A RET inhibitor, its pharmaceutical composition and its use

Abstract

The present invention belongs to the field of medicine, and relates to a new RET inhibitor, a pharmaceutical composition thereof and its use. Specifically, the present invention relates to a compound represented by formula (I), or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the compound represented by formula (I), and the present invention also relates to a pharmaceutical composition comprising the compound, and the use of the compound and its pharmaceutical composition in the preparation of a drug, which is particularly used for the treatment and prevention of RET-related diseases and disorders, including cancer, irritable bowel syndrome and / or pain associated with irritable bowel syndrome.

Description

Technical Field

[0001] The present invention belongs to the field of medicine. Specifically, the present invention relates to new compounds that exhibit inhibition of rearranged during transfection (RET) kinase, pharmaceutical compositions comprising the compounds, and use of the compounds or their pharmaceutical compositions in the preparation of drugs, which are particularly useful for treating and preventing RET-related diseases and conditions, including cancer, irritable bowel syndrome and / or pain associated with irritable bowel syndrome. Background Art

[0002] Re-arranged during transfection (RET) kinase is a receptor tyrosine kinase belonging to the cadherin superfamily, and its activation involves multiple downstream pathways of cell proliferation and survival.

[0003] It is reported that the results of abnormal RET gene production (point mutation, chromosomal translocation, chromosomal inversion, gene amplification) involve canceration. RET fusion protein is associated with several cancers, including papillary thyroid cancer and non-small cell lung cancer. The identification of RET fusion protein as a driver of certain cancers has promoted the use of multikinase inhibitors with RET inhibitory activity to treat patients whose tumors express RET fusion protein. It is reported that multikinase inhibitors such as sorafenib, sunitinib, vandetanib, and ponatinib show cell proliferation inhibition effects on cell lines expressing KIF5B-RET (J Clin Oncol 30, 2012, suppl; Abstract no: 7510). In addition, it is reported that the multikinase inhibitor cabozantinib showed partial efficacy in two patients with RET fusion gene-positive non-small cell lung cancer (Cancer Discov, 3 (6), Jun 2013, p. 630-5). However, these drugs cannot always be administered at levels sufficient to inhibit RET, which is caused by toxicity caused by inhibition of targets other than RET. In addition, one of the biggest challenges in treating cancer is the ability of tumor cells to develop resistance to treatment. Reactivation of kinases via mutations is a common mechanism of drug resistance. When resistance occurs, patients' treatment options are usually very limited, and in most cases cancer progression is not inhibited. WO 2017011776 discloses a single-target RET kinase inhibitor that has a good preventive or therapeutic effect on cancers related to RET and its mutations. There is still a need to further develop compounds that inhibit RET and its resistance mutants to deal with cancers related to RET gene abnormalities. Summary of the invention

[0004] The present invention provides a novel compound exhibiting inhibition of rearranged during transfection (RET) kinase, wherein the compound has a good inhibitory effect on RET wild type and RET gene mutants, and compared with other kinases, the compound of the present invention has a good inhibitory selectivity for RET wild type and RET gene mutants.

[0005] The excellent properties of certain parameters of the compounds of the present invention, such as half-life, clearance rate, selectivity, bioavailability, chemical stability, metabolic stability, membrane permeability, solubility, etc., can lead to the reduction of side effects, the expansion of therapeutic index or the improvement of tolerability.

[0006] In one aspect, the present invention provides a compound represented by formula (I), or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the compound represented by formula (I),

[0007]

[0008] in,

[0009] X 1 , X 2 , X 3 , X 4 and X 5 Each independently is CR 4 or N;

[0010] Y is O, NH or S;

[0011] T is a bond, alkylene, carbocyclylene, heterocyclylene, arylene, heteroarylene, alkylene-O-alkylene, alkylene-NH-alkylene, alkylenecarbocyclylene, alkyleneheterocyclylene, carbocyclylalkylene, heterocyclylalkylene, alkylenearylene, alkyleneheteroarylene, arylenealkylene, heteroarylenealkylene, alkyleneheterocyclylalkylene, or alkyleneheteroarylenealkylene, and said T is optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of D, OH, F, Cl, Br, I, CN, NH2, oxo, alkyl, hydroxyalkyl, haloalkyl, carbocyclyl, heterocyclyl, alkoxy, alkoxyalkoxy, aryl, heteroaryl, and alkylamino;

[0012] E is a bond, -NR 6 -or-O-;

[0013] Ring A is a carbocyclylene or heterocyclylene, and the ring A is optionally substituted by 1, 2, 3 or 4 groups selected from F, Cl, Br, OH, oxo, NR 5 R 6 , R 5 O-、R 5 (C=O)NR 6-, substituted by substituents of aminoalkyl, alkyl, alkoxy, haloalkyl, hydroxyalkyl, carbocyclyl, heterocyclyl, heterocyclylalkyl and alkoxyalkyl;

[0014] Q is a key, -(CR 3 R 3a ) t O-、-(CR 3 R 3a ) t O(CR 3 R 3a ) f -、-(CR 3 R 3a ) f -、-(CR 3 R 3a ) t -NR 6 -、-(CR 3 R 3a ) t -NR 6 (CR 3 R 3a ) f -、-(C=O)(CR 3 R 3a ) t -、-(C=O)(CR 3 R 3a ) t -S(=O)2(CR 3 R 3a ) f -、-(C=O)(CR 3 R 3a ) t -NR 6 (CR 3 R 3a ) f -、-(C=O)(CR 3 R 3a ) t -O(CR 3 R 3a ) f -、-(C=O)NR 5 O(CR 3 R 3a ) f -、-S(=O)2-NR 6 -(CR 3 R 3a ) t -、-(CR 3 R 3a ) f -(C=O)-, -(CR3 R 3a ) t -(C=O)-NR 5 -(CR 3 R 3a ) t -、-S(=O)2(CR 3 R 3a ) t -、-(CR 3 R 3a ) f -S(=O)2(CR 3 R 3a ) t -, -S(=O)2O-, -O(C=O)-, -(C=O)NR 6 -or-NR 6 (C=O)(CR 3 R 3a ) t -;

[0015] Each f is independently 1, 2, 3 or 4;

[0016] Each t is independently 0, 1, 2, 3 or 4;

[0017] M is H, D, heteroaryl, aryl, carbocyclyl or heterocyclyl, and M is optionally substituted by 1, 2, 3 or 4 groups selected from D, F, Cl, CN, OH, NR 5 R 6 , alkyl, alkoxy, haloalkyl, hydroxyalkyl, haloalkoxy, aryl, alkoxyalkyl, oxo, alkylacyl, heterocyclyl and cycloalkyl substituents;

[0018] R 1 is H, D, CN, F, Cl, Br, alkyl or cycloalkyl, wherein the alkyl and cycloalkyl are each independently optionally substituted with 1, 2, 3 or 4 substituents selected from F, Cl, Br, CN, NH2, OH and NO2;

[0019] R 2 is H, D, alkyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl, alkoxyalkyl, arylalkyl, heteroarylalkyl or aminoalkyl, and R 2 Optionally, 1, 2, 3 or 4 selected from F, Cl, Br, OH, NR 5 R 6 , R 5 O-、R 5 O(C=O)-、R 5 (C=O)-、NR 5 R 6 (C=O)NR5 -、R 5 Substituted by S(=O)2-, NO2, CN, CF3, alkyl, alkoxy and cycloalkyl substituents;

[0020] Each R 3 and R 3a is independently OH, F, H, D, CN, Cl, Br, NH2, hydroxyalkyl, alkyl, alkylamino, alkoxy, haloalkoxy, cycloalkyl, haloalkyl, cycloalkylalkyl, aryl or heteroaryl;

[0021] or, R 3 , R 3a It forms a carbocyclic or heterocyclic ring with the same carbon atom to which it is attached;

[0022] Each R 4 is independently H, D, alkyl, F, Cl, Br or alkoxy, wherein the alkyl and alkoxy groups are independently optionally substituted with 1, 2, 3 or 4 substituents selected from F, Cl, Br, CN, NH2, OH and NO2;

[0023] Each R 5 are independently H, D, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxyalkyl, aryloxyalkyl, aminoalkyl, carbocyclylalkyl or heterocyclylalkyl, and R 5 is optionally substituted with 1, 2, 3 or 4 substituents selected from F, Cl, Br, OH, NH2, alkyl, alkynyl, alkylsulfonyl, alkoxy, aryl and heteroaryl; and

[0024] Each R 6 are independently H or alkyl.

[0025] In some embodiments, T is a bond, C 1-6 Alkylene, 3-12 membered carbocyclylene, 3-12 membered heterocyclylene, C 6-10 Arylene, 5-10 membered heteroarylene, C 1-6 Alkylene-OC 1-6 Alkylene, C 1-6 Alkylene-NH-C 1-6 Alkylene, C 1-6 Alkylene-(3-12 membered carbocyclyl), C 1-6 Alkylene-(3-12 membered heterocyclylene), (3-12 membered carbocyclylene)-C 1-6 Alkylene, (3-12 membered heterocyclylene)-C 1-6 Alkylene, C 1-6 Alkylene C 6-10 Arylene, C 1-6 Alkylene-(5-10 membered heteroarylene), C6-10 Arylene C 1-6 Alkylene, (5-10 membered heteroarylene)-C 1-6 Alkylene, C 1-6 Alkylene-(3-12 membered heterocyclylene)-C 1-6 Alkylene or C 1-6 Alkylene-(5-10 membered heteroarylene)-C 1-6 wherein T is optionally substituted by 1, 2, 3 or 4 groups selected from D, OH, F, Cl, Br, I, CN, NH2, oxo, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 haloalkyl, 3-12 membered carbocyclic group, 3-12 membered heterocyclic group, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkoxy, C 6-10 Aryl, 5-10 membered heteroaryl and C 1-6 The amino group is substituted with an alkylamino group.

[0026] In some embodiments, T is a bond, C 1-6 Alkylene, 3-6 membered carbocyclylene, 3-6 membered heterocyclylene, C 6-10 Arylene, 5-10 membered heteroarylene, C 1-4 Alkylene-OC 1-4 Alkylene, C 1-4 Alkylene-NH-C 1-4 Alkylene, C 1-4 Alkylene-(3-6 membered carbocyclyl), C 1-4 Alkylene-(3-6 membered heterocyclylene), (3-6 membered carbocyclylene)-C 1-4 Alkylene, (3-6 membered heterocyclylene)-C 1-4 Alkylene, C 1-4 Alkylene C 6-10 Arylene, C 6-10 Arylene C 1-4 Alkylene, (5-6 membered heteroarylene)-C 1-4 Alkylene, C 1-4 Alkylene-(5-6 membered heteroarylene), C 1-4 Alkylene-(3-6 membered heterocyclylene)-C 1-4 Alkylene or C 1-4 Alkylene-(5-6 membered heteroarylene)-C 1-4 wherein T is optionally substituted by 1, 2, 3 or 4 groups selected from D, OH, F, Cl, Br, I, CN, NH2, oxo, C 1-4 Alkyl, C 1-4 Hydroxyalkyl, C 1-4haloalkyl, 3-6 membered carbocyclic group, 3-6 membered heterocyclic group, C 1-4 Alkoxy, C 1-4 Alkoxy C 1-4 Alkoxy, C 6-10 Aryl, 5-6 membered heteroaryl and C 1-4 The amino group is substituted with an alkylamino group.

[0027] In some embodiments, T is a bond, -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -CH2CH(CH3)-, -CH2CH(CH3)CH2-, -CH2C(CH3)2-, -(CH2)2CH(CH3)-, -(CH2)2OCH2-, -(CH2)2NHCH2-, -(CH2)3NHCH2-, -(CH2)2-cyclopentylidene, -CH2-cyclopentylidene, -CH2-cyclobutylene, -(CH2)2-piperidinylene, -(CH2)2-piperazinylene, -(CH2)2-piperazinylene-CH2-, -CH2-tetrahydropyranylene, -(CH2)2-tetrahydropyranylene, -CH2- wherein T is pyridinyl, cyclobutylene, cyclopentylene, azetidinyl, azetidinyl-CH2-, octahydropentalenyl, spiro[4.4]nonyl, octahydrocyclopentapyrrolyl, -(CH2)2-octahydrocyclopentapyrrolyl, -(CH2)2-2-azaspiro[3.4]octanyl, -(CH2)2-3-azabicyclo[3.1.1]heptanyl, phenylene, -CH2-oxazolyl-CH2- or -CH2-imidazolyl-CH2-, and T is optionally substituted with 1, 2, 3 or 4 substituents selected from D, F, Cl, Br, I, CN, NH2, OH, oxo, methyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclopentyl, cyclopropylidene, azetidinyl, chloromethyl, fluoromethyl, cyclohexyl, methoxymethoxy, and methylamino.

[0028] In some embodiments, ring A is a 3-12 membered carbocyclylene or a 3-12 membered heterocyclylene, and the ring A is optionally substituted by 1, 2, 3 or 4 selected from F, Cl, Br, OH, oxo, NR 5 R 6 , R 5 O-、R 5 (C=O)NR 6 -、C 1-6 Aminoalkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, 3-12 membered carbocyclic group, 3-12 membered heterocyclic group, (3-12 membered heterocyclic group)-C1-6 Alkyl and C 1-6 Alkoxy C 1-6 substituted by an alkyl substituent;

[0029] Each R 5 Independently H, D, C 1-6 Alkyl, 3-6 membered carbocyclic group, 3-6 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, C 6-10 Aryl C 1-6 Alkyl, (5-10 membered heteroaryl)-C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 6-10 Aryloxy C 1-6 Alkyl, C 1-6 aminoalkyl, (3-6 membered carbocyclic)-C 1-6 Alkyl or (3-6 membered heterocyclic)-C 1-6 alkyl, and the R 5 Optionally, 1, 2, 3 or 4 selected from F, Cl, Br, OH, NH2, C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Alkylsulfonyl, C 1-6 Alkoxy, C 6-10 substituted with aryl and 5-10 membered heteroaryl substituents; and

[0030] R 6 H, D or C 1-6 alkyl.

[0031] In some embodiments, Ring A is of the following sub-structure:

[0032]

[0033] Among them, each Z 1 and Z 2 are independently CH2 or NH;

[0034] Z 4 is CH or N;

[0035] Each Z 3 and Z 5 is independently a bond, CH2, O, S, NH, C=O, S=O or S(=O)2;

[0036] m is 0, 1 or 2;

[0037] n, m1 and n1 are each independently 0 or 1;

[0038] Each substructure of ring A is independently optionally substituted by 1, 2, 3 or 4 groups selected from F, Cl, Br, OH, oxo, NR 5 R 6 , R 5 O-、R 5 (C=O)NR 6 -、C 1-4 Aminoalkyl, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, 3-6 membered carbocyclyl, 3-6 membered heterocyclyl, 3-6 membered heterocyclylalkyl and C 1-4 Alkoxy C 1-4 substituted by an alkyl substituent;

[0039] Each R 5 are independently H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylethyl, cyclobutylmethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, methoxymethyl, methoxyethyl, ethoxyethyl, phenylmethyl, phenylethyl, phenyl-n-propyl, pyridylmethyl, pyridylethyl, pyridyl-n-propyl, phenoxymethyl, phenoxyethyl, phenoxy-n-propyl, azetidinyl, oxetanyl or tetrahydropyranyl, and said R 5 optionally substituted with 1, 2, 3 or 4 substituents selected from F, Cl, Br, OH, NH2, CH3S(=O)2-, CH3CH2S(=O)2-, CH(CH3)2S(=O)2-, C(CH3)3S(=O)2-, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, ethynyl, methoxy, ethoxy, n-propoxy, phenyl, pyridyl, pyrazolyl and pyrimidinyl; and

[0040] Each R 6 is independently H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.

[0041] In some embodiments, Ring A is of the following sub-structure:

[0042]

[0043] And each sub-formula of Ring A is independently optionally substituted by 1, 2, 3 or 4 substituents selected from F, Cl, Br, oxo, OH, NH2, NHCH3, CH3(C=O)NH-, methyl, ethyl, n-propyl, methoxy, ethoxy, isopropoxy, CF3, hydroxymethyl, 2-hydroxyethyl, cyclopropyl, cyclohexyl, pyrrolidinyl, piperidinyl and tetrahydrofuranyl.

[0044] In some embodiments, M is H, D, 5-10 membered heteroaryl, C 6-10 aryl, 3-12 membered carbocyclyl or 3-12 membered heterocyclyl; and M is optionally substituted by 1, 2, 3 or 4 selected from F, Cl, CN, OH, NR 5 R 6 , C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkoxy, C 6-10 Aryl, C 1-6 Alkoxy C 1-6 Alkyl, oxo, C 1-6 Alkyl acyl, 3-7 membered heterocyclic group and C 3-7 Substituted by a cycloalkyl substituent;

[0045] Among them, each R 5 and R 6 Has the definition as described in the present invention.

[0046] In some embodiments, M is H, D, pyridinyl, pyrimidinyl, pyridazinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, pyrazinyl, phenyl, cyclopentyl, cyclopropyl, cyclohexyl, cyclobutyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, morpholinyl, tetrahydrothiopyranyl, oxetanyl, 1,2-dihydropyridinyl, 7-azabicyclo[2.2.1]heptanyl, hexahydrofuro[3,4-c]pyrrolyl, 3-azabicyclo[3.1.0]hexanyl, octahydropyrrolo[1,2-a]pyrazinyl, or 5-azaspiro[2.4]heptanyl; and M is optionally substituted with 1, 2, 3 or 4 substituents selected from D, F, Cl, CN, OH, CF3, CHCl2, CHF2, CH2F, CF3CH2, NH2, NHCH3, CH2OH, N(CH3)2, trifluoromethoxy, 2,2,2-trifluoroethoxy, methoxy, ethoxy, isopropoxy, tert-butoxy, methyl, ethyl, n-propyl, isopropyl, phenyl, methoxymethyl, methoxyethyl, oxo, formyl, acetyl, morpholinyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, cyclopropyl and cyclohexyl.

[0047] In some embodiments, R 2 H, D, C 1-6 Alkyl, C 2-6 Alkynyl, 3-12 membered carbocyclic group, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, (3-12 membered carbocyclyl)-C 1-6Alkyl, (3-12 membered heterocyclic)-C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 6-10 Aryl C 1-6 Alkyl, (5-10 membered heteroaryl)-C 1-6 Alkyl or C 1-6 aminoalkyl, and the R 2 Optionally, 1, 2, 3 or 4 selected from F, Cl, Br, OH, NR 5 R 6 , R 5 O-、R 5 O(C=O)-、R 5 (C=O)-、NR 5 R 6 (C=O)NR 5 -、R 5 S(=O)2-,NO2,CN,CF3,C 1-6 Alkyl, C 1-6 Alkoxy and C 3-12 Substituted by a cycloalkyl substituent;

[0048] Among them, each R 5 and R 6 Has the definition as described in the present invention.

[0049] In some embodiments, R 2 H, D, C 1-4 Alkyl, C 2-4 alkynyl, 3-10 membered carbocyclyl, 3-10 membered heterocyclyl, phenyl, 5-10 membered heteroaryl, (3-10 membered carbocyclyl)-C 1-4 Alkyl, (3-10 membered heterocyclic)-C 1-4 Alkyl, C 1-4 Alkoxy C 1-4 Alkyl, phenyl C 1-4 Alkyl, (5-10 membered heteroaryl)-C 1-4 Alkyl or C 1-4 aminoalkyl, and the R 2 Optionally, 1, 2, 3 or 4 selected from F, Cl, Br, OH, NR 5 R 6 , R 5 O-、R 5 O(C=O)-、R 5 (C=O)-、NR 5 R 6 (C=O)NR 5 -、R 5 S(=O)2-,NO2,CN,CF3,C 1-4Alkyl, C 1-4 Alkoxy and C 3-6 Substituted by a cycloalkyl substituent;

[0050] Among them, each R 5 and R 6 Has the definition as described in the present invention.

[0051] In some embodiments, R 2 is H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, ethynyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentylmethyl, cyclopropylmethyl, cyclobutylmethyl, cyclohexylmethyl, spiro[4.4]nonylmethyl, azaspiro[4.4]nonylmethyl, bicyclo[3.3.0]octanyl, pyrrolidinyl, azetidinyl, piperidinyl, morpholinyl, azetidinylmethyl, piperidinylmethyl, morpholinylmethyl, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, n-propoxymethyl , isopropoxymethyl, isopropoxyethyl, n-butoxymethyl, isobutoxymethyl, tert-butoxymethyl, tert-butoxyethyl, phenyl, pyridyl, imidazolyl, pyrazolyl, pyrimidinyl, 3H-indolyl, indolyl, benzimidazolyl, 3,8a-dihydroindolazinyl, phenylmethyl, 3,8a-dihydroindolazinylmethyl, pyridylmethyl, imidazolylmethyl, pyrazolylmethyl, pyrimidinylmethyl, 3H-indolylmethyl, indolylmethyl, benzimidazolylmethyl, NH2CH2-, NH2(CH2)2- or N(CH3)2(CH2)2-, and said R 2 Optionally substituted by 1, 2, 3 or 4 substituents selected from F, Cl, Br, OH, NH2, NO2, CN, CF3, C(CH3)3O(C=O)-, CH3(C=O)-, NH2(C=O)NH-, NHCH3(C=O)NH-, CH3S(=O)2-, methyl, methoxy, ethoxy, n-propoxy, isopropoxy, phenoxy, pyridyloxy, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0052] In some embodiments, R 1 is H, D, CN, F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl are each independently optionally substituted with 1, 2, 3 or 4 substituents selected from F, Cl, Br, CN, NH2, OH and NO2; and

[0053] Each R 4independently H, D, F, Cl, Br, CN, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butylmethoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butylmethoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy and tert-butoxy are each independently and optionally substituted with 1, 2, 3 or 4 substituents selected from F, Cl, Br, CN, NH2, OH and NO2.

[0054] In some embodiments, each R 3 and R 3a are independently OH, F, H, D, CN, Cl, Br, NH2, C 1-6 Hydroxyalkyl, C 1-6 Alkyl, C 1-6 Alkylamino, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-7 Cycloalkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl C 1-6 Alkyl, C 6-10 Aryl or 5-10 membered heteroaryl;

[0055] or, R 3 , R 3a Together with the same C atom connected to it, it forms a 3-7 membered carbocyclic ring or a 3-7 membered heterocyclic ring.

[0056] In some embodiments, each R 3 and R 3a is independently OH, F, CF3, CHCl2, CHF2, H, D, CN, Cl, Br, NH2, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, methyl, ethyl, N(CH3)2, methoxy, ethoxy, isopropoxy, tert-butoxy, trifluoromethoxy, cyclopropyl, cyclopentyl, cyclopropylmethyl, cyclopentylethyl, cyclopentylmethyl, phenyl, pyridyl or pyrazinyl;

[0057] or, R 3 , R 3a Together with the same C atom to which it is attached, it forms cyclopentane, cyclopropane, cyclobutane, tetrahydropyran, tetrahydrofuran, piperidine or pyrrolidine.

[0058] In some embodiments, Q is a bond, -O-, -(CH2)2O-, -(CH2)2OC(CH3)2CH2-, -CH2-, -(CH2)2-, -(CH2)3-, -CH2CH(CH3)CH2-, -CH2CH(CH3)CH2NHCH2-, -CH2N(CH3)CH2-, -(C=O)OC(CH3)2CH2-, -(C=O)(CH2)2S(=O)2CH2-, -(C=O)CH(OH)CH2-, -(C=O)CH(OH)-, -(C=O)CH(OH)CH2-, -(C=O)-, -S(=O)2-, -(C=O)CH2CH(O H)-, -(C=O)CH2-, -(C=O)CH(CH2OH)-, -(C=O)C(CH3)2-, -(C=O)CH2NHC(CH3)2CH2-, -(C=O)CH2CH(N(CH3)2)-, -(C=O)(CH2)2CH(N(CH3)2)-, -(C=O )C(CH3)2CH2-, -(C=O)C(OH)(CH3)CH2-, -(C=O)CH2OCH2-, -(C=O)(CH2)3-, -(C=O)CH(NH2)-, -(C=O)(CH2)3N(CH3)CH2-, -(C=O)(CH2)2-, -(C=O)CH 2CH(OH)CH2-, -(C=O)CF2CH2-, -(C=O)CH(OH)C(CH3)2CH2-, -(C=O)CH2C(CH3)2-, -(C=O)CH2C(CH3)2CH2-, -(C=O)CH2C(CH3)(OH)CH2-, -S(=O)2CH 2-, -S(=O)2CH2C(CH3)2CH2-, -(C=O)CH(OCH3)-, -(C=O)NHCH(CH2OH)(CH2)2-, -(C=O)NH-, -(C=O)OCH2C(CH3)2-, -(C=O)N(CH3)-, -(C=O)N(CH2CH2 CH2CH3)-, -(C=O)N(CH2CH3)(CH2)2-, -(C=O)NHC(CH3)2CH2-, -(C=O)N(CH3)(CH2)2-, -(C=O)NHCH2CH(CH3)CH2-, -(C=O)NHCH2-, -(C=O)NH(CH2)2O CH2-, -(C=O)N(CH3)CH2CH(OCH3)-, -S(=O)2NHC(CH3)2CH2-, -CH2CH(OH)C(CH3)2CH2-, -CH(CH3)CH(OH)-, -CH2(C=O)NHCH(CH3)CH2-, -CH2(C=O)-,-(CH2)2(C=O)N(CH3)CH2-, -CH2CH(OH)-, -CH2CH(OH)CH2-, -CH2CH(OH)CH(CH3)CH2-, -(C=O)CH(N(CH3)2)-, -(C=O)C(CH3) 2)CH2OCH2-, -(C=O)C(OCH3)(CF3)-, -(C=O)N(CH2CH2OCH3)CH2CH(OCH3)-, -CH2CH(OCF3)-, -CH2CH(OCH(CH3)2)-, -CH2CH( OC(CH3)3)-, -CH2CF2-, -CH(CH3)-, -CH2CH(OCH3)C(CH3)2-, -CH2CH(N(CH3)2)-, -NH-, -(C=O)NHOCH2-, -(C=O)NHOCH2(CHO H)-, -S(=O)2(CH2CH3)-, -S(=O)2O-, -S(=O)2-NHC(CH3)2-, -(CH2)2S(=O)2-, -(CH2)3S(=O)2CH(CH3)CH2-, -NH(C=O)CH2-,

[0059] In some embodiments, the compound described in the present invention has a structure of formula (I-1), or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the structure of formula (I-1),

[0060]

[0061] in,

[0062] Each Z 1a and Z 2a are independently CH or N;

[0063] Each Z 3 and Z 5 is independently a bond, CH2, O, S, NH, C=O, S=O or S(=O)2;

[0064] m is 0, 1 or 2;

[0065] and may be optionally substituted by 1, 2, 3 or 4 selected from F, Cl, Br, OH, oxo, NR 5 R 6 , R 5 O-、R 5 (C=O)NR 6 -、C 1-4 Aminoalkyl, C 1-4 Alkyl, C 1-4 Alkoxy, C1-4 Haloalkyl, C 1-4 Hydroxyalkyl, 3-6 membered carbocyclyl, 3-6 membered heterocyclyl, 3-6 membered heterocyclylalkyl and C 1-4 Alkoxy C 1-4 substituted by an alkyl substituent;

[0066] Each R 1 , R 2 , R 5 , R 6 , X 1 , X 2 , X 3 , X 4 , X 5 , T, E, Q and M have the definitions as described in the present invention.

