Bicyclic compound as well as preparation method and application thereof

Abstract

The invention discloses a bicyclic compound and an application of the bicyclic compound in a medicine, and particularly relates to a novel bicyclic compound and a medicine composition containing the novel bicyclic compound. The invention also relates to a method for preparing the compound, and application of the compound or the pharmaceutical composition in preparation of drugs for treating RIPK1 inhibitor mediated diseases and / or symptoms. The invention relates to the field of medicines, in particular to the application in preparing medicines for treating idiopathic pulmonary fibrosis, graft versus host disease, ulcerative colitis, rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, systemic inflammatory response syndrome, lupus erythematosus, Alzheimer's disease, psoriasis, non-alcoholic steatohepatitis and osteoarthritis.

Description

[0001] This application claims the following priorities:

[0002] CN202311874180.1, with an application date of December 29, 2023; Technical Field

[0003] The present invention relates to the field of chemical medicine technology, and particularly relates to a bicyclic compound, a preparation method thereof, and an application thereof. Background Art

[0004] Apoptosis is a highly regulated process involving the caspase family of cysteine proteases and characterized by cell shrinkage, chromatin condensation, and DNA degradation. Necroptosis, on the other hand, is a newly discovered form of non-apoptotic programmed cell death in recent years. It is regulated by death signals and exhibits necrotic-like structural features. This novel cell death mechanism is called "programmed necrosis" or "necroptosis" (Degterev et al, 2005). The two belong to different cell death mechanisms.

[0005] Receptor-interacting protein kinase 1 (RIPK1) is a protein with specific serine / threonine kinase activity. It has a similar N-terminal kinase domain to other protein kinases but has different binding domains. Studies have shown that RIPK1 regulates necroptosis through the RIPK1 / RIPK3 / MLKL signal transduction axis and plays a key regulatory role in the process of necroptosis.

[0006] The dysregulation of the necroptosis signaling pathway is closely related to inflammatory diseases (Khandia et al, 2016), such as systemic inflammatory response syndrome (SIRS), osteoarthritis, pancreatitis, non-alcoholic steatohepatitis (Vandenabeele et al, 2010). Studies have shown that the TNFα-induced SIRS disease model is highly correlated with RIPK1-dependent necroptosis (Duprez et al, 2011).

[0007] Necroptosis plays an important role in the pathogenesis of autoimmune diseases, such as graft-versus-host disease, inflammatory bowel disease (IBD), Crohn's disease, irritable bowel disease, irritable bowel syndrome, ulcerative colitis, rheumatoid arthritis (RA), psoriasis, and multiple sclerosis (MS), etc. (Vlantis et al, 2016; Khandia et al, 2016; Harris et al, 2017).

[0008] Programmed necrosis is also involved in the occurrence and development of neurodegenerative diseases, such as stroke, traumatic brain injury, Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Parkinson's disease (PD), etc. (Ofengeim et al, 2015).

[0009] Studies have shown that RIPK1 inhibitors can effectively inhibit tumor metastasis (Strilic et al, 2016).

[0010] In addition, programmed necrosis of cells is also involved in the process of pulmonary fibrosis, lung injury after infection, acute respiratory distress syndrome or chronic obstructive pulmonary disease (Lee et al, 2018; Sagel et al, 2015), peripheral vascular diseases, atherosclerosis, myocardial infarction, intermittent claudication in acute ischemic stroke (Feoktistova and Leverkus, 2015; Hepatology et al, 2013; Schreiber et, 2017), chronic kidney disease (Kurundkar et al, 2016)), neurodegenerative diseases, retinitis pigmentosa, retinal degeneration (Trichonas et al, 2010), lupus erythematosus, sepsis (Ito et al, 2016; Zhang et al, 2010).

[0011] At present, scientific researchers have carried out some studies in order to find therapeutic agents that can effectively inhibit RIPK1. PCT applications WO2020088194, WO2019213447, WO2018237370, WO2020146858, WO2021203011, WO2021046447, WO2021046407, WO2021046382, WO2022192533 and WO2022052861 disclose many small molecule compounds, which are used as RIPK1 inhibitors for preventing or treating RIPK1-related diseases. However, there is still an urgent clinical need for more and better RIPK1 inhibitors. Summary of the Invention

[0012] The present invention provides a compound, or a pharmaceutical composition thereof, which can be used as an RIPK1 inhibitor. The present invention further relates to the use of the compound or its pharmaceutical composition for preparing a drug, and the drug treats diseases and / or disorders by inhibiting RIPK1 with the compound. The present invention further describes the synthesis method of the compound. The compounds of the present invention exhibit excellent biological activity and pharmacokinetic properties.

[0013] Specifically:

[0014] On the one hand, the present invention relates to a compound, which is a compound represented by formula (I), or a stereoisomer, geometric isomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the compound represented by formula (I).

[0015]

[0016] Wherein:

[0017] X is N or CR 18 ;

[0018] Y1 is C or N;

[0019] Y2 is N, O, S, CR 19 or NR 21 ;

[0020] Y3 is N, O, S, CR 20 or NR 22 ;

[0021] Y4 is C or N;

[0022] Ring A is C 3-6 cycloalkyl, 3- to 8-membered heterocyclic group, C 6-10 aryl or 5- to 10-membered heteroaryl;

[0023] Each R a independently is H, D, F, Cl, Br, I, CN, hydroxy, nitro, amino, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 alkylamino, and the C 1-6 alkyl, C 1-6 alkoxy and C 1-6 alkylamino may independently be optionally substituted by 1, 2, 3, 4 or 5 substituents selected from D, F, Cl, Br, I, CN, oxo (=O), hydroxy, amino and nitro;

[0024] Ring P is a 4- to 10-membered nitrogen-containing heterocycle;

[0025] Each R p independently is H, D, F, Cl, Br, I, CN, hydroxy, amino, nitro, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 alkylamino, and the C 1-6 alkyl, C 1-6 alkoxy and C 1-6 alkylamino may independently be optionally substituted by 1, 2 or 3 substituents selected from D, F, Cl, Br, I, CN, oxo (=O), hydroxy, amino and nitro;

[0026] R 7 and R 8 each independently is H, D, F, Cl, Br, I, CN, hydroxy, oxo, amino, nitro, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 haloalkoxy, -C 1-6 alkylene-C 1-6 alkoxy, C 2-6 alkenyl or C 2-6 alkynyl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 haloalkoxy, -C 1-6 alkylene-C 1-6 alkoxy, C 2-6 alkenyl and C 2-6 alkynyl may each independently optionally be substituted with 1, 2, 3, 4 or 5 substituents selected from D, F, Cl, Br, I, CN, oxo(=O), hydroxy, amino and nitro; or R 7 together with R 8 and the carbon atom to which they are commonly attached forms -C(=O)-, a 3- to 6-membered carbocyclic ring or a 3- to 6-membered heterocyclic ring, and the 3- to 6-membered carbocyclic ring or 3- to 6-membered heterocyclic ring may each independently optionally be substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, CN, oxo(=O), hydroxy, amino and nitro;

[0027] Each R 9 and R 10 each independently is H, D, F, Cl, Br, I, CN, hydroxy, oxo, amino, nitro, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 haloalkoxy, -C 1-6 alkylene-C 1-6 alkoxy, C 2-6 alkenyl or C 2-6 alkynyl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C1-6 Hydroxyalkyl, C 1-6 Aminoalkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Halogenated alkoxy, -C 1-6 Alkylene-C 1-6 Alkoxy, C 2-6 Alkenyl and C 2-6 Alkynyl may independently optionally be substituted by 1, 2, 3, 4 or 5 substituents selected from D, F, Cl, Br, I, CN, oxo(=O), hydroxy, amino and nitro; or R 9 Together with R 10 And the carbon atom to which they are commonly attached forms -C(=O)-, a 3- to 6-membered carbocyclic ring or a 3- to 6-membered heterocyclic ring, and the 3- to 6-membered carbocyclic ring or 3- to 6-membered heterocyclic ring may independently optionally be substituted by 1, 2 or 3 substituents selected from D, F, Cl, Br, I, CN, oxo(=O), hydroxy, amino and nitro;

[0028] R 16 、R 21 And R 22 Each independently is H, D, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Aminoalkyl, -C 1-6 Alkylene-C 1-6 Alkoxy or C 3-6 Cycloalkyl;

[0029] R 11 、R 12 、R 13 、R 14 、R 15 、R 18 、R 19 And R 20 Each independently is H, D, F, Cl, Br, I, CN, hydroxy, amino, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl or a 3- to 6-membered heterocyclic group, and the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl and the 3- to 6-membered heterocyclic group may independently optionally be substituted by 1, 2, 3, 4 or 5 substituents selected from D, F, Cl, Br, I, CN, oxo(=O), hydroxy, amino and nitro;

[0030] R 17is H, D, S(=O)2R 23 , S(=O)R 24 , -C(=O)NR 25 R 26 , -C(=O)OR 27 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 haloalkoxy, -C 1-6 alkylene-C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 haloalkoxy, -C 1-6 alkylene-C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl may each independently optionally be

[0031] 1, 2, 3, 4 or 5 substituents selected from D, F, Cl, Br, I, CN, oxo(=O), hydroxy, amino, nitro, C 3-6 cycloalkyl, 3-6 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl substituents, wherein the C 3-6 cycloalkyl, 3-6 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl may each independently optionally be substituted by 1, 2, 3, 4 or 5 substituents selected from D, F, Cl, Br, I, CN, hydroxy, amino and nitro; R 23 , R 24 , R 25 , R 26 and R 27 are each independently H, D, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6Aminoalkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Halogenated alkoxy, -C 1-6 Alkylene-C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Aminoalkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Halogenated alkoxy, -C 1-6 Alkylene-C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl may each independently optionally be substituted with 1, 2, 3, 4 or 5 substituents selected from D, F, Cl, Br, I, CN, oxo(=O), hydroxy, amino, nitro, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl substituents, wherein the C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl may each independently optionally be substituted with 1, 2, 3, 4 or 5 substituents selected from D, F, Cl, Br, I, CN, hydroxy, amino and nitro;

[0032] m is 0, 1, 2, 3, 4, 5, 6, 7 or 8;

[0033] n is 0, 1, 2, 3, 4, 5, 6, 7 or 8;

[0034] y is 1, 2 or 3.

[0035] In some embodiments,

[0036] In some embodiments, ring P is a 4-6 membered nitrogen-containing heterocycle;

[0037] Each R p Independently is H, D, F, Cl, Br, I, CN, hydroxy, nitro, amino, C 1-3 Alkyl, C 1-3 Alkoxy or C1-3 an alkylamino group, wherein the C 1-3 alkyl group, C 1-3 alkoxy group and C 1-3 alkylamino group may each independently be optionally substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, CN, oxo(=O), hydroxy, amino and nitro.

[0038] In some embodiments,

[0039] each R p is independently H, D, F, Cl, Br, I, CN, hydroxy, nitro, amino, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, N-methylamino or N-ethylamino, and the methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, N-methylamino and N-ethylamino may each independently be optionally substituted with 1, 2, 3, 4 or 5 substituents selected from D, F, Cl, Br, I, CN, oxo(=O), hydroxy, amino and nitro.

[0040] In some embodiments, ring A is a C 3-6 cycloalkyl group, a 3- to 6-membered heterocyclic group, a C 6-10 aryl group or a 5- to 10-membered heteroaryl group;

[0041] In some embodiments, each R a is independently H, D, F, Cl, Br, I, CN, hydroxy, nitro, amino, C 1-3 alkyl group, C 1-3 alkoxy group or C 1-3 alkylamino group, wherein the C 1-3 alkyl group, C 1-3 alkoxy group and C 1-3 alkylamino group may each independently be optionally substituted with 1, 2, 3, 4 or 5 substituents selected from D, F, Cl, Br, I, CN, oxo(=O), hydroxy, amino and nitro.

[0042] In some embodiments, ring A is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl,

[0043] each R aIndependently H, D, F, Cl, Br, I, CN, hydroxy, nitro, amino, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, N-methylamino or N-ethylamino, and the methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, N-methylamino and N-ethylamino may independently optionally be substituted by 1, 2, 3, 4 or 5 substituents selected from D, F, Cl, Br, I, CN, oxo(=O), hydroxy, amino and nitro.

