CN117362304A

CN117362304A - Carboxamide substituted hetero tricyclic derivative, preparation method and application thereof

Info

Publication number: CN117362304A
Application number: CN202310816922.9A
Authority: CN
Inventors: 刘刚; 夏尚华; 李剑; 王英; 曾宏; 巩晓明; 潘德思; 鲁先平
Original assignee: Chengdu Weixin Pharmaceutical Co ltd; Shenzhen Chipscreen Biosciences Co Ltd
Current assignee: Chengdu Weixin Pharmaceutical Co ltd; Shenzhen Chipscreen Biosciences Co Ltd
Priority date: 2022-07-07
Filing date: 2023-07-05
Publication date: 2024-01-09
Also published as: WO2024008113A1

Abstract

The invention relates to a carboxamide substituted hetero tricyclic derivative shown in a formula (I), a preparation method and application thereof. The invention also relates to pharmaceutical compositions comprising said compounds as active ingredient and to the use of said compounds or pharmaceutical compositions for the treatment and/or prevention of related diseases mediated by PRMT 5.

Description

Carboxamide substituted hetero tricyclic derivative, preparation method and application thereof

Technical Field

The invention relates to the field of pharmaceutical chemistry, in particular to a formamide substituted hetero tricyclic derivative, a preparation method and application thereof.

Background

Epigenetic regulated gene expression plays an important biological role in protein maturation and cell differentiation and plays an important role in many human diseases. Arginine methyltransferase (PRMT) catalyzed arginine guanidino methylation is a common post-translational modification of eukaryotic cells, affecting various biological processes such as Cell signaling, gene transcription, mRNA translation, DNA recombination and repair (Cell mol. Life Sci.2015.72 (11): 2041-2059).

PRMT5 is one of the members of the PRMT family, whose mediated methylation plays an important role in maintaining normal intracellular homeostasis. However, more and more studies have shown that abnormal expression of PRMT5 is associated with multiple tumorigenesis, it is overexpressed in multiple tumors, and the mechanism of occurrence varies among tumors (Cell mol. Life Sci.2015.72 (11): 2041-2059).

Homozygous deletion of the oncogene is a key driver of tumorigenesis. Deletion of the cancer suppressor gene CDKN2A located on human chromosome 9p21 is one of the genes with the highest mutation frequency in tumors, and the incidence rate is 15%. Because of the close proximity to CDKN2A, the methylthioadenosine phosphorylase gene (MTAP) is often accompanied by deletions in tumors, which play an important role in the methionine and adenine rescue pathway (Cell Reports,2016, 15:574-587). The absence of MTAP can result in accumulation of its substrate methyl sulfadenosine (MTA), which, because of its structural similarity to S-adenosylmethionine (SAM), selectively competes with SAM for binding to PRMT5, inhibiting partial activity of PRMT5, sensitizing further inhibition of PRMT5, i.e., synthetic lethality (Science, 2016,VOL 351ISSUE 6278:1214-1217).

PRMT5, however, is a known, essential gene, and knocking out or siRNA silencing PRMT5 in normal tissues can result in abnormal physiological functions such as cytopenia, infertility, skeletal muscle loss, cardiac hypertrophy, etc. (Journal of Clinical Investigation,2015,125 (9): 3532-44). Currently, PRMT5 inhibitors at the clinical stage cannot lead to synthetic lethality with MTAP deletions. Thus, new strategies are needed to exploit the metabolic vulnerability caused by MTAP deletions.

The development of a small molecular inhibitor targeting PRMT 5-MTA can be preferentially acted on MTAP-deleted tumor cells, and the normal cells have low MTAP concentration and have no obvious inhibition effect on the normal cells because the normal cells have no MTAP, so that the therapeutic index (AACR Annual Meeting,2021,Abstract LB003) can be increased, and a new strategy is provided for tumor treatment.

Disclosure of Invention

Problems to be solved by the invention:

although several patent applications for PRMT5 inhibitors have been published, new compounds are still further developed based on the enormous market demand of MTAP-/-cancer patients, where the clinical efficacy of existing PRMT5 inhibitors is not ideal and there is a risk of hematological toxicity. Through continuous efforts, the inventor designs a compound with a structure shown in a general formula (I), and discovers that the compound with the structure shows excellent PRMT5 inhibition effect and action and has huge application prospect.

Solution for solving the problem:

the present inventors have made intensive studies in order to solve the above-mentioned problems and have found that a specific carboxamide-substituted hetero tricyclic derivative can achieve the desired object, and as a result, have completed the present invention.

In order to achieve the above object, the present invention provides the following technical solutions:

A compound of formula (I), or a tautomeric form thereof, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof:

wherein,selected from single bond or double bond;

x, Y, Z are independently selected from CR ⁴ R ⁵ ，NR ⁶ ，O，N，S，CR ⁴ ；

W is selected from CR ⁷ Or N;

R ⁴ ，R ⁵ ，R ⁶ ，R ⁷ independently selected from H, halogen, cyano, C ₁ -C ₃ Alkyl, C ₃ -C ₆ Cycloalkyl;

R ¹ selected from C ₁ -C ₆ Alkyl, C ₃ -C ₁₀ Cycloalkyl- (C) ₁ -C ₆ Alkyl group _m -, 4-10 membered heterocyclyl- (C) ₁ -C ₆ Alkyl group _m -, 5-to 10-membered heteroaryl- (C) ₁ -C ₆ Alkyl group _n -, 5-to 10-membered aryl- (C) ₁ -C ₆ Alkyl group _p -; wherein n=0 or 1, m=0 or 1, p=0 or 1; the heterocyclyl and heteroaryl each contain 1-4 heteroatoms selected from O, N or S and the ring atoms of the heterocyclyl may optionally be oxo; wherein the C ₁ -C ₆ Alkyl is optionally substituted with one or more R _i Substitution; the C is ₃ -C ₁₀ Cycloalkyl optionally substituted with one or more R _j Substitution; the 4-10 membered heterocyclyl is optionally substituted with one or more R _k Substitution; the 5-10 membered aryl, 5-10 membered heteroaryl are each optionally substituted with one or more R _l Substitution;

R ² selected from H, C ₁ -C ₃ Alkyl, C ₃ -C ₆ Cycloalkyl;

preferably, R ² Selected from H or methyl;

preferably, R ² Is H;

R ³ selected from the following groups:a 5-10 membered heterocyclyl, a 9-10 membered heteroaryl, wherein E is a 4-6 membered heterocyclyl, a, B are each independently selected from CH or N, y = 0,1 or 2; the heterocyclyl and heteroaryl each contain 1-4 heteroatoms selected from O, N or S and the ring atoms of the heterocyclyl may optionally be oxo; the 5-10 membered heterocyclyl, 9-10 membered heteroaryl are each optionally substituted with one or more R _s Substituted and when R ³ Is->When it has at least one substituent R _s ；

Wherein,

R ⁸ selected from H, C ₁ -C ₆ Alkyl, C ₃ -C ₆ Cycloalkyl; the C is ₁ -C ₆ Alkyl, C ₃ -C ₆ Cycloalkyl groups are each optionally substituted with 1 or more R _m Substitution;

R ⁹ selected from 5-8 membered heteroaryl groups containing 3 or more heteroatoms selected from O, N or S, said heteroaryl groups optionally being substituted with 1 or more R _n Substitution;

R ¹⁰ selected from one or more R _v Substituted C ₁ -C ₆ Alkyl, C ₃ -C ₆ Cycloalkyl- (C) ₁ -C ₆ Alkyl group _r -,4-8 membered heterocyclyl- (C) ₁ -C ₆ Alkyl group _q -wherein r = 0 or 1, q = 0 or 1, the 4-7 membered heterocyclyl contains 1-4 heteroatoms selected from O, N or S and the ring atoms of the heterocyclyl may optionally be oxo; the C is ₃ -C ₆ Cycloalkyl, 4-8 membered heterocyclyl are each optionally substituted with 1 or more R _v Substitution;

R ¹¹ and R is ¹² Each independently selected from H, cyano, C ₁ -C ₆ Alkyl, 5-8 membered heteroaryl containing 1-4 heteroatoms selected from O, N or S; or R is ¹¹ And R is ¹² The carbon-carbon double bond groups to which they are attached together form a 5-8 membered cycloalkenyl group;

R ¹³ selected from C ₁ -C ₆ Alkyl, C optionally substituted with one or more groups selected from cyano, halogen, hydroxy, optionally substituted with one or more groups selected from halogen, cyano, hydroxy ₁ -C ₆ Alkoxy, C optionally substituted by one or more halogen, cyano, hydroxy ₃ -C ₆ A cycloalkoxy group optionally substituted with one or more halogen-, cyano-, hydroxy-substituted substituents of a 4-7 membered heterocycloalkoxy group;

Each R ¹⁴ Each independently selected from hydrogen, halogen, cyano, C ₁ -C ₃ Alkyl, C ₁ -C ₃ Haloalkyl, C ₁ -C ₃ Alkoxy, C ₃ -C ₆ Cycloalkyl;

each R _s Each independently selected fromHalogen, cyano, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₆ Cycloalkyl- (C) ₁ -C ₆ Alkyl group _r -、C ₃ -C ₆ Cycloalkyl- (C) ₁ -C ₆ Alkyl group _r -O-, 4-8 membered heterocyclyl- (C) ₁ -C ₆ Alkyl group _r -, 4-8 membered heterocyclyl- (C) ₁ -C ₆ Alkyl group _r -O-, 5-6 membered heterocyclenyl, 5-8 membered heteroaryl, said 4-8 membered heterocyclyl, 5-8 membered heterocyclenyl, 5-8 membered heteroaryl each containing 1-4 heteroatoms selected from N, O, S and the ring atoms of said heterocyclyl may optionally be oxo; the C is ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₆ Cycloalkyl, 4-8 membered heterocyclyl, 5-8 membered heterocyclenyl, 5-8 membered heteroaryl, each optionally substituted with one or more groups selected from halogen, cyano, hydroxy, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Haloalkoxy, C ₁ -C ₆ alkyl-C (O) -, C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Alkoxy, C ₁ -C ₆ Alkoxy C ₁ -C ₆ Substituents for alkyl, -NR 'R ", wherein R' and R" are each independently selected from H, C ₁ -C ₆ Alkyl, or R 'and R' together with the nitrogen atom to which they are attached form a 4-8 membered heterocyclyl containing 1-4 heteroatoms selected from N, O, S and the ring atoms of the heterocyclyl may optionally be oxo;

Each R _i Each independently selected from C ₃ -C ₆ Cycloalkyl, C ₁ -C ₃ Alkoxy, C ₁ -C ₃ Alkyl, halogen or cyano;

each R _j Each independently selected from optionally being oneC substituted by one or more halogens ₁ -C ₃ Alkyl, hydroxy, halogen, cyano, or C optionally substituted with one or more halogens ₁ -C ₃ An alkoxy group;

each R _k Each independently selected from hydroxy, halogen, cyano, C optionally substituted with one or more halogens ₁ -C ₃ Alkoxy, C optionally substituted with one or more halogens ₁ -C ₃ Alkyl, optionally substituted with one or more C' s ₁ -C ₃ Alkyl substituted 5-10 membered heteroaryl optionally substituted C with 1, 2 or 3 cyano, halogen, hydroxy ₁ -C ₃ alkyl-C (O) -, the 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O, S;

each R _l Each independently selected from halogen, hydroxy, cyano, C optionally substituted with one or more substituents selected from halogen, cyano, hydroxy ₁ -C ₃ Alkyl, optionally substituted with one or more groups selected from halogen, cyano, hydroxy, -NR' R ", C ₁ -C ₃ C substituted by substituents of alkoxy ₁ -C ₃ An alkoxy group; wherein R 'and R' are each independently selected from H, methyl, ethyl, propyl, isopropyl, or R 'and R' together with the nitrogen atom to which they are attached form a 4-8 membered heterocyclic group containing 1-4 heteroatoms selected from N, O, S and the ring atoms of the heterocyclic group may optionally be oxo-ed;

Each R _m Each independently selected from hydroxy, cyano, halogen, -NR' R ", optionally substituted with 1, 2, 3 or 4 halogen, hydroxy, cyano, C ₁ -C ₃ Alkoxy substituted C ₁ -C ₃ An alkoxy group; wherein R 'and R' are each independently selected from H, methyl, ethyl, propyl, isopropyl, or R 'and R' together with the nitrogen atom to which they are attached form a 4-8 membered heterocyclic group containing 1-4 heteroatoms selected from N, O, S and the ring atoms of the heterocyclic group may optionally be oxo-ed;

each R _n Each independently selected from C ₁ -C ₆ Alkyl, C ₃ -C ₆ Cycloalkyl; the C is ₁ -C ₆ Alkyl, C ₃ -C ₆ Cycloalkyl groups are each optionally substituted with one or more groups selected from halogen, hydroxy, cyano, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₃ Substitution of the substituent of the alkoxy group;

each R _v Each independently selected from: c (C) ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkynyl, C optionally substituted with one or more halogens ₁ -C ₆ Alkoxy, cyano, -NR 'R ", wherein R' and R" are each independently selected from H, C ₁ -C ₆ Alkyl, or R 'and R' together with the nitrogen atom to which they are attached form a 4-8 membered heterocyclyl containing 1-4 heteroatoms selected from N, O, S and the ring atoms of the heterocyclyl may optionally be oxo; wherein when R is ¹⁰ Is C ₁ -C ₆ In the case of alkyl radicals, R _v Not C ₁ -C ₆ An alkyl group.

Or the invention provides the following technical scheme:

wherein,selected from single bond or double bond;

W is selected from CR ⁷ Or N;

R ¹ selected from C ₁ -C ₆ Alkyl, C ₃ -C ₁₀ Cycloalkyl- (C) ₁ -C ₆ Alkyl group _m -, 4-10 yuanHeterocyclyl- (C) ₁ -C ₆ Alkyl group _m -, 5-to 10-membered heteroaryl- (C) ₁ -C ₆ Alkyl group _n -, 5-to 10-membered aryl- (C) ₁ -C ₆ Alkyl group _p -; wherein n=0 or 1, m=0 or 1, p=0 or 1; the heterocyclyl and heteroaryl each contain 1-4 heteroatoms selected from O, N or S and the ring atoms of the heterocyclyl may optionally be oxo; wherein the C ₁ -C ₆ Alkyl is optionally substituted with one or more R _i Substitution; the C is ₃ -C ₁₀ Cycloalkyl optionally substituted with one or more R _j Substitution; the 4-10 membered heterocyclyl is optionally substituted with one or more R _k Substitution; the 5-10 membered aryl, 5-10 membered heteroaryl are each optionally substituted with one or more R _l Substitution;

R ² selected from H, C ₁ -C ₃ Alkyl, C ₃ -C ₆ Cycloalkyl;

R ³ selected from the following groups:a 5-10 membered heterocyclic group, a 9-10 membered heteroaryl group, wherein E is a 4-6 membered heterocyclic group, A, B are each independently selected from CH or N; the heterocyclyl and heteroaryl each contain 1-4 heteroatoms selected from O, N or S and the ring atoms of the heterocyclyl may optionally be oxo; the 5-10 membered heterocyclyl, 9-10 membered heteroaryl are each optionally substituted with one or more R _s Substituted and when R ³ Is->When it has at least one substituent R _s ；

Wherein,

R ⁹ selected from 5-8 membered heteroaryl groups containing 3 or more heteroatoms selected from O, N or S, which heteroaryl groups may beOptionally by 1 or more R _n Substitution;

R ¹⁴ Selected from hydrogen, halogen, cyano, C ₁ -C ₃ Alkyl, C ₁ -C ₃ Haloalkyl, C ₁ -C ₃ Alkoxy, C ₃ -C ₆ Cycloalkyl;

each R _s Each independently selected fromHalogen, cyano, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₆ Cycloalkyl- (C) ₁ -C ₆ Alkyl group _r -、C ₃ -C ₆ Cycloalkyl- (C) ₁ -C ₆ Alkyl group _r -O-、4-8Membered heterocyclyl- (C) ₁ -C ₆ Alkyl group _r -, 4-8 membered heterocyclyl- (C) ₁ -C ₆ Alkyl group _r -O-, 5-6 membered heterocyclenyl, 5-8 membered heteroaryl, said 4-8 membered heterocyclyl, 5-8 membered heterocyclenyl, 5-8 membered heteroaryl each containing 1-4 heteroatoms selected from N, O, S and the ring atoms of said heterocyclyl may optionally be oxo; the C is ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₆ Cycloalkyl, 4-8 membered heterocyclyl, 5-8 membered heterocyclenyl, 5-8 membered heteroaryl, each optionally substituted with one or more groups selected from halogen, cyano, hydroxy, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Haloalkoxy, C ₁ -C ₆ alkyl-C (O) -, C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Alkoxy, C ₁ -C ₆ Alkoxy C ₁ -C ₆ Substituents for alkyl, -NR 'R ", wherein R' and R" are each independently selected from H, C ₁ -C ₆ Alkyl, or R 'and R' together with the nitrogen atom to which they are attached form a 4-8 membered heterocyclyl containing 1-4 heteroatoms selected from N, O, S and the ring atoms of the heterocyclyl may optionally be oxo;

each R _j Each independently selected from C ₁ -C ₃ Alkyl, hydroxy, halogen, cyano, or C optionally substituted with one or more halogens ₁ -C ₃ An alkoxy group;

each R _k Each independently selected from hydroxy, halogen, cyano, C optionally substituted with one or more halogens ₁ -C ₃ Alkoxy, C optionally substituted with one or more halogens ₁ -C ₃ Alkyl, optionally substituted with one or more C' s ₁ -C ₃ Alkyl-substituted 5-10 membered heteroaryl optionally substituted with 1, 2 or 3 cyano, halogen, hydroxyC ₁ -C ₃ alkyl-C (O) -, the 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O, S;

each R _v Each independently selected from: c (C) ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkynyl, C optionally substituted with one or more halogens ₁ -C ₆ Alkoxy, cyano, -NR 'R ", wherein R' and R" are each independently selected from H, C ₁ -C ₆ Alkyl, or R 'and R' are attached to the nitrogen atomForming a 4-8 membered heterocyclyl, said 4-8 membered heterocyclyl containing 1-4 heteroatoms selected from N, O, S and the ring atoms of said heterocyclyl may optionally be oxo; wherein when R is ¹⁰ Is C ₁ -C ₆ In the case of alkyl radicals, R _v Not C ₁ -C ₆ An alkyl group.

Or the invention provides the following technical scheme:

wherein,selected from single bond or double bond;

W is selected from CR ⁷ Or N;

R ¹ selected from C ₁ -C ₆ Alkyl, C ₃ -C ₁₀ Cycloalkyl- (C) ₁ -C ₆ Alkyl group _m -, 4-10 membered heterocyclyl- (C) ₁ -C ₆ Alkyl group _m -, 5-to 10-membered heteroaryl- (C) ₁ -C ₆ Alkyl group _n -, 5-to 10-membered aryl- (C) ₁ -C ₆ Alkyl group _p -; wherein n=0 or 1, m=0 or 1, p=0 or 1; the heterocyclyl and heteroaryl each contain 1-4 heteroatoms selected from O, N or S and the ring atoms of the heterocyclyl may optionally be oxo; wherein the C ₁ -C ₆ Alkyl is optionally substituted with one or more R _i Substitution; the C is ₃ -C ₁₀ Cycloalkyl optionally substituted with one or more R _j Substitution; the 4-1The 0 membered heterocyclic group optionally being substituted by one or more R _k Substitution; the 5-10 membered aryl, 5-10 membered heteroaryl are each optionally substituted with one or more R _l Substitution;

R ² selected from H, C ₁ -C ₃ Alkyl, C ₃ -C ₆ Cycloalkyl;

preferably, R ² Selected from H or methyl;

preferably, R ² Is H;

Wherein,

R ¹⁰ selected from one or more R _v Substituted C ₁ -C ₆ Alkyl, C ₃ -C ₆ Cycloalkyl- (C) ₁ -C ₆ Alkyl group _r -,4-8 membered heterocyclyl- (C) ₁ -C ₆ Alkyl group _q -, wherein r=0 or 1, q=0 or 1, said 4-7 membered heterocyclyl contains 1-4 heterocycles selected from O, N or SAn atom and the ring atom of the heterocyclic group may optionally be oxo; the C is ₃ -C ₆ Cycloalkyl, 4-8 membered heterocyclyl are each optionally substituted with 1 or more R _v Substitution;

each R _j Each independently selected from C optionally substituted with one or more halogens ₁ -C ₃ Alkyl, hydroxy, halogen, cyano, or C optionally substituted with one or more halogens ₁ -C ₃ An alkoxy group;

each R _l Each independently selected from halogen, hydroxy, cyano, C optionally substituted with one or more substituents selected from halogen, cyano, hydroxy ₁ -C ₃ Alkyl, optionally substituted with one or more groups selected from halogen, cyano, hydroxy, -NR'R”、C ₁ -C ₃ C substituted by substituents of alkoxy ₁ -C ₃ An alkoxy group; wherein R 'and R' are each independently selected from H, methyl, ethyl, propyl, isopropyl, or R 'and R' together with the nitrogen atom to which they are attached form a 4-8 membered heterocyclic group containing 1-4 heteroatoms selected from N, O, S and the ring atoms of the heterocyclic group may optionally be oxo-ed;

In some embodiments, R ₂ Selected from H, methyl, ethyl, propylIsopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

In some embodiments, R ₂ Selected from H and methyl.

In some embodiments, R ₂ Selected from H.

In some embodiments, R ¹ Selected from C ₁ -C ₄ Alkyl, C ₃ -C ₅ Alkyl, C ₄ -C ₆ Alkyl, C ₃ -C ₆ Monocyclic cycloalkyl- (C) ₁ -C ₄ Alkyl group _m -、C ₄ -C ₅ Monocyclic cycloalkyl- (C) ₁ -C ₄ Alkyl group _m -、C ₅ -C ₆ Monocyclic cycloalkyl- (C) ₁ -C ₄ Alkyl group _m -、C ₅ -C ₇ Bicyclic cycloalkyl- (C) ₁ -C ₄ Alkyl group _m -、C ₉ -C ₁₀ Bicyclic cycloalkyl- (C) ₁ -C ₄ Alkyl group _m -, 5-6 membered monocyclic heterocyclyl- (C) ₁ -C ₄ Alkyl group _m -, 9-10 membered bicyclic heterocyclyl- (C) ₁ -C ₄ Alkyl group _m -, 5-6 membered monocyclic heteroaryl- (C) ₁ -C ₄ Alkyl group _n -, 9-10 membered bicyclic heteroaryl- (C) ₁ -C ₄ Alkyl group _n -, 5-to 10-membered aryl- (C) ₁ -C ₄ Alkyl group _p -; n=0 or 1, m=0 or 1, p=0 or 1; the heterocyclyl and heteroaryl each contain 1-4 heteroatoms selected from O, N or S and the ring atoms of the heterocyclyl may optionally be oxo; preferably, the heterocyclyl and heteroaryl each contain 1 to 3 heteroatoms selected from O or N; wherein the C ₁ -C ₄ Alkyl, C ₃ -C ₅ Alkyl, C ₄ -C ₆ Alkyl groups are each optionally substituted with one or more R _i Substitution; the C is ₃ -C ₆ Monocyclic cycloalkyl, C ₄ -C ₅ Monocyclic cycloalkyl, C ₅ -C ₆ Monocyclic cycloalkyl, C ₅ -C ₇ Bicyclic cycloalkyl, C ₉ -C ₁₀ Bicyclic cycloalkyl radicals each optionally being substituted with one or more R _j Substitution; the 5-6 membered monocyclic heterocyclic groups and 9-10 membered bicyclic heterocyclic groups are eachFrom optionally one or more R _k Substitution; the 5-6 membered monocyclic heteroaryl, 9-10 membered bicyclic heteroaryl, 5-10 membered aryl are each optionally substituted with one or more R _l And (3) substitution.

In some embodiments, R ¹ Selected from C ₁ -C ₆ Alkyl, C ₃ -C ₁₀ Cycloalkyl- (C) ₁ -C ₆ Alkyl group _m -, 4-10 membered heterocyclyl- (C) ₁ -C ₆ Alkyl group _m -, 5-to 10-membered heteroaryl- (C) ₁ -C ₆ Alkyl group _n -, 5-to 10-membered aryl- (C) ₁ -C ₆ Alkyl group _p -; n=0 or 1, m=0 or 1, p=0 or 1; the C is ₁ -C ₆ Alkyl is selected from methyl or methylene, ethyl or ethylene, propyl or propylene, isopropyl or isopropylene, isobutyl or isobutylene, sec-butyl or sec-butyl respectively, each of which is optionally substituted with 1, 2 or 3R _i Substitution; the C is ₃ -C ₁₀ Cycloalkyl is selected fromCyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, each optionally substituted with 1, 2 or 3R _j Substitution; said 5-10 membered heterocyclic group is selected from +.>Each of which is optionally substituted with 1, 2 or 3R _k Substitution; the 5-10 membered heteroaryl is selected from the group consisting of pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, -/->Each of which is optionally substituted with 1, 2 or 3R _l Substitution; the 5-10 membered aryl is selected from phenyl, naphthyl, each of which is optionally substituted with 1, 2 or 3R _l And (3) substitution.

In some embodiments, each R _i Each independently selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, F, cl, br, methoxy, ethoxy, propoxy, isopropoxy, cyano.

In some embodiments, each R _i Each independently selected from methyl, ethyl, cyclopropyl, methoxy, cyano.

In some embodiments, each R _j Each independently selected from methyl, ethyl, propyl, isopropyl, hydroxy, F, cl, br, cyano, -OCH ₂ F、-OCHF ₂ 、-OCF ₃ 、-OCH ₂ CH ₂ F、-OCH ₂ CHF ₂ 、-OCH ₂ CF ₃ Methoxy, ethoxy, propoxy, isopropoxy.

In some embodiments, each R _j Each independently selected from methyl, hydroxy, cyano, -OCHF ₂ 。

In some embodiments, each R _j Each independently selected from methyl, ethyl, propyl, isopropyl, hydroxy, F, cl, br, cyano, -OCH ₂ F、-OCHF ₂ 、-OCF ₃ 、-OCH ₂ CH ₂ F、-OCH ₂ CHF ₂ 、-OCH ₂ CF ₃ 、-CH ₂ F、-CHF ₂ 、-CF ₃ 、-CH ₂ CH ₂ F、-CH ₂ CHF ₂ 、-CH ₂ CF ₃ Methoxy, ethoxy, propoxy, isopropoxy.

In some embodiments, each R _j Each independently selected from methyl, hydroxy, cyano, -OCHF ₂ 、-CF ₃ 。

In some embodiments, each R _k Each independently selected from hydroxy, halogen, cyano, C optionally substituted with 1, 2 or 3F ₁ -C ₃ An alkoxy group.

In some embodiments, each R _k Each independently selected from methoxy, ethoxy, propoxy, isopropoxy, F, cl, br.

In some embodiments, each R _k Each independently selected from methoxy, F.

In some embodiments, each R _l Each independently selected from F, cl, Br, hydroxy, cyano, C optionally substituted by 1, 2 or 3 substituents selected from F, cl, cyano, hydroxy ₁ -C ₃ Alkyl, C optionally substituted with 1, 2 or 3 substituents selected from F, cyano, hydroxy, methoxy, ethoxy ₁ -C ₃ An alkoxy group.

In some embodiments, each R _l Each independently selected from F, cl, br, hydroxy, cyano, methyl or ethyl optionally substituted with 1, 2 or 3F.

In some embodiments, each R _l Each independently selected from F, cl, methyl.

In some embodiments, each R _l Each independently selected from F, cl, methyl, -CHF ₂ 。

In some embodiments, each R _l Each independently selected from methyl, -CHF ₂ 。

In some embodiments, R ¹ Selected from methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, and mixtures thereof,

In some embodiments, R ¹ Selected from methyl, ethyl, cyclopropyl,

In some embodiments, R ¹ Selected from cyclopropyl or

In some embodiments, R ¹ Selected from cyclopropyl or ethyl.

In some embodiments, R ¹ Selected from methyl, ethyl, isopropyl, cyclopropyl,

In some embodiments, R ¹ Selected from ethyl, cyclopropyl or

In some embodiments, R ¹ Selected from 5-10 membered heteroaryl- (C) ₁ -C ₆ Alkyl group _n -n=0 or 1; the heteroaryl group contains 1 to 4 heteroatoms selected from O, N or S; the 5-10 membered aryl is optionally substituted with one or more R _l And (3) substitution.

In some embodiments, R ¹ Selected from 5-6 membered monocyclic heteroaryl- (C) ₁ -C ₄ Alkyl group _n -n=0 or 1; the heteroaryl group contains 1 to 4 heteroatoms selected from O, N or S; the 5-6 membered monocyclic heteroaryl optionally being substituted with one or more R _l And (3) substitution.

In some embodiments, R ¹ Selected from 5-6 membered monocyclic heteroaryl- (C) ₁ -C ₄ Alkyl group _n -n=0 or 1; the heteroaryl group contains 1 to 3 heterocyclic atoms selected from O or N; the 5-6 membered monocyclic heteroaryl optionally being substituted with one or more R _l And (3) substitution.

In some embodiments, R ¹ Selected from the group consisting of pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl,Each of which is optionally substituted with 1, 2 or 3R _l And (3) substitution.

In some embodiments, R ¹ Selected from the group consisting ofWhich is optionally substituted with 1, 2 or 3R' s _l And (3) substitution.

In some embodiments, each R _l Each independently selected from C optionally substituted with 1, 2 or 3 substituents selected from F, cl, cyano, hydroxy ₁ -C ₃ An alkyl group.

In some embodiments, each R _l Each independently selected from methyl or ethyl optionally substituted with 1, 2 or 3F.

In some embodiments, each R _l Each independently selected from C ₁ -C ₃ An alkyl group.

In some embodiments, each R _l Each independently selected from methyl or ethyl.

In some embodiments, each R _l Each independently selected from methyl.

In some embodiments, R ¹ Selected from the group consisting of

In some embodiments, R ¹ Selected from C ₃ -C ₁₀ Cycloalkyl- (C) ₁ -C ₆ Alkyl group _m -, m=0 or 1, the C ₃ -C ₁₀ Cycloalkyl optionally substituted with one or more R _j And (3) substitution.

In some embodiments, R ¹ Selected from C ₃ -C ₁₀ Cycloalkyl group, the C ₃ -C ₁₀ Cycloalkyl optionally substituted with one or more R _j And (3) substitution.

In some embodiments, R ¹ Selected from C ₃ -C ₆ Monocyclic cycloalkyl, said C ₃ -C ₆ Monocyclic cycloalkyl optionally substituted with one or more R _j And (3) substitution.

In some embodiments, R ¹ Selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, each optionally substituted with 1, 2 or 3R _j And (3) substitution.

In some embodiments, R ¹ Selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

In some embodiments, R ¹ Selected from cyclopropyl.

In some embodiments, R ¹ Selected from C ₁ -C ₆ Alkyl, said C ₁ -C ₆ Alkyl is optionally substituted with one or more R _i And (3) substitution.

In some embodiments, R ¹ Selected from C ₁ -C ₄ Alkyl, said C ₁ -C ₄ Alkyl is optionally substituted with 1, 2 or 3R _i And (3) substitution.

In some embodiments, R ¹ Selected from methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, each of which is optionally substituted with 1, 2 or 3R _i And (3) substitution.

In some embodiments, R ¹ Selected from C ₁ -C ₄ An alkyl group.

In some embodiments, R ¹ Selected from methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl.

In some embodiments, R ¹ Selected from methyl or ethyl.

In some embodiments, R ¹ Selected from methyl groups.

In some embodiments, R ¹ Selected from ethyl groups.

In some embodiments, R ⁸ Selected from H, C ₁ -C ₃ Alkyl, C ₂ -C ₄ Alkyl, C ₃ -C ₆ Alkyl, C ₄ -C ₆ Alkyl, C ₅ -C ₆ Alkyl, C ₂ -C ₅ Alkyl, C ₃ -C ₅ Cycloalkyl, C ₄ -C ₆ Cycloalkyl, C ₄ -C ₅ Cycloalkyl, C ₅ -C ₆ Cycloalkyl; the alkyl, cycloalkyl are each optionally substituted with 1, 2, 3 or 4R' s _m And (3) substitution.

In some embodiments, R ⁸ Selected from H, methyl, ethyl, propyl, isopropyl, C ₄ Alkyl, C ₅ Alkyl, C ₆ Alkyl, cyclopropyl, C ₄ Cycloalkyl, C ₅ Cycloalkyl, C ₆ Cycloalkyl; the alkyl, cycloalkyl are each optionally substituted with 1, 2, 3 or 4R' s _m And (3) substitution.

In some embodiments, R ⁸ Selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, sec-butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; the methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl are each optionally substituted with 1, 2 or 3R' s _m And (3) substitution.

In some embodiments, R ⁸ Selected from H, methyl, ethyl, cyclopropyl; the methyl, ethyl, cyclopropyl groups are each optionally substituted with 1, 2 or 3R groups _m And (3) substitution.

In some embodiments, R ⁸ Selected from H, methyl, ethyl, isopropyl, cyclopropyl; the methyl, ethyl, isopropyl, cyclopropyl groups are each optionally substituted with 1, 2 or 3R groups _m And (3) substitution.

In some embodiments, each R _m Each independently selected from hydroxy, cyano, -NR' R ", C optionally substituted with 1, 2, 3 or 4 halogens ₁ -C ₃ An alkoxy group; wherein R 'and R' are each independently selected from H, methyl, ethyl, propyl, isopropyl, or R 'and R' together with the nitrogen atom to which they are attached form a 4-7 membered heterocyclic group containing 1-4 heteroatoms selected from N, O, S and the ring atoms of the heterocyclic group may optionally be oxo-substituted.

In some embodiments, eachR is a number of _m Each independently selected from hydroxy, cyano, N, N dimethylamino, C optionally substituted with 1, 2 or 3F ₁ -C ₃ An alkoxy group.

In some embodiments, each R _m Each independently selected from methoxy, hydroxy, cyano, N-dimethylamino, -OCH ₂ F、-OCHF ₂ 、-OCF ₃ 、-OCH ₂ CH ₂ F、-OCH ₂ CHF ₂ 、-OCH ₂ CF ₃ 。

In some embodiments, each R _m Each independently selected from methoxy, hydroxy, cyano, N-dimethylamino, -OCHF ₂ 、-OCF ₃ 。

In some embodiments, each R _m Each independently selected from halogen, hydroxy, cyano, -NR' R ", C optionally substituted with 1, 2, 3 or 4 halogens ₁ -C ₃ An alkoxy group; wherein R 'and R' are each independently selected from H, methyl, ethyl, propyl, isopropyl, or R 'and R' together with the nitrogen atom to which they are attached form a 4-7 membered heterocyclic group containing 1-4 heteroatoms selected from N, O, S and the ring atoms of the heterocyclic group may optionally be oxo-substituted.

In some embodiments, each R _m Each independently selected from halogen, hydroxy, cyano, N, N dimethylamino, C optionally substituted with 1, 2 or 3F ₁ -C ₃ An alkoxy group.

In some embodiments, each R _m Each independently selected from F, cl, br, methoxy, hydroxy, cyano, N-dimethylamino, -OCH ₂ F、-OCHF ₂ 、-OCF ₃ 、-OCH ₂ CH ₂ F、-OCH ₂ CHF ₂ 、-OCH ₂ CF ₃ 。

In some embodiments, each R _m Each independently selected from F, methoxy, hydroxy, cyano, N-dimethylamino, -OCHF ₂ 、-OCF ₃ 。

In some embodiments, R ⁸ Selected from H, methyl,Ethyl, methoxymethyl, hydroxymethyl, cyclopropyl,

In some embodiments, R ⁸ Selected from H, methyl, ethyl, methoxymethyl, hydroxymethyl, -CH ₂ F、-CF ₃ Cyclopropyl group,

In some embodiments, R ⁸ Selected from H, hydroxymethyl, -CH ₂ F、-CF ₃ Cyclopropyl group,

In some embodiments, R ⁸ Selected from H, hydroxymethyl, -CH ₂ F、-CF ₃ 、

In some embodiments, R ⁸ Selected from H.

In some embodiments, R ⁸ Selected from the group consisting of

In some embodiments, R ⁹ Selected from 5-8 membered heteroaryl groups containing 3 or more heteroatoms selected from O, N or S, said heteroaryl groups being selected fromThe heteroaryl group may optionally be substituted with 1, 2 or 3R _n And (3) substitution.

In some embodiments, each R _n Each independently selected from methyl, ethyl, C ₃ Alkyl, C ₄ Alkyl, C ₅ Alkyl, C ₆ Alkyl, cyclopropyl, C ₄ Cycloalkyl, C ₅ Cycloalkyl, C ₆ Cycloalkyl; the alkyl groups, cycloalkyl groups are each optionally substituted with one or more groups selected from halogen, hydroxy, cyano, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₃ The substituent of the alkoxy group is substituted.

In some embodiments, each R _n Each independently selected from methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl; the methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl are each optionally substituted with one or more groups selected from halogen, hydroxy, cyano, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₃ The substituent of the alkoxy group is substituted.

In some embodiments, each R _n Each independently selected from methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl; the methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl are each optionally substituted with one or more substituents selected from halogen, C ₁ -C ₃ The substituent of the alkoxy group is substituted.

In some embodiments, each R _n Each independently selected from methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl; the methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl are each optionally substituted by one or more substituents selected from methoxy, ethoxy.

In some embodiments, each R _n Each independently selected from methyl, ringPropyl, methoxymethyl.

In some embodiments, R ⁹ Selected from the group consisting of

In some embodiments, R ¹⁰ Selected from one or more R _v Substituted C ₁ -C ₆ Alkyl, C ₃ -C ₆ Cycloalkyl- (C) ₁ -C ₆ Alkyl group _r -,4-7 membered heterocyclyl- (C) ₁ -C ₆ Alkyl group _q -wherein r = 0 or 1, q = 0 or 1, the 4-7 membered heterocyclyl contains 1-4 heteroatoms selected from O, N or S and the ring atoms of the heterocyclyl may optionally be oxo; the C is ₃ -C ₆ Cycloalkyl, 4-7 membered heterocyclyl are each optionally substituted with 1 or more R _v And (3) substitution.

In some embodiments, R ¹⁰ Selected from one or more R _v Substituted C ₁ -C ₆ Alkyl, 4-7 membered heterocyclyl- (C) ₁ -C ₆ Alkyl group _q -wherein q = 0 or 1, the 4-7 membered heterocyclyl contains 1-4 heteroatoms selected from O, N or S and the ring atoms of the heterocyclyl may optionally be oxo; the 4-7 membered heterocyclic group may optionally be substituted with 1 or more R _v And (3) substitution.

In some embodiments, R ¹⁰ Selected from C ₁ -C ₄ Alkyl, C ₂ -C ₄ Alkyl, C ₃ -C ₅ Alkyl, C ₄ -C ₆ Alkyl, 5-6 membered heterocyclyl- (C) ₁ -C ₃ Alkyl group _q -wherein q = 0 or 1, the 5-6 membered heterocyclyl contains 1-4 heteroatoms selected from O, N or S and the ring atoms of the heterocyclyl may optionally be oxo; the alkyl groups being substituted by one or more R _v Substituted, said heterocyclyl being optionally substituted with 1 or more R _v And (3) substitution.

In some embodiments, R ¹⁰ Selected from methyl, ethyl, propyl, isopropyl, C ₄ Alkyl, C ₅ Alkyl, C ₆ Alkyl, 5-6 membered heterocyclyl- (C) ₁ -C ₃ Alkyl group _q -wherein q = 0 or 1, the 5-6 membered heterocyclyl contains 1-4 heteroatoms selected from O, N or S and the ring atoms of the heterocyclyl may optionally be oxo; the methyl, ethyl, propyl, isopropyl, C ₄ Alkyl, C ₅ Alkyl, C ₆ Alkyl is substituted with one or more R _v Substituted, said heterocyclyl being optionally substituted with 1 or more R _v And (3) substitution.

In some embodiments, R ¹⁰ Selected from methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl, pentyl, hexyl, 5-6 membered heterocyclyl- (C) ₁ -C ₃ Alkyl group _q -, wherein q=0 or 1, and the 5-6 membered heterocyclic group is selected fromThe methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl, pentyl, hexyl being substituted with 1 or more R _v Substitution ofEach optionally is substituted with 1, 2 or 3R _v And (3) substitution.

In some embodiments, each R _v Each independently selected from: c (C) ₁ -C ₃ Alkyl, C ₂ -C ₄ Alkynyl, C ₁ -C ₃ Alkoxy, halo C ₁ -C ₃ Alkoxy, cyano, -NR' R "; wherein R 'and R' are each independently selected from H, methyl, ethyl, propyl, isopropyl, or R 'and R' together with the nitrogen atom to which they are attached form a 4-7 membered heterocyclic group containing 1-4 heterocyclic atoms selected from O, N or S and the ring atoms of the heterocyclic group may optionally be oxo-substituted; wherein when R is ¹⁰ Is C ₁ -C ₆ In the case of alkyl radicals, R _v Not C ₁ -C ₃ An alkyl group.

In some embodiments, each R _v Each independently selected from: c (C) ₁ -C ₃ Alkyl, C ₂ -C ₄ Alkynyl, C ₁ -C ₃ Alkoxy, cyanoOCH ₂ F、-OCHF ₂ 、-OCF ₃ 、-OCH ₂ CH ₂ F、-OCH ₂ CHF ₂ 、-OCH ₂ CF ₃ -NR' R "; wherein R 'and R' are each independently selected from H, methyl, ethyl, propyl, isopropyl, or R 'and R' together with the nitrogen atom to which they are attached formWherein when R is ¹⁰ Is C ₁ -C ₆ In the case of alkyl radicals, R _v Not C ₁ -C ₃ An alkyl group.

In some embodiments, each R _v Each independently selected from: methyl, ethynyl, methoxy, cyano, -OCHF ₂ ，-OCF ₃ Amino, N-methylamino, N, N-dimethylamino,wherein when R is ¹⁰ Is C ₁ -C ₆ In the case of alkyl radicals, R _v Is not methyl.

In some embodiments, R ¹⁰ Selected from:

in some embodiments, R ¹¹ And R is ¹² Each independently selected from H, cyano, C ₁ -C ₃ Alkyl, C ₂ -C ₄ Alkyl, C ₃ -C ₆ Alkyl, C ₄ -C ₆ Alkyl, 5-6 membered heteroaryl containing 1-3 heteroatoms selected from O, N or S heteroatoms; or R is ¹¹ And R is ¹² The carbon-carbon double bond groups to which they are attached together form a 5-6 membered cycloalkenyl group, the 5-6 membered cycloalkenyl group being selected from

In some embodiments, R ¹¹ And R is ¹² Each independently selected from H, cyano, methyl, ethyl, propyl, isopropyl, C ₄ Alkyl, C ₅ Alkyl, C ₆ Alkyl, pyridyl, pyrazolyl, pyrimidinyl, pyrazinyl, pyridazinyl,Or R is ¹¹ And R is ¹² The carbon-carbon double bond groups to which they are attached together form a 5-6 membered cycloalkenyl group, said 5-6 membered cycloalkenyl group being selected from +.>

In some embodiments, R ¹¹ And R is ¹² Each independently selected from methyl, H, cyano,Or R is ¹¹ And R is ¹² The carbon-carbon double bond groups to which they are attached together form a 5-6 membered cycloalkenyl group, said 5-6 membered cycloalkenyl group being selected from +.>

In some embodiments, E is selected from 4-6 membered heterocyclyl, each of which contains 1-2 heteroatoms selected from O, N or S.

In some embodiments, E is selected from

In some embodiments, R ¹³ Selected from C ₁ -C ₄ Alkyl, C ₄ -C ₆ Alkyl, C ₃ -C ₅ Alkyl, C ₂ -C ₄ Alkyl, C optionally substituted with one or more groups selected from cyano, halogen, hydroxy, optionally substituted with one or more groups selected from halogen, cyano, hydroxy ₁ -C ₆ Alkoxy, optionally substituted with one or more halogen, cyano, amino, or amino groups,Hydroxy-substituted C ₃ -C ₆ A cycloalkoxy group optionally substituted with one or more halogen-, cyano-, hydroxy-substituted substituents of a 4-7 membered heterocycloalkoxy group.

In some embodiments, R ¹³ Selected from C ₁ -C ₄ Alkyl, C ₄ -C ₆ Alkyl, C ₃ -C ₅ Alkyl, C ₂ -C ₄ Alkyl, C optionally substituted with one or more groups selected from cyano, halogen, hydroxy, optionally substituted with one or more groups selected from halogen, cyano, hydroxy ₁ -C ₆ Alkoxy, C optionally substituted by one or more halogen, cyano, hydroxy ₃ -C ₆ A cycloalkoxy group optionally substituted with one or more halogen-, cyano-, hydroxy-substituted substituents of a 4-7 membered heterocycloalkoxy group; the C is ₁ -C ₆ Alkoxy is selected from methoxy, ethoxy, C ₃ Alkoxy, C ₄ Alkoxy, C ₅ Alkoxy, C ₆ An alkoxy group; the C is ₃ -C ₆ The cycloalkoxy group is selected from cyclopropyloxy, cyclobutyloxy, C ₅ Cycloalkoxy radicals C ₆ A cycloalkoxy group; the 4-7 membered heterocycloalkoxy group is selected from

In some embodiments, R ¹³ Selected from methyl, ethyl, C ₃ Alkyl, C ₄ Alkyl, C ₅ Alkyl, C ₆ Alkyl, C optionally substituted with one or more groups selected from cyano, halogen, hydroxy, optionally substituted with one or more groups selected from halogen, cyano, hydroxy ₁ -C ₆ Alkoxy, C ₃ -C ₆ Substituted with substituents of cycloalkoxy, 4-7 membered heterocycloalkoxy, said C ₁ -C ₆ Alkoxy is selected from methoxy, ethoxy, C ₃ Alkoxy, C ₄ Alkoxy, C ₅ Alkoxy, C ₆ An alkoxy group; the C is ₃ -C ₆ The cycloalkoxy group is selected from cyclopropyloxy, cyclobutyloxy, C ₅ Cycloalkoxy radicals C ₆ A cycloalkoxy group; the 4-7 membered heterocycloalkoxy group is selected from

In some embodiments, R ¹³ Selected from-CH ₂ CH ₂ F、-CH ₂ F。

In some embodiments, R ³ Selected from 5-6 membered heterocyclyl, said 5-6 membered heterocyclyl containing 1-2 heteroatoms selected from O, N or S and the ring atoms of said heterocyclyl may optionally be oxo-substituted.

In some embodiments, R ³ Selected from the group consisting of

In some embodiments, each R ¹⁴ Each independently selected from hydrogen, halogen, cyano, C ₁ -C ₃ Alkyl, C ₁ -C ₃ Haloalkyl, C ₁ -C ₃ An alkoxy group.

In some embodiments, each R ¹⁴ Each independently selected from hydrogen, halogen, cyano, C ₁ -C ₃ Alkyl, C ₁ -C ₃ A haloalkyl group.

In some embodiments, each R ¹⁴ Each independently selected from hydrogen, F, cl, br, cyano, methyl optionally substituted with F, ethyl optionally substituted with F, propyl optionally substituted with F, isopropyl optionally substituted with F.

In some embodiments, each R ¹⁴ Each independently selected from hydrogen, F, methyl, -CF ₃ 。

In some embodiments, eachR ¹⁴ Each independently selected from hydrogen, F, cl, br, cyano, methyl optionally substituted with F, ethyl optionally substituted with F, propyl optionally substituted with F, isopropyl optionally substituted with F, methoxy optionally substituted with F, ethoxy optionally substituted with F, propoxy optionally substituted with F, isopropoxy optionally substituted with F.

In some embodiments, each R ¹⁴ Each independently selected from hydrogen, F, cl, methyl, ethyl, methoxy, ethoxy, -CF ₃ 、-CHF ₂ 、-CH ₂ F。

In some embodiments, each R ¹⁴ Each independently selected from hydrogen, F, cl, methyl, ethyl, methoxy, ethoxy, -CF ₃ 、-CHF ₂ 、-CH ₂ F、-OCF ₃ 、-OCHF ₂ 、-OCH ₂ F。

In some embodiments, each R ¹⁴ Each independently selected from hydrogen, F, cl, methyl, methoxy, -CF ₃ 。

In some embodiments, each R ¹⁴ Each independently selected from hydrogen, F, cl, methyl, methoxy, -CF ₃ 、-OCH ₂ F。

In some embodiments, each R ¹⁴ Each independently selected from hydrogen, F, cl, methyl, methoxy.

In some embodiments, each R ¹⁴ Each independently selected from hydrogen, F, cl, methyl.

In some embodiments, each R ¹⁴ Each independently selected from hydrogen, F, methyl.

In some embodiments, each R ¹⁴ Each independently selected from Cl, methyl.

In some embodiments, R ¹⁴ Selected from Cl.

In some embodiments, R ¹⁴ Selected from methyl groups.

In some embodiments, each R _s Each independently selected fromHalogen, cyano, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₆ Cycloalkyl- (C) ₁ -C ₆ Alkyl group _r -、C ₃ -C ₆ Cycloalkyl- (C) ₁ -C ₆ Alkyl group _r -O-, 4-8 membered heterocyclyl- (C) ₁ -C ₆ Alkyl group _r -, 4-8 membered heterocyclyl- (C) ₁ -C ₆ Alkyl group _r -O-, 5-6 membered heterocyclenyl, 5-6 membered heteroaryl, each containing 1-4 heteroatoms selected from N, O, S and the ring atoms of the heterocyclyl may optionally be oxo; the C is ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₆ Cycloalkyl, 4-8 membered heterocyclyl, 5-6 membered heterocyclenyl, 5-6 membered heteroaryl, each optionally substituted with one or more groups selected from halogen, cyano, hydroxy, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Haloalkoxy, C ₁ -C ₆ alkyl-C (O) -, C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Alkoxy, C ₁ -C ₆ Alkoxy C ₁ -C ₆ Substituents for alkyl, -NR 'R ", wherein R' and R" are each independently selected from H, C ₁ -C ₆ Alkyl, or R 'and R' together with the nitrogen atom to which they are attached form a 4-8 membered heterocyclic group, said 4-8 membered heterocyclic group containing 1-4 heteroatoms selected from N, O, S and the ring atoms of said heterocyclic group may optionally be oxo-substituted.

In some embodiments, each R _s Each independently selected fromHalogen, cyano, C ₁ -C ₃ Alkyl, C ₄ -C ₆ Alkyl, C ₃ -C ₄ Alkyl, C ₂ -C ₃ Alkyl, C ₁ -C ₃ Alkoxy, C ₄ -C ₆ Alkoxy, C ₃ -C ₄ Alkoxy, C ₂ -C ₃ Alkoxy, C ₃ -C ₄ Cycloalkyl- (C) ₁ -C ₆ Alkyl group _r -、C ₅ -C ₆ Cycloalkyl- (C) ₁ -C ₆ Alkyl group _r -、C ₄ -C ₅ Cycloalkyl- (C) ₁ -C ₆ Alkyl group _r -、C ₃ -C ₄ Cycloalkyl- (C) ₁ -C ₆ Alkyl group _r -O-、C ₅ -C ₆ Cycloalkyl- (C) ₁ -C ₆ Alkyl group _r -O-、C ₄ -C ₅ Cycloalkyl- (C) ₁ -C ₆ Alkyl group _r -O-, 5-8 membered heterocyclyl- (C) ₁ -C ₆ Alkyl group _r -, 5-8 membered heterocyclyl- (C) ₁ -C ₆ Alkyl group _r -O-, 5-6 membered heterocyclenyl, 5-6 membered heteroaryl, each containing 1-4 heteroatoms selected from N, O, S and the ring atoms of the heterocyclyl may optionally be oxo; the alkyl, alkoxy, cycloalkyl, heterocyclyl, heterocyclenyl, heteroaryl groups are each optionally substituted with one or more groups selected from halogen, cyano, hydroxy, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Haloalkoxy, C ₁ -C ₆ alkyl-C (O) -, C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Alkoxy, C ₁ -C ₆ Alkoxy C ₁ -C ₆ Substituents for alkyl, -NR 'R ", wherein R' and R" are each independently selected from H, C ₁ -C ₆ Alkyl, or R 'and R' together with the nitrogen atom to which they are attached form a 4-8 membered heterocyclic group, said 4-8 membered heterocyclic group containing 1-4 heteroatoms selected from N, O, S and the ring atoms of said heterocyclic group may optionally be oxo-substituted.

In some embodiments, each R _s Each independently selected fromHalogen, cyano, C ₁ -C ₃ Alkyl, C ₄ -C ₆ Alkyl, C ₃ -C ₄ Alkyl, C ₂ -C ₃ Alkyl, C ₁ -C ₃ Alkoxy, C ₄ -C ₆ Alkoxy, C ₃ -C ₄ Alkoxy, C ₂ -C ₃ Alkoxy, C ₃ -C ₄ Cycloalkyl- (C) ₁ -C ₆ Alkyl group _r -、C ₅ -C ₆ Cycloalkyl- (C) ₁ -C ₆ Alkyl group _r -、C ₄ -C ₅ Cycloalkyl- (C) ₁ -C ₆ Alkyl group _r -、C ₃ -C ₄ Cycloalkyl- (C) ₁ -C ₆ Alkyl group _r -O-、C ₅ -C ₆ Cycloalkyl- (C) ₁ -C ₆ Alkyl group _r -O-、C ₄ -C ₅ Cycloalkyl- (C) ₁ -C ₆ Alkyl group _r -O-, 5-8 membered heterocyclyl- (C) ₁ -C ₆ Alkyl group _r -, 5-8 membered heterocyclyl- (C) ₁ -C ₆ Alkyl group _r -O-, 5-6 membered heterocyclenyl, 5-6 membered heteroaryl, each containing 1-4 heteroatoms selected from N, O, S and the ring atoms of the heterocyclyl may optionally be oxo; the alkyl, alkoxy, cycloalkyl, heterocyclyl, heterocyclenyl, heteroaryl groups are each optionally substituted with one or more groups selected from F, cl, cyano, hydroxy, C ₃ -C ₄ Cycloalkyl, C ₁ -C ₃ Haloalkyl, C ₁ -C ₃ Haloalkoxy, C ₁ -C ₃ alkyl-C (O) -, C ₁ -C ₃ Alkyl, C ₂ -C ₄ Alkynyl, C ₁ -C ₃ Alkoxy, C ₁ -C ₃ Alkoxy C ₁ -C ₃ Substituents for alkyl, -NR 'R ", wherein R' and R" are each independently selected from H, C ₁ -C ₃ Alkyl, or R 'and R' together with the nitrogen atom to which they are attached form a 4-8 membered heterocyclic group, said 4-8 membered heterocyclic group containing 1-4 heteroatoms selected from N, O, S and the ring atoms of said heterocyclic group may optionally be oxo-substituted.

In some embodiments, each R _s Each independently selected from Halogen, cyano, C ₁ -C ₃ Alkyl, C ₄ -C ₆ Alkyl, C ₃ -C ₄ Alkyl, C ₂ -C ₃ Alkyl, C ₁ -C ₃ Alkoxy, C ₄ -C ₆ Alkoxy, C ₃ -C ₄ Alkoxy, C ₂ -C ₃ Alkoxy, C ₃ -C ₄ Cycloalkyl- (C) ₁ -C ₆ Alkyl group _r -、C ₅ -C ₆ Cycloalkyl- (C) ₁ -C ₆ Alkyl group _r -、C ₄ -C ₅ Cycloalkyl- (C) ₁ -C ₆ Alkyl group _r -、C ₃ -C ₄ Cycloalkyl- (C) ₁ -C ₆ Alkyl group _r -O-、C ₅ -C ₆ Cycloalkyl- (C) ₁ -C ₆ Alkyl group _r -O-、C ₄ -C ₅ Cycloalkyl- (C) ₁ -C ₆ Alkyl group _r -O-, 5-8 membered heterocyclyl- (C) ₁ -C ₆ Alkyl group _r -, 5-8 membered heterocyclyl- (C) ₁ -C ₆ Alkyl group _r -O-, 5-6 membered heterocyclenyl, 5-6 membered heteroaryl, each containing 1-4 heteroatoms selected from N, O, S and the ring atoms of the heterocyclyl may optionally be oxo; the alkyl, alkoxy, cycloalkyl, heterocyclyl, heterocyclenyl, heteroaryl groups are each optionally substituted with one or more groups selected from F, cl, cyano, hydroxy, cyclopropyl, cyclobutyl, -CH ₂ CH ₂ F、-OCHF ₂ 、-OCF ₃ 、/>Methyl, acetylene, methoxy, methoxymethyl, N-methylamino, N-dimethylamino, -/-dimethylamino>Is substituted by a substituent of (a).

