A RET inhibitor, its pharmaceutical composition and its use

Abstract

The present invention belongs to the field of pharmaceuticals and relates to a RET inhibitor, its pharmaceutical composition and its use. 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 use of these compounds and their pharmaceutical compositions in the preparation of a medicament, which medicament is particularly used for treating and preventing RET-related diseases and disorders, including cancer, irritable bowel syndrome and / or pain associated with irritable bowel syndrome.

Description

Technical Field

[0001] The present invention belongs to the field of drugs. Specifically, the present invention relates to novel compounds presenting 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 (point mutations, chromosomal translocations, chromosomal inversions, gene amplifications) in the RET gene 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 associated with 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 promote 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, CF3, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, heterocyclic group, alkoxy, aryl, heteroaryl and alkylamino;

[0012] Ring G is a spirocarbocyclic group or a spiroheterocyclic 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, haloalkyl, alkoxy, cycloalkyl, alkoxyalkyl or hydroxyalkyl;

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

[0016] Ring A is a monocyclic group, and 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 -, aminoalkyl, alkyl, alkoxy, haloalkyl, hydroxyalkyl, carbocyclic group, heterocyclic group, heterocyclic alkyl and alkoxyalkyl;

[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(CR 2 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, CF3, 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 、R 3Independently OH, F, CF3, H, D, CN, Cl, Br, NH2, hydroxyalkyl, alkyl, alkylamino, alkoxy, haloalkoxy, cycloalkyl, 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 the 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 the 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 the 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, NH2, CF3, 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, NH2, CF3, methyl, ethyl, propyl, 2-hydroxyethyl, 1-hydroxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, methoxy, ethoxy, propoxy, butoxy, phenyl, methylamino and dimethylamino.

[0030] In some embodiments,

[0031] Ring G is a 6- to 12-membered spirocarbocyclic group or a 6- to 12-membered spiroheterocyclic 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 haloalkyl, C 1-6 alkoxy, C 3-7 cycloalkyl, C 1-6 alkoxyC 1-6 alkyl or C 1-6 hydroxyalkyl;

[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 1-6 alkoxy, C 6-10substituted by substituents of aryl and 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, 5- to 10-membered heteroaryl.

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

[0037]

[0038] wherein each ring T1 is independently a 4- to 7-membered carbocyclic or heteromonocyclic ring;

[0039] Z 1 and Z 2 are independently -CH2-, -O-, -S- or -NH-;

[0040] Z 3 is -O-, -S- or -NH-;

[0041] n1 is 0, 1 or 2;

[0042] n2 is 1, 2 or 3;

[0043] n3 is 0 or 1;

[0044] R a is 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 haloalkyl, C 1-6 alkoxy, C3-7 Naphthenyl, C 1-6 Alkoxy C 1-6 Alkyl or C 1-6 Hydroxyalkyl;

[0045] R 5 is H, D, C 1-6 Alkyl, 3 - 12 membered carbocyclic group, 3 - 12 membered heterocyclic group, C 6-10 Aryl or 5 - 10 membered heteroaryl, wherein the C 1-6 Alkyl, 3 - 12 membered carbocyclic group, 3 - 12 membered heterocyclic group, C 6-10 Aryl and 5 - 10 membered heteroaryl are each independently optionally substituted by 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 1-6 Alkoxy, C 6-10 Aryl and 5 - 10 membered heteroaryl substituents;

[0046] R 6 is 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;

[0047] R 7 is OH, C 1-6 Alkyl, C 3-6 Naphthenyl, 3 - 12 membered heterocyclic group, C 6-10 Aryl, 5 - 10 membered heteroaryl.

[0048] In some embodiments, ring G has the following sub - structural formula:

[0049]

[0050]

[0051] Each R aIndependently D, OH, NH2, F, CF3, 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, propyl, butyl, methoxy, ethoxy, cyclopropyl, cyclopentyl, methoxymethyl, methoxyethyl, ethoxymethyl, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 2-hydroxypropyl or 2-hydroxy-2-methylpropyl;

[0052] Each R 5 Independently H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, cyclopropyl, cyclopentyl, pyrrolidinyl, phenyl or 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;

[0053] 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;

[0054] Each R 7 Independently OH, methyl, ethyl, NH2, N(CH3)2, methyl, isopropyl, tert-butyl, cyclopropyl or phenyl.

[0055] In some embodiments, ring A is a 5- to 12-membered monocyclic group, and ring 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, C 1-6 alkoxy C 1-6 alkyl, C 3-6 alkylidene and 3- to 6-membered heteroalkylidene substituents.

[0056] In some embodiments, Ring A is the following substructural formula:

[0057]

[0058] wherein, Z 1a and Z 2a are each independently CH or N;

[0059] Z 3a and Z 4 are each independently CH2, O, S, NH, C═O, S═O or S(═O)2;

[0060] Each substructural formula of Ring 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.

[0061] In some embodiments, Ring A is the following substructural formula:

[0062]

[0063] wherein, each substructural formula of Ring 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.

[0064] 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, CF3, NR 5 R 6 , OR 7 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6Hydroxyalkyl, 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.

[0065] 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, 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.

[0066] In some embodiments, R 1 is H, D, CN, F, Cl, Br, methyl, or cyclopropyl, wherein the methyl and cyclopropyl may each independently be optionally substituted by 1, 2, 3, or 4 substituents selected from F, Cl, Br, CN, NH2, OH, and NO2;

[0067] 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 each independently be optionally substituted by 1, 2, 3, or 4 substituents selected from F, Cl, Br, CN, NH2, OH, and NO2.

[0068] In some embodiments, each R 2 , R 3 is independently OH, F, CF3, H, D, CN, Cl, Br, NH2, C 1-6 Hydroxyalkyl, C 1-6 Alkyl, C 1-6 Alkylamino, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-7cycloalkyl, C 3-7 cycloalkyl C 1-6 alkyl, C 6-10 aryl or 5-10-membered heteroaryl;

[0069] or, R 2 、R 3 and together with the same C atom to which they are attached form a 3-7-membered carbocyclic or 3-7-membered heterocyclic ring.

[0070] In some embodiments, each R 2 、R 3 is independently OH, F, CF3, 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;

[0071] or, R 2 、R 3 and together with the same C atom to which they are attached form cyclopentane, cyclopropane, cyclobutane, tetrahydropyran, tetrahydrofuran, piperidine or pyrrolidine.

[0072] In some embodiments, Q is a bond, -O-, -O(CH2)-, -(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)-, -S(=O)2-, -(C=O)CH2CH(OH)-, -(C=O)CH2-, -(C=O)CH(CH2OH)-, -(C=O)C(CH3)2-, -(C=O)CH2NHC(CH3)2CH2-, -(C=O)CH2CH(N(CH3)2)-, -(C=O)(CH2)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)CH 2-, -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-

[0073] 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:

[0074]

[0075] Wherein, is the following sub-structural formula:

[0076]

[0077] Wherein, each Z 2a is independently CH or N;

[0078] Z 3a and Z 4 are each independently CH2, O, S, NH, C=O, S=O or S(=O)2;

[0079] And each sub-structural 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 1-4Hydroxyalkyl, 3- to 12-membered carbocyclic group, 3- to 12-membered heterocyclic group, 3- to 12-membered heterocyclic group-C 1-4 alkyl and C 1-4 alkoxy C 1-4 alkyl substituted by substituents of;

[0080] 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 alkyl acyl, 3- to 7-membered heterocyclic group and C 3-7 cycloalkyl substituted by substituents of;

[0081] R 1 , X 1 , X 2 , X 3 , X 4 , X 5 , T, G, R a , q has the definitions as described in the present invention.

[0082] In some embodiments,

[0083] 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

[0084] 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.

[0085] 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,

[0086]

[0087]

[0088]

[0089]

[0090]

[0091]

[0092]

[0093]

[0094]

[0095]

[0096]

[0097]

[0098] On the other hand, the present invention provides a pharmaceutical composition comprising the compound of the present invention and a pharmaceutically acceptable adjuvant.

[0099] 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.

[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 the use of the compound or the pharmaceutical composition of the present invention for preventing or treating RET-related diseases.

[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 also provides a method for preventing or treating 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.

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

[0105] On the other hand, the present invention relates to intermediates for preparing the compounds represented by formula (I), (I-1), (I-2) or (I-3).

[0106] On the other hand, the present invention relates to methods for preparing, isolating and purifying the compounds represented by formula (I), (I-1), (I-2) or (I-3).

[0107] On the other hand, the present invention provides a pharmaceutical composition comprising the compound of the present invention and its pharmaceutically acceptable adjuvants. 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.

[0108] The present invention also provides a method for inhibiting cell proliferation in vitro or in vivo, the method comprising contacting cells with an effective amount of the compound or its pharmaceutical composition of the present invention.

[0109] 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.

[0110] 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 preventing or treating irritable bowel syndrome (IBS) and / or pain associated with IBS.

[0111] The present invention also provides the use of the compound or the pharmaceutical composition of the present invention for preventing or treating irritable bowel syndrome (IBS) and / or pain associated with IBS.

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

[0113] Specifically, the salts are pharmaceutically acceptable salts. The term "pharmaceutically acceptable" includes that the substance or composition must be suitable chemically or toxicologically, in relation to the other components of the formulation and the mammal to be treated.

[0114] The salts of the compounds of the 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), (I-1), (I-2) or (I-3), which are not necessarily pharmaceutically acceptable salts.

[0115] 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 scope of the present invention and are included in the compounds disclosed in 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.

[0116] The N-oxides of the compounds of the invention are also included within the scope of the invention. The N-oxides of the compounds of the invention can be prepared by oxidizing the corresponding nitrogenous basic substance with a conventional oxidizing agent (such as hydrogen peroxide) at elevated temperature in the presence of an acid such as acetic acid, or by reacting with a peracid in a suitable solvent, such as reacting with peracetic acid in dichloromethane, ethyl acetate or methyl acetate, or reacting with 3-chloroperoxybenzoic acid in chloroform or dichloromethane.

[0117] If the compound of the 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.

[0118] If the compound of the present invention is 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.

[0119] Definitions and General Terms

[0120] Certain embodiments of the present invention are now 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.

[0121] It should be further recognized that certain features of the present invention, for clarity, are described in multiple separate embodiments, but can 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 can also be provided separately or in any suitable sub-combination.

[0122] Unless otherwise specified, 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.

[0123] The term "patient" as used in the present invention refers to a human (including adults and children) or other animals. In some embodiments, the "patient" refers to a human.

[0124] The term "comprising" is an open-ended expression, that is, it includes the content specified in the present invention, but does not exclude other aspects.

[0125] "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.

[0126] 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.

[0127] Any mixture of the resulting stereoisomers can be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, for example, by chromatography and / or fractional crystallization, based on differences in the physical and chemical properties of the components.

[0128] The terms “tautomer” or “tautomeric form” refer to structural isomers of different energies that can interconvert through 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 through proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions that occur through the reorganization of some 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.

[0129] 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 asymmetric centers, the (Z), (E) isomers of double bonds, and the (Z), (E) conformational isomers. Thus, the 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.

[0130] Unless otherwise indicated, the structures 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. Accordingly, 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 are also within the scope of this invention. Additionally, unless otherwise indicated, the structures of the compounds described in this invention include one or more enriched isotopes of different atoms.

[0131] As described in this invention, the compounds of this invention may independently and optionally be substituted by one or more substituents, such as in the general formula compounds above, or in the specific examples, subclasses, and classes of compounds included in 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 may be substituted at each substitutable position of the group. When more than one position in the given structure can be substituted by one or more substituents selected from a specific group, the substituents may be the same or different at each position.

[0132] In addition, it should be noted that unless otherwise explicitly stated, in this invention, the description modes "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.

[0133] 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.

[0134] 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 the "alkyl" or "aryl" represents a linking alkylene group or arylene group, respectively.

[0135] The term "alkyl" refers to a saturated, straight-chain or branched-chain monovalent hydrocarbon radical containing 1 to 20 carbon atoms, wherein said alkyl radical may optionally be substituted by 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.

[0136] 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 radicals include, but are not limited to: -CH2-, -CH2CH2-, -CH(CH3)CH2-, and the like.

[0137] 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.

[0138] 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.

[0139] The term "oxo", i.e., ═O.

[0140] The term "hydroxyalkyl" means an alkyl group substituted by one or more hydroxyl groups. In some embodiments, the hydroxyalkyl means an alkyl group substituted by 1, 2, 3 or 4 hydroxyl groups. In some embodiments, the hydroxyalkyl means an alkyl group substituted by 1 or 2 hydroxyl groups. In some embodiments, the hydroxyalkyl means C 1-6 hydroxyalkyl, i.e., C 1-6 alkyl group is substituted by one or more hydroxyl groups, preferably, C 1-6 hydroxyalkyl means C 1-6 alkyl group is substituted by one hydroxyl group. In some embodiments, the hydroxyalkyl means C 1-4 hydroxyalkyl. In some embodiments, the hydroxyalkyl means C 1-3 hydroxyalkyl. Examples of hydroxyalkyl include, but are not limited to, HOCH2-, CH2OHCH2CH2CH2-, CH2OHCH2-, CH2OHCH2CHOHCH2-, CH(CH3)OHCH2CHOHCH2-, etc.