[0044] In some embodiments, R 7 and R 8 are each independently H, D, F, Cl, Br, I, CN, hydroxy, amino, nitro, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 aminoalkyl, C 1-3 alkoxy, C 1-3 alkylamino, C 1-3 haloalkoxy, -C 1-3 alkylene-C 1-3 alkoxy, C 2-3 alkenyl or C 2-3 alkynyl, and the C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 aminoalkyl, C 1-3 alkoxy, C 1-3 alkylamino, C 1-3 haloalkoxy, -C 1-3 alkylene-C 1-3 alkoxy, C 2-3 alkenyl and C 2-3 alkynyl may independently optionally be substituted by 1, 2, 3, 4 or 5 substituents selected from D, F, Cl, Br, I, CN, oxo(=O), hydroxy, amino and nitro; or R 7 and R 8 together with the carbon atom to which they are attached form -C(=O)-, a 3-6 membered carbocyclic ring or a 3-6 membered heterocyclic ring, and the 3-6 membered carbocyclic ring and the 3-6 membered heterocyclic ring may independently optionally be substituted by 1, 2 or 3 substituents selected from D, F, Cl, Br, I, CN, oxo(=O), hydroxy, amino and nitro;

[0045] Each R 9 and R 10 are independently H, D, F, Cl, Br, I, CN, hydroxy, amino, nitro, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3Hydroxyalkyl, C 1-3 Aminoalkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, C 1-3 Halogenated alkoxy, -C 1-3 Alkylene-C 1-3 Alkoxy, C 2-3 Alkenyl or C 2-3 Alkynyl, the C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Aminoalkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, C 1-3 Halogenated alkoxy, -C 1-3 Alkylene-C 1-3 Alkoxy, C 2-3 Alkenyl and C 2-3 Alkynyl may each independently be optionally substituted with 1, 2, 3, 4 or 5 substituents selected from D, F, Cl, Br, I, CN, oxo(=O), hydroxy, amino and nitro; or R 9 together with R 10 and the carbon atom to which they are commonly attached forms -C(=O)-, a 3- to 6-membered carbocyclic ring or a 3- to 6-membered heterocyclic ring, the 3- to 6-membered carbocyclic ring and the 3- to 6-membered heterocyclic ring may each independently be optionally substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, CN, oxo(=O), hydroxy, amino and nitro;

[0046] R 16 、R 21 and R 22 are each independently H, D, C 1-3 alkyl, C 1-3 halogenated alkyl, C 1-3 hydroxyalkyl, C 1-3 aminoalkyl, -C 1-3 alkylene-C 1-3 alkoxy or C 3-6 cycloalkyl;

[0047] R 11 、R 12 、R 13 、R 14 、R 15 、R 18 、R 19 and R 20 are each independently H, D, F, Cl, Br, I, CN, hydroxy, amino, nitro, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylamino, C 3-6a cycloalkyl group or a 3- to 6-membered heterocyclic group, said C 1-3 alkyl group, C 1-3 alkoxy group, C 1-3 alkylamino group, C 3-6 The cycloalkyl group and the 3- to 6-membered heterocyclic group may each independently optionally be substituted with 1, 2, 3, 4 or 5 substituents selected from D, F, Cl, Br, I, CN, oxo(=O), hydroxy, amino and nitro.

[0048] In some embodiments, R 7 and R 8 are each independently H, D, F, Cl, Br, I, CN, hydroxy, amino, nitro, methyl, ethyl, n-propyl, isopropyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, hydroxymethyl, hydroxyethyl, aminomethyl, aminoethyl, methoxy, ethoxy, n-propoxy, isopropoxy, N-methylamino, N-ethylamino, -OCHF2, -OCF3, -OCHFCH2F, -OCF2CHF2, -OCH2CF3, -OCH2CF2CHF2, -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, -CH2CH2OCH2CH3, vinyl, allyl, ethynyl, propargyl or 1-propynyl, and the methyl, ethyl, n-propyl, isopropyl, -CHF2, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, hydroxymethyl, hydroxyethyl, aminomethyl, aminoethyl, methoxy, ethoxy, n-propoxy, isopropoxy, N-methylamino, N-ethylamino, -OCHF2, -OCHFCH2F, -OCF2CHF2, -OCH2CF3, -OCH2CF2CHF2, -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, -CH2CH2OCH2CH3, vinyl, allyl, ethynyl, propargyl and 1-propynyl may each independently optionally be substituted with 1, 2, 3, 4 or 5 substituents selected from D, F, Cl, Br, I, CN, oxo(=O), hydroxy, amino and nitro; or R 7 and R 8 together with the carbon atom to which they are attached form -C(=O)-, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl or morpholinyl, and the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl and morpholinyl may each independently optionally be substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, CN, oxo(=O), hydroxy, amino and nitro;

[0049] Each R 9and R 10 independently is H, D, F, Cl, Br, I, CN, hydroxy, amino, nitro, methyl, ethyl, n - propyl, isopropyl, - CHF2, - CF3, - CHFCH2F, - CF2CHF2, - CH2CF3, - CH2CF2CHF2, hydroxymethyl, hydroxyethyl, aminomethyl, aminoethyl, methoxy, ethoxy, n - propoxy, isopropoxy, N - methylamino, N - ethylamino, - OCHF2, - OCF3, - OCHFCH2F, - OCF2CHF2, - OCH2CF3, - OCH2CF2CHF2, - CH2OCH3, - CH2OCH2CH3, - CH2CH2OCH3, - CH2CH2OCH2CH3, vinyl, allyl, ethynyl, propargyl or 1 - propynyl, and the methyl, ethyl, n - propyl, isopropyl, - CHF2, - CHFCH2F, - CF2CHF2, - CH2CF3, - CH2CF2CHF2, hydroxymethyl, hydroxyethyl, aminomethyl, aminoethyl, methoxy, ethoxy, n - propoxy, isopropoxy, N - methylamino, N - ethylamino, - OCHF2, - OCHFCH2F, - OCF2CHF2, - OCH2CF3, - OCH2CF2CHF2, - CH2OCH3, - CH2OCH2CH3, - CH2CH2OCH3, - CH2CH2OCH2CH3, vinyl, allyl, ethynyl, propargyl and 1 - propynyl may independently optionally be substituted by 1, 2, 3, 4 or 5 substituents selected from D, F, Cl, Br, I, CN, oxo(=O), hydroxy, amino and nitro; or R 9 together with R 10 forms - C(=O)-, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl or morpholinyl with the carbon atom to which they are commonly attached, and the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl and morpholinyl may independently optionally be substituted by 1, 2 or 3 substituents selected from D, F, Cl, Br, I, CN, oxo(=O), hydroxy, amino and nitro;

[0050] R 16 、R 21 and R 22 each independently is H, D, methyl, ethyl, n - propyl, isopropyl, - CHF2, - CF3, - CHFCH2F, - CF2CHF2, - CH2CF3, - CH2CF2CHF2, hydroxymethyl, hydroxyethyl, aminomethyl, aminoethyl, - CH2OCH3, - CH2OCH2CH3, - CH2CH2OCH3, - CH2CH2OCH2CH3, cyclopropyl or cyclobutyl;

[0051] R 11 、R 12 、R 13 、R 14 、R 15 、R 18 、R 19 and R 20 are each independently H, D, F, Cl, Br, I, CN, hydroxy, amino, nitro, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, N-methylamino, N-ethylamino, cyclopropyl, cyclobutyl, azetidinyl or oxetan-3-yl, and the methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, N-methylamino, N-ethylamino, cyclopropyl, cyclobutyl, azetidinyl and oxetan-3-yl may each independently optionally be substituted with 1, 2, 3, 4 or 5 substituents selected from D, F, Cl, Br, I, CN, oxo(=O), hydroxy, amino and nitro.

[0052] R 17 is H, D, S(=O)2R 23 、S(=O)R 24 、-C(=O)NR 25 R 26 、-C(=O)OR 27 、C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 aminoalkyl, C 1-3 alkoxy, C 1-3 alkylamino, C 1-3 haloalkoxy, -C 1-3 alkylene-C 1-3 alkoxy, C 2-3 alkenyl, C 2-3 alkynyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic group, C 6-10 aryl or 5- to 10-membered heteroaryl, and the C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 aminoalkyl, C 1-3 alkoxy, C 1-3 alkylamino, C 1-3 haloalkoxy, -C 1-3 alkylene-C 1-3 alkoxy, C 2-3 alkenyl, C 2-3 alkynyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic group, C 6-10Aryl and 5-10 membered heteroaryl may be independently and optionally substituted by 1, 2, 3, 4 or 5 substituents selected from D, F, Cl, Br, I, CN, oxo (=O), hydroxy, amino, nitro, phenyl and naphthyl, and the phenyl and naphthyl may be independently and optionally substituted by 1, 2, 3, 4 or 5 substituents selected from D, F, Cl, Br, I, CN, hydroxy, amino and nitro. 23 , R 24 , R 25 , R 26 and R 27 Each independently is H, D, S(=O)2R 23 、S(=O)R 24 、-C(=O)NR 25 R 26 、-C(=O)OR 27 , C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Aminoalkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, C 1-3 Haloalkoxy, -C 1-3 Alkylene-C 1-3 Alkoxy, C 2-3 Alkenyl, C 2-3 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Aminoalkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, C 1-3 Haloalkoxy, -C 1-3 Alkylene-C 1-3 Alkoxy, C 2-3 Alkenyl, C 2-3 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 The aryl and 5-10 membered heteroaryl groups may be independently and optionally substituted with 1, 2, 3, 4 or 5 substituents selected from D, F, Cl, Br, I, CN, oxo (=O), hydroxyl, amino, nitro, phenyl and naphthyl, and the phenyl and naphthyl groups may be independently and optionally substituted with 1, 2, 3, 4 or 5 substituents selected from D, F, Cl, Br, I, CN, hydroxyl, amino and nitro.

[0053] In some embodiments, R 17is H, D, methyl, ethyl, n-propyl, isopropyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, hydroxymethyl, hydroxyethyl, aminomethyl, aminoethyl, methoxy, ethoxy, n-propoxy, isopropoxy, N-methylamino, N-ethylamino, -OCHF2, -OCF3, -OCHFCH2F, -OCF2CHF2, -OCH2CF3, -OCH2CF2CHF2, -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, -CH2CH2OCH2CH3, vinyl, allyl, ethynyl, propargyl, 1-propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl,

[0054] The methyl, ethyl, n-propyl, isopropyl, -CHF2, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, hydroxymethyl, hydroxyethyl, aminomethyl, aminoethyl, methoxy, ethoxy, n-propoxy, isopropoxy, N-methylamino, N-ethylamino, -OCHF2, -OCHFCH2F, -OCF2CHF2, -OCH2CF3, -OCH2CF2CHF2, -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, -CH2CH2OCH2CH3, vinyl, allyl, ethynyl, propargyl, 1-propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl,

[0055] It may be independently and optionally substituted with 1, 2, 3, 4 or 5 substituents selected from D, F, Cl, Br, I, CN, oxo (=O), hydroxyl, amino, nitro, phenyl and naphthyl, and the phenyl and naphthyl may be independently and optionally substituted with 1, 2, 3, 4 or 5 substituents selected from D, F, Cl, Br, I, CN, hydroxyl, amino and nitro.

[0056] R 23 , R 24 , R 25 , R 26 and R 27Each independently is H, D, methyl, ethyl, n-propyl, isopropyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, hydroxymethyl, hydroxyethyl, aminomethyl, aminoethyl, methoxy, ethoxy, n-propoxy, isopropoxy, N-methylamino, N-ethylamino, -OCHF2, -OCF3, -OCHFCH2F, -OCF2CHF2, -OCH2CF3, -OCH2CF2CHF2, -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, -CH2CH2OCH2CH3, vinyl, allyl, ethynyl, propargyl, 1-propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl,

[0057] The methyl, ethyl, n-propyl, isopropyl, -CHF2, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, hydroxymethyl, hydroxyethyl, aminomethyl, aminoethyl, methoxy, ethoxy, n-propoxy, isopropoxy, N-methylamino, N-ethylamino, -OCHF2, -OCHFCH2F, -OCF2CHF2, -OCH2CF3, -OCH2CF2CHF2, -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, -CH2CH2OCH2CH3, vinyl, allyl, ethynyl, propargyl, 1-propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl,

[0058] may be independently optionally substituted with 1, 2, 3, 4 or 5 substituents selected from D, F, Cl, Br, I, CN, oxo(=O), hydroxy, amino, nitro, phenyl and naphthyl, and the phenyl and naphthyl may be independently optionally substituted with 1, 2, 3, 4 or 5 substituents selected from D, F, Cl, Br, I, CN, hydroxy, amino and nitro.

[0059] In some embodiments, the compounds of the present invention are compounds having one of the following structures or stereoisomers, geometric isomers, tautomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs of compounds having one of the following structures:

[0060]

[0061]

[0062] On the one hand, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) of the present invention, or a stereoisomer, geometric isomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or combination thereof.

[0063] On the one hand, the present invention relates to the use of the aforementioned compound or its pharmaceutical composition in the preparation of a drug for preventing, treating or alleviating a disease mediated by an RIPK1 inhibitor in a patient.

[0064] Some of these embodiments are that the disease mediated by the RIPK1 inhibitor of the present invention is an inflammatory disease, an autoimmune disease, a neurodegenerative disease or a tumor.

[0065] Some of these embodiments are that the disease mediated by the RIPK1 inhibitor is idiopathic pulmonary fibrosis, graft-versus-host disease, ulcerative colitis, rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, systemic inflammatory response syndrome, lupus erythematosus, Alzheimer's disease, psoriasis, non-alcoholic steatohepatitis, osteoarthritis, inflammatory bowel disease, acute ischemic stroke, neurodegenerative disease of the nervous system, frontotemporal dementia, Parkinson's disease, peripheral vascular disease, intermittent claudication, irritable bowel disease, irritable bowel syndrome, Crohn's disease, myocardial infarction, stroke, traumatic brain injury, atherosclerosis, sepsis, pancreatitis, retinitis pigmentosa, retinal degeneration, chronic kidney disease, post-infectious lung injury, acute respiratory distress syndrome or chronic obstructive pulmonary disease.

[0066] On the other hand, the present invention relates to a method for preparing, separating and purifying the compound contained in formula (I).

[0067] The foregoing only outlines certain aspects of the present invention and is not limited to these aspects. The content of these aspects and other aspects will be described in more specific and complete detail below.

[0068] Definitions and General Terms

[0069] The present invention will list in detail the documents corresponding to the determined and specific content, and the examples are accompanied by diagrams of structural formulas and chemical formulas. The present invention is expected to cover all options, variations, and equivalents that may be included in the existing field of the invention as defined by the claims. Those skilled in the art will recognize many methods and substances similar or equivalent to those described herein, which can be applied to the practice of the present invention. The present invention is not limited to the description of methods and substances. There are many documents and similar substances that are different from or conflict with the present application, including but not limited to the definitions of terms, the usage of terms, the described technologies, or the scope controlled by the present application.

