Bicyclic compound, preparation method therefor and use thereof

Abstract

Disclosed in the present invention are a bicyclic compound and a use thereof in a drug. The present invention specifically relates to a novel bicyclic compound and a pharmaceutical composition containing the compound. The present invention further relates to a method for preparing the compound and a use of the compound or the pharmaceutical composition in the preparation of a drug for treating a disease and / or condition mediated by an RIPK1 inhibitor, particularly in the preparation of a drug for treating diseases such as 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

Bicyclic compounds and their preparation methods and applications

[0001] This application claims priority to:

[0002] CN202311874145.X, with a filing date of December 29, 2023; Technical Field

[0003] The present invention relates to the technical field of chemical medicine, and in particular to a bicyclic compound and a preparation method and 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. Necrosis, on the other hand, is a recently discovered, independent form of programmed cell death that is regulated by death signals and exhibits necrosis-like structural features. This novel cell death mechanism is termed "programmed necrosis" or "necroptosis" (Degterev et al., 2005). These two mechanisms are distinct cell death mechanisms.

[0005] Receptor-interacting protein kinase 1 (RIPK1) is a protein with specific serine / threonine kinase activity. It shares a similar N-terminal kinase domain with other protein kinases, but possesses distinct binding domains. Studies have shown that RIPK1 regulates programmed cell death through the RIPK1 / RIPK3 / MLKL signaling axis, playing a key role in the process of programmed cell death.

[0006] Dysregulation of necroptosis signaling pathways is closely associated with inflammatory diseases (Khandia et al, 2016), such as systemic inflammatory response syndrome (SIRS), osteoarthritis, pancreatitis, and nonalcoholic steatohepatitis (Vandenabeele et al, 2010). Studies have shown that TNFα-induced SIRS disease models are highly correlated with RIPK1-dependent necroptosis (Duprez et al, 2011).

[0007] Programmed cell death 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) (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) (Ofengeim et al, 2015).

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

[0010] In addition, programmed cell necrosis is also involved in the process of pulmonary fibrosis, post-infectious lung injury, acute respiratory distress syndrome or chronic obstructive pulmonary disease (Lee et al, 2018; Sagel et al, 2015), peripheral vascular disease, atherosclerosis, myocardial infarction, acute ischemic stroke, intermittent claudication (Feoktistova and Leverkus, 2015; Hepatology et al, 2013; Schreiber et al, 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] Currently, researchers have conducted a number of studies to find therapeutic agents that can effectively inhibit RIPK1. PCT applications WO2020088194, WO2019213447, WO2018237370, WO2020146858, WO2021203011, WO2021046447, WO2021046407, WO2021046382, WO2022192533, and WO2022052861 disclose numerous small molecule compounds that are used as RIPK1 inhibitors to prevent or treat RIPK1-related diseases. However, there is still an urgent need for more and better RIPK1 inhibitors in clinical practice. Summary of the Invention

[0012] The present invention provides a compound, or a pharmaceutical composition thereof, that is useful as a RIPK1 inhibitor. The present invention further relates to the use of the compound or pharmaceutical composition thereof for preparing a medicament for treating a disease and / or condition by inhibiting RIPK1. The present invention further describes a method for synthesizing the compound. The compound of the present invention exhibits excellent biological activity and pharmacokinetic properties.

[0013] Specifically:

[0014] In one aspect, the present invention relates to 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 represented by formula (I).

[0015] in:

[0016] X is N or CR 15 ;

[0017] Y1 is C or N;

[0018] Y2 is N, O, S, or CR 16 or NR 18 ;

[0019] Y3 is N, O, S, or CR 17 or NR 19 ;

[0020] Y4 is C or N;

[0021] Ring A is C 6-10 Aryl or 5-10 membered heteroaryl;

[0022] Each R a are independently H, D, F, Cl, Br, I, CN, Hydroxyl, 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 Alkylamino 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;

[0023] R 1 、R 2 、R 4 、R 5 、R 6 and R 7 Each independently represents H, D, F, Cl, Br, I, CN, hydroxyl, amino, nitro, 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, C2-6 Alkenyl or C 2-6 Alkynyl, 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 and C 2-6 Alkynyl 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 1 With R 2 、R 4 With R 5 、R 6 With R 7 Each of the 3- to 6-membered carbon ring and the 3- to 6-membered heterocyclic ring optionally forms -C(=O)-, a 3- to 6-membered carbon ring or a 3- to 6-membered heterocyclic ring with the carbon atom to which they are commonly attached, wherein the 3- to 6-membered carbon ring or the 3- to 6-membered heterocyclic ring may be independently and optionally substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, CN, oxo (=O), hydroxy, amino and nitro;

[0024] R 3 、R 13 、R 18 and R 19 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;

[0025] R 8 、R 9 、R 10 、R 11 、R 12 、R 15 、R 16 and R 17 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 1-6Alkoxy, 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;

[0026] R 14 H, D, -S(=O)2R 20 、-S(=O)R 21 、-C(=O)NR 22 R 23 、-C(=O)OR 24 、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 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 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 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 substituted with aryl and 5-10 membered heteroaryl substituents, 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;

[0027] R20 、R 21 、R 22 、R 23 and R 24 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 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, 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 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 substituted with aryl and 5-10 membered heteroaryl substituents, 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;

[0028] n is 1, 2, 3, 4, 5, 6, 7 or 8.

[0029] In some embodiments, for

[0030] In some embodiments, Ring A is C 6-10 Aryl or 5-10 membered heteroaryl;

[0031] Each R a are independently H, D, F, Cl, Br, I, CN, Hydroxyl, 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 Alkylamino groups 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.

[0032] In some embodiments, Ring A is phenyl, naphthyl,

[0033] Each R a are 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, wherein the methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, N-methylamino and N-ethylamino 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.

[0034] In some embodiments, wherein R 1 、R 2 、R 4 、R 5 、R 6 and R 7 Each independently represents H, D, F, Cl, Br, I, CN, hydroxyl, amino, nitro, 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 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, C1-3 Alkylamino, C 1-3 Halogenated alkoxy, -C 1-3 Alkylene-C 1-3 Alkoxy, C 2-3 Alkenyl or C 2-3 Alkynyl 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 1 With R 2 、R 4 With R 5 、R 6 With R 7 They are optionally each formed with the carbon atom to which they are commonly attached, -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 optionally substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, CN, oxo (=O), hydroxyl, amino and nitro;

[0035] R 3 、R 13 、R 18 and R 19 Each independently is H, 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;

[0036] R 8 、R 9 、R 10 、R 11 、R 12 、R 15 、R 16 and R 17 Each independently represents 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.

[0037] In some embodiments, R 1 、R 2 、R 4 、R 5 、R 6 and R 7 Each is 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, 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 are 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 1 With R 2 、R 4 With R 5 、R 6 With R 7 Each of the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl and morpholinyl radicals optionally forms -C(=O)-, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl and morpholinyl radicals with the carbon atom to which they are attached, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl and morpholinyl radicals may be independently and optionally substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, CN, oxo (=O), hydroxy, amino and nitro radicals;

[0038] R 3 、R 13 、R 18 and R 19Each 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;

[0039] R 8 、R 9 、R 10 、R 11 、R 12 、R 15 、R 16 and R 17 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 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, R 14 H, D, S(=O)2R 20 、S(=O)R 21 、-C(=O)NR 22 R 23 、-C(=O)OR 24 、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, 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 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3aminoalkyl, 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, C 2-3 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl 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, 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, hydroxy, amino and nitro.

[0041] R 20 、R 21 、R 22 、R 23 、R 24 Each independently is H, D, 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, 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 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, C 2-3 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10Aryl and 5-10 membered heteroaryl 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, 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, hydroxy, amino and nitro.

[0042] In some embodiments, R 14 H, D, S(=O)2R 20 、S(=O)R 21 、-C(=O)NR 22 R 23 、-C(=O)OR 24 , 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 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.

[0043] R 20 、R 21 、R 22 、R 23 and R 24 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 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.

[0044] In some embodiments, the compound of the present invention 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:

[0045] In one aspect, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) of the present invention, or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.

[0046] In one aspect, the present invention relates to the use of the aforementioned compound or a pharmaceutical composition thereof in the preparation of a medicament for preventing, treating or alleviating a disease mediated by a RIPK1 inhibitor in a patient.

[0047] In some embodiments, the disease mediated by the RIPK1 inhibitor of the present invention is an inflammatory disease, an autoimmune disease, a neurodegenerative disease or a tumor.

[0048] In some embodiments, 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, 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.

[0049] In another aspect, the present invention relates to methods for preparing, isolating and purifying the compounds encompassed by formula (I).

[0050] The foregoing description only summarizes certain aspects of the present invention, but is not intended to limit the present invention to these aspects. These and other aspects will be described in more detail and fully below.

[0051] Definitions and General Terms

[0052] The present invention will list the literature corresponding to the specific content of the invention in detail, and the examples are accompanied by diagrams of structural formulas and chemical formulas. The present invention is intended to cover all options, variations and equivalents that may be included in the existing invention field as defined by the claims. Those skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which can be applied to the practice of the present invention. The present invention is in no way limited to the description of methods and materials. There are many documents and similar materials that differ or conflict with the present application, including but not limited to the definition of terms, the usage of terms, the technology described, or the scope controlled by the present application.

[0053] The following definitions apply to the present invention unless otherwise indicated. For purposes of the present invention, the chemical elements are defined according to the Periodic Table of the Elements, CAS version, and the Chemical Handbook, 75th Ed, 1994. In addition, general principles of organic chemistry are described in "Organic Chemistry," by 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, all of which are incorporated herein by reference.

[0054] The term "comprising" is an open expression, that is, including the contents specified in the present invention, but not excluding other contents.

[0055] Compounds as described herein may optionally be substituted with one or more substituents, as described in the general formulae of the present invention, or as described in the specific examples, subclasses, and classes of compounds encompassed by the present invention. It should be understood that the term "optionally substituted" is used interchangeably with the term "substituted or unsubstituted." In general, the term "optionally," whether preceded by the term "substituted," indicates that one or more hydrogen atoms in a given structure are replaced with the specified substituent. Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group. When more than one position in a given formula can be substituted with one or more substituents selected from the specified group, the substituents may be the same or different at each position.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, heterocyclyl, 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) 2 OH, -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 the like.

[0056] As used herein, the term "alkyl" includes saturated linear or branched monovalent hydrocarbon groups of 1-20 carbon atoms, or 1-10 carbon atoms, or 1-6 carbon atoms, or 1-4 carbon atoms, or 1-3 carbon atoms, or 1-2 carbon atoms, wherein the alkyl group may be independently optionally substituted with one or more substituents described herein. 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)CH2C H3), 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 and n-octyl, etc. The term "alkyl" and its prefix "alkane" as used herein include straight and branched saturated carbon chains. The term "alkylene" or "alkylene" as used herein refers to a saturated divalent hydrocarbon radical derived from a straight or branched saturated hydrocarbon by eliminating two hydrogen atoms. Examples of such radicals include, but are not limited to, methylene, ethylene, and isopropylene, etc.

[0057] The term "alkylene" refers to a saturated divalent hydrocarbon radical derived by removing two hydrogen atoms from a saturated straight-chain or branched hydrocarbon radical. Unless otherwise specified, an alkylene group contains 1-12 carbon atoms. In some embodiments, an alkylene group contains 1-6 carbon atoms; in other embodiments, an alkylene group contains 1-4 carbon atoms; in yet other embodiments, an alkylene group contains 1-3 carbon atoms; and in still other embodiments, an alkylene group contains 1-2 carbon atoms. Examples include methylene (-CH2-), ethylene (-CH2CH2-), isopropylene (-CH(CH3)CH2-), and the like.

[0058] The term "alkenyl" refers to a linear or branched monovalent hydrocarbon radical of 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 unsaturated, i.e., one CC is sp 2 double bond, wherein the alkenyl group can be independently and optionally substituted with one or more substituents described herein, including groups with "trans", "cis" or "E", "Z" orientations, wherein specific examples of alkenyl include, but are not limited to, vinyl (-CH=CH2), allyl (-CH2CH=CH2), and the like.

[0059] The term "alkynyl" refers to a linear or branched monovalent hydrocarbon group of 2-12 carbon atoms, or 2-8 carbon atoms, or 2-6 carbon atoms, or 2-4 carbon atoms, wherein at least one position is unsaturated, i.e., one C—C is an sp triple bond, wherein the alkynyl group may be independently and optionally substituted with one or more substituents described herein. Specific examples of alkynyl include, but are not limited to, ethynyl (-C≡CH), propargyl (-CH2C≡CH), and the like.

[0060] The term "heteroatom" means one or more of O, S, N, P and Si, including C, N, S and P in any oxidation state; in the form of primary, secondary, tertiary amines and quaternary ammonium salts; or in the form of a nitrogen atom in a heterocyclic ring being substituted with a hydrogen, 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 in the form of -CH2- in a heterocyclic ring being oxidized to form -C(=O)-.

[0061] The term "halogen" refers to F, Cl, Br or I.

[0062] The term "deuterium" refers to heavy hydrogen, D.

[0063] As used herein, the term "unsaturated" means that the moiety contains one or more degrees of unsaturation.

[0064] The term "alkoxy" or "alkyloxy" as used herein refers to an alkyl group, as defined herein, attached to the rest of the compound molecule via an oxygen atom. In some embodiments, the alkoxy group is C 1-4 Alkoxy groups; examples thereof include, but are not limited to, methoxy, ethoxy, propoxy, and butoxy, etc., and the alkoxy groups may be independently unsubstituted or substituted with one or more substituents described herein.

[0065] The term "alkylamino" or "alkylamino" as used herein refers to an alkyl group, as defined herein, attached to the rest of the compound molecule via a nitrogen atom. In some embodiments, the alkylamino group is C 1-4 Alkylamino groups; examples thereof include, but are not limited to, methylamino, ethylamino, propylamino, and butylamino groups. The alkylamino groups may be independently unsubstituted or substituted with one or more substituents described herein.

[0066] The term "cycloalkyl," "cycloalkane," or "carbocycle" refers to a monovalent or multivalent monocyclic, bicyclic, or tricyclic carbon ring system containing 3-12 carbon atoms, which may be saturated or contain one or more unsaturated bonds, but never aromatic. In one embodiment, a cycloalkyl group contains 3-10 carbon atoms; in another embodiment, a cycloalkyl group contains 3-8 carbon atoms; and in yet another embodiment, a cycloalkyl group contains 3-6 carbon atoms. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclohexenyl. The cycloalkyl groups may independently be unsubstituted or substituted with one or more substituents described herein.

[0067] The terms "heterocyclyl" and "heterocycle" are used interchangeably herein and refer to a saturated or partially unsaturated monocyclic, bicyclic, or tricyclic ring containing 3 to 12 ring atoms, never including aromatic rings, wherein at least one ring atom is a heteroatom. In one embodiment, "heterocyclyl" or "heterocycle" contains 3 to 10 ring atoms; in one embodiment, "heterocyclyl" or "heterocycle" contains 3 to 8 ring atoms; in another embodiment, "heterocyclyl" or "heterocycle" contains 5 to 8 ring atoms; in yet another embodiment, "heterocyclyl" or "heterocycle" contains 3 to 6 ring atoms; in yet another embodiment, "heterocyclyl" or "heterocycle" contains 5 to 6 ring atoms; in yet another embodiment, "heterocyclyl" or "heterocycle" contains 4 to 6 ring atoms; unless otherwise specified, a heterocyclyl group may be a carbon group or a nitrogen group, and heteroatoms have the meanings as described herein. 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, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxolane, dithiolanyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepine Base, diazepine thiazolinone Examples of heterocyclic groups in which the -CH2- group is replaced by -C(=O)- include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidinyl, 3,5-dioxopiperidinyl, pyrimidinedione, and 5,6-dihydropyridin-2(1H)-one. Examples of heterocyclic groups in which the sulfur atom is oxidized include, but are not limited to, sulfolane and 1,1-dioxothiomorpholinyl. The heterocyclic groups may be optionally substituted with one or more substituents described herein.

[0068] The term "aryl" refers to monocyclic, bicyclic, and tricyclic carbocyclic ring systems containing 6-14 ring atoms, or 6-12 ring atoms, or 6-10 ring atoms, wherein at least one ring is aromatic, wherein each ring comprises 3-7 ring atoms, and has one or more points of attachment to the rest of the molecule. The term "aryl" can be used interchangeably with the term "aromatic ring". Examples of aryl groups include phenyl, naphthyl, and anthracenyl. The aryl groups may be independently optionally substituted with one or more substituents described herein.

[0069] The term "heteroaryl" refers to monocyclic, bicyclic, and tricyclic ring systems containing 5-12 ring atoms, or 5-10 ring atoms, or 5-6 ring atoms, wherein at least one ring system is aromatic and at least one ring system contains one or more heteroatoms, wherein each ring contains 5-7 ring atoms and has one or more points of attachment to the rest of the molecule. The term "heteroaryl" can be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic compound". The heteroaryl group is optionally substituted with one or more substituents described herein. In one embodiment, the 5-10 heteroaryl group contains 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N, wherein the nitrogen atom can be further oxidized.

