RET Inhibitor, Pharmaceutical Composition Thereof, and Use Thereof

Abstract

The present invention belongs to the field of pharmaceuticals and relates to a RET inhibitor, its pharmaceutical composition and its uses. Specifically, the present invention relates to a compound represented by formula (I), or a stereoisomer, tautomer, N-oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the compound represented by formula (I). The present invention also relates to a pharmaceutical composition comprising these compounds, and the uses of these compounds and their pharmaceutical compositions in the preparation of drugs, which drugs are particularly used for treating and preventing diseases and disorders related to RET, 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 drugs. Specifically, the present invention relates to novel compounds that exhibit rearranged during transfection (RET) kinase inhibition, pharmaceutical compositions comprising the compounds, and the use of the compounds or their pharmaceutical compositions in the preparation of drugs, which are particularly used for treating and preventing RET-related diseases and disorders, including cancer, irritable bowel syndrome, and / or pain associated with irritable bowel syndrome. Background Art

[0002] The rearranged during transfection (RET) kinase is one of the receptor tyrosine kinases belonging to the cadherin superfamily, and its activation involves multiple downstream pathways of cell proliferation and survival.

[0003] It has been reported that abnormalities in the RET gene (point mutations, chromosomal translocations, chromosomal inversions, gene amplifications) are involved in carcinogenesis. RET fusion proteins are associated with several cancers, including papillary thyroid cancer and non-small cell lung cancer. The identification of RET fusion proteins as drivers of certain cancers has prompted the use of multi-kinase inhibitors with RET inhibitory activity to treat patients whose tumors express RET fusion proteins. It has been reported that multi-kinase inhibitors such as sorafenib, sunitinib, vandetanib, ponatinib, etc. exhibit cell proliferation inhibitory effects on cell lines expressing KIF5B-RET (J Clin Oncol 30, 2012, suppl; Abstract no: 7510). In addition, it has been reported that the multi-kinase 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 due to toxicity caused by the inhibition of targets other than RET. In addition, one of the greatest challenges in treating cancer is the ability of tumor cells to develop resistance to treatment. Reactivation of kinases via mutation is a common resistance mechanism. When resistance occurs, the treatment options for patients are usually very limited, and in most cases, cancer progression is not inhibited. WO 2017011776 discloses single-target RET kinase inhibitors, which have good preventive or therapeutic effects on cancers related to RET and its mutations. There is still a need to further develop compounds that inhibit RET and its resistant mutants to address cancers related to RET gene abnormalities. Summary of the Invention

[0004] The present invention provides a novel compound that exhibits rearrangement (RET) kinase inhibition during transfection. This class of compounds has good inhibitory effects on wild-type RET and RET gene mutants, and compared with other kinases, the compounds of the present invention have better inhibitory selectivity for wild-type RET 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 contribute to the reduction of side effects, the expansion of the therapeutic index, or the improvement of tolerance, etc.

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

[0007]

[0008] wherein,

[0009] X 1 、X 2 、X 3 、X 4 and X 5 are each independently CR 4 or N;

[0010] Y is O, NH or S;

[0011] T is a bond, alkylene, alkylene-O- or alkylene-NH-, and the said T is optionally substituted by 1, 2, 3 or 4 substituents selected from D, OH, F, Cl, Br, I, CN, NH2, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, heterocyclic group, alkoxy, aryl, heteroaryl and alkylamino;

[0012] Ring G is a fused carbocyclic group or a fused heterocyclic group;;

[0013] q is 0, 1, 2, 3 or 4;

[0014] Each R a is independently D, OH, NH2, F, Cl, Br, I, CN, NR 5 R 6 、OR 7 、-NR 6 C(=O)R 7 、-S(=O)2R 7 、-S(=O)R 7 、-C(=O)R 7 、-C(=O)OR 7, oxo, alkyl, alkoxy, cycloalkyl, haloalkyl, alkoxyalkyl, hydroxyalkyl or hydroxyalkoxy;

[0015] E is a bond, -NR 6 -, or -O-;

[0016] Ring A is a monocyclic group, and ring A is optionally substituted by 1, 2, 3 or 4 substituents selected from F, Cl, Br, OH, oxo, NR 5 R 6 , R 5 (C═O)NR 6 (C═O)NR

[0017] Q is a bond, -(CR 2 R 3 ) t O-, -(CR 2 R 3 ) t O(CR 2 R 3 ) f -, -(CR 2 R 3 ) f -, -(CR 2 R 3 ) t -NR 6 -, -(CR 2 R 3 ) t -NR 6 (CR 2 R 3 ) f -, -(C═O)(CR 2 R 3 ) t -, -(C═O)(CR 2 R 3 ) t -S(═O)2(CR 2 R 3 ) f -, -(C═O)(CR 2 R 3 ) t -NR 6 (CR 2 R 3 ) f -, -(C═O)(CR 2 R 3 ) t -O(CR2 R 3 ) f -, -(C=O)NR 6 O(CR 2 R 3 ) f -, -S(=O)2-NR 6 -(CR 2 R 3 ) t -, -(CR 2 R 3 ) f -(C=O)-, -(CR 2 R 3 ) t -(C=O)-NR 6 -(CR 2 R 3 ) t -, -S(=O)2(CR 2 R 3 ) t -, -(CR 2 R 3 ) f -S(=O)2(CR 2 R 3 ) t -, -S(=O)2O-, -O(C=O)-, -(C=O)NR 6 - or -NR 6 (C=O)-;

[0018] Each f is independently 1, 2, 3 or 4;

[0019] Each t is independently 0, 1, 2, 3 or 4;

[0020] M is H, D, heteroaryl, aryl, cycloalkyl or heterocyclic group, and M is optionally substituted by 1, 2, 3 or 4 substituents selected from D, F, Cl, CN, OH, NR 5 R 6 , OR 7 , alkyl, alkoxy, haloalkyl, hydroxyalkyl, haloalkoxy, aryl, alkoxyalkyl, oxo, alkyl acyl, heterocyclic group and cycloalkyl;

[0021] R 1 is H, D, CN, F, Cl, Br, alkyl or cycloalkyl, wherein the alkyl and cycloalkyl may be independently optionally substituted by 1, 2, 3 or 4 substituents selected from F, Cl, Br, CN, NH2, OH and NO2;

[0022] Each R 2 and R 3independently OH, F, H, D, CN, Cl, Br, NH2, hydroxyalkyl, alkyl, alkylamino, alkoxy, haloalkoxy, cycloalkyl, haloalkyl, cycloalkylalkyl, aryl or heteroaryl;

[0023] or, R 2 , R 3 and the same C atom to which they are attached form a carbocyclic or heterocyclic ring;

[0024] each R 4 independently is H, D, F, Cl, Br, alkyl or alkoxy, wherein said alkyl and alkoxy are each independently optionally substituted with 1, 2, 3 or 4 substituents selected from F, Cl, Br, CN, NH2, OH and NO2;

[0025] each R 5 independently is H, D, alkyl, carbocyclic group, heterocyclic group, aryl or heteroaryl, wherein said alkyl, carbocyclic group, heterocyclic group, aryl and heteroaryl are each independently optionally substituted with 1, 2, 3 or 4 substituents selected from F, Cl, Br, OH, NH2, alkylamino, alkyl, alkylsulfonyl, alkoxy, aryl and heteroaryl;

[0026] each R 6 independently is H, D, alkyl or alkoxyalkyl, wherein said alkyl and alkoxyalkyl are each independently optionally substituted with 1, 2, 3 or 4 substituents selected from F, Cl, Br, CN, NH2, OH and NO2;

[0027] each R 7 independently is OH, alkyl, cycloalkyl, heterocyclic group, aryl or heteroaryl.

[0028] In some embodiments, T is a bond, C 1-6 alkylene, C 1-6 alkylene - O - or C 1-6 alkylene - NH -, and T is optionally substituted with 1, 2, 3 or 4 substituents selected from D, OH, F, Cl, Br, I, CN, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 3 - 7 - membered heterocyclic group, C 1-6 alkoxy, C 6-10 aryl, 5 - 12 - membered heteroaryl and C 1-6 alkylamino.

[0029] In some embodiments, T is a bond, -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -(CH2)O-, -(CH2)2-O-, -(CH2)3O- or -(CH2)2-NH-, and T is optionally substituted with 1, 2, 3 or 4 substituents selected from D, OH, F, Cl, Br, I, CN, CF3, CHF2, CHCl2, methyl, ethyl, propyl, 2-hydroxyethyl, 1-hydroxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, pyrrolidinyl, piperidinyl, tetrahydrofuryl, tetrahydropyranyl, oxetanyl, methoxy, ethoxy, propoxy, butoxy, phenyl, methylamino and dimethylamino.

[0030] In some embodiments,

[0031] Ring G is a 4- to 12-membered fused carbocyclic group or a 4- to 12-membered fused heterocyclic group;

[0032] Each R a is independently D, OH, NH2, F, Cl, Br, I, CN, NR 5 R 6 、OR 7 、-NR 6 C(=O)R 7 、-S(=O)2R 7 、-S(=O)R 7 、-C(=O)R 7 、-C(=O)OR 7 、oxo, C 1-6 alkyl, C 1-6 alkoxy, C 3-7 cycloalkyl, C 1-6 haloalkyl, C 1-6 alkoxyC 1-6 alkyl, C 1-6 hydroxyalkyl or C 1-6 hydroxyalkoxy;

[0033] Each R 5 is independently H, D, C 1-6 alkyl, a 3- to 12-membered carbocyclic group, a 3- to 12-membered heterocyclic group, C 6-10 aryl or a 5- to 10-membered heteroaryl, wherein the C 1-6 alkyl, 3- to 12-membered carbocyclic group, 3- to 12-membered heterocyclic group, C 6-10 aryl and 5- to 10-membered heteroaryl are each independently optionally substituted with 1, 2, 3 or 4 substituents selected from F, Cl, Br, OH, NH2, C 1-6 alkylamino, C 1-6 alkyl, C 1-6 alkylsulfonyl, C 1-6Substituted by alkoxy, C 6-10 aryl, and substituents of 5- to 10-membered heteroaryl;

[0034] Each R 6 is independently H, D, C 1-6 alkyl, or C 1-6 alkoxy C 1-6 alkyl, wherein the C 1-6 alkyl and C 1-6 alkoxy C 1-6 alkyl are each independently optionally substituted by 1, 2, 3, or 4 substituents selected from F, Cl, Br, CN, NH2, OH, and NO2;

[0035] Each R 7 is independently OH, C 1-6 alkyl, C 3-6 cycloalkyl, 3- to 12-membered heterocyclic group, C 6-10 aryl, or 5- to 10-membered heteroaryl.

[0036] In some embodiments, ring G is the following substructural formula:

[0037]

[0038] Wherein,

[0039] Each T 1 is independently a 3- to 6-membered carbocyclic monoring or a 3- to 6-membered heterocyclic monoring;

[0040] Each Z 4 is independently CH or N;

[0041] Z 1 is NH, O, S, or CH2;

[0042] Each Z 2 and Z 3 are independently O, S, or NH;

[0043] Each n1 is independently 0, 1, or 2;

[0044] n2 is 0, 1, 2, or 3.

[0045] In some embodiments, ring G is the following substructural formula:

[0046]

[0047] Each R aIndependently D, OH, NH2, F, CF3, CHCl2, CHF2, CH2F, CF3CH2, Cl, Br, I, CN, NH2, NHCH3, -NHC(=O)CH3, -S(=O)2CH3, -S(=O)CH3, -C(=O)CH3, -C(=O)OH, -C(=O)OC(CH3)3, oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, methoxy, ethoxy, cyclopropyl, cyclopentyl, methoxymethyl, ethoxymethyl, methoxyethyl, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 2-hydroxypropyl, 2-hydroxy-2-methylpropyl, 2-hydroxyethoxy or 1-hydroxyethoxy;

[0048] Each R 5 Independently H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, cyclopropyl, cyclopentyl, pyrrolidinyl, phenyl, pyrazolyl; wherein said methyl, ethyl, n-propyl, cyclopropyl, cyclopentyl, pyrrolidinyl, phenyl and pyrazolyl are each independently optionally substituted with 1, 2, 3 or 4 substituents selected from F, Cl, Br, OH, NH2, methyl, -S(=O)2CH3, methoxy, ethoxy and phenyl;

[0049] Each R 6 Independently H, D, methyl, ethyl, n-propyl, n-butyl, methoxymethyl, ethoxymethyl or methoxyethyl, wherein said methyl, ethyl, n-propyl, n-butyl, methoxymethyl, ethoxymethyl and methoxyethyl are each independently optionally substituted with 1, 2, 3 or 4 substituents selected from F, Cl, Br, CN, NH2, OH and NO2;

[0050] Each R 7 Independently OH, methyl, ethyl, NH2, N(CH3)2, methyl, isopropyl, tert-butyl, cyclopropyl or phenyl.

[0051] In some embodiments, ring A is a 3- to 12-membered monocyclic group, and A is optionally substituted with 1, 2, 3 or 4 substituents selected from F, Cl, Br, OH, oxo, NR 5 R 6 、R 5 (C=O)NR 6 -、amino C 1-6 alkyl、C 1-6 alkyl、C 1-6 alkoxy、C 1-6 haloalkyl、C 1-6 hydroxyalkyl、3- to 12-membered carbocyclic group、3- to 12-membered heterocyclic group、3- to 12-membered heterocyclic group-C 1-6 alkyl and C 1-6 alkoxy C 1-6 alkyl.

[0052] In some embodiments, Ring A is the following substructural formula:

[0053]

[0054] wherein, Z 1a and Z 2a are each independently CH or N;

[0055] Z 3a and Z 4a are each independently CH2, O, S, NH, C═O, S═O or S(═O)2;

[0056] Each substructural formula of A is independently optionally substituted by 1, 2, 3 or 4 substituents selected from F, Cl, Br, OH, oxo, NR 5 R 6 、R 5 (C═O)NR 6 -, amino C 1-4 alkyl, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, 3-12 membered carbocyclic group, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group-C 1-4 alkyl and C 1-4 alkoxy C 1-4 alkyl.

[0057] In some embodiments, Ring A is the following substructural formula:

[0058]

[0059] wherein, each substructural formula of A 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.

[0060] In some embodiments, M is H, D, 5-10 membered heteroaryl, C 6-10 aryl, C 3-7 cycloalkyl or 3-12 membered heterocyclic group; and M is optionally substituted by 1, 2, 3 or 4 substituents selected from D, F, Cl, CN, OH, NR 5 R 6 , OR 7 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6Halogenated alkyl, 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- to 7-membered heterocyclic group and C 3-7 Substituted by substituents of cycloalkyl.

[0061] In some embodiments, M is H, D, pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, pyrazinyl, phenyl, cyclopentyl, cyclopropyl, cyclohexyl, cyclobutyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, morpholinyl, tetrahydrothiopyranyl, oxetanyl, 1,2-dihydropyridyl, 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 by 1, 2, 3 or 4 substituents selected from D, F, Cl, CN, OH, CF3, CHCl2, CHF2, CH2F, CF3CH2, NH2, NHCH3, N(CH3)2, trifluoromethoxy, 2,2,2-trifluoroethoxy, methoxy, ethoxy, isopropoxy, tert-butoxy, methyl, ethyl, n-propyl, isopropyl, phenyl, methoxymethyl, hydroxymethyl, methoxyethyl, oxo, formyl, acetyl, morpholinyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, cyclopropyl and cyclohexyl;

[0062] In some embodiments, R 1 is H, D, CN, F, Cl, Br, methyl or cyclopropyl, wherein the methyl and cyclopropyl may be independently optionally substituted by 1, 2, 3 or 4 substituents selected from F, Cl, Br, CN, NH2, OH and NO2;

[0063] Each R 4 is independently H, D, F, Cl, Br, methyl, ethyl, n-propyl, methoxy or ethoxy, wherein the methyl, ethyl, n-propyl, methoxy and ethoxy may be independently optionally substituted by 1, 2, 3 or 4 substituents selected from F, Cl, Br, CN, NH2, OH and NO2.

[0064] In some embodiments, each R 2 and R 3 are independently OH, F, H, D, CN, Cl, Br, NH2, C 1-6 Hydroxyalkyl, C 1-6 Alkyl, C 1-6 Alkylamino, C 1-6alkoxy, C 1-6 haloalkoxy, C 3-7 cycloalkyl, C 1-6 haloalkyl, C 3-7 cycloalkylC 1-6 alkyl, C 6-10 aryl or 5 - 10 - membered heteroaryl;

[0065] or, R 2 、R 3 and the same C atom to which they are attached form a 3 - 7 - membered carbocyclic or 3 - 7 - membered heterocyclic ring.

[0066] In some embodiments, each R 2 and R 3 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;

[0067] or, R 2 、R 3 and the same C atom to which they are attached form cyclopentane, cyclopropane, cyclobutane, tetrahydropyran, tetrahydrofuran, piperidine or pyrrolidine.

[0068] 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(OH)-, -(C=O)CH2-, -(C=O)C(CH3)2-, -(C=O)CH2NHC(CH3)2CH2-, -(C=O)CH2CH(N(CH3)2)-, -(C=O)(CH2)2N(CH3)CH2-, -(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)CH2CH(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)2CH2-, -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(CH2CH2CH2CH3)-, -(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)2OCH2-, -(C=O)N(CH3)(CH2)2OCH2-, -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)2CH2OCH2-, -(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)NHOCH2CH(OH)-, -S(=O)2(CH2CH3)-, -S(=O)2O-, -S(=O)2-NHC(CH3)2-, -(CH2)2S(=O)2-

[0069] In some embodiments, the compound of the present invention is a compound represented by formula (I-1), (I-2) or (I-3), or a stereoisomer, tautomer, N-oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof:

[0070]

[0071] Wherein, is the following substructural formula:

[0072]

[0073] Wherein each Z 2a is independently CH or N;

[0074] Z 3a and Z 4a are each independently CH2, O, S, NH, C=O, S=O or S(=O)2;

[0075] And each substructural formula of is independently optionally substituted with 1, 2, 3 or 4 substituents selected from F, Cl, Br, OH, oxo, NR 5 R 6 、R 5 (C=O)NR 6 -, amino C 1-4 alkyl, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, 3-12 membered carbocyclic group, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group-C 1-4Alkyl and C 1-4 Alkoxy C 1-4 is substituted by substituents of the alkyl group;

[0076] M a is a 5- to 10-membered heteroaryl or C 6-10 aryl, and M a is optionally substituted by 1, 2, 3, or 4 substituents selected from F, Cl, CN, OH, NR 5 R 6 、OR 7 、C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkoxy, C 6-10 aryl, C 1-6 alkoxy C 1-6 alkyl, oxo, C 1-6 alkylacyl, 3- to 7-membered heterocyclic group, and C 3-7 is substituted by substituents of the cycloalkyl group;

[0077] R 1 、X 1 、X 2 、X 3 、X 4 、X 5 、T, G, R a 、q have the definitions as described in the present invention.

[0078] In some embodiments,

[0079] is the following substructural formula: and each substructural formula of 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 tetrahydrofuryl; and

[0080] M a is pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, pyrazinyl, or phenyl, and M aOptionally substituted with 1, 2, 3, or 4 substituents selected from D, F, Cl, CN, OH, CF3, CHCl2, CHF2, CH2F, CF3CH2, NH2, NHCH3, N(CH3)2, trifluoromethoxy, 2,2,2-trifluoroethoxy, methoxy, ethoxy, isopropoxy, tert-butoxy, methyl, ethyl, n-propyl, isopropyl, phenyl, methoxymethyl, hydroxymethyl, methoxyethyl, oxo, formyl, acetyl, morpholinyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, cyclopropyl, and cyclohexyl.

[0081] In some embodiments, the compounds of the present invention have one of the following structures, or their stereoisomers, tautomers, N-oxides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs.

[0082]

[0083]

[0084]

[0085]

[0086]

[0087]

[0088]

[0089]

[0090]

[0091]

[0092]

[0093]

[0094]

[0095]

[0096] On the other hand, the present invention provides a pharmaceutical composition comprising the compound of the present invention and a pharmaceutically acceptable adjuvant.

[0097] On the other hand, the present invention also provides the use of the compound of the present invention or the pharmaceutical composition of the present invention in the preparation of a drug for preventing or treating RET-related diseases.

[0098] In some embodiments, RET-related diseases include cancer, irritable bowel syndrome, and / or pain associated with irritable bowel syndrome.

[0099] On the other hand, the present invention also provides for the use of the compounds or pharmaceutical compositions of the present invention for the prevention or treatment of RET-related diseases.

[0100] In some embodiments, RET-related diseases include cancer, irritable bowel syndrome, and / or pain associated with irritable bowel syndrome.

[0101] On the other hand, the present invention also provides a method for the prevention or treatment of RET-related diseases, the method comprising administering to a patient a therapeutically effective amount of the compound or its pharmaceutical composition of the present invention.

[0102] In some embodiments, RET-related diseases include cancer, irritable bowel syndrome, and / or pain associated with irritable bowel syndrome.

[0103] On the other hand, the present invention relates to intermediates for preparing the compounds of formula (I), (I-1), (I-2), or (I-3).

[0104] On the other hand, the present invention relates to methods for the preparation, isolation, and purification of the compounds of formula (I), (I-1), (I-2), or (I-3).

[0105] 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 adjuvants of the present invention include, but are not limited to, carriers, excipients, diluents, solvents, or combinations thereof. In some embodiments, the pharmaceutical composition can be in liquid, solid, semi-solid, gel, or spray dosage forms.

[0106] The present invention also provides a method for inhibiting cell proliferation in vitro or in vivo, the method comprising contacting a cell with an effective amount of the compound or its pharmaceutical composition of the present invention.

[0107] The present invention also provides a method for treating irritable bowel syndrome (IBS) and / or pain associated with IBS in a patient in need of treatment, the method comprising administering to the patient a therapeutically effective amount of the compound or its pharmaceutical composition of the present invention.

[0108] The present invention also provides the use of the compound or the pharmaceutical composition of the present invention in the preparation of a drug for the prevention or treatment of irritable bowel syndrome (IBS) and / or pain associated with IBS.

[0109] The present invention also provides for the use of the compounds of the present invention or the pharmaceutical compositions of the present invention for preventing or treating irritable bowel syndrome (IBS) and / or pain associated with IBS.

[0110] Unless otherwise indicated, all stereoisomers, geometric isomers, tautomers, N-oxides, hydrates, solvates, metabolites, salts and pharmaceutically acceptable prodrugs of the compounds of the present invention are within the scope of the present invention.

[0111] Specifically, the salts are pharmaceutically acceptable salts. The term "pharmaceutically acceptable" includes that the substance or composition must be suitable chemically or toxicologically and in relation to the other components of the formulation and the mammal to be treated.

[0112] The salts of the compounds of the present invention also include salts of intermediates used in the preparation or purification of the compounds of formula (I), (I-1), (I-2) or (I-3) or of the separated enantiomers of the compounds of formula (I), (IA), (I-1), (I-2) or (I-3), which are not necessarily pharmaceutically acceptable salts.

