Bicyclic compound as well as preparation method and application thereof

Abstract

The invention discloses a bicyclic compound and an application of the bicyclic compound in a medicine, and particularly relates to a novel bicyclic compound and a medicine composition containing the novel bicyclic compound. The invention also relates to a method for preparing the compound, and application of the compound or the pharmaceutical composition in preparation of drugs for treating RIPK1 inhibitor mediated diseases and / or symptoms. The invention relates to the field of medicines, in particular to the application of the medicines in preparing medicines 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, osteoarthritis and the like.

Description

Bicyclic compounds and their preparation methods and applications

[0001] This application claims priority to:

[0002] CN202211736665.X, application date December 30, 2022. 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.

[0012] Summary of the Invention

[0013] 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.

[0014] Specifically:

[0015] 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).

[0016] in:

[0017] X is N or CR 15 ;

[0018] Y1 is C or N;

[0019] Y2 is N, O, S, or CR 16 or NR 18 ;

[0020] Y3 is N, O, S, or CR 17 or NR 19 ;

[0021] Y4 is C or N;

[0022] Ring A is C 6-10 Aryl or 5-10 membered heteroaryl;

[0023] Each R a are independently H, D, F, Cl, Br, I, CN, hydroxy, nitro, amino, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Alkylamino, the C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 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;

[0024] 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 Haloalkoxy, -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 Haloalkoxy, -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;

[0025] R 3 、R 13 、R 18 and R 19 Each independently is H, 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;

[0026] 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;

[0027] R 14 -LR b , where L is a bond, -O-, or -NR c - or C 1-6 alkylene;

[0028] R b H, 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 Haloalkoxy, -C 1-6 Alkylene-C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the C 1-6 Alkyl, C 1-6 Halogenated alkyl, 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 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;

[0029] R c H or C 1-6 alkyl;

[0030] n is 1, 2, 3, 4, 5, 6, 7 or 8.

[0031] In some embodiments, for

[0032] In some embodiments, Ring A is C 6-10 Aryl or 5-10 membered heteroaryl;

[0033] Each R a are independently H, D, F, Cl, Br, I, CN, hydroxy, nitro, amino, C 1-3 Alkyl, C 1-3 Alkoxy or C 1-3 Alkylamino, the C 1-3 Alkyl, C 1-3 Alkoxy and C 1-3 Alkylamino groups may be optionally substituted independently with 1, 2, 3, 4, or 5 substituents selected from D, F, Cl, Br, I, CN, oxo (=O), hydroxy, amino, or nitro.

[0034] In some embodiments, Ring A is phenyl, naphthyl,

[0035] Each R a 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 optionally substituted with 1, 2, 3, 4 or 5 substituents selected from D, F, Cl, Br, I, CN, oxo (=O), hydroxy, amino or nitro.

[0036] In some embodiments, 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 Haloalkoxy, -C 1-3 Alkylene-C 1-3 Alkoxy, C 2-3 Alkenyl or C 2-3 Alkynyl, the C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C1-3 aminoalkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, C 1-3 Haloalkoxy, -C 1-3 Alkylene-C 1-3 Alkoxy, C 2-3 Alkenyl and C 2-3 Alkynyl may 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), hydroxy, amino and nitro;

[0037] 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;

[0038] 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 3-6Cycloalkyl 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.

[0039] 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 7Each 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;

[0040] R 3 、R 13 、R 18 and R 19 Each is independently H, methyl, ethyl, n-propyl, isopropyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, hydroxymethyl, hydroxyethyl, aminomethyl, aminoethyl, -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, -CH2CH2OCH2CH3, cyclopropyl or cyclobutyl;

[0041] 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.

[0042] In some embodiments, R 14 -LR b , where L is a bond, -O-, or -NR c - or C 1-3 alkylene;

[0043] R b H, 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 Haloalkoxy, -C 1-3 Alkylene-C 1-3 Alkoxy, C 2-3 Alkenyl, C 2-3 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the C 1-3 Alkyl, C 1-3 Halogenated alkyl, 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 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;

[0044] R c H or C 1-3 alkyl.

[0045] In some embodiments, R 14 -LR b , where L is a bond, -O-, or -NR c -, methylene or ethylene;

[0046] R b is H, 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, 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;

[0047] R c is H or methyl.

[0048] 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:

[0049] 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.

[0050] 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.

[0051] 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.

[0052] 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.

[0053] In another aspect, the present invention relates to methods for preparing, isolating and purifying the compounds encompassed by formula (I).

[0054] 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.

[0055] Definitions and General Terms

[0056] 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.

[0057] 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," 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.

[0058] The term "comprising" is an open expression, that is, including the contents specified in the present invention, but not excluding other contents.

[0059] 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.

[0060] 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.

[0061] 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.

[0062] 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.

[0063] 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.

[0064] 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)-.

[0065] The term "halogen" refers to F, Cl, Br or I.

[0066] The term "deuterium" refers to heavy hydrogen, D.

[0067] As used herein, the term "unsaturated" means that the moiety contains one or more degrees of unsaturation.

[0068] 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.

[0069] 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.

[0070] 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.

[0071] 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.

[0072] 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.

[0073] 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.

[0074] 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.

[0075] 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.

[0076] 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.

[0077] 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.

[0078] 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.

[0079] 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.

[0080] 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.

[0081] 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.

[0082] 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.

[0083] "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.

[0084] 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.

[0085] 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.

[0086] 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.

[0087] The "hydrate" of the present invention refers to an association compound formed when the solvent molecule is water.

[0088] 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.

[0089] "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.

[0090] 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).

[0091] 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.

[0092] 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.

[0093] The term "RIPK1 inhibitor" used herein refers to a substance that can inhibit the activity of RIPK1.

[0094] General synthesis process

[0095] 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.

[0096] 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.

[0097] 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 known reagents other than 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.

[0098] 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.

[0099] 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.

[0100] 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.

[0101] 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.

[0102] 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).

[0103] 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, 6 min, flow rate: 1 mL / min). Mobile phase: 0%-95% (CH3CN) in (H2O containing 0.1% formic acid: CH3CN = 90:10), electrospray ionization (ESI), detection at 210 nm / 254 nm, and DAD.

[0104] 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.

[0105] The following abbreviations are used throughout the present invention: PE petroleum ether EtOAc / EA ethyl acetate mg milligram mmol millimole mL milliliter g gram M mole / liter rpm revolutions / minute μM micromole / liter μL microliter DCM dichloromethane MeOH methanol min minute CDCl3 deuterated chloroform nL nanoliter DIPEA N,N-diisopropylethylamine DMF N,N-dimethylformamide nM nanomolar / liter Pd(PPh3)4 tetrakis(triphenylphosphine)palladium h hour Pd(dppf)Cl2 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride MsCl methanesulfonyl chloride DMSO-d6 deuterated dimethyl sulfoxide DMSO dimethyl sulfoxide HATU O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate X-Phos 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl X-Phos-Pd-G2 Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)

[0106] 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 、R 14 、R a and n have the same meanings as those described in the present invention. Boc is a commonly used protecting group tert-butyloxycarbonyl.

[0107] Reaction Scheme 1

[0108] The compound represented by formula (3) 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).

[0109] Reaction Scheme 2

[0110] The compound represented by formula (8) can be prepared by reaction scheme 2: the compound represented by formula (4) and the compound represented by formula (5) are condensed to obtain the compound represented by formula (6). The compound represented by formula (6) and the compound represented by formula (7) are coupled to obtain the compound represented by formula (8).

[0111] Reaction Scheme 3

[0112] The compound represented by formula (20) can be prepared by reaction scheme 3: The compound represented by formula (9) reacts with the compound represented by formula (10) to obtain the compound represented by formula (11). The compound represented by formula (11) reacts with dimethyl sulfoxide and lithium chloride to obtain the compound represented by formula (12). The compound represented by formula (12) is reduced to obtain the compound represented by formula (13). The compound represented by formula (13) reacts with sodium borohydride to obtain the compound represented by formula (14). The compound represented by formula (14) is Boc-protected to obtain the compound represented by formula (15). The compound represented by formula (15) reacts with methanesulfonyl chloride to obtain the compound represented by formula (16). The compound represented by formula (16) undergoes intramolecular cyclization to obtain the compound represented by formula (17). The compound represented by formula (17) removes the Boc group to obtain the compound represented by formula (18). The compound represented by formula (18) reacts with the compound represented by formula (3) to obtain the compound represented by formula (19). The compound represented by formula (19) is coupled with the compound represented by formula (8) to obtain the compound represented by formula (20).

[0113] Reaction Scheme 4

[0114] The compound represented by formula (19) can also be prepared by reaction scheme 4: the compound represented by formula (18) is reacted with the compound represented by formula (2) to obtain the compound represented by formula (21). The compound represented by formula (21) is reacted with the compound represented by formula (1) to obtain the compound represented by formula (19).

[0115] Reaction Scheme 5

[0116] The compound represented by formula (20) can also be prepared by reaction scheme 5: the compound represented by formula (6) is reacted with the compound represented by formula (7) to obtain the compound represented by formula (22). The compound represented by formula (22) is reacted with the compound represented by formula (19) to obtain the compound represented by formula (20). DETAILED DESCRIPTION

[0117] 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.

