Macrolide compound, and preparation method therefor and use thereof

Abstract

The present invention relates to a macrolide compound, and a preparation method therefor and the use thereof. Specifically disclosed is a compound as shown in formula I or a pharmaceutically acceptable salt thereof. The compound of the present invention exhibits a significant antibacterial activity, comprising the antibacterial activity against bacteria resistant to macrolide drugs such as azithromycin. The compound described herein has a low hepatotoxicity and superior safety compared to other macrolide compounds. The compound can be used for infectious diseases, etc.

Description

Macrolide compounds, methods of making and uses thereof

[0001] This application claims priority from Chinese patent application 2024105393354 with a filing date of 2024 / 4 / 30, Chinese patent application 2024108334165 with a filing date of 2024 / 6 / 26, Chinese patent application 2024110199640 with a filing date of 2024 / 7 / 29, Chinese patent application 2024112779778 with a filing date of 2024 / 9 / 12, Chinese patent application 2024114746800 with a filing date of 2024 / 10 / 22, Chinese patent application 2024114925853 with a filing date of 2024 / 10 / 24, Chinese patent application 2024118433487 with a filing date of 2024 / 12 / 13, Chinese patent application 2025100642374 with a filing date of 2025 / 1 / 15, Chinese patent application 2025101081409 with a filing date of 2025 / 1 / 23. This application incorporates the entire contents of the above-mentioned Chinese patent applications. TECHNICAL FIELD

[0002] The present application relates to the field of organic medicines, in particular to a macrolide compound, a method for preparing the same and uses thereof. BACKGROUND

[0003] Macrolide antibiotics are a class of drugs with similar chemical structure and antibacterial action. They are widely used in clinical practice due to their strong antibacterial activity, broad antibacterial spectrum, significant therapeutic effect and low resistance. Studies have shown that macrolide antibiotics can bind to L27 and L22 proteins of the 50s subunit of bacterial ribosomes, inhibit bacterial protein synthesis and exert antibacterial action. Macrolide antibacterial drugs can be used to treat infections caused by Gram-positive cocci (G+ cocci) and atypical pneumonia pathogens, and can be used as an appropriate alternative drug for patients allergic to penicillin for the treatment of upper and lower respiratory tract and soft tissue infections, and are widely used in clinical practice. However, the long-term use of macrolide drugs has led to the problem of antibiotic resistance, with a doubling of the resistance rate over the past 10 years. The three main reasons for bacterial biological resistance to macrolides are ribosome methylation encoded by the erm gene, mutations in ribosomal RNA or peptides, and extracellular efflux mediated by the mef and msr genes.

[0004] Currently, the rate of introduction of new antibiotics is not sufficient to address the growing problem of drug resistance, and the need for innovation in this area is increasingly urgent due to the increasing exchange of populations and increasing population density between different regions of the world. The main macrolide antibiotics on the market, azithromycin and erythromycin, have been on the market for many years and are mainly used to treat infections caused by gram-positive bacteria and mycoplasma pneumoniae, but due to the abuse of antibiotics, the sensitivity of pathogens is not high. At the same time, azithromycin is a commonly used drug for the treatment of community-acquired pneumonia, especially pneumonia caused by mycoplasma pneumoniae, and at least 80% of the population has shown significant drug resistance, and children under the age of 8 are facing the dilemma of no available drugs. If the problem of drug resistance continues, the use of quinolone drugs with significant side effects will threaten children's health. It is urgent to develop safe and effective alternative drugs with strong targeting.

[0005] With the development of macrolide drugs, after the launch of azithromycin, the related clinical trials of macrolide drugs telithromycin and solithromycin have also been carried out. Telithromycin does not show effective antibacterial activity against azithromycin-resistant mycoplasma pneumoniae strains, while solithromycin has certain antibacterial activity, but due to the influence of solithromycin hepatotoxicity, after the completion of phase III clinical trials, it has not been able to meet the corresponding safety evaluation standards, and FDA has rejected its marketing application. Therefore, after the launch of azithromycin, there is no macrolide drug that can truly solve the problem of azithromycin resistance and has good safety evaluation, and the clinical demand has not been met. SUMMARY

[0006] In order to overcome the shortcomings of the prior art, such as the small number of macrolide compounds and the easy emergence of drug resistance when used as antibiotics, the present application provides a macrolide compound, a preparation method thereof and the use thereof, which has good antibacterial activity against gram-positive bacteria and gram-negative bacteria.

[0007] The compounds described herein can be used to treat conditions caused by pathogens, such as gram-positive bacteria, gram-negative bacteria, anaerobes, mycoplasma pneumoniae or chlamydia pneumoniae. More specifically, conditions caused by staphylococci, streptococci, enterococci, haemophilus, moraxella, chlamydia, mycoplasma, legionella, mycobacterium, helicobacter, clostridium, bacteroides, corynebacterium, bacillus, enterobacter or any combination thereof. Methods of preparing the compounds described herein, pharmaceutical compositions containing the compounds described herein and methods of treating bacterial and mycoplasma infections are also provided.

[0008] The compounds described herein exhibit significant antibacterial activity, including against bacteria resistant to macrolide drugs such as azithromycin. The compounds described herein have low hepatotoxicity, and are safer than other macrolide compounds. The compounds described herein can be used to treat community-acquired pneumonia, upper and lower respiratory tract infections, and hospital-acquired lung infections.

[0009] The present application provides a compound shown in formula I, a solvate thereof, a crystal form thereof, a deuterated compound thereof, a pharmaceutically acceptable salt thereof, or a solvate of a pharmaceutically acceptable salt thereof,

[0010] wherein,

[0011] L is alkylene or alkenylene; the alkylene and the alkenylene are optionally substituted with one or more deuterium;

[0012] X is CR 1 R 2 or the is optionally substituted with one or two deuterium;

[0013] Ring A is heteroaryl; the heteroaryl is a heteroaryl having one or more heteroatoms selected from the group consisting of N, O and S, and the number of heteroatoms is one or more; the heteroaryl is optionally substituted with one or more deuterium;

[0014] R 1 and R 2 are independently H, deuterium, OH, NH2, CN, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, O-alkyl, O-cycloalkyl, or heteroaryl; the alkyl, the alkenyl, the alkynyl, the cycloalkyl, the cycloalkenyl, the O-alkyl, the O-cycloalkyl, and the heteroaryl are optionally substituted with any substituent; the heteroaryl is a heteroaryl having one or more heteroatoms selected from the group consisting of N, O and S, and the number of heteroatoms is one or more;

[0015] Alternatively, R 1 , R 2 and the carbon atom to which they are attached together form a heterocyclyl; the heterocyclyl is a heterocyclyl having one or more heteroatoms selected from the group consisting of N, O and S, and the number of heteroatoms is independently one or more; the heterocyclyl is optionally substituted with any substituent;

[0016] R is

[0017] R 3 is H, deuterium, CN, CONR 3-1 R 3-2 , COOR 3-3, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, or heteroaryl; the alkyl, the alkenyl, the alkynyl, the cycloalkyl, the aryl, and the heteroaryl are optionally substituted with any substituent;

[0018] R 3-1 , R 3-2 , and R 3-3 are independently H or alkyl; the alkyl is optionally substituted with any substituent;

[0019] R 4 is H or alkyl; the alkyl is optionally substituted with any substituent;

[0020] R 5 is H, deuterium, alkyl, aryl, heteroaryl, or heterocyclyl; the alkyl, the aryl, the heteroaryl, and the heterocyclyl are optionally substituted with any substituent; the heteroaryl is a heteroaryl having one or more heteroatoms selected from the group consisting of N, O, and S; the heterocyclyl is a heterocyclyl having one or more heteroatoms selected from the group consisting of N, O, and S;

[0021] R 6 is H, deuterium, or methyl.

[0022] In one aspect, in the compounds of Formula I, or pharmaceutically acceptable salts thereof, certain groups are defined as follows, and the definitions of groups not mentioned are as described in any aspect of the present application (hereinafter referred to as “in one aspect”).

[0023] In one aspect, each heteroaryl is independently a 5-14 membered heteroaryl, preferably a 5-10 membered heteroaryl, more preferably a 5-6 membered heteroaryl or an 8-10 membered heteroaryl; wherein the 5-6 membered heteroaryl is independently a 5-6 membered heteroaryl having one or two heteroatoms selected from the group consisting of N, O, and S, and the number of heteroatoms is one, two, three, or four, preferably a pyridyl (e.g., ), an azole (e.g., pyrazole or imidazole, and e.g., ), a triazole (e.g., 1,2,3-triazole or 1,2,4-triazole, and e.g., ), a pyrimidinyl (e.g., ), a thiazolyl (e.g., ), an oxazolyl (e.g., ), a tetrazole (e.g., ); and the 8-10 membered heteroaryl is independently an 8-10 membered heteroaryl having one or two heteroatoms selected from the group consisting of N and O, and the number of heteroatoms is one, two, or three, preferably a benzo[c][1,2,5]oxadiazolyl (e.g., ) or benzopyridyl (e.g., quinolinyl or isoquinolinyl, again for example ).

[0024] In one aspect, the pyrazolyl is

[0025] In one aspect, the pyridyl is

[0026] In one aspect, the 5-14 membered heteroaryl is independently pyridyl, e.g., 2-pyridyl, 3-pyridyl, or 4-pyridyl;

[0027] In one aspect, each alkyl can independently be C 1-10 alkyl, preferably C 1-6 alkyl, e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, or t-butyl.

[0028] In one aspect, each alkylene can independently be C 1-10 alkylene, preferably C 1-6 alkylene, more preferably C 1-4 alkylene, e.g.,

[0029] In one aspect, the C 1-10 alkylene is

[0030] In one aspect, each alkenyl can independently be C 2-10 alkenyl, preferably C 2-6 alkenyl, more preferably C 2-4 alkenyl, e.g.,

[0031] In one aspect, each alkenylene can independently be C 2-10 alkenylene, preferably C 2-6 alkenylene, more preferably C 2-4 alkenylene, e.g.,

[0032] In one aspect, each alkynyl can independently be C 2-10 alkynyl, preferably C 2-6 alkynyl, more preferably C 2-4 alkynyl, e.g.,

[0033] In one aspect, each cycloalkyl can independently be C 3-14 cycloalkyl, preferably C 3-10 cycloalkyl, more preferably C3-8 cycloalkyl, e.g. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0034] In one aspect, each cycloalkyl group can independently be monocycloalkyl, spirocycloalkyl, bridged cycloalkyl or fused cycloalkyl, preferably C 3-14 monocycloalkyl, C 3-14 spirocycloalkyl, C 3-14 bridged cycloalkyl or C 3-14 fused cycloalkyl, more preferably C 3-14 monocycloalkyl.

[0035] In one aspect, the alkyl group in each O-alkyl group can independently be C 1-10 alkyl, preferably C 1-6 alkyl, e.g. methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl or t-butyl.

[0036] In one aspect, the cycloalkyl group in each O-cycloalkyl group can independently be C 3-14 cycloalkyl, preferably C 3-10 cycloalkyl, more preferably C 3-8 cycloalkyl, e.g. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0037] In one aspect, the cycloalkyl group in each O-cycloalkyl group can independently be monocycloalkyl, spirocycloalkyl, bridged cycloalkyl or fused cycloalkyl, preferably C 3-14 monocycloalkyl, C 3-14 spirocycloalkyl, C 3-14 bridged cycloalkyl or C 3-14 fused cycloalkyl, more preferably C 3-14 monocycloalkyl.

[0038] In one aspect, each C 3-14 monocycloalkyl can independently be C 3-10 monocycloalkyl, preferably C 3-8 monocycloalkyl, e.g. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0039] In one aspect, each C 3-14 spirocycloalkyl can independently be C 3-10 spirocycloalkyl, preferably C 3-8 spirocycloalkyl.

[0040] In one aspect, each C 3-14 bridged cycloalkyl can independently be C 3-10 bridged cycloalkyl, preferably C 3-8 bridged cycloalkyl.

[0041] In one aspect, each C 3-14 fused cycloalkyl can independently be C 3-10and cycloalkyl, preferably C 3-8 and cycloalkyl.

[0042] In one aspect, each cycloalkenyl can independently be C 3-14 cycloalkenyl, preferably C 3-10 cycloalkenyl, more preferably C 3-8 cycloalkenyl.

[0043] In one aspect, each cycloalkenyl can independently be monocycloalkenyl, spirocycloalkenyl, bridged cycloalkenyl, or fused cycloalkenyl, preferably C 3-14 monocycloalkenyl, C 3-14 spirocycloalkenyl, C 3-14 bridged cycloalkenyl, or C 3-14 fused cycloalkenyl, more preferably C 3-14 monocycloalkenyl.

[0044] In one aspect, each C 3-14 monocycloalkenyl can independently be C 3-10 monocycloalkenyl, preferably C 3-8 monocycloalkenyl.

[0045] In one aspect, each C 3-14 spirocycloalkenyl can independently be C 3-10 spirocycloalkenyl, preferably C 3-8 spirocycloalkenyl.

[0046] In one aspect, each C 3-14 bridged cycloalkenyl can independently be C 3-10 bridged cycloalkenyl, preferably C 3-8 bridged cycloalkenyl.

[0047] In one aspect, each C 3-14 fused cycloalkenyl can independently be C 3-10 fused cycloalkenyl, preferably C 3-8 fused cycloalkenyl.

[0048] In one aspect, each heterocyclyl can independently be 3-14 membered heterocyclyl, preferably 3-10 membered heterocyclyl, more preferably 3-8 membered heterocyclyl, for example, oxiranyl or azacyclohexyl.

[0049] In one aspect, each heterocyclyl can independently be monoheterocyclyl, spiroheterocyclyl, fused heterocyclyl, or bridged heterocyclyl, preferably 3-14 membered monoheterocyclyl, 3-14 membered spiroheterocyclyl, 3-14 membered fused heterocyclyl, or 3-14 membered bridged heterocyclyl, more preferably 3-14 membered monoheterocyclyl.

[0050] In one aspect, each 3-14 membered monoheterocyclyl can independently be 3-10 membered monoheterocyclyl, preferably 3-8 membered monoheterocyclyl, for example, oxiranyl or azacyclohexyl.

[0051] In one aspect, each 3-14 membered spiroheterocyclyl group can independently be a 3-10 membered spiroheterocyclyl group, preferably a 3-8 membered spiroheterocyclyl group.

[0052] In one aspect, each 3-14 membered fused heterocyclyl group can independently be a 3-10 membered fused heterocyclyl group, preferably a 3-8 membered fused heterocyclyl group.

[0053] In one aspect, each 3-14 membered bridged heterocyclyl group can independently be a 3-10 membered bridged heterocyclyl group, preferably a 3-8 membered bridged heterocyclyl group.

[0054] In one aspect, the heteroatom species in each heterocyclyl group is N, and the number of heteroatoms is independently 1 or 2.

[0055] In one aspect, each heterocyclyl group is independently a partially saturated 3-14 membered heterocyclyl group, the number of double bonds in the partially saturated 3-14 membered heterocyclyl group being 1 or 2; preferably, the partially saturated 3-14 membered heterocyclyl group is a partially saturated 5-6 membered heterocyclyl group, for example Also for example

[0056] In one aspect, each aryl group can independently be a C 6-14 aryl, preferably a C 6-10 aryl, more preferably phenyl or naphthyl.

[0057] In one aspect, the halogen is fluorine, chlorine, bromine or iodine, for example fluorine.

[0058] In one aspect,

[0059] L is C 1-10 alkylene or C 2-10 alkenylene; the C 1-10 alkylene and the C 2-10 alkenylene is optionally substituted with 1 or more deuterium;

[0060] X is CR 1 R 2 or the C is optionally substituted with one or two deuterium;

[0061] Ring A is a 5-14 membered heteroaryl group; the heteroatoms of the 5-14 membered heteroaryl group are selected from 1, 2 or 3 of N, O and S, the number of heteroatoms being 1, 2, 3 or 4; the 5-14 membered heteroaryl group is optionally substituted with 1 or more deuterium;

[0062] R 1 and R 2Independently, H, deuterium, OH, NH2, CN, halogen, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-14 cycloalkyl, C 5-14 Cycloalkenyl, OC 1-10 Alkyl, OC 3-14 cycloalkyl or 5-14-membered heteroaryl; the C 1-10 Alkyl, the C 2-10 alkenyl, the C 2-10 alkynyl group, the C 3-14 cycloalkyl, C 5-14 cycloalkenyl, the OC 1-10 Alkyl, the OC 3-14 The cycloalkyl group and the 5-14 heteroaryl group are optionally surrounded by one, two, or three R groups. 1-1 Substitution; the 5-14 membered heteroaryl group is a 5-14 membered heteroaryl group whose heteroatoms are selected from 1, 2 or 3 of N, O and S, and whose number of heteroatoms is 1, 2, 3 or 4;

[0063] Each R 1-1 Independently deuterium, OH, halogen, SO3R 1-1-1 or COOR 1-1-2 ;

[0064] R 1-1-1 and R 1-1-2 Independently H or C 1-10 Alkyl; the C 1-10 Alkyl groups may optionally be substituted with one or more deuterium groups;

[0065] Or, R 1 R 2 Together with the carbon atom attached thereto, a 3-14 membered heterocyclic group is formed; the 3-14 membered heterocyclic group is a 3-14 membered heterocyclic group in which the heteroatoms are selected from one or two of N, O and S, and the number of heteroatoms is independently one or two; the 3-14 membered heterocyclic group is optionally substituted by one or more deuteriums;

[0066] R is

[0067] R 3 For H, deuterium, CN, CONR 3-1 R 3-2 COOR 3-3 C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-14 cycloalkyl, C 6-14 Aryl and 5-14 heteroaryl groups; the C 1-10 Alkyl, the C2-10 alkenyl, said C 2-10 alkynyl, said C 3-14 cycloalkyl, said C 6-14 aryl and said 5-14 membered heteroaryl are optionally substituted with 1, 2, or 3 R 3-4 ; said 5-14 membered heteroaryl is a 5-14 membered heteroaryl having 1, 2, 3, or 4 heteroatoms selected from N, O, and S;

[0068] R 3-1 , R 3-2 , and R 3-3 are independently H or C 1-10 alkyl; said C 1-10 alkyl is optionally substituted with one or more deuterium;

[0069] each R 3-4 is independently deuterium, OH, halogen, NR 3-4-1 R 3-4-2 , C 1-10 alkyl or 5-14 membered heteroaryl; said C 1-10 alkyl and said 5-14 membered heteroaryl are optionally substituted with 1, 2, or 3 R 3-4-4 ; said 5-14 membered heteroaryl is a 5-14 membered heteroaryl having 1, 2, 3, or 4 heteroatoms selected from N, O, and S;

[0070] R 3-4-1 and R 3-4-2 are independently H, or C 1-10 alkyl; said C 1-10 alkyl is optionally substituted with one or more deuterium;

[0071] R 3-4-3 is C 1-10 alkyl; said C 1-10 alkyl is optionally substituted with one or more deuterium;

[0072] each R 3-4-4 is independently deuterium, OH, NR a R b , or C 1-10 alkyl; said C 1-10 alkyl is optionally substituted with 1, 2, or 3 R 3-4-4-1 ;

[0073] R a and R b are independently H, or C 1-10 alkyl; said C 1-10alkyl is optionally substituted with one, two, or three R

[0074] each R 3-4-4-1 is independently deuterium, OH, or NH2;

[0075] R 4 is H or C 1-10 alkyl; said C 1-10 alkyl is optionally substituted with one, two, or three R 4-1 substituents;

[0076] each R 4-1 is independently deuterium, OH, CN, halo, NR a R b , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-14 cycloalkyl, or C 5-14 cycloalkenyl; said C 1-10 alkyl, said C 2-10 alkenyl, said C 2-10 alkynyl, said C 3-14 cycloalkyl, and said C 5-14 cycloalkenyl is optionally substituted with one or more deuterium;

[0077] R a and R b are independently H, or C 1-10 alkyl; said C 1-10 alkyl is optionally substituted with one, two, or three deuterium;

[0078] R 5 is H, deuterium, C 1-10 alkyl, C 3-14 cycloalkyl, C 6-14 aryl, 5-14 membered heteroaryl, or 3-14 membered heterocyclyl; said C 1-10 alkyl, said C 6-14 aryl, said 5-14 membered heteroaryl, and said 3-14 membered heterocyclyl is optionally substituted with one, two, or three R 5-1 substituents; said 5-14 membered heteroaryl is a 5-14 membered heteroaryl having 1, 2, or 3 heteroatoms selected from N, O, and S, and having 1, 2, 3, or 4 of the heteroatoms; said 3-14 membered heterocyclyl is a 3-14 membered heterocyclyl having 1, 2, or 3 heteroatoms selected from N, O, and S, and having 1, 2, 3, or 4 of the heteroatoms;

[0079] each R 5-1 is independently deuterium, cyano, halo, oxo, hydroxyl, NR 5-1-1 R 5-1-2 , C1-10 Alkyl, OC 1-10 Alkyl, C 3-6 cycloalkyl, -NH-CO-C 1- 10 Alkyl; the C 1-10 Alkyl, the OC 1-10 Alkyl groups and the -NH-CO-C 1-10 Alkyl groups may be optionally substituted with one or more deuterium, halogen, or hydroxyl groups;

[0080] R 5-1-1 and R 5-1-2 Independently H or C 1-10 Alkyl; the C 1-10 Alkyl groups may be optionally surrounded by one, two, or three R's. 5-1-1-1 replace;

[0081] Each R 5-1-1-1 Independently, it is either deuterium or a 5-14 heteroaryl group; the 5-14 heteroaryl group is a 5-14 heteroaryl group with one, two, or three heteroatoms selected from N, O, and S, and the number of heteroatoms is one, two, three, or four; the 5-14 heteroaryl group is optionally substituted with one or more deuterium groups;

[0082] R 6 It can be H, deuterium, or methyl.

[0083] In one embodiment, the 5-14-membered heteroaryl group in ring A can be a nitrogen-containing 5-14-membered heteroaryl group with 2, 3, or 4 heteroatoms, preferably a nitrogen-containing 5-6-membered heteroaryl group with 2, 3, or 4 heteroatoms, more preferably imidazolyl, 1,2,3-triazole, 1,2,4-triazole, or tetrazolium, for example...

[0084] In one scheme, in L, the C 1-10 Alkylene can be C 1-6 Alkylene, preferably C 1-4 Alkylene, for example

[0085] In one scheme, in L, the C 2-10 The subalkenyl group can be C 2-6 Alkenyl group, preferably C 2-4 imidene groups, for example

[0086] In one of the schemes, R 1 R 2 R 3 R 4 R 5 R 3-1 R3-2 , R 3-3 , R 3-4 , R 5-1 , R 1-1-1 , R 1-1-2 , R 3-4-1 , R 3-4-2 , R 3-4-3 , R 3-4-4 , R 5-1- 1 , R 5-1-2 , R a and R b , the C 1-10 alkyl group can independently be a C 1-6 alkyl group, preferably a methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl or t-butyl group.

[0087] In one aspect, R 1 , R 2 and R 3 , the C 2-10 alkenyl group can independently be a C 2-6 alkenyl group, preferably a C 2-4 alkenyl group, for example

[0088] In one aspect, R 1 , R 2 and R 3 , the C 2-10 alkynyl group can independently be a C 2-6 alkynyl group, preferably a C 2-4 alkynyl group, for example

[0089] In one aspect, R 3 and R 5 , the C 3-14 cycloalkyl group can independently be a C 3-10 cycloalkyl group, preferably a C 3-8 cycloalkyl group, more preferably a C 3-8 monocycloalkyl group, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0090] In one aspect, R 1 , R 2 and R 5-1 , the C 1-10 alkyl group in the O-C 1-10 alkyl group can independently be a C 1-6 alkyl group, preferably a methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl or t-butyl group.

[0091] In one aspect, R 1 , R2 R 3 R 5 R 3-4 and R 5-1-1-1 In this context, the 5-14-membered heteroaryl group can be independently a 5-6-membered heteroaryl group or an 8-10-membered heteroaryl group;

[0092] The 5-6 membered heteroaryl group can be independently defined as "a 5-6 membered heteroaryl group whose heteroatoms are selected from one or two of N, O, and S, and whose number of heteroatoms is one, two, three, or four", preferably pyridyl (e.g., ), diazoles (e.g., pyrazole or imidazole, and for example...) ), triazoles (e.g., 1,2,3-triazole or 1,2,4-triazole, and for example...) ), pyrimidine group (e.g.) ), thiazolyl (e.g.) ), oxazolyl (e.g.) ), tetrazolium (e.g.) The 8-10 membered heteroaryl group can independently be "an 8-10 membered heteroaryl group with one or two heteroatoms of N or O, and with one, two or three heteroatoms", preferably benzo[c][1,2,5]oxadiazolyl (e.g. ) or benzopyridyl (e.g., quinolinyl or isoquinolinyl, and for example...) ).

[0093] In one of the schemes, R 1 R 2 The 3-14 membered heterocyclic group formed together with the carbon atom attached thereto can be a 3-8 membered heterocyclic group, preferably a 3-8 membered oxocyclic group, more preferably a 3-6 membered oxocyclic group, such as an oxopropyl group.

[0094] In one of the schemes, R 3 and R 5 In, the C 6-14 The aryl group can independently be C 6-10 Aryl, preferably phenyl or naphthyl (e.g.) ).

[0095] In one of the schemes, R 5 In this context, the 3-14 membered heterocyclic group can be a 3-10 membered heterocyclic group, preferably a 3-8 membered heterocyclic group, more preferably a 3-8 membered nitrogen heterocyclic group or a 3-8 membered oxygen heterocyclic group, such as piperidinyl (and for example...). ).

[0096] In one scheme, L is C 1-10 Alkylene or C 2-10 alkenyl group; preferably C1-6 Alkylene or C 2-6 alkenyl; more preferably C 1-6 Alkylene.

[0097] In one scheme, L is C 4-6 Alkylene; the C 4-6 The alkylene group may optionally be substituted with one or more deuterium groups; preferably, L is C. 4-6 Alkylene.

[0098] In one scheme, L is "1" connects to ring A, R L Independently H, D, or -CH3, preferably, one of the R L For H, another R L It can be H, D, or -CH3.

[0099] In one scheme, X is CR 1 R 2 or

[0100] In one scheme, X is CR 1 R 2 .

[0101] In one of the schemes, R 1 and R 2 Independently halogen or C 1-6 alkyl.

[0102] In one of the schemes, R 1 H or halogen; R 2 C 1-6 Alkyl; preferably, R 1 It is a halogen; R 2 C 1-6 Alkyl group. In one embodiment, ring A is a 5-10-membered heteroaryl group, preferably a 5-6-membered heteroaryl group, more preferably a diazole (e.g., imidazole), a triazole (e.g., 1,2,3-triazole or 1,2,4-triazole) or a tetraazole.

[0103] In one embodiment, ring A is a 5-membered heteroaryl group, wherein the heteroatoms in the 5-membered heteroaryl group are selected from one, two, or three of N, O, and S, and the number of heteroatoms is 1, 2, or 3.

[0104] In one of the schemes, R 1 and R 2 Independently, H, deuterium, OH, CN, halogen, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 acetylinyl, OC 1-10 Alkyl or 5-14-membered heteroaryl; the C 1-10alkyl, said C 2-10 alkenyl, said C 2-10 alkynyl, said O-C 1-10 alkyl and said 5-14 membered heteroaryl are optionally substituted with 1, 2, or 3 R 1-1 ; said 5-14 membered heteroaryl is a 5-14 membered heteroaryl having 1, 2, or 3 heteroatoms selected from N, O, and S, and having 1, 2, 3, or 4 carbon atoms;

[0105] Preferably, R 1 and R 2 are independently H, OH, CN, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, O-C 1-10 alkyl, or 5-14 membered heteroaryl; said C 1-10 alkyl, said C 2-10 alkenyl, said C 2-10 alkynyl, said O-C 1-10 alkyl and said 5-14 membered heteroaryl are optionally substituted with 1, 2, or 3 R 1-1 ; said 5-14 membered heteroaryl is a 5-14 membered heteroaryl having 1, 2, or 3 heteroatoms selected from N, O, and S, and having 1, 2, 3, or 4 carbon atoms;

[0106] More preferably, R 1 and R 2 are independently H, OH, halogen, or C 1-10 alkyl;

[0107] For example, R 1 is C 1-10 alkyl, R 2 is H, OH, or halogen; or R 1 is C 1-10 alkyl, R 2 is H or halogen;

[0108] For another example, R 1 is C 1-6 alkyl, R 2 is H, OH, or halogen; or R 1 is C 1-6 alkyl, R 2 is H or halogen.

[0109] In one aspect, each R 1-1 is independently OH, halogen, SO3R 1-1-1 , or COOR 1-1-2 .

[0110] In one aspect, R 1-1-1 and R1-1-2 Independently H or C 1-10 Alkyl; preferably H or C 1-6 alkyl.

[0111] In one of the schemes, R 1 R 2 Together with the carbon atom attached thereto, it forms a 3-14 membered heterocyclic group; the 3-14 membered heterocyclic group is a 3-14 membered heterocyclic group in which the heteroatoms are selected from one or two of N, O and S, and the number of heteroatoms is independently one or two; preferably, R 1 R 2 Together with the carbon atom attached to it, it forms a 3-6 membered oxoheterocyclic group.

[0112] In one of the schemes, R 3 For deuterium, CN, CONR 3-1 R 3-2 COOR 3-3 C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-14 cycloalkyl, C 6-14 Aryl or 5-14 heteroaryl; the C 1-10 Alkyl, the C 2-10 alkenyl, the C 2-10 alkynyl group, the C 3-14 cycloalkyl, the C 6-14 The aryl group and the 5-14 heteroaryl group are optionally surrounded by one, two, or three R groups. 3-4 Substitution; the 5-14 membered heteroaryl group is a 5-14 membered heteroaryl group whose heteroatoms are selected from 1, 2 or 3 of N, O and S, and whose number of heteroatoms is 1, 2, 3 or 4;

[0113] Preferably, R 3 For CN, CONR 3-1 R 3-2 COOR 3-3 C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-14 cycloalkyl, C 6-14 Aryl or 5-14 heteroaryl; the C 1-10 Alkyl, the C 2-10 alkenyl, the C 2-10 alkynyl group, the C 3-14 cycloalkyl, the C 6-14 The aryl group and the 5-14 heteroaryl group are optionally surrounded by one, two, or three R groups. 3-4substituted; said 5-14 membered heteroaryl is a 5-14 membered heteroaryl having 1, 2, or 3 heteroatoms selected from N, O, and S, and having 1, 2, 3, or 4 of the heteroatoms;

[0114] More preferably, R 3 is H, C 1-10 alkyl, or 5-14 membered heteroaryl; said 5-6 membered heteroaryl is a 5-6 membered heteroaryl having 1, 2, or 3 heteroatoms selected from N, O, and S, and having 1, 2, 3, or 4 of the heteroatoms;

[0115] For example, R 3 is H, C 1-6 alkyl, or 5-6 membered heteroaryl; again for example, R 3 is H or C 1-6 alkyl; again for example, H or C 1-4 alkyl; more for example, H.

[0116] In one aspect, R 3-1 , R 3-2 , and R 3-3 are independently H or C 1-10 alkyl; preferably H or C 1-6 alkyl.

[0117] In one aspect, each R 3-4 is independently OH, halogen, NR 3-4-1 R 3-4-2 , C 1-10 alkyl, 5-14 membered heteroaryl; said C 1-10 alkyl and said 5-14 membered heteroaryl are optionally substituted with 1, 2, or 3 R 3-4-4 ; said 5-14 membered heteroaryl is a 5-14 membered heteroaryl having 1, 2, or 3 heteroatoms selected from N, O, and S, and having 1, 2, 3, or 4 of the heteroatoms;

[0118] Preferably, each R 3-4 is independently OH, NR 3-4-1 R 3-4-2 , C 1-10 alkyl, or 5-14 membered heteroaryl;

[0119] More preferably, each R 3-4 is independently OH, NR 3-4-1 R 3-4-2 , C 1-6 alkyl, or 5-6 membered heteroaryl.

[0120] In one preferred aspect, R 3-4-1 and R 3-4-2 are independently H, or C1-10 Alkyl; preferably, R 3-4-1 and R 3-4-2 H independently Or C 1-6 alkyl.

[0121] In one of the schemes, R 3-4-3 C 1-10 Alkyl; preferably C 1-6 alkyl.

[0122] In a certain scheme, each R 3-4-4 Independent of OH and NR a R b Or C 1-10 Alkyl groups; preferably OH or NR a R b Or C 1-6 alkyl.

[0123] In one of the schemes, R a and R b H independently Or C 1-10 Alkyl; preferably H, Or C 1-6 alkyl.

[0124] In a certain optimal solution, each R 3-4-4-1 Independently OH or NR a R b ; preferably OH or NH2.

[0125] In a certain scheme, R is

[0126] In a certain scheme, R is R 6 For H, R 3 C 1-6 alkyl.

[0127] In one of the schemes, R 4 For H or C 1-10 Alkyl; preferably H or C 1-6 Alkyl; more preferably H or C 1-4 alkyl.

[0128] In one of the schemes, R 4 C 1-6 Alkyl; for example, C 1-4 alkyl.

[0129] In one of the schemes, R 5 For H, C 1-10 Alkyl, C 6-14 Aryl, 5-14 membered heteroaryl, or 3-14 membered heterocyclic; the C1-10 alkyl, said C 6-14 aryl, said 5-14 membered heteroaryl, and said 3-14 membered heterocyclyl are optionally substituted with 1, 2, or 3 R 5-1 ; said 5-14 membered heteroaryl is a 5-14 membered heteroaryl having 1, 2, or 3 heteroatoms selected from N, O, and S, and having 1, 2, 3, or 4 carbon atoms; and said 3-14 membered heterocyclyl is a 3-14 membered heterocyclyl having 1, 2, or 3 heteroatoms selected from N, O, and S, and having 1, 2, 3, or 4 carbon atoms;

[0130] preferably, R 5 is H, C 6-14 aryl, 5-14 membered heteroaryl; said C 6-14 aryl and said 5-14 membered heteroaryl are optionally substituted with 1, 2, or 3 R 5- 1 ; said 5-14 membered heteroaryl is a 5-14 membered heteroaryl having 1, 2, or 3 heteroatoms selected from N, O, and S, and having 1, 2, 3, or 4 carbon atoms;

[0131] more preferably, R 5 is H, C 6-14 aryl, 5-10 membered heteroaryl; said C 6-14 aryl and said 5-10 membered heteroaryl are optionally substituted with 1, 2, or 3 R 5-1 ; said 5-10 membered heteroaryl is a 5-10 membered heteroaryl having 1, 2, or 3 heteroatoms selected from N, O, and S, and having 1, 2, 3, or 4 carbon atoms;

[0132] for example, R 5 is C 6-14 aryl; said C 6-14 aryl is optionally substituted with 1, 2, or 3 R 5-1 .

