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 diseases and disorders related to RET, including cancer, irritable bowel syndrome and / or pain associated with irritable bowel syndrome.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceuticals. Specifically, the present invention relates to novel compounds that exhibit rearranged during transfection (RET) kinase inhibition, pharmaceutical compositions comprising the compounds, and the use of the compounds or their pharmaceutical compositions in the preparation of a medicament, which is particularly useful 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 related to 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 led to 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 inhibitory effects on cell proliferation in cell lines expressing KIF5B-RET (J Clin Oncol 30, 2012, suppl; Abstract no: 7510). Additionally, 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. Furthermore, 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 during transfection (RET) kinase inhibition. Such compounds have good inhibitory effects on wild-type RET and RET gene mutants, and compared with other kinases, the compounds of the present invention have better inhibitory selectivity for wild-type RET and RET gene mutants.

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

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

[0007]

[0008] wherein,

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

[0010] Y is O, NH or S;

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

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

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

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

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

[0016] Ring A is a monocyclic group, and ring A is optionally substituted by 1, 2, 3 or 4 substituents selected from F, Cl, Br, OH, oxo, NR 5 R 6 , R 5 (C═O)NR 6 -, 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, OH, NR 5 R 6 , OR 7 , alkyl, alkoxy, haloalkyl, hydroxyalkyl, haloalkoxy, aryl, alkoxyalkyl, oxo, alkyl acyl, heterocyclic group and cycloalkyl;

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

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

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

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

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

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

[0027] each R 7 is independently 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, NH2, CN, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 3 - 7 - membered heterocyclic group, C 1-6 alkoxy, C 6-10 aryl, 5 - 12 - membered heteroaryl and C 1-6 alkylamino.

[0029] In some embodiments, T is a bond, -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -(CH2)-O-, -(CH2)2-O-, -(CH2)3-O- or -(CH2)2-NH-, and T is optionally substituted with 1, 2, 3 or 4 substituents selected from D, OH, F, Cl, Br, I, NH2, CN, CF3, CHF2, CHCl2, 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 bridged carbocyclic group or a 6- to 12-membered bridged heterocyclic group;

[0032] Each R a is independently D, OH, NH2, F, Cl, Br, I, CN, NR 5 R 6 、OR 7 、-NR 6 C(=O)R 7 、-S(=O)2R 7 、-S(=O)R 7 、-C(=O)R 7 、-C(=O)OR 7 、oxo, C 1-6 alkyl, C 1-6 alkoxy, C 3-7 cycloalkyl, C 1-6 haloalkyl, C 1-6 alkoxyC 1-6 alkyl 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, C6-10 substituted 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 said 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] wherein,

[0038] Each Z 1 is independently CH or N;

[0039] Each Z 2 is independently CH, NH, O, S, S(=O) or S(=O)2-;

[0040] Each m and n is independently 0, 1 or 2;

[0041] 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 alkoxy, C 3-7 cycloalkyl, C 1-6 haloalkyl, C 1-6 alkoxy C 1-6 alkyl or C 1-6 hydroxyalkyl;

[0042] R5 is H, D, C 1-6 alkyl, 3- to 12-membered carbocyclic group, 3- to 12-membered heterocyclic group, C 6-10 aryl or 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 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- to 10-membered heteroaryl;

[0043] 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;

[0044] R 7 is OH, C 1-6 alkyl, C 3-6 cycloalkyl, 3- to 12-membered heterocyclic group, C 6-10 aryl, 5- to 10-membered heteroaryl.

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

[0046]

[0047] Each R a is independently D, OH, NH2, F, CF3, CHCl2, CHF2, CH2F, CF3CH2, Cl, Br, I, CN, NH2, NHCH3, N(CH3)2, -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, ethoxymethyl, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 2-hydroxypropyl or 2-hydroxy-2-methylpropyl;

[0048] Each R 5Independently 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;

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

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

[0051] In some embodiments, ring A is a 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 substituted with subcycloalkyl and 3- to 6-membered subheterocycloalkyl.

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

[0053]

[0054] Wherein, Z 1a and Z 2a Each independently is CH or N;

[0055] Z 3 and Z 4 Each independently is CH2, O, S, NH, C=O, S=O or S(=O)2;

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

[0057] In some embodiments, ring A is the following sub - structural formula:

[0058]

[0059] Wherein, each sub - structural formula of A is independently optionally substituted by 1, 2, 3 or 4 substituents selected from F, Cl, Br, OH, oxo, NH2, NHCH3, CH3(C=O)NH -, methyl, ethyl, n - propyl, methoxy, ethoxy, isopropoxy, CF3, hydroxymethyl, 2 - hydroxyethyl, cyclopropyl, cyclohexyl, pyrrolidinyl, piperidinyl and tetrahydrofuryl.

[0060] In some embodiments, M is H, D, 5 - 10 - membered heteroaryl, C 6-10 aryl, C 3-7 cycloalkyl or 3 - 12 - membered heterocyclic group; and M is optionally substituted by 1, 2, 3 or 4 substituents selected from 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 - 7 - membered heterocyclic group and C 3-7 cycloalkyl.

[0061] In some embodiments, M is H, D, pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, pyrazinyl, phenyl, cyclopentyl, cyclopropyl, cyclohexyl, cyclobutyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, morpholinyl, tetrahydrothiopyranyl, oxetanyl, 1,2-dihydropyridyl, 7-azabicyclo[2.2.1]heptanyl, hexahydrofuro[3,4-c]pyrrolyl, 3-azabicyclo[3.1.0]hexanyl, octahydropyrrolo[1,2-a]pyrazinyl or 5-azaspiro[2.4]heptanyl; and M is optionally substituted 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.

[0062] 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 with 1, 2, 3 or 4 substituents selected from F, Cl, Br, CN, NH2, OH and NO2;

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

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

[0065] Or, R 2 、R3 form 3- to 7-membered carbocyclic or 3- to 7-membered heterocyclic rings with the same C atom to which they are attached.

[0066] In some embodiments, each R 2 and R 3 are independently OH, F, CF3, CHCl2, CHF2, H, D, CN, Cl, Br, NH2, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, methyl, ethyl, N(CH3)2, methoxy, ethoxy, isopropoxy, tert-butoxy, trifluoromethoxy, cyclopropyl, cyclopentyl, cyclopropylmethyl, cyclopentylethyl, cyclopentylmethyl, phenyl, pyridyl or pyrazinyl;

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

[0068] In some embodiments, Q is a bond, -O-, -(CH2)2O-, -O(CH2)-, -(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)CH2--CH2CH(OH)-, -CH2CH(OH)CH2-, -CH2CH(OH)CH(CH3)CH2-, -(C=O)CH(N(CH3)2)-, -(C=O)C(CH3)2CH2OCH2-, -(C=O)C(OCH3)(CF3)-, -(C=O)N(CH2CH2OCH3)CH2CH(OCH3)-, -CH2CH(OCF3)-, -CH2CH(OCH(CH3)2)-, -CH2CH(OC(CH3)3)-, -CH2CF2-, -CH(CH3)-, -CH2CH(OCH3)C(CH3)2-, -CH2CH(N(CH3)2)-, -NH-, -(C=O)NHOCH2-, -(C=O)NHOCH2CH(OH)-, -S(=O)2(CH2CH3)-, -S(=O)2O-, -S(=O)2-NHC(CH3)2-, -(CH2)2S(=O)2-

[0069] In some embodiments, the compounds of the present invention are compounds represented by formula (I-1), (I-2) or (I-3), or their stereoisomers, tautomers, N-oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs:

[0070]

[0071] Wherein, is the following substructural formula:

[0072]

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

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

[0075] And each substructural formula of is independently optionally substituted with 1, 2, 3 or 4 substituents selected from F, Cl, Br, OH, oxo, NR 5 R 6 、R 5 (C=O)NR 6 -, amino C 1-4 alkyl, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4Hydroxyalkyl, 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 are substituted by substituents;

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

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

[0078] In some embodiments,

[0079] is the following substructural formula: and each substructural formula of is independently optionally substituted by 1, 2, 3, or 4 substituents selected from F, Cl, Br, OH, oxo, NH2, NHCH3, CH3(C=O)NH-, methyl, ethyl, n-propyl, methoxy, ethoxy, isopropoxy, CF3, hydroxymethyl, 2-hydroxyethyl, cyclopropyl, cyclohexyl, pyrrolidinyl, piperidinyl, and tetrahydrofuryl; and

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

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

[0082]

[0083]

[0084]

[0085]

[0086]

[0087]

[0088]

[0089]

[0090]

[0091]

[0092]

[0093]

[0094]

[0095]

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

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

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

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

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

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

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

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

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

[0105] On the other hand, the present invention provides a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable adjuvant thereof. In some embodiments, the adjuvants described herein 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 form.

[0106] Also provided herein are methods for inhibiting cell proliferation in vitro or in vivo, the methods comprising contacting cells with an effective amount of the compound described herein or a pharmaceutical composition thereof.

[0107] Also provided herein is 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 described herein or a pharmaceutical composition thereof.

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

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

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

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

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

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

[0114] The N-oxides of the compounds of the present invention are also included within the scope of the present invention. The N-oxides of the compounds of the present invention can be prepared by oxidizing the corresponding nitrogen-containing basic substances using common oxidizing agents (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.

[0115] If the compound of the present invention is basic, the desired salts can be prepared by any suitable method provided in the literature, for example, using inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid, etc. Or using organic acids such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid and salicylic acid; pyranose acids such as glucuronic acid and galacturonic acid; α-hydroxy acids such as citric acid and tartaric acid; amino acids such as aspartic acid and glutamic acid; aromatic acids such as benzoic acid and cinnamic acid; sulfonic acids such as p-toluenesulfonic acid, ethanesulfonic acid, etc.

[0116] If the compounds of the present invention are acidic, the desired salts can be prepared by suitable methods, such as using inorganic bases or organic bases, such as ammonia (primary, secondary, tertiary amines), alkali metal hydroxides or alkaline earth metal hydroxides, and the like. Suitable salts include, but are not limited to, organic salts derived from amino acids, such as glycine and arginine, ammonia, such as primary, secondary and tertiary amines, and cyclic amines, such as piperidine, morpholine and piperazine, etc., and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.

[0117] Definitions and General Terms

[0118] Certain embodiments of the present invention will now be described in detail, with examples illustrated by the accompanying structural and chemical formulas. The present invention is intended to cover all alternatives, modifications and equivalent technical solutions, which are all included within the scope of the present invention as defined in the claims. Those skilled in the art should recognize that many methods and materials similar or equivalent to those described herein can be used to practice the present invention. The present invention is in no way limited to the methods and materials described herein. In the case where one or more of the incorporated documents, patents and similar materials are different from or contradictory to the present application (including but not limited to the defined terms, term applications, described technologies, etc.), the present application shall prevail.

[0119] It should be further recognized that certain features of the present invention, for the sake of 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 the sake of brevity, are described in a single embodiment, but can also be provided separately or in any suitable sub-combination.

[0120] 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 related to the present invention are incorporated herein by reference in their entirety.

[0121] 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.

[0122] 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.

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

[0124] The stereochemical definitions and rules used in this invention generally follow S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984), McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., “Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., New York, 1994.

[0125] Any mixture of 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 the differences in the physical and chemical properties of the components.

[0126] The terms “tautomer” or “tautomeric form” refer to structural isomers of different energies that can interconvert through a low energy barrier. If tautomerism is possible (e.g., in solution), a chemical equilibrium of the 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 tautomerism is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerism is phenol-keto tautomerism. A specific example of phenol-keto tautomerism is the interconversion of pyridin-4-ol and pyridin-4(1H)-one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of this invention are within the scope of this invention.

[0127] Unless otherwise indicated, the structural formulas described in this invention include all isomeric forms (e.g., enantiomeric, diastereomeric, and geometric (or conformational) isomers): for example, the R, S configurations containing asymmetric centers, the (Z), (E) isomers of double bonds, and the (Z), (E) conformational isomers. Therefore, 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.

[0128] Unless otherwise indicated, the structural formulas and the compounds described in the present 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 stereochemical isomers, enantiomers, diastereomers, geometric isomers, conformational isomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts and prodrugs of the compounds of the present invention also fall within the scope of the present invention. Additionally, unless otherwise indicated, the structural formulas of the compounds described in the present invention include one or more different atoms of enriched isotopes.

[0129] As described in the present invention, the compounds of the present invention may independently and optionally be substituted with one or more substituents, such as the compounds of the general formula above, or as in the specific examples, subclasses, and classes of compounds included in the present invention. It should be understood that the term "independently and optionally substituted with" may 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 structural formula can be substituted with one or more substituents selected from a specific group, the substituents may be the same or different at each position.

[0130] In addition, it should be noted that unless otherwise explicitly stated, in the present 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.

[0131] In various parts of this specification, the substituents of the disclosed compounds of the present invention are disclosed according to group types or ranges. In particular, the present invention includes each independent secondary combination of each member of these group types and ranges. For example, the term "C 1-6 alkyl" specifically refers to methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl and C6 alkyl independently disclosed.

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

[0133] The term "alkyl" means a saturated straight-chain or branched-chain monovalent hydrocarbon radical containing 1 to 20 carbon atoms, wherein the alkyl radical may optionally be substituted 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.

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

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

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

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

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

[0139] The term "hydroxyalkyl" refers to an alkyl group substituted by one or more hydroxyl groups. In some embodiments, hydroxyalkyl refers to an alkyl group substituted by 1, 2, 3, or 4 hydroxyl groups. In some embodiments, hydroxyalkyl refers to an alkyl group substituted by 1 or 2 hydroxyl groups. In some embodiments, hydroxyalkyl refers to C 1-6 hydroxyalkyl, i.e., C 1-6 alkyl is substituted by one or more hydroxyl groups; preferably, C 1-6 hydroxyalkyl refers to C 1-6 alkyl is substituted by one hydroxyl group. In some embodiments, hydroxyalkyl refers to C 1-4 hydroxyalkyl. In some embodiments, hydroxyalkyl refers to C 1-3 hydroxyalkyl. Examples of hydroxyalkyl include, but are not limited to, OHCH2-, CH2OHCH2CH2CH2-, CH2OHCH2-, CH2OHCH2CHOHCH2-, CH(CH3)OHCH2CHOHCH2-, and the like.

[0140] The term "alkoxy" means that an alkyl group is connected to the rest of the molecule through an oxygen atom, where the alkyl group has the meaning as described in the present invention. Unless otherwise specified in detail, the alkoxy group contains 1 to 12 carbon atoms. In one embodiment, the alkoxy group contains 1 to 6 carbon atoms; in another embodiment, the alkoxy group contains 1 to 4 carbon atoms; in yet another embodiment, the alkoxy group contains 1 to 3 carbon atoms. The alkoxy group may optionally be substituted by one or more substituents described in the present invention. Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH3), ethoxy (EtO, -OCH2CH3), 1-propoxy (n-PrO, n-propoxy, -OCH2CH2CH3), 2-propoxy (i-PrO, i-propoxy, -OCH(CH3)2), 1-butoxy (n-BuO, n-butoxy, -OCH2CH2CH2CH3), 2-methyl-1-propoxy (i-BuO, i-butoxy, -OCH2CH(CH3)2), 2-butoxy (s-BuO, s-butoxy, -OCH(CH3)CH2CH3), 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC(CH3)3), 1-pentyloxy (n-pentyloxy, -OCH2CH2CH2CH2CH3), 2-pentyloxy (-OCH(CH3)CH2CH2CH3), 3-pentyloxy (-OCH(CH2CH3)2), 2-methyl-2-butoxy (-OC(CH3)2CH2CH3), 3-methyl-2-butoxy (-OCH(CH3)CH(CH3)2), 3-methyl-1-butoxy (-OCH2CH2CH(CH3)2), 2-methyl-1-butoxy (-OCH2CH(CH3)CH2CH3), and the like.

