WO2021249319A1 - Tricyclic compound, pharmaceutical composition, and use thereof - Google Patents

Abstract

Provided in the present application are a tricyclic compound, an isomer, pharmaceutically acceptable salt, and pharmaceutical composition thereof and the use thereof, wherein the tricyclic compound has a structure as shown by formula I. The tricyclic compound has a significant inhibitory effect on the activity of RET kinase and can effectively inhibit the proliferation of cancer cells. The tricyclic compound can be used as a RET kinase inhibitor and can be used in the preparation of a drug for treating RET kinase-mediated diseases, has a good therapeutic effect on RET kinase-mediated diseases such as cancer and has a wide application prospect.

Description

Tricyclic compound, pharmaceutical composition and application thereof Technical field

This application belongs to the technical field of medicinal chemistry, and specifically relates to a class of tricyclic compounds, pharmaceutical compositions containing such compounds, and applications of such compounds or pharmaceutical compositions in the preparation of medicines.

Background technique

RET is a receptor tyrosine kinase. In normal tissues, RET plays a key role in fetal kidney development and neurogenesis. However, the variation of RET promotes ligand-independent and sustained activation of RET kinase, thereby driving tumorigenesis (Reference 1). RET kinase can be activated oncogenically through gene rearrangement or point mutations. The RET gene rearrangement produces a continuously activated fusion protein dimer. The most common RET fusion proteins are KIF5B-RET, CCDC6-RET, NCOA4-RET and TRIM33-RET (Reference 2). RET fusion is present in 10-20% of papillary thyroid carcinoma (PTC), 1-2% of non-small cell lung cancer (NSCLC) (document 3-4) and other cancers (document 5). RET mutations can occur in extracellular cysteine residues (such as C620R, C634R, or C634W), causing abnormal receptor dimerization, or in intracellular kinase regions (such as V804L, V804M, or M918T), promoting independent Ligand kinase activation. RET mutations mainly exist in medullary thyroid carcinoma (MTC).

RET inhibitors have been clinically proven to be effective in the treatment of lung cancers with RET mutations in MTC and RET fusion-positive lung cancers (References 6-10). For example, vandetanib and cabozantinib have been approved for the treatment of metastatic or locally advanced MTC. However, these drugs have limited disease control. The reason is that these multi-kinase inhibitors were originally designed to inhibit other kinases. The activity of inhibiting RET kinase is lower than that of other kinases. This results in off-target side effects and limits the ability of patients. Tolerable dose.

Therefore, it is essential to develop a new RET kinase inhibitor to inhibit RET kinase activity and cellular activity of RET fusion and mutation, effectively inhibit RET fusion and RET mutation tumors in animals, and realize the treatment of RET-driven cancer. The research focus of the field.

Citation

1.Jhiang,SM.The RET proto-oncogene in human cancers.Oncogene 2000,19:5590-5597.

2.Kato, S.et al.RET aberrations in diverse cancers: next-generation sequencing of 4871 patients. Clin. Cancer Res. 2017, 23(8): 1988-1997.

3.Giuseppe B.et al. Targeting RET-rearranged non-small-cell lung cancer: future prospects. Lung Cancer: Targets and Therapy 2019, 10: 27-36.

4. Christoph, J.et al. Targeted therapy for RET-rearranged non-small cell lung cancer: Clinical development and future directions.OncoTargets and Therapy 2019, 12: 7857-7864.

5.Le Rolle, AF.et al. Identification and characterization of RET fusions in advanced colorectal cancer.Oncotarget 2015, 6: 28929-28937.

6.Kurzrock, R.et al. Activity of XL184 (Cabozantinib), an oral tyrosine kinase inhibitor, in patients with medullary thyroid cancer.J.Clin.Oncol.2011,29(19):2660-2666.

7.Elisei,R.et al.Cabozantinib in progressive medullary thyroid cancer.J.Clin.Oncol.2013,31(29):3639-3646.

8.Wells, SA Jr.et al. Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial.J.Clin.Oncol.2012,30(2):134-141.

9.Drilon, A.et al. Cabozantinib in patients with advanced RET-rearranged non-smallcell lung cancer:an open-label,single-centre,phase 2,single-arm trial.Lancet Oncol.2016,17:1653-1560 .

10.Lee, S.H.et al. Vandetanib in pretreated patients with advanced non-small cell lung cancer harboring RET rearrangement: a phase II clinical trial.Ann.Oncol.2017,28:292-297.

Summary of the invention

This application provides a tricyclic compound, a pharmaceutical composition and applications thereof.

In the first aspect, this application provides a tricyclic compound having a structure as shown in Formula I:

in

R ^{1 is} selected from H, halogen, C1-C10 linear or branched alkyl, C3-C10 cycloalkyl, C2-C10 heterocycloalkyl, C6-C20 aryl or C3-C20 heteroaryl;

R ² and R ³ are each independently selected from H, C1-C10 straight or branched chain alkyl, C3-C10 cycloalkyl; said R ² and R ^{3 are} not connected or connected to form a ring through a chemical bond;

R ^{4 is} selected from H, C1～C10 straight or branched chain alkyl, C3～C10 cycloalkyl, C2～C10 heterocycloalkyl, C6～C20 aryl, C3～C20 heteroaryl, COR ^a , CONR ^b R ^c , CO ₂ R ^d , SO ₂ R ^a or SO ₂ NR ^b R ^c ; the linear or branched alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are unsubstituted or substituted by 1 ~3 (for example, 1, 2, or 3) R ^4a substitutions;

R ^{4a is} selected from D, halogen, cyano, OR ^a1 , SR ^a1 , NR ^b1 R ^c1 , COR ^a1 , CONR ^b1 R ^c1 , CO ₂ R ^d1 , SO ₂ R ^a1 , SO ₂ NR ^b1 R ^c1 , C1～C10 Straight or branched chain alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C2-C10 heterocycloalkyl, C6-C20 aryl or C3-C20 heteroaryl; Straight-chain or branched alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl are unsubstituted or substituted with 1 to 3 (for example, 1, 2, or 3) R ^4b ;

R ^a , R ^b , R ^c , ^Rd , R ^a1 , R ^b1 , R ^c1 , R ^d1 are each independently selected from H, C1～C10 linear or branched alkyl, C2～C10 alkenyl, C2～C10 Alkynyl, C3-C10 cycloalkyl, C2-C10 heterocycloalkyl, C6-C20 aryl or C3-C20 heteroaryl; the straight or branched chain alkyl, alkenyl, alkynyl, cycloalkyl , Heterocycloalkyl, aryl, and heteroaryl are unsubstituted or substituted with 1 to 4 (for example, 1, 2, 3, or 4) R ⁵ ;

R ^4b and R ⁵ are each independently selected from D, halogen, cyano, hydroxyl, unsubstituted or halogenated C1～C10 linear or branched alkyl, C2～C10 alkenyl, C2～C10 alkynyl, C3～C10 Cycloalkyl, C2～C10 heterocycloalkyl, C6～C20 aryl, C3～C20 heteroaryl, OR ^a2 , SR ^a2 , NR ^b2 R ^c2 , COR ^a2 , CONR ^b2 R ^c2 , CO ₂ R ^d2 , SO ₂ R ^a2 , SO ₂ NR ^b2 R ^c2 , NR ^b2 COR ^d2 , NR ^a2 CONR ^b2 R ^c2 , NR ^b2 SO ₂ R ^d2 , NR ^b2 SO ₂ NR ^b2 R ^c2 or SOR ^a2 ; and

R ^a2 , R ^b2 , R ^c2 , and R ^d2 are each independently selected from H, C1-C10 linear or branched alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C2- C10 heterocycloalkyl, C6-C20 aryl or C3-C20 heteroaryl.

In the above groups, the two substituents R ^b and R ^c , R ^b1 and R ^c1 , R ^b2 and R ^c2 connected to the same N are not connected to each other, or are connected through a chemical bond to form a heterocycloalkyl group; heterocycloalkyl unsubstituted or 1 to 3 (e.g. 1, 2 or 3) substituents, the same substituents as the choice of the R ^5.

In this application, all of C1 to C10 may be C1, C2, C3, C4, C5, C6, C7, C8, C9 or C10.

The C3 to C10 can all be C3, C4, C5, C6, C7, C8, C9 or C10.

The C2 to C10 can all be C2, C3, C4, C5, C6, C7, C8, C9 or C10.

The C6 to C20 can all be C6, C10, C12, C13, C14, C16, C18, C19, C20, etc.

The C3 to C20 can all be C3, C4, C5, C6, C10, C12, C13, C14, C16, C18, C19, C20, etc.

Preferably, the azatricyclic compound has a structure as shown in formula IA:

In formula IA, R ¹ and R ⁴ each independently have the same defined range as in formula I.

Specifically, in formula IA, R ^{1 is} selected from H, halogen, C1-C10 linear or branched alkyl, C3-C10 cycloalkyl, C2-C10 heterocycloalkyl, C6-C20 aryl or C3-C20 Heteroaryl

R ^{4 is} selected from H, C1～C10 straight or branched chain alkyl, C3～C10 cycloalkyl, C2～C10 heterocycloalkyl, C6～C20 aryl, C3～C20 heteroaryl, COR ^a , CONR ^b R ^c , CO ₂ R ^d , SO ₂ R ^a or SO ₂ NR ^b R ^c ; the linear or branched alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are unsubstituted or substituted by 1 ～3 R ^4a substitutions;

R ^{4a is} selected from D, halogen, cyano, OR ^a1 , SR ^a1 , NR ^b1 R ^c1 , COR ^a1 , CONR ^b1 R ^c1 , CO ₂ R ^d1 , SO ₂ R ^a1 , SO ₂ NR ^b1 R ^c1 , C1～C10 Straight or branched chain alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C2-C10 heterocycloalkyl, C6-C20 aryl or C3-C20 heteroaryl; Straight or branched chain alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl are unsubstituted or substituted with 1 to 3 R ^4b ;

R ^a , R ^b , R ^c , ^Rd , R ^a1 , R ^b1 , R ^c1 , R ^d1 are each independently selected from H, C1～C10 linear or branched alkyl, C2～C10 alkenyl, C2～C10 Alkynyl, C3-C10 cycloalkyl, C2-C10 heterocycloalkyl, C6-C20 aryl or C3-C20 heteroaryl; the straight or branched chain alkyl, alkenyl, alkynyl, cycloalkyl , Heterocycloalkyl, aryl, and heteroaryl are unsubstituted or substituted with 1 to 4 R ⁵ ;

R ^4b and R ⁵ are each independently selected from D, halogen, cyano, hydroxyl, unsubstituted or halogenated C1-C10 linear or branched alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 Cycloalkyl, C2～C10 heterocycloalkyl, C6～C20 aryl, C3～C20 heteroaryl, OR ^a2 , SR ^a2 , NR ^b2 R ^c2 , COR ^a2 , CONR ^b2 R ^c2 , CO ₂ R ^d2 , SO ₂ R ^a2 , SO ₂ NR ^b2 R ^c2 , NR ^b2 COR ^d2 , NR ^a2 CONR ^b2 R ^c2 , NR ^b2 SO ₂ R ^d2 , NR ^b2 SO ₂ NR ^b2 R ^c2 or SOR ^a2 ; and

R ^a2 , R ^b2 , R ^c2 , and R ^d2 are each independently selected from H, C1-C10 linear or branched alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C2- C10 heterocycloalkyl, C6-C20 aryl or C3-C20 heteroaryl.