[0070] Examples of heteroaryl groups include, but are not limited to, furanyl, imidazolyl (e.g., N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), isoxazolyl, oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), pyrrolyl (e.g., N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), pyridinyl, pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyridazinyl, thiazole 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, 1,2,3 ... oxadiazole, pyrazinyl, 1,3,5-triazinyl; also include the following bicyclic rings, but are in no way limited to these bicyclic rings: benzimidazolyl, benzofuranyl, benzothiophenyl, indolyl (such as 2-indolyl), purinyl, quinolyl (such as 2-quinolyl, 3-quinolyl, 4-quinolyl), 1,2,3,4-tetrahydroisoquinolyl, 1,3-benzodioxolyl, indolinyl, isoquinolyl (such as 1-isoquinolyl), [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl and [1,2,4]triazolo[1,5-a]pyridinyl, and the like.

[0071] The term "haloalkyl" or "haloalkoxy" refers to an alkyl or alkoxy group substituted with one or more halogen atoms. Examples include, but are not limited to, trifluoromethyl, trifluoromethoxy, and the like.

[0072] The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups. Examples include, but are not limited to, hydroxymethyl, hydroxyethyl, and the like.

[0073] The term "aminoalkyl" refers to an alkyl group substituted with one or more amino groups. Examples include, but are not limited to, aminomethyl, aminoethyl, and the like.

[0074] As described herein, a substituent group is attached to a ring by a bond to form a ring system, which indicates that the substituent group can be substituted at any substitutable position on the ring. For example, formula (a) indicates that the substituent group R can be substituted at any substitutable position on the pyridine ring.

[0075] As described herein, a ring system formed by a linker attached to a ring (e.g., Formula b) represents that the linker can be attached to the rest of the molecule at any available position on the ring system. Formula b represents that any available position on the octahydrocyclopenta[c]pyrrole ring can be attached to the rest of the molecule.

[0076] In addition, it should be noted that, unless otherwise explicitly stated, the descriptions used throughout this document, “each ... and ... are independently,” “... and ... are each independently,” and “... and ... are respectively independently,” are interchangeable and should be understood in a broad sense. They may mean that in different groups, the specific options expressed by the same symbols do not affect each other, or that in the same group, the specific options expressed by the same symbols do not affect each other.

[0077] Unless otherwise indicated, the structural formulas described herein include all isomeric forms (e.g., enantiomers, diastereomers, geometric isomers, or conformational isomers): for example, R and S configurations containing asymmetric centers, (Z) and (E) isomers of double bonds, and (Z) and (E) conformational isomers. Therefore, individual stereochemical isomers of the compounds of the present invention, or mixtures of such enantiomers, diastereomers, geometric isomers, or conformational isomers thereof, are within the scope of the present invention.

[0078] Unless otherwise indicated, the structural formulas and compounds described herein include all isomeric forms (e.g., enantiomers, diastereomers, geometric isomers, or conformers), N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, and prodrugs. Therefore, individual stereochemical isomers, enantiomers, diastereomers, geometric isomers, conformers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, and prodrugs of the compounds of the present invention are also within the scope of the present invention. Furthermore, unless otherwise indicated, the structural formulas of the compounds described herein include enriched isotopes of one or more different atoms.

[0079] "Metabolite" refers to a product obtained by metabolism in vivo of a specific compound described herein, or a pharmaceutically acceptable salt, analog, or derivative thereof, which exhibits similar activity in vivo or in vitro as the compound of formula (I). The metabolites of a compound can be identified by techniques known in the art, and their activity can be characterized by assays as described herein. Such products can be obtained by administering the compound through oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, or enzymatic cleavage. Accordingly, the present invention includes metabolites of a compound, including metabolites produced by contacting a compound of the present invention with a mammal for a period of time.

[0080] The definitions and conventions of stereochemistry used herein are generally those of 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 the present invention may contain asymmetric centers or chiral centers and therefore exist as different stereoisomers. All stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers, atropisomers, and mixtures thereof, such as racemic mixtures, form part of the present 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 an optically active compound, the prefix D, L or R, S is used to indicate the absolute configuration of the molecule about its chiral center. The prefixes d, l, or (+), (-) are used to designate the sign of rotation of plane-polarized light in a compound. (-) or l means the compound is levorotatory, and the prefix (+) or d means the compound is dextrorotatory. These stereoisomers have the same chemical structure, but their stereostructures are different. Specific stereoisomers can be enantiomers, and a mixture of isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which may result in a lack of stereoselectivity or stereospecificity during chemical reactions. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomers that lacks optical activity.

[0081] The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are interconvertible via a low energy barrier. For example, proton tautomers (i.e., prototropic tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions by reorganization of bonding electrons.

[0082] As used herein, "pharmaceutically acceptable salts" refer to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in S.M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66:1-19, 1977. Pharmaceutically acceptable salts formed with non-toxic acids include, but are not limited to, inorganic acid salts formed by reaction with amino groups, such as hydrochlorides, hydrobromides, phosphates, sulfates, and perchlorates; organic acid salts, such as acetates, oxalates, maleates, tartrates, citrates, succinates, and malonates; or salts obtained by other methods described in the literature, such as ion exchange. Other pharmaceutically acceptable salts include adipate, malate, 2-hydroxypropionate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C 1-4 The present invention also contemplates quaternary ammonium salts formed by any compound containing a N group. Water-soluble or oil-soluble or dispersed products can be obtained by quaternization. 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 counter ions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C 1-8 Sulfonates and aromatic sulfonates.

[0083] The "hydrate" of the present invention refers to an association compound formed when the solvent molecule is water.

[0084] The "solvate" of the present invention refers to an association formed between one or more solvent molecules and the compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol.

[0085] "Esters" herein refer to esters of compounds of formula (I) containing hydroxy groups that are hydrolyzable in vivo. Such esters are, for example, pharmaceutically acceptable esters that hydrolyze in the human or animal body to produce the parent alcohol. Examples of in vivo hydrolyzable esters of compounds of formula (I) containing hydroxy groups include, but are not limited to, phosphate, acetoxymethoxy, 2,2-dimethylpropionyloxymethoxy, alkanoyl, benzoyl, phenylacetyl, alkoxycarbonyl, dialkylcarbamoyl, and N-(dialkylaminoethyl)-N-alkylcarbamoyl groups.

[0086] The "nitrogen oxide" of the present invention refers to when a compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form an N-oxide. Special examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen atoms in nitrogen-containing heterocyclic rings. The corresponding amine can be treated with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., 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 LW Deady (Syn. Comm. 1977, 7, 509-514), for example, in an inert solvent (e.g., dichloromethane), by reacting the amine compound with m-chloroperoxybenzoic acid (MCPBA).

[0087] The term "prodrug" as used in the present invention refers to a compound that is converted into a compound represented by formula (I) in vivo. Such conversion is affected by the hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissues. The prodrug compound of the present invention can be an ester. In the existing invention, esters that can be used 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 containing a hydroxyl group can be acylated to produce a prodrug form. Other prodrug forms include phosphates, such as these phosphate compounds, which are obtained by phosphorylating a hydroxyl group on the parent compound. For a complete discussion of prodrugs, see T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium 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 SJ Hecker et al, Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345.

[0088] Unless otherwise indicated herein or the context clearly indicates a contrary meaning, the terms "a", "an", "the" and similar terms used in the context of the present invention (especially in the context of the claims) may be construed to include both the singular and the plural.

[0089] The term "RIPK1 inhibitor" used herein refers to a substance that can inhibit the activity of RIPK1.

[0090] General synthesis process

[0091] To illustrate the present invention, the following examples are listed. However, it should be understood that the present invention is not limited to these examples, which are only provided to provide methods for practicing the present invention.

[0092] Generally, the compounds of the present invention can be prepared by the methods described herein, wherein the substituents are as defined herein unless otherwise specified. The following reaction schemes and examples are provided to further illustrate the present invention.

[0093] Those skilled in the art will recognize that the chemical reactions described herein can be used to appropriately prepare other compounds of the present invention, and that 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 non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art through modifications, such as appropriate protection of interfering groups, by utilizing other known reagents in addition to those described herein, or by making conventional modifications to the reaction conditions. In addition, the reactions disclosed herein or known reaction conditions are also generally applicable to the preparation of other compounds of the present invention.

[0094] In the examples described below, all temperatures are set forth in degrees Celsius unless otherwise indicated. Reagents were purchased from commercial suppliers such as Anhui Zesheng Technology Co., Ltd., Shanghai Shaoyuan Reagent Co., Ltd., Shanghai Myrel Chemical Technology Co., Ltd., and Shanghai MacLean Biochemical Technology Co., Ltd. and used without further purification. Unless otherwise indicated, general reagents were purchased 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.

[0095] 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.

[0096] The following reactions were generally carried out under a positive pressure of nitrogen or argon or with a drying tube over anhydrous solvents (unless otherwise indicated), reaction flasks were plugged with suitable rubber stoppers, and substrates were introduced via syringe. All glassware was dried.

[0097] The silica gel column was purchased from Tianjin Bona Aijieer Technology Co., Ltd. Silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Plant.

[0098] 1H NMR spectra were recorded on a Bruker 500 MHz NMR spectrometer. 1H NMR spectra were recorded in CDCl3, DMSO-d6, CD3OD, or acetone-d6 solvents (in ppm) using TMS (0 ppm) or chloroform (7.26 ppm) as reference standards. When multiple peaks are present, the following abbreviations are used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broadened), brs (broadened singlet), dd (doublet of doublets), and dt (doublet of triplets). Coupling constants, J, are expressed in Hertz (Hz).

[0099] Low-resolution mass spectrometry (MS) data were collected using an Agilent G6125C quadrupole HPLC-MS (column model: XBridge BEH C18, 4.6 x 50 mm, 2.5 μm, flow rate: 1 mL / min, 6 min). Mobile phase: 0% to 95% (CH3CN) in (H2O containing 0.1% formic acid: CH3CN = 90:10), electrospray ionization (ESI), detection at 210 nm / 254 nm, and DAD.

[0100] Compounds were purified using Cheetah Pro medium-pressure rapid purification preparative chromatography (Tianjin Bona Aijieer Technology Co., Ltd.) at 210 nm / 254 nm with UV detection.

[0101] The following reaction schemes describe the steps for preparing the compounds of the present invention. Unless otherwise indicated, wherein Ring A, X, Y1, Y2, Y3, Y4, R 1 、R 2 、R 3 、R 8 、R 9 、R 10 、R 11 、R 12 Has the definition as described in the present invention.

[0102] Reaction Scheme 1

[0103] The compound represented by formula (3-1) can be prepared by reaction scheme 1: the compound represented by formula (1) and the compound represented by formula (2) react to obtain the compound represented by formula (3-1).

[0104] Reaction Scheme 2

[0105] The compound represented by formula (3-2) can also be prepared by reaction scheme 2: the compound represented by formula (1) is reacted with triphosgene to obtain the compound represented by formula (3-2).

[0106] Reaction Scheme 3

[0107] The compound represented by formula (6) or (7) can be prepared by reaction scheme 3: the compound represented by formula (4) and the compound represented by formula (5) are condensed to obtain the compound represented by formula (6) or (7).

[0108] Reaction Scheme 4

[0109] The compound represented by formula (19) can be prepared by reaction scheme 4: the compound represented by formula (8) and the compound represented by formula (9) react to obtain the compound represented by formula (10). The compound represented by formula (10) reacts with dimethyl sulfoxide and lithium chloride to obtain the compound represented by formula (11). The compound represented by formula (11) is reduced to obtain the compound represented by formula (12). The compound represented by formula (12) reacts with sodium borohydride to obtain the compound represented by formula (13). The compound represented by formula (13) is Boc-protected to obtain the compound represented by formula (14). The compound represented by formula (14) reacts with methanesulfonyl chloride to obtain the compound represented by formula (15). The compound represented by formula (15) undergoes intramolecular cyclization to obtain the compound represented by formula (16). The N-Boc position of the compound represented by formula (16) is removed to obtain the compound represented by formula (17). The compound represented by formula (17) reacts with the compound represented by formula (3-1) or (3-2) to obtain the compound represented by formula (18). The compound represented by formula (18) is coupled with the compound represented by formula (6) or formula (7) to obtain the compound represented by formula (19).

[0110] Reaction Scheme 5

[0111] The compound represented by formula (26) can be prepared by reaction scheme 5: the compound represented by formula (8) and the compound represented by formula (9) react to obtain the compound represented by formula (10). The compound represented by formula (10) reacts with hydrochloric acid and Fe powder to obtain the compound represented by formula (20). The compound represented by formula (20) undergoes intramolecular cyclization to obtain the compound represented by formula (21). The compound represented by formula (21) reacts with the compound represented by formula (22) to obtain the compound represented by formula (23). The compound represented by formula (23) is reduced to produce the compound represented by formula (24). The compound represented by formula (24) reacts with formula (3-1) or (3-2) to obtain the compound represented by formula (25). The compound represented by formula (25) is coupled with the compound represented by formula (6) or formula (7) to obtain the compound represented by formula (26).

[0112] Reaction Scheme 6

[0113] The compound represented by formula (30) can be prepared by reaction scheme 6: the compound represented by formula (21) is fluorinated to produce the compound represented by formula (27). The compound represented by formula (27) is reduced to produce the compound represented by formula (28). The compound represented by formula (28) is reacted with formula (3-1) or (3-2) to produce the compound represented by formula (29). The compound represented by formula (29) is coupled with the compound represented by formula (6) or formula (7) to produce the compound represented by formula (30). DETAILED DESCRIPTION

[0114] The present invention is described below with reference to specific examples. It should be noted that these examples are merely illustrative and do not limit the present invention in any way.

[0115] Example 1 Synthesis of 6'-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(1-(3-fluorophenyl)cyclopropyl)spiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-1'(2'H)-carboxamide (Compound 1)

[0116] Step 1: Synthesis of p-nitrophenyl (1-(3-fluorophenyl)cyclopropyl)carbamate

[0117] 4-Nitrophenyl chloroformate (533 mg, 2.64 mmol) was slowly added to a mixture of 3-fluorophenylcyclopropylamine (200 mg, 1.32 mmol) and diisopropylethylamine (342 mg, 2.65 mmol) in dichloromethane (5 mL) and tetrahydrofuran (5 mL) at 0°C. The mixture was allowed to react at room temperature for 24 hours. The mixture was concentrated under reduced pressure, quenched with water (10 mL), and extracted with ethyl acetate (7 mL x 3). The organic phases were combined and washed sequentially with water (7 mL x 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) = 35%) to yield 413 mg of a white solid.

[0118] LC-MS(ESI):[M+H] + =317.2

[0119] Step 2: Synthesis of (2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)boronic acid

[0120] To a solution of 7-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine (100 mg, 0.47 mmol) and pinacol diboronate (215 mg, 0.85 mmol) in 1,4-dioxane (2 mL) were added potassium acetate (115 mg, 1.17 mmol) and 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (38 mg, 0.05 mmol). The mixture was heated to 100°C under a nitrogen atmosphere and reacted for 8 hours. The mixture was cooled to room temperature, diluted with ethyl acetate (10 mL), filtered through celite, and concentrated under reduced pressure to yield 53 mg of a black liquid. The crude product was used directly in the next reaction.

[0121] LC-MS(ESI):[M+H] + =179.0

[0122] Step 3: Synthesis of diethyl 2-(5-bromo-3-nitropyridin-2-yl)malonate

[0123] 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 allowed to react at room temperature for 14 hours. The reaction mixture was poured into ice water (100 mL) to quench the mixture. Dilute hydrochloric acid was slowly added with stirring to adjust the pH to 3-4. The mixture was extracted with ethyl acetate (60 mL × 3), and the organic phases were combined. The organic phases were washed sequentially 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 the product as a yellow solid.

[0124] LC-MS(ESI):[M+H] + =361.1

[0125] 1 H NMR (500MHz, CDCl3) δ8.87(d,J=2.1Hz,1H),8.62(d,J=2.2Hz,1H),5.46(s,1H),4.37–4.26(m,4H),1.35–1.22(m,6H).

[0126] Step 4: Synthesis of ethyl 2-(3-amino-5-bromopyridin-2-yl)acetate

[0127] To a solution of diethyl 2-(5-bromo-3-nitropyridin-2-yl)malonate (1.10 g, 3.05 mmol) and iron powder (0.51 g, 9.14 mmol) in ethanol (10 mL) was slowly added dropwise hydrochloric acid (0.17 g, 4.57 mmol), then heated to 82°C for 1 hour. Filter through celite, and wash the residue twice with hot ethanol. Saturated sodium bicarbonate solution was slowly added to the filtrate with stirring to adjust the pH to neutral, and the mixture was concentrated under reduced pressure. Dilute with ethyl acetate (20 mL) and stir at room temperature overnight. The organic phase was washed with water (10 mL x 3) and saturated brine (10 mL x 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 yield 405 mg of the product as a brown solid.