[0118] Example 1 Synthesis of (S)-6-(2-(cyclopropanecarboxamido)benzo[d]thiazol-6-yl)-N-(1-(3-fluorophenyl)ethyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxamide (Compound 1)

[0119] Step 1: Synthesis of 4-nitrophenyl (S)-(1-(3-fluorophenyl)ethyl)carbamate

[0120] A solution of 4-nitrophenyl chloroformate (200 mg, 0.99 mmol) in dichloromethane (10 mL) was cooled to -40°C and stirred for 10 minutes. A solution of (S)-1-(3-fluorophenyl)ethan-1-amine (92 mg, 0.66 mmol) and N,N-diisopropylethylamine (253 mg, 1.98 mmol) in dichloromethane (2 mL) was then slowly added dropwise to the cooled solution, which was stirred at -40°C for 2 hours. The solution was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: EA:PE (v / v) = 1:15) to afford 200 mg of a pale yellow solid product in a 66.2% yield.

[0121] 1 H NMR(400MHz, CDCl3)δ8.16(d,J=9.0Hz,2H),7.35–7.19(m,3H),7.08(d,J=7.6Hz,1H),6.95(d dd,J=15.0,10.4,5.8Hz,2H),5.32(d,J=6.2Hz,1H),4.89–4.81(m,1H),1.51(d,J=6.8Hz,3H).

[0122] Step 2: Synthesis of N-(6-bromobenzo[d]thiazol-2-yl)cyclopropanecarboxamide

[0123] 6-Bromobenzo[d]thiazol-2-amine (1.0 g, 4.37 mmol) and cyclopropanecarboxylic acid (0.41 g, 4.8 mmol) were added to N,N-dimethylformamide (15 mL), followed by HATU (2.49 g, 6.55 mmol) and triethylamine (0.88 g, 8.74 mmol). The mixture was stirred at 60°C overnight. The mixture was concentrated under reduced pressure, and ethyl acetate (20 mL) and water (10 mL) were added for extraction. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent EA:PE (v / v) = 1:1) to give 1.0 g of the product as a white solid in a yield of 77.1%.

[0124] LC-MS(ESI):[M+H] + =299.2.

[0125] Step 3: Synthesis of N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)cyclopropanecarboxamide

[0126] To a solution of N-(6-bromobenzo[d]thiazol-2-yl)cyclopropanecarboxamide (0.9 g, 3.03 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane) (0.92 g, 3.63 mmol), and potassium acetate (0.74 g, 7.57 mmol) in 1,4-dioxane (10 mL) was added Pd(dppf)Cl2 (0.16 g, 0.21 mmol). The mixture was stirred at 100°C under a nitrogen atmosphere overnight. The mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: MeOH:DCM (v / v) = 1:20) to afford 140 mg of the product as a white solid in a 13.4% yield.

[0127] LC-MS(ESI):[M+H] + =345.4.

[0128] Step 4: Synthesis of diethyl 2-(5-bromo-3-nitropyridin-2-yl)malonate

[0129] Diethyl malonate (10.0 g, 42.12 mmol) was added to tetrahydrofuran (100 mL), cooled to 0°C, and sodium hydride (2.02 g, 84.23 mmol) was added. The mixture was stirred in an ice bath for 1 hour. 5-Bromo-2-chloro-3-nitropyridine (10.0 g, 42.12 mmol) was added dropwise to tetrahydrofuran (20 mL) and stirred overnight at room temperature. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: EA:PE (v / v) = 1:5) to afford 11.6 g of the product as a colorless oil in a 76.3% yield.

[0130] 1 H NMR (400MHz, CDCl3) δ8.81(d,J=2.0Hz,1H),8.55(d,J=2.0Hz,1H),5.39(s,1H),4.26–4.21(m,4H),1.22(t,J=7.0Hz,6H).

[0131] Step 5: Synthesis of ethyl 2-(5-bromo-3-nitropyridin-2-yl)acetate

[0132] To a mixture of diethyl 2-(5-bromo-3-nitropyridin-2-yl)malonate (11.1 g, 30.74 mmol) in dimethyl sulfoxide (111 mL) and water (3.1 mL) was added lithium chloride (1.30 g, 30.74 mmol), and the mixture was heated to 100°C and allowed to react overnight. Water (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent EA:PE (v / v) = 1:10) to afford 6.7 g of the product as a colorless, transparent oil in a 75.4% yield.

[0133] 1 H NMR (400MHz, CDCl3) δ8.78(d,J=2.0Hz,1H),8.50(d,J=2.0Hz,1H),4.21(s,2H),4.12(q,J=7.0Hz,2H),1.19(t,J=7.0Hz,3H).

[0134] Step 6: Synthesis of ethyl 2-(3-amino-5-bromopyridin-2-yl)acetate

[0135] To a mixed solvent of ethyl 2-(5-bromo-3-nitropyridin-2-yl)acetate (3.0 g, 10.38 mmol) in ethanol (20 mL) and water (20 mL) were added ammonium chloride (5.55 g, 103.78 mmol) and iron powder (1.74 g, 31.13 mmol), and the mixture was heated to 80°C for 2 h. The reaction solution was filtered through celite, concentrated under reduced pressure, diluted with water (20 mL), and extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent EA:PE (v / v) = 1:5) to give 1.6 g of a light yellow solid product with a yield of 59.5%.

[0136] LC-MS(ESI):[M+H] + =259.2.

[0137] Step 7: Synthesis of 2-(3-amino-5-bromopyridin-2-yl)ethan-1-ol

[0138] A solution of ethyl 2-(3-amino-5-bromopyridin-2-yl)acetate (0.8 g, 3.09 mmol) in ethanol (20 mL) was cooled to 0°C, followed by the addition of sodium borohydride (0.93 g, 24.70 mmol) and the reaction mixture was allowed to warm to room temperature for 4 h. The reaction was quenched with saturated aqueous ammonium chloride (10 mL) and extracted with dichloromethane (20 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by silica gel column chromatography (eluent: EA:PE (v / v) = 1:1) afforded 600 mg of the product as a white solid in an 89.5% yield.

[0139] LC-MS(ESI):[M+H] + =218.1.

[0140] Step 8: Synthesis of tert-butyl (5-bromo-2-(2-hydroxyethyl)pyridin-3-yl)carbamate

[0141] 2-(3-Amino-5-bromopyridin-2-yl)ethan-1-ol (0.56 g, 2.58 mmol) and di-tert-butyl dicarbonate (0.84 g, 3.87 mmol) were added to 1,4-dioxane (10 mL) and heated to 80°C with stirring overnight. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: EA:PE (v / v) = 1:5) to afford 300 mg of a white solid product in a 36.7% yield.

[0142] LC-MS(ESI):[M+H] + =317.3.

[0143] Step 9: Synthesis of ethyl 2-(5-bromo-3-((tert-butoxycarbonyl)amino)pyridin-2-yl)methanesulfonate

[0144] Add tert-butyl (5-bromo-2-(2-hydroxyethyl)pyridin-3-yl)carbamate (0.3 g, 0.95 mmol) to dichloromethane (10 mL), followed by triethylamine (0.29 g, 2.84 mmol). Cool the mixture to 0°C, add MsCl (0.16 g, 1.42 mmol), and react at this temperature for 1 hour. Concentrate under reduced pressure to obtain 350 mg of a crude gray product, which is used directly in the next step.

[0145] Step 10: Synthesis of tert-butyl 6-bromo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxylate

[0146] To a solution of ethyl 2-(5-bromo-3-((tert-butoxycarbonyl)amino)pyridin-2-yl)methanesulfonate (0.35 g, 0.89 mmol) in 1,4-dioxane (8 mL) was added cesium carbonate (0.92 g, 2.84 mmol), heated to 120°C for overnight, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent EA:PE (v / v) = 1:3) to give 160 mg of a white solid product in a yield of 60.4%.

[0147] LC-MS(ESI):[M+H] + =301.3.

[0148] Step 11: Synthesis of 6-bromo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine

[0149] To a solution of tert-butyl 6-bromo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (160 mg, 0.54 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (2.5 mL) and stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent EA:PE (v / v) = 1:3) to afford 85 mg of the product as a white solid in an 80.0% yield.

[0150] 1 H NMR (400MHz, DMSO-d6) δ7.64(d,J=2.0Hz,1H),6.84(d,J=2.0Hz,1H),6.07(s,1H),3.53(t,J=8.8Hz,2H),2.93(t,J=8.8Hz,2H).

[0151] Step 12: Synthesis of (S)-6-bromo-N-(1-(3-fluorophenyl)ethyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxamide

[0152] To a solution of 6-bromo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (100 mg, 0.5 mmol) and 4-nitrophenyl (S)-(1-(3-fluorophenyl)ethyl)carbamate (170 mg, 0.56 mmol) in dichloromethane (10 mL) was added DIPEA (214 mg, 1.67 mmol), and the mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent EA:PE (v / v) = 1:3) to afford 80 mg of the product as a light yellow solid in a 39.3% yield.

[0153] 1 H NMR (400MHz, DMSO-d6) δ8.11–8.00(m,2H),7.39–7.32(m,1H),7.26–7.21(m,3H),7.04(t,J=8 .0Hz,1H),4.99–4.91(m,1H),4.15–4.02(m,2H),3.18(t,J=8.8Hz,2H),1.45(d,J=7.0Hz,3H).