[0070] The present invention will apply the following definitions unless otherwise indicated. For the purposes of the present invention, chemical elements are defined according to the Periodic Table of the Elements, CAS version, and the Handbook of Chemistry and Physics, 75th Ed., 1994. In addition, general principles of organic chemistry can be found in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry," by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007. Therefore, all content incorporates the references.

[0071] The term "comprising" is an open-ended expression, meaning including the content specified in the present invention, but not excluding other aspects.

[0072] The compounds described herein may optionally be substituted by one or more substituents, such as the general formula compounds in the present invention, or special examples, subclasses, and a class of compounds included in the present invention as in the examples. It should be understood that the term "optionally substituted" can be used interchangeably with the term "substituted or unsubstituted". Generally, the term "optionally", whether before or after the term "substituted", means that one or more hydrogen atoms in the given structure are replaced by specific substituents. Unless otherwise indicated, an optional substituent group may have a substituent at each substitutable position of the group. When more than one position in the given structural formula can be substituted by one or more substituents selected from a specific group, the substituents may be the same or different at each position.Wherein the substituents may be, but are not limited to, hydrogen, F, Cl, Br, I, nitro, cyano, oxo(=O), hydroxy, alkyl, hydroxyalkyl, alkylamino, aminoalkyl, haloalkoxy, cycloalkyl, amino, aryl, heterocyclic group, heteroaryl, alkenyl, alkynyl, cycloalkyloxy, alkoxy, alkoxyalkyl, haloalkyl, -COOH, -alkylene-C(=O)O-alkyl, -alkylene-S(=O)2-alkyl, -alkylene-S(=O)2-amino, -S(=O)2-alkyl, -S(=O)2-amino, -S(=O)2OH, -O-alkylene-C(=O)O-alkyl, -O-alkylene-S(=O)2-alkyl, -O-alkylene-S(=O)2-amino, -O-alkylene-S(=O)2OH, -C(=O)NH2, -C(=O)NH-alkyl, -C(=O)N(alkyl)-alkyl, -C(=O)NHS(=O)2-alkyl, -C(=O)NHS(=O)2-amino, -C(=O)NHS(=O)2OH, -N(haloalkyl)-alkyl, -N(alkyl)-S(=O)2-alkyl, -NHS(=O)2-alkyl, -NHS(=O)2-haloalkyl, -N(alkyl)S(=O)2-haloalkyl, -N(alkyl)S(=O)2-alkylamino, -NHC(=O)-alkyl, -NHC(=O)-haloalkyl, -N(alkyl)C(=O)-haloalkyl, -N(alkyl)C(=O)-alkylamino, -N(alkyl)C(=O)O-alkyl, -NHC(=O)O-alkyl, -NHC(=O)O-haloalkyl, -N(alkyl)C(=O)O-haloalkyl, -N(alkyl)C(=O)O-aminoalkyl, -NHC(=O)-NH2, -NHC(=O)NH-(alkyl), -NHC(=O)NH(haloalkyl), -NHC(=O)N(alkyl)-alkyl, -OC(=O)-alkyl, -OC(=O)-amino, -OC(=O)-alkylamino, -OC(=O)-aminoalkyl, -OC(=O)-alkoxy, -C(=O)N(alkyl)S(=O)2-alkyl, -C(=O)N(alkyl)S(=O)2-amino, -C(=O)NH-S(=O)2OH, -C(=NH)NH2, -C(=NH)NH-alkyl, -C(=NH)N(alkyl)-alkyl, -C(=N-alkyl)-NH2, -C(=O)NH-alkylene-S(=O)2OH, -C(=O)NHC(=O)OH, -C(=O)NHC(=O)O-alkyl, -C(=O)N(alkyl)C(=O)O-alkyl, -C(=O)NH-alkylene-C(=O)OH and -C(=O)NH-alkylene-C(=O)O-alkyl, and so on.

[0073] The term "alkyl" as used in the present invention includes saturated straight-chain or branched-chain monovalent hydrocarbon groups having 1 to 20 carbon atoms, or 1 to 10 carbon atoms, or 1 to 6 carbon atoms, or 1 to 4 carbon atoms, or 1 to 3 carbon atoms, or 1 to 2 carbon atoms, wherein the alkyl group may independently and optionally be substituted by one or more substituents described in the present invention. Further examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), n-propyl (n-Pr, -CH2CH2CH3), isopropyl (i-Pr, -CH(CH3)2), n-butyl (n-Bu, -CH2CH2CH2CH3), isobutyl (i-Bu, -CH2CH(CH3)2), sec-butyl (s-Bu, -CH(CH3)CH2CH3), tert-butyl (t-Bu, -C(CH3)3), n-pentyl (-CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), n-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), n-heptyl, n-octyl, and the like. The term "alkyl" and its prefix "alk" as used herein include both straight-chain and branched-chain saturated carbon chains. The term "alkylene" or "sub-alkyl" as used herein refers to a saturated divalent hydrocarbon group obtained by eliminating two hydrogen atoms from a straight-chain or branched-chain saturated hydrocarbon, and examples of such groups include, but are not limited to, methylene, ethylene, and isopropylidene, and the like.

[0074] The term "alkylene" refers to a saturated divalent hydrocarbon radical obtained by removing two hydrogen atoms from a saturated straight-chain or branched-chain hydrocarbon radical. Unless otherwise specified in detail, the alkylene radical contains 1 to 12 carbon atoms. In some embodiments, the alkylene radical contains 1 to 6 carbon atoms; in other embodiments, the alkylene radical contains 1 to 4 carbon atoms; in still other embodiments, the alkylene radical contains 1 to 3 carbon atoms; and in yet other embodiments, the alkylene radical contains 1 to 2 carbon atoms. Such examples include methylene (-CH2-), ethylene (-CH2CH2-), isopropylidene (-CH(CH3)CH2-), and the like.

[0075] The term "alkenyl" refers to a straight-chain or branched-chain monovalent hydrocarbon radical having 2 to 12 carbon atoms, or 2 to 8 carbon atoms, or 2 to 6 carbon atoms, or 2 to 4 carbon atoms, wherein at least one position is in an unsaturated state, i.e., a C-C is a sp 2 double bond, and the alkenyl radical may be independently and optionally substituted by one or more substituents described in the present invention, including groups with "trans", "cis" or "E", "Z" orientations, and specific examples of the alkenyl include, but are not limited to, vinyl (-CH=CH2), allyl (-CH2CH=CH2), and the like.

[0076] The term "alkynyl" refers to a straight-chain or branched-chain monovalent hydrocarbon radical having 2 to 12 carbon atoms, or 2 to 8 carbon atoms, or 2 to 6 carbon atoms, or 2 to 4 carbon atoms, wherein at least one position is in an unsaturated state, i.e., a C-C is a sp triple bond, and the alkynyl radical may be independently and optionally substituted by one or more substituents described in the present invention, and specific examples of the alkynyl include, but are not limited to, ethynyl (-C≡CH), propargyl (-CH2C≡CH), and the like.

[0077] The term "heteroatom" refers to one or more of O, S, N, P, and Si, including any oxidized form of C, N, S, and P; the form of primary, secondary, tertiary amines, and quaternary ammonium salts; or the form in which the hydrogen on the nitrogen atom in a heterocycle is substituted, for example, N (such as N in 3,4-dihydro-2H-pyrrolyl), NH (such as NH in pyrrolidinyl), or NR (such as NR in N-substituted pyrrolidinyl); or -CH2- in a heterocycle is oxidized to form -C(=O)-.

[0078] The term "halogen" refers to F, Cl, Br, or I.

[0079] The term "deuterium" refers to heavy hydrogen, D.

[0080] The term "unsaturated" as used in the present invention means that the moiety contains one or more degrees of unsaturation.

[0081] The term "alkoxy" or "alkyloxy" as used in the present invention refers to an alkyl group, as defined in the present invention, which is attached to other parts of the compound molecule through an oxygen atom. In some embodiments, the alkoxy group is C 1-4 alkoxy; such examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, etc. And the alkoxy group may be independently unsubstituted or substituted by one or more substituents described in the present invention.

[0082] The term "alkylamino" or "alkyamino" as used in the present invention refers to an alkyl group, as defined in the present invention, which is attached to other parts of the compound molecule through an N atom. In some embodiments, the alkylamino group is C 1-4 alkylamino; such examples include, but are not limited to, methylamino, ethylamino, propylamino, butylamino, etc. And the alkylamino group may be independently unsubstituted or substituted by one or more substituents described in the present invention.

[0083] The term "cycloalkyl" or "cycloalkane" refers to a monocyclic, bicyclic or tricyclic carbocyclic system containing 3-12 carbon atoms, which is a saturated ring or a ring containing one or more unsaturated bonds, but does not contain an aromatic ring at all. In one embodiment, the cycloalkyl group contains 3-10 carbon atoms; in another embodiment, the cycloalkyl group contains 3-8 carbon atoms; in yet another embodiment, the cycloalkyl group contains 3-6 carbon atoms. Such examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, etc. The cycloalkyl group may be independently unsubstituted or substituted by one or more substituents described in the present invention.

[0084] The terms "heterocyclic group" and "heterocycle" are used interchangeably herein and both refer to a saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring containing 3 to 12 ring atoms, and definitely not containing an aromatic ring, wherein at least one ring atom is a heteroatom. In one embodiment, the "heterocyclic group" or "heterocycle" contains 3 to 10 ring atoms; in one embodiment, the "heterocyclic group" or "heterocycle" contains 3 to 8 ring atoms; in another embodiment, the "heterocyclic group" or "heterocycle" contains 5 to 8 ring atoms; in yet another embodiment, the "heterocyclic group" or "heterocycle" contains 3 to 6 ring atoms; still in one embodiment, the "heterocyclic group" or "heterocycle" contains 5 to 6 ring atoms; again in one embodiment, the "heterocyclic group" or "heterocycle" contains 4 to 6 ring atoms; unless otherwise specified, the heterocyclic group can be a carbon-based or nitrogen-based group, and the heteroatom has the meaning as described in the present invention. Examples of heterocyclic groups include, but are not limited to: oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1,3-dioxolanyl, dithiolanyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxolanyl, dithiolanyl, thioxolanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl and 1,2,3,6-tetrahydropyridinyl. Examples of the -CH2- group in the heterocyclic group being replaced by -C(=O)- include, but are not limited to: 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidinone, 3,5-dioxopiperidinyl, pyrimidinedione and 5,6-dihydropyridin-2(1H)-one. Examples of the sulfur atom in the heterocyclic group being oxidized include, but are not limited to, sulfolanyl and 1,1-dioxothiomorpholinyl. The described heterocyclic group can be optionally substituted by one or more substituents described in the present invention. yl yl yl

[0085] The term "aryl" refers to a monocyclic, bicyclic and tricyclic carbocyclic system containing 6 to 14 ring atoms, or 6 to 12 ring atoms, or 6 to 10 ring atoms, wherein at least one ring is aromatic, each ring contains a ring composed of 3 to 7 atoms, and there is one or more attachment points connected to the rest of the molecule. The term "aryl" can be used interchangeably with the term "aromatic ring". Examples of aryl groups can include phenyl, naphthyl and anthracenyl. The described aryl group can be independently optionally substituted by one or more substituents described in the present invention.

[0086] The term "heteroaryl" refers to monocyclic, bicyclic, and tricyclic systems containing 5 - 12 ring atoms, or 5 - 10 ring atoms, or 5 - 6 ring atoms, wherein at least one ring system is an aromatic ring and at least one ring system contains one or more heteroatoms, and each ring contains a ring composed of 5 - 7 atoms and has one or more attachment points connected to the rest of the molecule. The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic compound". The heteroaryl group is optionally substituted by one or more substituents described in the present invention. In one embodiment, the heteroaryl composed of 5 - 10 atoms contains 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N, and the nitrogen atom may be further oxidized.

[0087] Examples of heteroaryl groups include, but are not limited to: furyl, imidazolyl (such as N - imidazolyl, 2 - imidazolyl, 4 - imidazolyl, 5 - imidazolyl), isoxazolyl, oxazolyl (such as 2 - oxazolyl, 4 - oxazolyl, 5 - oxazolyl), pyrrolyl (such as N - pyrrolyl, 2 - pyrrolyl, 3 - pyrrolyl), pyridyl, pyrimidinyl (such as 2 - pyrimidinyl, 4 - pyrimidinyl, 5 - pyrimidinyl), pyridazinyl, thiazolyl (such as 2 - thiazolyl, 4 - thiazolyl, 5 - thiazolyl), tetrazolyl (such as 5 - tetrazolyl), triazolyl, thiophenyl (such as 2 - thiophenyl, 3 - thiophenyl), pyrazolyl, isothiazolyl, 1,2,3 - oxadiazolyl, 1,2,5 - oxadiazolyl, 1,2,4 - oxadiazolyl, 1,2,3 - triazolyl, 1,2,3 - thiadiazolyl, 1,3,4 - thiadiazolyl, 1,2,5 - thiadiazolyl, pyrazinyl, 1,3,5 - triazinyl; also include the following bicyclics, but are by no means limited to these bicyclics: benzimidazolyl, benzofuryl, benzothiophenyl, indolyl (such as 2 - indolyl), purinyl, quinolinyl (such as 2 - quinolinyl, 3 - quinolinyl, 4 - quinolinyl), 1,2,3,4 - tetrahydroisoquinolinyl, 1,3 - benzodioxolyl, indolinyl, isoquinolinyl (such as 1 - isoquinolinyl, 3 - isoquinolinyl, or 4 - isoquinolinyl), imidazo[1,2 - a]pyridyl, pyrazolo[1,5 - a]pyridyl, pyrazolo[1,5 - a]pyrimidinyl, imidazo[1,2 - b]pyridazinyl, [1,2,4]triazolo[4,3 - b]pyridazinyl, [1,2,4]triazolo[1,5 - a]pyrimidinyl, and [1,2,4]triazolo[1,5 - a]pyridyl, etc.