[0133] In an embodiment, when the 5-14 membered heteroaryl in R 5 is optionally substituted with 1, 2, or 3 R 5-1 , R 5-1 may be bonded to the 5-14 membered heteroaryl through a heteroatom (e.g., N) or a carbon atom; for example, (e.g., R ) or (e.g., R ).

[0134] In an embodiment, each R 5-1 is independently deuterium, halogen, oxo, hydroxyl, NR 5-1-1 R5-1-2 , C 1-10 alkyl, O-C 1-10 alkyl, C 3-6 cycloalkyl, -NH-CO-C 1-10 alkyl; said C 1-10 alkyl, said O-C 1-10 alkyl and said -NH-CO-C 1-10 alkyl is optionally substituted with one or more deuterium, halogen, hydroxyl.

[0135] In one aspect, each R 5-1 is independently halogen, oxo, hydroxyl, NR 5-1-1 R 5-1-2 , C 1-10 alkyl, O-C 1-10 alkyl, C 3-6 cycloalkyl; preferably, each R 5-1 is independently oxo, NR 5-1-1 R 5-1-2 , C 1-10 alkyl or O-C 1-10 alkyl; more preferably, each R 5-1 is independently oxo, NR 5-1-1 R 5-1-2 , C 1- 6alkyl or O-C 1-6 alkyl; for example, each R 5-1 is independently NR 5-1-1 R 5-1-2 ; for another example, each R 5-1 is independently NH2.

[0136] In one aspect, R 5-1-1 and R 5-1-2 are independently H or C 1-10 alkyl; preferably H or C 1-6 alkyl.

[0137] In one aspect, each R 5-1-1-1 is independently 5-14 membered heteroaryl; said 5-14 membered heteroaryl is a 5-14 membered heteroaryl having 1, 2, or 3 kinds of heteroatoms selected from N, O, and S, and having 1, 2, 3, or 4 number of heteroatoms; preferably, each R 5-1-1-1 is independently 5-10 membered heteroaryl; more preferably, each R 5-1-1-1 is independently 5-6 membered heteroaryl.

[0138] In one aspect, R 5 is 5-6 membered heteroaryl having 1 or 2 number of heteroatoms selected from N; said 5-6 membered heteroaryl is optionally substituted with 1, 2, or 3 R 5-1substituted; preferably, the number of heteroatoms is 2.

[0139] In one aspect, R 5 is pyridyl; said pyridyl is optionally substituted with 1, 2, or 3 R 5-1 substituents.

[0140] In one aspect, R 5 is 5-6 membered heteroaryl, the kind of heteroatom in said 5-6 membered heteroaryl is N, and the number of heteroatoms is 1 or 2; said 5-6 membered heteroaryl is substituted with 1, 2, or 3 R 5-1 substituents; and at least one R 5-1 is hydroxy;

[0141] Preferably, said 5-6 membered heteroaryl is substituted with 2 or 3 R 5-1 substituents, at least one R 5-1 is oxo; and, at least one R 5-1 is amino.

[0142] In one aspect, R 5 is 5-6 membered heteroaryl, the kind of heteroatom in said 5-6 membered heteroaryl is N, and the number of heteroatoms is 1 or 2; said 5-6 membered heteroaryl is substituted with 4 or 5 R 5-1 substituents; and at least one R 5-1 is hydroxy;

[0143] Preferably, said 5-6 membered heteroaryl is substituted with 2 or 3 R 5-1 substituents, at least one R5-1is oxo; and, at least one R5-1is amino.

[0144] In one aspect, R 5 is partially saturated 5-6 membered heterocyclyl, the kind of heteroatom in said partially saturated 5-6 membered heterocyclyl is N, and the number of heteroatoms is independently 1 or 2; said partially saturated 5-6 membered heterocyclyl is substituted with 1, 2, or 3 R 5-1 substituents, and at least one R 5-1 is oxo.

[0145] Preferably, said partially saturated 5-6 membered heterocyclyl is substituted with 2 or 3 R 5-1 substituents, at least one R 5-1 is oxo; and, at least one R 5-1 is amino.

[0146] In one aspect, R 5 is partially saturated 5-6 membered heterocyclyl, the kind of heteroatom in said partially saturated 5-6 membered heterocyclyl is N, and the number of heteroatoms is independently 1 or 2; said partially saturated 5-6 membered heterocyclyl is substituted with 4 or 5 R 5-1 substituents, and at least one R5-1 is oxo;

[0147] R is preferably -NH2, deuterium, halogen, oxo, or C 5-1 is oxo; and, R 5-1 is amino.

[0148] In one aspect, R 5-1 is independently -NH2, deuterium, halogen, oxo, or C 1-6 alkyl, for example -NH2, deuterium, halogen, or C 1-6 alkyl.

[0149] In one aspect, R 5-1 is independently -NH2, deuterium, halogen, oxo, or C 1-6 alkyl.

[0150] In one aspect, R 5-1 is -NH2.

[0151] In one aspect, R 5-1 is independently deuterium, halogen, oxo, or C 1-6 alkyl; for example, independently deuterium, halogen, or C 1-6 alkyl.

[0152] In one aspect, R 5-1 is independently deuterium, halogen, oxo, or C 1-6 alkyl.

[0153] In one aspect, each R 5-1 is independently deuterium, cyano, halogen, hydroxyl, -NH2, -NH-C 1-4 alkyl, C 1-4 alkyl, or O-C 1-4 alkyl.

[0154] In one aspect, each R 5-1 is independently deuterium, halogen, oxo, or C 1-4 alkyl, C 1-4 alkyl, or O-C 1-4 alkyl.

[0155] In one aspect, each R 5-1 is cyano.

[0156] In one aspect, R 6 is H or methyl.

[0157] In one aspect, R 6 is H.

[0158] In one aspect, the compound of Formula I is selected from any of the following aspects:

[0159] Aspect 1:

[0160] L is C 1-10 alkylene or C 2-10 alkenylene; said C 1-10 alkylene and said C 2-10 alkenylene are optionally substituted with one or more deuterium;

[0161] X is CR 1 R 2 or said is optionally substituted with one or two deuterium;

[0162] ring A is a 5-14 membered heteroaryl; said 5-14 membered heteroaryl is a 5-14 membered heteroaryl having 1, 2, or 3 heteroatoms selected from N, O, and S, and having 1, 2, 3, or 4 of the heteroatoms; said 5-14 membered heteroaryl is optionally substituted with one or more deuterium;

[0163] R 1 and R 2 are independently H, deuterium, OH, CN, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, O-C 1-10 alkyl, or 5-14 membered heteroaryl; said C 1-10 alkyl, said C 2-10 alkenyl, said C 2-10 alkynyl, said O-C 1-10 alkyl, and said 5-14 membered heteroaryl are optionally substituted with one, two, or three R 1-1 ; said 5-14 membered heteroaryl is a 5-14 membered heteroaryl having 1, 2, or 3 heteroatoms selected from N, O, and S, and having 1, 2, 3, or 4 of the heteroatoms;

[0164] each R 1-1 is independently deuterium, OH, halogen, SO3R 1-1-1 , or COOR 1-1-2 ;

[0165] R 1-1-1 and R 1-1-2 are independently H or C 1-10 alkyl; said C 1-10 alkyl is optionally substituted with one or more deuterium;

[0166] alternatively, R 1 , R 2 , and the carbon atom to which they are attached together form a 3-14 membered heterocyclyl; said 3-14 membered heterocyclyl is a 3-14 membered heterocyclyl having 1 or 2 heteroatoms selected from N, O, and S, and having 1 or 2 of the heteroatoms; said 3-14 membered heterocyclyl is optionally substituted with one or more deuterium;

[0167] R is

[0168] R 3 is H, deuterium, CN, CONR 3-1 R 3-2 , COOR 3-3 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-14 cycloalkyl, C 6-14 aryl or 5-14 membered heteroaryl; said C 1-10 alkyl, said C 2-10 alkenyl, said C 2-10 alkynyl, said C 3-14 cycloalkyl, said C 6-14 aryl and said 5-14 membered heteroaryl are optionally substituted with 1, 2, or 3 R 3-4 ; said 5-14 membered heteroaryl is a 5-14 membered heteroaryl having 1, 2, 3, or 4 heteroatoms selected from N, O, and S;

[0169] R 3-1 , R 3-2 , and R 3-3 are independently H or C 1-10 alkyl; said C 1-10 alkyl is optionally substituted with one or more deuterium;

[0170] each R 3-4 is independently deuterium, OH, halogen, NR 3-4-1 R 3-4-2 , C 1-10 alkyl or 5-14 membered heteroaryl; said C 1-10 alkyl and said 5-14 membered heteroaryl are optionally substituted with 1, 2, or 3 R 3-4-4 ; said 5-14 membered heteroaryl is a 5-14 membered heteroaryl having 1, 2, 3, or 4 heteroatoms selected from N, O, and S;

[0171] R 3-4-1 and R 3-4-2 are independently H, or C 1-10 alkyl; said C 1-10 alkyl is optionally substituted with one or more deuterium;

[0172] R 3-4-3 is C 1-10 alkyl; said C 1-10 alkyl is optionally substituted with one or more deuterium;

[0173] each R 3-4-4 is independently deuterium, OH, NR a R b or C 1-10 alkyl; said C 1-10 alkyl is optionally substituted with 1, 2, or 3 R 3-4-4-1 ;

[0174] R a and R b are independently H, or C 1-10 alkyl; said C 1-10 alkyl is optionally substituted with one or more deuterium;

[0175] each R 3-4-4-1 is independently deuterium, OH, or NH2;

[0176] R4is H or C 1-10 alkyl; said C 1-10 alkyl is optionally substituted with 1 or more deuterium;

[0177] R 5 is H, deuterium, C 1-10 alkyl, C 3-14 cycloalkyl, C 6-14 aryl, 5-14 membered heteroaryl, or 3-14 membered heterocyclyl; said C 1-10 alkyl, said C 3-14 cycloalkyl, said C 6-14 aryl, said 5-14 membered heteroaryl, and said 3-14 membered heterocyclyl are optionally substituted with 1, 2, or 3 R 5-1 ; said 5-14 membered heteroaryl is a 5-14 membered heteroaryl having 1, 2, or 3 heteroatoms selected from N, O, and S, and having 1, 2, 3, or 4 ring members; said 3-14 membered heterocyclyl is a 3-14 membered heterocyclyl having 1, 2, or 3 heteroatoms selected from N, O, and S, and having 1, 2, 3, or 4 ring members;

[0178] each R 5-1 is independently deuterium, halogen, oxo, hydroxyl, NR 5-1-1 R 5-1-2 , C 1-10 alkyl, or O-C 1-10 alkyl; said C 1-10 alkyl and said O-C 1-10 alkyl are optionally substituted with one or more deuterium;

[0179] R 5-1-1 and R 5-1-2 are independently H or C 1-10 alkyl; said C1-10 alkyl is optionally substituted with 1, 2, or 3 R 5-1-1-1 substituents;

[0180] each R 5-1-1-1 is independently deuterium or 5-14 membered heteroaryl; said 5-14 membered heteroaryl is a 5-14 membered heteroaryl having 1, 2, or 3 heteroatoms selected from N, O, and S, and having 1, 2, 3, or 4 of said heteroatoms; said 5-14 membered heteroaryl is optionally substituted with one or more deuterium;

[0181] R 6 is H, deuterium, or methyl;

[0182] Scheme 2:

[0183] L is C 1-6 alkylene or C 2-6 alkenylene; said C 1-6 alkylene and said C 2-6 alkenylene are optionally substituted with 1 or more deuterium;

[0184] X is CR 1 R 2 or said is optionally substituted with one or two deuterium;

[0185] Ring A is 5-10 membered heteroaryl; said 5-10 membered heteroaryl is a 5-10 membered heteroaryl having 1, 2, or 3 heteroatoms selected from N, O, and S, and having 1, 2, 3, or 4 of said heteroatoms; said 5-14 membered heteroaryl is optionally substituted with 1 or more deuterium;

[0186] R 1 and R 2 are independently H, deuterium, OH, CN, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, O-C 1-6 alkyl, or 5-10 membered heteroaryl; said C 1-6 alkyl, said C 2-6 alkenyl, said C 2-6 alkynyl, said O-C 1-6 alkyl, and said 5-10 membered heteroaryl are optionally substituted with 1, 2, or 3 R 1-1 substituents; said 5-10 membered heteroaryl is a 5-10 membered heteroaryl having 1, 2, or 3 heteroatoms selected from N, O, and S, and having 1, 2, 3, or 4 of said heteroatoms;

[0187] each R 1-1 is independently deuterium, OH, halogen, SO3R 1-1-1 or COOR1-1-2 ;

[0188] R 1-1-1 and R 1-1-2 are independently H or C 1-6 alkyl; said C 1-6 alkyl is optionally substituted with one or more deuterium;

[0189] or, R 1 , R 2 and the carbon atom to which they are attached form a 3-6 membered heterocyclyl; said 3-6 membered heterocyclyl is a 3-6 membered heterocyclyl having 1 or 2 heteroatoms selected from N, O, and S, the number of heteroatoms being independently 1 or 2; said 3-6 membered heterocyclyl is optionally substituted with 1 or more deuterium;

[0190] R is

[0191] R 3 is deuterium, CN, CONR 3-1 R 3-2 , COOR 3-3 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, or 5-10 membered heteroaryl; said C 1-6 alkyl, said C 2-6 alkenyl, said C 2-6 alkynyl, said C 3-10 cycloalkyl, said C 6-10 aryl, and said 5-10 membered heteroaryl are optionally substituted with 1, 2, or 3 R 3-4 ; said 5-10 membered heteroaryl is a 5-10 membered heteroaryl having 1, 2, or 3 heteroatoms selected from N, O, and S, the number of heteroatoms being 1, 2, 3, or 4;

[0192] R 3-1 , R 3-2 , and R 3-3 are independently H or C 1-6 alkyl; said C 1-6 alkyl is optionally substituted with one or more deuterium;

[0193] each R 3-4 is independently deuterium, OH, halogen, NR 3-4-1 R 3-4-2 , C 1-6 alkyl, or 5-10 membered heteroaryl; said C 1-6 alkyl and said 5-10 membered heteroaryl are optionally substituted with 1, 2, or 3 R 3-4-4substituted; the 5-10 membered heteroaryl is a 5-10 membered heteroaryl having 1, 2, or 3 heteroatoms selected from N, O, and S, and having 1, 2, 3, or 4 rings;

[0194] R 3-4-1 and R 3-4-2 are independently H, or C 1-6 alkyl; the C 1-6 alkyl is optionally substituted with one or more deuterium;

[0195] R 3-4-3 is C 1-6 alkyl; the C 1-6 alkyl is optionally substituted with one or more deuterium;

[0196] each R 3-4-4 is independently deuterium, OH, NR a R b or C 1-6 alkyl; the C 1-6 alkyl is optionally substituted with 1, 2, or 3 R 3-4-4-1 ;

[0197] R a and R b are independently H, or C 1-6 alkyl; the C 1-6 alkyl is optionally substituted with one or more deuterium;

[0198] each R 3-4-4-1 is independently deuterium, OH, or NH2;

[0199] R 4 is H or C 1-6 alkyl;

[0200] R 5 is H, deuterium, C 1-6 alkyl, C 3-10 cycloalkyl, C 6-14 aryl, 5-14 membered heteroaryl, or 3-10 membered heterocyclyl; the C 1-6 alkyl, C 3-10 cycloalkyl, the C 6-14 aryl, the 5-14 membered heteroaryl, and the 3-10 membered heterocyclyl are optionally substituted with 1, 2, or 3 R 5-1 ; the 5-14 membered heteroaryl is a 5-14 membered heteroaryl having 1, 2, or 3 heteroatoms selected from N, O, and S, and having 1, 2, 3, or 4 rings; the 3-10 membered heterocyclyl is a 3-10 membered heterocyclyl having 1, 2, or 3 heteroatoms selected from N, O, and S, and having 1, 2, 3, or 4 rings.

[0201] each R 5-1 independently deuterium, halogen, oxo, hydroxyl, NR 5-1-1 R 5-1-2 , C 1-6 alkyl or O-C 1-6 alkyl; said C 1-6 alkyl and said O-C 1-6 alkyl are optionally substituted with one or more deuterium;

[0202] R 5-1-1 and R 5-1-2 are independently H or C 1-6 alkyl; said C 1-6 alkyl is optionally substituted with 1, 2, or 3 R 5-1-1-1 ;

[0203] each R 5-1-1-1 is independently deuterium or 5-10 membered heteroaryl; said 5-10 membered heteroaryl is a 5-10 membered heteroaryl having 1, 2, or 3 heteroatoms selected from N, O, and S, and having 1, 2, 3, or 4 of the heteroatoms; said 5-10 membered heteroaryl is optionally substituted with one or more deuterium;

[0204] R 6 is H, deuterium, or methyl;

[0205] Scheme 3:

[0206] L is C 1-10 alkylene or C 2-10 alkenylene; said C 1-10 alkylene and said C 2-10 alkenylene are optionally substituted with 1 or more deuterium;

[0207] X is CR 1 R 2 or said is optionally substituted with one or two deuterium;

[0208] Ring A is 5-14 membered heteroaryl; said 5-14 membered heteroaryl is a 5-14 membered heteroaryl having 1, 2, or 3 heteroatoms selected from N, O, and S, and having 1, 2, 3, or 4 of the heteroatoms; said 5-14 membered heteroaryl is optionally substituted with 1 or more deuterium;

[0209] R 1 and R 2 are independently H, deuterium, OH, NH2, CN, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-14 cycloalkyl, C5-14 cycloalkenyl, O-C 1-10 alkyl, O-C 3-14 cycloalkyl or 5-14 membered heteroaryl; said C 1-10 alkyl, said C 2-10 alkenyl, said C 2-10 alkynyl, said C 3-14 cycloalkyl, C 5-14 cycloalkenyl, said O-C 1-10 alkyl, said O-C 3-14 cycloalkyl and said 5-14 membered heteroaryl are optionally substituted with 1, 2, or 3 R 1-1 ; said 5-14 membered heteroaryl is a 5-14 membered heteroaryl having 1, 2, or 3 heteroatoms selected from N, O, and S, and having 1, 2, 3, or 4 carbon atoms;

[0210] each R 1-1 is independently deuterium, OH, halogen, SO3R 1-1-1 , or COOR 1-1-2 ;

[0211] R 1-1-1 and R 1-1-2 are independently H or C 1-10 alkyl; said C 1-10 alkyl is optionally substituted with one or more deuterium;

[0212] alternatively, R 1 , R 2 and the carbon atom to which they are attached form a 3-14 membered heterocyclyl; said 3-14 membered heterocyclyl is a 3-14 membered heterocyclyl having 1 or 2 heteroatoms selected from N, O, and S, and having 1 or 2 carbon atoms;

[0213] R is

[0214] R 3 is deuterium, C 1-10 alkyl or 5-14 membered heteroaryl; said C 1-10 alkyl and said 5-14 membered heteroaryl are optionally substituted with 1, 2, or 3 R 3-4 ;

[0215] each R 3-4 is independently deuterium, OH, NR 3-4-1 R3-4-2, C 1-10 alkyl or 5-14 membered heteroaryl; said C 1-10 alkyl and said 5-14 membered heteroaryl are optionally substituted with 1, 2, or 3 R 3-4-4substituted; said 5-14 membered heteroaryl is a 5-14 membered heteroaryl having 1, 2, or 3 heteroatoms selected from N, O, and S, and having 1, 2, 3, or 4 of the heteroatoms; and said 3-14 membered heterocyclyl is a 3-14 membered heterocyclyl having 1, 2, or 3 heteroatoms selected from N, O, and S, and having 1, 2, 3, or 4 of the heteroatoms;

[0216] R 3-4-1 and R 3-4-2 are independently H, or C 1-10 alkyl; said C 1-10 alkyl is optionally substituted with one or more deuterium;

[0217] each R 3-4-4 is independently deuterium, OH, NRaR b or C 1-10 alkyl; said C 1-10 alkyl is optionally substituted with 1, 2, or 3 R 3-4-4-1 ;

[0218] R a and R b are independently H, or C 1-10 alkyl; said C 1-10 alkyl is optionally substituted with one or more deuterium;

[0219] each R 3-4-4-1 is independently deuterium, OH, or NH2;

[0220] R 4 is H or C 1-10 alkyl; said C 1-10 alkyl is optionally substituted with one or more deuterium;

[0221] R 5 is H, deuterium, C 1-10 alkyl, C 6-14 aryl, 5-14 membered heteroaryl, or 3-14 membered heterocyclyl; said C 1-10 alkyl, said C 6-14 aryl, said 5-14 membered heteroaryl, and said 3-14 membered heterocyclyl are optionally substituted with 1, 2, or 3 R 5-1 ; said 5-14 membered heteroaryl is a 5-14 membered heteroaryl having 1, 2, or 3 heteroatoms selected from N, O, and S, and having 1, 2, 3, or 4 of the heteroatoms; and said 3-14 membered heterocyclyl is a 3-14 membered heterocyclyl having 1, 2, or 3 heteroatoms selected from N, O, and S, and having 1, 2, 3, or 4 of the heteroatoms;

[0222] each R 5-1 is independently deuterium, halogen, oxo, hydroxyl, NR 5-1-1 R 5-1-2 , C 1-10 alkyl, or O-C1-10 alkyl; said C 1-10 alkyl and said O-C 1-10 alkyl is optionally substituted with one or more deuterium;

[0223] R 5-1-1 and R 5-1-2 are independently H or C 1-10 alkyl; said C 1-10 alkyl is optionally substituted with 1, 2, or 3 R 5-1-1-1 substituents;

[0224] each R 5-1-1-1 is independently deuterium or 5-14 membered heteroaryl; said 5-14 membered heteroaryl is a 5-14 membered heteroaryl having 1, 2, or 3 heteroatoms selected from N, O, and S, and having 1, 2, 3, or 4 number of heteroatoms; said 5-14 membered heteroaryl is optionally substituted with one or more deuterium;

[0225] R 6 is H, deuterium, or methyl.

[0226] Scheme 4:

[0227] L is C 1-10 alkylene or C 2-10 alkenylene; said C 1-10 alkylene and said C 2-10 alkenylene is optionally substituted with 1 or more deuterium;

[0228] X is CR 1 R 2 or said is optionally substituted with one or two deuterium;

[0229] Ring A is azole, triazole, or tetrazole;

[0230] R 1 and R 2 are independently H, deuterium, OH, NH2, CN, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-14 cycloalkyl, C 5-14 cycloalkenyl, O-C 1-10 alkyl, O-C 3-14 cycloalkyl, or 5-14 membered heteroaryl; said C 1-10 alkyl, said C 2-10 alkenyl, said C 2-10 alkynyl, said C 3-14 cycloalkyl, C 5-14 cycloalkenyl, said O-C 1-10 alkyl, said O-C3-14 Cycloalkyl and said 5-14 membered heteroaryl are optionally substituted with 1, 2, or 3 R 1-1 ; said 5-14 membered heteroaryl is a 5-14 membered heteroaryl having 1, 2, or 3 heteroatoms selected from N, O, and S, and having 1, 2, 3, or 4 carbon atoms;

[0231] R 1-1 is independently deuterium, OH, halogen, SO3R 1-1-1 , or COOR 1-1-2 ;

[0232] R 1-1-1 and R 1-1-2 are independently H or C 1-10 alkyl; said C 1-10 alkyl is optionally substituted with one or more deuterium;

[0233] or, R 1 , R 2 , and the carbon atom to which they are attached form a 3-14 membered heterocyclyl; said 3-14 membered heterocyclyl is a 3-14 membered heterocyclyl having 1 or 2 heteroatoms selected from N, O, and S, and having 1 or 2 carbon atoms;

[0234] R is

[0235] R 3 is H, deuterium, CN, CONR 3-1 R 3-2 , COOR 3-3 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-14 cycloalkyl, C 6-14 aryl, or 5-14 membered heteroaryl; said C 1-10 alkyl, said C 2-10 alkenyl, said C 2-10 alkynyl, said C 3-14 cycloalkyl, said C 6-14 aryl, and said 5-14 membered heteroaryl are optionally substituted with 1, 2, or 3 R 3-4 ; said 5-14 membered heteroaryl is a 5-14 membered heteroaryl having 1, 2, or 3 heteroatoms selected from N, O, and S, and having 1, 2, 3, or 4 carbon atoms;

[0236] R 3-1 , R 3-2 , and R 3-3 are independently H or C 1-10 alkyl; said C 1-10alkyl is optionally substituted with one or more deuterium;

[0237] each R 3-4 is independently deuterium, OH, halogen, NR 3-4-1 R 3-4-2 , C 1-10 alkyl or 5-14 membered heteroaryl; said C 1-10 alkyl and said 5-14 membered heteroaryl are optionally substituted with 1, 2, or 3 R 3-4-4 ; said 5-14 membered heteroaryl is a 5-14 membered heteroaryl having 1, 2, 3, or 4 heteroatoms selected from N, O, and S;

[0238] R 3-4-1 and R 3-4-2 are independently H, or C 1-10 alkyl; said C 1-10 alkyl is optionally substituted with one or more deuterium;

[0239] R 3-4-3 is C 1-10 alkyl; said C 1-10 alkyl is optionally substituted with one or more deuterium;

[0240] each R 3-4-4 is independently deuterium, OH, NR a R b or C 1-10 alkyl; said C 1-10 alkyl is optionally substituted with 1, 2, or 3 R 3-4-4-1 ;

[0241] R a and R b are independently H, or C 1-10 alkyl; said C 1-10 alkyl is optionally substituted with one or more deuterium;

[0242] each R 3-4-4-1 is independently deuterium, OH, or NH2;

[0243] R 4 is H or C 1-10 alkyl; said C 1-10 alkyl is optionally substituted with 1, 2, or 3 R 4-1 ;

[0244] each R 4-1 is independently deuterium, OH, CN, halogen, NR a R b , C 1-10 alkyl, C2-10 alkenyl, C 2-10 alkynyl group, C 3-14 cycloalkyl or C 5-14 Cycloalkenyl; the C 1-10 Alkyl, the C 2-10 alkenyl, the C 2-10 alkynyl group, the C 3-14 cycloalkyl and the C 5-14 The cycloalkenyl group may be optionally substituted with one or more deuterium groups;

[0245] R a and R b H independently Or C 1-10 Alkyl; the C 1-10 The alkyl group may be optionally substituted with one, two, or three deuterium atoms;

[0246] R 5 H, deuterium, C 1-10 Alkyl, C 3-14 cycloalkyl, C 6-14 Aryl, 5-14 membered heteroaryl, or 3-14 membered heterocyclic; the C 1-10 Alkyl, the C 3-14 cycloalkyl, the C 6-14 The aryl group, the 5-14 membered heteroaryl group, and the 3-14 membered heterocyclic group are optionally surrounded by one, two, or three R groups. 5-1 Substitution; the 5-14 membered heteroaryl group is a 5-14 membered heteroaryl group whose heteroatoms are selected from 1, 2, or 3 of N, O, and S, and whose number of heteroatoms is 1, 2, 3, or 4; the 3-14 membered heterocyclic group is a 3-14 membered heterocyclic group whose heteroatoms are selected from 1, 2, or 3 of N, O, and S, and whose number of heteroatoms is 1, 2, 3, or 4.

[0247] Each R 5-1 Independently deuterium, halogen, oxo, hydroxyl, NR 5-1-1 R 5-1-2 C 1-10 Alkyl or OC 1-10 Alkyl; the C 1-10 Alkyl groups and the OC 1-10 Alkyl groups may optionally be substituted with one or more deuterium groups;

[0248] R 5-1-1 and R 5-1-2 Independently H or C 1-10 Alkyl; the C 1-10 Alkyl groups may be optionally surrounded by one, two, or three R's. 5-1-1-1 replace;

[0249] Each R 5-1-1-1independently deuterium or 5-14 membered heteroaryl; said 5-14 membered heteroaryl is a 5-14 membered heteroaryl having 1, 2, or 3 heteroatoms selected from N, O, and S, and having 1, 2, 3, or 4 of said heteroatoms; said 5-14 membered heteroaryl is optionally substituted with one or more deuterium;

[0250] R 6 is H, deuterium, or methyl;

[0251] R 5 is 5-14 membered heteroaryl;

[0252] Scheme 5:

[0253] L is C 1-10 alkylene; said C 1-10 alkylene is optionally substituted with 1 or more deuterium;

[0254] X is CR 1 R 2 ;

[0255] ring A is 5-14 membered heteroaryl; said 5-14 membered heteroaryl is a 5-14 membered heteroaryl having 1, 2, or 3 heteroatoms selected from N, O, and S, and having 1, 2, 3, or 4 of said heteroatoms; said 5-14 membered heteroaryl is optionally substituted with one or more deuterium;

[0256] R 1 and R 2 are independently deuterium, halogen, or C 1-10 alkyl;

[0257] R is

[0258] R 3 is deuterium, C 1-10 alkyl, or 5-14 membered heteroaryl; said C 1-10 alkyl and said 5-14 membered heteroaryl are optionally substituted with 1, 2, or 3 R 3-4 ;

[0259] each R 3-4 is independently deuterium, OH, NR 3-4-1 R 3-4-2 , C 1-10 alkyl, or 5-14 membered heteroaryl; said C 1-10 alkyl and said 5-14 membered heteroaryl are optionally substituted with 1, 2, or 3 R 3-4-4 ; said 5-14 membered heteroaryl is a 5-14 membered heteroaryl having 1, 2, or 3 heteroatoms selected from N, O, and S, and having 1, 2, 3, or 4 of said heteroatoms;

[0260] R 3-4-1 and R3-4-2 H independently Or C 1-10 Alkyl; the C 1-10 The alkyl group may optionally be substituted with one or more deuterium groups;

[0261] Each R 3-4-4 Independent of deuterium, OH, NR a R b Or C 1-10 Alkyl; the C 1-10 Alkyl groups are optionally surrounded by one, two, or three R's. 3-4-4-1 replace;

[0262] R a and R b H independently Or C 1-10 Alkyl; the C 1-10 The alkyl group may optionally be substituted with one or more deuterium groups;

[0263] Each R 3-4-4-1 It can be independently deuterium, OH, or NH2;

[0264] R 4 For H or C 1-10 Alkyl; the C 1-10 Alkyl groups may optionally be substituted with one or more deuterium groups;

[0265] R 5 C 6-14 Aryl; the C 6-14 The aryl group is optionally surrounded by one, two, or three R groups. 5-1 replace;

[0266] Each R 5-1 Independently, it can be either deuterium or NH2;

[0267] R 6 It can be H, deuterium, or methyl;

[0268] Option 6:

[0269] L is C 1-10 Alkylene or C 2-10 alkenyl; the C 1-10 alkylene and the C 2-10 The alkenyl group may be optionally substituted with one or more deuterium groups;

[0270] X is CR 1 R 2 or The It can be replaced by one or two deuteriums;

[0271] Ring A is diazole, triazole, or tetraazole;

[0272] R 1 and R 2 independently H, deuterium, OH, CN, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, O-C 1-10 alkyl, or 5-14 membered heteroaryl; said C 1-10 alkyl, said C 2-10 alkenyl, said C 2-10 alkynyl, said O-C 1-10 alkyl, and said 5-14 membered heteroaryl are optionally substituted with 1, 2, or 3 R 1-1 ; said 5-14 membered heteroaryl is a 5-14 membered heteroaryl having 1, 2, or 3 heteroatoms selected from N, O, and S, and having 1, 2, 3, or 4 carbon atoms;

[0273] R 1-1 independently deuterium, OH, halogen, SO3R 1-1-1 , or COOR 1-1-2 ;

[0274] R 1-1-1 and R 1-1-2 independently H or C 1-10 alkyl; said C 1-10 alkyl is optionally substituted with one or more deuterium;

[0275] or, R 1 , R 2 and the carbon atom to which they are attached together form a 3-14 membered heterocyclyl; said 3-14 membered heterocyclyl is a 3-14 membered heterocyclyl having 1 or 2 heteroatoms selected from N, O, and S, and having 1 or 2 carbon atoms;

[0276] R is

[0277] R 3 is H, deuterium, CN, CONR 3-1 R 3-2 , COOR 3-3 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-14 cycloalkyl, C 6-14 aryl, or 5-14 membered heteroaryl; said C 1-10 alkyl, said C 2-10 alkenyl, said C 2-10 alkynyl, said C 3-14 cycloalkyl, said C 6-14The aryl group and the 5-14 heteroaryl group are optionally surrounded by one, two, or three R groups. 3-4 Substitution; the 5-14 membered heteroaryl group is a 5-14 membered heteroaryl group whose heteroatoms are selected from 1, 2 or 3 of N, O and S, and whose number of heteroatoms is 1, 2, 3 or 4;

[0278] R 3-1 R 3-2 and R 3-3 Independently H or C 1-10 Alkyl; the C 1-10 Alkyl groups may optionally be substituted with one or more deuterium groups;

[0279] Each R 3-4 Independently deuterium, OH, halogen, Or C 1-10 alkyl;

[0280] R 3-4-3 C 1-10 Alkyl; the C 1-10 The alkyl group may optionally be substituted with one or more deuterium groups;

[0281] R 4 For H or C 1-10 Alkyl; the C 1-10 Alkyl groups may optionally be substituted with one or more deuterium groups;

[0282] R 5 H, deuterium, C 1-10 Alkyl, C 3-14 cycloalkyl, C 6-14 Aryl, 5-14 membered heteroaryl, or 3-14 membered heterocyclic; the C 1-10 Alkyl, the C 3-14 cycloalkyl, the C 6-14 The aryl group, the 5-14 membered heteroaryl group, and the 3-14 membered heterocyclic group are optionally surrounded by one, two, or three R groups. 5-1 Substitution; the 5-14 membered heteroaryl group is a 5-14 membered heteroaryl group whose heteroatoms are selected from 1, 2, or 3 of N, O, and S, and whose number of heteroatoms is 1, 2, 3, or 4; the 3-14 membered heterocyclic group is a 3-14 membered heterocyclic group whose heteroatoms are selected from 1, 2, or 3 of N, O, and S, and whose number of heteroatoms is 1, 2, 3, or 4.

