CN113527292B - RET inhibitor, pharmaceutical composition and application thereof - Google Patents

Abstract

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

Description

RET inhibitor, pharmaceutical composition and application thereof

Technical Field

The present invention is in the field of medicaments, in particular, the present invention relates to novel compounds exhibiting a transfection-phase Rearrangement (RET) kinase inhibition, pharmaceutical compositions comprising said compounds, the use of compounds or pharmaceutical compositions thereof in the manufacture of a medicament, in particular for the treatment and prevention of RET related diseases and disorders, including cancer, irritable bowel syndrome and/or pain associated with irritable bowel syndrome.

Background

Transfected rearrangement (Re-arranged during transfection, RET) kinases are one of the receptor-type tyrosine kinases belonging to the cadherin superfamily that activate a number of downstream pathways involved in cell proliferation and survival.

The consequences of abnormal RET gene production (point mutations, chromosomal translocations, chromosomal inversion, gene amplification) are reported to be related to canceration. RET fusion proteins are associated with several cancers, including papillary thyroid cancers and non-small cell lung cancers. RET fusion proteins are identified as driving factors for certain cancers, which motivates the use of multi-kinase inhibitors with RET inhibiting activity to treat patients whose tumors express RET fusion proteins. Multiple kinase inhibitors such as sorafenib (Sorafenib), sunitinib, vandetanib, and pluratinib have been reported to exhibit cell proliferation inhibition (J Clin Oncol 30,2012,suppl;Abstract no:7510) on cell lines expressing KIF 5B-RET. In addition, the multi-kinase inhibitor cabotinib was reported to exhibit partial efficacy in two patients with non-small cell lung Cancer positive for RET fusion gene (Cancer discover, 3 (6), jun 2013, p.630-5). However, these drugs cannot always be administered at a level sufficient to inhibit RET due to toxicity resulting from inhibition of targets other than RET. Furthermore, one of the biggest challenges in treating cancer is the ability of tumor cells to develop resistance to treatment. Kinase reactivation via mutation is a common drug resistance mechanism. When resistance occurs, the treatment options for patients are often very limited and in most cases cancer progression is not inhibited. WO 2017011776 discloses single-target RET kinase inhibitors having good preventive or therapeutic effects on RET and its mutation-related cancers. There is still a need to further develop compounds that inhibit RET and its resistant mutants to cope with cancers associated with abnormal RET genes.

Disclosure of Invention

The invention provides a novel compound for inhibiting a transfection-phase Rearrangement (RET) kinase, which has good inhibition effect on RET wild type and RET gene mutant, and has better inhibition selectivity on RET wild type and RET gene mutant compared with other kinases.

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

In one aspect, the invention provides a compound of formula (I), or a stereoisomer, tautomer, nitroxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of a compound of formula (I),

Wherein, the

X ¹、X²、X³、X⁴ and X ⁵ are each independently CR ⁴ or N;

y is O, NH or S;

t is a bond, alkylene-O-or alkylene-NH-, and said T is optionally substituted with 1,2,3 or 4 substituents selected from D, OH, F, cl, br, I, CN, NH ₂、CF₃, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, heterocyclyl, alkoxy, aryl, heteroaryl and alkylamino;

ring G is spirocarbocyclyl or spiroheterocyclyl;

q is 0, 1,2, 3 or 4;

Each R ^a is independently D、OH、NH₂、F、Cl、Br、I、CN、NR⁵R⁶、OR⁷、-NR⁶C(＝O)R⁷、-S(＝O)₂R⁷、-S(＝O)R⁷、-C(＝O)R⁷、-C(＝O)OR⁷、 oxo, alkyl, haloalkyl, alkoxy, cycloalkyl, alkoxyalkyl, or hydroxyalkyl;

e is a bond, -NR ⁶ -, or-O-;

Ring a is a monocyclic subunit, and a is optionally substituted with 1, 2,3 or 4 substituents selected from F, cl, br, OH, oxo, NR ⁵R⁶、R⁵(C＝O)NR⁶ -, aminoalkyl, alkyl, alkoxy, haloalkyl, hydroxyalkyl, carbocyclyl, heterocyclyl, heterocyclylalkyl and alkoxyalkyl;

Q is a bond 、-(CR²R³)_tO-、-(CR²R³)_tO(CR²R³)_f-、-(CR²R³)_f-、-(CR²R³)_t-NR⁶-、-(CR²R³)_t-NR⁶(CR²R³)_f-、-(C＝O)(CR²R³)_t、-(C＝O)(CR²R³)_t-S(＝O)₂(CR²R³)_f、-(C＝O)(CR²R³)_t-NR⁶(CR²R³)_f-、-(C＝O)(CR²R³)_t-O(CR²R³)_f-、-(C＝O)NR⁶O(CR²R³)_f-、-S(＝O)₂-NR⁶-(CR²R³)_t-、(CR²R³)_f-(C＝O)-、(CR²R³)_t-(C＝O)-NR⁶-(CR²R³)_t-、-S(＝O)₂(CR²R³)_t-、-(CR²R³)_f-S(＝O)₂(CR²R³)_t、-S(＝O)₂O-、-O(C＝O)-、-(C＝O)NR⁶- or-NR ⁶ (c=o) -;

Each f is independently 1,2,3 or 4;

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

M is H, D, heteroaryl, aryl, cycloalkyl or heterocyclyl, and M is optionally substituted with 1, 2, 3 or 4 substituents selected from D, F, cl, CN, CF ₃、OH、NR⁵R⁶、OR⁷, alkyl, alkoxy, haloalkyl, hydroxyalkyl, haloalkoxy, aryl, alkoxyalkyl, oxo, alkanoyl, heterocyclyl and cycloalkyl;

r ¹ is H, D, CN, F, cl, br, alkyl or cycloalkyl, wherein the alkyl and cycloalkyl groups are independently optionally substituted with 1, 2,3 or 4 substituents selected from F, cl, br, CN, NH ₂, OH and NO ₂;

Each R ²、R³ is independently OH, F, CF ₃、H、D、CN、Cl、Br、NH₂, hydroxyalkyl, alkyl, alkylamino, alkoxy, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl or heteroaryl;

Or, R ²、R³ and the same C atom to which they are attached form a carbocycle or heterocycle;

Each R ⁴ is independently H, D, F, cl, br, alkyl or alkoxy, wherein each of said alkyl and alkoxy is independently optionally substituted with 1,2, 3 or 4 substituents selected from F, cl, br, CN, NH ₂, OH and NO ₂;

Each R ⁵ is independently H, D, alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl, wherein each of said alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with 1,2, 3, or 4 substituents selected from F, cl, br, OH, NH ₂, alkylamino, alkyl, alkylsulfonyl, alkoxy, aryl, and heteroaryl;

Each R ⁶ is independently H, D, alkyl or alkoxyalkyl, wherein each of the alkyl and alkoxyalkyl is independently optionally substituted with 1, 2, 3, or 4 substituents selected from F, cl, br, CN, NH ₂, OH, and NO ₂;

Each R ⁷ is independently OH, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.

In some embodiments, T is a bond, C _1-6 alkylene, C _1-6 alkylene-O-, or C _1-6 alkylene-NH-, and T is optionally substituted with 1,2,3, or 4 substituents selected from D, OH, F, cl, br, I, CN, NH ₂、CF₃、C_1-6 alkyl, C _1-6 hydroxyalkyl, C _1-6 haloalkyl, C _3-7 cycloalkyl, 3-7 membered heterocyclyl, C _1-6 alkoxy, C _6-10 aryl, 5-12 membered heteroaryl, and C _1-6 alkylamino.

In some embodiments, T is a bond 、-CH₂-、-(CH₂)₂-、-(CH₂)₃-、-(CH₂)₄-、-(CH₂)₅-、-(CH₂)₆-、-(CH₂)O-、-(CH₂)₂-O-、-(CH₂)₃O- or- (CH ₂)₂ -NH-, and the T is optionally substituted with 1, 2, 3, or 4 substituents selected from D, OH, F, cl, br, I, CN, NH ₂、CF₃, methyl, ethyl, propyl, 2-hydroxyethyl, 1-hydroxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, methoxy, ethoxy, propoxy, butoxy, phenyl, methylamino, and dimethylamino.

In some embodiments of the present invention, in some embodiments,

Ring G is a 6-12 membered spirocarbocyclyl or a 6-12 membered spiroheterocyclyl;

Each R ^a is independently D、OH、NH₂、F、Cl、Br、I、CN、NR⁵R⁶、OR⁷、-NR⁶C(＝O)R⁷、-S(＝O)₂R⁷、-S(＝O)R⁷、-C(＝O)R⁷、-C(＝O)OR⁷、 oxo, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _3-7 cycloalkyl, C _1-6 alkoxyc _1-6 alkyl, or C _1-6 hydroxyalkyl;

Each R ⁵ is independently H, D, C _1-6 alkyl, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl, C _6-10 aryl, or 5-10 membered heteroaryl, wherein said C _1-6 alkyl, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl, C _6-10 aryl, and 5-10 membered heteroaryl are each independently optionally substituted with 1,2, 3, or 4 substituents selected from F, cl, br, OH, NH ₂、C_1-6 alkylamino, C _1-6 alkyl, C _1-6 alkylsulfonyl, C _1-6 alkoxy, C _6-10 aryl, and 5-10 membered heteroaryl;

Each R ⁶ is independently H, D, C _1-6 alkyl or C _1-6 alkoxyc _1-6 alkyl, wherein the C _1-6 alkyl and C _1-6 alkoxyc _1-6 alkyl are each independently optionally substituted with 1,2, 3, or 4 substituents selected from F, cl, br, CN, NH ₂, OH, and NO ₂;

Each R ⁷ is independently OH, C _1-6 alkyl, C _3-6 cycloalkyl, 3-12 membered heterocyclyl, C _6-10 aryl, 5-10 membered heteroaryl.

In some embodiments, ring G is of the following sub-structural formula:

wherein each ring T1 is independently a 4-7 membered carbon monocyclic or heteromonocyclic ring;

Z ¹ and Z ² are independently-CH ₂ -, -O-, -S-or-NH-;

Z ³ is-O- -S-or-NH-;

n1 is 0,1 or 2;

n2 is 1,2 or 3;

n3 is 0 or 1;

R ^a is D、OH、NH₂、F、Cl、Br、I、CN、NR⁵R⁶、OR⁷、-NR⁶C(＝O)R⁷、-S(＝O)₂R⁷、-S(＝O)R⁷、-C(＝O)R⁷、-C(＝O)OR⁷、 oxo, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _3-7 cycloalkyl, C _1-6 alkoxy C _1-6 alkyl or C _1-6 hydroxyalkyl;

R ⁵ is H, D, C _1-6 alkyl, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl, C _6-10 aryl, or 5-10 membered heteroaryl, wherein said C _1-6 alkyl, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl, C _6-10 aryl, and 5-10 membered heteroaryl are each independently optionally substituted with 1,2, 3, or 4 substituents selected from F, cl, br, OH, NH ₂、C_1-6 alkylamino, C _1-6 alkyl, C _1-6 alkylsulfonyl, C _1-6 alkoxy, C _6-10 aryl, and 5-10 membered heteroaryl;

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 with 1,2, 3 or 4 substituents selected from F, cl, br, CN, NH ₂, OH and NO ₂;

R ⁷ is OH, C _1-6 alkyl, C _3-6 cycloalkyl, 3-12 membered heterocyclyl, C _6-10 aryl, 5-10 membered heteroaryl.

In some embodiments, ring G is of the following sub-structural formula:

Each R ^a is independently D、OH、NH₂、F、CF₃、Cl、Br、I、CN、NH₂、NHCH₃、-NHC(＝O)CH₃、-S(＝O)₂CH₃、-S(＝O)CH₃、-C(＝O)CH₃、-C(＝O)OH、-C(＝O)OC(CH₃)₃、 oxo, methyl, ethyl, propyl, butyl, methoxy, ethoxy, cyclopropyl, cyclopentyl, methoxymethyl, methoxyethyl, ethoxymethyl, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 2-hydroxypropyl, or 2-hydroxy-2-methylpropyl;

Each R ⁵ is independently H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, cyclopropyl, cyclopentyl, pyrrolidinyl, phenyl, or pyrazolyl, wherein each of said methyl, ethyl, n-propyl, cyclopropyl, cyclopentyl, pyrrolidinyl, phenyl, and pyrazolyl is independently optionally substituted with 1,2, 3, or 4 substituents selected from F, cl, br, OH, NH ₂, methyl, -S (=O) ₂CH₃, methoxy, ethoxy, and phenyl;

Each R ⁶ is independently H, D, methyl, ethyl, n-propyl, n-butyl, methoxymethyl, ethoxymethyl, or methoxyethyl, wherein each of the methyl, ethyl, n-propyl, n-butyl, methoxymethyl, ethoxymethyl, and methoxyethyl is independently optionally substituted with 1, 2, 3, or 4 substituents selected from F, cl, br, CN, NH ₂, OH, and NO ₂;

Each R ⁷ is independently OH, methyl, ethyl, NH ₂、N(CH₃)₂, methyl, isopropyl, tert-butyl, cyclopropyl, or phenyl.

In some embodiments, ring a is a 5-12 membered monocyclic alkylene, and ring a is optionally substituted with 1, 2, 3, or 4 substituents selected from F, cl, br, OH, oxo, NR ⁵R⁶、R⁵(C＝O)NR⁶ -, amino C _1-6 alkyl, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl C _1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, C _3-6 cycloalkylene, and 3-6 membered heterocycloalkylene.

In some embodiments, ring a is of the following sub-structural formula:

Wherein Z ^1a and Z ^2a are each independently CH or N;

Z ^3a and Z ⁴ are each independently CH ₂, O, S, NH, C = O, S =o or S (=o) ₂;

Each sub-structural formula of ring a is independently optionally substituted with 1,2, 3 or 4 substituents selected from F, cl, br, OH, oxo, NR ⁵R⁶、R⁵(C＝O)NR⁶ -, amino C _1-4 alkyl, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _1-4 hydroxyalkyl, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl-C _1-4 alkyl and C _1-4 alkoxy C _1-4 alkyl.

In some embodiments, ring a is of the following sub-structural formula:

Wherein each substructure of ring a is independently optionally substituted with 1,2,3 or 4 substituents selected from F, cl, br, OH, oxo, NH ₂、NHCH₃、CH₃ (c=o) NH-, methyl, ethyl, n-propyl, methoxy, ethoxy, isopropoxy, CF ₃, hydroxymethyl, 2-hydroxyethyl, cyclopropyl, cyclohexyl, pyrrolidinyl, piperidinyl and tetrahydrofuranyl.

In some embodiments, M is H, D, 5-10 membered heteroaryl, C _6-10 aryl, C _3-7 cycloalkyl, or 3-12 membered heterocyclyl, and M is optionally substituted with 1, 2, 3, or 4 substituents selected from D, F, cl, CN, OH, CF ₃、NR⁵R⁶、OR⁷、C_1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 haloalkoxy, C _6-10 aryl, C _1-6 alkoxyC _1-6 alkyl, oxo, C _1-6 alkanoyl, 3-7 membered heterocyclyl, and C _3-7 cycloalkyl.

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

In some embodiments, R ¹ is H, D, CN, F, cl, br, methyl, or cyclopropyl, wherein the methyl and cyclopropyl groups are independently optionally substituted with 1,2, 3, or 4 substituents selected from F, cl, br, CN, NH ₂, OH, and NO ₂;

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 groups may independently be optionally substituted with 1,2,3 or 4 substituents selected from F, cl, br, CN, NH ₂, OH and NO ₂.

In some embodiments, each R ²、R³ is independently OH, F, CF ₃、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 _3-7 cycloalkyl C _1-6 alkyl, C _6-10 aryl, or 5-10 membered heteroaryl;

or R ²、R³ and the same C atom to which they are attached form a 3-7 membered carbocyclic ring or a 3-7 membered heterocyclic ring.

In some embodiments, each R ²、R³ is independently OH, F, CF ₃、H、D、CN、Cl、Br、NH₂, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, methyl, ethyl, N (CH ₃)₂, methoxy, ethoxy, isopropoxy, t-butoxy, trifluoromethoxy, cyclopropyl, cyclopentyl, cyclopropylmethyl, cyclopentylethyl, cyclopentylmethyl, phenyl, pyridinyl, or pyrazinyl;

Or R ²、R³ and the same C atom to which they are attached form cyclopentane, cyclopropane, cyclobutane, tetrahydropyran, tetrahydrofuran, piperidine or pyrrolidine.

In some embodiments, Q is a bond 、-O-、-O(CH₂)-、-(CH₂)₂O-、-(CH₂)₂OC(CH₃)₂CH₂-、-CH₂-、-(CH₂)₂-、-(CH₂)₃-、-CH₂CH(CH₃)CH₂-、-CH₂CH(CH₃)CH₂NHCH₂-、-CH₂N(CH₃)CH₂-、-(C＝O)OC(CH₃)₂CH₂-、-(C＝O)(CH₂)₂S(＝O)₂CH₂-、-(C＝O)CH(OH)CH₂-、-(C＝O)CH(OH)-、-(C＝O)-、-S(＝O)₂-、-(C＝O)CH₂CH(OH)-、-(C＝O)CH₂-、-(C＝O)CH(CH₂OH)-、-(C＝O)C(CH₃)₂-、-(C＝O)CH₂NHC(CH₃)₂CH₂-、-(C＝O)CH₂CH(N(CH₃)₂)-、-(C＝O)(CH₂)₂N(CH₃)CH₂-、-(C＝O)C(CH₃)₂CH₂-、-(C＝O)C(OH)(CH₃)CH₂-、-(C＝O)CH₂OCH₂-、-(C＝O)(CH₂)₃-、-(C＝O)CH(NH₂)-、-(C＝O)(CH₂)₃N(CH₃)CH₂-、-(C＝O)(CH₂)₂-、-(C＝O)CH₂CH(OH)CH₂-、-(C＝O)CF₂CH₂-、-(C＝O)CH(OH)C(CH₃)₂CH₂-、-(C＝O)CH₂C(CH₃)₂-、-(C＝O)CH₂C(CH₃)₂CH₂-、-(C＝O)CH₂C(CH₃)(OH)CH₂-、-S(＝O)₂CH₂-、-S(＝O)₂CH₂C(CH₃)₂CH₂-、-(C＝O)CH(OCH₃)-、-(C＝O)NHCH(CH₂OH)(CH₂)₂-、-(C＝O)NH-、-(C＝O)OCH₂C(CH₃)₂-、-(C＝O)N(CH₃)-、-(C＝O)N(CH₂CH₂CH₂CH₃)-、-(C＝O)N(CH₂CH₃)(CH₂)₂-、-(C＝O)NHC(CH₃)₂CH₂-、-(C＝O)N(CH₃)(CH₂)₂-、-(C＝O)NHCH₂CH(CH₃)CH₂-、-(C＝O)NHCH₂-、-(C＝O)NH(CH₂)₂OCH₂-、-(C＝O)N(CH₃)(CH₂)₂OCH₂-、-S(＝O)₂NHC(CH₃)₂CH₂-、-CH₂CH(OH)C(CH₃)₂CH₂-、-CH(CH₃)CH(OH)-、-CH₂(C＝O)NHCH(CH₃)CH₂-、-CH₂(C＝O)-、-(CH₂)₂(C＝O)N(CH₃)CH_2-、-CH₂CH(OH)-、-CH₂CH(OH)CH₂-、-CH₂CH(OH)CH(CH₃)CH₂-、-(C＝O)CH(N(CH₃)₂)-、-(C＝O)C(CH₃)₂CH₂OCH₂-、-(C＝O)C(OCH₃)(CF₃)-、-(C＝O)N(CH₂CH₂OCH₃)CH₂CH(OCH₃)-、-CH₂CH(OCF₃)-、-CH₂CH(OCH(CH₃)₂)-、-CH₂CH(OC(CH₃)₃)-、-CH₂CF₂-、-CH(CH₃)-、-CH₂CH(OCH₃)C(CH₃)₂-、-CH₂CH(N(CH₃)₂)-、-NH-、-(C＝O)NHOCH₂-、-(C＝O)NHOCH₂CH(OH)-、-S(＝O)₂(CH₂CH₃)-、-S(＝O)₂O-、-S(＝O)₂-NHC(CH₃)₂-、-(CH₂)₂S(＝O)₂-、

In some embodiments, the compounds of the present invention are compounds of formula (I-1), (I-2), or (I-3), or stereoisomers, tautomers, nitroxides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs thereof:

wherein, the The following sub-structural formula is shown as follows:

wherein each Z ^2a is independently CH or N;

Z ^3a and Z ⁴ are each independently CH ₂, O, S, NH, C = O, S =o or S (=o) ₂;

And is also provided with Independently optionally substituted with 1, 2, 3 or 4 substituents selected from F, cl, br, OH, oxo, NR ⁵R⁶、R⁵(C＝O)NR⁶ -, amino C _1-4 alkyl, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _1-4 hydroxyalkyl, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl-C _1-4 alkyl and C _1-4 alkoxy C _1-4 alkyl;

M ^a is 5-10 membered heteroaryl or C _6-10 aryl, and M ^a is optionally substituted with 1, 2,3 or 4 substituents selected from F, cl, CN, OH, NR ⁵R⁶、OR⁷、C_1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 haloalkoxy, C _6-10 aryl, C _1-6 alkoxyc _1-6 alkyl, oxo, C _1-6 alkanoyl, 3-7 membered heterocyclyl and C _3-7 cycloalkyl;

R ¹、X¹、X²、X³、X⁴、X⁵、T、G、R^a, q have the definitions according to the invention.