[0113] In the structures disclosed in the present invention, when the stereochemistry of any particular chiral atom is not specified, then all stereoisomers of that structure are contemplated within the present invention and are included in the present invention as the disclosed compounds of the present invention. When the stereochemistry is specified by a solid wedge or a dashed line representing a particular configuration, then the stereoisomers of that structure are thereby defined and specified.

[0114] The N-oxides of the compounds of the present invention are also included within the scope of the present invention. The N-oxides of the compounds of the present invention can be prepared by oxidizing the corresponding nitrogenous basic substances using common oxidizing agents (such as hydrogen peroxide) under elevated temperature conditions in the presence of an acid such as acetic acid, or by reacting with a peracid in a suitable solvent, for example, reacting with peracetic acid in dichloromethane, ethyl acetate or methyl acetate, or reacting with 3-chloroperoxybenzoic acid in chloroform or dichloromethane.

[0115] If the compound of the present invention is basic, the desired salts 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.

[0116] If the compounds of the present invention are acidic, the desired salts can be prepared by suitable methods, such as using inorganic or organic bases, such as ammonia (primary, secondary, tertiary amines), alkali metal hydroxides or alkaline earth metal hydroxides, and the like. 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 amines, 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.

[0117] Definitions and General Terms

[0118] Certain embodiments of the present invention will now be described in detail, with examples illustrated by the accompanying structural and chemical formulas. The present invention is intended to cover all alternatives, modifications and equivalent technical solutions, which are all included within the scope of the present invention as defined in the claims. Those skilled in the art should recognize 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 case where one or more of the incorporated documents, patents and similar materials are different from or contradictory to the present application (including but not limited to the defined terms, term applications, described technologies, etc.), the present application shall prevail.

[0119] It should be further recognized that certain features of the present invention, for clarity, are described in multiple separate embodiments, but may also be provided in combination in a single embodiment. Conversely, various features of the present invention, for brevity, are described in a single embodiment, but may also be provided separately or in any suitable sub-combination.

[0120] Unless otherwise stated, all scientific and 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 pertains. All patents and published publications referred to in the present invention are incorporated herein by reference in their entirety.

[0121] The term "patient" as used in the present invention refers to humans (including adults and children) or other animals. In some embodiments, the "patient" refers to humans.

[0122] The term "comprising" is an open-ended expression, i.e., it includes the content specified in the present invention, but does not exclude other aspects.

[0123] "Stereoisomers" refer to compounds having the same chemical structure, but different arrangements of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometric isomers (cis / trans isomers), atropisomers, and the like.

[0124] The stereochemical definitions and rules used in this invention generally follow S.P. 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.

[0125] Any mixture of stereoisomers obtained can be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, for example, by chromatography and / or fractional crystallization, based on the differences in the physical and chemical properties of the components.

[0126] The terms “tautomer” or “tautomeric form” refer to structural isomers of different energies that can interconvert via a low energy barrier. If tautomerization is possible (e.g., in solution), a chemical equilibrium of tautomers can be achieved. For example, proton tautomers (also called prototropic tautomers) include interconversions that occur via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions that occur via reorganization of some of the bonding electrons. A specific example of keto-enol tautomerization is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerization is phenol-keto tautomerization. A specific example of phenol-keto tautomerization is the interconversion of pyridin-4-ol and pyridin-4(1H)-one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of this invention are within the scope of this invention.

[0127] Unless otherwise indicated, the structural formulas described in this invention include all isomeric forms (e.g., enantiomeric, diastereomeric, and geometric (or conformational) isomers): for example, the R, S configurations containing an asymmetric center, the (Z), (E) isomers of double bonds, and the (Z), (E) conformational isomers. Thus, individual stereochemical isomers or mixtures of their enantiomers, diastereomers, or geometric isomers (or conformational isomers) of the compounds of this invention are within the scope of this invention.

[0128] Unless otherwise indicated, the structural formulas and the compounds described in this invention include all isomeric forms (such as enantiomers, diastereomers, geometric isomers or conformational isomers), N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts and prodrugs. Therefore, the individual stereoisomers, enantiomers, diastereomers, geometric isomers, conformational isomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts and prodrugs of the compounds of this invention also fall within the scope of this invention. Additionally, unless otherwise indicated, the structural formulas of the compounds described in this invention include one or more enriched isotopes of different atoms.

[0129] As described in this invention, the compounds of this invention can independently and optionally be substituted by one or more substituents, such as the compounds of the general formula above, or like the specific examples, subclasses, and a class of compounds included in the examples of this invention. It should be understood that the term "independently and optionally substituted by..." can be used interchangeably with the term "substituted or unsubstituted". Generally, the term "substituted" means that one or more hydrogen atoms in the given structure are replaced by specific substituents. Unless otherwise indicated, an optional substituent group can be substituted at each substitutable position of the group. When there is more than one position in the given structural formula that can be substituted by one or more substituents selected from a specific group, the substituents can be the same or different at each position.

[0130] In addition, it should be noted that, unless otherwise clearly indicated, in this invention, the description methods "each... independently is", "... each independently is" and "... independently is" can be interchanged and should be understood in a broad sense. It can either mean that among different groups, the specific options expressed between the same symbols do not affect each other, or it can also mean that within the same group, the specific options expressed between the same symbols do not affect each other.

[0131] In each part of this specification, the substituents of the compounds disclosed in this invention are disclosed according to the group types or ranges. Specifically, this invention includes each independent secondary combination of each member 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 independently disclosed.

[0132] In each part of this invention, linking substituents are described. When the structure clearly requires a linking group, the Markush variables listed for this group should be understood as linking groups. For example, if the structure requires a linking group and the Markush group definition for this variable lists "alkyl" or "aryl", then it should be understood that this "alkyl" or "aryl" represents a linked alkylene group or arylene group respectively.

[0133] The term "alkyl" means a saturated straight-chain or branched-chain monovalent hydrocarbon radical containing 1 to 20 carbon atoms, wherein the alkyl radical may optionally be substituted with one or more substituents described in the present invention. Unless otherwise specified in detail, the alkyl radical contains 1-20 carbon atoms. In one embodiment, the alkyl radical contains 1-12 carbon atoms; in another embodiment, the alkyl radical contains 1-6 carbon atoms; in yet another embodiment, the alkyl radical contains 1-4 carbon atoms; still in one embodiment, the alkyl radical contains 1-3 carbon atoms. Examples of alkyl radicals 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, -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.

[0134] When the alkyl group is a linking group and "alkyl" is listed in the definition of the Markush group, then "alkyl" means a linked alkylene group.

[0135] The term "alkylene" refers to a saturated divalent hydrocarbon radical obtained by removing two hydrogen atoms from a saturated straight-chain or branched-chain hydrocarbon radical. Examples of alkylene groups include, but are not limited to: -CH2-, -CH2CH2-, -CH(CH3)CH2-, and the like.

[0136] The term "alkylene-O-" means that the alkylene is connected to other parts of the molecule through an oxygen atom, where the alkylene has the definition as described in the present invention.

[0137] The term "alkylene-NH-" means that the alkylene is connected to other parts of the molecule through NH, where the alkylene has the definition as described in the present invention.

[0138] The term "oxo", i.e., =O.

[0139] The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups. In some embodiments, hydroxyalkyl refers to an alkyl group substituted with 1, 2, 3, or 4 hydroxy groups. In some embodiments, hydroxyalkyl refers to an alkyl group substituted with 1 or 2 hydroxy groups. In some embodiments, hydroxyalkyl refers to C 1-6 Hydroxyalkyl, i.e., C 1-6 Alkyl is substituted with one or more hydroxy groups; preferably, C 1-6 Hydroxyalkyl refers to C 1-6 Alkyl is substituted with one hydroxy group. In some embodiments, hydroxyalkyl refers to C 1-4 Hydroxyalkyl. In some embodiments, hydroxyalkyl refers to C 1-3 Hydroxyalkyl. Examples of hydroxyalkyl include, but are not limited to, HOCH2-, CH2OHCH2CH2CH2-, CH2OHCH2-, CH2OHCH2CHOHCH2-, CH(CH3)OHCH2CHOHCH2-, and the like.

[0140] The term "alkoxy" means that an alkyl group is connected to the rest of the molecule through an oxygen atom, where the alkyl group has the meaning as described in the present invention. Unless otherwise specified in detail, 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 optionally be substituted by one or more substituents described in the present invention. 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 - 1 - butoxy (-OCH2CH2CH(CH3)2), 2 - methyl - 1 - butoxy (-OCH2CH(CH3)CH2CH3), and so on.

[0141] The term "alkoxyalkyl" means an alkyl group substituted by an alkoxy group, where the alkoxy group and the alkyl group have the definitions as described in the present invention. In some embodiments, alkoxyalkyl means C 1-6 alkoxy C 1-6 alkyl; in other embodiments, alkoxyalkyl means C 1-4 alkoxy C 1-4 alkyl; in other embodiments, alkoxyalkyl means C 1-4 alkoxy C 1-3 alkyl; in some embodiments, alkoxyalkyl means C 1-3 alkoxy C 1-3 alkyl. Examples of alkoxyalkyl include, but are not limited to, methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, methoxy - n - propyl, methoxy - isopropyl, ethoxyethyl, ethoxy - n - propyl, n - propoxyethyl, isopropoxyethyl, n - propoxy - n - propyl, etc.

[0142] The term "halogen" means F (fluorine), Cl (chlorine), Br (bromine) or I (iodine).

[0143] The term "haloalkyl" means an alkyl group substituted with one or more halogen atoms. In some embodiments, haloalkyl means C 1-6 haloalkyl, i.e., C 1-6 alkyl substituted with one or more halogens. In some embodiments, haloalkyl means C 1-4 haloalkyl. In some embodiments, haloalkyl means C 1-3 haloalkyl. Such examples include, but are not limited to, monofluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 1,2-difluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, 1-chloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1,2-dichloroethyl, 1,1-dichloroethyl, 2,2-dichloroethyl, 1,1-dibromoethyl, and the like.

[0144] The term "cycloalkyl" means a monovalent saturated monocyclic carbocyclic system. The -CH2- groups in cycloalkyl can optionally be replaced by -C(=O)-. In some embodiments, cycloalkyl contains 3-7 ring carbon atoms, i.e., C 3-7 cycloalkyl. In one embodiment, cycloalkyl contains 3-6 carbon atoms, i.e., C 3-6 cycloalkyl; in another embodiment, cycloalkyl contains 3-5 carbon atoms, i.e., C 3-5 cycloalkyl. Examples of cycloalkyl include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. Examples of the -CH2- groups in the carbocyclic ring that can be replaced by -C(=O)- include but are not limited to: cyclopentanone, cyclobutanone, etc. The cycloalkyl group can independently and optionally be substituted with one or more substituents described in the present invention.

[0145] The term "cycloalkylene" means a divalent saturated monocyclic carbocyclic system. The -CH2- groups in cycloalkylene can optionally be replaced by -C(=O)-. In some embodiments, cycloalkylene contains 3-7 ring carbon atoms, i.e., C 3-7 cycloalkylene. In one embodiment, cycloalkylene contains 3-6 carbon atoms, i.e., C 3-6 cycloalkylene; in another embodiment, cycloalkyl contains 3-5 carbon atoms, i.e., C 3-5 cycloalkylene. Examples of cycloalkylene include but are not limited to 1,1-cyclopropylene, 1,2-cyclopropylene, 1,1-cyclopentylene, 1,1-cyclohexylene, 1,3-cyclopentylene, etc. The cycloalkylene group can independently and optionally be substituted with one or more substituents described in the present invention.

[0146] The term "monocyclic" refers to a saturated or partially unsaturated monocyclic carbocyclic or monocyclic heterocyclic system, wherein the carbocyclic and heterocyclic rings have the definitions as described in the present invention. Among them, the monocyclic carbocyclic system is a monocyclic carbon ring, and the monocyclic heterocyclic system is a monocyclic heterocycle.

[0147] The term "monocyclic group" refers to a monovalent saturated or partially unsaturated monocyclic carbocyclic or monocyclic heterocyclic system, wherein the carbocyclic and heterocyclic rings have the definitions as described in the present invention. In the monocyclic group, the -CH2- group can be optionally replaced by -C(=O)-. In some embodiments, the monocyclic group contains 3-7 ring atoms, that is, the monocyclic group is a 3-7 membered monocyclic group; in some other embodiments, the monocyclic group contains 3-6 ring atoms, that is, the monocyclic group is a 3-6 membered monocyclic group. Examples of the monocyclic group include but are not limited to: cyclopropyl, cyclopentyl, cyclohexyl, 1,2-cyclopentadienyl, pyrrolidinyl, tetrahydrofuranyl, morpholinyl, furyl, etc. Preferably, the monocyclic group described in the present invention is a monovalent saturated monocyclic carbocyclic or monocyclic heterocyclic system. The monocyclic group can be independently optionally substituted by one or more substituents described in the present invention.

[0148] The term "sub-monocyclic group" refers to a divalent saturated or partially unsaturated monocyclic carbocyclic or monocyclic heterocyclic system, wherein the carbocyclic and heterocyclic rings have the definitions as described in the present invention. In the sub-monocyclic group, the -CH2- group can be optionally replaced by -C(=O)-. In some embodiments, the sub-monocyclic group contains 3-7 ring atoms, that is, the sub-monocyclic group is a 3-7 membered sub-monocyclic group; in some other embodiments, the sub-monocyclic group contains 3-6 ring atoms, that is, the sub-monocyclic group is a 3-6 membered sub-monocyclic group. Preferably, the sub-monocyclic group described in the present invention is a divalent saturated monocyclic carbocyclic or monocyclic heterocyclic system. Examples of the sub-monocyclic group include but are not limited to: sub-cyclopropyl, sub-cyclopentyl, sub-cyclohexyl, 1,2-sub-cyclopentadienyl, sub-pyrrolidinyl, etc. The sub-monocyclic group can be independently optionally substituted by one or more substituents described in the present invention.

[0149] The term "sub-monocyclic heterocyclic group" refers to a divalent saturated or partially unsaturated monocyclic heterocyclic system, wherein the heterocyclic ring has the definition as described in the present invention. In the sub-monocyclic heterocyclic group, the -CH2- group can be optionally replaced by -C(=O)-. In some embodiments, the sub-monocyclic heterocyclic group contains 3-7 ring atoms, that is, the sub-monocyclic heterocyclic group is a 3-7 membered sub-monocyclic heterocyclic group; in some other embodiments, the sub-monocyclic heterocyclic group contains 3-6 ring atoms, that is, the sub-monocyclic heterocyclic group is a 3-6 membered sub-monocyclic heterocyclic group. Preferably, the sub-monocyclic heterocyclic group described in the present invention is a divalent saturated monocyclic heterocyclic system.

[0150] The term "heterocyclic group alkyl" refers to an alkyl group substituted by a heterocyclic group, wherein the heterocyclic group and the alkyl group have the definitions as described in the present invention. In some embodiments, the heterocyclic group alkyl is a 3-12 membered heterocyclic group C 1-6alkyl; in some other embodiments, heteroalkyl is a 3- to 6-membered heteroalkyl C 1-6 alkyl; in some embodiments, heteroalkyl is a 3- to 6-membered heteroalkyl C 1-4 alkyl. Examples of heteroalkyl include, but are not limited to: pyrrolidinylmethyl, piperidinylmethyl, and the like.

[0151] The term "haloalkoxy" means an alkoxy group substituted with one or more halogen atoms, wherein halogen and alkoxy have the definitions as described in the present invention. In some embodiments, the haloalkoxy group means C 1-6 haloalkoxy, that is, C 1-6 alkyl in which the alkoxy is substituted with one or more halogens. In some embodiments, the haloalkoxy means C 1-4 haloalkoxy. In some embodiments, the haloalkoxy means C 1-3 haloalkoxy. Such examples include, but are not limited to, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoroethoxy, 1,2-difluoroethoxy, monochloroethoxy, and the like.

[0152] The term "alkylacyl" means that an alkyl group is connected to the rest of the molecule through a carbonyl group, wherein the alkyl has the definition as described in the present invention, and the carbonyl group means -C(=O)-. In some embodiments, the alkylacyl means C 1-6 alkylacyl; in some other embodiments, the alkylacyl means C 1-4 alkylacyl. Examples of alkylacyl include, but are not limited to: formyl, acetyl, and the like.

[0153] The term "cycloalkylalkyl" means an alkyl substituted with a cycloalkyl. Wherein the cycloalkyl and the alkyl have the definitions as described in the present invention. In some embodiments, the cycloalkylalkyl means C 3-7 cycloalkyl C 1-6 alkyl; in some other embodiments, the cycloalkylalkyl means C 3-6 cycloalkyl C 1-6 alkyl; in some other embodiments, the cycloalkylalkyl means C 3-6 cycloalkyl C 1-4 alkyl. Examples of cycloalkylalkyl include, but are not limited to: cyclopropylmethyl, cyclopentylethyl, cyclohexylmethyl, and the like.

[0154] The term "aryl" refers to a monovalent aryl group formed by removing one hydrogen atom from the ring carbon atoms of an aromatic ring. Examples of aryl groups can include phenyl, naphthyl, and anthracenyl. When aryl is a linking group and "aryl" is listed in the definition of the Markush group, then "aryl" refers to a linked arylene group. When M is aryl as defined in the present invention, it means that M contains a linked arylene group. The term "arylene" refers to a divalent aryl group formed by removing two hydrogen atoms from the ring carbon atoms of an aromatic ring. Examples of aryl represented as a linked arylene group can include phenylene, naphthylene, and anthracenylene. The aryl group may be independently optionally substituted with one or more substituents described in the present invention.

[0155] The term "heteroaryl" refers to a monovalent aromatic ring group formed by removing one hydrogen atom from the ring atoms of a heteroaromatic ring. The heteroaryl group is optionally substituted with one or more substituents described in the present invention. In one embodiment, a heteroaryl having 5 to 10 atoms or a 5- to 10-membered heteroaryl 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- to 6-membered heteroaryl having 5 to 6 ring atoms, which 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-membered heteroaryl having 5 ring atoms, which contains 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. Examples of heteroaryl groups include, but are not limited to, 2-furyl, 3-furyl, 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, 5-pyrimidinyl, pyridazinyl (such as 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (such as 5-tetrazolyl), triazolyl (such as 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (such as 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, pyrazinyl, 1,3,5-triazinyl; also include the following bicyclics, but are by no means limited to these bicyclics: benzimidazolyl, benzofuryl, benzothienyl, indolyl (such as 2-indolyl), purinyl, quinolinyl (such as 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), isoquinolinyl (such as 1-isoquinolinyl, 3-isoquinolinyl, or 4-isoquinolinyl), imidazo[1,2-a]pyridyl, pyrazolo[1,5-a]pyridyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyridyl, and so on. When the heteroaryl is a linking group and the heteroaryl is listed in the definition of the Markush group, the heteroaryl represents a linked sub-heteroaryl. As defined in the present invention, when M is a heteroaryl, it means that M contains a linked sub-heteroaryl group. The term "sub-heteroaryl" refers to a divalent heteroaromatic ring group formed by removing two hydrogen atoms from the ring atoms of a heteroaryl. The heteroaryl can be independently optionally substituted with one or more substituents described in the present invention.

[0156] The terms "carbocyclic group" and "carbocycle" are used interchangeably and refer to a saturated or partially unsaturated monocyclic, bicyclic, or polycyclic system in which all ring atoms are carbon atoms, including monocyclic carbocyclic groups, bridged carbocyclic groups, fused carbocyclic groups, and spirocarbocyclic groups.

[0157] The terms "fused carbocycle" and "fused carbocyclic group" are used interchangeably and both refer to a non-aromatic saturated or partially unsaturated bicyclic or polycyclic system that shares two adjacent ring carbon atoms and has carbon atoms as ring atoms. In some embodiments, the fused carbocyclic group is a 4- to 12-membered fused carbocyclic group. In some embodiments, the fused carbocyclic group is a 5- to 12-membered fused carbocyclic group. Examples of fused carbocyclic groups include, but are not limited to: bicyclo[2.1.0]pentyl, bicyclo[3.1.0]heptyl, bicyclo[4.1.0]heptyl, bicyclo[3.2.0]heptyl, bicyclo[4.2.0]octyl, octahydro-1H-indenyl, octahydrobicyclopentadienyl, decahydronaphthyl, decahydro-1H-benz[7]annulenyl, etc.

[0158] The terms "fused heterocycle" and "fused heterocyclic group" are used interchangeably and both refer to a non-aromatic saturated or partially unsaturated bicyclic or polycyclic system that shares two adjacent ring atoms and has at least one heteroatom selected from O, N, and S as ring atoms. In some embodiments, the fused heterocyclic group is a 4- to 12-membered fused heterocyclic group. In some embodiments, the fused heterocyclic group is a 5- to 12-membered fused heterocyclic group. Examples of fused heterocyclic groups include, but are not limited to: 3-azabicyclo[3.1.0]hexyl, 2-oxa-5-azabicyclo[2.2.0]hexyl, 2,5-diazabicyclo[2.2.0]hexyl, 2-azabicyclo[2.2.0]hexyl, 2-azabicyclo[2.1.0]pentyl, 2-azabicyclo[3.1.0]hexyl, 3-oxabicyclo[3.1.0]hexyl, octahydrocyclopenta[c]pyrrole, octahydropyrrolo[3,4-c]pyrrole, hexahydrofuro[3,2-b]furan, hexahydrofuro[2,3-b]furan, octahydropyrrolo[3,4-b]pyrrole, hexahydro-1H-thieno[3,4-c]pyrrole, hexahydro-1H-furo[3,4-c]pyrrole, hexahydro-2H-[1,4]dioxino[2,3-c]pyrrole, octahydro-[1,4]dioxino[2,3-c]pyridine, etc.

[0159] The terms "heterocyclic" or "heterocyclic group" are used interchangeably and both denote a monovalent non-aromatic saturated or partially unsaturated monocyclic, bicyclic or polycyclic system having 3 - 12 ring atoms, with at least 1 carbon atom and containing 1, 2 or 3 heteroatoms selected from O, N and S. Unless otherwise specified, the heterocyclic group can be carbon-based or nitrogen-based, and the -CH2- group can optionally be replaced by -C(=O)-. The sulfur atom of the ring can optionally be oxidized to an S-oxide, and the nitrogen atom of the ring can optionally be oxidized to an N-oxide. The heterocycle can be monocyclic or bicyclic; specifically, the bicyclic system can be a fused heterobicyclic, spiro heterobicyclic or bridged heterobicyclic. In some embodiments, the heterocyclic group contains 4 - 7 ring atoms, i.e., represents a 4 - 7 membered heterocyclic group; examples of the heterocyclic group include, but are not limited to: oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1,3-dioxolanyl, dithiacyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxolanyl, dithiolanyl, thioxolanyl, homopiperazinyl, homopiperidinyl, 1,1-dioxo-1,3-thiomorpholine, etc. Examples of the heterocyclic group in which the -CH2- group is replaced by -C(=O)- include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidinone, 3,5-dioxopiperidinyl. Examples of the heterocyclic group in which the nitrogen atom is oxidized to an N-oxide include, but are not limited to, 1,1-dioxo-1,3-thiomorpholine. When the heterocycle or heterocyclic group is a linking group and the heterocycle or heterocyclic group is listed for the definition of the Markush group, the heterocycle or heterocyclic group represents a linked subheterocyclic group. The term "subheterocyclic group" denotes a divalent heterocyclic group formed by removing two hydrogen atoms from the ring atoms of the heterocycle. The heterocycle or heterocyclic group can be independently and optionally substituted by one or more substituents described in the present invention.

