Nitrogen-containing polycyclic condensed ring system compounds, pharmaceutical compositions thereof, production methods, and uses

Abstract

The present invention relates to a nitrogen-containing polycyclic fused ring compound represented by formula I, its pharmaceutical composition, preparation method and use. Such a compound can be a highly selective and highly effective RET inhibitor, and has a strong inhibitory effect on RET gatekeeper residue mutant RET V804M mutation, RET solvent front residue mutant G810R and other clinically relevant RET mutants and RET-wt. The compound can also significantly inhibit the growth of TT cell line derived from thyroid cancer and Ba / F3 cells transformed with various RET mutants, and the inhibitory effect is stronger than that of the selective RET inhibitor LOXO-292. In addition, the compound can significantly block the autophosphorylation of cellular RET and its downstream pathway, and significantly induce the death of TT cells. [Formula 1] JPEG2024505711000472.jpg41169

Description

Technical Field

[0001] This application claims the priority of a Chinese patent application for invention, with the application number 202110172167.6 and the title "Nitrogen-containing polycyclic condensed ring compounds, pharmaceutical compositions thereof, production methods and uses", which was filed with the China National Intellectual Property Administration on February 8, 2021. The said prior application is incorporated herein by reference in its entirety.

[0002] The present invention relates to the field of medicinal chemistry, and more specifically, to nitrogen-containing polycyclic condensed ring compounds, pharmaceutical compositions thereof, production methods and uses.

Background Art

[0003] According to research, the onset of many diseases, including papillary thyroid carcinoma (PTC) (Cell, 1990, 60(4):557~563), medullary thyroid carcinoma (MTC) (Thyroid, 2009, 19(6):565~612), multiple endocrine neoplasia type II (MEN2) (Endocr Rev, 2006, 27(5): 535~560), Hirschsprung's disease (Proc Natl Acad Sci USA, 2000, 97(1):268~273), and lung adenocarcinoma (Nat Med, 2012, 18(3):375~377), is closely related to RET gene mutations. Currently, only four RET fusion genes, namely KIF5B-RET, CCDC6-RET, TRIM33-RET, and NCOA4-RET, have been reported in non-small cell lung cancer, and KIF5B-RET is the most common RET fusion gene in non-small cell lung cancer (Cancer, 2013, 119(8):1486~1494). KIF5B-RET is a fusion gene formed by the chromosomal inversion (p11;q11) of the KIF5B (kinesin family member 5B) gene and the RET gene. It was first confirmed in adenocarcinoma of non-smoking Koreans through whole-genome and transcriptome sequencing. KIF5B-RET has a very low prevalence in lung cancer, is more commonly found in non-smokers and adenocarcinoma patients, and excludes other mutations such as EGFR, KRAS, BRAF, ErbB2, and EML4-ALK (Genome Res, 2012, 22(3):436~445). The KIF5B-RET fusion protein contains a motor domain and a coiled-coil domain of KIF5B. The RET tyrosine kinase activity of this fusion protein is abnormally activated by the dimerization of the coiled-coil domain, thus promoting the development of lung tumors (Cancer, 2011, 117(12):2709~2718).In the study by Qian et al. (Mol Cancer, 2014, 13:176), it has been demonstrated that the KIF5B-RET fusion kinase has significant carcinogenic activity both in vitro and in vivo, and the STAT3 signaling pathway may be a major downstream mediator of tumorigenesis. There is evidence indicating that KIF5B-RET can regulate the constitutive activation of STAT3. The KIF5B-RET fusion kinase can bind to STAT3, directly phosphorylate and activate STAT3-Tyr705, mediate the activation of STAT3-Tyr705 via the JAK / STAT3-dependent pathway, and also induce the phosphorylation of Ser727 via the RAS / RAF / MEK / ERK1 pathway.

[0004] RET fusions have been shown to be drivers in several cancers and to promote the application of multi-kinase inhibitors that already have RET inhibitory activity for treating tumor patients carrying RET fusion proteins. Currently, there are no approved drugs available for targeting this oncogene, and currently, the treatment methods for RET-specific cancers are limited to multi-kinase inhibitors and chemotherapy. However, these non-specific treatments do not have a good objective response rate (ORR) clinically and have very high off-target toxicity. Furthermore, one of the biggest challenges in cancer treatment is that tumor cells acquire drug resistance after a certain treatment stage. When drug resistance occurs, the treatment options for patients generally become extremely limited, and in most cases, the cancer progresses without being inhibited. Currently, RET kinase signaling has already been discovered to play an important role in various human cancers such as thyroid cancer. Among them, the RET gatekeeper residue RET 804V mutation is a factor that causes tumor resistance to currently approved non-selective RET inhibitors (such as cabozantinib and vandetanib). One of the important mutations in the RET extracellular domain or intracellular domain of sporadic familial medullary thyroid cancer, namely, the gatekeeper residue V804M mutation in the kinase ATP binding site, causes a decrease in the affinity of conventional drugs for the ATP binding site.Although the selective RET inhibitor LOXO-292 (Selpercatinib) can avoid the above-mentioned RET 804V mutation, other mutations may occur after the use of the selective RET inhibitor, leading to drug resistance. For example, in non-small cell lung cancer, mutations in the solvent front residue G810 in the kinase ATP binding site, such as G810R, G810S, and G801C mutations, are caused, resulting in a decrease in the binding site of LOXO-292 to ATP, thereby causing drug resistance and tumor progression. This has been reported in the literature (RET Solvent Front Mutations Mediate Acquired Resistance to Selective RET Inhibition in RET-Driven Malignancies, Journal of Thoracic Oncology, 2020, Vol.15, No 4, 541~549). Therefore, it is necessary to develop a RET mutation inhibitor with improved performance.

Summary of the Invention

[0005] To improve the above problems, the present invention provides a compound represented by the following formula I, its stereoisomer, racemate, tautomer, isotope label, nitrogen oxide or pharmaceutically acceptable salt:

Chemical Formula

Chemical Formula

[0006] For example, when NH2 is substituted with two substituents R c , the two substituents R c are unsubstituted or optionally substituted with R fA 5- to 20-membered heteroaryl group or 3- to 20-membered heterocyclyl group substituted with one, two or more substituents independently selected from, for example, unsubstituted or optionally R f A 5-, 6- or 7-membered heteroaryl group substituted with one, two or more substituents independently selected from, or unsubstituted or optionally R f A 3-, 4-, 5-, 6- or 7-membered heterocyclyl group substituted with one, two or more substituents independently selected from can be formed;

[0007] According to an embodiment of the present invention, X 1 X 2 X 3 X 4 X 5 X 6 X 7 are the same or different and are independently selected from CR 1 or N, for example, at least one of X 1 X 2 X 3 X 4 X 5 X 6 X 7 is N, for example 1, 2, 3, 4, 5, 6 or 7 are N;

[0008] According to an embodiment of the present invention, X 8 is selected from CR 1 R 1’ or NR 1 ;

[0009] According to an embodiment of the present invention, each R 1 and R 1’ are the same or different and are independently selected from H, halogen, CN, OH, C 1-6 alkyl group, C 3-10 cycloalkyl group, C 1-6 alkyloxy group;

[0010] According to an embodiment of the present invention, A is selected from H, halogen, CN, OH, C 1-6 alkyl group, C 1-6 alkyloxy group;

[0011] According to an embodiment of the present invention, D and E are the same or different and are independently of each other H, halogen, CN, unsubstituted or optionally substituted with one, two or more substituents selected independently from R c substituted NH2 or -O-R 21 selected from, provided that at least one of D and E is not H, for example, at least one of D and E is -O-R 21 or unsubstituted or optionally substituted with one, two or more substituents selected independently from R c substituted NH2;

[0012] According to an embodiment of the present invention, R 21 is selected from an unsubstituted or optionally substituted C d alkyl group with one, two or more substituents selected from R 1-6 ;

[0013] According to an embodiment of the present invention, R 2 and R 3 together with the linked N atom can form an unsubstituted or optionally substituted 5- to 20-membered heteroaryl group or 3- to 20-membered heterocyclyl group with one, two or more substituents selected independently from R f , for example, a 5-, 6- or 7-membered heteroaryl group or a 3-, 4-, 5-, 6- or 7-membered heterocyclyl group;

[0014] According to an embodiment of the present invention, each R 01 , R 02 , R 03 , R 04 is the same or different and is independently of each other H, C 1-6 alkyl group, C 1-6 alkyloxy group;

[0015] According to an embodiment of the present invention, each R a , R b , R c , R d , R e , R fare the same or different and, independently of each other, are halogen, NH2, CN, OH, unsubstituted or optionally substituted with one, two or more R g substituted C 1-6 alkyl group, C 1-6 alkyloxy group, C 3-10 cycloalkyl group, C 3-10 cycloalkyloxy group, C 2-6 alkynyloxy group, a 3- to 8-membered heterocyclyl group, a 3- to 8-membered heteroaryl group;

[0016] According to an embodiment of the present invention, each R g is the same or different and, independently of each other, is selected from OH, halogen or C 3-10 cycloalkyl group;

[0017] According to an embodiment of the present invention, G is halogen, C 3-10 cycloalkyl group, C 3-10 cycloalkyl-NH-, C 6-14 aryl group, a 5- to 14-membered heteroaryl group, a 3- to 12-membered heterocyclyl group, and is, for example, a 6- to 12-membered heterocyclyl group having a monocyclic, bicyclic, tricyclic or bridged ring structure that may contain 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, provided that at least one of the heteroatoms is selected from N, and for example 1, 2 or 3 heteroatoms are selected from N.

[0018] According to an embodiment of the present invention, K is -C 1-6 alkyl-C 3-10 cycloalkyl group, -C 1-6 alkyl-C 6-14 aryl group, -C 1-6 alkyl-5- to 14-membered heteroaryl group, -C 1-6 alkyl-3- to 10-membered heterocyclyl group, -C(O)NH2, -C(O)-C 3-10 cycloalkyl group, -C(O)-C 6-14 aryl group, -C(O)-5- to 14-membered heteroaryl group, -C(O)-3- to 10-membered heterocyclyl group, -C(O)-C 1-6 alkyl-C3-10 a cycloalkyl group, -C(O)-C 1-6 alkyl-C 6-14 an aryl group, -C(O)-C 1-6 alkyl-5- to 14-membered heteroaryl group, -C(O)-C 1-6 alkyl-3- to 10-membered heterocyclyl group, wherein among them, the above C 3-10 cycloalkyl group, C 6-14 aryl group, 5- to 14-membered heteroaryl group, 3- to 10-membered heterocyclyl group, -C(O)-C 3-10 cycloalkyl group, -C(O)-C 6-14 aryl group, -C(O)-5- to 14-membered heteroaryl group, -C(O)-3- to 10-membered heterocyclyl group, -C(O)-C 1-6 alkyl-C 3-10 cycloalkyl group, -C(O)-C 1-6 alkyl-C 6-14 aryl group, -C(O)-C 1-6 alkyl-5- to 14-membered heteroaryl group, -C(O)-C 1-6 on the ring or acyclic group of alkyl-3- to 10-membered heterocyclyl group, or -C(O)NH2 is optionally further substituted with one, two or more groups selected from OH, halogen, CN, C 1-6 alkyl group, C 1-6 alkyloxy group, and among them, the above heterocyclyl group may be a pyridinyl group (e.g., pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyridin-5-yl, pyridin-6-yl), and the aryl group may be a phenyl group;

[0019] Alternatively, K is absent, H, OH, phenyl-C(O)-, phenyl-C(O)-NH-, phenyl-C(O)-NH-C f alkyl-, phenyl-oxy-C(O)-NH-, phenylalkyl-NH-C(O)-, phenylalkyl-C(O)-NH-, pyridinyl-C(O)-, pyridinyl-C(O)-NH-, pyridinyl-C(O)-NH-C 1-6 alkyl-, independently selected from one, two or more substituents optionally substituted with R 1-6Alkyl-, pyridinyl-oxy-C(O)-NH-, pyridinylalkyl-NH-C(O)-, pyridinylalkyl-C(O)-NH-, pyrrolidinyl-C(O)-NH-, pyrrolidinyl-oxy-C(O)-NH-, C 1-6 Alkyl-C(O)-, C 1-6 Alkyl-C(O)-NH-, C 1-6 Alkyl-oxy-C(O)-NH-, C 3-8 Cycloalkyl-C(O)-NH-, C 3-8 Cycloalkyl-oxy-C(O)-NH-, pyridinyl-NH-C(O)-, C 1-6 Alkyl-NH-C(O)-, C 3-8 Cycloalkyl-NH-C(O)-, pyridinyl-oxy-, pyridinylalkyl-oxy-, pyridinyl-oxyalkyl-, phenyl-oxy-, phenylalkyl-oxy-, phenyl-oxyalkyl-, C 1-6 Alkyl-S(O)2-, C 1-6 Alkyl-S(O)2-NH-, C 1-6 Alkyl-NH-S(O)2-, pyridinylC 1-6 Alkyl-, pyridinyl-S(O)2-, pyridinyl-C 1-6 Alkyl-S(O)2-, pyridinyl-S(O)2-NH-, pyridinyl-NH-S(O)2-, pyridinyl-C 1-6 Alkyl-NH-, phenylC 1-6 Alkyl-, phenyl-S(O)2-, phenyl-C 1-6 Alkyl-S(O)2-, phenyl-S(O)2-NH-, phenyl-NH-S(O)2-, phenyl-C 1-6 Alkyl-NH-, C 1-6 Alkyl-oxy-C(O)-,

Chemical formula

[0020] According to an exemplary embodiment of the present invention, among them, X 1 、X 2 、X 3 、X 4 、X 5 、X 6 、X7 are the same or different and are independently selected from CH or N, for example, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 at least one of is N, for example 1, 2, 3, 4, 5, 6 or 7 are N;

[0021] According to an exemplary embodiment of the present invention, X 8 is selected from NR 1 ;

[0022] According to an exemplary embodiment of the present invention, R 01 is a methoxy group;

[0023] According to an exemplary embodiment of the present invention, R 02 is H;

[0024] According to an exemplary embodiment of the present invention, R 03 is a methyl group and R 04 is H;

[0025] According to an exemplary embodiment of the present invention, R 1 is H,

[0026] According to an exemplary embodiment of the present invention, A is selected from H, NH2, methyl group, ethyl group, propyl group, isopropyl group;

[0027] According to an exemplary embodiment of the present invention, E is selected from H, NH2;

[0028] According to an exemplary embodiment of the present invention, D is selected from halogen, BnO-, H, CN, NH2, OCH3, COOH, B(OH)2,

Chemical formula

[0029] According to an exemplary embodiment of the present invention, G is selected independently from one, two or more substituents selected from F, unsubstituted or optionally R e substituted with

Chemical formula

[0030] According to an exemplary embodiment of the present invention, when the group G is substituted with R e R e substitutes the H in -CH2-, -CH= that constitutes the group G, for example

Chemical formula

[0031] According to an embodiment of the present invention, unless otherwise specified, the chemical bond labeled with a wavy line indicates the connection site with other groups. For example, if there are two wavy lines in the group G, either one of them can be connected to the ring where X 1 X 2 X 3 and X 4 are located, and the other is connected to the group K when the group K exists.

[0032] According to an exemplary embodiment of the present invention, when the ring-forming atoms of the group G include carbon atoms and nitrogen atoms, the group G can be connected to the ring where X 1 X 2 X 3 and X 4 are located through one of the carbon atoms and nitrogen atoms (for example, one of the ring-forming atoms labeled with a wavy line in the above exemplary group), and can be connected to the group K through the other of the carbon atoms and nitrogen atoms.

[0033] According to an exemplary embodiment of the present invention, K is absent, H, OH, unsubstituted or optionally R fphenyl-C(O)-, phenyl-C(O)-NH-, phenyl-C(O)-NH-C substituted with one, two or more substituents independently selected from 1-6 alkyl-, phenyloxy-C(O)-NH-, phenylalkyl-NH-C(O)-, phenylalkyl-C(O)-NH-, pyridinyl-C(O)-, pyridinyl-C(O)-NH-, pyridinyl-C(O)-NH-C 1-6 alkyl-, pyridyloxy-C(O)-NH-, pyridinylalkyl-NH-C(O)-, pyridinylalkyl-C(O)-NH-, pyrrolidinyl-C(O)-NH-, pyrrolidyloxy-C(O)-NH-, C 1-6 alkyl-C(O)-, C 2-6 alkenyl-C(O)-, C 1-6 alkyl-C(O)-NH-, C 1-6 alkyloxy-C(O)-NH-, C 3-8 cycloalkyl-C(O)-NH-, C 3-8 cycloalkyloxy-C(O)-NH-, pyridinyl-NH-C(O)-, C 1-6 alkyl-NH-C(O)-, C 3-8 cycloalkyl-NH-C(O)-, pyridyloxy-, pyridinylalkyloxy-, pyridyloxyalkyl-, phenyloxy-, phenylalkyloxy-, phenyloxyalkyl-, C 1-6 alkyl-S(O)2-, C 1-6 alkyl-S(O)2-NH-, C 1-6 alkyl-NH-S(O)2-, pyridinylC 1-6 alkyl-, pyridinyl-S(O)2-, pyridinyl-C 1-6 alkyl-S(O)2-, pyridinyl-S(O)2-NH-, pyridinyl-NH-S(O)2-, pyridinyl-C 1-6 alkyl-NH-, phenylC 1-6 alkyl-, phenyl-S(O)2-, phenyl-C 1-6 alkyl-S(O)2-, phenyl-S(O)2-NH-, phenyl-NH-S(O)2-, phenyl-C 1-6 alkyl-NH-, C 1-6 alkyloxy-C(O)-, [Chemical formula] Selected from the following.

[0034] According to an embodiment of the present invention, the compound represented by the above formula I has a structure represented by the following formula II or III: [Chemical formula] Among them, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , R 01 , R 02 , R 03 , R 04 , A, D, E, G, K, m have the definitions described above.

[0035] According to an embodiment of the present invention, the compound represented by the above formula I has a structure represented by the following formula IV or V: [Chemical formula] Among them, X 1 , X 2 , X 3 , X 4 , X 5 , R 01 , R 03 , R 04 , A, D, E, G, K have the definitions described above.

[0036] According to an embodiment of the present invention, the above compound is selected from the following compounds: [Chemical formula] JPEG0007716777000011.jpg216169 JPEG0007716777000012.jpg196169 JPEG0007716777000013.jpg228169 JPEG0007716777000014.jpg234169 JPEG0007716777000015.jpg228169 JPEG0007716777000016.jpg222169 JPEG0007716777000017.jpg202169 JPEG0007716777000018.jpg234169 JPEG0007716777000019.jpg228169 JPEG0007716777000020.jpg234169 JPEG0007716777000021.jpg202169 JPEG0007716777000022.jpg190169 JPEG0007716777000023.jpg196169 JPEG0007716777000024.jpg234169 JPEG0007716777000025.jpg228169 JPEG0007716777000026.jpg222169 JPEG0007716777000027.jpg190169 JPEG0007716777000028.jpg196169 JPEG0007716777000029.jpg222169 JPEG0007716777000030.jpg222169 JPEG0007716777000031.jpg222169 JPEG0007716777000032.jpg222169 JPEG0007716777000033.jpg216169 JPEG0007716777000034.jpg210169 JPEG0007716777000035.jpg228169 JPEG0007716777000036.jpg210169 JPEG0007716777000037.jpg204169 JPEG0007716777000038.jpg211169 JPEG0007716777000039.jpg204169 JPEG0007716777000040.jpg229169

[0037] The present invention further provides a method for producing a compound represented by formula I, comprising the following steps:

Chemical formula

[0038] Alternatively, the above production method includes the following steps:

Chemical formula

[0039] Alternatively, the above production method includes the following steps:

Chemical formula

[0040] Alternatively, the above production method includes reacting a compound of formula I substituted with a protecting group under conditions for removing the protecting group to obtain a compound of formula I. Among them, depending on the substituents in the compound of formula I, the protecting group may be at least one selected from a hydroxy protecting group, an amino protecting group, etc.

[0041] The present invention further provides a method for producing a compound represented by formula II, which includes the following steps: Reacting a compound of formula II-1 with compound R 21 -L to obtain a compound of formula II,

Chemical formula

[0042] According to an embodiment of the present invention, the above leaving group is selected from OH, halogen, or OTf.

[0043] According to an embodiment of the present invention, the above reaction is carried out in the presence of a base, for example, in the presence of potassium carbonate.

[0044] According to an embodiment of the present invention, the temperature of the above reaction is 50 to 100 °C, and the reaction time is 1 to 24 hours.

[0045] According to an embodiment of the present invention, the above reaction may be carried out in the presence of an organic solvent (for example, DMF).

[0046] The present invention further provides a method for producing a compound of formula II-1, which includes reacting a compound of formula II-2 to produce a compound of formula II-1,

Chemical formula

[0047] According to an embodiment of the present invention, the above reaction is carried out in the presence of hydrazine monohydrate, and X 7 is N, and X 8 is NH.

[0048] According to an embodiment of the present invention, the above reaction is carried out in the presence of an organic solvent (for example, DMF).

[0049] According to an embodiment of the present invention, the above reaction is carried out under heating conditions.

[0050] The present invention further provides a compound represented by the above formula I-1, formula I-2, formula I-3, formula II-1 or formula II-2.

[0051] The present invention further provides the use of a compound represented by formula I-1, formula I-2, formula I-3 or formula II-1 for producing a compound represented by formula I.

[0052] The present invention further provides a pharmaceutical composition comprising at least one selected from a compound represented by formula I, its stereoisomers, racemates, tautomers, isotope labels, nitrogen oxides or pharmaceutically acceptable salts, for example, at least one therapeutically effective amount selected from a compound represented by formula I, its stereoisomers, racemates, tautomers, isotope labels, nitrogen oxides or pharmaceutically acceptable salts.

[0053] According to an embodiment of the present invention, the pharmaceutical composition further comprises one, two or more pharmaceutically acceptable auxiliary materials, for example, a carrier and / or an excipient.

[0054] According to an embodiment of the present invention, the pharmaceutical composition further comprises one or more additional therapeutic agents.

[0055] The present invention further provides a method for inhibiting cell growth in vitro or in vivo, which comprises contacting a cell with an effective amount of a compound represented by formula I according to the present invention, a stereoisomer, a racemate, a tautomer, an isotope label, a nitrogen oxide, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0056] The present invention further provides a method for treating a RET gene and / or RET kinase-mediated disease, which comprises administering to a patient a therapeutically effective amount of at least one of a compound represented by formula I according to the present invention, a stereoisomer, a racemate, a tautomer, an isotope label, a nitrogen oxide or a pharmaceutically acceptable salt thereof.

[0057] According to an embodiment of the present invention, when RET, the RET gene or RET kinase is described, it is shown that it is selected from, but not limited to, RET genes or RET kinases of RET-wt, V804M, V804L, V804E, G810R, G810S, G810C, G810V and S904F.