Preferably, the R ^{1 is} selected from H or halogen.

Preferably, the azatricyclic compound has a structure as shown in formula IB:

In formula IB, R ¹ and R ⁴ each independently have the same defined range as in formula I.

Specifically, in formula IB, R ^{1 is} selected from H, halogen, C1-C10 linear or branched alkyl, C3-C10 cycloalkyl, C2-C10 heterocycloalkyl, C6-C20 aryl or C3-C20 Heteroaryl

R ^{4 is} selected from H, C1～C10 straight or branched chain alkyl, C3～C10 cycloalkyl, C2～C10 heterocycloalkyl, C6～C20 aryl, C3～C20 heteroaryl, COR ^a , CONR ^b R ^c , CO ₂ R ^d , SO ₂ R ^a or SO ₂ NR ^b R ^c ; the linear or branched alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are unsubstituted or substituted by 1 ～3 R ^4a substitutions;

R ^{4a is} selected from D, halogen, cyano, OR ^a1 , SR ^a1 , NR ^b1 R ^c1 , COR ^a1 , CONR ^b1 R ^c1 , CO ₂ R ^d1 , SO ₂ R ^a1 , SO ₂ NR ^b1 R ^c1 , C1～C10 Straight or branched chain alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C2-C10 heterocycloalkyl, C6-C20 aryl or C3-C20 heteroaryl; Straight or branched chain alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl are unsubstituted or substituted with 1 to 3 R ^4b ;

R ^a , R ^b , R ^c , ^Rd , R ^a1 , R ^b1 , R ^c1 , R ^d1 are each independently selected from H, C1～C10 linear or branched alkyl, C2～C10 alkenyl, C2～C10 Alkynyl, C3-C10 cycloalkyl, C2-C10 heterocycloalkyl, C6-C20 aryl or C3-C20 heteroaryl; the straight or branched chain alkyl, alkenyl, alkynyl, cycloalkyl , Heterocycloalkyl, aryl, and heteroaryl are unsubstituted or substituted with 1 to 4 R ⁵ ;

R ^4b and R ⁵ are each independently selected from D, halogen, cyano, hydroxyl, unsubstituted or halogenated C1～C10 linear or branched alkyl, C2～C10 alkenyl, C2～C10 alkynyl, C3～C10 Cycloalkyl, C2～C10 heterocycloalkyl, C6～C20 aryl, C3～C20 heteroaryl, OR ^a2 , SR ^a2 , NR ^b2 R ^c2 , COR ^a2 , CONR ^b2 R ^c2 , CO ₂ R ^d2 , SO ₂ R ^a2 , SO ₂ NR ^b2 R ^c2 , NR ^b2 COR ^d2 , NR ^a2 CONR ^b2 R ^c2 , NR ^b2 SO ₂ R ^d2 , NR ^b2 SO ₂ NR ^b2 R ^c2 or SOR ^a2 ; and

R ^a2 , R ^b2 , R ^c2 , and R ^d2 are each independently selected from H, C1-C10 linear or branched alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C2- C10 heterocycloalkyl, C6-C20 aryl or C3-C20 heteroaryl.

Preferably, the R ^{1 is} selected from H or halogen.

Preferably, the R ^{4 is} selected from C1 to C10 (e.g., C1, C2, C3, C4, C5, C6, C7, C8, C9 or C10) linear or branched alkyl, C3 to C10 (e.g. C3, C4 , C5, C6, C7, C8, C9 or C10) cycloalkyl, C2-C10 (e.g. C2, C3, C4, C5, C6, C7, C8, C9 or C10) heterocycloalkyl, COR ^a or CONR ^b R ^c ; The linear or branched alkyl, cycloalkyl, and heterocycloalkyl are unsubstituted or substituted with 1 to 3 (for example, 1, 2, or 3) R ^4a .

Preferably, the R ^{4a is} selected from D, halogen, cyano, OR ^a1 , C1～C10 (for example, C1, C2, C3, C4, C5, C6, C7, C8, C9 or C10) linear or branched alkanes Group, C3-C10 (e.g. C3, C4, C5, C6, C7, C8, C9 or C10) cycloalkyl, C2-C10 (e.g. C2, C3, C4, C5, C6, C7, C8, C9 or C10) Heterocycloalkyl, C6-C20 (e.g. C6, C10, C12, C13, C14, C16, C18, C19 or C20, etc.) aryl or C3-C20 (e.g. C3, C4, C5, C6, C10, C12, C13) , C14, C16, C18, C19 or C20, etc.) heteroaryl; the straight or branched chain alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl is unsubstituted or is 1 to 3 ( For example, 1, 2 or 3) R ^4b substitution.

Preferably, the R ^a , R ^b , R ^c , ^Rd , R ^a1 , R ^b1 , R ^c1 , and R ^d1 are each independently selected from H, C1 to C10 (e.g., C1, C2, C3, C4, C5, C6, C7, C8, C9 or C10) straight or branched chain alkyl, C3-C10 (e.g. C3, C4, C5, C6, C7, C8, C9 or C10) cycloalkyl, C2-C10 (e.g. C2, C3, C4, C5, C6, C7, C8, C9 or C10) heterocycloalkyl, C6～C20 (e.g. C6, C10, C12, C13, C14, C16, C18, C19 or C20, etc.) aryl or C3～ C20 (such as C3, C4, C5, C6, C10, C12, C13, C14, C16, C18, C19 or C20, etc.) heteroaryl; the straight or branched chain alkyl, cycloalkyl, heterocycloalkyl , Aryl, and heteroaryl are unsubstituted or substituted with 1 to 4 (for example, 1, 2, 3, or 4) R ⁵ .

Preferably, the R ^4b and R ⁵ are each independently selected from D, halogen, cyano, hydroxyl, unsubstituted or halogenated C1～C10 (e.g. C1, C2, C3, C4, C5, C6, C7, C8, C9 or C10) straight or branched chain alkyl, C3-C10 (e.g. C3, C4, C5, C6, C7, C8, C9 or C10) cycloalkyl or C2-C10 (e.g. C2, C3, C4, C5, C6, C7, C8, C9 or C10) heterocycloalkyl.

Preferably, the tricyclic compound includes any one of the following compounds:

On the other hand, the present application provides a stereoisomer, geometric isomer, tautomer of the above-mentioned tricyclic compound, or a pharmaceutically acceptable salt thereof.

In another aspect, the present application provides a pharmaceutical composition comprising an active ingredient and at least one pharmaceutically acceptable carrier or excipient, the active ingredient comprising the tricyclic compound as described above, and/or, The above-mentioned stereoisomers, geometric isomers, tautomers or pharmaceutically acceptable salts thereof.

On the other hand, the present application provides a tricyclic compound as described above, stereoisomers, geometric isomers, tautomers or pharmaceutically acceptable salts thereof as described above, and drugs as described above Application of the composition in preparing a medicine for inhibiting RET kinase.

Preferably, the RET kinase includes RET mutant kinase and RET fusion protein kinase.

On the other hand, the present application provides a tricyclic compound as described above, stereoisomers, geometric isomers, tautomers or pharmaceutically acceptable salts thereof as described above, and drugs as described above Application of the composition in the preparation of a medicine for treating diseases mediated by RET kinase.

Preferably, the disease is cancer.

Preferably, the cancer includes breast cancer, small cell lung cancer, non-small cell lung cancer, bronchoalveolar cancer, prostate cancer, bile duct cancer, bone cancer, bladder cancer, head and neck cancer, kidney cancer, liver cancer, gastrointestinal tissue cancer, esophagus Cancer, ovarian cancer, pancreatic cancer, skin cancer, testicular cancer, thyroid cancer, uterine cancer, cervical cancer, vaginal cancer, leukemia, multiple myeloma or lymphoma.

Compared with the prior art, this application has the following beneficial effects:

The present application provides a novel tricyclic compound of chemical structure, which has the effect of kinase activity of RET significant inhibition, half RET kinase inhibition IC ₅₀ concentrations as low as 0.53 ~ 2.1nM, and can effectively inhibit the proliferation of cancer cells, can be As RET kinase inhibitors and preparation of drugs for the treatment of RET kinase-mediated diseases, it has a good therapeutic effect in RET kinase-mediated cancers and other diseases, and has broad application prospects.

detailed description

The technical solution of the present application will be further explained through specific implementations below. Those skilled in the art should understand that the described embodiments are only to help understand the application, and should not be regarded as specific limitations to the application.

The term "halo" or "halogen" in this application includes fluorine, chlorine, bromine, and iodine.

The term "straight or branched chain alkyl" refers to a straight or branched saturated hydrocarbon group. Examples of alkyl groups include methyl (Me), ethyl (Et), propyl (e.g., n-propyl, isopropyl), butyl (e.g., n-butyl, isobutyl, tert-butyl), pentyl ( Such as n-pentyl, isopentyl, neopentyl), hexyl (e.g. n-hexyl, 2-hexyl, 3-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl , 3-ethylpentyl-1 etc.), heptyl (e.g. n-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, 2-methylhexyl, 3-methylhexyl, 2, 2-dimethylpentyl, 3,3-dimethylpentyl, 3-ethylpentyl-1, etc.), octyl (e.g. 1-octyl, 2-octyl, 2-ethylhexyl, etc.) , Nonyl (such as 1-nonyl), decyl (such as n-decyl, etc.), and similar groups. More preferably, it refers to a linear or branched alkyl group having 1, 2, 3, 4, 5, and 6 carbon atoms. Unless defined to the contrary, all group definitions in this application are as defined herein.

The term "haloalkyl" refers to an alkyl group having one or more halogen substituents. The alkyl group and halo or halogen are as defined above. Examples of haloalkyl groups include CH ₂ F, CHF ₂ , CF ₃ , C ₂ F ₅ , CCl ₃ , and the like.

The term "alkenyl" refers to a hydrocarbyl group having one or more C=C double bonds. Examples of alkenyl groups include vinyl, propenyl, allyl, 1-butenyl, 2-butenyl, 1,3-butadienyl, 1-pentenyl, 2-pentenyl, 1, 3-pentadienyl, 1-hexenyl, 2-hexenyl, etc., and similar groups.

The term "alkynyl" refers to a hydrocarbyl group having one or more C≡C triple bonds. Examples of alkynyl groups include ethynyl, propynyl, propargyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 1-hexynyl, 2-hexynyl Groups, etc., and similar groups.

The term "cycloalkyl" refers to a non-aromatic carbocyclic ring, including cyclized alkyl, cyclized alkenyl, and cyclized alkynyl. Cycloalkyl groups may be monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings) ring systems, including spirocyclic rings. In certain embodiments, cycloalkyl groups can have 3, 4, 5, 6, 7, 8, 9, 10 carbon atoms. The cycloalkyl group may further have 0, 1, 2, or 3 C=C double bonds and/or 0, 1, or 2 C≡C triple bonds. Also included in the definition of cycloalkyl are those moieties that have one or more aromatic rings fused to the cycloalkyl ring (for example, having a shared bond), such as pentane, pentene, hexane, and hexane. Benzo derivatives of alkenes, etc., and similar compounds. The cycloalkyl group having one or more fused aromatic rings may be connected through an aromatic part or a non-aromatic part. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadiene Group, adamantyl group, indenyl group, tetrahydronaphthyl group and similar groups.

