Nitrogen-containing polycyclic fused ring compounds, pharmaceutical compositions thereof, methods for preparation and uses thereof

Abstract

The present invention relates to the field of medicinal chemistry, and specifically to a nitrogen-containing polycyclic fused ring compound represented by Formula I, as well as pharmaceutical compositions, preparation methods, and uses thereof. The compounds of the present invention can be used as highly selective and highly effective RET inhibitors, and this type of compound has relatively strong inhibitory activity against all RET gatekeeper residue mutants, RET V804M mutation, RET solvent front residue mutant RET G810R, as well as other clinically relevant RET mutants and RET wt. Furthermore, the compounds can significantly inhibit the growth of TT cell lines derived from thyroid cancer and Ba / F3 cells metastasized from various RET mutants, and significantly induce the death of TT cells.

Description

Detailed Description of the Invention

[0001] This application claims priority from an earlier application, filed with the State Intellectual Property Office of the People's Republic of China on August 5, 2019, under application number 201910719005.2, entitled "Nitrogen-containing polycyclic fused ring compounds, pharmaceutical compositions, preparation methods and uses thereof," the entire contents of which are incorporated herein by reference.

[0002] [Technical Field] The present invention relates to the field of pharmaceutical chemistry, specifically to nitrogen-containing polycyclic fused ring compounds, pharmaceutical compositions thereof, preparation methods and uses thereof.

[0003] [Technical background] The RET (Rearranged During Transfection) proto-oncogene was first demonstrated in 1985 by transfecting NIH3T3 (mouse embryonic fibroblast cell line) cells with human lymphoma DNA (Cell, 1985, 42(2):581-588). The RET proto-oncogene is located on chromosome 10q11.2, spans 60 kb of DNA, contains 21 exons, and encodes the 1100 amino acid RET protein: The RET protein is a tyrosine kinase receptor and contains one extracellular domain consisting of cysteines, one transmembrane domain, and one intracellular domain capable of tyrosine kinase catalysis (Mol Cell Endocrinol, 2010, 322(1-2): 2-7). RET is involved in cell proliferation, nerve conduction, cell migration, and cell differentiation, and induces cell proliferation by activating various downstream pathways, such as RAS / RAF / MEK / ERK, PI3K / AKT, and STAT pathways, via signals from the ligand / receptor complex / RET multiprotein complex (J Clin Oncol, 2012, 30(2): 200-202).

[0004] As research has progressed, it has been found that the occurrence of many diseases is closely related to mutations in the RET gene, including papillary thyroid carcinoma (PTC) (Cell, 1990, 60(4):557-563), medullary thyroid carcinoma (MTC) (Hyroid, 2009, 19(6):565-612), multiple endocrine neoplasia type 2 (MEN2) (Endocr Rev, 2006, 27(5):535-560), congenital megacolon (Proc Natl Acad Sci USA, 2000, 97(1):268-273), and lung adenocarcinoma (Nat Med, 2012, 18(3):565-560). 375-377). Currently, only four RET fusion genes, KIF5B-RET, CCDC6-RET, TRIM33-RET, and NCOA4-RET, have been reported in non-small cell lung cancer (NSCLC), with KIF5B-RET being the most common RET fusion gene in NSCLC (Cancer, 2013, 119(8): 1486-1494). KIF5B-RET is a type of fusion gene formed by a chromosomal inversion (p11;q11) between the KIF5B (kinesin family member 5B) gene and the RET gene. It was first identified in adenocarcinomas of Korean non-smokers through whole-genome and transcriptome sequencing. Although the incidence of KIF5B-RET in lung cancer is very low, it is frequently found in non-smokers and adenocarcinoma patients, and is exclusively associated with other mutations, such as EGFR, KRAS, BRAF, ErbB2, and EML4-ALK (Genome Res, 2012, 22(3): 436-445). The KIF5B-RET fusion protein contains the motor domain and the coiled-coil domain of KIF5B, and the dimerization of the coiled-coil domain aberrantly activates the RET tyrosine kinase activity of the fusion protein, promoting lung tumorigenesis (Cancer, 2011, 117(12): 2709-2718).A study by Qian et al. (Mol Cancer, 2014, 13:176) confirmed that the KIF5B-RET fusion kinase possesses significant oncogenic activity both in vitro and in vivo, suggesting that the STAT3 signaling pathway may be a major downstream mediator of tumorigenesis. Evidence was found that KIF5B-RET can regulate sustained STAT3 activation. KIF5B-RET fusion kinase binds to STAT3 and directly phosphorylates and activates STAT3-Tyr705; it can also mediate STAT3-Tyr705 activation via the JAK / STAT3-dependent pathway and trigger Ser727 phosphorylation via the RAS / RAF / MEK / ERK1 pathway.

[0005] RET fusions have proven to be a driving force in some cancers, prompting the application of multikinase inhibitors with RET inhibitory activity to treat patients with tumors bearing RET fusion proteins. Currently, there are no approved drugs targeting this oncogene, and current treatments for RET-specific cancers are limited to multikinase inhibitors and chemotherapy. However, these non-specific therapies not only have poor ORR (objective response rate) in clinical symptoms, but also suffer from significant off-target toxicities. One of the greatest challenges in cancer treatment is the development of resistance in tumor cells after a period of treatment. Once resistance is acquired, patients typically have very limited treatment options, and in most cases, the cancer progresses uncontrollably.

[0006] RET kinase signaling plays an important role in many human cancers, including thyroid cancer. Mutations at the RET gatekeeper residue, RET 804V, are a key cause of tumor resistance to currently approved nonselective RET inhibitors (e.g., cabozantinib and vandetanib). One of the key mutations in the extracellular or intracellular domain of RET in isolated familial medullary thyroid carcinoma (MSTC) is the gatekeeper residue V804M mutation at the kinase ATP-binding site, which reduces the affinity of existing drugs for the ATP-binding site. According to a study published in the journal Thoracic Oncology, 2020, Vol. 15, No. 4, 541-549, the selective RET inhibitor LOXO-292 (selpercatinib) can avoid the RET 804V mutation. However, other mutations that lead to resistance can still occur even after treatment with this selective RET inhibitor. For example, in non-small cell lung cancer, mutations at the solvent front residue G810 in the kinase ATP binding site (G810R, G810S, and G801C) can reduce the binding site of LOXO-292 to ATP, resulting in drug resistance and cancer progression. Therefore, it is necessary to develop compounds with excellent RET mutation inhibitor activity.

[0007] [Contents of the invention] To alleviate the above-mentioned problems, the present invention provides a compound represented by formula I or a pharmaceutically acceptable salt thereof:

[0008] [ka]

[0009] X 1 , X 2 , X 3 , X 4 , X5 , X 6 , X 7 are homologous or different, each independently CR 1 or selected from N; X8 is CR 1 R 1’ or NR 1 Selected from; Among them: Each R 1 and R 1’ are the same or different and are each independently selected from H, halogen, CN, NH2 or OH; Or, Each R 1 and R 1’ are identical or different, each independently unsubstituted or optionally substituted with one, two or three R a The following groups substituted with: C 1-6 Alkyl group, C 3-6 Cyclic alkyl group, C 1-6 Alkoxy group or C 3-6 selected from cyclic alkyl groups and oxy groups; Each R a are the same or different, each independently a halogen, CN, OH, C 1-6 Alkyl group, C 3-6 Cyclic alkyl group or C 1-6 selected from alkoxy groups; A is selected from H, halogen, CN, OH or NH2, or A is unsubstituted or optionally contains one, two or three R b The following groups substituted with: C 1-6 Alkyl group, C 2-6 Alkenyl group, C 3-6 Cyclic alkyl group, C 1-6 Alkoxy group or C 3-6 selected from cyclic alkyl groups and oxy groups; Each R b are the same or different, each independently a halogen, CN, OH, C 1-6 Alkyl group, C 3-6 Cyclic alkyl group or C 1-6 selected from alkoxy groups; D, E are the same or different and are each independently selected from H, halogen, CN, OH, or NH2; or D, E are the same or different and are each independently unsubstituted or optionally substituted with one, two, or three R c The following groups substituted with: -C 1-6 Alkyl group, -C 1-6 Alkoxy group, -O(CH2) n O(CH2) n C 3-6 Carbocycle, -O(CH2) n -3-8 membered heterocycle or -O(CH2) n C 6-10 Selected from aromatic rings; Each R c are the same or different, each independently a halogen, CN, OH, oxo (=O), C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 cyclic alkyl group, 3-10 membered heterocyclic group, 5-7 membered heteroaryl group, 6-10 membered aryl group, C 1-6 selected from an alkoxy group, a 3- to 6-membered cyclic alkyloxy group, or a 3- to 8-membered heterocyclic oxy group; each n is identical or different and is independently selected from 0, 1, 2, or 3; D, E and R above c The number and type of heteroatoms in each heterocycle, heterocyclic group, and heteroaryl group in the formula (I) may be the same or different, and each independently contains 1, 2, or 3 heteroatoms, each of which is selected from N, O, or S; G is selected from the following groups: (1) A 4-8 membered saturated heterocycle containing two heteroatoms; (2) 7-10 membered saturated bridged heterocycles containing two heteroatoms; (3) 7-11 membered saturated heterospirocycles containing two heteroatoms; or (4) a 7-10 membered saturated bicyclo-fused heterocycle containing two heteroatoms, the heteroatoms being selected from N or O, each ring being independently optionally unsubstituted or substituted with 1, 2, 3, or 4 R G and each R G are homologous or different, and each R Gare independently H, halogen, OH, NH2, C 1-6 Alkyl, halogen-substituted C 1-6 Alkyl group, C 1-6 C substituted with alkoxy or halogen 1-6 selected from alkoxy groups; K is unsubstituted or optionally contains 1, 2, 3 or 4 R K is selected from the following groups substituted with: C 1-6 Alkyl group, C 3-6 Cyclic alkyl group, C 6-10 Aryl group, -C 1-6 Alkylene C 6-10 Aromatic ring, -COC 1-6 Alkylene Group C 6-10 aromatic ring, -C 1-6 Alkylene 5-10 membered aromatic heterocycle, -COC 1-6 Alkylene 5-10 membered aromatic heterocycle, -CONR K1 R K2 , 3-10 membered heterocyclic group, C 1-6 Alkoxy group, C 3-6 Cyclic alkyloxy group, C 6-10 an aryloxy group, a 5- to 10-membered heteroaryloxy group, or a 3- to 10-membered heterocyclic oxy group; Each R K are identical or different, each independently representing the following groups: -CN, OH, -NH2, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 C substituted with cyclic alkyl groups and halogens 1-6 C substituted with alkyl group or halogen 1-6 selected from alkoxy groups; R K1 and R K2 are identical or different, each independently representing the following groups: -CN, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 C substituted with cyclic alkyl groups and halogens 1-6 C substituted with alkyl group or halogen 1-6 selected from alkoxy groups; Each of the aromatic heterocycles, heterocycles, and heterocyclic groups in K may be the same or different and each independently contain 1 or 2 N atoms.

[0010] In a preferred embodiment, the present invention also provides a compound of formula I or a pharmaceutically acceptable salt thereof, wherein X 1 , X 3 and X 4 are all independently CR 1 Selected from.

[0011] In a preferred embodiment, the present invention also provides a compound of formula I or a pharmaceutically acceptable salt thereof, wherein X 5 is CR 1 Selected from.

[0012] In a preferred embodiment, the present invention also provides a compound of formula I or a pharmaceutically acceptable salt thereof, wherein X 8 is NR 1 Selected from.

[0013] In a preferred embodiment, the present invention also provides a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein each R 1 and R 1’ are identical or different and are each independently selected from H, F, Cl, Br, CN, NH2 or OH; or Each R 1 and R 1’ are identical or different, each independently unsubstituted or optionally substituted with one, two or three R a The following groups are substituted with: C 1-3 Alkyl group, C 4-6 Cyclic alkyl group, C 1-3 Alkoxy group or C 4-6 The cyclic alkyl group and the oxy group are selected from the group consisting of cyclic alkyl groups and oxy groups.

[0014] In a preferred embodiment, the present invention also provides a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein each R 1 and R 1’ are identical or different and are each independently selected from H, F, Cl, CN or NH2; or Each R 1 and R 1’ are identical or different, each independently unsubstituted or optionally substituted with one, two or three R a The following groups substituted with: It is selected from a methyl group, an ethyl group, a propyl group, a 5-membered cyclic alkyl group, a 6-membered cyclic alkyl group, a methoxy group, an ethoxy group, a propoxy group, a 5-membered cyclic alkyloxy group, and a 6-membered cyclic alkyloxy group.

[0015] In a preferred embodiment, the present invention also provides a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein each R a are homologous or different, each independently F, Cl, Br, CN, OH, C 1-3 Alkyl group, C 4-6 Cyclic alkyl group or C 1-3 selected from alkoxy groups; In a preferred embodiment, the present invention also provides a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein each R a are the same or different and are each independently selected from F, Cl, CN, OH, a methyl group, an ethyl group, a propyl group, a 5-membered cyclic alkyl group, a 6-membered cyclic alkyl group, a methoxy group, an ethoxy group, a propoxy group, a 5-membered cyclic alkyloxy group, and a 6-membered cyclic alkyloxy group.

[0016] In a preferred embodiment, the present invention also provides a compound of formula I or a pharmaceutically acceptable salt thereof, wherein X 1 is selected from CH.

[0017] In a preferred embodiment, the present invention also provides a compound of formula I or a pharmaceutically acceptable salt thereof, wherein X 3 is selected from CH.

[0018] In a preferred embodiment, the present invention also provides a compound of formula I or a pharmaceutically acceptable salt thereof, wherein X 5 is selected from -CH.

[0019] In a preferred embodiment, the present invention also provides a compound of formula I or a pharmaceutically acceptable salt thereof, wherein X5 is selected from CH.

[0020] In a preferred embodiment, the present invention also provides a compound of formula I or a pharmaceutically acceptable salt thereof, wherein X 8 is selected from NH.

[0021] In a preferred embodiment, the present invention also provides a compound of formula I or a pharmaceutically acceptable salt thereof, wherein X 1 , X 3 , X 4 and X 5 are all selected from CH, and X 8 is selected from NH.

[0022] In a preferred embodiment, the present invention also provides a compound of formula I or a pharmaceutically acceptable salt thereof, wherein X 2 is selected from N.

[0023] In a preferred embodiment, the present invention also provides a compound of formula I or a pharmaceutically acceptable salt thereof, wherein X 6 is selected from N.

[0024] In a preferred embodiment, the present invention also provides a compound of formula I or a pharmaceutically acceptable salt thereof, wherein X 7 is selected from N.

[0025] In a preferred embodiment, the present invention also provides a compound of formula I or a pharmaceutically acceptable salt thereof, wherein X 1 , X 3 , X 4 and X 5 are all selected from CH, and X 2 , X 6 and X 7 are all chosen from N, and X 8 is selected from NH.

[0026] In a preferred embodiment, the present invention also provides a compound of formula I or a pharmaceutically acceptable salt thereof, wherein A is selected from H, F, Cl, Br, CN, OH, or NH2; A is unsubstituted or optionally contains 1, 2 or 3 R b The following groups substituted with: C 1-3 Alkyl group, C 4-6 Cyclic alkyl group, C 1-3 Alkoxy group or C 4-6 selected from cyclic alkyl groups and oxy groups; Each R b are homologous or different, each independently F, Cl, Br, CN, OH, C 1-3 Alkyl group or C 1-3 The alkoxy group is selected from the group consisting of alkoxy groups.

[0027] In a preferred embodiment, the present invention also provides a compound of formula I or a pharmaceutically acceptable salt thereof, wherein A is selected from H, F, Cl, CN, OH, or NH2; A is unsubstituted or optionally contains 1, 2 or 3 R b The following groups substituted with: selected from a methyl group, an ethyl group, a propyl group, a 5-membered cyclic alkyl group, a 6-membered cyclic alkyl group, a methoxy group, an ethoxy group, a propoxy group, a 5-membered cyclic alkyloxy group, and a 6-membered cyclic alkyloxy group; Each R b are the same or different and are each independently selected from F, Cl, a methyl group, an ethyl group, a methoxy group, and an ethoxy group.

[0028] In a preferred embodiment, the present invention also provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein A is selected from H, -F, -Cl, -CN, -OH, -NH2, or -CH3.

[0029] In a preferred embodiment, the present invention also provides a compound of formula I or a pharmaceutically acceptable salt thereof, wherein D and E are the same or different and are each independently selected from H, F, Cl, Br, CN, OH, or NH2; D and E are identical or different, each independently unsubstituted or optionally substituted with 1, 2 or 3 R c The following groups substituted with: -C 1-3 Alkyl group, -C 1-3 Alkoxy group, -O(CH2)n O(CH2) n C 3-6 Carbocycle, -O(CH2) n -4-6 membered heterocycle, -O(CH2) n C6 aromatic ring or -O(CH2) n C 10 It is selected from aromatic rings.

[0030] In a preferred embodiment, the present invention also provides a compound of formula I or a pharmaceutically acceptable salt thereof, wherein D and E are the same or different and are each independently selected from H, F, Cl, Br, CN, OH, or NH2; D and E are identical or different, each independently unsubstituted or optionally substituted with 1, 2 or 3 R c The following groups substituted with: Methyl group, ethyl group, propyl group, methoxy group, ethoxy group, propoxy group, -O(CH2) n O(CH2) n -3-membered carbocycle, -O(CH2) n O(CH2) n -4-membered carbocycle, -O(CH2) n O(CH2) n -5-membered carbocycle, -O(CH2) n -5-membered heterocycle, -O(CH2) n -6-membered heterocycle or -O(CH2) n -benzene ring.

[0031] In a preferred embodiment, the present invention also provides a compound of formula I or a pharmaceutically acceptable salt thereof, wherein D and E are the same or different and are each independently selected from H, F, Cl, Br, CN, OH, or NH2; D and E are identical or different, each independently unsubstituted or optionally substituted with 1, 2 or 3 R c The following groups substituted with: Methyl group, methoxy group, -O(CH2) n O(CH2) n -3-membered carbocycle, -O(CH2) n -6-membered heterocycle or -O(CH2) n -benzene ring.

[0032] In a preferred embodiment, the present invention also provides a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein each n is the same or different and is independently selected from 0, 1, or 2.

[0033] In a preferred embodiment, the present invention also provides a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein each n is the same or different and is independently selected from 1 or 2.

[0034] In a preferred embodiment, the present invention also provides a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein each R c are homologous or different, each independently F, Cl, Br, CN, OH, C 1-3 Alkyl group, C 3-5 Cyclic alkyl group, 4-6 membered heterocyclic ring, 5-6 membered heteroaryl group, phenyl group, C 1-3 It is selected from an alkoxy group, a 3- to 5-membered alkyloxy group, and a 4- to 6-membered saturated heterocyclic oxy group.

[0035] In a preferred embodiment, the present invention also provides a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein each R c are the same or different and are each independently selected from F, Cl, Br, CN, OH, a methyl group, an ethyl group, a propyl group, a 3-membered alkyl group, a 4-membered alkyl group, a 4-membered saturated heterocyclic group, a 5-membered saturated heterocyclic group, a 6-membered saturated heterocyclic group, a 5-membered heteroaryl group, a 6-membered heteroaryl group, a phenyl group, a methoxy group, an ethoxy group, a propoxy group, a 3-membered alkyloxy group, a 4-membered alkyloxy group, a 5-membered saturated heterocyclic group, and a 6-membered saturated heterocyclic group.

[0036] In a preferred embodiment, the present invention also provides a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein each R care the same or different and are each independently selected from F, Cl, Br, CN, OH, a methyl group, an ethyl group, a propyl group, a 3-membered alkyl group, a 4-membered alkyl group, a 4-membered saturated heterocyclic group, a 5-membered saturated heterocyclic group, a 6-membered saturated heterocyclic group, a 5-membered heteroaryl group, a 6-membered heteroaryl group, a phenyl group, a methoxy group, an ethoxy group, a propoxy group, a 3-membered alkyloxy group, a 4-membered alkyloxy group, a 5-membered saturated heterocyclic group, and a 6-membered saturated heterocyclic group.

[0037] In a preferred embodiment, the present invention also provides a compound of formula I or a pharmaceutically acceptable salt thereof, wherein D, E and R c The number and type of heteroatoms in each heterocycle, heterocyclic group, and heteroaryl group may be the same or different, and each independently contains 1 or 2 heteroatoms, and the heteroatoms are selected from N and O.

[0038] In a preferred embodiment, the present invention also provides a compound of formula I or a pharmaceutically acceptable salt thereof, wherein D, E and R c The number and type of heteroatoms in each heterocycle, heterocyclic group, and heteroaryl group may be the same or different, and each independently contains one N atom and / or one O atom.

[0039] In a preferred embodiment, the present invention also provides a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein each R c are homologous or different, each independently F, Cl, Br, OH, CN,

[0040] [ka]

[0041] Selected from.

[0042] In a preferred embodiment, the present invention also provides a compound of formula I or a pharmaceutically acceptable salt thereof, wherein D is -H, -Br, -Cl, -CH3, -NH2,

[0043] [ka]

[0044] Selected from.

[0045] In a preferred embodiment, the present invention also provides a compound of formula I or a pharmaceutically acceptable salt thereof, wherein E is -H, -Br, -CN, NH2, -CH3, CF3,

[0046] [ka]

[0047] Selected from.

[0048] In a preferred embodiment, the present invention also provides a compound of formula I or a pharmaceutically acceptable salt thereof, wherein E is selected from H and D is -H, -Br, -Cl, -CH3, -NH2,

[0049] [ka]

[0050] Selected from.

[0051] In a preferred embodiment, the present invention also provides a compound of formula I or a pharmaceutically acceptable salt thereof, wherein G is a group as follows: It is selected from 5-, 6-, 7- or 8-membered saturated heterocycles containing two N atoms.

[0052] In a preferred embodiment, the present invention also provides a compound of formula I or a pharmaceutically acceptable salt thereof, wherein G is a group as follows: It is selected from a saturated 5-membered heterocycle containing two N atoms, a saturated 6-membered heterocycle containing two N atoms, a saturated 7-membered heterocycle containing two N atoms, and a saturated 8-membered heterocycle containing two N atoms.

[0053] In a preferred embodiment, the present invention also provides a compound of formula I or a pharmaceutically acceptable salt thereof, wherein G is a group as follows:

[0054] [ka]

[0055] Selected from.

[0056] In a preferred embodiment, the present invention also provides a compound of formula I or a pharmaceutically acceptable salt thereof, wherein G is a group as follows: saturated 7-, 8- or 9-membered bridged heterocycles containing two N or O atoms.

[0057] In a preferred embodiment, the present invention also provides a compound of formula I or a pharmaceutically acceptable salt thereof, wherein G is a group as follows: It is selected from a saturated 8-membered bridged heterocycle containing two N or O atoms or a saturated 9-membered bridged heterocycle containing two N atoms.

[0058] In a preferred embodiment, the present invention also provides a compound of formula I or a pharmaceutically acceptable salt thereof, wherein G is a group as follows: It is selected from a saturated 8-membered bridged heterocycle containing two N atoms or a saturated 9-membered bridged heterocycle containing two N atoms.

[0059] In a preferred embodiment, the present invention also provides a compound of formula I or a pharmaceutically acceptable salt thereof, wherein G is a group as follows:

[0060] [ka]

[0061] Selected from.

[0062] In a preferred embodiment, the present invention also provides a compound of formula I or a pharmaceutically acceptable salt thereof, wherein G is a group as follows:

[0063] [ka]

[0064] Selected from.

[0065] In a preferred embodiment, the present invention also provides a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein each R G are homologous or different, and each R G are independently H, F, Cl, Br, OH, NH2, C 1-3 C substituted with alkyl group, F or Cl 1-3 Alkyl group or C 1-3 The alkoxy group is selected from the group consisting of alkoxy groups.

[0066] In a preferred embodiment, the present invention also provides a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein each R G are homologous or different, and each R G are independently selected from H, NH, a methyl group, an ethyl group, a propyl group, a methyl group substituted with F, an ethyl group substituted with F, a propyl group substituted with F, a methoxy group, an ethoxy group, and a propoxy group.

[0067] In a preferred embodiment, the present invention also provides a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein each R G are homologous or different, and each R G are independently selected from H, NH2, a methyl group, a methyl group substituted with F, or a methoxy group.

[0068] In a preferred embodiment, the present invention also provides a compound of formula I or a pharmaceutically acceptable salt thereof, wherein K is unsubstituted or optionally substituted with one, two or more R K The following groups substituted with: K is unsubstituted or optionally 1, 2 or 3 R K The following groups substituted with: C 1-3 Alkyl groups and C 5-6 Cyclic alkyl group, phenyl group, -C 1-3Alkylene benzene ring, -COC 1-3 Alkylene benzene ring, -COC 1-3 Alkylenebiphenyl ring, -C 1-3 Alkylene group 5-8 membered aromatic heterocycle, -COC 1-3 Alkylene 5-8 membered aromatic heterocycle, -CONR K1 R K2 , 5-6 membered heterocyclic group, C 1-3 Alkoxy group, C 3-6 Cyclic alkyloxy group, C 6-10 It is selected from an aryloxy group, a 5- to 8-membered heteroaryloxy group, or a 5- to 8-membered heterocyclicoxy group.

[0069] In a preferred embodiment, the present invention also provides a compound of formula I or a pharmaceutically acceptable salt thereof, wherein K is unsubstituted or optionally substituted with one, two or more R K The following groups substituted with: K is unsubstituted or optionally contains one or two R K The following groups substituted with: C 1-3 Alkyl group, C 5-6 Cyclic alkyl group, phenyl group, -C 1-3 Alkylene benzene ring, -COCH2 benzene ring, -COCH2CH2 benzene ring, -COCH2 biphenyl ring, -CH2-6-membered aromatic heterocycle, -CH2CH2-6-membered aromatic heterocycle, -CO CH2-6-membered aromatic heterocycle, -COCH2CH2-6-membered aromatic heterocycle, -CONR K1 R K2 , a 5-membered heterocyclic group, a 6-membered heterocyclic group, a methoxy group, a C5 cyclic alkyloxy group, a phenyloxy group, a 6-membered heteroaryloxy group, or a 6-membered heterocyclic oxy group.