[0058] The present invention further provides a method for treating a RET-related disease or disorder in a patient in need of treatment, which comprises administering to the patient a therapeutically effective amount of a compound represented by formula I according to the present invention, a stereoisomer, a racemate, a tautomer, an isotope label, a nitrogen oxide or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0059] The present invention further provides a method for treating cancer and / or inhibiting metastasis associated with a specific cancer in a patient in need of treatment, which comprises administering to the patient a therapeutically effective amount of a compound represented by formula I according to the present invention, its stereoisomers, racemates, tautomers, isotope labels, nitrogen oxides or pharmaceutically acceptable salts, or a pharmaceutical composition thereof.

[0060] The present invention further provides a method for treating irritable bowel syndrome (IBS) and / or pain associated with IBS in a patient in need of treatment, which comprises administering to the patient a therapeutically effective amount of a compound represented by formula I according to the present invention, its stereoisomers, racemates, tautomers, isotope labels, nitrogen oxides or pharmaceutically acceptable salts, or a pharmaceutical composition thereof.

[0061] The present invention further provides a method for providing supportive care to a cancer patient, which comprises administering to the patient a therapeutically effective amount of a compound represented by formula I according to the present invention, its stereoisomers, racemates, tautomers, isotope labels, nitrogen oxides or pharmaceutically acceptable salts, or a pharmaceutical composition thereof, and includes prevention or minimization of gastrointestinal diseases (such as diarrhea) associated with treatment (including chemotherapy treatment).

[0062] The present invention further provides the use of at least one of a compound represented by formula I according to the present invention, its stereoisomers, racemates, tautomers, isotope labels, nitrogen oxides, or pharmaceutically acceptable salts in the manufacture of a drug, wherein the drug is used for the treatment of RET kinase-mediated diseases, inhibition of RET kinase activity, treatment of cancer and / or inhibition of metastasis associated with a specific cancer, treatment of irritable bowel syndrome (IBS) or pain associated with IBS, providing supportive care to cancer patients, treatment of RET-related diseases or conditions, reversing or preventing acquired resistance to anticancer agents, progression of anticancer agent resistance in an individual, delaying and / or preventing an increase in the likelihood of resistance to the progression of anticancer agents.

[0063] According to an embodiment of the present invention, the above RET-related disease or disorder is selected from RET gene and / or RET kinase-mediated diseases, among which RET, RET gene or RET kinase is selected from RET-wt, V804M, V804L, V804E, G810R, G810S, G810C, G810V and S904F RET genes or RET kinases, but is not limited thereto.

[0064] The present invention further provides the use of at least one of a compound represented by formula I, its stereoisomers, racemates, tautomers, isotope labels, nitrogen oxides, or pharmaceutically acceptable salts thereof in the manufacture of a drug for treating RET kinase-mediated diseases.

[0065] The present invention further provides the use of at least one of a compound represented by formula I, its stereoisomers, racemates, tautomers, isotope labels, nitrogen oxides, or pharmaceutically acceptable salts thereof in the manufacture of a drug for treating cancer and / or inhibiting metastasis associated with a specific cancer.

[0066] The present invention further provides the use of at least one of a compound represented by formula I, its stereoisomers, racemates, tautomers, isotope labels, nitrogen oxides, or pharmaceutically acceptable salts thereof in the manufacture of a drug for treating irritable bowel syndrome (IBS) or pain associated with IBS.

[0067] The present invention further provides the use of at least one of a compound represented by formula I, its stereoisomers, racemates, tautomers, isotope labels, nitrogen oxides, or pharmaceutically acceptable salts thereof in the manufacture of a drug for providing supportive therapy to cancer patients, and the above supportive therapy includes the prevention or minimization of gastrointestinal disorders such as diarrhea associated with treatment (including chemotherapy treatment).

[0068] The present invention further provides the use of at least one of a compound represented by formula I, its stereoisomers, racemates, tautomers, isotope labels, nitrogen oxides, or pharmaceutically acceptable salts thereof in the manufacture of a drug for inhibiting RET kinase activity.

[0069] The present invention further provides the use of at least one of a compound represented by formula I, its stereoisomers, racemates, tautomers, isotope labels, nitrogen oxides, or pharmaceutically acceptable salts thereof in the manufacture of a drug for treating RET-related diseases or disorders.

[0070] The present invention includes (a) determining whether the above cancer is related to dysregulation of the RET gene, RET kinase, or the expression or activity or level of either of them (e.g., RET-related cancer), and (b) when it is determined that the above cancer is related to dysregulation of the RET gene, RET kinase, or the expression or activity or level of either of them (e.g., RET-related cancer), administering to the patient a therapeutically effective amount of at least one of a compound represented by formula I, its stereoisomers, racemates, tautomers, isotope labels, nitrogen oxides, or pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof. The present invention further provides a method for treating cancer in a patient in need thereof.

[0071] The present invention further provides a method for reversing or preventing acquired resistance to an anticancer agent, which includes administering to a patient who is at risk of progressing to or having acquired resistance to an anticancer agent at least one of a compound represented by formula I, its stereoisomers, racemates, tautomers, isotope labels, nitrogen oxides, or pharmaceutically acceptable salts thereof in a therapeutically effective amount.

[0072] The present invention further provides a method for delaying and / or preventing the progression of anticancer agent resistance in an individual, which includes administering to the individual an effective amount of at least one of a compound represented by formula I, its stereoisomers, racemates, tautomers, isotope labels, nitrogen oxides, or pharmaceutically acceptable salts thereof, and administering an effective amount of an anticancer agent before, during, or after that.

[0073] The present invention further provides a method for treating an individual suffering from cancer and having an increased potential for resistance to the progression of an anti-cancer agent, which comprises co-administering to the individual (a) an effective amount of at least one of a compound represented by formula I, its stereoisomers, racemates, tautomers, isotope labels, nitrogen oxides, or pharmaceutically acceptable salts, and (b) an effective amount of an anti-cancer agent.

[0074] The present invention further provides a method for treating an individual suffering from RET-related cancer, which comprises administering at least one of a compound represented by formula I, its stereoisomers, racemates, tautomers, isotope labels, nitrogen oxides, or pharmaceutically acceptable salts before, during, or after administering another anti-cancer agent, wherein the cancer has one or more RET inhibitor-resistant mutations, and the RET inhibitor-resistant mutations increase the resistance of the cancer to an anti-RET inhibitor other than at least one of a compound represented by formula I, its stereoisomers, racemates, tautomers, isotope labels, nitrogen oxides, or pharmaceutically acceptable salts (e.g., RET-wt, substitutions at amino acid positions 804, 810, 904, such as V804M, V804L, V804E, G810R, G810S, G810C, G810V, S904F).

[0075] The present invention further provides a method for treating an individual suffering from RET-related cancer, which comprises administering at least one of a compound represented by formula I, its stereoisomers, racemates, tautomers, isotope labels, nitrogen oxides, or pharmaceutically acceptable salts before, during, or after administering another anti-cancer agent.

[0076] The present invention provides a method for treating cancer (e.g., RET-related cancer) in a patient in need thereof, which comprises administering to the patient a therapeutically effective amount of at least one of a compound of general formula I or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0077] In some embodiments of any of the methods or uses described in the present invention, the cancer (e.g., RET-related cancer) is a blood cancer. In some embodiments of any of the methods or uses described in the present invention, the cancer (e.g., RET-related cancer) is a solid tumor. In some embodiments of any of the methods or uses described in the present invention, the cancer (e.g., RET-related cancer) is lung cancer (e.g., small cell lung cancer or non-small cell lung cancer), papillary thyroid cancer, medullary thyroid cancer, differentiated thyroid cancer, recurrent thyroid cancer, refractory differentiated thyroid cancer, lung adenocarcinoma, bronchioloalveolar carcinoma, multiple endocrine neoplasia type 2A or 2B (MEN2A or MEN2B, respectively), pheochromocytoma, parathyroid hyperplasia, breast cancer, colorectal cancer (e.g., metastatic colorectal cancer), papillary renal cell carcinoma, gastrointestinal mucosal gangliocytoma, inflammatory myofibroblastic tumor, or cervical cancer. In some embodiments of any of the methods or uses described in the present invention, the cancer (e.g., RET-related cancer) is acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), juvenile cancer, adrenocortical carcinoma, anal cancer, appendiceal cancer, astrocytoma, atypical teratoid / rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brainstem glioma, brain tumor, breast cancer, bronchial tumor, Burkitt lymphoma, carcinoid tumor, cancer of unknown primary, cardiac tumor, cervical cancer, childhood cancer, chordoma, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myeloproliferative tumor, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, bile duct cancer, ductal carcinoma in situ of breast, fetal tumor, endometrial cancer, ependymoma, esophageal cancer, nasal neuroblastoma, Ewing sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, extrahepatic bile duct cancer, eye cancer, fallopian tube cancer, fibrous histiocytoma of bone, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, gestational trophoblastic disease, glioma, hairy cell tumor, hairy cell leukemia, head and neck cancer, heart cancer, hepatocellular carcinoma, histiocytosis, Hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumor, pancreatic neuroendocrine tumor, Kaposi sarcoma, kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, lip and oral cavity cancer, liver cancer, lung cancer, lymphoma, macroglobulinemia, malignant fibrous histiocytoma of bone, bone cancer, melanoma, Merkel cell carcinoma, mesothelioma, metastatic cervical squamous cell carcinoma, midline cancer, mouth cancer, multiple endocrine neoplasia syndrome,Selected from multiple myeloma, fungating polyps, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasm, myeloid leukemia, myelogenous leukemia, multiple myeloma, myeloproliferative neoplasm, nasal and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, oral cancer, oral cavity cancer, lip cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pituitary cancer, plasmacytoma, pleuropulmonary blastoma, pregnancy and breast cancer, primary central nervous system lymphoma, primary peritoneal cancer, prostate cancer, rectal cancer, renal cell cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, Sézary syndrome, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell cancer, squamous cell cancer of the neck, stomach cancer, T cell lymphoma, testicular cancer, laryngeal cancer, thymoma and thymic cancer, thyroid cancer, transitional cell cancer of the renal pelvis and ureter, cancer of unknown primary origin, urethral cancer, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, and Wilms tumor.

[0078] In some embodiments, a blood cancer (e.g., a blood cancer that is a cancer associated with RET) is selected from leukemia, lymphoma (non-Hodgkin lymphoma), Hodgkin's disease (also called Hodgkin lymphoma), and myeloma, e.g., acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML), chronic neutrophilic leukemia (CNL), acute undifferentiated leukemia (AUL), anaplastic large cell lymphoma (ALCL), prelymphocytic leukemia (PML), juvenile myelomonocytic leukemia (JMML), adult T cell ALL, AML with trilineage myelodysplasia (AML / TMDS), mixed lineage leukemia (MLL), myelodysplastic syndrome (MDS), myeloproliferative disorder (MPD), and multiple myeloma (MM). Other examples of blood cancers include myeloproliferative disorders (MPD) such as polycythemia vera (PV), essential thrombocythemia (ET), and idiopathic primary myelofibrosis (IMF / IPF / PMF). In one embodiment, the blood cancer (e.g., a blood cancer that is a RET-associated cancer) is AML or CMML.

[0079] In some embodiments, the cancer (e.g., RET-related cancer) is a solid tumor. Examples of solid tumors (e.g., solid tumors that are RET-related cancers) include, for example, thyroid cancer (e.g., papillary thyroid cancer, medullary thyroid cancer), lung cancer (e.g., lung adenocarcinoma, small cell lung cancer), pancreatic cancer, pancreatic ductal cancer, breast cancer, colon cancer, colorectal cancer, prostate cancer, renal cell cancer, head and neck tumors, neuroblastoma, and melanoma. See, for example, Nature Reviews Cancer, 2014, 14, 173 - 186.

[0080] In some embodiments, the cancer is selected from lung cancer, papillary thyroid cancer, medullary thyroid cancer, differentiated thyroid cancer, recurrent thyroid cancer, refractory differentiated thyroid cancer, multiple endocrine neoplasia type 2A or 2B (MEN2A or MEN2B, respectively), pheochromocytoma, parathyroid hyperplasia, breast cancer, colorectal cancer, papillary renal cell cancer, gangliocytoma of the gastrointestinal mucosa, and cervical cancer.

[0081] In some embodiments, the patient is human.

[0082] The compounds of formula I and their pharmaceutically acceptable salts are also applicable to the treatment of cancers related to RET.

[0083] The present invention further provides a method for treating irritable bowel syndrome (IBS) in a patient in need thereof, comprising: (a) determining whether IBS is associated with a dysregulation of the RET gene, RET kinase, or the expression, activity, or level of either one thereof; and (b) when it is determined that IBS is associated with a dysregulation of the RET gene, RET kinase, or the expression, activity, or level of either one thereof, administering to the patient at least one of a therapeutically effective amount of a compound of general formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0084] The present invention further provides a combination of drugs for treating irritable bowel syndrome (IBS) in a patient in need thereof, comprising administration of (a) at least one of a compound represented by formula I, its stereoisomers, racemates, tautomers, isotope labels, nitrogen oxides, or pharmaceutically acceptable salts, (b) another therapeutic agent, and (c) optionally at least one pharmaceutically acceptable carrier for use simultaneously, separately, or sequentially for the treatment of IBS, wherein the amounts of at least one of the compound represented by formula I, its stereoisomers, racemates, tautomers, isotope labels, nitrogen oxides, or pharmaceutically acceptable salts and the other therapeutic agent are effective together in the treatment of IBS. The present invention further provides a pharmaceutical composition comprising such a combination. The present invention further provides the use of such a combination in the manufacture of a drug for treating IBS. The present invention further provides a commercial package or product comprising such a combination as a combined preparation for use simultaneously, alone, or in sequence; and relates to a method for treating IBS in a patient in need thereof.

[0085] When used as a drug, the compounds of the present invention may be administered in the form of a pharmaceutical composition. These compositions can be manufactured according to methods well known in the pharmaceutical art and can be administered via various routes depending on the need for local or systemic treatment and the area to be treated. Local administration (e.g., transdermal, cutaneous, ocular, and intranasal, including administration to mucous membranes including vaginal and rectal), pulmonary administration (e.g., by inhalation or insufflation of powders and aerosols, including by nebulizer; intratracheal, intranasal administration), oral or parenteral administration may be used. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion, or intracranial administration such as intrathecal and intraventricular. It may be administered parenterally in a single bolus form or, for example, by a continuous perfusion pump. Pharmaceutically compositions and formulations administered locally can include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, solutions and powders. Normal pharmaceutical carriers, water, powder or oily bases, thickeners, etc. may be essential or may be required. Coated condoms, gloves, etc. may also be useful.

[0086] When manufacturing the composition of the present invention, generally, the active ingredient is mixed with an excipient, diluted with the excipient, or placed in a carrier such as a capsule, sachet, paper or other container form. When the excipient is used as a diluent, it may be a solvent, a carrier or a solid, semi-solid or liquid substance used as a medium for the active ingredient. Accordingly, the composition may be in the form of tablets, pills, powders, topical application agents, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (dissolved in a solid or liquid solvent), for example, ointments containing an active compound reaching 10% by weight, soft and hard gelatin capsules, suppositories, sterile injection solutions and sterile packaged powders.

[0087] Some examples of suitable excipients include lactose, glucose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup and methylcellulose. The formulation may further contain lubricants such as talc, magnesium stearate and mineral oil, wetting agents, emulsifying agents and suspending agents, preservatives such as methyl benzoate and hydroxypropyl benzoate, sweeteners and flavoring agents. The composition of the present invention can be manufactured by methods known in the art so as to provide an immediate release, sustained release or delayed release action of the active ingredient after administration to a patient.

[0088] The composition may be manufactured in unit dosage form and contains from about 5 to 1000 mg, more generally from about 100 to 500 mg of the active ingredient per dose. The term "unit dosage form" refers to physically discrete single dosage units suitable for use in human patients and other mammals, each unit containing a predetermined amount of the active substance mixed with a suitable pharmaceutical excipient calculated to produce the desired therapeutic effect.

[0089] The range of effective dosages of the active compound may be very large and is usually administered in a pharmaceutically effective amount. However, it can be understood that the amount of the compound actually administered is usually determined by a physician according to relevant circumstances including the disease condition to be treated, the selected route of administration, the actual compound to be administered, the age, weight and reaction of the individual patient, and the severity of the patient's symptoms.

[0090] Regarding the manufacture of solid compositions such as tablets, the main active ingredient is mixed with a pharmaceutical excipient to form a solid preliminary preparation composition which is a homogeneous mixture containing the compound of the present invention. When these preliminary preparation compositions are homogeneous, it means that the active ingredient is usually uniformly distributed throughout the composition, so that the composition can be easily divided into equally effective unit dosage forms such as tablets, pills and capsules. Then, the solid preliminary preparation is divided into unit dosage forms containing, for example, about 0.1 to 1000 mg of the active ingredient of the present invention of the above type.

[0091] The tablets or pills of the present invention can be coated or compounded to obtain a dosage form that provides the advantage of a sustained action. For example, tablets or pills contain an internal dosage component and an external dosage component, and the latter is in the form of a coating for the former. The two components can be separated by an enteric layer, and the enteric layer is used to prevent disintegration in the stomach so that the internal component completely passes through the duodenum or is released in a delayed manner. A plurality of substances can be used for such an enteric layer or coating agent, and such substances include a plurality of high molecular acids and mixtures of high molecular acids with substances such as shellac, cetyl alcohol and cellulose acetate.

[0092] Liquid forms for oral or injectable administration into which the compounds and compositions of the present invention can be incorporated include aqueous solutions, syrups appropriately corrected in taste, water or oil suspensions, emulsions corrected in taste with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, elixirs and similar pharmaceutical solvents.

[0093] Compositions for inhalation or insufflation include solutions, suspensions, and powders dissolved in pharmaceutically acceptable water or organic solvents or mixtures thereof. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. In some embodiments, the composition is administered via the oral or nasal respiratory route to achieve local or systemic effects. The composition can be nebulized by using an inert gas. The nebulized solution may be inhaled directly by a nebulizing device, or the nebulizing device may be connected to a face mask tent or an intermittent positive pressure ventilator. The solution, suspension, or powder composition may be administered orally or nasally by a device that delivers the formulation in an appropriate manner.

[0094] The amount of the compound or composition administered to a patient is not constant and is determined by factors such as the drug being administered, the purpose of administration such as prophylaxis or treatment, the condition of the patient, and the method of administration. In the case of therapeutic applications, an amount of the composition sufficient to cure or at least partially inhibit the symptoms of the disease and its complications can be administered to a patient suffering from the disease. The effective dose should depend on the condition of the disease being treated and the judgment of the attending clinician, which depends on factors such as the severity of the disease, the age, weight, and general condition of the patient.

[0095] The composition administered to a patient may be in the form of the above pharmaceutical compositions. These compositions can be sterilized by conventional sterilization techniques or by filtration sterilization. The aqueous solution packaging can be used as is, or lyophilized, and the lyophilized formulation can be mixed with a sterile aqueous carrier prior to administration. The pH of the compound formulation is usually 3 - 11, more preferably 5 - 9, and most preferably 7 - 8. It can be understood that pharmaceutical salts are formed by using some of the above-mentioned excipients, carriers, or stabilizers.

[0096] The therapeutic dosage of the compounds of the present invention can be determined, for example, by the specific use to be treated, the method of administering the compound, the health and condition of the patient, and the judgment of the prescribing physician. The ratio or concentration of the compounds of the present invention in the pharmaceutical composition is not constant and depends on various factors including dosage, chemical properties (e.g., hydrophobicity) and route of administration. For example, the compounds of the present invention can be provided for parenteral administration by a physiologically buffered aqueous solution containing about 0.1 to 10% w / v of the compound. Some typical dosage ranges are from about 1 μg / kg to about 1 g / kg body weight per day. In some embodiments, the dosage range is from about 0.01 mg / kg to about 100 mg / kg body weight per day. The dosage is likely to depend on variables such as the type and degree of progression of the disease or disorder, the general health of the specific patient, the relative biological efficacy of the selected compound, the excipient formulation and its route of administration. The effective dosage can be obtained by extrapolation from a dose-response curve derived from in vitro or animal model test systems.

[0097] Definitions and Explanations of Terms Unless otherwise specified, the definitions of the groups and terms described in the specification and claims of this application include their exemplary definitions, illustrative definitions, preferred definitions, definitions described in tables, definitions of specific compounds in the examples, etc., and can be arbitrarily combined or joined with each other. After such combination and joining, the definitions of the groups and the structures of the compounds should belong to the scope described in the specification of this application.

[0098] Unless otherwise specified, the numerical ranges described in this specification and the claims are to be construed as including at least each specific integer value therein. For example, the numerical range "1 to 40" corresponds to the integer values 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 in the numerical range "1 to 10" and the integer values 11, 12, 13, 14, 15,......, 35, 36, 37, 38, 39, 40 in the numerical range "11 to 40". In the present application, among one, two or more used when describing substituents, "more" should be understood to refer to an integer of ≧3, such as 3, 4, 5, 6, 7, 8, 9 or 10. In addition, when a numerical range is defined as "number", it should be understood that the two endpoints of the range, each integer in the range and each decimal in the range are described. For example, "numbers from 0 to 10" not only describes each integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, but also should be understood to describe at least the sum of each integer and 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9 therein.

[0099] The term "halogen" refers to fluorine, chlorine, bromine and iodine.

[0100] "C 1-40 alkyl group" should be understood to preferably refer to a linear or branched saturated monovalent hydrocarbon group having 1 to 40 carbon atoms. For example, "C 1-6"Alkyl group" refers to a straight-chain or branched-chain alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms. The above alkyl group is, for example, a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, an isopropyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, an isopentyl group, a 2-methylbutyl group, a 1-methylbutyl group, a 1-ethylpropyl group, a 1,2-dimethylpropyl group, a neopentyl group, a 1,1-dimethylpropyl group, a 4-methylpentyl group, a 3-methylpentyl group, a 2-methylpentyl group, a 1-methylpentyl group, a 2-ethylbutyl group, a 1-ethylbutyl group, a 3,3-dimethylbutyl group, a 2,2-dimethylbutyl group, a 1,1-dimethylbutyl group, a 2,3-dimethylbutyl group, a 1,3-dimethylbutyl group or a 1,2-dimethylbutyl group, etc. or their isomers.