The term "heterocycloalkyl" refers to a non-aromatic heterocyclic ring in which one or more of the atoms forming the ring is a heteroatom such as O, N, P, or S. Heterocyclyl groups can include monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings) ring systems as well as spirocyclic rings. Examples of preferred "heterocycloalkyl" include but are not limited to: aziridinyl, azetidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, pyrrolidinyl, oxazolidinyl , Thiazolidinyl, imidazolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, morpholinyl, thiomorpholinyl, piperazinyl, piperidinyl, and similar groups. Also included in the definition of heterocycloalkyl are those moieties that have one or more aromatic rings fused to a non-aromatic heterocycloalkyl ring (for example, with a shared bond), such as 2,3-dihydrobenzene Furanyl, 1,3-benzodioxole, benzo-1,4-dioxanyl, phthalimide, naphthalimide, and similar Group. Heterocycloalkyl groups having one or more fused aromatic rings may be connected through aromatic or non-aromatic moieties.

The term "aryl" refers to monocyclic or polycyclic (for example, having 2, 3, or 4 condensed rings) aromatic hydrocarbons, such as phenyl, naphthyl, anthryl, phenanthryl, indenyl, and the like.

The term "heteroaryl" refers to an aromatic heterocyclic ring having at least one heteroatom ring member such as O, N, or S. Heteroaryl groups include monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings) ring systems. Any N atom that forms a ring in the heterocyclic group can also be oxidized to form an N-oxide. Examples of preferred "heteroaryl groups" include, but are not limited to: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, thienyl, imidazolyl, triazolyl, tetrazolyl, thiazole Group, isothiazolyl, 1,2,4-thiadiazolyl, pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, benzofuranyl, benzothienyl, benzo Thiazolyl, indolyl, indazolyl, quinolinyl, isoquinolinyl, purinyl, carbazolyl, benzimidazolyl, pyrrolopyridyl, pyrrolopyrimidinyl, pyrazolopyridyl, pyrazole Pyrimidine group, and similar groups.

The term "tricyclic compound", as used herein, is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes.

The tricyclic compound of the present application may be asymmetric, for example having one or more stereo centers. Unless otherwise defined, all stereoisomers can be enantiomers and diastereomers. The compounds of the application containing asymmetrically substituted carbon atoms can be separated into optically pure or racemic forms. Optically pure forms can be prepared by resolution of racemates, or by using chiral synthons or chiral reagents.

The tricyclic compounds of the present application may also include tautomeric forms. The new form of tautomers is produced by the exchange of single bonds and adjacent double bonds together with the migration of protons.

The tricyclic compound of the present application may also include all isotopic forms of atoms present in the intermediate or final compound. Isotopes include those atoms that have the same atomic number but different mass numbers. For example, isotopes of hydrogen include deuterium and tritium.

The application also includes pharmaceutically acceptable salts of the tricyclic compounds. "Pharmaceutically acceptable salt" refers to a derivative of a compound in which the parent compound is converted into its salt form by the presence of a base part, or the parent compound is converted to it by the presence of an acid part Derivatives of modified compounds in the salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, salts of inorganic or organic acids with basic groups (such as ammonia), or salts with inorganic or organic bases of acidic groups (such as carboxylic acids). The pharmaceutically acceptable salts of the present application can be synthesized from the parent compounds of Formula I, Formula IA, and Formula IB by reacting the free base forms of these compounds with 1 to 4 equivalents of an appropriate acid in a solvent system. Suitable salts are listed in Remington’s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, 1418 and Journal of Pharmaceutical Science, 66, 2, 1977.

The tricyclic compounds of the present application and their pharmaceutically acceptable salts also include solvate forms or hydrate forms. Generally speaking, the solvate form or the hydrate form and the unsolvated form or the non-hydrate form are equivalent, and both are included in the scope of the present application. Some compounds of the present application may exist in multiple crystalline forms or amorphous forms. In general, all physical forms of the compound are included in the scope of this application.

The application also includes prodrugs of the tricyclic compounds. A prodrug is a pharmacological substance (i.e., drug) derived from the parent drug. Once administered, the prodrug is metabolized in the body to become the parent drug. Prodrugs can be prepared by substituting one or more functional groups present in the compound. The preparation and use of prodrugs can be found in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems", Vol. 14 of the AACS Symposium Series and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Found in Pharmaceutical Association and Pergamon Press, 1987.

In a specific embodiment, the tricyclic compound includes the following compounds:

(4-Amino-9,9-dimethyl-5-(1H-pyrrole[2,3-b]pyridin-2-yl)-8,9-dihydropyrazine[1',2':1, 5]pyrrole[2,3-d]pyrimidine-7(6H)-yl)(tetrahydro-2H-pyran-4-yl)methanone

(4-Amino-5-(3-chloro-1H-pyrrole[2,3-b]pyridin-2-yl)-9,9-dimethyl-8,9-dihydropyrazine[1',2 ':1,5]pyrrole[2,3-d]pyrimidine-7(6H)-yl)(tetrahydro-2H-pyran-4-yl)methanone

5-(3-Chloro-1H-pyrrole[2,3-b]pyridin-2-yl)-9,9-dimethyl-7-((tetrahydro-2H-pyran-4-yl)methyl )-6,7,8,9-Tetrahydropyrazine[1',2':1,5]pyrrole[2,3-d]pyrimidin-4-amine

(4'-Amino-5'-(1H-pyrrole[2,3-b]pyridin-2-yl)-6'H-spiro[cyclopropane-1,9'-pyrazine[1',2': 1,5]pyrrole[2,3-d]pyrimidine]-7'(8'H)-yl)(tetrahydro-2H-pyran-4-yl)methanone

(4'-Amino-5'-(3-chloro-1H-pyrrole[2,3-b]pyridin-2-yl)-6'H-spiro[cyclopropane-1,9'-pyrazine[1' ,2':1,5]pyrrole[2,3-d]pyrimidine]-7'(8'H)-yl)(tetrahydro-2H-pyran-4-yl)methanone

5-(3-Chloro-1H-pyrrole[2,3-b]pyridin-2-yl)-7-(2-methoxyethyl)-9,9-dimethyl-6,7,8, 9-tetrahydropyrazine[1',2':1,5]pyrrole[2,3-d]pyrimidin-4-amine

(4-Amino-5-(3-chloro-1H-pyrrole[2,3-b]pyridin-2-yl)-9,9-dimethyl-N-(tetrahydro-2H-pyran-4- Yl)-8,9-dihydropyrazine[1',2':1,5]pyrrole[2,3-d]pyrimidine-7(6H)carboxamide

(4-Amino-9,9-dimethyl-5-(1H-pyrrole[2,3-b]pyridin-2-yl)-8,9-dihydropyrazine[1',2':1, 5]pyrrole[2,3-d]pyrimidine-7(6H)-yl)(2-(trifluoromethyl)pyridin-4-yl)methanone

(4-Amino-5-(3-chloro-1H-pyrrole[2,3-b]pyridin-2-yl)-9,9-dimethyl-8,9-dihydropyrazine[1',2 ':1,5]pyrrole[2,3-d]pyrimidine-7(6H)-yl)(2-(trifluoromethyl)pyridin-4-yl)methanone

5-(3-Chloro-1H-pyrrole[2,3-b]pyridin-2-yl)-9,9-dimethyl-7-((2-(trifluoromethyl)pyridin-4-yl) Methyl)-6,7,8,9-tetrahydropyrazine[1',2':1,5]pyrrole[2,3-d]pyrimidin-4-amine

(S)-1-(4-Amino-9,9-dimethyl-5-(1H-pyrrole[2,3-b]pyridin-2-yl)-8,9-dihydropyrazine[1' ,2':1,5]pyrrole[2,3-d]pyrimidin-7(6H)-yl)-2-hydroxypropan-1-one

(S)-1-(4-Amino-5-(3-chloro-1H-pyrrole[2,3-b]pyridin-2-yl)-9,9-dimethyl-8,9-dihydropyridine Oxazine[1',2':1,5]pyrrole[2,3-d]pyrimidin-7(6H)-yl)-2-hydroxypropan-1-one

(S)-1-(4-Amino-5-(3-chloro-1H-pyrrole[2,3-b]pyridin-2-yl)-9,9-dimethyl-8,9-dihydropyridine Oxazine[1',2':1,5]pyrrole[2,3-d]pyrimidine-7(6H)-yl)propan-2-ol

(R)-1-(4-Amino-9,9-dimethyl-5-(1H-pyrrole[2,3-b]pyridin-2-yl)-8,9-dihydropyrazine[1' ,2':1,5]pyrrole[2,3-d]pyrimidin-7(6H)-yl)-2-hydroxypropan-1-one

(R)-1-(4-Amino-5-(3-chloro-1H-pyrrole[2,3-b]pyridin-2-yl)-9,9-dimethyl-8,9-dihydropyridine Oxazine[1',2':1,5]pyrrole[2,3-d]pyrimidin-7(6H)-yl)-2-hydroxypropan-1-one

(R)-1-(4-Amino-5-(3-chloro-1H-pyrrole[2,3-b]pyridin-2-yl)-9,9-dimethyl-8,9-dihydropyridine Oxazine[1',2':1,5]pyrrole[2,3-d]pyrimidine-7(6H)-yl)propan-2-ol

(R)-(4-Amino-5-(3-chloro-1H-pyrrole[2,3-b]pyridin-2-yl)-9,9-dimethyl-8,9-dihydropyrazine[ 1',2':1,5]pyrrole[2,3-d]pyrimidin-7(6H)-yl)(tetrahydrofuran-2-yl)methanone

(R)-5-(3-chloro-1H-pyrrole[2,3-b]pyridin-2-yl)-9,9-dimethyl-7-((tetrahydrofuran-2-yl)methyl)- 6,7,8,9-Tetrahydropyrazine[1',2':1,5]pyrrole[2,3-d]pyrimidin-4-amine

(S)-(4-Amino-5-(3-chloro-1H-pyrrole[2,3-b]pyridin-2-yl)-9,9-dimethyl-8,9-dihydropyrazine[ 1',2':1,5]pyrrole[2,3-d]pyrimidin-7(6H)-yl)(tetrahydrofuran-2-yl)methanone

(S)-5-(3-Chloro-1H-pyrrole[2,3-b]pyridin-2-yl)-9,9-dimethyl-7-((tetrahydrofuran-2-yl)methyl)- 6,7,8,9-Tetrahydropyrazine[1',2':1,5]pyrrole[2,3-d]pyrimidin-4-amine

1-(4-Amino-5-(3-chloro-1H-pyrrole[2,3-b]pyridin-2-yl)-9,9-dimethyl-8,9-dihydropyrazine[1' ,2':1,5]pyrrole[2,3-d]pyrimidin-7(6H)-yl)-2-hydroxyethane-1-one

2-(4-Amino-5-(3-chloro-1H-pyrrole[2,3-b]pyridin-2-yl)-9,9-dimethyl-8,9-dihydropyrazine[1' ,2':1,5]pyrrole[2,3-d]pyrimidine-7(6H)-yl)ethane-1-ol

