CN112574235A - RET inhibitor, pharmaceutical composition and application thereof - Google Patents

Abstract

The invention belongs to the field of medicine, and relates to a RET inhibitor, a pharmaceutical composition thereof and the use thereof. Specifically, the present invention relates to a compound represented by formula (I), or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, solvate, metabolite of the compound represented by formula (I) Products, pharmaceutically acceptable salts or prodrugs, the present invention also relates to pharmaceutical compositions comprising said compounds, and the use of said compounds and pharmaceutical compositions thereof in the manufacture of medicaments, especially for the treatment and Prevention of RET-related diseases and disorders, including cancer, irritable bowel syndrome, and/or pain associated with irritable bowel syndrome.

Description

A kind of RET inhibitor, its pharmaceutical composition and use thereof

technical field

The present invention belongs to the field of medicine, and in particular, the present invention relates to a novel compound exhibiting inhibition of transfection phase rearrangement (RET) kinase, a pharmaceutical composition comprising the compound, the use of the compound or its pharmaceutical composition in the preparation of medicine, the The drugs are particularly useful 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 technique

Re-arranged during transfection (RET) is one of the receptor-type tyrosine kinases belonging to the cadherin superfamily, which activates multiple downstream pathways involved in cell proliferation and survival.

The results of abnormal production of the RET gene (point mutation, chromosomal translocation, chromosomal inversion, gene amplification) have been reported to be involved in carcinogenesis. RET fusion proteins are associated with several cancers, including papillary thyroid cancer and non-small cell lung cancer. The identification of RET fusion proteins as a driver of certain cancers has prompted the use of multikinase inhibitors with RET inhibitory activity to treat patients whose tumors express RET fusion proteins. It has been reported that sorafenib, sunitinib, vandetanib, ponatinib and other multi-kinase inhibitors exhibited cell proliferation inhibition on cell lines expressing KIF5B-RET (J Clin Oncol 30, 2012 , suppl; Abstract no: 7510). In addition, it was reported that the multikinase inhibitor cabozantinib showed partial efficacy in two RET fusion gene-positive non-small cell lung cancer patients (Cancer Discov, 3(6), Jun 2013, p.630-5). However, these drugs cannot always be administered at levels sufficient to inhibit RET due to toxicity due to inhibition of targets other than RET. Furthermore, one of the biggest challenges in treating cancer is the ability of tumor cells to become resistant to treatment. Kinase reactivation via mutation is a common resistance mechanism. When resistance develops, patients often have very limited treatment options, and in most cases cancer progression is unchecked. WO 2017011776 discloses a single-target RET kinase inhibitor, which has a good preventive or therapeutic effect on RET and its mutation-related cancers. There is still a need to further develop compounds that inhibit RET and its resistant mutants to deal with cancers associated with abnormal RET genes.

SUMMARY OF THE INVENTION

The present invention provides a new compound exhibiting the inhibition of transfection phase rearrangement (RET) kinase, the compound has good inhibitory effect on RET wild type and RET gene mutant, and has better inhibitory effect on RET wild type and RET gene mutant Good inhibitory selectivity.

The excellent properties of certain parameters of the compounds of the present invention, such as half-life, clearance rate, selectivity, bioavailability, chemical stability, metabolic stability, membrane permeability, solubility, etc., can promote the reduction of side effects, the treatment of Expansion of the index or improvement of tolerance, etc.

In one aspect, the present invention provides a compound represented by formula (I), or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, solvate, metabolites, pharmaceutically acceptable salts or prodrugs,

in,

X ¹ , X ² , X ³ , X ⁴ and X ⁵ are each independently CR ⁴ or N;

Y is O, NH or S;

T is a bond, alkylene, alkylene-O-, alkylene-O-alkylene, or alkylene-NH-, and said T is optionally selected from 1, 2, 3, or 4 From D, OH, F, Cl, Br, I, CN, _NH2 , alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, heterocyclyl, alkoxy, aryl, heteroaryl or alkylamino substituted by the substituent;

Ring G is bridged carbocyclyl or bridged heterocyclyl;

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

R ^a is D, OH, NH ₂ , F, Cl, Br, I, CN, NR ⁵ R ⁶ , OR ⁷ , -NR ⁶ C(=O)R ⁷ , -S(=O) ₂ R ⁷ , - S(=O)R ⁷ , -C(=O)R ⁷ , -C(=O)OR ⁷ , oxo, alkyl, alkoxy, cycloalkyl, haloalkyl, alkoxyalkyl or hydroxy alkyl;

E is a bond, -NR ⁶ - or -O-;

Ring A is a bridged cyclylene, a biocyclylene, or a spirocyclylene, and Ring A is optionally surrounded by 1, ² , 3, or 4 selected from F, Cl, Br, OH, oxo, ^NR5R6 , R ⁵ (C=O)NR ⁶ -, aminoalkyl, alkyl, alkoxy, haloalkyl, hydroxyalkyl, carbocyclyl, heterocyclyl, heterocyclylalkyl, alkoxyalkyl, Substituted by cycloalkylene and heterocycloalkylene substituents;

Q is a bond, -(CR ² R ³ ) _t O-, -(CR ² R ³ ) _f -, -(CR ² R ³ ) _t -NR ⁶ -, -(C=O)(CR ² R ³ ) _t -, -(C=O)(CR ² R ³ ) _t -(S=O) ₂ (CR ² R ³ ) _f -, -(C=O)(CR ² R ³ ) _t -NR ⁶ ( CR ² R ³ ) _f -, -(C=O)(CR ² R ³ ) _t -O(CR ² R ³ ) _f -, -(C=O)NR ⁶ O(CR ² R ³ ) _f -, -(S ⁼ O) ₂ ^{- NR6-} ( ^CR2R3 ) _t -,-( ^CR2R3 ) _f- (C=O)-,-( ^CR2R3 ) _t- (C ⁼ O) -NR ⁶ -(CR ² R ³ ) _t -, -(S=O) ₂ (CR ² R ³ ) _t -, -(CR ² R ³ ) _f -(S=O) ₂ (CR ² R ³ ) _t- , -(S=O) ₂ O-, -O(C=O)-, -(C=O)NR ⁶ - 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 composed of 1, 2, 3, or 4 selected from D, F, Cl, CN, OH, ^{NR5R 6} , OR ⁷ , substituted by substituents of alkyl, haloalkyl, hydroxyalkyl, haloalkoxy, aryl, alkoxyalkyl, oxo, alkylacyl, heterocyclyl and cycloalkyl;

R ¹ is H, D, CN, F, Cl, Br, alkyl or cycloalkyl, wherein said alkyl and cycloalkyl can be independently optionally selected by 1, 2, 3 or 4 selected from F, Substituents of Cl, Br, CN, NH ₂ , OH and NO ₂ are substituted;

Each R2 and ^R3 is independently OH, F, H, D, CN, Cl, Br, ^NH2 , _hydroxyalkyl , alkyl, alkylamino, alkoxy, haloalkoxy, cycloalkyl, haloalkoxy radical, cycloalkylalkyl, aryl or heteroaryl;

Or, R ² , R ³ and the same C atom connected to it form a carbocyclic or heterocyclic ring;

R ⁴ is H, D, F, Cl, Br, alkyl or alkoxy, wherein said alkyl and alkoxy are each independently optionally selected from F, Cl, Substituents of Br, CN, NH ₂ , OH and NO ₂ are substituted;

R ⁵ is H, D, alkyl, carbocyclyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, carbocyclyl, heterocyclyl, aryl and heteroaryl are each independently optional is substituted with 1, 2, 3 or 4 substituents selected from F, Cl, Br, OH, _NH2 , alkylamino, alkyl, alkylsulfonyl, alkoxy, aryl and heteroaryl ;

R ⁶ is H, D, alkyl or alkoxyalkyl, wherein each of said alkyl and alkoxyalkyl is independently optionally 1, 2, 3 or 4 selected from F, Cl, Br, CN , NH ₂ , OH and NO ₂ substituents;

^R7 is OH, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl.

In some embodiments, T is a bond, C _1-6 alkylene, C _1-6 alkylene-O-, C _1-6 alkylene-OC _1-6 alkylene, or C _1-6 alkylene alkylene-NH-, and T is optionally selected by 1, 2, 3, or 4 selected from D, OH, F, Cl, Br, I, CN, _NH2 , _C1-6 alkyl, _{C1- 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 substituents.

In some embodiments, T is a bond, _-CH2- , -( _CH2 ) _2- , -( _CH2 ) _3- , -( _CH2 ) _4- , -( _CH2 ) _5- , -( CH ₂ ) ₆ -, -(CH ₂ ) ₂ -O-, -(CH ₂ ) ₂ -O-CH ₂ - or -(CH ₂ ) ₂ -NH-, and the T is optionally separated by 1, 2 , 3 or 4 selected from D, OH, F, Cl, Br, I, CN, NH ₂ , CF ₃ , CHF ₂ , CHCl ₂ , methyl, ethyl, propyl, 2-hydroxyethyl, 1- Hydroxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, methoxy, ethoxy, propoxy substituted with substituents of phenyl, butoxy, phenyl, methylamino and dimethylamino.

In some embodiments,

Ring G is a 6-12-membered bridged carbocyclyl or a 6-12-membered bridged heterocyclyl;

R ^a is D, OH, NH ₂ , F, Cl, Br, I, CN, NR ⁵ R ⁶ , OR ⁷ , -NR ⁶ C(=O)R ⁷ , -S(=O) ₂ R ⁷ , - S(=O)R ⁷ , -C(=O)R ⁷ , -C(=O)OR ⁷ , oxo, C _1-6 alkyl, C _1-6 alkoxy, C _3-7 cycloalkane group, C _1-6 haloalkyl, 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 -membered aryl or 5-10-membered heteroaryl, wherein the C _1-6 alkyl, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl, _C6-10 membered aryl and 5-10 membered heteroaryl are each independently optionally substituted by 1, 2, 3 or 4 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 substituted by substituents of 5-10-membered heteroaryl groups;

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 The groups are each independently optionally substituted with 1, ₂ , 3 or 4 substituents selected from F, Cl, Br, CN, _NH2 , OH and NO2;

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

In some embodiments, Ring G is of the following substructure:

其中，

in,

each Z1 is independently CH or N ^; and

Each Z2 is independently ^CH2 , C=O, NH, O, S, S=(O) or S=(O _{)2- .}

In some embodiments, Ring G is of the following substructure:

^Ra is D, OH, _NH2 , F, _CF3 , _CHCl2 , _CHF2 , _CH2F , _CF3CH2 , Cl, Br, I, CN, _NH2 , _NHCH3 , N( _{CH3 ) 2} , -NHC(=O)CH ₃ , -S(=O) ₂ CH ₃ , -S(=O)CH ₃ , -C(=O)CH ₃ , -C(=O)OH, -C(= O)OC( _CH3 ) ₃ , oxo, methyl, ethyl, propyl, butyl, methoxy, ethoxy, cyclopropyl, cyclopentyl, methoxymethyl, ethoxymethyl group, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 2-hydroxypropyl, 2-hydroxy-2-methylpropyl;

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

R ⁶ is H, D, methyl, ethyl, n-propyl, n-butyl, methoxymethyl, ethoxymethyl or methoxyethyl, wherein the methyl, ethyl, n-propyl group, n-butyl, methoxymethyl, ethoxymethyl, and methoxyethyl are each independently optionally 1, 2, 3, or 4 selected from F, Cl, Br, CN, _NH2 , Substituents of OH and NO ₂ are substituted;

^R7 is OH, methyl, ethyl, _NH2 , N( _CH3 ) ₂ , methyl, isopropyl, tert-butyl, cyclopropyl or phenyl.

In some embodiments, Ring A is a 5-12 membered bridged cyclylene group, a 5-12 membered piocyclylene group, or a 5-12 membered spirocyclylene group, and Ring A is optionally surrounded by 1, 2, 3, or 4 selected from F, Cl, Br, OH, oxo, NR ⁵ R ⁶ , R ⁵ (C=O)NR ⁶ -, amino C _1-6 alkyl, C _1-6 alkyl, C _1-6 alkane Oxygen, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, 3-12-membered carbocyclyl, 3-12-membered heterocyclyl, 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 substituents.

In some embodiments, Ring A is of the following substructure:

wherein each Z ^1a and Z ^2a is independently CH ₂ or NH;

each of Z ^3a and Z ^7a is independently CH or N;

Z ^4a is O, S or NH;

each Z ^5a and Z ^6a is independently CH ₂ , O, S, S(=O), S(=O) ₂ , C(=O) or NH;

each of m and t is independently 0, 1 or 2;

each of n and t1 is independently 0 or 1;

wherein each substructure of Ring A is independently optionally replaced by 1, 2, 3 or 4 selected from F, ^Cl , Br, OH, oxo, ^NR5R6 , ^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 heteroalkyl Cyclyl, 3-12-membered heterocyclyl C _1-4 alkyl, C _1-4 alkoxy C _1-4 alkyl, C _3-6 cycloalkylene and 3-6 membered heterocycloalkylene Substituents are substituted.

In some embodiments, Ring A is of the following substructure:

wherein each sub-formula of Ring A is independently optionally replaced by 1, 2, 3 or 4 selected from F, Cl, Br, OH, oxo, _NH2 , _NHCH3 , _CH3 (C=O)NH-, methyl , ethyl, n-propyl, methoxy, ethoxy, isopropoxy, CF ₃ , hydroxymethyl, 2-hydroxyethyl, cyclopropyl, cyclohexyl, pyrrolidinyl, piperidinyl, Substituents of tetrahydrofuranyl, cyclopropylene, cyclohexylene and pyrrolidylene.

In some embodiments, M is H, D, 5-10 membered heteroaryl, _C6-10 aryl, _C3-7 cycloalkyl, or 3-12 membered heterocyclyl; and M is optionally 1 , 2, 3 or 4 are selected from D, F, Cl, CN, OH, NR ⁵ R ⁶ , OR ⁷ , C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 haloalkoxy, C _6-10 aryl, C _1-6 alkoxy, C _1-6 alkyl, oxo, C _1-6 alkyl acyl, 3-7 membered heterocyclyl and C _{3- 7} cycloalkyl substituents are substituted.

In some embodiments, M is H, D, pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, pyrazinyl, phenyl, cyclopentyl, cyclopropyl, cyclo Hexyl, cyclobutyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, morpholinyl, tetrahydrothiopyranyl, oxetanyl, 1,2-dihydro Pyridyl, 7-azabicyclo[2.2.1]heptyl, hexahydrofuro[3,4-c]pyrrolyl, 3-azabicyclo[3.1.0]hexyl, octahydropyrrolo[ 1,2-a]pyrazinyl or 5-azaspiro[2.4]heptyl; and M is optionally 1, 2, 3 or 4 selected from D, F, Cl, CN, OH, CF ₃ , CHCl ₂ , CHF ₂ , CH ₂ F, CF ₃ CH ₂ , NH ₂ , NHCH ₃ , N(CH ₃ ) ₂ , trifluoromethoxy, 2,2,2-trifluoroethoxy, methoxy , ethoxy, isopropoxy, tert-butoxy, methyl, ethyl, n-propyl, isopropyl, phenyl, methoxymethyl, methoxyethyl, oxo, formyl, substituted by substituents of acetyl, morpholinyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, cyclopropyl and cyclohexyl;

In some embodiments, R ¹ is H, D, CN, F, Cl, Br, methyl, ethyl, or cyclopropyl, wherein said methyl, ethyl, and cyclopropyl are independently optionally 1, ₂ , 3 or 4 substituents selected from F, Cl, Br, CN, _NH2 , OH and NO2;

R ⁴ is H, D, F, Cl, Br, methyl, ethyl, n-propyl, methoxy or ethoxy, wherein said methyl, ethyl, n-propyl, methoxy and ethyl The oxy groups can be independently optionally substituted with 1, ₂ , 3 or 4 substituents selected from F, Cl, Br, CN, _NH2 , OH and NO2.

In some embodiments, each R ² and R ³ is independently OH, F, H, D, CN, Cl, Br, NH ₂ , C _1-6 hydroxyalkyl, C _1-6 alkyl, C _{1- 6} alkylamino, C _1-6 alkoxy, C _1-6 haloalkoxy, C _3-7 cycloalkyl, C _1-6 haloalkyl, C _3-7 cycloalkyl, C _1-6 alkyl, C _6-10 aryl or 5-10 membered heteroaryl;

Alternatively, R ² , R ³ and the same carbon 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 and R ³ is independently OH, F, CF ₃ , CHCl ₂ , CHF ₂ , H, D, CN, Cl, Br, NH ₂ , hydroxymethyl, 2-hydroxyethyl , 1-hydroxyethyl, methyl, ethyl, N(CH ₃ ) ₂ , methoxy, ethoxy, isopropoxy, tert-butoxy, trifluoromethoxy, cyclopropyl, cyclopentyl cyclopropylmethyl, cyclopentylethyl, cyclopentylmethyl, phenyl, pyridyl or pyrazinyl;

^{Alternatively} , R2, ^R3 and the same carbon atom to which they are attached form cyclopentane, cyclopropane, cyclobutane, tetrahydropyran, tetrahydrofuran, piperidine or pyrrolidine.

In some embodiments, Q is a bond, -O-, -( _CH2 )2O-, _-CH2- , -( _CH2 ) _2- , -( _{CH2 ) 3-} , -CH2CH ₍ CH ₃ )CH ₂ -, -CH ₂ CH(CH ₃ )CH ₂ NHCH ₂ -, -(C=O)OC(CH ₃ ) ₂ CH ₂ -, -(C=O)(CH ₂ ) ₂ (S =O) ₂ CH ₂ -, -(C=O)CH(OH)-, -(C=O)CH(OH)CH ₂ -, -(C=O)-, -(S=O) ₂ - , -(C=O)CH ₂ CH(OH)-, -(C=O)CH ₂ -, -(C=O)CH(CH ₂ OH)-, -(C=O)C(CH ₃ ) ₂ -, -(C=O)CH ₂ NHC(CH ₃ ) ₂ CH ₂ -, -(C=O)CH ₂ CH(N(CH ₃ ) ₂ )-, -(C=O)(CH ₂ ) ₂ N(CH ₃ )CH ₂ -, -(C=O)C(CH ₃ ) ₂ CH ₂ -, -(C=O)C(OH)(CH ₃ )CH ₂ -, -(C=O) CH ₂ OCH ₂ -, -(C=O)(CH ₂ ) ₃ -, -(C=O)CH(NH ₂ )-, -(C=O)(CH ₂ ) ₃ N(CH ₃ )CH ₂ -, -(C=O)( _CH2 ) _2- , -(C=O)CH2CH(OH)CH2-, _- (C=O) _CF2CH2- , _- (C=O) _CH (OH)C(CH ₃ ) ₂ CH ₂ -, -(C=O)CH ₂ C(CH ₃ ) ₂ CH ₂ -, -(C=O)CH ₂ C(CH ₃ )(OH)CH ₂ - , -(S=O) ₂ CH ₂ -, -(S=O) ₂ CH ₂ C(CH ₃ ) ₂ CH ₂ -, -(C=O)CH(OCH ₃ )-, -(C=O) NHCH(CH ₂ OH)(CH ₂ ) ₂ -, -(C=O)NH-, -(C=O)N(CH ₃ )-, -(C=O)N(CH ₂ CH ₂ CH ₂ CH ₃ )-, -(C=O)N(CH ₂ CH ₃ )(CH ₂ ) ₂ -, -(C=O)NHC(CH ₃ ) ₂ CH ₂ -, -(C=O)N(CH ₃ )(CH ₂ ) ₂ -, -(C=O)NHCH ₂ CH(CH ₃ )CH ₂ -, -(C=O)NHCH ₂ -, -(C=O)NH(CH ₂ ) ₂ OCH ₂ - , -(C=O)N(CH ₃ )(CH ₂ ) ₂ OCH ₂ -, -(S=O) ₂ NHC(CH ₃ ) ₂ CH ₂ -, -CH ₂ CH(OH)C(CH ₃ ) ₂ CH ₂ -, -CH(CH ₃ )CH(OH)-, -CH ₂ (C=O)NHCH(CH ₃ )CH ₂ -, -CH ₂ (C=O)-, -(CH ₂ ) ₂ (C=O)N(CH ₃ )CH ₂ -, -CH ₂ CH(OH)-, -CH ₂ CH(OH)CH ₂ -, -CH ₂ CH(OH)CH(CH ₃ )CH ₂ -, -(C=O)CH(N(CH ₃ ) ₂ )-, -(C=O)C(CH ₃ ) ₂ CH ₂ OCH ₂ -, -(C=O)C(OCH ₃ )(CF ₃ )-, -(CH ₂ ) ₃ S(=O) ₂ CH(CH ₃ ) CH ₂ -, -(C=O)N(CH ₂ CH ₂ OCH ₃ )CH ₂ CH(OCH ₃ )-, -CH ₂ CH(OCF ₃ )-, -CH ₂ CH(OCH(CH ₃ ) ₂ )-, -CH ₂ CH(OC(CH ₃ ) ₃ )-, -CH ₂ CF ₂ -, -CH(CH ₃ )-, -CH ₂ CH(OCH ₃ )C(CH ₃ ) ₂ -, - CH ₂ CH(N(CH ₃ ) ₂ )-, -NH-, -(C=O)NHOCH ₂ -, -(C=O)NHOCH ₂ (CHOH)-, -(S=O) ₂ (CH ₂ CH ₃ )-, -(S=O) ₂ O-, -(S=O) ₂ -NHC(CH ₃ ) ₂ -, -(CH ₂ ) ₂ (S=O) ₂ -,

In some embodiments, the compounds of the present invention have the structure of formula (I-1), or a stereoisomer, geometric isomer, tautomer, nitrogen oxide of the structure of formula (I-1) , solvates, metabolites, pharmaceutically acceptable salts or prodrugs,

in,

Ring A1 is the following substructure:

wherein each Z ^1a and Z ^2a is independently CH ₂ or NH;

And each substructure of ring A1 is independently optionally 1, 2, 3 or 4 selected from F, Cl, Br, OH, oxo, NR ⁵ R ⁶ , R ⁵ (C=O)NR ⁶ -, amino C _1-4 alkyl, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _1-4 hydroxyalkyl, 3-12-membered carbocyclyl, 3-12-membered heteroalkyl Cyclyl, 3-12-membered heterocyclyl C _1-4 alkyl, C _1-4 alkoxy C _1-4 alkyl, C _3-6 cycloalkylene and 3-6 membered heterocycloalkylene Substituents are substituted.

In some embodiments, Ring A1 is of the substructural formula:

wherein each sub-formula of Ring A1 is independently optionally replaced by 1, 2, 3 or 4 selected from F, Cl, Br, OH, oxo, NH ₂ , NHCH ₃ , CH ₃ (C=O)NH-, methyl , ethyl, n-propyl, methoxy, ethoxy, isopropoxy, CF ₃ , hydroxymethyl, 2-hydroxyethyl, cyclopropyl, cyclohexyl, pyrrolidinyl, piperidinyl, Substituents of tetrahydrofuranyl, cyclopropylene, cyclohexylene and pyrrolidylene.

In some embodiments, the compounds of the present invention have the structure of formula (I-3) or (I-4), or a stereoisomer, geometric isomeric form of the structure of formula (I-3) or (I-4) isomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs,

wherein each of Z ¹ , Z ² , Z ^3a and Z ^7a is independently CH or N;

each of m and t is independently 0, 1 or 2;

each of n and t1 is independently 0 or 1;

独立任选地被1、2、3或4个选自F、Cl、Br、OH、氧代、NR⁵R⁶、R⁵(C＝O)NR⁶-、氨基C_1-4烷基、C_1-4烷基、C_1-4烷氧基、C_1-4卤代烷基、C_1-4羟基烷基、3-12元碳环基、3-12元杂环基、3-12元杂环基C_1-4烷基、C_1-4烷氧基C_1-4烷基、C_3-6亚环烷基和3-6元亚杂环烷基的取代基所取代。each of them

independently optionally replaced by 1, 2, 3 or 4 selected from F, Cl, Br, OH, oxo, NR ⁵ R ⁶ , R ⁵ (C=O)NR ⁶ -, amino C _1-4 alkyl, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _1-4 hydroxyalkyl, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl, 3-12 membered Substituents of heterocyclyl C _1-4 alkyl, C _1-4 alkoxy C _1-4 alkyl, C _3-6 cycloalkylene and 3-6 membered heterocycloalkylene.

为以下子结构式：In some embodiments,

is the following substructure:

为以下子结构式：

is the following substructure:

的各子结构式独立任选地被1、2、3或4个选自F、Cl、Br、OH、氧代、NH₂、NHCH₃、CH₃(C＝O)NH-、甲基、乙基、正丙基、甲氧基、乙氧基、异丙氧基、CF₃、羟基甲基、2-羟基乙基、环丙基、环己基、吡咯烷基、哌啶基、四氢呋喃基、亚环丙基、亚环己基和亚吡咯烷基的取代基所取代。in

Each substructure of is independently optionally replaced by 1, 2, 3 or 4 selected from F, Cl, Br, OH, oxo, NH ₂ , NHCH ₃ , CH ₃ (C=O)NH-, methyl, ethyl , n-propyl, methoxy, ethoxy, isopropoxy, CF ₃ , hydroxymethyl, 2-hydroxyethyl, cyclopropyl, cyclohexyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, Substituents of cyclopropylene, cyclohexylene and pyrrolidylene.

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

On the other hand, the present invention also provides the use of the compound of the present invention or the pharmaceutical composition of the present invention in the preparation of a 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.

On the other hand, the present invention also provides the compound of the present invention or the pharmaceutical composition of the present invention 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 present invention also provides a method for preventing or treating a RET-related disease, the method comprising administering to a patient a therapeutically effective amount of the compound of the present 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 the preparation of 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 represented by formula (I), (I-1), (I-2) or (I-3).

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

Unless otherwise indicated, all stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, salts and pharmaceutically acceptable prodrugs of the compounds of the present invention are belong to the scope of the present invention.

Specifically, the salts are pharmaceutically acceptable salts. The term "pharmaceutically acceptable" includes substances or compositions that must be chemically or toxicologically suitable in relation to the other components that make up the formulation and the mammal for which it is to be treated.

The salts of the compounds of the present invention also include intermediates for preparing or purifying the compounds represented by formula (I), (I-1), (I-2) or (I-3) or formulas (I), (I- Salts of the separated enantiomers of the compounds represented by 1), (I-2) or (I-3), but not necessarily pharmaceutically acceptable salts.

Detailed Description of the Invention

Definitions and General Terms

Certain embodiments of the invention will now be described in detail, examples of which are illustrated by the accompanying structural and chemical formulae. The present invention is intended to cover all alternatives, modifications and equivalents, which are included within the scope of the present invention as defined by the claims. One skilled in the art will recognize that many methods and materials similar or equivalent to those described herein could be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated literature, patents, and similar materials differs from or contradicts this application (including, but not limited to, terms defined, uses of terms, techniques described, etc.), this Application shall prevail.

It should further be appreciated that certain features of the invention, which are, for clarity, described in the context of multiple separate embodiments, can 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, can also be provided separately or in any suitable subcombination.

Unless otherwise defined, 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 "subject" as used herein refers to an animal. Typically the animal is a mammal. A subject, for example, also refers to primates (eg, humans, male or female), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, and the like. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.

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

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

"Stereoisomers" refer to compounds that have the same chemical structure, but differ in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis/trans), atropisomers, etc. .

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 mixtures of any stereoisomers may be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers on the basis of differences in the physicochemical properties of the components, for example, by chromatography and/or fractional crystallization.

The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are interconvertible through a low energy barrier. A chemical equilibrium of tautomers can be achieved if tautomerism is possible (eg, in solution). For example, protontautomers (also known as prototropic tautomers) include interconversions by migration of protons, such as keto-enol isomerization and imine-ene Amine isomerization. Valence tautomers include interconversions by recombination of some of the bonding electrons. A specific example of keto-enol tautomerism is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerism is phenol-ketone tautomerism. A 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 present invention are within the scope of the present invention.

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

Unless otherwise indicated, the structural formulas described herein and the compounds described include all isomeric forms (such as enantiomers, diastereomers, geometric or conformational isomers), nitrogen oxides, Hydrates, solvates, metabolites, pharmaceutically acceptable salts and prodrugs. Thus, individual stereochemical isomers, enantiomers, diastereomers, geometric isomers, conformers, nitrogen oxides, hydrates, solvates, metabolites, Pharmaceutically acceptable salts and prodrugs of the compounds are also within the scope of the present invention. Additionally, unless otherwise indicated, the structural formulae of the compounds described herein include enriched isotopes of one or more different atoms.

As described herein, the compounds of the present invention may be independently optionally substituted with one or more substituents, such as the compounds of the general formula above, or as in the Examples, subclasses, and subclasses encompassed by the present invention. a class of compounds. 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 have been replaced with a specified substituent. Unless otherwise indicated, an optional substituent group may be substituted at each substitutable position of the group. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, the substituents can be substituted identically or differently at each position.

In addition, it should be noted that, unless clearly stated otherwise, the description modes "each independently" and "...independently" and "...independently" used in the present invention can be interchanged, and both are interchangeable. It should be understood in a broad sense. It can either mean that in different groups, the specific options expressed between the same symbols do not affect each other, or it can mean that in the same group, the specific options expressed between the same symbols do not affect each other.

