Pyrimidinone Compounds and Their Uses

Abstract

The present invention relates to pyrimidinone compounds and their uses. Specifically, the present invention relates to pyrimidinone compounds of formula (I), pharmaceutical compositions containing them, and their preparation methods and uses, wherein each variable is as defined in the specification.

Description

Technical Field

[0001] The present invention relates to pyrimidinone compounds, pharmaceutical compositions containing them, and their preparation methods and uses. Background Art

[0002] Receptor-interacting protein kinase 1 (RIPK1) belongs to serine / threonine protein kinases and is an important cell signal transduction molecule. In 1995, Stanger et al. discovered the first member of the RIP family, RIPK1, through a yeast two-hybrid experiment. Its C-terminus is a death domain (DD), which can interact with the death receptor family member Fas, so it was named receptor-interacting protein (Stanger BZ. et al., Cell. 1995, 81: 513-523). The N-terminus of RIPK1 is a serine / threonine-specific kinase domain, which can catalyze the autophosphorylation of RIPK1 at serine / threonine residue sites; the C-terminus is a death domain, through which it interacts with other proteins containing the death domain; between the N-terminus and the C-terminus is an intermediate domain, one segment of which is a homotypic interaction motif (RIP homotypic interaction motif, RHIM), which is the domain for the interaction between RIPK1 and RIPK3 (Grootjans S, et al., Cell Death Differ. 2017, 24(7): 1184-1195).

[0003] Necroptosis is a new type of programmed cell death, regulated by intracellular signaling factors, and plays an important role in the process of individual development and the occurrence and development of diseases. The mechanisms triggering necroptosis include tumor necrosis factor (TNFα), Fas, TNF-related apoptosis-inducing ligand (TRAIL), interferon (IFN), lipopolysaccharide (LPS), double-stranded RNA and DNA damage, endoplasmic reticulum stress, viral infection, and the use of anticancer drugs. RIPK1 is a key molecule regulating apoptosis, necroptosis, and inflammatory signaling pathways, and is involved in many important biological processes such as embryonic development, hematopoiesis system development, and immune homeostasis maintenance (Ofengeim D, et al., Nat Rev Mol Cell Biol. 2013, 14:727-736). Taking necroptosis induced by TNFα as an example, after TNFα binds to TNFR1, the receptor trimerizes, and then recruits multiple molecules including RIPK1 through the death domain, activating the NF-κB signaling pathway, generating a large number of cytokines, and promoting cell survival (Kelliher MA, et al., Immunity. 1998, 8:297-303). In different cell types and microenvironments, RIPK1 recruits Fas-associated protein with death domain (FADD) and procaspase 8, triggering apoptosis (Feoktistova M, et al., Mol Cell. 2011, 43:449-463). When the apoptotic pathway is inhibited, RIPK1 interacts with RIPK3 through the RHIM domain, promoting the autophosphorylation of RIPK3. Autophosphorylated RIPK3 phosphorylates MLKL, promoting the formation of a trimer of MLKL and its translocation to the plasma membrane, resulting in swelling and rupture of the cell membrane and leakage of intracellular contents, causing necroptosis (Cai Z, et al., Nat Cell Biol. 2014, 16:55-65). Therefore, regulating the kinase activity of RIPK1 can affect apoptosis, necroptosis, and the inflammatory response triggered by intracellular substances released after cell disintegration.

[0004] The important role of RIPK1 in regulating cell death and inflammation has made selective RIPK1 inhibitors one of the current research hotspots for treating various diseases. Current studies have shown that RIPK1 inhibitors have potential therapeutic effects on a variety of diseases, including central nervous system degenerative diseases, peripheral inflammation, and autoimmune diseases. These diseases include multiple sclerosis (Ofengeim D, et al., Cell Rep. 2015, 10:1836-1849), Huntington's disease (Zhu S, et al., Cell Death Dis. 2011, 2:e115-24), Alzheimer's disease (Caccamo A, et al., Nat Neurosci. 2017, 20:1236-1246), Parkinson's disease (Lin QS, et al., Lab Invest. 2020, 100(3):503-511), amyotrophic lateral sclerosis (Re DB, et al., Neuron. 2014, 81(5):1001-1008), retinitis pigmentosa (Murakami Y, et al., Proc Natl Acad Sci U S A. 2012, 109(36):14598-603), retinal degeneration (Jang KH, et al., Exp Eye Res. 2019, 180:8-17), age-related macular degeneration (AMD) (Murakami Y, et al., Cell Death Differ. 2013, 21:270-7), inflammatory bowel diseases including Crohn's disease and ulcerative colitis (Liu ZY, et al., Am J Cancer Res. 2015, 5(10):3174-85), psoriasis (Duan X, et al., Cell Death Dis. 2020, 11(2):134), rheumatoid arthritis (Jhun J, et al., J Transl Med. 2019, 17(1):84), including the heart (Oerlemans MIFJ, et al., Basic Res Cardiol. 2012, 107:270), brain (Degterev A, et al., Nat Chem Biol. 2005, 1:112-119), and kidney (Linkermann A, et al., Kidney Int.Ischemia-reperfusion injury of parenchymatous organs (Lau A, et al., Am J Transplant. 2013, 13: 2805-18), kidney transplant rejection (Lau A, et al., Am J Transplant. 2013, 13: 2805-18), asthma (Zhang H, et al., J Cell Physiol. 2019, 234(9): 15080–15088), chronic obstructive pulmonary disease (Mizumura K, et al., Respir Investig. 2016, 54(6): 407-412), non-alcoholic fatty liver disease (Majdi A, et al., J Hepatol. 2020, 72(4): 627-635), alcoholic fatty liver (Wang S, et al., Oncotarget. 2016, 7: 17681-17698), atherosclerosis (Lin J, et al., Cell Rep. 2013, 3: 200-10; Karunakaran D, et al., FASEB J. 2018, 32(supplement): 38.1-38.1), sepsis / systemic inflammatory response syndrome (Duprez L, et al., Immunity. 2011, 35(6): 908-18), organ damage caused by chemotherapeutic drugs (Xu Y, et al., J Am Soc Nephrol. 2015, 26(11): 2647-58), Gaucher's disease (Vitner EB, et al., Nat Med. 2014, 20, 204-208), and malignant tumors (Wang W, et al., Cancer Cell. 2018, 34(5): 757-774; Strilic B, et al., Nature. 2016, 536(7615): 215-8). New RIPK1 inhibitors are needed to treat these diseases, especially inflammatory or autoimmune diseases. The present invention addresses these needs.

[0005] Brief Description of the Invention

[0006] The present invention provides a compound of formula (I):

[0007]

[0008] or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein:

[0009] R1 is hydrogen, C1-6 alkyl, C 1-6 haloalkyl, cyano-substituted C 1-6 alkyl, -(C 1-6 alkylene) n -C 3-6 cycloalkyl, -(C 1-6 alkylene) n -phenyl, -(C 1-6 alkylene) n -4-6-membered heterocyclic group or -(C 1-6 alkylene) n -5-6-membered heteroaryl; wherein the C 3-6 cycloalkyl, phenyl, 4-6-membered heterocyclic group and 5-6-membered heteroaryl are each optionally substituted by one or more groups independently selected from the following: halogen, -CN, -OH, -NH2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, -O(C 1-6 alkyl), -O(C 1-6 haloalkyl), -NH(C 1-6 alkyl) and -N(C 1-6 alkyl)2;

[0010] R2 is hydrogen, halogen, -CN, -NH2, C 1-6 alkyl, C 1-6 haloalkyl, -O(C 1-6 alkyl), -O(C 1-6 haloalkyl), -NH(C 1-6 alkyl) or -N(C 1-6 alkyl)2;

[0011] Z is O, NR3 or CR4R5;

[0012] R3 is hydrogen or C 1-6 alkyl;

[0013] R4 and R5 are each independently selected from: hydrogen, halogen, -CN, -OH, C 1-6 alkyl, C 1-6 haloalkyl, -O(C 1-6 alkyl), -O(C 1-6 haloalkyl) and C 3-6 cycloalkyl;

[0014] is phenyl or 5-6-membered heteroaryl, each of which is optionally substituted by one or more groups independently selected from the following: halogen, -CN, -OH, -NH2, C 1-6 alkyl, C 2-6Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, -O(C 1-6 Alkyl), -O(C 1-6 Halogenated alkyl), -NH(C 1-6 Alkyl) and -N(C 1-6 Alkyl)2;

[0015] is a 5- to 12-membered heteroaryl, which is optionally substituted by one or more groups independently selected from the following: halogen, -CN, -OH, oxo, -NH2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -O(C 1-6 Alkyl), -O(C 1-6 Halogenated alkyl), -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, -(C 1-6 Alkylene) n -C 3-6 Cycloalkyl, -(C 1-6 Alkylene) n -Phenyl, -(C 1-6 Alkylene) n -4- to 6-membered heterocyclic group and -(C 1-6 Alkylene) n -5- to 6-membered heteroaryl; wherein, the phenyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocyclic group and 5- to 6-membered heteroaryl are each optionally substituted by one or more groups independently selected from the following: halogen, -CN, -OH, -NH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, -O(C 1-6 Alkyl), -O(C 1-6 Halogenated alkyl), -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2 and C 3-6 Cycloalkyl;

[0016] n is 0 or 1;

[0017] p is 0 or 1.

[0018] The present invention also provides a pharmaceutical composition, which comprises a compound of formula (I) of the present invention (for example, any of the exemplified compounds herein) or a pharmaceutically acceptable salt thereof, and optionally comprises a pharmaceutically acceptable carrier.

[0019] The present invention also provides a method for inhibiting the activity of RIPK1 in vivo or in vitro, which comprises contacting a RIPK1 with an effective amount of a compound of formula (I) of the present invention (e.g., any example compound herein) or a pharmaceutically acceptable salt thereof.

[0020] The present invention also provides a method for treating a disease in an individual that is partially or completely mediated by RIPK1, which comprises administering to an individual in need thereof an effective amount of a compound of formula (I) of the present invention (e.g., the compound of formula (I-1) or any example compound herein) or a pharmaceutically acceptable salt thereof.

[0021] The present invention also provides a method for treating an autoimmune disease, an inflammatory disease, a neurodegenerative disease or cancer in an individual, which comprises administering to an individual in need thereof an effective amount of a compound of formula (I) of the present invention (e.g., the compound of formula (I-1) or any example compound herein) or a pharmaceutically acceptable salt thereof.

[0022] The present invention also provides the use of a compound of formula (I) of the present invention (e.g., the compound of formula (I-1) or any example compound herein) or a pharmaceutically acceptable salt thereof in the treatment of a disease in an individual that is partially or completely mediated by RIPK1.

[0023] The present invention also provides the use of a compound of formula (I) of the present invention (e.g., the compound of formula (I-1) or any example compound herein) or a pharmaceutically acceptable salt thereof in the treatment of an autoimmune disease, an inflammatory disease, a neurodegenerative disease or cancer in an individual.

[0024] The present invention also provides the use of a compound of formula (I) of the present invention (e.g., the compound of formula (I-1) or any example compound herein) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a disease in an individual that is partially or completely mediated by RIPK1.

[0025] The present invention also provides the use of a compound of formula (I) of the present invention (e.g., the compound of formula (I-1) or any example compound herein) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating an autoimmune disease, an inflammatory disease, a neurodegenerative disease or cancer in an individual. DETAILED DESCRIPTION OF THE INVENTION

[0027] Definition

[0028] The following words, phrases and symbols used in this application have the meanings described below, unless otherwise indicated in the context in which they are used.

[0029] A dash (“-”) not between two letters or symbols indicates the attachment site of a substituent. For example, -O(C 1-6 alkyl) means attachment to the rest of the molecule through an oxygen atom to C 1-6 alkyl.

[0030] As used herein, the term “alkyl” refers to a straight-chain or branched-chain saturated hydrocarbon group having 1-18 carbon atoms, preferably 1-10 carbon atoms, particularly preferably 1-6 carbon atoms, and further preferably 1-4 carbon atoms. For example, “C 1-6 alkyl” represents an alkyl group having 1-6 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

[0031] As used herein, the term “alkylene” refers to a straight-chain or branched-chain saturated divalent hydrocarbon group having 1-18 carbon atoms, preferably 1-10 carbon atoms, particularly preferably 1-6 carbon atoms, and further preferably 1-4 carbon atoms. For example, “C 1-6 alkylene” represents a straight-chain or branched-chain alkylene having 1-6 carbon atoms. For example, the straight-chain alkylene -(CH2) n -, where n is an integer from 1 to 6, such as -CH2-, -CH2-CH2-, -CH2-CH2-CH2-, etc., or a branched-chain alkylene, such as -CH2-CH(CH3)-CH2-, -CH(CH3)-CH2-, -CH(CH3)-, etc.

[0032] As used herein, the term “alkenyl” refers to a straight-chain or branched-chain unsaturated hydrocarbon group having one or more, such as 1, 2, or 3 carbon-carbon double bonds (C═C), having 2-10 carbon atoms, preferably 2-6 carbon atoms, and more preferably 2-4 carbon atoms. For example, “C 2-6 alkenyl” represents an alkenyl group having 2-6 carbon atoms with 1, 2, or 3, preferably 1 or 2 carbon-carbon double bonds. Examples of alkenyl groups include, but are not limited to, vinyl, propenyl, allyl, and 2-butenyl. The attachment point of the alkenyl group can be on the double bond or not on the double bond.

[0033] As used herein, the term “alkynyl” refers to a straight-chain or branched-chain unsaturated hydrocarbon group having one or more, such as 1, 2, or 3 carbon-carbon triple bonds (C≡C), having 2-10 carbon atoms, preferably 2-6 carbon atoms, and more preferably 2-4 carbon atoms. For example, “C 2-6 alkynyl” represents an alkynyl group having 2-6 carbon atoms with 1, 2, or 3, preferably 1 or 2 carbon-carbon triple bonds. Examples of alkynyl groups include, but are not limited to, ethynyl, 2-propynyl, and 2-butynyl. The attachment point of the alkynyl group can be on the triple bond or not on the triple bond.

[0034] As used herein, the term "halogen" or "halo" refers to fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine and bromine, more preferably fluorine and chlorine.

[0035] As used herein, the term "haloalkyl" refers to an alkyl group as defined herein in which one or more hydrogen atoms, such as 1, 2, 3, 4, 5 or 6 hydrogen atoms, are replaced by halogen atoms, and when more than one hydrogen atom is replaced by halogen atoms, the halogen atoms may be the same or different from each other. C 1-6 Haloalkyl refers to an alkyl group having 1-6 carbon atoms in which one or more hydrogen atoms, such as 1, 2, 3, 4, 5 or 6 hydrogen atoms, are replaced by halogen atoms. Examples of haloalkyl include, but are not limited to, -CF3, -CHF2, -CH2CF3, -CH(CH3)CF3, -CH(CF3)2, etc.

[0036] As used herein, the term "cyano-substituted alkyl" refers to an alkyl group as defined herein in which one or more hydrogen atoms, such as 1, 2 or 3 hydrogen atoms, are replaced by cyano groups. For example, "cyano-substituted C 1-6 alkyl" refers to a straight-chain or branched-chain saturated hydrocarbon group having 1-6 carbon atoms in which one or more hydrogen atoms, such as 1, 2 or 3 hydrogen atoms, are replaced by cyano groups. Examples of cyano-substituted alkyl include, but are not limited to, cyanomethyl, 1-cyanoethyl, 1-cyanopropyl, etc.

[0037] As used herein, the term "cycloalkyl" refers to a saturated or partially unsaturated cyclic hydrocarbon group containing 3-12, such as 3-8 or 3-6, ring carbon atoms; it may have one or more rings, such as 1, 2 or 3 rings, preferably 1 or 2 rings, most preferably 1 ring (i.e., monocyclic). Cycloalkyl includes fused or bridged rings as well as spiro rings. The rings of cycloalkyl may be saturated, or one or more, such as one or two, double bonds may be contained in its rings (i.e., partially unsaturated), but it is not completely conjugated and is not an "aryl" as defined in the present invention. "C 3-12 cycloalkyl" represents a monocyclic or bicyclic cycloalkyl having 3-12 ring carbon atoms, more preferably a saturated monocyclic or bicyclic cycloalkyl having 3-12 ring carbon atoms. "C 3-6 cycloalkyl" represents a monocyclic cycloalkyl having 3-6 ring carbon atoms, more preferably a saturated monocyclic cycloalkyl having 3-6 ring carbon atoms. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[4.1.0]heptyl, bicyclo[3.1.1]heptyl, spiro[3.3]heptyl, spiro[2.2]pentyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cycloheptenyl, cyclooctenyl and bicyclo[3.1.1]hept-2-ene.

[0038] As used herein, the term "heterocyclic group" or "heterocycle" refers to: a saturated or partially unsaturated ring having 3 to 12, such as 3 to 8, 4 to 7, or 4 to 6 ring atoms, containing one or more (such as 1, 2, or 3, preferably 1 or 2) ring heteroatoms independently selected from N, O, and S, and the remaining ring atoms being carbon atoms; it may have one or more rings, such as 1, 2, or 3, preferably having 1 or 2 rings. Preferably, "3- to 12-membered heterocyclic group" means a monocyclic or bicyclic heterocycloalkyl group having 3 to 12 ring atoms, which is saturated or partially unsaturated, preferably saturated, having 1, 2, or 3, preferably 1 or 2 ring heteroatoms selected from N, O, and S, and the remaining ring atoms being carbon atoms; "4- to 6-membered heterocyclic group" means a monocyclic heterocyclic group having 4 to 6 ring atoms, which is saturated or partially unsaturated, preferably saturated, having 1, 2, or 3, preferably 1 or 2 ring heteroatoms selected from N, O, and S, and the remaining ring atoms being carbon atoms. The N and S in the heterocyclic group may be optionally oxidized. The point of attachment of the heterocyclic group may be on an N heteroatom or a carbon atom. The heterocyclic group includes fused or bridged rings as well as spiro rings. The rings of the heterocyclic group may be saturated, or one or more, such as one or two double bonds (i.e., partially unsaturated) may be contained on its ring, but it is not completely conjugated and is not a "heteroaryl" as defined in the present invention. Examples of the heterocyclic group include, but are not limited to: oxiranyl, aziridinyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuryl, tetrahydropyranyl, dioxolanyl, dioxanyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, pyrazolidinyl, and oxaspiro[3.3]heptanyl.

[0039] As used herein, the term "aryl" or "aromatic ring" refers to a carbocyclic hydrocarbon group composed of one ring or multiple fused rings having 6 to 14 carbon atoms, wherein at least one ring is an aromatic ring. Examples of the aryl include, but are not limited to: phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, indenyl, indanyl, azulyl, preferably phenyl and naphthyl, and most preferably phenyl.

[0040] As used herein, the term "heteroaryl" or "heteroaromatic ring" refers to an aromatic hydrocarbon group having 5 to 12 ring atoms, such as having 5 to 10 ring atoms, 5 to 9 ring atoms, 5 to 6 ring atoms, or 6 ring atoms (i.e., 5- to 12-membered heteroaryl, 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, 5- to 6-membered heteroaryl, or 6-membered heteroaryl), containing one or more, such as 1, 2, 3, or 4, preferably 1, 2, or 3 ring heteroatoms independently selected from N, O, and S, and the remaining ring atoms being carbon atoms; it may have one or more rings, such as 1, 2, or 3, preferably having 1 or 2 rings. Preferably, the heteroaryl is:

[0041] A monocyclic aromatic hydrocarbon group having 5, 6 or 7 ring atoms (i.e., a 5-7 membered monocyclic heteroaryl group) (preferably a monocyclic aromatic hydrocarbon group having 5 or 6 ring atoms (i.e., a 5-6 membered monocyclic heteroaryl group)), which contains one or more, such as 1, 2, 3 or 4, preferably 1, 2 or 3 ring heteroatoms independently selected from N, O and S (preferably N and O) in the ring, and the remaining ring atoms are carbon atoms; or

[0042] A bicyclic aromatic hydrocarbon group having 8-12 ring atoms (i.e., an 8-12 membered bicyclic heteroaryl group) (preferably a bicyclic aromatic hydrocarbon group having 8, 9, 10 ring atoms (i.e., an 8-10 membered bicyclic heteroaryl group), more preferably a bicyclic aromatic hydrocarbon group having 8 or 9 ring atoms (i.e., an 8-9 membered bicyclic heteroaryl group)), which contains one or more, such as 1, 2, 3 or 4, preferably 2, 3 or 4 ring heteroatoms independently selected from N, O and S (preferably N) in the ring, and the remaining ring atoms are carbon atoms, wherein at least one ring is an aromatic ring. For example, the bicyclic heteroaryl group includes a 5-6 membered heteroaryl ring fused to a 5-6 membered cycloalkyl ring; the bicyclic heteroaryl group also includes a 5-6 membered heteroaryl ring fused to a 5-6 membered heterocyclic group ring.

[0043] When the total number of S and O atoms in the heteroaryl group exceeds 1, these S and O heteroatoms are not adjacent to each other.

[0044] Examples of monocyclic heteroaryl groups include, but are not limited to, pyridyl, N-oxidopyridyl, pyrazinyl, pyrimidinyl, triazinyl (e.g., s-triazinyl), pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, and 1,3,4-oxadiazolyl), thiazolyl, isothiazolyl, thiadiazolyl, tetrazolyl, triazolyl (e.g., 1,2,3-triazolyl and 1,2,4-triazolyl), thienyl, furyl, pyranyl, pyrrolyl, pyridazinyl. Examples of bicyclic heteroaryl groups include, but are not limited to, benzodioxolyl, benzoxazolyl, benzisoxazolyl, benzothienyl, benzothiazolyl, benzisothiazolyl, imidazopyridyl (e.g., imidazo[1,2-a]pyridyl), imidazopyridazinyl (e.g., imidazo[1,2-b]pyridazinyl), pyrrolopyridyl (e.g., 1H-pyrrolo[2,3-b]pyridyl), pyrrolopyrimidinyl (e.g., pyrrolo[3,4-d]pyrimidinyl), pyrrolotriazolyl (e.g., pyrrolo[1,2-b][1,2,4]triazolyl), dihydropyrrolotriazolyl (e.g., 6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazolyl), pyrazolopyridyl (e.g., 1H-pyrazolo[3,4-b]pyridyl and pyrazolo[4,3-c]pyridyl), pyrazolopyrimidinyl (e.g., pyrazolo[3,4-d]pyrimidinyl and pyrazolo[1,5-a]pyrimidinyl), triazolopyridyl (e.g., [1,2,4]triazolo[4,3-a]pyridyl and [1,2,4]triazolo[1,5-a]pyridyl), tetrazolopyridyl (e.g., tetrazolo[1,5-a]pyridyl), benzofuryl, benzimidazolinyl, indolyl, indazolyl, purinyl, quinolinyl, isoquinolinyl, and quinazolinyl.

[0045] As used herein, the term "hydroxy" refers to the –OH group.

[0046] As used herein, the term "oxo" refers to the =O group.

[0047] As used herein, the term "cyano" refers to the -CN group.

[0048] If a structural formula herein contains an asterisk "*", it means that the chiral center at the position marked with "*" in the compound is a single configuration of (R) configuration or (S) configuration; wherein the content of the compound with the single configuration marked with "*" is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 100%, or any value between these listed values).

[0049] If a structural formula in this text contains “(RS)”, it means that the chiral center at the position marked with “(RS)” in the compound has two configurations, (R) and (S), i.e., the compound is a mixture of the two configurations.

[0050] As used herein, the terms “optionally”, “optional” or “optionally” mean that the subsequent described event or circumstance may or may not occur, and the description includes the case where the event or circumstance occurs and the case where the event or circumstance does not occur. For example, “optionally substituted alkyl” includes “unsubstituted alkyl” and “substituted alkyl” as defined herein. Those skilled in the art should understand that for any group containing one or more substituents, the group does not include any substitution patterns that are spatially unrealistic, chemically incorrect, synthetically infeasible, and / or inherently unstable.