[0141] 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 - l - propoxy (i - BuO, i - butoxy, -OCH2CH(CH3)2), 2 - butoxy (s - BuO, s - butoxy, -OCH(CH3)CH2CH3), 2 - methyl - 2 - propoxy (t - BuO, t - butoxy, -OC(CH3)3), 1 - pentyloxy (n - pentyloxy, -OCH2CH2CH2CH2CH3), 2 - pentyloxy (-OCH(CH3)CH2CH2CH3), 3 - pentyloxy (-OCH(CH2CH3)2), 2 - methyl - 2 - butoxy (-OC(CH3)2CH2CH3), 3 - methyl - 2 - butoxy (-OCH(CH3)CH(CH3)2), 3 - methyl - l - butoxy (-OCH2CH2CH(CH3)2), 2 - methyl - l - butoxy (-OCH2CH(CH3)CH2CH3), and so on.

[0142] 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 alkoxyC 1-6 alkyl; in other embodiments, alkoxyalkyl means C 1-4 alkoxyC 1-4 alkyl; in other embodiments, alkoxyalkyl means C 1-4 alkoxyC 1-3 alkyl; in some embodiments, alkoxyalkyl means C 1-3 alkoxyC 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.

[0143] The term "halogen" means F (fluorine), Cl (chlorine), Br (bromine) or I (iodine).

[0144] 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, monochloromethyl, dichloromethyl, trichloromethyl, 1-chloroethyl, 1,2-dichloroethyl, 1,1-dichloroethyl, 2,2-dichloroethyl, 1,1-dibromoethyl, and the like.

[0145] The term "cycloalkyl" means a monovalent saturated monocyclic carbocyclic system. The -CH2- groups in cycloalkyl may 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 carbocycle being replaced by -C(=O)- include, but are not limited to: cyclopentanone, cyclobutanone, etc. The cycloalkyl groups may independently and optionally be substituted with one or more substituents described in the present invention.

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

[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. The -CH2- groups in the monocyclic group can optionally be replaced by -C(=O)-. In some embodiments, the monocyclic group contains 3 to 7 ring atoms, i.e., the monocyclic group is a 3- to 7-membered monocyclic group; in other embodiments, the monocyclic group contains 3 to 6 ring atoms, i.e., the monocyclic group is a 3- to 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. The -CH2- groups in the sub-monocyclic group can optionally be replaced by -C(=O)-. In some embodiments, the sub-monocyclic group contains 3 to 7 ring atoms, i.e., the sub-monocyclic group is a 3- to 7-membered sub-monocyclic group; in other embodiments, the sub-monocyclic group contains 3 to 6 ring atoms, i.e., the sub-monocyclic group is a 3- to 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. The -CH2- groups in the sub-monocyclic heterocyclic group can optionally be replaced by -C(=O)-. In some embodiments, the sub-monocyclic heterocyclic group contains 3 to 7 ring atoms, i.e., the sub-monocyclic heterocyclic group is a 3- to 7-membered sub-monocyclic heterocyclic group; in other embodiments, the sub-monocyclic heterocyclic group contains 3 to 6 ring atoms, i.e., the sub-monocyclic heterocyclic group is a 3- to 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- to 12-membered heterocyclic group C 1-6 alkyl; in other embodiments, the heterocyclic group alkyl is a 3- to 6-membered heterocyclic group C 1-6 alkyl; in some embodiments, the heterocyclic group alkyl is a 3- to 6-membered heterocyclic group C 1-4 alkyl. Examples of the heterocyclic group alkyl include, but are not limited to: pyrrolidinylmethyl, piperidinylmethyl, etc.

[0151] The term "haloalkoxy" means an alkoxy group substituted by one or more halogen atoms, wherein the halogen and the alkoxy have the definitions as described in the present invention. In some embodiments, the haloalkoxy group represents C 1-6 haloalkoxy, namely C 1-6 alkyl in which the alkoxy is substituted by one or more halogens. In some embodiments, the haloalkoxy group represents C 1-4 haloalkoxy. In some embodiments, the haloalkoxy group represents C 1-3 haloalkoxy. Examples thereof 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 represents -C(=O)-. In some embodiments, the alkylacyl represents C 1-6 alkylacyl; in other embodiments, the alkylacyl represents C 1-4 alkylacyl. Examples of alkylacyl include, but are not limited to: formyl, acetyl, etc.

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

[0154] The term "aryl" means a monovalent aryl ring group formed by removing a hydrogen atom from the ring carbon atoms of an aromatic ring. Examples of aryl groups may include phenyl, naphthyl, and anthracenyl. When the aryl is a linking group and "aryl" is listed in the definition of the Markush group, then "aryl" means a linked arylene group. As defined in the present invention, when M is aryl, it means that M contains a linked arylene group. The term "arylene" means a divalent aryl ring 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 may include phenylene, naphthylene, and anthrylene. The aryl group may be independently optionally substituted by 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 a ring atom 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. When M is a heteroaryl in the definition of the present invention, 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 a ring atom 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 "spirocarbocycle" and "spirocarbocyclic group" are used interchangeably and both refer to a non-aromatic saturated or partially unsaturated bicyclic or polycyclic system formed by two carbocycles sharing a single carbon atom. In the spirocarbocycle, the -CH2- group may optionally be replaced by -C(=O)-. In some embodiments, the spirocarbocycle contains 7-12 ring carbon atoms, i.e., represents a 7-12 membered spirocarbocycle; in other embodiments, the spirocarbocycle contains 7-10 ring carbon atoms, i.e., represents a 7-10 membered spirocarbocycle. Examples of spirocarbocycles include, but are not limited to: spiro[4.4]nonane, spiro[3.4]octane, spiro[4.5]decane, etc. When the spirocarbocycle or spirocarbocyclic group is a linking group and the spirocarbocycle or spirocarbocyclic group is defined in the Markush group listing, the spirocarbocycle or spirocarbocyclic group represents a linked spirocarbocyclic moiety. The term "spirocarbocyclic moiety" refers to a divalent spirocarbocyclic group formed by removing two hydrogen atoms from the ring atoms of the spirocarbocycle. The spirocarbocycle or spirocarbocyclic group may independently and optionally be substituted by one or more substituents described in the present invention.

[0158] The terms "heterocycle" or "heterocyclic group" are used interchangeably and denote a monovalent non-aromatic saturated or partially unsaturated monocyclic, bicyclic or polycyclic system having 3 to 12 ring atoms, with at least 1 carbon atom and containing 1, 2 or 3 heteroatoms selected from O, N or 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 to 7 ring atoms, i.e., represents a 4- to 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, dithiolanyl, 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 -CH2- group in the heterocyclic group being replaced by -C(=O)- include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidinone, 3,5-dioxopiperidinyl. Examples of the nitrogen atom in the heterocyclic group being 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 defined in the Markush group listing, 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 optionally substituted by one or more substituents described in the present invention.

[0159] The terms "spiroheterocycle" or "spiroheterocyclyl" are used interchangeably and both represent a non-aromatic saturated or partially unsaturated ring system formed by two rings sharing a carbon atom, and the system contains 1, 2, or 3 heteroatoms selected from O, N, and S. The -CH2- group in the spiroheterocycle can 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. In some embodiments, the spiroheterocycle contains 7 - 12 ring atoms, that is, a 7 - 12-membered spiroheterocycle; in other embodiments, the spiroheterocycle contains 7 - 10 ring atoms, that is, a 7 - 10-membered spiroheterocycle. Examples of spiroheterocycles include, but are not limited to: 4,7-diazaspiro[2.5]octane, 2,8-diazaspiro[4.5]decane, 2,7-diazaspiro[4.5]decane, 2,7-diazaspiro[3.5]decane, 2,6-diazaspiro[3.3]heptane, 2,7-diazaspiro[4.4]nonane, 3-azaspiro[5.5]undecane, 2,7-diazaspiro[4.4]nonan-1-one, etc. When the spiroheterocycle or spiroheterocyclyl is a linking group and the spiroheterocycle or spiroheterocyclyl is listed for the definition of the Markush group, the spiroheterocycle or spiroheterocyclyl represents a linked spiroheterocyclylene group. The term "spiroheterocyclylene" represents a divalent spiroheterocyclic group formed by removing two hydrogen atoms from the ring atoms of the spiroheterocycle. The spiroheterocycle or spiroheterocyclyl can be independently and optionally substituted by one or more substituents described in the present invention.

[0160] The term "aminoalkyl" represents an alkyl group substituted by one or more amino groups. In some embodiments, the term "aminoalkyl" represents an alkyl group substituted by one amino group. In some embodiments, the term "aminoalkyl" represents aminoC 1-6 alkyl. In other embodiments, the term "aminoalkyl" represents aminoC 1-4 alkyl. In other embodiments, the term "aminoalkyl" represents 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" represents an amino group substituted by one or two alkyl groups. In some embodiments, the term "alkylamino" represents C 1-6 alkylamino, that is, an amino group substituted by one or two C 1-6 alkyl groups. In other embodiments, the term "alkylamino" represents C 1-4 alkylamino. In other embodiments, the term "alkylamino" represents C 1-3Alkylamino. 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, and the like.

[0162] The term "alkylsulfonyl" means alkyl-S(=O)2-, i.e., the alkyl is linked to the rest of the molecule through -S(=O)2-. In some embodiments, alkylsulfonyl represents C 1-6 alkylsulfonyl; in other embodiments, alkylsulfonyl represents C 1-4 alkylsulfonyl; in other embodiments, alkylsulfonyl represents C 1-3 alkylsulfonyl. Examples of alkylsulfonyl include, but are not limited to, methylmethanesulfonyl, ethylmethanesulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, and the like.

[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 ring A is connected to Q. For example, when ring A is when, 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 ring 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, G3, and G4 of ring G respectively represent ring T 1 and T 2a , ring T 1 and T 2b , ring T 1 and T 2c , ring T 1 and T 2da formed spiro ring, and the attachment points of each of the G1, G2, G3, and G4 rings can be connected to the rest of the molecule at any connectable position on the G1, G2, G3, and G4 rings respectively; preferably, the attachment points of each of the G1, G2, G3, and G4 rings can be at each T on the G1, G2, G3, and G4 rings 1 ring and be connected to the rest of the molecule at any connectable position. For example, in the G1 ring, the attachment point can be at any connectable position on the T 1 ring and be connected to the rest of the molecule at any connectable position, and the attachment point can also be at any connectable position on the T 2a ring and be connected to the rest of the molecule at any connectable position; preferably, the attachment point is at any connectable position on the T 1 ring and be connected to the rest of the molecule at any connectable position. The sub-structural formulas G1, G2, G3, and G4 of ring G are shown below.

[0167]

[0168] The term "protecting group" or "PG" refers to a substituent that is usually used to block or protect a special functionality when reacting with other functional groups. For example, "a protecting group for an amino group" refers to a substituent that is connected 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-fluorenylmethoxycarbonyl (Fmoc). Similarly, "a protecting group for a hydroxyl 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 protecting group for a carboxyl group" refers to a substituent of a carboxyl group that is used to block or protect the functionality of the carboxyl group. General carboxyl protecting groups include -CH2CH2SO2Ph, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrobenzenesulfonyl)ethyl, 2-(diphenylphosphino)ethyl, nitroethyl, and so on. 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" used in the present invention represents a compound that is converted in vivo into the compound shown in formula (I). Such a conversion is affected by the hydrolysis of the prodrug in the blood or the enzymatic conversion of the prodrug into the parent structure in the blood or tissue. The prodrug compounds of the present invention can be esters. In the existing inventions, esters that can be used as prodrugs include phenyl esters, aliphatic (C1-24 ) 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 these phosphate ester compounds are 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 obtained by other methods described in books and literature such as ion exchange method to obtain these salts. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, 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, etc. The salts obtained by appropriate bases include alkali metals, alkaline earth metals, ammonium and N + (C 1-4 alkyl)4 salts. 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, etc. Pharmaceutically acceptable salts further include appropriate, non-toxic ammonium, quaternary ammonium salts and amine cations formed by counterbalancing ions 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 forms 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 forms 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 forms or in forms 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] "Nitrogen oxides" in the present invention refers to 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 amine can be treated with an oxidizing agent such as hydrogen peroxide or a peracid (such as a peroxycarboxylic acid) to form an N-oxide (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), where, for example, in an inert solvent such as dichloromethane, the amine compound is reacted with meta-chloroperoxybenzoic acid (MCPBA).

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

[0177] The term "RET-related cancer" as used in the present invention refers to cancers associated with the RET gene, the RET kinase (also referred to as the RET kinase protein or RET kinase in the present invention), or a dysregulation of the expression or activity or level of any one of them. Non-limiting examples of RET-related cancers are described in the present invention. The dysregulation of the RET gene, the 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, the RET kinase, or the expression or activity or level of any one of them includes one or more deletions (such as a deletion of 4 amino acids), insertions, or point mutations in the RET kinase. In some embodiments, the dysregulation of the RET gene, the RET kinase, or the expression or activity or level of any one of them includes a 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, non-specific functional bowel disease, functional abdominal pain syndrome, chronic idiopathic constipation, functional esophageal disorders, functional gastroduodenal disorders, functional anorectal pain, inflammatory bowel disease, etc.