[0160] The term "aminoalkyl" denotes an alkyl group substituted by one or more amino groups. In some embodiments, the term "aminoalkyl" denotes an alkyl group substituted by one amino group. In some embodiments, the term "aminoalkyl" denotes aminoC 1-6 alkyl. In other embodiments, the term "aminoalkyl" denotes aminoC 1-4 alkyl. In other embodiments, the term "aminoalkyl" denotes aminoC 1-3 alkyl. Examples of aminoalkyl include, but are not limited to, aminomethyl, aminoethyl, aminopropyl, aminoisopropyl, aminoisobutyl, aminotert-butyl, 1,2-diaminoethyl, etc.

[0161] The term "alkylamino" means an amino group substituted with one or two alkyl groups. In some embodiments, the term "alkylamino" means C 1-6 alkylamino, that is, an amino group substituted with one or two C 1-6 alkyl groups. In other embodiments, the term "alkylamino" means C 1-4 alkylamino. In other embodiments, the term "alkylamino" means C 1-3 alkylamino. Examples of alkylamino include, but are not limited to, methylamino, ethylamino, n-propylamino, isopropylamino, isobutylamino, tert-butylamino, dimethylamino, diethylamino, di-n-propylamino, diisopropylamino, diisobutylamino, di-tert-butylamino, etc.

[0162] The term "alkylsulfonyl" means alkyl-S(=O)2-, that is, the alkyl group is connected to the rest of the molecule through -S(=O)2-. In some embodiments, alkylsulfonyl means C 1-6 alkylsulfonyl; in other embodiments, alkylsulfonyl means C 1-4 alkylsulfonyl; in other embodiments, alkylsulfonyl means C 1-4 alkylsulfonyl. Examples of alkylsulfonyl include, but are not limited to, methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, etc.

[0163] In the general formula of the compounds of the present invention, the left end of Q is connected to ring A, and the right end of Q is connected to M. For example, when Q is -(S=O)2NR 6 -, then represents Similarly, the left end of ring A is connected to E, and the right end of A is connected to Q. For example, when ring A is then represents

[0164] In the general formula of the compounds of the present invention, when T is alkylene-O- or alkylene-NH-, it means that the alkylene end of T is connected to Y, and the O end or NH end of T is connected to G. When T is -(CH2)2O-, it represents

[0165] As described in the present invention, unless otherwise specified in detail, the ring substituents can be connected to the rest of the molecule through any connectable position on the ring. For example, piperidinyl includes piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, and piperidin-4-yl.

[0166] In the present invention, the sub-structural formulas G1, G2, and G3 of ring G respectively represent ring T 1 and T 2a, ring T 1 and T 2b , ring T 1 and T 2c The fused ring formed with T, and the attachment points of each of the G1, G2, and G3 rings can be connected to the rest of the molecule at any connectable position on the G1, G2, and G3 rings respectively; preferably, the attachment points of each of the G1, G2, and G3 rings can be connected to the rest of the molecule at any connectable position on each of the T 1 rings of the G1, G2, and G3 rings. For example, in the G1 ring, the attachment point can be connected to the rest of the molecule at any connectable position on the T 1 ring, and the attachment point can also be connected to the rest of the molecule at any connectable position on the T 2a ring; preferably, the attachment point is connected to the rest of the molecule at any connectable position on the T 1 ring. The substructural formulas of the G1, G2, and G3 rings of ring G are shown below.

[0167]

[0168] The term "protecting group" or "PG" refers to a substituent that is typically used to block or protect a particular functionality when reacting with other functional groups. For example, an "amino protecting group" refers to a substituent that is attached to an amino group to block or protect the functionality of the amino group in a compound. Suitable amino protecting groups include acetyl, trifluoroacetyl, tert-butoxycarbonyl (BOC, Boc), benzyloxycarbonyl (CBZ, Cbz), and 9-fluorenylmethyloxycarbonyl (Fmoc). Similarly, a "hydroxy protecting group" refers to a substituent of a hydroxyl group that is used to block or protect the functionality of the hydroxyl group. Suitable protecting groups include acetyl and silyl. A "carboxyl protecting group" refers to a substituent of a carboxyl group that is used to block or protect the functionality of the carboxyl group. Common carboxyl protecting groups include -CH2CH2SO2Ph, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrobenzenesulfonyl)ethyl, 2-(diphenylphosphino)ethyl, nitroethyl, etc. General descriptions of protecting groups can be found in 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.

[0169] The term "prodrug" as used in the present invention represents a compound that is converted in vivo into the compound represented by formula (I). Such conversion is affected by the hydrolysis of the prodrug in the blood or by enzymatic conversion in the blood or tissues into the parent structure. The prodrug compounds of the present invention can be esters. In the existing inventions, esters that can serve as prodrugs include phenyl esters, aliphatic (C 1-24 ) esters, acyloxymethyl esters, carbonates, carbamates, and amino acid esters. For example, a compound in the present invention contains a hydroxyl group, and it can be acylated to obtain a compound in the prodrug form. Other prodrug forms include phosphate esters, such as those obtained by phosphorylating the hydroxyl groups on the parent compound. A complete discussion of prodrugs can be found in the following references: T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium 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 S. J. Hecker et al., Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345.

[0170] "Metabolite" refers to the product obtained by the metabolic action of a specific compound or its salt in vivo. The metabolites of a compound can be identified by techniques well known in the art, and their activities can be characterized by experimental methods as described in the present invention. Such products can be obtained by methods such as oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, etc. of the administered compound. Accordingly, the present invention includes the metabolites of the compounds, including the metabolites produced by contacting the compounds of the present invention with mammals for a sufficient period of time.

[0171] The "pharmaceutically acceptable salts" used in the present invention refer to the organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in the literature: S.M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19. The salts formed from pharmaceutically acceptable non-toxic acids include, but are not limited to, inorganic acid salts formed by reacting with amino groups such as hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, and organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, or these salts can be obtained by other methods described in books and literature such as ion exchange method. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, malonate, mesylate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and so on. The salts obtained by appropriate bases include salts of alkali metals, alkaline earth metals, ammonium and N + (C 1-4 (alkyl)4. The present invention also contemplates quaternary ammonium salts formed from any compound containing a group of N. 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 so on. Pharmaceutically acceptable salts further include appropriate, non-toxic ammonium, quaternary ammonium salts and amine cations formed with counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C 1-8 sulfonates and aromatic sulfonates.

[0172] The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, basic or acidic moieties by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid form of these compounds with a stoichiometric amount of a suitable base (such as hydroxides, carbonates, bicarbonates, 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 both. Generally, in appropriate cases, a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile is used. Lists of additional suitable salts can be found, for example, in "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).

[0173] In addition, the compounds disclosed in the present invention, including their salts, can also be obtained in their hydrate form or in a form containing their solvents (such as ethanol, DMSO, etc.) for their crystallization. The compounds disclosed in the present invention can inherently or by design form solvates with pharmaceutically acceptable solvents (including water); thus, the present invention is intended to include solvated and unsolvated forms.

[0174] The "solvate" of the present invention refers to an association formed by one or more solvent molecules with the compounds 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 in which the solvent molecule is water.

[0175] As used herein, "nitrogen oxides" means that when a compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form N-oxides. Specific examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen atoms in nitrogen-containing heterocycles. The corresponding amines can be treated with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid) 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 L.W. Deady (Syn. Comm. 1977, 7, 509-514), in which, for example, in an inert solvent such as dichloromethane, an amine compound is reacted with meta-chloroperoxybenzoic acid (MCPBA).

[0176] As used herein, the term "treating" any disease or disorder means, in some embodiments, ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of its clinical symptoms). In other embodiments, "treating" means alleviating or improving at least one physical parameter, including physical parameters that may not be perceptible to the patient. In other embodiments, "treating" means modulating the disease or disorder physically (e.g., stabilizing the perceptible symptoms) or physiologically (e.g., stabilizing the physical parameters) or both. In other embodiments, "treating" means preventing or delaying the onset, occurrence, or worsening of the disease or disorder.

[0177] As used herein, the term "RET-related cancer" means a cancer associated with the RET gene, RET kinase (also referred to herein as RET kinase protein or RET kinase), or a dysregulation of the expression or activity or level of any one of them. Non-limiting examples of RET-related cancers are described herein. The dysregulation of the RET gene, RET kinase, or the expression or activity or level of any one of them is one or more point mutations in the RET gene.

[0178] In some embodiments, the dysregulation of the RET gene, RET kinase, or the expression or activity or level of any one of them includes one or more deletions (e.g., deletion of 4 amino acids), insertions, or point mutations in the RET kinase. In some embodiments, the dysregulation of the RET gene, RET kinase, or the expression or activity or level of any one of them includes the deletion of one or more residues of the RET kinase, resulting in constitutive activity of the RET kinase domain.

[0179] The term "irritable bowel syndrome" includes diarrhea-predominant, constipation-predominant or alternating bowel patterns, functional flatulence, functional constipation, functional diarrhea, unspecified functional bowel disorder, functional abdominal pain syndrome, chronic idiopathic constipation, functional esophageal disorder, functional gastroduodenal disorder, functional anorectal pain, inflammatory bowel disease, and the like.

[0180] Any structural formula given in the present invention is also intended to represent both the non-isotope-enriched form and the isotope-enriched form of these compounds. The isotope-enriched compounds have the structure depicted by the general formula given in the present invention, except that one or more atoms are replaced by atoms having a selected atomic weight or mass number. Exemplary isotopes that can be incorporated 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 O, 18 O, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I.

[0181] On the other hand, the compounds of the present invention include isotope-enriched compounds as defined in the present invention, for example, those in which radioactive isotopes are present, such as 3 H, 14 C and 18 F, or those in which non-radioactive isotopes are present, such as 2 H and 13 C. Such isotope-enriched compounds can be used in metabolic studies (using 14 C), reaction kinetics studies (using, for example, 2 H or 3 H), detection or imaging techniques, such as positron emission tomography (PET) or single photon emission computed tomography (SPECT) including determination of the tissue distribution of a drug or a substrate, or can be used in radiotherapy of patients. 18 F-enriched compounds are particularly desirable for PET or SPECT studies. The isotope-enriched compounds of formula (I) can be prepared by conventional techniques familiar to those skilled in the art or by replacing the originally used unlabeled reagents with suitable isotope-labeled reagents as described in the examples and preparation procedures of the present invention.

[0182] In addition, heavier isotopes, especially deuterium (i.e., 2Substitution with H or D can provide certain therapeutic advantages, which are brought about by higher metabolic stability. For example, an increased in vivo half-life or a reduced dose requirement or an improved therapeutic index. It should be understood that deuterium in the present invention is regarded as a substituent of the compound of formula (I). The concentration of such heavier isotopes, especially deuterium, can be defined by an isotopic enrichment factor. The term "isotopic enrichment factor" as used in the present invention refers to the ratio between the isotopic abundance of the designated isotope and the natural abundance. If a substituent of a compound of the present invention is designated as deuterium, the compound has an isotopic enrichment factor 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) for each designated deuterium atom. The pharmaceutically acceptable solvates of the present invention include those solvates in which the crystallization solvent can be isotopically substituted, such as D2O, acetone-d6, DMSO-d6.

[0183] Compounds of the present invention, their pharmaceutical compositions, formulations and administrations

[0184] The present invention provides compounds of the present invention or their pharmaceutical compositions that inhibit wild-type RET and RET mutants. Additionally, the compounds of the present invention or their pharmaceutical compositions have inhibitory selectivity for both wild-type RET and RET gene mutants relative to other kinases, resulting in reduced toxicity associated with the inhibition of other kinases.

[0185] The pharmaceutical compositions of the present invention include compounds represented by formula (I), (I-1), (I-2) or (I-3), the compounds listed in the present invention, or the compounds of the examples. The amount of the compound in the compositions of the present invention can effectively treat or alleviate RET-related diseases or disorders in a patient, including RET-related cancers, irritable bowel syndrome and / or pain associated with irritable bowel syndrome.

[0186] 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.

[0187] When preparing the compositions provided herein, the active ingredient is usually mixed with an excipient, diluted by the excipient or encapsulated in such a carrier in the form of, for example, a capsule, a sachet, paper or other container. If an excipient is used as a diluent, it can be a solid, semisolid or liquid material, which is used as a carrier, carrier or medium for the 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 a tablet, a pill, a powder, a lozenge, a capsule, a cachet, an elixir, a suspension, an emulsion, a solution, a syrup, an aerosol (solid form or in a liquid medium), for example, an ointment containing up to 10% by weight of the active compound, a soft and hard gelatin capsule, a suppository, a sterile injection solution and a sterile packaged powder. In one embodiment, the composition is formulated for oral administration. In one embodiment, the composition is formulated into a tablet or a capsule.

[0188] When available for treatment, a therapeutically effective amount of a compound of the present invention, particularly a compound represented by formula (I), (I-1), (I-2) or (I-3) and its pharmaceutically acceptable salts can be administered as a raw chemical, and can also be provided as an active ingredient of a pharmaceutical composition. Therefore, the present invention also provides a pharmaceutical composition, which comprises a therapeutically effective amount of a compound of the present invention, particularly a compound represented by formula (I), (I-1), (I-2) or (I-3) or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable adjuvants, and the adjuvants include but are not limited to carriers, diluents or excipients, etc. The term "therapeutically effective amount" as used herein refers to the total amount of each active component sufficient to show a meaningful patient benefit (such as 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 whether administered in combination, sequentially or simultaneously. The compounds of the present invention, particularly the compounds represented by formula (I), (I-1), (I-2) or (I-3) and their pharmaceutically acceptable salts are as described above. The carrier, diluent or excipient must be acceptable in the sense of being compatible with the other ingredients of the formulation and not harmful to its recipient. According to another aspect of the present invention, there is also provided a method for preparing a pharmaceutical preparation, which comprises mixing a compound of the present invention, particularly a compound represented by formula (I), (I-1), (I-2) or (I-3) or its pharmaceutically acceptable salt 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 that, within the scope of reasonable medical judgment, are suitable for contact with patient tissues without excessive toxicity, irritation, allergic reaction or other problems and complications commensurate with a reasonable benefit / risk ratio, and are effective for the intended use.

[0189] The amount of the active ingredient combined with one or more adjuvants to prepare a single dosage form will necessarily vary according to the host to be treated and the specific route of administration. The amount of the compound represented by formula (I), (I-1), (I-2) or (I-3) mixed with the carrier material to prepare a single dosage form of the active ingredient will vary according to 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 age, sex, weight and condition of the patient. Preferred unit dosage forms are unit dosage forms containing the daily dose or divided dose or a suitable fraction thereof of the active ingredient described above. Treatment can be started with a small dose that is clearly lower than the optimal dose of the compound. Thereafter, the dose can be increased in smaller increments until the optimal effect is achieved in this case. Generally, the most desirable concentration level at which the compound is administered is one that can generally provide effective results in anti-tumor aspects without causing any harmful or toxic side effects.

[0190] The composition containing the compound 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 the active ingredient. The term "unit dosage form" refers to physically discrete units suitable as a single dose for a human subject or other patient, each unit containing a predetermined amount of the active material (i.e., the compound of general formula I as provided herein) and a suitable pharmaceutical excipient, and the predetermined amount is calculated to be capable of producing the desired therapeutic effect.

[0191] The pharmaceutical composition is suitable for administration by any suitable route, such as by oral (including buccal or sublingual), rectal, nasal, topical (including oral, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intradermal, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intralesional, intravenous or subdermal injection or infusion) routes. Such preparations can be prepared by any known method in the pharmaceutical art, for example by mixing the active ingredient with a carrier or excipient. Oral administration or injection administration is preferred.

[0192] The present invention also provides a method for treating an individual suffering from a RET-related cancer, the method comprising administering the compound of the present invention before, during or after administering another anti-cancer drug (e.g., not the compound of the present invention).

[0193] 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., including a RET-related cancer having one or more RET inhibitor-resistant mutations) (e.g., using a kit approved by a regulatory agency, such as an FDA-approved kit, to identify the RET gene, RET kinase or the dysregulation of the expression or activity or level of any of them in the patient or a biopsy sample of the patient, or by performing any non-limiting example of the assays 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 anti-cancer agent (e.g., another RET inhibitor, e.g., a RET inhibitor not the 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 (e.g., after tumor resection or radiotherapy) with other anti-cancer agents.

[0194] In some embodiments of any of the methods described herein, a compound of 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 selected from one or more other therapeutic regimens or therapeutic (e.g., chemotherapeutic) agents.

[0195] Non-limiting examples of other therapeutic agents include: other RET-targeted therapeutic agents (i.e., other RET kinase inhibitors: RET inhibitors that are not the compounds described in the present invention), receptor tyrosine kinase-targeted therapeutic agents, signal transduction pathway inhibitors, checkpoint inhibitors, apoptosis pathway regulators (e.g., Obataclax); cytotoxic chemotherapeutic agents, angiogenesis-targeted therapeutic agents, immunotargeting agents, and radiotherapy.

[0196] In some embodiments, the other RET-targeted therapeutic agent is a multi-kinase inhibitor that exhibits RET inhibitory activity.

[0197] Non-limiting examples of RET-targeted therapeutic agents include alectinib, 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-(methylamino)pyrimidin-4-yl]oxyphenyl]urea), PZ-1, RPI-1 (1,3-dihydro-5,6-dimethoxy-3-[(4-hydroxyphenyl)methylene]-H-indol-2-one), RXDX-105 (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).

[0198] Other therapeutic agents include RET inhibitors, such as those described, for example, in the following: U.S. Patent 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; WO2012 / 053606; WO 2009 / 017838; WO 2008 / 031551; WO 2007 / 136103; WO 2007 / 087245; WO2007 / 057399; WO 2005 / 051366; WO 2005 / 062795; and WO 2005 / 044835; and J. Med. Chem. 2012, 55(10), 4872 - 4876, which are hereby incorporated by reference in their entireties.

[0199] Also provided herein are methods of treating cancer, comprising administering to a patient in need thereof a pharmaceutical combination for treating cancer, which comprises (a) a compound of formula (I), (I - 1), (I - 2) or (I - 3) or a pharmaceutically acceptable salt or solvate thereof, (b) other therapeutic agents, and (c) optionally at least one pharmaceutically acceptable carrier, for use simultaneously, separately or sequentially for treating cancer, wherein the amount of the compound of formula (I), (I - 1), (I - 2) or (I - 3) or a pharmaceutically acceptable salt or solvate thereof and the amount of the other therapeutic agents are jointly effective in treating cancer.

[0200] The compounds and compositions described herein can be administered alone or in combination with other compounds (including other RET modulating compounds) or other therapeutic agents. In some embodiments, the compounds or compositions of the invention can be administered 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 invention can be administered simultaneously or sequentially with other therapeutic agents by the same or different routes of administration. The compounds of the invention can be included in a single formulation or in separate formulations together with other therapeutic agents.

[0201] In some embodiments, the compounds of the present invention can be used in combination with one or more other therapeutic agents or therapies for the treatment of irritable bowel syndrome (IBS), and the other therapeutic agents or therapies act through 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 with a compound of formula (I), (I-1), (I-2) or (I-3) or a pharmaceutically acceptable salt or solvate thereof as part of the same or separate dosage forms, via the same or different routes of administration, and according to the same or different dosing schedules. Non-limiting examples of other therapeutic agents for the treatment of irritable bowel syndrome (IBS) include probiotics, fiber supplements (such as psyllium, methylcellulose), antidiarrheal agents (such as loperamide), bile acid binders (such as cholestyramine, colestipol, colesevelam), anticholinergic and antispasmodic agents (such as scopolamine, dicyclomine), antidepressants (such as tricyclic antidepressants such as imipramine or nortriptyline or selective serotonin reuptake inhibitors (SSRI) such as fluoxetine or paroxetine), antibiotics (such as rifaximin), alosetron and lubiprostone.

[0202] Use of the compounds and pharmaceutical compositions of the present invention

[0203] The present invention also provides the use of the compounds or the pharmaceutical compositions of the present invention in the preparation of a medicament for preventing or treating RET-related diseases or disorders, wherein the RET-related diseases or disorders include RET-related cancers, irritable bowel syndrome and / or pain associated with irritable bowel syndrome.

[0204] The present invention provides the compounds of the present invention or their pharmaceutical compositions that inhibit wild-type RET and RET mutants, for example, RET mutants resistant to current standard-of-care treatments ("RET-resistant mutants"). In addition, the compounds of the present invention or their pharmaceutical compositions have inhibitory selectivity for both wild-type RET and RET gene mutants relative to other kinases, resulting in reduced toxicity associated with the inhibition of other kinases.

[0205] The present invention provides the use of the compounds of the present invention or their pharmaceutical compositions that inhibit wild-type RET and RET mutants in the preparation of a medicament for preventing or treating diseases or disorders related to wild-type RET and RET mutants.

[0206] In some embodiments of any method or use described herein, the cancer (e.g., RET-related cancer) is a hematological cancer. In some embodiments of any method or use described herein, the cancer (e.g., RET-related cancer) is a solid tumor. In some embodiments of any method or use 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, bronchioloalveolar carcinoma, multiple endocrine neoplasia type 2A or 2B (MEN2A or MEN2B, respectively), pheochromocytoma, parathyroid hyperplasia, breast cancer, colorectal cancer (e.g., metastatic colorectal cancer), papillary renal cell carcinoma, gangliocytomatosis of the gastrointestinal mucosa, inflammatory myofibroblastic tumor or cervical cancer.In some embodiments of any method or use of the present invention, the cancer (e.g., RET-related cancer) is selected from: acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), adolescent cancer, adrenocortical carcinoma, anal cancer, appendiceal cancer, astrocytoma, atypical teratoid / rhabdoid tumor, basal cell carcinoma, cholangiocarcinoma, bladder cancer, bone cancer, brainstem glioma, brain tumor, breast cancer, bronchial tumor, Burkitt lymphoma, carcinoid tumor, cancer of unknown primary, cardiac tumor, cervical cancer, childhood cancer, chordoma, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myeloproliferative neoplasm, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, cholangiocarcinoma, ductal carcinoma in situ, embryonal tumor, endometrial cancer, ependymoma, esophageal cancer,esthesioneuroblastoma, Ewing sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, extrahepatic cholangiocarcinoma, 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, hair cell leukemia, hairy cell leukemia, head and neck cancer, heart cancer, hepatocellular carcinoma, histiocytosis, Hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumor, pancreatic neuroendocrine tumor, Kaposi sarcoma, kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, lip and oral cavity cancer, liver cancer, lung cancer, lymphoma, macroglobulinemia, malignant fibrous histiocytoma of bone, bone cancer, melanoma, Merkel cell carcinoma, mesothelioma, metastatic squamous neck cancer, midline carcinoma, mouth cancer, multiple endocrine neoplasia syndrome, multiple myeloma, mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasm, myeloid leukemia, myelogenous leukemia, multiple myeloma, myeloproliferative neoplasm, nasal and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, oral cavity cancer, oral cancer, lip cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, paranasal sinus and nasal cavity cancer, parathyroid carcinoma, 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, Sézary 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, throat cancer, thymoma and thymic carcinoma, 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 Wilms tumor.