[0283] Each R 5-1 Independently deuterium, halogen, oxo, hydroxyl, NR 5-1-1 R 5-1-2 C 1-10 Alkyl or OC 1-10 Alkyl; the C 1-10 Alkyl groups and the OC 1-10alkyl is optionally substituted with 1, 2, or 3 R ;

[0284] R 5-1-1 and R 5-1-2 are independently H or C 1-10 alkyl; said C 1-10 alkyl is optionally substituted with 1, 2, or 3 R 5-1-1-1 ;

[0285] each R 5-1-1-1 is independently deuterium or 5-14 membered heteroaryl; said 5-14 membered heteroaryl is a 5-14 membered heteroaryl having 1, 2, or 3 heteroatoms selected from N, O, and S, and having 1, 2, 3, or 4 of said heteroatoms; said 5-14 membered heteroaryl is optionally substituted with one or more deuterium;

[0286] R 6 is H, deuterium, or methyl;

[0287] when ring A is triazole, R 5 is 5-14 membered heteroaryl;

[0288] Scheme 7:

[0289] L is C 1-6 alkylene; said C 1-6 alkylene is optionally substituted with 1 or more deuterium;

[0290] X is CR 1 R 2 ;

[0291] ring A is 5-10 membered heteroaryl; said 5-10 membered heteroaryl is a 5-10 membered heteroaryl having 1, 2, or 3 heteroatoms selected from N, O, and S, and having 1, 2, 3, or 4 of said heteroatoms; said 5-10 membered heteroaryl is optionally substituted with 1 or more deuterium;

[0292] R 1 and R 2 are independently deuterium, halogen, or C 1-6 alkyl;

[0293] R is

[0294] R 3 is deuterium, C 1-6 alkyl, or 5-10 membered heteroaryl; said C 1-6 alkyl and said 5-10 membered heteroaryl are optionally substituted with 1, 2, or 3 R 3-4 ;

[0295] each R 3-4 is independently deuterium, OH, NR 3-4-1 R 3-4-2 , C1-6 alkyl or 5-10 membered heteroaryl; said C 1-6 alkyl and said 5-10 membered heteroaryl are optionally substituted with 1, 2, or 3 R 3-4-4 substituents; said 5-10 membered heteroaryl is a 5-10 membered heteroaryl having 1, 2, or 3 heteroatoms selected from N, O, and S, and having 1, 2, 3, or 4 carbon atoms;

[0296] R 3-4-1 and R 3-4-2 are independently H, or C 1-6 alkyl; said C 1-6 alkyl is optionally substituted with one or more deuterium;

[0297] each R 3-4-4 is independently deuterium, OH, NR a R b or C 1-6 alkyl; said C 1-6 alkyl is optionally substituted with 1, 2, or 3 R 3-4-4-1 substituents;

[0298] R a and R b are independently H, or C 1-6 alkyl; said C 1-6 alkyl is optionally substituted with one or more deuterium;

[0299] each R 3-4-4-1 is independently deuterium, OH, or NH2;

[0300] R 4 is H or C 1-6 alkyl; said C 1-6 alkyl is optionally substituted with one or more deuterium;

[0301] R 5 is C 6-14 aryl; said C 6-14 aryl is optionally substituted with 1, 2, or 3 R 5-1 substituents;

[0302] each R 5-1 is independently deuterium or NH2;

[0303] R 6 is H, deuterium, or methyl;

[0304] Scheme 8:

[0305] L is C 1-6 alkylene or C 2-6 alkenylene; said C 1-6 alkylene and said C2-6 alkenylene is optionally substituted with one or more deuterium;

[0306] X is CR 1 R 2 or said is optionally substituted with one or two deuterium;

[0307] Ring A is azole, triazole or tetrazole;

[0308] R 1 and R 2 are independently H, deuterium, OH, CN, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, O-C 1-6 alkyl or 5-10 membered heteroaryl; said C 1-6 alkyl, said C 2-6 alkenyl, said C 2-6 alkynyl, said O-C 1-6 alkyl and said 5-10 membered heteroaryl are optionally substituted with one, two or three R 1-1 ; said 5-10 membered heteroaryl is a 5-10 membered heteroaryl having 1, 2, 3 or 4 heteroatoms selected from N, O and S;

[0309] each R 1-1 is independently deuterium, OH, halogen, SO3R 1-1-1 or COOR 1-1-2 ;

[0310] R 1-1-1 and R 1-1-2 are independently H or C 1-6 alkyl; said C 1-6 alkyl is optionally substituted with one or more deuterium;

[0311] or R 1 , R 2 and the carbon atom to which they are attached form a 3-6 membered heterocyclyl; said 3-6 membered heterocyclyl is a 3-6 membered heterocyclyl having 1 or 2 heteroatoms selected from N, O and S, the number of heteroatoms being independently 1 or 2; said 3-6 membered heterocyclyl is optionally substituted with one or more deuterium;

[0312] R is

[0313] R 3 is H, deuterium, CN, CONR 3-1 R 3-2 , COOR 3-3 , C 1-6 alkyl, C2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl; said C 1-6 alkyl, said C 2-6 alkenyl, said C 2-6 alkynyl, said C 3-10 cycloalkyl, said C 6-10 aryl and said 5-10 membered heteroaryl are optionally substituted with 1, 2, or 3 R 3-4 ; said 5-10 membered heteroaryl is a 5-10 membered heteroaryl having 1, 2, 3, or 4 heteroatoms selected from N, O, and S;

[0314] R 3-1 , R 3-2 , and R 3-3 are independently H or C 1-6 alkyl; said C 1-6 alkyl is optionally substituted with one or more deuterium;

[0315] each R 3-4 is independently deuterium, OH, halogen, , or C 1-6 alkyl;

[0316] R 3-4-3 is C 1-6 alkyl; said C 1-6 alkyl is optionally substituted with one or more deuterium;

[0317] R 4 is H or C 1-6 alkyl; said C 1-6 alkyl is optionally substituted with one or more deuterium;

[0318] R 5 is H, deuterium, C 1-6 alkyl, C 3-10 cycloalkyl, C 6-14 aryl, 5-14 membered heteroaryl, or 3-10 membered heterocyclyl; said C 1-6 alkyl, said C 3-10 cycloalkyl, said C 6-14 aryl, said 5-14 membered heteroaryl, and said 3-10 membered heterocyclyl are optionally substituted with 1, 2, or 3 R 5-1 ; said 5-14 membered heteroaryl is a 5-14 membered heteroaryl having 1, 2, 3, or 4 heteroatoms selected from N, O, and S; said 3-10 membered heterocyclyl is a 3-10 membered heterocyclyl having 1, 2, 3, or 4 heteroatoms selected from N, O, and S.

[0319] each R 5-1 is independently deuterium, halogen, oxo, hydroxyl, NR 5-1-1 R 5-1-2 , C 1-6 alkyl or O-C 1-6 alkyl; said C 1-6 alkyl and said O-C 1-6 alkyl are optionally substituted with one or more deuterium;

[0320] R 5-1-1 and R 5-1-2 are independently H or C 1-6 alkyl; said C 1-6 alkyl is optionally substituted with 1, 2, or 3 R 5-1-1-1 ;

[0321] each R 5-1-1-1 is independently deuterium or 5-10 membered heteroaryl; said 5-10 membered heteroaryl is a 5-10 membered heteroaryl having 1, 2, or 3 heteroatoms selected from N, O, and S, the number of heteroatoms being 1, 2, 3, or 4; said 5-10 membered heteroaryl is optionally substituted with one or more deuterium;

[0322] R 6 is H, deuterium, or methyl;

[0323] when ring A is triazole, R 5 is 5-14 membered heteroaryl;

[0324] Scheme 9:

[0325] L is C 1-6 alkylene;

[0326] X is CR 1 R 2 ;

[0327] ring A is 5-6 membered heteroaryl; said 5-6 membered heteroaryl is a 5-6 membered heteroaryl having 1, 2, or 3 heteroatoms selected from N, O, and S, the number of heteroatoms being 1, 2, 3, or 4;

[0328] R 1 is C 1-6 alkyl;

[0329] R 2 is halogen;

[0330] R is

[0331] R 3 is C 1-6 alkyl or 5-6 membered heteroaryl; said C 1-6alkyl and said 5-6 membered heteroaryl are optionally substituted with 1, 2, or 3 R 3-4 substituted;

[0332] each R 3-4 is independently OH, NR 3-4-1 R 3-4-2 , C 1-6 alkyl or 5-6 membered heteroaryl; said C 1-6 alkyl and said 5-6 membered heteroaryl are optionally substituted with 1, 2, or 3 R 3-4-4 substituted; said 5-6 membered heteroaryl is a 5-6 membered heteroaryl having 1, 2, or 3 heteroatoms selected from N, O, and S, and having 1, 2, 3, or 4 ring members;

[0333] R 3-4-1 and R 3-4-2 are independently H, or C 1-6 alkyl;

[0334] each R 3-4-4 is independently OH, NR a R b or C 1-6 alkyl; said C 1-6 alkyl is optionally substituted with 1, 2, or 3 R 3-4-4-1 substituted;

[0335] R a and R b are independently H, or C 1-6 alkyl;

[0336] each R 3-4-4-1 is independently OH or NH2;

[0337] R 4 is H or C 1-6 alkyl;

[0338] R 5 is C 6-14 aryl; said C 6-14 aryl is optionally substituted with 1, 2, or 3 R 5-1 substituted;

[0339] each R 5-1 is independently NH2;

[0340] R 6 is H;

[0341] Scheme 10:

[0342] L is C 1-6 alkylene or C 2-6 alkenylene;

[0343] X is CR 1 R 2 ;

[0344] Ring A is tetrazole;

[0345] R 1 is C 1-6 alkyl;

[0346] R 2 is H, OH, or halo;

[0347] R is

[0348] R 3 is H, C 1-6 alkyl or 5-6 membered heteroaryl; said 5-6 membered heteroaryl is a 5-6 membered heteroaryl having 1, 2, or 3 heteroatoms selected from N, O, and S, and having 1, 2, 3, or 4 of said heteroatoms;

[0349] R 4 is H or C 1-6 alkyl;

[0350] R 5 is H, C 6-14 aryl or 5-10 membered heteroaryl; said C 6-14 aryl and said 5-10 membered heteroaryl are optionally substituted with 1, 2, or 3 R 5-1 ; said 5-10 membered heteroaryl is a 5-10 membered heteroaryl having 1, 2, or 3 heteroatoms selected from N, O, and S, and having 1, 2, 3, or 4 of said heteroatoms;

[0351] each R 5-1 is, independently, oxo, hydroxyl, NR 5-1-1 R 5-1-2 , C 1-6 alkyl or O-C 1-6 alkyl;

[0352] R 5-1-1 and R 5-1-2 are, independently, H or C 1-6 alkyl; said C 1-6 alkyl is optionally substituted with 1, 2, or 3 R 5-1-1-1 ;

[0353] each R 5-1-1-1 is, independently, 5-6 membered heteroaryl; said 5-6 membered heteroaryl is a 5-6 membered heteroaryl having 1, 2, or 3 heteroatoms selected from N, O, and S, and having 1, 2, 3, or 4 of said heteroatoms;

[0354] R 6H.

[0355] In one aspect, the compound of Formula I is:

[0356] R 5 is a partially saturated 5-6 membered heterocyclyl, the heteroatom species of which is N, and the number of heteroatoms is 1 or 2; said partially saturated 5-6 membered heterocyclyl is substituted with 1, 2, 3, 4, or 5 R 5-1 ; and at least one R 5-1 is oxo;

[0357] R 5-1 is independently -NH2, deuterium, halogen, oxo, or C 1-6 alkyl;

[0358] Ring A is a 5-membered heteroaryl, the heteroatom species of which is selected from one, two, or three of N, O, and S, and the number of heteroatoms is 1, 2, or 3;

[0359] L is C 4-6 alkylene; said C 4-6 alkylene is optionally substituted with 1 or more deuterium;

[0360] X is CR 1 R 2 ;

[0361] R 1 is halogen;

[0362] R 2 is C 1-6 alkyl

[0363] R is R 6 is H, R 3 is C 1-6 alkyl

[0364] R 4 is C 1-6 alkyl.

[0365] In one aspect, the compound of Formula I is:

[0366] R 5 is a 5-6 membered heteroaryl, the heteroatom species of which is N, and the number of heteroatoms is 1 or 2; said 5-6 membered heteroaryl is substituted with 1, 2, 3, 4, or 5 R 5-1 ; and at least one R 5-1 is hydroxyl;

[0367] R 5-1 is independently -NH2, deuterium, halogen, hydroxyl, or C1-6 alkyl;

[0368] ring A is a 5-membered heteroaryl, the kind of heteroatoms in said 5-membered heteroaryl being selected from one, two or three of N, O and S, the number of heteroatoms being one, two or three;

[0369] L is C 4-6 alkylene; said C 4-6 alkylene is optionally substituted with one or more deuterium;

[0370] X is CR 1 R 2 ;

[0371] R 1 is halogen;

[0372] R 2 is C 1-6 alkyl

[0373] R is R 6 is H, R 3 is C 1-6 alkyl;

[0374] R 4 is C 1-6 alkyl.

[0375] In a certain preferred embodiment, in said compound of formula I,

[0376] R 5 is a partially saturated 5-6 membered heterocyclyl, the kind of heteroatoms in said partially saturated 5-6 membered heterocyclyl being N, the number of heteroatoms being one or two; said partially saturated 5-6 membered heterocyclyl is substituted with two, three, four or five R 5-1 , and at least one R 5-1 is oxo, and at least one R 5-1 is amino;

[0377] R 5-1 is independently -NH2, deuterium, halogen, oxo or C 1-6 alkyl;

[0378] ring A is a 5-membered heteroaryl, the kind of heteroatoms in said 5-membered heteroaryl being selected from one, two or three of N, O and S, the number of heteroatoms being one, two or three;

[0379] L is C 4-6 alkylene; said C 4-6 alkylene is optionally substituted with one or more deuterium;

[0380] X is CR 1 R 2 ;

[0381] R 1 halogen;

[0382] R 2 C 1-6 alkyl;

[0383] R is R 6 H, R 3 C 1-6 alkyl;

[0384] R 4 C 1-6 alkyl.

[0385] In a certain preferred embodiment, the compound of Formula I is

[0386] R 5 5-6 membered heteroaryl, the kind of heteroatoms in said 5-6 membered heteroaryl is N, the number of heteroatoms is 1 or 2; said 5-6 membered heteroaryl is substituted with 2, 3, 4 or 5 R 5-1 ; and at least one R 5-1 is hydroxyl, and, at least one R 5-1 is amino;

[0387] R 5-1 is independently -NH2, deuterium, halogen, hydroxyl or C 1-6 alkyl;

[0388] ring A is 5-membered heteroaryl, the kind of heteroatoms in said 5-membered heteroaryl is selected from one, two or three of N, O and S, the number of heteroatoms is 1, 2 or 3;

[0389] L is C 4-6 alkylene; said C 4-6 alkylene is optionally substituted with 1 or more deuterium;

[0390] X is CR 1 R 2 ;

[0391] R 1 halogen;

[0392] R 2 C 1-6 alkyl;

[0393] R is R 6 H, R 3 C 1-6 alkyl;

[0394] R 4 C 1-6alkyl.

[0395] In one aspect, the compound of Formula I is a compound of Formula I-X1:

[0396] t is 0, 1, 2, or 3;

[0397] R 5-1 independently deuterium, cyano, halogen, hydroxyl, -NH2, -NH-C 1-4 alkyl, C 1-4 alkyl, or O-C 1-4 alkyl;

[0398] Ring A is a 5-6 membered heteroaryl, the kind of heteroatoms in said 5-6 membered heteroaryl being selected from one, two, or three of N, O, and S, the number of heteroatoms being 1, 2, 3, or 4;

[0399] R L independently H, D, or -CH3;

[0400] X is CR 1 R 2 ;

[0401] R 1 is H or halogen;

[0402] R 2 is C 1-6 alkyl;

[0403] R 6 is H, R 3 is H or C 1-6 alkyl;

[0404] R 4 is H or C 1-6 alkyl;

[0405] Preferably, in the compound of Formula I-X1:

[0406] t is 0, 1, 2, or 3;

[0407] R 5-1 independently deuterium, cyano, hydroxyl, halogen, -NH2, -NH-C 1-4 alkyl, C 1-4 alkyl, or O-C 1-4 alkyl;

[0408] Ring A is a 5-membered heteroaryl, the kind of heteroatoms in said 5-membered heteroaryl being selected from one, two, or three of N, O, and S, the number of heteroatoms being 1, 2, 3, or 4;

[0409] R Lindependently H, D, or -CH3;

[0410] X is CR 1 R 2 ;

[0411] R 1 is halogen;

[0412] R 2 is C 1-4 alkyl;

[0413] R 6 is H, R 3 is H;

[0414] R 4 is H or C 1-4 alkyl;

[0415] More preferably, the compound according to Formula I-X1 is a compound according to Formula I-X2:

[0416] t is 0, 1, or 2;

[0417] R 5-1 is independently D, -CH3, halogen, -NH2, -O-CH3, hydroxyl, or -NH-CH3;

[0418] R L is H, D, or -CH3;

[0419] Ring A is a 5-membered heteroaryl, the kind of heteroatom in the 5-membered heteroaryl being selected from one, two, or three of N, O, and S, the number of heteroatoms being 1, 2, 3, or 4;

[0420] R4is H, methyl, ethyl, propyl, or isopropyl, preferably methyl.

[0421] In one aspect, the compound according to Formula I-X2 is a compound according to Formula I-X2-A, I-X2-B, I-X2-C, I-X2-D, I-X2-E, I-X2-F, or I-X2-G:

[0422] In one aspect, the compound according to Formula I-X1 is a compound according to Formula I-X1-1 or I-X1-2:

[0423] In one aspect, in the compound according to Formula I:

[0424] R 5 is pyridazinyl; the pyridazinyl is optionally substituted with 1, 2, or 3 R 5-1 ;

[0425] R 5-1 independently deuterium, hydroxyl, NR 5-1-1 R 5-1-2 , -O-C 1-6 alkyl or C 1-6 alkyl;

[0426] R 5-1-1 and R 5-1-2 are independently H or C 1-6 alkyl;

[0427] ring A is a 5-membered heteroaryl, the kind of heteroatoms in said 5-membered heteroaryl being selected from one, two or three of N, O and S, the number of heteroatoms being one, two or three;

[0428] L is C 4-6 alkylene; said C 4-6 alkylene is optionally substituted with one or more deuterium;

[0429] X is CR 1 R 2 ;

[0430] R 1 is halogen;

[0431] R 2 is C 1-6 alkyl;

[0432] R is R 6 is H, R 3 is C 1-6 alkyl;

[0433] R 4 is C 1-6 alkyl;

[0434] Preferably, said compound according to Formula I is a compound according to Formula I-3:

[0435] (W 1 i.e. ring A)

[0436] wherein:

[0437] R L is selected from H, D or -CH3;

[0438] W 1 is a 5-membered heteroaryl, the kind of heteroatoms in said 5-membered heteroaryl being selected from one, two or three of N, O and S, the number of heteroatoms being one, two or three;

[0439] t is 0, 1 or 2;

[0440] R 5-1 independently D, -CH3, halogen, -NH2, -O-CH3, hydroxyl, or -NH-CH3;

[0441] More preferably, the compound of Formula I is a compound of Formula I-3-A or I-3-B:

[0442] (W 1 i.e. ring A is

[0443] wherein:

[0444] R L selected from H, D, or -CH3;

[0445] W 1 is a 5-membered heteroaryl, the heteroatom species in the 5-membered heteroaryl is selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three;

[0446] t is 0, 1, or 2;

[0447] R 5-1 independently D, -CH3, halogen, -NH2, -O-CH3, hydroxyl, or -NH-CH3.

[0448] In an embodiment, L is

[0449] In an embodiment, L is

[0450] In an embodiment, ring A is a diazole, a triazole, or a tetrazole; wherein the diazole is preferably an imidazole, and the triazole is preferably a 1,2,3-triazole.

[0451] In an embodiment, ring A is an imidazolyl, a triazolyl, a tetrazolyl, a pyrazolyl, a 1,3,4-thiadiazolyl, a 1,3,4-oxadiazolyl, a 1,2,4-oxadiazole, an oxazolyl, an isoxazolyl, or a thiazolyl.

[0452] In an embodiment, ring A is a pyrazolyl, a 1,3,4-thiadiazolyl, a 1,3,4-oxadiazolyl, a 1,2,4-oxadiazole, an oxazolyl, an isoxazolyl, or a thiazolyl.

[0453] In an embodiment, ring A is Preferably, the bond is to L.

[0454] In an embodiment, ring A is Preferably, the bond is to L.

[0455] In an embodiment, For wherein the "1" position is attached to L and the "2" position is attached to R 5 ; preferably, For wherein the "1" position is attached to L and the "2" position is attached to R 5 .

[0456] In one aspect, R 1-1-2 is CH3.

[0457] In one aspect, R 1-1-1 is H.

[0458] In one aspect, R 1-1 is OH, halogen, COOCH3, or SO3H.

[0459] In one aspect, R 1 is H, F, OH, or CH3; for example, R 1 is H or F, and further for example, F.

[0460] In one aspect, R 2 is H, F, OH, CN, OCH3, CH3, CH2F, CH2OH, for example, R 2 is methyl.

[0461] In one aspect, R 1 , R 2 and the carbon atom to which they are attached form

[0462] In one aspect, X is for example, X is and further for example,

[0463] In one aspect, R a and R b are independently H, or methyl.

[0464] In one aspect, R 3-4-3 is independently CH3.

[0465] In one aspect, R 3-1 and R 3-2 are independently H.

[0466] In one aspect, R 3-3 is independently CH2CH3.

[0467] In one aspect, R 3-4 independently OH, F, NH2,

[0468] In one aspect, R 3 is H, methyl, cyano, for example H.

[0469] In one aspect, R 4 is H or methyl, for example methyl.

[0470] In one aspect, R 5-1-1-1 independently

[0471] In one aspect, R 5-1-1 and R 5-1-2 independently H or

[0472] In one aspect, R 5-1 independently Cl, F, CH3, OCH3, NH2, OH, C2H5, -CH2F, -CF3, -CHF2, cyclopropyl, n-propyl, i-propyl, deuterium, -NH-COCH3, -NH-COCF3.

[0473] In one aspect, R 5 is H,

[0474] In one aspect, R 5 is also

[0475] In one aspect, the compound of Formula I is selected from any one of the following compounds:

[0476] The present application also provides a pharmaceutical composition comprising (i) the compound of Formula I, solvate, crystal form, deuterated product or pharmaceutically acceptable salt thereof described above; and (ii) a pharmaceutically acceptable carrier. The compound of Formula I, solvate, crystal form, deuterated product or pharmaceutically acceptable salt thereof is used in a therapeutically effective amount.

[0477] The present application also provides use of a compound of Formula I or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of upper and lower respiratory tract and soft tissue infections.

[0478] In one aspect, the medicament is for the treatment of upper and lower respiratory tract or soft tissue infections, such as lower respiratory tract infections, such as pneumonia, such as community-acquired pneumonia or hospital-acquired pneumonia.

[0479] The present application also provides use of a compound of Formula I, a pharmaceutically acceptable salt thereof or the above-mentioned pharmaceutical composition in the manufacture of a medicament for the prevention and / or treatment of a bacterial-related disease.

[0480] In one aspect, the medicament can be a medicament for inhibiting the activity of bacteria.

[0481] In one aspect, the medicament is a medicament for inhibiting the activity of mycoplasma or chlamydia.

[0482] In one aspect, the medicament is an anti-pathogen medicament, preferably an anti-bacterial, mycoplasma or chlamydia medicament, such as an anti-mycoplasma medicament.

[0483] In one aspect, the bacteria can be Gram-positive bacteria and / or Gram-negative bacteria; wherein the Gram-positive bacteria can be selected from one or more of Staphylococcus aureus, Streptococcus pneumoniae and Streptococcus pyogenes; and the Gram-negative bacteria can be Moraxella catarrhalis and / or Haemophilus influenzae.

[0484] In one aspect, the bacteria are preferably Streptococcus pneumoniae and / or Streptococcus pyogenes.

[0485] In one aspect, the bacteria are selected from one or more of Gram-positive bacteria, Gram-negative bacteria and anaerobic bacteria; such as Staphylococcus (e.g. Staphylococcus aureus), Streptococcus (e.g. Streptococcus pneumoniae, Streptococcus pyogenes), Enterococcus, Haemophilus (e.g. Haemophilus influenzae), Moraxella (e.g. Moraxella catarrhalis), Legionella, Mycobacterium, Helicobacter, Clostridium, Bacteroides, Corynebacterium, Bacillus, Enterobacter or any combination thereof.

[0486] In one aspect, the bacterial-related disease can be upper and lower respiratory tract and soft tissue infections, preferably pneumonia.

[0487] In one aspect, the bacterial-related disease is upper respiratory tract infection, lower respiratory tract infection or soft tissue infection.

[0488] The present application also provides a use of the compound of Formula I, solvate, crystal form, deuterated form, pharmaceutically acceptable salt thereof or the pharmaceutical composition in the manufacture of a medicament for preventing and / or treating a disease associated with mycoplasma or chlamydia.

[0489] In one embodiment, the chlamydia is Chlamydia pneumoniae.

[0490] In one embodiment, the mycoplasma is Mycoplasma pneumoniae.

[0491] In one embodiment, the disease associated with bacteria, mycoplasma or chlamydia is an upper or lower respiratory tract or soft tissue infection, for example, a lower respiratory tract infection, for example, pneumonia, for example, community-acquired pneumonia or hospital-acquired pneumonia.

[0492] The present application also provides a use of the compound of Formula I, pharmaceutically acceptable salt thereof or the pharmaceutical composition in the manufacture of an antibiotic.

[0493] In one embodiment, the antibiotic is an antibacterial drug.

[0494] In one embodiment, the antibiotic is an antimycoplasmal or antichlamydial drug.

[0495] The present application also provides a method of treating a disease associated with bacteria, mycoplasma (e.g., Mycoplasma pneumoniae) or chlamydia, comprising administering to a subject in need of such treatment a compound of Formula I, preferably a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition.

[0496] Definitions of terms

[0497] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. Definitions of terms not discussed below are found in The Merck Index, 13thEd., 2001, the Encyclopedia of Pharmaceutical Technology, 2ndEd., 2006, and the Dictionary of Pharmacological Methods, 2006.

[0498] The term "pharmaceutically acceptable salt" means a salt prepared from a relatively non-toxic, pharmaceutically acceptable acid or base. Alkali addition salts can be prepared from the neutral form of the compound in solution or suspension by contacting the compound with a sufficient amount of a pharmaceutically acceptable base to produce the alkali addition salt. Acid addition salts can be prepared from the neutral form of the compound in solution or suspension by contacting the compound with a sufficient amount of a pharmaceutically acceptable acid to produce the acid addition salt. When the compound contains both a relatively acidic functionality and a relatively basic functionality, it can be converted to either a base or acid addition salt.

[0499] The term "solvate" refers to a compound of the present application in combination with a stoichiometric or non-stoichiometric amount of solvent. The solvent molecules in the solvate can be present in ordered or disordered arrangements.

[0500] The term "solvate of a pharmaceutically acceptable salt" refers to a compound in combination with a pharmaceutically acceptable (relatively non-toxic, safe, and physiologically acceptable) acid or base, a solvent, wherein the pharmaceutically acceptable salt has the same meaning as the term "pharmaceutically acceptable salt" above, and the solvent is stoichiometric or non-stoichiometric.

[0501] The term "deuterated" refers to the H atoms in "compound", "pharmaceutically acceptable salt", "crystal form", "solvate", and "solvate of a pharmaceutically acceptable salt" can be present in non-natural abundance. For example, the natural abundance of H refers to about 99.985% protium, about 0.015% deuterium; the non-natural abundance refers to about 95% deuterium. That is, one or more H atoms in "compound", "pharmaceutically acceptable salt", "crystal form", "solvate", and "solvate of a pharmaceutically acceptable salt" can be deuterium atoms present in non-natural abundance.

[0502] "Crystal form" refers to the crystalline structure of certain compounds of the present application in a solid state, arranged in a regular pattern. Certain compounds of the present application can exist in more than one crystal form, and the present application is intended to include each and every crystal form and mixtures thereof.

[0503] The end of a structural fragment indicates that the structural fragment is attached to the rest of the molecule at this point. For example, indicates a cyclohexyl group.

[0504] A wedge and a dashed line indicate the absolute configuration of a stereocenter.

[0505] The term "one or more" or "one or more than two" means 1, 2, 3, 4, 5, 6, 7, 8, 9, or more.

[0506] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0507] The term "oxo" refers to =O or -O - , the oxygen atom replacing two hydrogens or lone pair electrons on the same carbon or nitrogen atom, in the form =O or -O - . For example

[0508] The term "alkyl" refers to a saturated straight or branched chain monovalent hydrocarbon group having the indicated number of carbon atoms. For example, C 1-10alkyl, refers to an alkyl group having from 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) carbon atoms, and also, for example, C 1-6 alkyl, refers to an alkyl group having from 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) carbon atoms, and also, for example, C 1-4 alkyl. Examples include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, and the like.

[0509] The term "alkylene" is a divalent radical, which is attached to the remainder of the molecule by two single bonds, with the remainder of the definition being the same as for the term "alkyl." Examples include, but are not limited to,

[0510] The term "alkenyl" refers to a straight or branched chain monovalent hydrocarbon group having the specified number of carbon atoms and at least one site of sp 2 double bond, and includes groups having "cis" and "trans" orientations or "E" and "Z" orientations. For example, C 2-10 alkenyl, refers to an alkenyl group having from 2 to 10 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10) carbon atoms, and also, for example, C 2-6 alkenyl, refers to an alkenyl group having from 2 to 10 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10) carbon atoms, and also, for example, C 2-4 alkenyl. Examples include, but are not limited to,

[0511] The term "alkenylene" is a divalent radical, which is attached to the remainder of the molecule by two single bonds, with the remainder of the definition being the same as for the term "alkenyl." Examples include, but are not limited to,

[0512] The term "alkynyl" refers to a straight or branched chain monovalent hydrocarbon group having the specified number of carbon atoms and at least one site of sp 3 triple bond, for example, C 2- 10 alkynyl, refers to an alkynyl group having from 2 to 10 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10) carbon atoms, and also, for example, C 2-6 alkynyl, refers to an alkynyl group having from 2 to 10 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10) carbon atoms, and also, for example, C 2-4 alkynyl. Examples include, but are not limited to,

[0513] The term "cycloalkyl" refers to a saturated, monocyclic or polycyclic ring hydrocarbon group having the specified number of carbon atoms, wherein polycyclic rings share one carbon atom, two non-adjacent carbon atoms, or, two carbon atoms and a bond between them, for example, C 3-14 cycloalkyl, refers to a cycloalkyl group having from 3 to 14 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14) ring carbon atoms, and also, for example, C 3-10 cycloalkyl, refers to a cycloalkyl group having from 3 to 14 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14) ring carbon atoms, and also, for example, C 3-8 ​​​​Cycloalkyl. "Cycloalkyl" includes monocycloalkyl, spirocycloalkyl, fused cycloalkyl, and bridged cycloalkyl groups.

[0514] The term "monocycloalkyl" refers to a "cycloalkyl" group that is monocyclic. For example, C 3-14 Monocycloalkyl, for example, C 3-10 Monocycloalkyl, for example, C 3-8 Monocycloalkyl. Specific examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0515] The term "bridged cycloalkyl" refers to a "cycloalkyl" group that is polycyclic (e.g., 2 or 3), with rings sharing two or more non-adjacent carbon atoms. For example, C 3-14 Bridged cycloalkyl, for example, C 3-10 Bridged cycloalkyl, for example, C 3-8 Bridged cycloalkyl.

[0516] The term "spirocycloalkyl" refers to a "cycloalkyl" group that is polycyclic (e.g., 2 or 3), with rings sharing one carbon atom. For example, C 3-14 Spirocycloalkyl, for example, C 3-10 Spirocycloalkyl, for example, C 3-8 Spirocycloalkyl.

[0517] The term "fused cycloalkyl" refers to a "cycloalkyl" group that is polycyclic (e.g., 2 or 3), with rings sharing two carbon atoms and a bond. For example, C 3-14 Fused cycloalkyl, for example, C 3-10 Fused cycloalkyl, for example, C 3-8 Fused cycloalkyl.

[0518] The term "cycloalkenyl" refers to an unsaturated, monocyclic or polycyclic ring hydrocarbon group having the number of carbon atoms specified, wherein polycyclic rings share one carbon atom, two non-adjacent carbon atoms, or two carbon atoms and a bond, and can contain one or more double bonds, but no ring has a fully conjugated pi-electron system. For example, C 3-14 Cycloalkenyl refers to a cycloalkenyl group having 3-14 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14) ring carbon atoms, for example, C 3-10 Cycloalkenyl, for example, C 3-8 Cycloalkenyl. "Cycloalkenyl" includes monocycloalkenyl, spirocycloalkenyl, fused cycloalkenyl, and bridged cycloalkenyl groups.

[0519] The term "monocycloalkenyl" refers to a "cycloalkenyl" group that is monocyclic. For example, C 3-14 Monocycloalkenyl, for example, C 3-10 Monocycloalkenyl, for example, C 3-8 Monocycloalkenyl.

[0520] The term "bridged cycloalkenyl" refers to a polycyclic (e.g., 2 or 3) "cycloalkenyl" in which the rings share two or more non-adjacent carbon atoms. For example, C 3-14 bridged cycloalkenyl, for example, C 3-10 bridged cycloalkenyl, more for example, C 3-8 bridged cycloalkenyl.

[0521] The term "spirocycloalkenyl" refers to a polycyclic (e.g., 2 or 3) "cycloalkenyl" in which the rings share one carbon atom. For example, C 3-14 spirocycloalkenyl, for example, C 3-10 spirocycloalkenyl, more for example, C 3-8 spirocycloalkenyl.

[0522] The term "fused cycloalkenyl" refers to a polycyclic (e.g., 2 or 3) "cycloalkenyl" in which the rings share two carbon atoms and a bond. For example, C 3-14 fused cycloalkenyl, for example, C 3-10 fused cycloalkenyl, more for example, C 3-8 fused cycloalkenyl.

[0523] The term "heterocyclyl" refers to a cyclic hydrocarbon substituent that is non-aromatic, has a specified number of ring atoms, a specified number of heteroatoms (e.g., 1, 2, 3, 4, or 5), a specified kind of heteroatoms (one or more of N, O, and S), saturated or unsaturated (partially saturated), monocyclic or polycyclic, in which the polycyclic rings share one atom, two non-adjacent atoms, or two atoms and a bond, and can contain one or more double bonds. Heterocyclyl is attached to the remainder of the molecule through a carbon atom or a heteroatom; heterocyclyl is attached to the remainder of the molecule through a ring having a heteroatom or a ring having no heteroatom. "Heterocyclyl" includes monoheterocyclyl, spiroheterocyclyl, fused heterocyclyl, and bridged heterocyclyl.

[0524] The term "monoheterocyclyl" refers to a monocyclic "heterocyclyl". For example, C 3-14 monoheterocyclyl, for example, C 3-10 monoheterocyclyl, more for example, C 3-8 monoheterocyclyl. Particular examples include, but are not limited to, oxiranyl or azacyclohexyl, and the like.