[0154] Step 13: Synthesis of (S)-6-(2-(cyclopropanecarboxamido)benzo[d]thiazol-6-yl)-N-(1-(3-fluorophenyl)ethyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxamide

[0155] To a mixed solution of (S)-6-bromo-N-(1-(3-fluorophenyl)ethyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxamide (80 mg, 0.22 mmol) and N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)cyclopropanecarboxamide (80 mg, 0.23 mmol) in dioxane (6 mL) and water (1.5 mL) were added potassium carbonate (91 mg, 0.66 mmol) and tetrakistriphenylphosphine palladium (25 mg, 0.02 mmol). The reaction was allowed to proceed at 85°C overnight under a nitrogen atmosphere. The mixture was concentrated under reduced pressure, diluted with water (5 mL), and extracted with dichloromethane (5 mL). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by preparative liquid chromatography (eluent: acetonitrile: H2O (v / v) = 50%) to give 9.1 mg of a white solid product with a yield of 8.3%.

[0156] LC-MS(ESI):[M+H] + =502.1

[0157] 1H NMR (400MHz, DMSO-d6) δ12.69(s,1H),8.30(d,J=2.0Hz,1H),8.26(d,J=2.0Hz,1H) ,8.23(d,J=1.4Hz,1H),7.79(d,J=8.4Hz,1H),7.65(dd,J=8.4,1.8Hz,1H),7.40–7. 34(m,1H),7.26–7.18(m,3H),7.07–7.01(m,1H),5.01–4.92(m,1H),4.20–4.03(m,2 H), 3.30–3.23 (m, 2H), 2.05–1.98 (m, 1H), 1.46 (d, J = 7.0Hz, 3H), 1.00–0.93 (m, 4H).

[0158] Example 2 Synthesis of (S)-6-(2-acetylaminobenzo[d]thiazol-6-yl)-N-(1-(3-fluorophenyl)ethyl)indoline-1-carboxamide (Compound 2)

[0159] Step 1: Synthesis of 4-nitrophenyl 6-bromoindoline-1-carboxylate

[0160] To a solution of 6-bromoindoline (0.50 g, 2.48 mmol) and 4-dimethylaminopyridine (0.30 g, 2.48 mmol) in tetrahydrofuran (10 mL) at 0°C was added 4-nitrophenyl chloroformate (0.55 g, 2.73 mmol) in portions. The reaction was continued at 0°C for 2 hours. Ethyl acetate (30 mL) was added for dilution, the mixture was filtered, and the solvent was removed under reduced pressure. A 1:1 ethyl acetate / petroleum ether solution (15 mL) was added, the mixture was stirred thoroughly, and then filtered. The filter cake was washed with a mixture of ethyl acetate and petroleum ether (1:1, v / v) and dried to obtain 720 mg of a light yellow solid in a yield of 79.9%.

[0161] Step 2: Synthesis of (S)-6-bromo-N-(1-(3-fluorophenyl)ethyl)indoline-1-carboxamide

[0162] To a solution of 6-bromoindoline-1-carboxylic acid p-nitrophenyl ester (260 mg, 0.72 mmol) and potassium carbonate (420 mg, 3.04 mmol) in DMF (7 mL) was added (S)-1-(3-fluorophenyl)ethanamine (203 mg, 1.46 mmol). The mixture was heated to 80°C and allowed to react for 4 h. The reaction was quenched with water (30 mL) and extracted with ethyl acetate (15 mL x 3). The organic phases were combined and washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The product was purified by silica gel column chromatography (eluent: EA:PE (v / v) = 20%) to obtain 204 mg of a white solid product in a yield of 78.4%.

[0163] LC-MS(ESI):[M+H] + =363.1.

[0164] Step 3: Synthesis of N-(6-bromobenzo[d]thiazol-2-yl)acetamide

[0165] 6-Bromobenzo[d]thiazol-2-amine (3.00 g, 13.10 mmol) and 4-dimethylaminopyridine (1.92 g, 15.71 mmol) were added to dichloromethane (30 mL), followed by the dropwise addition of acetic anhydride (1.67 g, 16.37 mmol) in an ice bath. The mixture was allowed to react overnight at room temperature. Water (30 mL) was added to quench the reaction, followed by extraction with ethyl acetate (35 mL x 3). The organic phases were combined and washed with 1M dilute hydrochloric acid solution (30 mL x 2), followed by water (30 mL) and saturated brine (30 mL) each. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield 3.45 g of a yellow solid product in a 97.2% yield.

[0166] LC-MS (ESI): [M+H]+=271.0.

[0167] Step 4: Synthesis of N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)acetamide

[0168] N-(6-bromobenzo[d]thiazol-2-yl)acetamide (2.3 g, 8.48 mmol), pinacol diboronate (3.23 g, 12.72 mmol), potassium acetate (3.33 g, 33.93 mmol), and 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (0.62 g, 0.85 mmol) were added to dimethyl sulfoxide (50 mL). The reaction was continued at 90°C under a nitrogen atmosphere for 4 h. The mixture was cooled to room temperature and filtered through celite. The filtrate was diluted with water (100 mL) and extracted with ethyl acetate (35 mL x 3). The organic phases were combined. The residue was washed with water (100 mL × 2) and saturated brine (100 mL × 2), and the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent EA:PE (v / v) = 20%) to give 2.43 g of a white solid product with a yield of 90.0%.

[0169] LC-MS(ESI):[M+H] + =319.3;

[0170] 1 H NMR (500MHz, CDCl3) δ12.39(s,1H),8.26(s,1H),7.71(s,2H),2.21(s,3H),1.31(s,12H).

[0171] Step 5: Synthesis of (S)-6-(2-acetylaminobenzo[d]thiazol-6-yl)-N-(1-(3-fluorophenyl)ethyl)indoline-1-carboxamide

[0172] A mixture of (S)-6-bromo-N-(1-(3-fluorophenyl)ethyl)indoline-1-carboxamide (100 mg, 0.28 mmol), N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)acetamide (107 mg, 0.34 mmol), potassium carbonate (76 mg, 0.55 mmol), and 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (12 mg, 0.01 mmol) in 1,4-dioxane (4 mL) and water (2 mL) was heated to 80°C under a nitrogen atmosphere for 2 h. The mixture was cooled to room temperature and filtered through celite. The filtrate was diluted with water (20 mL) and extracted with ethyl acetate (10 mL x 3). The organic phases were combined. The organic phase was washed successively with water (10 mL × 2) and saturated brine (5 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent MeOH:DCM (v / v) = 1%) to give 55 mg of an off-white solid product in a yield of 40.1%.

[0173] LC-MS(ESI):[M+H]+ =475.4;

[0174] 1 H NMR(500MHz, CDCl3)δ10.50(br,1H),8.26(s,1H),8.01(s,1H),7.73(d,J=8.5 Hz,1H),7.66(d,J=8.5Hz,1H),7.34–7.30(m,1H),7.23–7.13(m,3H),7.08(d,J =10.1Hz,1H),7.01–6.91(m,1H),5.19–5.10(m,1H),4.79(d,J=7.0Hz,1H),4. 00(t,J=8.5Hz,2H),3.24(t,J=8.6Hz,2H),2.29(s,3H),1.56(d,J=7.0Hz,3H).

[0175] Example 3 Synthesis of (S)-6-(2-(2-cyclopropylacetylamino)benzo[d]thiazol-6-yl)-N-(1-(3-fluorophenyl)ethyl)indoline-1-carboxamide (Compound 3)

[0176] Step 1: Synthesis of N-(6-bromobenzo[d]thiazol-2-yl)cyclopropaneacetamide

[0177] A solution of cyclopropylacetic acid (131 mg, 1.31 mmol), HATU (498 mg, 1.31 mmol), and N,N-diisopropylethylamine (212 mg, 1.64 mmol) in N,N-dimethylformamide (3 mL) was stirred at room temperature for 30 minutes. 6-Bromobenzo[d]thiazol-2-amine (250 mg, 1.09 mmol) was then added and allowed to react at room temperature for 20 hours. The reaction was quenched by the addition of water (30 mL) and extracted with ethyl acetate (15 mL x 3). The organic phases were combined and washed with 1 M dilute hydrochloric acid solution (15 mL x 2), followed by water (15 mL) and saturated brine (10 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield 301 mg of a yellow solid product in an 88.7% yield.

[0178] 1 H NMR (500MHz, CDCl3) δ9.58(br,1H),7.94(d,J=2.0Hz,1H),7.62(d,J=8.6Hz,1H),7.53(dd,J=8 .7,2.0Hz,1H),3.51–3.44(m,1H),2.46(d,J=7.2Hz,2H),0.78–0.73(m,2H),0.35–0.31(m,2H).

[0179] Step 2: Synthesis of N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)cyclopropaneacetamide

[0180] A mixture of N-(6-bromobenzo[d]thiazol-2-yl)cyclopropaneacetamide (580 mg, 1.86 mmol), pinacol diboron (710 mg, 2.80 mmol), potassium acetate (732 mg, 7.46 mmol), and 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (137 mg, 0.19 mmol) in dimethyl sulfoxide (10 mL) was heated to 80°C under a nitrogen atmosphere overnight. The mixture was cooled to room temperature and filtered through celite. The filtrate was diluted with water (50 mL) and extracted with ethyl acetate (25 mL x 3). The organic phases were combined. The organic phase was washed successively with water (25 mL × 3) and saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent EA:PE (v / v) = 30%) to give 598 mg of an orange-pink solid product in a yield of 89.3%.

