Pyrrolopyridinone compounds, processes for their preparation and uses thereof

Abstract

Provided are pyrrolopyridinone compounds represented by formula (I) or pharmaceutically acceptable salts thereof, pharmaceutical preparations, pharmaceutical compositions, and uses thereof, which are useful for the preparation of a medicament for treating or preventing a disease mediated by MAP4K1.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, specifically to pyrrolopyridone compounds and their preparation methods, as well as the use of said compounds in the preparation of medicaments for the treatment or prevention of HPK1-mediated diseases and related diseases. Background Technology

[0002] Hematopoietic progenitor kinase 1 (HPK1), also known as MAP4K1 (mitogen-activated protein kinase kinase kinase kinase 1), is a serine / threonine kinase and a member of the MAP4K family. Besides HPK1, the family also includes five other members: MAP4K2, MAP4K3, MAP4K4, MAP4K5, and MAP4K6.

[0003] The main processes by which HPK1 participates in regulating TCR are as follows: (1) TCR binds to extracellular antigens via MHC, thereby activating the TCR pathway and transmitting signals to downstream adaptor proteins; (2) adaptor proteins tyrosine kinases Lck and Zap70 activate SLP76, which then phosphorylates HPK1; (3) activated HPK1 then phosphorylates the receptor protein SLP-76; (4) the phosphorylation of SLP-76 provides multiple protein binding sites for the 14-3-3 (TCR pathway inhibitory protein) receptor protein, forming a complex; (5) the phosphorylated complex of SLP-76 participates in the downregulation of the Erk signaling pathway and is connected to the ubiquitination and degradation process of SLP76, thereby leading to a decrease in the TCR signaling pathway and T cell proliferation. In summary, HPK1 can negatively regulate the TCR signaling pathway. Therefore, HPK1 can serve as a new regulatory mechanism for T cell-mediated immune responses and become a new target for immune anti-tumor therapy.

[0004] T cell receptor (TCR)-mediated T cell activation plays a crucial role in thymic T cell development, T cell subset differentiation, and effector T cell function. The TCR specifically recognizes MHC-presented antigenic peptides on the surface of antigen-presenting cells and converts these extracellular antigenic peptides into signals that can be transmitted into the cell via the MHC (major histocompatibility complex). MHC molecules on the surface of antigen-presenting cells include MHC class II and MHC class I molecules, which are specifically recognized by their corresponding co-receptors CD4 and CD8 molecules on the surface of CD4+ and CD8+ T cells, respectively, subsequently activating downstream signaling pathways. Typical intracellular signals of TCR activation include MAPK (mitogen-activated protein kinases), PKC (protein kinase C), and calcium signaling pathways. The activation of these signals ultimately activates specific gene expression in T cells, leading to cell proliferation and differentiation into effector T cells.

[0005] Due to their important role in immunity, HPK1 inhibitors play a crucial role in malignant solid tumors or hematologic malignancies (such as acute myeloid leukemia, bladder epithelial carcinoma, breast cancer, colon cancer, lung cancer, pancreatic cancer, and melanoma), autoimmune diseases (such as systemic lupus erythematosus and psoriatic arthritis), and inflammatory responses.

[0006] WO2021050964, WO2016205942, CN109721620A, WO2019238067, WO2020103896, and WO2021000925 disclose HPK1 inhibitors and their uses.

[0007] HPK1 can bind to many adaptor proteins, such as the SLP-76 family, CARD11, HIS, HIP-55, GRB2 family, LAT, and CRK family, and interact with them to activate the JNK / SAPK signaling pathway in hematopoietic stem cells, thereby negatively regulating the TCR pathway. Currently, there are no marketed drugs targeting HPK1. To better meet the enormous clinical demand, this invention aims to provide a novel compound with HPK1 inhibitory activity, possessing favorable physicochemical properties and drug-like characteristics. It exhibits good HPK1 selectivity, and the compound or its pharmaceutically acceptable salts demonstrate good safety, efficacy, and bioavailability. Therefore, the compound of this invention has good application potential in the treatment of HPK1-mediated diseases. Summary of the Invention

[0008] One object of the present invention is to provide pyrrolopyridone compounds that have good HPK1 inhibitory activity, exhibit good HPK1 selectivity, and have good drugability, and can be used to treat or prevent HPK1-mediated diseases.

[0009] In a first embodiment, the present invention discloses pyrrolopyridone compounds of formula (I). The first embodiment includes the following aspects:

[0010] Aspect 1: A compound of general formula (I)

[0011]

[0012] Or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a protac chimeric thereof, wherein

[0013] R 1 Selected from hydrogen or -C 1-8 Alkyl group, the -C 1-8 Alkyl groups are optionally substituted with at least one substituent R. 1d replace;

[0014] R 1d Independently, it is hydrogen, amino, halogen, -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, oxo, -CN, -NO2;

[0015] X is selected from NH or NC. 1-8 alkyl;

[0016] R 2 Selected from hydrogen, carboxyl, cyano, nitro, halogen atom, -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR 2a -SO2R 2a -SO2NR 2a R 2b -COR 2a -CO2R 2a -CONR 2a R 2b -POR 2a R 2b -NR 2a R 2b -NR 2a COR 2b -NR 2a CONR 2b R2c -NR 2a CO2R 2b -NR 2a SO2NR 2b R 2c -NR 2a SO2R 2b The -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 The alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups are each optionally substituented by at least one R group. 2d replace;

[0017] R 2a R 2b and R 2c Each is independently hydrogen, hydroxyl, and -C. 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 Alkyne, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 The alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups are each optionally substituented by at least one R group. 2e Replace; or

[0018] (R 2a and R 2b ), (R 2b and R 2c ), or (R 2c and R 2a These atoms, together with one or more atoms to which they are attached, form 3 to 12-membered rings, the rings containing 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur as one or more ring members, the rings optionally being substituents R. 2e replace;

[0019] R 2d and R 2e Each is independently hydrogen, amino, halogen, -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 Alkyne, cycloalkyl, heterocyclic, aryl, heteroaryl, oxo, -CN, -NO2, -OR 2f -SO2R 2f -SO2NR 2f R 2g -COR 2f -CO2R 2f -CONR 2f R 2g -NR2f R 2g -NR 2f COR 2g -NR 2f CONR 2g R 2h -NR 2f CO2R 2f -NR 2f SO2NR 2g R 2h , or -NR 2f SO2R 2g The -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 The alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups are each optionally selected from at least one halogen, -C 1-8 Alkyl, -OR 2i -NR 2i R 2j Substitution with cycloalkyl, heterocyclic, aryl, or heteroaryl substituents;

[0020] R 2f R 2g R 2h R 2i and R 2j Each is independently hydrogen, -C 1-8 Alkyl, C 1-8 Alkoxy-C 1-8 Alkyl-, -C 2-8 alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl;

[0021] R 3 Selected from hydrogen, hydroxyl, carboxyl, cyano, nitro, halogen atom, -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR 3a -SR 3a -SO2R 3a -SO2NR 3a R 3b -COR 3a -CO2R 3a -CONR 3a R 3b -POR 3a R 3b -NR 3a R 3b -NR 3a COR 3b -NR3a CONR 3b R 3c -NR 3a CO2R 3b -NR 3a SO2NR 3b R 3c -NR 3a SO2R 3b The -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 The alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups are each optionally substituented by at least one R group. 3d replace;

[0022] R 3a R 3b and R 3c Each is independently hydrogen, hydroxyl, and -C. 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 Alkyne, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 The alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups are each optionally substituented by at least one R group. 3e Replace; or

[0023] (R 3a and R 3b ), (R 3b and R 3c ), or (R 3c and R 3a These atoms, together with one or more atoms to which they are attached, form 3 to 12-membered rings, the rings containing 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur as one or more ring members, the rings optionally being substituents R. 3e replace;

[0024] R 3d and R 3e Each is independently hydrogen, amino, halogen, -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 Alkyne, cycloalkyl, heterocyclic, aryl, heteroaryl, oxo, -CN, -NO2, -OR 3f -SO2R 3f -SO2NR 3f R 3g -COR 3f -CO2R 3f -CONR3f R 3g -NR 3f R 3g -NR 3f COR 3g -NR 3f CONR 3g R 3h -NR 3f CO2R 3f -NR 3f SO2NR 3g R 3h , or -NR 3f SO2R 3g The -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl are each optionally surrounded by at least one R 3k Substituent substitution; or

[0025] (R 3f and R 3g ), (R 3g and R 3h These atoms, together with one or more atoms to which they are attached, form 3 to 12-membered rings, the rings containing 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur as one or more ring members, the rings optionally being substituents R. 3k replace;

[0026] Each R 3k Independently selected from halogens, -C 1-8 Alkyl, -OR 3i -NR 3i R 3j cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the -C 1-8 Alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally selected from at least one group chosen from hydrogen, -C 1-8 Alkyl, C 1-8 Alkoxy-C 1-8 Alkyl-, -C 2-8 alkenyl, -C 2-8 Substitution with alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups;

[0027] R 3f R 3g R 3h R 3i and R 3j Each is independently hydrogen, -C 1-8 Alkyl, C 1-8 Alkoxy-C 1-8 Alkyl-, -C2-8 alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl;

[0028] X 1 X 2 X 3 X 4 Each can be independently selected from N or C, provided that the valence theory has been satisfied (i.e., the obtained valence is chemically possible);

[0029] R 4 Selected from hydrogen, hydroxyl, amino, oxo, carboxyl, cyano, nitro, halogen atom, -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR 4a -SR 4a -SO2R 4a -SO2NR 4a R 4b -COR 4a -CO2R 4a -CONR 4a R 4b -POR 4a R 4b -NR 4a R 4b -NR 4a COR 4b -NR 4a CONR 4b R 4c -NR 4a CO2R 4b -NR 4a SO2NR 4b R 4c -NR 4a SO2R 4b The -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 The alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups are each optionally substituented by at least one R group. 4d replace;

[0030] R 4a R 4b and R 4c Each is independently hydrogen, hydroxyl, and -C. 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 Alkyne, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the -C 1-8Alkyl, -C 2-8 alkenyl, -C 2-8 The alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups are each optionally substituented by at least one R group. 4e Replace; or

[0031] (R 4a and R 4b ), (R 4b and R 4c ), or (R 4c and R 4a These atoms, together with one or more atoms to which they are attached, form 3 to 12-membered rings, the rings containing 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur as one or more ring members, the rings optionally being substituents R. 4e replace;

[0032] R 4d and R 4e Each is independently hydrogen, amino, halogen, -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 Alkyne, cycloalkyl, heterocyclic, aryl, heteroaryl, oxo, -CN, -NO2, -OR 4f -SO2R 4f -SO2NR 4f R 4g -COR 4f -CO2R 4f -CONR 4f R 4g -NR 4f R 4g -NR 4f COR 4g -NR 4f CONR 4g R 4h -NR 4f CO2R 4f -NR 4f SO2NR 4g R 4h , or -NR 4f SO2R 4g The -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl are each optionally surrounded by at least one R 4k Substituent substitution;

[0033] Each R 4k Independently selected from halogens, -C 1-8 Alkyl, -OR4i -NR 4i R 4j cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the -C 1-8 Alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally selected from at least one group chosen from hydrogen, -C 1-8 Alkyl, C 1-8 Alkoxy-C 1-8 Alkyl-, -C 2-8 alkenyl, -C 2-8 Substitution with alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups;

[0034] R 4f R 4g R 4h R 4i and R 4j Each is independently hydrogen, -C 1-8 Alkyl, C 1-8 Alkoxy-C 1-8 Alkyl-, -C 2-8 alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl;

[0035] n can be 0, 1, 2, 3 or 4, provided that the valence theory is satisfied (i.e., the resulting valence is chemically possible).

[0036] Aspect 2: According to the compound of aspect 1, wherein X is NH, it is one of the preferred options.

[0037] Aspect 3: A compound according to any one of Aspects 1-2, wherein X 1 X 2 X 3 X 4 Both are C, which is one of the preferred options.

[0038] Aspect 4: A compound according to any one of Aspects 1-2, wherein X 1 X 2 X 3 X 4 One of them is N, and the rest are C.

[0039] Aspect 5: A compound according to any one of Aspects 1-2, wherein X 1 X 2 X 3 X 4 Any two of them are N, and the rest are C.

[0040] Aspect 6: Compounds according to any one of Aspects 1-5, wherein R 1 Hydrogen is one of the preferred options.

[0041] Aspect 7: Compounds according to any one of Aspects 1-5, wherein R 1 Selected from -C 1-8 Alkyl group, preferably -C 1-6 Alkyl, more preferably methyl.

[0042] Aspect 8: Compounds according to any one of Aspects 1-5, wherein R 1 It is optionally substituent by at least one R 1d Replacement -C 1-8 Alkyl (preferably -C) 1-6 Alkyl, more preferably methyl or ethyl), R 1d It is a halogen, preferably fluorine, chlorine, or bromine, with fluorine being more preferred.

[0043] Aspect 9: According to the compound of aspect 8, where R 1 yes

[0044]

[0045] Aspect 10: Compounds according to any one of Aspects 1-9, wherein R 2 Selected from hydrogen, cyano, -SO2R 2a -POR 2a R 2b Optionally substituent R 2d Replacement -C 1-8 alkyl.

[0046] Aspect 11: According to the compound of aspect 10, where R 2 It is hydrogen or cyano.

[0047] Aspect 12: According to the compound of aspect 10, where R 2 Yes - SO2R 2a .

[0048] Aspect 13: According to the compound of aspect 12, wherein R 2a Selected from -C 1-8 Alkyl group, preferably -C 1-6 Alkyl, more preferably methyl.

[0049] Aspect 14: A compound according to any one of Aspects 12-13, wherein R 2 yes

[0050]

[0051] Aspect 15: According to the compound of aspect 10, where R 2 Yes - POR 2a R 2b .

[0052] Aspect 16: According to the compound of aspect 15, wherein R 2a R 2b Selected from -C 1-8 Alkyl group, preferably -C 1-6 Alkyl, more preferably methyl.

[0053] Aspect 17: A compound according to any one of Aspects 15-16, wherein R 2 yes

[0054]

[0055] Aspect 18: According to the compound of aspect 10, where R 2 It is optionally substituent by at least one R 2d Replacement -C 1-8 Alkyl group, preferably -C 1-6 Alkyl, more preferably methyl.

[0056] Aspect 19: According to the compound of aspect 18, where R 2d It is selected from halogens, preferably fluorine, chlorine, or bromine, and more preferably fluorine.

[0057] Aspect 20: A compound according to any one of Aspects 18-19, wherein R 2 yes

[0058] Aspect 21: A compound according to any one of Aspects 10-20, wherein R 2 It is H, cyano, Preferred cyano, A more preferred option is cyano.

[0059] Aspect 22: A compound according to any one of aspects 1-21, wherein R 3 It is hydrogen, -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, wherein the -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 The alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups are each optionally substituented by at least one R group. 3d replace;

[0060] Where R 3d It is hydrogen, amino, halogen, -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 Alkyne, cycloalkyl, heterocyclic, aryl, heteroaryl, oxo, -CN, -NO2, -OR3f -SO2R 3f -SO2NR 3f R 3g -COR 3f -CO2R 3f -CONR 3f R 3g -NR 3f R 3g -NR 3f COR 3g -NR 3f CONR 3g R 3h -NR 3f CO2R 3f -NR 3f SO2NR 3g R 3h , or -NR 3f SO2R 3g The -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 The alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups are each optionally selected from at least one halogen, -C 1-8 Alkyl, -OR 3i , or -NR 3i R 3j Substituents; or

[0061] (R 3f and R 3g ), (R 3g and R 3h These atoms, together with one or more atoms to which they are attached, form 3 to 12-membered rings, the rings containing 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur as one or more ring members, the rings optionally being substituents R. 3k replace;

[0062] R 3f R 3g R 3h R 3i R 3j and R 3k Each is independently hydrogen, -C 1-8 Alkyl group, preferably -C 1-6 Alkyl, more preferably methyl or ethyl.

[0063] Aspect 23: According to the compound of aspect 22, where R 3 It is optionally halogenated, -C 1-8 Alkyl, -OR 3f , or -NR 3f R3g Substituted aryl, wherein R 3f and R 3g Each is independently hydrogen or -C 1-8 Alkyl group, preferably -C 1-6 Alkyl, more preferably methyl or ethyl.

[0064] Aspect 24: According to the compound of aspect 23, wherein the aryl group is phenyl.

[0065] Aspect 25: A compound according to any one of Aspects 23-24, wherein R 3 Selected from

[0066] Aspect 26: According to the compound of aspect 22, where R 3 It is optionally substituent R 3d Substituted heteroaryl groups.

[0067] Aspect 27: According to the compound of aspect 26, the heteroaryl group is a 5, 6 or 7-membered heteroaryl group comprising one, two or three heteroatoms independently selected from oxygen, nitrogen or sulfur.

[0068] Aspect 28: The compound according to aspect 27, wherein the heteroaryl group is pyridyl, pyrroleyl, pyrimidinyl, pyrazolyl, oxazolyl, or triazolyl.

[0069] Aspect 29: According to the compound of aspect 26, the heteroaryl group is an 8- to 12-membered fused heteroaryl group comprising one, two, or three heteroatoms independently selected from oxygen, nitrogen, or sulfur.

[0070] Aspect 30: The compound according to aspect 29, wherein said heteroaryl group is

[0071] Aspect 31: A compound according to any one of Aspects 26-30, wherein R 3d It is hydrogen, halogen, amino, oxo group, -C 1-8 Alkyl, -CONR 3f R 3g -NR 3f COR 3g , where R 3f and R 3g Each is independently hydrogen or -C 1-8 Alkyl group, preferably -C 1-6 Alkyl, more preferably methyl or ethyl; or

[0072] (R 3f and R 3gThese, together with one or more atoms to which they are attached, form 3 to 12-membered rings, the rings containing 0, 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen or sulfur as one or more ring members.

[0073] Aspect 32: According to the compound of aspect 31, wherein R 3d It is -C 1-8 Alkyl group preferred -C 1-6 Alkyl, more preferably methyl or ethyl.

[0074] Aspect 33: According to the compound of aspect 31, where R 3d It consists of hydrogen, halogens, and amino groups.

[0075] Aspect 34: According to the compound of aspect 31, wherein R 3d Yes -NR 3f COR 3g Chinese R 3f and R 3g Each is independently hydrogen or -C 1-8 Alkyl group, preferably -C 1-6 Alkyl, more preferably methyl or ethyl.

[0076] Aspect 35: According to the compound of aspect 34, where -NR 3f COR 3g yes

[0077] Aspect 36: According to the compound of aspect 31, where R 3d Yes - CONR 3f R 3g R 3f and R 3g Each is independently hydrogen or -C 1-8 Alkyl group, preferably -C 1-6 Alkyl, more preferably methyl or ethyl.

[0078] Aspect 37: According to the compound of aspect 36, where R 3f and R 3g Together with one or more atoms to which they are attached, they form 3 to 12-membered rings, preferably 4 to 6-membered rings, which contain 0, 1, 2 or 3 additional heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as one or more ring members.

[0079] Aspect 38: A compound according to any one of Aspects 36-37, wherein -CONR 3f R 3g Selected from

[0080]

[0081] Aspect 39: A compound according to any one of Aspects 26-38, wherein R 3 Selected from

[0082]

[0083] Aspect 40: According to the compound of aspect 22, where R 3 It is hydrogen.

[0084] Aspect 41: According to the compound of aspect 22, wherein R 3 It is -C 1-8 Alkyl groups, preferably -C 1-6 Alkyl, more preferably methyl, ethyl, or isopropyl.

[0085] Aspect 42: According to the compound of aspect 22, wherein R 3 It is a cycloalkyl group, preferably C10. 3-6 Cycloalkyl, more preferably

[0086] Aspect 43: According to the compound of aspect 22, where R 3 It is optional that at least one substituent R 3d Substituted heterocyclic groups, wherein R 3d It is hydrogen, halogen, amino, oxo group, halogen, -C 1-8 Alkyl, -OR 3f -NR 3f R 3g -CONR 3f R 3g -NR 3f COR 3g , where R 3f and R 3g Each is independently hydrogen or -C 1-8 Alkyl group, preferably -C 1-6 Alkyl, more preferably methyl or ethyl.

[0087] Aspect 44: According to the compound of aspect 40, the heterocyclic group is a 4- to 7-membered ring containing one or two heteroatoms independently selected from nitrogen, oxygen or sulfur, preferably a 5, 6 or 7-membered saturated ring containing a nitrogen or oxygen atom as a ring member.

[0088] Aspect 45: The compound according to aspect 44, wherein the heterocyclic group is piperidinyl, tetrahydropyrrolyl, tetrahydropyran, or piperazine.

[0089] Aspect 46: A compound according to any one of Aspects 40-45, wherein R 3d It is hydrogen, halogen, amino, oxo group, -C 1-8 Alkyl, -CONR 3f R3g -NR 3f COR 3g , where R 3f and R 3g Each is independently hydrogen or -C 1-8 Alkyl group, preferably -C 1-6 Alkyl, more preferably methyl or ethyl.

[0090] Aspect 47: According to the compound of aspect 46, where R 3d It is a hydrogen, oxo group or -C 1-8 Alkyl group, preferably -C 1-6 Alkyl, more preferably methyl or ethyl.

[0091] Aspect 48: A compound according to any one of Aspects 40-47, wherein R 3 Selected from

[0092]

[0093] Aspect 49: A compound according to any one of Aspects 22-48, wherein R 3 Selected from H, methyl, ethyl, isopropyl, H, ethyl, isopropyl, are preferred

[0094] Aspect 50: Compounds according to any one of Aspects 1-48, where n is 1, 2 or 3, R 4 It is as defined in equation (I).

[0095] Aspect 51: A compound according to any one of Aspects 1-50, wherein R 4 Selected from hydrogen, -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR 4a -SR 4a -SO2R 4a -SO2NR 4a R 4b -COR 4a -CO2R 4a -CONR 4a R 4b -POR 4a R 4b -NR 4a R 4b -NR 4a COR 4b -NR 4aCO2R 4b -NR 4a SO2R 4b The -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 The alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups are each optionally substituented by at least one R group. 4d replace;

[0096] R 4a R 4b Each is independently hydrogen, hydroxyl, and -C. 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 Alkyne, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 The alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups are each optionally substituented by at least one R group. 4e replace;

[0097] R 4d and R 4e Each is independently hydrogen, amino, halogen, -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 Alkyne, cycloalkyl, heterocyclic, aryl, heteroaryl, oxo, -CN, -NO2, -OR 4f -SO2R 4f -SO2NR 4f R 4g -COR 4f -CO2R 4f -CONR 4f R 4g -NR 4f R 4g -NR 4f COR 4g -NR 4f CONR 4g R 4h -NR 4f CO2R 4f -NR 4f SO2NR 4g R 4h , or -NR 4f SO2R 4g The -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl are each optionally surrounded by at least one R4k Substituent substitution; or

[0098] Each R 4k Independently selected from halogens, -C 1-8 Alkyl, -OR 4i -NR 4i R 4j cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the -C 1-8 Alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally selected from at least one group chosen from hydrogen, -C 1-8 Alkyl, C 1-8 Alkoxy-C 1-8 Alkyl-, -C 2-8 alkenyl, -C 2-8 Substitution with alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups;

[0099] R 4f R 4g R 4h R 4i and R 4j Each is independently hydrogen, -C 1-8 Alkyl, C 1-8 Alkoxy-C 1-8 Alkyl-, -C 2-8 alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl.

[0100] Aspect 52: According to the compound of aspect 51, wherein R 4 It is a ring selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups, wherein each of the cycloalkyl, heterocyclic, aryl, or heteroaryl groups is optionally substituent by at least one substituent R. 4d replace;

[0101] R 4d Independently, it is hydrogen, amino, halogen, -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 Alkyne, cycloalkyl, heterocyclic, aryl, heteroaryl, oxo, -CN, -NO2, -OR 4f -SO2R 4f -SO2NR 4f R 4g -COR 4f -CO2R 4f -CONR 4f R 4g -NR 4f R 4g -NR 4f COR 4g -NR4f CONR 4g R 4h -NR 4f CO2R 4f -NR 4f SO2NR 4g R 4h , or -NR 4f SO2R 4g The -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl are each optionally surrounded by at least one R 4k Substituent substitution; or

[0102] Each R 4k Independently selected from halogens, -C 1-8 Alkyl, -OR 4i -NR 4i R 4j cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the -C 1-8 Alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally selected from at least one group chosen from hydrogen, -C 1-8 Alkyl, C 1-8 Alkoxy-C 1-8 Alkyl-, -C 2-8 alkenyl, -C 2-8 Substitution with alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups;

[0103] R 4f R 4g R 4h R 4i and R 4j Each is independently hydrogen, -C 1-8 Alkyl, C 1-8 Alkoxy-C 1-8 Alkyl-, -C 2-8 alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl.

[0104] Aspect 53: According to the compound of aspect 52, wherein R 4 It is optionally substituent R 4d Substituted cycloalkyl groups;

[0105] The R mentioned 4d Independently selected from halogens, oxo groups, and -C 1-8 Alkyl, -OR 4f , or -NR 4f R 4g The -C 1-8Alkyl optional -OR 4i -NR 4i R 4j replace;

[0106] Where R 4f R 4g R 4i and R 4j Each is independently hydrogen or -C 1-8 Alkyl group, preferably -C 1-6 Alkyl, more preferably methyl or ethyl.

[0107] Aspect 54: According to the compound of aspect 53, wherein R 4 Is it arbitrarily R 4d Substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl.

[0108] Aspect 55: According to the compound of aspect 54, where R 4d It is arbitrarily assigned to -NR 4i R 4j Replacement -C 1-8 Alkyl group, preferably -C 1-6 Alkyl, more preferably methyl or ethyl.

[0109] Aspect 56: According to the compound of aspect 55, where R 4i and R 4j It is hydrogen or -C independently 1-8 Alkyl group, preferably -C 1-6 Alkyl, more preferably methyl.

[0110] Aspect 57: A compound according to any one of Aspects 53-56, wherein R 4 yes

[0111] Aspect 58: According to the compound of aspect 52, where R 4 It is optionally substituent R 4d Substituted heterocyclic groups;

[0112] Aspect 59: Compounds according to aspect 58, wherein the heterocyclic group is a 4, 5, 6 or 7-membered heterocyclic group comprising one, two or three heteroatoms independently selected from oxygen, nitrogen or sulfur.

[0113] Aspect 60: According to the compound of aspect 59, wherein the heterocyclic group is a monocyclic 4, 5, 6 or 7-membered saturated heterocyclic group containing one or two nitrogen atoms as ring members.

[0114] Aspect 61: Compounds according to Aspect 60 and Aspect 59, wherein the heterocyclic group is piperidinyl or piperazine.

[0115] Aspect 62: According to the compound of aspect 59, wherein the heterocyclic group is a monocyclic 4, 5, 6 or 7-membered saturated heterocyclic group containing one or two oxygen atoms as ring members.

[0116] Aspect 63: According to the compound of aspect 62, the heterocyclic group is

[0117] Aspect 64: According to the compound of aspect 59, wherein the heterocyclic group is a monocyclic 4, 5, 6 or 7-membered saturated heterocyclic group containing a nitrogen atom and an oxygen atom as ring members.

[0118] Aspect 65: According to the compound of aspect 64, the heterocyclic group is

[0119] Aspect 66: According to aspect 58, the compound wherein the heterocyclic group is a 7- to 12-membered fused heterocyclic group comprising one, two or three heteroatoms independently selected from oxygen, nitrogen or sulfur.

[0120] Aspect 67: According to aspect 66, the heterocyclic group is an 8-10 membered spirocyclic heterocyclic group containing 1-2 nitrogen atoms, preferably

[0121] Aspect 68: According to the compound of aspect 66, wherein the heterocyclic group is an 8-10 membered bridged ring heterocyclic group containing 1-2 nitrogen atoms, preferably

[0122] Aspect 69: A compound according to any one of Aspects 52-68, wherein R 4 It is optionally substituted with at least one substituent R 4d The replaced ring, wherein the ring is selected from C 3-10 Cycloalkyl, 4, 5, 6, or 7-membered heterocyclic groups comprising one or two heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur, or 7 to 12-membered fused heterocyclic groups comprising one, two, or three heteroatoms independently selected from oxygen, nitrogen, or sulfur;

[0123] Furthermore, R 4 It is optionally substituted with at least one substituent R 4d The substitutions are 4-7 membered monocyclic heterocyclic groups or 7-9 membered fused heterocyclic groups containing one or two heteroatoms independently selected from nitrogen and oxygen.

[0124] Aspect 70: According to the compound of aspect 69, where R 4 It is optionally substituent R 4d The substituted ring, wherein the ring is cyclopropyl, piperidinyl, piperazine, or... Piperidinyl, piperazineyl, More Further optimization

[0125] Aspect 71: A compound according to any one of Aspects 58-70 and Aspect 67, wherein R 4d Independently selected from hydrogen, halogen, oxo group, -C 1-8 Alkyl groups, cycloalkyl groups. Hydrogen, halogens, oxo groups, -C 1-8 Alkyl, cycloalkyl, heterocyclic, -OR 4f , or -NR 4f R 4g The -C 1-8 Alkyl, cycloalkyl, and heterocyclic groups are each optionally substituent R as defined in formula (I). 4k Replace, where R 4f R 4g As defined in formula (I), it is preferably hydrogen or -C 1-6 Alkyl, more preferably methyl or ethyl.

[0126] Aspect 72: According to the compound of aspect 71, wherein R 4k Selected from halogens, heterocyclic groups, and -C 1-8 Alkyl, -OR 4i -NR 4i R 4j ,

[0127] Where R 4i and R 4j Each is independently hydrogen or -C 1-8 Alkyl group, preferably -C 1-6 Alkyl, more preferably methyl or ethyl.

[0128] Aspect 73: According to the compound of aspect 71, wherein R 4d It is hydrogen.

[0129] Aspect 74: According to the compound of aspect 71, wherein R 4d It is -C 1-8 Alkyl group, preferably -C 1-6 Alkyl, more preferably methyl or ethyl.

[0130] Aspect 75: According to the compound of aspect 71, wherein R 4d It is optional to be at least one -OR 4i Replacement -C 1-8 Alkyl group, preferably -C 1-6 Alkyl, more preferably methyl or ethyl.

[0131] Aspect 76: According to the compound of aspect 75, wherein R 4i Is it hydrogen or -C? 1-8 Alkyl group, preferably -C 1-6Alkyl, more preferably methyl or ethyl.

[0132] Aspect 77: A compound according to any one of Aspects 75-76, wherein R 4d yes

[0133] Aspect 78: According to the compound of aspect 71, wherein R 4d It is optionally subject to at least one -NR 4i R 4j Replacement -C 1-8 Alkyl group, preferably -C 1-6 Alkyl, more preferably methyl or ethyl.

[0134] Aspect 79: According to the compound of aspect 78, where R 4i and R 4j It is hydrogen or -C independently 1-8 Alkyl group, preferably -C 1-6 Alkyl, more preferably methyl.

[0135] Aspect 80: According to the compound of aspect 71, wherein R 4d -C is optionally substituted with at least one heterocyclic group. 1-8 Alkyl group, preferably -C 1-6 Alkyl, more preferably methyl or ethyl.

[0136] Aspect 81: According to aspect 80, the heterocyclic group is a 4, 5, 6, or 7-membered heterocyclic group containing one or two heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur.

[0137] Aspect 82: A compound according to any one of Aspects 80-81, wherein R 4d yes

[0138]

[0139] Aspect 83: According to the compound of aspect 71, wherein R 4d It is a cycloalkyl group, preferably C10. 4-6 Cycloalkyl, more preferably C4 cycloalkyl.

[0140] Aspect 84: According to the compound of aspect 71, wherein R 4d It is a 4, 5, 6, or 7-membered heterocyclic group containing one or two heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur.

[0141] Aspect 85: According to the compound of aspect 84, wherein R 4d yes

[0142] Aspect 86: A compound according to any one of aspects 71-85, wherein R4d Independently selected from hydrogen, halogen, oxo group, -C 1-8 Alkyl, cycloalkyl, heterocyclic, -OR 4f , or -NR 4f R 4g The -C 1-8 Alkyl, cycloalkyl, and heterocyclic groups are each optionally substituented by at least one R group. 4k replace,

[0143] R 4k Each is selected from halogens, heterocyclic groups, and -C groups. 1-8 Alkyl, -OR 4i -NR 4i R 4j ,

[0144] R 4i and R 4j Each is independently hydrogen or -C 1-8 Alkyl group, preferably -C 1-6 Alkyl, more preferably methyl or ethyl;

[0145] Furthermore,

[0146] R 4d It is H, -C 1-8 Alkyl group, the -C 1-8 Alkyl groups are optionally substituted with at least one substituent R. 4k Replace; R 4k Independently, it is a heterocyclic group or a hydroxyl group;

[0147] Aspect 87: A compound according to any one of aspects 71-85, wherein R 4d yes

[0148] Hydrogen, methyl, ethyl Preferred hydrogen, methyl, ethyl,

[0149] Aspect 88: A compound according to any one of aspects 52-87, wherein R 4 yes

[0150] Preferred More Further optimization

[0151] Aspect 89: According to the compound of aspect 51, where R 4 It is selected from hydrogen, -C 1-8 Alkyl, -C 2-8 alkenyl, -C2-8 Alkyne group, -OR 4a -SR 4a -SO2R 4a -SO2NR 4a R 4b -COR 4a -CO2R 4a -CONR 4a R 4b -POR 4a R 4b -NR 4a R 4b -NR 4a COR 4b -NR 4a CO2R 4b -NR 4a SO2R 4b The -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 Each of the alkynyl groups is optionally substituent for at least one R group. 4d replace;

[0152] R 4a R 4b Each is independently hydrogen, hydroxyl, and -C. 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 Alkyne, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 The alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups are each optionally substituented by at least one R group. 4e replace;

[0153] R 4d and R 4e Each is independently hydrogen, amino, halogen, -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 Alkyne, cycloalkyl, heterocyclic, aryl, heteroaryl, oxo, -CN, -NO2, -OR 4f -SO2R 4f -SO2NR 4f R 4g -COR 4f -CO2R 4f -CONR 4f R 4g -NR 4f R 4g -NR 4f COR4g -NR 4f CONR 4g R 4h -NR 4f CO2R 4f -NR 4f SO2NR 4g R 4h , or -NR 4f SO2R 4g The -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl are each optionally surrounded by at least one R 4k Substituent substitution; or

[0154] Each R 4k Independently selected from halogens, -C 1-8 Alkyl, -OR 4i -NR 4i R 4j cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the -C 1-8 Alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally selected from at least one group chosen from hydrogen, -C 1-8 Alkyl, C 1-8 Alkoxy-C 1-8 Alkyl-, -C 2-8 alkenyl, -C 2-8 Substitution with alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups;

[0155] R 4f R 4g R 4h R 4i and R 4j Each is independently hydrogen, -C 1-8 Alkyl, C 1-8 Alkoxy-C 1-8 Alkyl-, -C 2-8 alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl.

[0156] Aspect 90: According to the compound of aspect 89, where R 4 It is hydrogen.

[0157] Aspect 91: According to the compound of aspect 89, where R 4 It is -C 1-8 Alkyl group, preferably -C 1-6 Alkyl, more preferably methyl or ethyl.

[0158] Aspect 92: According to the compound of aspect 89, where R4 It is optionally substituent by at least one R 4d Replacement -C 1-8 Alkyl (preferably -C) 1-6 Alkyl, more preferably methyl or ethyl), R 4d Independently is -NR 4f R 4g R 4f R 4g Each is independently hydrogen, -C 1-8 alkyl.

[0159] Aspect 93: According to the compound of aspect 92, wherein R 4 yes

[0160] Aspect 94: According to the compound of aspect 89, where R 4 Yes - NR 4a R 4b R 4a R 4b Each is either hydrogen or -C. 1-8 Alkyl (preferably -C) 1-6 Alkyl, more preferably methyl or ethyl), or cycloalkyl (preferably monocyclic-C) 3-8 cycloalkyl, more preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), wherein the -C 1-8 The alkyl and cycloalkyl groups are each optionally substituent R as defined in formula (I). 4e replace.

[0161] Aspect 95: According to the compound of aspect 94, wherein R 4e It is independently hydrogen, amino, or halogen (preferably fluorine, chlorine, or bromine, more preferably fluorine).

[0162] Aspect 96: A compound according to any one of Aspects 94-95, wherein R 4 yes

[0163] Aspect 97: According to the compound of aspect 52, wherein R 4 It is -SR 4a , where R 4a It is -C 1-8 Alkyl (preferably -C) 1-6 Alkyl (more preferably methyl or ethyl) or cycloalkyl (preferably monocyclic -C) 3-8 cycloalkyl, more preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), wherein the -C 1-8 The alkyl and cycloalkyl groups are each optionally substituent R as defined in formula (I). 4e replace.

[0164] Aspect 98: According to the compound of aspect 97, where R 4 yes

[0165]

[0166] Aspect 99: According to the compound of aspect 52, where R 4 Yes -NR 4a SO2R 4b , where R 4a and R 4b Each is independently hydrogen or -C 1-8 Alkyl (preferably -C) 1-6 Alkyl (more preferably methyl or ethyl) or cycloalkyl (preferably monocyclic -C) 3-8 cycloalkyl, more preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), wherein the -C 1-8 The alkyl and cycloalkyl groups are each optionally substituent R as defined in formula (I). 4e replace.

[0167] Aspect 100: According to the compound of aspect 99, where R 4 yes

[0168]

[0169] Aspect 101: According to the compound of aspect 52, wherein R 4 Yes - OR 4a R 4a It is -C 1-8 Alkyl (preferably -C) 1-6 Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl, ), the -C 1-8 The alkyl group is optionally substituent for at least one R group. 4e Replace; R 4e It is hydrogen, halogen (preferably fluorine or chlorine, more preferably fluorine), or cycloalkyl (preferably C). 3-6 Cycloalkyl, more preferably C3 cycloalkyl), heterocyclic, aryl, -CONR 4f R 4g -CO2R 4f , or -NR 4f R 4g The cycloalkyl, heterocyclic, and aryl groups are each optionally surrounded by at least one R 4k Substituent substitution;

[0170] R 4k Selected from halogens (preferably fluorine, chlorine, bromine, more preferably fluorine), -C 1-8 Alkyl (preferably -C) 1-6 Alkyl group, more preferably methyl group;

[0171] R4f R 4g and R 4h Each is independently hydrogen or -C 1-8 Alkyl (preferably -C) 1-6 Alkyl group, more preferably methyl group.

[0172] Aspect 102: According to the compound of aspect 101, wherein R 4e It is a cycloalkyl group, preferably C10. 3-6 Cycloalkyl, more preferably C3 cycloalkyl.

[0173] Aspect 103: The compound according to aspect 102, wherein the cycloalkyl group is optionally surrounded by at least one R 4k Substituent substitution, R 4k Selected from halogens (preferably fluorine, chlorine, bromine, more preferably fluorine), -C 1-8 Alkyl (preferably -C) 1-6 Alkyl group, more preferably methyl group.

[0174] Aspect 104: According to the compound of aspect 101, wherein R 4e It is a heterocyclic group, which is a 4, 5, 6 or 7-membered heterocyclic group containing one or two or three heteroatoms independently selected from oxygen, nitrogen or sulfur, preferably a 4, 5, 6 or 7-membered saturated ring containing a nitrogen or oxygen atom as a ring member, more preferably a tetrahydropyrrole ring.

[0175] Aspect 105: Compounds according to aspects 101-104, wherein R 4 It is methoxy, ethoxy, isopropoxy,

[0176]

[0177] Aspect 106: According to the compound of aspect 52, wherein R 4 Yes - OR 4a R 4a It is a cycloalkyl group (preferably C14) 3-6 Cycloalkyl (more preferably C3 cycloalkyl), or heterocyclic (preferably tetrahydrofuranyl, azahexacyclobutyl, pyrrolidinyl, piperidinyl), wherein the cycloalkyl or heterocyclic group is optionally substituted with at least one substituent R. 4e Replace; R 4e It is hydrogen, halogen (preferably fluorine or chlorine, more preferably fluorine), cycloalkyl, aryl, -CONR 4f R 4g -CO2R 4f , or -NR 4f R 4g ;R 4f R 4g and R 4h Each is independently hydrogen or -C 1-8Alkyl (preferably -C) 1-6 Alkyl group, more preferably methyl group.

[0178] Aspect 107: According to the compound of aspect 106, wherein R 4 yes

[0179]

[0180] Aspect 108: According to the compounds of aspects 89-107, wherein R 4 It is H, -C 1-8 Alkyl, -OR 4a -NR 4a R 4b -SR 4a -NR 4a SO2R 4b The -C 1-8 Alkyl groups are optionally substituted with at least one substituent R. 4d replace;

[0181] R 4a R 4b Each is either hydrogen or -C. 1-8 Alkyl (preferably -C) 1-6 Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl, ), or cycloalkyl (preferably monocyclic-C 3-8 Cycloalkyl, more preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), or heterocyclic (preferably tetrahydrofuranyl, azahexylbutyl, pyrrolidinyl, piperidinyl), wherein the -C 1-8 Alkyl, cycloalkyl, and heterocyclic groups are each optionally substituented by at least one R group. 4e replace;

[0182] R 4d R 4e Each of these elements is independently hydrogen, halogen (preferably fluorine or chlorine, more preferably fluorine), or cycloalkyl (preferably C). 3-6 Cycloalkyl, more preferably C3 cycloalkyl), heterocyclic, aryl, -CONR 4f R 4g -CO2R 4f , or -NR 4f R 4g The cycloalkyl, heterocyclic, and aryl groups are each optionally surrounded by at least one R 4k Substituent substitution;

[0183] R 4k Selected from halogens (preferably fluorine, chlorine, bromine, more preferably fluorine), -C 1-8 Alkyl (preferably -C) 1-6 Alkyl group, more preferably methyl group;

[0184] R 4f R 4g Each is independently hydrogen or -C 1-8 Alkyl (preferably -C) 1-6 Alkyl group, more preferably methyl group.

[0185] Aspect 109: According to the compound of aspect 108, wherein R 4 It is H, -C 1-8 Alkyl, -OR 4a ;

[0186] R 4a It is -C 1-8 Alkyl, cycloalkyl, and the -C 1-8 Alkyl and cycloalkyl groups are each optionally substituented by at least one R group. 4e replace;

[0187] R 4e It is a halogen, a cycloalkyl group, wherein the cycloalkyl group is optionally surrounded by at least one R 4k Substituent substitution;

[0188] R 4k Independently selected from halogens, -C 1-8 alkyl.