1-(4-Amino-9,9-dimethyl-5-(1H-pyrrole[2,3-b]pyridin-2-yl)-8,9-dihydropyrazine[1',2': 1,5]pyrrole[2,3-d]pyrimidine-7(6H)-yl)ethane-1-one

1-(4-Amino-5-(3-chloro-1H-pyrrole[2,3-b]pyridin-2-yl)-9,9-dimethyl-8,9-dihydropyrazine[1' ,2':1,5]pyrrole[2,3-d]pyrimidin-7(6H)-yl)-2-ethane-1-one

1-(4-Amino-5-(3-bromo-1H-pyrrole[2,3-b]pyridin-2-yl)-9,9-dimethyl-8,9-dihydropyrazine[1' ,2':1,5]pyrrole[2,3-d]pyrimidin-7(6H)-yl)-2-ethane-1-one

(4-Amino-9,9-dimethyl-5-(1H-pyrrole[2,3-b]pyridin-2-yl)-8,9-dihydropyrazine[1',2':1, 5]pyrrole[2,3-d]pyrimidin-7(6H)-yl)(2-methylpyridin-4-yl)methanone

(4-Amino-5-(3-chloro-1H-pyrrole[2,3-b]pyridin-2-yl)-9,9-dimethyl-8,9-dihydropyrazine[1',2 ':1,5]pyrrole[2,3-d]pyrimidin-7(6H)-yl)(2-methylpyridin-4-yl)methanone

(S)-1-(4-Amino-5-(3-chloro-1H-pyrrole[2,3-b]pyridin-2-yl)-9,9-dimethyl-8,9-dihydropyridine Oxazine[1',2':1,5]pyrrole[2,3-d]pyrimidin-7(6H)-yl)-2-morpholinopropan-1-one

(R)-1-(4-Amino-5-(3-chloro-1H-pyrrole[2,3-b]pyridin-2-yl)-9,9-dimethyl-8,9-dihydropyridine Oxazine[1',2':1,5]pyrrole[2,3-d]pyrimidin-7(6H)-yl)-2-morpholinopropan-1-one

1-(4'-Amino-5'-(1H-pyrrole[2,3-b]pyridin-2-yl)-6'H-spiro[cyclopropane-1,9'-pyrazine[1',2 ':1,5]pyrrole[2,3-d]pyrimidine]-7'(8'H)-yl)ethane-1-one

1-(4'-amino-5'-(3-chloro-1H-pyrrole[2,3-b]pyridin-2-yl)-6'H-spiro[cyclopropane-1,9'-pyrazine[ 1',2':1,5]pyrrole[2,3-d]pyrimidine]-7'(8'H)-yl)ethane-1-one

1-(4'-amino-5'-(3-chloro-1H-pyrrole[2,3-b]pyridin-2-yl)-6'H-spiro[cyclopropane-1,9'-pyrazine[ 1',2':1,5]pyrrole[2,3-d]pyrimidine]-7'(8'H)-yl)-2-methylpropan-1-one

(S)-1-(4'-amino-5'-(3-chloro-1H-pyrrole[2,3-b]pyridin-2-yl)-6'H-spiro[cyclopropane-1,9' -Pyrazine[1',2':1,5]pyrrole[2,3-d]pyrimidine]-7'(8'H)-yl)-2-hydroxypropan-1-one

(R)-1-(4'-amino-5'-(3-chloro-1H-pyrrole[2,3-b]pyridin-2-yl)-6'H-spiro[cyclopropane-1,9' -Pyrazine[1',2':1,5]pyrrole[2,3-d]pyrimidine]-7'(8'H)-yl)-2-hydroxypropan-1-one

(4-Amino-5-(3-chloro-1H-pyrrole[2,3-b]pyridin-2-yl)-9,9-dimethyl-N-(2,2,2-trifluoroethyl )-8,9-Dihydropyrazine[1',2':1,5]pyrrole[2,3-d]pyrimidine-7(6H)carboxamide

4'-amino-5'-(3-chloro-1H-pyrrole[2,3-b]pyridin-2-yl)-N-(2,2,2-trifluoroethyl)-6'H-spiro [Cyclopropane-1,9'-pyrazine[1',2':1,5]pyrrole[2,3-d]pyrimidine]-7'(8'H)formamide

4-amino-5-(3-chloro-1H-pyrrole[2,3-b]pyridin-2-yl)-9,9-dimethyl-N-(1-methyl-1H-pyrazole-4 -Yl)-8,9-dihydropyrazine[1',2':1,5]pyrrole[2,3-d]pyrimidine-7(6H)carboxamide

4-amino-5-(3-chloro-1H-pyrrole[2,3-b]pyridin-2-yl)-N-cyclopropyl-9,9-dimethyl-8,9-dihydropyrazine [1',2':1,5]pyrrole[2,3-d]pyrimidine-7(6H)formamide

4'-Amino-5'-(3-chloro-1H-pyrrole[2,3-b]pyridin-2-yl)-N-cyclopropyl-6'H-spiro[cyclopropane-1,9'- Pyrazine[1',2':1,5]pyrrole[2,3-d]pyrimidine]-7'(8'H)formamide

4'-Amino-5'-(3-chloro-1H-pyrrole[2,3-b]pyridin-2-yl)-N-(1-methyl-1H-pyrazol-4-yl)-6' H-spiro[cyclopropane-1,9'-pyrazine[1',2':1,5]pyrrole[2,3-d]pyrimidine]-7'(8'H)formamide

1-(4-Amino-5-(3-chloro-1H-pyrrole[2,3-b]pyridin-2-yl)-9,9-dimethyl-8,9-dihydropyrazine[1' ,2':1,5]pyrrole[2,3-d]pyrimidin-7(6H)-yl)-2-morpholinylethane-1-one

5-(3-Chloro-1H-pyrrole[2,3-b]pyridin-2-yl)-9,9-dimethyl-7-(2-morpholinoethyl)-6,7,8, 9-Tetrahydropyrazine[1',2':1,5]pyrrole[2,3-d]pyrimidin-4-amine

4-Amino-5-(3-chloro-1H-pyrrole[2,3-b]pyridin-2-yl)-9,9-dimethyl-N-(2-morpholinoethyl)-8, 9-Dihydropyrazine[1',2':1,5]pyrrole[2,3-d]pyrimidine-7(6H)carboxamide

(4-Amino-5-(3-chloro-1H-pyrrole[2,3-b]pyridin-2-yl)-9,9-dimethyl-8,9-dihydropyrazine[1',2 ':1,5]pyrrole[2,3-d]pyrimidin-7(6H)-yl)(cyclopropyl)methanone

(4-Amino-5-(3-chloro-1H-pyrrole[2,3-b]pyridin-2-yl)-9,9-dimethyl-8,9-dihydropyrazine[1',2 ':1,5]pyrrole[2,3-d]pyrimidin-7(6H)-yl)(1-methylpiperidin-4-yl)methanone

(4-Amino-5-(3-chloro-1H-pyrrole[2,3-b]pyridin-2-yl)-9,9-dimethyl-8,9-dihydropyrazine[1',2 ':1,5]pyrrole[2,3-d]pyrimidine-7(6H)-yl)(1-methyl-1H-pyrazol-4-yl)methanone

1-(4-Amino-5-(3-chloro-1H-pyrrole[2,3-b]pyridin-2-yl)-9,9-dimethyl-8,9-dihydropyrazine[1' ,2':1,5]pyrrole[2,3-d]pyrimidin-7(6H)-yl)-2-methylpropan-1-one

(R)-(4-Amino-5-(3-chloro-1H-pyrrole[2,3-b]pyridin-2-yl)-9,9-dimethyl-8,9-dihydropyrazine[ 1',2':1,5]pyrrole[2,3-d]pyrimidin-7(6H)-yl)(1-methylpyrrolidin-3-yl)methanone

(S)-(4-Amino-5-(3-chloro-1H-pyrrole[2,3-b]pyridin-2-yl)-9,9-dimethyl-8,9-dihydropyrazine[ 1',2':1,5]pyrrole[2,3-d]pyrimidin-7(6H)-yl)(1-methylpyrrolidin-3-yl)methanone

4-amino-5-(3-chloro-1H-pyrrole[2,3-b]pyridin-2-yl)-9,9-dimethyl-N-(1-methylpiperidin-4-yl) -8,9-Dihydropyrazine[1',2':1,5]pyrrole[2,3-d]pyrimidine-7(6H)carboxamide

(S)-4-Amino-5-(3-chloro-1H-pyrrole[2,3-b]pyridin-2-yl)-9,9-dimethyl-N-(1-methylpyrrolidine- 3-yl)-8,9-dihydropyrazine[1',2':1,5]pyrrole[2,3-d]pyrimidine-7(6H)carboxamide

(R)-4-Amino-5-(3-chloro-1H-pyrrole[2,3-b]pyridin-2-yl)-9,9-dimethyl-N-(1-methylpyrrolidine- 3-yl)-8,9-dihydropyrazine[1',2':1,5]pyrrole[2,3-d]pyrimidine-7(6H)carboxamide

This application provides a pharmaceutical composition, which is composed of the tricyclic compound or its N-oxide derivative, individual isomers, or a mixture of isomers thereof, and a pharmaceutically acceptable salt and a pharmaceutically acceptable salt. Accepted carrier or excipient composition. The pharmaceutical composition of the present application can be administered by oral administration, parenteral administration (injection administration), spray inhalation, topical administration, rectal administration, nasal cavity administration, vaginal administration, intraperitoneal administration or via The implanted reservoir is administered.

In another aspect of the application, the tricyclic compound and pharmaceutically acceptable salt may be used in combination with one or more other drugs. When combined medication, the tricyclic compound of the present application and the combined medication may play a superimposed or synergistic effect. The drugs used in combination can be small molecule drugs, monomer clone drugs, fusion protein drugs and anti-insensitive DNA drugs.

In a specific embodiment, the tricyclic compound can be obtained by the following preparation route:

In the above preparation route, R ¹ , R ² , R ³ , R ⁴ each independently have the same selection range as in Formula I; Cbz and SEM both represent an amino protecting group; X represents a coupling reaction with -NH- Active groups, such as hydroxyl, halogen, etc.; Y represents an active group capable of substitution reaction, exemplary R ¹ Y includes NCS or NBS, etc.; DIEA is N,N-diisopropylethylamine.

Example 1

(4-Amino-9,9-dimethyl-5-(1H-pyrrole[2,3-b]pyridin-2-yl)-8,9-dihydropyrazine[1',2':1, 5]pyrrole[2,3-d]pyrimidine-7(6H)-yl)(tetrahydro-2H-pyran-4-yl)methanone

Step 1. Synthesis of tert-butyl (2-cyanopropan-2-yl) carbamate

In a 1L round bottom flask, 2-amino-2-methylpropionitrile hydrochloride (25.0 g, 208.3 mmol) was dissolved in tetrahydrofuran (THF, 350 mL) and placed in an ice water bath to cool. _{K 2} CO ₃ (57.5 g, 416.6 mmol) was added to the above system _{and H 2} O was slowly added until K ₂ CO _{3 was} completely dissolved, then Boc anhydride (45.8 g, 210.0 mmol) was added, and the reaction was heated to 50° C. for 16 h. After the reaction was completed, the layers were separated, and the aqueous phase was extracted with ethyl acetate (EtOAc). The ester phase and the THF phase were combined, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. Petroleum ether (200 mL) was added to the obtained residue, placed in an ice-water bath and stirred for 30 min, filtered and dried to obtain 30 g of a white solid product with a yield of 73%. LCMS (ESI): m/z=185 (M+H) ⁺ .