[0070] In a preferred embodiment, the present invention also provides a compound or a pharmaceutically acceptable salt thereof represented by Formula I, wherein each aromatic heterocycle, heterocycle, heterocyclic group, aromatic ring, aryl group, or cycloalkyl group in K is the same or different, and each aromatic heterocycle, heterocycle, or heterocyclic group contains one N atom.

[0071] In a preferred embodiment, the present invention also provides a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein each R K are each independently one of the following groups: -CN, OH, -NH2, C 1-3 Alkyl group, C 1-3 Alkoxy group, C 3-6 Ring alkyl group, C substituted with F 1-3 Alkyl groups, C substituted with Cl 1-3 Alkyl groups, C substituted with F 1-3 C substituted with alkoxy group or Cl 1-3 The alkoxy group is selected from the group consisting of alkoxy groups.

[0072] In a preferred embodiment, the present invention also provides a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein each R K are each independently one of the following groups: It is selected from -CN, OH, -NH2, a methyl group, an ethyl group, a methoxy group, and an ethoxy group.

[0073] In a preferred embodiment, the present invention also provides a compound of formula I or a pharmaceutically acceptable salt thereof, wherein R K1 and R K2 are identical or different, each independently representing the following groups: -CN, C 1-3 Alkyl group, C 1-3 Alkoxy group, C 4-5 Ring alkyl group, C substituted with F 1-3 Alkyl groups, C substituted with Cl 1-3 Alkyl groups, C substituted with F 1-3 C substituted with alkoxy group or Cl 1-3 The alkoxy group is selected from the group consisting of alkoxy groups.

[0074] In a preferred embodiment, the present invention also provides a compound of formula I or a pharmaceutically acceptable salt thereof, wherein R K1 and R K2 are identical or different, each independently, one of the following groups: It is selected from -CN, OH, -NH2, a methyl group, an ethyl group, a methoxy group, and an ethoxy group.

[0075] In a preferred embodiment, the present invention also provides a compound of formula I or a pharmaceutically acceptable salt thereof, wherein K is one of the following groups:

[0076] [ka]

[0077] Selected from.

[0078] In a preferred embodiment, the present invention also provides a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the heterocyclic group, heterocycle, aromatic heterocycle, heteroaryl group, or aromatic heterogroup contains 1, 2, or 3 heteroatoms, and the heteroatoms are selected from N and O.

[0079] In a preferred embodiment, the present invention also provides a compound or a pharmaceutically acceptable salt thereof represented by Formula I, wherein the heterocyclic group, heterocycle, aromatic heterocycle, heteroaryl group, or aromatic heterogroup contains one or two heteroatoms, and the heteroatoms are selected from N and O.

[0080] In a preferred embodiment, the present invention also provides a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the heterocyclic group, heterocycle, aromatic heterocycle, heteroaryl group, or aromatic heterocycle is a 4-, 5-, 6-, 7-, or 8-membered ring containing one heteroatom, and the heteroatom is selected from N and O.

[0081] In a preferred embodiment, the present invention also provides a compound of formula I or a pharmaceutically acceptable salt thereof, wherein the heterocyclic group, heterocycle, aromatic heterocycle, heteroaryl group, or aromatic heterocycle is a 4-, 5-, 6-, 7-, or 8-membered heterocycle containing two heteroatoms, and the heteroatoms are selected from N and O.

[0082] In a preferred embodiment, the present invention also provides a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the heterocyclic group, heterocycle, aromatic heterocycle, heteroaryl group, or aromatic heterocycle is a 4-, 5-, 6-, 7-, or 8-membered ring containing two heteroatoms, and the heteroatoms are selected from N.

[0083] In a preferred embodiment, the present invention also provides a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the heterocyclic group, heterocycle, aromatic heterocycle, heteroaryl group, or aromatic heterocycle is a 5- or 6-membered ring containing two heteroatoms, and the heteroatoms are selected from N.

[0084] In a preferred embodiment, the present invention also provides a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the heterocyclic group, heterocycle, aromatic heterocycle, heteroaryl group, or aromatic heterocycle is a 6-membered ring containing two heteroatoms, and the heteroatoms are selected from N.

[0085] In a preferred embodiment, the present invention also provides a compound or a pharmaceutically acceptable salt thereof according to Formula II:

[0086] [ka]

[0087] Among them, R 22 is H, halogen, CN, -C 1-6 Alkyl group, -C 1-6 Alkoxy group, -O(CH2) m -C 1-6 Alkyl group or -O(CH2) m -C 1-6 alkoxy groups, each C 1-6 Alkyl groups and their respective C 1-6 All alkoxy groups are unsubstituted or halogenated, C 1-6 Alkyl group or C 1-6 may be substituted with an alkoxy group, and m=0, 1 or 2; R 21 is H, NH2 or -C 1-3 selected from alkyl groups; R 23 are H, NH2, -C 1-3 Alkyl group or -C 1-3 The alkoxy group is selected from the group consisting of alkoxy groups.

[0088] In a preferred embodiment, the present invention also provides a compound of formula II or a pharmaceutically acceptable salt thereof, wherein R 22 are H, F, Cl, Br, CN, -C 1-3 Alkyl group, -C 1-3 Alkoxy group, -O(CH2) m -C 1-3 Alkyl group or -O(CH2) m -C 1-3 alkoxy groups, each C 1-3 Alkyl groups and their respective C 1-3 The alkoxy groups are all unsubstituted or substituted with F, Cl, Br, C 1-3 Alkyl group or C 1-3 alkoxy-substituted; R 21 is selected from H, NH2 or a methyl group; R 23 is selected from H, NH2, a methyl group, or a methoxy group.

[0089] In a preferred embodiment, the present invention also provides a compound of formula II or a pharmaceutically acceptable salt thereof, wherein R 22 are H, F, Cl, Br, CN, -C 1-3 Alkyl group, -C 1-3 Alkoxy group, -O(CH2) m -C 1-3 Alkyl group or -O(CH2) m -C 1-3 alkoxy groups, each C 1-3 Alkyl groups and their respective C 1-3 The alkoxy groups are all unsubstituted or substituted with F, Cl, Br, C 1-3 Alkyl group or C 1-3 alkoxy-substituted; R 21 is selected from H; R 23 is selected from methoxy groups.

[0090] In a preferred embodiment, the present invention also provides a compound of formula II or a pharmaceutically acceptable salt thereof, wherein R 22 is H, F, Cl, CN, methyl group, ethyl group, methoxy group, ethoxy group, -O(CH2) m Methyl group, -O(CH2) m Ethyl group, -O(CH2) m Methoxy group or -O(CH2) m ethoxy groups, wherein each of the methyl, ethyl, methoxy and ethoxy groups is unsubstituted or substituted with F, Cl, Br, methyl, ethyl, methoxy or ethoxy; In a preferred embodiment, the present invention also provides a compound of formula II, or a pharmaceutically acceptable salt thereof, wherein m=1 or 2.

[0091] The present invention also provides the following compound or a pharmaceutically acceptable salt thereof:

[0092] [ka]

[0093] .

[0094] The present invention also provides the following compound or a pharmaceutically acceptable salt thereof:

[0095] [ka]

[0096] TIFF0007732668000013.tif82169

[0097] .

[0098] The present invention also provides a pharmaceutical composition, which comprises a therapeutically effective amount of the above compound or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable adjuvant material.

[0099] As a preferred embodiment, the present invention also provides the use of the above-mentioned compound or a pharmaceutically acceptable salt thereof and the above-mentioned pharmaceutical composition in the manufacture of a medicament.

[0100] As a preferred embodiment, the present invention also provides a preferred scheme for the above use, in which the above drug is used to treat, inhibit or prevent a disease or disorder caused by the RET gene, the RET kinase protein, or any one or more mutations, expression, activity or levels of the RET gene, the RET kinase protein, or any one or more mutations, expression, activity or levels of the RET kinase protein.

[0101] As a preferred embodiment, the present invention also provides a preferred version of the above-mentioned use, in which one or more points of the RET gene are mutated to result in the translation of a RET protein having one or more amino acid substitutions at one or more of the following amino acid positions: 2, 3, 4, 5, 6, 7, 8, 11, 12, 13, 20, 32, 34, 40, 56, 64, 67, 114, 136, 145, 180, 200, 292, 294, 321, 330, 338, 360, 373, 393, 423, 432, 446, 505, 506, 510, 511, 513, 515, 525, 531, 532 , 533, 550, 591, 593, 595, 600, 602, 603, 606, 609, 611, 616, 618, 619, 620, 623, 624, 630, 631, 632, 633, 634, 635, 636, 640, 641, 648, 649, 664, 665, 666, 675, 686, 689, 691, 694 , 700, 706, 713, 732, 736, 748, 750, 765, 766, 768, 769, 770, 771, 777, 778, 781, 788, 790, 791, 802, 804, 805, 806, 810, 818, 819, 823, 836, 841, 843, 844, 848, 852, 865, 870, 873 , 876, 881, 882, 883, 884, 886, 891, 897, 898, 900, 901, 904, 905, 907, 908, 911, 912, 918, 919, 921, 922, 930, 961, 972, 981, 982, 1009, 1015, 1017, 1041, 1062, 1064 and 1096.

[0102] As a preferred embodiment, the present invention also provides a preferred version of the above-mentioned use, in which one or more points of the RET gene are mutated to result in the translation of a RET protein having one or more amino acid substitutions at one or more of the following amino acid positions: 32, 34, 40, 56, 64, 67, 114, 145, 292, 321, 330, 338, 360, 393, 423, 446, 510, 511, 513, 515, 525, 531, 532, 533, 550, 591, 593, 595, 600, 602, 603, 606, 609, 611, 616, 618, 619, 620, 623, 624, 630, 631, 632, 634, 635, 636, 640, 641, 648, 649, 664, 665, 666, 675, 686, 689, 691, 694, 700, 706, 713, 732, 736, 748, 75 0, 765, 766, 768, 769, 770, 771, 777, 778, 781, 788, 790, 791, 804, 805, 806, 810, 818, 819, 823, 826, 833, 836, 841, 843, 844, 848, 852, 865, 870, 873, 876, 881, 883, 884, 886, 891, 897, 898, 900, 901, 904, 905, 907, 908, 911, 912, 918, 919, 921, 922, 930, 961, 972, 981, 982, 1009, 1015, 1017, 1041, 1064 and 1096.

[0103] As a preferred embodiment, the present invention also provides a preferred version of the above-mentioned use, in which one or more points in the RET gene are mutated to result in the translation of a RET protein with one or more of the following amino acid substitutions: S32L、D34S、L40P、 L56M、P64L、 R67H、 R114H、V145G、 V292M、 G321R、R330Q、 T338I、 R360W、F393L、 G423R、 G446R、A510V、 E511K、 G513D、C515S、 C515W、 R525W、C531R、 G533C、 G533S、G550E、 V591I、 G593E、E595D、 E595A、 R600Q、I602V、 K603Q、 K603E、Y606C、 C609C、 C609Y、C609S、 C609G、 C609R、C609F、 C609W、 C611R、C611S、 C611G、 C611Y、C611F、 C611W、 E616Q、C618S、 C618Y、 C618R、C618G、 C618F、 C618W、F619F、 C620S、 C620W、C620R、 C620G、 C620L、C620Y、 C620F、 E623K、D624N、 C630A、 C630R、C630S、 C630Y、 C630F、C630W、 D631N、 D631Y、D631A、 D631G、 D631V、D631E、 E632K、 E632G、C634W、 C634Y、 C634S、C634R、 C634F、 C634G、C634L、 C634A、 C634T、R635G、 T636P、 T636M、A640G、 A641S、 A641T、V648I、 S649L、 A664D、H665Q、 K666E、 K666M、K666N、 K666R、 T675T S686N、S689T、 G691S、 R694Q、M700L、 V706M、 V706A、E713K、 E732K、 G736R、G748C、 A750P、 S765P、P766S、 P766M、 E768Q、E768D、 L769L、 R770Q、D771N、 N777S、 V778I、Q781R、 I788I、 L790F、Y791F、 Y791N、 V804L、V804M、 V804E、 E805K、Y806E、 Y806F、 Y806S、Y806G、 Y806C、 Y806H、Y806N、 Y806Y、 G810R、G810S、 G810A、 E818K、S819I、 G823E、 Y826M、Y826S、 R833C、S836S, P841L, P841P, E843D, R844W, R844Q, R844L, M848T, I852M, L865V, L870F, R873W, A876V, L881V, A883F, A883S, A883T, E884K, R886W, S891A, S891S, R897Q, D898V, Y900F, E901K, S904F, S904S, S904C, Y905F, K907E, K907M, R908K, G911D, R912P, R912Q, M918T, M918V, M918L, A919V, E921K, S922P, S922Y, T930M, F961L, R972G, Y981F, R982C, Ml009V, Y1015F, D1017N, V1041G, M1064T and Y1096F.

[0104] As a preferred embodiment, the present invention also provides a preferred method for the above-mentioned use, in which the mutations at one or more points in the RET gene occur in one or more exons 10, 11, 13, 14, 15 and 16 of the human RET gene.

[0105] As a preferred embodiment, the present invention also provides a preferred scheme for the above use, in which the RET gene fusion is selected from the following: BCR-RET, CLIP 1-RET, KIF5B-RET, CCDC6-RET, NCOA4-RET, TRIM33-RET, ERC1-RET, FGFR1OP-RET, RET-MBD1, RET-RAB61P2, RET-PRKAR1A, RET-TRIM24, RET-GOLGA5, HOOGA5. KIAA1217-RET, MPRIP-RET, HRH4-RET, RIA-RET, RET-PTC4, FRMD4A-RET, SQSTM1-RET, AFAP1L2-RET , PPFIBP2-RET, EML4-RET, PARD3-RET, MYH10-RET, HTIF1 / RET, AFAP1-RET, RASGEF1A-RET, TEL-RET.

[0106] In a preferred embodiment, the present invention also provides a preference for the above use, wherein the RET gene, RET kinase protein, or any one or more mutations, expression, activity or level disruption thereof is a RET gene fusion.

[0107] As a preferred embodiment, the present invention also provides a preferred method for the above use, wherein the disease or disorder caused by the disruption of the expression, activity or level of the RET gene, RET kinase protein, or any one or more thereof is cancer or cancer metastasis.

[0108] As a preferred embodiment, the present invention also provides a preferred method for the above use, wherein the disease or disorder caused by the disruption of the expression, activity or level of the RET gene, RET kinase protein, or any one thereof is selected from one or more of the following diseases: Lung cancer, papillary thyroid cancer, medullary thyroid carcinoma, differentiated thyroid cancer, recurrent thyroid cancer, poorly differentiated thyroid cancer, multiple endocrine neoplasia type 2A or type 2B (MEN2A or MEN2B, respectively), chromaffin tumor, parathyroid hyperplasia, breast cancer, colorectal cancer, papillary renal cell carcinoma, gastrointestinal mucosal ganglioneuroma (MEN2A or MEN2B, respectively), chromaffin tumor, parathyroid hyperplasia, breast cancer, colorectal cancer, papillary renal cell carcinoma, gastrointestinal mucosal ganglioneuroma, and combinations thereof.

[0109] The present invention also provides a method for treating, preventing, or preventing a disease or condition mediated by RET activity, the method comprising: (1) determining whether the disease or disorder is associated with a disruption in the expression, activity, or level of the RET gene, RET kinase, or any one or more thereof; (2) If it is determined that the disease or disorder is associated with a disorder in the expression, activity, or level of the RET gene, RET kinase, or any one or more thereof, administering to the patient an effective amount of a compound provided by the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided by the present invention.

[0110] As a preferred embodiment, the present invention also provides a preferred method for treating the above-mentioned disease or condition mediated by RET activity, wherein the disease or condition is cancer and / or cancer metastasis.

[0111] As a preferred embodiment, the present invention also provides a preferred version of the above-mentioned treatment method, in which one or more points in the RET gene are mutated to result in the translation of a RET protein with one or more amino acid substitutions at one or more of the following amino acid positions: 2, 3, 4, 5, 6, 7, 8, 11, 12, 13, 20, 32, 34, 40, 56, 64, 67, 114, 136, 145, 180, 200, 292, 294, 321, 330, 338, 360, 373, 393, 423, 432, 446, 505, 506, 510, 511, 513, 515, 525, 531, 532 , 533, 550, 591, 593, 595, 600, 602, 603, 606, 609, 611, 616, 618, 619, 620, 623, 624, 630, 631, 632, 633, 634, 635, 636, 640, 641, 648, 649, 664, 665, 666, 675, 686, 689, 691, 694 , 700, 706, 713, 732, 736, 748, 750, 765, 766, 768, 769, 770, 771, 777, 778, 781, 788, 790, 791, 802, 804, 805, 806, 810, 818, 819, 823, 836, 841, 843, 844, 848, 852, 865, 870, 873 , 876, 881, 882, 883, 884, 886, 891, 897, 898, 900, 901, 904, 905, 907, 908, 911, 912, 918, 919, 921, 922, 930, 961, 972, 981, 982, 1009, 1015, 1017, 1041, 1062, 1064 and 1096.

[0112] As a preferred embodiment, the present invention also provides a preferred version of the above-mentioned treatment method, in which one or more points in the RET gene are mutated to result in the translation of a RET protein with one or more amino acid substitutions at one or more of the following amino acid positions: 32, 34, 40, 56, 64, 67, 114, 145, 292, 321, 330, 338, 360, 393, 423, 446, 510, 511, 513, 515, 525, 531, 532, 533, 550, 591, 593, 595, 600, 602, 603, 606, 609, 6 11, 616, 618, 619, 620, 623, 624, 630, 631, 632, 634, 635, 636, 640, 641, 648, 649, 664, 665, 666, 675, 686, 689, 691, 694, 700, 706, 713, 732, 736, 748, 750, 765, 766, 768, 769, 770, 771, 777, 778, 781, 788, 790, 791, 804, 805, 806, 810, 818, 819, 823, 826, 833, 836, 841, 843, 844, 848, 852, 865, 870, 873, 876, 881 , 883, 884, 886, 891, 897, 898, 900, 901, 904, 905, 907, 908, 911, 912, 918, 919, 921, 922, 930, 961, 972, 981, 982, 1009, 1015, 1017, 1041, 1064 and 1096.

[0113] In a preferred embodiment, the present invention also provides a preferred version of the above-mentioned treatment method, in which one or more points in the RET gene are mutated, leading to the translation of a RET protein containing one or more of the following amino acid substitutions: S32L、D34S、L40P、 L56M、P64L、 R67H、 R114H、V145G、 V292M、 G321R、R330Q、 T338I、 R360W、F393L、 G423R、 G446R、A510V、 E511K、 G513D、C515S、 C515W、 R525W、C531R、 G533C、 G533S、G550E、 V591I、 G593E、E595D、 E595A、 R600Q、I602V、 K603Q、 K603E、Y606C、 C609C、 C609Y、C609S、 C609G、 C609R、C609F、 C609W、 C611R、C611S、 C611G、 C611Y、C611F、 C611W、 E616Q、C618S、 C618Y、 C618R、C618G、 C618F、 C618W、F619F、 C620S、 C620W、C620R、 C620G、 C620L、C620Y、 C620F、 E623K、D624N、 C630A、 C630R、C630S、 C630Y、 C630F、C630W、 D631N、 D631Y、D631A、 D631G、 D631V、D631E、 E632K、 E632G、C634W、 C634Y、 C634S、C634R、 C634F、 C634G、C634L、 C634A、 C634T、R635G、 T636P、 T636M、A640G、 A641S、 A641T、V648I、 S649L、 A664D、H665Q、 K666E、 K666M、K666N、 K666R、 T675T S686N、S689T、 G691S、 R694Q、M700L、 V706M、 V706A、E713K、 E732K、 G736R、G748C、 A750P、 S765P、P766S、 P766M、 E768Q、E768D、 L769L、 R770Q、D771N、 N777S、 V778I、Q781R、 I788I、 L790F、Y791F、 Y791N、 V804L、V804M、 V804E、 E805K、Y806E、 Y806F、 Y806S、Y806G、 Y806C、 Y806H、Y806N、 Y806Y、 G810R、G810S、 G810A、 E818K、S819I、 G823E、 Y826M、Y826S、 R833C、S836S, P841L, P841P, E843D, R844W, R844Q, R844L, M848T, I852M, L865V, L870F, R873W, A876V, L881V, A883F, A883S, A883T, E884K, R886W, S891A, S891S, R897Q, D898V, Y900F, E901K, S904F, S904S, S904C, Y905F, K907E, K907M, R908K, G911D, R912P, R912Q, M918T, M918V, M918L, A919V, E921K, S922P, S922Y, T930M, F961L, R972G, Y981F, R982C, Ml009V, Y1015F, D1017N, V1041G, M1064T and Y1096F.

[0114] As a preferred embodiment, the present invention also provides a preferred method of the above-mentioned treatment method, in which the mutation at one or more points in the RET gene occurs in one or more exons 10, 11, 13, 14, 15 and 16 of the human RET gene.

[0115] As a preferred embodiment, the present invention also provides a preferred method of treatment, wherein the RET gene fusion is selected from the following: BCR-RET, CLIP 1-RET, KIF5B-RET, CCDC6-RET, NCOA4-RET, TRIM33-RET, ERC1-RET, FGFR1OP-RET, RET-MBD1, RET-RAB61P2, RET-PRKAR1A, RET-TRIM24, RET-GOLGA5, HOOGA5. KIAA1217-RET, MPRIP-RET, HRH4-RET, RIA-RET, RET-PTC4, FRMD4A-RET, SQSTM1-RET, AFAP1L2-RET , PPFIBP2-RET, EML4-RET, PARD3-RET, MYH10-RET, HTIF1 / RET, AFAP1-RET, RASGEF1A-RET, TEL-RET.

[0116] In a preferred embodiment, the present invention also provides a preferred method of treatment as described above, wherein the RET gene, RET kinase protein, or any one or more mutations, expression, activity or levels thereof are disrupted by a RET gene fusion.

[0117] As a preferred embodiment, the present invention also provides a preferred method for treating the above-mentioned disease, wherein the disease mediated by RET activity is selected from one or more of the following diseases: Lung cancer, papillary thyroid cancer, medullary thyroid carcinoma, differentiated thyroid cancer, recurrent thyroid cancer, poorly differentiated thyroid cancer, multiple endocrine neoplasia type 2A or type 2B (MEN2A or MEN2B, respectively), chromaffin tumor, parathyroid hyperplasia, breast cancer, colorectal cancer, papillary renal cell carcinoma, gastrointestinal mucosal ganglioneuroma (MEN2A or MEN2B, respectively), chromaffin tumor, parathyroid hyperplasia, breast cancer, colorectal cancer, papillary renal cell carcinoma, gastrointestinal mucosal ganglioneuroma, and combinations thereof.