[0088] The term "haloalkyl" or "haloalkoxy" refers to an alkyl or alkoxy group substituted by one or more halogen atoms, and examples of such include, but are not limited to, trifluoromethyl, trifluoromethoxy, etc.

[0089] The term "hydroxyalkyl" refers to an alkyl group substituted by one or more hydroxyl groups, and examples of such include, but are not limited to, hydroxymethyl, hydroxyethyl, etc.

[0090] The term "aminoalkyl" means that an alkyl group is substituted by one or more amino groups. Examples of such include, but are not limited to, aminomethyl, aminoethyl, and the like.

[0091] As described in the present invention, a ring system formed by a substituent drawing a bond to a ring represents that the substituent can be substituted at any substitutable position on the ring. For example, formula (a) represents that the substituent R can be mono-substituted or multi-substituted at any possible substitutable position on the pyridine ring.

[0092]

[0093] As described in the present invention, a ring system formed by a connecting bond drawing to a ring (as shown in formula b) represents that the connecting bond can be connected to the rest of the molecule at any connectable position on the ring system. Formula b represents that any possible connectable position on the octahydrocyclopenta[c]pyrrole ring can be connected to the rest of the molecule.

[0094]

[0095] In addition, it should be noted that unless otherwise explicitly indicated, throughout this text, the description methods "each... and... independently is", "... and... each independently is", and "... and... are respectively independently" can be interchanged and should be understood in a broad sense. It can either mean that among different groups, the specific options expressed between the same symbols do not affect each other, or it can also mean that within the same group, the specific options expressed between the same symbols do not affect each other.

[0096] Unless otherwise indicated, the structural formulas described in the present invention include all isomeric forms (such as enantiomers, diastereomers, geometric isomers, or conformational isomers): for example, the R and S configurations containing an asymmetric center, the (Z) and (E) isomers of a double bond, and the conformational isomers of (Z) and (E). Therefore, a single stereochemical isomer of the compounds of the present invention or a mixture of its enantiomers, diastereomers, geometric isomers, or conformational isomers all fall within the scope of the present invention.

[0097] Unless otherwise indicated, the structural formulas and the compounds described in the present invention include all isomeric forms (such as enantiomers, diastereomers, geometric isomers or conformational isomers), N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts and prodrugs. Accordingly, the individual stereoisomers, enantiomers, diastereomers, geometric isomers, conformational isomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts and prodrugs of the compounds of the present invention also fall within the scope of the present invention. Additionally, unless otherwise indicated, the structural formulas of the compounds described in the present invention include one or more enriched isotopes of different atoms.

[0098] "Metabolite" refers to the product obtained by the metabolic action in vivo of a specific compound described in the present invention or its pharmaceutically acceptable salt, analogue or derivative, which exhibits similar activity to the compound of formula (I) in vivo or in vitro. The metabolites of a compound can be identified by techniques well known in the art, and their activities can be characterized by test methods as described in the present invention. Such products can be obtained by methods such as oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, or enzymatic cleavage of the administered compound. Accordingly, the present invention includes the metabolites of the compounds, including the metabolites produced by contacting the compounds of the present invention with mammals for a sufficient period of time.

[0099] In this invention, the definitions and conventions of stereochemistry are generally referred to the following literature: S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. The compounds of this invention may contain asymmetric or chiral centers, and thus different stereoisomers exist. All stereoisomeric forms of the compounds of this invention, including but not limited to, diastereomers, enantiomers, atropisomers, and their mixtures, such as racemic mixtures, form a part of this invention. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. When describing optically active compounds, the prefixes D, L or R, S are used to denote the absolute configuration of the chiral center of the molecule. The prefixes d, l or (+), (-) are used to name the sign of the rotation of plane-polarized light by the compound, (-) or l means that the compound is levorotatory, and the prefix (+) or d means that the compound is dextrorotatory. The chemical structures of these stereoisomers are the same, but their stereostructures are different. A specific stereoisomer may be an enantiomer, and a mixture of isomers is usually called a racemic mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which may result in no stereoselectivity or stereospecificity during a chemical reaction. The terms "racemic mixture" and "racemate" refer to a mixture of two enantiomers in equimolar amounts, lacking optical activity.

[0100] The term "tautomer" or "tautomeric form" refers to isomers of structures of different energies that can interconvert through a low energy barrier. For example, proton tautomers (i.e., prototropic tautomers) include interconversions through proton migration, such as keto-enol and imine-enamine tautomerizations. Valence (valency) tautomers include interconversions that reconstitute the bonding electrons.

[0101] The "pharmaceutically acceptable salts" used in the present invention refer to the organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well-known in the art and are described, for example, in the literature: S.M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19, 1977. The salts formed from non-toxic pharmaceutically acceptable acids include, but are not limited to: inorganic acid salts formed by reacting with amino groups, such as hydrochloride, hydrobromide, phosphate, sulfate, perchlorate; organic acid salts, such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate; or these salts can be obtained by other methods described in the literature, such as ion exchange method. Other pharmaceutically acceptable salts include adipate, malate, 2-hydroxypropionate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, mesylate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. The salts obtained by appropriate bases include salts of alkali metals, alkaline earth metals, ammonium and N+(C 1-4 alkyl)4. The present invention also contemplates quaternary ammonium salts formed from any compound containing a group N. Water-soluble, oil-soluble or dispersed products can be obtained by quaternization. The alkali metals or alkaline earth metals that can form salts include sodium, lithium, potassium, calcium, magnesium, etc. Pharmaceutically acceptable salts further include appropriate, non-toxic ammonium, quaternary ammonium salts and amine cations formed by counterbalancing ions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C 1-8 sulfonates and aromatic sulfonates.

[0102] The "hydrate" of the present invention refers to the association formed by solvent molecules being water.

[0103] The "solvate" of the present invention refers to the association formed by one or more solvent molecules and the compounds of the present invention. The solvents that can form solvates include, but are not limited to: water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, aminoethanol.

[0104] The "ester" of the present invention refers to a compound of formula (I) containing a hydroxyl group that forms a hydrolyzable ester in vivo. Such esters are, for example, pharmaceutically acceptable esters that hydrolyze in a human or animal body to produce the parent alcohol. The groups of the hydrolyzable esters in vivo of the compound of formula (I) containing a hydroxyl group include, but are not limited to: phosphate group, acetoxymethoxy, 2,2-dimethylpropionyloxymethoxy, alkanoyl, benzoyl, phenylacetyl, alkoxycarbonyl, dialkylcarbamoyl, and N-(dialkylaminoethyl)-N-alkylcarbamoyl, etc.

[0105] The "nitroxide" of the present invention refers to when a compound contains several amine functional groups, one or more than one nitrogen atom can be oxidized to form an N-oxide. Specific examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen atoms in nitrogen-containing heterocycles. The corresponding amine can be treated with an oxidizing agent such as hydrogen peroxide or a peracid (such as peroxycarboxylic acid) to form an N-oxide (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages). In particular, N-oxides can be prepared by the method of L.W. Deady (Syn. Comm. 1977, 7, 509-514), for example, in an inert solvent (such as dichloromethane), reacting the amine compound with meta-chloroperoxybenzoic acid (MCPBA).

[0106] The term "prodrug" used in the present invention represents a compound that is converted in vivo into the compound shown in formula (I). Such conversion is affected by the hydrolysis of the prodrug in the blood or its enzymatic conversion in the blood or tissues into the parent structure. The prodrug compounds of the present invention can be esters. In the existing inventions, esters that can serve as prodrugs include phenyl esters, aliphatic (C 1-24)Esters, acyloxymethyl esters, carbonates, carbamates, and amino acid esters. For example, a compound of the present invention contains a hydroxyl group, and it can be acylated to obtain a compound in the prodrug form. Other prodrug forms include phosphate esters, such as these phosphate ester compounds are obtained by phosphorylating the hydroxyl groups on the parent body. A complete discussion of prodrugs can be found in the following references: T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J. Rautio et al, Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255 - 270, and S. J. Hecker et al, Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328 - 2345.

[0107] Unless otherwise specified herein or the context clearly dictates the contrary, the terms "a", "an", "the", and similar terms used in the context of the present invention (especially in the context of the claims) can be construed to include both the singular and the plural.

[0108] The term "RIPK1 inhibitor" as used herein refers to a substance that can inhibit the activity of RIPK1.

[0109] General synthesis process

[0110] To describe the present invention, the following examples are listed. However, it should be understood that the present invention is not limited to these examples, but only provides methods for practicing the present invention.

[0111] Generally, the compounds of the present invention can be prepared by the methods described in the present invention, unless otherwise specified, where the definitions of the substituents are as described in the present invention. The following reaction schemes and examples are used to further illustrate the content of the present invention.

[0112] Those skilled in the art will recognize that the chemical reactions described in the present invention can be used to appropriately prepare other compounds of the present invention, and other methods for preparing the compounds of the present invention are considered to be within the scope of the present invention. For example, the synthesis of those non-illustrative compounds according to the present invention can be successfully accomplished by those skilled in the art through modification methods, such as appropriately protecting interfering groups, by using other known reagents in addition to those described in the present invention, or making some routine modifications to the reaction conditions. Additionally, the reactions or known reaction conditions disclosed in the present invention are also generally recognized as applicable to the preparation of other compounds of the present invention.

[0113] For the examples described below, unless otherwise indicated, all temperatures are in degrees Celsius. Reagents were purchased from commercial suppliers such as Anhui Zesheng Technology Co., Ltd., Shanghai Shaoyuan Reagent Co., Ltd., Shanghai Merck Chemical Technology Co., Ltd., and Shanghai Macklin Biochemical Co., Ltd., and were used without further purification. Unless otherwise indicated, general reagents were obtained from Shantou Xilong Chemical Factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, Tianjin Damao Chemical Reagent Factory, Yantai Jiangyou Silica Gel Development Co., Ltd., and Qingdao Ocean Chemical Factory.

[0114] Anhydrous tetrahydrofuran, N,N-dimethylformamide, 1,4-dioxane, and acetonitrile were dried over molecular sieves. Dichloromethane, ethyl acetate, petroleum ether, and methanol were of analytical grade.

[0115] The following reactions were generally carried out under a positive pressure of nitrogen or argon or with a drying tube placed over an anhydrous solvent (unless otherwise indicated), the reaction flasks were stoppered with appropriate rubber stoppers, and the substrates were injected via syringe. Glassware was dried.

[0116] The silica gel column used was a Flash silica gel column purchased from Tianjin Agela Technologies Co., Ltd. Silica gel (300 - 400 mesh) was purchased from Qingdao Ocean Chemical Factory.

[0117] 1H NMR spectra were recorded using a Bruker 500 MHz nuclear magnetic resonance spectrometer. 1H NMR spectra were referenced to TMS (0 ppm) or chloroform (7.26 ppm) with CDCl3, DMSO-d6, CD3OD, or acetone-d6 as solvents (in ppm). When multiplets occurred, the following abbreviations were used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broadened), brs (broadened singlet), dd (doublet of doublets), dt (doublet of triplets). Coupling constants J were expressed in Hertz (Hz).

[0118] The determination conditions for low-resolution mass spectrometry (MS) data were as follows: Agilent G6125C quadrupole HPLC-MS (column model: XBridge BEH C18, 4.6 x 50 mm, 2.5 μm, 6 min, flow rate 1 mL / min. Mobile phase: 0% - 95% (CH3CN) in (H2O containing 0.1% formic acid:CH3CN = 90:10), electrospray ionization (ESI), detected with DAD at 210 nm / 254 nm).

[0119] Compound purification was performed using a Cheetah Pro medium-pressure rapid purification preparative chromatograph from Tianjin Bonna Aijier Technology Co., Ltd., detected with UV at 210 nm / 254 nm.

[0120] The following reaction scheme describes the steps for preparing the compounds of the present invention. Unless otherwise specified, where X, A, P, Y1, Y2, Y3, Y4, R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R a 、R p 、m, n, y have the definitions as described in the present invention.

[0121] Reaction Scheme 1

[0122]

[0123] Formula (3 ) or ( 4 ) The compound shown can be prepared by the following Reaction Scheme 1: The compound of formula ( 1 ) and the compound of formula ( 2 ) react to obtain the compound of formula ( 3 ) or ( 4 ) shown.

[0124] Reaction Scheme 2

[0125]

[0126] The compound of formula ( 10 ) can also be prepared by the following Reaction Scheme 2: The compound of formula ( 5 ) and the compound of formula ( 6 ) react to obtain the compound of formula ( 7 ) shown. The compound of formula ( 7 ) and the compound of formula ( 8 ) react to obtain the compound of formula ( 9 ) shown. The compound of formula ( 9 ) and the compound of formula ( 3 ) or the compound of formula ( 4 ) react to obtain the compound of formula ( 10 ) shown. Detailed Embodiments

[0127] The present invention will be described below with reference to specific embodiments. It should be noted that these embodiments are merely illustrative and do not limit the present invention in any way.

[0128] Synthesis of (S)-(6'-(2-Amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)spiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-1'(2'H)-yl)(2-(4-fluorophenyl)pyrrolidin-1-yl)methanone (Compound 1)

[0129]

[0130] Step 1: Synthesis of (S)-2-(4-Fluorophenyl)pyrrolidine-1-carboxylic acid p-nitrophenyl ester

[0131] 4-Nitrophenyl chloroformate (244 mg, 1.21 mmol) was slowly added to a mixed solution of (S)-2-(4-fluorophenyl)pyrrolidine (100 mg, 0.61 mmol) and diisopropylethylamine (156 mg, 1.21 mmol) in dichloromethane (10 mL) and tetrahydrofuran (10 mL) at 0 °C, and the reaction was carried out at room temperature for 24 hours. The reaction was concentrated under reduced pressure, quenched by adding water (10 mL), extracted with ethyl acetate (7 mL × 3), and the organic phases were combined. The organic phase was washed successively with water (7 mL × 3) and saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent EA:PE (v / v) = 10%-35%) to obtain 218 mg of a pale yellow solid.