In some embodiments of the present invention, in some embodiments,

The following sub-structural formula is shown as follows:

And is also provided with Independently optionally substituted with 1,2, 3 or 4 substituents selected from F, cl, br, OH, oxo, NH ₂、NHCH₃、CH₃ (C=O) NH-, methyl, ethyl, n-propyl, methoxy, ethoxy, isopropoxy, CF ₃, hydroxymethyl, 2-hydroxyethyl, cyclopropyl, cyclohexyl, pyrrolidinyl, piperidinyl and tetrahydrofuranyl, and

M ^a is pyridinyl, pyrimidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, pyrazinyl, or phenyl, and M ^a is optionally substituted with 1,2, 3, or 4 substituents selected from D、F、Cl、CN、OH、CF₃、CHCl₂、CHF₂、CH₂F、CF₃CH₂、NH₂、NHCH₃、N(CH₃)₂、 trifluoromethoxy, 2-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.

In some embodiments, the compounds of the present invention have one of the following structures, or stereoisomers, tautomers, nitroxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof,

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

In another aspect, the invention also provides the use of the compound of the invention or the pharmaceutical composition of the invention in the preparation of a medicament for preventing or treating RET-related diseases.

In some embodiments, the RET related disease includes cancer, irritable bowel syndrome and/or pain associated with irritable bowel syndrome.

In another aspect, the invention also provides a compound of the invention or a pharmaceutical composition of the invention for use in the prevention or treatment of RET-related disorders.

In some embodiments, the RET related disease includes cancer, irritable bowel syndrome and/or pain associated with irritable bowel syndrome.

In another aspect, the invention also provides a method of preventing or treating RET-related disorders comprising administering to a patient a therapeutically effective amount of a compound of the invention or a pharmaceutical composition thereof.

In some embodiments, the RET related disease includes cancer, irritable bowel syndrome and/or pain associated with irritable bowel syndrome.

In another aspect, the present invention relates to intermediates for preparing compounds of formula (I), (I-1), (I-2) or (I-3).

In another aspect, the present invention relates to methods for the preparation, isolation and purification of compounds of formula (I), (I-1), (I-2) or (I-3).

In another aspect, the invention provides a pharmaceutical composition comprising a compound of the invention and pharmaceutically acceptable adjuvants thereof. In some embodiments, adjuvants described herein include, but are not limited to, carriers, excipients, diluents, vehicles, or combinations thereof. In some embodiments, the pharmaceutical composition may be in a liquid, solid, semi-solid, gel or spray form.

Also provided herein are methods of inhibiting cell proliferation in vitro or in vivo comprising contacting a cell with an effective amount of a compound of the invention or a pharmaceutical composition thereof.

Also provided herein are methods of treating Irritable Bowel Syndrome (IBS) and/or pain associated with IBS in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition thereof.

The invention also provides the use of a compound of the invention or a pharmaceutical composition of the invention in the manufacture of a medicament for the prophylactic or therapeutic treatment of Irritable Bowel Syndrome (IBS) and/or pain associated with IBS.

The invention also provides the use of a compound of the invention or a pharmaceutical composition of the invention for the prophylaxis or treatment of Irritable Bowel Syndrome (IBS) and/or pain associated with IBS.

Unless otherwise indicated, all stereoisomers, geometric isomers, tautomers, nitroxides, hydrates, solvates, metabolites, salts and pharmaceutically acceptable prodrugs of the compounds of the invention are within the scope of the invention.

In particular, salts are pharmaceutically acceptable salts. The term "pharmaceutically acceptable" includes substances or compositions that must be suitable for chemical or toxicological use, in relation to the other components that make up the formulation and the mammal being treated.

Salts of the compounds of the present invention also include salts of the isolated enantiomers of the compounds of formula (I), (I-1), (I-2) or (I-3) or intermediates used in the preparation or purification of the compounds of formula (I), (I-1), (I-2) or (I-3), but are not necessarily pharmaceutically acceptable salts.

In the structures disclosed herein, when the stereochemistry of any particular chiral atom is not indicated, then all stereoisomers of that structure are contemplated as being within the present invention and are included as presently disclosed compounds. When stereochemistry is indicated by the solid wedge (solid wedge) or dashed line representing a particular configuration, then the stereoisomers of that structure are so defined and defined.

Nitrogen oxides of the compounds of the present invention are also included within the scope of the present invention. The nitrogen oxides of the compounds of the invention may be prepared by oxidizing the corresponding nitrogen-containing basic species at elevated temperatures using customary oxidizing agents, such as hydrogen peroxide, in the presence of an acid such as acetic acid, or by reaction with peracetic acid in a suitable solvent, such as dichloromethane, ethyl acetate or methyl acetate, or with 3-chloroperoxybenzoic acid in chloroform or dichloromethane.

If the compounds of the present invention are basic, the desired salts may be prepared by any suitable method provided in the literature, for example, using mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like. Or 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, pyronic acids such as glucuronic acid and galacturonic acid, alpha-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, and the like.

If the compounds of the invention are acidic, the desired salts can be prepared by suitable methods, for example, using inorganic or organic bases, such as ammonia (primary, secondary, tertiary), alkali 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, and cyclic ammonia such as piperidine, morpholine and piperazine, and the like, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.

Definitions and general terms

Reference will now be made in detail to certain embodiments of the application, examples of which are illustrated in the accompanying structural and chemical formulas. The application is intended to cover all alternatives, modifications and equivalents, which may be included within the scope of the application as defined by the appended claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the present application. The present application is in no way limited to the methods and materials described herein. In the event of one or more of the incorporated references, patents and similar materials differing from or contradictory to the present application (including but not limited to defined terms, term application, described techniques, etc.), the present application controls.

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

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference in their entirety.

The term "patient" as used herein refers to a human (including adults and children) or other animals. In some embodiments, "patient" refers to a human.

The term "comprising" is an open-ended expression, i.e., including what is indicated by the invention, but not excluding other aspects.

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

The stereochemical definitions and rules used in the present 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.

The resulting mixture of any stereoisomers may be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, e.g., by chromatography and/or fractional crystallization, depending on the differences in the physicochemical properties of the components.

The term "tautomer" or "tautomeric form" refers to structural isomers having different energies that can be interconverted by a low energy barrier (low energy barrier). If tautomerism is possible (e.g., in solution), chemical equilibrium of the tautomers can be achieved. For example, proton tautomer (protontautomer) (also known as proton transfer tautomer (prototropic tautomer)) includes interconversions by proton transfer, such as keto-enol isomerisation and imine-enamine isomerisation. Valence tautomers (valence tautomer) include interconversions by recombination of some of the bond-forming electrons. Specific examples of keto-enol tautomerism are tautomerism of pentane-2, 4-dione and 4-hydroxypent-3-en-2-one tautomer. Another example of tautomerism is phenol-ketone tautomerism. One specific example of phenol-ketone tautomerism is the interconversion of pyridin-4-ol and pyridin-4 (1H) -one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

Unless otherwise indicated, the structural formulae described herein include all isomeric forms (e.g., enantiomers, diastereomers, and geometric isomers (or conformational isomers)), such as the R, S configuration containing an asymmetric center, the (Z), (E) isomers of double bonds, and the conformational isomers of (Z), (E). Thus, individual stereochemical isomers of the compounds of the invention, or enantiomers, diastereomers, or mixtures of geometric isomers (or conformational isomers) thereof, are all within the scope of the invention.

Unless otherwise indicated, the structural formulae described herein and the compounds described herein include all isomeric forms (e.g., enantiomers, diastereomers, geometric isomers, or conformational isomers), nitroxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts and prodrugs. Thus, compounds of the individual stereochemical isomers, enantiomers, diastereomers, geometric isomers, conformational isomers, nitroxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts and prodrugs of the compounds of the invention are also within the scope of the invention. In addition, unless otherwise indicated, the structural formulae of the compounds described herein include enriched isotopes of one or more different atoms.

The compounds of the invention, as described herein, may independently be optionally substituted with one or more substituents, such as those of the general formula above, or as exemplified by the specific examples provided herein, subclasses, and classes of compounds encompassed by the invention. It is to be understood that the term "independently optionally substituted" is used interchangeably with the term "substituted or unsubstituted. In general, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced with a specific substituent. An optional substituent group may be substituted at each substitutable position of the group unless otherwise indicated. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, then the substituents may be the same or different at each position.

In addition, unless explicitly stated otherwise, the description as used in this disclosure is "each..and". Independently "and". Independently "can be interchanged, and is to be understood broadly as meaning that specific items expressed between the same symbols in different groups do not affect each other, or that specific items expressed between the same symbols in the same groups do not affect each other.

In the various parts of the present specification, substituents of the presently disclosed compounds are disclosed in terms of the type or scope of groups. It is specifically noted that the present invention includes each individual subcombination of the individual members of these group classes and ranges. For example, the term "C _1-6 alkyl" refers specifically to independently disclosed methyl, ethyl, C ₃ alkyl, C ₄ alkyl, C ₅ alkyl, and C ₆ alkyl.

In the various parts of the invention, linking substituents are described. When the structure clearly requires a linking group, the markush variables recited for that group are understood to be linking groups. For example, if the structure requires a linking group and the markush group definition for that variable enumerates an "alkyl" or "aryl" group, it will be understood that the "alkyl" or "aryl" represents a linked alkylene group or arylene group, respectively.

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

The term "alkylene" means a saturated divalent hydrocarbon group resulting from the removal of two hydrogen atoms from a saturated straight or branched hydrocarbon group. Examples of alkylene groups include, but are not limited to, -CH ₂-、-CH₂CH₂-、-CH(CH₃)CH₂ -, and the like.

The term "alkylene-O-" means an alkylene group attached to the rest of the molecule through an oxygen atom, wherein the alkylene group has the definition as described herein.

The term "alkylene-NH-" means that the alkylene group is attached to the rest of the molecule via NH, wherein the alkylene group has the definition as described herein.

The term "oxo", i.e., =o.

The term "hydroxyalkyl" denotes an alkyl group substituted with one or more hydroxy groups. In some embodiments, hydroxyalkyl represents alkyl substituted with 1, 2, 3, or 4 hydroxy groups. In some embodiments, hydroxyalkyl represents alkyl substituted with 1 or 2 hydroxyl groups. In some embodiments, hydroxyalkyl means C _1-6 hydroxyalkyl, i.e., C _1-6 alkyl is substituted with one or more hydroxy groups, preferably C _1-6 hydroxyalkyl means C _1-6 alkyl is substituted with one hydroxy group. In some embodiments, hydroxyalkyl represents C _1-4 hydroxyalkyl. In some embodiments, hydroxyalkyl represents C _1-3 hydroxyalkyl. Examples of hydroxyalkyl groups include, but are not limited to ,HOCH₂-、CH₂OHCH₂CH₂CH₂-、CH₂OHCH₂-、CH₂OHCH₂CHOHCH₂-、CH(CH₃)OHCH₂CHOHCH₂-, and the like.

The term "alkoxy" means that the alkyl group is attached to the remainder of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy groups contain 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, and in yet another embodiment, the alkoxy group contains 1 to 3 carbon atoms. The alkoxy group may be optionally substituted with one or more substituents described herein. Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH ₃), ethoxy (EtO, -OCH ₂CH₃), 1-propoxy (n-PrO, n-propoxy, -OCH ₂CH₂CH₃), 2-propoxy (i-PrO, i-propoxy, -OCH (CH ₃)₂), 1-butoxy (n-BuO, n-butoxy, -OCH ₂CH₂CH₂CH₃), 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH ₂CH(CH₃)₂), 2-butoxy (s-BuO), s-butoxy, -OCH (CH ₃)CH₂CH₃), 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC (CH ₃)₃), 1-pentoxy (n-pentoxy), -OCH ₂CH₂CH₂CH₂CH₃), 2-pentyloxy (-OCH (CH ₃)CH₂CH₂CH₃), 3-pentyloxy (-OCH (CH ₂CH₃)₂), 2-methyl-2-butoxy (-OC (CH ₃)₂CH₂CH₃), 3-methyl-2-butoxy (-OCH (CH ₃)CH(CH₃)₂), 3-methyl-l-butoxy (-OCH ₂CH₂CH(CH₃)₂), 2-methyl-l-butoxy (-OCH ₂CH(CH₃)CH₂CH₃), and the like.

The term "alkoxyalkyl" refers to an alkyl group substituted with one alkoxy group, wherein the alkoxy and alkyl groups have the definitions as described herein. In some embodiments, alkoxyalkyl represents C _1-6 alkoxyaC _1-6 alkyl, in other embodiments alkoxyalkyl represents C _1-4 alkoxyaC _1-4 alkyl, in other embodiments alkoxyalkyl represents C _1-4 alkoxyaC _1-3 alkyl, in some embodiments alkoxyalkyl represents C _1-3 alkoxyaC _1-3 alkyl. Examples of alkoxy groups include, but are not limited to, methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, methoxy-n-propyl, methoxyisopropyl, ethoxyethyl, ethoxy-n-propyl, n-propoxyethyl, isopropoxyethyl, n-propoxyn-propyl, and the like.

The term "halogen" means F (fluorine), cl (chlorine), br (bromine) or I (iodine).

The term "haloalkyl" means an alkyl group substituted with one or more halogen atoms. In some embodiments, haloalkyl represents a C _1-6 haloalkyl, i.e., an alkyl group in which the C _1-6 alkyl group is substituted with 1 or more halogens. In some embodiments, haloalkyl represents C _1-4 haloalkyl. In some embodiments, haloalkyl represents C _1-3 haloalkyl. Examples include, but are not limited to, monofluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 1, 2-difluoroethyl, 1-difluoroethyl, 2-difluoroethyl, monochloromethyl, dichloromethyl, trichloromethyl, 1-chloroethyl, 1, 2-dichloroethyl, 1-dichloroethyl, 2-dichloroethyl, 1-dibromoethyl, and the like.

The term "cycloalkyl" denotes a monovalent saturated monocyclic carbocyclic ring system. the-CH ₂ -group in cycloalkyl groups may optionally be replaced by-C (=O) -. In some embodiments, cycloalkyl contains 3 to 7 ring carbon atoms, i.e., C _3-7 cycloalkyl. In one embodiment, cycloalkyl contains 3 to 6 carbon atoms, i.e., C _3-6 cycloalkyl, and in another embodiment, cycloalkyl contains 3 to 5 carbon atoms, i.e., C _3-5 cycloalkyl. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. Examples of carbon rings in which the-CH ₂ -group may be replaced by-C (=O) -include, but are not limited to, cyclopentanone, cyclobutanone, and the like. The cycloalkyl groups may independently be optionally substituted with one or more substituents described herein.

The term "monocyclic" means a saturated or partially unsaturated monocyclic carbocycle or monocyclic heterocyclic ring system, wherein carbocycles and heterocyclic rings have the definitions as described herein. Wherein the monocyclic carbocyclic ring system is a carbon monocyclic ring and the monocyclic heterocyclic ring system is a heteromonocyclic ring.

The term "monocyclic group" means a monovalent saturated or partially unsaturated monocyclic carbocycle or monocyclic heterocycle system wherein carbocycle and heterocycle have the definitions as set forth herein. the-CH ₂ -group in the monocyclic group may optionally be replaced by-C (=o) -. In some embodiments, the monocyclic group contains 3-7 ring atoms, i.e., the monocyclic group is a 3-7 membered monocyclic group, and in other embodiments, the monocyclic group contains 3-6 ring atoms, i.e., the monocyclic group is a 3-6 membered monocyclic group. Examples of monocyclic groups include, but are not limited to, cyclopropyl, cyclopentyl, cyclohexyl, 1, 2-cyclopentadienyl, pyrrolidinyl, tetrahydrofuranyl, morpholinyl, furanyl, and the like. Preferably, the monocyclic group according to the present invention is a monovalent saturated monocyclic carbocycle or a monocyclic heterocyclic ring system. The monocyclic groups may independently be optionally substituted with one or more substituents described herein.

The term "monocyclic subunit" means a divalent saturated or partially unsaturated monocyclic carbocycle or monocyclic heterocycle system wherein carbocycles and heterocycles have the definitions as described herein. the-CH ₂ -group in the monocyclic subunit may optionally be replaced by-C (=o) -. In some embodiments, the monocyclic subunit comprises 3 to 7 ring atoms, i.e., the monocyclic subunit is a 3-7 membered monocyclic subunit, and in other embodiments, the monocyclic subunit comprises 3 to 6 ring atoms, i.e., the monocyclic subunit is a 3-6 membered monocyclic subunit. Preferably, the monocyclic subunit of the present invention is a divalent saturated monocyclic carbocycle or a monocyclic heterocyclic ring system. Examples of the monocyclic subunit include, but are not limited to, cyclopropylene, cyclopentylene, cyclohexylene, 1, 2-cyclopentadienyl, pyrrolidinylene, and the like. The monocyclic subunit may independently be optionally substituted with one or more substituents described herein.