[0118] The present invention provides compounds of Formula I, their stereoisomers, racemates, tautomers, isotopic markers, nitrogen oxides, or pharmaceutically acceptable salts:

[0119] [ka]

[0120] Among them, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 are homologous or different, each independently CR 1 or selected from N; X 8 is CR 1 R 1’ or NR 1 Selected from; Among them, R 1 and R 1’ are identical or different, each independently H, halogen, CN, OH, unsubstituted or optionally one, two or more Ra The following groups substituted with: C 1-40 Alkyl group, C 2-40 Alkenyl group, C 2-40 Alkynyl group, C 3-40 Cyclic alkyl group, C 3-40 Ring alkenyl group, C 3-40 Ring alkynyl group, C 1-40 Alkyloxy group, C 2-40 Alkenyloxy group, C 2-40 Alkynyloxy group, C 3-40 Cyclic alkyloxy group, C 3-40 Ring alkenyl group, oxy group, C 3-40 Ring alkynyl group, oxy group, NR 2 R 3 , -C(O)R 4 , -OCR 5 , -S(O)2R 6 , OS(O)2R 7 Selected from; A is H, halogen, CN, OH, NH, unsubstituted or optionally substituted with one, two or more R b The following groups substituted with: 1-40 Alkyl group, C 2-40 Alkenyl group, C 2-40 Alkynyl group, C 3-40 Cyclic alkyl group, C 3-40 Ring alkenyl group, C 3-40 Ring alkynyl group, C 1-40 Alkyloxy group, C 2-40 Alkenyloxy group, C 2-40 Alkynyloxy group, C 3-40 Cyclic alkyloxy group, C 3-40 Ring alkenyl group, oxy group, C 3-40 Ring alkynyl group, oxy group, NR 2 R 3 , -C(O)R 4 , -OCR 5 , -S(O)2R 6 , OS(O)2R 7 Selected from; D and E are the same or different and each independently represents H, halogen, CN, OH, -OR 21 , unsubstituted or optionally containing one, two or more R cThe following groups substituted with: C 1-40 Alkyl group, C 2-40 Alkenyl group, C 2-40 Alkynyl group, C 3-40 Cyclic alkyl group, C 3-40 Ring alkenyl group, C 3-40 Ring alkynyl group, C 6-20 aryl group, 5-20 membered heteroaryl group, 3-20 membered heterocyclic group, and NH2, provided that at least one of D and E is -OR 21 Selected from; R 21 is H, unsubstituted or optionally containing one, two or more R d The following groups substituted with: C 1-40 Alkyl group, C 2-40 Alkenyl group, C 2-40 Alkynyl group, C 3-40 Cyclic alkyl group, C 3-40 Ring alkenyl group, C 3-40 Ring alkynyl group, C 6-20 selected from an aryl group, a 5- to 20-membered heteroaryl group, and a 3- to 20-membered heterocyclic group; G is unsubstituted or optionally contains one, two or more R e The following groups substituted with: C 3-40 Cyclic alkyl group, C 3-40 Ring alkenyl group, C 3-40 Ring alkynyl group, C 6-20 Aryl group, 5-20 membered heteroaryl group, 3-20 membered heterocyclic group, C 3-40 Cyclic alkyloxy group, C 3-40 Ring alkenyl group, oxy group, C 3-40 Ring alkynyl group, oxy group, C 6-20 selected from an aryloxy group, a 5- to 20-membered heteroaryloxy group, and a 3- to 20-membered heterocyclicoxy group; K is unsubstituted or optionally contains one, two or more R f The following groups substituted with: H, halogen, CN, OH, unsubstituted or optionally 1, 2 or more R g The following groups substituted with: C 1-40 Alkyl group, C2-40 Alkenyl group, C 2-40 Alkynyl group, C 3-40 Cyclic alkyl group, C 3-40 Ring alkenyl group, C 3-40 Ring alkynyl group, C 6-20 Aryl group, 5-20 membered heteroaryl group, 3-20 membered heterocyclic group, C 1-40 Alkyloxy group, C 2-40 Alkenyloxy group, C 2-40 Alkynyloxy group, C 3-40 Cyclic alkyloxy group, C 3-40 Ring alkenyl group, oxy group, C 3-40 Ring alkynyl group, oxy group, C 6-20 Aryloxy group, 5-20 membered heteroaryloxy group, 3-20 membered heterocyclic oxy group, NR 2 R 3 , -C(O)R 4 , -OCR 5 , -S(O)2R 6 , OS(O)2R 7 Selected from; Each R 2 are homologous or different, each independently H, C 1-40 Alkyl group, C 2-40 Alkenyl group, C 2-40 Alkynyl group, C 3-40 Cyclic alkyl group, C 3-40 Ring alkenyl group, C 3-40 Ring alkynyl group, C 6-20 Aryl group, 5-20 membered heteroaryl group, 3-20 membered heterocyclic group, -C(O)R 4 , -S(O)2R 6 Selected from; Each R 3 are homologous or different, each independently H, C 1-40 Alkyl group, C 2-40 Alkenyl group, C 2-40 Alkynyl group, C 3-40 Cyclic alkyl group, C 3-40 Ring alkenyl group, C 3-40 Ring alkynyl group, C 6-20 Aryl group, 5-20 membered heteroaryl group, 3-20 membered heterocyclic group, -C(O)R 4 , -S(O)2R 6 Selected from; Or R 2 and R 3 forms, together with the N atom to which it is attached, a 5- to 20-membered heteroaryl group or a 3- to 20-membered heterocyclic group; Each R 4 are homologous or different, each independently H, C 1-40 Alkyl group, C 2-40 Alkenyl group, C 2-40 Alkynyl group, C 3-40 Cyclic alkyl group, C 3-40 Ring alkenyl group, C 3-40 Ring alkynyl group, C 6-20 Aryl group, 5-20 membered heteroaryl group, 3-20 membered heterocyclic group, C 1-40 Alkyloxy group, C 2-40 Alkenyloxy group, C 2-40 Alkynyloxy group, C 3-40 Cyclic alkyloxy group, C 3-40 Ring alkenyl group, oxy group, C 3-40 Ring alkynyl group, oxy group, C 6-20 Aryloxy group, 5-20 membered heteroaryloxy group, 3-20 membered heterocyclic oxy group, NR 2 R 3 Selected from; Each R 5 are homologous or different, each independently H, C 1-40 Alkyl group, C 2-40 Alkenyl group, C 2-40 Alkynyl group, C 3-40 Cyclic alkyl group, C 3-40 Ring alkenyl group, C 3-40 Ring alkynyl group, C 6-20 Aryl group, 5-20 membered heteroaryl group, 3-20 membered heterocyclic group, C 1-40 Alkyl carbonyl, C 2-40 Alkenyl carbonyl, C 2-40 Alkynyl carbonyl, C 3-40 Ring alkyl carbonyl, C 3-40 Ring alkenyl carbonyl, C 3-40 Ring alkynyl carbonyl, C 6-20 selected from aryl carbonyl, 5- to 20-membered heteroaryl carbonyl, and 3- to 20-membered heterocyclic carbonyl; Each R 6 are homologous or different, each independently H, C 1-40 Alkyl group, C 2-40 Alkenyl group, C 2-40 Alkynyl group, C 3-40 Cyclic alkyl group, C 3-40 Ring alkenyl group, C 3-40 Ring alkynyl group, C 6-20 Aryl group, 5-20 membered heteroaryl group, 3-20 membered heterocyclic group, C 1-40 Alkyloxy group, C 2-40 Alkenyloxy group, C 2-40 Alkynyloxy group, C 3-40 Cyclic alkyloxy group, C 3-40 Ring alkenyl group, oxy group, C 3-40 Ring alkynyl group, oxy group, C 6-20 Aryloxy group, 5-20 membered heteroaryloxy group, 3-20 membered heterocyclic oxy group, NR 2 R 3 Selected from; Each R 7 are homologous or different, each independently H, C 1-40 Alkyl group, C 2-40 Alkenyl group, C 2-40 Alkynyl group, C 3-40 Cyclic alkyl group, C 3-40 Ring alkenyl group, C 3-40 Ring alkynyl group, C 6-20 selected from an aryl group, a 5- to 20-membered heteroaryl group, and a 3- to 20-membered heterocyclic group; Each R a , R b , R c , R d , R e , R f are the same or different, each independently halogen, CN, OH, SH, oxo (=O), NO2, unsubstituted or optionally one, two or more R g The following groups substituted with: 1-40 Alkyl group, C 2-40 Alkenyl group, C 2-40 Alkynyl group, C 3-40 Cyclic alkyl group, C 3-40 Ring alkenyl group, C 3-40 Ring alkynyl group, C6-20 Aryl group, 5-20 membered heteroaryl group, 3-20 membered heterocyclic group, C 1-40 Alkyloxy group, C 2-40 Alkenyloxy group, C 2-40 Alkynyloxy group, C 3-40 Cyclic alkyloxy group, C 3-40 Ring alkenyl group, oxy group, C 3-40 Ring alkynyl group, oxy group, C 6-20 Aryloxy group, 5-20 membered heteroaryloxy group, 3-20 membered heterocyclic oxy group, NR 2 R 3 , -C(O)R 4 , -OCR 5 , -S(O)2R 6 , OS(O)2R 7 Selected from; Each R g are the same or different, each independently halogen, CN, OH, SH, oxo (=O), NO2, unsubstituted or optionally one, two or more R h The following groups substituted with: 1-40 Alkyl group, C 2-40 Alkenyl group, C 2-40 Alkynyl group, C 3-40 Cyclic alkyl group, C 3-40 Ring alkenyl group, C 3-40 Ring alkynyl group, C 6-20 Aryl group, 5-20 membered heteroaryl group, 3-20 membered heterocyclic group, C 1-40 Alkyloxy group, C 2-40 Alkenyloxy group, C 2-40 Alkynyloxy group, C 3-40 Cyclic alkyloxy group, C 3-40 Ring alkenyl group, oxy group, C 3-40 Ring alkynyl group, oxy group, C 6-20 Aryloxy group, 5-20 membered heteroaryloxy group, 3-20 membered heterocyclic oxy group, NR 2 R 3 , -C(O)R 4 , -OCR 5 , -S(O)2R 6 , OS(O)2R 7 or a cyclic group (C 3-40 Cyclic alkyl group, C3-40 Ring alkenyl group, C 3-40 When different positions of a cyclic group (including but not limited to cyclic alkynyl groups, 3- to 20-membered heterocyclic groups, etc.) are substituted with two or more substituents, two of the substituents may also form a bridged ring with the cyclic group, and the bridge atoms other than the bridgehead atoms in the bridged ring may contain 1, 2, 3, 4, or 5 divalent groups selected from CH2, O, and NH; Each R h are the same or different, each independently halogen, CN, OH, SH, oxo (=O), NO2, unsubstituted or optionally one, two or more R g The following groups substituted with: 1-40 Alkyl group, C 2-40 Alkenyl group, C 2-40 Alkynyl group, C 3-40 Cyclic alkyl group, C 3-40 Ring alkenyl group, C 3-40 Ring alkynyl group, C 6-20 Aryl group, 5-20 membered heteroaryl group, 3-20 membered heterocyclic group, C 1-40 Alkyloxy group, C 2-40 Alkenyloxy group, C 2-40 Alkynyloxy group, C 3-40 Cyclic alkyloxy group, C 3-40 Ring alkenyl group, oxy group, C 3-40 Ring alkynyl group, oxy group, C 6-20 Aryloxy group, 5-20 membered heteroaryloxy group, 3-20 membered heterocyclic oxy group, NR 2 R 3 , -C(O)R 4 , -OCR 5 , -S(O)2R 6 , OS(O)2R 7 Selected from; Or, a cyclic group (C 3-40 Cyclic alkyl group, C 3-40 Ring alkenyl group, C 3-40When different positions of a cyclic group (including, but not limited to, a cyclic alkynyl group, a 3- to 20-membered heterocyclic group, etc.) are substituted with two or more substituents, two of the substituents may also form a bridged ring with the cyclic group, and the bridge atoms other than the bridgehead atoms in the bridged ring may contain 1, 2, 3, 4 or 5 divalent groups selected from CH2, O, and NH; Or, when one atom (for example: carbon atom) is substituted with two or more substituents, two of the above substituents together with the atom to which it is connected form a cyclic group (C 3-40 Cyclic alkyl group, C 3-40 Ring alkenyl group, C 3-40 The aryl group may form a heterocyclic ring (including, but not limited to, alkynyl groups, 3- to 20-membered heterocyclic groups).

[0121] In the embodiment of the present invention, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 are homologous or different, each independently CR 1 or N; for example, X 1 ,X 2 ,X 3 ,X 4 , X 5 , X 6 , X 7 at least one of which is N, for example 1, 2, 3, 4, 5, 6 or 7 of which are N; In the embodiment of the present invention, X 8 is CR 1 R 1’ or NR 1 Selected from; In the embodiment of the present invention, each R 1 and R 1’ are the same or different, each independently H, halogen, CN, OH, C 1-6 Alkyl group, C 3-10 Cyclic alkyl group, C 1-6 selected from alkyloxy groups; In the embodiment of the present invention, A is H, halogen, CN, OH, C 1-6 Alkyl group, C 1-6selected from alkyloxy groups; In the embodiment of the present invention, D and E are the same or different, and each independently represent H, halogen, CN, NH or -OR. 21 The condition is that at least one of D and E is -OR 21 Selected from; In the embodiment of the present invention, R 2 is unsubstituted or optionally contains one, two or more R d C replaced by 1-6 selected from alkyl groups; In the embodiment of the present invention, each R a , R b , R c , R d , R e , R f are identical or different, each independently halogen, CN, OH, unsubstituted or optionally one, two or more R g The following groups substituted with: C 1-6 Alkyl group, C 1-6 Alkyloxy group, C 3-10 Cyclic alkyl group, C 3-10 selected from cyclic alkyl groups and oxy groups; In the embodiment of the present invention, each R g are the same or different, each independently a halogen or C 3-10 selected from cyclic alkyl groups; In the embodiment of the present invention, G is C 3-10 Cyclic alkyl group, C 6-14 It is selected from an aryl group, a 5- to 14-membered heteroaryl group, and a 3- to 10-membered heterocyclic group, such as a 6- to 7-membered monocyclic, bicyclic, or bridged heterocyclic group, which may contain 1, 2, or 3 heteroatoms independently selected from N, O, and S; In an embodiment of the present invention, K is -C 1-6 Alkyl group-C 3-10 Cyclic alkyl group, -C 1-6 Alkyl group-C 6-14 Aryl group, -C 1-6 alkyl group, 5-14 membered heteroaryl group, -C 1-6Alkyl group -3-10 membered heterocyclic group, -C(O)NH2, -C(O)-C 3-10 Cyclic alkyl group, -C(O)-C 6-14 Aryl group, -C(O)-5-14 membered heteroaryl group, -C(O)-3-10 membered heterocyclic group, -C(O)-C 1-6 Alkyl group-C 3-10 Cyclic alkyl group, -C(O)-C 1-6 Alkyl group-C 6-14 Aryl group, -C(O)-C 1-6 Alkyl group - 5-14 membered heteroaryl group, -C(O)-C 1-6 alkyl group-3-10 membered heterocyclic group, among which the above C 3-10 Cyclic alkyl group, C 6-14 Aryl group, 5-14 membered heteroaryl group, 3-10 membered heterocyclic group, -C(O)-C 3-10 Cyclic alkyl group, -C(O)-C 6-14 Aryl group, -C(O)-5-14 membered heteroaryl group, -C(O)-3-10 membered heterocyclic group, -C(O)-C 1-6 Alkyl group-C 3-10 Cyclic alkyl group, -C(O)-C 1-6 Alkyl group-C 6-14 Aryl group, -C(O)-C 1-6 Alkyl group - 5-14 membered heteroaryl group, -C(O)-C 1-6 alkyl group - selected from cyclic or non-cyclic groups of 3-10 membered heterocyclic groups, or -C(O)NH2 may further optionally contain one, two or more OH, halogen, CN, C 1-6 Alkyl group, C 1-6 The heterocyclic group may be a pyridine 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.

[0122] In the exemplary embodiment of the present invention, 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7are identical or different and are each 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 which is N, for example, 1, 2, 3, 4, 5, 6, or 7 of which is N; In an exemplary embodiment of the present invention, X 8 is NR 1 Selected from; In an exemplary embodiment of the present invention, R 1 is H; In exemplary embodiments of the present invention, A is selected from H, NH, methyl, ethyl, propyl, and isopropyl; In an exemplary embodiment of the present invention, E is H; In an exemplary embodiment of the present invention, D is selected from the following groups: Halogen, BnO-, H, CN, NH2, OCH3,

[0123] [ka]

[0124] ; In an exemplary embodiment of the present invention, G is

[0125] [ka]

[0126] Selected from; In an exemplary embodiment of the present invention, K is

[0127] [ka]

[0128] Selected from; In an embodiment of the present invention, the compound has the structure shown in the following formula:

[0129] [ka]

[0130] Among them, X 1 , X 2 , X 3 , X 4 , X 5 , A, D, E, G, and K have the definitions set forth above.

[0131] Illustratively, the compound of formula I is selected from the following compounds:

[0132] [ka]

[0133] TIFF0007732668000020.tif128169

[0134] .

[0135] The present invention also provides a method for preparing a compound of formula I, comprising the steps of: Compound of Formula I-1 and Compound R 21 -L may be reacted to prepare compounds of formula I:

[0136] [ka]

[0137] Among them, A, D, E, G, K, and X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , R 21 has the definition set forth above; L is selected from leaving groups.

[0138] In an embodiment of the present invention, the leaving group is selected from halogen or OTf.

[0139] In the practice of the present invention, the reaction is carried out in the presence of an alkali, for example potassium carbonate.

[0140] In the embodiment of the present invention, the reaction temperature is 50-100°C, and the reaction time is 1-24 hours.

[0141] In the practice of the present invention, the reaction can be carried out in the presence of an organic solvent (for example: DMF).

[0142] The present invention further provides a method for preparing a compound of formula I-1, including the preparation of a compound of formula I-1 from a compound of formula I-2:

[0143] [ka]

[0144] Among them, A, D, E, G, K, and X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 has the definition given above.

[0145] In an embodiment of the present invention, the reaction is carried out in the presence of hydrazine hydrate, and X 7 is N and X 8 is NH.

[0146] In the practice of the present invention, the reaction is carried out in the presence of an organic solvent (eg, DMF).

[0147] In the present invention, the reaction is carried out under heating conditions.

[0148] The present invention further provides compounds of formula I-1 or I-2:

[0149] [ka]

[0150] The present invention further provides the use of a compound of formula I-1 or I-2 in the production of a compound of formula I.

[0151] The present invention further provides pharmaceutical compositions comprising a therapeutically effective amount of at least one of a compound of Formula I, its stereoisomers, racemates, tautomers, isotopic markers, nitroxides, or pharmaceutically acceptable salts.

[0152] In an embodiment of the present invention, the pharmaceutical composition further comprises one, two or more pharmaceutically acceptable carriers or excipients.

[0153] In some embodiments of the present invention, the pharmaceutical composition further comprises one or more other therapeutic agents.

[0154] Also provided herein is a method for inhibiting cell proliferation in vitro or in vivo, comprising contacting a cell with an effective amount of a compound of Formula I according to the present invention, a stereoisomer, a racemate, a tautomer, an isotopic marker, a nitroxide, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0155] The present invention also provides a method for treating a disease mediated by RET kinase, comprising administering to a patient a therapeutically effective amount of at least one of a compound of Formula I, its stereoisomers, racemates, tautomers, isotopic markers, nitroxides, and pharmaceutically acceptable salts.

[0156] The present invention also provides a method for treating a RET-related disease or condition in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound of Formula I of the present invention, its stereoisomer, racemate, tautomer, isotopic marker, nitroxide, pharmaceutically acceptable salt, or pharmaceutical composition thereof.

[0157] Also provided herein are methods for treating cancer and / or inhibiting metastasis associated with certain cancers in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound of Formula I of the present invention, its stereoisomer, racemate, tautomer, isotopic marker, nitroxide, pharmaceutically acceptable salt, or pharmaceutical composition thereof.

[0158] The present invention also provides a method for treating irritable bowel syndrome (IBS) and / or pain associated with IBS in a patient in need of such treatment, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula I of the present invention, its stereoisomer, racemate, tautomer, isotopic marker, nitroxide, pharmaceutically acceptable salt, or pharmaceutical composition thereof.

[0159] The present invention also provides a method of supportive care for cancer patients, including preventing or minimizing gastrointestinal disorders (e.g., diarrhea) associated with treatment (including chemotherapy), comprising administering to the patient a therapeutically effective amount of a compound of Formula I of the present invention, its stereoisomer, racemate, tautomer, isotopic marker, nitroxide, pharmaceutically acceptable salt, or pharmaceutical composition thereof.

[0160] The present invention also provides the use of at least one of the compounds of Formula I, their stereoisomers, racemates, tautomers, isotopic markers, nitroxides, and pharmaceutically acceptable salts in the manufacture of a medicament for treating a disease mediated by RET kinase.

[0161] The present invention also provides the use of at least one of the compounds of Formula I, its stereoisomers, racemates, tautomers, isotopic markers, nitroxides, and pharmaceutically acceptable salts in the manufacture of a medicament for use in treating cancer and / or inhibiting metastasis associated with certain cancers.

[0162] The present invention also provides the use of at least one of a compound of Formula I, its stereoisomers, racemates, tautomers, isotopic markers, nitroxides, and pharmaceutically acceptable salts in the manufacture of a medicament for treating irritable bowel syndrome (IBS) or pain associated with IBS.

[0163] The present invention also provides the use of at least one of a compound of Formula I, its stereoisomers, racemates, tautomers, isotopic markers, nitroxides, and pharmaceutically acceptable salts in the manufacture of a medicament for use in providing supportive care to cancer patients, including the prevention or minimization of gastrointestinal disorders associated with treatment (including chemotherapy), such as diarrhea.

[0164] The present invention also provides the use of at least one of the compounds of formula I, their stereoisomers, racemates, tautomers, isotopic markers, nitroxides, and pharmaceutically acceptable salts in the manufacture of a medicament for inhibiting RET kinase activity.

[0165] The present invention also provides the use of at least one of the compounds of Formula I, their stereoisomers, racemates, tautomers, isotopic markers, nitroxides, and pharmaceutically acceptable salts in the manufacture of a medicament for treating a RET-related disease or condition.

[0166] The present invention also provides a method for treating cancer in a patient in need thereof, said method comprising: (a) determining whether the cancer is associated with a disruption in the expression, activity, or level of the RET gene, RET kinase, or any one of them (e.g., a RET-associated cancer); (b) If the cancer is determined to be associated with a disruption in the expression, activity, or level of the RET gene, RET kinase, or any one of them (e.g., a RET-associated cancer), administering to the patient a therapeutically effective amount of at least one of a compound of Formula I, its stereoisomer, racemate, tautomer, isotopic marker, nitroxide, or pharmaceutically acceptable salt, or a pharmaceutical composition thereof.

[0167] The present invention also provides a method for reversing or preventing acquired resistance to an anticancer drug, the method comprising administering a therapeutically effective amount of at least one of a compound of Formula I, its stereoisomer, racemate, tautomer, isotopic marker, nitroxide, or pharmaceutically acceptable salt to a patient who has developed or is at risk of developing acquired resistance to an anticancer drug.

[0168] The present invention also provides a method for delaying and / or preventing the development of anticancer drug resistance in an individual patient, said method comprising administering to the individual an effective amount of at least one of a compound of Formula I, its stereoisomers, racemates, tautomers, isotopic markers, nitroxides, and pharmaceutically acceptable salts, before, during, or after the administration of an effective amount of an anticancer drug.

[0169] The present invention also provides a method of treating an individual with cancer and an increased likelihood of developing resistance to anti-cancer drugs, the method comprising co-administering to the individual (a) an effective amount of at least one of a compound of Formula I, its stereoisomers, racemates, tautomers, isotopic markers, nitroxides, or pharmaceutically acceptable salts, and (b) an effective amount of an anti-cancer drug.

[0170] The present invention further provides a method of treating an individual having a RET-associated cancer, wherein the cancer harbors one or more RET inhibitor-resistant mutations that increase the cancer's resistance to a RET inhibitor other than at least one of the compounds of Formula I, their stereoisomers, racemates, tautomers, isotopic markers, nitroxides, and pharmaceutically acceptable salts (e.g., substitutions at amino acid positions 804, 810, and 904, e.g., V804M, V804L, V804E, G810R, G810S, G810C, G810V, and S904F), the method comprising administering at least one of the compounds of Formula I, their stereoisomers, racemates, tautomers, isotopic markers, nitroxides, and pharmaceutically acceptable salts before, during, or after administration of another anticancer drug.

[0171] The present invention further provides a method of treating an individual with a RET-associated cancer, the method comprising administering at least one of a compound of Formula I, its stereoisomers, racemates, tautomers, isotopic markers, nitroxides, and pharmaceutically acceptable salts, before, during, or after administration of another type of anti-cancer drug.

[0172] The present invention provides a method for treating cancer (e.g., RET-associated cancer) in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of at least one compound of Formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. <Terms and definitions> Unless otherwise specified, the definitions of groups and terms described in the specification and claims of this application, including illustrative definitions, exemplary definitions, preferred definitions, definitions given in tables, definitions of specific compounds in the examples, etc., can be arbitrarily combined or linked with each other. The group definitions and compound structures after such combinations or linkages are to be considered within the scope of the specification of this application.

[0173] Unless otherwise specified, the numerical ranges described in this specification and claims are equivalent to reciting at least each specific integer value. For example, the numerical range "1-40" is equivalent to reciting each integer value in the numerical range "1-10," i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and each integer value in the numerical range "11-40," i.e., 11, 12, 13, 14, 15, ..., 35, 36, 37, 38, 39, 40. It should be understood that when describing substituents in this specification, "more," as used in the context of 1, 2, or more, refers to an integer equal to or greater than 3, including 3, for example, 3, 4, 5, 6, 7, 8, 9, or 10.

[0174] The term "halogen" refers to fluorine, chlorine, bromine and iodine.

[0175] "C 1-40 The term "alkyl group" should be understood to denote preferentially linear or branched saturated monovalent hydrocarbon groups having 1-40 carbon atoms, for example: "C 1-6 The term "alkyl group" refers to a straight or branched chain alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms. Examples of the alkyl group include methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, and 1,2-dimethylbutyl, and isomers thereof.

[0176] "C 2-40The term "alkenyl group" should be understood to denote preferentially a linear or branched monovalent hydrocarbyl, which contains one or more double bonds and has 2-40 carbon atoms, preferably "C 2-6 "C alkenyl group." 2-6 An "alkenyl group" is to be understood to denote preferentially a linear or branched monovalent hydrocarbyl group, which contains one or more double bonds and has 2, 3, 4, 5 or 6 carbon atoms, in particular 2 or 3 carbon atoms ("C 2-3It is understood that when the alkenyl group contains one or more double bonds, the double bonds may be separated or conjugated with each other. Examples of the alkenyl group include vinyl, allyl, (E)-2-methyl vinyl, (Z)-2-methyl vinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, pent-4-enyl, (E)-pent-3-enyl, (Z)-pent-3-enyl, (E)-pent-2-enyl, (Z)-pent-2-enyl, (E)-pent-1-enyl. (Z)-pent-1-enyl, hex-5-enyl, (E)-hex-4-enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-3-enyl, (E)-hex-2-enyl, (Z)-hex-2-enyl, (E)-hex-1-enyl, (Z)-hex-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl, 2- Methylprop-1-enyl, (E)-1-methylprop-1-enyl, (Z)-1-methylprop-1-enyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, 1-methylbut-3-enyl, 3-methylbut-2-enyl, (E)-2-methylbut-2-enyl, (Z)-2-methylbut-2-enyl, (E)-1-methylbut-2-enyl, (Z)-1-methylbut (E)-2-enyl, (E)-3-methylbut-1-enyl, (Z)-3-methylbut-1-enyl, (E)-2-methylbut-1-enyl, (Z)-2-methylbut-1-enyl, (E)-1-methylbut-1-enyl, (Z)-1-methylbut-1-enyl, 1,1-dimethylprop-2-enyl, 1-ethylprop-1-enyl, 1-propylvinyl, and 1-isopropylvinyl.

