WO2021043209A1

WO2021043209A1 - Ret inhibitor, pharmaceutical composition and use thereof

Info

Publication number: WO2021043209A1
Application number: PCT/CN2020/113240
Authority: WO
Inventors: 谢洪明; 罗明; 张英俊; 杨桂珍; 王凯; 何锦
Original assignee: 广东东阳光药业有限公司
Priority date: 2019-09-04
Filing date: 2020-09-03
Publication date: 2021-03-11
Also published as: CN112442050A

Abstract

The present invention relates to an RET inhibitor in the field of medicine, a pharmaceutical composition and the use thereof. Specifically, the present invention relates to a compound as shown in formula (I), or a stereoisomer, a geometrical isomer, a tautomer, a nitrogen oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug of the compound as shown in formula (I), and also relates to a pharmaceutical composition containing the compounds, and the use of the compounds and the pharmaceutical composition thereof in preparing a drug that is particularly used for treating and preventing diseases and disorders associated with RET, including cancers, irritable bowel syndrome and/or aches and pains associated with irritable bowel syndrome.

Description

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

Related application

This application claims the priority of Chinese patent application number 201910831591.X, which was submitted to the State Intellectual Property Office on September 4, 2019, and all of its contents are hereby incorporated by reference.

Technical field

The present invention belongs to the field of medicine. Specifically, the present invention relates to a novel compound exhibiting transfection-period rearrangement (RET) kinase inhibition, a pharmaceutical composition containing the compound, the use of the compound or the pharmaceutical composition thereof in the preparation of medicines. 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 tyrosine kinases belonging to the cadherin superfamily, which activates multiple downstream pathways involved in cell proliferation and survival.

It is reported that the result of abnormal RET gene (point mutation, chromosome translocation, chromosome inversion, gene amplification) is related to canceration. The RET fusion protein is associated with several cancers, including papillary thyroid cancer and non-small cell lung cancer. The identification of RET fusion protein as a driving factor for certain cancers has prompted the use of multi-kinase inhibitors with RET inhibitory activity to treat patients whose tumors express RET fusion protein. It is reported that multi-kinase inhibitors such as Sorafenib, sunitinib, vandetanib, and punatinib exhibit cell proliferation inhibitory effects on cell lines expressing KIF5B-RET (J Clin Oncol 30, 2012 ,suppl; Abstract no:7510). In addition, it is reported that the multi-kinase inhibitor cabozantinib showed partial efficacy in two non-small cell lung cancer patients with positive RET fusion gene (Cancer Discov, 3(6), Jun2013, p.630-5). However, these drugs cannot always be administered at a level sufficient to inhibit RET due to toxicity due to the inhibition of targets other than RET. In addition, one of the biggest challenges in treating cancer is the ability of tumor cells to develop resistance to treatment. Reactivation of kinases through mutations is a common resistance mechanism. When drug resistance occurs, the patient's treatment options are usually very limited, and cancer progression is not inhibited in most cases. WO 2017011776 discloses a single-target RET kinase inhibitor, which has a good preventive or therapeutic effect on RET and mutation-related cancers. There is still a need to further develop compounds that inhibit RET and its resistant mutants to deal with cancers related to abnormal RET genes.

Summary of the invention

The present invention provides a new compound that exhibits the inhibition of transfection-period rearrangement (RET) kinase. The compound has a good inhibitory effect on RET wild-type and RET gene mutants, and has a better effect on RET wild-type and RET gene mutants. Good inhibition selectivity.

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

In one aspect, the present invention provides a compound represented by formula (I), or stereoisomers, geometric isomers, tautomers, nitrogen oxides, solvates, Metabolites, pharmaceutically acceptable salts or prodrugs,

among them,

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- or alkylene-NH-, and the T is optionally selected from D, OH, F, Cl, Br by 1, 2, 3, or 4 , I, CN, NH ₂ , CF ₃ , alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, heterocyclyl, alkoxy, aryl, heteroaryl or alkylamino substituents;

Ring G is a spirocarbocyclyl or spiroheterocyclic group;

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

R ^a is D, OH, NH ₂ , F, CF ₃ , 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, alkoxyalkyl or hydroxyl alkyl;

E is a bond, -NR ⁶ -, or -O-;

Ring A is a bridging cyclylene, tetracyclylene or spirocyclylene, and A is optionally selected from F, Cl, Br, OH, oxo, NR ⁵ R ⁶ , R ⁵ (C=O)NR ⁶ -, aminoalkyl, alkyl, alkoxy, haloalkyl, hydroxyalkyl, carbocyclyl, heterocyclyl, heterocyclylalkyl, alkoxyalkyl, alkylene Substituted by substituents of cycloalkyl and monoheterocyclylene;

Q is a key, -(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 -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;

M is H, D, heteroaryl, aryl, cycloalkyl or heterocyclyl, and M is optionally 1, 2, 3 or 4 selected from D, F, Cl, CN, CF ₃ , OH, Substituted by substituents of NR ⁵ R ⁶ , OR ⁷ , alkyl, haloalkyl, hydroxyalkyl, haloalkoxy, aryl, alkoxyalkyl, oxo, alkyl acyl, heterocyclyl, cycloalkyl ；

R ¹ is H, D, CN, F, Cl, Br, alkyl or cycloalkyl, wherein said alkyl and cycloalkyl can be independently optionally selected from F, Substituted by Cl, Br, CN, NH ₂ , OH and NO _{2 substituents;}

Each R ² , R ^{3 is} independently OH, F, CF ₃ , H, D, CN, Cl, Br, NH ₂ , hydroxyalkyl, alkyl, alkylamino, alkoxy, haloalkoxy, cycloalkane Group, cycloalkylalkyl, aryl, heteroaryl;

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

R ⁴ is H, D, F, Cl, Br, alkyl or alkoxy, wherein the alkyl and alkoxy are each independently optionally selected from F, Cl, Replaced by substituents of Br, CN, NH ₂ , OH and NO _2;

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

R ⁶ is H, D, alkyl or alkoxyalkyl, wherein the alkyl and alkoxyalkyl are each independently optionally selected from F, Cl, Br, CN , NH ₂ , OH and NO ₂ substituents;

R ⁷ is OH, alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl.

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

In some embodiments, T is a bond, -CH ₂ -, -(CH ₂ ) ₂ -, -(CH ₂ ) ₃ -, -(CH ₂ ) ₄ -, -(CH ₂ ) ₅ -, -( CH ₂ ) ₆ -, -(CH ₂ ) ₂ -O- or -(CH ₂ ) ₂ -NH-, and the T is optionally selected from 1, 2, 3 or 4 selected from D, OH, F, Cl, Br, I, CN, CF ₃ , methyl, ethyl, propyl, 2-hydroxyethyl, 1-hydroxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, pyrrolidinyl, piperidine Substituents are substituted by substituents of phenyl, tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, methoxy, ethoxy, propoxy, butoxy, phenyl, methylamino, and dimethylamino.

In some embodiments,

G is a 6-12 membered spiro carbocyclic group or a 6-12 membered spiro heterocyclic group;

R ^a is D, OH, NH ₂ , F, CF ₃ , 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} cycloalkyl, C _1-6 alkoxy C _1-6 alkyl, C _1-6 hydroxyalkyl;

R ⁵ is H, D, C _1-6 alkyl, 3-12 membered carbocyclic group, 3-12 membered heterocyclic group, C _6-10 aryl group or 5-10 membered heteroaryl group, wherein the C _1-6 alkyl, 3-12 membered carbocyclic group, 3-12 membered heterocyclic group, C _6-10 aryl group and 5-10 membered heteroaryl group are each independently optionally selected by 1, 2, 3 or 4 Substituted by a substituent selected from F, Cl, Br, OH, NH ₂ , C _1-6 alkylamino, alkyl, alkylsulfonyl, alkoxy, aryl and heteroaryl;

R ⁶ is H, D, C _1-6 alkyl or C _1-6 alkoxy C _1-6 alkyl, wherein the C _1-6 alkyl and C _1-6 alkoxy C _1-6 alkane The groups are each independently optionally substituted with 1, 2, 3 or 4 substituents selected from F, Cl, Br, CN, NH ₂ , OH and NO ₂ ;

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

In some embodiments, G is the following sub-structure:

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

Z ¹ and Z ^{2 are} independently -CH ₂ -, -O-, -S-, -NH-;

Z ³ is -O-, -S-, -NH-;

n1 is 0, 1 or 2;

n2 is 1, 2 or 3;

n3 is 0 or 1.

In some embodiments, G is the following sub-structure:

R ^a is _{D, OH, NH 2, F} , CF 3, Cl, Br, I, CN, NH 2, NHCH 3, -NHC (= O) CH 3, -S (= O) 2 CH 3, -S (=O)CH ₃ , -C(=O)CH ₃ , -C(=O)OH, oxo, methyl, ethyl, propyl, butyl, methoxy, ethoxy, cyclopropyl , Cyclopentyl, methoxymethyl, ethoxymethyl, 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 the methyl group , Ethyl, n-propyl, cyclopropyl, cyclopentyl, pyrrolidinyl, phenyl and pyrazolyl are each independently optionally selected from F, Cl, Br, OH, NH ₂ , methyl, -S(=O) ₂ CH ₃ , methoxy, ethoxy and phenyl substituents;

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 each independently optionally selected from F, Cl, Br, CN, NH ₂ , Substituted by OH and NO _{2 substituents;}

R ⁷ is OH, methyl, ethyl, NH ₂ , N(CH ₃ ) ₂ , n-propyl, isopropyl, tert-butyl, cyclopropyl or phenyl.

In some embodiments, A is a 5-12-membered bridge sub-ring group, a 5-12-membered azimuth sub-ring group, or a 5-12-membered spiro sub-ring group, and A is optionally selected from 1, 2, 3, or 4 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 carbocyclic group, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group C _1-6 alkyl, C _1-6 Alkoxy C _1-6 alkyl, C _3-6 cycloalkylene and 3-6 membered monoheterylidene substituents are substituted.

In some embodiments, A is the following sub-structure:

Wherein, Z ^1a and Z ^{2a are} each independently -CH ₂ -or -NH-;

Z ^3a is -CH- or -N-;

Z ^4a is -O-, -S- or -NH-;

Each of Z ^5a and Z ^{6a is} independently -CH ₂ -, -O-, -S-, -S(=O)-, -S(=O) _2- , -C(=O)- or -NH- ；

m and t are each independently 0, 1 or 2;

n and t1 are each independently 0 or 1;

Wherein each sub-structure of A is independently optionally selected from F, Cl, Br, OH, oxo, NR ⁵ R ⁶ , R ⁵ (C=O) NR ⁶ -, amino C _1-4 alkyl, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _1-4 hydroxyalkyl, 3-12 membered carbocyclic group, 3-12 membered heterocyclic ring Group, 3-12 membered heterocyclyl C _1-4 alkyl, C _1-4 alkoxy C _1-4 alkyl, C _3-6 cycloalkylene and 3-6 membered monoheterocyclylene substitution Substituted by the group.

In some embodiments, A is the following sub-structure:

Wherein, each sub-structure of A is independently optionally 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, tetrahydrofuran Group, cyclopropylene, cyclohexylene, and pyrrolidinylene substituents.

In some embodiments, M is H, D, 5-10 membered heteroaryl, C _6-10 aryl, C _3-7 cycloalkyl, or 3-12 membered heterocyclyl; and M is optionally substituted by 1 , 2, 3 or 4 selected from D, F, Cl, CN, OH, CF ₃ , NR ⁵ R ⁶ , OR ⁷ , C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxy alkane Group, C _1-6 haloalkoxy, C _6-10 aryl, C _1-6 alkoxy C _1-6 alkyl, oxo, C _1-6 alkyl acyl, 3-7 membered heterocyclic group, 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, hexahydrofuran[3,4-c]pyrrolyl, 3-azabicyclo[3.1.0]hexyl, octahydropyrrolo[ 1,2-a]pyrazinyl or 5-azaspiro[2.4]heptanyl; 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, Substituted by substituents of tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, cyclopropyl and cyclohexyl;

In some embodiments, R ¹ is H, D, CN, F, Cl, Br, methyl, ethyl, or cyclopropyl, wherein the methyl, ethyl and cyclopropyl can be independently optionally 1, 2, 3 or 4 substituents selected from F, Cl, Br, CN, NH ₂ , OH and NO ₂ ;

R ⁴ is H, D, F, Cl, Br, methyl, ethyl, n-propyl, methoxy or ethoxy, wherein the methyl, ethyl, n-propyl, methoxy and ethyl group may be optionally independently substituted with 1,2, 3 or 4 substituents selected from F, Cl, Br, CN, NH 2, OH , NO ₂ substituted by a substituent.

In some embodiments, each R ² and R ^{3 is} independently OH, F, CF ₃ , 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 _3-7 cycloalkyl, C _1-6 alkyl, C _6-10 Aryl or 5-10 membered heteroaryl;

Or, R ² , R ³ and the same C atom connected to them form a 3-7 membered carbocyclic ring or a 3-7 membered heterocyclic ring.

In some embodiments, each R ² , R ^{3 is} independently OH, F, CF ₃ , 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, cyclopentyl ethyl, cyclopentyl methyl, phenyl, pyridyl, pyrazinyl;

Or, R ² , R ³ and the same C atom connected to them form cyclopentane, cyclopropane, cyclobutane, tetrahydropyran, tetrahydrofuran, piperidine or pyrrolidine.

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

among them,

Ring A1 is the following sub-structure:

Wherein Z ^1a and Z ^{2a are} each independently CH ₂ or NH;

And each sub-structure of A1 is independently optionally selected from F, Cl, Br, OH, oxo, NR ⁵ R ⁶ , R ⁵ (C=O)NR ⁶ -, amino C _1-4 alkyl, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _1-4 hydroxyalkyl, 3-12 membered carbocyclic group, 3-12 membered heterocyclic ring Group, 3-12 membered heterocyclyl C _1-4 alkyl, C _1-4 alkoxy C _1-4 alkyl, C _3-6 cycloalkylene and 3-6 membered monoheterocyclylene substitution Substituted by the group.

In some embodiments, A1 is a sub-structure:

Wherein each sub-structure of A1 is independently optionally 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, tetrahydrofuran Group, cyclopropylene, cyclohexylene, and pyrrolidinylene substituents.

In some embodiments, the compound described in the present invention has a structure of formula (I-2) or (I-3), or a stereoisomer of a structure of formula (I-2) or (I-3), geometrically different Constructs, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs,

Wherein, Z ¹ , Z ² and Z ^{3a are} each independently CH or N;

m and t are each independently 0, 1 or 2;

n and t1 are each independently 0 or 1;

among them

Independently and 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 carbocyclic group, 3-12 membered heterocyclic group, 3-12 membered The heterocyclic group C _1-4 alkyl, C _1-4 alkoxy C _1-4 alkyl, C _3-6 cycloalkylene and 3-6 membered monoheterocyclylene substituents are substituted.

In some embodiments,

Is the following sub-structure:

Is the following sub-structure:

among them

Each sub-structure formula of 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 Group, n-propyl, methoxy, ethoxy, isopropoxy, CF ₃ , hydroxymethyl, 2-hydroxyethyl, cyclopropyl, cyclohexyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, Cyclopropylene, cyclohexylene and pyrrolidinylene substituents are substituted.

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 the prevention or treatment of RET-related diseases.

In some embodiments, RET-related diseases include 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 the prevention or treatment of RET-related diseases.

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

In another aspect, the present invention relates to methods for the preparation, separation 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. In some embodiments, the adjuvants described in the present invention include, but are not limited to, carriers, excipients, diluents, solvents, 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 It belongs to the scope of the present invention.

Specifically, the salt is a pharmaceutically acceptable salt. The term "pharmaceutically acceptable" includes that the substance or composition must be chemically or toxicologically suitable and related to the other components of the formulation and the mammal used for treatment.

The salts of the compounds of the present invention also include intermediates or intermediates for the preparation or purification of compounds represented by formula (I), (I-1), (I-2) or (I-3) or formula (I), (I- 1) The salt of the separated enantiomer of the compound shown in (I-2) or (I-3), but not necessarily a pharmaceutically acceptable salt.

Detailed description of the invention

Definitions and general terms

Now certain embodiments of the present invention will be described in detail, examples of which are illustrated by the accompanying structural formulas and chemical formulas. The present invention intends to cover all alternatives, modifications and equivalent technical solutions, which are all included in the scope of the present invention as defined by the claims. Those skilled in the art should recognize that many methods and materials similar or equivalent to those described herein can be used to practice the present invention. The invention is by no means limited to the methods and materials described herein. In the case where one or more of the combined documents, patents and similar materials are different from or contradictory to this application (including but not limited to the defined terms, term application, described technology, etc.), this Application shall prevail.

It should be further recognized that certain features of the present invention, for the sake of clarity, have been described in multiple independent embodiments, but may also be provided in combination in a single embodiment. Conversely, the various features of the present invention are described in a single embodiment for the sake of brevity, but they can also be provided individually or in any suitable sub-combination.

Unless otherwise specified, all scientific and technological terms used in the present invention have the same meanings as commonly understood by those skilled in the art to which the present invention belongs. All patents and publications related to the present invention are incorporated into the present invention in its entirety by reference.

The term "subject" used in the present invention refers to an animal. Typically the animal is a mammal. The subject, for example, also refers to primates (such as humans, males or females), 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" used in the present invention 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, includes the content 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 the atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis/trans) isomers, atropisomers, etc. .

The stereochemistry definitions and rules used in the present invention generally follow SPParker, 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.

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

The term "tautomer" or "tautomeric form" refers to structural isomers with different energies that can be converted into each other through a low energy barrier. If tautomerism is possible (as in solution), the chemical equilibrium of tautomers can be reached. For example, proton tautomers (also called prototropic tautomers) include interconversions through proton migration, such as keto-enol isomerization and imine-ene Amine isomerization. Valence tautomers include interconversion through the recombination of some bond-forming electrons. Specific examples of keto-enol tautomerism are 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 pyridine-4-ol and pyridine-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 other aspects indicate, the structural formula described in the present invention includes all isomeric forms (such as enantiomers, diastereomers, and geometric isomers (or conformational isomers)): for example, those containing asymmetric centers R and S configurations, (Z) and (E) isomers of the double bond, and (Z) and (E) conformational isomers. Therefore, a single stereochemical isomer of the compound of the present invention or a mixture of its enantiomers, diastereomers, or geometric isomers (or conformational isomers) belongs to the scope of the present invention.

Unless other aspects indicate, the structural formula and the compounds described in the present invention include all isomeric forms (such as enantiomers, diastereomers, geometric isomers or conformational isomers), nitrogen oxides, Hydrates, solvates, metabolites, pharmaceutically acceptable salts and prodrugs. Therefore, individual stereochemical isomers, enantiomers, diastereomers, geometric isomers, conformational isomers, nitrogen oxides, hydrates, solvates, metabolites, Pharmaceutically acceptable salts and prodrug compounds also fall within the scope of the present invention. In addition, unless otherwise indicated, the structural formulas of the compounds described in the present invention include enriched isotopes of one or more different atoms.

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

In addition, it should be noted that, unless explicitly pointed out in other ways, the description methods used in the present invention are interchangeable with "each ... independently being" and "... each independently being" and "... independently being". Should be understood in a broad sense, it can mean that the specific options expressed between the same symbols in different groups do not affect each other, or it can mean the specific options expressed between the same symbols in the same group Do not affect each other.

In each part of this specification, the substituents of the compounds disclosed in the present invention are disclosed according to the group type or scope. In particular, the present invention includes each independent sub-combination of each member of these group types and ranges. For example, the term "C _1-6 alkyl" refers particularly to the disclosure independently methyl, ethyl, C ₃ alkyl, C ₄ alkyl, C ₅ alkyl, and C ₆ alkyl.

In each part of the present invention, linking substituents are described. When the structure clearly requires a linking group, the Markush variables listed for the group should be understood as the linking group. For example, if the structure requires a linking group and the Markush group definition of the variable lists "alkyl" or "aryl", it should be understood that the "alkyl" or "aryl" respectively represents the attached Alkylene group or arylene group.

The term "alkyl" refers to a saturated linear or branched monovalent hydrocarbon group containing 1 to 20 carbon atoms, wherein the alkyl group may optionally be substituted by one or more substituents described in the present invention 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 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, -CH ₃ ), ethyl (Et, -CH ₂ CH ₃ ), n-propyl (n-Pr, -CH ₂ CH ₂ CH ₃ ), 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 ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-pentyl (-CH(CH ₃ )CH ₂ CH ₂ CH ₃ ), 3-pentyl (-CH(CH ₂ CH ₃ ) ₂ ), 2-methyl -2-butyl (-C(CH ₃ ) ₂ CH ₂ CH ₃ ), 3-methyl-2-butyl (-CH(CH ₃ )CH(CH ₃ ) ₂ ), 3-methyl-1- Butyl (-CH ₂ CH ₂ CH(CH ₃ ) ₂ ), 2-methyl-1-butyl (-CH ₂ CH(CH ₃ )CH ₂ CH ₃ ), n-hexyl (-CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-hexyl (-CH(CH ₃ )CH ₂ CH ₂ CH ₂ CH ₃ ), 3-hexyl (-CH(CH ₂ CH ₃ )(CH ₂ CH ₂ CH ₃ )), 2-Methyl-2-pentyl (-C(CH ₃ ) ₂ CH ₂ CH ₂ CH ₃ ), 3-methyl-2-pentyl (-CH(CH ₃ )CH(CH ₃ )CH ₂ CH ₃ ), 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 so on.

When an alkyl group is a linking group, and "alkyl" is listed for the Markush group definition, then "alkyl" means the connected alkylene group.