[0101] "C 2-40 The term "alkenyl group" preferably refers to a straight-chain or branched-chain monovalent hydrocarbon group containing one or more double bonds and having 2 to 40 carbon atoms, and is preferably understood as a "C 2-6 alkenyl group". "C 2-6 alkenyl group" preferably contains one or more double bonds and has 2, 3, 4, 5 or 6 carbon atoms, especially 2 or 3 carbon atoms ("C 2-3It should be understood to represent a linear or branched monovalent hydrocarbon group having an "alkenyl group"), and when the alkenyl group contains two or more double bonds, it should be understood that the double bonds may be separated or conjugated to each other. The alkenyl group is, for example, a vinyl group, an allyl group, an (E)-2-methylvinyl group, a (Z)-2-methylvinyl group, an (E)-but-2-enyl group, a (Z)-but-2-enyl group, an (E)-but-1-enyl group, a (Z)-but-1-enyl group, a pent-4-enyl group, an (E)-pent-3-enyl group, a (Z)-pent-3-enyl group, an (E)-pent-2-enyl group, a (Z)-pent-2-enyl group, an (E)-pent-1-enyl group, a (Z)-pent-1-enyl group, a hex-5-enyl group, an (E)-hex-4-enyl group, a (Z)-hex-4-enyl group, an (E)-hex-3-enyl group, a (Z)-hex-3-enyl group, an (E)-hex-2-enyl group, a (Z)-hex-2-enyl group, an (E)-hex-1-enyl group, a (Z)-hex-1-enyl group, an isopropenyl group, a 2-methylprop-2-enyl group, a 1-methylprop-2-enyl group, a 2-methylprop-1-enyl group, an (E)-1-methylprop-1-enyl group, a (Z)-1-methylprop-1-enyl group, a 3-methylbut-3-enyl group, a 2-methylbut-3-enyl group, a 1-methylbut-3-enyl group, a 3-methylbut-2-enyl group, an (E)-2-methylbut-2-enyl group, a (Z)-2-methylbut-2-enyl group, an (E)-1-methylbut-2-enyl group, a (Z)-1-methylbut-2-enyl group, an (E)-3-methylbut-1-enyl group, a (Z)-3-methylbut-1-enyl group, an (E)-2-methylbut-1-enyl group, a (Z)-2-methylbut-1-enyl group, an (E)-1-methylbut-1-enyl group, a (Z)-1-methylbut-1-enyl group, a 1,1-dimethylprop-2-enyl group, a 1-ethylprop-1-enyl group, a 1-propylvinyl group, a 1-isopropylvinyl group.

[0102] "C2- 40The term "alkynyl group" refers to a straight-chain or branched-chain monovalent hydrocarbon group containing one or more triple bonds and having 2 to 40 carbon atoms, and should preferably be understood as a "C2-C6-alkynyl group". The term "C2-C6-alkynyl group" preferably refers to a straight-chain or branched-chain monovalent hydrocarbon group containing one or more triple bonds and having 2, 3, 4, 5 or 6 carbon atoms, particularly 2 or 3 carbon atoms (a "C2-C3-alkynyl group"). The above C2-C6-alkynyl group is, for example, an ethynyl group, a prop-1-ynyl group, a prop-2-ynyl group, a but-1-ynyl group, a but-2-ynyl group, a but-3-ynyl group, a pent-1-ynyl group, a pent-2-ynyl group, a pent-3-ynyl group, a pent-4-ynyl group, a hex-1-ynyl group, a hex-2-ynyl group, a hex-3-ynyl group, a hex-4-ynyl group, a hex-5-ynyl group, a 1-methylprop-2-ynyl group, a 2-methylbut-3-ynyl group, a 1-methylbut-3-ynyl group, a 1-methylbut-2-ynyl group, a 3-methylbut-1-ynyl group, a 1-ethylprop-2-ynyl group, a 3-methylpent-4-ynyl group, a 2-methylpent-4-ynyl group, a 1-methylpent-4-ynyl group, a 2-methylpent-3-ynyl group, a 1-methylpent-3-ynyl group, a 4-methylpent-2-ynyl group, a 1-methylpent-2-ynyl group, a 4-methylpent-1-ynyl group, a 3-methylpent-1-ynyl group, a 2-ethylbut-3-ynyl group, a 1-ethylbut-3-ynyl group, a 1-ethylbut-2-ynyl group, a 1-propylprop-2-ynyl group, a 1-isopropylprop-2-ynyl group, a 2,2-dimethylbut-3-ynyl group, a 1,1-dimethylbut-3-ynyl group, a 1,1-dimethylbut-2-ynyl group or a 3,3-dimethylbut-1-ynyl group. In particular, the above alkynyl group is an ethynyl group, a prop-1-ynyl group or a prop-2-ynyl group.

[0103] "C 3-40 The term "cycloalkyl group" refers to a saturated monovalent monocyclic, bicyclic hydrocarbon ring or bridged cycloalkane having 3 to 40 carbon atoms, and should preferably be understood as a "C 3-10 cycloalkyl group". "C 3-10The term "cycloalkyl group" should be understood to mean a saturated monocyclic, bicyclic hydrocarbon ring or bridged cycloalkane having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. The above C 3-10 The cycloalkyl group may be, for example, a monocyclic hydrocarbon group such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, a cyclononyl group or a cyclodecyl group, or may be a bicyclic hydrocarbon group such as a decahydronaphthalene ring.

[0104] The term "3- to 20-membered heterocyclyl group" refers to a saturated monocyclic, bicyclic hydrocarbon ring or bridged cycloalkane containing a non-aromatic cyclic group having a total ring-forming atom number of 3 to 20 (for example, 3, 4, 5, 6, 7, 8, 9, 10, etc.) of 1 to 5 heteroatoms independently selected from N, O, and S, preferably a "3- to 10-membered heterocyclyl group". The term "3- to 10-membered heterocyclyl group" refers to a saturated monocyclic, bicyclic hydrocarbon ring or bridged cycloalkane containing 1 to 5, preferably 1 to 3 heteroatoms independently selected from N, O, and S, for example, 1, 2, or 3 heteroatoms independently selected from N, O, and S. The above heterocyclyl group can be linked to the rest of the molecule by any one of the above carbon atoms or a nitrogen atom (if present). In particular, the above heterocyclyl group includes, but is not limited to, 4-membered rings such as azetidinyl group, oxetanyl group (for example, azetidin-1-yl); 5-membered rings such as tetrahydrofuryl group, dioxolyl group, pyrrolidinyl group, imidazolidinyl group, pyrazolidinyl group, pyrrolinyl group; or 6-membered rings such as tetrahydropyranyl group, piperidinyl group, morpholinyl group, dithianyl group, thiomorpholinyl group, piperazinyl group or trithianyl group; or 7-membered rings such as diazepanyl group. Optionally, the above heterocyclyl group may be benzo-fused. The above heterocyclyl group may be bicyclic, for example, a 5,5-membered ring such as hexahydrocyclopenta[c]pyrrol-2(1H)-yl ring, or a 5,6-membered bicyclic ring such as hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl ring, but is not limited thereto. The nitrogen atom-containing ring may be partially unsaturated, that is, it may contain one or more double bonds, for example, 2,5-dihydro-1H-pyrrolyl group, 4H-[1,3,4]thiadiazinyl group, 4,5-dihydrooxazolyl group or 4H-[1,4]thiazinyl group, but is not limited thereto, or it may be benzo-fused, for example, dihydroisoquinolinyl group, but is not limited thereto. According to the present invention, the above heterocyclyl group is non-aromatic.When the above 3- to 20-membered heterocyclic group is linked to other groups to form the compounds of the present invention, the carbon atoms in the 3- to 20-membered heterocyclic group may be linked to other groups, and the hetero atoms in the 3- to 20-membered heterocyclic ring may also be linked to other groups. For example, when the 3- to 20-membered heterocyclic group is selected from piperazinyl groups, the nitrogen atom in the piperazinyl group may be linked to other groups. Or, when the 3- to 20-membered heterocyclic group is selected from piperidinyl groups, the nitrogen atom and the para-position carbon atom in the piperidinyl ring may be linked to other groups.

[0105] 「C 6-20 The term "C 6-14 aryl group」 preferably refers to a monocyclic, bicyclic or tricyclic hydrocarbon ring that is monovalent aromatic or partially aromatic and has 6 to 20 carbon atoms, and is preferably understood to be a 「C 6-14 aryl group」. The term "C 6-14 aryl group」 preferably refers to a monocyclic, bicyclic or tricyclic hydrocarbon ring that is monovalent aromatic or partially aromatic and has 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms (「C 10 aryl group」), in particular, for example, a phenyl group; or a ring having 6 carbon atoms such as a biphenyl group (「C6 aryl group」), or a ring having 9 carbon atoms such as an indanyl group or an indenyl group (「C9 aryl group」), or a ring having 10 carbon atoms such as a tetrahydronaphthyl group, a dihydronaphthyl group or a naphthyl group (「C 13 aryl group」), or a ring having 13 carbon atoms such as a fluorenyl group (「C 14 aryl group」), or a ring having 14 carbon atoms such as an anthryl group (「C 6-20 aryl group」). When the above C 6-20 aryl group is substituted, it may be mono-substituted or multi-substituted. Also, the substitution site is not limited, and for example, substitution at the ortho-position, para-position, or meta-position may be possible.

[0106] The term "5- to 20-membered heteroaryl group" includes a monocyclic, bicyclic or tricyclic aromatic ring system having 5 to 20 ring atoms and containing 1 to 5 heteroatoms independently selected from N, O and S, and should be understood, for example, as a "5- to 14-membered heteroaryl group". The term "5- to 14-membered heteroaryl group" has 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms, particularly 5 or 6 or 9 or 10 carbon atoms, and contains 1 to 5, preferably 1 to 3 heteroatoms independently selected from N, O and S, and in each case may also be benzo-fused, and should be understood to include a monocyclic, bicyclic or tricyclic aromatic ring system. In particular, heteroaryl groups include thienyl groups, furanyl groups, pyrrolyl groups, oxazolyl groups, thiazolyl groups, imidazolyl groups, pyrazolyl groups, isoxazolyl groups, isothiazolyl groups, oxadiazolyl groups, triazolyl groups, thiadiazolyl groups, thia-4H-pyrazolyl groups, etc., and their benzo derivatives such as benzofuranyl groups, benzothienyl groups, benzoxazolyl groups, benzoisoxazolyl groups, benzimidazolyl groups, benzotriazolyl groups, indazolyl groups, indolyl groups, isoindolyl groups, etc., or pyridinyl groups, pyridazinyl groups, pyrimidinyl groups, pyrazinyl groups, triazinyl groups, etc., and their benzo derivatives such as quinolyl groups, quinazolinyl groups, isoquinolyl groups, etc., or azocinyl groups, indolizinyl groups, purinyl groups, etc., and their benzo derivatives, or cinnolinyl groups, phthalazinyl groups, quinazolinyl groups, quinoxalinyl groups, naphthyridinyl groups, pteridinyl groups, carbazolyl groups, acridinyl groups, phenazinyl groups, phenothiazinyl groups, phenoxazinyl groups, etc. When the above 5- to 20-membered heteroaryl group is linked to other groups to form the compounds of the present invention, the carbon atoms in the 5- to 20-membered heteroaryl group ring may be linked to other groups, and the heteroatoms in the 5- to 20-membered heteroaryl group ring may also be linked to other groups. When the above 5- to 20-membered heteroaryl group is substituted, it may be mono-substituted or multi-substituted.Also, the substitution site is not restricted. For example, the hydrogen atom linked to a carbon atom in the heteroaryl group ring may be substituted, or the hydrogen atom linked to a heteroatom in the heteroaryl group ring may be substituted.

[0107] Unless otherwise specified, a heterocyclyl group, heteroaryl group or heteroarylene group includes all its possible isomeric forms, such as its positional isomers. Therefore, as non-limiting examples for some explanations, it may include forms substituted at one, two or more positions among its 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12- positions (if present) or forms bonded to other groups, including pyridin-2-yl, pyridinylidene-2-yl, pyridin-3-yl, pyridinylidene-3-yl, pyridin-4-yl and pyridinylidene-4-yl; thienyl groups or thienylidenyl groups including thien-2-yl, thienylidene-2-yl, thien-3-yl, thienylidene-3-yl; pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl.

[0108] The term "oxo" refers to an oxy substitution (=O) formed by oxidizing a carbon atom, nitrogen atom or sulfur atom in a substituent.

[0109] Unless otherwise specified, the definitions of the terms in this specification are similarly applicable to groups containing the term. For example, the definition of a C 1-6 alkyl group definition is applicable to C 1-6 alkyloxy group, -N(C 1-6 alkyl)2, -NHC 1-6 alkyl group or -S(O)2-C 1-6 alkyl group and the like.

[0110] One skilled in the art can understand that the compounds represented by Formula I can exist in the form of various pharmaceutically acceptable salts. When these compounds have a basic center, they can form acid addition salts; when these compounds have an acidic center, they can form base addition salts; when these compounds contain both an acidic center (e.g., a carboxyl group) and a basic center (e.g., an amino group), they can further form inner salts.

[0111] The compounds of the present invention may exist in the form of solvates (e.g., hydrates), among which the compounds of the present invention include polar solvents, especially, for example, water, methanol or ethanol, which are components of the crystal lattice of the above compounds. The amount of the polar solvent, especially water, may exist in a stoichiometric ratio or a non-stoichiometric ratio.

[0112] Due to their molecular structure, the compounds of the present invention may be chiral, so there may be various enantiomeric forms. Therefore, these compounds can exist in a racemic form or an optically active form. The compounds of the present invention or their intermediates can be isolated into enantiomeric compounds or used for synthesis in this form by chemical or physical methods well known to those skilled in the art. In the case of a racemic amine, diastereomers are produced from the mixture by reaction with an optically active resolving reagent. Examples of suitable resolving reagents include, for example, optically active acids such as R and S forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (e.g., N-benzoylproline or N-benzenesulfonylproline) or various optically active camphorsulfonic acids. Enantiomeric resolution by chromatography can also be well performed by an optically active resolving reagent (e.g., dinitrobenzoylphenylglycine immobilized on silica gel, cellulose triacetate or other carbohydrate derivatives or chiral derivatized methacrylate polymer). Suitable eluents for this purpose are solvent mixtures containing water or alcohol, such as hexane / isopropanol / acetonitrile.

[0113] The term "tautomer" refers to a functional group isomer generated by the rapid movement of a certain atom within a molecule between two positions. The compounds of the present invention can exhibit tautomerism. Tautomeric compounds can have two or more types of interconvertible species. Proton-transfer tautomers are due to the movement of a hydrogen atom covalently bonded between two atoms. Tautomers generally exist in an equilibrium state, and when attempting to isolate a single tautomer, a mixture is usually produced whose physicochemical properties typically match those of a mixture of compounds. The position of the equilibrium is determined by the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones, such as acetaldehyde, the keto form is dominant, while in phenol, the enol form is dominant. The present invention includes all tautomeric forms of the compounds.

[0114] The corresponding stable isomers can be isolated by known methods, such as extraction, filtration, or column chromatography.

[0115] The term "patient" refers to any animal including mammals, preferably a mouse, rat, other rodents, rabbit, dog, cat, pig, cow, sheep, horse, or primate, and most preferably a human.

[0116] As used herein, the phrase "therapeutically effective amount" refers to the amount of an active compound or drug that elicits a biological or medical response sought by a researcher, veterinarian, physician, or other clinician in a tissue, system, animal, individual, or human, and includes one or more of the following: (1) Prevention of a disease: for example, preventing a disease, disorder, or condition in an individual who is susceptible to infection by the disease, disorder, or condition but in whom the pathology or symptoms of the disease have not been experienced or manifested. (2) Inhibition of a disease: for example, inhibiting a disease, disorder, or condition in an individual in whom the pathology or symptoms of the disease, disorder, or condition have been experienced or manifested (i.e., preventing further progression of the pathology and / or symptoms). (3) Alleviation of a disease: for example, alleviating a disease, disorder, or condition in an individual in whom the pathology or symptoms of the disease, disorder, or condition have been experienced or manifested (i.e., reversing the pathology and / or symptoms).

Advantages of the Invention

[0117] The compound of the present invention can be used as a RET inhibitor having high selectivity or inhibitory action. For example, it has excellent inhibitory action against RET gatekeeper residue mutant RET V804M, RET solvent tip residue mutant G810R and other clinically relevant RET mutants and RET-wt. In addition, the preferred compound of the present invention can efficiently inhibit the growth of TT cell line derived from thyroid cancer and Ba / F3 cells transformed with various RET mutants, block the autophosphorylation of cellular RET and its downstream pathway, and significantly induce the death of TT cells. In addition, the preferred compound of the present invention further has good pharmacokinetic properties, and when used as an active ingredient, it can be administered to patients at a relatively small dose, reducing the treatment cost of patients.

Examples

[0118] Hereinafter, in accordance with specific examples, the technical solution of the present invention will be described in more detail. It should be understood that the following examples are merely illustrative explanations and interpretations of the present invention, and should not be construed as limiting the scope of the claims of the present invention. Any technology realized based on the above content of the present invention is included within the scope of the claims of the present invention.

[0119] Unless otherwise specified, the raw materials and reagents used in the following examples are all commercially available products or can be manufactured by known methods.

[0120] Example 1: Preparation of Compound 1 Step A: N-(1-(5-(6-Ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)-5-fluoro-2-methylbenzamide

Chemical formula

[0121] Example 2: Preparation of Compound 3 Step A: 1-Amino-3-bromo-5-methoxypyridin-1-ium 2,4,6-trimethylbenzenesulfonate

Chemical formula

[0122] Step B: 4-Bromo-2-fluoro-6-methoxypyrazolo[1,5-a]pyridine

Chemical formula

[0123] Step C: 4-Bromo-2-fluoro-6-methoxypyrazolo[1,5-a]pyridine-3-aldehyde

Chemical formula

[0124] Step D: 4-Bromo-6-methoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridine

Chemical formula

[0125] Step E: 4-Bromo-6-hydroxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridine

Chemical formula

[0126] Step F: 4-Bromo-6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridine

Chemical formula

[0127] Step G: 6-Ethoxy-4-(6-fluoropyridin-3-yl)-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridine

Chemical formula

[0128] Step H: tert-Butyl (1-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)carbamate

Chemical formula

[0129] Step I: 1-(5-(6-Ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-amine hydrochloride

Chemical formula

[0130] Step J: 3-Chloro-N-(1-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)pyridine-2-carboxamide

Chemical formula

[0131] Example 3: Preparation of Compound 4

Chemical Structure

[0132] Example 4: Preparation of Compound 8

Chemical Structure

[0133] Example 5: Preparation of Compound 11 Step A: Ethyl 4-((tert-butylcarbonyl)amino)-1-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidine-4-carboxylate

Chemical Structure

[0134] Step B: Ethyl 4-(amino)-1-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidine-4-carboxylate

Chemical formula

[0135] Step C: Ethyl 4-(2,6-difluorobenzamide)-1-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidine-4-carboxylate

Chemical formula

[0136] Step D: N-(1-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(hydroxymethyl)piperidin-4-yl)-2,6-difluorobenzamide [Chemical formula] Ethyl 4-(2,6-difluorobenzamido)-1-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidine-4-carboxylate (30 mg, 0.05 mmol) and 2 mL of THF were added to a reaction flask. LiAlH4 (1.9 mg, 0.05 mmol) was added at 0 °C and reacted for 1 h. Water was added and stirred to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The product was obtained by separation using column chromatography, with m / z = 548 [M+1] + , 11H NMR (400 MHz, DMSO-d6) δ 12.65 (s, 1H), 8.59 (d, 1H), 8.52 (d, 1H), 8.36 (s, 1H), 8.04 (dd, 1H), 7.60 (s, 1H), 7.50 (tt, 1H), 7.27 (d, 1H), 7.22 - 7.08 (m, 3H), 4.87 (t, 1H), 4.28 (d, 2H), 4.18 (q, 2H), 3.63 (d, 2H), 3.19 (t, 2H), 2.24 (d, 2H), 1.68 (td, 4.3 Hz, 2H), 1.41 (t, 3H).

[0137] Example 6: Preparation of Compound 12 Step A: Ethyl 4-(3-chloromethylpyridineamide)-1-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidine-4-carboxylate

Chemical Structure

[0138] Step B: 3-Chloro-N-(1-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(hydroxymethyl)piperidin-4-yl)-pyridinecarboxamide

Chem.

[0139] Example 7: Preparation of Compound 15 Step A: tert-Butylcarbonyl(1-5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(hydroxymethyl)piperidin-4-yl)carbamate

Chem.

[0140] Step B: tert-Butylcarbonyl(1-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-formylpiperidin-4-yl)carbamate

Chemical formula

[0141] Step C: tert-Butylcarbonyl(4-((2-methylamino)methyl)-1-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidin-4-yl)carbamate [Chemical formula] tert-Butylcarbonyl(1-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-formylpiperidin-4-yl)carbamate (505 mg, 1 mmol), dimethylamine in tetrahydrofuran solution (2 M / L, 3 mL, 3 mmol), NaBH(OAc)3 (424 mg, 2 mmol), and DCE (10 mL) were added to a reaction flask and reacted at 25 °C for 12 h. The reaction was monitored by LCMS to ensure complete reaction. Water was added and stirred to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The product was separated by column chromatography to obtain 400 mg of the product, with m / z = 534.2 [M+1] + It was

[0142] Step D: 4-((2-Methylamino)methyl)-1-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidin-4-amine hydrochloride [Chemical formula] tert-Butylcarbonyl(4-((2-methylamino)methyl)-1-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidin-4-yl)carbamate (100 mg, 0.19 mmol) and 2 mL of methanol saturated with hydrogen chloride gas were added to a reaction flask and reacted at 25 °C for 5 h. The solvent was directly rotary evaporated to obtain 80 mg of the product, with m / z = 435.2 [M+1]+ It was.

[0143] Step E: 3-chloro-N-(4-((2-methylamino)methyl)-1-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidin-4-yl)picolinamide [Chemical formula] 4-((2-methylamino)methyl)-1-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidin-4-amine (80 mg, 0.19 mmol), 3-chloropicolinic acid (29.8 mg, 0.19 mmol), HATU (72.2 mg, 0.19 mmol), DIEA (73.5 mg, 0.57 mmol), and DMF (10 mL) were added to a reaction flask and reacted at 25 °C for 15 h. Water was added and stirred to quench, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 60 mg of the product, m / z = 574.2 [M+1] + , 1 H NMR (400 MHz, DMSO-d6) δ 12.69 (s, 1H), 8.62 - 8.49 (m, 3H), 8.28 (s, 1H), 8.08 - 7.98 (m, 2H), 7.60 (s, 1H), 7.52 (dd, J = 8.2, 4.7 Hz, 1H), 7.27 (d, J = 2.1 Hz, 1H), 7.10 (d, J = 9.0 Hz, 1H), 4.26 - 4.13 (m, 4H), 3.25 (d, J = 12.4 Hz, 2H), 2.70 (s, 2H), 2.38 (d, J = 13.2 Hz, 2H), 2.31 (s, 6H), 2.30 (d, J = 4.2 Hz, 1H), 1.63 (td, J = 13.0, 12.4, 4.1 Hz, 2H), 1.41 (t, J = 6.9 Hz, 3H), 1.24 (s, 1H), 0.85 (d, J = 7.3 Hz, 1H), 0.5 (s, 1H) It was.