[0051] As used herein, the term “substituted” or “substituted by...” means that one or more hydrogen atoms on a given atom or group are replaced by one or more substituents selected from a given group of substituents, provided that the normal valence of the given atom is not exceeded. When the substituent is oxo (i.e., ═O), two hydrogen atoms on a single atom are replaced. Such combinations are permitted only when the combination of substituents and / or variables results in a chemically correct and stable compound. A chemically correct and stable compound means that the compound is stable enough to be isolated from the reaction mixture and subsequently formulated into a preparation having at least practical utility.

[0052] Unless otherwise specified, the substituents are named into the core structure. For example, it should be understood that when (cycloalkyl)alkyl is listed as a possible substituent, it means that the point of attachment of the substituent to the core structure is in the alkyl part.

[0053] As used herein, the term “substituted by one or more groups” means that one or more hydrogen atoms on a given atom or group are independently replaced by one or more substituents selected from the given group. In some embodiments, “substituted by one or more groups” means that the given atom or group is substituted by 1, 2, 3, 4, 5 or 6, preferably 1, 2, 3 or 4, substituents independently selected from the given group.

[0054] Those skilled in the art should understand that some compounds of formula (I) may contain one or more chiral centers, and thus there are two or more stereoisomers. The racemic mixtures, individual isomers, and enantiomer-enriched mixtures of these isomers, as well as the diastereomers and specifically diastereomer-enriched mixtures when there are two chiral centers, are all within the scope of the present invention. Those skilled in the art should also understand that the present invention includes all individual stereoisomers (such as enantiomers), racemic mixtures, or partially resolved mixtures of the compounds of formula (I), and, where appropriate, includes their individual tautomers.

[0055] As used herein, the term "stereoisomer" refers to compounds having the same chemical constitution but differing in the spatial arrangement of atoms or groups. Stereoisomers include enantiomers, diastereomers, etc.

[0056] As used herein, the terms "enantiomer" and "enantiomorph" are used interchangeably and refer to two stereoisomers of a compound that are non-superimposable mirror images of each other.

[0057] As used herein, the terms "diastereomer" and "diastereoisomer" are used interchangeably and refer to stereoisomers having two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting point, boiling point, spectral properties, or biological activity. Mixtures of diastereomers can be separated by high-resolution analytical methods such as electrophoresis and chromatography such as HPLC.

[0058] Stereochemical definitions and conventions may follow S.P. Parker, editor, 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. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. When describing optically active compounds, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule with respect to its chiral center. The prefixes d and l or (+) and (-) are used to denote the sign of rotation of plane-polarized light by the compound, where (-) or l indicates that the compound is levorotatory. A compound with the prefix (+) or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. A particular stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is commonly called a racemic mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur in cases where a chemical reaction or process is not stereoselective or stereospecific. The terms “racemic mixture” and “racemate” refer to an equimolar mixture of two enantiomers that is not optically active.

[0059] In some embodiments, the present invention provides compounds having various stereoisomeric purities, i.e., enantiomeric or diastereomeric purities expressed as different “ee” or “de” values. In some embodiments, the compounds of formula (I) described herein have an enantiomeric purity of at least 60% ee (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% ee, or any value between these listed values). In some embodiments, the compounds of formula (I) described herein have an enantiomeric purity greater than 99.9% ee. In some embodiments, the compounds of formula (I) described herein have a diastereomeric purity of at least 60% de (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% de, or any value between these listed values). In some embodiments, the compounds of formula (I) described herein have a diastereomeric purity greater than 99.9% de.

[0060] The term "enantiomeric excess" or "ee" refers to how much of one enantiomer is present relative to the other. For a mixture of R and S enantiomers, the percent enantiomeric excess is defined as │R - S│ * 100, where R and S are the molar or weight fractions of the respective enantiomers in the mixture and R + S = 1. If the specific rotation of a chiral substance is known, the percent enantiomeric excess is defined as ([a]obs / [a]max) * 100, where [a]obs is the specific rotation of the enantiomer mixture and [a]max is the specific rotation of the pure enantiomer.

[0061] The term "diastereomeric excess" or "de" refers to how much of one diastereomer is present relative to the other and is defined by analogy to enantiomeric excess. Thus, for a mixture of diastereomers D1 and D2, the percent diastereomeric excess is defined as │D1 – D2│ * 100, where D1 and D2 are the molar or weight fractions of the respective diastereomers in the mixture and D1 + D2 = 1.

[0062] The determination of diastereomeric excess and enantiomeric excess can be accomplished using a variety of analytical techniques (including nuclear magnetic resonance spectroscopy, chiral column chromatography, and / or polarimetry) and according to conventional protocols familiar to those skilled in the art.

[0063] Racemic mixtures can be used as such or can be resolved into their individual isomers. Resolution can yield stereochemically pure compounds or mixtures enriched in one or more isomers. Methods for separating isomers are well known (see Allinger N.L. and Eliel E.L., "Topics in Stereochemistry", Volume 6, Wiley Interscience, 1971) and include physical methods such as chromatography using chiral adsorbents. Individual isomers in chiral form can be prepared from chiral precursors. Alternatively, individual isomers can be separated chemically by forming diastereomeric salts of the mixture with a chiral acid (e.g., the individual enantiomers of 10-camphorsulfonic acid, camphoric acid, α-bromocamphoric acid, tartaric acid, diacetyltartaric acid, malic acid, pyrrolidone-5-carboxylic acid, etc.), fractionally crystallizing the salts, and then liberating one or both of the resolved bases, optionally repeating the process to obtain one or two isomers that are substantially free of the other isomer, i.e., isomers with an optical purity > 95%. Or, the racemate can be covalently linked to a chiral compound (auxiliary) to form diastereomers, which can be separated by chromatography or fractional crystallization, followed by chemical removal of the chiral auxiliary to obtain pure enantiomers.

[0064] The term "tautomer" refers to functional group isomers resulting from the rapid movement of an atom within a molecule between two positions. Tautomers can interconvert with each other. For example, the enol form and the keto form are typical tautomers.

[0065] "Pharmaceutically acceptable salts" refer to salts of the free acids or bases of the compounds of formula (I) that are non-toxic, biologically tolerable, or otherwise biologically suitable for administration to an individual. For example, pharmaceutically acceptable salts are acid addition salts, including, for example, addition salts derived from inorganic acids and organic acids. The inorganic acids include, for example, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and nitric acid. The organic acids include, for example, p-toluenesulfonic acid, salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, etc. For a general description of pharmaceutically acceptable salts, see, for example: S.M. Berge et al., "Pharmaceutical Salts", J. Pharm. Sci., 1977, 66: 1-19, and Handbook of Pharmaceutical Salts, Properties, Selection, and Use, edited by Stahl and Wermuth, Wiley-VCH and VHCA, Zurich, 2002.

[0066] Furthermore, if the compounds described herein are obtained in the form of acid addition salts, their free base forms can be obtained by basifying a solution of the acid addition salt. Conversely, if the product is in the free base form, its acid addition salts, particularly pharmaceutically acceptable acid addition salts, can be obtained by conventional procedures for preparing acid addition salts from basic compounds by dissolving the free base in a suitable solvent and treating the solution with an acid. Those skilled in the art can determine various synthetic methods for preparing non-toxic pharmaceutically acceptable acid addition salts or base addition salts without undue experimentation.

[0067] The term "solvate" means a solvate addition form containing a stoichiometric or non-stoichiometric amount of a solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the solid state, thereby forming a solvate. If the solvent is water, the solvate formed is a hydrate, and when the solvent is ethanol, the solvate formed is an ethanolate. Hydrates are formed by the combination of one or more molecules of water with one molecule of the substance, where the water retains its molecular state of H2O, and such combinations can form one or more hydrates, such as hemihydrates, monohydrates, and dihydrates.

[0068] The term "deuterated compound" means a compound formed by replacing one or more, such as 1, 2, or 3 hydrogen atoms in a compound with its isotope deuterium. Among them, the content of deuterium isotope at the substitution position of deuterium element (deuteration degree) is at least greater than the content of natural deuterium isotope. In some embodiments, the deuterated compound in the compound of formula (I) or its sub-formula (I-1) has a deuteration degree of at least 50% (such as 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or any value between these listed values). In some embodiments, the compound of formula (I) or its sub-formula (I-1) has a deuteration degree greater than 99.9% and up to 100%.

[0069] As used herein, the terms "group" and "radical" are synonyms and are used to denote a functional group or molecular fragment that can be linked to other molecular fragments.

[0070] The term "active ingredient" is used to denote a chemical substance having biological activity, such as the compound of formula (I) of the present invention (for example, any of the exemplified compounds herein) or a pharmaceutically acceptable salt thereof. In some embodiments, the "active ingredient" is a chemical substance having pharmaceutical use, and its drug activity can be determined by appropriate in vitro or in vivo tests (such as preclinical or clinical trials).

[0071] The term "disposing" or "treating" a disease or disorder means administering one or more pharmaceutical substances, particularly the compound of formula (I) or a pharmaceutically acceptable salt thereof described herein, to an individual suffering from the disease or disorder, or having symptoms of the disease or disorder, or having a constitution predisposed to the disease or disorder, for the purpose of curing, alleviating, relieving, altering, treating, improving, ameliorating, or affecting the disease or disorder, the symptoms of the disease or disorder, or the constitution predisposed to the disease or disorder. Thus, "treatment" as described herein includes prophylactic treatment, curative treatment, and palliative treatment. In some embodiments, the disease or disorder is an autoimmune disease or an inflammatory disease.

[0072] When referring to a chemical reaction, the terms "processing", "contacting", and "reacting" mean adding or mixing two or more reagents under appropriate conditions to produce the indicated and / or desired product. It should be understood that the reaction producing the indicated and / or desired product may not necessarily directly result from the combination of the two initially added reagents, i.e., one or more intermediates may be present in the mixture, and these intermediates ultimately lead to the formation of the indicated and / or desired product.

[0073] As used herein, the term "effective amount" refers to an amount of an RIPK1 inhibitor that is generally sufficient to produce a beneficial therapeutic effect in a patient in need of treatment for a disease or disorder that is partially or fully mediated by RIPK1 activity. The effective amount of the active ingredient in the present invention can be determined by conventional methods (such as modeling, dose escalation studies or clinical trials) in combination with conventional influencing factors (such as the route of administration, the pharmacokinetics of the drug ingredient, the severity of the disease or disorder, the individual's prior or ongoing treatment, the individual's health status and response to the drug, and the judgment of the attending physician).

[0074] Typical dosage ranges are from about 0.0001 to about 200 mg of active ingredient / kg body weight / day, such as from about 0.001 to 100 mg / kg body weight / day, or about 0.01 to 35 mg / kg body weight / day, or about 0.1 to 10 mg / kg body weight / day, administered once daily or in multiple divided doses (e.g., twice daily, three times daily, four times daily). For a 70-kg person, a suitable dosage is, for example, from about 0.05 to about 7 grams / day, or about 0.2 to about 5 grams / day.

[0075] The term "inhibit" refers to a decrease in the baseline activity of a biological activity. The term "inhibit RIPK1 activity" refers to a decrease in RIPK1 activity resulting from a direct or indirect response to the presence of a compound of formula (I) and / or a pharmaceutically acceptable salt thereof as described herein, relative to the RIPK1 activity in the absence of the compound of formula (I) and / or a pharmaceutically acceptable salt thereof. The decrease in activity can be caused by a direct interaction of a compound of formula (I) and / or a pharmaceutically acceptable salt thereof as described herein with RIPK1, or by an interaction of a compound of formula (I) and / or a pharmaceutically acceptable salt thereof as described herein with one or more other factors that in turn affect RIPK1 activity. For example, the presence of a compound of formula (I) and / or a pharmaceutically acceptable salt thereof as described herein can decrease the activity of RIPK1 by directly binding to RIPK1, can decrease the activity of RIPK1 by directly or indirectly affecting another factor, or can decrease the activity of RIPK1 by directly or indirectly reducing the amount of RIPK1 present in a cell or an organism.

[0076] As used herein, the term "individual" refers to mammals and non-mammals. Mammals refer to any member of the class Mammalia, which includes but is not limited to: humans; non-human primates, such as chimpanzees and other ape and monkey species; farm animals, such as cows, horses, sheep, goats, and pigs; domestic animals, such as rabbits, dogs, and cats; laboratory animals, including rodents, such as rats, mice, and guinea pigs; etc. Examples of non-mammals include but are not limited to birds, etc. The term "individual" does not limit a specific age or gender. In some embodiments, the individual is a human.

[0077] The term "pharmaceutically acceptable" means that the substance so qualified is suitable for use in the manufacture of pharmaceutical compositions which are generally safe, non-toxic and have no undesirable properties, whether biological or otherwise, and in particular are suitable for human pharmaceutical use.

[0078] As used herein, the term "about" means approximate, around, substantially or approximately. When the term "about" is used in connection with a numerical range, it modifies that range by extending the boundaries above and below the given numerical values. In general, the term "about" is used herein to modify a given numerical value by up to 20% above or below that value.

[0079] Technical and scientific terms not specifically defined herein have the meanings commonly understood by those skilled in the art to which this invention pertains. Specific embodiments

[0080] Embodiment 1. A compound of formula (I):

[0081]

[0082] or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereoisomer or tautomer thereof, wherein:

[0083] R1 is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, cyano-substituted C 1-6 alkyl, -(C 1-6 alkylene) n -C 3-6 cycloalkyl, -(C 1-6 alkylene) n -phenyl, -(C 1-6 alkylene) n -4-6-membered heterocyclic group or -(C 1-6 alkylene) n -5-6-membered heteroaryl; wherein said C 3-6 cycloalkyl, phenyl, 4-6-membered heterocyclic group and 5-6-membered heteroaryl are each optionally substituted by one or more groups independently selected from: halogen, -CN, -OH, -NH2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, -O(C 1-6 alkyl), -O(C 1-6 haloalkyl), -NH(C 1-6 alkyl) and -N(C 1-6 alkyl)2;

[0084] R2 is hydrogen, halogen, -CN, -NH2, C1-6 alkyl, C 1-6 haloalkyl, -O(C 1-6 alkyl), -O(C 1-6 haloalkyl), -NH(C 1-6 alkyl) or -N(C 1-6 alkyl)2;

[0085] Z is O, NR3 or CR4R5;

[0086] R3 is hydrogen or C 1-6 alkyl;

[0087] R4 and R5 are each independently selected from: hydrogen, halogen, -CN, -OH, C 1-6 alkyl, C 1-6 haloalkyl, -O(C 1-6 alkyl), -O(C 1-6 haloalkyl) and C 3-6 cycloalkyl;

[0088] is phenyl or a 5- to 6-membered heteroaryl, each of which is optionally substituted by one or more groups independently selected from the following: halogen, -CN, -OH, -NH2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, -O(C 1-6 alkyl), -O(C 1-6 haloalkyl), -NH(C 1-6 alkyl) and -N(C 1-6 alkyl)2;

[0089] is a 5- to 12-membered heteroaryl, which is optionally substituted by one or more groups independently selected from the following: halogen, -CN, -OH, oxo, -NH2, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -O(C 1-6 alkyl), -O(C 1-6 haloalkyl), -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, -(C 1-6 alkylene) n -C 3-6 cycloalkyl, -(C 1-6 alkylene) n -phenyl, -(C 1-6 alkylene) n -4- to 6-membered heterocyclic group and -(C1-6 (alkylene) n -5- or 6-membered heteroaryl; wherein the phenyl, C 3-6 cycloalkyl, 4- to 6-membered heterocyclic group and 5- to 6-membered heteroaryl are each optionally substituted by one or more groups independently selected from the following: halogen, -CN, -OH, -NH2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, -O(C 1-6 alkyl), -O(C 1-6 haloalkyl), -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2 and C 3-6 cycloalkyl;

[0090] n is 0 or 1;

[0091] p is 0 or 1.

[0092] Embodiment 2. The compound of formula (I) according to Embodiment 1 or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereoisomer or tautomer thereof, wherein: R1 is C 1-6 alkyl, C 1-6 haloalkyl, cyano-substituted C 1-6 alkyl, -(C 1-6 alkylene) n -C 3-6 cycloalkyl or -(C 1-6 alkylene) n -4- to 6-membered heterocyclic group; wherein the C 3-6 cycloalkyl and 4- to 6-membered heterocyclic group are each optionally substituted by one or more groups independently selected from the following: halogen, -CN, -OH, -NH2, C 1-6 alkyl, C 1-6 haloalkyl, -O(C 1-6 alkyl), -O(C 1-6 haloalkyl), -NH(C 1-6 alkyl) and -N(C 1-6 alkyl)2.

[0093] Embodiment 3. The compound of formula (I) according to Embodiment 2 or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereoisomer or tautomer thereof, wherein: R1 is C 1-6 alkyl, C 1-6 haloalkyl, cyano-substituted C 1-6 alkyl, -(C 1-6 alkylene)n -C 3-6 cycloalkyl or -(C 1-6 alkylene) n -4- to 6-membered heterocyclic group; wherein said C 3-6 cycloalkyl and 4- to 6-membered heterocyclic group are each optionally substituted by one or more groups independently selected from: halogen and C 1-6 alkyl.

[0094] Embodiment 4. The compound of formula (I) according to Embodiment 3 or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein: R1 is C 1-6 alkyl, preferably, R1 is methyl or isopropyl.

[0095] Embodiment 5. The compound of formula (I) according to Embodiment 3 or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein: R1 is C 1-6 haloalkyl, -(C 1-6 alkylene) n -C 3-6 cycloalkyl or -(C 1-6 alkylene) n -4- to 6-membered heterocyclic group; wherein said C 3-6 cycloalkyl is optionally substituted by one or more groups independently selected from: halogen and C 1-6 alkyl;

[0096] Preferably, R1 is -(C 1-6 alkylene) n -C 3-6 cycloalkyl, wherein said C 3-6 cycloalkyl is optionally substituted by one or more halogens, and n is 0 or 1; or R1 is a 4- to 6-membered heterocyclic group, wherein said 4- to 6-membered heterocyclic group is oxetanyl, tetrahydrofuranyl or tetrahydropyranyl.

[0097] Embodiment 6. The compound of formula (I) according to any one of Embodiments 1-5 or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein: R2 is hydrogen, -NH2, C 1-6 alkyl, -NH(C 1-6 alkyl) or -N(C 1-6 alkyl)2; preferably, R2 is hydrogen, -NH2 or C 1-6 alkyl; more preferably, R2 is hydrogen.

[0098] Embodiment 7. A compound of formula (I) according to any one of Embodiments 1-6, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereoisomer or tautomer thereof, wherein: p is 0 and Z is CR4R5; more preferably, p is 0 and Z is CH2.

[0099] Embodiment 8. A compound of formula (I) according to any one of Embodiments 1-7, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereoisomer or tautomer thereof, wherein: is phenyl or a 5-6 membered heteroaryl, each optionally substituted by one or more groups independently selected from: halogen, C 1-6 alkyl and C 1-6 haloalkyl;

[0100] Preferably, is phenyl or pyridyl, each optionally substituted by one or more groups independently selected from: halogen, C 1-6 alkyl and C 1-6 haloalkyl;

[0101] More preferably, is phenyl, optionally substituted by one or more groups independently selected from: halogen, C 1-6 alkyl or C 1-6 haloalkyl; or is pyridyl.

[0102] Embodiment 9. A compound of formula (I) according to any one of Embodiments 1-8, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereoisomer or tautomer thereof, wherein, is a 5-12 membered heteroaryl, preferably a 5-10 membered heteroaryl, more preferably a 5-9 membered heteroaryl, optionally substituted by one or more groups independently selected from: halogen, C 1-6 alkyl, -(C 1-6 alkylene) n -C 3-6 cycloalkyl, -(C 1-6 alkylene) n -phenyl, -(C 1-6 alkylene) n -4-6 membered heterocyclic group and -(C 1-6 alkylene) n -5-6 membered heteroaryl; wherein the phenyl, C 3-6 cycloalkyl, 4-6 membered heterocyclic group and 5-6 membered heteroaryl are each optionally substituted by one or more halogens.

[0103] Embodiment 10. The compound of formula (I) according to Embodiment 1 or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein the compound of formula (I) is a compound of formula (I-1):

[0104]

[0105] wherein,

[0106] R1 is C 1-6 alkyl, C 1-6 haloalkyl, cyano-substituted C 1-6 alkyl, -(C 1-6 alkylene) n -C 3-6 cycloalkyl or -(C 1-6 alkylene) n -4-6 membered heterocyclic group; wherein the C 3-6 cycloalkyl and 4-6 membered heterocyclic group are each optionally substituted by one or more groups independently selected from: halogen and C 1-6 alkyl; preferably, R1 is C 1-6 alkyl, C 1-6 haloalkyl, -(C 1-6 alkylene) n -C 3-6 cycloalkyl or -(C 1-6 alkylene) n -4-6 membered heterocyclic group; wherein the C 3-6 cycloalkyl is optionally substituted by one or more groups independently selected from: halogen and C 1-6 alkyl;

[0107] R2 is hydrogen, -NH2, C 1-6 alkyl, -NH(C 1-6 alkyl) or -N(C 1-6 alkyl)2; preferably, R2 is hydrogen, -NH2 or C 1-6 alkyl; more preferably, R2 is hydrogen;

[0108] is a 5-12 membered heteroaryl, preferably a 5-10 membered heteroaryl, more preferably a 5-9 membered heteroaryl, which is optionally substituted by one or more groups independently selected from: halogen, C 1-6 alkyl, -(C 1-6 alkylene) n -C 3-6 cycloalkyl, -(C 1-6 alkylene) n -phenyl, -(C 1-6 alkylene)n -4- to 6-membered heterocyclic group and -(C 1-6 alkylene) n -5- to 6-membered heteroaryl; wherein said phenyl, C 3-6 cycloalkyl, 4- to 6-membered heterocyclic group and 5- to 6-membered heteroaryl are each optionally substituted with one or more halogens;

[0109] n is 0 or 1.

[0110] Embodiment 11. A compound of formula (I) according to any one of Embodiments 1-10 or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein, is a triazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrimidinyl, pyrazolopyrimidinyl, pyrazolopyridyl or dihydropyrrolotriazolyl group, each of which is optionally substituted with one or more groups independently selected from the following: halogen, C 1-6 alkyl, -(C 1-6 alkylene) n -C 3-6 cycloalkyl, -(C 1-6 alkylene) n -phenyl, -(C 1-6 alkylene) n -4- to 6-membered heterocyclic group and -(C 1-6 alkylene) n -5- to 6-membered heteroaryl; wherein said phenyl, C 3-6 cycloalkyl, 4- to 6-membered heterocyclic group and 5- to 6-membered heteroaryl are each optionally substituted with one or more halogens.

[0111] Embodiment 12. A compound of formula (I) according to Embodiment 11 or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein,

[0112] selected from

[0113]

[0114] each of which is optionally substituted with one or more groups independently selected from the following: halogen, C 1-6 alkyl, -(C 1-6 alkylene) n -C 3-6 cycloalkyl, -(C 1-6 alkylene) n -phenyl, -(C 1-6 alkylene) n -4- to 6-membered heterocyclic group and -(C 1-6 alkylene)n -5-6 membered heteroaryl; wherein said phenyl, C 3-6 cycloalkyl, 4-6 membered heterocyclic group and 5-6 membered heteroaryl are each optionally substituted with one or more halogens;

[0115] Preferably, selected from

[0116]

[0117] each of which is optionally substituted with one or more groups independently selected from the following: halogen, C 1-6 alkyl, -(C 1-6 alkylene) n -C 3-6 cycloalkyl, -(C 1-6 alkylene) n -phenyl, -(C 1-6 alkylene) n -4-6 membered heterocyclic group and -(C 1-6 alkylene) n -5-6 membered heteroaryl; wherein said phenyl, C 3-6 cycloalkyl, 4-6 membered heterocyclic group and 5-6 membered heteroaryl are each optionally substituted with one or more halogens.