[0132] Step 2: Synthesis of (2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)boronic acid

[0133] Potassium acetate (115 mg, 1.17 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (38 mg, 0.05 mmol) were added to a solution of 7-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine (100 mg, 0.47 mmol) and bis(pinacolato)diboron (215 mg, 0.85 mmol) in 1,4-dioxane (2 mL). The mixture was placed under a nitrogen atmosphere and heated to 100 °C for 8 hours. After cooling to room temperature, it was diluted with ethyl acetate (10 mL), filtered through diatomaceous earth, and concentrated under reduced pressure to obtain 53 mg of a black liquid, which was used directly in the next step as the crude product.

[0134] LC-MS (ESI): [M+H] + = 179.0

[0135] Step 3: Synthesis of diethyl 2-(5-bromo-3-nitropyridin-2-yl)malonate

[0136] Potassium carbonate (1.63 g, 11.79 mmol) was added to a solution of 5-bromo-2-chloro-3-nitropyridine (1.00 g, 4.21 mmol) and diethyl malonate (0.94 g, 5.90 mmol) in DMF (20 mL), and the reaction was carried out at room temperature for 14 hours. The reaction solution was poured into ice water (100 mL) to quench the reaction, and dilute hydrochloric acid was slowly added with stirring to adjust the pH to 3-4. It was extracted with ethyl acetate (60 mL × 3), and the organic phases were combined. The organic phase was washed successively with water (60 mL × 3) and saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent EA:PE (v / v) = 0-15%) to obtain 1.10 g of a yellow solid product.

[0137] LC-MS(ESI): [M+H] + = 361.1

[0138] Step 4: Synthesis of Ethyl 2-(3-amino-5-bromopyridin-2-yl)acetate

[0139] Diethyl 2-(5-bromo-3-nitropyridin-2-yl)malonate (1.10 g, 3.05 mmol) and iron powder (0.51 g, 9.14 mmol) were added to ethanol (10 mL), and hydrochloric acid (0.17 g, 4.57 mmol) was slowly dropped in, then heated to 82 °C and reacted for 1 hour. Filtered through diatomaceous earth, the residue was washed twice with hot ethanol. While stirring, saturated sodium bicarbonate solution was slowly added to the filtrate to adjust the pH to neutral, and concentrated under reduced pressure. Diluted with ethyl acetate (20 mL) and stirred overnight at room temperature. The organic phase was taken, washed successively with water (10 mL × 3) and saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated and purified by silica gel column chromatography (eluent EA:PE (v / v) = 0 - 15%), and 405 mg of brown solid product was obtained.

[0140] LC-MS(ESI): [M+H] + = 259.0

[0141] Step 5: Synthesis of 6-Bromo-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one

[0142] Acetic acid (87 mg, 1.45 mmol) was added to a toluene (4 mL) solution of ethyl 2-(3-amino-5-bromopyridin-2-yl)acetate (125 mg, 0.48 mmol), then heated to 110 °C and reacted for 14 hours. Concentrated under reduced pressure, and separated and purified by silica gel column chromatography (eluent EA:PE (v / v) = 10 - 35%), and 78 mg of pale yellow solid product was obtained.

[0143] LC-MS(ESI): [M+H] + = 213.0

[0144] Step 6: Synthesis of 6'-Bromospiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-2'(1'H)-one

[0145] To a solution of 6-bromo-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one (0.89 g, 4.18 mmol) and 1,2-dibromoethane (2.35 g, 12.53 mmol) in DMF (10 mL), sodium hydride (1.00 g, 25.11 mmol) was added portionwise, and the reaction was carried out at room temperature for 18 hours. The reaction mixture was quenched by pouring it into ice water (50 mL), and extracted with ethyl acetate (30 mL × 3). The organic phases were combined. The organic phase was washed successively with water (30 mL × 3) and saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent 100% DCM) to obtain 570 mg of a white solid product.

[0146] LC-MS(ESI): [M+H] + = 239.1

[0147] Step 7: Synthesis of 6'-bromo-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]

[0148] Sodium borohydride (450 mg, 11.90 mmol) was added to a solution of 6'-bromospiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridin]-2'(1'H)-one (570 mg, 2.38 mmol) in THF (40 mL). A 47% boron trifluoride diethyl etherate solution (5.10 g, 16.62 mmol) was slowly added dropwise at 0 °C, and the mixture was stirred at 0 °C for 10 minutes and then at room temperature for 12 hours. The reaction mixture was quenched by adding saturated ammonium chloride solution (10 mL) under an ice bath, and the mixture was stirred at room temperature overnight. Water (50 mL) was added for dilution, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined. The organic phase was washed successively with water (30 mL × 3) and saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent 100% DCM) to obtain 320 mg of a pale yellow solid product.

[0149] LC-MS(ESI): [M+H] + = 225.0

[0150] Step 8: Synthesis of (S)-(6'-bromospiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridin]-1'(2'H)-yl)(2-(4-fluorophenyl)pyrrolidin-1-yl)methanone

[0151] Cesium carbonate (497 mg, 1.52 mmol) was added to a solution of 6'-bromo-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine] (136 mg, 0.61 mmol) and (S)-2-(4-fluorophenyl)pyrrolidine-1-carboxylic acid 4-nitrophenyl ester (200 mg, 0.61 mmol) in DMF (10 mL). The mixture was heated to 80 °C and reacted for 14 hours. After cooling to room temperature, the reaction was quenched by adding water (25 mL), and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed successively with water (20 mL × 3) and saturated brine (15 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The product was purified by silica gel column chromatography (eluent EA:PE (v / v) = 10 - 30%), and 100 mg of a pale yellow solid was obtained.

[0152] LC-MS (ESI): [M+H] + = 418.0

[0153] Step 9: Synthesis of (S)-(6'-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)spiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-1'(2'H)-yl)(2-(4-fluorophenyl)pyrrolidin-1-yl)methanone

[0154] To a mixture of (S)-(6'-bromospiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-1'(2'H)-yl)(2-(4-fluorophenyl)pyrrolidin-1-yl)methanone (100 mg, 0.24 mmol) and (2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)boronic acid (86 mg, 0.48 mmol) in a mixture of 1,4-dioxane (8 mL) and water (2 mL), potassium phosphate (127 mg, 0.6 mmol) and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)palladium(II) (38 mg, 0.05 mmol) were added. The reaction mixture was placed under a nitrogen atmosphere and heated to 85 °C for 12 h. After cooling to room temperature, the mixture was filtered through diatomaceous earth. The filtrate was diluted with water (15 mL), and the mixture was extracted with ethyl acetate (8 mL × 3). The organic phases were combined, washed successively with water (10 mL × 3) and saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The product was purified by silica gel column chromatography (eluent MeOH:DCM (v / v) = 0 - 10%), and 24 mg of a yellow solid was obtained.

[0155] LC-MS (ESI): [M+H] + = 470.2

[0156] 11H NMR (500 MHz, DMSO-d6) δ 8.56 (d, J = 7.0 Hz, 1H), 8.32 (s, 1H), 7.79 (s, 1H), 7.53 (s, 1H), 7.35–7.32 (m, 2H), 7.14–7.07 (m, 3H), 6.02 (s, 2H), 5.02–4.98 (m, 1H), 4.34 (d, J = 10.1 Hz, 1H), 4.01 (d, J = 10.0 Hz, 1H), 3.75–3.65 (m, 2H), 2.38–2.35 (m, 1H), 2.00–1.97 (m, 1H), 1.89–1.87 (m, 1H), 1.71–1.69 (m, 1H), 1.32–1.22 (m, 2H), 1.17–1.13 (m, 2H).

[0157] Synthesis of (S)-(6'-(2-Aminobenzothiazol-6-yl)spiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-1'(2'H)-yl)(2-(4-fluorophenyl)pyrrolidin-1-yl)methanone (Compound 2) in Example 2

[0158]

[0159] Step 1: Synthesis of tert-Butyl (6-bromobenzothiazol-2-yl)carbamate

[0160] To a solution of 6-bromobenzothiazol-2-amine (500 mg, 2.18 mmol) in dichloromethane (10 mL) was added di-tert-butyl dicarbonate (571 mg, 2.62 mmol) and 4-dimethylaminopyridine (27 mg, 0.22 mmol), and the reaction was carried out overnight at room temperature. The mixture was concentrated under reduced pressure, 7 mol / L ammonia in methanol solution (2 mL, 14.00 mmol) was added, and the reaction was carried out for 2 hours at room temperature. The mixture was concentrated under reduced pressure, slurried with water (5 mL), filtered, and dried to obtain 710 mg of a light yellow solid product.

[0161] LC-MS (ESI): [M-55] + = 272.9

[0162] Step 2: Synthesis of tert-Butyl (6-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzothiazol-2-yl)carbamate

[0163] To a solution of tert-butyl (6-bromobenzo[d]thiazol-2-yl)carbamate (710 mg, 2.16 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane) (657 mg, 2.59 mmol) in 1,4-dioxane (20 mL) were added potassium acetate (529 mg, 5.39 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (176 mg, 0.22 mmol). The mixture was placed under a nitrogen atmosphere and heated to 100 °C and reacted overnight. After cooling to room temperature, it was filtered through diatomaceous earth. Diluted with water (20 mL), extracted with ethyl acetate (20 mL × 3), and the organic phases were combined. The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 730 mg of a black viscous product. The crude product was directly used for the next step.

[0164] LC-MS(ESI):[M+H] + =377.2

[0165] Step 3: Synthesis of tert-butyl (S)-(6-(1'-(2-(4-fluorophenyl)pyrrolidine-1-carbonyl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-6'-yl)benzo[d]thiazol-2-yl)carbamate

[0166] To a solution of (S)-(6'-bromospiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-1'(2'H)-yl)(2-(4-fluorophenyl)pyrrolidin-1-yl)methanone (202 mg, 0.49 mmol) (synthesized according to the method in Step 8 of Example 1) and tert-butyl (6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)carbamate (210 mg, 0.56 mmol) in 1,4-dioxane (6 mL) and water (1.5 mL) were added potassium phosphate (206 mg, 0.97 mmol) and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)palladium(II) (38 mg, 0.05 mmol). The mixture was placed under a nitrogen atmosphere and heated to 85 °C and reacted overnight. After cooling to room temperature, it was filtered through diatomaceous earth. Diluted with water (20 mL), extracted with ethyl acetate (15 mL × 3), and the organic phases were combined. The organic phase was washed successively with water (10 mL × 3) and saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 350 mg of a yellow viscous oil. The crude product was directly used for the next step.

[0167] Step 4: Synthesis of (S)-(6'-(2-Aminobenzothiazol-6-yl)spiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-1'(2'H)-yl)(2-(4-fluorophenyl)pyrrolidin-1-yl)methanone

[0168] At 0 °C, trifluoroacetic acid (3 mL) was slowly added to a solution of tert-butyl (S)-(6-(1'-(2-(4-fluorophenyl)pyrrolidine-1-carbonyl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-6'-yl)benzothiazol-2-yl)carbamate (350 mg, 0.60 mmol) in dichloromethane (6 mL). After the addition was complete, the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure, diluted with water (10 mL), and the pH was adjusted to weakly basic with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate (15 mL × 3), and the organic layers were combined. The organic layer was washed successively with water (10 mL × 3) and saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent EA:DCM (v / v) = 10 - 35%), to give 129 mg of a cream solid product.

[0169] LC-MS (ESI): [M+H] + = 486.1

[0170] 1 1H NMR (500 MHz, DMSO-d6) δ 8.19 (s, 1H), 7.89 (s, 1H), 7.72 (s, 1H), 7.56–7.49 (m, 2H), 7.44–7.36 (m, 2H), 7.35–7.30 (m, 2H), 7.14–7.06 (m, 2H), 4.99 (t, J = 8.0 Hz, 1H), 4.32 (d, J = 10.1 Hz, 1H), 4.06–3.96 (m, 1H), 3.75–3.63 (m, 2H), 2.40–2.32 (m, 1H), 2.01–1.97 (m, 1H), 1.92–1.83 (m, 1H), 1.74–1.64 (m, 1H), 1.29–1.22 (m, 2H), 1.14–1.09 (m, 2H).

[0171] Example 3 Synthesis of (6'-(2-Amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)spiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-1'(2'H)-yl)(2-(3-fluorophenyl)pyrrolidin-1-yl)methanone (Compound 3)

[0172]

[0173] Compound 3 was prepared according to the method of Example 1.

[0174] LC-MS(ESI):[M+H] + =470.2

[0175] 1 H NMR(500MHz,DMSO-d6)δ8.56(d,J=7.0Hz,1H),8.35–8.31(m,1H),7.81(d,J=2.1Hz,1H),7.53(s,1H),7.34(q,J=7.4Hz,1H),7.18–7.06(m,3H),7.04–6.98(m,1H),6.02(s,2H),5.02(t,J=8.0Hz,1H),4.36(d,J=10.1Hz,1H),4.06(d,J=10.1Hz,1H),3.78–3.64(m,2H),2.43–2.34(m,1H),1.99(s,1H),1.93–1.83(m,1H),1.75–1.66(m,1H),1.33–1.11(m,4H).

[0176] Synthesis of Example 4 (S)-(6'-(2-Amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)spiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-1'(2'H)-yl)(2-(4-(trifluoromethyl)phenyl)pyrrolidin-1-yl)methanone (Compound 4)

[0177]

[0178] Compound 2 was prepared according to the method of Example 1.