[0067] In some embodiments, The substructure is: and Each sub-structural formula is independently optionally substituted by 1, 2, 3 or 4 substituents selected from F, Cl, Br, OH, oxo, NH2, NHCH3, CH3(C=O)NH-, methyl, ethyl, n-propyl, methoxy, ethoxy, isopropoxy, CF3, hydroxymethyl, 2-hydroxyethyl, cyclopropyl, cyclohexyl, pyrrolidinyl, piperidinyl and tetrahydrofuranyl.

[0068] In some embodiments, the compound described in the present invention has a structure of formula (I-2), or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the structure of formula (I-2).

[0069]

[0070] in,

[0071] Ring A1 is the following substructure:

[0072] Z 1 and Z 2 are each independently CH or N;

[0073] Each substructure of ring A1 is independently optionally substituted by 1, 2, 3 or 4 groups selected from F, Cl, Br, OH, oxo, NR 5 R 6 , R 5 O-、R 5 (C=O)NR 6 -、C 1-4 Aminoalkyl, C 1-4 Alkyl, C1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, 3-6 membered carbocyclyl, 3-6 membered heterocyclyl, 3-6 membered heterocyclylalkyl and C 1-4 Alkoxy C 1-4 substituted by an alkyl substituent;

[0074] Each R 1 , R 2 , R 5 , R 6 , X 1 , X 2 , X 3 , X 4 , X 5 , T, E, Q and M have the definitions as described in the present invention.

[0075] In some embodiments, Ring A1 is the following substructure:

[0076]

[0077] Each sub-formula of ring A1 is independently optionally substituted by 1, 2, 3 or 4 substituents selected from F, Cl, Br, OH, oxo, NH2, NHCH3, CH3(C=O)NH-, methyl, ethyl, n-propyl, methoxy, ethoxy, isopropoxy, CF3, hydroxymethyl, 2-hydroxyethyl, cyclopropyl, cyclohexyl, pyrrolidinyl, piperidinyl and tetrahydrofuranyl.

[0078] In some embodiments, the compound described in the present invention has a structure of formula (I-3), or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the structure of formula (I-3).

[0079]

[0080] wherein ring A2 is

[0081] Z 1 , Z 2 and Z 4 are each independently CH or N;

[0082] m is 0, 1 or 2;

[0083] n, m1 and n1 are each independently 0 or 1;

[0084] and Each independently optionally substituted by 1, 2, 3 or 4 selected from F, Cl, Br, OH, oxo, NR 5 R 6 , R5 O-、R 5 (C=O)NR 6 -、C 1-4 Aminoalkyl, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, 3-6 membered carbocyclyl, 3-6 membered heterocyclyl, 3-6 membered heterocyclylalkyl and C 1-4 Alkoxy C 1-4 substituted by an alkyl substituent;

[0085] Each R 1 , R 2 , R 5 , R 6 , X 1 , X 2 , X 3 , X 4 , X 5 , T, E, Q and M have the definitions as described in the present invention.

[0086] In some embodiments,

[0087] Ring A2 is

[0088] And each sub-structure of ring A2 is independently optionally substituted by 1, 2, 3 or 4 substituents selected from F, Cl, Br, oxo, OH, NH2, NHCH3, CH3(C=O)NH-, methyl, ethyl, n-propyl, methoxy, ethoxy, isopropoxy, CF3, hydroxymethyl, 2-hydroxyethyl, cyclopropyl, cyclohexyl, pyrrolidinyl, piperidinyl and tetrahydrofuranyl.

[0089] In some embodiments, the compounds described herein have one of the following structures, or a stereoisomer, tautomer, N-oxide, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof,

[0090]

[0091]

[0092]

[0093]

[0094]

[0095]

[0096]

[0097]

[0098]

[0099]

[0100]

[0101]

[0102] In another aspect, the present invention provides a pharmaceutical composition comprising the compound of the present invention and a pharmaceutically acceptable adjuvant.

[0103] On the other hand, the present invention also provides use of the compound of the present invention or the pharmaceutical composition of the present invention in the preparation of a medicament for preventing or treating RET-related diseases.

[0104] In some embodiments, RET-related diseases include cancer, irritable bowel syndrome, and / or pain associated with irritable bowel syndrome.

[0105] On the other hand, the present invention also provides the compound of the present invention or the pharmaceutical composition of the present invention for use in preventing or treating RET-related diseases.

[0106] In some embodiments, RET-related diseases include cancer, irritable bowel syndrome, and / or pain associated with irritable bowel syndrome.

[0107] On the other hand, the present invention also provides a method for preventing or treating RET-related diseases, comprising administering a therapeutically effective amount of the compound of the present invention or a pharmaceutical composition thereof to a patient.

[0108] In some embodiments, RET-related diseases include cancer, irritable bowel syndrome, and / or pain associated with irritable bowel syndrome.

[0109] In another aspect, the present invention relates to an intermediate for preparing a compound represented by formula (I), (I-1), (I-2) or (I-3).

[0110] On the other hand, the present invention relates to methods for preparing, isolating and purifying the compounds represented by formula (I), (I-1), (I-2) or (I-3).

[0111] On the other hand, the present invention provides a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable adjuvant thereof. In some embodiments, the adjuvant of the present invention includes, but is not limited to, a carrier, an excipient, a diluent, a solvent, or a combination thereof. In some embodiments, the pharmaceutical composition can be a liquid, solid, semisolid, gel or spray formulation.

[0112] Unless otherwise indicated, all stereoisomers, geometric isomers, tautomers, N-oxides, hydrates, solvates, metabolites, salts and pharmaceutically acceptable prodrugs of the compounds of the invention are within the scope of the invention.

[0113] In particular, the salts are pharmaceutically acceptable salts. The term "pharmaceutically acceptable" includes that the substance or composition must be suitable chemically and toxicologically with respect to the other ingredients that make up the formulation and with the mammal to be treated.

[0114] The salts of the compounds of the present invention also include intermediates or products of formula (I), (I-1), (I-2) or (I-3) for preparing or purifying the compounds of formula (I), (I-1), (I-2) or (I-3).

[0115] The salts of the isolated enantiomers of the compounds represented by (I-1), (I-2) or (I-3) are not necessarily pharmaceutically acceptable salts.

[0116] In structures disclosed herein, when the stereochemistry of any particular chiral atom is not indicated, all stereoisomers of the structure are contemplated within the present invention and are included as compounds disclosed herein. When stereochemistry is indicated by a solid wedge or dashed line representing a particular configuration, the stereoisomers of the structure are thus unambiguous and defined.

[0117] Nitrogen oxides of the compounds of the invention are also included within the scope of the invention. Nitrogen oxides of the compounds of the invention can be prepared by oxidation of the corresponding nitrogen-containing basic substance using a conventional oxidizing agent (e.g., hydrogen peroxide) in the presence of an acid such as acetic acid at elevated temperatures, or by reaction with a peracid in a suitable solvent, such as peracetic acid in methylene chloride, ethyl acetate or methyl acetate, or with 3-chloroperoxybenzoic acid in chloroform or methylene chloride.

[0118] If the compound of the present invention is basic, the desired salt can be prepared by any suitable method provided in the literature, for example, using inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid, etc. Or using organic acids such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid and salicylic acid; pyranose acids such as glucuronic acid and galacturonic acid; α-hydroxy acids such as citric acid and tartaric acid; amino acids such as aspartic acid and glutamic acid; aromatic acids such as benzoic acid and cinnamic acid; sulfonic acids such as p-toluenesulfonic acid, ethanesulfonic acid, etc.

[0119] If the compound of the present invention is acidic, the desired salt can be prepared by a suitable method, for example, using an inorganic base or an organic base, such as ammonia (primary, secondary, tertiary), an alkali metal hydroxide or an alkaline earth metal hydroxide, etc. Suitable salts include, but are not limited to, organic salts derived from amino acids, such as glycine and arginine, ammonia, such as primary, secondary and tertiary, and cyclic amines, such as piperidine, morpholine and piperazine, etc., and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.

[0120] Detailed description of the invention

[0121] Definitions and general terms

[0122] Certain embodiments of the present invention are now described in detail, examples of which are illustrated by the accompanying structural formulas and chemical formulae. The present invention is intended to encompass all substitutions, modifications, and equivalent technical solutions, which are all included within the scope of the present invention as defined in the claims. It should be appreciated by those skilled in the art that many methods and materials similar or equivalent to those described herein can be used to practice the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the combined documents, patents, and similar materials differ from or contradict the present application (including but not limited to defined terms, term applications, described technologies, etc.), the present application shall prevail.

[0123] It should be further appreciated that certain features of the invention, which for clarity are described in multiple separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which for brevity are described in a single embodiment, may also be provided separately or in any suitable sub-combination.

[0124] Unless otherwise specified, all technical terms used in the present invention have the same meaning as commonly understood by those skilled in the art to which the present invention belongs. All patents and publications related to the present invention are incorporated herein by reference in their entirety.

[0125] The term "subject" as used in the present invention refers to an animal. Typically, the animal is a mammal. Subjects, for example, also refer to primates (e.g., humans, male or female), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.

[0126] The term "patient" used in the present invention refers to humans (including adults and children) or other animals. In some embodiments, "patient" refers to humans.

[0127] The term "comprising" is an open expression, that is, including the contents specified in the present invention but not excluding other contents.

[0128] "Stereoisomers" refer to compounds with the same chemical structure but different arrangements of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis / trans isomers), atropisomers, and the like. Unless otherwise indicated, all stereoisomers or mixtures of stereoisomers of the structural formula described in the present invention are within the scope of the present invention. In addition, unless otherwise indicated, the structural formula of the compounds described in the present invention includes one or more enriched isotopes of different atoms.

[0129] The stereochemical definitions and conventions used herein generally follow SP Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994.

[0130] Any resulting mixture of stereoisomers can be separated into the pure or substantially pure geometric isomers, enantiomers, diastereomers on the basis of the differences in the constituent physicochemical properties, for example, by chromatography and / or fractional crystallization.

[0131] The term "tautomer" or "tautomeric form" refers to structural isomers with different energies that can be mutually converted through a low energy barrier. If tautomerism is possible (such as in solution), a chemical equilibrium of tautomers can be reached. For example, proton tautomers (protontautomers) (also known as prototropic tautomers) include mutual conversions by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include mutual conversions by the reorganization of some bonding electrons. A specific example of keto-enol tautomerism is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-ene-2-one tautomers. Another example of tautomerism is phenol-keto tautomerism. A specific example of phenol-keto tautomerism is the interconversion of pyridine-4-ol and pyridine-4 (1H)-one tautomers. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

[0132] As described herein, the compounds of the present invention may be independently optionally substituted with one or more substituents, such as the general formula compounds above, or as specific examples in the embodiments, subclasses, and classes of compounds encompassed by the present invention. It should be understood that the terms "independently optionally substituted" or "optionally substituted" are used interchangeably with the term "substituted or unsubstituted". In general, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced by a specific substituent. Unless otherwise indicated, an optional substituent group may be substituted at each substitutable position of the group. When more than one position in a given structural formula can be substituted by one or more substituents selected from a specific group, the substituents may be substituted the same or differently at each position.

[0133] In addition, it should be noted that, unless explicitly stated otherwise, the description methods used in the present invention, "each... is independently" and "... are each independently" and "... are independently" can be interchanged and should be understood in a broad sense, which can mean that in different groups, the specific options expressed by the same symbols do not affect each other, or that in the same group, the specific options expressed by the same symbols do not affect each other.

[0134] In various parts of this specification, the substituents of the compounds disclosed in the present invention are disclosed according to group types or ranges. It is particularly pointed out that the present invention includes each independent subcombination of the individual members of these group types and ranges. For example, the term "C 1-6 "Alkyl" specifically refers to methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl and C6 alkyl as disclosed independently.

[0135] In various parts of the present invention, linking substituents are described. When the structure clearly requires a linking group, the Markush variable listed for that group should be understood as a linking group. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl", it should be understood that the "alkyl" or "aryl" represents an alkylene group or an arylene group, respectively, that is linked.

[0136] The term "alkyl" means a saturated straight or branched monovalent hydrocarbon group containing 1 to 20 carbon atoms, wherein the alkyl group may be optionally substituted with one or more substituents described herein. Unless otherwise specified, the alkyl group contains 1-20 carbon atoms. In one embodiment, the alkyl group contains 1-12 carbon atoms; in another embodiment, the alkyl group contains 1-6 carbon atoms; in yet another embodiment, the alkyl group contains 1-4 carbon atoms; in yet another embodiment, the alkyl group contains 1-3 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), n-propyl (n-Pr, -CH2CH2CH3), isopropyl (i-Pr, -CH(CH3)2), n-butyl (n-Bu, -CH2CH2CH2CH3), isobutyl (i-Bu, -CH2CH(CH3)2), sec-butyl (s-Bu, -CH(CH3)CH2CH3), tert-butyl (t-Bu, -CH(CH3)CH2CH3), u, -C(CH3)3), n-pentyl (-CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1 -butyl (-CH2CH(CH3)CH2CH3), n-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3 ), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), n-heptyl, n-octyl, and the like.

[0137] When alkyl is the connecting group, then "alkyl" means the connecting alkylene group. As defined in the present invention, M is the connecting alkylene group. The term "alkylene" means a saturated divalent hydrocarbon group obtained by removing two hydrogen atoms from a saturated straight or branched hydrocarbon. Examples of alkyl groups representing the connecting alkylene group include, but are not limited to: -CH2-, -CH2CH2-, -CH(CH3)CH2-, and the like.

[0138] The term "alkynyl" refers to a straight or branched monovalent hydrocarbon group containing 2-12 carbon atoms, wherein there is at least one unsaturated site, i.e., a carbon-carbon sp triple bond, wherein the alkynyl group may be optionally substituted with one or more substituents described herein. In one embodiment, the alkynyl group contains 2-6 carbon atoms; in another embodiment, the alkynyl group contains 2-10 carbon atoms; the alkynyl group contains 2-4 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propargyl (-CH2C≡CH), 1-propynyl (-C≡C-CH3), and the like. When the alkynyl group is a linking group, and "alkynyl" is listed for the Markush group definition, then "alkynyl" refers to a linked alkynylene group. Examples of alkynyl groups represented as linked alkynylene groups include, but are not limited to: -C≡C-, -CH2C≡C-, -CH2C≡CCH2-, and the like.

[0139] The terms "cycloalkyl" or "cycloalkane" are used interchangeably and refer to a monovalent saturated monocyclic carbon ring system of 3-7 carbon atoms. The -CH2- group in the carbon ring may be optionally replaced by -C(=O)- (or -(C=O)-). In one embodiment, the cycloalkyl contains 3-6 carbon atoms, i.e., C 3-6 In another embodiment, the cycloalkyl group contains 3-5 carbon atoms, i.e., C 3-5 Cycloalkyl. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. Examples of -CH2- groups in carbocyclic rings that may be replaced by -C(=O)- include, but are not limited to, cyclopentanone, cyclobutanone, and the like. When a cycloalkyl group is a linking group, and "cycloalkyl" is listed for the Markush group definition, "cycloalkyl" represents a linked cycloalkylene group. The term "cycloalkylene" represents a divalent cycloalkane group formed by removing two hydrogen atoms from the ring carbon atoms of a cycloalkyl group. The cycloalkyl group or cycloalkane may be independently and optionally substituted with one or more substituents described herein. The term "cycloalkylene" represents a divalent saturated monocyclic carbon system formed by removing two hydrogen atoms from a carbon atom in a saturated carbocyclic ring. In some embodiments, cycloalkylene represents C 3-12 In other embodiments, cycloalkylene represents C 3-10 In other embodiments, cycloalkylene represents C 3-6Examples of cycloalkylene groups include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, and the like.

[0140] The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxyl groups. In some embodiments, hydroxyalkyl refers to an alkyl group substituted with 1, 2, 3, or 4 hydroxyl groups. In some embodiments, hydroxyalkyl refers to an alkyl group substituted with one or two hydroxyl groups. In some embodiments, hydroxyalkyl refers to a C 1-6 Hydroxyalkyl, i.e. C 1-6 The alkyl group is substituted with one or more hydroxyl groups, preferably C 1-6 Hydroxyalkyl means, that is, C 1-6 In some embodiments, hydroxyalkyl represents C 1-4 In some embodiments, hydroxyalkyl represents C 1-3 Hydroxyalkyl. Examples of hydroxyalkyl include, but are not limited to, CH2(OH)-, CH2(OH)CH2CH2CH2-, CH2(OH)CH2-, CH2(OH)CH2CH(OH)CH2-, CH(CH3)(OH)CH2CH(OH)CH2-, and the like.

[0141] The term "alkoxy" means an alkyl group attached to the rest of the molecule via an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy group contains 1-12 carbon atoms. In one embodiment, the alkoxy group contains 1-6 carbon atoms; in another embodiment, the alkoxy group contains 1-4 carbon atoms; in yet another embodiment, the alkoxy group contains 1-3 carbon atoms. The alkoxy group may be optionally substituted with one or more substituents as described herein. Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH3), ethoxy (EtO, -OCH2CH3), 1-propoxy (n-PrO, n-propoxy, -OCH2CH2CH3), 2-propoxy (i-PrO, i-propoxy, -OCH(CH3)2), 1-butoxy (n-BuO, n-butoxy, -OCH2CH2CH2CH3), 2-methyl-1-propoxy (i-BuO, i-butoxy, -OCH2CH(CH3)2), 2-butoxy (s-BuO, s-butoxy, -OCH(CH3)CH2CH3), 2-methyl-2- Propoxy (t-BuO, t-butoxy, -OC(CH3)3), 1-pentyloxy (n-pentyloxy, -OCH2CH2CH2CH2CH3), 2-pentyloxy (-OCH(CH3)CH2CH2CH3), 3-pentyloxy (-OCH(CH2CH3)2), 2-methyl-2-butoxy (-OC(CH3)2CH2CH3), 3-methyl-2-butoxy (-OCH(CH3)CH(CH3)2), 3-methyl-l-butoxy (-OCH2CH2CH(CH3)2), 2-methyl-l-butoxy (-OCH2CH(CH3)CH2CH3), and the like.

[0142] The term "alkoxyalkyl" refers to an alkyl group substituted with an alkoxy group, wherein alkoxy and alkyl have the definitions described herein. In some embodiments, alkoxyalkyl refers to a C 1-6 Alkoxy C 1-6 Alkyl; in other embodiments, alkoxyalkyl represents C 1-4 Alkoxy C 1-4 Alkyl; in other embodiments, alkoxyalkyl represents C 1-4 Alkoxy C 1-3 Alkyl; in some embodiments, alkoxyalkyl represents C 1-3 Alkoxy C 1-3Examples of alkoxy groups include, but are not limited to, methoxymethyl, ethoxymethyl, n-propoxymethyl, isopropoxymethyl, methoxyethyl, methoxy-n-propyl, methoxy-isopropyl, ethoxyethyl, ethoxy-n-propyl, ethoxy-isopropyl, n-propoxyethyl, isopropoxyethyl, n-propoxy-n-propyl, n-propoxy-isopropyl, isopropoxy-n-propyl, isopropoxy-isopropyl, and the like.

[0143] The term "alkoxyalkoxy" refers to an alkoxy group substituted with an alkoxy group, wherein the alkoxy group has the definition as described herein. In some embodiments, alkoxyalkoxy refers to a C 1-6 Alkoxy C 1-6 Alkoxy; in other embodiments, alkoxyalkyl represents C 1-4 Alkoxy C 1-4 Alkoxy; in other embodiments, alkoxyalkyl represents C 1-4 Alkoxy C 1-3 Alkoxy; in some embodiments, alkoxyalkyl represents C 1-3 Alkoxy C 1-3 Alkoxy. Examples of alkoxyalkoxy include, but are not limited to, methoxymethoxy, ethoxymethoxy, n-propoxymethoxy, isopropoxymethoxy, methoxyethoxy, methoxy-n-propoxy, methoxyisopropoxy, ethoxyethoxy, ethoxy-n-propoxy, ethoxyisopropoxy, n-propoxyethoxy, isopropoxyethoxy, n-propoxy-n-propoxy, n-propoxyisopropoxy, isopropoxy-n-propoxy, and the like.

[0144] The term "halogen" means F (fluorine), Cl (chlorine), Br (bromine) or I (iodine).

[0145] The term "oxo" means =0.

[0146] The term "haloalkyl" means an alkyl group substituted with one or more halogen atoms, such examples include, but are not limited to, monofluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 1,2-difluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, monochloromethyl, dichloromethyl, trichloromethyl, 2-chloroethyl, 1-chloroethyl, 1,2-dichloroethyl, 1,1-dichloroethyl, 2,2-dichloroethyl, 1,1-dibromoethyl, and the like.

[0147] The term "haloalkoxy" means an alkoxy group substituted with one or more halogen atoms, examples of which include, but are not limited to, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, 1-fluoroethoxy, 2-fluoroethoxy, 1,2-difluoroethoxy, 1,1-difluoroethoxy, 2,2-difluoroethoxy, monochloromethoxy, dichloromethoxy, trichloromethoxy, 2-chloroethoxy, 1,2-dichloroethoxy, 1,1-dichloroethoxy, 2,2-dichloroethoxy, 1,1-dibromoethoxy, and the like.

[0148] The term "alkylacyl" means an alkyl group attached to the rest of the molecule through a carbonyl group, wherein alkyl has the definition as described herein and carbonyl represents -C(=O)-. In some embodiments, alkylacyl represents C 1-6 Alkyl acyl; in other embodiments, alkyl acyl represents C 1-4 Alkyl acyl. Examples of alkyl acyl include, but are not limited to, formyl, acetyl, and the like.

[0149] The term "aromatic ring" or "aromatic hydrocarbon" refers to monocyclic, bicyclic and tricyclic carbon ring systems containing 6-14 ring atoms, or 6-12 ring atoms, or 6-10 ring atoms, wherein at least one ring system is aromatic, and wherein each ring system contains 3-7 ring atoms. Examples of aromatic rings may include benzene, naphthalene and anthracene.

[0150] The term "aryl" refers to a monovalent aromatic ring group formed by removing a hydrogen atom from a ring carbon atom of an aromatic ring. Examples of aryl groups may include phenyl, naphthyl and anthracenyl. When aryl is a connecting group, aryl represents a connected arylene group. As defined in the present invention, M is a connected arylene group. The term "arylene" refers to a divalent aromatic ring group formed by removing two hydrogen atoms from a ring carbon atom of an aromatic ring. Examples of arylene groups represented by aryl as a connection may include phenylene, naphthyl and anthracenyl. The aryl or arylene group may be independently and optionally substituted by one or more substituents described in the present invention.

[0151] The term "heteroaromatic ring" refers to monocyclic, bicyclic and tricyclic ring systems containing 5-12 ring atoms, or 5-10 ring atoms, or 5-6 ring atoms, wherein at least one ring system is aromatic and at least one ring system contains one or more heteroatoms, and wherein each ring system contains 5-7 ring atoms.

[0152] The term "heteroaryl" refers to a monovalent aromatic ring group formed by removing a hydrogen atom from a ring atom of a heteroaromatic ring. The heteroaryl group is optionally substituted with one or more substituents described herein. In one embodiment, the 5-10-atom heteroaryl or 5-10-membered heteroaryl group contains 1, 2, 3 or 4 heteroatoms independently selected from O, S and N. In some embodiments, the term "heteroaryl" refers to a heteroaromatic ring group or a 5-6-membered heteroaromatic group containing 5-6 ring atoms, wherein 1, 2, 3 or 4 heteroatoms independently selected from O, S and N are contained. In some embodiments, the term "heteroaryl" refers to a heteroaromatic ring group or a 5-membered heteroaromatic group containing 5 ring atoms, wherein 1, 2, 3 or 4 heteroatoms independently selected from O, S and N are contained. Examples of heteroaryl groups include, but are not limited to, 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl , 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, pyrazinyl, 1,3,5-triazinyl; also includes the following bicyclic rings, but is by no means limited to these bicyclic rings: benzimidazolyl, benzofuranyl, benzothiophenyl, indolyl (such as 2-indolyl), purinyl, quinolyl (such as 2-quinolyl, 3-quinolyl, 4-quinolyl), isoquinolyl (such as 1-isoquinolyl), [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyridinyl, etc. When heteroaryl is a linking group, heteroaryl represents a linked heteroaryl group. As defined in the present invention, M is a linked heteroaryl group. The term "heteroaryl group" refers to a divalent heteroaromatic ring group formed by removing two hydrogen atoms from the ring atoms of the heteroaryl group. The heteroaryl or heteroaryl group may be independently and optionally substituted with one or more substituents described in the present invention.

[0153] The term "aryloxy" refers to aryl-O-, i.e., an aryl group is attached to the rest of the molecule via an oxygen atom, wherein the aryl group has the definition as described herein. Examples of aryloxy include, but are not limited to, phenoxy, naphthoxy, and the like.