[0189] Aspect 110: Compounds according to aspects 89-109, wherein R 4 It is H, methyl, H, methyl, preferred More preferably methyl, Further optimization of methyl groups,

[0190] Aspect 111: According to the compound of aspect 50, where n is 1, and R 4 It is defined as in any of aspects 52-88.

[0191] Aspect 112: According to the compound of aspect 111, wherein R 4 In X 2 Or X 3 In position.

[0192] Aspect 113: According to the compound of aspect 50, where n is 2, the first R 4 As defined in any of aspects 52-88, the second R 4 It is as defined in any of aspects 89-107.

[0193] Aspect 114: According to the compound of aspect 113, where the first R 4 In X 2 In position, the second R 4 In X 1 Or X 3 In position.

[0194] Aspect 115: According to the compound of aspect 113, where the first R 4 In X 3 In position, the second R 4 In X 2 Or X 4 In position.

[0195] Aspect 116: Based on the compound of aspect 50, where n is 3, the first R 4 As defined in any of aspects 52-88, the second and third R 4 It is as defined in any of aspects 89-107.

[0196] Aspect 117: According to the compound of aspect 116, where the first R 4 In X 2 In position, the second R 4 In X 1 In position, the third R 4 In X 3 In position.

[0197] Aspect 118: According to the compound of aspect 116, where the first R 4 In X 3 In position, the second R 4 In X 2 In position, the third R 4 In X 4 In position.

[0198] In a second embodiment, the present invention discloses pyrrolopyridone compounds of formula (II). The second embodiment includes the following aspects:

[0199] Aspect 1: A compound of general formula (II)

[0200]

[0201] Or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a protac chimeric thereof, wherein

[0202] R 1 Selected from hydrogen or -C 1-8 Alkyl group, the -C 1-8 Alkyl groups are optionally substituted with at least one substituent R. 1d replace;

[0203] R 1d Independently, it is hydrogen, amino, halogen, -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, oxo, -CN, -NO2;

[0204] X is selected from NH or NC. 1-8 alkyl;

[0205] R 2 Selected from hydrogen, carboxyl, cyano, nitro, halogen atom, -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR 2a -SO2R 2a -SO2NR 2a R 2b -COR 2a -CO2R 2a -CONR 2a R 2b -POR 2a R 2b -NR 2a R 2b -NR 2a COR 2b -NR 2a CONR 2b R 2c -NR 2a CO2R 2b -NR 2a SO2NR 2b R 2c -NR 2a SO2R 2b The -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 The alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups are each optionally substituented by at least one R group. 2d replace;

[0206] R 2a R 2b and R 2c Each is independently hydrogen, hydroxyl, and -C. 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 Alkyne, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the -C 1-8 Alkyl, -C 2-8alkenyl, -C 2-8 The alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups are each optionally substituented by at least one R group. 2e Replace; or

[0207] (R 2a and R 2b ), (R 2b and R 2c ), or (R 2c and R 2a These atoms, together with one or more atoms to which they are attached, form 3 to 12-membered rings, the rings containing 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur as one or more ring members, the rings optionally being substituents R. 2e replace;

[0208] R 2d and R 2e Each is independently hydrogen, amino, halogen, -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 Alkyne, cycloalkyl, heterocyclic, aryl, heteroaryl, oxo, -CN, -NO2, -OR 2f -SO2R 2f -SO2NR 2f R 2g -COR 2f -CO2R 2f -CONR 2f R 2g -NR 2f R 2g -NR 2f COR 2g -NR 2f CONR 2g R 2h -NR 2f CO2R 2f -NR 2f SO2NR 2g R 2h , or -NR 2f SO2R 2g The -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 The alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups are each optionally selected from at least one halogen, -C 1-8 Alkyl, -OR 2i -NR 2i R 2j Substitution with cycloalkyl, heterocyclic, aryl, or heteroaryl substituents;

[0209] R 2f R 2g R 2h R 2i and R 2j Each is independently hydrogen, -C 1-8 Alkyl, C 1-8 Alkoxy-C 1-8 Alkyl-, -C 2-8 alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl;

[0210] R 3 Selected from hydrogen, hydroxyl, carboxyl, cyano, nitro, halogen atom, -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR 3a -SR 3a -SO2R 3a -SO2NR 3a R 3b -COR 3a -CO2R 3a -CONR 3a R 3b -POR 3a R 3b -NR 3a R 3b -NR 3a COR 3b -NR 3a CONR 3b R 3c -NR 3a CO2R 3b -NR 3a SO2NR 3b R 3c -NR 3a SO2R 3b The -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 The alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups are each optionally substituented by at least one R group. 3d replace;

[0211] R 3a R 3b and R 3c Each is independently hydrogen, hydroxyl, and -C. 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8Alkyne, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 The alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups are each optionally substituented by at least one R group. 3e Replace; or

[0212] (R 3a and R 3b ), (R 3b and R 3c ), or (R 3c and R 3a These atoms, together with one or more atoms to which they are attached, form 3 to 12-membered rings, the rings containing 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur as one or more ring members, the rings optionally being substituents R. 3e replace;

[0213] R 3d and R 3e Each is independently hydrogen, amino, halogen, -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 Alkyne, cycloalkyl, heterocyclic, aryl, heteroaryl, oxo, -CN, -NO2, -OR 3f -SO2R 3f -SO2NR 3f R 3g -COR 3f -CO2R 3f -CONR 3f R 3g -NR 3f R 3g -NR 3f COR 3g -NR 3f CONR 3g R 3h -NR 3f CO2R 3f -NR 3f SO2NR 3g R 3h , or -NR 3f SO2R 3g The -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl are each optionally surrounded by at least one R 3k Substituent substitution; or

[0214] (R3f and R 3g ), (R 3g and R 3h These atoms, together with one or more atoms to which they are attached, form 3 to 12-membered rings, the rings containing 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur as one or more ring members, the rings optionally being substituents R. 3k replace;

[0215] Each R 3k Independently selected from halogens, -C 1-8 Alkyl, -OR 3i -NR 3i R 3j cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the -C 1-8 Alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally selected from at least one group chosen from hydrogen, -C 1-8 Alkyl, C 1-8 Alkoxy-C 1-8 Alkyl-, -C 2-8 alkenyl, -C 2-8 Substitution with alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups;

[0216] R 3f R 3g R 3h R 3i and R 3j Each is independently hydrogen, -C 1-8 Alkyl, C 1-8 Alkoxy-C 1-8 Alkyl-, -C 2-8 alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl;

[0217] X 1 X 2 X 3 X 4 Each can be independently selected from N or C, provided that the valence theory has been satisfied (i.e., the obtained valence is chemically possible);

[0218] R 5 Selected from hydrogen, hydroxyl, amino, oxo, carboxyl, cyano, nitro, halogen atom, -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR 5a -SR 5a -SO2R 5a -SO2NR 5a R5b -COR 5a -CO2R 5a -CONR 5a R 5b -POR 5a R 5b -NR 5a R 5b -NR 5a COR 5b -NR 5a CONR 5b R 5c -NR 5a CO2R 5b -NR 5a SO2NR 5b R 5c -NR 5a SO2R 5b The -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 The alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups are each optionally substituented by at least one R group. 5d replace;

[0219] R 5a R 5b and R 5c Each is independently hydrogen, hydroxyl, and -C. 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 Alkyne, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 The alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups are each optionally substituented by at least one R group. 5e Replace; or

[0220] (R 5a and R 5b ), (R 5b and R 5c ), or (R 5c and R 5a These atoms, together with one or more atoms to which they are attached, form 3 to 12-membered rings, the rings containing 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur as one or more ring members, the rings optionally being substituents R. 5e replace;

[0221] R 5d and R 5e Each is independently hydrogen, amino, halogen, -C 1-8Alkyl, -C 2-8 alkenyl, -C 2-8 Alkyne, cycloalkyl, heterocyclic, aryl, heteroaryl, oxo, -CN, -NO2, -OR 5f -SO2R 5f -SO2NR 5f R 5g -COR 5f -CO2R 5f -CONR 5f R 5g -NR 5f R 5g -NR 5f COR 5g -NR 5f CONR 5g R 5h -NR 5f CO2R 5f -NR 5f SO2NR 5g R 5h , or -NR 5f SO2R 5g The -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl are each optionally surrounded by at least one R 5k Substituent substitution;

[0222] Each R 5k Independently selected from halogens, -C 1-8 Alkyl, -OR 5i -NR 5i R 5j cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the -C 1-8 Alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally selected from at least one group chosen from hydrogen, -C 1-8 Alkyl, C 1-8 Alkoxy-C 1-8 Alkyl-, -C 2-8 alkenyl, -C 2-8 Substitution with alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups;

[0223] R 5f R 5g R 5h R 5i and R 5j Each is independently hydrogen, -C 1-8 Alkyl, C 1-8 Alkoxy-C 1-8 Alkyl-, -C2-8 alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl;

[0224] s can be 0, 1, 2 or 3, provided that the valence theory is satisfied (i.e., the resulting valence is chemically possible);

[0225] Cy1 is selected from cycloalkyl, heterocyclic, aryl, or heteroaryl groups, each optionally marked with t R groups. 6 replace;

[0226] R 6 Selected from hydrogen, hydroxyl, amino, oxo, carboxyl, cyano, nitro, halogen atom, -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR 6a -SR 6a -SO2R 6a -SO2NR 6a R 6b -COR 6a -CO2R 6a -CONR 6a R 6b -POR 6a R 6b -NR 6a R 6b -NR 6a COR 6b -NR 6a CONR 6b R 6c -NR 6a CO2R 6b -NR 6a SO2NR 6b R 6c -NR 6a SO2R 6b The -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 The alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups are each optionally substituented by at least one R group. 6d replace;

[0227] R 6a R 6b and R 6c Each is independently hydrogen, hydroxyl, and -C. 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 Alkyne, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the -C1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 The alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups are each optionally substituented by at least one R group. 6e Replace; or

[0228] (R 6a and R 6b ), (R 6b and R 6c ), or (R 6c and R 6a These atoms, together with one or more atoms to which they are attached, form 3 to 12-membered rings, the rings containing 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur as one or more ring members, the rings optionally being substituents R. 6e replace;

[0229] R 6d and R 6e Each is independently hydrogen, amino, halogen, -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 Alkyne, cycloalkyl, heterocyclic, aryl, heteroaryl, oxo, -CN, -NO2, -OR 6f -SO2R 6f -SO2NR 6f R 6g -COR 6f -CO2R 6f -CONR 6f R 6g -NR 6f R 6g -NR 6f COR 6g -NR 6f CONR 6g R 6h -NR 6f CO2R 6f -NR 6f SO2NR 6g R 6h , or -NR 6f SO2R 6g The -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl are each optionally surrounded by at least one R 6k Substituent substitution;

[0230] Each R 6k Independently selected from halogens, -C 1-8Alkyl, -OR 6i -NR 6i R 6j cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the -C 1-8 Alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally selected from at least one group chosen from hydrogen, -C 1-8 Alkyl, C 1-8 Alkoxy-C 1-8 Alkyl-, -C 2-8 alkenyl, -C 2-8 Substitution with alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups;

[0231] R 6f R 6g R 6h R 6i and R 6j Each is independently hydrogen, -C 1-8 Alkyl, C 1-8 Alkoxy-C 1-8 Alkyl-, -C 2-8 alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl;

[0232] t can be 0, 1, 2, 3 or 4, provided that the valence theory is satisfied (i.e., the resulting valence is chemically possible).

[0233] Aspect 2: According to the compound of aspect 1, wherein X is NH, it is one of the preferred options.

[0234] Aspect 3: A compound according to any one of Aspects 1-2, wherein X 1 X 2 X 3 X 4 Both are C, which is one of the preferred options.

[0235] Aspect 4: A compound according to any one of Aspects 1-2, wherein X 1 X 2 X 3 X 4 One of them is N, and the rest are C.

[0236] Aspect 5: A compound according to any one of Aspects 1-2, wherein X 1 X 2 X 3 X 4 Any two of them are N, and the rest are C.

[0237] Aspect 6: Compounds according to any one of Aspects 1-5, wherein R 1 Hydrogen is one of the preferred options.

[0238] Aspect 7: Compounds according to any one of Aspects 1-5, wherein R 1 Selected from -C 1-8 Alkyl group, preferably -C 1-6 Alkyl, more preferably methyl.

[0239] Aspect 8: Compounds according to any one of Aspects 1-5, wherein R 1 It is optionally substituent by at least one R 1d Replacement -C 1-8 Alkyl (preferably -C) 1-6 Alkyl, more preferably methyl or ethyl), R 1d It is a halogen, preferably fluorine, chlorine, or bromine, with fluorine being more preferred.

[0240] Aspect 9: According to the compound of aspect 8, where R 1 yes

[0241]

[0242] Aspect 10: Compounds according to any one of Aspects 6-9, wherein R 1 Selected from hydrogen, -C 1-8 Alkyl group, optionally substituted with at least one substituent R 1d Replacement -C 1-8 Alkyl (preferably -C) 1-6 Alkyl, more preferably methyl or ethyl), R 1d It is a halogen, preferably fluorine, chlorine, or bromine, more preferably fluorine, and preferably hydrogen, methyl, Hydrogen is preferred;

[0243] Aspect 11: A compound according to any one of Aspects 1-10, wherein R 2 Selected from hydrogen, cyano, -SO2R 2a -POR 2a R 2b Optionally substituent R 2d Replacement -C 1-8 alkyl.

[0244] Aspect 12: According to the compound of aspect 10, where R 2 It is either hydrogen or cyano, preferably cyano.

[0245] Aspect 13: According to the compound of aspect 10, where R 2 Yes - SO2R 2a .

[0246] Aspect 14: According to the compound of aspect 12, wherein R 2a Selected from -C 1-8 Alkyl group, preferably -C1-6 Alkyl, more preferably methyl.

[0247] Aspect 15: A compound according to any one of Aspects 12-13, wherein R 2 yes

[0248]

[0249] Aspect 16: According to the compound of aspect 10, where R 2 Yes - POR 2a R 2b .

[0250] Aspect 17: According to the compound of aspect 15, wherein R 2a R 2b Selected from -C 1-8 Alkyl group, preferably -C 1-6 Alkyl, more preferably methyl.

[0251] Aspect 18: A compound according to any one of Aspects 15-16, wherein R 2 yes

[0252]

[0253] Aspect 19: According to the compound of aspect 10, where R 2 It is optionally substituent by at least one R 2d Replacement -C 1-8 Alkyl group, preferably -C 1-6 Alkyl, more preferably methyl.

[0254] Aspect 20: According to the compound of aspect 19, wherein R 2d It is selected from halogens, preferably fluorine, chlorine, or bromine, and more preferably fluorine.

[0255] Aspect 21: A compound according to any one of Aspects 19-19, wherein R 2 yes

[0256] Aspect 22: A compound according to any one of Aspects 10-20, wherein R 2 It is H, cyano, Preferred cyano, A more preferred option is cyano.

[0257] Aspect 23: A compound according to any one of Aspects 1-22, wherein R 3 It is hydrogen, -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, wherein the -C1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 The alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups are each optionally substituented by at least one R group. 3d replace;

[0258] Where R 3d It is hydrogen, amino, halogen, -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 Alkyne, cycloalkyl, heterocyclic, aryl, heteroaryl, oxo, -CN, -NO2, -OR 3f -SO2R 3f -SO2NR 3f R 3g -COR 3f -CO2R 3f -CONR 3f R 3g -NR 3f R 3g -NR 3f COR 3g -NR 3f CONR 3g R 3h -NR 3f CO2R 3f -NR 3f SO2NR 3g R 3h , or -NR 3f SO2R 3g The -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 The alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups are each optionally selected from at least one halogen, -C 1-8 Alkyl, -OR 3i , or -NR 3i R 3j Substituents; or

[0259] (R 3f and R 3g ), (R 3g and R 3h These atoms, together with one or more atoms to which they are attached, form 3 to 12-membered rings, the rings containing 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur as one or more ring members, the rings optionally being substituents R. 3k replace;

[0260] R 3f R 3g R3h R 3i R 3j and R 3k Each is independently hydrogen, -C 1-8 Alkyl group, preferably -C 1-6 Alkyl, more preferably methyl or ethyl.

[0261] Aspect 24: According to the compound of aspect 22, where R 3 It is optionally halogenated, -C 1-8 Alkyl, -OR 3f , or -NR 3f R 3g Substituted aryl, wherein R 3f and R 3g Each is independently hydrogen or -C 1-8 Alkyl group, preferably -C 1-6 Alkyl, more preferably methyl or ethyl.

[0262] Aspect 25: According to the compound of aspect 23, wherein the aryl group is phenyl.

[0263] Aspect 26: A compound according to any one of Aspects 23-24, wherein R 3 Selected from

[0264] Aspect 27: According to the compound of aspect 22, where R 3 It is optionally substituent R 3d Substituted heteroaryl groups.

[0265] Aspect 28: According to the compound of aspect 26, said heteroaryl is a 5, 6 or 7-membered heteroaryl containing one, two or three heteroatoms independently selected from oxygen, nitrogen or sulfur.

[0266] Aspect 29: The compound according to aspect 27, wherein the heteroaryl group is pyridyl, pyrroleyl, pyrimidinyl, pyrazolyl, oxazolyl, or triazolyl.

[0267] Aspect 30: According to the compound of aspect 26, the heteroaryl group is an 8- to 12-membered fused heteroaryl group comprising one, two, or three heteroatoms independently selected from oxygen, nitrogen, or sulfur.

[0268] Aspect 31: The compound according to aspect 29, wherein said heteroaryl group is

[0269] Aspect 32: A compound according to any one of Aspects 26-30, wherein R 3d It is hydrogen, halogen, amino, oxo group, -C 1-8 Alkyl, -CONR 3f R 3g-NR 3f COR 3g , where R 3f and R 3g Each is independently hydrogen or -C 1-8 Alkyl group, preferably -C 1-6 Alkyl, more preferably methyl or ethyl; or

[0270] (R 3f and R 3g These, together with one or more atoms to which they are attached, form 3 to 12-membered rings, the rings containing 0, 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen or sulfur as one or more ring members.

[0271] Aspect 33: According to the compound of aspect 31, where R 3d It is -C 1-8 Alkyl group preferred -C 1-6 Alkyl, more preferably methyl or ethyl.

[0272] Aspect 34: According to the compound of aspect 31, wherein R 3d It consists of hydrogen, halogens, and amino groups.

[0273] Aspect 35: According to the compound of aspect 31, wherein R 3d Yes -NR 3f COR 3g Chinese R 3f and R 3g Each is independently hydrogen or -C 1-8 Alkyl group, preferably -C 1-6 Alkyl, more preferably methyl or ethyl.

[0274] Aspect 36: According to the compound of aspect 35, where -NR 3f COR 3g yes

[0275] Aspect 37: According to the compound of aspect 31, wherein R 3d Yes - CONR 3f R 3g Chinese R 3f and R 3g Each is independently hydrogen or -C 1-8 Alkyl group, preferably -C 1-6 Alkyl, more preferably methyl or ethyl.

[0276] Aspect 38: According to the compound of aspect 36, where R 3f and R 3gTogether with one or more atoms to which they are attached, they form 3 to 12-membered rings, preferably 4 to 6-membered rings, which contain 0, 1, 2 or 3 additional heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as one or more ring members.

[0277] Aspect 39: A compound according to any one of Aspects 36-37, wherein -CONR 3f R 3g Selected from

[0278]

[0279] Aspect 40: A compound according to any one of Aspects 26-38, wherein R 3 Selected from

[0280]

[0281] Aspect 41: According to the compound of aspect 22, wherein R 3 It is hydrogen.

[0282] Aspect 42: According to the compound of aspect 22, wherein R 3 It is -C 1-8 Alkyl groups, preferably -C 1-6 Alkyl, more preferably methyl, ethyl, or isopropyl.

[0283] Aspect 43: According to the compound of aspect 22, where R 3 It is a cycloalkyl group, preferably C10. 3-6 Cycloalkyl, more preferably

[0284] Aspect 44: According to the compound of aspect 22, where R 3 It is optionally substituent by at least one R 3d Substituted heterocyclic groups, wherein R 3d It is hydrogen, halogen, amino, oxo group, -C 1-8 Alkyl, -OR 3f -NR 3f R 3g -CONR 3f R 3g -NR 3f COR 3g , where R 3f and R 3g Each is independently hydrogen or -C 1-8 Alkyl group, preferably -C 1-6 Alkyl, more preferably methyl or ethyl.

[0285] Aspect 45: According to the compound of aspect 40, the heterocyclic group is a 4- to 7-membered ring containing one or two heteroatoms independently selected from nitrogen, oxygen or sulfur, preferably a 5, 6, or 7-membered saturated ring containing a nitrogen or oxygen atom as a ring member.

[0286] Aspect 46: The compound according to aspect 44, wherein the heterocyclic group is piperidinyl, tetrahydropyrrolyl, tetrahydropyran, or piperazine.

[0287] Aspect 47: A compound according to any one of Aspects 40-45, wherein R 3d It is hydrogen, halogen, amino, oxo group, -C 1-8 Alkyl, -CONR 3f R 3g -NR 3f COR 3g , where R 3f and R 3g Each is independently hydrogen or -C 1-8 Alkyl group, preferably -C 1-6 Alkyl, more preferably methyl or ethyl.

[0288] Aspect 48: According to the compound of aspect 46, where R 3d It is a hydrogen, oxo group or -C 1-8 Alkyl group, preferably -C 1-6 Alkyl, more preferably methyl or ethyl.

[0289] Aspect 49: A compound according to any one of Aspects 40-47, wherein R 3 Selected from

[0290]

[0291] Aspect 50: A compound according to any one of Aspects 22-48, wherein R 3 Selected from H, methyl, ethyl, isopropyl, H, ethyl, isopropyl, are preferred

[0292] Aspect 51: A compound according to any one of Aspects 1-50, wherein s is 0, 1 or 2, R 5 It is as defined in equation (II).

[0293] Aspect 52: A compound according to any one of Aspects 1-50, wherein R 5 Selected from hydrogen, -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR 5a -SR 5a -SO2R 5a -SO2NR 5a R 5b -COR 5a -CO2R 5a -CONR 5a R 5b -POR 5a R 5b -NR 5a R 5b -NR 5a COR 5b --NR 5a CO2R 5b -NR 5a SO2R 5 The -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 The alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups are each optionally substituented by at least one R group. 5d replace;

[0294] R 5a R 5b Each is independently hydrogen, hydroxyl, and -C. 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 Alkyne, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 The alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups are each optionally substituented by at least one R group. 5e replace;

[0295] R 5d and R 5e Each is independently hydrogen, amino, halogen, -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 Alkyne, cycloalkyl, heterocyclic, aryl, heteroaryl, oxo, -CN, -NO2, -OR 5f -SO2R 5f -SO2NR 5f R 5g -COR 5f -CO2R 5f -CONR 5f R 5g -NR 5f R 5g-NR 5f COR 5g -NR 5f CONR 5g R 5h -NR 5f CO2R 5f -NR 5f SO2NR 5g R 5h , or -NR 5f SO2R 5g The -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl are each optionally surrounded by at least one R 5k Substituent substitution; or

[0296] Each R 5k Independently selected from halogens, -C 1-8 Alkyl, -OR 5i -NR 5i R 5j cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the -C 1-8 Alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally selected from at least one group chosen from hydrogen, -C 1-8 Alkyl, C 1-8 Alkoxy-C 1-8 Alkyl-, -C 2-8 alkenyl, -C 2-8 Substitution with alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups;

[0297] R 5f R 5g R 5h R 5i and R 5j Each is independently hydrogen, -C 1-8 Alkyl, C 1-8 Alkoxy-C 1-8 Alkyl-, -C 2-8 alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl.

[0298] Aspect 53: According to the compound of aspect 52, wherein R 5 It is hydrogen.

[0299] Aspect 54: According to the compound of aspect 52, wherein R 5 It is -C 1-8 Alkyl group, preferably -C 1-6 Alkyl, more preferably methyl or ethyl.

[0300] Aspect 55: According to the compound of aspect 52, wherein R 5 It is optionally substituent by at least one R 5d Replacement -C 1-8 Alkyl (preferably -C) 1-6 Alkyl, more preferably methyl or ethyl), R 5d Independently is -NR 5f R 5g R 5f R 5g Each is independently hydrogen, -C 1-8 alkyl.

[0301] Aspect 56: According to the compound of aspect 55, where R 5 yes

[0302] Aspect 57: According to the compound of aspect 52, wherein R 5 Yes -NR 5a R 5b R 5a R 5b Each is either hydrogen or -C. 1-8 Alkyl (preferably -C) 1-6 Alkyl, more preferably methyl or ethyl), or cycloalkyl (preferably monocyclic-C) 3-8 cycloalkyl, more preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), wherein the -C 1-8 The alkyl and cycloalkyl groups are each optionally substituent R as defined in formula (II). 5e replace.

[0303] Aspect 58: According to the compound of aspect 57, where R 5e It is independently hydrogen, amino, or halogen (preferably fluorine, chlorine, or bromine, more preferably fluorine).

[0304] Aspect 59: A compound according to any one of Aspects 57-58, wherein R 5 yes

[0305] Aspect 60: According to the compound of aspect 52, wherein R 5 It is -SR 5a , where R 5a It is -C 1-8 Alkyl (preferably -C) 1-6 Alkyl (more preferably methyl or ethyl) or cycloalkyl (preferably monocyclic -C) 3-8 cycloalkyl, more preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), wherein the -C 1-8 The alkyl and cycloalkyl groups are each optionally substituent R as defined in formula (II). 5e replace.

[0306] Aspect 61: According to the compound of aspect 60, wherein R 5 yes

[0307]

[0308] Aspect 62: According to the compound of aspect 52, wherein R 5 Yes -NR 5a SO2R 5b , where R 5a and R 5b Each is independently hydrogen or -C 1-8 Alkyl (preferably -C) 1-6 Alkyl (more preferably methyl or ethyl) or cycloalkyl (preferably monocyclic -C) 3-8 cycloalkyl, more preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), wherein the -C 1-8 The alkyl and cycloalkyl groups are each optionally substituent R as defined in formula (II). 5e replace.

[0309] Aspect 63: According to the compound of aspect 99, where R 5 yes

[0310]

[0311] Aspect 64: According to the compound of aspect 52, wherein R 5 Yes - OR 5a R 5a It is -C 1-8 Alkyl (preferably -C) 1-6 Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl, ), the -C 1-8 The alkyl group is optionally substituent for at least one R group. 5e Replace; R 5e It is hydrogen, halogen (preferably fluorine or chlorine, more preferably fluorine), or cycloalkyl (preferably C). 3-6 Cycloalkyl, more preferably C3 cycloalkyl), heterocyclic, aryl, -CONR 5f R 5g -CO2R 5f , or -NR 5f R 5g The cycloalkyl, heterocyclic, and aryl groups are each optionally surrounded by at least one R 5k Substituent substitution;

[0312] R 5k Selected from halogens (preferably fluorine, chlorine, bromine, more preferably fluorine), -C 1-8 Alkyl (preferably -C) 1-6 Alkyl group, more preferably methyl group;

[0313] R 5f R 5g Each is independently hydrogen or -C 1-8 Alkyl (preferably -C) 1-6 Alkyl group, more preferably methyl group.

[0314] Aspect 65: According to the compound of aspect 101, wherein R 5e It is a cycloalkyl group, preferably C10. 3-6 Cycloalkyl, more preferably C3 cycloalkyl.

[0315] Aspect 66: The compound according to aspect 65, wherein the cycloalkyl group is optionally surrounded by at least one R 5k Substituent substitution, R 5k Selected from halogens (preferably fluorine, chlorine, bromine, more preferably fluorine), -C 1-8 Alkyl (preferably -C) 1-6 Alkyl group, more preferably methyl group.

[0316] Aspect 67: According to the compound of aspect 101, wherein R 5e It is a heterocyclic group, which is a 4, 5, 6 or 7-membered heterocyclic group containing one or two or three heteroatoms independently selected from oxygen, nitrogen or sulfur, preferably a 4, 5, 6 or 7-membered saturated ring containing a nitrogen or oxygen atom as a ring member, more preferably a tetrahydropyrrole ring.

[0317] Aspect 68: According to the compounds of aspects 101-104, where R 5 It is methoxy, ethoxy, isopropoxy,

[0318]

[0319] Aspect 69: According to the compound of aspect 52, where R 5 Yes - OR 5a R 5a It is a cycloalkyl group (preferably C14) 3-6 Cycloalkyl (more preferably C3 cycloalkyl), or heterocyclic (preferably tetrahydrofuranyl, azahexacyclobutyl, pyrrolidinyl, piperidinyl), wherein the cycloalkyl or heterocyclic group is optionally substituted with at least one substituent R. 5e Replace; R 5e It is hydrogen, halogen (preferably fluorine or chlorine, more preferably fluorine), cycloalkyl, aryl, -CONR 5f R 5g -CO2R 5f , or -NR 5f R 5g ;R 5f R 5g and R 5h Each is independently hydrogen or -C 1-8 Alkyl (preferably -C)1-6 Alkyl group, more preferably methyl group.

[0320] Aspect 70: According to the compound of aspect 106, wherein R 5 yes

[0321]

[0322] Aspect 71: According to the compound of aspect 52, wherein R 5 It is H, -C 1-8 Alkyl, -OR 5a -NR 5a R 5b -SR 5a -NR 5a SO2R 5b The -C 1-8 Alkyl groups are optionally substituted with at least one substituent R. 5d replace;

[0323] R 5a R 5b Each is either hydrogen or -C. 1-8 Alkyl (preferably -C) 1-6 Alkyl, more preferably methyl, ethyl, isopropyl or n-propyl, ), or cycloalkyl (preferably monocyclic-C 3-8 Cycloalkyl, more preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), or heterocyclic (preferably tetrahydrofuranyl, azahexylbutyl, pyrrolidinyl, piperidinyl), wherein the -C 1-8 Alkyl, cycloalkyl, and heterocyclic groups are each optionally substituented by at least one R group. 5e replace;

[0324] R 5d R 5e Each of these elements is independently hydrogen, halogen (preferably fluorine or chlorine, more preferably fluorine), or cycloalkyl (preferably C). 3-6 Cycloalkyl, more preferably C3 cycloalkyl), heterocyclic, aryl, -CONR 5f R 5g -CO2R 5f , or -NR 5f R 5g The cycloalkyl, heterocyclic, and aryl groups are each optionally surrounded by at least one R 5k Substituent substitution;

[0325] R 5k Selected from halogens (preferably fluorine, chlorine, bromine, more preferably fluorine), -C 1-8 Alkyl (preferably -C) 1-6 Alkyl group, more preferably methyl group;

[0326] R5f R 5g Each is independently hydrogen or -C 1-8 Alkyl (preferably -C) 1-6 Alkyl group, more preferably methyl group.

[0327] Aspect 72: According to the compound of aspect 71, wherein R 5 It is H, -C 1-8 Alkyl, -OR 5a ;

[0328] R 5a It is -C 1-8 Alkyl, cycloalkyl, and the -C 1-8 Alkyl and cycloalkyl groups are each optionally substituented by at least one R group. 5e replace;

[0329] R 5e It is a halogen, a cycloalkyl group, wherein the cycloalkyl group is optionally surrounded by at least one R 5k Substituent substitution;

[0330] R 5k Independently selected from halogens, -C 1-8 alkyl.

[0331] Aspect 73: A compound according to any one of Aspects 52-72, wherein R 5 It is H, methyl, H, methyl, preferred More preferably methyl, Further optimization of methyl groups,

[0332] Aspect 74: A compound according to any one of Aspects 1-107, wherein Cy1 is selected from cycloalkyl, heterocyclic, aryl, or heteroaryl groups, each optionally constituting t R 6 Substitution, t is 0, 1 or 2, and R 6 It is as defined in equation (II).

[0333] Aspect 75: According to the compound of aspect 74, wherein Cy1 is C 3-10 Cycloalkyl, preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, more preferably cyclopropyl.

[0334] Aspect 76: The compound according to aspect 74, wherein Cy1 is a 4, 5, 6, or 7-membered heterocyclic group containing one or two heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur.

[0335] Aspect 77: According to the compound of aspect 76, wherein Cy1 is a monocyclic 4, 5, 6 or 7-membered saturated heterocyclic group containing one or two nitrogen atoms as ring members.

[0336] Aspect 78: A compound according to any one of Aspects 76-77, wherein Cy1 is piperidinyl or piperazine.

[0337] Aspect 79: According to the compound of aspect 76, wherein Cy1 is a monocyclic 4, 5, 6 or 7-membered saturated heterocyclic group containing one or two oxygen atoms as ring members.

[0338] Aspect 80: According to the compound of aspect 79, where Cy1 is

[0339] Aspect 81: According to the compound of aspect 76, wherein Cy1 is a monocyclic 4, 5, 6 or 7-membered saturated heterocyclic group containing a nitrogen atom and an oxygen atom as ring members.

[0340] Aspect 82: According to the compound of aspect 81, where Cy1 is

[0341] Aspect 83: According to aspect 74, the compound wherein Cy1 is a 7- to 12-membered fused heterocyclic group comprising one, two, or three heteroatoms independently selected from oxygen, nitrogen, or sulfur.

[0342] Aspect 84: According to aspect 83, the heterocyclic group is an 8-10 membered spirocyclic heterocyclic group containing 1-2 nitrogen atoms, preferably

[0343] Aspect 85: According to aspect 83, the heterocyclic group is an 8-10 membered bridged heterocyclic group containing 1-2 nitrogen atoms, preferably

[0344] Aspect 86: A compound according to any one of Aspects 74-85, wherein Cy1 is selected from C 3-10 Cycloalkyl, 4, 5, 6, or 7-membered heterocyclic groups comprising one or two heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur, or 7 to 12-membered fused heterocyclic groups comprising one, two, or three heteroatoms independently selected from oxygen, nitrogen, or sulfur;

[0345] Furthermore, Cy1 is a 4-7 member monocyclic heterocyclic group or a 7-9 member fused heterocyclic group containing one or two heteroatoms independently selected from nitrogen and oxygen.

[0346] Aspect 87: A compound according to any one of Aspects 74-84, wherein Cy1 is cyclopropyl, piperidinyl, piperazinyl, Piperidinyl, piperazineyl, More Further optimization

[0347] Aspect 88: A compound according to any one of Aspects 74-87, wherein R 6 Independently selected from hydrogen, halogen, oxo group, -C 1-8 Alkyl, cycloalkyl, heterocyclic, -OR 6a , or -NR 6a R 6b The -C 1-8 Alkyl, cycloalkyl, and heterocyclic groups are each optionally substituent R as defined in formula (II). 6d Replace, where R 6a R 6b As defined in formula (II), hydrogen or -C is preferred. 1-6 Alkyl, more preferably methyl or ethyl.

[0348] Aspect 89: According to the compound of aspect 88, the R... 6d Each is selected from halogens, heterocyclic groups, and -C groups. 1-8 Alkyl, -OR 6f -NR 6f R 6g ,

[0349] Where R 6f and R 6g Each is independently hydrogen or -C 1-8 Alkyl group, preferably -C 1-6 Alkyl, more preferably methyl or ethyl.

[0350] Aspect 90: According to the compound of aspect 88, where R 6 It is hydrogen.

[0351] Aspect 91: According to the compound of aspect 88, where R 6 It is -C 1-8 Alkyl group, preferably -C 1-6 Alkyl, more preferably methyl or ethyl.

[0352] Aspect 92: According to the compound of aspect 88, where R 6 It is optional to be at least one -OR 6f Replacement -C 1-8 Alkyl group, preferably -C 1-6 Alkyl, more preferably methyl or ethyl.

[0353] Aspect 93: According to the compound of aspect 92, wherein R 6f Is it hydrogen or -C? 1-8 Alkyl group, preferably -C 1-6Alkyl, more preferably methyl or ethyl.

[0354] Aspect 94: A compound according to any one of aspects 92-93, wherein R 6 yes

[0355] Aspect 95: According to the compound of aspect 88, where R 6 It is optionally subject to at least one -NR 6f R 6g Replacement -C 1-8 Alkyl group, preferably -C 1-6 Alkyl, more preferably methyl or ethyl.

[0356] Aspect 96: According to the compound of aspect 95, where R 6f and R 6g It is hydrogen or -C independently 1-8 Alkyl group, preferably -C 1-6 Alkyl, more preferably methyl.

[0357] Aspect 97: According to the compound of aspect 88, wherein R 6 -C is optionally substituted with at least one heterocyclic group. 1-8 Alkyl group, preferably -C 1-6 Alkyl, more preferably methyl or ethyl.

[0358] Aspect 98: According to aspect 97, the heterocyclic group is a 4, 5, 6, or 7-membered heterocyclic group containing one or two heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur.

[0359] Aspect 99: A compound according to any one of Aspects 97-98, wherein R 6 yes

[0360]

[0361] Aspect 100: According to the compound of aspect 88, where R 6 It is a cycloalkyl group, preferably C10. 4-6 Cycloalkyl, more preferably C4 cycloalkyl.

[0362] Aspect 101: According to the compound of aspect 88, where R 6 It is a 4, 5, 6, or 7-membered heterocyclic group containing one or two heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur.

[0363] Aspect 102: According to the compound of aspect 101, wherein R 6 yes

[0364] Aspect 103: Compounds of any one of Aspects 74-102, wherein

[0365] R 6 Independently selected from hydrogen, halogen, oxo group, -C 1-8 Alkyl, cycloalkyl, heterocyclic, -OR 6a , or -NR 6a R 6b The -C 1-8 Alkyl, cycloalkyl, and heterocyclic groups are each optionally substituented by at least one R group. 6d replace,

[0366] R 6d Each is selected from halogens, heterocyclic groups, and -C groups. 1-8 Alkyl, -OR 6f -NR 6f R 6g ;

[0367] R 6f and R 6g Each is independently hydrogen or -C 1-8 Alkyl group, preferably -C 1-6 Alkyl, more preferably methyl or ethyl;

[0368] Furthermore,

[0369] R 6 It is H, -C 1-8 Alkyl group, the -C 1-8 Alkyl groups are optionally substituted with at least one substituent R. 6d Replace; R 6d It is a heterocyclic group or a hydroxyl group on its own.

[0370] Aspect 104: A compound according to any one of aspects 88-102, wherein R 6 It is hydrogen, methyl, ethyl, Preferred hydrogen, methyl, ethyl,

[0371] Aspect 105: A compound according to any one of Aspects 74-104, wherein

[0372] The structural part is

[0373] Preferred More Further optimization

[0374] Aspect 106: According to any one of Aspects 1-107, Cy1 is defined as in any one of Aspects 74-105.

[0375] Aspect 107: According to the compound of aspect 106, wherein Cy1 in X 2 In position.

[0376] Aspect 108: According to the compound of aspect 106, wherein Cy1 in X 3 In position.

[0377] Aspect 109: Based on the compound in aspect 107, R 5 As defined in any of aspects 50-107, s is 0, 1, or 2.

[0378] Aspect 110: According to the compound of aspect 109, where s is 1, R 5 In X 1 Or X 3 In position.

[0379] Aspect 111: According to the compound of aspect 109, where s is 2, the first R 5 In X 1 In position, the second R 5 In X 3 In position.

[0380] Aspect 112: Based on the compound in aspect 108, R 5 As defined in any of aspects 52-107, s is 0, 1, or 2.

[0381] Aspect 113: According to the compound of aspect 112, where s is 1, R 5 In X 2 Or X 4 In position.

[0382] Aspect 114: According to the compound of aspect 112, where s is 2, the first R 5 In X 2 In position, the second R 5 In X 4 In position.

[0383] Aspect 115: A compound according to any one of aspects 1-114, wherein:

[0384] R 1 It is H;

[0385] X is NH;

[0386] X 1 X 2 X3 X 4 It is C;

[0387] R 2 It is cyano, Cyano group is preferred;

[0388] R 3 It is H, -C 1-8 Alkyl, cycloalkyl, aryl, and said aryl group optionally substituted with at least one substituent R 3d Replace; and

[0389] R 3d It is -C 1-8 alkyl;

[0390] R 5 It is H, -C 1-8 Alkyl, -OR 5a ;and

[0391] R 5a It is -C 1-8 Alkyl, cycloalkyl, and the -C 1-8 Alkyl and cycloalkyl groups are each optionally substituented by at least one R group. 5e Replace; and

[0392] R 5e It is a halogen, a cycloalkyl group, wherein the cycloalkyl group is optionally surrounded by at least one R 5k Substituent substitution; and

[0393] R 5k Independently selected from halogens, -C 1-8 alkyl;

[0394] s is 0, 1, or 2;

[0395] Cy1 is a heterocyclic group, which is optionally divided by t R groups. 6 replace;

[0396] R 6 It is H, -C 1-8 Alkyl group, the -C 1-8 Alkyl groups are optionally substituted with at least one substituent R. 6d Replace; and

[0397] R 6d Independently, it is a heterocyclic group or a hydroxyl group;

[0398] t is 0, 1, or 2.

[0399] Aspect 116: According to the compound of aspect 115, the R 3 It is H, -C 1-6 Alkyl, C 3-10Cycloalkyl, 6-membered aryl, wherein the 6-membered aryl group is optionally substituted with at least one substituent R. 3d Replace; and R 3d It is -C 1-3 alkyl.

[0400] Aspect 117: According to the compound of aspect 116, the R... 3 It is H, ethyl, isopropyl,

[0401] Aspect 118: According to the compound of aspect 115, the R... 5 It is H, -C 1-6 Alkyl, -OR 5a ;and

[0402] R 5a It is -C 1-6 Alkyl, C 3-10 cycloalkyl, and the -C 1-6 Alkyl, C 3-10 Each cycloalkyl group is optionally substituent for at least one R group. 5e Replace; and

[0403] R 5e It is halogen, C 3-10 cycloalkyl, the C 3-10 cycloalkyl groups are optionally surrounded by at least one R 5k Substituent substitution; and

[0404] R 5k Independently selected from halogens, -C 1-6 alkyl.

[0405] Aspect 119: According to the compound of aspect 118, the R 5 It is H, -C 1-3 Alkyl groups, preferably H-, methyl, Preferred methyl, More preferably methyl,

[0406] Aspect 120: According to the compound of aspect 115, the Cy1 is a 4-7 member monocyclic heterocyclic group or a 7-9 member fused heterocyclic group containing one or two heteroatoms independently selected from nitrogen and oxygen.

[0407] Aspect 121: According to the compound of aspect 120, the Cy1 is Preferred More

[0408] Aspect 122: According to the compound of aspect 115, the R...6 It is H, -C 1-6 Alkyl group, the -C 1-6 Alkyl groups are optionally substituted with at least one substituent R. 6d Replace; and

[0409] R 6d It is either a hydroxyl group or contains one or two 4-6 membered heterocyclic groups independently selected from nitrogen and oxygen;

[0410] Aspect 123: According to the compound of aspect 122, the R... 6 It is H, methyl, ethyl,

[0411] Aspect 124: According to the compound of aspect 115, the... The structure is Preferred More

[0412] Aspect 125: According to any one of aspects 115-119, Cy1 is as defined in any one of aspects 120-124.