The term "subunit" denotes a divalent saturated or partially unsaturated monocyclic heterocyclic ring system, wherein the heterocyclic ring has the definition as described in the present invention. the-CH ₂ -group in the subunit-heterocyclic group may optionally be replaced by-C (=o) -. In some embodiments, the monoene group comprises 3-7 ring atoms, i.e., the monoene group is a 3-7 membered monoene group, and in other embodiments, the monoene group comprises 3-6 ring atoms, i.e., the monoene group is a 3-6 membered monoene group. Preferably, the subunit heterocyclyl groups described herein are divalent saturated monocyclic heterocyclic ring systems.

The term "heterocyclylalkyl" denotes an alkyl group substituted with a heterocyclyl group, wherein heterocyclyl and alkyl have the definitions as described herein. In some embodiments, the heterocyclylalkyl is a 3-12 membered heterocyclylC _1-6 alkyl, in other embodiments the heterocyclylalkyl is a 3-6 membered heterocyclylC _1-6 alkyl, in some embodiments the heterocyclylalkyl is a 3-6 membered heterocyclylC _1-4 alkyl. Examples of heterocyclylalkyl groups include, but are not limited to, pyrrolidinylmethyl, piperidinylmethyl, and the like.

The term "haloalkoxy" denotes an alkoxy group substituted with one or more halogen atoms, wherein halogen and alkoxy have the definition as described herein. In some embodiments, haloalkoxy represents C _1-6 haloalkoxy, i.e., alkyl in which the C _1-6 alkoxy is substituted with 1 or more halogens. In some embodiments, haloalkoxy represents C _1-4 haloalkoxy. In some embodiments, haloalkoxy represents C _1-3 haloalkoxy. Examples include, but are not limited to, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoroethoxy, 1, 2-difluoroethoxy, monochloroethoxy, and the like.

The term "alkanoyl" means an alkyl group attached to the remainder of the molecule through a carbonyl group, wherein alkyl has the definition as described herein, and carbonyl represents-C (=o) -. In some embodiments, the alkanoyl represents a C _1-6 alkanoyl, and in other embodiments, the alkanoyl represents a C _1-4 alkanoyl. Examples of alkanoyl groups include, but are not limited to, formyl, acetyl, and the like.

The term "cycloalkylalkyl" refers to an alkyl group substituted with a cycloalkyl group. Wherein cycloalkyl and alkyl have the definitions as described herein. In some embodiments, cycloalkylalkyl represents C _3-7 cycloalkyl C _1-6 alkyl, in other embodiments cycloalkylalkyl represents C _3-6 cycloalkyl C _1-6 alkyl, in other embodiments cycloalkylalkyl represents C _3-6 cycloalkyl C _1-4 alkyl. Examples of cycloalkylalkyl groups include, but are not limited to, cyclopropylmethyl, cyclopentylethyl, cyclohexylmethyl, and the like.

The term "aryl" refers to a monovalent aromatic ring radical formed by the removal of a hydrogen atom from a ring carbon atom of an aromatic ring. Examples of aryl groups may include phenyl, naphthyl and anthracenyl. When aryl is a linking group, and "aryl" is recited for this markush group definition, then "aryl" means a linked arylene group. When M is aryl, as defined herein, then M is taken to mean that M comprises a linked arylene group. The term "arylene" refers to a divalent aromatic ring radical formed by the removal of two hydrogen atoms from a ring carbon atom of an aromatic ring. Examples of aryl groups represented as linked arylene groups may include phenylene, naphthylene, and anthracenylene. The aryl groups may independently be optionally substituted with one or more substituents described herein.

The term "heteroaryl" refers to a monovalent aromatic ring radical formed by the removal of a hydrogen atom from a ring atom of a heteroaromatic ring. The heteroaryl group is optionally substituted with one or more substituents described herein. In one embodiment, the 5-10 atom composition heteroaryl or 5-10 membered heteroaryl contains 1,2,3 or 4 heteroatoms independently selected from O, S and N. In some embodiments, the term "heteroaryl" means a heteroaryl ring group containing 5-6 ring atoms or a 5-6 membered heteroaryl group containing 1,2,3, or 4 heteroatoms independently selected from O, S, and N. In some embodiments, the term "heteroaryl" denotes a heteroaryl ring group or a 5 membered heteroaryl group containing 5 ring atoms, which contains 1,2,3 or 4 heteroatoms independently selected from O, S and N. Examples of heteroaryl groups include, but are not limited to, 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (e.g., 2-pyrazolyl), isothiazolyl, 1,2, 3-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 3-triazolyl, 1, 3-dithiotriazinyl, 1, 3-dithio, 3-triazolyl, 1, 3-triazolyl; also included are bicyclic rings of, but in no way limited to, benzimidazolyl, benzofuranyl, benzothienyl, indolyl (e.g., 2-indolyl), purinyl, quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), isoquinolinyl (e.g., 1-isoquinolinyl, 3-isoquinolinyl, or 4-isoquinolinyl), and, imidazo [1,2-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 the like. When heteroaryl is a linking group, and heteroaryl is recited for this markush group definition, then heteroaryl represents a linked heteroarylene group. When M is heteroaryl, as defined herein, then M comprises a linked heteroarylene group. The term "heteroarylene" refers to a divalent heteroaryl ring radical formed by removing two hydrogen atoms from a ring atom of a heteroaryl group. The heteroaryl groups may independently be optionally substituted with one or more substituents described herein.

The terms "carbocyclyl" and "carbocyclyl" are used interchangeably to refer to a saturated or partially unsaturated monocyclic, bicyclic or polycyclic ring system having ring atoms that are both carbon atoms, including Shan Tanhuan groups, bridged carbocyclyl groups, and carbocyclyl groups and spiro carbocyclyl groups.

The terms "spirocarbocyclyl" and "spirocarbocyclyl" are used interchangeably and refer to a non-aromatic, saturated or partially unsaturated bicyclic or polycyclic ring system formed by two carbocycles sharing one carbon atom. the-CH ₂ -group in the spirocarbocyclic ring may optionally be replaced by-C (=o) -. In some embodiments, the spirocarbocycle contains 7-12 ring carbon atoms, meaning a 7-12 membered spirocarbocycle, and in other embodiments, the spirocarbocycle contains 7-10 ring carbon atoms, meaning a 7-10 membered spirocarbocycle. Examples of spiro carbocycles include, but are not limited to, spiro [4.4] nonane, spiro [3.4] octane, spiro [4.5] decane, and the like. When a spiro carbocycle or spiro carbocyclyl is a linking group, and spiro carbocycle or spiro carbocyclyl is recited for this markush group definition, then spiro carbocycle or spiro carbocyclyl represents a linked spirocarbocyclylene group. The term "spiroylene" refers to a divalent spirocarbocyclic radical formed by removing two hydrogen atoms from the ring atoms of a spirocarbocyclic ring. The spirocarbocycle or spirocarbocyclyl may independently be optionally substituted with one or more substituents described herein.

The terms "heterocycle" or "heterocyclyl" are used interchangeably and each represent a monovalent, non-aromatic, saturated or partially unsaturated, monocyclic, bicyclic or polycyclic ring system having 3 to 12 ring atoms, and containing at least 1 carbon atom, 1, 2 or 3 heteroatoms selected from O, N or S. Unless otherwise indicated, the heterocyclyl group may be a carbon or nitrogen group, and the-CH ₂ -group may optionally be replaced by-C (=o) -. The sulfur atom of the ring may optionally be oxidized to an S-oxide and the nitrogen atom of the ring may optionally be oxidized to an N-oxide. The heterocyclic ring may be a single ring or a double ring, and specifically the double ring system may be a heterodouble ring, a spiroheterodouble ring or a bridged heterodouble ring. In some embodiments, the heterocyclic group contains 4-7 ring atoms, i.e., represents a 4-7 membered heterocyclic group, examples of which include, but are not limited to, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxacyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thiaxalkyl, homopiperazinyl, homopiperidinyl, 1-dioxo-1, 3-thiomorpholin, and the like. Examples of the substitution of the-CH ₂ -group in the heterocyclyl group by-C (=o) -include, but are not limited to, 2-oxo-pyrrolidinyl, oxo-1, 3-thiazolidinyl, 2-piperidonyl, 3, 5-dioxopiperidyl. Examples of the nitrogen atom in the heterocyclic group being oxidized to an N-oxy compound include, but are not limited to, 1-dioxo-1, 3-thiomorpholine. When a heterocycle or heterocyclyl is the linking group and a heterocycle or heterocyclyl is recited for this markush definition, then the heterocycle or heterocyclyl represents the linked heterocyclylene. The term "heterocyclylene" refers to a divalent heterocyclic group formed by removal of two hydrogen atoms from a ring atom of a heterocycle. The heterocycle or heterocyclyl may independently be optionally substituted with one or more substituents described herein.

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

The term "aminoalkyl" refers to an alkyl group substituted with one or more amino groups. In some embodiments, the term "aminoalkyl" refers to an alkyl group substituted with one amino group. In some embodiments, the term "aminoalkyl" refers to an amino C _1-6 alkyl group. In other embodiments, the term "aminoalkyl" means an amino C _1-4 alkyl group. In other embodiments, the term "aminoalkyl" means an amino C _1-3 alkyl group. Examples of aminoalkyl groups include, but are not limited to, aminomethyl, aminoethyl, amino-n-propyl, amino-isopropyl, amino-isobutyl, amino-t-butyl, 1, 2-diaminoethyl, and the like.

The term "alkylamino" means an amino group substituted with one or two alkyl groups. In some embodiments, the term "alkylamino" means a C _1-6 alkylamino, i.e., an amino group substituted with one or two C _1-6 alkyl groups. In other embodiments, the term "alkylamino" means a C _1-4 alkylamino. In other embodiments, the term "alkylamino" means a C _1-3 alkylamino. Examples of alkylamino groups include, but are not limited to, methylamino, ethylamino, n-propylamino, isopropylamino, isobutylamino, t-butylamino, dimethylamino, diethylamino, di-n-propylamino, diisopropylamino, diisobutylamino, di-t-butylamino, and the like.

The term "alkylsulfonyl" denotes an alkyl-S (=o) ₂ -, i.e. an alkyl group is attached to the remainder of the molecule through-S (=o) ₂ -. In some embodiments, alkylsulfonyl represents C _1-6 alkylsulfonyl, in other embodiments alkylsulfonyl represents C _1-4 alkylsulfonyl, in other embodiments alkylsulfonyl represents C _1-3 alkylsulfonyl. Examples of alkylsulfonyl groups include, but are not limited to, methylsulfonyl, ethylmethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, and the like.

In the general formula of the compounds of the invention, the left-terminal linker ring A of Q is linked to the right-terminal linker M of Q, e.g., when Q is- (S=O) ₂NR⁶ -, thenRepresentation ofLikewise, the left end of ring A is connected to E and the right end of ring A is connected to Q, e.g., when ring A isIn the time-course of which the first and second contact surfaces,Representation of

In the general formula of the compounds of the invention, when T is alkylene-O-or alkylene-NH-,The alkylene end of T is attached to ring Y and the O-or NH-end of T is attached to G. If T is- (CH ₂)₂ O-,Representation of

As described herein, unless otherwise specified, a ring substituent may be attached to the remainder of the molecule through any available position on the ring. For example, piperidinyl includes piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, and piperidin-4-yl.

In the present invention, each of the substructures G1, G2, G3 and G4 of ring G represents a spiro ring formed by rings T ¹ and T ^2a, T ¹ and T ^2b, T ¹ and T ^2c, and T ¹ and T ^2d, respectively, and the attachment points of each of the G1, G2, G3 and G4 rings may be attached to the remainder of the molecule at any of the connectable positions on the G1, G2, G3 and G4 rings, respectively, preferably the attachment points of each of the G1, G2, G3 and G4 rings may be attached to the remainder of the molecule at any of the connectable positions on the G1, G2, G3 and G4 rings, respectively. For example, in the G1 ring, the attachment point may be attached to the remainder of the molecule at any available position on the T ¹ ring, or the attachment point may be attached to the remainder of the molecule at any available position on the T ^2a ring, preferably the attachment point is attached to the remainder of the molecule at any available position on the T ¹ ring. The sub-formulae G1, G2, G3 and G4 of ring G are shown below.

The term "protecting group" or "PG" refers to a substituent that is commonly used to block or protect a particular functionality when reacted with other functional groups. For example, by "protecting group for an amino group" is meant a substituent attached to the amino group to block or protect the functionality of the amino group in the compound, suitable amino protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC ), benzyloxycarbonyl (CBZ ) and 9-fluorenylmethoxycarbonyl (Fmoc). Similarly, "hydroxy protecting group" refers to the functionality that a substituent of a hydroxy group serves to block or protect the hydroxy group, and suitable protecting groups include acetyl and silyl. "carboxy protecting group" refers to the functionality of a substituent of a carboxy group to block or protect the carboxy group, and typical carboxy protecting groups include-CH ₂CH₂SO₂ Ph, cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxymethyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrobenzenesulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitroethyl, and the like. General description 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.

The term "prodrug" as used herein means a compound that is converted in vivo to a compound of formula (I). Such conversion is effected by hydrolysis of the prodrug in the blood or enzymatic conversion to the parent structure in the blood or tissue. The prodrug of the invention can be esters, and in the prior invention, the esters can be phenyl esters, aliphatic (C _1-24) esters, acyloxymethyl esters, carbonic esters, carbamates and amino acid esters as the prodrugs. For example, one compound of the invention may contain a hydroxyl group, i.e., it may be acylated to provide the compound in a prodrug form. Other prodrug forms include phosphates, such as those obtained by phosphorylation of a hydroxyl group on the parent. For a complete discussion of prodrugs, reference may be made to the following documents ：T.Higuchi and V.Stella,Pro-drugs as Novel Delivery Systems,Vol.14of 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.

"Metabolite" refers to a product obtained by metabolizing a specific compound or salt thereof in vivo. The metabolites of a compound may be identified by techniques well known in the art and their activity may be characterized by employing the assay methods as described herein. Such products may be obtained by oxidation, reduction, hydrolysis, amidization, deamination, esterification, degreasing, enzymatic cleavage, etc. of the administered compound. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a period of time sufficient.

As used herein, "pharmaceutically acceptable salts" refers to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in document ：S.M.Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences,1977,66:1-19.. Pharmaceutically acceptable non-toxic acid forming salts include, but are not limited to, inorganic acid salts formed by reaction with amino groups such as hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, and organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, or by other methods described in the literature such as ion exchange. Other pharmaceutically acceptable salts include adipic acid salts, alginates, ascorbates, aspartic acid salts, benzenesulfonates, benzoic acid salts, bisulfate salts, borates, butyric acid salts, camphoric acid salts, cyclopentylpropionates, digluconate, dodecylsulfate, ethanesulfonate, formate salts, fumaric acid salts, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, caproate, hydroiodic acid salts, 2-hydroxy-ethanesulfonate salts, lactobionic aldehyde salts, lactate salts, laurate salts, lauryl sulfate, malate salts, malonate salts, methanesulfonate salts, 2-naphthalenesulfonate salts, nicotinate salts, nitrate salts, oleate salts, palmitate salts, pamoate salts, pectate salts, persulfate salts, 3-phenylpropionate salts, picrate salts, pivalate salts, propionate salts, stearate salts, thiocyanate salts, p-toluenesulfonate salts, undecanoate salts, valerate salts, and the like. Salts obtained with suitable bases include the alkali metal, alkaline earth metal, ammonium and N ⁺(C_1-4 alkyl) ₄ salts. The present invention also contemplates quaternary ammonium salts formed from any compound containing a group of N. The water-soluble or oil-soluble or dispersible product may be obtained by quaternization. Alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and counter-ion forming amine cations such as halides, hydroxides, carboxylates, sulphates, phosphates, nitrates, C _1-8 sulphonates and aromatic sulphonates.

Pharmaceutically acceptable salts of the invention can be synthesized from the parent compound, basic or acidic moiety using conventional chemical methods. In general, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of a suitable base (e.g., na, ca, mg or K hydroxide, carbonate, bicarbonate, etc.), or by reacting the free base forms of these compounds with a stoichiometric amount of a suitable acid. Such reactions are generally carried out in water or an organic solvent or a mixture of both. Generally, it is desirable to use a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile where appropriate. A list of further suitable salts can be found in, for example, "Remington's Pharmaceutical Sciences", 20 th edition, mack Publishing Company, easton, pa., (1985), and "handbook of pharmaceutically acceptable salts: properties, choices and applications (Handbook of Pharmaceutical Salts：Properties,Selection,and Use)",Stahl and Wermuth(Wiley-VCH,Weinheim,Germany,2002).

In addition, the compounds disclosed herein, including their salts, may also be obtained in the form of their hydrates or in the form of solvents (e.g., ethanol, DMSO, etc.) containing them, for their crystallization. The disclosed compounds may form solvates inherently or by design with pharmaceutically acceptable solvents (including water) and, thus, the invention is intended to include both solvated and unsolvated forms.

"Solvate" according to the present invention refers to an association of one or more solvent molecules with a compound according to the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethylsulfoxide, ethyl acetate, acetic acid, and aminoethanol. The term "hydrate" refers to an association of solvent molecules that are water.

"Nitroxide" in the present invention means that when a compound contains several amine functions, 1 or more than 1 nitrogen atom can be oxidized to form an N-oxide. Specific examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen atoms of nitrogen-containing heterocycles. The corresponding amine may be treated with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid) to form an N-oxide (see Advanced Organic Chemistry, WILEY INTERSCIENCE, 4 th edition, jerry March, pages). In particular, the N-oxides can be prepared by the method L.W.Deady (Syn.Comm.1977, 7, 509-514) in which an amine compound is reacted with m-chloroperoxybenzoic acid (MCPBA), for example in an inert solvent such as methylene chloride.

The term "treating" as used herein refers in some embodiments to ameliorating a disease or disorder (i.e., slowing or preventing or alleviating the progression of the disease or at least one clinical symptom thereof). In other embodiments, "treating" refers to moderating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treating" refers to modulating a disease or disorder physically (e.g., stabilizing a perceived symptom) or physiologically (e.g., stabilizing a parameter of the body) or both. In other embodiments, "treating" refers to preventing or delaying the onset, or exacerbation of a disease or disorder.

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

In some embodiments, the deregulation of the expression or activity or level of the RET gene, the RET kinase or any of them comprises one or more deletions (e.g., deletion of amino acid 4), insertions or point mutations in the RET kinase. In some embodiments, the deregulation of the expression or activity or level of a RET gene, a RET kinase or any one thereof comprises a deletion of one or more residues of the RET kinase, resulting in constitutive activity of the RET kinase domain.

The term "irritable bowel syndrome" includes diarrhea predominant, constipation predominant or alternating stool patterns, functional bloating, functional constipation, functional diarrhea, nonspecific functional bowel disease, functional abdominal pain syndrome, chronic idiopathic constipation, functional esophageal disease, functional gastroduodenal disease, functional anorectal pain, inflammatory bowel disease, and the like.

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

In another aspect, the compounds of the invention include isotopically enriched compounds defined herein, for example, those in which a radioisotope, such as ³H,¹⁴ C and ¹⁸ F, is present, or in which a non-radioisotope, such as ² H and ¹³ C, is present. Such isotopically enriched compounds are useful in metabolic studies (using ¹⁴ C), kinetic 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 drug or substrate tissue distribution assays, or in radiation therapy of patients. ¹⁸ F-enriched compounds are particularly desirable for PET or SPECT studies. Isotopically enriched compounds of formula (I) can be prepared by conventional techniques familiar to those skilled in the art or by describing the examples and processes of preparation of the present invention using a suitable isotopically labelled reagent in place of the one previously used unlabelled reagent.