[0177] "C 2-40The term "alkynyl group" is understood to denote a linear or branched monovalent hydrocarbyl group having 2-40 carbon atoms, including one or more triple bonds, preferably a "C2-C6-alkynyl group". The term "C2-C6-alkynyl group" is understood to denote preferentially a linear or branched monovalent hydrocarbyl group having 2, 3, 4, 5 or 6 carbon atoms, including one or more triple bonds, in particular 2 or 3 carbon atoms ("C2-C3-alkynyl group"). Examples of the C2-C6-alkynyl group include ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, hex-5-ynyl, 1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-3-ynyl, 1-methylbut-2-ynyl, 3-methylbut-1-ynyl, 1-ethylprop-2-ynyl, 3-methylpent-4-ynyl, 2-methyl Examples include pent-4-ynyl, 1-methylpent-4-ynyl, 2-methylpent-3-ynyl, 1-methylpent-3-ynyl, 4-methylpent-2-ynyl, 1-methylpent-2-ynyl, 4-methylpent-1-ynyl, 3-methylpent-1-ynyl, 2-ethylbut-3-ynyl, 1-ethylbut-3-ynyl, 1-ethylbut-2-ynyl, 1-propylprop-2-ynyl, 1-isopropylprop-2-ynyl, 2,2-dimethylbut-3-ynyl, 1,1-dimethylbut-3-ynyl, 1,1-dimethylbut-2-ynyl, and 3,3-dimethylbut-1-ynyl. In particular, the alkynyl group is an ethynyl group, a prop-1-ynyl group or a prop-2-ynyl group.

[0178] "C 3-40The term "cyclic alkyl group" is understood to denote a saturated monovalent monocyclic, bicyclic hydrocarbon ring or bridged ring alkane, having 3-40 carbon atoms, preferably "C 3-10 "C alkyl group". 3-10 The term "cyclic alkyl group" is understood to denote a saturated monovalent monocyclic, bicyclic hydrocarbon ring or bridged ring alkane having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. 3-10 The cyclic alkyl group may be a monocyclic hydrocarbon group, such as a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl group, or a dicyclohydrocarbyl group, such as a decahydro-naphthalene ring.

[0179] The term "3- to 20-membered heterocyclic group" refers to a saturated monovalent monocyclic, bicyclic hydrocarbon ring or bridged-ring alkane, which is a non-aromatic cyclic group having a total of 3 to 20 atoms (e.g., 3, 4, 5, 6, 7, 8, 9, 10, etc.) in the ring and containing 1 to 5 heteroatoms independently selected from N, O, and S, and is preferably a "3- to 10-membered heterocyclic group." The term "3- to 10-membered heterocyclic group" refers to a saturated monovalent monocyclic, bicyclic hydrocarbon ring or bridged-ring alkane, which is a non-aromatic cyclic group having 1 to 5 heteroatoms independently selected from N, O, and S, and 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 heterocyclic group can be bonded to the remainder of the molecule through any one of the carbon atoms or the nitrogen atom (if present). In particular, the heterocyclic group includes, but is not limited to, the following: four-membered rings, such as azetidinyl and oxetanyl; 5-membered rings, such as tetrahydrofuranyl, dioxy heterocyclic pentenyl, pyrrolidinyl, imidazolidinyl, pyrazolidine, pyrrolinyl; or a six-membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithiane, thiomorpholinyl, piperazine or trithiane; or 7-membered ring, such as a diazacycloheptane group. Optionally, the heterocyclic group may be benzo-fused. The heterocyclic group may be bicyclic, such as, but not limited to, a 5,5-membered ring, such as a hexahydrocyclopenta[c]pyrrole-2(1H)-group, or a 5,6-membered bicyclic ring, such as a hexahydropyrrolo[1,2-a]pyrazine-2(1H)-group. The ring containing the nitrogen atom may be partially unsaturated, i.e., it may contain one or more double bonds, such as, but not limited to, 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadiazine, 4,5-dihydrooxazole, or 4H-[1,4]thiazine, or it may be benzo-fused, such as, but not limited to, a dihydroisoquinoline group. In the present invention, the heterocyclic group is non-aromatic. When the above-mentioned 3- to 20-membered heterocyclic group is bonded to another group to form a compound of the present invention, a carbon atom on the 3- to 20-membered heterocyclic group may be bonded to another group, or a heteroatom on the ring of the 3- to 20-membered heterocyclic group may be bonded to another group. For example, when the 3- to 20-membered heterocyclic group is selected from a piperazine group, the nitrogen atom on the piperazine group may be bonded to another group. Or, when the 3- to 20-membered heterocyclic group is selected from a piperidinyl group, the nitrogen atom on the piperidinyl ring and the carbon atom on the para position thereof may be bonded to another group.

[0180] "C 6-20 The term "aryl group" is understood to denote preferentially a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 6-20 carbon atoms, and preferably "C 6-14 "C" is an aryl group. 6-14 The term "aryl group" refers to a monovalent aromatic or partially aromatic monocyclic, bicyclic, or tricyclic hydrocarbon ring having 6, 7, 8, 9, 10, 11, 12, 13, or 14 carbon atoms ("C 6-14 It is to be understood that the term "aryl group" refers preferentially to rings having 6 carbon atoms ("C6 aryl group"), such as, for example, a phenyl group; or a biphenyl group, or a ring having 9 carbon atoms ("C aryl group"), for example an indanyl or indenyl group, or a ring having 10 carbon atoms ("C 10 aryl group), such as tetrahydronaphthyl, dihydronaphthyl, or naphthyl groups, or a ring having 13 carbon atoms ("C 13 aryl group), such as a fluorenyl group, or a ring having 14 carbon atoms ("C 14 aryl group), for example, an anthranyl group. 6-20 When an aryl group is substituted, the substitution may be single or multiple, and the position of the substituent is not limited, and examples thereof include ortho-, para-, and meta-position substitution.

[0181] The term "5- to 20-membered heteroaryl group" shall be understood to include monovalent monocyclic, bicyclic, or tricyclic aromatic ring systems such as: They have 5-20 ring atoms and contain 1-5 heteroatoms independently selected from N, O and S, for example, "5-14 membered heteroaryl group." The term "5-14 membered heteroaryl group" is to be understood to include monovalent monocyclic, bicyclic or tricyclic aromatic ring systems having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 5 or 6 or 9 or 10 carbon atoms, and containing 1-5 heteroatoms independently selected from N, O and S, preferably 1-3 heteroatoms independently selected from N, O and S, which may in each case be benzo-fused. In particular, the heteroaryl group is selected from thienyl, furanyl, pyrrolyl, oxazole, thiazolyl, imidazolyl, pyrazole, isoxazole, isothiazolyl, oxadiazole, triazole, thiadiazole, thia-4H-pyrazole, etc., and their benzo derivatives, such as benzofuranyl, benzothiophenyl, benzoxazole, benzisoxazole, benzimidazolyl, benzotriazolyl, indazole, indole, isoindole, etc.; or pyridinyl, pyridazinyl, pyrimidine group, pyrazinyl, triazine group, etc., and benzo derivatives thereof, such as quinoline group, quinazolinyl, isoquinoline group, etc.; or azocinyl, indolizine, purine groups, etc. and their benzo derivatives; Examples of the 5-20-membered heteroaryl group include cinnoline, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridine, pteridinyl, carbazole, azetidinyl, phenazinyl, phenothiazine, and phenoxazine. When the 5-20-membered heteroaryl group is bonded to another group to form a compound of the present invention, a carbon atom on the 5-20-membered heteroaryl ring may be bonded to another group, or a heteroatom on the 5-20-membered heteroaryl ring may be bonded to another group. When the 5-20-membered heteroaryl group is substituted, it may be single-substituted or multi-substituted. The position of the substitution is not limited; for example, a hydrogen atom bonded to a carbon atom on the heteroaryl ring may be substituted, or a hydrogen atom bonded to a heteroatom on the heteroaryl ring may be substituted.

[0182] Unless otherwise specified, the heterocyclic group, heteroaryl group or heteroarylidene includes all possible isomeric forms, for example positional isomers. Thus, some illustrative, non-limiting examples include substitution or bonding at one, two or more positions in the 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, etc. positions (if present) of the thienyl or thiophene subunits, including thienyl-2-, thiophene subunit-2-, thienyl-3-, and thiophene subunit-3-, pyrazole-1-, pyrazole-3-, pyrazole-4-, and pyrazole-5- groups. The term "oxo" refers to an oxy group (=O) formed by oxidation of a carbon, nitrogen, or sulfur atom in a substituent. Unless otherwise stated, the definitions of terms used in this text apply equally to groups containing those terms, e.g., C 1-6 The definition of alkyl group is C 1-6 Alkyloxy group, -N(C 1-6 alkyl group)2, -NHC 1-6 Alkyl group or -S(O)2-C 1-6 This also applies to alkyl groups, etc. As will be understood by those skilled in the art, the compounds of Formula I can exist in various pharmaceutically acceptable salt forms. If these compounds contain a basic center, they can form acid addition salts; if these compounds contain an acid center, they can form base addition salts. If these compounds contain both an acid center (e.g., carboxyl) and a basic center (e.g., amino group), they can also form internal salts. The compounds of the present invention may exist in the form of solvates (e.g., hydrates), in which the compounds of the present invention contain polar solvents as structural elements of the compound crystal lattice, in particular water, methanol or ethanol. The amount of polar solvent, in particular water, may be present in a stoichiometric or non-stoichiometric ratio. Based on their molecular structure, the compounds of the present invention may be chiral and therefore may exist in various enantiomeric forms. Therefore, these compounds may exist in racemic or optically active forms. The compounds of the present invention or their intermediates can be separated into enantiomeric compounds by chemical or physical methods known to those skilled in the art, or used in synthesis in this form. In the case of racemic amines, diastereomers can be prepared from the mixture by reaction with an optically active resolving agent. Examples of suitable resolving agents include optically active acids, such as R and S tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, citric acid, lactic acid, appropriate N-protected amino acids (e.g., N-benzoylproline or N-phenylsulfonylproline), or various optically active camphorsulfonic acids. Enantiomer separation can also be performed using optically active resolving agents (e.g., dinitrobenzoylphenylglycine, cellulose triacetate, or other carbohydrate derivatives or chiral derivatized methacrylate polymers immobilized on silica gel), or by chromatography. Suitable eluents for this purpose are solvent mixtures containing water or alcohols, for example hexane / isopropanol / acetonitrile. The term "tautomer" refers to an isomer of a functional group resulting from the rapid movement of one atom between two positions within a molecule. The compounds of the present invention may exhibit tautomerism. Tautomeric compounds have two or more interconvertible species. Prototropic tautomers result from the migration of a covalently bonded hydrogen atom between two atoms. Tautomers generally exist in equilibrium, and attempts to separate a single tautomer usually produce a mixture whose physical and chemical properties are consistent with the mixture of compounds. The position of equilibrium is determined by the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones, such as acetaldehyde, the ketone form predominates, while in phenol, the enol form predominates. The present invention encompasses all tautomeric forms of the compounds. The corresponding stable isomers are separated by known methods, such as extraction, filtration, column chromatography, etc. The term "patient" refers to any animal, including a mammal, preferably a mouse, rat, other rodent, rabbit, dog, cat, pig, cow, sheep, horse or primate, and most preferably a human. As used herein, the term "therapeutically effective amount" refers to an amount of an active compound or pharmaceutical agent that elicits the biological or medical response in a tissue, system, animal, individual, or human that a researcher, veterinarian, physician, or other clinician is looking for, and includes one or more of the following: (1) disease prevention: e.g., preventing a disease, imbalance, or condition in an individual who is susceptible to the disease or imbalance or condition, but who has not yet experienced or manifested the disease pathology or condition; (2) disease suppression: e.g., inhibiting a disease, imbalance, or condition (i.e., preventing further development of the pathology and / or condition) in an individual who is experiencing or manifesting the pathology or condition of the disease, imbalance, or condition; or (3) disease mitigation: alleviating a disease, imbalance, or condition (i.e., reversing the pathology and / or condition) in an individual who is experiencing or manifesting the pathology or condition of the disease, imbalance, or condition.

[0183] DESCRIPTION OF THE DRAWINGS Figure 1 shows the inhibitory effects of compounds on TT cell-derived human medullary thyroid cancer xenograft model tumors; FIG. 2 shows the inhibitory effect of compounds on Ba / F3 cell KIF5B-RET-V804M fusion xenograft model tumors.

[0184] [Effects of the Invention] The compounds of the present invention can be highly selective and / or highly effective RET inhibitors. These compounds have relatively strong inhibitory effects against the RET gatekeeper residue mutant RET V804M, the RET solvent front residue mutant G810R, and other clinically relevant RET mutants and wild-type RET. The compounds also significantly inhibit the proliferation of thyroid cancer-derived TT cell lines and Ba / F3 cells transformed with various RET mutants, with favorable inhibitory effects. Furthermore, the compounds significantly block cellular RET autophosphorylation and its downstream pathways, significantly inducing TT cell death. Furthermore, the compounds of representative examples of the present invention have particularly excellent pharmacokinetic properties, and when used as active ingredients, they can be administered to patients at relatively low doses, thereby reducing the cost of treatment for patients.

[0185] [Method of implementing the invention] The technical solution of the present invention will be described in more detail below with reference to specific examples. It should be understood that the following examples are merely for illustrative purposes and are not to be construed as limiting the scope of the present invention. Any technology realized based on the above content of the present invention is within the scope of the present invention. Unless otherwise specified, all raw materials and reagents used in the following examples are commercially available products or can be prepared by known methods. Example 1

[0186] 6-(2-methoxyethoxy)-4-(6-(6-((6-methoxypyridine-3-)methylene)-3,6-diazabicyclo[3.3.1]heptane-3-)pyridine-3-amino)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-3-amino (Compound 1) Step A: 2-Fluoro-6-hydroxyl-4-(6-(6-((6-methoxypyridine-3-yl)methylene)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridine-3-yl)pyrazole[1,5-a]pyridine-3-carbaldehydeoxy group

[0187] [ka]

[0188] To a solution of 2-fluoro-6-hydroxyl-4-(6-(6-((6-methoxypyridine-3-yl)methylene)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridine-3-yl)pyrazole[1,5-a]pyridine-3-carbaldehyde (100 mg, 0.21 mmol) in ethanol (5.0 mL) was added hydroxylamine hydrochloride (15 mg, 0.21 mmol), heated to reflux for 12 h, and then concentrated directly for use in the next reaction. Step B: 2-fluoro-6-hydroxyl-4-(6-(6-((6-methoxypyridine-3-)methylene)-3,6-diazabicyclo[3.3.1]heptane-3-)pyridine-3-)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-3-acetonitrile

[0189] [ka]

[0190] Acetic anhydride (5.0 mL) was added to the 2-fluoro-6-hydroxyl-4-(6-(6-((6-methoxypyridine-3-yl)methylene)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridine-3-yl)pyrazole[1,5-a]pyridine-3-carbaldehyde oxime obtained in Step A, and the mixture was heated to 80°C and reacted for 2 hours. The reaction mixture was poured into ice water, stirred for 30 minutes, filtered, and the solid obtained was purified by column chromatography to give the product (31 mg). m / z = 472 [M+1] + . Step C: 2-fluoro-6-(2-methoxyethoxy)-4-(6-(6-((6-methoxypyridine-3-)methylene)-3,6-diazabicyclo[3.3.1]heptane-3-)pyridine-3-)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-3-acetonitrile

[0191] [ka]

[0192] To a solution of 2-fluoro-6-hydroxyl-4-(6-(6-((6-methoxypyridine-3-)methylene)-3,6-diazabicyclo[3.3.1]heptane-3-)pyridine-3-)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-3-acetonitrile (30 mg, 0.06 mmol) in DMF (2.0 mL), 2-bromoethyl methyl ether (9 mg, 0.06 mmol) and potassium carbonate (8.3 mg, 0.06 mmol) were added, heated to 80 °C, and reacted for 12 hours. Water was added, and the mixture was extracted with ethyl acetate. The combined organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to obtain the product (28 mg). 1 HNMR (400MHz, DMSO-d6) δ 8.65 (d, 1H), 8.42 (d, 1H), 8.07 (d, 1H), 7.87 (d, 1H), 7.70 (d, 1H), 7.45 (d, 1H), 6.76-6.81 (m, 2H), 4.23-4.25 (m, 2H), 3.82 (s, 3H), 3.67-3.71 (m, 7H), 3.49-3.51 (m, 5H), 2.51 (d, 1H), 1.61 (d, 1H), 1.23 (s, 1H). m / z=530[M+1] + . Step C: 6-(2-methoxyethoxy)-4-(6-(6-((6-methoxypyridine-3-)methylene)-3,6-diazabicyclo[3.3.1]heptane-3-)pyridine-3-)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-3-amino

[0193] [ka]

[0194] A solution of 2-fluoro-6-(2-methoxyethoxy)-4-(6-(6-((6-methoxypyridine-3-)methylene)-3,6-diazabicyclo[3.3.1]heptane-3-)pyridine-3-)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-3-acetonitrile (20 mg, 0.04 mmol) in DMF (2.0 mL) was added with hydrazine hydrate (0.2 mL), heated to 100 °C, and reacted for 12 hours. Water was added, and the mixture was extracted with ethyl acetate. The combined organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by reverse phase column chromatography to obtain the product trifluoroacetic acid (3.3 mg). 1 HNMR (400MHz, DMSO-d6) δ 10.51 (brs, 2H), 9.56 (s, 1H), 9.37 (s, 1H), 8.38-8.49 (m, 3H), 7.86-7.89 (m, 2H), 7.32 (d, 1H), 6.92-6.94 (m, 1H), 6.80 (d, 1H), 4.64 (m, 3H), 4.46 (d, 2H), 4.22-4.25 (m, 4H), 3.87-3.90 (m, 5H), 3.70 (s, 2H), 3.32 (s, 3H), 2.09-2.10 (m, 1H). m / z=542[M+1] + . Example 2

[0195] 6-Bromo-4-(6-(6-((6-methoxypyridine-3-)methylene)-3,6-diazabicyclo[3.3.1]heptane-3-)pyridine-3-)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (Compound 2) Step A: 4-(benzyloxy)-6-bromo-2-fluoropyrazole[1,5-a]pyridine-3-carbaldehyde

[0196] [ka]

[0197] Phosphorus oxychloride (1.0 g, 6.5 mmol) was added dropwise to a solution of 4-(benzyloxy)-6-bromo-2-fluoropyrazole[1,5-a]pyridine (380 mg, 1.2 mmol) in DMF (10 mL) at 0°C. After the addition was complete, the mixture was allowed to warm to room temperature and react overnight. The reaction mixture was poured into 100 mL of ice water, adjusted to pH 7 with 2N NaOH solution, extracted with ethyl acetate, and the combined organic phases were concentrated under reduced pressure and separated by column chromatography to obtain the product (400 mg). m / z = 350 [M+1] + . Step B: 6-Bromo-2-fluoro-4-hydroxylpyrazole[1,5-a]pyridine-3-carbaldehyde

[0198] [ka]

[0199] A mixture of 4-(benzyloxy)-6-bromo-2-fluoropyrazole[1,5-a]pyridine-3-carbaldehyde (100 mg, 0.28 mmol) and palladium on carbon (10 mg) was added to methanol (10.0 mL) at room temperature, and the mixture was purged with hydrogen gas three times using a hydrogen balloon. The mixture was then allowed to react overnight at room temperature. Water was added, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give the product. m / z = 259 [M+1] + .1 HNMR (400MHz, DMSO-d6) δ 11.96 (s, 1H), 10.03 (s, 1H), 8.76 (d, 1H), 7.13 (d, 1H). Step C: 6-Bromo-2-fluoro-3-carbaldehyde pyrazole [1,5-a] pyridine-4-trifluoroethyl sulfonate

[0200] [ka]

[0201] To a solution of 6-bromo-2-fluoro-4-hydroxypyrazole[1,5-a]pyridine-3-carbaldehyde (52 mg, 0.2 mmol) in DMF (5 mL), N-phenyl-bis(trifluoromethanesulfonimide) (71 mg, 0.2 mmol) and N,N-diisopropylethylamine (78 mg, 0.6 mmol) were added, and the mixture was allowed to react at room temperature for 12 hours. Water was added, and the mixture was extracted with ethyl acetate. The combined organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to obtain the product (85 mg). m / z = 392 [M+1] + . Step D: 6-Bromo-2-fluoro-4-(6-(6-((6-methoxypyridine-3-yl)methylene)-3,6-diazabicyclo[3.3.1]heptane-3-yl)pyridine-3-yl)pyrazole[1,5-a]pyridine-3-carbaldehyde

[0202] [ka]

[0203] The procedure is the same as in Step F of Example 7 to obtain the product (10 mg). m / z=537 [M+1] + . Step E: 6-Bromo-4-(6-(6-((6-methoxypyridine-3-)methylene)-3,6-diazabicyclo[3.3.1]heptane-3-)pyridine-3-)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine

[0204] [ka]

[0205] The procedure was the same as in Step H of Example 7 to obtain the product (5.4 mg). m / z=531 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.96 (s, 1H), 9.67 (d, 1H), 8.717 (d, 1H), 8.12-8.13 (m, 2H), 7.87-7.88 (m, 2H), 7.74 (dd, 1H), 6.92 (d, 1H), 6.71 (d, 1H), 3.74-3.88 (m, 5H), 3.72 (d, 2H), 3.48 (s, 2H), 3.34 (s, 2H), 2.49 (d, 1H), 1.58 (d, 1H). Example 3

[0206] 6-(benzyloxy)-4-(6-(6-((6-methoxypyridine-3-)methylene)-3,6-diazabicyclo[3.3.1]heptane-3-)pyridine-3-)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (compound 3)

[0207] [ka]

[0208] To a solution of 4-(6-(6-((6-methoxypyridin-3-)methylene)-3,6-diazabicyclo[3.1.1]heptane-3-)pyridin-3-)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-ol (150 mg, 0.3 mmol) in DMF (10.0 mL), benzyl chloride (38 mg, 0.3 mmol) and potassium carbonate (83 mg, 0.6 mmol) were added, heated to 60 °C, and reacted for 12 hours. Water was added, and the mixture was extracted with ethyl acetate. The combined organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to obtain the product (35 mg). m / z = 559 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.65 (s, 1H), 8.60-8.63 (dd, 2H), 8.08-8.10 (m, 2H), 7.69 (dd, 1H), 7.67 (s, 1H), 7.51-7.53 (m, 2H), 7.40-7.44 (m, 2H), 7.34-7.37 (m, 2H), 6.91 (d, 1H), 6.77 (d, 1H), 5.25 (s, 2H), 3.74-3.80 (m, 5H), 3.68 (brs, 2H), 3.51-3.58 (m, 4H), 2.51 (d, 1H), 1.58 (d, 1H). Example 4

[0209] 4-(6-(6-((6-methoxypyridine-3-)methylene)3,6-diazabicyclo[3.1.1]heptane-3-)pyridine-3-)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (Compound 4)

[0210] [ka]

[0211] A solution of 6-bromo-4-(6-(6-((6-methoxypyridine-3-)methylene)-3,6-diazabicyclo[3.3.1]heptane-3-)pyridine-3-)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (30 mg, 0.056 mmol) in tetrahydrofuran was added to palladium on carbon (3 mg). The mixture was reacted at room temperature under 1 atmosphere of hydrogen gas, filtered, concentrated under reduced pressure, and separated by column chromatography to obtain the product (1.6 mg). m / z = 453 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.71 (s, 1H), 8.81 (d, 1H), 8.64 (d, 1H), 8.11 (d, 2H), 7.70 (s, 2H), 7.52 (d, 1H), 7.21 (m, 1H), 6.92 (d, 1H), 6.79 (d, 1H), 3.81 (s, 3H), 3.73-3.79 (m, 2H), 3.65-3.70 (m, 2H), 3.55-3.62 (m, 2H), 3.49-3.53 (s, 2H), 2.53 (d, 1H), 1.61 (d, 1H). Example 5

[0212] 4-(6-(6-((6-methoxypyridine-3-yl)methylene)-3,6-diazabicyclo[3.3.1]heptane-3-yl)pyridine-3-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-6-cyano (compound 5)

[0213] [ka]

[0214] A solution of 6-bromo-4-(6-(6-((6-methoxypyridine-3-methylene)-3,6-diazabicyclo[3.3.1]heptane-3-pyridine-3-methylene)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (30 mg, 0.057 mmol) in DMF (5 mL) was added with tetrakis(triphenylphosphine)palladium (6.6 mg, 0.006 mol) and zinc cyanide (6.7 mg, 0.057 mol). The mixture was heated to 100°C for 12 hours, concentrated under reduced pressure, and purified by column chromatography to give the product (14 mg). m / z = 478 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 13.01 (s, 1H), 9.66 (d, 1H), 8.67 (d, 1H), 8.10-8.15 (m, 2H), 7.81-7.82 (m, 2H), 7.72 (dd, 1H), 6.95 (d, 1H), 6.79 (d, 1H), 3.77-3.83 (m, 5H), 3.70 (d, 2H), 3.53 (s, 2H), 3.33 (s, 2H), 2.52 (d, 1H), 1.61 (d, 1H). Example 6

[0215] 4-(6-(6-((6-methoxypyridine-3-yl)methylene)-3,6-diazabicyclo[3.3.1]heptane-3-yl)pyridine-3-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-6-amino (Compound 6) Step A: 6-((diphenylmethylene)amino)-2-fluoro-4-(6-((6-methoxypyridine-3-yl)methylene)-3,6-diazabicyclo[3.3.1]heptane-3-yl)pyridine-3-yl)pyrazole[1,5-a]pyridine-3-carbaldehyde

[0216] [ka]