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

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

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

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

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

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

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

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

[0149] The term "monocyclic heterocyclic moiety" refers to a divalent saturated or partially unsaturated monocyclic heterocyclic system, where the heterocyclic ring has the definition as described in the present invention. In the monocyclic heterocyclic moiety, the -CH2- group can be optionally replaced by -C(=O)-. In some embodiments, the monocyclic heterocyclic moiety contains 3-7 ring atoms, that is, the monocyclic heterocyclic moiety is a 3-7 membered monocyclic heterocyclic moiety; in other embodiments, the monocyclic heterocyclic moiety contains 3-6 ring atoms, that is, the monocyclic heterocyclic moiety is a 3-6 membered monocyclic heterocyclic moiety. Preferably, the monocyclic heterocyclic moiety 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, where the heterocyclic group and the alkyl group have the definitions as described in the present invention. In some embodiments, the heterocyclic group alkyl is a 3-12 membered heterocyclic group C 1-6alkyl; in some other embodiments, heterocyclic alkyl is a 3- to 6-membered heterocyclic C 1-6 alkyl; in some embodiments, heterocyclic alkyl is a 3- to 6-membered heterocyclic C 1-4 alkyl. Examples of heterocyclic alkyl include, but are not limited to: pyrrolidinylmethyl, piperidinylmethyl, and the like.

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

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

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

[0154] The term "aryl" means a monovalent aryl ring group formed by removing one hydrogen atom from a ring carbon atom of an aromatic ring. Examples of aryl groups can include phenyl, naphthyl, and anthracenyl. When aryl is a linking group and "aryl" is listed in the definition of the Markush group, then "aryl" means a linked arylene group. When M is aryl as defined in the present invention, it means that M contains a linked arylene group. The term "arylene" means a divalent aryl ring group formed by removing two hydrogen atoms from a ring carbon atom of an aromatic ring. Examples of aryl represented as a linked arylene group can include phenylene, naphthylene, and anthracenylene. The aryl group may be independently optionally substituted 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 the ring atoms of a heteroaromatic ring. The heteroaryl group is optionally substituted with one or more substituents described in the present invention. In one embodiment, a heteroaryl or 5- to 10-membered heteroaryl composed of 5 to 10 atoms 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 5-membered heteroaryl containing 5 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 5- to 6-membered heteroaryl containing 5 to 6 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]pyridinyl, pyrazolo[1,5-a]pyridinyl, 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]pyridinyl, and so on. When the heteroaryl is a linking group and the heteroaryl is listed for the definition of the Markush group, the heteroaryl represents a linked sub-heteroaryl. As defined in the present invention, when M is a heteroaryl, it means that M contains a linked sub-heteroaryl group. The term "sub-heteroaryl" refers to a divalent heteroaromatic ring group formed by removing two hydrogen atoms from the ring atoms of a heteroaryl. The heteroaryl can be independently and 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 "bridged carbocycle" and "bridged carbocyclic group" are used interchangeably and both refer to a non-aromatic saturated or partially unsaturated bicyclic or polycyclic system that shares two or more non-adjacent ring carbon atoms and has carbon atoms as ring atoms. The -CH2- group in the bridged carbocycle can optionally be replaced by -C(=O)-. In some embodiments, the bridged carbocycle contains 6-12 ring carbon atoms, i.e., represents a 6-12 membered bridged carbocycle; in other embodiments, the bridged carbocycle contains 6-10 ring carbon atoms, i.e., represents a 6-10 membered bridged carbocycle. Examples of bridged carbocycles include, but are not limited to: bicyclo[3.1.1]heptane, bicyclo[3.2.1]octane, bicyclo[2.2.2]octane, bicyclo[2.2.0]hexane, octahydro-1H-indene, etc. When the bridged carbocycle or bridged carbocyclic group is a linking group and the bridged carbocycle or bridged carbocyclic group is listed for the definition of the Markush group, the bridged carbocycle or bridged carbocyclic group represents a linked sub-bridged carbocyclic group. The term "sub-bridged carbocyclic group" refers to a divalent bridged carbocyclic group formed by removing two hydrogen atoms from the ring atoms of the bridged carbocycle. The bridged carbocycle or bridged carbocyclic group can be independently and optionally substituted by one or more substituents described in the present invention.

[0158] The terms "heterocyclic" 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 and S. Unless otherwise specified, the heterocyclic group can be carbon-based or nitrogen-based, and the -CH2- group can optionally be replaced by -C(=O)-. The sulfur atom of the ring can optionally be oxidized to an S-oxide, and the nitrogen atom of the ring can optionally be oxidized to an N-oxide. The heterocycle can be monocyclic or bicyclic; specifically, the bicyclic system can be a fused heterobicyclic, spiro heterobicyclic or bridged heterobicyclic. In some embodiments, the heterocyclic group contains 4 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, tetrahydrofuryl, dihydrofuryl, 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 heterocyclylene group. The term "heterocyclylene group" denotes a divalent heterocyclic group formed by removing two hydrogen atoms from the ring atoms of the heterocycle. The heterocycle or heterocyclic group can be independently and optionally substituted by one or more substituents described in the present invention.

[0159] The terms "bridged heterocycle" or "bridged heterocyclic group" are used interchangeably and both refer to a non-aromatic saturated or partially unsaturated bicyclic or polycyclic system that shares two or more non-adjacent ring atoms, and the system contains at least 1 carbon atom and contains 1, 2 or 3 heteroatoms selected from O, N, S. The -CH2- group in the bridged heterocycle 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 bridged heterocycle contains 6-12 ring atoms, i.e., a 6-12 membered bridged heterocycle; in other embodiments, the bridged heterocycle contains 6-10 ring atoms, i.e., a 6-10 membered bridged heterocycle. Examples of bridged heterocycles include, but are not limited to: 3,6-diazabicyclo[3.1.1]heptane, 3,8-diazabicyclo[3.2.1]octane, 2-azabicyclo[2.2.1]heptane, 6-azabicyclo[3.1.1]heptane, 3-azabicyclo[3.1.1]heptane, 8-azabicyclo[3.2.1]octane, 3--azabicyclo[3.2.1]octane, 2-diazabicyclo[2.2.2]octane, etc. When the bridged heterocycle or bridged heterocyclic group is a linking group and the bridged heterocycle or bridged heterocyclic group is defined for this Markush group, the bridged heterocycle or bridged heterocyclic group represents a linked sub-bridged heterocyclic group. The term "sub-bridged heterocyclic group" represents a divalent bridged heterocyclic group formed by removing two hydrogen atoms from the ring atoms of the bridged heterocycle. The bridged heterocycle or bridged heterocyclic group 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 amino-C 1-6 alkyl. In other embodiments, the term "aminoalkyl" represents amino-C 1-4 alkyl. In other embodiments, the term "aminoalkyl" represents amino-C 1-3 alkyl. Examples of aminoalkyl include, but are not limited to, aminomethyl, aminoethyl, aminopropyl, aminoisopropyl, aminoisobutyl, amino-tert-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, i.e., 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 connected 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 1-4 alkylsulfonyl. Examples of alkylsulfonyl include, but are not limited to, methylsulfonyl, ethylsulfonyl, 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-, 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] The term "protecting group" or "PG" refers to a substituent that is typically used to block or protect a particular functionality when reacting with other functional groups. For example, an "amino protecting group" refers to a substituent attached to an amino group to block or protect the functionality of the amino group in a compound. Suitable amino protecting groups include acetyl, trifluoroacetyl, tert-butoxycarbonyl (BOC, Boc), benzyloxycarbonyl (CBZ, Cbz), and 9-fluorenylmethoxycarbonyl (Fmoc). Similarly, a "hydroxy protecting group" refers to a substituent of a hydroxy group that is used to block or protect the functionality of the hydroxy group. Suitable protecting groups include acetyl and silyl. A "carboxy protecting group" refers to a substituent of a carboxy group that is used to block or protect the functionality of the carboxy group. Common carboxy protecting groups include -CH2CH2SO2Ph, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrobenzenesulfonyl)ethyl, 2-(diphenylphosphino)ethyl, nitroethyl, and the like. 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.

[0167] The term "prodrug" as used in the present invention represents a compound that is converted in vivo to a compound represented by formula (I). Such conversion is affected by hydrolysis of the prodrug in the blood or enzymatic conversion in the blood or tissues to the parent structure. The prodrug compounds of the present invention can be esters. In existing inventions, esters that can serve as prodrugs include phenyl esters, aliphatic (C 1-24)Esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound in the present invention contains a hydroxyl group, and it can be acylated to obtain a compound in the prodrug form. Other prodrug forms include phosphate esters, such as these phosphate ester compounds are obtained by phosphorylating the hydroxyl groups on the parent body. 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.

[0168] "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 its activity 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, degreasing, 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.

[0169] The "pharmaceutically acceptable salts" used in the present invention refer to the organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in the literature: S.M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19. The salts formed from pharmaceutically acceptable non-toxic acids include, but are not limited to, inorganic acid salts formed by reacting with amino groups such as hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, and organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, or these salts can be obtained by other methods described in books and literature such as ion exchange method. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and so on. The salts obtained by appropriate bases include salts of alkali metals, alkaline earth metals, ammonium and N + (C 1-4 (alkyl)4. The present invention also contemplates quaternary ammonium salts formed by any compound containing a group of N. Water-soluble or oil-soluble or dispersible products can be obtained by quaternization. Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and so on. Pharmaceutically acceptable salts further include appropriate, non-toxic ammonium, quaternary ammonium salts and amine cations formed by counterbalancing ions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C 1-8 sulfonates and aromatic sulfonates.

[0170] The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, basic or acidic moieties by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid form of these compounds with a stoichiometric amount of a suitable base (such as hydroxides, carbonates, bicarbonates, etc. of Na, Ca, Mg or K), or by reacting the free base form of these compounds with a stoichiometric amount of a suitable acid. Such reactions are usually carried out in water or an organic solvent or a mixture of both. Generally, in appropriate cases, a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile is used. Lists of additional suitable salts can be found, for example, in "Remington's Pharmaceutical Sciences", 20th Edition, Mack Publishing Company, Easton, Pa., (1985); and "Handbook of Pharmaceutical Salts: Properties, Selection, and Use", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[0171] In addition, the compounds disclosed in the present invention, including their salts, can also be obtained in their hydrate form or in a form containing a solvent (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.

[0172] The "solvate" of the present invention refers to an association formed by one or more solvent molecules with the compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid and aminoethanol. The term "hydrate" refers to an association in which the solvent molecule is water.

[0173] "Nitrogen oxides" in the present invention refer 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 peroxycarboxylic acid) to form N-oxides (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages). In particular, N-oxides can be prepared by the method of L.W. Deady (Syn. Comm. 1977, 7, 509 - 514), where, for example, in an inert solvent such as dichloromethane, the amine compound is reacted with m-chloroperoxybenzoic acid (MCPBA).

[0174] 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 the perceptible symptoms) or physiologically (e.g., stabilizing the physical parameters) or both. In other embodiments, "treating" refers to preventing or delaying the onset, occurrence, or worsening of the disease or disorder.

[0175] The term "RET-related cancer" as used in the present invention refers to cancers associated with the RET gene, RET kinase (also referred to herein as RET kinase protein or RET kinase), or dysregulation of the expression or activity or level of any of them. Non-limiting examples of RET-related cancers are described in the present invention. The dysregulation of the RET gene, RET kinase, or the expression or activity or level of any of them is one or more point mutations in the RET gene.

[0176] In some embodiments, the dysregulation of the RET gene, RET kinase, or the expression or activity or level of any 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, RET kinase, or the expression or activity or level of any of them includes the deletion of one or more residues of the RET kinase, resulting in constitutive activity of the RET kinase domain.

[0177] 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.

[0178] Any structural formula given in the present invention is also intended to represent both the non-isotope-enriched form and the isotope-enriched form of these compounds. Isotope-enriched compounds have the structure depicted by the general formula given in the present invention, except that one or more atoms are replaced by atoms having a selected atomic weight or mass number. Exemplary isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I.

[0179] On the other hand, the compounds of the present invention include isotope-enriched compounds as defined in the present invention, for example, those in which radioactive isotopes are present, such as 3 H, 14 C and 18 F, or those in which non-radioactive isotopes are present, such as 2 H and 13 C. Such isotope-enriched compounds can be used 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 a drug or a substrate, or can be used in radiotherapy of patients. 18 F-enriched compounds are particularly desirable for PET or SPECT studies. The isotope-enriched compounds of formula (I) can be prepared by conventional techniques familiar to those skilled in the art or by substituting the originally used unlabeled reagents with appropriate isotope-labeled reagents as described in the examples and preparation procedures of the present invention.

[0180] 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 of formula (I). The concentration of such heavier isotopes, especially deuterium, can be defined by the isotopic enrichment factor. The term "isotopic enrichment factor" as used in the present invention refers to the ratio between the isotopic abundance of the designated isotope and the natural abundance. If a substituent of the 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.

[0181] The compounds of the present invention, their pharmaceutical compositions, formulations and administrations

[0182] 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, thereby resulting in a reduction in the toxicity associated with the inhibition of other kinases.

[0183] 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 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.

[0184] 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 references: 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 references herein indicates that different adjuvants can be applied to the formulation of pharmaceutically acceptable compositions and their well-known preparation methods. Except to the extent that any conventional adjuvant is incompatible with the compounds of the present invention, such as any adverse biological effects produced or interactions with any other component of the pharmaceutically acceptable composition in a harmful manner, their use is also contemplated within the scope of the present invention.

[0185] In preparing the compositions provided herein, the active ingredient is usually admixed with an excipient, diluted by the excipient or enclosed within a carrier such as, 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 acts 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. Thus, 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 capsule.

[0186] 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 represented by formula (I), (I-1), (I-2) or (I-3) or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable adjuvants, which adjuvants include, but are 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 the active ingredients that elicits a therapeutic effect whether administered in combination, sequentially or simultaneously. The compounds of the present invention, particularly the compounds represented by formula (I), (I-1), (I-2) or (I-3) and their pharmaceutically acceptable salts are as described above. The carrier, diluent or excipient must be acceptable in the sense of being compatible with the other ingredients of the formulation and not 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 represented by formula (I), (I-1), (I-2) or (I-3) or its pharmaceutically acceptable salt with one or more pharmaceutically acceptable carriers, diluents or excipients. 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 use.

[0187] 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) combined 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 the daily dose or a divided dose or an appropriate fraction thereof of the active ingredient described above. Treatment may be initiated with a small dose that is demonstrably lower than the optimum dose of the compound. Thereafter, the dose may be increased in smaller increments until the optimum effect is achieved in the circumstances. Generally, it is most desirable to administer the compound at a concentration level that will generally provide effective results in anti-tumor treatment without causing any harmful or toxic side effects.

[0188] Compositions containing the compounds of the present invention can be formulated into unit dosage forms, each dosage containing from about 5 to about 1,000 mg (1 g), more usually from 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 of general formula I as provided herein) and a suitable pharmaceutical excipient, the predetermined amount being calculated to produce the desired therapeutic effect.

[0189] The pharmaceutical compositions are suitable for administration by any suitable route, such as by oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intradermal, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intralesional, intravenous or subdermal injection or infusion) routes. Such preparations can be made 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.

[0190] 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).