[0180] Any structural formula given by the present invention is also intended to represent both the non-isotope-enriched form and the isotope-enriched form of these compounds. Isotope-enriched compounds have the structure depicted by the general formula given by the present invention, except that one or more atoms are replaced by atoms having the 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 by 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 for 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 drugs or substrates, or can be used in radiotherapy of patients. 18 F-enriched compounds are particularly desirable for PET or SPECT studies. Isotope-enriched compounds of formula (I) can be prepared by conventional techniques familiar to those skilled in the art or by substituting the originally used unlabeled reagents with appropriate 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 increase in the in vivo half-life or a decrease in the dose requirement or an improvement in the therapeutic index. It should be understood that deuterium in the present invention is regarded as a substituent of the compound represented by formula (I). The concentration of such heavier isotopes, especially deuterium, can be defined by the isotopic enrichment factor. The term "isotopic enrichment factor" 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] The compounds of the present invention, their pharmaceutical compositions, formulations and administrations

[0184] The present invention provides the 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 a reduction in toxicity associated with the inhibition of other kinases.

[0185] The pharmaceutical compositions of the present invention include the 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 pharmaceutical 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 compositions of the present invention further comprise pharmaceutically acceptable adjuvants, which, as used in the present invention, include any solvent, diluent, or other liquid excipient, dispersing or suspending agent, surfactant, isotonic agent, thickening agent, emulsifying agent, preservative, solid binder or lubricant, etc., suitable for the particular target dosage form. As described in the following literature: In Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. D.B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J.C. Boylan, 1988 - 1999, Marcel Dekker, New York, the combined content of the literature herein indicates that different adjuvants can be applied to the formulation of pharmaceutically acceptable compositions and their well-known preparation methods. Except for the range in which any conventional adjuvant is incompatible with the compounds of the present invention, such as any adverse biological effects produced or interactions with any other components of the pharmaceutically acceptable composition in a harmful manner, their use is also within the scope contemplated by the present invention.

[0187] In preparing the compositions provided by the present invention, the active ingredient is usually admixed with an excipient, diluted by the excipient or enclosed within such a carrier in the form of, for example, a capsule, sachet, paper or other container. If the excipient is used as a diluent, it can be a solid, semi-solid or liquid material which serves as a vehicle, carrier or medium for the active ingredient. Suitable carriers include, but are not limited to, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, low melting wax, cocoa butter, etc. Accordingly, the compositions can be tablets, pills, powders, lozenges, cachets, capsules, elixirs, suspensions, emulsions, solutions, syrups, aerosols (in solid form or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders. In one embodiment, the composition is formulated for oral administration. In one embodiment, the composition is formulated as a tablet or a capsule.

[0188] When available for treatment, a therapeutically effective amount of a compound of the present invention, particularly a compound of 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. Accordingly, the present invention also provides a pharmaceutical composition which comprises a therapeutically effective amount of a compound of the present invention, particularly a compound of formula (I), (I-1), (I-2) or (I-3) or its pharmaceutically acceptable salts and one or more pharmaceutically acceptable adjuvants, including but not limited to carriers, diluents or excipients, etc. As used herein, the term "therapeutically effective amount" 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 elicits a therapeutic effect whether administered in combination, sequentially or simultaneously. The compounds of the present invention, particularly the compounds of 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 injurious to its recipient. According to another aspect of the present invention, there is also provided a method for preparing a pharmaceutical preparation which comprises admixing a compound of the present invention, particularly a compound of formula (I), (I-1), (I-2) or (I-3) or its pharmaceutically acceptable salts with one or more pharmaceutically acceptable carriers, diluents or excipients. As used in the present invention, the term "pharmaceutically acceptable" refers to such compounds, materials, compositions and / or dosage forms that, within the scope of sound medical judgment, are suitable for contact with the tissues of a patient without excessive toxicity, irritation, allergic response or other problems and complications commensurate with a reasonable benefit / risk ratio and are effective for their intended uses.

[0189] The amount of the active ingredient combined with one or more adjuvants to produce a single dosage form will necessarily vary depending on the host to be treated and the particular 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 produce a single dosage form of the active ingredient will vary depending on the disease to be treated, the severity of the disease, the time of administration, the route of administration, the excretion rate of the compound used, the duration of treatment and the age, sex, weight and condition of the patient. Preferred unit dosage forms are those containing a daily dose or a divided dose or an appropriate fraction thereof of the above-described active ingredient of the present invention. Treatment may be initiated with a small dose that is clearly lower than the optimal dose of the compound. Thereafter, the dose is increased in smaller increments until the optimal effect is achieved in the circumstances. Generally, the most desirable concentration level at which the compound is administered is one that will generally provide effective results in anti-tumor aspects without causing any harmful or toxic side effects.

[0190] Compositions containing the compounds of the present invention can be formulated into unit dosage forms, each dosage 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 dosage for a human subject or other patient, each unit containing a predetermined amount of the active material (i.e., a compound represented by formula (I), (I-1), (I-2), or (I-3) as provided by the present invention herein) and a suitable pharmaceutical excipient, and the predetermined amount is calculated to be capable of producing the desired therapeutic effect.

[0191] The pharmaceutical compositions are suitable for administration by any suitable route, such as orally (including buccal or sublingual), rectally, nasally, topically (including buccal, sublingual, or transdermal), vaginally, or parenterally (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 RET-related cancers 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 a dysregulation in the expression, activity, or level of the RET gene, RET kinase, or any one 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 represented by 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 represented by formula (I), (I-1), (I-2), or (I-3) or a pharmaceutically acceptable salt or solvate thereof, or has been previously treated with other anti-cancer agents (e.g., after tumor resection or radiotherapy).

[0194] In some embodiments of any of the methods of the present invention, the 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, said at least one other therapeutic agent being 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 of 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, vandetanib, 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] The present invention also provides methods for 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 in treating cancer, wherein the amounts of the compound of formula (I), (I - 1), (I - 2) or (I - 3) or a pharmaceutically acceptable salt or solvate thereof and the other therapeutic agents are jointly effective in treating cancer.

[0200] The compounds and compositions of the present invention 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 present 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 present invention can be administered simultaneously or sequentially with other therapeutic agents by the same or different routes of administration. The compounds of the present 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 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, as the compounds of formula (I), (IA), (I-1), (I-2) or (I-3) or their pharmaceutically acceptable salts or solvates. Non-limiting examples of other therapeutic agents for the treatment of irritable bowel syndrome (IBS) include probiotics, fiber supplements (e.g., psyllium, methylcellulose), antidiarrheal agents (e.g., loperamide), bile acid binders (e.g., cholestyramine, colestipol, colesevelam), anticholinergic and antispasmodic agents (e.g., scopolamine, dicyclomine), antidepressants (e.g., tricyclic antidepressants such as imipramine or nortriptyline or selective serotonin reuptake inhibitors (SSRI) such as fluoxetine or paroxetine), antibiotics (e.g., 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"). 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.

[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 of the methods or uses described herein, the cancer (e.g., RET-related cancer) is a hematological cancer. In some embodiments of any of the methods or uses described herein, the cancer (e.g., RET-related cancer) is a solid tumor. In some embodiments of any of the methods or uses described herein, the cancer (e.g., RET-related cancer) is lung cancer (e.g., small cell lung cancer or non-small cell lung cancer), papillary thyroid cancer, medullary thyroid cancer, differentiated thyroid cancer, recurrent thyroid cancer, refractory differentiated thyroid cancer, lung adenocarcinoma, 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, gangliocytoma of the gastrointestinal mucosa, inflammatory myofibroblastic tumor, or cervical cancer.In some embodiments of any of the methods or uses described herein, the cancer (e.g., RET-related cancer) is selected from: 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, stomach 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 or pharmaceutically acceptable salt or solvate that is not a compound 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), the treatment being by combination administration or as a subsequent treatment to an existing drug treatment (e.g., another RET kinase inhibitor that is not a compound of formula (I), (I-1), (I-2), or (I-3) or its pharmaceutically acceptable salt or solvate). Exemplary RET kinase inhibitors are described herein (e.g., other RET kinase inhibitors that are not a compound of formula (I), (I-1), (I-2), or (I-3) or its pharmaceutically acceptable salt or solvate). 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 method or use 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 amount and by any route of administration to be effective in treating or alleviating the severity of the disease. The exact amount required will vary according to the patient, depending on race, age, general condition of the patient, severity of the infection, particular factors, mode of administration, and the like. The compound or composition can be used in a pharmaceutical 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 Marine 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 multiple peaks appeared, 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), a G1329A autosampler and a G1315B DAD detector were applied for analysis, and an ESI source was 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), a G1329A autosampler and a G1315D DAD detector were applied for analysis, and an ESI source was applied to the LC-MS spectrometer.

[0220] Both of the above spectrometers were equipped with an Agilent Zorbax SB-C18 column, with specifications 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 specifications of 2.1×30 mm, 4 μm, for 10 minutes, the flow rate was 0.6 mL / min, 5 - 95% of (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 were used throughout the present invention:

[0223] LiAlH4 lithium aluminum hydride

[0224] THF Tetrahydrofuran

[0225] DCM Dichloromethane

[0226] TEA, Et3N Triethylamine

[0227] K2CO3 Potassium carbonate

[0228] DMF N,N-Dimethylformamide

[0229] MeOH Methanol

[0230] NaH Sodium hydride

[0231] KMnO4 Potassium permanganate

[0232] PE Petroleum ether

[0233] EA Ethyl acetate

[0234] DCE 1,2-Dichloroethane

[0235] DIPEA N,N-Diisopropylethylamine

[0236] n-BuLi n-Butyllithium

[0237] DMA, DMAC N,N-Dimethylacetamide

[0238] Boc tert-Butyloxycarbonyl

[0239] t-BuOK Potassium tert-butoxide

[0240] NaHCO3 Sodium bicarbonate

[0241] NaOH Sodium hydroxide

[0242] DMSO Dimethyl sulfoxide

[0243] mL Milliliter

[0244] mg Milligram

[0245] mmol Millimole

[0246] ℃ Degree Celsius

[0247] h Hour

[0248] TLC Thin layer chromatography

[0249] g Gram

[0250] % Percent

[0251] mol / L Mole per liter

[0252] The following synthetic schemes describe 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, R a 、q have the definitions as described in the present invention.

[0253] Synthetic Scheme 1

[0254] Synthetic scheme for intermediate (IA-1a):

[0255]

[0256] The intermediate compound of formula (IA-1a) can be prepared by referring to the synthetic steps of the above intermediate synthetic scheme. Among them is the following sub-structural 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 2 is 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).

[0257] Synthesis scheme of intermediate (IA-1b):

[0258]

[0259] The intermediate compound of formula (IA-1b) can be prepared according to the synthesis steps of the synthesis scheme of intermediate (IA-1b). Among them, Hal 2 is F, Cl, Br or I, preferably Cl or Br; the compound of formula (IA-1a-6) reacts 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 (such as in DMSO solvent, under alkaline conditions, such as K2CO3) to obtain the compound of formula (IA-1b).

[0260] Synthesis scheme of intermediate (IA-5):

[0261]

[0262] The intermediate compound of formula (IA-5) can be prepared according to the synthesis steps of the synthesis scheme of intermediate (IA-5). Among them, Hal 2 and Hal are each independently F, Cl, Br or I, preferably Cl or Br. The compound of formula (IA-1a-6) reacts with the compound of formula (IA-2) under suitable conditions (such as alkaline conditions, the base is K2CO3) in a suitable solvent (such as N,N-dimethylacetamide, N,N-dimethylformamide) to obtain the compound of formula (IA-5).

[0263] Synthesis scheme 1:

[0264]

[0265] The compound of formula (IA) can be prepared according to the synthesis steps of synthesis 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 alkaline conditions, the base is K2CO3) in a suitable solvent (such as N,N-dimethylacetamide, N,N-dimethylformamide) to obtain the compound of formula (IA).

[0266] Synthesis scheme 2:

[0267]

[0268] The compound of formula (IAa) can be prepared according to the synthesis steps of synthesis scheme 2. Among them, Hal 1 and Hal 2 are each independently F, Cl, Br or I, preferably Cl or Br; represents a spiro ring containing a nitrogen atom and 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).

[0269] Synthesis Scheme 3

[0270]

[0271] The compound of formula (IA) can be obtained by referring to the synthesis steps of Synthesis Scheme 3. Among them, Ms is methanesulfonyl. 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).

[0272] Synthesis Scheme 4

[0273]

[0274] The compound of formula (IAb) can be obtained by referring to the synthesis steps of Synthesis Scheme 4. Among them, Hal 2 is F, Cl, Br, I, preferably Cl, Br; the compound of formula (IA-5) couples 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

[0275] Intermediate 1: 4-(6-fluoropyridin-3-yl)-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile

[0276]

[0277] Step 1: 6-bromo-4-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile

[0278] At room temperature, 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, the mixture was transferred to 0 °C and dodecyl mercaptan (97 mL, 397 mmol) was slowly added. After the addition was completed, the reaction was carried out overnight at 45 °C. 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, the mixture was allowed to stand, filtered, and the filter cake was washed repeatedly with water and petroleum ether 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] + 。

[0279] Step 2: 3-bromo-3-cyanopyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate

[0280] 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 below -10 °C, and trifluoromethanesulfonic anhydride (50 mL, 297.2 mmol) was slowly added. After stirring for 1 h, the mixture was allowed to rise to room temperature and react 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 evaporated to dryness, 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).

[0281] Step 3: 6-bromo-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0282] Under nitrogen protection, 3-bromo-3-cyanopyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate (61.5 g, 166 mmol), 2-fluoropyridine-5-boronic 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 mixture was allowed to return to room temperature naturally and reacted 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, the filtrate was concentrated by rotary evaporation, and purified by silica gel column chromatography (eluent PE / DCM (v / v) = 2:1 - 0:1) to obtain 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-d6)) 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).