[0413] Aspect 126: According to the compound of aspect 125, wherein Cy1 in X 2 In position.

[0414] Aspect 127: According to the compound of aspect 125, wherein Cy1 in X 3 In position.

[0415] Aspect 128: Based on the compound in aspect 126, R 5 As defined in any of Aspects 118-119, s is 0, 1, or 2.

[0416] Aspect 129: According to the compound of aspect 128, where s is 1, R 5 In X 1 Or X 3 In position.

[0417] Aspect 130: According to the compound of aspect 128, where s is 2, the first R 5 In X 1 In position, the second R 5 In X 3 In position.

[0418] Aspect 131: According to the compound in aspect 127, R 5As defined in any of Aspects 118-119, s is 0, 1, or 2.

[0419] Aspect 132: According to the compound of aspect 131, where s is 1, R 5 In X 2 Or X 4 In position.

[0420] Aspect 133: According to the compound of aspect 131, where s is 2, the first R 5 In X 2 In position, the second R 5 In X 4 In position.

[0421] This invention provides the compounds described above, or pharmaceutically acceptable salts thereof, or stereoisomers thereof, or protac intercalations thereof, wherein the compounds are selected from the exemplary compounds disclosed herein, as shown in Table 1 below:

[0422] Table 1:

[0423]

[0424]

[0425]

[0426] The present invention also relates to pharmaceutical compositions comprising any compound of the present invention or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a protac chimera thereof, which may optionally contain one or more pharmaceutical carriers and be formulated into any pharmaceutically acceptable pharmaceutical preparation.

[0427] In one specific embodiment of the present invention, the aforementioned pharmaceutical composition may further comprise one or more second therapeutic agents. The second therapeutic agent may be an antimetabolite, growth factor inhibitor, mitotic inhibitor, antitumor hormone, alkylating agent, metalloid, topoisomerase inhibitor, hormonal drug, immunomodulator, tumor suppressor gene, cancer vaccine, immune checkpoint inhibitor, or antibody or small molecule drug related to tumor immunotherapy.

[0428] The present invention also relates to pharmaceutical formulations comprising any compound of the present invention or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a protac chimeric thereof, and one or more pharmaceutical carriers.

[0429] The pharmaceutical carrier described herein can be one or more solid or liquid fillers or gel substances suitable for human use. The pharmaceutical carrier can be any conventional carrier and / or diluent in the field of pharmaceutical formulations, preferably having sufficient purity and sufficiently low toxicity, and being compatible with the active ingredient of the present invention without significantly reducing the efficacy of the active ingredient. For example, the pharmaceutical carrier can be a filler, binder, disintegrant, lubricant, aqueous solvent, or non-aqueous solvent.

[0430] The pharmaceutical preparations described herein can be formulated into any pharmaceutically acceptable dosage form and administered to patients or subjects requiring this treatment via any suitable route of administration, such as oral, parenteral, rectal, or pulmonary administration. For oral administration, they can be formulated as solid dosage forms, such as capsules, tablets, pills, lozenges, sugar-coated tablets, granules, powders, ointments, creams, and drops; or as liquid dosage forms, such as elixirs, syrups, emulsions, dispersants, suspensions, solutions, and sprays. For parenteral administration, they can be formulated as injections, sterile powders for injection, etc.

[0431] The compounds shown in Formula I and their pharmaceutically acceptable salt stereoisomers and protac chimeric compounds provided by this invention have excellent HPK1 highly selective inhibitory activity and can treat and / or prevent HPK1-mediated diseases and related diseases.

[0432] The present invention provides a method for inhibiting HPK1 activity, the method comprising administering to a subject a compound disclosed herein, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a protac chimera thereof, including compounds of formula (I), compounds of formula (II), or specific compounds illustrated herein.

[0433] The compounds provided by this invention possess excellent HPK1 inhibitory activity, favorable physicochemical properties and pharmaceutical characteristics, and good selectivity. Specifically, they exhibit high selectivity for HPK1 compared to MAP4K2, MAP4K4, MAP4K5, and MAP4K6, for example, selectivity that is 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, or 100 times higher, or compared to MAP4K3, for example, selectivity that is 5, 8, 10, 20, 25, 30, 35, 40, 45, 50, or 100 times higher. The compounds of this invention, or their pharmaceutically acceptable salts, have good safety, efficacy, and bioavailability, thus showing good application potential in the treatment of HPK1-mediated diseases.

[0434] WO2016205942A1 discloses reference compound A. Surprisingly, the compounds of the present invention, which contain pyrrolopyridone, exhibit enhanced HPK1 selectivity.

[0435] The present invention also relates to a method of treating a patient suffering from a disease modulotropic by HPK1, comprising administering to the subject an effective amount of a compound of the present invention (such as a compound of formula (I), a compound of formula (II), or a specific compound illustrated herein) or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a protac chimera thereof.

[0436] The present invention also relates to a method for inhibiting HPK1 activity in patients requiring HPK1 activity inhibition, comprising administering to the patient an effective amount of a compound of the present invention (such as a compound of formula (I), a compound of formula (II), or a specific compound illustrated herein) or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a protac chimera thereof.

[0437] This invention also relates to the use of any compound of the invention or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a protac chimera thereof, in the preparation of a medicament for the treatment or prevention of HPK1-mediated diseases. HPK1 plays a negative feedback regulatory role in T cell-mediated signaling pathways. Therefore, HPK1 inhibitors can be used as immunotherapeutic drugs to treat cancer or non-cancerous proliferative diseases, including but not limited to lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, breast cancer, ductal carcinoma of the breast, head and neck cancer, endometrial cancer, uterine cancer, rectal cancer, liver cancer, kidney cancer, renal pelvis cancer, esophageal cancer, esophageal adenocarcinoma, glioma, prostate cancer, thyroid cancer, female reproductive system cancers, carcinoma in situ, lymphoma, neurofibromatosis, bone cancer, skin cancer, brain cancer, colon cancer, testicular cancer, gastrointestinal stromal tumors, oral cancer, pharyngeal cancer, multiple myeloma, leukemia, non-Hodgkin's lymphoma, choriocarcinoma of the colon, melanoma, cytomas and sarcomas, and myelodysplastic syndrome.

[0438] The present invention also relates to a method of treating a patient with cancer, comprising administering to the patient an effective amount of an HPK1 inhibitor (e.g., a compound of formula (I)) or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a protac chimera thereof, and an effective amount of a second anticancer treatment (e.g., a chemotherapeutic agent, a targeted therapy agent, radiation or surgery).

[0439] The present invention also relates to a method of treating a patient with cancer, comprising administering to the subject an effective amount of an HPK1 inhibitor (e.g., a compound of formula (I)) or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a protac chimera thereof, and an effective amount of an immunomodulator such as a checkpoint inhibitor (e.g., an anti-PD-1 antibody, an anti-CTLA4 antibody, or an anti-PD-L1 antibody) or a tryptophan oxidation inhibitor (e.g., an IDO1, IDO2, or a TDO2 inhibitor).

[0440] This invention further relates to HPK1 inhibitors (e.g., compounds of formula (I), or pharmaceutically acceptable salts thereof, or stereoisomers thereof, or protac chimeric thereof) and PD-1 inhibitors (such as nivolumab, pembrolizumab, pidilizumab, BMS). The use of combinations of 936559, MPDL3280A, MSB0010718C, or MEDI4736 in the preparation of medicaments for the treatment or prevention of HPK1-mediated diseases, including lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, breast cancer, ductal carcinoma of the breast, head and neck cancer, endometrial cancer, uterine cancer, rectal cancer, liver cancer, kidney cancer, renal pelvis cancer, esophageal cancer, esophageal adenocarcinoma, glioma, prostate cancer, thyroid cancer, female reproductive system cancers, carcinoma in situ, lymphoma, neurofibromatosis, bone cancer, skin cancer, brain cancer, colon cancer, testicular cancer, gastrointestinal stromal tumor, oral cancer, pharyngeal cancer, multiple myeloma, leukemia, non-Hodgkin lymphoma, choriocarcinoma of the colon, melanoma, cell tumor and sarcoma, and myelodysplastic syndrome.

[0441] definition

[0442] The compounds described in this invention are named according to their chemical structural formulas. If the name of the compound does not match the chemical structural formula when referring to the same compound, the chemical structural formula shall prevail.

[0443] Unless otherwise stated, the scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. However, for a better understanding of this invention, definitions of some terms are provided below. When the definitions and interpretations of terms provided in this invention differ from the meanings commonly understood by those skilled in the art, the definitions and interpretations provided in this invention shall prevail.

[0444] As used herein (including the appended aspects), unless the context clearly specifies otherwise, singular forms such as “a,” “an,” and “the” include their corresponding plural indicators.

[0445] Unless the context clearly specifies otherwise, the term “or” is used to mean the terms “and / or” and is used interchangeably with them.

[0446] The term "protac chimera" refers to a bifunctional compound formed by combining the compounds of the present invention with E3 ligase ligands, which recruits proteins targeting E3 ubiquitin ligases to degrade the targets targeted by the compounds of the present invention.

[0447] The term "alkyl" refers to a hydrocarbon group selected from straight-chain and branched saturated hydrocarbon groups containing 1 to 18 carbon atoms (such as 1 to 12, further such as 1 to 10, even further such as 1 to 8, or 1 to 6, or 1 to 4). Examples of alkyl groups containing 1 to 6 carbon atoms (i.e., C46, ​​C56, C6 ... 1-6 Alkyl groups include, but are not limited to, methyl, ethyl, 1-propyl or n-propyl (“n-Pr”), 2-propyl or isopropyl (“i-Pr”), 1-butyl or n-butyl (“n-Bu”), 2-methyl-1-propyl or isobutyl (“i-Bu”), 1-methylpropyl or sec-butyl (“s-Bu”), 1,1-dimethylethyl or tert-butyl (“t-Bu”), 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, and 3,3-dimethyl-2-butyl.

[0448] The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).

[0449] The term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by one or more halogen atoms (such as fluorine, chlorine, bromine, and iodine). Examples of haloalkyl groups include halogenated C-type alkyl groups. 1-8 Alkyl, Halogenated C 1-6 Alkyl or halogenated C 1-4 Alkyl groups, but not limited to -CF3, -CH2Cl, -CH2CF3, -CHCl2, CF3, etc.

[0450] The term "alkenyl" refers to a hydrocarbon group selected from straight-chain and branched hydrocarbon groups containing at least one C=C double bond and 2 to 18 (such as 2 to 8, further such as 2 to 6) carbon atoms. Alkenyl (e.g., C...) 2-6Examples of alkenyl groups include, but are not limited to, ethenyl (or vinyl), propenyl, propenyl-2-alkenyl, 2-methylpropenyl, butenyl, butenyl-2-alkenyl, butenyl-3-alkenyl, butenyl-1,3-dienyl, 2-methylbutenyl-1,3-dienyl, hexenyl-1-alkenyl, hexenyl-2-alkenyl, hexenyl-3-alkenyl, hexenyl-4-alkenyl, and hexenyl-1,3-dienyl.

[0451] The term "alkynyl" refers to a hydrocarbon group selected from straight-chain and branched hydrocarbon groups containing at least one C≡C triple bond and 2 to 18 (such as 2 to 8, further such as 2 to 6) carbon atoms. Alynyl (e.g., C≡C triple bond) 2-6 Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl (propynyl), 1-butynyl, 2-butynyl and 3-butynyl.

[0452] The term "alkyloxy" or "alkoxy" refers to an alkyl group as defined above, which is partially attached to the parent molecule via an oxygen atom. Alkyloxy groups (e.g., C16) 1-6 Alkyloxy or C 1-4 Examples of alkyloxy groups include, but are not limited to, methoxy, ethoxy, isopropoxy, propoxy, n-butoxy, tert-butoxy, pentoxy, and hexoxy.

[0453] The term "alkoxy-alkyl-" refers to an alkyl group as defined above, further substituted with an alkoxy group as defined above. Alkoxy-alkyl- (e.g., C10) 1-8 Alkoxy-C 1-8 Examples of alkyl- include, but are not limited to, methoxymethyl, ethoxymethyl, isopropoxymethyl, or propoxymethyl.

[0454] The term "cycloalkyl" refers to a hydrocarbon group selected from saturated cyclic hydrocarbon groups, including monocyclic and polycyclic (e.g., bicyclic and tricyclic) groups, including fused cycloalkyl, bridged cycloalkyl, or spirocycloalkyl.

[0455] For example, a cycloalkyl group may contain 3 to 12 (such as 3 to 10, further such as 3 to 8, further such as 3 to 6, 3 to 5, or 3 to 4) carbon atoms. Even further, for example, the cycloalkyl group may be selected from monocyclic groups containing 3 to 12 (such as 3 to 10, further such as 3 to 8, 3 to 6) carbon atoms. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl. Specifically, saturated monocyclic cycloalkyl groups (e.g., C16, C26, C36, C46, ​​C56, C6 ... 3-8 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In a preferred embodiment, the cycloalkyl group is a monocyclic ring (abbreviated as C10) containing 3 to 6 carbon atoms.3-6 Cycloalkyl groups, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of bicyclic cycloalkyl groups include those having 7 to 12 ring atoms arranged in a fused bicyclic arrangement selected from the [4,4], [4,5], [5,5], [5,6], or [6,6] ring systems, or arranged in a bridging bicyclic arrangement selected from bicyclic [2.2.1]heptane, bicyclic [2.2.2]octane, and bicyclic [3.2.2]nonane. Other examples of bicyclic cycloalkyl groups include those arranged in a bicyclic arrangement selected from the [5,6] and [6,6] ring systems, where wavy lines indicate attachment points. The ring may be saturated or have at least one double bond (i.e., partially unsaturated), but is not fully conjugated and is not aromatic, as aromatic is defined herein.

[0456] The term "spirocycloalkyl" refers to a cyclic structure containing a carbon atom and consisting of at least two rings sharing a common atom. The term "7- to 12-membered spirocycloalkyl" refers to a cyclic structure containing 7 to 12 carbon atoms and consisting of at least two rings sharing a common atom.

[0457] The term "fused cycloalkyl" refers to a fused ring containing carbon atoms and formed by two or more rings sharing two adjacent atoms. The term "4- to 10-membered fused cycloalkyl" refers to a fused ring containing 4 to 10 cyclic carbon atoms and formed by two or more rings sharing two adjacent atoms.

[0458] Examples include, but are not limited to, bicyclo[1.1.0]butyl, bicyclo[2.1.0]pentyl, bicyclo[3.1.0]hexyl, bicyclo[4.1.0]heptyl, bicyclo[3.3.0]octyl, bicyclo[4.2.0]octyl, decahydronaphthalene, and benzo3 to 8-membered cycloalkyl, benzoC 4-6 Cycloalkenyl, 2,3-dihydro-1H-indenyl, 1H-indenyl, 1,2,3,4-tetrazolyl, 1,4-dihydronaphthyl, etc. A preferred embodiment is an 8- to 9-membered fused ring, where the fused ring refers to a cyclic structure containing 8 to 9 ring atoms in the above examples.

[0459] The term "bridged cycloalkyl" refers to a cyclic structure containing carbon atoms and consisting of two rings sharing two non-adjacent atoms. The term "7- to 10-membered bridged cycloalkyl" refers to a cyclic structure containing 7 to 12 carbon atoms and consisting of two rings sharing two non-adjacent atoms.

[0460] The term "cycloalkenyl" refers to a non-aromatic cyclic alkyl group with 3 to 10 carbon atoms, having a monocyclic or polycyclic structure and having at least one double bond, preferably 1 to 2 double bonds. In one embodiment, the cycloalkenyl group is cyclopentenyl (1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl) or cyclohexenyl (1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl), preferably cyclohexenyl.

[0461] The term "cycloalkynyl" refers to a non-aromatic cycloalkyl group with 5 to 10 carbon atoms, which has a monocyclic or polycyclic structure and at least one triple bond.

[0462] The term "aryl" used alone or in combination with other terms refers to a group selected from the following:

[0463] -5- and 6-membered carbon rings, aromatic rings, such as phenyl;

[0464] - Bicyclic ring systems, such as 7- to 12-membered bicyclic ring systems, wherein at least one ring is a carbocyclic ring and is aromatic, such as naphthyl and indanyl; and

[0465] - Tricyclic ring systems, such as 10- to 15-membered tricyclic ring systems, wherein at least one ring is a carbocyclic ring and is aromatic, such as fluorene.

[0466] The terms "aromatic hydrocarbon ring" and "aryl" are used interchangeably throughout the published text herein. In some embodiments, the monocyclic or bicyclic aromatic hydrocarbon ring has 5 to 10 cyclic carbon atoms (i.e., C64, C16, C2 ... 5-10 Aryl). Examples of monocyclic or bicyclic aromatic hydrocarbon rings include, but are not limited to, phenyl, naphth-1-yl, naphth-2-yl, anthraceneyl, phenanthrene, etc. In some embodiments, the aromatic hydrocarbon ring is a naphthyl ring (naphth-1-yl or naphth-2-yl) or a phenyl ring. In some embodiments, the aromatic hydrocarbon ring is a phenyl ring.

[0467] The term "heteroaryl" refers to a group selected from the following:

[0468] - A 5, 6 or 7-membered aromatic monocyclic ring containing at least one heteroatom, for example 1 to 4 heteroatoms, or 1 to 3 heteroatoms in some embodiments, and 1 to 2 heteroatoms in some embodiments, wherein the heteroatoms are selected from nitrogen (N), sulfur (S) and oxygen (O), and the remaining ring atoms are carbon.

[0469] - A 7- to 12-membered bicyclic ring containing at least one heteroatom, for example, 1 to 4 heteroatoms, or in some embodiments 1 to 3 heteroatoms, or in other embodiments 1 or 2 heteroatoms, said heteroatom being selected from N, O, and S, the remaining ring atoms being carbon, and wherein at least one ring is aromatic and at least one heteroatom is present in the aromatic ring; and

[0470] - A tricyclic ring of 11 to 14 members, comprising at least one heteroatom, for example, 1 to 4 heteroatoms, or 1 to 3 heteroatoms in some embodiments, or 1 or 2 heteroatoms in other embodiments, wherein the heteroatom is selected from N, O and S, the remaining ring atoms are carbon, and wherein at least one ring is aromatic and at least one heteroatom is present in the aromatic ring.

[0471] When the total number of S and O atoms in a heteroaryl group exceeds 1, those heteroatoms are not adjacent to each other. In some embodiments, the total number of S and O atoms in the heteroaryl group is no greater than 2. In some embodiments, the total number of S and O atoms in the aromatic heterocycle is no greater than 1. When a heteroaryl group contains more than one heteroatom ring member, the heteroatoms may be the same or different. The nitrogen atom in one or more rings of the heteroaryl group may be oxidized to form an N-oxide. As used herein, the term "C-linked heteroaryl" means that the heteroaryl group is linked to the core molecule by a bond from a C-atom of the heteroaryl ring.

[0472] The terms "ring of aromatic heterocycle" and "heteroaryl" are used interchangeably throughout the disclosed text herein. In some embodiments, the monocyclic or bicyclic aromatic heterocycle has 5, 6, 7, 8, 9, or 10 cyclic members, wherein 1, 2, 3, or 4 heteroatomic ring members are independently selected from nitrogen (N), sulfur (S), and oxygen (O), and the remaining ring members are carbon. In some embodiments, the monocyclic or bicyclic aromatic heterocycle is a monocyclic or bicyclic ring comprising 1 or 2 heteroatomic ring members independently selected from nitrogen (N), sulfur (S), and oxygen (O). In some embodiments, the monocyclic or bicyclic aromatic heterocycle is a 5- to 6-membered heteroaryl ring, which is monocyclic and has 1 or 2 heteroatomic ring members independently selected from nitrogen (N), sulfur (S), and oxygen (O). In some embodiments, the ring of the monocyclic or bicyclic aromatic heterocycle is an 8- to 10-membered heteroaryl ring, which is bicyclic and has one or two heteroatom ring members independently selected from nitrogen, sulfur, and oxygen.

[0473] Examples of heteroaryl or monocyclic or bicyclic aromatic heterocycles include, but are not limited to (as numbered from the linking position specified as priority 1), pyridyl (such as 2-pyridyl, 3-pyridyl or 4-pyridyl), cyclophosphino, pyrazinyl, 2,4-pyrimidinyl, 3,5-pyrimidinyl, 2,4-imidazolyl, imidazopyridyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, thiazolyl, thiadiazolyl (such as 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl or 1,3,4-thiadiazolyl). Tetraazolyl, thiopheneyl (such as thiophene-2-yl, thiophene-3-yl), triazinyl, benzothiopheneyl, furanyl (furyl or furanyl), benzofuranyl, benzimidazolyl, indoleyl, isoydinolyl, indolinyl, oxadiazolyl (such as 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl or 1,3,4-oxadiazolyl), phthalazinyl, pyrazinyl, pyridazinyl, pyrroleyl, triazolyl (such as 1,2,3-triazolyl, 1,2,4-triazolyl or 1,3... ,4-triazolyl), quinolinyl, isoquinolinyl, pyrazolyl, pyrrolopyridyl (such as 1H-pyrrolo[2,3-b]pyridin-5-yl), pyrazolopyridyl (such as 1H-pyrazolo[3,4-b]pyridin-5-yl), benzoxazolyl (such as benzo[d]oxazol-6-yl), pteridinyl, purineyl, 1-oxa-2,3-diazolyl, 1-oxa-2,4-diazolyl, 1-oxa-2,5-diazolyl, 1-oxa-3,4-diazolyl, 1-thiazolyl -2,3-diazolyl, 1-thia-2,4-diazolyl, 1-thia-2,5-diazolyl, 1-thia-3,4-diazolyl, furazanyl (such as furazan-2-yl, furazan-3-yl), benzofurazanyl, benzothiophene, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxolinyl, naphthidyl, furan-pyridyl, benzothiazolyl (such as benzo[d]thiazolyl-6-yl), indazole (such as 1H-indazole-5-yl), and 5,6,7,8-tetrahydroisoquinoline.

[0474] The terms “heterocyclic group,” “heterocyclic,” or “heterocyclic” are interchangeable and refer to a non-aromatic heterocyclic group containing one or more heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, with the remaining ring members being carbon. This includes monocyclic rings, fused rings, bridging rings, and spirocyclic rings; that is, groups containing monocyclic heterocyclic groups, bridging heterocyclic groups, spirocyclic groups, and fused heterocyclic groups. As used herein, the term “optionally oxidized sulfur” refers to S, SO, or SO2.

[0475] The term "monocyclic heterocyclic group" refers to a monocyclic group in which at least one ring member is a heteroatom selected from nitrogen, oxygen, or optionally oxidized sulfur. The heterocycle can be saturated or partially saturated.

[0476] Exemplary monocyclic 4- to 9-membered heterocyclic groups include, but are not limited to (as numbered from the connection position specified as priority 1), pyrrolid-1-yl, pyrrolid-2-yl, pyrrolid-3-yl, imidazolidine-2-yl, imidazolidine-4-yl, pyrrolid-2-yl, pyrrolid-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, 2,5-piperazinyl, pyranyl, morpholinyl, morpholino, morpholin-2-yl, morpholin-3-yl, ethylene oxide, azahexacyclic propane-1-yl, and azahexacyclic. Propane-2-yl, azircyclooctane-1-yl, azircyclooctane-2-yl, azircyclooctane-3-yl, azircyclooctane-4-yl, azircyclooctane-5-yl, thiocyclopropane, azircyclobutane-1-yl, azircyclobutane-2-yl, azircyclobutane-3-yl, oxetane, thiocyclobutane, 1,2-dithiocyclobutane, 1,3-dithiocyclobutane, dihydropyridyl, tetrahydropyridyl, thiomorpholinyl, oxetanethionylhexyl, piperazine, homopiperazine, homopiperidinyl Azaheptan-1-yl, Azaheptan-2-yl, Azaheptan-3-yl, Azaheptan-4-yl, Oxyheptanyl, Thioheptanyl, 1,4-oxathionylhexyl, 1,4-dioxathionylheptanyl, 1,4-oxaazaheptanyl, 1,4-dithionylheptanyl, 1,4-thionylheptanyl and 1,4-diazaheptanyl, 1,4-dithionylhexyl, 1,4-azathionylhexyl, Oxyzonyl , diazaphenyl, thiazaphenyl, dihydrothiophenyl, dihydropyranyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, 1,4-dioxacyclohexyl, 1,3-dioxapentyl, pyrazolinyl, pyrazolylalkyl, dithiaalkyl, dithiacyclopentyl, pyrazolylalkyl, imidazolinyl, pyrimidinoneyl, or 1,1-dioxo-thiomorpholinyl.

[0477] The term "spiroheterocyclic group" refers to a 5- to 20-membered polycyclic heterocyclic group having rings linked by a shared carbon atom (called a spiro atom), comprising one or more heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, with the remaining ring members being carbon. One or more rings of the spiroheterocyclic group may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. Preferably, the spiroheterocyclic group is 6- to 14-membered, and more preferably 7- to 12-membered. Depending on the number of shared spiro atoms, spiroheterocyclic groups are classified as monospirocyclic, dispirocyclic, or polyspirocyclic, and preferably refer to monospirocyclic or dispirocyclic groups, and more preferably 4-membered / 4-membered, 3-membered / 5-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospirocyclic groups. Representative examples of spirochetal groups include, but are not limited to, the following groups: 2,3-dihydrospiro[indene-1,2'-pyrrolidine] (e.g., 2,3-dihydrospiro[indene-1,2'-pyrrolidine]-1'-yl), 1,3-dihydrospiro[indene-2,2'-pyrrolidine] (e.g., 1,3-dihydrospiro[indene-2,2'-pyrrolidine]-1'-yl), azaspiro[2,4]heptane (e.g., 5-azaspiro[2,4]heptane-5-yl), azaspiro[3,4]octane (e.g., 6-azaspiro[3,4]octane-6-yl), 2-oxa-6 -azaspiro[3.4]octane (e.g., 2-oxa-6-azaspiro[3.4]octane-6-yl), azaspiro[3.4]octane (e.g., 6-azaspiro[3.4]oct-6-yl), azaspiro[3.4]octane (e.g., 6-azaspiro[3.4]oct-6-yl), 1,7-dioxaspiro[4.5]decane, 2-oxa-7-azaspiro[4.4]nonane (e.g., 2-oxa-7-azaspiro[4.4]non-7-yl), 7-oxaspiro[3.5]nonyl and 5-oxaspiro[2.4]heptyl.

[0478] The term "fused heterocyclic group" refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms (carbon and carbon or carbon and nitrogen) with another ring, containing one or more heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, with the remaining ring members being carbon. One or more rings of a fused heterocyclic group may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. Preferably, the fused heterocyclic group is 6- to 14-membered, more preferably 7- to 12-membered, and even more preferably 7- to 10-membered. Depending on the number of member rings, fused heterocyclic groups are classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic fused heterocyclic groups, and even more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic groups. Representative examples of fused heterocycles include, but are not limited to, the following groups: octahydrocyclopentadienzo[c]pyrrole (e.g., octahydrocyclopentadienzo[c]pyrrole-2-yl), octahydropyrrolo[3,4-c]pyrroleyl, octahydroisoindolyl, isoindololinyl (e.g., isoindololin-2-yl or isoindololin-5-yl), octahydro-benzo[b][1,4]dioxin, dihydropyridooxazinyl (e.g., 2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazinyl) or dihydrobenzooxazonyl (e.g., 5-oxo-3,4-dihydrobenzo[f][1,4]... [Oxazonyl), benzozazafonyl (e.g., 2,3,4,5-tetrahydro-1-oxo-2-benzozazafon-6-yl), benzooxazonyl (e.g., 5-oxo-2,3,4,5-tetrahydro-1,4-benzooxazon-8-yl), dihydroisoquinolinyl (e.g., 1-oxo-2-methyl-3,4-dihydroisoquinolin-6-yl), tetrahydroisoquinolinyl (e.g., 2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl), dihydrobenzoxazine (e.g., 3,4-dihydro-2H-1,4-benzoxazine-6-yl).

[0479] The term "bridging heterocyclic group" refers to a 5- to 14-membered polycyclic heterocyclic alkyl group in which each pair of rings shares two unconnected atoms, comprising one or more heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, with the remaining ring members being carbon. One or more rings of the bridging heterocyclic group may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. Preferably, the bridging heterocyclic group is 6- to 14-membered, and more preferably 7- to 10-membered. Depending on the number of member rings, bridging heterocyclic groups are classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridging heterocyclic groups, and preferably refer to bicyclic, tricyclic, or tetracyclic bridging heterocyclic groups, and more preferably bicyclic or tricyclic bridging heterocyclic groups. Representative examples of bridging heterocyclic groups include, but are not limited to, the following groups: 2-azabicyclo[2.2.1]heptyl, azabicyclo[3.1.0]hexyl, 2-azabicyclo[2.2.2]octyl, and 2-azabicyclo[3.3.2]decyl.

[0480] The term "alkylene" refers to a divalent alkyl group as defined above, meaning a length of 1 to 18 carbon atoms (C2). 1-18 The alkylene group is a saturated straight-chain or branched divalent hydrocarbon group, wherein the alkylene group may optionally be independently substituted with one or more of the following substituents. In another embodiment, the alkylene group has one to eight carbon atoms (C1 to C2). 1-8 ) or one to six carbon atoms (C 1-6 Examples of alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), etc.

[0481] The term "alkenyl" refers to a divalent alkenyl group as defined above, meaning a length of two to eight carbon atoms (C20-C40). 2-8 ) has at least one unsaturated position, i.e., carbon-carbon sp 2 A divalent hydrocarbon group with a double bond, either straight-chain or branched, wherein the alkenyl group may optionally be independently substituted with one or more substituents described herein and includes groups having "cis" and "trans" orientations or "E" and "Z" orientations. Examples include, but are not limited to, vinylidene (-CH=CH-), allylidene (-CH2CH=CH-), etc.

[0482] The term "hydantoinyl" refers to a divalent ynyl group as defined above, meaning a group with a length of three to eight carbon atoms (C0). 3-8 A divalent hydrocarbon group, either straight-chain or branched, having at least one unsaturated position, i.e., a carbon-carbon sp triple bond, wherein the ynylene group may optionally be independently substituted with one or more substituents described in this application. Examples include, but are not limited to, propynylene (propynylene, -CH2C≡C-), etc.

[0483] The term "cycloalkylene" refers to a divalent cycloalkyl group as defined above. The term "heterocyclic" refers to a divalent heterocyclic group as defined above. The term "aryl" refers to a divalent aryl group as defined above. The term "heteroaryl" refers to a divalent heteroaryl group as defined above.

[0484] The compounds disclosed herein may contain asymmetric centers and therefore may exist as enantiomers. "Enantiomer" refers to two stereoisomers of a compound that are non-overlapping mirror images of each other. Where the compounds disclosed herein have two or more asymmetric centers, they may also exist as diastereomers. Enantiomers and diastereomers belong to a broader class of stereoisomers. This is intended to include all such possible stereoisomers as substantially pure enantiomers, their racemic mixtures, and mixtures of diastereomers. This is intended to include all stereoisomers of the compounds disclosed herein and / or their pharmaceutically acceptable salts. Unless otherwise specifically mentioned, reference to one isomer applies to all possible isomers. Whenever an isomer composition is not specified, all possible isomers are included.

[0485] As used herein, the term "substantially pure" means that the target stereoisomer contains no more than 35% by weight (e.g., no more than 30%, further such as no more than 25%, or even further such as no more than 20%) of any other one or more stereoisomers. In some embodiments, the term "substantially pure" means that the target stereoisomer contains no more than 10% by weight (e.g., no more than 5%, such as no more than 1%) of any other one or more stereoisomers.

[0486] When the compounds disclosed herein contain alkene double bonds, such double bonds are intended to include both E and Z geometric isomers unless otherwise specified.

[0487] When the compounds disclosed herein contain a disubstituted cyclohexyl or cyclobutyl group, the substituents found on the cyclohexyl or cyclobutyl ring can be formed in cis and trans arrangements. Cis formation means that both substituents are found above the two substituent positions on the carbon atom, while trans formation means that they are on opposite sides.

[0488] "Pharmaceutically acceptable salts" are those salts that, within reasonable medical judgment, are suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic reactions, etc., and in proportion to a reasonable benefit / risk ratio. Pharmaceutically acceptable salts may be prepared in situ during the final isolation and purification of the compounds disclosed herein, or by reacting a free base functional group with a suitable organic acid or by reacting an acidic group with a suitable base.

[0489] Furthermore, if the compounds disclosed herein are obtained as acid addition salts, the free base can be obtained by alkalizing the solution of the acid salt. Conversely, if the product is a free base, the addition salt, such as pharmaceutically acceptable addition salts, can be produced by following conventional procedures for preparing acid addition salts from base compounds, by dissolving the free base in a suitable organic solvent and / or water and treating the solution with acid. Those skilled in the art will recognize the various synthetic methods available for preparing non-toxic, pharmaceutically acceptable addition salts without the need for excessive experimentation.

[0490] As defined herein, “pharmaceutically acceptable salts” include salts of at least one compound of formula (I) and salts of stereoisomers of the compound of formula (I), such as enantiomer salts and / or diastereomer salts.

[0491] When applied to animals, humans, experimental subjects, cells, tissues, organs, or biological fluids, the terms "administration," "administering," "treating," and "treatment" mean contact between an exogenous agent, therapeutic agent, diagnostic agent, or composition and the animal, human, subject, cell, tissue, organ, or biological fluid. Treatment of cells encompasses contact between the reagent and the cell, as well as contact between the reagent and a fluid, wherein the fluid contacts the cell. The terms "administration" and "treatment" also mean in vitro and ex vivo treatment of, for example, cells by means of a reagent, diagnostic agent, conjugated compound, or another cell. The term "subject" as used herein includes any organism, preferably an animal, more preferably a mammal (e.g., rat, mouse, dog, cat, and rabbit), and most preferably a human.

[0492] The term "effective amount" or "therapeutic effective amount" refers to an amount of an active ingredient (such as a compound) that, when administered to a subject to treat a disease or at least one clinical symptom of a disease or disorder, is sufficient to affect such treatment of the disease, disorder, or symptom. "Therapeutic effective amount" can vary with: the compound, the disease, disorder, and / or the symptoms of the disease or disorder, the severity of the disease, disorder, and / or the symptoms of the disease or disorder, the age of the subject to be treated, and / or the weight of the subject to be treated. In any given example, the appropriate amount will be clear to those skilled in the art or can be determined by routine experiments. In some embodiments, "therapeutic effective amount" is the amount of at least one compound disclosed herein and / or at least one stereoisomer thereof and / or at least one pharmaceutically acceptable salt thereof that is effective in "treating" (as defined above) a subject's disease or disorder. In the case of combination therapies, "therapeutic effective amount" refers to the total amount of the combination of substances used to effectively treat the disease, disorder, or symptom.

[0493] Pharmaceutical compositions comprising the compounds disclosed herein can be administered to subjects in need via oral, inhalation, rectal, parenteral, or topical administration. For oral administration, the pharmaceutical composition can be a conventional solid formulation such as tablets, powders, granules, capsules, etc., a liquid formulation such as an aqueous or oil suspension, or other liquid formulations such as syrups, solutions, suspensions, etc. For parenteral administration, the pharmaceutical composition can be a solution, aqueous solution, oil suspension concentrate, lyophilized powder, etc. Preferably, the formulation of the pharmaceutical composition is selected from tablets, coated tablets, capsules, suppositories, nasal sprays, or injections, more preferably tablets or capsules. The pharmaceutical composition can be administered as a single unit with a precise dose. Furthermore, the pharmaceutical composition may also contain additional active ingredients.

[0494] All formulations of the pharmaceutical compositions disclosed herein can be produced using conventional methods in the pharmaceutical field. For example, the active ingredient can be mixed with one or more excipients to prepare the desired formulation. "Pharmaceutically acceptable excipients" refer to conventional pharmaceutical carriers suitable for the desired pharmaceutical formulation, such as: diluents, media such as water, various organic solvents, fillers such as starch, sucrose, etc., binders such as cellulose derivatives, alginate, gelatin, and polyvinylpyrrolidone (PVP); wetting agents such as glycerin; disintegrants such as agar, calcium carbonate, and sodium bicarbonate; absorption enhancers such as quaternary ammonium compounds; surfactants such as hexadecyl alcohol; absorption carriers such as kaolin and bentonite; lubricants such as talc, calcium stearate, magnesium stearate, polyethylene glycol, etc. In addition, the pharmaceutical compositions may also contain other pharmaceutically acceptable excipients, such as dispersants, stabilizers, thickeners, complexing agents, buffers, penetration enhancers, polymers, flavorings, sweeteners, and dyes.

[0495] The term “disease” refers to any illness, discomfort, ailment, symptom, or indication and is interchangeable with the terms “symptom” or “disorder”.

[0496] Throughout this specification and in subsequent aspects, unless the context otherwise requires, the term "comprising" and its variations ("comprises" and "comprising") are intended to indicate the presence of the feature that follows, but do not preclude the presence or addition of one or more other features. When used herein, the term "comprising" may be replaced by the terms "containing," "including," or sometimes "having."

[0497] Throughout the specification and in subsequent aspects, the term "C" is used. n-m The indicator includes a range of endpoints, where n and m are integers and indicate the number of carbons. Examples include C. 1-8 C 1-6 wait.

[0498] Unless otherwise expressly defined elsewhere in this document, all other technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art to which this invention pertains. Example

[0499] The present invention will be further described in detail below with reference to specific embodiments, but these embodiments are not intended to limit the scope of the present invention. The following embodiments are used to understand the method and core idea of ​​the present invention. For those skilled in the art, any possible changes or substitutions made without departing from the concept of the present invention are within the protection scope of the present invention. Experimental methods in the embodiments of the present invention that do not specify specific conditions are generally conventional conditions or conditions recommended by the raw material or product manufacturer; reagents that do not specify their source are generally conventional reagents that are commercially available.

[0500] Identification and characterization of compounds

[0501] The examples provide data on the preparation and structural identification of representative compounds represented by formula (I). 1 The 1H NMR spectra were obtained using a Bruker instrument (400 MHz), and chemical shifts are expressed in ppm. Tetramethylsilane internal standard (0.00 ppm) was used. 1 H NMR representation: s = singlet, d = doublet, t = triplet, m = multiplet, br = broadened, dd = doublet of doublet, dt = doublet of triplet. If the coupling constant is provided, the unit is Hz.

[0502] Mass spectrometry is performed using an LC / MS instrument, and the ionization method can be ESI or APCI.

[0503] Thin-layer chromatography (TLC) was performed using Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates.

[0504] The silica gel plates used have a diameter of 0.15mm to 0.2mm, while the thin-layer chromatography (TLC) separation and purification products use a diameter of 0.4mm to 0.5mm. Column chromatography generally uses Yantai Huanghai silica gel with a mesh size of 200-300 mesh as the carrier.

[0505] In the following examples, unless otherwise specified, all temperatures are in Celsius; unless otherwise specified, all starting materials and reagents are commercially available or synthesized according to known methods; commercially available materials and reagents are used directly without further purification; unless otherwise specified, they are purchased from manufacturers including but not limited to Aldrich Chemical Company, ABCR GmbH & Co. KG, Acros Organics, Shanghai Bid Pharmaceutical Technology Co., Ltd., and Shanghai Shaoyuan Reagent Co., Ltd.

[0506] CD3OD: Deuterated methanol.

[0507] CDCl3: Deuterated chloroform.

[0508] DMSO-d6: Deuterated dimethyl sulfoxide.

[0509] T3P: Tripropylphosphoanhydride.

[0510] DPPA: Diphenyl azidophosphate.

[0511] DIEA: N,N-diisopropylethylamine.

[0512] Unless otherwise specified in the examples, the solution in the reaction refers to an aqueous solution.

[0513] The compound is purified using column chromatography and thin-layer chromatography eluent systems selected from: A: petroleum ether and ethyl acetate system; B: dichloromethane and methanol system; C: dichloromethane and ethyl acetate system; D: dichloromethane and ethanol system. The volume ratio of the solvent varies depending on the polarity of the compound. Small amounts of acidic or basic reagents, such as acetic acid or triethylamine, may also be added to adjust the conditions.

[0514] Reference compound A is a compound of WO2016205942A1, prepared according to the method disclosed therein.

[0515]

[0516] Preparation Examples

[0517] Example 1: Preparation of compound C001

[0518]

[0519] Step 1: Preparation of 6-methoxy-5-azaindole-7-carboxaldehyde

[0520] 7-Bromo-6-methoxy-5-azaindole (600 mg, 2.64 mmol) was dissolved in tetrahydrofuran (10 mL). Butyllithium (1.6 M, 5 mL, 8 mmol) was slowly added dropwise to the reaction system at -78 °C, and the mixture was stirred for 0.5 h. Then, N,N-dimethylformamide (0.8 mL, 10 mmol) was added dropwise to the reaction system, and the mixture was stirred for 1 h. After the reaction was completed by TLC monitoring, the mixture was quenched with water, extracted with ethyl acetate (20 mL × 2), and the organic phases were combined. The mixture was washed with saturated brine (10 mL × 2), purified by vacuum distillation, and purified by column chromatography (petroleum ether / ethyl acetate = 4:1) to give 6-methoxy-5-azaindole-7-carboxaldehyde (420 mg, yield 90.3%).

[0521] Step 2: Preparation of 2-(6-methoxy-1H-pyrrolo[3,2-c]pyridin-7-yl)-5-(4-methylpiperazin-1-yl)-1H-benzo[d]imidazolium

[0522] Compound 6-methoxy-5-azaindole-7-carboxaldehyde (360 mg, 2.05 mmol) and 4-(4-methylpiperazin-1-yl)phenyl-1,2-diamine (515 mg, 2.5 mmol) were dissolved in acetic acid (5 mL), and iodine (50 mg, 0.2 mmol) was added. The mixture was stirred openly at room temperature for 20 h. After the reaction was completed by TLC monitoring, the mixture was quenched with ammonia, purified by vacuum distillation and column chromatography (MeOH:DCM = 1:9) to give 2-(6-methoxy-1H-pyrrolo[3,2-c]pyridin-7-yl)-5-(4-methylpiperazin-1-yl)-1H-benzo[d]imidazole (540 mg, yield 72.7%).