[0144] Example 8: Preparation of Compound 17 Step A: tert-Butyl carbonyl(1-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-ethylpiperazin-1-yl)methyl)piperidin-4-yl)carbamate

Chemical formula

[0145] Step B: 1-(5-(6-Ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-ethylpiperazin-1-yl)methyl)piperidin-4-amine hydrochloride

Chemical formula

[0146] Step C: N-(1-(5-(6-Ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-ethylpiperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide [Chemical formula] 4-((2-Methylamino)methyl)-1-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidin-4-amine (100 mg, 0.2 mmol), 2,5-difluorobenzoic acid (31.6 mg, 0.2 mmol), HATU (76.0 mg, 0.2 mmol), DIEA (77.4 mg, 0.6 mmol), and DMF (10 mL) were added to the reaction flask and reacted at 25 °C for 15 h. The reaction solution was poured into water and extracted with ethyl acetate. The organic phase was dried, the solvent was rotary evaporated, and the product was purified by silica gel column chromatography to obtain 67 mg of the product, m / z = 644.2 [M+1] + It was. 11H NMR (400 MHz, DMSO-d6): δ 12.65 (s, 1H), 8.59 (d, J = 2.8 Hz, 1H), 8.52 (d, J = 2.0 Hz, 1H), 8.13 (s, 1H), 8.04 (d, J = 8.8 Hz, 1H), 7.60 (s, 1H), 7.41 - 7.29 (m, 3H), 7.26 (d, J = 2.1 Hz, 1H), 7.10 (d, J = 9.0 Hz, 1H), 4.19 (m, 4H), 3.32 (s, 1H), 3.27 - 3.15 (m, 2H), 2.73 (s, 2H), 2.61 - 2.55 (m, 7H), 2.34 (d, J = 13.3 Hz, 4H), 1.62 (m, 2H), 1.41 (t, J = 6.9 Hz, 3H), 0.99 (m, 3H). m / z = 644.2[M+1] + 。

[0147] Example 9: Preparation of Compound 29 Step A: tert-Butylcarbonyl(1-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(methylmorpholine)piperidin-4-yl)carbamate

Chemical Structure

[0148] Step B: 1-(5-(6-Ethoxy-1hydro-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-ethylpiperazin-1-yl)methyl)piperidin-4-amine hydrochloride

Chemical formula

[0149] Step C: N-(1-(5-(6-Ethoxy-1hydro-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-ethylpiperazin-1-yl)methyl)piperidin-4-yl)-3-methylbutyramide

Chemical formula

[0150] Example 10: Preparation of Compound 31 Step A: ((3S,4R)-1-(5-Bromopyridin-2-yl)-4-hydroxypyrrolidin-3-yl)carbamic acid tert-butyl

Chemical Structure

[0151] Step B: tert-Butyl ((3S,4S)-1-(5-bromopyridin-2-yl)-4-(pyridin-2-yloxy)pyrrolidin-3-yl)carbamate

Chemical formula

[0152] Step C: tert-Butyl ((3S,4S)-1-(5-(6-ethoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(pyridin-2-yloxy)pyrrolidin-3-yl)carbamate

Chemical formula

[0153] Step D: (3S,4S)-1-(5-(6-Ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(pyridin-2-yloxy)pyrrolidin-3-amine

Chemical formula

[0154] Example 11: Preparation of Compound 33 Step A: 6-Benzyl-1-oxa-6-azaspiro[2.5]octane

Chem.

[0155] Step B: 6-Benzyl-1-thia-6-azaspiro[2.5]octane

Chem.

[0156] Step C: 1-Benzyl-4-methylpiperidine-4-thiol [Chemical formula] 6-Benzyl-1-thia-6-azaspiro[2.5]octane (4.3 g, 19.6 mmol) and tetrahydrofuran (50 mL) were sequentially added to a reaction flask, the temperature was lowered to 5 °C, lithium aluminum hydride (1.1 g, 29.4 mmol) was added, and the mixture was reacted for 1 hour while maintaining the temperature, and the reaction was completed. 5 mL of water was gradually added, saturated sodium hydroxide solution was added to adjust the pH value to 14, the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure to dryness, and purified by silica gel column chromatography to obtain 3.8 g of the product, m / z = 222 [M+1] + It was

[0157] Step D: 1-Benzyl-4-(isobutylthio)-4-methylpiperidine [Chemical formula] 1-Benzyl-4-methylpiperidine-4-thiol (1.3 g, 6 mmol) and 30 mL of N,N-dimethylformamide were sequentially added to a reaction flask, the temperature was lowered to 5 °C, 1-bromo-2-methylpropane (0.9 g, 6.6 mmol) was added, potassium carbonate (2.5 g, 18 mmol) was added, and the reaction was carried out at 40 °C for 16 hours until the reaction was complete. Water was added and stirred to quench the reaction, and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 1.0 g of the product, with m / z = 278 [M+1] + It was.

[0158] Step E: 1-Benzyl-4-(isobutylsulfonyl)-4-methylpiperidine

Chemical formula

[0159] Step F: 4-(Isobutylsulfonyl)-4-methylpiperidine

Chemical formula

[0160] Step G: 6-Ethoxy-4-(6-(4-(isobutylsulfonyl)-4-methylpiperidin-1-yl)pyridin-3-yl)-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridine

Chemical Structure

[0161] Example 12: Preparation of Compound 34

Chemical Structure

[0162] Example 13: Preparation of Compound 35 4-((Dimethylamino)methyl)-1-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N-isobutylpiperidine-4-carboxamide (Compound APS03035) Step A: 1-(5-Bromopyridin-2-yl)-4-formyl-N-isobutylpiperidine-4-carboxamide

Chem.

[0163] Step B: 1-(5-Bromopyridin-2-yl)-4-((dimethylamino)methyl)-N-isobutylpiperidine-4-carboxamide

Chem.

[0164] Step C: 1-(5-Bromopyridin-2-yl)-4-((dimethylamino)methyl)-N-isobutylpiperidine-4-carboxamide

Chem.

[0165] Example 14: Preparation of Compound 36 4-(Azetidin-1-ylmethyl)-1-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N-isobutylpiperidine-4-amide (Compound APS03036) Step A: 1-(5-Bromopyridin-2-yl)-4-(azetidin-1-ylmethyl)-N-isobutylpiperidine-4-carboxamide [Chemical formula] To a 50 mL reaction flask, 1-(5-bromopyridin-2-yl)-4-formyl-N-isobutylpiperidine-4-carboxamide (70 mg, 0.19 mmol), 1,2-dichloromethane (2 mL), azetidineamine (32.6 mg, 0.57 mmol), and sodium borohydride acetate (80.8 mg, 0.38 mmol) were added. After stirring at room temperature for 16 hours, it was quenched with water, and then the organic phase was rotary dried and separated by column chromatography to obtain 60 mg of the product, m / z = 409 / 411 [M+1] + It was as follows.

[0166] Step B: 4-(azetidin-1-ylmethyl)-1-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N-isobutylpiperidine-4-carboxamide [Chemical formula] To the reaction flask, 1-(5-bromopyridin-2-yl)-4-(azetidin-1-ylmethyl)-N-isobutylpiperidine-4-carboxamide (60 mg, 0.15 mmol), 6-ethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridine (65.3 mg, 0.18 mmol), tetrakis(triphenylphosphine)palladium (23 mg, 0.02 mmol), potassium carbonate (40.6 mg, 0.29 mmol), water (0.35 mL), and 1,4-dioxane (0.7 mL) were sequentially added. It was replaced with nitrogen gas three times, heated to 90 °C and reacted for 16 hours. The reaction solution was poured into water and extracted with dichloromethane, and then purified by column chromatography to obtain 6 mg of the product, m / z = 531 [M+1] + It was as follows. 11H NMR (400 MHz, DMSO-d6) δ 12.65 (s, 1H), 8.50 - 8.56 (m, 2H), 7.94 - 8.03 (m, 2H), 7.71 - 7.81 (m, 1H), 7.58 (s, 1H), 7.24 - 7.25 (m, 1H), 7.02 - 7.04 (m, 1H), 4.14 - 4.20 (m, 2H), 4.04 - 4.07 (m, 2H), 3.15 - 3.20 (m, 6H), 2.93 - 2.96 (m, 2H), 2.04 - 2.17 (m, 2H), 1.88 - 1.96 (m, 2H), 1.74 - 1.80 (m, 1H), 1.34 - 1.44 (m, 5H), 0.85 - 0.88 (m, 7H).

[0167] Example 15: Preparation of Compound 37 4-(Pyrrolidin-1-ylmethyl)-1-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N-isobutylpiperidine-4-carboxamide (Compound APS03037) Step A: 1-(5-Bromopyridin-2-yl)-4-(pyrrolidin-1-ylmethyl)-N-isobutylpiperidine-4-carboxamide

Chemical Structure

[0168] Step B: 4-(Pyrrolidin-1-ylmethyl)-1-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N-isobutylpiperidine-4-carboxamide

Chemical formula

[0169] Example 16: Preparation of Compound 39 [Chemical formula] (3S, 4S)-4-Amino-1-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidin-3-ol (256.5 mg, 0.51 mmol), 3-methylbutyric acid (78 mg, 0.77 mmol), DIEA (263 mg, 2.04 mmol), and DCM (10 mL), HATU (292 mg, 0.77 mmol) were placed in a 50 mL reaction flask, reacted at room temperature for 0.5 h, water was added and stirred to quench, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 6.4 mg of the product, m / z = 478 [M+1] + , 1 H NMR (400 MHz, DMSO-d6) δ 12.65 (s, 1H), 8.57 (s, 1H), 8.51 (s, 1H), 8.03 (d, 1H), 7.7 (d, 1H), 7.58 (s, 1H), 7.25 (s, 1H), 7.06 (d, 1H), 5.00 (br, 1H), 4.42 - 4.44 (m, 1H), 4.14 - 4.25 (m, 3H), 3.60 - 3.72 (m, 1H), 3.01 - 3.07 (m, 1H), 2.81 - 2.87 (m, 1H), 1.89 - 1.98 (m, 4H), 1.20 - 1.45 (m, 5H), 0.80 - 0.89 (m, 6H).

[0170] Example 17: Preparation of Compound 40 Step A: ((3R, 4S)-1-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-hydroxypiperidin-4-yl)amino tert-butyl carbonate [Chemical formula] To a reaction flask, add 6-ethoxy-4-(6-fluoropyridin-3-yl)-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridine (1.0 g, 3.3 mmol), tert-butyl ((3R, 4S)-3-hydroxypiperidin-4-yl)carbonate (720 mg, 3.3 mmol), DIEA (2.2 g, 10 mmol) and 20 mL of DMSO, react at 90 °C for 4 h, add water and stir to quench, extract with ethyl acetate, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and separate by column chromatography to obtain 1.4 g of the product, m / z = 494 [M+1] + It was.

[0171] Step B: ((3R, 4S)-1-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-hydroxypiperidin-4-yl)amino hydrochloride

Chemical formula

[0172] Step C: N-((3R, 4S)-1-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-hydroxypiperidin-4-yl)-3-methylbutyramide

Chemical formula

[0173] Example 18: Preparation of Compound 41

Chemical Structure

[0174] Example 19: Preparation of Compound 42

Chemical Structure

[0175] Example 20: Preparation of Compound 43

Chemical Structure

[0176] Example 21: Preparation of Compound 44 Step A: ((3S, 4S)-1-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-hydroxypiperidin-4-yl)carbamate

Chemical Structure

[0177] Step B: (3S, 4S)-4-amino-1-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidin-3-ol

Chemical formula

[0178] Step C: 2-chloro-N-((3S,4S)-1-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-hydroxypiperidin-4-yl)-6-fluorobenzamide [Chemical] (3S, 4S)-4-Amino-1-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidin-3-ol (256.5 mg, 0.51 mmol), DIEA (263 mg, 2.04 mmol), DCM (10 mL), and 2-chloro-6-fluorobenzoyl chloride (98 mg, 0.51 mmol) were placed in a 50 mL reaction flask, reacted at 0 °C for 0.5 h, quenched by adding water and stirring, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 26 mg of the product, m / z = 550 [M+1] + , 1 1H NMR (400 MHz, DMSO-d6) δ 12.65 (s, 1H), 8.69 (d, 1H), 8.58 (s, 1H), 8.57 (s, 1H), 8.02 - 8.05 (m, 1H), 7.58 (s, 1H), 7.07 - 7.49 (m, 5H), 5.07 (br, 1H), 4.40 - 4.44 (m, 1H), 4.14 - 4.22 (m, 3H), 3.92 - 3.95 (m, 1H), 3.50 - 3.51 (m, 1H), 3.16 - 3.22 (m, 1H), 2.96 - 3.01 (m, 1H), 2.01 - 2.11 (m, 1H), 1.37 - 1.48 (m, 4H).

[0179] Example 22: Preparation of Compound 45 [Chemical] (3S, 4S)-4-Amino-1-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidin-3-ol (256.5 mg, 0.51 mmol), DIEA (263 mg, 2.04 mmol), DCM (10 mL), and 3-(trifluoromethyl)pyridine-2-carbonyl chloride (107 mg, 0.51 mmol) were placed in a 50 mL reaction flask, reacted at 0 °C for 0.5 h, quenched by adding water and stirring, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 45 mg of the product, m / z = 567 [M+1] + , 1 1H-NMR (400 MHz, DMSO-d6) δ 12.65 (brs, 1H), 8.85 - 8.86 (d, J = 4.0 Hz, 1H), 8.62 - 8.64 (d, J = 8.0 Hz, 1H), 8.58 (s, 1H), 8.57 (s, 1H), 8.29 - 8.31 (m, 1H), 8.04 - 8.07 (m, 1H), 7.72 - 7.75 (m, 1H), 7.59 (s, 1H), 7.26 (s, 1H), 7.09 - 7.11 (m, 1H), 5.10 (s, 1H), 4.46 - 4.50 (m, 1H), 4.26 - 4.29 (m, 1H), 4.14 - 4.20 (m, 2H), 3.92 - 3.96 (m, 1H), 3.54 - 3.59 (m, 1H), 3.10 - 3.16 (m, 1H), 2.90 - 2.95 (m, 1H), 2.01 - 2.05 (m, 1H), 1.49 - 1.52 (m, 1H), 1.39 (t, J = 6.8 Hz, 3H).

[0180] Example 23: Preparation of Compound 46

Chem.

[0181] Example 24: Preparation of Compound 48 Step A: ((3S, 4R)-1-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-hydroxypiperidin-3-yl)carbamic acid tert-butyl

Chemical Structure

[0182] Step B: tert-Butyl ((3S,4S)-4-(1,3-phthalimido-2-yl)-1-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidin-3-yl)carbamate

Chemical formula

[0183] Step C: ((S,4S)-4-Amino-1-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidin-3-yl)tert-butyl carbamate

Chemical formula

[0184] Step D: N-((3S, 4S)-3-Amino-1-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidin-4-yl)-2-chloro-6-methylbenzamide

Chemical formula

[0185] Example 25: Preparation of Compound 50 Step A: (3S, 4S)-1-(5-(6-Ethoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyrazin-2-yl)-3-hydroxypiperidin-4-yl)amino carbonate tert-butyl

Chemical formula

[0186] Step B: (3S, 4S)-4-Amino-1-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyrazin-2-yl)-3-hydroxypiperidine hydrochloride

Chemical formula

[0187] Step C: 3-chloro-N-((3S, 4S)-(1-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyrazin-2-yl)-3-hydroxypiperidin-4-yl)-2-pyridinecarboxamide [Chemical formula] To the reaction flask, add (3S, 4S)-4-amino-1-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyrazin-2-yl)-3-hydroxypiperidine hydrochloride (80 mg, 0.16 mmol), 3-chloropyridine-2-carboxylic acid (38 mg, 0.24 mmol), DIEA (103 mg, 0.8 mmol), HATU (61 mg, 0.16 mmol) and 2 mL of DMF, react at 25 °C for 2 h, react completely. Add water and stir to quench, extract with dichloromethane, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and separate by column chromatography to obtain 37.6 mg of the product, m / z = 534.1 [M+1] + , 11H NMR (400 MHz, DMSO-d6) δ 12.45 (brs, 1H), 8.90 (s, 1H), 8.74 (d, J = 7.6 Hz, 1H), 8.71 (s, 1H), 8.55 (s, 1H), 8.01 (s, 1H), 7.72 (s, 1H), 7.47 (dd, J1 = 8.0 Hz, J2 = 6.0 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.28 (t, J = 8.8 Hz, 1H), 5.01 - 5.42 (m, 1H), 4.36 - 4.41 (m, 1H), 4.17 - 4.24 (m, 2H), 3.95 - 4.02 (m, 1H), 3.62 - 3.71 (m, 2H), 3.12 - 3.21 (m, 2H), 2.10 - 2.18 (m, 1H), 1.48 - 1.60 (m, 1H), 1.39 - 1.43 (m, 3H).

[0188] Example 26: Preparation of Compound 51 Step A: 2-Chloro-N-((3S,4S)-(1-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyrazin-2-yl)-3-hydroxypiperidin-4-yl)-6-fluorobenzamide [Chemical Structure] (3S,4S)-4-Amino-1-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyrazin-2-yl)-3-hydroxypiperidine hydrochloride (80 mg, 0.16 mmol), 2-chloro-6-fluorobenzoyl chloride (46 mg, 0.24 mmol), DIEA (103 mg, 0.8 mmol) and 2 mL of DMF were added to a reaction flask, and the mixture was reacted at 25 °C for 1 h until the reaction was complete. Water was added and stirred to quench the reaction, and the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 4.6 mg of the product, m / z = 551.1 [M+1]. + It was as follows. 11H NMR (400 MHz, DMSO-d6) δ 12.54 (brs, 1H), 8.91 (s, 1H), 8.72 (s, 1H), 8.59 (d, J=8.4Hz, 1H), 8.55 (s, 1H), 8.04 (s, 1H), 8.02 (s, 1H), 7.73 (s, 1H), 7.52 (dd, J1=8.4Hz, J2=4.8Hz, 1H), 5.01-5.28 (m, 1H), 4.44-4.52 (m, 1H), 4.25-4.33 (m, 1H), 4.17 (q, J=6.8Hz, 1H), 3.96-4.02 (m, 1H), 3.58-3.67 (m, 1H), 3.30-3.35 (m, 1H), 3.03-3.11 (m, 1H), 2.10-2.18 (m, 2H), 1.56-1.68 (m, 1H), 1.39 (t, J=6.8Hz, 3H).

[0189] Example 27: Preparation of Compound 55 Step A: 4-Bromo-6-ethoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridine

Chemical Structure

[0190] Step B: 6-Ethoxy-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridine

Chem.

[0191] Step C: 4-(5-Chloropyridin-2-yl)-6-ethoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridine

Chem.

[0192] Step D: tert-Butyl (1-(5-(6-ethoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyrazin-2-yl)-4-methylpiperidin-4-yl)carbamate [Chemical formula] To the reaction flask, 4-(5-chloropyrazin-2-yl)-6-ethoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridine (1.0 g, 2.5 mmol), tert-butyl (4-methylpiperidin-4-yl)carbamate (1.0 g, 5.0 mmol), DIEA (972 mg, 7.5 mmol) and 12 mL of DMSO were added. The mixture was reacted at 80 °C for 12 h. Water was added, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to obtain 1.3 g of the product, m / z = 577 [M+1] + It was.

[0193] Step E: (1-(5-(6-Ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyrazin-2-yl)-4-methylpiperidin-4-yl)amino hydrochloride

Chem.

[0194] Step F: 3-Chloro-N-(1-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyrazin-2-yl)-4-methylpiperidin-4-yl)-5-fluoropyridine-2-carboxamide

Chem.

[0195] Example 28: Preparation of Compound 56

Chem.

[0196] Example 29: Preparation of Compound 57 Step A: N-(1-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyrazin-2-yl)-4-methylpiperidin-4-yl)-2,3,6-trifluorobenzamide

Chem.

[0197] Example 30: Preparation of Compound 58 Step A: 2-Chloro-N-(1-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyrazin-2-yl)-4-methylpiperidin-4-yl)-5-fluorobenzamide

Chemical formula

[0198] Example 31: Preparation of Compound 59 Step A: 3-Chloro-N-(1-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyrazin-2-yl)-4-methylpiperidin-4-yl)-2-pyridinecarboxamide

Chemical Structure

[0199] Example 32: Preparation of Compound 87 1-(5-(6-Ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(hydroxymethyl)-N-isobutylpiperidin-4 -amide (Compound APS03087) Step A: Methyl 1-(5-bromopyridin-2-yl)piperidine-4-carboxylate

Chemical Structure

[0200] Step B: Methyl 4-((benzyloxy)methyl)-1-(5-bromopyridin-2-yl)piperidine-4-carboxylate

Chemical formula

[0201] Step C: Methyl 4-hydroxymethyl-1-(5-bromopyridin-2-yl)piperidine-4-carboxylate

Chemical formula

[0202] Step D: 4-Hydroxymethyl-1-(5-bromopyridin-2-yl)piperidine-4-carboxylic acid

Chemical formula

[0203] Step E: 1-(5-Bromopyridin-2-yl)-4-(hydroxymethyl)-N-isobutylpiperidine-4-carboxamide

Chemical formula

[0204] Step F: 1-(5-(6-Ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(hydroxymethyl)-N-isobutylpiperidine-4-carboxamide

Chemical formula

[0205] Example 33: Preparation of Compound 88 ((3S, 4S)-1-(5-(6-Ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-hydroxypiperidin-4-yl)carbamic acid tert-butyl [Chemical Structure] 6-Ethoxy-4-(6-fluoropyridin-3-yl)-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridine (50 mg, 0.17 mmol), ((3S, 4S)-3-Hydroxypiperidin-4-yl)carbamic acid tert-butyl (40 mg, 0.17 mmol), DIEA (65 mg, 0.5 mmol), DMSO (3 mL) were added to a reaction flask and reacted at 90 °C for 4 h. Water was added and stirred to quench the reaction, then extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 12 mg of the product, m / z = 494 [M + 1]. + , 11H NMR (400 MHz, DMSO-d6) δ 12.64 (brs, 1H), 8.56 (s, 1H), 8.50 (s, 1H), 8.01 (d, J = 8.8 Hz, 1H), 7.57 (s, 1H), 7.26 (s, 1H), 7.04 (d, J = 8.8 Hz, 1H), 6.72 (brs, 1H), 4.98 (d, J = 4.8 Hz, 1H), 4.43 - 4.46 (m, 1H), 4.20 - 4.27 (m, 1H), 4.15 (q, J = 6.8 Hz, 2H), 3.35 - 3.41 (m, 2H), 2.96 - 3.02 (m, 1H), 2.75 - 2.80 (m, 1H), 1.86 - 1.88 (m, 1H), 1.35 - 1.42 (m, 13H).

[0206] Example 34: Preparation of Compound 89

Chem.

[0207] Example 35: Preparation of Compound 91 Step A: 2-Chloro-N-((3S,4S)-(1-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyrazin-2-yl)-3-hydroxypiperidin-4-yl)-5-fluorobenzamide [Chemical formula] (3S,4S)-4-Amino-1-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyrazin-2-yl)-3-hydroxypiperidine hydrochloride (100 mg, 0.2 mmol), 2-chloro-5-fluorobenzoyl chloride (46 mg, 0.24 mmol), DIEA (129 mg, 1.0 mmol) and 2 mL of DMF were added to a reaction flask, and the mixture was reacted at 25 °C for 1 h until the reaction was complete. The reaction mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 8.5 mg of the product, m / z = 551.1 [M+1]. + , 11H NMR (400 MHz, DMSO-d6) δ 12.47 (brs, 1H), 8.91 (s, 1H), 8.72 (s, 1H), 8.55 (s, 1H), 8.47 (d, J = 8.0 Hz, 1H), 8.01 (s, 1H), 7.73 (s, 1H), 7.54 (dd, J1 = 8.8 Hz, J2 = 4.0 Hz, 1H), 7.40 - 7.43 (m, 1H), 7.31 - 7.36 (m, 1H), 5.25 (s, 1H), 4.42 - 4.46 (m, 1H), 4.28 - 4.32 (m, 1H), 4.17 (t, J = 6.8 Hz, 2H), 3.89 - 3.99 (m, 1H), 3.51 - 3.57 (m, 1H), 3.25 - 3.27 (m, 1H), 3.02 - 3.10 (m, 1H), 2.01 - 2.08 (m, 1H), 1.48 - 1.54 (m, 1H), 1.39 (t, J = 6.8 Hz, 3H).