[0525] The term "bridged heterocyclyl" refers to a polycyclic (e.g., 2 or 3) "heterocyclyl" in which the rings share two or more non-adjacent carbon atoms. For example, C 3-14 bridged heterocyclyl, for example, C 3-10 bridged heterocyclyl, more for example, C 3-8 bridged heterocyclyl.

[0526] The term "spiroheterocyclyl" refers to a polycyclic (e.g., 2 or 3) "heterocyclyl" in which the rings share one carbon atom. For example, C 3-14 spiroheterocyclyl, for example, C 3-10 spiroheterocyclyl, more for example, C 3-8 spiroheterocyclyl.

[0527] The term "fused heterocyclyl" refers to a polycyclic (e.g., 2 or 3) "heterocyclyl" in which the rings share two atoms and a bond. For example, C 3-14 fused heterocyclyl, for example, C 3-10 fused heterocyclyl, more for example, C 3-8 fused heterocyclyl.

[0528] The term "aryl" refers to a cyclic, unsaturated, monovalent hydrocarbon group having the specified number of carbon atoms (e.g., C 6-14 ) which is monocyclic or polycyclic (e.g., 2 or 3), in which case the rings share two atoms and a bond, and at least one ring is aromatic. For example, phenyl or naphthyl.

[0529] The term "heteroaryl" refers to a cyclic, unsaturated, monovalent group having aromaticity, the specified number of ring atoms (e.g., 5-14 membered, for example, 5-10 membered), the specified number of heteroatoms (e.g., 1, 2, 3, 4, or 5), the specified type of heteroatoms (one or more of N, O, and S), which is monocyclic or polycyclic, in which case the rings share two atoms and a bond. "Heteroaryl" includes monocyclic heteroaryl or fused ring heteroaryl. Fused ring heteroaryl refers to a heteroaryl in which the rings share two atoms and a bond. Heteroaryl is attached to the remainder of the molecule by a carbon atom or a heteroatom; heteroaryl is attached to the remainder of the molecule by a ring having a heteroatom or by a ring having no heteroatom; heteroaryl is attached to the remainder of the molecule by a ring having aromaticity or by a ring having no aromaticity. Heteroaryl includes, but is not limited to: and the like.

[0530] In general, the term "substituted" means that one or more hydrogens on the given structure are replaced by a particular substituent. Further, unless otherwise indicated, the substituents can be independent of one another. A substituent group can be substituted at any available substitutable position on the designated group. When a structure is given that does not specify a particular substituent, then the structure is intended to include any of the possible substituents known to one of skill in the art. When a structure is given that includes more than one substituent, then the substituents can be the same or different. When a structure is given that includes more than one substituent, then the substituents can be the same or different.

[0531] The expression "a group B optionally substituted by one or more groups A" means that the group B can be unsubstituted or substituted by one or more groups A. For example, the C 1-6 alkyl group is optionally substituted by 1, 2, or 3 R 3-2 substituted means that the C 1-6 alkyl group can be unsubstituted or substituted by 1, 2, or 3 R 3-2 substituted.

[0532] When no atom through which a recited substituent is attached to a chemical structure general formula including but not specifically mentioned compound is indicated, the substituent can be bonded through any atom thereof. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0533] When no substituents are indicated for an enumerated group, the group is meant to be unsubstituted. For example, when "C 1-6 alkyl" is recited without the proviso "unsubstituted or substituted", it means "C 1-6 alkyl" per se or "unsubstituted C 1-6 alkyl".

[0534] Further, it is noted that the description employed in this application "independently for" should be interpreted broadly, unless explicitly indicated otherwise, meaning that each individual described is independent of the other, and can be the same or different specific group independently. In more detail, the description "independently for" can mean that in different groups, the specific options expressed by the same symbol do not affect each other; or it can mean that in the same group, the specific options expressed by the same symbol do not affect each other.

[0535] The term "treatment" refers to therapeutic treatment. When used in relation to a particular condition, treatment refers to: (1) relieving one or more of the biological manifestations of the disease or condition, (2) interfering with (a) one or more points in the biological cascade leading to or causing the condition or (b) one or more of the biological manifestations of the condition, (3) ameliorating one or more symptoms, effects or side effects associated with the condition or one or more symptoms, effects or side effects associated with the treatment of the condition, or (4) slowing the development of the condition or one or more of the biological manifestations of the condition.

[0536] The term "prevention" refers to reducing the risk of developing a disease.

[0537] The term "therapeutically effective amount" refers to the amount of a compound that is sufficient to effect treatment or prevention of a disease or condition described herein when administered to a patient. The "therapeutically effective amount" will vary depending on the compound, the condition and its severity, and the age of the patient to be treated, but can be adjusted by those skilled in the art as needed. Amounts exceeding this range can also be used depending on the dosage form and the severity of the disease.

[0538] The term "subject" refers to any animal, typically a mammal, such as a human, in need of treatment or prevention of a disease. Mammals include, but are not limited to, bovines, equines, ovines, porcines, felines, canines, mice, rats, rabbits, guinea pigs, monkeys, humans, and the like.

[0539] The term "child" refers to a population from birth to 14 years of age, and can refer to a population under the age of 8.

[0540] The above-mentioned preferred conditions can be combined in any way without departing from the common general knowledge of the skilled person, i.e. resulting in further preferred embodiments of the application.

[0541] The reagents and starting materials used in the present application are commercially available.

[0542] The positive progress effect of the present application is that the compounds of the present application have antibacterial activity, i.e. have the effect of inhibiting bacterial activity, and can be used for preventing and / or treating diseases related to bacteria; further, the compounds of the present application can achieve antibacterial activity comparable to or better than that of azithromycin or solithromycin at a lower dosage; further, the compounds of the present application have a more optimal antibacterial effect on gram-positive bacteria.

[0543] The compounds of the present application exhibit significant antibacterial activity, including antibacterial activity against pathogens resistant to macrolide drugs such as azithromycin. The compounds described herein have low hepatotoxicity and are safer than other macrolide compounds; can be used for the treatment of community-acquired pneumonia, upper and lower respiratory tract infections, hospital-acquired pneumonia, etc.

[0544] The compounds of the present application solve the clinical treatment gap caused by azithromycin resistance, provide safe and efficient therapy for mycoplasma infection, and can be used for the treatment of mycoplasma pneumonia, especially in pediatric patients, and preferentially for azithromycin-resistant mycoplasma pneumonia, especially in pediatric patients, and explore the potential of broad-spectrum resistance to drug-resistant strains and reduce the risk of antibiotic abuse. DETAILED DESCRIPTION

[0545] The present application is further illustrated by the following examples, but the present application is not limited to the scope of the examples described. The experimental methods in the following examples are not specified, and are selected according to conventional methods and conditions, or according to the instructions of the goods.

[0546] Synthesis of intermediates

[0547] Synthesis of intermediate CLA-A6 & SOL-B1

[0548] Step one:

[0549] Clarithromycin (100 g, 133 mmol, 1.00 eq) was added to hydrochloric acid (12.0 M, 66.6 mL, 5.98 eq) and water (660 mL) at 25 °C for 2 hours. TLC (dichloromethane:methanol = 10:1) detection showed that the reaction was complete, and 300 mL of water was added to quench the reaction at 0 °C, and the pH was adjusted to 8 with ammonia water, and extracted with ethyl acetate (200 mL) three times, and the organic phase was dried with anhydrous sodium sulfate and concentrated to obtain white solid CLA-A1 (78.0 g) with a yield of 98.0%.

[0550] Step two:

[0551] Compound CLA-A1 (78.0 g, 132 mmol, 1.00 eq) was dissolved in 540 mL of anhydrous dichloromethane, and triethylamine (16.0 g, 158 mmol, 22.0 mL, 1.20 eq) and acetic anhydride (16.2 g, 158 mmol, 14.9 mL, 1.20 eq) were added sequentially at 0 °C, and stirred at 25 °C for 12 hours. TLC (dichloromethane:methanol = 10:1) detection showed that the reaction was complete. The system was added with 400 mL of water, and extracted with dichloromethane (200 mL) three times, and the organic phase was dried with anhydrous sodium sulfate and concentrated to obtain white solid CLA-A2 (83.0 g) with a yield of 99.0%.

[0552] Step three:

[0553] Compound CLA-A2 (83.0 g, 131 mmol, 1.00 eq) was dissolved in 500 mL of dichloromethane, and EDCI (166 g, 867 mmol, 6.60 eq) and DMSO (184 g, 2.36 mol, 184 mL, 18.0 eq) were added, and pyridine trifluoroacetate was dissolved in 150 mL of dichloromethane and added dropwise, and reacted at 25 °C for 3 hours. LCMS showed that the reaction was substantially complete. The reaction was cooled to 0 °C, and 300 mL of water was added, and extracted with dichloromethane (200 mL) three times, and the organic phase was dried with anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by column chromatography with isopropyl ether:triethylamine = 90:10 to obtain yellow solid CLA-A3 (83.0 g) with a yield of 99.0%.

[0554] Step four:

[0555] Compound CLA-A3 (50.0 g, 79.3 mmol, 1.00 eq) was dissolved in 350 mL of dichloromethane, and then pyridine (37.6 g, 476 mmol, 38.4 mL, 6.00 eq) and triphosgene (29.5 g, 99.5 mmol, 1.25 eq) were added at 0 °C, and the mixture was stirred at 25 °C for 2 h. LCMS showed that the reaction was substantially complete. The reaction was cooled to 0 °C, and 300 mL of water was added. The mixture was extracted with dichloromethane (200 mL) three times. The organic phase was dried over anhydrous sodium sulfate and concentrated to give a yellow solid CLA-A4 (30.0 g) in a yield of 57.0%.

[0556] Step five:

[0557] Compound CLA-A4 (30.0 g, 45.7 mmol, 1.00 eq) was dissolved in 200 mL of ethyl acetate, and then DBU (14.6 g, 96.0 mmol, 14.4 mL, 2.10 eq) was added at 80 °C, and the mixture was stirred for 3 h. LCMS showed that the reaction was substantially complete. The reaction was cooled to room temperature, and 200 mL of water was added. The mixture was extracted with ethyl acetate (200 mL) three times. The organic phase was dried over anhydrous sodium sulfate and concentrated. 50.0 mL of acetonitrile was added to the crude product, and the mixture was ultrasonicated for 10 min. The mixture was filtered to give a white solid CLA-A5 (10.0 g) in a yield of 35.0%.

[0558] Step six:

[0559] Compound CLA-A5 (5.00 g, 8.17 mmol, 1.00 eq) was dissolved in 35 mL of dichloromethane, and then DBU (3.73 g, 24.5 mmol, 3.70 mL, 3.00 eq) and CDI (3.98 g, 24.5 mmol, 3.00 eq) were added at -25 °C, and the mixture was stirred at 25 °C for 12 h. TLC (petroleum ether: ethyl acetate = 5:1) detection showed that the reaction was complete. 300 mL of water was added, and the mixture was extracted with dichloromethane (50.0 mL) three times. The organic phase was dried over anhydrous sodium sulfate and concentrated to give a white solid CLA-A6 (4.00 g) in a yield of 69.0%.

[0560] Step seven:

[0561] The CLA-A6 (96.0 g, 87 mmol, 1.00 eq) was dissolved in 500 mL of anhydrous THF, replaced with argon for 3 times, cooled to -40 °C, and then DBU (13.25 g, 87 mmol, 1.00 eq) was added dropwise. The temperature was controlled at -40 °C, and then NFSI (27.4 g, 87 mmol, 1.00 eq) dissolved in 200 mL of THF was added dropwise. After 1.5 hours of incubation, the reaction was naturally warmed to ambient temperature. After the reaction was completed, it was quenched with saturated NaHCO3 aqueous solution, and then extracted with DCM until complete. The DCM was combined, washed with saturated NaCl, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography to obtain a light yellow solid SOL-B1 (34.3 g, purity 91%, yield 54%). LCMS (ESI) m / z = 724.50 [M+H] + .

[0562] Example 1 XNW 9228

[0563] Step one:

[0564] At room temperature, XNW9228-A0 (500 mg, 4.76 mmol, 1 eq), dibutyltin oxide (592 mg, 2.38 mmol, 0.5 eq), azidotrimethylsilane (1.64 g, 14.27 mmol, 3 eq) and NMP (10 mL) were sequentially added to a single-neck flask. The reaction system was replaced with argon for 3 times, and then heated to 150 °C and stirred for 4 hours. After the reaction system was cooled to room temperature, it was directly used in the next step reaction. LCMS (ESI): m / z = 149.0 [M+H] + .

[0565] Step two:

[0566] At room temperature, potassium carbonate (1.97 g, 14.28 mmol, 3 eq), potassium iodide (790 mg, 4.76 mmol, 1 eq) and N-(4-bromobutyl)phthalimide (1.62 g, 5.71 mmol, 1.2 eq) were sequentially added to a solution of the XNW9228-A1 (705 mg, 4.76 mmol, 1 eq) in NMP (10 mL). The reaction system was heated to 35 °C and stirred overnight. After dilution with ethyl acetate and water, the reaction system was filtered, and the aqueous phase was extracted with ethyl acetate twice. The organic phases were combined, washed with water and saturated brine once, dried, filtered, concentrated to obtain a crude product, which was purified by medium pressure normal phase column chromatography (DCM / 10% MeOH = 5%-35%) to obtain a light yellow solid XNW9228-A2 (500 mg, yield: 29.90%). LCMS (ESI): m / z = 350.0 [M+H] + .

[0567] Step three:

[0568] XNW9228-A2 (500 mg, 1.42 mmol, 1 eq) was suspended in acetonitrile (5 mL) and water (1 mL) at room temperature, and 80% hydrazine hydrate (356 mg, 7.12 mmol, 5 eq) was added. The reaction system was heated to 75 °C and stirred for 4 hours. The reaction system was concentrated to get the crude product, which was purified by medium pressure normal phase over column (DCM / 10% MeOH (7M, NH3) in DCM = 0-70%) and concentrated to get yellowish oil XNW9228-A3 (200 mg, yield: 64.10%). LCMS (ESI): m / z = 220.0 [M+H] + .

[0569] Step four:

[0570] XNW9228-A3 (200 mg, 0.81 mmol, 1 eq) and SOL-B1 (585 mg, 0.81 mmol, 1 eq) were dissolved in acetonitrile (5 mL) and water (1 mL) at room temperature, and the reaction system was heated to 75 °C and stirred overnight. After cooling to room temperature, SOL-B1 (585 mg, 0.81 mmol, 1 eq) was added, and the system was heated to 75 °C and stirred overnight. The reaction system was concentrated, and then prepared by prep-HPLC (0.1% TFA) and prep-HPLC (0.1% NH3.H2O), and finally lyophilized to obtain white solid XNW9228 (27 mg, purity: 97.7%).

[0571] 1H NMR (400 MHz, Methanol-d4) δ 9.32 (dd, Ji, J2= 1.6 Hz, 5.2 Hz, 1H), 9.50 (dd, Ji, J2= 2.0 Hz, 8.8 Hz, 1H), 7.94 (dd, Ji, J2= 5.2 Hz, 8.8 Hz, 1H), 4.87-4.86 (m, 2H), 4.76 (dd, Ji, J2= 2.8 Hz, 10.0 Hz, 1H), 4.30 (d, J = 7.2 Hz, 1H), 4.03-4.00 (m, 1H), 3.82-3.75 (m, 1H), 3.62-3.54 (m, 2H), 3.50-3.45 (m, 1H), 3.38 (s, 1H), 3.28-3.24 (m, 1H), 3.19-3.13 (m, 1H), 2.79-2.73 (m, 1H), 2.61-2.51 (m, 1H), 2.42 (s, 6H), 2.35 (s, 3H), 2.13-2.06 (m, 2H), 1.91-1.79 (m, 3H), 1.70-1.61 (m, 4H), 1.57-1.54 (m, 3H), 1.51 (s, 3H), 1.27-1.26 (m, 7H), 1.23 (d, J = 7.2 Hz, 3H), 1.18 (d, J = 6.8 Hz, 3H), 0.97 (d, J = 7.2 Hz, 3H), 0.87 (t, J = 7.6 Hz, 3H). LCMS (ESI): m / z = 833.63 [M+H] + .

[0572] Example 2 XNW 9229

[0573] Step one:

[0574] Into a single neck flask was added XNW9229-A0 (1 g, 7.72 mmol, 1 eq), zinc cyanide (906 mg, 7.72 mmol, 1 eq), zinc powder (100 mg, 1.54 mmol, 0.2 eq), Pd(dppf)Cl2.CH2Cl2(378 mg, 0.46 mmol, 0.06 eq), NiCl2(50 mg, 0.38 mmol, 0.05 eq), DMAP (943 mg, 7.72 mmol, 1 eq) and DMF (15 mL) at room temperature. The reaction was purged with argon for 3 times before heating to 110 °C and stirring overnight. The reaction was cooled to room temperature before filtration. The filter cake was washed with DCM / MeOH (10 / 1) and the filtrate was concentrated to give the crude product. The crude product was purified by medium pressure normal phase column (DCM / 10% MeOH = 0-50%) to give the crude product XNW9229-A1 (1 g) as a light pink solid. LCMS: contains ~50% DMAP. LCMS (ESI): m / z = 120.9 [M+H] + .

[0575] Step two:

[0576] Into a single neck flask was added XNW9229-A1 (1 g, 4.16 mmol, 1 eq), azidotrimethylsilane (1.44 g, 12.49 mmol, 3 eq), dibutyltin oxide (518.27 mg, 2.08 mmol, 0.5 eq) and NMP (10 mL) at room temperature. The reaction was purged with argon for 3 times before heating to 150 °C and stirring for 4 hours. The reaction was cooled to room temperature before direct use in the next step. LCMS (ESI): m / z = 164.0 [M+H] + .

[0577] Step three:

[0578] To a solution of XNW9229-A2 (1.1 g, 6.74 mmol) in NMP (10 mL) was added potassium iodide (1.12 g, 6.74 mmol, 1 eq), cesium carbonate (4.39 g, 13.49 mmol, 2 eq) and N-(4-bromobutyl)phthalimide (2.30 g, 8.09 mmol, 1.2 eq) sequentially at room temperature. The reaction was stirred at 60 °C overnight. After the reaction was cooled to room temperature, N-(4-bromobutyl)phthalimide (2.30 g, 8.09 mmol, 1.2 eq) and cesium carbonate (4.39 g, 13.49 mmol, 2 eq) were added and stirred at 100 °C overnight. The reaction was filtered and the filtrate was directly purified by medium pressure reverse phase column (0.1% HCOOH in H2O / CH3CN = 5%-50%) and lyophilized to give 380 mg of product. Further purification by medium pressure normal phase column (DCM / 10% MeOH = 0-40%) gave XNW9229-A3 (200 mg, yield: 8.10%) as a white solid. LCMS (ESI): m / z = 365.2 [M+H] + .

[0579] Step Four:

[0580] XNW9229-A3 (200 mg, 0.54 mmol, 1 eq) was dissolved in acetonitrile (5 mL) and water (1 mL) at room temperature, and 80% hydrazine hydrate (137 mg, 2.73 mmol, 5 eq) was added. The reaction was stirred at 75 °C for 4 h. The reaction was concentrated to give a crude product, which was purified by medium pressure normal phase column (DCM / 20% MeOH (7M, NH3) in DCM = 0-100%) to give XNW9229-A4 (40 mg, yield: 31.28%) as a white solid. LCMS (ESI): m / z = 235.0 [M+H] + .

[0581] Step Five:

[0582] XNW9229-A4 (40 mg, 0.17 mmol, 1 eq) and SOL-B1 (148 mg, 0.20 mmol, 1.2 eq) were dissolved in acetonitrile (3 mL) and water (0.5 mL) at room temperature, and the reaction was stirred at 75 °C overnight. After cooling to room temperature, SOL-B1 (148 mg, 0.20 mmol, 1.2 eq) was added, and the reaction was stirred at 75 °C overnight. The reaction was concentrated, and prep-HPLC (0.1% TFA) and prep-HPLC (0.1% NH4HCO3) were used for preparation, and then lyophilized to give XNW9229 (2 mg, purity: 98.5%) as a white solid.

[0583] 1 H NMR (400 MHz, Methanol-d4) δ 8.05 (d, J = 9.2 Hz, 1H), 7.06 (d, J = 9.2 Hz, 1H), 4.81-4.78 (m, 4H), 4.30 (d, J = 7.6 Hz, 1H), 4.05 (d, J = 10.8 Hz, 1H), 3.81-3.74 (m, 1H), 3.06-3.43 (m, 3H), 3.43 (s, 1H), 3.26-3.13 (m, 2H), 2.66-2.53 (m, 2H), 2.40 (s, 3H), 2.34 (s, 6H), 2.11-2.04 (m, 2H), 1.92-1.83 (m, 2H), 1.77-1.74 (m, 1H), 1.69 (s, 2H), 1.67-1.62 (m, 2H), 1.60-1.56 (m, 2H), 1.52 (s, 3H), 1.29-1.24 (m, 10H), 1.19 (d, J = 6.8 Hz, 3H), 0.97 (d, J = 7.2 Hz, 3H), 0.88 (t, J = 7.6 Hz, 3H). LCMS (ESI): m / z = 848.72 [M+H] + .

[0584] Example 3 XNW9316

[0585] XNW9228 (500 mg, 0.60 mmol, 1 eq) was dissolved in water (1 mL) and methanol (5 mL) at room temperature, and then elemental iodine (206 mg, 0.81 mmol, 1.35 eq) was added. The reaction system was heated to 60 °C and stirred for 3 hours. After sodium acetate (271 mg, 3.30 mmol, 5.5 eq) was added to the reaction system, it was continuously stirred at 60 °C overnight. The reaction system was concentrated to obtain a crude product, which was dissolved in water and dichloromethane, and then NaHCO3(aq.) was added. The aqueous phase was extracted with dichloromethane three times. After the organic phases were combined, they were dried, filtered, and concentrated to obtain a crude product, which was prepared by prep-HPLC (NH3. water) and freeze-dried to obtain white solid XNW9316 (100 mg, purity: 99.95%).

[0586] 1H NMR (400 MHz, Methanol-d4) δ 9.31 (dd, Ji, J2= 1.6 Hz, 5.2 Hz, 1H), 8.50 (dd, Ji, J2= 2.0 Hz, 8.8 Hz, 1H), 7.94 (dd, Ji, J2= 5.2 Hz, 8.8 Hz, 1H), 4.87-4.86 (m, 2H), 4.76 (dd, Ji, J2= 2.8 Hz, 10.0 Hz, 1H), 4.29 (d, J = 7.6 Hz, 1H), 4.04-4.01 (m, 1H), 3.82-3.75 (m, 1H), 3.66-3.54 (m, 2H), 3.52-3.45 (m, 1H), 3.40 (s, 1H), 3.19-3.14 (m, 1H), 3.06-3.01 (m, 1H), 2.57-2.48 (m, 2H), 2.37 (s, 3H), 2.36 (s, 3H), 2.14-2.06 (m, 2H), 2.00-1.96 (m, 1H), 1.91-1.81 (m, 2H), 1.70-1.59 (m, 4H), 1.57-1.53 (m, 3H), 1.51 (s, 3H), 1.28-1.17 (m, 13H) 0.97 (d, J = 6.8 Hz, 3H), 0.87 (t, J = 7.2 Hz, 3H). LCMS (ESI): m / z = 819.73 [M+H] + .

[0587] Example 4 XNW9298

[0588] XNW9316 (50 mg, 0.061 mmol, 1 eq) and acetone (7 mg, 0.12 mmol, 2 eq) were dissolved in dichloromethane (3 mL) at room temperature, then acetic acid (4 mg, 0.061 mmol, 1 eq) was added. After the reaction system was stirred at room temperature for 30 minutes, NaBH3CN (8 mg, 0.12 mmol, 2 eq) was added. The reaction system was continuously stirred at room temperature for 4 hours. After acetone (7 mg, 0.12 mmol, 2 eq) was added to the reaction system, it was stirred at room temperature for 30 minutes, and then NaBH3CN (8 mg, 0.12 mmol, 2 eq) was added. The reaction system was stirred at room temperature overnight. The reaction system was quenched with water and extracted with dichloromethane three times. After the organic phases were combined, they were concentrated to obtain a crude product, which was prepared by prep-HPLC (NH3. water) and freeze-dried to obtain white solid XNW9298 (6.5 mg, purity: 99.89%).

[0589] 1H NMR (400 MHz, Methanol-d4) δ 9.31 (dd, Ji, J2= 1.6 Hz, 5.2 Hz, 1H), 8.50 (dd, Ji, J2= 2.0 Hz, 8.8 Hz, 1H), 7.94 (dd, Ji, J2= 5.2 Hz, 8.8 Hz, 1H), 4.89 - 4.85 (m, 2H), 4.76 (dd, Ji, J2= 2.8 Hz, 10.0 Hz, 1H), 4.32 (d, J = 7.2 Hz, 1H), 4.03 - 4.00 (m, 1H), 3.82 - 3.75 (m, 1H), 3.62 - 3.54 (m, 2H), 3.51 - 3.44 (m, 1H), 3.40 (s, 1H), 3.20 - 3.12 (m, 2H), 2.99 - 2.95 (m, 1H), 2.80 - 2.74 (m, 1H), 2.58 - 2.50 (m, 1H), 2.36 (s, 3H), 2.26 (s, 3H), 2.14 - 2.06 (m, 2H), 1.91 - 1.82 (m, 2H), 1.74 - 1.61 (m, 5H), 1.59 - 1.54 (m, 3H), 1.51 (s, 3H), 1.32 - 1.29 (m, 4H), 1.25 - 1.23 (m, 6H), 1.19 (d, J = 6.8 Hz, 3H), 1.11 - 1.07 (m, 6H), 0.97 (d, J = 6.8 Hz, 3H), 0.87 (t, J = 7.6 Hz, 3H). LCMS (ESI): m / z = 861.73 [M+H] + .

[0590] Example 5 XNW93

[0591] Step one:

[0592] XNW9305-A0 (5 g, 23.01 mmol, 1 eq) was dissolved in acetonitrile (70 mL) and acetone (70 mL) at room temperature, then potassium carbonate (6.36 g, 46.03 mmol, 2 eq) and iodomethane (4.90 g, 34.52 mmol, 1.5 eq) were added. The reaction system was heated to 45 °C and stirred overnight. The reaction system was concentrated to get the crude product, then dissolved in dichloromethane and water, the aqueous phase was extracted with dichloromethane twice. The organic phase was combined, dried, filtered and concentrated to get the crude product XNW9305-A1 (5 g) as a light yellow oil. LCMS (ESI): m / z = 132.19 [M+H-56] + .

[0593] Step two:

[0594] XNW9305-A1 (5 g, 21.62 mmol, 1 eq) and hydrazine hydrate (5.40 g, 108.09 mmol, 5 eq) were dissolved in methanol (50 mL) at room temperature, and the reaction system was heated to 65 °C and stirred overnight. The reaction system was concentrated to obtain a crude product, which was purified by medium-pressure reverse-phase column chromatography (water / acetonitrile = 5%-35%) to obtain colorless oil XNW9305-A2 (4 g, yield: 80%), which became solid after standing for a long time. LCMS (ESI): m / z = 132.20 [M+H-56] + .

[0595] Step three:

[0596] 3-carboxypyridazine (500 mg, 4.04 mmol, 0.85 eq) was suspended in DMF (10 mL) at room temperature, and then HATU (2.17 g, 5.71 mmol, 1.2 eq), triethylamine (962 mg, 9.51 mmol, 2 eq) and XNW9305-A2 (1.1 g, 4.76 mmol, 1 eq) were added in sequence. The reaction system was stirred at room temperature overnight. The reaction system was directly purified by medium-pressure reverse-phase column chromatography (0.1% HCOOH in H2O / CH3CN = 5%-50%) and then freeze-dried to obtain yellowish oil XNW9305-A3 (0.8 g, yield: 49.86%). LCMS (ESI): m / z = 238.23 [M+H-Boc] + .

[0597] Step four:

[0598] XNW9305-A3 (800 mg, 2.37 mmol, 1 eq) and Lawesson's reagent (623 mg, 1.54 mmol, 0.65 eq) were dissolved in THF (15 mL) at room temperature, and the reaction system was heated to reflux and stirred overnight. The reaction system was concentrated to obtain a crude product, which was purified by medium-pressure normal-phase column chromatography (dichloromethane / 10% methanol = 0-35%) to obtain red solid XNW9305-A4 (400 mg, yield: 50.29%). LCMS (ESI): m / z = 336.32 [M+H] + .

[0599] Step five:

[0600] XNW9305-A4 (400 mg, 1.19 mmol) was dissolved in dichloromethane (6 mL) at room temperature, and TFA (2 mL) was added. The reaction system was stirred at room temperature for 2 hours. The reaction system was concentrated to give a crude product, which was dissolved in methanol, and the pH was adjusted to basic with NaHC03(aq.), and then concentrated to give a crude product, which was dissolved in dichloromethane / methanol (10 / 1), and then sonicated, filtered, and the filtrate was concentrated to give a crude product, which was a dark green oil XNW9305-A5 (400 mg). LCMS (ESI): m / z = 236.20 [M+H] + .

[0601] Step six:

[0602] XNW9305-A5 (280 mg, 1.19 mmol, 1 eq) was suspended in acetonitrile (10 mL) at room temperature, and then DBU (543 mg, 3.57 mmol, 3 eq) and SOL-B1 (1.03 g, 1.43 mmol, 1.2 eq) were added. The reaction system was stirred at 50 °C for 4 hours. After water (5 mL) was added to the reaction system, it was heated to 75 °C and stirred overnight. The reaction system was concentrated to give a crude product, which was diluted with dichloromethane and water, and the aqueous phase was extracted twice with dichloromethane. The organic phases were combined and concentrated to give a crude product, which was prepared by prep-HPLC (TFA) and prep-HPLC (NH3. water), and then lyophilized to give 150 mg of a white solid. After SFC purification, the white solid XNW9305 (59 mg, purity: 99.28%) was obtained by lyophilization.

[0603] 1H NMR (400 MHz, Methanol-d4) δ 9.26 (dd, Ji, J2= 1.6 Hz, 5.2 Hz, 1H), 8.59 (dd, Ji, J2= 2.0 Hz, 8.8 Hz, 1H), 7.91 (dd, Ji, J2= 5.2 Hz, 8.8 Hz, 1H), 4.83 - 4.80 (m, 2H), 4.29 (d, J = 7.2 Hz, 1H), 4.05 (d, J = 10.0 Hz, 1H), 3.84 - 3.77 (m, 1H), 3.62 - 3.48 (m, 3H), 3.43 (s, 1H), 3.28 - 3.18 (m, 4H), 2.66 - 2.57 (m, 2H), 2.40 (s, 3H), 2.35 (s, 6H), 1.94 - 1.84 (m, 4H), 1.79 - 1.75 (m, 1H), 1.67 - 1.56 (m, 5H), 1.53 (s, 4H), 1.31 (s, 3H), 1.26 - 1.22 (m, 7H), 1.20 (d, J = 6.8 Hz, 3H), 0.98 (d, J = 6.8 Hz, 3H), 0.90 (t, J = 7.2 Hz, 3H). LCMS (ESI): m / z = 849.64 [M+H] + .

[0604] Example 6 XNW9319

[0605] XNW9316 (50 mg, 0.061 mmol, 1 eq) and acetaldehyde (5 mg, 0.12 mmol, 2 eq) were dissolved in DCE (3 mL) at room temperature, then acetic acid (4 mg, 0.061 mmol, 1 eq) was added. After the reaction system was stirred at room temperature for 30 min, NaBH3CN (8 mg, 0.12 mmol, 2 eq) was added, and the reaction system was stirred at room temperature overnight. The reaction system was quenched with water and extracted with dichloromethane three times. The organic phase was combined and concentrated to give a crude product, which was prepared by prep-HPLC (NH3. water) and lyophilized to give white solid XNW9319 (12 mg, purity: 98.7%).

[0606] 1H NMR (400 MHz, Methanol-d4) δ 9.31 (dd, Ji, J2= 1.6 Hz, 5.2 Hz, 1H), 8.50 (dd, Ji, J2= 2.0 Hz, 8.8 Hz, 1H), 7.94 (dd, Ji, J2= 5.2 Hz, 8.8 Hz, 1H), 4.87-4.85 (m, 2H), 4.76 (dd, Ji, J2= 2.8 Hz, 10.0 Hz, 1H), 4.29 (d, J = 7.6 Hz, 1H), 4.04-4.00 (m, 1H), 3.82-3.75 (m, 1H), 3.61-3.54 (m, 2H), 3.50-3.45 (m, 1H), 3.40 (s, 1H), 3.26-3.15 (m, 2H), 2.72-2.61 (m, 2H), 2.57-2.48 (m, 2H), 2.36 (s, 3H), 2.28 (s, 3H), 2.14-2.06 (m, 2H), 1.92-1.82 (m, 2H), 1.75-1.61 (m, 5H), 1.59-1.54 (m, 3H), 1.51 (s, 3H), 1.30-1.27 (m, 4H), 1.26-1.23 (m, 6H), 1.19 (d, J = 6.8 Hz, 3H), 1.09 (t, J = 6.8 Hz, 3H), 0.97 (d, J = 7.2 Hz, 3H), 0.87 (t, J = 7.2 Hz, 3H). LCMS (ESI): m / z = 847.64 [M+H] + .

[0607] Example 7 XNW9312

[0608] Step one:

[0609] Into a reaction flask was added XNW9312-A1 (500 mg, 1.44 mmol, 1.0 eq), N2H4.H2O (85% aqueous solution) (359 mg, 7.18 mmol, 5.0 eq), ACN (20 mL) and H2O (4 mL) at room temperature, under the protection of argon balloon, heated in oil bath at 70 °C for 8 hours. Remove acetonitrile under reduced pressure, the concentrated solution was passed through a reversed-phase column, 10 mmol / L NH4HCO3:ACN system, to obtain XNW9312-A2 (270 mg, yield: 86.19%), LCMS (ESI): m / z = 219.03 [M+H] + .