[0181] LC-MS(ESI):[M+H] + =359.3.

[0182] Step 3: Synthesis of (S)-6-(2-(2-cyclopropylacetylamino)benzo[d]thiazol-6-yl)-N-(1-(3-fluorophenyl)ethyl)indoline-1-carboxamide

[0183] A mixture of (S)-6-bromo-N-(1-(3-fluorophenyl)ethyl)indoline-1-carboxamide (172 mg, 0.47 mmol) (synthesis, see Example 2, Step 2), N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)cyclopropaneacetamide (255 mg, 0.71 mmol), potassium carbonate (131 mg, 0.95 mmol), and 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (38 mg, 0.05 mmol) in 1,4-dioxane (6 mL) and water (3 mL) was heated to 80°C under a nitrogen atmosphere for 4 h. The mixture was cooled to room temperature and filtered through celite. The filtrate was diluted with water (20 mL) and extracted with ethyl acetate (10 mL x 3). The organic phases were combined. The residue was washed with water (10 mL x 2) and saturated brine (5 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: MeOH:DCM (v / v) = 5%) to give 173 mg of a white solid product with a yield of 70.5%.

[0184] LC-MS(ESI):[M+H] + =515.3;

[0185] 1 H NMR (500MHz, CDCl3) δ9.99(br,1H),8.26(s,1H),8.02(s,1H),7.74(d,J=8.3Hz,1H),7.66(d,J =8.6Hz,1H),7.31(d,J=7.7Hz,1H),7.23–7.13(m,3H),7.08(d,J=10.0Hz,1H),6.99–6.90(m,1 H),5.19–5.10(m,1H),4.86–4.76(m,1H),4.00(t,J=8.8Hz,2H),3.23(t,J=8.7Hz,2H),2.44(d ,J=7.3Hz,2H),1.56(d,J=6.9Hz,3H),1.15–1.06(m,1H),0.76–0.65(m,2H),0.32–0.23(m,2H).

[0186] Example 4 Synthesis of (S)-6-(2-acetylamino-[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 4)

[0187] Step 1: Synthesis of N-(7-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)acetamide

[0188] Compound 7-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine (1.00 g, 4.37 mmol) and 4-dimethylaminopyridine (1.92 g, 15.17 mmol) were added to dichloromethane (30 mL), followed by the dropwise addition of acetic anhydride (1.67 g, 16.37 mmol) at 0°C. The reaction was allowed to react overnight at room temperature. Water (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL). The organic phase was collected and washed sequentially with saturated sodium carbonate solution (15 mL) and saturated brine (15 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford 215 mg of a dark yellow solid product with an 18.0% yield.

[0189] LC-MS(ESI):[M+H] + =255.0.

[0190] Step 2: Synthesis of (2-acetylamino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)boronic acid

[0191] N-(7-Bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)acetamide (150 mg, 0.59 mmol), bis(pinacolato)diboron (299 mg, 1.18 mmol), potassium acetate (115 mg, 1.18 mmol), and 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (48 mg, 0.06 mmol) were added to 1,4-dioxane (5 mL). The atmosphere was replaced with nitrogen three times and the mixture was heated to 90°C for 4 h. After cooling to room temperature, the mixture was filtered through Celite. The filtrate was added with water (15 mL) and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with water (10 mL x 3) and saturated brine (10 mL x 2), and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure to obtain 230 mg of a tan solid, which was used directly in the next reaction.

[0192] LC-MS(ESI):[M+H] + =221.1.

[0193] Step 3: Synthesis of 4-nitrophenyl 6-bromo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxylate

[0194] 6-Bromo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (200 mg, 0.99 mmol) and 4-dimethylaminopyridine (217 mg, 1.09 mmol) were dissolved in tetrahydrofuran (10 mL). 4-Nitrophenyl chloroformate (121 mg, 0.99 mmol) was then added portionwise at 0°C. The reaction was continued at 0°C for 1 h. Water (10 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (7 mL × 3). The organic phases were combined and washed with water (5 mL × 3) and saturated brine (5 mL × 2), then dried over anhydrous sodium sulfate. The mixture was filtered, concentrated under reduced pressure, and purified by preparative thin-layer chromatography (developing solvent: PE:EA (v / v) = 1:1). Anhydrous methanol (5 mL) was added, stirred thoroughly, and filtered. The filter cake was washed with petroleum ether and dried to yield 155 mg of an off-white solid in a yield of 42.9%.

[0195] LC-MS(ESI):[M+H] + =364.1;

[0196] 1 H NMR (500MHz, DMSO-d6) δ8.34(d,J=9.0Hz,2H),8.27(d,J=1.0Hz,1H),8.01(s,1H),7.58(d,J=8.0Hz,2H),4.37–4.23(m,2H),3.28–3.19(m,2H).

[0197] Step 4: Synthesis of (S)-6-bromo-N-(1-(3-fluorophenyl)ethyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxamide

[0198] 6-Bromo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxylic acid p-nitrophenyl ester (150 mg, 0.41 mmol) and potassium carbonate (238 mg, 1.71 mmol) were added to DMF (3 mL), followed by (S)-1-(3-fluorophenyl)ethanamine (347 mg, 2.51 mmol). The mixture was heated to 80°C for 4 h. The reaction was quenched with water (15 mL) and extracted with ethyl acetate (10 mL × 3). The organic phases were combined and washed with water (10 mL × 3) and saturated brine (10 mL × 2), then dried over anhydrous sodium sulfate. The product was filtered, concentrated under reduced pressure, and purified by preparative thin-layer chromatography (developing solvent PE:EA = 1:1) to obtain 93 mg of the product as a white solid in a 62.0% yield.

[0199] LC-MS(ESI):[M+H] + =364.2.

[0200] Step 5: Synthesis of (S)-6-(2-acetylamino-[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

[0201] Compound (S)-6-bromo-N-(1-(3-fluorophenyl)ethyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxamide (93 mg, 0.26 mmol), (2-acetamido-[1,2,4]triazolo[1,5-a]pyridin-7-yl)boronic acid (112 mg, 0.51 mmol), potassium phosphate (108 mg, 0.51 mmol), and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)palladium(II)] (20 mg, 0.03 mmol) were added to 1,4-dioxane (3 mL) and water (0.6 mL). The atmosphere was replaced with nitrogen three times and the mixture was heated to 80°C for 2 h. The mixture was cooled to room temperature and filtered through celite. The filtrate 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 × 2) and saturated brine (10 mL × 2), and dried over anhydrous sodium sulfate. The product was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent EA:PE (v / v) = 50-100%) to obtain 14 mg of a brown solid product in a yield of 10.9%.

[0202] LC-MS(ESI):[M+H] + =460.4;

[0203] 1 H NMR (500MHz, DMSO-d6) δ10.78(s,1H),8.86(d,J=7.1Hz,1H),8.42(d,J=1.3Hz,1H),8.29(s,1H),7.87(s,1H),7.39–7.33(m,2H),7 .25–7.21(m,2H),7.08–7.01(m,1H),5.03–4.94(m,1H),4.19–4.07(m,2H),3.29–3.27(m,2H),2.15(s,3H),1.47(d,J=7.1Hz,3H).

[0204] Example 5 Synthesis of (S)-6-(2-(cyclopropanecarboxamido)-[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 5)

[0205] Step 1: Synthesis of N-(7-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide

[0206] 7-Bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine (3.0 g, 14.08 mmol) and triethylamine (2.8 g, 28.16 mmol) were added to pyridine (40 mL) and stirred on ice for 10 minutes. Cyclopropanecarbonyl chloride (2.9 g, 28.16 mmol) was then added dropwise on ice. The temperature was gradually raised to room temperature and the reaction was allowed to proceed for 6 hours. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: MeOH:DCM (v / v) = 1:10) to afford 560 mg of the product as a colorless oil in a 14.1% yield.

[0207] LC-MS(ESI):[M+H] + =281.2;

[0208] 1 H NMR (400MHz, DMSO-d6) δ11.14(s,1H),8.80(dd,J=7.2,0.6Hz,1H),8.04(dd,J =2.0,0.6Hz,1H),7.29(dd,J=7.2,2.2Hz,1H),2.02(s,1H),0.84–0.81(m,4H).

[0209] Step 2: Synthesis of (2-(cyclopropanecarboxamido)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)boronic acid

[0210] N-(7-Bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide (50 mg, 0.18 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane) (137 mg, 0.54 mmol) were added to 1,4-dioxane (10 mL). Potassium acetate (53 mg, 0.54 mmol) was added, and the atmosphere was purged with nitrogen three times. X-Phos (16 mg, 0.02 mmol) and X-Phos-Pd-G2 (19 mg, 0.04 mmol) were added, and the atmosphere was purged with nitrogen again three times. The reaction was heated to 95°C and stirred overnight. The mixture was concentrated under reduced pressure, and the resulting crude product was used directly in the next step.