[0208] Example 36: Preparation of Compound 101 Step A: tert-Butyl 4-(N-isopropylsulfonyl)piperidine-1-carboxylate

Chemical formula

[0209] Step B: N-Isopropylpiperidine-4-sulfonamide

Chemical formula

[0210] Step C: 1-(5-(6-Ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N-isopropylpiperidine-4-sulfonamide

Chemical formula

[0211] Example 37: Preparation of Compound 102 Step A: 4-Hydroxy-4-(benzenesulfonamidomethylene)piperidine-1-carboxylic acid tert-butyl [Chemical formula] To a reaction flask were added 4-(acylaminomethylene)-4-hydroxypiperidine-1-carboxylic acid tert-butyl (230 mg, 1 mmol), dichloromethane (10 mL), and triethylamine (200 mg, 2 mmol). The temperature was lowered to 10°C, and benzoyl chloride (194 mg, 1.1 mmol) was added. The mixture was reacted for 1 hour. Water was added and stirred to quench the reaction. The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 300 mg of the product, m / z = 371 [M+1] + It was.

[0212] Step B: N-((4-Hydroxypiperidin-4-yl)methylene)benzenesulfonamide [Chemical formula] To the reaction flask, 4-hydroxy-4-(benzenesulfonamidomethylene)piperidine-1-carboxylic acid tert-butyl (300 mg, 0.8 mmol) and a 1,4-dioxane solution of HCl (4 M, 10 mL) were sequentially added, and the mixture was reacted at room temperature for 1 hour until the reaction was complete. It was concentrated under reduced pressure to obtain 320 mg of the product, which was used directly in the next reaction, m / z = 271 [M+1] + It was.

[0213] Step C: N-((1-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-hydroxypiperidin-4-yl)methylene)benzenesulfonamide [Chemical formula] To the reaction flask, DMSO (2 mL), DIEA (0.5 mL), N-((4-hydroxypiperidin-4-yl)methylene)benzenesulfonamide (300 mg, 0.8 mmol), 6-ethoxy-4-(6-fluoropyridin-3-yl)-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridine (100 mg, 0.3 mmol) were sequentially added, and the mixture was reacted at 100 °C for 16 hours. Water was added and stirred to quench the reaction. It was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 93 mg of the product, m / z = 548 [M+1] + It was. 11H NMR (400 MHz, DMSO-d6) δ 12.64 (s, 1H), 8.58 (d, J = 2.6 Hz, 1H), 8.51 (d, J = 2.1 Hz, 1H), 8.03 (dd, J = 8.9, 2.6 Hz, 1H), 7.86 - 7.78 (m, 2H), 7.69 - 7.53 (m, 5H), 7.26 (d, J = 2.1 Hz, 1H), 7.08 (d, J = 9.0 Hz, 1H), 4.60 (s, 1H), 4.23 - 4.07 (m, 4H), 3.35 - 3.24 (m, 2H), 2.72 (d, J = 6.7 Hz, 2H), 1.60 (td, J = 12.8, 12.1, 4.4 Hz, 2H), 1.48 (d, J = 13.2 Hz, 2H), 1.40 (t, J = 6.9 Hz, 3H).

[0214] Example 38: Preparation of Compound 103 Step A: tert-Butyl 4-(pyridin-2-yloxy)piperidine-1-carboxylate

Chemical Structure

[0215] Step B: 2-(piperidin-4-yloxy)pyridine

Chemical Structure

[0216] Step C: 6-Ethoxy-4-(6-(4-(pyridin-2-yloxy)piperidin-1-yl)pyridin-3-yl)-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]piperidine

Chemical formula

[0217] Example 39: Preparation of Compound 104 Step A: tert-Butyl 4-((6-methylpyridazin-3-yl)oxy)piperidine-1-carboxylate

Chemical Structure

[0218] Step B: 3-Methyl-6-(pyridin-4-yloxy)pyridazine

Chemical formula

[0219] Step C: 6-Ethoxy-4-(6-(4-((6-methylpyridazin-3-yl)oxy)piperidin-1-yl)pyridin-3-yl)-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridine

Chemical formula

[0220] Example 40: Preparation of Compound 107 (3S,4S)-4-((2-Chloro-6-fluorophenyl)amino)-1-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidin-3-ol [Chemical formula] (3S, 4S)-4-Amino-1-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidin-3-ol hydrochloride (100 mg, 0.2 mmol), 1-chloro-2-(chloromethyl)-3-fluorophenyl (50 mg, 0.2 mmol), Cs2CO3 (130 mg, 0.4 mmol), and DMF (3 mL) were added to a reaction flask and reacted at 50 °C for 12 h. The reaction solution was poured into 30 mL of water, extracted with ethyl acetate, the organic phase was dried, the solvent was rotary evaporated, and purified by column chromatography to obtain 4.6 mg of the product, m / z = 535 [M+1] +It was as follows. 1 H-NMR (400 MHz, DMSO-d6) δ 12.65 (brs, 1H), 8.56 (s, 1H), 8.50 (s, 1H), 8.01 (d, J = 8.8 Hz, 1H), 7.58 (s, 1H), 7.31 - 7.42 (m, 2H), 7.22 - 7.30 (m, 2H), 7.05 (d, J = 8.8 Hz, 1H), 5.18 (d, J = 4.0 Hz, 1H), 4.42 - 4.48 (m, 1H), 4.29 - 4.35 (m, 1H), 4.14 (m, 2H), 3.81 - 3.98 (m, 2H), 3.20 - 3.28 (m, 2H), 2.88 - 2.98 (m, 1H), 2.66 - 2.74 (m, 1H), 2.41 - 2.47 (m, 2H), 2.10 - 2.20 (m, 1H), 1.37 (m, 3H).

[0221] Example 41: Preparation of Compound 118 N-((3aR, 6aS)-5-(5-(6-Ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)hexahydropyridino[3,4-c]pyrrol-2(1H)-yl)-2-chloro-6-fluorobenzamide

Chemical Structure

[0222] Example 42: Preparation of Compound 150 Step A: Ethyl 4-(2,5-difluorobenzamido)-1-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidine-4-carboxylate [Chemical formula] Ethyl 4-((tert-butylcarbonyl)amino)-1-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidine-4-carboxylate hydrochloride (120 mg, 0.26 mmol), 2,5-difluorobenzoic acid (37.9 mg, 0.24 mmol), DIEA (100 mg, 0.78 mmol), HATU (108 mg, 0.28 mmol), and DMF (2 mL) were added to a reaction flask, reacted at 25 °C for 12 h, quenched by adding water and stirring, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 78 mg of the product, m / z = 590 [M+1] + It was.

[0223] Step B: N-(1-(5-(6-Ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(hydroxymethyl)piperidin-4-yl)-2,5-difluorobenzamide

Chemical formula

[0224] Example 43: Preparation of Compound 151 Step A: tert-Butyl 3-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate [Chemical formula] To a three-necked flask, 4-bromo-6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridine (0.28 g, 1 mmol), 1,4-dioxane (2.8 mL), tert-butyl 6-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-3-carboxylate (0.52 g, 1.3 mmol), lithium carbonate (148 mg, 2 mmol), tetrakis(triphenylphosphine)palladium (23 mg, 0.02 mmol), and water (1.4 mL) were sequentially added. The temperature was raised to 90 °C and the reaction was carried out for 24 hours. Water was added and stirred to quench the reaction. The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 230 mg of the product, m / z = 476.2 [M+1] + It was.

[0225] Step B: 4-(6-(3,6-Diazabicyclo[3.1.1]heptan-6-yl)pyridin-3-yl)-6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridine [Chemical formula] To a three-necked flask, 3-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl (200 mg, 0.42 mmol), methanol (4 mL), and m-dimethoxybenzene (2.9 mg, 0.02 mmol) were sequentially added. Sulfuric acid (98%, 168 mg, 1.68 mmol) was added, and the temperature was raised to 55 °C and reacted for 4 hours. Water was added and stirred to quench, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 300 mg of the product, m / z = 376.2 [M+1] + It was

[0226] Step C: 6-Ethoxy-4-(6-(3-(((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptyl-6-yl)pyridin-3-yl)-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridine [Chemical formula] To a three-necked flask, 4-(6-(3,6-diazabicyclo[3.1.1]heptan-6-yl)pyridin-3-yl)-6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridine (180 mg, 0.27 mmol), n-propanol (3.6 mL), triethylamine (136.2 mg, 1.35 mmol), 6-methoxypyridine-3-carbaldehyde (111 mg, 0.81 mmol), and Pic-BH3 (86.7 mg, 0.81 mmol) were sequentially added. While maintaining the temperature at 50 °C, it was stirred for 24 hours. Water was added and stirred to quench, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 70 mg of the product, m / z = 497 [M+1] + , 11H NMR (400 MHz, DMSO-d6) δ 12.67 (s, 1H), 8.53 - 8.56 (m, 2H), 7.99 - 8.02 (m, 1H), 7.76 - 7.76 (m, 1H), 7.59 (s, 1H), 7.31 - 7.32 (m, 1H), 7.19 - 7.22 (m, 1H), 6.69 - 6.71 (m, 1H), 6.49 - 6.52 (m, 1H), 4.38 - 4.40 (m, 2H), 4.16 - 4.21 (m, 2H), 3.74 (s, 3H), 3.56 (s, 2H), 3.21 - 3.24 (m, 2H), 2.69 - 2.72 (m, 2H), 2.56 - 2.60 (m, 1H), 1.75 - 1.77 (d, 1H), 1.39 - 1.42 (m, 3H).

[0227] Example 44: Preparation of Compound 152 Step A: tert-Butyl (3aR, 6aS)-5-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)hexahydropyridino[3,4-c]pyrrole-2(1H)-carboxylate

Chemical Structure

[0228] Step B: 6-Ethoxy-4-(6-((3aR, 6aS)-hexahydropyridino[3,4-c]pyrrol-2(1H)-yl)pyridin-3-yl)-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridine hydrochloride

Chem.

[0229] Step C: 6-Ethoxy-4-(6-((3aR, 6aS)-5-((6-Methoxypyridin-3-yl)methylene)-hexahydropyridino[3,4-c]pyrrol-2(1H)-yl)pyridin-3-yl)-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridine

Chem.

[0230] Example 45: Preparation of Compound 155 Step A: (1R, 5S)-3-(5-(6-Ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl [Chemical formula] Add 6-ethoxy-4-(6-fluoropyridin-3-yl)-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridine (292 mg, 1.0 mmol), tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (250 mg, 1.2 mmol), DIEA (506 mg, 3.9 mmol) and 3 mL of DMSO to a reaction flask, react at 95 °C for 4 h, add water, stir to quench, extract with dichloromethane, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and separate by column chromatography to obtain 208 mg of the product, m / z = 490 [M+1] + It was

[0231] Step B: 4-(6-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)-6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridine hydrochloride

Chemical formula

[0232] Step C: (2-Chloro-6-fluoro)((1R,5S)-3-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)benzamide

Chemical formula

[0233] Example 46: Preparation of Compound 156 Step A: 6-Ethoxy-4-(6-((1R, 5S)-8-((6-methoxypyridin-3-yl)methyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyrazole

Chemical Structure

[0234] Example 47: Preparation of Compound 157 Step A: (1R, 5S)-8-(5-(6-Ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl

Chemical Structure

[0235] Step B: 4-(6-((1R, 5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)pyridin-3-yl)-6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridine hydrochloride [Chemical formula] To the reaction flask, (1R, 5S)-tert-butyl 3-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200 mg, 0.4 mmol), 3 mL of methanol, 5 N methanolic hydrochloric acid solution (3 mL, 15 mmol) were added, and the reaction was carried out at 25 °C for 4 h until the reaction was complete, concentrated under reduced pressure to obtain 280 mg of the product, which was used directly in the next reaction, m / z = 390 [M+1] + It was.

[0236] Step C: (2-chloro-6-fluoro)((1R, 5S)-8-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)benzamide [Chemical formula] 4-(6-((1R, 5S)-3,8-Diazabicyclo[3.2.1]octan-8-yl)pyridin-3-yl)-6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridine hydrochloride (100 mg, 0.2 mmol), 3-chloro-6-fluorobenzoyl chloride (43 mg, 0.22 mmol), DIEA (155 mg, 1.2 mmol), and 2 mL of DMF were added to a reaction flask, and the mixture was reacted at 25 °C for 1 h. Water was added and stirred to quench the reaction. The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 23.2 mg of the product, m / z = 546 [M+1]. + It was. 1 H NMR (400 MHz, CD3OD-d3) δ 8.59 (s, 1H), 8.30 (s, 1H), 8.02 (d, J = 8.8 Hz, 1H), 7.65 (s, 1H), 7.46 - 7.52 (m, 1H), 7.42 - 7.44 (m, 1H), 7.17 - 7.27 (m, 2H), 7.03 (d, J = 8.8 Hz, 1H), 4.82 - 4.87 (m, 1H), 4.63 - 4.68 (m, 1H), 4.42 (t, J = 11. -- 2 Hz, 1H), 4.12 (q, J = 7.2 Hz, 2H), 3.57 (t, J = 13.6 Hz, 1H), 3.18 - 2.24 (m, 1H), 1.92 - 2.18 (m, 4H), 1.45 (t, J = 6.8 Hz, 3H).

[0237] Example 48: Preparation of Compound 158 Step A: 6-Ethoxy-4-(6-((1R, 5S)-3-((6-methoxypyridin-3-yl)methyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-8-yl)-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyrazole

Chemical formula

[0238] Example 49: Preparation of Compound 159 Step A: tert-Butyl 5-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylate [Chemical formula] 6-Ethoxy-4-(6-fluoropyridin-3-yl)-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridine (318 mg, 1.1 mmol), tert-butyl 2,5-diazabicyclo[2.2.2]octane-2-carboxylate (250 mg, 1.2 mmol), DIEA (414 mg, 3.2 mmol), and DMSO (5 mL) were added to a reaction flask and reacted at 90 °C for 12 h. Water was added and stirred to quench the reaction. The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 500 mg of the product, m / z = 490 [M+1] + It was.

[0239] Step B: 4-(6-(2,5-Diazabicyclo[2.2.2]octan-2-yl)pyridin-3-yl)-6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridine hydrochloride

Chemical formula

[0240] Step C: (2-Chloro-6-fluorophenyl)-5-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-2,5-diazabicyclo[2.2.2]octan-2-yl)methyl ketone

Chemical formula

[0241] Example 50: Preparation of Compound 160 6-Ethoxy-4-(6-(5-((6-methoxypyridin-3-yl)methyl)-2,5-diazabicyclo[2.2.2]octan-2-yl)pyridin-3-yl)-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridine

Chemical Structure

[0242] Example 51: Preparation of Compound 161 (2-Chloro-6-fluorophenyl)(6-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)methylene

Chemical Structure

[0243] Example 52: Preparation of Compound 164 Step A: tert-Butyl 7-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate

Chemical Structure

[0244] Step B: 4-(6-(4,7-Diazaspiro[2.5]octan-7-yl)pyridin-3-yl)-6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridine hydrochloride

Chemical formula

[0245] Step C: N-(7-(5-(6-Ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4,7-diazaspiro[2.5]octan-4-yl)-2-chloro-6-fluorobenzamide

Chemical formula

[0246] Example 53: Preparation of Compound 165 6-Ethoxy-4-(6-(4-((6-methoxypyridin-3-yl)methylene)-4,7-diazaspiro[2.5]octan-7-yl)pyridin-3-yl)-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridine

Chemical Structure

[0247] Example 54: Preparation of Compound 169 Step A: tert-Butyl 7-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-oxa-7,9-azabicyclo[3.3.1]nonane-9-carboxylate

Chemical Structure

[0248] Step B: 7-(5-(6-Ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-oxa-7,9-azabicyclo[3.3.1]nonane hydrochloride

Chemical formula

[0249] Step C: N-(7-(5-(6-Ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-oxa-7,9-azabicyclo[3.3.1]nonan-9-yl)-2-chloro-6-fluorobenzamide

Chemical formula

[0250] Example 55: Preparation of Compound 114 Step A: 7-(5-(6-Ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-9-((6-methoxypyridin-3-yl)methylene)-3-oxa-7,9-azabicyclo[3.3.1]nonane [Chemical formula] 7-(5-(6-Ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-oxa-7,9-azabicyclo[3.3.1]nonane (100 mg, 0.2 mmol), 6-methoxy-3-pyridinecarboxaldehyde (83 mg, 0.6 mmol), Pic-BH3 (64 mg, 0.6 mmol), Et3N (120 mg, 1.2 mmol), and n-propanol (5 mL) were added to a reaction flask and reacted at 45 °C for 16 h. Water was added and stirred to quench the reaction. The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 6.5 mg of the product, m / z = 527 [M+1]. + , 1 1H NMR (400 MHz, DMSO-d6) δ 12.66 (s, 1H), 8.61 (d, J = 2.6 Hz, 1H), 8.52 (d, J = 2.0 Hz, 1H), 8.18 (d, J = 2.3 Hz, 1H), 8.06 (dd, J = 8.9, 2.6 Hz, 1H), 7.77 (dd, J = 8.5, 2.4 Hz, 1H), 7.60 (s, 1H), 7.26 (d, J = 2.1 Hz, 1H), 6.95 (d, J = 9.0 Hz, 1H), 6.83 (d, J = 8.5 Hz, 1H), 4.19 (q, J = 6.9 Hz, 2H), 4.05 (d, J = 13.1 Hz, 2H), 3.93 (s, 2H), 3.83 (d, J = 14.8 Hz, 7H), 3.47 - 3.57 (m, 2H), 2.83 (d, J = 3.3 Hz, 2H), 1.41 (t, J = 6.9 Hz, 3H).

[0251] Example 56: Preparation of Compound 149 6-Ethoxy-4-(6-(6-(4-(methanesulfonyl)benzylidene)-3,6-diazabicyclo[3.1.1]heptan-3-yl)-pyridin-3-yl)-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridine [Chemical formula] 4-(6-(3,6-Diazabicyclo[3.1.1]heptan-3-yl)-6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridine (300 mg, 0.8 mmol), 6-methoxy-3-pyridinealdehyde (165 mg, 1.2 mmol), Et3N (202 mg, 2.0 mmol), Pic-BH3 (128 mg, 1.2 mmol), DMSO (10 mL) were added to a reaction flask, reacted at 45 °C for 48 h, water was added and stirred to quench, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 71.4 mg of the product, m / z = 544 [M+1] + , 1 1H-NMR (400 MHz, DMSO-d6) δ 12.65 (brs, 1H), 8.65 (s, 1H), 8.52 (s, 1H), 8.11 (d, J = 8.8 Hz, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.58 - 7.70 (m, 3H), 7.27 (s, 1H), 6.91 (d, J = 8.8 Hz, 1H), 4.16 - 4.21 (m, 2H), 3.51 - 3.83 (m, 8H), 3.20 (s, 3H), 2.58 - 2.65 (m, 1H), 1.57 - 1.65 (m, 1H), 1.39 - 1.42 (m, 3H).

[0252] Example 57: Preparation of Compound 170 2-Chloro-N-(((1R, 5S, 6S)-3-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-azabicyclo[3.1.0]hex-6-yl)-6-fluorobenzamide Step A: (1R, 5S, 6S)-3-(5-(6-Ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-azabicyclo[3.1.0]hex-6-ylamine hydrochloride

Chemical formula

[0253] Step B: 2-Chloro-N-((1R, 5S, 6S)-3-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-azabicyclo[3.1.0]hex-6-yl)-6-fluorobenzamide

Chemical formula

[0254] Example 58: Preparation of Compound 171 (1R, 5S, 6S)-3-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N-(((6-methoxypyridin-3-yl)methylene)-3-azabicyclo[3.1.0]-6-hexylamine

Chemical Structure

[0255] Example 59: Preparation of Compound 172 2-Chloro-N-(((1R, 5S, 6R)-3-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-azabicyclo[3.1.0]hex-6-yl)-6-fluorobenzamide Step A: (1R, 5S, 6R)-3-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-azabicyclo[3.1.0]-6-hexylamine hydrochloride

Chemical Structure

[0256] Step B: 2-Chloro-N-((1R, 5S, 6R)-3-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-azabicyclo[3.1.0]hex-6-yl)-6-fluorobenzamide

Chemical formula

[0257] Example 60: Preparation of Compound 173 (1R, 5S, 6R)-3-(5-(6-Ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N-(((6-methoxypyridin-3-yl)methylene)-3-azabicyclo[3.1.0]hexylamine

Chemical Structure

[0258] Example 61: Preparation of Compound 174 2-Chloro-N-(((3aR, 5S, 6aS)-2-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-octahydrocyclopentyl[c]pyrrol-5-yl)-6-fluorobenzamide Step A: 2-Chloro-6-fluoro-N-(((3aR, 5S, 6aS)-octahydrocyclopentyl[c]pyrrol-5-yl)benzamide hydrochloride [Chemical formula] To the reaction flask were added (3aR, 5S, 6aS)-5-aminohexahydrocyclopentyl[c]pyrrol-2(1H)-tert-butyl carbonate hydrochloride (120 mg, 0.53 mmol), dichloromethane (2 mL), triethylamine (107 mg, 1.06 mmol), and 6-fluoro-2-chlorobenzoyl chloride (113 mg, 0.58 mmol). The mixture was stirred at room temperature for 1 hour. Water was added, and the mixture was extracted twice with DCM. After concentration until no more solvent was obtained, methanol (1 mL) and 1,4-dioxane / hydrogen chloride (4 M, 2 mL) were added to the residue, and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to obtain 140 mg of the product, which was used directly in the next reaction, m / z = 283 [M+1]. + It was as follows.

[0259] Step B: 2-Chloro-N-(((3aR, 5S, 6aS)-2-(5-(6-Ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-octahydrocyclopentyl[c]pyrrol-5-yl)-6-fluorobenzamide [Chemical Formula] To the reaction flask, add 2-chloro-6-fluoro-N-(((3aR, 5S, 6aS)-octahydrocyclopentyl[c]pyrrol-5-yl)benzamide hydrochloride (65 mg, 0.2 mmol), 2 mL of DMSO, DIEA (65.7 mg, 0.51 mmol), 6-ethoxy-4-(6-fluoropyridin-3-yl)-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridine (65 mg, 0.2 mmol), heat to 90 °C and react for 24 hours. Add water, stir to quench, extract with dichloromethane, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and separate by column chromatography to obtain 30 mg of the product, m / z = 560 [M+1] + , 1 1H NMR (400 MHz, DMSO-d6) δ 12.64 (s, 1H), 8.80 - 8.82 (m, 1H), 8.50 - 8.55 (m, 2H), 7.80 - 8.02 (m, 1H), 7.57 (s, 1H), 7.43 - 7.48 (m, 1H), 7.35 - 7.37 (m, 1H), 7.26 - 7.31 (m, 1H), 7.21 - 7.22 (m, 1H), 6.72 - 6.74 (m, 1H), 4.29 - 4.35 (m, 1H), 4.14 - 4.19 (m, 2H), 3.59 - 3.63 (m, 2H), 3.49 - 3.52 (m, 2H), 2.78 - 2.80 (m, 2H), 2.32 - 2.38 (m, 2H), 1.37 - 1.50 (m, 5H).