[0128] LC-MS(ESI):[M+H] + =259.0

[0129] Step 5: Synthesis of 6-bromo-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one

[0130] Acetic acid (87 mg, 1.45 mmol) was added to a solution of ethyl 2-(3-amino-5-bromopyridin-2-yl)acetate (125 mg, 0.48 mmol) in toluene (4 mL). The mixture was heated to 110°C and reacted for 14 hours. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: EA:PE (v / v) = 10-35%) to give 78 mg of the product as a pale yellow solid.

[0131] LC-MS(ESI):[M+H] + =213.0

[0132] Step 6: Synthesis of 6'-bromospiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridin]-2'(1'H)-one

[0133] 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) were dissolved in DMF (10 mL). Sodium hydride (1.00 g, 25.11 mmol) was added portionwise and allowed to react at room temperature for 18 hours. The reaction mixture was poured into ice water (50 mL) for quenching and extracted with ethyl acetate (30 mL × 3). The organic phases were combined and washed 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 the product as a white solid.

[0134] LC-MS(ESI):[M+H] + =239.1

[0135] Step 7: Synthesis of 6'-bromo-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]

[0136] Sodium borohydride (450 mg, 11.90 mmol) was added to a solution of 6'-bromospiro[cyclopropyl-1,3'-pyrrolo[3,2-b]pyridin]-2'(1'H)-one (570 mg, 2.38 mmol) in THF (40 mL). A 47% boron trifluoride etherate solution (5.10 g, 16.62 mmol) was slowly added dropwise at 0°C. Stirring was continued at 0°C for 10 minutes, then the mixture was warmed to room temperature and reacted for 12 hours. The reaction mixture was quenched by the addition of saturated ammonium chloride solution (10 mL) under ice-cooling, and the mixture was stirred at room temperature overnight. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (30 mL x 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 light yellow solid product.

[0137] LC-MS(ESI):[M+H] + =225.0

[0138] Step 8: Synthesis of 6'-bromo-N-(1-(3-fluorophenyl)cyclopropyl)spiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-1'(2'H)-carboxamide

[0139] Potassium carbonate (184 mg, 1.33 mmol) was added to a solution of 6'-bromo-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine] (150 mg, 0.67 mmol) and p-nitrophenyl (1-(3-fluorophenyl)cyclopropyl)carbamate (210 mg, 0.66 mmol) in DMF (5 mL). The reaction mixture was heated to 80°C for 14 hours. The mixture was cooled to room temperature, quenched with water (25 mL), and extracted with ethyl acetate (20 mL × 3). The organic phases were combined. The organic phases were washed sequentially 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%) to obtain 123 mg of the product as a pale yellow solid.

[0140] LC-MS(ESI):[M+H] + =402.2

[0141] Step 9: Synthesis of 6'-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(1-(3-fluorophenyl)cyclopropyl)spiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-1'(2'H)-carboxamide

[0142] The compound 6'-bromo-N-(1-(3-fluorophenyl)cyclopropyl)spiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-1'(2'H)-carboxamide (60 mg, 0.15 mmol), (2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)boronic acid (53 mg, 0.30 mmol), potassium phosphate (63 mg, 0.30 mmol), and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)palladium(II)] (12 mg, 0.01 mmol) were added to 1,4-dioxane (4 mL) and water (1 mL). The mixture was heated to 85°C under a nitrogen atmosphere and reacted overnight. The mixture was cooled to room temperature and filtered through celite. The mixture was diluted with water (15 mL), extracted with ethyl acetate (8 mL × 3), and the organic phases were combined. The 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) = 10%) to obtain 30 mg of the product as a white solid.

[0143] LC-MS(ESI):[M+H] + =456.3

[0144] 1 H NMR (500MHz, DMSO-d6) δ8.55(d,J=7.0Hz,1H),8.31(d,J=2.1Hz,1H),8.22(d,J=2.1Hz,1H),7.70(s,1H),7.52(d,J=2.0Hz,1H),7.31(q,J=7. 5Hz,1H),7.12–7.02(m,3H),6.97(td,J=8.4,2.5Hz,1H),6.02(s,2H),4.16(s,2H),1.29(s,2H),1.27(d,J=2.8Hz,4H),1.16(d,J=2.9Hz,2H).

[0145] Example 2 Synthesis of 6'-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(1-(4-(trifluoromethyl)phenyl)cyclopropyl)spiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-1'(2'H)-carboxamide (Compound 2)

[0146] Step 1: Synthesis of 1-(1-isocyanatocyclopropyl)-4-(trifluoromethyl)benzene

[0147] A solution of 1-(4-(trifluoromethyl)phenyl)cyclopropylamine (100 mg, 0.50 mmol) and triethylamine (100 mg, 0.99 mmol) in toluene (2 mL) was slowly added to a solution of triphosgene (55 mg, 0.18 mmol) in toluene (3 mL) at 0°C. The reaction mixture was heated to 70°C for 5 hours. The mixture was cooled to room temperature, filtered through celite, and concentrated under reduced pressure to yield 90 mg of an orange viscous solution. The crude product was used directly in the next step.

[0148] Step 2: Synthesis of 6'-bromo-N-(1-(4-(trifluoromethyl)phenyl)cyclopropyl)spiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-1'(2'H)-carboxamide

[0149] A solution of 1-(1-isocyanatocyclopropyl)-4-(trifluoromethyl)benzene (89 mg, 0.39 mmol) in dichloromethane (2 mL) was added to a solution of 6'-bromo-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine] (80 mg, 0.36 mmol) (see the synthesis method in Step 7 of Example 1) and triethylamine (54 mg, 0.53 mmol) in dichloromethane (3 mL) and tetrahydrofuran (1 mL). The mixture was allowed to react at room temperature overnight. The mixture was quenched with water (5 mL) and extracted with ethyl acetate (10 mL × 3). The organic phases were combined. The organic phases were washed with water (10 mL × 3) and saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by slurrying (EA:PE (v / v) = 20%) to obtain 150 mg of an off-white solid product.

[0150] LC-MS(ESI):[M+H] + =452.0

[0151] 1 H NMR (500MHz, DMSO-d6) δ8.03(d,J=2.0Hz,1H),7.98(d,J=2.0Hz,1H),7.80(s,1H),7.62(d,J=8.1Hz ,3H),7.42(d,J=8.2Hz,2H),4.13(s,2H),1.33–1.31(m,4H),1.21–1.20(m,2H),1.14–1.12(m,2H).

[0152] Step 3: Synthesis of 6'-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(1-(4-(trifluoromethyl)phenyl)cyclopropyl)spiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-1'(2'H)-carboxamide

[0153] To a mixed solution of 6'-bromo-N-(1-(4-(trifluoromethyl)phenyl)cyclopropyl)spiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-1'(2'H)-carboxamide (150 mg, 0.33 mmol) and (2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)boronic acid (150 mg, 0.84 mmol) (see the synthesis method of Step 2 in Example 1) in 1,4-dioxane (6 mL) and water (1.5 mL) were added potassium phosphate (176 mg, 0.83 mmol) and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)palladium(II)] (52 mg, 0.07 mmol), and the mixture was heated to 85°C under a nitrogen atmosphere and reacted overnight. Cool to room temperature and filter through celite. Dilute with water (20 mL), extract with ethyl acetate (15 mL × 3), and combine the organic phases. The organic phases are washed sequentially 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) = 10-50%) to obtain 53 mg of the product as a light brown solid.

[0154] LC-MS(ESI):[M+H] + =506.2

[0155] 1 H NMR (500MHz, DMSO-d6) δ8.54(d,J=7.0Hz,1H),8.32(d,J=2.1Hz,1H),8.22(d,J=2.0Hz,1H),7.78(s,1H),7.63(d,J=8.2Hz,2H),7.52(d,J=2.0 Hz,1H),7.44(d,J=8.1Hz,2H),7.09(dd,J=7.0,2.0Hz,1H),6.02(s,2H) ,4.17(s,2H),1.39–1.32(m,4H),1.32–1.26(m,2H),1.19–1.15(m,2H).

[0156] Example 3 Synthesis of (S)-6-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-3,3-difluoro-N-(1-(3-fluorophenyl)ethyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxamide (Compound 3)

[0157] Step 1: Synthesis of 6-bromo-3,3-difluoro-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one

[0158] To a solution of 6-bromo-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one (6.90 g, 32.39 mmol) (see the synthesis method in Step 5 of Example 1) in DMF (300 mL) was slowly added sodium hydride (3.24 g, 80.97 mmol) at 0°C. Stirring was continued at 0°C for 10 min, followed by the addition of a solution of N-fluorobisbenzenesulfonamide (20.43 g, 64.78 mmol) in DMF (50 mL). The mixture was allowed to react at 0°C for 2 h. The reaction mixture was poured into ice water (1000 mL) for quenching, extracted with ethyl acetate (200 mL x 3), and the organic phases were combined. The organic phase was washed successively with saturated sodium bicarbonate solution (300 mL) and saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent EA:PE (v / v) = 0-10%) to give 3.36 g of a light yellow solid product.

[0159] LC-MS(ESI):[M+H] + =249.1

[0160] Step 2: Synthesis of 6-bromo-3,3-difluoro-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine

[0161] Sodium borohydride (5.10 g, 134.93 mmol) was added to a solution of 6-bromo-3,3-difluoro-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one (4.80 g, 19.28 mmol) in THF (320 mL). A 47% boron trifluoride etherate solution (41.220 g, 134.93 mmol) was slowly added dropwise at 0°C. Stirring was continued at 0°C for 10 minutes, then the mixture was warmed to room temperature and reacted for 6 hours. The reaction mixture was quenched by the addition of saturated ammonium chloride solution (150 mL) under ice-cooling, and the mixture was stirred at room temperature overnight. The mixture was diluted with water (300 mL) and extracted with ethyl acetate (300 mL x 3). The organic phases were combined. The organic phase was washed with saturated brine (300 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (EA:PE (v / v) = 0-15%) to obtain 1.14 g of a light yellow solid product.

[0162] LC-MS(ESI):[M+H] + =234.8

[0163] Step 3: Synthesis of (S)-6-bromo-3,3-difluoro-N-(1-(3-fluorophenyl)ethyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxamide

[0164] (S)-1-Fluoro-3-(1-isocyanatoethyl)benzene (216 mg, 1.31 mmol) (synthesized according to Example 2, Step 1) was added to a solution of 6-bromo-3,3-difluoro-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (70 mg, 0.90 mmol) and triethylamine (90 mg, 0.89 mmol) in dichloromethane (5 mL) and allowed to react overnight at room temperature. The mixture was cooled to room temperature, quenched with water (25 mL), and extracted with ethyl acetate (20 mL × 3). The organic phases were combined. The organic phases were washed sequentially 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) = 20-50%) to obtain 71 mg of the product as a pale yellow solid.

[0165] LC-MS(ESI):[M+H] + =400.0

[0166] Step 4: Synthesis of (S)-6-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-3,3-difluoro-N-(1-(3-fluorophenyl)ethyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxamide

[0167] To a solution of (S)-6-bromo-3,3-difluoro-N-(1-(3-fluorophenyl)ethyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxamide (60 mg, 0.15 mmol) and (2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)boronic acid (53 mg, 0.30 mmol) (see the synthesis method of Step 2 in Example 1) in 1,4-dioxane (4 mL) and water (1 mL) were added potassium phosphate (63 mg, 0.30 mmol) and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)palladium(II)] (12 mg, 0.01 mmol). The mixture was heated to 85°C under a nitrogen atmosphere and reacted overnight. The mixture was cooled to room temperature and filtered through celite. The mixture was diluted with water (15 mL), extracted with ethyl acetate (8 mL × 3), and the organic phases were combined. The 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 obtain 4 mg of an off-white solid product.

[0168] LC-MS(ESI):[M+H] + =454.0

[0169] 1H NMR (500MHz, DMSO-d6) δ8.71–8.68(m,1H),8.62(d,J=7.0Hz,1H),8.54(s,1H),7.69(s,1H),7.44(d,J=7.4Hz,1H),7.37(q,J=7.4Hz,1H), 7.28–7.23(m,2H),7.17(d,J=6.9Hz,1H),7.08–7.02(m,1H),6.09(s,2H),4.96(t,J=7.4Hz,1H),4.68–4.51(m,2H),1.47(d,J=7.1Hz,3H).

[0170] Example 4 Synthesis of (S)-6'-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(1-(3-fluorophenyl)ethyl)spiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-1'(2'H)-carboxamide (Compound 4)

[0171] To (S)-6'-bromo-N-(1-(3-fluorophenyl)ethyl)spiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-1'(2'H)-carboxamide (0.86 g, 2.21 mmol) (synthetic method of Reference Example 1) and (2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)boronic acid (0.78 g, 4.43 mmol) (step 1 of Reference Example 1) were added. To a mixed solution of 1,4-dioxane (20 mL) and water (5 mL) prepared according to the synthesis method of step 2, potassium phosphate (1.17 g, 5.53 mmol) and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)palladium(II)] (348 mg, 0.44 mmol) were added. The mixture was heated to 85°C under a nitrogen atmosphere and reacted overnight. The mixture was cooled to room temperature and filtered through celite. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (25 mL × 3). The organic phases were combined. The organic phases were washed sequentially with water (25 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:DCM (v / v) = 50%) to obtain 709 mg of the product as a light brown solid.

[0172] LC-MS(ESI):[M+H] + =444.2

[0173] 1H NMR(500MHz,DMSO-d6)δ8.56(d,J=7.0Hz,1H),8.31(d,J=2.0Hz,1H),8.21(d,J=2.0Hz, 1H),7.53(d,J=2.0Hz,1H),7.37(q,J=7.6Hz,1H),7.27–7.22(m,2H),7.15(d,J=7.8Hz, 1H),7.09(dd,J=7.0,2.0Hz,1H),7.04(td,J=8.9,2.2Hz,1H),6.02(s,2H),5.03–4.93( m,1H),4.25–4.16(m,2H),1.46(d,J=7.1Hz,3H),1.29–1.26(m,2H),1.21–1.14(m,2H).

[0174] Example 5 Synthesis of 6'-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(1-(4-(trifluoromethyl)phenyl)cyclopropyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxamide (Compound 5)

[0175] Step 1: Synthesis of 6-bromo-N-(1-(4-(trifluoromethyl)phenyl)cyclopropyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxamide

[0176] A solution of 1-(1-isocyanatocyclopropyl)-4-(trifluoromethyl)benzene (176 mg, 0.77 mmol) in dichloromethane (3 mL) was added to a solution of 6-bromo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (140 mg, 0.70 mmol) (see the synthesis method in Example 1) and triethylamine (142 mg, 1.41 mmol) in dichloromethane (3 mL) and tetrahydrofuran (3 mL). The mixture was allowed to react overnight at room temperature. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (EA:PE (v / v) = 10-30%) to obtain 91 mg of the product as a brownish-yellow solid.

[0177] LC-MS(ESI):[M+H] + =425.9

[0178] Step 2: Synthesis of 6'-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(1-(4-(trifluoromethyl)phenyl)cyclopropyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxamide

[0179] To a solution of 6-bromo-N-(1-(4-(trifluoromethyl)phenyl)cyclopropyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxamide (90 mg, 0.21 mmol) and (2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)boronic acid (75 mg, 0.42 mmol) in 1,4-dioxane (4 mL) and water (1 mL) were added potassium phosphate (112 mg, 0.53 mmol) and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)palladium(II)] (33 mg, 0.04 mmol). The mixture was heated to 85°C under a nitrogen atmosphere and reacted overnight. The mixture was cooled to room temperature and filtered through celite. The mixture was diluted with water (20 mL), extracted with ethyl acetate (15 mL × 3), and the organic phases were combined. The 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 EA:DCM (v / v) = 10-50%) to obtain 69 mg of an off-white solid product.

[0180] LC-MS(ESI):[M+H] + =480.2

[0181] 1 H NMR (500MHz, DMSO-d6) δ8.55(d,J=7.0Hz,1H),8.38(d,J=2.1Hz,1H),8.26(d,J=2.1Hz,1H),7.83(s,1H),7.62(d,J=8.2Hz,2H),7.5 3(s,1H),7.43(d,J=8.1Hz,2H),7.12–7.07(m,1H),6.02(s,2H),4.10(t,J=8.7Hz,2H),3.29–3.23(m,2H),1.35(s,2H),1.34(s,2H).

[0182] Example 6 Synthesis of 6-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(1-(3-fluorophenyl)cyclopropyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxamide (Compound 6)

[0183] To a solution of 6'-bromo-N-(1-(3-fluorophenyl)cyclopropyl)spiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-1'(2'H)-carboxamide (154 mg, 0.41 mmol) and (2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)boronic acid (146 mg, 0.82 mmol) in 1,4-dioxane (8 mL) and water (2 mL) were added potassium phosphate (217 mg, 1.02 mmol) and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)palladium(II)] (64 mg, 0.08 mmol). The mixture was stirred and heated to 85°C under a nitrogen atmosphere overnight. The mixture was cooled to room temperature and filtered through celite. The mixture was diluted with water (20 mL), extracted with ethyl acetate (10 mL × 3), and the organic phases were combined. The organic phases were washed successively with water (10 mL × 2) and saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent EA:DCM (v / v) = 35%) to obtain 95 mg of the product as a light brown solid.