[0191] The present invention provides a method for treating cancer in a patient in need thereof, the method comprising: (a) determining whether the cancer in the patient is a RET-related cancer (e.g., including a RET-related cancer having one or more RET inhibitor-resistant mutations) (e.g., using a kit approved by a regulatory agency, such as an FDA-approved kit, to identify the RET gene, RET kinase or the expression or activity or level of 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 of formula (I), (I-1), (I-2) or (I-3) or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition thereof. Some embodiments of these methods further comprise administering to the subject another anti-cancer agent (e.g., another RET inhibitor, e.g., a RET inhibitor that is not the compound of the present invention). In some embodiments, the subject has been previously treated with a RET inhibitor that is not a compound of formula (I), (I-1), (I-2) or (I-3) or a pharmaceutically acceptable salt or solvate thereof, or has been previously treated (e.g., after tumor resection or radiotherapy) with other anti-cancer agents.

[0192] In some embodiments of any of the methods described herein, a compound of formula (I), (I-1), (I-2) or (I-3) (or a pharmaceutically acceptable salt or solvate thereof) is used in combination with a therapeutically effective amount of at least one other therapeutic agent selected from one or more other therapeutic regimens or therapeutic (e.g., chemotherapeutic) agents.

[0193] Non-limiting examples of other therapeutic agents include: other RET-targeted therapeutic agents (i.e., other RET kinase inhibitors: RET inhibitors that are not the compounds described in the present invention), receptor tyrosine kinase-targeted therapeutic agents, signal transduction pathway inhibitors, checkpoint inhibitors, apoptosis pathway regulators (e.g., Obataclax); cytotoxic chemotherapeutic agents, angiogenesis-targeted therapeutic agents, immune-targeted agents, and radiotherapy.

[0194] In some embodiments, the other RET-targeted therapeutic agent is a multi-kinase inhibitor that exhibits RET inhibitory activity.

[0195] Non-limiting examples of RET-targeted therapeutic agents include alectinib, apatinib, cabozantinib (XL-184), dovitinib, lenvatinib, motesanib, nintedanib, ponatinib, regorafenib, sitravatinib (MGCD516), sunitinib, sorafenib, vatalanib, vandetanib, AUY-922 (5-(2,4-dihydroxy-5-isopropyl-phenyl)-N-ethyl-4-[4-(morpholinomethyl)phenyl]isoxazole-3-carboxamide), BLU6864, BLU-667, DCC-2157, NVP-AST487 (1-[4-[(4-ethylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-3-[4-[6-(methylamino)pyrimidin-4-yl]oxyphenyl]urea), PZ-1, RPI-1 (1,3-dihydro-5,6-dimethoxy-3-[(4-hydroxyphenyl)methylene]-H-indol-2-one), RXDX-105 (1-(3-(6,7-dimethoxyquinazolin-4-yl)oxy)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea), SPP86 (1-isopropyl-3-(phenylethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine), and TG101209 (N-(1,1-dimethylethyl)-3-[[5-methyl-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-4-pyrimidinyl]amino]benzenesulfonamide).

[0196] 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.

[0197] Also provided herein are methods of treating cancer, comprising administering to a patient in need thereof a pharmaceutical combination for treating cancer, which comprises (a) a compound of formula (I), (I-1), (I-2) or (I-3) or a pharmaceutically acceptable salt or solvate thereof, (b) other therapeutic agents, and (c) optionally at least one pharmaceutically acceptable carrier, for simultaneous, separate or sequential use in treating cancer, wherein the amount of the compound of formula (I), (I-1), (I-2) or (I-3) or a pharmaceutically acceptable salt or solvate thereof and the amount of the other therapeutic agents are jointly effective in treating cancer.

[0198] The compounds and compositions described herein may be administered alone or in combination with other compounds (including other RET modulating compounds) or other therapeutic agents. In some embodiments, the compounds or compositions of the invention may be administered in combination with one or more compounds selected from the following: cabozantinib (COMETRIQ), vandetanib (CALPRESA), sorafenib (NEXAVAR), sunitinib (SUTENT), regorafenib (STAVARGA), ponatinib (ICLUSIG), bevacizumab (AVASTIN), crizotinib (XALKORI) or gefitinib (IRESSA). The compounds or compositions of the invention may be administered simultaneously or sequentially with other therapeutic agents by the same or different routes of administration. The compounds of the invention may be included in a single formulation or in separate formulations together with other therapeutic agents.

[0199] 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, together with a compound of formula (I), (I-1), (I-2) or (I-3) or a pharmaceutically acceptable salt or solvate thereof. Non-limiting examples of other therapeutic agents for the treatment of irritable bowel syndrome (IBS) include probiotics, fiber supplements (such as psyllium, methylcellulose), antidiarrheal agents (such as loperamide), bile acid binders (such as cholestyramine, colestipol, colesevelam), anticholinergic and antispasmodic agents (such as scopolamine, dicyclomine), antidepressants (such as tricyclic antidepressants, such as imipramine or nortriptyline or selective serotonin reuptake inhibitors (SSRI) such as fluoxetine or paroxetine), antibiotics (such as rifaximin), alosetron and lubiprostone.

[0200] Use of the Compounds and Pharmaceutical Compositions of the Present Invention

[0201] 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 the prevention or treatment of 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.

[0202] 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.

[0203] 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 the prevention or treatment of diseases or disorders related to wild-type RET and RET mutants.

[0204] 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, gangliocytomatosis of the gastrointestinal mucosa, inflammatory myofibroblastic tumor or cervical cancer.In some embodiments of any method or use 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, myeloid 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 cancer, parathyroid carcinoma, penile cancer, pharyngeal cancer, pheochromocytoma, pituitary cancer, plasmacytoma, pleuropulmonary blastoma, pregnancy and breast cancer, primary central nervous system lymphoma, primary peritoneal cancer, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, Sézary syndrome, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, squamous neck cancer, gastric cancer, T-cell lymphoma, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, cancer of unknown primary, urethral cancer, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, and Wilms tumor.

[0205] 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.

[0206] 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 RET inhibitor-resistant mutations (which result in increased resistance to compounds or pharmaceutically acceptable salts or solvates other than those of formula (I), (I-1), (I-2) or (I-3), such as substitutions at amino acid position 804, such as V804M, V804L or V804E), said treatment by combination administration or as a subsequent treatment to an existing drug treatment (e.g., other RET kinase inhibitors that are not compounds or pharmaceutically acceptable salts or solvates of formula (I), (I-1), (I-2) or (I-3)). Exemplary RET kinase inhibitors are described herein (e.g., other RET kinase inhibitors that are not compounds or pharmaceutically acceptable salts or solvates of formula (I), (I-1), (I-2) or (I-3)). In some embodiments, the RET kinase inhibitor can be selected from cabozantinib, vandetanib, alectinib, sorafenib, lenvatinib, ponatinib, dovitinib, sunitinib, foretinib, BLU667, and BLU6864.

[0207] In some embodiments of any of the methods or uses described herein, the irritable bowel syndrome (IBS) includes diarrhea-predominant, constipation-predominant or alternating, functional bloating, functional constipation, functional diarrhea, unspecified functional bowel disorder, functional abdominal pain syndrome, chronic idiopathic constipation, functional esophageal disease, functional gastroduodenal disease, functional anorectal pain, and inflammatory bowel disease.

[0208] According to the methods of the present invention, the compounds and compositions can be in any dosage and by any route of administration to be effective in treating or alleviating the severity of the disease. The exact amount required will vary depending on the patient, depending on race, age, general condition of the patient, severity of the infection, particular factors, mode of administration, and the like. The compounds or compositions can be used in combination with one or more other therapeutic agents, as discussed in the present invention.

[0209] General synthetic methods of the compounds of the present invention

[0210] Generally, the compounds of the present invention can be prepared by the methods described in the present invention, unless otherwise specified, wherein the definitions of the substituents are 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.

[0211] Those skilled in the art will recognize that: the chemical reactions described in the present invention can be used to appropriately prepare many other compounds of the present invention, and other methods for preparing the compounds of the present invention are considered to be within the scope of the present invention. For example, the synthesis of those non-illustrative compounds according to the present invention can be successfully accomplished by those skilled in the art through modification methods, such as appropriately protecting interfering groups, by using other known reagents in addition to those described in the present invention, or making some conventional modifications to the reaction conditions. In addition, the reactions or known reaction conditions disclosed in the present invention are also generally recognized to be applicable to the preparation of other compounds of the present invention.

[0212] In the following examples described, unless otherwise indicated, all temperatures are in degrees Celsius. Unless otherwise specified, the reagents can be purchased from the market. For example, the reagents can be purchased from commercial suppliers such as LinkChem, Aldrich Chemical Company, Inc., Arco Chemical Company, and Alfa Chemical Company, and are used without further purification, unless otherwise indicated. General reagents are purchased from Shantou Xilong Chemical Factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, Tianjin Haoyu Chemical Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Ocean Chemical Factory.

[0213] Anhydrous tetrahydrofuran is dried by refluxing with metallic sodium. Anhydrous dichloromethane and chloroform are dried by refluxing with calcium hydride. Ethyl acetate, N,N-dimethylacetamide, and petroleum ether are dried in advance with anhydrous sodium sulfate before use.

[0214] The following reactions are generally carried out under a positive pressure of nitrogen or argon or with a drying tube placed over an anhydrous solvent (unless otherwise indicated). The reaction flasks are stoppered with appropriate rubber stoppers, and the substrates are injected through a syringe. The glassware is dried.

[0215] The chromatographic column used was a silica gel column. The silica gel (300 - 400 mesh) was purchased from Qingdao Ocean Chemical Factory. Nuclear magnetic resonance spectra were recorded in CDC13 or DMSO-d6 as solvents (reported in ppm), using TMS (0 ppm) or chloroform (7.25 ppm) as reference standards. When multiplets occurred, the following abbreviations were used: s (singlet), d (doublet), t (triplet), m (multiplet), br (broadened), dd (doublet of doublets), dt (doublet of triplets). The coupling constant J was expressed in Hertz (Hz).

[0216] Low-resolution mass spectrometry (MS) data were determined using a spectrometer of Agilent 6320 series LC-MS equipped with a G1312A binary pump and a G1316A TCC (column temperature maintained at 30 °C), with a G1329A autosampler and a G1315B DAD detector applied for analysis, and an ESI source applied to the LC-MS spectrometer.

[0217] Low-resolution mass spectrometry (MS) data were determined using a spectrometer of Agilent 6120 series LC-MS equipped with a G1311A quaternary pump and a G1316A TCC (column temperature maintained at 30 °C), with a G1329A autosampler and a G1315D DAD detector applied for analysis, and an ESI source applied to the LC-MS spectrometer.

[0218] Both of the above spectrometers were equipped with an Agilent Zorbax SB-C18 column with a specification of 2.1×30 mm, 5 μm. The injection volume was determined by the sample concentration; the flow rate was 0.6 mL / min; the HPLC peaks were recorded and read at UV-Vis wavelengths of 210 nm and 254 nm. The mobile phase was a 0.1% formic acid acetonitrile solution (phase A) and a 0.1% formic acid ultrapure water solution (phase B).

[0219] Compound purification was evaluated by an Agilent 1100 series high performance liquid chromatography (HPLC), where UV detection was at 210 nm and 254 nm, a Zorbax SB-C18 column with a specification of 2.1×30 mm, 4 μm, for 10 minutes, the flow rate was 0.6 mL / min, with a gradient of 5 - 95% (0.1% formic acid acetonitrile solution) to (0.1% formic acid aqueous solution), and the column temperature was maintained at 40 °C.

[0220] The following abbreviations are used throughout this invention:

[0221] EA ethyl acetate

[0222] PE Petroleum ether

[0223] KI Potassium iodide

[0224] DCM Dichloromethane

[0225] CH3OH Methanol

[0226] TLC Thin layer chromatography

[0227] DMF N,N-Dimethylformamide

[0228] t-BuOK Potassium tert-butoxide

[0229] K2CO3 Potassium carbonate

[0230] DMA,DMAC N,N-Dimethylacetamide

[0231] THF Tetrahydrofuran

[0232] Na2SO4 Sodium sulfate

[0233] NaHCO3 Sodium bicarbonate

[0234] EDCI 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

[0235] DMAP 4-Dimethylaminopyridine

[0236] HCl / EA Ethyl acetate solution of hydrogen chloride

[0237] DMSO Dimethyl sulfoxide

[0238] CH3CN Acetonitrile

[0239] DCE 1,2-Dichloroethane

[0240] DIPEA N,N-Diisopropylethylamine

[0241] OTf Trifluoromethanesulfonyloxy

[0242] ℃ Degree Celsius, g gram

[0243] mmol Millimole

[0244] mL Milliliter

[0245] L Liter

[0246] min Minute

[0247] h Hour

[0248] % Percent

[0249] N,mol / L Mole per liter

[0250] mg milligram

[0251] 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 has the definitions as described in the present invention.

[0252] Synthetic Scheme 1

[0253] Synthetic scheme for intermediate (IA-1a):

[0254]

[0255] 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 2is a hydroxyl protecting group, such as benzyl, etc. The compound of formula (IA-1a-1) and the compound of formula (IA-1a-2) undergo a coupling reaction in a suitable solvent (such as dioxane, etc.) under suitable coupling agent conditions (such as a palladium coupling agent, preferably PdCl2(dppf)CH2Cl2) to obtain the compound of formula (IA-1a-3); the compound of formula (IA-1a-3) and the compound of formula (IA-1a-4) undergo a coupling reaction in a suitable solvent (such as toluene, etc.) under suitable coupling agent conditions (such as a palladium coupling agent, preferably PdCl2(dppf)CH2Cl2) to obtain the compound of formula (IA-1a-5); the compound of formula (IA-1a-5) reacts under suitable reaction conditions (such as in the presence of sodium hydroxide and hydrogen peroxide, in a tetrahydrofuran solvent) to obtain the compound of formula (IA-1a-6); the compound of formula (IA-1a-6) and the compound of formula (IA-1a-7) undergo a coupling reaction to obtain the compound of formula (IA-1a-8); the compound of formula (IA-1a-8) and the compound of formula (IA-1a-9) react under basic conditions to obtain the compound of formula (IA-1a-10); the compound of formula (IA-1a-10) is deprotected from amino 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).

[0256] Synthesis scheme of intermediate (IA-1b):

[0257]

[0258] The intermediate compound of formula (IA-1b) can be prepared by referring 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) and the compound of formula (IA-4) or a salt of the compound of formula (IA-4) (such as hydrochloride, formate, etc.) undergo a coupling reaction under suitable conditions (such as in a DMSO solvent, under basic conditions, such as K2CO3) to obtain the compound of formula (IA-1b).

[0259] Synthesis scheme of intermediate (IA-5):

[0260]

[0261] The intermediate compound of formula (IA-5) can be prepared by referring to the synthesis steps of the synthesis scheme of intermediate (IA-5). Among them, Hal 2Hal 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 basic conditions, and the base is K2CO3) in a suitable solvent (such as N,N-dimethylacetamide, N,N-dimethylformamide) to obtain the compound of formula (IA-5).

[0262] Synthesis Scheme 1:

[0263]

[0264] The compound of formula (IA) can be prepared by referring 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 basic conditions, and the base is K2CO3) in a suitable solvent (such as N,N-dimethylacetamide, N,N-dimethylformamide) to obtain the compound of formula (IA).

[0265] Synthesis Scheme 2:

[0266]

[0267] The compound of formula (IAa) can be prepared by referring 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 bridged ring containing a nitrogen atom and is substituted by q R a where q and R a have the definitions as described in the present invention. The compound of formula (IA-1) reacts with the compound of formula (IAa-2) under suitable conditions (such as basic conditions, and the base is K2CO3) in a suitable solvent (such as acetonitrile) to obtain the compound of formula (IAa-3); the compound of formula (IAa-3) reacts with the compound of formula (IAa-4) under suitable conditions (such as basic conditions, and the base is K2CO3) in a suitable solvent (such as N,N-dimethylacetamide) to obtain the compound of formula (IAa).