Step 2. Synthesis of tert-butyl (1-amino-2-methylpropan-2-yl) carbamate

In a 1L round-bottom flask, tert-butyl (2-cyanopropan-2-yl) carbamate (30.0 g, 163.0 mmol) was dissolved in THF (500 mL) and placed in an ice-water bath to cool. _{LiAlH 4} (6.2 g, 163.0 mmol) was slowly added to the above system, and the reaction was allowed to rise at room temperature for 16 hours. After the reaction was completed, the above reaction system was placed in an ice water bath to cool, and ice water (50 mL) was slowly dropped into it, and stirred for 30 min. After filtering, the filter residue was washed with THF/MeOH (tetrahydrofuran/methanol=20/1). The filtrate was concentrated to obtain 25 g of oil, which was directly used in the next reaction. LCMS (ESI): m/z=189 (M+H) ⁺ .

Step 3. Synthesis of benzyl (2-tert-butoxycarbonylamino-2-methylpropanyl) carbamate

In a 1L round bottom flask, tert-butyl (1-amino-2-methylpropan-2-yl) carbamate (25.0g, 133.0mmol) was dissolved in CH ₂ Cl ₂ (400 mL), and three Ethylamine (Et ₃ N, 40.3 g, 399.0 mmol) and N-benzyloxycarbonyloxysuccinimide (49.7 g, 199.5 mmol) were reacted at room temperature for 1 h. After the reaction is completed, water is added, the organic phase is washed with water, dried with anhydrous Na ₂ SO ₄ , filtered and concentrated to obtain a solid 38 g, which is directly used in the next reaction. LCMS (ESI): m/z=323 (M+H) ⁺ .

Step 4. Synthesis of benzyl (2-amino-2-methylpropanyl) carbamate

Under ice water bath, dissolve concentrated hydrochloric acid (50mL) in methanol (150mL), and add benzyl (2-tert-butoxycarbonylamino-2-methylpropanyl) carbamate (38.0g, 118.0mmol) at room temperature Reaction for 1h. After the reaction was completed, it was diluted with water, the methanol was removed by a rotary evaporator, and the aqueous phase was extracted with EtOAc. The ester phase was discarded, and the aqueous phase was _{adjusted to basic with Na 2} CO ₃ and extracted with EtOAc. The ester phase was washed with saturated NaCl aqueous solution, dried with anhydrous Na ₂ SO ₄ , filtered and concentrated to obtain 18 g of oil, which was directly used in the next reaction. LCMS (ESI): m/z=223 (M+H) ⁺ .

Step 5. Synthesis of benzyl (2-((6-chloropyrimidin-4-yl)amino)-2-methylpropanyl) carbamate

In a 250mL round bottom flask, add 4,6-dichloropyrimidine (10.0g, 67.6mmol), benzyl (2-amino-2-methylpropanyl) carbamate (18.0g, 81.1mmol), KF (3.9 g, 67.6 mmol), N,N-diisopropylethylamine (DIEA, 17.4 g, 135.2 mmol) and dimethyl sulfoxide (DMSO, 100 mL) were heated to 90° C. to react for 1 h. After the reaction was completed, it was diluted with water and extracted with EtOAc. The ester phase was washed with saturated NaCl aqueous solution, dried with anhydrous Na ₂ SO ₄ , filtered and concentrated. The obtained residue was purified by silica gel column chromatography (volume ratio of petroleum ether PE and EtOAc was 4:1) to obtain 12.5 g of product with a yield of 55%. LCMS (ESI): m/z=335 (M+H) ⁺ .

Step 6. Synthesis of benzyl (2-((6-chloro-5-iodopyrimidin-4-yl)amino)-2-methylpropanyl) carbamate

In a 250 mL round bottom flask, benzyl (2-((6-chloropyrimidin-4-yl)amino)-2-methylpropanyl) carbamate (12.5g, 37.4mmol) was dissolved in glacial acetic acid ( 100mL), placed in an ice water bath to cool. Add N-iodosuccinimide (NIS, 25.2g, 112.2mmol) to the above system, and react at room temperature for 16h. After the reaction was completed, the reaction solution was poured into ice water, and extracted with EtOAc. The ester phase was _{washed with saturated Na 2} SO ₃ aqueous solution, Na ₂ CO ₃ aqueous solution and NaCl aqueous solution in turn, dried with anhydrous Na ₂ SO ₄ , filtered and concentrated to obtain 15.8 g of solid as the product, which was directly used in the next step reaction. LCMS (ESI): m/z=461 (M+H) ⁺ .

Step 7. Synthesis of benzyl (2-((6-chloro-5-(3,3-diethoxyprop-1-yn-1-yl)pyrimidin-4-yl)amino)-2-methylpropane Base) carbamate

In a 250mL round-bottomed flask protected by nitrogen, benzyl(2-((6-chloro-5-iodopyrimidin-4-yl)amino)-2-methylpropanyl)carbamate (15.8g, 34.3 mmol) and 3,3-diethoxyprop-1-yne (13.2 g, 103.0 mmol) were dissolved in THF (60 mL)/acetonitrile (MeCN, 60 mL). Add CuI (190mg, 1.0mmol) and Et ₃ N (10.4g, 103.0mmol) to the above system, stir until CuI is dissolved, and then add 1,1'-bis(diphenylphosphino)ferrocene palladium chloride Pd (dppf) Cl ₂ (1.2g, 1.7mmol), heated to 60°C and reacted for 16h. After the reaction was completed, water was added and extracted with EtOAc. The ester phase was washed with saturated NaCl aqueous solution, dried with anhydrous Na ₂ SO ₄ , filtered and concentrated. The obtained residue was purified by silica gel column chromatography (PE:EtOAc volume ratio 4:1) to obtain 13.2 g of the product with a yield of 84%. LCMS (ESI): m/z=461 (M+H) ⁺ .

Step 8. Synthesis of benzyl (2-(4-chloro-6-(diethoxymethyl)-7H-pyrrole[2,3-d]pyrimidin-7-yl)-2-methylpropanyl)amino Formate

In a 150 mL round bottom flask, add benzyl (2-((6-chloro-5-(3,3-diethoxyprop-1-yn-1-yl)pyrimidin-4-yl)amino)- 2-methylpropane-yl) carbamate _{(13.2g, 28.7mmol), Cs 2} CO 3 (23.4g, 71.8mmol) and MeCN (70mL), the reaction was heated at reflux for 90 deg.] C 2h. After the reaction was completed, it was filtered, and the filter residue was washed with EtOAc. The filtrate was diluted with EtOAc, washed with saturated NaCl aqueous solution, dried with anhydrous Na ₂ SO ₄ , filtered and concentrated to obtain 11.5 g of solid as the product, which was directly used in the next reaction. LCMS (ESI): m/z=461 (M+H) ⁺ .

Step 9. Synthesis of benzyl (2-(5-bromo-4-chloro-6-(diethoxymethyl)-7H-pyrrole[2,3-d]pyrimidin-7-yl)-2-methyl Propyl) carbamate

In a 250mL round bottom flask, benzyl (2-(4-chloro-6-(diethoxymethyl)-7H-pyrrole[2,3-d]pyrimidin-7-yl)-2-methyl Propyl) carbamate (11.5 g, 25.0 mmol) was dissolved in CH ₂ Cl ₂ (100 mL). Add N-bromosuccinimide (NBS, 4.5 g, 25.0 mmol) and glacial acetic acid (0.5 mL) to the above system, and react at room temperature for 1 h. After the reaction was completed, the reaction solution was poured into ice water, and extracted with EtOAc. The ester phase was _{washed with saturated Na 2} SO ₃ aqueous solution, Na ₂ CO ₃ aqueous solution and NaCl aqueous solution in turn, dried with anhydrous Na ₂ SO ₄ , filtered and concentrated to obtain 12.3 g of solid as the product, which was directly used in the next step reaction. LCMS (ESI): m/z=539, 541 (M+H) ⁺ .

Step 10. Synthesis of benzyl (2-(4-amino-5-bromo-6-(diethoxymethyl)-7H-pyrrole[2,3-d]pyrimidin-7-yl)-2-methyl Propyl) carbamate

In a 500mL airtight jar, add benzyl (2-(5-bromo-4-chloro-6-(diethoxymethyl)-7H-pyrrole[2,3-d]pyrimidin-7-yl)- 2-Methylpropanyl) carbamate (12.3g, 22.8mmol), dioxane (Dioxane, 50mL) and ammonia (25%, 300mL) were heated to 120°C to react for 16h. After the reaction was completed, water was added and extracted with EtOAc. The ester phase was washed with saturated NaCl aqueous solution, dried with anhydrous Na ₂ SO ₄ , filtered and concentrated. The obtained residue was purified by silica gel column chromatography (CH ₂ Cl ₂ :MeOH volume ratio 40:1) to obtain 8.6 g of product with a yield of 72%. LCMS (ESI): m/z=520, 522 (M+H) ⁺ .

Step 11. Synthesis of 5-bromo-9,9-dimethyl-8,9-dihydropyrazine[1',2':1,5]pyrrole[2,3-d]pyrimidin-4-amine

Benzyl (2-(4-amino-5-bromo-6-(diethoxymethyl)-7H-pyrrole[2,3-d]pyrimidin-7-yl)-2-methylpropanyl)amino The formate (8.6g, 16.5mmol) was dispersed in HBr (25% solution, 50mL) and reacted at room temperature for 16h. Completion of the reaction, diluted with water, extracted in CH ₂ Cl _2, the organic phase discarded, the aqueous phase Na ₂ CO ₃ aqueous solution was made basic and _{extracted 2} CH Cl, CH ₂ Cl ₂ phase was washed with aqueous NaCl solution, no Water was _{dried with Na 2} SO ₄ , filtered and concentrated to obtain 4.2 g of solid as the product, which was directly used in the next reaction. LCMS (ESI): m/z=294, 296 (M+H) ⁺ .

Step 12. Synthesis of 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole[2,3-b]pyridine

In a 250 mL round bottom flask, 1H-pyrrole [2,3-b]pyridine (11.8 g, 100.0 mmol) was dissolved in THF (100 mL), K ₂ CO ₃ (27.6 g, 200.0 mmol) was added, and the mixture was stirred for 30 min. Drop 2-(trimethylsilyl)ethoxymethyl chloride (SEM-Cl, 20.0g, 120.0mmol) into the above system, and react at room temperature for 16h. After the reaction was completed, it was diluted with water and extracted with EtOAc. The ester phase was washed with saturated NaCl aqueous solution, dried with anhydrous Na ₂ SO ₄ , filtered and concentrated. The obtained residue was purified by silica gel column chromatography (PE:EtOAc volume ratio 20:1) to obtain 19.2 g of product with a yield of 77%. LCMS (ESI): m/z=249 (M+H) ⁺ .