In various parts of this specification, the substituents of the compounds disclosed in the present invention are disclosed in terms of group type or scope. Specifically, the present invention includes each and every independent subcombination of each member of these group species and ranges. For example, the term " _C1-6 alkyl" specifically refers to the independently disclosed methyl, ethyl, C3 alkyl, _C4 alkyl, _C5 alkyl and _C6 alkyl groups _.

In various parts of the present invention, linking substituents are described. When the structure clearly requires a linking group, the Markush variables listed for that group should be understood to be the linking group. For example, if the structure requires a linking group and the Markush group definition for that variable recites "alkyl" or "aryl", it should be understood that the "alkyl" or "aryl" respectively represents the linking An alkylene group or an arylene group.

The term "alkyl" refers to a saturated straight or branched chain monovalent hydrocarbon group containing 1 to 20 carbon atoms, wherein the alkyl group may be optionally substituted by one or more substituents described herein replaced. Unless otherwise specified, alkyl groups contain 1-20 carbon atoms. In one embodiment, the alkyl group contains 1-12 carbon atoms; in another embodiment, the alkyl group contains 1-6 carbon atoms; in yet another embodiment, the alkyl group contains 1 -4 carbon atoms; in yet another embodiment, the alkyl group contains 1-3 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me, _-CH3 ), ethyl (Et, -CH2CH3), n _{- propyl} (n _- Pr, _{-CH2CH2CH3 )} ), isopropyl (i-Pr, -CH(CH ₃ ) ₂ ), n-butyl (n-Bu, -CH ₂ CH ₂ CH ₂ CH ₃ ), isobutyl (i-Bu, -CH ₂ CH ) (CH ₃ ) ₂ ), sec-butyl (s-Bu, -CH(CH ₃ )CH ₂ CH ₃ ), tert-butyl (t-Bu, -C(CH ₃ ) ₃ ), n-pentyl (-CH 2CH2CH2CH2CH3), ₂ -pentyl (-CH( _{CH3 ) CH2CH2CH3 )} , _{3 -} pentyl (-CH( _{CH2CH3 ) 2 )} , ₂ -methyl -2-butyl(-C(CH3)2CH2CH3), ₃ -methyl- _{2-butyl(-CH(CH3)CH(CH3)2 ) , 3 - methyl} -1- Butyl ( _-CH2CH2CH ( _CH3 ) ₂ ), ₂ -methyl- ₁ -butyl (-CH2CH( _CH3 ) _{CH2CH3 )} , n _- hexyl _{( -CH2CH2CH2 CH2CH2CH3} ), ₂ -hexyl (-CH( _CH3 ) _{CH2CH2CH2CH3 )} , _{3 -} hexyl (-CH( _{CH2CH3 ) ( CH2CH2CH3 ) )} , 2-methyl-2-pentyl(-C( _CH3 )2CH2CH2CH3), ₃ -methyl- ₂ -pentyl(-CH( _{CH3 ) CH} ( _{CH3 ) CH2CH3} ), 4-methyl-2-pentyl (-CH(CH ₃ )CH ₂ CH(CH ₃ ) ₂ ), 3-methyl-3-pentyl (-C(CH ₃ )(CH ₂ CH ₃ ) ₂ ), 2-methyl-3-pentyl (-CH(CH ₂ CH ₃ )CH(CH ₃ ) ₂ ), 2,3-dimethyl-2-butyl (-C(CH ₃ ) ₂ CH (CH ₃ ) ₂ ), 3,3-dimethyl-2-butyl (-CH(CH ₃ )C(CH ₃ ) ₃ ), n-heptyl, n-octyl, and the like.

When an alkyl group is the linking group, and "alkyl" is recited for that Markush group definition, then "alkyl" represents the attached alkylene group.

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

The term "alkylene-O-" means that an alkylene group is attached to the rest of the molecule through an oxygen atom, wherein the alkylene group is as defined herein.

The term "alkylene-NH-" means that an alkylene group is attached to the rest of the molecule through NH, wherein the alkylene group is as defined herein.

The term "oxo", ie =O, refers to the case where two hydrogens on a carbon atom are replaced by =O, ie _-CH2- is replaced by =O to become -C(=O)-.

The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups. In some embodiments, hydroxyalkyl represents an alkyl group substituted with 1, 2, 3, or 4 hydroxy groups. In some embodiments, hydroxyalkyl represents an alkyl group substituted with 1 or 2 hydroxy groups. In some embodiments, hydroxyalkyl represents C _1-6 hydroxyalkyl, ie, C _1-6 alkyl substituted with 1 or more hydroxy groups, preferably, C _1-6 hydroxyalkyl represents 1 hydroxy Substituted C _1-6 alkyl. 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, _OHCH2- , _{CH2OHCH2CH2CH2-} , _CH2OHCH2- , _{CH2OHCH2CHOHCH2-} , _{CH ( CH3 ) OHCH2CHOHCH2- , etc.} .

The term "alkoxy" means that an 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 1-12 carbon atoms. In one embodiment, the alkoxy group contains 1-6 carbon atoms; in another embodiment, the alkoxy group contains 1-4 carbon atoms; in yet another embodiment, the alkoxy group The group contains 1-3 carbon atoms. The alkoxy groups 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 ₂ CH ₃ ), 1-propoxy (n-PrO, n- Propoxy, -OCH ₂ CH ₂ CH ₃ ), 2-propoxy (i-PrO, i-propoxy, -OCH(CH ₃ ) ₂ ), 1-butoxy (n-BuO, n- Butoxy, -OCH ₂ CH ₂ CH ₂ CH ₃ ), 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH ₂ CH(CH ₃ ) ₂ ), 2-butanyl Oxy (s-BuO, s-butoxy, -OCH(CH ₃ )CH ₂ CH ₃ ), 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC(CH ₃ ) ₃ ), ₁ -pentyloxy (n _- pentyloxy, -OCH2CH2CH2CH2CH3), _{2 -} pentyloxy (-OCH _{( CH3 ) CH2CH2CH3 )} , 3-pentyloxy (-OCH(CH ₂ CH ₃ ) ₂ ), 2-methyl-2-butoxy (-OC(CH ₃ ) ₂ CH ₂ CH ₃ ), 3-methyl-2-butoxy group (-OCH(CH ₃ )CH(CH ₃ ) ₂ ), 3-methyl-1-butoxy (-OCH ₂ CH ₂ CH(CH ₃ ) ₂ ), 2-methyl-1-butoxy (-OCH ₂ CH(CH ₃ )CH ₂ CH ₃ ), etc.

The term "alkoxyalkyl" refers to an alkyl group substituted with one alkoxy group, wherein alkoxy and alkyl have the definitions as described herein. In some embodiments, alkoxyalkyl represents C _1-6 alkoxy C _1-6 alkyl; in other embodiments, alkoxyalkyl represents C _1-4 alkoxy C _1-4 alkyl; in other embodiments, alkoxyalkyl represents C _1-4 alkoxy C _1-3 alkyl; in some embodiments, alkoxyalkyl represents C _1-3 alkoxy C _1-3 alkyl. Examples of alkoxyalkyl include, but are not limited to, methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, methoxypropyl, ethoxyethyl, ethoxy propylpropyl, propoxyethyl, propoxypropyl, etc.

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 group, ie, 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 a C _1-3 haloalkyl. Such examples include, but are not limited to, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, 1,2-difluoroethyl, 1,1-difluoroethyl, 2, 2-difluoroethyl, monochloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1,2-dichloroethyl, 1,1-dichloroethyl, 2,2-dichloroethyl Chloroethyl, 1,1-dibromoethyl, etc.

The term "cycloalkyl" refers to a monovalent saturated monocyclic carbocyclic ring system. The _-CH2- group in the cycloalkyl can be optionally replaced by -C(=O)-. In some embodiments, the cycloalkyl group contains 3-7 ring carbon atoms, ie, a _{C3-7cycloalkyl} group. In one embodiment, the cycloalkyl group contains 3-6 carbon atoms, ie, a _C3-6 cycloalkyl; in another embodiment, the cycloalkyl group contains 3-5 carbon atoms, ie, a _C3-5 ring alkyl. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. Examples of carbocyclic _-CH2- groups that can be replaced by -C(=O)- include, but are not limited to: cyclopentanone, cyclobutanone, and the like. The cycloalkyl groups can be independently optionally substituted with one or more substituents described herein.

The term "cycloalkylene" refers to a divalent saturated monocyclic carbocyclic ring system. The _-CH2- group in the cycloalkylene may optionally be replaced by -C(=O)-. In some embodiments, a cycloalkylene group contains 3-7 ring carbon atoms, ie, a _{C3-7cycloalkylene} group. In one embodiment, the cycloalkylene group contains 3-6 carbon atoms, ie, _C3-6 cycloalkylene; in another embodiment, the cycloalkylene group contains 3-5 carbon atoms, ie, _{C3- 5} Cycloalkylene, examples of cycloalkylene include but are not limited to 1,1-cyclopropylene, 1,2-cyclopropylene, 1,1-cyclopentylene, 1,1-cyclohexylene , 1,3-cyclopentylene, etc. The cycloalkylene groups can be independently optionally substituted with one or more substituents described herein.

The term "monocyclic" refers to a saturated or unsaturated monocyclic carbocyclic or monocyclic heterocyclic ring system, wherein carbocyclic and heterocyclic rings are as defined herein. The monocyclic carbocyclic ring system is a carbon monocyclic ring, and the monocyclic heterocyclic ring system is a heteromonocyclic ring.

The term "monocyclyl" denotes a monovalent saturated or unsaturated monocyclic carbocyclic or monocyclic heterocyclic ring system, wherein carbocyclic and heterocyclic have the meanings as described herein. The _-CH2- group in the monocyclic group can be optionally replaced by -C(=O)-. In some embodiments, the monocyclyl group contains 3-7 ring atoms, that is, the monocyclyl group is a 3-7 membered monocyclyl group; in other embodiments, the monocyclyl group contains 3-6 ring atoms, that is, the monocyclyl group is a monocyclyl group. The cyclic 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 described in the present invention is a monovalent saturated monocyclic carbocyclic ring or a monocyclic heterocyclic ring system. The monocyclic groups can be independently optionally substituted with one or more substituents described herein.

The term "monocyclylene" refers to a divalent saturated or unsaturated monocyclic carbocyclic or monocyclic heterocyclic ring system, wherein carbocyclic and heterocyclic rings are as defined herein. The _-CH2- group in the monocyclylene may optionally be replaced by -C(=O)-. In some embodiments, the monocyclylene group contains 3-7 ring atoms, ie, the monocyclylene group is a 3-7 membered monocyclylene group; in other embodiments, the monocyclylene group contains 3-6 rings Atom, that is, a monocyclylene group is a 3-6 membered monocyclylene group. Preferably, the monocyclic group described in the present invention is a divalent saturated monocyclic carbocyclic ring or a monocyclic heterocyclic ring system. Examples of monocyclylene groups include, but are not limited to, cyclopropylene, cyclopentylene, cyclohexylene, 1,2-cyclopentadienylene, pyrrolidylene, and the like. The monocyclylene groups can be independently optionally substituted with one or more substituents described herein.

The term "monoheterocyclylene" refers to a divalent saturated or unsaturated monocyclic heterocyclic ring system, wherein heterocycle has the definition as described herein. The _-CH2- group in the monoheterocyclylene may optionally be replaced by -C(=O)-. In some embodiments, the monoheterocyclylene group contains 3-7 ring atoms, ie, the monoheterocyclylene group is a 3-7 membered monoheterocyclylene group; in other embodiments, the monoheterocyclylene group contains 3 -6 ring atoms, i.e. a monoheterocyclylene group is a 3-6 membered monoheterocyclylene group. Preferably, the monoheterocyclic group described in the present invention is a divalent saturated monocyclic heterocyclic ring system.

The term "heterocycloalkylene" refers to a divalent saturated monocyclic heterocyclic ring system. The _-CH2- group in a heterocycloalkylene may optionally be replaced by -C(=O)-. In some embodiments, the heterocycloalkylene group contains 3-7 ring atoms, ie, the heterocycloalkylene group is a 3-7 membered heterocycloalkylene group; in other embodiments, the heterocycloalkylene group contains 3 -6 ring atoms, ie heterocycloalkylene is a 3-6 membered heterocycloalkylene. Examples of heterocycloalkylene include, but are not limited to, piperidinyl, morpholinyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, and the like.

The term "heterocyclylalkyl" refers to an alkyl group substituted with a heterocyclyl group, wherein heterocyclyl and alkyl are as defined herein. In some embodiments, heterocyclylalkyl is a 3-12 membered heterocyclyl C _1-6 alkyl; in other embodiments, heterocyclylalkyl is a 3-6 membered heterocyclyl C _1-6 Alkyl; in some embodiments, heterocyclylalkyl is a 3-6 membered heterocyclylC _1-4 alkyl. Examples of heterocyclylalkyl 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 definitions as described herein. In some embodiments, haloalkoxy represents C _1-6 haloalkoxy, ie, C _1-6 alkoxy substituted with 1 or more halogens. In some embodiments, haloalkoxy represents C _1-4 haloalkoxy. In some embodiments, haloalkoxy represents C _1-3 haloalkoxy. Such examples include, but are not limited to, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoroethoxy, 1,2-difluoroethoxy, monochloroethoxy, and many more.

The term "alkylacyl" means that an alkyl group is attached to the remainder of the molecule through a carbonyl group, wherein alkyl has the definition as described herein, and carbonyl means -C(=O)-. In some embodiments, alkylacyl represents _C1-6 alkylacyl; in other embodiments, alkylacyl represents _C1-4 alkylacyl. Examples of alkylacyl 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 are as defined 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 _{C3-6cycloalkylC1-4alkyl} . 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 group formed by removing a hydrogen atom from a ring carbon atom of an aromatic ring. Examples of aryl groups may include phenyl, naphthyl, and anthracene. When an aryl group is a linking group, and "aryl" is recited for that Markush group definition, then "aryl" means the attached arylene group. The term "arylene" refers to a divalent aromatic ring group formed by removing two hydrogen atoms from a ring carbon atom of an aromatic ring. Examples of aryl groups represented as attached arylene groups may include phenylene, naphthylene, and anthracene. The aryl groups can be independently optionally substituted with one or more substituents described herein.

The term "heteroaryl" refers to a monovalent aromatic ring group formed by removing one hydrogen atom from a ring atom of a heteroaromatic ring. The heteroaryl group is optionally substituted with one or more substituents described herein. In one embodiment, a 5-10 atom heteroaryl or a 5-10 membered heteroaryl contains 1, 2, 3 or 4 heteroatoms independently selected from O, S and N. In some embodiments, the term "heteroaryl" refers to a heteroaryl or 5-membered heteroaryl containing 5 ring atoms containing 1, 2, 3, or 4 heteroaryl groups independently selected from O, S, and N. atom. Examples of heteroaryl groups include, but are not limited to, 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl , 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2- Pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (such as 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (such as 5-tetrazolyl), triazolyl (such as 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (such as 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-oxadiazolyl Triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, pyrazinyl, 1,3,5- Triazinyl; also including, but in no way limited to, the following bicyclic rings: benzimidazolyl, benzofuranyl, benzothienyl, indolyl (eg 2-indolyl), purinyl, quinolinyl (such as 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), isoquinolinyl (such as 1-isoquinolinyl, 3-isoquinolinyl or 4-isoquinolinyl), imidazole [1,2-a]pyridyl, pyrazolo[1,5-a]pyridyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, [1,2,4]Triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazole and [1,5-a]pyridyl, etc. When heteroaryl is the linking group, and heteroaryl is listed for that Markush group definition, then heteroaryl represents the attached heteroarylene. The term "heteroarylene" refers to a divalent heteroaromatic ring group formed by removing two hydrogen atoms from the ring atoms of a heteroaryl group. The heteroaryl groups can be independently optionally substituted with one or more substituents described herein.

The term "bridged cyclylene" refers to a divalent non-aromatic saturated or partially unsaturated bicyclic or polycyclic ring system sharing two or more non-adjacent ring atoms, including bridged carbocyclylene and bridged heterocyclylene ring base. In some embodiments, the bridged cyclylene group is a 5-12 membered bridged cyclylene group. The bridged cyclylene groups can be independently optionally substituted with one or more substituents described herein.

The term "apocyclylene" refers to a divalent, non-aromatic, saturated or partially unsaturated bicyclic or polycyclic ring system that shares two adjacent ring atoms, including orthocarbocyclylene and heterocyclylene. In some embodiments, the hypocyclyl group is a 5-12 membered hypocyclyl group. The heterocyclylene groups can be independently optionally substituted with one or more substituents described herein.

The term "spirocyclylene" refers to a non-aromatic saturated or partially unsaturated bicyclic or polycyclic ring system formed by two rings sharing one carbon atom, including spirocarbocyclylene and spiroheterocyclylene. In some embodiments, the spirocyclylene group is a 5-12 membered spirocyclylene group. The spirocyclylene groups can be independently optionally substituted with one or more substituents described herein.

The terms "carbocyclyl" and "carbocycle" are used interchangeably to refer to saturated or partially unsaturated monocyclic, bicyclic or polycyclic ring systems in which the ring atoms are all carbon atoms, including monocarbocyclyl, bridged carbocyclyl, and carbocyclyl and spirocarbocyclyl.

The terms "bridged carbocycle" and "bridged carbocyclyl" are used interchangeably and both refer to a non-aromatic saturated or partially unsaturated bicyclic or polycyclic ring system sharing two or more non-adjacent ring carbon atoms, And the ring atoms are carbon atoms. The _-CH2- group in the bridged carbocycle may optionally be replaced by -C(=O)-. In some embodiments, the bridged carbocycle contains 6-12 ring carbon atoms, representing a 6-12 membered bridged carbocycle; in other embodiments, the bridged carbocycle contains 6-10 ring carbon atoms, representing 6 -10-membered bridged carbon ring. Examples of bridged carbocycles include, but are not limited to: bicyclo[3.1.1]heptane, bicyclo[3.2.1]octane, bicyclo[2.2.2]octane, bicyclo[2.2.0]hexane, Octahydro-1H-indene, et al. When a bridged carbocycle or bridged carbocyclyl group is a linking group, and a bridged carbocycle or bridged carbocyclyl group is listed for that Markush group definition, then the bridged carbocycle or bridged carbocyclyl group represents the attached bridged carbon ring base. The term "bridged carbocyclylene" refers to a divalent bridged carbocyclic group formed by removing two hydrogen atoms from a ring atom of a bridged carbocyclic ring. The bridged carbocycle or bridged carbocyclyl group can be independently optionally substituted with one or more substituents described herein.

The terms "spirocarbocycle" and "spirocarbocyclyl" are used interchangeably and both refer to a non-aromatic saturated or partially unsaturated bicyclic or polycyclic ring system formed by two carbocyclic rings sharing one carbon atom. The _-CH2- group in the spirocarbocycle may optionally be replaced by -C(=O)-. In some embodiments, the spirocarbocycle contains 7-12 ring carbon atoms, representing 7-12 membered spirocarbocycle; in other embodiments, the spirocarbocycle contains 7-10 ring carbon atoms, representing 7 -10-membered spirocarbocycle. Examples of spirocarbocycles include, but are not limited to, spiro[4.4]nonane, spiro[3.4]octane, spiro[4.5]decane, and the like. When spirocarbocycle or spirocarbocyclyl is the linking group, and spirocarbocycle or spirocarbocyclyl is listed for that Markush group definition, then spirocarbocycle or spirocarbocyclyl represents the attached spirocarbon ring base. The term "spirocarbocyclylene" refers to a divalent spirocarbocyclic group formed by removing two hydrogen atoms from a spirocarbocyclic ring atom. The spirocarbocycle or spirocarbocyclyl groups can be independently optionally substituted with one or more substituents described herein.

The terms "heterocycle" or "heterocyclyl" are used interchangeably, and both refer to a monovalent, non-aromatic, saturated or partially unsaturated monocyclic, bicyclic or polycyclic ring system having 3 to 12 ring atoms in which the It contains at least 1 carbon atom, and contains 1, 2 or 3 heteroatoms selected from O, N and S. Unless otherwise specified, heterocyclyl can be carbon or nitrogen, and _-CH2- groups can be optionally replaced by -C(=O)-. Ring sulfur atoms can optionally be oxidized to S-oxides, and ring nitrogen atoms can optionally be oxidized to N-oxygen compounds. In some embodiments, a heterocyclyl group contains 4-7 ring atoms, meaning a 4-7 membered heterocyclyl group; examples of heterocyclyl groups include, but are not limited to: oxiranyl, azetidinyl, oxygen Heterocyclobutyl, thietidine, pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydro Furanyl, Tetrahydrothienyl, Dihydrothienyl, 1,3-Dioxopentyl, Dithiocyclopentyl, Tetrahydropyranyl, Dihydropyranyl, 2H-pyranyl, 4H-pyranyl pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidine base, 1,1-dioxo-1,3-thiomorpholine, etc. Examples of heterocyclyl groups where the _-CH2- group is substituted with -C(=O)- include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidine Keto, 3,5-dioxopiperidinyl. Examples of nitrogen atoms in a heterocyclyl group that are oxidized to N-oxygen compounds include, but are not limited to, 1,1-dioxo-1,3-thiomorpholine. When a heterocycle or heterocyclyl is a linking group, and a heterocycle or heterocyclyl is listed for the Markush group definition, then the heterocycle or heterocyclyl represents the linked heterocyclylene. The term "heterocyclylene" refers to a divalent heterocyclic group formed by removing two hydrogen atoms from a ring atom of a heterocyclic ring. The heterocycle or heterocyclyl group can be independently optionally substituted with one or more substituents described herein.

The terms "bridged heterocycle" or "bridged heterocyclyl" are used interchangeably and both refer to a non-aromatic saturated or partially unsaturated bicyclic or polycyclic ring system sharing two or more non-adjacent ring atoms, and The system contains at least 1 carbon atom, and contains 1, 2 or 3 heteroatoms selected from O, N and S. The _-CH2- group in the bridged heterocycle may optionally be replaced by -C(=O)-. Ring sulfur atoms can optionally be oxidized to S-oxides, and ring nitrogen atoms can optionally be oxidized to N-oxygen compounds. In some embodiments, the bridged heterocycle contains 6-12 ring atoms, representing a 6-12 membered bridged heterocycle; in other embodiments, the bridged heterocycle contains 6-10 ring atoms, representing 6-10 Metabridged heterocycle. Examples of bridged heterocycles include, but are not limited to: 3,6-diazabicyclo[3.1.1]heptane, 3,8-diazabicyclo[3.2.1]octane, 2-azabicyclo[2.2. 1]Heptane, 6-azabicyclo[3.1.1]heptane, 3-azabicyclo[3.1.1]heptane, 8-azabicyclo[3.2.1]octane, 3-azabicyclo [3.2.1]Octane, 2-diazabicyclo[2.2.2]octane, , etc. When bridged heterocycle or bridged heterocyclyl is a linking group, and bridged heterocycle or bridged heterocyclyl is listed for that Markush group definition, then bridged heterocycle or bridged heterocyclyl represents the linked bridged heterocycle ring base. The term "bridged heterocyclylene" refers to a divalent bridged heterocyclic group formed by removing two hydrogen atoms from the ring atoms of a bridged heterocyclic ring. The bridged heterocycle or bridged heterocycle group can be independently optionally substituted with one or more substituents described herein.

The terms "spiroheterocycle" or "spiroheterocyclyl" can be used interchangeably, and both refer to a non-aromatic saturated or partially unsaturated ring system formed by two rings sharing one carbon atom, and the system contains 1, 2 one or three heteroatoms selected from O, N, S. The _-CH2- group in the spiroheterocycle can be optionally replaced by -C(=O)-. Ring sulfur atoms can optionally be oxidized to S-oxides, and ring nitrogen atoms can optionally be oxidized to N-oxygen compounds. In some embodiments, the spiroheterocycle contains 7-12 ring atoms, representing 7-12 membered spiroheterocycle; in other embodiments, the spiroheterocycle contains 7-10 ring atoms, representing 7-10 A membered spiro heterocycle. Examples of spiroheterocycles include, but are not limited to: 4,7-diazaspiro[2.5]octane, 2,8-diazaspiro[4.5]decane, 2,7-diazaspiro[4.5]decane alkane, 2,7-diazaspiro[3.5]decane, 2,6-diazaspiro[3.3]heptane, 2,7-diazaspiro[4.4]nonane, 3-azaspiro[ 5.5] Undecane, 2,7-diazaspiro[4.4]nonan-1-one, etc. When spiroheterocycle or spiroheterocyclyl is the linking group, and spiroheterocycle or spiroheterocyclyl is listed for that Markush group definition, then spiroheterocycle or spiroheterocyclyl represents the attached spiroheterocycle ring base. The term "spiroheterocyclylene" refers to a divalent spiroheterocyclic group formed by removing two hydrogen atoms from the ring atoms of a spiroheterocyclic ring. The spiroheterocycle or spiroheterocyclyl can be independently 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 amino C _1-6 alkyl. In other embodiments, the term "aminoalkyl" refers to _{aminoC1-4alkyl} . In other embodiments, the term "aminoalkyl" refers to amino _C1-3 alkyl. Examples of aminoalkyl groups include, but are not limited to, aminomethyl, aminoethyl, amino-n-propyl, aminoisopropyl, aminoisobutyl, amino-tert-butyl, 1,2-diaminoethyl, and the like.

The term "alkylamino" refers to an amino group substituted with one or two alkyl groups. In some embodiments, the term "alkylamino" refers to _C1-6 alkylamino, ie, represents an amino group substituted with one or two _C1-6 alkyl groups. In other embodiments, the term "alkylamino" refers to _C1-4 alkylamino. In other embodiments, the term "alkylamino" refers to _C1-3 alkylamino. Examples of alkylamino include, but are not limited to, methylamino, ethylamino, n-propylamino, isopropylamino, isobutylamino, tert-butylamino, dimethylamino, diethylamino, di-n- propylamino, diisopropylamino, diisobutylamino, di-tert-butylamino, etc.

The term "alkylsulfonyl" means an alkyl group -S(=O) _2- , ie the alkyl group is attached to the rest of the molecule through -S(=O) _2- . In some embodiments, alkylsulfonyl represents _C1-6 alkylsulfonyl; in other embodiments, alkylsulfonyl represents _C1-4 alkylsulfonyl; in other embodiments, alkyl Sulfonyl represents a C _1-4 alkylsulfonyl group. Examples of alkylsulfonyl groups include, but are not limited to, methylmethanesulfonyl, ethylmethanesulfonyl, n-propylmethanesulfonyl, isopropylmethanesulfonyl, n-butylmethanesulfonyl, and the like.

表示

同样，环A的左端连接E，A的右端连接Q。In the general formula (I) of the compound of the present invention, the left end of Q is connected to ring A, and the right end of Q is connected to M. For example, when Q is -(S=O) ₂ NR ⁶ -, then

express

Likewise, the left end of ring A is connected to E, and the right end of A is connected to Q.

表示

In the general formula (I) of the compound of the present invention, when T is alkylene-O- or alkylene-NH-,

express

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

As described in the present invention, if there are two attachment points on a loop connected to the rest of the molecule, the two attachment points can be attached to the rest of the molecule at any linkable position on the loop, and the two ends of the attachment can be interchanged . For example, the substructure a1 of Ring A represents that any two positions on the ring that may be connected can serve as a point of attachment (ie, a point of attachment), and the two ends of the point of attachment can be interchanged. Preferably, if a loop has two attachment points attached to the rest of the molecule, then the two attachment points can be attached to the rest of the molecule at any linkable position on the loop, and the two attachment points are attached to the loop on two different ring atoms.

Preferably, in the present invention, if a ring is a concatenated ring or a spiro ring formed by two sub-rings, and the two attachment points on the ring are respectively located on the two sub-rings, the two attachment points are respectively on the two sub-rings Any linkable position on the link is linked to the rest of the molecule, and the two ends of the link can be interchanged. For example, the substructure a2 of ring A preferably represents that the two attachment points on the ring are connected to the rest of the molecule on the H1 ring and the H2 ring, respectively, and the two ends of the connection can be interchanged; the substructure a3 of ring A preferably Indicates that the two attachment points on the loop are connected to the rest of the molecule on the H1' loop and the H2' loop, respectively, while the two ends of the link can be interchanged.

The term "protecting group" or "PG" refers to a substituent group that is commonly used to block or protect specific functionality when it reacts with other functional groups. For example, "amino protecting group" refers to 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, Boc), benzyloxycarbonyl (CBZ, Cbz) and 9-fluorenemethyleneoxycarbonyl (Fmoc). Similarly, a "hydroxyl protecting group" refers to a substituent of a hydroxy group used to block or protect the functionality of the hydroxy group, suitable protecting groups include acetyl and silyl. "Carboxyl protecting group" means that the substituent of the carboxyl group is used to block or protect the functionality of the carboxyl group. General carboxyl protecting groups include -CH ₂ CH ₂ SO ₂ Ph, cyanoethyl, 2-(trimethylsilane) yl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrobenzenesulfonyl)ethyl, 2-(diphenyl) phosphino)ethyl, nitroethyl, and the like. For a general description of protecting groups, reference can be made to the literature: TW. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991; and PJ Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.