[0523] Step 3: Preparation of compound C001

[0524] 2-(6-methoxy-1H-pyrrolo[3,2-c]pyridin-7-yl)-5-(4-methylpiperazin-1-yl)-1H-benzi[d]imidazole (100 mg, 0.28 mmol) was dissolved in 4 M 1,4-dioxane hydrochloric acid solution (4 mL), heated to 90 °C, and stirred for 5 h. After the reaction was completed by TLC monitoring, ammonia was added to quench the reaction, and the mixture was purified by vacuum distillation and column chromatography (MeOH:DCM = 1:9) to give compound C001 (40 mg, yield 41.0%).

[0525] MS m / z (ESI): 349.2 [M+H] + ;

[0526] 1 H NMR (400MHz, DMSO-d6) δ: 12.40 (s, 1H), 12.27 (s, 1H), 11.21 (s, 1H), 8.04 (s, 1H), 7.56 (d, J = 8.7Hz, 1H), 7.31 (d ,J=3.5Hz,1H),7.26(s,1H),6.97(dd,J=8.8,2.3Hz,1H),6.44(d,J=3.4Hz,1H),3.85–3.06(m,8H),2.81(s,3H).

[0527] Example 2: Preparation of compound C002

[0528]

[0529] Step 1: Preparation of 7-bromo-6-methoxy-1H-pyrrolo[3,2-c]pyridine-3-carboxaldehyde

[0530] Phosphorus oxychloride (5.27 g, 34.4 mmol) was dissolved in N,N-dimethylformamide (5 mL) and stirred at 0 °C for 10 min. Then, 7-bromo-6-methoxy-5-azaindole (1.3 g, 5.73 mmol) was dissolved in N,N-dimethylformamide (5 mL) and slowly added dropwise to the reaction system. The reaction was stirred at 0 °C for 3 h. After the reaction was completed by TLC monitoring, the reaction was quenched with saturated sodium carbonate solution, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, and purified by column chromatography (petroleum ether / ethyl acetate = 3:1) to give 7-bromo-6-methoxy-1H-pyrrolo[3,2-c]pyridine-3-carboxaldehyde (436 mg, yield 30.0%).

[0531] Step 2: Preparation of 7-bromo-6-methoxy-1H-pyrrolo[3,2-c]pyridine-3-carboxynitrile

[0532] The compound 7-bromo-6-methoxy-1H-pyrrolo[3,2-c]pyridine-3-carboxaldehyde (436 mg, 1.72 mmol) was dissolved in dimethylformamide (5 mL), and hydroxylamine hydrochloride (257 mg, 3.7 mmol), ethyl acetate solution of 1-propylphosphonic anhydride (2.4 g, 3.7 mmol), and triethylamine (0.51 mL, 3.7 mmol) were added. The mixture was heated to 100 °C and reacted for 2.5 h. After the reaction was completed by TLC monitoring, the mixture was quenched with water, extracted with EA, and the organic phases were combined, washed with saturated brine, and purified by column chromatography (petroleum ether / ethyl acetate = 6:1) under reduced pressure to give 7-bromo-6-methoxy-1H-pyrrolo[3,2-c]pyridine-3-carboxynitrile (430 mg, yield 99.2%).

[0533] Step 3: Preparation of 7-formyl-6-methoxy-1H-pyrrole[3,2-c]pyridine-3-carboxynitrile

[0534] 7-Bromo-6-methoxy-1H-pyrrolo[3,2-c]pyridine-3-carboxylonitrile (430 mg, 1.71 mmol) was dissolved in tetrahydrofuran (10 mL). Butyllithium (3.2 mL, 5.13 mmol) was slowly added dropwise to the reaction system at -78 °C, and the mixture was stirred for 0.5 h. Then, N,N-dimethylformamide (0.53 mL, 6.84 mmol) was added dropwise to the reaction system, and the mixture was stirred for 1 h. After the reaction was completed by TLC monitoring, the mixture was quenched with water, extracted with EA, and the organic phases were combined, washed with saturated brine, and purified by column chromatography (petroleum ether / ethyl acetate = 4:1) under reduced pressure to give 7-formyl-6-methoxy-1H-pyrrolo[3,2-c]pyridine-3-carboxylonitrile (180 mg, yield 52.4%).

[0535] Step 4: Preparation of 6-methoxy-7-(5-(4-methylpiperazin-1-yl)-1H-benzo[d]imidazol-2-yl)-1H-pyrrolo[3,2-c]pyridine-3-carboxynitrile

[0536] Compound 7-formyl-6-methoxy-1H-pyrrolo[3,2-c]pyridine-3-carboxylonitrile (170 mg, 0.84 mmol) and 4-(4-methylpiperazin-1-yl)phenyl-1,2-diamine (260 mg, 1.26 mmol) were dissolved in N,N-dimethylformamide (3 mL) solution, and sodium metabisulfite (240 mg, 1.26 mmol) was added. The mixture was heated to 90 °C and reacted for 16 h. After the reaction was completed by TLC monitoring, the mixture was purified by vacuum distillation and column chromatography (MeOH:DCM = 1:6) to give 6-methoxy-7-(5-(4-methylpiperazin-1-yl)-1H-benzo[d]imidazol-2-yl)-1H-pyrrolo[3,2-c]pyridine-3-carboxylonitrile (140 mg, yield 43.0%).

[0537] Step 5: Preparation of compound C002

[0538] 140 mg (0.36 mmol) of compound 6-methoxy-7-(5-(4-methylpiperazin-1-yl)-1H-benzo[d]imidazol-2-yl)-1H-pyrrolo[3,2-c]pyridine-3-carboxynitrile was dissolved in 8 mL of 4 M 1,4-dioxane hydrochloric acid solution. The mixture was heated to 90 °C and stirred for 4 h. After the reaction was completed by TLC monitoring, the mixture was quenched with ammonia, purified by vacuum distillation and column chromatography (MeOH:DCM = 1:6) to give compound C002 (70 mg, yield 56.6%).

[0539] MS m / z (ESI): 374.2 [M+H] + .

[0540] 1 H NMR (400MHz, DMSO-d6) δ12.78(s,1H),12.39(s,1H),10.87(s,1H),8.20(s,1H),8.19(s,1H),7.57(d,J=8.4 Hz,1H),7.28(s,1H),7.00(dd,J=8.8,2.3Hz,1H),3.70(s,2H),3.50(s,2H),3.27–3.07(m,8H),2.82(s,3H).

[0541] Example 3: Preparation of compound C003

[0542]

[0543] Step 1: Preparation of 3-bromo-2-methoxypyridine-4-amine

[0544] At 0 °C, NBS (14.3 g, 80 mmol) was slowly added to a solution of 2-methoxypyridine-4-amine (10.0 g, 80 mmol) in dichloromethane (500 mL). The ice bath was removed, and the reaction mixture was stirred at room temperature for 2 h. TLC (petroleum ether / ethyl acetate = 3 / 1) showed that the reaction was complete. The reaction mixture was directly concentrated to dryness to obtain a crude product, which was purified by rapid column chromatography (petroleum ether / ethyl acetate = 6:1) to give 3-bromo-2-methoxypyridine-4-amine (16.2 g, yield 94.7%).

[0545] Step 2: Preparation of 3-bromo-5-iodo-2-methoxypyridine-4-amine

[0546] At room temperature, NIS (12.2 g, 54.1 mmol) was added fractionally to a solution of 3-bromo-2-methoxypyridine-4-amine (10.0 g, 49.2 mmol) in acetonitrile (400 mL) and (10 mL). The reaction mixture was stirred at room temperature for 16 h. TLC (petroleum ether / ethyl acetate = 20 / 1) showed that the reaction was complete. The reaction mixture was concentrated, and the residue was dissolved in ethyl acetate (300 mL). The solution was washed with water, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by rapid column chromatography (petroleum ether:ethyl acetate = 20:1) to give 3-bromo-5-iodo-2-methoxypyridine-4-amine (11.8 g, yield 71.4%).

[0547] Step 3: Preparation of 3-bromo-2-methoxy-5-(o-tolylethynyl)pyridine-4-amine

[0548] At room temperature, 3-bromo-5-iodo-2-methoxypyridine-4-amine (5.66 g, 17.22 mmol), triethylamine (9.55 mL, 68.87 mmol), cuprous iodide (0.01 mL, 0.34 mmol), and palladium dichloride (0.27 g, 0.34 mmol) were added to a 10 mL THF solution, purged three times with nitrogen, and then 2-methylphenylacetylene (2.00 g, 17.22 mmol) was added under nitrogen protection. The reaction mixture was stirred at room temperature for 10 h. The reaction was detected by TLC (petroleum ether / ethyl acetate = 20 / 1). The reaction mixture was poured into 100 mL of water and extracted with ethyl acetate. The organic phases were combined. The organic phase was washed with a saturated ammonium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by rapid column chromatography (petroleum ether: ethyl acetate = 7:1) to give 3-bromo-2-methoxy-5-(o-tolylethynyl)pyridine-4-amine (4.82 g, yield 88.28%).

[0549] Step 4: Preparation of 7-bromo-6-methoxy-2-(o-tolyl)-1H-pyrrolo[3,2-c]pyridine

[0550] 3-Bromo-2-methoxy-5-(o-tolylethynyl)pyridine-4-amine (3.80 g, 11.98 mmol) was dissolved in toluene (20 mL), and then indium tribromide (2.12 g, 5.99 mmol) was added. The mixture was purged with nitrogen three times, and the temperature was raised to 125 °C under nitrogen atmosphere. The reaction mixture was stirred at this temperature for 1 h. The reaction was stopped by TLC (petroleum ether / dichloromethane = 1 / 1). The reaction mixture was concentrated to obtain a crude product, which was purified by rapid column chromatography (petroleum ether:dichloromethane = 2:1) to obtain 7-bromo-6-methoxy-2-(o-tolyl)-1H-pyrrolo[3,2-c]pyridine (3.25 g, yield 85.5%).

[0551] Step 5: Preparation of 7-bromo-6-methoxy-2-(o-tolyl)-1H-pyrrolo[3,2-c]pyridine-3-carboxaldehyde

[0552] Phosphorus oxychloride (1.46 g, 9.5 mmol) was dissolved in N,N-dimethylformamide (5 mL) and stirred at 0 °C for 10 min. Then, 7-bromo-6-methoxy-2-(o-tolyl)-1H-pyrrolo[3,2-c]pyridine (1 g, 3.15 mmol) was dissolved in N,N-dimethylformamide (5 mL) and slowly added dropwise to the reaction system. The mixture was then stirred at room temperature for 12 h. After the reaction was completed by TLC monitoring, the reaction was quenched with saturated sodium carbonate solution, extracted with EA, and the organic phases were combined, washed with saturated brine, and purified by column chromatography (EA:PE = 1:3) under reduced pressure to give 7-bromo-6-methoxy-2-(o-tolyl)-1H-pyrrolo[3,2-c]pyridine-3-carboxaldehyde (950 mg, yield 82.7%).

[0553] Step 6: Preparation of 7-bromo-6-methoxy-2-(o-tolyl)-1H-pyrrolo[3,2-c]pyridine-3-carboxylonitrile

[0554] 1.07 g (3.1 mmol) of 7-bromo-6-methoxy-2-(o-tolyl)-1H-pyrrolo[3,2-c]pyridine-3-carboxaldehyde was dissolved in N,N-dimethylformamide (5 mL), and hydroxylamine hydrochloride (431 mg, 6.2 mmol), ethyl acetate solution of 1-propylphosphonic anhydride (3.95 g, 6.2 mmol), and triethylamine (0.86 mL, 6.2 mmol) were added. The mixture was heated to 100 °C and reacted for 12 h. After the reaction was completed by TLC monitoring, the mixture was quenched with water, extracted with EA, and the organic phases were combined, washed with saturated brine, and purified by column chromatography under reduced pressure (EA:PE = 1:4) to give 650 mg (61.3%) of 7-bromo-6-methoxy-2-(o-tolyl)-1H-pyrrolo[3,2-c]pyridine-3-carboxylonitrile.

[0555] Step 7: Preparation of 7-formyl-6-methoxy-2-(o-tolyl)-1H-pyrrolo[3,2-c]pyridine-3-carboxynitrile

[0556] 7-Bromo-6-methoxy-2-(o-tolyl)-1H-pyrrolo[3,2-c]pyridine-3-carboxylonitrile (350 mg, 1.03 mmol) was dissolved in tetrahydrofuran (10 mL). Butyllithium (1.9 mL, 3.09 mmol) was slowly added dropwise to the reaction system at -78 °C, and the mixture was stirred for 0.5 h. Then, N,N-dimethylformamide (0.32 mL, 4.12 mmol) was added dropwise to the reaction system, and the temperature was slowly raised to 0 °C, and the mixture was stirred for 2 h. After the reaction was completed by TLC monitoring, water was added to quench the reaction mixture, followed by extraction with EA. The organic phases were combined, washed with saturated brine, and purified by column chromatography under reduced pressure (EA:PE = 1:3) to give 7-formyl-6-methoxy-2-(o-tolyl)-1H-pyrrolo[3,2-c]pyridine-3-carboxylonitrile (200 mg, yield 66.7%).

[0557] Step 8: Preparation of 6-methoxy-7-(5-(4-methylpiperazin-1-yl)-1H-benzo[d]imidazol-2-yl)-2-(o-tolyl)-1H-pyrrolo[3,2-c]pyridine-3-carboxynitrile

[0558] Compound 7-formyl-6-methoxy-2-(o-tolyl)-1H-pyrrolo[3,2-c]pyridine-3-carboxylonitrile (200 mg, 0.69 mmol) and 4-(4-methylpiperazin-1-yl)phenyl-1,2-diamine (284 mg, 1.38 mmol) were dissolved in N,N-dimethylformamide (5 mL), and sodium metabisulfite (262 mg, 1.38 mmol) was added. The mixture was heated to 90 °C and reacted for 12 h. After the reaction was completed by TLC monitoring, the mixture was purified by column chromatography under reduced pressure (MeOH:DCM = 1:9) to give 6-methoxy-7-(5-(4-methylpiperazin-1-yl)-1H-benzo[d]imidazol-2-yl)-2-(o-tolyl)-1H-pyrrolo[3,2-c]pyridine-3-carboxylonitrile (230 mg, yield 69.8%).

[0559] Step 9: Preparation of compound C003

[0560] 230 mg (0.48 mmol) of compound 6-methoxy-7-(5-(4-methylpiperazin-1-yl)-1H-benzo[d]imidazol-2-yl)-2-(o-tolyl)-1H-pyrrolo[3,2-c]pyridine-3-carboxynitrile (4 mL) was dissolved in ethanol solution, and 6 mL of 4 M 1,4-dioxane hydrochloric acid solution was added. The mixture was heated to 90 °C and stirred for 3 h. After the reaction was completed by TLC monitoring, the mixture was quenched with ammonia, purified by vacuum distillation, and column chromatography (MeOH:DCM = 1:6) to give compound C003 (80 mg, yield 17.2%).

[0561] 1 H NMR (400MHz, DMSO-d6) δ12.82(s,1H),12.39(s,1H),11.18(s,1H),8.24(s,1H),7.66–7.60(m,1H),7.60–7.51(m,2H),7.50(s,1H),7. 43(dd,J=7.4,1.7Hz,1H),7.26(s,1H),6.99(dd,J=8.8,2.3Hz,1H),3.69(s,2H),3.47(s,1H),3.16(s,5H),2.80(s,3H),2.46(s,3H).

[0562] MS m / z(ESI): 464.20 [M+H] + .

[0563] Example 4: Preparation of compound C004

[0564]

[0565] Step 1: 2-Amino-6-bromo-3-nitrophenol

[0566] In a 250 mL round-bottom flask, 2-bromo-5-nitrophenol (5.0 g, 22.9 mmol), 1,1,1-trimethylhydrazine-1-iodide (5.1 g, 25.2 mmol), and dimethyl sulfoxide (100 mL) were added. The mixture was cooled to 0 °C with stirring, and sodium tert-butoxide (6.6 g, 68.7 mmol) was added. The mixture was then brought to room temperature and reacted for 18 hours. The reaction was monitored by LC-MS until completion. The reaction solution was poured into 100 mL of ice water, and the pH was adjusted to 5 with 4 M hydrochloric acid. The mixture was extracted with ethyl acetate, and the combined organic phases were washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and evaporated to dryness to give 2-amino-6-bromo-3-nitrophenol (4.7 g, yield: 88.1%).

[0567] MS m / z(ESI): 233.0 [M+H] + .

[0568] Step 2: 3-Bromo-2-ethoxy-6-nitroaniline

[0569] In a 100 mL round-bottom flask, 2-amino-6-bromo-3-nitrophenol (700 mg, 3.0 mmol), potassium carbonate powder (1.24 g, 9.0 mmol), and acetonitrile (40 mL) were added. Iodoethane (468 mg, 3.3 mmol) was added dropwise to the mixture, and the reaction was carried out at room temperature for 18 hours. The reaction was monitored by LCMS until completion. The reaction solution was poured into 100 mL of water and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and evaporated to dryness to give 3-bromo-2-ethoxy-6-nitroaniline (600 mg, yield: 76.6%).

[0570] Step 3: 2-ethoxy-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-6-nitroaniline

[0571] In a 100 mL round-bottom flask, 3-bromo-2-ethoxy-6-nitroaniline (600 mg, 2.3 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1,2,3,6-tetrahydropyridine (564 mg, 2.53 mmol) were dissolved in 36 mL of 1,4-dioxane, and 4 mL of potassium carbonate (952 mg, 6.9 mmol) solution was added dropwise. The mixture was purged with nitrogen three times, and Pd(dppf)Cl2 (146 mg, 0.2 mmol) was added, followed by another three purgings. The mixture was heated to 90 °C and reacted for 2 hours. The reaction was monitored by LCMS until completion. The reaction solution was poured into water (100 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (DCM:MeOH = 50:1) to obtain 2-ethoxy-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-6-nitroaniline (500 mg, yield: 78.5%).

[0572] MS m / z(ESI): 278.0 [M+H] +

[0573] Step 4: Preparation of 3-ethoxy-4-(1-methylpiperidin-4-yl)phenyl-1,2-diamine

[0574] In a 100 mL round-bottom flask, 2-ethoxy-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-6-nitroaniline (250 mg, 1.0 mmol) was dissolved in 30 mL of ethanol, and PtO2 (25 mg, 0.11 mmol) was added under nitrogen atmosphere. The reaction system was purged with hydrogen three times, and then the reaction was carried out at room temperature for 16 h under hydrogen pressure (15 psi). TLC (dichloromethane / methanol = 10 / 1) showed that the reaction was complete. The reaction solution was filtered through a diatomaceous earth layer and washed with methanol. The filtrate was concentrated to give 200 mg of crude 3-ethoxy-4-(1-methylpiperidin-4-yl)phenyl-1,2-diamine.

[0575] MS m / z (ESI): 250.2 [M+H] +

[0576] Step 5: Preparation of 7-(4-ethoxy)-5-(1-methylpiperidin-4-yl)-1H-benzo[d]imidazol-2-yl)-6-methoxy-1H-pyrrolo[3,2-c]pyridine-3-nitrile

[0577] 7-Formyl-6-methoxy-1H-pyrrolo[3,2-c]pyridine-3-carboxynitrile and 3-(ethoxy)-4-(1-methylpiperidin-4-yl)phenyl-1,2-diamine (371 mg, 1.49 mmol) were dissolved in N,N-dimethylformamide (10 mL), and sodium metabisulfite (564.3 mg, 2.97 mmol) was added. The mixture was heated to 90 °C and reacted for 16 h. After the reaction was completed by TLC monitoring, the mixture was purified by column chromatography under reduced pressure (methanol:dichloromethane = 1:6) to give 7-(4-ethoxy)-5-(1-methylpiperidin-4-yl)-1H-benzo[d]imidazol-2-yl)-6-methoxy-1H-pyrrolo[3,2-c]pyridine-3-nitrile (120 mg, yield 26.6%).

[0578] MS m / z (ESI): 431.2 [M+H] +

[0579] Step 6: Preparation of compound C004

[0580] 7-(4-ethoxy)-5-(1-methylpiperidin-4-yl)-1H-benzo[d]imidazol-2-yl)-6-methoxy-1H-pyrrolo[3,2-c]pyridine-3-onitrile (112 mg, 0.26 mmol) was dissolved in 8 mL of 4 M 1,4-dioxane hydrochloric acid solution, heated to 90 °C, and stirred for 4 h. After the reaction was completed by TLC monitoring, ammonia was added to quench the reaction, and the mixture was distilled under reduced pressure to obtain compound C004 (25.24 mg, yield 23.3%). The preparation and purification conditions were: flow rate 20 mL / min, C18 xbridge column, 10 mmol ammonium bicarbonate system, and acetonitrile gradient of 27-35%. Subsequent similar preparation and purification methods can refer to these conditions.

[0581] MS m / z (ESI): 417.3 [M+H] + ;

[0582] 1 H NMR (400MHz, DMSO-d6) δ12.49(s,1H),11.92-11.23(m,1H),8.26(d,J=11.7Hz,3H),7.37(d,J=8.4Hz,1H),7.04(d,J=8.3Hz,1H),4.63(s,2H),3 .03(s,2H),2.93(d,J=11.5Hz,2H),2.27(d,J=23.0Hz,3H),2.05(d,J=11.8Hz,2H),1.71(dd,J=37.5,11.9Hz,3H),1.37(dt,J=10.8,7.0Hz,3H).

[0583] Example 5: Preparation of compound C005

[0584]

[0585] Step 1: 2-Amino-6-bromo-3-nitrophenol

[0586] In a 250 mL round-bottom flask, 2-bromo-5-nitrophenol (5.0 g, 22.9 mmol), 1,1,1-trimethylhydrazine-1-iodide (5.1 g, 25.2 mmol), and dimethyl sulfoxide (100 mL) were added. The mixture was cooled to 0 °C with stirring, and sodium tert-butoxide (6.6 g, 68.7 mmol) was added. The mixture was then brought to room temperature and reacted for 18 hours. The reaction was monitored by LC-MS until completion. The reaction solution was poured into 100 mL of ice water, and the pH was adjusted to 5 with 4 M hydrochloric acid. The mixture was extracted with ethyl acetate, and the combined organic phases were washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and evaporated to dryness to give 2-amino-6-bromo-3-nitrophenol (4.7 g, 88.1% yield).

[0587] MS m / z(ESI):233.0, 235.0[M+H] + .

[0588] Step 2: 3-Bromo-2-(cyclopropylmethoxy)-6-nitroaniline

[0589] In a 100 mL round-bottom flask, 2-amino-6-bromo-3-nitrophenol (700 mg, 3.0 mmol), potassium carbonate powder (1.24 g, 9.0 mmol), and acetonitrile (40 mL) were added. Bromomethylcyclopropane (446 mg, 3.3 mmol) was then added dropwise. The mixture was heated to 80 °C and reacted for 18 hours. The reaction was monitored by LCMS until completion. The reaction solution was poured into 100 mL of water and extracted with ethyl acetate. The combined organic phases were washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and evaporated to dryness to give 3-bromo-2-(cyclopropylmethoxy)-6-nitroaniline (650 mg, 75.5% yield).

[0590] Step 3: 2-(cyclopropylmethoxy)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-6-nitroaniline

[0591] In a 100 mL round-bottom flask, 3-bromo-2-(cyclopropylmethoxy)-6-nitroaniline (650 mg, 2.3 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1,2,3,6-tetrahydropyridine (564 mg, 2.53 mmol) were dissolved in 36 mL of 1,4-dioxane, and 4 mL of potassium carbonate (952 mg, 6.9 mmol) solution was added dropwise. The mixture was purged with nitrogen three times, and Pd(dppf)Cl2 (146 mg, 0.2 mmol) was added, followed by another three purgings. The mixture was heated to 90 °C and reacted for 2 hours. The reaction was monitored by LCMS until completion. The reaction solution was poured into 100 mL of water and extracted with ethyl acetate. The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (DCM:MeOH = 50:1) to obtain 2-(cyclopropylmethoxy)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-6-nitroaniline (500 mg, yield 72%).

[0592] MS m / z(ESI): 304.0 [M+H] +

[0593] Step 4: Preparation of 3-(cyclopropylmethoxy)-4-(1-methylpiperidin-4-yl)phenyl-1,2-diamine

[0594] In a 100 mL round-bottom flask, 2-(cyclopropylmethoxy)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-6-nitroaniline (250 mg, 0.83 mmol) was dissolved in methanol (30 mL), and PtO2 (25 mg, 0.11 mmol) was added under nitrogen atmosphere. The reaction system was purged with hydrogen three times, and then the reaction was carried out at room temperature for 16 h under hydrogen pressure (15 psi). TLC (dichloromethane / methanol = 10 / 1) showed that the reaction was complete. The reaction solution was filtered through a diatomaceous earth layer and washed with methanol. The filtrate was concentrated to give 3-(cyclopropylmethoxy)-4-(1-methylpiperidin-4-yl)phenyl-1,2-diamine (200 mg, yield 87.6%).

[0595] MS m / z(ESI): 276.0 [M+H] +

[0596] Step 5: Preparation of 7-(4-(cyclopropylmethoxy)-5-(1-methylpiperidin-4-yl)-1H-benzo[d]imidazol-2-yl)-6-methoxy-1H-pyrrolo[3,2-c]pyridine-3-nitrile

[0597] 7-Formyl-6-methoxy-1H-pyrrolo[3,2-c]pyridine-3-carboxylonitrile (200 mg, 0.99 mmol) and 3-(cyclopropylmethoxy)-4-(1-methylpiperidin-4-yl)phenyl-1,2-diamine (403 mg, 1.49 mmol) were dissolved in N,N-dimethylformamide (10 mL), and sodium metabisulfite (564.3 mg, 2.97 mmol) was added. The mixture was heated to 90 °C and reacted for 16 h. After the reaction was completed by TLC monitoring, the mixture was purified by column chromatography under reduced pressure (MeOH:DCM = 1:6) to give 7-(4-(cyclopropylmethoxy)-5-(1-methylpiperidin-4-yl)-1H-benzo[d]imidazol-2-yl)-6-methoxy-1H-pyrrolo[3,2-c]pyridine-3-carboxylonitrile (120 mg, yield 26.6%).

[0598] MS m / z(ESI): 457.0 [M+H] +

[0599] Step 6: Preparation of compound C005

[0600] 7-(4-(cyclopropylmethoxy)-5-(1-methylpiperidin-4-yl)-1H-benzo[d]imidazol-2-yl)-6-methoxy-1H-pyrrolo[3,2-c]pyridine-3-onitrile (120 mg, 0.26 mmol) was dissolved in 8 mL of 4 M 1,4-dioxane hydrochloric acid solution, heated to 90 °C, and stirred for 4 h. After the reaction was completed by TLC monitoring, ammonia was added to quench the reaction, and the mixture was distilled under reduced pressure to obtain compound C005 (13.58 mg, yield 11.9%).

[0601] 1 H NMR(400MHz,DMSO-d6)δ12.47(s,1H),11.53(s,1H),8.32–8.18(m,3H),7.36(s,1H),7.04(s,1H),4.45 (s,2H),3.00(d,J=10.3Hz,4H),2.31(s,3H),1.80–1.64(m,4H),1.25(s,1H),0.54(s,1H),0.32(s,2H).

[0602] MS m / z (ESI): 443.2 [M+H] +

[0603] Example 6: Preparation of compound C006

[0604]

[0605] Step 1: 3-Bromo-2-(2,2-difluoroethoxy)-6-nitroaniline

[0606] In a 100 mL round-bottom flask at room temperature, 2-amino-6-bromo-3-nitrophenol (50 mg, 0.21 mmol) was dissolved in anhydrous acetonitrile (30 mL), followed by the addition of 1,1-difluoro-2-iodoethane (82 mg, 0.42 mmol) and K₂CO₃ (86.9 mg, 0.63 mmol). The reaction was monitored by TLC (petroleum ether:ethyl acetate = 5:1) to indicate completion, and the reaction mixture was quenched in water (60 mL). The mixture was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to give 3-bromo-2-(2,2-difluoroethoxy)-6-nitroaniline (55 mg, yield 88.1%).

[0607] MS m / z (ESI): 314.1 [M+H] +

[0608] Step 2: Preparation of 2-(2,2-difluoroethoxy)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-6-nitroaniline

[0609] In a 250 mL round-bottom flask, 3-bromo-2-(2,2-difluoroethoxy)-6-nitroaniline (50 mg, 0.17 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1,2,3,6-tetrahydropyridine (56 mg, 0.255 mmol) were dissolved in 1,4-dioxane (9 mL) and H₂O (1 mL). Under nitrogen protection, Pd(dppf)Cl₂ (12 mg, 0.17 mmol) and K₂CO₃ (70 mg, 0.51 mmol) were added, respectively. The mixture was then heated to 90 °C and reacted for 2 hours to obtain a black suspension. The reaction was monitored by TLC until completion. The reaction solution was then poured into water (20 mL) and extracted with ethyl acetate. The organic phases were combined. The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated by filtration to obtain the crude product. The crude product was subjected to column chromatography (petroleum ether: ethyl acetate = 10:1) to give 2-(2,2-difluoroethoxy)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-6-nitroaniline (40 mg, yield 76.4%).

[0610] MS m / z (ESI): 314.1 [M+H] +

[0611] Step 3: Preparation of 3-(2,2-difluoroethoxy)-4-(1-methylpiperidin-4-yl)phenyl-1,2-diamine

[0612] In a 100 mL round-bottom flask, 2-(2,2-difluoroethoxy)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-6-nitroaniline (230 mg, 0.73 mmol) was dissolved in 30 mL of ethanol, and PtO2 (25 mg, 0.11 mmol) was added under nitrogen atmosphere. The reaction system was purged with hydrogen three times, and then the reaction was carried out at room temperature for 16 h under hydrogen pressure (15 psi). TLC (dichloromethane / methanol = 10 / 1) showed that the reaction was complete. The reaction solution was filtered through a diatomaceous earth layer and washed with methanol. The filtrate was concentrated to give 3-(2,2-difluoroethoxy)-4-(1-methylpiperidin-4-yl)phenyl-1,2-diamine (200 mg, 96.1% yield).

[0613] MS m / z(ESI): 286.2 [M+H] +

[0614] Step 4: Preparation of 7-(4-(2,2-difluoroethoxy)-5-(1-methylpiperidin-4-yl)-1H-benzo[d]imidazol-2-yl)-6-methoxy-1H-pyrrolo[3,2-c]pyridine-3-carboxynitrile

[0615] 3-(2,2-difluoroethoxy)-4-(1-methylpiperidin-4-yl)phenyl-1,2-diamine (50 mg, 0.16 mmol) and 7-formyl-6-methoxy-1H-pyrrolo[3,2-c]pyridine-3-carboxynitrile (65 mg, 0.24 mmol) were dissolved in N,N-dimethylformamide (5 mL), and sodium metabisulfite (91.2 mg, 0.48 mmol) was added. The mixture was heated to 90 °C and reacted for 16 h. After the reaction was completed by TLC monitoring, the mixture was purified by column chromatography (MeOH:DCM = 1:6) under reduced pressure to give 7-(4-(2,2-difluoroethoxy)-5-(1-methylpiperidin-4-yl)-1H-benzo[d]imidazol-2-yl)-6-methoxy-1H-pyrrolo[3,2-c]pyridine-3-carboxynitrile (60 mg, yield 80.0%).

[0616] LCMS m / z(ESI): 467.1 [M+H] +

[0617] Step 5: Preparation of compound C006

[0618] 7-(4-(2,2-difluoroethoxy)-5-(1-methylpiperidin-4-yl)-1H-benzo[d]imidazol-2-yl)-6-methoxy-1H-pyrrolo[3,2-c]pyridine-3-carboxynitrile (250 mg, 0.53 mmol) was dissolved in 10 mL of 4 M 1,4-dioxane hydrochloric acid solution, heated to 90 °C, and stirred for 2 h. After the reaction was completed by TLC monitoring, ammonia was added to quench the reaction, and the mixture was distilled under reduced pressure to obtain compound C006 (26.38 mg, yield 11%).

[0619] 1 H NMR (400MHz, DMSO-d6) δ12.59(s,1H),11.96–11.20(m,1H),8.34–8.10(m,3H),7.42(d,J=8.3Hz,1H),7.06(d,J=8.4Hz,1H),6.63–6.13 (m,1H),4.91(s,2H),3.11(t,J=11.2Hz,1H),2.92(d,J=10.9Hz,2H),2.24(s,3H),2.04(t,J=9.9Hz,2H),1.73(dd,J=22.3,10.1Hz,4H).

[0620] MS m / z (ESI): 453.4 [M+H] +

[0621] Example 7: Preparation of compound C010

[0622]

[0623] Step 1: Preparation of 3-bromo-2-methoxy-6-nitroaniline

[0624] K₂CO₃ (1.78 mg, 12.87 mol) and iodomethane (710 mg, 5 mmol) were added to a solution of 2-amino-6-bromo-3-nitrophenol (1 g, 4.29 mmol) in anhydrous acetonitrile (30 mL). The mixture was stirred at 80 °C for 16 h, and the reaction was monitored by TLC until completion. The reaction mixture was poured into water (60 mL), extracted with ethyl acetate, and the organic phases were combined. The organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was then subjected to silica gel column chromatography (PE:E). A =10:1) Purification yielded 3-bromo-2-methoxy-6-nitroaniline (800 mg, yield 75%).

[0625] MS m / z(ESI): 247.0 [M+H] +

[0626] Step 2: Preparation of 2-methoxy-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-6-nitroaniline

[0627] 3-Bromo-2-methoxy-6-nitroaniline (800 mg, 3.24 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1,2,3,6-tetrahydropyridine (867 mg, 3.89 mmol) were dissolved in 1,4-dioxane (27 mL) and H₂O (4 mL). Then, under nitrogen protection, Pd(dppf)Cl₂ (234 mg, 0.32 mmol) and K₂CO₃ (1.34 g, 9.72 mmol) were added to the mixture. After the addition was complete, the reaction mixture was heated to 90 °C and stirred for 2 h. The reaction was monitored by TLC until complete. The reaction mixture was poured into water (20 mL), extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was then subjected to column chromatography (PE:E) A =10:1) Purification yielded 2-methoxy-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-6-nitroaniline (500 mg, yield 59%).

[0628] MS m / z(ESI): 264.0 [M+H] +

[0629] Step 3: Preparation of 3-methoxy-4-(1-methylpiperidin-4-yl)phenyl-1,2-diamine

[0630] 2-Methoxy-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-6-nitroaniline (500 mg, 1.9 mmol) was dissolved in ethanol (30 mL), and PtO2 (250 mg, 1.1 mmol) was added under nitrogen protection. The reaction system was purged with hydrogen three times, and then stirred at room temperature for 16 h under hydrogen pressure (15 psi). The reaction was monitored by TLC until completion. The reaction solution was filtered through diatomaceous earth, the filter residue was washed with methanol, and the filtrate was collected. The filtrate was concentrated under reduced pressure to give 3-methoxy-4-(1-methylpiperidin-4-yl)phenyl-1,2-diamine (400 mg, yield 89.6%), a brown solid.

[0631] MS m / z(ESI): 236.0 [M+H] +

[0632] Step 4: Preparation of 6-methoxy-7-(4-methoxy-5-(1-methylpiperidin-4-yl)-1Hbenzo[d]imidazol-2-yl)-1Hpyrrolo[3,2-c]pyridine-3-carbamate

[0633] 3-Methoxy-4-(1-methylpiperidin-4-yl)phenyl-1,2-diamine (400 mg, 1.70 mmol) and 7-formyl-6-methoxy-1H-pyrrolo[3,2-c]pyridine-3-carboxynitrile (510 mg, 2.55 mmol) were dissolved in N,N-dimethylformamide (5 mL), and sodium metabisulfite (1.29 g, 6.8 mmol) was added. The mixture was heated to 90 °C and stirred for 16 h. After the reaction was completed by TLC monitoring, the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (MeOH:DCM = 1:6) to give 6-methoxy-7-(4-methoxy-5-(1-methylpiperidin-4-yl)-1Hbenzo[d]imidazol-2-yl)-1Hpyrrolo[3,2-c]pyridine-3-carboxynitrile (300 mg, yield 41.2%), a yellow solid.

[0634] MS m / z(ESI): 417.0 [M+H] +

[0635] Step 5: Preparation of compound C010

[0636] 6-Methoxy-7-(4-methoxy-5-(1-methylpiperidin-4-yl)-1Hbenzo[d]imidazol-2-yl)-1Hpyrrolo[3,2-c]pyridine-3-carbamate (100 mg, 0.239 mmol) was dissolved in 10 mL of 4 M 1,4-dioxane hydrochloric acid solution, heated to 90 °C, and stirred for 2 h. The reaction was monitored by TLC until completion, quenched with ammonia, concentrated under reduced pressure, and the residue was purified by HPLC to obtain compound C010 (11.3 mg, yield 11.7%).

[0637] MS m / z (ESI): 403.1 [M+H] +

[0638] 1 H NMR (400MHz, DMSO-d6) δ12.48(s,1H),8.29-8.22(m,3H),7.38(d,J=8.2Hz,1H),7.04(d,J=8.3 Hz, 1H), 4.28 (s, 3H), 3.00-2.90 (m, 4H), 2.24 (s, 3H), 2.08 (t, J = 11.3Hz, 2H), 1.80-1.6 (m, 4H).

[0639] Example 8: Preparation of compound C011

[0640]

[0641] Step 1: Preparation of 3-bromo-2-(difluoromethoxy)-6-nitroaniline

[0642] At room temperature, 2-amino-6-bromo-3-nitrophenol (500 mg, 2.15 mmol) was dissolved in anhydrous DMF (10 mL), followed by the addition of sodium difluorochloroacetate (650 mg, 4.3 mmol) and sodium carbonate (275 mg, 2.58 mmol). The mixture was heated and stirred for 16 hours. TLC monitoring (petroleum ether:ethyl acetate = 5:1) indicated the end of the reaction, and the reaction solution was quenched in water (60 mL). The mixture was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to give 3-bromo-2-(difluoromethoxy)-6-nitroaniline (450 mg, yield 75.8%).

[0643] MS m / z(ESI): 283.0 [M+H] +

[0644] Step 2: Preparation of 2-(difluoromethoxy)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-6-nitroaniline

[0645] 3-Bromo-2-(difluoromethoxy)-6-nitroaniline (360 mg, 1.3 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1,2,3,6-tetrahydropyridine (423.7 mg, 1.9 mmol) were dissolved in 1,4-dioxane (18 mL) and H₂O (2 mL). Under nitrogen protection, Pd(dppf)Cl₂ (95 mg, 0.13 mmol) and K₂CO₃ (538 mg, 3.9 mmol) were added, respectively. The mixture was then heated to 90 °C and reacted for 2 h to obtain a black suspension. The reaction was monitored by TLC until completion. The reaction solution was then poured into water (40 mL) and extracted with ethyl acetate. The organic phases were combined. The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated by filtration to obtain the crude product. The crude product was subjected to column chromatography (petroleum ether: ethyl acetate = 10:1) to give 2-(difluoromethoxy)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-6-nitroaniline (320 mg, yield 84.5%).

[0646] MS m / z(ESI): 300.1 [M+H] +

[0647] Step 3: Preparation of 3-(difluoromethoxy)-4-(1-methylpiperidin-4-yl)phenyl-1,2-diamine

[0648] 2-(difluoromethoxy)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-6-nitroaniline (300 mg, 1.0 mmol) was dissolved in ethanol (30 mL), and PtO2 (30 mg, 0.13 mmol) was added under nitrogen atmosphere. The reaction system was purged with hydrogen three times, and then reacted at room temperature for 16 h under hydrogen pressure (15 psi). TLC (dichloromethane / methanol = 10 / 1) showed that the reaction was complete. The reaction solution was filtered through a diatomaceous earth layer and washed with methanol. The filtrate was concentrated to give 3-(difluoromethoxy)-4-(1-methylpiperidin-4-yl)phenyl-1,2-diamine (260 mg), and the crude product was used directly in the next step.

[0649] MS m / z(ESI): 272.1 [M+H] +

[0650] Step 4: Preparation of 7-(4-(difluoromethoxy)-5-(1-methylpiperidin-4-yl)-1Hbenzi[d]imidazol-2-yl)-6-methoxy-1H-pyrrolo[3,2-c]pyridine-3-carbamate

[0651] 7-Formyl-6-methoxy-1H-pyrrolo[3,2-c]pyridine-3-carboxylonitrile (114 mg, 0.57 mmol) and 3-(difluoromethoxy)-4-(1-methylpiperidin-4-yl)phenyl-1,2-diamine (150 mg, 0.57 mmol) were dissolved in N,N-dimethylformamide (10 mL), and sodium metabisulfite (433 mg, 2.28 mmol) was added. The mixture was heated to 90 °C and reacted for 16 h. After the reaction was completed by TLC monitoring, the mixture was purified by column chromatography under reduced pressure (MeOH:DCM = 1:6) to give 7-(4-(difluoromethoxy)-5-(1-methylpiperidin-4-yl)-1Hbenzo[d]imidazol-2-yl)-6-methoxy-1H-pyrrolo[3,2-c]pyridine-3-carboxylonitrile (130 mg, 51.3% yield).

[0652] MS m / z (ESI): 453.1 [M+H] +

[0653] Step 5: Preparation of compound C011

[0654] 7-(4-(difluoromethoxy)-5-(1-methylpiperidin-4-yl)-1Hbenzi[d]imidazol-2-yl)-6-methoxy-1H-pyrrolo[3,2-c]pyridine-3-carbamate (150 mg, 0.33 mmol) was dissolved in 8 mL of 4 M 1,4-dioxane hydrochloric acid solution, heated to 90 °C, and stirred for 4 h. After the reaction was completed by TLC monitoring, ammonia was added to quench the reaction, and the mixture was distilled under reduced pressure to prepare and purified compound C011 (21.13 mg, yield 14.8%).

[0655] MS m / z(ESI): 439.1 [M+H] +

[0656] 1 H NMR (400MHz, DMSO-d6) δ12.71(s,1H),8.61–8.27(m,4H),7.92(d,J=71.5Hz,1H),7.58(d,J=8.3Hz,1H),7.16(d,J=8.4Hz,1H),3.03( d,J=11.8Hz,1H),2.94(d,J=10.6Hz,2H),2.25(s,3H),2.08(t,J=10.9Hz,2H),1.79(dd,J=21.8,12.1Hz,2H),1.69(d,J=10.8Hz,2H).

[0657] Example 9: Preparation of compound C013

[0658]

[0659] Step 1: Preparation of 3-bromo-6-nitro-2-(2,2,2-trifluoroethoxy)aniline

[0660] 2-Amino-6-bromo-3-nitrophenol (800 mg, 3.44 mmol) was dissolved in anhydrous acetonitrile (30 mL), followed by the addition of 2,2,2-trifluoroethyltrifluoromethanesulfonate (968 mg, 4.16 mmol) and K₂CO₃ (950.88 mg, 6.88 mmol). The reaction was monitored by TLC (petroleum ether:ethyl acetate = 5:1) until completion, at which point the reaction solution was quenched in water (60 mL). The mixture was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was then subjected to column chromatography (PE:E)... A =10:1) Purification yielded 3-bromo-6-nitro-2-(2,2,2-trifluoroethoxy)aniline (800 mg, yield 73.8%).

