otherwise specified, the term "cyano" refers to the -CN group.

[0411] Unless otherwise specified, the term "alkoxy" is used to denote an alkyl group (including cycloalkyl or haloalkyl) having a specific number of carbon atoms connected by an oxygen bridge. Typical alkoxy groups include C... 1-6 Alkoxy groups, such as: C1, C2, C3, C4, C5, C6 alkoxy groups; C3, C4, C5, C6 cycloalkoxy groups; and C1, C2, C3, C4, C5, C6 haloalkoxy groups. Examples of alkoxy groups include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, S-pentoxy, hexoxy, and 2-ethylbutoxy. Examples of cycloalkoxy groups include, but are not limited to: cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexoxy. Examples of haloalkoxy groups include, but are not limited to: fluoromethoxy, chloromethoxy, difluoromethoxy, dichloromethoxy, trifluoromethoxy, trichloromethoxy, 2,2-difluoroethoxy, 2,2,2-dichloroethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, pentafluoroethoxy, and pentachloroethoxy.

[0412] Unless otherwise specified, the term "haloalkyl" is used to indicate that an alkyl group is substituted by one or more halogen atoms, wherein the alkyl group has the meaning as described in this invention. For example, the term "C1-C6 haloalkyl" is intended to include C1, C2, C3, C4, C5, C6 alkyl groups substituted by one or more halogen atoms. Unless otherwise specified, examples of C1-C6 haloalkyl include, but are not limited to: fluoromethyl, chloromethyl, difluoromethyl, dichloromethyl, trifluoromethyl, trichloromethyl, 2,2-difluoroethyl, 2,2,2-dichloroethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, pentafluoroethyl, and pentachloroethyl.

[0413] Unless otherwise specified, the term "aryl" refers to an all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group having a conjugated π-electron system. Typically, aryl groups have 6 to 10 ring carbon atoms, i.e., C6466667 ... 6-10 Aryl. Examples of aryl groups include phenyl, naphthyl, preferably phenyl. The term "arylene" refers to a divalent hydrocarbon group derived from a monocyclic or fused bicyclic or polycyclic system (where at least one ring contains a fully conjugated π-electron system) having well-known aromatic characteristics. Typically, arylene groups contain 6-10 ring carbon atoms, i.e., C64-C ... 6-10 Aryl groups. Examples of aryl groups include, but are not limited to, phenylene and naphthylene.

[0414] Compounds are processed manually or Software naming conventions are used; commercially available compounds use supplier catalog names. Detailed Implementation

[0415] The present invention will be further illustrated below with reference to specific embodiments and test examples, but this does not limit the scope of the invention in any way.

[0416] Example 1: Synthesis of Compound 1

[0417]

[0418] Synthetic route

[0419]

[0420] Step 1: Synthesis of Compound 1-1

[0421] The following compounds were added sequentially to an anhydrous dioxane (450 mL) solution of 1-bromo-3,5-difluorobenzene (20.01 g, 103.70 mmol, 11.94 mL, 1.3 eq) and cyclopentanone (6.71 g, 79.77 mmol, 7.06 mL, 1 eq): palladium acetate (1.79 g, 7.98 mmol, 0.1 eq), sodium acetate (6.54 g, 79.77 mmol, 1 eq), tert-octylamine (3.09 g, 23.93 mmol, 3.99 mL, 0.3 eq), tetrahydropyrrole (1.70 g, 23.93 mmol, 2.00 mL, 0.3 eq), and tris(o-tolyl)phosphine (4.86 g, 15.95 mmol, 0.2 eq). After purging with nitrogen three times, the mixture was stirred at 110 °C for 12 hours. The reaction was monitored by LC-MS to ensure complete reaction of the starting materials. The reaction solution was filtered and concentrated to obtain a crude product. The crude product was purified by reverse-phase [water (formic acid)-acetonitrile system], and after concentration under reduced pressure to remove acetonitrile, it was extracted with ethyl acetate (500 mL * 3) and concentrated under reduced pressure to obtain compound 1-1 (2.8 g, 13.52 mmol, yield 16.94%), which was a dark brown oil. (ESI) m / z = 195.1 [MH] + . 1 H NMR (400MHz, CHLOROFORM-d) δ6.86-6.61 (m, 3H), 3.31 (dd, J = 8.4, 11.6Hz, 1H), 2.56-2. 46(m,2H),2.37-2.25(m,1H),2.24-2.12(m,1H),2.12-2.02(m,1H),2.01-1.89(m,1H).