[0268] Synthesis Scheme 3

[0269]

[0270] The compound of formula (IA) can be prepared by referring to the synthesis steps of Synthesis Scheme 3. Among them, Ms is a mesyl group. The compound of formula (IA-1) reacts with the compound of formula (IA-3) under suitable conditions (such as basic conditions, and the base is K2CO3) in a suitable solvent (such as N,N-dimethylformamide) to obtain the compound of formula (IA).

[0271] Synthesis Scheme 4

[0272]

[0273] The compound of formula (IAb) can be prepared by referring to the synthesis steps of Synthesis Scheme 4. Among them, Hal 2 is F, Cl, Br or I, preferably Cl or Br; the compound of formula (IA-5) is coupled 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

[0274] Intermediate 1: 4-(6-Fluoropyridin-3-yl)-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile

[0275]

[0276] Step 1: 6-Bromo-4-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile

[0277] Under room temperature conditions, 6-bromo-4-methoxypyrazolo[1,5-a]pyridine-3-carbonitrile (50 g, 198.36 mmol), water (16.5 mL, 916 mmol), sodium hydroxide (16.03 g, 396.8 mmol), and DMAC (500 mL) were successively added to a 1 L single-necked flask. After stirring at room temperature for 5 min, it was transferred to 0 °C and dodecyl mercaptan (97 mL, 397 mmol) was slowly added. After the addition was completed, the reaction was transferred to 45 °C and stirred overnight. The reaction solution was poured into 3 L of ice water, and saturated citric acid aqueous solution was slowly added to adjust the pH to 5. After stirring for half an hour, it was allowed to stand, filtered, and the filter cake was washed with water and petroleum ether multiple times and dried at 60 °C to obtain 44.1 g of a yellow solid, which is the target product (yield 93.4%). Rf = 0.35 (PE / EA (v / v) = 3 / 1). LC-MS: m / z = 239.05 [M+H] + .

[0278] Step 2: 3-Bromo-3-cyanopyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate

[0279] Add 6-bromo-4-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile (44.1 g, 185 mmol), pyridine (45 mL, 559 mmol), and DCM (800 mL) to a 1 L single-necked flask. Cool the temperature to below -10 °C, and slowly add trifluoromethanesulfonic anhydride (50 mL, 297.2 mmol). After stirring for 1 h, allow the reaction mixture to warm to room temperature overnight. Rotavapor the DCM under reduced pressure, dilute with water (250 mL), extract with EA (500 mL × 3), collect the organic phase, wash with saturated brine (250 mL), dry over anhydrous sodium sulfate, filter, evaporate the filtrate, and purify by silica gel column chromatography (eluent PE / EA (v / v) = 50 / 1 - 25 / 1) to obtain 61.5 g of a yellowish solid, which is the target product with a yield of 89.7%. Rf = 0.45 (PE / EA (v / v) = 5 / 1).

[0280] Step 3: 6-Bromo-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0281] Under a nitrogen atmosphere, add 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) to a 1 L three-necked flask. Cool the temperature to -10 °C and slowly add a potassium acetate solution (115 mL, 345 mmol, 3 mol / L). Stir at this temperature for 1 h, then allow the reaction mixture to return to room temperature and continue the reaction overnight. Filter, wash the filter cake with EA (500 mL × 3), separate the organic phase from the filtrate, wash with water (500 mL), wash with saturated brine (250 mL), dry over anhydrous sodium sulfate, filter, evaporate the filtrate, and purify by silica gel column chromatography (eluent PE / DCM (v / v) = 2:1 - 0:1) to obtain 49 g of a white solid, which is 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).

[0282] 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

[0283] Under nitrogen protection, 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), redistilled toluene (150 mL) were successively added into a 250 mL single-necked flask. 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. Filtered through diatomaceous earth, the filter cake was washed with EA (50 mL×3). The organic phase was washed with water (250 mL), washed with saturated brine (250 mL), dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation. Column chromatography on silica gel (eluent PE / DCM(v / v) = 2:1 / 0:1) was carried out, and 8.5 g of orange solid was obtained after rotary evaporation of the collected fraction, which was the target product (yield 93.0%). Rf = 0.15 (DCM). 1 1H 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).

[0284] Step 5: 4-(6-Fluoropyridin-3-yl)-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile

[0285] In a 250 mL single-necked flask, 4-(6-fluoropyridin-3-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (8.5 g, 23 mmol), tetrahydrofuran (120 mL) were added successively. Under ice bath conditions, sodium hydroxide solution (60 mL, 120 mmol, 2 mol / L), hydrogen peroxide (14 mL, 140 mmol, 30 mass%) were slowly added, and stirred at low temperature. After monitoring the reaction to completion by TLC, sodium thiosulfate solution (50 mL, 150 mmol, 3 mol / L) was slowly added. After restoring to room temperature, water (250 mL) was added, and extracted with EA (250 mL × 2). The combined organic phases were washed with 0.1 M NaOH solution (500 mL × 2). All the aqueous phases were combined, the pH was adjusted to 4 with dilute hydrochloric acid, stirred at room temperature for 15 min, and filtered to obtain a wet filter cake. The mother liquor was extracted with EA (250 mL × 3), all the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated by rotary evaporation, and purified by silica gel column chromatography (eluent DCM / MeOH (v / v) = 100 / 0 - 10 / 1) to obtain a light yellow solid. All the solids were combined and dried at 50 °C to obtain 5.1 g of a light yellow solid, which was the target product (yield 86.0%). Rf = 0.25 (DCM / MeOH (v / v) = 100 / 1). LC-MS: m / z = 255.10 [M+H] + 。 1 HNMR(400MHz,DMSO-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).

[0286] 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

[0287]

[0288] Step 1: tert-Butyl 4-hydroxy-4-(pyridin-2-ylmethyl)piperidine-1-carboxylate

[0289] 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 completion of 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. 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).

[0290] Step 2: 4-(Pyridin-2-ylmethyl)piperidin-4-ol hydrochloride

[0291] 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+H] + 。

[0292] 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

[0293] In a 10 mL microwave tube, 4-(2-pyridylmethyl)piperidin-4-ol hydrochloride (430 mg, 1.880 mmol), 4-(6-fluoro-3-pyridyl)-6-hydroxy-pyrazolo[1,5-a]pyridine-3-carbonitrile (Intermediate 2, 240 mg, 0.944 mmol), potassium carbonate (522 mg, 3.777 mmol), DMSO (2.4 mL) were added, and the reaction was heated at 85 °C under microwave 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. 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).

[0294] Intermediate 3: 6-(2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)ethoxy)-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0295]

[0296] Step 1: (1S,4S)-5-(2-chloroethyl)-2-oxa-5-azabicyclo[2.2.1]heptane

[0297] At 0 °C, (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (1.00 g, 7.38 mmol) was dissolved in acetone (15 mL), potassium carbonate (3.06 g, 22.1 mmol) and potassium iodide (1.84 g, 11.1 mmol) were added. After stirring for 15 min, 1-bromo-2-chloroethane (1.59 g, 11.1 mmol) was slowly added, and the mixture was stirred at room temperature for 4 h. The reaction was monitored by TLC (first PE / EA (v / v = 2 / 1) and then DCM / CH3OH (v / v = 20 / 1), Rf = 0.31) and was complete. The reaction was quenched by slowly adding water, and the mixture was extracted with EA (10 mL × 3), washed with water, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography with eluent DCM / CH3OH (v / v = 40 / 1 - 20 / 1) to obtain 0.49 g of a colorless viscous liquid, which was the target product with a yield of 41%. 1 1H NMR (400 MHz, CDCl3) δ 4.41 (s, 1H), 4.01 (d, J = 7.9 Hz, 1H), 3.70–3.61 (m, 1H), 3.56 (s, 1H), 3.53 (d, J = 6.9 Hz, 2H), 3.06–2.94 (m, 2H), 2.94–2.88 (m, 1H), 2.58 (d, J = 9.9 Hz, 1H), 1.87 (d, J = 9.8 Hz, 1H), 1.76 (d, J = 9.8 Hz, 1H).

[0298] Step 2: 6-(2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)ethoxy)-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0299] 4-(6-Fluoropyridin-3-yl)-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile (Intermediate 1, 20 mg, 0.07868 mmol) and (1S,4S)-5-(2-chloroethyl)-2-oxa-5-azabicyclo[2.2.1]heptane (20 mg, 0.12374 mmol) were dissolved in DMF (6 mL), potassium carbonate (22 mg, 0.15918 mmol) was slowly added, and the mixture was stirred for 10 min. The temperature was raised to 50 °C and the reaction was stirred for 12 h. The reaction was monitored by TLC (first PE / EA (v / v = 2 / 1) and then DCM / CH3OH (v / v = 10 / 1), Rf = 0.07), and the raw materials were completely reacted. The reaction was cooled to room temperature and stopped. 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 with eluent DCM / CH3OH (v / v = 50 / 1 - 20 / 1) to obtain 12 mg of a yellowish-brown solid with a yield of 40%, which was the target product. LC-MS: m / z = 380.3 [M+H]+ . 1 1H NMR (400 MHz, CDCl3) δ 8.41 (d, J = 3.4 Hz, 1H), 8.28 (s, 1H), 8.24 (s, 1H), 8.08–7.98 (m, 1H), 7.21 (d, J = 1.9 Hz, 1H), 7.18–7.11 (m, 1H), 4.51 (s, 1H), 4.30 (brs, 2H), 4.22–4.16 (m, 1H), 3.93–3.80 (m, 1H), 3.76 (d, J = 8.2 Hz, 1H), 3.36–3.26 (m, 1H), 3.25 (brs, 2H), 2.83 (d, J = 8.8 Hz, 1H), 1.91 (d, J = 9.5 Hz, 2H).

[0300] Intermediate 4: tert-Butyl 6-(2-((3-cyano-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl)oxy)ethyl)-3,6-diazabicyclo[3.1.1]heptane-3-carboxylate

[0301]

[0302] Step 1: tert-Butyl 6-(2-chloroethyl)-3,6-diazabicyclo[3.1.1]heptane-3-carboxylate

[0303] To a 25 mL single-necked flask was added tert-butyl 3,6-diazabicyclo[3.1.1]heptane-3-carboxylate (300 mg, 1.51 mmol), CH3CN (4 mL), K2CO3 (730 mg, 5.28 mmol), KI (380 mg, 2.2892 mmol), and 1-bromo-2-chloroethane (0.4 mL, 5 mmol). After addition, the reaction was carried out at room temperature for 63 h. After the reaction stopped, the reaction mixture was filtered to remove insoluble solids, and the filtrate was purified by silica gel column chromatography (eluent: DCM / MeOH (v / v = 30 / 1)) to obtain 300 mg of the brown liquid as the product, with a yield of 76.03%. LC-MS: m / z = 261.10 [M + H] + . 1 1H NMR (400 MHz, CDCl3) δ 3.72 (s, 1H), 3.68–3.64 (m, 2H), 3.63 (d, J = 3.2 Hz, 1H), 3.55 (t, J = 6.3 Hz, 2H), 3.39 (t, J = 11.6 Hz, 2H), 2.78 (t, J = 6.2 Hz, 2H), 2.62 (dd, J = 13.9, 6.4 Hz, 1H), 1.74 (s, 1H), 1.51 (s, 9H).

[0304] Step 2: tert-Butyl 6-(2-((3-cyano-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl)oxy)ethyl)-3,6-diazabicyclo[3.1.1]heptane-3-carboxylate

[0305] Into a 25 mL single-necked flask were successively added 4-(6-fluoropyridin-3-yl)-6H-pyrazolo[1,5-a]pyridine-3-carbonitrile (Intermediate 1, 250 mg, 0.9835 mmol), potassium carbonate (420 mg, 3.0388 mmol), tert-butyl 6-(2-chloroethyl)-3,6-diazabicyclo[3.1.1]heptane-3-carboxylate (300 mg, 1.1505 mmol), DMF (5 mL), and the mixture was reacted at 80 °C for 15 h. After the reaction stopped, 10 mL of water was added to the reaction solution, and the mixture was extracted with EA (40 mL × 2). The organic phase was washed with water (5 mL × 3), saturated brine (5 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was purified by silica gel column chromatography (the eluent was DCM-DCM / MeOH (v / v = 20 / 1)) to obtain 300 mg of a yellow solid as the product, with a yield of 66.41%. LC-MS: m / z = 479.30 [M+H] + Intermediate 5: tert-Butyl 3-(2-((3-cyano-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl)oxy)ethyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate

[0306]

[0307] Step 1: tert-Butyl 3-(2-chloroethyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate

[0308] Into a 25 mL single-necked flask were added tert-butyl 3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (500 mg, 2.52 mmol), CH3CN (4 mL), K2CO3 (1.22 g, 8.83 mmol), KI (630 mg, 3.80 mmol), and 1-bromo-2-chloroethane (0.65 mL, 7.9 mmol). After the addition was completed, the mixture was reacted at 35 °C for 18 h. After the reaction stopped, the reaction solution was suction filtered, the filter cake was washed with EA multiple times, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (the eluent was DCM-DCM / MeOH (v / v = 20 / 1)) to obtain 150 mg of a liquid as the product, with a yield of 22.81%. LC-MS: m / z = 261.10 [M+H] + 。 11H NMR (400 MHz, CDCl3) δ 4.06 (s, 2H), 3.57 (t, J = 6.9 Hz, 2H), 3.31–3.07 (m, 2H), 2.96–2.85 (m, 4H), 2.40 (dd, J = 13.7, 6.3 Hz, 1H), 1.66 (d, J = 8.0 Hz, 1H), 1.45 (s, 9H).

[0309] Step 2: tert-Butyl 3-(2-((3-cyano-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl)oxy)ethyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate

[0310] In a 25 mL single-necked flask, 4-(6-fluoropyridin-3-yl)-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile (Intermediate 1, 120 mg, 0.47 mmol), potassium carbonate (200 mg, 1.45 mmol), tert-butyl 3-(2-chloroethyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (150 mg, 0.58 mmol), and DMF (2.5 mL) were successively added, and the reaction was carried out at 80 °C for 2 h. After stopping the reaction, 10 mL of water was added to the reaction solution, and it was extracted with EA (40 mL × 2). The organic phase was washed with water (10 mL × 3), saturated brine (10 mL × 2), dried over anhydrous sodium sulfate and then filtered. The filtrate was purified by silica gel column chromatography (eluent: DCM-DCM / MeOH (v / v = 20 / 1)), and 130 mg of solid was obtained as the product.

[0311] Intermediate 6: 1-((6-Methoxypyridin-3-yl)methyl)piperazine trihydrochloride

[0312]

[0313] Step 1: tert-Butyl 4-((6-methoxypyridin-3-yl)methyl)piperazine-1-carboxylate

[0314] In a single-necked flask, tert-butyl piperazine-1-carboxylate (1.0 g, 5.4 mmol) and 6-methoxypyridine-3-carbaldehyde (800 mg, 5.83 mmol) were added, and DCE (12 mL) was added to dissolve them. Acetic acid (0.3 mL, 5 mmol) was added, and then sodium triacetoxyborohydride (5.7 g, 27 mmol) was added under stirring. After the addition, the reaction was carried out at room temperature. The reaction was carried out at room temperature for 23.5 h. The reaction solution was concentrated and purified by silica gel column chromatography (eluent: PE / EA (v / v = 1 / 1)), and 1.4 g of a colorless liquid was obtained as the product, with a yield of 85.0%. LC-MS: m / z = 308.25 [M+H] + 。 11H 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).