[0207] In some embodiments, the RET-related cancers of the present invention are 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 gangliocytoma, and cervical cancer. In some embodiments, the RET-related cancer is RET fusion lung cancer or medullary thyroid cancer.

[0208] In some embodiments, the compounds of formula (I), (I-1), (I-2) or (I-3) and their pharmaceutically acceptable salts and solvates can be used to treat patients with cancers having a RET inhibitor-resistant mutation (which results in increased resistance to a compound, pharmaceutically acceptable salt or solvate other than the compounds of formula (I), (I-1), (I-2) or (I-3)), such as a substitution at amino acid position 804, such as V804M, V804L or V804E), by co-administration or as a subsequent treatment to an existing drug treatment (e.g., other RET kinase inhibitors other than the compounds of formula (I), (I-1), (I-2) or (I-3) or their pharmaceutically acceptable salts or solvates). Exemplary RET kinase inhibitors are described herein (e.g., other RET kinase inhibitors other than the compounds of formula (I), (I-1), (I-2) or (I-3) or their pharmaceutically acceptable salts or solvates). In some embodiments, the RET kinase inhibitor can be selected from cabozantinib, vandetanib, alectinib, sorafenib, lenvatinib, ponatinib, dovitinib, sunitinib, foretinib, BLU667, and BLU6864.

[0209] In some embodiments of any of the methods or uses described herein, the irritable bowel syndrome (IBS) includes diarrhea-predominant, constipation-predominant or alternating, functional bloating, functional constipation, functional diarrhea, unspecified functional bowel disorder, functional abdominal pain syndrome, chronic idiopathic constipation, functional esophageal disease, functional gastroduodenal disease, functional anorectal pain, and inflammatory bowel disease.

[0210] According to the methods of the present invention, the compounds and compositions can be in any dosage and by any route of administration to be effectively used to manage or reduce the severity of the disease. The exact amount required will vary according to the patient's condition, depending on race, age, general condition of the patient, severity of the infection, particular factors, mode of administration, and the like. The compounds or compositions can be used in combination with one or more other therapeutic agents, as discussed in the present invention.

[0211] General synthetic methods of the compounds of the present invention

[0212] 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.

[0213] 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.

[0214] 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.

[0215] 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.

[0216] 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.

[0217] The chromatographic column used was a silica gel column. The silica gel (300 - 400 mesh) was purchased from Qingdao Ocean Chemical Factory. Nuclear magnetic resonance spectra were recorded in CDC13 or DMSO-d6 as solvents (reported in ppm), using TMS (0 ppm) or chloroform (7.25 ppm) as reference standards. When multiplets occurred, the following abbreviations were used: s (singlet), d (doublet), t (triplet), m (multiplet), br (broadened), dd (doublet of doublets), dt (doublet of triplets). The coupling constant J was expressed in Hertz (Hz).

[0218] Low-resolution mass spectrometry (MS) data were determined using a spectrometer of Agilent 6320 series LC-MS equipped with a G1312A binary pump and a G1316A TCC (column temperature maintained at 30 °C), with a G1329A autosampler and a G1315B DAD detector applied for analysis, and an ESI source applied to the LC-MS spectrometer.

[0219] Low-resolution mass spectrometry (MS) data were determined using a spectrometer of Agilent 6120 series LC-MS equipped with a G1311A quaternary pump and a G1316A TCC (column temperature maintained at 30 °C), with a G1329A autosampler and a G1315D DAD detector applied for analysis, and an ESI source applied to the LC-MS spectrometer.

[0220] Both of the above spectrometers were equipped with an Agilent Zorbax SB-C18 column with a specification 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 peaks were recorded and read at UV-Vis wavelengths of 210 nm and 254 nm. The mobile phase was a 0.1% formic acid acetonitrile solution (phase A) and a 0.1% formic acid ultrapure water solution (phase B).

[0221] Compound purification was evaluated by an Agilent 1100 series high performance liquid chromatography (HPLC), where UV detection was at 210 nm and 254 nm, a Zorbax SB-C18 column with a specification of 2.1×30 mm, 4 μm, for 10 minutes, the flow rate was 0.6 mL / min, with a 5 - 95% (0.1% formic acid acetonitrile solution) of (0.1% formic acid aqueous solution), and the column temperature was maintained at 40 °C.

[0222] The following abbreviations are used throughout the present invention:

[0223] LiAlH4 lithium aluminum hydride

[0224] THF Tetrahydrofuran

[0225] DCM Dichloromethane

[0226] NaH Sodium hydride

[0227] H2 Hydrogen

[0228] PE Petroleum ether

[0229] EA Ethyl acetate

[0230] K2CO3 Potassium carbonate

[0231] DCE 1,2 - Dichloroethane

[0232] STAB Sodium triacetoxyborohydride

[0233] N2 Nitrogen

[0234] MeOH Methanol

[0235] NaBH4 Sodium borohydride

[0236] CH3I Methyl iodide

[0237] Ag2O Silver oxide

[0238] HCl Hydrochloric acid

[0239] PBr3 Phosphorus tribromide

[0240] DMF N,N - Dimethylformamide

[0241] Zn Zinc

[0242] TMSCl Trimethylchlorosilane

[0243] Et3N Triethylamine

[0244] MsCl Methanesulfonyl chloride

[0245] NaBH4 Sodium borohydride

[0246] DMAP 4 - Dimethylaminopyridine

[0247] DMSO Dimethyl sulfoxide

[0248] EtOH Ethanol

[0249] t - BuOK Potassium tert - butoxide

[0250] H2O Water

[0251] HCl / EA Hydrochloric acid in ethyl acetate

[0252] mL milliliter

[0253] min minute

[0254] g gram

[0255] mmol millimole

[0256] % percentage

[0257] mg milligram

[0258] ℃ degree Celsius

[0259] TLC thin layer chromatography

[0260] N mol / L, mole per liter

[0261] rt room temperature

[0262] n-BuLi n-butyllithium

[0263] DMAC N,N-dimethylacetamide

[0264] Boc tert-butoxycarbonyl

[0265] EDCI 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride

[0266] The following synthetic scheme describes the steps for preparing the compounds disclosed in the present invention. Unless otherwise specified, R 1 , X 1 , X 2 , X 3 , X 4 , X 5 , E, A, Q, M, T, G, R a and q have the definitions as described in the present invention.

[0267] Synthesis scheme of intermediate (IA-1a):

[0268]

[0269] The intermediate compound of formula (IA-1a) can be prepared by referring to the synthesis steps of the above intermediate synthesis scheme. Among them is the following substructural formula: Hal 1 and Hal 2 are each independently F, Cl, Br or I, preferably Cl or Br; Pg 1 is an amino protecting group, such as Boc, etc.; Pg 2is a hydroxyl protecting group, such as benzyl, etc. The compound of formula (IA-1a-1) and the compound of formula (IA-1a-2) undergo a coupling reaction in a suitable solvent (such as dioxane, etc.) under suitable coupling agent conditions (such as a palladium coupling agent, preferably PdCl2(dppf)CH2Cl2) to obtain the compound of formula (IA-1a-3); the compound of formula (IA-1a-3) and the compound of formula (IA-1a-4) undergo a coupling reaction in a suitable solvent (such as toluene, etc.) under suitable coupling agent conditions (such as a palladium coupling agent, preferably PdCl2(dppf)CH2Cl2) to obtain the compound of formula (IA-1a-5); the compound of formula (IA-1a-5) reacts under suitable reaction conditions (such as in the presence of sodium hydroxide and hydrogen peroxide, in a tetrahydrofuran solvent) to obtain the compound of formula (IA-1a-6); the compound of formula (IA-1a-6) and the compound of formula (IA-1a-7) undergo a coupling reaction to obtain the compound of formula (IA-1a-8); the compound of formula (IA-1a-8) and the compound of formula (IA-1a-9) react under basic conditions to obtain the compound of formula (IA-1a-10); the compound of formula (IA-1a-10) is deprotected from the amino group under acidic conditions to obtain the compound of formula (IA-1a-11); the compound of formula (IA-1a-11) and the compound of formula (IA-1a-12) react under basic conditions to obtain the compound of formula (IA-1a-13); the compound of formula (IA-1a-13) is reduced under suitable conditions (such as H2, Pd / C) to obtain the compound of formula (IA-1a).

[0270] Synthesis scheme of intermediate (IA-1b):

[0271]

[0272] The intermediate compound of formula (IA-1b) can be prepared by referring to the synthesis steps of the above intermediate synthesis scheme. Among them, Hal 2 is F, Cl, Br or I, preferably Cl, Br; the compound of formula (IA-1a-6) and the compound of formula (IA-4) or a salt of the compound of formula (IA-4) (such as hydrochloride, formate, etc.) undergo a coupling reaction under suitable conditions (such as in a DMSO solvent, under basic conditions, such as K2CO3) to obtain the compound of formula (IA-1b).

[0273] Synthesis scheme 1:

[0274]

[0275] The compound of formula (IA) can be prepared according to the synthetic steps of Synthetic Scheme 1. Among them, Hal is F, Cl, Br or I, preferably Cl or Br. The compound of formula (IA-1) reacts with the compound of formula (IA-2) under suitable conditions (such as basic conditions, and the base is K2CO3) in a suitable solvent (such as N,N-dimethylacetamide, N,N-dimethylformamide) to obtain the compound of formula (IA).

[0276] Synthetic Scheme 2:

[0277]

[0278] The compound of formula (IAa) can be prepared according to the synthetic steps of Synthetic Scheme 2. Among them, Hal 1 and Hal 2 are each independently F, Cl, Br or I, preferably Cl or Br; represents a fused ring containing a nitrogen atom and is substituted by q R a where q and R a have the definitions as described in the present invention. The compound of formula (IA-1) reacts with the compound of formula (IAa-2) under suitable conditions (such as basic conditions, and the base is K2CO3) in a suitable solvent (such as acetonitrile) to obtain the compound of formula (IAa-3); the compound of formula (IAa-3) reacts with the compound of formula (IAa-4) under suitable conditions (such as basic conditions, and the base is K2CO3) in a suitable solvent (such as N,N-dimethylacetamide) to obtain the compound of formula (IAa).

[0279] Synthetic Scheme 3

[0280]

[0281] The compound of formula (IA) can be prepared according to the synthetic steps of Synthetic Scheme 3. Among them, Ms is a mesyl group. The compound of formula (IA-1) reacts with the compound of formula (IA-3) under suitable conditions (such as basic conditions, and the base is K2CO3) in a suitable solvent (such as N,N-dimethylformamide) to obtain the compound of formula (IA).

[0282] Synthetic Scheme 4

[0283]

[0284] The compound of formula (IAb) can be prepared according to the synthetic steps of Synthetic Scheme 4. Among them, Hal 2Each of He and Hal is independently F, Cl, Br or I, preferably Cl or Br; the compound of formula (IA-2) or the compound of formula (IA-3) reacts with the compound of formula (IA-1a-6) under suitable conditions (such as basic conditions, and the base is K2CO3) in a suitable solvent (such as N,N-dimethylacetamide, N,N-dimethylformamide) to obtain the compound of formula (IA-5); the compound of formula (IA-5) undergoes a coupling reaction with the compound of formula (IA-4) or a salt of the compound of formula (IA-4) (such as hydrochloride, formate, etc.) under suitable conditions to obtain the compound of formula (IAb). Specific Examples

[0285] Intermediate 1: 6-Hydroxy-4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0286]

[0287] Step 1: tert-Butyl 4-hydroxy-4-(pyridin-2-ylmethyl)piperidine-1-carboxylate

[0288] Under nitrogen protection, 9 mL of THF and 0.644 mL (6.52 mmol) of 2-methylpyridine were added to a 50 mL two-necked flask. A n-hexane solution of n-BuLi (2.2 mL, 5.5 mmol, 2.5 mol / L) was slowly added at -78 °C. After reacting for 45 min, the reaction was transferred to room temperature and reacted for 2 h, and then a THF (6 mL) solution of tert-butyl 4-oxopiperidine-1-carboxylate (1 g, 5.019 mmol) was added at -78 °C. After completion of the addition, the reaction was continued for 2 h and then reacted at room temperature for 2 h. The reaction solution was quenched with saturated ammonium chloride solution (10 mL), extracted with EA (30 mL × 2), the organic phase was washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation. Column chromatography on silica gel (eluent PE / EA (v / v = 10 / 1 - 1 / 1)) gave 1.176 g of a pale yellow oil (yield 80.14%), which was the target product. LC-MS (ES-API): m / z = 293.40 [M+H] + 。 1 H NMR (400 MHz, CDCl3) δ 8.49–8.44 (m, 1H), 7.61 (td, J = 7.7, 1.7 Hz, 1H), 7.15 (dd, J = 7.0, 5.4 Hz, 1H), 7.09 (d, J = 7.7 Hz, 1H), 3.76 (s, 2H), 3.72–3.61 (m, 1H), 3.21 (s, 2H), 2.87 (s, 2H), 1.47 (d, J = 3.2 Hz, 4H), 1.42 (s, 9H).

[0289] Step 2: 4-(Pyridin-2-ylmethyl)piperidin-4-ol hydrochloride

[0290] In a 25 mL single-necked flask, 4-hydroxy-4-(pyridin-2-ylmethyl)piperidine-1-carboxylic acid tert-butyl ester (550 mg, 1.881 mmol) and hydrochloric acid ethyl acetate solution (10 mL, 40 mmol, 4 mol / L) were added, and the mixture was stirred at room temperature for 3 h. TLC showed that the reaction was complete. The reaction solution was directly evaporated to dryness to obtain a yellow oil, which was dried in an oven at 60 °C to obtain 0.430 g of a yellow solid in the theoretical amount, which was the target product. LC-MS (ES-API): m / z = 193.40 [M+H] + 。

[0291] 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

[0292] In a 10 mL microwave tube, 4-(2-pyridylmethyl)piperidin-4-ol hydrochloride (430 mg, 1.880 mmol), 4-(6-fluoro-3-pyridyl)-6-hydroxy-pyrazolo[1,5-a]pyridine-3-carbonitrile (Intermediate 2, 240 mg, 0.944 mmol), potassium carbonate (522 mg, 3.777 mmol), and DMSO (2.4 mL) were added, and the mixture was heated at 85 °C by microwave for 6 h. TLC showed that the reaction was complete. The reaction solution was diluted with water (12 mL), and extracted with EA (30 mL×2). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. Silica gel column chromatography (eluent: pure EA - EA / MeOH (v / v: 50 / 1)) gave 0.19 g of a brownish-yellow solid (yield 47%), which was the target product. LC-MS (ES-API): m / z = 427.20 [M+H] + 。 1 H NMR (400 MHz, MeOD) δ 8.46 (d, J = 4.2 Hz, 1H), 8.23 (d, J = 2.8 Hz, 2H), 8.18 (d, J = 2.0 Hz, 1H), 7.75 (d, J = 5.5 Hz, 1H), 7.70 (dd, J = 9.0, 2.6 Hz, 1H), 7.34 (d, J = 7.8 Hz, 1H), 7.29–7.24 (m, 1H), 7.12 (d, J = 1.9 Hz, 1H), 6.89 (d, J = 8.9 Hz, 1H), 4.06 (d, J = 13.2 Hz, 2H), 3.38 (dd, J = 18.1, 7.6 Hz, 2H), 2.97 (s, 2H), 1.77–1.69 (m, 2H), 1.62 (d, J = 13.3 Hz, 2H).

[0293] Intermediate 2: 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] Under room temperature conditions, 6-bromo-4-methoxypyrazolo[1,5-a]pyridine-3-carbonitrile (50 g, 198.36 mmol), water (16.5 mL, 916 mmol), sodium hydroxide (16.03 g, 396.8 mmol), and DMAC (500 mL) were successively added to a 1 L single-necked flask. After stirring at room temperature for 5 min, it was transferred to 0 °C and dodecyl mercaptan (97 mL, 397 mmol) was slowly added. After the addition was completed, the reaction was transferred to 45 °C and stirred overnight. The reaction solution was poured into 3 L of ice water, and saturated aqueous citric acid solution was slowly added to adjust the pH to 5. After stirring for half an hour, it was allowed to stand, filtered, and the filter cake was washed with water and petroleum ether multiple times and dried at 60 °C to obtain 44.1 g of a yellow solid, which was the target product (yield 93.4%). Rf = 0.35 (PE / EA (v / v) = 3 / 1). LC-MS: m / z = 239.05 [M+H] + 。

[0297] Step 2: 3-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 1 L single-necked flask. The temperature was lowered to below -10 °C, and trifluoromethanesulfonic anhydride (50 mL, 297.2 mmol) was slowly added. After stirring for 1 h, it was allowed to rise to room temperature naturally and the reaction was carried out overnight. The DCM was removed by rotary evaporation 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 rotary evaporated, and purified by silica gel column chromatography (eluent PE / EA (v / v) = 50 / 1 - 25 / 1) to obtain 61.5 g of a pale yellow solid, which was the target product, with a yield of 89.7%. Rf = 0.45 (PE / EA (v / v) = 5:1).

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

[0300] Under nitrogen protection, 3-bromo-3-cyanopyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate (61.5 g, 166 mmol), 2-fluoropyridine-5-boronic acid ester (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 to a 1 L three-necked flask. The temperature was lowered to -10 °C, and a potassium acetate solution (115 mL, 345 mmol, 3 mol / L) was slowly added. After stirring at this temperature for 1 h, the reaction mixture was allowed to return to room temperature naturally and continue to react overnight. The mixture was filtered, and the filter cake was washed with EA (500 ml × 3). The organic phase was separated from the filtrate, washed with water (500 ml), saturated brine (250 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated by rotary evaporation. Purification by silica gel column chromatography (eluent PE / DCM (v / v) = 2:1 - 0:1) gave 49 g of a white solid, which was the target product with a yield of 93.0%. Rf = 0.50 (PE / EA (v / v) = 1 / 1). LC-MS: m / z = 318.10 [M+H] + 。 1 H NMR (400 MHz, DMSO) δ 9.49 (d, J = 1.2 Hz, 1H), 8.73 (s, 1H), 8.51 (d, J = 1.9 Hz, 1H), 8.27 (td, J = 8.2, 2.5 Hz, 1H), 7.86 (d, J = 1.2 Hz, 1H), 7.40 (dd, J = 8.4, 2.5 Hz, 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] Under nitrogen protection in a 250 mL single-necked flask, 6-bromo-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (8 g, 25.23 mmol), bis(pinacolato)diboron (10 g, 39.39 mmol), potassium acetate (10 g, 101.9 mmol), and freshly distilled toluene (150 mL) were successively added. After purging with nitrogen and then bubbling for 10 min, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (2.1 g, 2.6 mmol) was added. After purging with nitrogen and bubbling for 10 min, the reaction was heated at 120 °C overnight. The reaction mixture was filtered through diatomaceous earth, and the filter cake was washed with EA (50 mL × 3). The organic phase was washed with water (250 mL), then with saturated brine (250 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Column chromatography on silica gel (eluent PE / DCM(v / v) = 2:1 / 0:1) was carried out, and the fractions were collected and concentrated in vacuo to give 8.5 g of an orange solid, which was the target product (yield 93.0%). Rf = 0.15 (DCM). 1 H NMR(400MHz,CDCl3)δ8.99(s,1H),8.43(d,J=2.1Hz,1H),8.34(s,1H),8.02(td,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 250 mL single-necked flask, 4-(6-fluoropyridin-3-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (8.5 g, 23 mmol), tetrahydrofuran (120 mL) were successively added. Under ice bath conditions, sodium hydroxide solution (60 mL, 120 mmol, 2 mol / L), hydrogen peroxide (14 mL, 140 mmol, 30 mass%) were slowly added, and stirred at low temperature. After monitoring the reaction to completion by TLC, sodium thiosulfate solution (50 mL, 150 mmol, 3 mol / L) was slowly added. After restoring to room temperature, water (250 mL) was added, and extracted with EA (250 mL × 2). The combined organic phases were washed with 0.1 M NaOH solution (500 mL × 2). All the aqueous phases were combined, the pH was adjusted to 4 with dilute hydrochloric acid, stirred at room temperature for 15 min, filtered by suction to obtain a wet filter cake. The mother liquor was extracted with EA (250 mL × 3), all the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated by rotary evaporation, and purified by silica gel column chromatography (eluent DCM\MeOH(v / v) = 100 / 0 - 10 / 1) to obtain a light yellow solid. All the solids were combined and dried at 50 °C to obtain 5.1 g of a light yellow solid, which was the target product (yield 86.0%). Rf = 0.25 (DCM / MeOH(v / v) = 100 / 1). LC-MS: m / z = 255.10[M+H] + 。 1 HNMR(400MHz,DMSO)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 3: 4-(6-fluoropyridin-3-yl)-6-((2-methyloctahydrocyclopenta[c]pyrrol-5-yl)oxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0306]

[0307] Step 1: tert-Butyl 5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

[0308] At room temperature, tert-butyl 5-oxo-(1,3,3a,4,6,6a-hexahydro)cyclopenta[c]pyrrole-2-carboxylate (5.0 g, 22 mmol) was dissolved in EtOH (50 mL) in a single-necked flask, and NaBH4 (1.7 g, 45 mmol) was added portionwise with stirring. After 1 h, the reaction was monitored by TLC and found to be complete. Saturated ammonium chloride solution was added to the reaction mixture until no more bubbles were produced, and a large amount of white solid precipitated. The mixture was filtered by suction, and the filter cake was washed with 10 mL of ethanol. The filtrate was concentrated under reduced pressure to remove most of the ethanol, and a large amount of white solid precipitated. 30 mL of water was added, and the white solid dissolved. The solution was extracted twice with 100 mL of EA. The organic phases were combined, washed twice with 20 mL of water and once with 20 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then evaporated to dryness to obtain 4.8 g of white solid. The yield was 95.00%. Rf = 0.2 (PE:EA = 2:1). 1 1H NMR (400 MHz, CDCl3) δ 4.27 (p, J = 6.5 Hz, 1H), 3.47 (dd, J = 11.2, 8.0 Hz, 2H), 3.31 (dd, J = 11.2, 3.4 Hz, 2H), 2.62 - 2.53 (m, 2H), 2.13 (dd, J = 13.8, 7.4 Hz, 2H), 1.52 - 1.45 (m, 2H), 1.43 (s, 9H).