[0184] LC-MS(ESI):[M+H] + =430.1

[0185] 1 H NMR(500MHz,DMSO-d6)δ8.56(d,J=7.0Hz,1H),8.39–8.36(m,1H),8.27(s,1H),7.76(s,1H),7.54(s,1H),7.31(q,J=7.5Hz,1H),7.13–7.0 8(m,1H),7.08–7.01(m,2H),6.97(td,J=8.6,2.5Hz,1H),6.03(s,2H),4.09(t,J=8.8Hz,2H),3.29–3.24(m,2H),1.30(s,2H),1.28(s,2H).

[0186] Example 7 Synthesis of (S)-6'-(2-aminobenzo[d]thiazol-6-yl)-N-(1-(4-fluorophenyl)ethyl)spiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-1'(2'H)-carboxamide (Compound 7)

[0187] Step 1: Synthesis of tert-butyl (6-bromobenzo[d]thiazol-2-yl)carbamate

[0188] To a solution of 6-bromobenzo[d]thiazol-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 allowed to react at room temperature overnight. The mixture was concentrated under reduced pressure, and a 7 mol / L ammonia solution in methanol (2 mL, 14.00 mmol) was added and allowed to react at room temperature for 2 hours. The mixture was concentrated under reduced pressure, slurried with water (5 mL), filtered, and dried to yield 710 mg of a light yellow solid.

[0189] LC-MS(ESI):[M-55] + =272.9

[0190] Step 2: Synthesis of tert-butyl (6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)carbamate

[0191] 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]palladium dichloride dichloromethane complex (176 mg, 0.22 mmol). The mixture was heated to 100°C under a nitrogen atmosphere and reacted overnight. The mixture was cooled to room temperature and filtered through celite. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic phases were combined and washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield 730 mg of the product as a black viscous substance. The crude product was used directly in the next step.

[0192] LC-MS(ESI):[M+H] + =377.2

[0193] Step 3: Synthesis of tert-butyl (S)-(6-(1'-((1-(4-fluorophenyl)ethyl)carbamoyl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridin-6'-yl)benzo[d]thiazol-2-yl)carbamate

[0194] To the reaction mixture was added (S)-6'-bromo-N-(1-(4-fluorophenyl)ethyl)spiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-1'(2'H)-carboxamide (125 mg, 0.32 mmol) and tert-butyl (6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)carbamate (241 mg, 0.64 mmol). To a mixed solution of 1,4-dioxane (4 mL) and water (1 mL) containing 2-(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)palladium(II) (136 mg, 0.64 mmol) was added. The mixture was placed under a nitrogen atmosphere and heated to 85°C for overnight reaction. The mixture was cooled to room temperature and filtered through celite. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (15 mL x 3). The organic phases were combined, washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent EA:PE (v / v) = 0-50%) to obtain 90 mg of a dark yellow solid.

[0195] LC-MS(ESI):[M+H] + =560.2

[0196] Step 4: Synthesis of (S)-6'-(2-aminobenzo[d]thiazol-6-yl)-N-(1-(4-fluorophenyl)ethyl)spiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-1'(2'H)-carboxamide

[0197] To a solution of tert-butyl (S)-(6-(1'-((1-(4-fluorophenyl)ethyl)carbamoyl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridin]-6'-yl)benzo[d]thiazol-2-yl)carbamate (90 mg, 0.16 mmol) in dichloromethane (1 mL) was slowly added dropwise at 0°C. The mixture was allowed to react at room temperature for 1 hour. The mixture was concentrated under reduced pressure, diluted with water (10 mL), and extracted with dichloromethane (10 mL x 3). The organic phases were combined. The organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield 41 mg of the product as an orange solid.

[0198] LC-MS(ESI):[M+H] + =460.2

[0199] 1H NMR(500MHz,DMSO-d6)δ8.18–8.14(m,2H),7.89(d,J=1.9Hz,1H),7.52(s,2H),7.47–7.35(m,4H),7.17–7.10(m,2H),7.0 6(d,J=7.6Hz,1H),4.98–4.91(m,1H),4.15(d,J=2.4Hz,2H),1.44(d,J=7.0Hz,3H),1.25–1.22(m,2H),1.14–1.11(m,2H).

[0200] Example 8 Synthesis of (S)-6-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(1-(6-fluoropyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxamide (Compound 8)

[0201] Step 1: Synthesis of (R,E)-N-((6-fluoropyridin-3-yl)methylene)-2-methylpropane-2-sulfonamide

[0202] To a solution of 6-fluoronicotinaldehyde (1.00 g, 7.99 mmol) in tetrahydrofuran (20 mL) was added tetraisopropyl titanate (4.54 g, 15.99 mmol) dropwise and stirred at room temperature for 10 minutes. (R)-2-methylpropane-2-sulfonamide (0.97 g, 7.99 mmol) was then added and allowed to react at 50°C for 4 hours. The mixture was cooled to room temperature and quenched with saturated brine (20 mL). The mixture was filtered through celite and the filtrate was extracted with ethyl acetate (10 mL x 3). The collected organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield 1.15 g of a white solid product.

[0203] LC-MS(ESI):[M+H] + =229.2

[0204] Step 2: Synthesis of (R)-N-((S)-1-(6-fluoropyridin-3-yl)ethyl)-2-methylpropane-2-sulfonamide

[0205] To a solution of (R,E)-N-((6-fluoropyridin-3-yl)methylene)-2-methylpropane-2-sulfonamide (3.30 g, 14.46 mmol) in tetrahydrofuran (100 mL) was slowly added dropwise a 3M methylmagnesium bromide solution in diethyl ether (33.7 mL, 101.22 mmol) at -20°C. The reaction was continued at -20°C for 1 hour. The mixture was quenched by the dropwise addition of saturated aqueous ammonium chloride (20 mL) at -20°C, and extracted with ethyl acetate (100 mL x 3). The organic phase was collected, washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by silica gel column chromatography (eluent: EA:PE (v / v) = 0-20%) afforded 532 mg of the product as a white solid.

[0206] LC-MS(ESI):[M+H] + =245.3

[0207] 1 H NMR(500MHz,DMSO-d6)δ8.21(d,J=2.6Hz,1H),8.00–7.93(m,1H),7.15(dd,J=8.5,2.8H z,1H),5.50(d,J=5.5Hz,1H),4.52(p,J=6.7Hz,1H),1.49(d,J=6.8Hz,3H),1.11(s,9H).

[0208] Step 3: Synthesis of (S)-1-(6-fluoropyridin-3-yl)ethane-1-amine hydrochloride

[0209] A solution of (R)-N-((S)-1-(6-fluoropyridin-3-yl)ethyl)-2-methylpropane-2-sulfonamide (240 mg, 0.98 mmol) in dichloromethane (5 mL) was cooled to 0°C and slowly added dropwise with a 4 mol / L hydrochloric acid solution in dioxane (1.7 mL, 6.80 mmol). The mixture was allowed to react at room temperature for 2 hours. The mixture was concentrated under reduced pressure to yield 140 mg of a white solid product.

[0210] LC-MS(ESI):[M-35.5] + =141.1

[0211] Step 4: Synthesis of 4-nitrophenyl (S)-(1-(6-fluoropyridin-3-yl)ethyl)carbamate

[0212] To a solution of (S)-1-(6-fluoropyridin-3-yl)ethane-1-amine hydrochloride (130 mg, 0.74 mmol) in dichloromethane (5 mL) was added N,N-diisopropylethylamine (381 mg, 2.94 mmol). A solution of p-nitrophenyl chloroformate (297 mg, 1.47 mmol) in tetrahydrofuran (5 mL) was added dropwise under a cold water bath. The mixture was allowed to react at room temperature overnight. The mixture was quenched with water (10 mL) and extracted with dichloromethane (10 mL x 3). The collected organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent EA:PE (v / v) = 0-20%) to obtain 110 mg of a white solid.

[0213] Step 5: Synthesis of (S)-6-bromo-N-(1-(6-fluoropyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxamide

[0214] To a solution of 4-nitrophenyl (S)-(1-(6-fluoropyridin-3-yl)ethyl)carbamate (107 mg, 0.35 mmol) and 6-bromo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (70 mg, 0.35 mmol) in N,N-dimethylformamide (7 mL) was added potassium carbonate (122 mg, 0.88 mmol) and heated to 80°C overnight. The reaction was quenched by the addition of water (30 mL) and extracted with ethyl acetate (15 mL × 3). The collected organic phase was washed with saturated brine (15 mL × 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent EA:PE (v / v) = 0-40%) to give 60 mg of the product as a light yellow solid.

[0215] LC-MS(ESI):[M] + =365.1

[0216] Step 6: Synthesis of (S)-6-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(1-(6-fluoropyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxamide

[0217] To a mixed solution of (S)-6-bromo-N-(1-(6-fluoropyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxamide (60 mg, 0.16 mmol) and (2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)boronic acid (58 mg, 0.33 mmol) in 1,4-dioxane (4 mL) and water (1 mL) were added potassium phosphate (87 mg, 0.41 mmol) and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)palladium(II)] (13 mg, 0.02 mmol). The mixture was heated to 85°C under a nitrogen atmosphere and reacted overnight. The mixture was cooled to room temperature and filtered through celite. The filtrate was diluted with water (10 mL) and extracted with ethyl acetate (10 mL × 3). The collected organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated and purified by Prep-HPLC (eluent CH3CN:H2O (v / v) = 50%) to give 3 mg of a white solid product.

[0218] LC-MS(ESI):[M+H] + =419.3

[0219] 1 H NMR(500MHz,DMSO-d6)δ8.56(d,J=7.0Hz,1H),8.37(d,J=2.0Hz,1H),8.28–8 .23(m,2H),8.06–7.99(m,1H),7.54(d,J=1.9Hz,1H),7.24(d,J=7.7Hz,1H), 7.15(dd,J=8.5,2.7Hz,1H),7.09(dd,J=7.0,2.0Hz,1H),6.03(s,2H),5.03( p,J=7.2Hz,1H),4.17–4.01(m,2H),3.28–3.24(m,2H),1.50(d,J=7.1Hz,3H).

[0220] Example 9 Synthesis of 6'-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3,5-difluoro-2-((tetrahydropyran-4-yl)oxy)benzyl)spiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-1'(2'H)-carboxamide (Compound 9)

[0221] Step 1: Synthesis of 3,5-difluoro-2-((tetrahydropyran-4-yl)oxy)benzonitrile

[0222] To a solution of tetrahydropyran-4-ol (390 mg, 3.82 mmol) in tetrahydrofuran (9 mL) at 0°C, sodium hydride (92 mg, 2.29 mmol) was added. The mixture was reacted at 0°C under a nitrogen atmosphere for 10 min. 2,3,5-Trifluorobenzonitrile (300 mg, 1.91 mmol) was then added, and the mixture was heated to 55°C and allowed to react overnight. After cooling to room temperature, saturated aqueous ammonium chloride (5 mL) was slowly added dropwise to quench the reaction. The mixture was extracted with ethyl acetate (15 mL x 3), and the organic phases were combined. The organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield 602 mg of the product as an orange viscous substance. The crude product was used directly in the next step.

[0223] Step 2: Synthesis of 3,5-difluoro-2-((tetrahydropyran-4-yl)oxy)benzylamine

[0224] To a solution of 3,5-difluoro-2-((tetrahydropyran-4-yl)oxy)benzonitrile (457 mg, 1.91 mmol) in tetrahydrofuran (5 mL) at 0°C under a nitrogen atmosphere was added a 1 M borane tetrahydrofuran complex solution (13.4 mL, 13.37 mmol) and heated to 65°C overnight. The mixture was cooled to 0°C and quenched with methanol (5 mL) and diluted with ethyl acetate (15 mL). The organic phase was washed sequentially with saturated aqueous ammonium chloride (15 mL) and saturated brine (15 mL). The organic phase was collected, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel thin layer chromatography (eluent: DCM:MeOH (v / v) = 10:1) to obtain 75 mg of the product as a light yellow viscous substance.

[0225] LC-MS(ESI):[M+H] + =244.2

[0226] Step 3: Synthesis of 4-(2,4-difluoro-6-(isocyanomethyl)phenoxy)tetrahydropyran

[0227] To a solution of triphosgene (34 mg, 0.11 mmol) in toluene (3 mL) was added a solution of 3,5-difluoro-2-((tetrahydropyran-4-yl)oxy)benzylamine (75 mg, 0.31 mmol) and triethylamine (62 mg, 0.62 mmol) in toluene (2 mL) at 0°C. The mixture was heated to 70°C for 5 h. The mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to obtain 72 mg of a yellow viscous product.

[0228] LC-MS (ESI): no signal peak

[0229] Step 4: Synthesis of 6'-bromo-N-(3,5-difluoro-2-((tetrahydropyran-4-yl)oxy)benzyl)spiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-1'(2'H)-carboxamide

[0230] To a solution of 6'-bromo-1'-, 2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine] (50 mg, 0.22 mmol) and triethylamine (45 mg, 0.45 mmol) in tetrahydrofuran (5 mL) was added a solution of 4-(2,4-difluoro-6-(isocyanomethyl)phenoxy)tetrahydropyran (72 mg, 0.27 mmol) in dichloromethane (5 mL) at 0°C and allowed to react overnight at room temperature. The mixture was quenched with water (5 mL) and extracted with dichloromethane (10 mL x 3). The organic phases were collected, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent EA:PE (v / v) = 0-30%) to give 58 mg of the product as an off-white solid.

[0231] LC-MS(ESI):[M] + =494.1

[0232] 1 H NMR (500MHz, DMSO-d6) δ8.07(d,J=2.0Hz,1H),7.99(d,J=2.0Hz,1H),7.45–7.40(m,1H),7.22–7.15(m,1H),7.04–6.99(m,1H),4.39(d,J=5 .7Hz,2H),4.28–4.21(m,1H),4.14(s,2H),3.92–3.86(m,2H),3.42–3.33(m,2H),1.97–1.92(m,2H),1.73–1.63(m,2H),1.22–1.11(m,4H).

[0233] Step 5: Synthesis of 6'-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3,5-difluoro-2-((tetrahydropyran-4-yl)oxy)benzyl)spiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-1'(2'H)-carboxamide

[0234] Potassium phosphate (47 mg, 0.22 mmol) and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)palladium(II)] (9 mg, 0.01 mmol) were added to a mixed solution of 6'-bromo-N-(3,5-difluoro-2-((tetrahydropyran-4-yl)oxy)benzyl)spiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-1'(2'H)-carboxamide (55 mg, 0.11 mmol) and (2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)boronic acid (92-2) (30 mg, 0.17 mmol) in 1,4-dioxane (4 mL) and water (1 mL), placed under a nitrogen atmosphere, and heated to 80°C for reaction overnight. Cool to room temperature and filter through celite. Dilute with water (10 mL) and extract with ethyl acetate (10 mL x 3). Combine the organic phases. Wash with saturated brine (10 mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Purify by silica gel column chromatography (eluent: MeOH:DCM (v / v) = 0-10%) to obtain 28 mg of a brown solid. Purify by HPLC to obtain 8 mg of a white solid product.

[0235] LC-MS(ESI):[M+H] + =548.2

[0236] 1 H NMR (500MHz, DMSO-d6) δ8.57(d,J=7.0Hz,1H),8.32(d,J=2.0Hz,1H),8.25(d,J=2.0Hz,1H),7. 54(d,J=2.0Hz,1H),7.40(t,J=5.9Hz,1H),7.22–7.15(m,1H),7.13–7.08(m,1H),7.06–7.01(m ,1H),6.02(s,2H),4.43(d,J=5.6Hz,2H),4.29–4.22(m,1H),4.18(s,2H),3.92–3.86(m,2H),3 .43–3.36(m,2H),2.04–1.92(m,3H),1.73–1.64(m,2H),1.29–1.26(m,2H),1.20–1.17(m,2H).

[0237] Example 10 Synthesis of 6-(2-(cyclopropanecarboxamide)benzo[d]thiazol-6-yl)-3,3-difluoro-N-(1-(3-fluorophenyl)cyclopropyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxamide (Compound 10)

[0238] Step 1: Synthesis of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-amine

[0239] To a solution of 6-bromobenzo[d]thiazol-2-amine (95 mg, 0.41 mmol) and 4,4,4',4',5,5',5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane) (208 mg, 0.82 mmol) in 1,4-dioxane (10 mL) was added potassium acetate (102 mg, 1.04 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (34 mg, 0.04 mmol). The mixture was heated to 90°C under a nitrogen atmosphere and reacted overnight. The mixture was cooled to room temperature and filtered through celite. The residue was washed with a mixture of DCM and MeOH (10:1) (30 mL x 3). The filtrate was dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield 106 mg of a black solid, which was used directly in the next reaction.