[0661] MS m / z (ESI): 315.1 [M+H] +

[0662] Step 2: Preparation of 3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-6-nitro-2-(2,2,2-trifluoroethoxy)aniline

[0663] 3-Bromo-6-nitro-2-(2,2,2-trifluoroethoxy)aniline (100 mg, 0.32 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)-1,2,3,6-tetrahydropyridine (107.10 mg, 0.48 mmol) were dissolved in 1,4-dioxane (18 mL) and H₂O (2 mL). Under nitrogen protection, Pd(dppf)Cl₂ (4.4 mg, 0.032 mmol) and K₂CO₃ (836.68 mg, 0.96 mmol) were added, respectively. The mixture was then heated to 90 °C and reacted for 2 hours to obtain a black suspension. The reaction was monitored by TLC until completion. The reaction solution was then poured into water (40 mL) and extracted with ethyl acetate. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was subjected to column chromatography (PE:E) A =10:1) to obtain 3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-6-nitro-2-(2,2,2-trifluoroethoxy)aniline (320 mg, yield 84.5%).

[0664] MS m / z(ESI): 332.1 [M+H] +

[0665] Step 3: Preparation of 4-(1-methylpiperidin-4-yl)-3-(2,2,2-trifluoroethoxy)phenyl-1,2-diamine

[0666] 3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-6-nitro-2-(2,2,2-trifluoroethoxy)aniline (150 mg, 0.45 mmol) was dissolved in ethanol (30 mL), and PtO2 (204 mg, 0.9 mmol) was added under nitrogen atmosphere. The reaction system was purged with hydrogen three times, and then the reaction was carried out at room temperature for 16 h under hydrogen pressure (15 psi). TLC (dichloromethane / methanol = 10 / 1) showed that the reaction was complete. The reaction solution was filtered through a diatomaceous earth layer and washed with methanol. The filtrate was concentrated to give 4-(1-methylpiperidin-4-yl)-3-(2,2,2-trifluoroethoxy)benzene-1,2-diamine (90 mg, crude product), a brown solid.

[0667] MS m / z(ESI): 305 [M+H] +

[0668] Step 4: Preparation of 6-methoxy-7-(5-(1-methylpiperidin-4-yl)-4-(2,2,2-trifluoroethoxy)-1H-benzo[d]imidazol-2-yl)-1H-pyrrolo[3,2-c]pyridine-3-carbamate

[0669] 4-(1-methylpiperidin-4-yl)-3-(2,2,2-trifluoroethoxy)benzene-1,2-diamine (50 mg, 0.16 mmol) and 7-formyl-6-methoxy-1H-pyrrolo[3,2-c]pyridine-3-carbamate (38.63 mg, 0.192 mmol) were dissolved in N,N-dimethylformamide (10 mL) solution, sodium metabisulfite (91.24 mg, 0.48 mmol) was added, and the mixture was heated to 90 °C and reacted for 16 h. After the reaction was completed by TLC monitoring, the mixture was purified by vacuum distillation and column chromatography (MeOH:DCM = 1:6) to give 6-methoxy-7-(5-(1-methylpiperidin-4-yl)-4-(2,2,2-trifluoroethoxy)-1H-benzo[d]imidazol-2-yl)-1H-pyrrolo[3,2-c]pyridine-3-carbamate (67 mg, yield 86.4%).

[0670] MS m / z (ESI): 485.1 [M+H] +

[0671] Step 5: Preparation of compound C013

[0672] 150 mg (0.31 mmol) of 6-methoxy-7-(5-(1-methylpiperidin-4-yl)-4-(2,2,2-trifluoroethoxy)-1H-benzo[d]imidazol-2-yl)-1H-pyrrolo[3,2-c]pyridine-3-carbamate was dissolved in 8 mL of 4 M 1,4-dioxane hydrochloric acid solution. The mixture was heated to 90 °C and stirred for 4 h. After the reaction was completed by TLC monitoring, the mixture was quenched with ammonia and distilled under reduced pressure to obtain compound C013 (56.84 mg, yield 40.3%).

[0673] MS m / z(ESI): 4711 [M+H] +

[0674] 1 H NMR (400MHz, DMSO-d6) δ12.47(s,1H),11.53(s,1H),8.23(d,J=20.0Hz,3H),7.35(s,1H),7.05(s,1H),4 .60(s,2H),3.09(s,1H),2.97(d,J=11.4Hz,2H),2.28(s,3H),2.12(t,J=10.2Hz,2H),1.82–1.60(m,4H).

[0675] Example 10: Preparation of compound C016

[0676]

[0677] Step 1: Preparation of 3-bromo-6-nitro-2-propoxyaniline

[0678] 2-Amino-6-bromo-3-nitrophenol (50 mg, 0.21 mmol) was dissolved in anhydrous acetonitrile (30 mL). Then, 1-iodopropane (72 mg, 0.42 mmol) and K₂CO₃ (86.9 mg, 0.63 mmol) were added to the reaction mixture. The mixture was stirred at room temperature and monitored by TLC until the starting material disappeared. The reaction solution was then poured into water (60 mL). The mixture was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to give 3-bromo-6-nitro-2-propoxyaniline (45 mg, yield 77.9%).

[0679] MS m / z (ESI): 274.9, 276.9 [M+H] +

[0680] Step 2: Preparation of 3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-6-nitro-2-propoxyaniline

[0681] 3-Bromo-6-nitro-2-propoxyaniline (360 mg, 1.3 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1,2,3,6-tetrahydropyridine (423.7 mg, 1.9 mmol) were added to 1,4-dioxane (18 mL) and H₂O (2 mL). Under nitrogen protection, Pd(dppf)Cl₂ (95 mg, 0.13 mmol) and K₂CO₃ (538 mg, 3.9 mmol) were added. The mixture was stirred at 90 °C for 2 h, and the reaction was monitored by TLC until completion. The reaction solution was then poured into water (40 mL), extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed with saturated brine (50 mL), dried over anhydrous sulfuric acid, filtered, and the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to give 3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-6-nitro-2-propoxyaniline (320 mg, yield 84.5%).

[0682] MS m / z(ESI): 292.1 [M+H] + .

[0683] Step 3: Preparation of 4-(1-methylpiperidin-4-yl)-3-propoxyphenyl-1,2-diamine

[0684] 3-(1-Methyl-1,2,3,6-tetrahydropyridin-4-yl)-6-nitro-2-propoxyaniline (300 mg, 1.0 mmol) was dissolved in ethanol (30 mL), and PtO2 (30 mg, 0.13 mmol) was added under nitrogen protection. The reaction system was purged with hydrogen three times, and then stirred at room temperature for 16 h under hydrogen pressure (15 psi). TLC showed that the reaction was complete. The reaction solution was filtered through diatomaceous earth, and the filter cake was washed with methanol. The filtrate was collected. The filtrate was concentrated under reduced pressure to give 4-(1-methylpiperidin-4-yl)-3-propoxyphenyl-1,2-diamine (260 mg, yield 96.2%).

[0685] MS m / z(ESI): 264.2 [M+H] +

[0686] Step 4: 6-Methoxy-7-(5-(1-methylpiperidin-4-yl)-4-propoxy-1H-benzo[d]imidazol-2-yl)-1H-pyrrolo[3,2-c]pyridine-3-nitrile

[0687] 7-Formyl-6-methoxy-1H-pyrrolo[3,2-c]pyridine-3-carboxylonitrile (114 mg, 0.57 mmol) and 4-(1-methylpiperidin-4-yl)-3-propoxyphenyl-1,2-diamine (150 mg, 0.57 mmol) were dissolved in N,N-dimethylformamide (10 ml), and sodium metabisulfite (433 mg, 2.28 mmol) was added. The reaction system was heated to 90 °C and stirred for 16 h. The reaction was monitored by TLC until it ended. The residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (MeOH:DCM = 1:6) to give 6-methoxy-7-(5-(1-methylpiperidin-4-yl)-4-propoxy-1H-benzo[d]imidazol-2-yl)-1H-pyrrolo[3,2-c]pyridine-3-carboxylonitrile (130 mg, yield 51.3%) as a yellow solid.

[0688] MS m / z (ESI): 445.3 [M+H] +

[0689] Step 5: Preparation of compound C016

[0690] 150 mg (0.33 mmol) of 6-methoxy-7-(5-(1-methylpiperidin-4-yl)-4-propoxy-1H-benzo[d]imidazol-2-yl)-1H-pyrrolo[3,2-c]pyridine-3-onitrile was dissolved in 8 mL of 4 M 1,4-dioxane hydrochloric acid solution. The mixture was heated to 90 °C and stirred for 4 h. After the reaction was completed by TLC monitoring, the mixture was quenched with ammonia, distilled under reduced pressure, and purified by HPLC to obtain compound C016 (21.13 mg, yield 14.8%).

[0691] MS m / z (ESI): 431.6 [M+H] +

[0692] 1 H NMR(400MHz,DMSO-d6)δ12.47(s,1H),11.53(br,1H),8.26-8.20(m,3H),7.35(s,1H),7.05(s,1H),4.60(s,2 H), 3.09 (s, 1H), 2.97 (d, J = 11.4Hz, 2H), 2.28 (s, 3H), 2.12 (t, J = 10.2Hz, 2H), 1.82-1.67 (m, 6H), 1.08 (s, 3H).

[0693] Example 11: Preparation of compound C017

[0694]

[0695] Step 1: Preparation of 3-bromo-2-(2,2-difluoroethoxy)-6-nitroaniline

[0696] At room temperature, 2-amino-6-bromo-3-nitrophenol (50 mg, 0.21 mmol) was dissolved in anhydrous acetonitrile (30 mL), followed by the addition of 1-iodo-2-methylpropane (77.28 mg, 0.42 mmol) and K₂CO₃ (86.9 mg, 0.63 mmol). The reaction was monitored by TLC (petroleum ether:ethyl acetate = 5:1) until completion, at which point the reaction solution was quenched in water (60 mL). The mixture was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was then subjected to column chromatography (PE:E)... A The mixture was purified at a ratio of 10:1 to obtain 3-bromo-2-(2,2-difluoroethoxy)-6-nitroaniline (60 mg, yield 99.0%).

[0697] MS m / z(ESI): 289.1 [M+H] +

[0698] Step 2: Preparation of 2-(2,2-difluoroethoxy)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-6-nitroaniline

[0699] 3-Bromo-2-(2,2-difluoroethoxy)-6-nitroaniline (60 mg, 0.20 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1,2,3,6-tetrahydropyridine (56 mg, 0.255 mmol) were dissolved in 1,4-dioxane (9 mL) and H₂O (1 mL). Under nitrogen protection, Pd(dppf)Cl₂ (12 mg, 0.17 mmol) and K₂CO₃ (70 mg, 0.51 mmol) were added, respectively. The mixture was then heated to 90 °C and reacted for 2 h to obtain a black suspension. The reaction was monitored by TLC until completion. The reaction solution was then poured into water (20 mL) and extracted with ethyl acetate. The organic phases were combined. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was subjected to column chromatography (PE:E) A =10:1) to obtain 2-(2,2-difluoroethoxy)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-6-nitroaniline (50 mg, yield 82%).

[0700] MS m / z (ESI): 306.1 [M+H] +

[0701] Step 3: Preparation of 3-(2,2-difluoroethoxy)-4-(1-methylpiperidin-4-yl)phenyl-1,2-diamine

[0702] 2-(2,2-difluoroethoxy)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-6-nitroaniline (56 mg, 0.73 mmol) was dissolved in ethanol (30 mL), and PtO2 (25 mg, 0.11 mmol) was added under nitrogen atmosphere. The reaction system was purged with hydrogen three times, and then reacted at room temperature for 16 h under hydrogen pressure (15 psi). TLC (dichloromethane / methanol = 10 / 1) showed that the reaction was complete. The reaction solution was filtered through a diatomaceous earth layer and washed with methanol. The filtrate was concentrated to give 3-(2,2-difluoroethoxy)-4-(1-methylpiperidin-4-yl)phenyl-1,2-diamine (50 mg, 98.6% yield).

[0703] MS m / z(ESI): 278.2 [M+H] +

[0704] Step 4: Preparation of 7-(4-(2,2-difluoroethoxy)-5-(1-methylpiperidin-4-yl)-1H-benzo[d]imidazol-2-yl)-6-methoxy-1H-pyrrolo[3,2-c]pyridine-3-carboxynitrile

[0705] 3-(2,2-difluoroethoxy)-4-(1-methylpiperidin-4-yl)phenyl-1,2-diamine (50 mg, 0.16 mmol) and 7-formyl-6-methoxy-1H-pyrrolo[3,2-c]pyridine-3-carboxynitrile (65 mg, 0.24 mmol) were dissolved in N,N-dimethylformamide (5 mL), and sodium metabisulfite (91.2 mg, 0.48 mmol) was added. The mixture was heated to 90 °C and reacted for 16 h. After the reaction was completed by TLC monitoring, the mixture was purified by vacuum distillation and column chromatography (MeOH:DCM = 1:6) to give 7-(4-(2,2-difluoroethoxy)-5-(1-methylpiperidin-4-yl)-1H-benzo[d]imidazol-2-yl)-6-methoxy-1H-pyrrolo[3,2-c]pyridine-3-carboxynitrile (60 mg, 80% yield).

[0706] MS m / z (ESI): 459.3 [M+H] +

[0707] Step 5: Preparation of 7-(4-(2,2-difluoroethoxy)-5-(1-methylpiperidin-4-yl)-1H-benzo[d]imidazol-2-yl)-6-oxo-5,6-dihydro-1H-pyrrolo[3,2-c]pyridine-3-carboxynitrile

[0708] 7-(4-(2,2-difluoroethoxy)-5-(1-methylpiperidin-4-yl)-1H-benzo[d]imidazol-2-yl)-6-methoxy-1H-pyrrolo[3,2-c]pyridine-3-carboxynitrile (250 mg, 0.53 mmol) was dissolved in 10 mL of 4 M 1,4-dioxane hydrochloric acid solution, heated to 90 °C, and stirred for 2 h. After the reaction was completed by TLC monitoring, ammonia was added to quench the reaction, and the mixture was distilled under reduced pressure to obtain 7-(4-(2,2-difluoroethoxy)-5-(1-methylpiperidin-4-yl)-1H-benzo[d]imidazol-2-yl)-6-oxo-5,6-dihydro-1H-pyrrolo[3,2-c]pyridine-3-carboxynitrile (26.38 mg, yield 11%).

[0709] MS m / z (ESI): 445.2 [M+H] +

[0710] 1H NMR (400MHz, DMSO-d6) δ12.39(s,1H),11.60(s,1H),8.26(s,3H),7.37(d,J=8.3Hz,1H),7.05(d,J=8.4Hz,1H),4.33( s,2H),3.12(s,1H),2.92(d,J=10.9Hz,2H),2.24(s,3H),2.16–2.10(m,3H),1.85–1.70(m,4H),1.09(d,J=8.3Hz,6H).

[0711] Example 12: Preparation of compound CO20

[0712]

[0713] Step 1: Preparation of tert-butyl 2-(2-amino-6-bromo-3-nitrophenoxy)methyl)pyrrolidine-1-carboxylic acid

[0714] In a 100 mL round-bottom flask at room temperature, 2-amino-6-bromo-3-nitrophenol (500 mg, 2.48 mmol) was dissolved in toluene (20 mL), followed by the addition of 2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (578 mg, 2.48 mmol) and tri-tert-butylphosphine (1.2 g, 5.47 mmol). The reaction mixture was stirred for 1 hour at room temperature under a nitrogen atmosphere. Then, diisopropyl azodicarbonate (1.2 g, 5.47 mmol) was added at -10 °C under a nitrogen atmosphere, and the reaction mixture was stirred for 16 hours at room temperature under a nitrogen atmosphere. The reaction mixture was then concentrated. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 10:1) to give 2-(2-amino-6-bromo-3-nitrophenoxy)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester (300 mg, yield 33.5%).

[0715] Step 2: Preparation of tert-butyl 2-((2-amino-6-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-3-nitrophenoxy)methyl)pyrrolidine-1-carboxylic acid ester

[0716] In a 250 mL round-bottom flask, tert-butyl 2-(2-amino-6-bromo-3-nitrophenoxy)methylpyrrolidine-1-carboxylic acid (83 mg, 0.20 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)-1,2,3,6-tetrahydropyridine (56 mg, 0.255 mmol) were dissolved in 1,4-dioxane (9 mL) and H₂O (1 mL). Under nitrogen protection, Pd(dppf)Cl₂ (12 mg, 0.17 mmol) and K₂CO₃ (70 mg, 0.51 mmol) were added, respectively. The mixture was then heated to 90 °C and reacted for 2 hours to obtain a black suspension. The reaction was monitored by TLC until completion. The reaction mixture was then poured into water (20 mL) and extracted with ethyl acetate. The organic phases were combined. The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated by filtration to obtain the crude product. The crude product was subjected to column chromatography (petroleum ether: ethyl acetate = 10:1) to give tert-butyl 2-((2-amino-6-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-3-nitrophenoxy)methyl)pyrrolidine-1-carboxylic acid ester (63 mg, 0.146 mmol, yield 73%).

[0717] MS m / z(ESI): 433.2 [M+H] + .

[0718] Step 3: Preparation of tert-butyl 2-(2,3-diamino-6-(1-methylpiperidin-4-yl)phenoxy)methyl)pyrrolidine-1-carboxylic acid

[0719] In a 100 mL round-bottom flask, tert-butyl 2-((2-amino-6-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-3-nitrophenoxy)methyl)pyrrolidine-1-carboxylic acid ester (63 mg, 0.146 mmol) was dissolved in 30 mL of ethanol. PtO2 (50 mg, 0.22 mmol) was added under nitrogen atmosphere. The reaction system was purged three times with hydrogen, and then the reaction was carried out at room temperature for 16 h under hydrogen (15 psi) pressure. TLC (dichloromethane / methanol = 10 / 1) showed the reaction was complete. The reaction solution was filtered through a diatomaceous earth layer and washed with methanol. The filtrate was concentrated to give tert-butyl 2-(2,3-diamino-6-(1-methylpiperidin-4-yl)phenoxy)methyl)pyrrolidine-1-carboxylic acid ester (50 mg, yield 84.8%).

[0720] MS m / z (ESI): 405.2 [M+H] + .

[0721] Step 4: Preparation of tert-butyl 2-((2-(3-cyano-6-methoxy-1H-pyrrolo[3,2-c]pyridin-7-yl)-5-(1-methylpiperidin-4-yl)-1H-benzo[d]imidazol-4-yl)oxy)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester of 2-(2,3-diamino-6-(1-methylpiperidin-4-yl)phenoxy)methyl)pyrrolidine-1-carboxylic acid (50 mg, 0.12 mmol) and 7-formyl-6-methoxy-1H-pyrrolo[3,2-c]pyridin-3-carboxylonitrile (65 mg, 0.24 mmol) were dissolved in N,N-dimethylformamide (5 ml) solution, sodium metabisulfite (91.2 mg, 0.48 mmol) was added, and the mixture was heated to 90 °C and reacted for 16 h. After the reaction was completed under TLC monitoring, the mixture was purified by vacuum distillation and column chromatography (methanol: dichloromethane = 1:6) to give tert-butyl 2-((2-(3-cyano-6-methoxy-1H-pyrrolo[3,2-c]pyridin-7-yl)-5-(1-methylpiperidin-4-yl)-1H-benzo[d]imidazol-4-yl)oxy)methyl)pyrrolidin-1-carboxylic acid ester (65 mg, yield 93%).

[0722] Step 5: Preparation of compound CO20

[0723] 65 mg (0.11 mmol) of tert-butyl 2-((2-(3-cyano-6-methoxy-1H-pyrrolo[3,2-c]pyridin-7-yl)-5-(1-methylpiperidin-4-yl)-1H-benzi[d]imidazol-4-yl)oxy)methyl)pyrrolidine-1-carboxylic acid ester was dissolved in 10 mL of 4 M 1,4-dioxane hydrochloric acid solution. The mixture was heated to 90 °C and stirred for 2 h. After the reaction was completed by TLC monitoring, ammonia was added to quench the reaction, and the mixture was distilled under reduced pressure to prepare and purified compound CO20 (46.3 mg, yield 89.3%).

[0724] MS m / z (ESI): 472.2 [M+H] + ;

[0725] 1 H NMR (400MHz, DMSO-d6) δ8.26(d,J=9.3Hz,4H),8.20(s,1H),7.39(d,J=8.3Hz,1H),7.04(d,J=8.3Hz,1H),4.59–4.55(m,2H),3.8 2–3.80(m,1H),3.23–3.18(m,2H),3.07–3.02(m,1H),2.97(d,J=8.9Hz,2H),2.29(s,3H),2.23–2.05(m,2H),1.79–1.71(m,8H).

[0726] Example 13: Preparation of compound C044

[0727]

[0728]

[0729] Step 1: Preparation of 7-formyl-6-methoxy-2-(o-tolyl)-1H-pyrrole[3,2-c]pyridine-3-carboxynitrile

[0730] Under nitrogen protection at room temperature, 1.6 M n-butyllithium (4.00 mL, 6.40 mmol) was dissolved in THF (11.0 mL), and the reaction system was then cooled to -78 °C. Acetonitrile (340 μL, 7.00 mmol) was then slowly added dropwise to the reaction system, and the mixture was stirred for 15 min. Then, a solution of 7-bromo-6-methoxy-2-(o-tolyl)-1H-pyrrolo[3,2-c]pyridine-3-carboxylonitrile (300 mg, 0.88 mmol) in THF (3.00 mL) was added dropwise to the reaction system. The mixture was slowly heated to room temperature (not less than 2 h), and stirred for 30 min. The reaction was monitored by LC-MS and TLC until the product was formed. The reaction solution was poured into an aqueous solution of NH4Cl (30 mL). The solution was then extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed three times with saturated brine (50 mL). The solution was then dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by rapid column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give 7-formyl-6-methoxy-2-(o-tolyl)-1H-pyrrolo[3,2-c]pyridine-3-carboxylonitrile (82 mg, yield 32%).

[0731] MS m / z(ESI): 292.1 [M+H] + .

[0732] Step 2: Preparation of 7-(4-ethoxy-5-(1-methylpiperidin-4-yl)-1Hbenzi[d]imidazol-2-yl)-6-methoxy-2-(o-tolyl)-1Hpyrrolo[3,2-c]pyridine-3-carboxynitrile

[0733] 7-Formyl-6-methoxy-2-(o-tolyl)-1H-pyrrolo[3,2-c]pyridine-3-carboxylonitrile (82 mg, 0.28 mmol) and 3-ethoxy-4-(1-methylpiperidin-4-yl)phenyl-1,2-diamine (69.7 mg, 0.28 mmol) were dissolved in N,N-dimethylformamide (5 ml) solution, and sodium metabisulfite (91.2 mg, 0.48 mmol) was added. The mixture was heated to 90 °C and reacted for 16 h. After the reaction was completed by TLC monitoring, the mixture was purified by column chromatography under reduced pressure (MeOH:DCM = 1:6) to give 7-(4-ethoxy-5-(1-methylpiperidin-4-yl)-1Hbenzi[d]imidazol-2-yl)-6-methoxy-2-(o-tolyl)-1Hpyrrolo[3,2-c]pyridine-3-carboxylonitrile (80 mg, yield 55%).

[0734] MS m / z(ESI): 521.1 [M+H] +

[0735] Step 3: Preparation of compound C044

[0736] 7-(4-ethoxy-5-(1-methylpiperidin-4-yl)-1Hbenzimidazol-2-yl)-6-methoxy-2-(o-tolyl)-1Hpyrrolo[3,2-c]pyridine-3-carboxynitrile (80 mg, 0.154 mmol) was dissolved in 10 mL of 4 M 1,4-dioxane hydrochloric acid solution, heated to 90 °C, and stirred for 2 h. After the reaction was completed by TLC monitoring, ammonia was added to quench the reaction, and the mixture was distilled under reduced pressure to obtain compound C044 (33.46 mg, yield 43.3%).

[0737] MS m / z (ESI): 507.4 [M+H] + ;

[0738] 1 H NMR(400MHz,DMSO-d6)δ12.45(br,s,1H),11.5(br,s,1H),8.29(s,1H),8.21(s,1H), 7.67(d,J=7.9Hz,1H),7.59-7.50(m,2H),7.46(t,J=7.1Hz,1H),7.37(d,J=8.3Hz,1H ),7.04(d,J=8.4Hz,1H),4.50-4.45(m,2H),3.05-3.01(m,1H),2.94(d,J=11.0Hz,2H ), 2.49 (s, 3H), 2.26 (s, 3H), 2.11 (t, J = 10.4Hz, 2H), 1.86-1.58 (m, 4H), 1.28 (s, 3H).

[0739] Example 14: Compound CP46

[0740]

[0741] Step 1: Preparation of tert-butyl 2-methyl-4-((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylic acid

[0742] Under nitrogen protection, a solution of tert-butyl 2-methyl-4-oxoperidin-1-carboxylic acid (1.0 g, 4.69 mmol) in anhydrous tetrahydrofuran (30 mL) was cooled to -50 °C, and lithium bis(trimethylsilyl)amino (5.16 mL, 5.16 mmol) was added dropwise, with stirring at -50 °C for 1 h. Then, 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (1.9 g, 5.16 mmol) was added. The reaction mixture was brought to room temperature and stirred for 1 h. The reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to give tert-butyl 2-methyl-4-((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylic acid (1.5 g, 92.7% yield).

[0743] Step 2: Preparation of tert-butyl 4-(3-amino-2-(2,2-difluoroethoxy)-4-nitrophenyl)-2-methyl-3,6-dihydropyridine-1(2H)-carboxylic acid

[0744] Potassium carbonate (160 mg, 1.15 mmol) and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (43 mg, 0.05 mmol) were added to a solution of 2-methyl-4-((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (200 mg, 0.57 mmol) and 2-(2,2-difluoroethoxy)-6-nitro-3-(4,4,5,5-tetramethyl-1,3,2-dioxobenzofuran-2-yl)aniline (220 mg, 0.63 mmol) in 1,4-dioxane (20 mL) and water (4 mL). The mixture was stirred at 90 °C for 2 h. The reaction mixture was cooled to room temperature, filtered, and the filtrate was extracted with ethyl acetate. The organic phases were combined. The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to give tert-butyl 4-(3-amino-2-(2,2-difluoroethoxy)-4-nitrophenyl)-2-methyl-3,6-dihydropyridine-1(2H)-carboxylic acid (110 mg, yield 46.7%).

[0745] Step 3: Preparation of tert-butyl 4-(3,4-diamino-2-(2,2-difluoroethoxy)phenyl)-2-methylpiperidine-1-carboxylic acid

[0746] At room temperature, 110 mg (0.26 mmol) of 4-(3-amino-2-(2,2-difluoroethoxy)-4-nitrophenyl)-2-methyl-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester was dissolved in 20 mL of ethanol, followed by the addition of platinum dioxide (110 mg). The reaction mixture was stirred at 50 °C under a hydrogen atmosphere for 16 h. The reaction mixture was filtered, and the filtrate was concentrated to give 100 mg (99%) of 4-(3,4-diamino-2-(2,2-difluoroethoxy)phenyl)-2-methylpiperidine-1-carboxylic acid tert-butyl ester.

[0747] Step 4: Preparation of 3-(2,2-difluoroethoxy)-4-(1,2-dimethylpiperidin-4-yl)phenyl-1,2-diamine

[0748] 100 mg (0.26 mmol) of 4-(3,4-diamino-2-(2,2-difluoroethoxy)phenyl)-2-methylpiperidin-1-carboxylic acid tert-butyl ester was dissolved in anhydrous tetrahydrofuran (20 mL), and then 2.85 mL (2.85 mmol) of lithium aluminum hydride was added at 0 °C. The reaction mixture was stirred at 90 °C for 3 h. After cooling to room temperature, sodium sulfate decahydrate was slowly added, filtered, and the filtrate was concentrated and purified by reverse-phase column chromatography to obtain 20 mg (25.7%) of 3-(2,2-difluoroethoxy)-4-(1,2-dimethylpiperidin-4-yl)phenyl-1,2-diamine.

[0749] Step 5: Preparation of 7-(4-(2,2-difluoroethoxy)-5-(1,2-dimethylpiperidin-4-yl)-1Hbenzi[d]imidazol-2-yl)-6-methoxy-1H-pyrrolo[3,2-c]pyridine-3-carbamate

[0750] At room temperature, 3-(2,2-difluoroethoxy)-4-(1,2-dimethylpiperidin-4-yl)phenyl-1,2-diamine (20 mg, 0.06 mmol) and 7-formyl-6-methoxy-1H-pyrrolo[3,2-c]pyridine-3-carbamate (14 mg, 0.06 mmol) were dissolved in N,N-dimethylformamide (10 mL), and then sodium metabisulfite (26 mg, 0.13 mmol) was added. The reaction mixture was stirred at 90 °C for 16 h. The reaction solution was extracted three times with ethyl acetate and water. The organic phases were combined, dried with anhydrous sodium sulfate, and concentrated to give 7-(4-(2,2-difluoroethoxy)-5-(1,2-dimethylpiperidin-4-yl)-1Hbenzo[d]imidazol-2-yl)-6-methoxy-1H-pyrrolo[3,2-c]pyridine-3-carbamate (20 mg, yield 69.4%).

[0751] MS m / z (ESI): 481.3 [M+H] +

[0752] Step 6: Preparation of compound CP46

[0753] At room temperature, 7-(4-(2,2-difluoroethoxy)-5-(1,2-dimethylpiperidin-4-yl)-1Hbenzi[d]imidazol-2-yl)-6-methoxy-1H-pyrrolo[3,2-c]pyridine-3-carbamate (20 mg, 0.04 mmol) was added to a solvent of hydrochloric acid / dioxane (5 mL), and the reaction mixture was stirred at 90 °C for 3 hours. After the reaction was completed as monitored by LC-MS, the reaction mixture was concentrated, and the crude product was purified to obtain compound CP46 (2.19 mg, 11.7%).

[0754] MS m / z (ESI): 447.1 [M+H] + ;

[0755] 1 H NMR (400MHz, DMSO-d6) δ12.59(br,1H),8.35(s,2H),8.25(d,J=3.3Hz,2H),7.41(d,J=8.3Hz,1H),7.06(t,J=8.7Hz,1H),6.40(tt,J=54. 2,3.0Hz,1H),4.91(br,2H),2.92(d,J=10.7Hz,1H),2.59(d,J=11.5Hz,1H),2.36–2.07(m,5H),1.80–1.37(m,4H),1.06(d,J=6.1Hz,3H).

[0756] Example 15: Preparation of compound CP47

[0757]

[0758] Step 1: Preparation of 4-(4-bromo-2,6-dimethylphenyl)morpholine

[0759] At room temperature, potassium carbonate (5.2 g, 37.48 mmol) and potassium iodide (4.1 g, 24.99 mmol) were added to a solution of 4-bromo-2,6-dimethylaniline (5.0 g, 24.99 mmol) and 1-bromo-2-(2-bromoethoxy)ethane (8.7 g, 37.48 mmol) in N,N-dimethylformamide (60 mL). The reaction mixture was stirred at 90 °C for 16 hours. The reaction was monitored by LC-MS until completion. The reaction mixture was filtered, the filtrate was concentrated, and the crude product was purified by column chromatography to give 4-(4-bromo-2,6-dimethylphenyl)morpholine (3.2 g, yield 47.4%).

[0760] Step 2: Preparation of 4-(4-bromo-2,6-dimethyl-3-nitrophenyl)morpholine

[0761] At room temperature, 1 g (3.70 mmol) of 4-(4-bromo-2,6-dimethylphenyl)morpholine was dissolved in 15 mL of concentrated sulfuric acid and stirred in an ice-water bath for 3–5 minutes. Potassium nitrate (412 mg, 4.07 mmol) was slowly added in portions, and the mixture was stirred at 0 °C for 40 minutes. After the reaction was complete, the reaction mixture was slowly added dropwise to 100 mL of ice water and extracted with ethyl acetate. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography to give 800 mg (68.6% yield) of 4-(4-bromo-2,6-dimethyl-3-nitrophenyl)morpholine.

[0762] Step 3: Preparation of N-(3,5-dimethyl-4-morpholino-2-nitrophenyl)-2,2,2-trifluoroacetamide

[0763] At room temperature, Pd2(dba)3 (145 mg, 0.158 mmol), Xantphos (184 mg, 0.317 mmol), and cesium carbonate (1.6 g, 4.759 mmol) were added to a solution of 4-(4-bromo-2,6-dimethyl-3-nitrophenyl)morpholine (500 mg, 1.59 mmol) and trifluoroacetamide (215 mg, 1.904 mmol) in 1,4-dioxane (15 mL). The reaction mixture was stirred at 110 °C for 16 hours. The reaction mixture was filtered, the filtrate was concentrated, and extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and concentrated to obtain the crude product. The crude product was purified by column chromatography to give N-(3,5-dimethyl-4-morpholine-2-nitrophenyl)-2,2,2-trifluoroacetamide (200 mg, yield 36.4%).

[0764] MS m / z(ESI): 348.0 [M+H].

[0765] Step 4: Preparation of 3,5-dimethyl-4-morpholino-2-nitroaniline

[0766] At room temperature, N-(3,5-dimethyl-4-morpholine-2-nitrophenyl)-2,2,2-trifluoroacetamide (200 mg, 0.81 mmol) and lithium hydroxide (58 mg, 2.43 mmol) were dissolved in ethanol (5 mL) and water (1 mL), and the reaction mixture was stirred at 60 °C for 16 h. The reaction mixture was concentrated to remove ethanol, then extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and concentrated to give 3,5-dimethyl-4-morpholine-2-nitroaniline (170 mg, yield 83.6%).

[0767] MS m / z(ESI): 252.1 [M+H] + .

[0768] Step 5: Preparation of 3,5-dimethyl-4-morpholinone-1,2-diamine

[0769] At room temperature, 3,5-dimethyl-4-morpholino-2-nitroaniline (170 mg, 0.68 mmol), iron powder (151 mg, 2.71 mmol), and ammonium chloride (289 mg, 5.41 mmol) were dissolved in ethanol (3 mL) and water (3 mL). The reaction mixture was stirred at 70 °C for 3 h. The reaction mixture was filtered, and the filtrate was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and concentrated to give 3,5-dimethyl-4-morpholinophenyl-1,2-diamine (110 mg, yield 73.2%).

[0770] MS m / z(ESI): 222.1 [M+H] + .

[0771] Step 6: Preparation of 2-cyclopropyl-7-(4,6-dimethyl-5-morpholino-1H-benzo[d]imidazol-2-yl)-6-methoxy-1H-pyrrolo[3,2-c]pyridine-3-carbamate

[0772] At room temperature, 3,5-dimethyl-4-morpholinophenyl-1,2-diamine (110 mg, 0.50 mmol), 2-cyclopropyl-7-formyl-6-methoxy-1H-pyrrole[3,2-c]pyridine-3-carbamate (181 mg, 0.74 mmol) and sodium metabisulfite (378 mg, 1.99 mmol) were dissolved in N,N-dimethylformamide (5 mL), and the reaction solution was stirred at 90 °C for 2 hours. After the reaction was completed as monitored by LC-MS, the reaction solution was added dropwise to 50 mL of water to precipitate the solid. The solid was filtered to obtain a filter cake. The filter cake was dissolved in methanol and concentrated, and then concentrated 1 to 2 times with acetonitrile to obtain crude product 2-cyclopropyl-7-(4,6-dimethyl-5-morpholino-1H-benzo[d]imidazol-2-yl)-6-methoxy-1H-pyrrole[3,2-c]pyridine-3-carbamate (200 mg, yield 90.5%).

[0773] MS m / z(ESI): 443.1 [M+H] + .

[0774] Step 7: Preparation of compound CP47

[0775] At room temperature, trimethylchlorosilane (50 mg, 0.45 mmol) was added to a solution of 2-cyclopropyl-7-(4,6-dimethyl-5-morpholino-1H-benzo[d]imidazol-2-yl)-6-methoxy-1H-pyrrolo[3,2-c]pyridine-3-carbamate (100 mg, 0.23 mmol) and sodium iodide (68 mg, 0.45 mmol) in acetonitrile (10 mL). The reaction mixture was stirred at 30 °C for 4 hours. The reaction mixture was concentrated, dissolved in N,N-dimethylformamide, filtered, and the filtrate was purified by high performance liquid chromatography to give compound CP47 (44.15 mg, yield 44.8%).

[0776] MS m / z (ESI): 429.1 [M+H] + .

[0777] 1 H NMR(400MHz,DMSO-d6)δ12.71(br,1H),11.81(br,1H),8.11(s,1H),7.39(s,1H),3.77-3.69(m,4H),3.21 -3.13(m,2H),3.02(d,J=12.0Hz,2H),2.63(s,3H),2.45(s,3H),2.32(t,J=8.8Hz,1H),1.30-1.19(m,4H).

[0778] Example 16: Preparation of compound C048

[0779]

[0780] 1. Preparation of 2-(cyclopropylmethoxy)-6-nitro-3-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)aniline

[0781] Step 1: Preparation of 3-bromo-2-(cyclopropylmethoxy)-6-nitroaniline

[0782] At room temperature, 2-amino-6-bromo-3-nitrobenzene (4.5 g, 19.31 mmol) and K₂CO₃ (5.34 g, 38.62 mmol) were dissolved in acetonitrile (135 mL), and the reaction vessel was stirred at 25 °C for 0.5 h. Then, (iodomethyl)cyclopropane (4.2 g, 23.17 mmol) was added, and the reaction mixture was heated to 80 °C and stirred for 16 h. The reaction mixture was filtered through diatomaceous earth, and the filtrate was evaporated to dryness. The crude product was purified by rapid column chromatography (petroleum ether / ethyl acetate) to give 3-bromo-2-(cyclopropylmethoxy)-6-nitrobenzene (4 g, yield 72.1%).

[0783] Step 2: Preparation of 2-(cyclopropylmethoxy)-6-nitro-3-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)aniline

[0784] At room temperature, 3-bromo-2-(cyclopropylmethoxy)-6-nitroaniline (4.1 g, 14.29 mmol), pinacol diboronate (6.1 g, 23.96 mmol), KOAc (4.2 g, 42.82 mmol), and Pd(dppf)Cl2 (1.3 g, 1.428 mmol) were added to dioxane (80 mL), and the mixture was stirred at 90 °C for 12 h. The mixture was extracted with ethyl acetate and H2O, and the organic phases were combined, washed with brine (50 mL * 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by rapid column chromatography (petroleum ether / ethyl acetate) and reversed-phase column chromatography (acetonitrile / water) to give 2-(cyclopropylmethoxy)-6-nitro-3-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)aniline (1.4 g, yield 29.3%).

[0785] 2. Preparation of compound C048

[0786] Step 1: Preparation of 2-(cyclopropylmethoxy)-3-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-6-nitroaniline

[0787] At room temperature, 1-ethyl-1,2,3,6-tetrahydropyridine-4-trifluoromethanesulfonate (534 mg, 2.095 mmol), 2-(cyclopropylmethoxy)-6-nitro-3-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)aniline (700 mg, 2.095 mmol), Pd(dppf)Cl2 (171 mg, 0.209 mmol), and K2CO3 (868 mg, 6.28 mmol) were dissolved in 1,4-dioxane (13.5 mL) and water (1.5 mL). The mixture was stirred at 90 °C for 2 h. The reaction was monitored by LC-MS until completion, and the mixture was filtered and the filtrate was concentrated. The crude product was purified by rapid column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give 2-(cyclopropylmethoxy)-3-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-6-nitroaniline (300 mg, yield 45.9%).

[0788] Step 2: Preparation of 3-(cyclopropylmethoxy)-4-(1-ethylpiperidin-4-yl)phenyl-1,2-diamine

[0789] PtO2 (400 mg) was added to a solution of 2-(cyclopropylmethoxy)-3-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-6-nitroaniline (200 mg) in ethanol (60 mL). The mixture was stirred at 50 °C under H2 for 16 h. The mixture was filtered and the filtrate was concentrated to give 3-(cyclopropylmethoxy)-4-(1-ethylpiperidin-4-yl)phenyl-1,2-diamine (183 mg, 100% yield).

[0790] MS m / z(ESI): 290.2 [M+H] + .

[0791] Step 3: Preparation of 7-(4-(cyclopropylmethoxy)-5-(1-ethylpiperidin-4-yl)-1Hbenzi[d]imidazol-2-yl)-6-methoxy-1H-pyrrolo[3,2-c]pyridine-3-nitrile

[0792] 7-Formyl-6-methoxy-1H-pyrrolo[3,2-c]pyridine-3-carboxylonitrile (104 mg, 0.5 mmol) and 3-(cyclopropylmethoxy)-4-(1-ethylpiperidin-4-yl)phenyl-1,2-diamine (150 mg, 0.5 mmol) were dissolved in N,N-dimethylformamide (10 mL), and sodium metabisulfite (380 mg, 2.0 mmol) was added. The mixture was heated to 90 °C and reacted for 16 h. After the reaction was completed by TLC monitoring, the mixture was purified by column chromatography (methanol:dichloromethane = 1:6) under reduced pressure to give 7-(4-(cyclopropylmethoxy)-5-(1-ethylpiperidin-4-yl)-1Hbenzo[d]imidazol-2-yl)-6-methoxy-1H-pyrrolo[3,2-c]pyridine-3-carboxylonitrile (120 mg, yield 52%).

[0793] MS m / z(ESI): 471 [M+H] + .

[0794] Step 4: Preparation of compound C048

[0795] 7-(4-(cyclopropylmethoxy)-5-(1-ethylpiperidin-4-yl)-1Hbenzi[d]imidazol-2-yl)-6-methoxy-1H-pyrrolo[3,2-c]pyridine-3-carbamate (150 mg, 0.32 mmol) was dissolved in 8 mL of 4 M 1,4-dioxane hydrochloric acid solution, heated to 100 °C, and stirred for 10 mins. After the reaction was completed by TLC monitoring, ammonia was added to quench the reaction, and the mixture was distilled under reduced pressure to prepare and purified compound C048 (1.83 mg, yield 1.25%).