[0309] Step 2: tert-butyl 5-((methylsulfonyl)oxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

[0310] At 0 °C, tert-butyl 5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (700 mg, 3.08 mmol) was dissolved in DCM (15.4 mL) in a single-necked flask. Triethylamine (624 mg, 6.17 mmol) was added, and after stirring until clear, methanesulfonyl chloride (388 mg, 3.39 mmol) was added dropwise. After the addition was complete, the reaction was carried out at this temperature for 2 h. 20 mL of water and 50 mL of DCM were added to the reaction mixture, and the organic phase was separated. The aqueous phase was extracted once with 50 mL of EA. The organic phases were combined, washed twice with 20 mL of water and once with 20 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then evaporated to dryness. Purification by column chromatography (eluent: EA / PE (v / v) = 1 / 3) gave 910 mg of colorless oil (yield 96.76%). Rf = 0.2 (PE / EA (v / v) = 2 / 1). 11H NMR (400 MHz, CDCl3) δ 5.14 - 5.05 (m, 1H), 3.51 (d, J = 6.8 Hz, 2H), 3.34 (s, 2H), 2.98 (s, 3H), 2.70 - 2.60 (m, 2H), 2.35–2.27 (m, 2H), 1.83 (dt, J = 14.2, 5.3 Hz, 2H), 1.44 (s, 9H).

[0311] Step 3: tert-Butyl 5-((3-cyano-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl)oxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

[0312] Dissolve 4-(6-fluoro-3-pyridinyl)-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile (Intermediate 2, 500 mg, 1.97 mmol), tert-butyl 5-((methylsulfonyl)oxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (900 mg, 2.95 mmol), and potassium carbonate (828 mg, 5.91 mmol) in DMF (20 mL), transfer to an oil bath at 50 °C and heat overnight. Pour the reaction solution into 100 mL of ice water, extract with EA (300 mL × 3), combine the organic phases, wash with water (200 mL × 3), wash with 200 mL of saturated brine, dry the organic phase over anhydrous sodium sulfate, filter and concentrate by rotary evaporation, and perform silica gel column chromatography (eluent: EA / PE (v / v) = 1 / 4 - 1 / 1) to obtain 350 mg of a white solid. Yield 38.39%. Rf = 0.5 (PE:EA = 1:1).

[0313] LC-MS: m / z = 408.15 [M-tBu + 2H] + 。 1 1H NMR (400 MHz, CDCl3) δ 8.38 (s, 1H), 8.21 (s, 1H), 8.14 (d, J = 1.8 Hz, 1H), 8.03 - 7.98 (m, 1H), 7.12 (dd, J = 8.9, 2.4 Hz, 2H), 4.91 - 4.87 (m, 1H), 3.58 - 3.51 (m, 2H), 3.29 - 3.20 (m, 2H), 2.94 - 2.87 (m, 2H), 2.26 (dd, J = 14.4, 5.9 Hz, 2H), 1.91 (d, J = 14.9 Hz, 2H), 1.47 (s, 9H).

[0314] Step 4: 4-(6-Fluoropyridin-3-yl)-6-((octahydrocyclopenta[c]pyrrol-5-yl)oxy)pyrazolo[1,5-a]pyridine-3-carbonitrile dihydrochloride

[0315] At room temperature, tert-butyl 5-((3-cyano-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl)oxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (350 mg, 0.76 mmol) was dissolved in HCl / EA (20 mL, 100 mmol, 5 mol / L). A white solid gradually precipitated out under stirring. After 3 h, TLC detected that the reaction was completed. The reaction solution was filtered by suction, and the filter cake was washed with a small amount of EA and dried by suction to obtain 280 mg of a white solid. It was used in the next reaction without further purification. The yield was 92.75%. Rf = 0.01 (PE / EA (v / v) = 1 / 1). LC-MS: m / z = 364.30 [M+H] + 。

[0316] Step 5: 4-(6-Fluoropyridin-3-yl)-6-((2-methyloctahydrocyclopenta[c]pyrrol-5-yl)oxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0317] In a single-necked flask, 4-(6-fluoropyridin-3-yl)-6-((octahydrocyclopenta[c]pyrrol-5-yl)oxy)pyrazolo[1,5-a]pyridine-3-carbonitrile dihydrochloride (280 mg, 0.70 mmol) and paraformaldehyde (105 mg, 3.50 mmol) were dissolved in DCE (14 mL), glacial acetic acid (9 mg, 0.15 mmol) was added dropwise, and the mixture was transferred to an oil bath at 50 °C for heating. After 30 min, NaHB(OAc)3 (446 mg, 2.10 mmol) was added, and after the addition, the reaction was kept warm overnight. The reaction solution was filtered by suction, the filter cake was washed with 10 mL of DCM, and the filtrate was concentrated and purified by column chromatography (eluent: MeOH / DCM (v / v) = 1 / 100 - 1 / 20) to obtain 165 mg of a white solid. The yield was 62.43%. (Rf = 0.4, MeOH:DCM = 1:10). LC-MS: m / z = 378.30 [M+H] + 。 1 1H NMR (400 MHz, CDCl3) δ 8.38 (d, J = 1.7 Hz, 1H), 8.25 - 8.19 (m, 2H), 8.06 - 7.97 (m, 1H), 7.12 (dd, J = 6.5, 4.5 Hz, 2H), 4.95 - 4.89 (m, 1H), 2.93 - 2.86 (m, 2H), 2.79 - 2.74 (m, 2H), 2.43 (s, 3H), 2.27 - 2.22 (m, 2H), 1.99 - 1.88 (m, 4H).

[0318] Intermediate 4: 4-(6-Fluoropyridin-3-yl)-6-(2-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0319]

[0320] Step 1: 5-(2-chloroethyl)hexahydro-1H-furo[3,4-c]pyrrole

[0321] Under nitrogen protection, add hexahydro-1H-furo[3,4-c]pyrrole (2.0 g, 18 mmol), potassium carbonate (12.0 g, 86.8 mmol) into a 25 mL three-necked flask. After dissolving with acetonitrile (20 mL, 383 mmol), slowly add 1-bromo-2-chloroethane (13 g, 90.649 mmol), and stir at room temperature overnight. After the reaction is completed, directly evaporate the reaction solution to dryness under reduced pressure. The residue is purified by silica gel column chromatography (eluent: PE / EA (v / v) = 100 / 1 - 2 / 1) to obtain 5.1 g of a yellow clear liquid, which is the target product (yield 97.0%). Rf = 0.35 (EA). LC-MS: m / z = 176.50 [M+H] + 。 1 1H NMR (400 MHz, CDCl3) δ 3.76 (dd, J = 8.7, 5.1 Hz, 2H), 3.61 - 3.53 (m, 4H), 2.86 - 2.72 (m, 6H), 2.34 (d, J = 5.0 Hz, 2H).

[0322] Step 2: 4-(6-fluoropyridin-3-yl)-6-(2-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0323] Add 4-(6-fluoropyridin-3-yl)-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile (intermediate 2, 0.5 g, 2 mmol), potassium carbonate (0.8 g, 6 mmol), 5-(2-chloroethyl)hexahydro-1H-furo[3,4-c]pyrrole (0.7 g, 4 mmol) into a 25 mL single-necked flask in sequence and dissolve with DMF (5 mL). Heat in an oil bath at 85 °C overnight. Under low temperature conditions, add water (50 mL) for dilution, extract with EA (100 mL × 3), combine the organic phases, wash with saturated brine (50 mL), dry over anhydrous sodium sulfate, filter, evaporate the filtrate to dryness, and purify by silica gel column chromatography (eluent PE / EA (v / v) = 4 / 1 - 2 / 1) to obtain 0.43 g of a yellow solid, which is the target product (yield 60.0%). LCMS: m / z = 327.10 [M+H] + 。 1 1H NMR (400 MHz, CDCl 3)δ8.38(d, J = 2.1 Hz, 1H), 8.26–8.18(m, 2H), 8.01(td, J = 8.4, 2.5 Hz, 1H), 7.20(d, J = 2.0 Hz, 1H), 7.12(dd, J = 8.4, 2.7 Hz, 1H), 4.17(t, J = 5.4 Hz, 2H), 3.76(dd, J = 8.6, 6.0 Hz, 2H), 3.63(dd, J = 8.8, 1.7 Hz, 2H), 2.93(t, J = 5.0 Hz, 4H), 2.86(s, 2H), 2.42(dd, J = 8.3, 2.7 Hz, 2H).

[0324] Intermediate 5: 5-(Azetidin-3-yloxy)-2-methoxypyridine dihydrochloride

[0325]

[0326] Step 1: tert-Butyl N-Boc-3-((methylsulfonyl)oxy)azetidine-1-carboxylate

[0327] Under ice-water bath conditions, N-Boc-3-hydroxyazetidine (4.00 g, 23.1 mmol) was dissolved in DCM (50 mL), 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 mixture was stirred at room temperature for 2 h. The reaction was monitored by TLC (PE / EA (v / v) = 2 / 1, Rf = 0.30), and the raw material reacted completely. The reaction was quenched by slowly adding water, extracted with DCM (20 mL × 3), washed with saturated NaHCO3 solution, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (eluent: PE / EA (v / v) = 8 / 1 - 3 / 1) to obtain 4.41 g of a colorless viscous liquid, with a yield of 76%. 1 1H NMR (400 MHz, 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).

[0328] Step 2: N-Boc-3-((6-methoxypyridin-3-yl)oxy)azetidine

[0329] 5-Hydroxy-2-methoxypyridine (2.00 g, 16.0 mmol) and N-Boc-3-((methylsulfonyl)oxy)azetidine (4.82 g, 19.2 mmol) were dissolved in DMF (30 mL). t-BuOK (3.59 g, 32.0 mmol) was added slowly, and the mixture was stirred for 10 min. The temperature was raised to 50 °C and the reaction was stirred for 12 h. The reaction was monitored by TLC (PE / EA (v / v) = 3 / 1, Rf = 0.29), and the raw materials reacted completely. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with EA (20 mL × 3), washed with water, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (eluent: PE / EA (v / v) = 10 / 1 - 4 / 1) to obtain 2.03 g of a yellowish brown solid with a yield of 45%. LC-MS: m / z = 281.3 [M+H] + 。 1 H NMR (400 MHz, CDCl3) δ 7.57 (d, J = 2.9 Hz, 1H), 7.17–7.06 (m, 1H), 6.67 (d, J = 8.9 Hz, 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).

[0330] Step 3: 5-(Azetidin-3-yloxy)-2-methoxypyridine dihydrochloride

[0331] To a 25 mL single-necked flask were successively added N-Boc-3-((6-methoxypyridin-3-yl)oxy)azetidine (600 mg, 0.21 mmol) and HCl / EA (3N, 2.5 mL). The mixture was stirred at rt for 1 h, and the reaction solution was rotary evaporated to a pale yellow solid, which was directly used in the next step. LC-MS: m / z = 181.1 [M+H] + Intermediate 6: 1-((6-Methoxypyridin-3-yl)methyl)piperazine dihydrochloride

[0332]

[0333] Step 1: tert-Butyl 4-((6-methoxypyridin-3-yl)methyl)piperazine-1-carboxylate

[0334] In a 25 mL single-necked flask, 6-methoxypyridine-3-carbaldehyde (600 mg, 4.38 mmol), tert-butyl piperazine-1-carboxylate (980 mg, 5.26 mmol), sodium triacetoxyborohydride (2.8 g, 13 mmol), and 1,2-dichloroethane (12 mL) were successively added, and the mixture was stirred at room temperature for 5 h. After the reaction was completed, the mixture was filtered, the filtrate was concentrated by rotary evaporation, and the residue was purified by silica gel column chromatography (PE / EA (v / v) = 1 / 1) to obtain 1.32 g of a yellowish-brown oil, which was the target product (yield 98.1%, Rf = 0.1 (PE / EA (v / v = 10 / 1)). LC-MS: m / z = 308.60 [M+H] + 。 1 1H NMR (400 MHz, CDCl3) δ 8.03 (d, J = 1.8 Hz, 1H), 7.55 (dd, J = 8.5, 2.3 Hz, 1H), 6.71 (d, J = 8.5 Hz, 1H), 3.91 (s, 3H), 3.46 (s, 2H), 3.44–3.38 (m, 4H), 2.44–2.33 (m, 4H), 1.44 (s, 9H).

[0335] Step 2: 1-((6-Methoxypyridin-3-yl)methyl)piperazine hydrochloride

[0336] In a 50 mL single-necked flask, tert-butyl 4-((6-methoxypyridin-3-yl)methyl)piperazine-1-carboxylate (1.32 g, 4.29 mmol) and hydrochloric acid ethyl acetate solution (25 ml, 4 mol / L) were successively added, and the mixture was stirred at room temperature overnight. The solvent was directly concentrated by rotary evaporation to obtain a viscous oily substance, which was dried in an oven at 60 °C under vacuum to obtain 1.2 g of a white solid, which was the target product, with a yield of 100% and Rf = 0.0 (PE / EA = 1:1). LC-MS: m / z = 208.20 [M-2HCl]+.

[0337] Example 1: tert-Butyl 5-((3-cyano-4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl)oxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

[0338]

[0339] Step 1: tert-Butyl 5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

[0340] Under ice bath conditions, in a 50 mL single-necked flask, LiAlH4 (0.35 g, 9.2 mmol) was slowly added to anhydrous THF (15 mL). After stirring for 15 min, tert-butyl 5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (1.03 g, 4.57 mmol) was slowly added, and the mixture was stirred at room temperature for 2 h. The reaction was monitored by TLC (PE:EA = 4:1, iodine fuming, Rf = 0.18) until completion. The reaction was quenched with saturated Na2SO4 solution, filtered by suction, and the filtrate was concentrated to obtain 0.89 g of a brownish-yellow viscous liquid (yield 86%), which was the target product. 1 1H NMR (400 MHz, CDCl3) δ 4.34–4.23 (m, 1H), 3.54–3.45 (m, 2H), 3.38–3.28 (m, 2H), 2.81–2.64 (m, 1H), 2.62–2.52 (m, 2H), 2.20–2.12 (m, 2H), 1.75–1.57 (m, 1H), 1.45 (s, 9H).

[0341] Step 2: tert-Butyl 5-((methylsulfonyl)oxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

[0342] Under ice bath conditions, in a 50 mL single-necked flask, tert-butyl 5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (0.50 g, 2.2 mmol) was dissolved in DCM (20 mL). NaH (0.18 g, 4.5 mmol) was slowly added, and the mixture was stirred for 10 min. Methylsulfonyl chloride (0.2 mL, 3 mmol) was slowly added, and the mixture was stirred at room temperature for 3 h. The reaction was monitored by TLC (PE:EA = 4:1, iodine fuming) until completion. The reaction was quenched by slowly adding water, and the mixture was extracted with DCM (20 mL × 3). The organic phases were combined, washed with water, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography (eluent PE:EA = 10:1 - 5:1) to obtain 0.48 g of a colorless viscous liquid (yield 71%), which was the target product.

[0343] Step 3: tert-Butyl 5-((3-cyano-4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl)oxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

[0344] Under nitrogen protection, 6-hydroxy-4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Intermediate 1, 35 mg, 0.082 mmol), K2CO3 (46 mg, 0.330 mmol), DMF (3 mL), tert-butyl 5-((methylsulfonyl)oxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (51 mg, 0.167 mmol) were added to a 10 mL single-necked flask, and the reaction was heated at 60 °C in an oil bath. TLC showed that the reaction was complete. The reaction was quenched by adding 15 mL of water, and the mixture was extracted with EA (30 mL × 2). The organic phases were combined, washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated by rotary evaporation. The residue was purified by silica gel column chromatography (pure DCM - DCM:MeOH (v / v = 10:1)), and 38 mg of a pale yellow solid (yield 73%) was obtained, which was the target product. LC-MS (ES-API): m / z = 636.30 [M+H] + 。 1 H NMR (400 MHz, CDCl3) δ 8.51 (d, J = 4.0 Hz, 1H), 8.29 (d, J = 1.8 Hz, 1H), 8.18 (s, 1H), 8.05 (s, 1H), 7.65 (dd, J = 10.8, 7.4 Hz, 2H), 7.22–7.17 (m, 1H), 7.12 (d, J = 7.7 Hz, 1H), 7.02 (s, 1H), 6.76 (d, J = 8.9 Hz, 1H), 4.08 (d, J = 12.9 Hz, 2H), 3.55–3.44 (m, 4H), 3.23 (s, 2H), 2.93 (s, 2H), 2.92–2.87 (m, 2H), 2.25 (dd, J = 14.1, 5.7 Hz, 2H), 1.94–1.83 (m, 3H), 1.68–1.60 (m, 5H), 1.46 (s, 9H).

[0345] Example 2: 4-(6-(4-Hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)-6-((2-methyloctahydrocyclopenta[c]pyrrol-5-yl)oxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0346]

[0347] Step 1: 4-(6-(4-Hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)-6-((octahydrocyclopenta[c]pyrrol-5-yl)oxy)pyrazolo[1,5-a]pyridine-3-carbonitrile trihydrochloride

[0348] In a 10 mL single-necked flask, add tert-butyl 5-((3-cyano-4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl)oxy)hexahydrocyclopentadiene[c]pyrrole-2(1H)-carboxylate (41 mg, 0.065 mmol), hydrochloric acid / ethyl acetate solution (2 mL, 8 mmol, 4 mol / L), and stir at room temperature for 1 h. TLC shows that the reaction is complete. The reaction solution is directly evaporated to dryness, and the residue is dried at 60 °C to obtain 39.25 mg of a yellowish-white solid, which is the target product. LC-MS (ES-API): m / z = 536.20 [M - 3HCl + H] + 。

[0349] Step 2: 4-(6-(4-Hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)-6-((2-methyloctahydrocyclopentadiene[c]pyrrol-5-yl)oxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0350] In a 10 mL single-necked flask, add 4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)-6-((octahydrocyclopentadiene[c]pyrrol-5-yl)oxy)pyrazolo[1,5-a]pyridine-3-carbonitrile trihydrochloride (40 mg, 0.066 mmol), paraformaldehyde (10 mg, 0.333 mmol), dissolve in DCE (4 mL), then add STAB (44 mg, 0.202 mmol), and heat the reaction overnight in an oil bath at 50 °C. TLC shows that the reaction is complete. Evaporate directly to dryness, and the residue is purified by silica gel column chromatography (eluent pure DCM - DCM:MeOH (v / v = 10:1)) to obtain 10 mg of a yellowish-white solid (yield 28%), which is the target product. LC-MS (ES-API): m / z = 500.30 [M + H] + 。 1 H NMR (400 MHz, CDCl3) δ 8.52 (d, J = 4.3 Hz, 1H), 8.28 (s, 1H), 8.19 (s, 1H), 8.11 (s, 1H), 7.65 (t, J = 8.2 Hz, 2H), 7.22–7.17 (m, 1H), 7.13 (d, J = 7.7 Hz, 1H), 7.01 (s, 1H), 6.77 (d, J = 8.9 Hz, 1H), 4.08 (d, J = 13.0 Hz, 2H), 3.52–3.44 (m, 2H), 3.26–3.14 (m, 2H), 3.13–3.06 (m, 2H), 2.94 (s, 2H), 2.84 (s, 2H), 2.69 (s, 3H), 2.27–2.10 (m, 4H), 1.69–1.60 (m, 6H).

[0351] Example 3: 4-(6-(4-Hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)-6-((3-methoxybicyclo[3.1.0]hexan-6-yl)methoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0352]

[0353] Step 1: Ethyl 3-hydroxybicyclo[3.1.0]hexane-6-carboxylate

[0354] Into a 50 mL two-necked flask were successively added ethyl 3-oxobicyclo[3.1.0]hexane-6-carboxylate (370 mg, 2.20 mmol), MeOH (10 mL). Under N2 protection, the mixture was stirred at -5 °C, and then NaBH4 (105 mg, 2.78 mmol) was added. The stirring was maintained at this low temperature for 1 h. The reaction was quenched by adding 15 mL of ammonium chloride solution. After concentration under reduced pressure, 20 mL of water was added, and the mixture was extracted with EA (15 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the residue was purified by silica gel column chromatography (PE / EA = 5:1) to obtain 270 mg of an oily liquid (yield 72%). LC-MS: m / z = 171.2 [M+H] + 。 1 1H NMR (400 MHz, CDCl3) δ 4.38 (t, J = 6.4 Hz, 1H), 4.09 (q, J = 7.1 Hz, 2H), 2.15 (m, 2H), 1.98 (t, J = 2.9 Hz, 1H), 1.88 (m, 3H), 1.84 (s, 1H), 1.25 (m, 3H).

[0355] Step 2: Ethyl 3-methoxybicyclo[3.1.0]hexane-6-carboxylate

[0356] Into a 50 mL single-necked flask were successively added ethyl 3-hydroxybicyclo[3.1.0]hexane-6-carboxylate (270 mg, 1.59 mmol), Ag2O (2230 mg, 9.62 mmol), and CH3I (15 mL, 241 mmol). The mixture was heated and stirred overnight in an oil bath at 45 °C. The reaction solution was filtered, washed with EA (10 mL × 3), the filtrate was concentrated, and the residue was purified by silica gel column chromatography (PE / EA = 3:1) to obtain 246 mg of an oily liquid (yield 80%). LC-MS: m / z = 185.2 [M+H] + 。 11H NMR (400 MHz, CDCl3) δ 4.11 - 4.04 (m, 2H), 3.81 - 3.75 (m, 1H), 3.17 (s, 3H), 1.99 (m, 4H), 1.84 (m, 2H), 1.80 (t, J = 2.9 Hz, 1H), 1.23 (t, J = 6.2 Hz, 3H).

[0357] Step 3: (3 - Methoxybicyclo[3.1.0]hexan - 6 - yl)methanol

[0358] To a 50 mL two - necked flask, add ethyl 3 - methoxybicyclo[3.1.0]hexane - 6 - carboxylate (246 mg, 1.34 mmol), THF (10 mL) under N2 protection. At - 10 °C, a solution of diisobutylaluminum hydride in THF (1 N) (4 mL) was slowly injected and added dropwise within 10 min, then stirred at rt overnight. After TLC detection showed the reaction was complete, 1 N HCl was slowly injected at low temperature to adjust the pH of the aqueous phase to 4 - 5. The aqueous phase was extracted with EA (20 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was separated by silica gel column chromatography with PE / EA = 3:1 as the eluent to obtain 146 mg of an oily liquid (yield 76%). LC - MS: m / z = 142.3 [M] + . 1 1H NMR (400 MHz, CDCl3) δ 3.80 (t, J = 6.1 Hz, 1H), 3.37 (d, J = 7.1 Hz, 2H), 3.18 (s, 3H), 1.99–1.92 (m, 2H), 1.90 - 1.85 (m, 2H), 1.24 (m, 1H), 1.17 (m, 2H).