[0283] 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

[0284] 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 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) and then with saturated brine (250 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent PE / DCM (v / v) = 2 / 1 - 0 / 1), and 8.5 g of an orange solid was obtained after concentration in vacuo, which was the target product (yield 93.0%). Rf = 0.15 (DCM). 1 H NMR (400 MHz, CDCl3) δ 8.99 (s, 1H), 8.43 (d, J = 2.1 Hz, 1H), 8.34 (s, 1H), 8.02 (td, J = 8.0, 2.5 Hz, 1H), 7.66 (s, 1H), 7.13 (dd, J = 8.5, 2.8 Hz, 1H), 1.40 (s, 12H).

[0285] Step 5: 4-(6-Fluoropyridin-3-yl)-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile

[0286] In a 250 mL single-necked flask, successively add 4-(6-fluoropyridin-3-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (8.5 g, 23 mmol), tetrahydrofuran (120 mL). Under ice bath conditions, slowly add sodium hydroxide solution (60 mL, 120 mmol, 2 mol / L), hydrogen peroxide (14 mL, 140 mmol, 30 mass%), and stir at low temperature. After monitoring the reaction to completion by TLC, slowly add sodium thiosulfate solution (50 mL, 150 mmol, 3 mol / L). After restoring to room temperature, add water (250 mL), extract with EA (250 mL×2), combine the organic phases and wash with 0.1 M NaOH solution (500 mL×2). Combine all the aqueous phases, adjust the pH to 4 with dilute hydrochloric acid, stir at room temperature for 15 min, filter by suction to obtain a wet filter cake. Extract the mother liquor with EA (250 mL×3), combine all the organic phases, dry over anhydrous sodium sulfate, filter, concentrate by rotary evaporation, and purify by silica gel column chromatography (eluent DCM\MeOH(v / v)=100 / 0 - 10 / 1) to obtain a light yellow solid. Combine all the solids, dry at 50 °C to obtain 5.1 g of a light yellow solid, which is the target product (yield 86.0%). Rf = 0.25 (DCM / MeOH(v / v)=100 / 1). LC-MS: m / z = 255.10[M+H] + 。 1 H NMR(400MHz,DMSO-d6)δ10.44-10.37(m,1H),8.54(s,1H),8.49-8.46(m,1H),8.42-8.40(m,1H),8.26-8.21(m,1H),7.40-7.35(m,1H),7.32-7.30(m,1H)。

[0287] Intermediate 2: 6-Hydroxy-4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0288]

[0289] Step 1: tert-Butyl 4-hydroxy-4-(pyridin-2-ylmethyl)piperidine-1-carboxylate

[0290] In a 50 mL two-necked flask under nitrogen protection, THF (9 mL) and 2-methylpyridine (0.644 mL, 6.52 mmol) were added. A solution of n-BuLi in hexane (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 solution of tert-butyl 4-oxopiperidine-1-carboxylate (1 g, 5.019 mmol) in THF (6 mL) was added at -78 °C. After the addition, the reaction 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. Purification by silica gel column chromatography (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).

[0291] Step 2: 4-(Pyridin-2-ylmethyl)piperidin-4-ol dihydrochloride

[0292] 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 concentrated by rotary evaporation 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 - 2HCl + H] + 。

[0293] 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

[0294] In a 10 mL microwave tube, 4-(2-pyridylmethyl)piperidin-4-ol dihydrochloride (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), DMSO (2.4 mL) were added, and the reaction was carried out under microwave irradiation at 85 °C for 6 h. TLC showed that the reaction was completed. The reaction solution was diluted with water (12 mL), extracted with EA (30 mL×2), the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation. Purification by silica gel column chromatography (eluent: pure EA - EA / MeOH (v / v: 50 / 1)) gave 0.19 g of a yellowish brown solid (yield 47%), which was the target product. LC-MS (ES-API): m / z = 427.20 [M + H] + 。 1 H NMR (400 MHz, CD3OD) 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).

[0295] Intermediate 3: 6-(2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)ethoxy)-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0296]

[0297] Step 1: 6-(2-chloroethyl)-2-oxa-6-azaspiro[3.3]heptane

[0298] 2-Oxa-6-azaspiro[3.3]heptane (2.0 g, 20 mmol), potassium carbonate (15 g, 108.5 mmol), 1-bromo-2-chloroethane (8.0 mL, 97.0 mmol) were added to a 100 mL single-necked flask, and then acetonitrile (20 mL) was added. After addition, the reaction was carried out at room temperature. After the reaction was completed, the insoluble solid was removed by suction filtration, the filter cake was washed with methanol, the organic phases were combined, concentrated, and the residue was purified by silica gel column chromatography to obtain 860 mg of the product.1 1H NMR (400 MHz, CDCl3): δ 4.74 (s, 4H), 3.47 - 3.39 (m, 6H), 2.72 (t, J = 6.3 Hz, 2H).

[0299] Step 2: 6-(2-(2-Oxa-6-azaspiro[3.3]heptan-6-yl)ethoxy)-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0300] Into a 25 mL flask, 4-(6-fluoropyridin-3-yl)-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile (Intermediate 1, 500 mg, 1.97 mmol), potassium carbonate (825 mg, 5.97 mmol), 6-(2-chloroethyl)-2-oxa-6-azaspiro[3.3]heptane (850 mg, 5.26 mmol), and DMA (6 mL) were successively added, and the reaction was carried out at 80 °C. After the reaction was detected to be complete by TLC, 20 mL of water was added to the reaction solution, and it was extracted with EA (80 mL × 2). The organic phase was washed with water (15 mL × 3), saturated brine (15 mL × 6), dried over anhydrous sodium sulfate, filtered, and the filtrate was purified by silica gel column chromatography (eluent: EA / MeOH (v / v) = 1 / 0 - 20 / 1) to obtain 210 mg of a yellow solid as the product. LC-MS: m / z = 380.20 [M+H] + 。 1 1H NMR (400 MHz, CDCl3) δ 8.38 (d, J = 2.2 Hz, 1H), 8.21 (s, 1H), 8.19 (d, J = 2.0 Hz, 1H), 8.01 (td, J = 8.4, 2.5 Hz, 1H), 7.18 (d, J = 2.0 Hz, 1H), 7.13 (dd, J = 8.4, 2.8 Hz, 1H), 4.75 (s, 4H), 4.03 (t, J = 5.2 Hz, 2H), 3.52 (s, 4H), 2.87 (t, J = 5.2 Hz, 2H). Intermediate 4: 5-(Azetidin-3-yloxy)-2-methoxypyridine dihydrochloride

[0301]

[0302] Step 1: tert-Butyl N-Boc-3-((methylsulfonyl)oxy)azetidine-1-carboxylate

[0303] Under ice 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, methanesulfonyl 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 materials 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) δ 5.23–5.12 (m, 1H), 4.30–4.19 (m, 2H), 4.10–4.03 (m, 2H), 3.04 (s, 3H), 1.42 (s, 9H).

[0304] Step 2: N-Boc-3-((6-methoxypyridin-3-yl)oxy)azetidine

[0305] 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 slowly added, and the mixture was stirred for 10 min. The temperature was raised to 50 °C and 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 temperature was lowered 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 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).

[0306] Step 3: 5-(Azetidin-3-yloxy)-2-methoxypyridine dihydrochloride

[0307] To a 25 mL single-necked flask, N-Boc-3-((6-methoxypyridin-3-yl)oxy)azetidine (600 mg, 0.21 mmol), HCl / EA (3N, 2.5 mL) were added successively. Stir at rt for 1 h. The reaction solution was rotary evaporated to a pale yellow solid, which was directly used for the next reaction. LC-MS: m / z = 181.1 [M - 2HCl + H] + 。

[0308] Intermediate 5: 6-Hydroxy-4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0309]

[0310] Step 1: tert-Butyl 4-((6-methoxypyridin-3-yl)methyl)piperazine-1-carboxylate

[0311] To 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), 1,2-dichloroethane (12 mL) were added successively. Stir at room temperature for 5 h. After the reaction was completed, it was filtered. The filtrate was rotary evaporated, and the residue was purified by silica gel column chromatography (PE / EA = 1:1) to obtain 1.32 g of a brownish yellow 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 H 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).

[0312] Step 2: 1-((6-Methoxypyridin-3-yl)methyl)piperazine dihydrochloride

[0313] 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 added successively, and the mixture was stirred at room temperature overnight. The solvent was directly evaporated to dryness to obtain a viscous oily substance, which was placed in an oven and dried under vacuum at 60 °C to obtain 1.2 g of a white solid as the target product, with a yield of 100%, Rf = 0.0 (PE / EA = 1:1). LC-MS: m / z = 208.20 [M - 2HCl] + 。

[0314] Step 3: 6-Hydroxy-4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0315] In a 10 mL microwave tube, 4-(6-fluoropyridin-3-yl)-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile (Intermediate 1, 300 mg, 1.18 mmol), 1-((6-methoxypyridin-3-yl)methyl)piperazine dihydrochloride (496 mg, 1.77 mmol), and DIPEA (0.78 mL, 4.72 mmol) were added successively, and the mixture was dissolved in dimethyl sulfoxide (3 mL). The reaction was heated at 85 °C under microwave for 8 h. After the reaction was completed, water (20 mL) was added to the reaction solution, and the mixture was extracted with EA (100 mL × 5). The combined organic phases were washed with water (100 mL × 2) and saturated brine (100 mL) respectively, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness. The residue was purified by silica gel column chromatography (PE / EA (v / v = 5 / 1 - 1 / 2)) to obtain 112 mg of a yellow solid as the target product (yield 21.5%), Rf = 0.15 (PE / EA = 1:1). LC-MS: m / z = 442.70 [M + H] + 。

[0316] Intermediate 6: 6-(2-(8-oxa-2-azaspiro[4.5]dec-2-yl)ethoxy)-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0317]

[0318] Step 1: 2-(2-chloroethyl)-8-oxa-2-azaspiro[4.5]decane

[0319] In a 100 mL single-necked flask, 8-oxa-3-azaspiro[4.5]decane (2.5 g, 18 mmol), potassium carbonate (8.5 g, 62 mmol) were successively added, and acetonitrile (40 mL) was added to dissolve them. Then 1-bromo-2-chloroethane (2.5 mL, 30 mmol) was added, and the reaction was carried out at room temperature. After the reaction was detected by TLC and the solution was allowed to stand, the supernatant was clarified and then filtered, concentrated, and purified by silica gel column chromatography (the eluent was PE / EA (v / v) = 2 / 11 / 1), and 1.2 g of a pale yellow liquid was obtained as the product. 1 1H NMR (400 MHz, CDCl3) δ 3.63 (t, J = 5.3 Hz, 4H), 3.56 (t, J = 7.0 Hz, 2H), 2.78 (t, J = 7.0 Hz, 2H), 2.65 (t, J = 6.9 Hz, 2H), 2.49 (s, 2H), 1.69 (t, J = 6.9 Hz, 2H), 1.63 - 1.53 (m, 4H).

[0320] Step 2: 6-(2-(8-oxa-2-azaspiro[4.5]dec-2-yl)ethoxy)-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0321] In a 50 mL flask, 4-(6-fluoro-3-pyridinyl)-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile (Intermediate 1, 300 mg, 1.18 mmol), potassium carbonate (510 mg, 3.69 mmol), 3-(2-chloroethyl)-8-oxa-3-azaspiro[4.5]decane (370 mg, 1.82 mmol), DMA (5 mL) were successively added, and the reaction was carried out at 80 °C. After the reaction was detected by TLC and the reaction solution was added with 20 mL of water, it was extracted with EA (80 mL × 2). The organic phase was washed with water (15 mL × 3), washed with saturated brine (15 mL × 6), dried over anhydrous sodium sulfate and then filtered. The filtrate was purified by silica gel column chromatography (the eluent was DCM / MeOH (v / v) = 20 / 1 - 10 / 1), and 135 mg of a yellow solid was obtained as the product. LC-MS: m / z = 422.20 [M+H] + 。 11H NMR (400 MHz, CDCl3) δ 8.39 (d, J = 2.1 Hz, 1H), 8.24 (d, J = 1.9 Hz, 1H), 8.22 (s, 1H), 8.02 (td, J = 8.3, 2.5 Hz, 1H), 7.21 (d, J = 1.9 Hz, 1H), 7.13 (dd, J = 8.4, 2.8 Hz, 1H), 4.16 (t, J = 5.6 Hz, 2H), 3.67 - 3.63 (m, 4H), 2.94 (t, J = 5.5 Hz, 2H), 2.73 (t, J = 6.9 Hz, 2H), 2.56 (s, 2H), 1.72 (t, J = 6.9 Hz, 2H), 1.62 - 1.57 (m, 4H).