Step 13. Synthesis of (1-((2-(Trimethylsilyl)ethoxy)methyl)-1H-pyrrole[2,3-b]pyridin-2-yl)boronic acid

In a 500mL three-necked round bottom flask with a nitrogen protection and a thermometer, 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole[2,3-b]pyridine (19.2g , 77.4mmol) was dissolved in THF (200mL), placed in a dry ice/acetone bath and cooled to -65°C. Then slowly drop in n-BuLi (n-BuLi, 1.6M, 58mL, 92.8mmol), react for 30min, drop in a THF solution (50mL) of triisopropyl borate (17.5g, 92.8mmol), maintain the temperature and react for 1h . After the reaction was completed, the reaction was carefully _{quenched with saturated aqueous NH 4} Cl, diluted with water, and extracted with EtOAc. The ester phase was washed with saturated NaCl aqueous solution, dried with anhydrous Na ₂ SO ₄ , filtered and concentrated. The obtained residue was dispersed in petroleum ether, stirred for 30 min, filtered, and the filtrate was concentrated to obtain 12.7 g of solid as the product, which was directly used in the next reaction. LCMS (ESI): m/z=293 (M+H) ⁺ .

Step 14. Synthesis of 9,9-dimethyl-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole[2,3-b]pyridine-2- Yl)-8,9-dihydropyrazine[1',2':1,5]pyrrole[2,3-d]pyrimidin-4-amine

In a 50mL round-bottom flask, under the protection of nitrogen, add 5-bromo-9,9-dimethyl-8,9-dihydropyrazine[1',2':1,5]pyrrole[2,3- d]Pyrimidine-4-amine (1.2g, 4.1mmol), (1-((2-(Trimethylsilyl)ethoxy)methyl)-1H-pyrrole[2,3-b]pyridine-2 -Base) boric acid (1.8g, 6.2mmol), Pd(dppf)Cl ₂ (150mg, 0.2mmol), tetra-n-butylammonium fluoride (n-Bu ₄ NF, 104mg, 0.4mmol), Na ₂ CO ₃ ( 869 mg, 8.2 mmol), DMSO (15 mL) and H ₂ O (5 mL), and react at 80° C. for 3 h. After the completion of the reaction, the reaction solution was poured into water and extracted with EtOAc. The ester phase was washed with saturated NaCl solution, dried with anhydrous Na ₂ SO ₄ , filtered and concentrated. The obtained residue was purified by silica gel column chromatography (CH ₂ Cl ₂ :MeOH volume ratio 60:1) to obtain 1.6 g of the product, with a yield of 85%. LCMS (ESI): m/z=462 (M+H) ⁺ .

Step 15. Synthesis of 9,9-dimethyl-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole[2,3-b]pyridine-2- Yl)-6,7,8,9-tetrahydropyrazine[1',2':1,5]pyrrole[2,3-d]pyrimidin-4-amine

In a 50mL round bottom flask, 9,9-dimethyl-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole [2,3-b] Pyridin-2-yl)-8,9-dihydropyrazine[1',2':1,5]pyrrole[2,3-d]pyrimidin-4-amine (1.6g, 3.5mmol) dissolved in CH ₂ Cl ₂ (20 mL)/MeOH (10 mL), CNBH ₃ Na (661 mg, 10.5 mmol) was added, and the reaction was carried out at room temperature for 16 h. After the completion of the reaction, the reaction solution was poured into ice water, stirred for 30 min, and then extracted _{with CH 2} Cl _2. The organic phase was washed with saturated NaCl solution, dried with anhydrous Na ₂ SO ₄ , filtered and concentrated to obtain 1.1 g of solid, which was the product, which was directly used in the next reaction. LCMS (ESI): m/z=464 (M+H) ⁺ .

Step 16. Synthesis of (4-amino-9,9-dimethyl-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole [2,3-b ]Pyridin-2-yl)-8,9-dihydropyrazine[1',2':1,5]pyrrole[2,3-d]pyrimidine-7(6H)-yl)(tetrahydro-2H- Pyran-4-yl)methanone

9,9-Dimethyl-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole[2,3-b]pyridin-2-yl)-6 ,7,8,9-Tetrahydropyrazine[1',2':1,5]pyrrole[2,3-d]pyrimidin-4-amine (150mg, 0.32mmol) dissolved in CH ₂ Cl ₂ (5mL) , Add 4-dimethylaminopyridine (DMAP, 78mg, 0.64mmol), tetrahydropyran-4-carboxylic acid (50mg, 0.38mmol) and 1-ethyl-3(3-dimethylpropylamine) carbodiimide (EDCI, 123mg, 0.64mmol), react at room temperature for 0.5h. After the reaction was completed, water was added and extracted _{with CH 2} Cl _2. The organic phase was washed with saturated NaCl solution, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The obtained residue was purified by silica gel column chromatography (CH ₂ Cl ₂ :MeOH volume ratio 40:1) to obtain 150 mg of product with a yield of 82%. LCMS (ESI): m/z=576 (M+H) ⁺ .

Step 17. Synthesis of (4-amino-9,9-dimethyl-5-(1H-pyrrole[2,3-b]pyridin-2-yl)-8,9-dihydropyrazine[1',2 ':1,5]pyrrole[2,3-d]pyrimidine-7(6H)-yl)(tetrahydro-2H-pyran-4-yl)methanone

In a 50mL round bottom flask, (4-amino-9,9-dimethyl-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole [2 ,3-b]pyridin-2-yl)-8,9-dihydropyrazine[1',2':1,5]pyrrole[2,3-d]pyrimidin-7(6H)-yl)(tetra Hydrogen-2H-pyran-4-yl)methanone (150mg, 0.26mmol) was dissolved in CH ₂ Cl ₂ (5mL), trifluoroacetic acid (2mL) was added, the reaction was carried out at room temperature for 1h, and then concentrated under reduced pressure to remove the solvent and trifluoride Acetic acid. The residue was dissolved in methanol (5 mL), ammonia water (25%, 5 mL) was added, and the reaction was carried out at room temperature for 8 hours. After the reaction was completed, water was added and extracted _{with CH 2} Cl _2. The organic phase was washed with saturated NaCl solution, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The obtained residue was purified by silica gel column chromatography (CH ₂ Cl ₂ :MeOH volume ratio 20:1) to obtain 85 mg of the product, with a yield of 73%. LCMS (ESI): m/z=446 (M+H) ⁺ .

¹ H-NMR (400MHz, CDCl ₃ ): δ 11.82 (s, 1H), 8.15 (s, 1H), 8.06 (d, J = 4.8 Hz, 1H), 7.94 (d, J = 7.7 Hz, 1H) ,7.13(dd,J=8.0,4.8Hz,1H),6.53(s,1H),5.37(s,2H),4.85-4.53(m,3H),3.97-3.71(m,4H),3.45-3.30 (m, 2H), 2.05-1.58 (m, 10H).

Example 2

(4-Amino-5-(3-chloro-1H-pyrrole[2,3-b]pyridin-2-yl)-9,9-dimethyl-8,9-dihydropyrazine[1',2 ':1,5]pyrrole[2,3-d]pyrimidine-7(6H)-yl)(tetrahydro-2H-pyran-4-yl)methanone

In a 50mL round bottom flask, (4-amino-9,9-dimethyl-5-(1H-pyrrole[2,3-b]pyridin-2-yl)-8,9-dihydropyrazine[ 1',2':1,5]pyrrole[2,3-d]pyrimidine-7(6H)-yl)(tetrahydro-2H-pyran-4-yl)methanone (100mg, 0.22mmol) dissolved in CH ₂ Cl ₂ (5 mL), add N-chlorosuccinimide (NCS, 27 mg, 0.20 mmol), and react at room temperature for 10 min. After the reaction was completed, water was added and extracted _{with CH 2} Cl _2. The organic phase was washed with saturated NaCl solution, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The obtained residue was purified by silica gel column chromatography (CH ₂ Cl ₂ :MeOH volume ratio 20:1) to obtain 90 mg of the product with a yield of 85%. LCMS (ESI): m/z=480 (M+H) ⁺ .

¹ H-NMR (400MHz, CDCl ₃ ): δ 11.82 (s, 1H), 8.15 (s, 1H), 8.06 (d, J = 4.8 Hz, 1H), 7.94 (d, J = 7.7 Hz, 1H) ,7.13(dd,J=8.0,4.8Hz,1H),5.37(s,2H),4.85-4.53(m,3H),3.97-3.71(m,4H),3.45-3.30(m,2H),2.05 -1.58(m,10H).

Example 3

5-(3-Chloro-1H-pyrrole[2,3-b]pyridin-2-yl)-9,9-dimethyl-7-((tetrahydro-2H-pyran-4-yl)methyl )-6,7,8,9-Tetrahydropyrazine[1',2':1,5]pyrrole[2,3-d]pyrimidin-4-amine

In a 50mL round bottom flask, (4-amino-5-(3-chloro-1H-pyrrole[2,3-b]pyridin-2-yl)-9,9-dimethyl-8,9-bis Hydropyrazine[1',2':1,5]pyrrole[2,3-d]pyrimidine-7(6H)-yl)(tetrahydro-2H-pyran-4-yl)methanone (50mg, 0.11 mmol) was dissolved in THF (10 mL), boron trifluoride ether (312 mg, 2.2 mmol) and sodium borohydride (83.6 mg, 2.2 mmol) were added, and the mixture was heated to 70° C. to react for 2 h. The reaction system was cooled to room temperature, and 5 mL of 5% hydrochloric acid aqueous solution was carefully dropped to quench the reaction, 10 mL of methanol was added, and the reaction was heated to 70° C. for 2 h. After the reaction was completed, water was added and extracted _{with CH 2} Cl _2. The organic phase was washed with saturated NaCl solution, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The obtained residue was purified by silica gel column chromatography (CH ₂ Cl ₂ :MeOH volume ratio 20:1) to obtain 30 mg of the product, with a yield of 59%. LCMS (ESI): m/z=466 (M+H) ⁺ .

¹ H-NMR (400MHz, CDCl ₃ ): δ 11.82 (s, 1H), 8.15 (s, 1H), 8.06 (d, J = 4.8 Hz, 1H), 7.94 (d, J = 7.7 Hz, 1H) ,7.13(dd,J=8.0,4.8Hz,1H),5.37(s,2H),4.85-4.53(m,3H),3.97-3.71(m,4H),3.45-3.30(m,2H),2.96 -2.61 (m, 2H), 2.05-1.58 (m, 10H).

Example 4

(4'-Amino-5'-(1H-pyrrole[2,3-b]pyridin-2-yl)-6'H-spiro[cyclopropane-1,9'-pyrazine[1',2': 1,5]pyrrole[2,3-d]pyrimidine]-7'(8'H)-yl)(tetrahydro-2H-pyran-4-yl)methanone

Step 1. Synthesis of benzyl ((1-aminocyclopropyl)methyl) carbamate

Using 1-amino-1-cyclopropyl cyanide hydrochloride as the starting material, the above-mentioned target compound was synthesized according to the method in steps 1 to 4 of Example 1. LCMS (ESI): m/z=221 (M+H) ⁺ .

Step 2. Synthesis of 4,6-dichloro-5-iodopyrimidine

Under the protection of nitrogen, add 2,2,6,6-tetramethylpiperidine (8.5g, 60.0mmol) and dry THF (80mL) into a 500mL round-bottomed three-necked flask with a thermometer, and place on dry ice/acetone. Cool to -78°C in the bath. Drop n-BuLi (1.6M, 60mL) into the above system, and slowly raise it to -20°C for 1 hour after the addition is complete. Then, maintaining -20°C, drip ZnCl ₂ (14.0 g, 102.7 mmol) in THF (100 mL) solution, after dripping, it can naturally rise to room temperature and react for 1 h. After the reaction was completed, the solvent was distilled off under reduced pressure, and the remainder was dissolved in fresh THF (80 mL) to prepare solution A.