[0240] LC-MS(ESI):[M+H] + =277.2

[0241] Step 2: Synthesis of 6-(2-(cyclopropanecarboxamido)benzo[d]thiazol-6-yl)-3,3-difluoro-N-(1-(3-fluorophenyl)cyclopropyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxamide

[0242] To a mixed solution of 6-bromo-3,3-difluoro-N-(1-(3-fluorophenyl)cyclopropyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxamide (53 mg, 0.13 mmol) (synthesis method according to Example 3) and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-amine (80 mg, 0.29 mmol) in water (2 mL) and 1,4-dioxane (10 mL) were added potassium phosphate (55 mg, 0.26 mmol) and tetrakis(triphenylphosphine)palladium (15 mg, 0.01 mmol). The mixture was heated to 90°C under a nitrogen atmosphere and reacted overnight. The mixture was cooled to room temperature, filtered through celite, and the residue was washed with a mixture of DCM and MeOH (10:1) (10 mL x 3). The filtrate was washed successively with water (10 mL × 3) and saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by high performance liquid chromatography to obtain 5 mg of a white solid product.

[0243] LC-MS(ESI):[M+H] + =482.3

[0244] 1H NMR (500MHz, DMSO-d6) δ8.65(s,1H),8.56(s,1H),8.11(s,1H),7.99(s,1H),7.68(s,2H),7.60(d,J=7.5Hz,1H),7.47(d,J=6.2Hz ,1H),7.37(d,J=5.4Hz,1H),7.20–7.09(m,2H),7.07–6.98(m,1H),4.58(t,J=16.9Hz,2H),1.42–1.36(m,2H),1.36–1.34(m,2H).

[0245] Example 11 Synthesis of 6'-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(2-chloro-4-fluorobenzyl)spiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-1'(2'H)-carboxamide (Compound 11)

[0246] Step 1: Synthesis of 2-chloro-4-fluoro-1-(isocyanomethyl)benzene

[0247] Dissolve triphosgene (48.2 mg, 0.16 mmol) in toluene (5 mL) and add (2-chloro-4-fluorophenyl)methanamine (70 mg, 0.44 mmol) and triethylamine (44.4 mg, 0.44 mmol) dissolved in toluene (2 mL) dropwise with stirring at 0°C. Heat to 70°C and react for 5 h. After the reaction is complete, filter, wash the filter cake with toluene (5 mL x 3), collect the filtrate, and concentrate under reduced pressure. This yields 70 mg of a colorless, transparent liquid, which is used directly in the next step.

[0248] Step 2: Synthesis of 6'-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(2-chloro-4-fluorobenzyl)spiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-1'(2'H)-carboxamide

[0249] Compound 7-(1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridin]-6'-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (45 mg, 0.16 mmol) and triethylamine (32.7 mg, 0.32 mmol) were dissolved in a mixture of dichloromethane (5 mL) and tetrahydrofuran (1 mL). 2-Chloro-4-fluoro-1-(isocyanatomethyl)benzene (45 mg, 0.24 mmol) dissolved in a mixture of dichloromethane (1 mL) and tetrahydrofuran (0.2 mL) was added dropwise with stirring at 0°C. After addition, the mixture was allowed to warm to room temperature and react overnight. The mixture was concentrated under reduced pressure, and the crude product was purified by high-performance liquid chromatography to yield 11.7 mg of a white solid product.

[0250] LC-MS(ESI):[M+H] + =464.1

[0251] 1 H NMR (500MHz, DMSO-d6) δ8.58(d,J=6.8Hz,1H),8.33(s,1H),8.25(s,1H),7.54(s,1H),7.53–7.39(m,3H),7.21(t,J=8. 1Hz,1H),7.11(d,J=6.6Hz,1H),6.03(s,2H),4.41(d,J=4.5Hz,2H),4.18(s,2H),1.34–1.27(m,2H),1.21–1.13(m,2H).

[0252] Example 12 Synthesis of (S)-6'-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(1-(3,4-difluorophenyl)ethyl)spiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-1'(2'H)-carboxamide (Compound 12)

[0253] Step 1: Synthesis of (S)-1,2-difluoro-4-(1-isocyanatoethyl)benzene

[0254] A solution of (S)-1-(3,4-difluorophenyl)ethanamine (400 mg, 2.55 mmol) and triethylamine (515 mg, 5.09 mmol) in toluene (10 mL) was slowly added to a solution of triphosgene (279 mg, 0.94 mmol) in toluene (15 mL) at 0°C. The reaction temperature was raised to 70°C and the mixture was reacted for 5 hours. The mixture was cooled to room temperature, filtered through celite, and concentrated under reduced pressure to yield 456 mg of a white solid. The crude product was used directly in the next step.

[0255] Step 2: Synthesis of (S)-6'-bromo-N-(1-(3,4-difluorophenyl)ethyl)spiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-1'(2'H)-carboxamide

[0256] A solution of (S)-1,2-difluoro-4-(1-isocyanatoethyl)benzene (456 mg, 2.49 mmol) in dichloromethane (4 mL) was added to a solution of 6'-bromo-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine] (348 mg, 1.55 mmol) and triethylamine (313 mg, 3.09 mmol) in dichloromethane (6 mL) and tetrahydrofuran (2 mL). The mixture was allowed to react at room temperature overnight. The mixture was then concentrated under reduced pressure. The product was isolated and purified by silica gel column chromatography (EA:PE (v / v) = 10%) to give 558 mg of the product as an off-white solid.

[0257] LC-MS(ESI):[M+H] + =408.0

[0258] 1 H NMR(500MHz, CDCl3)δ8.26(d,J=2.0Hz,1H),8.01(d,J=2.0Hz,1H),7.20–7.07(m,3H),5.05(t,J=6.9Hz,1H) ,4.65(d,J=6.8Hz,1H),4.00(d,J=3.3Hz,2H),1.53(d,J=7.0Hz,3H),1.44–1.40(m,2H),1.08–1.04(m,2H).

[0259] Step 3: Synthesis of (S)-6'-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(1-(3,4-difluorophenyl)ethyl)spiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-1'(2'H)-carboxamide

[0260] To a solution of (S)-6'-bromo-N-(1-(3,4-difluorophenyl)ethyl)spiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-1'(2'H)-carboxamide (180 mg, 0.44 mmol) and (2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)boronic acid (156.0 mg, 0.88 mmol) in 1,4-dioxane (8 mL) and water (2 mL) were added potassium phosphate (234 mg, 1.10 mmol) and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)palladium(II)] (69 mg, 0.09 mmol). The mixture was heated to 85°C under a nitrogen atmosphere and reacted overnight. The mixture was cooled to room temperature and filtered through celite. The mixture was diluted with water (20 mL), extracted with ethyl acetate (15 mL × 3), and the organic phases were combined. The 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 EA:DCM (v / v) = 10-50%) to obtain 57 mg of a white solid product.

[0261] LC-MS(ESI):[M+H] + =462.1

[0262] 1 H NMR (500MHz, DMSO-d6) δ8.56(d,J=7.0Hz,1H),8.30(d,J=2.1Hz,1H),8.21(d,J=2.1Hz,1H),7.5 3(d,J=2.1Hz,1H),7.46(ddd,J=12.1,7.8,2.2Hz,1H),7.41–7.32(m,1H),7.27–7.23(m,1H),7. 15(d,J=7.6Hz,1H),7.09(dd,J=7.0,2.0Hz,1H),6.02(s,2H),4.95(p,J=7.2Hz,1H),4.21(d,J= 9.9Hz,1H),4.16(d,J=9.9Hz,1H),1.44(d,J=7.1Hz,3H),1.29–1.26(m,2H),1.20–1.16(m,2H).

[0263] Example 13 Synthesis of (S)-6-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(1-(2-fluorophenyl)ethyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxamide (Compound 13)

[0264] Step 1: Synthesis of (S)-1-fluoro-2-(1-isocyanoethyl)benzene

[0265] To a solution of triphosgene (78.9 mg, 0.27 mmol) in toluene (5 mL) was added dropwise (S)-1-(2-fluorophenyl)ethane-1-amine (100 mg, 0.72 mmol) and triethylamine (145.4 mg, 1.44 mmol) dissolved in toluene (2 mL) at 0°C. After addition, the mixture was heated to 70°C and allowed to react for 5 h. After completion of the reaction, the mixture was filtered, the filter cake was washed with toluene (5 mL x 3), and the filtrate was collected and concentrated under reduced pressure. 84 mg of a colorless, transparent liquid was obtained, which was used directly in the next reaction.

[0266] Step 2: Synthesis of (S)-6-bromo-N-(1-(2-fluorophenyl)ethyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxamide

[0267] To a mixed solution of 6-bromo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (67 mg, 0.34 mmol) and triethylamine (233.8 mg, 2.31 mmol) in dichloromethane (5 mL) and tetrahydrofuran (1 mL) was added dropwise (S)-1-fluoro-2-(1-isocyanatoethyl)benzene (83.4 mg, 0.50 mmol) dissolved in a mixed solution of dichloromethane (2 mL) and tetrahydrofuran (0.4 mL) at 0°C. The mixture was allowed to react overnight at room temperature. The mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (EA:PE = 50-70%) to give 59 mg of the product as a white solid.

[0268] LC-MS(ESI):[M+H] + =364.2

[0269] Step 3: Synthesis of (S)-6-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(1-(2-fluorophenyl)ethyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxamide

[0270] To a mixed solution of (S)-6-bromo-N-(1-(2-fluorophenyl)ethyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxamide (69 mg, 0.19 mmol) and (2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)boronic acid (67.4 mg, 0.38 mmol) in water (1 mL) and 1,4-dioxane (5 mL) were added potassium phosphate (80.4 mg, 0.38 mmol) and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (29.8 mg, 0.04 mmol), and the mixture was heated to 100°C under a nitrogen atmosphere and reacted overnight. The mixture was cooled to room temperature and filtered. The filtrate was diluted with ethyl acetate (10 mL), washed with water (10 mL × 3) and saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and analyzed by high performance liquid chromatography to obtain 9 mg of a white solid product.

[0271] LC-MS(ESI):[M+H] + =418.3

[0272] 1 H NMR(500MHz,DMSO-d6)δ8.56(d,J=6.4Hz,1H),8.37(s,1H),8.24(s,1H),7.53(d,J=11.7Hz,2H),7.31–7 .07(m,5H),6.03(s,2H),5.29–5.18(m,1H),4.20–4.09(m,2H),3.29–3.27(m,2H),1.47(d,J=6.4Hz,3H).

[0273] Example 14 Synthesis of tert-butyl (6-(1'-((1-(3-fluorophenyl)cyclopropyl)carbamoyl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-6'-yl)benzo[d]thiazol-2-yl)carbamate (Compound 14)

[0274] Compound 14 was prepared by referring to the method of Example 7.

[0275] LC-MS(ESI):[M+H] + =472.1

[0276] 1H NMR (500MHz, DMSO-d6) δ8.20–8.16(m,2H),7.90(s,1H),7.65(s,1H),7.55–7.51(m,2H),7.43(d,J=8.4Hz,1H),7.36(d,J=8. 3Hz,1H),7.31(q,J=7.3Hz,1H),7.09–7.02(m,2H),6.97(t,J=8.7Hz,1H),4.14(s,2H),1.29–1.25(m,6H),1.14–1.09(m,2H).

[0277] Example 15 Synthesis of 6'-(2-aminophenyl[d]triazol-6-yl)-N-(1-(4-(trifluoromethyl)phenyl)cyclopropyl)spiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-1'(2'H)-carboxamide (Compound 15)

[0278] Compound 15 was prepared by referring to the method of Example 7.

[0279] LC-MS(ESI):[M+H] + =522.20

[0280] 1 H NMR (500MHz, DMSO-d6) δ8.21(s,2H),7.99(s,1H),7.77(s,1H),7.63(d,J=8.2Hz,2H),7.52(d,J=8.4Hz,1 H),7.47–7.40(m,3H),4.17(s,2H),3.57(s,2H),1.37–1.31(m,4H),1.29–1.26(m,2H),1.17–1.14(m,2H).

[0281] Example 16 Synthesis of 6'-(2-aminobenzo[d]thiazol-6-yl)-N-(1-(4-fluorophenyl)cyclopropyl)spiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-1'(2'H)-carboxamide (Compound 16)

[0282] Compound 16 was prepared by referring to the method of Example 7.

[0283] LC-MS(ESI):[M+H] + =472.1

[0284] 1H NMR (500MHz, DMSO-d6) δ8.17(s,2H),7.89(d,J=1.9Hz,1H),7.64(s,1H),7.52(s,2H),7.42(d,J=8.3,1.8Hz,1H),7.37(d,J=8.2Hz, 1H),7.33–7.28(m,2H),7.11–7.06(m,2H),4.11(s,2H),1.32–1.28(m,2H),1.27–1.25(m,2H),1.20–1.16(m,2H),1.13–1.09(m,2H).

[0285] Example 17 Synthesis of (S)-6'-(2-aminobenzo[d]thiazol-6-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)spiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-1'(2'H)-carboxamide (Compound 17)

[0286] Compound 17 was prepared by referring to the method of Example 7.

[0287] LC-MS(ESI):[M+H] + =610.2

[0288] 1 H NMR (500MHz, DMSO-d6) δ8.18–8.13(m,2H),7.88(d,J=1.9Hz,1H),7.69(d,J=8.0Hz,2H),7.63(d,J=7.9Hz,2H),7.52(s,2H),7.43–7. 35(m,2H),7.18(d,J=7.4Hz,1H),5.04–4.97(m,1H),4.24–4.14(m,2H),1.47(d,J=7.1Hz,3H),1.26–1.23(m,2H),1.15–1.12(m,2H).

[0289] Example 18 Synthesis of (S)-6'-(2-aminobenzo[d]thiazol-6-yl)-N-(1-(3-fluorophenyl)ethyl)spiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-1'(2'H)-carboxamide (Compound 18)

[0290] Compound 18 was prepared by referring to the method of Example 7.

[0291] LC-MS(ESI):[M+H] + =460.2

[0292] 1 H NMR(500MHz,DMSO-d6)δ8.18–8.14(m,2H),7.89(d,J=2.0Hz,1H),7.52(s,2H),7 .42(dd,J=8.4,1.9Hz,1H),7.39–7.34(m,2H),7.24(d,J=8.7Hz,2H),7.09(d,J= 7.7Hz,1H),7.06–7.01(m,1H),5.00–4.92(m,1H),4.20(d,J=9.9Hz,1H),4.15(d ,J=9.9Hz,1H),1.45(d,J=7.1Hz,3H),1.24(q,J=3.0Hz,2H),1.15–1.12(m,2H).

[0293] Example 19 Synthesis of (S)-6'-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(1-(3,5-difluorophenyl)ethyl)spiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-1'(2'H)-carboxamide (Compound 19)

[0294] Compound 19 was prepared by referring to the method of Example 2.

[0295] LC-MS(ESI):[M+H] + =462.2

[0296] 1 H NMR (500MHz, DMSO-d6) δ8.55(d,J=6.9Hz,1H),8.31(d,J=1.3Hz,1H),8.21(d,1H),7.52(s,1H),7.19–7.11(m,3H),7.10–7.02( m,2H),6.02(s,2H),4.25(d,J=9.9Hz,1H),4.16(d,J=9.8Hz,1H),1.44(d,J=7.0Hz,3H),1.28–1.26(m,2H),1.20–1.15(m,2H).

[0297] Example 20 Synthesis of (S)-6'-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(1-(4-fluorophenyl)ethyl)spiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-1'(2'H)-carboxamide (Compound 20)

[0298] Compound 20 was prepared by referring to the method of Example 2.

[0299] LC-MS(ESI):[M+H] + =444.2

[0300] 1 H NMR (500MHz, DMSO-d6) δ8.56(d,J=7.0Hz,1H),8.30(d,J=2.1Hz,1H),8.21(d,J=2.0Hz,1H),7.53(d,J=2.0Hz,1H),7.45(dd,J=8.4,5.5H z,2H),7.18–7.07(m,4H),6.03(s,2H),4.97(t,J=7.3Hz,1H),4.18(s,2H),1.45(d,J=7.0Hz,3H),1.30–1.26(m,2H),1.20–1.14(m,2H).

[0301] Example 21 Synthesis of (S)-6'-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)spiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-1'(2'H)-carboxamide (Compound 21)

[0302] Compound 21 was prepared by referring to the method of Example 2.

[0303] LC-MS(ESI):[M+H] + =494.1

[0304] 1 H NMR (500MHz, DMSO-d6) δ8.55(d,J=7.0Hz,1H),8.31(s,1H),8.20(s,1H),7.69(d,J=7.9Hz,2H),7.63(d,J=8.0Hz,2H),7.52(s,1H),7.23(d,J =7.5Hz,1H),7.08(d,J=7.0Hz,1H),6.02(s,2H),5.04–5.00(m,1H),4.21(d,J=10.1Hz,2H),1.48(d,J=7.1Hz,3H),1.27(s,2H),1.18(s,2H).

[0305] Example 22 Synthesis of 6'-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(1-(5-cyano-2-fluorophenyl)ethyl)spiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-1'(2'H)-carboxamide (Compound 22)

[0306] Compound 22 was prepared by referring to the method of Example 2.

[0307] LC-MS(ESI):[M+H] + =469.3.