[0154] The term "aryloxyalkyl" refers to an alkyl group substituted with an aryloxy group, wherein the aryloxy and alkyl groups have the definitions described herein. In some embodiments, the aryloxyalkyl group refers to a C 6-10 Aryloxy C 1-6 Alkyl; in other embodiments, aryloxyalkyl represents phenoxy C 1-6 Alkyl; in other embodiments, aryloxyalkyl represents phenoxy C 1-4 Specific examples of aryloxyalkyl include, but are not limited to, phenoxymethyl, phenoxyethyl, phenoxy-n-propyl, phenoxy-isopropyl, phenoxy-n-butyl, phenoxy-isobutyl, phenoxy-tert-butyl, and the like.

[0155] The term "monocarbocyclyl" refers to a monovalent saturated or partially unsaturated non-aromatic monocyclic carbocyclic system, wherein the ring atoms are carbon atoms. In some embodiments, the monocarbocyclyl is a 3-7-membered monocarbocyclyl; in other embodiments, the monocarbocyclyl is a 3-6-membered monocarbocyclyl. Examples of monocarbocyclyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentadienyl, cyclohexenyl, and the like. When the monocarbocyclyl is a linking group, the monocarbocyclyl represents a linked sub-monocarbocyclyl. The term "sub-monocarbocyclyl" refers to a divalent bridged carbocyclic group formed by removing two hydrogen atoms from the ring atoms of the monocarbocyclic ring. The monocarbocyclyl or sub-monocarbocyclyl may be independently and optionally substituted with one or more substituents described herein.

[0156] The terms "bridged carbocycle" and "bridged carbocyclyl" are used interchangeably and both refer to non-aromatic saturated or partially unsaturated bicyclic or polycyclic ring systems that share two or more carbon atoms, and the ring atoms are carbon atoms. The -CH2- group in the bridged carbocycle can be optionally replaced by -C(=O)-. In some embodiments, the bridged carbocycle contains 6-12 ring carbon atoms, that is, it represents a 6-12-membered bridged carbocycle; in other embodiments, the bridged carbocycle contains 6-10 ring carbon atoms, that is, it represents a 6-10-membered bridged carbocycle. Examples of bridged carbocycles include, but are not limited to: bicyclo[3.1.1]heptane, bicyclo[3.2.1]octane, bicyclo[2.2.2]octane, bicyclo[2.2.0]hexane, octahydro-1H-indene, etc. When the bridged carbocycle or bridged carbocyclyl is a connecting group, the bridged carbocycle or bridged carbocyclyl represents a connected subbridged carbocyclyl. The term "bridged carbocyclic group" refers to a divalent bridged carbocyclic group formed by removing two hydrogen atoms from the ring atoms of the bridged carbocyclic ring. The bridged carbocyclic ring or bridged carbocyclic group may be independently and optionally substituted with one or more substituents described herein.

[0157] The terms "spirocarbocycle" and "spirocarbocyclyl" are used interchangeably and both refer to a non-aromatic saturated or partially unsaturated ring system formed by two carbocyclic rings sharing a carbon atom. The -CH2- group in the spirocarbocycle can be optionally replaced by -C(=O)-. In some embodiments, the spirocarbocycle contains 7-12 ring carbon atoms, i.e., a 7-12-membered spirocarbocycle; in other embodiments, the spirocarbocycle contains 7-10 ring carbon atoms, i.e., a 7-10-membered spirocarbocycle. Examples of spirocarbocycles include, but are not limited to, spiro[4.4]nonane, spiro[3.4]octane, spiro[4.5]decane, etc. When a spirocarbocycle or spirocarbocyclyl is a linking group, the spirocarbocycle or spirocarbocyclyl represents a linked sub-spirocarbocyclyl. The term "sub-spirocarbocyclyl" refers to a divalent spirocarbocyclic group formed by removing two hydrogen atoms from the ring atoms of the spirocarbocycle. The spirocarbocycle or spirocarbocyclyl can be independently and optionally substituted with one or more substituents described herein.

[0158] The term "carbocyclyl" refers to a monovalent saturated or unsaturated non-aromatic carbocyclic ring system, wherein the ring atoms are carbon atoms, including monocarbocyclyl, bridged carbocyclyl and spirocarbocyclyl, wherein monocarbocyclyl, bridged carbocyclyl and spirocarbocyclyl have the definitions as described herein. In some embodiments, carbocyclyl refers to a 3-12-membered carbocyclyl; in other embodiments, carbocyclyl refers to a 3-10-membered carbocyclyl; in other embodiments, carbocyclyl refers to a 3-7-membered carbocyclyl; in other embodiments, carbocyclyl refers to a 3-6-membered carbocyclyl. The carbocyclyl may be independently and optionally substituted with one or more substituents described herein. When the carbocyclyl is a linking group, the term "carbocyclyl" is referred to as "carbocyclylene".

[0159] The term "carbocyclylene" refers to a divalent carbocyclic ring system obtained by removing two hydrogen atoms from a carbocyclic hydrocarbon, including monocarbocyclylene, bridged carbocyclylene and spirocarbocyclylene, wherein monocarbocyclylene, bridged carbocyclylene and spirocarbocyclylene have the definitions as described herein. In some embodiments, carbocyclylene represents a 3-12-membered carbocyclylene; in other embodiments, carbocyclylene represents a 3-10-membered carbocyclylene; in other embodiments, carbocyclylene represents a 3-7-membered carbocyclylene. The carbocyclylene may be independently and optionally substituted with one or more substituents described herein.

[0160] The terms "monoheterocycle" or "monoheterocyclyl" are used interchangeably and refer to a monovalent non-aromatic saturated or partially unsaturated monocyclic ring system containing at least 1 carbon atom and 1, 2 or 3 heteroatoms selected from O, N, and S. Unless otherwise specified, the heterocyclyl group may be a carbon group or a nitrogen group, and the -CH2- group may be optionally replaced by -C(=O)- (or -(C=O)-). The sulfur atom of the ring may be optionally oxidized to an S-oxide, and the nitrogen atom of the ring may be optionally oxidized to an N-oxide. In some embodiments, the heterocycle contains 3-7 ring atoms, i.e., a 3-7 membered heterocycle; in some embodiments, the monoheterocycle contains 4-7 ring atoms, i.e., a 4-7 membered heterocycle; in other embodiments, the heterocycle contains 4-6 ring atoms, i.e., a 4-6 membered heterocycle. Examples of monocyclic heterocycles include, but are not limited to, oxirane, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxolanyl, dithiolanyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, 1,1-dioxo-1,3-thiomorpholine, and the like. Examples of heterocyclic groups in which the -CH2- group is replaced by -C(=O)- include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidone, 3,5-dioxopiperidinyl. Examples of heterocyclic groups in which the nitrogen atom is oxidized to an N-oxygen compound include, but are not limited to, 1,1-dioxo-1,3-thiomorpholine. When a monoheterocyclic ring or a monoheterocyclic group is a connecting group, the heterocyclic ring or heterocyclic group represents a connected sub-heterocyclic group. The term "sub-monoheterocyclic group" means a divalent heterocyclic group formed by removing two hydrogen atoms from the ring atoms of a monoheterocyclic ring. The monoheterocyclic ring or monoheterocyclic group may be independently and optionally substituted by one or more substituents described in the present invention.

[0161] The terms "bridged heterocycle" or "bridged heterocyclic group" are used interchangeably and refer to a non-aromatic saturated or partially unsaturated bicyclic or polycyclic system that shares two or more carbon atoms and contains at least one carbon atom and one, two or three heteroatoms selected from O, N, and S. The -CH2- group in the bridged heterocycle can be optionally replaced by -C(=O)- (or -(C=O)-). The sulfur atom of the ring can be optionally oxidized to S-oxide, and the nitrogen atom of the ring can be optionally oxidized to N-oxide. In some embodiments, the bridged heterocycle contains 6-12 ring atoms, i.e., it represents a 6-12-membered bridged heterocycle; in other embodiments, the bridged heterocycle contains 6-10 ring atoms, i.e., it represents a 6-10-membered bridged heterocycle. Examples of bridged heterocycles include, but are not limited to, 3,6-diazabicyclo[3.1.1]heptane, 3,8-diazabicyclo[3.2.1]octane, 2-azabicyclo[2.2.1]heptane, octahydroimidazo[1,5-c]pyrimidine, 6-azabicyclo[3.1.1]heptane, 3-azabicyclo[3.1.1]heptane, 8-azabicyclo[3.2.1]octane, 3-azabicyclo[3.2.1]octane, 2-diazabicyclo[2.2.2]octane, and the like. When a bridged heterocycle or bridged heterocyclic group is a connecting group, the bridged heterocycle or bridged heterocyclic group represents a subbridged heterocyclic group connected. The term "subbridged heterocyclic group" refers to a divalent bridged heterocyclic group formed by removing two hydrogen atoms from the ring atoms of the bridged heterocycle. The bridged heterocycle or bridged heterocyclic group may be independently and optionally substituted with one or more substituents described herein.

[0162] The terms "spiroheterocycle" or "spiroheterocyclyl" can be used interchangeably, and both refer to a non-aromatic saturated or partially unsaturated ring system formed by two rings sharing a carbon atom, and the system contains 1, 2 or 3 heteroatoms selected from O, N, and S. The -CH2- group in the spiroheterocycle can be optionally replaced by -C(=O)-. The sulfur atom of the ring can be optionally oxidized to S-oxide, and the nitrogen atom of the ring can be optionally oxidized to N-oxide. In some embodiments, the spiroheterocycle contains 7-12 ring atoms, that is, it represents a 7-12-membered spiroheterocycle; in other embodiments, the spiroheterocycle contains 7-10 ring atoms, that is, it represents a 7-10-membered spiroheterocycle. Examples of spiroheterocycles include, but are not limited to, 4,7-diazaspiro[2.5]octane, 2,8-diazaspiro[4.5]decane, 2,7-diazaspiro[4.5]decane, 2,7-diazaspiro[3.5]decane, 2,6-diazaspiro[3.3]heptane, 2,7-diazaspiro[4.4]nonane, 3-azaspiro[5.5]undecane, 2,7-diazaspiro[4.4]nonane-1-one, etc. When a spiroheterocycle or a spiroheterocyclyl is a linking group, the spiroheterocycle or spiroheterocyclyl represents a linked spiroheterocyclyl substituent. The term "spiroheterocyclyl substituent" represents a divalent spiroheterocyclic group formed by removing two hydrogen atoms from the ring atoms of the spiroheterocycle. The spiroheterocycle or spiroheterocyclyl may be independently and optionally substituted with one or more substituents described herein.

[0163] The term "heterocyclyl" refers to a monovalent non-aromatic saturated or partially unsaturated heterocyclic ring system, and the system contains at least 1 carbon atom, 1, 2 or 3 heteroatoms selected from O, N, S. The heterocyclyl can be a monocyclic or bicyclic ring system; specifically, the bicyclic ring system can be a heterobicyclic ring, a spiro heterobicyclic ring or a bridged heterobicyclic ring. Specific heterocyclyls include monoheterocyclyls, bridged heterocyclyls and or spiro heterocyclyls, wherein monoheterocyclyls, bridged heterocyclyls and spiro heterocyclyls have the definitions described in the present invention. In some embodiments, heterocyclyls represent 3-12 membered heterocyclyls; in other embodiments, heterocyclyls represent 3-10 membered heterocyclyls; in other embodiments, heterocyclyls represent 3-7 membered heterocyclyls; in other embodiments, heterocyclyls represent 3-6 membered heterocyclyls.

[0164] When the heterocyclic group is a linking group, the term "heterocyclic group" is represented by "heterocyclic group". That is, the term "heterocyclic group" represents a divalent heterocyclic system formed by removing two hydrogen atoms from a carbon atom in a heterocyclic ring, wherein the system contains at least 1 carbon atom and contains 1, 2 or 3 heteroatoms selected from O, N, and S. Heterocyclic groups include monoheterocyclic groups, sub-bridged heterocyclic groups, and sub-spiro heterocyclic groups, wherein monoheterocyclic groups, sub-bridged heterocyclic groups, and sub-spiro heterocyclic groups have the definitions described in the present invention. In some embodiments, heterocyclic groups represent a divalent heterocyclic system formed by removing two hydrogen atoms from the same carbon atom in a heterocyclic ring. In some embodiments, heterocyclic groups represent 3-7 membered heterocyclic groups; in other embodiments, heterocyclic groups represent 3-6 membered heterocyclic groups. Examples of heterocyclic groups include, but are not limited to, oxirane groups, aziridine groups, oxetane groups, oxolanyl groups, aziridine groups, and the like.

[0165] The term "alkylaryl" refers to an aryl group substituted by an alkyl group, wherein alkyl and aryl have the definitions described herein. 1-6 Alkyl-C 6-10 Aryl, i.e. C 1-6 Alkyl substituted C 6-10 Aryl; in other embodiments, "alkylaryl" means C 1-4 Alkylphenyl, i.e. C 1-4 Alkyl substituted phenyl. Examples of alkylaryl include, but are not limited to, methylphenyl, ethylphenyl, propylphenyl, methylnaphthyl, etc. When alkylaryl is a linking group, alkylaryl represents a linked alkylenearyl. As defined in the present invention, M is a linked alkylenearyl group. The term "alkylenearylene" represents a divalent alkylenearylene group formed by removing a hydrogen atom from the alkyl of the alkyl aromatic ring and a hydrogen atom from the ring atom of the aromatic ring. The alkylaryl group or the alkylenearylene group may be independently and optionally substituted with one or more substituents described in the present invention.

[0166] The term "arylalkyl" refers to an alkyl group substituted by an aryl group, wherein alkyl and aryl have the definitions described herein. In some embodiments, "arylalkyl" refers to a C 6-10 Aryl C 1-6 Alkyl, i.e. C 6-10 Aryl substituted C 1-6 Alkyl; in other embodiments, "arylalkyl" means phenyl C 1-6 Alkyl, that is, C substituted by phenyl 1-6 Alkyl; in other embodiments, "arylalkyl" means phenyl C 1-4 Alkyl, that is, C substituted by phenyl 1-4Alkyl. Examples of arylalkyl include, but are not limited to, phenylmethyl, phenylethyl, phenylpropyl, phenyl n-butyl, phenyl isobutyl, phenyl tert-butyl, naphthylmethyl, etc. When arylalkyl is a linking group, arylalkyl represents a linked arylene alkylene group. As defined in the present invention, M is a linked arylene alkylene group. The term "arylene alkylene" represents a divalent alkylene arylene group formed by removing a hydrogen atom from the aryl group of an aryl alkane and removing a hydrogen atom from a ring atom of an alkane. The arylalkyl group or the arylene alkylene group may be independently and optionally substituted with one or more substituents described in the present invention.

[0167] The term "alkylheteroaryl" refers to a heteroaryl group substituted by an alkyl group. wherein alkyl and heteroaryl have the definitions described herein. In some embodiments, "alkylheteroaryl" refers to a C 1-6 Alkyl-(5-10 membered heteroaryl), i.e., C 1-6 alkyl-substituted 5-10 membered heteroaryl; in other embodiments, "alkylheteroaryl" means C 1-4 Alkyl-(5-6 membered heteroaryl), i.e. 1-4 Alkyl-substituted 5-6 membered heteroaryl. Examples of alkyl heteroaryl include, but are not limited to, methyl pyridyl, ethyl pyridyl, propyl pyridyl, methyl pyrazolyl, ethyl pyrazolyl, propyl pyrazolyl, methyl pyrimidinyl, methyl pyrazinyl, methyl benzimidazolyl, methyl benzpyrazolyl, etc. When alkyl heteroaryl is a linking group, alkyl heteroaryl represents the linked alkylene heteroaryl. The term "alkylene heteroaryl" represents a divalent alkylene heteroaryl group formed by removing a hydrogen atom from the alkyl of the alkyl heteroaromatic ring and a hydrogen atom from the ring atom of the heteroaromatic ring. The alkyl heteroaryl group or the alkylene heteroaryl group may be independently and optionally substituted with one or more substituents described in the present invention.

[0168] The term "heteroarylalkyl" refers to an alkyl group substituted with a heteroaryl group. Wherein alkyl and heteroaryl have the definitions described herein. In some embodiments, "heteroarylalkyl" refers to (5-10 membered heteroaryl)-C 1-6 Alkyl, i.e. C substituted by 5-10 membered heteroaryl 1-6 In other embodiments, "heteroarylalkyl" refers to (5-10 membered heteroaryl)-C 1-4 Alkyl, i.e. C substituted by 5-10 membered heteroaryl 1-4 In other embodiments, "heteroarylalkyl" refers to (5-6 membered heteroaryl)-C 1-4 Alkyl, i.e. C substituted by 5-6 membered heteroaryl 1-4Alkyl. Examples of heteroarylalkyl include, but are not limited to, imidazolylmethyl, imidazolylethyl, pyridylmethyl, pyridylethyl, pyridylpropyl, pyrazolylmethyl, pyrazolylethyl, pyrazolylpropyl, imidazolylmethyl, imidazolylethyl, pyrimidinylmethyl, pyrazinylmethyl, imidazolylmethyl, imidazolylethyl, benzimidazolylmethyl, benzopyrazolylmethyl, pyrazolo[1,5-a]pyrimidinylmethyl, etc. When heteroarylalkyl is a linking group, heteroarylalkyl represents a linked heteroarylalkylene group. The term "alkyleneheteroarylalkylene" represents a divalent alkyleneheteroarylalkylene group formed by removing a hydrogen atom from the heteroaryl group of a heteroarylalkane and removing a hydrogen atom from an alkane. The heteroarylalkyl group or alkyleneheteroarylalkylene group may be independently and optionally substituted with one or more substituents described herein.

[0169] The term "alkyleneheterocyclylenealkylene" means that the heterocyclyl group on the heterocyclylalkyl group is substituted with an alkylene group. In some embodiments, alkyleneheterocyclylenealkylene represents a C 1-6 Alkylene-(3-12 membered heterocyclylene)-C 1-6 In other embodiments, alkyleneheterocyclylalkylene represents C 1-6 Alkylene-(3-6 membered heterocyclylene)-C 1-6 In other embodiments, alkyleneheterocyclylalkylene represents C 1-4 Alkylene-(3-6 membered heterocyclylene)-C 1-4 Examples of alkylene heterocyclylene alkylene include, but are not limited to, -CH2-piperazinylene-CH2-, -CH2-piperidinylene-CH2-, etc. The alkylene heterocyclylene alkylene may be independently and optionally substituted with one or more substituents described herein.

[0170] The term "alkyleneheteroarylalkylene" means that the heteroaryl on the heteroarylalkyl is substituted with an alkylene. In some embodiments, alkyleneheteroarylalkylene means C 1-6 Alkylene-(5-10 membered heteroarylene)-C 1-6 In other embodiments, alkyleneheteroarylalkylene represents C 1-4 Alkylene-(5-10 membered heteroarylene)-C 1-4 In other embodiments, alkyleneheteroarylalkylene represents C 1-4 Alkylene-(5-6 membered heteroarylene)-C 1-4 Examples of alkyleneheteroarylenealkylene include, but are not limited to, -CH2-oxazolylene-CH2-, -CH2-imidazolylene-CH2-, etc. The alkyleneheteroarylenealkylene may be independently and optionally substituted with one or more substituents described herein.

[0171] The term "aminoalkyl" refers to an alkyl group substituted with one or more amino groups. In some embodiments, the term "aminoalkyl" refers to an alkyl group substituted with one amino group. In some embodiments, the term "aminoalkyl" refers to a C 1-6 In other embodiments, the term "aminoalkyl" refers to C 1-4 In other embodiments, the term "aminoalkyl" refers to C 1-3 Aminoalkyl. Examples of aminoalkyl include, but are not limited to, aminomethyl, aminoethyl, amino-n-propyl, aminoisopropyl, aminoisobutyl, aminotert-butyl, 1,2-diaminoethyl, and the like.

[0172] The term "alkylamino" refers to an amino group substituted with an alkyl group. In some embodiments, the term "alkylamino" refers to a C 1-6 In other embodiments, the term "alkylamino" refers to C 1-4 In other embodiments, the term "alkylamino" refers to C 1-3 Alkylamino. Examples of alkylamino include, but are not limited to, methylamino, ethylamino, n-propylamino, isopropylamino, isobutylamino, tert-butylamino, and the like.

[0173] The term "alkylsulfonyl" refers to an alkyl-S(=O)2-, i.e., an alkyl group is attached to the rest of the molecule via -S(=O)2-. 1-6 Alkylsulfonyl; in other embodiments, alkylsulfonyl represents C 1-4 Alkylsulfonyl; in other embodiments, alkylsulfonyl represents C 1-4 Alkylsulfonyl. Examples of alkylsulfonyl include, but are not limited to, methylmethylsulfonyl, ethylmethylsulfonyl, n-propylmethylsulfonyl, isopropylmethylsulfonyl, n-butylmethylsulfonyl, and the like.

[0174] The term "carbocyclylalkyl" means that a hydrogen atom on an alkyl group is replaced by a carbocyclyl group. Wherein alkyl and carbocyclyl have the definitions described herein. In some embodiments, carbocyclylalkyl represents (3-12 membered carbocyclyl)-C 1-6 Alkyl; in some embodiments, carbocyclylalkyl represents (3-10 membered carbocyclyl)-C 1-6 Alkyl; in other embodiments, carbocyclylalkyl represents (3-10 membered carbocyclyl)-C 1-4 Alkyl; in other embodiments, carbocyclylalkyl represents (3-6 membered carbocyclyl)-C 1-4Alkyl. Examples of carbocyclylalkyl include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclopentylethyl, cyclopentyl-n-propyl, cyclopropylethyl, cyclopropyl-n-propyl, cyclobutylethyl, cyclobutylpropyl, cyclohexylethyl, cyclohexylmethyl, etc. When carbocyclylalkyl is represented as a linking group, then carbocyclylalkyl represents the linked carbocyclylene alkylene. The term "carbocyclylene alkylene" represents a divalent carbocyclylene alkylene group formed by removing a hydrogen atom from the carbocyclyl of a carbocyclyl alkane and removing a hydrogen atom from an alkane. The carbocyclylalkyl and carbocyclylene alkylene groups may be independently and optionally substituted with one or more substituents described in the present invention.

[0175] The term "alkylcarbocyclyl" means that the hydrogen atoms on the carbocyclyl are replaced by alkyl groups, wherein alkyl and carbocyclyl have the definitions described herein. 1-6 Alkyl-(3-12 membered carbocyclyl); in some embodiments, alkylcarbocyclyl represents C 1-6 Alkyl-(3-10 membered carbocyclyl); in some embodiments, alkylcarbocyclyl represents C 1-6 Alkyl-(3-6 membered carbocyclyl); in some embodiments, alkylcarbocyclyl represents C 1-4 Alkyl-(3-6 membered carbocyclyl), examples of alkyl carbocyclyl include, but are not limited to, methylcyclopropyl, ethylcyclopropyl, methylcyclobutyl, methylcyclopentyl, ethylcyclohexyl, methylcyclohexyl, etc. When the alkyl carbocyclyl is represented as a linking group, the alkyl carbocyclyl represents a linked alkylene carbocyclyl. The term "alkylene carbocyclyl" represents a divalent alkylene carbocyclyl group formed by removing a hydrogen atom from the alkyl group of an alkyl carbocyclic hydrocarbon and removing a hydrogen atom from a carbocyclic hydrocarbon. The alkyl carbocyclyl and alkylene carbocyclyl groups may be independently and optionally substituted with one or more substituents described in the present invention.

[0176] The term "heterocyclylalkyl" refers to an alkyl group substituted by a heterocyclyl group, wherein alkyl and heterocyclyl are as defined herein. In some embodiments, "heterocyclylalkyl" refers to (3-12 membered heterocyclyl)-C 1-6 In other embodiments, heterocyclylalkyl represents (3-10 membered heterocyclyl)-C 1-6 In other embodiments, heterocyclylalkyl represents (3-7 membered heterocyclyl)-C 1-6 In other embodiments, heterocyclylalkyl represents (3-6 membered heterocyclyl)-C 1-4Alkyl. Examples of heterocyclylalkyl include, but are not limited to, azetidinylmethyl, pyrrolidinylmethyl, morpholinylmethyl, morpholinylethyl, piperazinylmethyl, piperazinylethyl, 2-oxopyrrolidinylmethyl, 2-oxopyrrolidinylethyl, oxetanylmethyl, tetrahydrofuranylmethyl, etc. When heterocyclylalkyl is a linking group, the term "heterocyclylalkyl" is represented by "heterocyclylene alkylene". The term "heterocyclylene alkylene" represents a divalent heterocyclylene alkylene group formed by removing a hydrogen atom from the heterocyclyl group of a heterocyclyl alkane and removing a hydrogen atom from an alkane. . The heterocyclylalkyl or heterocyclylene alkylene group may be independently and optionally substituted with one or more substituents described in the present invention.

[0177] The term "alkylheterocyclyl" refers to a heterocyclyl group substituted by an alkyl group, wherein the alkylheterocyclyl group has the definition as described herein. In some embodiments, "alkylheterocyclyl" refers to a C 1-6 Alkyl-(3-12 membered heterocyclyl); "Alkyl heterocyclyl" means C 1-6 Alkyl-(3-10 membered heterocyclyl); in other embodiments, "alkyl heterocyclyl" refers to C 1-4 Alkyl-(3-10 membered heterocyclyl); in other embodiments, "alkyl heterocyclyl" refers to C 1-4 Alkyl-(3-6 membered heterocyclyl). Examples of alkyl heterocyclyl include, but are not limited to, isopropylazetidinyl, methylpiperidinyl, methyloxetanyl, methylpyrrolidinyl, methylmorpholinyl, methylimidazolidinyl, and the like. When the alkyl heterocyclyl is a linking group, the term "alkyl heterocyclyl" is represented by "alkylene heterocyclyl". The term "alkylene heterocyclyl" represents a divalent alkylene heterocyclyl group formed by removing a hydrogen atom from the alkyl group of an alkyl heterocyclic hydrocarbon and removing a hydrogen atom from a heterocyclic hydrocarbon. The alkyl heterocyclic group or alkylene heterocyclyl group may be independently and optionally substituted with one or more substituents described herein.