In some embodiments, each R _s Each independently selected fromF. Cl, cyano, methyl, methoxy, ethoxy, cyclopropyl, cyclopropyloxy,

Said methyl, methoxy, ethoxy, cyclopropyl, cyclopropyloxy,/i> Each optionally being substituted with one or more groups selected from F, cl, cyano, hydroxy, cyclopropyl, cyclobutyl, -CH ₂ CH ₂ F、-OCHF ₂ 、-OCF ₃ 、/>Methyl, acetylene, methoxy, methoxymethyl, N-methylamino, N-dimethylamino, -/-dimethylamino>Is substituted by a substituent of (a).

Said methyl, methoxy, ethoxy, cyclopropyl, cyclopropyloxy,/i>/>Each optionally being substituted with one or more groups selected from F, cl, cyano, hydroxy, cyclopropyl, cyclobutyl, -CH ₂ CH ₂ F、-OCHF ₂ 、-OCF ₃ 、/>Methyl, acetylene, methoxy, methoxymethyl, amino, N-methylamino, N-dimethylamino, -/-dimethylamino>Is substituted by a substituent of (a).

In some embodiments, each R _s Each independently selected from Cl, cyano, methyl, -CF ₃ 、-CHF ₂ 、-OCF ₃ Ethoxy, cyclopropyl, cyclopropyloxy,

In some embodiments, each R _s Each independently selected from F, cl, cyano, methyl, -CF ₃ 、-CHF ₂ 、-OCF ₃ Methoxy, ethoxy, cyclopropyl, cyclopropyloxy,

In some embodiments, each R _s Each independently of the otherSelected from F, cl, methyl, methoxy,

In some embodiments, R ³ Selected from:

in some embodiments, R ³ Selected from:

in some embodiments, R ³ Selected from the group consisting ofWhere y=0, 1 or 2./>

In some embodiments, R ³ Selected from the group consisting ofIn some embodiments, R ³ Selected from the group consisting ofWhere y=0, 1 or 2.

In some embodiments, R ³ Selected from the group consisting ofWhere y=0, 1 or 2.

In some embodiments, R ³ Selected from the group consisting ofIn some embodiments, R ³ Selected from the group consisting ofIn some embodiments, R ³ Selected from->In some embodiments, R ³ Selected from->

In some embodiments, R ³ Selected from the group consisting of

In some embodiments of the present invention, in some embodiments,selected from: />Therein W, R ⁴ 、R ⁵ 、R ⁶ Each definition is as defined in formula I.

In some embodiments of the present invention, in some embodiments,selected from: />Therein W, R ⁴ 、R ⁶ Each definition is as defined in formula I.

In some embodiments, R ⁴ ，R ⁵ ，R ⁶ ，R ⁷ Independently selected from H, halogen, C ₁ -C ₃ Alkyl, C ₃ -C ₆ Cycloalkyl groups.

In some embodiments, R ⁴ ，R ⁵ ，R ⁶ ，R ⁷ Independently selected from H, F, cl, br, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, and cyclohexyl.

In some embodiments, R ⁴ ，R ⁵ ，R ⁶ ，R ⁷ Independently selected from H, F, cl, methyl, cyclopropyl.

In some embodiments, R ⁷ Selected from H, F, cl, br, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclohexyl; r is R ⁴ ，R ⁵ ，R ⁶ Each independently selected from H, methyl, ethyl, propyl.

In some embodiments, R ⁷ Selected from H, F, cl, methyl, cyclopropyl; r is R ⁴ ，R ⁵ ，R ⁶ Each independently selected from H, methyl.

In some embodiments, R ⁷ Selected from H, F, cl, methyl; r is R ⁴ ，R ⁵ ，R ⁶ Each independently selected from H, methyl.

In some embodiments of the present invention, in some embodiments,selected from:

/>

in some embodiments of the present invention, in some embodiments,selected from: />

in some embodiments of the present invention, in some embodiments,selected from->Selected from:

in some embodiments of the present invention, in some embodiments, Selected from: />

In some embodiments of the present invention, in some embodiments,selected from: />/>

In some embodiments, formula I has the following general structure IA:wherein R is ¹ 、R ² 、R ³ The definition is as described in formula I.

In some embodiments, formula I has a general structure selected from any of the following structures IA-1, IA-2, IB:wherein R is ¹ 、R ³ X, Y, Z, W are defined as in formula I.

In some embodiments, formula I has a general structure selected from any of the following:

wherein R is ¹ 、R ³ 、R ⁷ Each definition is as defined in formula I.

In some embodiments, R ⁴ ，R ⁵ ，R ⁶ ，R ⁷ Independently selected from H, F, cl, methyl.

In some embodiments, R ⁷ Independently selected from H, F, cl; r is R ⁴ ，R ⁵ ，R ⁶ Independently selected from H, methyl.

In some embodiments, W is CH, N, CF, CCl.

Wherein A is,B、R ⁷ 、R ⁸ Each definition is as defined in formula I.

in A, B, R ⁷ 、R ⁸ Each definition is as defined in formula I.

Herein, m, n, p, y, r refers to the number of the identification groups, which are independent of each other and do not affect each other, each time they occur. For example, define R ¹ Selected from C ₃ -C ₁₀ Cycloalkyl- (C) ₁ -C ₆ Alkyl group _m -, 4-10 membered heterocyclyl- (C) ₁ -C ₆ Alkyl group _m -, 5-to 10-membered heteroaryl- (C) ₁ -C ₆ Alkyl group _n -, 5-to 10-membered aryl- (C) ₁ -C ₆ Alkyl group _p -; where n=0 or 1, m=0 or 1, p=0 or 1 … … schemes may include several or more of the following:

1)R ¹ selected from C ₃ -C ₁₀ Cycloalkyl, 4-10 membered heterocyclyl- (C) ₁ -C ₆ Alkyl) -, 5-10 membered heteroaryl- (C ₁ -C ₆ Alkyl) -, 5-10 membered aryl;

2)R ¹ selected from C ₃ -C ₁₀ Cycloalkyl, 4-10 membered heterocyclyl, 5-10 membered heteroaryl, 5-10 membered aryl;

3)R ¹ selected from C ₃ -C ₁₀ Cycloalkyl- (C) ₁ -C ₆ Alkyl) -, 4-10 membered heterocyclyl, 5-10 membered heteroaryl, 5-10 membered aryl- (C) ₁ -C ₆ Alkyl) -.

In some embodiments, formula I is selected from any one of the following specific compounds:

/>

as used herein, the term "pharmaceutically acceptable salt" of a compound of formula (i) refers to an organic addition salt or organic complex salt formed from the compound and a pharmaceutically acceptable organic acid/organic base, or a mono-salt formed from the compound and a pharmaceutically acceptable anion/cation, including normal, acid or basic salts of the compound.

Pharmaceutically acceptable salts can be obtained using standard procedures well known in the art, for example, by reacting a sufficient amount of the basic/acidic compound with a suitable acid/base that provides a pharmaceutically acceptable anion/cation.

The preparation method comprises the following steps:

the invention also provides a method for preparing the compound. The preparation of the compounds of formula (I) of the present invention may be accomplished by the following exemplary methods and examples, which should not be construed as limiting the scope of the invention in any way. The compounds of the present invention may also be synthesized by synthetic techniques known to those skilled in the art, or by a combination of synthetic methods known in the art and methods of the present invention. The product from each step is obtained using separation techniques known in the art including, but not limited to, extraction, filtration, distillation, crystallization, chromatographic separation, and the like. The starting materials and chemical reagents required for the synthesis may be synthesized conventionally according to literature (as provided by scibinder) or purchased.

The synthetic process route I is as follows:

step one: treating a compound of formula IA '-1 with a compound of formula R-M under coupling conditions well known in the art to provide a compound of formula IA' -2;

step two: under reductive amination conditions well known in the art, using NH ₂ R ¹ Treatment of the compound of formula IA' -2The compound can be obtained as a compound shown in the formula IA' -3;

step three: treating a compound of formula IA ' -3 with a compound of formula IA ' -4 under condensation conditions well known in the art to provide a compound of formula IA ';

wherein Q is halogen, M is H, halogen, boric acid or borate, R is R ⁹ 、-OR ¹⁰ 、 X、Y、Z、W、A、B、E、R ¹ 、R ² 、R ⁸ 、R ⁹ 、R ¹⁰ 、R ¹¹ 、R ¹² 、R ¹³ 、R ¹⁴ The definition is as defined in formula (I) herein.

A second synthetic process route:

step two: treating the compound of IA '-2 with hydroxylamine hydrochloride to obtain a compound of formula IA' -5;

step three: treating the compound of IA '-5 with zinc powder to obtain a compound of formula IA' -6;

step four: under reductive amination conditions well known in the art, R is used ¹ Treatment of a compound of formula IA '-6 with a compound of=o gives a compound of formula IA' -3;

Step five: treating a compound of formula IA ' -3 with a compound of formula IA ' -4 under condensation conditions well known in the art to provide a compound of formula IA ';

wherein Q is halogen, M is H, halogen, boric acid or borate, R is defined as R ⁹ 、-OR ¹⁰ 、X、Y、Z、W、A、B、E、R ¹ 、R ² 、R ⁸ 、R ⁹ 、R ¹⁰ 、R ¹¹ 、R ¹² 、R ¹³ 、R ¹⁴ The definition is as defined in formula (I) herein.

A synthesis process route III:

step one: under reductive amination conditions well known in the art, using NH ₂ R ¹ The compound shown in the formula I-2 can be obtained by treating the compound shown in the formula I-1;

step two: treating a compound of formula I-2 with a compound of IA' -4 under condensation conditions well known in the art to provide a compound of formula I;

therein X, Y, Z, W, R ¹ 、R ² 、R ³ The definition is as defined in formula (I) herein.

The synthetic process route is four:

step one: treating the compound shown in the formula I-1 with hydroxylamine hydrochloride to obtain a compound shown in the formula I-3;

step two: treating the compound shown in the formula I-3 with zinc powder to obtain a compound shown in the formula I-4;

step three: under reductive amination conditions well known in the art, R is used ¹ Treatment of a compound of formula I-4 with a compound of=o gives a compound of formula I-2;

step four: treating a compound of formula I-2 with a compound of IA' -4 under condensation conditions well known in the art to provide a compound of formula I;

A fifth synthetic process route:

step one: under reductive amination conditions well known in the art, using NH ₂ R ¹ The compound shown in the formula IA '-1 can be treated to obtain a compound shown in the formula IA' -7;

step two: treating a compound of formula IA '-7 with a compound of formula R-M under coupling conditions well known in the art to provide a compound of formula IA' -3;

A synthesis process route six:

step one: under reductive amination conditions well known in the art, R is used ¹ Treatment of a compound of formula IA '-6 with a compound of=o gives a compound of formula IA' -7;

A seventh synthetic process route:

step one: under coupling conditions well known in the art, byThe compound shown in the formula IA '-3-1 can be obtained by treating the compound shown in the formula IA' -7;

step two: the compound shown in IA '-3-1 is subjected to TMS protecting group removal conditions well known in the art to obtain a compound shown in IA' -8;

step three: treating a compound of formula IA ' -8 with a compound of formula IA ' -4 under condensation conditions well known in the art to provide a compound of formula IA ';

wherein Q is halogen, X, Y, Z, W, A, B, R ¹ 、R ² 、R ¹⁴ The definition is as defined in formula (I) herein.

A synthetic process route eight:

step one: treating a compound of formula IA ' -7 with a compound of formula IA ' -4 under condensation conditions well known in the art to provide a compound of formula IA ' -9;

step two: treating a compound of formula IA '-9 with a compound of formula R-M under coupling conditions well known in the art to provide a compound of formula IA';

A synthesis process route nine:

step one: under coupling conditions well known in the art, byThe compound shown in the formula IA '-10 can be obtained by treating the compound shown in the formula IA' -9;

step two: the compound shown in IA' -10 is subjected to TMS removal (tetramethylsilane) as is well known in the art

The compound shown as IA' -X is obtained by the condition treatment of protecting groups;

step three: the compounds of formula IA' -X may be subjected to fluorination conditions well known in the art to provide compounds of formula IA ";

wherein Q is halogen, M is H, halogen, boric acid or borate, R ¹⁵ 、R ¹⁶ Independently selected from hydrogen or methyl, X, Y, Z, W, A, B, R ¹ 、R ² 、R ¹⁴ The definition is as defined in formula (I) herein.

A synthesis process route is ten:

/>

step one: under coupling conditions well known in the art, R is used ⁸ -treating the compound of formula IA '-8 with a compound of formula M to obtain a compound of formula IA' -11;

step two: treating a compound of formula IA ' -11 with a compound of formula IA ' -4 under condensation conditions well known in the art to provide a compound of formula IA ';

wherein M is halogen, boric acid or borate, X, Y, Z, W, A, B, R ¹ 、R ² 、R ⁸ 、R ¹⁴ The definition is as defined in formula (I) herein.

Pharmaceutical composition:

the invention also provides a pharmaceutical composition for treating and/or preventing diseases related to abnormal PRMT5 expression, which comprises a therapeutically and/or prophylactically effective amount of the compound as described above or a tautomeric form thereof, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, and optionally a pharmaceutical adjuvant.

In some embodiments, the disease associated with abnormal PRMT5 expression is a tumor or cancer.

In some embodiments, the disease associated with abnormal PRMT5 expression refers to a MTAP deleted disease associated with abnormal PRMT5 expression.

In some embodiments, the disease associated with abnormal PRMT5 expression is referred to as MTAP-deleted tumor or cancer.

Methods of preparing various pharmaceutical compositions containing certain amounts of the active ingredient are known or will be apparent to those of skill in the art in light of the present disclosure. Methods of preparing the pharmaceutical compositions include incorporation of suitable pharmaceutical excipients, carriers, diluents, and the like, as described in REMINGTON' S PHARMACEUTICAL SCIENCES, martin, e.w., ed., mack Publishing Company,19th ed. (1995).

The present invention also provides a PRMT5 inhibitor comprising a therapeutically and/or prophylactically effective amount of a compound as described hereinbefore, or a tautomeric form thereof, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof.

The medical application comprises the following steps:

the invention also provides the use of a compound as hereinbefore described or a tautomeric form thereof, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, or a pharmaceutical composition as hereinbefore described, in the preparation of a PRMT5 inhibitor.

The invention also provides the compound or a tautomeric form thereof, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, or a pharmaceutical composition as described above, in the preparation of a medicament for treating and/or preventing diseases related to abnormal PRMT5 expression.

The invention also provides the use of a compound as described above or a tautomeric form thereof, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, or a pharmaceutical composition as described above, in the treatment and/or prevention of a disease associated with abnormal PRMT5 expression.

The present invention also provides a compound as described above or a tautomeric form thereof, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, or a pharmaceutical composition as described above, for use in the treatment and/or prevention of a disease associated with abnormal PRMT5 expression.

The present invention also provides a method of treating and/or preventing a disease associated with abnormal PRMT5 expression comprising administering to a subject in need thereof a therapeutically and/or prophylactically effective amount of a compound as described above, or a tautomeric form thereof, or a pharmaceutically acceptable salt form thereof, or a deuterated compound thereof, or a pharmaceutical composition as described above.

In the present invention, "treatment" generally means obtaining a desired pharmacological and/or physiological effect. The effect may be prophylactic according to the prevention of the disease or symptoms thereof, in whole or in part; and/or may be therapeutic in terms of partial or complete stabilization or cure of the disease and/or side effects due to the disease. As used herein, "treatment" encompasses any treatment of a disease in a patient, including: (a) Disease or symptoms that occur in a patient that is prevented but has not yet been diagnosed with the disease; (b) inhibiting the symptoms of the disease, i.e., arresting its development; or (c) alleviating a symptom of the disease, i.e., causing regression of the disease or symptom.

In the present invention, "subject", "individual in need thereof" refers to a vertebrate. In certain embodiments, a vertebrate refers to a mammal. Mammals include, but are not limited to, livestock (such as cattle), pets (such as cats, dogs, and horses), primates, mice, and rats. In certain embodiments, the mammal refers to a human.

In the present invention, an "effective amount" refers to an amount effective to achieve the desired therapeutic or prophylactic effect at the necessary dosages and times. The "therapeutically effective amount" of a substance/molecule of the invention may vary depending on factors such as the disease state, age, sex and weight of the individual, the ability of the substance/molecule to elicit a desired response in the individual, and the like. A therapeutically effective amount also encompasses an amount of the substance/molecule that has a therapeutic benefit over any toxic or detrimental effect. "prophylactically effective amount" refers to an amount effective to achieve the desired prophylactic effect at the dosages and for the time necessary. Generally, but not necessarily, since the prophylactic dose is for the subject prior to the onset of the disease or early in the disease, the prophylactically effective amount will be less than the therapeutically effective amount. In the case of cancer, a therapeutically effective amount of the drug may reduce the number of cancer cells; reducing the tumor volume; inhibit (i.e., slow, preferably stop to some extent) infiltration of cancer cells into surrounding organs; inhibit (i.e., slow, preferably stop to some extent) tumor metastasis; inhibit tumor growth to a certain extent; and/or to some extent, alleviate one or more symptoms associated with cancer.

Definition of terms:

in accordance with the convention in the art,a bond as used in the formulae herein is described as the point of attachment of the moiety or substituent to the parent or host structure.

A dash "-" that does not appear between two letters or symbols is used to indicate a point of attachment for a substituent. For example, C ₁ -C ₃ alkyl-C (O) -is attached to the remainder of the molecule through a C atom in-C (O) -.

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

The term "alkyl" as used herein is meant to include both branched and straight chain saturated aliphatic hydrocarbon groups having the indicated number of carbon atoms. For example, "C _1-6 Alkyl "means C ₁ 、C ₂ 、C ₃ 、C ₄ 、C ₅ And C ₆ . In addition, e.g. "C _1-6 Alkyl "refers to an alkyl group having 1 to 6 carbon atoms. The alkyl group may be unsubstituted or substituted such that one or more hydrogens thereof are replaced with another chemical group. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl (e.g., n-propyl Propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, tert-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), and the like. Those skilled in the art will appreciate that C herein _1-6 Alkyl groups containing monovalent C _1-6 Alkyl, divalent C _1-6 An alkylene group.

The term "alkoxy" refers to any of the above alkyl groups (e.g., C _1-6 Alkyl, C _1-4 Alkyl, C _1-3 Alkyl, etc.) linked to the rest of the molecule through an oxygen atom (-O-).

The term "halogenated C _1-6 Alkyl "or" halo C _1-6 Alkoxy "means that one or more (e.g., 2, 3) hydrogen atoms in the alkyl or alkoxy group are replaced with a halogen atom, such as fluorine, chlorine, bromine. The definition of alkyl or alkoxy is as described above. In some embodiments, the term "halo C _1-6 Alkyl "is preferably fluoro, and may be-CF, for example ₃ 、-CHF ₂ 、-CH ₂ F、-CH ₂ CH ₂ F、-CH ₂ CHF ₂ 、-CH ₂ CF ₃ Etc. In some embodiments, the term "halo C _1-6 Alkoxy "is preferably fluoro, and may be-OCF, for example ₃ 、-OCHF ₂ 、-OCH ₂ F、-OCH ₂ CH ₂ F、-OCH ₂ CHF ₂ 、-OCH ₂ CF ₃ Etc.

The term "hydroxy-substituted C _1-6 Alkyl "means that one hydrogen atom of the alkyl group is substituted with a hydroxyl group, and the definition of the alkyl group is as described above. By way of example, the "hydroxy-substituted C _1-6 The alkyl "may be hydroxymethyl.

"alkenyl" refers to a hydrocarbon group comprising a straight or branched chain configuration and having one or more carbon-carbon double bonds that may be present at any stable point along the chain. For example, "C _2-6 Alkenyl "is meant to include C ₂ 、C ₃ 、C ₄ 、C ₅ And C ₆ . Examples of alkenyl groups include, but are not limited to, vinyl, 1-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl,2-methyl-2-propenyl, 4-methyl-3-pentenyl, and the like.

"alkynyl" refers to a hydrocarbon group comprising a straight or branched configuration and having one or more carbon-carbon triple bonds that may be present at any stable point along the chain. For example "C _2-6 Alkynyl "is meant to include C ₂ 、C ₃ 、C ₄ 、C ₅ And C ₆ Alkynyl groups. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.

It will be appreciated by those skilled in the art that when "-CO-" is used herein, this refers to a group

The term "substituted" as used herein means that any one or more hydrogens on the designated atom or group are replaced with a selection from the designated group, provided that the designated atom's normal valence is not exceeded.

The term "cycloalkyl" refers to a cyclized alkyl group and includes monocyclic, bicyclic, or polycyclic ring systems. E.g. C _3-10 Cycloalkyl is meant to include C ₃ 、C ₄ 、C ₅ 、C ₆ 、C ₇ 、C ₈ 、C ₉ And C ₁₀ Cycloalkyl groups. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. "cycloalkyl" includes all carbocyclic groups except aryl groups as defined below. Including but not limited to when the cycloalkyl is bicyclic or tricyclic, at least one of which is a saturated carbocyclic ring or carbocyclic residue, and one or both of which may be aromatic, non-aromatic, saturated or unsaturated carbocyclic rings, e.g As used herein, "carbocycle" or "carbocycle residue" refers to any stable 3-, 4-, 5-, 6-, or 7-membered single or bicyclic or 7-, 8-, 9-, 10-, 11-, 12-membered bicyclic or tricyclic ring, any of which may be saturated, partially saturated, unsaturated, or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, and ringPentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptenyl, cycloheptyl, adamantyl, cyclooctyl, phenyl, naphthyl, and the like. As indicated above, bridged rings are also included within the definition of carbocyclic rings, e.g., [2,2]Bicyclooctane. Preferred carbocycles are cyclopropyl, cyclobutyl, cyclopentyl and phenyl, unless otherwise specified. A bridging ring is created when one or more carbon atoms connects two non-adjacent carbon atoms. Preferred bridges are one or two carbon atoms. It should be noted that the bridge always converts a single ring into a double ring. In the case of ring bridging, the substituents described for the ring may also be present on the bridge. All terms "cycloalkyl" herein do not include "aryl" as defined below, but include "spirocycloalkyl", "bridged cycloalkyl" as described below.

The term "aryl" refers to a monocyclic, bicyclic or tricyclic aromatic hydrocarbon group having 5 to 14 carbon atoms in the ring portion, and the manner in which two rings of a bicyclic aryl may be attached includes bridged, fused, spiro. Such as phenyl and naphthyl, each of which may be substituted. As used herein, "aryl" refers to an aromatic ring when the aryl is bicyclic or tricyclic.

The terms "heterocycle", "heterocyclic" or "heterocyclyl" are used interchangeably and refer to substituted and unsubstituted 4-to 8-membered monocyclic, 8-to 10-membered bicyclic and 10-to 14-membered tricyclic groups, wherein at least one ring has at least one heteroatom (O, S or N), and the heteroatom-containing ring preferably has 1, 2 or 3 heteroatoms selected from O, S and N. Each heteroatom-containing ring in the group may contain 1 or 2 oxygen or sulfur atoms and/or 1 to 4 nitrogen atoms, with the proviso that the total number of heteroatoms in each ring is 4 or less, and with the further proviso that the ring contains at least one carbon atom, in some preferred embodiments, the heteroatoms refer to only N or O and the total number is no more than 3, preferably only 1-2 heteroatoms. The nitrogen and sulfur atoms may optionally be oxidized and the nitrogen atom may optionally be quaternized, and the ring atoms on the heterocycle may optionally be substituted with =o (oxo) when the valency permits. (e.g.: ). The fused rings completing the bi-and tri-cyclic groups may contain only carbon atoms and may be saturated, partially saturated or fully unsaturated, aromatic or non-aromatic. The heterocyclic group may be attached at any available nitrogen or carbon atom. All terms "heterocycle", "heterocycloalkyl", "heterocyclic" and "heterocyclyl" herein do not include "heteroaryl" as defined below, but include "spiroheterocycloalkyl", "heterobridged cycloalkyl" and "heterocycloalkenyl" as described below. In particular, heterocycloalkyl groups herein may include monocyclic heterocycloalkyl, bicyclic heterocycloalkyl, tricyclic heterocycloalkyl, cycloalkyl-heteroaryl, heterocyclyl-heteroaryl, cycloalkyl-heterocyclyl, and the like, i.e., include all heteroatom-containing cyclic groups except heteroaryl as defined below.

Exemplary monocyclic heterocyclic groups include azetidinyl, oxetanyl, pyrrolidinyl, imidazolinyl, oxazolidinyl, isoxazolinyl, thiazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazetidinyl, 1-pyridonyl, 4-piperidonyl, tetrahydropyranyl, morpholinyl, 1, 3-dioxolanyl, and the like. Exemplary bicyclic heterocyclic groups include quinuclidinyl. Other monocyclic heterocyclic groups include:

The term "saturated heterocyclic group" refers to a heterocyclic group as described above, wherein the monocyclic group, or the bicyclic group, or the tricyclic group is in a fully saturated state. The "heterocyclyl" is as described above. As an example, the saturated heterocyclic group may be morpholinyl (e.g) Piperidinyl (e.g.)>) Piperazinyl->Etc.

The term "heterocycloalkyl" refers to a heterocyclic group in which all ring atoms are fully saturated in the heterocyclic ring as defined above, e.g

The term "heterocycloalkenyl" refers to a heterocyclic group having at least one carbon-carbon double bond in a heterocycle as defined above, e.g

The term "heteroaryl" refers to substituted and unsubstituted aryl groups as described above having at least one heteroatom (O, N or S) in at least one ring, including aromatic 5-or 8-membered monocyclic, 8-or 10-membered bicyclic and 10-to 14-membered tricyclic groups, the heteroatom-containing ring preferably having 1, 2 or 3 heteroatoms selected from O, N or S. Each heteroatom-containing ring of a heteroaryl group may contain 1 or 2 oxygen or sulfur atoms and/or 1 to 4 nitrogen atoms, provided that the total number of heteroatoms in each ring is 4 or less and that each ring has at least one carbon atom. The nitrogen and sulfur atoms may optionally be oxidized and the nitrogen atoms may optionally be quaternized. Heteroaryl groups which are bicyclic or tricyclic are each a fully aromatic ring.

The term "spirocycloalkyl" refers to a bicyclic structure having one common ring atom, and each monocyclic ring has 3 to 7 carbon atoms. Exemplary spirocycloalkyl groups include, but are not limited to: spiro [4.5] decane, spiro [3.4] octane, spiro [2.3] hexane.

The term "spiroheterocyclyl" or "spiroheterocycloalkyl" refers to a bicyclic structure having one common ring carbon atom, and each monocyclic ring is a saturated or unsaturated monovalent monocyclic group having 4 to 8 ring atoms, wherein 1 or 2 ring atoms are selected from N, O or S (O) _n Wherein n is an integer from 0 to 2 and the remaining ring atoms are C. In addition, 1 or 2 ring carbon atoms in the heterocyclyl ring may optionally be replaced by a-CO-group. Exemplary spiroheterocyclyl groups include, but are not limited to: 5-azaScrew [2.3]]Hexane, 6-oxaspiro [3.4]]-7-octanone.

The term "bridged cyclic group" or "bridged cycloalkyl" refers to a saturated monocyclic 4 to 7 membered hydrocarbon group in which two non-adjacent ring atoms pass through (CRR) _n A group or bond linkage, wherein n is an integer from 1 to 3, and each R is independently H or methyl (wherein, (CRR) _n Groups are also referred to herein as bridging groups). Bridged cycloalkyl groups are optionally substituted with one or two substituents independently selected from alkyl, halo, alkoxy, hydroxy or cyano, wherein alkyl, alkoxy are each as defined above. Examples of bridged cycloalkyl groups include, but are not limited to, bicyclo [2.2.1 ]Heptane, bicyclo [2.2.2]Octane, and the like. It will be understood herein that when two non-adjacent ring atoms of a monocyclic 4-to 7-membered hydrocarbon group are connected by a bond, the "bridged cycloalkyl" may be referred to as "fused cycloalkyl" or "fused ring alkyl".

The term "heterobridged cyclic" or "heterobridged cycloalkyl" refers to a saturated monocyclic ring having 4 to 7 ring carbon atoms, wherein two non-adjacent ring atoms pass through (CRR) _n A group or bond linkage, wherein n is an integer from 1 to 3, and each R is independently H or methyl (wherein, (CRR) _n A group is also referred to herein as a "bridging" group); and further wherein one or both ring carbon atoms (including carbon atoms in the bridging group) are replaced by heteroatoms selected from N, O or S (O) n, where n is an integer from 0 to 2. The bridged heterocyclyl may be optionally substituted with one or two substituents independently selected from alkyl, halo, alkoxy, hydroxy or cyano, wherein alkyl, alkoxy are each as defined above. Examples include, but are not limited to, 2-azabicyclo [2.2.2]Octane, quinuclidine, 7-oxabicyclo [2.2.1]Heptane, and the like. It will be understood herein that when two non-adjacent ring atoms of a monocyclic 4-to 7-membered hydrocarbon group are connected by a bond, the "heterobridged cycloalkyl" may be referred to as "heterocycloalkyl" or "heterofused ring alkyl".

Unless otherwise indicated, when referring to an explicitly named aryl (e.g., phenyl), cycloalkyl (e.g., cyclohexyl), heterocycle (e.g., pyrrolidinyl, piperidinyl, morpholinyl), or heteroaryl (e.g., imidazolyl, pyrazolyl, triazolyl), the reference is meant to include rings having from 0 to 3, preferably from 0 to 2 substituents, which are optionally selected from the substituents described above for aryl, cycloalkyl, heterocycle, and/or heteroaryl.

The term "heteroatom" shall include oxygen, sulfur and nitrogen.

The term "halogen" shall include "F, cl, br, I".

When the term "unsaturated" is used herein to refer to a ring or group, the ring or group may be fully unsaturated or partially unsaturated.

From all of the above descriptions, it will be apparent to those skilled in the art that any group whose name is a compound name, e.g. "C _3-10 cycloalkyl-C (O) - ", shall mean moieties conventionally derived therefrom, e.g., from C _3-10 Cycloalkyl substituted carbonyl, wherein cycloalkyl is as defined above. Other similar compound names may be understood with reference to the foregoing.

The term "optional" means optional or not. For example, "optionally 1 to 3R ^d Substituted C _1-6 Alkyl ", which means, the C _1-6 Alkyl can be substituted with 1 to 3R ^d Substituted or not by 1 to 3R ^d Substituted. Other similar definitions may be understood with reference to the foregoing.

The term "the ring atoms of the 5-10 membered heterocyclyl may optionally be oxo" means that the ring atoms on the heterocycle may optionally be substituted with =o (oxo) (e.g.:ring atom CH of ₂ After oxo the radical +.>)。

Throughout the specification, groups and substituents thereof may be selected by one skilled in the art to provide stable moieties and compounds useful as pharmaceutically acceptable compounds and/or intermediate compounds useful in the preparation of pharmaceutically acceptable compounds.

As used herein, unless expressly indicated otherwise, the description that "…" are each independently selected from "may mean that the particular items expressed between the same or different symbols in different groups do not affect each other, or that the particular items expressed between the same or different symbols in the same groups do not affect each other.

The term "XXX substituted at any substitutable position with one or more substituents selected from YYY" means that XXX may be substituted at any substitutable position with one or more substituents selected from YYY. When XXX is substituted with a plurality of substituents selected from YYY at any substitutable position, the plurality of substituents may be the same or different. Wherein the plurality is 2 or more, preferably 2, 3 or 4, more preferably 2 or 3. For example, C _1-6 Alkyl substituted at any substitutable position by one or more substituents selected from cyano and hydroxy, which represents, C _1-6 The alkyl group may be substituted with one or more cyano groups at any substitutable position, may be substituted with one or more hydroxy groups at any substitutable position, and may be substituted with one or more cyano groups and hydroxy groups (e.g., one cyano group and one hydroxy group, or two cyano groups and two hydroxy groups, etc.) at any substitutable position simultaneously.

In this context, the compound name is based on the compound structure when the compound name is inconsistent with the compound structure.

The invention has the following effects:

the compound shown in the formula (I) has good PRMT5 inhibition effect, and particularly has excellent PRMT5 inhibition activity on PRMT5 of MTAP-deleted tumors; can be used as a medicament for the treatment and/or prevention of diseases associated with the action. Furthermore, the data of the compound provided by the invention in the liver microsome stability test and the mouse PK drug generation test are obviously superior to those of the existing compound, and the compound shows excellent patent drug properties.

Detailed Description

It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. In addition, although any methods, devices, and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods, devices, and materials are now described.

The structure of the compound is determined by Nuclear Magnetic Resonance (NMR) or Mass Spectrometry (MS). NMR was performed using Bruker ASCENA-400 nuclear magnetic resonance apparatus using deuterated dimethyl sulfoxide (DMSO-d 6), deuterated chloroform (CDCl 3), deuterated methanol (CD) ₃ OD), internal standard Tetramethylsilane (TMS), chemical shift of 10 ^-6 (ppm) is given as a unit.

Reaction monitoring and MS determination a thermofiser ESQ (ESI) mass spectrometer was used.

HPLC was performed using a Siemens Feu 3000 DAD high pressure liquid chromatograph (GL Sciences ODS-HL HP 3.mu.m3.0X100 mm column).

The thin layer chromatography silica gel plate uses Qingdao ocean GF254 silica gel plate, the specification of the silica gel plate used by the Thin Layer Chromatography (TLC) is 0.15-0.2 mm, and the specification of the thin layer chromatography separation and purification product is 0.9-1.0 mm. Column chromatography uses 200-300 mesh silica gel of Qingdao ocean as a carrier, and a system used by a developing agent comprises the following components: methylene chloride and methanol systems; b: petroleum ether and ethyl acetate systems, and the volume ratio of the solvent is adjusted according to the polarity of the compounds. The biotage isera one type preparative liquid phase is used for purification of the medium pressure preparative liquid phase.

In the following examples, all reaction materials were purchased from suppliers in the scibinder database, and for example, some reagents in the examples of the present invention were purchased from manufacturers such as saen chemical technology (Shanghai), shanghai Shaoshao reagent Limited, nanjing pharmaceutical technology Co., jiangsu Aikang biological medicine research and development Co., shanghai Bi medicine Co., ltd, unless otherwise specified. Further, unless otherwise indicated, all starting materials used in the examples of the present invention were analytically pure.

In the examples below, the percentages of solutions relating to solid substances are mass percentages unless otherwise indicated; the ratio of the two liquids is referred to as volume percent.

Shorthand paraphrasing

Example 1: 4-amino-N- (2, 3-dihydro-1H-indenyl) -N- { [5- (3-methoxyprop-1-ynyl) pyridin-2-yl ] methyl } -1, 3-dihydrofuro [4,3-c ] quinoline-8-carboxamide

Preparation of N- ((5-bromopyridin-2-yl) methyl) -2, 3-dihydro-1H-inden-1-amine (1 c) to a solution of (5-bromopyridin-2-yl) methylamine (200 mg,1.07 mmol) and 2, 3-dihydro-1H-inden-1-one (212.1 mg,1.60 mmol) in THF (10 mL) was added isopropyl titanate (607.9 mg,2.14 mmol), and the reaction mixture was stirred at 25℃for 12 hours, and sodium borohydride (60.6 mg,1.60 mmol) was added at 0℃followed by stirring at room temperature for 2 hours. The reaction solution is extracted by adding 2N hydrochloric acid solution, and the pH value is=3-5. Ethyl acetate (5 mL) and water (5 mL) were added to dilute, the mixture was separated, the aqueous phase was adjusted to ph=8 to 9 with saturated sodium carbonate solution, ethyl acetate (10 mL) was added to extract, and the organic phase was concentrated and subjected to thin layer chromatography (dichloromethane: methanol=15:1) to give compound 1c (380 mg, purity 70%). ESI-MS (m/z): 303.07[ M+H ]] ⁺ . Preparation of N- ((5- (3-methoxyprop-1-ynyl) pyridin-2-yl) methyl) -2, 3-dihydro-1H-inden-1-amine (1 d) compound 1c (200 mg,0.66 mmol), 3-methoxyprop-1-yne (92.5 mg,1.32 mmol), cuprous iodide (62.8 mg,0.33 mmol), tetrakis (triphenylphosphine) palladium (152.5 mg,0.13 mmol), triethylamine (0.44 mL,2.64 mmol) were dissolved in N-methylpyrrolidone (2 mL), nitrogen was displaced 3 times, after microwave reaction of the reaction solution at 70 ℃ for 3 hours, the reaction solution was diluted with ethyl acetate (5 mL) and water (5 mL), the solid was precipitated, filtered, the filtrate was separated, and the organic phase was concentrated to obtain crude product by thin layer chromatography (dichloromethane: methanol=10:1) to give 1d (170 mg). ESI-MS (m/z): 293.15[ M+H ] ] ⁺ 。

4-amino-N- (2, 3-dihydro-1H-indenyl) -N- { [5- (3-methoxyprop-1-ynyl) pyridin-2-yl]Methyl } -1, 3-dihydrofuro [4,3-c ]]Preparation of quinoline-8-carboxamide (1)To a solution of compound 1d (50 mg,0.17 mmol) in N, N-dimethylacetamide (2 mL) was added intermediate 1e (39.1 mg,0.17mmol, see WO 2022/115377 A1), triethylamine (0.08 mL,0.60 mmol), tripyrrolidinylphosphonium bromide hexafluorophosphate (103.6 mg,0.22 mmol), followed by reaction at 25℃for 18 hours. After the completion of the reaction, the reaction mixture was filtered, and the filtrate was purified by high-pressure liquid chromatography to give Compound 1 (10 mg). ESI-MS (m/z): 505.28[ M+H ]] ⁺ .1H NMR(400MHz,DMSO-d ₆ )δ8.56(s,1H),7.96–7.13(m,9H),6.94(s,2H),5.51–5.38(m,3H),5.02(s,2H),4.69–4.64(m,1H),4.35(s,2H),4.08–4.05(m,1H),3.34(s,3H),2.87–2.81(m,2H),2.04–1.97(m,2H).

Example 2: 4-amino-N-cyclopropyl-N- ((5-ethynylpyridin-2-yl) methyl) -1, 3-dihydrofuro [4,3-c ] quinoline-8-carboxamide

Preparation of N- ((5-bromopyridin-2-yl) methyl) cyclopropylamine (2 b)

5-bromopyridine-2-carbaldehyde (186 mg,1.0 mmol), cyclopropylamine (62 mg,1.1 mmol) and acetic acid (7.2 g,38.7 mmol) were dissolved in methylene chloride (100 mL), and sodium triacetylborohydride (10.2 g,48.4 mmol) was added to the reaction mixture, which was reacted at 25℃for 18 hours. The reaction mixture was quenched with water (50 mL), pH was adjusted to 8 with saturated aqueous sodium bicarbonate, extracted with dichloromethane (100 ml×3), the organic phases were combined, concentrated and purified by thin layer chromatography (dichloromethane: methanol=95:5) to give compound 2b (227 mg). ESI-MS (m/z): 227.03[ M+H ] ] ⁺ 。

Preparation of N- ((5- ((trimethylsilyl) ethynyl) pyridin-2-yl) methyl) cyclopropylamine (2 c)

Compound 2b (227 g,1 mmol), ethynyl trimethylsilane (186 mg,2.0 mmol), cuprous iodide (38 mg,0.2 mmol), tetrakis (triphenylphosphine) palladium (115 mg,0.1 mmol) and N, N-diisopropylethylamine (640 mg,5.0 mmol) were dissolved in N-methylpyrrolidone (2 mL). The nitrogen is replaced for 3 times, and the reaction is carried out for 3 hours at the temperature of 70 ℃ by microwaves. The reaction solution was diluted with ethyl acetate (20 mL) and water (20 mL), solids were precipitated, filtered, the filtrate was separated, and the organic phase was concentrated and concentrated to a thin fractionLayer preparative chromatography (dichloromethane: methanol=92:8) gave 2c (160 mg). ESI-MS (m/z): 245.22[ M+H ]] ⁺ 。

Preparation of N- ((5-ethynylpyridin-2-yl) methyl) cyclopropylamine (2 d)

Compound 2c (160 mg,0.65 mmol) was dissolved in tetrahydrofuran (5 mL), 1M tetrabutylammonium fluoride tetrahydrofuran solution (1 mL) was added, and the reaction mixture was stirred at 25℃for 1h. The reaction was quenched with water (5 mL), extracted with ethyl acetate (5 mL x 3) and the organic phase concentrated to give the crude product by thin layer chromatography (dichloromethane: methanol=93:7) to give 2d (115 mg). ESI-MS (m/z): 173.14[ M+H ]] ⁺ 。

Preparation of 4-amino-N-cyclopropyl-N- ((5-ethynylpyridin-2-yl) methyl) -1, 3-dihydrofuro [4,3-c ] quinoline-8-carboxamide (2)

To a solution of compound 2d (50 mg,0.17 mmol) in N, N-dimethylacetamide (2 mL) was added compound 1e (39.1 mg,0.17 mmol), triethylamine (0.08 mL,0.6 mmol) and tripyrrolidinylphosphonium bromide hexafluorophosphate (103.6 mg,0.22 mmol) successively. The reaction solution was reacted at 25℃for 18 hours, filtered, and the filtrate was purified by high pressure liquid chromatography to give Compound 2 (10 mg). ESI-MS (m/z): 385.21[ M+H ]] ⁺ .1HNMR(600MHz,DMSO-d ₆ )δ8.67(d,J＝2.4Hz,1H),7.91(dd,J＝7.8,2.4Hz,1H),7.70(s,2H),7.56–7.54(m,1H),7.40–7.39(m,1H),6.68(s,2H),5.34(s,2H),5.02(t,J＝3.6Hz,2H),4.77(s,2H),4.42(s,1H),2.94–2.91(m,1H),0.52–0.46(m,4H).

Example 3: 4-amino-N- (2-cyanocyclopentyl) -N- ((5-ethynylpyridin-2-yl) methyl) -1, 3-dihydrofuran [3,4-c ] quinoline-8-carboxamide

Preparation of 2- ((5-bromopyridin-2-yl) methyl) amino) cyclopentane-1-carbonitrile (3 a) (5-bromopyridin-2-yl) carboxamide (187 mg,1.0 mmol), 2-cyanocyclopentanone (109 mg,1.0 mmol) and acetic acid (72 mg,1.2 mmol) were dissolved in dichloromethane (5 mL) and sodium triacetoxyborohydride (424 mg,2.0 mmol) was added. The reaction mixture was quenched with water (10 mL) at 25℃for 18 hours, and the pH was adjusted to 8 with saturated aqueous sodium bicarbonateMethyl chloride extraction (100 ml x 3), concentration of the organic phase followed by thin layer chromatography (dichloromethane: methanol=95:5) afforded intermediate 3a (110 mg). ESI-MS (m/z): 279.92[ M+H ]] ⁺ 。

Preparation of 2- (((5- ((trimethylsilyl) ethynyl) pyridin-2-yl) methyl) amino) cyclopentane-1-carbonitrile (3 b)

Compound 3a (110 mg,0.39 mmol), ethynyl trimethylsilane (77.2 mg,0.785 mmol), cuprous iodide (15.23 mg,0.08 mmol), tetrakis (triphenylphosphine) palladium (46.2 mg,0.04 mmol) and N, N-diisopropylethylamine (258 mg,0.08 mmol) were dissolved in N-methylpyrrolidone (2 mL), nitrogen was replaced 3 times, the reaction mixture was diluted with ethyl acetate (20 mL) and water (20 mL) to give a solid, the solid was filtered, the filtrate was separated, and the organic phase was concentrated to give crude product which was purified by thin layer chromatography (dichloromethane: methanol=92:8) to give 3b (130 mg). ESI-MS (m/z): 298.20[ M+H ]] ⁺ 。

Preparation of 2- (((5-ethylpyridin-2-yl) methyl) amino) cyclopentane-1-carbonitrile (3 c) Compound 3b (130 mg,0.44 mmol) was dissolved in tetrahydrofuran (5 mL), 1M tetrabutylammonium fluoride tetrahydrofuran solution (1 mL) was added, and stirred at 25℃for 1h. The reaction was quenched with water (5 mL), extracted with ethyl acetate (5 mL x 3) and the organic phase concentrated to give the crude product by thin layer chromatography (dichloromethane: methanol=93:7) to give 3c (65 mg). ESI-MS (m/z): 226.12[ M+H ]] ⁺ 。

4-amino-N- (2-cyanocyclopentyl) -N- ((5-ethynylpyridin-2-yl) methyl) -1, 3-dihydrofuran [3,4-c]Preparation of quinoline-8-carboxamide (3) to a solution of compound 3c (22.5 mg,0.10 mmol) in N, N-dimethylacetamide (2 mL) was added compound 1e (23 mg,0.10 mmol), triethylamine (0.03 mL,0.30 mmol), tripyrrolidinylphosphonium bromide hexafluorophosphate (57.15 mg,0.15 mmol), and the reaction was reacted at 25℃for 18 hours. The reaction solution was filtered, and the filtrate was purified by high pressure liquid chromatography to give compound 3 (10 mg). ESI-MS (m/z): 438.2[ M+H ] ] ⁺ . ¹ H NMR(600MHz,DMSO-d ₆ )δ8.68–8.65(m,1H),7.89–7.87(m,1H),7.56–7.34(m,4H),6.70-6.68(m,2H),5.30-5.17(m,2H),5.01-4.98(m,2H),4.73–4.66(m,2H),4.64–4.56(m,1H),4.43–4.42(m,1H),2.01–1.57(m,6H)。

Example 4: 4-amino-N- ((5-ethynylpyridin-2-yl) methyl) -N- (tetrahydro-2H-pyran-4-yl) methyl-1, 3-dihydrofuran [3,4-c ] quinoline-8-carboxamide

Preparation of 1- (5-bromopyridin-2-yl) -N- ((tetrahydro-2H-pyran-4-yl) methyl) carboxamide (4 a)

Compound 2a (187 mg,1.0 mmol), (tetrahydro-2H-pyran-4-yl) carboxamide (127 mg,1.1 mmol) and acetic acid (72 mg,1.2 mmol) were dissolved in dichloromethane (5 mL) and sodium triacetylborohydride (424 mg,2.0 mmol) was added and the reaction was reacted at 25℃for 18 hours. Quench with water (50 mL), adjust pH to 8 with saturated aqueous sodium bicarbonate, extract with dichloromethane (100 mL x 3), concentrate the organic phase and obtain 4a (252 mg) by thin layer chromatography (dichloromethane: methanol=95:5). ESI-MS (m/z): 287.21[ M+H ]] ⁺ 。

Preparation of 1- (tetrahydro-2H-pyran-4-yl) -N- ((5- ((trimethylsilyl) ethynyl) pyridin-2-yl) methyl) methylamine (4 b)

Compound 4a (252 mg,0.88 mmol) was dissolved in N-methylpyrrolidone (2 mL), ethynyl trimethylsilane (173.7 mg,1.77 mmol), cuprous iodide (33.52 mg,0.18 mmol), tetrakis (triphenylphosphine) palladium (102 mg,0.09 mmol) and N, N-diisopropylethylamine (218 mg,4.40 mol) were added, nitrogen was substituted 3 times, and the reaction was carried out at 70℃for 3 hours by microwaves. The reaction mixture was diluted with ethyl acetate (20 mL) and water (20 mL), a solid was precipitated, filtered, and the filtrate was separated, and the organic phase was concentrated and subjected to thin layer chromatography (dichloromethane: methanol=92:8) to give 4b (163 mg). ESI-MS (m/z): 303.17[ M+H ] ] ⁺ 。

Preparation of 1- (5-ethylpyridin-2-yl) -N- ((tetrahydro-2H-pyran-4-yl) methyl) carboxamide (4 c) Compound 4b (163 mg,0.54 mmol) was dissolved in tetrahydrofuran (5 mL), 1M tetrabutylammonium fluoride in tetrahydrofuran (1 mL) was added and stirred at 25℃for 1H. The reaction was quenched with water (5 mL), extracted with ethyl acetate (5 mL x 3), the organic phases were combined, concentrated and purified by thin layer chromatography (dichloromethane: methanol=93:7) to give 4c (150 mg). ESI-MS (m/z): 231.17[ M+H ]] ⁺ 。

4-amino-N- ((5-ethynyl pyridine)-2-yl) methyl) -N- (tetrahydro-2H-pyran-4-yl) methyl-1, 3-dihydrofuran [3,4-c]Preparation of quinoline-8-carboxamide (4) Compound 4c (50 mg,0.22 mmol) was dissolved in N, N-dimethylacetamide (2 mL), and Compound 1e (50 mg,0.22 mmol), triethylamine (0.08 mL,0.60 mmol) and tripyrrolidinylphosphonium bromide hexafluorophosphate (152 mg,0.22 mmol) were added and reacted at 25℃for 18 hours. The reaction solution was filtered, and the filtrate was purified by high pressure liquid chromatography to give compound 4 (25 mg). ESI-MS (m/z): 443.2[ M+H ]] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ8.67–8.66(m,1H),7.94–7.83(m,1H),7.68–

7.22(m,4H),6.66(s,2H),5.35–4.99(m,4H),4.78–4.68(m,2H),4.44(s,1H),3.85–3.13(m,6H),1.99–1.44(m,5H).

Example 5: 4-amino-N-cyclobutyl-N- ((5-ethynylpyridin-2-yl) methyl) -1, 3-dihydrofuran [3,4-c ] quinoline-8-carboxamide

Preparation of N- ((5-bromopyridin-2-yl) methyl) cyclobutylamine (5 a) Compound 2a (186 mg,1.0 mmol), cyclobutylamine (71.12 mg,1.1 mmol) and acetic acid (72 mg,1.2 mmol) were dissolved in dichloromethane (5 mL) and sodium triacetylborohydride (424 mg,2.0 mmol) was added. The reaction was reacted at 25 ℃ for 18 hours, quenched with water (50 mL), pH adjusted to 8 with saturated aqueous sodium bicarbonate, extracted with dichloromethane (100 mL x 3), and the organic phase concentrated and chromatographed by thin layer chromatography (dichloromethane: methanol=95:5) to give 5a (240 mg). ESI-MS (m/z): 242.94[ M+H ] ] ⁺ 。

Preparation of N- ((5- ((trimethylsilyl) ethynyl) pyridin-2-yl) methyl) cyclobutylamine (5 b)

Compound 5a (240 mg,1.0 mmol) was dissolved in N-methylpyrrolidone (2 mL), ethynyl trimethylsilane (196 mg,2.0 mmol), cuprous iodide (38 mg,0.2 mmol), tetrakis (triphenylphosphine) palladium (116 mg,0.1 mmol) and N, N-diisopropylethylamine (640 mg,5.0 mmol) were added, nitrogen was replaced 3 times, and the reaction was carried out at 70℃for 3 hours by microwaves. Diluting the reaction solution with ethyl acetate (20 mL) and water (20 mL), precipitating solid, filtering, separating filtrate, concentrating organic phase, and performing thin-layer preparative chromatographyMethylene chloride: methanol=92:8) to give 5b (136 mg). ESI-MS (m/z): 259.18[ M+H ]] ⁺ 。

Preparation of N- ((5-ethynylpyridin-2-yl) methyl) cyclobutylamine (5 c)

Compound 5b (136 mg,0.53 mmol) was dissolved in tetrahydrofuran (5 mL), 1M tetrabutylammonium fluoride tetrahydrofuran solution (1 mL) was added, and the reaction mixture was stirred at 25℃for 1h. The reaction was quenched with water (5 mL), extracted with ethyl acetate (5 mL x 3) and the crude product concentrated in the organic phase was chromatographed on thin layer (dichloromethane: methanol=93:7) to give 5c (90 mg). ESI-MS (m/z): 187.15[ M+H ]] ⁺ 。

Preparation of 4-amino-N-cyclobutyl-N- ((5-ethynylpyridin-2-yl) methyl) -1, 3-dihydrofuran [3,4-c ] quinoline-8-carboxamide (5)

To a solution of compound 5c (50 mg,0.27 mmol) in N, N-dimethylacetamide (2 mL) was added compound 1e (61 mg,0.27 mmol), triethylamine (54.5 mg,0.54 mmol) and tripyrrolidinylphosphonium bromide hexafluorophosphate (189 mg,0.41 mmol), and the reaction was reacted at 25℃for 18 hours. After the completion of the reaction, the reaction mixture was filtered, and the filtrate was purified by high-pressure liquid chromatography to give Compound 5 (31 mg). ESI-MS (m/z): 399.3[ M+H ] ] ⁺ . ¹ H NMR(600MHz,DMSO-d ₆ )δ8.65(d,J＝1.8Hz,1H),7.88(dd,J＝7.8,1.8Hz,1H),7.59-7.51(m,3H),7.30(d,J＝7.8Hz,1H),6.74(s,2H),5.34(s,2H),5.02(s,2H),4.82(s,2H),4.45-4.35(m,2H),2.14-2.07(m,2H),1.96–1.95(m,2H),1.51–1.31(m,2H).

Example 6: 4-amino-N- ((5-ethynylpyridin-2-yl) methyl) -N-isobutyl-1, 3-dihydrofuran [3,4-c ] quinoline-8-carboxamide

Preparation of N- ((5-bromopyridin-2-yl) methyl) -2-methylpropan-1-amine (6 a) Compound 2a (186 mg,1.0 mmol), 2-methylpropan-1-amine (80 mg,1.1 mmol) and acetic acid (72 mg,1.2 mmol) were dissolved in dichloromethane (5 mL), and sodium triacetoxyborohydride (424 mg,2.0 mmol) was added. The reaction was allowed to react at 25℃for 18 hours, quenched with water (50 mL), pH adjusted to 8 with saturated aqueous sodium bicarbonate, extracted with dichloromethane (100 mL. Times.3),the organic phase was concentrated and then chromatographed on thin layer (dichloromethane: methanol=95:5) to give 6a (229 mg). ESI-MS (m/z): 245.08[ M+H ]] ⁺ . Preparation of 2-methyl-N- ((5- ((trimethylsilyl) ethynyl) pyridin-2-yl) methyl) propan-1-amine (6 b)

Compound 6a (229 mg,0.94 mmol) was dissolved in N-methylpyrrolidone (2 mL), ethynyl trimethylsilane (185 mg,1.88 mmol), cuprous iodide (36 mg,0.19 mmol), tetrakis (triphenylphosphine) palladium (109 mg,0.09 mmol) and N, N-diisopropylethylamine (606 mg,4.7 mol) were added, nitrogen was substituted 3 times, and the reaction was carried out at 70℃for 3 hours by microwaves. The reaction mixture was diluted with ethyl acetate (20 mL) and water (20 mL), a solid was precipitated, filtered, and the filtrate was separated, and the organic phase was concentrated and subjected to thin layer chromatography (dichloromethane: methanol=92:8) to give 6b (155 mg). ESI-MS (m/z): 261.21[ M+H ] ] ⁺ 。

Preparation of N- ((5-ethylpyridin-2-yl) methyl) -2-methylpropan-1-amine (6 c) Compound 6b (155 mg,0.6 mmol) was dissolved in tetrahydrofuran (5 mL), 1M tetrabutylammonium fluoride tetrahydrofuran solution (1 mL) was added, and stirred at 25℃for 1h. The reaction was quenched with water (5 mL), extracted with ethyl acetate (5 mL x 3), the organic phases were combined, concentrated and purified by thin layer chromatography (dichloromethane: methanol=93:7) to give 6c (85 mg). ESI-MS (m/z): 189.14[ M+H ]] ⁺ 。

Preparation of 4-amino-N- ((5-ethynylpyridin-2-yl) methyl) -N-isobutyl-1, 3-dihydrofuran [3,4-c ] quinoline-8-carboxamide (6)

To a solution of compound 6c (23 mg,0.12 mmol) in N, N-dimethylacetamide (2 mL) was added compound 1e (28 mg,0.12 mmol), triethylamine (24.2 mg,0.24 mmol) and tripyrrolidinylphosphonium bromide hexafluorophosphate (84 mg,0.18 mmol), and reacted at 25℃for 18 hours. After the completion of the reaction, the reaction mixture was filtered, and the filtrate was purified by high-pressure liquid chromatography to give Compound 6 (16 mg). ESI-MS (m/z): 401.2[ M+H ]] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ8.62(s,1H),7.86–7.46(m,5H),6.69(s,2H),5.35(s,2H),5.01(s,2H),4.78-4.74(m,1H),4.52–4.48(m,1H),4.40(s,1H),3.85–3.81(m,2H),1.38–0.67(m,7H).