[0796] MS(ESI) m / z: 457.3 [M+H] + ;

[0797] 1 H NMR (400MHz, DMSO-d6) δ8.38(s,3H),8.26(s,2H),7.37(d,J=8.1Hz,1H),7.06(d,J=8.5Hz,1H),4.36(s,2H),3.05-3.01(m,1H),2.67-2.23(m,1H), 2.36(dd,J=16.2,9.0Hz,3H),2.05-2.01(m,2H),1.73-1.69(m,4H),1.26- 1.21(m,1H),1.04(t,J=7.2Hz,3H),0.55-0.50(m,2H),0.34-0.30(m,2H).

[0798] Example 17: Preparation of compound C049

[0799]

[0800] 1. Preparation of 2-isobutoxy-6-nitro-3-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)aniline

[0801] Step 1: Preparation of 3-bromo-2-isobutoxy-6-nitroaniline

[0802] At room temperature, 2-amino-6-bromo-3-nitrobenzene (5 g, 21.46 mmol) and K₂CO₃ (5.9 g, 42.91 mmol) were dissolved in acetonitrile (50 mL), and the reaction vessel was stirred at 25 °C for 0.5 h. Then, 1-iodo-2-methylpropane (4.7 g, 25.75 mmol) was added, and the reaction mixture was heated to 80 °C and stirred for 16 h. The reaction mixture was filtered through diatomaceous earth, and the filtrate was evaporated to dryness. The crude product was purified by rapid column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give 3-bromo-2-isobutoxy-6-nitrobenzylamine (2.4 g, yield 38.7%).

[0803] MS m / z (ESI): 288.9, 290.9 [M+H] + .

[0804] Step 2: Preparation of 2-isobutoxy-6-nitro-3-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)aniline

[0805] At room temperature, 3-bromo-2-isobutoxy-6-nitroaniline (2.3 g, 7.98 mmol), pinacol diboronate (6.1 g, 23.96 mmol), KOAc (2.3 g, 23.96 mmol), and Pd(dppf)Cl2 (584 mg, 0.798 mmol) were added to dioxane (30 mL), and the mixture was stirred at 90 °C for 12 h. The mixture was extracted with ethyl acetate and water, and the organic phases were combined, washed with brine (50 mL * 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by rapid column chromatography (petroleum ether / ethyl acetate = 8 / 1) and reversed-phase column chromatography (acetonitrile / water) to obtain 2-isobutoxy-6-nitro-3-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)aniline (1.3 g, yield 48.6%).

[0806] MS m / z (ESI): 337.1 [M+H] + .

[0807] 2. Preparation of compound C049

[0808] Step 1: Preparation of 3-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-2-isobutoxy-6-nitroaniline

[0809] At room temperature, 1-ethyl-1,2,3,6-tetrahydropyridine-4-trifluoromethanesulfonate (771 mg, 2.97 mmol), 2-3 (1 g, 2.97 mmol), Pd(dppf)Cl2 (218 mg, 0.297 mmol), and K2CO3 (1.2 g, 8.92 mmol) were dissolved in 1,4-dioxane (18 mL) and water (2 mL). The mixture was stirred at 90 °C for 2 h. The reaction was monitored by LC-MS until completion, the mixture was filtered, and the filtrate was concentrated. The crude product was purified by rapid column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give 3-(1-ethyl-1,2,3,6-tetrahydropyridine-4-yl)-2-isobutoxy-6-nitroaniline (600 mg, yield 63.2%).

[0810] MS m / z (ESI): 320.1 [M+H] + .

[0811] Step 2: Preparation of 4-(1-ethylpiperidin-4-yl)-3-isobutoxyphenyl-1,2-diamine

[0812] PtO2 (400 mg) was added to a solution of 200 mg 3-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-2-isobutoxy-6-nitroaniline in ethanol (60 mL). The mixture was stirred at 50 °C under hydrogen atmosphere for 2 days. The mixture was filtered and the filtrate was concentrated to give 150 mg 4-(1-ethylpiperidin-4-yl)-3-isobutoxyphenyl-1,2-diamine (yield 82.2%).

[0813] MS m / z(ESI): 292.2 [M+H] + .

[0814] Step 3: Preparation of 7-(5-(1-ethylpiperidin-4-yl)-4-isobutoxy-1H-benzo[d]imidazol-2-yl)-6-methoxy-1H-pyrrolo[3,2-c]pyridine-3-nitrile

[0815] 7-Formyl-6-methoxy-1H-pyrrolo[3,2-c]pyridine-3-carboxylonitrile (68.34 mg, 0.34 mmol) and 4-(1-ethylpiperidin-4-yl)-3-isobutoxyphenyl-1,2-diamine (100 mg, 0.34 mmol) were dissolved in N,N-dimethylformamide (10 mL), and sodium metabisulfite (261 mg, 1.37 mmol) was added. The mixture was heated to 90 °C and reacted for 16 h. After the reaction was completed by TLC monitoring, the mixture was purified by column chromatography (methanol:dichloromethane = 1:6) under reduced pressure to give 7-(5-(1-ethylpiperidin-4-yl)-4-isobutoxy-1H-benzo[d]imidazol-2-yl)-6-methoxy-1H-pyrrolo[3,2-c]pyridine-3-carboxylonitrile (90 mg, yield 58.8%).

[0816] MS m / z(ESI): 473.1 [M+H] + .

[0817] Step 4: Preparation of compound C049

[0818] 7-(5-(1-ethylpiperidin-4-yl)-4-isobutoxy-1H-benzo[d]imidazol-2-yl)-6-methoxy-1H-pyrrolo[3,2-c]pyridine-3-onitrile (130 mg, 0.28 mmol) was dissolved in 8 mL of 4 M 1,4-dioxane hydrochloric acid solution. The mixture was heated to 100 °C and stirred for 10 min. After the reaction was completed by TLC monitoring, the mixture was quenched with ammonia, distilled under reduced pressure, and purified to obtain compound C049 (15.95 mg, yield 12.5%) as a yellow solid.

[0819] MS m / z (ESI): 459.2 [M+H] + ;

[0820] 1 H NMR(400MHz, DMSO-d6)δ12.46(s,1H),8.27(d,J=9.3Hz,3H),7.35(s,1H),7.07(s,1H),4.50(d,J=92.5Hz,2H),3.06–3.02(m,2H), 2.38(dt,J=20.5,10.3Hz,3H),2.17-2.08(m,1H),2.02-1.98(m,2H),1.73-1.70(m,4H),1.09(d,J=6.6Hz,6H),1.04-1.01(m,3H).

[0821] Example 18: Preparation of compound C050

[0822]

[0823] Step 1: Preparation of compound C050

[0824] 30 mg (0.05 mmol) of 4-(2-(3-cyano-6-methoxy-1H-pyrrolo[3,2-c]pyridin-7-yl)-4-(2,2-difluoroethoxy)-1H-benzo[d]imidazol-5-yl)piperidine-1-carboxylic acid tert-butyl ester was added to 8 mL of 4 mol / L 1,4-dioxane hydrochloric acid solution and stirred at 100 °C for 1 h. After the reaction was completed by TLC monitoring, ammonia was added to quench the reaction, and the mixture was concentrated under reduced pressure to give compound C050 (5.82 mg, yield 26.5%).

[0825] MS m / z(ESI):[M+H] + =439.0.

[0826] 1 H NMR (400MHz, DMSO-d6) δ8.42(s,1H),8.26(d,J=13.4Hz,2H),7.43(d,J=8.3Hz,1H),7.02 (d,J=8.3Hz,1H),6.64-6.26(m,1H),4.93(s,2H),3.23(s,1H),2.84(s,4H),1.76(s,4H).

[0827] Example 19: Preparation of compound C051

[0828]

[0829] Step 1: Preparation of 1-ethyl-1,2,3,6-tetrahydropyridine-4-yltrifluoromethanesulfonate

[0830] 1-Ethylpiperidin-4-one (1.0 g, 7.86 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL), purged with nitrogen, and cooled to -50°C. Lithium di(trimethylsilyl)amino (8.7 mL, 8.65 mmol, 1.0 M in THF) was added, and the reaction was carried out at this temperature for 1 hour. Then, N-phenylbis(trifluoromethanesulfonyl)imide (3.1 g, 8.65 mmol) was added, and the reaction was allowed to proceed to room temperature for another 1 hour. After the reaction was complete, the mixture was quenched with saturated ammonium chloride, extracted three times with ethyl acetate, and the organic phases were combined, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was then subjected to silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 1) to give 1-ethyl-1,2,3,6-tetrahydropyridine-4-yltrifluoromethanesulfonate (1.4 g, yield 67%).

[0831] 1 H NMR (400MHz, CDCl3) δ5.75-5.73(m,1H),3.13(t,J=4.0Hz,2H),2.73(d,J=8.0Hz,2H),2.57-2.52(m,2H),2.55-2.46(m,2H),1.12(t,J=8.0Hz,2H).

[0832] Step 2: Preparation of 2-(2,2-difluoroethoxy)-3-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-6-nitroaniline

[0833] 1-Ethyl-1,2,3,6-tetrahydropyridine-4-yltrifluoromethanesulfonate (233 mg, 0.89 mmol) and 3-(2,2-difluoroethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxophenylboronic acid-2-yl)phenyl-1,2-diamine (306 mg, 0.89 mmol) were dissolved in anhydrous 1,4-dioxane (9.0 mL), and then Pd(dppf)Cl2 (66 mg, 0.09 mmol), potassium carbonate (369 mg, 2.67 mmol), and water (1.0 mL) were added. The mixture was heated to 90°C and reacted for 2 hours. After the reaction was complete, the product was extracted three times with ethyl acetate. The organic phases were combined, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was then purified by silica gel plate chromatography (dichloromethane:methanol = 10:1) to obtain 2-(2,2-difluoroethoxy)-3-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-6-nitroaniline (150 mg, yield 52%).

[0834] MS(ESI) m / z: 328.2 [M+H] + .

[0835] Step 3: Preparation of 3-(2,2-difluoroethoxy)-4-(1-ethylpiperidin-4-yl)phenyl-1,2-diamine

[0836] 2-(2,2-difluoroethoxy)-3-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-6-nitroaniline (150 mg, 0.47 mmol) was dissolved in ethanol (6.0 mL), and platinum dioxide (150 mg) was added. The mixture was purged with hydrogen and heated to 50 °C for 20 hours. After the reaction was complete, the mixture was filtered and concentrated to give 3-(2,2-difluoroethoxy)-4-(1-ethylpiperidin-4-yl)phenyl-1,2-diamine (137 mg, 100% yield).

[0837] MS(ESI) m / z: 300.2 [M+H] + .

[0838] Step 4: Preparation of 7-(4-(2,2-difluoroethoxy)-5-(1-ethylpiperidin-4-yl)-1Hbenzi[d]imidazol-2-yl)-6-methoxy-1H-pyrrolo[3,2-c]pyridine-3-carboxynitrile

[0839] 3-(2,2-difluoroethoxy)-4-(1-ethylpiperidin-4-yl)phenyl-1,2-diamine (137 mg, 0.53 mmol) and reactant 7-formyl-6-methoxy-1H-pyrrole[3,2-c]pyridine-3-carbamate (235 mg, 1.17 mmol) were dissolved in anhydrous N,N-dimethylformamide (10 mL), heated to 90°C and reacted for 20 minutes. Then sodium metabisulfite (300 mg) was added, and the mixture was stirred at 90°C for 3 hours under nitrogen protection. After the reaction was completed, the mixture was filtered and concentrated, then extracted three times with ethyl acetate. The organic phases were combined, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give 7-(4-(2,2-difluoroethoxy)-5-(1-ethylpiperidin-4-yl)-1Hbenzo[d]imidazol-2-yl)-6-methoxy-1H-pyrrolo[3,2-c]pyridine-3-carboxynitrile (150 mg, yield 68.2%).

[0840] MS(ESI) m / z: 481.3 [M+H] + .

[0841] Step 5: Preparation of compound C051

[0842] A mixture of 7-(4-(2,2-difluoroethoxy)-5-(1-ethylpiperidin-4-yl)-1Hbenzo[d]imidazol-2-yl)-6-methoxy-1H-pyrrolo[3,2-c]pyridine-3-carboxynitrile and hydrochloric acid was heated to 100°C and refluxed for 1 hour. After cooling, the pH was adjusted to neutral with saturated sodium bicarbonate, and then extracted three times with ethyl acetate. The organic phases were combined, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was then used to prepare compound C051 (5.74 mg, yield 2%) by HPLC.

[0843] MS(ESI) m / z: 476.3 [M+H] + ;

[0844] 1 H NMR (400MHz, DMSO-d6) δ12.86(s,1H),12.65(s,1H),9.14(s,1H),8.27(d,J=8.0Hz,2H),7.47(d,J=8.0Hz,1H),7.00(t,J=8.0 Hz,1H),6.45-6.30(m,1H),5.05-4.97(m,2H),3.61(d,J=8.0Hz,2H),3.24-3.04(m,4H),1.99-1.88(m,4H),1.27-1.20(m,4H).

[0845] Example 20: Preparation of compound C052

[0846]

[0847] Step 1: Preparation of 7-(4-(2,2-difluoroethoxy)-5-(piperidin-4-yl)-1Hbenzi[d]imidazol-2-yl)-6-oxo-5,6-dihydro-1H-pyrrolo[3,2-c]pyridine-3-carbamate

[0848] 150 mg (0.27 mmol) of 4-(2-(3-cyano-6-methoxy-1H-pyrrolo[3,2-c]pyridin-7-yl)-4-(2,2-difluoroethoxy)-1H-benzo[d]imidazol-5-yl)piperidine-1-carboxylic acid tert-butyl ester was dissolved in 8 mL of 4 mol / L 1,4-dioxane hydrochloric acid solution and stirred at 100 °C for 1 h. After the reaction was completed by TLC monitoring, ammonia was added to quench the reaction. The reaction solution was concentrated under reduced pressure to give 127 mg (99% yield) of 7-(4-(2,2-difluoroethoxy)-5-(piperidine-4-yl)-1Hbenzo[d]imidazol-2-yl)-6-oxo-5,6-dihydro-1H-pyrrolo[3,2-c]pyridin-3-carbamate.

[0849] MS m / z (ESI): 438.2 [M+H] +

[0850] Step 2: Preparation of compound C052

[0851] Sodium triacetylborohydride (726 mg, 3.4 mmol) was added to a solution of 7-(4-(2,2-difluoroethoxy)-5-(piperidin-4-yl)-1Hbenzi[d]imidazol-2-yl)-6-oxo-5,6-dihydro-1H-pyrrolo[3,2-c]pyridine-3-carbamate (127 mg, 0.27 mmol) and oxetane-3-one (244.8 mg, 3.4 mmol) to obtain 1,2-dichloroethane (20 mL). The mixture was stirred at room temperature for 16 h. The reaction solution was distilled under reduced pressure, and the residue was prepared by chiral HPLC to give compound C052 (3.44 mg, yield 2.5%).

[0852] MS m / z (ESI): 495.1 [M+H] + .

[0853] 1 H NMR (400MHz, DMSO-d6) δ8.26(s,1H),8.16(s,1H),7.40(d,J=7.6Hz,1H),7.05(d,J=8.5Hz,1H),6.40(s,1H), 4.91(s,2H),4.55(t,J=6.5Hz,2H),4.46(t,J=6.1Hz,2H),2.83(d,J=11.1Hz,2H),1.86(s,4H),1.72(s,4H).

[0854] Example 21: Preparation of compound C053

[0855]

[0856] Step 1: Preparation of tert-butyl 4-(3-amino-2-(2,2-difluoroethoxy)-4-nitrophenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid

[0857] Under nitrogen protection, Pd(dppf)Cl2 (246 mg, 0.337 mmol) and K2CO3 (1.4 g, 10.11 mmol) were added to a solution of 3-bromo-2-(2,2-difluoroethoxy)-6-nitroaniline (1 g, 3.37 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (1.04 g, 3.37 mmol) to obtain 1,4-dioxane (80 mL) and H2O (10 mL). The mixture was stirred at 90 °C for 2 h. The reaction solution was poured into water (40 mL), extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the residue was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 10:1) to give tert-butyl 4-(3-amino-2-(2,2-difluoroethoxy)-4-nitrophenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid (1 g, yield 74.2%).

[0858] MS m / z (ESI): 400.1 [M+H] + .

[0859] Step 2: Preparation of tert-butyl 4-(3,4-diamino-2-(2,2-difluoroethoxy)phenyl)piperidine-1-carboxylic acid

[0860] 1 g (2.5 mmol) of 4-(3-amino-2-(2,2-difluoroethoxy)-4-nitrophenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester was dissolved in 30 mL of ethanol, and 300 mg of PtO2 was added under a nitrogen atmosphere. The reaction system was purged three times with hydrogen and stirred at room temperature for 16 h under hydrogen pressure (15 psi). The reaction solution was filtered through a diatomaceous earth layer, and the filter residue was washed with methanol. The filtrate was concentrated under reduced pressure to obtain 900 mg (97%) of 4-(3,4-diamino-2-(2,2-difluoroethoxy)phenyl)piperidine-1-carboxylic acid tert-butyl ester.

[0861] MS m / z(ESI): 372.2 [M+H] + .

[0862] Step 3: Preparation of tert-butyl 4-(2-(3-cyano-6-methoxy-1H-pyrrolo[3,2-c]pyridin-7-yl)-4-(2,2-difluoroethoxy)-1H-benzo[d]imidazol-5-yl)piperidine-1-carboxylic acid

[0863] Sodium metabisulfite (950 mg, 4.8 mmol) was added to 7-formyl-6-methoxy-1H-pyrrolo[3,2-c]pyridine-3-carboxylonitrile (487.6 mg, 2.4 mmol) and 4-(3,4-diamino-2-(2,2-difluoroethoxy)phenyl)piperidine-1-carboxylic acid tert-butyl ester (900 mg, 2.4 mmol) to obtain a solution of N,N-dimethylformamide (20 mL), which was stirred at 90 °C for 16 h. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (MeOH:DCM = 1:6) to give 4-(2-(3-cyano-6-methoxy-1H-pyrrolo[3,2-c]pyridin-7-yl)-4-(2,2-difluoroethoxy)-1H-benzo[d]imidazol-5-yl)piperidine-1-carboxylic acid tert-butyl ester (900 mg, yield 67.9%).

[0864] MS m / z (ESI): 553.1 [M+H] + .

[0865] Step 4: Preparation of 7-(4-(2,2-difluoroethoxy)-5-(piperidin-4-yl)-1Hbenzo[d]imidazol-2-yl)-6-methoxy-1H-pyrrolo[3,2-c]pyridine-3-carbamate

[0866] 4-(2-(3-cyano-6-methoxy-1H-pyrrolo[3,2-c]pyridin-7-yl)-4-(2,2-difluoroethoxy)-1H-benzo[d]imidazol-5-yl)piperidine-1-carboxylic acid tert-butyl ester (250 mg, 0.45 mmol) was dissolved in 4 mol / L HCl / 1,4-dioxane solution (8 mL) and stirred at room temperature for 2 h. After the reaction was completed by TLC monitoring, ammonia was added to quench the reaction, and the solution was concentrated under reduced pressure to give 7-(4-(2,2-difluoroethoxy)-5-(piperidine-4-yl)-1Hbenzo[d]imidazol-2-yl)-6-methoxy-1H-pyrrolo[3,2-c]pyridin-3-carbamate (160 mg, yield 78.6%).

[0867] Step 5: Preparation of 7-(4-(2,2-difluoroethoxy)-5-(1-(2-hydroxyethyl)piperidin-4-yl)-1Hbenzi[d]imidazol-2-yl)-6-methoxy-1H-pyrrolo[3,2-c]pyridine-3-carbamate

[0868] 7-(4-(2,2-difluoroethoxy)-5-(piperidin-4-yl)-1Hbenzi[d]imidazol-2-yl)-6-methoxy-1H-pyrrole (240 mg, 0.53 mmol) was dissolved in anhydrous acetonitrile (30 mL), followed by the addition of 2-iodoform-1-ol (91 mg, 0.53 mmol) and K₂CO₃ (220 mg, 1.59 mmol). The mixture was stirred at 80 °C for 16 h. The reaction solution was poured into water (60 mL), extracted with ethyl acetate (50 mL x 2), and the organic phases were combined. The organic phase was washed with saturated brine (30 mL * 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to give 7-(4-(2,2-difluoroethoxy)-5-(1-(2-hydroxyethyl)piperidin-4-yl)-1Hbenzo[d]imidazol-2-yl)-6-methoxy-1H-pyrrolo[3,2-c]pyridine-3-carbamate (180 mg, yield 68.6%).

[0869] MS m / z (ESI): 497.3 [M+H] + .

[0870] Step 6: Preparation of compound C053

[0871] 180 mg (0.36 mmol) of 4-(2-(3-cyano-6-methoxy-1H-pyrrolo[3,2-c]pyridin-7-yl)-4-(2,2-difluoroethoxy)-1H-benzo[d]imidazol-5-yl)piperidine-1-carboxylic acid tert-butyl ester was dissolved in 8 mL of 4 mol / L HCl / 1,4-dioxane solution and stirred at 100 °C for 2 h. After the reaction was completed by TLC monitoring, ammonia was added, and the mixture was concentrated under reduced pressure. The residue was purified by HPLC to obtain compound C053 (11.82 mg, yield 7.4%).

[0872] MS m / z (ESI): 483.2 [M+H] + .

[0873] 1 H NMR (400MHz, DMSO-d6) δ12.83(br,1H),12.64(s,1H),11.53(s,1H),8.27(s,2H),7.46(d,J=8.3Hz,1H),7.03(s,1H),6.42(t,J=42 .7Hz,1H),5.32(s,1H),5.00(td,J=15.6,3.0Hz,2H),3.77(s,2H),3.58(s,2H),3.39(s,1H),3.21(s,4H),1.96(d,J=29.6Hz,4H).

[0874] Example 22: Compound C054

[0875]

[0876] Step 1: Preparation of 8-methyl-8-azabicyclo[3.2.1]oct-2-en-3-yltrifluoromethane sulfonate

[0877] Under nitrogen protection, a solution of 1.1 g (7.86 mmol) of anhydrous tetrahydrofuran in 20 mL was cooled to -50 °C, and a 1.0 mol / L solution of lithium di(trimethylsilyl)amino in tetrahydrofuran in 8.7 mL (8.65 mmol) was slowly added dropwise, with stirring for 1 h. Then, N-phenylbis(trifluoromethanesulfonyl)imide (3.1 g (8.65 mmol) was added. After the addition was complete, the reaction mixture was moved to room temperature and stirred for 1 h. A saturated ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic phases were then combined. The organic phase was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (EA:PE = 1:1) to obtain 8-methyl-8-azabicyclo[3.2.1]oct-2-en-3-yltrifluoromethanesulfonate (1.4 g, yield 63%).

[0878] Step 2: Preparation of 2-(2,2-difluoroethoxy)-3-(8-methyl-8-azabicyclo[3.2.1]oct-2-en-3-yl)-6-nitroaniline

[0879] 8-Methyl-8-azabicyclo[3.2.1]oct-2-en-3-yltrifluoromethanesulfonate (241 mg, 0.89 mmol) and 2-(2,2-difluoroethoxy)-6-nitro-3-(4,4,5,5-tetramethyl-1,3,2-dioxobenzofuran-2-yl)aniline (306 mg, 0.89 mmol) were dissolved in anhydrous 1,4-dioxane (9.0 mL), followed by the addition of Pd(dppf)Cl2 (66 mg, 0.09 mmol), potassium carbonate (369 mg, 2.67 mmol), and water (1.0 mL). The mixture was heated to 90 °C and stirred for 2 h. The reaction solution was diluted with water, extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was subjected to silica gel plate column chromatography (MeOH:DCM = 1:10) to give 2-(2,2-difluoroethoxy)-3-(8-methyl-8-azabicyclo[3.2.1]oct-2-en-3-yl)-6-nitroaniline (170 mg, yield 58%).

[0880] (ESI)m / z:340.2[M+H] + .

[0881] Step 3: Preparation of 3-(2,2-difluoroethoxy)-4-(8-methyl-8-azabicyclo[3.2.1]octane-3-yl)phenyl-1,2-diamine

[0882] 2-(2,2-difluoroethoxy)-3-(8-methyl-8-azabicyclo[3.2.1]oct-2-en-3-yl)-6-nitroaniline (150 mg, 0.44 mmol) was dissolved in ethanol (6.0 mL), and platinum dioxide (150 mg) was added. The system was stirred at 50 °C for 20 h under a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was collected. The filtrate was concentrated under reduced pressure to give 3-(2,2-difluoroethoxy)-4-(8-methyl-8-azabicyclo[3.2.1]octane-3-yl)phenyl-1,2-diamine (130 mg, 95% yield).

[0883] (ESI)m / z:312.2[M+H] + .

[0884] Step 4: Preparation of 7-(4-(2,2-difluoroethoxy)-5-(8-methyl-8-azabicyclo[3.2.1]octane-3-yl)-1Hbenzo[d]imidazol-2-yl)-6-methoxy-1H-pyrrole[3,2-c]pyridine-3-carbatriene

[0885] 3-(2,2-difluoroethoxy)-4-(8-methyl-8-azabicyclo[3.2.1]octane-3-yl)phenyl-1,2-diamine (130 mg, 0.51 mmol) and reactant 7-formyl-6-methoxy-1H-pyrrole[3,2-c]pyridine-3-carboxynitrile (235 mg, 1.17 mmol) were dissolved in anhydrous DMF (10 mL) and heated to 90 °C with stirring for 20 min. Under nitrogen protection, sodium metabisulfite (300 mg) was added and the mixture was stirred at 90 °C for 3 h. The reaction mixture was filtered, the filtrate was diluted with water, extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude product 7-(4-(2,2-difluoroethoxy)-5-(8-methyl-8-azabicyclo[3.2.1]octane-3-yl)-1Hbenzo[d]imidazol-2-yl)-6-methoxy-1H-pyrrole[3,2-c]pyridine-3-carbatriene (140 mg). The crude product was used directly in the next step.

[0886] Ms(ESI)m / z:=493.3[M+H] + .

[0887] Step 5: Preparation of compound C054

[0888] The crude product 7-(4-(2,2-difluoroethoxy)-5-(8-methyl-8-azabicyclo[3.2.1]octane-3-yl)-1Hbenzo[d]imidazol-2-yl)-6-methoxy-1H-pyrrole[3,2-c]pyridine-3-carbatriene (140 mg) obtained in the previous step was dissolved in 10 mL of 4 mol / L HCl / 1,4-dioxane solution and stirred at 100 °C for 1 h. The reaction solution was cooled to room temperature, the pH was adjusted to neutral with saturated sodium bicarbonate, and the mixture was extracted with ethyl acetate. The organic phases were combined. The organic phases were washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by HPLC to obtain compound C054 (16.82 mg, yield 12.4%).

[0889] Ms(ESI)m / z:[M+H] + =479.3.

[0890] 1 H NMR (400MHz, DMSO-d6) δ12.57(s,1H),8.25(s,4H),7.39(d,J=8.3Hz,1H),7.09(d,J=8.5Hz,1H),6.61-6.21(m,1H),4.96-4.90(m,2H ),3.59(d,J=6.4Hz,1H),3.47-3.41(m,2H),2.37-2.28(m,2H),2.25(s,3H),2.16-2.04(m,2H),1.61-1.58(m,2H),1.52-1.39(m,2H).

[0891] Example 23: Preparation of compound C056

[0892]

[0893] Step 1: Preparation of 4-methyl-3-((trimethylsilyl)ethynyl)pyridine

[0894] Ethynyltrimethylsilane (16 g, 163.08 mmol) was added to a TEA (150 mL) solution of 3-iodo-4-methylpyridine (13.7 g, 54.36 mmol), followed by the addition of Pd(PPh3)2Cl2 (954 mg, 1.36 mmol) and CuI (1.04 g, 5.44 mmol). The reaction mixture was stirred at 105 °C under N2 atmosphere for 16 hours. After the reaction was complete as shown by LC-MS, the reaction mixture was filtered through diatomaceous earth. Water (200 mL) was added to the filtrate, and the resulting solution was extracted with ethyl acetate (100 mL × 3). The combined organic extracts were washed with sodium bicarbonate aqueous solution and brine, dried over anhydrous sodium sulfate, filtered under reduced pressure, and the solvent was concentrated to obtain the crude product. The residue was purified by silica gel chromatography to give 4-methyl-3-((trimethylsilyl)ethynyl)pyridine (8 g, yield 66.7%).

[0895] 1 H NMR (400MHz, DMSO-d6) δ7.21(td,J=8.4,7.0Hz,1H),6.83–6.61(m,2H),3.67(d,J=6.7Hz,3H),0.00(s,9H).

[0896] Step 2: Preparation of 4-methyl-3-ynylpyridine

[0897] K₂CO₃ (822 mg, 5.95 mmol) was added to a methanol (10 mL) solution of 4-methyl-3-((trimethylsilyl)ethynyl)pyridine (441 mg, 1.98 mmol), and the mixture was stirred at room temperature for 2 hours. The mixture was then extracted with water (100 mL) and methyl tert-butyl ether (10 mL x 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by rapid silica gel chromatography (SiO₂, 0-50% ethyl acetate: petroleum ether) to give 4-methyl-3-ethynylpyridine (200 mg, yield 67.3%).

[0898] 1 H NMR (400MHz, DMSO-d6) δ7.40 (dd, J = 15.5, 8.4Hz, 1H), 6.97-6.80 (m, 2H), 4.51 (s, 1H), 3.86 (s, 3H).

[0899] Step 3: Preparation of 3-bromo-2-methoxy-5-((4-methylpyridin-3-yl)ethynyl)pyridine-4-amine

[0900] 4-Methyl-3-ynylpyridine (438 mg, 1.33 mmol) and TEA (539 mg, 5.33 mmol) were added to a THF (3 mL) solution of 3-bromo-5-iodo-2-methoxypyridine-4-amine (200 mg, 1.33 mmol), followed by the addition of Pd(PPh3)2Cl2 (19 mg, 0.03 mmol) and CuI (5 mg, 0.03 mmol). The reaction mixture was stirred at room temperature under N2 for 16 hours. After the reaction was complete as shown by LC-MS, the reaction mixture was filtered through diatomaceous earth. Water (20 mL) was added to the filtrate, and the resulting solution was extracted with ethyl acetate (10 mL × 3). The combined organic extracts were washed with saturated sodium bicarbonate aqueous solution and brine, dried over anhydrous sodium sulfate, filtered, and the solvent was concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography (SiO2, ethyl acetate / petroleum ether = 10% elution) to obtain 3-bromo-2-methoxy-5-((4-methylpyridin-3-yl)ethynyl)pyridine-4-amine (300 mg, yield 64.5%).

[0901] 1 H NMR (400MHz, DMSO-d6) δ7.98(s,1H),7.47-7.39(m,1H),7.03-6.92(m,2H),6.30(s,2H),3.95(s,3H),3.89(s,3H).

[0902] Step 4: Preparation of 7-bromo-6-methoxy-2-(4-methylpyridin-3-yl)-1H-pyrrole[3,2-c]pyridine

[0903] t-BuOK (128 mg, 1.14 mmol) was added to a solution of 3-bromo-2-methoxy-5-((4-methylpyridin-3-yl)ethynyl)pyridine-4-amine (200 mg, 0.57 mmol) in NMP (3 mL), and the mixture was stirred at 100 °C for 2 h. After the reaction was complete, water (20 mL) was added, and the resulting solution was adjusted to pH 7 with hydrochloric acid (1 mol / L), and then extracted with ethyl acetate (20 mL x 3). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and the solvent was concentrated under reduced pressure. The residue was purified by rapid column chromatography to give 7-bromo-6-methoxy-2-(4-methylpyridin-3-yl)-1H-pyrrole[3,2-c]pyridine (150 mg, 75% yield).

[0904] 1H NMR (400MHz, DMSO-d6) δ11.40(s,1H),8.42(s,1H),7.46(dt,J=15.2,7.6Hz,1H),7.07–6.91(m,2H),6.72(s,1H),3.95(s,3H),3.83(s,3H).

[0905] Step 5: Preparation of 7-bromo-3-iodo-6-methoxy-2-(4-methylpyridin-3-yl)-1H-pyrrole[3,2-c]pyridine

[0906] NIS (2.23 g, 9.90 mmol) was added to a dimethyl sulfoxide (100 mL) solution of 7-bromo-6-methoxy-2-(4-methylpyridin-3-yl)-1H-pyrrolo[3,2-c]pyridine (3.0 g, 9.34 mmol) at 0 °C. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solvent was removed under reduced pressure. The remaining crude product was washed with water and petroleum ether and dried to give 7-bromo-3-iodo-6-methoxy-2-(4-methylpyridin-3-yl)-1H-pyrrolo[3,2-c]pyridine (3.6 g, 86% yield).

[0907] 1 H NMR (400MHz, DMSO-d6) δ12.22 (s, 1H), 8.59-8.44 (m, 2H), 8.20 (s, 1H), 7.44 (d, J = 5.2Hz, 1H), 3.98 (s, 3H), 2.23 (s, 3H).

[0908] Step 6: Preparation of 7-bromo-6-methoxy-2-(4-methylpyridin-3-yl)-1H-pyrrolo[3,2-c]pyridine-3-carboxynitrile

[0909] Zn(CN)₂ (529 mg, 4.50 mmol) was added to a solution of 7-bromo-3-iodo-6-methoxy-2-(4-methylpyridin-3-yl)-1H-pyrrolo[3,2-c]pyridine (2 g, 4.50 mmol) in N,N-dimethylformamide (50 mL), followed by the addition of Pd(PPh₃)₄ (2.6 g, 2.25 mmol). The mixture was stirred under nitrogen and at 80 °C for 1 hour. Water (200 mL) was added, and a solid precipitated in the reaction solution. The precipitate was filtered. The residue was washed with water and dried to obtain the crude product. The crude product was purified by reverse-phase chromatography to give 7-bromo-6-methoxy-2-(4-methylpyridin-3-yl)-1H-pyrrolo[3,2-c]pyridine-3-carboxynitrile (500 mg, yield 32.3%).

[0910] 1H NMR (400MHz, DMSO-d6) δ12.91 (s, 1H), 8.63 (dd, J = 14.3, 9.2Hz, 2H), 7.68-7.44 (m, 2H), 4.00 (s, 3H), 2.36 (s, 3H).

[0911] Step 7: Preparation of 6-methoxy-2-(4-methylpyridin-3-yl)-7-vinyl-1H-pyrrole[3,2-c]pyridine-3-carboxynitrile

[0912] 7-Bromo-6-methoxy-2-(4-methylpyridin-3-yl)-1H-pyrrolo[3,2-c]pyridine-3-carboxynitrile (4.5 g, 18.7 mmol), potassium trifluoro(vinyl)-14-borane (5.0 g, 37.3 mmol), N-cyclohexyl-N-methylcyclohexaneamine (7.3 g, 37.3 mmol), [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II) (1.4 g, 1.9 mmol), and 1,4-dioxane (30 mL) were stirred at 90 °C for 16 hours. The reaction mixture was concentrated, diluted with ethyl acetate (500 mL), washed with water (500 mL), and the aqueous phase was saturated with sodium chloride and extracted with tetrahydrofuran (500 mL x 2). The combined organic layers were dried and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1 to 5:1) to give 6-methoxy-2-(4-methylpyridin-3-yl)-7-vinyl-1H-pyrrolo[3,2-c]pyridine-3-carboxynitrile (2.5 g, yield 71%).

[0913] MS (m / z): 190.2 [M+H] + .

[0914] Step 8: Preparation of 7-formyl-6-methoxy-2-(4-methylpyridin-3-yl)-1H-pyrrolo[3,2-c]pyridine-3-carboxynitrile

[0915] Potassium osmium tetroxide (VI) (40 mg, 0.1 mmol) was added to an acetone / water (15 mL, 3:2) solution of 6-methoxy-2-(4-methylpyridin-3-yl)-7-vinyl-1H-pyrrole[3,2-c]pyridine-3-carboxynitrile (600 mg, 2.3 mmol), 4-methylmorpholine N-oxide (796 mg, 6.8 mmol), and sodium periodate (963 mg, 4.5 mmol) and stirred at room temperature for 16 h. LC-MS showed the product as the main peak. Ethyl acetate (500 mL) was added to the reaction solution and the mixture was washed with water (500 mL). Sodium chloride was added to the aqueous phase to form a saturated solution, and the mixture was extracted with THF (500 mL x 2). The combined organic layers were dried and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1 to 3:1) to give 7-formyl-6-methoxy-2-(4-methylpyridin-3-yl)-1H-pyrrolo[3,2-c]pyridine-3-carboxynitrile (300 mg, yield 50%).

[0916] Step 9: Preparation of 7-(4-(2,2-dimethylethoxy)-5-(1-methylpiperidin-4-yl)-1H-benzo[d]imidazol-2-yl)-6-methoxy-1H-pyrrolo[3,2-c]pyridine-3-carboxynitrile

[0917] 3-(2,2-dimethylethoxy)-4-(1-methylpiperidin-4-yl)phenyl-1,2-diamine (50 mg, 0.16 mmol) and 7-formyl-6-methoxy-1H-pyrrolo[3,2-c]pyridine-3-carboxynitrile (65 mg, 0.24 mmol) were dissolved in N,N-dimethylformamide (5 ml) solution, and sodium metabisulfite (91.2 mg, 0.48 mmol) was added. The mixture was heated to 90 °C and reacted for 16 h. After the reaction was completed by TLC monitoring, the mixture was purified by vacuum distillation and column chromatography (methanol:dichloromethane = 1:6) to give 7-(4-(2,2-dimethylethoxy)-5-(1-methylpiperidin-4-yl)-1H-benzo[d]imidazol-2-yl)-6-methoxy-1H-pyrrolo[3,2-c]pyridine-3-carboxynitrile (60 mg, yield 80.0%).

[0918] Step 10: Preparation of compound C056

[0919] 7-(4-(2,2-dimethylethoxy)-5-(1-methylpiperidin-4-yl)-1H-benzo[d]imidazol-2-yl)-6-methoxy-1H-pyrrolo[3,2-c]pyridine-3-carboxynitrile (250 mg, 0.53 mmol) was dissolved in 10 mL of 4 M 1,4-dioxane hydrochloric acid solution, heated to 90 °C, and stirred for 2 h. After the reaction was completed by TLC monitoring, ammonia was added to quench the reaction, and the mixture was distilled under reduced pressure to obtain compound C056 (26.38 mg, yield 11%).

[0920] MS (m / z): 453.4 [M+H] + ;

[0921] 1 H NMR(400MHz,DMSO-d6)δ12.59(s,1H),11.96-11.20(m,1H),8.34-8.10(m,3H), 7.42(d,J=8.3Hz,1H),7.06(d,J=8.4Hz,1H),6.63–6.13(m,1H),4.91(br,2H),3 .99–3.73(m,4H),3.15–3.04(m,2H),2.92(d,J=10.9Hz,2H),2.31(s,3H),2.24( s,3H),2.22–2.15(m,1H),2.04(t,J=9.9Hz,2H),1.73(dd,J=22.3,10.1Hz,6H).

[0922] Example 24: Preparation of compound C057

[0923]

[0924] Step 1: Preparation of 7-(5-(1-methylpiperidin-4-yl)-1Hbenzimidazol-2-yl)-2-(4-methylpyridin-3-yl)-6-oxo-5,6-dihydro-1H-pyrrolo[3,2-c]pyridine-3-carboxynitrile

[0925] Compound 7-formyl-6-methoxy-2-(o-tolyl)-1H-pyrrolo[3,2-c]pyridine-3-carboxylonitrile (70 mg, 0.24 mmol) and 4-(4-methylpiperazin-1-yl)phenyl-1,2-diamine (49 mg, 0.24 mmol) were dissolved in N,N-dimethylformamide (5 mL), and sodium metabisulfite (180 mg, 0.96 mmol) was added. The mixture was heated to 90 °C and reacted for 12 h. After the reaction was completed by TLC monitoring, the mixture was purified by column chromatography under reduced pressure (methanol:dichloromethane = 1:9) to give 6-methoxy-7-(5-(1-methylpiperidin-4-yl)-1Hbenzo[d]imidazol-2-yl)-2-(4-methylpyridin-3-yl)-1Hpyrrolo[3,2-c]pyridine-3-carboxylonitrile (80 mg, 70% yield).

[0926] Step 2: Preparation of compound C057

[0927] 230 mg (0.48 mmol) of compound 6-methoxy-7-(5-(1-methylpiperidin-4-yl)-1Hbenzi[d]imidazol-2-yl)-2-(4-methylpyridin-3-yl)-1Hpyrrolo[3,2-c]pyridine-3-carboxynitrile (4 mL) was dissolved in ethanol solution, and 6 mL of 4 M 1,4-dioxane hydrochloric acid solution was added. The mixture was heated to 90 °C and stirred for 3 h. After the reaction was completed by TLC monitoring, the mixture was quenched with ammonia, purified by vacuum distillation and column chromatography (MeOH:DCM = 1:6) to give compound C057 (8.52 mg, yield 3.82%).

[0928] MS m / z(ESI): 464.30 [M+H] + ;

[0929] 1 H NMR (400MHz, DMSO-d6) δ12.51(br,1H),8.75(s,1H),8.63(d,J=5.1Hz,1H),8.30(s,1H),7.60(d,J=8.4Hz,1H),7.55(s,1H),7.51(d,J=5.1 Hz,1H),7.09(d,J=8.3Hz,1H),2.90(d,J=10.4Hz,2H),2.47(s,3H),2.35-2.31(m,1H),2.21(s,3H),2.08-2.03(m,2H),1.78-1.13(m,4H).

[0930] Example 25: Preparation of compound C058

[0931]

[0932] Step 1: Preparation of ((2-fluoro-6-methoxyphenyl)ethynyl)trimethylsilane

[0933] Ethynyltrimethylsilane (16 g, 163.08 mmol) was added to a TEA solution of 1-fluoro-2-iodo-3-methoxybenzene (13.7 g, 54.36 mmol) in 150 mL, followed by the addition of Pd(PPh3)2Cl2 (954 mg, 1.36 mmol) and CuI (1.04 g, 5.44 mmol). The reaction mixture was stirred at 105 °C under N2 atmosphere for 16 hours. After the reaction was complete as indicated by LC-MS, the reaction mixture was filtered through diatomaceous earth. Water (200 mL) was added to the filtrate, and the resulting solution was extracted with ethyl acetate (100 mL × 3). The combined organic extracts were washed with NaHCO3 aqueous solution and brine, dried over anhydrous sodium sulfate, filtered under reduced pressure, and the solvent was concentrated to obtain the crude product. The residue was purified by silica gel chromatography to give ((2-fluoro-6-methoxyphenyl)ethynyl)trimethylsilane (8 g, yield 66.7%).

[0934] 1 H NMR (400MHz, DMSO-d6) δ7.21(td,J=8.4,7.0Hz,1H),6.83–6.61(m,2H),3.67(d,J=6.7Hz,3H),0.00(s,9H).