[0260] Example 62: Preparation of Compound 176 2-Chloro-N-(((3aR,5R,6aS)-2-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-octahydrocyclopentyl[c]pyrrol-5-yl)-6-fluorobenzamide Step A: 2-Chloro-6-fluoro-N-(((3aR,5R,6aS)-octahydrocyclopentyl[c]pyrrol-5-yl)benzamide hydrochloride

Chem.

[0261] Step B: 2-Chloro-N-(((3aR,5R,6aS)-2-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-octahydrocyclopentyl[c]pyrrol-5-yl)-6-fluorobenzamide

Chem.

[0262] Example 63: Preparation of Compound 180 (2-Chloro-6-fluorophenyl)((3aR, 7aS)-2-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)octahydro-1H-4,7-epiiminoisoindol-8-yl)methyl ketone Step A: (2-Chloro-6-fluorophenyl)((3aR, 7aS)-octahydro-1H-4,7-epiiminoisoindol-8-yl)methyl ketone hydrochloride

Chemical Structure

[0263] Step B: (2-Chloro-6-fluorophenyl)((3aR, 7aS)-2-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)octahydro-1H-4,7-epiiminoisoindol-8-yl)methyl ketone

Chemical Structure

[0264] Example 64: Preparation of Compound 128 6-Ethoxy-4-(6-(((3aR,7aS)-8-(((6-methoxypyridin-3-yl)methyl)octahydro-2H-4,7-epiaminoisoindol-2-yl)pyridin-3-yl)-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridine Step A: (3aR,7aS)-8-(((6-methoxypyridin-3-yl)methyl)octahydro-1H-4,7-epiaminoisoindole hydrochloride

Chemical Structure

[0265] Step B: 6-Ethoxy-4-(6-(((3aR, 7aS)-8-(((6-methoxypyridin-3-yl)methyl)octahydro-2H-4,7-epiaminoisoindol-2-yl)pyridin-3-yl)-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridine

Chemical Structure

[0266] Example 65: Preparation of Compound 183 Step A: 3-Phenyl-6-ethyl-(1R, 5S, 6R)-3-azabicyclo[3.1.0]hexane-3,6-carboxylate

Chem.

[0267] Step B: (1R, 5S, 6R)-3-Azabicyclo[3.1.0]hexane-6-carboxylic acid ethyl ester

Chem.

[0268] Step C: (1R, 5S, 6R)-3-(5-Bromopyridin-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid ethyl ester

Chem.

[0269] Step D: ((1R, 5S, 6R)-3-(5-Bromopyridin-2-yl)-3-azabicyclo[3.1.0]hexan-6-yl)methanol

Chemical formula

[0270] Step E: tert-Butyl (((1R, 5S, 6R)-3-(5-bromopyridin-2-yl)-3-azabicyclo[3.1.0]hexan-6-yl)methyl)(tert-butoxycarbonyl)carbamate

Chemical formula

[0271] Step F: tert-Butyl (((1R, 5S, 6R)-3-(5-(6-Ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-azabicyclo[3.1.0]hexan-6-yl)methyl)(tert-butoxycarbonyl)carbamate

Chemical formula

[0272] Step G: ((1R, 5S, 6S)-3-(5-(6-Ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-azabicyclo[3.1.0]hexan-6-yl)methylamine hydrochloride

Chemical Structure

[0273] Step H: 2-Chloro-N-(((1R, 5S, 6S)-3-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-azabicyclo[3.1.0]hexan-6-yl)methyl)-6-fluorobenzamide

Chemical formula

[0274] Example 66: Preparation of Compound 184 Step A: N-(((1R, 5S, 6S)-3-(5-(6-Ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-azabicyclo[3.1.0]hexan-6-yl)methyl)-1-(6-methoxypyridin-3-yl)-N-((6-methoxypyridin-3-yl)methyl)methylamine

Chemical formula

[0275] Example 67: Preparation of Compound 187 Step A: tert-Butyl 5-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-2,5-diazaspiro[3.4]octane-5-carboxylate

Chem.

[0276] Step B: 4-(6-(2,5-Diazaspiro[3.4]octan-2-yl)pyridin-3-yl)-6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridine

Chem.

[0277] Step C: (2-Chloro-6-fluorophenyl)-5-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-2,5-diazaspiro[3.4]octan-5-yl)methyl ketone [Chemical formula] 4-(6-(2,6-Diazaspiro[3.4]octan-2-yl)pyridin-3-yl)-6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridine hydrochloride (500 mg, 1.18 mmol), 2-chloro-6-fluorobenzoyl chloride (250 mg, 1.29 mmol), Et3N (358 mg, 3.54 mmol), DMF (5 mL) were added to a reaction flask, reacted at 25 °C for 12 h, water was added and stirred to quench, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 398 mg of the product, m / z = 546 [M+1] + , 1 1H NMR (400 MHz, DMSO-d6): δ 12.65 (s, 1H), 8.57 (d, J = 2.4 Hz, 1H), 8.52 (d, J = 2.1 Hz, 1H), 8.06 (m, 1H), 7.59 (s, 1H), 7.53 (m, 1H), 7.49 - 7.34 (m, 2H), 7.27 (d, J = 2.1 Hz, 1H), 6.69 (d, J = 8.6 Hz, 1H), 4.86 (t, J = 8.4 Hz, 2H), 4.18 (q, J = 6.9 Hz, 2H), 4.05 (dd, J = 9.6, 7.8 Hz, 2H), 3.23 (td, J = 6.6, 1.9 Hz, 2H), 2.42 (t, J = 6.8 Hz, 2H), 1.91 - 1.78 (m, 2H), 1.40 (t, J = 6.9 Hz, 3H).

[0278] Example 68: Preparation of Compound 188 6-Ethoxy-4-(6-(5-((6-methoxypyridin-3-yl)methyl)-2,5-diazaspiro[3.4]octan-2-yl)pyridin-3-yl)-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridine

Chem.

[0279] Example 69: Preparation of Compound 189 Step A: tert-Butyl 5-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-2,6-diazaspiro[3.4]octane-6-carboxylate

Chem.

[0280] Step B: 4-(6-(2,6-Diazaspiro[3.4]octan-2-yl)pyridin-3-yl)-6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridine hydrochloride

Chem.

[0281] Step C: (2-Chloro-6-fluorophenyl)-5-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-2,6-diazaspiro[3.4]octan-6-yl)methyl ketone

Chem.

[0282] Example 70: Preparation of Compound 190 6-Ethoxy-4-(6-(6-((6-Methoxypyridin-3-yl)methyl)-2,6-diazaspiro[3.4]octan-2-yl)pyridin-3-yl)-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridine

Chem.

[0283] Example 71: Preparation of Compound 191 Step A: tert-Butyl 2-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate [Chemistry] 6-Ethoxy-4-(6-fluoropyridin-3-yl)-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridine (250 mg, 0.8 mmol), tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (230 mg, 0.9 mmol), DIEA (520 mg, 4 mmol), and DMSO (2 mL) were added to a reaction flask, and the mixture was reacted at 90 °C for 16 h. Water was added and stirred to quench the reaction. The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 390 mg of the product, m / z = 504 [M+1]. + It was as follows.

[0284] Step B: 4-(6-(2,7-Diazaspiro[3.5]nonan-2-yl)pyridin-3-yl)-6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridine hydrochloride [Chemistry] tert-Butyl 2-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (390 mg, 0.7 mmol) was added to a methanol solution of HCl (4 M, 5 mL), and the mixture was reacted at 25 °C for 4 h. The mixture was concentrated under reduced pressure to obtain 370 mg of the product, which was used directly in the next reaction, m / z = 404 [M+1]. + It was as follows.

[0285] Step C: N-(2-(5-(6-Ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-2,7-diazaspiro[3.5]nonan-7-yl)-2-chloro-6-fluorobenzamide [Chemistry] 4-(6-(2,7-Diazaspiro[3.5]nonan-2-yl)pyridin-3-yl)-6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridine (100 mg, 0.2 mmol), 2-chloro-6-fluorobenzoyl chloride (46 mg, 0.2 mmol), Et3N (100 mg, 1.0 mmol), and DMF (2 mL) were added to a reaction flask and reacted at 25 °C for 16 h. Water was added and stirred to quench the reaction. The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 47 mg of the product, m / z = 560 [M+1] + It was as follows. 1 H NMR (400 MHz, DMSO-d6) δ 12.65 (s, 1H), 8.53 (dd, J = 10.4, 2.3 Hz, 2H), 8.03 (dd, J = 8.6, 2.5 Hz, 1H), 7.48 - 7.59 (m, 2H), 7.33 - 7.49 (m, 2H), 7.23 (d, J = 2.1 Hz, 1H), 6.60 (d, J = 8.7 Hz, 1H), 4.18 (q, J = 7.0 Hz, 2H), 3.80 - 3.91 (m, 4H), 3.73 (tq, J = 13.6, 7.4, 6.9 Hz, 2H), 3.15 - 3.26 (m, 2H), 1.71 - 1.91 (m, 4H), 1.40 (t, J = 6.9 Hz, 3H).

[0286] Example 72: Preparation of Compound 192 6-Ethoxy-4-(6-(7-((6-methoxypyridin-3-yl)methylene)-2,7-diazaspiro[3.5]nonan-2-yl)pyridin-3-yl)-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridine

Chemical Structure

[0287] Example 73: Preparation of Compound 193 Step A: tert-Butyl 2-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-2,6-diazaspiro[3.5]nonane-6-carboxylate

Chemical Structure

[0288] Step B: 4-(6-(2,6-Diazaspiro[3.5]nonan-2-yl)pyridin-3-yl)-6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridine hydrochloride

Chemical formula

[0289] Step C: N-(2-(5-(6-Ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-2,6-diazaspiro[3.5]nonan-6-yl)-2-chloro-6-fluorobenzamide

Chemical formula

[0290] Example 74: Preparation of Compound 194 6-Ethoxy-4-(6-(6-((6-methoxypyridin-3-yl)methylene)-2,6-diazaspiro[3.5]nonan-2-yl)pyridin-3-yl)-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridine

Chemical Structure

[0291] Example 75: Preparation of Compound 195 Step A: tert-Butyl 2-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-2,8-diazaspiro[4.5]decane-8-carboxylate

Chemical Structure

[0292] Step B: 4-(6-(2,8-Diazaspiro[4.5]decane-2-yl)pyridin-3-yl)-6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridine

Chemical formula

[0293] Step C: N-(2-(5-(6-Ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-2,8-diazaspiro[4.5]decane-8-yl)-2-chloro-6-fluorobenzamide

Chemical formula

[0294] Example 76: Preparation of Compound 196 6-Ethoxy-4-(6-(8-((6-methoxypyridin-3-yl)methylene)-2,8-diazaspiro[4.5]dec-2-yl)pyridin-3-yl)-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridine

Chemical Structure

[0295] Example 77: Preparation of Compound 197 Step A: tert-Butyl 2-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-2,7-diazaspiro[4.5]octane-7-carboxylate [Chemical formula] 6-Ethoxy-4-(6-fluoropyridin-3-yl)-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridine (310 mg, 1.04 mmol), tert-butyl 2,7-diazaspiro[4.5]octane-7-carboxylate (250 mg, 1.04 mmol), DIEA (430 mg, 3.12 mmol), and DMSO (5 mL) were added to a reaction flask and reacted at 90 °C for 12 h. Water was added and stirred to quench the reaction. The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 350 mg of the product, m / z = 518 [M+1]. + It was as follows.

[0296] Step B: 4-(6-(2,7-Diazaspiro[4.5]octan-2-yl)pyridin-3-yl)-6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridine hydrochloride [Chemical formula] To tert-butyl 2-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-2,7-diazaspiro[4.5]octane-7-carboxylate (350 mg, 0.676 mmol), a methanol solution of HCl (4 M, 10 mL) was added and reacted at 25 °C for 4 h. The mixture was concentrated under reduced pressure to obtain 320 mg of the product, which was used directly in the next reaction, m / z = 418 [M+1]. + It was as follows.

[0297] Step C: N-(2-(5-(6-Ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-2,7-diazaspiro[4.5]octan-7-yl)-2-chloro-6-fluorobenzamide [Chemical formula] 4-(6-(2,7-Diazaspiro[4.5]octan-2-yl)pyridin-3-yl)-6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridine hydrochloride (160 mg, 0.3 mmol), 2-chloro-6-fluorobenzoyl chloride (58 mg, 0.3 mmol), DIEA (194 mg, 1.5 mmol), and DCM (5 mL) were added to a reaction flask, and the reaction was carried out at 25 °C for 1 h. Water was added and stirred to quench the reaction. The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 48.3 mg of the product, m / z = 573 [M+1] + , 1 1H-NMR (400 MHz, DMSO-d6) δ 12.63 (brs, 1H), 8.57 (s, 1H), 8.50 (s, 1H), 8.02 (d, J = 8.8 Hz, 1H), 7.32 - 7.59 (m, 4H), 7.23 (s, 1H), 6.68 (d, J = 8.8 Hz, 1H), 4.15 - 4.20 (m, 2H), 3.45 - 3.73 (m, 4H), 3.01 - 3.39 (m, 4H), 1.45 - 2.13 (m, 6H), 1.37 - 1.41 (m, 3H).

[0298] Example 78: Preparation of Compound 198 6-Ethoxy-4-(6-(7-((6-methoxypyridin-3-yl)methylene)-2,7-diazaspiro[4.5]octan-2-yl)pyridin-3-yl)-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridine

Chemical Structure

[0299] Example 79: Preparation of Compound 199 Step A: tert-Butyl 2-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-2,6-diazaspiro[4.5]octane-6-carboxylate [Chemical Structure] 6-Ethoxy-4-(6-fluoropyridin-3-yl)-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridine (125 mg, 0.4 mmol), tert-butyl 2,6-diazaspiro[4.5]octane-6-carboxylate (100 mg, 0.4 mmol), DIEA (1.5 g, 2.0 mmol), and DMSO (3 mL) were added to a reaction flask and reacted at 90 °C for 12 h. Water was added, stirred to quench the reaction, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 200 mg of the product, m / z = 518 [M+1] + It was.

[0300] Step B: 4-(6-(2,6-Diazaspiro[4.5]octan-2-yl)pyridin-3-yl)-6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridine hydrochloride

Chemical formula

[0301] Step C: N-(2-(5-(6-Ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-2,6-diazaspiro[4.5]octan-6-yl)-2-chloro-6-fluorobenzamide

Chemical formula

[0302] Example 80: Preparation of Compound 200 6-Ethoxy-4-(6-(6-((6-methoxypyridin-3-yl)methylene)-2,6-diazaspiro[4.5]octan-2-yl)pyridin-3-yl)-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridine

Chemical Structure

[0303] Example 81: Preparation of Compound 201 Step A: tert-Butyl 7-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-2-yl)pyridin-2-yl)-1,7-diazaspiro[3.5]nonane-1-carboxylate

Chemical Structure

[0304] Step B: 4-(6-(1,7-Diazaspiro[3.5]nonan-7-yl)pyridin-3-yl)-6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridine hydrochloride

Chemical formula

[0305] Step C: N-(7-(5-(6-Ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-1,7-diazaspiro[3.5]nonan-1-yl)-2-chloro-6-fluorobenzamide

Chemical formula

[0306] Example 82: Preparation of Compound 202 Step A: tert-Butyl 7-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate

Chemical Structure

[0307] Step B: 4-(6-(2,7-Diazaspiro[3.5]nonan-7-yl)pyridin-3-yl)-6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridine hydrochloride

Chemical formula

[0308] Step C: N-(7-(5-(6-Ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-2,7-diazaspiro[3.5]nonan-2-yl)-2-chloro-6-fluorobenzamide

Chemical formula

[0309] Example 83: Preparation of Compound 203 6-Ethoxy-4-(6-(2-((6-methoxypyridin-3-yl)methylene)-2,7-diazaspiro[3.5]octan-7-yl)pyridin-3-yl)-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridine

Chemical Structure

[0310] Example 84: Preparation of Compound 206 Step A: tert-Butyl 8-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-1,8-diazaspiro[4.5]decane-1-carboxylate

Chemical Structure

[0311] Step B: 4-(6-(1,8-Diazaspiro[4.5]dec-8-yl)pyridin-3-yl)-6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridine hydrochloride

Chemical formula

[0312] Step C: N-(8-(5-(6-Ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-1,8-diazaspiro[4.5]decan-1-yl)-2-chloro-6-fluorobenzamide

Chemical formula

[0313] Example 85: Preparation of Compound 207 6-Ethoxy-4-(6-(1-((6-methoxypyridin-3-yl)methylene)-1,8-diazaspiro[4.5]octan-8-yl)pyridin-3-yl)-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridine

Chemical Structure

[0314] Example 86: Preparation of Compound 208 Step A: tert-Butyl 8-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate

Chemical Structure

[0315] Step B: 4-(6-(2,8-Diazaspiro[4.5]dec-8-yl)pyridin-3-yl)-6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridine hydrochloride

Chemical formula

[0316] Step C: N-(8-(5-(6-Ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-2,8-diazaspiro[4.5]dec-2-yl)-2-chloro-6-fluorobenzamide

Chemical formula

[0317] Example 87: Preparation of Compound 209 Step A: 6-Ethoxy-4-(6-(2-((6-methoxypyridin-3-yl)methylene)-2,8-diazaspiro[4.5]decan-8-yl)pyridin-3-yl)-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridine

Chemical Structure

[0318] Example 88: Preparation of Compound 210 Step A: tert-Butyl 7-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-2,7-diazaspiro[4.5]decane-2-carboxylate

Chemical Structure

[0319] Step B: 4-(6-(2,7-Diazaspiro[4.5]decane-7-yl)pyridin-3-yl)-6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridine [Chemical formula] To a reaction flask, methanol (5 mL), tert-butyl 7-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-2,7-diazaspiro[4.5]decane-2-carboxylate (525 mg, 1.0 mmol) and a 1,4-dioxane solution of 6 N HCl (4.0 mL, 24.0 mmol) were sequentially added. The reaction was carried out with stirring at room temperature for 30 min. Water was added and stirred to quench the reaction. After adjusting the pH to 10 with 1 N NaOH, the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and then concentrated to obtain 301 mg of the product, which was used directly in the next reaction, m / z = 418 [M+1] + It was.

[0320] Step C: N-(7-(5-(6-Ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-2,7-diazaspiro[4.5]decan-2-yl)-2-chloro-6-fluorobenzamide [Chemical formula] 4-(6-(2,7-Diazaspiro[4.5]decan-7-yl)pyridin-3-yl)-6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridine (63 mg, 0.15 mmol), DMF (1 mL), and diisopropylethylamine (58 mg, 0.45 mmol) were sequentially added to a reaction flask. The mixture was cooled to 5 °C in an ice bath, and a solution of 2-chloro-6-fluorobenzoyl chloride (29 mg, 0.15 mmol) in DMF (0.2 mL) was added dropwise. The reaction was carried out with stirring at room temperature for 16 hours. Water was added and stirred to quench the reaction. The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 23 mg of the product, m / z = 574 [M+1] + , 1 1H-NMR (400 MHz, DMSO-d6) δ 12.64 (brs, 1H), 8.50 - 8.55 (m, 2H), 7.97 - 8.04 (m, 1H), 7.30 - 7.61 (m, 4H), 7.25 (s, 1H), 7.01 - 7.12 (m, 1H), 4.16 - 4.18 (m, 2H), 3.33 - 3.70 (m, 6H), 3.22 - 3.28 (m, 1H), 3.12 - 3.19 (m, 1H), 1.52 - 2.01 (m, 6H), 1.38 - 1.43 (m, 3H).

[0321] Example 89: Preparation of Compound 211 Step A: 6-Ethoxy-4-(6-(2-((6-Methoxypyridin-3-yl)methylene)-2,8-diazaspiro[4.5]decan-8-yl)pyridin-3-yl)-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridine [Chemical formula] To a reaction flask, 1,2-dichloroethane (2 mL), methanol (1 mL), 4-(6-(2,7-diazaspiro[4.5]decane-7-yl)pyridin-3-yl)-6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridine (63 mg, 0.15 mmol), 6-methoxy-3-pyridinealdehyde (21 mg, 0.15 mmol) and acetic acid (2 drops) were sequentially added. The temperature was raised to 45 °C and the mixture was reacted for 1 hour. Then sodium triacetoxyborohydride (96 mg, 0.45 mmol) was added and stirring was continued at 45 °C for 16 hours. Water was added and the mixture was stirred to quench. It was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 16 mg of the product, m / z = 539 [M+1] + , 1 1H-NMR (400 MHz, DMSO-d6) δ 12.65 (brs, 1H), 8.53 (s, 1H), 8.51 (s, 1H), 8.02 - 8.15 (m, 1H), 7.98 (d, J = 8.8 Hz, 1H), 7.62 - 7.75 (m, 1H), 7.58 (s, 1H), 7.24 (s, 1H), 7.00 (d, J = 8.8 Hz, 1H), 6.69 - 6.79 (m, 1H), 4.15 - 4.20 (m, 2H), 3.76 (s, 3H), 3.34 - 3.75 (m, 8H), 3.16 - 3.18 (m, 1H), 1.91 (s, 1H), 1.49 - 1.68 (m, 6H), 1.38 - 1.42 (m, 3H).

[0322] Example 90: Preparation of Compound 212 Step A: tert-Butyl 7-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-1,7-diazaspiro[4.5]decane-1-carboxylate [Chemical formula] To the reaction flask, 6-ethoxy-4-(6-fluoropyridin-3-yl)-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridine (297 mg, 1.0 mmol), tert-butyl 1,7-diazaspiro[4.5]decane-1-carboxylate (240 mg, 1.0 mmol), diisopropylethylamine (390 mg, 3.0 mmol) and DMSO (4 mL) were sequentially added. The reaction solution was heated to 100 °C and reacted for 16 hours. Water was added and stirred to quench, then extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 500 mg of the product, m / z = 518 [M+1] + It was.

[0323] Step B: 4-(6-(1,7-Diazaspiro[4.5]decane-7-yl)pyridin-3-yl)-6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridine

Chemical Structure

[0324] Step C: N-(7-(5-(6-Ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-1,7-diazaspiro[4.5]decan-1-yl)-2-chloro-6-fluorobenzamide

Chem.

[0325] Example 91: Preparation of Compound 213 6-Ethoxy-4-(6-(1-((6-methoxypyridin-3-yl)methylene)-1,7-diazaspiro[4.5]decan-7-yl)pyridin-3-yl)-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridine

Chem.