[0217] A solution of 6-bromo-2-fluoro-4-(6-((6-methoxypyridine-3-methylene)methylene)-3,6-diazabicyclo[3.3.1]heptane-3-pyridine-3-methylene)pyrazole[1,5-a]pyridine-3-carbaldehyde (180 mg, 0.34 mmol) in dioxane (30 mL) was added to dibenzophenone imine (60 mg, 0.34 mmol), tris(dibenzylideneacetone)dipalladium-chloroform (5.1 mg, 0.005 mmol), Xantphos (11 mg, 0.005 mmol), and cesium carbonate (330 mg, 1.0 mmol). The mixture was heated to 100 °C and reacted for 12 hours. The mixture was concentrated under reduced pressure and separated by column chromatography to obtain the product (130 mg). m / z = 638 [M+1]. + . Step B: 6-amino-2-fluoro-4-(6-((6-methoxypyridine-3-yl)methylene)-3,6-diazabicyclo[3.3.1]heptane-3-yl)pyridine-3-yl)pyrazole[1,5-a]pyridine-3-carbaldehyde

[0218] [ka]

[0219] To a solution of 6-((diphenylmethylene)amino)-2-fluoro-4-(6-((6-methoxypyridine-3-)methylene)-3,6-diazabicyclo[3.3.1]heptane-3-)pyridine-3-)pyrazole[1,5-a]pyridine-3-carbaldehyde (30 mg, 0.05 mmol) in tetrahydrofuran (3 mL), 3N hydrochloric acid (2 mL) was added, stirred at room temperature for 12 hours, concentrated under reduced pressure, and separated by column chromatography to obtain the product (22 mg). m / z = 474 [M+1] + . Step C: 4-(6-(6-((6-methoxypyridine-3-)methylene)-3,6-diazabicyclo[3.3.1]heptane-3-)pyridine-3-)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-6-amino

[0220] [ka]

[0221] The same procedure as in Step H of Example 7 was used to obtain the target product (2.7 mg). m / z=468[M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 8.56 (d, 1H), 8.11 (d, 1H), 8.03 (m, 2H), 7.69-7.72 (m, 1H), 7.50 (s, 1H), 7.01 (s, 1H), 6.92 (d, 1H), 6.79 (d, 1H), 5.24 (s, 2H), 3.75-3.83 (m, 5H), 3.70 (d, 2H), 3.53 (m, 4H), 2.51 (d, 1H), 1.61 (d, 1H). Example 7

[0222] 6-(2-methoxyethoxy)-4-(6-(6-((6-methoxypyridine-3-)methyl)-3,6-diazabicyclo[3.3.1]heptane-3-)pyridine-3-)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (Compound 7) Step A: tert-butyl ((methanesulfonyl)oxy)carbamate

[0223] [ka]

[0224] Triethylamine (13.0 mL, 93.3 mmol) was slowly added dropwise under constant pressure to a stirred solution of mesitylene-2-sulfonyl chloride (20.0 g, 91.5 mmol) and tert-butyl N-hydroxycarbamate (12.2 g, 91.5 mmol) in tert-butyl methyl ether (500 mL) in an ice bath, while maintaining the reaction temperature below 5°C during the addition. The reaction mixture was stirred in an ice bath for 4.0 hours, filtered under reduced pressure to remove triethylamine hydrochloride, and washed three times with tert-butyl methyl ether. The entire filtrate was concentrated under reduced pressure in a water bath below 15°C to remove most of the tert-butyl methyl ether. N-hexane was added to the concentrated residue in an ice bath and stirred vigorously for 10 minutes to precipitate a large amount of white solid, which was filtered under reduced pressure, washed twice with n-hexane, and dried in vacuo to obtain the product (26.1 g). m / z = 316 [M+1] + . Step B: O-Mesitylenesulfonylhydroxylamine

[0225] [ka]

[0226] At 0°C, add tert-butyl (methanesulfonyloxy)carbamate (10.0 g, 31.7 mmol) in a batch to trifluoroacetic acid (80 mL). After the addition, stir the reaction mixture at 0°C for 3 hours. After confirming the completion of the reaction by TLC spot plate, pour the reaction mixture into a large amount of ice water and stir for 15 minutes. A large amount of white solid precipitates. Filter under reduced pressure, wash the filter with a large amount of water until the solid's pH becomes neutral, and filter under reduced pressure until the water content of the solid is about 20%. This solid can be used directly in the next reaction step without further purification. Step C: 2,4,6-trimethylbenzenesulfonate 1-amino-3-bromo-5-benzyloxypyridin-1-onium

[0227] [ka]

[0228] At 0°C, 3-bromo-5-benzyloxypyridine (6.0 g, 32.0 mmol) was added to a solution of O-mesitylenesulfonylhydroxylamine (6.8 g, 31.7 mmol) in dichloromethane (50 mL). The mixture was stirred at 0°C for 3 hours, resulting in the precipitation of a large amount of white solid. After the reaction was complete, diethyl ether (50 mL) was added to the reaction mixture at 0°C and stirred for 10 minutes. The mixture was then filtered under reduced pressure, rinsed with diethyl ether, and dried in vacuo to obtain the product (15 g). This product was used directly in the next reaction step without further purification. m / z=281 [M+1] + . Step D: 6-(benzyloxy)-4-bromo-2-fluoropyrazole[1,5-a]pyridine and 4-(benzyloxy)-6-bromo-2-fluoropyrazole[1,5-a]pyridine

[0229] [ka]

[0230] At room temperature, potassium carbonate (1.4 g, 10.0 mmol) is added to a solution of 1-amino-3-bromo-5-benzyloxypyridin-1-onium 2,4,6-trimethylbenzenesulfonate (1.0 g, 2.3 mmol) in DMF (30 mL); the reaction mixture is cooled to 0°C, and 2,2-difluorovinyl p-toluenesulfonate (0.5 g, 2.3 mmol) is added in batches. The mixture is warmed to room temperature and stirred for 1 hour, and then stirred at 90°C for another 1 hour. After the reaction is completed, the mixture is cooled to room temperature, quenched with water, extracted with ethyl acetate, and the combined organic phases are washed with water, concentrated under reduced pressure, and separated by column chromatography to give 6-(benzyloxy)-4-bromo-2-fluoropyrazole[1,5-a]pyridine (118 mg). 1 HNMR (400MHz, CDCl3) δ 7.90 (s, 1H), 7.34-7.44 (m, 5H), 7.32(s, 1H), 6.08 (d, 1H), 5.02 (s, 2H),m / z=322[M+1] +, 4-(benzyloxy)-6-bromo-2-fluoropyrazole[1,5-a]pyridine (280 mg) was obtained; 1 HNMR (400MHz, CDCl3) δ8.07 (s, 1H), 7.80-7.82 (m, 5H), 6.61 (s, 1H), 6.18 (d, 1H), 5.15 (s, 2H),m / z=322[M+1] + . Step E: 6-(benzyloxy)-4-bromo-2-fluoropyrazole[1,5-a]pyridine-3-carbaldehyde

[0231] [ka]

[0232] Phosphorus oxychloride (1.0 g, 6.5 mmol) was added dropwise to a solution of 6-(benzyloxy)-4-bromo-2-fluoropyrazole[1,5-a]pyridine (380 mg, 1.2 mmol) in DMF (10 mL) at 0°C. After the addition was complete, the mixture was allowed to warm to room temperature and react overnight. The reaction mixture was poured into 100 mL of ice water, adjusted to pH 7 with 2N NaOH solution, extracted with ethyl acetate, and the combined organic phases were concentrated under reduced pressure. The product (400 mg) was obtained by column chromatography. m / z = 350 [M+1] + ; 1 HNMR (400MHz, DMSO-d6) δ 10.49 (s, 1H), 8.80-8.87 (m, 1H), 8.09 (d, 1H), 7.45-7.58 (m, 2H), 7.36-7.44 (m, 3H), 5.20 (s, 2H). Step F: 6-(benzyloxy)-2-fluoro-4-(6-((6-methoxypyridine-3-)methylene)-3,6-diazabicyclo[3.1.1]heptane-3-)pyridine-3-)pyrazole[1,5-a]pyridine-3-carbaldehyde

[0233] [ka]

[0234] 6-(benzyloxy)-4-bromo-2-fluoropyrazole[1,5-a]pyridine (23 mg, 0.067 mmol) and 6-((6-methoxypyridine-3-methylene)-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)pyridine-2-yl)-3,6-diazabicyclo[3.1.1]heptane (28 mg, 0.067 mmol) (prepared with reference to the method in WO2018 / 71447), tetrakis(triphenylphosphine)palladium (15 mg, 0.013 mol), potassium carbonate (36 mg, 0.264 mol), 1,4-dioxane (2 mL), and HO (1 mL) were mixed and vented with nitrogen gas three times. The mixture was then heated at 90 °C for 2 hours. LCMS confirmed the completion of the reaction and the presence of the product. Water was added, extracted with ethyl acetate, and the combined organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to obtain the product (25 mg). m / z=565[M+1] + . Step G: 2-Fluoro-6-hydroxyl-4-(6-(6-((6-methoxypyridine-3-yl)methylene)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridine-3-yl)pyrazole[1,5-a]pyridine-3-carbaldehyde

[0235] [ka]

[0236] To a solution of 6-(benzyloxy)-2-fluoro-4-(6-((6-methoxypyridine-3-methylene)-3,6-diazabicyclo[3.1.1]heptane-3-)pyridine-3-)pyrazole[1,5-a]pyridine-3-carbaldehyde (100 mg, 0.18 mmol) and palladium on carbon (5 mg) was added methanol (10.0 mL), and the mixture was subjected to hydrogen gas exchange three times using a hydrogen balloon. The mixture was then allowed to react overnight at room temperature. Water was added, and the mixture was extracted with ethyl acetate. The combined organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to obtain the product. 1 HNMR (400MHz, DMSO-d6) δ 10.42 (s, 1H), 9.37 (s, 1H), 8.32 (s, 1H), 8.23 ​​(s, 1H), 8.09 (s, 1H), 7.79 (d, 1H), 7.70 (d, 1H), 7.25 (s, 1H), 6.78 (t, 2H), 3.82 (s, 3H), 3.64-3.75 (m, 4H), 3.48-3.60 (m, 4H), 2.51 (d, 1H), 1.60 (d, 1H). + . Step H: 4-(6-(6-((6-methoxypyridine-3-)methylene)-3,6-diazabicyclo[3.1.1]heptane-3-)pyridine-3-)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-ol

[0237] [ka]

[0238] A solution of 2-fluoro-6-hydroxyl-4-(6-(6-((6-methoxypyridine-3-)methylene)-3,6-diazabicyclo[3.1.1]heptane-3-)pyridine-3-)pyrazole[1,5-a]pyridine-3-carbaldehyde (250 mg, 0.53 mmol) in DMF (5.0 mL) was added with hydrazine hydrate (0.5 mL) and heated to 100 °C for 12 hours. Water was added, and the mixture was extracted with ethyl acetate. The combined organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to obtain the product (170 mg). m / z = 469 [M+1] + , 1 HNMR (400MHz, DMSO-d6) δ 12.59 (s, 1H), 9.97 (s, 1H), 8.61 (s, 1H), 8.24 (d, 2H), 8.06-8.11 (m, 2H), 7.72 (dd, 1H), 7.58 (s, 1H), 7.15 (d, 1H), 6.93 (d, 1H), 6.79 (d, 1H), 3.72-3.83 (m, 5H), 3.69 (s, 2H), 3.35 (brs, 3H), 2.51 (d, 1H), 1.61 (d, 1H). Step I: 6-(2-methoxyethoxy)-4-(6-(6-((6-methoxypyridine-3-)methylene)-3,6-diazabicyclo[3.1.1]heptane-3-)pyridine-3-)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine

[0239] [ka]

[0240] To a solution of 4-(6-(6-((6-methoxypyridin-3-)methylene)-3,6-diazabicyclo[3.1.1]heptane-3-)pyridin-3-)-1H-pyrazole[3',4':3,4]pyrazo[1,5-a]pyridin-6-ol (150 mg, 0.3 mmol) in DMF (10.0 mL), 2-bromoethyl methyl ether (40 mg, 0.3 mmol) and potassium carbonate (83 mg, 0.6 mmol) were added, heated to 80 °C, and reacted for 12 hours. Water was added, and the mixture was extracted with ethyl acetate. The combined organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to give the product (84 mg). 1 HNMR (400MHz, DMSO-d6) δ 12.66 (s, 1H), 8.65(d, 1H), 8.56 (d, 1H), 8.13(m, 2H), 7.69-7.72 (m, 1H), 7.63 (s, 1H), 7.30 (s, 1H), 6.93 (d, 1H), 6.79 (d, 1H), 4.26-4.28 (m, 2H), 3.83 (s, 3H), 3.72-3.79 (m, 6H), 3.47-3.70 (m, 7H), 2.51 (d, 1H), 1.61 (d, 1H), m / z=527[M+1] + . Example 8

[0241] 1-((4-(6-(6-((6-methoxypyridine-3-)methylene)-3,6-diazabicyclo[3.1.1]heptane-3-)pyridine-3-)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-6-)oxy)-2-methylpropan-2-ol (Compound 8)

[0242] [ka]

[0243] 4-(6-(6-((6-methoxypyridin-3-)methylene)-3,6-diazabicyclo[3.1.1]heptane-3-)pyridin-3-)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-ol (150 mg, 0.32 mmol), isobutylene oxide (350 mg, 4.8 mmol), potassium carbonate (133 mg, 0.96 mmol), DMF (5.0 mL), and the mixture was heated to 80 °C for 12 h. Water was added, and the mixture was extracted with ethyl acetate. The combined organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by reverse-phase column chromatography to give the product trifluoroacetic acid (78 mg). m / z = 541 [M+1] + . Example 9

[0244] 6-ethoxy-4-(6-(6-((6-methoxypyridine-3-)methylene)-3,6-diazabicyclo[3.3.1]heptane-3-)pyridine-3-)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (Compound 9)

[0245] [ka]

[0246] To a solution of 4-(6-(6-((6-methoxypyridin-3-)methylene)-3,6-diazabicyclo[3.1.1]heptane-3-)pyridin-3-ol)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-ol (150 mg, 0.3 mmol) in DMF (10.0 mL), 2-iodoethane (47 mg, 0.3 mmol) and potassium carbonate (83 mg, 0.6 mmol) were added and heated to 60 °C for 12 h. Water was added, followed by extraction with ethyl acetate. The combined organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to give the product (125 mg). 1H NMR (400MHz, DMSO-d6) δ 12.66 (s, 1H), 8.65(d, 1H), 8.53 (d, 1H), 8.10-8.12 (m, 2H), 7.62-7.72 (m, 2H), 7.27 (s, 1H), 6.93 (d, 1H), 6.79 (d, 1H), 4.16-4.21 (m, 2H), 3.82 (s, 3H), 3.77 (d, 2H), 3.67 (d, 2H), 3.56 (m, 2H), 3.51 (s, 2H), 2.51 (d, 1H), 1.61 (d, 1H), 1.39-1.42 (m, 3H), m / z=497[M+1] + . Example 10

[0247] 2-((4-(6-(6-((6-methoxypyridine-3-yl)methylene)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridine-3-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-6-yl)oxy)ethan-1-ol (Compound 10)

[0248] [ka]

[0249] To a solution of 4-(6-(6-((6-methoxypyridin-3-)methylene)-3,6-diazabicyclo[3.1.1]heptane-3-)pyridin-3-)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-ol (150 mg, 0.3 mmol) in DMF (10.0 mL), ethylene carbonate (26 mg, 0.3 mmol) and potassium carbonate (83 mg, 0.6 mmol) were added, heated to 80 °C, and reacted for 12 h. Water was added, and the mixture was extracted with ethyl acetate. The combined organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to give the product (30 mg). m / z = 513 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ 12.64 (s, 1H), 8.62 (d, 1H), 8.53 (d, 1H), 8.09 (dt, 2H), 7.72-7.63 (m, 1H), 7.60 (s, 1H), 7.26 (d, 1H), 6.90 (d, 1H), 6.75 (dd, 1H), 4.96 (t, 1H), 4.14 (t, 2H), 3.80 (s, 3H), 3.80-3.73 (m, 4H), 3.67 (d, 2H), 3.58 (s, 1H), 3.51 (s, 2H), 2.51 (d, 1H), 1.57 (t, 1H), 1.23 (d, 1H). Example 11

[0250] 6-Butoxy-((4-(6-(6-((6-methoxypyridine-3-methylene)methylene)-3,6-diazabicyclo[3.1.1]heptane-3-pyridine-3-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-6-yl)oxy)ethan-1-ol (Compound 11)

[0251] [ka]

[0252] To a solution of 4-(6-(6-((6-methoxypyridin-3-)methylene)-3,6-diazabicyclo[3.1.1]heptane-3-)pyridin-3-)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-ol (150 mg, 0.3 mmol) in DMF (10.0 mL), 1-bromobutane (41 mg, 0.3 mmol) and potassium carbonate (83 mg, 0.6 mmol) were added and heated to 80 °C for 12 h. Water was added and the mixture was extracted with ethyl acetate. The combined organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to give the product (43 mg). m / z = 525 [M+1] + , 1H NMR (400 MHz, DMSO-d6) δ 12.63 (s, 1H), 8.63 (d, 1H), 8.51 (d, 1H), 8.09 (dt, 2H), 7.68 (dd, 1H), 7.60 (s, 1H), 7.25 (d, 1H), 6.89 (d, 1H), 6.76 (d, 1H), 4.11 (t, 2H), 3.81 (s, 3H), 3.80-3.79 (m, 2H), 3.76 (d, 1H), 3.67 (d, 2H), 3.51 (s, 2H), 2.51 (d, 1H), 1.79-1.69 (m, 2H), 1.58 (d, 1H), 1.53-1.42 (m, 2H), 1.22 (d, 1H), 0.95 (t, 3H). Example 12

[0253] 6-(3-fluoropropoxy)-4-(6-(6-((6-methoxypyridine-3-)methylene)-3,6-diazabicyclo[3.1.1]heptane-3-)pyridine-3-)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (Compound 12)

[0254] [ka]

[0255] To a solution of 4-(6-(6-((6-methoxypyridin-3-)methylene)-3,6-diazabicyclo[3.1.1]heptane-3-)pyridin-3-)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-ol (150 mg, 0.3 mmol) in DMF (10.0 mL), 1-bromo-3-fluoropropane (42 mg, 0.3 mmol) and potassium carbonate (83 mg, 0.6 mmol) were added and heated to 80 °C for 12 h. Water was added, and the mixture was extracted with ethyl acetate. The combined organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to give the product (35 mg). m / z = 529 [M+1] + ,1 H NMR (400 MHz, DMSO-d6) δ 12.65 (s, 1H), 8.63 (d, 1H), 8.57 (d, 1H), 8.09 (dd, 1H), 8.08 (s, 1H), 7.68 (dd, 1H), 7.61 (s, 1H), 7.28 (d, 1H), 6.90 (d, 1H), 6.76 (d, 1H), 4.71 (t, 1H), 4.59 (t, 1H), 4.23 (t, 2H), 3.81 (s, 3H), 3.80-3.72 (m, 2H), 3.67 (d, 2H), 3.57 (s, 2H), 3.51 (s, 2H), 2.51 (d, 1H), 2.16 (dt, 2H), 1.58 (d, 1H). Example 13

[0256] 6-(4-Fluorobutoxy)-4-(6-(6-((6-methoxypyridine-3-yl)methylene)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridine-3-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (Compound 13)

[0257] [ka]

[0258] To a solution of 4-(6-(6-((6-methoxypyridin-3-)methylene)-3,6-diazabicyclo[3.1.1]heptane-3-)pyridin-3-)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-ol (150 mg, 0.3 mmol) in DMF (10.0 mL), 1-bromo-4-fluorobutane (47 mg, 0.3 mmol) and potassium carbonate (83 mg, 0.6 mmol) were added and heated to 80 °C for 12 h. Water was added and the mixture was extracted with ethyl acetate. The combined organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to give the product (60 mg). m / z = 543 [M+1] + ,1 H NMR (400 MHz, DMSO-d6) δ 12.64 (s, 1H), 8.63 (d, 1H), 8.53 (d, 1H), 8.13-8.05 (m, 2H), 7.68 (dd, 1H), 7.61 (s, 1H), 7.27 (d, 1H), 6.90 (d, 1H), 6.76 (d, 1H), 4.59 (s, 1H), 4.47 (t, 1H), 4.20-4.12 (m, 2H), 3.81 (s, 3H), 3.80-3.71 (m, 2H), 3.67 (d, 2H), 3.58 (s, 2H), 3.51 (s, 2H), 2.52 (d, 1H), 1.87 (s, 2H), 1.86-1.76 (m, 2H), 1.58 (d, 1H). Example 14

[0259] 6-(2-chloroethoxy)-4-(6-(6-((6-methoxypyridine-3-)methylene)-3,6-diazabicyclo[3.1.1]heptane-3-)pyridine-3-)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (Compound 14)

[0260] [ka]

[0261] To a solution of 4-(6-(6-((6-methoxypyridine-3-)methylene)-3,6-diazabicyclo[3.1.1]heptane-3-)pyridin-3-ol)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-ol (150 mg, 0.3 mmol) in DMF (10.0 mL), 1-chloro-2-iodoethane (57 mg, 0.3 mmol) and potassium carbonate (83 mg, 0.6 mmol) were added and heated to 80 °C for 12 h. Water was added and the mixture was extracted with ethyl acetate. The combined organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to give the product (6 mg). m / z = 531 [M+1]+ , 1 H NMR (400 MHz, DMSO-d6) δ 12.67 (s, 1H), 8.62 (dd, 2H), 8.10 (dd, 1H), 8.09 (s, 1H), 7.68 (dd, 1H), 7.63 (s, 1H), 7.30 (d, 1H), 6.90 (d, 1H), 6.76 (d, 1H), 4.46-4.39 (m, 2H), 4.01 (dd, 2H), 3.81 (s, 3H), 3.76 (d, 2H), 3.67 (d, 2H), 3.57 (s, 2H), 3.51 (s, 2H), 2.58-2.50 (m, 1H), 1.58 (d, 1H). Example 15

[0262] 6-(2-bromoethoxy)-4-(6-(6-((6-methoxypyridine-3-)methylene)-3,6-diazabicyclo[3.1.1]heptane-3-)pyridine-3-)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (Compound 15)

[0263] [ka]

[0264] To a solution of 4-(6-(6-((6-methoxypyridin-3-)methylene)-3,6-diazabicyclo[3.1.1]heptane-3-)pyridin-3-)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-ol (150 mg, 0.3 mmol) in DMF (10.0 mL), 2-bromoethyl trifluoromethanesulfonate (77 mg, 0.3 mmol) and potassium carbonate (83 mg, 0.6 mmol) were added, heated to 80 °C, and reacted for 12 h. Water was added, and the mixture was extracted with ethyl acetate. The combined organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to give the product (16 mg). m / z = 575 [M+1] + , 1H NMR (400 MHz, DMSO-d6) δ 12.68 (s, 1H), 8.61-8.67 (dd, 2H), 8.11-8.15 (m, 2H), 7.71 (d, 1H), 7.64 (s, 1H), 7.32 (d, 1H), 6.93 (d, 1H), 6.80 (d, 1H), 4.53 (t, 2H), 3.87-3.90 (m, 2H), 3.53-3.82 (m, 11H), 2.51 (d, 1H), 1.51-1.62 (m, 1H). Example 16

[0265] 6-(2-fluoroethoxy)-4-(5-(6-((6-methoxypyridine-3-)methylene)-3,6-diazabicyclo[3.1.1]heptane-3-)pyrazine-2-)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (Compound 16)

[0266] [ka]

[0267] Step A: 3-(5-chloropyrazine-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-tert-butyl carbonate

[0268] [ka]

[0269] At room temperature, 2-chloro-5-fluoropyrazine (6.9 g, 0.052 mol) and tert-butyl 3,6-diazabicyclo[3.1.1]heptane-6-carbonate (11.5 g, 0.058 mol) were added to a 250 mL single-neck flask, and DMSO (20 mL) was added. The mixture was then incubated at 120 °C overnight. The DMSO was removed under reduced pressure, and methanol was added to dissolve the mixture. Saturated sodium hydroxide solution was slowly added in an ice-water bath to adjust the pH to approximately 13, and the mixture was stirred for 2 hours. The methanol was concentrated under reduced pressure, and the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain the product (12 g, 74% yield). m / z = 311 [M+1] + . Step B: 3-(5-chloropyrazine-2-yl)-3,6-diazabicyclo[3.1.1]heptane dihydrochloride

[0270] [ka]

[0271] Add 3-(5-chloropyrazine-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-tert-butyl carbonate (5.0 g, 14 mmol) and hydrogen chloride in dioxane (15 mL) to a 100 mL single-neck flask, stir at room temperature for 2 h, and then concentrate directly to the next reaction. m / z = 211 [M+1] + . Step C: 3-(5-chloropyrazine-2-yl)-6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane

[0272] [ka]

[0273] A 100 mL single-neck flask was charged with 6-methoxynicotinaldehyde (0.21 g, 1.9 mmol), 3-(5-chloropyrazine-2-yl)-3,6-diazabicyclo[3.1.1]heptane dihydrochloride (0.4 g, 1.9 mmol), sodium borohydride acetate (1.2 g, 5.8 mmol), and 20 mL of dichloromethane. The mixture was stirred at room temperature for 12 hours. After the reaction was confirmed by TLC spot plate, water was added and the mixture was extracted with ethyl acetate. The combined organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to obtain the product, 3-(5-chloropyrazine-2-yl)-6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane (0.5 g, 80% yield). m / z = 332 [M+1] + . 1 HNMR (400MHz, DMSO-d6) δ 8.25 (d, 1H), 8.09 (s, 1H), 7.99 (d, 1H), 7.69 (dd, 1H), 6.78 (d, 1H), 3.83 (s, 3H), 3.71 (m, 4H), 3.51 (m, 4H), 2.51 (d, 1H), 1.59 (d, 1H). Step D: 6-((6-methoxypyridine-3-methyl)methyl)-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-pyrazine-2-)-3,6-diazabicyclo[3.1.1]heptane