[0118] Embodiment 13. The compound of formula (I) according to Embodiment 12 or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereoisomer or tautomer thereof, wherein, is optionally substituted with one or more groups independently selected from the following: C 1-6 alkyl, -(C 1-6 alkylene) n -C 3-6 cycloalkyl, -(C 1-6 alkylene) n -phenyl, -(C 1-6 alkylene) n -4-6 membered heterocyclic group and -(C 1-6 alkylene) n -5-6 membered heteroaryl; wherein said C 3-6 cycloalkyl, 4-6 membered heterocyclic group and 5-6 membered heteroaryl are each optionally substituted with one or more halogens, and n is 0 or 1.

[0119] Embodiment 14. The compound of formula (I) according to Embodiment 13 or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereoisomer or tautomer thereof, wherein,

[0120] is optionally substituted by one or more groups independently selected from: C 1-6 alkyl;

[0121] or

[0122] is optionally substituted by one or more groups independently selected from: -(C 1-6 alkylene) n -C 3-6 cycloalkyl, where n is 0 or 1; wherein the C 3-6 cycloalkyl is optionally substituted by one or more halogens;

[0123] or

[0124] is optionally substituted by one or more groups independently selected from: -(C 1-6 alkylene) n -phenyl, where n is 0 or 1;

[0125] or

[0126] is optionally substituted by one or more groups independently selected from: 4- to 6-membered heterocyclic group; wherein the 4- to 6-membered heterocyclic group is oxetanyl;

[0127] or

[0128] is optionally substituted by one or more groups independently selected from: 5- to 6-membered heteroaryl; wherein the 5- to 6-membered heteroaryl is pyridyl.

[0129] Embodiment 15. A compound of formula (I) according to Embodiment 1 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is selected from Compounds 1-19, 22-48 and 53-95:

[0130]

[0131]

[0132]

[0133]

[0134]

[0135]

[0136]

[0137]

[0138]

[0139]

[0140]

[0141]

[0142]

[0143]

[0144]

[0145] Embodiment 16. A pharmaceutical composition, the pharmaceutical composition comprising a compound of any one of Embodiments 1-15 or a pharmaceutically acceptable salt thereof, and optionally comprising a pharmaceutically acceptable carrier.

[0146] Embodiment 17. A method for inhibiting RIPK1 activity in vivo or in vitro, the method comprising contacting RIPK1 with an effective amount of a compound of any one of Embodiments 1-15 or a pharmaceutically acceptable salt thereof.

[0147] Embodiment 18. A method for treating a disease in an individual that is partially or completely mediated by RIPK1, the method comprising administering to the individual an effective amount of a compound of any one of Embodiments 1-15 or a pharmaceutically acceptable salt thereof.

[0148] Embodiment 19. The method according to Embodiment 18, wherein the disease is selected from autoimmune diseases, inflammatory diseases, neurodegenerative diseases, and cancers.

[0149] Embodiment 20. A compound of any one of Embodiments 1-15 or a pharmaceutically acceptable salt thereof, for use as a medicament.

[0150] Embodiment 21. A compound of any one of Embodiments 1-15 or a pharmaceutically acceptable salt thereof, for treating a disease in an individual that is partially or completely mediated by RIPK1.

[0151] Embodiment 22. The compound or a pharmaceutically acceptable salt thereof according to Embodiment 21, wherein the disease is selected from autoimmune diseases, inflammatory diseases, neurodegenerative diseases, and cancers.

[0152] Use of a compound according to any one of embodiments 1 - 15 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a disease in an individual that is partially or fully mediated by RIPK1.

[0153] Embodiment 24. The use according to embodiment 23, wherein the disease is selected from autoimmune diseases, inflammatory diseases, neurodegenerative diseases, and cancers.

[0154] Embodiment 25. A pharmaceutical combination comprising a compound according to any one of embodiments 1 - 15 or a pharmaceutically acceptable salt thereof, and at least one additional therapeutic agent.

[0155] Embodiment 26. The pharmaceutical combination according to embodiment 25, wherein the therapeutic agent is an anti - inflammatory agent or an anti - tumor agent; preferably, the anti - tumor agent is selected from radiotherapy agents, chemotherapy agents, immunotherapy agents, and targeted therapy agents.

[0156] The diseases that are partially or fully mediated by RIPK1 as described herein may more specifically be selected from multiple sclerosis, systemic scleroderma, inflammatory bowel disease (including Crohn's disease, ulcerative colitis), psoriasis, atopic dermatitis, asthma, chronic obstructive pulmonary disease, Behçet's disease, rheumatoid arthritis, spinal arthritis, osteoarthritis, systemic juvenile idiopathic arthritis (SoJIA), retinitis pigmentosa, retinal degeneration, age - related macular degeneration, pancreatitis, ischemic - reperfusion injury of parenchymal organs, organ transplant rejection, sepsis, systemic inflammatory response syndrome, organ damage caused by chemotherapeutic drugs, non - alcoholic fatty liver, alcoholic fatty liver, atherosclerosis, Gaucher's disease, Huntington's disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), and spinal muscular atrophy (SMA).

[0157] The autoimmune diseases or inflammatory diseases as described herein may more specifically be selected from multiple sclerosis, systemic scleroderma, inflammatory bowel disease (including Crohn's disease, ulcerative colitis), psoriasis, atopic dermatitis, asthma, chronic obstructive pulmonary disease, Behçet's disease, rheumatoid arthritis, spinal arthritis, osteoarthritis, systemic juvenile idiopathic arthritis (SoJIA), ischemic - reperfusion injury of parenchymal organs, organ transplant rejection, sepsis, systemic inflammatory response syndrome, systemic lupus erythematosus, and autoimmune nephritis.

[0158] The neurodegenerative diseases described herein may more specifically be selected from Parkinson's disease (PD), multiple system atrophy (MSA), Alzheimer's disease (AD), frontotemporal lobar dementia, Huntington's disease (HD), corticobasal degeneration, spinocerebellar ataxia (SCA), amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), hereditary motor and sensory neuropathy (CMT), etc.

[0159] The cancer described herein may be a solid tumor or a hematological malignancy (such as leukemia, lymphoma or myeloma).

[0160] General synthesis method

[0161] The compound of formula (I) described herein or a pharmaceutically acceptable salt thereof can be synthesized using commercially available starting materials, by methods known in the art or by the methods disclosed in the present application. The synthetic methods shown in Routes 1-2 illustrate the general synthetic methods of the compounds of the present invention.

[0162]

[0163] As shown in Route 1, the compound of formula i-1 reacts with the compound of formula i-2 through a coupling reaction and a deprotection reaction to obtain an amino compound of formula i-3, which then reacts with the carboxylic acid compound of formula i-4 through a condensation reaction to obtain the compound of formula (I). Among them, R1, R2, Z, p, are as defined above; X is a halogen; PG is a protecting group; B(OR)2 is boric acid or a borate ester.

[0164]

[0165] As shown in Route 2, the compound of formula ii-1 reacts with the compound of formula ii-2 through a condensation reaction to obtain a compound of formula ii-3, which then reacts with the boric acid or borate ester of formula ii-4 through a coupling reaction to obtain the compound of formula (I); or the compound of formula ii-3 first reacts with bis(pinacolato)diboron to obtain a compound of formula ii-5, which then reacts with the halogenated compound of formula ii-6 through a coupling reaction to obtain the compound of formula (I). Among them, R1, R2, Z, p, are as defined above; X is a halogen; B(OR)2 is boric acid or a borate ester.

[0166] The substituents of the compounds obtained by the above methods can be further modified to obtain other desired compounds. Synthetic chemical transformation methods can be referred to, for example: R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser’s Reagents for Organic Synthesis, John Wiley and Sons (1994); Encyclopedia of Reagents for Organic Synthesis, edited by L. Paquette, John Wiley and Sons (1995) and its subsequent editions.

[0167] Before use, the compounds of formula (I) or their pharmaceutically acceptable salts described herein can be purified by column chromatography, high performance liquid chromatography, crystallization or other suitable methods.

[0168] Pharmaceutical composition and uses

[0169] Compositions comprising the compounds of formula (I) or their pharmaceutically acceptable salts described herein can be administered in various known ways, such as orally, parenterally, by inhalation or implantation, etc. The term “parenterally” as used herein includes subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intra-arterial, intrasynovial, intrasternal, intraspinal, intralesional and intracranial injection or infusion.

[0170] Compositions for oral administration can be in any orally acceptable dosage form, including but not limited to: tablets, capsules, pills, powders, emulsions, and aqueous suspensions, dispersions and solutions. Commonly used tablet carriers include lactose and corn starch. Lubricants such as magnesium stearate are also often added to tablets. When administered orally in capsule form, useful diluents include lactose and dried corn starch. When administered orally in the form of an aqueous suspension or emulsion, an emulsifying agent or suspending agent can be used to suspend or dissolve the active ingredient in the oil phase. If necessary, certain sweetening agents, flavoring agents or pigments can also be added.

[0171] Sterile injectable compositions, such as aqueous or oleaginous suspensions, can be formulated according to techniques known in the art using suitable dispersing or wetting agents (e.g., Tween 80) and suspending agents. The sterile injectable compositions can also be sterile injectable solutions or suspensions in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol. Pharmaceutically acceptable carriers and solvents that can be used include, in particular, mannitol, water, Ringer's solution, and normal saline. In addition, sterile, fixed oils such as synthetic mono- or di-glycerides are commonly used as solvents or suspending media. Fatty acids such as oleic acid and its glyceride derivatives, as well as natural pharmaceutically acceptable oils such as olive oil or castor oil (especially in their polyoxyethylated forms), are commonly used in the preparation of injectable compositions. These oil solutions or suspensions can also contain long-chain alcohol diluents or dispersing agents or carboxymethyl cellulose or similar dispersing agents.

[0172] Inhalation compositions can be prepared according to techniques well-known in the pharmaceutical formulation art using benzyl alcohol or other suitable preservatives, absorption enhancers to increase bioavailability, fluorocarbons, and / or other solubilizing or dispersing agents known in the art, and can also be made into solutions in saline.

[0173] Topical compositions can be formulated in the form of oils, creams, lotions, ointments, etc. Suitable carriers for the compositions include vegetable or mineral oils, white petrolatum (white soft paraffin), branched-chain fats or oils, animal fats, and high molecular weight alcohols (i.e., alcohols having more than 12 carbon atoms). In some embodiments, the pharmaceutically acceptable carrier is a carrier in which the active ingredient is soluble. If desired, the composition can also contain emulsifying agents, stabilizers, wetting agents, and antioxidants, as well as substances that impart color or flavor thereto. In addition, a transdermal penetration enhancer can be added to the topical preparation. Examples of such enhancers can be found in U.S. Patent Nos. 3,989,816 and 4,444,762.

[0174] Creams can be formulated from a mixture of mineral oil, self-emulsifying beeswax, and water, with the active ingredient dissolved in a small amount of an oil such as almond oil being incorporated therein. An example of a cream contains, by weight, approximately 40 parts water, approximately 20 parts beeswax, approximately 40 parts mineral oil, and approximately 1 part almond oil. Ointments can be formulated by mixing a solution of the active ingredient in a vegetable oil such as almond oil with warm soft paraffin and cooling the mixture. An example of an ointment contains, by weight, approximately 30% almond oil and approximately 70% white soft paraffin.

[0175] A pharmaceutically acceptable carrier refers to a carrier that is compatible with the active ingredient in the composition (and in some embodiments, can stabilize the active ingredient) and is harmless to the individual being treated. For example, solubilizing agents such as cyclodextrins (which can form specific, more soluble complexes with the compounds of formula (I) or their pharmaceutically acceptable salts described herein) can be used as pharmaceutical excipients to deliver the active ingredient. Examples of other carriers include colloidal silica, magnesium stearate, cellulose, sodium lauryl sulfate, and pigments such as D&C Yellow #10.

[0176] In some embodiments, the amount of the compound of formula (I) or its pharmaceutically acceptable salt in a tablet can be 1, 5, 10, 15, 20, 25, 50, 75, 80, 85, 90, 95, 100, 125, 150, 200, 250, 300, 400, and 500 mg. In some embodiments, the amount of the compound of formula (I) or its pharmaceutically acceptable salt in a capsule can be 1, 5, 10, 15, 20, 25, 50, 75, 80, 85, 90, 95, 100, 125, 150, 200, 250, 300, 400, and 500 mg.

[0177] Suitable in vitro experiments can be used to evaluate the actual utility of the compounds of formula (I) or their pharmaceutically acceptable salts described herein in inhibiting RIPK1 activity. The use of the compounds of formula (I) or their pharmaceutically acceptable salts described herein in treating autoimmune diseases, inflammatory diseases, neurodegenerative diseases, or cancer can be further detected by in vivo tests. For example, the compounds of formula (I) or their pharmaceutically acceptable salts described herein can be administered to an animal (such as a mouse model) suffering from an autoimmune disease or an inflammatory disease, and then its therapeutic effect can be evaluated. If the results of the preclinical trials are successful, the dose range and administration route for animals such as humans can also be predicted.

[0178] The compounds of formula (I) or their pharmaceutically acceptable salts described herein can be used to achieve beneficial therapeutic or prophylactic effects, for example, in individuals suffering from autoimmune diseases or inflammatory diseases.

[0179] The term "autoimmune disease" refers to a disease or disorder caused by the body's immune response to its own antigens, resulting in damage to its own tissues or organs. Examples of autoimmune diseases include, but are not limited to: chronic obstructive pulmonary disease (COPD), allergic rhinitis, lupus erythematosus, myasthenia gravis, multiple sclerosis (MS), rheumatoid arthritis (RA), collagen-induced arthritis, psoriasis, inflammatory bowel disease (IBD), asthma, idiopathic thrombocytopenic purpura (ITP), and myeloproliferative diseases, such as myelofibrosis, post-polycythemia vera / essential thrombocytosis myelofibrosis (post-PV / ET myelofibrosis).

[0180] The term "inflammatory disease" or "inflammatory disorder" refers to a pathological condition that causes inflammation, especially due to neutrophil chemotaxis. Non-limiting examples of inflammatory diseases include systemic and local inflammation, inflammation associated with immunosuppression, organ transplant rejection, allergic reactions, inflammatory skin diseases (including psoriasis and atopic dermatitis); systemic scleroderma and sclerosis; reactions associated with inflammatory bowel disease (IBD, such as Crohn's disease and ulcerative colitis); ischemia-reperfusion injury, including surgical tissue reperfusion injury, myocardial ischemia such as myocardial infarction, cardiac arrest, post-cardiac surgery reperfusion and abnormal vasoconstriction responses of coronary vessels after percutaneous coronary angioplasty, stroke and abdominal aortic aneurysm surgery tissue reperfusion injury; secondary cerebral edema after stroke; cranial trauma, hemorrhagic shock; asphyxia; adult respiratory distress syndrome; acute lung injury; Behçet's disease; dermatomyositis; polymyositis; multiple sclerosis (MS); dermatitis; meningitis; encephalitis; uveitis; osteoarthritis; lupus nephritis; autoimmune diseases such as rheumatoid arthritis (RA), Sjögren's syndrome, vasculitis; diseases involving leukocyte extravasation; septicemia or trauma secondary to central nervous system (CNS) inflammatory diseases, multiple organ injury syndrome; alcoholic hepatitis; bacterial pneumonia; antigen-antibody complex-mediated diseases, including glomerulonephritis; sepsis; sarcoidosis; immunopathological reactions caused by tissue / organ transplantation; pulmonary inflammation, including pleurisy, alveolitis, vasculitis, pneumonia, chronic bronchitis, bronchiectasis, diffuse panbronchiolitis, hypersensitivity pneumonitis, idiopathic pulmonary fibrosis (IPF), and cystic fibrosis, etc. Preferred indications include, but are not limited to, chronic inflammation, autoimmune diabetes, rheumatoid arthritis (RA), rheumatoid spondylitis, gouty arthritis and other joint disorders, multiple sclerosis (MS), asthma, systemic lupus erythematosus, adult respiratory distress syndrome, Behçet's disease, psoriasis, chronic pulmonary inflammatory diseases, graft-versus-host reaction, Crohn's disease, ulcerative colitis, inflammatory bowel disease (IBD), Alzheimer's disease and pyresis, and any disease associated with inflammation and related disorders.

[0181] In some embodiments, the autoimmune disease or inflammatory disease is selected from multiple sclerosis, systemic scleroderma, inflammatory bowel disease, Crohn's disease, ulcerative colitis, psoriasis, atopic dermatitis, asthma, chronic obstructive pulmonary disease, Behçet's disease, rheumatoid arthritis, spondyloarthritis, osteoarthritis, systemic juvenile idiopathic arthritis (SoJIA), ischemic reperfusion injury of solid organs, organ transplant rejection, sepsis, systemic inflammatory response syndrome, systemic lupus erythematosus and autoimmune nephritis.

[0182] The compounds of formula (I) or their pharmaceutically acceptable salts described herein can be used to achieve beneficial therapeutic or prophylactic effects, for example, in individuals suffering from neurodegenerative diseases to achieve beneficial therapeutic or prophylactic effects.

[0183] The term "Neurodegenerative Diseases" refers to neurodegenerative diseases or disorders of the nervous system caused by neuronal degeneration and apoptosis. Examples of neurodegenerative diseases include, but are not limited to: Parkinson's disease (PD), multiple system atrophy, Alzheimer's disease (AD), frontotemporal dementia, Huntington's disease (HD), corticobasal degeneration, spinocerebellar ataxia, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), hereditary motor and sensory neuropathy (CMT), etc.

[0184] The compounds of formula (I) or their pharmaceutically acceptable salts described herein can be used to achieve beneficial therapeutic or prophylactic effects, for example, in individuals suffering from cancer to achieve beneficial therapeutic or prophylactic effects.

[0185] As used herein, the term "cancer" refers to a cellular disorder characterized by uncontrolled or dysregulated cell proliferation, reduced cell differentiation, the ability to inappropriately invade surrounding tissues, and / or the ability to establish new foci of growth at other sites. The term "cancer" includes, but is not limited to: solid tumors and hematological malignancies. The term "cancer" includes cancers of the skin, tissues, organs, bones, cartilage, blood, and blood vessels. The term "cancer" includes both primary cancers and metastatic cancers.

[0186] Non-limiting examples of solid tumors include pancreatic cancer; bladder cancer; colorectal cancer; breast cancer, including metastatic breast cancer; prostate cancer, including androgen-dependent and androgen-independent prostate cancer; testicular cancer; kidney cancer, including, for example, metastatic renal cell carcinoma; urothelial cancer; liver cancer; hepatocellular carcinoma; lung cancer, including, for example, non-small cell lung cancer (NSCLC), bronchioloalveolar carcinoma (BAC), and lung adenocarcinoma; ovarian cancer, including, for example, progressive epithelial cancer or primary peritoneal cancer; cervical cancer; endometrial cancer; gastric cancer; esophageal cancer; head and neck cancer, including, for example, head and neck squamous cell carcinoma; skin cancer, including, for example, melanoma and basal cell carcinoma; neuroendocrine cancer, including metastatic neuroendocrine tumors; brain tumors, including, for example, glioma, anaplastic oligodendroglioma, adult glioblastoma multiforme, and adult anaplastic astrocytoma; bone cancer; sarcoma, including, for example, Kaposi's sarcoma; adrenal cancer; mesothelioma; choriocarcinoma; muscle cancer; connective tissue cancer; and thyroid cancer.

[0187] Non-limiting examples of hematological malignancies include acute myeloid leukemia (AML); chronic myeloid leukemia (CML), including accelerated phase CML and blast crisis of CML (CML-BP); acute lymphoblastic leukemia (ALL); chronic lymphocytic leukemia (CLL); Hodgkin lymphoma; non-Hodgkin lymphoma (NHL); follicular lymphoma; mantle cell lymphoma (MCL); B-cell lymphoma; T-cell lymphoma; diffuse large B-cell lymphoma (DLBCL); multiple myeloma (MM); Waldenstrom's macroglobulinemia; myelodysplastic syndrome (MDS), including refractory anemia (RA), refractory anemia with ringed sideroblasts (RARS), refractory anemia with excess blasts (RAEB), and refractory anemia with excess blasts in transformation (RAEB-T); and myeloproliferative syndrome.

[0188] In addition, the compounds of formula (I) described herein (e.g., the compounds of formula (I-1) herein or any of the example compounds) or their pharmaceutically acceptable salts can be administered in combination with additional therapeutic agents for the treatment of autoimmune diseases, inflammatory diseases or cancer. The additional therapeutic agent can be administered separately from the compounds of formula (I) described herein or their pharmaceutically acceptable salts, or can be included in a pharmaceutical composition according to the present disclosure, such as a fixed-dose combination product. In some embodiments, the additional therapeutic agent is an agent known or found to be effective in treating a disease that is mediated in part or in whole by RIPK1, such as another RIPK1 inhibitor or a compound that can effectively antagonize another target associated with the particular disease. The combination administration can be used to enhance efficacy (e.g., by including a compound that enhances the potency or effectiveness of the compounds of formula (I) described herein or their pharmaceutically acceptable salts in the combination), reduce one or more side effects, or reduce the dose of the compounds of formula (I) described herein or their pharmaceutically acceptable salts required.

[0189] In some embodiments, a compound of formula (I) as described herein (e.g., a compound of formula (I-1) herein or any of the example compounds) or a pharmaceutically acceptable salt thereof can be administered in combination with an anti-inflammatory agent.

[0190] Examples of anti-inflammatory agents include, but are not limited to, corticosteroids (such as fluticasone propionate, beclometasone dipropionate, momestasone furoate, triamcinolone acetonide, or budesonide), disease modifying agents (such as antimalarials, methotrexate, sulfasalazine, masalazine, azathioprine, 6-mercaptopurine, metronidazole, D-penicillamine), non-steroidal anti-inflammatory drugs (such as acetaminophen, aspirin, sodium salicylate, cromoglycate sodium, magnesium salicylate, choline magnesium trisalicylate, salsalate, ibuprofen, naproxen, diclofenac, diflunisal, etodolac, fenoprofen calcium, flurbiprofen, piroxicam, indomethacin, ketoprofen, ketorolac tromethamine, meclofenamic acid, meclofenamate sodium, mefenamic acid, nabumetone, oxaprozin, phenyl butylnitrone (PBN), sulindac, or tolmetin), COX-2 inhibitors, cytokine synthesis / release inhibitors (such as anti-cytokine antibodies, anti-cytokine receptor antibodies, etc.).

[0191] In some embodiments, a compound of formula (I) as described herein (e.g., a compound of formula (I-1) herein or any of the exemplified compounds) or a pharmaceutically acceptable salt thereof may be administered in combination with an anti-tumor agent. As used herein, the term "anti-tumor agent" refers to any agent administered to a subject having cancer for the purpose of treating cancer, including but not limited to radiotherapy agents, chemotherapy agents, immunotherapy agents, targeted therapy agents, and the like.

[0192] Non-limiting examples of chemotherapy agents include topoisomerase I inhibitors (e.g., irinotecan, topotecan, camptothecin and their analogs or metabolites and doxorubicin); topoisomerase II inhibitors (e.g., etoposide, teniposide, mitoxantrone, demethoxydaunorubicin and daunorubicin); alkylating agents (e.g., melphalan, chlorambucil, busulfan, thiotepa, ifosfamide, carmustine, lomustine, semustine, streptozocin, dacarbazine, methotrexate, mitomycin C and cyclophosphamide); DNA intercalating agents (e.g., cisplatin, oxaliplatin and carboplatin); DNA intercalating agents and free radical generators such as bleomycin; nucleoside analogs (e.g., 5-fluorouracil, capecitabine, gemcitabine, fludarabine, cytarabine, azacitidine, mercaptopurine, thioguanine, pentostatin and hydroxyurea); paclitaxel, taxotere and related analogs; vincristine, vinblastine and related analogs; sedatives and related analogs (e.g., CC-5013 and CC-4047).