The term "prodrug" as used in the present invention refers to the conversion of a compound into a compound of formula (I) in vivo. Such conversion is effected by hydrolysis of the prodrug in blood or enzymatic conversion to the parent structure in blood or tissue. The prodrug compounds of the present invention can be esters. In the existing invention, esters that can be used as prodrugs include phenyl esters, aliphatic (C _1-24 ) esters, acyloxymethyl esters, carbonate esters , carbamates and amino acid esters. For example, a compound of the present invention contains a hydroxyl group, which can be acylated to give the compound in prodrug form. Other prodrug forms include phosphates, such as these phosphates are phosphorylated by the hydroxyl group on the parent. A complete discussion of prodrugs can be found in the following literature: T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J. Rautio et al., Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and SJ Hecker et al., Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328 -2345.

"Metabolite" refers to a product obtained by metabolism of a specific compound or salt thereof in vivo. Metabolites of a compound can be identified by techniques well known in the art, and their activity can be characterized using assays as described herein. Such products may be obtained by subjecting the administered compound to oxidation, reduction, hydrolysis, amidation, deamidation, esterification, delipidation, enzymatic cleavage, and the like. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a sufficient period of time.

As used herein, "pharmaceutically acceptable salts" refer to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in the literature: SM Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19. Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, inorganic acid salts formed by reaction with amino groups including hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, And organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, or obtained by other methods such as ion exchange method described in books and literature these salts. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, besylate, benzoate, bisulfate, borate, butyrate, camphoric acid Salt, camphorsulfonate, cyclopentylpropionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate Salt, Gluconate, Hemisulfate, Heptanoate, Caproate, Hydroiodide, 2-Hydroxy-ethanesulfonate, Lacturonate, Lactate, Laurate, Lauryl Sulfate, Malonate, Malonate, Mesylate, 2-Naphthalenesulfonate, Nicotinate, Nitrate, Oleate, Palmitate, Pamoate, Pectate, Persulfate, 3 - Phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Salts obtained with appropriate bases include 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 an N-group. Water- or oil-soluble or dispersible products can be obtained by quaternization. Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include appropriate, non-toxic ammonium, quaternary ammonium salts and amine cations that resist the formation of counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, _{C1 -8} Sulfonates and aromatic sulfonates.

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, basic or acidic moieties, 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 (eg, hydroxide, carbonate, bicarbonate, etc. of Na, Ca, Mg, or K), or by The preparations are carried out by reacting the free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are usually carried out in water or an organic solvent or a mixture of the two. Generally, where appropriate, the use of non-aqueous media such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile is required. In, for example, "Remington's Pharmaceutical Sciences", 20th Edition, Mack Publishing Company, Easton, Pa., (1985); and "Handbook of Pharmaceutical Salts: Properties, Selection, and Use )", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002) may find additional lists of suitable salts.

In addition, the compounds disclosed herein, including their salts, can also be obtained in their hydrate form or in a form containing a solvent (eg, ethanol, DMSO, etc.) for their crystallization. Compounds of the present disclosure may form solvates, inherently or by design, with pharmaceutically acceptable solvents, including water; thus, the present invention is intended to include both solvated and unsolvated forms.

A "solvate" of the present invention refers to an association of one or more solvent molecules with a compound of the present invention. Solvate-forming solvents include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol. The term "hydrate" refers to an association in which the solvent molecule is water.

"Nitrogen oxide" in the present invention means that when the compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form an N-oxide. Particular examples of N-oxides are N-oxides of tertiary amines or N-oxides containing nitrogen heterocyclic nitrogen atoms. The corresponding amines can be treated with oxidizing agents such as hydrogen peroxide or peracids (eg, peroxycarboxylic acids) to form N-oxides (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages). In particular, N-oxides can be prepared by the method of L.W. Deady (Syn. Comm. 1977, 7, 509-514) in which, for example, in an inert solvent such as dichloromethane, an amine compound is combined with m-chloroperoxybenzoic acid (MCPBA) reaction.

The term "treating" any disease or disorder, as used herein, in some embodiments refers to ameliorating the disease or disorder (ie, slowing or arresting or alleviating the development of the disease or at least one clinical symptom thereof). In other embodiments, "treating" refers to alleviating or improving at least one physical parameter, including a physical parameter that may not be perceived by a patient. In other embodiments, "treating" refers to modulating a disease or disorder physically (eg, stabilizing an observable symptom) or physiologically (eg, stabilizing a physical parameter), or both. In other embodiments, "treating" refers to preventing or delaying the onset, occurrence or worsening of a disease or disorder.

As used herein, the term "RET-associated cancer" refers to a cancer that is associated with or has dysregulation 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 herein. The dysregulation of the expression or activity or level of the RET gene, RET kinase, or any of them is one or more point mutations in the RET gene.

The phrase "dysregulated expression or activity or level of the RET gene, RET kinase, or any of them" refers to a genetic mutation (e.g., a translocation of the RET gene that results in the expression of a fusion protein, resulting in a protein that contains at least one amino acid deletion compared to the wild-type RET protein). Deletion in the RET gene expressed by a RET protein, or a mutation in the RET gene that results in the expression of a RET protein with one or more point mutations, or a RET protein that results in a deletion of at least one amino acid in the RET protein compared to the wild-type RET protein alternatively spliced form of RET mRNA), or RET gene amplification that results in overexpression of the RET protein or autocrine activity resulting from the overexpression of the cellular RET gene, resulting in the activity of the kinase domain of the RET protein in the cell increased pathogenicity (eg, constitutive activation of the kinase domain of the RET protein). As another example, dysregulation of the expression or activity or level of the RET gene, RET kinase, or any of these may be a mutation in the RET gene encoding a RET protein that is in contrast to the protein encoded by the RET gene that does not contain the mutation ratio, constitutively active or having increased activity. For example, dysregulation of the expression or activity or level of the RET gene, RET kinase, or any of these can be the result of a gene or chromosomal translocation that results in the expression of a fusion protein comprising a first functional kinase domain-containing The RET part and the second part of the chaperone (ie not RET). In some examples, dysregulation of a RET gene, RET protein, or expression or activity can be the result of gene translation of one RET gene to another RET gene.

Dysregulation of the expression or activity or level of RET kinases, RET genes, or any (eg, one or more) thereof may contribute to tumorigenesis. For example, dysregulation of RET kinase, RET gene, or the expression or activity or level of any of them can be a translocation, overexpression, activation, amplification or mutation of a RET kinase, RET gene or RET kinase domain. Translocations can include translocations involving a RET kinase domain, mutations can include mutations involving RET ligand binding sites, and amplification can be a RET gene. Other dysregulations can include RET mRNA splice variants and RET autocrine/paracrine signaling, which may also contribute to tumorigenesis.

In some embodiments, dysregulation of the expression or activity or level of the RET gene, RET kinase, or any one thereof comprises one or more deletions (eg, deletion of amino acid at position 4), insertions or point mutations in RET kinase. In some embodiments, dysregulation of the expression or activity or level of the RET gene, RET kinase, or any one thereof comprises 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 alternate bowel patterns, functional flatulence, functional constipation, functional diarrhea, nonspecific functional bowel disease, functional abdominal pain syndrome, chronic idiopathic Idiopathic constipation, functional esophageal disease, functional gastroduodenal disease, functional anorectal pain, inflammatory bowel disease, etc.

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

In another aspect, the compounds of the present invention include isotopically enriched compounds as defined in the present invention, for example, those compounds in which radioactive isotopes, such as ³ H, ¹⁴ C and ¹⁸ F are present, or in which non-radioactive isotopes, such as ² H and ¹³ C. Such isotopically enriched compounds can be used in metabolic studies (using ¹⁴ C), reaction kinetic studies (using eg ² H or ³ H), detection or imaging techniques such as positron emission tomography (PET) or including drugs or Single photon emission computed tomography (SPECT) for substrate tissue distribution measurements, or may be used in radiation therapy of patients. ¹⁸ F-enriched compounds are particularly ideal 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 as described in the examples and preparation procedures of the present invention, using suitable isotopically labeled reagents to replace the previously used unlabeled reagents.

In addition, substitution of heavier isotopes, particularly deuterium (ie, ² H or D), may provide certain therapeutic advantages that result from greater metabolic stability. For example, increased in vivo half-life or reduced dosage requirements or improved therapeutic index. It should be understood that deuterium in the present invention is considered as a substituent of compounds of formula (I), (I-1), (I-2), (I-3) or (I-4). The concentration of such heavier isotopes, especially deuterium, can be defined by an isotopic enrichment factor. The term "isotopic enrichment factor" as used herein refers to the ratio between the isotopic abundance and the natural abundance of a given isotope. If a substituent of a compound of the present invention is designated as deuterium, the compound has for each designated deuterium atom at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), At least 4500 (67.5% deuterium incorporated), at least 5000 (75% deuterium incorporated), at least 5500 (82.5% deuterium incorporated), at least 6000 (90% deuterium incorporated), at least 6333.3 (95% deuterium incorporated) deuterium incorporation), an isotopic enrichment factor of 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, eg, _D2O , acetone _- d6, _DMSO -d6.

Description of Compounds of the Invention

The present invention provides a new compound exhibiting the inhibition of transfection phase rearrangement (RET) kinase, the compound has good inhibitory effect on RET wild type and RET gene mutant, and has better inhibitory effect on RET wild type and RET gene mutant Good inhibitory selectivity.

In one aspect, the present invention provides a compound represented by formula (I), or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, solvate, metabolites, pharmaceutically acceptable salts or prodrugs,

Wherein, R ¹ , X ¹ , X ² , X ³ , X ⁴ , X ⁵ , E, A, Q, M, T, Y, G, R ^a , q have the definitions as described in the present invention.

In some embodiments, X ¹ , X ² , X ³ , X ⁴ , and X ⁵ are each independently CR ⁴ or N.

In some embodiments, Y is O, NH or S.

In some embodiments, T is a bond, alkylene, alkylene-O-, alkylene-O-alkylene, or alkylene-NH-, and said T is optionally replaced by 1, 2 , 3 or 4 selected from D, OH, F, Cl, Br, I, CN, NH ₂ , alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, heterocyclyl, alkoxy, aryl, hetero substituted with aryl or alkylamino substituents.

In some embodiments, Ring G is bridged carbocyclyl or bridged heterocyclyl.

In some embodiments, q is 0, 1, 2, 3, or 4.

In some embodiments, ^Ra is D, OH, _NH2 , F, Cl, Br, I, ^CN , ^NR5R6 , ^OR7 , ^-NR6C (=O) ^R7 , -S(=O ) ₂ R ⁷ , -S(=O)R ⁷ , -C(=O)R ⁷ , -C(=O)OR ⁷ , oxo, alkyl, alkoxy, cycloalkyl, haloalkyl, alkane oxyalkyl or hydroxyalkyl.

In some embodiments, E is a bond, ^-NR6- or -O-.

In some embodiments, Ring A is a bridged cyclylene, a biocyclylene, or a spirocyclylene, and Ring A is optionally surrounded by 1, 2, 3, or 4 selected from F, Cl, Br, OH, oxygen Substituted, NR ⁵ R ⁶ , R ⁵ (C=O)NR ⁶ -, aminoalkyl, alkyl, alkoxy, haloalkyl, hydroxyalkyl, carbocyclyl, heterocyclyl, heterocyclylalkyl, Substituents of alkoxyalkyl, cycloalkylene and heterocycloalkylene.

In some embodiments, Q is a bond, -(CR2R3) ^tO- , -( ^CR2R3 ) _f- , ^- ( ^CR2R3 _{)t -} ^{NR6- , -} (C=O )(CR ² R ³ ) _t -, -(C=O)(CR ² R ³ ) _t -(S=O) ₂ (CR ² R ³ ) _f -, -(C=O)(CR ² R ³ ) _t -NR ⁶ (CR ² R ³ ) _f -, -(C=O)(CR ² R ³ ) _t -O(CR ² R ³ ) _f -, -(C=O)NR ⁶ O(CR ² R ³ ) _f -, -(S=O) ₂ -NR ⁶ -(CR ² R ³ ) _t -, -(CR ² R ³ ) _f -(C=O)-, -(CR ² R ³ ) _t -(C=O)-NR ⁶ -(CR ² R ³ ) _t -, -(S=O) ₂ (CR ² R ³ ) _t -, -(CR ² R ³ ) _f -(S=O) ₂ (CR ² R ³ ) _t -, -(S=O) ₂ O-, -O(C=O)-, -(C=O)NR ⁶ - or -NR ⁶ (C=O)-;

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

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

In some embodiments, M is H, D, heteroaryl, aryl, cycloalkyl, or heterocyclyl, and M is optionally composed of 1, 2, 3, or 4 selected from D, F, Cl, CN ^Substitution of , OH, ^NR5R6 , ^OR7 , alkyl, haloalkyl, hydroxyalkyl, haloalkoxy, aryl, alkoxyalkyl, oxo, alkylacyl, heterocyclyl and cycloalkyl base substituted.

In some embodiments, R ¹ is H, D, CN, F, Cl, Br, alkyl, or cycloalkyl, wherein said alkyl and cycloalkyl may independently be optionally separated by 1, 2, 3, or ₄ substituents selected from F, Cl, Br, CN, _NH2 , OH and NO2.

_In some embodiments, each R2 and ^R3 is independently OH, F, H, D, CN, Cl, Br, ^NH2 , hydroxyalkyl, alkyl, alkylamino, alkoxy, haloalkoxy , cycloalkyl, haloalkyl, cycloalkylalkyl, aryl or heteroaryl;

Or, R ² , R ³ and the same carbon atom to which they are attached form a carbocyclic or heterocyclic ring;

^In some embodiments, R4 is H, D, F, Cl, Br, alkyl, or alkoxy, wherein each of said alkyl and alkoxy is independently optionally separated by 1, 2, 3, or 4 Substituents selected from F, Cl, Br, CN, _NH2 , OH and _NO2 .

In some embodiments, R ⁵ is H, D, alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl, wherein said alkyl, carbocyclyl, heterocyclyl, aryl and heterocyclyl Aryl groups are each independently optionally replaced by 1, 2, 3 or 4 groups selected from F, Cl, Br, OH, _NH2 , alkylamino, alkyl, alkylsulfonyl, alkoxy, aryl and heteroaryl substituted by the substituents of the base.

^In some embodiments, R is H, D, alkyl, or alkoxyalkyl, wherein each of said alkyl and alkoxyalkyl is independently optionally selected from F by 1, 2, 3, or 4 , Cl, Br, CN, NH ₂ , OH and NO ₂ substituents.

In some embodiments, R ⁷ is OH, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.

In some embodiments, T is a bond, C _1-6 alkylene, C _1-6 alkylene-O-, C _1-6 alkylene-OC _1-6 alkylene, or C _1-6 alkylene Alkylene-NH-, and T is optionally separated by 1, 2, 3, or 4 selected from D, OH, F, Cl, Br, I, CN, _C1-6 alkyl, _C1-6 hydroxyalkane base, 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 substituents are substituted.

In some embodiments, T is a bond, _-CH2- , -( _CH2 ) _2- , -( _CH2 ) _3- , -( _CH2 ) _4- , -( _CH2 ) _5- , -( CH ₂ ) ₆ -, -(CH ₂ ) ₂ -O-, -(CH ₂ ) ₂ -O-CH ₂ - or -(CH ₂ ) ₂ -NH-, and the T is optionally separated by 1, 2 , 3 or 4 selected from D, OH, F, Cl, Br, I, CN, NH ₂ , CF ₃ , CHF ₂ , CHCl ₂ , methyl, ethyl, propyl, 2-hydroxyethyl, 1- Hydroxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, methoxy, ethoxy, propoxy substituted with substituents of phenyl, butoxy, phenyl, methylamino and dimethylamino.

In some embodiments, Ring G is 6-12 membered bridged carbocyclyl or 6-12 membered bridged heterocyclyl.

In some embodiments, ^Ra is D, OH, _NH2 , F, Cl, Br, I, ^CN , ^NR5R6 , ^OR7 , ^-NR6C (=O) ^R7 , -S(=O ) ₂ R ⁷ , -S(=O)R ⁷ , -C(=O)R ⁷ , -C(=O)OR ⁷ , oxo, C _1-6 alkyl, C _1-6 alkoxy, C _3-7 cycloalkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 alkyl or C _1-6 hydroxyalkyl.

In some embodiments, R ⁵ is H, D, C _1-6 alkyl, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl, C _6-10 membered aryl, or 5-10 membered heteroaryl , wherein said C _1-6 alkyl group, 3-12-membered carbocyclic group, 3-12-membered heterocyclic group, C _6-10 -membered aryl group and 5-10-membered heteroaryl group are each independently optionally replaced by 1, 2, 3 or 4 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 substituents.

In some embodiments, 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 The radicals C _1-6 alkyl are each independently optionally substituted with 1, ₂ , 3 or 4 substituents selected from F, Cl, Br, CN, _NH2 , OH and NO2.

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

In some embodiments, Ring G is of the following substructure:

其中，

in,

each Z1 is independently CH or N ^; and

Each Z ² is independently CH ₂ , C=O, NH, O, S, S=(O) or S=(O) ₂ .

In some embodiments, Ring G is of the following substructure:

In some embodiments, ^Ra is D, OH, F, _CF3 , _CHCl2 , _CHF2 , _CH2F , _CF3CH2 , Cl, Br, I, CN, _NH2 , _NHCH3 , N( _{CH 3} ) ₂ , --NHC(=O)CH ₃ , -S(=O) ₂ CH ₃ , -S(=O) CH ₃ , -C(=O) CH ₃ , -C(=O)OH, -C(=O)OC( _CH3 ) ₃ , oxo, methyl, ethyl, propyl, butyl, methoxy, ethoxy, cyclopropyl, cyclopentyl, methoxymethyl, Ethoxymethyl, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 2-hydroxypropyl, 2-hydroxy-2-methylpropyl.

^In some embodiments, R is H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, cyclopropyl, cyclopentyl, pyrrolidinyl, phenyl, or pyrazolyl; wherein the methyl, ethyl, n-propyl, cyclopropyl, cyclopentyl, pyrrolidinyl, phenyl and pyrazolyl groups are each independently optionally selected from 1, 2, 3 or 4 groups selected from F, Substituents of Cl, Br, OH, _NH2 , methyl, -S( ₌ O) _2CH3 , methoxy, ethoxy and phenyl.

In some embodiments, R ⁶ is H, D, methyl, ethyl, n-propyl, n-butyl, methoxymethyl, ethoxymethyl, or methoxyethyl, wherein the methyl , ethyl, n-propyl, n-butyl, methoxymethyl, ethoxymethyl and methoxyethyl are each independently optionally substituted by 1, 2, 3 or 4 selected from F, Cl, Br , CN, NH ₂ , OH and NO ₂ substituents.

In some embodiments, ^R7 is OH, methyl, ethyl, _NH2 , N( _CH3 ) ₂ , methyl, isopropyl, tert-butyl, cyclopropyl, or phenyl.

In some embodiments, Ring A is a 5-12 membered bridged cyclylene group, a 5-12 membered piocyclylene group, or a 5-12 membered spirocyclylene group, and Ring A is optionally surrounded by 1, 2, 3, or 4 selected from F, Cl, Br, OH, oxo, NR ⁵ R ⁶ , R ⁵ (C=O)NR ⁶ -, amino C _1-6 alkyl, C _1-6 alkyl, C _1-6 alkane Oxygen, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, 3-12-membered carbocyclyl, 3-12-membered heterocyclyl, 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 substituents.

In some embodiments, Ring A is of the following substructure:

wherein each Z ^1a and Z ^2a is independently CH ₂ or NH;

each of Z ^3a and Z ^7a is independently CH or N;

Z ^4a is O, S or NH;

each Z ^5a and Z ^6a is independently CH ₂ , O, S, S(=O), S(=O) ₂ , C(=O) or NH;

each of m and t is independently 0, 1 or 2;

each of n and t1 is independently 0 or 1;

wherein each substructure of Ring A is independently optionally replaced by 1, 2, 3 or 4 selected from F, ^Cl , Br, OH, oxo, ^NR5R6 , ^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 heteroalkyl Cyclyl, 3-12-membered heterocyclyl C _1-4 alkyl, C _1-4 alkoxy C _1-4 alkyl, C _3-6 cycloalkylene and 3-6 membered heterocycloalkylene Substituents are substituted.

In some embodiments, Ring A is of the following substructure:

wherein each sub-formula of Ring A is independently optionally replaced by 1, 2, 3 or 4 selected from F, Cl, Br, OH, oxo, _NH2 , _NHCH3 , _CH3 (C=O)NH-, methyl , ethyl, n-propyl, methoxy, ethoxy, isopropoxy, CF ₃ , hydroxymethyl, 2-hydroxyethyl, cyclopropyl, cyclohexyl, pyrrolidinyl, piperidinyl, Substituents of tetrahydrofuranyl, cyclopropylene, cyclohexylene and pyrrolidylene.

In some embodiments, M is H, D, 5-10 membered heteroaryl, _C6-10 aryl, _C3-7 cycloalkyl, or 3-12 membered heterocyclyl; and M is optionally 1 , 2, 3 or 4 are selected from D, F, Cl, CN, OH, NR ⁵ R ⁶ , OR ⁷ , C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 haloalkoxy, C _6-10 aryl, C _1-6 alkoxy, C _1-6 alkyl, oxo, C _1-6 alkyl acyl, 3-7 membered heterocyclyl and C _{3- 7} cycloalkyl substituents are substituted.

In some embodiments, M is H, D, pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, pyrazinyl, phenyl, cyclopentyl, cyclopropyl, cyclo Hexyl, cyclobutyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, morpholinyl, tetrahydrothiopyranyl, oxetanyl, 1,2-dihydro Pyridyl, 7-azabicyclo[2.2.1]heptyl, hexahydrofuro[3,4-c]pyrrolyl, 3-azabicyclo[3.1.0]hexyl, octahydropyrrolo[ 1,2-a]pyrazinyl or 5-azaspiro[2.4]heptyl; and M is optionally 1, 2, 3 or 4 selected from D, F, Cl, CN, OH, CF ₃ , CHCl ₂ , CHF ₂ , CH ₂ F, CF ₃ CH ₂ , NH ₂ , NHCH ₃ , N(CH ₃ ) ₂ , trifluoromethoxy, 2,2,2-trifluoroethoxy, methoxy , ethoxy, isopropoxy, tert-butoxy, methyl, ethyl, n-propyl, isopropyl, phenyl, methoxymethyl, methoxyethyl, oxo, formyl, Substituents of acetyl, morpholinyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, cyclopropyl and cyclohexyl.

且M任选地被1、2、3或4个选自D、F、Cl、CN、OH、CF₃、NH₂、NHCH₃、N(CH₃)₂、三氟甲氧基、2,2,2-三氟乙氧基、甲氧基、乙氧基、异丙氧基、叔丁氧基、甲基、乙基、正丙基、异丙基、苯基、甲氧基甲基、甲氧基乙基、氧代、甲酰基、乙酰基、吗啉基、吡咯烷基、哌啶基、四氢呋喃基、四氢吡喃基、哌嗪基、环丙基和环己基的取代基所取代。In some embodiments, M is phenyl,

and M is optionally 1, 2, 3 or 4 selected from D, F, Cl, CN, OH, CF ₃ , NH ₂ , NHCH ₃ , N(CH ₃ ) ₂ , trifluoromethoxy, 2, 2,2-Trifluoroethoxy, methoxy, ethoxy, isopropoxy, tert-butoxy, methyl, ethyl, n-propyl, isopropyl, phenyl, methoxymethyl , methoxyethyl, oxo, formyl, acetyl, morpholinyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, cyclopropyl and cyclohexyl substituents replaced.

In some embodiments, M is

In some embodiments, R ¹ is H, D, CN, F, Cl, Br, methyl, ethyl, or cyclopropyl, wherein said methyl, ethyl, and cyclopropyl are independently optionally 1, ₂ , 3 or 4 substituents selected from F, Cl, Br, CN, _NH2 , OH and NO2.

In some embodiments, R ⁴ is H, D, F, Cl, Br, methyl, ethyl, n-propyl, methoxy or ethoxy, wherein said methyl, ethyl, n-propyl , methoxy and ethoxy can be independently optionally substituted with 1, ₂ , 3 or 4 substituents selected from F, Cl, Br, CN, _NH2 , OH and NO2.

In some embodiments, each R ² and R ³ is independently OH, F, H, D, CN, Cl, Br, NH ₂ , C _1-6 hydroxyalkyl, C _1-6 alkyl, C _{1- 6} alkylamino, C _1-6 alkoxy, C _1-6 haloalkoxy, C _3-7 cycloalkyl, C _1-6 haloalkyl, C _3-7 cycloalkyl, C _1-6 alkyl, C _6-10 aryl or 5-10 membered heteroaryl;

Or, R ² , R ³ and the same carbon 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 and R ³ is independently OH, F, CF ₃ , CHCl ₂ , CHF ₂ , H, D, CN, Cl, Br, NH ₂ , hydroxymethyl, 2-hydroxyethyl , 1-hydroxyethyl, methyl, ethyl, N(CH ₃ ) ₂ , methoxy, ethoxy, isopropoxy, tert-butoxy, trifluoromethoxy, cyclopropyl, cyclopentyl cyclopropylmethyl, cyclopentylethyl, cyclopentylmethyl, phenyl, pyridyl or pyrazinyl;

^{Alternatively} , R2, ^R3 and the same carbon atom to which they are attached form cyclopentane, cyclopropane, cyclobutane, tetrahydropyran, tetrahydrofuran, piperidine or pyrrolidine.

In some embodiments, Q is a bond, -O-, -( _CH2 )2O-, _-CH2- , -( _CH2 ) _2- , -( _{CH2 ) 3-} , -CH2CH ₍ CH ₃ )CH ₂ -, -CH ₂ CH(CH ₃ )CH ₂ NHCH ₂ -, -(C=O)OC(CH ₃ ) ₂ CH ₂ -, -(C=O)(CH ₂ ) ₂ (S =O) ₂ CH ₂ -, -(C=O)CH(OH)-, -(C=O)CH(OH)CH ₂ -, -(C=O)-, -(S=O) ₂ - , -(C=O)CH ₂ CH(OH)-, -(C=O)CH ₂ -, -(C=O)CH(CH ₂ OH)-, -(C=O)C(CH ₃ ) ₂ -, -(C=O)CH ₂ NHC(CH ₃ ) ₂ CH ₂ -, -(C=O)CH ₂ CH(N(CH ₃ ) ₂ )-, -(C=O)(CH ₂ ) ₂ N(CH ₃ )CH ₂ -, -(C=O)C(CH ₃ ) ₂ CH ₂ -, -(C=O)C(OH)(CH ₃ )CH ₂ -, -(C=O) CH ₂ OCH ₂ -, -(C=O)(CH ₂ ) ₃ -, -(C=O)CH(NH ₂ )-, -(C=O)(CH ₂ ) ₃ N(CH ₃ )CH ₂ -, -(C=O)( _CH2 ) _2- , -(C=O)CH2CH(OH)CH2-, _- (C=O) _CF2CH2- , _- (C=O) _CH (OH)C(CH ₃ ) ₂ CH ₂ -, -(C=O)CH ₂ C(CH ₃ ) ₂ CH ₂ -, -(C=O)CH ₂ C(CH ₃ )(OH)CH ₂ - , -(S=O) ₂ CH ₂ -, -(S=O) ₂ CH ₂ C(CH ₃ ) ₂ CH ₂ -, -(C=O)CH(OCH ₃ )-, -(C=O) NHCH(CH ₂ OH)(CH ₂ ) ₂ -, -(C=O)NH-, -(C=O)N(CH ₃ )-, -(C=O)N(CH ₂ CH ₂ CH ₂ CH ₃ )-, -(C=O)N(CH ₂ CH ₃ )(CH ₂ ) ₂ -, -(C=O)NHC(CH ₃ ) ₂ CH ₂ -, -(C=O)N(CH ₃ )(CH ₂ ) ₂ -, -(C=O)NHCH ₂ CH(CH ₃ )CH ₂ -, -(C=O)NHCH ₂ -, -(C=O)NH(CH ₂ ) ₂ OCH ₂ - , -(C=O)N(CH ₃ )(CH ₂ ) ₂ OCH ₂ -, -(S=O) ₂ NHC(CH ₃ ) ₂ CH ₂ -, -CH ₂ CH(OH)C(CH ₃ ) ₂ CH ₂ -, -CH(CH ₃ )CH(OH)-, -CH ₂ (C=O)NHCH(CH ₃ )CH ₂ -, -CH ₂ (C=O)-, -(CH ₂ ) ₂ (C=O)N(CH ₃ )CH ₂ -, -CH ₂ CH(OH)-, -CH ₂ CH(OH)CH ₂ -, -CH ₂ CH(OH)CH(CH ₃ )CH ₂ -, -(C=O)CH(N(CH ₃ ) ₂ )-, -(C=O)C(CH ₃ ) ₂ CH ₂ OCH ₂ -, -(C=O)C(OCH ₃ )(CF ₃ )-, -(CH ₂ ) ₃ S(=O) ₂ CH(CH ₃ ) CH ₂ -, -(C=O)N(CH ₂ CH ₂ OCH ₃ )CH ₂ CH(OCH ₃ )-, -CH ₂ CH(OCF ₃ )-, -CH ₂ CH(OCH(CH ₃ ) ₂ )-, -CH ₂ CH(OC(CH ₃ ) ₃ )-, -CH ₂ CF ₂ -, -CH(CH ₃ )-, -CH ₂ CH(OCH ₃ )C(CH ₃ ) ₂ -, - CH ₂ CH(N(CH ₃ ) ₂ )-, -NH-, -(C=O)NHOCH ₂ -, -(C=O)NHOCH ₂ (CHOH)-, -(S=O) ₂ (CH ₂ CH ₃ )-, -(S=O) ₂ O-, -(S=O) ₂ -NHC(CH ₃ ) ₂ -, -(CH ₂ ) ₂ (S=O) ₂ -,

In some embodiments, the compounds described herein have the structure of formula (IA), or a stereoisomer, geometric isomer, tautomer, nitroxide, solvate, metabolites, pharmaceutically acceptable salts or prodrugs,

Wherein, R ¹ , X ¹ , X ² , X ³ , X ⁴ , X ⁵ , E, A, Q, M, T, G, ^Ra and q have the definitions as described in the present invention.