[0308] 1 H NMR(500MHz,DMSO-d6)δ8.60–8.51(m,1H),8.34–8.29(m,1H),8.22–8.16(m,1H ),8.07–8.01(m,1H),7.86–7.79(m,1H),7.54–7.50(m,1H),7.47–7.40(m,1H),7 .27–7.19(m,1H),7.12–7.04(m,1H),6.01(s,2H),5.28–5.16(m,1H),4.36–4.2 6(m,1H),4.20–4.13(m,1H),1.46(s,3H),1.32–1.26(m,2H),1.21–1.18(m,2H).

[0309] Example 23 Synthesis of (S)-6'-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(1-(4-cyano-2-fluorophenyl)ethyl)spiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-1'(2'H)-carboxamide (Compound 23)

[0310] Compound 23 was prepared by referring to the method of Example 2.

[0311] 1 H NMR (500MHz, DMSO-d6) δ8.54(d,J=7.0Hz,1H),8.31(d,J=2.0Hz,1H),8.17(d,J=2.0Hz ,1H),7.81(d,J=10.1Hz,1H),7.75–7.67(m,2H),7.51(d,J=2.1Hz,1H),7.30(d,J=7.1H z,1H),7.07(dd,J=7.0,2.0Hz,1H),6.01(s,2H),5.24–5.18(m,1H),4.26(d,J=9.9Hz,1 H),4.20(d,J=9.9Hz,1H),1.45(d,J=7.1Hz,3H),1.29–1.26(m,2H),1.20–1.17(m,2H).

[0312] LC-MS(ESI):[M+H] + =469.2

[0313] Example 24 Synthesis of (S)-6'-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(1-(4-cyano-2-fluorophenyl)ethyl)spiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-1'(2'H)-carboxamide (Compound 24)

[0314] Compound 24 was prepared by referring to the method of Example 2.

[0315] LC-MS(ESI):[M+H] + =494.2

[0316] 1 H NMR (500MHz, DMSO-d6) δ8.55(d,J=7.0Hz,1H),8.30(s,1H),8.19(s,1H),7.69(d,J=8.1Hz,2H),7.63(d,J=8.1Hz,2H),7.52(s,1H),7.23(d,J=7.5H z,1H),7.07(d,J=7.0Hz,1H),6.01(s,2H),5.02(t,J=7.3Hz,1H),4.21(q ,J=9.9Hz,2H),1.48(d,J=7.1Hz,3H),1.18(s,2H),0.85(t,J=6.7Hz,2H).

[0317] Example 25 Synthesis of (S)-6'-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)spiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-1'(2'H)-carboxamide (Compound 25)

[0318] Compound 25 was prepared by referring to the method of Example 2.

[0319] LC-MS(ESI):[M+H] + =510.2

[0320] 1H NMR (500MHz, DMSO--d6) δ8.56(d,J=6.9Hz,1H),8.30(d,J=2.0Hz,1H),8.21(d,J=2.1Hz,1H),7.56–7.51(m,3H),7.31(d,J=8.2Hz,2H),7.17(d,J=7. 6Hz,1H),7.08(d,J=7.0,2.0Hz,1H),6.02(s,2H),5.02–4.96(m,1H),4.23 –4.14(m,2H),1.46(d,J=7.1Hz,3H),1.29–1.25(m,2H),1.19–1.15(m,2H).

[0321] Example 26 Synthesis of (S)-6'-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)spiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-1'(2'H)-carboxamide (Compound 26)

[0322] Compound 26 was prepared by referring to the method of Example 2.

[0323] LC-MS(ESI):[M+H] + =494.3

[0324] 1 H NMR (500MHz, DMSO--d6) δ8.78(d,J=1.9Hz,1H),8.22(d,J=2.0Hz,1H),8.12(d,J=2.0Hz,1H),7.71–7.66(m,2H),7.65–7.60(m,3H),7.40(d,J=9.1 Hz,1H),7.22(d,J=7.4Hz,1H),6.04(s,2H),5.05–4.98(m,1H),4.20(q,J =9.9Hz,2H),1.48(d,J=7.1Hz,3H),1.27–1.23(m,2H),1.17–1.14(m,2H).

[0325] Example 27 Synthesis of (S)-6'-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(1-(2-fluoro-5-(trifluoromethoxy)phenyl)ethyl)spiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-1'(2'H)-carboxamide (Compound 27)

[0326] Compound 27 was prepared by referring to the method of Example 2.

[0327] LC-MS(ESI):[M+H] + =528.2

[0328] 1 H NMR (500MHz, DMSO-d6) δ8.56(d,J=7.0Hz,1H),8.32(s,1H),8.19(s,1H),7.56–7.51(m,2H),7.32(d,J=8.9Hz,2H),7.26(d,J=7.5Hz, 1H),7.09(d,J=7.0Hz,1H),6.02(s,2H),5.26–5.20(m,1H),4.27–4.16(m,2H),1.46(d,J=7.0Hz,3H),1.30–1.27(m,2H),1.20(s,2H).

[0329] Example 28 Synthesis of (S)-6'-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(1-(3-cyano-4-fluorophenyl)ethyl)spiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-1'(2'H)-carboxamide (Compound 28)

[0330] Compound 28 was prepared by referring to the method of Example 2.

[0331] LC-MS(ESI):[M+H] + =456.3

[0332] 1 H NMR(500MHz,DMSO-d6)δ8.56(d,J=6.9Hz,1H),8.33–8.29(m,1H),8.20(d,J=2.2Hz,1 H),7.95(dd,J=6.1,2.4Hz,1H),7.84–7.81(m,1H),7.54–7.45(m,2H),7.18(d,J=7.3H z,1H),7.09(d,J=6.8Hz,1H),6.02(s,2H),5.00(p,J=7.2Hz,1H),4.24(d,J=9.8Hz,1H ),4.16(d,J=9.9Hz,1H),1.46(d,J=7.0Hz,3H),1.30–1.26(m,2H),1.20–1.17(m,2H).

[0333] Example 29 Synthesis of (S)-6'-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(1-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)ethyl)spiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-1'(2'H)-carboxamide (Compound 29)

[0334] Compound 29 was prepared by referring to the method of Example 2.

[0335] LC-MS(ESI):[M+H] + =544.2

[0336] 1 H NMR (500MHz, DMSO-d6) δ8.55(d,J=7.0Hz,1H),8.30(d,J=2.0Hz,1H),8.20(d,J=2.0Hz,1H),7.52(d,J=2.0Hz,1 H),7.23(dd,J=9.8,3.1Hz,1H),7.09(dd,J=7.0,2.0Hz,1H),7.06–7.00(m,2H),7.00–6.96(m,1H),6.01(s,2H) ,5.32–5.27(m,1H),4.63–4.58(m,1H),4.27(d,J=9.9Hz,1H),4.20(d,J=9.9Hz,1H),3.89–3.84(m,2H),3.54–3 .48(m,2H),2.01–1.95(m,2H),1.69–1.62(m,2H),1.39(d,J=6.9Hz,3H),1.28–1.27(m,2H),1.25–1.09(m,2H).

[0337] Example 30 Synthesis of (S)-6'-(2-(cyclopropanecarboxamide)benzo[d]thiazol-6-yl)-N-(1-phenylethyl)spiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-1'(2'H)-carboxamide (Compound 30)

[0338] Compound 30 was prepared by referring to the method of Example 2.

[0339] LC-MS(ESI):[M+H] + =510.2

[0340] 1H NMR (500MHz, DMSO-d6) δ12.65(s,1H),8.24–8.18(m,3H),7.78(d,J=8.1Hz,1H),7.63(d,J=8.5Hz,1H),7.48–7.27(m,4H),7.22(d,J=7.4Hz, 1H),7.08(d,J=7.6Hz,1H),4.97–4.93(m,1H),4.18(s,2H),2.03–2.00(m,1H),1.46(d,J=7.0Hz,3H),1.27–1.24(m,4H),1.07–0.89(m,4H).

[0341] Example 31 Synthesis of (R)-6'-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(1-(3-(trifluoromethoxy)phenyl)ethyl)spiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-1'(2'H)-carboxamide (Compound 31)

[0342] Compound 31 was prepared by referring to the method of Example 2.

[0343] LC-MS(ESI):[M+H] + =510.1.

[0344] 1 H NMR (500MHz, DMSO-d6) δ8.55(d,J=7.1Hz,1H),8.32–8.29(m,1H),8.20(d,J=1.9Hz,1H),7.52(s,1H),7.46–7.44(m,2H),7.40–7.38(m ,1H),7.23–7.19(m,3H),6.01(s,2H),5.05–4.97(m,1H),4.19(q,J=9.8Hz,2H),1.46(d,J=7.1Hz,3H),1.25–1.22(m,2H),1.18(s,2H).

[0345] Example 32 Synthesis of (S)-6'-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(1-(2,4-difluorophenyl)ethyl)spiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-1'(2'H)-carboxamide (Compound 32)

[0346] Compound 32 was prepared by referring to the method of Example 1.

[0347] LC-MS(ESI):[M+H]+ =462.1

[0348] 1 H NMR (500MHz, DMSO-d6) δ8.56(d,J=6.9Hz,1H),8.31(s,1H),8.20(s,1H),7.56(dd,J=18.9,11.7Hz,2H),7.22–7.14(m,2H),7.08 (dd,J=12.8,7.0Hz,2H),6.02(s,2H),5.23–5.14(m,1H),4.21(q,J=9.9Hz,2H),1.44(d,J=6.8Hz,3H),1.27(s,2H),1.18(s,2H).

[0349] Example 33 Synthesis of (S)-6'-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(1-(4-cyanophenyl)ethyl)spiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-1'(2'H)-carboxamide (Compound 33)

[0350] Compound 33 was prepared by referring to the method of Example 2.

[0351] LC-MS(ESI):[M+H] + =451.20

[0352] 1 H NMR(500MHz,Chloroform-d)δ8.27(s,1H),8.24–8.16(m,2H),7.58(d,J=7.8Hz,2H),7.47(s,1H),7.41(d,J=7.9Hz,2H),6.96(d ,J=7.0Hz,1H),5.13–5.04(m,1H),4.76–4.72(m,1H),4.46(s,2H),4.02(s,2H),1.50(d,J=7.0Hz,3H),1.45(s,2H),1.06(s,2H).

[0353] Example 34 Synthesis of (S)-6'-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(1-(5-fluoropyridin-2-yl)ethyl)spiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-1'(2'H)-carboxamide (Compound 34)

[0354] Compound 34 was prepared by referring to the method of Example 2.

[0355] LC-MS(ESI):[M+H] + =445.2

[0356] 1 H NMR(500MHz,DMSO-d6)δ8.56(d,J=7.0Hz,1H),8.50(d,J=2.9Hz,1H),8.31(d,J=2 .1Hz,1H),8.21(d,J=2.0Hz,1H),7.69(td,J=8.8,2.9Hz,1H),7.58–7.51(m,2H), 7.15(d,J=7.5Hz,1H),7.09(dd,J=7.0,2.0Hz,1H),6.03(s,2H),5.05–5.00(m,1H ),4.25–4.17(m,2H),1.48(d,J=7.0Hz,3H),1.28–1.26(m,2H),1.19–1.16(m,2H).

[0357] Example 35 Synthesis of 6'-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(1-(6-(trifluoromethyl)pyridin-3-yl)spiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-1'(2'H)-carboxamide (Compound 35)

[0358] Compound 35 was prepared by referring to the method of Example 2.

[0359] LC-MS(ESI):[M+H] + =495.2

[0360] 1 H NMR(500MHz,DMSO--d6)δ8.83(d,J=2.2Hz,1H),8.55(d,J=7.0Hz,1H),8.31(d,J=2.0Hz,1H),8 .19(d,J=2.1Hz,1H),8.10(dd,J=8.1,2.2Hz,1H),7.88(d,J=8.2Hz,1H),7.52(d,J=2.0Hz,1H), 7.31(d,J=7.3Hz,1H),7.08(dd,J=7.0,2.0Hz,1H),6.02(s,2H),5.12–5.05(m,1H),4.24(d,J= 9.8Hz,1H),4.18(d,J=9.8Hz,1H),1.53(d,J=7.1Hz,3H),1.31–1.25(m,2H),1.21–1.14(m,2H).

[0361] Example 36 Synthesis of (S)-6-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(1-(3-fluorophenyl)ethyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxamide (Compound 36)

[0362] Compound 36 was prepared by referring to the method of Example 5.

[0363] LC-MS(ESI):[M+H] + =418.2

[0364] 1 H NMR(500MHz,DMSO-d6)δ8.56(d,J=7.0Hz,1H),8.36(d,J=2.0Hz,1H),8.25(d ,J=2.1Hz,1H),7.53(s,1H),7.41–7.33(m,1H),7.27–7.22(m,2H),7.20(d,J =7.8Hz,1H),7.09(dd,J=6.9,2.0Hz,1H),7.07–7.00(m,1H),6.03(s,2H),5. 03–4.94(m,1H),4.19–4.05(m,2H),3.29–3.24(m,2H),1.47(d,J=7.1Hz,3H).

[0365] Example 37 Synthesis of (S)-6'-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(1-(2-chloro-4-fluorophenyl)ethyl)spiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-1'(2'H)-carboxamide (Compound 37)

[0366] Compound 37 was prepared by referring to the method of Example 2.

[0367] LC-MS(ESI):[M+H] + =478.1

[0368] 1H NMR (500MHz, DMSO-d6) δ8.67(d,J=6.4Hz,1H),8.34(s,1H),8.22(s,1H),7.70–7.59(m,2H),7.38(d,J=7.1Hz,1H),7.34–7.26 (m,2H),7.26–7.17(m,1H),5.35–5.15(m,1H),4.24(dd,J=25.1,9.5Hz,2H),1.42(d,J=6.4Hz,3H),1.30(s,2H),1.21(s,2H).

[0369] Example 38 Synthesis of (S)-6'-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(1-(2-fluorophenyl)ethyl)spiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-1'(2'H)-carboxamide (Compound 38)

[0370] Compound 38 was prepared by referring to the method of Example 2.

[0371] LC-MS(ESI):[M+H] + =444.2

[0372] 1 H NMR (500MHz, DMSO-d6) δ8.59(d,J=6.9Hz,1H),8.32(d,J=1.6Hz,1H),8.20(d,J=1.6Hz,1H),7.56(s,1H),7.55–7.48(m,1H),7.31– 7.25(m,1H),7.22–7.10(m,4H),5.26–5.20(m,1H),4.26–4.18(m,2H),1.45(d,J=7.0Hz,3H),1.30–1.26(m,2H),1.22–1.17(m,2H).

[0373] Example 39 Synthesis of (S)-6'-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-N-(1-(3,4-difluorophenyl)ethyl)spiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-1'(2'H)-carboxamide (Compound 39)

[0374] Compound 39 was prepared by referring to the method of Example 2.

[0375] LC-MS(ESI):[M+H] + =462.2

[0376] 1 H NMR (500MHz, DMSO-d6) δ8.79(d,J=2.0Hz,1H),8.22(d,J=2.0Hz,1H),8.14(d,J=2.0Hz,1H),7.6 3(dd,J=9.1,1.9Hz,1H),7.47(ddd,J=12.1,7.9,2.2Hz,1H),7.41(d,J=9.1Hz,1H),7.39–7.33(m ,1H),7.24(t,J=6.5Hz,1H),7.12(d,J=7.6Hz,1H),6.04(s,2H),4.94(p,J=7.2Hz,1H),4.21(d,J =9.9Hz,1H),4.15(d,J=9.9Hz,1H),1.44(d,J=7.1Hz,3H),1.27–1.23(m,2H),1.17–1.13(m,2H).

[0377] Example 40 Synthesis of 6-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-3,3-difluoro-N-(1-(3-fluorophenyl)cyclopropyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxamide (Compound 40)

[0378] Compound 40 was prepared by referring to the method of Example 3.

[0379] LC-MS(ESI):[M+H] + =466.4

[0380] 1 H NMR(500MHz,DMSO-d6)δ8.71(s,1H),8.60(d,J=27.6Hz,1H),7.98(s,1H),7.74–7.67(m,1H),7.63–7.40(m,2H),7.36–7.2 9(m,1H),7.24–7.16(m,1H),7.13–7.07(m,1H),7.02–6.94(m,1H),6.10(s,2H),4.55(t,J=15.6Hz,2H),1.36–1.18(m,4H).

[0381] Example 41 Synthesis of 6'-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(1-(3-chlorophenyl)cyclopropyl)spiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-1'(2'H)-carboxamide (Compound 41)

[0382] Compound 41 was prepared by referring to the method of Example 2.

[0383] LC-MS(ESI):[M+H] + =472.1

[0384] 1 H NMR(500MHz,DMSO-d6)δ8.55(d,J=6.9Hz,1H),8.31(s,1H),8.22(s,1H),7.70(s,1H),7.52(s,1H),7.32(d ,J=8.0Hz,2H),7.27(d,J=8.2Hz,2H),7.09(d,J=6.9Hz,1H),6.02(s,2H),4.14(s,2H),1.28–1.14(m,8H).