[0326] Example 92: Preparation of Compound 214 Step A: tert-Butyl 9-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-2,9-diazaspiro[5.5]undecane-2-carboxylate

Chem.

[0327] Step B: 4-(6-(2,9-Diazaspiro[5.5]undecan-9-yl)pyridin-3-yl)-6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridine

Chem.

[0328] Step C: N-(9-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-2,9-diazaspiro[5.5]undecan-2-yl)-2-chloro-6-fluorobenzamide [Chemical formula] 4-(6-(2,9-Diazaspiro[5.5]undecan-9-yl)pyridin-3-yl)-6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridine (130 mg, 0.3 mmol), DMF (2 mL), and diisopropylethylamine (117 mg, 0.9 mmol) were successively added to a reaction flask. It was cooled to 5 °C in an ice bath, and a solution of 2-chloro-6-fluorobenzoyl chloride (58 mg, 0.3 mmol) in DMF (0.2 mL) was added dropwise, and the reaction was carried out with stirring at room temperature for 16 h. Water was added and stirred to quench, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 45 mg of the product, m / z = 588 [M+1] + , 11H-NMR (400 MHz, DMSO-d6) δ 12.65 (brs, 1H), 8.59 (s, 1H), 8.53 (s, 1H), 8.04 (d, J = 8.8 Hz, 1H), 7.60 (s, 1H), 7.36 - 7.56 (m, 3H), 7.27 (s, 1H), 7.10 (d, J = 8.8 Hz, 1H), 4.14 - 4.20 (m, 2H), 3.80 - 3.95 (m, 2H), 3.48 - 3.72 (m, 4H), 3.15 - 3.28 (m, 2H), 1.47 - 1.77 (m, 8H), 1.38 - 1.42 (m, 3H).

[0329] Example 93: Preparation of Compound 215 6-Ethoxy-4-(6-(2-((6-methoxypyridin-3-yl)methylene)-2,9-diazaspiro[5.5]undecan-9-yl)pyridin-3-yl)-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridine [Chemical Structure] To a reaction flask, 1,2-dichloroethane (2 mL), methanol (1 mL), 4-(6-(2,9-diazaspiro[5.5]undecan-9-yl)pyridin-3-yl)-6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridine (65 mg, 0.15 mmol), 6-methoxypyridine-3-carbaldehyde (62 mg, 0.45 mmol) and acetic acid (2 drops) were sequentially added. After heating to 45 °C and reacting for 2 hours, sodium triacetoxyborohydride (160 mg, 0.75 mmol) was added and stirring was continued at 45 °C for 16 hours. Water was added and stirred to quench, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 17 mg of the product, m / z = 553 [M + 1]. + , 11H-NMR (400 MHz, DMSO-d6) δ 12.65 (broad singlet, 1H), 8.54 (singlet, 1H), 8.50 (singlet, 1H), 8.05 (singlet, 1H), 8.00 (doublet, J = 8.8 Hz, 1H), 7.65 (doublet, J = 8.8 Hz, 1H), 7.57 (singlet, 1H), 7.24 (singlet, 1H), 7.01 (doublet, J = 8.8 Hz, 1H), 6.79 (doublet, J = 8.8 Hz, 1H), 4.14 - 4.20 (multiplet, 2H), 3.82 (singlet, 3H), 3.55 - 3.67 (multiplet, 2H), 3.42 - 3.50 (multiplet, 2H), 3.40 (singlet, 1H), 3.16 - 3.18 (multiplet, 1H), 2.10 - 2.42 (multiplet, 4H), 1.30 - 1.60 (multiplet, 11H).

[0330] Example 94: Preparation of Compound 216 Step A: tert-Butyl 9-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylate [Chemical formula] To the reaction flask were sequentially added 6-ethoxy-4-(6-fluoropyridin-3-yl)-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridine (297 mg, 1.0 mmol), tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (254 mg, 1.0 mmol), diisopropylethylamine (390 mg, 3.0 mmol), and DMSO (3 mL). The reaction mixture was heated to 100 °C and reacted for 16 hours. Water was added and stirred to quench the reaction, and then extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 540 mg of the product, m / z = 532 [M + 1]. + It was as follows.

[0331] Step B: 4-(6-(3,9-Diazaspiro[5.5]undecan-3-yl)pyridin-3-yl)-6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridine

Chem.

[0332] Step C: N-(9-(5-(6-Ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3,9-diazaspiro[5.5]undecan-3-yl)-2-chloro-6-fluorobenzamide

Chem.

[0333] Example 95: Preparation of Compound 217 6-Ethoxy-4-(6-(9-((6-methoxypyridin-3-yl)methylene)-3,9-diazaspiro[5.5]undecan-3-yl)pyridin-3-yl)-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridine [Chemical formula] 4-(6-(3,9-Diazaspiro[5.5]undecan-3-yl)pyridin-3-yl)-6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridine (43 mg, 0.1 mmol), DMF (1 mL), potassium carbonate (35 mg, 0.3 mmol) and 5-(chloromethyl)-2-methoxypyridine (16 mg, 0.1 mmol) were sequentially added to a reaction flask and reacted with stirring at room temperature for 16 h. Water was added and stirred for quenching, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 12.0 mg of the product, m / z = 553 [M+1] + , 1 1H-NMR (400 MHz, DMSO-d6) δ 12.64 (brs, 1H), 8.56 (s, 1H), 8.50 (s, 1H), 8.04 (s, 1H), 8.01 (d, J = 8.8 Hz, 1H), 7.63 (d, J = 8.8 Hz, 1H), 7.57 (s, 1H), 7.24 (s, 1H), 7.02 (d, J = 8.8 Hz, 1H), 6.79 (d, J = 8.8 Hz, 1H), 4.14 - 4.19 (m, 2H), 3.82 (s, 3H), 3.58 - 3.65 (m, 4H), 3.42 (s, 2H), 3.28 - 3.41 (m, 4H), 1.41 - 1.59 (m, 8H), 1.37 - 1.41 (m, 3H).

[0334] Example 96: Preparation of Compound 218 Step A: 2-(5-(6-Ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-2,9-diazaspiro[5.5]undecane-9-carboxylic acid tert-butyl

Chemical Structure

[0335] Step B: 4-(6-(2,9-Diazaspiro[5.5]undecan-2-yl)pyridin-3-yl)-6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridine [Chemical formula] To the reaction flask, methanol (5 mL), tert-butyl 2-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-2,9-diazaspiro[5.5]undecane-9-carboxylate (550 mg, 1.0 mmol) and 1,4-dioxane solution of 6 N HCl (4.0 mL, 24.0 mmol) were sequentially added, and the reaction was carried out with stirring at room temperature for 30 min. Water (3 mL) was added, the pH was adjusted to 10 with 1 N NaOH, and then extracted twice with dichloromethane (30 mL). The extract was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated to obtain 355 mg of the product, m / z = 432 [M+1] + It was.

[0336] Step C: N-(2-(5-(6-Ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-2,9-diazaspiro[5.5]undecan-9-yl)-2-chloro-6-fluorobenzamide

Chem.

[0337] Example 97: Preparation of Compound 219 6-Ethoxy-4-(6-(9-((6-Methoxypyridin-3-yl)methylene)-2,9-diazaspiro[5.5]undecan-2-yl)pyridin-3-yl)-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridine [Chemical formula] To the reaction flask, 1,2-dichloroethane (2 mL), methanol (1 mL), 4-(6-(2,9-diazaspiro[5.5]undecan-2-yl)pyridin-3-yl)-6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridine (65 mg, 0.15 mmol), 6-methoxy-3-pyridinecarboxaldehyde (24 mg, 0.17 mmol) and acetic acid (2 drops) were sequentially added. After heating to 45 °C and reacting for 2 hours, sodium triacetoxyborohydride (96 mg, 0.45 mmol) was added and stirring was continued at 45 °C for 16 hours. Water was added, stirred to quench, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 15.8 mg of the product, m / z = 553 [M+1] + , 1 1H-NMR (400 MHz, DMSO-d6) δ 12.64 (brs, 1H), 8.55 (s, 1H), 8.50 (s, 1H), 8.04 - 8.18 (m, 1H), 8.00 (d, J = 8.8 Hz, 1H), 7.65 - 7.73 (m, 1H), 7.58 (s, 1H), 7.25 (s, 1H), 7.03 - 7.15 (m, 1H), 6.75 - 6.90 (m, 1H), 4.14 - 4.20 (m, 2H), 3.83 (s, 3H), 3.30 - 3.65 (m, 8H), 3.17 (s, 1H), 1.91 (s, 1H), 1.38 - 1.68 (m, 11H).

[0338] Example 98: Preparation of Compound 220 Step A: tert-Butyl 6-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-2,6-diazaspiro[3.4]octane-2-carboxylate [Chemical formula] To the reaction flask, 6-ethoxy-4-(6-fluoropyridin-3-yl)-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridine (297 mg, 1.0 mmol), tert-butyl 2,6-diazaspiro[3.4]octane-2-carboxylate (212 mg, 1.0 mmol), diisopropylethylamine (390 mg, 3.0 mmol) and DMSO (4 mL) were sequentially added. The reaction solution was heated to 100 °C and reacted for 16 hours. Water was added and stirred to quench, then extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 520 mg of the product, m / z = 490 [M+1] + It was.

[0339] Step B: 4-(6-(2,6-Diazaspiro[3.4]octan-6-yl)pyridin-3-yl)-6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridine [Chemical formula] To the reaction flask, methanol (4 mL), tert-butyl 6-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-2,6-diazaspiro[3.4]octane-2-carboxylate (520 mg, 1.0 mmol) and 1,4-dioxane solution of 6 N HCl (2.0 mL, 12.0 mmol) were sequentially added, and the reaction was carried out with stirring at room temperature for 30 min. Water (10 mL) was added, and the pH was adjusted to 10 with 1 N NaOH, then extracted twice with dichloromethane (40 mL). The extract was dried over anhydrous sodium sulfate and then concentrated to obtain 310 mg of the product, m / z = 390 [M+1] + .

[0340] Step C: N-(6-(5-(6-Ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-chloro-6-fluorobenzamide

Chemical Structure

[0341] Example 99: Preparation of Compound 221 6-Ethoxy-4-(6-(2-((6-Methoxypyridin-3-yl)methylene)-2,6-diazaspiro[3.4]octan-6-yl)pyridin-3-yl)-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridine

Chemical formula

[0342] Example 100: Preparation of Compound 227 4-(6-(6-((6-Methoxypyridin-3-yl)methylene)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-(prop-2-yn-1-yloxy)-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridine

Chem.

[0343] Example 101: Preparation of Compound 228 Methyl 2-((4-(6-(6-((6-Methoxypyridin-3-yl)methylene)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-6-yl)ether)acetate

Chem.

[0344] Example 102: Preparation of Compound 229 Step A: Ethyl 1-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(((6-methoxypyridin-3-yl)methyl)amino)piperidine-4-carboxylate

Chemical Structure

[0345] Step B: (1-(5-(6-Ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(((6-methoxypyridin-3-yl)methyl)amino)piperidin-4-yl)methanol

Chemical formula

[0346] Example 103: Preparation of Compound 232 Step A: 4-(6-(6-((6-Methoxypyridin-3-yl)methylene)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridine-6-trifluoromethanesulfonate

Chemical Structure

[0347] Step B: 4-(6-(6-((6-Methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptyl-3-yl)pyridin-3-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridine

Chem.

[0348] Step C: 4-(6-(6-((6-Methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptyl-3-yl)pyridin-3-yl)-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-6-yl)boronic acid

Chem.

[0349] Step D: 6-(azetidin-1-yl)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptyl-3-yl)pyridin-3-yl)-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridine

Chemical formula

[0350] Example 104: Preparation of Compound 233 Synthesis of N-((3R,4S)-1-(5-(6-ethoxy-1H-pyrazolo[3',4':3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidin-3-ol

Chemical formula

[0351] Example 105: Preparation of Compound 234 Step A: tert-Butyl (1-(5-bromopyridin-2-yl)-4-((dimethylamino)methyl)piperidin-4-yl)carbamate [Chemistry] To a 50 mL reaction flask, add tert-butyl (1-(5-bromopyridin-2-yl)-4-formylpiperidin-4-yl)carbamate (200 mg, 0.52 mmol), 1,2-dichloromethane (2 mL), dimethylamine (0.78 mL, 1.56 mmol), and sodium borohydride acetate (220 mg, 1.04 mmol). Stir at room temperature for 16 hours, then add water to quench, concentrate, and separate by column chromatography to obtain 177 mg of the product, m / z = 413 / 415 [M+1] + It was.

[0352] Step B: 1-(5-Bromopyridin-2-yl)-4-((dimethylamino)methyl)piperidin-4-amine hydrochloride [Chemistry] Add tert-butyl (5-bromopyridin-2-yl)-4-((dimethylamino)methyl)piperidin-4-yl)carbamate (177 mg, 0.43 mmol) and hydrogen chloride gas in methanol (4 M, 2 mL) to a reaction flask and react at 25 °C for 5 h. Rotate and dry directly to obtain 250 mg of the product, m / z = 313 / 315 [...

Claims

1. A compound represented by the following formula I, its stereoisomers, racemates, tautomers, isotope labels or pharmaceutically acceptable salts: 【Chemical 1】 Among them, Q is 【Chemical Formula 2】 selected from; X 1 、 X 2 、 X 3 、 X 4 、 X 5 、 X 6 、 X 7 are the same or different and are independently of each other CR 1 or selected from N; X 8 is selected from CR 1 R 1’ or NR 1 ; Among them, each R 1 and R 1’ are the same or different and, independently of each other, are H, halogen, CN, OH, an unsubstituted or optionally substituted C a alkyl group, C 1-40 alkenyl group, C 2-40 alkynyl group, C 2-40 cycloalkyl group, C 3-40 cycloalkenyl group, C 3-40 cycloalkynyl group, C 3-40 alkyloxy group, C 1-40 alkenyloxy group, C 2-40 alkynyloxy group, C 2-40 cycloalkyloxy group, C 3-40 cycloalkenyloxy group, C 3-40 cycloalkynyloxy group, NR 3-40 R 2 R 3 -C(O)R 4 -OCR 5 -S(O) 2 R 6 OS(O) 2 R 7 selected from; A is H, halogen, CN, OH, NH 2 , unsubstituted or optionally R b C substituted with one, two or more substituents independently selected from 1-40 Alkyl group, C 2-40 Alkenyl group, C 2-40 Alkynyl group, C 3-40 Cycloalkyl groups, C 3-40 Cycloalkenyl group, C 3-40 Cycloalkynyl group, C 1-40 Alkyloxy group, C 2-40 Alkenyloxy group, C 2-40 Alkynyloxy group, C 3-40 Cycloalkyloxy group, C 3-40 Cycloalkenyloxy group, C 3-40 Cycloalkynyloxy group, NR 2 R 3 , -C(O)R 4 , -OCR 5 , -S(O) 2 R 6 , OS (O) 2 R 7 Selected from: E is H or NH 2 ; D is H, halogen, CN, OH, B(OH) 2 , -C(O)R 4 , -OCR 5 , -S(O) 2 R 6 , OS(O) 2 R 7 , -O-R 21 , C(O)OR 22 , -P(O)R 23 R 24 , unsubstituted or optionally substituted with one, two or more substituents independently selected from R c and is a C 1-40 alkyl group, C 2-40 alkenyl group, C 2-40 alkynyl group, C 3-40 cycloalkyl group, C 3-40 cycloalkenyl group, C 3-40 cycloalkynyl group, C 6-20 aryl group, 5- to 20-membered heteroaryl group, 3- to 20-membered heterocyclyl group, NH 2 selected from; R 21 、R 22 、R 23 、R 24 are the same or different and are each independently H, unsubstituted or optionally substituted with one, two or more substituents independently selected from R d selected from a C 1-40 alkyl group, C 2-40 alkenyl group, C 2-40 alkynyl group, C 3-40 cycloalkyl group, C 3-40 cycloalkenyl group, C 3-40 cycloalkynyl group, C 6-20 aryl group, 5- to 20-membered heteroaryl group, 3- to 20-membered heterocyclyl group; G is a 5- to 20-membered heteroaryl group in which at least one heteroatom selected from N is substituted with one, two or more substituents independently selected from halogen, unsubstituted or optionally substituted with R e a 3- to 20-membered heterocyclyl group in which at least one heteroatom selected from N, a C 3-40 selected from cycloalkyl-NH-, wherein the 3- to 20-membered heterocyclyl group in which at least one heteroatom is selected from N is selected from the following: [Chemical Formula 3] ; K is selected independently from one, two or more substituents selected from non-existence, H, halogen, CN, OH, unsubstituted or optionally R f substituted C 1-40 alkyl group, C 2-40 alkenyl group, C 2-40 alkynyl group, C 3-40 cycloalkyl group, C 3-40 cycloalkenyl group, C 3-40 cycloalkynyl group, C 6-20 aryl group, 5- to 20-membered heteroaryl group, 3- to 20-membered heterocyclyl group, C 1-40 alkyloxy group, C 2-40 alkenyloxy group, C 2-40 alkynyloxy group, C 3-40 cycloalkyloxy group, C 3-40 cycloalkenyloxy group, C 3-40 cycloalkynyloxy group, C 6-20 aryloxy group, 5- to 20-membered heteroaryloxy group, 3- to 20-membered heterocyclyloxy group, C 6-20 arylC 1-40 alkyl group, 5- to 20-membered heteroarylC 1-40 alkyl group, 3- to 20-membered heterocyclylC 1-40 alkyl group, -NR 2 R 3 , -C(O)R 4 , -OCR 5 , -S(O) 2 R 6 , OS(O) 2 R 7 selected from; Each R 2 is the same or different and, independently of one another, is H, unsubstituted or optionally substituted with one, two or more substituents independently selected from f C-alkyl group, C 1-40 alkenyl group, C 2-40 alkynyl group, C 2-40 cycloalkyl group, C 3-40 cycloalkenyl group, C 3-40 cycloalkynyl group, C 3-40 aryl group, 5- to 20-membered heteroaryl group, 3- to 20-membered heterocyclyl group, -C(O)R 6-20 , -S(O) 4 R 2 ; selected from 6 ; Each R 3 is the same or different and, independently of one another, is H, unsubstituted or optionally substituted with one, two or more substituents independently selected from f C-alkyl group, C-alkenyl group, C-alkynyl group, C-cycloalkyl group, C-cycloalkenyl group, C-cycloalkynyl group, C-aryl group, 5-20 membered heteroaryl group, 3-20 membered heterocyclyl group, -C(O)R, -S(O)R 1-40 ; 2-40 ; 2-40 ; 3-40 ; 3-40 ; 3-40 ; 6-20 ; 4 ; 2 ; 6 selected from; Alternatively, R 2 and R 3 together with the linked N atom form a 5- to 20-membered heteroaryl group or a 3- to 20-membered heterocyclyl group which is unsubstituted or optionally substituted with one, two or more substituents independently selected from R f ; Each R 4 is the same or different and, independently of one another, is H, unsubstituted or optionally substituted with one, two or more substituents independently selected from f C-alkyl group, C-alkenyl group, C-alkynyl group, C-cycloalkyl group, C-cycloalkenyl group, C-cycloalkynyl group, aryl group, 5- to 20-membered heteroaryl group, 3- to 20-membered heterocyclyl group, C-alkyloxy group, C-alkenyloxy group, C-alkynyloxy group, C-cycloalkyloxy group, C-cycloalkenyloxy group, C-cycloalkynyloxy group, aryloxy group, 5- to 20-membered heteroaryloxy group, 3- to 20-membered heterocyclyloxy group, arylC-alkyl group, 5- to 20-membered heteroarylC-alkyl group, 3- to 20-membered heterocyclylC-alkyl group, -NRR 1-40 alkyl group, C 2-40 alkenyl group, C 2-40 alkynyl group, C 3-40 cycloalkyl group, C 3-40 cycloalkenyl group, C 3-40 cycloalkynyl group, C 6-20 aryl group, 5- to 20-membered heteroaryl group, 3- to 20-membered heterocyclyl group, C 1-40 alkyloxy group, C 2-40 alkenyloxy group, C 2-40 alkynyloxy group, C 3-40 cycloalkyloxy group, C 3-40 cycloalkenyloxy group, C 3-40 cycloalkynyloxy group, C 6-20 aryloxy group, 5- to 20-membered heteroaryloxy group, 3- to 20-membered heterocyclyloxy group, C 6-20 arylC 1-40 alkyl group, 5- to 20-membered heteroarylC 1-40 alkyl group, 3- to 20-membered heterocyclylC 1-40 alkyl group, -NR 2 R 3 selected from; Each R 5 is the same or different and, independently of one another, is H, unsubstituted or optionally substituted with one, two or more substituents independently selected from f C alkyl group, C 1-40 alkenyl group, C 2-40 alkynyl group, C 2-40 cycloalkyl group, C 3-40 cycloalkenyl group, C 3-40 cycloalkynyl group, C 3-40 aryl group, 5- to 20-membered heteroaryl group, 3- to 20-membered heterocyclyl group, C 6-20 alkylcarbonyl group, C 1-40 alkenylcarbonyl group, C 2-40 alkynylcarbonyl group, C 2-40 cycloalkylcarbonyl group, C 3-40 cycloalkenylcarbonyl group, C 3-40 cycloalkynylcarbonyl group, C 3-40 arylcarbonyl group, 5- to 20-membered heteroarylcarbonyl group, 3- to 20-membered heterocyclylcarbonyl group; 6-20 selected from Each R 6 is the same or different and, independently of one another, is H, unsubstituted or optionally substituted with one, two or more substituents independently selected from f C-alkyl group, C-alkenyl group, C-alkynyl group, C-cycloalkyl group, C-cycloalkenyl group, C-cycloalkynyl group, C-aryl group, 5- to 20-membered heteroaryl group, 3- to 20-membered heterocyclyl group, C-alkyloxy group, C-alkenyloxy group, C-alkynyloxy group, C-cycloalkyloxy group, C-cycloalkenyloxy group, C-cycloalkynyloxy group, C-aryloxy group, 5- to 20-membered heteroaryloxy group, 3- to 20-membered heterocyclyloxy group, C-arylC-alkyl group, 5- to 20-membered heteroarylC-alkyl group, 3- to 20-membered heterocyclylC-alkyl group, -NRR selected from 1-40 alkyl group, 2-40 alkenyl group, 2-40 alkynyl group, 3-40 cycloalkyl group, 3-40 cycloalkenyl group, 3-40 cycloalkynyl group, 6-20 aryl group, 5- to 20-membered heteroaryl group, 3- to 20-membered heterocyclyl group, 1-40 alkyloxy group, 2-40 alkenyloxy group, 2-40 alkynyloxy group, 3-40 cycloalkyloxy group, 3-40 cycloalkenyloxy group, 3-40 cycloalkynyloxy group, 6-20 aryloxy group, 5- to 20-membered heteroaryloxy group, 3- to 20-membered heterocyclyloxy group, 6-20 arylC 1-40 alkyl group, 5- to 20-membered heteroarylC 1-40 alkyl group, 3- to 20-membered heterocyclylC 1-40 alkyl group, -NR 2 R 3 selected from; Each R 7 is the same or different and, independently of each other, is H, unsubstituted or optionally substituted with one, two or more substituents independently selected from f C-alkyl group, C-alkenyl group, C-alkynyl group, C-cycloalkyl group, C-cycloalkenyl group, C-cycloalkynyl group, aryl group, 5-20 membered heteroaryl group, 3-20 membered heterocyclyl group; 1-40 C-alkyl group, C-alkenyl group, C-alkynyl group, C-cycloalkyl group, C-cycloalkenyl group, C-cycloalkynyl group, aryl group, 5-20 membered heteroaryl group, 3-20 membered heterocyclyl group; 2-40 C-alkyl group, C-alkenyl group, C-alkynyl group, C-cycloalkyl group, C-cycloalkenyl group, C-cycloalkynyl group, aryl group, 5-20 membered heteroaryl group, 3-20 membered heterocyclyl group; 2-40 C-alkyl group, C-alkenyl group, C-alkynyl group, C-cycloalkyl group, C-cycloalkenyl group, C-cycloalkynyl group, aryl group, 5-20 membered heteroaryl group, 3-20 membered heterocyclyl group; 3-40 C-alkyl group, C-alkenyl group, C-alkynyl group, C-cycloalkyl group, C-cycloalkenyl group, C-cycloalkynyl group, aryl group, 5-20 membered heteroaryl group, 3-20 membered heterocyclyl group; 3-40 C-alkyl group, C-alkenyl group, C-alkynyl group, C-cycloalkyl group, C-cycloalkenyl group, C-cycloalkynyl group, aryl group, 5-20 membered heteroaryl group, 3-20 membered heterocyclyl group; 3-40 C-alkyl group, C-alkenyl group, C-alkynyl group, C-cycloalkyl group, C-cycloalkenyl group, C-cycloalkynyl group, aryl group, 5-20 membered heteroaryl group, 3-20 membered heterocyclyl group; 6-20 is selected from an aryl group, a 5- to 20-membered heteroaryl group, and a 3- to 20-membered heterocyclyl group; m is 0, 1, 2, 3, 4, 5, 6, 7 or 8; Each R 01 、R 02 、R 03 、R 04 is the same or different and, independently of one another, is H, halogen, CN, OH, SH, oxo (=O), NO 2 , an unsubstituted or optionally substituted C g alkyl group, C 1-40 alkenyl group, C 2-40 alkynyl group, C 2-40 cycloalkyl group, C 3-40 cycloalkenyl group, C 3-40 cycloalkynyl group, C 3-40 aryl group, 5- to 20-membered heteroaryl group, 3- to 20-membered heterocyclyl group, C 6-20 alkyloxy group, C 1-40 alkenyloxy group, C 2-40 alkynyloxy group, C 2-40 cycloalkyloxy group, C 3-40 cycloalkenyloxy group, C 3-40 cycloalkynyloxy group, C 3-40 aryloxy group, 5- to 20-membered heteroaryloxy group, 3- to 20-membered heterocyclyloxy group, C 6-20 aryloxy group, 5- to 20-membered heteroaryloxy group, 3- to 20-membered heterocyclyloxy group, C 6-20 arylC 1-40 alkyl group, 5- to 20-membered heteroarylC 1-40 alkyl group, 3- to 20-membered heterocyclylC 1-40 alkyl group, -NR 2 R 3 , -C(O)R 4 , -OCR 5 , -S(O) 2 R 6 , OS(O) 2 R 7 selected from; Each R a 、R b 、R c 、R d 、R e 、R f are the same or different and are, independently of each other, halogen, CN, OH, SH, oxo (=O), NO 2 and are unsubstituted or optionally substituted with one, two or more substituents independently selected from R g and are C 1-40 alkyl group, C 2-40 alkenyl group, C 2-40 alkynyl group, C 3-40 cycloalkyl group, C 3-40 cycloalkenyl group, C 3-40 cycloalkynyl group, C 6-20 aryl group, 5- to 20-membered heteroaryl group, 3- to 20-membered heterocyclyl group, C 1-40 alkyloxy group, C 2-40 alkenyloxy group, C 2-40 alkynyloxy group, C 3-40 cycloalkyloxy group, C 3-40 cycloalkenyloxy group, C 3-40 cycloalkynyloxy group, C 6-20 aryloxy group, 5- to 20-membered heteroaryloxy group, 3- to 20-membered heterocyclyloxy group, C 6-20 arylC 1-40 alkyl group, 5- to 20-membered heteroarylC 1-40 alkyl group, 3- to 20-membered heterocyclylC 1-40 alkyl group, -NR 2 R 3 、-C(O)R 4 、-OCR 5 、-S(O) 2 R 6 、OS(O) 2 R 7 and are selected from; Each R g is the same or different and, independently of one another, is halogen, CN, OH, SH, oxo(=O), NO 2 , an unsubstituted or optionally R h -independently selected one, two or more substituents substituted C 1-40 alkyl group, C 2-40 alkenyl group, C 2-40 alkynyl group, C 3-40 cycloalkyl group, C 3-40 cycloalkenyl group, C 3-40 cycloalkynyl group, C 6-20 aryl group, 5- to 20-membered heteroaryl group, 3- to 20-membered heterocyclyl group, C 1-40 alkyloxy group, C 2-40 alkenyloxy group, C 2-40 alkynyloxy group, C 3-40 cycloalkyloxy group, C 3-40 cycloalkenyloxy group, C 3-40 cycloalkynyloxy group, C 6-20 aryloxy group, 5- to 20-membered heteroaryloxy group, 3- to 20-membered heterocyclyloxy group, C 6-20 arylC 1-40 alkyl group, 5- to 20-membered heteroarylC 1-40 alkyl group, 3- to 20-membered heterocyclylC 1-40 alkyl group, -NR 2 R 3 , -C(O)R 4 , -OCR 5 , -S(O) 2 R 6 , OS(O) 2 R 7 selected from, or, when different positions of a cyclic group selected from a cycloalkyl group, a cycloalkenyl group, a cycloalkynyl group and a 3- to 20-membered heterocyclyl group are substituted with two or more substituents, two of the substituents may also form a bridged ring with the cyclic group, wherein the bridging atoms other than the bridgehead atoms in the bridged ring may include 1, 2, 3, 4 or 5 divalent groups selected from CH 2 , O, NH; Each R h is the same or different and, independently of one another, is halogen, CN, OH, SH, oxo (=O), NO 2 , an unsubstituted or optionally R i -substituted C 1-40 alkyl group, C 2-40 alkenyl group, C 2-40 alkynyl group, C 3-40 cycloalkyl group, C 3-40 cycloalkenyl group, C 3-40 cycloalkynyl group, C 6-20 aryl group, 5- to 20-membered heteroaryl group, 3- to 20-membered heterocyclyl group, C 1-40 alkyloxy group, C 2-40 alkenyloxy group, C 2-40 alkynyloxy group, C 3-40 cycloalkyloxy group, C 3-40 cycloalkenyloxy group, C 3-40 cycloalkynyloxy group, C 6-20 aryloxy group, 5- to 20-membered heteroaryloxy group, 3- to 20-membered heterocyclyloxy group, C 6-20 arylC 1-40 alkyl group, 5- to 20-membered heteroarylC 1-40 alkyl group, 3- to 20-membered heterocyclylC 1-40 alkyl group, -NR 2 R 3 , -C(O)R 4 , -OCR 5 , -S(O) 2 R 6 , OS(O) 2 R 7 selected from; Each R i is the same or different and, independently of one another, is halogen, CN, OH, SH, oxo(=O), NO 2 , an unsubstituted or optionally substituted C j alkyl group, C 1-40 alkenyl group, C 2-40 alkynyl group, C 2-40 cycloalkyl group, C 3-40 cycloalkenyl group, C 3-40 cycloalkynyl group, C 3-40 aryl group, 5- to 20-membered heteroaryl group, 3- to 20-membered heterocyclyl group, C 6-20 alkyl group, C 1-40 alkyloxy group, C 2-40 alkenyloxy group, C 2-40 alkynyloxy group, C 3-40 cycloalkyloxy group, C 3-40 cycloalkenyloxy group, C 3-40 cycloalkynyloxy group, C 6-20 aryloxy group, 5- to 20-membered heteroaryloxy group, 3- to 20-membered heterocyclyloxy group, C 6-20 arylC 1-40 alkyl group, 5- to 20-membered heteroarylC 1-40 alkyl group, 3- to 20-membered heterocyclylC 1-40 alkyl group, -NR 2 R 3 , -C(O)R 4 , -OCR 5 , -S(O) 2 R 6 , OS(O) 2 R 7 selected from; Alternatively, when two or more different positions of a cyclic group selected from a cycloalkyl group, a cycloalkenyl group, a cycloalkynyl group, and a heterocyclyl group are substituted with substituents, two of the substituents can also form a bridged ring with the cyclic group, wherein the bridging atoms other than the bridgehead atoms in the bridged ring are CH 2 , O, NH and can contain one, two, three, four or five divalent groups selected therefrom; Alternatively, when one atom selected from a carbon atom or a nitrogen atom is substituted with two or more substituents, two of the substituents, together with the atom to which they are commonly bonded, are unsubstituted or optionally R f which is independently selected from one, two or more substituents substituted with one, two or more substituents independently selected from f and can also form a cyclic group substituted with one, two or more substituents independently selected from A compound, its stereoisomers, racemates, tautomers, isotope labels or pharmaceutically acceptable salts.