[0178] In the general formula of the compound of the present invention, the left end of Q is connected to the ring A, and the right end of Q is connected to M. For example, when Q is -S(=O)2NR 5 -When express

[0179] In the general formula of the compound of the present invention, T is a connecting group, and its two ends can be connected interchangeably to and group Y, for example, when T is a specific group -CH2CH(CH3)-, express or Two cases; for example, when T is a specific group -(CH2)2OCH2-, express or Two situations.

[0180] As described herein, unless otherwise specified, the ring substituents can be connected to the rest of the molecule via any connectable position on the ring. For example, piperidinyl includes piperidin-1-yl, piperidin-2-yl, piperidin-3-yl and piperidin-4-yl.

[0181] As described in the present invention, if there are two attachment points on a ring connected to the rest of the molecule, the two attachment points can be connected to the rest of the molecule at any connectable position on the ring, and the two ends of the connection can be interchanged. For example, the substructure a1 of ring A represents that any two possible positions on the ring can be used as connection points (i.e., attachment points), and the two ends of the connection points can be interchanged. Preferably, if there are two attachment points on a ring connected to the rest of the molecule, the two attachment points can be connected to the rest of the molecule at any connectable position on the ring, and the two attachment points are attached to two different ring atoms on the ring.

[0182]

[0183] Preferably, in the present invention, if a ring is a cyclic ring or a spirocyclic ring formed by two sub-rings, and the two attachment points on the ring are respectively located on the two sub-rings, then the two attachment points are connected to the rest of the molecule at any connectable positions on the two sub-rings, and the two ends of the connection can be interchanged. For example, the sub-structural formula a2 of ring A preferably indicates that the two attachment points on the ring are connected to the rest of the molecule on the H1 ring and the H2 ring, respectively, and the two ends of the connection can be interchanged; the sub-structural formula a3 of ring A preferably indicates that the two attachment points on the ring are connected to the rest of the molecule on the H1' ring and the H2' ring, respectively, and the two ends of the connection can be interchanged.

[0184]

[0185] Specifically, for example, when ring A is When , it means that the two attachment points on the A ring can be connected interchangeably to the E and Q groups in the general formula of the compound of the present invention, that is: Expressed as

[0186] The term "protecting group" or "PG" refers to a substituent that reacts with other functional groups, usually to block or protect a particular functionality. For example, an "amino protecting group" refers to a substituent attached to an amino group to block or protect the functionality of the amino group in the compound. Suitable amino protecting groups include acetyl, trifluoroacetyl, tert-butyloxycarbonyl (BOC, Boc), benzyloxycarbonyl (CBZ, Cbz) and 9-fluorenylmethyleneoxycarbonyl (Fmoc). Similarly, a "hydroxy protecting group" refers to a substituent of a hydroxy group that blocks or protects the functionality of the hydroxy group. Suitable protecting groups include acetyl and silyl. A "carboxyl protecting group" refers to a substituent of a carboxyl group that blocks or protects the functionality of the carboxyl group. Typical carboxyl protecting groups include -CH2CH2SO2Ph, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrobenzenesulfonyl)ethyl, 2-(diphenylphosphino)ethyl, nitroethyl, and the like. For a general description of protecting groups, please refer to the literature: T W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991; and P J Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.

[0187] The term "prodrug" as used in the present invention refers to a compound that is converted into a compound of formula (I) in vivo. Such conversion is affected by the hydrolysis of the prodrug in the blood or by the conversion of the prodrug into the parent structure by enzymes in the blood or tissues. The prodrug compounds of the present invention may be esters. In the prior invention, esters that can be used as prodrugs include phenyl esters, aliphatic (C 1-24) esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound of the present invention contains a hydroxyl group, which can be acylated to obtain a prodrug form of the compound. Other prodrug forms include phosphates, such as these phosphate compounds obtained by phosphorylation of the hydroxyl group on the parent. For a complete discussion of prodrugs, please refer to the following literature: T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J. Rautio et al., Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and SJ Hecker et al., Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345.

[0188] "Metabolite" refers to a product obtained by the metabolism of a specific compound or salt thereof in vivo. The metabolites of a compound can be identified by techniques known in the art, and their activity can be characterized by experimental methods as described herein. Such products can be obtained by administering the compound through oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, etc. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a period of time.

[0189] The "pharmaceutically acceptable salt" used in the present invention refers to organic salts and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in the literature: SM Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19. Pharmaceutically acceptable salts formed by non-toxic acids include, but are not limited to, inorganic acid salts formed by reaction with amino groups, such as hydrochlorides, hydrobromides, phosphates, sulfates, perchlorates, and organic acid salts such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, or other methods described in books and literature, such as ion exchange methods, to obtain these salts. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 The present invention also contemplates quaternary ammonium salts formed by any compound containing a N group. Water-soluble or oil-soluble or dispersible products can be obtained by quaternization. Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include appropriate, non-toxic ammonium, quaternary ammonium salts and amine cations formed by counter ions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C 1-8 Sulfonates and aromatic sulfonates.

[0190] The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, the basic or acidic part by conventional chemical methods. In general, such salts can be prepared by reacting the free acid form of these compounds with a stoichiometric amount of a suitable base (such as a hydroxide, carbonate, bicarbonate, etc. of Na, Ca, Mg or K), or by reacting the free base form of these compounds with a stoichiometric amount of a suitable acid. Such reactions are usually carried out in water or an organic solvent or a mixture of the two. Generally, in appropriate cases, it is necessary to use a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile. For example, "Remington's Pharmaceutical Sciences", 20th edition, Mack Publishing Company, Easton, Pa., (1985); and "Handbook of Pharmaceutical Salts: Properties, Selection, and Use", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002) can be found in some other suitable salt lists.

[0191] In addition, the compounds disclosed in the present invention, including their salts, can also be obtained in the form of their hydrates or in the form of solvents (such as ethanol, DMSO, etc.) for their crystallization. The compounds disclosed in the present invention can form solvates with pharmaceutically acceptable solvents (including water) inherently or by design; therefore, the present invention is intended to include both solvated and unsolvated forms.

[0192] The "solvate" of the present invention refers to an association formed by one or more solvent molecules and the compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid and aminoethanol. The term "hydrate" refers to an association formed by the solvent molecule being water.

[0193] The "nitrogen oxide" of the present invention refers to when the compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form N-oxides. Special examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen-containing heterocyclic nitrogen atoms. The corresponding amines can be treated with oxidants such as hydrogen peroxide or peracids (e.g., peroxycarboxylic acids) to form N-oxides (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages). In particular, N-oxides can be prepared by the method of LW Deady (Syn. Comm. 1977, 7, 509-514), wherein, for example, in an inert solvent such as dichloromethane, the amine compound is reacted with meta-chloroperoxybenzoic acid (MCPBA).

[0194] As used herein, the term "treating" any disease or condition, in some embodiments, refers to ameliorating the disease or condition (i.e., slowing or preventing or alleviating the development of the disease or at least one clinical symptom thereof). In other embodiments, "treating" refers to alleviating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treating" refers to regulating the disease or condition physically (e.g., stabilizing perceptible symptoms) or physiologically (e.g., stabilizing physical parameters), or both. In other embodiments, "treating" refers to preventing or delaying the onset, occurrence, or worsening of a disease or condition.

[0195] The term "RET-related cancer" as used herein refers to a cancer associated with a disordered expression, activity or level of the RET gene, RET kinase (also referred to as RET kinase protein or RET kinase in the present invention), or any one of them. The present invention describes non-limiting examples of RET-related cancers. The disordered expression, activity or level of the RET gene, RET kinase, or any one of them is one or more point mutations in the RET gene. In some embodiments, the disordered expression, activity or level of the RET gene, RET kinase, or any one of them includes one or more deletions (e.g., a deletion of amino acid 4), insertions, or point mutations in the RET kinase.

[0196] The term "irritable bowel syndrome" includes diarrhea-predominant, constipation-predominant or alternating bowel patterns, functional bloating, functional constipation, functional diarrhea, nonspecific functional bowel disorder, functional abdominal pain syndrome, chronic idiopathic constipation, functional esophageal disease, functional gastroduodenal disease, functional anorectal pain, inflammatory bowel disease, etc.

[0197] Any structural formula given herein is also intended to represent non-isotopically enriched forms of these compounds as well as isotopically enriched forms. Isotopically enriched compounds have structures depicted by the general formula given herein except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Exemplary isotopes that can be introduced into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 Oh, 18 Oh, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I.

[0198] In another aspect, the compounds of the invention include isotopically enriched compounds as defined herein, for example, wherein a radioactive isotope is present, such as 3 H, 14 C and 18 Those compounds of F, or in which non-radioactive isotopes are present, such as 2 H and 13 C. This type of isotope-enriched compound can be used for metabolic studies (using 14 C), reaction kinetics studies (using e.g. 2 H or 3 H), detection or imaging techniques, such as positron emission tomography (PET) or single photon emission computed tomography (SPECT) including drug or substrate tissue distribution determination, or may be used in radiation therapy of the patient. 18 F-enriched compounds are particularly ideal for PET or SPECT studies. Isotopically enriched compounds of formula (I), (I-1), (I-2) or (I-3) can be prepared by conventional techniques familiar to those skilled in the art or by using suitable isotopically labeled reagents to replace the unlabeled reagents used originally as described in the examples and preparation processes of the present invention.

[0199] In addition, heavier isotopes, especially deuterium (i.e. 2H or D) can provide certain therapeutic advantages, which are brought about by higher metabolic stability. For example, an increase in half-life in vivo or a reduction in dosage requirements or an improvement in therapeutic index. It should be understood that deuterium in the present invention is regarded as a substituent of the compound of formula (I), (I-1), (I-2) or (I-3). The concentration of such heavier isotopes, especially deuterium, can be defined by an isotopic enrichment factor. The term "isotopic enrichment factor" used in the present invention refers to the ratio between the isotopic abundance and the natural abundance of a specified isotope. Where a substituent of a compound of the invention is designated as deuterium, the compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). Pharmaceutically acceptable solvates according to the invention include those wherein the solvent of crystallization may be isotopically substituted, for example D2O, acetone-d6, DMSO-d6.

[0200] Compounds of the present invention and pharmaceutical compositions, preparations and administration thereof

[0201] The present invention provides compounds of the present invention or pharmaceutical compositions thereof that inhibit wild-type RET and RET mutants. In addition, relative to other kinases, the compounds of the present invention or pharmaceutical compositions thereof have inhibitory selectivity for both wild-type RET and RET gene mutants, thereby reducing toxicity associated with inhibiting other kinases.

[0202] The pharmaceutical composition of the present invention includes a compound represented by formula (I), (I-1), (I-2) or (I-3), a compound listed in the present invention, or a compound of the embodiment. The amount of the compound in the pharmaceutical composition of the present invention can effectively treat or alleviate RET-related diseases or conditions in patients, including RET-related cancers, irritable bowel syndrome and / or pain associated with irritable bowel syndrome.

[0203] As described in the present invention, the pharmaceutically acceptable composition of the present invention further comprises a pharmaceutically acceptable adjuvant, which, as used in the present invention, includes any solvent, diluent, or other liquid excipient, dispersant or suspending agent, surfactant, isotonic agent, thickener, emulsifier, preservative, solid binder or lubricant, etc., suitable for a specific target dosage form. As described in the following documents: In Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. DB Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and JC Boylan, 1988-1999, Marcel Dekker, New York, the contents of the documents herein are combined to show that different adjuvants can be applied to the preparation of pharmaceutically acceptable compositions and their known preparation methods. Except insofar as any conventional adjuvant is incompatible with the compounds of the present invention, for example by producing any undesirable biological effect or interacting in a deleterious manner with any other component of the pharmaceutically acceptable composition, their use is contemplated by the present invention.

[0204] When preparing the pharmaceutical composition provided by the invention, active ingredient is usually mixed with excipient, diluted by excipient or encapsulated in such carrier in the form of capsule, pouch, paper or other container, for example. If excipient is used as diluent, it can be solid, semisolid or liquid material, which is used as carrier, carrier or medium of active ingredient. Suitable carriers include but are not limited to magnesium carbonate, magnesium stearate, talcum powder, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth gum, methylcellulose, sodium carboxymethylcellulose, low melting point wax, cocoa butter, etc. Therefore, the composition can be tablets, pills, powders, lozenges, capsules, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (solid form or in liquid medium), for example, ointments containing up to 10% by weight of active compound, soft and hard gelatin capsules, suppositories, sterile injection solutions and aseptically packaged powders. In one embodiment, the composition is formulated for oral administration. In one embodiment, the composition is formulated into tablets or capsules.

[0205] When used for treatment, a therapeutically effective amount of the compound of the present invention, especially the compound shown in formula (I), (I-1), (I-2) or (I-3) and a pharmaceutically acceptable salt thereof, can be administered as a raw chemical drug, and can also be provided as an active ingredient of a pharmaceutical composition. Therefore, the present invention also provides a pharmaceutical composition, which includes a therapeutically effective amount of the compound of the present invention, especially the compound shown in formula (I), (I-1), (I-2) or (I-3) or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable adjuvants, including but not limited to carriers, diluents or excipients, etc. The term "therapeutically effective amount" used in the present invention refers to the total amount of each active ingredient sufficient to show a significant patient benefit (e.g., a reduction in cancer cells). When a single active ingredient is administered alone, the term refers only to that ingredient. When used in combination, the term refers to the combined amount of active ingredients that causes a therapeutic effect regardless of the combination, sequential or simultaneous administration. The compounds of the present invention, especially the compounds shown in formula (I), (I-1), (I-2) or (I-3) and their pharmaceutically acceptable salts, as described above, must be acceptable in the sense of being compatible with the other ingredients of the formulation and harmless to the recipient thereof. According to another aspect of the present invention, a method for preparing a pharmaceutical preparation is also provided, which comprises mixing the compounds of the present invention, especially the compounds shown in formula (I), (I-1), (I-2) or (I-3) or their pharmaceutically acceptable salts with one or more pharmaceutically acceptable carriers, diluents or excipients. The term "pharmaceutically acceptable" as used in the present invention refers to such compounds, raw materials, compositions and / or dosage forms, which are suitable for contact with patient tissues without excessive toxicity, irritation, allergic reactions or other problems and complications symmetrical to a reasonable benefit / risk ratio within the scope of reasonable medical judgment, and are effectively used for the intended purpose.

[0206] The amount of active ingredient combined with one or more adjuvants to prepare a single dosage form will necessarily vary depending on the host being treated and the specific route of administration. The amount of active ingredient mixed with a carrier material to prepare a single dosage form of a compound shown in formula (I), (I-1), (I-2) or (I-3) will vary depending on the disease to be treated, the severity of the disease, the time of administration, the route of administration, the excretion rate of the compound used, the treatment time, and the patient's age, sex, body weight and condition. A preferred unit dosage form is a unit dosage form containing the daily dose or divided dose of the above-mentioned active ingredient of the present invention or its appropriate fraction. Treatment can be started with a small dose that is significantly lower than the optimal dose of the compound. Thereafter, the dose is increased in smaller increments until the best effect is achieved in this case. In general, the concentration level at which the compound is most ideally administered is generally effective in anti-tumor aspects without causing any harmful or toxic side effects.

[0207] Compositions containing the compounds of the present invention can be formulated into unit dosage forms, each dose containing about 5 to about 1,000 mg (1 g), more usually about 100 mg to about 500 mg of active ingredient. The term "unit dosage form" refers to physically discrete units suitable for use as single doses for human subjects or other patients, each unit containing a predetermined amount of active material (i.e., a compound of formula (I) as provided by the present invention) and a suitable pharmaceutical excipient, the predetermined amount being calculated to produce the desired therapeutic effect.

[0208] The pharmaceutical composition is suitable for administration by any suitable route, for example, by oral (including oral or sublingual), rectal, nasal, topical (including oral, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intradermal, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intralesional, intravenous or subdermal injection or infusion) route. Such preparations can be prepared by any known method in the field of pharmacy, for example, by mixing the active ingredient with a carrier or excipient. Oral administration or injection is preferred.

[0209] The present invention also provides a method of treating an individual suffering from a RET-related cancer, the method comprising administering a compound of the present invention before, during, or after administering another anti-cancer agent (eg, not a compound of the present invention).

[0210] The present invention provides a method for treating cancer in a patient in need thereof, the method comprising: (a) determining whether the cancer in the patient is a RET-related cancer (e.g., a RET-related cancer comprising one or more RET inhibitor resistance mutations) (e.g., using a regulatory agency-approved, e.g., FDA-approved, kit to identify a disorder of expression or activity or level of a RET gene, RET kinase, or any one thereof in a patient or in a biopsy sample of a patient, or by performing any non-limiting example of the assay described herein); and (b) if the cancer is determined to be a RET-related cancer, administering to the patient a therapeutically effective amount of a compound of formula (I), (I-1), (I-2) or (I-3), or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof. Some embodiments of these methods further comprise administering to the subject another anticancer agent (e.g., another RET inhibitor, e.g., a RET inhibitor that is not a compound of the present invention). In some embodiments, the subject has been previously treated with a RET inhibitor that is not a compound of Formula (I), (I-1), (I-2) or (I-3) or a pharmaceutically acceptable salt or solvate thereof, or has been previously treated with other anticancer agents (e.g., after tumor resection or radiation therapy).

[0211] In some embodiments of any of the methods described herein, the compound represented by Formula (I), (I-1), (I-2) or (I-3) (or a pharmaceutically acceptable salt or solvate thereof) is used in combination with a therapeutically effective amount of at least one other therapeutic agent, wherein the at least one other therapeutic agent is selected from one or more other therapies or treatments (e.g., chemotherapy) agents.

[0212] Non-limiting examples of other therapeutic agents include: other RET targeted therapeutics (i.e., other RET kinase inhibitors, not RET inhibitors of the compounds described herein), receptor tyrosine kinase targeted therapeutics, signal transduction pathway inhibitors, checkpoint inhibitors, apoptosis pathway modulators (e.g., Obataclax); cytotoxic chemotherapeutics, angiogenesis targeted therapeutics, immune targeted agents, and radiation therapy.

[0213] In some embodiments, the additional RET targeted therapeutic is a multi-kinase inhibitor that exhibits RET inhibitory activity.

[0214] Non-limiting examples of RET-targeted therapeutics include alatinib, apatinib, cabozantinib (XL-184), dovitinib, lenvatinib, motesanib, nintedanib, ponatinib, regorafenib, sitravatinib (MGCD516), sunitinib, sorafenib, vatalanib, vandetanib, AUY-922 (5-(2,4-dihydroxy-5-isopropyl-phenyl)-N-ethyl-4-[4-(morpholinomethyl)phenyl]isoxazole-3-carboxamide), BLU6864, BLU-667, DCC-2157, NVP-AST487 (1-[4-[(4-ethylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-3-[4-[6-(methyl)piperidinib]-1-yl)methyl]-1-[(trifluoromethyl)phenyl]-3-[(trifluoromethyl)phenyl ... 1-(3-(6,7-dimethoxyquinazolin-4-yl)oxy)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea), SPP86 (1-isopropyl-3-(phenylethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine) and TG101209 (N-(1,1-dimethylethyl)-3-[[5-methyl-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-4-pyrimidinyl]amino]benzenesulfonamide).

[0215] Other therapeutic agents include RET inhibitors, such as those described in, for example, U.S. Pat. Nos. 7,504,509; 8,299,057; 8,399,442; 8,067,434; 8,937,071; 9,006,256; and 9,035,063; U.S. Publication Nos. 2014 / 0121239; 20160176865; 2011 / 0053934; 2011 / 0301157; 2010 / 0324065; 2009 / 0227556; 2009 / 0130229; 2009 / 0099167; 2005 / 0209195; International Publication Nos. WO 2014 / 184069; WO 2014 / 072220; WO 2012 / 053606; WO 2009 / 017838; WO 2008 / 031551; WO 2007 / 136103; WO 2007 / 087245; WO 2007 / 057399; WO 2005 / 051366; WO 2005 / 062795; and WO 2005 / 044835; and J. Med. Chem. 2012, 55(10), 4872-4876, all of which are incorporated herein by reference in their entirety.

[0216] The present invention also provides a method for treating cancer, comprising administering to a patient in need thereof a drug combination for treating cancer, which comprises (a) a compound of the general formula (I) or a pharmaceutically acceptable salt or solvate thereof, (b) other therapeutic agents, and (c) optionally at least one pharmaceutically acceptable carrier, for simultaneous, separate or sequential use in treating cancer, wherein the amount of the compound of the general formula (I) or a pharmaceutically acceptable salt or solvate thereof and the amount of the other therapeutic agent are jointly effective in treating cancer.

[0217] The compounds and compositions of the present invention can be used alone or in combination with other compounds (including other RET regulating compounds) or other therapeutic agents. In some embodiments, the compounds or compositions of the present invention can be used in combination with one or more compounds selected from the following: cabozantinib (COMETRIQ), vandetanib (CALPRESA), sorafenib (NEXAVAR), sunitinib (SUTENT), regorafenib (STAVARGA), ponatinib (ICLUSIG), bevacizumab (Avastin), crizotinib (XALKORI) or gefitinib (IRESSA). The compounds or compositions of the present invention can be used simultaneously or successively with other therapeutic agents by the same or different routes of administration. The compounds of the present invention can be included in a single preparation or in a separate preparation together with other therapeutic agents.

[0218] In some embodiments, the compounds of the present invention can be used to treat irritable bowel syndrome (IBS) in combination with one or more other therapeutic agents or therapies that act by the same or different mechanisms of action and are effective in the treatment of irritable bowel syndrome. According to standard pharmaceutical practices known to those skilled in the art, the at least one other therapeutic agent can be administered as part of the same or separate dosage form, via the same or different routes of administration, and according to the same or different administration schedules with the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof. Non-limiting examples of other therapeutic agents used to treat irritable bowel syndrome (IBS) include probiotics, fiber supplements (e.g., psyllium, methylcellulose), antidiarrheals (e.g., loperamide), bile acid binders (e.g., cholestyramine, colestipol, colesevelam), anticholinergics and antispasmodics (e.g., scopolamine, dicyclomine), antidepressants (e.g., tricyclic antidepressants such as imipramine or nortriptyline or selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine or paroxetine), antibiotics (e.g., rifaximin), alosetron, and lubiprostone.

[0219] Uses of the compounds and pharmaceutical compositions of the present invention

[0220] The present invention also provides use of the compound of the present invention or the pharmaceutical composition of the present invention in the preparation of a medicament for preventing or treating RET-related diseases or conditions, wherein the RET-related diseases or conditions include RET-related cancers, irritable bowel syndrome and / or pain associated with irritable bowel syndrome.

[0221] The present invention provides compounds of the present invention or pharmaceutical compositions thereof that inhibit RET wild-type and RET mutants, for example, RET mutants that are resistant to current standard of care treatments ("RET resistant mutants"). In addition, relative to other kinases, the compounds of the present invention or pharmaceutical compositions thereof have inhibitory selectivity for both RET wild-type and RET gene mutants, thereby resulting in reduced toxicity associated with inhibiting other kinases.

[0222] The present invention provides use of the compound of the present invention or its pharmaceutical composition for inhibiting RET wild-type and RET mutants in the preparation of a drug for preventing or treating diseases or disorders associated with RET wild-type and RET mutants.

[0223] In some embodiments of any of the methods or uses described herein, the cancer (e.g., RET-related cancer) is a hematological cancer. In some embodiments of any of the methods or uses described herein, the cancer (e.g., RET-related cancer) is a solid tumor. In some embodiments of any of the methods or uses described herein, the cancer (e.g., RET-related cancer) is lung cancer (e.g., small cell lung cancer or non-small cell lung cancer), papillary thyroid cancer, medullary thyroid cancer, differentiated thyroid cancer, recurrent thyroid cancer, refractory differentiated thyroid cancer, lung adenocarcinoma, bronchiolar lung cancer, multiple endocrine neoplasia type 2A or 2B (MEN2A or MEN2B, respectively), pheochromocytoma, parathyroid hyperplasia, breast cancer, colorectal cancer (e.g., metastatic colorectal cancer), papillary renal cell carcinoma, ganglioneuroma of the gastrointestinal mucosa, inflammatory myofibroblastic tumor, or cervical cancer.In some embodiments of any of the methods or uses described herein, the cancer (e.g., RET-related cancer) is selected from the group consisting of acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), juvenile cancer, adrenocortical carcinoma, anal cancer, appendix cancer, astrocytoma, atypical teratoma / rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchial tumor, Burkitt's lymphoma, carcinoid tumor, cancer of unknown primary, heart tumor, cervical cancer, childhood cancer, chordoma, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myeloproliferative neoplasms, colon cancer, colorectal cancer, Craniopharyngioma, cutaneous T-cell lymphoma, bile duct cancer, ductal carcinoma in situ, embryonal tumor, endometrial cancer, ependymoma, esophageal cancer, esthesia neuroblastoma, Ewing sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, extrahepatic bile duct cancer, eye cancer, fallopian tube cancer, fibrous histiocytoma of bone, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, gestational trophoblastic disease, glioma, hairy cell tumor, hairy cell leukemia, head and neck cancer, heart cancer, hepatocellular carcinoma, histiocytosis, Hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumor, pancreatic neuroendocrine tumor, Kaposi sarcoma, kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, lip and oral cancer, liver cancer, lung cancer, lymphoma, macroglobulinemia, malignant fibrous histiocytoma of bone, bone cancer, melanoma, merkel cell carcinoma, mesothelioma, metastatic squamous neck cancer, midline carcinoma, mouth cancer, multiple endocrine neoplasia syndrome, multiple myeloma, mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasms, myeloid leukemia, myeloid leukemia, multiple myeloma, myeloproliferative neoplasms, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-hodgkin lymphoma, non-small cell lung cancer, mouth cancer, oral cancer, lip cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, papilloma disease, paraganglioma, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pituitary cancer, plasmacytoma, pleuropulmonary blastoma, pregnancy and breast cancer, primary central nervous system lymphoma, primary peritoneal cancer, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, Sezary syndrome, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, squamous neck cancer, gastric cancer, T-cell lymphoma, testicular cancer, pharyngeal cancer, thymoma and thymic cancer, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, cancer of unknown primary, urethral cancer, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, and Wilm's tumor.