[0322] Example 1: 6-(2-((6-Oxaspiro[3.3]heptan-2-yl)oxy)ethoxy)-4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0323]

[0324] Step 1: Ethyl 2-(6-oxaspiro[3.3]heptan-2-yloxy)acetate

[0325] In a 25 mL two-necked flask, NaH (127 mg, 3.175 mmol) was added. The flask was evacuated under nitrogen protection, dissolved in anhydrous THF (10 mL) at 0 °C, and liquid 6-oxaspiro[3.3]heptan-2-ol (300 mg, 2.628 mmol) was added. After addition, the mixture was stirred at room temperature for 2 h and then transferred to 0 °C. Ethyl 2-bromoacetate (0.32 mL, 2.9 mmol) was slowly added. After addition, the mixture was stirred at room temperature. TLC showed that the reaction was complete (oxidized by KMnO4). 15 mL of water was added to quench the reaction, and the mixture was extracted with EA (60 mL × 2). The combined organic phases were washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation. The residue was purified by silica gel column chromatography (eluent PE / EA (v / v) = 10 / 1 - 1 / 1) to obtain 0.222 g of an oily liquid (yield 42.2%), which was the target product. 1 1H NMR (400 MHz, CDCl3) δ 4.63 (d, J = 12.0 Hz, 4H), 4.19 (q, J = 7.1 Hz, 2H), 3.94 (s, 2H), 3.93–3.85 (m, 1H), 2.61–2.52 (m, 2H), 2.23–2.14 (m, 2H), 1.26 (t, J = 7.1 Hz, 3H).

[0326] Step 2: 2-(6-Oxaspiro[3.3]heptan-2-yloxy)ethanol

[0327] In a 25 mL two-necked flask, LiAlH4 (0.085 g, 2.2 mmol) and 5 mL of THF were added to form a solution. The mixture was evacuated under nitrogen protection. Ethyl 2-(6-oxaspiro[3.3]heptan-2-yloxy)acetate (222 mg, 1.109 mmol) was dissolved in THF (3 mL) and slowly added to the two-necked flask at 0 °C, and the reaction was carried out under insulation. TLC (oxidized by KMnO4) showed that the reaction was completed. 10 mL of saturated ammonium chloride solution was added to quench the reaction. The mixture was extracted with EA (20 mL × 2), and the combined organic phases were washed with 15 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated by rotary evaporation, and the residue was purified by silica gel column chromatography (eluent pure DCM - DCM / EA (v / v = 4 / 1 - 1 / 4)) to obtain 0.103 g of a pale yellow oil (yield 58.7%), which was the target product. 1 1H NMR (400 MHz, CDCl3) δ 4.65 (d, J = 16.7 Hz, 4H), 3.83 (dd, J = 13.9, 7.0 Hz, 1H), 3.73–3.63 (m, 2H), 3.46–3.36 (m, 2H), 2.68–2.47 (m, 2H), 2.15–2.08 (m, 2H).

[0328] Step 3: 2-(6-oxaspiro[3.3]heptan-2-yloxy)ethyl methanesulfonate

[0329] Under ice bath conditions, 2-(6-oxaspiro[3.3]heptan-2-yloxy)ethanol (100 mg, 0.632 mmol) was added to a 10 mL single-necked flask and dissolved in DCM (1.5 mL). TEA (0.133 mL, 0.947 mmol) was added, and methanesulfonyl chloride (0.065 mL, 0.83 mmol) was slowly added dropwise. Then the mixture was allowed to warm to room temperature and react. TLC showed that the reaction was completed. 3 mL of water was added to quench the reaction. The mixture was extracted with DCM (15 mL × 2), and the combined organic phases were washed with 8 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated by rotary evaporation to obtain a yellow liquid, which was directly used in the next step of the reaction.

[0330] Step 4: 6-(2-((6-oxaspiro[3.3]heptan-2-yl)oxy)ethoxy)-4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0331] Add 2-(6-oxaspiro[3.3]heptan-2-yloxy)ethyl methanesulfonate (22 mg, 0.093 mmol), K2CO3 (26 mg, 0.186 mmol), and 6-hydroxy-4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (20 mg, 0.04530 mmol) to a 5 mL single-necked flask. Dissolve with DMF (1.0 mL), and stir the reaction at 60 °C overnight. TLC plate shows that the reaction is complete. Add 10 mL of water for washing, extract with EA (40 mL × 2), combine the organic phases, wash with 20 mL of saturated brine, dry over anhydrous sodium sulfate, filter, rotary evaporate, and purify the residue by silica gel column chromatography (eluent pure DCM - DCM / MeOH (v / v = 10 / 1)) to obtain 0.004 g of a pale yellow solid (yield 20%), which is the target product. LC-MS (ES-API): m / z = 582.20 [M+H] + 。 1 H NMR (400 MHz, CDCl3) δ 8.31 (s, 1H), 8.19 (s, 1H), 8.15 (s, 1H), 8.10 (s, 1H), 7.70 (d, J = 8.6 Hz, 1H), 7.54 (s, 1H), 7.11 (d, J = 2.3 Hz, 1H), 6.79–6.74 (m, 2H), 4.66 (d, J = 18.9 Hz, 4H), 4.16–4.12 (m, 2H), 3.94 (s, 3H), 3.89 (d, J = 7.1 Hz, 1H), 3.69 (ddd, J = 13.0, 7.6, 4.7 Hz, 8H), 2.64–2.55 (m, 4H), 2.35–2.32 (m, 2H), 2.24–2.20 (m, 2H).

[0332] Example 2: 4-(6-(4-Hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)-6-((6-hydroxy-6-methylspiro[3.3]heptan-2-yl)methoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0333]

[0334] Step 1: Methyl 6-hydroxy-6-methyl-spiro[3.3]heptane-2-carboxylate

[0335] In a 50 mL two-necked flask, under nitrogen protection, methyl 6-oxospiro[3.3]heptane-2-carboxylate (1000 mg, 5.946 mmol) was added, dissolved in THF (10 mL), placed in a low-temperature bath at -40 °C, and a THF solution of methylmagnesium bromide (3.0 mL, 9.0 mmol, 3 mol / L) was slowly added. The reaction was kept warm for 2 h. TLC showed that the reaction was complete. 20 mL of saturated ammonium chloride was added to quench the reaction, and the mixture was extracted with EA (50 mL × 2). The combined organic phases were washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated by rotary evaporation, and purified by silica gel column chromatography (eluent PE / EA (v / v) = 8 / 1 - 2 / 1) to obtain 0.343 g of a transparent oil (yield 32%), which was the target product. 1 1H NMR (400 MHz, CDCl3) δ 3.65 (s, 3H), 3.01 (p, J = 8.5 Hz, 1H), 2.35–2.07 (m, 8H), 1.31 (s, 3H).

[0336] Step 2: 2-(Hydroxymethyl)-6-methylspiro[3.3]heptan-6-ol

[0337] In a 25 mL two-necked flask, LiAlH4 (92 mg, 2.424 mmol) was added, and 3 mL of THF was added to form a solution. Under nitrogen protection, methyl 6-hydroxy-6-methylspiro[3.3]heptane-2-carboxylate (342 mg, 1.856 mmol) was dissolved in 10 mL of THF and slowly added to the two-necked flask at 0 °C. After the addition was complete, the temperature was raised to room temperature and the reaction was carried out overnight. TLC showed that the reaction was complete. 5 mL of water and 10 mL of saturated ammonium chloride solution were added to quench the reaction, and the mixture was extracted with EA (30 mL × 2). The combined organic phases were washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated by rotary evaporation, and the residue was purified by silica gel column chromatography (eluent PE / EA (v / v = 4 / 1 - 1 / 2) to obtain 0.272 g of a transparent oil (yield 94%), which was the target product. 1 1H NMR (400 MHz, CDCl3) δ 3.55 (d, J = 6.8 Hz, 2H), 2.43–2.31 (m, 1H), 2.25–2.04 (m, 6H), 1.78 (dd, J = 19.0, 8.3 Hz, 2H), 1.64 (s, 2H), 1.31 (s, 3H).

[0338] Step 3: (6-Hydroxy-6-methylspiro[3.3]heptan-2-yl) methanesulfonate

[0339] Under ice bath conditions, 2-(hydroxymethyl)-6-methyl-spiro[3.3]heptan-6-ol (60 mg, 0.384 mmol) was added to a 10 mL single-necked flask, dissolved in DCM (1.5 mL), TEA (0.09 mL, 0.6 mmol) was added, methanesulfonyl chloride (0.04 mL, 0.5 mmol) was slowly added dropwise, and then the reaction was allowed to rise to room temperature naturally for 30 min. TLC showed that the reaction was complete. 3 mL of water was added to quench the reaction, and it was extracted with DCM (15 mL×2), washed with 8 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was rotary evaporated, and the residue was purified by flash silica gel column chromatography (eluent PE / EA (v / v = 4 / 1 - 1 / 2)) to obtain 0.063 g of a transparent oil (yield 70%), which was the target product.

[0340] Step 4: 4-(6-(4-Hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)-6-((6-hydroxy-6-methylspiro[3.3]hept-2-yl)methoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0341] 6-Hydroxy-4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Intermediate 2, 30 mg, 0.071 mmol), K2CO3 (39 mg, 0.279 mmol), and DMF (3 mL) were added to a 10 mL single-necked flask. After purging with nitrogen for 5 min, (6-hydroxy-6-methyl-spiro[3.3]hept-2-yl)methyl sulfonate (33 mg, 0.141 mmol) was added, and the reaction was heated at 60 °C in an oil bath overnight. TLC showed that the reaction was complete. 15 mL of water was added, and it was extracted with EA (40 mL×2). The combined organic phases were washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was rotary evaporated, and the residue was purified by silica gel column chromatography (pure DCM - DCM / MeOH (v / v = 15 / 1)) to obtain 13 mg of a pale yellow solid (yield 33%), which was the target product. LC-MS (ES-API): m / z = 565.25 [M+H] + 。 11H NMR (400 MHz, CDCl3) δ 8.52 (d, J = 4.2 Hz, 1H), 8.30 (d, J = 2.2 Hz, 1H), 8.18 (s, 1H), 8.07 (d, J = 1.9 Hz, 1H), 7.71–7.60 (m, 2H), 7.22–7.17 (m, 1H), 7.13 (d, J = 7.7 Hz, 1H), 7.07 (d, J = 1.9 Hz, 1H), 6.77 (d, J = 8.9 Hz, 1H), 4.09 (d, J = 12.9 Hz, 2H), 3.93 (d, J = 6.4 Hz, 2H), 3.54–3.43 (m, 2H), 2.94 (s, 2H), 2.75–2.66 (m, 1H), 2.22 (dt, J = 23.5, 11.5 Hz, 4H), 2.12 (s, 2H), 2.00–1.93 (m, 2H), 1.72–1.56 (m, 6H), 1.34 (s, 3H).

[0342] Example 3: 6-(2-((7-Azaspiro[3.4]octan-2-yl)oxy)ethoxy)-4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0343]

[0344] Step 1: tert-Butyl 2-(2-ethoxy-2-oxoethoxy)-7-azaspiro[3.4]octane-7-carboxylate

[0345] In a 25 mL two-necked flask, NaH (72 mg, 1.8 mmol) was added. After evacuating and filling with nitrogen multiple times, the flask was placed at 0 °C and anhydrous THF (17 mL) was added to form a suspension. tert-Butyl 2-hydroxy-7-azaspiro[3.4]octane-7-carboxylate (340 mg, 1.496 mmol) was added. After addition, the temperature was raised to room temperature and the mixture was stirred for 2 h. The reaction mixture was transferred to 0 °C, and ethyl 2-bromoacetate (0.183 mL, 1.65 mmol) was slowly added. Then the mixture was stirred at room temperature overnight. TLC showed that the reaction was complete. The reaction mixture was quenched with 15 mL of water and extracted with EA (60 mL × 2). The organic phase was washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation. Purification by silica gel column chromatography (eluent PE / EA (v / v = 10 / 1 - 2 / 1)) gave 0.143 g (yield 31%) of an oily liquid, which was the target product. LC-MS (ES-API): m / z = 258.1 [M - 56 + H] + . 11H NMR (400 MHz, CDCl3) δ 4.21 (q, J = 7.1 Hz, 2H), 4.11–4.03 (m, 1H), 4.00–3.95 (m, 2H), 3.37–3.21 (m, 4H), 2.33–2.21 (m, 2H), 2.10–1.97 (m, 2H), 1.88–1.75 (m, 2H), 1.44 (s, 9H), 1.28 (t, J = 7.1 Hz, 3H).

[0346] Step 2: tert-Butyl 2-(2-hydroxyethoxy)-7-azaspiro[3.4]octane-7-carboxylate

[0347] In a 25 mL two-necked flask, add LiAlH4 (40.5 mg, 1.07 mmol), add 3 mL of THF to form a suspension, evacuate under nitrogen protection for several times. Dissolve tert-butyl 2-(2-ethoxy-2-oxoethoxy)-7-azaspiro[3.4]octane-7-carboxylate (134 mg, 0.428 mmol) in 3 mL of THF, and slowly add it to the two-necked flask at -40 °C in a low-temperature bath. Keep the reaction at this temperature for 1 h. TLC shows that the reaction is complete. Add 12 mL of water to quench the reaction, extract with EA (25 mL × 2). Wash the organic phase with 15 mL of saturated brine, dry over anhydrous sodium sulfate, filter, rotary evaporate the filtrate, and purify by silica gel column chromatography (eluent PE / EA (v / v = 4 / 1 - 1 / 4)) to obtain 0.101 g of a transparent oily substance (yield 87%), which is the target product. LC-MS (ES-API): m / z = 216.3 [M - 56 + H] + 。 1 1H NMR (400 MHz, CDCl3) δ 4.04–3.94 (m, 1H), 3.75–3.67 (m, 2H), 3.46–3.41 (m, 2H), 3.37–3.21 (m, 4H), 2.32–2.20 (m, 2H), 2.14 (s, 1H), 2.00–1.89 (m, 2H), 1.85–1.78 (m, 2H), 1.43 (s, 9H).