Furthermore, substitution of heavier isotopes, particularly deuterium (i.e., ² H or D), may afford certain therapeutic advantages resulting from greater metabolic stability. For example, increased in vivo half-life or reduced dosage requirements or improved therapeutic index. It is to be understood that deuterium in the present invention is considered as a substituent of the compound of formula (I). The concentration of such heavier isotopes, particularly deuterium, can be defined by an isotopic enrichment factor. The term "isotopically enriched factor" as used herein refers to the ratio between the isotopic abundance and the natural abundance of a specified isotope. If a substituent of a compound of the invention is designated as deuterium, the compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). Pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent may be isotopically substituted, e.g. D ₂ O, acetone-D ₆、DMSO-d₆.

Compounds of the present invention and pharmaceutical compositions, formulations and administration thereof

The present invention provides compounds of the invention or pharmaceutical compositions thereof that inhibit wild-type RET and RET mutants. In addition, the compounds of the present invention or pharmaceutical compositions thereof have inhibitory selectivity for both wild-type RET and RET gene mutants over other kinases, resulting in reduced toxicity associated with inhibition of other kinases.

The pharmaceutical composition of the present invention comprises a compound represented by formula (I), (I-1), (I-2) or (I-3), a compound listed in the present invention, or a compound of the examples. The amount of the compound in the pharmaceutical compositions of the invention is effective to treat or reduce RET-associated diseases or conditions in a patient, including RET-associated cancers, irritable bowel syndrome and/or pain associated with irritable bowel syndrome.

As described herein, the pharmaceutically acceptable compositions of the present invention further comprise pharmaceutically acceptable adjuvants, which as used herein, include any solvent, diluent, or other liquid excipient, dispersant or suspending agent, surfactant, isotonic agent, thickening agent, emulsifying agent, preservative, solid binder or lubricant, and the like, as appropriate for the particular target dosage form. ：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,, as described in the following documents, taken together with the content of the documents herein, demonstrate that various adjuvants can be employed in the preparation of pharmaceutically acceptable compositions and their known methods of preparation. In addition to the extent to which any conventional adjuvant is incompatible with the compounds of the present invention, such as any adverse biological effects produced or interactions with any other component of the pharmaceutically acceptable composition in a deleterious manner, their use is also contemplated by the present invention.

In preparing the compositions provided herein, the active ingredient is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, for example, a capsule, pouch, paper or other container. If an excipient is used as a diluent, it may be a solid, semi-solid, or liquid material, which acts as a carrier, vehicle, 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, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. Thus, the compositions may be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid 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.

When useful in therapy, 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 pharmaceutically acceptable salts thereof, may be administered as a raw chemical, and may also be provided as an active ingredient in a pharmaceutical composition. Accordingly, the present disclosure also provides pharmaceutical compositions comprising a therapeutically effective amount of a compound of the present invention, particularly a compound of formula (I), (I-1), (I-2) or (I-3), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable adjuvants, including, but not limited to, carriers, diluents or excipients, and the like. The term "therapeutically effective amount" as used herein refers to the total amount of each active ingredient sufficient to exhibit a meaningful patient benefit (e.g., cancer cytopenia). When separate active ingredients are used for separate administration, the term refers only to the ingredient. When applied in combination, the term refers to the combined amounts of the active ingredients that, when administered sequentially or simultaneously, result in a therapeutic effect. The compounds of the present invention, especially the compounds of formula (I), (I-1), (I-2) or (I-3) and pharmaceutically acceptable salts thereof, 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 deleterious to the recipient thereof. According to a further aspect of the present disclosure there is also provided a process for the preparation of a pharmaceutical formulation, which process comprises homogenising a compound of the present invention, in particular a compound of formula (I), (I-1), (I-2) or (I-3), or a pharmaceutically acceptable salt thereof, with one or more pharmaceutically acceptable carriers, diluents or excipients. The term "pharmaceutically acceptable" as used herein refers to compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio, and are effective for use in the intended use.

The amount of active ingredient combined with one or more adjuvants to prepare a single dosage form will necessarily vary depending upon the host treated and the particular route of administration. The amount of the compound of formula (I), (I-1), (I-2) or (I-3) in admixture with a carrier material to prepare a single dosage form will vary depending upon the disease to be treated, the severity of the disease, the time of administration, the route of administration, the rate of excretion of the compound used, the time of treatment and the age, sex, weight and condition of the patient. Preferred unit dosage forms are those containing a daily dose or divided dose of the above-described active ingredient of the invention or a suitable fraction thereof. Treatment may be initiated with a small dose that is significantly less than the optimal dose of the compound. Thereafter, the dosage is increased in smaller increments until the optimal effect is reached in this case. In general, the most desirable levels of concentration at which the compound is administered are those that generally provide effective results in terms of anti-tumor efficacy without causing any deleterious or toxic side effects.

Compositions comprising the compounds of the invention may be formulated in unit dosage forms, each dosage comprising from about 5 to about 1,000mg (1 g), more typically from about 100mg to about 500mg, of the active ingredient. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects or other patients, each unit containing a predetermined quantity of active material, i.e., a compound of formula (I), (I-1), (I-2) or (I-3) as provided herein, calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.

The pharmaceutical composition is suitable for administration by any suitable route, for example 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 true subcutaneous injection or infusion) route. Such formulations may be prepared by any method known in the pharmaceutical arts, for example, by mixing the active ingredient with carriers or excipients. Oral administration or injection administration is preferred.

The invention also provides methods of treating an individual having RET-associated cancer comprising administering a compound of the invention before, during or after administration of another anti-cancer agent (e.g., not a compound of the invention).

The invention provides methods for treating cancer in a patient in need thereof, comprising (a) determining whether the cancer in the patient is a RET related cancer (e.g., a RET related cancer comprising a RET related cancer having one or more RET inhibitor resistance mutations) (e.g., using regulatory agency approved, e.g., FDA approved, kits to identify deregulation of the expression or activity or level of the RET gene, RET kinase, or any of them in the patient or in biopsy samples of the patient, or by performing any non-limiting examples of the assays described herein), and (b) 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, if the cancer is determined to be a RET related cancer. 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 a compound of the invention). In some embodiments, the subject was 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 was previously treated (e.g., after excision of a tumor or radiation therapy) with another anticancer agent.

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 additional therapeutic agent selected from one or more additional therapeutic or therapeutic (e.g., chemotherapeutic) agents.

Non-limiting examples of other therapeutic agents include other RET targeted therapeutic agents (i.e., other RET kinase inhibitors: RET inhibitors that are not compounds of the present invention), receptor tyrosine kinase targeted therapeutic agents, signal transduction pathway inhibitors, checkpoint inhibitors, apoptosis pathway modulators (e.g., obataclax), cytotoxic chemotherapeutic agents, angiogenesis targeted therapeutic agents, immune targeting agents, and radiation therapies.

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

Non-limiting examples of RET targeted therapeutic agents include alatinib, apatinib, cabotinib (XL-184), multi-vitamin tinib, lenvatinib, mo Taisha ni, niladinib, ponatinib, lei Gela non-ni, statinib (sitravatinib) (MGCD 516), sunitinib, sorafenib, valatinib, 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-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).

Other therapeutic agents include RET inhibitors such as those described, for example, in U.S. Pat. Nos. 7,504,509, 8,299,057, 8,399,442, 8,067,434, 8,937,071, 9,006,256, and 9,035,063, U.S. publication No. 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, all of which are incorporated herein by reference in their entirety.

The present invention also provides a method of treating cancer comprising administering to a patient in need thereof a pharmaceutical combination comprising (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 co-effective in treating cancer.

The compounds and compositions of the invention may be administered alone or in combination with other compounds (including other RET modulating compounds) or other therapeutic agents. In some embodiments, a compound or composition of the invention may be administered in combination with one or more compounds selected from the group consisting of Cabozantine (COMETRIQ), vandetanib (CALPRESA), sorafenib (NEXAVAR), sunitinib (SUTENT), lei Gela non-ni (STAVARGA), plaitinib (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 with other therapeutic agents in a single formulation or in separate formulations.

In some embodiments, the compounds of the present invention may be used to treat Irritable Bowel Syndrome (IBS) in combination with one or more other therapeutic agents or therapies that are effective in the treatment of irritable bowel syndrome by acting through the same or different mechanisms of action. The at least one additional therapeutic agent may be administered with the compound of formula (I), (IA), (I-1), (I-2), or (I-3), or a pharmaceutically acceptable salt or solvate thereof, as part of the same or separate dosage form, via the same or different route of administration, and according to the same or different administration schedule, according to standard pharmaceutical practice known to those skilled in the art. Non-limiting examples of other therapeutic agents for the treatment of Irritable Bowel Syndrome (IBS) include probiotics, fiber supplements (e.g. psyllium, methylcellulose), antidiarrheals (e.g. loperamide), bile acid binders (e.g. cholestyramine, colestipol, colesevelam), anticholinergic and anticonvulsants (e.g. hyoscyamine, dicyclomine), antidepressants (e.g. tricyclic antidepressants such as imipramine or nortriptyline or selective 5-hydroxytryptamine reuptake inhibitors (SSRI) such as fluoxetine or paroxetine), antibiotics (e.g. rifaximin), alosetron and lubiprostone.

Use of the compounds and pharmaceutical compositions of the invention

The invention also provides the use of a compound of the invention or a pharmaceutical composition of the invention in the manufacture of a medicament for the prevention or treatment of a RET related disease or disorder, wherein the RET related disease or disorder comprises RET related cancer, irritable bowel syndrome and/or pain associated with irritable bowel syndrome.

The present invention provides compounds of the invention or pharmaceutical compositions thereof that inhibit wild-type RET and RET mutants, e.g., RET mutants that are resistant to current standard of care treatment ("RET resistant mutants"). In addition, the compounds of the present invention or pharmaceutical compositions thereof have inhibitory selectivity for both wild-type RET and RET gene mutants over other kinases, resulting in reduced toxicity associated with inhibition of other kinases.

The invention provides application of the compound or the pharmaceutical composition thereof for inhibiting wild RET and RET mutants in preparation of medicines for preventing or treating diseases or symptoms related to the wild RET and RET mutants.

In some embodiments of any of the methods or uses described herein, the cancer (e.g., RET related cancer) is a hematologic cancer. In some embodiments of any of the methods or uses described herein, the cancer (e.g., RET related cancer) is a solid tumor. In some embodiments of any of the methods or uses described herein, the cancer (e.g., RET related cancer) is lung cancer (e.g., small cell lung cancer or non-small cell lung cancer), papillary thyroid cancer, medullary thyroid cancer, differentiated thyroid cancer, recurrent thyroid cancer, refractory differentiated thyroid cancer, lung adenocarcinoma, bronchiolar lung cancer, multiple endocrine tumors of type 2A or 2B (MEN 2A 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 of the methods or uses described herein, the cancer (e.g., RET-associated cancer) is selected from the group consisting of Acute Lymphoblastic Leukemia (ALL), acute Myelogenous Leukemia (AML), juvenile cancer, adrenocortical cancer, anal cancer, Appendix cancer, astrocytoma, atypical teratoma/rhabdoid tumor, basal cell carcinoma, cholangiocarcinoma, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchogenic tumor, burkitt's lymphoma, carcinoid tumor, unknown primary carcinoma, heart tumor, cervical cancer, childhood cancer, chordoma, chronic Lymphocytic Leukemia (CLL), chronic Myelogenous Leukemia (CML), chronic myeloproliferative neoplasm, colon cancer, colorectal cancer, craniopharyngeal pipe tumor, cutaneous T-cell lymphoma, cholangiocarcinoma, ductal carcinoma in situ, embryonal tumor, endometrial cancer, ependymoma, esophageal cancer, sensoroblastoma, ewing sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, extrahepatic cholangiocarcinoma, eye cancer, fallopian tube cancer, bone fibrous histiocytoma, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, gestational trophoblastic disease, glioma, hairy cell tumor, hairy cell leukemia, head and neck cancer, heart cancer, hepatocellular carcinoma, histiocytosis, hodgkin lymphoma, hypopharynx cancer, intraocular melanoma, islet cell tumor, pancreatic neuroendocrine tumor, kaposi sarcoma, kidney cancer, langerhans' histiocytosis, laryngeal cancer, leukemia, lip and mouth cancer, liver cancer, lung cancer, lymphoma, macroglobulinemia, bone malignant fibrous histiocytoma, bone cancer, melanoma, merkel cell carcinoma, mesothelioma, metastatic squamous neck cancer, midline carcinoma, oral cancer, multiple endocrine tumor syndrome, multiple myeloma, mycosis granuloma, myelodysplastic syndrome, myelodysplasia/myeloproliferative neoplasm, myelogenous leukemia, multiple myeloma, myeloproliferative neoplasms, nasal and sinus cancers, nasopharyngeal cancers, neuroblastomas, non-hodgkin's lymphoma, non-small cell lung cancer, oral cancer, lip cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, paranasal sinus and nasal cavity cancers, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pituitary cancer, plasmacytoma, pleural-pulmonary blastoma, pregnancy and breast cancer, primary central nervous system lymphoma, primary peritoneal cancer, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland carcinoma, sarcoma, szebra's syndrome, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, squamous neck cancer, gastric cancer, T-cell lymphoma, testicular cancer, pharyngeal cancer, thymus and thymus cancer, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, unknown primary cancer, carcinoma of the urinary tract, carcinoma, wilm's tumor of the uterus, uterine tumor, wilm's tumor, carcinoma of the uterus, and the uterus.

In some embodiments, the RET related cancer of the present invention is selected from lung cancer, papillary thyroid cancer, medullary thyroid cancer, differentiated thyroid cancer, recurrent thyroid cancer, refractory differentiated thyroid cancer, multiple endocrine tumors of type 2A or 2B (MEN 2A 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.

In some embodiments, the compounds of formula (I), (I-1), (I-2), or (I-3), and pharmaceutically acceptable salts and solvates thereof, are useful in treating patients suffering from RET inhibitor resistance mutations that 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, e.g., V804M, V804L or V804E), by co-administration or subsequent treatment as an existing pharmaceutical treatment (e.g., other RET kinase inhibitors other than those of formula (I), (I-1), (I-2), or (I-3), or pharmaceutically acceptable salts or solvates thereof). Described herein are exemplary RET kinase inhibitors (e.g., other RET kinase inhibitors that are not compounds of formula (I), (I-1), (I-2), or (I-3), or pharmaceutically acceptable salts or solvates thereof). In some embodiments, the RET kinase inhibitor may be selected from the group consisting of cabotinib, vandetanib, alatinib, sorafenib, lenvatinib, pluratinib, multi-vitamin tinib, sunitinib, fortinib (foretinib), BLU667, and BLU6864.

In some embodiments of any of the methods or uses described herein, the Irritable Bowel Syndrome (IBS) comprises diarrhea predominant, constipation predominant, or alternating, functional abdominal distension, functional constipation, functional diarrhea, unspecific functional bowel disorder, functional abdominal pain syndrome, chronic idiopathic constipation, functional esophageal disease, functional gastroduodenal disease, functional anorectal pain, and inflammatory bowel disease.

The compounds and compositions according to the methods of the invention can be in any amount and by any route effective for treating or lessening the severity of the disease. The exact amount necessary will vary depending on the patient's condition, depending on the race, age, general condition of the patient, severity of the infection, particular factors, mode of administration, and the like. The compounds or compositions may be used in combination with one or more other therapeutic agents, as discussed herein.

General methods for the Synthesis of Compounds of the invention

In general, the compounds of the invention may be prepared by the methods described herein, unless otherwise indicated, wherein the substituents are as defined in formula (I), (I-1), (I-2) or (I-3). The following reaction schemes and examples are provided to further illustrate the present invention.

Those skilled in the art will recognize that the chemical reactions described herein can be used to suitably prepare many other compounds of the present invention, and that 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-exemplified compounds according to the invention can be successfully accomplished by modification methods, such as appropriate protection of interfering groups, by use of other known reagents in addition to those described herein, or by some conventional modification of the reaction conditions, by those skilled in the art. In addition, the reactions disclosed herein or known reaction conditions are also well-known to be applicable to the preparation of other compounds of the present invention.

The examples described below are given unless otherwise indicated that all temperatures are given in degrees celsius. Unless otherwise indicated, reagents were commercially available, e.g., reagents were purchased from commercial suppliers such as Ling Kai medicine, ALDRICH CHEMICAL Company, inc., arco Chemical Company and ALFA CHEMICAL Company, and were used without further purification unless otherwise indicated. The general reagents were purchased from Shandong Chemicals, guangdong Chemicals, guangzhou Chemicals, tianjin Chemie, inc., qingdao Tenglong chemical Co., ltd., and Qingdao ocean chemical works.

The anhydrous tetrahydrofuran is obtained by reflux drying of metallic sodium. The anhydrous methylene chloride and chloroform are obtained by reflux drying of calcium hydride. Ethyl acetate, N-dimethylacetamide and petroleum ether were dried over anhydrous sodium sulfate in advance for use.

The following reaction is typically carried out under nitrogen or argon pressure or with a dry tube (unless otherwise indicated) over anhydrous solvent, the reaction flask is capped with a suitable rubber stopper and the substrate is injected through a syringe. The glassware was all dried.

The chromatographic column is a silica gel column. Silica gel (300-400 mesh) was purchased from Qingdao ocean chemical plant. Nuclear magnetic resonance spectroscopy was performed using CDC1 ₃ or DMSO-d ₆ as a solvent (reported in ppm) and TMS (0 ppm) or chloroform (7.25 ppm) as reference standards. When multiple peaks occur, the abbreviations s (singlet ), d (doublet, doublet), t (triplet ), m (multiplet, multiplet), br (broadened, broad), dd (doublet of doublets, doublet), dt (doublet of triplets, doublet) will be used. Coupling constant J, expressed in hertz (Hz).

Low resolution Mass Spectrometry (MS) data were determined by a spectrometer of the Agilent6320 series LC-MS equipped with a G1312A binary pump and a G a 1316A TCC (column temperature maintained at 30 ℃) for analysis, a G1329A autosampler and a G1315B DAD detector for analysis, and an ESI source for LC-MS spectrometer.

Low resolution Mass Spectrometry (MS) data were determined by a spectrometer of the Agilent6120 series LC-MS equipped with a G1311A quaternary pump and a G1316A TCC (column temperature maintained at 30 ℃), a G1329A autosampler and a G1315D DAD detector were applied for analysis, and an ESI source was applied to the LC-MS spectrometer.

Both spectrometers were equipped with Agilent Zorbax SB-C18 columns, 2.1X130 mm,5 μm in size. The injection volume was determined by the sample concentration, the flow rate was 0.6mL/min, and the peak of the HPLC was recorded by UV-Vis wavelengths at 210nm and 254 nm. The mobile phase was a 0.1% acetonitrile formate solution (phase a) and a 0.1% ultrapure formate solution (phase B).

Compound purification was assessed by Agilent 1100 series High Performance Liquid Chromatography (HPLC), with UV detection at 210nm and 254nm, a Zorbax SB-C18 column, specification 2.1 x 30mm,4 μm,10 min, flow rate 0.6mL/min,5-95% (0.1% formic acid in acetonitrile) of 0.1% formic acid in water, column temperature maintained at 40 ℃.