In some embodiments, the compounds of the present invention have the structure of formula (I-1), or a stereoisomer, geometric isomer, tautomer, nitrogen oxide of the structure of formula (I-1) , solvates, metabolites, pharmaceutically acceptable salts or prodrugs,

Wherein, R ¹ , X ¹ , X ² , X ³ , X ⁴ , X ⁵ , E, Q, M, T, G, R ^a , q have the definitions as described in the present invention;

Ring A1 is the following substructure:

wherein each Z ^1a and Z ^2a is independently CH ₂ or NH;

And each substructure of ring A1 is independently optionally 1, 2, 3 or 4 selected from F, Cl, Br, OH, oxo, NR ⁵ R ⁶ , R ⁵ (C=O)NR ⁶ -, amino C _1-4 alkyl, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _1-4 hydroxyalkyl, 3-12-membered carbocyclyl, 3-12-membered heteroalkyl Cyclyl, 3-12-membered heterocyclyl C _1-4 alkyl, C _1-4 alkoxy C _1-4 alkyl, C _3-6 cycloalkylene and 3-6 membered heterocycloalkylene Substituents are substituted.

In some embodiments, Ring A1 is of the substructural formula:

wherein each sub-formula of Ring A1 is independently optionally replaced by 1, 2, 3 or 4 selected from F, Cl, Br, OH, oxo, NH ₂ , NHCH ₃ , CH ₃ (C=O)NH-, methyl , ethyl, n-propyl, methoxy, ethoxy, isopropoxy, CF ₃ , hydroxymethyl, 2-hydroxyethyl, cyclopropyl, cyclohexyl, pyrrolidinyl, piperidinyl, Substituents of tetrahydrofuranyl, cyclopropylene, cyclohexylene and pyrrolidylene.

In some embodiments, the compounds described herein have the structure of formula (IA1), or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, solvate, metabolites, pharmaceutically acceptable salts or prodrugs,

Wherein, R ¹ , X ¹ , X ² , X ³ , X ⁴ , X ⁵ , A, T, G, R ^a , q have the definitions as described in the present invention;

Wherein, M ¹ is a heteroaryl group or an aryl group.

In some embodiments, M ¹ is 5-10 membered heteroaryl or C _6-10 aryl; and M is optionally composed of 1, 2, 3, or 4 selected from D, F, Cl, CN, OH, NR ⁵ R ⁶ , OR ⁷ , C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 haloalkoxy, C _6-10 aryl, C _1-6 alkane Substituents of oxy C _1-6 alkyl, oxo, C _1-6 alkyl acyl, 3-7 membered heterocyclyl and C _3-7 cycloalkyl.

In some embodiments, M ¹ is pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, pyrazinyl, phenyl; pyridyl, pyrimidinyl, pyrazolyl, imidazole base, oxazolyl, isoxazolyl, pyrazinyl, phenyl.

In some embodiments, M ¹ is

In some embodiments, the compounds described herein have the structure of formula (I-1aa), or a stereoisomer, geometric isomer, tautomer, nitrogen oxide of the structure of formula (I-1aa) , solvates, metabolites, pharmaceutically acceptable salts or prodrugs,

Wherein, R ¹ , X ¹ , X ² , X ³ , X ⁴ , X ⁵ , T, G, R ^a , q, A1, M ¹ have the definitions as described in the present invention.

In some embodiments, the compound of the present invention has the structure of formula (I-2) or (I-3), or a stereoisomer, geometric isomeric form of the structure of formula (I-2) or (I-3) isomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs,

Wherein, R ¹ , X ¹ , X ² , X ³ , X ⁴ , X ⁵ , E, Q, M, T, G, R ^a , q have the definitions as described in the present invention;

each of Z ¹ , Z ² , Z ^3a and Z ^7a is independently CH or N;

each of m and t is independently 0, 1 or 2;

each of n and t1 is independently 0 or 1;

独立任选地被1、2、3或4个选自F、Cl、Br、OH、氧代、NR⁵R⁶、R⁵(C＝O)NR⁶-、氨基C_1-4烷基、C_1-4烷基、C_1-4烷氧基、C_1-4卤代烷基、C_1-4羟基烷基、3-12元碳环基、3-12元杂环基、3-12元杂环基C_1-4烷基、C_1-4烷氧基C_1-4烷基、C_3-6亚环烷基和3-6元亚杂环烷基的取代基所取代。each of them

independently optionally replaced by 1, 2, 3 or 4 selected from F, Cl, Br, OH, oxo, NR ⁵ R ⁶ , R ⁵ (C=O)NR ⁶ -, amino C _1-4 alkyl, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _1-4 hydroxyalkyl, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl, 3-12 membered Substituents of heterocyclyl C _1-4 alkyl, C _1-4 alkoxy C _1-4 alkyl, C _3-6 cycloalkylene and 3-6 membered heterocycloalkylene.

为以下子结构式：In some embodiments,

is the following substructure:

为以下子结构式：

is the following substructure:

的各子结构式独立任选地被1、2、3或4个选自F、Cl、Br、OH、氧代、NH₂、NHCH₃、CH₃(C＝O)NH-、甲基、乙基、正丙基、甲氧基、乙氧基、异丙氧基、CF₃、羟基甲基、2-羟基乙基、环丙基、环己基、吡咯烷基、哌啶基、四氢呋喃基、亚环丙基、亚环己基和亚吡咯烷基的取代基所取代。in

Each substructure of is independently optionally replaced by 1, 2, 3 or 4 selected from F, Cl, Br, OH, oxo, NH ₂ , NHCH ₃ , CH ₃ (C=O)NH-, methyl, ethyl , n-propyl, methoxy, ethoxy, isopropoxy, CF ₃ , hydroxymethyl, 2-hydroxyethyl, cyclopropyl, cyclohexyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, Substituents of cyclopropylene, cyclohexylene and pyrrolidylene.

In some embodiments, the compounds described herein have one of the following structures, or stereoisomers, geometric isomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs of

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

On the other hand, the present invention also provides the use of the compound of the present invention or the pharmaceutical composition of the present invention in the preparation of a 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.

On the other hand, the present invention also provides the compound of the present invention or the pharmaceutical composition of the present invention 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 present invention also provides a method for preventing or treating RET-related diseases, the method comprising administering to a patient a therapeutically effective amount of the compound of the present 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 an intermediate for the preparation of a compound of formula (I), (I-1), (IA), (IA1), (I-1aa), (I-2) or (I-3) body.

In another aspect, the present invention relates to the preparation of compounds represented by formula (I), (I-1), (IA), (IA1), (I-1aa), (I-2) or (I-3), Methods of isolation and purification.

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

Also provided herein is a method of inhibiting cell proliferation in vitro or in vivo, the method comprising contacting the cell with an effective amount of a compound described herein or a pharmaceutical composition thereof.

Also provided herein is a method of treating irritable bowel syndrome (IBS) and/or pain associated with IBS in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of the invention or its pharmaceutical composition.

The present invention also provides use of the compound of the present invention or the pharmaceutical composition of the present invention in the preparation of a medicament for preventing or treating irritable bowel syndrome (IBS) and/or pain associated with IBS.

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

Unless otherwise indicated, all stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, salts and pharmaceutically acceptable prodrugs of the compounds of the present invention are belong to the scope of the present invention.

Specifically, the salts are pharmaceutically acceptable salts. The term "pharmaceutically acceptable" includes substances or compositions that must be chemically or toxicologically suitable in relation to the other components that make up the formulation and the mammal for which it is to be treated.

Salts of compounds of the present invention also include compounds of formula (I), (IA), (IA1), (I-1aa), (I-1), (I-2) or (I-3) used in the preparation or purification of Intermediates of the compounds shown or separated enantiomers of compounds of formula (I), (I-1), (IA), (IA1), (I-1aa), (I-2) or (I-3) salts of the structures, but not necessarily pharmaceutically acceptable salts.

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

Nitrogen oxides of the compounds of the present invention are also included within the scope of the present invention. Oxidation of the corresponding nitrogen-containing basic species can be accomplished by using common oxidizing agents such as hydrogen peroxide at elevated temperature in the presence of an acid such as acetic acid, or by reaction with a peracid in a suitable solvent, such as in dichloromethane , ethyl acetate or methyl acetate react with peracetic acid, or react with 3-chloroperoxybenzoic acid in chloroform or dichloromethane to prepare nitrogen oxides of the compounds of the present invention.

If the compounds of the present invention are basic, the desired salts can be prepared by any suitable method provided in the literature, for example, using mineral acids such as hydrochloric, hydrobromic, sulfuric, nitric and phosphoric acids and the like. Alternatively use 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; pyranonic acids such as glucuronic acid and galactose aldehydes; alpha-hydroxy acids, such as citric and tartaric acids; amino acids, such as aspartic acid and glutamic acid; aromatic acids, such as benzoic and cinnamic acids; sulfonic acids, such as p-toluenesulfonic acid, ethanesulfonic acid, and many more.

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

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, eg, RET mutants that are resistant to current standard of care treatments ("RET-resistant mutants"). In addition, compounds of the present invention or pharmaceutical compositions thereof may be selective for wild-type RET relative to 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), (IA), (IA1), (I-1aa), (I-1), (I-2) or (I-3), the present invention Listed compounds, or compounds of the Examples. The amount of the compound in the compositions of the present invention is effective to treat or alleviate a RET-related disease or disorder in a patient, including RET-related cancer, irritable bowel syndrome, and/or pain associated with irritable bowel syndrome.

As described in the present invention, the pharmaceutically acceptable compositions of the present invention further comprise pharmaceutically acceptable adjuvants, such as used in the present invention, including any solvents, diluents, or other liquid excipients, dispersing agents Or suspending agents, surfactants, isotonic agents, thickening agents, emulsifiers, preservatives, solid binders or lubricants, etc., suitable for the specific target dosage form. As described in: 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, summarizing the contents of this document, shows that various adjuvants can be used in the formulation of pharmaceutically acceptable compositions and their well-known methods of preparation. Except to the extent that any conventional adjuvants are incompatible with the compounds of the present invention, such as any adverse biological effect or interaction in a detrimental manner with any other component of a pharmaceutically acceptable composition, they The use of is also within the scope of the present invention.

In preparing the compositions provided herein, the active ingredient is usually mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, for example, a capsule, sachet, paper, or other container. If an excipient is used as a diluent, it can be a solid, semi-solid or liquid material which acts as a vehicle, carrier or medium for the active ingredient. Suitable carriers include, but are not limited to, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low Melting point wax, cocoa butter, etc. Thus, the composition may be in the form of a tablet, pill, powder, lozenge, sachet, cachet, elixir, suspension, emulsion, solution, syrup, aerosol (in solid form or in a liquid medium) , such as ointments, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders containing up to 10% by weight of the active compound. 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 invention, especially of formula (I), (IA), (IA1), (I-1aa), (I-1), (I-2) or (I- 3) The compounds and their pharmaceutically acceptable salts can be administered as raw chemicals and can also be provided as active ingredients of pharmaceutical compositions. Accordingly, the present disclosure also provides pharmaceutical compositions comprising a therapeutically effective amount of a compound of the present invention, especially of formulae (I), (IA), (IA1), (I-1aa), (I-1) , (I-2) or (I-3) compound or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable adjuvants, including but not limited to carriers, diluents or excipients, Wait. As used herein, the term "therapeutically effective amount" refers to the total amount of each active ingredient sufficient to demonstrate a meaningful patient benefit (eg, reduction in cancer cells). When a single active ingredient is used to be administered alone, the term refers to that ingredient only. When used in combination, the term refers to the combined amounts of active ingredients that, whether administered in combination, sequentially or simultaneously, result in a therapeutic effect. Compounds of the present invention, especially compounds of formula (I), (IA), (IA1), (I-1aa), (I-1), (I-2) or (I-3) and pharmaceutically acceptable compounds thereof Salt as above. The carrier, diluent or excipient must be acceptable in the sense of being compatible with the other ingredients of the formulation and not injurious to its recipient. According to another aspect of the content of the present invention, there is also provided a method for the preparation of a pharmaceutical formulation, the method comprising combining a compound of the present invention, especially of formulae (I), (IA), (IA1), (I-1aa), (I -1), (I-2) or (I-3) compound or a pharmaceutically acceptable salt thereof is mixed 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 that, within the scope of sound medical judgment, are suitable for use in contact with patient tissue without undue toxicity, irritation , allergic reactions or other problems and complications commensurate with a reasonable benefit/risk ratio and are effective for the intended use.

The amount of active ingredient to be 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. Amount of Active Ingredient for Compound of Formula (I), (IA), (IA1), (I-1aa), (I-1), (I-2) or (I-3) Mixed with Carrier Material to Prepare Single Dosage Form This will vary depending on 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 sub-dose, or an appropriate fraction thereof, of the active ingredient herein above. Treatment can be initiated with small doses that are clearly below the optimal dose of the compound. Thereafter, increase the dose in smaller increments until the best effect under the circumstances is achieved. In general, the compound is optimally administered at a concentration level that generally provides effective results in anti-tumor without causing any deleterious or toxic side effects.

Compositions containing the compounds of the present invention may be formulated in unit dosage form, each dose containing from about 5 to about 1,000 mg (1 g), more usually from about 100 mg to about 500 mg, of the active ingredient. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects or other patients, each unit containing a predetermined quantity of active material (ie, a compound of formula I as provided herein) in association with an appropriate drug. With excipients, the predetermined amount is calculated to produce the desired therapeutic effect.

In some embodiments, the compositions provided herein contain from about 5 mg to about 50 mg of active ingredient. One of ordinary skill in the art will understand that this embodies about 5 mg to about 10 mg, about 10 mg to about 15 mg, about 15 mg to about 20 mg, about 20 mg to about 25 mg, about 25 mg to about 30 mg, about 30 mg to about 35 mg, about 35 mg to about 40 mg, about 40 mg to about 45 mg, or about 45 mg to about 50 mg of the compound or composition of active ingredient.

In some embodiments, the compositions provided herein contain from about 50 mg to about 500 mg of active ingredient. One of ordinary skill in the art will appreciate that this embodies the inclusion of about 50 mg to about 100 mg, about 100 mg to about 150 mg, about 150 mg to about 200 mg, about 200 mg to about 250 mg, about 250 mg to about 300 mg, about 350 mg to about 400 mg or about 450 mg to about 500 mg of the active ingredient compound or composition.

In some embodiments, the compositions provided herein contain from about 500 mg to about 1,000 mg of active ingredient. One of ordinary skill in the art will understand that this embodies the inclusion of about 500 mg to about 550 mg, about 550 mg to about 600 mg, about 600 mg to about 650 mg, about 650 mg to about 700 mg, about 700 to about 750 mg, about 750 mg to about 800 mg, about 800 mg To about 850 mg, about 850 mg to about 900 mg, about 900 mg to about 950 mg, or about 950 mg to about 1,000 mg of a compound or composition of active ingredient.

The pharmaceutical compositions are suitable for administration by any suitable route, such as oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, dermal intra-, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intralesional, intravenous or subdermal injection or infusion) routes. Such formulations may be prepared by any method known in the art of pharmacy, for example by admixing the active ingredient with a carrier or excipient. Oral administration or injection administration is preferred.

The present invention also provides a method of treating an individual with RET-related cancer, the method comprising administering a compound of the present invention before, during or after administration of another anticancer drug (eg, not a compound of the present invention).

The present invention provides methods for treating cancer in a patient in need thereof, the methods comprising: (a) determining whether the cancer in the patient is a RET-related cancer (eg, comprising having one or more RET inhibitor resistant Sexually mutated RET-related cancers) (eg, using regulatory agency-approved, eg, FDA-approved, kits to identify expression of RET genes, RET kinases, or any of these in a patient or in a biopsy sample of a patient or dysregulation of activity or level, or by performing any non-limiting example of an assay described herein); and (b) if the cancer is determined to be a RET-related cancer, administering to the patient a therapeutically effective amount of formula (I), (IA) ), (IA1), (I-1aa), (I-1), (I-2) or (I-3), or a pharmaceutically acceptable salt or solvate or a pharmaceutical composition thereof. Some embodiments of these methods further comprise administering to the subject another anticancer agent (eg, another RET inhibitor, eg, a RET inhibitor that is not a compound described herein). In some embodiments, the subject was previously treated with a compound other than Formula (I), (IA), (IA1 ), (I-1aa), (I-1 ), (I-2), or (I-3) or its RET inhibitor treatment with a pharmaceutically acceptable salt or solvate, or prior (eg, after tumor resection or radiation therapy) treatment with other anticancer agents.

In some embodiments of any of the methods described herein, the compound of Formula (I), (IA), (IA1), (I-1aa), (I-1), (I-2), or (I-3) The compound (or a pharmaceutically acceptable salt or solvate thereof) is used in combination with a therapeutically effective amount of at least one other therapeutic agent selected from one or more other therapies or treatments (e.g. chemotherapy) reagents.

Non-limiting examples of other therapeutic agents include: other RET-targeted therapeutics (ie, other RET kinase inhibitors: RET inhibitors that are not compounds of the invention), receptor tyrosine kinase-targeted therapeutics, signal transduction Pathway inhibitors, checkpoint inhibitors, modulators of apoptotic pathways (eg Obataclax); cytotoxic chemotherapeutics, angiogenesis-targeted therapeutics, immune-targeting agents, and radiation therapy.

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

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

Other therapeutic agents include RET inhibitors, such as those described in, eg, US Patent Nos. 7,504,509; 8,299,057; 8,399,442; 8,067,434; 8,937,071; 9,006,256; and 9,035,063; 2011/0301157; 2010; 2009/0227556; 2009/0130229; 2009/0099167; 2005/0209195; international open number wo 2014/184069; wo 2014/072220; wo2012/053606; wo 2009/017838; wo 2008/03155151551 WO 2007/136103; WO 2007/087245; WO2007/057399; WO 2005/051366; WO 2005/062795; Incorporated herein by reference in its entirety.

Also provided herein are methods of treating cancer, comprising administering to a patient in need thereof a pharmaceutical combination for treating cancer comprising (a) a compound of general formula I, or a pharmaceutically acceptable salt or solvate thereof, (b) other treatments agent, and (c) optionally at least one pharmaceutically acceptable carrier, for simultaneous, separate or sequential use in the treatment of cancer, wherein a compound of general formula (I) or a pharmaceutically acceptable salt or solvate thereof The amount of the drug and the amount of the other therapeutic agent are co-effective in treating cancer.

The compounds and compositions described herein can be administered alone or in combination with other compounds (including other RET modulating compounds) or other therapeutic agents. In some embodiments, a compound or composition of the invention may be administered in combination with one or more compounds selected from the group consisting of cabozantinib (COMETRIQ), vandetanib (CALPRESA), sorafenib (NEXAVAR) ), sunitinib (SUTENT), regrafenib (STAVARGA), ponatinib (ICLUSIG), bevacizumab (Avastin), crizotinib (XALKORI), or gefitinib (IRESSA) ). The compounds or compositions of the present invention may be administered simultaneously or sequentially with other therapeutic agents by the same or different routes of administration. The compounds of the present 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 are useful in the treatment of irritable bowel syndrome (IBS) in combination with one or more other therapeutic agents or therapies that act through the same or different mechanisms of action Effective in the treatment of irritable bowel syndrome. The at least one other therapeutic agent may be part of the same or separate dosage form as the compound of general formula (I), or a pharmaceutically acceptable salt or solvate thereof, according to standard pharmaceutical practice known to those skilled in the art, Administration is via the same or different routes of administration, and according to the same or different administration schedules. Non-limiting examples of other therapeutic agents for the treatment of irritable bowel syndrome (IBS) include probiotics, fiber supplements (eg, psyllium, methylcellulose), antidiarrheals (eg, loperamide), bile Acid binders (eg, cholestyramine, colestipol, colesevelam), anticholinergics and anticonvulsants (eg, hyoscyamine, dicyclomine), antidepressants (eg, tricyclic antidepressants) , such as imipramine or nortriptyline or selective serotonin reuptake inhibitors (SSRIs such as fluoxetine or paroxetine), antibiotics (such as rifaximin), alosetron and lubiprostone .

Use of the Compounds and Pharmaceutical Compositions of the Invention

The present invention also provides the use of the compound of the present invention or the pharmaceutical composition of the present invention in the preparation of a medicament for preventing or treating RET-related diseases or disorders, wherein RET-related diseases or disorders include RET-related cancers , 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, eg, RET mutants that are resistant to current standard of care treatments ("RET-resistant mutants"). In addition, compounds of the present invention or pharmaceutical compositions thereof may be selective for wild-type RET relative to other kinases, resulting in reduced toxicity associated with inhibition of other kinases.

The present invention provides the use of the compound of the present invention that inhibits wild-type RET and RET mutants or a pharmaceutical composition thereof in the preparation of a medicament for preventing or treating wild-type RET and RET mutant-related diseases or conditions.

In some embodiments of any of the methods or uses described herein, the cancer (eg, RET-related cancer) is a hematological cancer. In some embodiments of any of the methods or uses described herein, the cancer (eg, RET-associated cancer) is a solid tumor. In some embodiments of any of the methods or uses described herein, the cancer (eg, RET-associated cancer) is lung cancer (eg, small cell lung cancer or non-small cell lung cancer), papillary thyroid cancer, medullary thyroid cancer, differentiated thyroid carcinoma, recurrent thyroid cancer, refractory differentiated thyroid cancer, lung adenocarcinoma, bronchiolar carcinoma, multiple endocrine tumors type 2A or 2B (MEN2A or MEN2B, respectively), pheochromocytoma, parathyroid hyperplasia, breast cancer carcinoma, colorectal cancer (eg metastatic colorectal cancer), papillary renal cell carcinoma, gangliomatosis of the gastrointestinal mucosa, inflammatory myofibroblastic tumor or cervical cancer. In some embodiments of any of the methods or uses described herein, the cancer (eg, RET-related cancer) is selected from the group consisting of: acute lymphoblastic leukemia (ALL), acute myeloid 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, bronchial tumor, primary tumor Lymphoma, carcinoid tumor, cancer of unknown primary, cardiac tumor, cervical cancer, childhood cancer, chordoma, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myeloproliferative tumor, colon cancer, Colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, cholangiocarcinoma, ductal carcinoma in situ, embryonal tumor, endometrial cancer, ependymoma, esophageal cancer, sensory neuroblastoma, Ewing's sarcoma, Extracranial germ cell tumor, extragonadal germ cell tumor, extrahepatic cholangiocarcinoma, eye cancer, fallopian tube cancer, fibrous histiocytoma of bone, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), Germ cell tumor, gestational trophoblastic disease, glioma, hairy cell tumor, hairy cell leukemia, head and neck cancer, heart cancer, hepatocellular carcinoma, histiocytosis, Hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma Tumor, Islet Cell Tumor, Pancreatic Neuroendocrine Tumor, Kaposi's Sarcoma, Kidney Cancer, Langerhans Cell Histiocytosis, Laryngeal Cancer, Leukemia, Lip and Mouth Cancer, Liver Cancer, Lung Cancer, Lymphoma, Macroglobulinemia disease, malignant fibrous histiocytoma of bone, bone cancer, melanoma, Merkel cell carcinoma, mesothelioma, metastatic squamous neck cancer, midline carcinoma, oral cancer, multiple endocrine neoplasia syndrome, multiple myeloma , Mycosis fungoides granuloma, myelodysplastic syndrome, myelodysplastic/myeloproliferative neoplasms, myeloid leukemia, myeloid leukemia, multiple myeloma, myeloproliferative neoplasms, nasal cavity and sinus cancer, nasopharyngeal carcinoma, Neuroblastoma, Non-Hodgkin's Lymphoma, Non-Small Cell Lung Cancer, Oral Cancer, Oral Cancer, Lip Cancer, Oropharyngeal Cancer, Osteosarcoma, Ovarian Cancer, Pancreatic Cancer, Papillomatosis, Paraganglioma, Paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pituitary cancer, plasmacytoma, pleuropulmonary blastoma, pregnancy and breast cancer, primary central nervous system lymphoma, Primary Peritoneal Cancer, Prostate Cancer, Rectal Cancer, Renal Cell Carcinoma, Retinoblastoma, Rhabdomyosarcoma, Salivary Gland Cancer, Sarcoma, Sezari Syndrome, Skin Cancer, Small Cell Lung Cancer, Small Intestinal Cancer, Soft Tissue Sarcoma, Squamous Cell Carcinoma, squamous cervical cancer, gastric cancer, T-cell lymphoma, testicular cancer, throat cancer, thymoma and thymus cancer, thyroid cancer, transitional cell carcinoma of renal pelvis and ureter, cancer of unknown primary, urethral cancer, uterine cancer, uterine sarcoma , vaginal cancer, vulvar cancer and Wilm's tumor.

In some embodiments, the RET-related cancer of the invention is selected from the group consisting of lung cancer, papillary thyroid cancer, medullary thyroid cancer, differentiated thyroid cancer, relapsed thyroid cancer, refractory differentiated thyroid cancer, type 2A or 2B multiple endocrine tumors (MEN2A or MEN2B, respectively), pheochromocytoma, parathyroid hyperplasia, breast cancer, colorectal cancer, papillary renal cell carcinoma, gastrointestinal mucosal gangliocytoma, and cervical cancer. In some embodiments, the RET-related cancer is RET fusion lung cancer or medullary thyroid cancer.

In some embodiments, compounds of formula (I), (IA), (IA1), (I-1aa), (I-1), (I-2) or (I-3) and pharmaceutically acceptable The salts and solvates are useful for the treatment of patients with RET inhibitor resistance mutations that result in 2) or (1-3) compounds or pharmaceutically acceptable salts or solvates of increased resistance, such as a substitution at amino acid position 804, such as V804M, V804L or V804E) in cancer patients, said treatment By co-administration or as an existing drug treatment (eg, not of formula (I), (IA), (IA1), (I-1aa), (I-1), (I-2) or (I-3) compound or a pharmaceutically acceptable salt or solvate thereof, other RET kinase inhibitors). Exemplary RET kinase inhibitors (eg, not of formula (I), (IA), (IA1 ), (I-1aa), (I-1 ), (I-2), or (I-3) are described herein. compound or other RET kinase inhibitor of a pharmaceutically acceptable salt or solvate thereof). In some embodiments, the RET kinase inhibitor may be selected from the group consisting of cabozantinib, vandetanib, alatinib, sorafenib, lenvatinib, ponatinib, dovitinib, sunitinib , 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 bloating, functional constipation, functional diarrhea, Specific functional bowel disorders, functional abdominal pain syndrome, chronic idiopathic constipation, functional esophageal disease, functional gastroduodenal disease, functional anorectal pain, and inflammatory bowel disease.

According to the methods of the present invention, the compounds and compositions may be administered in any amount and by any route of administration effective for treating or reducing the severity of the disease. The exact amount necessary will vary from patient to patient, depending on race, age, general condition of the patient, severity of infection, particular factors, mode of administration, and the like. A compound or composition may be administered in pharmaceutical combination with one or more other therapeutic agents, as discussed herein.

General Synthesis of Compounds of the Invention

Generally, the compounds of the present invention can be prepared by the methods described in the present invention, unless otherwise specified, wherein the substituents are as defined in formula (I), (IA), (IA1), (I-1aa), ( I-1), (I-2) or (I-3). The following reaction schemes and examples serve to further illustrate the content of 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 Inside. For example, the synthesis of those non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art by modifying methods, such as appropriate protection of interfering groups, by using other known reagents in addition to those described herein, or by combining The reaction conditions were modified routinely. In addition, the reactions disclosed herein or known reaction conditions are also acknowledged to be applicable to the preparation of other compounds of the present invention.

In the examples described below, all temperatures are in degrees Celsius unless otherwise indicated. Unless otherwise stated, reagents can be purchased from the market. For example, reagents can be purchased from commercial suppliers such as Linkchem Pharmaceuticals, Aldrich Chemical Company, Inc., Arco Chemical Company and Alfa Chemical Company, and are used without further purification, unless indicated otherwise. Common reagents were purchased from Shantou Xilong Chemical Reagent Factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, Tianjin Haoyuyu Chemical Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Ocean Chemical Factory.