The term "alkylene" refers to a saturated divalent hydrocarbon group obtained by removing two hydrogen atoms from a saturated linear or branched hydrocarbon group. Examples of alkylene groups include, but are not limited to: -CH ₂ -, -CH ₂ CH ₂ -, -CH(CH ₃ )CH ₂ -, and the like.

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

The term "alkylene-NH-" means that an alkylene group is connected to other parts of the molecule through NH, wherein the alkylene group has the definition as described in the present invention.

The term "oxo", namely =0, means that two hydrogens on a carbon atom are replaced by =0, that is, -CH _2- is replaced by =0 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 means an alkyl group substituted with 1 or 2 hydroxy groups. In some embodiments, hydroxyalkyl represents C _1-6 hydroxyalkyl, that is, C _1-6 alkyl is substituted by one or more hydroxy groups. Preferably, C _1-6 hydroxyalkyl represents C _{1 -6} Alkyl group substituted with 1 hydroxy group. In some embodiments, hydroxyalkyl represents C _1-4 hydroxyalkyl. In some embodiments, hydroxyalkyl represents C _1-3 hydroxyalkyl. Examples of hydroxyalkyl groups include, but are not limited to, OHCH ₂ -, CH ₂ OHCH ₂ CH ₂ CH ₂ -, CH ₂ OHCH ₂ -, CH ₂ OHCH ₂ CHOHCH ₂ -, CH(CH ₃ )OHCH ₂ CHOHCH ₂ -, ( CH ₃ )OHCH-, etc.

The term "alkoxy" means that the alkyl group is connected to the rest of the molecule through an oxygen atom, where the alkyl group has the meaning as described in the present invention. Unless otherwise specified, the alkoxy group contains 1-12 carbon atoms. In one embodiment, the alkoxy group contains 1-6 carbon atoms; in another embodiment, the alkoxy group contains 1-4 carbon atoms; in another embodiment, the alkoxy group The group contains 1-3 carbon atoms. The alkoxy group may be optionally substituted with one or more substituents described in this invention. 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-but Oxygen (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, -OCH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-pentyloxy (-OCH(CH ₃ )CH ₂ CH ₂ CH ₃ ), 3-pentoxy (-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 an alkoxy group, wherein the alkoxy group and the alkyl group have the definitions as described in the present invention. 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 alkoxy groups include, but are not limited to, methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, methoxypropyl, ethoxyethyl, ethoxypropyl Group, propoxyethyl, propoxypropyl, etc.

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

The term "haloalkyl" means that an alkyl group is substituted with one or more halogen atoms. In some embodiments, haloalkyl represents C _1-6 haloalkyl, that is, an alkyl in which C _1-6 alkyl is substituted with one or more halogens. In some embodiments, haloalkyl represents C _1-4 haloalkyl. In some embodiments, haloalkyl represents 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-di Chloroethyl, 1,1-dibromoethyl, etc.

The term "cycloalkyl" refers to a monovalent saturated monocyclic carbocyclic ring system. The -CH ₂ -group in the cycloalkyl group can be optionally replaced by -C(=O)-. In some embodiments, the cycloalkyl group contains 3-7 ring carbon atoms, that is, a _C3-7 cycloalkyl group. In one embodiment, the cycloalkyl group contains 3-6 carbon atoms, that is, C _3-6 cycloalkyl; in another embodiment, the cycloalkyl group contains 3-5 carbon atoms, that is, C _3-5 ring alkyl. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. _{Examples of the -CH 2} -group in the carbocyclic ring that can be replaced by -C(=O)- include, but are not limited to: cyclopentanone, cyclobutanone, and the like. The cycloalkyl group may be independently optionally substituted with one or more substituents described in the present invention.

The term "cycloalkylene" refers to a divalent saturated monocyclic carbocyclic ring system. The -CH ₂ -group in the cycloalkylene group can be optionally replaced by -C(=O)-. In some embodiments, the cycloalkylene group contains 3-7 ring carbon atoms, that is, a _C3-7 cycloalkylene group. In one embodiment, cycloalkylene containing 3-6 carbon atoms, i.e. C _3-6 cycloalkylene; In another embodiment, a cycloalkyl group containing 3-5 carbon atoms, i.e., C _{3- 5} Cycloalkylene, examples of cycloalkylene include but are not limited to 1,1-cyclopropylene, 1,2-cyclopropylene, 1,1-cyclopentylene, 1,1-cyclohexylene , 1,3-cyclopentylidene, etc. The cycloalkylene group may be independently optionally substituted with one or more substituents described in the present invention.

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

The term "monocyclic group" means a monovalent saturated or unsaturated monocyclic carbocyclic or monocyclic heterocyclic ring system, wherein the carbocyclic and heterocyclic ring have the definitions as described in the present invention. _{The -CH 2} -group in the monocyclic group can be optionally replaced by -C(=O)-. In some embodiments, a monocyclic group contains 3-7 ring atoms, that is, a monocyclic group is a 3-7 membered monocyclic group; in other embodiments, a monocyclic group contains 3-6 ring atoms, that is, a monocyclic group contains 3-6 ring atoms. 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 or monocyclic heterocyclic ring system. The monocyclic group may be independently optionally substituted with one or more substituents described in the present invention.

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

The term "monoheterocyclylene" refers to a divalent saturated or unsaturated monocyclic heterocyclic ring system, wherein the heterocyclic ring has the definition as described in the present invention. The -CH ₂ -group in the monoheterocyclylene can be optionally replaced by -C(=O)-. In some embodiments, the monoheterocyclylene contains 3-7 ring atoms, that is, the monoheterocyclylene is a 3-7 membered monoheterocyclylene; in other embodiments, the monoheterocyclylene contains 3 -6 ring atoms, that is, monoheterocyclylene is 3-6 membered monoheterocyclylene. Preferably, the monocyclic heterocyclic group of the present invention is a divalent saturated monocyclic heterocyclic ring system.

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

The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogen atoms, wherein halogen and alkoxy have the definitions described in the present invention. In some embodiments, the haloalkoxy group represents a C _1-6 haloalkoxy group, that is, an alkyl group in which the C _1-6 alkoxy group is substituted with one 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 "alkyl acyl" means that the alkyl group is connected to the rest of the molecule through a carbonyl group, where the alkyl group has the definition as described in the present invention, and the carbonyl group represents -C(=O)-. In some embodiments, alkyl acyl represents C _1-6 alkyl acyl; in other embodiments, alkyl acyl represents C _1-4 alkyl acyl. Examples of alkyl acyl include, but are not limited to: formyl, acetyl, and the like.

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

The term "aromatic ring" or "aromatic hydrocarbon" means a monocyclic, bicyclic and tricyclic carbocyclic ring system containing 6-14 ring atoms, or 6-12 ring atoms, or 6-10 ring atoms, of which at least one The ring system is aromatic, where each ring system contains a ring composed of 3-7 atoms. Examples of aromatic rings may include benzene, naphthalene, and anthracene.

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 anthracenyl. When an aryl group is a linking group, and "aryl" is listed for the Markush group definition, then "aryl" means a linked arylene group. When M is an aryl group in the definition of the present invention, it means that M is a linked arylene group. The term "arylene" refers to a divalent aromatic ring group formed by removing two hydrogen atoms from the ring carbon atoms of an aromatic ring. Examples of the aryl group represented as an attached arylene group may include a phenylene group, a naphthylene group, and an anthrylene group. The aryl group may be independently optionally substituted with one or more substituents described in the present invention.

The term "heteroaromatic ring" refers to monocyclic, bicyclic and tricyclic ring systems containing 5-12 ring atoms, or 5-10 ring atoms, or 5-6 ring atoms, in which at least one ring system is aromatic, And at least one ring system contains one or more heteroatoms, wherein each ring system contains a ring composed of 5-7 atoms.

The term "heteroaryl" refers to a monovalent aromatic ring group formed by removing a hydrogen atom from a ring atom of a heteroaromatic ring. The heteroaryl group is optionally substituted with one or more substituents described in the present invention. In one embodiment, the 5-10 atom heteroaryl group or the 5-10 membered heteroaryl group contains 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. In some embodiments, the term "heteroaryl" means a heteroaromatic ring group containing 5 ring atoms or a 5-membered heteroaryl group, which contains 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- Triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, pyrazinyl, 1,3,5- Triazinyl; also includes the following bicyclics, but not limited to these bicyclics: benzimidazolyl, benzofuranyl, benzothienyl, indolyl (such as 2-indolyl), purinyl, quinolinyl (Such as 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), isoquinolinyl (such as 1-isoquinolinyl, 3-isoquinolinyl or 4-isoquinolinyl), imidazole And [1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, [1,2,4]Triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazole And [1,5-a]pyridyl, etc. When a heteroaryl group is a linking group, and a heteroaryl group is listed for the Markush group definition, the heteroaryl group means a connected heteroarylene group. When M is a heteroaryl group in the definition of the present invention, it means that M is a connected heteroarylene group. 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 group may be independently optionally substituted with one or more substituents described in the present invention.

The term "bridged ring group" refers to a bivalent non-aromatic saturated or partially unsaturated bicyclic or polycyclic ring system that shares two or more non-adjacent ring atoms, including bridged carbocyclyls and bridged heterocycles. Ring base. In some embodiments, the bridging ring group is a 5-12 membered bridging ring group. The bridging cyclylene group may be independently optionally substituted with one or more substituents described in the present invention.

The term "amidocyclylene" refers to a divalent non-aromatic saturated or partially unsaturated bicyclic or polycyclic ring system that shares two adjacent ring atoms, including carbocyclylene and heterocyclylene. In some embodiments, the oxocyclylene group is a 5-12 membered oxocyclylene group. The pyrimidine group may be independently optionally substituted with one or more substituents described in the present invention.

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 is a 5-12 membered spirocyclylene. The spirocyclylene group may be independently optionally substituted with one or more substituents described in the present invention.

The terms "carbocyclic group" and "carbocyclic ring" can be used interchangeably to indicate a saturated or partially unsaturated monocyclic, bicyclic or polycyclic ring system in which the ring atoms are all carbon atoms, including monocarbocyclic groups, bridged carbocyclic groups, And carbocyclyl and spirocarbocyclyl.

The terms "bridged carbocyclic ring" and "bridged carbocyclic group" can be 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 -CH 2} -group in the bridged carbocyclic ring can be optionally replaced by -C(=O)-. In some embodiments, the bridged carbocyclic ring contains 6-12 ring carbon atoms, which means 6-12 membered carbon ring; in other embodiments, the bridged carbocyclic ring contains 6-10 ring carbon atoms, which means 6 -10 bridged carbon ring. Examples of bridged carbocyclic rings include, but are not limited to: bicyclo[3.1.1]heptane, bicyclo[3.2.1]octane, bicyclo[2.2.2]octane, bicyclo[2.2.0]hexane, Octahydro-1H-indene, etc. When a bridged carbocyclic ring or a bridged carbocyclic group is a linking group, and a bridged carbocyclic ring or a bridged carbocyclic group is listed for the Markush group definition, then the bridged carbocyclic ring or bridged carbocyclic group means the connected subbridged carbon Ring base. The term "bridged carbocyclic group" means a divalent bridged carbocyclic group formed by removing two hydrogen atoms from the ring atoms of the bridged carbocyclic ring. The bridged carbocyclic or bridged carbocyclic group may be independently optionally substituted with one or more substituents described in the present invention.

The terms "spirocarbocyclic" and "spirocarbocyclyl" can be 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 -CH 2} -group in the spirocarbocyclic ring can be optionally replaced by -C(=O)-. In some embodiments, the spiro carbocyclic ring contains 7-12 ring carbon atoms, which means 7-12 membered spiro carbocyclic ring; in other embodiments, the spiro carbocyclic ring contains 7-10 ring carbon atoms, which means 7 -10 membered spiro carbon ring. Examples of spirocarbocyclic rings include, but are not limited to: spiro[4.4]nonane, spiro[3.4]octane, spiro[4.5]decane, and the like. When a spirocarbocyclic or spirocarbocyclic group is a linking group, and a spirocarbocyclic or spirocarbocyclic group is listed for the definition of the Markush group, the spirocarbocyclic or spirocarbocyclic group means the connected spirocarbocyclic group Ring base. The term "spirocarbocyclylene" means a divalent spirocarbocyclic group formed by removing two hydrogen atoms from the ring atoms of a spirocarbocyclic ring. The spirocarbocyclic or spirocarbocyclic group may be independently optionally substituted with one or more substituents described in the present invention.

The terms "heterocyclic ring" or "heterocyclic group" can be used interchangeably, and both refer to a monovalent non-aromatic saturated or partially unsaturated monocyclic, bicyclic or polycyclic ring system with 3-12 ring atoms, and in this system It contains at least one carbon atom and one, two or three heteroatoms selected from O, N, and S. Unless otherwise specified, the heterocyclic group may be a carbon group or a nitrogen group, and the -CH ₂ -group may be optionally replaced by -C(=O)-. The sulfur atom of the ring can be optionally oxidized to an S-oxide, and the nitrogen atom of the ring can be optionally oxidized to an N-oxygen compound. In some embodiments, the heterocyclic group contains 4-7 ring atoms, which means a 4-7 membered heterocyclic group; examples of heterocyclic groups include but are not limited to: oxirane, azetidinyl, oxygen Heterocyclobutyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuryl, dihydro Furanyl, tetrahydrothienyl, dihydrothienyl, 1,3-dioxocyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl Pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thiazinyl, homopiperazinyl, homopiperidine Group, 1,1-dioxo-1,3-thiomorpholine, etc. Examples of the -CH ₂ -group substituted by -C(=O)- in the heterocyclic group include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidine Ketone, 3,5-dioxopiperidinyl. Examples of the nitrogen atom in the heterocyclic group being oxidized to an N-oxygen compound include, but are not limited to, 1,1-dioxo-1,3-thiomorpholine. When a heterocyclic ring or a heterocyclic group is a linking group, and a heterocyclic ring or a heterocyclic group is exemplified for the Markush group definition, the heterocyclic ring or a heterocyclic group means a connected heterocyclylene group. The term "heterocyclylene" refers to a divalent heterocyclic group formed by removing two hydrogen atoms from the ring atoms of a heterocyclic ring. The heterocyclic ring or heterocyclic group may be independently optionally substituted by one or more substituents described in the present invention.

The terms "bridged heterocyclic ring" or "bridged heterocyclic group" can be 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 one carbon atom and one, two or three heteroatoms selected from O, N, and S. _{The -CH 2} -group in the bridged heterocycle can be optionally replaced by -C(=O)-. The sulfur atom of the ring can be optionally oxidized to an S-oxide, and the nitrogen atom of the ring can be optionally oxidized to an N-oxygen compound. In some embodiments, the bridged heterocyclic ring contains 6-12 ring atoms, which means 6-12 membered heterocyclic ring; in other embodiments, the bridged heterocyclic ring contains 6-10 ring atoms, which means 6-10 ring atoms. Member bridge 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 a bridged heterocyclic ring or a bridged heterocyclic group is a linking group, and a bridged heterocyclic ring or a bridged heterocyclic group is listed for the definition of the Markush group, the bridged heterocyclic ring or a bridged heterocyclic group means a connected sub-bridged heterocycle. Ring base. The term "bridged heterocyclic group" means a bivalent bridged heterocyclic group formed by removing two hydrogen atoms from the ring atoms of the bridged heterocyclic ring. The bridged heterocyclic ring or bridged heterocyclic group may be independently optionally substituted by one or more substituents described in the present invention.

The terms "spiroheterocycle" or "spiroheterocycle" 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 -CH 2} -group in the spiro heterocycle can be optionally replaced by -C(=O)-. The sulfur atom of the ring can be optionally oxidized to an S-oxide, and the nitrogen atom of the ring can be optionally oxidized to an N-oxygen compound. In some embodiments, the spiro heterocyclic ring contains 7-12 ring atoms, which means 7-12 membered spiro heterocyclic ring; in other embodiments, the spiro heterocyclic ring contains 7-10 ring atoms, which means 7-10 ring atoms. Membered spiro heterocyclic ring. Examples of spiro heterocycles 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]nonane-1-one, etc. When a spiro heterocyclic ring or a spiro heterocyclic group is a linking group, and a spiro heterocyclic ring or a spiro heterocyclic group is listed for the definition of the Markush group, the spiro heterocyclic ring or a spiro heterocyclic group represents a connected spiro heterocyclic group. Ring base. The term "spiroheterocyclylene" means a divalent spiroheterocyclic group formed by removing two hydrogen atoms from the ring atoms of the spiroheterocyclic ring. The spiro heterocyclic ring or spiro heterocyclic group may be independently optionally substituted by one or more substituents described in the present invention.

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 amino C _1-4 alkyl. In other embodiments, the term "aminoalkyl" refers to amino C _1-3 alkyl. Examples of aminoalkyl include, but are not limited to, aminomethyl, aminoethyl, aminon-propyl, aminoisopropyl, aminoisobutyl, aminotert-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" means C _1-6 alkylamino, that is, an amino group substituted with _{one or two C 1-6 alkyl groups.} In other embodiments, the term "alkylamino" means C _1-4 alkylamino. In other embodiments, the term "alkylamino" refers to C _1-3 alkylamino. Examples of alkylamino groups include, but are not limited to, methylamino, ethylamino, n-propylamino, isopropylamino, isobutylamino, tert-butylamino, dimethylamino, diethylamino, di-n-propylamino, Propylamino, diisopropylamino, diisobutylamino, di-tert-butylamino, etc.

The term "alkylsulfonyl" means an alkyl group -S(=O) ₂ -, that is, the alkyl group is connected to the rest of the molecule _{through -S(=O) 2 -.} In some embodiments, alkylsulfonyl represents C _1-6 alkylsulfonyl; in other embodiments, alkylsulfonyl represents C _1-4 alkylsulfonyl; in other embodiments, alkyl Sulfonyl means C _1-4 alkylsulfonyl. Examples of alkylsulfonyl groups include, but are not limited to, methylmethanesulfonyl, ethylmethanesulfonyl, n-propylmethanesulfonyl, isopropylmethanesulfonyl, n-butylmethanesulfonyl, and the like.

In the general formula 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

Means

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

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

Means

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

The term "protecting group" or "PG" refers to when a substituent reacts with other functional groups, it is usually used to block or protect specific functionality. For example, "amino protecting group" refers to a substituent connected to an amino group to block or protect the functionality of the amino group in the compound. Suitable amino protecting groups include acetyl, trifluoroacetyl, and tert-butoxycarbonyl. (BOC, Boc), benzyloxycarbonyl (CBZ, Cbz) and 9-fluorenemethyleneoxycarbonyl (Fmoc). Similarly, "hydroxyl protecting group" refers to a substituent of a hydroxyl group used to block or protect the functionality of the hydroxyl group. Suitable protecting groups include acetyl and silyl groups. "Carboxyl protecting group" refers to the substituent of the carboxyl group 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) Phosphonyl) ethyl, nitroethyl, etc. For a general description of protecting groups, refer to the literature: T W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991; and PJ Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.

The term "prodrug" used in the present invention represents the conversion of a compound into a compound represented by formula (I) in vivo. Such conversion is affected by the hydrolysis of the prodrug in the blood or the enzymatic conversion of the prodrug into the maternal structure in the blood or tissues. The prodrug compounds of the present invention can be esters. In the existing invention, esters can be used as prodrugs including phenyl esters, aliphatic (C _1-24 ) esters, acyloxymethyl esters, and carbonates. , Carbamates and amino acid esters. For example, a compound in the present invention contains a hydroxyl group, that is, it can be acylated to obtain a compound in the form of a prodrug. Other prodrug forms include phosphate esters. For example, these phosphate ester compounds are obtained by phosphorylation of the parent hydroxyl group. For a complete discussion of prodrugs, refer to the following documents: 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 the product obtained by the metabolism of a specific compound or its salt in the body. The metabolites of a compound can be identified by techniques well known in the art, and its activity can be characterized by experimental methods as described in the present invention. Such products can be obtained by oxidizing, reducing, hydrolyzing, amidating, deamidating, esterifying, degreasing, enzymatic cleavage and the like of the administered compound. Correspondingly, the present invention includes the metabolites of the compound, including the metabolites produced by fully contacting the compound of the present invention with a mammal for a period of time.

The "pharmaceutically acceptable salt" used in the present invention refers to the organic and inorganic salts of the compound of the present invention. Pharmaceutically acceptable salts are well-known in the field, as described in the literature: SMBerge 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 include hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, And organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, or other methods described in books and literature such as ion exchange These salts. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphoric acid Salt, camphor sulfonate, cyclopentyl propionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate Salt, gluconate, hemisulfate, heptanoate, caproate, hydroiodide, 2-hydroxy-ethanesulfonate, lacturonate, lactate, laurate, lauryl sulfate, Malate, malonate, methanesulfonate, 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 the quaternary ammonium salt formed by any compound containing the N group. Water-soluble or oil-soluble or dispersed 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 comprise suitable amine cation nontoxic ammonium, quaternary ammonium, and the counterion, such as halide, hydroxide, carboxylate, sulfated, phosphorylated compounds, nitrate compounds, C _{1 -8} Sulfonates and aromatic sulfonates.

The pharmaceutically acceptable salt of the present invention can be synthesized from the parent compound, basic or acidic moiety by conventional chemical methods. Generally speaking, such salts can be obtained by reacting the free acid form of these compounds with a stoichiometric amount of a suitable base (such as hydroxide, carbonate, bicarbonate, etc.) of Na, Ca, Mg or K, or by reacting These compounds are prepared by reacting the free base form of these compounds with a stoichiometric amount of a suitable acid. This type of reaction is usually carried out in water or an organic solvent or a mixture of the two. Generally, where appropriate, it is necessary to use a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol, or acetonitrile. 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) can find a list of other suitable salts.