[0359] Step 4: 6 - (Bromomethyl)-3 - methoxybicyclo[3.1.0]hexane

[0360] To a 25 mL single - necked flask, add (3 - methoxybicyclo[3.1.0]hexan - 6 - yl)methanol (93 mg, 0.65 mmol), DCM (4.0 mL). At - 5 °C, PBr3 (0.15 mL, 1.60 mmol) was slowly added. After addition, the reaction continued for 1.5 h. After TLC showed the reaction was complete, 3.0% potassium carbonate solution (25 mL) was added. The organic phase was collected, and the aqueous phase was extracted with DCM (10 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and directly used for the next step of the reaction.

[0361] Step 5: 4 - (6 - (4 - Hydroxy - 4 - (pyridin - 2 - ylmethyl)piperidin - 1 - yl)pyridin - 3 - yl)-6 - ((3 - methoxybicyclo[3.1.0]hexan - 6 - yl)methoxy)pyrazolo[1,5 - a]pyridine - 3 - carbonitrile

[0362] To a 10 mL two-necked flask, 6-hydroxy-4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Intermediate 1, 31 mg, 0.073 mmol), K2CO3 (43 mg, 0.31 mmol), DMF (3.0 mL), and 6-(bromomethyl)-3-methoxybicyclo[3.1.0]hexane (0.20 mmol) were added successively. Under N2 protection, the reaction mixture was heated and stirred at 36 °C for 4 h. The reaction solution was added to EA (25 mL), washed with water (15 mL × 3), the combined aqueous phases were extracted with EA (10 mL), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by silica gel column chromatography using DCM / MeOH (v / v = 15:1) as the eluent to obtain 22 mg of a pale yellow solid with a yield of 55%. LC-MS: m / z = 551.2 [M+H] + 。 1 H NMR (400 MHz, CDCl3) δ 8.52 (d, J = 4.2 Hz, 1H), 8.30 (d, J = 2.3 Hz, 1H), 8.17 (s, 1H), 8.05 (d, J = 2.0 Hz, 1H), 7.70–7.60 (m, 2H), 7.19 (dd, J = 7.1, 5.6 Hz, 1H), 7.12 (m, 2H), 6.77 (d, J = 8.9 Hz, 1H), 4.09 (m, 2H), 3.83 (m, 1H), 3.78 (d, J = 7.1 Hz, 2H), 3.56–3.42 (m, 2H), 3.20 (s, 3H), 2.94 (s, 2H), 1.99 (m, 4H), 1.68–1.61 (m, 5H), 1.51–1.45 (m, 1H), 1.34 (m, 2H). HPLC: 93.09%.

[0363] Example 4: 4-(6-(4-Hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)-6-(2-(3-hydroxybicyclo[3.1.0]hexan-3-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0364]

[0365] Step 1: Ethyl 2-(3-hydroxybicyclo[3.1.0]hexan-3-yl)acetate

[0366] Add Zn powder (930 mg, 14.22 mmol) to a 50 mL single-necked flask. Under N₂ protection, add anhydrous THF (20 mL) and TMSCl (0.20 mL, 1.6 mmol), and stir the reaction under reflux in an oil bath for 1 h. Bicyclo[3.1.0]hexan-3-one (760 mg, 7.91 mmol) and ethyl bromoacetate (1.10 mL, 9.92 mmol) are dissolved in THF (2 mL) and slowly added to the reaction flask. After addition, maintain reflux stirring and react for 8 h. After the reaction solution is cooled, filter it, wash the filter cake with EA (10 mL × 5), and concentrate the filtrate. The residue is separated by silica gel column chromatography with PE / EA (v / v = 6 / 1) as the eluent to obtain 830 mg of an oily liquid with a yield of 57%. LC-MS: m / z = 185.2 [M+H] + 。 1 ¹H NMR (400 MHz, CDCl₃) δ 4.15 (q, J = 7.1 Hz, 2H), 3.35 (s, 1H), 2.52 (s, 2H), 1.89 (m, 4H), 1.26 (m, 5H), 0.81 (m, 1H), 0.47 (m, 1H).

[0367] Step 2: 3-(2-Hydroxyethyl)bicyclo[3.1.0]hexan-3-ol

[0368] Add LiAlH₄ (211 mg, 5.56 mmol) to a 50 mL single-necked flask. Under N₂ protection, add THF (5 mL). At -10 °C, 2-(3-hydroxybicyclo[3.1.0]hexan-3-yl)ethyl acetate (390 mg, 2.12 mmol) dissolved in THF (5 mL) is slowly added. After addition, continue stirring and reacting for 1 h. Slowly add 10 mL of saturated ammonium chloride solution to quench the reaction at low temperature. Extract with EA (15 mL × 3), combine the organic phases, dry over sodium sulfate, filter, concentrate the filtrate. The residue is separated by silica gel column chromatography with PE / EA (v / v = 2 / 1) as the eluent to obtain 75 mg of an oily liquid with a yield of 25%. LC-MS: m / z = 165.2 [M+Na] + , 1 ¹H NMR (400 MHz, CDCl₃) δ 3.84 (t, J = 5.6 Hz, 2H), 3.05 (s, 1H), 2.93 (s, 1H), 1.94 (m, 2H), 1.83 (d, J = 13.8 Hz, 2H), 1.75 (t, J = 5.7 Hz, 2H), 1.33–1.21 (m, 2H), 0.71 (q, J = 4.0 Hz, 1H), 0.48 (m, 1H).

[0369] Step 3: 2-(3-Hydroxybicyclo[3.1.0]hexan-3-yl)ethyl methanesulfonate

[0370] To a 25 mL single-necked flask, 3-(2-hydroxyethyl)bicyclo[3.1.0]hexan-3-ol (102 mg, 0.72 mmol), DCM (4 mL), Et3N (0.15 mL, 1.1 mmol) were successively added. At -5 °C, MsCl (0.09 mL, 1 mmol) was slowly added dropwise. After addition, the reaction mixture was stirred for 1.5 h. At low temperature, the reaction solution was added to H2O (20 mL), and extracted with DCM (15 mL × 3). The combined organic phases were dried over sodium sulfate, filtered, and the filtrate was concentrated. The residue was separated by silica gel column chromatography using PE / EA (v / v = 2 / 1) as the eluent to obtain 108 mg of an oily liquid with a yield of 68%. 1 1H NMR (400 MHz, CDCl3) δ 4.38 (t, J = 6.8 Hz, 2H), 3.14 (s, 1H), 3.01 (s, 3H), 2.00 (m, 4H), 1.81 (s, 1H), 1.78 (s, 1H), 1.31 (m, 2H), 0.71 (m, 1H), 0.50 (m, 1H).

[0371] Step 4: 4-(6-(4-Hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)-6-(2-(3-hydroxybicyclo[3.1.0]hexan-3-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0372] To a 10 mL two-necked flask, 6-hydroxy-4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Intermediate 1, 32 mg, 0.075 mmol), K2CO3 (37 mg, 0.27 mmol), DMF (3.0 mL) were successively added. Under N2 protection, the reaction mixture was heated and stirred at 50 °C for 4 h. The reaction solution was added to EA (25 mL), washed with water (10 mL × 3), the aqueous phase was extracted with EA (10 mL), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was separated by silica gel column chromatography using DCM / MeOH = 20:1 as the eluent to obtain 30 mg of a pale yellow solid with a yield of 73%. LC-MS: m / z = 551.3 [M+H] + 。 11H NMR (400 MHz, CDCl3) δ 8.51 (d, J = 4.2 Hz, 1H), 8.29 (d, J = 2.2 Hz, 1H), 8.18 (s, 1H), 8.12 (d, J = 1.9 Hz, 1H), 7.70–7.58 (m, 2H), 7.22–7.15 (m, 1H), 7.12 (d, J = 7.7 Hz, 1H), 7.05 (d, J = 2.0 Hz, 1H), 6.76 (d, J = 8.9 Hz, 1H), 4.19 (t, J = 6.4 Hz, 2H), 4.13–4.04 (m, 2H), 3.54–3.41 (m, 2H), 2.94 (m, 3H), 2.06 (m, 4H), 1.85 (s, 1H), 1.64 (m, 4H), 1.36–1.30 (m, 2H), 1.29–1.22 (m, 2H), 0.75 (dd, J = 8.2, 4.0 Hz, 1H), 0.51 (m, 1H).

[0373] Example 5: 4-(6-(4-Hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)-6-(2-(((3R,3aR,6R,6aR)-6-methoxyhexahydrofuro[3,2-b]furan-3-yl)oxy)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0374]

[0375] Step 1: (3R, 3aR, 6R, 6aR)-6-Methoxyhexahydrofuro[3,2-b]furan-3-ol

[0376] Add dehydrated mannitol (11.0 g, 75.3 mmol), Ag2O (13.2 g, 57.0 mmol), DCM (120 mL), and CH3I (9.20 mL, 148 mmol) to a 250 mL single-necked flask, and stir the reaction mixture at 40 °C for 20 h. After the reaction solution is cooled, filter it through diatomaceous earth, wash the filter cake with EA (10 mL × 5), and concentrate the filtrate. Separate the residue by silica gel column chromatography with PE / EA = 1:1 as the eluent to obtain 6.23 g of a white solid with a yield of 52%. 1 1H NMR (400 MHz, CDCl3) 4.57 (t, J = 4.8 Hz, 1H), 4.51 (t, J = 5.2 Hz, 1H), 4.28 (m, 1H), 4.08 (dd, J = 8.6, 6.5 Hz, 1H), 4.02 - 3.91 (m, 2H), 3.73 - 3.64 (m, 2H), 3.47 (s, 3H), 2.84 (d, J = 8.5 Hz, 1H).

[0377] Step 2: Ethyl 2-(((3R,3aR,6R,6aR)-6-methoxyhexahydrofuro[3,2-b]furan-3-yl)oxy)acetate

[0378] Add NaH (88 mg, 2.2 mmol) to a 50 mL single-necked flask. Under N2 protection, add THF (8 mL). At -4 °C, (3R,3aR,6R,6aR)-6-methoxyhexahydrofuro[3,2-b]furan-3-ol (263 mg, 1.64 mmol) dissolved in THF (4 mL) was slowly added. After addition, stir the reaction at rt for 2 - 3 h. The reaction solution was reacted at -4 °C, and ethyl bromoacetate (0.21 mL, 1.9 mmol) was slowly added. After addition, stir at rt for 3 h. Add EA (5 mL) and 10 mL of ammonium chloride solution to the reaction solution. Separate the aqueous phase and extract it with EA (15 mL × 3). Combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate the filtrate, and separate the residue by silica gel column chromatography with PE / EA (v / v = 1 / 1) as the eluent to obtain 146 mg of an oily liquid with a yield of 36%. LC-MS: m / z = 247.2 [M+H] + 。 1 1H NMR (400 MHz, CDCl3) δ 4.58 (m, 2H), 4.25 (m, 2H), 4.21–4.12 (m, 3H), 4.08 (m, 2H), 3.98–3.90 (m, 1H), 3.79 (t, J = 8.4 Hz, 1H), 3.70 (t, J = 8.5 Hz, 1H), 3.45 (s, 3H), 1.28 (t, J = 7.1 Hz, 3H).

[0379] Step 3: 2-(((3R,3aR,6R,6aR)-6-methoxyhexahydrofuro[3,2-b]furan-3-yl)oxy)ethan-1-ol

[0380] Add LiAlH4 (53 mg, 1.40 mmol) to a 50 mL single-necked flask in sequence. Under N2 protection, add THF (5 mL). At -65 °C, 2-(((3R,3aR,6R,6aR)-6-methoxyhexahydrofuro[3,2-b]furan-3-yl)oxy)ethyl acetate (135 mg, 0.55 mmol) dissolved in THF (5 mL) was slowly added. After addition, continue to stir the reaction for 1 h. Slowly add 10 mL of saturated ammonium chloride solution to quench the reaction at low temperature. Extract with EA (15 mL × 3). Combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate the filtrate, and separate the residue by silica gel column chromatography with PE / EA (v / v = 1 / 6) as the eluent to obtain 65 mg of an oily liquid with a yield of 58%. LC-MS: m / z = 205.1 [M+H] + 。 11H NMR (400 MHz, CDCl3) δ 4.59 (m, 2H), 4.10–4.02 (m, 3H), 3.98–3.90 (m, 1H), 3.78–3.72 (m, 2H), 3.72–3.63 (m, 4H), 3.46 (s, 3H), 2.84 (s, 1H).

[0381] Step 4: 2-(((3R,3aR,6R,6aR)-6-Methoxyhexahydrofuro[3,2-b]furan-3-yl)oxy)ethyl methanesulfonate

[0382] To a 25 mL single-necked flask were successively added 2-(((3R,3aR,6R,6aR)-6-methoxyhexahydrofuro[3,2-b]furan-3-yl)oxy)ethan-1-ol (42 mg, 0.21 mmol), DCM (3 mL), Et3N (0.05 mL, 0.40 mmol). At -5 °C, MsCl (0.06 mL, 0.8 mmol) was slowly added dropwise. After the addition, the reaction mixture was stirred for 10 h. At low temperature, H2O (15 mL) was added to the reaction solution, and the mixture was extracted with DCM (15 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was separated by silica gel column chromatography using PE / EA (v / v = 1 / 3) as the eluent to obtain 46 mg of an oily liquid with a yield of 79%. 1 1H NMR (400 MHz, CDCl3) δ 4.55 (m, 2H), 4.36 (t, J = 4.5 Hz, 2H), 4.10–4.04 (m, 1H), 4.00 (m, 2H), 3.91 (m, 2H), 3.63 - 3.76 (m, 3H), 3.43 (s, 3H), 3.04 (s, 3H).

[0383] Step 5: 4-(6-(4-Hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)-6-(2-((((3R,3aR,6R,6aR)-6-methoxyhexahydrofuro[3,2-b]furan-3-yl)oxy)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0384] To a 10 mL two-necked flask, 6-hydroxy-4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Intermediate 1, 32 mg, 0.075 mmol), K2CO3 (28 mg, 0.20 mmol), DMF (3.0 mL), and 2-(((3R,3aR,6R,6aR)-6-methoxyhexahydrofuro[3,2-b]furan-3-yl)oxy)ethyl methanesulfonate (37 mg, 0.13 mmol) were added successively. Under N2 protection, the mixture was heated and stirred at 50 °C for 8 h. The reaction mixture was added to EA (20 mL), washed with water (10 mL × 3), the combined aqueous phases were extracted with EA (10 mL), the combined organic phases were dried over sodium sulfate, filtered, and the filtrate was concentrated. The residue was separated by silica gel column chromatography using DCM / MeOH (v / v = 20 / 1) as the eluent to obtain 15 mg of a pale yellow solid with a yield of 32%. LC-MS: m / z = 613.3 [M+H] + 。 1 H NMR (400 MHz, CDCl3) δ 8.51 (d, J = 4.3 Hz, 1H), 8.29 (d, J = 2.2 Hz, 1H), 8.18 (s, 1H), 8.15 (d, J = 1.9 Hz, 1H), 7.66 (m, 2H), 7.22–7.16 (m, 1H), 7.12 (m, 2H), 6.76 (d, J = 8.9 Hz, 1H), 4.65–4.55 (m, 2H), 4.18 (m, 3H), 4.13–3.99 (m, 6H), 3.98–3.87 (m, 2H), 3.73 (m, 2H), 3.54–3.45 (m, 2H), 3.46 (s, 3H), 2.94 (s, 2H), 1.65 (m, 4H).

[0385] Example 6: tert-Butyl 5-(2-((3-cyano-4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl)oxy)ethyl)-5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

[0386]

[0387] Step 1: tert-Butyl 5-(2-ethoxy-2-oxoethyl)-5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

[0388] Zinc powder (542 mg, 8.30 mmol) was added to a 50 mL two-necked flask. After connecting a reflux condenser, nitrogen was displaced, and then anhydrous THF (8 mL) and TMSCl (0.1 mL, 0.8 mmol) were added. The mixture was refluxed at 80 °C for 40 min. Then, tert-butyl 5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (1.0 g, 4.40 mmol) and ethyl dibromoacetate (920 mg, 5.51 mmol) dissolved in THF (10 mL) were slowly added. After the addition, the reaction was continued in an oil bath at 80 °C. After the reaction was completed as detected by TLC, the reaction solution was filtered to remove Zn powder, and the filtrate was directly concentrated and subjected to silica gel column chromatography. The eluent was PE:EA (v / v = 5 / 1), and 683 mg of a colorless liquid was obtained as the product. 1 1H NMR (400 MHz, CDCl3) δ 4.19 (q, J = 7.1 Hz, 2H), 3.69 (s, 1H), 3.55 (dd, J = 11.0, 8.2 Hz, 2H), 3.36 (dd, J = 11.1, 3.7 Hz, 2H), 2.74 - 2.61 (m, 2H), 2.57 (s, 2H), 1.91 (dd, J = 13.8, 8.1 Hz, 2H), 1.80 (dd, J = 13.8, 4.6 Hz, 2H), 1.45 (s, 9H), 1.29 (t, J = 7.1 Hz, 3H).

[0389] Step 2: tert-butyl 5-hydroxy-5-(2-hydroxyethyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

[0390] Lithium aluminum hydride (71 mg, 1.81 mmol) and THF (4 mL) were added to a 50 mL two-necked flask. After nitrogen was displaced, tert-butyl 5-(2-ethoxy-2-oxoethyl)-5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (230 mg, 0.73 mmol) dissolved in THF (6 mL) was added dropwise at -45 °C, and the reaction was carried out at this temperature. After the reaction was completed as detected by TLC, water was added to quench the reaction. The mixture was extracted with EA (30 mL × 2), and the organic phase was washed with water (10 mL × 3), saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and subjected to silica gel column chromatography. The eluent was PE:EA (v / v = 1 / 1 - 0 / 1), and 100 mg of a colorless liquid was obtained as the product. 1 1H NMR (400 MHz, CDCl3) δ 3.92 (t, J = 5.5 Hz, 2H), 3.50 (dd, J = 11.2, 8.1 Hz, 2H), 3.41 (dd, J = 11.1, 3.1 Hz, 2H), 2.73 - 2.67 (m, 2H), 2.02 (dd, J = 13.7, 8.5 Hz, 2H), 1.85 - 1.81 (m, 2H), 1.76 (dd, J = 13.7, 3.9 Hz, 2H), 1.47 (s, 9H).

[0391] Step 3: tert-Butyl 5-hydroxy-5-(2-((methylsulfonyl)oxy)ethyl)hexahydrocyclopenta[c]pyrrole-2((1H)-carboxylate

[0392] Add tert-butyl 5-hydroxy-5-(2-hydroxyethyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (140 mg, 0.52 mmol) to a 10 mL single-necked flask, add dichloromethane (2 mL) to dissolve it, add triethylamine (0.1 mL, 0.7 mmol), add methanesulfonyl chloride (0.08 mL, 0.9 mmol) under ice bath, and react at room temperature. After the reaction of the raw materials was detected by TLC, add 5 mL of water to the reaction solution, extract with DCM (15 mL × 2), combine the organic phases, wash with water (5 mL × 2), wash with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate the filtrate, and perform silica gel column chromatography. The eluent is PE:EA (v / v = 2:1 - 1:1), and 60 mg of a pale yellow liquid is obtained as the product. 1 HNMR(400MHz,CDCl3)δ4.44(t,J=6.7Hz,2H),3.51-3.43(m,2H),3.43-3.35(m,2H),3.02(s,3H),2.81-2.70(m,2H),2.16(s,1H),2.04-1.97(m,4H),1.73(d,J=11.6Hz,2H),1.45(s,9H).

[0393] Step 4: tert-Butyl 5-(2-((3-cyano-4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl)oxy)ethyl)-5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

[0394] 6-Hydroxy-4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Intermediate 1, 28 mg, 0.066 mmol), tert-butyl 5-hydroxy-5-(2-((methylsulfonyl)oxy)ethyl)hexahydrocyclopenta[c]pyrrole-2((1H)-carboxylate (30 mg, 0.086 mmol), potassium carbonate (16 mg, 0.11 mmol), and DMF (0.6 mL) were added to a 5 mL single-necked flask. After dissolution, the reaction was carried out at 70 °C in an oil bath. After the reaction was completed as detected by TLC, 5 mL of water was added to the reaction solution, and the mixture was extracted with EA (15 mL × 2). The combined organic phases were washed with water (5 mL × 3), washed with saturated brine (5 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and subjected to silica gel column chromatography. The eluent was DCM:MeOH (v / v = 20 / 1), and 30 mg of a yellow solid was obtained as the product. LC-MS: m / z = 680.40 [M+H] + 。 1 H NMR (400 MHz, CDCl3) δ 8.52 (d, J = 4.7 Hz, 1H), 8.30 (d, J = 2.3 Hz, 1H), 8.19 (s, 1H), 8.15 (d, J = 2.0 Hz, 1H), 8.02 (s, 1H), 7.70 - 7.61 (m, 2H), 7.13 (d, J = 7.7 Hz, 1H), 7.06 (d, J = 1.9 Hz, 1H), 6.77 (d, J = 9.1 Hz, 1H), 4.24 (t, J = 6.2 Hz, 2H), 4.09 (d, J = 13.3 Hz, 2H), 3.48 (d, J = 8.0 Hz, 4H), 3.41 (d, J = 8.2 Hz, 2H), 2.95 (d, J = 6.6 Hz, 4H), 2.88 (s, 2H), 2.77 (s, 2H), 2.13 - 2.02 (m, 4H), 1.76 (d, J = 13.3 Hz, 2H), 1.45 (s, 9H).

[0395] Example 7: 6-(Bicyclo[3.1.0]hex-3-yloxy)-4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0396]

[0397] Step 1: Bicyclo[3.1.0]hexan-3-ol

[0398] To a 50 mL two-necked flask, bicyclo[3.1.0]hexan-3-one (415 mg, 4.32 mmol), MeOH (15 mL) were added successively. Under a N2 atmosphere, NaBH4 (193 mg, 5.10 mmol) was added, and the mixture was stirred at -5 °C for 3 h. The reaction solution was concentrated, water (20 mL) was added, and it was extracted with EA (25 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was separated by silica gel column chromatography with PE / EA = 5:1 as the eluent to obtain 225 mg of an oily liquid with a yield of 53%. 1 1H NMR (400 MHz, CDCl3) δ 4.36 (m, 1H), 2.13 - 2.04 (m, 2H), 1.73 (s, 1H), 1.69 (s, 1H), 1.46 (s, broad, 1H), 1.29 - 1.24 (m, 2H), 0.55 - 0.43 (m, 2H).