[0610] Step two:

[0611] Into a reaction flask was placed XNW9312-A2 (220 mg, 1.01 mmol, 1.0 eq), DBU (140 mg, 916 μmol, 0.9 eq) and ACN (5 mL) stirred to dissolve, then SOL-B1 (803 mg, 1.11 mmol, 1.1 eq) was added. The reaction was heated at 50 °C in an oil bath for 6 h under argon protection. LCMS monitoring showed that the raw material was completely reacted, and the intermediate LCMS (ESI): m / z = 438.55, 874.63 [M+H] + Into a reaction flask was placed 2.5 mL of water, and the reaction was heated at 70 °C in an oil bath for 16 h under argon protection. The acetonitrile was removed by concentration under reduced pressure, 60 mL of dichloromethane was added to the concentrate, and water was washed (30 mL x 3 times); the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a yellow sticky substance. Liquid phase preparation purification, freeze-drying to obtain white solid XNW9312 (24 mg, purity: 96.70%), 1 HNMR (400 MHz, Methanol-d4) δ 9.17 (dd, J = 5.0, 1.8 Hz, 1H), 8.70 (s, 1H), 8.43 (dd, J = 8.4, 1.6 Hz, 1H), 7.87 (dd, J = 8.4, 5.0 Hz, 1H), 4.83 (d, J = 2.8 Hz, 1H), 4.70 - 4.53 (m, 2H), 4.33 (d, J = 7.6 Hz, 1H), 4.08 (dd, J = 10.8, 1.6 Hz, 1H), 3.88 - 3.76 (m, 1H), 3.67 - 3.48 (m, 3H), 3.46 (s, 1H), 3.31 - 3.17 (m, 2H), 2.71 - 2.55 (m, 2H), 2.38 (s, 3H), 2.37 (s, 6H), 2.09 - 1.84 (m, 4H), 1.83 - 1.75 (m, 1H), 1.71 - 1.55 (m, 10H), 1.34 - 1.22 (m, 14H), 1.02 (d, J = 6.8 Hz, 3H), 0.91 (t, J = 7.4 Hz, 3H), LCMS (ESI): m / z = 416.98, 832.72 [M+H] + .

[0612] Example 8 XNW 9278

[0613] Step one:

[0614] XNW9278-A1 (3.00 g, 24.17 mmol) was dissolved in methanol (60 mL) at room temperature, followed by the addition of concentrated sulfuric acid (2.00 mL), the reaction system was replaced with argon for 3 times, and then the temperature was increased to 75 °C and stirred overnight. After the reaction was completed, the reaction system was cooled to room temperature and concentrated. Then it was dissolved in water (30 mL), the pH was adjusted to 8-9 with sodium carbonate solid, extracted with ethyl acetate (25 mL) for three times, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain XNW9278-A2 (2.5 g, 18.10 mmol, yield 74.87%) as a brown solid. LCMS (ESI) m / z = 139.1 [M+H] + .

[0615] Step two:

[0616] XNW9278-A2 (3.50 g, 25.34 mmol) was dissolved in ammonia-methanol solution (7 M, 15.00 mL) at room temperature, and the reaction system was placed in a sealed tube and stirred at 70 °C overnight. After the reaction was completed, the reaction system was cooled to room temperature and concentrated to obtain XNW9278-A3 (3 g, 24.37 mmol, yield 96.17%) as a yellow solid. LCMS (ESI) m / z = 124.1 [M+H] + .

[0617] Step three:

[0618] XNW9278-A3 (3.00 g, 24.37 mmol) and triethylamine (4.93 g, 48.74 mmol) were dispersed in dichloromethane (150 mL) at room temperature, the reaction system was cooled to 0 °C, and a solution of TFAA (6.14 g, 29.24 mmol) in dichloromethane (50 mL) was added dropwise. After the addition was completed, the temperature was increased to room temperature and stirred for 3 hours. After the reaction was completed, the reaction was quenched with water (20 mL), washed with saturated sodium bicarbonate solution (40 mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by medium pressure normal phase column chromatography (PE / EA = 0-50%) to obtain XNW9278-A4 (2.1 g, 19.98 mmol, yield 82.00%) as a yellow solid. LCMS (ESI) m / z = 106.1 [M+H] + .

[0619] Step four:

[0620] XNW9278-A4 (2.10 g, 19.98 mmol) was dispersed in N-methylpyrrolidone (25 mL) at room temperature, followed by the addition of azidotrimethylsilane (6.91 g, 59.94 mmol) and dibutyltin oxide (2.49 g, 9.99 mmol). The reaction system was replaced with argon for 3 times, and was stirred at 150 °C for 4 hours. After the reaction was completed, the reaction system was directly used for the next step. LCMS (ESI) m / z = 149.1 [M+H] + .

[0621] Step five:

[0622] Cesium carbonate (19.99 g, 61.37 mmol), potassium iodide (5.09 g, 30.68 mmol) and N-(4-bromobutyl)phthalimide (8.66 g, 30.68 mmol) were added to the reaction system of step four at room temperature, and the reaction system was stirred at 40 °C overnight. After the reaction was completed, the reaction system was filtered, washed with ethyl acetate (50 mL) for 2 times, the combined filtrate was washed with saturated brine for 3 times, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a crude product. The crude product was purified by medium pressure normal phase over column (DCM / MeOH = 0-10%) to give XNW9278-A6 (3.9 g, 11.16 mmol, yield 54.58%) as a yellow solid. LCMS (ESI) m / z = 367.2 [M+H] + .

[0623] Step six:

[0624] XNW9278-A6 (3.90 g, 11.16 mmol) was dissolved in methanol (60 mL) at room temperature, followed by the addition of hydrazine hydrate (3.50 mL, 55.82 mmol), and the reaction system was stirred at 75 °C for 4 hours. After the reaction was completed, the reaction system was concentrated, diluted with dichloromethane / methanol (10:1, 60 mL), filtered, and the filtrate was concentrated to give a crude product. The crude product was purified by medium pressure normal phase over column (DCM / MeOH (containing 7M NH3) = 0-10%) to give XNW9278-A7 (2 g, 9.12 mmol, yield 81.71%) as a yellow oil. LCMS (ESI) m / z = 220.2 [M+H] + .

[0625] Step seven:

[0626] SOL-B1 (660.28 mg, 912.22 μmol) and XNW9278-A7 (200.00 mg, 912.22 μmol) were dissolved in acetonitrile (5 mL) and water (1 mL) at room temperature, the reaction system was heated to 75 °C and stirred overnight. After cooling to room temperature, SOL-B1 (660.28 mg, 912.22 μmol) was added, and the reaction system was heated to 75 °C and stirred overnight. The reaction system was directly prepared by prep-HPLC (0.1% TFA) and prep-HPLC (0.1% NH4HCO3), and then freeze-dried to obtain white solid XNW9278 (40 mg, 48.02 μmol, yield: 5.26%).

[0627] 1 H NMR (400 MHz, Methanol-d4) δ 9.89 (dd, J = 2.3, 1.3 Hz, 1H), 9.41 (dd, J = 5.3, 1.3 Hz, 1H), 8.39 (dd, J = 5.4, 2.2 Hz, 1H), 4.86-4.83 (m, 2H), 4.71 (dd, J = 10.2, 2.7 Hz, 1H), 4.29 (d, J = 7.3 Hz, 1H), 4.01 (dd, J = 10.6, 1.6 Hz, 1H), 3.82-3.72 (m, 1H), 3.64-3.50 (m, 2H), 3.49-3.41 (m, 1H), 3.34 (s, 1H), 3.22 (dd, J = 10.3, 7.3 Hz, 1H), 3.16 (q, J = 6.3, 5.8 Hz, 1H), 2.69-2.60 (m, 1H), 2.59-2.49 (m, 1H), 2.34 (s, 6H), 2.26 (s, 3H), 2.12-2.00 (m, 2H), 1.92-1.80 (m, 2H), 1.80-1.73 (m, 1H), 1.70-1.57 (m, 2H), 1.56-1.45 (m, 8H), 1.28-1.17 (m, 13H), 0.96 (d, J = 6.9 Hz, 3H), 0.86 (t, J = 7.4 Hz, 3H).

[0628] LCMS (ESI): m / z = 833.3 [M+H] + .

[0629] Example 9 XNW 9303

[0630] Step one:

[0631] XNW9303-A1 (10.00 g, 53.99 mmol) was dispersed in acetone (100 mL) at room temperature, then XNW9303-A2 (16.14 g, 70.19 mmol) was added, the reaction system was replaced with argon for 3 times, and then was stirred at 65 °C overnight. After the reaction was completed, the reaction system was cooled to room temperature, filtered with diatomite, and the filter cake was washed with acetone (20 mL). The filtrate was concentrated to obtain a crude product. The crude product was purified by column chromatography (PE / EA = 0-35%) to obtain XNW9303-A3 (15.3 g, 51.66 mmol, yield 95.69%) as colorless oil. LCMS (ESI) m / z = 296.1 [M+H] + .

[0632] Step two:

[0633] XNW9303-A4 (3.00 g, 28.54 mmol) was dispersed in N-methylpyrrolidone (50 mL) at room temperature, then azidotrimethylsilane (9.87 g, 85.63 mmol) and dibutyltin oxide (3.55 g, 14.27 mmol) were added, the reaction system was replaced with argon for 3 times, and then was stirred at 150 °C for 4 hours. After the reaction was completed, the reaction system was directly used in the next step. LCMS (ESI) m / z = 149.1 [M+H] + .

[0634] Step three:

[0635] Cesium carbonate (27.91 g, 85.67 mmol), potassium iodide (4.74 g, 28.56 mmol) and XNW9303-A3 (8.46 g, 28.56 mmol) were sequentially added to the reaction system of step two at room temperature, the reaction system was heated to 50 °C and stirred overnight. After the reaction was completed, the reaction system was filtered, washed with ethyl acetate (30 mL) twice, the combined filtrate was washed with saturated brine for 3 times, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by column chromatography (DCM / MeOH = 0-10%) to obtain XNW9303-A6 (5.4 g, 14.86 mmol, yield 52.04%) as yellow oil. LCMS (ESI) m / z = 364.5 [M+H] + .

[0636] Step four:

[0637] XNW9303-A6 (5.40 g, 14.86 mmol) was dissolved in methanol (60 mL) at room temperature, then hydrazine hydrate (5 mL, 74.30 mmol) was added, and the reaction system was warmed to 75 °C and stirred for 4 h. After the reaction was completed, the reaction system was concentrated, diluted with dichloromethane / methanol (10:1, 60 mL), filtered, and the filtrate was concentrated to give a crude product. The crude product was purified by medium-pressure normal-phase column chromatography (DCM / MeOH (containing 7M NH3) = 0-10%) to give XNW9303-A7 (1.89 g, 8.10 mmol, 54.52% yield) as a colorless oil. LCMS (ESI) m / z = 234.2 [M+H] + .

[0638] Step five:

[0639] SOL-B1 (1.02 g, 1.41 mmol) and XNW9303-A7 (300.00 mg, 1.29 mmol) were dissolved in acetonitrile (7 mL) at room temperature, then DBU (783.15 mg, 5.14 mmol) was added, and the reaction system was heated to 60 °C and stirred for 3 h. After the reaction was completed, the reaction system was cooled to room temperature, water (3.5 mL) was added, and the system was heated to 70 °C and stirred overnight. After the reaction was completed, the reaction system was cooled to room temperature, dichloromethane (25 mL) and water (20 mL) were separated, the aqueous phase was extracted with dichloromethane (15 mL), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a crude product. The crude product was directly prepared by prep-HPLC (0.1% TFA) and prep-HPLC (0.1% NH4HCO3), and then lyophilized to give XNW9303 (8 mg, 9.45 µmol, 0.73% yield) as a white solid.

[0640] 1H NMR (400 MHz, Methanol-d4) δ 9.34 - 9.28 (m, 1H), 8.54 - 8.47 (m, 1H), 7.98 - 7.91 (m, 1H), 5.28 - 5.14 (m, 1H), 4.74 (td, J = 10.3, 2.8 Hz, 1H), 4.28 (dd, J = 7.3, 4.6 Hz, 1H), 4.07 - 3.96 (m, 1H), 3.72 - 3.41 (m, 4H), 3.37 (d, J = 12.5 Hz, 1H), 3.27 - 3.10 (m, 2H), 2.67 - 2.58 (m, 1H), 2.57 - 2.46 (m, 1H), 2.37 (s, 1H), 2.33 (s, 6H), 2.30 (s, 2H), 2.17 - 1.98 (m, 2H), 1.94 - 1.79 (m, 2H), 1.78 - 1.69 (m, 4H), 1.67 - 1.46 (m, 9H), 1.29 - 1.15 (m, 14H), 0.95 (d, J = 6.8 Hz, 3H), 0.86 (dt, J = 11.2, 7.4 Hz, 3H).

[0641] LCMS (ESI): m / z = 847.6 [M+H] + .

[0642] Example 10 XNW9227

[0643] Step one:

[0644] The 6-chloro-4-amino pyridazine (3 g, 23.16 mmol, 1 eq) was suspended in THF (60 mL) at room temperature, then triethylamine (9.37 g, 92.63 mmol, 4 eq), 4-dimethylaminopyridine (565 mg, 4.63 mmol, 0.2 eq) and di-tert-butyl dicarbonate (12.64 g, 57.89 mmol, 2.5 eq) were added successively. The reaction system was stirred at room temperature overnight. The reaction system was concentrated to get the crude product, which was dissolved in ethyl acetate. The organic phase was washed with water, HCl (0.5 M) and saturated brine once, then dried, filtered and concentrated to get the crude product, which was purified by column chromatography (PE / EA = 0-35%) to get the yellow solid XNW9227-A1 (4 g, yield: 52.38%). LCMS (ESI): m / z = 330.06 [M+H] + .

[0645] Step two:

[0646] Into a single-neck flask, was added XNW9227-A1 (3 g, 9.10 mmol, 1 eq), zinc cyanide (1.07 g, 9.10 mmol, 1 eq), nickel chloride (59 mg, 0.45 mmol, 0.05 eq), Pd(dppf)Cl2.DCM (446 mg, 0.55 mmol, 0.06 eq), zinc powder (118 mg, 1.82 mmol, 0.2 eq), 4-dimethylaminopyridine (1.11 g, 9.10 mmol, 1 eq) and DMF (30 mL) successively at room temperature. The reaction system was replaced with argon for 3 times, and then heated to 100 °C and stirred for 8 hours. The reaction system was cooled to room temperature, diluted with ethyl acetate, and then washed with water and saturated brine for 1 time each. After drying, filtration and concentration, the crude product was purified by medium pressure normal phase column (PE / EA = 5%-50%) to obtain yellow solid XNW9227-A2 (1.1 g, yield: 54.91%). LCMS (ESI): m / z = 221.06 [M+H] + .

[0647] Step three:

[0648] Into a single-neck flask, was added XNW9227-A2 (1.1 g, 4.99 mmol, 1 eq), azidotrimethylsilane (1.72 g, 14.98 mmol, 3 eq) and dibutyltin oxide (623.11 mg, 2.50 mmol, 0.5 eq) in toluene (30 mL) at room temperature. The reaction system was replaced with argon for 3 times, and then heated to 140 °C and stirred for 4 hours. After the reaction system was cooled to room temperature, filtration and drying of the filter cake, the crude product was obtained as yellow solid XNW9227-A3 (1.3 g). LCMS (ESI): m / z = 264.24 [M+H] + .

[0649] Step four:

[0650] XNW9227-A3 (1.3 g, 4.94 mmol, 1 eq) was dissolved in DMF (20 mL) at room temperature, then cesium carbonate (3.22 g, 9.88 mmol, 2 eq) and potassium iodide (820 mg, 4.94 mmol, 1 eq) were added. After the reaction system was stirred at room temperature for 10 min, N-(4-bromobutyl)phthalimide (1.25 g, 4.94 mmol, 1 eq) was added. The reaction system was stirred at room temperature overnight. After the reaction system was filtered, it was washed with ethyl acetate. After the filtrate was washed with water and saturated brine once, it was dried, filtered, and concentrated to obtain a crude product, which was purified by medium pressure normal phase over a column (DCM / 10% MeOH = 0-35%) to obtain brown oil XNW9227-A4 (570 mg, yield: 26.51%) and yellow oil isomer (600 mg). LCMS (ESI): m / z = 435.33 [M+H] + .

[0651] Step five:

[0652] XNW9227-A4 (570 mg, 1.31 mmol, 1 eq) was dissolved in 1,4-dioxane (3 mL) at room temperature, then HCl (4M in 1,4-dioxane) (10 mL) was added. The reaction system was stirred at room temperature for 2 h. After the reaction system was filtered, the filter cake was dried to obtain yellow solid XNW9227-A5 (300 mg, yield: 74.44%). LCMS (ESI): m / z = 235.04 [M+H] + .

[0653] Step six:

[0654] XNW9227-A5 (300 mg, 0.98 mmol, 1 eq) was suspended in acetonitrile (10 mL) at room temperature, then DBU (595 mg, 3.91 mmol, 4 eq) and SOL-B1 (848 mg, 1.17 mmol, 1.2 eq) were added. The reaction system was stirred at 50°C overnight. After water (5 mL) was added to the reaction system, it was heated to 75°C and stirred for 4 h. After the reaction system was filtered, it was directly prepared by prep-HPLC (TFA) and prep-HPLC (NH3.H2O), and then lyophilized to obtain white solid XNW9227 (95 mg, purity: 99.88%).

[0655] 1H NMR (400 MHz, Methanol-d4) δ 8.63 (d, J = 2.8 Hz, 1H), 7.51 (d, J = 2.8 Hz, 1H), 5.14-4.97 (m, 2H), 4.76-4.73 (m, 1H), 4.31 (d, J = 7.2 Hz, 1H), 4.10-4.07 (m, 1H), 3.76-3.69 (m, 1H), 3.62-3.48 (m, 3H), 3.39 (s, 1H), 3.26-3.15 (m, 2H), 2.66-2.54 (m, 2H), 2.34 (s, 3H), 2.33 (s, 6H), 2.04-1.96 (m, 2H), 1.90-1.83 (m, 2H), 1.77-1.71 (m, 4H), 1.67-1.56 (m, 4H), 1.51 (s, 3H), 1.30-1.23 (m, 10H), 1.19 (d, J = 6.8 Hz, 3H), 0.95 (d, J = 6.8 Hz, 3H), 0.84 (t, J = 7.2 Hz, 3H). LCMS (ESI): m / z = 848.74 [M+H] + .

[0656] Example 11 XNW9335

[0657] Step one:

[0658] To a three-necked flask filled with argon, was added methyl isobutyrate (5 g, 48.96 mmol, 1 eq) in THF (50 mL) at -70 °C. After the reaction system was stirred at -70 °C for 10 min, lithium diisopropylamide (2.0 M in THF / Hexanes) (5.51 g, 51.40 mmol, 1.05 eq) was added dropwise slowly. After the addition was completed, the reaction system was stirred at -70 °C for 2 h. Then 1,3-dibromopropane (8.90 g, 44.06 mmol, 0.9 eq) was added dropwise. After the addition was completed, the reaction system was slowly warmed to room temperature and stirred overnight.

[0659] The reaction was quenched with HC1 (1 M) at 0 °C, concentrated, extracted with ethyl acetate twice. The organic phase was combined, washed with HC1 (0.5 M), water and saturated brine once, dried, filtered, concentrated to give the crude red-brown oil XNW9336-A1 (7 g).

[0660] Step two:

[0661] XNW9336-A1 (6 g, 26.89 mmol, 1 eq) was dissolved in DMF (60 mL) at room temperature, and then potassium phthalimide (4.98 g, 26.89 mmol, 1 eq) was added. The reaction system was heated to 80 °C and stirred overnight. The reaction system was diluted with water and extracted with ethyl acetate twice. The organic phase was combined, washed with water and saturated brine once, dried, filtered, and concentrated to give a crude product, which was purified by medium pressure normal phase column (PE / DCM = 0-50%) to give XNW9336-A2 (3 g, yield: 38.56%) as a colorless oil. LCMS (ESI): m / z = 290.24 [M+H] + .

[0662] Step three:

[0663] XNW9336-A2 (1.5 g, 5.18 mmol, 1 eq) was dissolved in HCl (6 M) (15 mL) at room temperature, and the reaction system was heated to 90 °C and stirred overnight. The reaction system was concentrated and extracted with DCM three times. The organic phase was combined, dried, filtered, and concentrated to give a crude product, XNW9336-A3 (1.1 g, yield: 77.07%) as a light yellow oil. LCMS (ESI): m / z = 230.17 [M+H] + .

[0664] Step four:

[0665] Methyl pyridazine-3-carboxylate (2 g, 14.48 mmol, 1 eq) was suspended in methanol (20 mL) at room temperature, and the reaction system was heated to 60 °C and stirred for 5 minutes, and then 85% hydrazine hydrate (724.86 mg, 14.48 mmol, 1 eq) was added. The reaction system was stirred at 60 °C overnight. The reaction system was cooled to 0 °C, and then MTBE (40 mL) was added. After stirring for 30 minutes, a large amount of solid was precipitated, which was filtered, and the filter cake was washed with MTBE and dried to give XNW9335-A1 (1.6 g, yield: 80.00%) as a light yellow solid. LCMS (ESI): m / z = 139.14 [M+H] + .

[0666] Step five:

[0667] XNW9336-A3 (1.1 g, 4.00 mmol, 1 eq) and XNW9335-A1 (607 mg, 4.40 mmol, 1.1 eq) were dissolved in DMF (15 mL) at room temperature, and then HATU (2.28 g, 5.99 mmol, 1.5 eq) and triethylamine (1.21 g, 11.99 mmol, 3 eq) were added successively. The reaction system was stirred at room temperature overnight. The reaction system was quenched with water and extracted with ethyl acetate twice. The organic phase was combined and washed with water and saturated brine once, dried, filtered, and concentrated to give a crude product, which was purified by medium pressure normal phase column (DCM / 10% MeOH = 0-30%) to give XNW9335-A2 (460 mg, yield: 29.12%) as a light yellow oil. LCMS (ESI): m / z = 396.28 [M+H] + .

[0668] Step six:

[0669] XNW9335-A2 (460 mg, 1.16 mmol, 1 eq) was dissolved in THF (10 mL) at room temperature, and then Lawesson's reagent (470 mg, 1.16 mmol, 1 eq) was added. The reaction system was heated to 80°C and stirred overnight. The reaction system was concentrated to give a crude product, which was purified by medium pressure normal phase column (DCM / 10% MeOH = 0-35%) to give XNW9335-A3 (400 mg, yield: 87.39%) as a light yellow oil. LCMS (ESI): m / z = 394.22 [M+H] + .

[0670] Step seven:

[0671] XNW9335-A3 (400 mg, 1.02 mmol, 1 eq) was dissolved in methanol (7 mL) at room temperature, and then 85% hydrazine hydrate (255 mg, 5.08 mmol, 5 eq) was added. The reaction system was heated to 70°C and stirred for 4 hours. The reaction system was concentrated to give a crude product, which was purified by medium pressure normal phase column (DCM / 10% MeOH (7M NH3) in DCM = 0-50%) to give XNW9335-A4 (160 mg, yield: 59.76%) as a light yellow oil. LCMS (ESI): m / z = 264.22 [M+H] + .

[0672] Step eight:

[0673] XNW9335-A4 (160 mg, 0.61 mmol) was dissolved in acetonitrile (6 mL) at room temperature, and then DBU (185 mg, 1.22 mmol, 2 eq) and SOL-B1 (528 mg, 0.73 mmol, 1.2 eq) were added. The reaction system was stirred at 50 °C overnight. After adding water (3 mL) to the reaction system, it was heated to 75 °C and stirred for 4 h. After the reaction system was filtered, it was directly prepared by prep-HPLC (TFA) and prep-HPLC (NH3.H2O), and then lyophilized to obtain white solid XNW9335 (38 mg, purity: 99.61%).

[0674] 1 H NMR (400 MHz, Methanol-d4) δ 9.26 (dd, Ji, J2= 1.6 Hz, 4.8 Hz, 1H), 8.62 (dd, Ji, J2= 1.6 Hz, 8.8 Hz, 1H), 7.92 (dd, Ji, J2= 5.2 Hz, 8.8 Hz, 1H), 4.80 - 4.77 (m, 2H), 4.28 (d, J = 7.2 Hz, 1H), 4.03 - 4.00 (m, 1H), 3.74 - 3.67 (m, 1H), 3.59 - 3.54 (m, 1H), 3.49 - 3.41 (m, 2H), 3.36 (s, 1H), 3.25 - 3.20 (m, 1H), 3.17 - 3.12 (m, 1H), 2.65 - 2.49 (m, 2H), 2.32 (s, 6H), 2.30 (s, 3H), 1.92 - 1.74 (m, 5H), 1.65 - 1.53 (m, 9H), 1.50 - 1.45 (m, 7H), 1.28 - 1.26 (m, 6H), 1.22 - 1.17 (m, 6H), 0.95 (d, J = 7.2 Hz, 3H), 0.87 (t, J = 7.6 Hz, 3H). LCMS (ESI): m / z = 877.75 [M+H] + .

[0675] Example 12 XNW9329

[0676] Step one:

[0677] To the reaction vessel were added compound SOL-B1 (4.01 g, 5.54 mmol, 1.1 eq), 9329-INT (1.1 g, 5.04 mmol, 1 eq), DBU (1.53 g, 10.08 mmol, 2.0 eq) and acetonitrile (30 mL), and the reaction was stirred at 50 °C for 5 h. LC-MS showed significant XNW9329-1, and the system was cooled to room temperature. The reaction was directly concentrated and subjected to the next step.

[0678] Step two:

[0679] To the reaction system of the last step, methanol (10 mL) was added, heated to 45 °C and reacted overnight. LC-MS was used to monitor the disappearance of the raw material. The reaction solution was directly rotary evaporated to dryness. The obtained crude product was purified by preparative purification to obtain white solid XNW9329-2 (600 mg). LCMS (ESI): m / z = 417.00, 832.72 [M+H] + .

[0680] Step three:

[0681] To the reaction vessel, compound 9329-2 (0.6 g, 0.72 mmol, 1 eq), sodium acetate (0.71 g, 8.64 mmol, 12 eq), CH3OH (40 mL) and water (10 mL) were added. The reaction was carried out at 60 °C for 3 hours. Iodine (0.73 g, 2.88 mmol, 4.0 eq) was added and the reaction was continued to stir for 3 hours. After the reaction was completed, sodium thiosulfate solution (50 ml) was added to the system. Ethyl acetate (50 ml*2) was used for extraction. The organic layer was dried and rotary evaporated to dryness. The white solid product 9329-3 (0.2 g, yield: 33.9%) was obtained by purification preparation. LCMS (ESI): m / z = 409.99, 818.68 [M+H] + .

[0682] Step four:

[0683] To the reaction bottle, 9329-3 (50 mg, 0.061 mmol, 1.0 eq), acetaldehyde (0.02 mL, 0.12 mmol, 2.0 eq), DCE (10 mL), CH3COOH (0.54 mg, 0.0061 mmol, 0.1 eq) and NaBH3CN (15 mg, 0.244 mmol, 4.0 eq) were added at room temperature. An argon balloon was used for protection. The reaction was stirred at room temperature for 16 hours. The reaction solution was diluted with 40 mL of dichloromethane and washed with water (20 mL x 3 times). The organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The white solid XNW9329 (21.24 mg, purity 97.8%) was obtained by preparative purification. 1H NMR (400 MHz, Methanol-d4) δ 9.17 (dd, J = 4.9, 1.7 Hz, 1H), 8.71 (s, 1H), 8.44 (dd, J = 8.6, 1.7 Hz, 1H), 7.88 (dd, J = 8.6, 5.0 Hz, 1H), 4.84 (dd, J = 10.1, 2.8 Hz, 2H), 4.63 (hept, J = 6.7 Hz, 2H), 4.33 (d, J = 7.3 Hz, 1H), 4.07 (dd, J = 10.6, 1.6 Hz, 1H), 3.82 (ddd, J = 13.8, 8.9, 4.6 Hz, 1H), 3.68 - 3.56 (m, 1H), 3.52 (ddd, J = 10.5, 7.2, 3.5 Hz, 1H), 3.45 (s, 1H), 3.32 - 3.17 (m, 2H), 2.79 - 2.64 (m, 2H), 2.58 (dddd, J = 19.3, 12.3, 6.9, 3.9 Hz, 2H), 2.37 (s, 3H), 2.32 (s, 3H), 2.03 (dd, J = 8.0, 5.6 Hz, 2H), 1.89 (dd, J = 14.6, 3.1 Hz, 2H), 1.77 (ddd, J = 12.9, 4.2, 2.0 Hz, 1H), 1.73 - 1.68 (m, 1H), 1.66 (s, 2H), 1.63 (d, J = 7.1 Hz, 1H), 1.59 (d, J = 7.3 Hz, 2H), 1.56 (s, 4H), 1.32 (d, J = 5.4 Hz, 3H), 1.28 (dd, J = 6.6, 2.3 Hz, 7H), 1.23 (d, J = 6.9 Hz, 3H), 1.13 (t, J = 7.1 Hz, 3H), 1.01 (d, J = 6.9 Hz, 3H), 0.91 (t, J = 7.4 Hz, 3H). LCMS (ESI): m / z = 423.90, 846.46 [M+H]+.

[0684] Example 13 XNW9354

[0685] XNW9354 was synthesized with reference to XNW9329, white solid was obtained, purity: 99.84%.

[0686] 1H NMR (400 MHz, Methanol-d4) δ 8.45 (s, 1H), 8.04 (d, J = 9.3 Hz, 1H), 7.08 (d, J = 9.2 Hz, 1H), 4.56 (hept, J = 7.0 Hz, 2H), 4.34 (d, J = 7.3 Hz, 1H), 4.11 (dd, J = 10.6, 1.6 Hz, 1H), 3.82 (ddd, J = 13.8, 8.8, 4.7 Hz, 1H), 3.63 (t, J = 6.9 Hz, 1H), 3.60 (s, 1H), 3.63 - 3.51 (m, 1H), 3.48 (s, 1H), 3.32 - 3.18 (m, 2H), 2.72 - 2.56 (m, 2H), 2.42 (s, 2H), 2.37 (s, 6H), 2.01 (ddd, J = 9.1, 6.5, 2.8 Hz, 1H), 1.98 (s, 1H), 1.91 (ddd, J = 14.6, 8.1, 3.4 Hz, 2H), 1.80 (ddd, J = 12.6, 4.3, 2.0 Hz, 1H), 1.71 (d, J = 21.4 Hz, 4H), 1.68 - 1.59 (m, 1H), 1.57 (s, 3H), 1.36 - 1.21 (m, 12H), 1.02 (d, J = 6.9 Hz, 3H), 0.92 (t, J = 7.4 Hz, 3H). LCMS (ESI): m / z = 847.77 [M+H]+.

[0687] Example 14 XNW 9377

[0688] Synthetic procedure is referred to XNW9305.

[0689] White solid XNW9377 (23 mg, purity: 99.95%).

[0690] 1H NMR (400 MHz, Methanol-d4) δ 8.56 (d, J = 2.8 Hz, 1H), 7.57 (d, J = 2.8 Hz, 1H), 4.82-4.78 (m, 2H), 4.29 (d, J = 7.2 Hz, 1H), 4.09-4.06 (m, 1H), 3.82-3.76 (m, 1H), 3.62-3.48 (m, 3H), 3.46 (s, 1H), 3.26-3.18 (m, 4H), 2.66-2.56 (m, 2H), 2.45 (s, 3H), 2.33 (s, 6H), 1.94-1.81 (m, 4H), 1.77-1.62 (m, 7H), 1.53 (s, 3H), 1.31-1.20 (m, 13H), 0.98 (d, J = 7.2 Hz, 3H), 0.90 (t, J = 7.2 Hz, 3H). LCMS (ESI): m / z = 864.68 [M+H] + .

[0691] Example 15 XNW 9378

[0692] Step one:

[0693] Methyl 6-amino pyridazine-3-carboxylate (1 g, 6.53 mmol, 1 eq) was dissolved in THF (20 mL) at room temperature, then triethylamine (2.64 g, 26.12 mmol, 4 eq), 4-dimethylaminopyridine (160 mg, 1.31 mmol, 0.2 eq) and di-tert-butyl dicarbonate (3.56 g, 16.33 mmol, 2.5 eq) were added successively. The reaction system was stirred at room temperature overnight. The reaction system was concentrated to get the crude product, which was slurried with petroleum ether / ethyl acetate (10 / 1), filtered, the filter cake was washed with petroleum ether, and dried to get the light yellow solid XNW9378-A1 (1.9 g, yield: 82.34%). LCMS (ESI): m / z = 354.14 [M+H-100] + .

[0694] Step two:

[0695] XNW9378-A1 (1.9 g, 5.38 mmol, 1 eq) was dissolved in THF (20 mL) and water (6 mL) at room temperature, then lithium hydroxide monohydrate (677 mg, 16.13 mmol, 3 eq) was added. The reaction system was stirred at room temperature overnight. The reaction system was concentrated to get the crude product, which was adjusted to pH = 4-6 with HC1 (1 M) at 0 °C, a large amount of solid precipitated, which was filtered, and the filter cake was dried to get the light yellow solid XNW9378-A2 (0.6 g, yield: 46.65%). LCMS (ESI): m / z = 240.18 [M+H]+ .

[0696] The subsequent synthesis steps refer to XNW9305.

[0697] White solid XNW9378 (40 mg, purity: 99.82%). 1 H NMR (400 MHz, Methanol-d4) δ 8.11 (d, J = 9.2 Hz, 1H), 7.02 (d, J = 9.2 Hz, 1H), 4.86-4.85 (m, 2H), 4.30 (d, J = 7.2 Hz, 1H), 4.09-4.06 (m, 1H), 3.82-3.75 (m, 1H), 3.62-3.46 (m, 3H), 3.46 (s, 1H), 3.26-3.18 (m, 4H), 2.65-2.55 (m, 2H), 2.44 (s, 3H), 2.33 (s, 6H), 1.94-1.73 (m, 5H), 1.70-1.58 (m, 5H), 1.53 (s, 3H), 1.31-1.20 (m, 13H), 0.99 (d, J = 7.2 Hz, 3H), 0.90 (t, J = 7.2 Hz, 3H). LCMS (ESI): m / z = 864.70 [M+H] + .

[0698] Example 16 XNW 9404

[0699] Step one:

[0700] XNW9378-A3 (460 mg, 1.02 mmol, 1 eq) was dissolved in DCM (20 mL) at room temperature, and then triethylamine (514 mg, 5.08 mmol, 5 eq) and p-toluenesulfonyl chloride (143 mg, 2.03 mmol, 2 eq) were added successively. The reaction system was stirred at room temperature overnight. The reaction system was quenched with water and extracted with ethyl acetate. The organic phase was washed with water and saturated brine once, dried, filtered, and concentrated to obtain a crude product, which was purified by medium pressure normal phase column (DCM / 10% MeOH = 0-40%) to obtain white solid XNW9404-A1 (280 mg, yield: 63.39%). LCMS (ESI): m / z = 435.32 [M+H] + .

[0701] Step two:

[0702] XNW9404-A1 (270 mg, 0.62 mmol, 1 eq) was dissolved in DCM (4 mL) and TFA (2 mL) was added at room temperature. The reaction system was stirred at room temperature for 1-2 hours. The reaction system was concentrated to get the crude product, which was dissolved in DCM and concentrated again, and the process was repeated 3 times to get the crude product XNW9404-A2 (300 mg) as a yellowish oil. LCMS (ESI): m / z = 235.04 [M+H] + .