[0385] Example 42 Synthesis of 6'-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(1-(3-(trifluoromethyl)phenyl)cyclopropyl)spiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-1'(2'H)-carboxamide (Compound 42)

[0386] Compound 42 was prepared by referring to the method of Example 2.

[0387] LC-MS(ESI):[M+H] + =506.1

[0388] 1 H NMR(500MHz,DMSO-d6)δ8.65(d,J=7.0Hz,1H),8.34(s,1H),8.23(s,1H),7.81(s,1H),7.63–7.60(m,2H), 7.56–7.51(m,3H),7.25(d,J=7.0Hz,1H),4.16(s,2H),1.31(s,4H),1.29–1.26(m,2H),1.20–1.17(m,2H).

[0389] Example 43 Synthesis of 6'-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(1-(3-methoxyphenyl)cyclopropyl)spiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-1'(2'H)-carboxamide (Compound 43)

[0390] Compound 43 was prepared by referring to the method of Example 2.

[0391] LC-MS(ESI):[M+H]+ =468.2

[0392] 1 H NMR (500MHz, DMSO) δ8.55(d,J=7.0Hz,1H),8.31(d,J=1.6Hz,1H),8.22(d,J =1.7Hz,1H),7.66(s,1H),7.52(s,1H),7.21–7.17(m,1H),7.09(dd,J=7.1,1 .6Hz,1H),6.83(d,J=7.7Hz,1H),6.77(s,1H),6.73(dd,J=8.1,2.6Hz,1H),6 .01(s,2H),4.15(s,2H),3.72(s,3H),1.25–1.23(m,6H),1.18–1.14(m,2H).

[0393] Example 44 Synthesis of 6'-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(1-(3-chlorophenyl)cyclopropyl)spiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-1'(2'H)-carboxamide (Compound 44)

[0394] Compound 44 was prepared by referring to the method of Example 2.

[0395] LC-MS(ESI):[M+H] + =472.2

[0396] 1 H NMR(500MHz,DMSO-d6)δ8.56(s,1H),8.32(s,1H),8.22(s,1H),7.72(s,1H),7.53(s ,1H),7.42–7.18(m,4H),7.11(s,1H),6.02(s,2H),4.16(s,2H),1.33–1.23(m,8H).

[0397] Example 45 Synthesis of (S)-6'-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(1-(4-methoxyphenyl)ethyl)spiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-1'(2'H)-carboxamide (Compound 45)

[0398] Compound 45 was prepared by referring to the method of Example 2.

[0399] LC-MS(ESI):[M+H] + =456.2

[0400] 1 H NMR(500MHz,DMSO-d6)δ8.56(d,J=7.0Hz,1H),8.31–8.27(m,1H),8.21(d,J=2 .0Hz,1H),7.52(s,1H),7.32(d,J=8.2Hz,2H),7.11–7.06(m,1H),7.03(d,J=7. 8Hz,1H),6.88(d,J=8.2Hz,2H),6.02(s,2H),4.95–4.88(m,1H),4.20–4.12(m, 2H),3.73(s,3H),1.43(d,J=7.1Hz,3H),1.27–1.24(m,2H),1.18–1.14(m,2H).

[0401] Example 46 Synthesis of 6'-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(1-(4-fluorophenyl)cyclopropyl)spiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-1'(2'H)-carboxamide (Compound 46)

[0402] Compound 46 was prepared by referring to the method of Example 2.

[0403] LC-MS(ESI):[M+H] + =456.2

[0404] 1 H NMR (500MHz, DMSO-d6) δ8.55(d,J=7.0Hz,1H),8.31(d,J=2.0Hz,1H),8.22(d,J=2.0Hz,1H),7.68(s,1H),7.52(d,J =2.1Hz,1H),7.34–7.27(m,2H),7.12–7.05(m,3H),6.02(s,2H),4.13(s,2H),1.28–1.22(m,4H),1.21–1.13(m,4H).

[0405] Example 47 Synthesis of N-benzyl-6'-(2-(cyclopropanecarboxamide)benzo[d]thiazol-6-yl)spiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-1'(2'H)-carboxamide (Compound 47)

[0406] Compound 47 was prepared by referring to the method of Example 2.

[0407] LC-MS(ESI):[M+H]+ =496.2

[0408] 1 H NMR(500MHz,DMSO-d6)δ12.66(s,1H),8.47–8.12(m,3H),7.80(d,J=8.2Hz,1H),7.65(d,J=8.6Hz,1H), 7.53–7.11(m,6H),4.37(s,2H),4.14(s,2H),2.08–2.00(m,1H),1.29–1.24(m,4H),1.05–0.92(m,4H).

[0409] Example 48 Synthesis of 6'-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(pyrimidin-2-ylmethyl)spiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-1'(2'H)-carboxamide (Compound 48)

[0410] Compound 48 was prepared by referring to the method of Example 2.

[0411] LC-MS(ESI):[M+H] + =414.2

[0412] 1 H NMR(500MHz,DMSO-d6)δ8.78(d,J=4.9Hz,2H),8.56(d,J=7.0Hz,1H),8.32(d, J=2.0Hz,1H),8.23(d,J=2.0Hz,1H),7.54(d,J=2.0Hz,1H),7.45(t,J=5.9Hz, 1H),7.39(t,J=4.9Hz,1H),7.10(dd,J=7.0,2.0Hz,1H),6.02(s,2H),4.55(d, J=5.6Hz,2H),4.17(s,2H),1.28(q,J=4.0,3.5Hz,2H),1.20(t,J=3.3Hz,2H).

[0413] Example 49 Synthesis of 6-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(1-(2-fluorophenyl)cyclopropyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxamide (Compound 49)

[0414] Compound 49 was prepared by referring to the method of Example 13.

[0415] LC-MS(ESI):[M+H]+ =430.3

[0416] 1 H NMR (500MHz, DMSO-d6) δ8.56(d,J=6.5Hz,1H),8.34(s,1H),8.23(s,1H),7.65(s,1H),7.60(t,J=6.9Hz,1H),7.54(s, 1H),7.26(d,J=5.1Hz,1H),7.16–7.07(m,3H),6.03(s,2H),3.98(t,J=8.3Hz,2H),3.22(t,J=8.1Hz,2H),1.22(s,4H).

[0417] Example 50 Synthesis of (S)-6-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(1-(3,4-difluorophenyl)ethyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxamide (Compound 50)

[0418] Compound 50 was prepared by referring to the method of Example 13.

[0419] LC-MS(ESI):[M+H] + =436.3

[0420] 1 H NMR (500MHz, DMSO-d6) δ8.57(d,J=6.9Hz,1H),8.37(s,1H),8.25(s,1H),7.54(s,1H),7.47(t,J=10.1Hz,1H),7.40–7.34(m,1H),7.25(t,J=6.3Hz, 1H),7.19(d,J=7.8Hz,1H),7.09(d,J=7.0Hz,1H),6.03(s,2H),4.96(t,J =7.3Hz,1H),4.15–4.07(m,2H),3.27–3.17(m,2H),1.46(d,J=7.1Hz,3H).

[0421] Example 51 Synthesis of 6-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(1-(6-fluoropyridin-3-yl)cyclopropyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxamide (Compound 51)

[0422] Compound 51 was prepared by referring to the method of Example 13.

[0423] LC-MS(ESI):[M+H] + =431.3

[0424] 1 H NMR (500MHz, DMSO-d6) δ8.56(d,J=7.0Hz,1H),8.38(d,J=2.1Hz,1H),8.26(d,J=2.1Hz,1H),8.15(d,J=2.7Hz,1H),7.86(td,J=8.3,2.6Hz,1 H),7.80(s,1H),7.54(d,J=2.0Hz,1H),7.10(dd,J=6.9,2.2Hz,2H),6.03(s,2H),4.06(t,J=8.7Hz,2H),3.26(t,J=8.6Hz,2H),1.28(s,4H).

[0425] Example 52 Synthesis of 6'-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(1-(2-fluorophenyl)cyclopropyl)spiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-1'(2'H)-carboxamide (Compound 52)

[0426] Compound 52 was prepared by referring to the method of Example 13.

[0427] LC-MS(ESI):[M+H] + =456.3

[0428] 1 H NMR (500MHz, DMSO-d6) δ8.56(d,J=7.0Hz,1H),8.28(d,J=2.1Hz,1H),8.18(d,J=2.1Hz,1H),7.64–7.58(m,1H),7.56(s,1H),7.53(d,J =2.0Hz,1H),7.30–7.22(m,1H),7.16–7.06(m,3H),6.02(s,2H),4.05(s,2H),1.25–1.22(m,2H),1.21–1.18(m,4H),1.14–1.11(m,2H).

[0429] Example 53 Synthesis of 6-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(1-(3,4-difluorophenyl)cyclopropyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxamide (Compound 53)

[0430] Compound 53 was prepared by referring to the method of Example 13.

[0431] LC-MS(ESI):[M+H] + =448.4

[0432] 1 H NMR (500MHz, DMSO-d6) δ8.56(d,J=7.0Hz,1H),8.38(d,J=2.2Hz,1H),8.26(d,J=2.2Hz,1H),7.76(s,1H),7.54(d,J=2.1Hz, 1H),7.36–7.25(m,2H),7.11–7.09(m,2H),6.04(s,2H),4.07(t,J=8.7Hz,2H),3.27(t,J=8.7Hz,2H),1.27(d,J=7.0Hz,4H).

[0433] Example 54 Synthesis of (S)-N-(1-(3-fluorophenyl)ethyl)-6'-(2-((tetrahydro-2H-pyran-4-yl)amino)benzo[d]thiazol-6-yl)spiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-1'(2'H)-carboxamide (Compound 54)

[0434] Step 1: Synthesis of 4-nitrophenyl (R)-(1-(3-fluorophenyl)ethyl)carbamate

[0435] 4-Nitrophenyl chloroformate (579 mg, 2.87 mmol) was slowly added to a mixture of (S)-1-(3-fluorophenyl)ethanamine (200 mg, 1.44 mmol) and diisopropylethylamine (371 mg, 2.87 mmol) in dichloromethane (10 mL) and tetrahydrofuran (10 mL) at 0°C. The mixture was allowed to warm to room temperature and allowed to react for 24 hours. The mixture was concentrated under reduced pressure, quenched with water (10 mL), and extracted with ethyl acetate (7 mL x 3). The organic phases were combined and washed sequentially with water (7 mL x 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) = 35%) to yield 400 mg of a light yellow solid.

[0436] Step 2: Synthesis of 6-bromo-N-(tetrahydro-2H-pyran-4-yl)benzo[d]thiazol-2-amine

[0437] Tetrahydropyrone (100 mg, 1.00 mmol), 2-amino-6-bromobenzothiazole (343 mg, 1.50 mmol), and tetraisopropyl titanate (852 mg, 3.00 mmol) were added to dichloroethane (5 mL). The mixture was heated to 85°C and allowed to react overnight. Ethanol (5 mL) and sodium borohydride (76 mg, 2.00 mmol) were then added and allowed to react for 4.5 hours. The mixture was cooled to room temperature, water (10 mL) was added, and the mixture was stirred for 30 minutes. The mixture was filtered and the residue was washed with ethanol. The organic phase of the filtrate was washed with water (7 mL x 3) and then 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) = 20%) to yield 256 mg of a white solid.

[0438] LC-MS(ESI):[M+H] + =315.0

[0439] Step 3: Synthesis of N-(tetrahydro-2H-pyran-4-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-amine

[0440] 6-Bromo-N-(tetrahydro-2H-pyran-4-yl)benzo[d]thiazol-2-amine (256 mg, 0.82 mmol), pinacol diboron (311 mg, 1.23 mmol), potassium acetate (200 mg, 2.04 mmol), and 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (67 mg, 0.08 mmol) were added to 1,4-dioxane (10 mL). The mixture was heated to 100°C under a nitrogen atmosphere and reacted for 8 hours. The mixture was cooled to room temperature, diluted with ethyl acetate (10 mL), filtered through celite, and concentrated under reduced pressure to obtain 356 mg of a black liquid. The crude product was used directly in the next reaction.

[0441] LC-MS(ESI):[M+H] + =361.1

[0442] Step 4: Synthesis of diethyl 2-(5-bromo-3-nitropyridin-2-yl)malonate

[0443] 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 allowed to react at room temperature for 14 hours. The reaction mixture was poured into ice water (100 mL) to quench the mixture. Dilute hydrochloric acid was slowly added with stirring to adjust the pH to 3-4. The mixture was extracted with ethyl acetate (60 mL × 3), and the organic phases were combined. The organic phases were washed sequentially 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 the product as a yellow solid.

[0444] LC-MS(ESI):[M+H] + =361.1

[0445] Step 5: Synthesis of ethyl 2-(3-amino-5-bromopyridin-2-yl)acetate

[0446] 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). Hydrochloric acid (0.17 g, 4.57 mmol) was slowly added dropwise, and the mixture was heated to 82°C for 1 hour. Filter through celite, and the residue was washed twice with hot ethanol. Saturated sodium bicarbonate solution was slowly added to the filtrate with stirring to adjust the pH to neutral, and the mixture was concentrated under reduced pressure. Dilute with ethyl acetate (20 mL) and stir at room temperature overnight. The organic phase was washed 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:PE (v / v) = 0-15%) to obtain 405 mg of the product as a brown solid.

[0447] LC-MS(ESI):[M+H] + =259.0

[0448] Step 6: Synthesis of 6-bromo-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one

[0449] Acetic acid (87 mg, 1.45 mmol) was added to a solution of ethyl 2-(3-amino-5-bromopyridin-2-yl)acetate (125 mg, 0.48 mmol) in toluene (4 mL). The mixture was heated to 110°C and reacted for 14 hours. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: EA:PE (v / v) = 10-35%) to give 78 mg of the product as a pale yellow solid.

[0450] LC-MS(ESI):[M+H]+ =213.0

[0451] Step 7: Synthesis of 6'-bromospiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridin]-2'(1'H)-one

[0452] 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) were dissolved in DMF (10 mL). Sodium hydride (1.00 g, 25.11 mmol) was slowly added and allowed to react at room temperature for 18 hours. The reaction mixture was poured into ice water (50 mL) for quenching and extracted with ethyl acetate (30 mL × 3). The organic phases were combined and washed sequentially 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 the product as a white solid.

[0453] LC-MS(ESI):[M+H] + =239.1

[0454] Step 8: Synthesis of 6'-bromo-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]

[0455] Sodium borohydride (450 mg, 11.90 mmol) was added to a solution of 6'-bromospiro[cyclopropyl-1,3'-pyrrolo[3,2-b]pyridin]-2'(1'H)-one (570 mg, 2.38 mmol) in THF (40 mL). A 47% boron trifluoride etherate solution (5.10 g, 16.62 mmol) was slowly added dropwise at 0°C. Stirring was continued at 0°C for 10 minutes, then the mixture was warmed to room temperature and reacted for 12 hours. The reaction mixture was quenched by the addition of saturated ammonium chloride solution (10 mL) under ice-cooling, and the mixture was stirred at room temperature overnight. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (30 mL x 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 light yellow solid product.

[0456] LC-MS(ESI):[M+H] + =225.0

[0457] Step 9: Synthesis of (S)-6'-bromo-N-(1-(3-fluorophenyl)ethyl)spiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-1'(2'H)-carboxamide

[0458] Potassium carbonate (261 mg, 1.89 mmol) was added to a solution of 6'-bromo-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine] (170 mg, 0.76 mmol) and 4-nitrophenyl (R)-(1-(3-fluorophenyl)ethyl)carbamate (230 mg, 0.76 mmol) in DMF (10 mL). The reaction mixture was heated to 80°C for 14 hours. The mixture was cooled to room temperature, quenched with water (25 mL), and extracted with ethyl acetate (20 mL × 3). The organic phases were combined. The organic phases were washed 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%) to obtain 134 mg of a pale yellow solid.

[0459] LC-MS(ESI):[M+H] + =392.0

[0460] Step 10: Synthesis of (S)-N-(1-(3-fluorophenyl)ethyl)-6'-(2-((tetrahydro-2H-pyran-4-yl)amino)benzo[d]thiazol-6-yl)spiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-1'(2'H)-carboxamide

[0461] Compound (S)-6'-bromo-N-(1-(3-fluorophenyl)ethyl)spiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-1'(2'H)-carboxamide (130 mg, 0.33 mmol), N-(tetrahydro-2H-pyran-4-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-amine (240 mg , 0.67 mmol), potassium phosphate (177 mg, 0.83 mmol), and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)palladium(II)] (52 mg, 0.07 mmol) were added to 1,4-dioxane (8 mL) and water (2 mL), and the mixture was heated to 85°C under a nitrogen atmosphere for 12 h. The mixture was cooled to room temperature and filtered through celite. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (8 mL × 3). The organic phases were combined. The organic phases were washed sequentially 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 separated and purified by silica gel column chromatography (eluent: MeOH:DCM (v / v) = 0-10%) to obtain 31 mg of a light yellow solid product.