In addition, the compounds disclosed in the present invention, including their salts, can also be obtained in the form of their hydrates or in the form of containing their solvents (for example, ethanol, DMSO, etc.), and used for their crystallization. The compounds disclosed in the present invention can form solvates inherently or by design with pharmaceutically acceptable solvents (including water); therefore, the present invention is intended to include solvated and unsolvated forms.

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

The "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. Specific examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen-containing heterocyclic nitrogen atoms. The corresponding amine can be treated with an oxidizing agent such as hydrogen peroxide or peracid (such as peroxycarboxylic acid) to form N-oxide (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages). In particular, N-oxides can be prepared by the method of LWDeady (Syn.Comm.1977, 7,509-514), in which, for example, in an inert solvent such as dichloromethane, the amine compound is combined with m-chloroperoxybenzoic acid (MCPBA) reaction.

The term "treating" any disease or condition as used in the present invention, in some embodiments refers to ameliorating the disease or condition (ie slowing down or preventing or reducing 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 physical parameters that may not be perceived by the patient. In other embodiments, "treatment" refers to the regulation of the disease or condition physically (e.g., stabilizing the perceptible symptoms) or physiologically (e.g., stabilizing the parameters of the body) or both. In other embodiments, "treating" refers to preventing or delaying the onset, occurrence, or worsening of a disease or condition.

The term "RET-associated cancer" as used herein refers to a cancer that is related to or has a disorder in the expression or activity or level of RET gene, RET kinase (also referred to herein as RET kinase protein or RET kinase), or any of them. This article describes non-limiting examples of RET-related cancers. The disorder of the expression or activity or level of the RET gene, RET kinase, or any one of them is one or more point mutations in the RET gene.

The phrase "the expression or activity or level of RET gene, RET kinase, or any one of them is dysregulated" refers to a genetic mutation (for example, a translocation of the RET gene that results in the expression of a fusion protein, resulting in a loss of at least one amino acid compared to the wild-type RET protein Deletion in the RET gene expressed by the RET protein, or mutation in the RET gene that causes the expression of the RET protein with one or more point mutations, or the RET protein resulting in the deletion of at least one amino acid in the RET protein compared with the wild-type RET protein Alternative splicing form of RET mRNA), or RET gene amplification, which leads to overexpression of RET protein or autocrine activity caused by overexpression of cellular RET gene, resulting in the activity of the kinase domain of RET protein in the cell Increased pathogenicity (e.g., constitutive activation of the kinase domain of the RET protein). As another example, the expression or activity or level of RET gene, RET kinase, or any one of them may be a mutation in a RET gene encoding a RET protein that is similar to a protein encoded by a RET gene that does not contain the mutation. Ratio, with constitutive activity or with increased activity. For example, the expression or activity or level of RET gene, RET kinase, or any one of them may be the result of gene or chromosomal translocation, which leads to the expression of a fusion protein comprising the first functional kinase domain. The RET part and the second part of the chaperone protein (ie not RET). In some examples, the disorder of RET gene, RET protein, or expression or activity may be the result of gene translation of one RET gene and another RET gene.

Disregulation of the expression or activity or level of RET kinase, RET gene, or any (for example, one or more) of them may contribute to tumorigenesis. For example, the disorder of RET kinase, RET gene, or the expression or activity or level of any one of them may be translocation, overexpression, activation, amplification, or mutation of RET kinase, RET gene, or RET kinase domain. The translocation may include a translocation involving the RET kinase domain, the mutation may include a mutation involving the RET ligand binding site, and the amplification may be the RET gene. Other disorders can include RET mRNA splicing variants and RET autocrine/paracrine signaling, which may also contribute to tumorigenesis.

In some embodiments, the imbalance in the expression or activity or level of RET gene, RET kinase, or any of them includes one or more deletions (for example, deletion of amino acid at position 4), insertions, or point mutations in RET kinase. In some embodiments, the dysregulation of the expression or activity or level of the RET gene, RET kinase, or any of them includes the deletion of one or more residues of RET kinase, resulting in constitutive activity of the RET kinase domain.

The term "irritable bowel syndrome" includes diarrhea-dominated, constipation-dominated or alternating bowel patterns, functional bloating, functional constipation, functional diarrhea, non-specific functional bowel disease, functional abdominal pain syndrome, chronic characteristic Primary constipation, functional esophagus disease, functional gastroduodenal disease, functional anorectal pain, inflammatory bowel disease, etc.

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

On the other hand, 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 non-radioactive isotopes such as ² H and ¹³ C. Such isotopically enriched compounds can be used for metabolism studies (using ¹⁴ C), reaction kinetics studies (using, for example, ² H or ³ H), detection or imaging techniques, such as positron emission tomography (PET) or including drugs or Single-photon emission computed tomography (SPECT), which measures the distribution of substrate tissue, may be used in radiotherapy of patients. ¹⁸ F-enriched compounds are particularly ideal for PET or SPECT research. The isotope-enriched compound represented by formula (I) can be prepared by conventional techniques familiar to those skilled in the art or as described in the examples and preparation process of the present invention, using a suitable isotope-labeled reagent instead of the previously used unlabeled reagent.

In addition, the substitution of heavier isotopes, particularly deuterium (ie, ² H or D), can provide certain therapeutic advantages due to higher metabolic stability. For example, the increase in the half-life in the body or the decrease in dosage requirements or the improvement of the therapeutic index. It should be understood that deuterium in the present invention is regarded as a substituent of the compound of formula (I), (I-1), (I-2), (I-3) or (I-4). The isotope enrichment factor can be used to define the concentration of such heavier isotopes, especially deuterium. The term "isotopic enrichment factor" used in the present invention refers to the ratio between the isotopic abundance and the natural abundance of the specified isotope. If the substituent of the compound of the present invention is designated as deuterium, the compound has at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), for each designated deuterium atom, At least 4500 (67.5% deuterium doping), at least 5000 (75% deuterium doping), at least 5500 (82.5% deuterium doping), at least 6000 (90% deuterium doping), at least 6333.3 (95% deuterium doping) Deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation) isotope enrichment factor. The pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent may be isotopically substituted, such as D ₂ O, acetone-d ₆ , DMSO-d ₆ .

Description of the compounds of the invention

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

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- or alkylene-NH-, and the T is optionally selected by 1, 2, 3, or 4 selected from D, OH , F, Cl, Br, I, CN, NH ₂ , CF ₃ , alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, heterocyclyl, alkoxy, aryl, heteroaryl or alkylamino Substituents are substituted.

In some embodiments, Ring G is spirocarbocyclyl or spiroheterocyclyl.

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

In some embodiments, R ^a is _{D, OH, NH 2, F} , CF 3, 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, alkane Oxyalkyl or hydroxyalkyl.

In some embodiments, E is a bond, -NR ⁶ -, or -O-.

In some embodiments, ring A is a bridging cyclylene, oxocyclylene, or spirocyclylene, and A is optionally substituted by 1, 2, 3, or 4 selected from F, Cl, Br, OH, oxo , NR ⁵ R ⁶ , R ⁵ (C=O)NR ⁶ -, aminoalkyl, alkyl, alkoxy, haloalkyl, hydroxyalkyl, carbocyclyl, heterocyclyl, heterocyclylalkyl, alkane Substituents of oxyalkyl, cycloalkylene and monoheterocyclylene are substituted.

In some embodiments, 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 -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 1, 2, 3, or 4 selected from D, F, Cl, CN , CF ₃ , OH, NR ⁵ R ⁶ , OR ⁷ , alkyl, haloalkyl, hydroxyalkyl, haloalkoxy, aryl, alkoxyalkyl, oxo, alkyl acyl, heterocyclic, cycloalkane Substituents of the group are substituted.

In some embodiments, 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 It is substituted by 4 substituents selected from F, Cl, Br, CN, NH ₂ , OH and NO ₂ .

In some embodiments, each R ² , R ^{3 is} independently OH, F, CF ₃ , H, D, CN, Cl, Br, NH ₂ , hydroxyalkyl, alkyl, alkylamino, alkoxy, Halogenated alkoxy, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl;

In some embodiments, R ⁴ is H, D, F, Cl, Br, alkyl, or alkoxy, wherein the alkyl and alkoxy are each independently optionally substituted by 1, 2, 3, or 4 Substituted by substituents selected from F, Cl, Br, CN, NH ₂ , OH and NO _2.

In some embodiments, R ⁵ is H, D, alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl, carbocyclyl, heterocyclyl, aryl and hetero The aryl groups are each independently optionally selected from F, Cl, Br, OH, NH ₂ , alkylamino, alkyl, alkylsulfonyl, alkoxy, aryl and heteroaryl groups. Substituents of the group are substituted.

In some embodiments, R ⁶ is H, D, alkyl, or alkoxyalkyl, wherein the alkyl and alkoxyalkyl are each independently optionally selected from F , Cl, Br, CN, NH ₂ , OH and NO ₂ substituents.

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

In some embodiments, G is 6-12 membered spirocarbocyclyl or 6-12 membered spiroheterocyclyl.

In some embodiments, R ^a is _{D, OH, NH 2, F} , CF 3, 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 alkane Oxy group, C _3-7 cycloalkyl, C _1-6 alkoxy C _1-6 alkyl, 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 aryl, or 5-10 membered heteroaryl , Wherein the C _1-6 alkyl group, 3-12 membered carbocyclic group, 3-12 membered heterocyclic group, C _6-10 aryl group and 5-10 membered heteroaryl group are each independently optionally grouped by 1, Replaced by 2, 3 or 4 substituents selected from F, Cl, Br, OH, NH ₂ , C _1-6 alkylamino, alkyl, alkylsulfonyl, alkoxy, aryl and heteroaryl .

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 C _1-6 alkyl groups are each independently optionally substituted with 1, 2, 3, or 4 substituents selected from F, Cl, Br, CN, NH ₂ , OH, and NO ₂ .

In some embodiments, G is the following sub-structure:

Z ¹ and Z ^{2 are} independently -CH ₂ -, -O-, -S-, -NH-;

Z ³ is -O-, -S-, -NH-;

n1 is 0, 1 or 2;

n2 is 1, 2 or 3;

n3 is 0 or 1.

In some embodiments, G is the following sub-structure:

In some embodiments, R ^a is _{D, OH, NH 2, F} , CF 3, Cl, Br, I, CN, NH 2, NHCH 3, -NHC (= O) CH 3, -S (= O) ₂ CH ₃ , -S(=O)CH ₃ , -C(=O)CH ₃ , -C(=O)OH, oxo, methyl, ethyl, propyl, butyl, methoxy, ethyl Oxygen, cyclopropyl, cyclopentyl, methoxymethyl, ethoxymethyl, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 2-hydroxypropyl, 2-hydroxy-2 -Methylpropyl.

In some embodiments, 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 selected from F, Substituted by Cl, Br, OH, NH ₂ , methyl, -S(=O) ₂ CH ₃ , methoxy, ethoxy and phenyl substituents.

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 selected from F, Cl, Br , CN, NH ₂ , OH and NO ₂ substituents.

In some embodiments, R ⁷ is OH, methyl, ethyl, NH ₂ , N(CH ₃ ) ₂ , n-propyl, isopropyl, tert-butyl, cyclopropyl, or phenyl.

In some embodiments, A is a 5-12-membered bridge sub-ring group, a 5-12-membered azimuth sub-ring group, or a 5-12-membered spiro sub-ring group, and A is optionally selected from 1, 2, 3, or 4 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 carbocyclic group, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group C _1-6 alkyl, C _1-6 Alkoxy C _1-6 alkyl, C _3-6 cycloalkylene and 3-6 membered monoheterocyclic group are substituted.

In some embodiments, A is the following sub-structure:

Wherein, Z ^1a and Z ^{2a are} each independently -CH ₂ -or -NH-;

Z ^3a is -CH- or -N-;

Z ^4a is -O-, -S- or -NH-;

m and t are each independently 0, 1 or 2;

n and t1 are each independently 0 or 1;

In some embodiments, A is the following sub-structure:

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, hexahydrofuran[3,4-c]pyrrolyl, 3-azabicyclo[3.1.0]hexyl, octahydropyrrolo[ 1,2-a]pyrazinyl or 5-azaspiro[2.4]heptanyl; 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, Substituents of tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, cyclopropyl and cyclohexyl.

In some embodiments, M is phenyl,

And M is optionally selected from 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 the methyl, ethyl and cyclopropyl can be independently optionally It is substituted by 1, 2, 3 or 4 substituents selected from F, Cl, Br, CN, NH ₂ , OH and NO ₂ .

In some embodiments, R ⁴ is H, D, F, Cl, Br, methyl, ethyl, n-propyl, methoxy or ethoxy, wherein the 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, NH ₂ , OH and NO ₂ .

In some embodiments, the compound of the present invention has a structure of formula (IA), or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, solvate, Metabolites, pharmaceutically acceptable salts or prodrugs,

among them,

Ring A1 is the following sub-structure:

Wherein Z ^1a and Z ^{2a are} each independently CH ₂ or NH;

In some embodiments, A1 is a sub-structure:

Wherein, Z ¹ , Z ² and Z ^{3a are} each independently CH or N;

m and t are each independently 0, 1 or 2;

n and t1 are each independently 0 or 1;

among them

Independently and 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 carbocyclic group, 3-12 membered heterocyclic group, 3-12 membered The heterocyclic group C _1-4 alkyl, C _1-4 alkoxy C _1-4 alkyl, C _3-6 cycloalkylene and 3-6 membered monoheterocyclylene substituents are substituted.

In some embodiments,

Is the following sub-structure:

Is the following sub-structure:

among them

In some embodiments, the compound of the present invention has one of the following structures, or its stereoisomers, geometric isomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable Salt or prodrug of

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

In another aspect, the present invention relates to a method for the preparation, separation and purification of the compound represented by formula (I), (I-1), (IA), (I-2) or (I-3).

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

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

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 the prevention or treatment of irritable bowel syndrome (IBS) and/or pain associated with IBS.

The present invention also provides the compound of the present invention or the pharmaceutical composition of the present invention for the prevention or treatment of irritable bowel syndrome (IBS) and/or pain associated with IBS.

The salt of the compound of the present invention also includes intermediates or formula (I) used to prepare or purify the compound represented by formula (I), (IA), (I-1), (I-2) or (I-3) , (I-1), (IA), (I-2) or (I-3), the salt of the separated enantiomers of the compound, but not necessarily a pharmaceutically acceptable salt.

In the structure disclosed in the present invention, when the stereochemistry of any specific chiral atom is not specified, all stereoisomers of the structure are considered in the present invention and are included in the present invention as the compound disclosed in the present invention . When the stereochemistry is indicated by a solid wedge or dashed line representing a specific configuration, then the stereoisomer of the structure is clear and defined.

The nitrogen oxides of the compounds of the present invention are also included in the scope of the present invention. It can be done by using common oxidants (such as hydrogen peroxide) at elevated temperature, in the presence of acids such as acetic acid, to oxidize the corresponding nitrogen-containing basic substances, or by reacting with peracids in a suitable solvent, such as in dichloromethane , Ethyl acetate or methyl acetate with peracetic acid, or with 3-chloroperoxybenzoic acid in chloroform or dichloromethane to prepare the nitrogen oxide of the compound of the present invention.

If the compound of the present invention is basic, the desired salt can be prepared by any suitable method provided in the literature, for example, using inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like. Or 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 acid such as glucuronic acid and galactose Alkyl acid; α-hydroxy acid, such as citric acid and tartaric acid; amino acid, such as aspartic acid and glutamic acid; aromatic acid, such as benzoic acid and cinnamic acid; sulfonic acid, such as p-toluenesulfonic acid, ethanesulfonic acid, and many more.

If the compound of the present invention is acidic, the desired salt can be prepared by a suitable method, for example, using inorganic or organic bases such as ammonia (primary, secondary, tertiary), alkali metal hydroxide or alkaline earth Metal hydroxide, 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 obtain inorganic salts from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.

The compound of the present invention and its pharmaceutical composition, preparation and administration

The present invention provides compounds of the present invention or pharmaceutical compositions thereof that inhibit wild-type RET and RET mutants, for example, RET mutants that are resistant to current standard care treatments ("RET resistant mutants"). In addition, compared to other kinases, the compound of the present invention or its pharmaceutical composition may be selective for wild-type RET, resulting in reduced toxicity associated with the inhibition of other kinases.

The pharmaceutical composition of the present invention includes the compounds represented by formula (I), (IA), (I-1), (I-2) or (I-3), the compounds listed in the present invention, or the compounds of the examples Compound. The amount of the compound in the composition of the present invention can effectively treat or alleviate RET-related diseases or disorders in patients, including RET-related cancer, irritable bowel syndrome, and/or pain associated with irritable bowel syndrome.

As described in the present invention, the pharmaceutically acceptable composition of the present invention further comprises pharmaceutically acceptable adjuvants, which, like those used in the present invention, include any solvents, diluents, or other liquid excipients, dispersants Or suspending agents, surfactants, isotonic agents, thickeners, emulsifiers, preservatives, solid binders or lubricants, etc., suitable for specific target dosage forms. As described in the following documents: In Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. DBTroy, Lippincott, Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick, and 1999-JCB Marcel Dekker, New York, combining the contents of the literature here, shows that different adjuvants can be applied to the preparation of pharmaceutically acceptable compositions and their well-known preparation methods. Except for any conventional adjuvants that are incompatible with the compounds of the present invention, such as any adverse biological effects or interactions with any other components of the pharmaceutically acceptable composition in a harmful manner, they The use of is also the scope of the present invention.

In preparing the compositions provided herein, the active ingredients are usually mixed with excipients, diluted with excipients, or packaged in such carriers in the form of, for example, capsules, sachets, paper or other containers. If the excipient is used as a diluent, it can be a solid, semi-solid or liquid material, which serves as a vehicle, carrier or medium for the active ingredient. Suitable carriers include, but are not limited to, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, low Melting point wax, cocoa butter, etc. Therefore, the composition can be a tablet, pill, powder, lozenge, sachet, cachet, elixirs, suspensions, emulsions, solutions, syrups, aerosols (solid form or in a liquid medium) , For example, ointments, soft and hard gelatin capsules, suppositories, sterile injection solutions and powders in sterile packaging 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 used in therapy, a therapeutically effective amount of the compound of the present invention, especially a compound of formula (I), (IA), (I-1), (I-2) or (I-3) and pharmaceutically acceptable compounds thereof The salt can be administered as an unprocessed chemical and can also be provided as an active ingredient in a pharmaceutical composition. Therefore, the content of the present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of the compound of the present invention, especially formula (I), (IA), (I-1), (I-2) or (I- 3) The compound or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable adjuvants, the adjuvants include but are not limited to carriers, diluents or excipients, and the like. The term "therapeutically effective amount" as used herein refers to the total amount of each active ingredient sufficient to show a meaningful patient benefit (e.g., reduction of cancer cells). When a separate active ingredient is used for separate administration, the term refers only to that ingredient. When used in combination, the term refers to the combined amount of active ingredients that cause a therapeutic effect regardless of the combination, when administered sequentially or simultaneously. The compounds of the present invention, especially the compounds of formula (I), (IA), (I-1), (I-2) or (I-3), and their pharmaceutically acceptable salts are as described above. The carrier, diluent or excipient must be acceptable in the sense of being compatible with the other ingredients of the formulation and harmless to the recipient. According to another aspect of the present invention, there is also provided a method for preparing a pharmaceutical preparation, which method comprises combining the compound of the present invention, especially formula (I), (IA), (I-1), (I-2) or (I-3) The compound or its pharmaceutically acceptable salt is mixed with one or more pharmaceutically acceptable carriers, diluents or excipients. The term "pharmaceutically acceptable" used in the present invention refers to such compounds, raw materials, compositions and/or dosage forms, which are within the scope of reasonable medical judgment and are suitable for contact with patient tissues without excessive toxicity or irritation. , Allergies, or other problems and complications that are commensurate with a reasonable benefit/risk ratio, and are effectively used for the intended purpose.

The amount of active ingredient combined with one or more adjuvants to prepare a single dosage form will have to vary according to the host to be treated and the specific route of administration. The compound of formula (I), (IA), (I-1), (I-2) or (I-3) is mixed with a carrier material to prepare a single dosage form. The amount of active ingredient will depend on the disease to be treated and the severity of the disease. The degree, time of administration, route of administration, excretion rate of the compound used, treatment time, and patient's age, sex, weight and condition vary. A preferred unit dosage form is a unit dosage form containing a daily dose or sub-dose or an appropriate fraction of the above-mentioned active ingredients herein. Treatment can be initiated in small doses that are clearly below the optimal dose of the compound. Thereafter, increase the dose in smaller increments until the best effect is achieved in this case. In general, the most ideal concentration level of the compound administered is usually to provide effective results in anti-tumor without causing any harmful or toxic side effects.

The composition containing the compound of the present invention can be formulated into a unit dosage form, each dosage containing about 5 to about 1,000 mg (1 g), more usually about 100 mg to about 500 mg of the active ingredient. The term "unit dosage form" refers to physically discrete units suitable as a single dose for human subjects or other patients, each unit containing a predetermined amount of active material (ie, a compound of general formula I as provided herein) and a suitable drug. With excipients, the predetermined amount is calculated to produce the desired therapeutic effect.

In some embodiments, the compositions provided herein contain about 5 mg to about 50 mg of active ingredient. Those of ordinary skill in the art will understand that this embodies the inclusion of 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 the active ingredient.

In some embodiments, the compositions provided herein contain about 50 mg to about 500 mg of active ingredient. Those of ordinary skill in the art will understand 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 active ingredient compound or composition.

In some embodiments, the compositions provided herein contain about 500 mg to about 1,000 mg of active ingredient. Those 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 the active ingredient compound or composition.