A solution of 4,6-dichloropyrimidine (6.0 g, 40.5 mmol) in THF (80 mL) was dropped into the resulting solution A, and reacted at room temperature for 1 h. Then the above reaction system was placed in an ice-water bath to cool, and I ₂ (14.0 g, 55.1 mmol) in THF (60 mL) was added dropwise, and the reaction system was raised to room temperature for 16 h. After the reaction was completed, the reaction system was placed in an ice-water bath to cool, diluted with water, and 5% Na ₂ SO ₃ solution was added dropwise until the color faded, and the reaction system was extracted with EtOAc. The ester phase was washed with saturated NaCl solution, dried with anhydrous Na ₂ SO ₄ , filtered and concentrated. The obtained residue was purified by silica gel column chromatography (PE:EtOAc volume ratio 40:1) to obtain 5.6 g of product with a yield of 51%.

Step 3. Synthesis of benzyl ((1-((6-chloro-5-iodopyrimidin-4-yl)amino)cyclopropylmethyl)aminocarbonate

In a 250mL round bottom flask, add 4,6-dichloro-5-iodopyrimidine (10.0g, 36.6mmol), benzyl((1-aminocyclopropyl)methyl)carbamate (9.6g, 43.9mmol), KF (2.1g, 36.6mmol), DIEA (9.4g, 73.2mmol) and DMSO (100mL), heated to 90°C and reacted for 1h. After the reaction was completed, it was diluted with water and extracted with EtOAc. The ester phase was washed with saturated NaCl aqueous solution, dried with anhydrous Na ₂ SO ₄ , filtered and concentrated. The obtained residue was purified by silica gel column chromatography (PE:EtOAc volume ratio 4:1) to obtain 13.2 g of the product, with a yield of 79%. LCMS (ESI): m/z=459 (M+H) ⁺ .

Step 4. Synthesis of 5'-bromo-8'H-spiro[cyclopropane-1,9'-pyrazine[1',2':1,5]pyrrole[2,3-d]pyrimidine]-4'- ammonia

Using benzyl ((1-aminocyclopropyl)methyl) carbamate as a raw material, the above-mentioned target compound was synthesized according to the method in steps 7-11 of Example 1. LCMS (ESI): m/z=292, 294 (M+H) ⁺ .

Step 5. Synthesis of (4'-amino-5'-(1H-pyrrole[2,3-b]pyridin-2-yl)-6'H-spiro[cyclopropane-1,9'-pyrazine[1' ,2':1,5]pyrrole[2,3-d]pyrimidine]-7'(8'H)-yl)(tetrahydro-2H-pyran-4-yl)methanone

Using 5'-bromo-8'H-spiro[cyclopropane-1,9'-pyrazine[1',2':1,5]pyrrole[2,3-d]pyrimidine]-4'-ammonia as raw material , According to the method in step 14-17 of Example 1 to synthesize the above-mentioned target compound. LCMS (ESI): m/z=430 (M+H) ⁺ .

¹ H-NMR (400MHz, CDCl ₃ ): δ 11.82 (s, 1H), 8.15 (s, 1H), 8.06 (d, J = 4.8 Hz, 1H), 7.94 (d, J = 7.7 Hz, 1H) ,7.13(dd,J=8.0,4.8Hz,1H),6.53(s,1H),5.37(s,2H),4.85-4.53(m,3H),3.97-3.71(m,4H),3.45-3.30 (m,2H),2.46-1.58(m,8H).

Example 5

(4'-Amino-5'-(3-chloro-1H-pyrrole[2,3-b]pyridin-2-yl)-6'H-spiro[cyclopropane-1,9'-pyrazine[1' ,2':1,5]pyrrole[2,3-d]pyrimidine]-7'(8'H)-yl)(tetrahydro-2H-pyran-4-yl)methanone

Take (4'-amino-5'-(1H-pyrrole[2,3-b]pyridin-2-yl)-6'H-spiro[cyclopropane-1,9'-pyrazine[1',2':1,5]pyrrole[2,3-d]pyrimidine]-7'(8'H)-yl)(tetrahydro-2H-pyran-4-yl)methanone as the raw material, according to the example 2 Methods Synthesize the above target compounds. LCMS (ESI): m/z=464 (M+H) ⁺ .

¹ H-NMR (400MHz, CDCl ₃ ): δ 11.82 (s, 1H), 8.15 (s, 1H), 8.06 (d, J = 4.8 Hz, 1H), 7.94 (d, J = 7.7 Hz, 1H) ,7.13(dd,J=8.0,4.8Hz,1H),5.37(s,2H),4.85-4.53(m,3H),3.97-3.71(m,4H),3.45-3.30(m,2H),2.46 -1.58(m,8H).

Example 6

5-(3-Chloro-1H-pyrrole[2,3-b]pyridin-2-yl)-7-(2-methoxyethyl)-9,9-dimethyl-6,7,8, 9-Tetrahydropyrazine[1',2':1,5]pyrrole[2,3-d]pyrimidin-4-amine

Step 1. Synthesis of 7-(2-methoxyethyl)-9,9-dimethyl-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H- Pyrrole[2,3-b]pyridin-2-yl)-6,7,8,9-tetrahydropyrazine[1',2':1,5]pyrrole[2,3-d]pyrimidine-4- amine

9,9-Dimethyl-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole[2,3-b]pyridin-2-yl)-6 ,7,8,9-Tetrahydropyrazine[1',2':1,5]pyrrole[2,3-d]pyrimidin-4-amine (300mg, 0.64mmol) dissolved in DMSO (5mL), add K ₂ CO ₃ (177 mg, 1.28 mmol), react at room temperature for 0.5 h, add 2-bromoethyl methyl ether (133 mg, 0.96 mmol), and heat to 70° C. to react for 2 h. After the reaction was completed, water was added and extracted _{with CH 2} Cl _2. The organic phase was washed with saturated NaCl solution, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The obtained residue was purified by silica gel column chromatography (CH ₂ Cl ₂ :MeOH volume ratio 40:1) to obtain 270 mg of the product, with a yield of 81%. LCMS (ESI): m/z=522 (M+H) ⁺ .

Step 2. Synthesis of 5-(3-chloro-1H-pyrrole[2,3-b]pyridin-2-yl)-7-(2-methoxyethyl)-9,9-dimethyl-6, 7,8,9-Tetrahydropyrazine[1',2':1,5]pyrrole[2,3-d]pyrimidin-4-amine

Take 7-(2-methoxyethyl)-9,9-dimethyl-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole [2 ,3-b]pyridin-2-yl)-6,7,8,9-tetrahydropyrazine[1',2':1,5]pyrrole[2,3-d]pyrimidin-4-amine as raw material , According to the method in step 17 of Example 1 and the method in Example 2 in order to synthesize the above-mentioned target compound. LCMS (ESI): m/z=426 (M+H) ⁺ .

¹ H-NMR (400MHz, CDCl ₃ ): δ 11.86 (s, 1H), 8.22 (s, 1H), 8.01 (d, J = 4.8 Hz, 1H), 7.94 (dd, J = 7.9, 1.5 Hz, 1H), 7.12 (dd, J = 7.9, 4.8 Hz, 1H), 5.37 (s, 2H), 3.75 (s, 2H), 3.52 (t, J = 5.5 Hz, 2H), 3.30 (s, 3H), 2.96-2.61 (m, 4H), 1.86 (s, 6H).

Example 7

(4-Amino-5-(3-chloro-1H-pyrrole[2,3-b]pyridin-2-yl)-9,9-dimethyl-N-(tetrahydro-2H-pyran-4- Yl)-8,9-dihydropyrazine[1',2':1,5]pyrrole[2,3-d]pyrimidine-7(6H)carboxamide

Step 1. Synthesis of 4-amino-9,9-dimethyl-N-(tetrahydro-2H-pyran-4-yl)-5-(1-((2-(trimethylsilyl)ethoxy (Yl)methyl)-1H-pyrrole[2,3-b]pyridin-2-yl)-8,9-dihydropyrazine[1',2':1,5]pyrrole[2,3-d] Pyrimidine-7(6H) formamide

In a 50 mL round bottom flask, 4-aminotetrahydropyran (174 mg, 1.7 mmol) was dissolved in dimethylformamide (DMF, 10 mL). Add N',N-carbonyldiimidazole (CDI, 275mg, 1.7mmol) and Et ₃ N (343mg, 3.4mmol) to the above system, react at room temperature for 2h, and then add 9,9-dimethyl-5-(1 -((2-(Trimethylsilyl)ethoxy)methyl)-1H-pyrrole[2,3-b]pyridin-2-yl)-6,7,8,9-tetrahydropyrazine[ 1 ', 2': 1,5] pyrrolo [2,3-d] pyrimidin-4-amine (200mg, 0.43mmol) in CH ₂ Cl ₂ (10mL) was stirred at rt for 8h. After the reaction was completed, water was added and extracted _{with CH 2} Cl _2. The organic phase was washed with saturated NaCl solution, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The obtained residue was purified by silica gel column chromatography (CH ₂ Cl ₂ :MeOH volume ratio 40:1) to obtain 160 mg of the product, with a yield of 63%. LCMS (ESI): m/z=591 (M+H) ⁺ .

Step 2. Synthesis of (4-amino-5-(3-chloro-1H-pyrrole[2,3-b]pyridin-2-yl)-9,9-dimethyl-N-(tetrahydro-2H-pyridine Pyran-4-yl)-8,9-dihydropyrazine[1',2':1,5]pyrrole[2,3-d]pyrimidine-7(6H)carboxamide

Take 4-amino-9,9-dimethyl-N-(tetrahydro-2H-pyran-4-yl)-5-(1-((2-(trimethylsilyl)ethoxy)methyl Yl)-1H-pyrrole[2,3-b]pyridin-2-yl)-8,9-dihydropyrazine[1',2':1,5]pyrrole[2,3-d]pyrimidine-7 (6H) Formamide was used as a raw material, and the above-mentioned target compound was synthesized according to the method in step 17 of Example 1 and the method in Example 2 in sequence. LCMS (ESI): m/z=495 (M+H) ⁺ .

¹ H-NMR (400MHz, CDCl ₃ ): δ 11.82 (s, 1H), 8.15 (s, 1H), 8.06 (d, J = 4.8 Hz, 1H), 7.94 (d, J = 7.7 Hz, 1H) ,7.13(dd,J=8.0,4.8Hz,1H),5.37(s,2H),4.85-4.53(m,3H),3.97-3.71(m,4H),3.57(s,1H),3.45-3.30 (m, 2H), 2.05-1.58 (m, 10H).

Examples 8 to 52 shown in Table 1 below were prepared according to the methods in Examples 1 to 7.

Table 1

Test case 1

The method for testing the inhibitory activity of tricyclic compounds on RET kinase is as follows:

The mobility change assay (MSA) was used to detect the inhibitory activity of the tricyclic compound on kinase RET under Km ATP (IC ₅₀ ). RET kinase was purchased from Carna Company (Cat. No.: 08-159, batch number: 13CBS-0134F), and Kinase Substrate 2 was purchased from GL Biochem (Cat. No.: 112394, batch number: P191104-TL112394).