The following abbreviations are used throughout the present invention:

LiAlH ₄ lithium aluminum hydride

THF tetrahydrofuran

DCM dichloromethane

TEA, et ₃ N triethylamine

K ₂CO₃ Potassium carbonate

DMF N, N-dimethylformamide

MeOH methanol

NaH sodium hydride

KMnO ₄ Potassium permanganate

PE Petroleum ether

EA ethyl acetate

DCE 1, 2-dichloroethane

DIPEA N, N-diisopropylethylamine

N-BuLi n-butyllithium

DMA, DMAC N, N-dimethylacetamide

Boc

T-BuOK potassium tert-butoxide

NaHCO ₃ sodium bicarbonate

NaOH sodium hydroxide

DMSO dimethyl sulfoxide

ML of

Mg

Mmol millimoles

Degree C

H hours

TLC thin layer chromatography

G

% Percent

Mol/L mol/liter

The following synthetic schemes describe the steps for preparing the disclosed compounds. R ¹、X¹、X²、X³、X⁴、X⁵、E、A、Q、M、T、R^a, q have the definitions as described herein unless otherwise indicated.

Synthesis scheme 1

Synthetic scheme for intermediate (IA-1 a):

intermediate compounds of formula (IA-1 a) may be prepared by reference to the synthetic steps of the above intermediate synthesis scheme. Wherein the method comprises the steps of The following sub-structural formula is shown as follows: Hal ¹ and Hal ² are each independently F, cl, br or I, preferably Cl or Br, pg ¹ is an amino protecting group, e.g. Boc, etc., pg ² is a hydroxy protecting group, e.g. benzyl, etc. The coupling reaction of the compound of formula (IA-1 a-1) with the compound of formula (IA-1 a-2) under suitable coupling agent conditions (e.g., palladium coupling agent, preferably PdCl ₂(dppf)CH₂Cl₂) in a suitable solvent (e.g., dioxane, etc.) to give the compound of formula (IA-1 a-3), the coupling reaction of the compound of formula (IA-1 a-3) with the compound of formula (IA-1 a-4) under suitable coupling agent conditions (e.g., palladium coupling agent, preferably PdCl ₂(dppf)CH₂Cl₂) in a suitable solvent (e.g., toluene, etc.) to give the compound of formula (IA-1 a-5), the coupling reaction of the compound of formula (IA-1 a-5) under suitable reaction conditions (e.g., in the presence of sodium hydroxide and hydrogen peroxide, in tetrahydrofuran solvent) to give a compound of formula (IA-1 a-6), coupling the compound of formula (IA-1 a-6) with the compound of formula (IA-1 a-7) to give a compound of formula (IA-1 a-8), reacting the compound of formula (IA-1 a-8) with the compound of formula (IA-1 a-9) under alkaline conditions to give a compound of formula (IA-1 a-10), deaminating the compound of formula (IA-1 a-10) under acidic conditions to give a compound of formula (IA-1 a-11), reacting the compound of formula (IA-1 a-11) with the compound of formula (IA-1 a-12) under alkaline conditions to give a compound of formula (IA-1 a-13), and reducing the compound of formula (IA-1 a-13) under suitable conditions (e.g., H ₂, pd/C) to give a compound of formula (IA-1 a).

Synthetic scheme for intermediate (IA-1 b):

Intermediate compounds of formula (IA-1 b) may be prepared by reference to the synthetic steps of the intermediate (IA-1 b) synthesis scheme. Wherein Hal ² is F, cl, br or I, preferably Cl or Br, and the compound of formula (IA-1 a-6) is coupled with the compound of formula (IA-4) or a salt of the compound of formula (IA-4) (e.g., hydrochloride, formate, etc.) under suitable conditions (e.g., in DMSO solvent, under alkaline conditions, e.g., K ₂CO₃) to give the compound of formula (IA-1 b).

Intermediate (IA-5) Synthesis scheme:

Intermediate compounds of formula (IA-5) may be prepared by reference to the synthetic steps of the intermediate (IA-5) synthesis scheme. Wherein Hal ² and Hal are each independently F, cl, br or I, preferably Cl or Br. The compound of formula (IA-1 a-6) is reacted with the compound of formula (IA-2) under suitable conditions (e.g., basic conditions, base K ₂CO₃) in a suitable solvent (e.g., N-dimethylacetamide, N-dimethylformamide) to provide the compound of formula (IA-5).

Synthesis scheme 1:

The compounds of formula (IA) may be prepared by reference to the synthetic procedure of scheme 1. Wherein Hal is F, cl, br or I, preferably Cl or Br. The compound of formula (IA-1) is reacted with the compound of formula (IA-2) under suitable conditions (e.g., basic conditions, base K ₂CO₃) in a suitable solvent (e.g., N-dimethylacetamide, N-dimethylformamide) to provide the compound of formula (IA).

Synthesis scheme 2:

The compounds of formula (IAa) can be prepared by reference to the synthetic procedure of synthetic scheme 2. Wherein Hal ¹ and Hal ² are each independently F, cl, br or I, preferably Cl or Br; Represents a spiro ring containing a nitrogen atom and is substituted with q R ^a, wherein q and R ^a have the definitions as described herein. The compound of formula (IA-1) and the compound of formula (IAa-2) are reacted under proper conditions (such as alkaline condition, base is K ₂CO₃) in proper solvent (such as acetonitrile) to obtain the compound of formula (IAa-3), and the compound of formula (IAa-3) and the compound of formula (IAa-4) are reacted under proper conditions (such as alkaline condition, base is K ₂CO₃) in proper solvent (such as N, N-dimethylacetamide) to obtain the compound of formula (IAa).

Synthesis scheme 3

The compounds of formula (IA) can be obtained by reference to the synthetic procedure of synthesis scheme 3. Wherein Ms is methanesulfonyl. The compound of formula (IA-1) is reacted with the compound of formula (IA-3) under suitable conditions (e.g., basic conditions, base K ₂CO₃) in a suitable solvent (e.g., N-dimethylformamide) to provide the compound of formula (IA).

Synthesis scheme 4

The compound of formula (IAb) can be obtained by reference to the synthetic procedure of scheme 4. Wherein Hal ² is F, cl, br, I, preferably Cl, br, and 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) (e.g., hydrochloride, formate, etc.) under suitable conditions to provide the compound of formula (IAb).

DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION

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

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

6-Bromo-4-methoxypyrazolo [1,5-a ] pyridine-3-carbonitrile (50 g,198.36 mmol), water (16.5 mL, 912 mmol), sodium hydroxide (16.03 g,396.8 mmol) and DMAC (500 mL) were added sequentially to a 1L single-necked flask, stirred at room temperature for 5min, and then dodecyl mercaptan (97 mL,397 mmol) was slowly added at 0℃and after the addition was completed, the reaction was allowed to proceed to 45℃overnight. The reaction solution was poured into 3L of ice water, and saturated aqueous citric acid solution was slowly added to adjust ph=5, stirred for half an hour, then allowed to stand, filtered, and the filter cake was washed with water and petroleum ether several times, and dried at 60 ℃ to obtain 44.1g of a yellow solid, which was the target product (yield 93.4%). Rf=0.35 (PE/EA (v/v) =3/1). LC-MS: m/z=239.05 [ m+h ] ⁺.

Step 2 3-bromo-3-cyanopyrazolo [1,5-a ] pyridin-4-yl triflate

To a 1L single vial was added 6-bromo-4-hydroxypyrazolo [1,5-a ] pyridine-3-carbonitrile (44.1 g,185 mmol), pyridine (45 mL,559 mmol), DCM (800 mL), the temperature was reduced below-10℃and trifluoromethanesulfonic anhydride (50 mL,297.2 mmol) was slowly added, and after stirring for 1h, the reaction was allowed to spontaneously warm to room temperature overnight. The DCM was dried under reduced pressure, diluted with water (250 mL), extracted with EA (500 mL. Times.3), the organic phase was collected, washed with saturated brine (250 mL), dried over anhydrous sodium sulfate, filtered, dried over spin-on-filtrate, and purified by column chromatography on silica gel (eluent PE/EA (v/v) =50/1-25/1) to give 61.5g of the title product as a yellow-like solid in 89.7% yield. Rf=0.45 (PE/EA (v/v) =5/1).

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

3-Bromo-3-cyanopyrazolo [1,5-a ] pyridin-4-yl trifluoromethanesulfonate (61.5 g,166 mmol), 2-fluoropyridine-5-borate (44.5 g,200 mmol), a [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride dichloromethane complex (6.8 g,8.3 mmol), 1, 4-dioxane (850 mL) were added to a 1L three-necked flask under nitrogen, the temperature was reduced to-10℃and potassium acetate solution (115 mL,345mmol,3 mol/L) was slowly added, and after stirring at this temperature for 1h, the reaction was continued at room temperature overnight. Filtering, washing filter cake with EA (500 mL×3), washing the filtrate with water (500 m l), washing the filtrate with saturated saline (250 mL), drying with anhydrous sodium sulfate, filtering, spin-drying the filtrate, purifying by silica gel column chromatography (eluent PE/DCM (v/v) =2:1-0:1), to obtain 49g of white solid, namely the target product, yield 93.0％.Rf＝0.50(PE/EA(v/v)＝1/1).LC-MS：m/z＝318.10[M+H]⁺.¹H NMR(400MHz,DMSO-d₆))δ9.49(d,J＝1.2Hz,1H),8.73(s,1H),8.51(d,J＝1.9Hz,1H),8.27(td,J＝8.2,2.5Hz,1H),7.86(d,J＝1.2Hz,1H),7.40(dd,J＝8.4,2.5Hz,1H).

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

6-Bromo-4- (6-fluoropyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile (8 g,25.23 mmol), pinacol ester (10 g,39.39 mmol), potassium acetate (10 g,101.9 mmol), redistilled toluene (150 mL), bubbling for another 10min after nitrogen substitution, and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex (2.1 g,2.6 mmoles) were sequentially added under nitrogen protection to the flask, and the reaction was heated at 120℃overnight after bubbling for 10min with nitrogen substitution. Filtering with diatomite, washing (50 ml×3) filter cake with EA, washing the organic phase with saturated salt water (250 mL), drying with anhydrous sodium sulfate, filtering, spin-drying, purifying with silica gel column chromatography (eluent PE/DCM (v/v) =2/1-0/1), collecting spin-drying to obtain orange solid 8.5g, which is the target product (yield) 93.0％).Rf＝0.15(DCM).¹H NMR(400MHz,CDCl₃)δ8.99(s,1H),8.43(d,J＝2.1Hz,1H),8.34(s,1H),8.02(td,J＝8.0,2.5Hz,1H),7.66(s,1H),7.13(dd,J＝8.5,2.8Hz,1H),1.40(s,12H).

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

To a 250mL single flask, 4- (6-fluoropyridin-3-yl) -6- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile (8.5 g,23 mmol) and tetrahydrofuran (120 mL) were sequentially added, and under ice-bath conditions, sodium hydroxide solution (60 mL,120mmol,2 mol/L) and hydrogen peroxide (14 mL,140mmol,30 mass%) were slowly added and stirred at low temperature. After completion of the TLC monitoring, a sodium thiosulfate solution (50 mL,150mmol,3 mol/L) was slowly added, and after returning to room temperature, water (250 mL), EA extraction (250 mL. Times.2) was performed, and the combined organic phases were washed with a 0.1M NaOH solution (500 mL. Times.2). All aqueous phases were combined, the pH was adjusted to 4 with dilute hydrochloric acid, stirred at room temperature for 15min, and suction filtered to give a wet cake. The mother liquor was extracted with EA (250 ml×3), all organic phases were combined, dried over anhydrous sodium sulfate, filtered, spin-dried and purified by column chromatography on silica gel (eluent DCM/MeOH (v/v) =100/0-10/1) to give a pale yellow solid. Combining all solids, oven drying at 50deg.C to give pale yellow solid 5.1g as target product (yield 86.0％).Rf＝0.25(DCM/MeOH(v/v)＝100/1).LC-MS：m/z＝255.10[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ10.44-10.37(m,1H),8.54(s,1H),8.49-8.46(m,1H),8.42-8.40(m,1H),8.26-8.21(m,1H),7.40-7.35(m,1H),7.32-7.30(m,1H).

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

Step 1 4-hydroxy-4- (pyridin-2-ylmethyl) piperidine-1-carboxylic acid tert-butyl ester

50ML double-necked flask was charged with THF (9 mL) and 2-methylpyridine (0.640 mL,6.52 mmol) under nitrogen protection, a solution of n-BuLi in n-hexane (2.2 mL,5.5mmol,2.5 mol/L) was slowly added at 78℃and after 45min the reaction was transferred to room temperature for 2h, and a solution of tert-butyl 4-oxopiperidine-1-carboxylate (1 g,5.019 mmol) in THF (6 mL) was then added at-78 ℃. After the addition, the reaction is continued for 2 hours, and then the mixture is placed at room temperature for 2 hours. The reaction mixture was quenched with saturated ammonium chloride solution (10 mL), extracted with EA (30 mL. Times.2), and the organic phase was washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and dried. Purification by column chromatography on silica gel (eluent PE/EA (v/v=10/1-1/1) gave 1.176g (yield 80.14%) as the target product as a pale yellow oil .LC-MS(ES-API):m/z＝293.40[M+H]⁺.¹H NMR(400MHz,CDCl₃)δ8.49–8.44(m,1H),7.61(td,J＝7.7,1.7Hz,1H),7.15(dd,J＝7.0,5.4Hz,1H),7.09(d,J＝7.7Hz,1H),3.76(s,2H),3.72–3.61(m,1H),3.21(s,2H),2.87(s,2H),1.47(d,J＝3.2Hz,4H),1.42(s,9H).

Step 2 4- (pyridin-2-ylmethyl) piperidin-4-ol dihydrochloride

In a 25mL single-necked flask, tert-butyl 4-hydroxy-4- (pyridin-2-ylmethyl) piperidine-1-carboxylate (550 mg,1.881 mmol) and ethyl acetate hydrochloride solution (10 mL,40mmol,4 mol/L) were added and the mixture was stirred at room temperature for 3h. TLC shows that the reaction is finished, the reaction liquid is directly dried by spin to obtain yellow oily matter, and the yellow oily matter is put into an oven for drying at 60 ℃ to obtain 0.430g of theoretical yellow solid, namely the target product. LC-MS (ES-API) m/z=193.40 [ M-2HCl+H ] ⁺.

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

To a 10mL microwave tube was added 4- (2-pyridylmethyl) piperidin-4-ol dihydrochloride (430 mg, 1.660 mmol), 4- (6-fluoro-3-pyridinyl) -6-hydroxy-pyrazolo [1,5-a ] pyridine-3-carbonitrile (intermediate 2,240mg,0.944 mmol), potassium carbonate (522 mg,3.777 mmol), DMSO (2.4 mL), and the reaction was heated by microwave 85℃for 6h. TLC showed that the reaction was completed, the reaction solution (12 mL) was diluted with water, extracted with EA (30 mL. Times.2), and the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and spun-dried. Purifying by silica gel column chromatography (eluent: pure EA-EA/MeOH (v/v: 50/1)) to obtain 0.19g (yield 47%) of a brown yellow solid, which is the target product .LC-MS(ES-API):m/z＝427.20[M+H]⁺.¹H NMR(400MHz,CD₃OD)δ8.46(d,J＝4.2Hz,1H),8.23(d,J＝2.8Hz,2H),8.18(d,J＝2.0Hz,1H),7.75(d,J＝5.5Hz,1H),7.70(dd,J＝9.0,2.6Hz,1H),7.34(d,J＝7.8Hz,1H),7.29–7.24(m,1H),7.12(d,J＝1.9Hz,1H),6.89(d,J＝8.9Hz,1H),4.06(d,J＝13.2Hz,2H),3.38(dd,J＝18.1,7.6Hz,2H),2.97(s,2H),1.77–1.69(m,2H),1.62(d,J＝13.3Hz,2H).

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

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

To a 100mL single flask was added 2-oxa-6-azaspiro [3.3] heptane (2.0 g,20 mmol), potassium carbonate (15 g,108.5 mmol), 1-bromo-2-chloroethane (8.0 mL,97.0 mmol), acetonitrile (20 mL) and the mixture was reacted at room temperature after the addition was completed. After the reaction, insoluble solids were removed by suction filtration, the filter cake was washed with methanol, the organic phases were combined, concentrated, and the residue was purified by silica gel column chromatography to give 860mg of the product. ¹H NMR(400MHz,CDCl₃ ) Delta 4.74 (s, 4H), 3.47-3.39 (m, 6H), 2.72 (t, j=6.3 hz, 2H).

Step 2 6- (2- (2-oxa-6-azaspiro [3.3] hept-6-yl) ethoxy) -4- (6-fluoropyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile

To a 25mL flask was added 4- (6-fluoropyridin-3-yl) -6-hydroxypyrazolo [1,5-a ] pyridine-3-carbonitrile (intermediate 1,500mg,1.97 mmol), potassium carbonate (823mg, 5.97 mmol), 6- (2-chloroethyl) -2-oxa-6-azaspiro [3.3] heptane (850 mg,5.26 mmol), DMA (6 mL), and reacted at 80 ℃. After the TLC detection reaction is completed, 20mL of water is added into the reaction solution, EA (80 mL multiplied by 2) is extracted, an organic phase is washed with water (15 mL multiplied by 3), saturated saline is washed with water (15 mL multiplied by 6), anhydrous sodium sulfate is dried and then filtered, and filtrate is purified by silica gel column chromatography (eluent is EA/MeOH (v/v) =1/0-20/1), so that 210mg of yellow solid is obtained as a product .LC-MS：m/z＝380.20[M+H]⁺.¹H NMR(400MHz,CDCl₃)δ8.38(d,J＝2.2Hz,1H),8.21(s,1H),8.19(d,J＝2.0Hz,1H),8.01(td,J＝8.4,2.5Hz,1H),7.18(d,J＝2.0Hz,1H),7.13(dd,J＝8.4,2.8Hz,1H),4.75(s,4H),4.03(t,J＝5.2Hz,2H),3.52(s,4H),2.87(t,J＝5.2Hz,2H). intermediate 4:5- (azetidin-3-yloxy) -2-methoxypyridine dihydrochloride

Step 1N-Boc-3- ((methylsulfonyl) oxy) azetidine-1-carboxylic acid tert-butyl ester

N-Boc-3-hydroxyazetidine (4.00 g,23.1 mmol) was dissolved in DCM (50 mL) under ice-water bath, et ₃ N (4.66 g,46.1 mmol) was slowly added, stirred for 10min, methanesulfonyl chloride (2.91 g,25.4 mmol) was slowly added, and the mixture was allowed to warm to room temperature and stirred for 2h. TLC monitored reaction (PE/EA (v/v) =2/1, rf=0.30) and starting material was complete. Slowly adding water for quenching reaction, extracting with DCM (20 mL×3), washing with saturated NaHCO ₃ solution, drying with anhydrous sodium sulfate, concentrating, purifying with silica gel column chromatography (eluent: PE/EA (v/v) =8/1-3/1) to obtain colorless viscous liquid 4.41g, and yield 76％.¹H NMR(400MHz,CDCl₃)δ5.23–5.12(m,1H),4.30–4.19(m,2H),4.10–4.03(m,2H),3.04(s,3H),1.42(s,9H).