The pharmaceutical composition is suitable for administration by any suitable route, such as oral (including oral or sublingual), rectal, nasal, topical (including buccal, sublingual, or transdermal), vaginal or parenteral (including subcutaneous, skin) Intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intralesional, intravenous or subdermal injection or infusion) route. Such preparations can be prepared according to any known method in the field of pharmacy, for example, by mixing 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 suffering from RET-related cancer, the method comprising administering the compound of the present invention before, during, or after the administration of another anticancer drug (e.g., not the compound of the present invention).

The present invention provides a method for treating cancer in a patient in need, the method comprising: (a) determining whether the cancer in the patient is a RET-related cancer (e.g., comprising having one or more RET inhibitors Sexually mutated RET-related cancers, RET-related cancers) (e.g., using regulatory agency approved, such as FDA approved, kits to identify the expression of RET gene, RET kinase, or any of them in a patient or in a patient’s biopsy sample Or an imbalance in activity or level, or by performing any non-limiting example of the assay described herein); and (b) if the cancer is determined to be a RET-related cancer, then administering to the patient a therapeutically effective amount of formula (I), (IA ), (I-1), (I-2) or (I-3), or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof. Some embodiments of these methods further include administering to the subject another anti-cancer agent (e.g., another RET inhibitor, such as a RET inhibitor that is not a compound of the invention). In some embodiments, the subject was previously treated with a compound of formula (I), (IA), (I-1), (I-2), or (I-3) or a pharmaceutically acceptable salt or solvate thereof RET inhibitor treatment, or previously (e.g. after tumor removal or radiation therapy) with other anticancer agents.

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

Non-limiting examples of other therapeutic agents include: other RET targeted therapeutic agents (ie, other RET kinase inhibitors: RET inhibitors that are not the compounds of the present invention), receptor tyrosine kinase targeted therapeutic agents, signal transduction agents Pathway inhibitors, checkpoint inhibitors, apoptotic pathway modulators (such as Obataclax); cytotoxic chemotherapeutics, angiogenesis targeted therapies, immune targeting agents, and radiotherapy.

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

Non-limiting examples of RET targeted therapeutic agents include alatinib, apatinib, cabozantinib (XL-184), dovetinib, levatinib, motesanib, nintedanib, puna Tinib, Regulafenib, 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-methylprop-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, for example, U.S. Patent Nos. 7,504,509; 8,299,057; 8,399,442; 8,067,434; 8,937,071; 9,006,256; and 9,035,063; U.S. Publication Nos. 2014/0121239; 20160176865; 2011/0053934; 2011/0301157; 2010/0324065; 2009/0227556; 2009/0130229; 2009/0099167; 2005/0209195; International Publication No. WO 2014/184069; WO 2014/072220; WO2012/053606; WO 2009/017838; WO 2008/031551 ; WO 2007/136103; WO 2007/087245; WO 2007/057399; WO 2005/051366; WO 2005/062795; and WO 2005/044835; and J. Med. Chem. 2012, 55(10), 4872-4876, which All are incorporated in this article by reference in their entirety.

This article also provides a method of treating cancer, including administering to a patient in need a drug combination for treating cancer, which includes (a) a compound of general formula I or a pharmaceutically acceptable salt or solvate thereof, and (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 the compound of formula I or a pharmaceutically acceptable salt or solvate thereof The amount and the amount of other therapeutic agents are jointly effective in the treatment of 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, the compound or composition of the present 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), regulafenib (STAVARGA), prnatinib (ICLUSIG), bevacizumab (Avastin), crizotinib (XALKORI), or gefitinib (IRESSA) ). The compounds or compositions of the present invention can be administered simultaneously or sequentially with other therapeutic agents through the same or different administration routes. The compounds of the present invention may be contained in a single formulation or in separate formulations together with other therapeutic agents.

In some embodiments, the compounds of the present invention can be used to treat 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. According to standard pharmaceutical practice known to those skilled in the art, the at least one other therapeutic agent may be part of the same or separate dosage form as the compound of formula I or a pharmaceutically acceptable salt or solvate thereof, via the same Or different administration routes, and administration 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 (e.g. psyllium, methylcellulose), antidiarrheal drugs (e.g. loperamide), bile Acid binding agents (e.g. cholestyramine, colestipol, colesevelam), anticholinergics and anticonvulsants (e.g. scopolamine, bicyclic amine), antidepressants (e.g. tricyclic antidepressants) , Such as imipramine or nortriptyline or selective serotonin reuptake inhibitors (SSRI) such as fluoxetine or paroxetine), antibiotics (such as rifaximin), alosetron and lubiprostone .

Uses of the compounds and pharmaceutical compositions of the present 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 the prevention or treatment of 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 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 drugs for preventing or treating wild-type RET and RET mutant-related diseases or disorders.

In some embodiments of any of the methods or uses described herein, the cancer (e.g., RET-related cancer) is a hematological cancer. In some embodiments of any of the methods or uses described herein, the cancer (e.g., RET-related cancer) is a solid tumor. In some embodiments of any of the methods or uses described herein, the cancer (eg, RET-related 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 of type 2A or 2B (MEN2A or MEN2B, respectively), pheochromocytoma, parathyroid hyperplasia, breast Cancer, colorectal cancer (e.g. metastatic colorectal cancer), papillary renal cell carcinoma, gangliocytomatosis of the gastrointestinal mucosa, inflammatory myofibroblastoma or cervical cancer. In some embodiments of any of the methods or uses described herein, the cancer (eg, RET-related cancer) is selected from: acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), juvenile cancer, adrenal cortical 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, Burki Special lymphoma, carcinoid tumor, unknown primary cancer, heart tumor, cervical cancer, childhood cancer, chordoma, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myeloproliferative tumor, colon cancer, Colorectal cancer, craniopharyngioma, skin T-cell lymphoma, cholangiocarcinoma, ductal carcinoma in situ, embryonic tumor, endometrial carcinoma, ependymoma, esophageal carcinoma, sensory neuroblastoma, Ewing sarcoma, Extracranial germ cell tumor, extragonadal germ cell tumor, extrahepatic cholangiocarcinoma, eye cancer, fallopian tube cancer, bone fibrous histiocytoma, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), Germ cell tumor, gestational trophoblastic disease, glioma, hairy cell tumor, hairy cell leukemia, head and neck cancer, heart cancer, hepatocellular carcinoma, histiocytosis, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanin Tumor, islet cell tumor, pancreatic neuroendocrine tumor, Kaposi's sarcoma, kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, lip and oral cavity cancer, liver cancer, lung cancer, lymphoma, macroglobulinemia Syndrome, bone malignant fibrous histiocytoma, bone cancer, melanoma, Merkel cell carcinoma, mesothelioma, metastatic squamous neck cancer, midline carcinoma, oral cancer, multiple endocrine tumor syndrome, multiple myeloma , Mycosis mycosis fungoides, myelodysplastic syndrome, myelodysplastic/myeloproliferative tumor, myeloid leukemia, myelogenous leukemia, multiple myeloma, myeloproliferative tumor, 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 bowel cancer, soft tissue sarcoma, squamous cell Carcinoma, squamous neck cancer, gastric cancer, T cell lymphoma, testicular cancer, throat cancer, thymoma and thymic cancer, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, unknown primary cancer, urethral cancer, uterine cancer, uterine sarcoma , Vaginal cancer, vulvar cancer and Wilm’s tumor.

In some embodiments, the RET-related cancer of the present invention is selected from lung cancer, papillary thyroid cancer, medullary thyroid cancer, differentiated thyroid cancer, recurrent thyroid cancer, refractory differentiated thyroid cancer, multiple type 2A or 2B 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, the compound of formula (I), (IA), (I-1), (I-2) or (I-3) and pharmaceutically acceptable salts and solvates thereof can be used to treat patients There are mutations that are resistant to RET inhibitors (which lead to compounds other than formula (I), (IA), (I-1), (I-2) or (I-3) or pharmaceutically acceptable salts or solvates The resistance of the drug is increased, such as the substitution at amino acid position 804, such as V804M, V804L, or V804E). The treatment is administered in combination or as an existing drug treatment (e.g., not of formula (I), ( IA), (I-1), (I-2) or (I-3), or a pharmaceutically acceptable salt or solvate thereof (other RET kinase inhibitor). Described herein are exemplary RET kinase inhibitors (e.g., compounds other than formula (I), (IA), (I-1), (I-2), or (I-3) or a pharmaceutically acceptable salt thereof Or other RET kinase inhibitors of solvates). In some embodiments, the RET kinase inhibitor may be selected from cabozantinib, vandetanib, alatinib, sorafenib, levatinib, prnatinib, dovitinib, sunitinib , Foretinib, BLU667 and BLU6864.

In some embodiments of any of the methods or uses described herein, the irritable bowel syndrome (IBS) includes diarrhea predominant, constipation predominant or alternating, functional bloating, functional constipation, functional diarrhea, non 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 method of the present invention, the compounds and compositions can be administered in any amount and any route of administration to effectively treat or reduce the severity of the disease. The exact amount required will vary according to the patient's condition, which depends on race, age, general condition of the patient, severity of infection, special factors, method of administration, and so on. The compound or composition can be used in drug combination with one or more other therapeutic agents, as discussed in the present invention.

General synthesis method of the compound of the present invention

Generally, the compounds of the present invention can be prepared by the methods described in the present invention, unless otherwise specified, and the substituents are defined as formula (I), (IA), (I-1), (I-2) Or as shown in (I-3). The following reaction schemes and examples are used to further illustrate the content of the present invention.

Those skilled in the art will recognize that the chemical reactions described in the present invention can be used to appropriately prepare many other compounds of the present invention, and other methods for preparing the compounds of the present invention are considered to be within the scope of the present invention. Inside. For example, the synthesis of non-exemplified compounds according to the present invention can be successfully completed by those skilled in the art through modification methods, such as appropriate protection of interfering groups, by using other known reagents in addition to those described in the present invention, or The reaction conditions are modified regularly. In addition, the reactions disclosed in the present invention or known reaction conditions are also recognized to be applicable to the preparation of other compounds of the present invention.

In the examples described below, all temperatures are set to degrees Celsius unless otherwise indicated. Unless otherwise stated, the reagents can be purchased from the market. For example, the reagents can be purchased from commodity suppliers such as Lingkai Pharmaceutical, Aldrich Chemical Company, Inc., Arco Chemical Company and Alfa Chemical Company. They are used without further purification. Unless otherwise indicated. General reagents are purchased from Shantou Xilong Chemical Plant, Guangdong Guanghua Chemical Reagent Plant, Guangzhou Chemical Reagent Plant, Tianjin Haoyuyu Chemical Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Ocean Chemical Plant.

Anhydrous tetrahydrofuran is obtained by refluxing and drying with sodium metal. Anhydrous dichloromethane and chloroform are obtained by refluxing and drying with calcium hydride. Ethyl acetate, N,N-dimethylacetamide and petroleum ether are dried in advance with anhydrous sodium sulfate.

The following reactions are generally carried out under a positive pressure of nitrogen or argon or a drying tube on an anhydrous solvent (unless otherwise indicated), the reaction flask is plugged with a suitable rubber stopper, and the substrate is injected through a syringe. The glassware is all dried.

The chromatographic column is a silica gel column. Silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Plant. NMR spectroscopy uses CDC1 ₃ or DMSO-d ₆ as the solvent (reported in ppm), and uses TMS (0 ppm) or chloroform (7.25 ppm) as the reference standard. When multiple peaks appear, the following abbreviations will be used: s (singlet, singlet), d (doublet, doublet), t (triplet, triplet), m (multiplet, multiplet), br (broadened, wide Peak), dd (doublet of doublets, doublet of doublet), dt (doublet of triplets, doublet of doublet). Coupling constant, expressed in Hertz (Hz).

Low-resolution mass spectrometry (MS) data is measured by an Agilent 6320 series LC-MS spectrometer equipped with a G1312A binary pump and a G1316A TCC (column temperature maintained at 30°C). The G1329A automatic sampler and G1315B DAD detector are used For analysis, the ESI source is applied to the LC-MS spectrometer.

Low-resolution mass spectrometry (MS) data is measured by Agilent 6120 series LC-MS spectrometer equipped with G1311A quaternary pump and G1316A TCC (column temperature maintained at 30°C). G1329A automatic sampler and G1315D DAD detector are used for analysis , ESI source is used in LC-MS spectrometer.

The above two spectrometers are equipped with Agilent Zorbax SB-C18 column, the specification is 2.1×30mm, 5μm. The injection volume is determined by the sample concentration; the flow rate is 0.6 mL/min; the HPLC peak is recorded and read by UV-Vis wavelengths at 210 nm and 254 nm. The mobile phases are 0.1% formic acid acetonitrile solution (phase A) and 0.1% formic acid ultrapure aqueous solution (phase B).

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

The following abbreviations are used throughout the present invention:

DMAC, DMA N,N-2-methylacetamide

PdCl ₂ (dppf)CH ₂ Cl ₂ [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex

H ₂ hydrogen

Pd/C Palladium on carbon

NaOH Sodium hydroxide

NH ₄ Cl Ammonium Chloride

K ₂ CO ₃ Potassium Carbonate

MeOH methanol

PE Petroleum ether

EA Ethyl acetate

DCM Dichloromethane

L rise

mg milligrams

ml,mL milliliter

min minutes

NaHCO ₃

℃ Celsius, temperature

THF Tetrahydrofuran

g Gram

mass% mass%

N,mol/L mol/L

DMF N,N-Dimethylformamide

mmol

NaH Sodium hydride

LiAlH ₄ Lithium Tetrahydrogen Aluminum

TLC Thin Layer Chromatography

h hours

HCl Hydrogen chloride

DMSO Dimethyl sulfoxide

The following synthetic schemes describe the steps for preparing the compounds disclosed in this invention. Unless otherwise ^{^{indicated, R 1, X 1, X}} 2, X 3, X 4, X 5, E, A, Q, M, T, R a, q have the definitions as described in the present invention.

Synthesis scheme 1

Intermediate (IA-1a) synthesis scheme:

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 sub-structure:

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. The compound of formula (IA-1a-1) and the compound of formula (IA-1a-2) under suitable coupling agent conditions (such as palladium coupling agent, preferably PdCl ₂ (dppf)CH ₂ Cl ₂ ) in a suitable solvent ( For example, the coupling reaction occurs in dioxane, etc.) to obtain the compound of formula (IA-1a-3); the compound of formula (IA-1a-3) and the compound of formula (IA-1a-4) are 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.) to produce a compound of formula (IA-1a-5); formula (IA-1a) -5) The compound is reacted under suitable reaction conditions (for example, in the presence of sodium hydroxide and hydrogen peroxide, in a tetrahydrofuran solvent) to obtain a compound of formula (IA-1a-6); a compound of formula (IA-1a-6) and The compound of formula (IA-1a-7) undergoes coupling reaction to obtain the compound of formula (IA-1a-8); the compound of formula (IA-1a-8) and the compound of formula (IA-1a-9) are reacted under basic conditions to obtain The compound of formula (IA-1a-10); the compound of formula (IA-1a-10) is deamino-protected under acidic conditions to obtain the compound of formula (IA-1a-11); the compound of formula (IA-1a-11) and the compound of formula (IA -1a-12) Compounds of formula (IA-1a-13) are reacted under basic conditions; Compounds of formula (IA-1a-13) are _{reduced under suitable conditions (such as H 2} , Pd/C) to obtain formula ( IA-1a) Compound.

Intermediate (IA-2a) synthesis scheme:

The intermediate compound of formula (IA-2a) can be obtained by referring to the synthesis steps of the intermediate (IA-2a) synthesis scheme. Among them, Hal and Hal ² are each independently F, Cl, Br, and I, preferably Cl and Br. The compound of formula (IA-1a-6) and the compound 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) The reaction in) yields the compound of formula (IA-2a).

Synthesis scheme 1:

The compound of formula (IA) can be obtained by referring to the synthetic steps of Synthetic Scheme 1. Among them, Hal is F, Cl, Br, and I, preferably Cl and Br. The compound of formula (IA-1) and the compound of formula (IA-2) are in a suitable solvent (such as N,N-dimethylacetamide) under suitable _{conditions (such as basic conditions, the base is K 2} CO ₃₎ The reaction takes place to obtain the compound of formula (IA).

Synthesis scheme 2

The compound of formula (IA1) can be obtained by referring to the synthetic steps of Synthetic Scheme 2. The compound of formula (IA-1) and the compound of formula (IA-3) under suitable conditions (such as basic conditions, the base is K ₂ CO ₃ ) in a suitable solvent (such as N,N-dimethylformamide amide) The reaction occurs in the process to obtain the compound of formula (IA1).

Synthesis scheme 3

The compound of formula (IA) can be obtained by referring to the synthetic steps of Synthetic Scheme 3. The compound of formula (IA-1) and the compound of formula (IA-4) under suitable conditions (such as basic conditions, the base is K ₂ CO ₃ ) in a suitable solvent (such as N,N-dimethylformamide amide) The reaction occurs in the compound to obtain the compound of formula (IA).

Synthesis scheme 4

The compound of formula (IA2) can be obtained by referring to the synthetic steps of Synthetic Scheme 4. The compound of formula (IA-2a) and the compound of formula (IA-5) are heated in a suitable solvent (such as DMSO) _{under suitable conditions (such as basic conditions, the base is K 2} CO _{3) to react to obtain formula (IA2)} Compound.

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, add 6-bromo-4-methoxypyrazolo[1,5-a]pyridine-3-carbonitrile (50g, 198.36mmol) and water (16.5mL, 916mmol) in a 1L single-mouth flask in sequence , Sodium hydroxide (16.03g, 396.8mmol), DMA (500mL), stirred at room temperature for 5min, then transferred to 0°C, slowly added dodecanethiol (97mL, 397mmol), after the addition, the reaction was transferred to 45°C overnight. Pour the reaction solution into 3L ice water, slowly add saturated citric acid water to adjust the PH=5, stir for half an hour and then let stand, filter, wash the filter cake with water and petroleum ether several times, and dry at 60°C to obtain 44.1g of yellow solid. 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 triflate

Add 6-bromo-4-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile (44.1g, 185mmol), pyridine (45mL, 559mmol), DCM (800mL) into a 1L single-mouth flask, and the temperature drops to Below -10°C, slowly add trifluoromethanesulfonic anhydride (50mL, 297.2mmol), stir for 1h and then naturally warm to room temperature and react overnight. The DCM was spin-dried under reduced pressure, diluted with water (250ml), extracted with EA (500ml×3), the organic phase was collected, washed with saturated brine (250mL), dried over anhydrous sodium sulfate, filtered, the filtrate was spin-dried, and silica gel column chromatography Purified (eluent PE/EA=50:1 -25:1) to obtain 61.5 g of a yellow-like solid, which is the target product, with a yield of 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

Add 3-bromo-3-cyanopyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate (61.5g, 166mmol), 2-fluoropyridine to a 1L three-necked flask under nitrogen protection -5-Borate (44.5g, 200mmol), [1,1'-bis(diphenylphosphine)ferrocene] dichloropalladium dichloromethane complex (6.8g, 8.3mmol), 1, 4-Dioxane (850mL), slowly add potassium acetate solution (115mL, 345mmol, 3mol/L) when the temperature drops to -10°C. After stirring at this temperature for 1 hour, it will naturally return to room temperature and continue 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 spots, spin-dry to obtain 49g of white solid, which is the target product, 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 = 1.9 Hz, 1H), 8.27 (td, J = 8.2, 2.5 Hz, 1H), 7.86 (d, J = 1.2 Hz, 1H), 7.40 (dd, J = 8.4, 2.5 Hz, 1H).

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

Add 6-bromo-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (8g, 25.23mmol) in a 250mL single-mouth flask under nitrogen protection, and Pinacol borate (10g, 39.39mmol), potassium acetate (10g, 101.9mmol), redistilled toluene (150mL), after nitrogen replacement, bubbling for 10 minutes and then adding [1,1'-bis(diphenylphosphine) Ferrocene] palladium dichloride dichloromethane complex (2.1g, 2.6mmo), nitrogen replacement and bubbling for 10 minutes, heating at 120°C for overnight reaction. Filter through diatomaceous earth, 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, 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 ): 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), in an ice bath, slowly add sodium hydroxide solution (60mL, 120mmol, 2mol /L), hydrogen peroxide (14mL, 140mmol, 30mass%), 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), EA extraction (250mL×2), the combined organic phases are washed with 0.1M NaOH solution (500mL×2 ). Combine all the aqueous phases, adjust the pH to 4 with dilute hydrochloric acid, stir at room temperature for 15 minutes, and filter with suction to obtain a wet cake. Extract mother liquor with EA (250ml×3), combine all organic phases, dry with anhydrous sodium sulfate, filter, spin-dry, silica gel column chromatography (eluent DCM\MeOH (v/v=100/0-100/1) to obtain Light yellow solid. Combine all solids and dry at 50°C to obtain 5.1 g of light yellow solid, which is the target product (yield 86.0%). Rf=0.25 (DCM\MeOH(v/v=100/1)). LC-MS : M/z=255.10[M+H] ⁺ .