[0422] Step 2: Synthesis of Compounds 1-2

[0423] Compound 1-1 (2.8 g, 14.27 mmol, 1 eq) was added to N,N-dimethylformamide (65 mL) along with N,N-dimethylformamide dimethyl acetal (8.50 g, 71.36 mmol, 9.48 mL, 5 eq). After purging with nitrogen three times, the mixture was stirred at 110 °C for 1 hour. The reaction mixture was monitored by LCMS to ensure complete reaction of the starting material. The reaction solution was poured into water (500 mL) and extracted with ethyl acetate (300 mL x 3). The organic phase was washed three times with saturated brine and concentrated under reduced pressure to obtain compound 1-2 (3 g, crude product), which was a yellow solid. (ESI) m / z = 252.0 [M+H] + .

[0424] Step 3: Synthesis of compounds 1-3

[0425] Hydrazine hydrate (717.22 mg, 12.18 mmol, 694.98 μL, 85% purity, 1.02 eq) was added to a 60 mL ethanol solution of compounds 1-2 (3 g, 11.94 mmol, 1 eq). The reaction mixture was stirred at 100 °C for 12 h. The reaction mixture was monitored by LC-MS to ensure complete reaction of the starting material. The reaction mixture was concentrated to obtain a crude product. The crude product was purified by column chromatography (ethyl acetate / petroleum ether = 10-20%) to give compounds 1-3 (1.55 g, 6.73 mmol, yield 56.36%) as a yellow oil. (ESI) m / z = 221.0 [M+H] + .

[0426] Step 3: Synthesis of compounds 1-4

[0427] To a solution of compounds 1-3 (180 mg, 817.37 μmol, 1 eq) and 3-bromophenylboronic acid (246.22 mg, 1.23 mmol, 1.5 eq) in acetonitrile (4 mL), copper acetate (296.93 mg, 1.63 mmol, 2 eq) and pyridine (258.62 mg, 3.27 mmol, 263.89 μL, 4 eq) was added. The reaction mixture was stirred at 60 °C for 12 hours under an oxygen atmosphere. The reaction mixture was monitored by LCMS to ensure complete reaction of the starting materials. The reaction mixture was filtered and concentrated to obtain a crude product. The crude product was purified by reverse-phase [water (formic acid)-acetonitrile system] and concentrated under reduced pressure to obtain compounds 1-4 (150 mg, 397.42 μmol, yield 48.62%) as a yellow gel. (ESI) m / z = 375.1 / 377.1 [M+H] + . 1 H NMR(400MHz,CHLOROFORM-d)δ7.83(t,J=2.0Hz,1H),7.58(s,1H),7.55(td,J=1.2,8.0Hz,1H),7 .36-7.31(m,1H),7.27-7.22(m,1H),6.88-6.79(m,2H),6.64(s,1H),4.37-4.27(m,1H),2.95(br d, J=8.4Hz, 1H), 2.76 (s, 2H), 2.35 (tdd, J=6.8, 8.4, 13.2Hz, 1H).