[0179] LC-MS(ESI):[M+H] + =520.4

[0180] 1 H NMR(500MHz,DMSO-d6)δ8.56(d,J=6.7Hz,1H),8.33(s,1H),7.80(s,1H),7.65(d,J=7.8Hz,2H),7.58–7.50(m,3H),7.09(d,J=7.0Hz,1H),6.02(s,2H),5.12–5.04(m,1H),4.38(d,J=10.1Hz,1H),4.07(d,J=10.1Hz,1H),3.80–3.66(m,2H),2.46–2.37(m,1H),2.04–1.89(m,2H),1.74–1.65(m,1H),1.33–1.11(m,4H).

[0181] Synthesis of (6'-(2-Amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)spiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-1'(2'H)-yl)(2-(3-fluorophenyl)-4-methylpyrrolidin-1-yl)methanone (Compound 5), Example 5

[0182]

[0183] Step 1: Synthesis of (6'-Bromospiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-1'(2'H)-yl)(2-(3-fluorophenyl)-4-methylpyrrolidin-1-yl)methanone

[0184] Potassium carbonate (196 mg, 1.42 mmol) was added to a solution of 4-nitrophenyl 6'-bromospiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-1'(2'H)-carboxylate (180 mg, 0.46 mmol) and 2-(3-fluorophenyl)-4-methylpyrrolidine (99 mg, 0.55 mmol) in DMF (10 mL). The mixture was heated to 65 °C and reacted for 1.5 h. After cooling to room temperature, the reaction was quenched by adding water (25 mL), and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed successively with water (20 mL × 3) and saturated brine (15 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The product was purified by silica gel column chromatography (eluent EA:PE (v / v) = 10 - 30%), and 168 mg of a yellow liquid product was obtained.

[0185] LC-MS (ESI): [M+H] + = 430.2

[0186] Step 2: Synthesis of (6'-(2-Amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)spiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-1'(2'H)-yl)(2-(3-fluorophenyl)-4-methylpyrrolidin-1-yl)methanone

[0187] To a mixed solution of (6'-bromospiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-1'(2'H)-yl)(2-(3-fluorophenyl)-4-methylpyrrolidin-1-yl)methanone (168 mg, 0.39 mmol) and (2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)boronic acid (139 mg, 0.78 mmol) in 1,4-dioxane (8 mL) and water (2 mL) were added potassium phosphate (207 mg, 0.98 mmol) and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)palladium(II) (61 mg, 0.08 mmol). The mixture was heated to 85 °C under a nitrogen atmosphere and reacted for 12 h. After cooling to room temperature, it was filtered through diatomaceous earth. Diluted with water (15 mL), extracted with ethyl acetate (8 mL × 3), and the organic phases were combined. The organic phase was washed successively with water (10 mL × 3) and saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent MeOH:DCM (v / v) = 0 - 10%), to obtain 66 mg of a yellow solid product.

[0188] LC-MS(ESI): [M+H] + = 484.4

[0189] 1 1H NMR (500 MHz, DMSO-d6) δ 8.56 (d, J = 6.9 Hz, 1H), 8.34 (s, 1H), 7.81 (s, 1H), 7.54 (d, J = 5.8 Hz, 1H), 7.35–7.31 (m, 1H), 7.18–7.07 (m, 3H), 7.02–6.99 (m, 1H), 6.02 (s, 2H), 5.03–5.00 (m, 1H), 4.39 (d, J = 10.1 Hz, 1H), 4.09–4.03 (m, 1H), 3.78 (t, J = 8.5 Hz, 1H), 2.37–2.24 (m, 1H), 2.08 (s, 1H), 1.39–1.13 (m, 6H), 1.08–1.04 (m, 3H).

[0190] Synthesis of Example 6 (S)-(6-(2-Amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)(2-(4-fluorophenyl)pyrrolidin-1-yl)methanone (Compound 6)

[0191]

[0192] Step 1: Synthesis of (S)-(6-bromo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)(2-(4-fluorophenyl)pyrrolidin-1-yl)methanone

[0193] A solution of phosgene (72 mg, 0.24 mmol) in dichloromethane (6 mL) was added with a solution of (S)-2-(4-fluorophenyl)pyrrolidine (100 mg, 0.61 mmol) and N,N-diisopropylethylamine (156 mg, 1.21 mmol) in dichloromethane (2 mL) at 0 °C. After reacting at 0 °C for 30 minutes, a solution of 6-bromo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (150 mg, 0.75 mmol) and N,N-diisopropylethylamine (156 mg, 1.21 mmol) in dichloromethane (2 mL) was added. The reaction was warmed to room temperature and stirred for 1 hour. The reaction mixture was concentrated under reduced pressure directly and purified by silica gel column chromatography (eluent EA:PE (v / v) = 0 - 50%), giving 25 mg of a light yellow solid.

[0194] LC-MS (ESI): [M] + = 390.1

[0195] 1 1H NMR (500 MHz, DMSO-d6) δ 8.05 (d, J = 2.0 Hz, 1H), 7.64 (d, J = 2.0 Hz, 1H), 7.36–7.29 (m, 2H), 7.13–7.06 (m, 2H), 4.96 (t, J = 8.0 Hz, 1H), 4.24–4.15 (m, 1H), 4.01–3.92 (m, 1H), 3.77–3.68 (m, 1H), 3.63 (t, J = 9.0 Hz, 1H), 3.22–3.12 (m, 1H), 3.12–3.01 (m, 1H), 2.35 (d, J = 11.9 Hz, 1H), 1.97 (d, J = 7.5 Hz, 1H), 1.90–1.79 (m, 1H), 1.72–1.63 (m, 1H).

[0196] Step 2: Synthesis of (S)-(6-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)(2-(4-fluorophenyl)pyrrolidin-1-yl)methanone

[0197] To a mixed solution of (S)-(6-bromo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)(2-(4-fluorophenyl)pyrrolidin-1-yl)methanone (25 mg, 0.06 mmol) and (2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)boronic acid (23 mg, 0.13 mmol) in 1,4-dioxane (4 mL) and water (1 mL) were added potassium phosphate (34 mg, 0.16 mmol) and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)palladium(II) (5 mg, 0.01 mmol). The mixture was placed under a nitrogen atmosphere and heated to 85 °C and reacted overnight. After cooling to room temperature, it was filtered through diatomaceous earth. Diluted with water (10 mL), extracted with ethyl acetate (10 mL × 3), and the organic phases were combined. Washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated and purified by Prep-HPLC (eluent CH3CN:H2O (v / v) = 50%), to obtain 5 mg of a white solid product.

[0198] LC-MS (ESI): [M+H] + = 444.1

[0199] 1 1H NMR (500 MHz, DMSO-d6) δ 8.57 (d, J = 6.9 Hz, 1H), 8.39 (d, J = 2.0 Hz, 1H), 7.79 (d, J = 2.0 Hz, 1H), 7.55 (s, 1H), 7.38–7.32 (m, 2H), 7.14–7.07 (m, 3H), 6.03 (s, 2H), 5.00 (t, J = 7.9 Hz, 1H), 4.21 (q, J = 9.7 Hz, 1H), 4.04–3.96 (m, 1H), 3.81–3.72 (m, 1H), 3.66 (t, J = 8.7 Hz, 1H), 3.25–3.07 (m, 2H), 2.41–2.33 (m, 1H), 1.99 (s, 1H), 1.93–1.82 (m, 1H), 1.76–1.67 (m, 1H).

[0200] Example 7 Synthesis of (S)-(6-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)(2-(3,5-difluorophenyl)pyrrolidin-1-yl)methanone (Compound 7)

[0201]

[0202] Compound 7 was prepared according to the method of Reference Example 6.

[0203] LC-MS (ESI): [M+H] + = 462.2

[0204] 1 H NMR (500 MHz, DMSO-d6) δ 8.56 (d, J = 6.9 Hz, 1H), 8.42–8.39 (m, 1H), 7.83 (d, J = 2.1 Hz, 1H), 7.56–7.54 (m, 2H), 7.12–6.99 (m, 3H), 6.03 (s, 2H), 5.02 (t, J = 7.9 Hz, 1H), 4.27–4.21 (m, 1H), 4.13–4.05 (m, 1H), 3.83–3.75 (m, 1H), 3.70–3.63 (m, 1H), 3.28–3.25 (m, 1H), 3.22–3.13 (m, 1H), 2.42–2.34 (m, 1H), 2.04–1.95 (m, 1H), 1.92–1.82 (m, 1H), 1.75–1.66 (m, 1H).

[0205] Synthesis of Example 8 (S)-(6-(2-Amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)(2-(4-(trifluoromethyl)phenyl)pyrrolidin-1-yl)methanone (Compound 8)

[0206]

[0207] Compound 8 was prepared according to the method of Reference Example 6.

[0208] LC-MS (ESI): [M+H] + = 494.4

[0209] 1 H NMR (500 MHz, DMSO-d6) δ 8.57 (d, J = 7.0 Hz, 1H), 8.43–8.38 (m, 1H), 7.84–7.79 (m, 1H), 7.65 (d, J = 8.0 Hz, 2H), 7.59–7.53 (m, 3H), 7.11 (d, J = 7.0 Hz, 1H), 6.03 (s, 2H), 5.08 (t, J = 8.0 Hz, 1H), 4.25 (q, J = 9.7 Hz, 1H), 4.10–4.01 (m, 1H), 3.85–3.76 (m, 1H), 3.75–3.66 (m, 1H), 3.26–3.13 (m, 2H), 2.48–2.37 (m, 1H), 2.08–1.97 (m, 1H), 1.97–1.86 (m, 1H), 1.79–1.66 (m, 1H).

[0210] Synthesis of Example 9 (6-(2-Amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)(2-(3-fluorophenyl)pyrrolidin-1-yl)methanone (Compound 9)

[0211]

[0212] Compound 9 was prepared according to the method of Reference Example 6.

[0213] LC-MS (ESI): [M+H] + = 444.4

[0214] 1 1H NMR (500 MHz, DMSO-d6) δ 8.57 (d, J = 5.0 Hz, 1H), 8.40 (s, 1H), 7.82 (s, 1H), 7.56 (s, 1H), 7.34 (d, J = 7.7 Hz, 1H), 7.22–7.06 (m, 3H), 7.02 (s, 1H), 6.03 (s, 2H), 5.08–4.97 (m, 1H), 4.29–4.18 (m, 1H), 4.09–3.99 (m, 1H), 3.83–3.74 (m, 1H), 3.72–3.64 (m, 1H), 3.20–3.16 (m, 2H), 2.42–2.37 (m, 1H), 2.02–1.97 (m, 1H), 1.92–1.86 (m, 1H), 1.78–1.69 (m, 1H).

[0215] Synthesis of Example 10 (6-(2-Amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)(2-(3-fluorophenyl)-4-methylpyrrolidin-1-yl)methanone (Compound 10)

[0216]

[0217] Step 1: Synthesis of tert-Butyl 4-Methyl-2-oxopyrrolidine-1-carboxylate

[0218] 4-Dimethylaminopyridine (0.25 g, 2.02 mmol) was added to a solution of 4-methyl-2-pyrrolidone (1 g, 10.09 mmol) in DCM (10 mL). At 0 °C, di-tert-butyl dicarbonate (2.75 g, 12.61 mmol) was added dropwise, and the reaction was carried out at room temperature for 3 hours. Then, the reaction mixture was quenched with water and extracted with dichloromethane (30 mL × 3). The organic layers were combined, washed successively with water (60 mL × 3) and saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent EA:PE (v / v) = 20 - 35%), to obtain 2.1 g of a yellow liquid product.

[0219] Step 2: Synthesis of tert-butyl (4-(3-fluorophenyl)-2-methyl-4-oxobutyl)carbamate

[0220] m-Fluoroiodobenzene (1.60 g, 7.21 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), placed under a nitrogen atmosphere, and cooled in an ice bath. Isopropylmagnesium chloride (3.6 mL, 2.0 mol / L in THF) was slowly added, and the reaction was carried out at room temperature for 3 hours. A solution of tert-butyl 4-methyl-2-oxopyrrolidine-1-carboxylate (1.58 g, 7.93 mmol) in anhydrous tetrahydrofuran (10 mL) was rapidly added to the above reaction mixture, and the reaction was carried out at room temperature for 3 hours. The reaction mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate (30 mL × 3). The organic layers were combined, washed successively with water (30 mL × 3) and saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 1.98 g of a crude yellow liquid.

[0221] Step 3: Synthesis of 5-(3-fluorophenyl)-3-methyl-3,4-dihydro-2H-pyrrole (775 - 3)

[0222] (S)-N-(3-(1,3-dioxolan-2-yl)-1-(4-(trifluoromethyl)phenyl)propyl)-2-methylpropane-2-sulfonamide (1.98 g, 6.7 mmol) and TFA (1 mL) were added to a solution of DCM (20 mL), and the reaction was carried out at room temperature overnight. The pH was adjusted to 8 - 9 with aqueous sodium carbonate solution, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic layers were combined, washed successively with water (20 mL × 3) and saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent EA:PE (v / v) = 20 - 35%) to obtain 0.82 g of a yellow liquid product.

[0223] LC-MS (ESI): [M + H] + = 178.2

[0224] Step 4: Synthesis of 2-(3-fluorophenyl)-4-methylpyrrolidine

[0225] Sodium borohydride (192 mg, 35.08 mmol) was slowly added to a solution of 5-(3-fluorophenyl)-3-methyl-3,4-dihydro-2H-pyrrole (450 mg, 2.54 mmol) in methanol (20 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with water and extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed successively with water (20 mL × 3) and saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 0.34 g of a yellow liquid product.