Step 2N-Boc-3- ((6-methoxypyridin-3-yl) oxy) azetidine

5-Hydroxy-2-methoxypyridine (2.00 g,16.0 mmol) and N-Boc-3- ((methylsulfonyl) oxy) azetidine (4.82 g,19.2 mmol) were dissolved in DMF (30 mL), t-BuOK (3.59 g,32.0 mmol) was slowly added and stirred for 10min. The temperature was raised to 50℃and the reaction was stirred for 12h. TLC monitored reaction (PE/EA (v/v) =3/1, rf=0.29) and starting material was complete. Cooling to room temperature, adding water, extracting with EA (20 mL. Times.3), washing with water, drying over anhydrous sodium sulfate, and concentrating. The residue was purified by silica gel column chromatography (eluent: PE/EA (v/v) =10/1-4/1) to give 2.03g of yellow-brown solid, yield 45％.LC-MS：m/z＝281.3[M+H]⁺.¹H NMR(400MHz,CDCl₃)δ7.57(d,J＝2.9Hz,1H),7.17–7.06(m,1H),6.67(d,J＝8.9Hz,1H),4.85–4.75(m,1H),4.30–4.19(m,2H),4.00–3.93(m,2H),3.85(s,3H),1.42(s,9H).

Step 3 5- (azetidin-3-yloxy) -2-methoxypyridine dihydrochloride

N-Boc-3- ((6-methoxypyridin-3-yl) oxy) azetidine (600 mg,0.21 mmol), HCl/EA (3N, 2.5 mL) was added sequentially to a 25mL single-necked flask, and rt was stirred for 1h, and the reaction mixture was dried to a pale yellow solid, which was directly added for the next reaction. LC-MS: m/z=181.1 [ m-2hcl+h ] ⁺.

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

Step 1:4- ((6-methoxypyridin-3-yl) methyl) piperazine-1-carboxylic acid tert-butyl ester

To a 25mL single-necked flask was added 6-methoxypyridine-3-carbaldehyde (600 mg,4.38 mmol), tert-butyl piperazine-1-carboxylate (480 mg,5.26 mmol), sodium triacetoxyborohydride (2.8 g,13 mmol), 1, 2-dichloroethane (12 mL) in sequence, and the mixture was stirred at room temperature for 5h. After the reaction, the mixture was filtered, the filtrate was dried by spin-drying, and the residue was purified by silica gel column chromatography (PE/ea=1:1) to give 1.32g of a tan oil as the target product (yield 98.1％,Rf＝0.1(PE/EA(v/v)＝10/1)).LC-MS：m/z＝308.60[M+H]⁺.¹H NMR(400MHz,CDCl₃)δ8.03(d,J＝1.8Hz,1H),7.55(dd,J＝8.5,2.3Hz,1H),6.71(d,J＝8.5Hz,1H),3.91(s,3H),3.46(s,2H),3.44–3.38(m,4H),2.44–2.33(m,4H),1.44(s,9H).

Step 2:1- ((6-methoxypyridin-3-yl) methyl) piperazine dihydrochloride

To a 50mL single-necked flask was added in order tert-butyl 4- ((6-methoxypyridin-3-yl) methyl) piperazine-1-carboxylate (1.32 g,4.29 mmol), ethyl acetate hydrochloride solution (25 mL,4 mol/L) and stirred at room temperature overnight. The solvent was directly spin-dried to give a viscous oily substance, which was placed in an oven at 60 ℃ and dried under vacuum to give 1.2g of a white solid as the target product in 100% yield with rf=0.0 (PE/ea=1:1). LC-MS: m/z=208.20 [ m-2HCl ] ⁺.

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

To a 10mL microwave tube was added 4- (6-fluoropyridin-3-yl) -6-hydroxypyrazolo [1,5-a ] pyridine-3-carbonitrile (intermediate 1,300mg,1.18 mmol), 1- ((6-methoxypyridin-3-yl) methyl) piperazine dihydrochloride (496 mg,1.77 mmol), DIPEA (0.78 mL,4.72 mmol) and dissolved in dimethyl sulfoxide (3 mL) and reacted by heating at 85℃for 8h with microwaves. After the reaction, water (20 mL) was added to the reaction mixture, EA was extracted (100 mL. Times.5), the organic phases were combined, each was washed with water (100 mL. Times.2), saturated brine (100 mL) and dried over anhydrous sodium sulfate, and the filtrate was dried by spin-drying to give 112mg of a yellow solid as the target product (yield 21.5%), rf=0.15 (PE/EA=1:1), LC-MS: m/z=442.70 [ M+H ] ⁺.

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

Step 12- (2-chloroethyl) -8-oxa-2-azaspiro [4.5] decane

To a 100mL single flask was added 8-oxa-3-azaspiro [4.5] decane (2.5 g,18 mmol), potassium carbonate (8.5 g,62 mmol), acetonitrile (40 mL) was added to dissolve the same, and then 1-bromo-2-chloroethane (2.5 mL,30 mmol) was added to react at room temperature. Standing the solution after TLC detection reaction, clarifying the upper layer, filtering, concentrating, and purifying by silica gel column chromatography (eluent PE/EA (v/v) =2/11/1 to obtain pale yellow liquid 1.2g as product) .¹H NMR(400MHz,CDCl₃)δ3.63(t,J＝5.3Hz,4H),3.56(t,J＝7.0Hz,2H),2.78(t,J＝7.0Hz,2H),2.65(t,J＝6.9Hz,2H),2.49(s,2H),1.69(t,J＝6.9Hz,2H),1.63-1.53(m,4H).

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

To a 50mL flask was added 4- (6-fluoro-3-pyridinyl) -6-hydroxypyrazolo [1,5-a ] pyridine-3-carbonitrile (intermediate 1,300mg,1.18 mmol), potassium carbonate (510 mg,3.69 mmol), 3- (2-chloroethyl) -8-oxa-3-azaspiro [4.5] decane (370 mg,1.82 mmol), DMA (5 mL), and reacted at 80 ℃. After TLC detection reaction is finished, 20mL of water is added into the reaction solution, EA (80 mL multiplied by 2) is extracted, an organic phase is washed with water (15 mL multiplied by 3), saturated saline is washed with water (15 mL multiplied by 6), anhydrous sodium sulfate is dried and then filtered, and filtrate is purified by silica gel column chromatography (eluent is DCM/MeOH (v/v) =20/1-10/1), so that 135mg of yellow solid is obtained as a product .LC-MS：m/z＝422.20[M+H]⁺.¹H NMR(400MHz,CDCl₃)δ8.39(d,J＝2.1Hz,1H),8.24(d,J＝1.9Hz,1H),8.22(s,1H),8.02(td,J＝8.3,2.5Hz,1H),7.21(d,J＝1.9Hz,1H),7.13(dd,J＝8.4,2.8Hz,1H),4.16(t,J＝5.6Hz,2H),3.67-3.63(m,4H),2.94(t,J＝5.5Hz,2H),2.73(t,J＝6.9Hz,2H),2.56(s,2H),1.72(t,J＝6.9Hz,2H),1.62-1.57(m,4H).

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

Step 1 Ethyl 2- (6-oxaspiro [3.3] hept-2-yloxy) acetate

In a 25mL double-necked flask, naH (127 mg,3.175 mmol) was added, vacuum was applied under nitrogen protection, anhydrous THF (10 mL) was added at 0℃for dissolution, liquid 6-oxaspiro [3.3] heptan-2-ol (300 mg, 2.6278 mmol) was added, the reaction was stirred at room temperature after the addition was completed for 2 hours, then the reaction was transferred to 0℃and ethyl 2-bromoacetate (0.32 mL,2.9 mmol) was slowly added, and the reaction was stirred at room temperature after the addition was completed. TLC showed that the reaction was completed (KMnO ₄ oxidation), quenched with 15mL of water, extracted with EA (60 mL. Times.2), washed with 30mL of a saturated saline solution of the combined organic phase, dried over anhydrous sodium sulfate, filtered, spin-dried, and the residue was purified by column chromatography on silica gel (eluent PE/EA (v/v) =10/1-1/1), to give 0.222g (yield 42.2%) of oily liquid, which was the target product .¹HNMR(400MHz,CDCl₃)δ4.63(d,J＝12.0Hz,4H),4.19(q,J＝7.1Hz,2H),3.94(s,2H),3.93–3.85(m,1H),2.61–2.52(m,2H),2.23–2.14(m,2H),1.26(t,J＝7.1Hz,3H).

Step 2- (6-oxaspiro [3.3] hept-2-yloxy) ethanol

In a 25mL double-necked flask, liAlH ₄ (0.085 g,2.2 mmol) and THF 5mL were added to prepare a solution, the solution was evacuated under nitrogen protection, ethyl 2- (6-oxaspiro [3.3] hept-2-yloxy) acetate (222 mg,1.109 mmol) was dissolved in THF (3 mL), and the solution was slowly added to the double-necked flask at 0℃to perform a thermal reaction. TLC plate (KMnO ₄ oxidation) showed completion of the reaction, quenching reaction by adding 10mL of saturated ammonium chloride solution, extraction by EA (20 mL. Times.2), washing with 15mL of saturated saline solution, drying over anhydrous sodium sulfate, filtration, spin-drying, column chromatography of the residue on silica gel (eluent pure DCM-DCM/EA (v/v=4/1-1/4), yield 0.103g (yield 58.7%) as the target product .¹H NMR(400MHz,CDCl₃)δ4.65(d,J＝16.7Hz,4H),3.83(dd,J＝13.9,7.0Hz,1H),3.73–3.63(m,2H),3.46–3.36(m,2H),2.68–2.47(m,2H),2.15–2.08(m,2H).

Step 3 2- (6-oxaspiro [3.3] hept-2-yloxy) ethylmethanesulfonate

2- (6-Oxaspiro [3.3] hept-2-yloxy) ethanol (100 mg, 0.630 mmol) was added to a 10mL single flask under ice-bath conditions, DCM (1.5 mL) was dissolved, TEA (0.133 mL,0.947 mmol) was added, methanesulfonyl chloride (0.065 mL,0.83 mmol) was slowly added dropwise, and the mixture was allowed to spontaneously warm to room temperature for reaction. TLC showed that the reaction was quenched by addition of 3mL of water, extracted with DCM (15 mL. Times.2), the organic phases combined, washed with 8mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried by spin to give a yellow liquid that was directly taken into the next reaction.

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

5ML of a single port flask was charged with 2- (6-oxaspiro [3.3] hept-2-yloxy) ethyl methanesulfonate (22 mg,0.093 mmol), K ₂CO₃ (26 mg,0.186 mmol), 6-hydroxy-4- (6- (4- ((6-methoxypyridin-3-yl) methyl) piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile (20 mg,0.04530 mmol), dissolved in DMF (1.0 mL) and stirred at 60℃overnight. TLC plates showed that the reaction was completed, washed with 10mL of water, extracted with EA (40 mL. Times.2), washed with 20mL of a saturated organic phase brine, dried over anhydrous sodium sulfate, filtered, and spin-dried, and the residue was purified by silica gel column chromatography (eluent pure DCM-DCM/MeOH (v/v=10/1) to give 0.004g (yield 20%) of a pale yellow solid, which was the target product .LC-MS(ES-API):m/z＝582.20[M+H]⁺.¹H NMR(400MHz,CDCl₃)δ8.31(s,1H),8.19(s,1H),8.15(s,1H),8.10(s,1H),7.70(d,J＝8.6Hz,1H),7.54(s,1H),7.11(d,J＝2.3Hz,1H),6.79–6.74(m,2H),4.66(d,J＝18.9Hz,4H),4.16–4.12(m,2H),3.94(s,3H),3.89(d,J＝7.1Hz,1H),3.69(ddd,J＝13.0,7.6,4.7Hz,8H),2.64–2.55(m,4H),2.35–2.32(m,2H),2.24–2.20(m,2H).

EXAMPLE 2 4- (6- (4-hydroxy-4- (pyridin-2-ylmethyl) piperidin-1-yl) pyridin-3-yl) -6- ((6-hydroxy-6-methyl-spiro [3.3] hept-2-yl) methoxy) pyrazolo [1,5-a ] pyridine-3-carbonitrile

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

In a 50mL double flask, methyl 6-oxospiro [3.3] heptane-2-carboxylate (1000 mg,5.946 mmol) was added under nitrogen protection, dissolved in THF (10 mL), placed in a low temperature tank at-40℃and a THF solution of methyl magnesium bromide (3.0 mL,9.0mmol,3 mol/L) was slowly added, and the reaction was continued for 2 hours. TLC showed that the reaction was completed, quenched by addition of 20mL of saturated ammonium chloride, extracted with EA (50 mL. Times.2), washed with 30mL of a combined organic phase saturated brine, dried over anhydrous sodium sulfate, filtered, spun-dried, and purified by silica gel column chromatography (eluent PE/EA (v/v) =8/1-2/1) to give 0.343g (yield 32%) of a transparent oil, which was the target product. ¹H NMR(400MHz,CDCl₃ ) Delta 3.65 (s, 3H), 3.01 (p, j=8.5 hz, 1H), 2.35-2.07 (m, 8H), 1.31 (s, 3H).

Step 2- (hydroxymethyl) -6-methyl-spiro [3.3] heptan-6-ol

In a 25mL double-necked flask, liAlH ₄ (92 mg,2.424 mmol) was added, 3mL of THF was added to prepare a solution, and 6-hydroxy-6-methyl-spiro [3.3] heptane-2-carboxylic acid methyl ester (348 mg, 1.850 mmol) was dissolved in 10mL of THF under nitrogen protection, and the solution was slowly added to the double-necked flask at 0℃and allowed to react overnight at room temperature after the completion of the dropwise addition. TLC showed that the reaction was completed, quenched with 5mL of water and 10mL of saturated ammonium chloride solution, extracted with EA (30 mL. Times.2), washed with 20mL of saturated brine, combined with the organic phase, dried over anhydrous sodium sulfate, filtered, spin-dried, and the residue was chromatographed on silica gel (eluent PE/EA (v/v=4/1-1/2), giving 0.272g (yield 94%) of a transparent oil, which was the target product .¹H NMR(400MHz,CDCl₃)δ3.55(d,J＝6.8Hz,2H),2.43–2.31(m,1H),2.25–2.04(m,6H),1.78(dd,J＝19.0,8.3Hz,2H),1.64(s,2H),1.31(s,3H).

Step 3 (6-hydroxy-6-methyl-spiro [3.3] hept-2-yl) methylsulfonate

2- (Hydroxymethyl) -6-methyl-spiro [3.3] heptane-6-ol (60 mg,0.384 mmol) was added to a 10mL single flask under ice-bath conditions, DCM (1.5 mL) was dissolved, TEA (0.09 mL,0.6 mmol) was added, methanesulfonyl chloride (0.04 mL,0.5 mmol) was slowly added dropwise, and then the mixture was allowed to spontaneously warm to room temperature for 30min. TLC showed that the reaction was quenched by addition of 3mL of water, extracted with DCM (15 mL. Times.2), washed with 8mL of saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was spin-dried and the residue was purified by flash column chromatography on silica gel (eluent PE/EA (v/v=4/1-1/2) to give 0.063g (yield 70%) of the title product.

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

To a 10mL single port flask was added 6-hydroxy-4- (6- (4-hydroxy-4- (pyridin-2-ylmethyl) piperidin-1-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile (intermediate 2,30mg,0.071 mmol), K ₂CO₃ (39 mg,0.279 mmol), DMF (3 mL), after bubbling nitrogen for 5min, (6-hydroxy-6-methyl-spiro [3.3] hept-2-yl) methylsulfonate (33 mg,0.141 mmol) and the oil bath was heated at 60℃overnight. TLC showed that the reaction was completed, 15mL of water, EA (40 mL. Times.2) was added, the mixture was washed with 30mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried by spin-drying, and the residue was purified by silica gel column chromatography (pure DCM-DCM/MeOH (v/v=15/1)) to give 13mg (yield 33%) of a pale yellow solid, which was the target product .LC-MS(ES-API):m/z＝565.25[M+H]⁺.¹H NMR(400MHz,CDCl₃)δ8.52(d,J＝4.2Hz,1H),8.30(d,J＝2.2Hz,1H),8.18(s,1H),8.07(d,J＝1.9Hz,1H),7.71–7.60(m,2H),7.22–7.17(m,1H),7.13(d,J＝7.7Hz,1H),7.07(d,J＝1.9Hz,1H),6.77(d,J＝8.9Hz,1H),4.09(d,J＝12.9Hz,2H),3.93(d,J＝6.4Hz,2H),3.54–3.43(m,2H),2.94(s,2H),2.75–2.66(m,1H),2.22(dt,J＝23.5,11.5Hz,4H),2.12(s,2H),2.00–1.93(m,2H),1.72–1.56(m,6H),1.34(s,3H).

EXAMPLE 3 6- (2- ((7-azaspiro [3.4] oct-2-yl) oxy) ethoxy) -4- (6- (4-hydroxy-4- (pyridin-2-ylmethyl) piperidin-1-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile

Step 12- (2-ethoxy-2-oxoethoxy) -7-azaspiro [3.4] octane-7-carboxylic acid tert-butyl ester

In a 25mL double-necked flask, naH (72 mg,1.8 mmol) was added, the flask was evacuated under nitrogen protection for a plurality of times, the flask was placed at 0℃and anhydrous THF (17 mL) was added to prepare a suspension, tert-butyl 2-hydroxy-7-azanaphtho [3.4] octane-7-carboxylate (340 mg,1.496 mmol) was added, and the mixture was warmed to room temperature after the addition and stirred for 2 hours. Transfer to 0 ℃, add 2-bromoethyl acetate slowly (0.183 ml,1.65 mmol) and stir the reaction at room temperature overnight. TLC showed that the reaction was completed, the reaction solution was quenched with 15mL of water, extracted with EA (60 mL. Times.2), washed with 30mL of an organic phase saturated brine, dried over anhydrous sodium sulfate, filtered, spin-dried, and purified by silica gel column chromatography (eluent PE/EA (v/v=10/1-2/1)), to give 0.143g (yield 31%) of an oily liquid, which was the target product .LC-MS(ES-API):m/z＝258.1[M-56+H]⁺.¹H NMR(400MHz,CDCl₃)δ4.21(q,J＝7.1Hz,2H),4.11–4.03(m,1H),4.00–3.95(m,2H),3.37–3.21(m,4H),2.33–2.21(m,2H),2.10–1.97(m,2H),1.88–1.75(m,2H),1.44(s,9H),1.28(t,J＝7.1Hz,3H).

Step 2- (2-hydroxyethoxy) -7-azaspiro [3.4] octane-7-carboxylic acid tert-butyl ester

In a 25mL double-necked flask, liAlH ₄ (40.5 mg,1.07 mmol) was added, 3mL of THF was added to prepare a suspension, the suspension was evacuated under nitrogen protection, tert-butyl 2- (2-ethoxy-2-oxoethoxy) -7-azaspiro [3.4] octane-7-carboxylate (134 mg,0.428 mmol) was dissolved in 3mL of THF, and the solution was slowly added to the double-necked flask at a low temperature of-40℃and the reaction was continued for 1h. TLC showed that the reaction was completed, quenched with 12mL of water, extracted with EA (25 mL. Times.2), washed with 15mL of saturated organic phase brine, dried over anhydrous sodium sulfate, filtered, the filtrate was dried by spin-drying, and purified by silica gel column chromatography (eluent PE/EA (v/v=4/1-1/4) to give 0.101g (yield 87%) of a transparent oily substance, which was the target product .LC-MS(ES-API):m/z＝216.3[M-56+H]⁺.¹H NMR(400MHz,CDCl₃)δ4.04–3.94(m,1H),3.75–3.67(m,2H),3.46–3.41(m,2H),3.37–3.21(m,4H),2.32–2.20(m,2H),2.14(s,1H),2.00–1.89(m,2H),1.85–1.78(m,2H),1.43(s,9H).