The compound to be tested was formulated with DMSO to 100 times the final reaction concentration, starting from 1 μM, and successively diluting 10 concentrations at a 3-fold dilution ratio. Then use Echo550 to transfer 0.25μL to a 384-well reaction plate. Use 1x kinase buffer (50mM HEPES, pH=7.5, 0.0015% Brij-35, 10mM MgCl ₂ , 2mM DTT) to prepare a 2.5-fold final concentration of kinase solution, and then add 10μL of 2.5-fold final concentration to each compound well The kinase solution, shake and mix, and incubate at room temperature for 10 minutes. Prepare a mixed solution of 25/15 times the final concentration of ATP and the substrate Kinase Substrate 2 with 1 times the kinase buffer, and add 15 μL of the 25/15 times the final concentration of the ATP and substrate mixed solution to each well (RET kinase The final concentration is 1nM, the final concentration of substrate is 3μM, and the final concentration of ATP is 16μM), shake and mix well and react at room temperature for 60min. Finally, add 30 μL stop solution (100mM HEPES, pH=7.5, 0.0015% Brij-35, 0.2% Coating Reagent#3, 50mM EDTA) to stop the reaction. Use the drug screening platform CaliperEZ Reader II to read the conversion rate data, and then convert the conversion rate into inhibition rate data. According to the inhibition rate data of each concentration, the Logit method was used to calculate the IC _{50 of the} half inhibition concentration. The results are shown in Table 2.

Table 2

Test case 2

The test of tricyclic compounds inhibiting the proliferation of cancer cells is as follows:

Human thyroid cancer cell TT (RET C634W mutant) was used to detect the inhibition of cell proliferation by the tricyclic compound described in this application.

100 μL of F-12K broth (Invitrogen, catalog number: 21127-022) containing 10% fetal bovine serum containing 5000 TT cells (ATCC, catalog number: TCHu-78) was added to a 96-well culture plate (Corning#3903) ), place in a carbon dioxide incubator and cultivate overnight. On the second day, add 0.5μL of the test compound to each well (configure 8 continuous concentration gradients with DMSO, the initial concentration is 1μM, 3 times dilution), set two replicates for each concentration, and set a cell-free well (blank Control) and DMSO wells (solvent control). After the drug was added, the cells were cultured at 37°C and 5% carbon dioxide for 7 days. Finally, 100 μL of CellTiter-Glo reagent (Promega, catalog number: G7571) was added to each well, the luminescence signal was detected with Flex Station3 (Molecular Devices), and the IC ₅₀ value of the compound's inhibition of cell proliferation was calculated with XLfit software. The results are shown in Table 3.

table 3

Example IC ₅₀ (nM) Example IC ₅₀ (nM) Example IC ₅₀ (nM) 1 3.5 19 11 37 5.7 2 4.4 20 8.5 38 1.5 3 16 twenty one 19 39 4.8 4 11 twenty two 12 40 12 5 twenty two twenty three 9.8 41 19 6 twenty three twenty four 7.9 42 12 7 3.5 25 13 43 11 8 9.3 26 6.4 44 2.5 9 10 27 7.5 45 11 10 8.5 28 11 46 5.5 11 12 29 70 47 2.0 12 8.5 30 12 48 8.5 13 9.2 31 15 49 9.5 14 16 32 18 50 7.0 15 15 33 twenty two 51 11 16 5.5 34 15 52 4.0 17 12 35 0.5 cabozantinib 256 18 10 36 1.5 To To

Combining the data in Table 2 and Table 3, it can be seen that the tricyclic compound provided in this application can effectively inhibit the activity of RET kinase, and the IC ₅₀ of the half inhibitory concentration of RET kinase is as low as 0.53 to 2.1 nM, and it can also effectively inhibit the growth of cancer cells. _{Proliferation, the IC 50} value for TT of human thyroid cancer cells is as low as 0.5 ~ 23 nM, and its activity is significantly improved compared to the existing drug cabozantinib.

The applicant declares that this application uses the above-mentioned examples to illustrate the tricyclic compounds, pharmaceutical compositions and applications thereof, but this application is not limited to the above-mentioned examples, which does not mean that this application must rely on the above-mentioned examples for implementation . Those skilled in the art should understand that any improvement to this application, the equivalent replacement of each raw material of the product of this application, the addition of auxiliary components, the selection of specific methods, etc., fall within the scope of protection and disclosure of this application.

Claims (12)

A tricyclic compound having a structure as shown in formula I:

Wherein, R ^{1 is} selected from H, halogen, C1-C10 linear or branched alkyl, C3-C10 cycloalkyl, C2-C10 heterocycloalkyl, C6-C20 aryl or C3-C20 heteroaryl; R ² and R ³ are each independently selected from H, C1-C10 straight or branched chain alkyl, C3-C10 cycloalkyl; said R ² and R ^{3 are} not connected or connected to form a ring through a chemical bond; R ^{4 is} selected from H, C1～C10 straight or branched chain alkyl, C3～C10 cycloalkyl, C2～C10 heterocycloalkyl, C6～C20 aryl, C3～C20 heteroaryl, COR ^a , CONR ^b R ^c , CO ₂ R ^d , SO ₂ R ^a or SO ₂ NR ^b R ^c ; the linear or branched alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are unsubstituted or substituted by 1 ～3 R ^4a substitutions; R ^{4a is} selected from D, halogen, cyano, OR ^a1 , SR ^a1 , NR ^b1 R ^c1 , COR ^a1 , CONR ^b1 R ^c1 , CO ₂ R ^d1 , SO ₂ R ^a1 , SO ₂ NR ^b1 R ^c1 , C1～C10 Straight or branched chain alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C2-C10 heterocycloalkyl, C6-C20 aryl or C3-C20 heteroaryl; Straight or branched chain alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl are unsubstituted or substituted with 1 to 3 R ^4b ; R ^a , R ^b , R ^c , ^Rd , R ^a1 , R ^b1 , R ^c1 , R ^d1 are each independently selected from H, C1～C10 linear or branched alkyl, C2～C10 alkenyl, C2～C10 Alkynyl, C3-C10 cycloalkyl, C2-C10 heterocycloalkyl, C6-C20 aryl or C3-C20 heteroaryl; the straight or branched chain alkyl, alkenyl, alkynyl, cycloalkyl , Heterocycloalkyl, aryl, and heteroaryl are unsubstituted or substituted with 1 to 4 R ⁵ ; R ^4b and R ⁵ are each independently selected from D, halogen, cyano, hydroxyl, unsubstituted or halogenated C1～C10 linear or branched alkyl, C2～C10 alkenyl, C2～C10 alkynyl, C3～C10 Cycloalkyl, C2～C10 heterocycloalkyl, C6～C20 aryl, C3～C20 heteroaryl, OR ^a2 , SR ^a2 , NR ^b2 R ^c2 , COR ^a2 , CONR ^b2 R ^c2 , CO ₂ R ^d2 , SO ₂ R ^a2 , SO ₂ NR ^b2 R ^c2 , NR ^b2 COR ^d2 , NR ^a2 CONR ^b2 R ^c2 , NR ^b2 SO ₂ R ^d2 , NR ^b2 SO ₂ NR ^b2 R ^c2 or SOR ^a2 ; and R ^a2 , R ^b2 , R ^c2 , and R ^d2 are each independently selected from H, C1-C10 linear or branched alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C2- C10 heterocycloalkyl, C6-C20 aryl or C3-C20 heteroaryl. The tricyclic compound according to claim 1, wherein the tricyclic compound has a structure as shown in formula IA:

Wherein, R ¹ and R ⁴ each independently have the same limited range as in Formula I. The tricyclic compound according to claim 2, wherein the R ^{1 is} selected from H or halogen. The tricyclic compound according to claim 1, wherein the tricyclic compound has a structure as shown in formula IB:

Wherein, R ¹ and R ⁴ each independently have the same limited range as in Formula I. The tricyclic compound according to claim 4, wherein the R ^{1 is} selected from H or halogen. The tricyclic compound according to any one of claims 1 to 5, wherein the R ^{4 is} selected from C1 to C10 linear or branched chain alkyl, C3 to C10 cycloalkyl, C2 to C10 heterocycloalkyl, COR ^a or CONR ^b R ^c ; the straight or branched chain alkyl, cycloalkyl, and heterocycloalkyl are unsubstituted or substituted with 1 to 3 R ^4a ; Optionally, the R ^{4a is} selected from D, halogen, cyano, OR ^a1 , C1-C10 linear or branched alkyl, C3-C10 cycloalkyl, C2-C10 heterocycloalkyl, C6-C20 aryl Group or C3～C20 heteroaryl group; the straight or branched chain alkyl group, cycloalkyl group, heterocycloalkyl group, aryl group, heteroaryl group is unsubstituted or substituted with 1 to 3 R ^4b ; Optionally, the R ^a , R ^b , R ^c , ^Rd , R ^a1 , R ^b1 , R ^c1 , and R ^d1 are each independently selected from H, C1-C10 linear or branched alkyl, C3-C10 Cycloalkyl, C2～C10 heterocycloalkyl, C6～C20 aryl or C3～C20 heteroaryl; the straight or branched chain alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl Unsubstituted or substituted by 1 to 4 R ⁵ ; Optionally, the R ^4b and R ⁵ are each independently selected from D, halogen, cyano, hydroxyl, unsubstituted or halogenated C1-C10 linear or branched alkyl, C3-C10 cycloalkyl or C2- C10 heterocycloalkyl. The tricyclic compound according to any one of claims 1 to 6, wherein the tricyclic compound includes any one of the following compounds:

A stereoisomer, geometric isomer, tautomer of the tricyclic compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprising an active ingredient and at least one pharmaceutical carrier or excipient, the active ingredient comprising the tricyclic compound according to any one of claims 1 to 7, and/or as claimed 8 said stereoisomers, geometric isomers, tautomers or pharmaceutically acceptable salts thereof. A tricyclic compound as claimed in any one of claims 1 to 7, a stereoisomer, geometric isomer, tautomer as claimed in claim 8 or a pharmaceutically acceptable salt thereof or as The use of the pharmaceutical composition of claim 9 in the preparation of a medicament for inhibiting RET kinase. A tricyclic compound as claimed in any one of claims 1 to 7, a stereoisomer, geometric isomer, tautomer as claimed in claim 8 or a pharmaceutically acceptable salt thereof or as Use of the pharmaceutical composition of claim 9 in the preparation of a medicament for the treatment of diseases mediated by RET kinase; Optionally, the RET kinase includes RET mutant kinase and RET fusion protein kinase. The use according to claim 11, wherein the disease is cancer; Optionally, the cancer includes breast cancer, small cell lung cancer, non-small cell lung cancer, bronchoalveolar cancer, prostate cancer, bile duct cancer, bone cancer, bladder cancer, head and neck cancer, kidney cancer, liver cancer, gastrointestinal tissue cancer, Esophageal cancer, ovarian cancer, pancreatic cancer, skin cancer, testicular cancer, thyroid cancer, uterine cancer, cervical cancer, vaginal cancer, leukemia, multiple myeloma or lymphoma.