Example 7: 4-amino-N- ((5-ethynylpyridin-2-yl) methyl) -N-methyl-1, 3-dihydrofuro [3,4-c ] quinoline-8-carboxamide

Preparation of ((5- ((trimethylsilyl) ethynyl) pyridin-2-yl) methyl tert-butylcarbamate (7 b)

Compound 7a (200 mg,0.66 mmol) was dissolved in N-methylpyrrolidone (2 mL), ethynyl trimethylsilane (130.4 mg,1.33 mmol), cuprous iodide (63.2 mg,0.33 mmol), tetrakis (triphenylphosphine) palladium (152.5 mg,0.13 mmol) and N, N-diisopropylethylamine (0.44 mL,2.64 mmol) were added, nitrogen was substituted 3 times, and the reaction was carried out at 70℃for 3 hours under microwaves. The reaction solution was diluted with ethyl acetate (5 mL) and water (5 mL), a solid was precipitated, filtered, and the filtrate was separated, and the organic phase was concentrated and subjected to thin layer chromatography (dichloromethane: methanol=92:8) to give 7b (180 mg). ESI-MS (m/z): 319.2[ M+H ]] ⁺

Preparation of 1- (5-ethynylpyridin-2-yl) -N-methyl methylamine (7 c)

Compound 7b (180 mg,0.57 mmol) was dissolved in tetrahydrofuran (2 mL), 4M dioxane hydrochloride (1 mL) was added, and the mixture was stirred at 25℃for 1h. The reaction mixture was dried by spinning, the crude product was dissolved in tetrahydrofuran (2 mL), 1M tetrabutylammonium fluoride tetrahydrofuran solution (1 mL) was added, and the mixture was stirred at 25℃for 1h. The reaction was quenched with water (5 mL), extracted with ethyl acetate (5 mL x 3) and the organic phase concentrated and purified by thin layer chromatography (dichloromethane: methanol=93:7) to give 7c (250 mg). ESI-MS (m/z): 147.09[ M+H ]] ⁺

Preparation of 4-amino-N- ((5-ethynylpyridin-2-yl) methyl) -N-methyl-1, 3-dihydrofuro [3,4-c ] quinoline-8-carboxamide (7)

To a solution of compound 7c (50 mg,0.17 mmol) in N, N-dimethylacetamide (2 mL) was added compound 1e (39.1 mg,0.17 mmol), triethylamine (0.08 mL,0.60 mmol) and tripyrrolidinylphosphonium bromide hexafluorophosphate (103.6 mg,0.22 mmol), and the reaction was reacted at 25℃for 18 hours. Filtration and purification of the filtrate by high pressure liquid chromatography gave compound 7 (10 mg). ESI-MS (m/z): 359.13[ M+H ]] ⁺ . ¹ H NMR(600MHz,DMSO-d ₆ )δ8.69(s,1H),7.92(d,J＝7.8Hz,1H),7.62(m,3H),7.51–6.88(m,3H),5.38–5.17(m,2H),5.02(s,2H),4.78–4.62(m,2H),4.44(s,1H),3.00(s,3H).

Example 8: 4-amino-N- (1-cyanoprop-2-yl) -N- ((5-ethynylpyridin-2-yl) methyl) -1, 3-dihydrofuro [3,4-c ] quinoline-8-carboxamide

Preparation of 3- (((5-bromopyridin-2-yl) methyl) amino) butyronitrile (8 a)

Compound 1a (300 mg,1.60 mmol) and 3-oxo-butyronitrile (200 mg,2.41 mmol) were dissolved in THF (10 mL), isopropyl titanate (911.9 mg,3.21 mmol) was added and the reaction was stirred at 25℃for 12 hours. Cooled to 0 ℃, sodium cyanoborohydride (131 mg,2.09 mmol) was added, followed by stirring at room temperature for 2 hours, the reaction mixture was quenched with 1mL of aqueous ammonia, filtered with stirring 5mL of methanol, the filter cake was rinsed with dichloromethane, and the mother liquor was concentrated and purified by thin layer preparative chromatography (dichloromethane: methanol=15:1) to give 8a (120 mg). ESI-MS (m/z): 255.95[ M+H ]] ⁺

Preparation of N- (((5- ((trimethylsilyl) ethynyl) pyridin-2-yl) methyl) amino) butyronitrile (8 b)

Compound 8a (120 mg,0.47 mmol) was dissolved in N-methylpyrrolidone (2 mL), ethynyl trimethylsilane (92.8 mg,0.94 mmol) was added, cuprous iodide (45.0 mg,0.24 mmol), tetrakis (triphenylphosphine) palladium (109.1 mg,0.09 mmol) and N, N-diisopropylethylamine (0.31 mL,1.89 mmol) were added, nitrogen was replaced 3 times, after 3 hours of reaction at 70℃with microwaves, the reaction mixture was diluted with ethyl acetate (5 mL) and water (5 mL) to precipitate a solid, the solid was filtered, the filtrate was separated, and the organic phase was concentrated and then subjected to thin-layer chromatography (dichloromethane: methanol=92:8) to give 8b (150 mg). ESI-MS (m/z): 272.15[ M+H ]] ⁺

Preparation of 3- ((5-ethynylpyridin-2-yl) methyl) amino) butyronitrile (8 c)

Compound 8b (150 mg,0.44 mmol) was dissolved in tetrahydrofuran (2 mL), 1M tetrabutylammonium fluoride in tetrahydrofuran (1 mL) was added, and the mixture was stirred at 25℃for 1h. The reaction was quenched with water (5 mL), extracted with ethyl acetate (5 mL x 3), the organic phases were combined, concentrated and purified by thin layer chromatography (dichloromethane: methanol=93:7) to give 8c (90 mg). ESI-MS (m/z): 200.12[ M+H ]] ⁺

Preparation of 4-amino-N- (1-cyanoprop-2-yl) -N- ((5-ethynylpyridin-2-yl) methyl) -1, 3-dihydrofuro [3,4-c ] quinoline-8-carboxamide (8)

To a solution of compound 8c (51.9 mg,0.26 mmol) in N, N-dimethylacetamide (2 mL) was added compound 1e (50 mg,0.22 mmol), triethylamine (0.11 mL,0.76 mmol) and tripyrrolidinylphosphonium bromide hexafluorophosphate (131.6 mg,0.28 mmol), and reacted at 25℃for 18 hours. After the completion of the reaction, the reaction mixture was filtered, and the filtrate was purified by high-pressure liquid chromatography to give compound 8 (5 mg). ESI-MS (m/z): 412.13[ M+H ] ] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ8.65(d,J＝1.8Hz,1H),7.85(s,1H),7.59–7.47(m,4H),6.69(s,2H),5.27(s,2H),5.00(s,2H),4.68–4.64(m,2H),4.42(s,1H),3.06–3.01(m,2H),2.88–2.76(s,1H),1.23(d,J＝6.4Hz,3H).

Example 9: 4-amino-N- (cyclopropylmethyl) -N- ((5-ethynylpyridin-2-yl) methyl) -1, 3-dihydrofuro [3,4-c ] quinoline-8-carboxamide

Preparation of 1- (5-bromopyridin-2-yl) -N- (cyclopropylmethyl) methylamine (9 a) Compound 2a (400 mg,2.15 mmol), cyclopropylmethylamine (229 mg,3.23 mmol), acetic acid (481.5 mg,2.58 mmol) were dissolved in dichloromethane (10 mL), sodium triacetylborohydride (680 mg,3.23 mmol) was added and stirred at 25℃for 12 hours. The reaction solution was quenched with water (50 mL), pH was adjusted to 8 with saturated aqueous sodium bicarbonate, extracted with dichloromethane (100 ml×3), the organic phases were combined, concentrated and purified by thin layer chromatography (dichloromethane: methanol=95:5) to give 9a (400 mg). ESI-MS (m/z): 255.95[ M+H ] +

Preparation of 1-cyclopropyl-N- ((5- ((trimethylsilyl) ethynyl) pyridin-2-yl) methyl) methylamine (9 b)

Compound 9a (400 mg,1.66 mmol) was dissolved in N-methylpyrrolidone (4 mL), ethynyl trimethylsilane (325.8 mg,3.32mmol, cuprous iodide (158.0 mg,0.83 mmol), tetrakis (triphenylphosphine) palladium (383.4 mg,0.33 mmol) and N, N-diisopropylethylamine (1.10 mL,6.64mm mol), nitrogen were added3 times of replacement and reaction at 70 ℃ for 3 hours. The reaction solution was diluted with ethyl acetate (10 mL) and water (10 mL), a solid was precipitated, filtered, and the filtrate was separated, and the organic phase was concentrated and subjected to thin layer chromatography (dichloromethane: methanol=92:8) to give 9b (600 mg). ESI-MS (m/z): 259.19[ M+H ] ] ⁺

Preparation of 1-cyclopropyl-N- ((5-ethynylpyridin-2-yl) methyl) methylamine (9 c) Compound 9b (600 mg,1.63 mmol) was dissolved in tetrahydrofuran (2 mL), 1M tetrabutylammonium fluoride tetrahydrofuran solution (1 mL) was added, and stirred at 25℃for 1h. The reaction was quenched with water (5 mL), extracted with ethyl acetate (5 mL x 3), the organic phases were combined, concentrated and purified by thin layer chromatography (dichloromethane: methanol=93:7) to give 9c (120 mg). ESI-MS (m/z): 187.14[ M+H ]] ⁺

Preparation of 4-amino-N- (cyclopropylmethyl) -N- ((5-ethynylpyridin-2-yl) methyl) -1, 3-dihydrofuro [3,4-c ] quinoline-8-carboxamide (9)

To a solution of compound 9c (48.6 mg,0.26 mmol) in N, N-dimethylacetamide (2 mL) was added compound 1e (50 mg,0.22 mmol), triethylamine (0.11 mL,0.76 mmol) and tripyrrolidinylphosphonium bromide hexafluorophosphate (131.6 mg,0.28 mmol), and reacted at 25℃for 18 hours. The reaction solution was filtered, and the filtrate was purified by high pressure liquid chromatography to give compound 9 (17 mg). ESI-MS (m/z): 399.16[ M+H ]] ⁺ . ¹ H NMR(600MHz,DMSO-d ₆ )δ13.67(s,1H),8.82–8.48(m,3H),7.87–7.73(m,4H),7.49–7.31(m,1H),5.48–5.33(m,2H),5.10–5.08(m,2H),4.91(s,1H),4.67(s,1H),4.44(s,1H),3.30–3.16(m,2H),1.09–0.87(m,1H),0.46–0.29(m,2H),0.18–0.01(m,2H).

Example 10: 4-amino-N-ethyl-N- ((5- (prop-1-yn-1-yl) pyridin-2-yl) methyl) -1, 3-dihydrofuro [3,4-c ] quinoline-8-carboxamide

Preparation of ethyl tert-butyl ((5- (prop-1-yn-1-yl) pyridin-2-yl) methyl) carbamate (10 b)

Compound 10a (140 mg,0.44 mmol) was dissolved in N-methylpyrrolidone (2 mL) and propyne was added35.6mg,0.89 mmol), cuprous iodide (42.3 mg,0.22 mmol), tetrakis (triphenylphosphine) palladium (102.7 mg,0.09 mmol) and N, N-diisopropylethylamine (0.29 mL,1.78 mmol), nitrogen substitution 3 times, and microwave 70℃were reacted for 3 hours. The reaction solution was diluted with ethyl acetate (5 mL) and water (5 mL), a solid was precipitated, filtered, and the filtrate was separated, and the organic phase was concentrated and subjected to thin layer chromatography (dichloromethane: methanol=92:8) to give 10b (100 mg). ESI-MS (m/z): 275.17[ M+H ]] ⁺

Preparation of N- ((5- (prop-1-yn-1-yl) pyridin-2-yl) methyl) ethanamine (10 c)

Compound 10b (100 mg,0.36 mmol) was dissolved in tetrahydrofuran (2 mL), 4M dioxane hydrochloride (1 mL) was added, and the reaction was stirred at 25℃for 1h. The reaction was quenched with water (5 mL), extracted with ethyl acetate (5 mL x 3), the organic phases were combined, concentrated and purified by thin layer chromatography (dichloromethane: methanol=93:7) to give 10c (50 mg). ESI-MS (m/z): 175.13[ M+H ]] ⁺

Preparation of 4-amino-N-ethyl-N- ((5- (prop-1-yn-1-yl) pyridin-2-yl) methyl) -1, 3-dihydrofuro [3,4-c ] quinoline-8-carboxamide (10)

To a solution of compound 10c (46 mg,0.26 mmol) in N, N-dimethylacetamide (2 mL) was added compound 1e (50 mg,0.22 mmol), triethylamine (0.11 mL,0.76 mmol) and tripyrrolidinylphosphonium bromide hexafluorophosphate (131.6 mg,0.28 mmol), and reacted at 25℃for 18 hours. After the completion of the reaction, the reaction mixture was filtered, and the filtrate was purified by high-pressure liquid chromatography to give compound 10 (15 mg). ESI-MS (m/z): 387.39[ M+H ] ] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ8.60–8.31(m,3H),7.80–7.69(m,4H),7.41–7.27(m,1H),5.46–5.29(m,2H),5.07(s,2H),4.75–4.55(m,2H),2.09(s,3H),1.11–1.05(m,3H).

Example 11: 4-amino-N- ((5-ethynylpyridin-2-yl) methyl) -N-isopropyl-1, 3-dihydrofuro [3,4-c ] quinoline-8-carboxamide

Preparation of N- ((5-bromopyridin-2-yl) methyl) propan-2-amine (11 a)

Compound 2a (400mg,2.15 mmol), propan-2-amine hydrochloride (308.4 mg,3.23 mmol), acetic acid (481.5 mg,2.58 mmol) were dissolved in dichloromethane (10 mL), sodium triacetylborohydride (680.3 mg,3.23 mmol) was added and stirred at 25℃for 12 hours. The reaction solution was quenched with water (50 mL), pH was adjusted to 8 with saturated aqueous sodium bicarbonate, extracted with dichloromethane (100 ml×3), the organic phases were combined, concentrated and purified by thin layer chromatography (dichloromethane: methanol=95:5) to give 11a (400 mg). ESI-MS (m/z): 229.01[ M+H ]] ⁺

Preparation of N- ((5- ((trimethylsilyl) ethynyl) pyridin-2-yl) methyl) propan-2-amine (11 b)

Compound 11a (150 mg,0.65 mmol) was dissolved in N-methylpyrrolidone (2 mL), ethynyl trimethylsilane (128.6 mg,1.31 mmol), cuprous iodide (62.4 mg,0.33 mmol), tetrakis (triphenylphosphine) palladium (151.3 mg,0.13 mmol) and N, N-diisopropylethylamine (0.43 mL,2.62 mmol) were added, nitrogen was substituted 3 times, and the reaction was carried out at 70℃for 3 hours under microwaves. The reaction solution was diluted with ethyl acetate (5 mL) and water (5 mL), a solid was precipitated, filtered, and the filtrate was separated, and the organic phase was concentrated and subjected to thin layer chromatography (dichloromethane: methanol=92:8) to give 11b (80 mg). ESI-MS (m/z): 247.18[ M+H ] ] ⁺

Preparation of N- ((5-ethynylpyridin-2-yl) methyl) propan-2-amine (11 c)

Compound 11b (80 mg,0.32 mmol) was dissolved in tetrahydrofuran (2 mL), 1M tetrabutylammonium fluoride in tetrahydrofuran (1 mL) was added, and the mixture was stirred at 25℃for 1h. The reaction was quenched with water (5 mL), extracted with ethyl acetate (5 mL x 3), the organic phases were combined, concentrated and purified by thin layer chromatography (dichloromethane: methanol=93:7) to give 11c (50 mg). ESI-MS (m/z): 175.14[ M+H ]] ⁺

Preparation of 4-amino-N- ((5-ethynylpyridin-2-yl) methyl) -N-isopropyl-1, 3-dihydrofuro [3,4-c ] quinoline-8-carboxamide (11)

To a solution of compound 11c (46 mg,0.26 mmol) in N, N-dimethylacetamide (2 mL) was added compound 1e (50 mg,0.22 mmol), triethylamine (0.11 mL,0.76 mmol) and tripyrrolidinylphosphonium bromide hexafluorophosphate (131.6 mg,0.28 mmol), and reacted at 25℃for 18 hours. After the completion of the reaction, the reaction mixture was filtered, and the filtrate was purified by high-pressure liquid chromatography to give compound 11 (10 mg). ESI-MS (m)/z):387.13[M+H] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ8.63(d,J＝2.1Hz,1H),7.85(s,1H),7.56–7.43(m,4H),6.68(s,2H),5.34(s,2H),5.01(s,2H),4.65(s,2H),4.41(s,1H),3.01–2.94(m,1H),1.11(d,J＝6.8Hz,6H).

Example 12: 4-amino-N-isopropyl-N- ((5- (prop-1-yn-1-yl) pyridin-2-yl) methyl) -1, 3-dihydrofuro [3,4-c ] quinoline-8-carboxamide

Preparation of N- ((5- (prop-1-yn-1-yl) pyridin-2-yl) methyl) prop-2-amine (12 a)

Compound 11a (100 mg,0.44 mmol) was dissolved in N-methylpyrrolidone (2 mL), propyne (35 mg,0.87 mmol), cuprous iodide (41.6 mg,0.22 mmol), tetrakis (triphenylphosphine) palladium (100.9 mg,0.09 mmol) and N, N-diisopropylethylamine (0.29 mL,1.78 mmol) were added, nitrogen was substituted 3 times, and the reaction was carried out at 70℃for 3 hours by microwaves. The reaction mixture was diluted with ethyl acetate (5 mL) and water (5 mL), a solid was precipitated, filtered, and the filtrate was separated, and the organic phase was concentrated and subjected to thin layer chromatography (dichloromethane: methanol=92:8) to give 12a (50 mg). ESI-MS (m/z): 189.18[ M+H ] ] ⁺

Preparation of 4-amino-N-isopropyl-N- ((5- (prop-1-yn-1-yl) pyridin-2-yl) methyl) -1, 3-dihydrofuro [3,4-c ] quinoline-8-carboxamide (12)

To a solution of compound 12a (50 mg,0.26 mmol) in N, N-dimethylacetamide (2 mL) was added compound 1e (50 mg,0.22 mmol), triethylamine (0.11 mL,0.76 mmol) and tripyrrolidinylphosphonium bromide hexafluorophosphate (131.6 mg,0.28 mmol), and reacted at 25℃for 18 hours. After the completion of the reaction, the reaction mixture was filtered, and the filtrate was purified by high-pressure liquid chromatography to give compound 12 (23 mg). ESI-MS (m/z): 401.15[ M+H ]] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ8.54(d,J＝1.8Hz,1H),7.78–7.67(m,4H),7.39–7.23(m,1H),5.42–5.24(m,2H),5.06(s,2H),4.65–4.58(m,2H),2.08(s,3H),1.10(d,J＝6.8Hz,6H).

Example 13: 4-amino-N- ((5-ethynylpyridin-2-yl) methyl) -N-isopropyl-1-methyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide

To a solution of compound 11c (43 mg,0.25 mmol) in N, N-dimethylacetamide (2 mL) was added 13a (50 mg,0.21mmol, see WO 2022/115377 A1), triethylamine (0.10 mL,0.72 mmol) and tripyrrolidinylphosphonium bromide hexafluorophosphate (125.1 mg,0.27 mmol) and reacted at 25℃for 18 hours. The reaction solution was filtered, and the filtrate was purified by high pressure liquid chromatography to give compound 13 (10 mg). ESI-MS (m/z): 399.15[ M+H ]] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ8.64(d,J＝2.0Hz,1H),8.25(s,2H),7.87(d,J＝8.0Hz,1H),7.58(s,2H),7.42(d,J＝8.0Hz,1H),7.12(s,2H),4.69(s,2H),4.40–4.37(m,5H),1.15(d,J＝6.8Hz,6H).

Example 14: 4-amino-N- ((5-ethynylpyridin-2-yl) methyl) -1-methyl-N- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [4,3-c ] quinoline-8-carboxamide

Preparation of N- ((5-bromopyridin-2-yl) methyl) -1-methyl-1H-pyrazol-4-amine (14 a)

Compound 2a (372 mg,2.00 mmol), 1-methylpyrazol-4-amine (194.2 mg,2.00 mmol), acetic acid (144 mg,2.4 mmol) were dissolved in dichloromethane (20 mL), sodium triacetylborohydride (884 mg,4.0 mmol) was added, and then the reaction solution was reacted at 25℃for 18 hours. The reaction solution was quenched with water (50 mL), pH was adjusted to 8 with saturated aqueous sodium bicarbonate, extracted with dichloromethane (100 mL x 3), the organic phases were combined and concentrated to give crude product which was chromatographed on thin layer (dichloromethane: methanol=95:5) to give 14a (320 mg). ESI-MS (m/z): 269.06[ M+H ]] ⁺ .

Preparation of 1-methyl-N- ((5- ((trimethylsilyl) ethynyl) pyridin-2-yl) methyl) -1H-pyrazol-4-amine (14 b)

Compound 14a (267 mg,1 mmol), ethynyl trimethylsilane (196 mg,2 mmol), cuprous iodide (38 mg,0.2 mmol), tetra (triphenylenePhosphine) palladium (116 mg,0.1 mmol) was dissolved in N-methylpyrrolidone (2 mL), nitrogen was replaced 3 times, the reaction mixture was subjected to microwave reaction at 70℃for 3 hours, ethyl acetate (20 mL) and water (20 mL) were added to dilute the reaction mixture, a solid was separated out, the filtrate was filtered, and the organic phase was concentrated to obtain a crude product, which was subjected to thin layer chromatography (dichloromethane: methanol=92:8) to obtain 14b (180 mg). ESI-MS (m/z): 285.2[ M+H ] ] ⁺ .

Preparation of N- ((5-ethylpyridin-2-yl) methyl) -1-methyl-1H-pyrazol-4-amine (14 c)

Compound 14b (151 mg,0.53 mmol) was dissolved in tetrahydrofuran (5 mL), 1M tetrabutylammonium fluoride tetrahydrofuran solution (1 mL) was added, the reaction was stirred for 1 hour at 25 ℃, the reaction was quenched with water (5 mL), extracted with ethyl acetate (5 mL x 3), the organic phases were combined and the organic phase concentrated to give crude product by thin layer chromatography (dichloromethane: methanol=93:7) to give 14c (85 mg). ESI-MS (m/z): 213.09[ M+H ]] ⁺ .

Preparation of 4-amino-N- ((5-ethynylpyridin-2-yl) methyl) -1-methyl-N- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [4,3-c ] quinoline-8-carboxamide (14)

To a solution of compound 14c (53.5 mg,0.21 mmol) in N, N-dimethylacetamide (1 mL) was added 13a (50 mg,0.21 mmol), triethylamine (73.1 mg,0.72 mmol), tripyrrolidinylphosphonium bromide hexafluorophosphate (125.1 mg,0.27 mmol), followed by reaction at 25℃for 18 hours. After the completion of the reaction, the reaction mixture was filtered, and the filtrate was purified by high-pressure liquid chromatography to give compound 14 (5 mg). ESI-MS (m/z): 437.16[ M+H ]] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ8.67(d,J＝2.0Hz,1H),8.24(s,2H),7.92(dd,J＝8.0,2.4Hz,1H),7.70(s,1H),7.62(dd,J＝8.4,2.0Hz,1H),7.49(d,J＝8.4Hz,2H),7.26(s,1H),7.17(s,2H),5.11(s,2H),4.44(s,1H),4.20(s,3H),3.67(s,3H).

Example 15: 4-amino-N- (1- (5-ethynylpyridin-2-yl) ethyl) -N, 1-dimethyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide

Preparation of N-methyl-1- (5- ((trimethylsilyl) ethynyl) pyridin-2-yl) ethan-1-amine (15 b)

The compound 1- (5-bromopyridin-2-yl) -N-methylethyl-1-amine (230 g,1.07 mmol) was dissolved in N-methylpyrrolidone (2 mL), ethynyl trimethylsilane (210 mg,2.14 mmol), cuprous iodide (40.7 mg,0.21 mmol), tetrakis (triphenylphosphine) palladium (123.6 mg,0.11 mmol) and triethylamine (0.74 mL,5.35 mmol) were added, nitrogen was substituted 3 times, and after microwave reaction at 70℃for 3 hours. The reaction mixture was diluted with ethyl acetate (20 mL) and water (20 mL), a solid was precipitated, filtered, and the filtrate was separated, and the organic phase was concentrated and subjected to thin layer chromatography (dichloromethane: methanol=92:8) to give 15b (184 mg). ESI-MS (m/z): 233.23[ M+H ]] ⁺ 。

Preparation of 1- (5-ethynylpyridin-2-yl) -N-methylethyl-1-amine (15 c)

Compound 15b (184 mg,0.79 mmol) was dissolved in tetrahydrofuran (3 mL), 1M tetrabutylammonium fluoride in tetrahydrofuran (1 mL) was added, and the mixture was stirred at 25℃for 1h. The reaction was quenched with water (5 mL), extracted with ethyl acetate (5 mL x 3), the organic phases were combined, concentrated and purified by thin layer chromatography (dichloromethane: methanol=93:7) to give 15c (120 mg). ESI-MS (m/z): 161.19[ M+H ]] ⁺ 。

Preparation of 4-amino-N- (1- (5-ethynylpyridin-2-yl) ethyl) -N, 1-dimethyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide (15)

Compound 15c (32 mg,0.20 mmol) was dissolved in N, N-dimethylacetamide (2 mL), 13a (48.4 mg,0.20 mmol), triethylamine (0.07 mL,0.50 mmol) and tripyrrolidinylphosphonium bromide hexafluorophosphate (156 mg,0.30 mmol) were added and reacted at 25℃for 18 hours. After the completion of the reaction, the mixture was filtered, and the filtrate was purified by high pressure liquid chromatography to give compound 15 (5 mg). ESI-MS (m/z): 385.24[ M+H ] ] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ8.73(s,1H),8.27(s,2H),7.96(dd,J＝8.0 2.4Hz,1H),7.62(s,2H),7.48-7.46(m,1H),7.17(s,2H),4.47(s,1H),4.41–4.32(m,4H),2.83(s,3H),1.64(d,J＝6.8Hz,3H).

Example 16: 4-amino-N-cyclopropyl-N- (5-ethynylpyridin-2-yl) methyl) -1-methyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide

To a solution of compound 2d (52 mg,0.3 mmol) in N, N-dimethylacetamide (5 mL) was added compound 13a (73 mg,0.3 mmol), triethylamine (106 mg,1.05 mmol) and tripyrrolidinylphosphonium bromide hexafluorophosphate (182 mg,0.39 mmol), and the addition was completed at room temperature for 4 hours. After the reaction was completed, water (10 mL) was added, extraction was performed with ethyl acetate (10 ml×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was spun off and purified by reverse phase chromatography (acetonitrile: 0.05% ammonium bicarbonate aqueous solution=0:100% -40%: 60%) to give compound 16 (26 mg). ESI-MS (m/z): 397.2[ M+H ]] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ8.71(d,J＝1.6Hz,1H),8.44(s,1H),8.28(s,1H),7.94(d,J＝8.0,2.0Hz,1H),7.74(d,J＝8.4Hz,1H),7.60(d,J＝8.4Hz,1H),7.45(d,J＝8.0Hz,1H),7.18(s,2H),4.84(s,2H),4.45(s,1H),4.40(s,3H),3.06–3.02(s,1H),0.56–0.51(m,4H).

Example 17: 4-amino-N- (1- (5-ethynylpyridin-2-yl) ethyl) -7-fluoro-N, 1-dimethyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide

To a solution of compound 15c (18.5 mg,0.12 mmol) in N, N-dimethylacetamide (2 mL) was added 17a (31 mg,0.12mmol, see WO 2022/115377 A1), triethylamine (0.04 mL,0.29 mmol) and tripyrrolidinylphosphonium bromide hexafluorophosphate (90.0 mg,0.17 mmol), reacted at 25℃for 18 hours, the reaction mixture was diluted with ethyl acetate (10 mL) and water (10 mL), the separated liquid and the organic phase concentrated to give crude product, which was purified by high pressure liquid chromatography to give compound 17 (8 mg). ESI-MS (m/z): 403.2[ M+H ] ] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ8.71(s,1H),8.27–8.19(m,2H),7.99–7.92(m,1H),7.49–7.27(m,2H),5.96–5.93and 5.09–5.05(m,1H),4.46(s,1H),4.40–4.25(m,3H),2.83–2.75(m,3H),1.65–1.60(m,3H)

Example 18: 4-amino-N- (1- (5-ethynylpyridin-2-yl) methyl) -7-fluoro-N, 1-dimethyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide

To a solution of compound 7c (17.5 mg,0.12 mmol) in N, N-dimethylacetamide (2 mL) was added 17a (31 mg,0.12 mmol), triethylamine (0.04 mL,0.29 mmol), tripyrrolidinylphosphonium bromide hexafluorophosphate (90.0 mg,0.17 mmol), and the reaction was reacted at 25℃for 18 hours. Ethyl acetate (10 mL) and water (10 mL) were added to dilute, and the organic phase was concentrated and purified by high pressure liquid chromatography to give compound 18 (12.3 mg). ESI-MS (m/z): 389.23[ M+H ]] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ8.70(s,1H),8.28–8.16(m,2H),8.00–7.88(m,1H),7.44–7.26(m,4H),4.86(s,1H),4.64(s,1H),4.46(s,1H),4.40and 4.18(s,3H),3.04and 3.00(s,3H).

Example 19: 4-amino-N- (1- (5-ethynylpyridin-2-yl) methyl) -7-fluoro-N-isopropyl-1-methyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide

To a solution of compound 11c (40 mg,0.23 mmol) in N, N-dimethylacetamide (2 mL) was added 17a (31 mg,0.12 mmol), triethylamine (0.04 mL,0.29 mmol) and tripyrrolidinylphosphonium bromide hexafluorophosphate (90.0 mg,0.17 mmol), and the mixture was reacted at 25℃for 18 hours. The reaction mixture was diluted with ethyl acetate (10 mL) and water (10 mL), and the separated solution was concentrated and purified by high pressure liquid chromatography to give compound 19 (28.3 mg). ESI-MS (m/z): 417.17[ M+H ]] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ8.67–8.59(m,1H),8.30–7.75(m,3H),7.44–7.23(m,4H),4.78–4.55(m,2H),4.42-4.40(m,3H),4.21(s,1H),4.06–3.99(m,1H),1.20–1.12(m,6H).

Example 20: 4-amino-N- (1- (5-ethynylpyridin-2-yl) methyl) -7-fluoro-1-methyl-N- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [4,3-c ] quinoline-8-carboxamide

To a solution of compound 14c (40.8 mg,0.19 mmol) in N, N-dimethylacetamide (2 mL) was added compound 17a (50 mg,0.19 mmol), triethylamine (0.07 mL,0.48 mmol) and tripyrrolidinylphosphonium bromide hexafluorophosphate (150 mg,0.29 mmol), and the reaction was reacted at 25℃for 18 hours. After the completion of the reaction, the reaction mixture was filtered, and the filtrate was purified by high-pressure liquid chromatography to give compound 20 (20 mg). ESI-MS (m/z): 455.24[ M+H ]] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ8.67–8.63(m,1H),8.27–8.20(m,2H),7.98–7.85(m,1H),7.60–7.50(m,2H),7.31–7.12(m,4H),5.77(s,1H),5.09–5.03(m,2H),4.45and 4.36(s,3H),3.80and 3.58(s,3H).

Example 21: 4-amino-N- ((5-ethynylpyridin-2-yl) methyl) -7-fluoro-N-methyl-1, 3-dihydrofuran [3,4-c ] quinoline-8-carboxamide

To a solution of compound 7c (18.3 mg,0.12 mmol) in N, N-dimethylacetamide (2 mL) was added compound 21a (31 mg,0.12mmol, see WO 2022/115377 A1), triethylamine (0.04 mL,0.31 mmol), tripyrrolidinylphosphonium bromide hexafluorophosphate (97.5 mg,0.19 mmol) and the reaction was allowed to react at 25℃for 18 hours. After the completion of the reaction, the reaction mixture was filtered, and the filtrate was purified by high-pressure liquid chromatography to give compound 21 (11.4 mg). ESI-MS (m/z): 377.14[ M+H ]] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ8.68–8.65(m,1H),7.97and 7.88(dd,J＝8.1,2.2Hz,1H),7.65and 7.53(d,J＝7.6Hz,1H),7.44–7.21(m,2H),6.95(s,2H),5.39–5.17(m,2H),5.03–4.97(m,2H),4.82and 4.57(s,2H),4.46(s,1H),3.04and 2.95(s,3H).

Example 22: 4-amino-N-cyclopropyl-N- ((5-ethynylpyridin-2-yl) methyl) -7-fluoro-1, 3-dihydrofuran [3,4-c ] quinoline-8-carboxamide

To a solution of compound 2d (20.7 mg,0.12 mmol) in N, N-dimethylacetamide (2 mL) was added compound 21a (31 mg,0.12 mmol), triethylamine (0.04 mL,0.31 mmol) and tripyrrolidinylphosphonium bromide hexafluorophosphate (97.5 mg,0.19 mmol), and the mixture was reacted at 25℃for 18 hours. After the reaction, filtering, purifying the filtrate with high pressure liquid chromatography column to obtain compound 22 (4.7 mg) ESI-MS (m/z): 403.20[ M+H ] ] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ8.70–8.66(m,3H),7.97–7.92(m,2H),7.71(d,J＝10.4Hz,1H),7.43(d,J＝8.1Hz,1H),5.48(s,2H),5.11(s,2H),4.84(s,2H),4.46(s,1H),2.87–2.84(m,1H),0.57–0.44(m,4H).

EXAMPLE 23 4-amino-N- ((5-ethynylpyridin-2-yl) methyl) -7-fluoro-N- (1-methyl-1H-pyrazol-4-yl) -1, 3-dihydrofuran [3,4-c ] quinoline-8-carboxamide

To a solution of compound 14c (51.3 mg,0.24 mmol) in N, N-dimethylacetamide (1 mL) was added compound 21a (50 mg,0.20 mmol), triethylamine (71.4 mg,0.71 mmol) and tripyrrolidinylphosphonium bromide hexafluorophosphate (122.1 mg,0.26 mmol), and the mixture was reacted at 25℃for 18 hours. After the completion of the reaction, the reaction mixture was filtered, and the filtrate was purified by high-pressure liquid chromatography to give compound 23 (10 mg). ESI-MS (m/z): 443.16[ M+H ]] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ8.66–8.62(m,1H),7.97–7.94(m,1H),7.62–7.56(m,2H),7.49(d,J＝8.0Hz,1H),7.12–7.09(m,2H),6.81(s,2H),5.32(s,2H),5.07(s,2H),4.99(s,2H),4.45(s,1H),3.58(s,3H).

Example 24: 4-amino-N- ((5-ethynylpyridin-2-yl) methyl) -7-fluoro-N-isopropyl-1, 3-dihydrofuran [3,4-c ] quinoline-8-carboxamide

N, N-Dimethylacetoacetyl to Compound 11c (41.8 mg,0.24 mmol)To a solution of amine (1 mL) was added compound 21a (50 mg,0.20 mmol), triethylamine (71.4 mg,0.71 mmol) and tripyrrolidinylphosphonium bromide hexafluorophosphate (122.1 mg,0.26 mmol), and the mixture was reacted at 25℃for 18 hours. After the completion of the reaction, the reaction mixture was filtered, and the filtrate was purified by high-pressure liquid chromatography to give compound 24 (10 mg). ESI-MS (m/z): 404.9[ M+H ]] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ8.61and 8.57(s,1H),7.95(m,1H),7.65–7.16(m,4H),6.84and 6.76(s,2H),5.36–5.16(m,2H),5.02–4.95(m,2H),4.76–4.52(m,2H),4.42(s,1H),3.96–3.89(m,1H),1.18and 1.09(d,J＝6.4Hz,6H).

Example 25: 4-amino-N- ((5-ethynylpyridin-2-yl) methyl) -N-isobutyl-3-methyl-1, 3-dihydrofuran [3,4-c ] quinoline-8-carboxamide

To a solution of compound 6c (37.0 mg,0.20 mmol) in N, N-dimethylacetamide (1 mL) was added compound 25a (48 mg,0.20mmol, see WO 2022/115377 A1), triethylamine (0.06 mL,0.40 mmol) and tripyrrolidinylphosphonium bromide hexafluorophosphate (153.4 mg,0.29 mmol), and reacted at 25℃for 18 hours. After the completion of the reaction, the reaction mixture was filtered, and the filtrate was purified by high-pressure liquid chromatography to give compound 25 (22 mg). ESI-MS (m/z): 415.2[ M+H ]] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ8.67–8.63(m,1H),7.89–7.86(m,1H),7.59–7.48(m,4H),6.60(s,2H),5.43–5.25(m,3H),4.78–4.74(m,1H),4.52–4.48(m,1H),4.40(s,1H),3.85–3.82(m,1H),1.65–1.58(m,1H),1.42–1.38(m,3H),1.15–1.09(m,3H),0.83–0.68(m,3H).

Example 26: 4-amino-N- ((5-ethynylpyridin-2-yl) methyl) -3-methyl-N- (1-methylcyclopropyl) ethyl) -1, 3-dihydrofuran [3,4-c ] quinoline-8-carboxamide

Preparation of 1- (5-bromopyridin-2-yl) -N- ((1-methylcyclopropyl) methyl) methylamine (26 a)

Compound 2a (186 mg,1.0 mmol), (methylcyclopropyl) methylamine (85.2 mg,1.0 mmol), acetic acid (224 mg,1.2 mmol) were dissolved in dichloromethane (10 mL), sodium triacetylborohydride (422 mg,2 mmol) was added, and the reaction solution was reacted at 25℃for 18 hours. The reaction was quenched with water (50 mL), pH was adjusted to 8 with saturated aqueous sodium bicarbonate, extracted with dichloromethane (100 mL x 3), the organic phases combined, concentrated and purified by thin layer chromatography (dichloromethane: methanol=95:5) to give compound 26a (228 mg). ESI-MS (m/z): 257.1[ M+H ] ] ⁺ 。

Preparation of 1- (1-methylcyclopropyl) -N- ((5- ((trimethylsilyl) ethynyl) pyridin-2-yl) methyl) methylamine (26 b)

Compound 26a (228 mg,0.89 mmol) was dissolved in N-methylpyrrolidone (2 mL), ethynyl trimethylsilane (175.5 mg,1.79 mmol), cuprous iodide (34 mg,0.18 mmol), tetrakis (triphenylphosphine) palladium (103.2 mg,0.09 mmol) and triethylamine (0.62 mL,4.47 mmol) were added, nitrogen was substituted 3 times, and the mixture was reacted at 70℃for 3 hours under microwaves. The reaction mixture was diluted with ethyl acetate (20 mL) and water (20 mL), a solid was precipitated, filtered, and the organic phase was concentrated and subjected to thin layer chromatography (dichloromethane: methanol=92:8) to give compound 26c (180 mg). ESI-MS (m/z): 273.17[ M+H ]] ⁺ 。

Preparation of 1- (5-ethynylpyridin-2-yl) -N- (1-methylcyclopropyl) methyl) methylamine (26 c)

Compound 26b (180 mg,0.74 mmol) was dissolved in tetrahydrofuran (5 mL), 1M tetrabutylammonium fluoride in tetrahydrofuran (0.6 mL) was added, and the reaction was stirred at 25℃for 1h. The reaction was quenched with water (5 mL), extracted with ethyl acetate (5 mL x 3), the organic phases were combined and concentrated to give crude product which was chromatographed on thin layer (dichloromethane: methanol=93:7) to give compound 26c (110 mg).

Preparation of 4-amino-N- ((5-ethynylpyridin-2-yl) methyl) -3-methyl-N- (1-methylcyclopropyl) ethyl) -1, 3-dihydrofuran [3,4-c ] quinoline-8-carboxamide (26)

To a solution of compound 26c (49.7 mg,0.25 mmol) in N, N-dimethylacetamide (2 mL) was added compound 25a (60.4 mg,0.25 mmol), triethylamine (0.07 mL,0.50 mmol) and tripyrrolidinylphosphonium bromide hexafluorophosphate (194 mg,0.37 mmol), and the mixture was reacted at 25℃for 18 hours. Reaction junctionAfter the reaction, the reaction mixture was filtered, and the filtrate was purified by a high pressure liquid chromatography column to give Compound 26 (36 mg). ESI-MS (m/z): 427.25[ M+H ]] ⁺ . ¹ H NMR(600MHz,DMSO-d ₆ )δ8.66(m,1H),7.89(s,1H),7.60–7.24(m,4H),6.59(s,2H),5.41–5.11(m,3H),4.91–4.73(m,2H),4.43(s,1H),3.37–3.24(m,2H),1.42–1.38(m,3H),1.01–0.86(m,3H),0.29–0.20(m,4H).

Example 27: 4-amino-N- ((5-ethynylpyridin-2-yl) methyl) -3-methyl-N- (1-methyl-1H-pyrazol-4-yl) -1, 3-dihydrofuran [3,4-c ] quinoline-8-carboxamide

To a solution of compound 14c (42.4 mg,0.20 mmol) in N, N-dimethylacetamide (2 mL) was added compound 25a (48.9 mg,0.20 mmol), triethylamine (0.06 mL,0.40 mmol) and tripyrrolidinylphosphonium bromide hexafluorophosphate (156 mg,0.30 mmol), and the mixture was reacted at 25℃for 18 hours. After the reaction, the reaction mixture was filtered, and the filtrate was purified by a high pressure liquid chromatography column to give Compound 27 (24 mg). ESI-MS (m/z): 439.21[ M+H ]] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ8.66(s,1H),7.93–7.90(m,1H),7.68–7.57(m,2H),7.50–7.36(m,3H),7.25–7.12(m,1H),6.62(s,2H),5.44–5.14(m,3H),5.06(s,2H),4.44(s,1H),3.67(s,3H),1.41(d,J＝6.4Hz,3H).

Example 28: 4-amino-N-ethyl-N- (1- (5-ethynylpyridin-2-yl) ethyl) -3-methyl-1, 3-dihydrofuran [3,4-c ] quinoline-8-carboxamide

Preparation of 1- (5-bromopyridin-2-yl) -N-ethylen-1-amine (28 b)

Compound 28a (200 mg,1.0 mmol), ethylamine (45.1 mg,1.0 mmol) and acetic acid (186.6, 1 mmol) were dissolved in dichloromethane (10 mL), sodium triacetyl borohydride (210.9 mg,1 mmol) was added and reacted at 25℃for 18 hours. The reaction mixture was quenched with water (50 mL), adjusted to pH 8 with saturated aqueous sodium bicarbonate, and quenched with dichloromethane Alkane extraction (100 ml x 3), combining the organic phases, concentrating the organic phase and subjecting it to thin layer chromatography (dichloromethane: methanol=95:5) to give 28b (150 mg). ESI-MS (m/z): 229.06[ M+H ]] ⁺

Preparation of N-ethyl-1- (5- ((trimethylsilyl) ethynyl) pyridin-2-yl) ethan-1-amine (28 c)

Compound 28b (150 mg,0.65 mmol) was dissolved in N-methylpyrrolidone (2 mL), ethynyl trimethylsilane (128.6 mg,1.31 mmol), cuprous iodide (24.9 mg,0.13 mmol), tetrakis (triphenylphosphine) palladium (75.7 mg,0.07 mmol) and triethylamine (0.45 mL,3.27 mmol) were added, nitrogen was replaced 3 times, and the reaction was carried out at 70℃for 3 hours by microwaves. The reaction solution was diluted with ethyl acetate (20 mL) and water (20 mL), a solid was precipitated, filtered, and the filtrate was separated, and the organic phase was concentrated and subjected to thin layer chromatography (dichloromethane: methanol=92:8) to give compound 28c (120 mg). ESI-MS (m/z): 247.19[ M+H ]] ⁺

Preparation of N-ethyl-1- (5-ethylpyridin-2-yl) ethan-1-amine (28 d)

Compound 28c (110 mg,0.45 mmol) was dissolved in tetrahydrofuran (3 mL), 1M tetrabutylammonium fluoride in tetrahydrofuran (0.7 mL) was added, and the reaction was stirred at 25℃for 1h. The reaction was quenched with water (5 mL), extracted with ethyl acetate (5 mL x 3), the organic phases were combined, concentrated and purified by thin layer chromatography (dichloromethane: methanol=93:7) to give compound 28d (70 mg). ESI-MS (m/z): 175.16[ M+H ] ] ⁺

Preparation of 4-amino-N-ethyl-N- (1- (5-ethynylpyridin-2-yl) ethyl) -3-methyl-1, 3-dihydrofuran [3,4-c ] quinoline-8-carboxamide (28)

To a solution of compound 28d (34.8 mg,0.20 mmol) in N, N-dimethylacetamide (2 mL) was added compound 25a (48.8 mg,0.20 mmol), triethylamine (0.06 mL,0.40 mmol) and tripyrrolidinylphosphonium bromide hexafluorophosphate (156 mg,0.30 mmol), and the mixture was reacted at 25℃for 18 hours. The reaction solution was filtered, and the filtrate was concentrated and purified by high pressure liquid chromatography to give compound 28 (32 mg). ESI-MS (m/z): 401.14[ M+H ]] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ8.69(s,1H),7.93–7.90(m,1H),7.59–7.54(m,3H),7.40(s,1H),6.58(s,2H),5.45–5.21(m,4H),4.45(s,1H),3.45–3.39(m,1H),3.14–3.03(m,1H),1.64(d,J＝6.4Hz,3H),1.42(d,J＝6.0Hz,3H),0.99–0.92(m,3H).

Example 29: 4-amino-N- ((5-ethynylpyridin-2-yl) methyl) -N-isopropyl-3-methyl-1, 3-dihydrofuro [3,4-c ] quinoline-8-carboxamide

To a solution of compound 11c (42.8 mg,0.25 mmol) in N, N-dimethylacetamide (2 mL) was added compound 25a (50 mg,0.21 mmol), triethylamine (0.10 mL,0.72 mmol) and tripyrrolidinylphosphonium bromide hexafluorophosphate (125.1 mg,0.27 mmol), and reacted at 25℃for 18 hours. The reaction solution was filtered, and the filtrate was purified by high pressure liquid chromatography to give compound 29 (5 mg). ESI-MS (m/z): 401.20[ M+H ]] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ8.65(d,J＝2.0Hz,1H),7.88(d,J＝8.0Hz,1H),7.57–7.42(m,4H),6.56(s,2H),5.56–5.04(m,3H),4.67(s,2H),4.40(s,1H),4.27–4.05(m,1H),1.43(d,J＝6.4Hz,3H),1.13(d,J＝6.8Hz,6H).

Example 30: 4-amino-5- (cyclopropylethynyl) pyridine-2-methyl) -3-methyl-1-methylpyrazol-4-yl) -1, 3-dihydrofuran [3,4-c ] quinoline-8-carboxamide

Preparation of 5-cyclopropylethynyl pyridin-2-ylmethyl-1-methyl-4-aminopyrazole (30 a)

To a solution of the compound 5-bromopyridine-2-methyl-1-methyl-4-aminopyrazole (267 mg,1 mmol) in N-methylpyrrolidone (5 mL) was added, in order, ethynylcyclopropane (132 mg,2 mmol), cuprous iodide (95 mg,0.5 mmol), N, N-diisopropylethylamine (0.70 mL,4 mmol) and tetrakis (triphenylphosphine) palladium (230 mg,0.2 mmol) under nitrogen. After the addition, the reaction was completed for 3 hours at 70 ℃ with microwaves, extracted with ethyl acetate (20 ml×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was spun off to give compound 30a (150 mg) by column chromatography (methanol: dichloromethane=1:10). ESI-MS (m/z): 253.1[ M+H ]] ⁺ .

Preparation of 4-amino-5- (cyclopropylethynyl) pyridine-2-methyl) -3-methyl-1-methylpyrazol-4-yl) -1, 3-dihydrofuran [3,4-c ] quinoline-8-carboxamide (30)

To a solution of compound 30a (54 mg,0.2 mmol) in N, N-dimethylacetamide (3 mL) was added compound 25a (49 mg,0.2 mmol), triethylamine (71 mg,0.7 mmol) and tripyrrolidinylphosphonium bromide hexafluorophosphate (121 mg,0.26 mmol), and the mixture was reacted at room temperature for 4 hours. The reaction mixture was extracted with water (20 mL), ethyl acetate (20 mL. Times.3), the organic phase was dried over saturated brine, filtered, spin-dried and purified by reverse phase chromatography (acetonitrile: 0.05% ammonium bicarbonate aqueous solution=0:100% -40%: 60%) to give compound 30 (19 mg). ESI-MS (m/z): 479.2[ M+H ] ] ⁺ 。 ¹ H NMR(400MHz,DMSO-d ₆ ))δ8.53(d,J＝1.6Hz,1H),7.77(d,J＝8.0,2.0Hz,1H),7.60–7.39(m,5H),7.15(s,1H),6.64(s,2H),5.42–5.40(m,2H),5.23–5.17(m,2H),5.02(s,2H),3.66(s,3H),1.61–1.57(m,1H),1.40(d,J＝6.4Hz,3H),0.96–0.90(m,2H),0.80–0.75(m,2H).

Example 31: preparation of 4-amino-N- ((-5- (3-methoxyprop-1-yn-1-yl) pyridin-2-yl) methyl-3-methyl-N- (1-methyl-1H-pyrazol-4-yl) -1, 3-dihydrofuran [3,4-c ] quinoline-8-carboxamide

Preparation of N- ((5- (3-methoxy-1-alkynyl-1-yl) pyridin-2-yl) methyl-1-methyl-1H-pyrazol-4-amino) (31 a)

To a solution of the compound 5-bromopyridine-2-methyl-1-methyl-4-aminopyrazole (267 mg,1 mmol) in N-methylpyrrolidone (5 mL) was added successively 3-methoxypropyne (140 mg,2 mmol), cuprous iodide (95 mg,0.5 mmol), N, N-diisopropylethylamine (0.70 mL,4 mmol) and tetrakis (triphenylphosphine) palladium (230 mg,0.2 mmol) under nitrogen, and after the addition, the reaction was completed at 70℃for 3 hours, extracted with ethyl acetate (20 mL. Times.3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried by spin-drying to give the compound 31a (115 mg) via column chromatography (methanol: dichloromethane=1:10). ESI-MSm/z):257.1[M+H] ⁺ .

4-amino-N- ((-5- (3-methoxyprop-1-yn-1-yl) pyridin-2-yl) methyl-3-methyl-N- (1-methyl-1H-pyrazol-4-yl) -1, 3-dihydrofuran [3, 4-c)]Preparation of quinoline-8-carboxamide (31) to a solution of compound 31a (51 mg,0.2 mmol) in N, N-dimethylacetamide (3 mL) was added compound 25a (49 mg,0.2 mmol), triethylamine (71 mg,0.7 mmol) and tripyrrolidinylphosphonium bromide hexafluorophosphate (121 mg,0.26 mmol), reacted at room temperature for 4 hours, after completion of the reaction, water (20 mL) was added to extract with ethyl acetate (20 mL. Times.3), the organic phases were combined, saturated brine wash, dried over anhydrous sodium sulfate, filtered, the solvent was spun off, and purified by reverse phase chromatography (acetonitrile: 0.05% ammonium bicarbonate aqueous solution=0:100% -40:100%) to give compound 31 (17 mg). ESI-MS (m/z): 483.2[ M+H ] ] ⁺ 。 ¹ H NMR(400MHz,DMSO-d ₆ ))δ8.64(s,1H),7.90(d,J＝8.0Hz,1H),7.60–7.18(m,6H),6.64(s,2H),5.42–5.40(m,1H),5.23–5.14(m,2H),5.06(s,2H),4.37(s,2H),3.66(s,3H),1.41(d,J＝6.0Hz,3H).

Example 32: preparation of 4-amino-3-methyl-N- (1-methyl-1H-pyrazol-4-yl) -N- (5-prop-1-yn-1-yl) pyridin-2-methyl) -1, 3-dihydrofuran [3,4-c ] quinoline-8-carboxamide

Preparation of 5-propynylpyridin-2-methyl-4-amine (32 a)

To a solution of the compound 5-bromopyridine-2-methyl-1-methyl-4-aminopyrazole (267 mg,1 mmol) in N-methylpyrrolidone (5 mL) were added successively, under nitrogen, propyne (80 mg,2 mmol), cuprous iodide (95 mg,0.5 mmol), N, N-diisopropylethylamine (0.70 mL,2 mmol) and tetrakis (triphenylphosphine) palladium (230 mg,0.2 mmol), and after the addition, the reaction was completed under microwave 70℃for 3 hours, extracted with ethyl acetate (20 mL. Times.3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was spun off, followed by column chromatography (methanol: dichloromethane=1:10) to give the compound 5-propynylpyridin-2-methyl-4-amine 32a (2.1 g). ESI-MS (m/z): 227.1[ M+H ]] ⁺ .

4-amino-3-methyl-N- (1-methyl-1H-pyrazol-4-yl) -N- (5-prop-1-yn-1-yl) pyridin-2-methyl) -1, 3-dihydrofuran [3,4-c]Preparation of quinoline-8-carboxamide (32) to a solution of compound 32a (45 mg,0.2 mmol) in N, N-dimethylacetamide (3 mL) was added compound 25a (49 mg,0.2 mmol), triethylamine (71 mg,0.7 mmol) and tripyrrolidinylphosphonium bromide hexafluorophosphate (121 mg,0.26 mmol), reacted at room temperature for 4 hours, after completion of the reaction, water (20 mL) was added to extract with ethyl acetate (20 mL. Times.3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the solvent was spun off, and purified by reverse phase chromatography (acetonitrile: 0.05% aqueous ammonium bicarbonate=0:100% -40%: 60%) to give compound 32 (22 mg). ESI-MS (m/z): 453.2[ M+H ] ] ⁺ 。 ¹ H NMR(400MHz,DMSO-d ₆ ))δ8.56(s,1H),7.80(d,J＝8.0,1.6Hz,1H),7.60–7.44(m,5H),7.16(s,1H),6.62(s,2H),5.42–5.39(m,1H),5.23–5.13(m,2H),5.03(s,2H),3.66(s,3H),2.09(s,3H),1.40(d,J＝6.4Hz,3H).

Example 33: 4-amino-N- ((5- (3-hydroxypropyl-1-yn-1-yl) pyridin-2-yl) methyl) -3-methyl-N- (1-methyl-1H-pyrazol-4-yl) -1, 3-dihydrofuran [3,4-c ] quinoline-8-carboxamide

4-amino-N- ((5-bromopyridin-2-yl) methyl) -3-methyl-N- (1-methyl-1H-pyrazol-4-yl-1, 3-dihydrofuran [3, 4-c)]Preparation of quinoline-8-carboxamide (33 a) to a solution of the compound 5-bromopyridine-2-methyl-1-methyl-4-aminopyrazole (133 mg,0.5 mmol) in N, N-dimethylacetamide (5 mL) was added compound 25a (123 mg,0.5 mmol), triethylamine (177 mg,1.75 mmol) and tripyrrolidinylphosphonium bromide hexafluorophosphate (303 mg,0.65 mmol), and after the addition was completed, water (10 mL) was extracted with ethyl acetate (20 mL. Times.3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was spun off to give compound 33a (110 mg) by column chromatography (methanol: dichloromethane=1:15). ESI-MS (m/z): 493.1[ M+H ]] ⁺ 4-amino-N- ((5- (3-hydroxy-prop-1-yn-1-yl) pyridin-2-yl)) Methyl) -3-methyl-N- (1-methyl-1H-pyrazol-4-yl) -1, 3-dihydrofuran [3,4-c]Preparation of quinoline-8-carboxamide (33) to a solution of compound 33a (74 mg,0.15 mmol) in N-methylpyrrolidone (3 mL) under nitrogen protection, (propynyloxy) trimethylsilane (20 mg,0.15 mmol), cuprous iodide (15 mg,0.075 mmol), N, N-diisopropylethylamine (0.1 mL,0.6 mmol) and tetrakis (triphenylphosphine) palladium (34 mg,0.03 mmol) were added sequentially, and after the addition, the reaction was completed under microwave 70℃for 3 hours, water (20 mL) was added, extracted with ethyl acetate (20 mL. Times.3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was spun off to give compound 33 (18 mg) by reverse phase chromatography (acetonitrile: 0.05% aqueous solution=0:100% -30%: 70%). ESI-MS (m/z): 469.2[ M+H ] ] ⁺ 。 ¹ H NMR(400MHz,DMSO-d ₆ )δ8.61(d,J＝1.6Hz,1H),7.86(d,J＝8.0,2.0Hz,1H),7.66–7.35(m,5H),7.19(s,1H),6.63(s,2H),5.44–5.41(m,2H),5.27–5.14(m,2H),5.05(s,2H),4.35(d,J＝6.0Hz,2H),3.67(s,3H),1.41(d,J＝6.4Hz,3H).