[0211] Step 3: Synthesis of (S)-6-(2-(cyclopropanecarboxamido)-[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

[0212] Compound (S)-6-bromo-N-(1-(3-fluorophenyl)ethyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxamide (100 mg, 0.27 mmol) (for synthesis, see Step 12 of Example 1) and (2-(cyclopropanecarboxamido)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)boronic acid (67 mg, 0.27 mmol) were added to 1,4-dioxane (10 mL) and water (2.5 mL). Potassium carbonate (112 mg, 0.81 mmol) was added, and the atmosphere was purged with nitrogen three times. Pd(PPh3)4 (35 mg, 0.03 mmol) was added, and the atmosphere was purged with nitrogen again three times. The mixture was heated to 85°C and stirred overnight. The residue was concentrated under reduced pressure and purified by preparative liquid phase purification (eluent: H2O:acetonitrile (v / v) = 50:50) to give 11 mg of a white solid product with a yield of 8.4%.

[0213] LC-MS(ESI):[M+H] + =486.2;

[0214] 1H NMR (400MHz, DMSO-d6) δ11.11(s,1H),8.89–8.84(m,1H),8.43(d,J=2.1Hz,1H),8.29(d,J=2.1Hz,1H),7.88(d,J=1.9Hz,1H),7.41–7.33(m,2H ),7.28–7.21(m,3H),7.08–7.01(m,1H),5.03–4.94(m,1H),4.22–4.05( m,2H),3.33–3.26(m,2H),1.47(d,J=7.1Hz,3H),0.84(d,J=6.2Hz,4H).

[0215] Example 6 Synthesis of (R)-6-(2-acetylaminobenzo[d]thiazol-6-yl)-N-(1-(3-fluorophenyl)ethyl)indoline-1-carboxamide (Compound 6)

[0216] Compound 6 was prepared by referring to the method of Example 2.

[0217] LC-MS(ESI):[M+H] + =475.3

[0218] 1 H NMR (500MHz, CDCl3) δ10.54(br,1H),8.19(s,1H),7.94(d,J=1.8Hz,1H),7.66(d ,J=8.5Hz,1H),7.59(dd,J=8.4,1.9Hz,1H),7.27–7.20(m,1H),7.16–7.08(m,3H) ,7.03–6.99(m,1H),6.91–6.86(m,1H),5.12–5.05(m,1H),4.72(d,J=7.0Hz,1H), 3.93(t,J=8.6Hz,2H),3.17(t,J=8.5Hz,2H),2.21(s,3H),1.49(d,J=6.9Hz,3H).

[0219] Example 7 Synthesis of (S)-6-(2-(cyclopropylcarboxamido)benzo[d]thiazol-6-yl)-N-(1-(3-fluorophenyl)ethyl)indoline-1-carboxamide (Compound 7)

[0220] Compound 7 was prepared by referring to the method of Example 2.

[0221] LC-MS(ESI):[M+H] + =501.4

[0222] 1 H NMR(500MHz,DMSO-d6)δ12.61(s,1H),8.14(d,J=11.5Hz,2H),7.75(d,J=8.3Hz,1H), 7.60(d,J=8.4Hz,1H),7.36(q,J=7.4Hz,1H),7.26–7.21(m,3H),7.18(d,J=7.9Hz,1H ),7.03(t,J=8.7Hz,1H),6.97(d,J=7.8Hz,1H),5.01–4.94(m,1H),4.14–4.00(m,2H) ,3.17(t,J=8.7Hz,2H),2.05–1.97(m,1H),1.46(d,J=7.0Hz,3H),1.00–0.92(m,4H).

[0223] Example 8 Synthesis of 6-(2-(cyclopropylcarboxamido)benzo[d]thiazol-6-yl)-N-(1-(3-fluorophenyl)cyclopropyl)-3,3-dimethylindoline-1-carboxamide (Compound 8)

[0224] Compound 8 was prepared by referring to the method of Example 2.

[0225] LC-MS(ESI):[M+H] + =541.4

[0226] 1 H NMR(500MHz,DMSO-d6)δ12.61(s,1H),8.17–8.11(m,2H),7.75(d,J=8.4Hz,1H),7.64–7.58(m,1H),7.53(s,1H),7.33–7.21(m,3H),7.08 –6.99(m,2H),6.99–6.93(m,1H),3.81(s,2H),2.04–2.00(m,1H),1.35(s,6H),1.31–1.27(m,2H),1.24–1.22(m,2H),0.98–0.94(m,4H).

[0227] Example 9 Synthesis of 6-(2-(cyclopropylcarboxamido)benzo[d]thiazol-6-yl)-N-(1-(3-fluorophenyl)cyclopropyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxamide (Compound 9)

[0228] Compound 9 was prepared by referring to the method of Example 1.

[0229] LC-MS(ESI):[M+H]+ =514.3

[0230] 1H NMR(500MHz,DMSO-d6)δ12.65(s,1H),8.31(d,J=2.1Hz,1H),8.28(d,J=2.1Hz,1H) ,8.23(d,J=2.0Hz,1H),7.78(d,J=8.4Hz,1H),7.73(s,1H),7.65(dd,J=8.5,1.9Hz ,1H),7.31(q,J=7.5Hz,1H),7.08–7.02(m,2H),6.99–6.94(m,1H),4.08(t,J=8.7H z,2H),3.28–3.23(m,2H),2.03–1.98(m,1H),1.31–1.26(m,4H),0.98–0.94(m,4H).

[0231] 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)

[0232] Compound 10 was prepared by referring to the method of Example 1.

[0233] LC-MS(ESI):[M+H] + =550.3

[0234] 1 H NMR(500MHz,DMSO-d6)δ12.76(s,1H),8.75–8.69(m,1H),8.64(s,1H),8.43(s ,1H),8.01(s,1H),7.88(d,J=8.4Hz,1H),7.81(d,J=8.3Hz,1H),7.37(dd,J=14 .5,7.7Hz,1H),7.20–7.11(m,2H),7.07–7.01(m,1H),4.60(t,J=17.6Hz,2H),2 .11–2.05(m,1H),1.41–1.37(m,2H),1.35(d,J=3.4Hz,2H),1.06–1.00(m,4H).

[0235] Example 11 Synthesis of 6'-(2-(cyclopropylcarboxamido)benzo[d]thiazol-6-yl)-N-(1-(3-fluorophenyl)cyclopropyl)spiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-1'(2'H)-carboxamide (Compound 11)

[0236] Step 1: Synthesis of diethyl 2-(5-bromo-3-nitropyridin-2-yl)malonate

[0237] 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 quenched by pouring into ice water (100 mL) and slowly added with dilute hydrochloric acid to adjust the pH to 3-4 with stirring. After completion of the reaction, 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 in a yield of 72.3%.

[0238] LC-MS(ESI):[M+H] + =361.1

[0239] 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).

[0240] Step 2: Synthesis of ethyl 2-(3-amino-5-bromopyridin-2-yl)acetate

[0241] 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). The mixture was then heated to 82°C for 1 hour. Filtered through celite, 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. Diluted with ethyl acetate (20 mL) and stirred 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 in a 51.3% yield.

[0242] LC-MS(ESI):[M+H] + =259.0

[0243] Step 3: Synthesis of 6-bromo-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one

[0244] 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 in a yield of 75.9%.

[0245] LC-MS(ESI):[M+H] + =213.0

[0246] Step 4: Synthesis of 6'-bromospiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridin]-2'(1'H)-one

[0247] 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: DCM) to obtain 570 mg of the product as a white solid in a 57.1% yield.

[0248] LC-MS(ESI):[M+H] + =239.1

[0249] Step 5: 6'-Bromo-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine] (structural formula: )

[0250] 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: DCM) to give 320 mg of a light yellow solid product in a yield of 59.7%.

[0251] LC-MS(ESI):[M+H] + =225.0.

[0252] Other steps refer to the method of Example 1. (6-bromo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine) was replaced with (6'-bromo-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]), ((S)-1-(3-fluorophenyl)ethan-1-amine) is replaced by (3-Fluorophenylcyclopropylamine).

[0253] LC-MS(ESI):[M+H] + =540.4

[0254] 1 H NMR(500MHz,DMSO-d6)δ12.64(s,1H),8.26–8.19(m,3H),7.77(d,J=8.3Hz,1H),7.69–7.62(m,2H),7.35–7.28(m,1H),7.09 –7.02(m,2H),6.99–6.94(m,1H),4.15(s,2H),2.02–1.99(m,1H),1.29–1.25(m,6H),1.16–1.11(m,2H),1.00–0.92(m,4H).

[0255] Example 12 Synthesis of (S)-6'-(2-(cyclopropylcarboxamido)benzo[d]thiazol-6-yl)-N-(1-(3-fluorophenyl)ethyl)spiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-1'(2'H)-carboxamide (Compound 12)

[0256] Compound 12 was prepared by referring to the method of Example 11.

[0257] LC-MS(ESI):[M+H] + =528.5

[0258] 1 H NMR(500MHz,DMSO-d6)δ12.64(s,1H),8.25–8.18(m,3H),7.78(d,J=8.4Hz,1H),7.63(d ,J=8.5Hz,1H),7.39–7.32(m,1H),7.24(d,J=8.6Hz,2H),7.11(d,J=7.7Hz,1H),7.07–7 .00(m,1H),4.99–4.93(m,1H),4.21(d,J=9.8Hz,1H),4.16(d,J=9.8Hz,1H),2.04–1.99 (m,1H),1.45(d,J=7.2Hz,3H),1.26–1.24(m,2H),1.17–1.14(m,2H),0.98–0.94(m,4H).