[0274] [ka]

[0275] In a 10 mL sealed tube, 3-(5-chloropyrazine-2-yl)-6-((6-methoxypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane (44 mg, 0.132 mmol), bis(pinacolato)diboron (50 mg, 0.198 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (10 mg, 0.013 mmol), potassium carbonate (39 mg, 0.396 mmol), and 1,4-dioxane (20 mL) were added, purged with nitrogen gas three times, and reacted at 100 °C for 3 hours. This reaction was directly carried on to the next step without the need for workup. Step E: 6-(benzyloxy)-2-fluoro-4-(5-(6-((6-methoxypyridine-3-)methylene)-3,6-diazabicyclo[3.1.1]heptane-3-)pyrazine-2-)pyrazole[1,5-a]pyridine-3-carbaldehyde

[0276] [ka]

[0277] 6-(benzyloxy)-4-bromo-2-fluoropyrazole[1,5-a]pyridine (23 mg, 0.067 mmol), 6-((6-methoxypyridine-3-methyl))-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-pyrazine-2-)-3,6-diazabicyclo[3.1.1]heptane (28 mg, 0.067 mmol), tetrakis(triphenylphosphine)palladium (15 mg, 0.013 mol), potassium carbonate (36 mg, 0.264 mol), 1,4-dioxane (2 mL), and HO (1 mL) were mixed and purged with nitrogen gas three times. The mixture was heated at 90 °C for 2 h. LCMS confirmed the completion of the reaction and the formation of the product. Add water, extract with ethyl acetate, wash the combined organic phase with water, dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and separate by column chromatography to obtain the product (20 mg): m / z=566[M+1] + . Step F: 2-Fluoro-6-hydroxyl-4-(5-(6-((6-methoxypyridine-3-yl)methylene)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyrazine-2-yl)pyrazole[1,5-a]pyridine-3-carbaldehyde

[0278] [ka]

[0279] 6-(benzyloxy)-2-fluoro-4-(5-(6-((6-methoxypyridine-3-methylene)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyrazine-2-yl)pyrazole[1,5-a]pyridine-3-carbaldehyde (100 mg, 0.18 mmol) and palladium on carbon (5 mg) were added to methanol (10.0 mL) at room temperature, purged with hydrogen gas three times using a hydrogen balloon, and allowed to react overnight at room temperature. Water was added, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to give the product. m / z = 476 [M+1] + . Step G: 4-(5-(6-((6-methoxypyridine-3-)methylene)3,6-diazabicyclo[3.1.1]heptane-3-)pyrazine-2-)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-ol

[0280] [ka]

[0281] A solution of 2-fluoro-6-hydroxyl-4-(5-(6-((6-methoxypyridine-3-yl)methylene)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyrazine-2-yl)pyrazole[1,5-a]pyridine-3-carbaldehyde (250 mg, 0.53 mmol) in DMF (5.0 mL) was added with hydrazine hydrate (0.5 mL) and heated to 100°C for 12 hours. Water was added, and the mixture was extracted with ethyl acetate. The combined organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to obtain the product (75 mg). m / z = 470 [M+1] + . Step H: 6-(2-fluoroethoxy)-4-(5-(6-((6-methoxypyridine-3-)methylene)3,6-diazabicyclo[3.1.1]heptane-3-)pyrazine-2-)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine

[0282] [ka]

[0283] To a solution of 4-(5-(6-((6-methoxypyridine-3-methylene)methylene)-3,6-diazabicyclo[3.1.1]heptane-3-methylene)pyrazine-2-methylene)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-ol (150 mg, 0.3 mmol) in DMF (10.0 mL), 1-fluoro-2-iodoethyl (52 mg, 0.3 mmol) and potassium carbonate (83 mg, 0.6 mmol) were added, heated to 80°C, and reacted for 12 hours. Water was added, and the mixture was extracted with ethyl acetate. The combined organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to obtain the product (34 mg). m / z = 516 [M+1] +,H NMR (400MHz, DMSO-d6) δ12.51 (s, 1H), 8.99 (s, 1H), 8.64 (d, 1H), 8.55 (s, 1H), 8.05-8.13 (m, 2H), 7.80 (d, 1H), 7.72 (dd, 1H), 6.79 (d, 1H), 4.90 (dd, 1H), 4.77 (d, 1H), 4.49 (dd, 2H), 3.83-3.87 (m, 5H), 3.65-3.71 (m, 4H), 3.56 (s, 2H), 2.56 (d, 1H), 1.62 (d, 1H). Example 17

[0284] (2S)-2-(((4-(6-((6-methoxypyridine-3-)methylene)-3,6-diazabicyclo[3.3.1]heptane-3-)pyridine-3-)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-6-)oxy)methyl)morpholine (Compound 17)

[0285] [ka]

[0286] To a solution of 4-(5-(6-((6-methoxypyridin-3-)methylene)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyrazine-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-ol (150 mg, 0.3 mmol) in DMF (10.0 mL), (2S)-tert-butyl 2-(bromomethyl)-4-morpholinecarboxylate (82 mg, 0.3 mmol) and potassium carbonate (83 mg, 0.6 mmol) were added, heated to 80 °C, and reacted for 12 hours. Hydrogen chloride in dioxane (1.5 mL, 4.0 M) was added, and the reaction was continued for 2 hours. Water was added, and the mixture was extracted with ethyl acetate. The combined organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to give the product (4.2 mg). m / z=567[M+1] + ,1 H NMR (400 MHz, DMSO-d6): 12.65 (s, 1H), 8.65 (s, 1H), 8.54(s, 1H), 8.10-8.12 (m, 2H), 7.63-7.72 (m, 2H), 7.30(s, 1H), 6.90 (d, 1H), 6.76 (d, 1H), 4.10 (d, 2H), 3.76-3.83 (m, 8H), 3.64-3.72 (m, 3H), 3.48-3.63 (m, 6H), 2.58-2.76 (m, 2H), 1.58-1.61 (m, 1H). Example 18

[0287] N,N-Diethyl-4-(5-(6-(2-fluoroethoxy)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-4-)pyridine-2-)piperazine-1-formamide (Compound 18) Step A: 4-(5-(6-(benzyloxy)-2-fluoro-3-carbaldehydepyrazole[1,5-a]pyridine-4-)pyridine-2-)piperazine-1-tert-butyl carbonate

[0288] [ka]

[0289] 6-(benzyloxy)-4-bromo-2-fluoropyrazole[1,5-a]pyridine (23 mg, 0.067 mmol), 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)pyridine-2-yl)piperazine-1-tert-butyl carbonate (26 mg, 0.067 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (10 mg, 0.013 mmol), potassium carbonate (36 mg, 0.264 mol), 1,4-dioxane (2 mL), and HO (1 mL) were mixed and purged with nitrogen gas three times. The mixture was then heated at 90 °C for 2 hours. LCMS confirmed the completion of the reaction and the presence of product. Water was added, extracted with ethyl acetate, and the combined organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to obtain the product (18 mg). m / z=532[M+1] + . Step B: 4-(5-(2-fluoro-3-carbaldehyde-6-hydroxylpyrazole[1,5-a]pyridine-4-group)pyridine-2-group)piperazine-1-tert-butyl carbonate

[0290] [ka]

[0291] To a solution of 4-(5-(6-(benzyloxy)-2-fluoro-3-carbaldehydopyrazole[1,5-a]pyridine-4-)pyridine-2-)piperazine-1-tert-butyl carbonate (96 mg, 0.18 mmol) and palladium on carbon (5 mg) was added methanol (10.0 mL) and the mixture was purged with hydrogen gas three times using a hydrogen balloon. The mixture was then allowed to react overnight at room temperature. Water was added, and the mixture was extracted with ethyl acetate. The combined organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to give the product. m / z=442 [M+1] + . Step C: 4-(5-(6-hydroxyl-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-4-group)pyridine-2-group)piperazine-1-tert-butyl carbonate

[0292] [ka]

[0293] To a solution of 4-(5-(2-fluoro-3-carbaldehyde-6-hydroxylpyrazole[1,5-a]pyridine-4-group)pyridine-2-group)piperazine-1-tert-butyl carbonate (234 mg, 0.53 mmol) in DMF (5.0 mL), hydrazine hydrate (0.5 mL) was added, heated to 100°C, and reacted for 12 hours. Water was added, and the mixture was extracted with ethyl acetate. The combined organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to obtain the product (82 mg). m / z = 436 [M+1] + . Step D: 4-(5-(6-(2-fluoroethoxy)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-4-)pyridine-2-)piperazine-1-tert-butyl carbonate

[0294] [ka]

[0295] To a solution of 4-(5-(6-hydroxyl-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-4-group)pyridine-2-group)piperazine-1-tert-butyl carbonate (130 mg, 0.3 mmol) in DMF (10.0 mL), 1-fluoro-2-iodoethyl (52 mg, 0.3 mmol) and potassium carbonate (83 mg, 0.6 mmol) were added, heated to 80°C, and reacted for 12 hours. Water was added, and the mixture was extracted with ethyl acetate. The combined organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to obtain the product (60 mg). m / z = 482 [M+1] + , 1 HNMR (400MHz, DMSO-d6) δ 12.70 (brs, 1H), 8.61 (d, 2H), 8.11 (dd, 1H), 7.60 (s, 1H), 7.33 (d, 1H), 7.10 (d, 1H), 4.88 (q, 1H), 4.76 (q, 1H), 4.46 (t, 1H), 4.39 (t, 1H), 3.65 (t, 4H), 3.49 (d, 4H), 1.44 (d, 9H). Step E: 6-(2-fluoroethoxy)-4-(6-(piperazine-1-)pyridine-3-)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine

[0296] [ka]

[0297] To a solution of 4-(5-(6-(2-fluoroethoxy)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-4-)pyridine-2-)piperazine-1-tert-butyl carbonate (63 mg, 0.13 mmol) in dioxane (2 mL), hydrogen chloride in dioxane (0.5 mL, 4.0 M) was added, and the mixture was reacted at room temperature for 12 hours. The mixture was concentrated under reduced pressure and used directly in the next reaction step. m / z=382 [M+1] + , 1HNMR (400MHz, DMSO-d6) δ 12.68 (s, 1H), 8.61 (t, 2H), 8.09 (d, 1H), 7.59 (s, 1H), 7.33 (d, 1H), 7.08 (d, 1H), 4.88 (t, 1H), 4.76 (q, 1H), 4.47 (t, 1H), 4.39 (t, 1H), 3.62 (s, 4H), 2.93 (s, 4H), 1.15 (s, 1H). Step F: N,N-diethyl-4-(5-(6-(2-fluoroethoxy)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-4-)pyridine-2-)piperazine-1-formamide

[0298] [ka]

[0299] To a solution of 6-(2-fluoroethoxy)-4-(6-(piperazine-1-)pyridine-3-)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (106 mg, 0.28 mmol) in dichloromethane (5 mL), diethylcarbamic acid chloride (40 mg, 0.3 mmol) and triethylamine (85 mg, 0.84 mmol) were added and reacted at room temperature for 12 hours. Water was added and the mixture was extracted with ethyl acetate. The combined organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to obtain the product (32.4 mg). m / z=481 [M+1] + , 1 H NMR (400MHz, DMSO-d6) δ 12.68 (s, 1H), 8.62 (d, 2H), 8.10 (dd, 1H), 7.58 (s, 1H), 7.34 (d, 1H), 7.09 (d, 1H), 4.88 (t, 1H), 4.76 (dd, 1H), 4.47 (t, 1H), 4.39 (t, 1H), 3.66 (t, 4H), 3.16-3.25 (m, 8H), 1.10 (t, 6H). Example 19

[0300] 1-(4-(5-(6-(2-fluoroethoxy)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-4-)pyridine-2-)piperazine-1-)-2-(pyridine-2-)ethan-1-one (Compound 19)

[0301] [ka]

[0302] To a solution of 6-(2-fluoroethoxy)-4-(6-(piperazine-1-)pyridine-3-)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (106 mg, 0.28 mmol) in dichloromethane (5 mL), 2-(pyridine-2-)acetic acid (41 mg, 0.3 mmol), HATU (114 mg, 0.3 mmol), and triethylamine (85 mg, 0.84 mmol) were added. The mixture was allowed to react at room temperature for 12 hours, and water was added. The mixture was extracted with ethyl acetate. The combined organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to obtain the product (32.4 mg). m / z = 501 [M+1] + , 1 H NMR (400MHz, DMSO-d6) δ 12.68 (s, 1H), 8.62 (d, 2H), 8.51 (t, 1H), 8.10 (dd, 1H), 7.73-7.78 (m, 1H), 7.58 (s, 1H), 7.34 (t, 2H), 7.28 (dd, 1H), 7.10 (d, 1H), 4.88 (t, 1H), 4.76 (t, 1H), 4.47 (d, 1H), 4.45 (d, 1H), 3.96 (s, 2H), 3.72 (m, 2H), 3.34 (s, 6H). Example 20

[0303] (R)-1-(4-(5-(6-(2-fluoroethoxy)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-4-)pyridine-2-)piperazine-1-)-2-hydroxyl-2-phenylethan-1-one (Compound 20)

[0304] [ka]

[0305] To a solution of 6-(2-fluoroethoxy)-4-(6-(piperazine-1-)pyridine-3-)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (106 mg, 0.28 mmol) in dichloromethane (5 mL), (R)-2-hydroxyl-2-phenylacetic acid (46 mg, 0.3 mmol), HATU (114 mg, 0.3 mmol), and triethylamine (85 mg, 0.84 mmol) were added. The mixture was allowed to react at room temperature for 12 hours, and water was added. The mixture was extracted with ethyl acetate. The combined organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to obtain the product (33 mg). m / z = 516 [M+1] + , 1 H NMR (400MHz, DMSO-d6) δ 12.68 (s, 1H), 8.61 (dd, 2H), 8.07 (dd, 1H), 7.56 (s, 1H), 7.29-7.43 (m, 6H), 7.04 (d, 1H), 5.78 (d, 1H), 5.51 (d, 1H), 4.88 (t, 1H), 4.76 (t, 1H), 4.46 (t, 1H), 4.38 (t, 1H), 3.38-3.68 (m, 7H), 3.26-3.29 (m, 1H). Example 21

[0306] (R)-1-(4-(5-(6-(2-fluoroethoxy)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-4-pyridine-2-piperazine-1-one)-2-methoxy-2-phenylethan-1-one (Compound 21)

[0307] [ka]

[0308] To a solution of 6-(2-fluoroethoxy)-4-(6-(piperazine-1-)pyridine-3-)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (106 mg, 0.28 mmol) in dichloromethane (5 mL), (R)-2-methoxy-2-phenylacetic acid (46 mg, 0.3 mmol), HATU (114 mg, 0.3 mmol), and triethylamine (85 mg, 0.84 mmol) were added. The mixture was allowed to react at room temperature for 12 hours, and water was added. The mixture was extracted with ethyl acetate. The combined organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to obtain the product (35 mg). m / z=530 [M+1] + , 1 H NMR (400MHz, DMSO-d6) δ 12.69 (s, 1H), 8.61 (dd, 2H), 8.08 (dd, 1H), 7.58 (s, 1H), 7.32-7.44 (m, 6H), 7.05 (d, 1H), 5.28 (s, 1H), 4.88 (t, 1H), 4.76 (t, 1H), 4.46 (t, 1H), 4.39 (d, 1H), 3.36-3.65 (m, 7H), 3.34 (s, 3H), 3.28 (brs, 1H). Example 22

[0309] (4-(5-(6-(2-fluoroethoxy)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-4-)pyridine-2-piperazine-1-(6-methoxypyridine-3-)methanone (Compound 22)

[0310] [ka]

[0311] To a solution of 6-(2-fluoroethoxy)-4-(6-(piperazine-1-)pyridine-3-)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (106 mg, 0.28 mmol) in dichloromethane (5 mL), 6-methoxynicotinic acid (46 mg, 0.3 mmol), HATU (114 mg, 0.3 mmol), and triethylamine (85 mg, 0.84 mmol) were added. The mixture was allowed to react at room temperature for 12 hours, and then water was added. The mixture was extracted with ethyl acetate. The combined organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to obtain the product (43 mg). m / z = 517 [M+1] + , 1 H NMR (400MHz, DMSO-d6) δ 12.69 (s, 1H), 8.63 (dd, 2H), 8.34 (d, 1H), 8.12 (dd, 1H), 7.86(dd, 1H), 7.59 (s, 1H), 7.34 (d, 1H), 7.11 (d, 1H), 6.93 (d, 1H), 4.87 (d, 1H), 4.75 (d, 1H), 4.47 (d, 1H), 4.39 (d, 1H), 3.92 (s, 3H), 3.73 (m, 8H). Example 23

[0312] (3-(5-(6-(2-fluoroethoxy)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-4-)pyridine-2-)3,6-diazabicyclo[3.3.1]heptane-6-)(6-methoxypyridine-3-)methyl ketone (Compound 23) Step A: 3-(5-bromopyridine-2-yl)-3,6-diazabicyclo[3.3.1]heptane-6-Boc

[0313] [ka]

[0314] To a solution of 5-bromo-2-fluoropyridine (5.3 g, 30 mmol) in dimethylformamide (50 mL), 6-(tert-butylcarbonyl)-3,6-diazabicyclo[3.1.1]heptane (6.0 g, 30 mmol) and potassium carbonate (7.0 g, 50 mmol) were added, heated to 120 °C, and reacted for 16 hours. Water was added, and the mixture was extracted with ethyl acetate. The combined organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to obtain the product (6.0 g). m / z = 354 [M+1] + . Step B: 3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-)pyridine-2-)-3,6-diazabicyclo[3.3.1]heptane-6-Boc

[0315] [ka]

[0316] In a 10 mL sealed tube, 3-(5-bromopyridine-2-yl)-3,6-diazabicyclo[3.3.1]heptane-6-Boc (47 mg, 0.132 mmol), bis(pinacolato)diboron (50 mg, 0.198 mmol), tetrakis(triphenylphosphine)palladium (15 mg, 0.013 mol), potassium acetate (39 mg, 0.396 mmol), and dimethyl sulfoxide (5 mL) were added. The mixture was purged with nitrogen three times and incubated at 100 °C for 3 h. After confirming completion of the reaction by LCMS, water was added and the mixture was extracted with ethyl acetate. The combined organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and used directly in the next reaction step. 1H NMR (400MHz, DMSO-d6) δ 8.35 (d, 1H), 7.73 (q, 1H), 6.63 (d, 1H), 4.20 (d, 2H), 3.39-3.42 (m, 4H), 3.97 (s, 2H), 1.47 (d, 1H), 1.27-1.30 (m, 20H). Step C: 3-(5-(6-(benzyloxy)-2-fluoro-3-carbaldehydepyrazole[1,5-a]pyridine-4-)pyridine-2-)-3,6-diazabicyclo[3.3.1]heptane-6-Boc

[0317] [ka]

[0318] Mix 6-(benzyloxy)-4-bromo-2-fluoropyrazole[1,5-a]pyridine (23 mg, 0.067 mmol), 3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)pyridine-2-yl)-3,6-diazabicyclo[3.3.1]heptane-6-Boc (27 mg, 0.067 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (10 mg, 0.013 mmol), cesium carbonate (86 mg, 0.264 mol), 1,4-dioxane (2 mL), and HO (1 mL). Purge the mixture with nitrogen gas three times and react at 90 °C for 12 h. Water was added, and the mixture was extracted with ethyl acetate. The combined organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to give the product (21 mg). m / z=544[M+1] + . Step D: 3-(5-(2-fluoro-3-carbaldehyde-6-hydroxylpyrazole[1,5-a]pyridine-4-group)pyridine-2-group)-3,6-diazabicyclo[3.3.1]heptane-6-Boc

[0319] [ka]

[0320] To a solution of 3-(5-(6-(benzyloxy)-2-fluoro-3-carbaldehydepyrazole[1,5-a]pyridine-4-pyridine-2-pyridine)-3,6-diazabicyclo[3.3.1]heptane-6-Boc (98 mg, 0.18 mmol) and palladium on carbon (5 mg) was added methanol (10.0 mL), purged with hydrogen gas three times using a hydrogen balloon, and allowed to react overnight at room temperature. Water was added, and the mixture was extracted with ethyl acetate. The combined organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to give the product. m / z=454 [M+1] + Step E: 3-(5-(6-hydroxyl-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-4-group)pyridine-2-group)-3,6-diazabicyclo[3.1.1]heptane-6-Boc

[0321] [ka]

[0322] To a solution of 3-(5-(2-fluoro-3-carbaldehyde-6-hydroxylpyrazole[1,5-a]pyridine-4-group)pyridine-2-group)-3,6-diazabicyclo[3.3.1]heptane-6-Boc (240 mg, 0.53 mmol) in DMF (5.0 mL), hydrazine hydrate (0.5 mL) was added and heated to 100°C for 12 hours. Water was added, and the mixture was extracted with ethyl acetate. The combined organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to obtain the product (92 mg). m / z = 448 [M+1] + . Step F: 3-(5-(6-(2-fluoroethoxy)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-4-)pyridine-2-)-3,6-diazabicyclo[3.1.1]heptane-6-Boc

[0323] [ka]

[0324] To a solution of 3-(5-(6-hydroxyl-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-4-group)pyridine-2-group)-3,6-diazabicyclo[3.1.1]heptane-6-Boc (134 mg, 0.3 mmol) in DMF (10.0 mL), 1-fluoro-2-iodoethyl (52 mg, 0.3 mmol) and potassium carbonate (83 mg, 0.6 mmol) were added and heated to 80°C for 12 hours. Water was added, and the mixture was extracted with ethyl acetate. The combined organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to obtain the product (60 mg). m / z = 494 [M+1] + , 1 H NMR (400MHz, DMSO-d6) δ 12.67 (s, 1H), 8.60-8.63 (m, 2H), 8.07-8.10 (m, 1H), 7.57 (s, 1H), 7.33 (d, 1H), 6.92 (d, 1H), 4.86-4.88 (q, 1H), 4.74-4.76 (t, 1H), 4.37-4.39 (t, 1H), 4.26 (d, 2H), 4.00-4.07 (m, 2H), 3.54 (d, 2H), 2.59 (d, 1H), 1.99 (s, 1H), 1.53 (d, 1H), 1.29 (s, 9H). Step H: 4-(6-(3,6-diazabicyclo[3.1.1]heptane-3-)pyridine-3-)-6-(2-fluoroethoxy)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine

[0325] [ka]

[0326] To a solution of 4-(5-(6-(2-fluoroethoxy)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-4-)pyridine-2-)piperazine-6-Boc (63 mg, 0.13 mmol) in dioxane (2 mL), hydrogen chloride in dioxane (0.5 mL, 4.0 M) was added, and the mixture was reacted at room temperature for 12 hours. The mixture was concentrated under reduced pressure and used directly in the next reaction step. m / z=394 [M+1] + , 1 H NMR (400MHz, DMSO-d6) δ 12.70 (s, 1H), 8.68 (s, 1H), 8.63 (s, 1H), 8.17 (s, 1H), 7.58 (s, 1H), 7.35 (s, 1H), 6.96 (s, 1H), 4.75-4.89 (m, 2H), 4.39-4.47 (m, 2H), 3.91-4.05 (m, 4H), 2.91 (brs, 2H), 1.92 (s, 1H), 1.15 (s, 2H). Step I: (3-(5-(6-(2-fluoroethoxy)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-4-)pyridine-2-)-3,6-diazabicyclo[3.1.1]heptane-6-)(6-methoxypyridine-3-)methyl ketone

[0327] [ka]

[0328] To a solution of 4-(6-(3,6-diazabicyclo[3.1.1]heptane-3-pyridine-3-yl)pyridine)-6-(2-fluoroethoxy)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (110 mg, 0.28 mmol) in dichloromethane (5 mL), 6-methoxynicotinic acid (46 mg, 0.3 mmol), HATU (114 mg, 0.3 mmol), and triethylamine (85 mg, 0.84 mmol) were added and reacted at room temperature for 12 hours. Water was added, and the mixture was extracted with ethyl acetate. The combined organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to give the product (3 mg). m / z = 529 [M+1] + , 1 HNMR (400MHz, DMSO-d6) δ 12.66 (s, 1H), 8.55-8.60 (m, 3H), 8.08 (dd, 1H), 8.00 (dd, 1H), 7.58 (s, 1H), 7.31 (d, 1H), 6.84-6.90 (m, 2H), 4.94 (brs, 1H), 4.86 (dd, 1H), 4.74 (dd, 1H), 4.61 (brs, 1H), 4.42-4.44 (m, 1H), 4.35-4.36 (m, 1H), 4.20 (d, 1H), 3.71 (d, 3H), 3.57 (m, 3H), 2.84 (q, 1H), 1.72 (d, 1H). Example 24

[0329] 6-Methoxy-4-(5-(6-((6-methoxypyridine-3-)methylene)-3,6-diazabicyclo[3.3.1]heptane-3-)pyrazine-2-)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (Compound 24) Step A: 2,4,6-trimethylbenzenesulfonate 1-amino-3-bromo-5-methoxypyridin-1-onium

[0330] [ka]