Example 34: 4-amino-N-ethyl-N- (1- (5-ethynylpyridin-2-yl) ethyl) -7-fluoro-3-methyl-1, 3-dihydrofuran [3,4-c ] quinoline-8-carboxamide

To a solution of compound 28d (23 mg,0.13 mmol) in N, N-dimethylacetamide (2 mL) was added compound 34a (34.1 mg,0.13 mmol), triethylamine (0.04 mL,0.26 mmol) and tripyrrolidinylphosphonium bromide hexafluorophosphate (103.1 mg,0.20 mmol), and the mixture was reacted at 25℃for 18 hours. After the completion of the reaction, the reaction mixture was filtered, and the filtrate was purified by high-pressure liquid chromatography to give compound 34 (9.5 mg). ESI-MS (m/z): 419.22[ M+H ]] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ8.71–8.69(m,1H),7.97–7.92(m,1H),7.63–7.57(m,1H),7.53–7.28(m,2H),6.74(s,2H),5.68–6.65(m,0.4H),5.46–5.26(m,3H),4.94–4.89(m,0.6H),4.47and 4.46(m,1H)3.53–3.17(m,2H),1.73–1.69(m,3H),1.43–1.40(m,3H),1.06–0.80(m,3H).

EXAMPLE 35 4-amino-N- [ (5-Acetylpyridin-2-yl) methyl ] -N- (1-methoxypropyl-2-yl ] -1, 3-dihydrofuran [4,3-c ] quinoline-8-carboxamide

Preparation of 1-methoxypropane-2-one- (5-bromopyridin-2-yl) carboxamide-N- ((5-bromopyrimidin-2-methyl) -1-methoxypropylamine-2-amine (35 a) to a solution of compound 1a (200 mg,1.07 mmol) in tetrahydrofuran (5 mL) were sequentially added 1-methoxypropanone (113.1 mg,1.28 mmol) and acetic acid (0.01 mL,0.21 mmol) and sodium triacetoxyborohydride (451.1 mg,2.14 mmol), and after the addition was completed at 25℃for 4 hours, after the completion of the reaction, the pH of the sodium carbonate solution was adjusted to about 7, and by normal phase column chromatography (petroleum ether/ethyl acetate=0:100% -50%: 50%) to give compound 35a (180 mg), ESI-MS (m/z): 261.1[ M+H ] ⁺ 。

Preparation of 1-methoxy-N- ((5- ((trimethylsilyl) ethynyl) pyridin-2-yl) methyl) propan-2-amine (35 b) to a solution of N-methylpyrrolidone (6 mL) of compound 35a (180 mg,0.69 mmol) was added sequentially trimethylsilylethylene (136.4 mg,1.39 mmol), cuprous iodide (52.9 mg,0.28 mmol), tetraphenylphosphonium palladium (160.6 mg,0.14 mmol) and triethylamine (0.48 mL,3.47 mmol), nitrogen was replaced, reacted for 3 hours at 90℃with microwaves, after completion of the reaction, celite was filtered, water (15 mL) was added, ethyl acetate was extracted (3X 10 mL), the organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give product 35b (140 mg) via normal phase column chromatography (dichloromethane/methanol=0:100% -6%: 94%) as ESI-MS (m/z): 277.2[ M+H ]] ⁺ 。

Preparation of N- ((5-ethylpyridin-2-yl) methyl) -1-methoxypropane-2-amine (35 c) to a solution of compound 35b (135 mg,0.49 mmol) in dichloromethane/methanol (2/1, 5 mL) was added potassium hydroxide (54.8 mg,0.98 mmol), after the addition was completed, the reaction was allowed to react at 25℃for 2 hours, after completion of the reaction, diluted hydrochloric acid was adjusted to pH=5, about 5, concentrated, dichloromethane (20 mL) was added, stirred, filtered, and the filtrate was concentrated to give product 35c (80 mg), ESI-MS (m/z): 205.1[ M+H] ⁺ 。

Preparation of 4-amino-N- [ (5-ethynylpyridin-2-yl) methyl ] -N- (1-methoxypropyl-2-yl ] -1, 3-dihydrofuran [4,3-c ] quinoline-8-carboxamide (35)

To a solution of compound 35c (40 mg,0.20 mmol) in N, N-dimethylacetamide (3 mL) was added sequentially compound 1e (35.9 mg,0.16 mmol), tripyrrolidinylphosphonium bromide hexafluorophosphate (91.3 mg,0.20 mmol) and triethylamine (0.11 mL,0.78 mmol), and after the completion of the reaction, the reaction solution was concentrated and subjected to reverse phase column chromatography (acetonitrile/0.05% aqueous formic acid=0:100% -50%: 50%) to give compound 35 (0.8 mg). ESI-MS (m/z): 417.2[ M+H ]] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ8.62(d,J＝1.6Hz,1H),7.89–7.87(m,1H),7.67–7.42(m,4H),6.67(s,2H),5.35–5.32(m,2H),5.02(s,2H),4.68–4.61(m,2H),4.39(s,1H),4.22–4.17(m,1H),3.21–3.07(m,5H),1.09–1.07(m,3H).

Example 36: 4-amino-N- ((5-ethynylpyridin-2-yl) methyl) -3-methyl-N- (1- (pyrimidin-2-yl) ethyl) -3H-pyrazolo [3,4-c ] quinoline-8-carboxamide

Preparation of 1- (pyrimidin-2-yl) -N- ((5- ((trimethylsilyl) ethynyl) pyridin-2-yl) methyl) ethan-1-amine (36 b)

Compound 36a (300 mg,0.82 mmol) N-methylpyrrolidone (3 mL) was added with ethynyl trimethylsilane (321.5 mg,3.27 mmol), cuprous iodide (78 mg,0.41 mmol), tetrakis (triphenylphosphine) palladium (189.2 mg,0.16 mmol) and N-N-diisopropylethylamine (0.54 mL,3.27 mmol), nitrogen substitution 3 times, and the reaction was carried out at 70℃for 3 hours under microwave. The reaction mixture was diluted with ethyl acetate (5 mL) and water (5 mL), a solid was precipitated, filtered, and the filtrate was separated, and the organic phase was concentrated and subjected to thin layer chromatography (dichloromethane: methanol=92:8) to give 36b (200 mg). ESI-MS (m/z): 311.13[ M+H ] ] ⁺

Preparation of N- ((5-ethynylpyridin-2-yl) methyl) -1- (pyrimidin-2-yl) ethan-1-amine (36 c)

Compound 36b (150 mg,0.44 mmol) was dissolved in tetrahydrofuran (2 mL), 1M tetrabutylammonium fluoride in tetrahydrofuran (1 mL) was added, and the mixture was stirred at 25℃for 1h. The reaction was quenched with water (5 mL), extracted with ethyl acetate (5 mL x 3) and the organic phases combinedThe organic phase was concentrated and then chromatographed on thin layer (dichloromethane: methanol=93:7) to give 36c (80 mg). ESI-MS (m/z): 239.15[ M+H ]] ⁺

Preparation of 4-amino-N- ((5-ethynylpyridin-2-yl) methyl) -3-methyl-N- (1- (pyrimidin-2-yl) ethyl) -3H-pyrazolo [3,4-c ] quinoline-8-carboxamide (36)

To a solution of compound 36c (52.1 mg,0.21 mmol) in N, N-dimethylacetamide (1 mL) was added compound 36d (50 mg,0.21mmol, see WO 2022/115377 A1), triethylamine (74.3 mg,0.73 mmol) and tripyrrolidinylphosphonium bromide hexafluorophosphate (127.2 mg,0.27 mmol), and the reaction was reacted at 25℃for 18 hours. After the completion of the reaction, the reaction mixture was filtered, and the filtrate was purified by high-pressure liquid chromatography to give compound 36 (5 mg). ESI-MS (m/z): 463.23[ M+H ]] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ8.81(d,J＝4.8Hz,2H),8.57–8.51(m,2H),8.29(s,1H),7.84(d,J＝8.0Hz,1H),7.62–7.34(m,4H),6.90(s,2H),5.46–5.42(m,1H),4.98–4.37(m,6H),1.62(d,J＝7.2Hz,3H).

Example 37: 4-amino-N- ((5-ethynylpyridin-2-yl) methyl) -7-fluoro-3-methyl-N- (1-methyl-1H-pyrazol-4-yl) -3H-pyrazolo [3,4-c ] quinoline-8-carboxamide

To a solution of compound 14c (58.7 mg,0.28 mmol) in N, N-dimethylacetamide (1 mL) was added compound 37a (60 mg,0.23mmol, see WO 2022/115377 A1), triethylamine (81.7 mg,0.81 mmol) and tripyrrolidinylphosphonium bromide hexafluorophosphate (139.8 mg,0.30 mmol), followed by reaction at 25℃for 18 hours. After the completion of the reaction, the reaction mixture was filtered, and the filtrate was purified by high-pressure liquid chromatography to give compound 37 (12 mg). ESI-MS (m/z): 455.19[ M+H ]] ⁺ . ¹ H NMR(400MHz,DMSO-d6)δ8.72–8.59(m,1H),8.55–8.34(m,1H),8.25–8.11(m,2H),8.01–7.79(m,1H),7.62–7.47(m,2H),7.16–7.11(m,1H),7.03(s,2H),5.10–4.99(m,2H),4.49–4.35(m,4H),3.57(s,3H).

Example 38: 4-amino-N-cyclopropyl-N- ((5-ethynylpyridin-2-yl) methyl) -3-methyl-1, 3-dihydrofuran [3,4-c ] naphthyridine-8-carboxamide

To a solution of compound 2d (42.1 mg,0.24 mmol) in N, N-dimethylacetamide (1 mL) was added compound 38a (50 mg,0.20mmol, see WO 2022/115377 A1), triethylamine (74.3 mg,0.73 mmol) and tripyrrolidinylphosphonium bromide hexafluorophosphate (123.6 mg,0.27 mmol), and reacted at 25℃for 18 hours. After the completion of the reaction, the reaction mixture was filtered, and the filtrate was purified by high-pressure liquid chromatography to give compound 38 (5 mg). ESI-MS (m/z): 400.17[ M+H ]] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ8.90(s,1H),8.68(s,1H),8.45(s,1H),8.07–7.86(m,1H),7.73(s,1H),7.45(d,J＝8.0Hz,1H),6.95(s,2H),5.48–5.25(m,3H),4.86–4.82(m,2H),4.43(s,1H),3.12–3.09(m,1H),1.44(d,J＝6.0Hz,3H),0.46–0.41(m,4H).

Example 39: 4-amino-N- (1- (difluoromethyl) -1H-pyrazol-4-yl) -N- ((5-ethynylpyridin-2-yl) methyl) -1-methyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide

Preparation of N- ((5-bromopyridin-2-yl) methyl) -1- (difluoromethyl) -1H-pyrazol-4-amine (39 a)

5-bromopyridine-2-carbaldehyde (5538 mg,3.00 mmol), (difluoromethyl) pyrazol-4-amine (399.3 mg,3.00 mmol) and acetic acid (671.8 mg,3.6 mmol) were dissolved in dichloromethane (10 mL), sodium triacetylborohydride (1.27 g,6 mmol) was added, and the reaction solution was then reacted at 25℃for 18 hours. The reaction solution was quenched with water (50 mL), pH was adjusted to 8 with saturated aqueous sodium bicarbonate, extracted with dichloromethane (100 mL x 3), the organic phases were combined and concentrated to give crude product by thin layer chromatography (dichloromethane: methanol=95:5) to give 39a (850 mg). ESI-MS (m/z): 303.07[ M+H ]] ⁺ .

Preparation of 1- (difluoromethyl) -N- ((5- ((trimethylsilyl) ethynyl) pyridin-2-yl) methyl) -1H-pyrazol-4-amine (39 b)

Compound 39a (303 mg,1.00 mmol), acetyltrimethylsilane (196.3 mg,2.00 mmol), cuprous iodide (38.1 mg,0.20 mmol), tetrakis (triphenylphosphine) palladium (115.5 mg,0.10 mmol) and N-N-diisopropylethylamine (0.69 mL,5.00 mmol) were dissolved in N-methylpyrrolidone (2 mL), nitrogen was displaced 3 times, after the reaction solution was subjected to microwave reaction at 70℃for 3 hours, ethyl acetate (20 mL) and water (20 mL) were added to dilute the reaction solution, a solid was precipitated, the filtrate was filtered, and the organic phase was concentrated to give a crude product by thin layer chromatography (dichloromethane: methanol=92:8) to give compound 39b (250 mg). ESI-MS (m/z): 321.18[ M+H ] ] ⁺ .

Preparation of 1- (difluoromethyl) -N- ((5-ethynylpyridin-2-yl) methyl) -1H-pyrazol-4-amine (39 c)

Compound 39b (200 mg,0.62 mmol) was dissolved in tetrahydrofuran (3 mL), 1M tetrabutylammonium fluoride tetrahydrofuran solution (0.94 mL,0.94 mmol) was added, and the reaction was stirred at 25℃for 1h. The reaction was quenched with water (5 mL), extracted with ethyl acetate (5 mL x 3), the organic phases were combined and concentrated to give the crude product by thin layer chromatography (dichloromethane: methanol=93:7) to give 39c (120 mg). ESI-MS (m/z): 249.17[ M+H ]] ⁺ .

Preparation of 4-amino-N- (1- (difluoromethyl) -1H-pyrazol-4-yl) -N- ((5-ethynylpyridin-2-yl) methyl) -1-methyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide (39)

To a solution of compound 39c (47.6 mg,0.19 mmol) in N, N-dimethylacetamide (2 mL) was added intermediate 13a (46.4 mg,0.19 mmol), triethylamine (0.07 mL,0.60 mmol), tripyrrolidinylphosphonium bromide hexafluorophosphate (149.7 mg,0.29 mmol), followed by reaction at 25℃for 18 hours. After the completion of the reaction, the reaction mixture was filtered, and the filtrate was purified by high-pressure liquid chromatography to give compound 39 (19 mg). ESI-MS (m/z): 473.28[ M+H ]] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ8.68(d,J＝2.2Hz,1H),8.32–8.25(m,3H),7.94–7.91(m,1H),7.86–7.58(m,3H),7.53–7.50(m,2H),7.22(s,2H),5.19(s,2H),4.46(s,1H),4.18(s,3H).

Example 40: 4-amino-N- ((5-ethynyl-4-methylpyridin-2-yl) methyl) -3-methyl-N- (1-methyl-1H-pyrazol-4-yl) -1, 3-dihydrofuro [3,4-c ] quinoline-8-carboxamide

Preparation of N- ((5-bromo-4-methylpyridin-2-yl) methyl) -1-methyl-1H-pyrazol-4-amine (40 b)

5-bromo-4-methylpyridine-2-carbaldehyde (400 mg,2.00 mmol), methylpyrazol-4-amine (213.6 mg,2.20 mmol) and acetic acid (447.8 mg,2.40 mmol) were dissolved in dichloromethane (10 mL), sodium triacetylborohydride (843.6 mg,4 mmol) was added, and the reaction was reacted at 25℃for 18 hours. The reaction solution was quenched with water (50 mL), pH was adjusted to 8 with saturated aqueous sodium bicarbonate, extracted with dichloromethane (100 mL x 3), the organic phases were combined and concentrated to give crude product which was chromatographed on thin layer (dichloromethane: methanol=95:5) to give 40b (358 mg). ESI-MS (m/z): 283.04[ M+H ]] ⁺ .

Preparation of 1-methyl-N- ((4-methyl-5- ((trimethylsilyl) ethynyl) pyridin-2-yl) methyl) -1H-pyrazol-4-amine (40 c)

Compound 40b (100 mg,0.36 mmol), acetyltrimethylsilane (69.8 mg,0.71 mmol), cuprous iodide (13.5 mg,0.07 mmol), tetrakis (triphenylphosphine) palladium (41.1 mg,0.04 mmol) and N-N-diisopropylethylamine (0.25 mL,1.78 mmol) were dissolved in N-methylpyrrolidone (2 mL), nitrogen was replaced 3 times, after the reaction solution was subjected to microwave reaction at 70℃for 3 hours, ethyl acetate (20 mL) and water (20 mL) were added to dilute the reaction solution, a solid was precipitated, the filtrate was filtered, and the organic phase was concentrated to give a crude product by thin layer chromatography (dichloromethane: methanol=92:8) to give 40c (80 mg). ESI-MS (m/z): 299.26[ M+H ] ] ⁺ .

Preparation of N- ((5-ethynyl-4-methylpyridin-2-yl) methyl) -1-methyl-1H-pyrazol-4-amine (40 d)

Compound 40c (120 mg,0.40 mmol) was dissolved in tetrahydrofuran (3 mL), 1M tetrabutylammonium fluoride tetrahydrofuran solution (0.60 mL,0.60 mmol) was added, and the reaction was stirred at 25℃for 1h. The reaction was quenched with water (5 mL), extracted with ethyl acetate (5 mL x 3), the organic phases were combined and concentrated to give the crude product by thin layer chromatography (dichloromethane: methanol=93:7) giving 40d (60 mg). ESI-MS (m/z): 227.17[ M+H ]] ⁺ .

Preparation of 4-amino-N- ((5-ethynyl-4-methylpyridin-2-yl) methyl) -3-methyl-N- (1-methyl-1H-pyrazol-4-yl) -1, 3-dihydrofuro [3,4-c ] quinoline-8-carboxamide (40)

To a solution of compound 40d (40 mg,0.18 mmol) in N, N-dimethylacetamide (2 mL) was added intermediate 25a (43.2 mg,0.18 mmol), triethylamine (0.05 mL,0.35 mmol), tripyrrolidinylphosphonium bromide hexafluorophosphate (138.0 mg,0.27 mmol), followed by reaction at 25℃for 18 hours. After the completion of the reaction, the reaction mixture was filtered, and the filtrate was purified by high-pressure liquid chromatography to give compound 40 (5 mg). ESI-MS (m/z): 453.28[ M+H ]] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ8.56(s,1H),7.60–7.19(m,5H),6.64(s,2H),5.48–5.14(m,3H),5.01(s,2H),4.61(s,1H),3.72–3.60(m,3H),2.42(s,3H),1.41(d,J＝6.4Hz,3H).

Example 41: 4-amino-3-chloro-N- ((5-ethynylpyridin-2-yl) methyl) -1-methyl-N- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [4,3-c ] quinoline-8-carboxamide

Preparation of methyl 4-amino-3-chloro-1-methyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxylate (41 b)

Compound 41a (128 mg,0.50mmol, for preparation, see WO 2022/115377 A1) was dissolved in N, N-dimethylformamide (3 mL), N-chlorosuccinimide (73.3 mg,0.55 mmol) was added, and the reaction was then allowed to react at 25℃for 18 hours. After completion of the reaction, water (10 mL) was added to the reaction mixture to precipitate a solid, which was filtered to obtain 41b (125 mg). ESI-MS (m/z): 291.14[ M+H ]] ⁺ .

Preparation of 4-amino-3-chloro-1-methyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxylic acid (41 c)

Compound 41b (125 mg,0.43 mmol) was dissolved in a mixed solution of methanol (3 mL), tetrahydrofuran (3 mL) and water (6 mL), lithium hydroxide (72.2 mg,2.46 mmol) was added, and the mixture was slowly warmed to 50℃and reacted at this temperature for 2 hours, the solvent was removed after the reaction, water (10 mL) was added, the pH was adjusted to about 6.5 with dilute hydrochloric acid, and a solid was precipitated, filtered and washed withWashing with water and drying gave compound 41c (100 mg). ESI-MS (m/z): 277.16[ M+H ]] ⁺ .

Preparation of 4-amino-3-chloro-N- ((5-ethynylpyridin-2-yl) methyl) -1-methyl-N- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [4,3-c ] quinoline-8-carboxamide (41)

To a solution of compound 14c (40 mg,0.19 mmol) in N, N-dimethylformamide (2 mL) were added compound 41c (14.6 mg,0.05 mmol), triethylamine (0.06 mL,0.40 mmol) and 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (107.5 mg,0.28 mmol), followed by reaction at 25℃for 18 hours. After the completion of the reaction, the reaction mixture was filtered, and the filtrate was purified by high-pressure liquid chromatography to give compound 41 (7 mg). ESI-MS (m/z): 471.24[ M+H ] ] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ10.66(s,1H),8.67(s,1H),8.10–7.81(m,4H),7.72–7.45(m,3H),7.30–7.16(m,1H),5.10(s,2H),4.45(s,1H),4.17(s,3H),3.67(s,3H).

Example 42: 4-amino-N- (4-ethynylbenzyl) -3-methyl-N- (1-methyl-1H-pyrazol-4-yl) -1, 3-dihydrofuro [3,4-c ] quinoline-8-carboxamide

Preparation of N- (4-bromobenzyl) -1-methyl-1H-pyrazol-4-ylamine (42 b) 4-bromobenzene-1-carbaldehyde (370 mg,2.00 mmol), methylpyrazol-4-amine (213.6 mg,2.20 mmol), acetic acid (447.8 mg,2.40 mmol) were dissolved in dichloromethane (10 mL), sodium triacetoxyborohydride (843.6 mg,4 mmol) was added, and the reaction was then reacted at 25℃for 18 hours. The reaction solution was quenched with water (50 mL), pH was adjusted to 8 with saturated aqueous sodium bicarbonate, extracted with dichloromethane (100 mL x 3), the organic phases were combined and concentrated to give crude product which was purified by thin layer chromatography (dichloromethane: methanol=95:5) to give 42b (470 mg). ESI-MS (m/z): 268.12[ M+H ]] ⁺ .

Preparation of 1-methyl-N- (4- (trimethylsilyl) ethynyl) benzyl) -1H-pyrazol-4-amine (42 c)

Compound 42b (470 mg,1.77 mmol), ethynyl trimethylsilane (346.9 mg,3.53 mmol), cuprous iodide (67.3 mg,0.35 mmol), and tetrakis(triphenylphosphine) palladium (204.1 mg,0.18 mmol) and N-N-diisopropylethylamine (1.22 mL,8.83 mmol) were dissolved in N-methylpyrrolidone (2 mL), nitrogen was displaced 3 times, after the reaction solution was subjected to microwave reaction at 70℃for 3 hours, ethyl acetate (20 mL) and water (20 mL) were added to dilute the reaction solution, a solid was separated out, filtration was carried out, the filtrate was separated, and the organic phase was concentrated to obtain a crude product which was subjected to thin layer chromatography (dichloromethane: methanol=92:8) to obtain 42c (488 mg). ESI-MS (m/z): 284.23[ M+H ] ] ⁺ Preparation of N- (4-ethylbenzyl) -1-methyl-1H-pyrazol-4-amine (42 d)

Compound 42c (488 mg,1.72 mmol) was dissolved in tetrahydrofuran (3 mL), 1M tetrabutylammonium fluoride tetrahydrofuran solution (2.58 mL,2.58 mmol) was added, and the reaction was stirred at 25℃for 1h. The reaction was quenched with water (5 mL), extracted with ethyl acetate (5 mL x 3), the organic phases were combined and concentrated to give the crude product by thin layer chromatography (dichloromethane: methanol=93:7) giving 42d (280 mg). ESI-MS (m/z): 212.18[ M+H ]] ⁺ .

Preparation of 4-amino-N- (4-ethynylbenzyl) -3-methyl-N- (1-methyl-1H-pyrazol-4-yl) -1, 3-dihydrofuran [3,4-c ] quinoline-8-carboxamide (42)

To a solution of compound 42d (42.4 mg,0.20 mmol) in N, N-dimethylacetamide (2 mL) was added compound 25a (49.0 mg,0.20 mmol), triethylamine (0.06 mL,0.40 mmol), and tripyrrolidinylphosphonium bromide hexafluorophosphate (156.6 mg,0.30 mmol), followed by reaction at 25℃for 18 hours. After the completion of the reaction, the reaction mixture was filtered, and the filtrate was purified by high-pressure liquid chromatography to give compound 42 (28 mg). ESI-MS (m/z): 438.18[ M+H ]] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ7.57–7.53(m,2H),7.48–7.46(m,3H),7.40–7.12(m,4H),6.64(s,2H),5.43–5.40(m,1H),5.27–5.14(m,2H),4.98and 4.94(s,2H),4.19(s,1H),3.65(s,3H),1.41and 1.40(s,3H).

Example 43: 4-amino-N- (4-ethynylbenzyl) -1-methyl-N- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [4,3-c ] quinoline-8-carboxamide

N, N-Di to intermediate 42d (42.4 mg,0.20 mmol) To a solution of methylacetamide (2 mL) was added intermediate 13a (48.4 mg,0.20 mmol), triethylamine (0.07 mL,0.50 mmol) and tripyrrolidinylphosphonium bromide hexafluorophosphate (156.0 mg,0.30 mmol), and the reaction was then allowed to react at 25℃for 18 hours. After the completion of the reaction, the reaction mixture was filtered, and the filtrate was purified by high-pressure liquid chromatography to give compound 43 (17 mg). ESI-MS (m/z): 436.32[ M+H ]] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ8.24(s,1H),8.20–8.19(m,1H),7.62–7.58(m,2H),7.50–7.47(m,3H),7.37–7.32(m,3H),7.19(s,2H),5.03(s,2H),4.20–4.18(m,4H),3.66(s,3H).

Example 44: 4-amino-N- ((5-ethynylpyridin-2-yl) methyl) -N- (3-fluorophenyl) -1, 3-dihydrofuro [3,4-c ] quinoline-8-carboxamide

Preparation of 3-fluoro-N- ((5- ((trimethylsilyl) ethynyl) pyridin-2-yl) methyl) aniline (44 b)

Compound 44a (500 mg,1.78 mmol), ethynyl trimethylsilane (349.3 mg,3.56 mmol), cuprous iodide (67.8 mg,0.36 mmol), tetrakis (triphenylphosphine) palladium (205.5 mg,0.18 mmol) and N-N-diisopropylethylamine (1.23 mL,8.89 mmol) were dissolved in N-methylpyrrolidone (2 mL), nitrogen was displaced 3 times, after the reaction solution was subjected to microwave reaction at 70℃for 3 hours, ethyl acetate (20 mL) and water (20 mL) were added to dilute the reaction solution, a solid was precipitated, the filtrate was filtered, and the organic phase was concentrated to give a crude product via thin layer chromatography (dichloromethane: methanol=92:8) to give 44b (380 mg). ESI-MS (m/z): 299.24[ M+H ]] ⁺ Preparation of N- ((5-ethylpyridin-2-yl) methyl) -3-fluoroaniline (44 c)

Compound 44b (300 mg,1.01 mmol) was dissolved in tetrahydrofuran (3 mL), 1M tetrabutylammonium fluoride tetrahydrofuran solution (1.51 mL,1.51 mmol) was added, and stirred at 25℃for 1h. The reaction was quenched with water (5 mL), extracted with ethyl acetate (5 mL x 3), the organic phases were combined and concentrated to give crude product which was purified by thin layer chromatography (dichloromethane: methanol=93:7) to give 44c (210 mg). ESI-MS (m/z): 227.20[ M+H ]] ⁺ 4-amino-N- ((5-ethynylpyridin-2-yl) methyl) -N- (3-fluorophenyl) -1, 3-dihydro-furo nePyrano [3,4-c]Preparation of quinoline-8-carboxamide (44) to Compound 1e (40.7 mg,0.18 mmol) was added 4M HCl in dioxane (2 mL), stirred at room temperature for 10 min, concentrated to give the hydrochloride salt, dichloromethane (3 mL) was added, oxalyl chloride (0.02 mL,0.27 mmol) was added, stirred at room temperature for 1h, concentrated directly to give the crude acid chloride, dichloromethane (3 mL), compound 44c (40 mg,0.18 mmol) and triethylamine (53.6 mg,0.53 mmol) were added, the reaction stirred at room temperature overnight, the reaction mixture was diluted with water (10 mL) and dichloromethane (10 mL), separated, the organic phase concentrated to give the crude product, and purified by high pressure liquid chromatography to give Compound 44 (5 mg). ESI-MS (m/z): 439.27[ M+H ]] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ8.64–8.63(m,1H),7.91–7.86(m,1H),7.54–7.51(m,2H),7.43–7.35(m,2H),7.26–7.19(m,2H),7.04–6.96(m,2H),6.75(s,2H),5.23(s,2H),5.17–5.15(m,2H),4.99–4.97(m,2H),4.43(s,1H).

Example 45: 4-amino-N- ((5-ethynylpyridin-2-yl) methyl) -1-methyl-N- (1-methyl-1H-pyrazol-4-yl) -1H-pyrazolo [4,3-c ] [1,7] naphthyridine-8-carboxamide

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To a solution of compound 14c (41.9 mg,0.20 mmol) in N, N-dimethylacetamide (1 mL) was added compound 45a (40 mg,0.16mmol, preparation method was referred to WO 2022/115377 A1), triethylamine (0.08 mL,0.58mmol and tripyrrolidinylphosphonium bromide hexafluorophosphate (99.7 mg,0.21 mmol), followed by reaction at 25℃for 18 hours, after completion of the reaction, purification by HPLC column to give compound 45 (12 mg). ESI-MS (m/z): 438.21[ M+H)] ⁺ . ¹ H NMR(400MHz,DMSO-d6)δ8.82–8.67(m,2H),8.42–8.24(m,2H),8.08–7.86(m,1H),7.61–7.43(m,4H),7.10(s,1H),5.27–5.12(m,2H),4.43–4.39(m,4H),3.81–3.59(m,3H).

Example 46: 4-amino-N-cyclopropyl-N- ((5-ethynylpyridin-2-yl) methyl) -1, 3-dihydrofuran [3,4-c ] [1,7] naphthyridine-8-carboxamide

To a solution of compound 2d (31.0 mg,0.18 mmol) in N, N-dimethylacetamide (1 mL) was added compound 46a (35 mg,0.15mmol, see WO 2022/115377 A1), triethylamine (0.07 mL,0.53 mmol) and tripyrrolidinylphosphonium bromide hexafluorophosphate (91.7 mg,0.20 mmol), followed by reaction at 25℃for 18 hours. After the completion of the reaction, compound 46 (5 mg) was purified by high pressure liquid chromatography. ESI-MS (m/z): 386.19[ M+H ]] ⁺ . ¹ H NMR(400MHz,DMSO-d6)δ8.93(s,1H),8.68(s,1H),7.96(d,J＝8.4Hz,1H),7.75(s,1H),7.45(d,J＝8.4Hz,1H),7.25–7.18(m,2H),5.39(s,2H),5.07(s,2H),4.84(s,2H),4.44(s,1H),2.36–2.32(m,1H),0.49–0.42(m,4H).

Example 47: 4-amino-N-cyclopropyl-N- ((5-ethynylpyridin-2-yl) methyl) -7-fluoro-1, 3-dihydrofuro [3,4-c ] quinoline-8-carboxamide

To a solution of compound 2d (41.3 mg,0.24 mmol) in N, N-dimethylacetamide (1 mL) was added compound 21a (50 mg,0.20 mmol), triethylamine (0.10 mL,0.71 mmol) and tripyrrolidinylphosphonium bromide hexafluorophosphate (122.1 mg,0.26 mmol), followed by reaction at 25℃for 18 hours. After the completion of the reaction, compound 47 (18 mg) was purified by high-pressure liquid chromatography. ESI-MS (m/z): 403.33[ M+H ] ] ⁺ . ¹ H NMR(400MHz,DMSO-d6)δ8.70(s,1H),8.40–8.15(m,2H),7.96(dd,J＝8.0,2.0Hz,1H),7.87(d,J＝7.2Hz,1H),7.65–7.52(m,1H),7.42(d,J＝8.0Hz,1H),5.46(s,2H),5.09(s,2H),4.83(s,2H),4.46(s,1H),2.88–2.82(m,1H),0.57–0.39(m,4H).

Example 48: 4-amino-N- ((5- (3-hydroxy-3-methylbut-1-yn-1-yl) pyridin-2-yl) methyl) -3-methyl-N- (1-methyl-1H-pyrazol-4-yl) -1, 3-dihydrofuran [3,4-c ] quinoline-8-carboxamide

4-amino-N- ((5-bromopyridin-2-yl) methyl) -3-methyl-N- (1-methyl-1H-pyrazol-4-yl) -1, 3-dihydrofuran [3,4-c]Preparation of quinoline-8-carboxamide (48 a) to a solution of compound 14a (106 mg,0.4 mmol) in N, N-dimethylacetamide (4 mL) was added compound 25a (98 mg,0.4 mmol), triethylamine (142 mg,1.4 mmol) and tripyrrolidinylphosphonium bromide hexafluorophosphate (243 mg,0.52 mmol), reacted at room temperature for 4 hours after the addition, and after the reaction was completed, water (10 mL) was extracted with ethyl acetate (10 mL. Times.3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was spun off to give compound 48a (105 mg) by column chromatography (methanol: dichloromethane=1:10). ESI-MS (m/z): 493.1[ M+H ]] ⁺ .

4-amino-3-methyl-N- (1-methyl-1H-pyrazol-4-yl) -N- ((5- (3-methyl-3- ((trimethylsilyl) oxy) but-1-yn-1-yl) pyridin-2-yl) methyl) -1, 3-dihydrofuro [3,4-c]Preparation of quinoline-8-carboxamide (48 b) to a solution of compound 48a (105 mg,0.24 mmol) in N-methylpyrrolidone (3 mL) under nitrogen protection was added sequentially ((1, 1-dimethyl-2-propynyl) oxy) trimethylsilane (113 mg,0.72 mmol), cuprous iodide (22 mg,0.12 mmol), N-diisopropylethylamine (124 mg,0.96 mmol) and tetrakis (triphenylphosphine) palladium (58 mg,0.05 mmol), after addition Yu Weibo ℃ for 3 hours, the reaction was completed, water (10 mL) was added, extracted with ethyl acetate (10 mL x 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was spun off to give compound 48b (65 mg) via column chromatography (methanol: dichloromethane=1:20). ESI-MS (m/z): 569.3[ M+H ] ] ⁺ .

Preparation of 4-amino-N- ((5- (3-hydroxy-3-methylbut-1-yn-1-yl) pyridin-2-yl) methyl) -3-methyl-N- (1-methyl-1H-pyrazol-4-yl) -1, 3-dihydrofuro [3,4-c ] quinoline-8-carboxamide (48)

Slowly adding 1,4 dioxane solution (1 mL, 4M) of hydrochloric acid to dichloromethane (1 mL) of compound 48b (65 mg,0.11 mmol) at 0deg.C, reacting at room temperature for 30 min, adding saturated sodium carbonate solution, adjusting pH to about 8, extracting with ethyl acetate (10 mL. Times.3), mixing organic phases, washing with saturated saline solution, drying with anhydrous sodium sulfate, filtering, eluting solvent, and subjecting to reverse phase chromatography (acetonitrile: 0.05% carbon)Aqueous ammonium acid hydrogen = 0:100% -60%: 40%) was purified to give compound 48 (19 mg). ESI-MS (m/z): 497.4[ M+H ]] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ8.56(d,J＝1.6Hz,1H),7.81(dd,J＝8.0,2.0Hz,1H),7.61–7.42(m,5H),7.17(s,1H),6.64(s,2H),5.57(s,1H),5.45–5.36(m,1H),5.24–5.18(m,2H),5.05(s,2H),3.66(s,3H),1.49(s,6H),1.41(d,J＝6.2Hz,3H).

Example 49: 4-amino-N- ((5-ethynylpyridin-2-yl) methyl) -N- (1-methyl-1H-pyrazol-4-yl) -1, 3-dihydrofuro [3,4-c ] quinoline-8-carboxamide

To a solution of compound 14c (43 mg,0.2 mmol) in N, N-dimethylacetamide (3 mL) was added compound 1e (46 mg,0.2 mmol), triethylamine (71 mg,0.7 mmol) and tripyrrolidinylphosphonium bromide hexafluorophosphate (122 mg,0.26 mmol), reacted at room temperature for 4 hours after the addition, water (10 mL) was added to extract with ethyl acetate (10 mL of x 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the solvent was removed, and purified by reverse phase chromatography (acetonitrile: 0.05% ammonium bicarbonate aqueous solution=0:100% -50%: 50%) to give compound 49 (15 mg). ESI-MS (m/z): 425.3[ M+H ] ] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ8.66(d,J＝1.6Hz,1H),7.91(dd,J＝8.0,2.0Hz,1H),7.59(s,2H),7.51–7.35(m,3H),7.17(s,1H),6.71(s,2H),5.23(s,2H),5.05(s,2H),5.01–4.99(m,2H),4.44(s,1H),3.66(s,3H).

Example 50: 4-amino-N- ((5-ethynylpyridin-2-yl) methyl) -3-methyl-N- (2- (trifluoromethyl) cyclopropyl) -1, 3-dihydrofuro [3,4-c ] quinoline-8-carboxamide

4-amino-N-cyclopropyl-N- ((5-ethynylpyridin-2-yl) methyl) -1, 3-dihydro-furo [3,4-c]Preparation of quinoline-8-carboxamide (50 a) to the compound 2- (trifluoromethyl) cyclopropan-1-amine (250 mg,2 mmol)N, N-diisopropylethylamine (0.42 mL,2.4 mmol) was added to a dichloromethane (10 mL), stirred at room temperature for 10 min, 2a (268 mg,2 mmol), acetic acid (0.15 mL,2.6 mmol) was added, sodium triacetoxyborohydride (848 mg,4 mmol) was added after 30 min, the reaction was continued for 3 h after the addition, water (20 mL) was added, extraction with dichloromethane (20 mL. Times.3) was completed, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the solvent was removed, and the compound 50a (350 mg) was obtained by column chromatography (ethyl acetate: petroleum ether=4:1). ESI-MS (m/z): 295.1[ M+H ]] ⁺ .

Preparation of 2- (trifluoromethyl) -N- ((5- ((trimethylsilyl) ethynyl) pyridin-2-yl) methyl) cyclopropan-1-amine (50 b)

To a solution of compound 50a (294 mg,1 mmol) in N-methylpyrrolidone (4 mL) under nitrogen, ethynyl trimethylsilane (200 mg,2 mmol), cuprous iodide (95 mg,0.5 mmol), N-diisopropylethylamine (0.7 mL,4 mmol) and tetrakis (triphenylphosphine) palladium (230 mg,0.2 mmol) were added in this order, and after the addition, the reaction was completed under microwave 70 ℃ for 3 hours, water (20 mL) was added, extracted with ethyl acetate (15 mL x 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was spun off to give compound 50b (152 mg) by column chromatography (methanol: dichloromethane=1:20). ESI-MS (m/z): 313.1[ M+H ] ] ⁺ Preparation of N- ((5-ethynylpyridin-2-yl) methyl) -2- (trifluoromethyl) cyclopropan-1-amine (50 c) tetrabutylammonium fluoride (207 mg,0.96 mmol) was slowly added to a solution of compound 50c (150 mg,0.48 mmol) in tetrahydrofuran (5 mL), stirred at room temperature for 15 min, water (10 mL) was added, extracted with ethyl acetate (15 mL x 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was spun off to give compound 50c (110 mg) by column chromatography (methanol: dichloromethane=1:20). ESI-MS (m/z): 241.1[ M+H ]] ⁺ .

4-amino-N- ((5-ethynylpyridin-2-yl) methyl) -3-methyl-N- (2- (trifluoromethyl) cyclopropyl) -1, 3-dihydrofuro [3,4-c]Preparation of quinoline-8-carboxamide (50) to a solution of Compound 50c (48 mg,0.2 mmol) in N, N-dimethylacetamide (5 mL) was added Compound 25a (46 mg,0.2 mmol), triethylamine (71 mg,0.7 mmol) and Tri-ethylaminePyrrolidinyl phosphonium bromide hexafluorophosphate (121 mg,0.26 mmol) was reacted at room temperature for 4 hours after the addition, water (10 mL) was added after the reaction was completed, extracted with ethyl acetate (10 mL. Times.3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the solvent was spun off, and purified by reverse phase chromatography (acetonitrile: 0.05% ammonium bicarbonate aqueous solution=0:100% -40%: 60%) to give compound 50 (14 mg). ESI-MS (m/z): 467.3[ M+H ] ] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ8.70(d,J＝1.6Hz,1H),7.92(d,J＝8.0Hz,1H),7.67–7.42(m,4H),6.64(s,2H),5.43–5.21(m,3H),4.82–4.70(m,2H),4.45(s,1H),2.32–2.27(m,1H),1.42(d,J＝5.2Hz,3H),1.16–1.03(m,2H).

Example 51: 4-amino-N- [ (5-ethynylpyridin-2-yl) methyl ] -N- [1- (3-fluoropyridin-2-yl) ethyl ] -3-methyl-1, 3-dihydrofuran [4,3-c ] quinoline-8-carboxamide

2- (1- { [ (5-bromopyridin-2-yl) methyl)]Preparation of amino } ethyl) -3-fluoropyridine (51 a) Compound 1a (200 mg,1.07 mmol), 1- (3-fluoropyridin-2-yl) ethan-1-one (178.5 mg,1.28 mmol) and acetic acid (0.08 mL,1.39 mmol) were dissolved in dichloromethane (10 mL), after stirring at 25℃for 0.5 h, sodium triacetylborohydride (338.3 mg,1.60 mmol) was added, the reaction stirred at room temperature for 2 h, the reaction mixture was quenched with 10mL saturated aqueous sodium bicarbonate, extracted with dichloromethane (10 mL. 3), the organic phases were combined, concentrated to give crude product and purified by thin layer chromatography (petroleum ether: ethyl=6:1) to give 51a (220 mg). ESI-MS (m/z): 311.99[ M+H ]] ⁺ .

Preparation of 3-fluoro-2- {1- [ ({ 5- [ (trimethylsilyl) ethynyl ] pyridin-2-yl } methyl) amino ] ethyl } pyridine (51 b)

Compound 51a (220 mg,0.71 mmol), acetyltrimethylsilane (208.9mg,2.13mmo l), cuprous iodide (67.6 mg,0.35 mmol), tetrakis (triphenylphosphine) palladium (163.9 mg,0.14 mmol) and N-N-diisopropylethylamine (0.47 mL,2.84 mmol) were dissolved in N-methylpyrrolidone (3 mL), nitrogen was replaced 3 times, and after microwave reaction at 70℃for 3 hours, the reaction mixture was added with ethyl acetate Ethyl acetate (10 mL) and water (10 mL) to precipitate a solid, filtering, separating the filtrate, and concentrating the organic phase to give crude product by thin layer chromatography (dichloromethane: methanol=92:8) to give 51b (150 mg). ESI-MS (m/z): 328.23[ M+H ]] ⁺ .

Preparation of 2- (1- { [ (5-ethynylpyridin-2-yl) methyl ] amino } ethyl) -3-fluoropyridine (51 c)

Compound 51b (150 mg,0.46 mmol) was dissolved in tetrahydrofuran (2 mL), 1M tetrabutylammonium fluoride in tetrahydrofuran (1 mL) was added, and the reaction was stirred at 25℃for 1h. The reaction was quenched with water (5 mL), extracted with ethyl acetate (5 mL x 3), the organic phases were combined and concentrated to give crude product which was chromatographed on thin layer (dichloromethane: methanol=93:7) to give 51c (45 mg). ESI-MS (m/z): 256.23[ M+H ]] ⁺ .

Preparation of 4-amino-N- [ (5-ethynylpyridin-2-yl) methyl ] -N- [1- (3-fluoropyridin-2-yl) ethyl ] -3-methyl-1, 3-dihydrofuran [4,3-c ] quinoline-8-carboxamide (51)

To a solution of compound 51c (40 mg,0.16 mmol) in N, N-dimethylacetamide (1 mL) was added compound 25a (38.3 mg,0.16 mmol), triethylamine (0.08 mL,0.55 mmol) and tripyrrolidinylphosphonium bromide hexafluorophosphate (103.6 mg,0.22 mmol), followed by reaction at 25℃for 18 hours. After the completion of the reaction, the reaction mixture was filtered, and the filtrate was purified by high-pressure liquid chromatography to give compound 51 (20 mg). ESI-MS (m/z): 482.18[ M+H ] ] ⁺ . ¹ H NMR(400MHz,DMSO-d6)δ8.80–8.43(m,3H),8.34(s,1H),8.08–7.50(m,5H),7.44–6.29(m,2H),558–5.27(m,3H),4.77–4.65(m,2H),4.41(s,1H),1.63–1.42(m,6H).

Example 52: 4-amino-N- [ (5-ethynylpyridin-2-yl) methyl ] -7-fluoro-3-methyl-N- (1-methylpyrazol-4-yl) -1, 3-dihydrofuran [4,3-c ] quinoline-8-carboxamide

To a solution of compound 14c (48.6 mg,0.23 mmol) in N, N-dimethylacetamide (1 mL) was added compound 34a (50 mg,0.19 mmol), triethylamine (0.09 mL,0.67 mmol), tripyrrolidinylphosphonium bromide hexafluorophosphate (115.6 mg,0.25 mmol)The reaction solution was then reacted at 25℃for 18 hours. The reaction solution was filtered, and the filtrate was purified by high pressure liquid chromatography to give compound 52 (10 mg). ESI-MS (m/z): 457.19[ M+H ]] ⁺ . ¹ H NMR(400MHz,DMSO-d6)δ8.66–8.65(m,1H),8.14–8.10(m,1H),7.97–7.94(m,1H),7.70(d,J＝7.2Hz,1H),7.60–7.57(m,1H),7.48(d,J＝8.0Hz,1H),7.27–7.12(m,3H),5.46–5.24(m,3H),5.07–4.96(m,2H),4.46(s,1H),3.81–3.59(m,3H),1.41(d,J＝6.4Hz,3H).

Example 53: 4-amino-N- [ (5-ethynyl-3-fluoropyridin-2-yl) methyl ] -3-methyl-N- (1-methylpyrazol-4-yl) -1, 3-dihydrofuran [4,3-c ] quinoline-8-carboxamide

Preparation of 5-bromo-3-fluoro-2- { [ (1-methylpyrazol-4-yl) amino ] methyl } pyridine (53 b)

1-methylpyrazol-4-amine hydrochloride (392.9 mg,2.94 mmol) was dissolved in dichloromethane (10 mL), N-N-diisopropylethylamine (0.49 mL,2.94 mmol) was added, after stirring at 25℃for 0.5 h 53a (500 mg,2.45 mmol) and acetic acid (0.21 mL,3.68 mmol) were added, after stirring at 25℃for 0.5 h sodium triacetylborohydride (930.4 mg,4.41 mmol) was added, the reaction stirred at room temperature for 12 h, quenched with 10mL saturated aqueous sodium bicarbonate, extracted with dichloromethane (10 mL. 3), the organic phases were combined, concentrated to give crude product and purified by thin layer chromatography (petroleum ether: ethyl ester=6:1) to give compound 53b (450 mg). ESI-MS (m/z): 285.04[ M+H ] ] ⁺ .

Preparation of 3-fluoro-2- { [ (1-methylpyrazol-4-yl) amino ] methyl } -5- [ (trimethylsilyl) ethynyl ] pyridine (53 c)

Compound 53b (450 mg,1.58 mmol), acetyltrimethylsilane (465.0 mg,4.74 mmol), cuprous iodide (150.3 mg,0.79 mmol), tetrakis (triphenylphosphine) palladium (364.8 mg,0.32 mmol) and N-N-diisopropylethylamine (1.05 mL,6.31 mmol) were dissolved in N-methylpyrrolidone (5 mL), nitrogen was replaced 3 times, the reaction mixture was subjected to microwave reaction at 70℃for 3 hours, ethyl acetate (10 mL) and water (10 mL) were added to dilute, the solid was precipitated, the filtrate was filtered, the filtrate was separated, and the organic phase was concentrated to give a crude productThin layer chromatography (dichloromethane: methanol=92:8) afforded 53c (440 mg). ESI-MS (m/z): 303.2[ M+H ]] ⁺ .

Preparation of 5-ethynyl-3-fluoro-2- { [ (1-methylpyrazol-4-yl) amino ] methyl } pyridine (53 d)

Compound 53c (440 mg,1.46 mmol) was dissolved in tetrahydrofuran (5 mL), 1M tetrabutylammonium fluoride in tetrahydrofuran (1 mL) was added, and the mixture was stirred at 25℃for 1h. The reaction was quenched with water (5 mL), extracted with ethyl acetate (15 mL x 3), the organic phases were combined, concentrated and purified by thin layer chromatography (dichloromethane: methanol=93:7) to give compound 53d (120 mg). ESI-MS (m/z): 231.16[ M+H ]] ⁺ .

Preparation of 4-amino-N- [ (5-ethynyl-3-fluoropyridin-2-yl) methyl ] -3-methyl-N- (1-methylpyrazol-4-yl) -1, 3-dihydrofuran [4,3-c ] quinoline-8-carboxamide (53)

To a solution of compound 53d (51.8 mg,0.23 mmol) in N, N-dimethylacetamide (1 mL) was added compound 25a (50 mg,0.20 mmol), triethylamine (0.10 mL,0.72 mmol) and tripyrrolidinylphosphonium bromide hexafluorophosphate (124.0 mg,0.27 mmol), followed by reaction at 25℃for 18 hours. After the completion of the reaction, the reaction mixture was filtered, and the filtrate was purified by high-pressure liquid chromatography to give compound 53 (3 mg). ESI-MS (m/z): 457.22[ M+H ]] ⁺ . ¹ H NMR(400MHz,DMSO-d6)δ8.57(s,1H),7.92(d,J＝6.4Hz,1H),7.62–7.38(m,4H),7.16(s,1H),6.63(s,2H),5.42–5.39(m,1H),5.27–5.10(m,4H),4.58(s,1H),3.66(s,3H),1.40(d,J＝6.0Hz,3H).

Example 54: 4-amino-N- [ (5-ethynylpyridin-2-yl) methyl ] -1, 7-dimethyl-N- (1-methylpyrazol-4-yl) pyrazolo [4,3-c ] quinoline-8-carboxamide

To a solution of compound 14c (49.7 mg,0.23 mmol) in N, N-dimethylacetamide (1 mL) was added compound 54a (60 mg,0.23mmol, see WO 2022/115377 A1), triethylamine (0.11 mL,0.82 mmol) and tripyrrolidinylphosphonium bromide hexafluorophosphate (141.9 mg,0.30 mmol), followed by reaction at 25℃for 18 hours. Spin drying of the reaction solutionPurification by HPLC column afforded compound 54 (15 mg). ESI-MS (m/z): 451.22[ M+H ]] ⁺ . ¹ H NMR(400MHz,DMSO-d6)δ8.73–8.64(m,1H),8.25–7.86(m,3H),7.59–7.32(m,3H),7.15(s,1H),7.03(s,2H),5.11–4.95(m,2H),4.45(s,1H),4.32–4.12(m,3H),3.82–3.53(m,3H),2.41(s,3H).

Example 55: 4-amino-N-cyclopropyl-N- [ (5-ethynylpyridin-2-yl) methyl ] -1, 7-dimethylpyrazolo [4,3-c ] quinoline-8-carboxamide

To a solution of compound 2d (39.6 mg,0.23 mmol) in N, N-dimethylacetamide (1 mL) was added compound 54a (60 mg,0.23 mmol), triethylamine (0.11 mL,0.82 mmol) and tripyrrolidinylphosphonium bromide hexafluorophosphate (141.9 mg,0.30 mmol), followed by reaction at 25℃for 18 hours. The reaction solution was dried by spin-drying, and purified by high-pressure liquid chromatography to give compound 55 (15 mg). ESI-MS (m/z): 411.18[ M+H ] ] ⁺ . ¹ H NMR(400MHz,DMSO-d6)δ8.70(s,1H),8.27–8.20(m,2H),8.99–7.92(m,1H),7.49–7.42(m,2H),7.04(s,2H),4.86(s,1H),4.53–4.12(m,4H),2.89–2.82(m,1H),2.37(s,3H),0.85–0.32(m,4H).

Example 56: 4-amino-N- [ (5-ethynylpyridin-2-yl) methyl ] -1,7, N-trimethylpyrazolo [4,3-c ] quinoline-8-carboxamide

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To a solution of compound 7c (41.9 mg,0.23 mmol) in N, N-dimethylacetamide (1 mL) was added compound 54a (60 mg,0.23 mmol), triethylamine (0.11 mL,0.82 mmol) and tripyrrolidinylphosphonium bromide hexafluorophosphate (141.9 mg,0.30 mmol), and the reaction was stirred at 25℃for 18 hours. The reaction mixture was dried by spin-drying, and purified by high-pressure liquid chromatography to give Compound 56 (7 mg). ESI-MS (m/z): 385.20[ M+H ]] ⁺ . ¹ H NMR(400MHz,DMSO-d6)δ8.70(s,1H),8.24–8.19(m,1H),8.08–7.87(m,2H),7.49–7.28(m,2H),7.05–7.01(m,2H),4.86–4.55(m,2H),4.47(s,1H),4.39–4.26(m,3H),3.05–2.90(m,3H),2.36(s,3H).

Example 57: 4-amino-N- [ (5-ethynylpyridin-2-yl) methyl ] -3, 7-dimethyl-N- (1-methylpyrazol-4-yl) -1, 3-dihydrofuran [4,3-c ] quinoline-8-carboxamide

To a solution of compound 14c (49.3 mg,0.23 mmol) in N, N-dimethylacetamide (1 mL) was added compound 57a (60 mg,0.23mmol, see WO 2022/115377 A1), triethylamine (0.11 mL,0.81 mmol), tripyrrolidinylphosphonium bromide hexafluorophosphate (140.8 mg,0.30 mmol), followed by reaction at 25℃for 18 hours. After the completion of the reaction, compound 57 (23 mg) was purified by high pressure liquid chromatography. ESI-MS (m/z): 453.17[ M+H ]] ⁺ . ¹ H NMR(400MHz,DMSO-d6)δ8.67–8.62(m,1H),8.12–7.08(m,6H),6.51–6.47(m,2H),5.38–4.82(m,5H),4.44(s,1H),3.84–3.50(m,3H),2.36(s,3H),1.41–1.38(m,3H).

Example 58: 4-amino-N- [ (5-ethynyl-3-fluoropyridin-2-yl) methyl ] -1-methyl-N- (1-methylpyrazol-4-yl) pyrazolo [4,3-c ] quinoline-8-carboxamide

To a solution of compound 53d (40 mg,0.17 mmol) in N, N-dimethylacetamide (1 mL) was added compound 13a (38.3 mg,0.16 mmol), triethylamine (0.08 mL,0.55 mmol), tripyrrolidinylphosphonium bromide hexafluorophosphate (95.7 mg,0.21 mmol), followed by reaction at 25℃for 18 hours. After the completion of the reaction, compound 58 (15 mg) was purified by high pressure liquid chromatography. ESI-MS (m/z): 455.15[ M+H ]] ⁺ . ¹ H NMR(400MHz,DMSO-d6)δ8.58–8.57(m,1H),8.23(s,1H),8.21(s,1H),7.93(dd,J＝10.4,1.6Hz,1H),7.68(s,1H),7.58–7.47(m,2H),7.23–7.17(m,3H),5.16(d,J＝1.6Hz,2H),4.59(s,1H),4.21(s,3H),3.67(s,3H).

Example 59: 4-amino-N- [ (5-ethynylpyridin-2-yl) methyl ] -7-methyl-N- (1-methylpyrazol-4-yl) -1, 3-dihydrofuro [4,3-c ] quinoline-8-carboxamide

To a solution of compound 14c (52.1 mg,0.25 mmol) in N, N-dimethylacetamide (1 mL) was added compound 59a (60 mg,0.25mmol, see WO 2022/115377 A1), triethylamine (0.12 mL,0.86 mmol), tripyrrolidinylphosphonium bromide hexafluorophosphate (148.8 mg,0.32 mmol), followed by reaction at 25℃for 18 hours. After the completion of the reaction, compound 59 (25 mg) was purified by high pressure liquid chromatography. ESI-MS (m/z): 439.44[ M+H ]] ⁺ .1H NMR(400MHz,DMSO-d6)δ8.67–8.62(m,1H),8.12–7.08(m,6H),6.60–6.56(m,2H),5.28–4.91(m,6H),4.46(s,1H),3.81–3.53(m,3H),2.37(s,3H).