[0428] Step 4: Synthesis of compounds 1-5

[0429] To a 1.5 mL solution of compounds 1-4 (130 mg, 346.47 μmol, 1 eq) and di-tert-butylazidooxalic acid (20.72 mg, 519.71 μmol, 116.07 μL, 1.5 eq) in toluene (1.5 mL), [(2-di-tert-butylphosphine-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate] (27.52 mg, 34.65 μmol, 0.1 eq) and cesium carbonate (338.66 mg, 1.04 mmol, 3 eq) were added. After purging with nitrogen three times, the reaction mixture was stirred at 100 °C under a nitrogen atmosphere for 12 hours. The reaction mixture was monitored by LCMS to ensure complete reaction of the starting materials. The reaction mixture was filtered and concentrated to obtain the crude product. The crude product was purified by column chromatography (ethyl acetate / petroleum ether = 10-20%) to give compounds 1-5 (200 mg, 330.44 μmol, yield 95.37%) as a yellow gel. (ESI) m / z = 527.4 [M+H] + .

[0430] Step 5: Synthesis of compounds 1-6

[0431] Trifluoroacetic acid (0.8 mL) was added to a solution of compounds 1-5 (200 mg, 379.81 μmol, 1 eq) in dichloromethane (4 mL). The reaction mixture was reacted at 25 °C for 1 hour. LC-MS monitoring showed complete disappearance of the reactants and the main peak being the target product. The reaction mixture was concentrated under reduced pressure to obtain crude product 1-6 (165 mg, TFA), a pale yellow oil, which was used directly in the next step. (ESI) m / z = 327.2 [M+H] + .

[0432] Step 6: Synthesis of Compound 1

[0433] To a solution of compounds 1-6 (165 mg, 374.69 μmol, 1 eq, TFA) in acetonitrile (1.5 mL), ethyl acetoacetate (58.51 mg, 449.63 μmol, 56.92 μL, 1.2 eq) was added. The reaction mixture was reacted at 60 °C for 1 hour. The reaction mixture was monitored by LCMS to ensure complete reaction of the starting materials. The reaction mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by reverse-phase preparation [water (formic acid)-acetonitrile system] and then lyophilized to obtain compound 1 (44.78 mg, 114.12 μmol, 30.46% yield, 100% purity) as a white solid. (ESI) m / z = 393.0 [M+H] + . 1H NMR(400MHz,CHLOROFORM-d)δ8.17(s,1H),7.84-7.79(m,1H),7.69(s,1H),7.53(ddd,J=1.2,2.0,8.4Hz,1H),7.43(s,1H),6.86(br d,J=6.8Hz,2H),6.66(tt,J=2.4,9.2Hz,1H),4.35(dd,J=6.8,8.4Hz,1H),3.46(s,2H), 3.03-2.92(m,1H),2.89-2.72(m,2H),2.38(tdd,J=6.8,8.4,12.8Hz,1H),2.22(s,3H).

[0434] Those skilled in the art can refer to the synthetic route of Example 1 and make appropriate adjustments to the reactants and reaction conditions to obtain synthetic methods for other compounds.

[0435] Experimental Example 1. In vitro inhibitory activity test of RIPK1

[0436] 1.1 Test Materials

[0437]

[0438] 1.2 Test Instruments

[0439]

[0440] 1.3 Test Methods

[0441] First, add 50 μL of the test compound to a 384-well dilution plate. Continuously dilute the test compound 1:3 with DMSO. Transfer 50 nL of diluted test compound solution per row to the 384-well detection plate using an Echo converter, with two replicates per column. Add 2.5 μL of enzyme working solution to each well of the 384-well detection plate, except for the low control well, and centrifuge at 1000 RPM for 1 min. Add 2.5 μL of 1x buffer to the low control well and incubate at 25°C for 10 min. Then add 2.5 μL of substrate working solution and incubate at 25°C for 120 min. Next, add 4 μL of ADP-Glo ​​reagent, centrifuge at 1000 RPM for 1 min, and incubate at 25°C for 60 min. Finally, add 8 μL of kinase assay reagent, centrifuge at 1000 RPM for 1 min, and incubate at 25°C for 60 min. Calculate the inhibition rate using an Envision 2104 reader, process the data using XLfit 5.3.1.3 software, and obtain the IC50 of the compound using a nonlinear fitting formula. 50 value.