[0703] Step three:

[0704] XNW9404-A2 (300 mg, 0.65 mmol, 1 eq) was suspended in acetonitrile (8 mL) and DBU (496 mg, 3.26 mmol, 5 eq) and SOL-B1 (566 mg, 0.78 mmol, 1.2 eq) were added at room temperature. The reaction system was stirred at 50 °C overnight.

[0705] After adding H2O (4 mL) to the reaction system, it was heated to 75 °C and stirred overnight. The reaction system was concentrated to get the crude product, which was diluted with dichloromethane and water, and the aqueous phase was extracted with dichloromethane twice. The organic phases were combined and concentrated to get the crude product, which was prepared by prep-HPLC (TFA) and prep-HPLC (NH3.H2O) and freeze-dried to get XNW9404 (100 mg, purity: 96.8%) as a white solid.

[0706] 1 H NMR (400 MHz, Methanol-d4) δ 8.00 (d, J = 9.2 Hz, 1H), 7.03 (d, J = 9.6 Hz, 1H), 4.86-4.85 (m, 2H), 4.30 (d, J = 7.2 Hz, 1H), 4.09-4.06 (m, 1H), 3.82-3.75 (m, 1H), 3.61-3.48 (m, 3H), 3.46 (s, 1H), 3.26-3.18 (m, 2H), 3.05 (t, J = 7.2 Hz, 2H), 2.65-2.54 (m, 2H), 2.46 (s, 3H), 2.33 (s, 6H), 1.96-1.84 (m, 4H), 1.78-1.73 (m, 1H), 1.69-1.61 (m, 6H), 1.53 (s, 3H), 1.30 (s, 3H), 1.27-1.23 (m, 7H), 1.20 (d, J = 6.8 Hz, 3H), 0.98 (d, J = 6.8 Hz, 3H), 0.88 (t, J = 7.6 Hz, 3H). LCMS (ESI): m / z = 848.72 [M+H] + .

[0707] Example 17 XNW 9406

[0708] Synthetic steps are referenced to XNW9404.

[0709] White solid XNW9406 (17 mg, purity: 98.3%).

[0710] 1 H NMR (400 MHz, Methanol-d4) δ 8.63 (d, J = 2.8 Hz, 1H), 7.46 (d, J = 2.8 Hz, 1H), 4.61 - 4.53 (m, 2H), 4.29 (d, J = 7.6 Hz, 1H), 4.08 - 4.05 (m, 1H), 3.82 - 3.75 (m, 1H), 3.60 - 3.48 (m, 3H), 3.45 (s, 1H), 3.26 - 3.17 (m, 2H), 3.07 (t, J = 7.2 Hz, 2H), 2.65 - 2.53 (m, 2H), 2.45 (s, 3H), 2.33 (s, 6H), 1.94 - 1.84 (m, 4H), 1.78 - 1.73 (m, 1H), 1.72 - 1.60 (m, 6H), 1.53 (s, 3H), 1.30 - 1.23 (m, 10H), 1.20 (d, J = 6.8 Hz, 3H), 0.98 (d, J = 7.2 Hz, 3H), 0.87 (t, J = 7.2 Hz, 3H). LCMS (ESI): m / z = 848.73 [M+H] + .

[0711] Example 18 XNW9413

[0712] Synthetic steps are referenced to XNW9404

[0713] White solid XNW9413 (45.44 mg, purity 97.1%). 1H NMR (400 MHz, Methanol-d4) δ 9.40 (dd, J = 5.1, 1.6 Hz, 1H), 8.52 (dd, J = 8.6, 1.6 Hz, 1H), 8.00 (dd, J = 8.6, 5.1 Hz, 1H), 4.85 (d, J = 2.9 Hz, 1H), 4.33 (d, J = 7.3 Hz, 1H), 4.08 (dd, J = 10.6, 1.6 Hz, 1H), 3.84 (td, J = 8.6, 4.1 Hz, 1H), 3.68 - 3.57 (m, 2H), 3.53 (ddd, J = 10.5, 7.0, 3.4 Hz, 1H), 3.48 (s, 1H), 3.31 - 3.20 (m, 2H), 3.15 (q, J = 7.1 Hz, 2H), 2.71 - 2.54 (m, 2H), 2.48 (s, 3H), 2.36 (s, 6H), 2.02 - 1.85 (m, 4H), 1.84 - 1.69 (m, 4H), 1.66 (s, 2H), 1.61 (s, 2H), 1.56 (s, 3H), 1.34 (s, 3H), 1.29 (t, J = 6.2 Hz, 7H), 1.24 (d, J = 6.9 Hz, 3H), 1.02 (d, J = 6.9 Hz, 3H), 0.91 (t, J = 7.4 Hz, 3H). LCMS (ESI): m / z = 417.43, 833.67 [M+H] + .

[0714] Example 19 XNW9383

[0715] Step one:

[0716] Into a reaction flask was added INT-T-D (236 mg, 1.01 mmol, 1.0 eq), ACN (10 mL) and DBU (616 mg, 4.05 mmol, 4.0 eq) and stirred to dissolve, finally added SOL-B1 (806 mg, 1.11 mmol, 1.1 eq), under argon balloon protection, heated in oil bath at 50 °C for 5 hours. LCMS monitoring of raw materials reaction, see intermediate state [M+H] = 445.52, 889.71; 5 mL water was added to the system, heated to 70 °C for another 5 hours. Concentrated under reduced pressure to remove acetonitrile, 80 mL dichloromethane was added to the concentrate, washed with water (20 mL x 3 times); the organic phase was concentrated under reduced pressure to give a yellow sticky material, which was purified by liquid phase preparation and freeze-dried to give white solid XNW9383 (23 mg, purity: 99.43%). 1H NMR (400 MHz, Methanol-d4) δ 8.50 (d, J = 2.8 Hz, 1H), 8.47 (s, 1H), 7.43 (d, J = 2.8 Hz, 1H), 4.83 (d, J = 4.8 Hz, 1H), 4.65 - 4.48 (m, 2H), 4.32 (d, J = 7.6 Hz, 1H), 4.09 (dd, J = 10.8, 1.6 Hz, 1H), 3.85 - 3.74 (m, 1H), 3.65 - 3.50 (m, 3H), 3.47 (s, 1H), 3.30 - 3.16 (m, 2H), 2.69 - 2.54 (m, 2H), 2.42 (s, 3H), 2.35 (s, 6H), 2.05 - 1.84 (m, 4H), 1.80 - 1.54 (m, 11H), 1.34 - 1.20 (m, 14H), 1.00 (d, J = 6.8 Hz, 3H), 0.90 (t, J = 7.4 Hz, 3H), LCMS (ESI): m / z = 424.49, 847.73 [M+H] + .

[0717] Example 20 XNW9391

[0718] Synthesis scheme refers to XNW9383

[0719] White solid XNW9391 (104 mg, purity: 99.06%).

[0720] 1H NMR (400 MHz, Methanol-d4) δ 9.03 (dd, J = 5.0, 1.6 Hz, 1H), 8.18 (dd, J = 8.8, 1.6 Hz, 1H), 7.98 (d, J = 1.2 Hz, 1H), 7.86 (d, J = 1.6 Hz, 1H), 7.76 (dd, J = 8.6, 5.0 Hz, 1H), 4.84 - 4.83 (m, 1H), 4.31 (d, J = 7.6 Hz, 1H), 4.19 (t, J = 6.8 Hz, 2H), 4.06 (dd, J = 10.4, 1.6 Hz, 1H), 3.86 - 3.74 (m, 1H), 3.66 - 3.49 (m, 3H), 3.47 (s, 1H), 3.29 - 3.17 (m, 2H), 2.69 - 2.54 (m, 2H), 2.40 (s, 3H), 2.34 (s, 6H), 1.97 - 1.83 (m, 4H), 1.80 - 1.54 (m, 11H), 1.32 - 1.19 (m, 14H), 1.00 (d, J = 6.8 Hz, 3H), 0.88 (t, J = 7.4 Hz, 3H). LCMS (ESI): m / z = 416.51, 831.75 [M+H] + .

[0721] Example 21 XNW9433

[0722] Step one: synthesis of 9433-1

[0723] 1L single neck flask, add 4-iodoimidazole (35.0g, 180.4mmol, 1.0eq), DMF 350ml, tert-butyl N-(4-bromobutyl)carbamate (45.5g, 180.4mmol, 1.0eq), cesium carbonate (117.6g, 360.8mmol, 2.0eq) in turn, argon protection, stirring at room temperature overnight, after the reaction is completed, normal phase purification, the target product 36.5g, yield 55%.

[0724] Step two: synthesis of 9433-2

[0725] 500ml single neck flask, 4-(tributylstannyl)pyridazine (25.0g, 64.3mmol, 1.0eq), 1,4-dioxane 250ml, 9433-1 (24.7g, 67.6mmol, 1.05eq), cesium fluoride (29.3g, 193.0mmol, 3.0eq), cuprous iodide (1.5g, 7.7mmol, 0.12eq), tetrakis(triphenylphosphine)palladium (3.7g, 3.2mmol, 0.05eq). The system was replaced by argon three times, and was raised to 90°C for 4h. After the reaction was completed, filter through diatomite, and the filter cake was eluted with DCM:MeOH=10:1 twice. The combined filtrate was rotary evaporated, and was purified by normal phase column to obtain the target product 14.2g, with a yield of 70%.

[0726] Step three: synthesis of 9433-INT

[0727] 250ml single neck flask, 9433-2 10g, dichloromethane 40ml, 4N HCl / 1,4-dioxane 20ml, the system was stirred at room temperature. After the reaction was completed, filter, and the filter cake was dried to obtain the target product 8.5g, which was directly used in the next step.

[0728] Step four: synthesis of 9433A1

[0729] Dissolve 217mg of crude XNW9433A1 and SOL-B1 (1086mg, 1.5mmol) in acetonitrile (5mL) and water (1mL), and heat the reaction system to 75°C and stir overnight. After the reaction was completed, it was directly used in the next step.

[0730] Step five: synthesis of 9433

[0731] Add 5ml of methanol to the reaction solution of the previous step, and continue to heat to 75°C. After the reaction was completed, evaporate the solvent, and freeze-dry to obtain white solid XNW9433 (152mg, purity: 98.00%).

[0732] 1H NMR (400 MHz, Methanol-d4) δ 9.58 (dd, J = 2.4, 1.2 Hz, 1H), 9.12 (dd, J = 5.6, 1.2 Hz, 1H), 8.05 (d, J = 1.2 Hz, 1H), 8.02 (dd, J = 5.6, 2.4 Hz, 1H), 7.88 (d, J = 1.2 Hz, 1H), 4.82 (dd, J = 10.4, 2.8 Hz, 1H), 4.30 (d, J = 7.6 Hz, 1H), 4.27 - 4.10 (m, 2H), 4.03 (dd, J = 10.8, 1.6 Hz, 1H), 3.85 - 3.74 (m, 1H), 3.66 - 3.46 (m, 3H), 3.44 (s, 1H), 3.28 - 3.16 (m, 2H), 2.68 - 2.51 (m, 2H), 2.34 (s, 6H), 2.30 (s, 3H), 1.95 - 1.74 (m, 5H), 1.69 - 1.53 (m, 10H), 1.30 - 1.19 (m, 14H), 0.99 (d, J = 6.8 Hz, 3H), 0.89 (t, J = 7.4 Hz, 3H). LCMS (ESI): m / z = 416.51, 831.70 [M+H] + .

[0733] Example 22 XNW9457

[0734] Step one:

[0735] Into a reaction bottle was added 2-bromopyridazine (1.6 g, 10.06 mmol, 1.0 eq), trimethylsilyl acetylene (2.97 g, 30.19 mmol, 3.0 eq), triethylamine (2.04 g, 20.13 mmol, 2.0 eq), cuprous iodide (19.17 mg, 0.01 mmol, 0.01 eq), PdCl2(dppf) (75.57 mg, 0.1 mmol, 0.01 eq), 100 ml tetrahydrofuran, argon protection, and the temperature was raised to 100 degrees overnight. After the reaction was completed, filtration was performed, and the filtrate was evaporated to dryness and directly used in the next step.

[0736] Step two:

[0737] Into the crude product of the previous step was added 50 ml of methanol, potassium carbonate (2.87 g, 20.08 mmol, 2.0 eq), and stirred at room temperature. After the reaction was completed, filtration was performed, and the solvent was evaporated to dryness and purified by normal phase to obtain 9557A2 (500 mg, 4.8 mmol) with a yield of 47.8%.

[0738] Step three:

[0739] 9457A2 (500 mg, 4.8 mmol, 1.0 eq), (1E)-5-(1,3-dioxoisoindolin-2-yl)pentanal oxime (1.18 g, 4.8 mmol, 1.0 eq), [bis(trifluoroacetoxy)iodo]benzene (3.08 g, 7.2 mmol, 1.5 eq), 10 ml tetrahydrofuran, stirring at room temperature for 2 hours, the reaction is completed, dry the solvent, normal phase purification, 9457A3 (600 mg, 1.72 mmol) is obtained, the yield is 35.9%.

[0740] Step four:

[0741] 9457A3 (600 mg, 1.72 mmol, 1.0 eq), 5 ml hydrazine hydrate, 10 ml acetonitrile, heating to reflux, after the reaction is completed, reversed phase preparation, 9457A4 (95 mg, 0.44 mmol) is obtained, the yield is 25.3%.

[0742] The remaining steps, refer to XNW9228, white solid XNW9457 (152 mg, purity: 96.4%) is obtained

[0743] 1 H NMR (400 MHz, Methanol-d4) δ 9.28 (dd, J = 5.0, 1.6 Hz, 1H), 8.29 (dd, J = 8.6, 1.6 Hz, 1H), 7.93 (dd, J = 8.6, 5.1 Hz, 1H), 7.19 (s, 1H), 4.44 (d, J = 6.5 Hz, 1H), 4.10 (dd, J = 10.5, 1.6 Hz, 1H), 3.88 - 3.72 (m, 2H), 3.63 (dd, J = 14.5, 7.5 Hz, 1H), 3.58 (s, 1H), 3.56 - 3.35 (m, 6H), 3.24 (q, J = 6.9 Hz, 1H), 2.90 (d, J = 16.4 Hz, 5H), 2.85 (d, J = 12.0 Hz, 4H), 2.49 (s, 3H), 2.08 (d, J = 12.5 Hz, 1H), 2.03 - 1.77 (m, 5H), 1.77 - 1.62 (m, 7H), 1.53 (d, J = 32.3 Hz, 5H), 1.45 - 1.33 (m, 7H), 1.33 - 1.15 (m, 7H), 1.03 (d, J = 6.9 Hz, 3H), 0.93 (t, J = 7.4 Hz, 3H). LCMS (ESI): m / z = 832.7 [M+H] + .

[0744] Example 23 XNW 9500

[0745] Synthesis of intermediate XNW9500-INT:

[0746] Step one:

[0747] To the reaction vessel was added compound N-benzyloxycarbonyl-N'-tert- butyloxycarbonylornithine (10 g, 25.35 mmol, 1 eq), tetrahydrofuran (120 mL), at -10 °C, 1M borane tetrahydrofuran solution (45.5 ml, 45.63 mmol, 1.8 eq) was added slowly, the reaction was carried out at room temperature for 2 hours. After the reaction was completed, methanol was added slowly to quench the system, the system was concentrated, the residue was dissolved in ethyl acetate, washed with water, the organic phase was dried and concentrated, and fast column chromatography was carried out to obtain colorless oil 9500-A (7 g, yield: 72.57%). LCMS (ESI): m / z = 381.23 [M+H] + .

[0748] Step two:

[0749] To the reaction vessel was added compound 9500-A (7 g, 18.4 mmol, 1 eq), methanol (100 mL), 10% Pd / C (1.4 g, 20% w) was added at room temperature, and the reaction was carried out at room temperature for 40 min. After the reaction was completed, filtration was carried out, and the filtrate was concentrated to obtain white waxy solid 9500-B (3.9 g, yield: 85.9%). LCMS (ESI): m / z = 247.19 [M+H] + .

[0750] Step three:

[0751] To the reaction vessel was added compound 2-pyridazinecarboxylic acid (302.2 mg, 2.44 mmol, 1.2 eq), N,N-dimethylformamide (5 mL), DIPEA (0.62 ml, 3.66 mmol, 1.8 eq) was added at 0 °C, and HATU (1.16 g, 3.04 mmol, 1.5 eq) was added. After stirring at 0 °C for 1 hour, the reaction liquid was added to 9500-B (500 mg, 2.03 mmol, 1 eq) in DMF (5 ml) at room temperature, and stirring was carried out overnight. After the reaction was completed, water was added to the system, and ethyl acetate was extracted, the organic phase was washed with water, saturated brine, dried and concentrated, and fast column chromatography was carried out to obtain orange oil 9500-C (600 mg, yield: 83.9%). LCMS (ESI): m / z = 353.21 [M+H] + .

[0752] Step four:

[0753] To a reaction vessel were added compound 9500-C (600 mg, 1.7 mmol, 1 eq), DCM (8 mL), 0 °C, and Dess-Martin Oxidizing Agent (793 mg, 1.87 mmol, 1.1 eq), stirred at room temperature for 2 hours, the reaction was completed, added with sodium bicarbonate (10 ml), saturated sodium thiosulfate (5 ml), extracted with ethyl acetate, the organic phase was dried and concentrated to give the crude 9500-D (600 mg). LCMS (ESI): m / z = 351.2 [M+H] + .

[0754] Step five:

[0755] To a reaction vessel were added compound 9500-D (600 mg, 1.7 mmol, 1 eq), DCM (20 mL), 0 °C, and triphenylphosphine (1.35 g, 5.14 mmol, 3 eq), 2,6-di-tert-butylpyridine (2.29 g, 11.99 mmol, 7 eq), 1,2-dibromo-tetrachloroethane (1.67 g, 5.14 mmol, 3 eq), stirred for 1 hour, then added with a solution of DBU (1.82 g, 11.99 mmol, 7 eq) in acetonitrile (10 ml), stirred at room temperature for 1 hour, the reaction was completed, the system was concentrated, the residue was dissolved in ethyl acetate, washed with water, the organic phase was dried and concentrated, and column chromatography gave 9500-E (410 mg, 72%). LCMS (ESI): m / z = 333.18 [M+H] + .

[0756] Step six:

[0757] To a reaction vessel were added compound 9500-E (410 mg, 1.23 mmol, 1 eq), EA (2 mL), 0 °C, and 4M hydrochloric acid in ethyl acetate (5 mol), stirred for 1 hour, the system precipitated a large amount of solid, filtered to give the crude hydrochloride salt XNW9500-INT (310 mg). LCMS (ESI): m / z = 233.18 [M+H] + .

[0758] Synthesis of compound XNW9500:

[0759] Step one:

[0760] Into a reaction vessel was placed compound SOL-B1 (400 mg, 0.55 mmol, 1 eq), XNW9500-INT (337 mg, 1.11 mmol, 2 eq) (calculated as two molecules of HCl), DBU (506 mg, 3.32 mmol, 6 eq), acetonitrile (10 mL), stirred at room temperature for 5 hours, the reaction was complete, the system was added water, EA extraction, the organic phase was concentrated to the crude product. The crude product was dissolved in acetonitrile / water (10 ml / 10 ml), reacted at 75°C overnight, the reaction solution was directly spin dried, and the obtained crude product was subjected to preparative purification to obtain white solid XNW9500 (180 mg, purity 99.69%). 1 H NMR (400 MHz, Methanol-d4) δ 9.26 (dd, J = 5.0, 1.7 Hz, 1H), 8.40 (dd, J = 8.6, 1.7 Hz, 1H), 7.91 (d, J = 1.0 Hz, 1H), 7.89 (dd, J = 8.6, 5.0 Hz, 1H), 4.85 (m, 1H), 4.29 (d, J = 7.3 Hz, 1H), 4.03 (dd, J = 10.6, 1.6 Hz, 1H), 3.74 (dt, J = 13.5, 6.6 Hz, 1H), 3.61 - 3.49 (m, 3H), 3.46 (s, 1H), 3.27 - 3.16 (m, 2H), 2.70 (t, J = 7.0 Hz, 2H), 2.66 - 2.53 (m, 2H), 2.44 (s, 3H), 2.35 (s, 6H), 1.94 - 1.83 (m, 2H), 1.74 (m, 4H), 1.67 - 1.56 (m, 6H), 1.53 (s, 3H), 1.29 (s, 3H), 1.27 - 1.23 (m, 7H), 1.20 (d, J = 6.9 Hz, 3H), 0.99 (d, J = 6.9 Hz, 3H), 0.88 (t, J = 7.4 Hz, 3H). LCMS (ESI): m / z = 832.44 [M+H] + .

[0761] Example 24 XNW 9502

[0762] Synthesis of intermediate XNW9502-INT:

[0763] The synthesis process of intermediate XNW9502-INT is similar to that of XNW9500-INT

[0764] Synthesis of compound XNW9502:

[0765] Step one:

[0766] To the reaction vessel was added compound SOL-B1 (400 mg, 0.55 mmol, 1 eq), XNW9500-INT (337 mg, 1.11 mmol, 2 eq) (calculated as two molecules of HCl), DBU (506 mg, 3.32 mmol, 6 eq), acetonitrile (10 mL), stirred at room temperature for 5 hours, the reaction was complete, the system was added water, EA extraction, the organic phase was concentrated to the crude product. The crude product was dissolved in acetonitrile / water (10 ml / 10 ml), 75°C reaction overnight, the reaction liquid was directly spin dried, the obtained crude product was purified by preparation to obtain white solid XNW9502 (160 mg, purity 98.84%). 1 H NMR (400 MHz, Methanol-d4) δ 9.75 (dd, J = 2.3, 1.2 Hz, 1H), 9.35 (dd, J = 5.4, 1.3 Hz, 1H), 8.21 (dd, J = 5.4, 2.3 Hz, 1H), 7.92 (d, J = 0.9 Hz, 1H), 4.82 - 4.78 (m, 1H), 4.28 (d, J = 7.3 Hz, 1H), 4.01 (dd, J = 10.6, 1.6 Hz, 1H), 3.73 (m, 1H), 3.61 - 3.45 (m, 4H), 3.43 (s, 1H), 3.25 - 3.16 (m, 2H), 2.73 - 2.66 (m, 2H), 2.61 - 2.50 (m, 2H), 2.35 (d, J = 9.6 Hz, 9H), 1.88 (d, J = 8.0 Hz, 1H), 1.79 - 1.73 (m, 2H), 1.71 - 1.66 (m, 2H), 1.63 - 1.51 (m, 9H), 1.28 (s, 3H), 1.24 (dd, J = 6.6, 3.3 Hz, 7H), 1.20 (d, J = 6.9 Hz, 3H), 0.98 (d, J = 7.0 Hz, 3H), 0.89 (d, J = 7.4 Hz, 3H). LCMS (ESI): m / z = 832.44 [M+H] + .

[0767] Example 25 XNW 9600

[0768] Synthesis of intermediate XNW9600-INT:

[0769] Step one:

[0770] To a reaction vessel were added compound 2-bromopyridazine (1 g, 6.29 mmol, 1 eq), boron ester (2.1 g, 7.55 mmol, 1.2 eq), palladium (0) tetraphenylphosphonium (0.73 g, 0.63 mmol, 0.1 eq), sodium carbonate (2 g, 18.87 mmol, 3 eq), toluene (20 mL), ethanol (6 mL), water (6 mL), argon protection, 100 °C, stirring for 3 hours, the reaction was concentrated, the residue was purified by flash column chromatography to obtain 9600-A (1.2 g, 82.5%). LCMS (ESI): m / z = 231.12 [M+H] + .

[0771] Step two:

[0772] To a reaction vessel were added compound 9600-A (1.2 g, 5.2 mmol, 1 eq), EA (5 mL), 4M hydrochloric acid ethyl acetate (10 mol) was added at room temperature, after stirring for 1 hour, a large amount of solid was precipitated in the system, filtration to obtain crude hydrochloride 9600-B (0.95 g). LCMS (ESI): m / z = 147.06 [M+H] + .

[0773] Step three:

[0774] To a reaction vessel were added compound 9600-B (0.95 g, 4.34 mmol, 1 eq) (calculated as two molecules of HCl), 4-(Boc-amino)butyl bromide (1.64 g, 6.5 mmol, 1.5 eq), cesium carbonate (7.06 g, 21.68 mmol, 5 eq), DMF (20 mL), stirring at room temperature for 12 hours, then add water, extract with EA, concentrate the organic phase and purify by flash column chromatography to obtain 9600-C (1 g, yield 72.6%). LCMS (ESI): m / z = 318.19 [M+H] + .

[0775] Step four:

[0776] To a reaction vessel were added compound 9500-C (1 g, 3.15 mmol, 1 eq), EA (5 mL), 4M hydrochloric acid ethyl acetate (10 mol) was added at room temperature, after stirring for 1 hour, a large amount of solid was precipitated in the system, filtration to obtain crude hydrochloride XNW9600-INT (0.9 g). LCMS (ESI): m / z = 218.19 [M+H] + .

[0777] Synthesis of compound XNW9600:

[0778] Step one:

[0779] To the reaction vessel was added compound SOL-B1 (400 mg, 0.55 mmol, 1 eq), XNW9600-INT (322 mg, 1.11 mmol, 2 eq) (calculated as two molecules of HCl), DBU (506 mg, 3.32 mmol, 6 eq), acetonitrile (10 mL), stirred at room temperature for 5 hours, the reaction was complete, the system was added water, EA extraction, the organic phase was concentrated to the crude product. The crude product was dissolved in acetonitrile / water (10 ml / 10 ml), reacted at 75°C overnight, the reaction solution was directly spin dried, and the obtained crude product was purified by preparation to obtain white solid XNW9600 (140 mg, purity 97.2%). 1 H NMR (400 MHz, Methanol-d4) δ 9.07 (dd, J = 4.9, 1.7 Hz, 1H), 8.29 (dd, J = 8.6, 1.7 Hz, 1H), 7.77 - 7.72 (m, 2H), 7.04 (d, J = 2.3 Hz, 1H), 4.81 (d, J = 3.1 Hz, 1H), 4.28 (h, J = 3.5, 3.0 Hz, 3H), 4.04 (dd, J = 10.5, 1.6 Hz, 1H), 3.75 (dt, J = 13.9, 6.9 Hz, 1H), 3.61 - 3.49 (m, 3H), 3.46 (s, 1H), 3.26 - 3.14 (m, 2H), 2.66 - 2.51 (m, 2H), 2.39 (s, 3H), 2.32 (s, 6H), 1.98 - 1.82 (m, 4H), 1.79 - 1.64 (m, 5H), 1.63 - 1.52 (m, 6H), 1.28 - 1.18 (m, 13H), 0.98 (d, J = 6.9 Hz, 3H), 0.87 (t, J = 7.4 Hz, 3H). LCMS (ESI): m / z = 831.46 [M+H] + .

[0780] Example 26 XNW9486

[0781] The synthesis steps of XNW9486-A6 refer to XNW9404.

[0782] Intermediate product XNW9486-A6 (1.09 g). LCMS (ESI): m / z = 220.04 [M+H] + .

[0783] The synthesis steps of XNW9486-A6 refer to XNW9404.

[0784] White solid product XNW9486 (21.1 mg, purity 99.93%).

[0785] 1H NMR (400 MHz, Methanol-d4) δ 9.85 (dd, J = 2.3, 1.3 Hz, 1H), 9.50 (dd, J = 5.4, 1.3 Hz, 1H), 8.32 (dd, J = 5.4, 2.3 Hz, 1H), 4.85 (dd, J = 10.3, 2.7 Hz, 1H), 4.34 (d, J = 7.3 Hz, 1H), 4.09 (dd, J = 10.6, 1.6 Hz, 1H), 3.84 (m, 1H), 3.67 - 3.59 (m, 2H), 3.54 (m, 1H), 3.46 (s, 1H), 3.30 - 3.20 (m, 2H), 3.14 (t, J = 7.0 Hz, 2H), 2.70 - 2.56 (m, 2H), 2.44 (s, 3H), 2.37 (s, 7H), 1.98 - 1.87 (m, 4H), 1.83 - 1.62 (m, 5H), 1.61 (s, 2H), 1.57 (s, 3H), 1.55 (s, 1H), 1.34 (s, 3H), 1.29 (dd, J = 6.6, 5.5 Hz, 7H), 1.24 (d, J = 6.9 Hz, 3H), 1.02 (d, J = 6.9 Hz, 3H), 0.92 (t, J = 7.4 Hz, 3H).

[0786] LCMS (ESI): m / z = 415.59, 833.84 [M+H] + .

[0787] Example 27 XNW9487

[0788] The subsequent synthesis steps refer to XNW9305.

[0789] Intermediate product XNW9487-A6 (1.88 g). LCMS (ESI): m / z = 236.08 [M+H] + .

[0790] The subsequent synthesis steps refer to XNW9305.

[0791] White solid XNW9487 (146.6 mg, purity: 99.84%).

[0792] 1H NMR (400 MHz, Methanol-d4) δ 9.87 (dd, J = 2.4, 1.2 Hz, 1H), 9.44 (dd, J = 5.5, 1.2 Hz, 1H), 8.31 (dd, J = 5.4, 2.3 Hz, 1H), 4.82 (dd, J = 10.0, 2.9 Hz, 1H), 4.34 (d, J = 7.3 Hz, 1H), 4.12 - 4.06 (m, 1H), 3.85 (m, 1H), 3.67 - 3.52 (m, 3H), 3.45 (s, 1H), 3.31 - 3.21 (m, 2H), 2.71 - 2.58 (m, 2H), 2.38 (d, J = 6.1 Hz, 10H), 1.99 - 1.87 (m, 4H), 1.81 (m, 1H), 1.76 - 1.59 (m, 6H), 1.57 (d, J = 4.0 Hz, 5H), 1.35 (s, 3H), 1.29 (dd, J = 6.6, 3.5 Hz, 8H), 1.25 (d, J = 6.8 Hz, 3H), 1.03 (d, J = 6.8 Hz, 3H), 0.95 (t, J = 7.4 Hz, 3H).

[0793] LCMS (ESI): m / z = 425.50, 849.66 [M+H] + .

[0794] Example 28 XNW9498

[0795] Synthesis scheme refers to XNW9383:

[0796] White solid XNW9498 (91 mg, purity: 99.66%).

[0797] 1H NMR (400 MHz, Methanol-d4) δ 8.42 (d, J = 2.8 Hz, 1H), 7.84 - 7.78 (dd, J = 5.4, 1.4 Hz, 2H), 7.24 (d, J = 2.8 Hz, 1H), 4.33 (d, J = 7.2 Hz, 1H), 4.17 (t, J = 7.0 Hz, 2H), 4.11 (dd, J = 10.6, 1.6 Hz, 1H), 3.86 - 3.75 (m, 1H), 3.66 - 3.52 (m, 3H), 3.50 (s, 1H), 3.31 - 3.19 (m, 2H), 2.70 - 2.57 (m, 2H), 2.47 (s, 3H), 2.36 (s, 6H), 1.98 - 1.83 (m, 4H), 1.81 - 1.57 (m, 11H), 1.35 - 1.21 (m, 14H), 1.02 (d, J = 6.8 Hz, 3H), 0.91 (t, J = 7.4 Hz, 3H). LCMS (ESI): m / z = 424.07, 846.87 [M+H] + .

[0798] Example 29 XNW9555

[0799] Synthesis scheme reference XNW9383:

[0800] White solid XNW9555 (126 mg, purity: 99.89%).

[0801] 1 H NMR (400 MHz, Methanol-d4) δ 9.21 (dd, J = 5.0, 1.8 Hz, 1H), 8.43 (dd, J = 8.4, 1.6 Hz, 1H), 7.86 (dd, J = 8.6, 5.0 Hz, 1H), 7.79 (s, 1H), 4.92 - 4.88 (m, 1H), 4.33 (d, J = 7.2 Hz, 1H), 4.10 (dd, J = 10.6, 1.6 Hz, 1H), 3.88 - 3.77 (m, 1H), 3.69 - 3.52 (m, 3H), 3.51 (s, 1H), 3.32 - 3.20 (m, 2H), 3.09 - 3.01 (m, 2H), 2.71 - 2.57 (m, 2H), 2.48 (s, 3H), 2.36 (s, 6H), 1.98 - 1.65 (m, 15H), 1.37 - 1.21 (m, 14H), 1.03 (d, J = 7.2 Hz, 3H), 0.94 (t, J = 7.4 Hz, 3H). LCMS (ESI): m / z = 425.03, 848.70 [M+H] + .

[0802] Example 30 XNW 9436

[0803] Synthetic steps are referenced to XNW9329

[0804] White solid XNW9436 (63.88 mg, purity 99.71 %). 1 H NMR (400 MHz, Methanol-d4) δ 8.64 (s, 1H), 8.30 (d, J = 8.7 Hz, 1H), 7.74 (d, J = 8.8 Hz, 1H), 4.83 (dd, J = 10.1, 2.9 Hz, 2H), 4.59 (h, J = 7.0 Hz, 2H), 4.32 (d, J = 7.3 Hz, 1H), 4.07 (dd, J = 10.6, 1.6 Hz, 1H), 3.80 (ddd, J = 13.7, 8.8, 4.7 Hz, 1H), 3.66 - 3.54 (m, 2H), 3.51 (ddd, J = 10.6, 7.1, 3.4 Hz, 1H), 3.45 (s, 1H), 3.30 - 3.16 (m, 2H), 2.74 (s, 3H), 2.70 - 2.52 (m, 2H), 2.37 (s, 3H), 2.35 (s, 6H), 2.01 (pd, J = 7.5, 6.9, 3.9 Hz, 2H), 1.90 (ddt, J = 14.6, 10.3, 3.7 Hz, 2H), 1.78 (ddd, J = 12.7, 4.3, 2.0 Hz, 1H), 1.69 (dd, J = 7.2, 3.0 Hz, 1H), 1.66 (s, 2H), 1.61 (s, 2H), 1.55 (s, 4H), 1.31 (s, 3H), 1.30 - 1.25 (m, 7H), 1.22 (d, J = 6.9 Hz, 3H), 1.00 (d, J = 6.9 Hz, 3H), 0.90 (t, J = 7.4 Hz, 3H). LCMS (ESI): m / z = 423.97, 846.68 [M+H] + .