[0462] LC-MS(ESI):[M+H] + =544.2

[0463] 1 H NMR(500MHz,DMSO-d6)δ8.19–8.13(m,2H),8.11(d,J=7.2Hz,1H),7.90(s,1H),7.42(s,2H),7.36(q ,J=7.4Hz,1H),7.24(d,J=8.4Hz,2H),7.10(d,J=7.7Hz,1H),7.06–7.02(m,1H),4.98–4.93(m,1H),4 .20(d,J=9.9Hz,1H),4.15(d,J=9.9Hz,1H),3.99–3.92(m,1H),3.89–3.85(m,2H),3.46–3.41(m,2H) ,2.01–1.94(m,2H),1.54–1.49(m,2H),1.45(d,J=7.2Hz,3H),1.25–1.23(m,2H),1.14–1.12(m,2H).

[0464] Example 55 Synthesis of (S)-N-(1-(4-ethynylphenyl)ethyl)-6'-(2-((tetrahydro-2H-pyran-4-yl)amino)benzo[d]thiazol-6-yl)spiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-1'(2'H)-carboxamide (Compound 55)

[0465] Compound 55 was prepared by referring to the method of Example 54.

[0466] LC-MS(ESI):[M+H] + =551.2

[0467] 1 H NMR(500MHz,DMSO-d6)δ8.17(s,1H),8.13–8.10(m,2H),7.89(s,1H),7.79(d,J=8.0Hz,2H),7. 60(d,J=8.0Hz,2H),7.44–7.39(m,2H),7.19(d,J=7.3Hz,1H),5.01–4.95(m,1H),4.21(d,J=9. 9Hz,1H),4.16(d,J=9.9Hz,1H),4.00–3.92(m,1H),3.89–3.85(m,2H),3.47–3.39(m,2H),1.99 –1.96(m,2H),1.54–1.48(m,2H),1.46(d,J=7.1Hz,3H),1.25–1.23(m,2H),1.15–1.12(m,2H).

[0468] Example 56 Synthesis of (S)-N-(1-(4-cyanophenyl)ethyl)-6'-(2-(ethylsulfonamido)benzo[d]thiazol-6-yl)spiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-1'(2'H)-carboxamide (Compound 56)

[0469] Step 1: Synthesis of N-(6-bromobenzo[d]thiazol-2-yl)ethanesulfonamide

[0470] Dissolve 2-amino-6-bromobenzothiazole (1 g, 4.37 mmol) and triethylamine (0.88 g, 8.73 mmol) in dichloromethane (10 mL). Slowly add ethylsulfonyl chloride (0.67 g, 5.24 mmol) under a nitrogen atmosphere and allow to react at room temperature for 3 hours. Dilute with water (10 mL) and extract with ethyl acetate (20 mL x 3). Combine the organic phases. Wash with water (20 mL x 2) and saturated brine (20 mL), dry over anhydrous sodium sulfate, and concentrate under reduced pressure. Purify by silica gel column chromatography (eluent: EA:PE (v / v) = 30%-50%) to yield 980 mg of a yellow liquid.

[0471] LC-MS(ESI):[M+H] + =322.9

[0472] Step 2: Synthesis of N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)ethanesulfonamide

[0473] To a solution of N-(6-bromobenzo[d]thiazol-2-yl)ethanesulfonamide (300 mg, 0.93 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane) (356 mg, 1.40 mmol), and potassium acetate (229 mg, 2.33 mmol) in dimethyl sulfoxide (10 mL) was added Pd(dppf)Cl2 (68 mg, 0.09 mmol). The mixture was stirred at 100°C under a nitrogen atmosphere overnight. Ethyl acetate (20 mL) and water (10 mL) were added, and the mixture was extracted. The organic phases were combined, concentrated under reduced pressure, and used directly in the next step.

[0474] LC-MS(ESI):[M+H] + =369.1

[0475] Step 3: Synthesis of (S)-N-(1-(4-cyanophenyl)ethyl)-6'-(2-(ethylsulfonamido)benzo[d]thiazol-6-yl)spiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-1'(2'H)-carboxamide

[0476] To the reaction mixture was added (S)-6'-bromo-N-(1-(4-cyanophenyl)ethyl)spiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-1'(2'H)-carboxamide (150 mg, 0.38 mmol) and N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)ethanesulfonamide (139 mg, 0.38 mm To a mixed solution of 1,4-dioxane (8 mL) and water (2 mL) containing 1,4-dioxane (8 mL) and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (59 mg, 0.08 mmol) was added. The mixture was heated to 85°C under a nitrogen atmosphere for 12 h. The mixture was cooled to room temperature and filtered through celite. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (8 mL × 3). The organic phases were combined. The organic phases were washed sequentially 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 separated and purified by silica gel column chromatography (eluent: MeOH:DCM (v / v) = 0-10%) to obtain 16 mg of a light yellow solid product.

[0477] LC-MS(ESI):[M+H] + =559.1

[0478] 1 H NMR(500MHz,DMSO-d6)δ13.03(s,1H),8.17–8.14(m,2H),8.02(s,1H),7.79( d,J=8.0Hz,2H),7.61–7.57(m,3H),7.36(d,J=8.5Hz,1H),7.21(d,J=7.3Hz, 1H), 4.98 (t, J = 7.2Hz, 1H), 4.22 (d, J = 9.9Hz, 1H), 4.17 (d, J = 10.0Hz, 1H), 3. 12–3.07(m,2H),1.45(d,J=7.2Hz,3H),1.26–1.20(m,5H),1.17–1.14(m,2H).

[0479] Experimental Example 1 RIPK1 kinase inhibitory activity test

[0480] 1. Experimental Materials

[0481] (1) Reagents are shown in Table 1 below.

[0482] Table 1

[0483] 2. Methods

[0484] (1) Compound dilution

[0485] Compounds (control compound RIPA-56 and compounds of the present application) were diluted in gradient: the compounds were dissolved in DMSO solvent to obtain a 10 mM compound solution, and then serially diluted 4-fold to obtain a total of 11 concentrations (the concentrations were 1000, 250, 62.5, 15.625, 3.906, 0.977, 0.244, 0.061, 0.015, 0.004 and 0 uM) of compound solutions.

[0486] (2) Experimental methods

[0487] This application uses ADP-Glo TM The kinase assay kit was used to determine the inhibitory activity of compounds against RIPK1 as follows:

[0488] (a) Transfer 100 nL / well of the diluted compound solution to a 384-well plate.

[0489] (b) Add 5 μL of the prepared RIPK1 enzyme solution to each well of a 384-well plate, centrifuge at 1000 rpm for 1 min, and incubate at 25°C for 15 min.

[0490] (c) Add 5 μL of the prepared substrate solution to each well of a 384-well plate, centrifuge at 1000 rpm for 1 min, and incubate at 25°C for 60 min. The final concentrations of the compounds are 10,000, 2,500, 625, 156.25, 39.06, 9.77, 2.44, 0.61, 0.15, 0.04, and 0 nM.

[0491] (d) Join ADP-Glo TM Reagent (Promega, V9102) was added to each well in an amount of 10 μL, centrifuged at 1000 rpm for 1 min, and incubated at 25°C for 60 min.

[0492] (e) Join ADP-Glo TM Kinase detection reagent (Promega, V9102) was added to each well in an amount of 20 μL, centrifuged at 1000 rpm for 1 min, and incubated at 25°C for 60 min.

[0493] (f) Read the fluorescence value using a microplate reader.

[0494] The mean and standard deviation of the DMSO wells and the 10,000 nM RIPA-56 wells were calculated, with the mean of the DMSO wells as the high value and the mean of the 10,000 nM RIPA-56 wells as the low value.

[0495] Compound well inhibition rate = 100 * (average reading of high value - reading of compound) / (average reading of high value - average reading of low value). IC of compound's inhibitory effect on RIPK1 was calculated using GraphPad Prism 8 nonlinear fitting formula. 50 value.

[0496] See Table 1 for the results.

[0497] Table 1. IC values ​​of the inhibitory effects of some compounds provided in some embodiments of the present invention on RIPK1 50 value

[0498] Results and Discussion: The compounds of the present invention exhibited excellent RIPK1 inhibitory activity.

[0499] Experimental Example 2 Pharmacokinetic Test

[0500] 1) Pharmacokinetic test in mice

[0501] Six male mice weighing 20-30 g were divided into two groups: one group received a single intravenous injection of 2 mg / kg, and the other group received a single oral dose of 10 mg / kg. Blood was collected at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after dosing. Plasma samples were pretreated and analyzed by LC / MS / MS in MRM mode. Appropriate standard curves were established to quantify the target compound in plasma samples and generate concentration-time curves. Pharmacokinetic parameters were calculated using a non-compartmental model using WinNonlin software.

[0502] 2) Pharmacokinetic test in rats

[0503] Six male rats weighing 200-300 g were divided into two groups: one group received a single intravenous injection of 1 mg / kg, and the other group received a single oral dose of 5 mg / kg. Blood was collected at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after dosing. Plasma samples were pretreated and analyzed by LC / MS / MS in MRM mode. Appropriate standard curves were established to quantify the target compound in plasma samples and generate concentration-time curves. Pharmacokinetic parameters were calculated using a non-compartmental model using WinNonlin software.

[0504] 3) Canine pharmacokinetic testing

[0505] Six beagle dogs weighing 9-15 kg were divided into two groups. One group received a single intravenous injection of 1 mg / kg, and blood was collected at 0.083, 0.25, 0.5, 1, 2, 4, 8, 24, and 48 hours after administration. The other group received a single oral dose of 5 mg / kg, and blood was collected at 0.25, 0.5, 1, 2, 4, 8, 24, 32, and 48 hours after administration. After pretreatment, plasma samples were analyzed by LC / MS / MS in MRM mode. Appropriate standard curves were established to quantify the target compound in plasma samples and generate drug concentration-time curves. Pharmacokinetic parameters were calculated using a non-compartmental model using WinNonlin software.

[0506] The results are shown in Tables 2-4.

[0507] Table 2 Pharmacokinetic parameters in mice

[0508] Table 3 Pharmacokinetic parameters in rats

[0509] Table 4 Pharmacokinetic parameters in dogs

[0510] Experimental conclusion: The compounds of the present invention exhibit excellent pharmacokinetic properties.

[0511] In the description of this specification, the reference terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" mean that the specific features, structures, materials or characteristics described in conjunction 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 terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described can be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art can combine and combine different embodiments or examples described in this specification and features of different embodiments or examples without contradiction.

Claims

1. 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): Wherein: X is N or CR 15 ; Y1 is C or N; Y2 is N, O, S, CR 16 or NR 18 ; Y3 is N, O, S, CR 17 or NR 19 ; Y4 is C or N; Ring A is C 6-10 aryl or 5- to 10-membered heteroaryl; Each R a is independently H, D, F, Cl, Br, I, CN, Hydroxy, nitro, amino, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 alkylamino, wherein the C 1-6 alkyl, C 1-6 alkoxy and C 1-6 alkylamino may each 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; R 1 、R 2 、R 4 、R 5 、R 6 and R 7 each independently is H, D, F, Cl, Br, I, CN, hydroxy, 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 1 and R 2 、R 4 and R 5 、R 6 and R 7 each optionally forms -C(=O)-, a 3- to 6-membered carbocyclic ring or a 3- to 6-membered heterocyclic ring with the carbon atom to which they are commonly attached, 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; R 3 , R 13 , R 18 and R 19 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 8 、R 9 、R 10 、R 11 、R 12 、R 15 、R 16 and R 17 are each independently 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, wherein 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 each 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; R 14 is H, D, -S(=O)2R 20 , -S(=O)R 21 , -C(=O)NR 22 R 23 , -C(=O)OR 24 , 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 substituted by 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, and 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 20 、R 21 、R 22 、R 23 and R 24 are each independently 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- to 8-membered heterocyclic group, C 6-10 aryl or 5- to 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- to 8-membered heterocyclic group, C 6-10 aryl and 5- to 10-membered heteroaryl may each independently be optionally substituted by 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- to 6-membered heterocyclic group, C 6-10 aryl and 5- to 10-membered heteroaryl, and the C 3-6 cycloalkyl, 3- to 6-membered heterocyclic group, C 6-10 aryl and 5- to 10-membered heteroaryl may each independently be optionally substituted by 1, 2, 3, 4 or 5 substituents selected from D, F, Cl, Br, I, CN, hydroxy, amino and nitro; n is 1, 2, 3, 4, 5, 6, 7 or 8.

2. The compound according to claim 1, wherein is 3. The compound according to claim 1 or 2, wherein ring A is C 6-10 aryl or 5- to 10-membered heteroaryl; Each R a is independently H, D, F, Cl, Br, I, CN, Hydroxy, nitro, amino, C 1-3 alkyl, C 1-3 alkoxy or C 1-3 alkylamino, wherein the C 1-3 alkyl, C 1-3 alkoxy and C 1-3 alkylamino may each 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.

4. The compound according to any one of claims 1-3, wherein ring A is phenyl, naphthyl, Each R a 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 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 or nitro.

5. The compound according to any one of claims 1-4, wherein R 1 , R 2 , R 4 , R 5 , R 6 and R 7 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 or C 2-3 -alkynyl may each 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 1 and R 2 , R 4 and R 5 , R 6 and R 7 may each optionally form, together with the carbon atom to which they are commonly attached, -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 each independently optionally be substituted by 1, 2 or 3 substituents selected from D, F, Cl, Br, I, CN, oxo(=O), hydroxy, amino and nitro; R 3 , R 13 , R 18 and R 19 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 8 、R 9 、R 10 、R 11 、R 12 、R 15 、R 16 and R 17 are each independently H, D, F, Cl, Br, I, CN, a hydroxyl group, an amino group, a nitro group, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylamino, C 3-6 cycloalkyl or a 3- to 6-membered heterocyclic group, wherein the C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylamino, C 3-6 cycloalkyl 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), a hydroxyl group, an amino group and a nitro group.

6. The compound according to any one of claims 1-5, wherein R 1 , R 2 , R 4 , R 5 , R 6 , and R 7 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 by 1, 2, 3, 4 or 5 substituents selected from D, F, Cl, Br, I, CN, oxo(=O), hydroxy, amino and nitro; or R 1 and R 2 , R 4 and R 5 , R 6 and R 7 each optionally form -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 each independently optionally be substituted by 1, 2 or 3 substituents selected from D, F, Cl, Br, I, CN, oxo(=O), hydroxy, amino and nitro; R 3 、R 13 、R 18 and R 19 each independently is H, methyl, ethyl, n-propyl, isopropyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, hydroxymethyl, hydroxyethyl, aminomethyl, aminoethyl, -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, -CH2CH2OCH2CH3, cyclopropyl or cyclobutyl; R 8 、R 9 、R 10 、R 11 、R 12 、R 15 、R 16 and R 17 each independently is H, D, F, Cl, Br, I, CN, a hydroxyl group, an amino group, a nitro group, a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a methoxy group, an ethoxy group, a n-propoxy group, an isopropoxy group, an N-methylamino group, an N-ethylamino group, a cyclopropyl group, a cyclobutyl group, an azetidinyl group or an oxetan-3-yl, and the methyl group, ethyl group, n-propyl group, isopropyl group, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, N-methylamino group, N-ethylamino group, cyclopropyl group, cyclobutyl group, azetidinyl group and oxetan-3-yl may each independently optionally be substituted by 1, 2, 3, 4 or 5 substituents selected from D, F, Cl, Br, I, CN, oxo(=O), a hydroxyl group, an amino group and a nitro group.

7. The compound according to any one of claims 1-6, wherein R 14 is H, D, S(=O)2R 20 , S(=O)R 21 , -C(=O)NR 22 R 23 , -C(=O)OR 24 , 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, wherein 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 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, phenyl and naphthyl, and the phenyl and naphthyl 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. R 20 、R 21 、R 22 、R 23 and R 24 are each independently 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- to 6-membered heterocyclic group, C 6-10 aryl or 5- to 10-membered heteroaryl, wherein 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 6-10 aryl and 5- to 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, phenyl and naphthyl, and the phenyl and naphthyl 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.

8. The compound according to any one of claims 1-7, wherein R 14 is H, D, S(=O)2R 20 , S(=O)R 21 , -C(=O)NR 22 R 23 , -C(=O)OR 24 , 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, 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, may be independently 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 optionally substituted by 1, 2, 3, 4 or 5 substituents selected from D, F, Cl, Br, I, CN, hydroxy, amino and nitro. R 20 、R 21 、R 22 、R 23 、R 24 Each 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, 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, 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.

9. The compound according to any one of claims 1-8, which is a compound having one of the following structures or a stereoisomer, geometric isomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of a compound having one of the following structures:

10. A pharmaceutical composition comprising the compound according to any one of claims 1-9; the pharmaceutical composition optionally further comprises a pharmaceutically acceptable excipient, carrier, adjuvant or any combination thereof.

11. Use of the compound according to any one of claims 1-9 or the pharmaceutical composition according to claim 10 in the preparation of a medicament for preventing, treating or alleviating a disease mediated by a RIPK1 inhibitor in a patient.

12. According to the use described in claim 11, wherein The disease mediated by the RIPK1 inhibitor is an inflammatory disease, an autoimmune disease, a neurodegenerative disease or a tumor.

13. The use according to claim 12, 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 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.

Images