[0224] In some embodiments, the RET-related cancer of the present invention is selected from lung cancer, papillary thyroid cancer, medullary thyroid cancer, differentiated thyroid cancer, recurrent thyroid cancer, refractory differentiated thyroid cancer, multiple endocrine neoplasia type 2A or 2B (MEN2A or MEN2B, respectively), pheochromocytoma, parathyroid hyperplasia, breast cancer, colorectal cancer, papillary renal cell carcinoma, gastrointestinal mucosal ganglioneuroma and cervical cancer. In some embodiments, the RET-related cancer is RET fusion lung cancer or medullary thyroid cancer.

[0225] In some embodiments, the compounds of Formula (I), (I-1), (I-2) or (I-3) and pharmaceutically acceptable salts and solvates thereof can be used to treat patients with cancers that have RET inhibitor resistance mutations (which result in increased resistance to a compound other than Formula (I), (I-1), (I-2), (I-3) or (I-4) or a pharmaceutically acceptable salt or solvate thereof, such as a substitution at amino acid position 804, such as V804M, V804L or V804E), by co-administration or as a follow-up to an existing drug therapy (e.g., other RET kinase inhibitors other than a compound of Formula (I), (I-1), (I-2) or (I-3) or a pharmaceutically acceptable salt or solvate thereof). The present invention describes exemplary RET kinase inhibitors (e.g., other RET kinase inhibitors other than a compound of Formula (I), (I-1), (I-2) or (I-3) or a pharmaceutically acceptable salt or solvate thereof). In some embodiments, the RET kinase inhibitor can be selected from cabozantinib, vandetanib, alatinib, sorafenib, lenvatinib, ponatinib, dovitinib, sunitinib, foretinib, BLU667 and BLU6864.

[0226] In some embodiments of any of the methods or uses described herein, the irritable bowel syndrome (IBS) includes diarrhea-predominant, constipation-predominant or alternating types, functional bloating, functional constipation, functional diarrhea, unspecified functional intestinal disorder, functional abdominal pain syndrome, chronic idiopathic constipation, functional esophageal disease, functional gastroduodenal disease, functional anorectal pain, and inflammatory bowel disease.

[0227] According to the method of the present invention, the compounds and compositions can be any dosage and any administration route to effectively treat or alleviate the severity of the disease. The exact amount required will vary according to the patient's condition, depending on age, the patient's general condition, the severity of the infection, special factors, mode of administration, etc. The compound or composition can be used in combination with one or more other therapeutic agents, as discussed herein.

[0228] General Synthesis Methods of Compounds of the Invention

[0229] Generally, the compounds of the present invention can be prepared by the methods described herein, unless otherwise specified, wherein the substituents are defined as shown in formula (I), (I-1), (I-2) or (I-3). The following reaction schemes and examples are used to further illustrate the content of the present invention.

[0230] Those skilled in the art will recognize that the chemical reactions described herein can be used to appropriately prepare many other compounds of the invention, and other methods for preparing the compounds of the invention are considered to be within the scope of the invention. For example, the synthesis of non-exemplified compounds according to the invention can be successfully accomplished by those skilled in the art through modification methods, such as appropriate protection of interfering groups, by utilizing other known reagents in addition to those described herein, or by making some conventional modifications to the reaction conditions. In addition, the reactions disclosed herein or known reaction conditions are also recognized to be applicable to the preparation of other compounds of the invention.

[0231] In the examples described below, all temperatures are in degrees Celsius unless otherwise indicated. Unless otherwise indicated, reagents can be purchased from commercial suppliers such as Lingkai Pharmaceutical, Aldrich Chemical Company, Inc., Arco Chemical Company and Alfa Chemical Company, and are not further purified when used, unless otherwise indicated. Common reagents are purchased from Shantou Xilong Chemical Factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, Tianjin Haoyuyu Chemical Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Ocean Chemical Factory.

[0232] Anhydrous tetrahydrofuran is obtained by drying under reflux over sodium metal. Anhydrous dichloromethane and chloroform are obtained by drying under reflux over calcium hydride. Ethyl acetate, N,N-dimethylacetamide and petroleum ether are dried over anhydrous sodium sulfate before use.

[0233] The following reactions were generally carried out under positive pressure of nitrogen or argon or with a drying tube over anhydrous solvents (unless otherwise indicated), reaction bottles were plugged with appropriate rubber stoppers, and substrates were injected via syringes. All glassware was dried.

[0234] The chromatographic column used was a silica gel column. Silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Plant. The NMR spectra were CDC13 or DMSO-d6 as solvents (reported in ppm), and TMS (0 ppm) or chloroform (7.25 ppm) as reference standards. When multiple peaks appear, the following abbreviations will be used: s (singlet), d (doublet), t (triplet), m (multiplet), br (broadened), dd (doublet of doublets), dt (doublet of triplets). The coupling constant J is expressed in Hertz (Hz).

[0235] Low-resolution mass spectrometry (MS) data were determined by an Agilent 6320 series LC-MS spectrometer equipped with a G1312A binary pump and a G1316A TCC (column temperature was maintained at 30 °C). A G1329A autosampler and a G1315B DAD detector were used for analysis, and an ESI source was applied to the LC-MS spectrometer.

[0236] Low-resolution mass spectrometry (MS) data were measured by an Agilent 6120 series LC-MS spectrometer equipped with a G1311A quaternary pump and a G1316A TCC (column temperature was maintained at 30 °C). A G1329A autosampler and a G1315D DAD detector were used for analysis, and an ESI source was applied to the LC-MS spectrometer.

[0237] Both spectrometers were equipped with an Agilent Zorbax SB-C18 column with a size of 2.1×30 mm, 5 μm. The injection volume was determined by the sample concentration; the flow rate was 0.6 mL / min; the HPLC peak was recorded and read by UV-Vis wavelengths at 210 nm and 254 nm. The mobile phases were 0.1% formic acid in acetonitrile (phase A) and 0.1% formic acid in ultrapure water (phase B).

[0238] Compound purification was evaluated by Agilent 1100 series high performance liquid chromatography (HPLC) with UV detection at 210 nm and 254 nm, a Zorbax SB-C18 column, 2.1×30 mm, 4 μm, 10 min, a flow rate of 0.6 mL / min, 5-95% (0.1% formic acid in acetonitrile) in (0.1% formic acid in water), and the column temperature was maintained at 40°C.

[0239] The following abbreviations are used throughout this invention:

[0240] TEA Triethylamine

[0241] DMF N,N-Dimethylacetamide

[0242] NaH Sodium hydride

[0243] DIPEA N,N-Diisopropylethylamine

[0244] EDCI 1-ethyl-3 (3-dimethylpropylamine) carbodiimide

[0245] DMAC N,N-Dimethylacetamide

[0246] DMAP 4-dimethylaminopyridine

[0247] DMSO Dimethyl sulfoxide

[0248] HATU 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate

[0249] DCM Dichloroethane

[0250] EA Ethyl acetate

[0251] PE Petroleum Ether

[0252] MeOH Methanol

[0253] MeOD deuterated methanol

[0254] NaOH Sodium hydroxide

[0255] NH4Cl Ammonium chloride

[0256] K2CO3 Potassium carbonate

[0257] THF Tetrahydrofuran

[0258] n-BuLi n-butyllithium

[0259] Boc tert-Butyloxycarbonyl

[0260] OMs Methanesulfonyloxy

[0261] mass%% mass percentage

[0262] mL milliliters

[0263] L Liter

[0264] mmol millimole

[0265] M,mol / L mole per liter

[0266] g

[0267] min

[0268] h hour

[0269] ℃ Celsius

[0270] TLC Thin layer chromatography

[0271] The following synthetic schemes describe the steps for preparing the compounds disclosed in the present invention. 1 , R 2 , X 1 , X 2 , X 3 , X 4 , X 5 , T, E, A, Q and M have the definitions as described in the present invention.

[0272] Synthesis scheme of intermediate (Ia)

[0273]

[0274] The synthesis of intermediate (Ia) can be obtained by referring to the synthesis steps of the above synthesis scheme of intermediate (Ia). 1 is F, Cl, Br or I, preferably Cl or Br; Hal 2 is F, Cl, Br or I, preferably F, Cl or Br; Alk is C 1-6 Alkyl, preferably C 1-4 Alkyl, more preferably methyl, ethyl, isopropyl or tert-butyl. Compound (Ia-1) reacts with a metal hydroxide (such as sodium hydroxide) under appropriate conditions (such as in the presence of dodecanethiol, water and N,N-dimethylacetamide) to obtain compound (Ia-2); compound (Ia-2) reacts with trifluoroacetic anhydride under appropriate conditions (such as pyridine) to obtain compound (Ia-3); compound (Ia-3) and compound (Ia-4) react under appropriate coupling agent conditions (such as palladium coupling agent, preferably [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex) in a suitable solvent ( The compound (Ia-5) is subjected to coupling reaction with the compound (Ia-6) under suitable coupling agent conditions (such as palladium coupling agent, preferably [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex) in a suitable solvent (such as toluene, etc.) to obtain compound (Ia-7); the compound (Ia-7) is reacted under suitable reaction conditions (such as in the presence of sodium hydroxide and hydrogen peroxide, in tetrahydrofuran solvent) to obtain a compound of formula (Ia).

[0275] Synthesis scheme of intermediate (Ib)

[0276]

[0277] The intermediate compound represented by formula (Ib) can be obtained by referring to the synthesis steps of the above synthesis scheme of intermediate (Ib). 1 and Hal 2 Each independently is F, Cl, Br or I, preferably Cl or Br; Pg 1 is an amino protecting group, such as Boc, etc.; Pg 2 is a hydroxyl protecting group, such as benzyl, etc.; Ring A a It is a 3-12 membered heterocyclic group, wherein at least two ring atoms are nitrogen atoms. The compound of formula (Ia) and the compound of formula (Ib-1) are subjected to coupling reaction to obtain the compound of formula (Ib-2); the compound of formula (Ib-2) and the compound of formula (Ib-3) are reacted under alkaline conditions to obtain the compound of formula (Ib-4); the compound of formula (Ib-4) is deaminated under acidic conditions to obtain the compound of formula (Ib-5) or the salt of the compound of formula (Ib-5); the compound of formula (Ib-5) or the salt of the compound of formula (Ib-5) is reacted with the compound of formula (Ib-6) under alkaline conditions to obtain the compound of formula (Ib-7); the compound of formula (Ib-7) is reduced under appropriate conditions (such as H2, Pd / C) to obtain the compound of formula (Ib).

[0278] Synthesis scheme of intermediate (Ic)

[0279]

[0280] The intermediate compound represented by formula (Ic) can be obtained by referring to the synthesis steps of the above synthesis scheme of intermediate (Ic). 2 is F, Cl, Br or I, preferably Cl or Br; Ring A b is a 3-12 membered heterocyclic group, wherein at least one of the ring atoms is a nitrogen atom. The compound of formula (Ia) is subjected to a coupling reaction with the compound of formula (Ic-1) or a salt of the compound of formula (Ic-1) (e.g., hydrochloride, formate, etc.) under suitable conditions (e.g., in DMSO solvent, under alkaline conditions, such as K2CO3) to obtain the compound of formula (Ic).

[0281] Synthesis Scheme 1

[0282]

[0283] Compound (IA) can be obtained by referring to the synthesis steps of Synthesis Scheme 1. 2 is F, Cl, Br or I, preferably F, Cl or Br; Ring A bis a 3-12 membered heterocyclic group, wherein at least one ring atom is a nitrogen atom. Compound (Ia) is subjected to a coupling reaction with compound (IA-1) under suitable conditions (such as in N,N-dimethylacetamide solvent, under alkaline conditions, such as K2CO3) to obtain compound (IA-2); compound (IA-2) is subjected to a coupling reaction with compound (Ic-1) or a salt of compound (Ic-1) (such as hydrochloride, formate, trifluoroacetate, etc.) under suitable conditions (such as in DMSO solvent, under alkaline conditions, such as K2CO3) to obtain compound (IA).

[0284] Synthesis Scheme 2

[0285]

[0286] Compound (IAA) can be obtained by referring to the synthesis steps of Synthesis Scheme 2. 1 is F, Cl, Br or I, preferably Cl or Br. Compound (Id) is subjected to coupling reaction with compound (IA-1) under appropriate conditions (such as in N,N-dimethylacetamide solvent, under basic conditions such as K2CO3) to give compound (IAA).

[0287] Synthesis Scheme 3

[0288]

[0289] Compound (IAA) can be obtained by referring to the synthesis steps of Synthesis Scheme 3. Compound (Id) and compound (IA-3) are subjected to coupling reaction under appropriate conditions (such as in N,N-dimethylformamide solvent, under basic conditions such as K2CO3) to obtain compound (IAA).

[0290] Synthesis Scheme 4

[0291]

[0292] Compound (IA) can be obtained by referring to the synthesis steps of Synthesis Scheme 4. 2 is F, Cl, Br or I, preferably F, Cl or Br; Ring A b is a 3-12 membered heterocyclic group, wherein at least one ring atom is a nitrogen atom. Compound (Ia) is subjected to a coupling reaction with compound (IA-3) under suitable conditions (such as in N,N-dimethylformamide solvent, under alkaline conditions, such as K2CO3) to obtain compound (IA-2); compound (IA-2) is subjected to a coupling reaction with compound (Ic-1) or a salt of compound (Ic-1) (such as hydrochloride, formate, trifluoroacetate, etc.) under suitable conditions (such as in DMSO solvent, under alkaline conditions, such as K2CO3) to obtain compound (IA). Specific embodiments

[0293] Intermediate 1: 4-(6-fluoropyridin-3-yl)-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile

[0294]

[0295] Step 1: 6-Bromo-4-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile

[0296] At room temperature, 6-bromo-4-methoxypyrazolo[1,5-a]pyridine-3-carbonitrile (50g, 198.36mmol), water (16.5mL, 916mmol), sodium hydroxide (16.03g, 396.8mmol), DMAE (500mL) were added in sequence in a 1L single-mouth bottle. After stirring at room temperature for 5 minutes, the mixture was transferred to 0℃ and dodecanethiol (97mL, 397mmol) was slowly added. After the addition was completed, the reaction was transferred to 45℃ overnight. The reaction solution was poured into 3L ice water, and saturated citric acid aqueous solution was slowly added to adjust the pH to 5. After stirring for half an hour, it was allowed to stand and filtered. The filter cake was washed with water and petroleum ether several times, and dried at 60℃ to obtain 44.1g of yellow solid, which was the target product (yield 93.4%). LC-MS (ES-API): m / z=239.05[M+H] + .

[0297] Step 2: 6-Bromo-3-cyanopyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate

[0298] 6-Bromo-4-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile (44.1 g, 185 mmol), pyridine (45 mL, 559 mmol), and DCM (800 mL) were added to a 1L single-mouth bottle. The temperature was lowered to below -10°C, and trifluoromethanesulfonic anhydride (50 mL, 297.2 mmol) was slowly added. After stirring for 1 hour, the mixture was naturally warmed to room temperature and reacted overnight. The DCM was dried under reduced pressure, diluted with water (250 mL), extracted with EA (500 mL × 3), the organic phase was collected, washed with saturated brine (250 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was dried, and purified by silica gel column chromatography (eluent: PE / EA (v / v) = 50 / 1-25 / 1) to obtain 61.5 g of off-yellow solid, which was the target product, with a yield of 89.7%.

[0299] Step 3: 6-Bromo-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0300] Under nitrogen protection, 6-bromo-3-cyanopyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate (61.5 g, 166 mmol), 2-fluoropyridine-5-boronate (44.5 g, 200 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (6.8 g, 8.3 mmol), and 1,4-dioxane (850 mL) were added into a 1L three-necked flask. The temperature was lowered to -10°C, and potassium acetate solution (115 mL, 345 mmol, 3 mol / L) was slowly added. The mixture was stirred at this temperature for 1 h and then naturally returned to room temperature and the reaction was continued overnight. Filter, wash the filter cake with EA (500 mL × 3), separate the organic phase from the filtrate, wash with water (500 mL), wash with saturated brine (250 mL), dry with anhydrous sodium sulfate, filter, spin dry the filtrate, purify by silica gel column chromatography (eluent: PE / DCM (v / v) = 2 / 1-0 / 1), and obtain 49 g of white solid, which is the target product, with a yield of 93.0%. LC-MS (ES-API): m / z = 318.10 [M+H] + ; 1 HNMR(400MHz,DMSO-d6)δ9.49(d,J=1.2Hz,1H),8.73(s,1H),8.51(d,J=1.9Hz,1H ), 8.27 (td, J = 8.2, 2.5Hz, 1H), 7.86 (d, J = 1.2Hz, 1H), 7.40 (dd, J = 8.4, 2.5Hz, 1H).

[0301] Step 4: 4-(6-fluoropyridin-3-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0302] In a 250mL single-necked bottle, 6-bromo-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (8 g, 25.23 mmol), bipyraclostrobin (10 g, 39.39 mmol), potassium acetate (10 g, 101.9 mmol), and redistilled toluene (150 mL) were added in sequence under nitrogen protection. After nitrogen replacement and bubbling for 10 min, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (2.1 g, 2.6 mmol) was added. After nitrogen replacement and bubbling for 10 min, the reaction was heated at 120°C overnight. Filter with diatomaceous earth, wash the filter cake with EA (50 mL × 3), wash the organic phase with water (250 mL), wash with saturated brine (250 mL), dry with anhydrous sodium sulfate, filter, and spin-dry. Purify by silica gel column chromatography (eluent: PE / DCM (v / v) = 2 / 1-0 / 1), collect and spin-dry to obtain 8.5 g of an orange-yellow solid, which is the target product (yield 93.0%). 1H NMR (400MHz, CDCl3) δ8.99 (s, 1H), 8.43 (d, J = 2.1Hz, 1H), 8.34 (s, 1H), 8.02 (t d, J=8.0, 2.5Hz, 1H), 7.66 (s, 1H), 7.13 (dd, J=8.5, 2.8Hz, 1H), 1.40 (s, 12H).

[0303] Step 5: 4-(6-Fluoropyridin-3-yl)-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile

[0304] In a 250mL single-mouth bottle, add 4-(6-fluoropyridin-3-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (8.5g, 23mmol) and tetrahydrofuran (120mL) in sequence. In an ice bath, slowly add sodium hydroxide solution (60mL, 120mmol, 2mol / L) and hydrogen peroxide (14mL, 140mmol, 30% content) and stir at low temperature. After the reaction is complete as monitored by TLC, slowly add sodium thiosulfate solution (50mL, 150mmol, 3mol / L). After returning to room temperature, add water (250mL), extract with EA (250mL×2), combine the organic phases and wash with 0.1M NaOH solution (500mL×2). Combine all aqueous phases, adjust the pH to 4 with dilute hydrochloric acid, stir at room temperature for 15 min, and filter to obtain a wet cake. Extract the mother liquor with EA (250 mL × 3), combine all organic phases, dry over anhydrous sodium sulfate, filter, spin dry, and purify by silica gel column chromatography (eluent: DCM\MeOH (v / v) = 100 / 0-100 / 1) to obtain a light yellow solid. Combine all solids and dry at 50°C to obtain 5.1 g of a light yellow solid, which is the target product (yield 86.0%). LC-MS (ES-API): m / z = 255.10 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ10.44-10.37(m,1H),8.54(s,1H),8.49-8.46(m,1H) ,8.42-8.40(m,1H),8.26-8.21(m,1H),7.40-7.35(m,1H),7.32-7.30(m,1H).

[0305] Intermediate 2: 4-(6-(3,6-diazabicyclo[3.1.1]hept-3-yl)pyridin-3-yl)-6-(benzyloxy)pyrazolo[1,5-a]pyridine-3-carbonitrile dihydrochloride

[0306]

[0307] Step 1: tert-Butyl 3-(5-(3-cyano-6-hydroxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate

[0308] In a 30 mL microwave tube, 4-(6-fluoropyridin-3-yl)-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile (Intermediate 1, 1.5 g, 5.9 mmol), 6-(tert-butyloxycarbonyl)-3,6-diazabicyclo[3.1.1]heptane (2.3 g, 12 mmol), N,N-diisopropylethylamine (2.0 mL, 12 mmol), dimethyl sulfoxide (15 mL) were added in sequence, sealed, and reacted at 80°C in a microwave for 8 h. Under low temperature conditions, water (50 mL) was added for dilution, EA was extracted (100 mL×5), the organic phases were combined, washed with saturated brine (250 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was spin-dried, and purified by silica gel chromatography (eluent: PE / EA (v / v) = 5 / 1-1 / 1.5), and 1.9 g of a yellow product was collected, which was the target product (yield 74.0%). LC-MS(ES-API):m / z=433.10[M+H] + .

[0309] Step 2: tert-Butyl 3-(5-(6-(benzyloxy)-3-cyanopyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate

[0310] In a 25 mL single-mouth bottle, tert-butyl 3-(5-(3-cyano-6-hydroxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6 carboxylate (1 g, 2.31 mmol), benzyl bromide (0.302 mL, 2.54 mmol), potassium carbonate (0.97 g, 6.93 mmol), N,N-dimethylformamide (10 mL) were added in sequence and stirred at 80°C overnight. Saturated ammonium chloride (100 mL) was added to quench at room temperature, and DCM (100 mL×3) was used for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried by spin drying. The residue was purified by silica gel chromatography (eluent PE / EA (v / v) = 5 / 1-2 / 1) to obtain 1.06 g of a yellow solid, which was the target product (yield 87.7%). LC-MS(ES-API):m / z=523.30[M+H] + ; 1H NMR (400MHz, CDCl3) δ8.37(s,1H),8.19(s,1H),8.17(d,J=1.9Hz,1H),7.74(d,J=8.7Hz,2H),7.42(dt,J=11.9,7.4Hz,5H),7.18(d,J=2.0Hz,1H),5 .13(s,2H),4.31(d,J=4.0Hz,2H),4.16(dd,J=8.7,4.4Hz,2H),3.55(dd, J=8.1,3.1Hz,2H),2.24–2.20(m,1H),2.01(d,J=5.5Hz,1H),1.38(s,9H).

[0311] Step 3: 4-(6-(3,6-diazabicyclo[3.1.1]hept-3-yl)pyridin-3-yl)-6-(benzyloxy)pyrazolo[1,5-a]pyridine-3-carbonitrile dihydrochloride)

[0312] 3-(5-(6-(Benzyloxy)-3-cyanopyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester (1.06 g, 2.03 mmol) and hydrochloric acid ethyl acetate solution (5 mL, 20 mmol, 4 mol / L) were mixed and reacted at room temperature overnight. The reaction solution was dried to obtain a yellow viscous substance, which was dried at 60°C to obtain 1.0 g of a yellow solid, which was the target product (yield 100%). LC-MS (ES-API): m / z = 423.30 [M-2HCl] + .

[0313] Intermediate 3: 5-(azetidin-3-yloxy)-2-methoxypyridine hydrochloride

[0314]

[0315] Step 1: tert-Butyl 3-((methylsulfonyl)oxy)azetidine-1-carboxylate

[0316] Under ice bath conditions, N-Boc-3-hydroxyazetidine (4.00 g, 23.1 mmol) was dissolved in DCM (50 mL) in a 100 mL single-mouth bottle, Et3N (4.66 g, 46.1 mmol) was slowly added, stirred for 10 min, methylsulfonyl chloride (2.91 g, 25.4 mmol) was slowly added, and the temperature was naturally raised to room temperature and stirred for 2 h. TLC showed that the reaction was complete. Water was slowly added to quench the reaction, DCM (20 mL × 3) was extracted, saturated NaHCO3 solution (40 mL) was washed, dried over anhydrous sodium sulfate, filtered, the filtrate was spin-dried, and purified by silica gel column chromatography (eluent: PE / EA (v / v) = 8 / 1-3 / 1) to obtain 4.41 g (yield 76%) of colorless viscous liquid, which was the target product. 1 H NMR (400MHz, CDCl3) δ5.23–5.12(m,1H),4.30–4.19(m,2H),4.10–4.03(m,2H),3.04(s,3H),1.42(s,9H).

[0317] Step 2: tert-Butyl 3-((6-methoxypyridin-3-yl)oxy)azetidine-1-carboxylate

[0318] In a 100mL single-mouth bottle, 5-hydroxy-2-methoxypyridine (2.00g, 16.0mmol) and tert-butyl 3-((methylsulfonyl)oxy)azetidine-1-carboxylate (4.82g, 19.2mmol) were dissolved in DMF (30mL), t-BuOK (3.59g, 32.0mmol) was slowly added, and the mixture was stirred for 10min and then heated to 50°C and stirred for 12h. TLC showed that the reaction was complete, and the mixture was cooled to room temperature, washed with 150mL of water, extracted with EA (300mL×2), and the organic phases were combined and washed with 100mL of water, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried. The residue was purified by silica gel column chromatography (eluent: PE / EA (v / v) = 10 / 1-4 / 1) to obtain 2.03g of yellow-brown solid, which was the target product (yield 45%). LC-MS(ES-API):m / z=281.3[M+H] + ; 1 HNMR(400MHz, CDCl3)δ7.57(d,J=2.9Hz,1H),7.17-7.06(m,1H),6.67(d,J=8.9Hz,1H ),4.85-4.75(m,1H),4.30-4.19(m,2H),4.00-3.93(m,2H),3.85(s,3H),1.42(s,9H).

[0319] Step 3: 5-(Azetidin-3-yloxy)-2-methoxypyridine hydrochloride

[0320] In a 25mL single-mouth bottle, add tert-butyl 3-((6-methoxypyridin-3-yl)oxy)azetidine-1-carboxylate (280mg, 1.00mmol) and ethyl acetate hydrochloride solution (5mL, 20mmol, 4mol / L), and stir at room temperature for 2h. TLC shows that the reaction is complete, and the product is directly spin-dried and placed in a drying oven at 60°C to obtain 0.21g of a brown-yellow solid. LC-MS (ES-API): m / z=181.10[M-HCl+H] + .