[0399] Step 2: Bicyclo[3.1.0]hexan-3-yl methanesulfonate

[0400] To a 25 mL single-necked flask, bicyclo[3.1.0]hexan-3-ol (202 mg, 2.06 mmol), DCM (6 mL), and Et3N (0.45 mL, 3.2 mmol) were added successively. At -5 °C, MsCl (0.21 mL, 2.70 mmol) was slowly added dropwise. After addition, the mixture was stirred for 3 h. At low temperature, H2O (20 mL) was added to the reaction solution, and it was extracted with DCM (15 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by silica gel column chromatography with PE / EA (v / v = 5 / 1) as the eluent to obtain 300 mg of a white solid with a yield of 82%. 1 1H NMR (400 MHz, CDCl3) δ 5.18 (t, J = 6.6 Hz, 1H), 2.95 (s, 3H), 2.33 - 2.19 (m, 2H), 2.09 (d, J = 15.2 Hz, 2H), 1.39 - 1.32 (m, 2H), 0.54 (m, 1H), 0.43 (m, 1H).

[0401] Step 3: 6-(Bicyclo[3.1.0]hexan-3-yloxy)-4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0402] To a 10 mL two-necked flask, 6-hydroxy-4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Intermediate 1, 26 mg, 0.061 mmol), K2CO3 (27 mg, 0.20 mmol), DMF (3.0 mL), and bicyclo[3.1.0]hexan-3-yl methanesulfonate (50 mg, 0.23 mmol) were added successively. Under N2 protection, the mixture was heated and stirred at 85 °C for 10 h. The reaction solution was added with EA (30 mL), washed with water (10 mL × 3), the aqueous phase was extracted with EA (10 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was separated by silica gel column chromatography with DCM / MeOH (v / v = 25 / 1) as the eluent to obtain 15 mg of a pale yellow solid with a yield of 49%. LC-MS: m / z = 507.2 [M+H] + 。 1 H NMR (400 MHz, CDCl3) δ 8.51 (d, J = 4.1 Hz, 1H), 8.28 (d, J = 2.2 Hz, 1H), 8.17 (s, 1H), 8.06 (d, J = 1.9 Hz, 1H), 7.65 (m, 2H), 7.23 - 7.17 (m, 1H), 7.12 (d, J = 7.7 Hz, 1H), 7.03 (d, J = 2.0 Hz, 1H), 6.76 (d, J = 8.9 Hz, 1H), 4.38 (m, 1H), 4.08 (d, J = 13.0 Hz, 2H), 3.54 - 3.42 (m, 2H), 2.95 (s, 4H), 2.93 (s, 1H), 2.88 (s, 4H), 2.40 (m, 2H), 2.00 (m, 2H), 0.86 (m, 1H), 0.54–0.49 (m, 1H).

[0403] Example 8: 6-(2-(((3R,3aR,6R,6aR)-6-methoxyhexahydrofuro[3,2-b]furan-3-yl)oxy)ethoxy)-4-(6-(3-((6-methoxypyridin-3-yl)oxy)azetidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0404]

[0405] Step 1: 4-(6-fluoropyridin-3-yl)-6-(2-(((3R,3aR,6R,6aR)-6-methoxyhexahydrofuro[3,2-b]furan-3-yl)oxy)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0406] To a 10 mL two-necked flask, 4-(6-fluoropyridin-3-yl)-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile (Intermediate 2, 20 mg, 0.079 mmol), K2CO3 (32 mg, 0.23 mmol), DMF (3.0 mL), 2-(((3R,3aR,6R,6aR)-6-methoxyhexahydrofuro[3,2-b]furan-3-yl)oxy)ethyl methanesulfonate (Step 4 of Example 5, 33 mg, 0.12 mmol) were added successively. Under N2 protection, the reaction was stirred at 45 °C for 8 h. The reaction solution was added with EA (20 mL), washed with water (10 mL × 3), the aqueous phase was extracted with EA (10 mL) again, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was separated by silica gel column chromatography with PE / EA (v / v = 1 / 1) as the eluent to obtain 27 mg of a pale yellow solid with a yield of 78%. LC-MS: m / z = 441.2 [M+H] + 。

[0407] Step 2: 6-(2-(((3R,3aR,6R,6aR)-6-methoxyhexahydrofuro[3,2-b]furan-3-yl)oxy)ethoxy)-4-(6-(3-((6-methoxypyridin-3-yl)oxy)azetidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0408] To a 10 mL two-necked flask, 4-(6-fluoropyridin-3-yl)-6-(2-(((3R,3aR,6R,6aR)-6-methoxyhexahydrofuro[3,2-b]furan-3-yl)oxy)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (19 mg, 0.043 mmol), K2CO3 (50 mg, 0.36 mmol), DMAP (8 mg, 0.065 mmol), DMSO (2.5 mL), 5-(azetidin-3-yloxy)-2-methoxypyridine hydrochloride (Intermediate 5, 43 mg, 0.20 mmol) were added successively. Under N2 protection, the reaction was stirred at 96 °C for 7 h. The reaction solution was added with EA (30 mL), washed with water (10 mL × 3), the aqueous phases were combined and extracted with EA (15 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was separated by silica gel column chromatography with DCM / MeOH (v / v = 20 / 1) as the eluent to obtain 4 mg of a pale yellow solid with a yield of 16%. LC-MS: m / z = 601.2 [M+H] + 。 11H NMR (400 MHz, CDCl3) δ 8.30 (d, J = 2.0 Hz, 1H), 8.21–8.16 (m, 2H), 7.70 (m, 2H), 7.19 (dd, J = 8.9, 3.0 Hz, 1H), 7.12 (d, J = 2.0 Hz, 1H), 6.72 (d, J = 8.9 Hz, 1H), 6.46 (d, J = 8.7 Hz, 1H), 5.10 (m, 2H), 4.60 (m, 2H), 4.55–4.47 (m, 2H), 4.22 - 4.18 (m, 5H), 4.08 - 4.04 (m, 4H), 3.90 (s, 3H), 3.79–3.68 (m, 2H), 3.46 (s, 3H). HPLC: 89.13%. Example 9: 4-(6-(3-((6-methoxypyridin-3-yl)oxy)azetidin-1-yl)pyridin-3-yl)-6-((2-methyloctahydrocyclopent[c]pyrrol-5-yl)oxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0409]

[0410] Step 1: tert-Butyl 3-hydroxyazetidine-1-carboxylate

[0411] At room temperature, tert-butyl 3-oxoazetidine-1-carboxylate (5.0 g, 29 mmol) was dissolved in EtOH (50 mL) in a single-necked flask. NaBH4 (1.1 g, 29 mmol) was added portionwise with stirring, and the reaction was stirred at room temperature. After the reaction was monitored by TLC and completed, saturated ammonium chloride solution was added to the reaction solution until no more bubbles were generated, and a large amount of white solid precipitated. The solid was filtered by suction, and the filter cake was washed with 10 mL of ethanol. The filtrate was concentrated under reduced pressure to remove most of the ethanol, 30 mL of water was added, and the mixture was extracted with EA (100 mL × 2). The organic phases were combined, washed with water (20 mL × 2) and saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and then evaporated to dryness. Silica gel column chromatography was carried out with an eluent of EA:PE (v / v) = 1 / 5) to obtain 5.0 g of a colorless oil. LC-MS: m / z = 118.10 [M - tBu + 2H] + , 1 1H-NMR (400 MHz, CDCl3) δ 4.53 (s, 1H), 4.13 - 4.09 (m, 2H), 3.78 (dd, J = 9.9, 4.1 Hz, 2H), 3.54 - 3.45 (m, 1H), 1.41 (s, 9H).

[0412] Step 2: tert-Butyl 3–((methylsulfonyl)oxy)azetidine-1-carboxylate

[0413] Under nitrogen protection, tert-butyl 3-hydroxyazetidine-1-carboxylate (500 mg, 2.89 mmol) was dissolved in DCM (15 mL) in a two-necked flask. NaH (0.14 g, 5.8 mmol) was added, and the mixture was transferred to 0 °C. MsCl (0.25 mL, 3.2 mmol) was added dropwise with stirring. After addition, the reaction was continued at this temperature. After the reaction was monitored by TLC and completed, water (20 mL) and DCM (50 mL) were added to the reaction solution. The organic phase was separated, and the aqueous phase was extracted with EA (50 mL). The organic phases were combined, washed with water (20 mL × 2), washed with saturated sodium chloride (20 mL), dried over anhydrous sodium sulfate, and then concentrated by rotary evaporation. Silica gel column chromatography (eluent EA:PE = 1:5) was performed to obtain 566 mg of a colorless oil, which was the target product. LC-MS: m / z = 196.10 [M-tBu+2H] + , m / z = 152.10 [M-Boc+H] + , 1 1H-NMR (400 MHz, CDCl3) δ 5.18 (tt, J = 6.7, 4.2 Hz, 1H), 4.26 (ddd, J = 10.3, 6.7, 1.0 Hz, 2H), 4.11 - 4.04 (m, 2H), 3.05 (s, 3H), 1.43 (s, 9H).

[0414] Step 3: tert-Butyl 3-((6-methoxypyridin-3-yl)oxy)azetidine-1-carboxylate

[0415] At room temperature, 5-hydroxy-2-methoxypyridine (2.00 g, 16.0 mmol) and tert-butyl 3–((methylsulfonyl)oxy)azetidine-1-carboxylate (4.82 g, 19.2 mmol) were dissolved in DMF (30 mL). t-BuOK (3.59 g, 32.0 mmol) was added slowly, and the mixture was stirred for 10 min and then heated to 50 °C and reacted overnight. The temperature was lowered to room temperature, water (200 mL) was added to the reaction solution, and the mixture was extracted with EA (200 mL × 3). The organic phases were combined, washed with water (200 mL × 3), and washed with saturated brine (200 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was subjected to silica gel column chromatography (eluent PE:EA (v / v = 10 / 1 - 4 / 1)) to obtain 2.03 g of a yellowish-brown solid. LC-MS: m / z = 281.40 [M+H] + , 1 1H-NMR (400 MHz, CDCl3) δ 7.57 (d, J = 2.9 Hz, 1H), 7.17 - 7.06 (m, 1H), 6.67 (d, J = 8.9 Hz, 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).

[0416] Step 4: 5-(azetidin-3-yloxy)-2-methoxypyridine dihydrochloride

[0417] At 0 °C, dissolve tert-butyl 3-((6-methoxypyridin-3-yl)oxy)azetidine-1-carboxylate (2.03 g, 7.24 mmol) in EA (10 mL), slowly add hydrochloric acid-ethyl acetate (12 mL, 36 mmol, 3 mol / L), allow to warm to room temperature naturally, and stir overnight. Stop the reaction and directly concentrate the reaction solution to obtain 1.47 g of a yellow-brown viscous liquid. LC-MS: m / z = 181.10 [M+H] + 。

[0418] Step 5: 4-(6-(3-((6-methoxypyridin-3-yl)oxy)azetidin-1-yl)pyridin-3-yl)-6-((2-methyloctahydrocyclopenta[c]pyrrol-5-yl)oxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0419] Dissolve 4-(6-fluoropyridin-3-yl)-6-((2-methyloctahydrocyclopenta[c]pyrrol-5-yl)oxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (Intermediate 3, 20 mg, 0.05 mmol) and 5-(azetidin-3-yloxy)-2-methoxypyridine dihydrochloride (18 mg, 0.08 mmol) in DMSO (2 mL), add potassium carbonate (22 mg, 0.16 mmol) and DMAP (4 mg, 0.03 mmol), transfer to an oil bath at 90 °C and heat for 6 h. Pour the reaction solution into 10 mL of water, extract with EA (30 mL × 2), combine the organic phases, wash with water (10 mL × 2), wash with saturated sodium chloride (30 mL), dry the organic phase over anhydrous sodium sulfate and rotary evaporate, and subject the residue to silica gel column chromatography (eluent MeOH:DCM = 1:100 - 1:20) to obtain 18 mg of an off-white solid. Rf = 0.4 (DCM:MeOH = 10:1). LC-MS: 538.20 [M+H] + , 11H-NMR (400 MHz, CDCl3) δ 8.29 (d, J = 1.7 Hz, 1H), 8.19 (s, 1H), 8.13 (d, J = 1.7 Hz, 1H), 7.69 (dd, J = 5.8, 2.6 Hz, 2H), 7.18 (dd, J = 9.0, 2.9 Hz, 1H), 7.02 (s, 1H), 6.72 (d, J = 8.9 Hz, 1H), 6.45 (d, J = 8.5 Hz, 1H), 5.13 - 5.03 (m, 1H), 4.98 - 4.93 (m, 1H), 4.50 (dd, J = 8.8, 6.6 Hz, 2H), 4.17 (dd, J = 9.2, 3.7 Hz, 2H), 3.90 (s, 3H), 3.17 - 2.98 (m, 4H), 2.82 - 2.63 (m, 4H), 2.61 (s, 3H), 2.34 - 2.28 (m, 2H). HPLC: 91.02%.

[0420] Example 10: 6-(2-(3-Hydroxybicyclo[3.1.0]hexan-3-yl)ethoxy)-4-(6-(3-((6-methoxypyridin-3-yl)oxy)azetidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0421]

[0422] Step 1: Ethyl 2-(3-hydroxybicyclo[3.1.0]hexan-3-yl)acetate

[0423] Add Zn powder (930 mg, 14.22 mmol) to a 50 mL single-necked flask. Under N2 protection, add anhydrous THF (20 mL) and TMSCl (0.20 ml, 1.6 mmol), and stir the reaction under reflux in an oil bath for 1 h. Bicyclo[3.1.0]hexan-3-one (760 mg, 7.91 mmol) and ethyl bromoacetate (1.10 mL, 9.92 mmol) dissolved in THF (2 mL) were slowly added. After addition, maintain reflux stirring for 6 - 8 h. After the reaction solution was cooled, it was filtered, washed with EA (10 mL × 5), and concentrated. The residue was separated by silica gel column chromatography with PE / EA (v / v = 6 / 1) as the eluent to obtain 830 mg of an oily liquid with a yield of 57%. LC-MS: m / z = 185.2 [M + H] + 。 1 1H NMR (400 MHz, CDCl3) δ 4.15 (q, J = 7.1 Hz, 2H), 3.35 (s, 1H), 2.52 (s, 2H), 1.89 (s, 4H), 1.26 (m, 5H), 0.81 (m, 1H), 0.47 (m, 1H).

[0424] Step 2: 3-(2-Hydroxyethyl)bicyclo[3.1.0]hexan-3-ol

[0425] Add LiAlH4 (211 mg, 5.56 mmol) into a 50 mL single-necked flask. Under N2 protection, add THF (5 mL). At -10 °C, slowly add 2-(3-hydroxybicyclo[3.1.0]hexan-3-yl)ethyl acetate (390 mg, 2.12 mmol) dissolved in THF (5 mL). After addition, continue stirring and reacting for 1 h. Slowly add 10 mL of saturated ammonium chloride solution at low temperature to quench the reaction. Extract with EA (15 mL × 3). Combine the organic phases, dry over sodium sulfate, filter, concentrate the filtrate, and separate the residue by silica gel column chromatography with PE / EA (v / v = 2 / 1) as the eluent to obtain 75 mg of an oily liquid with a yield of 25%. LC-MS: m / z = 165.2 [M+Na] + , 1 1H NMR (400 MHz, CDCl3) δ 3.84 (t, J = 5.6 Hz, 2H), 3.05 (s, 1H), 2.93 (s, 1H), 1.94 (m, 2H), 1.83 (d, J = 13.8 Hz, 2H), 1.75 (t, J = 5.7 Hz, 2H), 1.33–1.21 (m, 2H), 0.71 (q, J = 4.0 Hz, 1H), 0.48 (m, 1H).

[0426] Step 3: 2-(3-Hydroxybicyclo[3.1.0]hexan-3-yl)ethyl methanesulfonate

[0427] Add 3-(2-hydroxyethyl)bicyclo[3.1.0]hexan-3-ol (102 mg, 0.72 mmol), DCM (4 mL), and Et3N (0.15 mL, 1.1 mmol) into a 25 mL single-necked flask in sequence. At -5 °C, slowly add MsCl (0.09 ml, 1 mmol). After addition, stir and react for 1.5 h. At low temperature, add the reaction solution to H2O (20 mL), extract with DCM (15 mL × 3), combine the organic phases, dry over sodium sulfate, filter, and concentrate the filtrate. Separate the residue by silica gel column chromatography with PE / EA (v / v = 2 / 1) as the eluent to obtain 108 mg of an oily liquid with a yield of 68%. 1 1H NMR (400 MHz, CDCl3) δ 4.38 (t, J = 6.8 Hz, 2H), 3.14 (s, 1H), 3.01 (s, 3H), 2.00 (m, 4H), 1.81 (s, 1H), 1.78 (s, 1H), 1.31 (m, 2H), 0.71 (m, 1H), 0.50 (m, 1H).

[0428] Step 4: 4-(6-Fluoropyridin-3-yl)-6-(2-(3-hydroxybicyclo[3.1.0]hexan-3-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0429] Add 4-(6-fluoropyridin-3-yl)-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile (Intermediate 2, 50 mg, 0.20 mmol), K2CO3 (68 mg, 0.49 mmol), DMF (4.5 mL), 2-(3-hydroxybicyclo[3.1.0]hexan-3-yl)ethyl methanesulfonate (35 mg, 0.16 mmol) into a 10 mL two-necked flask in sequence. Under N2 protection, heat and stir the reaction at 50 °C for 12 h. Add EA (30 mL) to the reaction solution, wash with water (10 mL × 3), combine the aqueous phases, extract with EA (10 mL), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate. Separate the residue by silica gel column chromatography using PE / EA = 1:2 as the eluent to obtain 34 mg of white solid with a yield of 45%. LC-MS: m / z = 379.1 [M+H] + 。

[0430] Step 5: 6-(2-(3-Hydroxybicyclo[3.1.0]hexan-3-yl)ethoxy)-4-(6-(3-((6-methoxypyridin-3-yl)oxy)azetidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0431] Add 4-(6-fluoropyridin-3-yl)-6-(2-(3-hydroxybicyclo[3.1.0]hexan-3-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (33 mg, 0.087 mmol), K2CO3 (40 mg, 0.29 mmol), DMAP (6 mg, 0.049 mmol), DMSO (3.0 mL), 5-(azetidin-3-yloxy)-2-methoxypyridine dihydrochloride (50 mg, 0.23 mmol) into a 10 mL two-necked flask in sequence. Under N2 protection, heat and stir the reaction at 90 °C for 8 h. Add EA (30 mL) to the reaction solution, wash with water (15 mL × 3), extract the aqueous phase with EA (15 mL) once more, combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate. Separate the residue by silica gel column chromatography using PE / EA (v / v = 2 / 3) as the eluent to obtain 20 mg of light yellow solid with a yield of 41%. LC-MS: m / z = 539.2 [M+H] + 。 11H NMR (400 MHz, CDCl3) δ 8.28 (d, J = 2.0 Hz, 1H), 8.17 (s, 1H), 8.13 (d, J = 1.9 Hz, 1H), 7.67 (m, 2H), 7.17 (dd, J = 8.9, 3.0 Hz, 1H), 7.04 (d, J = 1.9 Hz, 1H), 6.71 (d, J = 8.9 Hz, 1H), 6.44 (d, J = 8.6 Hz, 1H), 5.11–4.99 (m, 1H), 4.48 (dd, J = 8.9, 6.6 Hz, 2H), 4.23–4.12 (m, 4H), 3.89 (s, 3H), 2.06 (m, 5H), 1.83 (d, J = 13.9 Hz, 2H), 1.34–1.29 (m, 2H), 0.74 (m, 1H), 0.50 (m, 1H). HPLC: 88.52%.

[0432] Example 11: 4-(6-(3-((6-Methoxypyridin-3-yl)oxy)azetidin-1-yl)pyridin-3-yl)-6-(2-(tetrahydro-2H-[1,4]dioxino[2,3-c]pyrrol-6(3H)-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0433]

[0434] Step 1: Tetrahydro-2H-[1,4]dioxino[2,3-c]pyrrole hydrochloride

[0435] To a 100 mL single-necked flask were successively added tert-butyl tetrahydro-2H-[1,4]dioxino[2,3-c]pyrrole-6(3H)-carboxylate (2230 mg, 9.73 mmol) and HCl / EA (4N) (18 mL), and the mixture was stirred at rt for 8 hours. The reaction of the starting material was monitored by TLC and found to be complete. The reaction solution was directly concentrated and used for the next reaction. LC-MS: m / z = 130.1 [M - HCl + H] + .

[0436] Step 2: 2-(Tetrahydro-2H-[1,4]dioxino[2,3-c]pyrrol-6(3H)-yl)ethanol

[0437] To a 100 mL single-necked flask, add hexahydro-2H-[1,4]dioxino[2,3-c]pyrrole hydrochloride (2.88 mmol, 476 mg), acetonitrile (12 mL), K2CO3 (1150 mg, 8.32 mmol) in sequence, and heat and stir the reaction at 85 °C for 12 h. Filter the reaction solution through diatomaceous earth, wash with EA (15 mL × 3), concentrate, subject the residue to silica gel column chromatography, using EA / MeOH (v / v = 5 / 1) as the eluent, to obtain 490 mg of an oily product with a yield of 98%. LC-MS: m / z = 174.2 [M+H] + 。 1 1H NMR (400 MHz, MeOD) δ 4.32 (m, 2H), 3.87 (m, 2H), 3.84–3.78 (m, 2H), 3.68–3.59 (m, 2H), 3.50 (dd, J = 11.9, 3.7 Hz, 2H), 3.33–3.26 (m, 2H), 3.21–3.15 (m, 2H).

[0438] Step 3: 2-(Tetrahydro-2H-[1,4]dioxino[2,3-c]pyrrol-6(3H)-yl)ethyl methanesulfonate

[0439] To a 25 mL single-necked flask, add 2-(tetrahydro-2H-[1,4]dioxino[2,3-c]pyrrol-6(3H)-yl)ethanol (113 mg, 0.65 mmol), DCM (6 mL), Et3N (0.14 mL, 1.0 mmol) in sequence. At -5 °C, slowly add MsCl (0.10 mL, 1.3 mmol). After addition, stir the reaction for 5 h. Filter the reaction solution, concentrate, subject the residue to silica gel column chromatography, using DCM / MeOH (v / v = 20 / 1) as the eluent, to obtain 66 mg of a solid with a yield of 40%. 1 1H NMR (400 MHz, CDCl3) 4.43 (t, J = 5.2 Hz, 2H), 4.19 (m, 2H), 3.89 3.79 (m, 4H), 3.67 3.56 (m, 4H), 3.15 (m, 2H), 3.10 (s, 3H).