[0193] Non-limiting examples of immunotherapeutic agents or targeted therapeutic agents include MEK inhibitors, RAF inhibitors, mTOR inhibitors, PAK inhibitors, CDK inhibitors, VEGFR inhibitors, PARP inhibitors, ERBB inhibitors, PI3K inhibitors, AKT inhibitors, IDO inhibitors, A2AR inhibitors, autophagy inhibitors, immune checkpoint inhibitors such as PD-1 inhibitors, PD-L1 inhibitors, etc. For example: Trametinib, Cobimetinib, Vemurafenib, Dabrafenib, Rapamycin, Temsirolimus, Everolimus, Palbociclib, Ribociclib, Fruquintinib, Olaparib, Niraparib, Neratinib, Chloroquine, Hydroxychloroquine, LXH254, Selumetinib, LY3214996, Abemaciclib, P1446A-05 (Voruciclib), LGX818 (Encorafenib), ARRY-162 (Binimetinib), Gefitinib, Imatinib mesylate, Cetuximab, Trastuzumab, Rituximab, Panitumumab, BYL719 (Alpelisib), Bevacizumab, Pembrolizumab, Atezolizumab, PDR001 (Spartalizumab), Durvalumab, Nivolumab, Avelumab, Libtayo (Cemiplimab), Tislelizumab, Toripalimab (JS001), Sintilimab, Camrelizumab, etc.

[0194] Example

[0195] The following examples illustrate the present invention and do not limit the present invention in any way. The data given (e.g., amounts, temperatures, etc.) are intended to ensure their accuracy, but those skilled in the art should understand that there will be some experimental errors and deviations. Unless otherwise stated, all parts are by weight, the temperature is in degrees Celsius, and the pressure is atmospheric or near atmospheric. All mass spectrometry data were measured by Agilent 6120 and 1100. All nuclear magnetic resonance data were measured by Varian 400MR. All reagents used in the present invention, except for the synthesized intermediates, were obtained from commercial sources. The names of all compounds except for the reagents were generated by Chemdraw 18.2.

[0196] In any structural formula of the present application, if there is a vacant valence on any atom, the vacant valence actually represents a hydrogen atom that is not specifically depicted for simplicity.

[0197] In the present application, if the name and structural formula of a compound are given simultaneously, in the case of inconsistency between the two, the structure of the compound shall prevail, unless the context indicates that the structure of the compound is incorrect while the name is correct.

[0198] List of abbreviations used in the following examples:

[0199] AcOH acetic acid

[0200] AgNO3 silver nitrate

[0201] BF3OEt2 boron trifluoride diethyl ether

[0202] CDCl3 deuterated chloroform

[0203] Cs2CO3 cesium carbonate

[0204] Cu(OAc)2 copper(II) acetate

[0205] DBU 1,8-diazabicyclo[5.4.0]undec-7-ene

[0206] DCM or CH2Cl2 dichloromethane

[0207] DCE 1,2-dichloroethane

[0208] DIEA N,N-diisopropylethylamine

[0209] DIAD diisopropyl azodicarboxylate

[0210] DEA diethylamine

[0211] DMF N,N-dimethylformamide

[0212] DMSO dimethyl sulfoxide

[0213] EA Ethyl acetate

[0214] EtOH Ethanol

[0215] HATU O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate

[0216] IPA Isopropyl alcohol

[0217] K2CO3 Potassium carbonate

[0218] KOAc Potassium acetate

[0219] LiOH Lithium hydroxide

[0220] MeOH Methanol

[0221] MeCN Acetonitrile

[0222] MeI Methyl iodide

[0223] MeONa Sodium methoxide

[0224] NaOH Sodium hydroxide

[0225] NCS N-chlorosuccinimide

[0226] NH2NH2 Hydrazine

[0227] NH4SO2O8 Ammonium persulfate

[0228] NMP N-methylpyrrolidone

[0229] Pd(dppf)Cl2 [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium Pd(PPh3)4 Tetrakis(triphenylphosphine)palladium

[0230] PPh3 Triphenylphosphine

[0231] PE Petroleum ether

[0232] POCl3 Phosphorus oxychloride

[0233] Pyridine Pyridine

[0234] SOCl2 Thionyl chloride

[0235] Ti(i-PrO)4 Tetraisopropyl orthotitanate

[0236] THF Tetrahydrofuran

[0237] TEA Triethylamine

[0238] TFA Trifluoroacetic acid

[0239] Tol Toluene

[0240] TLC Thin Layer Chromatography

[0241] p-TLC Preparative Thin Layer Chromatography

[0242] Zn(CN)₂ Zinc Cyanide

[0243] Example 1 - Preparation of Intermediates and Compounds

[0244] Intermediate 1

[0245] 5-Chloro-4-isobutylpyrimidine-2-carboxylic acid

[0246]

[0247] (A) Methyl 5-chloropyrimidine-2-carboxylate

[0248] Dissolve 5-chloropyrimidine-2-carboxylic acid (500 mg, 3.15 mmol) in methanol (20 mL), then slowly add SOCl₂ (0.5 mL), and then heat to 80 °C and react overnight. After the reaction is completed as detected by TLC (petroleum ether:ethyl acetate = 5:1), cool, concentrate the reaction solution under reduced pressure, and purify the residue by flash column chromatography (gradient elution with methanol / water = 0–100%) to obtain 500 mg of the product.

[0249] (B) Methyl 5-chloro-4-isobutylpyrimidine-2-carboxylate

[0250] Dissolve methyl 5-chloropyrimidine-2-carboxylate (500 mg, 2.90 mmol), L-leucine (760 mg, 5.80 mmol), and ammonium persulfate (3.04 g, 14.49 mmol) in a mixed solvent of DCE (10 mL) and water (9 mL). Then add TFA (218 μL, 2.90 mmol), and stir the solution at room temperature for 1 minute. After stirring, add 2 mol / L aqueous silver nitrate solution (1.45 mL, 2.90 mmol), and then heat to 80 °C and react for 24 hours. After the reaction is completed, cool the reaction solution, concentrate it under reduced pressure, and purify the residue by flash column chromatography (gradient elution with methanol / water = 0–100%) to obtain 80 mg of the product. MS (m / z) = 229 [M+H] + .

[0251] (C) 5-Chloro-4-isobutylpyrimidine-2-carboxylic acid

[0252] Methyl 5-chloro-4-isobutylpyrimidine-2-carboxylate (80 mg, 0.35 mmol) was dissolved in methanol (5 mL), and 2 M aqueous sodium hydroxide solution (1.0 mL, 2.0 mmol) was added. The reaction was carried out at room temperature for 2 hours. After the reaction was completed, 2 M aqueous hydrochloric acid solution was added until the pH was about 7. The mixed solution was concentrated under reduced pressure, and the residue was purified by flash column chromatography (gradient elution with methanol / water = 0–100%), to obtain 70 mg of the product. MS (m / z) = 215 [M+H] + .

[0253] Intermediate 2

[0254] 5-Bromo-2,3-dimethylpyrimidin-4(3H)-one

[0255]

[0256] 5-Bromo-2-methylpyrimidin-4(3H)-one (756 mg, 4 mmol), methyl iodide (568 mg, 4 mmol) and potassium carbonate (828 mg, 6 mmol) were added to DMF (5 mL). The mixture was stirred at room temperature for 2 hours under nitrogen protection. After the reaction was completed, water (10 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (gradient elution with PE / EA = 10%-50%) to obtain 500 mg of a pale yellow solid product. MS (m / z) = 203 [M+H] + .

[0257] The following intermediates were prepared by referring to the preparation process of Intermediate 2, using the corresponding raw materials and reagents, under the appropriate conditions recognized by those skilled in the art.

[0258]

[0259] Intermediate 6

[0260] (1-Methyl-6-oxo-1,6-dihydropyrimidin-5-yl)boronic acid

[0261]

[0262] 5-Bromo-3-methylpyrimidin-4(3H)-one (1 g, 5.29 mmol), bis(pinacolato)diboron (2.02 g, 7.94 mmol), KOAc (1.56 g, 15.87 mmol) and Pd(dppf)Cl2 (194 mg, 0.26 mmol) were added to dioxane (30 mL). The mixture was stirred at 120 °C for 2 h under nitrogen protection. The solvent was removed, and the residue was purified by flash column chromatography (eluted with a gradient of methanol / water (+0.1% formic acid) = 10% - 80%) to obtain 525 mg of a white solid product. MS (m / z) = 155 [M+H] + .

[0263] Intermediate 7

[0264] 1-Benzyl-1H-1,2,4-triazole-3-carboxylic acid

[0265]

[0266] (A) Methyl 1-benzyl-1H-1,2,4-triazole-3-carboxylate

[0267] Methyl 1H-1,2,4-triazole-3-carboxylate (2 g, 15.7 mmol), benzyl bromide (2 g, 15.7 mmol) and Cs2CO3 (7.68 g, 15.7 mmol) were added to DMF (100 mL). The mixture was stirred at room temperature for 5 h under nitrogen protection. After the reaction was completed, water (20 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (eluted with a gradient of PE / EA = 10% - 80%) to obtain 0.8 g of a white solid product. MS (m / z) = 218 [M+H] + .

[0268] (B) 1-Benzyl-1H-1,2,4-triazole-3-carboxylic acid

[0269] Methyl 1-benzyl-1H-1,2,4-triazole-3-carboxylate (0.8 g, 3.68 mmol) was dissolved in THF (20 mL), and then an aqueous solution of LiOH (0.46 g, 11.04 mmol dissolved in 5 mL of water) was added. The mixture was stirred at room temperature for 1 h, and then THF was removed. 2N hydrochloric acid was added to adjust the pH to 6. The solid was collected by filtration and washed with ice water 3 times. The filter cake was dried to obtain 0.5 g of the product. MS (m / z) = 204 [M+H] + .

[0270] Intermediate 8

[0271] Ethyl 5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate

[0272]

[0273] (A) tert-Butyl ((2-oxo-5-phenylpyrrolidin-1-yl)amino)carbamate

[0274] Methyl 4-oxo-4-phenylbutanoate (5 g, 26.03 mmol) was added to acetic acid (15 mL), and tert-butyl hydrazinecarboxylate (5.15 g, 39.04 mmol) was added at room temperature. The reaction was carried out at 40 °C overnight, then sodium cyanoborohydride (2.45 g, 39.04 mmol) was added, and the reaction was continued at this temperature for 4 h. After the reaction was completed, it was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash column chromatography (gradient elution with methanol / water = 0%-100%) to obtain 4.2 g of the target product. MS (m / z) = 221 [M - 56] + .

[0275] (B) 1-Amino-5-phenylpyrrolidin-2-one

[0276] tert-Butyl ((2-oxo-5-phenylpyrrolidin-1-yl)amino)carbamate (4.2 g, 15.20 mmol) was added to methanol (10 mL), and 4N hydrochloric acid (11.4 mL, 45.61 mmol) was added at room temperature. The reaction was carried out at 50 °C for 2 h. After the reaction was completed, it was cooled to room temperature and concentrated under reduced pressure to obtain 3.1 g of the target product. MS (m / z) = 177 [M + H] + .

[0277] (C) Ethyl (Z)-2-amino-2-((2-oxo-5-phenylpyrrolidin-1-yl)imino)acetate

[0278] 1-Amino-5-phenylpyrrolidin-2-one (2.5 g, 14.20 mmol) was added to ethanol (10 mL), and ethyl 2-ethoxy-2-iminoacetate (6.17 g, 42.6 mmol) was added at room temperature. The reaction was heated to reflux for 8 h. After the reaction was completed, it was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash column chromatography (gradient elution with methanol / water = 0%-100%) to obtain 3.2 g of the target product. MS (m / z) = 276 [M + H] + .

[0279] (D) Ethyl 5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate

[0280] Ethyl (Z)-2-amino-2-((2-oxo-5-phenylpyrrolidin-1-yl)imino)acetate (3.2 g, 11.63 mmol) was added to DCE (10 mL), and POCl3 (3 mL) was added at room temperature. The mixture was heated to 100 °C and reacted for 8 hours. After the reaction was completed, it was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluted with a gradient of methanol / water = 0%-100%) to obtain 1.8 g of the target product. MS (m / z) = 258 [M+H] + .

[0281] Intermediate 9

[0282] 5-Bromo-3-cyclopropylpyrimidin-4(3H)-one

[0283]

[0284] 5-Bromopyrimidin-4(3H)-one (500 mg, 2.86 mmol), cyclopropylamine (136 mg, 2.38 mmol) and DBU (534 mg, 3.57 mmol) were added to acetonitrile (10 mL), and HATU (1.2 g, 3.09 mmol) was added. The mixture was heated to 45 °C and reacted for 20 hours. After concentration under reduced pressure, the residue was purified by flash column chromatography (eluted with a gradient of methanol / water = 0%-100%) to obtain 200 mg of the target product. MS (m / z) = 216 [M+H] + .

[0285] The following intermediates were prepared by referring to the preparation process of Intermediate 9, using the corresponding raw materials and reagents, under suitable conditions recognized by those skilled in the art.

[0286]

[0287]

[0288]

[0289] Intermediate 20

[0290] Lithium 5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate

[0291]

[0292] Ethyl 5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate (100 mg, 0.39 mmol) was added to THF (4 mL), and an aqueous solution (0.8 mL) of lithium hydroxide monohydrate (49 mg, 1.17 mmol) was added. The reaction was carried out at room temperature for 2 hours. After concentration under reduced pressure, the residue was purified by flash column chromatography (gradient elution with methanol / water = 0%-100%) to give 92 mg of the target product. MS (m / z) = 230 [M - Li + 2H] + .

[0293] The following intermediate was prepared using Intermediate 7 (A) as the starting material according to the preparation process of Intermediate 20 under the suitable conditions recognized by those skilled in the art.

[0294]

[0295] Intermediate 22

[0296] Lithium 5-(2,6-difluorobenzyl)-4H-1,2,4-triazole-3-carboxylate

[0297]

[0298] (A) Methyl 2-(2,6-difluorophenyl)acetate

[0299] 2-(2,6-Difluorophenyl)acetic acid (1.0 g, 5.81 mmol) was added to methanol (15 mL), and SOCl2 (2 mL) was added. The mixture was heated to 50 °C and reacted for 2 hours. After concentration under reduced pressure, 1.08 g of the crude product was obtained. MS (m / z) = 187 [M + H] + .

[0300] (B) 2-(2,6-Difluorophenyl)acetohydrazide

[0301] Methyl 2-(2,6-difluorophenyl)acetate (1.08 g, 5.81 mmol) and hydrazine hydrate (2 mL) were added to ethanol (10 mL). The mixture was heated to 70 °C and reacted for 4 hours, then cooled to room temperature. The precipitated solid was filtered and dried to give 700 mg of the target product. MS (m / z) = 187 [M + H] + .

[0302] (C) Ethyl 2-(2-(2-(2,6-difluorophenyl)acetyl)hydrazino)-2-iminoacetate

[0303] 2-(2,6-Difluorophenyl)acetohydrazide (500 mg, 2.69 mmol) and ethyl 2-ethoxy-2-iminoacetate (390 mg, 2.69 mmol) were added to ethanol (10 mL). After heating to 70 °C and reacting for 4 h, the mixture was cooled to room temperature. The precipitated solid was filtered and dried to obtain 730 mg of the target product. MS (m / z) = 286 [M+H] + .

[0304] (D) Ethyl 5-(2,6-difluorobenzyl)-4H-1,2,4-triazole-3-carboxylate

[0305] Ethyl 2-(2-(2-(2,6-difluorophenyl)acetyl)hydrazino)-2-iminoacetate (315 mg, 1.10 mmol) was added to toluene (5 mL), and POCl3 (2 mL) was added dropwise. The mixture was refluxed overnight. After concentration under reduced pressure, the residue was purified by flash column chromatography (gradient elution with methanol / water = 0%-100%) to obtain 235 mg of the target product. MS (m / z) = 268 [M+H] + .

[0306] (E) Lithium 5-(2,6-difluorobenzyl)-4H-1,2,4-triazole-3-carboxylate

[0307] Referring to the preparation process of Intermediate 20, using ethyl 5-(2,6-difluorobenzyl)-4H-1,2,4-triazole-3-carboxylate as the raw material, the target product was prepared. MS (m / z) = 240 [M-Li+2H] + .

[0308] Intermediate 23

[0309] 1-Phenyl-1H-pyrazolo[3,4-d]pyrimidine-6-carboxylic acid

[0310]

[0311] (A) 6-Chloro-1-phenyl-1H-pyrazolo[3,4-d]pyrimidine

[0312] 6-Chloro-1H-pyrazolo[3,4-d]pyrimidine (1.6 g, 10.1 mmol), phenylboronic acid (2.5 g, 20.2 mmol), copper acetate (2.7 g, 15.2 mmol) and pyridine (1.6 g, 20.2 mmol) were added to DCE (15 mL). After heating to 80 °C and reacting overnight, the mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (gradient elution with methanol / water = 0%-100%) to obtain 377 mg of the target product. MS (m / z) = 231 [M+H] + .

[0313] (B) 1-Phenyl-1H-pyrazolo[3,4-d]pyrimidine-6-carbonitrile

[0314] 6-Chloro-1-phenyl-1H-pyrazolo[3,4-d]pyrimidine (377 mg, 1.63 mmol), zinc cyanide (125 mg, 1.06 mmol) and Pd(PPh3)4 (94 mg, 0.082 mmol) were added to DMF (5 mL), and the mixture was heated to 100 °C and reacted overnight. After concentration under reduced pressure, the residue was purified by flash column chromatography (eluting with a gradient of petroleum ether / ethyl acetate = 100%-0%) to obtain 335 mg of the target product. MS (m / z) = 222 [M+H] + .

[0315] (C) 1-Phenyl-1H-pyrazolo[3,4-d]pyrimidine-6-carboxylic acid

[0316] 1-Phenyl-1H-pyrazolo[3,4-d]pyrimidine-6-carbonitrile (335 mg, 1.52 mmol) was added to 6N hydrochloric acid (2 mL), and the mixture was heated to 100 °C and reacted for 4 hours. After concentration under reduced pressure, the residue was purified by flash column chromatography (eluting with a gradient of methanol / water = 0%-100%) to obtain 36 mg of the target product. MS (m / z) = 241 [M+H] + .

[0317] Intermediate 26

[0318] 1-(4-Bromo-3-chlorophenyl)cyclopropan-1-amine

[0319]

[0320] 4-Bromo-3-chlorobenzonitrile (2 g, 9.3 mmol) and titanium(IV) isopropoxide (3.9 g, 13.95 mmol) were added to THF (40 mL), and the mixture was stirred at room temperature for 10 minutes under nitrogen protection. Ethylmagnesium bromide (6.2 mL, 18.6 mmol) was added at 0 °C, and the mixture was stirred at 0 °C for 30 minutes and then at room temperature for 1 hour. Boron trifluoride diethyl etherate (2.64 g, 18.6 mmol) was added and stirred for 30 minutes, then dilute hydrochloric acid (3 mL, 3 mmol) was added and stirred for 30 minutes, and then NaOH solution (10 mL, 20 mmol) was added. The mixture was extracted with ethyl acetate (50 mL x 3), the organic phases were combined, washed with saturated brine (50 mL), concentrated under reduced pressure, and the residue was purified by flash column chromatography (eluting with a gradient of methanol / water (+0.5% formic acid) = 0%-100%) to obtain 400 mg of the title product. MS (m / z) = 246 [M+H] + , 248 [M+2H] + .

[0321] The following intermediates were prepared by referring to the preparation process of Intermediate 26, using the corresponding raw materials and reagents, under the appropriate conditions recognized by those skilled in the art.

[0322]

[0323]

[0324] Intermediate 30

[0325] 5-Benzylisoxazole-3-carboxylic acid

[0326]

[0327] (A)(E)-Ethyl 2-(hydroxyimino)acetate

[0328] Ethyl 2-oxoacetate (30 mL, 587.7 mmol) was added to ethanol (100 mL), and hydroxylamine (77.5 g, 1175.4 mmol, 50% toluene solution) was added at 0 °C. The reaction was carried out at room temperature for 2 hours. The reaction was monitored by LC-MS and quenched by adding water. The aqueous phase was extracted with ethyl acetate (150 mL x 2). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 20.62 g of crude product. MS (m / z) = 118 [M+H] + .

[0329] (B)(Z)-Ethyl 2-chloro-2-(hydroxyimino)acetate

[0330] (E)-Ethyl 2-(hydroxyimino)acetate (20.62 g, 176.3 mmol) was added to DMF (20 mL), and NCS (27 g, 176.3 mmol) was added at 0 °C. The mixture was stirred at room temperature for 16 hours. The reaction was quenched by adding water. The aqueous phase was extracted with ethyl acetate (150 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography (gradient elution with petroleum ether / ethyl acetate = 100% - 0%) to obtain 16.8 g of the title product. MS (m / z) = 152 [M+H]+.

[0331] (C)Ethyl 5-benzylisoxazole-3-carboxylate

[0332] Ethyl (Z)-2-chloro-2-(hydroxyimino)acetate (1.5 g, 9.9 mmol) was added to acetonitrile (20 mL). Propargylbenzene (576 mg, 4.96 mmol) and triethylamine (1.2 g, 11.88 mmol) were added at room temperature. The reaction was carried out at 90 °C for 6 hours under nitrogen protection. The reaction mixture was concentrated under reduced pressure, and the residue was purified by flash column chromatography (gradient elution with petroleum ether / ethyl acetate = 100% - 0%) to obtain 100 mg of the title product. MS (m / z) = 232 [M+H] + .

[0333] (D) 5-Benzylisoxazole-3-carboxylic acid

[0334] Ethyl 5-benzylisoxazole-3-carboxylate (100 mg, 0.432 mmol) was added to THF (2 mL), methanol (0.5 mL) and water (0.5 mL). Lithium hydroxide monohydrate (54 mg, 1.296 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction was monitored by LC-MS until completion. The reaction mixture was concentrated under reduced pressure, and the pH was adjusted to 7 with 1N dilute hydrochloric acid. A solid precipitated out, which was filtered to obtain 40 mg of the product. MS (m / z) = 204 [M+H] + .

[0335] Intermediate 31

[0336] 5-Benzyl-1,3-oxazole-2-carboxylic acid

[0337]

[0338] (A) Ethyl 2-oxo-2-((2-oxo-3-phenylpropyl)amino)acetate

[0339] 1-Amino-3-phenylpropan-2-one (500 mg, 3.35 mmol) was added to toluene (20 mL). Ethyl 2-chloro-2-oxoacetate (905 mg, 6.70 mmol) was added at room temperature. The reaction was carried out at 90 °C for 2 hours under nitrogen protection. The reaction was quenched with ice water, and the aqueous phase was extracted with ethyl acetate (20 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography (gradient elution with petroleum ether / ethyl acetate = 100% - 0%) to obtain 650 mg of the title product. MS (m / z) = 250 [M+H] + .

[0340] (B) Ethyl 5-benzyl-1,3-oxazole-2-carboxylate

[0341] Ethyl 2-oxo-2-((2-oxo-3-phenylpropyl)amino)acetate (650 mg, 2.6 mmol) was added to toluene (20 mL), and POCl3 (2000 mg, 13 mmol) was added. The reaction was carried out at 120 °C for 5 hours. The reaction was quenched by adding ice water, and the aqueous phase was extracted with ethyl acetate (20 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by flash column chromatography (gradient elution with petroleum ether / ethyl acetate = 100% - 0%) to obtain 530 mg of the title product. MS (m / z) = 232 [M+H] + .

[0342] (C) 5-Benzyl-oxazole-2-carboxylic acid

[0343] Referring to the preparation process of Intermediate 30 (D), using ethyl 5-benzyl-oxazole-2-carboxylate as the raw material, the product was prepared. MS (m / z) = 204 [M+H] + .