[0321] Intermediate 4: 6-hydroxy-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0322]

[0323] Step 1: (6-methoxypyridin-3-yl)methanol

[0324] At 0°C, 6-methoxy-3-pyridinecarboxaldehyde (0.4 g, 3 mmol), lithium aluminum tetrahydride (0.06 g, 2 mmol), and tetrahydrofuran (10 mL) were added to a 25 mL single-mouth bottle in sequence, and the reaction was allowed to react overnight at this temperature. EA (50 mL) was added, and the reaction mixture was diluted with water (50 mL). After extraction and separation, the organic phase was washed with saturated NH4Cl (50 mL) solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried by rotary evaporation. Purification was performed on a silica gel chromatography column (eluent: DCM / EA (v / v) = 4 / 1) to obtain 0.38 g of a light yellow liquid, which was the target product (yield 90.0%). LC-MS (ES-API): m / z = 140.15 [M+H]; 1 H NMR (400MHz, CDCl3) δ8.12 (d, J = 1.8 Hz, 1H), 7.62 (dd, J = 8.5, 2.4 Hz, 1H), 6.75 (d, J = 8.5 Hz, 1H), 4.62 (s, 2H), 3.93 (s, 3H).

[0325] Step 2: 5-(Bromomethyl)-2-methoxypyridine

[0326] In a 25 mL single-mouth bottle, (6-methoxypyridin-3-yl)methanol (0.38 g, 2.7 mmol), dichloromethane (8 mL) and phosphorus tribromide (0.31 mL, 3.3 mmol) were added in sequence and reacted at 0°C for 30 min. DCM (25 mL) was added to dilute, and saturated K2CO3 aqueous solution (25 mL) was washed, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried and directly used for the next step without further purification.

[0327] Step 3: 6-(Benzyloxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0328] In a 25 mL single-necked bottle, 4-(6-(3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-(benzyloxy)pyrazolo[1,5-a]pyridine-3-carbonitrile dihydrochloride (400 mg, 0.81 mmol), potassium carbonate (0.34 g, 2.42 mmol), and N,N-dimethylformamide (8 mL) were added in sequence, and then 5-(bromomethyl)-2-methoxypyridine (0.50 g, 2.5 mmol) was slowly added and stirred at room temperature overnight. The reaction solution was diluted with water (25 mL), extracted with EA (50 mL × 3), the organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was spin-dried, and purified by silica gel chromatography (eluent: DCM / MeOH (v / v) = 1 / 0-20 / 1) to obtain 0.29 g of a light yellow solid, which was the target product (yield 65.82%). LC-MS (ES-API): m / z = 544.10 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ8.39(s,1H),8.22-8.17(m,2H),8.11(s,1H),8.02(s,1H),7.78(d,J=8.8Hz,1H),7.42(dd,J=14.9,7.1Hz ,5H),7.19(s,1H),6.70(dd,J=13.9,8.5Hz,2H),5.13(s,2H),3.92(s,3H),3.80(s,4H),3.59(s,4H),2.22(s,1H),2.01(s,1H).

[0329] Step 4: 6-Hydroxy-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0330] 6-(Benzyloxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (0.29 g, 0.530 mmol), methanol (5 mL), palladium / carbon (0.03 g, content 10%) were added to a 50 mL single-mouth bottle in sequence. After hydrogen replacement several times, the mixture was stirred at room temperature overnight. The reaction solution was filtered, the filter cake was washed with methanol, and the filtrate was dried to obtain 240 mg of a light yellow solid, which was the target product. LC-MS (ES-API): m / z=454.30[M+H] + ; 1 H NMR (400MHz, CDCl3) δ8.39(d,J=1.7Hz,1H),8.28(d,J=2.0Hz,1H),8.21(s,1H),8.17–8.12(m,1H),7.81(dd,J=8.1,2.2Hz,2H),7.14(s,1H),6. 78(d,J=8.6Hz,1H),6.70(d,J=8.3Hz,1H),5.37(s,1H),4.00-3.90(m,5 H), 3.73 (s, 4H), 3.51 (s, 2H), 2.27–2.21 (m, 1H), 2.03 (d, J = 6.6Hz, 1H).

[0331] Intermediate 5: 6-Hydroxy-4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0332]

[0333] Step 1: tert-Butyl 4-hydroxy-4-(pyridin-2-ylmethyl)piperidine-1-carboxylate

[0334] In a 50mL two-necked flask under nitrogen protection, THF (9mL) and 2-methylpyridine (0.644mL, 6.52mmol) were added, and n-BuLi in n-hexane solution (2.2mL, 5.5mmol, 2.5mol / L) was slowly added at -78℃. After reacting for 45min, the mixture was transferred to room temperature for 2h, and then placed at -78℃ to add tert-butyl 4-oxopiperidin-1-carboxylate (1g, 5.019mmol) in THF (6mL). After the addition, the reaction was continued for 2h and then placed at room temperature for 2h. Saturated ammonium chloride solution (10mL) was added to the reaction solution to quench the reaction, and EA (30mL×2) was used for extraction. The organic phase was washed with saturated brine (15mL), dried over anhydrous sodium sulfate, filtered, and dried. Purification by silica gel column chromatography (eluent: PE / EA (v / v=10 / 1-1 / 1) gave 1.176 g (yield 80.14%) of a light yellow oil, which was the target product. LC-MS (ES-API): m / z=293.40 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ8.49–8.44(m,1H),7.61(td,J=7.7,1.7Hz,1H),7.15(dd,J=7.0,5.4Hz,1H),7.09(d,J =7.7Hz,1H),3.76(s,2H),3.72–3.61(m,1H),3.21(s,2H),2.87(s,2H),1.47(d,J=3.2Hz,4H),1.42(s,9H).

[0335] Step 2: 4-(Pyridin-2-ylmethyl)piperidin-4-ol hydrochloride

[0336] In a 25mL single-mouth bottle, add tert-butyl 4-hydroxy-4-(pyridin-2-ylmethyl)piperidine-1-carboxylate (550mg, 1.89mmol) and hydrochloric acid ethyl acetate solution (10mL, 40mmol, 4mol / L), and stir at room temperature for 3h. TLC shows that the reaction is complete, and the reaction liquid is directly spin-dried to obtain a yellow oil, which is placed in an oven at 60℃ to dry to obtain a theoretical amount of 0.430g of yellow solid, which is the target product. LC-MS (ES-API): m / z=193.40[M+H] + .

[0337] Step 3: 6-Hydroxy-4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0338] In a 10mL microwave tube, add 4-(2-pyridylmethyl)piperidin-4-ol hydrochloride (430mg, 1.88mmol), 4-(6-fluoro-3-pyridyl)-6-hydroxy-pyrazolo[1,5-a]pyridine-3-carbonitrile (Intermediate 2, 240mg, 0.94mmol), potassium carbonate (522mg, 3.78mmol), DMSO (2.4mL), and microwave 85℃ for 6h. TLC shows that the reaction is complete, and the reaction solution is diluted with water (12mL), extracted with EA (30mL×2), and the organic phase is washed with saturated brine (20mL), dried over anhydrous sodium sulfate, filtered, and spin-dried. Purify by silica gel column chromatography (eluent: pure EA-EA / MeOH (v / v=50 / 1)) to obtain 0.19g (yield 47%) of brown-yellow solid, which is the target product. LC-MS(ES-API):m / z=427.20[M+H] + ; 1 H NMR (400MHz, MeOD) δ8.46(d,J=4.2Hz,1H),8.23(d,J=2.8Hz,2H),8.18(d,J=2.0Hz, 1H),7.75(d,J=5.5Hz,1H),7.70(dd,J=9.0,2.6Hz,1H),7.34(d,J=7.8Hz,1H),7.29– 7.24(m,1H),7.12(d,J=1.9Hz,1H),6.89(d,J=8.9Hz,1H),4.06(d,J=13.2Hz,2H),3 .38(dd,J=18.1,7.6Hz,2H),2.97(s,2H),1.77–1.69(m,2H),1.62(d,J=13.3Hz,2H).

[0339] Intermediate 6: 6-hydroxy-4-(6-(6-(6-methoxynicotinoyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0340]

[0341] Step 1: 6-Methoxynicotinic acid

[0342] Under ice bath conditions, adjust the pH of sodium dihydrogen phosphate (1.1mL, 1.1mmol, 1.0mol / L) and hydrogen peroxide (0.41mL, 4.0mmol, 30%) solution to 2 with hydrochloric acid (12mol / L), then add 3-(6-methoxypyridin-3-yl)prop-2-yn-1-aldehyde (500mg, 3.65mmol) dissolved in acetonitrile (4mL), then slowly add sodium chlorite (363mg, 4.01mmol) three times, and continue stirring and reacting under ice bath for 2h. The reaction solution slowly returns to room temperature, is diluted with water (50mL), extracted with EA (100mL×3), the organic phases are combined, washed with saturated brine (100mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain 554mg of a yellow solid, which is the target product (yield: 99.26%). LC-MS (ES-API): m / z=154.15[M+H] + ; 1 H NMR (400MHz, CDCl3) δ8.91 (d, J = 2.1 Hz, 1H), 8.19 (dd, J = 8.7, 2.3 Hz, 1H), 6.80 (d, J = 8.7 Hz, 1H), 4.02 (s, 3H).

[0343] Step 2: 6-(Benzyloxy)-4-(6-(6-(6-methoxynicotinoyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0344] In a 25 mL single-necked bottle, 4-(6-(3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-(benzyloxy)pyrazolo[1,5-a]pyridine-3-carbonitrile hydrochloride (Intermediate 2, 770 mg, 1.55 mmol), HATU (895 mg, 2.33 mmol), 6-methoxynicotinic acid (285 mg, 1.87 mmol), and dimethyl sulfoxide (8 mL) were added in sequence, and triethylamine (1.0 mL, 6.23 mmol) was slowly added, and the mixture was stirred at room temperature overnight. After the reaction, water (25 mL) was added to the reaction solution, and EA (50 mL × 3) was used for extraction. The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel chromatography (eluent: DCM / MeOH (v / v = 1 / 0-40 / 1) to obtain 550 mg of a light yellow solid, which was the target product (yield 63.0%). LC-MS (ES-API): m / z = 558.30 [M+H] + .

[0345] Step 3: 6-Hydroxy-4-(6-(6-(6-methoxynicotinoyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0346] 6-(Benzyloxy)-4-(6-(6-(6-methoxynicotinoyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (0.55 g, 0.99 mmol), methanol (5 mL), tetrahydrofuran (15 mL) and palladium on carbon (0.06 g, 10% content) were added to a 50 mL single-mouth bottle in sequence. After hydrogen replacement several times, the mixture was stirred at room temperature overnight. The reaction solution was filtered, the filter cake was washed with methanol, and the filtrate was dried to obtain 0.4 g of a light yellow solid, which was the target product (yield 90.0%). LC-MS (ES-API): m / z=468.10[M+H] + .

[0347] Example 1: N-(1-(5-(3-cyano-6-(prop-2-yn-1-yloxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)-2-(4-methoxyphenyl)acetamide

[0348]

[0349] Step 1: tert-Butyl 4-(2-(4-methoxyphenyl)acetylamino)-4-methylpiperidine-1-carboxylate

[0350] 4-Amino-4-methyl-piperidine-1-carboxylic acid tert-butyl ester (500 mg, 2.33 mmol), DCM (10 mL), EDCI (0.67 g, 3.5 mmol), HOBt (0.47 g, 3.5 mmol), DIPEA (1.6 mL, 9.7 mmol), 2-(4-methoxyphenyl)acetic acid (0.47 g, 2.8 mmol) were added to a 25 mL single-mouth bottle in sequence, and the reaction was stirred at room temperature and monitored by TLC. The reaction was allowed to proceed overnight, and TLC showed that the reaction was complete. Water (15 mL) was added to the reaction solution, the organic phase was separated, the aqueous phase was extracted with DCM (20 mL × 2), the organic phases were combined, washed with saturated brine (25 mL), dried over anhydrous sodium sulfate, filtered, the mother liquor was spin-dried, and the residue was chromatographed on a silica gel column (eluent: PE / EA (v / v) = 7 / 1-3 / 1) to obtain 0.82 g of a transparent solid, which was the target product (yield 97%). 1H NMR (400MHz, CDCl3) δ7.15(d,J=8.5Hz,2H),6.89(d,J=8.6Hz,2H),5.07(s,1H),3.81(s,3H),3.62 (s,2H),3.46(s,2H),2.81(t,J=11.3Hz,2H),1.91(s,2H),1.71(s,2H),1.43(s,9H),1.35(s,3H).

[0351] Step 2: 2-(4-methoxyphenyl)-N-(4-methylpiperidin-4-yl)acetamide 2,2,2-trifluoroacetate

[0352] In a 50mL single-mouth bottle filled with tert-butyl 4-(2-(4-methoxyphenyl)acetylamino)-4-methylpiperidine-1-carboxylate (0.82g, 2.3mmol), DCM (9mL) and TFA (3mL) were added, and the reaction was stirred overnight at room temperature. The reaction was monitored by TLC. The reaction solution was directly spin-dried and the solvent was pumped to obtain a colorless transparent oily liquid product. The yield was calculated as 100%.

[0353] Step 3: 4-(6-fluoropyridin-3-yl)-6-(prop-2-yn-1-yloxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0354] In a 50mL single-mouth bottle, add 4-(6-fluoropyridin-3-yl)-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile (intermediate 1, 0.2g, 0.8mmol), K2CO3 (0.3g, 2mmol) and DMAC (10mL), 3-bromoprop-1-yne (0.1mL, 1mmol), react at 60°C overnight, and monitor the completion of the reaction by TLC. The reaction solution is cooled to room temperature naturally, NH4OH / H2O (v / v=1 / 1, 10mL) is added, and vigorously stirred for 15min. The obtained suspension is filtered, and the filter cake is washed with a small amount of water to obtain a dark brown solid. The solid is slurried by adding 2mL methanol and 20mL water at room temperature, filtered after 1h, and the filter cake is washed with a small amount of water, and vacuum dried at 50°C for 16h to obtain 0.17g of light brown solid, which is the target product (yield 70%). LC-MS(ES-API):m / z=293.05[M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ8.83(s,1H),8.64(s,1H),8.50(s,1H),8.29-8.24(m,1H),7.59(s,1H),7.41-7.37(m,1H),5.01(s,2H),3.72(s,1H).

[0355] Step 4: N-(1-(5-(3-cyano-6-(prop-2-yn-1-yloxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)-2-(4-methoxyphenyl)acetamide

[0356] In a 10 mL single-necked bottle, add 2-(4-methoxyphenyl)-N-(4-methylpiperidin-4-yl)acetamide 2,2,2-trifluoroacetate (0.39 g, 1.0 mmol), 4-(6-fluoropyridin-3-yl)-6-(prop-2-yn-1-yloxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (100 mg, 0.34 mmol) and DMSO (2 mL), N,N-diisopropylethylamine (0.3 mL, 2 mmol), and stir at 130 °C for 3 days. After the basic reaction was completed under TLC monitoring, the mixture was cooled to room temperature, 20 mL of ethyl acetate and 10 mL of water were added, the aqueous phase was separated and extracted with ethyl acetate (20 mL×2), the organic phases were combined and washed with saturated brine (15 mL), the organic phase was dried over anhydrous sodium sulfate, filtered and dried, and the residue was purified by silica gel column chromatography (eluent: PE / EA (v / v) = 10 / 1-1 / 1), and 7 mg of a light yellow solid was collected, which was the target product (yield 3.7%). LC-MS (ES-API): m / z = 535.2 [M+1] + ; 1 H NMR (400MHz, CDCl3) δ8.35–8.29(m,2H),7.74(d,J=11.3Hz,1H),7.52(s,1H),7.19(d,J=8.4Hz,2H),6.99(s,1H),6.90(d,J=8.4Hz,2H ), 6.80 (d, J = 8.3Hz, 1H), 5.36–5.32 (m, 2H), 4.08–3.92 (m, 4H), 3.81 (s, 3H), 3.50 (s, 2H), 3.10 (s, 1H), 2.04–1.99 (m, 4H), 1.42 (s, 3H).

[0357] Example 2: 6-((2-hydroxy-2-methylbut-3-yn-1-yl)oxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0358]

[0359] Step 1: 1-Chloro-2-methyl-4-(trimethylsilyl)but-3-yn-2-ol

[0360] In a 25mL double-necked flask, THF (4mL) and ethynyl (trimethyl) silane (0.321mL, 2.27mmol) were added in sequence under nitrogen protection. Stir at 0℃ for 5min, and then n-butyl lithium in n-hexane solution (0.91mL, 2.3mmol, 2.5mol / L) was slowly added. The reaction was continued for 30min. The mixture was transferred to -78℃ and 6mL of the prepared THF solution of 1-chloropropane-2-one (0.174mL, 2.16mmol) was slowly added. The reaction was continued for 10min at this temperature, and then the temperature was raised to 0℃ and the reaction was continued for 2h. TLC showed that the reaction was complete, and saturated ammonium chloride solution (10mL) was added to quench the reaction, and EA was extracted (10mL×2). The organic phases were combined and washed with saturated brine (10mL×2), dried over anhydrous sodium sulfate, and then spin-dried. The residue was purified by silica gel column chromatography (eluent: PE / EA (v / v) = 50 / 1-8 / 1) to obtain 0.25 g of a light yellow oil, which was the target product (yield 61%). 1 H NMR (400MHz, CDCl3) δ3.65 (d, J = 11.0 Hz, 1H), 3.56 (d, J = 11.0 Hz, 1H), 2.74 (s, 1H), 1.54 (s, 3H), 0.15 (s, 9H).

[0361] Step 2: 6-((2-hydroxy-2-methylbut-3-yn-1-yl)oxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0362] 1-Chloro-2-methyl-4-(trimethylsilyl)but-3-yn-2-ol (25 mg, 0.13 mmol), K2CO3 (25 mg, 0.18 mmol), 6-hydroxy-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Intermediate 4, 20 mg, 0.044 mmol), and DMAC (2 mL) were added sequentially into a 5 mL single-necked bottle and the reaction was stirred at 85 °C for 24 h. After the reaction was completed by TLC detection, the mixture was cooled to room temperature, water (10 mL) was added to the reaction solution, and EA was extracted (15 mL × 3). The organic phases were combined and washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and dried, and the residue was purified by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 100 / 0-100 / 5) to obtain 7 mg of a light yellow solid, which was the target product (yield 30%). LC-MS (ES-API): m / z = 536.20 [M+H] + ; 1H NMR (400MHz, CDCl3) δ8.42 (s, 1H), 8.23 ​​(s, 1H), 8.21 (d, J = 1.9Hz, 1H), 8.11 (s, 1H), 7.8 1-7.76(m,1H),7.53(d,J=8.6Hz,1H),7.09-7.06(m,1H),6.71(dd,J=14.0,8.6Hz,2H),4 .10(d,J=8.9Hz,1H),4.03(d,J=8.8Hz,1H),3.92(s,3H),3.91-3.78(m,5H),3.70-3.64( m,2H),3.63(s,2H),2.55(s,1H),2.37-2.31(m,1H),2.22(t,J=7.6Hz,1H),1.33(s,3H).

[0363] Example 3: 6-((2-hydroxybut-3-yn-1-yl)oxy)-4-(6-(3-((6-methoxypyridin-3-yl)oxy)azetidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0364]

[0365] Step 1: 4-(6-fluoropyridin-3-yl)-6-(2-hydroxyethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0366] 4-(6-fluoropyridin-3-yl)-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile (Intermediate 1, 400 mg, 1.57 mmol), K2CO3 (440 mg, 3.152 mmol), acetonitrile (16 mL) were added to a 50 mL single-mouth bottle, 2-bromoethanol (0.15 mL, 2.1 mmol) was added, and the mixture was heated to reflux in an 85 °C oil bath overnight. TLC showed that the reaction was complete, cooled to room temperature, filtered, washed with EA (30 mL), the filtrate was dried, and the residue was purified by silica gel column chromatography (eluent: PE / EA (v / v) = 2 / 1-1 / 4) to obtain 0.317 g of an orange-yellow solid, which was the target product (yield 67.5%). LC-MS (ES-API): m / z = 299.05 [M+H] + ; 1H NMR (400MHz, CDCl3) δ8.39(d,J=2.3Hz,1H),8.25(d,J=2.0Hz,1H),8.22(s,1H),8.02(td,J=8.4,2.6Hz, 1H), 7.21 (d, J=2.1Hz, 1H), 7.13 (dd, J=8.4, 2.5Hz, 1H), 4.20–4.17 (m, 2H), 4.06 (dd, J=9.2, 5.1Hz, 2H).

[0367] Step 2: 4-(6-fluoropyridin-3-yl)-6-(2-oxoethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0368] In a 25mL single-mouth bottle, 4-(6-fluoropyridin-3-yl)-6-(2-hydroxyethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (220mg, 0.738mmol), NaHCO3 (311mg, 3.68mmol), Dess-Martin periodinane (407mg, 0.96mmol) were added, dissolved in DCM (11mL), and stirred at room temperature overnight. TLC showed that the reaction was complete, 15mL of saturated sodium thiosulfate solution was added to quench the reaction, and DCM (30mL×2) was extracted, the organic phase was combined and washed with 20mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried by rotary evaporation. The residue was purified by silica gel column chromatography (eluent PE / EA (v / v) = 4 / 1-1 / 3) to obtain 0.162g of yellow-white solid, which was the target product (yield 74.1%). LC-MS(ES-API):m / z=296.00[M+H] + ; 1 H NMR (400MHz, CDCl3) δ9.88 (s, 1H), 8.40 (d, J = 2.0Hz, 1H), 8.24 (s, 1H), 8.18 (d, J = 2. 0Hz, 1H), 8.05–8.00 (m, 1H), 7.27 (s, 1H), 7.14 (dd, J = 8.4, 2.9Hz, 1H), 4.73 (s, 2H).

[0369] Step 3: 4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-4-(trimethylsilyl)but-3-yn-1-yl-oxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0370] A 50 mL double-necked bottle was evacuated under nitrogen protection, THF 8 mL and ethynyl (trimethyl) silane (0.143 mL, 1.01 mmol) were added, and the mixture was stirred in a -78 °C low temperature tank for 5 min. A hexane solution of n-butyl lithium (0.40 mL, 1.0 mmol, 2.5 mol / L) was slowly added, and the reaction was continued for 30 min. Then, 13 mL of a THF solution of 4-(6-fluoropyridin-3-yl)-6-(2-oxoethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (200 mg, 0.67 mmol) was added, and the reaction was continued at 0 °C for 10 min after the addition. TLC showed that the reaction was complete, and a saturated ammonium chloride solution (15 mL) was added to quench the reaction, and EA (40 mL × 2) was used for extraction. The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was dried by rotary evaporation. The residue was purified by silica gel column chromatography (eluent: PE / EA (v / v) = 10 / 1-1 / 2) to obtain 28 mg (yield 11%) of yellow-white solid, which was the target product. LC-MS (ES-API): m / z = 395.10 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ8.39(d,J=2.4Hz,1H),8.30(d,J=2.1Hz,1H),8.23(s,1H),8.01(td,J=8.4,2.6Hz,1H),7.24(d,J=2.1Hz,1H ), 7.13 (dd, J = 8.3, 2.7Hz, 1H), 4.83 (dd, J = 6.9, 3.4Hz, 1H), 4.22 (dd, J = 9.7, 3.5Hz, 1H), 4.15 (dd, J = 9.8, 7.2Hz, 1H), 0.19 (s, 9H).

[0371] Step 4: 6-((2-hydroxybut-3-yn-1-yl)oxy)-4-(6-(3-((6-methoxypyridin-3-yl)oxy)azetidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0372] In a 5mL single-mouth bottle, 4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-4-(trimethylsilyl)but-3-yn-1-yl-oxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (13 mg, 0.033 mmol), 5-(azetidin-3-yloxy)-2-methoxypyridine hydrochloride (Intermediate 3, 11 mg, 0.051 mmol) were added in sequence, DMSO (1 mL) was added to dissolve, K2CO3 (12 mg, 0.087 mmol) and DMAP (1 mg, 0.008 mmol) were added, and the mixture was heated at 90°C in an oil bath to react overnight. TLC showed that the reaction was complete, the reaction solution was cooled to room temperature, washed with 15 mL of water, extracted with EA (30 mL×2), the organic phase was washed with 15 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried. Purification by silica gel column chromatography (eluent: pure DCM-DCM / MeOH (v / v=25 / 1)) gave 12 mg of a yellow solid (yield 75%), which was the target product. LC-MS (ES-API): m / z=483.10 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ8.74(s,1H),8.58(s,1H),8.32(s,1H),7.81(dd,J=11.3,5.7Hz, 2H),7.40(dd,J=8.9,2.8Hz,1H),7.30(s,1H),6.81(d,J=9.0Hz,1H),6.57(d,J=8.5Hz,1H ),5.90(d,J=5.8Hz,1H),5.25–5.16(m,1H),4.62(d,J=5.6Hz,1H),4.49(dd,J=9.1,6.7Hz ,2H),4.22–4.10(m,2H),3.98(dd,J=9.2,3.6Hz,2H),3.81(s,3H),3.44(d,J=1.6Hz,1H).

[0373] Example 4: 6-((2-hydroxy-2-methylbut-3-yn-1-yl)oxy)-4-(6-(3-((6-methoxypyridin-3-yl)oxy)azetidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0374]

[0375] Step 1: 4-(6-fluoropyridin-3-yl)-6-(2-oxopropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0376] 4-(6-fluoropyridin-3-yl)-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile (1000mg, 3.934mmol) and K2CO3 (1100mg, 7.88mmol) were added to a 50mL single-mouth bottle, dissolved in acetonitrile (20mL), and 1-chloropropane-2-one (0.38mL, 4.7mmol) was added. The mixture was placed in an oil bath at 85°C and heated under reflux for overnight reaction. TLC showed that the reaction was complete, cooled to room temperature, filtered, washed with EA (20mL×3), the organic phases were combined and dried, and the residue was purified by silica gel column chromatography (eluent: PE / EA (v / v) = 10 / 1-1 / 5) to obtain 0.801g of yellow-white solid, which was the target product (yield 66%). LC-MS (ES-API): m / z = 311.10 [M+H] + .