[0440] Step 4: 4-(6-Fluoropyridin-3-yl)-6-(2-(tetrahydro-2H-[1,4]dioxino[2,3-c]pyrrol-6(3H)-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0441] To a 25 mL two-necked flask, 4-(6-fluoropyridin-3-yl)-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile (Intermediate 2, 90 mg, 0.35 mmol), K2CO3 (217 mg, 1.57 mmol), DMF (6.0 mL), and 2-(tetrahydro-2H-[1,4]dioxino[2,3-c]pyrrol-6(3H)-yl)ethyl methanesulfonate (35 mg, 0.16 mmol) were added successively. Under N2 protection, the mixture was heated with stirring at 90 °C for 12 h. The reaction solution was added to EA (30 mL), washed with water (10 mL × 3), and the aqueous phase was extracted once more with EA (10 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by silica gel column chromatography using EA / MeOH (v / v = 6 / 1) as the eluent to obtain 51 mg of a white solid with a yield of 35%. LC-MS: m / z = 410.1 [M+H] + Step 5: 4-(6-(3-((6-Methoxypyridin-3-yl)oxy)azetidin-1-yl)pyridin-3-yl)-6-(2-(tetrahydro-2H-[1,4]dioxino[2,3-c]pyrrol-6(3H)-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0442] To a 10 mL two-necked flask, 4-(6-fluoropyridin-3-yl)-6-(2-(tetrahydro-2H-[1,4]dioxino[2,3-c]pyrrol-6(3H)-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (11 mg, 0.027 mmol), K2CO3 (26 mg, 0.19 mmol), DMAP (6 mg, 0.049 mmol), DMSO (2.2 mL), and 5-(azetidin-3-yloxy)-2-methoxypyridine dihydrochloride (26 mg, 0.12 mmol) were added successively. Under N2 protection, the mixture was heated with stirring at 96 °C for 6 h. The reaction solution was added to EA (30 mL), washed with water (15 mL × 3), and the aqueous phase was extracted once more with EA (10 mL). The combined organic phases were dried over sodium sulfate, filtered, and concentrated. The residue was separated by silica gel column chromatography using DCM / MeOH = 15:1 as the eluent to obtain 6 mg of a pale yellow solid with a yield of 39%. LC-MS: m / z = 570.3 [M+H] + 。

[0443] Example 12: 4-(6-(4-Hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)-6-(2-(tetrahydro-2H-[1,4]dioxino[2,3-c]pyrrol-6(3H)-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0444]

[0445] To a 10 mL two-necked flask, 6-hydroxy-4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Intermediate 1, 21 mg, 0.049 mmol), K2CO3 (27 mg, 0.20 mmol), DMF (3.0 mL), and 2-(tetrahydro-2H-[1,4]dioxino[2,3-c]pyrrol-6(3H)-yl)ethyl methanesulfonate (Step 3 of Example 11, 33 mg, 0.13 mmol) were added successively. Under N2 protection, the mixture was heated with stirring at 70 °C for 10 h. The reaction solution was added with EA (20 mL) and washed with water (10 mL × 3). The aqueous phase was extracted with EA (10 mL) again. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was separated by silica gel column chromatography using EA / MeOH (v / v = 8 / 1) as the eluent to obtain 4 mg of a pale yellow solid with a yield of 14%. LC-MS: m / z = 582.2 [M+H] + 。

[0446] Example 13: 4-(6-(4-Hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)-6-(2-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0447]

[0448] Step 1: 5-(2-Chloroethyl)hexahydro-1H-furo[3,4-c]pyrrole

[0449] Under nitrogen protection, hexahydro-1H-furo[3,4-c]pyrrole (2.0 g, 18 mmol) and potassium carbonate (12.0 g, 86.8 mmol) were added to a 25 mL three-necked flask. After dissolving in acetonitrile (20 mL, 383 mmol), 1-bromo-2-chloroethane (13 g, 90.649 mmol) was slowly added, and the mixture was stirred at room temperature overnight. After the reaction was completed, the reaction solution was directly rotary evaporated. The residue was separated by silica gel column chromatography (eluent PE / EA (v / v) = 10 / 1 - 2 / 1) to obtain 5.1 g of a yellow clear solution, which was the target product (yield 97.0%). Rf = 0.35 (EA). LC-MS: m / z = 176.50 [M+H] + 。 1 1H NMR (400 MHz, CDCl3) δ 3.76 (dd, J = 8.7, 5.1 Hz, 2H), 3.61 - 3.53 (m, 4H), 2.86 - 2.72 (m, 6H), 2.34 (d, J = 5.0 Hz, 2H).

[0450] Step 2: 4-(6-(4-Hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)-6-(2-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0451] In a 5 mL single-necked flask, 6-hydroxy-4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Intermediate 1, 25 mg, 0.05862 mmol), 5-(2-chloroethyl)hexahydro-1H-furo[3,4-c]pyrrole (20.6 mg, 0.117 mmol), potassium carbonate (24.55 mg, 0.1759 mmol), DMF (0.5 mL) were added successively, and the mixture was heated at 85 °C in an oil bath overnight. After the reaction was completed, the reaction solution was diluted with water (10 mL), extracted with EA (25 mL × 3), the organic phase was collected, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated by rotary evaporation, and the residue was purified by silica gel column chromatography (eluent DCM / MeOH = 100 / 1 - 20 / 1) to obtain 25.2 mg of a yellow solid as the target product (yield 76%) (Rf = 0.2, DCM / MeOH = 30 / 1). LC-MS (ES-API): [M / 2 + H] = 283.80. 1 H NMR (400 MHz, CDCl3) δ 8.52 (d, J = 4.5 Hz, 1H), 8.30 (d, J = 2.3 Hz, 1H), 8.19 (s, 1H), 8.12 (d, J = 1.9 Hz, 1H), 7.69–7.62 (m, 2H), 7.22–7.17 (m, 1H), 7.13 (s, 1H), 7.12–7.10 (m, 1H), 6.77 (d, J = 8.9 Hz, 1H), 4.14 (t, J = 5.5 Hz, 2H), 4.09 (d, J = 12.9 Hz, 2H), 3.75 (dd, J = 8.7, 6.1 Hz, 2H), 3.63 (dd, J = 8.9, 2.0 Hz, 2H), 3.53–3.43 (m, 2H), 2.96–2.90 (m, 6H), 2.85 (s, 2H), 2.41 (dd, J = 8.7, 3.5 Hz, 2H), 1.65 (d, J = 3.9 Hz, 2H), 1.32 (dd, J = 23.3, 11.2 Hz, 2H).

[0452] Example 14: 4-(6-(3-((6-Methoxypyridin-3-yl)oxy)azetidin-1-yl)pyridin-3-yl)-6-(2-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0453]

[0454] In a 10 mL single-necked flask, 4-(6-fluoropyridin-3-yl)-6-(2-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (Intermediate 4, 25 mg, 0.06 mmol), 5-(azacycloheptan-3-yloxy)-2-methoxypyridine hydrochloride (Intermediate 5, 27.5 mg, 0.127 mmol), potassium carbonate (26.4 mg, 0.19 mmol), DMAP (0.8 mg, 0.007 mmol), and DMSO (1.0 mL) were added in sequence. After the substrate was dissolved, the reaction was heated in an oil bath at 90 °C. After the reaction was completed as detected by TLC, water (25 mL) was added to the reaction solution, and it was extracted with EA (50 mL × 3). The organic phases were combined, washed with water (50 mL), washed with saturated sodium chloride (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness and purified by silica gel column chromatography (eluent DCM / MeOH (v / v) = 100 / 1 - 20 / 1) to obtain 11.2 mg of a white solid as the product. LC-MS: m / z = 554.40 [M+H] + 。 1 H NMR (400 MHz, CDCl3) δ 8.30 (d, J = 2.0 Hz, 1H), 8.19 (s, 1H), 8.13 (d, J = 1.9 Hz, 1H), 7.70 (dd, J = 8.4, 2.4 Hz, 2H), 7.18 (dd, J = 8.9, 3.0 Hz, 1H), 7.11 (d, J = 1.9 Hz, 1H), 6.72 (d, J = 8.9 Hz, 1H), 6.45 (d, J = 8.6 Hz, 1H), 5.08 (dt, J = 10.1, 4.9 Hz, 1H), 4.55–4.43 (m, 2H), 4.22–4.08 (m, 4H), 3.94–3.88 (m, 3H), 3.75 (dd, J = 8.6, 6.1 Hz, 2H), 3.63 (dd, J = 8.8, 2.0 Hz, 2H), 2.91 (t, J = 5.5 Hz, 4H), 2.88–2.82 (m, 2H), 2.40 (dd, J = 8.5, 3.2 Hz, 2H).

[0455] Example 15: 4-(6-(4-((6-Methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)-6-(2-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0456]

[0457] In a 10 mL single-necked flask, 4-(6-fluoropyridin-3-yl)-6-(2-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (Intermediate 4, 25 mg, 0.064 mmol), 1-((6-methoxypyridin-3-yl)methyl)piperazine dihydrochloride (Intermediate 6, 31 mg, 0.127 mmol), potassium carbonate (26.4 mg, 0.191 mmol), DMAP (0.8 mg, 0.007 mmol), and DMSO (1.0 mL) were added in sequence. After the substrate was dissolved, it was heated in an oil bath at 90 °C. After the reaction was completed as detected by TLC, water (25 mL) was added to the reaction solution, and it was extracted with EA (50 mL × 2). The organic phase was washed with water (50 mL), washed with saturated sodium chloride (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (eluent DCM / MeOH (v / v) = 100 / 1 - 20 / 1) to obtain 11.2 mg of a white solid, which was the target product. 1 1H NMR (400 MHz, CDCl3) δ 8.31 (d, J = 1.8 Hz, 1H), 8.18 (s, 1H), 8.13 (s, 1H), 8.07 (s, 1H), 7.69 (dd, J = 8.8, 2.1 Hz, 1H), 7.62 (d, J = 8.5 Hz, 1H), 7.10 (d, J = 1.3 Hz, 1H), 6.74 (d, J = 8.4 Hz, 2H), 4.15 (t, J = 5.3 Hz, 2H), 3.94 (s, 3H), 3.76–3.71 (m, 2H), 3.67–3.60 (m, 6H), 3.50 (s, 2H), 2.93 (t, J = 5.3 Hz, 4H), 2.86 (s, 2H), 2.56 (t, J = 4.3 Hz, 4H), 2.41 (dd, J = 8.4, 3.1 Hz, 2H).

[0458] Example 16: 1-(5-(3-cyano-6-((2-methyloctahydrocyclopentadieno[c]pyrrol-5-yl)oxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N-(6-methoxypyridin-3-yl)azetidine-3-carboxamide

[0459]

[0460] Step 1: tert-Butyl 3-(((6-methoxypyridin-3-yl)carbamoyl)azetidine-1-carboxylate

[0461] At room temperature, add 1-Boc-azetidine-3-carboxylic acid (500 mg, 2.48 mmol) and 6-methoxypyridin-3-amine (370 mg, 2.98 mmol) into a 25 mL single-necked flask. Add DCM (12.5 mL) to dissolve, and add EDCI (715 mg, 3.73 mmol) and DMAP (31 mg, 0.25 mmol) under stirring. Continue the reaction at this temperature. After the reaction is completed as detected by TLC, add 10 mL of water to the reaction solution, extract with DCM (20 mL×3), combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. Perform silica gel column chromatography (eluent EA / PE (v / v) = 1 / 3 - 1 / 2) to obtain 760 mg of a pink viscous solid as the product, with a yield of 99.53%. LC-MS: m / z = 252.05 [M-tBu+2H] + ; 1 1H-NMR (400 MHz, CDCl3) δ 8.16 (d, J = 2.5 Hz, 1H), 7.92 (dd, J = 8.9, 2.7 Hz, 1H), 7.31 (s, 1H), 6.74 (d, J = 8.9 Hz, 1H), 4.23 - 4.17 (m, 2H), 4.12 (t, J = 8.5 Hz, 2H), 3.91 (s, 3H), 3.38 - 3.32 (m, 1H), 1.45 (s, 9H).

[0462] Step 2: N-(6-Methoxypyridin-3-yl)azetidine-3-carboxamide dihydrochloride

[0463] Dissolve tert-butyl 3-(((6-methoxypyridin-3-yl)carbamoyl)azetidine-1-carboxylate (760 mg, 2.47 mmol) in HCl / EA (10 mL, 50 mmol), and stir at room temperature. After the reaction is completed as detected by TLC, filter the reaction solution by suction, wash the filter cake with a small amount of EA, and dry the filter cake by suction to obtain 680 mg of a white solid as the product, with a yield of 98.14%. LC-MS: m / z = 208.10 [M-2HCl+H] + 。

[0464] Step 3: 1-(5-(3-Cyano-6-((2-methyloctahydrocyclopentadieno[c]pyrrol-5-yl)oxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N-(6-methoxypyridin-3-yl)azetidine-3-carboxamide

[0465] 4-(6-Fluoropyridin-3-yl)-6-((2-methyloctahydrocyclopenta[c]pyrrol-5-yl)oxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (Intermediate 3, 20 mg, 0.053 mmol), N-(6-methoxypyridin-3-yl)azetidine-3-carboxamide dihydrochloride (23 mg, 0.082 mmol) were dissolved in DMSO (2 mL), potassium carbonate (22 mg, 0.16 mmol) and DMAP (4 mg, 0.033 mmol) were added, and the mixture was transferred to an oil bath at 90 °C for heating. After the reaction was monitored by TLC and completed, the reaction solution was poured into 10 mL of water, extracted with EA (30 mL × 2), the organic phases were combined, washed with water (10 mL × 2), washed once with 10 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (eluent MeOH / DCM = 1 / 100 - 1 / 20) to obtain 20 mg of a beige solid as the product, with a yield of 66.84%. LC-MS: m / z = 565.20 [M+H] + 。 1 H NMR (400 MHz, CDCl3) δ 8.29 (d, J = 2.7 Hz, 2H), 8.18 (s, 1H), 8.14 (d, J = 1.8 Hz, 1H), 8.05 (s, 1H), 7.97 (dd, J = 8.9, 2.6 Hz, 1H), 7.67 (dd, J = 8.6, 2.3 Hz, 1H), 7.01 (d, J = 1.8 Hz, 1H), 6.73 (d, J = 8.9 Hz, 1H), 6.44 (d, J = 8.6 Hz, 1H), 5.00 - 4.96 (m, 1H), 4.33 (dt, J = 16.4, 8.0 Hz, 4H), 3.91 (s, 3H), 3.64 (td, J = 8.1, 4.1 Hz, 1H), 3.14 - 3.10 (m, 2H), 2.91 - 2.82 (m, 2H), 2.71 (s, 3H), 2.33 (dd, J = 13.4, 6.2 Hz, 2H), 2.24 - 2.19 (m, 2H), 2.05 - 1.98 (m, 1H), 1.70 - 1.56 (m, 1H).

[0466] Biological Activity Test Example:

[0467] Test Example 1: Test of the inhibitory activity of the inventive compound against Ret wt and Ret V804M kinases

[0468] 1. Experimental Purpose:

[0469] Use the HTRF method to test the inhibitory activity of a series of compounds against the two kinases Ret wt and Ret V804M, and calculate the IC 50 value.

[0470] 2. The experimental reagents and consumables used are as follows:

[0471] 1) HTRF KinEASE-TK kit (Cisbio, 62TK0PEC)

[0472] 2) Ret wt (Invitrogen, PV3082)

[0473] 3) Ret V804M (Signalchem, R02-12GG-10)

[0474] 4) MgCl2 (Sigma, M1028)

[0475] 5) ATP (Promega, V910B)

[0476] 6) DTT (Invitrogen, P2325)

[0477] 7) DMSO (Sigma, D8418)

[0478] 8) 384-well plate, white, low volume, round-bottom (Greiner, 784075)

[0479] 9) 384-Well Polypropylene microplate, Clear, Flatt Bottom, Bar Code (Labcyte, P-05525-BC)

[0480] 10) 96-well polypropylene plate (Nunc, 249944)

[0481] 11) Plate shaker (Thermo, 4625-1CECN / THZ Q)

[0482] 12) Centrifuge (Eppendorf, 5810R)

[0483] 13) Envision 2104 multi-label Reader (PerkinElmer, 2104-10-1)

[0484] 14) Echo (Labcyte, 550)

[0485] 3. Experimental procedures

[0486] 3.1 Preparation of 1x kinase reaction buffer:

[0487] 1 volume of 5X kinase reaction buffer and 4 volumes of water; 5 mM MgCl2; 1 mM DTT; 1 mM MnCl2.

[0488] 3.2 Transfer 10 nl of the diluted compound to each well using an Echo 550 reaction plate (784075, Greiner).

[0489] 3.3 Seal the reaction plate with a sealing film and centrifuge at 1000 g for 1 minute.

[0490] 3.4 Prepare 2X kinase using 1X enzyme reaction buffer.

[0491] 3.5 Add 5 μl of kinase (prepared in step 3) to each well of the reaction plate. Seal the plate with a sealing film and centrifuge at 1000 g for 30 seconds, then incubate at room temperature for 10 minutes.

[0492] 3.6 Prepare 4x TK-substrate-biotin and 4x ATP using 1X enzyme reaction buffer, mix well, and add 5 μl of the K-substrate-biotin / ATP mixture to each well of the reaction plate.

[0493] 3.7 Seal the plate with a sealing film and centrifuge at 1000 g for 30 seconds, then react at room temperature for 40 minutes.

[0494] 3.8 Prepare 4X Sa-XL 665 (250 nM) using HTRF detection buffer.

[0495] 3.9 Add 5 μl of Sa-XL 665 and 5 μl of TK-antibody-Cryptate to each well, centrifuge at 1000 g for 30 seconds, and react at room temperature for 1 hour.

[0496] 3.10 Read the fluorescence signals at 615 nm (Cryptate) and 665 nm (XL665) using an Envision 2104.

[0497] 4. Data Analysis

[0498] 4.1 Calculate the ratio (Ratio_665 / 615 nm) for each well.

[0499] 4.2 The inhibition rate is calculated as follows:

[0500]

[0501]

[0502]

[0503] 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.

[0504] 4.3 Calculate IC 50 And plot the inhibition curve of the compound:

[0505] Use the following non-linear fitting formula to obtain the IC 50 (Half maximal inhibitory concentration): Perform data analysis using Graphpad 6.0 software.

[0506] Y = Bottom + (Top - Bottom) / (1 + 10^((LogIC50 - X)*Hill Slope))

[0507] X: Log value of compound concentration Y: Inhibition rate (% inhibition)

[0508] V. The experimental results are shown in Table 1:

[0509] Table 1 Experimental results of the kinase inhibitory activities of the compounds of the present invention against Ret wt and Ret V804M

[0510]

[0511] As can be seen from Table 1, the compounds of the present invention have good inhibitory effects against Ret wt. In addition, the compounds of the present invention also have good inhibitory effects against Ret V804M.

[0512] In the description of this specification, the descriptions with reference to terms such as "one embodiment", "some embodiments", "some implementation schemes", "examples", "specific examples", or "some examples", etc. mean that the specific features, structures, materials, or characteristics described in connection 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 can be combined in a suitable manner in any one or more embodiments or examples. In addition, without conflict, those skilled in the art can combine and combine the different embodiments, implementation schemes, or examples described in this specification, as well as the features of different embodiments, implementation schemes, or examples.

[0513] Although the embodiments of the present invention have been shown and described above, it can be understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Those of ordinary skill in the art can make changes, modifications, substitutions, and variations to the above embodiments within the scope of the present invention without departing from the principles and spirit of the present invention. The scope of the present invention is defined by the claims and their equivalents.

Claims

1. A compound which is a compound of formula (I) or a pharmaceutically acceptable salt thereof: （I）, Wherein, X 1 is N; X 2 , X 3 , X 4 and X 5 Each independently is CR 4 ; Y is O; T is a bond, C 1-6 alkylene, C 1-6 alkylene - O - or C 1-6 alkylene - NH -; Ring G is the following substructural formula: , , , , , , , , , , , , , , , , , , , , , , , , , or ; Each R a is independently D, OH, NH2, F, CF3, CHCl2, CHF2, CH2F, CF3CH2, Cl, Br, I, CN, NH2, NHCH3, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, methoxy, ethoxy, methoxymethyl, ethoxymethyl, methoxyethyl, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 2-hydroxypropyl, 2-hydroxy-2-methylpropyl, 2-hydroxyethoxy or 1-hydroxyethoxy; q is 0, 1, 2, 3 or 4; E is a bond; Ring A is the following substructural formula: , , , , , , , , , or , Wherein, the N-connection end of each substructural formula of ring A is connected to E, and the other connection end is connected to Q. Each substructural formula of A is independently optionally substituted by 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-, -(CH2)2-, -(C=O)-, -CH(CH3)-, NH-, (C=O)N(CH3)- or -(C=O)NH-; M is a 5- to 10-membered heteroaryl; and M is optionally substituted by 1, 2, 3 or 4 substituents selected from D, 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 haloalkoxy and C 1-6 alkoxyC 1-6 alkyl; R 1 is CN; Each R 4 is independently H, D, F, Cl, Br, methyl, ethyl, n-propyl, methoxy or ethoxy; Each R 5 is independently H, D, methyl, ethyl, n-propyl, isopropyl or n-butyl; Each R 6 is independently H, D, methyl, ethyl, n-propyl or n-butyl.

2. The compound according to claim 1, wherein, T is a bond, -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -(CH2)O-, -(CH2)2O-, -(CH2)3O- or -(CH2)2NH-.

3. The compound according to claim 1, wherein, M is pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl or pyrazinyl; and M is optionally substituted by 1, 2, 3 or 4 substituents selected from D, F, Cl, CN, OH, CF3, CHCl2, CHF2, CH2F, CF3CH2, NH2, NHCH3, N(CH3)2, trifluoromethoxy, 2,2,2-trifluoroethoxy, methoxy, ethoxy, isopropoxy, tert-butoxy, methyl, ethyl, n-propyl, isopropyl, methoxymethyl, hydroxymethyl and methoxyethyl.

4. The compound according to claim 1 is a compound of formula (I-1), (I-2) or (I-3), or a pharmaceutically acceptable salt thereof: 、 or , Among them, is the following substructural formula: is the following substructural formula: , , , , , , , , or , and each substructural formula of which is independently and 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; and M a is a pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl or pyrazinyl group, and M a is optionally substituted with 1, 2, 3 or 4 substituents selected from D, F, Cl, CN, OH, CF3, CHCl2, CHF2, CH2F, CF3CH2, NH2, NHCH3, N(CH3)2, trifluoromethoxy, 2,2,2-trifluoroethoxy, methoxy, ethoxy, isopropoxy, tert-butoxy, methyl, ethyl, n-propyl, isopropyl, methoxymethyl, hydroxymethyl and methoxyethyl.

5. A compound has one of the following structures, or a pharmaceutically acceptable salt thereof, 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , or 。 6. A pharmaceutical composition comprising the compound according to any one of claims 1-5 and a pharmaceutically acceptable adjuvant.

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

8. The use according to claim 7, wherein The RET-related diseases are cancer, irritable bowel syndrome and / or pain associated with irritable bowel syndrome.

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