[0348] Step 3: tert-Butyl 2-(2-methylsulfonyloxyethoxy)-7-azaspiro[3.4]octane-7-carboxylate

[0349] Under ice bath conditions, 2-(2-hydroxyethoxy)-7-azaspiro[3.4]octane-7-carboxylic acid tert-butyl ester (95 mg, 0.350 mmol) was added to a 5 mL single-necked flask, dissolved in DCM (1.5 mL), TEA (0.074 mL, 0.53 mmol) was added, methanesulfonyl chloride (0.036 mL, 0.46 mmol) was slowly added dropwise, and then the reaction was allowed to rise to room temperature naturally for 1 h. TLC showed that the reaction was complete. The reaction was quenched by adding 3 mL of water, extracted with DCM (10 mL×2), the organic phase was washed with 5 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated by rotary evaporation, and purified by flash silica gel column chromatography (eluent PE:EA (v / v = 4 / 1 - 1 / 2)) to obtain 0.117 g of a yellow transparent oil (yield 96%), which was the target product. 1 1H NMR (400 MHz, CDCl3) δ 4.37–4.31 (m, 2H), 4.01 (p, J = 6.8 Hz, 1H), 3.63–3.57 (m, 2H), 3.37–3.21 (m, 4H), 3.05 (s, 3H), 2.33–2.21 (m, 2H), 2.02–1.90 (m, 2H), 1.87–1.77 (m, 2H), 1.44 (s, 9H).

[0350] Step 4: 2-(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)ethoxy)-7-azaspiro[3.4]octane-7-carboxylic acid tert-butyl ester

[0351] A 5 mL single-necked flask was charged with 6-hydroxy-4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Intermediate 2, 30 mg, 0.071 mmol), K2CO3 (39 mg, 0.280 mmol), dissolved in DMF (1.5 mL), and then 2-(2-methylsulfonyloxyethoxy)-7-azaspiro[3.4]octane-7-carboxylic acid tert-butyl ester (49 mg, 0.140 mmol) was added. The mixture was stirred at 60 °C overnight. TLC showed that the reaction was complete. The reaction mixture was washed with 10 mL of water, extracted with EA (40 mL×2), the organic phase was washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated by rotary evaporation, and purified by silica gel column chromatography (eluent pure DCM - DCM / MeOH (v / v = 10 / 1)) to obtain 26.5 mg of a pale yellow solid (yield 55.4%), which was the target product. LC-MS (ES-API): m / z = 680.30 [M+H] + 。 11H NMR (400 MHz, CDCl3) δ 8.52 (d, J = 4.2 Hz, 1H), 8.30 (d, J = 2.3 Hz, 1H), 8.19 (s, 1H), 8.13 (s, 1H), 7.72–7.62 (m, 2H), 7.22–7.17 (m, 1H), 7.13 (d, J = 7.5 Hz, 2H), 6.77 (d, J = 9.0 Hz, 1H), 4.18–4.13 (m, 2H), 4.12–4.03 (m, 3H), 3.78–3.72 (m, 2H), 3.52–3.45 (m, 2H), 3.38–3.25 (m, 4H), 2.94 (s, 2H), 2.35–2.25 (m, 2H), 2.06–1.97 (m, 2H), 1.87–1.80 (m, 2H), 1.66–1.63 (m, 4H), 1.45 (s, 9H).

[0352] Step 5: 6-(2-((7-Azaspiro[3.4]octan-2-yl)oxy)ethoxy)-4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile trihydrochloride

[0353] In a 10 mL single-necked flask, 2-(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)ethoxy)-7-azaspiro[3.4]octane-7-carboxylic acid tert-butyl ester (23.8 mg, 0.0350 mmol) and hydrochloric acid ethyl acetate solution (2 mL, 8 mmol, 4 mol / L) were added and stirred at room temperature for 1 h. TLC showed that the reaction was complete. The reaction solution was directly evaporated to dryness and dried under vacuum to obtain the theoretical amount of yellowish-white solid product. LC-MS (ES-API): m / z = 580.2 [M - 3HCl + H] + 。

[0354] Step 6: 6-(2-((7-Azaspiro[3.4]octan-2-yl)oxy)ethoxy)-4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0355] Under ice bath conditions, saturated sodium bicarbonate (1 mL) was added to a 5 mL single-necked flask containing 6-(2-((7-azaspiro[3.4]octan-2-yl)oxy)ethoxy)-4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile trihydrochloride (22.8 mg, 0.035 mmol). The pH was adjusted to make the solution alkaline, and 3 mL of DCM was added and stirred for 5 min. The organic phase was separated, and the aqueous phase was extracted with DCM (5 mL × 2). The organic phases were combined, washed with 5 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to obtain 14 mg of a pale yellow solid (yield 69%), which was the target product. LC-MS (ES-API): m / z = 580.2 [M+H] + 。 1 H NMR (400 MHz, CDCl3) δ 8.52 (d, J = 4.3 Hz, 1H), 8.30 (d, J = 2.1 Hz, 1H), 8.19 (s, 1H), 8.13 (d, J = 1.7 Hz, 1H), 7.70–7.61 (m, 2H), 7.21–7.17 (m, 1H), 7.13 (d, J = 7.5 Hz, 2H), 6.77 (d, J = 8.9 Hz, 1H), 4.18–4.12 (m, 2H), 4.07 (dd, J = 18.6, 14.6 Hz, 3H), 3.75 (d, J = 3.6 Hz, 2H), 3.53–3.44 (m, 2H), 3.07–2.84 (m, 6H), 2.33–2.25 (m, 3H), 2.07–2.01 (m, 2H), 1.84 (d, J = 7.3 Hz, 2H), 1.65 (d, J = 3.9 Hz, 4H).

[0356] Example 4: 6-(2-(2-Oxa-6-azaspiro[3.3]heptan-6-yl)ethoxy)-4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0357]

[0358] 6-(2-(2-Oxa-6-azaspiro[3.3]heptan-6-yl)ethoxy)-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Intermediate 3, 28 mg, 0.074 mmol), 4-(pyridin-2-ylmethyl)piperidin-4-ol hydrochloride (Intermediate 2 Step 2, 32 mg, 0.14 mmol), potassium carbonate (40 mg, 0.29 mmol), 4-dimethylaminopyridine (3 mg, 0.024 mmol), DMSO (1 mL) were added to a 5 mL single-necked flask and reacted in an oil bath at 90 °C. After the reaction was completed as detected by TLC, the reaction solution was cooled to room temperature, 5 mL of water was added, and it was extracted with EA (20 mL × 2). The organic phase was washed with water (10 mL × 4) and saturated brine (10 mL × 2), dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated by rotary evaporation, and the residue was purified by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 20 / 1 - 10 / 1) to obtain 34 mg of a yellow solid as the target product. LC-MS: m / z = 552.30 [M+H] + 。 1 H NMR (400 MHz, CDCl3) δ 8.52 (d, J = 4.4 Hz, 1H), 8.30 (d, J = 2.1 Hz, 1H), 8.19 (s, 1H), 8.09 (s, 1H), 7.70 - 7.62 (m, 2H), 7.23 - 7.18 (m, 1H), 7.13 (d, J = 7.8 Hz, 1H), 7.10 (d, J = 1.7 Hz, 1H), 6.77 (d, J = 8.9 Hz, 1H), 4.76 (s, 4H), 4.09 (d, J = 12.9 Hz, 2H), 4.01 (t, J = 5.0 Hz, 2H), 3.54 (s, 4H), 3.52 - 3.45 (m, 2H), 2.94 (s, 2H), 2.87 (t, J = 4.8 Hz, 2H), 1.67 - 1.61 (m, 4H).

[0359] Example 5: 4-(6-(4-Hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)-6-((6-methoxyspiro[3.3]heptan-2-yl)methoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0360]

[0361] Step 1: Methyl 6-hydroxyspiro[3.3]heptane-2-carboxylate

[0362] Methyl 6-oxospiro[3.3]heptane-2-carboxylate (1.4 g, 8.3 mmol) was added to a 100 mL two-necked flask. After displacing the nitrogen, 10 mL of THF was added to dissolve it. At -78 °C, lithium tri-tert-butoxyaluminum hydride (4.6 g, 17 mmol) dissolved in 15 mL of THF was added dropwise. After the addition was complete, the reaction was carried out at this temperature. After the reaction was completed, 30 mL of water was added to quench the reaction, and a large amount of white gel-like substance appeared. It was filtered by suction. The aqueous phase was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (50 mL), filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (eluent PE / EA (v / v) = 10 / 1) to obtain 1.2 g of a colorless liquid, which was the target product. Rf = 0.3 (PE / EA (v / v) = 5 / 1), LC-MS: m / z = 171.15 [M+H] + 。 1 1H NMR (400 MHz, CDCl3) δ 4.15 (p, J = 7.2 Hz, 1H), 3.64 (s, 3H), 3.01 (p, J = 8.5 Hz, 1H), 2.50 - 2.40 (m, 1H), 2.36 - 2.24 (m, 3H), 2.23 - 2.11 (m, 2H), 2.03 (s, 1H), 1.89 (m, 2H).

[0363] Step 2: Methyl 6-methoxyspiro[3.3]heptane-2-carboxylate

[0364] Methyl 6-hydroxyspiro[3.3]heptane-2-carboxylate (1.2 g, 7.1 mmol) was added to a 100 mL single-necked flask. THF (18 mL) was added to dissolve it. Sodium hydride (560 mg, 14.0 mmol, 60 mass%) was added in two portions at 10 °C. After 15 min, methyl iodide (1.0 mL, 16 mmol) was added, and the reaction was carried out at room temperature. After the reaction was completed, water (30 mL) was added to quench the reaction. It was extracted with ethyl acetate (50 mL × 3). The organic phase was washed with water (30 mL × 2) and then dried over anhydrous sodium sulfate, filtered and concentrated. Silica gel column chromatography (eluent PE / EA (v / v) = 20 / 1 - 5 / 1) gave 480 mg of a colorless liquid. Rf = 0.8 (PE / EA (v / v) = 5 / 1), 1 1H NMR (400 MHz, CDCl3) δ 3.79 - 3.70 (m, 1H), 3.66 (s, 3H), 3.19 (s, 3H), 3.03 (p, J = 8.5 Hz, 1H), 2.44 - 2.36 (m, 1H), 2.33 - 2.13 (m, 5H), 1.91 (m, 2H).

[0365] Step 3: (6-Methoxyspiro[3.3]heptan-2-yl)methanol

[0366] After replacing the nitrogen in a 25 mL two-necked flask, methyl 6-methoxyspiro[3.3]heptane-2-carboxylate (480 mg, 2.6 mmol) dissolved in 10 mL of THF was added. After stirring at 10 °C for 10 min, diisobutylaluminum hydride (8.0 mL, 8.0 mmol, 1 mol / L) was added dropwise. After the addition, the reaction was carried out at room temperature. After monitoring the reaction by TLC and quenching the reaction with water, the reaction solution became gel-like. 14 mL of HCl (1 N) was added to completely dissolve it. The solution was extracted with ethyl acetate (80 mL × 2). The organic phase was washed with water twice (30 mL × 2), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (eluent PE / EA (v / v) = 5 / 1) to obtain 330 mg of a colorless liquid. Rf = 0.3 (PE / EA (v / v) = 5:1), 1 1H NMR (400 MHz, CDCl3) δ 3.76 (p, J = 7.1 Hz, 1H), 3.56 (d, J = 6.8 Hz, 2H), 3.21 (s, 3H), 2.46 - 2.33 (m, 2H), 2.23 (dt, J = 11.6, 6.0 Hz, 1H), 2.13 - 2.00 (m, 2H), 1.96 - 1.84 (m, 2H), 1.78 (dd, J = 11.5, 5.8 Hz, 2H).

[0367] Step 4: (6-Methoxyspiro[3.3]hept-2-yl)methyl methanesulfonate

[0368] (6-Methoxyspiro[3.3]heptan-2-yl)methanol (340 mg, 2.2 mmol) was added to a 25 mL single-necked flask, and 4 mL of DCM was added to dissolve it. Triethylamine (0.7 mL, 5 mmol) was added, and methanesulfonyl chloride (0.3 mL, 3 mmol) was added dropwise at 0 °C. The reaction was carried out at room temperature. After the reaction was completed, 10 mL of water was added. The reaction solution was extracted with DCM (20 mL × 2). The combined organic phases were washed with water (20 mL × 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (eluent PE / EA (v / v) = 5 / 1) to obtain 340 mg of a liquid. Rf = 0.3 (PE:EA = 5:1), 11H NMR (400 MHz, CDCl3) δ 4.17 (d, J = 6.8 Hz, 2H), 3.77 (p, J = 7.1 Hz, 1H), 3.21 (s, 3H), 3.01 (s, 3H), 2.70 - 2.56 (m, 1H), 2.46 - 2.37 (m, 1H), 2.27 (dt, J = 11.6, 5.9 Hz, 1H), 2.21 - 2.08 (m, 2H), 1.91 (m, 4H). Step 5: 4-(6-(4-Hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)-6-((6-methoxyspiro[3.3]heptan-2-yl)methoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0369] 6-Hydroxy-4-[6-[4-hydroxy-4-(2-pyridinylmethyl)-1-piperidinyl]-3-pyridinyl]pyrazolo[1,5-a]pyridine-3-carbonitrile (Intermediate 2, 35 mg, 0.082 mmol), (6-methoxyspiro[3.3]hept-2-yl)methyl methanesulfonate (22 mg, 0.094 mmol), potassium carbonate (16 mg, 0.11 mmol), and DMF (0.6 mL) were added to a 5 mL single-necked flask and reacted at 90 °C in an oil bath. After the reaction was completed, 5 mL of water was added to the reaction solution, and the mixture was extracted with EA (20 mL × 3). The combined organic phases were washed with water (20 mL × 6), saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (eluent DCM / MeOH (v / v) = 30:1) to obtain 10 mg of a yellow solid. LC-MS: m / z = 565.90 [M + H] + , 1 1H NMR (600 MHz, CDCl3) δ 8.52 (d, J = 4.3 Hz, 1H), 8.31 (d, J = 2.3 Hz, 1H), 8.18 (s, 1H), 8.08 (d, J = 1.9 Hz, 1H), 7.66 (m, 2H), 7.22 - 7.18 (m, 1H), 7.14 (d, J = 7.7 Hz, 1H), 7.08 (d, J = 1.9 Hz, 1H), 6.77 (d, J = 8.9 Hz, 1H), 4.09 (d, J = 13.1 Hz, 2H), 3.94 (d, J = 6.4 Hz, 2H), 3.83 - 3.73 (m, 1H), 3.53 - 3.44 (m, 2H), 3.21 (s, 3H), 2.95 (s, 2H), 2.76 - 2.68 (m, 1H), 2.46 - 2.39 (m, 1H), 2.31 - 2.25 (m, 1H), 2.24 - 2.20 (m, 1H), 2.19 - 2.14 (m, 1H), 1.98 - 1.90 (m, 4H), 1.69 - 1.62 (m, 4H).