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 30mL microwave tube, add 4-(6-fluoropyridin-3-yl)-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile (1.5g, 5.9mmol), 6- (Tert-Butoxycarbonyl)-3,6-diazabicyclo[3.1.1]heptane (2.3g, 12mmol), N,N-diisopropylethylamine (2.0mL, 12mmol), dimethyl sulfoxide (15mL), sealed, and reacted in a microwave at 80°C for 8h. At low temperature, dilute with water (50mL), extract with EA (100mL×5), combine the organic phase, wash with saturated brine (250mL), dry with anhydrous sodium sulfate, filter, and spin-dry the filtrate to purify by silica gel chromatography (elution Reagent PE/EA=5:1-1; 1.5), 1.9 g of yellow product is collected, which is 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-diazide Heterobicyclo[3.1.1]heptane-3-tert-butyl-6-carboxylic acid ethyl ester

Add 3-(5-(3-cyano-6-hydroxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3,6-diazide in a 25mL single-necked flask Heterobicyclo[3.1.1]heptane-6-tert-butyl carboxylic acid (1g, 2.312mmol), benzyl bromide (0.302mL, 2.54mmol), potassium carbonate (0.9683g, 6.936mmol), N,N-di Methylformamide (10 mL) was stirred at 80°C overnight. Add saturated ammonium chloride (100mL) at room temperature to quench, extract with DCM (100mL×3), combine the organic phases, dry with anhydrous sodium sulfate, filter, and spin-dry the filtrate for purification by silica gel chromatography (eluent PE/EA =5:1-2:1), 1.06g of yellow solid is 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(400MHz, CDCl ₃ )δ8.37(s,1H), 8.19(s,1H), 8.17(d,J=1.9Hz,1H ), 7.74(d,J=8.7Hz,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 = 5.5 Hz, 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 (1.06g, 2.03mmol,), hydrochloric acid ethyl acetate solution (5mL, 20mmol, 4mol/L), react at room temperature overnight. The reaction solution was spin-dried to obtain a yellow viscous substance, which was 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].

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

At 0°C, 6-methoxy-3-pyridinecarboxaldehyde (0.4g, 3mmol), tetrahydrolithium aluminum (0.06g, 2mmol), and tetrahydrofuran (10mL) were sequentially added to a 25ml single-mouth flask, and reacted at this temperature overnight. EA (50 mL) was added, the reaction mixture was diluted with water (50 mL), and after extraction and separation, the _{organic layer was washed with saturated NH 4} Cl (50 mL) solution, dried with anhydrous sodium sulfate, filtered, the filtrate was spin-dried, and purified by silica gel column chromatography (Eluent DCM/EA=4:1), 0.38 g of light yellow liquid is the target product (yield 90.0%). LC-MS: m/z=140.15[M+H] ⁺ ; ¹ H NMR(400MHz, CDCl ₃ )δ8.12(d,J=1.8Hz,1H), 7.62(dd,J=8.5,2.4Hz, 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-neck flask, add (6-methoxypyridin-3-yl)methanol (0.38g, 2.7mmol), dichloromethane (8mL), and phosphorus tribromide (0.31mL, 3.3mmol) in sequence at 0°C. Reaction for 30min. Add DCM (25ml) to dilute, _{wash with saturated K 2} CO ₃ (25 mL) aqueous solution, dry the organic phase with anhydrous sodium sulfate, filter, spin-dry the filtrate, and directly transfer 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]hepta Alkyl-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

Add 4-(6-(3,6-diazabicyclo[3.1.1]heptan-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), and then slowly added 5-(bromo (Methyl)-2-methoxypyridine (0.50 g, 2.5 mmol), stirred at room temperature overnight. The reaction solution was diluted with water (25mL), extracted with EA (50mL×3), the organic phase was washed with saturated brine (50mL), dried with anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to purify by silica gel chromatography (eluent DCM/MeOH( v/v=1/0-20/1), 0.2889g of light yellow solid obtained is the target product (yield 65.82%). LC-MS: m/z=544.10[M+H] ⁺ ; ¹ H NMR( 400MHz, CDCl ₃ ): δ8.39(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

In a 50ml single-neck bottle, add 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 (0.288g, 0.530mmol), methanol (5mL), 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 washed with methanol, and the filtrate was spin-dried to obtain 240 mg of light yellow solid, which was the target product (yield 100.0%). LC-MS: m/z=454.30[M+H] ⁺ ; ¹ H NMR (400MHz, CDCl ₃ ): δ8.39(d,J=1.7Hz,1H), 8.28(d,J=2.0Hz,1H ), 8.21 (s, 1H), 8.17-8.12 (m, 1H), 7.81 (dd, J = 8.1, 2.2 Hz, 2H), 7.14 (s, 1H), 6.78 (d, J = 8.6 Hz, 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=6.6 Hz, 1H).

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

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

Add 2-oxa-6-azaspiro[3.3]heptane (2.0g, 20mmol), potassium carbonate (15g, 108.5mmol), 1-bromo-2-chloroethane (8.0mL, 97.0 mmol), acetonitrile (20 mL), react at room temperature after the addition is complete. After the reaction, the insoluble solid was removed by suction filtration, the filter cake was washed with methanol, the organic phases were combined, and the silica gel column chromatography was concentrated to obtain 860 mg of the product. ¹ H NMR (400MHz, CDCl ₃ ): δ 4.74 (s, 4H), 3.47 3.39 (m, 6H), 2.72 (t, J=6.3 Hz, 2H).

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

Add 4-(6-fluoropyridin-3-yl)-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile (500mg, 1.97mmol) and potassium carbonate (825mg, 5.97mmol) to a 25mL flask in sequence mmol), 6-(2-chloroethyl)-2-oxa-6-azaspiro[3.3]heptane (850 mg, 5.26 mmol), DMA (6 mL), react at 80°C. After the reaction is completed by TLC, add 20mL of water to the reaction solution, extract with EA (80mL×2), wash the organic phase with water (15mL×3), wash with saturated brine (15mL×6), dry with anhydrous sodium sulfate and filter, and filter the filtrate by silica gel column chromatography , The eluent is EA-EA/MeOH (v/v=20/1), and 210 mg of yellow solid is obtained as the product. LC-MS: m/z=380.20[M+H] ⁺ ; ¹ H NMR(400MHz, CDCl ₃ )δ8.38(d,J=2.2Hz,1H), 8.21(s,1H), 8.19(d, J = 2.0Hz, 1H), 8.01 (td, J = 8.4, 2.5 Hz, 1H), 7.18 (d, J = 2.0 Hz, 1H), 7.13 (dd, J = 8.4, 2.8 Hz, 1H), 4.75 ( s, 4H), 4.03 (t, J=5.2 Hz, 2H), 3.52 (s, 4H), 2.87 (t, J=5.2 Hz, 2H).

Example 1: 6-(2-(8-oxa-2-azaspiro[4.5]dec-2-yl)ethoxy)-4-(6-(6-((6-methoxypyridine -3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-methyl Nitrile

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

Add 8-oxa-2-azaspiro[4.5]decane (300mg, 2.12mmol), potassium carbonate (882mg, 6.38mmol), acetonitrile (3mL) to a 10mL flask in sequence, react on ice for 10min and add 1-bromo -2-Chloroethane (0.2mL, 2.55mmol), continue to react in an ice bath for 10 minutes, and then react overnight at room temperature. The reaction solution was directly spin-dried and subjected to silica gel column chromatography (eluent: PE:EA=1:1) to obtain 41 mg of light yellow solid, which was the target product (yield 9.5%). ¹ H NMR (400MHz, CDCl ₃ ): δ 3.62 (t, J = 5.3 Hz, 4H), 3.55 (t, J = 7.0 Hz, 2H), 2.77 (t, J = 7.0 Hz, 2H), 2.64 ( t, J = 6.9 Hz, 2H), 2.47 (s, 2H), 1.68 (t, J = 6.9 Hz, 2H), 1.63-1.47 (m, 4H).

Step 2: 6-(2-(8-oxa-2-azaspiro[4.5]dec-2-yl)ethoxy)-4-(6-(6-((6-methoxypyridine- 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-3 into a 5mL flask -Yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (20mg, 0.04mmol, see the synthesis of intermediate 1), 3-(2-chloroethyl)-8 -Oxa-3-azaspiro[4.5]decane (28mg, 0.14mmol), potassium carbonate (31mg, 0.22mmol), N,N-dimethylacetamide (0.8mL), react at 85℃ in oil bath overnight. After the reaction, the mixture was extracted with ethyl acetate (30 mL×3), and the combined organic phases were dried over anhydrous sodium sulfate, and then subjected to silica gel column chromatography (eluent DCM/MeOH (v/v=30/1-10/1)) to obtain 16 mg of light yellow solid is the target product (yield: 58.4%). Rf=0.1 (DCM/MeOH=20/1). LC-MS (ES-API): m/z=621.35[M+H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ8.40 (d, J = 2.1Hz, 1H), 8.21 (s, 1H), 8.16 (d, J = 2.1Hz, 1H), 8.10 (s, 1H), 7.78 (dd, J = 8.8, 2.4 Hz, 1H), 7.63 (dd, J = 8.5, 2.2 Hz, 1H), 7.15 (d, J = 1.9 Hz, 1H), 6.70 (dd, J = 11.9, 8.7 Hz) , 2H), 4.17 (t, J = 5.5 Hz, 2H), 3.92 (s, 3H), 3.83 (d, J = 11.7 Hz, 2H), 3.77 (d, J = 5.7 Hz, 2H), 3.65 (t ,J=5.2Hz,4H), 3.60(s,1H),3.58(s,2H), 2.96(t,J=5.5Hz,2H), 2.76(t,J=6.7Hz,2H), 2.69(dd ,J=13.7,6.7Hz,1H),2.59(s,2H),2.03(d,J=6.3Hz,2H),1.74(t,J=6.9Hz,2H),1.63-1.54(m,4H) .

Example 2: 6-(2-(2-oxa-6-azaspiro[3.3]hept-6-yl)ethoxy)-4-(6-(6-((6-methoxypyridine -3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-methyl Nitrile

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

Add 2-oxa-6-azaspiro[3.3]heptane (250mg, 2.52mmol), potassium carbonate (2.1g, 15.1mmol), 1-bromo-2-chloroethane (2.1mL, 13.0mmol), acetonitrile (2.5mL), react at room temperature. After the reaction, the filter cake was washed with methanol, the organic phase was concentrated, and silica gel column chromatography was performed to obtain 210 mg of a colorless transparent liquid, which is the target product (yield: 51.5%), Rf = 0.3 (EA/MeOH (v/v) )=5/1). ¹ H NMR (400MHz, CDCl ₃ ): δ 4.74 (s, 4H), 3.47-3.40 (m, 6H), 2.72 (t, J=6.3 Hz, 2H).

Step 2: 6-(2-(2-oxa-6-azaspiro[3.3]hepta-6-yl)ethoxy)-4-(6-(6-((6-methoxypyridine- 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-3 into a 5mL flask -Yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (25mg, 0.06mmol, see the synthesis of intermediate 1), 6-(2-chloroethyl)-2 -Oxa-6-azaspiro[3.3]heptane (5mg, 0.34mmol), potassium carbonate (60mg, 0.43mmol), N,N-dimethylacetamide (0.8mL), reaction under oil bath at 85℃ overnight. After the reaction, extract with ethyl acetate (10mL×3), combine the organic phases, dry with anhydrous sodium sulfate, filter the filtrate and spin dry silica gel column chromatography (eluent: DCM/MeOH=30/1-10/1), The collected light yellow solid 6mg is the target product (yield: 3.0%). Rf=0.1(DCM/MeOH(v/v=20/1). LC-MS(ES-API): m/z=579.80[M+H] ⁺ ; ¹ H NMR (400MHz, CDCl ₃ ): δ8. 41(d,J=2.1Hz,1H),8.23(s,1H),8.13(s,2H),7.80(dd,J=8.8,2.5Hz,1H),7.74(s,1H),7.10(dd ,J=8.5,2.5Hz,1H),6.73(dd,J=16.0,8.7Hz,2H),4.78(s,4H),4.05(t,J=4.8Hz,2H),3.94(s,3H) , 3.89(s, 2H), 3.66(s, 4H), 3.56(s, 4H), 2.90(s, 2H), 2.80(s, 1H), 2.63(s, 1H), 2.40-2.29(m, 1H) ), 2.28-2.18 (m, 1H).

Example 3: 6-(2-(1,4-Dioxa-8-azaspiro[4.5]dec-8-yl)ethoxy)-4-(6-(6-((6-methyl Oxypyridin-3-yl)methyl)-3,6 diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3 -Formonitrile

Step 1: 8-(2-chloroethyl)-1,4-dioxa-8-azaspiro[4.5]decane

Add 1,4-dioxa-8-azaspiro[4.5]decane hydrochloride (300mg, 1.67mmol), potassium carbonate (693mg, 5.01mmol), acetone (3.0mL) into a 10mL single-neck bottle, add After completion, 1-bromo-2-chloroethane (0.2mL, 2.004mmol) was slowly added under ice bath conditions, stirred for 10min and then returned to room temperature and reacted overnight. After the reaction, the acetone was removed by rotary evaporation, extracted with dichloromethane (10ml×2), the organic phases were combined and washed with water (10ml×2), dried with anhydrous sodium sulfate, filtered, and silica gel column chromatography (eluent: PE/EA) (v/v)=1/1) Collect and spin dry to obtain 43 mg of white solid, which is the target product (yield: 12.519%, Rf=0.3 (EA/MeOH(v/v)=5/1)). ¹ H NMR (400MHz, CDCl ₃ ): δ = 3.93 (s, 4H), 3.56 (t, J = 7.1 Hz, 2H), 2.74 (t, J = 7.1 Hz, 2H), 2.63-2.52 (m, 4H) ), 1.79-1.68 (m, 4H).

Step 2: 6-(2-(7-oxa-2-azaspiro[4.5]dec-2-yl)ethoxy)-4-(6-(6-((6-methoxypyridine- 3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

6-Hydroxy-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]hepta Alkyl-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (20mg, 0.04410mmol, see the synthesis of intermediate 1), 8-(2-chloroethyl )-1,4-dioxa-8-azaspiro[4.5]decane (18.2mg, 0.0885mmol), potassium carbonate (30.78mg, 0.2205mmol), DMA (0.5mL), heated in an oil bath at 80°C overnight. After the reaction, the reaction solution was diluted with water (10mL), extracted with EA (20mL×3), the organic phase was collected, washed with saturated brine (20mL), dried with anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to purify by silica gel chromatography. Eluent DCM/MeOH(v/v)=30/1-15/1, collect and spin dry to obtain 21mg of yellow solid, which is the target product (yield 76.47%) (Rf=0.45, DCM/MeOH(v/v) = 15/1). LC-MS: m/z=623.1[M+H] ⁺ ; ¹ H NMR (400MHz, CDCl ₃ ): δ8.39(s,1H), 8.20(s,1H), 8.16(s,1H), 8.10 (s, 1H), 7.77 (d, J = 7.2 Hz, 1H), 7.63 (d, J = 6.8 Hz, 1H), 7.14 (s, 1H), 6.70 (dd, J = 12.9, 8.7 Hz, 2H) , 4.17 (t, 2H), 3.96 (s, 4H), 3.92 (s, 3H), 3.84 (d, J = 11.3 Hz, 2H), 3.78 (d, J = 4.9 Hz, 2H), 3.66-3.53 ( m, 4H), 2.92 (t, J = 5.3 Hz, 2H), 2.73-2.67 (m, 4H), 2.10-2.01 (m, 2H), 1.82-1.76 (m, 4H).

Example 4: 6-((3,3-Dimethyl-1,5-dioxaspiro[5.5]undecane-9-yl)oxy)-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: 3,3-Dimethyl-1,5-dioxaspiro[5.5]undecane-9-ol

In a low temperature tank at -10℃, add a THF solution of lithium aluminum hydroxide (2.0mol/L, 100mg, 3mmol) in a 25mL double-necked flask, and slowly add 3,3-dimethyl-1,5 under nitrogen protection. -Dioxaspiro[5.5]undecane-9-one in THF solution (10 mL), after the dropwise addition, slowly return to room temperature and continue stirring for 2h. At low temperature, add saturated ammonium chloride aqueous solution (10mL) to quench, pour out and extract with EA (30mL×3), combine the organic phases, wash with saturated brine (50mL), dry the organic phase with anhydrous sodium sulfate, filter and spin dry , Silica gel chromatography column (eluent DCM/EA(v/v)=5/1), collect the target solution and spin-dry to obtain a white solid that is the target product (yield: 90.0%, Rf=0.5(EA/DCM( v/v)=1/8)). ¹ H NMR (400MHz, CDCl ₃ ): δ3.85-3.76 (m, 1H), 3.52 (d, J = 3.3 Hz, 4H), 2.12-2.09 (m, 1H), 1.81 (dd, J = 11.8, 5.6 Hz, 2H), 1.61 (d, J=9.9 Hz, 6H), 0.99 (s, 6H).

Step 2: 3,3-Dimethyl-1,5-dioxaspiro[5.5]undecane-9-yl methanesulfonate

Under ice bath conditions, add 3,3-dimethyl-1,5-dioxaspiro[5.5]undecane-9-ol (100mg, 0.4993mmol), dichloromethane (1mL ), triethylamine (0.105mL, 0.748mmol), slowly added methanesulfonyl chloride (0.05mL, 0.649mmol), after the dropwise addition, slowly returned to room temperature to continue the reaction for 2h. At low temperature, dilute with water (10mL), extract with DCM (25mL×3) _{, and wash the combined organic layer with saturated NaHCO 3} (30mL), saturated brine (30mL), and dry with anhydrous sodium sulfate. Purified by dry silica gel column chromatography (DCM/EA(v/v)=10/1), 131 mg of light yellow solution was obtained as the target product. (Yield: 94.2%, Rf=0.8 (EA/DCM(v/v)=1/10)). ¹ H NMR (400MHz, CDCl3): δ 4.86-4.79 (m, 1H), 3.49 (d, J = 13.9Hz, 4H), 3.01 (s, 3H), 1.99 (dd, J = 15.4, 9.2Hz, 2H), 1.91 (dd, J = 10.9, 5.6 Hz, 4H), 1.82 (dd, J = 13.1, 4.6 Hz, 2H), 0.96 (s, 6H).

Step 3: 6-((3,3-Dimethyl-1,5-dioxaspiro[5.5]undecane-9-yl)oxy)-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]hepta into a 5mL single-neck bottle in sequence Alkyl-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (25mg, 0.05513mmol, intermediate 1), 3,3-dimethyl-1,5 -Dioxaspiro[5.5]undecane-9-yl methanesulfonate (30.69mg, 0.1102mmol), potassium carbonate (24.06mg, 0.1654mmol), DMF (0.25mL), heated in an oil bath at 80°C overnight . After the reaction, the reaction solution was diluted with water (10mL), extracted with EA (20mL×3), the organic phase was collected, washed with saturated brine (20mL), dried with anhydrous sodium sulfate, filtered, the filtrate was spin-dried, and purified by silica gel column chromatography (Eluent DCM/MeOH(v/v)=50/1-40/1), 14.3mg of yellow solid is obtained, which is the target product (yield 40.8%), (Rf=0.4, DCM/MeOH(v/ v)=30/1). LC-MS: m/z=636.2[M+H] ⁺ ; ¹ H NMR (400MHz, CDCl ₃ ): δ8.40(d,J=2.2Hz,1H), 8.21(s,1H), 8.16(d ,J=1.7Hz,1H), 8.10(d,J=1.3Hz,1H), 7.77(dd,J=8.7,2.3Hz,1H), 7.63(d,J=6.3Hz,1H), 7.11(d ,J=1.8Hz,1H),6.70(dd,J=12.9,8.7Hz,2H),4.43-4.34(m,1H),3.92(s,3H),3.84(d,J=10.8Hz,2H) ,3.78(d,J=5.3Hz,2H),3.61(s,2H),3.58(s,2H),3.53(d,J=9.2Hz,4H), 2.69(dd,J=13.2,7.0Hz, 1H), 2.04 (dd, J=12.4, 5.9 Hz, 3H), 1.94 (dd, 4H), 1.84 (dd, J=12.5, 6.0 Hz, 2H), 0.98 (s, 6H).

Example 5: 6-((2-oxaspiro[3.3]heptane-6-yl)oxy)-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: 2-oxaspiro[3.3]hept-6yl methanesulfonate

Under ice bath conditions, sequentially add 2-oxaspiro[3.3]heptan-6-ol (100mg, 0.9mmol), dichloromethane (1mL), and triethylamine (0.2mL, 1.0mmol) into a 5mL single-neck flask. Slowly add methanesulfonyl chloride (0.09mL, 1mmol), after the addition is complete, slowly return to room temperature and continue the reaction for 2h. Under low temperature conditions, dilute with _{water (10mL), quench with saturated aqueous Na 2} SO ₄ (10 mL), extract with EA (30 mL×3) _{, and wash the combined organic layers with saturated NaHCO 3} (30 mL), and saturated brine ( 30 mL), washed, dried with anhydrous sodium sulfate, and then dried to obtain 0.16 g of light yellow oil, which is the target product. (Yield: 100%, Rf=0.8 (EA/PE(v/v)=1/10)). ¹ H NMR (400MHz, CDCl ₃ ): δ 4.83 (p, J = 7.2Hz, 1H), 4.68 (d, J = 8.2Hz, 4H), 2.97 (s, 3H), 2.82-2.74 (m, 2H ), 2.52–2.44 (m, 2H).

Step 2: 6-((2-oxaspiro[3.3]heptane-6-yl)oxy)-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]hepta into a 5mL single-neck bottle in sequence Alkyl-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (25mg, 0.05513mmol, intermediate 1), 2-oxaspiro[3.3]heptane-6 Methanesulfonate (21.2mg, 0.11mmol), potassium carbonate (24.06mg, 0.1654mmol), DMF (0.5mL), heated in an oil bath at 80°C overnight. After the reaction, the reaction solution was diluted with water (10mL), extracted with EA (25mL×3), the organic phase was collected, washed with saturated brine (20mL), dried with anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to purify by silica gel chromatography. The eluent DCM/MeOH(v/v)=100/1-20/1, collected and spin-dried to obtain a yellow solid 11.5mg which is the target product (yield 38%) (Rf=0.2, DCM/MeOH(v/v )=30/1). LC-MS: m/z=550.30 [M+H] ⁺ . ¹ H NMR(400MHz,CDCl ₃ )δ8.39(d,J=2.1Hz,1H), 8.21(s,1H), 8.12(d,J=1.8Hz,1H), 7.95(d,J=1.9Hz ,1H), 7.79(dd,J=8.9,2.4Hz,1H), 7.53(d,J=8.5Hz,1H), 7.05(d,J=2.0Hz,1H), 6.93(t,J=7.4Hz ,2H),4.75(d,J=20.2Hz,4H),4.57–4.52(m,1H),3.97–3.86(m,7H),3.73–3.65(m,4H),2.65–2.56(m,2H) ), 2.48–2.42 (m, 2H), 2.37–2.33 (m, 1H), 2.21 (d, J=7.6 Hz, 1H).