[0805] Example 31 XNW9437

[0806] Synthetic steps are referenced to XNW9329

[0807] White solid XNW9437 (66.24 mg, purity 96.0 %). 1H NMR (400 MHz, Methanol-d4) δ 8.56 (s, 1H), 8.30 (d, J = 9.2 Hz, 1H), 7.34 (d, J = 9.2 Hz, 1H), 4.85 (dd, J = 10.1, 2.9 Hz, 2H), 4.68 - 4.51 (m, 2H), 4.33 (d, J = 7.3 Hz, 1H), 4.17 (s, 3H), 4.09 (dd, J = 10.6, 1.6 Hz, 1H), 3.81 (td, J = 9.1, 4.5 Hz, 1H), 3.69 - 3.57 (m, 2H), 3.52 (ddt, J = 10.2, 6.6, 3.4 Hz, 1H), 3.46 (s, 1H), 3.32 - 3.17 (m, 2H), 2.63 (dtt, J = 17.1, 9.6, 3.3 Hz, 2H), 2.37 (d, J = 6.5 Hz, 9H), 2.09 - 1.88 (m, 4H), 1.85 - 1.75 (m, 2H), 1.74 - 1.68 (m, 2H), 1.64 (s, 2H), 1.62 - 1.59 (m, 1H), 1.56 (s, 3H), 1.35 - 1.26 (m, 10H), 1.23 (d, J = 6.9 Hz, 3H), 1.01 (d, J = 7.0 Hz, 3H), 0.92 (t, J = 7.4 Hz, 3H). LCMS (ESI): m / z = 431.99, 852.74 [M+H] + .

[0808] Example 32 XNW9438

[0809] Synthetic procedure referenced to XNW9329

[0810] White solid XNW9438 (17.44 mg, purity 99.61%). 1H NMR (400 MHz, Methanol-d4) δ 8.43 (s, 1H), 8.21 (d, J = 9.8 Hz, 1H), 7.14 (d, J = 9.8 Hz, 1H), 4.82 (dd, J = 10.1, 2.9 Hz, 2H), 4.63 - 4.49 (m, 2H), 4.34 (d, J = 7.3 Hz, 1H), 4.09 (dd, J = 10.6, 1.6 Hz, 1H), 3.81 (ddd, J = 13.8, 8.9, 4.6 Hz, 1H), 3.67 - 3.58 (m, 2H), 3.53 (ddd, J = 10.5, 7.5, 3.8 Hz, 1H), 3.45 (s, 1H), 3.31 - 3.17 (m, 2H), 2.72 - 2.56 (m, 2H), 2.36 (d, J = 4.9 Hz, 9H), 2.05 - 1.93 (m, 2H), 1.93 - 1.86 (m, 2H), 1.79 (ddd, J = 12.7, 4.4, 2.0 Hz, 1H), 1.73 (s, 2H), 1.71 - 1.65 (m, 3H), 1.65 - 1.58 (m, 2H), 1.56 (s, 3H), 1.33 (s, 3H), 1.31 - 1.27 (m, 7H), 1.24 (d, J = 6.8 Hz, 3H), 1.01 (d, J = 6.9 Hz, 3H), 0.92 (t, J = 7.4 Hz, 3H). LCMS (ESI): m / z = 424.99, 848.74 [M+H] + .

[0811] Example 33 XNW9439

[0812] Synthetic procedure refers to XNW9329

[0813] White solid XNW9439 (82.88 mg, purity 99.96%). 1H NMR (400 MHz, Methanol-d4) δ 9.05 (d, J = 2.1 Hz, 1H), 8.66 (s, 1H), 8.27 (dd, J = 2.1, 1.1 Hz, 1H), 4.83 (dd, J = 10.1, 2.9 Hz, 2H), 4.70 - 4.53 (m, 2H), 4.33 (d, J = 7.3 Hz, 1H), 4.08 (dd, J = 10.6, 1.6 Hz, 1H), 3.82 (ddd, J = 13.8, 8.9, 4.6 Hz, 1H), 3.67 - 3.59 (m, 2H), 3.52 (s, 1H), 3.45 (s, 1H), 3.31 - 3.17 (m, 2H), 2.71 - 2.56 (m, 2H), 2.54 (s, 3H), 2.36 (s, 9H), 2.02 (s, 2H), 1.89 (d, J = 14.6 Hz, 2H), 1.80 (ddd, J = 12.8, 4.3, 2.0 Hz, 1H), 1.74 - 1.67 (m, 1H), 1.66 (s, 2H), 1.63 - 1.58 (m, 3H), 1.56 (s, 3H), 1.33 (s, 3H), 1.29 (dd, J = 6.6, 3.2 Hz, 7H), 1.23 (d, J = 6.9 Hz, 3H), 1.01 (d, J = 6.9 Hz, 3H), 0.91 (t, J = 7.4 Hz, 3H). LCMS (ESI): m / z = 424.03, 846.78 [M+H] + .

[0814] Example 34 XNW9440

[0815] Synthetic procedure refers to XNW9329

[0816] White solid XNW9440 (45.88 mg, purity 99.8%). 1H NMR (400 MHz, Methanol-d4) δ 8.87 (d, J = 2.9 Hz, 1H), 8.64 (s, 1H), 7.96 (d, J = 2.9 Hz, 1H), 4.82 (dd, J = 10.0, 2.9 Hz, 1H), 4.69 - 4.54 (m, 2H), 4.33 (d, J = 7.3 Hz, 1H), 4.13 (s, 3H), 4.11 - 4.04 (m, 1H), 3.81 (ddd, J = 13.8, 9.1, 4.6 Hz, 1H), 3.67 - 3.55 (m, 2H), 3.52 (ddd, J = 10.6, 7.1, 3.4 Hz, 1H), 3.44 (s, 1H), 3.31 - 3.18 (m, 2H), 2.71 - 2.54 (m, 2H), 2.36 (s, 6H), 2.34 (s, 3H), 2.01 (ddt, J = 13.7, 9.5, 4.9 Hz, 2H), 1.90 (ddt, J = 14.6, 10.4, 3.8 Hz, 2H), 1.79 (ddd, J = 12.8, 4.3, 2.0 Hz, 1H), 1.72 - 1.66 (m, 1H), 1.65 (s, 2H), 1.60 (s, 2H), 1.55 (s, 4H), 1.32 (s, 3H), 1.28 (dd, J = 6.5, 1.9 Hz, 8H), 1.23 (d, J = 6.9 Hz, 3H), 1.01 (d, J = 6.9 Hz, 3H), 0.91 (t, J = 7.4 Hz, 3H). LCMS (ESI): m / z = 432.00, 862.74 [M+H] + .

[0817] Example 35 XNW9441

[0818] Synthetic procedure refers to XNW9329

[0819] White solid XNW9441 (50.66 mg, purity 99.82%). 1H NMR (400 MHz, Methanol-d4) δ 8.60 (s, 1H), 8.09 (d, J = 2.9 Hz, 1H), 7.11 (d, J = 2.9 Hz, 1H), 4.83 (dd, J = 10.1, 2.9 Hz, 2H), 4.68 - 4.50 (m, 2H), 4.36 (d, J = 7.2 Hz, 1H), 4.09 (dd, J = 10.6, 1.6 Hz, 1H), 3.80 (ddd, J = 13.8, 8.9, 4.7 Hz, 1H), 3.69 - 3.58 (m, 2H), 3.53 (ddd, J = 10.6, 7.3, 3.5 Hz, 1H), 3.44 (s, 1H), 3.35 - 3.28 (m, 1H), 3.21 (q, J = 6.9 Hz, 1H), 2.87 (ddd, J = 12.3, 10.3, 4.1 Hz, 1H), 2.59 (ddt, J = 13.8, 7.0, 3.4 Hz, 1H), 2.50 (s, 6H), 2.34 (s, 3H), 2.07 - 1.83 (m, 5H), 1.73 (s, 2H), 1.68 (s, 2H), 1.65 - 1.58 (m, 2H), 1.56 (s, 4H), 1.34 - 1.26 (m, 9H), 1.23 (d, J = 6.9 Hz, 3H), 1.01 (d, J = 6.9 Hz, 3H), 0.93 (t, J = 7.4 Hz, 3H). LCMS (ESI): m / z = 425.03, 848.82 [M+H] + .

[0820] Example 36 XNW9444

[0821] Synthetic procedure referenced to XNW9329

[0822] White solid XNW9444 (33.68 mg, purity 99.94%). 1H NMR (400 MHz, Methanol-d4) δ 8.44 (s, 1H), 7.98 (d, J = 9.4 Hz, 1H), 7.02 (d, J = 9.4 Hz, 1H), 4.85 (d, J = 2.9 Hz, 1H), 4.57 (h, J = 6.9 Hz, 2H), 4.34 (d, J = 7.3 Hz, 1H), 4.11 (dd, J = 10.5, 1.6 Hz, 1H), 3.81 (ddd, J = 13.8, 8.7, 4.8 Hz, 1H), 3.66 - 3.51 (m, 3H), 3.49 (s, 1H), 3.32 - 3.19 (m, 2H), 3.04 (s, 3H), 2.71 - 2.57 (m, 2H), 2.43 (s, 3H), 2.36 (s, 6H), 2.01 (ddt, J = 13.3, 8.9, 4.8 Hz, 2H), 1.91 (ddd, J = 14.6, 8.9, 3.5 Hz, 2H), 1.79 (ddd, J = 12.9, 4.3, 2.0 Hz, 1H), 1.74 (s, 2H), 1.68 (s, 3H), 1.64 (s, 1H), 1.61 (d, J = 2.7 Hz, 1H), 1.57 (s, 3H), 1.33 (s, 3H), 1.29 (t, J = 6.7 Hz, 7H), 1.24 (d, J = 6.8 Hz, 3H), 1.02 (d, J = 6.9 Hz, 3H), 0.92 (t, J = 7.4 Hz, 3H). LCMS (ESI): m / z = 431.49, 861.77 [M+H] + .

[0823] Example 37 XNW9557

[0824] Synthesis scheme refers to XNW9383:

[0825] White solid XNW9557 (41 mg, purity: 97.20%).

[0826] 1H NMR (400 MHz, Methanol-d4) δ 7.98 (d, J = 9.2 Hz, 1H), 7.58 (s, 1H), 6.99 (d, J = 9.2 Hz, 1H), 4.31 (d, J = 7.2 Hz, 1H), 4.07 (dd, J = 10.4, 1.6 Hz, 1H), 3.83 - 3.72 (m, 1H), 3.64 - 3.49 (m, 3H), 3.48 (s, 1H), 3.28 - 3.18 (m, 2H), 2.94 (t, J = 7.0 Hz, 2H), 2.75 - 2.64 (m, 1H), 2.63 - 2.53 (m, 1H), 2.45 (s, 3H), 2.38 (s, 6H), 1.97 - 1.82 (m, 2H), 1.80 - 1.53 (m, 13H), 1.32 - 1.20 (m, 14H), 0.99 (d, J = 6.8 Hz, 3H), 0.90 (t, J = 7.4 Hz, 3H). LCMS (ESI): m / z = 432.57, 863.81 [M+H] + .

[0827] Example 38 XNW9531

[0828] Step one:

[0829] Into a single neck flask, 3-bromopyridazine (3 g, 18.87 mmol, 1 eq), trimethylsilyacetylene (5.56 g, 56.61 mmol, 3 eq), Pd(PPh3)2Cl2(662 mg, 0.94 mmol, 0.05 eq), CuI (359 mg, 1.89 mmol, 0.1 eq), TEA (5.73 g, 56.61 mmol, 3 eq) and THF (30 mL) were added successively at room temperature. The reaction system was replaced with argon for 3 times, then heated to 70 °C and stirred overnight. After the reaction system was cooled to room temperature, it was filtered, and the filter cake was washed with DCM for 2 times. The filtrate was concentrated to get the crude product, which was purified by column (DCM / 10% MeOH = 0-100%) to get brown solid XNW9531-A1 (2.92 g, yield: 87.78%). LCMS (ESI): m / z = 177.33 [M+H] + .

[0830] Step two:

[0831] XNW9531-A1 (2.2 g, 12.48 mmol, 1 eq) was dissolved in THF (10 mL) and MeOH (5 mL) at room temperature, and then K2CO3 (3.45 g, 24.96 mmol, 2 eq) was added. The reaction system was stirred at room temperature for 2 h. The reaction system was filtered, the filter cake was washed with THF twice, and the filtrate was concentrated to obtain a crude product, which was purified by column chromatography (PE / EA = 0-100%) to obtain yellow oil XNW9531-A2 (1.27 g, yield: 97.75%). LCMS (ESI): m / z = 105.13 [M+H] + .

[0832] Step three:

[0833] XNW9531-A2 (450 mg, 4.32 mmol, 1 eq) in THF (10 mL) was added to a three-necked flask filled with argon at -70 °C, and the reaction system was stirred for 5-10 min, then n-BuLi (2.5 M in hexanes) (2.08 mL, 5.19 mmol, 1.2 eq) was slowly added dropwise. After the addition was completed, the reaction system was continued to be stirred at -70 °C for 30 min, and then 1-Boc-2-piperidinone (1.03 g, 5.19 mmol, 1.2 eq) in THF (10 mL) was added dropwise. After the addition was completed, the reaction system was continued to be stirred at -70 °C for 1-2 h. The reaction system was quenched with HCl (1 M) and extracted with ethyl acetate twice. The organic phase was combined, washed with water and saturated brine once, dried, filtered, and concentrated to obtain a crude product, which was purified by column chromatography (PE / EA = 0-75%) to obtain yellow oil XNW9531-A3 (230 mg, yield: 17.54%). LCMS (ESI): m / z = 325.45 [M+Na] + .

[0834] Step four:

[0835] XNW9531-A3 (230 mg, 0.76 mmol, 1 eq) was dissolved in acetonitrile (5 mL) at room temperature, and then 85% hydrazine hydrate (57 mg, 1.14 mmol, 1.5 eq) was added. The reaction system was heated to 80 °C and stirred for 8 h. The reaction system was concentrated to obtain a crude product, which was purified by column chromatography (DCM / 10% MeOH = 0-20%) to obtain yellow oil XNW9531-A4 (190 mg, yield: 78.96%). LCMS (ESI): m / z = 318.13 [M+H] + .

[0836] Step five:

[0837] XNW9531-A4 (190 mg, 598.64 μmol) was dissolved in DCM (4 mL) at room temperature, and then TFA (2 mL) was added. The reaction system was stirred at room temperature for 2 hours. The reaction system was concentrated to obtain a crude product, which was dissolved in DCM and concentrated again. The above operation was repeated for 3 times to obtain a crude product of brown oil XNW9531-A5 (280 mg). LCMS (ESI): m / z = 218.23 [M+H] + .

[0838] Step six:

[0839] XNW9531-A5 (260 mg, 0.59 mmol, 1 eq) and DBU (446 mg, 2.93 mmol, 5 eq) were dissolved in acetonitrile (7 mL) at room temperature, and then SOL-B1 (509.44 mg, 0.70 mmol, 1.2 eq) was added. The reaction system was stirred at 50 °C for 8 hours, and then water (3 mL) was added. The reaction system was heated to 75 °C and stirred overnight. After the reaction system was cooled to room temperature, it was filtered, and the filtrate was directly purified by prep-HPLC (TFA) and prep-HPLC (NH3·H2O) and then lyophilized to obtain white solid XNW9531 (90 mg, purity: 99.97%). 1 H NMR (400 MHz, Methanol-d4) δ 9.08 (dd, J1, J2 = 1.6 Hz, 4.8 Hz, 1H), 8.23 (d, J = 8.4 Hz, 1H), 7.75 (dd, J1, J2 = 5.2 Hz, 8.8 Hz, 1H), 6.86 (s, 1H), 4.85-4.84 (m, 2H), 4.29 (d, J = 7.6 Hz, 1H), 4.07-4.04 (m, 1H), 3.80-3.73 (m, 1H), 3.61-3.50 (m, 3H), 3.48 (s, 1H), 3.25-3.18 (m, 2H), 2.83-2.74 (m, 2H), 2.65-2.59 (m, 2H), 2.40 (s, 3H), 2.33 (s, 6H), 1.93-1.85 (m, 2H), 1.80-1.72 (m, 4H), 1.66-1.58 (m, 5H), 1.54 (s, 3H), 1.29-1.20 (m, 13H), 0.99 (d, J = 7.2 Hz, 3H), 0.88 (t, J = 7.6 Hz, 3H). LCMS (ESI): m / z = 831.82 [M+H] + .

[0840] Example 39 XNW9532

[0841] Step one:

[0842] To a flask, 3,5-dibromopyrazole (1 g, 4.43 mmol, 1 eq) and p-toluenesulfonic acid (76 mg, 0.44 mmol, 0.1 eq) were dissolved in DCM (15 mL) at room temperature, then 3,4-dihydro-2H-pyran (558 mg, 6.64 mmol, 1.5 eq) was added. The reaction system was stirred at room temperature overnight. The reaction system was concentrated to get the crude product, which was purified by medium pressure normal phase column (PE / DCM = 0-20%) to get white solid XNW9532-B1 (1 g, yield: 72.86%). LCMS (ESI): m / z = 224.80 [M+H-THP] + .

[0843] Step two:

[0844] To a flask, XNW9532-B1 (1.6 g, 5.16 mmol, 1 eq), N-Boc-3-butyn-1-amine (873 mg, 5.16 mmol, 1 eq), Pd(PPh3)2Cl2 (254 mg, 0.36 mmol, 0.07 eq), CuI (147 mg, 0.77 mmol, 0.15 eq), TEA (1.57 g, 15.48 mmol, 3 eq) and 1,4-dioxane (20 mL) were added sequentially at room temperature. The reaction system was replaced with argon for 3 times, then heated to 100 °C and stirred overnight. The reaction system was filtered, the filter cake was washed with ethyl acetate, and the filtrate was concentrated to get the crude product, which was purified by medium pressure normal phase column (PE / DCM = 0-100 to DCM / 10% MeOH = 10%-50%) to get yellow oil XNW9532-B2 (1 g, yield: 48.64%). LCMS (ESI): m / z = 214.06 [M+H-THP-Boc] + .

[0845] Step three:

[0846] Into a single neck flask, was added XNW9532-B2 (100 mg, 0.25 mmol, 1 eq), 4- (tributylstannyl)pyridazine (93 mg, 0.25 mmol), Pd(PPh3)4(15 mg, 0.012 mmol, 0.05 eq), CsF (114 mg, 0.75 mmol, 3 eq), CuI (10 mg, 0.05 mmol, 0.2 eq) and 1,4-dioxane (3 mL) successively at room temperature. The reaction system was purged with argon for 3 times and heated to 110 °C with stirring overnight. The reaction system was filtered, the filter cake was washed with DCM, and the filtrate was concentrated to give a crude product, which was purified by medium pressure normal phase over column (DCM / 10% MeOH = 0-25%) to give yellow oil XNW9532-B3 (50 mg, yield: 50.10%). LCMS (ESI): m / z = 398.39 [M+H] + .

[0847] Step four:

[0848] XNW9532-B3 (50 mg, 0.16 mmol, 1 eq) was dissolved in methanol (3 mL) at room temperature, and then Pd / C (10% on Carbon (wetted with ca. 55% Water)) (20 mg) was added. The reaction system was purged with hydrogen for 3-5 times and stirred at room temperature overnight. The reaction system was filtered, and the filtrate was concentrated to give a crude product, yellow oil XNW9532-A4 (50 mg). LCMS (ESI): m / z = 402.38 [M+H] + .

[0849] Step five:

[0850] XNW9532-A4 (50 mg, 0.12 mmol, 1 eq) was dissolved in HCl (4 M in 1,4-dioxane) (3 mL) at room temperature, and the reaction system was stirred at room temperature for 1-2 hours. The reaction system was removed supernatant, and then MTBE was added and ultrasonicated, and then the supernatant was removed. The solid was dried to give a crude product, yellow solid XNW9532-A5 (40 mg). LCMS (ESI): m / z = 218.38 [M+H] + .

[0851] Step six:

[0852] XNW9532-A5 (40 mg, 0.18 mmol, 1 eq) and DBU (139 mg, 0.92 mmol, 5 eq) were dissolved in acetonitrile (5 mL) at room temperature, then SOL-B1 (130 mg, 0.18 mmol, 1 eq) was added. The reaction was stirred at 50 °C for 8 hours, then water (3 mL) was added. The reaction was heated to 75 °C and stirred overnight. After the reaction was cooled to room temperature, it was filtered, and the filtrate was directly purified by prep-HPLC (TFA) and prep-HPLC (NH3.H2O), then lyophilized to give white solid XNW9532 (8 mg, purity: 97.8%). HNMR: (400 MHz, Methanol-d4) δ 9.63 (s, 1H), 9.16 (d, J = 5.2 Hz, 1H), 8.06 (dd, J1, J2 = 2.4 Hz, 5.6 Hz, 1H), 6.80 (s, 1H), 4.84-4.82 (m, 2H), 4.28 (d, J = 7.6 Hz, 1H), 4.04-4.01 (m, 1H), 3.79-3.72 (m, 1H), 3.60-3.48 (m, 3H), 3.45 (s, 1H), 3.24-3.17 (m, 2H), 2.83-2.72 (m, 2H), 2.66-2.51 (m, 2H), 2.34 (s, 3H), 2.33 (s, 6H), 1.94-1.84 (m, 2H), 1.77-1.69 (m, 4H), 1.64-1.57 (m, 5H), 1.53 (s, 3H), 1.27-1.19 (m, 13H), 0.90 (d, J = 6.8 Hz, 3H), 0.88 (t, J = 7.2 Hz, 3H). LCMS (ESI): m / z = 831.91 [M+H] + .

[0853] Example 40 XNW 9602

[0854] Synthesis of intermediate XNW9602-INT:

[0855] The synthesis of intermediate XNW9602-INT is similar to XNW9600-INT

[0856] Synthesis of compound XNW9602:

[0857] Step one:

[0858] Into a reaction vessel was placed compound SOL-B1 (400 mg, 0.55 mmol, 1 eq), XNW9602-INT (322 mg, 1.11 mmol, 2 eq) (calculated as two molecules of HCl), DBU (506 mg, 3.32 mmol, 6 eq), acetonitrile (10 mL), stirred at room temperature for 5 hours, the reaction was complete, the system was added water, EA extraction, the organic phase was concentrated to the crude product. The crude product was dissolved in acetonitrile / water (10 ml / 10 ml), reacted at 75°C overnight, the reaction solution was directly spin dried, and the obtained crude product was subjected to preparation purification to obtain white solid XNW9602 (140 mg, purity 99.1%). 1 H NMR (400 MHz, Chloroform-d) δ 9.64 (dd, J = 2.3, 1.3 Hz, 1H), 9.15 (dd, J = 5.5, 1.3 Hz, 1H), 8.07 (dd, J = 5.5, 2.3 Hz, 1H), 7.76 (d, J = 2.4 Hz, 1H), 6.95 (d, J = 2.4 Hz, 1H), 4.80 - 4.76 (m, 1H), 4.36 - 4.23 (m, 3H), 4.01 (dd, J = 10.6, 1.6 Hz, 1H), 3.74 (ddd, J = 14.0, 9.2, 4.8 Hz, 1H), 3.61 - 3.48 (m, 3H), 3.42 (s, 1H), 3.26 - 3.13 (m, 2H), 2.66 - 2.50 (m, 2H), 2.32 (s, 6H), 2.29 (s, 3H), 1.88 (dddd, J = 14.5, 12.9, 9.8, 4.6 Hz, 4H), 1.75 (ddd, J = 12.8, 4.3, 2.0 Hz, 1H), 1.70 - 1.61 (m, 4H), 1.60 - 1.49 (m, 6H), 1.28 - 1.21 (m, 10H), 1.19 (d, J = 6.8 Hz, 3H), 0.97 (d, J = 7.0 Hz, 3H), 0.86 (t, J = 7.4 Hz, 3H). LCMS (ESI): m / z = 831.46 [M+H] + .

[0859] Example 41 XNW 9495A & XNW9495B

[0860] Synthesis of intermediate XNW9495-INT:

[0861] Step one:

[0862] To the reaction vessel was added INT-1 (form ZG) (1 g, 2.44 mmol, 1 eq), 4- (tributylstannyl) pyridazine (1.08 g, 2.93 mmol, 1.2 eq), cesium fluoride (0.74 g, 4.89 mmol, 2 eq), cuprous iodide (93 mg, 0.49 mmol, 0.2 eq), tetrakis triphenylphosphine palladium (282 mg, 0.24 mmol, 0.1 eq), acetonitrile (15 mL), argon protection, 45 Celsius stirring for 2 hours, the reaction was complete, the system was filtered, the filtrate was concentrated, and 9495-A (0.77 g, 2.13 mmol, yield 87.2%) was obtained by flash column chromatography. LCMS (ESI): m / z = 362.2 [M+H] + .

[0863] Step two:

[0864] To the reaction vessel was added 9495-A (0.77 g, 2.13 mmol, 1 eq), 80% hydrazine hydrate (0.4 mL), methanol (5 mL), 75 Celsius stirring for 4 hours, the reaction was complete, the system was filtered, the filtrate was concentrated, and 9495-INT (0.42 g, 1.82 mmol, yield 85.2%) was obtained by flash column chromatography. LCMS (ESI): m / z = 232.2 [M+H] + Chiral resolution to obtain two configuration intermediates.

[0865] Synthesis of compound XNW 9495A, XNW 9495B:

[0866] Step one:

[0867] To the reaction vessel was added compound SOL-B1 (200 mg, 0.27 mmol, 1 eq), XNW 9495-INT (81 mg, 0.35 mmol, 1.3 eq), DBU (81 mg, 0.54 mmol, 2 eq), acetonitrile (6 mL), room temperature stirring for 5 hours, the reaction was complete, the system was added water, EA extraction, the organic phase was concentrated to the crude product. The crude product was dissolved in acetonitrile / water (5 ml / 5 ml), 75°C reaction overnight, the reaction liquid was directly rotary dried, and the obtained crude product was prepared and purified by high pressure to obtain white solid XNW 9495A (87 mg, purity 96%; RT = 5.64 min), 1H NMR (400 MHz, Methanol-d4) δ 9.58 (dd, J = 2.4, 1.2 Hz, 1H), 9.11 (dd, J = 5.5, 1.2 Hz, 1H), 8.09 (d, J = 1.2 Hz, 1H), 8.01 (dd, J = 5.5, 2.3 Hz, 1H), 7.92 (d, J = 1.2 Hz, 1H), 4.74 (dd, J = 10.2, 2.8 Hz, 1H), 4.43 - 4.34 (m, 1H), 4.26 (d, J = 7.3 Hz, 1H), 3.98 (dd, J = 10.5, 1.6 Hz, 1H), 3.68 (ddd, J = 14.6, 10.1, 4.7 Hz, 1H), 3.61 - 3.41 (m, 3H), 3.37 (s, 1H), 3.24 - 3.12 (m, 2H), 2.66 - 2.48 (m, 2H), 2.32 (s, 6H), 2.21 (s, 3H), 1.90 - 1.72 (m, 5H), 1.68 - 1.61 (m, 1H), 1.57 (dd, J = 14.1, 7.3 Hz, 7H), 1.50 (s, 4H), 1.41 - 1.27 (m, 2H), 1.27 - 1.20 (m, 9H), 1.18 (d, J = 6.8 Hz, 3H), 0.96 (d, J = 6.9 Hz, 3H), 0.84 (t, J = 7.4 Hz, 3H). LCMS (ESI): m / z = 845.47 [M+H] + .

[0868] XNW9495B (29 mg, 93.6% purity, RT = 5.68 min), 1H NMR (400 MHz, Methanol-d4) δ 9.57 (dd, J = 2.5, 1.2 Hz, 1H), 9.10 (dd, J = 5.5, 1.2 Hz, 1H), 8.13 (d, J = 1.3 Hz, 1H), 8.01 (dd, J = 5.5, 2.3 Hz, 1H), 7.92 (d, J = 1.2 Hz, 1H), 4.81 - 4.78 (m, 1H), 4.42 (q, J = 6.9 Hz, 1H), 4.28 (d, J = 7.3 Hz, 1H), 4.05 - 3.99 (m, 1H), 3.82 (ddd, J = 13.3, 8.0, 4.8 Hz, 1H), 3.60 - 3.45 (m, 3H), 3.40 (s, 1H), 3.26 - 3.12 (m, 2H), 2.66 - 2.48 (m, 2H), 2.32 (d, J = 5.8 Hz, 9H), 1.87 (ddt, J = 17.8, 10.8, 3.7 Hz, 4H), 1.79 - 1.73 (m, 1H), 1.72 - 1.62 (m, 4H), 1.58 - 1.51 (m, 7H), 1.43 (q, J = 7.3, 6.3 Hz, 1H), 1.33 - 1.21 (m, 11H), 1.18 (d, J = 6.9 Hz, 3H), 0.95 (d, J = 6.9 Hz, 3H), 0.88 (t, J = 7.4 Hz, 3H). LCMS (ESI): m / z = 845.47 [M+H] + .

[0869] Example 42 XNW 9536

[0870] Synthesis of intermediate XNW9536-INT:

[0871] Step one:

[0872] To the reaction vessel was added compound bis(tert-butoxycarbonyl)amine (5 g, 23 mmol, 1 eq), acetonitrile (60 mL), 5-bromovaleronitrile (3.7 g, 23 mmol, 1 eq) was added at room temperature, reaction was carried out at 90 °C for 5 h. After completion of the reaction, it was cooled, filtered, concentrated, the residue was purified by flash column chromatography to get colorless oil 9536-A (5 g, yield: 72.8 %). LCMS (ESI): m / z = 199.19 [M-100+H] + .

[0873] Step two:

[0874] To a reaction vessel were added compound 9536-A (5 g, 16.7 mmol, 1 eq), 95% ethanol (60 mL), hydroxylamine hydrochloride (5.8 g, 83.8 mmol, 5 eq) at room temperature, sodium carbonate (8.9 g, 83.8 mmol, 5 eq), and the reaction was stirred at 85 °C for 48 h. After the reaction was completed, it was cooled, filtered, and concentrated. The residue was purified by flash column chromatography to give compound 9536-B (2.5 g, yield: 45%) as a colorless oil. LCMS (ESI): m / z = 332.2 [M+H] + .

[0875] Step Three:

[0876] To a reaction vessel were added compound 9536-B (500 mg, 1.5 mmol, 1.1 eq), dichloromethane (60 mL), 3-carboxy pyridazine (170.2 mg, 1.37 mmol, 5 eq), HOBT (204 mg, 1.5 mmol, 1.1 eq), EDCI (289 mg, 1.5 mmol, 1.1 eq) at room temperature, and the reaction was stirred at room temperature for 2 h. After the reaction was completed, it was concentrated and dried. The residue was purified by flash column chromatography to give compound 9536-C (650 mg, crude) as a yellow oil. LCMS (ESI): m / z = 438.2 [M+H] + .

[0877] Step Four:

[0878] To a reaction vessel were added compound 9536-C (650 mg, crude), pyridine (3 mL), and the reaction was stirred at 100 °C for 3 h. After the reaction was completed, it was concentrated to give a residue, which was purified by flash column chromatography to give compound 9536-D (320 mg, yield: 50%) as a yellow oil. LCMS (ESI): m / z = 420.2 [M+H] + .

[0879] Step Five:

[0880] To a reaction vessel were added compound 9536-D (320 mg, 0.76 mmol, 1 eq), 4 M hydrochloric acid in ethyl acetate (5 mL), and the reaction was stirred at room temperature for 2 h. After the reaction was completed, it was concentrated to give XNW9536-INT (230 mg, yield: 97%) (two molecules of HCl were counted). LCMS (ESI): m / z = 234.1 [M+H] + .

[0881] Synthesis of compound XNW9536:

[0882] Step One:

[0883] Into a reaction vessel was placed compound SOL-B1 (400 mg, 0.55 mmol, 1 eq), XNW9536-INT (339 mg, 1.11 mmol, 2 eq) (calculated as two molecules of HCl), DBU (506 mg, 3.32 mmol, 6 eq), acetonitrile (10 mL), stirred at room temperature for 5 hours, the reaction was complete, the system was added water, EA extraction, the organic phase was concentrated to the crude product. The crude product was dissolved in acetonitrile / water (10 ml / 10 ml), 75°C reaction overnight, the reaction liquid was directly spin dried, the obtained crude product was purified by preparation to obtain white solid XNW9536 (21.3 mg, purity 94.5%). 1 H NMR (400 MHz, Methanol-d4) δ 9.41 (dd, J = 5.1, 1.7 Hz, 1H), 8.52 (dd, J = 8.6, 1.7 Hz, 1H), 8.00 (dd, J = 8.5, 5.1 Hz, 1H), 4.81 (dd, J = 10.1, 2.9 Hz, 1H), 4.28 (d, J = 7.3 Hz, 1H), 4.03 (dd, J = 10.7, 1.6 Hz, 1H), 3.77 (ddd, J = 13.5, 8.4, 4.7 Hz, 1H), 3.60 - 3.46 (m, 3H), 3.43 (s, 1H), 3.20 (dq, J = 18.8, 7.1 Hz, 2H), 2.93 (td, J = 6.9, 1.8 Hz, 2H), 2.66 - 2.52 (m, 2H), 2.45 (s, 3H), 2.32 (s, 6H), 1.94 - 1.80 (m, 4H), 1.79 - 1.59 (m, 6H), 1.53 (d, J = 10.8 Hz, 5H), 1.31 - 1.20 (m, 13H), 0.98 (d, J = 6.9 Hz, 3H), 0.88 (t, J = 7.4 Hz, 3H). LCMS (ESI): m / z = 833.4 [M+H] + .

[0884] Example 43 XNW 9537

[0885] The synthesis process of intermediate XNW9537-INT is similar to XNW9536-INT

[0886] Synthesis of compound XNW9537:

[0887] Step one:

[0888] Into a reaction vessel was added compound SOL-B1 (400 mg, 0.55 mmol, 1 eq), XNW9537-INT (339 mg, 1.11 mmol, 2 eq) (calculated as two molecules of HCl), DBU (506 mg, 3.32 mmol, 6 eq), acetonitrile (10 mL), stirred at room temperature for 5 hours, the reaction was complete, the system was added water, EA extraction, the organic phase was concentrated to the crude product. The crude product was dissolved in acetonitrile / water (10 ml / 10 ml), 75°C reaction overnight, the reaction liquid was directly spin dried, the obtained crude product was purified by preparation to obtain white solid XNW9537 (173 mg, purity 99.2%). 1 H NMR (400 MHz, Methanol-d4) δ 9.84 (dd, J = 2.3, 1.3 Hz, 1H), 9.52 (dd, J = 5.4, 1.3 Hz, 1H), 8.37 (dd, J = 5.3, 2.3 Hz, 1H), 4.77 (dd, J = 10.1, 2.8 Hz, 1H), 4.29 (d, J = 7.3 Hz, 1H), 4.02 (dd, J = 10.6, 1.6 Hz, 1H), 3.77 (ddd, J = 13.4, 8.4, 4.5 Hz, 1H), 3.61 - 3.45 (m, 3H), 3.40 (s, 1H), 3.25 - 3.14 (m, 2H), 2.92 (t, J = 6.8 Hz, 2H), 2.66 - 2.53 (m, 2H), 2.40 (s, 3H), 2.32 (s, 6H), 1.93 - 1.73 (m, 5H), 1.70 - 1.60 (m, 2H), 1.57 (d, J = 13.1 Hz, 3H), 1.51 (d, J = 6.1 Hz, 5H), 1.30 (s, 3H), 1.27 - 1.16 (m, 10H), 0.98 (d, J = 6.9 Hz, 3H), 0.88 (t, J = 7.4 Hz, 3H). LCMS (ESI): m / z = 833.4 [M+H] + .