[0344] Intermediate 32

[0345] Lithium 5-benzyl-1,3,4-oxadiazole-2-carboxylate

[0346]

[0347] Ethyl 5-benzyl-1,3,4-oxadiazole-2-carboxylate (70 mg, 0.301 mmol) was added to THF (2 mL), methanol (0.5 mL) and water (0.5 mL), and lithium hydroxide monohydrate (50 mg, 1.206 mmol) was added. The reaction was carried out at 60 °C for one hour. The reaction mixture was concentrated under reduced pressure and used directly in the next step without further purification. MS (m / z) = 205 [M+H] + .

[0348] Intermediate 33

[0349] Lithium 5-benzyl-1,2,4-oxadiazole-3-carboxylate

[0350]

[0351] (A) Ethyl 2-(hydroxyamino)-2-iminoacetate

[0352] Ethyl cyanoformate (2 g, 20 mmol) was added to ethanol (20 mL), and hydroxylamine hydrochloride (2 g, 30 mmol) and sodium carbonate (1.63 g, 15.4 mmol) were added. The reaction was carried out at room temperature for 2 hours. The reaction was quenched by adding ice water, and the aqueous phase was extracted with DCM (50 mL × 2). The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 2.3 g of the title product. MS (m / z) = 133 [M+H] + .

[0353] (B) Ethyl 2-imino-2-((2-phenylacetoxy)amino)acetate

[0354] Ethyl 2-(hydroxyamino)-2-iminoacetate (2.3 g, 18 mmol) was added to DCM (20 mL), and DIEA (4.6 g, 36 mmol) and 2-phenylacetyl chloride (2.7 g, 18 mmol) were added at -15 °C. The reaction was carried out overnight at room temperature. The reaction was quenched with ice water, and a solid was precipitated. The solid was filtered and dried to obtain 1.68 g of the title product. MS (m / z) = 251 [M+H] + .

[0355] (C) Ethyl 5-benzyl-1,2,4-oxadiazole-3-carboxylate

[0356] Ethyl 2-imino-2-((2-phenylacetoxy)amino)acetate (800 mg, 3.2 mmol) was added to pyridine (10 mL), and the reaction was carried out at 80 °C for 6 hours under nitrogen protection. The reaction mixture was concentrated under reduced pressure, and the residue was purified by flash column chromatography (gradient elution with petroleum ether / ethyl acetate = 100%-0%) to obtain 600 mg of the title product. MS (m / z) = 233 [M+H] + .

[0357] (D) Lithium 5-benzyl-1,2,4-oxadiazole-3-carboxylate

[0358] Ethyl 5-benzyl-1,2,4-oxadiazole-3-carboxylate (600 mg, 2.58 mmol) was added to THF (10 mL), methanol (2 mL) and water (2 mL), and lithium hydroxide monohydrate (325 mg, 7.74 mmol) was added. The reaction was carried out at room temperature for one hour. The reaction mixture was concentrated under reduced pressure, and the residue (500 mg) was used directly in the next step without further purification. MS (m / z) = 205 [M+H] + .

[0359] Intermediate 34

[0360] Lithium 1-(1-phenylethyl)-1H-1,2,4-triazole-3-carboxylate

[0361]

[0362] (A) Methyl 1-(1-phenylethyl)-1H-1,2,4-triazole-3-carboxylate

[0363] Methyl 1H-1,2,4-triazole-3-carboxylate (1 g, 7.87 mmol) was added to DMF (10 mL), and (1-bromoethyl)benzene (1737 mg, 9.44 mmol) and potassium carbonate (2.17 g, 15.74 mmol) were added. The reaction was carried out at room temperature for 16 hours. The mixture was concentrated under reduced pressure, and the residue was purified by flash column chromatography (gradient elution with methanol / water (+0.5% formic acid) = 0% - 100%) to obtain 1.5 g of the title product. MS (m / z) = 232 [M+H] + .

[0364] (B) Lithium 1-(1-phenylethyl)-1H-1,2,4-triazole-3-carboxylate

[0365] Methyl 1-(1-phenylethyl)-1H-1,2,4-triazole-3-carboxylate (1.5 g, 6.493 mmol) was added to methanol (10 mL) and water (2 mL), and lithium hydroxide monohydrate (817 mg, 19.47 mmol) was added. The reaction was carried out at room temperature for one hour. The mixture was concentrated under reduced pressure, and the residue was purified by flash column chromatography (gradient elution with methanol / water = 0% - 100%) to obtain 1.22 g of the title product. MS (m / z) = 218 [M+H] + .

[0366] Intermediate 35

[0367] Lithium 5-(1-phenylethyl)-4H-1,2,4-triazole-3-carboxylate

[0368]

[0369] (A) Methyl 2-phenylpropionate

[0370] (R)-2-Phenylpropionic acid (1.95 g, 12.98 mmol) was added to methanol (20 mL), and SOCl2 (2 mL) was added at 0 °C. The reaction was carried out at room temperature for 2 hours. The mixture was concentrated under reduced pressure, and the residue (2.18 g) was used directly in the next step without further purification. MS (m / z) = 165 [M+H] + .

[0371] (B) 2-Phenylpropionohydrazide

[0372] Methyl 2-phenylpropionate (2.18 g, 12.98 mmol) was added to ethanol (20 mL), and hydrazine hydrate (5 mL) was added at 0 °C. The reaction was carried out at 80 °C for 2 hours. The mixture was concentrated under reduced pressure, and the residue was purified by flash column chromatography (gradient elution with methanol / water = 0% - 100%) to obtain 1.96 g of the title product. MS (m / z) = 165 [M+H] + .

[0373] (C) Ethyl 2-imino-2-(2-(2-phenylpropanoyl)hydrazino)acetate

[0374] Ethyl 2-phenylpropionohydrazide (900 mg, 5.48 mmol) and ethyl 2-imino-2-methoxyacetate (1435 mg, 10.96 mmol) were added to ethanol (20 mL), and the reaction was carried out at 80 °C for 2 hours under nitrogen protection. After cooling to room temperature, a solid was precipitated, filtered and dried to obtain 1.4 g of the product. MS (m / z) = 264 [M+H] + .

[0375] (D) Ethyl 5-(1-phenylethyl)-4H-1,2,4-triazole-3-carboxylate

[0376] Ethyl 2-imino-2-(2-(2-phenylpropanoyl)hydrazino)acetate (1.4 g, 5.32 mmol) was added to toluene (20 mL), and POCl3 (10 mL) was added. The reaction was carried out at 120 °C for 24 hours. The solvent was concentrated under reduced pressure, and the residue was purified by flash column chromatography (elution gradient of methanol / water (+0.5% formic acid) = 0% - 100%) to obtain 563 mg of the title product. MS (m / z) = 246 [M+H] + .

[0377] (E) Lithium 5-(1-phenylethyl)-4H-1,2,4-triazole-3-carboxylate

[0378] Referring to the preparation process of Intermediate 34 (B), using ethyl 5-(1-phenylethyl)-4H-1,2,4-triazole-3-carboxylate as the raw material, the title product was prepared. MS (m / z) = 218 [M+H] + .

[0379] Intermediate 37 and Intermediate 38

[0380] (R)-Ethyl 5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate and (S)-ethyl 5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate

[0381]

[0382] The racemic compound was resolved by chiral HPLC to obtain optically pure enantiomeric intermediates 37 and 38 (HPLC conditions: column: AD-H 4.6 x 150 mm; mobile phase: hexane / ethanol = 70 / 30; flow rate: 0.5 mL / min; detector: UV 254 nm). The first eluate (Intermediate 37, Rf = 3.651 minutes) had an ee value of 100%, MS (m / z): 258 [M+H] +; The ee value of the second eluent (Intermediate 38, Rf = 4.350 minutes) is 99.98%, MS (m / z): 258 [M+H] + .

[0383] Intermediate 39

[0384] 1-(1-Cyclopropylethyl)-1H-pyrazolo[3,4-d]pyrimidine-6-carboxylic acid

[0385] (A) 6-Chloro-1-(1-cyclopropylethyl)-1H-pyrazolo[3,4-d]pyrimidine

[0386] Dissolve 6-chloro-1H-pyrazolo[3,4-d]pyrimidine (800 mg, 5.2 mmol), 1-cyclopropylethyl-1-ol (1.3 g, 15.6 mmol) and triphenylphosphine (2.0 g, 7.8 mmol) in tetrahydrofuran (10 mL), then slowly add DIAD (1.6 mL), and then heat to 60 °C and react overnight. The reaction solution is concentrated under reduced pressure, and the residue is purified by flash column chromatography (gradient elution with petroleum ether / ethyl acetate = 100%–0%), to obtain 420 mg of the product. MS (m / z) = 223 [M+H] + .

[0387] (B) 1-(1-Cyclopropylethyl)-1H-pyrazolo[3,4-d]pyrimidine-6-carbonitrile

[0388] Add 6-chloro-1-(1-cyclopropylethyl)-1H-pyrazolo[3,4-d]pyrimidine (420 mg, 1.88 mmol), zinc cyanide (120 mg, 1.13 mmol) and Pd(PPh3)4 (220 mg, 0.188 mmol) to DMF (5 mL), heat to 110 °C and react for 1.5 hours. After concentration under reduced pressure, the residue is purified by flash column chromatography (gradient elution with petroleum ether / ethyl acetate = 100%-0%), to obtain 310 mg of the product. MS (m / z) = 214 [M+H]+.

[0389] (C) 1-(1-Cyclopropylethyl)-1H-pyrazolo[3,4-d]pyrimidine-6-carboxylic acid

[0390] Add 1-(1-cyclopropylethyl)-1H-pyrazolo[3,4-d]pyrimidine-6-carbonitrile (310 mg, 1.45 mmol) to 1N sodium hydroxide (7 mL), heat to 110 °C and react for 1.5 hours. Cool, adjust the pH to 4 with 1N hydrochloric acid, concentrate under reduced pressure, and the residue is purified by flash column chromatography (gradient elution with methanol / water = 0%-100%), to obtain 377 mg of the target product. MS (m / z) = 233 [M+H]+ .

[0391] The following intermediates were prepared by referring to the preparation process of Intermediate 39, using the corresponding raw materials and reagents under the appropriate conditions recognized by those skilled in the art.

[0392]

[0393] Intermediate 42

[0394] 1-(Cyclobutylmethyl)-1H-pyrazolo[3,4-d]pyrimidine-6-carboxylic acid

[0395]

[0396] (A) 6-Chloro-1-(cyclobutylmethyl)-1H-pyrazolo[3,4-d]pyrimidine

[0397] 6-Chloro-1H-pyrazolo[3,4-d]pyrimidine (500 mg, 3.23 mmol), (bromomethyl)cyclobutane (965 mg, 6.46 mmol), potassium carbonate (890 mg, 6.46 mmol) and sodium iodide (970 mg, 6.46 mmol) were dissolved in NMP (5 mL), heated to 60 °C and reacted overnight. After cooling, water was added, and the mixture was extracted with ethyl acetate. The ethyl acetate extract was concentrated under reduced pressure, and the residue was purified by flash column chromatography (gradient elution with petroleum ether / ethyl acetate = 100%–0%) to obtain 310 mg of the product. MS (m / z) = 223 [M+H] + .

[0398] (B) 1-(Cyclobutylmethyl)-1H-pyrazolo[3,4-d]pyrimidine-6-carbonitrile

[0399] Referring to the preparation process of Intermediate 39 (B), using 6-chloro-1-(cyclobutylmethyl)-1H-pyrazolo[3,4-d]pyrimidine as the raw material, the title product was prepared. MS (m / z) = 214 [M+H] + .

[0400] (C) 1-(Cyclobutylmethyl)-1H-pyrazolo[3,4-d]pyrimidine-6-carboxylic acid

[0401] Referring to the preparation process of Intermediate 39 (C), using 1-(cyclobutylmethyl)-1H-pyrazolo[3,4-d]pyrimidine-6-carbonitrile as the raw material, the title product was prepared. MS (m / z) = 233 [M+H] + .

[0402] Intermediate 43

[0403] 1-(Pyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidine-6-carboxylic acid

[0404]

[0405] (A)(Z)-2,4-Dichloro-5-((2-(pyridin-2-yl)hydrazinyl)methyl)pyrimidine

[0406] Dissolve 2,4-dichloropyrimidine-5-carbaldehyde (500 mg, 2.8 mmol), 2-hydrazinylpyridine (310 mg, 2.8 mmol) and p-toluenesulfonic acid (540 mg, 2.8 mmol) in DMF (5 mL). After reacting at room temperature for 2 hours, add water (20 mL) and saturated sodium bicarbonate solution (10 mL), filter, and obtain 610 mg of the product, which is directly used for the next step. MS (m / z) = 268 [M+H] + .

[0407] (B)6-Chloro-1-(pyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidine

[0408] Dissolve (Z)-2,4-dichloro-5-((2-(pyridin-2-yl)hydrazinyl)methyl)pyrimidine (1.4 g, 5.2 mmol) in acetonitrile (30 mL), and heat to 140 °C for microwave reaction for 3 hours. After concentration under reduced pressure, the residue is purified by flash column chromatography (gradient elution with methanol / water = 0%-100%), and 125 mg of the product is obtained. MS (m / z) = 232 [M+H] + .

[0409] (C)1-(pyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidine-6-carbonitrile

[0410] Add 6-chloro-1-(pyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (125 mg, 0.54 mmol), zinc cyanide (35 mg, 0.32 mmol) and Pd(PPh3)4 (65 mg, 0.054 mmol) to DMF (5 mL), and heat to 110 °C for reaction for 1.5 hours. After concentration under reduced pressure, the residue is purified by flash column chromatography (gradient elution with petroleum ether / ethyl acetate = 100%-0%), and 121 mg of the product is obtained. MS (m / z) = 223 [M+H] + .

[0411] (D)Methyl 1-(pyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidine-6-carboxylate

[0412] 1-(Pyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidine-6-carbonitrile (121 mg, 0.5 mmol) was dissolved in methanol (5 mL), 4N hydrochloric acid in methanol solution (2.5 mL) was added, and the reaction was carried out at 20 °C for 20 hours and then at 50 °C for 3 hours. After cooling and concentration under reduced pressure, the residue was purified by flash column chromatography (gradient elution with methanol / water = 0%-100%) to give 50 mg of the product. MS (m / z) = 256 [M+H] + .

[0413] (E)1-(Pyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidine-6-carboxylic acid

[0414] Methyl 1-(pyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidine-6-carboxylate (50 mg, 0.22 mmol) was dissolved in tetrahydrofuran / water (5 mL / 1 mL), LiOH·H2O (50 mg, 1.10 mmol) was added, and the reaction was carried out at 25 °C for 2 hours. After concentration under reduced pressure, the pH was adjusted to 4 with 2N hydrochloric acid solution, and the mixture was extracted with ethyl acetate (3×10 mL). The ethyl acetate layer was concentrated, and the residue was purified by flash column chromatography (gradient elution with methanol / water = 0%-100%) to give 45 mg of the product. MS (m / z) = 242 [M+H] + .

[0415] Compound 1

[0416] 1-Isopropyl-N-(1-(4-(1-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)phenyl)cyclopropyl)-1H-pyrazolo[3,4-d]pyrimidine-6-carboxamide

[0417]

[0418] (A)5-(4-(1-Aminocyclopropyl)phenyl)-3-methylpyrimidin-4(3H)-one

[0419] 5-Bromo-3-methylpyrimidin-4(3H)-one (63 mg, 0.33 mmol), tert-butyl (1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropyl)carbamate (143 mg, 0.40 mmol), K2CO3 (137 mg, 0.99 mmol) and Pd(dppf)Cl2 (12 mg, 0.02 mmol) were added to 10 mL of dioxane and water (3:1), and the mixture was stirred at 120 °C for 5 h. The solvent was removed, and the residue was purified by flash column chromatography (gradient elution with methanol / water (+0.1% formic acid) = 10% - 80%) to obtain the crude product. At room temperature, 2N HCl in methanol solution (10 mL) was added to the crude product, and the mixture was stirred for 2 h. Then the solvent was removed to obtain 65 mg of a light yellow solid product. MS (m / z) = 242 [M+H] + .

[0420] (B) 1-Isopropyl-N-(1-(4-(1-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)phenyl)cyclopropyl)-1H-pyrazolo[3,4-d]pyrimidine-6-carboxamide

[0421] 5-(4-(1-Aminocyclopropyl)phenyl)-3-methylpyrimidin-4(3H)-one (65 mg, 0.27 mmol), 1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine-6-carboxylic acid (56 mg, 0.27 mmol), HATU (123 mg, 0.32 mmol) and TEA (82 mg, 0.81 mmol) were added to DCM (5 mL), and the mixture was stirred at room temperature for 2 h under nitrogen protection. The solvent was removed, and the residue was purified by flash column chromatography (gradient elution with methanol / water (+0.1% formic acid) = 10% - 80%) to obtain 90 mg of a white solid product. MS (m / z) = 430 [M+H] + .

[0422] 1 1H NMR (400 MHz, DMSO) δ 9.71 (s, 1H), 9.41 (s, 1H), 8.47 (d, J = 0.4 Hz, 1H), 8.44 (s, 1H), 8.07 (s, 1H), 7.61–7.56 (m, 2H), 7.28–7.24 (m, 2H), 5.34–5.24 (m, 1H), 3.44 (s, 3H), 1.50 (d, J = 6.7 Hz, 6H), 1.36–1.28 (m, 4H).

[0423] The following compounds were prepared by referring to the preparation process of Reference Compound 1, using the corresponding intermediates and reagents, under the appropriate conditions recognized by those skilled in the art.

[0424]

[0425]

[0426]

[0427]

[0428]

[0429]

[0430] Compound 23

[0431] N-(1-(3-fluoro-4-(1-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)phenyl)cyclopropyl)-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine-6-carboxamide

[0432]

[0433] (A) N-(1-(4-bromo-3-fluorophenyl)cyclopropyl)-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine-6-carboxamide

[0434] 1-(4-Bromo-3-fluorophenyl)cyclopropan-1-amine (100 mg, 0.43 mmol), 1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine-6-carboxylic acid (90 mg, 0.43 mmol), HATU (196 mg, 0.52 mmol) and TEA (130 mg, 0.52 mmol) were added to DCM (10 mL). The mixture was stirred at room temperature for 2 h under nitrogen protection. The solvent was removed and the residue was purified by flash column chromatography (gradient elution with methanol / water (+0.1% formic acid) = 10% - 80%) to give 100 mg of a white solid product. MS (m / z) = 419 [M+H] + .

[0435] (B) N-(1-(3-fluoro-4-(1-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)phenyl)cyclopropyl)-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine-6-carboxamide

[0436] N-(1-(4-Bromo-3-fluorophenyl)cyclopropyl)-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine-6-carboxamide (100 mg, 0.24 mmol), (1-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)boronic acid (38 mg, 0.24 mmol), K2CO3 (100 mg, 0.72 mmol) and Pd(dppf)Cl2 (12 mg, 0.02 mmol) were added to 10 mL of dioxane and water (3:1), and the mixture was stirred at 120 °C for 5 hours under nitrogen protection. The solvent was removed, and the residue was purified by flash column chromatography (gradient elution with methanol / water (+0.1% formic acid) = 10% - 80%) to obtain the crude product. The crude product was purified by preparative thin-layer chromatography (DCM / MeOH = 15 / 1) to obtain 50 mg of the white solid product. MS (m / z) = 448 [M+H] + .

[0437] 1 1H NMR (400 MHz, DMSO) δ 9.76 (s, 1H), 9.43 (d, J = 1.8 Hz, 1H), 8.48 (d, J = 5.4 Hz, 2H), 7.97 (s, 1H), 7.36 (t, J = 7.9 Hz, 1H), 7.12–7.08 (m, 2H), 5.35–5.24 (m, 1H), 3.45 (s, 3H), 1.51 (d, J = 6.7 Hz, 6H), 1.40–1.34 (m, 4H).

[0438] The following compounds were prepared according to the preparation process of reference compound 23, using the corresponding intermediates and reagents, under the appropriate conditions recognized by those skilled in the art.

[0439]

[0440]

[0441] Compound 28

[0442] 1-Isopropyl-N-(1-(4-(1-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)phenyl)cyclopropyl)-1H-pyrazolo[4,3-c]pyridine-6-carboxamide

[0443]

[0444] N-(1-(4-(1-Methyl-6-oxo-1,6-dihydropyrimidin-5-yl)phenyl)cyclopropyl)-1H-pyrazolo[4,3-c]pyridine-6-carboxamide (prepared with reference to the preparation process of Reference Compound 1 using 5-bromo-3-methylpyrimidin-4(3H)-one, tert-butyl (1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropyl)carbamate, and 1H-pyrazolo[4,3-c]pyridine-6-carboxylic acid as starting materials) (60.0 mg, 0.16 mmol) and isopropanol (18.6 mg, 0.31 mmol) were added to a mixed solvent of DCM (4 mL) and THF (4 mL). DIAD (62.6 mg, 0.31 mmol) and PPh3 (81.2 mg, 0.31 mmol) were added, and the reaction was carried out overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was purified by flash column chromatography (eluted with a gradient of methanol / water = 10% - 100%) to obtain 35 mg of the title product. MS (m / z) = 429 [M+H] + .

[0445] 1 1H NMR (400 MHz, DMSO) δ 9.51 (s, 1H), 9.19–9.09 (m, 1H), 8.43 (s, 1H), 8.41 (s, 1H), 8.31 (s, 1H), 8.07 (s, 1H), 7.57 (d, J = 8.3 Hz, 2H), 7.24 (d, J = 8.3 Hz, 2H), 5.35–4.97 (m, 1H), 3.45 (s, 3H), 1.48 (d, J = 6.6 Hz, 6H), 1.41–1.26 (m, 4H).

[0446] Compound 29

[0447] 1-Isopropyl-N-(1-(4-(1-isopropyl-6-oxo-1,6-dihydropyrimidin-5-yl)phenyl)cyclopropyl)-1H-pyrazolo[3,4-d]pyrimidine-6-carboxamide

[0448]

[0449] (A) 1-Isopropyl-N-(1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropyl)-1H-pyrazolo[3,4-d]pyrimidine-6-carboxamide

[0450] N-(1-(4-Bromophenyl)cyclopropyl)-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine-6-carboxamide (prepared from 1-(4-bromophenyl)cyclopropan-1-amine and 1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine-6-carboxylic acid according to the preparation process of reference compound 23(A)) (1 g, 2.5 mmol), bis(pinacolato)diboron (952 mg, 3.75 mmol), KOAc (735 mg, 7.5 mmol) and Pd(dppf)Cl2 (92 mg, 0.13 mmol) were added to dioxane (30 mL), and the mixture was stirred at 120 °C for 5 hours under nitrogen protection. The solvent was removed, and the residue was purified by flash column chromatography (eluted with a gradient of methanol / water (+0.1% formic acid) = 10% - 80%) to obtain 800 mg of a yellow solid product. MS (m / z) = 448 [M+H] + .

[0451] (B) 1-Isopropyl-N-(1-(4-(1-isopropyl-6-oxo-1,6-dihydropyrimidin-5-yl)phenyl)cyclopropyl)-1H-pyrazolo[3,4-d]pyrimidine-6-carboxamide

[0452] 1-Isopropyl-N-(1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropyl)-1H-pyrazolo[3,4-d]pyrimidine-6-carboxamide (120 mg, 0.27 mmol) and 5-bromo-3-isopropylpyrimidin-4(3H)-one (59 mg, 0.27 mmol) were added to a mixed solvent of dioxane (10 mL) and water (2 mL). Under nitrogen protection, Pd(dppf)Cl2 (20 mg, 0.027 mmol) and potassium carbonate (112 mg, 0.81 mmol) were added, and the mixture was heated to reflux for 2 hours. After cooling to room temperature, it was concentrated under reduced pressure, and the residue was purified by flash column chromatography (eluted with methanol / water (+0.5% formic acid) = 60%:40%) to obtain 23 mg of a pale yellow solid product. MS (m / z) = 458.2 [M+H] + .