Example 6: 6-(2-((2-oxaspiro[3.3]heptane-6-yl)oxy)ethoxy)-4-(6-(6-((6-methoxypyridine -3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-methyl Nitrile

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

Add NaH (127mg, 3.175mmol) into a 25mL two-neck flask, vacuum under nitrogen protection, add anhydrous THF (10mL) to dissolve at 0℃, add liquid 6-oxaspiro[3.3]heptan-2-ol ( 300mg, 2.628mmol), after the addition, the reaction was stirred at room temperature for 2h and then transferred to 0°C, ethyl 2-bromoacetate (0.32mL, 2.9mmol) was slowly added, and the reaction was stirred at room temperature after the addition. TLC spot plate, KMnO ₄ oxidation shows that the reaction is complete, add 15mL of water to quench, EA (60mL×2) extraction, organic phase is washed with 30mL saturated brine, dried with anhydrous sodium sulfate, filtered, spin-dried, silica gel column chromatography (elution Agent PE/EA (v/v)=10/1-1/1), 0.222 g of oily liquid (yield 42.2%) is obtained, which is the target product. ¹ H NMR (400MHz, CDCl ₃ ): δ4.63 (d, J = 12.0Hz, 4H), 4.19 (q, J = 7.1Hz, 2H), 3.94 (s, 2H), 3.93–3.85 (m, 1H ), 2.61–2.52(m,2H), 2.23–2.14(m,2H), 1.26(t,J=7.1Hz,3H).

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

In a 25mL two-neck flask, add LiAlH ₄ (0.085g, 2.2mmol) and 5mL of THF to make a solution. Vacuum under the protection of nitrogen to remove 2-(6-oxaspiro[3.3]heptan-2-yloxy) Ethyl acetate (222 mg, 1.109 mmol) was dissolved in 3 mL of THF, and slowly added to the two-neck flask at 0° C., and the reaction was kept warm. TLC dot plate (KMnO ₄ oxidation) shows that the reaction is complete, add 10 mL of saturated ammonium chloride solution to quench the reaction, extract with EA (20 mL×2), wash the organic phase with 15 mL of saturated brine, dry with anhydrous sodium sulfate, filter, and spin dry. Silica gel column chromatography (eluent pure DCM-DCM/EA ((v/v)4/1-1/4)) to obtain 0.103 g (yield 58.7%) of light yellow oil, which is the target product. ¹ H NMR (400MHz, CDCl ₃ ): δ4.65 (d, J=16.7Hz, 4H), 3.83 (dd, J=13.9, 7.0Hz, 1H), 3.73-3.63 (m, 2H), 3.46-3.36 (m,2H), 2.68–2.47(m,2H), 2.15–2.08(m,2H).

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

Under ice bath conditions, add 2-(6-oxaspiro[3.3]hept-2-yloxy)ethanol (100mg, 0.632mmol) into a 10mL single-necked flask, dissolve DCM (1.5mL), and add TEA (0.133mL) , 0.947mmol), slowly adding methanesulfonyl chloride (0.065mL, 0.83mmol) dropwise, and then naturally warm to room temperature for reaction. TLC showed that the reaction was complete. Add 3mL of water to quench the reaction, extract with DCM (15mL×2), wash with 8mL of saturated brine, dry with anhydrous sodium sulfate, filter, spin dry, and drain to obtain a theoretical amount of yellow liquid, which is directly put into the next step reaction .

Step 4: 6-(2-((2-oxaspiro[3.3]heptane-6-yl)oxy)ethoxy)-4-(6-(6-((6-methoxypyridine- 3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

Add 2-(6-oxaspiro[3.3]heptan-2-yloxy)ethyl methanesulfonate (32mg, 0.135mmol), K ₂ CO ₃ (37mg, 0.265mmol), 6- Hydroxy-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3 -Yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (30mg, 0.066mmol, Intermediate 1), dissolved in DMF (1.5mL), placed at 60°C and stirred for reaction for 8h. TLC dot plate shows that the reaction is complete, add 10 mL of water to wash, EA extraction (40 mL × 2), combine the organic phase and wash with 20 mL of saturated brine, dry with anhydrous sodium sulfate, filter, spin dry, silica gel column chromatography (eluent pure DCM- DCM/MeOH (v/v=10/1)) to obtain 0.011 g of light yellow solid (yield 28%), which is the target product. LC-MS: m/z=594.10[M+H] ⁺ ; ¹ H NMR (400MHz, CDCl ₃ ); δ8.40 (s, 1H), 8.21 (s, 1H), 8.16 (s, 1H), 8.11 (s, 1H), 7.78 (dd, J = 8.7, 2.1 Hz, 1H), 7.69 (d, J = 8.6 Hz, 1H), 7.16 (s, 1H), 6.71 (dd, J = 15.4, 8.6 Hz, 2H), 4.67(d,J=18.4Hz,4H), 4.17–4.13(m,2H), 3.92(s,3H), 3.90–3.87(m,1H), 3.85(s,3H), 3.75–3.72 (m, 2H), 3.66 (dd, J = 14.5, 7.5 Hz, 5H), 2.76 (dd, J = 6.0, 3.6 Hz, 1H), 2.65–2.57 (m, 2H), 2.21–2.15 (m, 2H ), 2.07–2.00 (m, 1H).

Example 7: 6-((1,4-Dioxaspiro[4.5]decane-8-yl)oxy)-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: 1,4-Dioxaspiro[4.5]decane-8-ol

Under ice bath conditions, 1,4-cyclohexanedione monoethylene glycol ketal (2.0 g, 13 mmol) and methanol (40 mL) were sequentially added to a 100 mL single-necked flask. Sodium borohydride (1.5g, 40mmol) was added in batches, and after the addition was completed, it was returned to room temperature and stirring continued. TLC showed that the reaction was complete after 2h. Concentrate the reaction solution to a solid, add water (20mL), extract with EA (50mL×3), combine the organic phases, wash with saturated brine (100mL), dry the organic phase with anhydrous sodium sulfate, filter and spin dry, and purify by silica gel column chromatography , Eluent DCM/EA (v/v) = 5/1, to obtain 1.89 g of colorless transparent liquid. ¹ H NMR (400MHz, CDCl ₃ ): δ4.02-3.85(m,4H),3.84-3.73(m,1H),1.93-1.74(m,5H),1.63(ddd,J=14.2,10.0,6.5 Hz, 4H).

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

Under ice bath conditions, add 1,4-dioxaspiro[4.5]decane-8-ol (200mg, 1.26mmol), dichloromethane (2mL), triethylamine (0.27mL, 1.89mmol), slowly add methanesulfonyl chloride (0.13mL, 1.64mmol), and return to room temperature and stir for 2h after the addition is complete. TLC showed that the reaction was complete. At low temperature, dilute with 30mL of water, extract with dichloromethane (50mL×3), _{wash the combined organic phase with saturated NaHCO 3,} wash with saturated brine, dry the organic phase with anhydrous sodium sulfate and spin dry, silica gel column Chromatography (DCM/EA(v/v)=10/1) collects and obtains 290 mg of a pale yellow solution. ¹ H NMR (400MHz, CDCl ₃ ): δ 4.90-4.78 (m, 1H), 3.95 (dd, J = 6.0, 3.9 Hz, 4H), 3.01 (s, 3H), 2.00 (dd, J = 12.2, 6.8Hz, 4H), 1.90-1.81(m, 2H), 1.68-1.61(m, 2H).

Step 3: 6-((1,4-Dioxaspiro[4.5]decane-8-yl)oxy)-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- 3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (40mg, 0.09mmol, intermediate 1), 1,4-dioxaspiro[4.5]dec- 8-methanesulfonate (65mg, 0.27mmol), cesium carbonate (115mg, 0.35mmol), DMA (1mL), react at 60°C overnight. The reaction solution was poured into 10mL ice water, extracted with EA (30mL×3), the combined organic phase was washed with saturated brine (20mL×3), the organic phase was dried with anhydrous sodium sulfate, filtered, the filtrate was spin-dried, and the residue was a silica gel column layer After analysis (eluent DCM/MeOH=25/1), 22 mg of white solid was collected. LC-MS: m/z=594.30[M+H] ⁺ ; ¹ H NMR(400MHz, CDCl ₃ )δ8.40(d,J=2.1Hz,1H), 8.21(s,1H), 8.17(d, J = 1.8Hz, 1H), 8.11 (d, J = 1.5 Hz, 1H), 7.78 (dd, J = 8.8, 2.3 Hz, 1H), 7.70 (d, J = 6.6 Hz, 1H), 7.12 (d, J = 1.8Hz, 1H), 6.70 (dd, J = 15.5, 8.7 Hz, 2H), 4.43-4.36 (m, 1H), 4.01-3.95 (m, 4H), 3.92 (s, 3H), 3.90-3.80 (m,4H),3.70-3.59(m,4H),2.81-2.71(m,1H),2.05-1.98(m,4H),1.96-1.93(m,1H),1.71-1.62(m,4H) .

Example 8: 6-(2-((6-Azaspiro[3.4]heptan-2-yl)oxy)ethoxy)-4-(6-(6-((6-methoxypyridine -3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-methyl Nitrile

Under ice bath conditions, filled with 6-(2-((6-azaspiro[3.4]octane-2-yl)oxy)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-Carboxonitrile dihydrochloride (10.8 mg, 0.016 mmol, compound of Example 9) was added to a 5 mL single-necked flask with 1 mL of saturated sodium bicarbonate solution to adjust the pH to alkaline, and 3 mL of DCM was added and stirred for 5 min. Separate the organic phase, and then extract with DCM (5 mL×2), wash the organic phase with 5 mL of saturated brine, dry with anhydrous sodium sulfate, filter, spin dry, and suck dry. A light yellow solid 6mg (60% yield) is obtained, which is the target product. LC-MS: m/z=607.2[M+H] ⁺ ; ¹ H NMR(400MHz,CDCl ₃ )δ8.41–8.37(m,1H), 8.21(s,1H), 8.16(d,J=1.8 Hz, 1H), 8.10 (d, J = 1.3 Hz, 1H), 7.78 (dd, J = 8.8, 2.3 Hz, 1H), 7.62 (dd, J = 8.5, 2.1 Hz, 1H), 7.17 (d, J =1.7Hz,1H),6.70(dd,J=12.2,8.7Hz,2H),4.21–4.14(m,2H),4.11–4.02(m,1H),3.92(s,3H), 3.83(d, J = 10.9 Hz, 2H), 3.76 (d, J = 5.2 Hz, 4H), 3.67-3.58 (m, 2H), 3.57 (s, 2H), 3.14-2.86 (m, 4H), 2.71-2.64 (m , 1H), 2.37-2.29 (m, 2H), 2.24-2.19 (m, 1H), 2.05 (dd, J=11.3, 5.7 Hz, 3H), 1.86 (d, J=7.1 Hz, 2H).

Example 9: 6-(2-((6-Azaspiro[3.4]octan-2-yl)oxy)ethoxy)-4-(6-(6-((6-methoxypyridine -3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-methyl Nitrile dihydrochloride

Step 1: 2-(2-Ethoxy-2-oxoethoxy)-6-azaspiro[3.4]octane-6-carboxylic acid tert-butyl ester

Add NaH (72mg, 1.8mmol) into a 25mL two-neck flask, vacuum several times under nitrogen protection, place it at 0℃, add anhydrous THF (17mL) to make a suspension, add 2-hydroxy-6-nitrogen Heterosspiro[3.4]octane-6-carboxylic acid tert-butyl ester (340mg, 1.496mmol), after the addition, the temperature was raised to room temperature and the reaction was stirred for 2h. Transfer to 0°C, slowly add ethyl 2-bromoacetate (0.183 mL, 1.65 mmol), and then stir at room temperature to react overnight. TLC showed that the reaction was complete, the reaction solution was quenched by adding 15 mL of water, extracted with EA (60 mL×2), and the organic phase was washed with 30 mL of saturated brine, dried with anhydrous sodium sulfate, filtered, spin-dried, and silica gel column chromatography (eluent PE/EA) (v/v)=10/1-2/1) to obtain 0.143 g of oily liquid (yield 31%), which is the target product. LC-MS: m/z=258.1 [M-56+H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ): δ4.21(q,J=7.1Hz,2H), 4.11–4.03(m,1H), 4.00–3.95(m,2H), 3.37–3.21(m,4H) , 2.33–2.21(m, 2H), 2.10–1.97(m, 2H), 1.88–1.75(m, 2H), 1.44(s, 9H), 1.28(t, J=7.1Hz, 3H).

Step 2: 2-(2-Hydroxyethoxy)-6-azaspiro[3.4]octane-6-carboxylic acid tert-butyl ester

In a 25mL two-neck flask, add LiAlH ₄ (40.5mg, 1.07mmol), add 3mL THF to make a suspension, vacuum for several times under the protection of nitrogen, and remove 2-(2-ethoxy-2-oxoethyl). (Oxy)-6-azaspiro[3.4]octane-6-carboxylic acid tert-butyl ester (134mg, 0.428mmol) was dissolved in 3mL THF, slowly added to the two-necked flask at a low temperature tank at -40℃, and the reaction was kept warm. 1h. TLC shows that the reaction is complete, add 12mL of water to quench the reaction, extract with EA (25mL×2), wash the organic phase with 15mL of saturated brine, dry with anhydrous sodium sulfate, filter, spin-dry the filtrate, and silica gel column chromatography (eluent PE/EA (v/v)=4/1-1/4) to obtain 0.101 g of a transparent oily substance (yield 87%), which is the target product. LC-MS: m/z=216.3[M-56+H] ⁺ ; ¹ H NMR (400MHz, CDCl ₃ ): δ4.04–3.94(m,1H), 3.75–3.67(m,2H), 3.46– 3.41(m, 2H), 3.37-3.21(m, 4H), 2.32-2.20(m, 2H), 2.14(s, 1H), 2.00-1.89(m, 2H), 1.85-1.78(m, 2H), 1.43(s, 9H).

Step 3: 2-(2-Methylsulfonyloxyethoxy)-6-azaspiro[3.4]octane-6-carboxylic acid tert-butyl ester

Under ice bath conditions, add 2-(2-hydroxyethoxy)-6-azaspiro[3.4]octane-6-carboxylic acid tert-butyl ester (95mg, 0.350mmol), DCM( 1.5mL) was dissolved, TEA (0.074mL, 0.53mmol) was added, methanesulfonyl chloride (0.036mL, 0.46mmol) was slowly added dropwise, and then it was naturally warmed to room temperature and reacted for 1h. TLC showed that the reaction was complete. The reaction was quenched by adding 3 mL of water, extracted with DCM (10 mL×2), and the organic phase was washed with 5 mL of saturated brine, dried with anhydrous sodium sulfate, filtered, and the filtrate was spin-dried. EA (v/v)=4/1-1/2) to obtain 0.117 g of a yellow transparent oily substance (yield 96%), which is the target product. ¹ H NMR (400MHz, CDCl ₃ ): δ 4.37-4.31 (m, 2H), 4.01 (p, J = 6.8Hz, 1H), 3.63-3.57 (m, 2H), 3.37-3.21 (m, 4H) ,3.05(s,3H),2.33–2.21(m,2H),2.02–1.90(m,2H),1.87–1.77(m,2H),1.44(s,9H).

Step 4: 2-(2-((3-cyano-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1 .1]Heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl)oxy)ethoxy)-6-azaspiro[3.4]octane -6-tert-butyl carboxylate

Add 2-(2-methylsulfonyloxyethoxy)-6-azaspiro[3.4]octane-6-carboxylic acid tert-butyl ester (46mg, 0.132mmol), K ₂ CO ₃ ( 37mg, 0.265mmol), 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 (30mg, 0.066mmol, intermediate 1), dissolved in DMF (1.5mL), placed at 60°C The reaction was stirred overnight. TLC shows that the reaction is complete, wash with 10mL of water, extract with EA (40mL×2), wash the organic phase with 20mL of saturated brine, dry with anhydrous sodium sulfate, filter, spin-dry the filtrate, and perform silica gel column chromatography (eluent pure DCM-DCM/ MeOH ((v/v)=10/1)) to obtain 22.6 mg of light yellow solid (yield 48.3%), which is the target product. LC-MS: m/z＝707.30[M+H] ⁺ ; ¹ H NMR(400MHz,CDCl ₃ )δ8.40(d,J＝2.1Hz,1H), 8.21(s,1H), 8.16(d, J = 1.5 Hz, 1H), 8.11 (d, J = 0.8 Hz, 1H), 7.78 (dd, J = 8.8, 2.4 Hz, 1H), 7.65 (dd, J = 4.4, 2.3 Hz, 1H), 7.17 ( s, 1H), 6.70 (dd, J = 13.4, 8.7 Hz, 2H), 4.21–4.13 (m, 2H), 4.12–4.04 (m, 1H), 3.92 (s, 3H), 3.87–3.74 (m, 6H), 3.65-3.54(m, 4H), 3.38-3.24(m, 4H), 2.71(s, 1H), 2.37-2.24(m, 2H), 2.18-1.89(m, 3H), 1.87-1.79( m, 2H), 1.45 (s, 9H).

Step 5: 6-(2-((6-Azaspiro[3.4]octan-2-yl)oxy)ethoxy)-4-(6-(6-((6-methoxypyridine- 3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile Dihydrochloride

Add 2-(2-((3-cyano-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diaza Bicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl)oxy)ethoxy)-6-azaspiro[3.4 ]Octane-6-carboxylic acid tert-butyl ester (19.2mg, 0.027mmol, hydrochloric acid ethyl acetate solution (2mL, 8mmol, 4mol/L), placed at room temperature and stirred for 1h. TLC shows that the reaction is complete, the reaction solution is directly rotated Dried and drained to obtain a theoretical amount of yellow-white solid product. LC-MS: m/z=607.2 [M+H] ⁺ .

Example 10: 4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine -3-yl)-6-((6-methoxyspiro[3.3]heptan-2-yl)methoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

Step 1: 6-Hydroxyspiro[3.3]heptane-2-carboxylic acid methyl ester

Add 6-oxospiro[3.3]heptane-2-carboxylic acid methyl ester (1.4g, 8.3mmol) into a 100mL two-neck flask, replace the nitrogen and add 10mL THF to dissolve it, add dropwise to 15Ml THF at -78℃ Lithium tri-tert-butoxy aluminum hydride (4.6g, 17mmol), react at this temperature after the dropwise addition. After the completion of the reaction, add 15 mL of water to quench, a large amount of white gum appeared, filtered by suction, extracted with water phase with ethyl acetate, concentrated on silica gel column chromatography, eluent PE/EA(v/v)=10/1, obtained colorless Liquid 1.2g is the target product. Rf=0.3(PE/EA(v/v)=5/1); LC-MS: m/z=171.15[M+H] ⁺ ; ¹ H NMR(400MHz, CDCl ₃ ): δ4.15(p, J = 7.2Hz, 1H), 3.64 (s, 3H), 3.01 (p, J = 8.5 Hz, 1H), 2.50-2.40 (m, 1H), 2.36-2.24 (m, 3H), 2.23-2.11 (m , 2H), 2.03 (s, 1H), 1.89 (m, 2H).

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

Add 6-hydroxyspiro[3.3]heptane-2-carboxylic acid methyl ester (1.2g, 7.1mmol) to a 100mL single-mouth flask, add THF (18mL) to dissolve it, add sodium hydride (560mg , 14.0mmol, 60mass%), add methyl iodide (1.0mL, 16mmol) after 15min, and react at room temperature. After the reaction was completed, it was quenched by adding water, extracted with ethyl acetate (20mL×2), the organic phase was washed twice with water and dried over anhydrous sodium sulfate, and concentrated on silica gel column chromatography. The eluent was PE/EA(v/v)=20/ 1-5/1, 480mg of colorless liquid is obtained. Rf=0.8(PE/EA(v/v)=5/1), ¹ H NMR(400MHz, CDCl ₃ ): δ3.79-3.70(m,1H), 3.66(s,3H), 3.19(s, 3H), 3.03 (p, J=8.5 Hz, 1H), 2.44-2.36 (m, 1H), 2.33-2.13 (m, 5H), 1.91 (m, 2H).

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

After replacing the nitrogen in a 25mL double-neck flask, add methyl 6-methoxyspiro[3.3]heptane-2-carboxylate (480mg, 2.6mmol) dissolved in 10mLTHF, stir at -10°C for 10min, and then add diisobutyl dropwise. Aluminum hydride (8.0mL, 8.0mmol, 1mol/L), react at room temperature after the addition is complete. After the reaction was completed, water was added to quench the reaction. The reaction solution appeared gelatinous. Add 14mL of HCl (1N) to completely dissolve it, extract with ethyl acetate (80mL×2), wash the organic phase twice with water, wash with saturated brine once, and concentrate the silica gel column. Chromatography, the eluent is PE/EA (v/v) = 5/1, and 330 mg of colorless liquid is obtained. Rf=0.3(PE/EA(v/v)=5/1), ¹ H NMR(400MHz, CDCl ₃ ): δ3.76(p,J=7.1Hz,1H), 3.56(d,J=6.8Hz ,2H),3.21(s,3H),2.46-2.33(m,2H),2.23(dt,J=11.6,6.0Hz,1H),2.13-2.00(m,2H),1.96-1.84(m,2H) ), 1.78 (dd, J=11.5, 5.8 Hz, 2H).