[0442] Experimental Example 2. DPPH Free Radical Scavenging Capacity Test

[0443] 2.1 Experimental Materials

[0444]

[0445] 2.2 Test Instruments

[0446]

[0447] 2.3 Test Methods

[0448] First, add 20 μL of the test compound to a 96-well plate and serially dilute it 1:2 with DMSO. Then, add 200 μL of 200 μM DPPH solution prepared with anhydrous ethanol to each well, gently shake, and incubate at room temperature in the dark for 30 minutes. Measure the absorbance at 517 nm using a microplate reader. Calculate the DPPH clearance rate using the following formula: DPPH clearance rate % = (1 - A i / A0)*100%, A i A0 refers to the absorbance value of the sample, while A0 refers to the absorbance value of the DMSO control group. Data was processed using XLfit 5.3.1.3 software, and the IC50 of the compounds was obtained using a nonlinear fitting formula. 50 value.

[0449] Experimental Example 3. MDA Anti-lipid peroxidation Capacity Test

[0450] 3.1 Test Materials

[0451]

[0452]

[0453] 3.2 Test Instruments

[0454]

[0455] 3.3 Test Methods

[0456] First, brain tissue homogenate was extracted: An adult male SD rat was anesthetized with isoflurane and euthanized by cervical dislocation. The whole brain was removed, washed twice in DPBS, and the meninges were dissected. The brain tissue was transferred to a 50 mL centrifuge tube containing 10 mL of DPBS, minced, and aliquoted into ten 1.5 mL centrifuge tubes. Three grinding beads were added to each tube, and the tissue was ground at 90 Hz for 60 min three times. The homogenate was then transferred to a new 50 mL centrifuge tube, and DPBS was added to a total volume of 30 mL. The mixture was then stirred. Next, 20 μL of the test compound was added to a 96-well plate and serially diluted 1:3 with DMSO. Then, 100 μL of brain tissue homogenate, 50 μL of DPBS, and 50 μL of 200 μg / mL vitamin C were added sequentially, and a series of concentrations of standards were prepared as standard curves. After shaking, the plate was incubated at 37 °C for 1 hour, and then 400 μL of MDA working solution was added, followed by heating at 100 °C for 15 minutes. After cooling to room temperature, centrifuge at 1000×g for 10 minutes, and transfer 200 μL of supernatant to a new plate. Measure the absorbance at 532 nm using a microplate reader. The MDA scavenging rate of the compound was calculated using the following formula: MDA scavenging rate % = [((A1-A0)-(A2-A0)) / ((A1-A0)-(A3-A0))]*100%, where A1 represents the absorbance of the high-control group, A2 represents the absorbance of the sample, A3 represents the absorbance of the low-control group, and A0 represents the absorbance of the blank group. Data were processed using XLfit 5.3.1.3 software, and the EC50 of the compound was obtained using a nonlinear fitting formula. 50 value.

Claims

1. A compound of Formula (I), a pharmaceutically acceptable salt, or a stereoisomer thereof: wherein: ###0001### (I) 2. The compound of claim 1, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein the compound is of Formula (II): ###0002### (II) X 1a selected from CR 1a or N; X 1b selected from CR 1b or N; X 1c selected from CR 1c or N; X 1d selected from CR 1d or N; X 1e selected from CR 1e or N; R 1a , R 1b , R 1c , R 1d , R 1e are each independently selected from the group consisting of: H, halogen, C 1-6 alkyl, or cyano; X 2a , X 2b , X 2c are each independently selected from: CH or N; X 3a selected from CR 3a or N; X 3b selected from CR 3b or N; X 3c selected from CR 3c or N; X 3d selected from CR 3d or N; X 3e selected from CR 3e ; R 3a , R 3b , R 3c are each independently selected from the group consisting of: H, halogen, or C 1-6 alkyl; R 3d and one of R 3e is selected from the other is selected from H, halo, or C 1-6 alkyl; L1is selected from a single bond, C 1-6 alkylene, or L2is selected from a single bond, C 6-10 arylene; R4is selected from: H, or C 1-6 alkyl.