[0315] Step 2: 1-((6-Methoxypyridin-3-yl)methyl)piperazine trihydrochloride

[0316] To a single-necked flask was added tert-butyl 4-((6-methoxypyridin-3-yl)methyl)piperazine-1-carboxylate (1.4 g, 4.6 mmol), MeOH (4 mL) was added, and HCl / MeOH (9 mL, 36 mmol, 4 mol / L) was added dropwise. After the addition was complete, the reaction was carried out at room temperature for 13 h. After the reaction was completed, filtration was carried out by suction, and the obtained solid was dried in vacuo at 60 °C to obtain 600 mg of a white solid, which was the product. LC-MS: m / z = 208.30 [M - 3HCl + H] + 。 1 1H NMR (400 MHz, DMSO-d6) 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).

[0317] Example 1: 6-(2-((1S,4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl)ethoxy)-4-(6-(3-((6-methoxypyridin-3-yl)oxo)azetidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0318]

[0319] Step 1: tert-Butyl 3-((6-methoxypyridin-3-yl)oxy)azetidine-1-carboxylate

[0320] 5-Hydroxy-2-methoxypyridine (2.00 g, 16.0 mmol) and tert-butyl 3-(methylsulfonyloxy)azetidine-1-carboxylate (4.82 g, 19.2 mmol) were dissolved in DMF (30 mL), and t-BuOK (3.59 g, 32.0 mmol) was added slowly. The mixture was stirred for 10 min. Then it was heated 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. It was cooled to room temperature, water was added, and the mixture was extracted with EA (20 mL × 3). The organic phases were combined, washed with water, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography with eluent PE / EA (v / v = 10 / 1 - 4 / 1) to obtain 2.03 g of a yellowish-brown solid with a yield of 64%, which was the target product. 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).

[0321] Step 2: 5-(Azetidin-3-yloxy)-2-methoxypyridine hydrochloride

[0322] At 0 °C, tert-butyl 3-((6-methoxypyridin-3-yl)oxy)azetidine-1-carboxylate (2.03 g, 7.24 mmol) was dissolved in EA (10 mL), and hydrochloric acid ethyl acetate (12 mL, 36 mmol, 3 mol / L) was added slowly. The mixture was allowed to warm to room temperature and stirred for 4 h. The reaction was monitored by TLC (PE / EA (v / v = 3 / 1), Rf = 0.17), and the raw materials reacted completely. The reaction was stopped and concentrated to obtain 1.47 g of a yellowish-brown viscous liquid, which was the target product (yield 94%). LC-MS: m / z = 181.3 [M - 2HCl+H] + 。

[0323] Step 3: 6-(2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)ethoxy)-4-(6-(3-((6-methoxypyridin-3-yl)oxo)azetidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0324] 6-(2-((1S,4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl)ethoxy)-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Intermediate 3, 40 mg, 0.11 mmol), 5-(azetidin-3-yloxy)-2-methoxypyridine dihydrochloride (28 mg, 0.17 mmol) were dissolved in DMSO (6 mL), DIPEA (81 mg, 0.63 mmol) and DMAP (2 mg, 0.02 mmol) were added, and the mixture was stirred for 10 min. The temperature was raised to 90 °C and the reaction was stirred for 12 h. The reaction was monitored by TLC (DCM / CH3OH = 10 / 1, Rf = 0.29) to completion. The reaction was stopped by cooling to room temperature, EA (20 mL × 3) was added, washed with water, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography, eluting with DCM / CH3OH (v / v = 30 / 1 - 10 / 1) to give 19 mg of a yellow-brown solid, yield 33%, which was the target product. LC-MS: m / z = 540.3 [M+H] + 。 1 H NMR (400 MHz, CDCl3) δ 8.30 (d, J = 2.0 Hz, 1H), 8.19 (s, 1H), 8.14 (d, J = 2.0 Hz, 1H), 7.69 (d, J = 2.6 Hz, 2H), 7.21–7.15 (m, 1H), 7.10 (d, J = 2.0 Hz, 1H), 6.72 (d, J = 8.9 Hz, 1H), 5.13–5.03 (m, 1H), 4.57–4.46 (m, 2H), 4.43 (s, 1H), 4.22–4.15 (m, 2H), 4.12 (d, J = 5.2 Hz, 2H), 4.09 (d, J = 7.9 Hz, 1H), 3.90 (s, 3H), 3.75–3.54 (m, 3H), 3.15–3.10 (m, 1H), 3.10–3.03 (m, 2H), 2.71–2.63 (m, 1H), 2.08–1.96 (m, 2H).

[0325] Example 2: 6-(2-(3,6-Diazabicyclo[3.1.1]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

[0326]

[0327] Step 1: tert-Butyl 6-(2-((3-cyano-4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl)oxy)ethyl)-3,6-diazabicyclo[3.1.1]heptane-3-carboxylate

[0328] 6-(2-((3-Cyano-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl)oxy)ethyl)-3,6-diazabicyclo[3.1.1]heptane-3-carboxylate (Intermediate 4, 50 mg, 0.10 mmol), 1-((6-methoxypyridin-3-yl)methyl)piperazine hydrochloride (48 mg, 0.15 mmol), potassium carbonate (66 mg, 0.48 mmol), and DMSO (1.5 mL, 99.9 mass%) were added to a single-necked flask, and the reaction was carried out at 90 °C in an oil bath for 20 h. After the reaction stopped, the reaction solution was cooled to room temperature, 5 mL of water was added, and the mixture was extracted with EA (20 mL × 2). The organic phase was washed with water (5 mL × 3), saturated brine (5 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: DCM-DCM / MeOH (v / v = 10 / 1)) to obtain 43 mg of a pale yellow solid as the product, with a yield of 61.81%. LC-MS: m / z = 666.30 [M+H] + 。 1 H NMR (400 MHz, CDCl3) δ 8.31 (s, 1H), 8.19 (s, 1H), 8.10 (d, J = 12.0 Hz, 2H), 7.70 (d, J = 8.7 Hz, 1H), 7.63 (d, J = 8.3 Hz, 1H), 7.06 (s, 1H), 6.75 (d, J = 8.4 Hz, 2H), 4.09 (s, 2H), 3.94 (s, 3H), 3.75–3.61 (m, 8H), 3.50 (s, 2H), 3.42 (t, J = 11.8 Hz, 2H), 2.89 (s, 2H), 2.62 (s, 1H), 2.56 (s, 4H), 2.17 (s, 1H), 1.50 (s, 9H).

[0329] Step 2: 6-(2-(3,6-Diazabicyclo[3.1.1]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

[0330] tert-Butyl 6-(2-((3-cyano-4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl)oxy)ethyl)-3,6-diazabicyclo[3.1.1]heptane-3-carboxylate (43 mg, 0.065 mmol) was added to a single-necked flask, dissolved in MeOH (0.5 mL) at room temperature, and HCl / MeOH (0.5 mL, 2 mmol, 4 mol / L) was added. The reaction was carried out at room temperature for 4 h. After the reaction stopped, the reaction solution was concentrated, dissolved in MeOH, potassium carbonate (188 mg) was added, and the mixture was stirred at room temperature for 30 min. At this time, the solution was alkaline. The reaction solution was directly concentrated and purified by silica gel column chromatography (eluent: DCM / MeOH (v / v = 1 / 1)) to obtain 25 mg of a pale yellow solid as the product, with a yield of 68.43%. LC-MS: m / z = 566.30 [M+H] + 。 1 H NMR (400 MHz, DMSO) δ 8.65 (s, 1H), 8.57 (s, 1H), 8.31 (s, 1H), 8.08 (s, 1H), 7.76 (dd, J = 8.8, 2.2 Hz, 1H), 7.67 (d, J = 6.5 Hz, 1H), 7.30 (s, 1H), 6.92 (d, J = 8.9 Hz, 1H), 6.80 (d, J = 8.4 Hz, 1H), 4.15 (s, 2H), 3.83 (s, 3H), 3.57 (s, 6H), 3.50 (s, 2H), 3.48 (s, 4H), 3.07 (d, J = 13.0 Hz, 2H), 2.94 (s, 2H), 2.46 (s, 4H), 1.95 (d, J = 9.1 Hz, 1H).

[0331] Example 3: 4-(6-(4-Hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)-6-(2-(3-oxo-8-azabicyclo[3.2.1]octan-8-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0332]

[0333] 4-(6-Fluoropyridin-3-yl)-6-(2-(3-oxo-8-azabicyclo[3.2.1]octan-8-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (30 mg, 0.074 mmol, Step 3 of Example 6), 4-(pyridin-2-ylmethyl)piperidin-4-ol hydrochloride (23.6 mg, 0.103 mmol), K2CO3 (40.9 mg, 0.296 mmol) and DMSO (2 mL) were added successively to a single-necked flask, and the mixture was stirred at 90 °C for 18 h. Water (10 mL) and EA (50 mL) were added, and the organic phase was washed with saturated sodium chloride (10 mL × 3). After evaporation under reduced pressure, the residue was purified by silica gel column chromatography (eluent: DCM-DCM / MeOH (v / v = 30 / 1)) to obtain 28 mg of a yellowish-white solid product, which was the target product, with a yield of 65.50%. LC-MS: m / z = 578.30 [M+H] + 。 1 H NMR (400 MHz, CDCl3) δ = 8.52 (d, J = 4.2 Hz, 1H), 8.30 (d, J = 2.2 Hz, 1H), 8.26–8.12 (m, 2H), 7.76–7.60 (m, 2H), 7.19 (dd, J = 6.8, 5.3 Hz, 1H), 7.16–7.06 (m, 2H), 6.77 (d, J = 8.9 Hz, 1H), 4.22 (t, J = 5.5 Hz, 2H), 4.09 (d, J = 13.1 Hz, 2H), 3.65 (s, 2H), 3.54–3.41 (m, 2H), 3.08 (t, J = 5.5 Hz, 2H), 2.94 (s, 2H), 2.71 (dd, J = 15.9, 3.4 Hz, 2H), 2.24 (d, J = 15.8 Hz, 2H), 2.13–2.02 (m, 2H), 1.67–1.63 (m, 4H), 1.27 (d, J = 12.3 Hz, 2H).

[0334] Example 4: 6-(2-(((1R,4R)-2-azabicyclo[2.2.1]hept-5-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

[0335]

[0336] Step 1: (1R,4R,5R)-5-hydroxy-2-azabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester

[0337] Under ice bath conditions, tert-butyl 5-oxo-2-azabicyclo[2.2.1]heptane-2-carboxylate (300 mg, 1.42 mmol) was added to a 10 mL single-necked flask, dissolved in methanol (6 mL). While maintaining this temperature, sodium borohydride (59.1 mg, 1.56 mmol) was slowly added. After completion, it was slowly restored to room temperature and stirred overnight. Under low-temperature conditions, water (10 mL) and saturated ammonium chloride aqueous solution (10 mL) were added to quench the reaction. It was extracted with EA (30 mL×3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated by rotary evaporation, and purified by silica gel column chromatography (eluent PE / EA (v / v) = 10 / 1 - 2 / 1) to obtain 0.295 g of a white solid, which was the target product. (Yield: 97.4%, Rf = 0.15 (EA / PE (v / v) = 1 / 3)). 1 1H NMR (400 MHz, CDCl3) δ 4.37 (d, J = 4.6 Hz, 1H), 4.18 (s, 0.5H), 4.06 (s, 0.5H), 3.66 (t, J = 10.0 Hz, 1H), 3.14 (t, J = 10.7 Hz, 1H), 2.57 (s, 1H), 2.06–1.99 (m, 1H), 1.68 (t, J = 11.4 Hz, 1H), 1.50–1.46 (m, 1H), 1.44 (s, 9H), 1.34–1.22 (m, 1H).

[0338] Step 2: (1R,4R) 5-(2-Ethoxy-2-oxoethoxy)-2-azabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester

[0339] Under ice bath and nitrogen protection conditions, sodium hydride (40.23 mg, 1.66 mmol) was successively added to a 25 mL two-necked flask, and (1R,4R,5R)-5-hydroxy-2-azabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (295 mg, 1.3832 mmol) dissolved in THF (15 mL) was added. After transferring to room temperature and stirring for 2 h, ethyl bromoacetate (0.19 mL, 1.7 mmol) was slowly added under ice bath conditions, and then slowly restored to room temperature and reacted overnight. Under low-temperature conditions, water (10 mL) was added to quench the reaction. It was extracted with EA (50 mL×3). The combined organic phases were washed with water and saturated brine (30 mL) respectively, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated by rotary evaporation, and silica gel column chromatography (eluent PE / EA (v / v) = 10 / 1 - 5 / 1) gave 0.145 g of a colorless oil, which was the target product. (Yield: 35.0%, Rf = 0.15 (EA / PE (v / v) = 1 / 3)).

[0340] Step 3: (1R,4R)-5-(2-Hydroxyethoxy)-2-azabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester

[0341] Under the condition of -20 °C, in a 25 mL single-necked flask, (1R,4R)-5-(2-ethoxy-2-oxoethoxy)-2-azabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (0.145 g, 0.484 mmol) was successively added. After dissolving in THF (5 mL), lithium aluminum hydride (46 mg, 1.21 mmol) was slowly added under nitrogen protection, and the reaction was continued at this temperature overnight. It was diluted with EA (50 mL), the reaction mixture was diluted with water (20 mL), the organic phase was separated, washed with water and saturated brine (30 mL) respectively, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated by rotary evaporation, and purified by silica gel column chromatography (eluent PE / EA (v / v) = 5 / 1 - 1 / 1) to obtain 0.108 g of a pale yellow liquid, which was the target product. (Yield: 86.7%, Rf = 0.25 (EA / PE = 1 / 2). Step 4: (1R,4R)-5-(2-(((methylsulfonyl)oxy)ethoxy)-2-azabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester

[0342] Under ice bath conditions, in a 5 mL single-necked flask, (1R,4R)-5-(2-hydroxyethoxy)-2-azabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (105 mg, 0.4081 mmol), dichloromethane (1.5 ml), and triethylamine (0.085 mL, 0.61 mmol) were successively added. Methanesulfonyl chloride (0.05 mL, 0.6 mmol) was slowly added. After the addition was completed, the temperature was slowly restored to room temperature and the reaction was continued for 2 h. Under low temperature conditions, it was quenched with saturated aqueous Na2SO4 solution (10 ml), extracted with EA multiple times (30 mL × 3), the combined organic phases were washed with saturated NaHCO3 (30 mL) and saturated brine (30 mL) respectively, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated by rotary evaporation, and the residue was purified by silica gel column chromatography (eluent: DCM / EA (v / v) = 10 / 1) to obtain 0.11 g of a light yellow oil, which was the target product. (Yield: 80%, Rf = 0.8 (DCM / EA (v / v) = 8 / 1).

[0343] Step 5: (1R,4R)-5-(2-((3-cyano-4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl)oxy)ethoxy)-2-azabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester

[0344] In a 5 mL single-necked flask, 6-hydroxy-4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Intermediate 2, 30 mg, 0.07 mmol), (1R,4R)-tert-butyl 5-(2-(((methylsulfonyl)oxy)ethoxy)-2-azabicyclo[2.2.1]heptane-2-carboxylate (47.2 mg, 0.14 mmol), potassium carbonate (31 mg, 0.21 mmol), and DMF (0.5 mL) were added successively, and the mixture was heated at 80 °C in an oil bath overnight. After the reaction was completed, the reaction solution was diluted with water (10 mL), extracted with EA (25 mL × 3), the organic phase was collected, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (eluent DCM / MeOH (v / v) = 100 / 1 - 20 / 1) to obtain 23.5 mg of a yellow solid, which was the target product (yield 50.2%) (Rf = 0.2, DCM / MeOH (v / v) = 30 / 1). LC-MS (ES-API): m / z = 666.30 [M+H] + 。 1 HNMR (400 MHz, CDCl3) δ 8.52 (d, J = 4.5 Hz, 1H), 8.30 (s, 1H), 8.19 (s, 1H), 8.14 (s, 1H), 7.69–7.62 (m, 2H), 7.19 (dd, J = 7.4, 5.1 Hz, 1H), 7.13 (d, J = 7.5 Hz, 2H), 6.77 (d, J = 9.0 Hz, 1H), 4.22 (s, 1H), 4.17 (s, 2H), 4.13–4.03 (m, 4H), 3.82–3.76 (m, 2H), 3.60–3.55 (m, 1H), 3.54–3.43 (m, 3H), 3.18–3.10 (m, 1H), 2.94 (s, 2H), 2.76 (s, 1H), 2.02–1.94 (m, 2H), 1.67–1.64 (m, 5H), 1.44 (s, 9H).