[0370] Example 6: 6-((1,4-Dioxaspiro[4.5]dec-8-yl)oxy)-4-(6-(3-((6-methoxypyridin-3-yl)oxy)azaspiro[3.1]hex-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0371]

[0372] Step 1: 6-(1,4-Dioxaspiro[4.5]dec-8-yloxy)-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0373] Add 4-(6-fluoro-3-pyridinyl)-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile (Intermediate 1, 400 mg, 1.57 mmol), potassium carbonate (652 mg, 4.72 mmol), DMF (8.0 mL), and 1,4-dioxaspiro[4.5]dec-8-yl methanesulfonate (Step 2 of Example 8, 560 mg, 2.37 mmol) into a 25 mL single-necked flask in sequence, and react at 50 °C overnight. Pour the reaction solution into 50 mL of ice water, extract with EA (100 mL × 3), combine the organic phases, wash with saturated brine (50 mL × 3), dry the organic phases over anhydrous sodium sulfate, filter, evaporate the filtrate to dryness, and subject the residue to silica gel column chromatography (eluent PE / EA (v / v) = 5 / 1 - 1 / 1) to collect 78 mg of a white solid. LC-MS: m / z = 395.10 [M+H] + 。 1 H NMR (400 MHz, CDCl3) δ 8.39 (d, J = 1.8 Hz, 1H), 8.23 (d, J = 1.8 Hz, 1H), 8.21 (s, 1H), 8.01 (td, J = 8.3, 2.4 Hz, 1H), 7.17 (d, J = 1.8 Hz, 1H), 7.12 (dd, J = 8.5, 2.8 Hz, 1H), 4.42 (dt, J = 10.2, 5.0 Hz, 1H), 3.98 (s, 4H), 2.03 (dd, J = 11.3, 5.8 Hz, 4H), 1.96 - 1.87 (m, 2H), 1.71 - 1.63 (m, 2H).

[0374] Step 2: 6-((1,4-Dioxaspiro[4.5]dec-8-yl)oxy)-4-(6-(3-((6-methoxypyridin-3-yl)oxy)azaspiro[3.1]hex-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0375] At room temperature, 5-(azetidin-3-yloxy)-2-methoxypyridine hydrochloride (25 mg, 0.14 mmol) and potassium carbonate (27 mg, 0.19 mmol) were added to a solution of 6-(1,4-dioxaspiro[4.5]decan-8-yloxy)-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (25 mg, 0.06 mmol) in DMSO (2 mL). After the addition of 4-dimethylaminopyridine (2 mg, 0.016 mmol), the reaction was carried out at 90 °C overnight. The reaction mixture was added to 10 mL of water, and extracted with EA (30 mL × 3). The combined organic phases were washed with saturated brine (30 mL × 2), separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent DCM / MeOH (v / v) = 100 / 0 - 100 / 10) to obtain 10 mg of a pale yellow solid product. LC-MS: m / z = 555.20 [M+H] + 。 1 H NMR (400 MHz, CDCl3) δ 8.31 (d, J = 2.0 Hz, 1H), 8.19 (s, 1H), 8.16 (d, J = 1.8 Hz, 1H), 7.70 (dd, J = 8.0, 2.5 Hz, 2H), 7.19 (dd, J = 9.0, 3.0 Hz, 1H), 7.09 (d, J = 1.9 Hz, 1H), 6.72 (d, J = 8.8 Hz, 1H), 6.45 (d, J = 8.6 Hz, 1H), 5.11 - 5.04 (m, 1H), 4.50 (dd, J = 8.8, 6.2 Hz, 2H), 4.42 - 4.35 (m, 1H), 4.18 (dd, J = 9.2, 3.6 Hz, 2H), 4.01 - 3.94 (m, 4H), 3.90 (s, 3H), 2.04 - 1.87 (m, 8H).

[0376] Example 7: 6-(2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)ethoxy)-4-(6-(3-((6-methoxypyridin-3-yl)oxy)azetidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0377]

[0378] 6-(2-(2-Oxa-6-azaspiro[3.3]heptan-6-yl)ethoxy)-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Intermediate 3, 30 mg, 0.080 mmol), 5-(azetidin-3-yloxy)-2-methoxypyridine hydrochloride (Intermediate 4, 30 mg, 0.14 mmol), potassium carbonate (35 mg, 0.25 mmol), 4-dimethylaminopyridine (2 mg, 0.016 mmol), DMSO (1 mL) were added to a 5 mL single-necked flask and reacted at 90 °C. After the reaction was completed as detected by TLC, the reaction solution was cooled to room temperature, 5 mL of water was added, and it was extracted with EA (20 mL × 2). The organic phase was washed with water (10 mL × 4) and saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated by rotary evaporation, and the residue was purified by silica gel column chromatography (eluent: EA - EA / MeOH (v / v = 10 / 1)) to obtain 15 mg of a pale yellow solid, which was the target product. LC-MS: m / z = 540.20 [M+H] + 。 1 H NMR (400 MHz, CDCl3) δ 8.30 (s, 1H), 8.19 (s, 1H), 8.12 (s, 1H), 7.70 (dd, J = 6.0, 2.5 Hz, 2H), 7.19 (dd, J = 8.9, 2.9 Hz, 1H), 7.10 (s, 1H), 6.73 (d, J = 8.9 Hz, 1H), 6.46 (d, J = 8.7 Hz, 1H), 5.14 - 5.04 (m, 1H), 4.76 (s, 4H), 4.55 - 4.46 (m, 2H), 4.18 (dd, J = 9.2, 3.7 Hz, 2H), 4.07 - 4.00 (m, 2H), 3.91 (s, 3H), 3.58 (s, 4H), 2.91 (s, 2H).

[0379] Example 8: 6-((1,4-Dioxaspiro[4.5]dec-8-yl)oxy)-4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0380]

[0381] Step 1: 1,4-Dioxaspiro[4.5]decan-8-ol

[0382] Under ice bath conditions, 1,4-cyclohexanedione monoethylene ketal (2.0 g, 13 mmol) and methanol (40 mL) were successively added to a 100 mL single-necked flask. Sodium borohydride (1.5 g, 40 mmol) was added in batches. After the addition was completed, the mixture was allowed to return to room temperature and stirred continuously. After 2 h, TLC showed that the reaction was complete. The reaction solution was concentrated to a solid, water (20 mL) was added, and the mixture was extracted with EA (50 mL × 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated by rotary evaporation. The residue was purified by silica gel column chromatography (eluent DCM / EA (v / v) = 5 / 1) to obtain 1.89 g of a colorless transparent liquid (yield 90%), which was the target product. 1 1H NMR (400 MHz, CDCl3) δ 4.02 - 3.85 (m, 4H), 3.84 - 3.73 (m, 1H), 1.93 - 1.74 (m, 5H), 1.63 (ddd, J = 14.2, 10.0, 6.5 Hz, 4H).

[0383] Step 2: 1,4-Dioxaspiro[4.5]dec-8-yl methanesulfonate

[0384] Under ice bath conditions, 1,4-dioxaspiro[4.5]decan-8-ol (200 mg, 1.26 mmol), dichloromethane (2 mL), and triethylamine (0.27 mL, 1.89 mmol) were successively added to a 5 mL single-necked flask. Methanesulfonyl chloride (0.13 mL, 1.64 mmol) was slowly added. After the addition was completed, the mixture was allowed to return to room temperature and stirred for 2 h. TLC showed that the reaction was complete. Under low-temperature conditions, 30 mL of water was added for dilution, and the mixture was extracted with dichloromethane (50 mL × 3). The combined organic phases were washed with saturated NaHCO3 and saturated brine, dried over anhydrous sodium sulfate, filtered, and the mother liquor was concentrated by rotary evaporation. The residue was purified by silica gel column chromatography (DCM / EA (v / v) = 10 / 1) to obtain 290 mg of a light yellow solution (yield 91.78%), which was the target product. 1 1H-NMR (400 MHz, CDCl3) δ 4.90 - 4.78 (m, 1H), 3.95 (dd, J = 6.0, 3.9 Hz, 4H), 3.01 (s, 3H), 2.00 (dd, J = 12.2, 6.8 Hz, 4H), 1.90 - 1.81 (m, 2H), 1.68 - 1.61 (m, 2H).

[0385] Step 3: 6-((1,4-Dioxaspiro[4.5]dec-8-yl)oxy)-4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0386] Add 6-hydroxy-4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Intermediate 2, 40 mg, 0.09 mmol), 1,4-dioxaspiro[4.5]dec-8-yl methanesulfonate (65 mg, 0.270 mmol), cesium carbonate (115 mg, 0.35 mmol), and DMA (1 mL) to a 5 mL single-necked flask, and react at 60 °C overnight. Pour the reaction solution into 10 mL of ice water, extract with EA (30 mL × 3), combine the organic phases, wash with saturated brine (20 mL × 3), dry the organic phase over anhydrous sodium sulfate, filter, evaporate the filtrate to dryness, and purify the residue by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 25 / 1) to obtain 20 mg of a white solid. LC-MS: m / z = 567.25 [M+H] + 。 1 H NMR (400 MHz, CDCl3) δ 8.52 (d, J = 4.0 Hz, 1H), 8.30 (d, J = 2.3 Hz, 1H), 8.18 (s, 1H), 8.14 (d, J = 1.8 Hz, 1H), 7.70 - 7.63 (m, 2H), 7.20 (dd, J = 6.9, 5.4 Hz, 1H), 7.13 (d, J = 7.7 Hz, 1H), 7.09 (d, J = 1.8 Hz, 1H), 6.77 (d, J = 8.9 Hz, 1H), 4.38 (dt, J = 9.5, 4.7 Hz, 1H), 4.12 - 4.05 (m, 2H), 4.00 - 3.95 (m, 4H), 3.53 - 3.44 (m, 2H), 2.94 (s, 2H), 2.04 - 1.98 (m, 4H), 1.69 - 1.60 (m, 8H).

[0387] Example 9: 6-(2-(8-oxa-2-azaspiro[4.5]dec-2-yl)ethoxy)-4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0388]

[0389] Add 6-(2-(8-oxa-2-azaspiro[4.5]decan-2-yl)ethoxy)-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Intermediate 6, 20 mg, 0.047 mmol), 4-(pyridin-2-ylmethyl)piperidin-4-ol hydrochloride (Step 2 of Intermediate 2, 20 mg, 0.10 mmol), potassium carbonate (20 mg, 0.14 mmol), 4-dimethylaminopyridine (3 mg, 0.025 mmol), and DMSO (1 mL) into a 5 mL single-necked flask, and react at 90 °C in an oil bath. After the reaction is completed as detected by TLC, cool the reaction solution to room temperature, add 5 mL of water, extract with EA (20 mL × 2), wash the organic phase with water (10 mL × 4), wash with saturated brine (10 mL × 2), dry over anhydrous sodium sulfate, filter, concentrate the filtrate by rotary evaporation, and purify the residue by silica gel column chromatography (eluent DCM / MeOH (v / v) = 30 / 1 - 20 / 1) to obtain 19 mg of a yellow solid as the product. LC-MS: m / z = 594.60 [M+H] + 。 1 H NMR (400 MHz, CDCl3) δ 8.52 (d, J = 4.6 Hz, 1H), 8.30 (d, J = 2.3 Hz, 1H), 8.19 (s, 1H), 8.14 (d, J = 1.9 Hz, 1H), 7.70 - 7.62 (m, 2H), 7.22 - 7.17 (m, 1H), 7.13 (d, J = 7.9 Hz, 2H), 6.77 (d, J = 8.9 Hz, 1H), 4.18 - 4.05 (m, 4H), 3.65 (t, J = 5.2 Hz, 4H), 3.53 - 3.43 (m, 2H), 2.94 (s, 4H), 2.75 (s, 2H), 2.58 (s, 2H), 1.77 - 1.69 (m, 4H), 1.65 - 1.59 (m, 6H).