:Step 4: (6-Methoxyspiro[3.3]heptan-2-yl)methanesulfonate

Add (6-methoxyspiro[3.3]heptan-2-yl)methanol (340mg, 2.2mmol) to a 25mL single-necked flask, add 4mL DCM to dissolve it, add triethylamine (0.7mL, 5mmol), at 0°C Methanesulfonyl chloride (0.3 mL, 3 mmol) was added dropwise, and the reaction was carried out at room temperature. After the completion of the reaction, the reaction solution was extracted with DCM (20mL×2), the organic phase was washed three times with water and saturated brine once, and column chromatography was concentrated. The eluent was PE/EA(v/v)=5/1 to obtain 340mg of liquid . Rf=0.3 (PE/EA(v/v)=5/1). ¹ H NMR (400MHz, CDCl ₃ ): δ4.17 (d, J = 6.8Hz, 2H), 3.77 (p, J = 7.1Hz, 1H), 3.21 (s, 3H), 3.01 (s, 3H), 2.70-2.56 (m, 1H), 2.46-2.37 (m, 1H), 2.27 (dt, J=11.6, 5.9 Hz, 1H), 2.21-2.08 (m, 2H), 1.91 (m, 4H).

Step 5: 4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine- 3-yl)-6-((6-methoxyspiro[3.3]heptan-2-yl)methoxy)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- 3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (20mg, 0.044mmol, Intermediate 1), potassium carbonate (24mg, 0.17mmol), (6-methyl Oxyspiro[3.3]heptan-2-yl)methanesulfonate (65mg, 0.28mmol) was added with DMF (0.8mL, 100mass%) and reacted at 90°C. React overnight. After the reaction, the reaction solution was cooled to room temperature, 5mL of water was added, and ethyl acetate (20mL×2) was added. The organic phase was washed 8 times with water and saturated brine once, dried over anhydrous sodium sulfate and concentrated by column chromatography. The eluent was DCM. /MeOH(v/v)=40:1 to obtain 13 mg of a yellow solid. Rf=0.3 (DCM/MeOH(v/v)=15/1), LC-MS: m/z=592.25[M+H] ⁺ , ¹ H NMR (400MHz, CDCl ₃ ): δ8.40(d, J = 2.1Hz, 1H), 8.20 (s, 1H), 8.10 (d, J = 1.9 Hz, 2H), 7.77 (dd, J = 8.8, 2.5 Hz, 1H), 7.63 (dd, J = 8.5, 2.1 Hz, 1H), 7.11 (d, J = 2.0 Hz, 1H), 6.69 (dd, J = 12.9, 8.7 Hz, 2H), 3.95 (d, J = 6.5 Hz, 2H), 3.92 (s, 3H), 3.83 (d, J = 12.7 Hz, 2H), 3.77 (d, J = 6.5 Hz, 2H), 3.60 (s, 1H), 3.58 (s, 2H), 3.21 (s, 3H), 2.76-2.71 (m , 2H), 2.46-2.40 (m, 1H), 2.35-2.10 (m, 4H), 2.08-1.88 (m, 2H), 1.98-1.91 (m, 4H).

Example 11: 6-((6-hydroxy-6-methylspiro[3.3]heptan-2-yl)methoxy)-4-(6-(6-((6-methoxypyridine-3 -Yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

Step 1: (6-Hydroxy-6-methylspiro[3.3]heptan-2-yl)methanesulfonate

Add 2-(hydroxymethyl)-6-methyl-spiro[3.3]heptane-6-ol (65mg, 0.42mmol) to a 10mL single-neck bottle, add dichloromethane (0.8mL) to dissolve it, add triethyl Amine (0.08mL, 0.6mmol), add methanesulfonyl chloride (0.06mL, 0.7mmol) at 0°C, and react at room temperature. TLC detects the completion of the reaction of the raw materials, stop the reaction, add 5 mL of water to the reaction solution, extract with DCM (15 mL×2), wash the organic phase with water (5 mL×2), wash with saturated brine, and dry with anhydrous sodium sulfate. The removal agent is PE/EA(v/v)=5/1-2/1, and 30mg of colorless liquid is obtained as the product. ¹ H NMR (400MHz, CDCl ₃ ) δ 4.15 (d, J = 6.8 Hz, 2H), 3.00 (s, 3H), 2.66-2.52 (m, 1H), 2.25-2.11 (m, 4H), 2.09 ( s, 2H), 1.88 (dd, J=19.5, 8.6 Hz, 2H), 1.72 (s, 1H), 1.32 (s, 3H).

Step 2: 6-((6-hydroxy-6-methylspiro[3.3]heptan-2-yl)methoxy)-4-(6-(6-((6-methoxypyridine-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- 3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (23mg, 0.05mmol, intermediate 1), (6-hydroxy-6-methylspiro[3.3] Hept-2-yl) methyl methanesulfonate (30mg, 0.13mmol), potassium carbonate (18mg, 0.13mmol), DMF (0.8mL), reacted overnight at 60°C in an oil bath. After the reaction was detected by TLC, the reaction solution was cooled to room temperature, 5mL of water was added, EA (20mL×2) was added, the organic phase was washed with water (5mL×4), saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated by silica gel column chromatography. The eluent is DCM/MeOH (v/v)=30/1-20/1, and 3 mg of yellow solid is obtained as the product. LC-MS: m/z=592.20 [M+H] ⁺ . ¹ H NMR(400MHz,CDCl ₃ )δ8.40(d,J=1.9Hz,1H),8.21(s,1H),8.11(s,2H),7.78(dd,J=8.8,2.2Hz,1H) ,7.69(s,1H),7.11(s,1H),6.71(dd,J=15.3,8.7Hz,2H),3.95(d,J=6.4Hz,2H),3.92(s,3H),3.90- 3.80(m,4H),3.70-3.60(m,4H),2.76-2.70(m,2H),2.37-2.30(d,J=13.6Hz,1H),2.27-2.24(m,3H),2.13( s, 2H), 2.04 (s, 1H), 2.01-1.84 (m, 3H), 1.35 (s, 3H).

Example 12: 6-(2-(2-oxa-6-azaspiro[3.3]heptane-6-yl)ethoxy)-4-(6-(5-(4-methoxybenzene Formyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

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

Add hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (1.0g, 4.7mmol), 4-methoxybenzoic acid (1.1g, 7.2mmol) into a 25mL single-mouth bottle DCM was added to dissolve it, and then 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.8g, 9.4mmol), 4-dimethylaminopyridine (1.2g, 9.8mmol), react at room temperature for 20h. After the reaction is stopped, add 10 mL of water to the reaction solution and extract with DCM (30 mL) in the aqueous phase. The organic phases are combined and washed with water (10 mL×2), dried over anhydrous sodium sulfate and concentrated. Silica gel column chromatography, eluent is DCM-DCM/MeOH (v/v=50/1), 1.3 g of colorless liquid is obtained as the product, and the yield is 81.25%. LC-MS: m/z=291.20[M-tBu+H] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ ): δ7.51(d,J=8.7Hz,2H), 6.95(d,J= 8.7Hz, 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]pyrrole-2(1H)-yl)(4-methoxyphenyl)methanone hydrochloride

Add 5-(4-methoxybenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (600mg, 1.732mmol) into a 25mL single-neck bottle, add EA( 5mL) to dissolve, add HCl/EA (4mL, 4mol/L), and react at room temperature for 1h after the addition is complete. After the reaction is detected by TLC, the reaction solution is directly concentrated and dried to obtain 470 mg of solid as the product, with a yield of 95.95%. LC-MS: m/z=247.25[M+H] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ ): δ7.50(d,J=8.7Hz,2H), 6.96(d,J=8.7Hz ,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 4: 6-(2-(2-oxa-6-azaspiro[3.3]heptan-6-6 yl)ethoxy)-4-(6-(5-(4-methoxybenzyl Acyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

Add 6-(2-(2-oxa-6-azaspiro[3.3]heptane-6-yl)ethoxy)-4-(6-fluoropyridin-3-yl)pyrazole to a 5mL single-mouth flask And [1,5-a]pyridine-3-carbonitrile (26mg, 0.06853mmol, intermediate 2), hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)(4-methoxy Phenyl) ketone hydrochloride (35 mg, 0.1096 mmol), potassium carbonate (55 mg, 0.39795 mmol), DMSO (1.5 mL), and reacted at 90°C in an oil bath for 15 hours. After cooling the reaction solution to room temperature, add 5mL of water, extract with EA (20mL×2), wash the organic phase with water (5mL×3), wash with saturated brine (5mL×2), dry with anhydrous sodium sulfate and filter, and concentrate the filtrate under reduced pressure. After analysis, the eluent was DCM-DCM/MeOH (v/v=10/1), and 7 mg of off-white solid was obtained as the product. Yield: 16.86%. LC-MS: m/z=606.30[M+H] ⁺ ; ¹ H NMR (400MHz, CDCl ₃ ): δ8.33(s,1H), 8.21(s,1H), 8.13(s,1H), 7.71 (d,J=7.1Hz,1H), 7.54(d,J=8.4Hz,2H), 7.12(s,1H), 6.93(d,J=8.5Hz,2H), 6.51(d,J=8.9Hz ,1H),4.78(s,4H),4.06(s,3H),3.91-3.70(m,7H),3.61(s,4H),3.54 (s,3H),3.11(d,J=18.5Hz, 2H), 2.93(s, 2H).

Example 13: 6-(2-(2-oxa-6-azaspiro[3.3]heptane-6-yl)ethoxy)-4-(6-(5-(2,3-dimethyl Benzoyl)hexahydropyrrolo[3,4-c]pyrrole-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)-carboxylic acid tert-butyl ester

Add hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (500mg, 2.3553mmol), 2,3-dimethylbenzoic acid (530mg, 3.5293mmol, ), add DCM to dissolve, then add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (903mg, 4.710mmol), 4-dimethylaminopyridine (580mg, 4.7475 mmol), react at room temperature for 17h. Add 10 mL of water to the reaction solution, extract the aqueous phase with DCM (30 mL), combine the organic phases and wash with water (10 mL×2), dry with anhydrous sodium sulfate and concentrate, and perform silica gel column chromatography. The eluent is PE-PE/EA (v/ v=1/1), 660 mg of colorless viscous liquid is obtained as the product, and the yield is 81.37%. LC-MS: m/z=289.25[M-tBu+H] ^{+; 1} H NMR (400MHz, DMSO-d ₆ ): δ7.18 (d, J=7.3 Hz, 1H), 7.12 (t, J= 7.5Hz, 1H), 7.01 (d, J = 7.3 Hz, 1H), 3.69 (dd, J = 12.3, 7.7 Hz, 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]pyrrole-2(1H)-yl)(2,3-dimethylphenyl)methanone hydrochloride

Add 5-(2,3-dimethylbenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (330mg, 0.9582mmol) into a 25mL single-mouth bottle, add EA (3mL) was used to dissolve it, and HCl/EA (2mL, 4mol/L) was added. After the addition, the reaction was carried out at room temperature for 1h. A white solid precipitated out during the reaction. After the reaction of the raw materials was detected by TLC, the reaction solution was directly concentrated to obtain a white solid, which was dried in a vacuum drying oven at 60° C. to obtain 260 mg of the product, with a yield of 85.54%. LC-MS: m/z=245.30[M+H] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ ): δ7.18(d,J=7.3Hz,1H), 7.13(t,J=7.5Hz ,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 4: 6-(2-(2-oxa-6-azaspiro[3.3]heptane-6-yl)ethoxy)-4-(6-(5-(2,3-dimethyl Benzoyl) hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

Add 6-(2-(2-oxa-6-azaspiro[3.3]heptane-6-yl)ethoxy)-4-(6-fluoropyridin-3-yl)pyrazole to a 10mL single-neck bottle And [1,5-a]pyridine-3-carbonitrile (26mg, 0.07mmol, Intermediate 2), (hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)(2,3 -Dimethylphenyl) ketone hydrochloride (32mg, 0.1009mmol), potassium carbonate (70mg, 0.51mmol), DMSO (1.5mL), reacted at 90°C in an oil bath for 13h. After cooling the reaction solution to room temperature, add 5mL of water, extract with EA (20mL×2), wash the organic phase with water (5mL×3), wash with saturated brine (5mL×2), dry with anhydrous sodium sulfate and filter, and concentrate the filtrate under reduced pressure. After analysis, the eluent was DCM/MeOH (v/v=50/1-10/1), and 7 mg of yellow solid was obtained as the product, and the yield was 16.92%. LC-MS: m/z=604.35[M+H] ⁺ ; ¹ H NMR (400MHz, CDCl ₃ ): δ8.31(d, J=2.1Hz, 1H), 8.19(s, 1H), 8.10(d ,J=1.6Hz,1H), 7.70(dd,J=8.7,2.4Hz,1H), 7.18–7.12(m,2H), 7.10(d,J=2.0Hz,1H), 7.05(d,J= 7.4Hz,1H),6.49(d,J=8.7Hz,1H),4.76(s,4H),4.07–3.97(m,3H),3.89–3.84(m,1H),3.80–3.70(m,3H) ), 3.60–3.54 (m, 2H), 3.49 (dd, J = 9.6, 5.3 Hz, 2H), 3.41 (dd, J = 11.5, 4.6 Hz, 1H), 3.19–3.12 (m, 2H), 3.09– 2.99 (m, 2H), 2.95-2.86 (m, 2H), 2.28 (s, 3H), 2.21 (s, 3H).

Example 14: 6-(2-(2-oxa-6-azaspiro[3.3]heptane-6-yl)ethoxy)-4-(6-(6-(4-methoxybenzene Formyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

Step 1: 6-(4-Methoxybenzoyl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester

Add 2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (500mg, 2.52mmol), 4-methoxybenzoic acid (576mg, 3.79mmol) into a 50mL single-necked flask, add DCM , Then add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (980mg, 5.11mmol), 4-dimethylaminopyridine (636mg, 5.2059mmol), react at room temperature for 18h . After stopping the reaction, add 5 mL of water to the reaction solution, extract the aqueous phase with DCM (20 mL), combine the organic phases and wash with water (5 mL×2), dry with anhydrous sodium sulfate and perform silica gel column chromatography. The eluent is DCM-DCM/MeOH (v /v=50/1), 270 mg of white solid is obtained as the product, and the yield is 32.21%. LC-MS: m/z=333.20[M+H] ⁺ ; ¹ H NMR (400MHz, CDCl ₃ ): δ7.60(d,J=8.7Hz,2H), 6.91(d,J=8.7Hz,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

Add 6-(4-methoxybenzoyl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (200mg, 0.6017mmol) into a 25mL single-neck flask, add DCM (2mL ) To dissolve, add trifluoroacetic acid (0.9 mL, 10 mmol) at 0°C, and react at room temperature for 6 hours after the addition is complete. The reaction solution was directly concentrated to obtain 130 mg of colorless liquid, which was the product, with a yield of 93.01%. LC-MS: 233.20 [M+H] ⁺ .

Step 3: 6-(2-(2-oxa-6-azaspiro[3.3]heptane-6-yl)ethoxy)-4-(6-(6-(4-methoxybenzyl Acyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

Add 6-(2-(2-oxa-6-azaspiro[3.3]heptane-6-yl)ethoxy)-4-(6-fluoropyridin-3-yl)pyrazole to a 5mL single-mouth flask And [1,5-a]pyridine-3-carbonitrile (26mg, 0.06853mmol, intermediate 2), (4-methoxyphenyl)(2,6-diazaspiro[3.3]heptan-2- Methyl) ketone (70 mg, 0.2605 mmol), potassium carbonate (55 mg, 0.39795 mmol), DMSO (1.5 mL), and reacted at 90°C in an oil bath for 20.5 hours. After cooling the reaction solution to room temperature, add 5mL of water, extract with EA (20mL×2), wash the organic phase with water (5mL×3), wash with saturated brine (5mL×2), dry with anhydrous sodium sulfate and filter, and concentrate the filtrate under reduced pressure. After analysis, the eluent was DCM-DCM/MeOH (v/v=20/1), and the yellow solid was obtained and TLC purified again to obtain 5 mg of off-white solid as the product. The yield was 12.33%. LC-MS: m/z=592.30[M+H] ⁺ ; ¹ H NMR (400MHz, CDCl ₃ ): δ 8.29 (s, 1H), 8.19 (s, 1H), 8.11 (s, 1H), 7.68 (dd,J=8.7,2.1Hz,1H),7.65(d,2H),7.10(s,1H),6.93(d,J=8.6Hz,2H),6.43(d,J=8.6Hz,1H) ,4.76(s,4H),4.47(d,J=36.3Hz,4H),4.27(s,4H),4.02(t,J=4.8Hz,2H),3.86(s,3H),3.55(s, 4H), 2.92–2.83 (m, 2H).

Example 15: 6-(2-(2-oxa-6-azaspiro[3.3]heptane-6-yl)ethoxy)-4-(6-(5-(3-fluoro-2- (Methylbenzoyl)hexahydropyrrolo[3,4-c]pyrrole-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)-carboxylic acid tert-butyl ester

Add hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (500mg, 2.36mmol,), 3-fluoro-2-methylbenzoic acid (550mg, 3.57 mmol), DCM was added to dissolve, and then 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (903mg, 4.710mmol), 4-dimethylaminopyridine (580mg, 4.75mmol), react 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 as the product, with a yield of 75.56%. LC-MS: m/z=293.20[M-tBu+H] ⁺ ; ¹ H NMR (400MHz, CDCl ₃ ): δ7.24-7.17 (m, 1H), 7.05 (d, J=9.0Hz, 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=1.4 Hz, 3H), 1.46 (s, 9H).

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

Add 5-(3-fluoro-2-methylbenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (620mg, 1.780mmol) into a 25mL single-mouth flask, Add EA (5mL) to dissolve, add HCl/EA (11mL, 4mol/L), and react at room temperature for 2h after the addition is complete. After the reaction is stopped, the reaction solution is directly concentrated to obtain 410 mg of white solid, which is the product, with a yield of 71.73%. LC-MS: m/z=249.20[M+H] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ ): δ7.30(dd,J=13.3,7.8Hz,1H), 7.20(t,J= 8.9Hz, 1H), 7.10 (d, J = 7.4 Hz, 1H), 3.73 (dd, J = 12.6, 7.8 Hz, 1H), 3.55 (dd, J = 12.7, 4.0 Hz, 1H), 3.44–3.21 ( m, 3H), 3.16–3.01 (m, 3H), 3.00–2.87 (m, 2H), 2.15 (d, J = 1.6 Hz, 3H).

Step 3: 6-(2-(2-oxa-6-azaspiro[3.3]heptane-6-yl)ethoxy)-4-(6-(5-(3-fluoro-2-methyl Benzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

Add 6-(2-(2-oxa-6-azaspiro[3.3]heptane-6-yl)ethoxy)-4-(6-fluoropyridin-3-yl)pyrazole to a 10mL single-neck bottle And [1,5-a]pyridine-3-carbonitrile (30mg, 0.07907mmol, Intermediate 2), (hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(3-fluoro -2-Methylphenyl) ketone hydrochloride (40mg, 0.1245mmol), potassium carbonate (70mg, 0.50648mmol), DMSO (1.5mL), reacted at 90°C in an oil bath for 12h. After stopping the reaction, the reaction solution was cooled to room temperature and added with 5mL of water, extracted with EA (30mL×2), washed with organic phase (5mL×3), washed with saturated brine (5mL×2), dried with anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure Silica gel column chromatography, the eluent was DCM/MeOH (v/v=50/1-10/1) to obtain a yellow solid, and TLC purification was performed again to obtain 5 mg of off-white solid as the product. The yield was 10.41%. LC-MS: m/z=608.35[M+H] ⁺ ; ¹ H NMR (400MHz, CDCl ₃ ): δ 8.33 (s, 1H), 8.21 (s, 1H), 8.13 (s, 1H), 7.72 (d,J=6.6Hz,1H),7.24–7.20(m,1H),7.12(s,1H),7.07–7.01(m,2H),6.52(d,J=8.7Hz,1H),4.78( s,4H),4.08–3.99(m,3H),3.91–3.87(m,1H), 3.76(dd,J=18.8,5.6Hz,2H), 3.60(s,3H),3.56–3.48(m, 3H), 3.45–3.41(m,1H), 3.21–3.16(m,2H), 3.11–3.05(m,1H), 2.93(s,2H), 2.26(s,3H).

Example 16: 6-(2-(2-oxa-6-azaspiro[3.3]heptane-6-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-carboxylic acid tert-butyl ester

Add 2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (500mg, 2.5219mmol), 3-fluoro-2-methylbenzoic acid (580mg, 3.76mmol) into a 50mL single-mouth flask, Add DCM, then add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (980mg, 5.112mmol), 4-dimethylaminopyridine (636mg, 5.2059mmol) at room temperature Reaction for 15h. After stopping the reaction, the reaction solution was added with 5mL saturated ammonium chloride solution, extracted with DCM (40mL×2), the organic phase was washed with water (10mL×2), dried over anhydrous sodium sulfate and chromatographed on silica gel column. The eluent was DCM-DCM/MeOH (v/v=50/1), 480 mg of colorless liquid is obtained as the product, and the yield is 56.92%. LC-MS: m/z=335.20[M+H] ⁺ ; ¹ H NMR (400MHz, CDCl ₃ ): δ7.22–7.14(m,1H), 7.09–6.98(m,2H), 4.29(s, 2H), 4.11 (d, J = 9.3 Hz, 2H), 4.03 (d, J = 4.7 Hz, 4H), 2.28 (d, J = 2.1 Hz, 3H), 1.43 (s, 9H).