Step 3 tert-butyl 2- (2-methylsulfonyloxy ethoxy) -7-azaspiro [3.4] octane-7-carboxylate

In a 5mL single flask, tert-butyl 2- (2-hydroxyethoxy) -7-azaspiro [3.4] octane-7-carboxylate (95 mg,0.350 mmol) was added under ice-bath conditions, DCM (1.5 mL) was dissolved, TEA (0.074 mL,0.53 mmol) was added, methanesulfonyl chloride (0.036 mL,0.46 mmol) was slowly added dropwise, and the mixture was allowed to react at room temperature for 1h. TLC showed that the reaction was completed, quenched with 3mL of water, extracted with DCM (10 mL. Times.2), washed with 5mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried and flash column chromatographed on silica gel (eluent PE: EA (v/v=4/1-1/2), giving 0.117g (96% yield) of a yellow transparent oil as the target product .¹H NMR(400MHz,CDCl₃)δ4.37–4.31(m,2H),4.01(p,J＝6.8Hz,1H),3.63–3.57(m,2H),3.37–3.21(m,4H),3.05(s,3H),2.33–2.21(m,2H),2.02–1.90(m,2H),1.87–1.77(m,2H),1.44(s,9H).

Step 4 2- (2- ((3-cyano-4- (6- (4-hydroxy-4- (pyridin-2-ylmethyl) piperidin-1-yl) -pyridin-3-yl) pyrazolo [1,5-a ] pyridin-6-yl) oxy) ethoxy) -7-azaspiro [3.4] octane-7-carboxylic acid tert-butyl ester

5ML of a single port flask was added 6-hydroxy-4- (6- (4-hydroxy-4- (pyridin-2-ylmethyl) piperidin-1-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile (intermediate 2,30mg,0.071 mmol), K ₂CO₃ (39 mg,0.280 mmol), DMF (1.5 mL) was added for dissolution, and 2- (2-methylsulfonyloxy ethoxy) -7-azaspiro [3.4] octane-7-carboxylic acid tert-butyl ester (49 mg,0.140 mmol) was added and left to stand at 60℃overnight with stirring. TLC showed that the reaction was completed, washing with 10mL of water, extraction with EA (40 mL. Times.2), washing with 20mL of saturated brine of the organic phase, drying over anhydrous sodium sulfate, filtration, spin-drying of the filtrate, purification by silica gel column chromatography (eluent pure DCM-DCM/MeOH (v/v=10/1) gave 26.5mg (yield 55.4%) of a pale yellow solid, which was the target product .LC-MS(ES-API):m/z＝680.30[M+H]⁺.¹H NMR(400MHz,CDCl₃)δ8.52(d,J＝4.2Hz,1H),8.30(d,J＝2.3Hz,1H),8.19(s,1H),8.13(s,1H),7.72–7.62(m,2H),7.22–7.17(m,1H),7.13(d,J＝7.5Hz,2H),6.77(d,J＝9.0Hz,1H),4.18–4.13(m,2H),4.12–4.03(m,3H),3.78–3.72(m,2H),3.52–3.45(m,2H),3.38–3.25(m,4H),2.94(s,2H),2.35–2.25(m,2H),2.06–1.97(m,2H),1.87–1.80(m,2H),1.66–1.63(m,4H),1.45(s,9H).

Step 5 6- (2- ((7-azaspiro [3.4] octyl-2-yl) oxy) ethoxy) -4- (6- (4-hydroxy-4- (pyridin-2-ylmethyl) -piperidin-1-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile tri-hydrochloride

In a10 mL single port flask, tert-butyl 2- (2- ((3-cyano-4- (6- (4-hydroxy-4- (pyridin-2-ylmethyl) piperidin-1-yl) -pyridin-3-yl) pyrazolo [1,5-a ] pyridin-6-yl) oxy) ethoxy) -7-azaspiro [3.4] octane-7-carboxylate (23.8 mg,0.0350 mmol) and ethyl acetate hydrochloride solution (2 mL,8mmol,4 mol/L) were added and the mixture was stirred at room temperature for 1h. TLC shows that the reaction is finished, the reaction solution is directly dried by spin-drying, and the theoretical amount of yellowish white solid product is obtained. LC-MS (ES-API) m/z=580.2 [ M-3HCl+H ] ⁺.

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

In a single flask containing 5mL of 6- (2- ((7-azaspiro [3.4] octyl-2-yl) oxy) ethoxy) -4- (6- (4-hydroxy-4- (pyridin-2-ylmethyl) -piperidin-1-yl) pyridin-3-yl ] pyrazolo [1,5-a ] pyridine-3-carbonitrile tri-hydrochloride (22.8 mg,0.035 mmol) was added saturated sodium bicarbonate (1 mL), pH was adjusted to alkaline by adding 3mL of DCM for 5min, the organic phase was separated, the aqueous phase was extracted with DCM (5 mL. Times.2), the organic phase was combined, washed with saturated brine 5mL, dried over anhydrous sodium sulfate, filtered and the filtrate was dried to give 14mg (yield 69%) of the title product as a pale yellow solid .LC-MS(ES-API):m/z＝580.2[M+H]⁺.¹H NMR(400MHz,CDCl₃)δ8.52(d,J＝4.3Hz,1H),8.30(d,J＝2.1Hz,1H),8.19(s,1H),8.13(d,J＝1.7Hz,1H),7.70–7.61(m,2H),7.21–7.17(m,1H),7.13(d,J＝7.5Hz,2H),6.77(d,J＝8.9Hz,1H),4.18–4.12(m,2H),4.07(dd,J＝18.6,14.6Hz,3H),3.75(d,J＝3.6Hz,2H),3.53–3.44(m,2H),3.07–2.84(m,6H),2.33–2.25(m,3H),2.07–2.01(m,2H),1.84(d,J＝7.3Hz,2H),1.65(d,J＝3.9Hz,4H).

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

To a 5mL single vial was added 6- (2- (2-oxa-6-azaspiro [3.3] hept-6-yl) ethoxy) -4- (6-fluoropyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile (intermediate 3,28mg,0.074 mmol), 4- (pyridin-2-ylmethyl) piperidin-4-ol hydrochloride (intermediate 2 step 2,32mg,0.14 mmol), potassium carbonate (40 mg,0.29 mmol), 4-dimethylaminopyridine (3 mg,0.024 mmol), DMSO (1 mL) and reacted at 90℃in an oil bath. After TLC detection, the reaction solution was cooled to room temperature, 5mL of water was added, EA (20 mL. Times.2) was extracted, the organic phase was washed with water (10 mL. Times.4), saturated brine (10 mL. Times.2), dried over anhydrous sodium sulfate, filtered, the filtrate was dried by spin-drying, and the residue was chromatographed on silica gel (eluent DCM/MeOH (v/v) =20/1-10/1) to give 34mg of a yellow solid as the target product .LC-MS：m/z＝552.30[M+H]⁺.¹H NMR(400MHz,CDCl₃)δ8.52(d,J＝4.4Hz,1H),8.30(d,J＝2.1Hz,1H),8.19(s,1H),8.09(s,1H),7.70-7.62(m,2H),7.23-7.18(m,1H),7.13(d,J＝7.8Hz,1H),7.10(d,J＝1.7Hz,1H),6.77(d,J＝8.9Hz,1H),4.76(s,4H),4.09(d,J＝12.9Hz,2H),4.01(t,J＝5.0Hz,2H),3.54(s,4H),3.52-3.45(m,2H),2.94(s,2H),2.87(t,J＝4.8Hz,2H),1.67-1.61(m,4H).

EXAMPLE 5 4- (6- (4-hydroxy-4- (pyridin-2-ylmethyl) piperidin-1-yl) pyridin-3-yl) -6- ((6-methoxyspiro [3.3] heptane-2-yl) methoxy) pyrazolo [1,5-a ] pyridine-3-carbonitrile

Step 1 6-hydroxy spiro [3.3] heptane-2-carboxylic acid methyl ester

To a100 mL double flask was added methyl 6-oxospiro [3,3] heptane-2-carboxylate (1.4 g,8.3 mmol), after nitrogen substitution, 10mL THF was added to dissolve it, lithium aluminum tri-tert-butoxide (4.6 g,17 mmol) dissolved in 15mL THF was added dropwise at-78℃and the reaction was carried out at this temperature after the addition was completed. After the reaction is finished, adding 30mL of water for quenching to obtain a large amount of white jelly, carrying out suction filtration, extracting an aqueous phase with ethyl acetate (50 mL multiplied by 3), combining an organic phase and saturated saline water for washing (50 mL), filtering, concentrating the filtrate, purifying the residue by silica gel column chromatography (eluent PE/EA (v/v) =10/1) to obtain 1.2g of colorless liquid, namely the target product .Rf＝0.3(PE/EA(v/v)＝5/1),LC-MS:m/z＝171.15[M+H]⁺.¹H NMR(400MHz,CDCl₃)δ4.15(p,J＝7.2Hz,1H),3.64(s,3H),3.01(p,J＝8.5Hz,1H),2.50-2.40(m,1H),2.36-2.24(m,3H),2.23-2.11(m,2H),2.03(s,1H),1.89(m,2H).

Step 2 6-Methoxyspiro [3.3] heptane-2-carboxylic acid methyl ester

To a 100mL single-necked flask was added methyl 6-hydroxy spiro [3.3] heptane-2-carboxylate (1.2 g,7.1 mmol), and dissolved by adding THF (18 mL), sodium hydride (560 mg,14.0mmol,60 mass%) was added in two portions at 10℃and methyl iodide (1.0 mL,16 mmol) was added after 15min to react at room temperature. After the reaction, adding water (30 mL) for quenching, extracting with ethyl acetate (50 mL×3), washing the organic phase with water (30 mL×2), drying with anhydrous sodium sulfate, and filtering and concentrating the silica gel column chromatography (eluent PE/EA (v/v) =20/1-5/1) to obtain colorless liquid 480mg.Rf＝0.8(PE/EA(v/v)＝5/1),¹H NMR(400MHz,CDCl₃)δ3.79-3.70(m,1H),3.66(s,3H),3.19(s,3H),3.03(p,J＝8.5Hz,1H),2.44-2.36(m,1H),2.33-2.13(m,5H),1.91(m,2H).

Step 3 (6-methoxy spiro [3.3] heptane-2-yl) methanol

After replacing nitrogen with a 25mL two-necked flask, methyl 6-methoxyspiro [3.3] heptane-2-carboxylate (480 mg,2.6 mmol) dissolved in 10mL THF was added, followed by dropwise addition of diisobutylaluminum hydride (8.0 mL,8.0mmol,1 mol/L) after stirring at 10℃for 10min, and reaction at room temperature was completed. After TLC monitoring the reaction, adding water to quench the reaction, adding 14mL of HCl (1N) to dissolve the reaction liquid completely, extracting with ethyl acetate (80 mL×2), washing the organic phase twice (30 mL×2), washing with saturated salt water (30 mL), drying with anhydrous sodium sulfate, filtering, concentrating the filtrate, purifying with silica gel column chromatography (eluent PE/EA (v/v) =5/1) to obtain colorless liquid 330mg.Rf＝0.3(PE/EA(v/v)＝5:1),¹H NMR(400MHz,CDCl₃)δ3.76(p,J＝7.1Hz,1H),3.56(d,J＝6.8Hz,2H),3.21(s,3H),2.46-2.33(m,2H),2.23(dt,J＝11.6,6.0Hz,1H),2.13-2.00(m,2H),1.96-1.84(m,2H),1.78(dd,J＝11.5,5.8Hz,2H).

Step 4 (6-methoxy spiro [3.3] hept-2-yl) methyl methanesulfonate

To a 25mL single vial was added (6-methoxyspiro [3.3] heptan-2-yl) methanol (340 mg,2.2 mmol), dissolved in 4mL DCM, triethylamine (0.7 mL,5 mmol) was added, and methylsulfonyl chloride (0.3 mL,3 mmol) was added dropwise at 0deg.C and reacted at room temperature. After the reaction was completed, 10mL of water was added, the reaction solution was extracted with DCM (20 ml×2), the organic phases were combined and washed with water (20 ml×3), saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (eluent PE/EA (v/v) =5/1) to give liquid 340mg.Rf＝0.3(PE:EA＝5:1),¹H NMR(400MHz,CDCl₃)δ4.17(d,J＝6.8Hz,2H),3.77(p,J＝7.1Hz,1H),3.21(s,3H),3.01(s,3H),2.70-2.56(m,1H),2.46-2.37(m,1H),2.27(dt,J＝11.6,5.9Hz,1H),2.21-2.08(m,2H),1.91(m,4H). step 5:4- (6- (4-hydroxy-4- (pyridin-2-ylmethyl) piperidin-1-yl) pyridin-3-yl) -6- ((6-methoxyspiro [3.3] heptan-2-yl) methoxy) pyrazolo [1,5-a ] pyridine-3-carbonitrile

To a 5mL single vial was added 6-hydroxy-4- [6- [ 4-hydroxy-4- (2-pyridylmethyl) -1-piperidinyl ] -3-pyridinyl ] pyrazolo [1,5-a ] pyridine-3-carbonitrile (intermediate 2,35mg,0.082 mmol), (6-methoxy spiro [3.3] hept-2-yl) methyl methanesulfonate (22 mg,0.094 mmol), potassium carbonate (16 mg,0.11 mmol), DMF (0.6 mL) and reacted at 90℃in an oil bath. After the reaction, 5mL of water was added to the reaction mixture, EA (20 mL. Times.3) was added to the mixture, the mixture was washed with water (20 mL. Times.6), saturated brine (20 mL) was added to the mixture, the mixture was dried over anhydrous sodium sulfate, the mixture was filtered, and the filtrate was concentrated and purified by silica gel column chromatography (eluent DCM/MeOH (v/v) =30:1) to give a yellow solid 10mg.LC-MS：m/z＝565.90[M+H]⁺,¹H NMR(600MHz,CDCl₃)δ8.52(d,J＝4.3Hz,1H),8.31(d,J＝2.3Hz,1H),8.18(s,1H),8.08(d,J＝1.9Hz,1H),7.66(m,2H),7.22-7.18(m,1H),7.14(d,J＝7.7Hz,1H),7.08(d,J＝1.9Hz,1H),6.77(d,J＝8.9Hz,1H),4.09(d,J＝13.1Hz,2H),3.94(d,J＝6.4Hz,2H),3.83-3.73(m,1H),3.53-3.44(m,2H),3.21(s,3H),2.95(s,2H),2.76-2.68(m,1H),2.46-2.39(m,1H),2.31-2.25(m,1H),2.24-2.20(m,1H),2.19-2.14(m,1H),1.98-1.90(m,4H),1.69-1.62(m,4H).

EXAMPLE 6- ((1, 4-dioxaspiro [4.5] dec-8-yl) oxy) -4- (6- (3- ((6-methoxypyridin-3-yl) oxy) azaspiro-1-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile

Step 1 6- (1, 4-dioxaspiro [4.5] dec-8-alkoxy) -4- (6-fluoropyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile

A25 mL single vial was charged with 4- (6-fluoro-3-pyridinyl) -6-hydroxypyrazolo [1,5-a ] pyridine-3-carbonitrile (intermediate 1,400mg,1.57 mmol), potassium carbonate (652 mg,4.72 mmol), DMF (8.0 mL), 1, 4-dioxaspiro [4.5] decane-8-methanesulfonate (example 8 step 2,560mg,2.37 mmol) and reacted at 50℃overnight. The reaction mixture was poured into 50mL of ice water, extracted with EA (100 mL. Times.3), the combined organic phases were washed with saturated brine (50 mL. Times.3), dried over anhydrous sodium sulfate, filtered, and the filtrate was dried by spin-drying, and the residue was purified by silica gel column chromatography (eluent PE/EA (v/v) =5/1-1/1) to give a white solid 78mg.LC-MS:m/z＝395.10[M+H]⁺.¹H NMR(400MHz,CDCl₃)δ8.39(d,J＝1.8Hz,1H),8.23(d,J＝1.8Hz,1H),8.21(s,1H),8.01(td,J＝8.3,2.4Hz,1H),7.17(d,J＝1.8Hz,1H),7.12(dd,J＝8.5,2.8Hz,1H),4.42(dt,J＝10.2,5.0Hz,1H),3.98(s,4H),2.03(dd,J＝11.3,5.8Hz,4H),1.96-1.87(m,2H),1.71-1.63(m,2H).

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

To a solution of 6- (1, 4-dioxaspiro [4.5] dec-8-alkoxy) -4- (6-fluoropyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile (25 mg,0.06 mmol) in DMSO (2 mL) was added 5- (azetidin-3-yloxy) -2-methoxypyridine hydrochloride (25 mg,0.14 mmol) and potassium carbonate (27 mg,0.19 mmol), 4-dimethylaminopyridine (2 mg,0.016 mmol) at room temperature and reacted overnight at 90 ℃. The reaction mixture was taken up in 10mL of water, extracted with EA (30 mL. Times.3), the combined organic phases were washed with saturated brine (30 mL. Times.2), the separated organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was dried under reduced pressure, and the residue was chromatographed on silica gel (eluent DCM/MeOH (v/v) =100/0-100/10) to give a pale yellow solid product 10mg.LC-MS:m/z＝555.20[M+H]⁺.¹H NMR(400MHz,CDCl₃)δ8.31(d,J＝2.0Hz,1H),8.19(s,1H),8.16(d,J＝1.8Hz,1H),7.70(dd,J＝8.0,2.5Hz,2H),7.19(dd,J＝9.0,3.0Hz,1H),7.09(d,J＝1.9Hz,1H),6.72(d,J＝8.8Hz,1H),6.45(d,J＝8.6Hz,1H),5.11-5.04(m,1H),4.50(dd,J＝8.8,6.2Hz,2H),4.42-4.35(m,1H),4.18(dd,J＝9.2,3.6Hz,2H),4.01-3.94(m,4H),3.90(s,3H),2.04-1.87(m,8H).

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

To a 5mL single vial was added 6- (2- (2-oxa-6-azaspiro [3.3] hept-6-yl) ethoxy) -4- (6-fluoropyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile (intermediate 3,30mg,0.080 mmo), 5- (azetidin-3-yloxy) -2-methoxypyridine hydrochloride (intermediate 4,30mg,0.14 mmole), potassium carbonate (35 mg,0.25 mmole), 4-dimethylaminopyridine (2 mg,0.016 mmole), DMSO (1 mL) and reacted at 90 ℃. After TLC detection, the reaction solution is cooled to room temperature, 5mL of water is added, EA (20 mL multiplied by 2) is extracted, an organic phase is washed with water (10 mL multiplied by 4), saturated saline water (10 mL multiplied by 2), anhydrous sodium sulfate is dried and filtered, the filtrate is dried by spin, and the residue is purified by silica gel column chromatography (eluent: EA-EA/MeOH (v/v=10/1)) to obtain light yellow solid, namely 15mg, the target product .LC-MS：m/z＝540.20[M+H]⁺.¹H NMR(400MHz,CDCl₃)δ8.30(s,1H),8.19(s,1H),8.12(s,1H),7.70(dd,J＝6.0,2.5Hz,2H),7.19(dd,J＝8.9,2.9Hz,1H),7.10(s,1H),6.73(d,J＝8.9Hz,1H),6.46(d,J＝8.7Hz,1H),5.14-5.04(m,1H),4.76(s,4H),4.55-4.46(m,2H),4.18(dd,J＝9.2,3.7Hz,2H),4.07-4.00(m,2H),3.91(s,3H),3.58(s,4H),2.91(s,2H).