Anhydrous tetrahydrofuran is obtained by refluxing and drying with metallic sodium. Anhydrous dichloromethane and chloroform were obtained by refluxing with calcium hydride. Ethyl acetate, N,N-dimethylacetamide and petroleum ether were previously dried over anhydrous sodium sulfate and used.

The following reactions are generally carried out under positive nitrogen or argon pressure or a drying tube is set over anhydrous solvent (unless otherwise indicated), the reaction flasks are plugged with suitable rubber stoppers, and the substrate is injected through a syringe. Glassware is dry.

The chromatographic column is a silica gel column. Silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Factory. NMR spectra were performed with CDC1 ₃ or DMSO-d ₆ as solvent (reported in ppm), with TMS (0 ppm) or chloroform (7.25 ppm) as reference standards. When multiplets are present, the following abbreviations are used: s (singlet), d (doublet), t (triplet), m (multiplet), br (broadened) peak), dd (doublet of doublets, double doublet), dt (doublet of triplets, double triplet). Coupling constant, expressed in Hertz (Hz).

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

Low-resolution mass spectrometry (MS) data were determined by an Agilent 6120 series LC-MS spectrometer equipped with a G1311A quaternary pump and G1316A TCC (column temperature maintained at 30°C), a G1329A autosampler and a G1315D DAD detector were used for analysis, ESI sources are used in LC-MS spectrometers.

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

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

The following abbreviations are used throughout this disclosure:

DMAC,DMA N,N-2-methylacetamide

PdCl ₂ (dppf)CH ₂ Cl ₂ [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex

_H2Hydrogen

Pd/C Palladium on Carbon

NaOH sodium hydroxide

NH ₄ Cl Ammonium Chloride

K ₂ CO ₃ Potassium Carbonate

MeOH, CH ₃ OH methanol

PE petroleum ether

EA Ethyl acetate

DCM dichloromethane

L liter

mg mg

ml,mL milliliter

min minutes

KI Potassium Iodide

DMF N,N-Dimethylformamide

HCl/EA Hydrogen chloride in ethyl acetate

DMSO Dimethyl sulfoxide

TLC Thin Layer Chromatography

CH ₃ CN Acetonitrile

The following synthetic schemes describe the steps for the preparation of the compounds disclosed herein. Unless otherwise specified, R ¹ , X ¹ , X ² , X ³ , X ⁴ , X ⁵ , E, A, Q, M, T, ^Ra , q have the definitions as described herein.

Synthesis Scheme 1

Synthetic scheme of intermediate (IA-1a):

Hal¹和Hal²各自独立地为F、Cl、Br、I，优选Cl、Br；Pg¹为氨基保护基团，例如Boc，等；Pg²为羟基保护基团，例如苄基，等。式(IA-1a-1)化合物与式(IA-1a-2)化合物在合适的偶联剂条件(如钯偶联剂，优选PdCl₂(dppf)CH₂Cl₂)下在合适的溶剂(如二氧六环，等)中发生偶联反应得到式(IA-1a-3)化合物；式(IA-1a-3)化合物与式(IA-1a-4)化合物在合适的偶联剂条件(如钯偶联剂，优选PdCl₂(dppf)CH₂Cl₂)下在合适的溶剂(如甲苯，等)中发生偶联反应得到式(IA-1a-5)化合物；式(IA-1a-5)化合物在合适的反应条件下(如在氢氧化钠和过氧化氢存在下，在四氢呋喃溶剂中)反应得到式(IA-1a-6)化合物；式(IA-1a-6)化合物与式(IA-1a-7)化合物经过偶联反应得到式(IA-1a-8)化合物；式(IA-1a-8)化合物与式(IA-1a-9)化合物在碱性条件下反应得到式(IA-1a-10)化合物；式(IA-1a-10)化合物在酸性条件下脱氨基保护得到式(IA-1a-11)化合物；式(IA-1a-11)化合物与式(IA-1a-12)化合物在碱性条件下反应得到式(IA-1a-13)化合物；式(IA-1a-13)化合物在合适的条件(如H₂,Pd/C)下还原得到式(IA-1a)化合物。The intermediate compound of formula (IA-1a) can be obtained by referring to the synthesis steps of the above intermediate synthesis scheme. where ring A is the following substructure:

Hal ¹ and Hal ² are each independently F, Cl, Br, I, preferably Cl, Br; Pg ¹ is an amino protecting group, such as Boc, etc.; Pg ² is a hydroxyl protecting group, such as benzyl, and the like. Compounds of formula (IA-1a-1) are combined with compounds of formula (IA-1a-2) under suitable coupling reagent conditions (such as a palladium coupling reagent, preferably PdCl ₂ (dppf)CH ₂ Cl ₂ ) in a suitable solvent ( Such as dioxane, etc.) in the coupling reaction to obtain the compound of formula (IA-1a-3); the compound of formula (IA-1a-3) and the compound of formula (IA-1a-4) under suitable coupling agent conditions (such as a palladium coupling agent, preferably PdCl ₂ (dppf)CH ₂ Cl ₂ ) in a suitable solvent (such as toluene, etc.) for a coupling reaction to obtain a compound of formula (IA-1a-5); formula (IA-1a) -5) The compound is reacted under suitable reaction conditions (such as in the presence of sodium hydroxide and hydrogen peroxide, in a tetrahydrofuran solvent) to obtain the compound of formula (IA-1a-6); the compound of formula (IA-1a-6) is reacted with The compound of formula (IA-1a-7) is obtained by coupling reaction to obtain the compound of formula (IA-1a-8); the compound of formula (IA-1a-8) is reacted with the compound of formula (IA-1a-9) under basic conditions to obtain The compound of formula (IA-1a-10); the compound of formula (IA-1a-10) is deaminated under acidic conditions to obtain the compound of formula (IA-1a-11); the compound of formula (IA-1a-11) and the compound of formula (IA-1a-11) are obtained -1a-12) The compound of formula (IA-1a-13) is obtained by reacting the compound under basic conditions; the compound of formula (IA-1a-13) is reduced under suitable conditions (such as H ₂ , Pd/C) to obtain the compound of formula ( IA-1a) Compounds.

Intermediate (IA-3) synthesis scheme:

Intermediate (IA-3) can be prepared by the above synthetic scheme, wherein Hal and Hal ² are F, Cl, Br, I, preferably Cl, Br. Compounds of formula (IA-1a-6) and compounds of formula (IA-2) under basic conditions (eg the base is K ₂ CO ₃ ) in a suitable solvent (eg N,N-dimethylformamide or DMSO) The reaction takes place to obtain the compound of formula (IA-3).

Synthesis Scheme 1:

The compound of formula (IA) can be obtained by referring to the synthetic steps of Synthesis Scheme 1. Among them, Hal is F, Cl, Br, and I, preferably Cl and Br. Compounds of formula (IA-1) and compounds of formula (IA-2) under suitable conditions (such as basic conditions, the base is K ₂ CO ₃ ) in a suitable solvent (such as N,N-dimethylacetamide or N , N-dimethylformamide) to obtain the compound of formula (IA).

Synthesis Scheme 2:

The compound of formula (IAa) can be obtained by referring to the synthetic steps of Synthesis Scheme 2. Compounds of formula (IA-3) and compounds of formula (IA-4) or salts of compounds of formula (IA-4) under basic conditions (eg the base is K ₂ CO ₃ ) in a suitable solvent (eg DMSO) to give the compounds (IAa).

specific embodiment

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

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

At room temperature, 6-bromo-4-methoxypyrazolo[1,5-a]pyridine-3-carbonitrile (50g, 198.36mmol) and water (16.5mL, 916mmol) were added to a 1L single-necked flask successively. , sodium hydroxide (16.03g, 396.8mmol), DMA (500mL), stirred at room temperature for 5min and then transferred to 0°C and slowly added dodecanethiol (97mL, 397mmol), after the addition, the reaction was transferred to 45°C overnight. Pour the reaction solution into 3L of ice water, slowly add saturated citric acid water to adjust pH=5, stir for half an hour, let stand, filter, wash the filter cake with water and petroleum ether for many times, and dry at 60°C to obtain 44.1g of yellow solids. The target product (yield 93.4%). Rf=0.35 (PE/EA=3:1); LC-MS: m/z=239.05 [M+H] ⁺ .

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

6-Bromo-4-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile (44.1g, 185mmol), pyridine (45mL, 559mmol), DCM (800mL) were added to a 1L single-necked flask, and the temperature dropped to Below -10°C, trifluoromethanesulfonic anhydride (50 mL, 297.2 mmol) was slowly added, and after stirring for 1 h, the mixture was naturally raised to room temperature and reacted overnight. Spin dry DCM under reduced pressure, add water (250 mL) to dilute, extract with EA (500 mL×3), collect the organic phase, wash with saturated brine (250 mL), dry with anhydrous sodium sulfate, filter, spin dry the filtrate, and perform silica gel column chromatography After purification (eluent PE/EA=50:1-25:1), 61.5 g of yellowish solid was obtained, which was the target product, and the yield was 89.7%. Rf=0.45 (PE/EA=5:1).

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

Under nitrogen protection, add 3-bromo-3-cyanopyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate (61.5g, 166mmol), 2-fluoropyridine into a 1L three-necked flask -5-Boronate ester (44.5 g, 200 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (6.8 g, 8.3 mmol), 1 , 4-Dioxane (850 mL), potassium acetate solution (115 mL, 345 mmol, 3 mol/L) was added slowly when the temperature dropped to -10 °C, stirred at this temperature for 1 h and then returned to room temperature naturally and continued the reaction overnight. Filter, wash the filter cake with EA (500mL×3), wash the organic phase with water (500mL), wash with saturated brine (250mL), dry with anhydrous sodium sulfate, filter, spin dry the filtrate, and purify by silica gel column chromatography (eluent PE/ DCM=2:1-0:1), collect the target point, spin dry to obtain 49 g of white solid, which is the target product, and the yield is 93.0%. Rf=0.50 (PE/EA=1:1). LC-MS: m/z=318.10 [M+H] ⁺ . ¹ H NMR(400MHz, DMSO)δ9.49(d,J=1.2Hz,1H),8.73(s,1H),8.51(d,J=1.9Hz,1H),8.27(td,J=8.2,2.5 Hz, 1H), 7.86 (d, J=1.2 Hz, 1H), 7.40 (dd, J=8.4, 2.5 Hz, 1H).

Step 4: 4-(6-Fluoropyridin-3-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)pyridine Azolo[1,5-a]pyridine-3-carbonitrile

6-Bromo-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (8g, 25.23mmol) was added successively in a 250mL single-necked flask under nitrogen protection, followed by Pinacol borate (10 g, 39.39 mmol), potassium acetate (10 g, 101.9 mmol), redistilled toluene (150 mL), purged with nitrogen for 10 min, and then added [1,1'-bis(diphenylphosphine)] Ferrocene] palladium dichloride dichloromethane complex (2.1 g, 2.6 mmol) was bubbled with nitrogen for 10 min, and then heated at 120 °C for overnight reaction. Filter through celite, wash the filter cake with EA (50mL×3), wash the organic phase with water (250mL), wash with saturated brine (250mL), dry with anhydrous sodium sulfate, filter, spin dry, and perform silica gel column chromatography (eluent PE /DCM=2:1-0:1), collect and spin dry to obtain 8.5 g of orange solid, which is the target product (yield 93.0%). Rf=0.15 (DCM). ¹ H NMR (400MHz, CDCl ₃ ) δ 8.99 (s, 1H), 8.43 (d, J=2.1 Hz, 1H), 8.34 (s, 1H), 8.02 (td, J=8.0, 2.5 Hz, 1H) , 7.66(s, 1H), 7.13(dd, J=8.5, 2.8Hz, 1H), 1.40(s, 12H).

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

Add 4-(6-fluoropyridin-3-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (8.5g, 23mmol), tetrahydrofuran (120mL), under ice bath condition, slowly add sodium hydroxide solution (60mL, 120mmol, 2mol /L), hydrogen peroxide (14 mL, 140 mmol, 30 mass%), stirring at low temperature. After the reaction is complete, slowly add sodium thiosulfate solution (50mL, 150mmol, 3mol/L), after returning to room temperature, add water (250mL), extract with EA (250mL×2), combine the organic phases and wash with 0.1M NaOH solution (500mL×2 ). All aqueous phases were combined, the pH was adjusted to 4 with dilute hydrochloric acid, stirred at room temperature for 15 min, and suction filtered to obtain a wet cake. The mother liquor was extracted with EA (250 mL×3), all the organic phases were combined, dried over anhydrous sodium sulfate, filtered, spin-dried, and subjected to silica gel column chromatography (eluent DCM\MeOH=100:0-100:1) to obtain a pale yellow solid. All solids were combined and dried at 50° C. to obtain 5.1 g of light yellow solid, which was the target product (yield 86.0%). Rf=0.25 (DCM\MeOH=100:1). LCMS: m/z=255.10 [M+H] ⁺ .

Step 6: 3-(5-(3-Cyano-6-hydroxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1 .1]Heptane-6-tert-butyl carboxylic acid

In a 30 mL microwave tube, 4-(6-fluoropyridin-3-yl)-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile (1.5 g, 5.9 mmol), 6- (tert-Butoxycarbonyl)-3,6-diazabicyclo[3.1.1]heptane (2.3 g, 12 mmol), N,N-diisopropylethylamine (2.0 mL, 12 mmol), dimethyl sulfoxide (15 mL), sealed, and reacted under microwave at 80 °C for 8 h. At low temperature, add water (50 mL) to dilute, extract with EA (100 mL×5), combine the organic phases and wash with saturated brine (250 mL), dry with anhydrous sodium sulfate, filter, and spin the filtrate to dry on silica gel column chromatography (eluting) agent PE/EA=5:1-1; 1.5), 1.9 g of yellow product was collected and obtained as the target product (yield 74.0%). Rf=0.5 (PE/EA=1:1.5). LC-MS: m/z=433.10 [M+H] ⁺ .

Step 7: 3-(5-(6-(Benzyloxy)-3-cyanopyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3,6-diaza Heterobicyclo[3.1.1]heptane-3-tert-butyl ester-6-carboxylate ethyl ester

3-(5-(3-cyano-6-hydroxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3,6-diaza Heterobicyclo[3.1.1]heptane-6-tert-butyl ester carboxylic acid (1 g, 2.312 mmol), benzyl bromide (0.302 mL, 2.54 mmol), potassium carbonate (0.9683 g, 6.936 mmol), N,N-di Methylformamide (10 mL), stirred at 80°C overnight. Add saturated ammonium chloride (100 mL) to quench at room temperature, extract with DCM (100 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and spin the filtrate to dry on silica gel column chromatography (eluent PE/EA). =5:1-2:1), 1.06 g of yellow solid was obtained as the target product (yield 87.7%). Rf=0.7 (PE/EA=1:1). LC-MS: m/z=523.30 [M+H]. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.37 (s, 1H), 8.19 (s, 1H), 8.17 (d, J=1.9 Hz, 1H), 7.74 (d, J=8.7 Hz, 2H), 7.42 (dt, J=11.9, 7.4Hz, 5H), 7.18 (d, J=2.0Hz, 1H), 5.13 (s, 2H), 4.31 (d, J=4.0Hz, 2H), 4.16 (dd, J= 8.7, 4.4Hz, 2H), 3.55 (dd, J=8.1, 3.1Hz, 2H), 2.24–2.20 (m, 1H), 2.01 (d, J=5.5Hz, 1H), 1.38 (s, 9H).

Step 8: 4-(6-(3,6-Diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-(benzyloxy)pyrazolo[1,5 -a]pyridine-3-carbonitrile hydrochloride

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

Step 9: (6-Methoxypyridin-3-yl)methanol

At 0°C, 6-methoxy-3-pyridinecarboxaldehyde (0.4 g, 3 mmol), lithium aluminum tetrahydrogen (0.06 g, 2 mmol), and tetrahydrofuran (10 mL) were sequentially added to a 25 mL single-necked flask, and the reaction was performed at this temperature overnight. EA (50 mL) was added, the reaction mixture was diluted with water (50 mL), after extraction and separation, the organic layer was washed with saturated NH ₄ Cl (50 mL) solution, dried over anhydrous sodium sulfate, filtered, the filtrate was spin-dried, and purified by silica gel column chromatography ( The eluent was DCM/EA=4:1), and 0.38 g of light yellow liquid was obtained as the target product (yield 90.0%). LC-MS: m/z=140.15 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.12 (d, J=1.8 Hz, 1H), 7.62 (dd, J=8.5, 2.4 Hz, 1H), 6.75 (d, J=8.5 Hz, 1H), 4.62 (s, 2H), 3.93 (s, 3H).

Step 10: 5-(Bromomethyl)-2-methoxypyridine

In a 25mL single-necked flask, successively added (6-methoxypyridin-3-yl)methanol (0.38g, 2.7mmol), dichloromethane (8mL), phosphorus tribromide (0.31mL, 3.3mmol), 0 ℃ The reaction was carried out for 30 minutes. DCM (25 mL) was added to dilute, washed with saturated aqueous K ₂ CO ₃ (25 mL) solution, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was spin-dried, and it was directly sent to the next step without further purification.

Step 11: 6-(Benzyloxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane Alk-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

4-(6-(3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-(benzyloxy)pyrazolo[ 1,5-a]pyridine-3-carbonitrile (400mg, 0.8074mmol), potassium carbonate (0.3382g, 2.423mmol), N,N-dimethylformamide (8mL), then slowly add 5-(bromo Methyl)-2-methoxypyridine (0.50 g, 2.5 mmol), stirred at room temperature overnight. The reaction solution was diluted with water (25 mL), extracted with EA (50 mL×3), the organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried and purified by silica gel column chromatography (eluent DCM/MeOH= 1:0-20:1), the obtained light yellow solid 0.2889g is the target product (yield 65.82%). LC-MS: m/z=544.10 [M+H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ 8.39(s, 1H), 8.22-8.17(m, 2H), 8.11(s, 1H), 8.02(s, 1H), 7.78(d, J=8.8Hz, 1H ),7.42(dd,J＝14.9,7.1Hz,5H),7.19(s,1H),6.70(dd,J＝13.9,8.5Hz,2H),5.13(s,2H),3.92(s,3H) , 3.80(s, 4H), 3.59(s, 4H), 2.22(s, 1H), 2.01(s, 1H).

Step 12: 6-Hydroxy-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3- yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

Into the 50mL single-neck flask, 6-(benzyloxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1 .1]Heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (0.288 g, 0.530 mmol), methanol (5 mL), palladium on carbon (0.03 g, 10% mass), replaced with hydrogen several times and stirred overnight at room temperature. The reaction solution was filtered, the filter cake was rinsed with methanol, and the filtrate was spin-dried to obtain 240 mg of pale yellow solid, which was the target product (yield 100.0%). LC-MS: m/z=454.30 [M+H]. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.39 (d, J=1.7 Hz, 1H), 8.28 (d, J=2.0 Hz, 1H), 8.21 (s, 1H), 8.17-8.12 (m, 1H) ,7.81(dd,J＝8.1,2.2Hz,2H),7.14(s,1H),6.78(d,J＝8.6Hz,1H),6.70(d,J＝8.3Hz,1H),5.37(s, 1H), 4.00-3.90(m, 5H), 3.73(s, 4H), 3.51(s, 2H), 2.27-2.21(m, 1H), 2.03(d, J=6.6Hz, 1H).

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

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

At 0 °C, (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (1.00 g, 7.38 mmol) was dissolved in acetone (15 mL), K ₂ CO ₃ ( 3.06 g, 22.1 mmol) and KI (1.84 g, 11.1 mmol), after stirring for 15 min, slowly add 1-bromo-2-chloroethane (1.59 g, 11.1 mmol), and naturally warm to room temperature and stir for 4 h. The reaction was monitored by TLC (PE/EA (v/v=2/1) first, then DCM/CH ₃ OH (v/v=20/1), Rf=0.31), and the reaction of the starting materials was complete. Slowly add water to quench the reaction, extract with EA (10 mL×3), wash the organic phase with water, dry with anhydrous sodium sulfate and concentrate, perform silica gel column chromatography, the eluent is DCM/CH ₃ OH (v/v=40/1-20 /1), 0.49 g of colorless viscous liquid was obtained as the target product, and the yield was 41%. ¹ H NMR (400MHz, CDCl ₃ ) δ 4.41(s, 1H), 4.01(d, J=7.9Hz, 1H), 3.70-3.61(m, 1H), 3.56(s, 1H), 3.53(d, J=6.9Hz, 2H), 3.06–2.94 (m, 2H), 2.94–2.88 (m, 1H), 2.58 (d, J=9.9Hz, 1H), 1.87 (d, J=9.8Hz, 1H), 1.76(d,J=9.8Hz,1H).

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

4-(6-Fluoropyridin-3-yl)-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile (20 mg, 0.08 mmol, intermediate 4) and (1S,4S)-5 -(2-Chloroethyl)-2-oxa-5-azabicyclo[2.2.1]heptane (20 mg, 0.12 mmol) was dissolved in DMF ( ₆ mL) and K2CO3 ( ₂₂ mg, 0.16 mmol) was added slowly ) and stirred for 10 min. Then the temperature was raised to 50°C for 12h. The reaction was monitored by TLC (PE/EA (v/v=2/1) first, then DCM/CH ₃ OH (v/v=10/1), Rf=0.07), and the reaction of the starting materials was complete. The reaction was stopped, the reaction solution was cooled to room temperature, extracted with EA (20 mL×3), the organic phase was washed with water, dried over anhydrous sodium sulfate and concentrated. Silica gel column chromatography, eluent DCM/CH ₃ OH (v/v)=50/1-20/1, to obtain 12 mg of yellow-brown solid, which is the target product, and the yield is 40%. LC-MS: m/z=380.3 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.41 (d, J=3.4 Hz, 1H), 8.28 (s, 1H), 8.24 (s, 1H), 8.08–7.98 (m, 1H), 7.21 (d, J=1.9Hz, 1H), 7.18–7.11 (m, 1H), 4.51 (s, 1H), 4.30 (brs, 2H), 4.22–4.16 (m, 1H), 3.93–3.80 (m, 1H), 3.76 (d, J=8.2Hz, 1H), 3.36–3.26 (m, 1H), 3.25 (brs, 2H), 2.83 (d, J=8.8 Hz, 1H), 1.91 (d, J=9.5Hz, 2H).

Intermediate 3: 4-(6-Fluoro-3-yl)-6-(2-(3-oxo-8-azabicyclo[3.2.1]octan-8-yl)ethoxy)pyrazole [1,5-a]pyridine-3-carbonitrile

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

8-oxo-3-azabicyclo[3.2.1]octane-3-carboxylate tert-butyl ester (1.0g, 4.4mmol) was added to the 25mL single-neck flask, EA (5mL) was added at room temperature to dissolve it, and the HCl/EA (6 mL, 24 mmol, 4 mol/L) was stirred at room temperature for 1 h. After the reaction, the reaction solution was directly concentrated to obtain 700 mg of white solid, which was the product, and the yield was 98.00%. LC-MS: m/z=126.25 [M+H] ⁺ .

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

25mL two-necked flask was added 3-azabicyclo[3.2.1]octane-8-one hydrochloride (300mg, 1.86mmol), potassium carbonate (1.1g, 7.6mmol), acetonitrile (5mL), 1-bromo- 2-Chloroethane (0.5 mL, 6 mmol) was added and reacted at room temperature for 15 h. After the reaction, the reaction solution was suction filtered to remove insolubles, and the filtrate was directly concentrated by silica gel column chromatography. The eluent was DCM/MeOH (v/v)=20/1, and 90 mg of colorless liquid was obtained as the product, and the yield was 25.84%. . LC-MS: m/z=188.20 [M+H] ⁺ .

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

4-(6-Fluoropyridin-3-yl)-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile (110mg, 0.4327mmol, Intermediate 4) was added successively to a 25mL single-neck flask, carbonic acid Potassium (178 mg, 1.2879 mmol), 3-(2-chloroethyl)-3-azabicyclo[3.2.1]octan-8-one (910 mg, 4.8489 mmol), dissolved in DMSO (2 mL), The reaction was carried out at 80°C for 2h. After the reaction was stopped, 10 mL of water was added to the reaction solution, extracted with EA (40 mL×2), the organic phase was washed with water (10 mL×4), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate and filtered, the filtrate was subjected to silica gel column chromatography, and the eluent was It was DCM/MeOH (v/v=10/1), and 70 mg of yellow solid was obtained as the product, and the yield was 39.90%. LC-MS: m/z=406.15 [M+H] ⁺ ; ¹ H NMR: (400 MHz, CDCl ₃ ) δ 8.40 (s, 1H), 8.27 (d, J=2.0 Hz, 1H), 8.23 (s ,1H),8.02(dd,J＝11.5,4.2Hz,1H),7.19(d,J＝2.0Hz,1H),7.13(dd,J＝8.5,2.7Hz,1H),4.24(t,J＝ 5.6Hz, 2H), 3.65(s, 2H), 3.09(t, J＝5.6Hz, 2H), 2.71(d, J＝12.6Hz, 2H), 2.25(d, J＝15.6Hz, 2H), 2.08 (s, 2H), 1.67 (d, J=8.0 Hz, 2H).

Intermediate 4: 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

At room temperature, 6-bromo-4-methoxypyrazolo[1,5-a]pyridine-3-carbonitrile (50g, 198.36mmol) and water (16.5mL, 916mmol) were added to a 1L single-necked flask successively. , sodium hydroxide (16.03g, 396.8mmol), DMAC (500mL), stirred at room temperature for 5min and then transferred to 0°C and slowly added dodecanethiol (97mL, 397mmol), after the addition, the reaction was transferred to 45°C overnight. Pour the reaction solution into 3L of ice water, slowly add saturated aqueous citric acid solution to adjust pH=5, stir for half an hour, let stand, filter, wash the filter cake with water and petroleum ether for many times, and dry at 60°C to obtain 44.1g of yellow solid. 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: 6-Bromo-3-cyanopyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate

6-Bromo-4-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile (44.1 g, 185 mmol), pyridine (45 mL, 559 mmol), DCM (800 mL) were added to a 1L single-necked flask, and the temperature dropped to Below -10°C, trifluoromethanesulfonic anhydride (50 mL, 297.2 mmol) was slowly added, and after stirring for 1 h, the mixture was naturally raised to room temperature and reacted overnight. Spin dry DCM under reduced pressure, add water (250 mL) to dilute, extract with EA (500 mL×3), collect the organic phase, wash with saturated brine (250 mL), dry with anhydrous sodium sulfate, filter, spin dry the filtrate, and perform silica gel column chromatography Purification (eluent: PE/EA (v/v=50/1-25/1)) to obtain 61.5 g of a yellowish solid, which is the target product, with a yield of 89.7%. Rf=0.45(PE/EA(v/v=5/1).

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

Under nitrogen protection, add 6-bromo-3-cyanopyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate (61.5g, 166mmol), 2-fluoropyridine to a 1L three-necked flask -5-Boronate ester (44.5 g, 200 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (6.8 g, 8.3 mmol), 1 , 4-Dioxane (850 mL), potassium acetate solution (115 mL, 345 mmol, 3 mol/L) was added slowly when the temperature dropped to -10 °C, stirred at this temperature for 1 h and then returned to room temperature naturally and continued the reaction overnight. Filter, wash the filter cake with EA (500mL×3), separate the organic phase from the filtrate, wash with water (500mL), wash with saturated brine (250mL), dry with anhydrous sodium sulfate, filter, spin dry the filtrate, and purify by silica gel column chromatography (eluting) Agent: PE/DCM (v/v=2/1-0/1) to obtain 49 g of white solid, which is the target product, yield 93.0%. Rf=0.50 (PE/EA (v/v=1/1) ).LC-MS: m/z=318.10[M+H] ⁺ ; ¹ H NMR (400MHz, DMSO) δ 9.49(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: 4-(6-Fluoropyridin-3-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)pyridine Azolo[1,5-a]pyridine-3-carbonitrile

6-Bromo-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (8g, 25.23mmol) was added successively in a 250mL single-necked flask under nitrogen protection, followed by Pinacol borate (10 g, 39.39 mmol), potassium acetate (10 g, 101.9 mmol), redistilled toluene (150 mL), purged with nitrogen for 10 min, and then added [1,1'-bis(diphenylphosphine)] Ferrocene] palladium dichloride dichloromethane complex (2.1 g, 2.6 mmol) was bubbled with nitrogen for 10 min, and then heated at 120 °C for overnight reaction. Filter through celite, wash the filter cake with EA (50mL×3), wash the organic phase with water (250mL), wash with saturated brine (250mL), dry with anhydrous sodium sulfate, filter, spin dry, and perform silica gel column chromatography (eluent PE /DCM (v/v=2/1-0/1), collect and spin dry to obtain 8.5g of orange solid, which is the target product (yield 93.0%). Rf=0.15 (DCM). ¹ H NMR (400MHz, CDCl ₃ )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, 2.8 Hz, 1H), 1.40 (s, 12H).