[0935] Step 2: Preparation of 2-ethynyl-1-fluoro-3-methoxybenzene

[0936] K₂CO₃ (822 mg, 5.95 mmol) was added to a MeOH (10 mL) solution of (2-fluoro-6-methoxyphenyl)ethynyl)trimethylsilane (441 mg, 1.98 mmol), and the mixture was stirred at room temperature for 2 hours. The mixture was then extracted with water (100 mL) and methyl tert-butyl ether (10 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude product was purified by rapid silica gel chromatography (SiO₂, 0-50% EtOAc: PE) to give 2-ethynyl-1-fluoro-3-methoxybenzene (200 mg, yield 67.3%).

[0937] 1 H NMR (400MHz, DMSO-d6) δ7.40 (dd, J=15.5, 8.4Hz, 1H), 6.97-6.80 (m, 2H), 4.51 (s, 1H), 3.86 (s, 3H).

[0938] Step 3: Preparation of 3-bromo-5-((2-fluoro-6-methoxyphenyl)ethynyl)-2-methoxypyridine-4-amine

[0939] 2-Ethynyl-1-fluoro-3-methoxybenzene (438 mg, 1.33 mmol) and TEA (539 mg, 5.33 mmol) were added to a THF (3 mL) solution of compound 3 (200 mg, 1.33 mmol), followed by the addition of Pd(PPh3)2Cl2 (19 mg, 0.03 mmol) and CuI (5 mg, 0.03 mmol). The reaction mixture was stirred at room temperature under N2 for 16 hours. After the reaction was complete as shown by LC-MS, the reaction mixture was filtered through diatomaceous earth. 20 mL of H2O was added to the filtrate, and the resulting solution was extracted with ethyl acetate (10 mL × 3). The combined organic extracts were washed with saturated NaHCO3 aqueous solution and brine, dried over anhydrous sodium sulfate, filtered, and the solvent was concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography (SiO2, ethyl acetate / petroleum ether = 10% elution) to obtain 3-bromo-5-((2-fluoro-6-methoxyphenyl)ethynyl)-2-methoxypyridine-4-amine (300 mg, yield 64.5%).

[0940] 1 H NMR (400MHz, DMSO-d6) δ7.98(s,1H),7.47-7.39(m,1H),7.03-6.92(m,2H),6.30(s,2H),3.95(s,3H),3.89(s,3H).

[0941] Step 4: Preparation of 7-bromo-2-(2-fluoro-6-methoxyphenyl)-6-methoxy-1H-pyrrole[3,2-c]pyridine

[0942] t-BuOK (128 mg, 1.14 mmol) was added to a solution of 3-bromo-5-((2-fluoro-6-methoxyphenyl)ethynyl)-2-methoxypyridine-4-amine (200 mg, 0.57 mmol) in NMP (3 mL), and the mixture was stirred at 100 °C for 2 h. After the reaction was complete, water (20 mL) was added, and the resulting solution was adjusted to pH 7 with hydrochloric acid (1 mol / L), and then extracted with ethyl acetate (20 mL x 3). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and the solvent was concentrated under reduced pressure. The residue was purified by rapid column chromatography to give 3-bromo-5-((2-fluoro-6-methoxyphenyl)ethynyl)-2-methoxypyridine-4-amine (150 mg, 75% yield).

[0943] 1H NMR (400MHz, DMSO-d6) δ11.40(s,1H),8.42(s,1H),7.46(dt,J=15.2,7.6Hz,1H),7.07–6.91(m,2H),6.72(s,1H),3.95(s,3H),3.83(s,3H).

[0944] Step 5: Preparation of 7-bromo-2-(2-fluoro-6-methoxyphenyl)-6-methoxy-1H-pyrrole[3,2-c]pyridine-3-carboxaldehyde

[0945] POCl3 (1.53 g, 8.54 mmol) was added to a DMF (12 mL) solution of 3-bromo-5-((2-fluoro-6-methoxyphenyl)ethynyl)-2-methoxypyridine-4-amine (1 g, 2.85 mmol) at 0 °C. The mixture was stirred at room temperature for 16 hours. The reaction was quenched with saturated NaHCO3 (20 mL), and the reaction solution was diluted with water to precipitate a solid. The solid was filtered, washed with water, and then freeze-dried under vacuum to give 3-bromo-5-((2-fluoro-6-methoxyphenyl)ethynyl)-2-methoxypyridine-4-amine (700 mg, yield 42.4%).

[0946] 1 H NMR (400MHz, DMSO-d6) δ12.66(s,1H),9.61(s,1H),8.84(s,1H),7.62(dd,J=15.2,7.7Hz,1H),7.17-6.97(m,2H),3.98(s,3H),3.81(s,3H).

[0947] Step 6: Preparation of 7-bromo-2-(2-fluoro-6-methoxyphenyl)-6-methoxy-1H-pyrrole[3,2-c]pyridine-3-carboxynitrile

[0948] NH₂OH·HCl (367 mg, 5.27 mmol) and TEA (1.06 g, 10.55 mmol) were added to a DMF (15 mL) solution of 3-bromo-5-((2-fluoro-6-methoxyphenyl)ethynyl)-2-methoxypyridine-4-amine (1 g, 2.64 mmol), and the mixture was stirred at room temperature for 1 hour. Then, T₃P (6.7 g, 21.10 mmol) was added, and the mixture was stirred at 100 °C for 16 hours. After the reaction was complete, water (20 mL) was added, and the resulting solution was extracted with ethyl acetate (20 mL x 3). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and the solvent was concentrated under reduced pressure to give the crude product. The residue was purified by rapid column chromatography to give 7-bromo-2-(2-fluoro-6-methoxyphenyl)-6-methoxy-1H-pyrrole[3,2-c]pyridine-3-carboxynitrile (266 mg, yield 26.8%).

[0949] Step 7: Preparation of 2-(2-fluoro-6-methoxyphenyl)-7-formyl-6-methoxy-1H-pyrrole[3,2-c]pyridine-3-carboxynitrile

[0950] A solution of 7-bromo-2-(2-fluoro-6-methoxyphenyl)-6-methoxy-1H-pyrrolo[3,2-c]pyridine-3-carboxynitrile (641 mg, 1.71 mmol) in tetrahydrofuran (50 mL) was cooled to -78 °C, and then a 2 mmol / L solution of n-BuLi in n-hexane (0.45 mL, 1.13 mmol) was slowly added. The reaction solution was stirred at -78 °C under N2 for 0.5 h. Then DMF (110 mg, 1.50 mmol) was added. The reaction solution was stirred at -78 °C under N2 for 2 h. The reaction mixture was quenched with a saturated NH4Cl solution (5 mL). The solution was extracted with water (20 mL) and ethyl acetate. The combined organic phases were washed with brine (20 mL), dried (Na2SO4), filtered, and concentrated to give 2-(2-fluoro-6-methoxyphenyl)-7-formyl-6-methoxy-1H-pyrrole[3,2-c]pyridine-3-carboxynitrile (455 mg, yield 82.1%).

[0951] Step 8: Preparation of 2-(2-fluoro-6-methoxyphenyl)-6-methoxy-7-(5-(1-methylpiperidin-4-yl)-1Hbenzi[d]imidazol-2-yl)-1Hpyrrolo[3,2-c]pyridine-3-carboxynitrile

[0952] Compound 2-(2-fluoro-6-methoxyphenyl)-7-formyl-6-methoxy-1H-pyrrolo[3,2-c]pyridine-3-carboxylonitrile (60 mg, 0.22 mmol) and compound 8 (107 mg, 0.33 mmol) were dissolved in DMF (5 mL). The mixture was stirred at room temperature for 20 minutes, and then Na2S2O5 (165 mg, 0.87 mmol) was added. The mixture was stirred at 90 °C for 4 h. TLC showed that the starting material reacted completely. The reaction solution was poured into ice water, and a solid precipitated. The mixture was filtered, and the residue was washed with water to give 2-(2-fluoro-6-methoxyphenyl)-6-methoxy-7-(5-(1-methylpiperidin-4-yl)-1Hbenzo[d]imidazol-2-yl)-1Hpyrrolo[3,2-c]pyridine-3-carboxylonitrile (60 mg, yield 35.7%).

[0953] LCMS(ESI) m / z: 511.5 [M+H] + .

[0954] Step 9: Preparation of compound C058

[0955] 2-(2-fluoro-6-methoxyphenyl)-6-methoxy-7-(5-(1-methylpiperidin-4-yl)-1Hbenzi[d]imidazol-2-yl)-1Hpyrrolo[3,2-c]pyridine-3-carboxynitrile (60 mg, 0.13 mmol) was dissolved in a dioxane solution (15 mL) of hydrochloric acid, and the mixture was stirred at 100 °C for 2 h. After the reaction was completed, the dioxane was evaporated to obtain the crude product. The crude product was purified by reverse-phase synthesis to obtain compound C058 (6.49 mg, yield 10.0%).

[0956] MS (m / z): 497.1 [M+H] + ;

[0957] 1 H NMR (400MHz, DMSO-d6) δ12.44(s,1H),8.30(s,1H),8.25(s,1H),7.71-7.63(m,1H),7.57(s,2H),7.18(d,J=8.6Hz,1H),7.10(dd,J =11.5,8.8Hz,2H),3.97(s,3H),2.89(d,J=10.7Hz,2H),2.57–2.52(m,1H),2.22(s,3H),2.02(t,J=10.5Hz,2H),1.84–1.62(m,4H).

[0958] Example 26: Preparation of compound C059

[0959]

[0960] Step 1: Preparation of 3-bromo-2-methoxy-4-aminopyridine

[0961] 2-Methoxy-4-aminopyridine (5 g, 0.4-0.32 mmol) was dissolved in DCM (50 mL). NBS (7.2 g, 40.32 mmol) was slowly added in portions at 0 °C. After the addition was complete, the mixture was brought to room temperature and stirred for 2 h. Water (50 mL) was then added to the reaction system, and the mixture was extracted with DCM (25 mL × 3). The organic phases were combined. The organic phases were washed with brine, dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure to give 3-bromo-2-methoxy-4-aminopyridine (6.0 g, 73% yield).

[0962] MS m / z(ESI): 205.1 [M+H] +

[0963] Step 2: Preparation of 3-bromo-5-iodo-2-methoxy-4-aminopyridine

[0964] 3-Bromo-2-methoxy-4-aminopyridine (6 g, 29.5 mmol) was dissolved in a mixed solution of acetonitrile (240 mL) and acetic acid (6 mL). NIS (7.3 g, 32.5 mmol) was slowly added to this mixture in portions. After the addition was complete, the mixture was stirred overnight at room temperature. Water (300 mL) and EA (100 mL x 3) were added to the reaction system, and the organic phases were combined. The organic phases were washed successively with sodium sulfite solution and saturated brine, dried over anhydrous Na₂SO₄, filtered, and the residue was concentrated under reduced pressure. The residue was then purified using preparative agar to obtain 3-bromo-5-iodo-2-methoxy-4-aminopyridine (9 g, 92.7% yield).

[0965] MS(ESI) m / z: 330.8 [M+H] +

[0966] Step 3: Preparation of 3-bromo-2-methoxy-5-(prop-1-ynyl-1-yl)-4-aminopyridine

[0967] 3-Bromo-5-iodo-2-methoxy-4-aminopyridine (3 g, 9.12 mmol) was dissolved in TEA (75 mL). Pd(PPh3)2Cl2 (160 mg, 0.23 mmol), CuI (174 mg, 0.91 mmol), and propyne were added under a nitrogen atmosphere. The mixture was stirred at room temperature for 16 h. The reaction mixture was then filtered, and 100 mL of water was added to the filtrate. The filtrate was extracted with DCM, and the organic phases were combined. The organic phases were washed successively with saturated ammonium chloride solution and saturated brine, dried over anhydrous Na2SO4, filtered, and the residue was concentrated under reduced pressure and purified by SGC to give 3-bromo-2-methoxy-5-(prop-1-ynyl-1-yl)-4-aminopyridine (1.0 g, yield 46.1%).

[0968] Step 4: Preparation of 7-bromo-6-methoxy-2-methyl-1H-pyrrole[3,2-c]pyridine

[0969] t-BuOK (591 mg, 5.27 mmol) was added to an NMP (8 mL) solution of 3-bromo-2-methoxy-5-(prop-1-ynyl-1-yl)-4-aminopyridine (635 mg, 2.63 mmol), and the mixture was stirred at 100 °C for 1 h. After the reaction was complete as indicated by LCMS, water (20 mL) was added to the mixture, and the pH was adjusted to weakly alkaline with 1 mol / L hydrochloric acid. The mixture was then extracted with ethyl acetate (10 mL × 3), and the organic phases were combined. The organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the residue was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane:methanol = 30:1) to give 7-bromo-6-methoxy-2-methyl-1H-pyrrole[3,2-c]pyridine (540 mg, 85.8%).

[0970] Step 5: Preparation of 7-bromo-3-iodo-6-methoxy-2-methyl-1H-pyrrole[3,2-c]pyridine

[0971] NIS (489 mg, 2.18 mmol) was added to a DMSO (8 mL) solution of 7-bromo-6-methoxy-2-methyl-1H-pyrrole[3,2-c]pyridine, and the mixture was stirred at room temperature for 16 h. After the reaction was complete, water (20 mL) was added to the reaction mixture, and the mixture was extracted with EA. The organic phases were combined. The organic phases were washed successively with saturated sodium sulfite solution and brine, dried over anhydrous Na2SO4, filtered, and the residue was concentrated under reduced pressure and purified by silica gel column chromatography (10% EtOAc / PE) to give 7-bromo-3-iodo-6-methoxy-2-methyl-1H-pyrrole[3,2-c]pyridine (600 mg, yield 79.2%).

[0972] 1H NMR (400MHz, DMSO-d6) δ11.81(s,1H),7.99(s,1H),3.93(s,3H),2.37(s,3H).

[0973] Step 6: Preparation of 7-bromo-6-methoxy-2-methyl-3-cyano-1H-pyrrole[3,2-c]pyridine

[0974] Zn(CN)₂ (417 mg, 3.55 mmol) was added to a DMF (40 mL) solution of 7-bromo-3-iodo-6-methoxy-2-methyl-1H-pyrrole[3,2-c]pyridine (1.3 g, 3.55 mmol). Then, under nitrogen protection, Pd(PPh₃)₄ was added to the system, and the mixture was stirred at 80 °C for 0.5 h. Water (100 mL) was then added to the mixture, resulting in the precipitation of a solid. The mixture was filtered, the filter cake was washed with water, and dried under vacuum to obtain the crude product. The crude product was purified by silica gel column chromatography (10-50% EtOAc / PE) to obtain 7-bromo-6-methoxy-2-methyl-3-cyano-1H-pyrrole[3,2-c]pyridine (500 mg, 53%).

[0975] 1 H NMR (400MHz, DMSO-d6) δ12.41(s,1H),8.38(s,1H),3.95(s,3H),2.54(s,3H).

[0976] Step 7: Preparation of 7-formyl-6-methoxy-2-methyl-1H-pyrrole[3,2-c]pyridine-3-carbamate

[0977] Under nitrogen protection, a solution of 7-bromo-6-methoxy-2-methyl-3-cyano-1H-pyrrolo[3,2-c]pyridine (100 mg, 1.71 mmol) in tetrahydrofuran (5 mL) was cooled to -78 °C, and then a 2.5 mol / L solution of n-butyllithium in n-hexane (0.45 mL, 1.13 mmol) was slowly added dropwise, and the mixture was stirred at -78 °C for 0.5 h. DMF (110 mg, 1.50 mmol) was then added, and the mixture was stirred at -78 °C for another 2 h. The reaction was then quenched by adding saturated NH4Cl solution (5 mL) and water (20 mL), and extracted with EA (20 mL × 3). The organic phases were then combined. The organic phase was washed with brine, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give 7-formyl-6-methoxy-2-methyl-1H-pyrrole[3,2-c]pyridine-3-carbamate (255 mg, yield 69.4%).

[0978] Step 8: Preparation of 7-(4-isobutoxy-5-(1-methylpiperidin-4-yl)-1Hbenzi[d]imidazol-2-yl)-6-methoxy-2-methyl-1H-pyrrolo[3,2-c]pyridine-3-carbamate

[0979] 7-Formyl-6-methoxy-2-methyl-1H-pyrrolo[3,2-c]pyridine-3-carbamate (60 mg, 0.22 mmol) and 3-isobutoxy-4-(1-methylpiperidin-4-yl)phenyl-1,2-diamine (70 mg, 0.33 mmol) were dissolved in DMF (5 ml). The mixture was stirred at room temperature for 20 minutes, and then Na2S2O5 (165 mg, 0.87 mmol) was added. The mixture was heated to 90 °C and stirred for 4 hours. TLC showed complete conversion of the starting material. The reaction solution was poured into ice water, and a solid precipitated out. The mixture was filtered, the filter cake was washed with water, and the solid was collected and dried under vacuum. The solid was 7-(4-isobutoxy-5-(1-methylpiperidin-4-yl)-1Hbenzo[d]imidazol-2-yl)-6-methoxy-2-methyl-1H-pyrrolo[3,2-c]pyridine-3-carbamate (60 mg, yield 57.8%).

[0980] MS(ESI) m / z: 473.5 [M+H] +

[0981] Step 9: Preparation of compound C059

[0982] 7-(4-isobutoxy-5-(1-methylpiperidin-4-yl)-1Hbenzi[d]imidazol-2-yl)-6-methoxy-2-methyl-1H-pyrrolo[3,2-c]pyridine-3-carbamate (60 mg, 0.13 mmol) and NaI (38 mg, 0.25 mmol) were added to acetonitrile (15 mL), followed by the addition of TMCS (28 mg, 0.25 mmol). The mixture was stirred at room temperature for 3 h. The reaction solution was then concentrated under reduced pressure, and the resulting residue was purified by reverse-phase reaction to give compound C059 (14.6 mg, 24.6% yield).

[0983] MS(ESI) m / z: 459.3 [M+H] +

[0984] 1H NMR (400MHz, DMSO-d6) δ8.27(s,1H),8.01(s,1H),7.35(d,J=8.1Hz,1H),7.04(d,J=8.3Hz,1H),4.29(br,2H),3.05(s,1H),2.93( d,J=11.1Hz,2H),2.58(s,3H),2.24(s,3H),2.19–2.12(m,1H),2.06(t,J=10.1Hz,2H),1.77–1.68(m,4H),1.12(d,J=6.7Hz,6H).

[0985] Example 27: Preparation of compound C060

[0986]

[0987] Step 1: Preparation of 3-bromo-2-methoxy-5-(but-1-ynyl-1-yl)-4-aminopyridine

[0988] 3-Bromo-5-iodo-2-methoxy-4-aminopyridine (1 g, 3.04 mmol) was dissolved in MeOH:DMA:H2O = 1:1:1 (15 mL). CsCO3 (1.49 g, 4.56 mmol), CuI (58 mg, 0.30 mmol), Pd(PPh3)2Cl2 (43 mg, 0.06 mmol), and but-1-ynyltrimethylsilane were added under a nitrogen atmosphere. The mixture was stirred at 80 °C for 16 h. After the reaction was complete, the reaction solution was filtered, 100 mL of water was added to the filtrate, and the mixture was extracted with DCM. The organic phases were combined. The organic phases were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by SGC to give 3-bromo-2-methoxy-5-(but-1-ynyl-1-yl)-4-aminopyridine (400 mg, yield 51.6%).

[0989] 1 H NMR (400MHz, DMSO-d6) δ7.79 (s, 1H), 6.10 (s, 2H), 3.84 (s, 3H), 2.50–2.43 (m, 2H), 1.18 (t, J = 7.5Hz, 3H).

[0990] Step 2: Preparation of 7-bromo-6-methoxy-2-ethyl-1H-pyrrole[3,2-c]pyridine

[0991] t-BuOK (440 mg, 3.92 mmol) was added to an NMP (8 mL) solution containing 3-bromo-2-methoxy-5-(but-1-ynyl-1-yl)-4-aminopyridine (500 mg, 1.96 mmol). The mixture was stirred at 100 °C for 1 h. After the reaction was complete as indicated by LCMS, water (20 mL) was added, and the resulting solution was adjusted to pH > 7 with hydrochloric acid (1 mol / L) and extracted with ethyl acetate (10 mL × 3). The organic phases were combined. The organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and the residue was concentrated under reduced pressure and purified by silica gel column chromatography to give 7-bromo-6-methoxy-2-ethyl-1H-pyrrole[3,2-c]pyridine (400 mg, yield 80.3%).

[0992] MS(ESI) m / z: 255.0 [M+H] + ;

[0993] Step 3: Preparation of 7-bromo-3-iodo-6-methoxy-2-ethyl-1H-pyrrole[3,2-c]pyridine

[0994] NIS (417 mg, 1.85 mmol) was added to a solution of 7-bromo-6-methoxy-2-ethyl-1H-pyrrolo[3,2-c]pyridine (450 mg, 1.76 mmol) in DMSO (8 mL), and the mixture was stirred at room temperature for 16 h. After the reaction was complete, water (20 mL) was added, and the mixture was extracted with EA (25 mL x 3), and the organic phases were combined. The organic phases were washed with saturated sodium sulfite solution and brine, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10% EtOAc / PE) to give 7-bromo-3-iodo-6-methoxy-2-ethyl-1H-pyrrolo[3,2-c]pyridine (550 mg, yield 82.2%).

[0995] Step 4: Preparation of 7-bromo-6-methoxy-2-ethyl-3-cyano-1H-pyrrole[3,2-c]pyridine

[0996] Zn(CN)₂ (616 mg, 5.25 mmol) was added to a DMF (40 mL) solution of 7-bromo-3-iodo-6-methoxy-2-ethyl-1H-pyrrole[3,2-c]pyridine (2 g, 5.25 mmol), and Pd(PPh₃)₄ was added under nitrogen protection. The mixture was stirred at 80 °C for 0.5 h, and then water (100 mL) was added, resulting in the precipitation of a solid. The mixture was filtered, the filter cake was washed with water, and dried to give the crude product. The crude product was subjected to silica gel column chromatography (10-50% EtOAc / PE) to give 7-bromo-6-methoxy-2-ethyl-3-cyano-1H-pyrrole[3,2-c]pyridine (800 mg, 55% yield), a yellow solid.

[0997] 1 H NMR (400MHz, DMSO-d6) δ12.39(s,1H),8.40(s,1H),3.95(s,3H),2.90(q,J=7.6Hz,2H),1.33(t,J=7.6Hz,3H).

[0998] Step 5: Preparation of 7-formyl-6-methoxy-2-ethyl-1H-pyrrole[3,2-c]pyridine-3-carbamate

[0999] Under nitrogen protection, a solution of 7-bromo-6-methoxy-2-ethyl-3-cyano-1H-pyrrolo[3,2-c]pyridine (400 mg, 1.43 mmol) in tetrahydrofuran (5 mL) was cooled to -78 °C, and then a 2.5 mol / L n-BuLi solution in n-hexane (1.7 mL, 4.28 mmol) was slowly added dropwise, and the mixture was stirred at -78 °C for 0.5 h. DMF (417 mg, 5.71 mmol) was then added to the system, and the mixture was stirred at -78 °C for another 2 h. A saturated NH4Cl solution and water were then added to the mixture, and the mixture was extracted with EA. The organic phases were then combined. The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and the residue obtained by concentration under reduced pressure was precipitated by silica gel column chromatography to obtain 7-formyl-6-methoxy-2-ethyl-1H-pyrrole[3,2-c]pyridine-3-carbamate (320 mg, yield 46.0%).

[1000] 1 H NMR (400MHz, DMSO-d6) δ12.48(s,1H),10.40(s,1H),8.70(s,1H),4.05(s,3H),2.95(dd,J=15.1,7.6Hz,2H),1.35(dd,J=9.4,1.0Hz,3H).

[1001] Step 6: Preparation of 7-(4-isobutoxy-5-(1-methylpiperidin-4-yl)-1Hbenzi[d]imidazol-2-yl)-6-methoxy-2-ethyl-1H-pyrrolo[3,2-c]pyridine-3-carbamate

[1002] 7-Formyl-6-methoxy-2-ethyl-1H-pyrrolo[3,2-c]pyridine-3-carbamate (74 mg, 0.27 mmol) and 3-isobutoxy-4-(1-methylpiperidin-4-yl)phenyl-1,2-diamine (92 mg, 0.40 mmol) were dissolved in DMF (5 mL), and the mixture was stirred at room temperature for 20 minutes. Then, Na2S2O5 (203 mg, 1.07 mmol) was added, and the mixture was stirred at 90 °C for 4 h. TLC showed complete conversion of the starting material. The reaction mixture was poured into ice water, and a solid precipitated. The solid was filtered, the filter cake was washed with water, and the solid was collected and dried under vacuum to give 7-(4-isobutoxy-5-(1-methylpiperidin-4-yl)-1Hbenzo[d]imidazol-2-yl)-6-methoxy-2-ethyl-1H-pyrrolo[3,2-c]pyridine-3-carbamate (70 mg, yield 53.3%).

[1003] MS (m / z): 487.5 [M+H] +

[1004] Step 7: Preparation of compound C060

[1005] 7-(4-isobutoxy-5-(1-methylpiperidin-4-yl)-1Hbenzi[d]imidazol-2-yl)-6-methoxy-2-ethyl-1H-pyrrolo[3,2-c]pyridine-3-carbamate (70 mg, 0.14 mmol) and NaI (43 mg, 0.29 mmol) were dissolved in acetonitrile (6 mL), and then TMCS (31 mg, 0.29 mmol) was added. The mixture was stirred at room temperature for 3 h. After the reaction was completed, the residue obtained by concentration under reduced pressure was purified by preparative agar (dichloromethane:methanol = 10:1) to give compound C060 (20.6 mg, yield 31.2%).

[1006] LCMS(ESI) m / z: 473.3 [M+H] +

[1007] 1H NMR (400MHz, DMSO-d6) δ14.15(s,1H),12.42(s,1H),8.27(s,1H),8.10(s,1H),7.35(d,J=7.2Hz,1 H),7.04(d,J=7.9Hz,1H),6.84(d,J=8.4Hz,1H),6.47(d,J=8.4Hz,1H),4.43(s,1H),4.15–3.99(m ,1H),3.05-2.91(m,4H),2.41(dd,J=7.4,3.3Hz,1H),2.13(dt,J=13.0,6.8Hz,4H),1.77-1.72(m, 2H),1.65–1.51(m,2H),1.37(t,J=7.6Hz,2H),1.11(dd,J=9.4,6.8Hz,6H),0.73(t,J=7.6Hz,1H).

[1008] Example 28: Preparation of compound C061

[1009]

[1010] Step 1: Preparation of 3-bromo-2-methoxy-5-(3-methyl-1-butynyl)-4-aminopyridine

[1011] The compound 3-bromo-5-iodo-2-methoxy-4-aminopyridine (5 g, 15.20 mmol) was dissolved in a solution of tetrahydrofuran (50 mL) and triethylamine (6.15 g, 60.80 mmol). Cuprous iodide (50 mg, 0.3040 mmol) and palladium dichloride (213.4 mg, 0.30 mmol) were added sequentially, purging with nitrogen. Then, 3-methyl-1-butyne (1.24 g, 18.24 mmol) was added, and the mixture was stirred overnight at room temperature. After the reaction was complete, the mixture was extracted with ethyl acetate (50 mL) and the organic phases were combined. The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and the residue obtained by vacuum distillation of the filtrate was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to give 3-bromo-2-methoxy-5-(3-methyl-1-butynyl)-4-aminopyridine (2.7 g, yield 66.3%).

[1012] MS(ESI) m / z: 268.9 [M+H] +

[1013] Step 2: Preparation of 7-bromo-6-methoxy-2-isopropyl-1H-pyrrole[3,2-c]pyridine

[1014] 2.5 g (9.33 mmol) of 3-bromo-2-methoxy-5-(3-methyl-1-butynyl)-4-aminopyridine was dissolved in NMP (40 mL), and t-BuOK (2.1 g, 18.66 mmol) was added. The reaction mixture was stirred at 100 °C for 1 h. After the reaction was complete, water was added to the mixture, and the pH was adjusted to 7 with 1 mol / L hydrochloric acid. The mixture was extracted with ethyl acetate, and the organic phases were combined. The organic phases were washed with brine, dried over anhydrous Na2SO4, filtered, and the residue was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to give 1.95 g (77.4%) of 7-bromo-6-methoxy-2-isopropyl-1H-pyrrole[3,2-c]pyridine.

[1015] MS(ESI) m / z: 270.8 [M+H] +

[1016] Step 3: Preparation of 7-bromo-3-iodo-6-methoxy-2-isopropyl-1H-pyrrole[3,2-c]pyridine

[1017] 7-Bromo-6-methoxy-2-isopropyl-1H-pyrrolo[3,2-c]pyridine (1.8 g, 6.72 mmol) was dissolved in DMSO (35 mL), and NIS (1.6 g, 7.05 mmol) was slowly added in portions with stirring. The mixture was stirred overnight at room temperature. After the reaction was complete, water (40 mL) was added to the mixture, and the mixture was extracted with ethyl acetate. The organic phases were combined. The organic phases were washed with brine, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to give 7-bromo-3-iodo-6-methoxy-2-isopropyl-1H-pyrrolo[3,2-c]pyridine (2.0 g, 75.5% yield).

[1018] MS(ESI) m / z: 395.0 [M+H] +

[1019] Step 4: Preparation of 7-bromo-6-methoxy-2-isopropyl-3-cyano-1H-pyrrole[3,2-c]pyridine

[1020] Under nitrogen protection, zinc cyanide (0.7 g, 5.84 mmol) and tetrakis(triphenylphosphine)palladium (1.35 g, 1.17 mmol) were added to a DMF (80 mL) solution of 7-bromo-3-iodo-6-methoxy-2-isopropyl-1H-pyrrolo[3,2-c]pyridine (2.32 g, 5.84 mmol), and the mixture was stirred at 80 °C for 0.5 h. After the reaction was complete, water was added to the reaction solution, and a solid precipitated. The solid was filtered through a Buchner funnel, and the filter cake was collected. The filter cake was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to give 7-bromo-6-methoxy-2-isopropyl-3-cyano-1H-pyrrolo[3,2-c]pyridine (1.6 g, yield 92.9%).

[1021] MS (m / z): 295.8 [M+H] +

[1022] Step 5: Preparation of 7-formyl-6-methoxy-2-isopropyl-1H-pyrrole[3,2-c]pyridine-3-carbamate

[1023] 7-Bromo-6-methoxy-2-isopropyl-3-cyano-1H-pyrrolo[3,2-c]pyridine (600 mg, 2.04 mmol) was dissolved in tetrahydrofuran (30 mL), and n-butyllithium (2.5 mL) was added at 0 °C, followed by stirring for 0.5 h. The mixture was then cooled to -78 °C, and DMF (600 mg, 8.16 mmol) was added to the reaction solution. The mixture was stirred at -78 °C for 2 h. After the reaction was complete, a saturated ammonium chloride solution was added to quench the reaction, followed by extraction with ethyl acetate. The organic phases were combined. The organic phases were washed with brine, dried over anhydrous Na2SO4, filtered, and the residue was concentrated under reduced pressure. The residue was then subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to give 7-formyl-6-methoxy-2-isopropyl-1H-pyrrolo[3,2-c]pyridine-3-carbamate (450 mg, 90.8% yield).

[1024] MS(m / z): 244.3 [M+H] +

[1025] Step 6: Preparation of 7-(4-propoxy-5-(1-methylpiperidin-4-yl)-1Hbenzi[d]imidazol-2-yl)-6-methoxy-2-isopropyl-1H-pyrrolo[3,2-c]pyridine-3-carbamate

[1026] 7-Formyl-6-methoxy-2-isopropyl-1H-pyrrolo[3,2-c]pyridine-3-carbamate (100 mg, 0.36 mmol) and 3-propoxy-4-(1-methylpiperidin-4-yl)phenyl-1,2-diamine (180 mg, 0.72 mmol) were dissolved in DMF and stirred at room temperature for 20 minutes. Sodium metabisulfite (275 mg, 1.44 mmol) was then added to the reaction mixture, and the mixture was stirred at 90 °C for 4 hours. After the reaction was complete, the solution was concentrated under vacuum to give 7-(4-isobutoxy-5-(1-methylpiperidin-4-yl)-1Hbenzo[d]imidazol-2-yl)-6-methoxy-2-isopropyl-1H-pyrrolo[3,2-c]pyridine-3-carbamate (170 mg, 94.4% yield).

[1027] LC\\MS(ESI)m / z:487.4[M+H] +

[1028] Step 7: Preparation of compound C061

[1029] 7-(4-propoxy-5-(1-methylpiperidin-4-yl)-1Hbenzi[d]imidazol-2-yl)-6-methoxy-2-isopropyl-1H-pyrrolo[3,2-c]pyridine-3-carbamate (170 mg, 0.36 mmol) was dissolved in acetonitrile (18 mL), and sodium iodide (108 mg, 0.72 mmol) and TMCS (78 mg, 0.72 mmol) were added. The mixture was stirred at room temperature for 3 h. After the reaction was completed, the residue obtained by concentration under reduced pressure was purified by HPLC to obtain compound C061 (1 mg, yield 0.6%).

[1030] LCMS(ESI) m / z: 473.2 [M+H] +

[1031] 1 H NMR (400MHz, DMSO-d6) δ12.49(s,1H),8.12(s,1H),7.62–7.48(m,1H),7.39(d,J=8.3Hz,1H),7.00(d,J=7.8Hz,1H),6.55(s,1H), 4.47(d,J=6.4Hz,2H),2.77(br,1H),2.49(s,3H),1.99-1.90(m,4H),1.46–1.30(m,6H),1.24–1.15(m,4H),1.10(d,J=6.7Hz,6H).

[1032] Example 29: Preparation of compound C062

[1033]

[1034] Step 1: Preparation of 3-bromo-2-methoxypyridine-4-amine

[1035] NBS (28.7 g, 161.3 mmol) was slowly added to a solution of 2-methoxypyridine-4-amine (20 g, 161.3 mmol) in dichloromethane (200 mL) at 0 °C. The ice bath was removed, and the reaction mixture was stirred at room temperature for 2 h. TLC (petroleum ether / ethyl acetate = 3 / 1) showed the reaction was complete. The reaction mixture was directly concentrated to dryness to obtain a crude product, which was purified by rapid column chromatography (petroleum ether / ethyl acetate = 6 / 1) to give 3-bromo-2-methoxypyridine-4-amine (25 g, yield 76.7%).

[1036] Step 2: Preparation of 3-bromo-5-iodo-2-methoxypyridine-4-amine

[1037] At room temperature, NIS (24.4 g, 108.37 mmol) was added fractionally to a solution of 3-bromo-2-methoxypyridine-4-amine (20 g, 98.52 mmol) in acetonitrile (200 mL) and acetic acid (20 mL). The reaction mixture was stirred at room temperature for 16 h. TLC (petroleum ether / ethyl acetate = 20 / 1) showed that the reaction was complete. The reaction mixture was concentrated, and the residue was dissolved in ethyl acetate (300 mL). The solution was washed with water, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by rapid column chromatography (petroleum ether / ethyl acetate = 20 / 1) to give 3-bromo-5-iodo-2-methoxypyridine-4-amine (30 g, yield 92.8%).

[1038] Step 3: Preparation of 3-bromo-5-(cyclopropynyl)-2-methoxypyridine-4-amine

[1039] At room temperature, 10 g (30.40 mmol) of 3-bromo-5-iodo-2-methoxypyridine-4-amine, 12.3 g (121.60 mmol) of triethylamine, 115 mg (0.61 mmol) of cuprous iodide, and 425 mg (0.61 mmol) of bis(triphenylphosphine)-palladium dichloride were added to a 100 mL THF solution. The mixture was purged three times with nitrogen, and then 2.0 g (30.40 mmol) of acetylide was added under nitrogen protection. The reaction mixture was stirred at room temperature for 16 h. The reaction was stopped by TLC (petroleum ether / ethyl acetate = 20 / 1). The reaction mixture was poured into 100 mL of water and extracted with ethyl acetate. The organic phases were combined. The organic phase was washed with a saturated ammonium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by rapid column chromatography (petroleum ether / ethyl acetate = 7 / 1) to give 3-bromo-5-(cyclopropynyl)-2-methoxypyridine-4-amine (7.3 g, yield 90.1%).

[1040] MS m / z: 269.0 [M+H] + ;

[1041] 1 H NMR (400MHz, DMSO-d6) δ7.78(s,1H),6.06(s,2H),3.83(s,3H),1.58(ddd,J=13.2,6.6,4.1,1H),0.88(ddd,J=11.3,5.2,2.9,2H),0.84–0.78(m,2H).

[1042] Step 4: Preparation of 7-bromo-2-cyclopropyl-6-methoxy-1H-pyrrole[3,2-c]pyridine

[1043] 3-Bromo-5-(cyclopropynyl)-2-methoxypyridine-4-amine (7.3 g, 27.34 mmol) was dissolved in toluene (80 mL), and then indium tribromide (4.8 g, 13.67 mmol) was added. The mixture was purged with nitrogen three times, and the temperature was raised to 125 °C under nitrogen atmosphere. The reaction mixture was stirred at this temperature for 2 h. The reaction was stopped by TLC (petroleum ether / dichloromethane = 1 / 1). The reaction mixture was concentrated to obtain a crude product, which was purified by rapid column chromatography (petroleum ether / dichloromethane = 2 / 1) to obtain 7-bromo-2-cyclopropyl-6-methoxy-1H-pyrrole[3,2-c]pyridine (830 mg, yield 11.5%).

[1044] MS (m / z): 266.9 [M+H] + ;

[1045] 1 H NMR (400MHz, DMSO-d6) δ11.32(s,1H),8.18(s,1H),6.12(d,J=1.7,1H),3.89(s,3H),2.01(d,J=16.5,1H),1.02–0.92(m,2H,),0.81–0.72(m,2H).

[1046] Step 5: Preparation of 7-bromo-2-cyclopropyl-6-methoxy-1H-pyrrole[3,2-c]pyridine-3-carbonal

[1047] Phosphorus oxychloride (4.13 g, 26.95 mmol) was dissolved in N,N-dimethylformamide (30 mL) and stirred at 0 °C for 10 min. Then, 7-bromo-2-cyclopropyl-6-methoxy-1H-pyrrole[3,2-c]pyridine (2.4 g, 8.98 mmol) was dissolved in N,N-dimethylformamide (10 mL) and slowly added dropwise to the reaction system. The mixture was then stirred at room temperature for 12 h. After the reaction was completed by TLC monitoring, the reaction was quenched with saturated sodium carbonate solution, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, and purified by column chromatography (ethyl acetate: petroleum ether = 1:3) to give 2 g of 7-bromo-2-cyclopropyl-6-methoxy-1H-pyrrole[3,2-c]pyridine-3-carbonal (yield 43.8%) as a yellow solid.

[1048] MS(m / z): 295.0 [M+H] + ;

[1049] 1 H NMR (400MHz, DMSO-d6) δ11.61(s,1H),10.17(s,1H),8.73(s,1H),3.94(s,3H),2.68(tt,J=8.6,5.3,1H),1.36–1.28(m,2H),1.24–1.19(m,2H).

[1050] Step 6: Preparation of 7-bromo-2-cyclopropyl-6-methoxy-1H-pyrrole[3,2-c]pyridine-3-carbamate

[1051] 7-Bromo-2-cyclopropyl-6-methoxy-1H-pyrrolo[3,2-c]pyridine-3-carbon aldehyde (2 g, 6.77 mmol) was dissolved in N,N-dimethylformamide (30 mL), and hydroxylamine hydrochloride (942 mg, 13.55 mmol), an ethyl acetate solution of 1-propylphosphonic anhydride (10.9 g, 33.88 mmol), and triethylamine (1.4 g, 13.55 mmol) were added. The mixture was heated to 100 °C and reacted for 12 h. After the reaction was completed by TLC monitoring, the mixture was quenched with water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, and purified by column chromatography (ethyl acetate: petroleum ether = 1:4) under reduced pressure to give 7-bromo-2-cyclopropyl-6-methoxy-1H-pyrrolo[3,2-c]pyridine-3-carbon nitrile (280 mg, yield 14.1%).

[1052] MS(m / z): 292.0 [M+H] + ;

[1053] 1H NMR (400MHz, DMSO-d6) δ12.18(s,1H,),8.33(s,1H),3.94(s,3H),2.23(ddd,J=10.4,8.5,5.3,1H),1.27–1.23(m,2H),1.22–1.18(m,2H).

[1054] Step 7: Preparation of 2-cyclopropyl-7-formyl-6-methoxy-1H-pyrrole[3,2-c]pyridine-3-carbamate

[1055] 7-Bromo-2-cyclopropyl-6-methoxy-1H-pyrrolo[3,2-c]pyridine-3-carbamate (210 mg, 0.72 mmol) was dissolved in tetrahydrofuran (8 mL). Butyllithium (0.9 mL, 2.16 mmol) was slowly added dropwise to the reaction system at -78 °C, and the mixture was stirred for 0.5 h. Then, N,N-dimethylformamide (210 mg, 2.88 mmol) was added dropwise to the reaction system, and the temperature was slowly raised to 0 °C, and the mixture was stirred for 2 h. After the reaction was completed by TLC monitoring, the mixture was quenched with water, extracted with dichloromethane, and the organic phases were combined, washed with saturated brine, and purified by column chromatography (ethyl acetate: petroleum ether = 1:3) under reduced pressure to give 2-cyclopropyl-7-formyl-6-methoxy-1H-pyrrolo[3,2-c]pyridine-3-carbamate (100 mg, yield 57.7%).

[1056] MS(m / z): 242.0 [M+H] + .

[1057] Step 8: Preparation of 2-cyclopropyl-6-methoxy-7-(5-(1-methylpiperidin-4-yl)-1Hbenzi[d]imidazol-2-yl)-1Hpyrrolo[3,2-c]pyridine-3-carbamate

[1058] 2-Cyclopropyl-7-formyl-6-methoxy-1H-pyrrolo[3,2-c]pyridine-3-carbamate (80 mg, 0.33 mmol) and 4-(1-methylpiperidin-4-yl)phenyl-1,2-diamine (103 mg, 0.5 mmol) were dissolved in N,N-dimethylformamide (2 mL) solution, and sodium metabisulfite (125 mg, 0.66 mmol) was added. The mixture was heated to 90 °C and reacted for 4 h. After the reaction was completed by TLC monitoring, the mixture was purified by column chromatography under reduced pressure (methanol:dichloromethane = 1:9) to give 2-cyclopropyl-6-methoxy-7-(5-(1-methylpiperidin-4-yl)-1Hbenzo[d]imidazol-2-yl)-1Hpyrrolo[3,2-c]pyridine-3-carbamate (120 mg, yield 85.4%).