[0259] Example 13 Synthesis of (S)-6'-2-(cyclopropanecarboxamide)benzo[d]thiazol-6-yl)-N-(1-(2-fluorophenyl)ethyl)spiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-1'(2'H)-carboxamide (Compound 13)

[0260] Compound 13 was prepared by referring to the method of Example 11.

[0261] LC-MS(ESI):[M+H] + =528.2

[0262] 1H NMR(500MHz,DMSO-d6)δ12.65(s,1H),8.27–8.18(m,3H),7.78(d,J=8.4Hz,1 H),7.64(dd,J=8.4,1.3Hz,1H),7.56–7.49(m,1H),7.32–7.25(m,1H),7.22– 7.11(m,3H),5.27–5.19(m,1H),4.22(q,J=9.9Hz,2H),2.05–1.97(m,1H),1. 45(d,J=7.0Hz,3H),1.31–1.26(m,2H),1.20–1.15(m,2H),1.01–0.93(m,4H).

[0263] Example 14 Synthesis of (S)-6-(2-(cyclopropanecarboxamide)benzo[d]thiazol-6-yl)-3,3-difluoro-N-(1-(3-fluorophenyl)ethyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxamide (Compound 14)

[0264] Compound 14 was prepared by referring to the method of Example 11.

[0265] LC-MS(ESI):[M+H] + =538.1

[0266] 1 H NMR (500MHz, DMSO-d6) δ12.71(s,1H),8.65(d,J=1.3Hz,1H),8.54(s,1H),8.36(s,1H),7.84(d, J=8.4Hz,1H),7.77–7.72(m,1H),7.45–7.40(m,1H),7.39–7.35(m,1H),7.29–7.24(m,2H),7.08–7.02(m,1 H),4.96(p,J=6.8Hz,1H),4.69–4.50(m,2H),2.06–1.99(m,1H),1.48(d,J=7.0Hz,3H),1.02–0.93(m,4H).

[0267] Example 15 Synthesis of (S)-6'-(2-(cyclopropylcarboxamido)benzo[d]thiazol-6-yl)-N-(1-(3,4-difluorophenyl)ethyl)spiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-1'(2'H)-carboxamide (Compound 15)

[0268] Compound 15 was prepared by referring to the method of Example 11.

[0269] LC-MS(ESI):[M+H] + =546.1

[0270] 1 H NMR(500MHz,DMSO-d6)δ12.65(s,1H),8.25–8.19(m,3H),7.78(d,J=8.4Hz,1H),7.63(dd,J=8 .4,1.9Hz,1H),7.47(ddd,J=12.1,7.8,2.2Hz,1H),7.40–7.33(m,1H),7.26–7.22(m,1H),7.1 0(d,J=7.6Hz,1H),4.94(p,J=7.2Hz,1H),4.21(d,J=9.9Hz,1H),4.15(d,J=9.9Hz,1H),2.04– 1.98(m,1H),1.44(d,J=7.1Hz,3H),1.26–1.25(m,2H),1.17–1.13(m,2H),0.98–0.95(m,4H).

[0271] Example 16 Synthesis of N-(1-(4-cyano-2-fluorophenyl)ethyl)-6'-(2-(cyclopropanecarboxamido)benzo[d]thiazol-6-yl)spiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-1'(2'H)-carboxamide (Compound 16)

[0272] Compound 16 was prepared by referring to the method of Example 11.

[0273] LC-MS(ESI):[M+H] + =553.1

[0274] 1 H NMR (500MHz, DMSO-d6) δ12.64(s,1H),8.30–8.13(m,3H),7.85–7.66(m,4H),7.62(d,J=8.4Hz,1H),7.27(d,J=7.3Hz,1H),5.24–5.1 7(m,1H),4.29–4.23(m,1H),4.19(d,J=9.9Hz,1H),2.03–1.98(m,1H),1.45(d,J=7.1Hz,3H),1.28–1.21(m,4H),0.97–0.94(m,4H).

[0275] Example 17 Synthesis of (R)-6'-(2-(cyclopropylcarboxamido)benzo[d]thiazol-6-yl)-N-(1-(3-(trifluoromethoxy)phenyl)ethyl)spiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-1'(2'H)-carboxamide (Compound 17)

[0276] Compound 17 was prepared by referring to the method of Example 11.

[0277] LC-MS(ESI):[M+H] + =594.2

[0278] 1 H NMR(500MHz,DMSO-d6)δ12.65(s,1H),8.25–8.18(m,3H),7.82–7.75(m,1H) ,7.63(d,J=8.5Hz,1H),7.48–7.43(m,2H),7.39(s,1H),7.21(d,J=7.4Hz,1 H),7.17(d,J=7.5Hz,1H),5.03–4.96(m,1H),4.23–4.14(m,2H),2.03–1.99 (m,1H),1.46(d,J=7.1Hz,3H),1.26(s,2H),1.15(s,2H),0.97–0.94(m,4H).

[0279] Example 18 Synthesis of (S)-6'-(2-(cyclopropanecarboxamide)benzo[d]thiazol-6-yl)-N-(1-(4-fluorophenyl)ethyl)spiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-1'(2'H)-carboxamide (Compound 18)

[0280] Compound 18 was prepared by referring to the method of Example 11.

[0281] LC-MS(ESI):[M+H] + =528.2

[0282] 1H NMR(500MHz,DMSO-d6)δ12.66(d,J=6.3Hz,1H),8.25–8.20(m,3H),7.81–7.76(m,1H),7.66–7.62(m,1H),7.46–7.43(m,2H),7.21 –7.05(m,3H),4.96(q,J=7.1Hz,1H),4.18(s,2H),2.09–1.93(m,1H),1.46(d,J=6.9Hz,3H),1.27–1.24(m,4H),1.09–0.91(m,4H).

[0283] Example 19 Synthesis of 6'-(2-(cyclopropylcarboxamido)benzo[d]thiazol-6-yl)-N-(1-(5-cyano-2-fluorophenyl)ethyl)spiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-1'(2'H)-carboxamide (Compound 19)

[0284] Compound 19 was prepared by referring to the method of Example 11.

[0285] LC-MS(ESI):[M+H] + =553.2

[0286] 1 H NMR(500MHz,DMSO-d6)δ8.24(s,1H),8.20(s,2H),8.04(d,J=6.9Hz,1H),7.86–7.80 (m,1H),7.77(d,J=8.4Hz,1H),7.63(d,J=8.6Hz,1H),7.43(t,J=9.3Hz,1H),7.19(d ,J=7.4Hz,1H),5.26–5.19(m,1H),4.30(d,J=9.8Hz,1H),4.16(d,J=9.8Hz,1H),2.0 4–1.98(m,1H),1.45(d,J=7.1Hz,3H),1.26(s,2H),1.17(s,2H),0.98–0.94(m,4H).

[0287] Example 20 Synthesis of (S)-6'-(2-(cyclopropanecarboxamide)benzo[d]thiazol-6-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)spiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-1'(2'H)-carboxamide (Compound 20)

[0288] Compound 20 was prepared by referring to the method of Example 11.

[0289] LC-MS(ESI):[M+H] + =594.1

[0290] 1 H NMR(500MHz, DMSO-d6)δ12.63(s,1H),8.38–8.14(m,3H),7.78(d,J=8.2Hz,1H),7.72–7.46(m,3H),7.45–7.25(m,2H),7.23–7.06(m ,1H),5.05–4.93(m,1H),4.26–4.12(m,2H),2.10–1.94(m,1H),1.46(d,J=6.9Hz,3H),1.26(s,2H),1.15(s,2H),1.05–0.89(m,4H).

[0291] Example 21 Synthesis of (S)-N-(1-(4-cyanophenyl)ethyl)-6'-(2-(cyclopropanecarboxamido)benzo[d]thiazol-6-yl)spiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-1'(2'H)-carboxamide (Compound 21)

[0292] Compound 21 was prepared by referring to the method of Example 11.

[0293] LC-MS(ESI):[M+H] + =535.1

[0294] 1 H NMR (500MHz, DMSO-d6) δ12.64(s,1H),8.23(d,J=1.9Hz,1H),8.19(d,J=2.0Hz,2H),7.80–7.88(m,3H),7.65–7.58(m,3H),7.20(d,J=7.4Hz,1H), 5.02–4.96(m,1H),4.23(d,J=9.9Hz,1H),4.17(d,J=9.9Hz,1H),2.04–1 .97(m,1H),1.46(d,J=7.1Hz,3H),1.32–1.22(m,6H),1.16–1.14(m,2H).

[0295] Example 22 Synthesis of (S)-6'-(2-(cyclopropanecarboxamide)benzo[d]thiazol-6-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)spiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-1'(2'H)-carboxamide (Compound 22)

[0296] Compound 22 was prepared by referring to the method of Example 11.

[0297] LC-MS(ESI):[M+H] + =578.2

[0298] 1 H NMR(500MHz,DMSO-d6)δ12.62(s,1H),8.25–8.18(m,3H),7.78(d,J=8.4Hz,1H),7.72–7.66 (m,2H),7.65–7.60(m,3H),7.21(d,J=7.3Hz,1H),5.01(p,J=7.2Hz,1H),4.20(q,J=9.9Hz,2H),2 .03–1.97(m,1H),1.48(d,J=7.1Hz,3H),1.28–1.25(m,2H),1.17–1.14(m,2H),0.98–0.94(m,4H).