[0453] 1 H NMR (400 MHz, DMSO) δ 9.72 (s, 1H), 9.43 (s, 1H), 8.53 (s, 1H), 8.48 (s, 1H), 8.07 (s, 1H), 7.58 (d, J = 8.3 Hz, 2H), 7.27 (d, J = 8.3 Hz, 2H), 5.38–5.26 (m, 1H), 5.03–4.90 (m, 1H), 1.51 (d, J = 6.7 Hz, 6H), 1.39 (d, J = 6.9 Hz, 6H), 1.34 (d, J = 8.4 Hz, 4H).

[0454] The following compounds were prepared with the corresponding intermediates and reagents according to the preparation process of Reference Compound 29 under the appropriate conditions recognized by those skilled in the art.

[0455]

[0456]

[0457]

[0458]

[0459]

[0460]

[0461]

[0462]

[0463]

[0464]

[0465]

[0466]

[0467]

[0468] Compound 53 and Compound 54

[0469] (S)-N-(1-(4-(1-Methyl-6-oxo-1,6-dihydropyrimidin-5-yl)phenyl)cyclopropyl)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide and (R)-N-(1-(4-(1-Methyl-6-oxo-1,6-dihydropyrimidin-5-yl)phenyl)cyclopropyl)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide

[0470]

[0471] The racemic compound N-(1-(4-(1-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)phenyl)cyclopropyl)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide (prepared from 5-bromo-3-methylpyrimidin-4(3H)-one, tert-butyl (1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropyl)carbamate and intermediate 20 according to the preparation process of reference compound 1) was resolved by chiral HPLC to obtain the optically pure enantiomeric compounds 53 and 54 (HPLC conditions: column: OJ-H 4.6x150mm; mobile phase: n-hexane / ethanol = 60 / 40; flow rate: 0.5 mL / min; detector: UV 254 nm). The first eluate (compound 53, Rf = 3.028 minutes) had an ee value of 100%, MS (m / z): 453 [M+H] + ; The second eluate (compound 54, Rf = 4.915 minutes) had an ee value of 99.78%, MS (m / z): 453 [M+H] + .

[0472] Compound 53: 1 H NMR (400 MHz, CDCl3) δ: 8.09 (s, 1H), 8.00 (s, 1H), 7.71 (s, 1H), 7.61–7.54 (m, 2H), 7.39–7.32 (m, 5H), 7.16–7.08 (m, 2H), 5.48–5.40 (m, 1H), 3.57 (s, 3H), 3.29–2.95 (m, 3H), 2.76–2.59 (m, 1H), 1.45–1.34 (m, 4H).

[0473] Compound 54: 1 H NMR (400 MHz, CDCl3) δ: 8.09 (s, 1H), 8.00 (s, 1H), 7.71 (s, 1H), 7.61–7.55 (m, 2H), 7.39–7.31 (m, 5H), 7.18–7.06 (m, 2H), 5.51–5.39 (m, 1H), 3.56 (s, 3H), 3.28–2.97 (m, 3H), 2.74–2.60 (m, 1H), 1.44–1.34 (m, 4H).

[0474] Compounds 55 and 56

[0475] (R)-N-(1-(4-(1-Methyl-6-oxo-1,6-dihydropyrimidin-5-yl)phenyl)cyclopropyl)-1-(1-phenylethyl)-1H-1,2,4-triazole-3-carboxamide and (S)-N-(1-(4-(1-Methyl-6-oxo-1,6-dihydropyrimidin-5-yl)phenyl)cyclopropyl)-1-(1-phenylethyl)-1H-1,2,4-triazole-3-carboxamide

[0476]

[0477] The racemic compound N-(1-(4-(1-Methyl-6-oxo-1,6-dihydropyrimidin-5-yl)phenyl)cyclopropyl)-1-(1-phenylethyl)-1H-1,2,4-triazole-3-carboxamide (prepared from 5-bromo-3-methylpyrimidin-4(3H)-one, tert-butyl (1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropyl)carbamate and intermediate 34 according to the preparation process of reference compound 1) was resolved by chiral HPLC to obtain the optically pure enantiomeric compounds 55 and 56 (HPLC conditions: column: Daicel OJ 4.6x150 mm; mobile phase: hexane / isopropanol (0.1% diethylamine) = 60:40; flow rate: 0.5 mL / min; detector: UV 254 nm). The first eluate (compound 55, Rf = 4.676 min) had an ee value of 99.85% and MS (m / z): 441 [M+H] + ; the second eluate (compound 56, Rf = 5.955 min) had an ee value of 99.89% and MS (m / z): 441 [M+H] + .

[0478] Compound 55: 1 H NMR (400 MHz, CD3OD) δ 8.54 (s, 1H), 8.36 (s, 1H), 8.04 (s, 1H), 7.59–7.53 (m, 2H), 7.35 (d, J = 4.4 Hz, 4H), 7.33–7.27 (m, 3H), 5.83–5.68 (m, J = 7.1 Hz, 1H), 3.55 (s, 3H), 1.93 (d, J = 7.1 Hz, 3H), 1.39–1.33 (m, 4H).

[0479] Compound 56: 11H NMR (400 MHz, CD3OD) δ 8.55 (s, 1H), 8.36 (s, 1H), 8.04 (s, 1H), 7.59–7.54 (m, 2H), 7.35 (d, J = 3.7 Hz, 4H), 7.33–7.29 (m, 3H), 5.82–5.66 (m, 1H), 3.55 (s, 3H), 1.93 (d, J = 7.1 Hz, 3H), 1.39–1.34 (m, 4H).

[0480] Compound 57 and Compound 58

[0481] (R)-N-(1-(4-(1-Methyl-6-oxo-1,6-dihydropyrimidin-5-yl)phenyl)cyclopropyl)-5-(1-phenylethyl)-4H-1,2,4-triazole-3-carboxamide and (S)-N-(1-(4-(1-Methyl-6-oxo-1,6-dihydropyrimidin-5-yl)phenyl)cyclopropyl)-5-(1-phenylethyl)-4H-1,2,4-triazole-3-carboxamide

[0482]

[0483] The racemic compound N-(1-(4-(1-Methyl-6-oxo-1,6-dihydropyrimidin-5-yl)phenyl)cyclopropyl)-5-(1-phenylethyl)-4H-1,2,4-triazole-3-carboxamide (prepared from 5-bromo-3-methylpyrimidin-4(3H)-one, tert-butyl (1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropyl)carbamate and Intermediate 35 according to the preparation process of Reference Compound 1) was resolved by chiral HPLC to obtain the optically pure enantiomeric compounds 57 and 58 (HPLC conditions: column: Daicel OJ 4.6 x 150 mm; mobile phase: n-hexane / ethanol (0.1% diethylamine) = 60:40; flow rate: 0.5 mL / min; detector: UV 254 nm). The first eluate (Compound 57, Rf = 6.485 min) had an ee value of 100%, MS (m / z): 441 [M+H] + ; the second eluate (Compound 58, Rf = 6.979 min) had an ee value of 99.90%, MS (m / z): 441 [M+H] + .

[0484] Compound 57: 11H NMR (400 MHz, DMSO) δ 9.26 (s, 1H), 8.44 (s, 1H), 8.06 (s, 1H), 7.58–7.54 (m, 2H), 7.35–7.26 (m, 4H), 7.26–7.14 (m, 3H), 4.38–4.21 (m, 1H), 3.45 (s, 3H), 1.61 (d, J = 7.2 Hz, 3H), 1.28–1.22 (m, 4H)

[0485] Compound 58: 1 1H NMR (400 MHz, DMSO) δ 9.24 (s, 1H), 8.44 (s, 1H), 8.06 (s, 1H), 7.62–7.53 (m, 2H), 7.35–7.26 (m, 4H), 7.26–7.13 (m, 3H), 4.36–4.25 (m, 1H), 3.45 (s, 3H), 1.61 (d, J = 7.2 Hz, 3H), 1.28–1.22 (m, 4H).

[0486] Compounds 80 and 81

[0487] (R)-1-Isopropyl-N-(1-(4-(6-oxo-1-(tetrahydrofuran-3-yl)-1,6-dihydropyrimidin-5-yl)phenyl)cyclopropyl)-1H-pyrazolo[3,4-d]pyrimidine-6-carboxamide and (S)-1-isopropyl-N-(1-(4-(6-oxo-1-(tetrahydrofuran-3-yl)-1,6-dihydropyrimidin-5-yl)phenyl)cyclopropyl)-1H-pyrazolo[3,4-d]pyrimidine-6-carboxamide

[0488]

[0489] The racemic compound 1-isopropyl-N-(1-(4-(6-oxo-1-(tetrahydrofuran-3-yl)-1,6-dihydropyrimidin-5-yl)phenyl)cyclopropyl)-1H-pyrazolo[3,4-d]pyrimidine-6-carboxamide (prepared from 1-(4-bromophenyl)cyclopropan-1-amine, 1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine-6-carboxylic acid and intermediate 45 according to the preparation process of reference compound 29) was resolved by chiral HPLC to obtain the optically pure enantiomeric compounds 80 and 81 (HPLC conditions: column: AD-H 4.6 x 50 mm; mobile phase: CO2:IPA (0.1% DEA) = 60:40; flow rate: 4 mL / min; detector: UV 254 nm). The first eluate (compound 80, Rf = 2.933 min) had an ee value of 100%, MS (m / z): 486.2 [M+H] +。The second eluent (Compound 81, Rf = 3.691 min) had an ee value of 99.17%, MS (m / z): 486.2 [M+H] + 。

[0490] Compound 80: 1 H NMR (400 MHz, CDCl3) δ 9.19 (s, 1H), 8.83 (s, 1H), 8.25 (s, 1H), 8.23–8.20 (m, 1H), 7.98 (s, 1H), 7.59–7.54 (m, 2H), 7.47–7.41 (m, 2H), 5.59–5.50 (m, 1H), 5.51–5.41 (m, 1H), 4.18 (td, J = 8.6, 6.1 Hz, 1H), 4.13–4.06 (m, 1H), 3.98–3.84 (m, 2H), 2.61 (dtd, J = 14.5, 8.7, 6.0 Hz, 1H), 2.14–2.04 (m, 1H), 1.57 (s, 6H), 1.49 (dd, J = 7.1, 5.5 Hz, 2H), 1.45–1.41 (m, 2H).

[0491] Compound 81: 1 H NMR (400 MHz, CDCl3) δ 9.19 (s, 1H), 8.83 (s, 1H), 8.25 (s, 1H), 8.22 (d, J = 0.4 Hz, 1H), 8.00–7.96 (m, 1H), 7.58–7.55 (m, 2H), 7.46–7.43 (m, 2H), 5.58–5.51 (m, 1H), 5.52–5.41 (m, 1H), 4.18 (td, J = 8.6, 6.0 Hz, 1H), 4.09 (d, J = 11.3 Hz, 1H), 3.98–3.86 (m, 2H), 2.61 (dtd, J = 14.5, 8.7, 6.1 Hz, 1H), 2.08 (ddd, J = 16.5, 11.1, 5.0 Hz, 1H), 1.59 (s, 6H), 1.49 (dd, J = 7.2, 5.5 Hz, 2H), 1.44 (d, J = 4.5 Hz, 2H).

[0492] Compounds 82 and 83

[0493] (R)-N-(1-(4-(1-(1-cyanoethyl)-6-oxo-1,6-dihydropyrimidin-5-yl)phenyl)cyclopropyl)-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine-6-carboxamide and (S)-N-(1-(4-(1-(1-cyanoethyl)-6-oxo-1,6-dihydropyrimidin-5-yl)phenyl)cyclopropyl)-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine-6-carboxamide

[0494]

[0495] The racemic compound N-(1-(4-(1-(1-cyanoethyl)-6-oxo-1,6-dihydropyrimidin-5-yl)phenyl)cyclopropyl)-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine-6-carboxamide (prepared from 1-(4-bromophenyl)cyclopropan-1-amine, 1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine-6-carboxylic acid and intermediate 36 according to the preparation process of reference compound 29) was resolved by chiral HPLC to obtain the optically pure enantiomeric compounds 82 and 83 (HPLC conditions: column: AD-H 4.6x50 mm; mobile phase: CO2:IPA(0.1% DEA) = 60 / 40; flow rate: 4 mL / min; detector: UV 254 nm). The first eluate (compound 82, Rf = 1.554 min) had an ee value of 100% and MS (m / z): 469.2 [M+H] + The second eluate (compound 83, Rf = 2.063 min) had an ee value of 99.88% and MS (m / z): 469.2 [M+H] +

[0496] Compound 82: 1 H NMR (400 MHz, CDCl3) δ 9.21 (s, 1H), 8.85 (s, 1H), 8.36 (s, 1H), 8.23 (s, 1H), 8.03 (s, 1H), 7.55 (d, J = 8.2 Hz, 2H), 7.43 (d, J = 8.1 Hz, 2H), 5.98–5.84 (m, 1H), 5.55–5.40 (m, 1H), 1.81 (d, J = 7.1 Hz, 3H), 1.58 (d, J = 6.6 Hz, 6H), 1.51–1.43 (m, 4H).

[0497] Compound 83: 1 H NMR (400 MHz, CDCl3) δ 9.19 (s, 1H), 8.84 (s, 1H), 8.34 (s, 1H), 8.23 (s, 1H), 8.02 (s, 1H), 7.55 (d, J = 8.3 Hz, 2H), 7.44 (d, J = 8.3 Hz, 2H), 5.90 (q, J = 7.0 Hz, 1H), 5.45 (dt, J = 13.1, 6.6 Hz, 1H), 1.81 (d, J = 7.1 Hz, 3H), 1.58 (d, J = 6.7 Hz, 6H), 1.52–1.42 (m, 4H).

[0498] Compounds 84 and 85 ​

[0499] (R)-N-(1-(4-(1-(1-cyclopropylethyl)-6-oxo-1,6-dihydropyrimidin-5-yl)phenyl)cyclopropyl)-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine-6-carboxamide and (S)-N-(1-(4-(1-(1-cyclopropylethyl)-6-oxo-1,6-dihydropyrimidin-5-yl)phenyl)cyclopropyl)-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine-6-carboxamide

[0500]

[0501] The racemic compound N-(1-(4-(1-(1-cyclopropylethyl)-6-oxo-1,6-dihydropyrimidin-5-yl)phenyl)cyclopropyl)-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine-6-carboxamide (prepared from 1-(4-bromophenyl)cyclopropan-1-amine, 1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine-6-carboxylic acid and intermediate 50 according to the preparation process of reference compound 29) was resolved by chiral HPLC to obtain the optically pure enantiomeric compounds 84 and 85 (HPLC conditions: column: IG-H 4.6x150 mm; mobile phase: ethanol:acetonitrile = 90 / 10; flow rate: 0.5 mL / min; detector: UV 254 nm). The first eluate (compound 84, Rf = 21.601 minutes) had an ee value of 100%, MS (m / z): 484.2 [M+H] + The second eluate (compound 85, Rf = 27.267 minutes) had an ee value of 100%, MS (m / z): 484.2 [M+H] +

[0502] Compound 84: 1 H NMR (400 MHz, CD3OD) δ 9.33 (s, 1H), 8.57 (s, 1H), 8.36 (s, 1H), 8.03 (s, 1H), 7.57 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 8.4 Hz, 2H), 5.47 - 5.40 (, 1H), 4.16 - 4.08 (m, 1H), 1.56 (d, J = 6.7 Hz, 6H), 1.52 (d, J = 6.8 Hz, 3H), 1.46 - 1.40 (m, 4H), 0.91–0.72 (m, 2H), 0.60–0.42 (m, 2H), 0.31 - 0.25 (m, 1H).

[0503] Compound 85: 1 ​1H NMR (400 MHz, CD3OD) δ 9.34 (s, 1H), 8.57 (s, 1H), 8.36 (s, 1H), 8.04 (s, 1H), 7.57 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 8.4 Hz, 2H), 5.48 - 5.41 (m, 1H), 4.16 - 4.09 (m, 1H), 1.57 (d, J = 6.7 Hz, 6H), 1.53 (d, J = 6.8 Hz, 3H), 1.45 (d, J = 11.8 Hz, 4H), 0.98–0.73 (m, 2H), 0.60–0.44 (m, 2H), 0.32 - 0.26 (td, J = 9.7, 5.1 Hz, 1H).

[0504] Compound 87 and Compound 88

[0505] N-(1-(4-(1-(trans-3-fluorocyclobutyl)-6-oxo-1,6-dihydropyrimidin-5-yl)phenyl)cyclopropyl)-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine-6-carboxamide and N-(1-(4-(1-(cis-3-fluorocyclobutyl)-6-oxo-1,6-dihydropyrimidin-5-yl)phenyl)cyclopropyl)-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine-6-carboxamide

[0506]

[0507] Compound N-(1-(4-(1-(3-fluorocyclobutyl)-6-oxo-1,6-dihydropyrimidin-5-yl)phenyl)cyclopropyl)-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine-6-carboxamide (prepared from 1-(4-bromophenyl)cyclopropan-1-amine, 1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine-6-carboxylic acid and intermediate 55 according to the preparation process of reference compound 29) was resolved by chiral HPLC to obtain Compound 87 and Compound 88 (HPLC conditions: column: OD-H 4.6 x 50 mm; mobile phase: CO2:IPA(0.1% DEA) = 60:40; flow rate: 4 mL / min; detector: UV 254 nm). The first eluate (Compound 87, Rf = 14.930 min) had an ee value of 100%, MS (m / z): 488.2 [M+H] + The second eluate (Compound 88, Rf = 21.254 min) had an ee value of 100%, MS (m / z): 488.2 [M+H] + .

[0508] Compound 87: 1H NMR (400 MHz, CD3OD) δ 9.32 (s, 1H), 8.35 (s, 1H), 8.32 (s, 1H), 8.02 (s, 1H), 7.55 (d, J = 8.4 Hz, 2H), 7.36 (d, J = 8.4 Hz, 2H), 5.51–5.39 (m, 1H), 5.37–5.20 (m, 1H), 5.19–5.12 (m, 1H), 2.92–2.73 (m, 4H), 1.56 (d, J = 6.7 Hz, 6H), 1.47–1.40 (m, 4H).

[0509] Compound 88: 1H NMR (400 MHz, CD3OD) δ 9.33 (s, 1H), 8.38 (s, 1H), 8.36 (s, 1H), 8.05 (s, 1H), 7.57 (d, J = 8.5 Hz, 2H), 7.37 (d, J = 8.6 Hz, 2H), 5.48–5.39 (m, 1H), 5.07–4.90 (m, 1H), 4.45–4.34 (m, 1H), 3.08–2.98 (m, 2H), 2.67–2.52 (m, 2H), 1.57 (d, J = 6.7 Hz, 6H), 1.47–1.41 (m, 4H).

[0510] Compound 89 and Compound 90

[0511] (R)-1-(1-Cyclopropylethyl)-N-(1-(4-(1-isopropyl-6-oxo-1,6-dihydropyrimidin-5-yl)phenyl)cyclopropyl)-1H-pyrazolo[3,4-d]pyrimidine-6-carboxamide and (S)-1-(1-Cyclopropylethyl)-N-(1-(4-(1-isopropyl-6-oxo-1,6-dihydropyrimidin-5-yl)phenyl)cyclopropyl)-1H-pyrazolo[3,4-d]pyrimidine-6-carboxamide

[0512]

[0513] The racemic compound 1-(1-cyclopropylethyl)-N-(1-(4-(1-isopropyl-6-oxo-1,6-dihydropyrimidin-5-yl)phenyl)cyclopropyl)-1H-pyrazolo[3,4-d]pyrimidine-6-carboxamide (i.e., Compound 59) was resolved by chiral HPLC to obtain the optically pure enantiomers Compound 89 and Compound 90 (HPLC conditions: column: AS-H 4.6x15 mm; mobile phase: CO2:ETOH(0.1% DEA) = 70:30; flow rate: 2.5 mL / min; detector: UV 254 nm). The first eluate (Compound 89, Rf = 3.919 min) had an ee value of 100%, MS (m / z): 484.2 [M+H] +。The second eluent (Compound 90, Rf = 4.260 min) has an ee value of 100%, MS (m / z): 484.2 [M+H] + 。

[0514] Compound 89: 1 H NMR (400 MHz, CDCl3) δ 9.19 (s, 1H), 8.79 (s, 1H), 8.23 (s, 1H), 8.12 (s, 1H), 7.97 (s, 1H), 7.60 - 7.54 (m, 2H), 7.48 - 7.40 (m, 2H), 5.20 - 5.08 (m, 1H), 4.58 - 4.41 (m, 1H), 1.67 - 1.62 (m, 3H), 1.49 - 1.39 (m, 11H), 0.74 - 0.63 (m, 1H), 0.48 - 0.30 (m, 3H).

[0515] Compound 90: 1 H NMR (400 MHz, CDCl3) δ 9.19 (s, 1H), 8.80 (s, 1H), 8.23 (s, 1H), 8.13 (s, 1H), 7.97 (s, 1H), 7.61 - 7.53 (m, 2H), 7.49 - 7.37 (m, 2H), 5.26 - 5.03 (m, 1H), 4.69 - 4.36 (m, 1H), 1.69 - 1.65 (m, 3H), 1.50 - 1.44 (m, 9H), 1.43 - 1.39 (m, 2H), 0.73 - 0.69 (m, 1H), 0.46 - 0.31 (m, 3H).

[0516] Example 2 - Determination of RIPK1 Kinase Activity

[0517] 1. Reagents and Materials

[0518] RIPK1 Recombinant Protein: Synthesized by Hutchison Whampoa Limited and commissioned by Medicilon (Shanghai Medicilon Inc.). (Resuspend 50 g of cell pellet in 250 mL of lysis buffer (50 mM Tris, pH 7.5, 250 mM NaCl, 1 mM DTT, protease inhibitor 1:50), set the power of the ultrasonic instrument on ice to 4, ultrasonically lyse the cells for 3 × 30 minutes; then centrifuge at 4°C and 15,000 g for 30 minutes to clarify the suspension, resuspend the soluble pellet to 10 mL of glutathione agarose and incubate at 4°C for 2 hours; then load the beads into a column, wash with lysis buffer (without protease inhibitor) until the baseline, and then elute with 20 mM reduced glutathione (50 mM Tris, pH 8). Collect the fraction identified by SDS-PAGE as containing the protein of interest (total volume is 10 mL), concentrate to about 5 mL and load onto a 300 mL superdex75 column (GE Healthcare) equilibrated with buffer (50 mM Tris, pH 7.5, 150 mM NaCl, 1 mM DTT, 10% glycerol, pH 7.5). The RIP1 protein elutes as a dimer on the superdex75 column. Determine the protein concentration by Bradford assay using BSA as a standard. The yield is 12.5 mg at 0.63 mg / mL. Aliquot the protein and freeze at -80°C for later use.)

[0519] Sequence of RIPK1 Recombinant Protein:

[0520]

[0521] ADP-Glo Kinase Assay Kit: Promega, catalog number V9102;

[0522] 384-Well White Flat-Bottom Polystyrene Microplate: Corning, catalog number 3574;

[0523] 96-Well Conical-Bottom Polystyrene Microplate: Thermo Scientific Nunc, catalog number 277143;

[0524] Envision Multimode Microplate Reader: PerkinElmer;

[0525] Mixmate Microplate Shaker: Eppendorf;

[0526] TS-2102 Incubator Shaker: TENSUC;

[0527] 2. Methods

[0528] (1) Principle:

[0529] The ADP-Glo Kinase Assay Kit can be used to detect the amount of ADP produced in kinase activity experiments, so as to distinguish the inhibitory effects of different compounds on RIPK1 kinase activity. The ADP-Glo experiment usually consists of three steps. First, the kinase converts ATP into ADP while phosphorylating the substrate. Then, an ATP depletion reagent is added to completely degrade all the ATP in the reaction system. Finally, a detection reagent is added to reduce ADP back to ATP, and at the same time, the energy of ATP is transferred to luciferin, emitting chemiluminescence that can be detected. Conduct the experiment according to the kit instructions.