[1059] MS(m / z): 427.0 [M+H] + .

[1060] Step 9: Preparation of compound C062

[1061] The compound 2-cyclopropyl-6-methoxy-7-(5-(1-methylpiperidin-4-yl)-1Hbenzi[d]imidazol-2-yl)-1Hpyrrolo[3,2-c]pyridine-3-carbamate (100 mg, 0.23 mmol) was dissolved in acetonitrile solution (2 mL), and trimethylchlorosilane (75 mg, 0.69 mmol) and sodium iodide (100 mg, 0.69 mmol) were added. The mixture was stirred at room temperature for 2 h. After the reaction was completed by TLC monitoring, compound C062 (69 mg, yield 71.3%) was prepared and purified.

[1062] MS(m / z): 413.2 [M+H] + ;

[1063] 1 H NMR(400MHz, DMSO-d6)δ12.43(s,2H),7.97(d,J=12.8Hz,1H),7.85–7.35(m,2H),7.10(dd,J=8.4,1.5Hz,1H),3 .00(d,J=10.7Hz,2H),2.60(d,J=11.3Hz,2H),2.32(s,3H),2.21(s,2H),2.06–1.63(m,4H),1.27–1.18(m,4H).

[1064] Example 30: Preparation of compound C063

[1065]

[1066] Step 1: Preparation of 3-bromo-2-ethoxy-6-nitroaniline

[1067] 2-Amino-6-bromo-3-nitrophenol (1 g, 4.29 mmol) was dissolved in anhydrous acetonitrile (30 mL), followed by the addition of iodoethane (803 mg, 5.15 mmol) and K₂CO₃ (1.78 mg, 12.87 mmol). TLC monitoring showed the reaction was complete, and the reaction mixture was quenched in water (60 mL). The mixture was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to give 3-bromo-2-ethoxy-6-nitroaniline (800 mg, yield 71.6%).

[1068] MS m / z(ESI):[M+H] + =261.0.

[1069] Step 2: Preparation of 2-ethoxy-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-6-nitroaniline

[1070] 3-Bromo-2-methoxy-6-nitroaniline (800 mg, 3.07 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1,2,3,6-tetrahydropyridine (821 mg, 3.68 mmol) were dissolved in 1,4-dioxane (27 mL) and H₂O (4 mL). Under nitrogen protection, Pd(dppf)Cl₂ (227 mg, 0.31 mmol) and K₂CO₃ (1.27 g, 9.21 mmol) were added, respectively. The mixture was then heated to 90 °C and reacted for 2 h to obtain a black suspension. The reaction was monitored by TLC until completion. The reaction solution was then poured into water (20 mL) and extracted with ethyl acetate (30 mL x 3). The organic phases were combined. The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was subjected to column chromatography (PE:EA = 10:1) to give 2-ethoxy-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-6-nitroaniline (500 mg, yield 59%).

[1071] MS m / z(ESI): 278.0 [M+H] + ;

[1072] Step 3: Preparation of 3-ethoxy-4-(1-methylpiperidin-4-yl)phenyl-1,2-diamine

[1073] 2-Ethoxy-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-6-nitroaniline (500 mg, 1.81 mmol) was dissolved in ethanol (30 mL), and PtO2 (250 mg, 1.1 mmol) was added under nitrogen atmosphere. The reaction system was purged with hydrogen three times, and then reacted at room temperature for 16 h under hydrogen pressure (15 psi). TLC showed that the reaction was complete. The reaction solution was filtered through a diatomaceous earth layer and washed with methanol. The filtrate was concentrated to give 3-ethoxy-4-(1-methylpiperidin-4-yl)phenyl-1,2-diamine (400 mg, yield 88.8%).

[1074] MS m / z(ESI): 250.0 [M+H] + .

[1075] Step 4: Preparation of 2-cyclopropyl-7-(4-ethoxy-5-(1-methylpiperidin-4-yl)-1H-benzo[d]imidazol-2-yl)-6-methoxy-1H-pyrrolo[3,2-c]pyridine-3-carbamate

[1076] 3-Ethoxy-4-(1-methylpiperidin-4-yl)phenyl-1,2-diamine (400 mg, 1.61 mmol) and 2-cyclopropyl-7-formyl-6-methoxy-1H-pyrrolo[3,2-c]pyridine-3-carbamate (386 mg, 1.61 mmol) were dissolved in N,N-dimethylformamide (5 mL), and sodium metabisulfite (1.22 mg, 6.44 mmol) was added. The mixture was heated to 90 °C and reacted for 16 h. After the reaction was completed by TLC monitoring, the mixture was purified by column chromatography under reduced pressure (MeOH:DCM = 1:6) to give 2-cyclopropyl-7-(4-ethoxy-5-(1-methylpiperidin-4-yl)-1H-benzo[d]imidazol-2-yl)-6-methoxy-1H-pyrrolo[3,2-c]pyridine-3-carbamate (300 mg, yield 40%).

[1077] MS m / z(ESI): 471.0 [M+H] + .

[1078] Step 5: Preparation of compound C063

[1079] 2-Cyclopropyl-7-(4-ethoxy-5-(1-methylpiperidin-4-yl)-1H-benzo[d]imidazol-2-yl)-6-methoxy-1H-pyrrolo[3,2-c]pyridine-3-carbamate (160 mg, 0.34 mmol) was dissolved in 6 mL of acetonitrile, followed by the addition of sodium iodide (102 mg, 0.68 mmol) and trimethylchlorosilane (73 mg, 0.68 mmol). The reaction was carried out at room temperature for 3 hours. After the reaction was completed by TLC monitoring, the product was sent for purification to obtain compound C063 (14.85 mg, yield 9.6%).

[1080] MS m / z(ESI): [M+H]+=457.2.

[1081] 1 H NMR(400MHz,DMSO-d6)δ12.62(s,1H),12.44(s,1H),11.41(br,1H),9.36(s,1 H),8.06(s,1H),7.38(d,J=8.6Hz,1H),6.98(d,J=8.4Hz,1H),4.74(d,J=7.1H z,2H),3.52(d,J=11.7Hz,2H),3.18(br,2H),2.83(s,3H),2.46-2.26(m,1H), 1.99-1.90(s,4H),1.48(t,J=7.0Hz,3H),1.33(d,J=6.3Hz,2H),1.15(s,2H).

[1082] Example 31: Preparation of compound C064

[1083]

[1084] Step 1: Preparation of 3-bromo-2-isobutoxy-6-nitroaniline

[1085] 1-Iodo-2-methylpropane (622 mg, 4.38 mmol) and K₂CO₃ (1.51 g, 10.94 mmol) were added to a solution of 2-amino-6-bromo-3-nitrophenol (850 mg, 3.65 mmol) in anhydrous acetonitrile (30 mL). The mixture was stirred at room temperature for 16 h. After the reaction was complete as monitored by TLC, the reaction solution was poured into water (60 mL), extracted with ethyl acetate (50 mL × 2), and the organic phases were combined. The organic phases were washed with saturated brine (30 mL²), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was then subjected to silica gel column chromatography (PE:E). A =10:1) Purification yielded 3-bromo-2-isobutoxy-6-nitroaniline (1 g, yield 95%).

[1086] MS m / z(ESI): 289.1 [M+H] +

[1087] Step 2: Preparation of 2-isobutoxy-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-6-nitroaniline

[1088] 3-Bromo-2-isobutoxy-6-nitroaniline (1 g, 3.47 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1,2,3,6-tetrahydropyridine (937 mg, 4.2 mmol) were dissolved in 1,4-dioxane (27 mL) and H₂O (4 mL). Under nitrogen protection, Pd(dppf)Cl₂ (292 mg, 0.4 mmol) and K₂CO₃ (1.45 g, 10.5 mmol) were added to the mixture. After the addition was complete, the mixture was heated to 90 °C and stirred for 2 h. The reaction was monitored by TLC until it was complete. The reaction solution was poured into water (20 mL), extracted with ethyl acetate (30 mL × 3), and the organic phases were combined. The organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the residue was concentrated under reduced pressure and subjected to silica gel column chromatography (PE:E). A =10:1) Purification yielded 2-isobutoxy-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-6-nitroaniline (1 g, yield 94%).

[1089] MS m / z (ESI): 306.1 [M+H] +

[1090] Step 3: Preparation of 3-isobutoxy-4-(1-methylpiperidin-4-yl)phenyl-1,2-diamine

[1091] 1 g (3.28 mmol) of 2-isobutoxy-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-6-nitroaniline was dissolved in ethanol (30 mL), and 500 mg (2.2 mmol) of PtO2 was added under nitrogen atmosphere. The reaction mixture was then purged three times with hydrogen and stirred at room temperature for 16 h under hydrogen atmosphere (15 psi). TLC showed that the reaction was complete. The reaction solution was filtered through diatomaceous earth, the residue was washed with methanol, and the filtrate was collected. The filtrate was concentrated under reduced pressure to give 750 mg (83% yield) of 3-isobutoxy-4-(1-methylpiperidin-4-yl)phenyl-1,2-diamine.

[1092] MS m / z(ESI): 278.2 [M+H] +

[1093] Step 4: Preparation of 2-cyclopropyl-7-(4-isobutoxy-5-(1-methylpiperidin-4-yl)-1H-benzo[d]imidazol-2-yl)-6-methoxy-1H-pyrrolo[3,2-c]pyridine-3-carbatriene

[1094] 3-Isobutoxy-4-(1-methylpiperidin-4-yl)phenyl-1,2-diamine (250 mg, 0.90 mmol) and 2-cyclopropyl-7-formyl-6-methoxy-1H-pyrrole[3,2-c]pyridine-3-carbamate (338 mg, 1.41 mmol) were dissolved in N,N-dimethylformamide (5 ml) solution, and sodium metabisulfite (1072 mg, 5.64 mmol) was added. The mixture was heated to 90 °C and stirred for 16 h. After the reaction was completed by TLC monitoring, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (MeOH:DCM = 1:6) to give 2-cyclopropyl-7-(4-isobutoxy-5-(1-methylpiperidin-4-yl)-1H-benzo[d]imidazol-2-yl)-6-methoxy-1H-pyrrolo[3,2-c]pyridine-3-carbatriene (100 mg, yield 22.2%).

[1095] MS m / z(ESI): 499.0 [M+H] +

[1096] Step 5: Preparation of compound C064

[1097] Sodium iodide (60 mg, 0.40 mmol) and trimethylchlorosilane (43 mg, 0.4 mmol) were added to a solution of 2-cyclopropyl-7-(4-isobutoxy-5-(1-methylpiperidin-4-yl)-1H-benzo[d]imidazol-2-yl)-6-methoxy-1H-pyrrolo[3,2-c]pyridine-3-carbotriene (250 mg, 0.53 mmol) in acetonitrile (6 mL). The mixture was stirred at room temperature for 3 hours. After the reaction was completed by TLC monitoring, the reaction solution was concentrated under reduced pressure. The residue was purified by HPLC to obtain compound C064 (10.23 mg, 10% yield).

[1098] MS m / z (ESI): 485.3 [M+H] +

[1099] 1 H NMR(400MHz,DMSO-d6)δ12.62(s,1H),12.48(s,1H),11.24(s,1H),9.36(s,1H) ,8.07(s,1H),7.32(d,J=8.3Hz,1H),6.98(d,J=7.6Hz,1H),4.44(d,J=6.3Hz,2 H),3.52(d,J=11.6Hz,2H),3.12(s,2H),2.84(s,3H),2.66(s,1H),2.32(s,1H) ,2.22–2.12(m,1H),1.94(s,4H),1.30(d,J=7.5Hz,2H),1.12(d,J=6.7Hz,7H).

[1100] Example 32: Preparation of compound C065

[1101]

[1102] Step 1: Preparation of 1-(bromomethyl)-1-methylcyclopropane

[1103] 1-(hydroxymethyl)-1-methylcyclopropane (1.0 g, 7.18 mmol) and CBr4 (5.4 g, 16.25 mmol) were dissolved in dichloromethane (30 mL). Under nitrogen protection, PPh3 (4.3 g, 16.25 mmol) was added at 0 °C. After the addition was complete, the mixture was allowed to return to room temperature and stirred for 3 h. TLC showed that the starting materials had disappeared. The resulting reaction solution was used directly in the next reaction without any further treatment.

[1104] Step 2: Preparation of 3-bromo-2-((1-methylcyclopropyl)methoxy)-6-nitroaniline

[1105] Potassium carbonate (4.8 g, 34.83 mmol) was added to a solution of 2-amino-6-bromo-3-nitrophenol (3.0 g, 12.77 mmol) in acetonitrile (30 mL). The mixture was stirred at room temperature for 20 minutes. Then, under nitrogen protection, the mixed solution obtained in step 1 was slowly added dropwise to the reaction mixture. After the addition was complete, the temperature was raised to 80 °C and stirred for 16 h. The mixture was cooled to room temperature, filtered through diatomaceous earth, and the filtrate was collected. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (EA / PE 0%–20%) to obtain 3-bromo-2-((1-methylcyclopropyl)methoxy)-6-nitroaniline (1.3 g, yield 37%).

[1106] MS:(ESI)m / z:303.2[M+H] +

[1107] Step 3: Preparation of 2-((1-methylcyclopropyl)methoxy)-6-nitro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaneboron-2-yl)aniline

[1108] 3-Bromo-2-((1-methylcyclopropyl)methoxy)-6-nitroaniline (344 mg, 1.27 mmol) was dissolved in 1,4-dioxane (20 mL), followed by the addition of (Bpin)₂ (3.3 g, 12.96 mmol), Pd(dppf)Cl₂ (316 mg, 0.43 mmol), and KOAc (1.3 g, 12.96 mmol). The mixture was heated to 90 °C and stirred for 16 h under nitrogen protection. After the reaction was complete, the mixture was extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by silica gel column chromatography (EA / PE 0%–10%) to give 2-((1-methylcyclopropyl)methoxy)-6-nitro-3-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)aniline (270 mg, yield 61.1%).

[1109] MS:(ESI)m / z:349.4[M+H] +

[1110] Step 4: Preparation of 3-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-2-((1-methylcyclopropyl)methoxy)-6-nitroaniline

[1111] Under nitrogen protection, 1-ethyl-1,2,3,6-tetrahydropyridine-4-trifluoromethanesulfonate (894 mg, 3.45 mmol), Pd(dppf)Cl2 (252 mg, 0.35 mmol), potassium carbonate (1.4 g, 10.35 mmol), and water (2 mL) were added to a solution of 3-(1-ethyl-1,2,3,6-tetrahydropyridine-4-yl)-2-((1-methylcyclopropyl)methoxy)-6-nitroaniline (270 mg, 0.80 mmol) in 1,4-dioxane (18 mL), and the mixture was heated to 90°C and stirred for 2 h. The reaction was cooled to room temperature, filtered, the filtrate was collected and concentrated, and the crude product was subjected to silica gel column chromatography (EA / PE 0%~100%) to give 3-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-2-((1-methylcyclopropyl)methoxy)-6-nitroaniline (348 mg, yield 30%).

[1112] MS:(ESI)m / z:332.4[M+H] +

[1113] Step 5: Preparation of 4-(1-ethylpiperidin-4-yl)-3-((1-methylcyclopropyl)methoxy)phenyl-1,2-diamine

[1114] 3-(1-Ethyl-1,2,3,6-tetrahydropyridin-4-yl)-2-((1-methylcyclopropyl)methoxy)-6-nitroaniline (249 mg, 0.80 mmol) was dissolved in ethanol (15 mL), and platinum dioxide (183 mg) was added. The mixture was heated to 50 °C and stirred for 20 h under a hydrogen atmosphere. The reaction was cooled to room temperature, filtered through diatomaceous earth, and the filtrate was collected and concentrated under reduced pressure to give 4-(1-ethylpiperidin-4-yl)-3-((1-methylcyclopropyl)methoxy)benzene-1,2-diamine (167 mg, yield 68.9%).

[1115] MS:(ESI)m / z:304.2[M+H] +

[1116] Step 6: Preparation of 2-cyclopropyl-7-(6-(1-ethylpiperidin-4-yl)-7-((1-methylcyclopropyl)methoxy)-1Hbenzi[d]imidazol-2-yl)-6-methoxy-1H-pyrrolo[3,2-c]pyridine-3-carbamate

[1117] 4-(1-ethylpiperidin-4-yl)-3-((1-methylcyclopropyl)methoxy)phenyl-1,2-diamine (167 mg, 0.55 mmol) and 2-cyclopropyl-7-formyl-6-methoxy-1H-pyrrolo[3,2-c]pyridine-3-carbamate (132 mg, 0.55 mmol) were added to anhydrous DMF (10 mL). The mixture was stirred at 90 °C for 20 minutes, and then sodium metabisulfite (418 mg, 2.20 mmol) was added. The mixture was then stirred at 90 °C for 2 hours under nitrogen protection. The reaction mixture was cooled to room temperature, extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give 2-cyclopropyl-7-(6-(1-ethylpiperidin-4-yl)-7-((1-methylcyclopropyl)methoxy)-1Hbenzo[d]imidazol-2-yl)-6-methoxy-1H-pyrrolo[3,2-c]pyridine-3-carbamate (278 mg, yield 96.5%).

[1118] LC-MS: (ESI) m / z: 525.5 [M+H] + ;

[1119] Step 7: Preparation of compound C065

[1120] A mixed solution of 2-cyclopropyl-7-(6-(1-ethylpiperidin-4-yl)-7-((1-methylcyclopropyl)methoxy)-1Hbenzo[d]imidazol-2-yl)-6-methoxy-1H-pyrrolo[3,2-c]pyridine-3-carbamate (278 mg, 0.53 mmol), TMSCl (115 mg, 1.06 mmol), NaI (159 mg, 1.06 mmol), and acetonitrile (4.0 mL) was stirred at room temperature for 2 h under nitrogen protection. After the reaction was complete, the mixture was extracted three times with ethyl acetate, the organic phases were combined, and washed successively with water and saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was used by HPLC to prepare compound C065 (20 mg, 7% yield).

[1121] MS(ESI) m / z: 511.5 [M+H] +

[1122] 1H NMR (400MHz, DMSO-d6) δ12.64(s,1H),9.33(s,1H),8.06(s,1H),7.40(d,J=8. 3Hz,1H),7.00(d,J=8.4Hz,1H),4.42(s,2H),3.62(d,J=11.3Hz,3H),3.24–3.1 4(m,3H),3.08(M,2H),2.40–2.26(m,1H),2.07–1.86(m,4H),1.36(s,3H),1.34 –1.21(m,5H),1.21–1.12(m,2H),0.65(t,J=4.5Hz,2H),0.47(t,J=4.7Hz,2H).

[1123] Example 33: Preparation of compound C066

[1124]

[1125]

[1126] 1. Preparation of methyl (1-fluorocyclopropyl)-4-methylbenzenesulfonate

[1127] Step 1: Preparation of (1-fluorocyclopropyl)methanol

[1128] Under nitrogen protection, lithium aluminum hydride (110 g, 110 mmol) was slowly added to a THF (100 mL) solution of 1-fluorocyclopropane-1-carboxylic acid (10.4 g, 100 mmol). The ice bath was removed, and the reaction mixture was stirred at room temperature for 3 h. TLC (dichloromethane / methanol = 10 / 1) showed that the reaction was complete. Sodium sulfate decahydrate (30 g) was added to the reaction mixture for quenching, and the mixture was filtered. The filtrate was directly concentrated to give (1-fluorocyclopropyl)methanol (9 g, 100% yield).

[1129] 1 H NMR (400MHz, DMSO-d6) δ4.98(t,J=5.9Hz,1H),3.65(d,J=5.9Hz,1H),3.35–3.30(m,1H),0.92(dt,J=13.5,6.5Hz,2H),0.75–0.58(m,2H).

[1130] Step 2: Preparation of methyl (1-fluorocyclopropyl)4-methylbenzenesulfonate

[1131] At 0 °C, TsCl (21 g, 110 mmol) was slowly added to an ultradry solution of (1-fluorocyclopropyl)methanol (9 g, 100 mmol) in 90 mL of dichloromethane. The ice bath was removed, and the reaction mixture was stirred at room temperature for 16 h. TLC (petroleum ether / ethyl acetate = 5 / 1) showed the reaction was complete. The reaction mixture was concentrated to obtain a crude product. The crude product was purified by rapid column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give methyl (1-fluorocyclopropyl)4-methylbenzenesulfonate (10 g, yield 41.7%).

[1132] 1 H NMR (400MHz, DMSO-d6) δ7.81(d,J=8.3Hz,2H),7.49(d,J=8.0Hz,2H),4.39(d,J=22 .7Hz, 2H), 2.43 (s, 3H), 1.06 (dt, J = 18.3, 7.1Hz, 2H), 0.78 (dt, J = 14.8, 7.2Hz, 2H).

[1133] 2. Preparation of compound C066

[1134] Step 1: Preparation of 3-fluoro-2-nitroaniline

[1135] 3-Fluoro-2-nitroaniline (40 g, 251.57 mmol) was dissolved in ammonia-methanol solution (200 mL) at room temperature and reacted for 48 hours. LC-MS showed that after the reaction was complete, water (300 mL) was added to the reaction solution, and the resulting solution was extracted with dichloromethane. The combined organic extracts were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered under reduced pressure, and the solvent was concentrated to obtain a mixture. The addition of petroleum ether (200 mL) to the mixture resulted in the precipitation of a red solid. The mixture was filtered to give 3-fluoro-2-nitroaniline (28 g, 70% yield).

[1136] MS m / z (ESI): 157.0 [M+H] + .

[1137] Step 2: Preparation of 4-bromo-3-fluoro-2-nitroaniline

[1138] In a 500 mL round-bottom flask, 28 g of 3-fluoro-2-nitroaniline (179.48 mmol) was dissolved in 300 mL of anhydrous N,N-dimethylformamide. The mixture was cooled to 0 °C, and NBS (31.8 g, 179.48 mmol) was added and stirred for 30 minutes. The temperature was then raised to 0 °C and reacted for 2 hours. LC-MS showed that the reaction was complete. The reaction mixture was then poured into 200 mL of water and extracted with ethyl acetate (100 mL x 2). The organic phases were combined. The organic phase was washed with 50 mL of saturated brine, then with saturated lithium chloride solution, dried over anhydrous sodium sulfate, and concentrated by filtration to give 28 g of 4-bromo-3-fluoro-2-nitroaniline (99.8% yield).

[1139] MS m / z(ESI): 234.9 [M+H] +

[1140] Step 3: Preparation of tert-butyl(4-bromo-3-fluoro-2-nitrophenyl)(tert-butoxycarbonyl)carbamate

[1141] In a 500 mL round-bottom flask, 24 g of 4-bromo-3-fluoro-2-nitroaniline (102.1 mmol) was dissolved in 250 mL of anhydrous tetrahydrofuran solution. Then, TEA (20.67 g, 204.2 mmol), DMAP (1.25 g, 10.2 mmol), and (Boc)₂O (44.57 g, 204.2 mmol) were added, and the mixture was stirred at room temperature for 5 h. After LC-MS analysis showed the reaction was complete, the reaction mixture was poured into 200 mL of water and extracted with ethyl acetate (100 mL x 2). The organic phases were combined. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain tert-butyl(4-bromo-3-fluoro-2-nitrophenyl)(tert-butyloxycarbonyl)carbamate (22 g, yield 91.6%).

[1142] Step 4: Preparation of 3-amino-6-bromo-2-nitrophenol

[1143] In a 500 mL three-necked flask, tert-butyl(4-bromo-3-fluoro-2-nitrophenyl)(tert-butyloxycarbonyl)carbamate (15 g, 64.65 mmol) was dissolved in anhydrous DMSO (300 mL), followed by the addition of potassium hydroxide aqueous solution (37.5 g / 75 mL). The mixture was heated to 100 °C and stirred for 16 h. After the reaction was complete as indicated by LC-MS, hydrochloric acid was added dropwise to neutralize the reaction solution to pH 7. The solution was then poured into water and extracted with ethyl acetate. The organic phases were combined. The organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain 3-amino-6-bromo-2-nitrophenol (5 g, yield 33.3%).

[1144] MS m / z(ESI): 230.9 [M+H] + . [1...

Claims

1. The compound represented by formula (I) or its pharmaceutically acceptable salt, or its stereoisomer, wherein R 1 It is hydrogen; X is selected from NH or NC. 1-8 alkyl; R 2 Selected from hydrogen, cyano, halogen atom, -C 1-8 Alkyl, -OR 2a -NR 2a R 2b The -C 1-8 Alkyl groups are optionally substituted with at least one substituent R. 2d replace; R 2a and R 2b Each is hydrogen independently; R 2d It is halogen; R 3 Selected from hydrogen, -C 1-8 Alkyl, C 3-6 Cycloalkyl, phenyl, 5- or 6-membered heteroaryl, wherein the C 3-6 Cycloalkyl, phenyl, or 5- or 6-membered heteroaryl groups are each optionally substituted with at least one R group. 3d replace; R 3d It is amino, halogen, -C 1-8 Alkyl, -CN, or -OR 3f ; R 3f Is it hydrogen or -C? 1-8 alkyl; X 1 X 2 X 3 X 4 Each can be independently selected from N or C, provided that the valence theory has been satisfied; n and R 4 The following conditions must be met: n can be 1, 2, or 3, provided that the valence theory is satisfied, and (1) When n is 1, R 4 It is a 4, 5, 6, or 7-membered heterocyclic group containing one or two independent heteroatoms selected from nitrogen, oxygen, or sulfur, or And R 4 Optionally substituent R 4d replace, R 4d It is hydrogen and -C independently. 1-8 Alkyl group, or a 4, 5, 6, or 7-membered heterocyclic group comprising one or two heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein the -C 1-8 Alkyl groups are optionally surrounded by an R 4k Substituent substitution, R 4k Selected from -OR 4i and a 4, 5, 6, or 7-membered heterocyclic group comprising one or two heteroatoms independently selected from nitrogen, oxygen, or sulfur. R 4i It is hydrogen, and The R 4 In X 2 Or X 3 In position; (2) When n is 2, The first R 4 It is a 4, 5, 6, or 7-membered heterocyclic group containing one or two independent heteroatoms selected from nitrogen, oxygen, or sulfur, or And R 4 Optionally substituent R 4d Replace, where R 4d It is hydrogen and -C independently. 1-8 Alkyl group, or a 4, 5, 6, or 7-membered heterocyclic group comprising one or two heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein the -C 1-8 Alkyl groups are optionally surrounded by an R 4k Substituent substitution, R 4k Selected from -OR 4i and a 4, 5, 6, or 7-membered heterocyclic group comprising one or two heteroatoms independently selected from nitrogen, oxygen, or sulfur, and R 4i It is hydrogen; The second R 4 yes: H； Optionally substituent R 4d Replacement -C 1-8 Alkyl, wherein R 4d Yes -NR 4f R 4g And R 4f R 4g Each is independently hydrogen or -C 1-8 alkyl; -OR 4a’ , where R 4a’ It is optionally substituent R 4e Replacement -C 1-8 Alkyl, R 4e It is halogen, C 3-6 Cycloalkyl, or a 4, 5, 6, or 7-membered heterocyclic group comprising one or two heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein the C 3-6 Cycloalkyl groups, or 4, 5, 6, or 7-membered heterocyclic groups comprising one or two heteroatoms independently selected from nitrogen, oxygen, or sulfur, are each optionally bounded by an R 4k Substituent substitution, and R 4k Selected from halogens, -C 1-8 Alkyl; or -NR 4a R 4b , where R 4a R 4b Each is independently hydrogen, or optionally substituent R. 4e’ Replacement -C 1-8 Alkyl, and R 4e’ It is halogen; and The first R 4 In X 2 In position, the second R 4 In X 1 Or X 3 In position, or The first R 4 In X 3 In position, the second R 4 In X 2 Or X 4 In position; (3) When n is 3 The first R 4 It is a 4, 5, 6, or 7-membered heterocyclic group containing one or two independent heteroatoms selected from nitrogen, oxygen, or sulfur, or And R 4 Optionally substituent R 4d Replace, where R 4d It is hydrogen and -C independently. 1-8 Alkyl group, or a 4, 5, 6, or 7-membered heterocyclic group comprising one or two heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein the -C 1-8 Alkyl groups are optionally surrounded by an R 4k Substituent substitution, R 4k Selected from -OR 4i and a 4, 5, 6, or 7-membered heterocyclic group comprising one or two heteroatoms independently selected from nitrogen, oxygen, or sulfur, and R 4i It is hydrogen; The second and third R 4 Each is: H； Optionally substituent R 4d Replacement -C 1-8 Alkyl, wherein R 4d Yes -NR 4f R 4g And R 4f R 4g Each is independently hydrogen or -C 1-8 alkyl; -OR 4a’ , where R 4a’ It is optionally substituent R 4e Replacement -C 1-8 Alkyl, R 4e It is halogen, C 3-6 Cycloalkyl, or a 4, 5, 6, or 7-membered heterocyclic group comprising one or two heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein the C 3-6 Cycloalkyl groups, or 4, 5, 6, or 7-membered heterocyclic groups comprising one or two heteroatoms independently selected from nitrogen, oxygen, or sulfur, are each optionally bounded by an R 4k Substituent substitution, and R 4k Selected from halogens, -C 1-8 Alkyl; or -NR 4a R 4b , where R 4a R 4b Each is independently hydrogen, or optionally substituent R. 4e’ Replacement -C 1-8 Alkyl, and R 4e’ It is halogen, and The first R 4 In X 2 In position, the second R 4 In X 1 In position, the third R 4 In X 3 In position, or The first R 4 In X 3 In position, the second R 4 In X 2 In position, the third R 4 In X 4 In position.

2. The compound according to claim 1, wherein R 3 Selected from hydrogen, -C 1-8 Alkyl, C 3-6 cycloalkyl, phenyl, pyridyl, and the C 3-6 Cycloalkyl, phenyl, or pyridyl groups are each optionally substituted with at least one R group. 3d replace.

3. The compound according to claim 1, wherein R is true when n is 1. 4 Or the first R when n is 2 or 3 4 It is optionally replaced by at least one of the said substituents R 4d Substituted piperidinyl, piperazine, , ,or .

4. The compound according to claim 3, wherein R is defined as follows when n is 1. 4 Or the first R when n is 2 or 3 4 It is optionally replaced by at least one of the said substituents R 4d Replacement , , ,or .

5. The compound according to claim 4, wherein R is true when n is 1. 4 Or the first R when n is 2 or 3 4 It is optionally replaced by at least one of the said substituents R 4d Replacement ,or .

6. The compound according to claim 3, wherein R 4d It is H, -C 1-8 Alkyl group, the -C 1-8 Alkyl groups are optionally substituted with at least one substituent R. 4k Replace; R 4k Independently, it is a 4, 5, or 6-membered heterocyclic group or hydroxyl group that independently contains one or two heteroatoms selected from nitrogen, oxygen, or sulfur.

7. The compound according to claim 3, wherein R 4d It is hydrogen, methyl, ethyl, , , , ,or .

8. The compound according to claim 7, wherein R 4d It is hydrogen, methyl, ethyl, , ,or .

9. The compound according to claim 3, wherein R is defined as follows when n is 1. 4 Or the first R when n is 2 or 3 4 yes: , , , , , , , , , , , ,or .

10. The compound according to claim 9, wherein R is defined as follows when n is 1. 4 Or the first R when n is 2 or 3 4 yes: , , , , , , , , , ,or .

11. The compound according to claim 9, wherein R is true when n is 1. 4 Or the first R when n is 2 or 3 4 yes: , , , , , , , ,or .

12. The compound according to claim 9, wherein R is true when n is 1. 4 Or the first R when n is 2 or 3 4 yes: , , , , , ,or .

13. The compound according to claim 1, wherein in the second R 4 and the third R 4 In the definition of each of them: The R 4a’ R 4a and R 4b -C 1-8 Alkyl groups are -C 1-6 Alkyl groups; and / or The R 4e and R 4e’ The halogens in it are fluorine, chlorine; and / or The R 4e C in 3-6 The cycloalkyl group is a C3 cycloalkyl group; and / or The R 4k The halogens in it are fluorine, chlorine, bromine; and / or The R 4k -C 1-8 Alkyl groups are -C 1-6 Alkyl groups; and / or The R 4f and R 4g -C 1-8 Alkyl groups are -C 1-6 alkyl.

14. The compound according to claim 13, wherein: The R 4a’ R 4a and R 4b -C 1-8 Alkyl groups are methyl, ethyl, isopropyl, n-propyl, ; and / or The R 4e and R 4e’ The halogen in it is fluorine; and / or The R 4k The halogen in it is fluorine; and / or The R 4k -C 1-8 Alkyl groups are methyl groups; and / or The R 4f and R 4g -C 1-8 Alkyl is methyl.

15. The compound according to claim 1, wherein: The second R 4 and the third R 4 Independently, H and -C 1-8 Alkyl, or -OR 4a’ ; in: The R 4a’ It is -C 1-8 Alkyl, and the -C 1-8 The alkyl group is optionally substituent for at least one R group. 4e replace; The R 4e Is it halogen, or C? 3-6 cycloalkyl, the C 3-6 cycloalkyl group is optionally surrounded by an R 4k Substituent substitution; The R 4k Independently selected from halogens, -C 1-8 alkyl.

16. The compound according to claim 1, wherein the second R 4 and the third R 4 Independently, H, methyl, , , , , , , , , , , , , , , , , ,or .

17. The compound of claim 16, wherein the second R 4 and the third R 4 Independently, H, methyl, , , , , , , ,or .

18. The compound of claim 16, wherein the second R 4 and the third R 4 It is methyl, , , , , , ,or .

19. The compound according to claim 16, wherein the second R 4 and the third R 4 It is methyl, , , , ,or .

20. The compound according to claim 1, wherein n is 1, and the R 4 In X 2 In position.

21. The compound according to claim 1, wherein n is 2.

22. The compound of claim 21, wherein the first R 4 In X 2 In position, the second R 4 In X 1 Or X 3 In position.

23. The compound according to claim 1, wherein n is 3.

24. The compound of claim 23, wherein the first R... 4 In X 2 In position, the second R 4 In X 1 In position, the third R 4 In X 3 In position.

25. Compounds represented by general formula (II) or its pharmaceutically acceptable salt, or its stereoisomer, wherein R 1 Selected from hydrogen; X is selected from NH or NC. 1-8 alkyl; R 2 Selected from hydrogen, cyano, halogen atom, -C 1-8 Alkyl, -OR 2a -NR 2a R 2b The -C 1-8 Alkyl groups are optionally substituted with at least one substituent R. 2d replace; R 2a and R 2b Each is hydrogen independently; R 2d It is halogen; R 3 Selected from hydrogen, -C 1-8 Alkyl, C 3-6 Cycloalkyl, phenyl, 5- or 6-membered heteroaryl, wherein the C 3-6 Cycloalkyl, phenyl, or 5- or 6-membered heteroaryl groups are each optionally substituted with at least one substituent R. 3d replace; R 3d It is amino, halogen, -C 1-8 Alkyl, -CN, or -OR 3f ; R 3f Is it hydrogen or -C? 1-8 alkyl; X 1 X 2 X 3 X 4 Each can be independently selected from N or C, provided that the valence theory has been satisfied; R 5 Selected from: hydrogen; Optionally substituent R 5d Replacement -C 1-8 alkyl; -OR 5a’ , where R 5a’ It is optionally substituent R 5e Replacement -C 1-8 Alkyl, and R 5e It is halogen, C 3-6 Cycloalkyl, or a 4, 5, 6, or 7-membered heterocyclic group comprising one or two heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein the C 3-6 Cycloalkyl groups, or 4, 5, 6, or 7-membered heterocyclic groups comprising one or two heteroatoms independently selected from nitrogen, oxygen, or sulfur, are each optionally bounded by an R 5k Substituent substitution; -NR 5a R 5b , where R 5a and R 5b Each is independently hydrogen or -C 1-8 Alkyl, the -C 1-8 The alkyl group is optionally substituent for at least one R group. 5e’ Replace, and R 5e’ It is halogen; R 5d Yes -NR 5f R 5g ; R 5k Selected from halogens, -C 1-8 alkyl; R 5f and R 5g Each is independently hydrogen or -C 1-8 alkyl; s can be 0, 1, or 2, provided that the valence theory is satisfied; Cy1 is selected from 4, 5, 6, or 7-membered heterocyclic groups containing one or two heteroatoms independently selected from nitrogen, oxygen, or sulfur, or Cy1 is randomly selected by t R 6 replace; R 6 Selected from hydrogen, -C 1-8 Alkyl group, or a 4, 5, 6, or 7-membered heterocyclic group comprising one or two heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein the -C 1-8 Alkyl groups are optionally substituted with one substituent R. 6d replace; R 6d It is a 4, 5, 6, or 7-membered heterocyclic group, or -OR, containing one or two independent heteroatoms selected from nitrogen, oxygen, or sulfur. 6f ; R 6f It is hydrogen; t can be 0, 1, or 2, provided that the valence theory is satisfied.

26. The compound according to claim 25, wherein R 3 Selected from hydrogen, -C 1-8 Alkyl, C 3-6 cycloalkyl, phenyl, pyridyl, and the C 3-6 Cycloalkyl, phenyl, or pyridyl groups are each optionally substituted with at least one R group. 3d replace.

27. The compound according to claim 25, wherein: The R 5a’ R 5a and R 5b -C 1-8 Alkyl groups are -C 1-6 Alkyl groups; and / or The R 5e and R 5e’ The halogens in it are fluorine, chlorine; and / or The R 5e C in 3-6 The cycloalkyl group is a C3 cycloalkyl group; and / or The R 5k The halogens in it are fluorine, chlorine, bromine; and / or The R 5k -C 1-8 Alkyl groups are -C 1-6 Alkyl groups; and / or The R 5f and R 5g -C 1-8 Alkyl groups are -C 1-6 alkyl.

28. The compound according to claim 27, wherein: The R 5a’ R 5a and R 5b -C 1-8 Alkyl groups are methyl, ethyl, isopropyl, n-propyl, ; and / or The R 5e and R 5e’ The halogen in it is fluorine; and / or The R 5k The halogen in it is fluorine; and / or The R 5k -C 1-8 Alkyl groups are methyl groups; and / or The R 5f and R 5g -C 1-8 Alkyl is methyl.

29. The compound according to claim 25, wherein R 5 Selected from H, methyl, , , , , , , , , , , , , , , , , , .

30. The compound according to claim 29, wherein R 5 Selected from H, methyl, , , , , , , , .

31. The compound according to claim 29, wherein R 5 Selected from methyl, , , , , , , .

32. The compound according to claim 29, wherein R 5 Selected from methyl, , , , , .

33. The compound according to claim 25, wherein Cy1 is piperidinyl, piperazine, or... , ,or .

34. The compound according to claim 33, wherein Cy1 is , , ,or .

35. The compound according to claim 34, wherein Cy1 is ,or .

36. The compound according to claim 25, wherein R 6 It is H, -C 1-8 Alkyl group, the -C 1-8 Alkyl groups are optionally substituted with at least one substituent R. 6d Replace; R 6d Independently, it is a 4, 5, or 6-membered heterocyclic group or hydroxyl group that independently contains one or two heteroatoms selected from nitrogen, oxygen, or sulfur.

37. The compound according to claim 25, wherein R 6 It is hydrogen, methyl, ethyl, , , , ,or .

38. The compound according to claim 37, wherein R 6 It is hydrogen, methyl, ethyl, , ,or .

39. The compound according to claim 25, wherein... The structural part is selected from: 、 、 、 、 、 、 、 、 、 、 、 、 。 40. The compound according to claim 25, wherein... The structural part is selected from: 、 、 、 、 、 、 、 、 、 、 。 41. The compound according to claim 25, wherein... The structural part is selected from: 、 、 、 、 、 、 、 、 。 42. The compound according to claim 25, wherein... The structural part is selected from: 、 、 、 、 、 、 。 43. The compound according to claim 25, wherein Cy1 is in X 2 In position, When s is 1, R 5 In X 1 Or X 3 In position; When s is 2, the first R 5 In X 1 In position, the second R 5 In X 3 In position.

44. The compound according to claim 25, wherein Cy1 is in X 3 In position, When s is 1, R 5 In X 2 Or X 4 In position; When s is 2, the first R 5 In X 2 In position, the second R 5 In X 4 In position.

45. The compound according to any one of claims 1-44, wherein... X is NH; and / or X 1 X 2 X 4 It is C, and X 3 It is C or N; and / or R 2 Selected from hydrogen, cyano, and optionally substituent R. 2d Replacement -C 1-8 alkyl.

46. ​​The compound according to claim 45, wherein... X 3 It is C; and / or R 2 Selected from cyano, .

47. The compound according to claim 46, wherein R 2 It is a cyano group.

48. The compound according to any one of claims 1-44, wherein: R 3f It is hydrogen, or -C 1-6 alkyl.

49. The compound according to claim 48, wherein: R 3f It is hydrogen, methyl, or ethyl.

50. The compound according to claim 1 or 25, wherein R 3 Selected from H, methyl, ethyl, isopropyl, , , , , , , , , , , , , .

51. The compound according to claim 50, wherein R 3 Selected from H, methyl, ethyl, isopropyl, , , , , , , .

52. The compound according to claim 50, wherein R 3 Selected from H, ethyl, isopropyl, , .

53. A compound, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein the compound is selected from: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 54. A pharmaceutical composition comprising the compound of any one of claims 1-53, or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, and a pharmaceutically acceptable pharmaceutical carrier.

55. A pharmaceutical composition comprising the compound of any one of claims 1-53 or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, and one or more other therapeutically active ingredients.

56. The use of any compound according to any one of claims 1-53, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, in the preparation of a medicament for treating and / or preventing HPK1-mediated related diseases, wherein the HPK1-mediated related diseases are selected from: lung cancer, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, breast cancer, head and neck cancer, endometrial cancer, rectal cancer, liver cancer, kidney cancer, renal pelvis cancer, esophageal cancer, prostate cancer, thyroid cancer, lymphoma, neurofibromatosis, skin cancer, brain cancer, colon cancer, testicular cancer, multiple myeloma, leukemia, choriocarcinoma, sarcoma, and myelodysplastic syndrome.

57. The use of any compound of claims 1-53 or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, in the preparation of a medicament for the treatment and / or prevention of HPK1-mediated related diseases, wherein the HPK1-mediated related diseases are selected from: ductal carcinoma of the breast, esophageal adenocarcinoma, oral cancer, pharyngeal cancer, glioma, non-Hodgkin lymphoma, melanoma, gastrointestinal stromal tumor, endometrial cancer, and bone cancer.

58. The use of any compound of claims 1-53 or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, in the preparation of a medicament for the treatment and / or prevention of HPK1-mediated related diseases, wherein the HPK1-mediated related disease is squamous cell carcinoma.

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