[0377] Step 2: 4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methyl-4-(trimethylsilyl)but-3-yn-1-yl)oxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0378] A 100mL double-necked flask was evacuated under nitrogen protection, and 20mL of THF and ethynyl (trimethyl) silane (0.342mL, 2.42mmol) were added. The mixture was placed in a -78℃ low temperature tank and stirred for 5min. A solution of n-butyl lithium in n-hexane (0.97mL, 2.4mmol, 2.5mol / L) was slowly added. After reacting for 30min, 30mL of a THF solution of 6-pyruvyloxy-4-(6-fluoro-3-pyridyl)pyrazolo[1,5-a]pyridine-3-carbonitrile (500mg, 1.611mmol) was added. After 10min of reaction, the mixture was placed at 0℃ and continued to react for 2h. TLC showed that the reaction was complete, and 15mL of a saturated ammonium chloride solution was added to quench the reaction. The mixture was extracted with EA (50mL×2), and the organic phases were combined, washed with 30mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was dried by rotary evaporation, and the residue was purified by silica gel column chromatography (eluent: PE / EA (v / v) = 6 / 1-1 / 2) to obtain 0.152 g of yellow-white solid, which was the target product (yield 23.1%). LC-MS (ES-API): m / z = 409.10 [M+H] + .

[0379] Step 3: 6-(2-Hydroxy-2-methyl-but-3-ynyloxy)-4-[6-[3-[(6-methoxy-3-pyridinyl)oxy]azetidin-1-yl]-3-pyridinyl]pyrazolo[1,5-a]pyridine-3-carbonitrile

[0380] In a 5mL single-mouth bottle, 4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methyl-4-(trimethylsilyl)but-3-yn-1-yl)oxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (30mg, 0.073mmol), 5-(azetidin-3-yloxy)-2-methoxypyridine hydrochloride (Intermediate 3, 24mg, 0.111mmol) were added in sequence, DMSO (1mL) was added to dissolve, K2CO3 (23mg, 0.17mmol) and DMAP (1.2mg, 0.01mmol) were added, and the mixture was heated at 90°C in an oil bath to react overnight. TLC showed that the reaction was complete, the reaction solution was cooled to room temperature, washed with 15mL of water, extracted with EA (30mL×2), the organic phase was washed with 15mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried by rotary evaporation. Purification by silica gel column chromatography (eluent: pure DCM-DCM / MeOH (v / v=15 / 1)) gave 20 mg of a yellow-white solid (yield 50%), which was the target product. LC-MS (ES-API): m / z=497.10 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ8.31(d,J=1.7Hz,1H),8.20(d,J=2.0Hz,2H),7.70(dd,J =7.3,2.3Hz,2H),7.19(dd,2H),6.72(d,J=8.9Hz,1H),6.45(d,J=8.6Hz,1H),5 .12–5.04(m,1H),4.50(dd,J=8.7,6.7Hz,2H),4.18(dd,J=9.2,3.8Hz,2H),4.0 5(dd,J=30.3,8.9Hz,2H),3.90(s,3H),2.88(s,1H),2.54(s,1H),1.65(s,3H).

[0381] Example 5: 4-(6-(3-((6-methoxypyridin-3-yl)oxy)azetidin-1-yl)pyridin-3-yl)-6-(prop-2-yn-1-yloxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0382]

[0383] Step 1: 4-(6-fluoropyridin-3-yl)-6-(propan-2-yl-1-yloxy)-pyrazolo[1,5-a]pyridine-3-carbonitrile

[0384] 4-(6-fluoropyridin-3-yl)-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile (Intermediate 1, 500 mg, 1.967 mmol) and K2CO3 (825 mg, 5.91 mmol) were added to a 25 mL single-mouth bottle, dissolved with DMAC (5 mL), and 3-bromoprop-1-yne (0.25 mL) was added. The mixture was heated in an 85°C oil bath overnight. TLC showed that the reaction was complete, and 30 mL of water was added to quench the reaction. EA (60 mL × 2) was used for extraction. The organic phases were combined and washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried by rotary evaporation. The residue was purified by silica gel column chromatography (eluent: PE / EA (v / v) = 10 / 1-1 / 5) to obtain 0.315 g of yellow solid (yield 55%), which was the target product. LC-MS (ES-API): m / z = 293.05 [M+H] + .

[0385] Step 2: 4-(6-(3-((6-methoxypyridin-3-yl)oxy)azetidin-1-yl)pyridin-3-yl)-6-(prop-2-yn-1-yloxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0386] In a 5mL single-mouth bottle, 4-(6-fluoropyridin-3-yl)-6-(propan-2-yl-1-yloxy)-pyrazolo[1,5-a]pyridine-3-carbonitrile (30mg, 0.103mmol), 5-(azetidin-3-yloxy)-2-methoxypyridine hydrochloride (Intermediate 3, 34mg, 0.16mmol) were added in sequence, DMSO (1mL) was added to dissolve, and K2CO3 (32mg, 0.23mmol) and DMAP (1.2mg, 0.01mmol) were added, and the mixture was heated at 90°C in an oil bath to react overnight. TLC showed that the reaction was complete, the reaction solution was cooled to room temperature, washed with 15mL of water, extracted with EA (30mL×2), the organic phase was washed with saturated brine (15mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was dried by rotary evaporation. Purification by silica gel column chromatography (eluent: pure DCM-DCM / MeOH (v / v=20 / 1)) gave 25 mg of a white solid (yield 54%), which was the target product. LC-MS (ES-API): m / z=453.20 [M+H] + ; 1H NMR (400MHz, CDCl3) δ8.31(t,2H),8.21(s,1H),7.72–7.68(m,2H),7.18(dd,J=9.0,2.8Hz,1H),7.13(d,J=1.5Hz,1H),6.72(d,J=8.9Hz,1H),6.4 6(d,J=8.6Hz,1H),5.12–5.05(m,1H),4.78(d,J=1.8Hz,2H),4.50(dd,J=8.5,6.9Hz,2H),4.18(dd,J=9.2,3.8Hz,2H),3.90(s,3H),2.64(s,1H).

[0387] Example 6: 6-(But-2-yn-1-yloxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0388]

[0389] Step 1: 2-Alkynylbutyl methanesulfonate

[0390] Under ice bath conditions, add but-2-yn-1-ol (500 mg, 7.13 mmol) to a 10 mL single-mouth bottle, dissolve it with DCM (5 mL), add TEA (1.5 mL, 11 mmol), slowly drop methanesulfonyl chloride (0.725 mL, 9.27 mmol), and naturally warm to room temperature to react. After TLC shows that the reaction is complete, add 3 mL of water to quench the reaction, extract with DCM (15 mL × 2), wash the organic phase with 8 mL of saturated brine, dry it with anhydrous sodium sulfate, and filter it. After the filtrate is concentrated, purify it with silica gel column chromatography (eluent: PE / EA (v / v) = 6 / 1-2 / 1), and obtain 0.58 g of light yellow oil with a yield of 55.00%, which is the target product. 1 H NMR (400MHz, CDCl3) δ4.81 (dd, J=4.7, 2.3Hz, 2H), 3.10 (s, 3H), 1.89 (t, J=2.4Hz, 3H).

[0391] Step 2: 6-(But-2-yn-1-yloxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0392] A 10 mL single-necked bottle was added with 2-alkynylbutyl methanesulfonate (20 mg, 0.14 mmol), K2CO3 (37 mg, 0.27 mmol), and 6-hydroxy-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Intermediate 4, 30 mg, 0.07 mmol), dissolved in DMF (1.5 mL), and reacted at 60°C overnight. After TLC showed that the reaction was complete, the reaction solution was cooled to room temperature, 15 mL of water was added, and EA (40 mL × 2) was used for extraction. The organic phase was washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography (eluent: pure DCM-DCM / MeOH (v / v=10 / 1)) to obtain 15.0 mg of a light yellow solid with a yield of 45.00%, which was the target product. LC-MS (ES-API): m / z=506.2[M+H] + ; 1 H NMR (400MHz, CDCl3) δ8.40(s,1H),8.30(s,1H),8.23(s,1H),8.11(s,1H),7.78(d,J=6.8Hz,1H),7.67(s,1H),7.14(s,1H),6.83–6.58 (m,2H),4.74(s,2H),3.87(d,J=39.1Hz,6H),3.60(s,3H),2.92(d,J=28.8Hz,2H),2.81–2.66(m,1H),1.89(s,3H),1.68–1.64(m,1H).

[0393] Example 7: 6-(But-2-yn-1-yloxy)-4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0394]

[0395] A 5 mL single-mouth bottle was added with 2-alkynylbutyl methanesulfonate (Example 6, step 1, 21 mg, 0.14 mmol), K2CO3 (39 mg, 0.28 mmol), 6-hydroxy-4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Intermediate 5, 30 mg, 0.07 mmol), and DMF (1.5 mL) was added for dissolution, and the reaction was carried out at 60°C. After TLC showed that the reaction was completed, the reaction solution was cooled to room temperature, washed with 15 mL of water, extracted with EA (40 mL×2), the organic phase was washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography (eluent: pure DCM-DCM / MeOH (v / v=10 / 1)) to obtain 20.0 mg of a yellow solid with a yield of 60.00%, which was the target product. LC-MS(ES-API):m / z=479.2[M+H] + ; 1 H NMR (400MHz, CDCl3) δ8.52(d,J=4.2Hz,1H),8.28(dd,J=11.1,2.1Hz,2H),8.20(s,1H),7.71–7.62(m,2H),7.22–7.16(m,1H),7.12(dd,J=8.4,5.0 Hz,2H),6.77(d,J=8.9Hz,1H),4.72(d,J=2.2Hz,2H),4.09(d,J=13.0Hz, 2H), 3.53–3.42 (m, 2H), 2.94 (s, 2H), 1.88 (s, 3H), 1.65 (d, J = 3.9Hz, 4H).

[0396] Example 8: 6-((2-hydroxy-2-methylbut-3-yn-1-yl)oxy)-4-(6-(3-(4-methoxyphenoxy)azetidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0397]

[0398] Step 1: 4-(6-fluoropyridin-3-yl)-6-(2-oxopropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0399] 4-(6-fluoropyridin-3-yl)-6-hydroxy-pyrazolo[1,5-a]pyridine-3-carbonitrile (Intermediate 1, 1000 mg, 3.93 mmol), K2CO3 (1100 mg, 7.88 mmol) were added to a 50 mL single-mouth bottle, acetonitrile (20 mL) was added to dissolve it, 1-chloropropane-2-one (0.38 mL, 4.7 mmol) was added, and the reaction was refluxed at 85°C overnight. After TLC showed that the reaction was complete, the reaction solution was cooled to room temperature, filtered, and the filter cake was washed with EA (50 mL) for several times. The organic phase was washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography (eluent: PE / EA (v / v) = 10 / 1-1 / 5) to obtain 0.80 g of yellow-white solid with a yield of 65.66%, which was the target product. LC-MS(ES-API):m / z=311.1[M+H] + .

[0400] Step 2: 4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methyl-4-trimethylsilanyl-but-3-ynyloxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0401] A 100 mL two-necked bottle was evacuated several times under nitrogen protection, and then anhydrous THF (20 mL) and ethynyl (trimethyl) silane (0.342 mL, 2.42 mmol) were added, and placed in a -78 ° C low temperature tank, and a n-butyl lithium hexane solution (0.97 mL, 2.4 mmol, 2.5 mol / L) was slowly added. After reacting for 30 minutes, 6-pyruvyloxy-4-(6-fluoro-3-pyridyl) pyrazolo[1,5-a]pyridine-3-carbonitrile (500 mg, 1.611 mmol) dissolved in THF (30 mL) was added, and the reaction was continued at 0 ° C for 2 hours after reacting for 5-10 minutes. After TLC showed that the reaction was complete, 15 mL of saturated ammonium chloride solution was added to quench the reaction, and EA (50 mL × 2) was used for extraction. The organic phase was washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography (eluent: PE / EA (v / v) = 6 / 1-1 / 2) to obtain 0.152 g of yellow-white solid with a yield of 23.10%, which was the target product. LC-MS (ES-API): m / z = 409.1 [M+H] + .

[0402] Step 3: 6-((2-hydroxy-2-methylbut-3-yn-1-yl)oxy)-4-(6-(3-(4-methoxyphenoxy)azetidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0403] 4-(6-fluoro-3-pyridyl)-6-(2-hydroxy-2-methyl-4-trimethylsilyl-butane-3-ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (25 mg, 0.061 mmol), 3-(4-methoxyphenoxy)azetidine hydrochloride (50 mg, 0.23 mmol), potassium carbonate (50 mg, 0.36 mmol), 4-dimethylaminopyridine (2 mg, 0.016 mmol) and DMSO (1 mL) were added to a 5 mL single-necked bottle and reacted at 90 °C in an oil bath. After the reaction of the raw materials was completed, the reaction solution was cooled to room temperature, 15 mL of water was added, and EA (40 mL × 2) was used for extraction. The organic phase was washed with water (10 mL × 4), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 80 / 1-50 / 1, and 20 mg of white solid was obtained, which was the target product (yield 30.32%). LC-MS (ES-API): m / z = 496.1 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ8.73(d,J=1.9Hz,1H),8.58(s,1H),8.32(d,J=1.8Hz,1H) ,7.79(dd,J=8.6,2.4Hz,1H),7.31(d,J=1.9Hz,1H),6.89-6.86(m,3H),6.78(d,J= 9.1Hz,1H),6.57(d,J=8.6Hz,1H),5.17-5.10(m,1H),4.47(dd,J=9.4,6.6Hz,2H) ,4.06(s,2H),3.95(dd,J=9.4,3.6Hz,2H),3.71(s,3H),3.38(s,1H),1.47(s,3H).

[0404] Example 9: 4-(6-(3-((6-methoxypyridin-3-yl)oxy)azetidin-1-yl)pyridin-3-yl)-6-(2-(prop-2-yn-1-yloxy)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0405]

[0406] Step 1: 4-(6-fluoropyridin-3-yl)-6-(2-hydroxyethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0407] 4-(6-fluoropyridin-3-yl)-6-hydroxy-pyrazolo[1,5-a]pyridine-3-carbonitrile (Intermediate 1, 500 mg, 1.97 mmol), K2CO3 (550 mg, 3.94 mmol), acetonitrile (15 mL) were added to a 50 mL single-mouth bottle to dissolve it, and 2-bromoethanol (0.167 mL, 2.36 mmol) was added. The reaction was refluxed at 85 ° C overnight. After TLC showed that the reaction was completed, the reaction solution was cooled to room temperature, filtered, and the filter cake was washed with EA (30 mL). The filtrate was concentrated and purified by silica gel column chromatography (eluent: PE / EA (v / v) = 2 / 1-1 / 4) to obtain 0.40 g of orange-yellow solid, with a yield of 67.70%, which was the target product. LC-MS (ES-API): m / z = 299.1 [M+H] + .

[0408] Step 2: 4-(6-fluoropyridin-3-yl)-6-(2-(prop-2-yn-1-yloxy)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0409] 4-(6-fluoropyridin-3-yl)-6-(2-hydroxyethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (130 mg, 0.44 mmol) was added to a 25 mL single-mouth bottle, anhydrous THF (6.5 mL) was added, and NaH (21 mg, 0.53 mmol) was added at 0°C. After reacting for 30 min, 3-bromopropyne (0.05 mL, 0.52 mmol) was added dropwise. After the addition, the temperature was raised to room temperature and stirred to react overnight. After TLC showed that the reaction was complete, the reaction solution was washed with water (15 mL), extracted with EA (60 mL × 2), and the organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography (eluent: PE / EA (v / v) = 6 / 1-1 / 4) to obtain 20.0 mg of a white solid with a yield of 31.00%, which was the target product. LC-MS(ES-API):m / z=337.15[M+H] + ; 1 H NMR (400MHz, CDCl3) δ8.38(d,J=2.0Hz,1H),8.25(d,J=1.9Hz,1H),8.22(s,1H),8.04–7.98(m,1H),7.23(d,J=2.0Hz, 1H), 7.13 (dd, J=8.4, 2.7Hz, 1H), 4.28 (d, J=2.3Hz, 2H), 4.26–4.22 (m, 2H), 3.98–3.95 (m, 2H), 2.49 (t, J=2.3Hz, 1H).

[0410] Step 3: 4-(6-(3-((6-methoxypyridin-3-yl)oxy)azetidin-1-yl)pyridin-3-yl)-6-(2-(prop-2-yn-1-yloxy)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0411] In a 5 mL single-necked bottle, 4-(6-fluoropyridin-3-yl)-6-(2-(prop-2-yn-1-yloxy)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (20 mg, 0.06 mmol), 5-(azetidin-3-yloxy)-2-methoxypyridine hydrochloride (Intermediate 3, 19 mg, 0.09 mmol) were added in sequence, DMSO (1 mL) was added to dissolve, K2CO3 (19 mg, 0.14 mmol) and DMAP (1.0 mg, 0.01 mmol) were added, and the reaction was heated at 90°C overnight. After TLC showed that the reaction was completed, the reaction solution was cooled to room temperature, washed with 15 mL of water, extracted with EA (30 mL×2), the organic phase was washed with 15 mL of saturated brine, dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated and purified by silica gel column chromatography (eluent: pure DCM-DCM / MeOH (v / v=20 / 1)), and 12.0 mg of white solid was obtained, with a yield of 41.00%, which was the target product. LC-MS (ES-API): m / z=497.2[M+H] + ; 1 H NMR(400MHz, CDCl3)δ8.30(d,J=1.6Hz,1H),8.19(s,1H),8.16(d,J=1.7Hz,1H),7 .70(d,J=6.1Hz,2H),7.53(dd,J=5.6,3.2Hz,1H),7.15(d,J=1.9Hz,1H),6.72(d, J=8.9Hz,1H),6.45(d,J=8.6Hz,1H),5.12–5.04(m,1H),4.53–4.46(m,2H),4.28( d,J=2.3Hz,2H),4.23–4.16(m,4H),4.00–3.94(m,2H),3.90(s,3H),2.49(s,1H).

[0412] Example 10: 6-(But-2-yn-1-yloxy)-4-(6-(6-(6-methoxynicotinoyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0413]

[0414] In a 5 mL single-necked bottle, 2-alkynylbutyl methanesulfonate (20 mg, 0.14 mmol), K2CO3 (36 mg, 0.26 mmol), and 6-hydroxy-4-(6-(6-(6-methoxynicotinoyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (30 mg, 0.07 mmol) were added, and DMF (1.5 mL) was added to dissolve the mixture, and the mixture was reacted at 60 °C. After TLC showed that the reaction was completed, the reaction solution was cooled to room temperature, 15 mL of water was added, and EA (40 mL×2) was used for extraction. The organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography (eluent: pure DCM-DCM / MeOH ((v / v=10 / 1)) to obtain 15.0 mg of a light yellow solid with a yield of 45.00%, which was the target product. LC-MS (ES-API): m / z=520.2[M+H] + ; 1 H NMR (400MHz, CDCl3) δ8.50 (d, J=1.5Hz, 1H), 8.30 (dd, J=12.8, 1.7Hz, 2H), 8.21 (s, 1H) ,7.89(dd,J=8.5,2.1Hz,1H),7.74(dd,J=8.8,2.2Hz,1H),7.11(d,J=1.7Hz,1H),6.77 (d,J=8.7Hz,1H),6.63(d,J=8.9Hz,1H),4.78–4.69(m,4H),4.38–4.24(m,1H),3.98(s ,3H),3.84–3.65(m,3H),2.93(dd,J=14.1,7.0Hz,1H),2.38–2.18(m,1H),1.88(s,3H).

[0415] Example 11: 6-(But-3-yn-1-yloxy)-4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0416]

[0417] Step 1: 3-Alkynylbutyl methanesulfonate

[0418] In a 25mL single-mouth bottle under ice bath conditions, add but-3-yn-1-ol (1000mg, 14.27mmol), dissolve in DCM (10mL), add TEA (3mL, 21.4mmol), slowly drop methanesulfonyl chloride (1.45mL, 18.5mmol), and naturally warm to room temperature to react. After TLC shows that the reaction is complete, add 8mL of water to quench the reaction, extract with DCM (20mL×2), wash the organic phase with 15mL of saturated brine, dry over anhydrous sodium sulfate, and filter. After the filtrate is concentrated, purify by silica gel column chromatography (eluent: PE / EA (v / v) = 10 / 1-2 / 1) to obtain 2.02g of light yellow oil with a yield of 95.50%, which is the target product. 1 H NMR (400MHz, CDCl3) δ4.30 (t, J = 6.7 Hz, 2H), 3.05 (s, 3H), 2.65 (td, J = 6.7, 2.6 Hz, 2H), 2.06 (t, J = 2.6 Hz, 1H).

[0419] Step 2: 6-(But-3-yn-1-yloxy)-4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0420] A 5 mL single-mouth bottle was added with 3-alkynylbutyl methanesulfonate (21 mg, 0.14 mmol), K2CO3 (39 mg, 0.28 mmol), 6-hydroxy-4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Intermediate 5, 30 mg, 0.07 mmol), and DMF (1.5 mL) was added to dissolve and reacted at 60°C. After TLC showed that the reaction was complete, the reaction solution was cooled to room temperature, 15 mL of water was added, and EA (40 mL×2) was extracted. The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography (eluent: pure DCM-DCM / MeOH (v / v=10 / 1)) to obtain 10.0 mg of a yellow solid with a yield of 30.00%, which was the target product. LC-MS(ES-API):m / z=479.2[M+H] + ; 1H NMR(400MHz, CDCl3) δ8.52(d,J=4.4Hz,1H),8.30(d,J=2.3Hz,1H),8.20(s,1H),8.1 3(d,J=2.0Hz,1H),7.70–7.62(m,2H),7.22–7.18(m,1H),7.14(s,1H),7.12(d,J=2. 1Hz,1H),6.77(d,J=8.9Hz,1H),4.15(t,J=6.7Hz,2H),4.12–4.04(m,2H),3.54–3.4 4(m,2H),2.94(s,2H),2.79–2.72(m,2H),2.08(t,J=2.6Hz,1H),1.66–1.64(m,4H).

[0421] Example 12: 6-(But-3-yn-1-yloxy)-4-(6-(6-(6-methoxynicotinoyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0422]

[0423] In a 5 mL single-necked bottle, 3-alkynylbutyl methanesulfonate (Example 11, step 1, 20 mg, 0.13 mmol), K2CO3 (36 mg, 0.27 mmol), 6-hydroxy-4-(6-(6-(6-methoxynicotinoyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Intermediate 6, 30 mg, 0.06 mmol) were added, DMF (1.5 mL) was added to dissolve it, and the mixture was reacted at 60°C. After TLC showed that the reaction was completed, the reaction solution was cooled to room temperature, water (15 mL) was added, and EA (40 mL × 2) was used for extraction. The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography (eluent: pure DCM-DCM / MeOH (v / v=10 / 1)) to obtain 10.0 mg of a yellow solid with a yield of 30.00%, which was the target product. LC-MS (ES-API): m / z=520.1[M+H] + ; 1H NMR (400MHz, CDCl3) δ8.49(d,J=1.8Hz,1H),8.32(d,J=2.0Hz,1H),8.20(s,1H),8.14(d,J=1.8Hz,1 H),7.88(dd,J=8.7,2.2Hz,1H),7.73(dd,J=8.8,2.3Hz,1H),7.11(d,J=1.8Hz,1H),6.77(d,J=8.6Hz ,1H),6.63(d,J=8.9Hz,1H),5.29(s,2H),4.75(d,J=5.9Hz,2H),4.14(t,J=6.7Hz,2H),3.97(s,3H) ,3.79–3.69(m,2H),2.79–2.74(m,2H),2.37–2.18(m,1H),2.08(t,J=2.4Hz,1H),2.06–1.97(m,1H).

[0424] Example 13: 6-(But-3-yn-1-yloxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0425]

[0426] To a 5 mL single-necked bottle were added 3-alkynylbutyl methanesulfonate (Example 11, step 1, 20 mg, 0.14 mmol), K2CO3 (37 mg, 0.27 mmol), 6-hydroxy-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Intermediate 4, 30 mg, 0.07 mmol), DMF (1.5 mL) was added to dissolve, and the mixture was reacted at 60°C overnight. After TLC showed that the reaction was complete, the reaction solution was cooled to room temperature, 15 mL of water was added, and EA (40 mL × 2) was used for extraction. The organic phase was washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography (eluent: pure DCM-DCM / MeOH (v / v = 10:1)) to obtain 12.0 mg of a light yellow solid with a yield of 36.00%, which was the target product. LC-MS (ES-API): m / z = 506.2 [M+H] + ; 1H NMR (400MHz, CDCl3) δ8.40(d,J=1.7Hz,1H),8.22(s,1H),8.15(d,J=1.5Hz,1H),8.10(s,1H) ,7.78(dd,J=8.6,2.1Hz,1H),7.64(d,J=7.8Hz,1H),7.15(d,J=1.5Hz,1H),6.70(dd,J=12.9, 8.7Hz,2H),4.16(t,J=6.7Hz,2H),3.92(s,3H),3.84(d,J=9.9Hz,2H),3.78(d,J=4.7Hz,2H), 3.59(s,4H),2.77(dd,J=6.5,4.1Hz,2H),2.73–2.66(m,1H),2.09(s,1H),2.05–1.95(m,1H).