[0345] Step 6: 6-(2-(((1R,4R)-2-azabicyclo[2.2.1]hept-5-yl)oxy)ethoxy)-4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile dihydrochloride

[0346] In a 25 mL single-necked flask, ((1R,4R)-5-(2-((3-cyano-4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl)oxy)ethoxy)-2-azabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (19 mg, 0.02854 mmol), ethyl acetate hydrochloride solution (0.5 mL, 2 mmol, 4 mol / L) were added successively, and stirred at room temperature overnight. After the reaction was completed, it was directly concentrated to dryness by rotary evaporation and then dried in an oven at 60 °C to obtain 18.22 mg of a yellow solid, which was the target product (yield 100%) (Rf = 0.1, DCM / MeOH = 20 / 1). LC-MS (ES-API): m / z = 566.20 [M - 2HCl + H] + 。

[0347] Example 5: 1-(5-(6-(2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)ethoxy)-3-cyanopyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N-(6-methoxypyridin-3-yl)azetidine-3-carboxamide

[0348]

[0349] Step 1: tert-Butyl 3-(((6-methoxypyridin-3-yl)carbamoyl)azetidine-1-carboxylate

[0350] At room temperature, 1-tert-butoxycarbonylazetidine-3-carboxylic acid (500 mg, 2.48 mmol) and 6-methoxypyridin-3-amine (370 mg, 2.98 mmol) were added to a 25 mL single-necked flask, dissolved in DCM (12.5 mL), and EDCI (715 mg, 3.73 mmol) and DMAP (31 mg, 0.25 mmol) were added with stirring. The reaction was continued at this temperature. After the reaction was completed as detected by TLC, 10 mL of water was added to the reaction solution, and it was extracted with DCM (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (eluent EA / PE (v / v) = 1 / 3 - 1 / 2) to obtain 760 mg of a pink viscous solid, which was the product. LC-MS: 252.05. 11H NMR (400 MHz, CDCl3) δ = 8.16 (d, J = 2.5 Hz, 1H), 7.92 (dd, J = 8.9, 2.7 Hz, 1H), 7.31 (s, 1H), 6.74 (d, J = 8.9 Hz, 1H), 4.23 - 4.17 (m, 2H), 4.12 (t, J = 8.5 Hz, 2H), 3.91 (s, 3H), 3.38 - 3.32 (m, 1H), 1.45 (s, 9H).

[0351] Step 2: N-(6-Methoxypyridin-3-yl)azetidine-3-carboxamide hydrochloride

[0352] Dissolve tert-butyl 3-(((6-methoxypyridin-3-yl)carbamoyl)azetidine-1-carboxylate (760 mg, 2.47 mmol) in HCl / EA (10 mL, 50 mmol, 4N), and stir at room temperature. After the reaction is completed as detected by TLC, filter the reaction solution by suction, wash the filter cake with a small amount of EA, and dry the filter cake by suction to obtain 680 mg of white solid as the product, with a yield of 98.14%. LC-MS: m / z = 208.1 [M - 2HCl + H] + .

[0353] Step 3: 1-(5-(6-(2-((1S,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-5-yl)ethoxy)-3-cyanopyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N-(6-methoxypyridin-3-yl)azetidine-3-carboxamide

[0354] At room temperature, sequentially add 6-(2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)ethoxy)-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Intermediate 3, 25 mg, 0.066 mmol), N-(6-methoxy-3-pyridinyl)azetidine-3-carboxamide hydrochloride (24.1 mg, 0.099 mmol), DMAP (1 mg, 0.008 mmol), potassium carbonate (23 mg, 0.166 mmol) and DMSO (2 mL) into a single-neck flask, and stir overnight at 90 °C. Add EA (150 mL) and water (30 mL), separate the organic phase, wash the organic phase with saturated brine (30 mL × 3), dry over anhydrous sodium sulfate, filter, concentrate the mother liquor under reduced pressure, and perform silica gel column chromatography (DCM - DCM / MeOH (v / v = 10 / 1)) to obtain 20.00 mg of white solid product, which is the target product (yield: 53.57%). LC-MS: m / z = 567.1 [M + H] + . 11H NMR (400 MHz, CDCl3) δ 8.29 (dd, J = 10.3, 2.1 Hz, 2H), 8.20 (s, 1H), 8.16 (d, J = 1.7 Hz, 1H), 8.02 (s, 1H), 7.97 (dd, J = 8.9, 2.6 Hz, 1H), 7.68 (dd, J = 8.5, 2.2 Hz, 1H), 7.11 (d, J = 1.8 Hz, 1H), 6.73 (d, J = 8.9 Hz, 1H), 6.45 (d, J = 8.6 Hz, 1H), 4.45 (s, 1H), 4.42–4.25 (m, 4H), 4.16 (d, J = 5.2 Hz, 2H), 4.14–4.10 (m, 1H), 3.91 (s, 3H), 3.80–3.57 (m, 4H), 3.16–3.09 (m, 2H), 2.71 (d, J = 9.8 Hz, 1H), 1.96 (d, J = 9.9 Hz, 1H), 1.82 (d, J = 9.6 Hz, 1H).

[0355] Example 6: 4-(6-(3-((6-Methoxypyridin-3-yl)oxy)azetidin-1-yl)pyridin-3-yl)-6-(2-(3-oxo-8-azabicyclo[3.2.1]octan-8-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0356]

[0357] Step 1: 8-Azabicyclo[3.2.1]octan-3-one hydrochloride

[0358] Dissolve tert-butyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (2 g, 8.88 mmol) in methanol (10 mL), add hydrochloric acid in methanol (22 mL, 88 mmol, 4 mol / L), and stir the reaction at 30 °C for 5.5 h. Rotary evaporate under reduced pressure to obtain 1.43 g of a colorless solid product, which is the product. The yield is calculated as 100%. LC-MS: m / z = 126.20 [M+H] + .

[0359] Step 2: 8-(2-Chloroethyl)-8-azabicyclo[3.2.1]octan-3-one

[0360] 8-Azabicyclo[3.2.1]octan-3-one hydrochloride (1.43 g, 8.85 mmol), potassium carbonate (4.89 g, 35.4 mmol), and acetonitrile (14.3 mL) were successively added to a single-necked flask. The mixture was stirred at room temperature for 10 min, and then 1-bromo-2-chloroethane (2.21 mL, 26.6 mmol) was added. The mixture was stirred at 30 °C overnight. The solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain 120 mg of a colorless liquid product, which was the product. Yield: 7.23%.

[0361] Step 3: 4-(6-Fluoropyridin-3-yl)-6-(2-(3-oxo-8-azabicyclo[3.2.1]octan-8-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0362] 4-(6-Fluoropyridin-3-yl)-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile (Intermediate 1, 147 mg, 0.58 mmol), 8-(2-chloroethyl)-8-azabicyclo[3.2.1]octan-3-one (120 mg, 0.64 mmol), potassium carbonate (240 mg, 1.74 mmol), and DMSO (2 mL) were successively added to a single-necked flask. The mixture was heated and stirred at 80 °C for 1.5 h. Water (10 mL) and DCM (50 mL) were added, and the organic phase was separated. The organic phase was washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: DCM - DCM / MeOH (v / v = 50 / 1)) to obtain 234 mg of a yellowish-white solid product, which was the target compound. Yield: 99.81%. LC-MS: m / z = 406.20 [M+H] + 。 1 H NMR (400 MHz, CDCl3) δ = 8.39 (d, J = 1.9 Hz, 1H), 8.27 (d, J = 1.9 Hz, 1H), 8.22 (s, 1H), 8.01 (td, J = 8.3, 2.5 Hz, 1H), 7.19 (d, J = 1.9 Hz, 1H), 7.13 (dd, J = 8.4, 2.9 Hz, 1H), 4.24 (t, J = 5.5 Hz, 2H), 3.66–3.63 (m, 2H), 3.08 (t, J = 5.6 Hz, 2H), 2.73–2.67 (m, 2H), 2.25 (d, J = 15.3 Hz, 2H), 2.11–2.06 (m, 2H), 1.70–1.65 (m, 2H).

[0363] Step 4: tert-Butyl 3-((methylsulfonyl)oxy)azetidine-1-carboxylate

[0364] In a two-necked flask, tert-butyl 3-hydroxyazetidine-1-carboxylate (2.00 g, 11.5 mmol) was dissolved in triethylamine (3.21 mL, 23.1 mmol). Methanesulfonyl chloride (1.09 mL, 14.1) was added under ice bath conditions, and the reaction was carried out at room temperature for 0.5 h. The reaction was quenched by adding water (5 mL), and the mixture was extracted with DCM (20 mL). The organic phase was washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and the mother liquor was rotary evaporated under reduced pressure. Purification by silica gel column chromatography (eluent: PE - PE / EA (v / v = 5 / 0 - 5 / 1)) gave 2.61 g of a colorless liquid product, which was the target product. Yield: 89.9%. LC-MS: m / z = 196.10 [M - tBu + 2H] + 。

[0365] Step 5: tert-Butyl 3-(((6-methoxypyridin-3-yl)oxy)azetidine-1-carboxylate

[0366] 6-Methoxypyridin-3-ol (1.24 g, 9.91 mmol) was dissolved in DMSO (7 L). Potassium tert-butoxide (1.70 g, 12.9 mmol) was added under stirring conditions. After stirring for 20 min, the temperature was raised to 100 °C, and tert-butyl 3-((methylsulfonyl)oxy)azetidine-1-carboxylate (2.61 g, 10.4 mmol) dissolved in DMSO (30 mL) was slowly added dropwise. The reaction was carried out at 100 °C for 20 h. Water (50 mL) and EA (300 mL) were added. The organic phase was washed with saturated sodium chloride (20 mL × 4), rotary evaporated under reduced pressure and purified by column chromatography (eluent: PE - PE / EA (v / v = 100 / 0 - 100 / 10)). The product showed no obvious color reaction with potassium permanganate at 254 nm and was also not obvious with iodine when the concentration was dilute; the bromine-containing raw material showed an obvious color reaction with potassium permanganate), and 1.64 g of a pale yellow oil was obtained, which was the target compound. Yield: 59.0%. LC-MS: m / z = 281.35 [M + H] + 。

[0367] Step 6: 5-(Azetidin-3-yloxy)-2-methoxypyridine dihydrochloride

[0368] tert-Butyl 3-(((6-methoxypyridin-3-yl)oxy)azetidine-1-carboxylate (1.64 g, 5.85 mmol) was dissolved in methanol (8.00 mL). Hydrochloric acid in methanol (15 mL, 4 mol / L) was added, and the reaction was stirred at room temperature for 7.5 h. Rotary evaporation under reduced pressure gave 1.48 g of a colorless solid product, which was the target product. Yield: 100%. LC-MS: m / z = 181.15 [M + H] + 。

[0369] Step 7: 4-(6-(3-((6-Methoxypyridin-3-yl)oxy)azetidin-1-yl)pyridin-3-yl)-6-(2-(3-oxo-8-azabicyclo[3.2.1]octan-8-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0370] 4-(6-Fluoropyridin-3-yl)-6-(2-(3-oxo-8-azabicyclo[3.2.1]octan-8-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (30 mg, 0.074 mmol), 5-(azetidin-3-yloxy)-2-methoxypyridine dihydrochloride (22.5 mg, 0.0889 mmol), K2CO3 (40.9 mg, 0.296 mmol) and DMSO (2 mL) were successively added into a single-necked flask, and the mixture was heated and stirred at 90 °C overnight. Water (10 mL) and EA (50 mL) were added. The organic phase was washed with saturated sodium chloride (10 mL×3), concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: DCM-DCM / MeOH (v / v = 30 / 1)) to obtain 18 mg of a yellowish-white solid product, which was the target compound, yield: 43.01%. LC-MS: m / z = 566.20 [M+H] + 。 1 H NMR (400 MHz, CDCl3) δ 8.31 (d, J = 2.0 Hz, 1H), 8.26–8.15 (m, 2H), 7.78–7.65 (m, 2H), 7.19 (dd, J = 8.9, 3.0 Hz, 1H), 7.11 (d, J = 1.8 Hz, 1H), 6.73 (d, J = 8.9 Hz, 1H), 6.46 (d, J = 8.6 Hz, 1H), 5.17–5.03 (m, 1H), 4.60–4.46 (m, 2H), 4.30–4.13 (m, 4H), 3.90 (s, 3H), 3.65 (s, 2H), 3.08 (t, J = 5.5 Hz, 2H), 2.72 (dd, J = 15.9, 3.4 Hz, 2H), 2.25 (d, J = 15.9 Hz, 2H), 2.14–2.06 (m, 2H), 1.72–1.62 (m, 2H).

[0371] Example 7: 1-(5-(3-Cyano-6-(2-(3-oxo-8-azabicyclo[3.2.1]octan-8-yl)ethoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N-(6-methoxypyridin-3-yl)azetidine-3-carboxamide

[0372]

[0373] 4-(6-Fluoropyridin-3-yl)-6-(2-(3-oxo-8-azabicyclo[3.2.1]octan-8-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (30 mg, 0.074 mmol, step 3 of Example 6), N-(6-methoxypyridin-3-yl)azetidine-3-carboxamide dihydrochloride (28.1 mg, 0.10 mmol), K2CO3 (40.9 mg, 0.30 mmol) and DMSO (2 mL) were added successively to a single-necked flask, and the mixture was stirred at 90 °C for 17 h. Water (10 mL) and EA (50 mL) were added. The organic phase was washed with saturated sodium chloride (10 mL×3), and the residue was dried under reduced pressure and purified by silica gel column chromatography (eluent: DCM-DCM / MeOH (v / v = 30 / 1)) to obtain 28 mg of a pale yellow solid product, which was the target product, with a yield of 63.85%. LC-MS: m / z = 593.30 [M+H] + 。 1 H NMR (400 MHz, CDCl3) δ 8.31 (d, J = 1.7 Hz, 1H), 8.24 (d, J = 2.2 Hz, 1H), 8.20 (d, J = 8.2 Hz, 2H), 8.06 (s, 1H), 7.95 (dd, J = 8.9, 2.4 Hz, 1H), 7.67 (dd, J = 8.6, 2.1 Hz, 1H), 7.10 (d, J = 1.5 Hz, 1H), 6.72 (d, J = 8.9 Hz, 1H), 6.43 (d, J = 8.6 Hz, 1H), 4.37–4.25 (m, 4H), 4.22 (t, J = 5.5 Hz, 2H), 3.90 (s, 3H), 3.64 (s, 2H), 3.60–3.51 (m, 1H), 3.07 (t, J = 5.5 Hz, 2H), 2.70 (dd, J = 15.9, 3.7 Hz, 2H), 2.24 (d, J = 15.9 Hz, 2H), 2.12–2.02 (m, 2H), 1.65 (q, J = 6.8 Hz, 2H).