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

Add 4-(6-fluoropyridin-3-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (8.5g, 23mmol), tetrahydrofuran (120mL), under ice bath condition, slowly add sodium hydroxide solution (60mL, 120mmol, 2mol /L), hydrogen peroxide (14 mL, 140 mmol, 30 mass%), stirring at low temperature. After monitoring the completion of the reaction by TLC, slowly add sodium thiosulfate solution (50mL, 150mmol, 3mol/L), after returning to room temperature, add water (250mL), extract with EA (250mL×2), combine the organic phases and wash with 0.1M NaOH solution (500mL) ×2). All aqueous phases were combined, the pH was adjusted to 4 with dilute hydrochloric acid, stirred at room temperature for 15 min, and suction filtered to obtain a wet filter cake. The mother liquor was extracted with EA (250 mL×3), all organic phases were combined, dried over anhydrous sodium sulfate, filtered, spun dry, and obtained by silica gel column chromatography (eluent DCM/MeOH (v/v=100/0-100/1) Light yellow solid. Combine all solids, oven dry at 50°C to obtain light yellow solid 5.1g and be the target product (yield 86.0%). Rf=0.25 (DCM\MeOH=100:1).LC-MS: m/z= 255.10[M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ 10.44-10.37(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).

Example 1: 6-(2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)ethoxy)-4-(6-(6- ((6-Methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5 -a]pyridine-3-carbonitrile

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

In a 50mL single-necked flask, (1S, 4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (300mg, 2.2126mmol), potassium carbonate (1.26g, 9.11mmol) were added successively, Acetone (4.5 mL) was stirred for 5 min in an ice bath, and then 1-bromo-2-chloro-ethane (0.3 mL, 4 mmol) was added dropwise, and the mixture was naturally raised to room temperature and reacted overnight. The reaction solution was filtered, the filter cake was washed with an appropriate amount of EA, the mother liquor was spin-dried, and silica gel column chromatography (eluent was PE/EA=7/1-4/1) was collected to obtain 102 mg of colorless oily liquid, which was the target product ( Yield: 28.52%). ¹ H-NMR (400MHz, CDCl ₃ ): δ4.40 (s, 1H), 4.00 (d, J=7.9Hz, 1H), 3.63 (dd, J=7.9, 1.6Hz, 1H), 3.56-3.48 ( m, 3H), 3.02-2.84 (m, 3H), 2.56 (d, J=9.9Hz, 1H), 1.85 (dd, J=9.8, 1.6Hz, 1H), 1.77-1.72 (m, 1H).

Step 2: 6-(2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)ethoxy)-4-(6-(6-( (6-Methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5- a]pyridine-3-carbonitrile

Add 6-hydroxy-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane into a 10mL single-necked flask in turn -3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (20 mg, 0.04410 mmol, see Intermediate 1 for synthesis), (1S,4S)-5-(2 -Chloroethyl)-2-oxa-5-azabicyclo[2.2.1]heptane (22 mg, 0.13611 mmol), potassium carbonate (0.025 g, 0.18 mmol), DMA (1.5 mL), oil bath 80 Stir overnight at °C. After TLC showed that the reaction was complete, the reaction solution was poured into ice water (10 mL), extracted with EA (30 mL×3), the organic phases were combined and washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and the mother liquor was spin-dried for silica gel column chromatography (DCM/MeOH=50/1-10/1), 11.3 mg of off-white solids were collected, which was the target product (yield 44.2%). LC-MS (ES-API): m/z=579.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.39 (d, J=2.2 Hz, 1H), 8.21 (s, 1H), 8.15 (d, J=1.9 Hz, 1H), 8.10 (d, J=1.7 Hz ,1H),7.78(dd,J＝8.8,2.4Hz,1H),7.65(dd,J＝8.5Hz,1H),7.13(d,J＝2.0Hz,1H),6.70(dd,J＝12.7, 8.7Hz, 2H), 4.43(s, 1H), 4.17-4.11(m, 2H), 4.09(d, J=8.0Hz, 1H), 3.92(s, 3H), 3.88-3.82(m, 2H), 3.82-3.78(m, 2H), 3.68(d, J=8.0Hz, 1H), 3.63-3.58(m, 4H), 3.16-3.05(m, 3H), 2.75-2.69(m, 1H), 2.70- 2.65(m,1H), 2.05-2.00(m,1H), 1.93-1.90(m,1H), 1.81-1.78(m,1H), 1.68-1.64(m,1H). HPLC: 89.75%.

Example 2: 6-(2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)ethoxy)-4-(6-(5 -(4-Methoxybenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3 - Formonitrile

Step 1: 5-(4-Methoxybenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate tert-butyl ester

In a 25mL single-neck flask, add tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-5-carboxylate (1.0g, 4.7mmol), 4-methoxybenzoic acid (1.1g, 7.2g) mmol), DCM was added to dissolve it, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.8 g, 9.4 mmol), 4-dimethylaminopyridine (1.2 g, 9.8 mmol), and reacted at room temperature for 20 h. After the reaction was stopped, 10 mL of water was added to the reaction solution, and the aqueous phase was extracted with DCM (30 mL). The organic phases were combined, washed with water (10 mL×2), dried over anhydrous sodium sulfate, and then concentrated. (v/v=50/1), 1.3 g of colorless liquid was obtained as the product, and the yield was 81.25%. LC-MS: m/z=291.20 [M-tBu+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.51 (d, J=8.7 Hz, 2H), 6.95 (d, J=8.7 Hz, 2H), 3.79(s, 3H), 3.68(s, 2H), 3.56–3.33(m, 4H), 3.20(s, 1H), 3.05(s, 1H), 2.85(s, 2H), 1.39 (s, 9H).

Step 2: (Hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(4-methoxyphenyl)methanone dihydrochloride

5-(4-methoxybenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate tert-butyl ester (600mg, 1.732mmol) was added to the 25mL single-necked flask, EA ( 5mL) to dissolve it, add HCl/EA (4mL, 16mmol, 4mol/L), and react at room temperature for 1h after the addition. After TLC detection, the reaction solution was directly concentrated and dried to obtain 470 mg of solid, which was the product, and the yield was 95.95%. LC-MS: m/z=247.25 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.50 (d, J=8.7 Hz, 2H), 6.96 (d, J=8.7 Hz, 2H), 3.78(s, 3H), 3.66(s, 2H), 3.54(d, J=3.1Hz, 1H), 3.52(d, J=2.6Hz, 1H), 3.32(s, 2H), 2.99( s, 4H).

Step 3: 6-(2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)ethoxy)-4-(6-(5- (4-Methoxybenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3- Formonitrile

6-(2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)ethoxy)-4-(6-fluoro Pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (26 mg, 0.06853 mmol, intermediate 2), hexahydropyrrolo[3,4-c]pyrrole-2 (1H) -yl)(4-methoxyphenyl)methanone dihydrochloride (30 mg, 0.1061 mmol), potassium carbonate (55 mg, 0.39795 mmol), DMSO (1.5 mL), and reacted in an oil bath at 90° C. for 14 h. The reaction solution was cooled to room temperature and then added with 5 mL of water, extracted with EA (20 mL×2), the organic phase was washed with water (5 mL×3), washed with saturated brine (5 mL×2), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to a silica gel column layer analysis, the eluent was DCM/MeOH (v/v=50/1-10/1), and 20 mg of yellow solid was obtained as the product, yield: 48.18%. LC-MS: m/z=606.30 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.31 (d, J=2.2 Hz, 1 H), 8.20 (s, 1 H), 8.14 (d, J=2.0Hz, 1H), 7.70(dd, J=8.7, 2.4Hz, 1H), 7.52(d, J=8.7Hz, 2H), 7.10(d, J=2.0Hz, 1H), 6.91(d, J=8.7Hz, 2H), 6.50(d, J=8.8Hz, 1H), 4.44(s, 1H), 4.16–4.10(m, 2H), 4.09(d, J=8.0Hz, 1H), 4.02( s, 1H), 3.84 (s, 4H), 3.77–3.72 (m, 1H), 3.69 (dd, 2H), 3.61 (s, 1H), 3.51 (s, 3H), 3.17–3.02 (m, 5H) , 2.67 (d, J=9.9Hz, 1H), 2.62 (s, 1H), 1.92 (d, J=9.8Hz, 1H), 1.80 (d, J=9.9Hz, 1H).

Example 3: 6-(2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)ethoxy)-4-(6-(5 -(2,3-Dimethylbenzoyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine -3-carbonitrile

Step 1: 5-(2,3-Dimethylbenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate tert-butyl ester

In a 25mL single-neck flask, add hexahydro-pyrrolo[3,4-c]pyrrole-2(1H)-carboxylate tert-butyl ester (500mg, 2.36mmol), 2,3-dimethylbenzoic acid (530mg, 3.5mmol) ,), DCM was added to dissolve, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (903 mg, 4.71 mmol), 4-dimethylaminopyridine (580 mg, 4.75mmol), reacted at room temperature for 17h. 10 mL of water was added to the reaction solution, the aqueous phase was extracted with DCM (30 mL), the organic phases were combined, washed with water (10 mL × 2), dried over anhydrous sodium sulfate, and concentrated, and subjected to silica gel column chromatography with PE-PE/EA (v/ v=1/1), 660 mg of colorless viscous liquid was obtained as the product, and the yield was 81.37%. LC-MS: m/z=289.25 [M-tBu+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.18 (d, J=7.3 Hz, 1H), 7.12 (t, J=7.5 Hz, 1H), 7.01 (d, J=7.3Hz, 1H), 3.69 (dd, J=12.3, 7.7Hz, 1H), 3.50 (s, 1H), 3.44–3.36 (m, 2H), 3.31–3.24 (m, 1H), 3.17 (dd, J=11.2, 4.8Hz, 1H), 3.03 (dd, J=11.2, 4.5Hz, 1H), 2.95–2.76 (m, 3H), 2.25 (s, 3H), 2.10(s, 3H), 1.39(s, 9H).

Step 2: (Hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2,3-dimethylphenyl)methanone dihydrochloride

5-(2,3-dimethylbenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate tert-butyl ester (330mg, 0.96mmol) was added to a 25mL single-necked flask, EA (3 mL) was dissolved, and HCl/EA (2 mL, 8 mmol, 4 mol/L) was added, and the reaction was performed at room temperature for 1 h after the addition was completed. A white solid was precipitated during the reaction. TLC detected the reaction of the raw materials and the reaction solution was directly concentrated to obtain a white solid, which was dried at 60° C. in a vacuum drying oven to obtain 260 mg of the product, with a yield of 85.54%. LC-MS: m/z=245.30 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO) δ 7.18 (d, J=7.3 Hz, 1H), 7.13 (t, J=7.5 Hz, 1H), 7.03(d,J＝7.3Hz,1H),3.73(dd,J＝12.6,7.9Hz,1H),3.54(dd,J＝12.6,4.1Hz,1H),3.39(dd,J＝10.7,4.8Hz , 1H), 3.29 (dd, J=10.9, 7.3 Hz, 2H), 3.11–2.99 (m, 3H), 3.00–2.86 (m, 2H), 2.25 (s, 3H), 2.12 (s, 3H).

Step 3: 6-(2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)ethoxy)-4-(6-(5- (2,3-Dimethylbenzoyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine- 3-carbonitrile

6-(2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)ethoxy)-4-(6-fluoro Pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (26 mg, 0.07 mmol, intermediate 2), (hexahydropyrrolo[3,4-c]pyrrole-2(1H )-yl)(2,3-dimethylphenyl)methanone dihydrochloride (30 mg, 0.11 mmol), potassium carbonate (55 mg, 0.40 mmol), DMSO (1.5 mL), and reacted in an oil bath at 90 °C for 13 h . The reaction solution was cooled to room temperature and then added with 5 mL of water, extracted with EA (20 mL×2), the organic phase was washed with water (5 mL×3), washed with saturated brine (5 mL×2), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to a silica gel column layer analysis, the eluent was DCM/MeOH (v/v=50/1-20/1), and 20 mg of yellow solid was obtained as the product, and the yield was 48.34%. LC-MS: m/z=604.30 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.31 (d, J=2.0 Hz, 1 H), 8.19 (s, 1 H), 8.15 (d, J=1.8Hz, 1H), 7.70 (dd, J=8.7, 2.3Hz, 1H), 7.18–7.09 (m, 3H), 7.05 (d, J=7.0Hz, 1H), 6.49 (d, J=8.7 Hz, 1H), 4.44 (s, 1H), 4.16–4.08 (m, 3H), 4.00 (dd, J=12.7, 7.7Hz, 1H), 3.87 (dd, J=10.5, 7.8Hz, 1H), 3.79 –3.70(m,2H),3.68(d,J=8.0Hz,1H),3.61(s,1H),3.54–3.46(m,2H),3.40(dd,J=10.8,4.1Hz,1H), 3.18–3.02(m, 6H), 2.67(d, J=10.1Hz, 1H), 2.28(s, 3H), 2.21(s, 3H), 1.92(d, J=10.0Hz, 1H), 1.79(d , J=9.7Hz, 1H).

Example 4: 6-(2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)ethoxy)-4-(6-(6 -(4-Methoxybenzoyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3- Formonitrile

Step 1: tert-Butyl 6-(4-Methoxybenzoyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

2,6-diazaspiro[3.3]heptane-2-carboxylate tert-butyl ester (500mg, 2.52mmol), 4-methoxybenzoic acid (576mg, 3.79mmol) were added to a 50mL single-neck flask, DCM was added, Then, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (980 mg, 5.11 mmol) and 4-dimethylaminopyridine (636 mg, 5.21 mmol) were added, and the reaction was carried out at room temperature for 18 h. 5 mL of water was added to the reaction solution, the aqueous phase was extracted with DCM (20 mL), the organic phases were combined and washed with water (5 mL×2), dried over anhydrous sodium sulfate, and then subjected to silica gel column chromatography. The eluent was DCM-DCM/MeOH (v/v= 50/1) to obtain 270 mg of white solid as the product, with a yield of 32.21%. LC-MS: m/z=333.20 [M+H] ⁺ ;

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.60 (d, J=8.7 Hz, 2H), 6.91 (d, J=8.7 Hz, 2H), 4.35 (d, J=28.9 Hz, 4H), 4.10 (s , 4H), 3.84(s, 3H), 1.44(s, 9H).

Step 2: (4-Methoxyphenyl)(2,6-diazaspiro[3.3]heptan-2-yl)methanone

6-(4-Methoxybenzoyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate tert-butyl ester (200 mg, 0.62 mmol) was added to a 25 mL single-necked flask, DCM (2 mL ) was dissolved, trifluoroacetic acid (0.9 mL, 10 mmol) was added at 0°C, and the reaction was performed at room temperature for 6 h after the addition was completed. The reaction solution was directly concentrated to obtain 130 mg of colorless liquid, which was the product, and the yield was 93.01%. LC-MS: m/z=233.20 [M+H] ⁺ .

Step 3: 6-(2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)ethoxy)-4-(6-(6- (4-Methoxybenzoyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-methan Nitrile

6-(2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)ethoxy)-4-(6-fluoro Pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (22 mg, 0.058 mmol, intermediate 2), (4-methoxyphenyl)(2,6-diazepine Spiro[3.3]hept-2-yl)methanone (40 mg, 0.17 mmol), potassium carbonate (55 mg, 0.40 mmol), DMSO (1.5 mL), and reacted at 90° C. for 14 h in an oil bath. The reaction solution was cooled to room temperature and then added with 5 mL of water, extracted with EA (20 mL×2), the organic phase was washed with water (5 mL×3), washed with saturated brine (5 mL×2), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to a silica gel column layer analysis, the eluent was DCM-DCM/MeOH (v/v=10/1), a yellow solid was obtained and purified by TLC again to obtain 16 mg of off-white solid, which was the product, and the yield was 12.33%. LC-MS: m/z=592.30 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.29 (d, J=1.9 Hz, 1 H), 8.19 (s, 1 H), 8.15 (d, J＝1.7Hz, 1H), 7.69(dd, J＝8.6, 2.2Hz, 1H), 7.65(d, J＝8.7Hz, 2H), 7.10(d, J＝1.8Hz, 1H), 6.93(d, J=8.7Hz, 2H), 6.43(d, J=8.6Hz, 1H), 4.51(s, 2H), 4.43(s, 3H), 4.27(s, 4H), 4.14–4.06(m, 3H), 3.85(s, 3H), 3.68(d, J=6.9Hz, 1H), 3.59(s, 1H), 3.14–3.01(m, 3H), 2.66(d, J=10.1Hz, 1H), 1.91(s , 1H), 1.79 (d, J=9.6Hz, 1H).

Example 5: 6-(2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)ethoxy)-4-(6-(5 -(3-Fluoro-2-methylbenzoyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-3-yl)pyrazolo[1,5-a] Pyridine-3-carbonitrile

Step 1: 5-(3-Fluoro-2-methylbenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate tert-butyl ester

In a 100mL single-neck flask, add hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate tert-butyl ester (500mg, 2.36mmol,), 3-fluoro-2-methylbenzoic acid (550mg, 3.57 mmol), 10 mL of DCM was added to dissolve it, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (903 mg, 4.71 mmol), 4-dimethylaminopyridine (580 mg) , 4.75mmol), and reacted at room temperature for 15h. After the reaction was stopped, the reaction solution was directly concentrated and subjected to silica gel column chromatography with DCM-DCM/MeOH (v/v=50/1) as the eluent to obtain 620 mg of a colorless viscous liquid, which was the product with a yield of 75.56%. LC-MS: m/z=293.20 [M-tBu+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.24-7.17 (m, 1H), 7.05 (d, J=9.0 Hz, 1H), 7.02–6.96 (m, 1H), 3.89 (dd, J=12.2, 8.0Hz, 1H), 3.70–3.50 (m, 3H), 3.41 (dd, J=11.3, 7.3Hz, 1H), 3.32 (s, 1H), 3.23–3.08 (m, 1H), 3.08–3.00 (m, 1H), 2.97 (d, J=6.5Hz, 1H), 2.90–2.81 (m, 1H), 2.23 (d, J=1.4Hz) , 3H), 1.46(s, 9H).

Step 2: (Hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(3-fluoro-2-methylphenyl)methanone dihydrochloride

5-(3-Fluoro-2-methylbenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate tert-butyl ester (620mg, 1.78mmol) was added to the 25mL single-necked flask, Add EA (5 mL) to dissolve it, add HCl/EA (11 mL, 44 mmol, 4 mol/L), and react at room temperature for 2 h after the addition is complete. After the reaction stopped, the reaction solution was directly concentrated to obtain 410 mg of white solid, which was the product, and the yield was 71.73%. LC-MS: m/z=249.20 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.30 (dd, J=13.3, 7.8 Hz, 1H), 7.20 (t, J=8.9 Hz, 1H), 7.10 (d, J=7.4Hz, 1H), 3.73 (dd, J=12.6, 7.8Hz, 1H), 3.55 (dd, J=12.7, 4.0Hz, 1H), 3.44–3.21 (m , 3H), 3.16–3.01 (m, 3H), 3.00–2.87 (m, 2H), 2.15 (d, J=1.6Hz, 3H).

Step 3: 6-(2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)ethoxy)-4-(6-(5- (3-Fluoro-2-methylbenzoyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine -3-carbonitrile

6-(2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)ethoxy)-4-(6-fluoro Pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (20 mg, 0.05271 mmol, intermediate 2), (hexahydropyrrolo[3,4-c]pyrrole-2(1H )-yl)(3-fluoro-2-methylphenyl)methanone dihydrochloride (30 mg, 0.1053 mmol), potassium carbonate (51 mg, 0.36900 mmol), DMSO (1.5 mL), and the reaction was carried out in an oil bath at 90 °C 15h. After the reaction was stopped, the reaction solution was cooled to room temperature, and 5 mL of water was added, extracted with EA (20 mL×2), the organic phase was washed with water (5 mL×3), washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure on a silica gel column Chromatography, the eluent was DCM-DCM/MeOH (v/v=10/1), 16 mg of yellow solid was obtained as the product, and the yield was 49.95%. LC-MS: m/z=608.40 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.31 (d, J=2.0 Hz, 1 H), 8.20 (s, 1 H), 8.15 (d, J=1.7Hz, 1H), 7.70 (dd, J=8.7, 2.3Hz, 1H), 7.23–7.17 (m, 1H), 7.10 (d, J=1.7Hz, 1H), 7.06–6.99 (m, 2H) ), 6.50(d, J＝8.7Hz, 1H), 4.45(s, 1H), 4.21–4.09(m, 3H), 4.00(dd, J＝12.7, 7.7Hz, 1H), 3.87(dd, J＝ 10.5, 7.8Hz, 1H), 3.80–3.65 (m, 5H), 3.55–3.47 (m, 2H), 3.41 (dd, J=10.9, 4.2Hz, 1H), 3.19–3.11 (m, 4H), 3.09 –3.02(m, 1H), 2.71(d, J=10.1Hz, 1H), 2.24(d, J=1.0Hz, 3H), 1.96(d, J=9.8Hz, 1H), 1.82(d, J= 9.8Hz, 1H).

Example 6: 6-(2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)ethoxy)-4-(6-(6 -(3-Fluoro-2-methylbenzoyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine -3-carbonitrile

Step 1: 6-(3-Fluoro-2-methylbenzoyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate tert-butyl ester

2,6-diazaspiro[3.3]heptane-2-carboxylate tert-butyl ester (500mg, 2.52mmol), 3-fluoro-2-methylbenzoic acid (580mg, 3.76mmol) were added to the 50mL single-neck flask, DCM was added, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (980 mg, 5.11 mmol), 4-dimethylaminopyridine (636 mg, 5.21 mmol), at room temperature The reaction was carried out for 15h. After the reaction was stopped, 5 mL of saturated ammonium chloride solution was added to the reaction solution, extracted with DCM (40 mL×2), the organic phase was washed with water (10 mL×2), dried over anhydrous sodium sulfate, and subjected to silica gel column chromatography. The eluent was DCM-DCM/MeOH. =(v/v=50/1), 480 mg of colorless liquid was obtained as the product, and the yield was 56.92%. LC-MS: m/z=335.20 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.22-7.14 (m, 1H), 7.09-6.98 (m, 2H), 4.29 (s, 2H) ), 4.11 (d, J=9.3Hz, 2H), 4.03 (d, J=4.7Hz, 4H), 2.28 (d, J=2.1Hz, 3H), 1.43 (s, 9H).

Step 2: (3-Fluoro-2-methylphenyl)(2,6-diazaspiro[3.3]hept-2-yl)methanone

6-(3-Fluoro-2-methylbenzoyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate tert-butyl ester (480mg, 1.43mmol) was added to the 25mL single-neck flask, It was dissolved in DCM (5 mL), trifluoroacetic acid (1.2 mL, 16 mmol) was added at 0°C, and the reaction was carried out at room temperature for 2.5 h. After TLC detected the reaction, the reaction solution was directly concentrated to obtain 330 mg of liquid, which was the product, and the yield was 98.12%. LC-MS: m/z=235.15 [M+H] ⁺ . Step 4: 6-(2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)ethoxy)-4-(6-(6- (3-Fluoro-2-methylbenzoyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine- 3-carbonitrile

6-(2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)ethoxy)-4-(6-fluoro Pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (23 mg, 0.06062 mmol, intermediate 2), (3-fluoro-2-methylphenyl) (2,6- Diazaspiro[3.3]hept-2-yl)methanone (60 mg, 0.26 mmol), potassium carbonate (55 mg, 0.40 mmol), DMSO (1.5 mL), and reacted in an oil bath at 90° C. for 15 h. After the reaction was stopped, the reaction solution was cooled to room temperature, 5 mL of water was added, extracted with EA (20 mL×2), the organic phase was washed with water (5 mL×3), washed with saturated brine (5 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure Silica gel column chromatography, the eluent was DCM/MeOH (v/v=50/1-10/1), 14 mg of off-white solid was obtained as the product, and the yield was 38.90%. LC-MS: m/z=594.25 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.28 (d, J=2.1 Hz, 1 H), 8.19 (s, 1 H), 8.15 (d, J=2.0Hz, 1H), 7.69 (dd, J=8.6, 2.3Hz, 1H), 7.23–7.18 (m, 1H), 7.11–7.04 (m, 3H), 6.42 (d, J=8.6Hz, 1H) ), 4.42(d, J＝11.7Hz, 3H), 4.30(d, J＝8.9Hz, 2H), 4.21(d, J＝8.7Hz, 2H), 4.15–4.07(m, 5H), 3.68(d , J＝8.1Hz, 1H), 3.60(s, 1H), 3.13–3.02(m, 3H), 2.66(d, J＝10.2Hz, 1H), 2.33(d, J＝2.0Hz, 3H), 1.91 (d, J=10.3 Hz, 1H), 1.79 (d, J=9.3 Hz, 1H).

Example 7: 4-(6-(6-(2,3-Dimethylbenzoyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-3-yl)- 6-(2-(3-oxo-8-azabicyclo[3.2.1]octan-8-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

Step 1: tert-Butyl 6-(2,3-Dimethylbenzoyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

2,6-diazaspiro[3.3]heptane-2-carboxylate tert-butyl ester (500mg, 2.52mmol), 2,3-dimethylbenzoic acid (570mg, 3.80mmol) were added to the 50mL single-neck flask, and the DCM, then added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (962 mg, 5.02 mmol), 4-dimethylaminopyridine (620 mg, 5.07 mmol), and reacted at room temperature 23h. After the reaction was stopped, 5 mL of saturated ammonium chloride solution was added to the reaction solution, extracted with DCM (30 mL×2), the organic phase was washed with water (10 mL×2), dried over anhydrous sodium sulfate, and subjected to silica gel column chromatography. The eluent was DCM to obtain colorless 360 mg of liquid is the product, and the yield is 43.20%. LC-MS: m/z=331.30 [M+H] ⁺ .

Step 2: (2,3-Dimethylphenyl)(2,6-diazaspiro[3.3]heptan-2-yl)methanone

6-(2,3-dimethylbenzoyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate tert-butyl ester (360mg, 1.090mmol) was added to a 25mL single-necked flask, DCM was added (4 mL) was dissolved, trifluoroacetic acid (0.8 mL, 10 mmol) was added at 0° C., and the reaction was carried out at room temperature for 2 h. After the reaction, the reaction solution was directly concentrated for the next step. LC-MS: m/z=231.10 [M+H] ⁺ .

Step 3: 4-(6-(6-(2,3-Dimethylbenzoyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-3-yl)-6 -(2-(3-oxo-8-azabicyclo[3.2.1]octan-8-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

4-(6-Fluoro-3-yl)-6-(2-(3-oxo-8-azabicyclo[3.2.1]octan-8-yl)ethoxy)pyridine was added to the 5mL single-necked flask Azolo[1,5-a]pyridine-3-carbonitrile (20 mg, 0.049 mmol, intermediate 3), 2,3-dimethylphenyl)(2,6-diazaspiro[3.3]heptane -2-yl)methanone (46 mg, 0.20 mmol), potassium carbonate (45 mg, 0.33 mmol), DMSO (1.0 mL), and reacted in an oil bath at 90° C. for 15 h. After the reaction was stopped, the reaction solution was cooled to room temperature, 5 mL of water was added, extracted with EA (20 mL×2), the organic phase was washed with water (5 mL×3), washed with saturated brine (5 mL×2), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure Silica gel column chromatography, the eluent was DCM/MeOH (v/v=10/1), and 5 mg of yellow solid was obtained as the product, and the yield was 16.46%. LC-MS: m/z=616.30 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.29 (d, J=1.8 Hz, 1 H), 8.19 (s, 2H), 7.69 (dd, J=8.6, 2.1Hz, 1H), 7.19 (d, J=6.5Hz, 1H), 7.15–7.08 (m, 3H), 6.42 (d, J=8.6Hz, 1H), 4.40 (s, 2H), 4.29(d,J=8.8Hz,2H),4.25–4.19(m,4H),4.10(s,2H),3.73(s,1H),3.61(d,J=4.4Hz,1H),3.09(t , J＝5.3Hz, 2H), 2.73(d, J＝14.3Hz, 2H), 2.30(s, 6H), 2.25(d, J＝15.8Hz, 2H), 2.12–2.07(m, 2H), 1.66 (d, J=7.9 Hz, 2H).

Example 8: 4-(6-(5-(2,3-Dimethylbenzoyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-3-yl) -6-(2-(3-oxo-8-azabicyclo[3.2.1]octan-8-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

Step 1: 5-(2,3-Dimethylbenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate tert-butyl ester

In a 25mL single-necked flask, add hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate tert-butyl ester (500mg, 2.36mmol), 2,3-dimethylbenzoic acid (530mg, 3.53mmol, ), DCM was added to dissolve it, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (903 mg, 4.71 mmol), 4-dimethylaminopyridine (580 mg, 4.7475 mmol), and reacted at room temperature for 17 h. 10 mL of water was added to the reaction solution, the aqueous phase was extracted with DCM (30 mL), the organic phases were combined, washed with water (10 mL × 2), dried over anhydrous sodium sulfate, and concentrated, and subjected to silica gel column chromatography with PE-PE/EA (v/ v=1/1), 660 mg of colorless viscous liquid was obtained as the product, and the yield was 81.37%. LC-MS: m/z=289.25 [M-tBu+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.18 (d, J=7.3 Hz, 1H), 7.12 (t, J=7.5 Hz, 1H), 7.01 (d, J=7.3Hz, 1H), 3.69 (dd, J=12.3, 7.7Hz, 1H), 3.50 (s, 1H), 3.44–3.36 (m, 2H), 3.31–3.24 (m, 1H), 3.17 (dd, J=11.2, 4.8Hz, 1H), 3.03 (dd, J=11.2, 4.5Hz, 1H), 2.95–2.76 (m, 3H), 2.25 (s, 3H), 2.10(s, 3H), 1.39(s, 9H).