[0530] (2) Reagent preparation:

[0531] 1.33× Kinase Buffer: Dilute the 5× kinase buffer (containing 250 mM sodium chloride, 150 mM magnesium chloride, 2.5 mg / ml bovine serum albumin, 0.1% CHAPS (3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate), and 5 mM dithiothreitol) with water to obtain 1.33× kinase buffer;

[0532] RIPK1 Enzyme Solution: Dissolve the kinase in 1.33× kinase buffer to a final working concentration of 40 nM;

[0533] ATP Solution: Dissolve the ATP stock solution (10 mM aqueous solution) in 1.33× kinase buffer to a final working concentration of 10 μM;

[0534] 4× Compound Preparation: Dilute the compound in a 3-fold serial dilution to finally obtain a 4% DMSO aqueous solution containing different concentrations of the compound. The final concentrations of the test compounds are 10, 3.33, 1.11, 0.37, 0.12, 0.04, 0.014, and 0.005 μM.

[0535] (3) Specific experimental steps:

[0536] This experiment has two control groups, with 8 replicates in each group, namely the 100% inhibition group (without kinase) and the 0% inhibition group (without inhibitor). Add 2.5 μl of the serially diluted compound to each well of the 384-well plate in duplicate, and add 4% DMSO solution to the control wells. Then, add 5 μl of RIPK1 enzyme solution to each well (except the 100% inhibition group), and add an equal volume of buffer to the 100% inhibition group. Then, add 2.5 μl of ATP solution to each well, shake the plate at 1000 rpm for 30 seconds, and centrifuge briefly. Then, place the 384-well plate in a shaking incubator in the dark and incubate at room temperature for 3 hours. After the enzyme reaction is completed, add 5 μl of ATP depletion solution to each well, centrifuge briefly, continue to place the 384-well plate in a shaking incubator in the dark, and incubate at room temperature for 1 hour; add 5 μl of ADP detection solution to each well, centrifuge briefly, and incubate at room temperature for 0.5 hour.

[0537] 3. Detection

[0538] Take out the 384-well plate and read the plate using an Envision multimode plate reader to detect the signal value of each well.

[0539] 4. Calculation

[0540] Use the average signal values of the 100% inhibition rate group and the 0% inhibition rate group as reference values, and calculate the inhibition rate (%) of each concentration of the compound based on the signal value of each well. Calculate using Model 205 in XL-Fit 5.3 software (ID Business Solutions Limited) to obtain the IC 50 value.

[0541] The inhibition rate calculation formula is as follows:

[0542] Inhibition rate (%) = 100% × (Average signal of 0% inhibition rate - Signal value of the detection well) / (Average signal of 0% inhibition rate - Average signal of 100% inhibition rate)

[0543] 5. Test results

[0544]

[0545]

[0546] *: Inhibition rate under the condition that the compound concentration is 3 μM

[0547] Example 3 - Detection of U937 cell viability

[0548] 1. Reagents and materials

[0549] U937 cells: U937 cells (human histiocytic lymphoma cell line) were purchased from the American Type Culture Collection (ATCC) cell bank. They were cultured normally in RPMI 1640 medium containing L-glutamine, 1.5 g / L sodium bicarbonate, 2.383 g / L HEPES solution, 0.11 g / L sodium pyruvate, and 4.5 g / L glucose, supplemented with 10% fetal bovine serum, in a cell culture incubator at 5% CO2 and 37°C;

[0550] RPMI 1640 medium: GIBCO, catalog number A10491-01;

[0551] Fetal bovine serum (FBS): GIBCO, catalog number 10099-141C;

[0552] Dimethyl sulfoxide (DMSO): Sigma, catalog number D2650;

[0553] Recombinant human tumor necrosis factor protein (hTNF-α): R&D system, catalog number 210-TA-100;

[0554] Pan-caspase inhibitor (Z-VAD-FMK): Selleckchem, catalog number S7023;

[0555] CellTiter-Glo Cell Viability Assay Kit (CellTiter-Glo 2.0 Cell Viability assay): Promega, catalog number G9242;

[0556] Microplate reader: Envision, Perkin Elmer;

[0557] 96-well plate: Corning, catalog number 3917.

[0558] 2. Methods

[0559] Take out U937 cells in the logarithmic growth phase, centrifuge to remove the culture medium, wash with PRMI1640 medium containing 1% FBS, and then dilute the U937 cells with RPMI 1640 medium containing 1% FBS to 2.5×10 5 cells / ml, inoculate 70 μL / well into a 96-well plate, that is, 1.75×10 4 cells / well, and culture in a cell incubator at 5% CO2 and 37 °C. After culturing for 1 hour, dilute the test compound with DMSO in a three-fold gradient to the corresponding concentration, and then dilute the DMSO solution at the corresponding concentration into RPMI 1640 medium containing 1% FBS. Add 10 μL / well of the diluted test compound at different concentrations (the final concentration of the test compound is 1.0, 0.333, 0.111, 0.037, 0.012, 0.004, 0.0014, and 0.0005 μM, and the final concentration of DMSO is 0.3%) or 10 μL / well of the control solution (3% DMSO) into the cell culture system respectively, with a total volume of 80 μL / well; then add 10 μL of the Z-VAD-FMK solution diluted with RPMI 1640 medium containing 1% FBS (final concentration is 50 μM) or 10 μL of the control solution (2.5% DMSO) to each well, with a total volume of 90 μL / well, and incubate in a cell incubator at 5% CO2 and 37 °C for 1 hour.

[0560] After incubating for 1 hour, add 10 μL of the recombinant human tumor necrosis factor protein diluted with RPMI 1640 medium containing 1% FBS (final concentration is 0.1 μg / mL) or 10 μL / well of the control solution (RPMI 1640 medium containing 1% FBS) to each well, and incubate in a cell incubator at 5% CO2 and 37 °C for 20 hours.

[0561] Remove the cell culture plate from the incubator and let it stand at room temperature for 30 minutes. Equilibrate the CellTiter-Glo Cell Viability Assay Reagent to room temperature. Add 50 μL of the CellTiter-Glo Cell Viability Assay Reagent to each well of the cell culture plate, then shake for 1 minute, and place it in the dark at room temperature for 10 minutes before detection.

[0562] 3. Detection

[0563] Take out the 96-well plate placed in the dark and detect the chemiluminescence using an Envision microplate reader as the signal value for each well.

[0564] Use the average signal value of the wells added with the mixture of recombinant human tumor necrosis factor protein (final concentration 0.1 μg / mL) and pan-caspase inhibitor (final concentration 50 μM) as the low value, and the average signal value of the wells without stimulation as the high value. Calculate the inhibition rate (%) of each concentration of the compound based on the signal value of each well, and then use the 205 model in XL-Fit 5.3 software (IDBusiness Solutions Limited) to calculate and obtain the IC 50 value.

[0565] The formula for calculating the inhibition rate is as follows:

[0566] Inhibition rate (%) = { (Signal value of wells treated with test compound - Signal value of wells treated with recombinant human tumor necrosis factor protein) / (Signal value of control wells - Signal value of wells treated with recombinant human tumor necrosis factor protein)} × 100%, where,

[0567] Wells treated with test compound: Represents the signal value of U937 cells treated with recombinant human tumor necrosis factor protein, pan-caspase inhibitor, and the test compound.

[0568] Wells treated with recombinant human tumor necrosis factor protein: Represents the signal value of U937 cells treated with recombinant human tumor necrosis factor protein and pan-caspase inhibitor without compound treatment.

[0569] Control wells: Represents the signal value of U937 cells without any special treatment.

[0570] 4. Test results

[0571]

[0572] The above test results prove that the compound of the present invention has a strong ability to inhibit necroptosis in U937 cells.

[0573] Example 4 - Detection of L929 cell viability

[0574] 1. Reagents and materials

[0575] L929 cells: L929 cells (mouse fibroblastoma cell line) were purchased from the American Type Culture Collection (ATCC) cell bank. They were cultured normally in MEM medium containing L-glutamine, supplemented with 10% fetal bovine serum, in a cell incubator with 5% CO2 at 37°C.

[0576] MEM medium: GIBCO, catalog number 11095080;

[0577] Fetal bovine serum (FBS): GIBCO, catalog number 10099-141C;

[0578] Dimethyl sulfoxide (DMSO): Sigma, catalog number D2650;

[0579] Trypsin-EDTA (0.25%): GIBCO, catalog number 25200072;

[0580] Recombinant mouse tumor necrosis factor protein (mTNF-α): R&D system, catalog number 410-MT-050;

[0581] Pan-caspase inhibitor (Z-VAD-FMK): Selleckchem, catalog number S7023;

[0582] CellTiter-Glo cell viability assay kit (CellTiter-Glo 2.0 Cell Viability assay): Promega, catalog number G9242;

[0583] Microplate reader: Envision, Perkin Elmer;

[0584] 96-well plates: Corning, catalog number 3917.

[0585] 2. Methods

[0586] L929 cells in the logarithmic growth phase were taken out, and the supernatant was discarded. Trypsin was added for digestion. After the cells detached, a medium containing 10% FBS was added to neutralize, and the supernatant was discarded after centrifugation. The cells were resuspended and counted with a medium containing 10% FBS, and seeded at 7×10 4 cells / ml, at 70 μL / well into 96-well plates, that is, 4.9×10 3 cells / well, and cultured overnight in a cell incubator with 5% CO2 at 37°C.

[0587] After overnight incubation, take out the 96-well plate, discard the culture medium, wash it with MEM medium containing 1% FBS, and then add 70 μL of MEM medium containing 1% FBS per well and culture it in a cell culture incubator at 5% CO2 and 37°C. After 1 hour of culture, serially dilute the test compound with DMSO to the corresponding concentrations, and then dilute the DMSO solutions with corresponding concentrations to MEM medium containing 1% FBS. Add 10 μL per well of the diluted test compound at different concentrations (final concentrations of the test compound are 10, 3.33, 1.11, 0.37, 0.12, 0.04, 0.014, and 0.005 μM, and the final concentration of DMSO is 0.3%) or 10 μL per well of the control solution (3% DMSO) into the cell culture system respectively, with a total volume of 80 μL per well; then add 10 μL per well of the Z-VAD-FMK solution diluted with MEM medium containing 1% FBS (final concentration is 5 μM) or 10 μL per well of the control solution (2.5% DMSO), with a total volume of 90 μL per well, and incubate in a cell culture incubator at 5% CO2 and 37°C for 1 hour.

[0588] After 1 hour of incubation, add 10 μL per well of the recombinant mouse tumor necrosis factor protein solution diluted with MEM medium containing 1% FBS (final concentration is 0.1 μg / mL) or 10 μL per well of the control solution (MEM medium containing 1% FBS), and incubate in a cell culture incubator at 5% CO2 and 37°C for 20 hours.

[0589] Take out the cell culture plate from the incubator and let it stand at room temperature for 30 minutes. Equilibrate the CellTiter-Glo cell viability assay reagent to room temperature, add 50 μL of the CellTiter-Glo cell viability assay reagent to each well of the cell culture plate, then shake for 1 minute, and place it in the dark at room temperature for 10 minutes for detection.

[0590] 3. Detection

[0591] Take out the 96-well plate placed in the dark, and use an Envision microplate reader to detect chemiluminescence as the signal value for each well.

[0592] Take the average signal value of the wells added with the mixture of recombinant mouse tumor necrosis factor protein (final concentration is 0.1 μg / mL) and pan-caspase inhibitor (final concentration is 5 μM) as the low value, and take the average signal value of the wells without stimulation as the high value. Calculate the inhibition rate (%) of each concentration of the compound based on the signal value of each well, and then use the 205 model in XL-Fit 5.3 software (IDBusiness Solutions Limited) to calculate and obtain the IC 50 value.

[0593] The formula for calculating the inhibition rate is as follows:

[0594] Inhibition rate (%) = { (well treated with test compound - well treated with recombinant murine tumor necrosis factor protein) / (control well - well treated with recombinant murine tumor necrosis factor protein)} × 100%, where,

[0595] Well treated with test compound: represents the signal value of L929 cells treated with recombinant murine tumor necrosis factor protein, pan-caspase inhibitor and test compound.

[0596] Well treated with recombinant murine tumor necrosis factor protein: represents the signal value of L929 cells treated with recombinant murine tumor necrosis factor protein and pan-caspase inhibitor without compound treatment.

[0597] Control well: represents the signal value of L929 cells without any special treatment.

[0598] 4. Test results

[0599]

[0600]

[0601] The above test results prove that the compound of the present invention has a strong ability to inhibit necroptosis in L929 cells.

[0602] Example 5 - Effect of the compound of the present invention on TNF-α-induced IL-1β in human whole blood

[0603] 1. Reagents and materials

[0604] Human blood samples were collected from healthy volunteers by venipuncture, and each volunteer's signed consent was obtained before blood collection;

[0605] RPMI 1640 medium: L-glutamine, 1.5 g / L NaHCO3, 2.383 g / L HEPES solution, 0.11 g / L sodium pyruvate and 4.5 g / L glucose; Gibco, catalog number A10491-01;

[0606] Dimethyl sulfoxide (DMSO): Sigma, catalog number D2650;

[0607] Recombinant human tumor necrosis factor protein (hTNF-α): R&D system, catalog number 210-TA-100;

[0608] Pan-Caspase inhibitor (Z-VAD-FMK): Selleckchem, catalog number S7023;

[0609] Smac mimetic - 164 (SM - 164): APEXBIO, Catalog number A8815;

[0610] Human IL - 1β / IL - 1F2 Quantikine ELISA Kit: R&D systems, Catalog number SLB50;

[0611] Envision Multifunctional Microplate Reader: PerkinElmer;

[0612] 96 - well clear flat bottom TC - treated culture microplate: Falcon, Catalog number 353072;

[0613] 96 - well U - bottom microplate: Corning, Catalog number 3799.

[0614] 2. Experimental protocol

[0615] Human whole blood anticoagulated with heparin was immediately used for human whole blood experiments. Heparin - anticoagulated human whole blood was diluted with an equal volume of RPMI1640 medium. The diluted blood was aliquoted and added to 96 - well plates, 90 μL per well.

[0616] Compound preparation: Dilute the compound stock solution with DMSO and perform 3 - fold serial dilutions to 8 concentration points. Then transfer the diluted compound to RPMI 1640 medium and mix.

[0617] Compound treatment and stimulation: Transfer 5 μL of the diluted compound to the corresponding wells. The final concentrations of the compound are 1.0, 0.333, 0.111, 0.037, 0.012, 0.004, 0.0014, and 0.0005 μM, with 0.3% DMSO in each well. For positive and negative control wells, add 5 μL of RPMI 1640 medium containing 3% DMSO. Incubate the microplate at 5% CO2, 37 °C for 1 hour.

[0618] Then add 5 μL of the stimulant mixture (TNF - α, Z - VAD - FMK, and SM - 164) with final concentrations of 20 μM, 1 μM, and 0.01 μg / mL respectively, except for the negative control wells. Add the same volume of RPMI 1640 medium to the negative control wells.

[0619] After incubating for 6 hours in a 37 °C / 5% CO2 incubator, add 100 μL of PBS to each well and centrifuge at 4000 rmp for 10 minutes. Collect 110 μL of the supernatant from each well and store at - 80 °C for ELISA.

[0620] 3. Detection

[0621] Prepare 100 μL of IL-1β standard (in duplicate) and add it to the designated wells. ELISA is performed according to the manufacturer's instructions. Finally, measure the absorbance of the ELISA plate at 450 nm / 570 nm using Envision.

[0622] 4. Data Calculation

[0623] The inhibition rate of the compound on the production of IL-1β induced by TNF-α, Z-VAD-FMK, and SM-164 in human whole blood is calculated as follows:

[0624] Calculate the IL-1β level using the IL-1β standard curve (the standard curve fitting equation is a four-parameter model)

[0625]

[0626] IL-1β level 刺激 : The concentration of IL-1β in the positive control wells with TNF-α, Z-VAD-FMK, SM-164 added and no compound;

[0627] IL-1β level 非刺激 : The concentration of IL-1β in the negative control wells without treatment with TNF-α, Z-VAD-FMK, SM-164, and compound;

[0628] IL-1β level 化合物 : The concentration of IL-1β in the wells treated with TNF-α, Z-VAD-FMK, SM-164, and compound.

[0629] The IC 50 value of the compound is determined using XLFit 5 software (ID Business Solutions Limited).

[0630] 5. Results

[0631]

[0632]

[0633] According to the above experiments, the tested compounds have a strong ability to inhibit the production of IL-1β induced by TNF-α, Z-VAD-FMK, and SM-164 in human whole blood.

[0634] Example 6 - In vivo inhibitory effect of the compound of the present invention on the RIPK1 target in a mouse SIRS model

[0635] Objective: To evaluate the in vivo efficacy of the compounds of the present invention in a hypothermia model induced by TNF-α + zVAD-FMK in a murine model of systemic inflammatory response syndrome (SIRS).

[0636] Methods: Before model establishment, C57BL / 6 mice (male, 6 - 8 weeks old, purchased from Shanghai Lingchang Biotechnology Co., Ltd.) were randomly grouped according to body weight. According to the grouping table (Table 1), each group was orally administered vehicle, positive compound 1 mg / kg (GSK-547), and different doses of the compounds of the present invention (test compounds).

[0637] Table 1 Grouping information for in vivo target inhibition study

[0638]

[0639] Thirty minutes after oral administration, mice were intravenously injected with zVAD-FMK (eybridge, batch number S02910-074-01) (16.7 mg / kg) or a solution of TNF-α (Novoprotein Scientific, product number CF09) + zVAD-FMK (0.325 mg / kg + 16.7 mg / kg) in phosphate buffered saline (PBS) at pH 7.2, which solution contained 2.5% DMSO. Three hours after model establishment, body temperature was measured using a rectal probe. And three hours after model establishment, cytokine and chemokine levels in plasma were detected by ELISA. All animals were monitored for survival status until 72 hours after model establishment.

[0640] Results:

[0641] To study the in vivo efficacy of the compounds of the present invention in TNF-induced SIRS, mice were pretreated with the compounds of the present invention. The test compounds were able to protect mice from TNF-α-induced hypothermia in a dose-dependent manner. Pretreatment with the test compounds was able to reduce mortality and systemic inflammation.

[0642] Example 7 - In vivo efficacy of the compounds of the present invention in a murine model of arthritis induced by bovine type II collagen

[0643] Objective:

[0644] To study the in vivo efficacy of the compounds of the present invention in a murine model of arthritis induced by bovine type II collagen.

[0645] Animals:

[0646] DBA1 mice, male, 7 - 9 weeks old, 18 - 20 g, provided by Vital River Laboratory Animal Technology Co., Ltd (Beijing, China).

[0647] Method:

[0648] Dissolve bovine type II collagen (CII, Chondrex, catalog number 20021) in 100 mM acetic acid (SPGC Sinopharm Chemical Reagent Co., Ltd (Shanghai, China), catalog number 10000218.) to prepare a solution with a concentration of 8 mg / ml, and stir overnight at 4°C. Mix 8 mg / ml type II collagen with an equal volume of CFA (Sigma, catalog number F5881), and use a high-speed homogenizer (FLUKO Equipment Shanghai Co., Ltd.) to make an emulsion on ice.

[0649] Before immunization, randomly select 5 mice as the normal group (naive). Anesthetize the remaining mice by intraperitoneal injection of isoflurane, and subcutaneously inject 0.05 ml of the emulsion (4 mg / ml CII / CFA) at about 1.5 - 2 cm away from the body at the base of the tail on days 0 and 21.

[0650] After the mouse model shows arthritis symptoms on the 24th day after the first immunization, randomly group and administer drugs to the mice induced by CII / CFA according to Table 2. The treatment group of etanercept (Sunshine Guojian Pharmaceutical (Shanghai) Co, Ltd) is intraperitoneally injected every other day (once every other day), and the control group and the treatment group of the compound of the present invention (test compound) are orally administered daily.

[0651] Table 2 Grouping and dosing regimen

[0652]

[0653] The severity of the arthritis symptoms in the four paws of the arthritic mice is scored every other day after the onset of arthritis, and the criteria are as follows:

[0654] 0, no signs of erythema and swelling;

[0655] 1, erythema and mild swelling are limited to the foot (tarsus) or ankle joint;

[0656] 2, erythema and mild swelling extend from the ankle to the midfoot;

[0657] 3, erythema and moderate swelling extend from the ankle joint to the metatarsophalangeal joint;

[0658] 4, erythema and severe swelling include the ankle, foot, and toes.

[0659] The severity of arthritis is determined by the sum of the scores of the four paws.

[0660] Score = sum of individual scores of the four claws.

[0661] One-Way ANOVA and subsequent Dunnett's test were used to calculate the differences between the vehicle group and the compound treatment groups by JMP.

[0662] The arthritis score of each animal before drug administration was regarded as the baseline (or regarded as 100% reaching inflammation inhibition). The change in arthritis score (SC) of each mouse was calculated according to the formula, where ScoreD24 is the score on the day of starting drug administration, and ScoreDt is the score on the day of drug administration at the t-th day:

[0663] SCDt = ScoreDt – ScoreD24.

[0664] The area under the score curve (AUC) was calculated based on the trapezoidal method according to the change in score of each mouse: AUC score = 1 / 2×(SCDt + SCD(t - 2))×(Dt - D(t - 2)) + 1 / 2×(SCD(t - 2) + SCD(t - 4))×(D(t - 2) - D(t - 4)) + …… + 1 / 2×(SCD26 + SCD24)×(D26 - D24)

[0665] The effect of treatment on the change in arthritis score was calculated based on the AUC value. The inhibition percentage of AUC was calculated using the following formula:

[0666] Inhibition rate (%) = (AUC 溶媒组 – AUC 治疗组 ) / (AUC 溶媒组 ) × 100%.

[0667] Results:

[0668] After immunizing mice with bovine type II collagen, severe inflammation and edema appeared in the paws. The arthritis score was measured by visual scoring to evaluate the in vivo efficacy of the test compound in this model.

[0669] In the vehicle-treated group of this study, the arthritis score of mice gradually increased. The treatment started on the 24th day after immunization. The positive control etanercept group was administered from the 24th day until the end of the experiment at a dose of 25 mg / kg once every other day. Compared with the vehicle control group, the treatment significantly blocked arthritis. The test compound at a dose of 15 mg / kg could also improve paw swelling.

[0670] The entire contents of all patents and non-patent documents listed in this article are incorporated herein by reference as if their entire contents were listed individually.