Example 60: 4-amino-N-ethyl-N- (4-ethynylbenzyl) -1-methyl-1H-pyrazolo [4,3-c ] [1,7] naphthyridine-8-carboxamide

Preparation of 4- ((trimethylsilyl) ethynyl) benzaldehyde (60 b) to a solution of compound 60a (1.0 g,5.41 mmol) in tetrahydrofuran (10 mL) was added cuprous iodide

(103.1 mg,0.54 mmol), triethylamine (5 mL,36.07 mmol), ditolylphosphine palladium dichloride (379.7 mg,0.54 mmol) and trimethylsilylacetylene (1.06 g,10.82 mmol) were reacted by microwaves at 75℃for 3 hours under nitrogen. Ethyl acetate (20 mL) was added to the reaction solution, which was filtered through celite, and the filtrate was concentrated to give product 60b (500 mg) by normal phase column chromatography (methanol/dichloromethane=1:20). ESI-MS (m/z): 203.1[ M+H ]] ⁺ .

Preparation of N- (4- ((trimethylsilyl) ethynyl) benzyl) ethylamine (60 c) to a mixed solution of compound 60b (200 mg,0.99 mmol) in dichloromethane/methanol (2 mL/2 mL) was added ethylamine hydrochloride (161.1 mg,1.98 mmol), N, N-diisopropylethylamine (0.33 mL,2 mmol) and sodium triacetoxyborohydride (417.0 mg,1.98 mmol), and the addition was reacted at 25℃for 3 hours. After the reaction is completedThe resulting solution was extracted with water (15 mL), dichloromethane (3×15 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give compound 60c (160.0 mg) by normal phase column chromatography (ethyl acetate/petroleum ether=1:5). ESI-MS (m/z): 232.1[ M+H ]] ⁺ .

Preparation of N- (4-ethynylbenzyl) ethylamine (60 d)

Tetrabutylammonium fluoride (180.8 mg,0.69 mmol) was added to a solution of compound 60c (160 mg,0.69 mmol) in tetrahydrofuran (5 mL), and reacted at 25℃for 2 hours. The reaction solution was concentrated, and subjected to normal phase column chromatography (ethyl acetate/petroleum ether=0-25%) to give compound 60d (80 mg). ESI-MS (m/z): 160.1[ M+H ] ] ⁺ .

Preparation of 4-amino-N-ethyl-N- (4-ethynylbenzyl) -1-methyl-1H-pyrazolo [4,3-c ] [1,7] naphthyridine-8-carboxamide (60)

To a solution of compound 60d (91.7 mg,0.38 mmol) in N, N-dimethylacetamide (5 mL) was added compound 45a (50 mg,0.31 mmol), triethylamine (0.13 mL,0.94 mmol) and tripyrrolidinylphosphonium bromide hexafluorophosphate (219.5 mg,0.47 mmol), and the addition was reacted overnight at 25 ℃. After completion of the reaction, water (10 mL) was added, extraction was performed with ethyl acetate (10×3 mL), the organic phases were washed three times with saturated brine, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and subjected to reverse phase column chromatography (acetonitrile/0.5% ammonium bicarbonate aqueous solution=0:100% -50%: 50%) to give compound 60 (17.0 mg). ESI-MS (m/z): 385.2[ M+H ]] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ8.81–8.79(m,1H),8.37–8.34(m,2H),7.53–7.38(m,6H),4.80–4.78(m,2H),4.46–4.38(m,3H),4.20–4.18(m,1H),3.45–3.42(m,2H),1.16–1.11(m,3H).

Example 61: 4-amino-7-chloro-N- ((5-ethynylpyridin-2-yl) methyl) -3-methyl-N- (1-methyl-1H-pyrazol-4-yl) -1, 3-dihydrofuro [3,4-c ] quinoline-8-carboxamide

To a solution of compound 14c (42.4 mg,0.20 mmol) in N, N-dimethylacetamide (2 mL) was added compound 61a (55.7 mg,0.20mmol, for preparation as described in WO 2022-115377 A1), triethylamine (0.06 mL,0.40 mmol) and tripyrrolidinylphosphonium bromide hexafluorophosphate (156.6 mg,0.30 mmol) were reacted at 25℃for 18 hours. The reaction solution was filtered, and the filtrate was purified by high pressure liquid chromatography to give compound 61 (10 mg). ESI-MS (m/z): 473.20[ M+H ] ] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ8.66–8.60(m,1H),7.98–7.81(m,1H),7.60–7.43(m,4H),7.28–7.13(m,1H),6.78–6.74(s,2H),5.41–5.17(m,3H),5.06–4.97(m,2H),4.45–4.43(s,1H),3.56(s,3H),1.41–1.39(m,3H).

Example 62: 4-amino-N- ((5-ethynylpyridin-2-yl) methyl) -N- ((3-fluoropyridin-2-yl) methyl) -3-methyl-1, 3-dihydrofuran [3,4-c ] quinoline-8-carboxamide

Preparation of 1- (5-bromopyridin-2-yl) -N- (2-fluorobenzyl) methylamine (62 a)

N, N-diisopropylethylamine (0.42 mL,2.4 mmol) was added to a dichloromethane (10 mL) solution of the compound (2-fluorophenyl) methylamine (250 mg,2 mmol) at room temperature, stirred for 10 minutes, 2a (365 mg,2 mmol), acetic acid (0.15 mL,2.6 mmol) was added, sodium triacetoxyborohydride (848 mg,4 mmol) was added after 30 minutes, the reaction was continued for 3 hours after the addition, water (20 mL) was added, extraction (20 mL. Times.3) with dichloromethane was performed, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed, followed by column chromatography (ethyl acetate: petroleum ether=1:3) to give the compound 62a (365 mg). ESI-MS (m/z): 295.1[ M+H ]] ⁺ .

Preparation of N- (2-fluorobenzyl) -1- (5- ((trimethylsilyl) ethyl) pyridin-2-yl) methylamine (62 b)

To a solution of compound 62a (254 mg,1 mmol) in N-methylpyrrolidone (4 mL) under nitrogen was added sequentially ethynyl trimethylsilane (200 mg,2 mmol), cuprous iodide (95 mg,0.5 mmol), N, N-diisopropylethylamine (0.7 mL,4 mmol) and tetrakis (triphenylphosphine) palladium (230 mg,0.2 mmol), and the addition was completed for 3 hours at Yu Weibo ℃. The reaction mixture was extracted with water (20 mL), ethyl acetate (15 mL. Times.3), and the organic phases were combined and saturated And brine, dried over anhydrous sodium sulfate, filtered, and spin-dried to give compound 62b (152 mg) by column chromatography (methanol: dichloromethane=1:20). ESI-MS (m/z): 313.1[ M+H ]] ⁺ .

Preparation of 1- (5-ethylpyridin-2-yl) -N- (2-fluorobenzyl) methylamine (62 c)

Tetrabutylammonium fluoride (207 mg,0.96 mmol) was slowly added to a solution of compound 62b (150 mg,0.48 mmol) in tetrahydrofuran (5 mL) at room temperature, stirred for 15 min, water (10 mL) was added after completion of the reaction, extracted with ethyl acetate (15 mL x 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried to give compound 62c (110 mg) via column chromatography (methanol: dichloromethane=1:20). ESI-MS (m/z): 241.1[ M+H ]] ⁺ .

Preparation of 4-amino-N- ((5-ethynylpyridin-2-yl) methyl) -N- ((3-fluoropyridin-2-yl) methyl) -3-methyl-1, 3-dihydrofuran [3,4-c ] quinoline-8-carboxamide (62)

To a solution of compound 62c (48 mg,0.2 mmol) in N, N-dimethylacetamide (5 mL) was added compound 25a (46 mg,0.2 mmol), triethylamine (71 mg,0.7 mmol) and tripyrrolidinylphosphonium bromide hexafluorophosphate (121 mg,0.26 mmol), and the addition was completed at room temperature for 4 hours. The reaction mixture was extracted with water (10 mL), ethyl acetate (10 mL. Times.3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was spun off and purified by reverse phase chromatography (acetonitrile: 0.05% ammonium bicarbonate aqueous solution=0:100% -40%: 60%) to give compound 62 (9 mg). ESI-MS (m/z): 468.3[ M+H ] ] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ8.72–8.15(m,2H),7.91(dd,J＝8.0,2.0Hz,1H),7.70–7.37(m,6H),6.62(s,2H),5.42–5.40(m,1H),5.16–5.10(m,2H),4.84–4.78(m,4H),4.45(s,1H),1.40(d,J＝6.4Hz,3H).

Example 63: 4-amino-N- ((5-ethynylpyridin-2-yl) methyl) -3-methyl-N- (1- (pyrimidin-2-yl) ethyl) -1, 3-dihydrofuro [3,4-c ] quinoline-8-carboxamide

Orientation methodTo a solution of compound 36c (48 mg,0.2 mmol) in N, N-dimethylacetamide (3 mL) was added 25a (49 mg,0.2 mmol), triethylamine (71 mg,0.7 mmol) and tripyrrolidinylphosphonium bromide hexafluorophosphate (122 mg,0.26 mmol), and the addition was completed at room temperature for 4 hours. The reaction mixture was added with water (10 mL), extracted with ethyl acetate (10 ml×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was spun off and purified by reverse phase chromatography (acetonitrile: 0.05% ammonium bicarbonate aqueous solution=0:100% -50%: 50%) to give compound 63 (11 mg). ESI-MS (m/z): 465.2[ M+H ]] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ8.82–8.80(m,2H),8.61–8.55(m,1H),7.84–7.35(m,6H),6.63(s,2H),5.42–4.41(m,7H),1.58(d,J＝7.2Hz,3H),1.43–1.39(m,3H).

Example 64: 4-amino-N- ((5-ethynylpyridin-2-yl) methyl) -N- (1- (pyrimidin-2-yl) ethyl) -1, 3-dihydrofuro [3,4-c ] quinoline-8-carboxamide

To a solution of compound 36c (48 mg,0.2 mmol) in N, N-dimethylacetamide (3 mL) was added compound 1e (46 mg,0.2 mmol), triethylamine (71 mg,0.7 mmol) and tripyrrolidinylphosphonium bromide hexafluorophosphate (122 mg,0.26 mmol), and the addition was completed at room temperature for 4 hours. The reaction mixture was added with water (10 mL), extracted with ethyl acetate (10 ml×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was spun off and purified by reverse phase chromatography (acetonitrile: 0.05% ammonium bicarbonate aqueous solution=0:100% -50%: 50%) to give compound 64 (14 mg). ESI-MS (m/z): 451.3[ M+H ] ] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ8.82(s,1H),8.80(s,1H),8.61–8.56(m,1H),7.83(dd,J＝8.0,2.0Hz,1H),7.71–7.36(m,5H),6.71(s,2H),5.40–4.41(m,8H),1.58(d,J＝7.2Hz,3H).

Example 65: 4-amino-N-cyclopropyl-N- ((5-ethynylpyridin-2-yl) methyl) -3-methyl-1, 3-dihydrofuran [3,4-c ] quinoline-8-carboxamide

To a solution of compound 2d (52 mg,0.3 mmol) in N, N-dimethylacetamide (3 mL) was added 25a (73 mg,0.2 mmol), triethylamine (106 mg,1.05 mmol) and tripyrrolidinylphosphonium bromide hexafluorophosphate (182 mg,0.39 mmol), and the addition was completed at room temperature for 4 hours. The reaction mixture was added with water (10 mL), extracted with ethyl acetate (10 ml×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was spun off and purified by reverse phase chromatography (acetonitrile: 0.05% ammonium bicarbonate aqueous solution=0:100% -50%: 50%) to give compound 65 (10 mg). ESI-MS (m/z): 399.2[ M+H ]] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ8.69(d,J＝1.6Hz,1H),7.93(dd,J＝8.0,2.0Hz,1H),7.74–7.72(m,2H),7.58–7.56(m,1H),7.41(d,J＝8.0Hz,1H),6.63(s,2H),5.45–5.27(m,3H),4.80(s,2H),4.44(s,1H),3.04–2.98(m,1H),1.44(d,J＝6.0Hz,3H),0.54–0.48(m,4H).

Example 66: 4-amino-N-cyclopropyl-N- (4- (3-hydroxy-3-methylbut-1-yn-1-yl) benzyl) -1-methyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide

Preparation of 4-amino-N- (4-bromobenzyl) -N-cyclopropyl-1-methyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide (66 b)

To a solution of compound 66a (225 mg,1 mmol) in N, N-dimethylacetamide (5 mL) was added compound 13a (242 mg,0.2 mmol), triethylamine (354 mg,3.5 mmol) and tripyrrolidinylphosphonium bromide hexafluorophosphate (606 mg,1.3 mmol), and the addition was completed at room temperature for 4 hours. The reaction mixture was added with water (20 mL), extracted with ethyl acetate (10 ml×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by column chromatography (methanol: dichloromethane=1:20) to give compound 66b (235 mg). ESI-MS (m/z): 450.1[ M+H ] ] ⁺ .

Preparation of 4-amino-N-cyclopropyl-1-methyl-N- (4- (3-methyl-3- ((trimethylsilyl) oxy) but-1-yn-1-yl) benzyl) -1H-pyrazolo [4,3-c ] quinoline-8-carboxamide (66 c)

To a solution of compound 66b (108 mg,0.24 mmol) in N-methylpyrrolidone (3 mL) under nitrogen was added ((1, 1-dimethyl-2-propynyl) oxy) trimethylsilane (113 mg,0.72 mmol), cuprous iodide (22 mg,0.12 mmol), N, N-diisopropylethylamine (124 mg,0.96 mmol) and tetrakis (triphenylphosphine) palladium (58 mg,0.05 mmol) in this order, followed by reaction at Yu Weibo 70 ℃for 3 hours. The reaction solution was added with water (20 mL), extracted with ethyl acetate (20 ml×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was spun off to give compound 66c (53 mg) by column chromatography (methanol: dichloromethane=1:20). ESI-MS (m/z): 526.3[ M+H ]] ⁺ .

Preparation of 4-amino-N-cyclopropyl-N- (4- (3-hydroxy-3-methylbut-1-yn-1-yl) benzyl) -1-methyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide (66)

To a solution of compound 66c (53 mg,0.1 mmol) in dichloromethane (1 mL) was slowly added 1,4 dioxane solution of hydrochloric acid (1 mL, 4M) at 0deg.C, and the addition was completed for 30 minutes at room temperature. The reaction mixture was added with saturated sodium carbonate solution to adjust the pH of the system to about 8, extracted with ethyl acetate (10 ml×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was spun off and purified by reverse phase chromatography (acetonitrile: 0.05% ammonium bicarbonate aqueous solution=0:100% -60%: 40%) to give compound 66 (17 mg). ESI-MS (m/z): 454.3[ M+H ] ] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ8.38(s,1H),8.27(s,1H),7.74–7.67(m,1H),7.60(d,J＝8.4Hz,1H),7.43–7.27(m,4H),7.17(s,2H),5.49(s,1H),4.74(s,2H),4.38(s,3H),2.88(s,1H),1.49(s,6H),0.55–0.49(m,4H).

Example 67: 4-amino-N- (1- (4-ethynylphenyl) ethyl) -N, 1-dimethyl-1H-pyrazolo [4,3-c ] [1,7] naphthyridine-8-carboxamide

Preparation of tert-butyl methyl (1- (4- (trimethylsilyl) ethynyl) phenyl) ethyl) carbamate (67 b)

Referring to the preparation of Compound 15b, replacement of 15a with 67a (2.0 g) gave Compound 67b (1.7 g), ESI-MS (m/z): 332.1[ M+H)] ⁺ 。

Preparation of 1- (4-ethynylphenyl) -N-methylethan-1-amine (67 c)

Referring to the preparation of Compound 15c, replacement of 15b with 67b (1.7 g) gave Compound 67c (1.0 g), ESI-MS (m/z): 160.15[ M+H ]] ⁺ 。

Preparation of 4-amino-N- (1- (4-ethynylphenyl) ethyl) -N, 1-dimethyl-1H-pyrazolo [4,3-c ] [1,7] naphthyridine-8-carboxamide (67)

To a solution of compound 67c (39 mg,0.25 mmol) in N, N-dimethylacetamide (3 mL) was added compound 45a (50 mg,0.21 mmol), triethylamine (64 mg,0.63 mmol) and tripyrrolidinylphosphonium bromide hexafluorophosphate (117 mg,0.25 mmol), and reacted at 25℃for 18 hours. The reaction solution was filtered, and the filtrate was purified by high pressure liquid chromatography to give compound 67 (11 mg). ESI-MS (m/z): 385.23[ M+H ]] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ8.86(s,1H),8.36–8.34(m,2H),7.55–7.41(m,6H),5.99–5.44(m,1H),4.45–4.42(m,3H),4.21(s,1H),2.77–2.69(m,3H),1.61–1.59(m,3H).

Example 68: 4-amino-N-cyclopropyl-N- (4-ethynylbenzyl) -1-methyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide

Preparation of N- (4- ((trimethylsilyl) ethynyl) benzyl) cyclopropylamine (68 b)

To a 30mL microwave tube was added reactant 68a (1000 mg,4.42 mmol), cuprous iodide (168.5 mg,0.88 mmol), tetrakis triphenylphosphine palladium (511.1 mg,0.44 mmol) and solvent N-methylpyrrolidone (5 mL), nitrogen sparge for 3 minutes, and N, N-diisopropylethylamine (2.2 mL,13.27 mmol), trimethylethynyl silicon (868.6 mg,8.85 mmol). The reaction solution was stirred at 70℃for 3 hours under microwave. After the completion of the reaction, the reaction was quenched with water, extracted three times with ethyl acetate (30 ml) and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Positive Xiang Zhuzhu chromatography(Petroleum ether: ethyl acetate=1:1) to give compound 68b (840 mg). ESI-MS (m/z): 245.0[ M+H ]] ⁺ .

Preparation of N- (4-ethylbenzyl) cyclopropylamine (68 c)

Compound 68b (800 mg,3.29 mmol) was dissolved in solvent tetrahydrofuran (5 mL), and 1M tetrabutylammonium fluoride tetrahydrofuran solution (6.58 mL) was slowly added. After the addition, stirring was carried out at 25℃for half an hour. The reaction solution was quenched with water, extracted with ethyl acetate (10 ml×3), and the organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by normal phase chromatography (petroleum ether: ethyl acetate=1:1) to give compound 68c (460 mg). ESI-MS (m/z): 172.2[ M+H ] ] ⁺ .

Preparation of 4-amino-N-cyclopropyl-N- (4-ethynylbenzyl) -1-methyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide (68)

Compound 68c (30 mg,0.18 mmol) was dissolved in N, N-dimethylacetamide (2 ml), and compound 13a (42.4 mg,0.18 mmol), triethylamine (72.88. Mu.L, 0.53 mmol) and tripyrrolidinylphosphonium bromide hexafluorophosphate (122.5 mg,0.26 mmol) were added and stirred at 25℃overnight. The reaction solution was quenched with water, extracted with ethyl acetate (10 ml×3), and the organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by reverse phase column chromatography (acetonitrile: water=0:100% -35%: 65%) to give compound 68 (16.2 mg). ESI-MS (m/z): 396.2[ M+H ]] ⁺ . ¹ H NMR(400MHz,DMSO)δ8.37(s,1H),8.26(s,1H),7.71(d,J＝8.8,1H),7.58(d,J＝8.4Hz,1H),7.50(d,J＝8.4Hz,2H),7.39(d,J＝8.0Hz,2H),7.24(s,2H),4.73(s,2H),4.36(s,3H),4.17(s,1H),2.89–2.86(m,1H),0.53-0.48(m,4H).

Example 69: 4-amino-N-cyclopropyl-N- (4-ethynylbenzyl) -1-methyl-1H-pyrazolo [4,3-c ] [1,7] naphthyridine-8-carboxamide

Compound 68c (30 mg,0.18 mmol) and 45a (42.6 mg,0.18 mmol) were dissolved in N, N-dimethylacetamide (2 ml), and triethylamine (72.88. Mu.L, 0.53 mmol) and tripyrrolidinylphosphonium bromide hexafluorophosphate (122.5) were addedmg,0.26 mmol). Stirred overnight at 25 ℃. The reaction solution was quenched with water, extracted with ethyl acetate (10 ml×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by reverse phase column chromatography (acetonitrile: water=0:100% -35%: 65%) to give compound 69 (2.6 mg). ESI-MS (m/z): 397.2[ M+H ] ] ⁺ .1H NMR(400MHz,DMSO)δ8.85(s,1H),8.35(s,1H),8.28(s,1H),7.52–7.41(m,2H),7.44(s,4H),4.77(s,2H),4.43(s,3H),4.17(s,1H),2.96–2.93(m,1H),0.46-035(m,4H).

Example 70: 4-amino-N-cyclopropyl-N- ((5-ethynyl-3-fluoropyridin-2-yl) methyl) -1-methyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide

Preparation of N- ((5-bromo-3-fluoropyridin-2-yl) methyl) cyclopropaneamine (70 b)

Compound 70a (500 mg,2.45 mmol), cyclopropylamine (279.9 mg,4.90 mmol) and acetic acid (522.69 μl,2.94 mmol) were added to dichloromethane (5 mL), and after the addition, stirring was performed at 20 ℃ for half an hour, sodium triacetoxyborohydride (1033.8 mg,4.90 mmol) was added, and stirring was performed at room temperature overnight. The reaction mixture was added with an ice potassium carbonate solution, extracted with dichloromethane (15 ml×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried by spin-drying, and purified by normal phase column chromatography (petroleum ether: ethyl acetate=1:1) to give compound 70b (180 mg). ESI-MS (m/z): 245.0[ M+H ]] ⁺ 。

Preparation of N- ((3-fluoro-5- ((trimethylsilyl) ethynyl) pyridin-2-yl) methyl) cyclopropylamine (70 c) reactant 70b (200 mg,0.82 mmol), cuprous iodide (31.1 mg,0.16 mmol), tetrakis triphenylphosphine palladium (94.3 mg,0.08 mmol) and solvent N-methylpyrrolidone (2 mL) were added to a 10mL microwave tube, nitrogen sparge for 3 minutes, N-diisopropylethylamine (405.49 μl,2.45 mmol) and trimethylethynyl silicon (160.3 mg,1.63 mmol) were added. Stirring was carried out at 70℃for 3 hours under microwaves. The reaction mixture was quenched with water, extracted with ethyl acetate (10 ml x 3), the organic phases combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated. Purifying by normal phase column Petroleum ether: ethyl acetate=1:1) to give 70c (102 mg,0.39 mmol). ESI-MS (m/z): 263.2[ M+H ]] ⁺

Preparation of N- ((5-ethynyl-3-fluoropyridin-2-yl) methyl) cyclopropylamine (70 d) Compound 70c (200 mg,0.76 mmol) was dissolved in tetrahydrofuran (2 ml) and 1M tetrabutylammonium fluoride in tetrahydrofuran (1143.29. Mu.L, 1.14 mmol) was slowly added. After the addition, the reaction was carried out at 25℃for half an hour. The reaction mixture was quenched with water, extracted with ethyl acetate (10 ml×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by normal phase chromatography (petroleum ether:

ethyl acetate=1:1) to give compound 70d (105 mg,0.55 mmol). ESI-MS (m/z): 191.1[ M+H ]] ⁺

Preparation of 4-amino-N-cyclopropyl-N- ((5-ethynyl-3-fluoropyridin-2-yl) methyl) -1-methyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide (70)

Compound 70d (30 mg,0.16 mmol), 13a (38.2 mg,0.16 mmol) were dissolved in N, N-dimethylacetamide (2 ml), and triethylamine (65.60. Mu.L, 0.47 mmol) and tripyrrolidinylphosphonium bromide hexafluorophosphate (110.3 mg,0.24 mmol) were added. After the addition, the reaction was carried out at 25℃overnight. The reaction solution was quenched with water, extracted with ethyl acetate (10 ml. Times.3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by reverse phase chromatography (acetonitrile: water=0:100% -35%: 65%) to give compound 70 (6.4 mg,0.02 mmol). ESI-MS (m/z): 415.2[ M+H ] ] ⁺ . ¹ H NMR(400MHz,DMSO)δ8.58(s,1H),8.40(s,1H),8.25(s,1H),7.95(d,J＝10.4Hz,1H),7.66(d,J＝8.4Hz,1H),7.57(d,J＝8.4Hz,1H),7.15(s,2H),4.89(s,2H),4.57(s,1H),4.37(s,3H),3.00–2.96(m,1H),0.58-0.52(m,4H).

Example 71: 4-amino-N-cyclopropyl-N- ((5-ethynyl-4-methylpyridin-2-yl) methyl) -1-methyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide

Preparation of N- ((5-bromo-4-methylpyridin-2-yl) methyl) cyclopropylamine (71 b)

Referring to the preparation of compound 70b, substituting 71a (500 mg,2.50 mmol) for 70a gave compound 71b (547 mg), ESI-MS (m/z): 241.1[ M+H ]] ⁺ 。

Preparation of N- ((4-methyl-5- ((trimethylsilyl) ethynyl) pyridin-2-yl) methyl) cyclopropylamine (71 c) referring to the preparation of compound 70c, 70b was replaced with 71b (400 mg,1.66 mmol) to give compound 71c (265 mg). ESI-MS (m/z): 259.0[ M+H ]] ⁺

Preparation of N- ((5-ethynyl-4-methylpyridin-2-yl) methyl) cyclopropylamine (71 d) reference the preparation of compound 70d substituting 71c (265 mg,1.03 mmol) for 70c gave compound 71d (176 mg). ESI-MS (m/z): 187.2[ M+H ]] ⁺

Preparation of 4-amino-N-cyclopropyl-N- ((5-ethynyl-4-methylpyridin-2-yl) methyl) -1-methyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide (71)

Compound 71d (30 mg,0.16 mmol), 13a (39.0 mg,0.16 mmol) were dissolved in N, N-dimethylacetamide (2 ml), and triethylamine (66.97. Mu.L, 0.48 mmol) and tripyrrolidinylphosphonium bromide hexafluorophosphate (112.6 mg,0.24 mmol) were added. After the addition, stirring was carried out at 25℃overnight. The reaction solution was quenched with water, extracted with ethyl acetate (10 ml. Times.3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by reverse phase chromatography (acetonitrile: water=0:100% -35%: 65%) to give compound 71 (13.5 mg). ESI-MS (m/z): 411.3[ M+H ] ] ⁺ . ¹ H NMR(400MHz,DMSO)δ8.59(s,1H),8.41(s,1H),8.25(s,1H),7.72-7.69(m,1H),7.58(d,J＝8.4Hz,1H),7.34(s,1H),7.15(s,2H),4.77(s,2H),4.59(s,1H),4.37(s,3H),3.02–2.98(m,1H),2.42(s,3H),0.54–0.51(m,4H).

EXAMPLE 72 4-amino-N- (cyclopropylmethyl) -N- [ (4-ethynylphenyl) methyl ] -3-methyl-1, 3-dihydrofuro [3,4-c ] naphthyridine-8-carboxamide

Preparation of 1-cyclopropyl-N- (4- ((trimethylsilyl) ethynyl) benzyl) methylamine (72 a)

Referring to the preparation of compound 60c, cyclopropylmethylamine (0.13 mL,1.48 mmol) was substituted for ethylamine to give compound 72a (136 mg). ESI-MS (m/z): 258.2[ M+H ]] ⁺ .

Preparation of 1-cyclopropyl-N- (4-ethynylbenzyl) methylamine (72 b)

Referring to the preparation of compound 60d, replacement of 60c with 72a (136 mg,0.53 mmol) afforded compound 72b (70 mg). ESI-MS (m/z): 186.2[ M+H ]] ⁺ .

Preparation of 4-amino-N- (cyclopropylmethyl) -N- [ (4-ethynylphenyl) methyl ] -3-methyl-1, 3-dihydrofuro [3,4-c ] naphthyridine-8-carboxamide (72)

To a solution of compound 38a (40.0 mg,0.16 mmol) in N, N-dimethylacetamide (3 mL) was added compound 72b (30.2 mg,0.16 mmol), triethylamine (0.07 mL,0.49 mmol) and tripyrrolidinylphosphonium bromide hexafluorophosphate (114.0 mg,0.24 mmol), and the addition was allowed to react overnight at 25 ℃. The reaction solution was added with water (10 mL), extracted with ethyl acetate (10 x 3 mL), washed with saturated brine, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by reverse phase column chromatography (acetonitrile/0.5% ammonium bicarbonate aqueous solution=0:100% -50%: 50%) to give compound 72 (2.84 mg). ESI-MS (m/z): 413.2[ M+H ] ] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ8.88–8.80(m,1H),7.79–7.76(m,1H),7.51–

7.32(m,4H),6.98(s,2H),5.49–5.26(m,3H),4.85(s,2H),4.18(s,1H),3.28–3.26(m,2H),1.45–1.41(m,3H),1.29–0.81(m,2H),0.47–0.21(m,3H).

EXAMPLE 73 4-amino-N- [ (4-ethynylphenyl) -N, 1-dimethyl-1H-pyrazolo [3,4-d ] naphthyridine-8-carboxamide

Preparation of N-methyl-1- (4- ((trimethylsilyl) ethynyl) phenyl) methylamine (73 a) to a solution of 60b (100 mg,0.49 mmol) in dichloromethane/methanol (4/1, 5 mL) was added methylamine, hydrochloride (66.7 mg,0.99 mmol), N, N-diisopropylethylamine (0.20 mL,1.24 mmol), sodium triacetoxyborohydride (208.5 mg,0.99 mmol) and acetic acid (0.01 mL)0.24 mmol) and reacted overnight at 25 ℃. The reaction solution was quenched with water (15 mL), extracted with dichloromethane (10 x 3 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give product 73a (80.0 mg) by normal phase column chromatography (ethyl acetate/petroleum ether=1:3). ESI-MS (m/z): 218.1[ M+H ]] ⁺ .

Preparation of 1- (4-ethylphenyl) -N-methylmethylamine (73 b) to a solution of compound 73a (80 mg,0.37 mmol) in tetrahydrofuran (5 mL) was added tetrabutylammonium fluoride (192.5 mg,0.74 mmol), and the addition was then reacted at 25℃for 2 hours. The reaction solution was concentrated, and subjected to normal phase column chromatography (ethyl acetate/petroleum ether=0:100% -30%: 100%) to give compound 73b (30 mg). ESI-MS (m/z): 146.1[ M+H ]] ⁺ .

4-amino-N- [ (4-ethynylphenyl) -N, 1-dimethyl-1H-pyrazolo [3,4-d]Preparation of naphthyridine-8-carboxamide (73) to a solution of compound 73b (20 mg,0.14 mmol) in N, N-dimethylethylamine (3 mL) was added compound 45a (40 mg,0.16 mmol), triethylamine (0.06 mL,0.41 mmol) and tripyrrolidinylphosphonium bromide hexafluorophosphate (96.3 mg,0.21 mmol), and the addition was reacted overnight at 25 ℃. The reaction solution was added with water (10 mL), extracted with ethyl acetate (10 x 3 mL), washed with saturated brine, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and subjected to reverse phase column chromatography (acetonitrile/0.5% ammonium bicarbonate=0:100% -50%: 50%) to give compound 73 (5.14 mg). ESI-MS (m/z): 371.2[ M+H ] ] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ8.88–881(m,1H),8.37–8.35(m,2H),7.57–7.33(m,6H),4.81–4.77(m,2H),4.46–4.39(m,3H),4.20–4.18(m,1H),3.05–2.96(m,3H).

EXAMPLE 74 4-amino-N- (4- (3-fluoropropyl-1-yn-1-yl) benzyl) -3-methyl-N- (1-methyl-1H-pyrazol-4-yl) -1, 3-dihydrofuran [3,4-c ] quinoline-8-carboxamide

4-amino-N- (4-bromobenzyl) -3-methyl-N- (1-methyl-1H-pyrazol-4-yl) -1, 3-dihydrofuran [3,4-c]Preparation of quinoline-8-carboxamide (74 a) to a solution of 42b (800 mg,3.01 mmol) in N, N-dimethylethylamine (10 mL) was added compound 25a (489.6 mg, 2.0)0 mmol), triethylamine (0.83 mL,6.01 mmol) and tripyrrolidinylphosphonium bromide hexafluorophosphate (1.40 g,3.01 mmol) were added and reacted overnight at 25 ℃. Adding water (20 mL) into the reaction solution, filtering, washing the filter cake with water, and drying to obtain compound 74a (600.0 mg) ESI-MS (m/z): 492.1[ M+H ]] ⁺ .

Preparation of 4-amino-N- (4- (3- ((tert-butyldimethylsilyl) oxy) prop-1-yn-1-yl) benzyl) -3-methyl-N- (1-methyl-1H-pyrazol-4-yl) -1, 3-dihydrofuran [3,4-c ] quinoline-8-carboxamide (74 b)

To a solution of 74a (200 mg,0.41 mmol) in N-methylpyrrolidone (5 mL) was added 2, 3-tetramethyl-4-oxo-3-cyclohepta-6-yne (0.16 mL,0.81 mmol), palladium tetraphenylphosphine (46.9 mg,0.04 mmol), cuprous iodide (15.5 mg,0.08 mmol), triethylamine (0.17 mL,1.23 mmol), and the mixture was reacted under nitrogen at 70℃for 3 hours. After completion of the reaction, celite was filtered, water (15 mL) was added, ethyl acetate extracted (3 x 10 mL), the organic phases were combined, washed three times with water, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and normal phase column chromatography (ethyl acetate/petroleum ether=1:2) gave compound 74b (50.0 mg). ESI-MS (m/z): 582.4[ M+H ] ] ⁺ .

Preparation of 4-amino-N- (4- (3-hydroxypropyl-1-yl) benzyl) -3-methyl-N- (1-methyl-1H-pyrazol-4-yl) -1, 3-dihydrofuran [3,4-c ] quinoline-8-carboxamide (74 c)

Tetrabutylammonium fluoride (33.7 mg,0.13 mmol) was added to a solution of 74b (50 mg,0.09 mmol) in tetrahydrofuran (5 mL), and the mixture was reacted at 25℃for 1 hour. After the completion of the reaction, the mixture was concentrated and subjected to normal phase column chromatography (methanol/dichloromethane=1:10) to give compound 74c (26.0 mg). ESI-MS (m/z): 468.1[ M+H ]] ⁺ .

Preparation of 4-amino-N- (4- (3-fluoropropyl-1-yn-1-yl) benzyl) -3-methyl-N- (1-methyl-1H-pyrazol-4-yl) -1, 3-dihydrofuran [3,4-c ] quinoline-8-carboxamide (74)

To a solution of 74c (25 mg,0.05 mmol) in dichloromethane (3 mL) was added diethylaminosulfur trifluoride (25.9 mg,0.16 mmol) and the mixture was reacted at 25℃for 2 hours. Adding saturated sodium bicarbonate solution to adjust pH to about 8, extracting with ethyl acetate (3×15mL), drying the organic phase with anhydrous sodium sulfate, filtering, concentrating the filtrate, and performing reverse phase column chromatography (acetonitrile/0.5% ammonium bicarbonate water solution=0:100% -50%: 50%) to obtain the final productTo compound 74 (1.23 mg). ESI-MS (m/z): 470.1[ M+H ]] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ8.35(s,1H),7.57–7.13(m,8H),6.64(s,2H),5.41(s,2H),5.29–5.14(m,3H),4.99(s,2H),3.65(s,3H),1.40(d,J＝6.2Hz,3H).

EXAMPLE 75 4-amino-N-cyclopropyl-1-methyl-N- { [5- (prop-1-yn-1-yl) pyridin-2-yl ] methyl } -1H-pyrazolo [4,3-c ] quinoline-8-carboxamide

Preparation of N- ((5- (prop-1-yn-1-yl) pyridin-2-yl) methyl) cyclopropylamine (75 a)

To a solution of compound 2b (200 mg,0.88 mmol) in N-methylpyrrolidone (4 mL) were added propyne (0.18 mL,2.64 mmol), tetrakis triphenylphosphine palladium (101.8 mg,0.09 mmol), cuprous iodide (33.6 mg,0.18 mmol) and triethylamine (0.49 mL,3.52 mmol), nitrogen was bubbled for 3 times, and the reaction was carried out at 80℃for 3 hours by microwave. Diatomite was filtered, the filtrate was extracted with water (15 mL), ethyl acetate (3 x 10 mL), the organic phases were combined, washed with water, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by normal phase column chromatography (ethyl acetate/petroleum ether=1:4) to give compound 75a (60.0 mg). ESI-MS (m/z): 187.1[ M+H ]] ⁺ .

Preparation of 4-amino-N-cyclopropyl-1-methyl-N- { [5- (prop-1-yn-1-yl) pyridin-2-yl ] methyl } -1H-pyrazolo [4,3-c ] quinoline-8-carboxamide (75)

To a solution of compound 13a (40 mg,0.17 mmol) in N, N-dimethylacetamide (5 mL) was added compound 75a (30.8 mg,0.17 mmol), tripyrrolidinylphosphonium bromide hexafluorophosphate (65.9 mg,0.25 mmol) and triethylamine (0.07 mL,0.50 mmol). After the addition, the reaction was carried out at 25℃for 2 hours. After completion of the reaction, water (15 mL) was added, extracted with ethyl acetate (15 mL x 3), the organic phase dried over anhydrous sodium sulfate, filtered, the filtrate concentrated, and reversed phase column chromatography (acetonitrile/0.5% ammonium bicarbonate water=0:100% -50%: 50%) gave compound 75 (2.0 mg). ESI-MS (m/z): 411.1[ M+H ] ] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ8.61(d,J＝2.2Hz,1H),8.44(s,1H),8.27(s,1H),7.83(dd,J＝8.4,2.2Hz,1H),7.74–7.72(m,1H),7.60(d,J＝8.4Hz,1H),7.40(d,J＝8.4Hz,1H),7.16(s,2H),4.81(s,2H),4.39(s,3H),3.05–3.00(m,1H),2.11(s,3H),0.56–0.52(m,4H).

EXAMPLE 76 4-amino-N- [ (5-Acetylpyridin-2-yl) methyl ] -N- (1-methoxypropan-2-yl) -1-methyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide

To a solution of compound 13a (19.8 mg,0.08 mmol) in N, N-dimethylacetamide (5 mL) was added O- (1H-benzotriazol-1-yl) -N, N, N ', N' -tetramethylisourea boron tetrafluoride (39.3 mg,0.12 mmol), compound 35c (19.6 mg,0.096 mmol), N, N-diisopropylethylamine (0.04 mL,0.24 mmol) and reacted overnight at 25 ℃. The reaction mixture was added with water (15 mL), extracted with ethyl acetate (10 x 3 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give compound 76 (0.9 mg) by normal phase column chromatography (methanol/dichloromethane=1:20). ESI-MS (m/z): 429.2[ M+H ]] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ8.65(d,J＝2.0Hz,1H),8.40(s,1H),8.27(s,1H),7.89(d,J＝8.2Hz,1H),7.63–7.48(m,3H),7.13(s,2H),4.72(s,2H),4.45–4.38(m,4H),3.12(s,3H),1.11(d,J＝6.8Hz,3H).

Example 77: 4-amino-7-cyclopropyl-N- ((5-ethynylpyridin-2-yl) methyl) -N, 1-dimethyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide

Preparation of methyl 4-amino-7-cyclopropyl-1-methyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxylate (77 b)

Compound 77a (200 mg,0.69mmol, for preparation see WO 2022/115377 A1) was dissolved in A1, 4-dioxane/water mixed solvent (8 mL/2 mL), and cyclopropylboronic acid (88.6 mg,1.03 mmol), potassium carbonate (237.7 mg,1.72 mmol) and tetrakis triphenylphosphine palladium (79.5 mg,0.07 mmol) were added sequentially, displaced three times by Bi Danqi and reacted overnight at 120℃under nitrogen. After the reaction, filtering, spin-drying the filtrate, and purifying by normal phase chromatographic column chromatography (II Methyl chloride: methanol=10:1) to give compound 77b (12 mg,0.04 mmol). ESI-MS (m/z): 297.1[ M+H ]] ⁺ 。

Preparation of 4-amino-7-cyclopropyl-1-methyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxylic acid (77 c)

Compound 77b (15 mg,0.05 mmol) was dissolved in a mixed solvent of methanol/tetrahydrofuran/water (2 mL/2mL/2 mL), and lithium hydroxide (6.4 mg,0.15 mmol) was added to react at 50℃for 18 hours. The reaction solution is concentrated to remove most of the organic solvent, then 1N hydrochloric acid solution is added to adjust the pH to 5-7, and the crude product of the product 77c is obtained by all spin drying and is directly used in the next step. ESI-MS (m/z): 283.1[ M+H ]] ⁺ .

Preparation of 4-amino-7-cyclopropyl-N- ((5-ethynylpyridin-2-yl) methyl) -N, 1-dimethyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide (77)

The crude 77c obtained in the previous step was dissolved in N, N-dimethylacetamide (1 mL), and Compound 7c (11.7 mg,0.08 mmol), N, N-diisopropylethylamine (26.40. Mu.L, 0.16 mmol) and O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethylurea hexafluorophosphate (30.3 mg,0.08 mmol) were added. After the addition, stirring was carried out at 25℃overnight. The reaction solution was quenched with water, extracted with ethyl acetate (10 ml×3), the organic phases combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated and purified by reverse phase chromatography (acetonitrile: water=0:100% -35%: 65%) to give compound 77 (5.4 mg,0.01 mmol). ESI-MS (m/z): 410.5[ M+H ] ] ⁺ . ¹ H NMR(400MHz,DMSO)δ8.66(s,1H),8.26(s,1H),8.21–8.16(m,1H),7.99-7.83(m,2H),7.47-7.27(m,1H),7.07–6.96(m,2H),4.87–4.54(m,2H),4.44(s,1H),4.36-4.12(m,3H),3.06-2.87(m,3H),2.09-1.93(m,1H),0.95-0.63(m,4H).

Example 78: 4-amino-N- (4-ethynylbenzyl) -N,1, 7-trimethyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide

Preparation of 4-amino-N, 1, 7-trimethyl-N- (4- ((trimethylsilyl) ethynyl) benzyl) -1H-pyrazolo [4,3-c ] quinoline-8-carboxamide (78 a)

Compound 73a (50 mg,0.23 mmol) was dissolved in N, N-dimethylacetamide (2 ml), compound 54a (58.9 mg,0.23 mmol), N, N-diisopropylethylamine (114.29. Mu.L, 0.69 mmol) and O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethylurea hexafluorophosphate (131.2 mg,0.34 mmol) were added, and the reaction mixture was stirred overnight at 25℃for quenching with water, extracted with ethyl acetate (10 ml. 3. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give compound 78a (50 mg) ESI-MS (m/z): 456.3[ M+H ] by normal phase column chromatography (dichloromethane: methanol=10:1)] ⁺ .

Preparation of 4-amino-N- (4-ethynylbenzyl) -N,1, 7-trimethyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide (78 b)

Compound 78a (50 mg,0.11 mmol) was dissolved in solvent tetrahydrofuran (1 mL), and 1M tetrabutylammonium fluoride tetrahydrofuran solution (164.62. Mu.L, 0.16 mmol) was slowly added, and the mixture was stirred at 25℃for half an hour. The reaction solution was quenched with water, extracted with ethyl acetate (10 ml×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give compound 78b (12 mg) by reverse phase column chromatography (acetonitrile: water=0:100% -35%: 65%). ESI-MS (m/z): 384.2[ M+H ] ] ⁺ . ¹ H NMR(400MHz,DMSO)δ8.22-8.17(m,1H),8.03-7.86(m,1H),7.53–7.42(m,4H),7.21(d,J＝8.0Hz,1H),7.02(s,2H),4.75(s,1H),4.45(s,1H),4.36–4.08(m,4H),3.04-2.73(m,3H),2.33-2.29(m,3H).

Example 79: 4-amino-N- (4-ethynylbenzyl) -3, 7-dimethyl-N- (1-methyl-1H-pyrazol-4-yl) -1, 3-dihydrofuran [3,4-c ] quinoline-8-carboxamide

Compound 42d (50 mg,0.24 mmol) was dissolved in N, N-dimethylacetamide (2 ml), 57a (61.1 mg,0.24 mmol), N, N-diisopropylethylamine (117.59. Mu.L, 0.71 mmol) and tripyrrolidinylphosphonium bromide hexafluorophosphate (165.5 mg,0.35 mmol) were added and stirred overnight at 25 ℃. Quenching the reaction solution with water, extracting with ethyl acetate (10 ml. Times.3), mixing the organic phases, washing with saturated saline water,drying over anhydrous sodium sulfate, filtering, concentrating the filtrate, and reversed phase chromatography (acetonitrile: water=0:100% -35%: 65%) gave compound 79 (24.3 mg,0.05 mmol). ESI-MS (m/z): 452.2[ M+H ]] ⁺ 。 ¹ H NMR(400MHz,DMSO)δ8.34–8.12(m,1H),7.55–7.00(m,7H),6.45(s,2H),5.36–5.15(m,3H),4.97(s,2H),4.18(s,1H),3.80(s,1H),3.52(s,3H),2.31(s,3H),1.38(d,J＝6.0Hz,3H).

Example 80: 4-amino-N- (4-ethynylbenzyl) -7-methyl-N- (1-methyl-1H-pyrazol-4-yl) -1, 3-dihydrofuran [3,4-c ] quinoline-8-carboxamide

Compound 42d (50 mg,0.24 mmol) was dissolved in N, N-dimethylacetamide (2 ml), 59a (46.2 mg,0.19 mmol) N, N-diisopropylethylamine (94.07. Mu.L, 0.57 mmol) and tripyrrolidinylphosphonium bromide hexafluorophosphate (132.4 mg,0.28 mmol) were added and stirred overnight at 25 ℃. The reaction solution was quenched with water, extracted with ethyl acetate (10 ml×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give compound 80 (10 mg) by reverse phase chromatography (acetonitrile: water=0:100% -40%: 60%). ESI-MS (m/z): 438.2[ M+H ] ] ⁺ . ¹ H NMR(400MHz,DMSO)δ7.55–7.11(m,7H),6.99(s,1H),6.62–6.49(m,2H),5.26–4.95(m,6H),4.18(s,1H),3.81–3.52(m,3H),2.31(s,3H).

Example 81: 4-amino-N-cyclopropyl-7-fluoro-N- ((5- (3-methoxypropyl-1-yn-1-yl) pyridin-2-yl) methyl) -1-methyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide

Preparation of N- ((5- (3-methoxyprop-1-yn-1-yl) pyridin-2-yl) methyl) cyclopropylamine (81 a)

To a solution of compound 2b (114 mg,0.5 mmol) in N-methylpyrrolidone (3 mL) under nitrogen protection was added 3-methoxyprop-1-yne (105 mg,1.5 mmol) in sequence, iodinated subunitCopper (10 mg,0.05 mmol), N, N-diisopropylethylamine (258 mg,2 mmol) and tetrakis (triphenylphosphine) palladium (23 mg,0.02 mmol) were reacted at Yu Weibo 70 ℃for 3 hours. The reaction mixture was added with water (10 mL), extracted with ethyl acetate (10 ml×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was spun off to give compound 81a (92 mg) by column chromatography (methanol: dichloromethane=1:20). ESI-MS (m/z): 217.1[ M+H ]] ⁺ .

Preparation of 4-amino-N-cyclopropyl-7-fluoro-N- ((5- (3-methoxypropyl-1-yn-1-yl) pyridin-2-yl) methyl) -1-methyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide (81)

To a solution of compound 81a (49.9 mg,0.23 mmol) in N, N-dimethylacetamide (2 ml) was added compound 17a (50 mg,0.19 mmol), N, N-diisopropylethylamine (95.49. Mu.L, 0.58 mmol) and tripyrrolidinylphosphonium bromide hexafluorophosphate (134.4 mg,0.29 mmol) at room temperature. After the addition, stirring was carried out at 25℃overnight. The reaction solution was quenched with water, extracted with ethyl acetate (10 ml×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by reverse phase chromatography (acetonitrile: water=0:100% -40%: 60%) to give compound 81 (6.5 mg). ESI-MS (m/z): 459.3[ M+H ] ] ⁺ . ¹ H NMR(400MHz,DMSO)δ8.66(s,1H),8.29–8.25(m,2H),7.93(d,J＝6.8Hz,1H),7.42(d,J＝6.8Hz,1H),7.31(d,J＝12.0Hz,1H),7.25(s,2H),4.84(s,2H),4.39–4.37(m,5H),3.35(s,3H),2.91–2.87(m,1H),0.56–0.44(m,4H).

Example 82: 4-amino-N-cyclopropyl-7-fluoro-N- ((5- (3-hydroxy-3-methylbut-1-yn-1-yl) pyridin-2-yl) methyl) -1-methyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide

Preparation of 4-amino-N- ((5-bromopyridin-2-yl) methyl) -N-cyclopropyl-7-fluoro-1-methyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide (82 a)

Compounds 2b (104.7 mg,0.46 mmol) and 17a (100 mg,0.38 mmol) were dissolved in N, N-dimethylacetamide (3 ml), N-diisopropylethylamine (190.98. Mu.L, 1.15 mmol) and 2- (7-doll) were addedAzobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (219.2 mg,0.58 mmol) was added and stirred at 25℃for 3 hours. The reaction solution was quenched with water, extracted with ethyl acetate (10 ml×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to give compound 82a (90 mg,0.19 mmol) by normal phase chromatography (dichloromethane: methanol=20:1). ESI-MS (m/z): 469.1[ M+H ]] ⁺ .

4-amino-N-cyclopropyl-7-fluoro-1-methyl-N- ((5- (3-methyl-3- ((trimethylsilyl) oxy) but-1-yn-1-yl) pyridin-2-yl) methyl) -1H-pyrazolo [4,3-c]Preparation of quinoline-8-carboxamide (82 b) in a 10mL microwave tube was added reactant 82a ((90 mg,0.19 mmol), cuprous iodide (7.2 mg,0.04 mmol), tetrakis triphenylphosphine palladium (22.0 mg,0.02 mmol) and solvent N-methylpyrrolidone (2 mL), nitrogen bubbling for 3 min, N-diisopropylethylamine (94.42. Mu.L, 0.57 mmol) and ((1, 1-dimethyl-2-propynyl) oxy) trimethylsilane (55.27. Mu.L, 0.28 mmol). The reaction solution was stirred at 70℃for 3 h in a microwave oven, the reaction solution was quenched with water, extracted with ethyl acetate (10 mL. Times.3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to give 82b (53 mg,0.10 mmol). ESI-MS (m/z): 545.3 M+H, reverse phase column chromatography (acetonitrile: 25%. 75%) ] ⁺ .

Preparation of 4-amino-N-cyclopropyl-7-fluoro-N- ((5- (3-hydroxy-3-methylbut-1-yn-1-yl) pyridin-2-yl) methyl) -1-methyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide (82)

Compound 82b (50 mg,0.09 mmol) was dissolved in dichloromethane (5 ml), 4M 1, 4-dioxane hydrochloride solution (114.74. Mu.L, 0.46 mmol) was further added, stirring was carried out at room temperature for 1 hour, and the reaction mixture was concentrated and then subjected to reverse phase column chromatography (acetonitrile: water=25%: 75%) to give 82 (35 mg) as a product. ESI-MS (m/z): 473.4[ M+H ]] ⁺ . ¹ H NMR(400MHz,DMSO)δ8.57(s,1H),8.26–8.15(m,2H),7.85-7.83(m,1H),7.40–7.27(m,4H),5.54(s,1H),4.83(s,2H),4.39(s,3H),2.89–2.84(m,1H),1.49(s,6H),0.55–0.43(m,4H).

Example 83: 4-amino-N-cyclopropyl-1, 7-dimethyl-N- ((5- (3, 3-trifluoropropyl-1-yn-1-yl) pyridin-2-yl) methyl) -1H-pyrazolo [4,3-c ] quinoline-8-carboxamide

Preparation of 4-amino-N-cyclopropyl-N- ((5-acetylenepyridin-2-yl) 1, 7-dimethyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide (83 a)

To a solution of compound 2d (85 mg,0.5 mmol) in N, N-dimethylacetamide (5 mL) was added compound 54a (128 mg,0.5 mmol), triethylamine (177 mg,1.75 mmol) and tripyrrolidinylphosphonium bromide hexafluorophosphate (303 mg,0.65 mmol), and the addition was completed at room temperature for 4 hours. The reaction mixture was added with water (20 mL), extracted with ethyl acetate (10 ml×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was spun off to give compound 83a by column chromatography (methanol: dichloromethane=1:20). ESI-MS (m/z): 411.2[ M+H ] ] ⁺ .

Preparation of 4-amino-N-cyclopropyl-1, 7-dimethyl-N- ((5- (3, 3-trifluoropropyl-1-yn-1-yl) pyridin-2-yl) methyl) -1H-pyrazolo [4,3-c ] quinoline-8-carboxamide (83)

To N, N-dimethylformamide (3 mL) of compound 83a were added diphenyl (trifluoromethyl) sulfonium triflate (128 mg,0.5 mmol), cuprous iodide (177 mg,1.75 mmol) and potassium carbonate (303 mg,0.65 mmol), and the mixture was reacted at 80℃for 2 hours. The reaction mixture was added with water (20 mL), extracted with ethyl acetate (10 ml×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried by spin-drying and subjected to reversed phase chromatography (acetonitrile: 0.05% ammonium bicarbonate aqueous solution=0:100% -60%: 40%) to give compound 83 (12 mg). ESI-MS (m/z): 479.2[ M+H ]] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ8.96(d,J＝1.6Hz,1H),8.26–8.20(m,3H),7.59–7.46(m,2H),7.04(s,2H),4.91(s,2H),4.41(s,3H),2.92–2.88(m,1H),2.37(s,3H),0.53–0.41(m,4H).

Example 84: 4-amino-N-cyclopropyl-7-fluoro-N- (4- (3-hydroxy-3-methylbut-1-yn-1-yl) benzyl) -1-methyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide

Preparation of 4-amino-N- (4-bromobenzyl) -N-cyclopropyl-7-fluoro-1-methyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide (84 a)

To a solution of compound 66a (113 mg,0.5 mmol) in N, N-dimethylacetamide (5 mL) was added compound 17a (130 mg,0.5 mmol), triethylamine (177 mg,1.75 mmol) and tripyrrolidinylphosphonium bromide hexafluorophosphate (303 mg,0.65 mmol), and the addition was completed at room temperature for 4 hours. The reaction mixture was added with water (20 mL), extracted with ethyl acetate (10 ml×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried by spin-drying and subjected to column chromatography (methanol: dichloromethane=1:15) to give compound 84a (82 mg). ESI-MS (m/z): 468.1[ M+H ] ] ⁺ .

Preparation of 4-amino-N-cyclopropyl-7-fluoro-1-methyl-N- (4- (3-methyl-3- ((trimethylsilyl) oxy) but-1-yn-1-yl) benzyl) -1H-pyrazolo [4,3-c ] quinoline-8-carboxamide (84 b)

To a solution of compound 84a (82 mg,0.18 mmol) in N-methylpyrrolidone (3 mL) was successively added ((1, 1-dimethyl-2-propynyl) oxy) trimethylsilane (85 mg,0.54 mmol), cuprous iodide (17 mg,0.09 mmol), N, N-diisopropylethylamine (93 mg,0.72 mmol) and tetrakis (triphenylphosphine) palladium (46 mg,0.04 mmol) under nitrogen, and the addition was completed for 3 hours at Yu Weibo ℃. The reaction solution was added with water (20 mL), extracted with ethyl acetate (10 ml×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried by column chromatography (methanol: dichloromethane=1:15) to give compound 84b (32 mg). ESI-MS (m/z): 544.2[ M+H ]] ⁺ .

Preparation of 4-amino-N-cyclopropyl-7-fluoro-N- (4- (3-hydroxy-3-methylbut-1-yn-1-yl) benzyl) -1-methyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide (84)

1,4 dioxane solution (1 mL, 4M) of hydrochloric acid was slowly added to a dichloromethane (1 mL) solution of compound 84b (32 mg,0.06 mmol) at 0℃and reacted at room temperature for 30 minutes after the addition, and the sample was fed for detection,

after the reaction, adding saturated sodium carbonate solution to make pH of the system about 8, extracting with ethyl acetate (10 mL. Times.3), mixing The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was spun off and purified by reverse phase chromatography (acetonitrile: 0.05% ammonium bicarbonate aqueous solution=0:100% -60%: 40%) to give compound 84 (3 mg). ESI-MS (m/z): 472.2[ M+H ]] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ8.27(s,1H),8.22(d,J＝6.4Hz,1H),7.66–7.54(m,1H),7.48–7.38(m,4H),7.33–7.26(m,2H),5.49(s,1H),4.77(s,2H),4.39(s,3H),2.70–2.68(m,1H),1.49(s,6H),054–0.42(m,4H).