Step 2: (Hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2,3-dimethylphenyl)methanone dihydrochloride

5-(2,3-dimethylbenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate tert-butyl ester (330mg, 0.96mmol) was added to a 25mL single-necked flask, EA (3 mL) was dissolved, and HCl/EA (2 mL, 8 mmol, 4 mol/L) was added, and the reaction was performed at room temperature for 1 h after the addition was completed. A white solid was precipitated during the reaction. TLC detected the reaction of the raw materials and the reaction solution was directly concentrated to obtain a white solid, which was dried at 60° C. in a vacuum drying oven to obtain 260 mg of the product, with a yield of 85.54%. LC-MS: m/z=245.30 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.18 (d, J=7.3 Hz, 1H), 7.13 (t, J=7.5 Hz, 1H), 7.03 (d, J=7.3Hz, 1H), 3.73 (dd, J=12.6, 7.9Hz, 1H), 3.54 (dd, J=12.6, 4.1Hz, 1H), 3.39 (dd, J=10.7 ,4.8Hz,1H),3.29(dd,J＝10.9,7.3Hz,2H),3.11-2.99(m,3H),3.00-2.86(m,2H),2.25(s,3H),2.12(s, 3H).

Step 3: 4-(6-(5-(2,3-Dimethylbenzoyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-3-yl)- 6-(2-(3-oxo-8-azabicyclo[3.2.1]octan-8-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

4-(6-Fluoro-3-yl)-6-(2-(3-oxo-8-azabicyclo[3.2.1]octan-8-yl)ethoxy)pyridine was added to the 5mL single-necked flask Azolo[1,5-a]pyridine-3-carbonitrile (20 mg, 0.049 mmol, Intermediate 3), (hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl) (2, 3-Dimethylphenyl)methanone dihydrochloride (27 mg, 0.085 mmol), potassium carbonate (45 mg, 0.33 mmol), DMSO (1.0 mL), and reacted in an oil bath at 90° C. for 16 h. After the reaction was stopped, the reaction solution was cooled to room temperature, and 5 mL of water was added, extracted with EA (20 mL×2), the organic phase was washed with water (5 mL×3), washed with saturated brine (5 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure Silica gel column chromatography, eluent is DCM/MeOH (v/v=20/1), 10 mg of yellow solid is obtained as the product, and the yield is 32.18%. LC-MS: m/z=630.30 [M+H] ⁺ ; ¹ H NMR: (400 MHz, CDCl ₃ ) δ 8.32 (s, 1H), 8.20 (s, 1H), 8.19 (s, 1H), 7.71 (d, J=8.5Hz, 1H), 7.18–7.09 (m, 3H), 7.05 (d, J=6.9Hz, 1H), 6.50 (d, J=8.7Hz, 1H), 4.24 (t, J= 4.6Hz, 2H), 4.01(dd, J=12.4, 7.7Hz, 1H), 3.85(d, J=7.8Hz, 1H), 3.80–3.71(m, 3H), 3.62(s, 1H), 3.51( d, J＝5.6Hz, 2H), 3.41(d, J＝6.8Hz, 1H), 3.20–3.00(m, 6H), 2.74(d, J＝15.1Hz, 2H), 2.28(s, 3H), 2.23(s, 1H), 2.21(s, 3H), 2.10(s, 2H), 1.67(d, J=7.8Hz, 2H).

Example 9: 6-(2-(2,5-Diazabicyclo[2.2.1]heptan-2-yl)ethoxy)-4-(6-(5-(3-fluoro-2- Methylbenzoyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-3-yl)pyrazolo1,5-a]pyridine-3-carbonitrile

Step 1: tert-Butyl 5-(2-Chloroethyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

In a 25mL single-neck flask, add 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate tert-butyl ester (400mg, 2.02mmol), add _CH3CN (6mL), add potassium carbonate (1.0g, 7.2 mmol), 1-bromo-2-chloroethane (0.5 mL, 6 mmol), and reacted at room temperature for 17 h after the addition was complete. After the reaction, the reaction solution was suction filtered, the filter cake EA was washed several times, and the filtrate was concentrated by silica gel column chromatography. rate 24.71%. LC-MS: m/z=261.20 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.30 (d, J=49.6 Hz, 1H), 3.51 (t, J=6.9 Hz, 3H) ,3.17(t,J＝8.7Hz,1H),3.01(dd,J＝26.6,9.4Hz,1H),2.91(t,J＝6.6Hz,2H),2.60(dd,J＝53.6,9.4Hz, 1H), 1.91–1.79 (m, 2H), 1.76–1.67 (m, 1H), 1.46 (s, 9H).

Step 2: 5-(2-((3-cyano-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl)oxy)ethyl)- 2,5-Diazabicyclo[2.2.1]heptane-2-carboxylate tert-butyl ester

4-(6-fluoropyridin-3-yl)-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile (50mg, 0.20mmol), potassium carbonate (85mg, 0.62 mmol), tert-butyl 5-(2-chloroethyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (130 mg, 0.50 mmol), DMF (2.5 mL), The reaction was carried out at 80°C for 5h. After the reaction was stopped, the reaction solution was cooled to room temperature, 10 mL of water was added, extracted with EA (40 mL×2), the organic phase was washed with water (5 mL×3), washed with saturated brine (5 mL), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure on a silica gel column Chromatography, the eluent was DCM/MeOH (v/v=10/1), 70 mg was obtained as the product, and the yield was 74.37%. LC-MS: m/z=479.30 [M+H] ⁺ .

Step 3: 5-(2-((3-Cyano-4-(6-(5-(3-fluoro-2-methylbenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2 (1H)-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl)oxy)ethyl)-2,5-diazabicyclo[2.2.1]heptane -2-Carboxylic acid tert-butyl ester

5-(2-((3-cyano-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl)oxy)ethyl )-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate tert-butyl ester (70 mg, 0.1463 mmol), (hexahydropyrrolo[3,4-c]pyrrole-2(1H) -yl)(3-fluoro-2-methylphenyl)methanone dihydrochloride (55 mg, 0.1712 mmol, Example 5, step 2), potassium carbonate (85 mg, 0.61501 mmol), DMSO (1.5 mL), oil The bath was reacted at 90°C for 24h. The reaction solution was cooled to room temperature and then added with 5 mL of water, extracted with EA (20 mL×2), the organic phase was washed with water (5 mL×3), washed with saturated brine (5 mL×2), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to a silica gel column layer analysis, the eluent was DCM/MeOH (v/v=10/1), and 70 mg of yellow solid was obtained as the product, and the yield was 67.70%. LC-MS: m/z=707.15 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.31 (d, J=2.2 Hz, 1 H), 8.19 (s, 1 H), 8.13 (d, J=1.9Hz, 1H), 7.70 (dd, J=8.7, 2.4Hz, 1H), 7.21–7.18 (m, 1H), 7.10 (d, J=1.9Hz, 1H), 7.04–7.00 (m, 2H) ), 6.50 (d, J=8.7Hz, 1H), 4.12–4.07 (m, 2H), 4.03–3.97 (m, 1H), 3.94–3.84 (m, 2H), 3.82–3.69 (m, 3H), 3.60(s, 2H), 3.53-3.48(m, 3H), 3.45-3.39(m, 2H), 3.22-3.13(m, 4H), 3.05(s, 3H), 2.24(d, J=1.6Hz, 3H), 1.46(s, 9H).

Step 4: 6-(2-(2,5-Diazabicyclo[2.2.1]heptan-2-yl)ethoxy)-4-(6-(5-(3-fluoro-2-methyl) ylbenzoyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-3-yl)pyrazolo1,5-a]pyridine-3-carbonitrile

Add 5-(2-((3-cyano-4-(6-(5-(3-fluoro-2-methylbenzoyl)hexahydropyrrolo[3,4-c]pyrrole to a 10mL single-neck bottle -2(1H)-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl)oxy)ethyl)-2,5-diazabicyclo[2.2.1] Heptane-2-carboxylate tert-butyl ester (70mg, 0.10mmol), add EA (2mL) to dissolve it, add HCl/EA (0.3mL, 1mmol, 4mol/L) under ice bath, naturally rise to room temperature and react for 30min . TLC detected that the reaction of the raw materials was completed, the reaction solution was directly concentrated, then 2 mL of methanol was added to dissolve it, potassium carbonate (200 mg, 1.45 mmol) was added, and the mixture was stirred at room temperature for 40 min to dissociate the base. The reaction solution was directly concentrated by silica gel column chromatography, the eluent was DCM/MeOH (v/v=10/1), and a yellow solid was obtained and purified by TLC again to obtain 24 mg of light yellow solid, which was the product, and the yield was 39.94%. LC-MS: m/z=607.30 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.31 (d, J=2.1 Hz, 1 H), 8.19 (s, 1 H), 8.12 (d, J=1.7Hz, 1H), 7.69 (dd, J=8.7, 2.3Hz, 1H), 7.20 (dd, J=13.1, 7.7Hz, 1H), 7.07 (d, J=1.8Hz, 1H), 7.04– 6.99(m, 2H), 6.49(d, J=8.7Hz, 1H), 4.21(s, 1H), 4.09(t, J=4.9Hz, 2H), 4.00(dd, J=12.8, 7.7Hz, 1H) ),3.86(dd,J＝10.5,7.7Hz,1H),3.80–3.73(m,2H),3.72(s,2H),3.61(d,J＝9.8Hz,1H),3.51(dd,J＝ 10.9, 6.4Hz, 2H), 3.41 (dd, J=11.0, 4.2Hz, 1H), 3.23 (d, J=12.2Hz, 1H), 3.20–3.16 (m, 2H), 3.15 (s, 2H), 3.04 (dd, J=12.3, 6.5Hz, 2H), 2.23 (s, 3H), 2.09 (d, J=10.6Hz, 1H), 2.00 (d, J=10.5Hz, 1H).

Example 10: 4-(6-(5-(3-Fluoro-2-methylbenzoyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-3-yl )-6-(2-(3-oxo-8-azabicyclo[3.2.1]octan-8-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

4-(6-Fluoro-3-yl)-6-(2-(3-oxo-8-azabicyclo[3.2.1]octan-8-yl)ethoxy)pyridine was added to the 5mL single-necked flask Azolo[1,5-a]pyridine-3-carbonitrile (25 mg, 0.06 mmol, Intermediate 3), (hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(3- Fluoro-2-methylphenyl)methanone dihydrochloride (32 mg, 0.10 mmol, step 2 of Example 5), potassium carbonate (53 mg, 0.38 mmol), DMSO (1.0 mL), and reacted in an oil bath at 90 °C for 13 h . After the reaction was stopped, the reaction solution was cooled to room temperature, and 5 mL of water was added, extracted with EA (20 mL×2), the organic phase was washed with water (5 mL×3), washed with saturated brine (5 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure Silica gel column chromatography, the eluent was DCM/MeOH (v/v=20/1), and 5 mg of solid was obtained as the product, and the yield was 12.79%. LC-MS: m/z=634.40 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.34 (d, J=1.9 Hz, 1 H), 8.22 (s, 1 H), 8.21 (s, 1H), 7.73 (dd, J=8.7, 2.2Hz, 1H), 7.24–7.20 (m, 1H), 7.12 (s, 1H), 7.06–7.01 (m, 2H), 6.52 (d, J=8.8Hz) ,1H),4.27(s,2H),4.02(dd,J=12.7,7.7Hz,1H),3.91-3.86(m,1H),3.82-3.73(m,3H),3.53(dd,J=10.1 ,6.2Hz,2H),3.43(dd,J＝11.0,4.2Hz,1H),3.18(dd,J＝11.0,5.1Hz,2H),3.14–3.10(m,2H),3.09–3.06(m, 1H), 2.77(d, J=15.7Hz, 2H), 2.64(s, 1H), 2.29(s, 1H), 2.26(s, 4H), 2.11(s, 2H), 1.69(d, J=8.0 Hz, 2H).

Example 11: 4-(6-(5-(4-Methoxybenzoyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-3-yl)-6 -(2-(3-oxo-8-azabicyclo[3.2.1]octan-8-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

4-(6-Fluoro-3-yl)-6-(2-(3-oxo-8-azabicyclo[3.2.1]octan-8-yl)ethoxy)pyridine was added to the 5mL single-necked flask Azolo[1,5-a]pyridine-3-carbonitrile (27 mg, 0.067 mmol, Intermediate 3), (hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(4- Methoxyphenyl)methanone dihydrochloride (35 mg, 0.11 mmol, Example 2, step 2), potassium carbonate (61 mg, 0.44 mmol), DMSO (1.5 mL), and reacted at 90° C. for 17 h in an oil bath. After the reaction was stopped, the reaction solution was cooled to room temperature, and 5 mL of water was added, extracted with EA (20 mL×2), the organic phase was washed with water (5 mL×3), and washed with brine (5 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure Silica gel column chromatography, eluent is DCM/MeOH (v/v=20/1), after the product is obtained, TLC is purified again to obtain 12 mg of yellow solid, which is the product, and the yield is 28.52%. LC-MS: m/z=632.30 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.32 (d, J=1.8 Hz, 1H), 8.20 (d, J=7.0 Hz, 2H) ,7.71(dd,J＝8.6,2.1Hz,1H),7.52(d,J＝8.6Hz,2H),7.10(d,J＝1.5Hz,1H),6.91(d,J＝8.6Hz,2H) ,6.50(d,J=8.8Hz,1H),4.24(t,J=5.2Hz,2H),4.02(s,1H),3.84(s,3H),3.73(s,1H),3.66(s, 4H), 3.61(d, J＝3.9Hz, 1H), 3.51(s, 3H), 3.11–3.08(m, 2H), 2.74(d, J＝14.7Hz, 2H), 2.25(d, J＝15.8 Hz, 2H), 2.09 (d, J=5.3 Hz, 2H), 1.67 (d, J=7.9 Hz, 2H), 1.29 (s, 2H).

Example 12: 4-(6-(6-(4-Methoxybenzoyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-3-yl)-6- (2-(3-oxo-8-azabicyclo[3.2.1]octan-8-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

4-(6-Fluoro-3-yl)-6-(2-(3-oxo-8-azabicyclo[3.2.1]octan-8-yl)ethoxy)pyridine was added to the 5mL single-necked flask Azolo[1,5-a]pyridine-3-carbonitrile (32 mg, 0.079 mmol, Intermediate 3), (4-methoxyphenyl)(2,6-diazaspiro[3.3]heptane- 2-yl)methanone (104 mg, 0.45 mmol, Example 4, step 2), potassium carbonate (70 mg, 0.51 mmol), DMSO (1.5 mL), and reacted in an oil bath at 90° C. for 16 h. After the reaction, the reaction solution was cooled to room temperature and then added with 5 mL of water, extracted with EA (20 mL×2), the organic phase was washed with water (5 mL×4), washed with saturated brine (5 mL×2), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure Silica gel column chromatography, the eluent is DCM/MeOH (v/v=10/1), after obtaining the product, the product was purified by TLC again to obtain 15 mg of yellow solid, which was the product, and the yield was 30.46%. LC-MS: m/z=618.30 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.29 (d, J=1.9 Hz, 1 H), 8.21-8.17 (m, 2H), 7.69 ( dd,J＝8.6,2.2Hz,1H),7.64(d,J＝8.7Hz,2H),7.09(d,J＝1.8Hz,1H),6.92(d,J＝8.7Hz,2H),6.42( d, J＝8.6Hz, 1H), 4.46(d, J＝39.3Hz, 4H), 4.26(s, 3H), 4.22(t, J＝5.5Hz, 2H), 3.85(s, 3H), 3.65( s,3H),3.08(t,J＝5.5Hz,2H),2.71(d,J＝13.4Hz,2H),2.24(d,J＝15.8Hz,2H),2.10–2.05(m,2H), 1.65 (d, J=7.9 Hz, 2H).

Example 13: 4-(6-(5-(4-Methoxybenzoyl)-2,5-diazabicyclo[2.2.1]octan-2-yl)pyridin-3-yl)- 6-(2-(3-oxo-8-azabicyclo[3.2.1]octan-8-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

Step 1: tert-Butyl 5-(4-Methoxybenzoyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

2,5-diazabicyclo[2.2.1]heptane-2-carboxylate tert-butyl ester (300mg, 1.51mmol), 4-methoxybenzoic acid (695mg, 4.57mmol) were added to the 25mL single-neck flask, and the This was dissolved in DCM (6 mL), followed by the addition of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (590 mg, 3.08 mmol), 4-dimethylaminopyridine (375 mg, 3.07 mmol), added and reacted at room temperature for 21h. After the reaction was stopped, 5 mL of saturated ammonium chloride solution was added to the reaction solution, the aqueous phase was extracted with DCM (20 mL×2), the organic phases were combined, washed with water (5 mL×2), dried over anhydrous sodium sulfate, and subjected to silica gel column chromatography. The eluent was DCM/MeOH (v/v=50/1), 400 mg of white solid was obtained as the product, and the yield was 79.53%.

LC-MS: m/z=333.25 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.49 (d, J=7.8 Hz, 2H), 6.93 (d, J=7.9 Hz, 2H) ,4.55–4.43(m,1H),3.84(s,3H),3.69(d,J=11.2Hz,1H),3.61–3.46(m,2H),3.40(s,1H),1.90(s,1H ), 1.83(d, J=9.9Hz, 2H), 1.49(s, 6H), 1.43(s, 3H).

Step 2: (2,5-Diazabicyclo[2.2.1]hept-2-yl)(4-methoxyphenyl)methanone hydrochloride

5-(4-methoxybenzoyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate tert-butyl ester (200mg, 0.60mmol) was added to the 25mL single-necked flask, EA was added (3 mL) to dissolve it, add HCl/EA (2.1 mL, 8.4 mmol, 4 mol/L), and react at room temperature for 4 h after the addition. After the reaction stopped, the reaction solution was directly concentrated to obtain 130 mg of white solid, which was the product, and the yield was 95.87%. LC-MS: m/z=233.20 [M+H] ⁺ .

Step 3: 4-(6-(5-(4-Methoxybenzoyl)-2,5-diazabicyclo[2.2.1]octan-2-yl)pyridin-3-yl)-6 -(2-(3-oxo-8-azabicyclo[3.2.1]octan-8-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

4-(6-Fluoro-3-yl)-6-(2-(3-oxo-8-azabicyclo[3.2.1]octan-8-yl)ethoxy)pyridine was added to the 5mL single-necked flask Azolo[1,5-a]pyridine-3-carbonitrile (27 mg, 0.067 mmol, Intermediate 3), (2,5-diazabicyclo[2.2.1]heptan-2-yl)(4-methyl) Oxyphenyl)methanone hydrochloride (30 mg, 0.1116 mmol), potassium carbonate (55 mg, 0.40 mmol), DMSO (1.5 mL), and reacted at 90° C. for 29 h in an oil bath. After the reaction, the reaction solution was cooled to room temperature and then added with 5 mL of water, extracted with EA (20 mL×2), the organic phase was washed with water (5 mL×4), washed with saturated brine (5 mL×2), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure Silica gel column chromatography, the eluent is DCM/MeOH (v/v)=10/1, after the product is obtained, TLC purification is performed again to obtain 5 mg of off-white solid, which is the product, and the yield is 12.15%. LC-MS: m/z=618.25 [M+H] ⁺ ; ¹ H NMR: (400 MHz, CDCl ₃ ) δ 8.28 (d, J=30.5 Hz, 1 H), 8.20 (s, 2H), 7.70 (d , J＝12.5Hz, 1H), 7.52(s, 2H), 7.10(d, J＝17.3Hz, 1H), 6.91(dd, J＝31.2, 7.5Hz, 2H), 6.50(dd, J＝37.0, 8.9Hz, 1H), 4.24(s, 2H), 3.84(d, J=15.9Hz, 4H), 3.71(s, 2H), 3.61(d, J=4.7Hz, 2H), 3.09(s, 2H) ,2.73(d,J＝15.6Hz,2H),2.25(d,J＝15.9Hz,2H),2.07(s,3H),2.03(s,2H),1.66(d,J＝8.0Hz,2H) , 0.88 (t, J=6.6Hz, 2H).

Example 14: 4-(6-(5-(3-Fluoro-2-methylbenzoyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridine-3- yl)-6-(2-(3-oxo-8-azabicyclo[3.2.1]octan-8-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-methyl Nitrile

Step 1: 5-(3-Fluoro-2-methylbenzoyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate tert-butyl ester

2,5-diazabicyclo[2.2.1]heptane-2-carboxylate tert-butyl ester (300mg, 1.51mmol) was added to a 25mL single-neck flask, 3-fluoro-2-methylbenzoic acid (463mg, 3.00 mmol), DCM (6 mL) was added to dissolve it, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (576 mg, 3.00 mmol), 4-dimethylaminopyridine (363 mg, 2.97 mmol), and reacted at room temperature for 17 h after the addition was completed. After the reaction was stopped, 5 mL of saturated ammonium chloride solution was added to the reaction solution, the aqueous phase was extracted with DCM (20 mL×2), the organic phases were combined, washed with water (5 mL×2), dried over anhydrous sodium sulfate, and subjected to silica gel column chromatography. The eluent was DCM/MeOH (v/v=50/1), 160 mg of colorless liquid was obtained as the product, and the yield was 31.62%. LC-MS: m/z=335.20 [M+H] ⁺ .

Step 2: 2,5-Diazabicyclo[2.2.1]hept-2-yl(3-fluoro-2-methylphenyl)methanone hydrochloride

5-(3-Fluoro-2-methyl-benzoyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate tert-butyl ester (160 mg, 0.48 mmol) was added to a 25 mL single-necked flask. ), add EA (3mL) to dissolve it, add HCl/EA (1.6mL, 6.4mmol, 4mol/L), and react at room temperature for 1.5h after completion. After the reaction stopped, the reaction solution was directly concentrated to obtain 125 mg of white solid, which was the product, and the yield was 96.51%. LC-MS: m/z=235.10 [M+H] ⁺ .

Step 3: 4-(6-(5-(3-Fluoro-2-methylbenzoyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl )-6-(2-(3-oxo-8-azabicyclo[3.2.1]octan-8-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

4-(6-Fluoro-3-yl)-6-(2-(3-oxo-8-azabicyclo[3.2.1]octan-8-yl)ethoxy)pyridine was added to the 5mL single-necked flask Azolo[1,5-a]pyridine-3-carbonitrile (25 mg, 0.062 mmol), 2,5-diazabicyclo[2.2.1]hept-2-yl(3-fluoro-2-methylbenzene yl) ketone hydrochloride (55 mg, 0.2032 mmol, intermediate 3), potassium carbonate (54 mg, 0.39 mmol), DMSO (1.5 mL), and reacted in an oil bath at 90° C. for 18 h. After the reaction, the reaction solution was cooled to room temperature, and then 5 mL of water was added, extracted with EA (20 mL×2), the organic phase was washed with water (5 mL×4), washed with saturated brine (5 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure Silica gel column chromatography, the eluent is DCM/MeOH (v/v=10/1), after the product is obtained, it is purified by TLC again to obtain 14 mg of light yellow solid, which is the product, and the yield is 36.63%. LC-MS: m/z=620.30 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.29 (d, J=25.2 Hz, 1 H), 8.25-8.14 (m, 2H), 7.72 ( dd, J=15.1, 5.9Hz, 1H), 7.25–7.15 (m, 1H), 7.14–6.92 (m, 3H), 6.49 (t, J=9.6Hz, 1H), 5.05 (d, J=13.3Hz) ,1H),4.24(d,J＝5.5Hz,2H),3.78(s,1H),3.70(d,J＝9.5Hz,1H),3.62(d,J＝7.7Hz,1H),3.48(d , J＝40.1Hz, 1H), 3.27 (dd, J＝24.6, 9.7Hz, 1H), 3.09 (dd, J＝10.5, 5.2Hz, 2H), 2.73 (d, J＝15.7Hz, 2H), 2.30 -2.19(m, 4H), 2.10(s, 3H), 2.04(s, 2H), 1.67(d, J=8.0Hz, 2H), 0.87(d, J=10.0Hz, 2H).

Example 15: 4-(6-(5-(2,3-Dimethylbenzoyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl )-6-(2-(3-oxo-8-azabicyclo[3.2.1]octan-8-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

Step 1: tert-Butyl 5-(2,3-Dimethylbenzoyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

2,5-diazabicyclo[2.2.1]heptane-2-carboxylate tert-butyl ester (300mg, 1.51mmol) was added to a 25mL single-neck flask, 2,3-dimethylbenzoic acid (463mg, 3.08mmol) was added ), DCM (6 mL) was added to dissolve it, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (576 mg, 3.00 mmol), 4-dimethylaminopyridine ( 363 mg, 2.97 mmol), and reacted at room temperature for 17 h after the addition was completed. After the reaction was stopped, 5 mL of saturated ammonium chloride solution was added to the reaction solution, the aqueous phase was extracted with DCM (20 mL×2), the organic phases were combined, washed with water (5 mL×2), dried over anhydrous sodium sulfate, and subjected to silica gel column chromatography. The eluent was DCM/MeOH (v/v=50/1), 210 mg of colorless liquid was obtained as the product, and the yield was 42.00%. LC-MS: m/z=331.30 [M+H] ⁺ .

Step 2: 2,5-Diazabicyclo[2.2.1]hept-2-yl(2,3-dimethylphenyl)methanone hydrochloride

5-(2,3-dimethylbenzoyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate tert-butyl ester (210mg, 0.64mmol) was added to the 25mL single-neck flask, EA (3 mL) was added to dissolve it, HCl/EA (2.4 mL, 9.6 mmol, 4 mol/L) was added, and the reaction was performed at room temperature for 1 h after the addition. After the reaction stopped, the reaction solution was directly concentrated to obtain 160 mg of white solid, which was the product, and the yield was 94.35%. LC-MS: m/z=231.15 [M+H] ⁺ .

Step 3: 4-(6-(5-(2,3-Dimethylbenzoyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl) -6-(2-(3-oxo-8-azabicyclo[3.2.1]octan-8-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

4-(6-Fluoro-3-yl)-6-(2-(3-oxo-8-azabicyclo[3.2.1]octan-8-yl)ethoxy)pyridine was added to the 5mL single-necked flask Azolo[1,5-a]pyridine-3-carbonitrile (26 mg, 0.064 mmol, Intermediate 3), 2,5-diazabicyclo[2.2.1]heptan-2-yl(2,3-di Methylphenyl)methanone hydrochloride (120 mg, 0.45 mmol), potassium carbonate (52 mg, 0.38 mmol), DMSO (1.5 mL), and reacted at 90° C. for 16.5 h in an oil bath. After the reaction, the reaction solution was cooled to room temperature and then added with 5 mL of water, extracted with EA (20 mL×2), the organic phase was washed with water (5 mL×4), washed with saturated brine (5 mL×2), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure Silica gel column chromatography, the eluent was DCM/MeOH (v/v=10/1), 13 mg of yellow solid was obtained as the product, and the yield was 32.92%. LC-MS: m/z=616.35 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.29 (dd, J=24.3, 1.9 Hz, 1 H), 8.20 (t, J=4.8 Hz, 2H), 7.74–7.65 (m, 1H), 7.22–7.05 (m, 4H), 6.49 (t, J=9.6Hz, 1H), 5.03 (d, J=17.0Hz, 1H), 4.23 (dd, J =11.4,5.7Hz,2H),3.78(s,1H),3.70(d,J=10.6Hz,1H),3.53–3.40(m,1H),3.25(dd,J=24.9,9.7Hz,1H) ,3.09(dd,J＝10.8,5.4Hz,2H),2.72(d,J＝16.1Hz,2H),2.32(s,2H),2.27(s,1H),2.25(s,2H),2.23( s, 3H), 2.10(s, 1H), 2.07(s, 2H), 2.02(s, 2H), 1.66(d, J=8.1Hz, 2H), 0.88(dd, J=9.5, 5.9Hz, 2H) ).