[0671] Although specific embodiments and examples are provided herein to illustrate the present invention, they are not intended to limit the scope of the present invention. Based on the present disclosure, those skilled in the art can obviously obtain other variations or equivalent solutions without departing from the spirit of the present invention, and these variations and equivalent solutions are all within the scope of the present invention. Sequence Listing <110> Hutchison MediPharma Limited (Shanghai) <120> Pyrimidinone Compounds and Their Uses <130> PF 210573PCT <160> 1 <170> PatentIn version 3.3 <210> 1 <211> 618 <212> PRT <213> Artificial <220> <223> Construct <400> 1 Met His His His His His His His His His His Ser Pro Ile Leu Gly 1 5 10 15 Tyr Trp Lys Ile Lys Gly Leu Val Gln Pro Thr Arg Leu Leu Leu Glu 20 25 30 Tyr Leu Glu Glu Lys Tyr Glu Glu His Leu Tyr Glu Arg Asp Glu Gly 35 40 45 Asp Lys Trp Arg Asn Lys Lys Phe Glu Leu Gly Leu Glu Phe Pro Asn 50 55 60 Leu Pro Tyr Tyr Ile Asp Gly Asp Val Lys Leu Thr Gln Ser Met Ala 65 70 75 80 Ile Ile Arg Tyr Ile Ala Asp Lys His Asn Met Leu Gly Gly Cys Pro 85 90 95 Lys Glu Arg Ala Glu Ile Ser Met Leu Glu Gly Ala Val Leu Asp Ile 100 105 110 Arg Tyr Gly Val Ser Arg Ile Ala Tyr Ser Lys Asp Phe Glu Thr Leu 115 120 125 Lys Val Asp Phe Leu Ser Lys Leu Pro Glu Met Leu Lys Met Phe Glu 130 135 140 Asp Arg Leu Cys His Lys Thr Tyr Leu Asn Gly Asp His Val Thr His 145 150 155 160 Pro Asp Phe Met Leu Tyr Asp Ala Leu Asp Val Val Leu Tyr Met Asp 165 170 175 Pro Met Cys Leu Asp Ala Phe Pro Lys Leu Val Cys Phe Lys Lys Arg 180 185 190 Ile Glu Ala Ile Pro Gln Ile Asp Lys Tyr Leu Lys Ser Ser Lys Tyr 195 200 205 Ile Ala Trp Pro Leu Gln Gly Trp Gln Ala Thr Phe Gly Gly Gly Asp 210 215 220 His Pro Pro Lys Ser Asp Leu Val Pro Arg Gly Ser Glu Asn Leu Tyr 225 230 235 240 Phe Gln Gly Met Gln Pro Asp Met Ser Leu Asn Val Ile Lys Met Lys 245 250 255 Ser Ser Asp Phe Leu Glu Ser Ala Glu Leu Asp Ser Gly Gly Phe Gly 260 265 270 Lys Val Ser Leu Cys Phe His Arg Thr Gln Gly Leu Met Ile Met Lys 275 280 285 Thr Val Tyr Lys Gly Pro Asn Cys Ile Glu His Asn Glu Ala Leu Leu 290 295 300 Glu Glu Ala Lys Met Met Asn Arg Leu Arg His Ser Arg Val Val Lys 305 310 315 320 Leu Leu Gly Val Ile Ile Glu Glu Gly Lys Tyr Ser Leu Val Met Glu 325 330 335 Tyr Met Glu Lys Gly Asn Leu Met His Val Leu Lys Ala Glu Met Ser 340 345 350 Thr Pro Leu Ser Val Lys Gly Arg Ile Ile Leu Glu Ile Ile Glu Gly 355 360 365 Met Cys Tyr Leu His Gly Lys Gly Val Ile His Lys Asp Leu Lys Pro 370 375 380 Glu Asn Ile Leu Val Asp Asn Asp Phe His Ile Lys Ile Ala Asp Leu 385 390 395 400 Gly Leu Ala Ser Phe Lys Met Trp Ser Lys Leu Asn Asn Glu Glu His 405 410 415 Asn Glu Leu Arg Glu Val Asp Gly Thr Ala Lys Lys Asn Gly Gly Thr 420 425 430 Leu Tyr Tyr Met Ala Pro Glu His Leu Asn Asp Val Asn Ala Lys Pro 435 440 445 Thr Glu Lys Ser Asp Val Tyr Ser Phe Ala Val Val Leu Trp Ala Ile 450 455 460 Phe Ala Asn Lys Glu Pro Tyr Glu Asn Ala Ile Cys Glu Gln Gln Leu 465 470 475 480 Ile Met Cys Ile Lys Ser Gly Asn Arg Pro Asp Val Asp Asp Ile Thr 485 490 495 Glu Tyr Cys Pro Arg Glu Ile Ile Ser Leu Met Lys Leu Cys Trp Glu 500 505 510 Ala Asn Pro Glu Ala Arg Pro Thr Phe Pro Gly Ile Glu Glu Lys Phe 515 520 525 Arg Pro Phe Tyr Leu Ser Gln Leu Glu Glu Ser Val Glu Glu Asp Val 530 535 540 Lys Ser Leu Lys Lys Glu Tyr Ser Asn Glu Asn Ala Val Val Lys Arg 545 550 555 560 Met Gln Ser Leu Gln Leu Asp Cys Val Ala Val Pro Ser Ser Arg Ser 565 570 575 Asn Ser Ala Thr Glu Gln Pro Gly Ser Leu His Ser Ser Gln Gly Leu 580 585 590 Gly Met Gly Pro Val Glu Glu Ser Trp Phe Ala Pro Ser Leu Glu His 595 600 605 Pro Gln Glu Glu Asn Glu Pro Ser Leu Gln 610 615

Claims

1. A compound of formula (I): or a pharmaceutically acceptable salt thereof, or a racemic mixture, enantiomer, diastereoisomer or tautomer thereof, wherein: R1 is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, cyano-substituted C 1-6 alkyl, -(C 1-6 alkylene) n -C 3-6 cycloalkyl, -(C 1-6 alkylene) n -phenyl, -(C 1-6 alkylene) n -4- to 6-membered heterocyclic group or -(C 1-6 alkylene) n -5- to 6-membered heteroaryl; wherein, The described C 3-6 The cycloalkyl, phenyl, 4- to 6-membered heterocyclic group, and 5- to 6-membered heteroaryl group are each optionally substituted with one or more groups independently selected from the following: halogen, -CN, -OH, -NH2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, -O(C 1-6 alkyl), -O(C 1-6 haloalkyl), -NH(C 1-6 alkyl), and -N(C 1-6 alkyl)2; R2 is hydrogen, halogen, -CN, -NH2, C 1-6 alkyl, C 1-6 haloalkyl, -O(C 1-6 alkyl), -O(C 1-6 haloalkyl), -NH(C 1-6 alkyl) or -N(C 1-6 alkyl)2; Z is O, NR3 or CR4R5; R3 is hydrogen or C 1-6 alkyl; R4 and R5 are each independently selected from: hydrogen, halogen, -CN, -OH, C 1-6 alkyl, C 1-6 haloalkyl, -O(C 1-6 alkyl), -O(C 1-6 haloalkyl) and C 3-6 cycloalkyl; is phenyl or a 5- or 6-membered heteroaryl, each optionally substituted by one or more groups independently selected from the following: halogen, -CN, -OH, -NH2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, -O(C 1-6 alkyl), -O(C 1-6 haloalkyl), -NH(C 1-6 alkyl) and -N(C 1-6 alkyl)2; is a 5-12 membered heteroaryl, which is optionally substituted by one or more groups independently selected from the following: halogen, -CN, -OH, oxo, -NH2, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -O(C 1-6 alkyl), -O(C 1-6 haloalkyl), -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, -(C 1-6 alkylene) n -C 3-6 cycloalkyl, -(C 1-6 alkylene) n -phenyl, -(C 1-6 alkylene) n -4-6 membered heterocyclic group and -(C 1-6 alkylene) n -5-6 membered heteroaryl; wherein, the phenyl, C 3-6 cycloalkyl, 4-6 membered heterocyclic group and 5-6 membered heteroaryl are each optionally substituted by one or more groups independently selected from the following: halogen, -CN, -OH, -NH2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, -O(C 1-6 alkyl), -O(C 1-6 haloalkyl), -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2 and C 3-6 cycloalkyl; n is 0 or 1; p is 0 or 1.

2. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, or their racemic mixture, enantiomers, diastereoisomers or tautomers, wherein: R1 is C 1-6 alkyl, C 1-6 haloalkyl, cyano-substituted C 1-6 alkyl, -(C 1-6 alkylene) n -C 3-6 cycloalkyl or -(C 1-6 alkylene) n -4- to 6-membered heterocyclic group; wherein, the C 3-6 cycloalkyl and 4- to 6-membered heterocyclic group are each optionally substituted by one or more groups independently selected from the following: halogen, -CN, -OH, -NH2, C 1-6 alkyl, C 1-6 haloalkyl, -O(C 1-6 alkyl), -O(C 1-6 haloalkyl), -NH(C 1-6 alkyl) and -N(C 1-6 alkyl)2.

3. The compound of formula (I) according to claim 2 or a pharmaceutically acceptable salt thereof, or a racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein: R1 is C 1-6 alkyl, C 1-6 haloalkyl, cyano-substituted C 1-6 alkyl, -(C 1-6 alkylene) n -C 3-6 cycloalkyl or -(C 1-6 alkylene) n -4- to 6-membered heterocyclic group; wherein, the C 3-6 cycloalkyl and 4- to 6-membered heterocyclic group are each optionally substituted by one or more groups independently selected from the following: halogen and C 1-6 alkyl.

4. A compound of formula (I) according to claim 3 or a pharmaceutically acceptable salt thereof, or an enantiomeric mixture, enantiomer, diastereoisomer or tautomer thereof, wherein: R1 is C 1-6 alkyl group.

5. The compound of formula (I) according to claim 3 or a pharmaceutically acceptable salt thereof, or an enantiomeric mixture, enantiomer, diastereoisomer or tautomer thereof, wherein: R1 is methyl or isopropyl.

6. A compound of formula (I) according to claim 3 or a pharmaceutically acceptable salt thereof, or an enantiomeric mixture, enantiomer, diastereoisomer or tautomer thereof, wherein: R1 is C 1-6 haloalkyl, -(C 1-6 alkylene) n -C 3-6 cycloalkyl or -(C 1-6 alkylene) n -4- to 6-membered heterocyclic group; wherein the 3-6 cycloalkyl is optionally substituted by one or more groups independently selected from: halogen and C 1-6 alkyl, and n is 0 or 1.

7. A compound of formula (I) according to claim 3, or a pharmaceutically acceptable salt thereof, or a racemic mixture, enantiomer, diastereoisomer or tautomer thereof, wherein: R1 is -(C 1-6 alkylene) n -C 3-6 cycloalkyl, wherein said C 3-6 cycloalkyl is optionally substituted with one or more halogens, and n is 0 or 1.

8. A compound of formula (I) according to claim 3 or a pharmaceutically acceptable salt thereof, or a racemic mixture, enantiomer, diastereoisomer or tautomer thereof, wherein: R1 is a 4- to 6-membered heterocyclic group, wherein the 4- to 6-membered heterocyclic group is oxetanyl, tetrahydrofuranyl or tetrahydropyranyl.

9. A compound of formula (I) according to any one of claims 1-8, or a pharmaceutically acceptable salt thereof, or a racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein: R2 is hydrogen, -NH2, C 1-6 alkyl, -NH(C 1-6 alkyl) or -N(C 1-6 alkyl)2.

10. A compound of formula (I) according to any one of claims 1-8, or a pharmaceutically acceptable salt thereof, or a racemic mixture, enantiomer, diastereoisomer or tautomer thereof, wherein: R2 is hydrogen, -NH2 or C 1-6 alkyl group.

11. A compound of formula (I) according to any one of claims 1-8, or a pharmaceutically acceptable salt thereof, or a racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein: R2 is hydrogen.

12. A compound of formula (I) according to any one of claims 1-8, or a pharmaceutically acceptable salt thereof, or a racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein: p is 0 and Z is CR4R5.

13. A compound of formula (I) according to any one of claims 1-8, or a pharmaceutically acceptable salt thereof, or a racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein: p is 0 and Z is CH2.

14. A compound of formula (I) according to any one of claims 1-8, or a pharmaceutically acceptable salt thereof, or an enantiomeric mixture, enantiomer, diastereoisomer or tautomer thereof, wherein: is phenyl or 5- or 6-membered heteroaryl, each optionally substituted by one or more groups independently selected from the following: halogen, C 1-6 alkyl, and C 1-6 haloalkyl.

15. A compound of formula (I) or a pharmaceutically acceptable salt thereof, or a racemic mixture, enantiomer, diastereomer or tautomer thereof, according to any one of claims 1 - 8, wherein: is phenyl or pyridyl, each of which is optionally substituted by one or more groups independently selected from the following: halogen, C 1-6 alkyl and C 1-6 haloalkyl.

16. A compound of formula (I) according to any one of claims 1-8, or a pharmaceutically acceptable salt thereof, or an enantiomeric mixture, enantiomer, diastereoisomer or tautomer thereof, wherein: is phenyl, which is optionally substituted by one or more groups independently selected from the following: halogen, C 1-6 alkyl or C 1-6 haloalkyl.

17. A compound of formula (I) according to any one of claims 1-8, or a pharmaceutically acceptable salt thereof, or a racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein: is a pyridyl group.

18. A compound of formula (I) according to any one of claims 1-8, or a pharmaceutically acceptable salt thereof, or a racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein, is a 5- to 12-membered heteroaryl, which is optionally substituted by one or more groups independently selected from the following: halogen, C 1-6 alkyl, -(C 1-6 alkylene) n -C 3-6 cycloalkyl, -(C 1-6 alkylene) n -phenyl, -(C 1-6 alkylene) n -4- to 6-membered heterocyclic group and -(C 1-6 alkylene) n -5- to 6-membered heteroaryl; wherein the phenyl, C 3-6 cycloalkyl, 4- to 6-membered heterocyclic group and 5- to 6-membered heteroaryl are each optionally substituted by one or more halogens.

19. A compound of formula (I) according to any one of claims 1-8, or a pharmaceutically acceptable salt thereof, or a racemic mixture, enantiomer, diastereoisomer or tautomer thereof, wherein, is a 5- to 10-membered heteroaryl optionally substituted by one or more groups independently selected from: halogen, C 1-6 alkyl, -(C 1-6 alkylene) n -C 3-6 cycloalkyl, -(C 1-6 alkylene) n -phenyl, -(C 1-6 alkylene) n -4- to 6-membered heterocyclic group and -(C 1-6 alkylene) n -5- to 6-membered heteroaryl; wherein the phenyl, C 3-6 cycloalkyl, 4- to 6-membered heterocyclic group and 5- to 6-membered heteroaryl are each optionally substituted by one or more halogens.

20. A compound of formula (I) according to any one of claims 1-8, or a pharmaceutically acceptable salt thereof, or an enantiomeric mixture, enantiomer, diastereoisomer or tautomer thereof, wherein, is a 5- to 9-membered heteroaryl optionally substituted by one or more groups independently selected from: halogen, C 1-6 alkyl, -(C 1-6 alkylene) n -C 3-6 cycloalkyl, -(C 1-6 alkylene) n -phenyl, -(C 1-6 alkylene) n -4- to 6-membered heterocyclic group, and -(C 1-6 alkylene) n -5- to 6-membered heteroaryl; wherein the phenyl, C 3-6 cycloalkyl, 4- to 6-membered heterocyclic group, and 5- to 6-membered heteroaryl are each optionally substituted by one or more halogens.

21. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, or a racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein, The compound of formula (I) is a compound of formula (I-1): wherein, R1 is C 1-6 alkyl, C 1-6 haloalkyl, cyano-substituted C 1-6 alkyl, -(C 1-6 alkylene) n -C 3-6 cycloalkyl or -(C 1-6 alkylene) n -4- to 6-membered heterocyclic group; wherein the C 3-6 cycloalkyl and 4- to 6-membered heterocyclic group are each optionally substituted by one or more groups independently selected from the following: halogen and C 1-6 alkyl; R2 is hydrogen, -NH2, C 1-6 alkyl, -NH(C 1-6 alkyl) or -N(C 1-6 alkyl)2; is a 5- to 12-membered heteroaryl optionally substituted by one or more groups independently selected from the following: halogen, C 1-6 alkyl, -(C 1-6 alkylene) n -C 3-6 cycloalkyl, -(C 1-6 alkylene) n -phenyl, -(C 1-6 alkylene) n -4- to 6-membered heterocyclic group and -(C 1-6 alkylene) n -5- to 6-membered heteroaryl; wherein the phenyl, C 3-6 cycloalkyl, 4- to 6-membered heterocyclic group and 5- to 6-membered heteroaryl are each optionally substituted by one or more halogens; n is 0 or 1.

22. The compound of formula (I) according to claim 21, or a pharmaceutically acceptable salt thereof, or their racemic mixture, enantiomers, diastereoisomers or tautomers, wherein, R1 is C 1-6 alkyl, C 1-6 haloalkyl, -(C 1-6 alkylene) n -C 3-6 cycloalkyl or -(C 1-6 alkylene) n -4- to 6-membered heterocyclic group; wherein said C 3-6 cycloalkyl is optionally substituted by one or more groups independently selected from: halogen and C 1-6 alkyl.

23. A compound of formula (I) according to claim 21 or 22, or a pharmaceutically acceptable salt thereof, or a racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein, R2 is hydrogen, -NH2 or C 1-6 alkyl group.

24. A compound of formula (I) according to claim 21 or 22, or a pharmaceutically acceptable salt thereof, or a racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein, R2 is hydrogen.

25. A compound of formula (I) according to claim 21 or 22, or a pharmaceutically acceptable salt thereof, or a racemic mixture, enantiomer, diastereoisomer or tautomer thereof, wherein, is a 5- to 10-membered heteroaryl, which is optionally substituted by one or more groups independently selected from the following: halogen, C 1-6 alkyl, -(C 1-6 alkylene) n -C 3-6 cycloalkyl, -(C 1-6 alkylene) n -phenyl, -(C 1-6 alkylene) n -4- to 6-membered heterocyclic group and -(C 1-6 alkylene) n -5- to 6-membered heteroaryl; wherein the phenyl, C 3-6 cycloalkyl, 4- to 6-membered heterocyclic group and 5- to 6-membered heteroaryl are each optionally substituted by one or more halogens.

26. A compound of formula (I) according to claim 21 or 22, or a pharmaceutically acceptable salt thereof, or an enantiomeric mixture, enantiomer, diastereoisomer or tautomer thereof, wherein, is a 5-9 membered heteroaryl, which is optionally substituted by one or more groups independently selected from the following: halogen, C 1-6 alkyl, -(C 1-6 alkylene) n -C 3-6 cycloalkyl, -(C 1-6 alkylene) n -phenyl, -(C 1-6 alkylene) n -4-6 membered heterocyclic group and -(C 1-6 alkylene) n -5-6 membered heteroaryl; wherein said phenyl, C 3-6 cycloalkyl, 4-6 membered heterocyclic group and 5-6 membered heteroaryl are each optionally substituted by one or more halogens.

27. A compound of formula (I) according to any one of claims 1-8, or a pharmaceutically acceptable salt thereof, or an enantiomeric mixture, enantiomer, diastereoisomer or tautomer thereof, wherein, is a triazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrimidinyl, pyrazolopyrimidinyl, pyrazolopyridyl or dihydropyrrolotriazolyl, each of which is optionally substituted by one or more groups independently selected from the following: halogen, C 1-6 alkyl, -(C 1-6 alkylene) n -C 3-6 cycloalkyl, -(C 1-6 alkylene) n -phenyl, -(C 1-6 alkylene) n -4-6 membered heterocyclic group and -(C 1-6 alkylene) n -5-6 membered heteroaryl; wherein the phenyl, C 3-6 cycloalkyl, 4-6 membered heterocyclic group and 5-6 membered heteroaryl are each optionally substituted by one or more halogens.

28. The compound of formula (I) according to claim 27 or a pharmaceutically acceptable salt thereof, or a racemic mixture, enantiomer, diastereoisomer or tautomer thereof, wherein, selected from Each of them is optionally substituted by one or more groups independently selected from the following: halogen, C 1-6 alkyl, -(C 1-6 alkylene) n -C 3-6 cycloalkyl, -(C 1-6 alkylene) n -phenyl, -(C 1-6 alkylene) n -4-6-membered heterocyclic group and -(C 1-6 alkylene) n -5-6-membered heteroaryl; wherein said phenyl, C 3-6 cycloalkyl, 4-6-membered heterocyclic group and 5-6-membered heteroaryl are each optionally substituted by one or more halogens.

29. The compound of formula (I) according to claim 27 or a pharmaceutically acceptable salt thereof, or a racemic mixture, enantiomer, diastereoisomer or tautomer thereof, wherein, selected from Each of them is optionally substituted by one or more groups independently selected from the following: halogen, C 1-6 alkyl, -(C 1-6 alkylene) n -C 3-6 cycloalkyl, -(C 1-6 alkylene) n -phenyl, -(C 1-6 alkylene) n -4-6-membered heterocyclic group and -(C 1-6 alkylene) n -5-6-membered heteroaryl; wherein the phenyl, C 3-6 cycloalkyl, 4-6-membered heterocyclic group and 5-6-membered heteroaryl are each optionally substituted by one or more halogens.

30. A compound of formula (I) according to claim 29, or a pharmaceutically acceptable salt thereof, or a racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein, is optionally substituted by one or more groups independently selected from: C 1-6 alkyl, -(C 1-6 alkylene) n -C 3-6 cycloalkyl, -(C 1-6 alkylene) n -phenyl, -(C 1-6 alkylene) n -4-6 membered heterocyclic group and -(C 1-6 alkylene) n -5-6 membered heteroaryl; wherein said C 3-6 cycloalkyl, 4-6 membered heterocyclic group and 5-6 membered heteroaryl are each optionally substituted by one or more halogens, and n is 0 or 1.

31. The compound of formula (I) according to claim 30 or a pharmaceutically acceptable salt thereof, or a racemic mixture, enantiomer, diastereoisomer or tautomer thereof, wherein, is optionally substituted by one or more groups independently selected from: C 1-6 alkyl.

32. The compound of formula (I) according to claim 30 or a pharmaceutically acceptable salt thereof, or a racemic mixture, enantiomer, diastereoisomer or tautomer thereof, wherein, is optionally substituted by one or more groups independently selected from: -(C 1-6 alkylene) n -C 3-6 cycloalkyl, where n is 0 or 1; wherein said C 3-6 cycloalkyl is optionally substituted by one or more halogens.

33. The compound of formula (I) according to claim 30 or a pharmaceutically acceptable salt thereof, or a racemic mixture, enantiomer, diastereoisomer or tautomer thereof, wherein, is optionally substituted by one or more groups independently selected from: -(C 1-6 alkylene) n -phenyl, where n is 0 or 1.

34. The compound of formula (I) according to claim 30 or a pharmaceutically acceptable salt thereof, or a racemic mixture, enantiomer, diastereoisomer or tautomer thereof, wherein, is optionally substituted by one or more groups independently selected from the following: 4- to 6-membered heterocyclic group; wherein, the 4- to 6-membered heterocyclic group is oxetanyl.

35. The compound of formula (I) according to claim 30 or a pharmaceutically acceptable salt thereof, or a racemic mixture, enantiomer, diastereoisomer or tautomer thereof, wherein, For it is optionally substituted by one or more groups independently selected from the following: 5- to 6-membered heteroaryl; wherein, the 5- to 6-membered heteroaryl is pyridyl.

36. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from Compounds 1-19, 22-48 and 53-95:

37. A pharmaceutical composition comprising the compound of any one of claims 1-36 or a pharmaceutically acceptable salt thereof, and optionally comprising a pharmaceutically acceptable carrier.

38. A non-therapeutic and non-diagnostic method for inhibiting RIPK1 activity in vitro, the method comprising contacting a RIPK1 with an effective amount of the compound of any one of claims 1-36 or a pharmaceutically acceptable salt thereof.

39. The compound of any one of claims 1-36 or a pharmaceutically acceptable salt thereof, for use as a medicament.

40. The compound of any one of claims 1-36 or a pharmaceutically acceptable salt thereof, for treating a disease in an individual that is partially or completely mediated by RIPK1.

41. The compound according to claim 40 or a pharmaceutically acceptable salt thereof, wherein the disease is selected from autoimmune diseases, inflammatory diseases, neurodegenerative diseases, and cancers.

42. Use of a compound according to any one of claims 1-36 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a disease in an individual that is partially or fully mediated by RIPK1.

43. The use according to claim 42, wherein the disease is selected from autoimmune diseases, inflammatory diseases, neurodegenerative diseases, and cancers.

44. A pharmaceutical combination product comprising a compound according to any one of claims 1-16 or a pharmaceutically acceptable salt thereof, and at least one additional therapeutic agent.

45. The pharmaceutical combination product according to claim 44, wherein the therapeutic agent is an anti-inflammatory agent or an anti-tumor agent.

46. The pharmaceutical combination product according to claim 45, wherein the anti-tumor agent is selected from radiotherapy agents, chemotherapy agents, immunotherapy agents, and targeted therapy agents.

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