Example 85: 4-amino-N-cyclopropyl-N- (4- (3-hydroxy-3-methylbut-1-yn-1-yl) benzyl) -1, 7-dimethyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide

Preparation of 4-amino-N- (4-bromobenzyl) -N-cyclopropyl-1, 7-dimethyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide (85 a)

To a solution of compound 66a (113 mg,0.5 mmol) in N, N-dimethylacetamide (5 mL) was added compound 54a (128 mg,0.5 mmol), triethylamine (177 mg,1.75 mmol) and tripyrrolidinylphosphonium bromide hexafluorophosphate (303 mg,0.65 mmol), and the addition was completed at room temperature for 4 hours. The reaction solution was added with water (20 mL), extracted with ethyl acetate (10 ml×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried by column chromatography (methanol: dichloromethane=1:15) to give compound 85a (75 mg). ESI-MS (m/z): 464.1[ M+H ]] ⁺ .

Preparation of 4-amino-N-cyclopropyl-1, 7-dimethyl-N- (4- (3-methyl-3- ((trimethylsilyl) oxy) but-1-yn-1-yl) benzyl) -1H-pyrazolo [4,3-c ] quinoline-8-carboxamide (85 b)

To a solution of compound 85a (75 mg,0.16 mmol) in N-methylpyrrolidone (3 mL) under nitrogen was added ((1, 1-dimethyl-2-propynyl) oxy) trimethylsilane (80 mg,0.49 mmol), cuprous iodide (15 mg,0.08 mmol), N, N-diisopropylethylamine (83 mg,0.64 mmol) and tetrakis (triphenylphosphine) palladium (34 mg,0.03 mmol) in this order, and the addition was completed for 3 hours at Yu Weibo ℃. The reaction mixture was quenched with water (20 mL) and quenched with ethyl acetateThe ester was extracted (10 ml x 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried by column chromatography (methanol: dichloromethane=1:15) to give compound 85b (41 mg). ESI-MS (m/z): 540.3[ M+H ]] ⁺ .

Preparation of preparation (85) of 4-amino-N-cyclopropyl-N- (4- (3-hydroxy-3-methylbut-1-yn-1-yl) benzyl) -1, 7-dimethyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide

To a solution of compound 85b (41 mg,0.07 mmol) in dichloromethane (1 mL) was slowly added 1,4 dioxane solution of hydrochloric acid (1 mL, 4M) at 0deg.C, and the addition was completed for 30 minutes at room temperature. The reaction solution was adjusted to pH 8 or so by adding saturated sodium carbonate solution, extracted with ethyl acetate (10 ml×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried and purified by reverse phase chromatography (acetonitrile: 0.05% ammonium bicarbonate aqueous solution=0:100% -60%: 40%) to give compound 85 (12 mg). ESI-MS (m/z): 468.3[ M+H ] ] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ8.23(s,1H),8.07–8.03(m,1H),7.47–7.41(m,5H),7.03(s,2H),5.48(s,1H),4.75(s,2H),4.35(s,3H),2.70–2.68(m,1H),2.34(d,J＝8.0Hz,3H),1.49(s,6H),0.50–0.38(m,4H).

Example 86: 4-amino-N-cyclopropyl-N- ((5- (3-methoxypropyl-1-yn-1-yl) pyridin-2-yl) methyl) -1, 7-dimethyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide

To a solution of compound 81a (45 mg,0.21 mmol) in N, N-dimethylacetamide (5 mL) was added compound 54a (54 mg,0.5 mmol), triethylamine (74 mg,0.74 mmol) and tripyrrolidinylphosphonium bromide hexafluorophosphate (127 mg,0.27 mmol), and the addition was completed at room temperature for 4 hours. The reaction mixture was added with water (20 mL), extracted with ethyl acetate (10 ml×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried by spin-drying and purified by reverse phase chromatography (acetonitrile: 0.05% ammonium bicarbonate aqueous solution=0:100% -60%: 40%) to give compound 86 (4 mg). ESI-MS (m/z): 455.3[M+H] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ8.68(d,J＝1.6Hz,1H),8.24–8.21(m,2H),7.95–7.92(m,1H),7.48–7.43(m,2H),7.03(s,2H),4.86(s,2H),4.42–4.36(m,5H),3.37(s,3H),2.88–2.84(m,1H),2.37(s,3H),0.52–0.39(m,4H).

Example 87: 4-amino-N-cyclopropyl-N- ((5- (3-methoxypropyl-1-yn-1-yl) pyridin-2-yl) methyl) -1-methyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide

To a solution of compound 81a (46 mg,0.21 mmol) in N, N-dimethylacetamide (5 mL) was added compound 13a (54 mg,0.5 mmol), triethylamine (74 mg,0.74 mmol) and tripyrrolidinylphosphonium bromide hexafluorophosphate (127 mg,0.27 mmol), and the addition was completed at room temperature for 4 hours. After the reaction was completed, water (20 mL) was added, extraction was performed with ethyl acetate (10 ml×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried by spin-drying and purified by reverse phase chromatography (acetonitrile: 0.05% ammonium bicarbonate aqueous solution=0:100% -60%: 40%) to give compound 87 (7 mg). ESI-MS (m/z): 441.2[ M+H ] ] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ8.69(d,J＝1.6Hz,1H),8.44(s,1H),8.27(s,1H),7.92(dd,J＝8.0,2.0Hz,1H),7.73(d,J＝8.4Hz,1H),7.60(d,J＝8.4Hz,1H),7.45(d,J＝8.0Hz,1H),7.16(s,2H),4.84(s,2H),4.40–4.38(m,3H),3.37(s,3H),3.04(s,1H),0.56–0.52(m,4H).

Example 88: 4-amino-N-cyclopropyl-N- ((5- (3-fluoroprop-1-yn-1-yl) pyridin-2-yl) methyl) -1-methyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide

Preparation of 4-amino-N- ((5-bromopyridin-2-yl) methyl) -N-cyclopropyl-1-methyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide (88 a)

To N, N-dimethylacetamide (8 mL) of Compound 2b (452 mg,2 mmol)To the solution were added compound 13a (284 mg,2 mmol), triethylamine (707 mg,7 mmol) and tripyrrolidinylphosphonium bromide hexafluorophosphate (1.21 g,2.6 mmol), and the mixture was reacted at room temperature for 4 hours. The reaction mixture was added with water (50 mL), extracted with ethyl acetate (20 ml×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was spun off to give compound 88a (380 mg) by column chromatography (methanol: dichloromethane=1:15). ESI-MS (m/z): 451.1[ M+H ]] ⁺ .

Preparation of 4-amino-N-cyclopropyl-N- ((5- (3-hydroxypropyl-1-yl) pyridin-2-yl) methyl) -1-methyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide (88 b)

To a solution of compound 88a (95 mg,0.21 mmol) in N-methylpyrrolidone (3 mL) under nitrogen was added (propynyloxy) trimethylsilane (81 mg,0.63 mmol), cuprous iodide (8 mg,0.04 mmol), N, N-diisopropylethylamine (108 mg,0.84 mmol) and tetrakis (triphenylphosphine) palladium (23 mg,0.02 mmol), and the addition was completed for 3 hours at Yu Weibo ℃. The reaction solution was added with water (20 mL), extracted with ethyl acetate (10 ml×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried by spin-drying, followed by column chromatography (methanol: dichloromethane=1:15) to give compound 88b (56 mg). ESI-MS (m/z): 427.2[ M+H ] ] ⁺ .

Preparation of 4-amino-N-cyclopropyl-N- ((5- (3-fluoroprop-1-yn-1-yl) pyridin-2-yl) methyl) -1-methyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide (88)

To a solution of compound 88b (56 mg,0.13 mmol) in dichloromethane (3 mL) was slowly added dropwise diethylaminosulfur trifluoride (42 mg,0.26 mmol) at-78deg.C, and the reaction was carried out at that temperature for 2 hours. The reaction mixture was taken up in saturated sodium bicarbonate (5 mL), extracted with dichloromethane (10 mL x 3), the combined organic phases washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the solvent was spun off and purified by reverse phase chromatography (acetonitrile: 0.05% ammonium bicarbonate aqueous solution = 0:100% -60%: 40%) to give compound 88 (3 mg). ESI-MS (m/z): 429.4[ M+H ]] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ8.73(d,J＝1.6Hz,1H),8.44(s,1H),8.28–8.26(m,2H),7.97(dd,J＝8.0,2.0Hz,1H),7.74(d,J＝8.4Hz,1H),7.60(d,J＝8.4Hz,1H),7.48(d,J＝8.0Hz,1H),7.18(s,2H),5.41(d,J＝46.8Hz,2H),4.85(s,2H),4.40(s,3H),3.07–3.04(m,1H),0.56–0.52(m,4H).

Example 90: 4-amino-N-cyclopropyl-N- ((5- (3- (dimethylamino) prop-1-yn-1-yl) pyridin-2-yl) methyl) -1-methyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide

N, N-dimethylpropan-2-en-1-amine (27 mg,0.33 mmol), cuprous iodide (4 mg,0.02 mmol), N, N-diisopropylethylamine (57 mg,0.44 mmol) and tetrakis (triphenylphosphine) palladium (12 mg,0.01 mmol) were added sequentially to a solution of N-methylpyrrolidone (3 mL) of compound 88a (50 mg,0.11 mmol) under nitrogen, and the reaction was carried out at Yu Weibo 70 ℃for 3 hours after the addition. The reaction mixture was added with water (10 mL), extracted with ethyl acetate (10 ml×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried by spin-drying and purified by reverse phase chromatography (acetonitrile: 0.05% ammonium bicarbonate aqueous solution=0:100% -60%: 40%) to give compound 90 (12 mg). ESI-MS (m/z): 454.0[ M+H ] ] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ8.66(d,J＝1.6Hz,1H),8.44(s,1H),8.28(s,1H),7.89(dd,J＝8.0,2.0Hz,1H),7.74(d,J＝8.4Hz,1H),7.61(d,J＝8.4Hz,1H),7.43(d,J＝8.0Hz,1H),7.20(s,2H),4.83(s,2H),4.40(s,3H),3.52(s,2H),3.04–3.02(m,1H),2.28(s,6H),0.56–0.45(m,4H).

Example 91: 4-amino-N-ethyl-N- ((5-ethynylpyridin-2-yl) methyl) -1-methyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide

Preparation of N- ((5-bromopyridin-2-yl) methyl) ethylamine (91 a)

2a (300 mg,1.61 mmol) and ethylamine hydrochloride (80 mg,1.1 mmol) were dissolved in dichloromethane (5 mL), N-diisopropylethylamine (0.32 mL,1.94 mmol) was added, and after stirring for 5 minutes glacial acetic acid (0.09 mL,1.61 mmol) was added and stirring was carried out at room temperature for 1 hour. Sodium borohydride acetate (340.3 mg,1.61 mmol) was added,stirring was continued for 1 hour. The reaction was quenched with water (50 mL), adjusted to pH 8 with saturated aqueous sodium bicarbonate, extracted with dichloromethane (100 mL x 3), the organic phases combined, concentrated and purified by normal phase column chromatography (petroleum ether: ethyl acetate=1:1) to give 91a (270 mg,1.26 mmol). ESI-MS (m/z): 215.1[ M+H ]] ⁺ .

Preparation of N- ((5- ((trimethylsilyl) ethynyl) pyridin-2-yl) methyl) ethanamine (91 b)

To a 10mL microwave tube was added reactant 91a (270 mg,1.26 mmol), cuprous iodide (47.8 mg,0.25 mmol), tetrakis triphenylphosphine palladium (145.1 mg,0.13 mmol) and solvent N-methylpyrrolidone (3 mL), nitrogen sparge for 3 minutes, and N, N-diisopropylethylamine (0.83 mL,5.02 mmol), trimethylethynyl silicon (246.5 mg,2.51 mmol). The reaction solution was stirred at 70℃for 3 hours under microwave. After the reaction was completed, the reaction was quenched with water, extracted with ethyl acetate (10 ml×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. n-Xiang Zhuzhu chromatography (petroleum ether: ethyl acetate=1:1) gave 91b (220 mg). ESI-MS (m/z): 233.2[ M+H ] ] ⁺ .

Preparation of N- ((5-ethynylpyridin-2-yl) methyl) ethylamine (91 c)

Compound 91b (220 mg,0.95 mmol) was dissolved in tetrahydrofuran (5 mL), 1M tetrabutylammonium fluoride tetrahydrofuran solution (1 mL) was added, and the reaction mixture was stirred at 25℃for 1h. The reaction was quenched with water (5 mL), extracted with ethyl acetate (5 mL x 3), the organic phases were combined and concentrated to give the crude product by thin layer chromatography (dichloromethane: methanol=93:7) to give 91c (120 mg). ESI-MS (m/z): 161.2[ M+H ]] ⁺ .

Preparation of 4-amino-N-ethyl-N- ((5-ethynylpyridin-2-yl) methyl) -1-methyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide (91)

To a solution of compound 91c (30 mg,0.19 mmol) in N, N-dimethylacetamide (2 mL) was added compound 13a (45.4 mg,0.19 mmol), N, N-diisopropylethylamine (0.03 mL,0.19 mmol) and tripyrrolidinylphosphonium bromide hexafluorophosphate (87.3 mg,0.19 mmol), and the addition was reacted at 25℃for 2 hours. The reaction mixture was quenched with water, extracted with ethyl acetate (10 ml 3), the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by reverse phase chromatography (ethyl acetateNitrile: water=0:100% -35%: 65%) to give compound 91 (24.5 mg). ESI-MS (m/z): 385.2[ M+H ]] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ8.67(s,1H),8.26–8.24(m,2H),7.90(d,J＝6.0Hz,1H),7.58(s,2H),7.44-7.42(m,1H),7.14(s,2H),4.74(s,2H),4.43-4.15(m,4H),3.43(q,J＝6.4Hz,2H),1.13(t,J＝6.4Hz,3H).

Example 92: 4-amino-N- (4- (3-hydroxy-3-methylbut-1-yn-1-yl) benzyl) -N,1, 7-trimethyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide

Preparation of 4-amino-N- (4-bromobenzyl) -N,1, 7-trimethyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide (92 b)

To a solution of compound 92a (209.9 mg,1.05 mmol) in N, N-dimethylacetamide (5 mL), compound 54a (256 mg,1.00 mmol), triethylamine (0.42 mL,3.00 mmol) and tripyrrolidinylphosphonium bromide hexafluorophosphate (698.2 mg,1.50 mmol) were reacted at 25℃for 18 hours. The reaction solution was diluted with ethyl acetate (20 mL) and water (20 mL), the solution was separated, and the organic phase was concentrated to obtain a crude product, which was subjected to column chromatography (dichloromethane: methanol=30:1) to obtain 92b (195 mg). ESI-MS (m/z): 438.17[ M+H ]] ⁺ 4-amino-N, 1, 7-trimethyl-N- (4- (3-methyl-3- ((trimethylsilyl) oxy) but-1-yn-1-yl) benzyl) -1H-pyrazolo [4,3-c]Preparation of quinoline-8-carboxamide (92 c) Compound 92b (140 mg,0.32 mmol) was dissolved in N-methylpyrrolidone (2 mL), ((1, 1-dimethyl-2-propynyl) oxy) trimethylsilane (99.8 mg,0.64 mmol), cuprous iodide (12.2 mg,0.06 mmol), tetrakis (triphenylphosphine) palladium (36.9 mg,0.03 mmol), triethylamine (0.18 mL,1.28 mmol) was added, nitrogen was displaced 3 times, and the reaction was carried out at 70℃for 3 hours by microwaves. The reaction solution was diluted with ethyl acetate (20 mL) and water (20 mL), a solid was precipitated, filtered, the filtrate was separated, and the organic phase was concentrated to obtain a crude product which was subjected to thin layer chromatography (dichloromethane: methanol=30:1) to obtain 92c (60 mg). ESI-MS (m/z): 514.4[ M+H ] ] ⁺ .

Preparation of 4-amino-N- (4- (3-hydroxy-3-methylbut-1-yn-1-yl) benzyl) -N,1, 7-trimethyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide (92)

Compound 92c (15 mg,0.03 mmol) was dissolved in dichloromethane (2 mL), 4M dioxane hydrochloride solution (0.04 mL,0.15 mmol) was added, and the reaction was stirred at 25℃for 1h. The reaction solution was quenched with water (5 mL), adjusted to pH 8 with saturated sodium carbonate solution, extracted with ethyl acetate (5 mL. Times.3), the organic phases were combined and concentrated to give crude product which was purified by thin layer chromatography (dichloromethane: methanol=20:1) to give 92 (5 mg). ESI-MS (m/z): 442.25[ M+H ]] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ8.23–8.20(m,1H),8.00–7.93(m,1H),7.46–7.36(m,4H),7.20–7.18(m,1H),7.02(s,2H),5.47(s,1H),4.75–4.15(m,5H),3.05–2.76(s,3H),2.34–2.32(s,3H),1.48–1.47(s,6H).

Example 93: 4-amino-N-cyclopropyl-N- (4-ethynyl-2-methoxybenzyl) -1-methyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide

Preparation of N- (2-methoxy-4- ((trimethylsilyl) ethynyl) benzyl) cyclopropylamine (93 b)

Compound 93a (500 mg,1.95 mmol), ethynyl trimethylsilane (383.4 mg,3.90 mmol), cuprous iodide (74.4 mg,0.39 mmol), tetrakis (triphenylphosphine) palladium (225.6 mg,0.20 mmol), N-N-diisopropylethylamine (1.35 mL,9.76 mmol) were dissolved in N-methylpyrrolidone (2 mL), nitrogen was substituted 3 times, and reacted at 70℃for 3 hours under microwaves. The reaction solution was diluted with ethyl acetate (20 mL) and water (20 mL), a solid was precipitated, filtered, the filtrate was separated, and the organic phase was concentrated to obtain a crude product which was subjected to thin layer chromatography (dichloromethane: methanol=10:1) to obtain 93b (254 mg). ESI-MS (m/z): 274.2[ M+H ] ] ⁺ .

Preparation of N- (4-ethynyl-2-methoxybenzyl) cyclopropylamine (93 c)

Compound 93b (254 mg,0.93 mmol) was dissolved in tetrahydrofuran (3 mL), 1M tetrabutylammonium fluoride in tetrahydrofuran (1.86 mL,1.86 mmol) was added and stirred at 25℃for 1h. The reaction was quenched with water (5 mL), extracted with ethyl acetate (5 mL x 3), the organic phases were combined, concentrated and purified by thin layer chromatography (dichloromethane: methanol=10:1) to giveTo 93c (110 mg). ESI-MS (m/z): 202.20[ M+H ]] ⁺ 4-amino-N-cyclopropyl-N- (4-ethynyl-2-methoxybenzyl) -1-methyl-1H-pyrazolo [4,3-c]Preparation of quinoline-8-carboxamide (93)

To a solution of compound 93c (40.2 mg,0.20 mmol) in N, N-dimethylacetamide (2 mL) was added compound 13a (48.4 mg,0.20 mmol), triethylamine (0.06 mL,0.40 mmol) and tripyrrolidinylphosphonium bromide hexafluorophosphate (156.6 mg,0.30 mmol), and the addition was completed for 18 hours at 25 ℃. The reaction solution was filtered, and the filtrate was purified by high pressure liquid chromatography to give 93 (6 mg). ESI-MS (m/z): 426.05[ M+H ]] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ8.37(s,1H),8.27(s,1H),7.72–7.70(m,1H),7.60(d,J＝8.4Hz,1H),7.30(d,J＝8.0Hz,1H),7.19–7.12(m,4H),4.67(s,2H),4.37(s,3H),4.19(s,1H),3.86(s,3H),2.89–2.82(m,1H),0.60–0.42(m,4H).

Example 94: 4-amino-N-cyclopropyl-N- ((5- (3-hydroxy-3-methylbut-1-yn-1-yl) pyridin-2-yl) methyl) -1, 7-dimethyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide

Preparation of 4-amino-N- ((5-bromopyridin-2-yl) methyl) -N-cyclopropyl-1, 7-dimethyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide (94 a)

Referring to the preparation of compound 82a, substituting 54a for 17a gave compound 94a (150 mg). ESI-MS (m/z): 465.2[ M+H ]] ⁺ .

4-amino-N-cyclopropyl-1, 7-dimethyl-N- ((5- (3-methyl-3- ((trimethylsilyl) oxy) but-1-yn-1-yl) pyridin-2-yl) methyl) -1H-pyrazolo [4,3-c]Preparation of quinoline-8-carboxamide (94 b) referring to the preparation of compound 82b, substitution of 94a (150 mg,0.30 mmol) for 82a afforded compound 94b (80 mg). ESI-MS (m/z): 541.27[ M+H ]] ⁺ .

Preparation of 4-amino-N-cyclopropyl-N- ((5- (3-hydroxy-3-methylbut-1-yn-1-yl) pyridin-2-yl) methyl) -1, 7-dimethyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide (94)

Compound 94b (80 mg,0.15 mmol) was dissolved in dichloromethaneAlkane (2 mL) was added 4M dioxane hydrochloride solution (0.04 mL,0.15 mmol) and the reaction stirred at 25℃for 1h. The reaction solution was quenched with water (5 mL), adjusted to pH 8 with saturated sodium carbonate solution, extracted with ethyl acetate (5 ml×3), the organic phases were combined and concentrated to give crude product which was purified by thin layer chromatography (dichloromethane: methanol=20:1) to give compound 94 (30 mg). ESI-MS (m/z): 469.29[ M+H ]] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ8.57(d,J＝1.6Hz,1H),8.23–8.17(m,2H),7.86–7.81(m,1H),7.47–7.44(m,2H),7.01(s,2H),5.56(s,1H),4.84(s,2H),4.40(s,3H),2.87–2.80(m,1H),2.37(s,3H),1.51(s,6H),0.52–0.39(m,4H).

Example 95: 4-amino-N- ((5-ethynyl 4-methylpyridin-2-yl) methyl) -7-methyl-N- (1-methyl-1H-pyrazol-4-yl) -1, 3-dihydrofuro [3,4-c ] quinoline-8-carboxamide

To a solution of compound 40d (45 mg,0.20 mmol) in N, N-dimethylacetamide (2 mL) was added compound 59a (48.6 mg,0.20 mmol), triethylamine (0.07 mL,0.50 mmol) and tripyrrolidinylphosphonium bromide hexafluorophosphate (139.0 mg,0.30 mmol), followed by reaction at 25℃for 18 hours. The reaction solution was filtered, and the filtrate was purified by high pressure liquid chromatography to give compound 95 (17.4 mg). ESI-MS (m/z): 453.27[ M+H ]] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ8.58–8.53(s,1H),7.55(s,1H),7.46–7.28(m,3H),7.16–7.07(m,1H),6.56–6.53(m,2H),5.28–4.98(m,6H),4.60(s,1H),3.82–3.55(m,3H),2.45–2.38(m,6H)

Example 96: 4-amino-7-chloro-N- ((5-ethynyl-4-methylpyridin-2-yl) methyl) -N- (1-methyl-1H-pyrazol-4-yl) -1, 3-dihydrofuro [3,4-c ] quinoline-8-carboxamide

To a solution of compound 40d (45 mg,0.20 mmol) in N, N-dimethylacetamide (2 mL) was added compound 96a (52.6 mg,0.20mmol,preparation methods refer to WO 2022/115377 A1), triethylamine (0.07 mL,0.50 mmol) and tripyrrolidinylphosphonium bromide hexafluorophosphate (139.0 mg,0.30 mmol). Followed by reaction at 25℃for 18 hours. The reaction solution was filtered, and the filtrate was purified by high pressure liquid chromatography to give compound 96 (15.5 mg). ESI-MS (m/z): 473.17[ M+H ]] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ8.56–8.51(m,1H),8.61–7.45(m,4H),7.16–7.12(m,1H),6.85–6.81(m,2H),5.33–5.31(m,2H),5.02–4.90(m,4H),4.61–4.59(m,1H),3.82–3.56(m,3H),2.45–2.31(s,3H).

Example 97: 4-amino-7-chloro-N- ((5-ethynylpyridin-2-yl) methyl) -N- (1-methyl-1H-pyrazol-4-yl) -1, 3-dihydrofuro [3,4-c ] quinoline-8-carboxamide

To a solution of compound 14c (45 mg,0.20 mmol) in N, N-dimethylacetamide (2 mL) was added compound 96a (52.4 mg,0.20 mmol), triethylamine (0.07 mL,0.50 mmol) and tripyrrolidinylphosphonium bromide hexafluorophosphate (139.0 mg,0.30 mmol), and the addition was reacted at 25℃for 18 hours. After the completion of the reaction, the reaction mixture was filtered, and the filtrate was purified by high-pressure liquid chromatography to give compound 97 (14 mg). ESI-MS (m/z): 459.15[ M+H ] ] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ8.67–8.61(m,1H),7.98–7.82(m,1H),7.61–7.12(m,5H),6.86–6.82(m,2H),5.34–5.32(m,2H),5.07(s,2H),5.01–4.97(m,2H),4.45–4.43(m,1H),3.82–3.56(m,3H).

Example 98: 4-amino-N- (1- (difluoromethyl) -1H-pyrazol-4-yl) -N- ((5-ethynylpyridin-2-yl) methyl) -7-methyl-1, 3-dihydrofuro [3,4-c ] quinoline-8-carboxamide

To a solution of compound 39c (40 mg,0.16 mmol) in N, N-dimethylacetamide (2 mL) was added compound 59a (39.4 mg,0.16 mmol), triethylamine (0.06 mL,0.40 mmol) and tripyrrolidinylphosphonium bromide hexafluorophosphate (125.8 m)g,0.24 mmol) followed by reaction at 25℃for 18 hours. After the completion of the reaction, the reaction mixture was filtered, and the filtrate was purified by high-pressure liquid chromatography to give 98 (8 mg). ESI-MS (m/z): 475.21[ M+H ]] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ8.71–8.64(m,1H),8.60and 8.15(s,1H),8.02–7.65(m,2H),7.53–7.40(m,3H),7.30–7.24(m,1H),6.58(s,2H),5.26–4.98(m,6H),4.44(s,1H),2.38(s,3H).

Example 100: 4-amino-N- ((4-chloro-5-ethynylpyridin-2-yl) methyl) -N-cyclopropyl-1-methyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide

Preparation of 5-bromo-2-methylpyridine 1-oxide (100 b)

To a solution of 5-bromo-2-methylpyridine (1.72 g,10 mmol) in dichloromethane (20 mL) at 0deg.C was added 3.45g,20mmol of m-chloroperoxybenzoic acid and the reaction was carried out at 25deg.C for 4 hours. The reaction solution was slowly added with saturated sodium carbonate solution, extracted with ethyl acetate (50 ml×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (methanol: dichloromethane=1:99) to give compound 100b (1.60 g). ESI-MS (m/z): 188.0[ M+H ] ] ⁺ .

Preparation of 5-bromo-2-methyl-4-nitropyridine 1-oxide (100 c)

To a solution of compound 100b (1.60 g,8.60 mmol) in concentrated sulfuric acid (4 mL) was slowly added a mixed solution of concentrated nitric acid (4 mL) and concentrated sulfuric acid (6.5 mL) at 0 ℃ and reacted at 80 ℃ for 12 hours after the addition, and after the reaction was completed, cooled to room temperature, the reaction system was poured into ice water, then sodium hydroxide solution (6N) was slowly added to bring the pH of the solution to about 8, dichloromethane extraction (50 ml×3), the organic phases were combined, saturated brine was washed, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography (methanol: dichloromethane=1:99) was performed to obtain compound 100c (1.59 g). ESI-MS (m/z): 233.0[ M+H ]] ⁺ .

Preparation of 5-bromo-4-chloro-2-methylpyridine 1-oxide (100 d)

To a solution of compound 100c (1.59 g,6.88 mmol) in dichloromethane (10 mL) at 0deg.C was slowly added a mixed solution of phosphorus oxychloride (3.17 g,20.65 mmol) and dichloromethane (5 mL), and the addition was completed at 25deg.C for 12 hours. After the reaction, the reaction system was poured into ice water, then diluted sodium hydroxide solution was slowly added to bring the pH of the solution to about 8, dichloromethane was extracted (50 ml. Times.3), the organic phases were combined, saturated brine was washed with water, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (methanol: dichloromethane=3)

2:98) to give compound 100d (1.22 g). ESI-MS (m/z): 223.9[ M+H ]] ⁺ .

Preparation of (5-bromo-4-chloropyridin-2-yl) methanol (100 e)

To a solution of compound 100d (1.22 g,5.50 mmol) in dichloromethane (10 mL) was slowly added trifluoroacetic anhydride (3.46 g,16.5 mmol) at 0 ℃, after the addition, the reaction system was warmed to 25 ℃ and reacted at that temperature for 12 hours, and after the reaction was completed, the reaction system was slowly poured into sodium hydroxide solution (6N) to bring the pH of the solution to about 8, extracted with dichloromethane (50 mL x 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography (methanol: dichloromethane=1:99) was performed to obtain compound 100e (580 mg). ESI-MS (m/z): 223.9[ M+H ]] ⁺ .

Preparation of 5-bromo-4-chloro-2- (chloromethyl) pyridine (100 f)

Thionyl chloride (356 mg,3 mmol) was slowly added to a solution of compound 100e (222 mg,1 mmol) in dichloromethane (10 mL) at 0deg.C, and after the addition, the reaction system was warmed to 25deg.C and reacted at this temperature for 2 hours, and after the reaction was completed, the solvent of the reaction system was spun off to give compound 100f (240 mg) which was directly used for the next reaction. ESI-MS (m/z): 241.9[ M+H ]] ⁺ .

Preparation of 5-bromopyridine-2-methyl-1-methyl-4-aminopyrazole (100 g) to a solution of Compound 100f (240 mg,1 mmol) in N, N-dimethylformamide (10 mL) was added cesium carbonate (650 mg,2 mmol), cyclopropylamine (114 mg,2 mmol) in this order, reacted at 25℃for 4 hours after the addition was completed, the reaction system was added with water (20 mL), extracted with ethyl acetate (20 mL. Times.3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated Column chromatography (petroleum ether: ethyl acetate=2:1) gave 100g of compound (192 mg). ESI-MS (m/z): 263.0[ M+H ]] ⁺ Preparation of N- ((4-chloro-5- ((trimethylsilyl) ethynyl) pyridin-2-yl) methyl) cyclopropylamine (100 h)

To a solution of 100g (192 mg,0.74 mmol) of the compound in N-methylpyrrolidone (2 mL) under nitrogen was added sequentially trimethylethynyl silicon (145 mg,1.48 mmol), cuprous iodide (29 mg,0.15 mmol), N, N-diisopropylethylamine (267 mg,2.22 mmol) and tetrakis (triphenylphosphine) palladium (80 mg,0.07 mmol). After the addition, the reaction was completed for 3 hours at 70 ℃ with microwaves, water (10 mL) was added, extraction was performed with ethyl acetate (20 ml×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was spun off, followed by column chromatography (petroleum ether: ethyl acetate=3:1) to give compound 100h (140 mg). ESI-MS (m/z): 279.1[ M+H ]] ⁺ .

Preparation of N- ((4-chloro-5-ethynylpyridin-2-yl) methyl) cyclopropylamine (100 i)

The compound (100 h) (140 mg,0.5 mmol) was dissolved in the solvent tetrahydrofuran (2 mL), and 1M tetrabutylammonium fluoride tetrahydrofuran solution (100. Mu.L, 1 mmol) was slowly added, and stirred at 25℃for half an hour after the addition. The reaction mixture was quenched with water (10 mL), extracted with ethyl acetate (10 ml×3), the organic phases combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to give compound 100i (90 mg) by column chromatography (petroleum ether: ethyl acetate=2:1). ESI-MS (m/z): 207.1[ M+H ] ] ⁺ .

Preparation of 4-amino-N- ((4-chloro-5-ethynylpyridin-2-yl) methyl) -N-cyclopropyl-1-methyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide (100)

To a solution of compound 100i (41 mg,0.2 mmol) in N, N-dimethylacetamide (3 mL) was added compound 13a (49 mg,0.2 mmol), triethylamine (71 mg,0.7 mmol) and tripyrrolidinylphosphonium bromide hexafluorophosphate (121 mg,0.26 mmol), and the mixture was reacted at room temperature for 4 hours. The reaction mixture was extracted with water (20 mL), ethyl acetate (20 mL. Times.3), the organic phase was dried over saturated brine, filtered, spin-dried and purified by reverse phase chromatography (acetonitrile: 0.05% ammonium bicarbonate aqueous solution=0:100% -40%: 60%) to give compound 100 (4 mg). ESI-MS (m/z): 431.1[ M+H] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ8.79(s,1H),8.44(s,1H),8.28(s,1H),7.73(d,J＝8.4Hz,1H),7.68(s,1H),7.60(d,J＝8.4Hz,1H),7.15(s,2H),4.84(s,2H),4.82(s,1H),4.40(s,3H),3.11–3.03(m,1H),0.59–0.52(m,4H).

Example 114: 4-amino-N-cyclopropyl-N- ((5- (3-hydroxy-3-methylbut-1-yn-1-yl) -4-methylpyridin-2-yl) methyl) -1, 7-dimethyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide

4-amino-N- ((5-bromo-4-methylpyridin-2-yl) methyl) -N-cyclopropyl-1, 7-dimethyl-1H-pyrazolo [4,3-c]Preparation of quinoline-8-carboxamide (114 a) Compound 71b (200 mg,0.83 mmol) was dissolved in N, N-dimethylformamide (5 ml), and 54a (212.7 mg,0.83 mmol), N, N-diisopropylethylamine (411.39. Mu.L, 2.49 mmol) and O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethylurea hexafluorophosphate (484.6 mg,1.24 mmol) were added. After the completion of the reaction, the reaction mixture was stirred overnight at 25℃and quenched with water, extracted three times with ethyl acetate (50 ml) and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by normal phase column chromatography (dichloromethane: methanol=10:1) to give compound 114a (272 mg. ESI-MS (m/z): 479.2[ M+H) ] ⁺ 4-amino-N-cyclopropyl-1, 7-dimethyl-N- ((4-methyl-5- (3-methyl-3- ((trimethylsilyl) oxy) but-1-yn-1-yl) pyridin-2-yl) methyl) -1H-pyrazolo [4,3-c]Preparation of quinoline-8-carboxamide (114 b) to a 10mL microwave tube was added reactant 114a (50 mg,0.10 mmol), cuprous iodide (4.0 mg,0.02 mmol), tetrakis triphenylphosphine palladium (12.1 mg,0.01 mmol) and solvent N-methylpyrrolidone (2 mL), nitrogen sparged for 3 min, N-diisopropylethylamine (51.83, 0.31 mmol), 3-methyl-3-trimethylsiloxy-1-butyne (48.9 mg,0.31 mmol). The reaction solution was stirred at 70℃for 3 hours under microwave. After the completion of the reaction, the reaction was quenched with water, extracted three times with ethyl acetate (25 ml) and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Preparative plate separation (dichloromethane: methanol=10:1) purification gave compound 114b (31 mg),ESI-MS(m/z):555.4[M+H] ⁺ .

preparation of 4-amino-N-cyclopropyl-N- ((5- (3-hydroxy-3-methylbut-1-yn-1-yl) -4-methylpyridin-2-yl) methyl) -1, 7-dimethyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide (114)

To a solution of compound 114b (31 mg,0.06 mmol) in methylene chloride (5 ml) was added 4M dioxane hydrochloride (69.84. Mu.L, 0.28 mmol), and the mixture was stirred at 25℃for 5 minutes, the reaction solution was concentrated, and reversed-phase chromatography (acetonitrile: 0.05% aqueous ammonium bicarbonate=0:100% -35:65%) gave compound 114 (10.4 mg), ESI-MS (M/z): 483.4[ M+H ] ] ⁺ . ¹ H NMR(400MHz,DMSO)δ8.49(s,1H),8.24–8.21(m,2H),7.45(s,1H),7.35(s,1H),7.01(s,2H),5.55(s,1H),4.81(s,2H),4.41(s,3H),2.88–2.81(m,1H),2.47–2.33(m,6H),1.53(s,6H),0.62–0.27(m,4H).

Example 115: 4-amino-N-cyclopropyl-7-fluoro-N- ((5- (3-hydroxy-3-methylbut-1-yn-1-yl) -4-methylpyridin-2-yl) methyl) -1-methyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide

Preparation of 4-amino-N- ((5-bromo-4-methylpyridin-2-yl) methyl) -N-cyclopropyl-7-fluoro-1-methyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide (115 a)

Compound 71b (200 mg,0.83 mmol) was dissolved in N, N-dimethylformamide (5 ml), and 17a (216.0 mg,0.83 mmol), N, N-diisopropylethylamine (411.39. Mu.L, 2.49 mmol) and O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethylurea hexafluorophosphate (484.6 mg,1.24 mmol) were added. After the completion of the reaction, the reaction mixture was stirred overnight at 25℃and quenched with water, extracted three times with ethyl acetate (50 ml) and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by normal phase column chromatography (dichloromethane: methanol=10:1) to give compound 115a (254 mg), ESI-MS (m/z): 483.1[ M+H] ⁺ .

Preparation of 4-amino-N-cyclopropyl-7-fluoro-1-methyl-N- ((4-methyl-5- (3-methyl-3- ((trimethylsilyl) oxy) but-1-yn-1-yl) pyridin-2-yl) methyl) -1H-pyrazolo [4,3-c ] quinoline-8-carboxamide (115 b)

To a 10mL microwave tube was added reactant 115a (50 mg,0.10 mmol), cuprous iodide (3.9 mg,0.02 mmol), tetrakis triphenylphosphine palladium (12.0 mg,0.01 mmol) and solvent N-methylpyrrolidone (2 mL), nitrogen sparge for 3 minutes, and N, N-diisopropylethylamine (51.41, 0.31 mmol), 3-methyl-3-trimethylsiloxy-1-butyne (48.5 mg,0.31 mmol). The reaction solution was stirred at 70℃for 3 hours under microwave. After the completion of the reaction, the reaction was quenched with water, extracted three times with ethyl acetate (25 ml) and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Preparative plate separation (dichloromethane: methanol=10:1) purification gave compound 115b (23 mg), ESI-MS (m/z): 559.4[ M+H) ] ⁺ .

Preparation of 4-amino-N-cyclopropyl-7-fluoro-N- ((5- (3-hydroxy-3-methylbut-1-yn-1-yl) -4-methylpyridin-2-yl) methyl) -1-methyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide (115)

115b (24 mg,0.04 mmol) and solvent dichloromethane (5 ml) were added sequentially at room temperature, 4M dioxane hydrochloride solution (53.70. Mu.L, 0.21 mmol) was added, the reaction mixture was stirred at 25℃for 5 minutes, after the reaction was completed, concentrated, and reversed phase chromatography (acetonitrile: 0.05% ammonium bicarbonate aqueous solution=0:100% -35:65%) afforded compound 115 (10.4 mg), ESI-MS (M/z): 487.3[ M+H ]] ⁺ . ¹ H NMR(400MHz,DMSO)δ8.47(s,1H),8.28–8.25(m,2H),7.36-7.28(m,2H),7.25(s,2H),5.53(s,1H),4.79(s,2H),4.39(s,3H),2.91-2.82(m,1H),2.40(s,3H),1.50(s,6H),0.56-0.35(m,4H).

Example 116: 4-amino-N- ((4-chloro-5- (3-hydroxy-3-methylbut-1-yn-1-yl) pyridin-2-yl) methyl) -N-cyclopropyl-7-fluoro-1-methyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide

Preparation of 4-amino-N- ((5-bromo-4-chloropyridin-2-yl) methyl) -N-cyclopropyl-7-fluoro-1-methyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide (116 a)

To 100g (208 mg,0.8 mmol) of N, N-dimethyl compoundTo a solution of dimethylformamide (5 mL) was added compound 17a (208 mg,0.8 mmol), N-diisopropylethylamine (206 mg,1.6 mmol) and 2- (7-azobenzotriazole) -N, N' -tetramethylurea hexafluorophosphate (458 mg,1.2 mmol), and after the addition was completed, the reaction was allowed to react at room temperature for 4 hours, water (20 mL) was added, extraction (20 mL of x 3) was performed with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was spun off to give compound 116a (180 mg) by column chromatography (methanol: dichloromethane=1:10). ESI-MS (m/z): 503.0[ M+H ] ] ⁺ .

Preparation of 4-amino-N- ((4-chloro-5- (3-methyl-3- ((trimethylsilyl) oxy) but-1-yn-1-yl) pyridin-2-yl) methyl) -N-cyclopropyl-7-fluoro-1-methyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide (116 b)

To a solution of compound 116a (51 mg,0.1 mmol) in N-methylpyrrolidone (1 mL) under nitrogen was added successively (propynyloxy) trimethylsilane (31 mg,0.2 mmol), cuprous iodide (4 mg,0.02 mmol), N, N-diisopropylethylamine (26 mg,0.2 mmol) and tetrakis (triphenylphosphine) palladium (12 mg,0.01 mmol). After the addition, the reaction was completed for 3 hours at 70 ℃ with microwaves, water (10 mL) was added, extracted with ethyl acetate (10 ml×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was spun off to give compound 116b (39 mg) by column chromatography (methanol: dichloromethane=1:10). ESI-MS (m/z): 579.2[ M+H ]] ⁺ .

Preparation of 4-amino-N- ((4-chloro-5- (3-hydroxy-3-methylbut-1-yn-1-yl) pyridin-2-yl) methyl) -N-cyclopropyl-7-fluoro-1-methyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide (116)

To a solution of compound 116b (39 mg,0.07 mmol) in dichloromethane (2 mL) was slowly added 1,4 dioxane solution of hydrochloric acid (2 mL, 4M) at 0deg.C. After the addition, the reaction was carried out at room temperature for 30 minutes, a saturated sodium carbonate solution was added to the reaction solution, the pH was adjusted to about 8, extraction was carried out with ethyl acetate (10 ml×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was spun off, followed by purification by reverse phase column chromatography (acetonitrile: 0.05% ammonium bicarbonate aqueous solution=0:100% -40:60%) to give compound 116 (19 mg). ESI-MS (m/z): 507.2[ M+H ] ] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ8.68(s,1H),8.34–8.26(m,2H),7.61(s,1H),7.34(d,J＝12.0Hz,1H),7.28(s,2H),5.64(s,1H),4.85(s,2H),4.41(s,3H),2.98–2.86(m,1H),1.53(s,6H),0.69–0.39(m,4H).

Example 117: 4-amino-N-cyclopropyl-7-fluoro-N- ((3-fluoro-5- (3-hydroxy-3-methylbut-1-yn-1-yl) pyridin-2-yl) methyl) -1-methyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide

Preparation of 4-amino-N- ((5-bromo-3-fluoropyridin-2-yl) methyl) -N-cyclopropyl-7-fluoro-1-methyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide (117 a)

To a 50mL eggplant-shaped bottle containing a stirrer were added 70b (50 mg,0.20 mmol), 17a (62 mg,0.24 mmol), N, N-diisopropylethylamine (52 mg,0.40 mmol) and N, N-dimethylacetamide (2 mL) in this order, and N, N, N ', N' -tetramethyl-O- (7-azabenzotriazol-1-yl) urea hexafluorophosphate (114 mg,0.30 mmol) was added thereto. After the addition, the reaction was stirred at room temperature overnight. The reaction mixture was extracted with water and ethyl acetate (10 ml×3), the organic phase was dried over anhydrous sodium sulfate, filtered and dried by spin-drying, and the resulting residue was purified by silica gel column chromatography (ethyl acetate: methanol=15:1) to give 117a (56 mg). ESI-MS (m/z): 487.1[ M+H ]] ⁺ .

Preparation of 4-amino-N-cyclopropyl-7-fluoro-N- ((3-fluoro-5- (3-methyl-3- ((trimethylsilyl) oxy) but-1-yn-1-yl) pyridin-2-yl) methyl) -1-methyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide (117 b)

To a 10mL microwave tube containing a stirrer was added 117a (50 mg,0.10 mmol) and N-methylpyrrolidone (2 mL) in sequence. Nitrogen was bubbled for 5 minutes, and 4-acetylene-1-methyl-1H-pyrazole 3-methyl-3-trimethylsilyloxy-1-butyne (80 mg,0.51 mmol), triethylamine (52 mg,0.51 mmol), cuprous iodide (4 mg,0.02 mmol) and tetrakis triphenylphosphine palladium (16 mg,0.01 mmol) were added thereto. Nitrogen was bubbled for 1 minute, and the reaction solution was heated to 75 ℃ with microwave and stirred for 3 hours. The reaction mixture was poured into water, extracted with ethyl acetate (10 ml. Times.3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure The solvent was removed, and the resulting residue was purified by column chromatography on silica gel (ethyl acetate: methanol=15:1) to give 117b (49 mg). ESI-MS (m/z): 563.3[ M+H ]] ⁺ .

Preparation of 4-amino-N-cyclopropyl-7-fluoro-N- ((3-fluoro-5- (3-hydroxy-3-methylbut-1-yn-1-yl) pyridin-2-yl) methyl) -1-methyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide (117)

To a 10mL eggplant-shaped bottle containing a stirrer, 117b (49 mg,0.09 mmol) and methylene chloride (5 mL) were sequentially added. To this was slowly added dropwise a 4M HCl 1, 4-dioxane solution (0.2 mL). The mixture was stirred at room temperature for 5 minutes. Saturated aqueous sodium bicarbonate solution was added, extraction was performed with ethyl acetate (10 ml×3), the obtained organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried, and the obtained residue was purified by reverse phase silica gel column chromatography (eluent: acetonitrile: 0.05% aqueous ammonium bicarbonate solution=0:100% -40%: 60%) to obtain 117 (26 mg). ESI-MS (m/z): 491.2[ M+H ]] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ8.49(s,1H),8.29–8.26(s,2H),7.84(d,J＝9.2Hz,1H),7.35–7.22(m,3H),5.61(s,1H),4.90(s,2H),4.40(s,3H),2.93–2.81(m,1H),1.51(s,6H),0.71–0.57(m,2H),0.54–0.38(m,2H).

Example 118: 4-amino-N- ((4-chloro-5- (3-hydroxy-3-methylbut-1-yn-1-yl) pyridin-2-yl) methyl) -N-cyclopropyl-1, 7-dimethyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide

4-amino-N- ((5-bromo-4-chloropyridin-2-yl) methyl) -N-cyclopropyl-1, 7-dimethyl-1H-pyrazolo [4,3-c]Preparation of quinoline-8-carboxamide (118 a) to a solution of 100g (208 mg,0.8 mmol) of N, N-dimethylformamide (5 mL) was added compound 54a (256 mg,0.8 mmol), N, N-diisopropylethylamine (206 mg,1.6 mmol) and 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (458 mg,1.2 mmol), the addition was reacted at room temperature for 4 hours, after the completion of the reaction, water (20 mL) was extracted with ethyl acetate (20 mL. Times.3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was spun off by column chromatography (methanol: di) Methyl chloride=1:10) to give compound 118a (164 mg). ESI-MS (m/z): 499.1[ M+H ]] ⁺ 4-amino-N- ((4-chloro-5- (3-methyl-3- ((trimethylsilyl) oxy) but-1-yn-1-yl) pyridin-2-yl) methyl) -N-cyclopropyl-1, 7-dimethyl-1H-pyrazolo [4,3-c ]]Preparation of quinoline-8-carboxamide (118 b) to a solution of N-methylpyrrolidone (1 mL) of compound 118a (51 mg,0.1 mmol) under nitrogen was added successively (propynyloxy) trimethylsilane (31 mg,0.2 mmol), cuprous iodide (4 mg,0.02 mmol), N, N-diisopropylethylamine (26 mg,0.2 mmol) and tetrakis (triphenylphosphine) palladium (12 mg,0.01 mmol). After the addition, the reaction was completed for 3 hours at 70 ℃ with microwaves, water (10 mL) was added, extracted with ethyl acetate (10 ml×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was spun off to give compound 118b (21 mg) by column chromatography (methanol: dichloromethane=1:10). ESI-MS (m/z): 575.2[ M+H ]] ⁺ .

Preparation of 4-amino-N- ((4-chloro-5- (3-hydroxy-3-methylbut-1-yn-1-yl) pyridin-2-yl) methyl) -N-cyclopropyl-1, 7-dimethyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide (118)

To a solution of compound 118b (21 mg,0.03 mmol) in dichloromethane (2 mL) was slowly added 1,4 dioxane solution of hydrochloric acid (2 mL, 4M) at 0deg.C. After the addition, the reaction was carried out at room temperature for 30 minutes, the reaction solution was added to a saturated sodium carbonate solution, the pH was adjusted to about 8, extraction was carried out with ethyl acetate (10 ml×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by filtration, followed by purification by reverse phase chromatography (acetonitrile: 0.05% ammonium bicarbonate aqueous solution=0:100% -40:60%) to give compound 118 (7 mg). ESI-MS (m/z): 503.3[ M+H ] ] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ8.67(s,1H),8.26–8.15(m,2H),7.73–7.65(m,1H),7.45(s,1H),7.02(s,2H),5.63(s,1H),4.84(s,2H),4.40(s,3H),2.95–2.80(m,1H),2.36(s,3H),1.53(s,6H),0.60–0.35(m,4H).

Example 119: 4-amino-N-cyclopropyl-N- ((3-fluoro-5- (3-hydroxy-3-methylbut-1-yn-1-yl) pyridin-2-yl) methyl) -1, 7-dimethyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide

Preparation of 4-amino-N- ((5-bromo-3-fluoropyridin-2-yl) methyl) -N-cyclopropyl-1, 7-dimethyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide (119 a)

To a 50mL eggplant-shaped bottle containing a stirrer were added 70b (50 mg,0.20 mmol), 54a (63 mg,0.24 mmol), N, N-diisopropylethylamine (52 mg,0.40 mmol) and N, N-dimethylacetamide (5 mL) in this order, followed by addition of urea N, N, N ', N' -tetramethyl-O- (7-azabenzotriazol-1-yl) hexafluorophosphate (114 mg,0.30 mmol). The mixture was stirred overnight at room temperature. The reaction mixture was extracted with water and ethyl acetate (10 ml×3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried, and the resulting residue was purified by silica gel column chromatography (ethyl acetate: methanol=15:1) to give 119a (53 mg). ESI-MS (m/z): 483.1[ M+H ]] ⁺ .

Preparation of 4-amino-N-cyclopropyl-N- ((3-fluoro-5- (3-methyl-3- ((trimethylsilyl) oxy) but-1-yn-1-yl) pyridin-2-yl) methyl) -1, 7-dimethyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide (119 b)

119a (50 mg,0.10 mmol) and N-methylpyrrolidone (2 mL) were added sequentially to a 10mL microwave tube containing a stirrer. Nitrogen was purged for 5 minutes, and 4-acetylene-1-methyl-1H-pyrazole 3-methyl-3-trimethylsilyloxy-1-butyne (81 mg,0.52 mmol), triethylamine (51 mg,0.50 mmol), cuprous iodide (4 mg,0.02 mmol) and tetrakis triphenylphosphine palladium (16 mg,0.01 mmol) were added thereto. Nitrogen was bubbled for 1 minute and the reaction was stirred at 75 ℃ for 3 hours under microwaves. The reaction mixture was extracted with water and ethyl acetate (10 ml×3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate: methanol=15:1) to give 119b (32 mg). ESI-MS (m/z): 559.5[ M+H ] ] ⁺ .

Preparation of 4-amino-N-cyclopropyl-N- ((3-fluoro-5- (3-hydroxy-3-methylbut-1-yn-1-yl) pyridin-2-yl) methyl) -1, 7-dimethyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide (119)

119b (32 mg,0.06 mmol) and methylene chloride (5 mL) were successively added to a 10mL eggplant-shaped bottle containing a stirrer. 1, 4-Dioxy containing 4M HCl was then slowly added dropwiseSix-ring solution (0.2 mL). After the addition, stirring was carried out at room temperature for 5 minutes. The reaction solution was added with saturated aqueous sodium bicarbonate, extracted with ethyl acetate (10 ml×3), washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and spin-dried, and the residue was purified by reverse phase silica gel column chromatography (acetonitrile: 0.05% aqueous ammonium bicarbonate=0:100% -40:60%) to give compound 119 (16 mg). ESI-MS (m/z): 487.2[ M+H ]] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ8.49(s,1H),8.23–8.05(m,2H),7.83(d,J＝8.0Hz,1H),7.44(s,1H),7.01(s,2H),5.61(s,1H),4.89(s,2H),4.39(s,3H),2.90–2.84(m,1H),2.35(s,3H),1.51(s,6H),0.68–0.53(m,2H),0.48–0.30(m,2H).

Example 132: 4-amino-7-chloro-N-cyclopropyl-N- ((5-ethynylpyridin-2-yl) methyl) -1-methyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide

2d (34.4 mg,0.20 mmol) and 132a (58.1 mg,0.20 mmol) were dissolved in N, N-dimethylacetamide (2 ml) as described in WO 2022/115377A 1), N-diisopropylethylamine (0.07 ml,0.50 mmol), tripyrrolidinylphosphonium bromide hexafluorophosphate (139.8 mg,0.3 mmol) were added, the reaction mixture was stirred overnight at 25℃after the completion of the reaction, the reaction was quenched with water, extracted with ethyl acetate (10 ml. Times.3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and normal phase column chromatography (dichloromethane: methanol=50:1) gave compound 132 (5.2 mg), ESI-MS (m/z): 431.09 M+H [ 10ml ]:3 ] ] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ8.70(s,1H),8.33–8.29(m,2H),7.97(d,J＝7.6Hz,1H),7.64(s,1H),7.51(d,J＝7.6Hz,1H),7.28(s,2H),4.86(s,2H),4.45–4.43(m,4H),2.91–2.86(m,1H),0.66–0.35(m,4H).

Example 133: 4-amino-N- ((5-ethynyl-3-fluoropyridin-2-yl) methyl) -3, 7-dimethyl-N- (1-methyl-1H-pyrazol-4-yl) -1, 3-dihydrofuro [3,4-c ] quinoline-8-carboxamide

Compound 53d (46 mg,0.20 mmol) and 57a (51.6 mg,0.20 mmol) were dissolved in N, N-dimethylacetamide (2 ml), N-diisopropylethylamine (0.07 ml,0.50 mmol) was added, tripyrrolidinylphosphonium bromide hexafluorophosphate (139.8 mg,0.3 mmol) was stirred overnight at 25℃after the completion of the reaction, quenched with water, extracted with ethyl acetate (10 ml. Times.3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and normal phase column chromatography (dichloromethane: methanol=50:1) gave compound 133 (12.7 mg), ESI-MS (m/z): 471.13[ M+H ]] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ8.57(s,1H),8.05–7.92(m,1H),7.56–7.08(m,4H),6.48–6.43(m,2H),5.40–5.13(m,5H),4.57(s,1H),3.81and 3.56(s,3H),2.37(s,3H),1.41and 1.40(s,3H).

Example 135: 4-amino-7-fluoro-N- ((5- (3-hydroxy-3-methylbut-1-yn-1-yl) pyridin-2-yl) methyl) -N, 1-dimethyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide

Preparation of 1- (5-bromopyridin-2-yl) -N-methyl methylamine (135 a)

To a solution of 5-bromopyridine-formaldehyde (1 g,5.38 mmol) in dichloromethane/methanol (10/1, 10 mL) was added methylamine hydrochloride (1.8 g,26.88 mmol), N, N-diisopropylethylamine (4.9 mL,29.57 mmol), sodium triacetoxyborohydride (2.3 g,10.75 mmol), and the mixture was reacted overnight at 25 ℃. To the reaction solution was added water (30 mL), extracted with dichloromethane (20 mL x 3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the crude product 135a (400 mg) by normal phase silica gel column chromatography (methanol/dichloromethane=0:100% -50%: 50%). ESI-MS (m/z): 201.1[ M+H ] ] ⁺ .