[0226] LC-MS (ESI): [M+H] + = 180.2

[0227] Step 5: Synthesis of (6-bromo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)(2-(3-fluorophenyl)-4-methylpyrrolidin-1-yl)methanone

[0228] Potassium carbonate (268 mg, 1.94 mmol) was added to a solution of 6-bromo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxylic acid p-nitrophenyl ester (230 mg, 0.63 mmol) and 2-(3-fluorophenyl)-4-methylpyrrolidine (113 mg, 0.63 mmol) in DMF (10 mL), and the mixture was heated to 65 °C and reacted for 1.5 hours. After cooling to room temperature, the reaction mixture was quenched with water (25 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed successively with water (20 mL × 3) and saturated brine (15 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent EA:PE (v / v) = 10 - 30%), giving 295 mg of a yellow liquid product.

[0229] LC-MS (ESI): [M+H] + = 404.4

[0230] Step 6: Synthesis of (6-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)(2-(3-fluorophenyl)-4-methylpyrrolidin-1-yl)methanone

[0231] To a solution of (6-bromo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)(2-(3-fluorophenyl)-4-methylpyrrolidin-1-yl)methanone (295 mg, 0.73 mmol) and (2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)boronic acid (260 mg, 1.46 mmol) in 1,4-dioxane (8 mL) and water (2 mL) were added potassium phosphate (387 mg, 1.82 mmol) and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)palladium(II) (115 mg, 0.15 mmol). The reaction mixture was heated to 85 °C under a nitrogen atmosphere for 12 h. After cooling to room temperature, the mixture was filtered through diatomaceous earth. The filtrate was diluted with water (15 mL) and extracted with ethyl acetate (8 mL × 3). The combined organic phases were washed successively with water (10 mL × 3) and saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent MeOH:DCM (v / v) = 0 - 10%), to give 13 mg of a pink solid product.

[0232] LC-MS (ESI): [M+H] + = 458.4

[0233] 1 1H NMR (500 MHz, DMSO-d6) δ 8.58–8.56 (m, 1H), 8.39 (t, J = 2.6 Hz, 1H), 7.81 (t, J = 2.4 Hz, 1H), 7.55 (d, J = 5.3 Hz, 1H), 7.36–7.30 (m, 1H), 7.19–7.09 (m, 3H), 7.02–6.98 (m, 1H), 6.03 (s, 2H), 4.30–3.95 (m, 3H), 3.75 (t, J = 8.6 Hz, 1H), 3.21–3.11 (m, 1H), 2.35–2.24 (m, 1H), 2.12–1.85 (m, 2H), 1.24 (d, J = 6.3 Hz, 2H), 1.08–1.03 (m, 3H).

[0234] Experimental Example 1 RIPK1 Kinase Inhibitory Activity Test

[0235] 1. Experimental Materials

[0236] (1) The reagents are shown in Table 1 below.

[0237] Table 1

[0238] Name Item Number Manufacturer ADP-Glo Kinase Assay Kit V9102 Promega RIPK1 R18058 SignalChem

[0239] 2. Methods

[0240] (1) Dilution of the compound

[0241] Gradient dilution of the compound (control compound RIPA-56 and the compound of the present application): Dissolve the compound with DMSO solvent to obtain a 10 mM compound solution, and then perform 4-fold serial dilution to obtain a total of 11 concentrations (the concentrations are 1000, 250, 62.5, 15.625, 3.906, 0.977, 0.244, 0.061, 0.015, 0.004, and 0 μM) of the compound solution.

[0242] (2) Experimental method

[0243] The present application uses the ADP-Glo TM kinase assay kit to determine the inhibitory activity of the compound against RIPK1, specifically as follows:

[0244] (a) Transfer 100 nL / well of the diluted compound solution to a 384-well plate.

[0245] (b) Add the prepared RIPK1 enzyme solution to each well of the 384-well plate at 5 μL, centrifuge at 1000 rpm for 1 min, and incubate at 25 °C for 15 min.

[0246] (c) Add the prepared substrate solution to each well of the 384-well plate at 5 μL, centrifuge at 1000 rpm for 1 min, and incubate at 25 °C for 60 min. The final concentration of the compound is 10000, 2500, 625, 156.25, 39.06, 9.77, 2.44, 0.61, 0.15, 0.04, and 0 nM.

[0247] (d) Add ADP-Glo TM reagent (Promega, V9102) to each well at 10 μL, centrifuge at 1000 rpm for 1 min, and incubate at 25 °C for 60 min.

[0248] (e) Add ADP-Glo TM kinase assay reagent (Promega, V9102) to each well at 20 μL, centrifuge at 1000 rpm for 1 min, and incubate at 25 °C for 60 min.

[0249] (f) Read the fluorescence value with a microplate reader.

[0250] Calculate the mean and standard deviation of the DMSO well and the 10000 nM RIPA-56 well. The mean of the DMSO well is used as the high value, and the mean of the 10000 nM RIPA-56 well is used as the low value.

[0251] Compound pore inhibition rate = 100 * (average reading of high value - reading of compound) / (average reading of high value - average reading of low value). Using the GraphPad Prism 8 non - linear fitting formula, calculate the IC 50 value of the inhibitory ability of the compound against RIPK1.

[0252] The results are shown in Table 1.

[0253] Table 1. IC 50 values of the inhibitory ability of the compounds provided in some embodiments of the present invention against RIPK1

[0254] Compound <![CDATA[IC 50 (nM)]]> 1 13.69 2 14.89 4 17.02 6 13.46 7 17.01

[0255] Results and discussion: The compounds of the present invention exhibit excellent RIPK1 inhibitory activity.

[0256] Experimental Example 2 Pharmacokinetic Test

[0257] 1) Pharmacokinetic test in mice

[0258] Take 6 male mice weighing 20 - 30 g, divide them into two groups. One group is given a single intravenous injection at 2 mg / kg, and the other group is given a single oral dose at 10 mg / kg. Blood samples are collected at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 h after administration. After pretreatment of the plasma samples, they are detected by LC / MS / MS in MRM mode, and a suitable standard curve is established to quantify the target compound in the plasma samples to obtain the drug concentration - time curve. The pharmacokinetic parameters are calculated using the non - compartmental model of WinNonlin software.

[0259] 2) Pharmacokinetic test in rats

[0260] Take 6 male rats weighing 200 - 300 g, divide them into two groups. One group is given a single intravenous injection at 1 mg / kg, and the other group is given a single oral dose at 5 mg / kg. Blood samples are collected at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 h after administration. After pretreatment of the plasma samples, they are detected by LC / MS / MS in MRM mode, and a suitable standard curve is established to quantify the target compound in the plasma samples to obtain the drug concentration - time curve. The pharmacokinetic parameters are calculated using the non - compartmental model of WinNonlin software.

[0261] 3) Pharmacokinetic test in dogs

[0262] Six beagle dogs weighing 9 - 15 kg were divided into two groups. One group was given a single intravenous injection at a dose of 1 mg / kg, and blood samples were collected at 0.083, 0.25, 0.5, 1, 2, 4, 8, 24, and 48 h after administration. The other group was given a single oral dose at a dose of 5 mg / kg, and blood samples were collected at 0.25, 0.5, 1, 2, 4, 8, 24, 32, and 48 h after administration. After pretreatment of the plasma samples, they were detected by LC / MS / MS in the MRM mode, and a suitable standard curve was established to quantify the target compounds in the plasma samples to obtain the drug concentration - time curve. The pharmacokinetic parameters were calculated using the non - compartmental model of WinNonlin software.

[0263] Experimental conclusion: The compounds of the present invention exhibit excellent pharmacokinetic properties.

[0264] In the description of this specification, the description with reference to terms such as "one embodiment", "some embodiments", "example", "specific example", or "some examples" means that the specific features, structures, materials, or characteristics described in connection with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above - mentioned terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials, or characteristics described can be combined in a suitable manner in any one or more embodiments or examples. In addition, without contradiction, those skilled in the art can combine and combine the different embodiments or examples described in this specification and the features of different embodiments or examples.

Claims

1. A compound, which is a compound as represented by formula (I), or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the compound as represented by formula (I), in: X is N or CR 18 ; Y1 is C or N; Y2 is N, O, S, CR 19 or NR 21 ; Y3 is N, O, S, CR 20 or NR 22 ; Y4 is C or N; Ring A is C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; Each R a are independently H, D, F, Cl, Br, I, CN, hydroxy, nitro, amino, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Alkylamino, the C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 The alkylamino group may be optionally substituted independently with 1, 2, 3, 4 or 5 substituents selected from D, F, Cl, Br, I, CN, oxo (=O), hydroxy, amino and nitro; Ring P is a 4-10 membered nitrogen-containing heterocyclic ring; Each R p are independently H, D, F, Cl, Br, I, CN, hydroxy, amino, nitro, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Alkylamino, the C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 The alkylamino group may be optionally substituted independently with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, CN, oxo (=O), hydroxy, amino and nitro; R 7 and R 8 Each is independently H, D, F, Cl, Br, I, CN, hydroxy, oxo, amino, nitro, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Aminoalkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Haloalkoxy, -C 1-6 Alkylene-C 1-6 Alkoxy, C 2-6 Alkenyl or C 2-6 Alkynyl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Aminoalkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Haloalkoxy, -C 1-6 Alkylene-C 1-6 Alkoxy, C 2-6 Alkenyl and C 2-6 Alkynyl may be optionally substituted independently with 1, 2, 3, 4 or 5 substituents selected from D, F, Cl, Br, I, CN, oxo (=O), hydroxy, amino and nitro; or R 7 With R 8 and the carbon atoms to which they are commonly attached form -C(=O)-, a 3-6 membered carbocyclic ring or a 3-6 membered heterocyclic ring, wherein the 3-6 membered carbocyclic ring or the 3-6 membered heterocyclic ring may be independently and optionally substituted by 1, 2 or 3 substituents selected from D, F, Cl, Br, I, CN, oxo (=O), hydroxyl, amino and nitro; Each R 9 and R 10 are independently H, D, F, Cl, Br, I, CN, hydroxy, oxo, amino, nitro, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Aminoalkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Haloalkoxy, -C 1-6 Alkylene-C 1-6 Alkoxy, C 2-6 Alkenyl or C 2-6 Alkynyl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Aminoalkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Haloalkoxy, -C 1-6 Alkylene-C 1-6 Alkoxy, C 2-6 Alkenyl and C 2-6 Alkynyl may be optionally substituted independently with 1, 2, 3, 4 or 5 substituents selected from D, F, Cl, Br, I, CN, oxo (=O), hydroxy, amino and nitro; or R 9 With R 10 and the carbon atoms to which they are commonly attached form -C(=O)-, a 3-6 membered carbocyclic ring or a 3-6 membered heterocyclic ring, wherein the 3-6 membered carbocyclic ring or the 3-6 membered heterocyclic ring may be independently and optionally substituted by 1, 2 or 3 substituents selected from D, F, Cl, Br, I, CN, oxo (=O), hydroxyl, amino and nitro; R 16 , R 21 and R 22 Each independently is H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Aminoalkyl, -C 1-6 Alkylene-C 1-6 Alkoxy or C 3-6 Cycloalkyl; R 11 , R 12 , R 13 , R 14 , R 15 , R 18 , R 19 and R 20 Each independently represents H, D, F, Cl, Br, I, CN, hydroxyl, amino, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl and 3-6 membered heterocyclyl may be independently optionally substituted with 1, 2, 3, 4 or 5 substituents selected from D, F, Cl, Br, I, CN, oxo (=O), hydroxy, amino and nitro; R 17 H, D, S(=O)2R 23 、S(=O)R 24 、-C(=O)NR 25 R 26 、-C(=O)OR 27 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Aminoalkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Haloalkoxy, -C 1-6 Alkylene-C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Aminoalkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Haloalkoxy, -C 1-6 Alkylene-C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 The aryl and 5-10 membered heteroaryl groups may be independently optionally substituted by 1, 2, 3, 4 or 5 groups selected from D, F, Cl, Br, I, CN, oxo (=O), hydroxy, amino, nitro, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 The C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl may be independently optionally substituted with 1, 2, 3, 4 or 5 substituents selected from D, F, Cl, Br, I, CN, hydroxy, amino and nitro; R 23 , R 24 , R 25 , R 26 and R 27 Each independently is H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Aminoalkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Haloalkoxy, -C 1-6 Alkylene-C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Aminoalkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Haloalkoxy, -C 1-6 Alkylene-C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 The aryl and 5-10 membered heteroaryl groups may be independently optionally substituted by 1, 2, 3, 4 or 5 groups selected from D, F, Cl, Br, I, CN, oxo (=O), hydroxy, amino, nitro, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 The C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl may be independently optionally substituted with 1, 2, 3, 4 or 5 substituents selected from D, F, Cl, Br, I, CN, hydroxy, amino and nitro; m is 0, 1, 2, 3, 4, 5, 6, 7 or 8; n is 0, 1, 2, 3, 4, 5, 6, 7 or 8; y is 1, 2, or 3.

2. The compound according to claim 1, wherein for 3. The compound according to claim 1 or 2, wherein ring P is a 4-6 membered nitrogen-containing heterocycle; Each R p are independently H, D, F, Cl, Br, I, CN, hydroxy, nitro, amino, C 1-3 Alkyl, C 1-3 Alkoxy or C 1-3 Alkylamino, the C 1-3 Alkyl, C 1-3 Alkoxy and C 1-3 The alkylamino group may be optionally substituted independently with 1, 2 or 3 substituents selected from the group consisting of D, F, Cl, Br, I, CN, oxo (=0), hydroxy, amino and nitro.