Using suitable starting materials, the target compounds (223)-(227) of Examples 223-227, the target compounds (19)-(85) of Examples 19-85, and the target compounds (87)-(87)-( 90), the target compound (189) of Example 189, the target compound (195) of Example 195, the target compound (202)-(206) of Examples 202-206, the target compound (208) of Example 208-210 -(210), the target compound (215)-(216) of Examples 215-216, the target compound (218) of Example 218, the target compound (220) of Example 220, refer to Example 1 or Synthesis Scheme 1 Synthetic route Prepared, the specific structure and characterization data are described in Table 1 below:

Table 1

Using suitable starting materials, target compounds (91)-(92) of Examples 91-92, target compounds (94)-(107) of Examples 94-107, target compounds (111)-(111)-( 122), the target compounds (126)-(135) of Examples 126-135, the target compounds (139)-(142) of Examples 139-142, the target compounds (150)-(170) of Examples 150-170 , the target compounds (173)-(177) of Examples 173-177, the target compounds (186)-(188) of Examples 186-188, the target compounds (190)-(194) of Examples 190-194, Target Compounds (196)-(201) of Examples 196-201, Target Compounds (207) of Example 207, Target Compounds (211)-(214) of Examples 211-214, Target Compounds (221) of Example 221 Reference Example 1 or Synthetic Scheme 1 synthetic route is prepared, and the specific structure and characterization data are described in Table 2 below:

Table 2

Using suitable starting materials, the target compound (228) of Example 228, the target compound (16)-(18) of Examples 16-18, the target compound (86) of Example 86, and the target compound (93) of Example 93 , the target compounds (108)-(110) of Examples 108-1110, the target compounds (123)-(125) of Examples 123-125, the target compounds (136)-(138) of Examples 136-138, Target Compounds (143)-(149) of Examples 143-149, Target Compounds (171)-(173) of Examples 171-173, Target Compounds (178)-(185) of Examples 178-185, Example 217 The target compound (217) of Example 219, the target compound (219) of Example 219, and the target compound (222) of Example 222 were prepared by referring to Example 2 or the synthetic route of Synthesis Scheme 2. The specific structures and characterization data are described in Table 3 below:

table 3

Biological activity test example:

Test case 1:

1. The purpose of the experiment:

The inhibitory activities of the series of compounds against the two kinases Ret wt and Ret V804M were tested by HTRF method, and IC ₅₀ values were calculated.

2. The experimental reagents and consumables used are 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 2104 multi-label Reader (PerkinElmer, 2104-10-1)

14) Echo (Labcyte, 550)

3. Experimental steps

3.1 Prepare 1x Kinase Reaction Buffer:

1 volume of 5X Kinase Reaction Buffer and 4 volumes of water; 5 mM MgCl2; 1 mM DTT; 1 mM MnCl2.

3.2 Use an Echo 550 reaction plate (784075, Greiner) to transfer 10nl of diluted compounds per well;

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

3.4 Prepare 2X Kinase with 1X Enzyme Reaction Buffer.

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

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

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

3.8 Prepare 4X Sa-XL 665 (250 nM) in HTRF detection buffer.

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

3.10 Fluorescence signals at 615 nm (Cryptate) and 665 nm (XL665) were read with Envision 2104.

4. Data analysis

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

4.2 The inhibition rate is calculated as follows:

所有阳性对照孔CEP-32496读值的平均值

Average of all positive control wells CEP-32496 readings

所有阴性对照孔DMSO孔读值的平均值

Average of all negative control wells DMSO well reads

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

4.3 Calculate _IC50 and plot inhibition curves for compounds:

The following nonlinear fitting formula was used to obtain the IC50 ( _50% inhibitory concentration) of the compounds: Data analysis was performed with Graphpad 6.0 software.

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

X: compound concentration log value Y: inhibition rate (% inhibition)

5. The experimental results are shown in Table A:

Table A Kinase inhibitory activity of compounds of the present invention

It can be seen from Table A that the compound of the present invention has a good inhibitory effect on Ret wt, and in addition, the compound of the present invention also has a good inhibitory effect on RetV804M.

In addition to the activities of the compounds of the present invention in Table A, other compounds of the present invention also have good Ret kinase inhibitory activity.

Test case 2:

1. The purpose of the experiment:

The 50% inhibitory concentration ( _IC50 ) of the compounds in serial tumor cells was tested by CTG method.

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

1) CellTiter-Glo (CTG) (Promega)

2) RPMI medium (Gibco)

3) FBS (Fetal Bovine Serum) (Gibco)

4)DMSO(Sigma)

5) Double antibody (Gibco)

6) 96-well cell culture plate, white wall impermeable bottom (Corning)

7) BAF3 (purchased from Shanghai Mingjin Bio)

8) BAF3-KIF5B-RET-WT (stably transformed cell line, constructed by the Pharmacology Department of Guangdong Dongguang Pharmaceutical Co., Ltd.)

3. Experimental steps:

1) Cell seeding

Cells BAF3 and BAF3-KIF5B-RET-WT in exponential growth phase were collected and counted by Vi-Cell XR cytometer. The cell suspension was adjusted to the corresponding concentration with RPMI complete medium (89% RPMI+10% FBS+1% double antibody). Add 90 μL of cell suspension to each well in a 96-well cell culture plate, and the final cell concentration is 2000 cells/well and cells/well, respectively.

2) Dosing treatment

a Working solution configuration: Dissolve each test compound in DMSO to a final concentration of 10 mM stock solution. 3X serial dilutions were prepared with stock solution and RPMI complete medium (89%RPMI+10%FBS+1% double antibody), a total of 10 concentrations of working solution, the final concentration of DMSO in each solution was 0.1%.

B-cell dosing: After the cells were incubated overnight, 10ul of working solutions corresponding to 10 gradient concentrations were added in sequence, and incubated in a 37°C, 5% CO2 incubator for 72 hours; at the same time, a negative control of no compound plus cells was set up.

3) plate reading detection

After 72 hours of drug treatment, according to the CTG operating instructions, add 50 μl (1/2 culture volume) of CTG solution pre-thawed and equilibrated to room temperature into each well, mix with a microplate shaker for 2 minutes, and place it at room temperature for 10 minutes. The fluorescence signal value was determined by a multifunctional microplate reader.

4) Data analysis

The cell viability was calculated by the formula: Vsample/Vvehicle control x100%. Where Vsample is the reading of the drug treatment group, and Vvehicle control is the average value of the solvent control group. Using GraphPad Prism 5.0 software, a nonlinear regression model was used to draw a sigmoid dose-survival curve and calculate the IC ₅₀ value. The experimental results are shown in Table B.

Table B In vitro cellular activity of compounds of the invention

It can be seen from Table B that the compounds of the present invention also have a good inhibitory effect on BAF3 cells transfected with KIF5B gene.

In the description of this specification, reference to the terms "one embodiment," "some embodiments," "some implementations," "example," "specific example," or "some examples" or the like is meant to incorporate the embodiment or The particular features, structures, materials, or characteristics described by way of example are included in at least one embodiment or example of the present invention. In this specification, schematic representations of the above terms do not necessarily refer to the same embodiment or example. 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, those skilled in the art may combine and combine the different embodiments, implementations or examples described in this specification and the features of the different embodiments, implementations or examples without conflicting each other.

Although the embodiments of the present invention have been shown and described above, it should be understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Variations, modifications, substitutions, and alterations to the above-described embodiments are possible without departing from the scope of the present invention, which is defined by the claims and their equivalents.

Claims (23)

1. A compound, which is the compound of formula (I) or its stereoisomer, geometric isomer, tautomer, nitroxide, solvate, metabolite, pharmaceutically acceptable salt or Prodrugs:

in, X ¹ , X ² , X ³ , X ⁴ and X ⁵ are each independently CR ⁴ or N; Y is O, NH or S; T is a bond, alkylene, alkylene-O-, alkylene-O-alkylene, or alkylene-NH-, and said T is optionally selected from 1, 2, 3, or 4 From D, OH, F, Cl, Br, I, CN, _NH2 , alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, heterocyclyl, alkoxy, aryl, heteroaryl or alkylamino substituted by the substituent; Ring G is bridged carbocyclyl or bridged heterocyclyl; q is 0, 1, 2, 3 or 4; R ^a is D, OH, NH ₂ , F, Cl, Br, I, CN, NR ⁵ R ⁶ , OR ⁷ , -NR ⁶ C(=O)R ⁷ , -S(=O) ₂ R ⁷ , - S(=O)R ⁷ , -C(=O)R ⁷ , -C(=O)OR ⁷ , oxo, alkyl, alkoxy, cycloalkyl, haloalkyl, alkoxyalkyl or hydroxy alkyl; E is a bond, -NR ⁶ - or -O-; Ring A is a bridged cyclylene, a biocyclylene, or a spirocyclylene, and Ring A is optionally surrounded by 1, ² , 3, or 4 selected from F, Cl, Br, OH, oxo, ^NR5R6 , R ⁵ (C=O)NR ⁶ -, aminoalkyl, alkyl, alkoxy, haloalkyl, hydroxyalkyl, carbocyclyl, heterocyclyl, heterocyclylalkyl, alkoxyalkyl, Substituted by cycloalkylene and heterocycloalkylene substituents; Q is a bond, -(CR ² R ³ ) _t O-, -(CR ² R ³ ) _f -, -(CR ² R ³ ) _t -NR ⁶ -, -(C=O)(CR ² R ³ ) _t -, -(C=O)(CR ² R ³ ) _t -(S=O) ₂ (CR ² R ³ ) _f -, -(C=O)(CR ² R ³ ) _t -NR ⁶ ( CR ² R ³ ) _f -, -(C=O)(CR ² R ³ ) _t -O(CR ² R ³ ) _f -, -(C=O)NR ⁶ O(CR ² R ³ ) _f -, -(S ⁼ O) ₂ ^{- NR6-} ( ^CR2R3 ) _t -,-( ^CR2R3 ) _f- (C=O)-,-( ^CR2R3 ) _t- (C ⁼ O) -NR ⁶ -(CR ² R ³ ) _t -, -(S=O) ₂ (CR ² R ³ ) _t -, -(CR ² R ³ ) _f -(S=O) ₂ (CR ² R ³ ) _t- , -(S=O) ₂ O-, -O(C=O)-, -(C=O)NR ⁶ - 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 composed of 1, 2, 3, or 4 selected from D, F, Cl, CN, OH, ^{NR5R 6} , OR ⁷ , substituted by substituents of alkyl, haloalkyl, hydroxyalkyl, haloalkoxy, aryl, alkoxyalkyl, oxo, alkylacyl, heterocyclyl and cycloalkyl; R ¹ is H, D, CN, F, Cl, Br, alkyl or cycloalkyl, wherein said alkyl and cycloalkyl can be independently optionally selected by 1, 2, 3 or 4 selected from F, Substituents of Cl, Br, CN, NH ₂ , OH and NO ₂ are substituted; Each R2 and ^R3 is independently OH, F, H, D, CN, Cl, Br, ^NH2 , _hydroxyalkyl , alkyl, alkylamino, alkoxy, haloalkoxy, cycloalkyl, haloalkoxy radical, cycloalkylalkyl, aryl or heteroaryl; Or, R ² , R ³ and the same carbon atom to which they are attached form a carbocyclic or heterocyclic ring; R ⁴ is H, D, F, Cl, Br, alkyl or alkoxy, wherein said alkyl and alkoxy are each independently optionally selected from F, Cl, Substituents of Br, CN, NH ₂ , OH and NO ₂ are substituted; R ⁵ is H, D, alkyl, carbocyclyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, carbocyclyl, heterocyclyl, aryl and heteroaryl are each independently optional is substituted with 1, 2, 3 or 4 substituents selected from F, Cl, Br, OH, _NH2 , alkylamino, alkyl, alkylsulfonyl, alkoxy, aryl and heteroaryl ; R ⁶ is H, D, alkyl or alkoxyalkyl, wherein each of said alkyl and alkoxyalkyl is independently optionally 1, 2, 3 or 4 selected from F, Cl, Br, CN , NH ₂ , OH and NO ₂ substituents; ^R7 is OH, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl. 2. The compound of claim 1, wherein, T is a bond, C _1-6 alkylene, C _1-6 alkylene-O-, C _1-6 alkylene-OC _1-6 alkylene, or C _1-6 alkylene-NH- , and T is optionally replaced by 1, 2, 3 or 4 selected from D, OH, F, Cl, Br, I, CN, NH ₂ , 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 alkane substituted with the amino group. 3. The compound of claim 1, wherein, T is a bond, _-CH2- , -( _CH2 ) _2- , -( _CH2 ) _3- , -( _CH2 ) _4- , -( _CH2 ) _5- , -( _CH2 ) _6- , -( _CH2 ) ₂ -O-, -( _CH2 ) ₂ -O-CH2- or -( _CH2 ) ₂ -NH-, and T is optionally selected from 1, ₂ , 3 or 4 From D, OH, F, Cl, Br, I, CN, _NH2 , _CF3 , _CHF2 , _CHCl2 , methyl, ethyl, propyl, 2-hydroxyethyl, 1-hydroxyethyl, cyclopropyl base, cyclobutyl, cyclopentyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, methoxy, ethoxy, propoxy, butoxy, Substituents of phenyl, methylamino and dimethylamino. 4. The compound of claim 1, wherein, Ring G is a 6-12-membered bridged carbocyclyl or a 6-12-membered bridged heterocyclyl; R ^a is D, OH, NH ₂ , F, Cl, Br, I, CN, NR ⁵ R ⁶ , OR ⁷ , -NR ⁶ C(=O)R ⁷ , -S(=O) ₂ R ⁷ , - S(=O)R ⁷ , -C(=O)R ⁷ , -C(=O)OR ⁷ , oxo, C _1-6 alkyl, C _1-6 alkoxy, C _3-7 cycloalkane group, C _1-6 haloalkyl, 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 -membered aryl or 5-10-membered heteroaryl, wherein the C _1-6 alkyl, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl, _C6-10 membered aryl and 5-10 membered heteroaryl are each independently optionally substituted by 1, 2, 3 or 4 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 substituted by substituents of 5-10-membered heteroaryl groups; 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 The groups are each independently optionally substituted with 1, ₂ , 3 or 4 substituents selected from F, Cl, Br, CN, _NH2 , OH and NO2; R ⁷ is OH, C _1-6 alkyl, C _3-6 cycloalkyl, 3-12 membered heterocyclyl, C _6-10 aryl or 5-10 membered heteroaryl. 5. The compound of claim 1, wherein, Ring G has the following substructure:

in, each Z1 is independently CH or N ^; and Each Z ² is independently CH ₂ , C=O, NH, O, S, S=(O) or S=(O) ₂ . 6. The compound of claim 1, wherein, Ring G has the following substructure:

^Ra is D, OH, F, _CF3 , _CHCl2 , _CHF2 , _CH2F , _CF3CH2 , Cl, Br, I, CN, _NH2 , _NHCH3 , N( _{CH3 )2 ,} -NHC (=O)CH ₃ , -S(=O) ₂ CH ₃ , -S(=O)CH ₃ , -C(=O)CH ₃ , -C(=O)OH, -C(=O)OC (CH ₃ ) ₃ , oxo, methyl, ethyl, propyl, butyl, methoxy, ethoxy, cyclopropyl, cyclopentyl, methoxymethyl, ethoxymethyl, hydroxy Methyl, 2-hydroxyethyl, 1-hydroxyethyl, 2-hydroxypropyl, 2-hydroxy-2-methylpropyl; R ⁵ is H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, cyclopropyl, cyclopentyl, pyrrolidinyl, phenyl or pyrazolyl; wherein said methyl , ethyl, n-propyl, cyclopropyl, cyclopentyl, pyrrolidinyl, phenyl and pyrazolyl are each independently optionally substituted by 1, 2, 3 or 4 selected from F, Cl, Br, OH, substituted with substituents of NH ₂ , methyl, -S(=O) ₂ CH ₃ , methoxy, ethoxy and phenyl; R ⁶ is H, D, methyl, ethyl, n-propyl, n-butyl, methoxymethyl, ethoxymethyl or methoxyethyl, wherein the methyl, ethyl, n-propyl group, n-butyl, methoxymethyl, ethoxymethyl, and methoxyethyl are each independently optionally 1, 2, 3, or 4 selected from F, Cl, Br, CN, _NH2 , Substituents of OH and NO ₂ are substituted; ^R7 is OH, methyl, ethyl, _NH2 , N( _CH3 ) ₂ , methyl, isopropyl, tert-butyl, cyclopropyl or phenyl. 7. The compound of claim 1, wherein, Ring A is a 5-12 membered bridged cyclylene group, a 5-12 membered dicyclocyclylene group, or a 5-12 membered spirocyclylene group, and Ring A is optionally surrounded by 1, 2, 3, or 4 members selected from F, Cl , Br, OH, oxo, NR ⁵ R ⁶ , R ⁵ (C=O)NR ⁶ -, amino C _1-6 alkyl, C _1-6 alkyl, C _1-6 alkoxy, C _{1- 6} haloalkyl, C _1-6 hydroxyalkyl, 3-12-membered carbocyclyl, 3-12-membered heterocyclyl, 3-12-membered heterocyclyl C _1-6 alkyl, C _1-6 alkoxy C Substituents of _1-6 alkyl, C _3-6 cycloalkylene and 3-6 membered heterocycloalkylene. 8. The compound of claim 1, wherein, Ring A is the following substructure:

wherein each Z ^1a and Z ^2a is independently CH ₂ or NH; each of Z ^3a and Z ^7a is independently CH or N; Z ^4a is O, S or NH; each Z ^5a and Z ^6a is independently CH ₂ , O, S, S(=O), S(=O) ₂ , C(=O) or NH; each of m and t is independently 0, 1 or 2; each of n and t1 is independently 0 or 1; wherein each substructure of Ring A is independently optionally replaced by 1, 2, 3 or 4 selected from F, ^Cl , Br, OH, oxo, ^NR5R6 , ^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 heteroalkyl Cyclyl, 3-12-membered heterocyclyl C _1-4 alkyl, C _1-4 alkoxy C _1-4 alkyl, C _3-6 cycloalkylene and 3-6 membered heterocycloalkylene Substituents are substituted. 9. The compound of claim 1, wherein, Ring A is the following substructure:

wherein each sub-formula of Ring A is independently optionally replaced by 1, 2, 3 or 4 selected from F, Cl, Br, OH, oxo, _NH2 , _NHCH3 , _CH3 (C=O)NH-, methyl , ethyl, n-propyl, methoxy, ethoxy, isopropoxy, CF ₃ , hydroxymethyl, 2-hydroxyethyl, cyclopropyl, cyclohexyl, pyrrolidinyl, piperidinyl, Substituents of tetrahydrofuranyl, cyclopropylene, cyclohexylene and pyrrolidylene. 10. The compound of claim 1, wherein, M is H, D, 5-10 membered heteroaryl, _C6-10 aryl, _C3-7 cycloalkyl, or 3-12 membered heterocyclyl; and M is optionally replaced by 1, 2, 3, or 4 one is selected from D, F, Cl, CN, OH, NR ⁵ R ⁶ , OR ⁷ , C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 haloalkoxy , C _6-10 aryl, C _1-6 alkoxy C _1-6 alkyl, oxo, C _1-6 alkyl acyl, 3-7 membered heterocyclyl and C _3-7 cycloalkyl substitution base substituted. 11. The compound of claim 1, wherein, M is H, D, pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, pyrazinyl, phenyl, cyclopentyl, cyclopropyl, cyclohexyl, cyclobutyl, Pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, morpholinyl, tetrahydrothiopyranyl, oxetanyl, 1,2-dihydropyridyl, 7-nitrogen Heterobicyclo[2.2.1]heptyl, hexahydrofuro[3,4-c]pyrrolyl, 3-azabicyclo[3.1.0]hexyl, octahydropyrrolo[1,2-a] pyrazinyl or 5-azaspiro[2.4]heptyl; and M is optionally 1, 2, 3 or 4 selected from D, F, Cl, CN, OH, _CF3 , _CHCl2 , _CHF2 , CH ₂ F, CF ₃ CH ₂ , NH ₂ , NHCH ₃ , N(CH ₃ ) ₂ , trifluoromethoxy, 2,2,2-trifluoroethoxy, methoxy, ethoxy, iso Propoxy, tert-butoxy, methyl, ethyl, n-propyl, isopropyl, phenyl, methoxymethyl, methoxyethyl, oxo, formyl, acetyl, morpholinyl , pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, cyclopropyl and cyclohexyl substituents. 12. The compound of claim 1, wherein, R ¹ is H, D, CN, F, Cl, Br, methyl, ethyl or cyclopropyl, wherein said methyl, ethyl and cyclopropyl may be independently optionally separated by 1, 2, 3 or 4 substituents selected from F, Cl, Br, CN, NH ₂ , OH and NO ₂ are substituted; R ⁴ is H, D, F, Cl, Br, methyl, ethyl, n-propyl, methoxy or ethoxy, wherein said methyl, ethyl, n-propyl, methoxy and ethyl The oxy groups can be independently optionally substituted with 1, ₂ , 3 or 4 substituents selected from F, Cl, Br, CN, _NH2 , OH and NO2. 13. The compound of claim 1, wherein, Each R ² and R ³ is independently OH, F, H, D, CN, Cl, Br, NH ₂ , C _1-6 hydroxyalkyl, C _1-6 alkyl, C _1-6 alkylamino, C _1-6 alkoxy, C _1-6 haloalkoxy, C _3-7 cycloalkyl, C _1-6 haloalkyl, C _3-7 cycloalkyl, C _1-6 alkyl, C _6-10 aryl or 5-10-membered heteroaryl; Alternatively, R ² , R ³ and the same carbon atom to which they are attached form a 3-7 membered carbocyclic ring or a 3-7 membered heterocyclic ring. 14. The compound of claim 1, wherein, Each R ² and R ³ is independently OH, F, CF ₃ , CHCl ₂ , CHF ₂ , H, D, CN, Cl, Br, NH ₂ , hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl , methyl, ethyl, N(CH ₃ ) ₂ , methoxy, ethoxy, isopropoxy, tert-butoxy, trifluoromethoxy, cyclopropyl, cyclopentyl, cyclopropylmethyl group, cyclopentylethyl, cyclopentylmethyl, phenyl, pyridyl or pyrazinyl; ^{Alternatively} , R2, ^R3 and the same carbon atom to which they are attached form cyclopentane, cyclopropane, cyclobutane, tetrahydropyran, tetrahydrofuran, piperidine or pyrrolidine. 15. The compound of claim 1, wherein, Q is a bond, -O-, -(CH ₂ ) ₂ O-, -CH ₂ -, -(CH ₂ ) ₂ -, -(CH ₂ ) ₃ -, -CH ₂ CH(CH ₃ )CH ₂ - , -CH ₂ CH(CH ₃ )CH ₂ NHCH ₂ -, -(C=O)OC(CH ₃ ) ₂ CH ₂ -, -(C=O)(CH ₂ ) ₂ (S=O) ₂ CH ₂ -, -(C=O)CH(OH)-, -(C=O)CH(OH)CH ₂ -, -(C=O)-, -(S=O) ₂ -, -(C=O )CH ₂ CH(OH)-, -(C=O)CH ₂ -, -(C=O)CH(CH ₂ OH)-, -(C=O)C(CH ₃ ) ₂ -, -(C =O)CH ₂ NHC(CH ₃ ) ₂ CH ₂ -, -(C=O)CH ₂ CH(N(CH ₃ ) ₂ )-, -(C=O)(CH ₂ ) ₂ N(CH ₃ ) CH ₂ -, -(C=O)C(CH ₃ ) ₂ CH ₂ -, -(C=O)C(OH)(CH ₃ )CH ₂ -, -(C=O)CH ₂ OCH ₂ -, -(C=O)(CH ₂ ) ₃ -, -(C=O)CH(NH ₂ )-, -(C=O)(CH ₂ ) ₃ N(CH ₃ )CH ₂ -, -(C= O)(CH ₂ ) ₂ -, -(C=O)CH ₂ CH(OH)CH ₂ -, -(C=O)CF ₂ CH ₂ -, -(C=O)CH(OH)C(CH ₃ ) ₂ CH ₂ -, -(C=O)CH ₂ C(CH ₃ ) ₂ CH ₂ -, -(C=O)CH ₂ C(CH ₃ )(OH)CH ₂ -, -(S=O ) ₂ CH ₂ -, -(S=O) ₂ CH ₂ C(CH ₃ ) ₂ CH ₂ -, -(C=O)CH(OCH ₃ )-, -(C=O)NHCH(CH ₂ OH) (CH ₂ ) ₂ -, -(C=O)NH-, -(C=O)N(CH ₃ )-, -(C=O)N(CH ₂ CH ₂ CH ₂ CH ₃ )-, -( C=O)N(CH ₂ CH ₃ )(CH ₂ ) ₂ -, -(C=O)NHC(CH ₃ ) ₂ CH ₂ -, -(C=O)N(CH ₃ )(CH ₂ ) ₂ -, -(C=O)NHCH2CH( _{CH3 )} CH2-, -(C=O) _NHCH2- , -(C=O)NH( _{CH2 ) 2OCH2-} , _- (C=O )N(CH ₃ )(CH ₂ ) ₂ OCH ₂ -, - (S=O) ₂ NHC(CH ₃ ) ₂ CH ₂ -, -CH ₂ CH(OH)C(CH ₃ ) ₂ CH ₂ -, -CH(CH ₃ )CH(OH)-, -CH ₂ (C =O)NHCH( _CH3 )CH2-, _-CH2 (C=O) _- , -( _{CH2 )2 (} C=O)N( _CH3 )CH2-, -CH2CH ₍ OH)- , -CH ₂ CH(OH)CH ₂ -, -CH ₂ CH(OH)CH(CH ₃ )CH ₂ -, -(C=O)CH(N(CH ₃ ) ₂ )-, -(C=O )C(CH ₃ ) ₂ CH ₂ OCH ₂ -, -(C=O)C(OCH ₃ )(CF ₃ )-, -(CH ₂ ) ₃ S(=O) ₂ CH(CH ₃ )CH ₂ - , -(C=O)N(CH ₂ CH ₂ OCH ₃ )CH ₂ CH(OCH ₃ )-, -CH ₂ CH(OCF ₃ )-, -CH ₂ CH(OCH(CH ₃ ) ₂ )-, - CH ₂ CH(OC(CH ₃ ) ₃ )-, -CH ₂ CF ₂ -, -CH(CH ₃ )-, -CH ₂ CH(OCH ₃ )C(CH ₃ ) ₂ -, -CH ₂ CH(N (CH ₃ ) ₂ )-, -NH-, -(C=O)NHOCH ₂ -, -(C=O)NHOCH ₂ (CHOH)-, -(S=O) ₂ (CH ₂ CH ₃ )-, -(S=O) ₂ O-, -(S=O) ₂ -NHC(CH ₃ ) ₂ -, -(CH ₂ ) ₂ (S=O) ₂ -,

16. The compound of claim 1 has the structure of formula (I-1), or the stereoisomer, geometric isomer, tautomer, nitrogen oxide, solvate of the structure of formula (I-1) , metabolites, pharmaceutically acceptable salts or prodrugs,

in, Ring A1 is the following substructure:

wherein each Z ^1a and Z ^2a is independently CH ₂ or NH; And each substructure of ring A1 is independently optionally 1, 2, 3 or 4 selected from F, Cl, Br, OH, oxo, NR ⁵ R ⁶ , R ⁵ (C=O)NR ⁶ -, amino C _1-4 alkyl, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _1-4 hydroxyalkyl, 3-12-membered carbocyclyl, 3-12-membered heteroalkyl Cyclyl, 3-12-membered heterocyclyl C _1-4 alkyl, C _1-4 alkoxy C _1-4 alkyl, C _3-6 cycloalkylene and 3-6 membered heterocycloalkylene Substituents are substituted. 17. The compound of claim 16, wherein, Ring A1 is a substructure:

wherein each substructure of ring A1 is independently optionally selected by 1, 2, 3 or 4 selected from F, Cl, Br, OH, oxo, NH ₂ , NHCH ₃ , CH ₃ (C=O)NH-, methyl , ethyl, n-propyl, methoxy, ethoxy, isopropoxy, CF ₃ , hydroxymethyl, 2-hydroxyethyl, cyclopropyl, cyclohexyl, pyrrolidinyl, piperidinyl, Substituents of tetrahydrofuranyl, cyclopropylene, cyclohexylene and pyrrolidylene. 18. the compound described in claim 1 has the structure of formula (I-2) or (I-3), or the stereoisomer, geometric isomer of formula (I-2) or (I-3) structure, Tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs,

wherein each of Z ¹ , Z ² , Z ^3a and Z ^7a is independently CH or N; each of m and t is independently 0, 1 or 2; each of n and t1 is independently 0 or 1; each of them

independently optionally by 1, 2, 3 or 4 selected from F, Cl, Br, OH, oxo, NR ⁵ R ⁶ , R ⁵ (C=O)NR ⁶ -, amino C _1-4 alkyl, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _1-4 hydroxyalkyl, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl, 3-12 membered Substituents of heterocyclyl C _1-4 alkyl, C _1-4 alkoxy C _1-4 alkyl, C _3-6 cycloalkylene and 3-6 membered heterocycloalkylene. 19. The compound of claim 18, wherein,

is the following substructure:

is the following substructure:

in

Each sub-structural formula of is independently optionally replaced by 1, 2, 3 or 4 selected from F, Cl, Br, OH, oxo, NH ₂ , NHCH ₃ , CH ₃ (C=O)NH-, methyl, ethyl , n-propyl, methoxy, ethoxy, isopropoxy, CF ₃ , hydroxymethyl, 2-hydroxyethyl, cyclopropyl, cyclohexyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, Substituents of cyclopropylidene, cyclohexylene and pyrrolidylene. 20. The compound of claim 1 has one of the following structures, or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug,

21. A pharmaceutical composition comprising the compound of any one of claims 1-20, and a pharmaceutically acceptable adjuvant. 22. Use of the compound of any one of claims 1-20 or the pharmaceutical composition of claim 21 in the preparation of a medicament for preventing or treating RET-related diseases. 23. The use of claim 22, wherein the RET-related disease comprises cancer, irritable bowel syndrome and/or pain associated with irritable bowel syndrome.