[0390] Example 10: 6-(2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)ethoxy)-4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0391]

[0392] Step 1: tert-Butyl 4-((6-methoxypyridin-3-yl)methyl)piperazine-1-carboxylate

[0393] Add tert-butyl piperazine-1-carboxylate (1.0 g, 5.4 mmol) and 6-methoxypyridine-3-carbaldehyde (800 mg, 5.8335 mmol) to a single-necked flask. Add DCE (12 mL) to dissolve them, then add acetic acid (0.3 mL, 5 mmol). After that, add sodium triacetoxyborohydride (5.7 g, 27 mmol) under stirring. After the addition, react at room temperature for 23.5 h. Concentrate the reaction solution and purify it by silica gel column chromatography (the eluent is PE / EA (v / v = 1 / 1)) to obtain 1.4 g of a colorless liquid as the product, with a yield of 85.0%. LC-MS: m / z = 308.25 [M+H] + 。 1 1H NMR (400 MHz, CDCl3) δ 8.06 (d, J = 1.9 Hz, 1H), 7.58 (dd, J = 8.5, 2.2 Hz, 1H), 6.74 (d, J = 8.5 Hz, 1H), 3.93 (s, 3H), 3.55 (s, 2H), 3.51–3.39 (m, 4H), 2.54–2.37 (m, 4H), 1.45 (s, 9H).

[0394] Step 2: 1-((6-Methoxypyridin-3-yl)methyl)piperazine trihydrochloride

[0395] Add tert-butyl 4-((6-methoxypyridin-3-yl)methyl)piperazine-1-carboxylate (1.4 g, 4.6 mmol) to a single-necked flask, add MeOH (4 mL), and dropwise add HCl / MeOH (9 mL, 36 mmol, 4 mol / L). After the addition, react at room temperature for 13 h. After the reaction is completed, filter by suction, and dry the obtained solid under vacuum at 60 °C to obtain 600 mg of a white solid as the product. LC-MS: m / z = 208.30 [M - 3HCl+H] + 。 1 1H NMR (400 MHz, DMSO) δ 8.41 (d, J = 1.8 Hz, 1H), 8.04 (dd, J = 8.6, 2.2 Hz, 1H), 6.91 (d, J = 8.6 Hz, 1H), 5.04 (s, 6H), 4.38 (s, 2H), 3.87 (s, 3H), 3.30 (s, 2H).

[0396] Step 3: 6-(2-(2-Oxa-6-azaspiro[3.3]heptan-6-yl)ethoxy)-4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0397] Add 6-(2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)ethoxy)-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Intermediate 3, 30 mg, 0.07907 mmol), 1-((6-methoxypyridin-3-yl)methyl)piperazine hydrochloride (34 mg, 0.12135 mmol), potassium carbonate (67 mg, 0.48477 mmol), DMSO (1.5 mL) into a 10 mL single-necked flask, and react at 90 °C in an oil bath for 17 h. After the reaction stops, cool the reaction solution to room temperature, add 5 mL of water, extract with EA (20 mL × 2), wash the organic phase with water (5 mL × 3), wash with saturated brine (5 mL × 2), dry over anhydrous sodium sulfate and filter. Concentrate the filtrate under reduced pressure and perform silica gel column chromatography (the eluent is DCM-DCM / MeOH (v / v = 30 / 1)). The obtained solid of 5 mg is the product, and the yield is 11.16%. LC-MS: m / z = 567.30 [M+H] + 。 1 H NMR (400 MHz, CDCl3) δ 8.31 (d, J = 2.2 Hz, 1H), 8.19 (s, 1H), 8.13–8.06 (m, 2H), 7.70 (dd, J = 8.8, 2.4 Hz, 1H), 7.66–7.60 (m, 1H), 7.09 (d, J = 1.8 Hz, 1H), 6.75 (d, J = 8.3 Hz, 2H), 4.75 (s, 4H), 4.01 (t, J = 4.9 Hz, 2H), 3.94 (s, 3H), 3.66 (s, 4H), 3.56–3.48 (m, 6H), 2.87 (d, J = 4.8 Hz, 2H), 2.57 (s, 4H).

[0398] Example 11: 6-(2-((6-azaspiro[3.4]octan-2-yl)oxy)ethoxy)-4-(6-(3-((6-methoxypyridin-3-yl)oxy)azetidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0399]

[0400] Step 1: tert-Butyl 2-(2-((3-cyano-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl)oxy)ethoxy)-6-azaspiro[3.4]octane-6-carboxylate

[0401] Add 4-(6-fluoropyridin-3-yl)-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile (Intermediate 1, 200 mg, 0.7868 mmol) and K2CO3 (326 mg, 2.3587 mmol) to a single-necked flask. Dissolve them in DMF (2 mL), then add tert-butyl 2-(2-(methylsulfonyloxy)ethoxy)-7-azaspiro[3.4]octane-7-carboxylate (Step 3 of Example 3, 350 mg, 1.002 mmol). Stir the reaction mixture at 60 °C for 28 h. Add 10 mL of water for washing, extract with DCM (100 mL × 2). Wash the organic phase with 20 mL of saturated brine, dry over anhydrous sodium sulfate, filter, evaporate the filtrate to dryness, and perform silica gel column chromatography (the eluent is pure DCM - DCM / MeOH (v / v = 10 / 1)) to obtain 200 mg of a pale yellow solid, which is the target compound with a yield of 50.08%. TLC shows that the reaction is complete and the raw materials have reacted completely. LC-MS: m / z = 452.00 [M - 56 + H] + 。

[0402] Step 2: tert-butyl 2-(2-((3-cyano-4-(6-(3-((6-methoxypyridin-3-yl)oxy)azetidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl)oxy)ethoxy)-6-azaspiro[3.4]octane-6-carboxylate

[0403] Add tert-butyl 2-(2-((3-cyano-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl)oxy)ethoxy)-6-azaspiro[3.4]octane-6-carboxylate (50 mg, 0.09850 mmol), 5-(azetidin-3-yloxy)-2-methoxypyridine hydrochloride (Intermediate 4, 37.4 mg, 0.148 mmol), K2CO3 (55 mg, 0.39795 mmol) and DMSO (2 mL) to a single-necked flask in sequence. Heat and stir at 100 °C for 14 h. Cool the reaction solution to room temperature, add 5 mL of water to quench the reaction, extract with DCM (100 mL), separate the organic phase, wash the organic phase with saturated brine (30 mL × 2), dry over anhydrous sodium sulfate, filter, evaporate the mother liquor under reduced pressure to dryness, and perform silica gel column chromatography to obtain 65.78 mg of a yellow oil, which is the target compound. LC-MS: m / z = 668.15 [M + H] + 。

[0404] Step 3: 6-(2-((6-azaspiro[3.4]octan-2-yl)oxy)ethoxy)-4-(6-(3-((6-methoxypyridin-3-yl)oxy)azetidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0405] Dissolve tert-butyl 2-(2-((3-cyano-4-(6-(3-((6-methoxypyridin-3-yl)oxy)azetidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl)oxy)ethoxy)-6-azaspiro[3.4]octane-6-carboxylate (51 mg, 0.07637 mmol) in DCM (0.2 mL), then add EA (0.5 mL), and dropwise add ethyl acetate hydrochloride (0.5 mL, 2 mmol, 4 mol / L). There is a viscous solid adhering to the bottle wall, and stir the reaction at room temperature for 1 h. Rotate the reaction solution to dryness under reduced pressure. Transfer the obtained solid to a conical flask with water (50 mL), directly add solid potassium carbonate until the pH is 12, add DCM (100 mL) for extraction, wash the organic phase with saturated brine (30 mL), dry over anhydrous sodium sulfate, filter, and directly rotate to dryness under reduced pressure to obtain a small amount of yellowish-white solid product, 25 mg, which is the target compound, yield: 69%. LC-MS: m / z = 568.10 [M+H] + 。 1 H NMR (400 MHz, DMSO-d6) δ = 8.67 (s, 1H), 8.56 (s, 1H), 8.30 (d, J = 1.9 Hz, 1H), 7.86–7.73 (m, 2H), 7.39 (dd, J = 9.0, 3.0 Hz, 1H), 7.29 (s, 1H), 6.80 (d, J = 8.9 Hz, 1H), 6.56 (d, J = 8.6 Hz, 1H), 5.20 (s, 1H), 4.47 (dd, J = 9.0, 6.4 Hz, 2H), 4.20 (s, 2H), 3.97 (dd, J = 9.5, 3.2 Hz, 2H), 3.80 (s, 3H), 3.64 (s, 2H), 3.50–3.48 (m, 2H), 3.37 (s, 2H), 2.78–2.73 (m, 1H), 2.20 (td, J = 12.8, 2.5 Hz, 2H), 1.90–1.81 (m, 2H), 1.73–1.63 (m, 2H).

[0406] Biological activity test example:

[0407] Test example 1: Test on the inhibitory activity of the inventive compound against Ret wt and Ret V804M kinases

[0408] 1. Experimental purpose:

[0409] 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.

[0410] 2. The experimental reagents and consumables used are as follows:

[0411] 1) HTRF KinEASE-TK kit (Cisbio, 62TK0PEC)

[0412] 2) Ret wt (Invitrogen, PV3082)

[0413] 3) Ret V804M (Signalchem, R02-12GG-10)

[0414] 4) MgCl2 (Sigma, M1028)

[0415] 5) ATP (Promega, V910B)

[0416] 6) DTT (Invitrogen, P2325)

[0417] 7) DMSO (Sigma, D8418)

[0418] 8) 384-well plate, white, low volume, round-bottom (Greiner, 784075)

[0419] 9) 384-Well Polypropylene microplate, Clear, Flatt Bottom, Bar Code (Labcyte, P-05525-BC)

[0420] 10) 96-well polypropylene plate (Nunc, 249944)

[0421] 11) Plate shaker (Thermo, 4625-1CECN / THZ Q)

[0422] 12) Centrifuge (Eppendorf, 5810R)

[0423] 13) Envision 2104 multi-label Reader (PerkinElmer, 2104-10-1)

[0424] 14) Echo (Labcyte, 550)

[0425] 3. Experimental procedures

[0426] 3.1 Preparation of 1x kinase reaction buffer:

[0427] 1 volume of 5X kinase reaction buffer and 4 volumes of water; 5 mM MgCl2; 1 mM DTT; 1 mM MnCl2.

[0428] 3.2 Transfer 10 nl of the diluted compound to each well using an Echo 550 reaction plate (784075, Greiner).

[0429] 3.3 Seal the reaction plate with a sealing film and centrifuge at 1000 g for 1 minute.

[0430] 3.4 Prepare 2X kinase using 1X enzyme reaction buffer.

[0431] 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

[0432] minutes.

[0433] 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.

[0434] 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.

[0435] 3.8 Prepare 4X Sa-XL 665 (250 nM) using HTRF detection buffer.

[0436] 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.

[0437] 3.10 Read the fluorescence signals at 615 nm (Cryptate) and 665 nm (XL665) using an Envision 2104.

[0438] 4. Data analysis

[0439] 4.1 Calculate the ratio (Ratio_665 / 615 nm) for each well

[0440] 4.2 The inhibition rate is calculated as follows:

[0441]

[0442] The average value of the readings of all positive control wells of CEP-32496

[0443] The average value of the readings of all negative control wells (DMSO wells)

[0444] 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.

[0445] 4.3 Calculate IC 50 And plot the inhibition curve of the compound:

[0446] Use the following non-linear fitting formula to obtain the IC 50 (Half maximal inhibitory concentration): Perform data analysis using Graphpad 6.0 software.

[0447] Y = Bottom + (Top - Bottom) / (1 + 10^((LogIC50 - X)*Hill Slope))

[0448] X: Logarithm value of compound concentration; Y: Inhibition rate (% inhibition)

[0449] 5. The experimental results are shown in Table 1:

[0450] Table 1 Experimental results of the kinase inhibitory activities of the compounds of the present invention against Ret wt and Ret V804M

[0451]

[0452] 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.

[0453] In the description of this specification, the description with reference to terms such as "one embodiment", "some embodiments", "some implementation schemes", "examples", "specific examples" or "some examples" means 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 expressions 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 contradiction, those skilled in the art can combine and combine the different embodiments, implementation schemes or examples described in this specification and the features of different embodiments, implementation schemes or examples.

[0454] 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 the 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 key, C 1-6 alkylene or C 1-6 alkylene-O-; Ring G is the following substructural formula: , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ; Each R a is independently D, OH, NH2, F, CF3, Cl, Br, I, CN, NH2, NHCH3, methyl, ethyl, propyl, butyl, methoxy, ethoxy, methoxymethyl, methoxyethyl, ethoxymethyl, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 2-hydroxypropyl or 2-hydroxy-2-methylpropyl; 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 ring A is independently and 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- or -(CH2)2-; 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, CF3, 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 or D; Each R 5 is independently H, D or C 1-6 alkyl; Each R 6 is independently H, D, C 1-6 alkyl or C 1-6 alkoxy C 1-6 alkyl, where the C 1-6 alkyl and C 1-6 alkoxy C 1-6 alkyl are each independently optionally substituted with 1, 2, 3 or 4 substituents selected from F, Cl, Br, CN, NH2, OH and NO2.

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)2-O- or -(CH2)3-O-.

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, 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 the compound of formula (I-1) or (I-2) or a pharmaceutically acceptable salt thereof: or Among them, 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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