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

Step 1, 4-dioxaspiro [4.5] dec-8-ol

1, 4-Cyclohexanedione monoethylene ketal (2.0 g,13 mmol) and methanol (40 mL) were added sequentially to a 100mL single-necked flask under ice-bath conditions. Sodium borohydride (1.5 g,40 mmol) was added in portions, and after the addition was completed, the mixture was returned to room temperature and stirred continuously. After 2h TLC showed the reaction was complete. The reaction mixture was concentrated to a solid, water (20 mL) was added, the mixture was extracted with EA (50 mL. Times.3), the organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and spun-dried, and the residue was purified by silica gel column chromatography (eluent DCM/EA (v/v) =5/1) to give 1.89g (yield 90%) of a colorless transparent liquid, which was the target product .¹H NMR(400MHz,CDCl₃)δ4.02-3.85(m,4H),3.84-3.73(m,1H),1.93-1.74(m,5H),1.63(ddd,J＝14.2,10.0,6.5Hz,4H).

Step 21, 4-dioxaspiro [4.5] decane-8-methanesulfonate

Under ice bath conditions, 1, 4-dioxaspiro [4.5] decan-8-ol (200 mg,1.26 mmol), methylene chloride (2 mL), triethylamine (0.27 mL,1.89 mmol) and methanesulfonyl chloride (0.13 mL,1.64 mmol) were sequentially added to a 5mL single-necked flask, and the mixture was stirred at room temperature for 2 hours after completion of the dropwise addition. TLC showed the reaction was complete. At low temperature, 30mL of water was added for dilution, dichloromethane extraction (50 mL. Times.3), the combined organic phases were washed with saturated NaHCO ₃, saturated brine, the organic phases were dried over anhydrous sodium sulfate, filtered, the mother liquor was dried by spinning, and the residue was purified by silica gel column chromatography (DCM/EA (v/v) =10/1) to give 290mg (yield 91.78%) of a pale yellow solution as the target product .¹H-NMR(400MHz,CDCl₃)δ4.90-4.78(m,1H),3.95(dd,J＝6.0,3.9Hz,4H),3.01(s,3H),2.00(dd,J＝12.2,6.8Hz,4H),1.90-1.81(m,2H),1.68-1.61(m,2H).

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

To a 5mL single vial was added 6-hydroxy-4- (6- (4-hydroxy-4- (pyridin-2-ylmethyl) piperidin-1-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile (intermediate 2,40mg,0.09 mmol), 1, 4-dioxaspiro [4.5] decane-8-methanesulfonate (65 mg,0.270 mmol), cesium carbonate (115 mg,0.35 mmol), DMA (1 mL), and reacted overnight at 60 ℃. The reaction solution was poured into 10mL of ice water, extracted with EA (30 ml×3), the combined organic phases were washed with saturated brine (20 ml×3), dried over anhydrous sodium sulfate, filtered, the filtrate was dried by spin-drying, and the residue was chromatographed on silica gel (eluent DCM/MeOH (v/v) =25/1) to give a white solid which was collected 20mg.LC-MS：m/z＝567.25[M+H]⁺.¹H NMR(400MHz,CDCl₃)δ8.52(d,J＝4.0Hz,1H),8.30(d,J＝2.3Hz,1H),8.18(s,1H),8.14(d,J＝1.8Hz,1H),7.70-7.63(m,2H),7.20(dd,J＝6.9,5.4Hz,1H),7.13(d,J＝7.7Hz,1H),7.09(d,J＝1.8Hz,1H),6.77(d,J＝8.9Hz,1H),4.38(dt,J＝9.5,4.7Hz,1H),4.12-4.05(m,2H),4.00-3.95(m,4H),3.53-3.44(m,2H),2.94(s,2H),2.04-1.98(m,4H),1.69-1.60(m,8H).

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

To a 5mL single vial was added 6- (2- (8-oxa-2-azaspiro [4.5] dec-2-yl) ethoxy) -4- (6-fluoropyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile (intermediate 6,20mg,0.047 mmol), 4- (pyridin-2-ylmethyl) piperidin-4-ol hydrochloride (intermediate 2 step2, 20mg,0.10 mmol), potassium carbonate (20 mg,0.14 mmol), 4-dimethylaminopyridine (3 mg,0.025 mmol), DMSO (1 mL), and reacted at 90℃in an oil bath. After TLC detection, the reaction solution is cooled to room temperature, 5mL of water is added, EA (20 mL multiplied by 2) is extracted, an organic phase is washed with water (10 mL multiplied by 4), saturated saline water (10 mL multiplied by 2), anhydrous sodium sulfate is dried and filtered, the filtrate is dried by spin, and the residue is purified by silica gel column chromatography (eluent DCM/MeOH (v/v) =30/1-20/1) to obtain yellow solid, namely 19mg of the product .LC-MS：m/z＝594.60[M+H]⁺.¹H NMR(400MHz,CDCl₃)δ8.52(d,J＝4.6Hz,1H),8.30(d,J＝2.3Hz,1H),8.19(s,1H),8.14(d,J＝1.9Hz,1H),7.70-7.62(m,2H),7.22-7.17(m,1H),7.13(d,J＝7.9Hz,2H),6.77(d,J＝8.9Hz,1H),4.18-4.05(m,4H),3.65(t,J＝5.2Hz,4H),3.53-3.43(m,2H),2.94(s,4H),2.75(s,2H),2.58(s,2H),1.77-1.69(m,4H),1.65-1.59(m,6H).

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

Step 1:4- ((6-methoxypyridin-3-yl) methyl) piperazine-1-carboxylic acid tert-butyl ester

To a single-necked flask was added tert-butyl piperazine-1-carboxylate (1.0 g,5.4 mmol), 6-methoxypyridine-3-carbaldehyde (800 mg,5.8335 mmol), DCE (12 mL) was added to dissolve it, acetic acid (0.3 mL,5 mmol) was added, and then sodium triacetoxyborohydride (5.7 g,27 mmol) was added while stirring, and after the addition was completed, the reaction was performed at room temperature. The reaction was carried out at room temperature for 23.5h. The reaction solution is concentrated and then purified by silica gel column chromatography (eluent PE/EA (v/v=1/1)) to obtain colorless liquid, 1.4g is the product, and the yield is high 85.0％.LC-MS:m/z＝308.25M+H]⁺.¹H NMR(400MHz,CDCl₃)δ8.06(d,J＝1.9Hz,1H),7.58(dd,J＝8.5,2.2Hz,1H),6.74(d,J＝8.5Hz,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).

Step 2:1- ((6-methoxypyridin-3-yl) methyl) piperazine dihydrochloride

In a single 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, HCl/MeOH (9 mL,36mmol,4 mol/L) was added dropwise and after the addition was complete, the reaction was carried out at room temperature for 13h. Filtering after the reaction is finished, and vacuum drying the obtained solid at 60 ℃ to obtain 600mg of white solid which is the product .LC-MS:m/z＝208.30[M-3HCl+H]⁺.¹H NMR(400MHz,DMSO)δ8.41(d,J＝1.8Hz,1H),8.04(dd,J＝8.6,2.2Hz,1H),6.91(d,J＝8.6Hz,1H),5.04(s,6H),4.38(s,2H),3.87(s,3H),3.30(s,2H).

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

To a 10mL single vial was added 6- (2- (2-oxa-6-azaspiro [3.3] hept-6-yl) ethoxy) -4- (6-fluoropyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile (intermediate 3,30mg,0.07907 mmol), 1- ((6-methoxypyridin-3-yl) methyl) piperazine hydrochloride (34 mg,0.12135 mmol), potassium carbonate (67 mg,0.48477 mmol), DMSO (1.5 mL) and reacted at 90℃for 17h in an oil bath. After the reaction was stopped, the reaction mixture was cooled to room temperature, 5mL of water was added, EA (20 mL. Times.2) was used for extraction, the organic phase was washed with water (5 mL. Times.3), saturated brine (5 mL. Times.2), dried over anhydrous sodium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure to give a silica gel column chromatography (eluent DCM-DCM/MeOH (v/v=30/1)), and 5mg of the obtained solid was the product in a yield 11.16％.LC-MS:m/z＝567.30[M+H]⁺.¹H NMR(400MHz,CDCl₃)δ8.31(d,J＝2.2Hz,1H),8.19(s,1H),8.13–8.06(m,2H),7.70(dd,J＝8.8,2.4Hz,1H),7.66–7.60(m,1H),7.09(d,J＝1.8Hz,1H),6.75(d,J＝8.3Hz,2H),4.75(s,4H),4.01(t,J＝4.9Hz,2H),3.94(s,3H),3.66(s,4H),3.56–3.48(m,6H),2.87(d,J＝4.8Hz,2H),2.57(s,4H).

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

Step 1 2- (2- ((3-cyano-4- (6-fluoropyridin-3-yl) pyrazolo [1,5-a ] pyridin-6-yl) oxy) ethoxy) -6-azaspiro [3.4] octanoic acid 6-carboxylic acid tert-butyl ester

4- (6-Fluoropyridin-3-yl) -6-hydroxypyrazolo [1,5-a ] pyridine-3-carbonitrile (intermediate 1,200mg,0.7868 mmol), K ₂CO₃ (326 mg,2.3587 mmol) and DMF (2 mL) were added to dissolve and tert-butyl 2- (2-methylsulfonyloxy ethoxy) -7-azaspiro [3.4] octane-7-carboxylate (example 3,350mg,1.002 mmol) was added and reacted at 60℃with stirring for 28h. 10mL of water was added for washing, DCM (100 mL. Times.2) was used for extraction, the organic phase was washed with 20mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried by spin-drying, followed by silica gel column chromatography (eluent pure DCM-DCM/MeOH (v/v=10/1)) to give 200mg of the title compound as a pale yellow solid in 50.08% yield. TLC showed the reaction was complete and the starting material was complete. LC-MS: m/z=452.00 [ m-56+h ] ⁺.

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

To a single vial was added, in order, tert-butyl 2- (2- ((3-cyano-4- (6-fluoropyridin-3-yl) pyrazolo [1,5-a ] pyridin-6-yl) oxy) ethoxy) -6-azaspiro [3.4] octoate (50 mg,0.09850 mmol), 5- (azetidin-3-yloxy) -2-methoxypyridine hydrochloride (intermediate 4,37.4mg,0.148 mmol), K ₂CO₃ (55 mg, 0.390995 mmol) and DMSO (2 mL), and the mixture was heated to 100℃with stirring for 14h. The reaction mixture was cooled to room temperature, quenched with water (5 mL), extracted with DCM (100 mL), the organic phase separated, dried over saturated brine (30 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and the mother liquor was dried under reduced pressure, followed by silica gel column chromatography to give 65.78mg of the title compound as a yellow oil. LC-MS: m/z=668.15 [ m+h ] ⁺.

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

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

Biological Activity test examples:

Test example 1 test of inventive Compounds for Retwt and Ret V804M kinase inhibitory Activity

1. The purpose of the experiment is as follows:

The inhibitory activity of the series of compounds on 2 kinases Ret wt, ret V804M was tested by HTRF and IC ₅₀ values were determined.

2. The experimental reagents and consumables used were as follows:

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

2)Ret wt(Invitrogen,PV3082)

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

4)MgCl₂(Sigma,M1028)

5)ATP(Promega,V910B)

6)DTT(Invitrogen,P2325)

7)DMSO(Sigma,D8418)

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

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

10)96-well polypropylene plate(Nunc,249944)

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

12)Centrifuge(Eppendorf,5810R)

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

14)Echo(Labcyte,550)

3. experimental procedure

3.1 Preparation of 1x kinase reaction buffer:

1 volume of 5 Xkinase reaction buffer and 4 volumes of water, 5mM MgCl ₂;1mM DTT;1mM MnCl₂.

3.2 Transfer of 10nl of diluted compound per well with an Echo 550 reaction plate (784075, greiner);

3.3 the reaction plate was sealed with a sealing plate membrane and centrifuged at 1000g for 1 min.

3.4 Preparation of 2X kinase with 1X enzyme reaction buffer.

3.5 Mu.l kinase (formulated in step 3) was added to each well in the reaction plate. Sealing the plate with sealing plate film, centrifuging for 30 seconds at 1000g, and standing at room temperature for 10 times

And (3) minutes.

3.6 Preparation of 4 XTK-substrate-biotin and 4 XATP with 1 Xenzyme reaction buffer, mixing well, and adding 5. Mu. l K-substrate-biotin/ATP mixture to the reaction plate.

3.7 Sealing the plates with sealing plate film 1000g and centrifuging for 30 seconds, reacting for 40 minutes at room temperature.

3.8 4 XSa-XL 665 (250 nM) was formulated in HTRF detection buffer.

3.9 Mu.l of Sa-XL 665 and 5. Mu.l of TK-anti-Cryptate were added per well and centrifuged at 1000g for 30 seconds and reacted at room temperature for 1 hour.

3.10 Fluorescence signals at 615nm (Cryptate) and 665nm (XL 665) were read with Envision 2104.

4. Data analysis

4.1 Calculating the Ratio per well (ratio_665/615 nm)

4.2 Inhibition was calculated as follows:

Average of CEP-32496 reads for all positive control wells

Mean value of DMSO well readings for all negative control wells

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

4.3 Calculation of IC ₅₀ and plotting inhibition curves for compounds:

IC ₅₀ (median inhibitory concentration) of the compounds was obtained using the following non-linear fit formula, data analysis was performed using Graphpad 6.0 software.

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

Log of compound concentration Y, inhibition (% inhibition)

5. The experimental results are shown in table 1:

TABLE 1 Experimental results of the kinase inhibitory Activity of the inventive Compounds on Ret wt, ret V804M

As shown in Table 1, the compounds of the present invention have a good inhibitory effect on Ret wt and, in addition, the compounds of the present invention have a good inhibitory effect on Ret V804M.

In the description of the present specification, the descriptions of the terms "one embodiment," "some embodiments," "some implementations," "examples," "particular examples," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, schematic representations of the above terms do not necessarily refer to the same embodiments or examples. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, the features of the different embodiments, implementations or examples and the different embodiments, implementations or examples described in this specification may be combined and combined by persons skilled in the art without contradiction.

Although embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and not to be construed as limiting the invention, and that changes, modifications, substitutions and variations may be made therein by those of ordinary skill in the art without departing from the spirit and scope of the invention, which is defined by the appended claims and their equivalents.

Claims (8)

1. A compound, which is a compound of formula (I) or a pharmaceutically acceptable salt thereof: （I）, in, X ¹ is N; X ² , X ³ , X ⁴ and X ⁵ are each independently CR ⁴ ; Y is O; T is a bond, C _1-6 alkylene or C _1-6 alkylene-O-; Ring G is the following substructure: , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ; each ^Ra is independently D, OH, _NH2 , F, _CF3 , Cl, Br, I, CN, _NH2 , _NHCH3 , methyl, ethyl, propyl, butyl, methoxy, ethoxy, methoxymethyl, methoxyethyl, ethoxymethyl, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 2-hydroxypropyl or 2-hydroxy-2-methylpropyl; E is a key; Ring A is the following substructure: , , , , , , ,or , wherein the N-connected end of each subformula of Ring A is connected to E, and the other connecting end is connected to Q, and each subformula of Ring A is independently and optionally substituted with 1, 2, 3 or 4 substituents selected from F, Cl, Br, OH, NH ₂ , NHCH ₃ , methyl, ethyl, n-propyl, methoxy, ethoxy, isopropoxy, CF ₃ , hydroxymethyl and 2-hydroxyethyl; Q is -O-, -CH ₂ - or -(CH ₂ ) ₂ -; M is a 5-10 membered heteroaryl group; and M is optionally substituted by 1, 2, 3 or 4 substituents selected from D, F, Cl, CN, OH, CF ₃ , NR ⁵ R ⁶ , C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 haloalkoxy and C _1-6 alkoxyC _1-6 alkyl; ^R1 is CN; Each R ⁴ is independently H or D; Each R ⁵ is independently H, D or C _1-6 alkyl; Each R ⁶ is independently H, D, C _1-6 alkyl or C _1-6 alkoxyC _1-6 alkyl, wherein the C _1-6 alkyl and C _1-6 alkoxyC _1-6 alkyl are each independently optionally substituted with 1, 2, 3 or 4 substituents selected from F, Cl, Br, CN, NH ₂ , OH and NO ₂ . 2. The compound according to claim 1, wherein T is a bond, _-CH2- , -( _CH2 ) _2- , -(CH2) _{3-, -(CH2)4- , -} ( _CH2 ) _5- , -( _CH2 ) _6- , -( _CH2 )-O-, -( _{CH2 ) 2} -O-, or -( _CH2 ) ₃ -O-. 3. The compound according to claim 1, wherein M is pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl or pyrazinyl; and M is optionally substituted with 1, 2, 3 or 4 substituents selected from D, F, Cl, CN, OH, _CF3 , _NH2 , _NHCH3 , N( _CH3 ) ₂ , trifluoromethoxy, 2,2,2-trifluoroethoxy, methoxy, ethoxy, isopropoxy, tert-butoxy, methyl, ethyl, n-propyl, isopropyl, methoxymethyl, hydroxymethyl and methoxyethyl. 4. The compound according to claim 1 is a compound represented by formula (I-1) or (I-2) or a pharmaceutically acceptable salt thereof: or in, The substructure is as follows: , , , , , , ,or ,and Each subformula of is independently optionally substituted with 1, 2, 3 or 4 substituents selected from F, Cl, Br, _OH , NH2, _NHCH3 , methyl, ethyl, n-propyl, methoxy, ethoxy, isopropoxy, _CF3 , hydroxymethyl and 2-hydroxyethyl; and ^Ma is pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl or pyrazinyl, and ^Ma is optionally substituted with 1, 2, 3 or 4 substituents selected from D, F, Cl, CN, OH, _CF3 , CHCl2, _CHF2 , _CH2F , _CF3CH2 , _NH2 , _NHCH3 , N( _CH3 ) ₂ , trifluoromethoxy, _{2,2,2 -} trifluoroethoxy, methoxy, ethoxy, isopropoxy, tert-butoxy, methyl, ethyl, n-propyl, isopropyl, methoxymethyl, hydroxymethyl and methoxyethyl. 5. A compound having one of the following structures, or a pharmaceutically acceptable salt thereof, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or . 6. A pharmaceutical composition comprising the compound according to any one of claims 1 to 5, and a pharmaceutically acceptable adjuvant. 7. Use of the compound according to any one of claims 1 to 5 or the pharmaceutical composition according to claim 6 in the preparation of a medicament for preventing or treating RET-related diseases. 8. The use according to claim 7, wherein the RET-related disease is cancer, irritable bowel syndrome and/or pain associated with irritable bowel syndrome.