[0299] Example 23 Synthesis of (S)-6'-(2-(cyclopropanecarboxamide)-[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 23)

[0300] Compound 23 was prepared by referring to the method of Example 11.

[0301] LC-MS(ESI):[M+H] + =512.2

[0302] 1 H NMR (500MHz, DMSO-d6) δ11.05 (s, 1H), 8.85 (d, J = 7.1Hz, 1H), 8.36 (d, J = 2. 1Hz,1H),8.26(d,J=2.1Hz,1H),7.86(s,1H),7.48–7.42(m,2H),7.37–7.32 (m,1H),7.18–7.13(m,3H),5.00–4.94(m,1H),4.19(s,2H),2.07(s,1H),1. 46(d,J=7.0Hz,3H),1.28(s,2H),1.20–1.17(m,2H),0.84(d,J=6.4Hz,4H).

[0303] Example 24 Synthesis of (S)-N-(1-(4-cyanophenyl)ethyl)-6'-(2-(cyclopropanecarboxamide)-1H-benzo[d]imidazol-6-yl)spiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-1'(2'H)-carboxamide (Compound 24)

[0304] Compound 24 was prepared by referring to the method of Example 11.

[0305] LC-MS(ESI):[M+H] + =518.2

[0306] 1 H NMR(500MHz,DMSO-d6)δ8.16(s,2H),7.79(d,J=7.9Hz,2H),7.63–7.58(m,3H),7.48(d,J=8.4Hz,1H),7.29(d,J=8.3Hz,1H),7.27–7.22(m,1H) ,7.21–7.12(m,2H),5.02–4.96(m,1H),4.24–4.13(m,2H),4.03(q,J=7 .1Hz,1H),1.46(d,J=7.1Hz,3H),1.26–1.23(m,4H),1.21–1.12(m,4H).

[0307] Example 25 Synthesis of (1-(2-(cyclopropanecarboxamide)benzo[d]thiazol-6-yl)-3,3-difluoro-N-(1-(3-fluorophenyl)cyclopropyl)-1H-pyrrolo[3,2-b]pyridine-6-carboxamide (Compound 25)

[0308] Compound 25 was prepared by referring to the method of Example 11.

[0309] LC-MS(ESI):[M+H] + =534.3

[0310] 1H NMR(500MHz,DMSO-d6)δ11.10(s,1H),8.91(d,J=7.0Hz,1H),8.75(d,J=1.7Hz,1 H),8.61(s,1H),8.03(s,1H),7.99(s,1H),7.44(dd,J=7.1,1.5Hz,1H),7.31(dd ,J=14.5,7.9Hz,1H),7.14–7.06(m,2H),7.01–6.94(m,1H),4.56(t,J=17.8Hz,2 H),2.04–1.97(m,1H),1.36–1.31(m,2H),1.31–1.29(m,2H),0.87–0.82(m,4H).

[0311] Example 26 Synthesis of (S)-6-(2-(cyclopropanecarboxamide)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(1-(3-fluorophenyl)ethyl)indoline-1-carboxamide (Compound 26)

[0312] Compound 26 was prepared by referring to the method of Example 11.

[0313] LC-MS(ESI):[M+H] + =485.4

[0314] 1 H NMR(500MHz,DMSO-d6)δ11.03(s,1H),8.81(d,J=6.9Hz,1H),8.21(s,1H),7.75(s,1H),7.40–7.34(m,1H),7.33–7.29(m,2H),7.27–7.21(m,2H ),7.07–6.98(m,2H),5.04–4.93(m,1H),4.15–4.01(m,2H),3.20(t,J=8 .3Hz,2H),2.11–2.03(m,1H),1.46(d,J=6.8Hz,3H),0.87–0.80(m,4H).

[0315] Example 27 Synthesis of (S)-6-(2-acetylamino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(1-(3-fluorophenyl)ethyl)indoline-1-carboxamide (Compound 27)

[0316] Compound 27 was prepared by referring to the method of Example 11.

[0317] LC-MS(ESI):[M+H] +=459.4

[0318] 1 H NMR (500MHz, DMSO-d6) δ10.74(s,1H),8.82(d,J=7.1Hz,1H),8.21(s,1H),7.75(s,1H),7.40–7.33(m,1H),7.33–7.28(m,2H),7.26 –7.21(m,2H),7.07–7.00(m,2H),5.01–4.95(m,1H),4.14–4.01(m,2H),3.20(t,J=8.7Hz,2H),2.15(s,3H),1.46(d,J=7.1Hz,3H).

[0319] Example 28 Synthesis of 6-(2-(cyclopropanecarboxamide)-[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 28)

[0320] Compound 28 was prepared by referring to the method of Example 4.

[0321] LC-MS(ESI):[M+H] + =548.8

[0322] 1 H NMR (500MHz, DMSO-d6) δ11.07(s,1H),8.84(d,J=7.1Hz,1H),8.44(d,J=2.3Hz,1H),8.31(d,J=2.2Hz,1H),7.90–7.84(m,2H),7.63(d,J=8.1Hz,2H) ,7.44(d,J=8.1Hz,2H),7.38–7.34(m,1H),4.12(t,J=8.7Hz,2H),3.33–3 .27(m,2H),2.12–2.01(m,1H),1.35(d,J=11.1Hz,4H),0.88–0.81(m,4H).

[0323] Example 29 Synthesis of 6-(2-(cyclopropanecarboxamide)-[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 29)

[0324] Compound 29 was prepared by referring to the method of Example 4.

[0325] LC-MS(ESI):[M+H] + =516.4

[0326] 1 H NMR (500MHz, DMSO-d6) δ11.05(s,1H),8.85(d,J=7.1Hz,1H),8.43(d,J=2.2Hz,1H),8.30(d,J=2.2Hz,1H),7.87(d,J=2.0Hz,1H), 7.77(s,1H),7.38–7.24(m,3H),7.10(d,J=8.7Hz,1H),4.08(t,J=8.7Hz,2H),3.26(s,2H),1.31–1.21(m,5H),0.87–0.81(m,4H).

[0327] Example 30 Synthesis of (S)-6-(2-acetylamino-[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 30)

[0328] Compound 30 was prepared by referring to the method of Example 4.

[0329] LC-MS(ESI):[M+H] + =478.3

[0330] 1 H NMR (500MHz, DMSO-d6) δ10.77(s,1H),8.87(d,J=7.1Hz,1H),8.42(d,J=2.1 Hz,1H),8.29(d,J=2.1Hz,1H),7.87(d,J=2.1Hz,1H),7.49–7.44(m,1H),7. 42–7.32(m,2H),7.27–7.23(m,1H),7.20(d,J=7.7Hz,1H),4.96(t,J=7.3Hz ,1H),4.20–3.99(m,2H),3.30–3.27(m,2H),2.15(s,3H),1.46(d,J=7.1Hz, 3H).

[0331] Example 31 Synthesis of 6-(2-acetylamino-[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 31)

[0332] Compound 31 was prepared by referring to the method of Example 4.

[0333] LC-MS(ESI):[M+H] + =490.3

[0334] 1 H NMR (500MHz, DMSO-d6) δ10.78(s,1H),8.86(d,J=7.1Hz,1H),8.43(d,J=2.1Hz,1H),8.30(d,J=2.1Hz,1H),7.87(s,1H),7 .77(s,1H),7.39–7.24(m,3H),7.10(d,J=8.7Hz,1H),4.08(t,J=8.7Hz,2H),3.26(s,2H),2.15(s,3H),1.28–1.22(m,4H).

[0335] Example 32 Synthesis of 6-(2-(cyclopropanecarboxamide)-[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 32)

[0336] Compound 32 was prepared by referring to the method of Example 4.

[0337] LC-MS(ESI):[M+H] + =498.4

[0338] 1 H NMR(500MHz,DMSO-d6)δ11.07(s,1H),8.85(d,J=7.1Hz,1H),8.44(s,1H),8 .32(s,1H),7.87(s,1H),7.78(s,1H),7.37(d,J=7.2Hz,1H),7.32(q,J=7.5 Hz,1H),7.10–7.02(m,2H),7.01–6.94(m,1H),4.10(t,J=8.8Hz,2H),3.32– 3.26(m,2H),2.12–1.98(m,1H),1.29(d,J=11.2Hz,4H),0.89–0.80(m,4H).

[0339] Example 33 Synthesis of 6-(2-(cyclopropanecarboxamide)imidazo[1,2-a]pyridin-6-yl)-N-(1-(3-fluorophenyl)cyclopropyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxamide (Compound 33)

[0340] Compound 33 was prepared by referring to the method of Example 4.

[0341] LC-MS(ESI):[M+H] + =497.3

[0342] 1 H NMR(500MHz,DMSO-d6)δ10.94(s,1H),8.88(s,1H),8.29–8.24(m,2H),8.09(s,1H),7.75(s,1H), 7.46(s,2H),7.31(dd,J=14.4,7.9Hz,1H),7.08–7.02(m,2H),6.99–6.94(m,1H),4.08(t,J= 8.7Hz,2H),3.27–3.23(m,2H),1.95–1.91(m,1H),1.28(d,J=7.3Hz,4H),0.84–0.75(m,4H).