[0427] Example 14: 6-((4-hydroxy-4-methylpent-2-yn-1-yl)oxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0428]

[0429] Step 1: 4-Methylpent-2-yne-1,4-diol

[0430] After vacuuming in a 100mL two-necked flask under nitrogen protection, add ethylmagnesium bromide tetrahydrofuran solution (1.0mol / L, 36mL, 36mmol), add prop-2-yn-1-ol (1000mg, 17.84mmol) dissolved in THF (10mL) at 0℃ in a low temperature tank, and react at room temperature after the addition is complete. After 3h, add acetone (1.24g, 21.40mmol) dissolved in THF (10mL), and continue to react at room temperature overnight. After TLC shows that the reaction is complete, add saturated ammonium chloride solution (20mL) dropwise to quench the reaction, extract with EA (60mL×2), wash the organic phase with saturated brine (30mL), dry with anhydrous sodium sulfate, and filter. After the filtrate is concentrated, purify by silica gel column chromatography (eluent: PE / EA (v / v)=4 / 1-1 / 2) to obtain 1.15g of light yellow oil with a yield of 56.29%, which is the target product. 1 H NMR (400MHz, CDCl3) δ4.26 (s, 2H), 3.46 (s, 2H), 1.50 (s, 6H).

[0431] Step 2: 4-Hydroxy-4-methyl-pent-2-yn-1-yl methanesulfonate

[0432] 4-Methylpent-2-yne-1,4-diol (500 mg, 4.38 mmol) was added to a 10 mL single-mouth bottle under ice bath conditions, DCM (5 mL) was added to dissolve, triethylamine (0.93 mL, 6.6 mmol, content 99.0%) was added, and methanesulfonyl chloride (0.45 mL, 5.8 mmol) was slowly added dropwise. After the addition was completed, the temperature was naturally raised to room temperature for 1.5 hours. After TLC showed that the reaction was completed, 8 mL of water was added to quench the reaction, and DCM (20 mL × 2) was extracted. The organic phase was washed with 15 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography (eluent: PE / EA (v / v) = 4 / 1-1 / 2) to obtain 0.43 g of a reddish brown oil with a yield of 50.9%, which was the target product. 1 H NMR (400MHz, CDCl3) δ4.86 (s, 2H), 3.12 (s, 3H), 1.52 (s, 6H).

[0433] Step 3: 6-((4-hydroxy-4-methylpent-2-yn-1-yl)oxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0434] 4-Hydroxy-4-methyl-pent-2-yn-1-yl methanesulfonate (26 mg, 0.14 mmol), K2CO3 (37 mg, 0.27 mmol), 6-hydroxy-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Intermediate 4, 30 mg, 0.07 mmol) were added to a 5 mL single-necked bottle, DMF (1.5 mL) was added to dissolve, and the reaction was carried out at 80°C overnight. After TLC showed that the reaction was complete, the reaction solution was cooled to room temperature, washed with 10 mL of water, extracted with EA (40 mL × 2), the organic phase was washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated and purified by silica gel column chromatography (eluent: pure DCM-DCM: MeOH (v / v = 10: 1)), and 15.0 mg of a light yellow solid was obtained with a yield of 41.00%, which was the target product. LC-MS (ES-API): m / z = 550.2 [M+H] + ; 1H NMR(400MHz, CDCl3)δ8.40(d,J=2.1Hz,1H),8.29(d,J=1.9Hz,1H),8.23(s,1H),8 .11(s,1H),7.79(dd,J=8.7,2.4Hz,1H),7.66(d,J=7.0Hz,1H),7.14(d,J=1.9Hz, 1H),6.70(dd,J=12.0,8.8Hz,2H),4.79(s,2H),3.92(s,3H),3.88–3.79(m,4H),3 .65–3.56(m,4H),2.73(s,1H),2.37–2.18(m,1H),2.07–1.97(m,1H),1.53(s,6H).

[0435] Example 15: 4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)-6-((4-hydroxy-4-methylpent-2-yn-1-yl)oxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0436]

[0437] 4-Hydroxy-4-methyl-pent-2-yn-1-yl methanesulfonate (Example 14, step 2, 27 mg, 0.14 mmol), K2CO3 (39 mg, 0.28 mmol), 6-hydroxy-4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Intermediate 5, 30 mg, 0.07 mmol) were added to a 5 mL single-mouth bottle, DMF (1.5 mL, content 100%) was added to dissolve, and the reaction was carried out at 80°C overnight. After TLC showed that the reaction was complete, the reaction solution was cooled to room temperature, washed with 10 mL of water, extracted with EA (40 mL × 2), the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated and purified by silica gel column chromatography (eluent: pure DCM-DCM / MeOH (v / v=10 / 1)), and 27.0 mg of yellow solid was obtained with a yield of 73.00%, which was the target product. LC-MS (ES-API): m / z=523.2[M+H] + ; 1H NMR (400MHz, CDCl3) δ8.51(d,J=3.2Hz,1H),8.30(d,J=1.8Hz,1H),8.26(d,J=1.5Hz,1H),8.20(s,1H),7.70–7.61(m,2H),7.22–7.16(m,1H),7.1 2(d,J=11.6Hz,2H),6.77(d,J=8.8Hz,1H),4.77(s,2H),4.09(d,J=13.0 Hz,2H),3.53–3.42(m,2H),2.94(s,2H),1.67–1.62(m,4H),1.52(s,6H).

[0438] Example 16: 6-((4-hydroxy-4-methylpent-2-yn-1-yl)oxy)-4-(6-(6-(6-methoxynicotinoyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0439]

[0440] 4-Hydroxy-4-methyl-pent-2-yn-1-yl methanesulfonate (Example 14, step 2, 25 mg, 0.13 mmol), K2CO3 (36 mg, 0.26 mmol), 6-hydroxy-4-(6-(6-(6-methoxynicotinoyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Intermediate 6, 30 mg, 0.06 mmol) were added to a 5 mL single-necked bottle, DMF (1.5 mL) was added to dissolve it, and the reaction was carried out at 80°C overnight. After TLC showed that the reaction was completed, the reaction solution was cooled to room temperature, washed with water (10 mL), extracted with EA (40 mL × 2), and the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography (eluent: pure DCM-DCM / MeOH (v / v=10 / 1)) to obtain 15.0 mg of a white solid with a yield of 41.00%, which was the target product. LC-MS (ES-API): m / z=564.2[M+H] + ; 1H NMR (400MHz, CDCl3) δ8.50(s,1H),8.33(d,J=1.2Hz,1H),8.28(d,J=1.2Hz,1H),8.21(s,1 H),7.89(d,J=6.5Hz,1H),7.74(d,J=8.4Hz,1H),7.11(s,1H),6.77(d,J=8.6Hz,1H),6.64 (d,J=8.5Hz,1H),4.78(s,2H),4.76(d,J=5.8Hz,2H),4.32(s,1H),3.98(s,3H),3.84–3.6 7(m,3H),2.93(dd,J=12.9,5.5Hz,1H),2.26–2.08(m,1H),2.06–1.91(m,1H),1.53(s,6H).

[0441] Example 17: 6-((4-hydroxy-4-methylpent-2-yn-1-yl)oxy)-4-(6-(3-((6-methoxypyridin-3-yl)oxy)azetidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0442]

[0443] Step 1: 4-(6-fluoropyridin-3-yl)-6-(2-hydroxyethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0444] 4-Hydroxy-4-methyl-pent-2-yn-1-yl methanesulfonate (Example 14 Step 2, 303 mg, 1.58 mmol), K2CO3 (439 mg, 3.14 mmol), 4-(6-fluoropyridin-3-yl)-6-hydroxy-pyrazolo[1,5-a]pyridine-3-carbonitrile (Intermediate 1, 200 mg, 0.79 mmol) were added to a 10 mL single-mouth bottle, and DMF (6 mL) was added to dissolve, and the mixture was reacted at 80°C overnight. After TLC showed that the reaction was complete, the reaction solution was cooled to room temperature, washed with water (20 mL), extracted with EA (70 mL×2), and the organic phase was washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography (eluent: PE / EA (v / v) = 2 / 1-1 / 2) to obtain 0.24 g of a yellow solid, which was the target product. LC-MS(ES-API):m / z=351.1[M+H] + ; 1H NMR (400MHz, DMSO-d6) δ8.79(d,J=2.0Hz,1H),8.64(s,1H),8.50(d,J=2.2Hz,1H),8.30–8 .23(m,1H),7.54(d,J=2.0Hz,1H),7.39(dd,J=8.4,2.4Hz,1H),4.98(s,2H),1.36(s,6H).

[0445] Step 2: 6-((4-hydroxy-4-methylpent-2-yn-1-yl)oxy)-4-(6-(3-((6-methoxypyridin-3-yl)oxy)azetidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0446] In a 5 mL single-necked bottle, 4-(6-fluoropyridin-3-yl)-6-(2-hydroxyethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (30 mg, 0.09 mmol) and 5-(azetidin-3-yloxy)-2-methoxypyridine hydrochloride (Intermediate 3, 28 mg, 0.13 mmol) were added in sequence, DMSO (1 mL) was added to dissolve, K2CO3 (27 mg, 0.20 mmol) and DMAP (1.0 mg, 0.01 mmol) were added, and the reaction was carried out at 90°C overnight. After TLC showed that the reaction was completed, the reaction solution was cooled to room temperature, washed with 15 mL of water, extracted with EA (30 mL×2), and the organic phase was washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography (eluent: pure DCM-DCM / MeOH (v / v=10 / 1)) to obtain 30.0 mg of a white solid with a yield of 70.00%, which was the target product. LC-MS (ES-API): m / z=511.1[M+H] + ; 1 H NMR (400MHz, CDCl3) δ8.29(d,J=13.0Hz,2H),8.21(s,1H),7.70(dd,J=11.6,2.5Hz,2H),7.18(dd,J=8.9,2.9Hz,1H),7.12(s,1H),6.72(d,J=8.9H z,1H),6.46(d,J=8.7Hz,1H),5.12–5.04(m,1H),4.78(s,2H),4.50(dd,J =8.5, 6.7Hz, 2H), 4.18 (dd, J = 9.0, 3.8Hz, 2H), 3.90 (s, 3H), 1.52 (s, 6H).

[0447] Example 18: 6-((3-cyclopropylprop-2-yn-1-yl)oxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0448]

[0449] Step 1: 3-Cyclopropylprop-2-yn-1-yl methanesulfonate

[0450] Under ice bath conditions, 3-cyclopropylprop-2-yn-1-ol (1000 mg, 10.40 mmol) was added to a 10 mL single-mouth bottle, DCM (10 mL) was used to dissolve it, triethylamine (2.92 mL, 20.8 mmol) was added, and methanesulfonyl chloride (1.06 mL, 13.6 mmol) was slowly added dropwise. After the addition was completed, the temperature was naturally raised to room temperature and reacted for 1 hour. After TLC showed that the reaction was completed, the concentrate was concentrated under reduced pressure, and the concentrate was extracted with EA (15 mL × 2), washed with saturated sodium bicarbonate solution (8 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain 0.33 g of brown oil with a yield of 18.00%, which was the target product. 1 H NMR (400MHz, CDCl3) δ4.81 (d, J = 2.1Hz, 2H), 3.10 (s, 3H), 1.30–1.27 (m, 1H), 0.85–0.74 (m, 4H).

[0451] Step 3: 6-((3-cyclopropylprop-2-yn-1-yl)oxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0452] 3-Cyclopropylprop-2-yn-1-yl methanesulfonate (23 mg, 0.13 mmol), K2CO3 (37 mg, 0.27 mmol), 6-hydroxy-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Intermediate 4, 30 mg, 0.07 mmol) were added to a 5 mL single-necked bottle, DMF (1.5 mL) was added to dissolve it, and the reaction was stirred at 65 °C overnight. After TLC showed that the reaction was complete, the reaction solution was cooled to room temperature, 10 mL of water was added, and EA (40 mL × 2) was used for extraction. The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography (eluent: pure DCM-DCM / MeOH (v / v=10 / 1)) to obtain 18.0 mg of a light yellow solid with a yield of 51.00%, which was the target product. LC-MS (ES-API): m / z=532.2[M+H] + ; 1 H NMR (400MHz, CDCl3) δ8.42–8.38(m,1H),8.28(d,J=1.8Hz,1H),8.23(s,1H),8.11(s,1H),7 .78(dd,J=8.7,2.4Hz,1H),7.65(d,J=7.5Hz,1H),7.13(d,J=1.8Hz,1H),6.70(dd,J=11.8, 8.8Hz,2H),4.73(d,J=1.5Hz,2H),3.92(s,3H),3.88–3.77(m,4H),3.66–3.56(m,4H),2.76 –2.67(m,1H),2.26–1.93(m,1H),1.38–1.35(m,1H),0.82–0.78(m,2H),0.75–0.70(m,2H).

[0453] Example 19: 6-((3-cyclopropylprop-2-yn-1-yl)oxy)-4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0454]

[0455] 3-Cyclopropylprop-2-yn-1-yl methanesulfonate (Example 18, step 1, 25 mg, 0.14 mmol), K2CO3 (39 mg, 0.28 mmol), 6-hydroxy-4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Intermediate 5, 30 mg, 0.07 mmol) were added to a 5 mL single-necked bottle, DMF (1.5 mL) was added to dissolve it, and the reaction was carried out at 65°C overnight. After TLC showed that the reaction was complete, the reaction solution was cooled to room temperature, water (10 mL) was added, and EA (40 mL × 2) was used for extraction. The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography (eluent: pure DCM-DCM / MeOH (v / v=10 / 1)) to obtain 25.0 mg of a yellow solid with a yield of 70.00%, which was the target product. LC-MS (ES-API): m / z=505.3[M+H] + ; 1 H NMR (400MHz, CDCl3) δ8.55–8.49(m,1H),8.30(d,J=2.1Hz,1H),8.25(d,J=1.8Hz,1H),8 .20(s,1H),7.73–7.62(m,2H),7.23–7.17(m,1H),7.13(d,J=7.7Hz,1H),7.10(d,J=1.7 Hz,1H),6.77(d,J=8.9Hz,1H),4.71(s,2H),4.16–4.03(m,2H),3.55–3.44(m,2H),2.94 (s,2H),1.65(d,J=3.6Hz,4H),1.38–1.32(m,1H),0.82–0.76(m,2H),0.75–0.68(m,2H).

[0456] Biological activity test example:

[0457] Test Example 1: Test of the inhibitory activity of the compounds of the present invention on Ret wt, RET CCDC-6, Ret M918T, Ret V804L, and Ret V804M kinases

[0458] 1. Experimental purpose:

[0459] The inhibitory activity of the series of compounds on six kinases, Ret wt, RET CCDC-6, Ret M918T, Ret V804L, and RetV804M, was tested using the HTRF method, and the IC 50 value.

[0460] 2. The experimental reagents and consumables used are as follows:

[0461] 1)HTRF KinEASE-TK kit (Cisbio, 62TK0PEC)

[0462] 2) Ret wt (Invitrogen, PV3082)

[0463] 3)Ret V804M (Signalchem, R02-12GG-10)

[0464] 4) MgCl2 (Sigma, M1028)

[0465] 5) ATP (Promega, V910B)

[0466] 6) DTT (Invitrogen, P2325)

[0467] 7) DMSO (Sigma, D8418)

[0468] 8)384-well plate, white, low volume, round-bottom (Greiner, 784075)

[0469] 9) 384-Well Polypropylene microplate, Clear, Flatt Bottom, Bar Code (Labcyte, P-05525-BC)

[0470] 10)96-well polypropylene plate(Nunc, 249944)

[0471] 11)Plate shaker (Thermo, 4625-1CECN / THZ Q)

[0472] 12)Centrifuge (Eppendorf, 5810R)

[0473] 13)Envision 2104multi-label Reader (PerkinElmer, 2104-10-1)

[0474] 14) Echo (Labcyte, 550)

[0475] 3. Experimental steps

[0476] 3.1 Prepare 1x kinase reaction buffer:

[0477] 1 volume of 5x Kinase Reaction Buffer and 4 volumes of water; 5 mM MgCl2; 1 mM DTT; 1 mM MnCl2.

[0478] 3.2 Transfer 10 nL of diluted compound to each well of an Echo 550 reaction plate (784075, Greiner);

[0479] 3.3 Seal the reaction plate with a sealing film and centrifuge at 1000g for 1 minute.

[0480] 3.4 Prepare 2x kinase using 1x kinase reaction buffer.

[0481] 3.5 Add 5 μL of kinase (prepared in step 3.4) to each well of the reaction plate. Seal the reaction plate with a sealing film and centrifuge at 1000 g for 30 seconds. Place at room temperature.

[0482] 10 minutes.

[0483] 3.6 Prepare 4x TK-substrate-biotin and 4x ATP with 1x kinase reaction buffer, mix well, and add 5 μL of K-substrate-biotin / ATP mixture to the reaction plate.

[0484] 3.7 Seal the reaction plate with sealing film and centrifuge at 1000g for 30 seconds. Incubate at room temperature for 40 minutes.

[0485] 3.8 Prepare 4x Sa-XL 665 (250 nM) in HTRF detection buffer.

[0486] 3.9 Add 5 μl Sa-XL 665 and 5 μl TK-antibody-Cryptate to each well, centrifuge at 1000 g for 30 seconds, and react at room temperature for 1 hour.

[0487] 3.10 Use Envision 2104 to read the fluorescence signals at 615 nm (Cryptate) and 665 nm (XL665).

[0488] 4. Data Analysis

[0489] 4.1 Calculate the ratio of each well (Ratio_665 / 615nm)

[0490] 4.2 The inhibition rate is calculated as follows:

[0491]

[0492] The average of CEP-32496 readings from all positive control wells

[0493] The average of all negative control DMSO well readings

[0494] Among them, the chemical name of CEP-32496 is: N-[3-[(6,7-dimethoxy-4-quinazolinyl)oxy]phenyl]-N'-[5-(2,2,2-trifluoro-1,1-dimethylethyl)-3-isoxazolyl]urea.

[0495] 4.3 Calculation of IC 50 :

[0496] The IC of the compound was obtained using the following nonlinear fitting formula: 50 (half inhibitory concentration), and data were analyzed using Graphpad 6.0 software.

[0497] Y=Bottom + (Top-Bottom) / (1 + 10 ^ ((LogIC 50 -X)×Hill Slope))

[0498] X: log value of compound concentration Y: inhibition rate (%inhibition)

[0499] 5. The experimental results are shown in Table A:

[0500] Table A Kinase inhibitory activity of the compounds of the present invention

[0501] Example <![CDATA[IC 50 (nM),Ret wt]]> <![CDATA[IC 50 (nM),Reject V804M]]> Example 1 5.16 - Example 3 0.22 1.67 Example 4 0.29 0.92 Example 5 5.89 33.54 Example 6 1.91 14.82 Example 7 9.72 51.35 Example 8 0.27 1.37 Example 9 0.46 6.36

[0502] Note: “-” in Table A means not tested.

[0503] As can be seen from Table A, the compounds of the present invention have good inhibitory effects on Ret wt and Ret V804M kinases; in addition, other compounds of the present invention have good inhibitory effects on Ret CCDC-6, Ret M918T, and Ret V804L kinases.

[0504] Test Example 2: Test of the cell proliferation inhibitory activity of the compounds of the present invention on BAF3-KIF5B-RET-WT cells

[0505] 1. Experimental purpose:

[0506] The CTG method was used to test the cell proliferation inhibitory activity of the compounds in BAF3-KIF5B-RET-WT tumor cells, and the half inhibitory concentration (IC 50 ).

[0507] 2. The experimental reagents and test samples used are as follows:

[0508] 1)CTG: CellTiter-Glo(Promega)

[0509] 2) RPMI-1640 medium (Gibco)

[0510] 3) FBS: Fetal bovine serum (Gibco)

[0511] 4) DMSO (Sigma)

[0512] 5) Double antibody: penicillin and streptomycin (HyClone)

[0513] 6) 96-well cell culture plate, white wall and opaque bottom (Corning)

[0514] 7) BAF3 cells (purchased from Shanghai Mingjin Biotechnology)

[0515] 8) BAF3-KIF5B-RET-WT cells (stable cell line, constructed by the Pharmacology Department of Guangdong East Sunshine Pharmaceutical Co., Ltd.)

[0516] 3. Experimental steps:

[0517] 1) Cell seeding

[0518] Collect BAF3 and BAF3-KIF5B-RET-WT cells in the exponential growth phase and count live cells using a Vi-Cell XR cell counter. Adjust the cell suspension to the corresponding concentration using RPMI-1640 complete medium (89% RPMI-1640 + 10% FBS + 1% double antibody). Add 90 μL of cell suspension to each well in a 96-well cell culture plate, with BAF3 and BAF3-KIF5B-RET-WT cell concentrations of 2,000 cells / well and 10,000 cells / well, respectively.

[0519] 2) Dosing treatment

[0520] a. Working solution preparation: Dissolve each test compound in DMSO to make a stock solution with a final concentration of 10 mM. Dilute the stock solution 100-fold with the stock solution and RPMI-1640 complete medium, and then perform 3-fold gradient dilution 9 times to obtain a total of 10 concentrations of working solutions, and the final DMSO concentration of each solution is 0.1%.

[0521] Adding drugs to b cells: After the cells were incubated overnight, 10 μl of the above 10 concentrations of working solution were added in sequence and placed in a 37°C, 5% CO2 incubator for 72 hours; at the same time, a negative control without adding compounds was set up.

[0522] 3) Plate reading test

[0523] After 72 hours of drug treatment, according to the CTG operating instructions, 50 μl (1 / 2 culture volume) of CTG solution that had been melted and equilibrated to room temperature was added to each well, mixed with a microplate shaker for 2 minutes, and placed at room temperature for 10 minutes before measuring the fluorescence signal value with a multifunctional microplate reader.

[0524] 4) Data analysis

[0525] Cell survival rate%: Vsample / Vvehicle control×100%. Vsample is the reading of the drug-treated group, and Vvehicle control is the average value of the solvent control group. GraphPad Prism 5.0 software was used to draw the S-shaped dose-survival rate curve using a nonlinear regression model and calculate the IC 50 The experimental results are shown in Table B.

[0526] Table B Results of the experimental study on the inhibitory activity of the compounds of the present invention on BAF3-KIF5B-RET-WT cells

[0527]

[0528] As shown in Table B, the compounds of the present invention also have a good inhibitory effect on the cell proliferation of BAF3-KIF5B-RET-WT cells.

[0529] In the description of this specification, the description with reference to the terms "one embodiment", "some embodiments", "some implementation schemes", "example", "specific example" or "some examples" etc. means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described may be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art may combine and combine the different embodiments, implementation schemes or examples described in this specification and the features of the different embodiments, implementation schemes or examples, without contradiction.

[0530] Although the embodiments of the present invention have been shown and described above, it is to be understood that the above embodiments are exemplary and are not to be construed as limitations on the present invention. A person skilled in the art may change, modify, substitute and vary the above embodiments within the scope of the present invention without departing from the principles and intent of the present invention. The scope of the present invention is defined by the claims and their equivalents.

Claims

1. A compound represented by formula (I), or a stereoisomer, tautomer or pharmaceutically acceptable salt of the compound represented by formula (I), (I)， in, X 1 , X 2 , X 3 , X 4 and X 5 Each independently is CR 4 or N; Y is O; T is for C 1-6 Alkylene, C 1-4 Alkylene-OC 1-4 Alkylene or C 1-4 Alkylene-NH-C 1-4 alkylene, and said T is optionally substituted by 1, 2, 3 or 4 selected from D, F, Cl, Br, I, CN, NH2, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Alkoxy C 1-4 Alkoxy and C 1-4 substituted by an alkylamino substituent; E is a key; Ring A is the following substructure: , , , , , , , , , , , , , , , ,or , and each subformula of Ring A is independently optionally substituted with 1, 2, 3 or 4 substituents selected from F, Cl, Br, OH, NH2, NHCH3, methyl, ethyl, n-propyl, methoxy, ethoxy, isopropoxy, CF3, hydroxymethyl and 2-hydroxyethyl; Q is -O-, -(CH2)2O-, -CH2-, -(CH2)2-, -(CH2)3-, -(C=O)CH(OH)CH2-, -(C=O)CH(OH)-, -(C=O)-, -(C=O)CH2CH(OH)-, -(C=O)CH2-, -(C=O)(CH2)2-, -(C=O)N(CH3)-, -NH- or -NH(C=O)CH2-; M is pyridyl, pyrimidinyl, pyridazinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, pyrazinyl or phenyl; and M is optionally substituted with 1, 2, 3 or 4 substituents selected from D, F, Cl, CN, OH, CF3, CHCl2, CHF2, CH2F, CF3CH2, NH2, NHCH3, CH2OH, N(CH3)2, trifluoromethoxy, 2,2,2-trifluoroethoxy, methoxy, ethoxy, isopropoxy, tert-butoxy, methyl, ethyl, n-propyl, isopropyl, phenyl, methoxymethyl, methoxyethyl, cyclopropyl and cyclohexyl; R 1 is CN; R 2 H, D or C 1-4 alkyl, and the R 2 Optionally, 1, 2, 3 or 4 selected from F, Cl, Br, OH, NO2, CN, CF3, C 1-4 Alkyl and C 1-4 substituted by an alkoxy substituent; Each R 4 and tert-butyl.

2. The compound according to claim 1, wherein T is -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -CH2CH(CH3)-, -CH2CH(CH3)CH2-, -CH2C(CH3)2-, -(CH2)2CH(CH3)-, -(CH2)2OCH2-, -(CH2)2NHCH2- or -(CH2)3NHCH2-, and said T is optionally substituted with 1, 2, 3 or 4 substituents selected from D, F, Cl, Br, I, CN, NH2, methyl, ethyl, methoxy, ethoxy, chloromethyl, fluoromethyl, methoxymethoxy and methylamino.

3. The compound according to claim 1, wherein R 2 is H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, ethynyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl NH2CH2- or NH2(CH2)2-, and said R 2 Optionally substituted with 1, 2, 3 or 4 substituents selected from F, Cl, Br, OH, CN, CF3, methyl, methoxy, ethoxy, n-propoxy and isopropoxy.

4. A compound having the following structure or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , or 。 5. A pharmaceutical composition comprising the compound according to any one of claims 1 to 4, and a pharmaceutically acceptable adjuvant.

6. Use of the compound according to any one of claims 1 to 4 or the pharmaceutical composition according to claim 5 in the preparation of a medicament for preventing or treating RET-related diseases.

7. The use according to claim 6, wherein The RET-related disease is cancer, irritable bowel syndrome or pain associated with irritable bowel syndrome.

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