[0374] Example 8: 4-(6-(4-((6-Methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)-6-(2-(3-oxo-8-azabicyclo[3.2.1]octan-8-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0375]

[0376] Step 1: tert-Butyl 4-((6-methoxypyridin-3-yl)methyl)piperazine-1-carboxylate

[0377] Add tert-butyl piperazine-1-carboxylate (1.0 g, 5.4 mmol) and 6-methoxypyridine-3-carbaldehyde (800 mg, 5.83 mmol) to a single-necked flask. Add DCE (12 mL) to dissolve them, add acetic acid (0.3 mL, 5 mmol), and then add sodium triacetoxyborohydride (5.7 g, 27 mmol) under stirring. After 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, which is 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).

[0378] Step 2: 1-((6-Methoxypyridin-3-yl)methyl)piperazine dihydrochloride

[0379] Add 4-((6-methoxypyridin-3-yl)methyl)piperazine-1-carboxylate tert-butyl ester (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 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, which is the product. LC-MS: m / z = 208.30 [M - 2HCl + H] + 。1H NMR (400 MHz, DMSO-d6) 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).

[0380] Step 3: 4-(6-(4-((6-Methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)-6-(2-(3-oxo-8-azabicyclo[3.2.1]octan-8-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0381] 4-(6-Fluoropyridin-3-yl)-6-(2-(3-oxo-8-azabicyclo[3.2.1]octan-8-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (30 mg, 0.074 mmol, Step 3 of Example 6), 1-((6-Methoxypyridin-3-yl)methyl)piperazine dihydrochloride (24.9 mg, 0.089 mmol), K2CO3 (40.9 mg, 0.30 mmol) and DMSO (2 mL) were added successively to a single-necked flask, and the mixture was heated and stirred at 90 °C for 27 h. Water (10 mL) and EA (50 mL) were added, and the organic phase was washed with saturated sodium chloride (10 mL × 3). Purification by thin-layer plate column chromatography gave 33 mg of a yellow solid product, which was the target product, with a yield of 97.85%. LC-MS: m / z = 593.35 [M+H] + 1H NMR (400 MHz, CDCl3) δ = 8.32 (s, 1H), 8.19 (d, J = 8.9 Hz, 2H), 8.13–8.02 (m, 1H), 7.81–7.55 (m, 2H), 7.10 (s, 1H), 6.75 (d, J = 8.3 Hz, 2H), 4.25 (d, J = 21.4 Hz, 2H), 3.94 (s, 3H), 3.65 (s, 5H), 3.59–3.32 (m, 4H), 3.08 (s, 2H), 2.71 (d, J = 15.2 Hz, 2H), 2.57 (s, 3H), 2.24 (d, J = 16.0 Hz, 2H), 2.09 (s, 2H), 1.66 (d, J = 7.5 Hz, 2H).

[0382] Example 9: 6-(2-(3,6-Diazabicyclo[3.1.1]heptan-3-yl)ethoxy)-4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0383]

[0384] Step 1: tert-Butyl 3-(2-((3-cyano-4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl)oxy)ethyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate

[0385] 3-(2-((3-Cyano-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl)oxy)ethyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester (Intermediate 5, 34 mg, 0.069 mmol), 4-(pyridin-2-ylmethyl)piperidin-4-ol hydrochloride (25 mg, 0.11 mmol), potassium carbonate (38 mg, 0.28 mmol), DMSO (1.5 mL) were added to a 10 mL single-necked flask and reacted at 90 °C in an oil bath for 21 h. After the reaction stopped, 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 (5 mL × 3) and saturated brine (5 mL × 2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: DCM-DCM / MeOH (v / v = 10 / 1)) to obtain 37 mg of a yellow solid as the product, with a yield of 82.70%. LC-MS: m / z = 651.30 [M+H] + 。 1 H NMR (400 MHz, CDCl3) δ 8.52 (d, J = 4.2 Hz, 1H), 8.30 (d, J = 2.2 Hz, 1H), 8.19 (s, 1H), 8.11 (d, J = 1.8 Hz, 1H), 7.71–7.62 (m, 2H), 7.23–7.17 (m, 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), 4.12 (dd, J = 16.4, 10.8 Hz, 6H), 3.52–3.43 (m, 2H), 3.24 (d, J = 42.3 Hz, 2H), 3.05 (t, J = 5.4 Hz, 2H), 2.94 (s, 4H), 2.62 (s, 1H), 2.42 (dd, J = 13.4, 6.3 Hz, 1H), 1.65 (d, J = 3.6 Hz, 4H), 1.45 (s, 9H).

[0386] Step 2: 6-(2-(3,6-Diazabicyclo[3.1.1]heptan-3-yl)ethoxy)-4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0387] To a single-necked flask was added tert-butyl 3-(2-((3-cyano-4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl)oxy)ethyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (37 mg, 0.05685 mmol), and HCl / MeOH (1.0 mL, 4.0 mmol, 4 mol / L) was added. The reaction was carried out at room temperature for 3.5 h. After the reaction was completed, the reaction solution was directly concentrated, then methanol was added to dissolve it, potassium carbonate (200 mg, 1.45 mmol) was added, and the mixture was stirred at room temperature for 1 h to completely liberate the base. After the reaction solution was filtered, it was directly concentrated to obtain 25 mg of a solid, which was the product with a yield of 79.86%. LC-MS: m / z = 551.30 [M+H] + 。 1 H NMR (400 MHz, DMSO-d6) δ 8.57 (s, 1H), 8.70 (s, 1H), 8.56 (s, 1H), 8.48 (d, J = 4.5 Hz, 1H), 8.29 (s, 1H), 7.71 (t, J = 7.7 Hz, 2H), 7.33 (d, J = 7.7 Hz, 1H), 7.29 (s, 1H), 7.26–7.21 (m, 1H), 6.91 (d, J = 8.9 Hz, 1H), 4.25 (t, J = 5.6 Hz, 2H), 4.18 (s, 1H), 4.02 (d, J = 12.8 Hz, 2H), 3.57 (s, 1H), 3.11 (d, J = 10.6 Hz, 2H), 2.96 (t, J = 5.6 Hz, 2H), 2.90 (s, 2H), 2.73 (d, J = 10.5 Hz, 2H), 2.54 (s, 2H), 2.20 (dd, J = 12.5, 6.0 Hz, 1H), 1.75 (s, 1H), 1.56–1.47 (m, 4H).

[0388] Example 10: 6-(2-(3,6-Diazabicyclo[3.1.1]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 tetrahydrochloride

[0389]

[0390] Step 1: tert-Butyl 6-(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)ethyl)-3,6-diazabicyclo[3.1.1]heptane-3-carboxylate

[0391] To a single-necked flask were successively added tert-butyl 6-(2-((3-cyano-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl)oxy)ethyl)-3,6-diazabicyclo[3.1.1]heptane-3-carboxylate (Intermediate 4, 44 mg, 0.092 mmol), 5-(azetidin-3-yloxy)-2-methoxypyridine dihydrochloride (40 mg, 0.16 mmol), K2CO3 (57.8 mg, 0.42 mmol) and DMSO (2 mL), and the mixture was heated with stirring at 100 °C for 19 h. Water (10 mL) and EA (50 mL) were added. The organic phase was washed with saturated sodium chloride (10 mL × 3), and after rotary evaporation under reduced pressure, the residue was purified by silica gel column chromatography (eluent: DCM - DCM / MeOH (v / v = 30 / 1)) to obtain 52 mg of a yellow solid product, which was the target compound, with a yield of 88.54%. LC-MS: m / z = 639.25 [M + H] + 。

[0392] Step 2: 6-(2-(3,6-Diazabicyclo[3.1.1]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 tetrahydrochloride

[0393] tert-Butyl 6-(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)ethyl)-3,6-diazabicyclo[3.1.1]heptane-3-carboxylate (52 mg, 0.08142 mmol) was dissolved in EA (0.5 mL), and ethyl acetate hydrochloride (1.0 mL, 4.0 mmol, 4 mol / L) (a solid precipitated out) was added, and the reaction was stirred at room temperature for 1 h. The yellowish-white solid product was obtained by filtration, weighing 40 mg, which was the target product. Yield: 71.79%. LC-MS: m / z = 539.10 [M + H] + 。 11H NMR (400 MHz, MeOD) δ 8.73 (s, 1H), 8.42 (s, 1H), 8.34 (s, 1H), 8.28 (d, J = 9.0 Hz, 1H), 8.17–8.06 (m, 2H), 7.69 (s, 1H), 7.50 (d, J = 9.3 Hz, 1H), 7.15 (d, J = 9.0 Hz, 1H), 5.47 (s, 1H), 4.77 (s, 2H), 4.68–4.51 (m, 5H), 4.45 (d, J = 14.1 Hz, 1H), 4.18 (s, 3H), 4.15–4.08 (m, 3H), 2.40 (d, J = 11.7 Hz, 1H), 2.03 (s, 1H), 1.61 (s, 1H), 1.40–1.29 (m, 2H), 1.19 (t, J = 7.0 Hz, 1H).

[0394] Example 11: 1-(5-(6-(2-(3,6-Diazabicyclo[3.1.1]heptan-3-yl)ethoxy)-3-cyano[1,5-a]pyridin-4-yl)pyridin-2-yl)-N-(6-methoxypyridin-3-yl)azetidine-3-carboxamide

[0395]

[0396] Step 1: tert-Butyl 3-(2-((3-cyano-4-(6-(3-((6-methoxypyridin-3-yl)carbamoyl)azetidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl)oxy)ethyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate

[0397] To a 10 mL single-necked flask was added tert-butyl 3-(2-((3-cyano-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl)oxy)ethyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (Intermediate 5, 28 mg, 0.057 mmol), N-(6-methoxy-3-pyridinyl)azetidine-3-carboxamide dihydrochloride (28 mg, 0.10 mmol), potassium carbonate (38 mg, 0.27494 mmol, 100 mass%), DMSO (1.5 mL), and the reaction was carried out at 90 °C in an oil bath for 11 h. After stopping the reaction, 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 (5 mL × 3), saturated brine (5 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: DCM-DCM / MeOH (v / v = 10 / 1)) to obtain 30 mg of a yellow solid as the product, with a yield of 79.60%. LC-MS: m / z = 666.40 [M+H] +。 1 1H NMR (400 MHz, CDCl3) δ 8.32 (d, J = 2.0 Hz, 1H), 8.23 (d, J = 2.5 Hz, 1H), 8.20 (s, 1H), 7.96 (dd, J = 8.9, 2.6 Hz, 1H), 7.72–7.65 (m, 2H), 7.10 (d, J = 1.9 Hz, 1H), 6.75 (d, J = 8.9 Hz, 1H), 6.46 (d, J = 8.6 Hz, 1H), 4.39–4.28 (m, 4H), 4.14 (s, 2H), 4.08 (s, 2H), 3.92 (s, 3H), 3.62–3.53 (m, 1H), 3.24 (d, J = 40.5 Hz, 2H), 3.05 (t, J = 5.2 Hz, 2H), 2.94 (s, 2H), 2.42 (dd, J = 13.4, 6.4 Hz, 1H), 1.67 (d, J = 8.2 Hz, 1H), 1.45 (s, 9H).

[0398] Step 2: 1-(5-(6-(2-(3,6-Diazabicyclo[3.1.1]heptan-3-yl)ethoxy)-3-cyano[1,5-a]pyridin-4-yl)pyridin-2-yl)-N-(6-methoxypyridin-3-yl)azetidine-3-carboxamide

[0399] To a single-necked flask was added tert-butyl 3-(2-((3-cyano-4-(6-(3-((6-methoxypyridin-3-yl)carbamoyl)azetidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl)oxy)ethyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (30 mg, 0.04507 mmol), and HCl / MeOH (1.0 mL, 4.0 mmol, 4 mol / L) was added. The reaction was carried out at room temperature for 4 h. After the reaction stopped, the reaction solution was concentrated and dissolved in methanol. Potassium carbonate (200 mg, 1.45 mmol) was added, and the mixture was stirred at room temperature for 1 h to liberate the base. The reaction solution was directly concentrated and purified by silica gel column chromatography (eluent: DCM / MeOH (v / v = 2 / 1)). TLC detection showed that the product and impurities were not separated. After collection and concentration, it was dissolved in DCM and MeOH, and purified by TLC. The eluent was DCM / MeOH (v / v = 10 / 1 - 1 / 1). Concentration gave 12 mg of solid as the product, with a yield of 47.08%. LC-MS: m / z = 566.30 [M+H] + 。 1HNMR(400MHz, DMSO) δ 10.63 (s, 1H), 8.73 (s, 1H), 8.58 (s, 1H), 8.46 (d, J = 2.3 Hz, 1H), 8.30 (d, J = 2.0 Hz, 1H), 7.98 (dd, J = 8.9, 2.5 Hz, 1H), 7.77 (dd, J = 8.6, 2.2 Hz, 1H), 7.30 (s, 1H), 6.79 (d, J = 8.9 Hz, 1H), 6.53 (d, J = 8.6 Hz, 1H), 4.29 (t, J = 5.1 Hz, 2H), 4.21 (t, J = 8.1 Hz, 4H), 4.11 (t, J = 7.0 Hz, 2H), 3.87–3.82 (m, 1H), 3.81 (s, 3H), 3.30–3.20 (m, 4H), 3.15 (s, 1H), 3.08 (t, J = 4.9 Hz, 2H), 2.70–2.60 (m, 1H), 2.04 (d, J = 9.1 Hz, 1H).

[0400] Example 12: 6-(2-(3,6-Diazabicyclo[3.1.1]heptan-3-yl)ethoxy)-4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile pentahydrochloride

[0401]

[0402] Step 1: tert-Butyl 3-(2-((3-cyano-4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl)oxy)ethyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate

[0403] 3-(2-((3-Cyano-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl)oxy)ethyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester (Intermediate 5, 33 mg, 0.06672 mmol), 1-((6-methoxypyridin-3-yl)methyl)piperazine trihydrochloride (Intermediate 6, 30 mg, 0.095 mmol), potassium carbonate (38 mg, 0.27 mmol), and DMSO (1.5 mL) were added to a 10 mL single-necked flask and reacted at 90 °C in an oil bath for 21 h. After the reaction stopped, 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 (5 mL × 3) and saturated brine (5 mL × 2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography (the eluent was DCM-DCM / MeOH (v / v = 10 / 1)) to obtain 27 mg of a yellow solid as the product, with a yield of 60.78%. LC-MS: m / z = 666.30 [M+H] + 。 1 H NMR (400 MHz, CDCl3) δ 8.32 (s, 1H), 8.19 (s, 1H), 8.13 (s, 1H), 8.08 (s, 1H), 7.70 (d, J = 8.9 Hz, 1H), 7.62 (d, J = 7.9 Hz, 1H), 7.09 (s, 1H), 6.75 (d, J = 8.6 Hz, 2H), 4.13 (t, J = 5.4 Hz, 2H), 4.08 (s, 2H), 3.94 (s, 3H), 3.65 (s, 4H), 3.50 (s, 2H), 3.24 (d, J = 41.2 Hz, 2H), 3.04 (t, J = 5.3 Hz, 2H), 2.93 (d, J = 8.3 Hz, 2H), 2.56 (s, 4H), 2.45–2.38 (m, 1H), 1.66 (d, J = 8.0 Hz, 1H), 1.44 (s, 9H).