[0343] Example 34 Synthesis of 6-(2-(cyclopropanecarboxamide)imidazo[1,2-a]pyridin-6-yl)-N-(1-(4-(trifluoromethyl)phenyl)cyclopropyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxamide (Compound 34)

[0344] Compound 34 was prepared by referring to the method of Example 4.

[0345] LC-MS(ESI):[M+H] + =547.4

[0346] 1 H NMR (500MHz, DMSO-d6) δ10.94(s,1H),8.87(s,1H),8.29(d,J=1.4Hz,1H),8.25(d,1H),8.09(s,1H),7.83(s,1H),7.63(d,J=8.2H z,2H),7.48–7.41(m,4H),4.10(t,J=8.6Hz,2H),3.29–3.26(m,2H),1.97–1.91(m,1H),1.35(d,J=8.3Hz,4H),0.84–0.77(m,4H).

[0347] Example 35 Synthesis of 6'-(2-(cyclopropanecarboxamide)imidazo[1,2-a]pyridin-6-yl)-N-(1-(3-fluorophenyl)cyclopropyl)spiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-1'(2'H)-carboxamide (Compound 35)

[0348] Compound 35 was prepared by referring to the method of Example 4.

[0349] LC-MS(ESI):[M+H] + =523.4

[0350] 1 H NMR(500MHz,DMSO-d6)δ10.93(s,1H),8.85(s,1H),8.21(s,2H),8.09(s,1H),7.69(s,1H),7.49–7.43(m,2H),7.35–7.27(m,1H),7.09–7 .02(m,2H),7.00–6.93(m,1H),4.15(s,2H),1.97–1.91(m,1H),1.28(s,2H),1.24(d,J=4.3Hz,4H),1.16–1.13(m,2H),0.83–0.77(m,4H).

[0351] Example 36 Synthesis of 6'-(2-(cyclopropanecarboxamide)imidazo[1,2-a]pyridin-6-yl)-N-(1-(4-(trifluoromethyl)phenyl)cyclopropyl)spiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-1'(2'H)-carboxamide (Compound 36)

[0352] Compound 36 was prepared by referring to the method of Example 4.

[0353] LC-MS(ESI):[M+H] + =573.4

[0354] 1 H NMR(500MHz,DMSO-d6)δ10.93(s,1H),8.85(s,1H),8.23–8.18(m,2H),8.08(s,1H),7.77(s,1H),7. 62(d,J=8.2Hz,2H),7.49–7.41(m,4H),4.17(s,2H),1.96–1.90(m,1H),1.34(d,J=9.8Hz,4H),1.26– 1.22(m,2H),1.17–1.13(m,2H),0.83–0.76(m,4H).

[0355] Example 37 Synthesis of 6-(2-acetylamino-[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 37)

[0356] Compound 37 was prepared by referring to the method of Example 4.

[0357] LC-MS(ESI):[M+H] + =472.4

[0358] 1 H NMR(500MHz,DMSO DMSO-d6)δ10.78(s,1H),8.86(d,J=7.0Hz,1H),8.40(s,1H),8.27(s,1H),7.87(s,1H),7.66(s,1H),7.60(t,J=7.4Hz,1H),7.36 (d,J=6.9Hz,1H),7.29–7.23(m,1H),7.14–7.08(m,2H),3.99(t,J=8.6Hz,2H),3.24(t,J=8.6Hz,2H),2.16(s,3H),1.21(s,4H).

[0359] Example 38 Synthesis of 6-(2-(cyclopropanecarboxamide)-[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 38)

[0360] Compound 38 was prepared by referring to the method of Example 4.

[0361] LC-MS(ESI):[M+H] + =498.4

[0362] 1H NMR (500MHz, DMSO-d6) δ11.06(s,1H),8.86(d,J=6.9Hz,1H),8.41(s,1H),8.27(s,1H),7.88(s,1H),7.66(s,1H),7.60(t,J=7.5Hz,1H),7.36(d,J= 6.9Hz,1H),7.29–7.24(m,1H),7.15–7.09(m,2H),3.99(t,J=8.6Hz,2H), 3.26–3.22(m,2H),2.15–1.97(m,1H),1.21(s,4H),0.84(d,J=5.4Hz,4H).

[0363] Experimental Example 1 RIPK1 kinase inhibitory activity test

[0364] 1. Experimental Materials

[0365] (1) Reagents are shown in Table 1 below.

[0366] Table 1

[0367] 2. Methods

[0368] (1) Compound dilution

[0369] Compounds (control compound RIPA-56 and the present compounds) were diluted as follows: the compounds were dissolved in DMSO to obtain a 10 mM solution, followed by 4-fold serial dilutions to obtain 11 concentrations (1000, 250, 62.5, 15.625, 3.906, 0.977, 0.244, 0.061, 0.015, 0.004, and 0 uM).

[0370] (2) Experimental methods

[0371] This application uses ADP-Glo TM The kinase assay kit was used to determine the inhibitory activity of compounds against RIPK1 as follows:

[0372] (a) Transfer 100 nL / well of the diluted compound solution to a 384-well plate.

[0373] (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.

[0374] (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.

[0375] (d) Add 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.

[0376] (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.

[0377] (f) Read the fluorescence value using a microplate reader.

[0378] 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.

[0379] 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.

[0380] See Table 1 for the results.

[0381] Table 1. IC values ​​of the inhibitory effects of some compounds provided in some embodiments of the present invention on RIPK1 50 value

[0382] Results and Discussion: The compounds of the present invention exhibited superior RIPK1 inhibitory activity.

[0383] Experimental Example 2 Pharmacokinetic Test

[0384] 1) Pharmacokinetic test in mice

[0385] 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.

[0386] 2) Pharmacokinetic test in rats

[0387] 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.

[0388] 3) Canine pharmacokinetic testing

[0389] 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 the plasma samples and generate drug concentration-time curves. Pharmacokinetic parameters were calculated using a non-compartmental model using WinNonlin software.

[0390] Experimental conclusion: The compounds of the present invention exhibit excellent pharmacokinetic properties.

[0391] 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, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the compound represented by formula (I), in: X is N or CR 15 ; Y1 is C or N; Y2 is N, O, S, or CR 16 or NR 18 ; Y3 is N, O, S, or CR 17 or NR 19 ; Y4 is C or N; Ring A is C 6-10 Aryl or 5-10 membered heteroaryl; Each R a are independently H, D, F, Cl, Br, I, CN, hydroxy, nitro, amino, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Alkylamino, the C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 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; 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 Haloalkoxy, -C 1-6 Alkylene-C 1-6 Alkoxy, C 2-6 Alkenyl or C 2-6 Alkynyl, the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Haloalkoxy, -C 1-6 Alkylene-C 1-6 Alkoxy, C 2-6 Alkenyl and C 2-6 Alkynyl may be 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; R 3 、R 13 、R 18 and R 19 Each independently is H, 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; 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 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl and 3-6 membered heterocyclyl may be independently optionally substituted with 1, 2, 3, 4 or 5 substituents selected from D, F, Cl, Br, I, CN, oxo (=O), hydroxy, amino and nitro; R 14 -LR b , where L is a bond, -O-, or -NR c - or C 1-6 alkylene; R b H, 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 Haloalkoxy, -C 1-6 Alkylene-C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the C 1-6 Alkyl, C 1-6 Halogenated alkyl, 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 be independently optionally substituted by 1, 2, 3, 4 or 5 groups selected from D, F, Cl, Br, I, CN, oxo (=O), substituted with hydroxy, amino and nitro substituents; R c H or C 1-6 alkyl; n is 1, 2, 3, 4, 5, 6, 7 or 8.

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

4. The compound according to any one of claims 1 to 3, wherein ring A is phenyl, naphthyl, Each R a 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 optionally substituted with 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 to 4, 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 Haloalkoxy, -C 1-3 Alkylene-C 1-3 Alkoxy, C 2-3 Alkenyl or C 2-3 Alkynyl, the C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 aminoalkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, C 1-3 Haloalkoxy, -C 1-3 Alkylene-C 1-3 Alkoxy, C 2-3 Alkenyl and C 2-3 Alkynyl may 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), hydroxy, amino and nitro; 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; 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 Base, 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.

6. The compound according to any one of claims 1 to 5, wherein 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; R 3 、R 13 、R 18 and R 19 Each is independently 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 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.

7. The compound according to any one of claims 1 to 6, wherein R 14 -LR b , where L is a bond, -O-, or -NR c - or C 1-3 alkylene; R b H, 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 Haloalkoxy, -C 1-3 Alkylene-C 1-3 Alkoxy, C 2-3 Alkenyl, C 2-3 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the C 1-3 Alkyl, C 1-3 Halogenated alkyl, 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 be independently optionally substituted with 1, 2, 3, 4 or 5 substituents selected from D, F, Cl, Br, I, CN, oxo (=O), hydroxy, amino and nitro; R c H or C 1-3 alkyl.

8. The compound according to any one of claims 1 to 7, wherein R 14 -LR b , where L is a bond, -O-, or -NR c -, methylene or ethylene; R b is H, 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, cyclo pentyl, 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, may be independently optionally substituted with 1, 2, 3, 4 or 5 substituents selected from D, F, Cl, Br, I, CN, oxo (=O), hydroxy, amino and nitro; R c is H or methyl.

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

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

12. The use according to 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 11, wherein The diseases mediated by the RIPK1 inhibitor are 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 diseases, 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.