[0331] At 0°C, 3-bromo-5-methoxypyridine (6.0g, 32.0mmol) was added to a solution of O-mesitylenesulfonylhydroxylamine (6.8g, 31.7mmol) in dichloromethane (50mL). The mixture was stirred at 0°C for 3 hours, resulting in the precipitation of a large amount of white solid. After the reaction was complete, diethyl ether (50mL) was added to the reaction mixture at 0°C and stirred for 10 minutes. The mixture was then filtered under reduced pressure, rinsed with diethyl ether, and dried in vacuo to obtain the product (15g), which was used directly in the next reaction step without further purification. m / z=204[M+1] + . Step B: 4-Bromo-2-fluoro-6-methoxypyrazole[1,5-a]pyridine

[0332] [ka]

[0333] To a solution of 1-amino-3-bromo-5-methoxypyridin-1-onium 2,4,6-trimethylbenzenesulfonate (1.0 g, 2.3 mmol) in DMF (30 mL) at room temperature, potassium carbonate (1.4 g, 10.0 mmol) was added. The reaction mixture was cooled to 0 °C, and 2,2-difluorovinyl p-toluenesulfonate (0.5 g, 2.3 mmol) was added in batches. The mixture was warmed to room temperature and stirred for 1 hour, then stirred at 90 °C for an additional 1 hour. After the reaction was completed, the mixture was cooled to room temperature, quenched with water, extracted with ethyl acetate, and the combined organic phase was washed with water, concentrated under reduced pressure, and separated by column chromatography to obtain the product (80 mg). m / z = 245 [M+1] + , 1 HNMR (400MHz, CDCl3) δ8.07 (s, 1H), 6.61 (s, 1H), 6.18 (d, 1H), 3.85 (s, 3H). Step C: 4-Bromo-2-fluoro-6-methoxypyrazole[1,5-a]pyridine-3-carbaldehyde

[0334] [ka]

[0335] Phosphorus oxychloride (1.0 g, 6.5 mmol) was added dropwise to a solution of 4-bromo-2-fluoro-6-methoxypyrazole[1,5-a]pyridine (294 mg, 1.2 mmol) in DMF (10 mL) at 0°C. After the addition was complete, the mixture was allowed to warm to room temperature and react overnight. The reaction mixture was poured into 100 mL of ice water, adjusted to pH 7 with 2N NaOH solution, extracted with ethyl acetate, and the combined organic phases were concentrated under reduced pressure. The product (240 mg) was obtained by column chromatography. m / z = 273 [M+1] + . 1 HNMR (400MHz, DMSO-d6) δ 10.51 (s, 1H), 8.72 (d, 1H), 8.04 (d, 1H), 3.87 (s, 3H). Step D: 4-Bromo-6-methoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine

[0336] [ka]

[0337] The procedure was the same as in Step E of Example 22, m / z=267 [M+1] + , 1 HNMR (400MHz, DMSO-d6) δ 12.82 (s, 1H), 8.67 (d, 1H), 7.92 (s, 1H), 7.62 (d, 1H), 3.89 (s, 3H). Step E: 6-Methoxy-4-(5-(6-((6-methoxypyridine-3-methyl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-pyrazine-2-)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine

[0338] [ka]

[0339] The procedure was the same as in Step E of Example 16. E, m / z = 484 [M+1] + , 1 H NMR (400MHz, DMSO-d6) δ 12.50 (s, 1H), 8.98 (d, 1H), 8.59 (dd, 2H), 8.13 (d, 1H), 8.03 (s, 1H), 7.70-7.74 (m, 2H), 6.79 (d, 1H), 3.94 (s, 3H), 3.82-3.87 (m, 5H), 3.65-3.71 (m, 4H), 3.56 (s, 2H), 2.49-2.56 (m, 1H), 1.64 (d, 1H). Example 25

[0340] 6-(2,2-Difluoroethoxy)-4-(5-(6-((6-methoxypyridine-3-)methylene)-3,6-diazabicyclo[3.3.1]heptane-3-)pyrazine-2-)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (Compound 25)

[0341] [ka]

[0342] To a solution of 4-(5-(6-((6-methoxypyridin-3-)methylene)-3,6-diazabicyclo[3.3.1]heptane-3-)pyrazine-2-ol)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-ol (150 mg, 0.3 mmol) in DMF (10.0 mL), 1,1-difluoro-2-iodoethyl (58 mg, 0.3 mmol) and potassium carbonate (83 mg, 0.6 mmol) were added, heated to 80°C, and reacted for 12 hours. Water was added, and the mixture was extracted with ethyl acetate. The combined organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to obtain the product (12 mg). m / z = 534 [M+1] +,H NMR (400MHz, DMSO-d6) δ 12.55 (s, 1H), 9.01 (s, 1H), 8.73 (s, 1H), 8.55 (s, 1H), 8.12 (s, 1H), 8.07(s, 1H), 7.83(s, 1H), 7.72 (d, 1H), 6.77 (d, 1H), 6.35-6.66 (m, 1H), 4.50-4.57 (m, 2H), 3.82-3.87 (m, 5H), 3.65-3.84 (m, 4H), 3.56-3.64 (m, 2H), 1.62-1.64 (m, 1H). Example 26

[0343] 2-((4-(6-(6-((6-methoxypyridine-3-yl)methylene)-3,6-diazabicyclo[3.3.1]heptane-3-yl)pyridine-3-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-6-yl)oxy)acetonitrile (Compound 26)

[0344] [ka]

[0345] To a solution of 4-(6-(6-((6-methoxypyridin-3-)methylene)-3,6-diazabicyclo[3.3.1]heptane-3-)pyridin-3-)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-ol (150 mg, 0.3 mmol) in DMF (10.0 mL), bromoacetonitrile (36 mg, 0.3 mmol) and potassium carbonate (83 mg, 0.6 mmol) were added, heated to 90 °C, and reacted for 12 hours. Water was added, and the mixture was extracted with ethyl acetate. The combined organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to obtain the product (62 mg). m / z = 508 [M+1] + , 1H NMR (400MHz, DMSO-d6) δ 12.76 (s, 1H), 8.81 (s, 1H), 8.67 (s, 1H), 8.10-8.14 (m, 2H), 7.68-7.71 (m, 2H), 7.43 (s, 1H), 6.92 (d, 1H), 6.76 (d, 1H), 5.37 (s, 2H), 3.68-3.82 (m, 8H), 3.53-3.68(m, 3H), 2.51 (d, 1H), 1.58-1.61(m, 1H). Example 27

[0346] 6-(2-(difluoromethoxy)ethoxy)-4-(6-(6-((6-methoxypyridine-3-)methylene)-3,6-diazabicyclo[3.3.1]heptane-3-)pyridine-3-)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (Compound 27)

[0347] [ka]

[0348] To a solution of 4-(6-(6-((6-methoxypyridine-3-)methylene)-3,6-diazabicyclo[3.3.1]heptane-3-)pyridin-3-)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-ol (150 mg, 0.3 mmol) in DMF (10.0 mL), 2-(difluoromethoxy)ethyl p-toluenesulfonate (80 mg, 0.3 mmol; see WO2016 / 123706 for preparation method) and potassium carbonate (83 mg, 0.6 mmol) were added, heated to 90°C, and reacted for 12 hours. Water was added, and the mixture was extracted with ethyl acetate. The combined organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to obtain the product (143 mg). m / z = 563 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ 12.67 (s, 1H), 8.60-8.66 (dd, 2H), 8.10-8.13 (m, 2H), 7.63-7.72 (m, 2H), 7.32 (s, 1H), 6.91(d, 1H), 6.76-6.80 (m, 1H), 4.37 (d, 2H), 4.23 (d, 2H), 3.76-3.83 (m, 5H), 3.68-3.70 (m, 3H), 3.53-3.69 (m, 4H), 2.51 (d, 1H), 1.61 (d, 1H). Example 28

[0349] 6-(2-(cyclopropyl methoxy)ethoxy)-4-(6-(6-((6-methoxypyridine-3-)methylene)-3,6-diazabicyclo[3.3.1]heptane-3-)pyridine-3-)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (Compound 28)

[0350] [ka]

[0351] To a solution of 4-(6-(6-((6-methoxypyridine-3-)methylene)-3,6-diazabicyclo[3.3.1]heptane-3-)pyridin-3-)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-ol (150 mg, 0.3 mmol) in DMF (10.0 mL), 2-(cyclopropylmethoxy)ethyl p-toluenesulfonate (81 mg, 0.3 mmol; see US Pat. No. 4,406,907 for preparation method) and potassium carbonate (83 mg, 0.6 mmol) were added, heated to 90°C, and reacted for 12 hours. Water was added, and the mixture was extracted with ethyl acetate. The combined organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to obtain the product (127 mg). m / z = 567 [M+1] + . Example 29

[0352] 6-Isopropoxy-4-(6-(6-((6-methoxypyridine-3-)methylene)-3,6-diazabicyclo[3.3.1]heptane-3-)pyridine-3-)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (Compound 29)

[0353] [ka]

[0354] To a solution of 4-(6-(6-((6-methoxypyridine-3-)methylene)-3,6-diazabicyclo[3.3.1]heptane-3-)pyridin-3-ol)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-ol (150 mg, 0.3 mmol) in DMF (10.0 mL), 2-iodopropane (51 mg, 0.3 mmol) and potassium carbonate (83 mg, 0.6 mmol) were added, heated to 80°C, and reacted for 12 hours. Water was added, and the mixture was extracted with ethyl acetate. The combined organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to give the product (133 mg). m / z = 511 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ 12.65 (s, 1H), 8.65 (d, 1H), 8.55 (d, 1H), 8.11 (d, 2H), 7.63-7.72 (m, 1H), 7.62 (s, 1H), 7.26 (d, 1H), 6.92 (d, 1H), 6.79 (d, 1H), 4.75 (m, 1H), 3.72-3.83 (m, 5H), 3.70 (d, 2H), 3.53-3.60 (m, 4H), 2.51 (d, 1H), 1.59 (d, 1H), 1.36 (d, 6H). Example 30

[0355] 4-(6-(6-((6-methoxypyridine-3-)methylene)-3,6-diazabicyclo[3.3.1]heptane-3-)pyridine-3-)-6-(2,2,2-trifluoroethoxy)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (Compound 30)

[0356] [ka]

[0357] To a solution of 4-(6-(6-((6-methoxypyridin-3-)methylene)-3,6-diazabicyclo[3.3.1]heptane-3-)pyridin-3-)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-ol (150 mg, 0.3 mmol) in DMF (10.0 mL), trifluoroethyl p-toluenesulfonic acid (76 mg, 0.3 mmol) and potassium carbonate (83 mg, 0.6 mmol) were added, heated to 120 °C, and reacted for 12 hours. Water was added, and the mixture was extracted with ethyl acetate. The combined organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to give the product (20 mg). m / z = 551 [M+1] + . 1 HNMR (400MHz, DMSO-d6) δ 12.72 (s, 1H), 8.75 (d, 1H), 8.66 (d, 1H), 8.08-8.13 (m, 2H), 7.65-7.71 (m, 2H), 7.41 (d, 1H), 6.92 (d, 1H), 6.74-6.77 (m, 1H), 4.92-4.98 (m, 2H), 3.75-3.81 (m, 5H), 3.64-3.68 (m, 2H), 3.52-3.68 (m, 4H), 2.51 (d, 1H), 1.55-1.59 (m, 1H). Example 31

[0358] 6-(2-fluoroethoxy)-4-(6-(6-((6-methoxypyridine-3-)methylene)-3,6-diazabicyclo[3.3.1]heptane-3-)pyridine-3-)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (Compound 31)

[0359] [ka]

[0360] To a solution of 4-(6-(6-((6-methoxypyridin-3-)methylene)-3,6-diazabicyclo[3.3.1]heptane-3-)pyridin-3-)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-ol (150 mg, 0.3 mmol) in DMF (10.0 mL), 1-bromo-2-fluoroethane (38 mg, 0.3 mmol) and potassium carbonate (83 mg, 0.6 mmol) were added, heated to 70 °C, and reacted for 12 hours. Water was added, and the mixture was extracted with ethyl acetate. The combined organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to obtain the product (139 mg). 1 HNMR (400MHz, DMSO-d6) δ 12.68 (s, 1H), 8.61-8.66 (d, 2H), 8.10-8.13 (m, 2H), 7.64-7.12 (m, 2H), 7.33 (d, 1H), 6.93 (d, 2H), 6.79 (d, 2H), 4.89 (t, 1H), 4.76 (t, 1H), 4.47 (t, 1H), 4.39 (t, 1H), 3.76-3.83 (m, 5H), 3.70 (d, 2H), 3.53-3.60 (m, 4H), 2.51 (d, 1H), 1.61 (d, 1H). m / z=515 [M+1] + . Example 32

[0361] 6-(2,2-Difluoroethoxy)-4-(6-(6-((6-methoxypyridine-3-)methylene)-3,6-diazabicyclo[3.3.1]heptane-3-)pyridine-3-)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (Compound 32)

[0362] [ka]

[0363] To a solution of 4-(6-(6-((6-methoxypyridine-3-)methylene)-3,6-diazabicyclo[3.3.1]heptane-3-)pyridin-3-ol)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-ol (150 mg, 0.3 mmol) in DMF (10.0 mL), 1,1-difluoro-2-iodoethane (58 mg, 0.3 mmol) and potassium carbonate (83 mg, 0.6 mmol) were added, heated to 70 °C, and reacted for 12 hours. Water was added, and the mixture was extracted with ethyl acetate. The combined organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to obtain the product (118 mg). 1 HNMR (400MHz, DMSO-d6) δ 12.69 (s, 1H), 8.69 (d, 1H), 8.66 (d, 1H), 8.10-8.13 (m, 2H), 7.71 (d, 1H), 7.65 (s, 1H), 7.57 (s, 1H), 6.91 (d, 1H), 6.76 (d, 1H), 6.38-6.62 (m, 1H), 4.52 (t, 2H), 3.80-3.83 (m, 5H), 3.68 (m, 2H), 3.53-3.62 (m, 4H), 2.51 (d, 1H), 1.58 (d, 1H),m / z=533 [M+1] + . Example 33

[0364] 6-(Difluoromethoxy)-4-(6-(6-((6-methoxypyridine-3-)methylene)-3,6-diazabicyclo[3.3.1]heptane-3-)pyridine-3-)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (Compound 33)

[0365] [ka]

[0366] To a solution of 4-(6-(6-((6-methoxypyridin-3-)methylene)-3,6-diazabicyclo[3.3.1]heptane-3-)pyridin-3-)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-ol (150 mg, 0.3 mmol) in DMF (10.0 mL), sodium chlorodifluoroacetate (46 mg, 0.3 mmol) and potassium carbonate (83 mg, 0.6 mmol) were added, heated to 80°C, and reacted for 12 hours. Water was added, and the mixture was extracted with ethyl acetate. The combined organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to obtain the trifluoroacetate salt of the product (118 mg). m / z = 519 [M+1] + , 1 H NMR (400 MHz, DMSO-d6): 8.64 (s, 1H), 8.54 (s, 1H), 8.10-8.26 (m, 2H), 7.80-7.89 (m, 2H), 7.56 (s, 1H), 7.28-7.34 (m, 1H), 7.06-7.09 (m, 1H), 6.89-6.97 (m, 1H), 3.76-3.93 (m, 11H), 2.51 (d, 1H), 2.02-2.08 (m, 1H). Example 34

[0367] 6-(2-cyclopropoxyethoxy)-4-(6-(6-((6-methoxypyridine-3-)methylene)-3,6-diazabicyclo[3.3.1]heptane-3-)pyridine-3-)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (Compound 34)

[0368] [ka]

[0369] To a solution of 4-(6-(6-((6-methoxypyridine-3-)methylene)-3,6-diazabicyclo[3.3.1]heptane-3-)pyridin-3-)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-ol (150 mg, 0.3 mmol) in DMF (10.0 mL), 2-(cyclopropyloxy)ethyl p-toluenesulfonate (77 mg, 0.3 mmol) and potassium carbonate (83 mg, 0.6 mmol) were added and heated to 70 °C for 12 hours. Water was added, and the mixture was extracted with ethyl acetate. The combined organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to give the trifluoroacetate salt of the product (132 mg). m / z = 553 [M+1] + . 1 H NMR (400 MHz, DMSO-d6): 8.73 (s, 1H), 8.69 (s, 1H), 8.15-8.19 (m, 2H), 7.85-7.89 (m, 2H), 7.48-7.52 (m, 1H), 6.93-6.98 (m, 2H), 4.61-4.65 (m, 2H), 4.48-4.50 (m, 2H), 4.02-4.12 (m, 4H), 3.79-3.98 (m, 8H), 3.48-3.53 (m, 1H), 2.08-2.12 (m, 2H), 1.68-1.80 (m, 1H). Example 35

[0370] 6-ethoxy-4-(6-(6-((6-methoxypyridine-3-)methylene)-3,6-diazabicyclo[3.3.1]heptane-3-)pyridine-3-)-3-methyl-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (Compound 35) Step A: 1-(6-(benzyloxy)-4-bromo-2-fluoropyrazole[1,5-a]pyridin-3-yl)ethan-1-one

[0371] [ka]

[0372] To 6-(benzyloxy)-4-bromo-2-fluoropyrazole[1,5-a]pyridine (220 mg, 0.69 mmol) at 0°C, acetic anhydride (2.0 mL) was added, followed by phosphoric acid (0.2 mL). The mixture was stirred at room temperature for 12 h, concentrated under reduced pressure, and purified by column chromatography to give the product (100 mg). m / z = 364 [M+1] + . Step B: 1-(4-bromo-2-fluoro-6-hydroxylpyrazole[1,5-a]pyridin-3-yl)ethan-1-one

[0373] [ka]

[0374] To a solution of 1-(6-benzyloxy)-4-bromo-2-fluoropyrazole[1,5-a]pyridin-3-ethan-1-one (100 mg, 0.28 mmol) and palladium on carbon (5 mg) was added methanol (10.0 mL) at room temperature, and the mixture was purged with hydrogen gas three times using a hydrogen balloon. The mixture was then allowed to react overnight at room temperature. Water was added, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give the product (65 mg). m / z = 274 [M+1] + . Step C: 1-(4-bromo-6-ethoxy-2-fluoropyrazole[1,5-a]pyridin-3-yl)ethan-1-one

[0375] [ka]

[0376] 1-(4-Bromo-2-fluoro-6-hydroxylpyrazole[1,5-a]pyridin-3-yl)ethan-1-one (110 mg, 0.36 mmol), iodoethane (56 mg, 0.4 mmol), and potassium carbonate (167 mg, 1.2 mmol) were added to DMF (2.0 mL) and heated to 60 °C for 12 hours. Water was added, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to give the product (100 mg). m / z = 302 [M+1] + . Step D: 4-Bromo-6-ethoxy-3-methyl-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine

[0377] [ka]

[0378] 1-(4-Bromo-6-ethoxy-2-fluoropyrazole[1,5-a]pyridin-3-yl)ethan-1-one (110 mg, 0.37 mmol) was dissolved in DMF (5.0 mL), hydrazine hydrate (0.5 mL) was added, and the mixture was heated to 120 °C. Water was added, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to obtain the product (72 mg). m / z = 296 [M+1] + . Step E: 6-ethoxy-4-(6-(6-((6-methoxypyridine-3-)methylene)-3,6-diazabicyclo[3.3.1]heptane-3-)pyridine-3-)-3-methyl-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine

[0379] [ka]

[0380] 4-Bromo-6-ethoxy-3-methyl-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (72 mg, 0.24 mmol), 6-((6-methoxypyridine-3-methylene)-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)pyridine-2-yl)-3,6-diazabicyclo[3.1.1]heptane (101 mg, 0.24 mmol) (Prepared with reference to the method of WO2018 / 71447), tetrakis(triphenylphosphine)palladium (18 mg, 0.013 mol), potassium carbonate (66 mg, 0.48 mol), 1,4-dioxane (2 mL), and HO (1 mL) were mixed and vented with nitrogen gas three times. The reaction was allowed to proceed at 90 °C for 2 hours. LCMS confirmed the completion of the reaction and the product was obtained. Water was added, and the mixture was extracted with ethyl acetate. The combined organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to obtain the product (36 mg). 1 HNMR (400MHz, DMSO-d6) δ 12.11 (s, 1H), 8.49 (d, 2H), 8.06 (s, 1H), 7.88 (d, 1H), 7.69 (d, 1H), 7.03 (s, 1H), 6.85 (dd, 2H), 4.17 (d, 2H), 3.67-3.82 (m, 3H), 3.49-3.56 (m, 4H), 3.44-3.54 (m, 4H), 2.51 (d, 1H), 1.98 (s, 3H), 1.60 (d, 1H), 1.40 (t, 3H). m / z=511[M+1] + . Example 36

[0381] 6-Methoxy-4-(6-(6-((6-methoxypyridine-3-)methylene)-3,6-diazabicyclo[3.3.1]heptane-3-)pyridine-3-)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (Compound 36)

[0382] [ka]

[0383] To a solution of 4-(6-(6-((6-methoxypyridin-3-)methylene)-3,6-diazabicyclo[3.3.1]heptane-3-)pyridin-3-)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-ol (150 mg, 0.3 mmol) in DMF (10.0 mL), iodomethane (43 mg, 0.3 mmol) and potassium carbonate (83 mg, 0.6 mmol) were added, heated to 60 °C, and reacted for 12 hours. Water was added, and the mixture was extracted with ethyl acetate. The combined organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to obtain the product (137 mg). 1 HNMR (400MHz, DMSO-d6) δ 12.66 (s, 1H), 8.64-8.65 (m, 1H), 8.55 (d, 1H), 7.63-7.71 (m, 3H), 7.28 (d, 1H), 6.93 (d, 1H), 6.79 (d, m / z=483[M+1] + . Example 37

[0384] 6-(cyclopropoxy)-4-(6-(6-((6-methoxypyridine-3-)methylene)-3,6-diazabicyclo[3.3.1]heptane-3-)pyridine-3-)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (compound 37)

[0385] [ka]

[0386] To a solution of 4-(6-(6-((6-methoxypyridin-3-)methylene)-3,6-diazabicyclo[3.3.1]heptane-3-)pyridin-3-)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-ol (150 mg, 0.3 mmol) in DMF (10.0 mL), cyclopropyl bromomethane (41 mg, 0.3 mmol) and potassium carbonate (83 mg, 0.6 mmol) were added, heated to 60 °C, and reacted for 12 hours. Water was added, and the mixture was extracted with ethyl acetate. The combined organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to give the product (66 mg). 1H NMR (400 MHz, DMSO-d6) δ 12.63 (s, 1H), 8.63 (s, 1H), 8.47 (s, 1H), 8.10 (m, 2H), 7.65 (m,1H), 7.60 (s, 1H), 7.29 (s, 1H), 6.90 (d, 1H), 6.77 (d, 1H), 3.96 (d, 2H), 3.81 (s, 3H), 3.4-3.75 (m, 8H), 2.51 (d, 1H), 1.60 (d, 1H), 0.75-0.85 (m, 1H), 0.59 (m, 2H), 0.36 (m,2H), m / z=523[M+1] + . Example 38

[0387] 4-(6-(6-((6-methoxypyridine-3-)methylene)-3,6-diazabicyclo[3.3.1]heptane-3-)pyridine-3-)-6-propoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (compound 38)

[0388] [ka]

[0389] To a solution of 4-(6-(6-((6-methoxypyridin-3-)methylene)-3,6-diazabicyclo[3.3.1]heptane-3-)pyridin-3-)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-ol (150 mg, 0.3 mmol) in DMF (10.0 mL), 1-bromopropane (37 mg, 0.3 mmol) and potassium carbonate (83 mg, 0.6 mmol) were added, heated to 60°C, and reacted for 12 hours. Water was added, and the mixture was extracted with ethyl acetate. The combined organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to give the product (96 mg). m / z = 511 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.63 (s, 1H), 8.63 (d, 1H), 8.51 (d, 1H), 8.08 (s, 2H), 7.77-7.65 (m, 1H), 7.60 (s, 1H), 7.26 (d, 1H), 6.90 (d, 1H), 6.76 (d, 1H), 4.08 (t, 2H), 3.81 (s, 3H), 3.76 (d, 2H), 3.67 (d, 2H), 3.58 (s, 1H), 3.52 (s, 2H), 2.51 (d, 1H), 1.78 (p, 2H), 1.58 (d, 1H), 1.22 (s, 1H), 1.02 (t, 3H). Example 39

[0390] 6-Isobutoxy-4-(6-(6-((6-methoxypyridine-3-)methylene)-3,6-diazabicyclo[3.3.1]heptane-3-)pyridine-3-)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (Compound 39)

[0391] [ka]

[0392] To a solution of 4-(6-(6-((6-methoxypyridin-3-)methylene)-3,6-diazabicyclo[3.3.1]heptane-3-)pyridin-3-)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-ol (150 mg, 0.3 mmol) in DMF (10.0 mL), 1-bromo-2-methylpropane (41 mg, 0.3 mmol) and potassium carbonate (83 mg, 0.6 mmol) were added, heated to 60 °C, and reacted for 12 hours. Water was added, and the mixture was extracted with ethyl acetate. The combined organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to give the product (33 mg). m / z = 525 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.63 (s, 1H), 8.64 (d, 1H), 8.51 (d, 1H), 8.12-8.07 (m, 2H), 7.69 (dd, 1H), 7.60 (s, 1H), 7.27 (d, 1H), 6.90 (d, 1H), 6.76 (d, 1H), 3.90 (d, 2H), 3.81 (s, 3H), 3.76 (d, 2H), 3.67 (d, 2H), 3.51 (s, 2H), 2.51 (d, 1H), 2.07 (dq, 1H), 1.58 (d, 1H), 1.24 (d, 2H), 1.02 (d, 6H). Example 40

[0393] 6-(2-Methoxy-2-methylpropoxy)-4-(6-(6-((6-methoxypyridine-3-)methylene)-3,6-diazabicyclo[3.3.1]heptane-3-)pyridine-3-)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (Compound 40)

[0394] [ka]

[0395] Biological activity measurement measurement example 1

[0396] The recombinant human transmembrane receptor (RET) is one of the identified proto-oncogenes. The single-pass transmembrane receptor tyrosine kinase encoded by this gene is essential for the development, maturation, and maintenance of many tissues and cell types. Under normal conditions, binding of glial cell line-derived neurotrophic factor (GDNF) family ligands to cell surface RET leads to dimerization and autophosphorylation of intracellular tyrosine residues, leading to downstream activation of the RAS-MAPK / PI3K-AKT and phospholipase Cγ (PLCγ) pathways, resulting in increased cell survival and proliferation. Activating RET mutations include C634W, M918T, gatekeeper mutations V804L and V804M, and solvent front mutation G810R. This test combines a peptide substrate and a single unique monoclonal antibody with HTRF technology, a highly sensitive and stable technique used to detect interactions between protein molecules. An enzyme phosphorylates the substrate, and then a Eu-labeled antibody binds to the phosphorylated substrate, and streptavidin-XL665 binds to all substrates. A TR-FRET signal is generated based on the principle of HTRF. Once an inhibitor (test compound) is added, a relatively weak TR-FRET signal is obtained, which is used to evaluate the inhibitory effect.