[0404] Step 2: 6-(2-(3,6-Diazabicyclo[3.1.1]heptan-3-yl)ethoxy)-4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0405] Add tert-butyl 3-(2-((3-cyano-4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl)oxy)ethyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (27 mg, 0.041 mmol) to a single-necked flask, add HCl / MeOH (1.0 mL, 4.0 mmol, 4 mol / L), and react at room temperature for 2 h. After the reaction stopped, the reaction solution was directly concentrated to obtain 20 mg of a solid, which was the product with a yield of 65.93%. LC-MS: m / z = 566.30 [M - 5HCl + H] + 。 1 H NMR (400 MHz, DMSO-d6) δ 8.89 (s, 1H), 8.64 (s, 1H), 8.40 (d, J = 13.6 Hz, 2H), 8.03 (d, J = 8.0 Hz, 1H), 7.95 (d, J = 8.5 Hz, 1H), 7.44 (s, 1H), 7.14 (d, J = 8.4 Hz, 1H), 6.93 (d, J = 8.3 Hz, 1H), 4.73 (s, 2H), 4.51 (d, J = 13.2 Hz, 2H), 4.37 (d, J = 14.6 Hz, 4H), 4.20 (d, J = 13.3 Hz, 3H), 3.88 (s, 6H), 3.43 (d, J = 6.5 Hz, 4H), 3.16 (s, 1H), 3.11 (s, 2H), 2.91 (s, 1H), 2.67 (s, 1H).

[0406] Example 13: 1-(5-(6-(2-(3,6-Diazabicyclo[3.1.1]heptan-6-yl)ethoxy)-3-cyanopyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N-(6-methoxypyridin-3-yl)azetidine-3-carboxamide tetrahydrochloride

[0407]

[0408] Step 1: tert-Butyl 6-(2-((3-cyano-4-(6-(3-((6-methoxypyridin-3-yl)carbamoyl)azetidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl)oxy)ethyl)-3,6-diazabicyclo[3.1.1]heptane-3-carboxylate

[0409] Add tert-butyl 6-(2-((3-cyano-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl)oxy)ethyl)-3,6-diazabicyclo[3.1.1]heptane-3-carboxylate (Intermediate 4, 47 mg, 0.098 mmol), N-(6-methoxypyridin-3-yl)azetidine-3-carboxamide dihydrochloride (45 mg, 0.16 mmol), potassium carbonate (62 mg, 0.45 mmol), and DMSO (1.5 mL) into a 10 mL single-necked flask. React at 90 °C in an oil bath for 16 h. After stopping the reaction, 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, filter, concentrate the filtrate under reduced pressure, and purify by silica gel column chromatography (the eluent is DCM - DCM / MeOH (v / v = 15 / 1)). Purify the obtained solid by TLC again, and the eluent is DCM / MeOH (v / v = 30 / 1 - 10 / 1) to obtain 32 mg of a pale yellow solid as the product, with a yield of 48.94%. LC-MS: m / z = 666.30 [M+H] + 。 1 H NMR (400 MHz, CDCl3) δ 8.31 (d, J = 1.9 Hz, 1H), 8.25 (d, J = 2.1 Hz, 1H), 8.20 (s, 1H), 8.14 (d, J = 1.6 Hz, 1H), 7.99–7.91 (m, 2H), 7.68 (dd, J = 8.6, 2.2 Hz, 1H), 7.07 (d, J = 1.7 Hz, 1H), 6.73 (d, J = 8.9 Hz, 1H), 6.44 (d, J = 8.6 Hz, 1H), 4.37–4.27 (m, 4H), 4.12 (s, 2H), 3.91 (s, 3H), 3.80–3.68 (m, 4H), 3.59–3.52 (m, 1H), 3.50–3.41 (m, 2H), 2.92 (s, 2H), 2.67 (s, 1H), 2.22 (s, 1H), 1.50 (s, 9H).

[0410] Step 2: 1-(5-(6-(2-(3,6-Diazabicyclo[3.1.1]heptan-6-yl)ethoxy)-3-cyanopyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N-(6-methoxypyridin-3-yl)azetidine-3-carboxamide

[0411] 6-(2-((3-Cyano-4-(6-(3-((6-Methoxypyridin-3-yl)carbamoyl)azetidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl)oxy)ethyl)3,6-diazabicyclo[3.1.1]heptane-3-carboxylic acid tert-butyl ester (32 mg, 0.048 mmol) was added to a single-necked flask, and HCl / dioxane (1.5 mL, 6.0 mmol, 4 mol / L) was added. The reaction was carried out at room temperature for 4 h. After the reaction stopped, the reaction solution was directly concentrated to obtain 25 mg of a white solid as the product, with a yield of 73.10%. LC-MS: m / z = 566.00 [M - 4HCl + H] + 。 1 H NMR (400 MHz, D2O) δ 8.58 (d, J = 2.5 Hz, 1H), 8.53 (d, J = 1.8 Hz, 1H), 8.41 (s, 1H), 8.23 (dd, J = 9.3, 2.6 Hz, 1H), 8.17–8.09 (m, 2H), 7.48 (s, 1H), 7.33 (d, J = 9.4 Hz, 1H), 7.01 (d, J = 9.2 Hz, 1H), 4.73–4.62 (m, 5H), 4.61–4.52 (m, 4H), 4.20 (d, J = 14.9 Hz, 2H), 4.10 (s, 3H), 4.06–3.97 (m, 2H), 3.85–3.76 (m, 2H), 3.67 (dd, J = 9.6, 4.7 Hz, 1H), 2.32 (s, 1H).

[0412] Biological activity test example:

[0413] Test example 1: Test of the inhibitory activity of the inventive compound against Ret wt and Ret V804M kinases

[0414] 1. Experimental purpose:

[0415] 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.

[0416] 2. The experimental reagents and consumables used are as follows:

[0417] 1) HTRF KinEASE-TK kit (Cisbio, 62TK0PEC)

[0418] 2) Ret wt (Invitrogen, PV3082)

[0419] 3) Ret V804M (Signalchem, R02-12GG-10)

[0420] 4) MgCl2 (Sigma, M1028)

[0421] 5) ATP (Promega, V910B)

[0422] 6) DTT (Invitrogen, P2325)

[0423] 7) DMSO (Sigma, D8418)

[0424] 8) 384-well plate, white, low volume, round-bottom (Greiner, 784075)

[0425] 9) 384-Well Polypropylene microplate, Clear, Flatt Bottom, Bar Code (Labcyte, P-05525-BC)

[0426] 10) 96-well polypropylene plate (Nunc, 249944)

[0427] 11) Plate shaker (Thermo, 4625-1CECN / THZ Q)

[0428] 12) Centrifuge (Eppendorf, 5810R)

[0429] 13) Envision 2104 multi-label Reader (PerkinElmer, 2104-10-1)

[0430] 14) Echo (Labcyte, 550)

[0431] 3. Experimental procedures

[0432] 3.1 Preparation of 1x kinase reaction buffer:

[0433] 1 volume of 5X kinase reaction buffer and 4 volumes of water; 5 mM MgCl2; 1 mM DTT; 1 mM MnCl2.

[0434] 3.2 Transfer 10 nl of the diluted compound into each well of the Echo 550 reaction plate (784075, Greiner);

[0435] 3.3 Seal the reaction plate with a sealing film and centrifuge at 1000 g for 1 minute.

[0436] 3.4 Prepare 2X kinase by mixing with 1X enzyme reaction buffer.

[0437] 3.5 Add 5 μl of the kinase prepared in step 3 to each well of the reaction plate. Seal the plate with a sealing film, centrifuge at 1000 g for 30 seconds, and incubate at room temperature for 10 minutes.

[0438] 3.6 Prepare 4X TK-substrate-biotin and 4X ATP by mixing with 1X enzyme reaction buffer, mix well, and add 5 μl of the K-substrate-biotin / ATP mixture to the reaction plate.

[0439] 3.7 Seal the plate with a sealing film, centrifuge at 1000 g for 30 seconds, and incubate at room temperature for 40 minutes.

[0440] 3.8 Prepare 4X Sa-XL 665 (250 nM) by mixing with HTRF detection buffer.

[0441] 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 incubate at room temperature for 1 hour.

[0442] 3.10 Read the fluorescence signals at 615 nm (Cryptate) and 665 nm (XL665) using Envision 2104.

[0443] 4. Data Analysis

[0444] 4.1 Calculate the ratio (Ratio_665 / 615 nm) for each well.

[0445] 4.2 The inhibition rate is calculated as follows:

[0446]

[0447] Average value of the readings of all positive control wells CEP-32496

[0448] Average value of the readings of all negative control wells DMSO

[0449] 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.

[0450] 4.3 Calculate IC 50 And plot the inhibition curve of the compound:

[0451] Use the following non-linear fitting formula to obtain the IC of the compound50 (half inhibitory concentration): Data analysis was performed using Graphpad 6.0 software.

[0452] Y=Bottom+(Top-Bottom) / (1+10^((LogIC50-X)×Hill Slope))

[0453] X: log value of compound concentration Y: inhibition rate (%inhibition)

[0454] 5. The experimental results are shown in Table 1:

[0455] Table 1 Experimental results of the kinase inhibitory activity of the compounds of the present invention on Ret wt and Ret V804M

[0456]

[0457] It can be seen from Table 1 that the compounds of the present invention have a good inhibitory effect on Ret wt. In addition, the compounds of the present invention also have a good inhibitory effect on RetV804M.

[0458] Test Example 2: Test of the inhibitory activity of the compounds of the present invention on BAF3 cells transfected with KIF5B gene

[0459] 1. Experimental purpose:

[0460] The CTG method was used to test the 50% inhibitory concentration (IC) of the compounds in a series of tumor cells. 50 ).

[0461] 2. The experimental reagents and test samples used are as follows:

[0462] 1) CellTiter-Glo (CTG) (Promega)

[0463] 2) RPMI medium (Gibco)

[0464] 3) FBS (fetal bovine serum) (Gibco)

[0465] 4) DMSO (Sigma)

[0466] 5) Double antibody (Gibco)

[0467] 6) 96-well cell culture plate, white wall and opaque bottom (Corning)

[0468] 7) BAF3 (purchased from Shanghai Mingjin Biotechnology)

[0469] 8) BAF3-KIF5B-RET-WT (stable cell line, constructed by the Pharmacology Department of Guangdong East Sunshine Pharmaceutical Co., Ltd.)

[0470] 3. Experimental procedures:

[0471] 1) Cell seeding

[0472] Collect cells BAF3 and BAF3-KIF5B-RET-WT in the exponential growth phase and perform viable cell counting using a Vi-Cell XR cell counter. Adjust the cell suspension to the appropriate concentration with RPMI complete medium (89% RPMI + 10% FBS + 1% penicillin-streptomycin). Add 90 μL of the cell suspension to each well of a 96-well cell culture plate, with final cell concentrations of 2000 cells / well and cells / well respectively.

[0473] 2) Drug treatment

[0474] a Preparation of working solution: Dissolve each test compound in DMSO to make a stock solution with a final concentration of 10 mM. Prepare a 3X serial dilution of the stock solution with RPMI complete medium (89% RPMI + 10% FBS + 1% penicillin-streptomycin) to obtain working solutions at 10 concentrations, with a final DMSO concentration of 0.1% in each solution.

[0475] b Adding drugs to cells: After the cells are incubated overnight, add 10 μL of the working solutions corresponding to the 10 gradient concentrations in sequence, and incubate in a 37°C, 5% CO2 incubator for 72 hours; at the same time, set up a negative control with cells but without the compound added.

[0476] 3) Plate reading and detection

[0477] After 72 hours of drug treatment, according to the CTG operation instructions, add 50 μL (1 / 2 culture volume) of the CTG solution that has been pre-melted and equilibrated to room temperature to each well, mix well with a microplate shaker for 2 minutes, and measure the fluorescence signal value with a multifunctional microplate reader after standing at room temperature for 10 minutes.

[0478] 4) Data analysis

[0479] The cell viability is calculated using the formula: Vsample / Vvehicle control x 100%. Where Vsample is the reading of the drug treatment group and Vvehicle control is the average value of the solvent control group. Use GraphPad Prism 5.0 software to plot an S-shaped dose-viability curve using a non-linear regression model and calculate the IC 50 value, and the experimental results are shown in Table 2.

[0480] Table 2 Experimental results of the inhibitory activity of the compounds of the present invention on BAF3 cells transfected with the KIF5B gene

[0481] Example <![CDATA[IC 50 (nM), BAF3-KIF5B-RET-WT]]> Example 3 31.05 Example 6 11.56 Example 7 57.7 Example 8 48.24 Example 9 160.5 Example 10 63.36 Example 12 162.6

[0482] As can be seen from Table 2, the compound of the present invention also has a good inhibitory effect on BAF3 cells transfected with the KIF5B gene.

[0483] In the description of the present 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 the present 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 the present specification and the features of different embodiments, implementation schemes or examples.

[0484] 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 purposes 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 C 1-6 alkylene, C 1-6 alkylene-O- or C 1-6 alkylene-NH-; Ring G is the following sub-structural formula: , , , , , , , , , , , , , , , , , , , or ; Each R a independently is D, OH, F, CF3, CHCl2, CHF2, CH2F, CF3CH2, Cl, Br, I, CN, NH2, NHCH3, N(CH3)2, oxo, methyl, ethyl, propyl, butyl, methoxy, ethoxy, methoxymethyl, ethoxymethyl, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 2-hydroxypropyl or 2-hydroxy-2-methylpropyl; q is 0, 1, 2, 3 or 4; E is a bond; Ring A is the following sub-structural formula: , or , Among them, Z 1a are each independently N, and Z 1a is connected to E; Z 2a each is independently CH or N; Z 3 and Z 4 each independently is CH2; Each substructural formula of A is independently optionally substituted by 1, 2, 3 or 4 substituents selected from F, Cl, Br, OH, NR 5 R 6 , amino C 1-4 alkyl, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 hydroxyalkyl and C 1-4 alkoxy C 1-4 alkyl; Q is -O-, -CH2-, -(CH2)2-, -(C=O)NH-, -(C=O)-, -CH(CH3)- or -(C=O)N(CH3)-; M is a 5- to 10-membered heteroaryl; and M 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 and C 1-6 alkoxyC 1-6 alkyl; R 1 is CN; Each R 4 is independently H, D, F, Cl, Br, methyl, ethyl, n-propyl, methoxy or ethoxy; Each R 5 is independently H, D, methyl, ethyl, n-propyl, isopropyl or n-butyl; Each R 6 independently is H, D, methyl, ethyl, n-propyl, n-butyl, methoxymethyl, ethoxymethyl or methoxyethyl; Each R 7 is independently methyl, ethyl, isopropyl or tert-butyl.

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

3. The compound according to claim 1, wherein, Ring A is the following sub-structural formula: , , , , or , Wherein, the N-connection end of each sub-structural formula of A is connected to E, and the other connection end is connected to Q. Each sub-structural formula of 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.

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

5. The compound according to claim 1 is the compound of formula (I-1), (I-2) or (I-3), or a pharmaceutically acceptable salt thereof: , or , Among them, is the following substructural formula: , or , Among them, each Z 2a is independently CH or N; Z 3 and Z 4 each independently is CH2; and each substructural formula of which is independently and optionally substituted by 1, 2, 3 or 4 substituents selected from F, Cl, Br, OH, NR 5 R 6 , amino C 1-4 alkyl, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 hydroxyalkyl and C 1-4 alkoxy C 1-4 alkyl; and M a is a 5- to 10-membered heteroaryl, and M a is optionally substituted with 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 and C 1-6 alkoxyC 1-6 alkyl.

6. The compound according to claim 5, wherein, is the following substructural formula: , , , , or , and each substructural formula of which 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; 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 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.

7. The compound has one of the following structures, or a pharmaceutically acceptable salt thereof, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

8. A pharmaceutical composition comprising the compound according to any one of claims 1-7 and a pharmaceutically acceptable adjuvant.

9. Use of the compound according to any one of claims 1-7 or the pharmaceutical composition according to claim 8 in the preparation of a drug for preventing or treating RET-related diseases.

10. The use according to claim 9, wherein, The RET-related diseases are cancer, irritable bowel syndrome and / or pain associated with irritable bowel syndrome.

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