Preparation of 4-amino-N- ((5-bromopyridin-2-yl) methyl) -7-fluoro-N, 1-dimethyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide (135 b)

To a solution of compound 135a (150 mg,0.75 mmol) in N, N-dimethylacetamide (5 mL) was added compound 17a (232.9 mg,0.90 mmol), 2- (7-azo)Benzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (370.4 mg,0.97 mmol) and N, N-diisopropylethylamine (0.37 mL,2.24 mmol) were reacted at 25℃for 2 hours. Water (20 mL) was added to the reaction solution, and the mixture was filtered, and the cake was washed with water, and dried, followed by normal phase silica gel column chromatography (dichloromethane/methanol=0:100% -15%: 85%) to give 135b (110 mg). ESI-MS (m/z): 443.1[ M+H ]] ⁺ .

Preparation of 4-amino-7-fluoro-N, 1-dimethyl-N- ((5- (3-methyl-3- ((trimethylsilyl) oxy) but-1-yn-1-yl) pyridin-2-yl) methyl) -1H-pyrazolo [4,3-c ] quinoline-8-carboxamide (135 c)

Compound 135b (50 mg,0.11 mmol), 3-methyl-3-trimethylsilyloxy-1-butyne (88.1 mg,0.56 mmol), cuprous iodide (8.4 mg,0.04 mmol), tetrakis (triphenylphosphine) palladium (25.2 mg,0.02 mmol), N, N-diisopropylethylamine (96. Mu.L, 0.55 mmol) were dissolved in N-methylpyrrolidone (5 mL), and the air was replaced with nitrogen 3 times, and reacted at 70℃for 3 hours under microwaves. The reaction solution was filtered through celite, water (20 mL) was added to the filtrate, extracted with ethyl acetate (20 ml×3), washed three times with saturated brine, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by normal phase silica gel column chromatography (dichloromethane: methanol=10:1) to give 135c (40 mg). ESI-MS (m/z): 519.2[ M+H ] ] ⁺ .

Preparation of 4-amino-7-fluoro-N- { [5- (3-hydroxy-3-methylbut-1-ynyl) pyridin-2-yl ] methyl } -1, N-dimethylpyrazolo [4,3-c ] quinoline-8-carboxamide (135)

To a solution of compound 135c (50 mg,0.11 mmol) in 1, 4-dioxane (5 mL) was added hydrochloric acid (23.85. Mu.L, 0.77 mmol), and the addition was completed for 10 minutes at 25 ℃. The reaction solution was concentrated, water (20 mL) was added, saturated sodium bicarbonate solution was adjusted to ph=8, filtered, and the cake was washed with water, dried, and subjected to reverse phase column chromatography (acetonitrile/0.05% aqueous formic acid=0:100% -50%: 50%) to give 135 (9.75 mg). ESI-MS (m/z): 447.4[ M+H ]] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ8.55–8.49(m,1H),8.26–8.08(m,2H),7.85–7.71(m,1H),7.38–7.13(m,3H),5.51(s,1H),4.80and 4.57(s,2H),4.35and 4.13(s,3H),2.99and 2.93(s,3H),1.46(s,3H),1.44(s,3H).

Example 136: 4-amino-N-ethyl-N- { [ 3-fluoro-5- (3-hydroxy-3-methylbut-1-ynyl) pyridin-2-yl ] methyl } -1, 7-dimethylpyrazolo [4,3-c ] quinoline-8-carboxamide

Preparation of N- ((5-bromo-3-fluoropyridin-2-yl) methyl) ethylamine (136 a) to a solution of the compound 5-bromo-3-fluoropyridin-2-carbaldehyde (280 mg,1.37 mmol) in dichloromethane (10 mL) was added compound ethylamine hydrochloride (559.3 mg,6.86 mmol), N, N-diisopropylethylamine (1.13 mL,6.85 mmol), sodium triacetoxyborohydride (866.8 mg,4.11 mmol), acetic acid (0.02 mL,0.27 mmol) and the addition was reacted overnight at 25 ℃. To the reaction solution was added water (20 mL), extracted with dichloromethane (20 mL x 3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give crude product, which was subjected to normal phase silica gel column chromatography (methanol/dichloromethane=1:20) to give 136a (150 mg). ESI-MS (m/z): 233.0[ M+H ] ] ⁺ .

Preparation of N- ((3-fluoro-5- (3-methyl-3- ((trimethylsilyl) oxy) but-1-yn-1-yl) pyridin-2-yl) methyl) ethanamine (136 b)

Compound 136a (150 mg,0.64 mmol), 3-methyl-3-trimethylsilyloxy-1-butyne (0.62 mL,3.22 mmol), cuprous iodide (24.4 mg,0.13 mmol), tetrakis (triphenylphosphine) palladium (74.0 mg,0.06 mmol), N, N-diisopropylethylamine (0.53 mL,3.20 mmol) were dissolved in N-methylpyrrolidone (5 mL), nitrogen was substituted for air 3 times, and reacted at 75℃for 3 hours under microwaves. The reaction solution was filtered through celite, water (20 mL) was added to the filtrate, extracted with ethyl acetate (20 ml×3), washed three times with saturated brine, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give crude product which was subjected to normal phase silica gel column chromatography (ethyl acetate/petroleum ether=1:2) to give 136b (130 mg). ESI-MS (m/z): 309.2[ M+H ]] ⁺ .

Preparation of 4-amino-N-ethyl-N- { [ 3-fluoro-5- (3-hydroxy-3-methylbut-1-ynyl) pyridin-2-yl ] methyl } -1, 7-dimethylpyrazolo [4,3-c ] quinoline-8-carboxamide (136)

To a solution of compound 136b (40 mg,0.13 mmol) in N, N-dimethylformamide (5 mL) was added compound 54a (26.7 mg,0.10 mmol), 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphateAcid ester (74.5 mg,0.20 mmol) and N, N-diisopropylethylamine (0.11 mL,0.65 mmol) were reacted overnight at 25 ℃. To the reaction solution was added water (20 mL), filtered, and the cake was washed with water, dried, and subjected to reverse phase column chromatography (acetonitrile/0.05% aqueous formic acid solution=0:100% -50%: 50%) to give 136 (12 mg). ESI-MS (m/z): 475.2[ M+H ] ] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ8.53–8.43(m,1H),8.25–8.18(m,1H),8.06–7.88(m,1H),7.87–7.66(m,1H),7.46–7.43(m,1H),7.04–6.97(m,2H),5.60(s,1H),4.91–4.60(m,2H),4.38and 4.16(s,3H),3.29–3.26(m,2H),2.37–2.32(m,3H),1.52–1.48(m,6H),1.17and 1.07(t,J＝7.2Hz,3H).

Example 138: 4-amino-N-cyclopropyl-N- ((4- (difluoromethoxy) -5-ethynylpyridin-2-yl) methyl) -1-methyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide

Preparation of methyl 4-hydroxypicolinate (138 b)

Compound 138a (5 g,35.95 mmol) was dissolved in methanol (100 mL), concentrated sulfuric acid (1.95 mL,35.95 mmol) was added dropwise, the reaction was allowed to react at 80 ℃ for 18 hours, after completion of the reaction, the reaction was cooled to room temperature, concentrated, saturated sodium bicarbonate solution was added to neutrality, ethyl acetate (100 ml×3) was added for extraction, dried over anhydrous sodium sulfate, concentrated, and normal phase column chromatography (petroleum ether: ethyl acetate=1:1) gave 138b (500 mg). ESI-MS (m/z): 154.04[ M+H ]] ⁺ .

Preparation of methyl 4-hydroxy-5-iodopicolinate (138 c)

Compound 138b (1000 mg,6.53 mmol) and potassium carbonate (992.9 mg,7.18 mmol) were dissolved in methanol (15 ml), iodine (1823.5 mg,7.18 mmol) was added under ice-bath, and the mixture was further transferred to 25℃for 3 hours, quenched by addition of 20% sodium bisulphite solution, acidified with 2M hydrochloric acid, and concentrated to give product 138c (920 mg). ESI-MS (m/z): 279.95[ M+H ]] ⁺ .

Preparation of methyl 4- (difluoromethoxy) -5-iodopicolinate (138 d)

Compound 138c (1.5 g,5.38 mmol) andpotassium carbonate (1.1 g,8.06 mmol) was dissolved in N, N-dimethylformamide (20 ml), sodium difluorochloroacetate (2.5 g,16.13 mmol) was added and the mixture was allowed to react at 90℃for 18 hours, after completion of the reaction, the reaction was quenched with water, extracted with ethyl acetate (50 ml. Times.3), dried over anhydrous sodium sulfate, concentrated, and purified by normal phase column chromatography (petroleum ether: ethyl acetate=1:1) to give 138d (800 mg). ESI-MS (m/z): 329.93[ M+H ] ] ⁺ .

Preparation of 4- (difluoromethoxy) -5-iodopyridine-carbaldehyde (138 e)

Compound 138d (600.0 mg,1.82 mmol) was dissolved in tetrahydrofuran (20 ml), nitrogen was replaced three times, nitrogen was purged down to-78 ℃, 1M diisobutylaluminum hydride solution of tetrahydrofuran was slowly added dropwise under stirring, the reaction was continued at-78 ℃ for 1 hour, the reaction was restored to room temperature after completion of the reaction, water was added to quench the reaction, sodium hydroxide solution was further added, stirring was 30 minutes, filtration, concentration was carried out to remove most of tetrahydrofuran, extraction was carried out with ethyl acetate (30 ml x 3), dried over anhydrous sodium sulfate, concentration was carried out, and normal phase column chromatography (petroleum ether: ethyl acetate=1:1) gave product 138e (365 mg). ESI-MS (m/z): 300.05[ M+H ]] ⁺ .

Preparation of N- ((4- (difluoromethoxy) -5-iodopyridin-2-yl) methyl) cyclopropylamine (138 f) Compound 138e (150 mg,0.50 mmol), cyclopropylamine (52.40. Mu.L, 0.75 mmol) was dissolved in dichloromethane (10 ml), acetic acid (28.71. Mu.L, 0.50 mmol), sodium triacetylborohydride (211.6 mg,1.00 mmol) was added, the reaction was completed at 25℃for 18 hours, saturated sodium bicarbonate solution was added to adjust pH to 8, dichloromethane (2X 25 ml) was extracted and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Positive Xiang Zhuzhu chromatography (dichloromethane: methanol=10:1) afforded product 138f (120 mg). ESI-MS (m/z): 340.94[ M+H ] ] ⁺ .

Preparation of 4-amino-N-cyclopropyl-N- ((4- (difluoromethoxy) -5-iodopyridin-2-yl) methyl) -1-methyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide (138 g)

Compound 138f (80 mg,0.24 mmol), 13a (57.0 mg,0.24 mmol) was dissolved in N, N-dimethylformamide (3 ml), and N, N-diisopropylethylamine (0.10 ml,0.59 mmol), 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (134.1 mg,0.35 mmol) was added) After the addition, the reaction was carried out at 25℃for 18 hours, after the completion of the reaction, the reaction was quenched with water, ethyl acetate (2X 25 ml) was extracted and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Positive Xiang Zhuzhu chromatography (dichloromethane: methanol=10:1) afforded 138g (87 mg) of product. ESI-MS (m/z): 565.19[ M+H ]] ⁺ 4-amino-N-cyclopropyl-N- ((4- (difluoromethoxy) -5- ((trimethylsilyl) ethynyl) pyridin-2-yl) methyl) -1-methyl-1H-pyrazolo [4,3-c]Preparation of quinoline-8-carboxamide (138 h) to a 10mL microwave tube was added 138g (50 mg,0.09 mmol), cuprous iodide (3.4 mg,0.02 mmol), tetrakis triphenylphosphine palladium (10.2 mg,0.01 mmol) and solvent N-methylpyrrolidone (2 mL), nitrogen sparge for 3 min, N-diisopropylethylamine (44.03. Mu.L, 0.27 mmol), trimethylethynyl silicon (26.1 mg,0.27 mmol). The reaction mixture was stirred at 70℃for 3 hours under microwave. After the completion of the reaction, the reaction was quenched with water, extracted three times with ethyl acetate (30 ml) and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Positive Xiang Zhuzhu chromatography (dichloromethane: methanol=10:1) afforded 138h (32 mg) of product. ESI-MS (m/z): 535.2[ M+H ] ] ⁺ .

Preparation of 4-amino-N-cyclopropyl-N- ((4- (difluoromethoxy) -5-ethynylpyridin-2-yl) methyl) -1-methyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide (138)

To a solution of compound 138h (30 mg,0.06 mmol) in tetrahydrofuran (3 mL) was added a solution of compound 1M tetrabutylammonium fluoride in tetrahydrofuran (120.00. Mu.L, 0.12 mmol), and the addition was completed for 30 minutes at 25 ℃. The reaction was quenched with water, extracted with ethyl acetate (2X 25 ml) and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. Reverse phase column chromatography (acetonitrile: 0.05% ammonium bicarbonate aqueous solution = 0:100% -35%: 65%) afforded product 138 (8.4 mg). ESI-MS (m/z): 463.12[ M+H ]] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ8.72(s,1H),8.42(s,1H),8.26(s,1H),7.70(dd,J＝8.4,1.6Hz,1H),7.59(d,J＝8.4,1H),7.58(t,J＝72.4,1H),7.28(s,1H),7.15(s,2H),4.83(s,2H),4.63(s,1H),4.37(s,3H),3.07–3.00(m,1H),0.60–0.39(m,4H).

Example 139: 4-amino-N-ethyl-N- ((5- (3-hydroxy-3-methylbut-1-yn-1-yl) -4-methylpyridin-2-yl) methyl) -1, 7-dimethyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide

Preparation of N- ((5-bromo-4-methylpyridin-2-yl) methyl) ethylamine (139 a)

Compound 71a (300 mg,1.50 mmol) was dissolved in dichloromethane (20 ml), N-diisopropylethylamine (2484.62. Mu.L, 15.00 mmol) was added, stirred at room temperature for 30 min, acetic acid (85.86. Mu.L, 1.50 mmol) and sodium triacetylborohydride (790.9 mg,3.75 mmol) were added, the reaction was completed at 25℃for 18 h, saturated sodium bicarbonate solution was added to adjust the pH to 8, dichloromethane (3X 50 ml) was extracted and the organic phase was combined, saturated brine was washed, dried over anhydrous sodium sulfate, filtered and concentrated. Positive Xiang Zhuzhu chromatography (dichloromethane: methanol=10:1) afforded product 139a (250 mg). ESI-MS (m/z): 229.11[ M+H ] ] ⁺ .

Preparation of 4-amino-N- ((5-bromo-4-methylpyridin-2-yl) methyl) -N-ethyl-1, 7-dimethyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide (139 b)

Compound 139a (50 mg,0.22 mmol), 54a (55.9 mg,0.22 mmol) was dissolved in N, N-dimethylformamide (3 ml), then N, N-diisopropylethylamine (90.38. Mu.L, 0.55 mmol), 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (124.5 mg,0.33 mmol) was added, the reaction was completed at 25℃for 18 hours, water-quenched reaction was added after the completion of the addition, ethyl acetate (2X 25 ml) was extracted and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Positive Xiang Zhuzhu chromatography (dichloromethane: methanol=10:1) afforded product 139b (80 mg). ESI-MS (m/z): 467.12[ M+H ]] ⁺ .

Preparation of 4-amino-N-ethyl-1, 7-dimethyl-N- ((4-methyl-5- (3-methyl-3- ((trimethylsilyl) oxy) but-1-yn-1-yl) pyridin-2-yl) methyl) -1H-pyrazolo [4,3-c ] quinoline-8-carboxamide (139 c)

In a 10mL microwave tube was added reactant 139b (80 mg,0.17 mmol), cuprous iodide (6.5 mg,0.03 mmol), and tetrakis triphenylphosphine palladium (19.6 mg)0.02 mmol) and solvent N-methylpyrrolidone (2 mL), nitrogen sparge for 3 min, N-diisopropylethylamine (84.48. Mu.L, 0.51 mmol), 3-methyl-3-trimethylsiloxy-1-butyne (66.9 mg,0.43 mmol) were added. The reaction mixture was stirred at 70℃for 3 hours under microwave. After the completion of the reaction, the reaction was quenched with water, extracted three times with ethyl acetate (30 ml) and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Preparation of the plate (dichloromethane: methanol=10:1) isolated product 139c (40 mg). ESI-MS (m/z): 543.20[ M+H ] ] ⁺ .

Preparation of 4-amino-N-ethyl-N- ((5- (3-hydroxy-3-methylbut-1-yn-1-yl) -4-methylpyridin-2-yl) methyl) -1, 7-dimethyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide (139)

To a solution of compound 139c (30 mg,0.06 mmol) in dichloromethane (3 mL) was added a solution of compound 4M in hydrogen chloride-dioxane (87.50. Mu.L, 0.35 mmol), and the mixture was reacted at 25℃for 10 minutes. Concentration at low temperature, reverse phase column chromatography (acetonitrile: 0.05% ammonium bicarbonate aqueous solution=0:100% -35%: 65%) afforded product 139 (25 mg). ESI-MS (m/z): 471.26[ M+H ]] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ8.46and 8.43(s,1H),8.22and 8.17(s,1H),8.03and 7.95(s,1H),7.46and 7.42(s,1H),7.36and 7.16(s,1H),7.00–6.97(m,2H),5.53and 5.52(s,1H),4.78and 4.42(s,2H),4.37and 4.10(s,3H),2.41–2.27(m,6H),1.50–1.49(m,6H),1.17and 1.01(t,J＝6.8Hz,3H).

Example 140: 4-amino-N-ethyl-7-fluoro-N- ((5- (3-hydroxy-3-methylbut-1-yn-1-yl) -4-methylpyridin-2-yl) methyl) -1-methyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide

Preparation of 4-amino-N- ((5-bromo-4-methylpyridin-2-yl) methyl) -N-ethyl-7-fluoro-1-methyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide (140 a)

Compound 139a (50 mg,0.22 mmol), 17a (57.2 mg,0.22 mmol) was dissolved in N, N-dimethylformamide (3 ml), followed by the addition of N, N-diisopropylethylamine (90.38. Mu.L, 0.55 mmol), 2- (7-azobenzo)Triazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (124.5 mg,0.33 mmol) was reacted at 25℃for 18 hours after the addition, quenched with water after the reaction, extracted with ethyl acetate (2X 25 ml) and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. Positive Xiang Zhuzhu chromatography (dichloromethane: methanol=10:1) afforded product 140a (100 mg). ESI-MS (m/z): 471.03[ M+H ] ] ⁺ 4-amino-N-ethyl-7-fluoro-1-methyl-N- ((4-methyl-5- (3-methyl-3- ((trimethylsilyl) oxy) but-1-yn-1-yl) pyridin-2-yl) methyl) -1H-pyrazolo [4,3-c]Preparation of quinoline-8-carboxamide (140 b) to a 10mL microwave tube was added reactant 140a (100 mg,0.21 mmol), cuprous iodide (8.1 mg,0.04 mmol), tetrakis triphenylphosphine palladium (24.5 mg,0.02 mmol) and solvent N-methylpyrrolidone (3 mL), nitrogen sparge for 3 min, N-diisopropylethylamine (105.44. Mu.L, 0.64 mmol), 3-methyl-3-trimethylsiloxy-1-butyne (82.9 mg,0.53 mmol). The reaction mixture was stirred at 70℃for 3 hours under microwave. After the completion of the reaction, the reaction was quenched with water, extracted three times with ethyl acetate (30 ml) and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Preparation of plates (dichloromethane: methanol=10:1) isolated product 140b (55 mg). ESI-MS (m/z): 547.30[ M+H ]] ⁺ .

Preparation of 4-amino-N-ethyl-7-fluoro-N- ((5- (3-hydroxy-3-methylbut-1-yn-1-yl) -4-methylpyridin-2-yl) methyl) -1-methyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide (140 b)

To a solution of compound 140b (30 mg,0.06 mmol) in dichloromethane (3 mL) was added a solution of compound 4M in hydrogen chloride-dioxane (112.50. Mu.L, 0.45 mmol), and the addition was completed for 10 minutes at 25 ℃. Concentration at low temperature, reverse phase column chromatography (acetonitrile: 0.05% ammonium bicarbonate aqueous solution = 0:100% -35%: 65%) afforded product 140 (27 mg). ESI-MS (m/z): 475.24[ M+H ] ] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ8.46and 8.43(s,1H),8.26–8.11(m,2H),7.38–7.18(m,4H),5.53and 5.51(s,1H),4.79and 4.52(s,2H),4.39and 4.15(s,3H),2.41and 2.27(s,3H),1.50–1.49(m,6H),1.14and 1.04(t,J＝6.8Hz,3H).

Example 141: 4-amino-N-ethyl-7-fluoro-N- ((5- (3-hydroxy-3-methylbut-1-yn-1-yl) pyridin-2-yl) methyl) -1-methyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide

Preparation of 4-amino-N- ((5-bromopyridin-2-yl) methyl) -N-ethyl-7-fluoro-1-methyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide (141 a)

To a solution of compound 91a (215 mg,1.0 mmol) in N, N-dimethylformamide (5 mL) were added compound 17a (260 mg,1.0 mmol), N-diisopropylethylamine (258 mg,2.0 mmol) and 2- (7-azobenzotriazole) -N, N' -tetramethylurea hexafluorophosphate (570 mg,1.5 mmol), and after the addition was completed, the reaction was completed, water (20 mL) was extracted with ethyl acetate (20 mL x 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was spun off to give compound 141a (284 mg) by column chromatography (methanol: dichloromethane=1:10). ESI-MS (m/z): 457.1[ M+H ]] ⁺ .

Preparation of 4-amino-N-ethyl-7-fluoro-1-methyl-N- ((5- (3-methyl-3- ((trimethylsilyl) oxy) but-1-yn-1-yl) pyridin-2-yl) methyl) -1H-pyrazolo [4,3-c ] quinoline-8-carboxamide (141 b)

To a solution of compound 141a (91 mg,0.2 mmol) in N-methylpyrrolidone (2 mL) under nitrogen was added successively (propynyloxy) trimethylsilane (62 mg,0.4 mmol), cuprous iodide (8 mg,0.04 mmol), N, N-diisopropylethylamine (52 mg,0.4 mmol) and tetrakis (triphenylphosphine) palladium (24 mg,0.02 mmol). After the addition, the reaction was completed for 3 hours at 70 ℃ with microwaves, water (10 mL) was added, extracted with ethyl acetate (10 ml×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was spun off to give compound 141b (52 mg) by column chromatography (methanol: dichloromethane=1:10). ESI-MS (m/z): 533.2[ M+H ] ] ⁺ .

Preparation of 4-amino-N-ethyl-7-fluoro-N- ((5- (3-hydroxy-3-methylbut-1-yn-1-yl) pyridin-2-yl) methyl) -1-methyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide (141)

To a solution of compound 141b (52 mg,0.1 mmol) in dichloromethane (2 mL) at 0deg.C was slowly addedAdding 1,4 dioxane solution (2 mL, 4M) of hydrochloric acid, reacting at room temperature for 30 min after the addition, carrying out sample feeding detection, adding saturated sodium carbonate solution after the reaction is finished, enabling the pH of the system to be about 8, extracting with ethyl acetate (10 mL x 3), combining organic phases, washing with saturated saline water, drying with anhydrous sodium sulfate, filtering, rotating out the solvent, and purifying by reversed phase chromatographic column chromatography (acetonitrile: 0.05% ammonium bicarbonate aqueous solution=0:100% -50%: 50%) to obtain compound 141 (28 mg). ESI-MS (m/z): 461.4[ M+H ]] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ8.59and 8.56(s,1H),8.29–8.14(m,2H),7.88and 7.78(d,J＝6.8Hz,1H),7.46–7.25(m,4H),5.56and 5.55(s,1H),4.85and 4.61(s,2H),4.39and 4.20(s,3H),3.61–3.35(m,2H),1.51–1.49(s,6H),1.17–1.06(m,3H).

Example 142: 4-amino-N-cyclopropyl-N- ((5-ethynylpyridin-2-yl) methyl) -7-fluoro-1-methyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide

Preparation of 4-amino-N-cyclopropyl-7-fluoro-1-methyl-N- ((5- ((trimethylsilyl) ethynyl) pyridin-2-yl) methyl) -1H-pyrazolo [4,3-c ] quinoline-8-carboxamide (142 a)

To a solution of compound 82a (85 mg,0.18 mmol) in N-methylpyrrolidone (2 mL) under nitrogen, ethynyl trimethylsilane (36 mg,0.36 mmol), cuprous iodide (8 mg,0.04 mmol), N-diisopropylethylamine (47 mg,0.36 mmol) and tetrakis (triphenylphosphine) palladium (23 mg,0.02 mmol) were added sequentially, the reaction was completed after the addition of Yu Weibo ℃ for 3 hours, water (20 mL) was added, extraction (20 mL x 3) with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was spun off to give compound 142a (48 mg) by column chromatography (methanol: dichloromethane=1:20). ESI-MS (m/z): 487.2[ M+H ] ] ⁺ .

Preparation of 4-amino-N-cyclopropyl-N- ((5-ethynylpyridin-2-yl) methyl) -7-fluoro-1-methyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide (142)

Compound 142a (48 mg,0.1 mmol) was added at room temperaturel) tetrahydrofuran (2 mL) was slowly added with tetrabutylammonium fluoride in tetrahydrofuran (0.2 mL,1 m), stirred for 15 min, water (10 mL) was added after the reaction was completed, extracted with ethyl acetate (10 mL x 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the solvent was spun off, and the column chromatography was reversed phase (acetonitrile: 0.05% ammonium bicarbonate aqueous solution = 0:100% -50%: 50%) purification gives compound 142 (16 mg). ESI-MS (m/z): 415.1[ M+H ]] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ8.70(d,J＝1.6Hz,1H),8.35–8.24(m,2H),7.97(s,J＝6.8Hz,1H),7.44(d,J＝6.8Hz,1H),7.33(d,J＝12.0Hz,1H),7.28(s,2H),4.86(s,2H),4.55–4.24(m,4H),2.93–2.88(m,1H),0.59–0.46(m,4H).

Example 143: 4-amino-N- ((5-ethynyl-3-fluoropyridin-2-yl) methyl) -7-fluoro-N- (1-methyl-1H-pyrazol-4-yl) -1, 3-dihydrofuran [3,4-c ] quinoline-8-carboxamide

To a solution of compound 53d (46 mg,0.2 mmol) in N, N-dimethylacetamide (3 mL) was added 21a (50 mg,0.2 mmol), triethylamine (71 mg,0.7 mmol) and tripyrrolidinylphosphonium bromide hexafluorophosphate (121 mg,0.26 mmol), and the addition was completed at room temperature for 4 hours. The reaction mixture was extracted with water (20 mL), ethyl acetate (20 ml×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was spun off and purified by reverse phase chromatography (acetonitrile: 0.05% ammonium bicarbonate aqueous solution=0:100% -50%: 50%) to give compound 143 (9 mg). ESI-MS (m/z): 461.0[ M+H ] ] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ8.56(s,1H),7.99–7.75(m,1H),7.60–7.44(m,2H),7.00–7.36(m,2H),6.79(s,2H),5.30(s,2H),5.13(s,2H),5.01–4.95(m,2H),4.58(s,1H),3.81and 3.58(s,3H).

Example 144: 4-amino-N- ((5-ethynyl-3-fluoropyridin-2-yl) methyl) -7-methyl-N- (1-methyl-1H-pyrazol-4-yl) -1, 3-dihydrofuran [3,4-c ] quinoline-8-carboxamide

To a solution of compound 53d (46 mg,0.2 mmol) in N, N-dimethylacetamide (3 mL) was added 59a (49 mg,0.2 mmol), triethylamine (71 mg,0.7 mmol) and tripyrrolidinylphosphonium bromide hexafluorophosphate (121 mg,0.26 mmol), and the addition was completed at room temperature for 4 hours. The reaction mixture was extracted with water (20 mL), ethyl acetate (20 ml×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was spun off and purified by reverse phase chromatography (acetonitrile: 0.05% ammonium bicarbonate aqueous solution=0:100% -50%: 50%) to give compound 144 (6 mg). ESI-MS (m/z): 457.1[ M+H ]] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ8.57(s,1H),7.96–7.76(m,1H),7.54–7.07(m,4H),6.53(s,2H),5.27(s,2H),5.13(s,2H),4.98(s,2H),4.58(s,1H),3.81and 3.55(s,3H),2.36(s,3H).

Example 145: 4-amino-N- ((5-ethynyl-4-methylpyridin-2-yl) methyl) -7-fluoro-N- (1-methyl-1H-pyrazol-4-yl) -1, 3-dihydrofuran [3,4-c ] quinoline-8-carboxamide

Preparation of 4-amino-7-fluoro-1, 3-dihydrofuran [3,4-c ] quinoline-8-carbonyl chloride hydrochloride (145 a) Compound 21a (100 mg,0.40 mmol) was dissolved in dichloromethane (5 ml), 4M hydrochloric acid-dioxane solution (250. Mu.L, 1 mmol) was added, stirred at room temperature for 30 minutes, concentrated and then dissolved in dichloromethane (5 ml), 1 drop of N, N-dimethylformamide and oxalyl chloride (102.26. Mu.L, 1.21 mmol) were added, stirred at room temperature for 1 hour, and after completion of the reaction, the product 145a (100 mg) was obtained by concentration.

Preparation of 4-amino-N- ((5-ethynyl-4-methylpyridin-2-yl) methyl) -7-fluoro-N- (1-methyl-1H-pyrazol-4-yl) -1, 3-dihydrofuran [3,4-c ] quinoline-8-carboxamide (145)

Compound 145a (50 mg,0.19 mmol) and 40d (42.4 mg,0.19 mmol) were dissolved in tetrahydrofuran (5 ml), N-diisopropylethylamine (77.63. Mu.L, 0.47 mmol) was added, and the addition was reacted at 25℃for 1 hour. The reaction solution was concentrated and subjected to reverse phase column chromatography (acetonitrile: 0.05% carbonic acid)Aqueous ammonium hydroxide=0:100% -35%: 65%) was isolated as compound 145 (10 mg). ESI-MS (m/z): 457.14[ M+H ]] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ8.55–8.50(m,1H),7.65–7.54(m,2H),7.35(s,1H),7.11–7.08(m,2H),6.78(s,2H),5.30–4.93(m,6H),4.59(s,1H),3.57(s,3H),2.43(s,3H).

Example 146: 4-amino-7-chloro-N- [ (5-ethynyl-3-fluoropyridin-2-yl) methyl ] -3-methyl-N- (1-methylpyrazol-4-yl) -1, 3-dihydrofuro [4,3-c ] quinoline-8-carboxamide

To a solution of compound 53d (69 mg,0.3 mmol) in N, N-dimethylacetamide (3 mL) was added 61a (84 mg,0.3 mmol), triethylamine (91 mg,0.9 mmol) and tripyrrolidinylphosphonium bromide hexafluorophosphate (210 mg,0.45 mmol), reacted at room temperature for 4 hours after the addition, water (20 mL) was added to extract with ethyl acetate (20 mL x 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the solvent was removed and purified by reverse phase chromatography (acetonitrile: 0.05% ammonium bicarbonate aqueous solution=0:100% -50%: 50%) to give compound 146 (21 mg). ESI-MS (m/z): 490.9[ M+H ] ] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ8.57and 8.55(s,1H),8.07–7.12(m,5H),6.77–6.71(m,2H),5.41–5.22(m,3H),5.12(s,2H),4.58and 4.57(s,1H),3.82and 3.57(s,3H),1.41–1.40(m,3H).

Example 147: 4-amino-N-cyclopropyl-7-fluoro-N- ((5- (3-hydroxy-3-methylbut-1-yn-1-yl) pyridin-2-yl) methyl) -1, 3-dihydrofuran [3,4-c ] quinoline-8-carboxamide

Preparation of 4-amino-N- ((5-bromopyridin-2-yl) methyl) -N-cyclopropyl-7-fluoro-1, 3-dihydrofuran [3,4-c ] quinoline-8-carboxamide (147 a)

21a (123.5 mg,0.5 mmol) and 2b (113 mg,0.5 mmol) were successively added to a 50mL eggplant-shaped bottle containing a stirrerN, N-diisopropylethylamine (129 mg,1.0 mmol) and N, N-dimethylacetamide (5 mL). To this was added urea N, N, N ', N' -tetramethyl-O- (7-azabenzotriazol-1-yl) hexafluorophosphate (284 mg,0.75 mmol). After the addition was completed, the reaction was stirred at room temperature overnight. The reaction mixture was poured into water, extracted with ethyl acetate (10 ml×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried, and the resulting residue was purified by silica gel column chromatography (ethyl acetate: methanol=15:1) to give 147a (60 mg). ESI-MS (m/z): 457.0[ M+H ]] ⁺ .

Preparation of 4-amino-N-cyclopropyl-7-fluoro-N- ((5- (3-methyl-3- ((trimethylsilyl) oxy) but-1-yn-1-yl) pyridin-2-yl) methyl) -1, 3-dihydrofurfuro [3,4-c ] quinoline-8-carboxamide (147 b)

Compound 147a (60 mg,0.13 mmol), 3-methyl-3-trimethylsilyloxy-1-butyne (41.0 mg,0.26 mmol), cuprous iodide (5.0 mg,0.03 mmol), tetrakis (triphenylphosphine) palladium (15.2 mg,0.01 mmol) and N, N-diisopropylethylamine (96. Mu.L, 0.66 mmol) were dissolved in N-methylpyrrolidone (2 mL), nitrogen was replaced 3 times, and reacted at 70℃for 3 hours under microwaves. The reaction solution was filtered through celite, water (20 mL) was added to the filtrate, extraction was performed with ethyl acetate (20 ml×3), saturated brine was washed three times, the organic phase was dried over anhydrous sodium sulfate, filtration was performed, and the filtrate was concentrated and then subjected to normal phase silica gel column chromatography (dichloromethane/methanol=0:100% -10%: 90%) to give compound 147b (40 mg). ESI-MS (m/z): 533.2[ M+H ] ] ⁺ .

Preparation of 4-amino-N-cyclopropyl-7-fluoro-N- ((5- (3-hydroxy-3-methylbut-1-yn-1-yl) pyridin-2-yl) methyl) -1, 3-dihydrofuro [3,4-c ] quinoline-8-carboxamide (147)

To a solution of compound 147b (40 mg,0.08 mmol) in 1, 4-dioxane (2 mL) was added hydrochloric acid (0.09 mL,0.38 mmol), and the addition was completed and reacted at 25℃for 10 minutes. The reaction solution was concentrated, water (20 mL) was added, ph=8 or so was adjusted with saturated sodium bicarbonate solution, and the mixture was filtered, and the cake was washed with water, dried and subjected to reverse phase column chromatography (acetonitrile/0.05% aqueous formic acid solution=0:100% -50%: 50%) to give compound 147 (28 mg). ESI-MS (m/z): 461.21[ M+H ]] ⁺ . ¹ H NMR(400MHz,DMSO-d6)δ8.59(s,1H),7.85(d,J＝8.4Hz,1H),7.63(d,J＝8.0Hz,1H),7.39(d,J＝8.0Hz,1H),7.31(d,J＝12.0Hz,1H),6.81(s,2H),5.56(s,1H),5.36(s,2H),5.02(s,2H),4.81(s,2H),2.86–2.80(m,1H),0.51–0.42(m,4H).

Example 148: 4-amino-N-ethyl-7-fluoro-N- { [ 3-fluoro-5- (3-hydroxy-3-methylbut-1-ynyl) pyridin-2-yl ] methyl } -1-methylpyrazolo [4,3-c ] quinoline-8-carboxamide

To a solution of compound 136b (40 mg,0.13 mmol) in N, N-dimethylformamide (3 mL) was added compound 17a (40.5 mg,0.16 mmol), 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (73.9 mg,0.19 mmol) and N, N-diisopropylethylamine (0.11 mL,0.65 mmol), and the addition was reacted at 25℃overnight. The reaction solution was concentrated and subjected to reverse phase column chromatography (acetonitrile/0.05% aqueous formic acid=0:100% -50%: 50%) to give compound 148 (13 mg). ESI-MS (m/z): 479.2[ M+H ] ] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ8.50–8.45(m,1H),8.26(d,J＝12.8Hz,1H),8.17–8.07(m,1H),7.83–7.68(m,1H),7.37–7.22(m,3H),5.60(s,1H),4.91and 4.69(s,2H),4.39and4.20(s,3H),3.60–3.44(m,2H),1.54–1.47(m,6H),1.18–1.10(m,3H).

Example 149: 4-amino-7-chloro-N-cyclopropyl-N- ((5- (3-hydroxy-3-methylbut-1-yn-1-yl) pyridin-2-yl) methyl) -1-methyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide

Preparation of 4-amino-N- ((5-bromopyridin-2-yl) methyl) -7-chloro-N-cyclopropyl-1-methyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide (149 a)

To a 50mL eggplant-shaped bottle containing a stirrer were added 132a (41.4 mg,0.15 mmol), 2b (34 mg,0.15 mmol), N-diisopropylethylamine (0.05 mL,0.37 mmol) and N, N-dimethylformamide (2 mL) in this order. To this was added urea N, N, N ', N' -tetramethyl-O- (7-azabenzotriazol-1-yl) hexafluorophosphate (85.73 mg,0.23 mmol). After the addition, the reaction solution was cooled to room temperatureStir overnight. The reaction mixture was poured into water, extracted three times with ethyl acetate, the organic phase was washed three times with saturated brine, the obtained organic phase was dried over anhydrous sodium sulfate, filtered, and dried by spin-drying, and the obtained residue was purified by silica gel column chromatography (ethyl acetate: methanol=15:1) to give 149a (45 mg). ESI-MS (m/z): 484.89[ M+H ]] ⁺ .

Preparation of 4-amino-7-chloro-N-cyclopropyl-1-methyl-N- ((5- (3-methyl-3- ((trimethylsilyl) oxy) but-1-yn-1-yl) pyridin-2-yl) methyl) -1H-pyrazolo [4,3-c ] quinoline-8-carboxamide (149 b)

Compound 149a (50 mg,0.10 mmol), 3-methyl-3-trimethylsilyloxy-1-butyne (32.2 mg,0.21 mmol), cuprous iodide (3.9 mg,0.02 mmol), tetrakis (triphenylphosphine) palladium (11.9 mg,0.01 mmol), N, N-diisopropylethylamine (0.07 mL,0.51 mmol) were dissolved in N-methylpyrrolidone (2 mL), nitrogen was substituted for air 3 times, and reacted at 70℃for 3 hours under microwaves. The reaction solution was filtered through celite, water (20 mL) was added to the filtrate, extraction was performed with ethyl acetate (20 ml×3), the saturated brine was washed three times, the organic phase was dried over anhydrous sodium sulfate, filtration was performed, and the filtrate was concentrated and then subjected to normal phase silica gel column chromatography (dichloromethane/methanol=0:100% -10%: 90%) to give 149b (40 mg). ESI-MS (m/z): 562.2[ M+H ] ] ⁺ .

Preparation of 4-amino-7-chloro-N-cyclopropyl-N- ((5- (3-hydroxy-3-methylbut-1-yn-1-yl) pyridin-2-yl) methyl) -1-methyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide (149)

To a solution of compound 149b (35 mg,0.06 mmol) in 1, 4-dioxane (2 mL) was added hydrochloric acid (0.08 mL,0.31 mmol), and the mixture was reacted at 25℃for 10 minutes. The reaction solution was concentrated, water (20 mL) was added, ph=8 was adjusted with saturated sodium bicarbonate solution, filtration was performed, the cake was washed with water, and the cake was dried and subjected to reverse phase column chromatography (acetonitrile/0.05% aqueous formic acid solution=0:100% -50%: 50%) to obtain compound 149 (24 mg). ESI-MS (m/z): 488.99[ M+H ]] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ8.59(s,1H),8.31–8.29(m,2H),7.86(d,J＝8.0Hz,1H),7.63(s,1H),7.47(d,J＝8.0Hz,1H),7.26(s,2H),5.57(s,1H),4.84(s,2H),4.43(s,3H),2.89–2.84(m,1H),1.51(s,6H),0.62–0.55(m,2H),0.43–0.36(m,2H).

Example 150: 4-amino-7-chloro-N-cyclopropyl-N- { [5- (3-hydroxy-3-methylbut-1-ynyl) pyridin-2-yl ] methyl } -1, 3-dihydrofuro [4,3-c ] quinoline-8-carboxamide

4-amino-N- ((5-bromopyridin-2-yl) methyl) -7-chloro-N-cyclopropyl-1, 3-dihydro-furfuryl [3,4-c ]]Preparation of quinoline-8-carboxamide (150 a) to a solution of compound 2b (113 mg,0.5 mmol) in N, N-dimethylformamide (5 mL) was added compound 96a (132 mg,0.5 mmol), N-diisopropylethylamine (129 mg,1 mmol) and 2- (7-azobenzotriazole) -N, N' -tetramethylurea hexafluorophosphate (284 mg,0.75 mmol), and after the addition was completed, the reaction was carried out at room temperature for 4 hours, water (20 mL) was added, extracted with ethyl acetate (20 ml×3), the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was spun off to give compound 150a (140 mg) by column chromatography (methanol: dichloromethane=1:10). ESI-MS (m/z): 474.9[ M+H ] ] ⁺ 4-amino-7-chloro-N-cyclopropyl-N- ((5- (3-methyl-3- ((trimethylsilyl) oxy) but-1-yn-1-yl) pyridin-2-yl) methyl) -1, 3-dihydrofuran [3,4-c]Preparation of quinoline-8-carboxamide (150 b) to a solution of compound 150a (140 mg,0.3 mmol) in N-methylpyrrolidone (2 mL) under nitrogen was added successively 3-methyl-3-trimethylsilyloxy-1-butyne (234 mg,1.5 mmol), cuprous iodide (12 mg,0.06 mmol), N, N-diisopropylethylamine (78 mg,0.6 mmol) and tetrakis (triphenylphosphine) palladium (34.7 mg,0.03 mmol). After the completion of the reaction at Yu Weibo ℃ for 3 hours, water (10 mL) was added, extraction was performed with ethyl acetate (10 ml×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by filtration, followed by column chromatography (methanol: dichloromethane=1:10) to give compound 150b (71 mg). ESI-MS (m/z): 549.0[ M+H ]] ⁺ .

Preparation of 4-amino-7-chloro-N-cyclopropyl-N- { [5- (3-hydroxy-3-methylbut-1-ynyl) pyridin-2-yl ] methyl } -1, 3-dihydrofuro [4,3-c ] quinoline-8-carboxamide (150)

To a solution of compound 150b (71 mg,0.13 mmol) in dichloromethane (2 mL) at 0deg.C was slowly added 1,4 dioxane solution (2 mL, 4M) of hydrochloric acid, the addition was completed in the roomAfter reaction at room temperature for 30 minutes, water (5 mL) was added thereto, a saturated sodium carbonate solution was added dropwise to adjust the pH of the system to about 8, extraction was performed with ethyl acetate (10 ml×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by filtration, followed by purification by reverse phase chromatography (acetonitrile: 0.05% ammonium bicarbonate aqueous solution=0:100% -40:60%) to give compound 150 (18 mg). ESI-MS (m/z): 476.9[ M+H ] ] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ8.59(d,J＝1.6Hz,1H),7.85(dd,J＝8.0,2.0Hz,1H),7.63(d,J＝6.8Hz,2H),7.44(d,J＝8.0Hz,1H),6.82(s,2H),5.54(s,1H),5.40–5.33(m,2H),5.05–5.00(m,2H),4.80(s,2H),2.84–2.76(m,1H),1.51(s,6H),0.60–0.31(m,4H).

Example 151: 4-amino-7-chloro-N-ethyl-N- ((5- (3-hydroxy-3-methylbut-1-yn-1-yl) pyridin-2-yl) methyl) -1-methyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide

Preparation of 4-amino-N- ((5-bromopyridin-2-yl) methyl) -7-chloro-N-ethyl-1-methyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide (151 a)

Compound 91a (50 mg,0.23 mmol), 132a (50 mg,0.18 mmol) was dissolved in N, N-dimethylformamide (3 ml), N, N-diisopropylethylamine (89.79. Mu.L, 0.54 mmol), 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (103.1 mg,0.27 mmol) was added thereto, the reaction was completed at 25℃for 18 hours, water was added to quench the reaction, ethyl acetate (2X 25 ml) was extracted and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Positive Xiang Zhuzhu chromatography (dichloromethane: methanol=10:1) afforded product 151a (80 mg). ESI-MS (m/z): 472.89[ M+H ]] ⁺ .

Preparation of 4-amino-7-chloro-N-ethyl-1-methyl-N- ((5- (3-methyl-3- ((trimethylsilyl) oxy) but-1-yn-1-yl) pyridin-2-yl) methyl) -1H-pyrazolo [4,3-c ] quinoline-8-carboxamide (151 b)

Into a 10mL microwave tube was added reactant 151a (80 mg,0.17 mmol), cuprous iodide (6.4 mg,0.03 mmol), and tetrad Triphenylphosphine palladium (19.5 mg,0.02 mmol) and solvent N-methylpyrrolidone (3 mL), nitrogen bubbling for 3 min, and N, N-diisopropylethylamine (83.90. Mu.L, 0.51 mmol), 3-methyl-3-trimethylsiloxy-1-butyne (132.0 mg,0.84 mmol) were added. The reaction solution was stirred at 70℃for 3 hours under microwave. After the completion of the reaction, the reaction was quenched with water, extracted three times with ethyl acetate (30 ml) and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Preparation of a plate (dichloromethane: methanol=10:1) isolation gives product 151b (50 mg). ESI-MS (m/z): 549.22[ M+H ]] ⁺ .

Preparation of 4-amino-7-chloro-N-ethyl-N- ((5- (3-hydroxy-3-methylbut-1-yn-1-yl) pyridin-2-yl) methyl) -1-methyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide (151)

To a solution of compound 151b (50 mg,0.09 mmol) in dichloromethane (3 mL) was added a solution of compound 4M in hydrogen chloride-dioxane (112.50. Mu.L, 0.45 mmol), and the addition was completed for 10 minutes at 25 ℃. Concentration at low temperature, reverse phase column chromatography (acetonitrile: 0.05% ammonium bicarbonate aqueous solution=0:100% -35%: 65%) afforded product 151 (23.4 mg). ESI-MS (m/z): 477.0[ M+H ]] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ8.56and 8.52(d,J＝2.0Hz,1H),8.28and 8.23(s,1H),8.18and 8.05(s,1H),7.86and 7.73(dd,J＝8.0,2.0Hz,1H),7.63and 7.58(s,1H),7.51–7.24(m,3H),5.53and 5.50(s,1H),5.09–4.43(m,2H),4.39and 4.18(s,3H),3.29–3.05(m,2H),1.49and 1.46(s,6H),1.16and 1.02(t,J＝6.8Hz,3H).

Example 152: 4-amino-7-chloro-N-ethyl-N- { [5- (3-hydroxy-3-methylbut-1-ynyl) pyridin-2-yl ] methyl } -1, 3-dihydrofuro [4,3-c ] quinoline-8-carboxamide

Preparation of 4-amino-N- ((5-bromopyridin-2-yl) methyl) -7-chloro-N-ethyl-1, 3-dihydrofuro [3,4-c ] quinoline-8-carboxamide (152 a)

To a solution of compound 91a (108 mg,0.5 mmol) in N, N-dimethylformamide (5 mL) were added compound 96a (132 mg,0.5 mmol), N, N-diisopropylethylamine (129 mg,1 mmol) and 2- (7-coupling)Azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (275 mg,0.75 mmol) was reacted at room temperature for 4 hours after the completion of the reaction, water (20 mL) was added, extracted with ethyl acetate (20 mL. Times.3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was spun off by column chromatography (methanol: dichloromethane = 1:10) to give compound 152a (138 mg). ESI-MS (m/z): 462.8[ M+H ]] ⁺ .

Preparation of 4-amino-7-chloro-N-ethyl-N- ((5- (3-methyl-3- ((trimethylsilyl) oxy) but-1-yn-1-yl) pyridin-2-yl) methyl) -1, 3-dihydrofurfuro [3,4-c ] quinoline-8-carboxamide (246 b)

To a solution of compound 152a (138 mg,0.3 mmol) in N-methylpyrrolidone (1 mL) under nitrogen was added successively 3-methyl-3-trimethylsiloxy-1-butyne (234 mg,1.5 mmol), cuprous iodide (12 mg,0.06 mmol), N, N-diisopropylethylamine (78 mg,0.6 mmol) and tetrakis (triphenylphosphine) palladium (34.7 mg,0.03 mmol). After the addition, the reaction was completed for 3 hours at 70 ℃ with microwaves, water (10 mL) was added, extracted with ethyl acetate (10 ml×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was spun off to give compound 152b (83 mg) by column chromatography (methanol: dichloromethane=1:10). ESI-MS (m/z): 537.1[ M+H ] ] ⁺ .

Preparation of 4-amino-7-chloro-N-ethyl-N- { [5- (3-hydroxy-3-methylbut-1-ynyl) pyridin-2-yl ] methyl } -1, 3-dihydrofuro [4,3-c ] quinoline-8-carboxamide (152)

To a solution of compound 152b (83 mg,0.15 mmol) in dichloromethane (2 mL) was slowly added 4M 1,4 dioxane solution (2 mL) of hydrochloric acid, reacted at room temperature for 30 minutes after the addition, and the sample was fed for detection, after the reaction was completed, water (5 mL) was added, saturated sodium carbonate solution was added dropwise to bring the pH of the system to about 8, extraction was performed with ethyl acetate (10 ml×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was spun off to obtain compound 152 (46 mg) by reverse phase chromatography (acetonitrile: 0.05% ammonium bicarbonate aqueous solution=0:100% -40%: 60%). ESI-MS (m/z): 465.0[ M+H ]] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ8.58and 8.52(d,J＝1.6Hz,1H),7.87and 7.74(dd,J＝8.0,2.4Hz,1H),7.65–7.20(m,1H),6.85and 6.80(s,2H),5.55and 5.54(s,1H),5.42–4.30(m,6H),3.22–3.01(m,2H),1.51and 1.49(s,6H),1.18and 1.00(t,J＝7.2Hz,3H).

Example 153: 4-amino-7-chloro-N- ((5- (3-hydroxy-3-methylbut-1-yn-1-yl) pyridin-2-yl) methyl) -N, 1-dimethyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide

Preparation of 4-amino-N- ((5-bromopyridin-2-yl) methyl) -7-chloro-N, 1-dimethyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide (153 a)

Compound 135a (50 mg,0.25 mmol), 132b (60 mg,0.22 mmol) was dissolved in N, N-dimethylformamide (3 ml), then N, N-diisopropylethylamine (107.75. Mu.L, 0.65 mmol), 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (123.7 mg,0.33 mmol) was added, the reaction was completed at 25℃for 18 hours, the reaction was quenched with water, ethyl acetate (2X 25 ml) was extracted and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Positive Xiang Zhuzhu chromatography (dichloromethane: methanol=10:1) afforded product 153a (52 mg). ESI-MS (m/z): 460.85[ M+H ] ] ⁺ .

Preparation of 4-amino-7-chloro-N, 1-dimethyl-N- ((5- (3-methyl-3- ((trimethylsilyl) oxy) but-1-yn-1-yl) pyridin-2-yl) methyl) -1H-pyrazolo [4,3-c ] quinoline-8-carboxamide (153 b)

To a 10mL microwave tube was added reactant 153a (50 mg,0.11 mmol), cuprous iodide (4.1 mg,0.02 mmol), tetrakis triphenylphosphine palladium (12.6 mg,0.01 mmol) and solvent N-methylpyrrolidone (2 mL), nitrogen sparge for 3 minutes, and N, N-diisopropylethylamine (54.05. Mu.L, 0.33 mmol), 3-methyl-3-trimethylsiloxy-1-butyne (85.0 mg,0.54 mmol). The reaction solution was stirred at 70℃for 3 hours under microwave. After the completion of the reaction, the reaction was quenched with water, extracted three times with ethyl acetate (30 ml) and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Preparation of a plate (dichloromethane: methanol=10:1) isolation gives product 153b (30 mg). ESI-MS (m/z): 535.16[ M+H ]] ⁺ .

Preparation of 4-amino-7-chloro-N- ((5- (3-hydroxy-3-methylbut-1-yn-1-yl) pyridin-2-yl) methyl) -N, 1-dimethyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxamide (153)

To a solution of compound 153b (30 mg,0.06 mmol) in dichloromethane (3 mL) was added a solution of compound 4M in hydrogen chloride-dioxane (75.0. Mu.L, 0.30 mmol), and the mixture was reacted at 25℃for 10 minutes. Concentration at low temperature, reverse phase column chromatography (acetonitrile: 0.05% ammonium bicarbonate aqueous solution = 0:100% -35%: 65%) afforded product 153 (16.8 mg). ESI-MS (m/z): 463.0[ M+H ] ] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ8.57and 8.56(d,J＝2.0Hz,1H),8.27and 8.23(s,1H),8.17and 8.10(s,1H),7.87and 7.75(dd,J＝8.0,2.0Hz,1H),7.62and 7.58(s,1H),7.48–7.23(m,3H),5.53and 5.51(s,1H),4.83and 4.52(s,2H),4.39and 4.18(s,3H),3.05and 2.88(s,3H),1.49and 1.47(s,6H).

Reference example 1:

the preparation process is referred to WO2022115377A1.

Reference example 2:

the preparation process is referred to WO2022115377A1.

Reference example 3:

the preparation process is referred to WO2022115377A1.

AM-9747：

The preparation process is referred to WO2021163344A1.

Biological evaluation

Test example 1 enzymatic assay evaluation

By measuring IC ₅₀ The compounds were evaluated for their inhibitory activity on human PRMT 5. Compounds were subjected to 4 Xgradient dilutions (starting concentration of 20. Mu.M, 4 Xdilutions, total of 8 concentration points) using a BioTek Precision automatic pipetting system using PRMT5 TR-FRET Assay Kit (BPS bioscience Catalog # 52171), and the test compounds were incubated in a 10. Mu.L reaction system with recombinant human PRMT5/MEP50 protein (BPS bioscience Catalog # 51048), 3. Mu. M S-adenomethionine (BPS bioscience Catalog #52120), 1 Xhistone H4 polypeptide (BPS bioscience Catalog # 52171) and 1. Mu.M MTA (Sigma catalyst#D 5011) at a final concentration of 5 ng/. Mu.L. After 120 minutes of incubation at 25 ℃, 10 μl of detection reagent (BPS bioscience Catalog # 52171), eu-labeled antibody diluted with detection buffer and dye-labeled antibody, was added, incubated for 60 minutes in a thermostatted incubator (25 ℃) and then the fluorescent signals of the reaction system at 620nm and 665nm were read by Tecan Spark using time-resolved fluorescence mode to determine the fluorescent (TR-FRET) signal by time-resolved fluorescence and according to the formula TR-fret= (Em 665nm/Em620 nm) as follows:

Inhibition ratio% = {1- [ (maximum fluorescence group fluorescence ratio-compound group fluorescence ratio)/(maximum fluorescence group fluorescence ratio-minimum fluorescence group fluorescence ratio) ] } 100%

Minimum fluorescence group fluorescence ratio: the control group was not added with enzymes and compounds, others were identical to the compound group;

maximum fluorescence ratio of fluorescence group: the control group had no compound added, others were identical to the compound group;

analysis of IC using GraphPad Prism 8.0 ₅₀ Data. Nonlinear regression analysis was used (y=bottom+ (Top-Bottom)/(1+10 ((log ic) ₅₀ -X) HillSlope) to fit an sigmoidal response (variable slope) curve, the compound activity data of example 1 are shown in table 1. Wherein Y is the inhibition rate, X is the compound concentration logarithmic value, top is the maximum response (inhibition rate at maximum compound concentration), bottom is the baseline response (inhibition rate at 0 compound concentration), hill SThe slope refers to IC ₅₀ Slope of curve, IC ₅₀ The concentration of the compound at half inhibition.

TABLE 1

Numbering of compounds	IC ₅₀ (nM)
		Compound 1	23

Conclusion: the results show that the compound has strong inhibition activity on human PRMT5 enzyme.

Test example 2 proliferation inhibitory Activity of the Compound of the present invention against human colon cancer cells

1. Construction of MTAP ^-/- HCT-116 cell line

Adopts gene editing tool CRISPR/Cas9 and sgRNA to co-transfect colon cancer cell strain HCT-116 (Nanjac Bai), and obtains MTAP with inactivated MTAP double alleles by detection methods such as Western Blotting, sanger sequencing and the like ^-/- HCT-116 cell line. MTAP ^-/- The HCT-116 cell line is used for compound selective screening evaluation based on MTAP deletion and PRMT5 synergistic mechanism, and comprises a symmetrical dimethyl arginine (SDMA) level test, a cell proliferation test and the like.