2. X 1 、 X 2 、 X 3 、 X 4 、 X 5 、 X 6 、 X 7 at least one of them is N; X 8 is selected from CR 1 R 1’ or NR 1 ; Each R 1 and R 1’ are the same or different and are, independently of one another, H, halogen, CN, OH, C 1-6 alkyl group, C 3-10 cycloalkyl group, C 1-6 alkyloxy group; A is selected from H, halogen, CN, OH, C 1-6 alkyl group, C 1-6 alkyloxy group; E is H or NH 2 ; D is -O-R 21 or unsubstituted or optionally substituted with one, two or more substituents independently selected from c NH substituted with 2 selected from; R 21 is selected from C d alkyl groups which are unsubstituted or optionally substituted with one, two or more substituents of R 1-6 ; R 2 and R 3 together with the linked N atom form a 5-, 6- or 7-membered heteroaryl group or a 3-, 4-, 5-, 6- or 7-membered heterocyclyl group which is unsubstituted or optionally substituted with one, two or more substituents independently selected from f R; Each R 01 , R 02 , R 03 , R 04 is the same or different and, independently of one another, is selected from H, C 1-6 alkyl group, C 1-6 alkyloxy group; Each R a , R b , R c , R d , R e , R f is the same or different and, independently of one another, is halogen, NH 2 , CN, OH, an unsubstituted or optionally substituted C g alkyl group with one, two or more R 1-6 substituents, a C 1-6 alkyloxy group, a C 3-10 cycloalkyl group, a C 3-10 cycloalkyloxy group, a C 2-6 alkynyloxy group, a 3- to 8-membered heterocyclyl group, a 3- to 8-membered heteroaryl group; Each R g is the same or different and, independently of one another, is OH, halogen or C 3-10 selected from cycloalkyl groups; G is a halogen or is unsubstituted or substituted with one, two or more substituents independently selected from R e and is optionally substituted with one, two or more substituents independently selected from 【Chemical Formula 4】 selected from; K is -C 1-6 alkyl-C 3-10 cycloalkyl group, -C 1-6 alkyl-C 6-14 aryl group, -C 1-6 alkyl-5- to 14-membered heteroaryl group, -C 1-6 alkyl-3- to 10-membered heterocyclyl group, -C(O)NH 2 , -C(O)-C 3-10 cycloalkyl group, -C(O)-C 6-14 aryl group, -C(O)-5- to 14-membered heteroaryl group, -C(O)-3- to 10-membered heterocyclyl group, -C(O)-C 1-6 alkyl-C 3-10 cycloalkyl group, -C(O)-C 1-6 alkyl-C 6-14 aryl group, -C(O)-C 1-6 alkyl-5- to 14-membered heteroaryl group, -C(O)-C 1-6 alkyl-3- to 10-membered heterocyclyl group, selected from among them, wherein said C 3-10 cycloalkyl group, C 6-14 aryl group, 5- to 14-membered heteroaryl group, 3- to 10-membered heterocyclyl group, -C(O)-C 3-10 cycloalkyl group, -C(O)-C 6-14 aryl group, -C(O)-5- to 14-membered heteroaryl group, -C(O)-3- to 10-membered heterocyclyl group, -C(O)-C 1-6 alkyl-C 3-10 cycloalkyl group, -C(O)-C 1-6 alkyl-C 6-14 aryl group, -C(O)-C 1-6 alkyl-5- to 14-membered heteroaryl group, -C(O)-C 1-6 on the ring or acyclic group of an alkyl-3- to 10-membered heterocyclyl group, or -C(O)NH 2 is further optionally substituted with one, two or more groups selected from OH, halogen, CN, C 1-6 alkyl group, C 1-6 alkyloxy group; Alternatively, K is phenyl-C(O)-, phenyl-C(O)-NH-, phenyl-C(O)-NH-C, phenyl-C(O)-NH-Calkyl-, phenyloxy-C(O)-NH-, phenylalkyl-NH-C(O)-, phenylalkyl-C(O)-NH-, pyridinyl-C(O)-, pyridinyl-C(O)-NH-, pyridinyl-C(O)-NH-Calkyl-, pyridyloxy-C(O)-NH-, pyridinylalkyl-NH-C(O)-, pyridinylalkyl-C(O)-NH-, pyrrolidinyl-C(O)-NH-, pyrrolidyloxy-C(O)-NH-, Calkyl-C(O)-, Calkyl-C(O)-NH-, Calkyloxy-C(O)-NH-, cycloalkyl-C(O)-NH-, cycloalkyloxy-C(O)-NH-, pyridinyl-NH-C(O)-, Calkyl-NH-C(O)-, cycloalkyl-NH-C(O)-, pyridyloxy-, pyridinylalkyloxy-, pyridyloxyalkyl-, phenyloxy-, phenylalkyl-oxy-, phenyloxyalkyl-, Calkyl-S(O)-, Calkyl-S(O)-NH-, Calkyl-NH-S(O)-, pyridinylCalkyl-, pyridinyl-S(O)-, pyridinyl-Calkyl-S(O)-, pyridinyl-S(O)-NH-, pyridinyl-Calkyl-NH-, phenylCalkyl-, phenyl-S(O)-, phenyl-Calkyl-, optionally substituted with one, two or more substituents independently selected from non-existence, H, OH, unsubstituted or optionally R f from 1-6 alkyl-, phenyloxy-C(O)-NH-, phenylalkyl-NH-C(O)-, phenylalkyl-C(O)-NH-, pyridinyl-C(O)-, pyridinyl-C(O)-NH-, pyridinyl-C(O)-NH-C 1-6 alkyl-, pyridyloxy-C(O)-NH-, pyridinylalkyl-NH-C(O)-, pyridinylalkyl-C(O)-NH-, pyrrolidinyl-C(O)-NH-, pyrrolidyloxy-C(O)-NH-, C 1-6 alkyl-C(O)-, C 1-6 alkyl-C(O)-NH-, C 1-6 alkyloxy-C(O)-NH-, C 3-8 cycloalkyl-C(O)-NH-, C 3-8 cycloalkyloxy-C(O)-NH-, pyridinyl-NH-C(O)-, C 1-6 alkyl-NH-C(O)-, C 3-8 cycloalkyl-NH-C(O)-, pyridyloxy-, pyridinylalkyloxy-, pyridyloxyalkyl-, phenyloxy-, phenylalkyl-oxy-, phenyloxyalkyl-, C 1-6 alkyl-S(O) 2 -, C 1-6 alkyl-S(O) 2 -NH-, C 1-6 alkyl-NH-S(O) 2 -, pyridinylC 1-6 alkyl-, pyridinyl-S(O) 2 -, pyridinyl-C 1-6 alkyl-S(O) 2 -, pyridinyl-S(O) 2 -NH-, pyridinyl-NH-S(O) 2 -, pyridinyl-C 1-6 alkyl-NH-, phenylC 1-6 alkyl-, phenyl-S(O) 2 -, phenyl-C 1-6 Alkyl-S(O) 2 -, Phenyl-S(O) 2 -NH-, Phenyl-NH-S(O) 2 -, Phenyl-C 1-6 Alkyl-NH-, C 1-6 Alkyloxy-C(O)-, 【Chemical Formula 5】 selected from, The compound, its stereoisomers, racemates, tautomers, isotope labels or pharmaceutically acceptable salts according to Claim 1, characterized in that.

3. X 1 、 X 2 、 X 3 、 X 4 、 X 5 、 X 6 、 X 7 are the same or different, independently selected from CH or N for each, and at least one of X 1 、 X 2 、 X 3 、 X 4 、 X 5 、 X 6 、 X 7 is N; X 8 is NR 1 selected from; R 01 is a methoxy group; R 02 is H; R 03 is a methyl group; R 04 is H; R 1 is H; A is selected from H, NH 2 , methyl group, ethyl group, propyl group, isopropyl group; E is selected from H, NH 2 selected from; D is halogen, BnO-, H, CN, NH 2 , OCH 3 , COOH, B(OH) 2 , [Chemical Formula 6] selected from the group of; G is substituted with one, two or more substituents independently selected from F, unsubstituted or optionally R e substituted with [Chemical Formula 7] selected from; Optionally, when the group G is replaced by R e R may replace the H in e -CH 2 - and -CH= that form the group G; K is independently selected from one, two or more substituents selected from non-existence, H, OH, unsubstituted or optionally R f substituted phenyl-C(O)-, phenyl-C(O)-NH-, phenyl-C(O)-NH-C 1-6 alkyl-, phenyloxy-C(O)-NH-, phenylalkyl-NH-C(O)-, phenylalkyl-C(O)-NH-, pyridinyl-C(O)-, pyridinyl-C(O)-NH-, pyridinyl-C(O)-NH-C 1-6 alkyl-, pyridyloxy-C(O)-NH-, pyridinylalkyl-NH-C(O)-, pyridinylalkyl-C(O)-NH-, pyrrolidinyl-C(O)-NH-, pyrrolidyloxy-C(O)-NH-, C 1-6 alkyl-C(O)-, C 2-6 alkenyl-C(O)-, C, C 1-6 alkyl-C(O)-NH-, C 1-6 alkyloxy-C(O)-NH-, C 3-8 cycloalkyl-C(O)-NH-, C 3-8 cycloalkyloxy-C(O)-NH-, pyridinyl-NH-C(O)-, C 1-6 alkyl-NH-C(O)-, C 3-8 cycloalkyl-NH-C(O)-, pyridyloxy-, pyridinylalkyloxy-, pyridyloxyalkyl-, phenyloxy-, phenylalkyloxy-, phenyloxyalkyl-, C 1-6 alkyl-S(O) 2 -, C 1-6 alkyl-S(O) 2 -NH-, C 1-6 alkyl-NH-S(O) 2 -, pyridinylC 1-6 alkyl-, pyridinyl-S(O) 2 -, pyridinyl-C 1-6 alkyl-S(O) 2 -, pyridinyl-S(O) 2 -NH-, pyridinyl-NH-S(O) 2 -, pyridinyl-C 1-6 alkyl-NH-, phenylC 1-6 alkyl-, phenyl-S(O) 2 - Phenyl - C 1-6 Alkyl - S(O) 2 - Phenyl - S(O) 2 - NH - Phenyl - NH - S(O) 2 - Phenyl - C 1-6 Alkyl - NH - C 1-6 Alkyloxy - C(O)- [Chemical Formula 8] selected from, The compound, its stereoisomers, racemates, tautomers, isotope labels or pharmaceutically acceptable salts according to Claim 1, characterized in that.

4. The compound has a structure represented by the following formula IV or V: 【Chemical Formula 9】 Among them, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , R 01 , R 02 , R 03 , R 04 , A, D, E, G, K, m have the definitions recited in claim 3 The compound, its stereoisomers, racemates, tautomers, isotope labels or pharmaceutically acceptable salts according to Claim 3, characterized in that.

5. The following 【Chemical 10】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 [Chemical] 【Chem.】 【Chem.】 【Chem.】 [Chemical] 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 [Chemical] [Chemical] 【Chem.】 【Chem.】 【Chem.】 [Chemical] [Chemical] selected from, The compound, its stereoisomers, racemates, tautomers, isotope labels or pharmaceutically acceptable salts, characterized in that.

6. A method for producing the compound of formula I according to any one of Claims 1 to 4, comprising one of the following steps: 【Chemical 11】 Among them, A, D, E, Q, G, K, X 5 , X 6 , X 7 , X 8 has the definition described in any one of claims 1 to 4; L 1 is selected from leaving groups; 【Chemical 12】 Among them, A, D, E, Q, G, K, X 5 , X 6 , X 7 , X 8 has the definition described in any one of claims 1 to 4; L 2 is selected from leaving groups; 【Chemical 13】 Among them, A, D, E, Q, G, K, X 5 , X 6 , X 7 , X 8 has the definition described in any one of claims 1 to 4; L 3 is selected from leaving groups; Optionally, the production method includes reacting a compound of formula I substituted with a protecting group under conditions for removing the protecting group to obtain a compound of formula I. The method for producing the compound of formula I according to any one of Claims 1 to 4, characterized in that.

7. A process for preparing a compound of formula II, said process comprising the step of reacting a compound of formula II-1 with a compound R 21 -L to obtain a compound of formula II: 【Chemical Formula 14】 Among them, A, E, G, K, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , R 21 has the definition described in any one of claims 1 to 4; L is selected from leaving groups; A method for producing the compound of formula II.

8. Selected from the compounds represented by formula I-1, formula I-2, formula I-3 in Claim 6, or the compound represented by formula II-1 in Claim 7, Compound.

9. Use of the compound according to Claim 8 for producing the compound represented by formula I according to any one of Claims 1 to 4.

10. Containing at least one selected from the compounds, their stereoisomers, racemates, tautomers, isotope labels or pharmaceutically acceptable salts according to any one of Claims 1 to 5, Optionally, further comprising one, two or more pharmaceutically acceptable auxiliary materials, Pharmaceutical composition.

11. Use of at least one of the compounds, their stereoisomers, racemates, tautomers, isotope labels or pharmaceutically acceptable salts according to any one of Claims 1 to 5 in the manufacture of a drug, The drug is used for the treatment of RET kinase-mediated diseases, inhibition of RET kinase activity, treatment of cancer and / or inhibition of metastases associated with certain cancers, treatment of irritable bowel syndrome (IBS) or pain associated with IBS, provision of supportive therapy to cancer patients, treatment of RET-related diseases or conditions, reversal or prevention of acquired resistance to anticancer agents, delay and / or prevention of the progression of anticancer agent resistance in an individual, and delay and / or prevention of an increase in the likelihood of resistance to the progression of anticancer agents; The supportive therapy includes prevention or minimization of gastrointestinal disorders associated with diarrhea; The RET-related disease or condition is selected from RET gene and / or RET kinase-mediated diseases, and the RET kinase is selected from RET-wt, V804M, V804L, V804E, G810R, G810S, G810C, G810V, and S904F; The cancer is selected from hematological cancers or solid tumors, Use.

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