[0397] [Table 1]

[0398] 1.2 Solution formulation All compounds are dissolved in DMSO to make up a 10 mM stock solution. Cabozantinib was diluted 3-fold in a gradient from 2 mM and 0.2 mM using DMSO to create a total of 10 concentrations. Other compounds are diluted 3-fold in a gradient with DMSO from a 10 mM stock solution to give a total of 10 concentrations. A 1000x positive control (0.1 mM Cabozantinib) and a 1000x negative control (100% DMSO) are made.

[0399] Shake on a plate shaker for 5 minutes. 1.3 Make 1x kinase buffer.

[0400] Add 4 volumes of distilled water to 1 volume of kinase buffer 5x; 5 mM MgCl2; 1 mM DTT. 1.4 Screening Methods a) 1 μl compound dilution is plated into all wells of the assay plate; b) Centrifuge the compound plate at 1000 g for 1 minute.

[0401] c) Seal the measuring plate.

[0402] d) Make 2x Ret wt (0.04 ng / μl) and 2x Ret V804M (0.2 ng / μl) and 2x RET G810R (2 ng / μl) in 1x kinase buffer.

[0403] e) 5 μl of 2× Ret wt or Ret V804M or RET G810R is placed in a 384-well assay plate.

[0404] f) Centrifuge the sample plate at 1000 g for 30 seconds and leave at room temperature for 10 minutes.

[0405] g) In 1x kinase buffer, make a solution of 5x TK-substrate-biotin (5 μM) in kinase buffer and 5x ATP (50 μM) in kinase buffer.

[0406] h) The reaction is started by adding 2 μl STK-substrate-biotin and 2 μl ATP (product of step g).

[0407] i) Centrifuge the sample plate at 1000 g for 30 seconds. Seal the measurement plate and leave it at room temperature for 30 minutes.

[0408] j) Make 4x Sa-XL 665 (250 nM) in HTRF assay buffer.

[0409] k) 5 μl of Sa-XL 665 and 5 μl of TK-antibody-Cryptate (product of step i) are placed in all wells of the measurement plate.

[0410] l) Centrifuge at 1000g for 30 seconds and leave at room temperature for 1 hour.

[0411] m) Read the fluorescence signal at 620 nm (Cryptate) and 665 nm (XL665) on an Envision 2104 reader or a BioTek microplate reader. 1.5 Data Analysis The ratio (665nm / 620nm) for each hole is calculated.

[0412] The formula for calculating % inhibition is as follows: Inhibition rate % = [1 - (test compound ratio - average positive control ratio) / (average negative control ratio - average positive control ratio)] x 100% Ratio: Generated from measured fluorescent signal values.

[0413] Positive control mean ratio is the mean ratio of the positive control (20 μM Cabozantinib) in the sample plate; The negative control mean ratio is the mean ratio of the negative control (0.1% DMSO) in the sample plate.

[0414] Nonlinear regression fit and compound IC 50 The values ​​(half median inhibitory concentrations) were calculated. Data were analyzed using the software GraphPad 6.0.

[0415] Y=Bottom +(Top-Bottom) / (1+10^((LogIC 50 -X)*Hill Slope)) X: Compound concentration Log value Y: Inhibition rate (% inhibition) Z' Factor Technical Equation: Z'=1-3(SDmin+SDmax) / (AVEmax-AVEmin) Min is the positive control drug 20μM Cabozantinib Ratio (665 / 620nM×10000), and Max is the negative control drug DMSO Ratio (665 / 620nM×10000).

[0416] SD is the standard error, and AVE is the average value of the ratio (665 / 620 nM × 10,000). Kinase results are shown in Tables 2, 3, and 4.

[0417] [Table 2]

[0418] [Table 3]

[0419] [Table 4]

[0420] The experimental results shown in Tables 2, 3, and 4 reveal the following: Compounds 1, 7, 9, 12, 27, 31, 32, 36, 38, and 39 all have significantly more inhibitory activity against RET wt than cabozantinib. Compounds 1, 7, 9, 12, 16, 17, 23, 27, 31, 32, 36, 38, and 39 all have significantly more inhibitory activity against RET V804M than cabozantinib. Compounds 3, 5, 7, 9, 10, 11, 12, 13, 14, 15, 16, 18, 19, 20, 21, 22, 24, 25, 26, 27, 30, 31, 32, 36, 38, and 39 all have significantly more inhibitory activity against RET G810R than cabozantinib and selpercatinib (LOXO-292). Measurement Example 2

[0421] [Table 5]

[0422] 2.2 Experimental Procedure a) Cabozantinib and test compounds (10 mM stock solution) were diluted 5-fold with 100% DMSO to 2 mM, and diluted 1:3 in a 384-well dilution plate to prepare 10 concentrations.

[0423] b) Using an Echo, 200 nL of the product from step a was transferred to a 384 cell culture plate. The gradient concentrations of cabozantinib and the test compound were 10,000, 3,333.3, 1,111.1, 370.4, 123.4, 41.1, 13.7, 4.5, 1.5, and 0.5 nM, and the final DMSO concentration was 0.5%.

[0424] c) The nutrient medium for the TT cell line contains 10% FBS and 1% penicillin-streptomycin.

[0425] d) The cell suspension was added to a compound-containing 384-well plate (product of step b), with 800 cells per well and a volume of 40 μL, and then cultured in a cell culture box for 72 h.

[0426] e) Take out the 384-well cell culture plate and add 20 μl CTG reagent.

[0427] f) Vibrate for 2 minutes in a high-speed vibrator, then leave at room temperature for 30 minutes.

[0428] The fluorescent signal is read on Envision. 2.3 Data Processing %inhibition = 100 × (HC - reading of test compound well) / (HC - LC) High control (HC, no control inhibition reading): 0.5% DMSO Low control (LC, with compound inhibition control): 1 μM CEP-32496 IC using GraphPad Prism 6 software 50 Calculate.

[0429] Y=Bottom + (Top-Bottom) / (1+10^((LogIC 50 -X)*HillSlope)); X: log of cpd concentration; Y: %inhibition; Top and Bottom: Plateaus in same units as Y; logIC 50 : same log units as X; HillSlope: Slope factor Cell results are shown in Table 5:

[0430] [Table 6]

[0431] The experimental results shown in Table 5 indicate that compounds 2, 3, 5, 6, 7, 8, 9, 10, 11, 12, 13, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 34, 36, 37, 38, and 39 are all significantly superior to cabozantinib in inhibiting the activity of TT cells.

[0432] Efficacy study of TT cell-derived human medullary thyroid carcinoma xenograft model 3.1 Cell culture TT tumor cells were cultured in F12K medium containing 10% inactivated fetal bovine serum, 100 U / mL penicillin, 100 μg / mL streptomycin, and 2 mM glutamine at 37°C in a 5% CO2 culture chamber. The initial cell density was 1 × 10 6 Cells are passaged by dividing them into bottles at a density of 1000 cells / ml every 3-4 days until the cells are full. Tumor cells in the logarithmic growth phase are used for in vivo tumor inoculation. 3.2 Tumor cell inoculation and sorting 1 x 10 TT tumor cells resuspended in serum-free F12K medium 7 + 100 μL of gel was inoculated subcutaneously into the right flank of the test animals. Tumors grew to approximately 224 mm 3 When they reached adulthood, they were divided into groups and administered drugs, with six animals per group. 3.3 Dosing, Tumor Measurements, and Experimental Endpoints Mice were orally administered the test compounds twice daily for 28 consecutive days. Tumor volume: The long and short diameters of the tumor were measured using a caliper. The volume was calculated using the formula: volume = 0.5 × long diameter × short diameter. 2 During the treatment period, animals were instructed to measure body weight and tumor size twice a week. Animal response after administration: At the same time as tumor measurement, the test animals were weighed. The relationship between the animal's weight change and the administration time was recorded. At the same time, the survival and health status, such as the activity and feeding status of the mice during the administration period, were observed. Relative tumor growth rate T / C (%) = TRTV / CRTV × 100% (TRTV: treatment group RTV; CRTV: negative control group RTV), where relative tumor volume (RTV) is calculated as RTV = Vt / V0, where V0 is the tumor volume measured at the time of grouping and administration (i.e., on the first day of administration), and Vt is the tumor volume measured at each administration. Tumor growth inhibition rate TGI (%) = (1-T / C) × 100%. In a TT human medullary thyroid carcinoma xenograft model, Compounds 9, 31, and 32 were administered at a dose of 10 mg / kg, and all exhibited significant tumor-inhibitory effects (TGI = 88.5%, TGI = 87.4%, and TGI = 86.9%), and the efficacy of all three groups was considerable. During the administration period, the animals in each group showed good general condition, including activity and feeding, and no significant weight loss or side effects were observed. Specific results are shown in Figure 1. Measurement Example 4

[0433] Efficacy study of Ba / F3 cell KIF5B-RET-V804M fusion xenograft model 4.1 Cell culture Ba / F3 KIF5B-RET-V804M tumor cells were cultured in RPMI-1640 medium containing 10% inactivated fetal bovine serum, 100 U / ml penicillin, 100 μg / ml streptomycin, and 2 mM glutamine in a culture chamber at 37°C in 5% CO2. When the cells reached full capacity every 3-4 days, they were bolted and passaged. Tumor cells in the logarithmic growth phase were used for in vivo tumor inoculation. 4.2 Tumor cell inoculation and sorting Resuspended in the same volume of PBS as Matrigel at a concentration of 5 × 10 7 100 μl / mouse of Ba / F3 KIF5B-RET-V804M tumor cells were subcutaneously inoculated into the right flank of BALB / c nude mice, and tumors grew to approximately 194 mm 3 When the animals reached adulthood, they were given drugs in groups, with six animals per group. 4.3 Dosing, Tumor Measurements, and Experimental Endpoints The test compound was orally administered to the mice twice a day for 14 consecutive days.

[0434] Tumor volume: The long and short diameters of the tumor were measured using a caliper. The volume was calculated using the formula: volume = 0.5 × long diameter × short diameter. 2 During the treatment period, animals were instructed to measure body weight and tumor size twice weekly. Post-administration animal response: The tumors were measured and the weight of the test animals was recorded. The relationship between weight change and administration time was also recorded. At the same time, the survival and health status of the mice, including their activity, feeding, and other general conditions during the administration period, were observed. Relative tumor growth rate T / C (%) = TRTV / CRTV × 100% (TRTV: treatment group RTV; CRTV: negative control group RTV), where relative tumor volume (RTV) is calculated as RTV = Vt / V0, where V0 is the tumor volume measured at the time of grouping and administration (on the first day of administration), and Vt is the tumor volume measured at each administration. Tumor growth inhibition rate TGI (%) = (1-T / C) × 100%. Selpercatinib, Compound 9, Compound 31, and Compound 32 were all administered at a dose of 10 mg / kg. At the end of the experiment (day 8 of administration), the tumor growth inhibition rates in the control group were 49%, 94%, 92%, and 96%, respectively. The tumor volumes in each treatment group were significantly smaller than those in the control group (p<0.05). The tumor volumes in the Compound 9, Compound 31, and Compound 32 groups were all significantly smaller than those in the selpercatinib group (p<0.05). At the end of the experiment (day 14 of administration), the tumor volumes in the Compound 9, Compound 31, and Compound 32 groups were all significantly smaller than those in the selpercatinib group (p<0.05). All tumor-bearing mice tolerated the treatment well throughout the treatment period. All mice in each group maintained normal body weight, showed no abnormal behavior, and were in good general condition. See Figure 2 for specific results. The present invention relates to the field of medicinal chemistry, and in particular to nitrogen-containing polycyclic fused ring compounds represented by Formula I, as well as pharmaceutical compositions, preparation methods, and uses thereof. The compounds of the present invention can be used as highly selective and highly effective RET inhibitors, and this type of compound has relatively strong inhibitory activity against all RET gatekeeper residue mutants, including the RET V804M mutation, the RET solvent front residue mutant RETG810R, other clinically relevant RET mutants, and RET wt. Furthermore, the compounds can significantly inhibit the growth of a TT cell line derived from thyroid cancer and Ba / F3 cells metastasized from various RET mutants, as well as significantly induce the death of TT cells. Although the present invention has been described herein with reference to exemplary embodiments, it should be understood that the scope of the present invention is not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principle of the present invention are intended to be included within the scope of the present invention. [Brief explanation of the drawings]

[0435] [Figure 1] Figure 1 shows the inhibitory effects of compounds on TT cell-derived human medullary thyroid cancer xenograft tumor models. [Figure 2] FIG. 2 shows the inhibitory effect of compounds on Ba / F3 cell KIF5B-RET-V804M fusion xenograft model tumors.

Claims

1. A compound of formula I or a stereoisomer, racemate, tautomer, or pharmaceutically acceptable salt thereof, 【Chemical 1】 Among them, X 1 , X 2 , X 3 and X 4 are homologous or different, each independently CR 1 and N; X 5 is CR 1 Selected from; X 6 and X 7 is N; X 8 is NR 1 and of which: Each R 1 are identical or different, each independently H, F, Cl, Br, CN, NH 2 and OH; or Each R 1 are homologous or different, each independently unsubstituted or one, two or three R a The following groups substituted with: C 1-3 Alkyl group, C 4-6 Cyclic alkyl group, C 1-3 Alkoxy groups and C 4-6 selected from cyclic alkyl groups and oxy groups; Each R a are homologous or different, each independently F, Cl, Br, CN, OH, C 1-3 Alkyl group, C 4-6 Cyclic alkyl group and C 1-3 alkoxy groups; A is H, NH 2 and C 1-6 alkyl groups; E is H; D is H, halogen, CN, OH, NH 2 and unsubstituted or one, two or three R c the following groups substituted with: -C 1-6 Alkyl group, -C 1-6 Alkoxy groups, and -O(CH 2 ) n O(CH 2 ) n C 3-6 selected from carbocyclic rings; Each R c are the same or different, and each independently represents halogen, CN, OH, oxo (=O), C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 selected from a cyclic alkyl group, a 3- to 10-membered heterocyclic group, a 6- to 10-membered aryl group, a 3- to 6-membered cyclic alkyloxy group, and a 3- to 8-membered heterocyclic oxy group; each n is identical or different and is independently selected from 0, 1, 2, and 3; The number and type of heteroatoms in each heterocycle and heterocyclic group in Rc are the same or different, and each independently contain one, two or three heteroatoms, and the heteroatoms are selected from N, O and S; G is one of the following groups: 【Chemistry 2】 each ring is independently selected from unsubstituted or 1, 2, 3, or 4 R G and each R G are homologous or different, and each R G are independently H, halogen, OH, NH 2 , C 1-6 Alkyl, halogen-substituted C 1-6 Alkyl group, C 1-6 Alkoxy and halogen substituted C 1-6 alkoxy groups; K is unsubstituted or contains one, two or more R K the following groups substituted with: -C 1-3 Alkylene benzene ring, -COC 1-3 Alkylenebenzene ring, -C 1-3 Alkylene group 5-8 membered aromatic heterocycle, -COC 1-3 Alkylene, 5-8 membered aromatic heterocycle, and -CONR K1 R K2 Selected from; Each R K are identical or different, each independently -CN, OH, -NH 2 , C 1-6 Alkyl groups, and C 1-6 Alkoxy groups, halogen-substituted C 1-6 alkyl groups; R K1 and R K2 are homologous or different, each independently C 1-6 alkyl groups; or K is unsubstituted or one or more R g -C(O)R substituted with 4 Selected from R 4 is selected from a phenyl group and a 5- to 6-membered heteroaryl group, and each R g are the same or different, each independently a halogen, CN, OH, SH, C 1-6 Alkyl groups, and C 1-6 selected from alkyloxy groups; The compound of formula I, or a stereoisomer, racemate, tautomer, or pharmaceutically acceptable salt thereof, wherein each aromatic heterocycle, heterocycle, or heterocyclic group in K is the same or different and each independently contains one or two N atoms.

2. X 1 , X 3 , X 4 and X 5 are all CR 1 Selected from; X 2 is N; X 6 and X 7 is N; X 8 is NR 1 and R 1 2. The compound of formula I according to claim 1, wherein is H, or a stereoisomer, racemate, tautomer or pharmaceutically acceptable salt thereof.

3. X 1 , X 3 , X 4 and X 5 is CH and X 2 is N and X 8 3. The compound of formula I according to claim 2, wherein is NH, or a stereoisomer, racemate, tautomer or pharmaceutically acceptable salt thereof.

4. A is H, NH 2 4. The compound of formula I according to claim 3, wherein the aryl group is selected from the group consisting of methyl, ethyl, and propyl, or a stereoisomer, racemate, tautomer, or pharmaceutically acceptable salt thereof.

5. A is H, NH 2 and -CH 3 5. The compound of formula I according to claim 4, wherein the compound is selected from the group consisting of:

6. D is H, F, Cl, Br, CN, OH, NH 2 and unsubstituted or one, two or three R c substituted with the following groups: methyl group, ethyl group, propyl group, methoxy group, ethoxy group, propoxy group, -O(CH 2 ) n O(CH 2 ) n -3-membered carbocycle, -O(CH 2 ) n O(CH 2 ) n -4-membered carbocyclic ring, and -O(CH 2 ) n O(CH 2 ) n - selected from 5-membered carbocyclic rings; each n is identical or different, and is independently selected from 0, 1, and 2; Each R c are homologous or different, each independently F, Cl, Br, CN, OH, C 1-3 Alkyl group, C 3-5 Cyclic alkyl group, 4-6 membered heterocyclic group, 5-6 membered heteroaryl group, phenyl group, C 1-3 selected from an alkoxy group, a 3- to 5-membered cyclic alkyloxy group, and a 4- to 6-membered saturated heterocyclic oxy group; The compound of formula I according to any one of claims 1 to 5, wherein the number and type of heteroatoms in each heterocycle, heterocyclic group, and heteroaryl group in Rc are the same or different, each independently containing 1 or 2 heteroatoms, and the heteroatoms are selected from N and O, or a stereoisomer, racemate, tautomer, or pharmaceutically acceptable salt thereof.

7. Each R c are identical or different, and each independently selected from F, Cl, Br, CN, OH, methyl, ethyl, propyl, a 3-membered alkyl group, a 4-membered alkyl group, a 4-membered saturated heterocyclic group, a 5-membered saturated heterocyclic group, a 6-membered saturated heterocyclic group, a 5-membered heteroaryl group, a 6-membered heteroaryl group, a phenyl group, a methoxy group, an ethoxy group, a propoxy group, a 3-membered alkyloxy group, a 4-membered alkyloxy group, a 5-membered saturated heterocyclic group, and a 6-membered saturated heterocyclic group.

8. Dは、-H、-Br、-Cl、-CH 3 、-NH 2 、BnO-、 【Chemistry 3】 7. The compound of formula I according to claim 6, wherein the compound is selected from the group consisting of:

9. Each R G are homologous or different, and each R G are each independently H, halogen, OH, or NH 2 , C 1-6 Alkyl, halogen-substituted C 1-6 Alkyl group, C 1-6 Alkoxy and halogen substituted C 1-6 6. The compound of formula I according to any one of claims 1 to 5, or a stereoisomer, racemate, tautomer or pharmaceutically acceptable salt thereof, characterized in that: the alkoxy group is selected from the group consisting of alkoxy groups.

10. Each R G are homologous or different, and each R G are each independently H, F, Cl, Br, OH, NH 2 , C 1-3 C substituted with alkyl group, F or Cl 1-3 Alkyl groups, and C 1-3 10. The compound of formula I according to claim 9, or a stereoisomer, racemate, tautomer or pharmaceutically acceptable salt thereof, wherein: R is selected from the group consisting of alkoxy groups.

11. Each R G are homologous or different, and each R G are each independently H, NH 2 11. The compound of formula I according to claim 10, wherein the aryl group is selected from the group consisting of methyl, ethyl, propyl, methyl substituted with F, ethyl substituted with F, propyl substituted with F, methoxy, ethoxy and propoxy.

12. X 1 , X 3 , X 4 and X 5 are all CR 1 Selected from; X 2 is N; X 6 and X 7 is N; X 8 is NR 1 and G is one of the following groups: 【Chemistry 4】 each ring is independently selected from unsubstituted or 1, 2, 3, or 4 R G and each R G are homologous or different, and each R G are independently H, F, Cl, Br, OH, NH 2 , C 1-3 C substituted with alkyl group, F or Cl 1-3 Alkyl groups, and C 1-3 6. The compound of formula I according to any one of claims 1 to 5, or a stereoisomer, racemate, tautomer or pharmaceutically acceptable salt thereof, characterized in that: the alkoxy group is selected from the group consisting of alkoxy groups.

13. Each R G are homologous or different, and each R G are each independently H, NH 2 13. The compound of formula I according to claim 12, or a stereoisomer, racemate, tautomer or pharmaceutically acceptable salt thereof, wherein the aryl group is selected from the group consisting of methyl, ethyl, propyl, methyl substituted with F, ethyl substituted with F, propyl substituted with F, methoxy, ethoxy and propoxy.

14. K is unsubstituted or contains one, two or more R K the following groups substituted with: -C 1-3 Alkylene benzene ring, -COC 1-3 Alkylenebenzene ring, -C 1-3 Alkylene group 5-8 membered aromatic heterocycle, -COC 1-3 Alkylene, 5-8 membered aromatic heterocycle, and -CONR K1 R K2 Selected from; Each R K are each independently -CN, OH, or -NH 2 , C 1-3 Alkyl group, C 1-3 Alkoxy group, C substituted with F 1-3 C substituted with alkyl groups and Cl 1-3 Alkyl groups, C substituted with F 1-3 Alkoxy and Cl-substituted C 1-3 alkoxy groups; R K1 and R K2 are homologous or different, each independently C 1-3 alkyl groups; or K is unsubstituted or one or more R g -C(O)R substituted with 4 Selected from R 4 is selected from a phenyl group and a pyridinyl group, and each R g are the same or different, each independently a halogen, CN, OH, C 1-6 Alkyl groups, and C 1-6 6. The compound of formula I according to any one of claims 1 to 5, or a stereoisomer, racemate, tautomer or pharmaceutically acceptable salt thereof, characterized in that: the alkyl group is selected from the group consisting of alkoxy, ...

15. K is unsubstituted or contains one, two or more R K the following groups substituted with: -C 1-3 Alkylene benzene ring, -COC 1-3 Alkylenebenzene ring, -C 1-3 Alkylene group 5-8 membered aromatic heterocycle, -COC 1-3 Alkylene, 5-8 membered aromatic heterocycle, and -CONR K1 R K2 Selected from; Each R K are each independently one of the following groups: -CN, OH, -NH 2 , selected from methyl, ethyl, methoxy and ethoxy groups; R K1 and R K2 are the same or different and are each independently selected from a methyl group and an ethyl group; or K is unsubstituted or one or more R g -C(O)R substituted with 4 Selected from R 4 is selected from a phenyl group and a pyridinyl group, and each R g are the same or different, each independently a halogen, CN, OH, C 1-3 Alkyl groups, and C 1-3 15. The compound of formula I according to claim 14, or a stereoisomer, racemate, tautomer or pharmaceutically acceptable salt thereof, wherein the alkyloxy group is selected from the group consisting of alkyloxy groups.

16. K is 【Chemistry 5】 6. A compound of formula I according to any one of claims 1 to 5, or a stereoisomer, racemate, tautomer or pharmaceutically acceptable salt thereof, selected from:

17. The compounds of formula I are as follows: 【Chemistry 6】 【change】 【change】 2. The compound of formula I according to claim 1, wherein the compound is selected from the group consisting of:

18. 18. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 17 or a stereoisomer, racemate, tautomer or pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable auxiliary material.

19. 18. Use of a compound according to any one of claims 1 to 17, or a stereoisomer, racemate, tautomer or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment, prevention or prevention of a disease or condition mediated by RET activity, comprising: (1) determining whether the disease or condition is associated with a disruption in the expression, activity or value of the RET gene, the RET kinase protein, or any one or more thereof; and (2) if it is determined that the disease or condition is associated with a disruption in the expression, activity or value of the RET gene, the RET kinase protein, or any one or more thereof.

20. The use described in claim 19, characterized in that the drug is used to inhibit the RET gatekeeper residue mutant RET V804M, the RET solvent front residue mutant G810R, and other clinically relevant RET mutants and wt-RET, or is used to inhibit the proliferation of TT cell lines derived from thyroid cancer and Ba / F3 cells transformed with various RET mutants, or is used to induce the death of TT cells.

21. A method for producing a compound of formula I-1, the method comprising reacting a compound of formula I-2 to produce a compound of formula I-1, 【Chemistry 7】 Among them, A, E, G, K, and X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , and X 8 has the definition according to any one of claims 1 to 17.

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