2. Cell proliferation

MTAP was cultured with complete medium McCoy's 5A (Gibco, 16600082)/10% FBS (Gibco, 10099141C)/1%p/s (Gibco, 15140122) ^-/- HCT-116 and wild-type HCT-116 cell lines, evaluation of Compound vs. MTAP ^-/- Inhibition-enhancing effect of HCT-116 cell proliferation selectivity. Day 0, 100 MTAPs per well were added to 96-well cell culture plates (Corning, 3599) ^-/- HCT-116 cells or wild type HCT-116 cells, placed at 37℃in 5% CO ₂ Culturing in an incubator. Compounds were subjected to 3 Xgradient dilutions (initial concentration 20. Mu.M, 3 Xdilution for a total of 8 concentration points) with DMSO (Sigma, D5879). Day 1, compound was diluted to multiple concentration points and cells were treated separately at 37 ℃, 5% co ₂ Culturing in incubator for 10 days; day 11, 20 μl MTS (CellTiter) was added per well A _Queous One Solution Cell Proliferation Assay) (Promega, G3581), at 37℃in 5% CO ₂ After 2hr further incubation in the incubator, the incubator was read by Tecan Spark (od=490 nM), after which data analysis software GraphPad Prism 8 was used to apply the equation "log (inhibitor) vs. normalized response-variable slope" (equation y=bottom+ (Top-Bottom)/(1+10++logic ( ₅₀ -X) ×hillslope)) to obtain IC of the compound by data analysis ₅₀ Values. Wherein Y is the inhibition ratio, X is the compound concentration logarithmic value, top is the maximum response (inhibition ratio at maximum compound concentration), bottom is the baseline response (inhibition ratio at 0 compound concentration), hill Slope is the IC ₅₀ Slope of curve, IC ₅₀ The concentration of the compound at half inhibition.

TABLE 2IC ₅₀ (μM)

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Conclusion: the results show that in each example of the present invention, the compounds 1 to 153 have strong proliferation inhibition activity on colon cancer cells deleted by human MTAP, which is less than or close to 0.1uM, and the compounds 1 to 153 have excellent inhibition selectivity on colon cancer cells deleted by human MTAP, which is more than 10 times, wherein the selectivity of the compounds 14 to 18, 26 to 28, 30 to 31, 33, 37 to 43, 48, 53, 55 to 56, 58, 60, 65, 68 to 71, 73, 75, 79, 81 to 82, 86 to 88, 90 to 92, 114 to 119, 136, 139, etc. is about 100 times or more.

Test example 3 human liver microsome stability experiment

Experimental materials: human liver microsomes (purchased from bisivt) were used for the experiment;

and (3) preparation of a reagent:

PBS：0.1M KH ₂ PO ₄ and K ₂ HPO ₄ Buffer, pH 7.4.

MgCl ₂ : weighing a certain amount of MgCl ₂ Preparation of 16mM MgCl with PBS ₂ A solution.

NADPH (Chinese name reduced nicotinamide adenine dinucleotide phosphate, available from sigma, cat# 481973-500 mg): an amount of NADPH was weighed out with 16mM MgCl ₂ The solution was formulated to 4mM NADPH, with a final incubation concentration of 1mM.

A compound: test compounds and positive compounds were formulated to 4 μm with PBS and the final incubation concentration was 1 μm.

Liver microsomes (purchased from BIOIVT, cat# X008070): the liver microsomes were diluted to 1mg/mL with PBS and the final incubation concentration was 0.5mg/mL.

The experimental steps are as follows:

adding the prepared compound to be tested or positive compound into a test tube, then adding the prepared NADPH, and uniformly mixing. Pre-incubating in a constant temperature oven at 37 ℃ and 220rpm for 5min, adding the prepared liver microsomes to initiate reaction, and repeating the pore operation. At 0min, 5min, 15min, 30min, 60min, adding a certain volume of ice acetonitrile solution containing internal standard into the corresponding tube to precipitate protein, shaking and vortex for 5min, centrifuging at 4000rpm for 10min, and collecting supernatant in 96-well plate. Put into LC-MS/MS for analysis. The concentration (peak area ratio) of the compound of the example was determined by LC-MS/MS, and the rate constant was obtained by plotting "Ln (residual amount of compound%)" versus "incubation time" in Excel, so as to calculate the half-life and intrinsic clearance of the drug, and provide a basis for the prediction of clearance in vivo.

Data analysis:

CL _int ＝(0.693/t _1/2 microsome) × [ hatching fluid volume (m L)/microsome protein mass (mg)]X [ microsomal protein mass (mg)/liver mass (g)]X liver mass (g)/body weight (kg)] ^[1]

CL _H ＝CL _int ×f _u ×Q _h /(CL _int ×f _u +Q _h )

In the method, in the process of the invention,

CL _int intrinsic clearance (ml/min/kg)

CL _H Liver clearance rate (ml/min/kg)

f _u -plasma protein binding ratio of 1

Q _h Liver blood flow

TABLE 3 Table 3

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Conclusion: test results show that in each embodiment of the invention, the compounds 1 to 153 have good human liver microsome stability and T _1/2 And the time is between 29 and 140 minutes, and compared with the existing compound AM-9747 and reference examples 1 and 2, the method is obviously prolonged.

Experimental example 4 mouse PK experimental materials: the experimental animals were healthy adult BALB/c female mice (supplied by the company of the biological technologies, inc. Of verruca Fukang, beijing);

the test process comprises the following steps:

mode of administration and sample collection for mice: BALB/c female mice were orally administered by gastric lavage (10 mg/kg, vehicle: 0.5% MC/0.2% Tween 80), and blood plasma was collected by centrifugation at 4000rpm for 10min at 60. Mu.L of whole blood of ocular fundus venous plexus at different time points of the mice, respectively, 0.25,0.5,1,2,4,6,8, 24 hours after administration.

Sample analysis:

a10. Mu.L sample of mouse plasma was taken, 190. Mu.L of acetonitrile solution containing an internal standard was added to precipitate the protein, vortexed for 10min, followed by centrifugation at 4000rpm for 10min, and the supernatant was taken in a 96-well plate. Put into LC-MS/MS for analysis. The LC-MS/MS method is used for measuring the drug concentration in plasma at different moments after the compound of the example is administrated by the stomach of the mice, and calculating relevant pharmacokinetic parameters, researching the pharmacokinetic behavior of the compound in the mice and evaluating the pharmacokinetic characteristics of the compound.

TABLE 4 Table 4

Conclusion: test results show that in each embodiment of the invention, the compounds 1-153 have good drug generation property and AUC _INF And the total molecular weight is 4000-25000, and is obviously better than the prior compounds such as AM-9747, reference example 1, reference example 2, reference example 3 and the like.

Industrial applicability

The compound has excellent PRMT5 inhibition activity, has strong proliferation inhibition activity on colon cancer cells deleted by human MTAP, has better inhibition selectivity on colon cancer cells deleted by human MTAP compared with colon cancer cells of MTAP Wild Type (WT), and can be used as a medicament for treating or preventing diseases related to the effect. Furthermore, the compound provided by the invention shows excellent drug substitution property, patentability, AUC and C in liver microsome stability test and mouse PK drug substitution test _max The equivalent drug level data are significantly better than those of the existing compounds such as AM-9747, reference example 1, reference example 2, reference example 3, and the like.

Reference to the literature ^[1] ：Davies B,Morris T.Physiological parameters in laboratory animals and humans.Pharm Res.1993；10:1093-5.

The foregoing is merely a preferred embodiment of the present invention and it should be noted that modifications and adaptations to those skilled in the art may be made without departing from the principles of the present invention, which are intended to be comprehended within the scope of the present invention.

Claims

1. A compound of formula (I), or a tautomeric form thereof, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof:

wherein,selected from single bond or double bond;

W is selected from CR ⁷ Or N;

R ² selected from H, C ₁ -C ₃ Alkyl, C ₃ -C ₆ Cycloalkyl;

preferably, R ² Selected from H or methyl;

preferably, R ² Is H;

Wherein,

each R _s Each independently selected fromHalogen, cyano, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₆ Cycloalkyl- (C) ₁ -C ₆ Alkyl group _r -、C ₃ -C ₆ Cycloalkyl- (C) ₁ -C ₆ Alkyl group _r -O-, 4-8 membered heterocyclyl- (C) ₁ -C ₆ Alkyl group _r -, 4-8 membered heterocyclyl- (C) ₁ -C ₆ Alkyl group _r -O-, 5-6 membered heterocyclenyl, 5-8 membered heteroaryl, said 4-8 membered heterocyclyl, 5-8 membered heterocyclenyl, 5-8 membered heteroaryl each containing 1-4 heteroatoms selected from N, O, S and the ring atoms of said heterocyclyl may optionally be oxo; the C is ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₆ Cycloalkyl, 4-8 membered heterocyclyl, 5-8 membered heterocyclenyl, 5-8 membered heteroaryl, each optionally substituted with one or more groups selected from halogen, cyano, hydroxy, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Haloalkoxy compoundsRadical, C ₁ -C ₆ alkyl-C (O) -, C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Alkoxy, C ₁ -C ₆ Alkoxy C ₁ -C ₆ Substituents for alkyl, -NR 'R ", wherein R' and R" are each independently selected from H, C ₁ -C ₆ Alkyl, or R 'and R' together with the nitrogen atom to which they are attached form a 4-8 membered heterocyclyl containing 1-4 heteroatoms selected from N, O, S and the ring atoms of the heterocyclyl may optionally be oxo;

each R _l Each independently selected from halogen, hydroxy, cyano, C optionally substituted with one or more substituents selected from halogen, cyano, hydroxy ₁ -C ₃ Alkyl, optionally substituted with one or more groups selected from halogen, cyano, hydroxy, -NR' R ", C ₁ -C ₃ C substituted by substituents of alkoxy ₁ -C ₃ An alkoxy group; wherein R 'and R' are each independently selected from H, methyl, ethyl, propyl, isopropyl, or R 'and R' together with the nitrogen atom to which they are attached form a 4-8 membered heterocyclic group, said 4-8 membered heterocyclic group containing 1-4 heteroatoms selected from N, O, S and the ring atoms of the heterocyclyl group may optionally be oxo-substituted;

2. A compound of formula (I), or a tautomeric form thereof, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof:

wherein,selected from single bond or double bond;

W is selected from CR ⁷ Or N;

R ² selected from H, C ₁ -C ₃ Alkyl, C ₃ -C ₆ Cycloalkyl;

preferably, R ² Selected from H or methyl;

preferably, R ² Is H;

R ³ selected from the following groups:a 5-10 membered heterocyclic group, a 9-10 membered heteroaryl group, wherein E is a 4-6 membered heterocyclic group, A and B are each independently selected from CH or N; the heterocyclyl and heteroaryl each contain 1-4 heteroatoms selected from O, N or S and the ring atoms of the heterocyclyl may optionally be oxo; the 5-10 membered heterocyclyl, 9-10 membered heteroaryl are each optionally substituted with one or more R _s Substituted and when R ³ Is->When it has at least one substituent R _s ；

Wherein,

R ¹³ Selected from C ₁ -C ₆ Alkyl, C optionally substituted with one or more groups selected from cyano, halogen, hydroxy, optionally substituted with one or more groups selected from halogen, cyano, hydroxy ₁ -C ₆ Alkoxy, optionally oneOr a plurality of halogen-, cyano-, hydroxy-substituted C ₃ -C ₆ A cycloalkoxy group optionally substituted with one or more halogen-, cyano-, hydroxy-substituted substituents of a 4-7 membered heterocycloalkoxy group;

each R _s Each independently selected fromHalogen, cyano, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₆ Cycloalkyl- (C) ₁ -C ₆ Alkyl group _r -、C ₃ -C ₆ Cycloalkyl- (C) ₁ -C ₆ Alkyl group _r -O-, 4-8 membered heterocyclyl- (C) ₁ -C ₆ Alkyl group _r -, 4-8 membered heterocyclyl- (C) ₁ -C ₆ Alkyl group _r -O-, 5-6 membered heterocyclenyl, 5-8 membered heteroaryl, said 4-8 membered heterocyclyl, 5-8 membered heterocyclenyl, 5-8 membered heteroaryl each containing 1-4 heteroatoms selected from N, O, S and the ring atoms of said heterocyclyl may optionally be oxo; the C is ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₆ Cycloalkyl, 4-8 membered heterocyclyl, 5-8 membered heterocyclenyl, 5-8 membered heteroaryl, each optionally substituted with one or more groups selected from halogen, cyano, hydroxy, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Haloalkoxy, C ₁ -C ₆ alkyl-C (O) -, C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Alkoxy, C ₁ -C ₆ Alkoxy C ₁ -C ₆ Substituents for alkyl, -NR 'R ", wherein R' and R" are each independently selected from H, C ₁ -C ₆ Alkyl, or R 'and R' together with the nitrogen atom to which they are attached form a 4-8 membered heterocyclic group containing 1-4 members selected from N, O,S and the ring atoms of the heterocyclic group may optionally be oxo;

each R _m Each independently selected from hydroxy, cyano, halogen, -NR' R ", optionally substituted with 1, 2, 3 or 4 halogen, hydroxy, cyano, C ₁ -C ₃ Alkoxy substituted C ₁ -C ₃ An alkoxy group; wherein R 'and R' are each independently selected from H, methyl, ethyl, propyl, isopropyl, or R 'and R' together with the nitrogen atom to which they are attached form a 4-8 membered heterocyclic ringA group, the 4-8 membered heterocyclyl containing 1-4 heteroatoms selected from N, O, S and the ring atoms of the heterocyclyl may optionally be oxo;

3. A compound of formula (I), or a tautomeric form thereof, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof:

wherein,selected from single bond or double bond;

W is selected from CR ⁷ Or N;

R ⁴ ，R ⁵ ，R ⁶ ，R ⁷ independently selected from the group consisting of H,halogen, cyano, C ₁ -C ₃ Alkyl, C ₃ -C ₆ Cycloalkyl;

R ² selected from H, C ₁ -C ₃ Alkyl, C ₃ -C ₆ Cycloalkyl;

preferably, R ² Selected from H or methyl;

preferably, R ² Is H;

Wherein,

each R _j Each independently selected from C optionally substituted with one or more halogens ₁ -C ₃ Alkyl, hydroxy, halogen, cyano, or optionally substituted with one or more halogenC of (2) ₁ -C ₃ An alkoxy group;

Each R _n Each independently selected from C ₁ -C ₆ Alkyl, C ₃ -C ₆ Cycloalkyl; the C is ₁ -C ₆ Alkyl, C ₃ -C ₆ Cycloalkyl groups are each optionally substituted with one or more groups selected from halogen, hydroxy, cyano, C ₃ -C ₆ Cycloalkyl radicals、C ₁ -C ₃ Substitution of the substituent of the alkoxy group;

4. The compound of any one of claims 1-3, or a tautomeric form thereof, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, wherein:

R ¹ selected from C ₁ -C ₄ Alkyl, C ₃ -C ₅ Alkyl, C ₄ -C ₆ Alkyl, C ₃ -C ₆ Monocyclic cycloalkyl- (C) ₁ -C ₄ Alkyl group _m -、C ₄ -C ₅ Monocyclic cycloalkyl- (C) ₁ -C ₄ Alkyl group _m -、C ₅ -C ₆ Monocyclic cycloalkyl- (C) ₁ -C ₄ Alkyl group _m -、C ₅ -C ₇ Bicyclic cycloalkyl- (C) ₁ -C ₄ Alkyl group _m -、C ₉ -C ₁₀ Bicyclic cycloalkyl- (C) ₁ -C ₄ Alkyl group _m -, 5-6 membered monocyclic heterocyclyl- (C) ₁ -C ₄ Alkyl group _m -, 9-10 membered bicyclic heterocyclyl- (C) ₁ -C ₄ Alkyl group _m -, 5-6 membered monocyclic heteroaryl- (C) ₁ -C ₄ Alkyl group _n -, 9-10 membered bicyclic heteroaryl- (C) ₁ -C ₄ Alkyl group _n -, 5-to 10-membered aryl- (C) ₁ -C ₄ Alkyl group _p -; n=0 or 1, m=0 or 1, p=0 or 1; the heterocyclic group and the heteroaryl group each contain 1 to 4 heterocyclic atoms selected from O, N or S and the heterocyclic groupOptionally oxo may be present on the ring atoms of (2); preferably, the heterocyclyl and heteroaryl each contain 1 to 3 heteroatoms selected from O or N; wherein the C ₁ -C ₄ Alkyl, C ₃ -C ₅ Alkyl, C ₄ -C ₆ Alkyl groups are each optionally substituted with one or more R _i Substitution; the C is ₃ -C ₆ Monocyclic cycloalkyl, C ₄ -C ₅ Monocyclic cycloalkyl, C ₅ -C ₆ Monocyclic cycloalkyl, C ₅ -C ₇ Bicyclic cycloalkyl, C ₉ -C ₁₀ Bicyclic cycloalkyl radicals each optionally being substituted with one or more R _j Substitution; the 5-6 membered monocyclic heterocyclyl, 9-10 membered bicyclic heterocyclyl are each optionally substituted with one or more R _k Substitution; the 5-6 membered monocyclic heteroaryl, 9-10 membered bicyclic heteroaryl, 5-10 membered aryl are each optionally substituted with one or more R _l Substitution;

preferably, R ¹ Selected from C ₁ -C ₆ Alkyl, C ₃ -C ₁₀ Cycloalkyl- (C) ₁ -C ₆ Alkyl group _m -, 4-10 membered heterocyclyl- (C) ₁ -C ₆ Alkyl group _m -, 5-to 10-membered heteroaryl- (C) ₁ -C ₆ Alkyl group _n -, 5-to 10-membered aryl- (C) ₁ -C ₆ Alkyl group _p -; n=0 or 1, m=0 or 1, p=0 or 1; the C is ₁ -C ₆ Alkyl is selected from methyl or methylene, ethyl or ethylene, propyl or propylene, isopropyl or isopropylene, isobutyl or isobutylene, sec-butyl or sec-butyl respectively, each of which is optionally substituted with 1, 2 or 3R _i Substitution; the C is ₃ -C ₁₀ Cycloalkyl is selected fromCyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, each optionally substituted with 1, 2 or 3R _j Substitution; said 5-10 membered heterocyclic group is selected from +.>Each of which is optionally substituted with 1, 2 or 3R _k Substitution; the 5-10 membered heteroaryl is selected from the group consisting of pyridinyl,Pyrimidinyl, pyridazinyl, pyrazinyl, </i >>Each of which is optionally substituted with 1, 2 or 3R _l Substitution; the 5-10 membered aryl is selected from phenyl, naphthyl, each of which is optionally substituted with 1, 2 or 3R _l Substitution;

preferably, each R _i Each independently selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, F, cl, br, methoxy, ethoxy, propoxy, isopropoxy, cyano;

preferably, each R _i Each independently selected from methyl, ethyl, cyclopropyl, methoxy, cyano;

preferably, each R _j Each independently selected from methyl, ethyl, propyl, isopropyl, hydroxy, F, cl, br, cyano, -OCH ₂ F、-OCHF ₂ 、-OCF ₃ 、-OCH ₂ CH ₂ F、-OCH ₂ CHF ₂ 、-OCH ₂ CF ₃ Methoxy, ethoxy, propoxy, isopropoxy;

preferably, each R _j Each independently selected from methyl, hydroxy, cyano, -OCHF ₂ ；

Preferably, each R _j Each independently selected from methyl, ethyl, propyl, isopropyl, hydroxy, F, cl, br, cyano, -OCH ₂ F、-OCHF ₂ 、-OCF ₃ 、-OCH ₂ CH ₂ F、-OCH ₂ CHF ₂ 、-OCH ₂ CF ₃ 、-CH ₂ F、-CHF ₂ 、-CF ₃ 、-CH ₂ CH ₂ F、-CH ₂ CHF ₂ 、-CH ₂ CF ₃ Methoxy, ethoxy, propoxy, isopropoxy;

preferably, each R _j Each independently selected from methyl, hydroxy, cyano, -OCHF ₂ 、-CF ₃ ；

Preferably, each R _k Each independently selected from hydroxy, halogen, cyano, C optionally substituted with 1, 2 or 3F ₁ -C ₃ An alkoxy group;

preferably, each R _k Each independently selected from methoxy, ethoxy, propoxy, isopropoxy, F, cl, br;

preferably, each R _k Each independently selected from methoxy, F;

preferably, each R _l Each independently selected from F, cl, br, hydroxy, cyano, C optionally substituted with 1, 2 or 3 substituents selected from F, cl, cyano, hydroxy ₁ -C ₃ Alkyl, C optionally substituted with 1, 2 or 3 substituents selected from F, cyano, hydroxy, methoxy, ethoxy ₁ -C ₃ An alkoxy group;

preferably, each R _l Each independently selected from F, cl, br, hydroxy, cyano, methyl or ethyl optionally substituted with 1, 2 or 3F;

preferably, each R _l Each independently selected from F, cl, methyl;

preferably, each R _l Each independently selected from F, cl, methyl, -CHF ₂ ；

Preferably, each R _l Each independently selected from methyl, -CHF ₂ ；

Preferably, R ¹ Selected from methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, and mixtures thereof,

Preferably, R ¹ Selected from methyl, ethyl, cyclopropyl,

Preferably, R ¹ Selected from cyclopropyl or

Or preferably, R ¹ Selected from cyclopropyl or ethyl;

or preferably, R ¹ Selected from methyl, ethyl, isopropyl, cyclopropyl,

Further preferably, R ¹ Selected from ethyl, cyclopropyl or

Or preferably, R ¹ Selected from 5-10 membered heteroaryl- (C) ₁ -C ₆ Alkyl group _n -n=0 or 1; the heteroaryl group contains 1 to 4 heteroatoms selected from O, N or S; the 5-10 membered aryl is optionally substituted with one or more R _l Substitution;

preferably, R ¹ Selected from 5-6 membered monocyclic heteroaryl- (C) ₁ -C ₄ Alkyl group _n -n=0 or 1; the heteroaryl group contains 1 to 4 heteroatoms selected from O, N or S; the 5-6 membered monocyclic heteroaryl optionally being substituted with one or more R _l Substitution;

preferably, R ¹ Selected from 5-6 membered monocyclic heteroaryl- (C) ₁ -C ₄ Alkyl group _n -n=0 or 1; the heteroaryl group contains 1 to 3 heterocyclic atoms selected from O or N; the 5-6 membered monocyclic heteroaryl optionally being substituted with one or more R _l Substitution;

preferably, R ¹ Selected from the group consisting of pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl,Each of which is provided withFrom optionally 1, 2 or 3R _l Substitution;

preferably, R ¹ Selected from the group consisting ofWhich is optionally substituted with 1, 2 or 3R' s _l Substitution;

preferably, each R _l Each independently selected from C optionally substituted with 1, 2 or 3 substituents selected from F, cl, cyano, hydroxy ₁ -C ₃ An alkyl group;

preferably, each R _l Each independently selected from methyl or ethyl optionally substituted with 1, 2 or 3F;

preferably, each R _l Each independently selected from C ₁ -C ₃ An alkyl group;

preferably, each R _l Each independently selected from methyl or ethyl;

preferably, each R _l Each independently selected from methyl;

preferably, R ¹ Selected from the group consisting of

Or preferably, R ¹ Selected from C ₃ -C ₁₀ Cycloalkyl- (C) ₁ -C ₆ Alkyl group _m -, m=0 or 1, the C ₃ -C ₁₀ Cycloalkyl optionally substituted with one or more R _j Substitution;

preferably, R ¹ Selected from C ₃ -C ₁₀ Cycloalkyl group, the C ₃ -C ₁₀ Cycloalkyl optionally substituted with one or more R _j Substitution;

preferably, R ¹ Selected from C ₃ -C ₆ Monocyclic cycloalkyl, said C ₃ -C ₆ Monocyclic cycloalkyl optionally being substitutedOne or more R _j Substitution;

preferably, R ¹ Selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, each optionally substituted with 1, 2 or 3R _j Substitution;

preferably, R ¹ Selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;

Further preferably, R ¹ Selected from cyclopropyl;

or preferably, R ¹ Selected from C ₁ -C ₆ Alkyl, said C ₁ -C ₆ Alkyl is optionally substituted with one or more R _i Substitution;

preferably, R ¹ Selected from C ₁ -C ₄ Alkyl, said C ₁ -C ₄ Alkyl is optionally substituted with 1, 2 or 3R _i Substitution;

preferably, R ¹ Selected from methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, each of which is optionally substituted with 1, 2 or 3R _i Substitution;

preferably, R ¹ Selected from C ₁ -C ₄ An alkyl group;

preferably, R ¹ Selected from methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl;

preferably, R ¹ Selected from methyl or ethyl;

preferably, R ¹ Selected from methyl;

preferably, R ¹ Selected from ethyl groups.

5. The compound of any one of claims 1-3, or a tautomeric form thereof, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, wherein:

R ⁸ selected from H, C ₁ -C ₃ Alkyl, C ₂ -C ₄ Alkyl, C ₃ -C ₆ Alkyl, C ₄ -C ₆ Alkyl, C ₅ -C ₆ Alkyl, C ₂ -C ₅ Alkyl, C ₃ -C ₅ Cycloalkyl, C ₄ -C ₆ Cycloalkyl, C ₄ -C ₅ Cycloalkyl, C ₅ -C ₆ Cycloalkyl; the alkyl, cycloalkyl are each optionally substituted with 1, 2, 3 or 4R' s _m Substitution;

or,

R ⁸ selected from H, methyl, ethyl, propyl, isopropyl, C ₄ Alkyl, C ₅ Alkyl, C ₆ Alkyl, cyclopropyl, C ₄ Cycloalkyl, C ₅ Cycloalkyl, C ₆ Cycloalkyl; the alkyl, cycloalkyl are each optionally substituted with 1, 2, 3 or 4R' s _m Substitution;

preferably, R ⁸ Selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, sec-butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; the methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl are each optionally substituted with 1, 2 or 3R' s _m Substitution;

preferably, R ⁸ Selected from H, methyl, ethyl, cyclopropyl; the methyl, ethyl, cyclopropyl groups are each optionally substituted with 1, 2 or 3R groups _m Substitution;

preferably, R ⁸ Selected from H, methyl, ethyl, isopropyl, cyclopropyl; the methyl, ethyl, isopropyl, cyclopropyl groups are each optionally substituted with 1, 2 or 3R groups _m Substitution;

preferably, each R _m Each independently selected from hydroxy, cyano, -NR' R ", C optionally substituted with 1, 2, 3 or 4 halogens ₁ -C ₃ An alkoxy group; wherein R 'and R' are each independently selected from H, methyl, ethyl, propyl, isopropyl, or R 'and R' together with the nitrogen atom to which they are attached form a 4-7 membered heterocyclic group containing 1-4 heteroatoms selected from N, O, S and the ring atoms of the heterocyclic group may optionally be oxo-substituted;

Preferably, each R _m Each independently selected from hydroxy, cyano, N, N dimethylamino, C optionally substituted with 1, 2 or 3F ₁ -C ₃ An alkoxy group;

preferably, each R _m Each independently selected from methoxy, hydroxy, cyano, N-dimethylamino, -OCH ₂ F、-OCHF ₂ 、-OCF ₃ 、-OCH ₂ CH ₂ F、-OCH ₂ CHF ₂ 、-OCH ₂ CF ₃ ；

Most preferably, each R _m Each independently selected from methoxy, hydroxy, cyano, N-dimethylamino, -OCHF ₂ 、-OCF ₃ ；

Preferably, each R _m Each independently selected from halogen, hydroxy, cyano, -NR' R ", C optionally substituted with 1, 2, 3 or 4 halogens ₁ -C ₃ An alkoxy group; wherein R 'and R' are each independently selected from H, methyl, ethyl, propyl, isopropyl, or R 'and R' together with the nitrogen atom to which they are attached form a 4-7 membered heterocyclic group containing 1-4 heteroatoms selected from N, O, S and the ring atoms of the heterocyclic group may optionally be oxo-substituted;

preferably, each R _m Each independently selected from halogen, hydroxy, cyano, N, N dimethylamino, C optionally substituted with 1, 2 or 3F ₁ -C ₃ An alkoxy group;

preferably, each R _m Each independently selected from F, cl, br, methoxy, hydroxy, cyano, N-dimethylamino, -OCH ₂ F、-OCHF ₂ 、-OCF ₃ 、-OCH ₂ CH ₂ F、-OCH ₂ CHF ₂ 、-OCH ₂ CF ₃ ；

Preferably, each R _m Each independently selected from F, methoxy, hydroxy, cyano, N-dimethylamino, -OCHF ₂ 、-OCF ₃ ；

Preferably, R ⁸ Selected from H, methyl, ethyl, methoxymethyl, hydroxymethyl, cyclopropyl,

Preferably, R ⁸ Selected from H, methyl, ethyl, methoxymethylRadical, hydroxymethyl, -CH ₂ F、-CF ₃ Cyclopropyl group,

Preferably, R ⁸ Selected from H, hydroxymethyl, -CH ₂ F、-CF ₃ Cyclopropyl group,

Preferably, R ⁸ Selected from H, hydroxymethyl, -CH ₂ F、-CF ₃ 、

Preferably, R ⁸ Selected from H;

preferably, R ⁸ Selected from the group consisting of/>

Or,

R ⁹ selected from 5-8 membered heteroaryl groups containing 3 or more heteroatoms selected from O, N or S, said heteroaryl groups being selected fromThe heteroaryl group may optionally be substituted with 1, 2 or 3R _n Substitution;

preferably, R ⁹ Selected from 5-8 membered heteroaryl groups containing 3 or more heteroatoms selected from O, N or S, said heteroaryl groups being selected fromThe heteroaryl group may optionally be substituted with 1, 2 or 3R _n Substitution;

preferably, each R _n Each independently selected from methyl, ethyl, C ₃ Alkyl, C ₄ Alkyl, C ₅ Alkyl, C ₆ Alkyl, cyclopropyl, C ₄ Cycloalkyl, C ₅ Cycloalkyl, C ₆ Cycloalkyl; the alkyl groups, cycloalkyl groups are each optionally substitutedOne or more selected from halogen, hydroxy, cyano, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₃ Substitution of the substituent of the alkoxy group;

preferably, each R _n Each independently selected from methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl; the methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl are each optionally substituted with one or more groups selected from halogen, hydroxy, cyano, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₃ Substitution of the substituent of the alkoxy group;

preferably, each R _n Each independently selected from methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl; the methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl are each optionally substituted with one or more substituents selected from halogen, C ₁ -C ₃ Substitution of the substituent of the alkoxy group;

preferably, each R _n Each independently selected from methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl; the methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl are each optionally substituted by one or more substituents selected from methoxy, ethoxy;

most preferably, each R _n Each independently selected from methyl, cyclopropyl, methoxymethyl;

most preferably, R ⁹ Selected from the group consisting of

Or,

R ¹⁰ selected from one or more R _v Substituted C ₁ -C ₆ Alkyl, C ₃ -C ₆ Cycloalkyl- (C) ₁ -C ₆ Alkyl group _r -,4-7 membered heterocyclyl- (C) ₁ -C ₆ Alkyl group _q -wherein r = 0 or 1, q = 0 or 1, the 4-7 membered heterocyclyl contains 1-4 heteroatoms selected from O, N or S and the ring atoms of the heterocyclyl may optionally be oxo; the C is ₃ -C ₆ Cycloalkyl, 4-7 membered heterocyclyl are each optionally substituted with 1 or more R _v Substitution;

preferably, R ¹⁰ Selected from one or more R _v Substituted C ₁ -C ₆ Alkyl, 4-7 membered heterocyclyl- (C) ₁ -C ₆ Alkyl group _q -wherein q = 0 or 1, the 4-7 membered heterocyclyl contains 1-4 heteroatoms selected from O, N or S and the ring atoms of the heterocyclyl may optionally be oxo; the 4-7 membered heterocyclic group may optionally be substituted with 1 or more R _v Substitution;

preferably, R ¹⁰ Selected from C ₁ -C ₄ Alkyl, C ₂ -C ₄ Alkyl, C ₃ -C ₅ Alkyl, C ₄ -C ₆ Alkyl, 5-6 membered heterocyclyl- (C) ₁ -C ₃ Alkyl group _q -wherein q = 0 or 1, the 5-6 membered heterocyclyl contains 1-4 heteroatoms selected from O, N or S and the ring atoms of the heterocyclyl may optionally be oxo; the alkyl groups being substituted by one or more R _v Substituted, said heterocyclyl being optionally substituted with 1 or more R _v Substitution;

preferably, R ¹⁰ Selected from methyl, ethyl, propyl, isopropyl, C ₄ Alkyl, C ₅ Alkyl, C ₆ Alkyl, 5-6 membered heterocyclyl- (C) ₁ -C ₃ Alkyl group _q -wherein q = 0 or 1, the 5-6 membered heterocyclyl contains 1-4 heteroatoms selected from O, N or S and the ring atoms of the heterocyclyl may optionally be oxo; the methyl, ethyl, propyl, isopropyl, C ₄ Alkyl, C ₅ Alkyl, C ₆ Alkyl is substituted with one or more R _v Substituted, said heterocyclyl being optionally substituted with 1 or more R _v Substitution;

most preferably, R ¹⁰ Selected from methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl, pentyl, hexyl, 5-6 membered heterocyclyl- (C) ₁ -C ₃ Alkyl group _q -, where q=0 or 1The 5-6 membered heterocyclic group is selected fromThe methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl, pentyl, hexyl being substituted with 1 or more R _v Substitution, said->Each optionally is substituted with 1, 2 or 3R _v Substitution;

preferably, each R _v Each independently selected from: c (C) ₁ -C ₃ Alkyl, C ₂ -C ₄ Alkynyl, C ₁ -C ₃ Alkoxy, halo C ₁ -C ₃ Alkoxy, cyano, -NR' R "; wherein R 'and R' are each independently selected from H, methyl, ethyl, propyl, isopropyl, or R 'and R' together with the nitrogen atom to which they are attached form a 4-7 membered heterocyclic group containing 1-4 heterocyclic atoms selected from O, N or S and the ring atoms of the heterocyclic group may optionally be oxo-substituted; wherein when R is ¹⁰ Is C ₁ -C ₆ In the case of alkyl radicals, R _v Not C ₁ -C ₃ An alkyl group;

preferably, each R _v Each independently selected from: c (C) ₁ -C ₃ Alkyl, C ₂ -C ₄ Alkynyl, C ₁ -C ₃ Alkoxy, cyano, -OCH ₂ F、-OCHF ₂ 、-OCF ₃ 、-OCH ₂ CH ₂ F、-OCH ₂ CHF ₂ 、-OCH ₂ CF ₃ -NR' R "; wherein R 'and R' are each independently selected from H, methyl, ethyl, propyl, isopropyl, or R 'and R' together with the nitrogen atom to which they are attached form Wherein when R is ¹⁰ Is C ₁ -C ₆ In the case of alkyl radicals, R _v Not C ₁ -C ₃ An alkyl group;

most preferably, each R _v Each independently selected from: methyl group, ethynyl group, methoxy group,cyano, -OCHF ₂ ，-OCF ₃ Amino, N-methylamino, N, N-dimethylamino,wherein when R is ¹⁰ Is C ₁ -C ₆ In the case of alkyl radicals, R _v Is not methyl;

most preferably, R ¹⁰ Selected from the group consisting ofOr,

R ¹¹ and R is ¹² Each independently selected from H, cyano, C ₁ -C ₃ Alkyl, C ₂ -C ₄ Alkyl, C ₃ -C ₆ Alkyl, C ₄ -C ₆ Alkyl, 5-6 membered heteroaryl containing 1-3 heteroatoms selected from O, N or S heteroatoms; or R is ¹¹ And R is ¹² The carbon-carbon double bond groups to which they are attached together form a 5-6 membered cycloalkenyl group, the 5-6 membered cycloalkenyl group being selected from

Preferably, R ¹¹ And R is ¹² Each independently selected from H, cyano, methyl, ethyl, propyl, isopropyl, C ₄ Alkyl, C ₅ Alkyl, C ₆ Alkyl, pyridyl, pyrazolyl, pyrimidinyl, pyrazinyl, pyridazinyl,Or R is ¹¹ And R is ¹² The carbon-carbon double bond groups to which they are attached together form a 5-6 membered cycloalkenyl group, said 5-6 membered cycloalkenyl group being selected from +.>

Preferably, R ¹¹ And R is ¹² Each independently selected from methyl, H, cyano,Or R is ¹¹ And R is ¹² The carbon-carbon double bond groups to which they are attached together form a 5-6 membered cycloalkenyl group, said 5-6 membered cycloalkenyl group being selected from +.>

Or,

e is selected from 4-6 membered heterocyclyl, each of said heterocyclyl and heteroaryl containing 1-2 heteroatoms selected from O, N or S;

Preferably E is selected from/>

Preferably E is selected from

Preferably, R ¹³ Selected from C ₁ -C ₄ Alkyl, C ₄ -C ₆ Alkyl, C ₃ -C ₅ Alkyl, C ₂ -C ₄ Alkyl, C optionally substituted with one or more groups selected from cyano, halogen, hydroxy, optionally substituted with one or more groups selected from halogen, cyano, hydroxy ₁ -C ₆ Alkoxy, C optionally substituted by one or more halogen, cyano, hydroxy ₃ -C ₆ A cycloalkoxy group optionally substituted with one or more halogen-, cyano-, hydroxy-substituted substituents of a 4-7 membered heterocycloalkoxy group;

preferably, R ¹³ Selected from C ₁ -C ₄ Alkyl, C ₄ -C ₆ Alkyl, C ₃ -C ₅ Alkyl, C ₂ -C ₄ Alkyl, C optionally substituted with one or more groups selected from cyano, halogen, hydroxy, optionally substituted with one or more groups selected from halogen, cyano, hydroxy ₁ -C ₆ Alkoxy, C optionally substituted by one or more halogen, cyano, hydroxy ₃ -C ₆ A cycloalkoxy group optionally substituted with one or more halogen-, cyano-, hydroxy-substituted substituents of a 4-7 membered heterocycloalkoxy group; the C is ₁ -C ₆ Alkoxy is selected from methoxy, ethoxy, C ₃ Alkoxy, C ₄ Alkoxy, C ₅ Alkoxy, C ₆ An alkoxy group; the C is ₃ -C ₆ The cycloalkoxy group is selected from cyclopropyloxy, cyclobutyloxy, C ₅ Cycloalkoxy radicals C ₆ A cycloalkoxy group; the 4-7 membered heterocycloalkoxy group is selected from

Or preferably, R ¹³ Selected from methyl, ethyl, C ₃ Alkyl, C ₄ Alkyl, C ₅ Alkyl, C ₆ Alkyl, C optionally substituted with one or more groups selected from cyano, halogen, hydroxy, optionally substituted with one or more groups selected from halogen, cyano, hydroxy ₁ -C ₆ Alkoxy, C ₃ -C ₆ Substituted with substituents of cycloalkoxy, 4-7 membered heterocycloalkoxy, said C ₁ -C ₆ Alkoxy is selected from methoxy, ethoxy, C ₃ Alkoxy, C ₄ Alkoxy, C ₅ Alkoxy, C ₆ An alkoxy group; the C is ₃ -C ₆ The cycloalkoxy group is selected from cyclopropyloxy, cyclobutyloxy, C ₅ Cycloalkoxy radicals C ₆ A cycloalkoxy group; the 4-7 membered heterocycloalkoxy group is selected from

Preferably, R ¹³ Selected from-CH ₂ CH ₂ F、-CH ₂ F；

Or,

R ³ selected from 5-6 membered heterocyclyl, said 5-6 membered heterocyclyl containing 1-2 heteroatoms selected from O, N or S and the ring atoms of said heterocyclyl may optionally be oxo;

preferably, R ³ Selected from the group consisting of

Or,

R ³ selected from the group consisting of

Preferably, R ³ Selected from the group consisting of

Preferably, each R ¹⁴ Each independently selected from hydrogen, halogen, cyano, C ₁ -C ₃ Alkyl, C ₁ -C ₃ Haloalkyl, C ₁ -C ₃ An alkoxy group;

preferably, each R ¹⁴ Each independently selected from hydrogen, halogen, cyano, C ₁ -C ₃ Alkyl, C ₁ -C ₃ A haloalkyl group;

preferably, each R ¹⁴ Each independently selected from hydrogen, F, cl, br, cyano, methyl optionally substituted with F, ethyl optionally substituted with F, propyl optionally substituted with F, isopropyl optionally substituted with F;

Preferably, each R ¹⁴ Each independently selected from hydrogen, F, methyl, -CF ₃ ；

Or preferably, each R ¹⁴ Each independently selected from hydrogen, F, cl, br, cyano, methyl optionally substituted with F, ethyl optionally substituted with F, propyl optionally substituted with F, isopropyl optionally substituted with F, methoxy optionally substituted with F, ethoxy optionally substituted with F, propoxy optionally substituted with F, isopropoxy optionally substituted with F;

preferably, each R ¹⁴ Each independently selected from hydrogen, F, cl, methyl, ethyl, methoxy, ethoxy, -CF ₃ 、-CHF ₂ 、-CH ₂ F；

Preferably, each R ¹⁴ Each independently selected from hydrogen, F, cl, methyl, ethyl, methoxy, ethoxy, -CF ₃ 、-CHF ₂ 、-CH ₂ F、-OCF ₃ 、-OCHF ₂ 、-OCH ₂ F；

Preferably, each R ¹⁴ Each independently selected from hydrogen, F, cl, methyl, methoxy, -CF ₃ ；

Preferably, each R ¹⁴ Each independently selected from hydrogen, F, cl, methyl, methoxy, -CF ₃ 、-OCH ₂ F；

Or preferably, each R ¹⁴ Each independently selected from hydrogen, F, cl, methyl, methoxy;

preferably, each R ¹⁴ Each independently selected from hydrogen, F, cl, methyl;

preferably, each R ¹⁴ Each independently selected from hydrogen, F, methyl;

preferably, each R ¹⁴ Each independently selected from Cl, methyl;

preferably, R ¹⁴ Selected from Cl;

preferably, R ¹⁴ Selected from methyl;

preferably, each R _s Each independently selected fromHalogen, cyano, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₆ Cycloalkyl- (C) ₁ -C ₆ Alkyl group _r -、C ₃ -C ₆ Cycloalkyl- (C) ₁ -C ₆ Alkyl group _r -O-, 4-8 membered heterocyclyl- (C) ₁ -C ₆ Alkyl group _r -, 4-8 membered heterocyclyl- (C) ₁ -C ₆ Alkyl group _r -O-, 5-6 membered heterocyclenyl, 5-6 membered heteroaryl, each containing 1-4 heteroatoms selected from N, O, S and the ring atoms of the heterocyclyl may optionally be oxo; the C is ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₆ Cycloalkyl, 4-8 membered heterocyclyl, 5-6 membered heterocyclenyl, 5-6 membered heteroaryl, each optionally substituted with one or more groups selected from halogen, cyano, hydroxy, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Haloalkoxy, C ₁ -C ₆ alkyl-C (O) -, C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Alkoxy, C ₁ -C ₆ Alkoxy C ₁ -C ₆ Substituents for alkyl, -NR 'R ", wherein R' and R" are each independentlyIs selected from H, C ₁ -C ₆ Alkyl, or R 'and R' together with the nitrogen atom to which they are attached form a 4-8 membered heterocyclyl containing 1-4 heteroatoms selected from N, O, S and the ring atoms of the heterocyclyl may optionally be oxo;

preferably, each R _s Each independently selected from Halogen, cyano, C ₁ -C ₃ Alkyl, C ₄ -C ₆ Alkyl, C ₃ -C ₄ Alkyl, C ₂ -C ₃ Alkyl, C ₁ -C ₃ Alkoxy, C ₄ -C ₆ Alkoxy, C ₃ -C ₄ Alkoxy, C ₂ -C ₃ Alkoxy, C ₃ -C ₄ Cycloalkyl- (C) ₁ -C ₆ Alkyl group _r -、C ₅ -C ₆ Cycloalkyl- (C) ₁ -C ₆ Alkyl group _r -、C ₄ -C ₅ Cycloalkyl- (C) ₁ -C ₆ Alkyl group _r -、C ₃ -C ₄ Cycloalkyl- (C) ₁ -C ₆ Alkyl group _r -O-、C ₅ -C ₆ Cycloalkyl- (C) ₁ -C ₆ Alkyl group _r -O-、C ₄ -C ₅ Cycloalkyl- (C) ₁ -C ₆ Alkyl group _r -O-, 5-8 membered heterocyclyl- (C) ₁ -C ₆ Alkyl group _r -, 5-8 membered heterocyclyl- (C) ₁ -C ₆ Alkyl group _r -O-, 5-6 membered heterocyclenyl, 5-6 membered heteroaryl, each containing 1-4 heteroatoms selected from N, O, S and the ring atoms of the heterocyclyl may optionally be oxo; the alkyl, alkoxy, cycloalkyl, heterocyclyl, heterocyclenyl, heteroaryl groups are each optionally substituted with one or more groups selected from halogen, cyano, hydroxy, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Haloalkoxy, C ₁ -C ₆ alkyl-C (O) -, C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Alkoxy, C ₁ -C ₆ Alkoxy C ₁ -C ₆ Substituents for alkyl, -NR 'R ", wherein R' and R" are each independently selected from H, C ₁ -C ₆ Alkyl, or R 'and R' together with the nitrogen atom to which they are attached form a 4-8 membered heterocyclyl containing 1-4 heteroatoms selected from N, O, S and the ring atoms of the heterocyclyl may optionally be oxo; / >

Preferably, each R _s Each independently selected fromHalogen, cyano, C ₁ -C ₃ Alkyl, C ₄ -C ₆ Alkyl, C ₃ -C ₄ Alkyl, C ₂ -C ₃ Alkyl, C ₁ -C ₃ Alkoxy, C ₄ -C ₆ Alkoxy, C ₃ -C ₄ Alkoxy, C ₂ -C ₃ Alkoxy, C ₃ -C ₄ Cycloalkyl- (C) ₁ -C ₆ Alkyl group _r -、C ₅ -C ₆ Cycloalkyl- (C) ₁ -C ₆ Alkyl group _r -、C ₄ -C ₅ Cycloalkyl- (C) ₁ -C ₆ Alkyl group _r -、C ₃ -C ₄ Cycloalkyl- (C) ₁ -C ₆ Alkyl group _r -O-、C ₅ -C ₆ Cycloalkyl- (C) ₁ -C ₆ Alkyl group _r -O-、C ₄ -C ₅ Cycloalkyl- (C) ₁ -C ₆ Alkyl group _r -O-, 5-8 membered heterocyclyl- (C) ₁ -C ₆ Alkyl group _r -, 5-8 membered heterocyclyl- (C) ₁ -C ₆ Alkyl group _r -O-, 5-6 membered heterocyclenyl, 5-6 membered heteroaryl, each containing 1-4 heteroatoms selected from N, O, S and the ring atoms of the heterocyclyl may optionally be oxo; the alkyl, alkoxy, cycloalkyl, heterocyclyl, heterocyclenyl, heteroaryl groups are each optionally substituted with one or more groups selected from F, cl, cyano, hydroxy, C ₃ -C ₄ Cycloalkyl, C ₁ -C ₃ Haloalkyl, C ₁ -C ₃ Haloalkoxy, C ₁ -C ₃ alkyl-C (O) -, C ₁ -C ₃ Alkyl, C ₂ -C ₄ Alkynyl, C ₁ -C ₃ Alkoxy, C ₁ -C ₃ Alkoxy C ₁ -C ₃ Substituents for alkyl, -NR 'R ", wherein R' and R" are each independently selected from H, C ₁ -C ₃ Alkyl, or R 'and R' together with the nitrogen atom to which they are attached form a 4-8 membered heterocyclyl containing 1-4 heteroatoms selected from N, O, S and the ring atoms of the heterocyclyl may optionally be oxo;

Preferably, each R _s Each independently selected fromHalogen, cyano, C ₁ -C ₃ Alkyl, C ₄ -C ₆ Alkyl, C ₃ -C ₄ Alkyl, C ₂ -C ₃ Alkyl, C ₁ -C ₃ Alkoxy, C ₄ -C ₆ Alkoxy, C ₃ -C ₄ Alkoxy, C ₂ -C ₃ Alkoxy, C ₃ -C ₄ Cycloalkyl- (C) ₁ -C ₆ Alkyl group _r -、C ₅ -C ₆ Cycloalkyl- (C) ₁ -C ₆ Alkyl group _r -、C ₄ -C ₅ Cycloalkyl- (C) ₁ -C ₆ Alkyl group _r -、C ₃ -C ₄ Cycloalkyl- (C) ₁ -C ₆ Alkyl group _r -O-、C ₅ -C ₆ Cycloalkyl- (C) ₁ -C ₆ Alkyl group _r -O-、C ₄ -C ₅ Cycloalkyl- (C) ₁ -C ₆ Alkyl group _r -O-, 5-8 membered heterocyclyl- (C) ₁ -C ₆ Alkyl group _r -, 5-8 membered heterocyclyl- (C) ₁ -C ₆ Alkyl group _r -O-, 5-6 membered heterocyclenyl, 5-6 membered heteroaryl, each containing 1-4 heteroatoms selected from N, O, S and the ring atoms of the heterocyclyl may optionally be oxo; the alkyl, alkoxy, cycloalkyl, heterocyclyl, heterocyclenyl, heteroaryl groups are each optionally substituted with one or more groups selected from F, cl, cyano, hydroxy, cyclopropyl, cyclobutylRadical, -CH ₂ CH ₂ F、-OCHF ₂ 、-OCF ₃ 、/>Methyl, acetylene, methoxy, methoxymethyl, N-methylamino, N-dimethylamino, -/-dimethylamino>Is substituted by a substituent of (a);

preferably, each R _s Each independently selected fromF. Cl, cyano, methyl, methoxy, ethoxy, cyclopropyl, cyclopropyloxy, -/-> Said methyl, methoxy, ethoxy, cyclopropyl, cyclopropyloxy,/i> Each optionally being substituted with one or more groups selected from F, cl, cyano, hydroxy, cyclopropyl, cyclobutyl, -CH ₂ CH ₂ F、-OCHF ₂ 、-OCF ₃ 、/>Methyl, acetylene, methoxy, methoxymethyl, N-methylamino, N-dimethylamino, -/-dimethylamino>Is substituted by a substituent of (a);

preferably, each R _s Each independently selected fromF. Cl, cyano, methyl, methoxy, ethoxy, cyclopropyl, cyclopropyloxy, -/-> Said methyl, methoxy, ethoxy, cyclopropyl, cyclopropyloxy,/i> Each optionally being substituted with one or more groups selected from F, cl, cyano, hydroxy, cyclopropyl, cyclobutyl, -CH ₂ CH ₂ F、-OCHF ₂ 、-OCF ₃ 、/>Methyl, acetylene, methoxy, methoxymethyl, amino, N-methylamino, N-dimethylamino, -/-dimethylamino>Is substituted by a substituent of (a);

preferably, each R _s Each independently selected from Cl, cyano, methyl, -CF ₃ 、-CHF ₂ 、-OCF ₃ Ethoxy, cyclopropyl, cyclopropyloxy,

Preferably, each R _s Each independently selected from F, cl, cyano, methyl, -CF ₃ 、-CHF ₂ 、-OCF ₃ Methoxy, ethoxy, cyclopropyl, cyclopropyloxy,/>

Preferably, each R _s Each independently selected from F, cl, methyl, methoxy,

R ³ Selected from:

preferably, R ³ Selected from:

or preferably, R ³ Selected from the group consisting ofWherein y=0, 1 or 2; preferably, R ³ Selected from->

Further preferably, R ³ Selected from the group consisting ofWherein y=0, 1 or 2;

preferably, R ³ Selected from the group consisting of

Preferably, R ³ Selected from the group consisting of

6. The compound of any one of claims 1-3, or a tautomeric form thereof, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, wherein:

radicals (C)Selected from: />Therein W, R ⁴ 、R ⁵ 、R ⁶ Each definition is defined as in formula I;

preferably, the method comprises the steps of,selected from: />Therein W, R ⁴ 、R ⁶ Each definition is defined as in formula I;

preferably, R ⁴ ，R ⁵ ，R ⁶ ，R ⁷ Independently selected from H, halogen, C ₁ -C ₃ Alkyl, C ₃ -C ₆ Cycloalkyl;

preferably, R ⁴ ，R ⁵ ，R ⁶ ，R ⁷ Independently selected from H, F, cl, br, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclohexyl;

preferably, R ⁴ ，R ⁵ ，R ⁶ ，R ⁷ Independently selected from H, F, cl, methyl, cyclopropyl;

or preferably, R ⁷ Selected from H, F, cl, br, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclohexyl; r is R ⁴ ，R ⁵ ，R ⁶ Each independently selected from H, methyl, ethyl, propyl;

preferably, R ⁷ Selected from H, F, cl, methyl, cyclopropyl; r is R ⁴ ，R ⁵ ，R ⁶ Each independently selected from H, methyl;

preferably, R ⁷ Selected from H, F, cl, methyl; r is R ⁴ ，R ⁵ ，R ⁶ Each independently selected from H, methyl;

preferably, the method comprises the steps of,selected from:

preferably, the method comprises the steps of,selected from: / >

Preferably, the method comprises the steps of,selected from:

preferably, the method comprises the steps of,selected from:

preferably, the method comprises the steps of,selected from: />

Preferably, the method comprises the steps of,selected from:

preferably, the method comprises the steps of,selected from:

preferably, the method comprises the steps of,selected from: />

7. The compound of any one of claims 1-6, or a tautomeric form thereof, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, wherein: formula I has a general structure IA selected from any of the following:

wherein R is ¹ 、R ² 、R ³ The definition is as defined in formula I;

alternatively, formula I has a general structure selected from any of the following formulas IA-1, IA-2, IB:

wherein R is ¹ 、R ³ X, Y, Z, W are defined as in formula I；

Preferably, R ⁴ ，R ⁵ ，R ⁶ ，R ⁷ Independently selected from H, F, cl, methyl;

preferably, R ⁷ Independently selected from H, F, cl; r is R ⁴ ，R ⁵ ，R ⁶ Independently selected from H, methyl;

preferably, W is CH, N, CF, CCl;

or preferably, formula I has a general structure selected from any of the following:

wherein R is ¹ 、R ³ 、R ⁷ Each definition is defined as in formula I;

further preferred, formula I has a general structure selected from any of the following:

in A, B, R ⁷ 、R ⁸ Each definition is as defined in formula I.

8. The compound as recited in claim 1 or 2, or a tautomeric form thereof, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, wherein formula I is selected from any one of the following specific compounds:

/>

9. A pharmaceutical composition for the treatment and/or prophylaxis of a disease associated with abnormal PRMT5 expression, characterized in that: the pharmaceutical composition comprises a therapeutically and/or prophylactically effective amount of a compound according to any one of claims 1-8, or a tautomeric form thereof, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, and optionally a pharmaceutical excipient;

preferably, the disease associated with abnormal PRMT5 expression is a tumor or cancer;

preferably, the disease related to abnormal PRMT5 expression refers to a disease related to abnormal PRMT5 expression, wherein MTAP is deleted;

preferably, the disease associated with abnormal PRMT5 expression refers to MTAP-deleted tumor or cancer.

10. A PRMT5 inhibitor, characterized by: the PRMT5 inhibitor comprising a therapeutically and/or prophylactically effective amount of the compound of any one of claims 1-8, or a tautomeric form thereof, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof.

11. Use of a compound according to any one of claims 1 to 8, or a tautomeric form thereof, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, or a pharmaceutical composition according to claim 9, in the manufacture of a PRMT5 inhibitor, and/or in the manufacture of a medicament for the treatment and/or prophylaxis of a disease associated with abnormal expression of PRMT5, and/or in the treatment and/or prophylaxis of a disease associated with abnormal expression of PRMT 5; and/or for the treatment and/or prevention of diseases associated with abnormal PRMT5 expression;

12. A method of treating and/or preventing a disease associated with abnormal PRMT5 expression, comprising administering to a subject in need thereof a therapeutically and/or prophylactically effective amount of a compound according to any one of claims 1-8, or a tautomeric form thereof, or a pharmaceutically acceptable salt form thereof, or a deuterated compound thereof, or a pharmaceutical composition according to claim 9;