3. The compound of claim 1, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein the compound is of Formula (III): ###0003### (III) wherein X 1b , X 1d , X 2c , L1, L2, R 1b , R 1d , R 3d , R 3e , R4 is as defined in claim 1.

4. The compound of claim 1, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein: ###0004### (IV) ###0005### (V) ###0006### (VI) ###0007### (VII) ###0008### (VIII) ###0009### (IX) ###0010### (X) ###0011### (XI) ###0012### (XII) ###0013### (XIII) ###0014### (XIV) ###0015### (XV) ###0016### (XVI) ###0017### (XVII) ###0018### (XVIII) ###0019### (XIX) ###0020### (XX) ###0021### (XXI) ###0022### (XXII) ###0023### (XXIII) ###0024### (XXIV) ###0025### (XXV) ###0026### (XXVI) ###0027### (XXVII) ###0028### (XXVIII) ###0029### (XXIX) ###0030### (XXX) ###0031### (XXXI) ###0032### (XXXII) ###0033### (XXXIII) ###0034### (XXXIV) ###0035### (XXXV) ###0036### (XXXVI) ###0037### (XXXVII) ###0038### (XXXVIII) ###0039### (XXXIX) ###0040### (XL) ###0041### (XLI) ###0042### (XLII) ###0043### (XLIII) ###0044### (XLIV) ###0045### (XLV) ###0046### (XLVI) ###0047### (XLVII) ###0048### (XLVIII) ###0049### (XLIX) ###0050### (L) ###0051### (LI) ###0052### (LII) ###0053### (LIII) ###0054### (LIV) ###0055### (LV) ###0056### (LVI) ###0057### (LVII) ###0058### (LVIII) ###0059### (LIX) ###0060### (LX) ###0061### (LXI) ###0062### (LXII) ###0063### (LXIII) ###0064### (LXIV) ###0065### (LXV) ###0066### (LXVI) ###0067### (LXVII) ###0068### (LXVIII) ###0069### (LXIX) ###0070### (LXX) ###0071### (LXXI) ###0072### (LXXII) ###0073### (LXXIII) ###0074### (LXXIV) ###0075### (LXXV) ###0076### (LXXVI) ###0077### (LXXVII) ###0078### (LXXVIII) ###0079### (LXXIX) ###0080### (LXXX) ###0081### (LXXXI) ###0082### (LXXXII) ###0083### (LXXXIII) ###0084### (LXXXIV) ###0085### (LXXXV) ###0086### (LXXXVI) ###0087### (LXXXVII) ###0088### (LXXXVIII) ###0089### wherein X 1b , X 1d , X 2c , X 3a , X 3b , X 3c , X 3d , L1, L2, R 1b , R 1d , R 3a , R 3b , R 3c , R 3d , R 3e , R4 is as defined in claim 1. ​ ​ X 1a selected from CR 1a ; X 1b selected from CR 1b ; X 1c selected from CR 1c ; X 1d selected from CR 1d ; X 1e selected from CR 1e ; R 1a , R 1b , R 1c , R 1d , R 1e are each independently selected from the group consisting of: H, halogen, C 1-6 alkyl, or cyano; ​ X 1a selected from CR 1a ; X 1b selected from N; X 1c selected from CR 1c ; X 1d selected from CR 1d ; X 1e selected from CR 1e ; R 1a , R 1c , R 1d , R 1e are each independently selected from the group consisting of: H, halogen, C 1-6 alkyl, or cyano. ​ ​ X 1b selected from CR 1b ; X 1d selected from CR 1d ; R 1b , R 1d each independently is selected from the group consisting of H, halogen, C 1-6 alkyl, or cyano; ​ X 1b selected from N; X 1d selected from CR 1d ; R 1d selected from: H, halogen, C 1-6 alkyl, or cyano. ​ wherein X 2a , X 2b are each independently selected from the group consisting of: N; X 2c is selected from the group consisting of: CH; or X 2a , X 2b , X 2c are each independently selected from the group consisting of: N. ​ ​ (1) X 3a selected from CR 3a ; X 3b selected from CR 3b ; X 3c selected from CR 3c ; X 3d selected from CR 3d ; X 3e selected from CR 3e ; R 3a , R 3b , R 3c , R 3e are each independently selected from the group consisting of: H, halogen, or C 1-6 alkyl; R 3d selected from ​ (2) X 3a selected from CR 3a ; X 3b selected from CR 3b ; X 3c selected from CR 3c ; X 3d selected from CR 3d ; X 3e selected from CR 3e ; R 3a , R 3b , R 3c , R 3d are each independently selected from the group consisting of: H, halogen, or C 1-6 alkyl; R 3e selected from or (3) X 3a selected from CR 3a ; X 3b selected from CR 3b ; X 3c selected from N; X 3d selected from CR 3d ; X 3e selected from CR 3e ; R 3a , R 3b , R 3e are each independently selected from the group consisting of H, halogen, or C 1-6 alkyl; R 3d is selected from the group consisting of or (4) X 3a selected from CR 3a ; X 3b selected from CR 3b ; X 3c selected from N; X 3d selected from CR 3d ; X 3e selected from CR 3e ; R 3a , R 3b , R 3d are each independently selected from the group consisting of: H, halogen, or C 1-6 alkyl; R 3e is selected from the group consisting of or (5) X 3a selected from N; X 3b selected from N; X 3c selected from CR 3c ; X 3d selected from CR 3d ; X 3e selected from CR 3e ; R 3c , R 3e each independently is selected from: H, halogen, or C 1-6 alkyl; R 3d is selected from or (6) X 3a selected from N; X 3b selected from N; X 3c selected from CR 3c ; X 3d selected from CR 3d ; X 3e selected from CR 3e ; R 3c , R 3d each independently is selected from: H, halogen, or C 1-6 alkyl; R 3e is selected from or (7) X 3a selected from N; X 3b selected from CR 3b ; X 3c selected from N; X 3d selected from CR 3d ; X 3e selected from CR 3e ; R 3b , R 3e are each independently selected from: H, halo, or C 1-6 alkyl; R 3d is selected from or (8) X 3a selected from N; X 3b selected from CR 3b ; X 3c selected from N; X 3d selected from CR 3d ; X 3e selected from CR 3e ; R 3b , R 3d are each independently selected from the group consisting of: H, halogen, or C 1-6 alkyl; R 3e selected from ​ (9) X 3a selected from CR 3a ; X 3b selected from N; X 3c selected from CR 3c ; X 3d selected from N; X 3e selected from CR 3e ; R 3a , R 3c , each independently selected from: H, halogen, or C 1-6 alkyl; R 3e selected from ​ L1is selected from a single bond, -CH2-, -(CH2)2-, -(CH2)3-, or ​ ​ R 1a , R 1b , R 1c , R 1d , R 1e each independently is selected from the group consisting of: H, F, Cl, Br, I, methyl, ethyl, n-propyl, i-propyl, or cyano; R 3a , R 3b , R 3c are each independently selected from the group consisting of: H, F, Cl, Br, I, methyl, ethyl, n-propyl, or isopropyl; R 3d and one of R 3e is selected from the other is selected from H, F, CI, Br, I, methyl, ethyl, n-propyl, or i-propyl; ​ ​

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