4. The compound according to claim 1, wherein for Each R p independently represent H, D, F, Cl, Br, I, CN, hydroxy, nitro, amino, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, N-methylamino or N-ethylamino, and the methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, N-methylamino and N-ethylamino may be independently and optionally substituted with 1, 2, 3, 4 or 5 substituents selected from D, F, Cl, Br, I, CN, oxo (=O), hydroxy, amino and nitro.

5. The compound according to claim 1, wherein ring A is C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; Each R a are independently H, D, F, Cl, Br, I, CN, hydroxy, nitro, amino, C 1-3 Alkyl, C 1-3 Alkoxy or C 1-3 Alkylamino, the C 1-3 Alkyl, C 1-3 Alkoxy and C 1-3 The alkylamino group may be optionally substituted independently with 1, 2, 3, 4 or 5 substituents selected from the group consisting of D, F, Cl, Br, I, CN, oxo (=0), hydroxy, amino and nitro.

6. The compound according to claim 1, wherein ring A is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, Each R a independently represent H, D, F, Cl, Br, I, CN, hydroxy, nitro, amino, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, N-methylamino or N-ethylamino, and the methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, N-methylamino and N-ethylamino may be independently and optionally substituted with 1, 2, 3, 4 or 5 substituents selected from D, F, Cl, Br, I, CN, oxo (=O), hydroxy, amino and nitro.

7. A compound according to any one of claims 1 to 6, wherein R 7 and R 8 Each independently represents H, D, F, Cl, Br, I, CN, hydroxyl, amino, nitro, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Aminoalkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, C 1-3 Haloalkoxy, -C 1-3 Alkylene-C 1-3 Alkoxy, C 2-3 Alkenyl or C 2-3 Alkynyl, the C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Aminoalkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, C 1-3 Haloalkoxy, -C 1-3 Alkylene-C 1-3 Alkoxy, C 2-3 Alkenyl and C 2-3 The alkynyl group may be optionally substituted independently with 1, 2, 3, 4 or 5 substituents selected from D, F, Cl, Br, I, CN, oxo (=O), hydroxy, amino and nitro; or R 7 With R 8 and the carbon atoms to which they are commonly attached form -C(=O)-, a 3-6 membered carbocyclic ring or a 3-6 membered heterocyclic ring, wherein the 3-6 membered carbocyclic ring and the 3-6 membered heterocyclic ring may be independently and optionally substituted by 1, 2 or 3 substituents selected from D, F, Cl, Br, I, CN, oxo (=O), hydroxyl, amino and nitro; Each R 9 and R 10 are independently H, D, F, Cl, Br, I, CN, hydroxy, amino, nitro, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Aminoalkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, C 1-3 Haloalkoxy, -C 1-3 Alkylene-C 1-3 Alkoxy, C 2-3 Alkenyl or C 2-3 Alkynyl, the C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Aminoalkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, C 1-3 Haloalkoxy, -C 1-3 Alkylene-C 1-3 Alkoxy, C 2-3 Alkenyl and C 2-3 The alkynyl group may be optionally substituted independently with 1, 2, 3, 4 or 5 substituents selected from D, F, Cl, Br, I, CN, oxo (=O), hydroxy, amino and nitro; or R 9 With R 10 and the carbon atoms to which they are commonly attached form -C(=O)-, a 3-6 membered carbocyclic ring or a 3-6 membered heterocyclic ring, wherein the 3-6 membered carbocyclic ring and the 3-6 membered heterocyclic ring may be independently and optionally substituted by 1, 2 or 3 substituents selected from D, F, Cl, Br, I, CN, oxo (=O), hydroxyl, amino and nitro; R 16 , R 21 and R 22 Each independently is H, D, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Aminoalkyl, -C 1-3 Alkylene-C 1-3 Alkoxy or C 3-6 Cycloalkyl; R 11 , R 12 , R 13 , R 14 , R 15 , R 18 , R 19 and R 20 Each is independently H, D, F, Cl, Br, I, CN, hydroxyl, amino, nitro, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, C 3-6 Cycloalkyl and 3-6 membered heterocyclyl may be independently optionally substituted with 1, 2, 3, 4 or 5 substituents selected from D, F, Cl, Br, I, CN, oxo (=O), hydroxy, amino and nitro.

8. The compound according to claim 1, wherein R 7 and R 8 Each of them is independently H, D, F, Cl, Br, I, CN, hydroxyl, amino, nitro, methyl, ethyl, n-propyl, isopropyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, hydroxymethyl, hydroxyethyl, aminomethyl, aminoethyl, methoxy, ethoxy, n-propoxy, isopropoxy, N-methylamino, N-ethylamino, -OCHF2, -OCF3, -OCHFCH2F, -OCF2CHF2, -OCH2CF3, -OCH2CF2CHF2, -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, -CH2CH2OCH2CH3, vinyl, allyl, ethynyl, propargyl or 1-propynyl, wherein the methyl, ethyl, n- Propyl, isopropyl, -CHF2, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, hydroxymethyl, hydroxyethyl, aminomethyl, aminoethyl, methoxy, ethoxy, n-propoxy, isopropoxy, N-methylamino, N-ethylamino, -OCHF2, -OCHFCH2F, -OCF2CHF2, -OCH2CF3, -OCH2CF2CHF2, -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, -CH2CH2OCH2CH3, vinyl, allyl, ethynyl, propargyl and 1-propynyl may be independently optionally substituted with 1, 2, 3, 4 or 5 substituents selected from D, F, Cl, Br, I, CN, oxo (=O), hydroxy, amino and nitro; or R 7 With R 8 and the carbon atom to which they are commonly attached form -C(=O)-, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl or morpholinyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl and morpholinyl may be independently and optionally substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, CN, oxo (=O), hydroxyl, amino and nitro; Each R 9 and R 10 and 1-propynyl. R, isopropyl, -CHF2, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, hydroxymethyl, hydroxyethyl, aminomethyl, aminoethyl, methoxy, ethoxy, n-propoxy, isopropoxy, N-methylamino, N-ethylamino, -OCHF2, -OCHFCH2F, -OCF2CHF2, -OCH2CF3, -OCH2CF2CHF2, -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, -CH2CH2OCH2CH3, vinyl, allyl, ethynyl, propargyl and 1-propynyl may be independently optionally substituted with 1, 2, 3, 4 or 5 substituents selected from D, F, Cl, Br, I, CN, oxo (=O), hydroxy, amino and nitro; or R 9 With R 10 and the carbon atom to which they are commonly attached form -C(=O)-, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl or morpholinyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl and morpholinyl may be independently and optionally substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, CN, oxo (=O), hydroxyl, amino and nitro; R 16 , R 21 and R 22 Each is independently H, D, methyl, ethyl, n-propyl, isopropyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, hydroxymethyl, hydroxyethyl, aminomethyl, aminoethyl, -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, -CH2CH2OCH2CH3, cyclopropyl or cyclobutyl; R 11 , R 12 , R 13 , R 14 , R 15 , R 18 , R 19 and R 20 Each is independently H, D, F, Cl, Br, I, CN, hydroxy, amino, nitro, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, N-methylamino, N-ethylamino, cyclopropyl, cyclobutyl, azetidinyl or oxetan-3-yl, and the methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, N-methylamino, N-ethylamino, cyclopropyl, cyclobutyl, azetidinyl and oxetan-3-yl may be independently and optionally substituted with 1, 2, 3, 4 or 5 substituents selected from D, F, Cl, Br, I, CN, oxo (=O), hydroxy, amino and nitro.

9. The compound according to claim 1, wherein R 17 H, D, S(=O)2R 23 、S(=O)R 24 、-C(=O)NR 25 R 26 、-C(=O)OR 27 , C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Aminoalkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, C 1-3 Haloalkoxy, -C 1-3 Alkylene-C 1-3 Alkoxy, C 2-3 Alkenyl, C 2-3 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Aminoalkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, C 1-3 Haloalkoxy, -C 1-3 Alkylene-C 1-3 Alkoxy, C 2-3 Alkenyl, C 2-3 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 The aryl and 5-10 membered heteroaryl groups may be independently and optionally substituted with 1, 2, 3, 4 or 5 substituents selected from D, F, Cl, Br, I, CN, oxo (=O), hydroxyl, amino, nitro, phenyl and naphthyl, and the phenyl and naphthyl groups may be independently and optionally substituted with 1, 2, 3, 4 or 5 substituents selected from D, F, Cl, Br, I, CN, hydroxyl, amino and nitro. R 23 , R 24 , R 25 , R 26 and R 27 Each independently is H, D, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Aminoalkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, C 1-3 Haloalkoxy, -C 1-3 Alkylene-C 1-3 Alkoxy, C 2-3 Alkenyl, C 2-3 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Aminoalkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, C 1-3 Haloalkoxy, -C 1-3 Alkylene-C 1-3 Alkoxy, C 2-3 Alkenyl, C 2-3 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 The aryl and 5-10 membered heteroaryl groups may be independently and optionally substituted with 1, 2, 3, 4 or 5 substituents selected from D, F, Cl, Br, I, CN, oxo (=O), hydroxyl, amino, nitro, phenyl and naphthyl, and the phenyl and naphthyl groups may be independently and optionally substituted with 1, 2, 3, 4 or 5 substituents selected from D, F, Cl, Br, I, CN, hydroxyl, amino and nitro.

10. The compound according to claim 1, wherein R 17 H, D, S(=O)2R 23 、S(=O)R 24 、-C(=O)NR 25 R 26 、-C(=O)OR 27 , methyl, ethyl, n-propyl, isopropyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, hydroxymethyl, hydroxyethyl, aminomethyl, aminoethyl, methoxy, ethoxy, n-propoxy, isopropoxy, N-methylamino, N-ethylamino, -OCHF2, -OCF3, -OCHFCH2F, -OCF2CHF2, -OCH2CF3, -OCH2CF2CHF2, -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, -CH2CH2OCH2CH3, vinyl, allyl, ethynyl, propargyl, 1-propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, The methyl, ethyl, n-propyl, isopropyl, -CHF2, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, hydroxymethyl, hydroxyethyl, aminomethyl, aminoethyl, methoxy, ethoxy, n-propoxy, isopropoxy, N-methylamino, N-ethylamino, -OCHF2, -OCHFCH2F, -OCF2CHF2, -OCH2CF3, -OCH2CF2CHF2, -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, -CH2CH2OCH2CH3, vinyl, allyl, ethynyl, propargyl, 1-propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, It may be independently and optionally substituted with 1, 2, 3, 4 or 5 substituents selected from D, F, Cl, Br, I, CN, oxo (=O), hydroxyl, amino, nitro, phenyl and naphthyl, and the phenyl and naphthyl may be independently and optionally substituted with 1, 2, 3, 4 or 5 substituents selected from D, F, Cl, Br, I, CN, hydroxyl, amino and nitro. R 23 , R 24 , R 25 , R 26 and R 27 Each is independently H, D, methyl, ethyl, n-propyl, isopropyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, hydroxymethyl, hydroxyethyl, aminomethyl, aminoethyl, methoxy, ethoxy, n-propoxy, isopropoxy, N-methylamino, N-ethylamino, -OCHF2, -OCF3, -OCHFCH2F, -OCF2CHF2, -OCH2CF3, -OCH2CF2CHF2, -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, -CH2CH2OCH2CH3, vinyl, allyl, ethynyl, propargyl, 1-propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, The methyl, ethyl, n-propyl, isopropyl, -CHF2, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, hydroxymethyl, hydroxyethyl, aminomethyl, aminoethyl, methoxy, ethoxy, n-propoxy, isopropoxy, N-methylamino, N-ethylamino, -OCHF2, -OCHFCH2F, -OCF2CHF2, -OCH2CF3, -OCH2CF2CHF2, -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, -CH2CH2OCH2CH3, vinyl, allyl, ethynyl, propargyl, 1-propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, It may be independently and optionally substituted with 1, 2, 3, 4 or 5 substituents selected from D, F, Cl, Br, I, CN, oxo (=O), hydroxyl, amino, nitro, phenyl and naphthyl, and the phenyl and naphthyl may be independently and optionally substituted with 1, 2, 3, 4 or 5 substituents selected from D, F, Cl, Br, I, CN, hydroxyl, amino and nitro.

11. The compound according to claim 1, which is a compound having one of the following structures or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of a compound having one of the following structures:

12. A pharmaceutical composition comprising the compound according to any one of claims 1 to 11; the pharmaceutical composition optionally further comprises a pharmaceutically acceptable excipient, carrier, adjuvant or any combination thereof.

13. Use of the compound according to any one of claims 1 to 11 or the pharmaceutical composition according to claim 12 in the preparation of a medicament for preventing, treating or alleviating a disease mediated by a RIPK1 inhibitor in a patient.

14. The use according to claim 13, wherein The disease mediated by the RIPK1 inhibitor is an inflammatory disease, an autoimmune disease, a neurodegenerative disease or a tumor.

15. The use according to claim 13, wherein The disease mediated by the RIPK1 inhibitor is idiopathic pulmonary fibrosis, graft-versus-host disease, ulcerative colitis, rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, systemic inflammatory response syndrome, lupus erythematosus, Alzheimer's disease, psoriasis, non-alcoholic fatty hepatitis, osteoarthritis, inflammatory bowel disease, acute ischemic stroke, neurodegenerative disease, frontotemporal dementia, Parkinson's disease, peripheral vascular disease, intermittent claudication, irritable bowel disease, irritable bowel syndrome, Crohn's disease, myocardial infarction, stroke, traumatic brain injury, atherosclerosis, sepsis, pancreatitis, retinitis pigmentosa, retinal degeneration, chronic kidney disease, post-infectious lung injury, acute respiratory distress syndrome or chronic obstructive pulmonary disease.

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