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

Add 6-(3-fluoro-2-methylbenzoyl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (480mg, 1.435 mmol) into a 25mL single-neck flask, add DCM (5 mL) was used to dissolve, 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 completion. After the reaction was detected by TLC, the reaction liquid was directly concentrated, and 330 mg of the liquid was obtained as the product with a yield of 98.12%. LC-MS: 235.15 [M+H] ⁺ .

Step 3: 6-(2-(2-oxa-6-azaspiro[3.3]heptane-6-yl)ethoxy)-4-(6-(6-(3-fluoro-2-methyl Benzoyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

Add 6-(2-(2-oxa-6-azaspiro[3.3]heptane-6-yl)ethoxy)-4-(6-fluoropyridin-3-yl)pyrazole to a 10mL single-neck bottle And [1,5-a]pyridine-3-carbonitrile (30mg, 0.08mmol, intermediate 1), (3-fluoro-2-methylphenyl)(2,6-diazaspiro[3.3]heptan Alk-2-yl) ketone (62 mg, 0.2646 mmol), potassium carbonate (65 mg, 0.47030 mmol), DMSO (1.5 mL), and reacted at 90°C in an oil bath for 15 hours. After stopping the reaction, the reaction solution was cooled to room temperature and added with 5mL of water, extracted with EA (20mL×2), washed the organic phase with water (5mL×3), washed with saturated brine (5mL×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=50/1-10/1), 27 mg of yellow solid was obtained as the product, and the yield was 57.52%. LC-MS: m/z=594.30[M+H] ⁺ ; ¹ H NMR (400MHz, CDCl ₃ ): δ8.28(d, J=2.1Hz, 1H), 8.19(s, 1H), 8.10(d ,J=1.9Hz,1H),7.68(dd,J=8.6,2.3Hz,1H),7.22-7.17(m,1H),7.11-7.04(m,3H),6.42(d,J=8.6Hz, 1H), 4.75 (s, 4H), 4.41 (s, 2H), 4.30 (d, J = 8.7 Hz, 2H), 4.22 (d, J = 8.8 Hz, 2H), 4.14 (s, 2H), 4.00 ( t, J = 5.1 Hz, 2H), 3.51 (s, 4H), 2.85 (t, J = 5.1 Hz, 2H), 2.33 (d, J = 1.8 Hz, 3H).

Using suitable raw materials, the target compounds (31)-(33) of Examples 31-33, the target compounds (37)-(38) of Examples 37-38, and the target compounds (40)-( 111), the target compound (224)-(244) of embodiment 224-244, the target compound (211)-(213) of embodiment 210-213, the target compound (215)-(223) of embodiment 215-223 It is prepared by referring to the synthesis route of Example 1 or Synthesis Scheme 1. The specific structure and characterization data are shown in Table 1 below:

Table 1

Using suitable raw materials, the target compounds (16)-(17) of Examples 17 and 245 were prepared by referring to the synthetic route of Example 6 or Synthetic Scheme 2. The specific structure and characterization data are described in Table 2 below:

Table 2

Using suitable raw materials, the target compounds (18)-(30) of Examples 18-30, the target compounds (34)-(36) of Examples 34-36, the target compounds (39) of Example 39, and the example 114 The target compound (114) of the embodiment, the target compound (117) of the embodiment 117, the target compound (120) of the embodiment 120, the target compound (123) of the embodiment 123, the target compound (125) of the embodiment 125, and the embodiment 129 -131 target compound (129)-(131), embodiment 133-134 target compound (133)-(134), embodiment 144-145 target compound (144)-(145), embodiment 158-160 The target compound (158)-(160), the target compound (165)-(171) of embodiment 165-171, the target compound (191)-(195) of embodiment 191-195, the target compound of embodiment 200 ( 200). The target compounds (204)-(214) of Examples 204-214 were prepared by referring to the synthetic route of Example 12 or Synthesis Scheme 4. The specific structure and characterization data are described in Table 3 below:

table 3

Using suitable raw materials, the target compounds (112)-(113) of Examples 112-113, the target compounds (115)-(116) of Examples 115-116, and the target compounds (118)-( 119), the target compound (121)-(122) of embodiment 121-122, the target compound (124) of embodiment 124, the target compound (126)-(128) of embodiment 126-128, the target of embodiment 132 Compound (132), the target compound (135)-(143) of embodiment 135-143, the target compound (146)-(157) of embodiment 146-157, the target compound (161)-( of embodiment 161-164) 164), the target compound (172)-(190) of embodiment 172-190, the target compound (196)-(199) of embodiment 196-199, the target compound (201)-(203) of embodiment 201-203 The target compounds (208)-(209) of Examples 208-209 can be prepared by referring to the synthetic route of Example 12 or Synthesis Scheme 4. The specific structure and characterization data are described in Table 4 below:

Table 4

Examples of biological activity test:

Test case 1:

1. The purpose of the experiment:

The HTRF method was used to test the inhibitory activity of the series of compounds on the two kinases Ret wt and Ret V804M, and the IC ₅₀ value was 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) MgCl ₂ (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; 5mM MgCl ₂ ; 1mM DTT; 1mM MnCl ₂ .

3.2 Use Echo 550 reaction plate (784075, Greiner) to transfer 10nl of diluted compound 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 5μl of kinase (prepared in step 3) to each well of the reaction plate. Seal the plate with sealing film and centrifuge at 1000g for 30 seconds, and leave it at room temperature for 10 minutes.

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

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

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

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

3.10 Use Envision 2104 to read 615nm (Cryptate) and 665nm (XL665) fluorescence signals.

4. Data analysis

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

4.2 The inhibition rate is calculated as follows:

The average value of CEP-32496 readings in all positive control wells

The average value of all negative control wells DMSO wells

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 the IC ₅₀ and draw the inhibition curve of the compound:

IC to give compound ₅₀ using the following equation nonlinear fit (half maximal inhibitory concentration): Data analysis was performed using Graphpad 6.0 Software.

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

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

5. The experimental results are shown in Table 5:

Table 5 Kinase inhibitory activity of the compounds of the present invention

In addition to the activity of the compounds of the present invention in Table 5, other compounds of the present invention also have good Ret kinase inhibitory activity, wherein the inhibitory activity against Ret wt kinase is 0-20 nM, and the inhibitory activity against Ret wt kinase Ret V804M is 0-300 nM; Preferably, the inhibitory activity against Ret wt kinase is 0-5 nM, and the inhibitory activity against Ret wt kinase Ret V804M is 0-100 nM, more preferably, the inhibitory activity against Ret wt kinase is 0-1 nM, and the inhibitory activity against Ret wt kinase is Ret V804M. It is 0-50nM. In particular, the compounds in Table 1 and Table 3 of the present invention have an inhibitory activity on Ret wt kinase of 0-10 nM, and their inhibitory activity on Ret wt kinase Ret V804M is preferably 0-100 nM. More preferably, the compounds in Table 1 and Table 3 of the present invention have an inhibitory activity against Ret wt kinase. The inhibitory activity against Ret wt kinase is 0-5 nM, and the inhibitory activity against Ret wt kinase Ret V804M is 0-50 nM. More preferably, the compounds in Table 1 and Table 3 of the present invention have inhibitory activity against Ret wt kinase of 0-1 nM; the present invention In Table 2, the compound's inhibitory activity on Ret wt kinase is 0-1 nM, and the inhibitory activity of Ret wt kinase Ret V804M is 0-20 nM.

In the description of this specification, the description with reference to the terms “one embodiment”, “some embodiments”, “some embodiments”, “examples”, “specific examples” or “some examples” etc. means to combine the embodiment or The specific features, structures, materials, or characteristics described in the examples are included in at least one embodiment or example of the present invention. In this specification, the schematic representation of the above-mentioned terms does not necessarily refer to the same embodiment or example. Moreover, the described specific features, structures, materials or characteristics may be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art can combine and combine different embodiments, embodiments, or examples, and features of different embodiments, embodiments, or examples described in this specification without contradicting each other.

Although the embodiments of the present invention have been shown and described above, it can be understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Those of ordinary skill in the art will not depart from the principle and purpose of the present invention. Under the circumstances, changes, modifications, substitutions and modifications can be made to the above-mentioned embodiments within the scope of the present invention, and the scope of the present invention is defined by the claims and their equivalents.

Claims

A compound, which is the compound of formula (I) or its stereoisomers, geometric isomers, tautomers, nitrogen oxide compounds, solvates, metabolites, pharmaceutically acceptable salts or prodrugs :

among them,

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- or alkylene-NH-, and the T is optionally selected from D, OH, F, Cl, Br by 1, 2, 3, or 4 , I, CN, NH 2 , CF 3 , alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, heterocyclyl, alkoxy, aryl, heteroaryl or alkylamino substituents;

Ring G is a spirocarbocyclyl or spiroheterocyclic group;

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

R a is D, OH, NH 2 , F, CF 3 , 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, alkoxyalkyl or hydroxyl alkyl;

E is a bond, -NR 6 -, or -O-;

Ring A is a bridging cyclylene, tetracyclylene or spirocyclylene, and A is optionally selected from F, Cl, Br, OH, oxo, NR 5 R 6 , R 5 (C=O)NR 6 -, aminoalkyl, alkyl, alkoxy, haloalkyl, hydroxyalkyl, carbocyclyl, heterocyclyl, heterocyclylalkyl, alkoxyalkyl, alkylene Substituted by substituents of cycloalkyl and monoheterocyclylene;

Q is a key, -(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 -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;

M is H, D, heteroaryl, aryl, cycloalkyl or heterocyclyl, and M is optionally 1, 2, 3 or 4 selected from D, F, Cl, CN, CF 3 , OH, Substituted by substituents of NR 5 R 6 , OR 7 , alkyl, haloalkyl, hydroxyalkyl, haloalkoxy, aryl, alkoxyalkyl, oxo, alkyl acyl, heterocyclyl, cycloalkyl ；

R 1 is H, D, CN, F, Cl, Br, alkyl or cycloalkyl, wherein said alkyl and cycloalkyl can be independently optionally selected from F, Substituted by Cl, Br, CN, NH 2 , OH and NO 2 substituents;

Each R 2 , R 3 is independently OH, F, CF 3 , H, D, CN, Cl, Br, NH 2 , hydroxyalkyl, alkyl, alkylamino, alkoxy, haloalkoxy, cycloalkane Group, cycloalkylalkyl, aryl, heteroaryl;

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

R 4 is H, D, F, Cl, Br, alkyl or alkoxy, wherein the alkyl and alkoxy are each independently optionally selected from F, Cl, Replaced by substituents of Br, CN, NH 2 , OH and NO 2;

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

R 6 is H, D, alkyl or alkoxyalkyl, wherein the alkyl and alkoxyalkyl are each independently optionally selected from F, Cl, Br, CN , NH 2 , OH and NO 2 substituents;

R 7 is OH, alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl.
The compound of claim 1, wherein

T is a bond, C 1-6 alkylene, C 1-6 alkylene-O- or C 1-6 alkylene-NH-, and T is optionally selected from 1, 2, 3 or 4 From D, OH, F, Cl, Br, I, CN, CF 3 , C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 3- It is substituted with a 7-membered heterocyclic group, a C 1-6 alkoxy group, a C 6-10 aryl group, a 5-12 membered heteroaryl group or a C 1-6 alkylamino group.
The compound according to any one of claims 1-2, wherein:

T is a bond, -CH 2 -, -(CH 2 ) 2 -, -(CH 2 ) 3 -, -(CH 2 ) 4 -, -(CH 2 ) 5 -, -(CH 2 ) 6 -, -(CH 2 ) 2 -O- or -(CH 2 ) 2 -NH-, and the T is optionally 1, 2, 3 or 4 selected from D, OH, F, Cl, Br, I, CN, CF 3 , methyl, ethyl, propyl, 2-hydroxyethyl, 1-hydroxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydrofuranyl Hydropyranyl, oxetanyl, methoxy, ethoxy, propoxy, butoxy, phenyl, methylamino and dimethylamino substituents are substituted.
The compound according to any one of claims 1-3, wherein:

G is a 6-12 membered spiro carbocyclic group or a 6-12 membered spiro heterocyclic group;

R a is D, OH, NH 2 , F, CF 3 , 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 cycloalkyl, C 1-6 alkoxy C 1-6 alkyl, C 1-6 hydroxyalkyl;

R 5 is H, D, C 1-6 alkyl, 3-12 membered carbocyclic group, 3-12 membered heterocyclic group, C 6-10 aryl group or 5-10 membered heteroaryl group, wherein the C 1-6 alkyl, 3-12 membered carbocyclic group, 3-12 membered heterocyclic group, C 6-10 aryl group and 5-10 membered heteroaryl group are each independently optionally selected by 1, 2, 3 or 4 Substituted by a substituent selected from F, Cl, Br, OH, NH 2 , C 1-6 alkylamino, alkyl, alkylsulfonyl, alkoxy, aryl and heteroaryl;

R 6 is H, D, C 1-6 alkyl or C 1-6 alkoxy C 1-6 alkyl, wherein the C 1-6 alkyl and C 1-6 alkoxy C 1-6 alkane The groups are each independently optionally substituted with 1, 2, 3 or 4 substituents selected from F, Cl, Br, CN, NH 2 , OH and NO 2 ;

R 7 is OH, C 1-6 alkyl, C 3-6 cycloalkyl, 3-12 membered heterocyclic group, C 6-10 aryl, 5-10 membered heteroaryl.
The compound according to any one of claims 1-4, wherein:

G is the following sub-structure:

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

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

Z 3 is -O-, -S-, -NH-;

n1 is 0, 1 or 2;

n2 is 1, 2 or 3;

n3 is 0 or 1.
The compound according to any one of claims 1-5, wherein:

G is the following sub-structure:

R a is D, OH, NH 2, F , CF 3, Cl, Br, I, CN, NH 2, NHCH 3, -NHC (= O) CH 3, -S (= O) 2 CH 3, -S (=O)CH 3 , -C(=O)CH 3 , -C(=O)OH, oxo, methyl, ethyl, propyl, butyl, methoxy, ethoxy, cyclopropyl , Cyclopentyl, methoxymethyl, ethoxymethyl, 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 the methyl group , Ethyl, n-propyl, cyclopropyl, cyclopentyl, pyrrolidinyl, phenyl and pyrazolyl are each independently optionally selected from F, Cl, Br, OH, NH 2 , methyl, -S(=O) 2 CH 3 , methoxy, ethoxy and phenyl substituents;

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 each independently optionally selected from F, Cl, Br, CN, NH 2 , Substituted by OH and NO 2 substituents;

R 7 is OH, methyl, ethyl, NH 2 , N(CH 3 ) 2 , n-propyl, isopropyl, tert-butyl, cyclopropyl or phenyl.
The compound according to any one of claims 1-6, wherein:

A is a 5-12-membered bridging cyclylene group, a 5-12-membered amidocycline group or a 5-12-membered spirocyclylene group, and A is optionally selected from F, Cl, Br by 1, 2, 3, or 4 , 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 haloalkane Group, C 1-6 hydroxyalkyl group, 3-12 membered carbocyclic group, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group C 1-6 alkyl, C 1-6 alkoxy C 1- 6 alkyl, C 3-6 cycloalkylene and 3-6 membered monoheterocyclylene substituents.
The compound according to any one of claims 1-7, wherein:

A is the following sub-structure:

Wherein, Z 1a and Z 2a are each independently -CH 2 -or -NH-;

Z 3a is -CH- or -N-;

Z 4a is -O-, -S- or -NH-;

Each of Z 5a and Z 6a is independently -CH 2 -, -O-, -S-, -S(=O)-, -S(=O) 2- , -C(=O)- or -NH- ；

m and t are each independently 0, 1 or 2;

n and t1 are each independently 0 or 1;

Wherein each sub-structure of A is independently optionally selected from F, Cl, Br, OH, oxo, NR 5 R 6 , R 5 (C=O) NR 6 -, amino C 1-4 alkyl, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, 3-12 membered carbocyclic group, 3-12 membered heterocyclic ring Group, 3-12 membered heterocyclyl C 1-4 alkyl, C 1-4 alkoxy C 1-4 alkyl, C 3-6 cycloalkylene and 3-6 membered monoheterocyclylene substitution Substituted by the group.
The compound according to any one of claims 1-8, wherein:

A is the following sub-structure:

Wherein, each sub-structure of A is independently optionally 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, tetrahydrofuran Group, cyclopropylene, cyclohexylene, and pyrrolidinylene substituents.
The compound according to any one of claims 1-9, wherein:

M is H, D, 5-10 membered heteroaryl, C 6-10 aryl, C 3-7 cycloalkyl or 3-12 membered heterocyclyl; and M is optionally selected by 1, 2, 3 or 4 One selected from D, F, Cl, CN, OH, CF 3 , NR 5 R 6 , OR 7 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 Halogenated alkoxy, C 6-10 aryl, C 1-6 alkoxy C 1-6 alkyl, oxo, C 1-6 alkyl acyl, 3-7 membered heterocyclic group, C 3-7 cycloalkane Substituents of the group are substituted.
The compound according to any one of claims 1-10, 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]heptanyl, hexahydrofuran[3,4-c]pyrrolyl, 3-azabicyclo[3.1.0]hexyl, octahydropyrrolo[1,2-a] Pyrazinyl or 5-azaspiro[2.4]heptanyl; 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, tetrahydropyridine Substituted by the substituents of pyranyl, piperazinyl, cyclopropyl and cyclohexyl;
The compound according to any one of claims 1-11, wherein:

R 1 is H, D, CN, F, Cl, Br, methyl, ethyl or cyclopropyl, wherein the methyl, ethyl and cyclopropyl can be independently optionally selected by 1, 2, 3 or 4 substituents selected from F, Cl, Br, CN, NH 2 , OH and NO 2 ;

R 4 is H, D, F, Cl, Br, methyl, ethyl, n-propyl, methoxy or ethoxy, wherein the methyl, ethyl, n-propyl, methoxy and ethyl group may be optionally independently substituted with 1,2, 3 or 4 substituents selected from F, Cl, Br, CN, NH 2, OH , NO 2 substituted by a substituent.
The compound according to any one of claims 1-12, wherein:

Each R 2 , R 3 is independently OH, F, CF 3 , H, D, CN, Cl, Br, NH 2 , C 1-6 hydroxyalkyl, C 1-6 alkyl, C 1-6 alkyl Amino, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-7 cycloalkyl, C 3-7 cycloalkyl, C 1-6 alkyl, C 6-10 aryl or 5-10 Yuan heteroaryl;

Or, R 2 , R 3 and the same C atom connected to them form a 3-7 membered carbocyclic ring or a 3-7 membered heterocyclic ring.
The compound according to any one of claims 1-13, wherein:

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

Or, R 2 , R 3 and the same C atom connected to them form cyclopentane, cyclopropane, cyclobutane, tetrahydropyran, tetrahydrofuran, piperidine or pyrrolidine.
The compound according to any one of claims 1-14, 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)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)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 )-,-(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 -,
The compound of any one of claims 1-15 has a structure of formula (I-1), or a stereoisomer, geometric isomer, tautomer, or nitrogen oxide of the structure of formula (I-1) , Solvates, metabolites, pharmaceutically acceptable salts or prodrugs,

among them,

Ring A1 is the following sub-structure:

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

And each sub-structure of A1 is independently optionally selected from F, Cl, Br, OH, oxo, NR 5 R 6 , R 5 (C=O)NR 6 -, amino C 1-4 alkyl, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, 3-12 membered carbocyclic group, 3-12 membered heterocyclic ring Group, 3-12 membered heterocyclyl C 1-4 alkyl, C 1-4 alkoxy C 1-4 alkyl, C 3-6 cycloalkylene and 3-6 membered monoheterocyclylene substitution Substituted by the group.
The compound of claim 16, wherein

A1 is the sub-structure formula:

Wherein each sub-structure of A1 is independently optionally 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, tetrahydrofuran Group, cyclopropylene, cyclohexylene, and pyrrolidinylene substituents.
The compound of any one of claims 1-15 has a structure of formula (I-2) or (I-3), or a stereoisomer of a structure of formula (I-2) or (I-3), and geometrical differences. Constructs, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs,

Wherein, Z 1 , Z 2 and Z 3a are each independently CH or N;

m and t are each independently 0, 1 or 2;

n and t1 are each independently 0 or 1;

among them
Independently and 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 carbocyclic group, 3-12 membered heterocyclic group, 3-12 membered The heterocyclic group C 1-4 alkyl, C 1-4 alkoxy C 1-4 alkyl, C 3-6 cycloalkylene and 3-6 membered monoheterocyclylene substituents are substituted.
The compound of claim 18, wherein

Is the following sub-structure:

Is the following sub-structure:

among them
Each sub-structure formula of 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 Group, n-propyl, methoxy, ethoxy, isopropoxy, CF 3 , hydroxymethyl, 2-hydroxyethyl, cyclopropyl, cyclohexyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, Cyclopropylene, cyclohexylene and pyrrolidinylene substituents are substituted.
The compound of any one of claims 1-19 has one of the following structures, or its stereoisomers, geometric isomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable Salt or prodrug of
A pharmaceutical composition comprising the compound according to any one of claims 1-20, and a pharmaceutically acceptable adjuvant.
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 the prevention or treatment of RET-related diseases.
The use according to claim 22, wherein RET-related diseases include cancer, irritable bowel syndrome and/or pain associated with irritable bowel syndrome.
The compound of any one of claims 1-20 or the pharmaceutical composition of claim 21 is used for the prevention or treatment of RET-related diseases.
The compound or pharmaceutical composition according to claim 24, wherein the RET-related disease is cancer, irritable bowel syndrome, or pain associated with irritable bowel syndrome.
A method for preventing or treating RET-related diseases, comprising administering to a patient an effective therapeutic amount of the compound according to any one of claims 1-20 or the pharmaceutical composition according to claim 21.
The method according to claim 26, wherein the RET-related disease is cancer, irritable bowel syndrome, or pain associated with irritable bowel syndrome.