[0889] Example 44 XNW 9562

[0890] Synthesis of intermediate XNW9562-INT Reference XNW9557

[0891] Synthesis of compound XNW9562:

[0892] To the reaction vessel was added compound SOL-B1 (400 mg, 0.55 mmol, 1 eq), XNW9562-INT (341 mg, 1.11 mmol, 2 eq) (as two molecules of HCl), DBU (506 mg, 3.32 mmol, 6 eq), acetonitrile (10 mL) and stirred at room temperature for 5 hours. The reaction was complete, the system was added water, extracted with EA, and the organic phase was concentrated to the crude product. The crude product was dissolved in acetonitrile / water (10 ml / 10 ml), and reacted at 75°C overnight. The reaction solution was directly spin-dried to obtain the crude product. The crude product was purified by preparative purification to obtain white solid XNW9562 (107 mg, purity 95%). 1 H NMR (400 MHz, Methanol-d4) δ 9.73 (dd, J = 2.4, 1.2 Hz, 1H), 9.28 (dd, J = 5.5, 1.2 Hz, 1H), 8.15 (dd, J = 5.4, 2.4 Hz, 1H), 7.78 (d, J = 1.0 Hz, 1H), 4.83 - 4.78 (m, 1H), 4.29 (d, J = 7.3 Hz, 1H), 4.03 (dd, J = 10.7, 1.6 Hz, 1H), 3.78 (dt, J = 13.3, 6.7 Hz, 1H), 3.59 - 3.45 (m, 3H), 3.43 (s, 1H), 3.26 - 3.17 (m, 2H), 3.04 (q, J = 6.7 Hz, 2H), 2.68 - 2.54 (m, 2H), 2.34 (d, J = 2.6 Hz, 9H), 1.95 - 1.83 (m, 2H), 1.79 - 1.73 (m, 2H), 1.70 - 1.52 (m, 11H), 1.29 - 1.19 (m, 13H), 0.98 (d, J = 6.9 Hz, 3H), 0.90 (t, J = 7.5 Hz, 3H). LCMS (ESI): m / z = 848.4 [M+H] + .

[0893] Example 45 XNW9643A & XNW9643B

[0894] Synthesis of reference XNW9305.

[0895] White solid product XNW9643A (11.2 mg, purity 98.0%, RT = 6.35 min).

[0896] 1H NMR (400 MHz, Methanol-d4) δ 9.87 (ddd, J = 9.5, 2.4, 1.2 Hz, 1H), 9.44 (dd, J = 5.4, 1.2 Hz, 1H), 8.32 (ddd, J = 5.6, 3.3, 2.4 Hz, 1H), 4.76 (dd, J = 10.1, 2.8 Hz, 1H), 4.32 (dd, J = 7.2, 1.4 Hz, 1H), 4.05 (ddd, J = 10.7, 6.5, 1.5 Hz, 1H), 3.93 - 3.62 (m, 1H), 3.62 - 3.46 (m, 4H), 3.39 (d, J = 4.1 Hz, 1H), 3.29 - 3.15 (m, 2H), 2.58 (s, 2H), 2.36 (d, J = 1.1 Hz, 7H), 2.31 (d, J = 4.3 Hz, 3H), 1.99 - 1.77 (m, 5H), 1.76 - 1.59 (m, 3H), 1.55 (ddd, J = 11.4, 7.1, 3.8 Hz, 9H), 1.48 (d, J = 7.1 Hz, 1H), 1.32 (d, J = 4.2 Hz, 3H), 1.30 - 1.25 (m, 7H), 1.22 (d, J = 6.8 Hz, 3H), 1.00 (dd, J = 6.9, 2.1 Hz, 3H), 0.92 (dt, J = 17.8, 7.4 Hz, 3H).

[0897] LCMS (ESI): m / z = 432.40, 863.41 [M+H] + .

[0898] White solid product XNW9643B (10.2 mg, purity 99.78% RT = 6.34 min).

[0899] 1H NMR (400 MHz, Methanol-d4) δ 9.88 (ddd, J = 9.6, 2.4, 1.2 Hz, 1H), 9.44 (dd, J = 5.4, 1.3 Hz, 1H), 8.32 (ddd, J = 5.6, 3.4, 2.4 Hz, 1H), 4.77 (dd, J = 10.0, 2.8 Hz, 1H), 4.33 (dd, J = 7.3, 1.5 Hz, 1H), 4.06 (ddd, J = 10.6, 6.6, 1.6 Hz, 1H), 3.77 - 3.64 (m, 1H), 3.63 - 3.48 (m, 4H), 3.40 (d, J = 4.1 Hz, 1H), 3.30 - 3.16 (m, 2H), 2.71 - 2.53 (m, 2H), 2.37 (d, J = 1.2 Hz, 7H), 2.32 (d, J = 4.3 Hz, 3H), 1.99 - 1.86 (m, 3H), 1.80 (ddd, J = 11.0, 4.5, 2.4 Hz, 1H), 1.74 - 1.61 (m, 2H), 1.56 (ddd, J = 11.9, 7.1, 3.9 Hz, 9H), 1.48 (s, 1H), 1.34 - 1.21 (m, 15H), 1.01 (dd, J = 7.0, 2.1 Hz, 3H), 0.93 (dt, J = 17.9, 7.5 Hz, 3H).

[0900] LCMS (ESI): m / z = 432.60, 863.74 [M+H] + .

[0901] Example 46 XNW9632

[0902] Step one:

[0903] Into a reaction vessel was placed oxalyl chloride (0.937 g, 7.38 mmol, 1.5 eq) and DCM (10 mL), cooled to -75 °C, added DMSO (1.92 g, 24.6 mmol, 5.0 eq) dropwise, stirred for 30 min at the same temperature. Added a mixture of compound 5-(N-tert-butoxycarbonylamino)-1-pentanol (1.0 g, 4.92 mmol, 1.0 eq) and DCM (10 mL) dropwise, stirred for 2 h at the same temperature, added triethylamine (2.98 g, 29.52 mmol, 6.0 eq), stirred for 30 min at room temperature. After the reaction was completed, directly concentrated at low temperature to give the crude product XNW9632-1, which was directly used in the next step.

[0904] Step two:

[0905] To a reaction vessel were added compound XNW9632-1 (0.99 g, 4.92 mmol, 1.0 eq), glyoxal aqueous solution (1.4 g, 39.25 mmol, 2.0 eq), ammonia aqueous solution (7 mL) and methanol (10 mL), and the reaction was allowed to proceed at room temperature for 18 hours. After the reaction was completed, the solvent was concentrated, dissolved in DCM, washed with water, washed with saturated brine, and the organic phase was dried and concentrated to obtain brown solid XNW9632-2, which was used directly in the next reaction. LCMS (ESI): m / z = 240.29 [M+1]+.

[0906] Step three:

[0907] To a reaction vessel were added compound XNW9632-2 (1.0 g, 4.2 mmol, 1.0 eq), NIS (2.17 g, 9.66 mmol, 2.3 eq) and DCM (30 mL), and the reaction was allowed to proceed at 0 °C for 6 hours. After the reaction was completed, it was directly concentrated and dried, and the product XNW9632-3 (1.8 g, yield: 87.37%) was obtained as a brown oil by flash column chromatography (DCM:MeOH = 50:1). LCMS (ESI): m / z = 492.07 [M+1]+.

[0908] Step four:

[0909] To a reaction vessel were added compound XNW9632-3 (1.8 g, 3.67 mmol, 1.0 eq), sodium sulfite (4.63 g, 36.7 mmol, 10.0 eq) and ethanol (15 mL), water (35 mL), and the reaction was allowed to proceed at 95 °C for 18 hours. After the reaction was completed, the solvent was concentrated, water was added, and the organic phase was extracted with DCM, dried and concentrated, and the product XNW9632-4 (1.0 g, yield: 74.6%) was obtained as a brown oil by flash column chromatography (DCM:MeOH = 50:1). LCMS (ESI): m / z = 492.08 [M+1]+.

[0910] Step five:

[0911] Into a reaction vessel was placed compound XNW9632-4 (0.5 g, 1.37 mmol, 1.0 eq), 4-(tributylstannyl)pyrazine (1.26 g, 3.42 mmol, 2.5 eq), tetrakis(triphenylphosphine)palladium (0.158 g, 0.137 mmol, 0.1 eq), copper(I) iodide (0.052 g, 0.274 mmol, 0.2 eq), cesium fluoride (1.0 g, 6.85 mmol, 5.0 eq) and 1.4-dioxane (20 mL), and the mixture was stirred at 100 °C for 18 h. After the reaction was completed, the solvent was concentrated, water was added, and the mixture was extracted with DCM. The organic phase was dried and concentrated, and the residue was purified by flash column chromatography (DCM:MeOH = 50:1) to give the product XNW9632-5 (0.3 g, yield: 69.0%) as a brown oil. LCMS (ESI): m / z = 318.36 [M+1]+.

[0912] Step six:

[0913] Into a reaction vessel was placed XNW9632-5 (0.3 g, 0.94 mmol, 1 eq), HCl / ethanol (4.7 mL, 18.9 mmol, 20 eq) and ethanol (10 mL), and the mixture was stirred at room temperature for 2 h. After the reaction was completed, the reaction mixture was directly concentrated to give the product XNW9632-6 (0.25 g, yield: 100%) as a light yellow oil. LCMS (ESI): m / z = 109.54, 218.06 [M+H]+.

[0914] Step seven:

[0915] Into a reaction vessel was placed compound SOL-B1 (748 mg, 1.03 mmol, 1.1 eq), XNW9632-6 (204 mg, 0.94 mmol, 1 eq), DBU (572 mg, 3.76 mmol, 4 eq) and acetonitrile (20 mL), and the mixture was heated to 50 °C for 4 h. LC-MS showed that XNW9632-7 was formed. The reaction mixture was directly concentrated, and the residue was used in the next step.

[0916] Step eight:

[0917] Into the reaction mixture of the previous step was added methanol (10 mL), and the mixture was heated to 45 °C overnight. LC-MS showed that the starting material was consumed. The reaction mixture was directly concentrated, and the residue was purified by preparative purification to give XNW9632 (2.75 mg, purity 99.93%) as a white solid. 1H NMR (400 MHz, Methanol-d4) δ 9.60 (d, J = 2.1 Hz, 1H), 9.11 (dd, J = 5.6, 1.2 Hz, 1H), 8.02 (s, 1H), 7.89 (s, 1H), 4.85 (dd, J = 9.8, 2.8 Hz, 1H), 4.32 (d, J = 7.3 Hz, 1H), 4.08 - 4.01 (m, 1H), 3.76 (ddd, J = 14.1, 9.6, 4.7 Hz, 1H), 3.65 - 3.50 (m, 3H), 3.47 (s, 1H), 3.31 - 3.17 (m, 2H), 2.86 (ddt, J = 29.5, 14.7, 7.7 Hz, 3H), 2.73 - 2.52 (m, 2H), 2.37 (s, 6H), 2.34 (s, 3H), 1.99 - 1.77 (m, 4H), 1.76 - 1.64 (m, 5H), 1.61 (d, J = 13.6 Hz, 2H), 1.56 (s, 3H), 1.35 - 1.26 (m, 10H), 1.23 (d, J = 6.8 Hz, 3H), 1.01 (d, J = 6.9 Hz, 3H), 0.91 (t, J = 7.4 Hz, 3H). LCMS (ESI): m / z = 416.53, 831.68 [M+H] + .

[0918] Example 47 XNW9606

[0919] Synthesis steps refer to XNW9433:

[0920] White solid XNW9606 (152.22 mg, 95.4%).

[0921] 1H NMR (400 MHz, Methanol-d4) δ 9.58 (m, 1H), 9.14 (dd, J = 8.0, 4.1 Hz, 1H), 8.04 (s, 1H), 8.02 (dd, J = 4.0, 2.0 Hz, 1H), 7.91 (s, 1H), 4.28 (d, J = 8 Hz, 1H), 4.34 (d, J = 7.3 Hz, 1H), 4.20 (td, J = 6.8, 1.9 Hz, 2H), 3.80 (m, 1H), 3.64 (dtd, J = 22.7, 7.5, 5.0 Hz, 3H), 3.30 - 3.20 (m, 2H), 3.19-2.98 (m, 1H), 2.74 - 2.59 (m, 2H), 2.43 (s, 3H), 2.37 (s, 6H), 2.01 - 1.83 (m, 4H), 1.83 - 1.76 (m, 3H), 1.72 (s, 2H), 1.71 - 1.60 (m, 2H), 1.58 (s, 3H), 1.36 - 1.22 (m, 13H), 1.22 (d, 8 Hz, 3H), 1.02 (d, J = 6.9 Hz, 3H), 0.87 (t, J = 7.4 Hz, 3H). LCMS (ESI): m / z = 406.95, 813.72 [M+H]+.

[0922] Biological Effect Example 1 Detection of antibacterial activity of test compounds

[0923] 1. Prepare the test plate according to the test plate layout and bacterial strain test procedure.

[0924] 2. Transfer 2 μL of the test compound from the dilution plate to the corresponding well of the test plate.

[0925] 3. Inoculum preparation

[0926] (1) Staphylococcus spp. and Moraxella catarrhalis

[0927] Use a sterile inoculating loop to scrape a small amount of the frozen bacteria and streak onto a TSA plate. Incubate in a general incubator at 35 ± 2 °C for about 20 hours.

[0928] Pick 10 single colonies from the above solid culture plate and resuspend in sterile normal saline (0.9% NaCl). Adjust the OD600 to ~0.15 using a spectrophotometer. Dilute the bacteria 300-fold using CAMHB to achieve an inoculum concentration of ~2 x 10 5 CFU / mL (Note: use the bacterial solution within 15 minutes).

[0929] (2) Streptococcus spp.

[0930] A small amount of the frozen bacteria was scraped with a sterile inoculating loop and streaked onto TSA plates with blood and incubated at 35 ± 2°C, 5% CO2 for 20 hours or so.

[0931] Ten single colonies were picked from the above solid culture plates and resuspended in sterile normal saline (0.9% NaCl) and the OD600 was adjusted to ~0.15 using a spectrophotometer. The above bacteria were diluted 300-fold into CAMHB with blood to achieve an inoculum concentration of ~2 x 10 5 CFU / mL (Note: the bacterial solution should be used within 15 minutes).

[0932] (3) Haemophilus influenzae

[0933] A small amount of the frozen bacteria was scraped with a sterile inoculating loop and streaked onto Chocolate agar plates and incubated at 35 ± 2°C, 5% CO2 for 20 hours or so.

[0934] Ten single colonies were picked from the above solid culture plates and resuspended in sterile normal saline (0.9% NaCl) and the OD600 was adjusted to ~0.15 using a spectrophotometer. The above bacteria were diluted 300-fold into HTM broth to achieve an inoculum concentration of ~2 x 10 5 CFU / mL (Note: the bacterial solution should be used within 15 minutes).

[0935] 4. Add 98 μL of the appropriate bacterial inoculum to the test plate.

[0936] 5. Cover the test plate with a sterile lid and centrifuge at 800 rpm for 30 seconds in a centrifuge and then shake at 400 rpm for 1 minute on a plate shaker.

[0937] 6. After mixing, place the test plate in an incubator at 35 ± 2°C for 20 hours.

[0938] 7. Perform colony counts.

[0939] 8. Place the test plate in a plate reading device and adjust the mirror to observe and record bacterial growth in each well.

[0940] 9. Take a photograph of each test plate using the QCount system.

[0941] 10. Read the OD values of the bacteria in each well using the SpectraMax plus 384. 600

[0942] 11. Report all raw data including compound information, CFU, MIC, etc.

[0943] Test strains are shown in Table 1:​

[0944] Table 1

[0945] The test results are shown in Table 2:

[0946] Table 2 MIC test results of compounds (μg / mL)

[0947] The test results show that the tested compounds exhibit significant antibacterial activity.

[0948] Biological effect Example 2 Detection of antibacterial activity of tested compounds in azithromycin-resistant gram-positive clinical strains

[0949] 1. Preparation of culture medium

[0950] MHIIA plate: 38 g of Mueller Hinton II Agar (Cation-Adjusted) powder was dissolved in 1 L of ultrapure water, mixed well, and autoclaved at 121°C for 15 minutes. 15 mL was taken from each petri dish to make a plate.

[0951] MHIIB: 22 g of Mueller Hinton II Broth (Cation-Adjusted) powder was dissolved in 1 L of ultrapure water, mixed well, and autoclaved at 121°C for 15 minutes.

[0952] 0.9% NaCl: 9 g + 1000 mL of ultrapure water, 121°C, autoclaved for 15 minutes.

[0953] MHIIB + 5% lysed horse blood: 3 mL of lysed horse blood was added to 57 mL of MHIIB, filtered and used immediately.

[0954] 2. Preparation of strains

[0955] The day before the experiment, the strains in glycerol tubes at -80°C were taken out, streaked onto the corresponding solid medium, and then the inoculated plates were incubated under the corresponding conditions for 20 h.

[0956] On the day of the experiment, several fresh monoclonal colonies were picked into 5 mL of physiological saline, mixed well, and the turbidity was adjusted to ~0.2 with a turbidimeter, which was equivalent to ~1x108CFU / mL. After dilution with the medium 200 times, this was the inoculum, which was ready for use.

[0957] 3. Preparation of compounds

[0958] 3.1 Preparation of stock solution

[0959] Compound: The compound was prepared in DMSO to a concentration of 3.2 mg / mL stock solution, and the 3.2 mg / mL compound stock solution was 100 times the highest starting concentration of the sub-plate.

[0960] Control compound: The control compound was prepared in DMSO to a concentration of 12.8 mg / mL stock solution, and then diluted 16 times to 0.8 mg / mL (3 μL stock solution plus 45 μL DMSO), and the 0.8 mg / mL control compound was 100 times the highest starting concentration of the sub-plate.

[0961] 3. Preparation of the compound stock plate

[0962] The first column of the stock plate was added with 40 μL of 100x starting concentration of the compound, and the second to twelfth columns were added with 20 μL of DMSO; 20 μL of the compound stock solution was transferred from the first column to the second column, and after thorough mixing, 20 μL was transferred to the third column, and the above steps were repeated until the eleventh column, to obtain a 2-fold gradient dilution of the compound, which was the compound stock plate.

[0963] 3.3 Preparation of the compound sub-plate and MIC test plate

[0964] 1 μL of the compound was transferred from the stock plate to the sub-plate using a multi-channel dispensing gun. Then 99 μL of the inoculum was transferred to the sub-plate using a multi-channel dispensing gun, which was the MIC test plate. The test concentrations of the compound and the control compound were as follows, and 1% DMSO was used as the growth control (GC).

[0965] 4. Incubation and reading

[0966] After all the test plates were placed in a 36.5°C incubator for 20 hours, the lowest compound concentration point at which the growth of the strain was completely or obviously inhibited was observed by naked eye, which was the MIC of the compound.

[0967] 5. Test strains (from Shanghai Medicinal Biotech Co., Ltd.) are shown in Table 3:

[0968] Table 3: Information table of gram-positive clinical strains

[0969] The test results show that the tested compound has relatively significant antibacterial activity in gram-positive strains (Staphylococcus aureus, Streptococcus pneumoniae) resistant to azithromycin.

[0970] Biological effect example 3: detection of the antibacterial activity of the tested compound in a clinical strain of Mycoplasma pneumoniae

[0971] 1. The frozen strain was taken out from -80°C and placed on ice, and then transferred to the biosafety cabinet in the cell room for thawing;

[0972] 2. Dilute the frozen strain with appropriate medium to a final concentration of 2-5 x 10 4 Copy number / μL, incubate the strain at 37°C, 5% CO2 incubator for 2h to recover the strain;

[0973] 3. After the incubation, dilute the drug:

[0974] a. Take 2.5 μL 12.8 mg / ml drug and add to 2 ml (3 x 10 4 ) of the bacterial solution to obtain a bacterial solution with a drug concentration of 16 ug / ml;

[0975] b. Take 500 μL of the bacterial solution from a to 500 μL of the bacterial solution to obtain a bacterial solution with a drug concentration of 8 μg / ml;

[0976] c. Take 500 μL of the bacterial solution from b to 500 μL of the bacterial solution to obtain a bacterial solution with a drug concentration of 4 μg / ml;

[0977] d. Take 500 μL of the bacterial solution from c to 500 μL of the bacterial solution to obtain a bacterial solution with a drug concentration of 2 μg / ml;

[0978] e. Take 500 μL of the bacterial solution from d to 500 μL of the bacterial solution to obtain a bacterial solution with a drug concentration of 1 μg / ml;

[0979] f. Take 500 μL of the bacterial solution from e to 500 μL of the bacterial solution to obtain a bacterial solution with a drug concentration of 0.5 μg / ml;

[0980] g. Take 500 μL of the bacterial solution from f to 500 μL of the bacterial solution to obtain a bacterial solution with a drug concentration of 0.25 μg / ml;

[0981] 4. Add the diluted bacterial solution to a 96-well plate at 135 μL per well and incubate at 37°C, 5% CO2 incubator, 3 parallel samples for each concentration of bacterial solution, and collect one sample at Day 1, Day 3, and Day 5, respectively, and store at -20°C for detection;

[0982] 5. qPCR detection:

[0983] a. Take the collected sample from -20°C and thaw;

[0984] b. Prepare a 10 μL system: 1 μL template + 5 μL Mix + 0.2 μL upstream primer (F) + 0.2 μL downstream primer (R) + 3.6 μL ddH2O;

[0985] c. Add the prepared 10 μL system to a 384-well plate and centrifuge at 1200 rpm for 2 min;

[0986] d. Machine detection (Bio-Rad / DFX Opus 384 Real-Time PCR System).

[0987] 6. Test strains and test results (from Shanghai Children's Medical Center Affiliated to Shanghai Jiao Tong University School of Medicine) are shown in Table 4:

[0988] Table 4 Mycoplasma pneumoniae strains tested and MIC values of test compounds (μg / mL)

[0989] The test results show that the test compounds exhibit significant anti-mycoplasma activity.

[0990] Example 4: CellTiter-Glo (CTG) method for testing 50% cell proliferation inhibition concentration (IC 50 ) and maximum inhibition rate of test compounds in HepG2 tumor cell line

[0991] I. In vitro liver toxicity evaluation system:

[0992] Drug damage to liver cells is one of the main causes of liver toxicity. The HepG2 cell line belongs to a human liver cancer cell, which has stronger proliferation and malignancy than human primary hepatocytes. By testing the degree of inhibition of cell proliferation of the drug in vitro, the damage of the test compound to liver cells can be fed back to evaluate the in vitro liver toxicity of the test compound. At the same time, by testing the damage of the test compound to primary hepatocytes of different species, the liver toxicity of the test compound can be evaluated.

[0993] II. Experimental steps:

[0994] 1. Observe the state of HepG2 cells (source: ATCC, batch number: HB-8065TM) under a microscope, and the cell fusion degree reaches 80-90%, and the cells are treated.

[0995] 2. Preheat the complete culture medium, DPBS and trypsin in a 37°C water bath.

[0996] 3. Use a pipette to suck the cell liquid in the culture bottle, and then discard the cell liquid.

[0997] 4. Wash once with 5mL DPBS (T75 flask).

[0998] 5. Add 3mL trypsin (T75 flask) and terminate digestion according to the cell digestion time.

[0999] 6. Add 6 mL complete medium (T75 flask) to terminate the digestion, transfer the T75 flask cell suspension to a 15 mL centrifuge tube, centrifuge at 1000 rpm for 5 min.

[1000] 7. Discard the supernatant, resuspend the cell pellet with complete medium, count the cells with a cell counter, and record the cell number and cell viability.

[1001] 8. Prepare the cell stock solution according to the cell counting results

[1002] 9. According to a certain layout, the prepared solution is dispensed into a 96-well plate using a syringe, and 100 μL is added to each well.

[1003] 10. Place the 96-well plate in a 37°C, 5% CO2 incubator for incubation.

[1004] 11. The next day, add the drug, 2-fold dilution for each compound, 9 concentrations, 2 replicates for each concentration, DMSO final concentration 0.5%, test compound dilution (stock solution 40 mM), cell plating 100 uL, the next day add drug 100 uL.

[1005] 12. Add the drug to the cells using a syringe, 100 μL per well, and place the culture plate in the incubator for incubation for 6 days.

[1006] 13. After 6 days of incubation, aspirate 100 μL of the culture medium from the culture plate, add 50 μL of CTG reagent, shake at low speed on a shaker for 2 minutes, then incubate at room temperature in the dark for 30 minutes, and immediately read the sample signal value on the enzyme marker.

[1007] 14. Interpret the results of the cell CTG test.

[1008] 15. Data processing:

[1009] The inhibition rate (IR) of the tested compound is calculated using the following formula: IR (%) = (1 - (RLU compound - RLU blank control) / (RLU solvent control - RLU blank control)) * 100%. The inhibition rates of different concentrations of compounds are calculated in Excel, and then the inhibition curve graph and related parameters, including the minimum inhibition rate, the maximum inhibition rate, and the IC 50 .

[1010] 16. The test results are shown in Table 5.

[1011] Table 5

[1012] wherein the hepatotoxicity IC 50(μM), A ≥ 100; 100 > B ≥ 80; 80 > C ≥ 70; D < 70. It can be seen that the test compound can improve liver toxicity. Biological effect example 5 test the in vitro protein binding rate of the test compound in CD-1 mice, SPRAGUE-DAWLEY rats, beagle dogs, cynomolgus monkeys and human plasma

[1013] The equilibrium dialysis method was used to determine the protein binding rate of the compound in CD-1 mice, Sprague-Dawley rats, beagle dogs, cynomolgus monkeys and human plasma. After dialysis, 20 μL of the dialyzed drug end plasma sample was removed to the sample receiving plate, and 100 μL of PBS was added. 100 μL of PBS sample was removed from the receiving end after dialysis to the sample receiving plate, and 20 μL of blank plasma was added. All samples were added with 600 μL of termination solution and mixed, and centrifuged at 4000 rpm for 15 minutes. After centrifugation, 200 μL of supernatant was aspirated, diluted with 200 μL of water / acetonitrile solution (1:1, v / v), and the concentration of the compound in the plasma and PBS was determined by LC-MS / MS method, and the recovery rate, binding rate and recovery rate were calculated.

[1014] Experimental results: the test compound has good PPB results, and a high proportion of free compounds to exert efficacy. And other ADME (absorption, distribution, metabolism and excretion) pharmacokinetic characteristics are also good.

[1015] Biological effect example 6 test the in vivo PK of the test compound in different species

[1016] Mouse PK: Male CD-1 mice (6-8 weeks old) were intravenously (IV) administered by tail vein bolus at a dose of 10 mg / kg or orally (PO) administered by gavage at a dose of 20 mg / kg and 100 mg / kg. The compound was prepared in a solvent of 5% DMSO+10% Solutol HS15+85% physiological saline (IV) or sterile water at pH 3.0 (PO). All animals were allowed to eat and drink freely during the experiment. Blood was collected by vein at 0.083, 0.25, 0.5, 1, 2, 4, 8, 24 and 48 hours after administration (n=3), and placed in tubes containing EDTA-K2 as an anticoagulant. The blood sample was centrifuged at 3500g, 4°C for 5 minutes, and the obtained plasma was analyzed by LC-MS / MS method, and the PK parameters were calculated by non-compartment model analysis method using WinNonlin software (version 8.3). 8.3 edition).

[1017] Rat PK: Male CD-1 mice (6-10 weeks old) were dosed intravenously (IV) by tail vein bolus at a dose of 10 mg / kg or orally (PO) by gavage at a dose of 30 mg / kg and 100 mg / kg. Compounds were formulated in a vehicle of 5% DMSO + 10% Solutol HS15 + 85% normal saline (IV) or sterile water at pH 3.0 (PO). All animals had free access to food and water during the experiment. Blood was collected by venipuncture (n=3) at 0.083, 0.25, 0.5, 1, 2, 4, 8, 24, and 48 hours post-dose and placed in tubes containing EDTA-K2 as an anticoagulant. Blood samples were centrifuged at 6800g, 2-8°C for 6 minutes and the resulting plasma was analyzed by LC-MS / MS method, and PK parameters were calculated using WinNonlin software (Version 7.0) by non-compartmental analysis methods. 7.0 version) by non-compartmental analysis methods.

[1018] Dog PK: Male beagle dogs (6-24 months old) were dosed intravenously (IV) by tail vein bolus at a dose of 10 mg / kg or orally (PO) by gavage at a dose of 50 mg / kg. Compounds were formulated in a vehicle of 5% DMSO + 10% Solutol HS15 + 85% normal saline (IV) or sterile water at pH 3.0 (PO). All animals had free access to food and water during the experiment. Blood was collected by venipuncture (n=2) at 0.083, 0.25, 0.5, 1, 2, 4, 8, 24, and 48 hours post-dose and placed in tubes containing EDTA-K2 as an anticoagulant. Blood samples were centrifuged at 3500g, 4°C for 5 minutes and the resulting plasma was analyzed by LC-MS / MS method, and PK parameters were calculated using WinNonlin software (Version 8.3) by non-compartmental analysis methods. 8.3 version) by non-compartmental analysis methods.

[1019] Monkey PK: Female cynomolgus monkeys (2.5-6 months old) were dosed intravenously (IV) by tail vein bolus at a dose of 10 mg / kg or orally (PO) by gavage at a dose of 50 mg / kg. Compounds were formulated in a vehicle of 5% DMSO + 10% Solutol HS15 + 85% normal saline (IV) or sterile water at pH 3.0 (PO). All animals had free access to food and water during the experiment. Blood was collected by venipuncture (n=2) at 0.083, 0.25, 0.5, 1, 2, 4, 8, 24, and 48 hours post-dose and placed in tubes containing EDTA-K2 as an anticoagulant. Blood samples were centrifuged at 3500g, 4°C for 5 minutes and the resulting plasma was analyzed by LC-MS / MS method, and PK parameters were calculated using WinNonlin software (Version 8.3) by non-compartmental analysis methods. 8.3 version) by non-compartmental model analysis methods.

[1020] Results: The test compound showed good in vivo PK in different species.

[1021] Biological effect Example 7 Testing the effect of the test compound on phospholipid accumulation in HepG2 cells

[1022] 1. Phospholipid accumulation evaluation system: Phospholipidosis is a lysosomal storage disorder characterized by the accumulation of large amounts of phospholipid complexes within the lysosomal membrane. There is currently evidence that cationic amphiphilic drugs (CADs), such as antibiotics, antidepressants, antihistamines and other prescription drugs are the cause of phospholipidosis.

[1023] Phospholipidosis induced by this class of drugs is usually reversible and does not cause adverse consequences; however, long-term exposure to specific drugs can lead to long-term toxic effects. Therefore, drug-induced cellular lipotoxicity leading to phospholipidosis should be evaluated at an early stage of drug development in order to minimize the potential risk thereof.

[1024] The objective of this study was to evaluate the effect of the test compound on phospholipid accumulation in HepG2 cells.

[1025] 2. Experimental procedure

[1026] 2.1 Cell plating

[1027] Day 1 : HepG2 cells (ATCC-HB-8065) resuspended in DMEM medium were seeded in PDL-coated 96-well plates (30000 cells / well / 100 μL). The cells were incubated overnight in a cell incubator at 37°C, 5% C02, relative humidity > 90%.

[1028] 2.2 Compound treatment

[1029] Day 2:

[1030] 1) After complete aspiration of the medium from the cell plates, 100 μL / well of LipidTOX detection reagent was added to the cell plates.

[1031] 2) The test compound was added to the cell plates with the Pico 8 instrument and the cells were incubated for 48 hours in a cell incubator at 37°C, 5% C02, relative humidity > 90%.

[1032] 2.3 Plate reading

[1033] Day 4:

[1034] 1) Take out the cell plate from the incubator, add 100 μL / well of 8% PFA fixative to fix the cells in the cell plate, and incubate the cell plate at room temperature for 30 minutes.

[1035] 2) Aspirate the PFA fixative and medium mixture from the cell plate.

[1036] 3) Wash the fixed cells with DPBS solution to remove residual PFA fixative.

[1037] 4) Dilute Hoechst 33342 from 10 mg / mL to 8 μg / mL working solution with DPBS, add 100 μL of Hoechst 33342 working solution to the fixed cell plate, and incubate at room temperature for 30 minutes.

[1038] 5) Wash the fixed cells with DPBS 3 times to remove Hoechst 33342.

[1039] 6) Scan the cell plate with the CQ1 instrument.

[1040] 3. Data analysis

[1041] The average values of the number of cells, the number of phospholipid deposits, and the total intensity of red signals (phospholipid deposits) were used as raw data for subsequent analysis.

[1042] 3.1 Inhibition rate (%) = (1 - average number of live cells in sample well / average number of live cells in DMSO control well) * 100.

[1043] 3.2 Fluorescence ratio of phospholipid deposits (normalized by the fluorescence signal value of the DMSO control well to the fluorescence signal of the sample well) = ((average value of phospholipid fluorescence signal value of sample well * total number of phospholipids in sample well) / number of cells in sample well) / average value {((average value of phospholipid deposition fluorescence intensity of DMSO control well * number of phospholipid deposits in DMSO control well) / number of live cells in DMSO control well)}

[1044] 3.3 Calculate the CC50 or EC50 value of the compound using Graph Pad Prism 6 software.

[1045] 3.4 Absolute CC 50 Value represents the concentration of the test compound corresponding to 50% effective inhibition. Relative EC 50 represents the concentration of the test compound corresponding to half of the maximum effective response value.

[1046] SUMMARY: This study is to investigate the effect of the compound on the phospholipid deposition of HepG2 cells. After co-treatment of adherent HepG2 cells with the compound and LipidTOX reagent for 48 hours, the cells were fixed with PFA and stained with Hoechst 33342, and then data were collected using CQ1 high-throughput fluorescence microscopy. The total number of cells, total number of phospholipids, and total intensity of red signal (total intensity of phospholipids) were used as raw data for subsequent analysis.

[1047] Experimental results: The tested compound showed a relatively significant phospholipid deposition result, with a relatively low safety risk.

[1048] Biological effect example 8 test the efficacy of the tested compound in an animal model infected with pathogenic microorganisms

[1049] I. Purpose of the experiment

[1050] Test the in vivo efficacy of the tested compound on mice infected with pathogenic microorganisms (Mycoplasma pneumoniae, Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus influenzae).

[1051] II. Experimental conditions

[1052] 2.1 Instrument information

[1053] Instrument information table

[1054] 2.2 Culture medium information

[1055] Culture medium information table

[1056] III. Experimental content

[1057] 3.1 Establishment of immunocompromised mouse model

[1058] Take the mice in each experimental group, first give cyclophosphamide 150 mg / kg at 4 days before infection, and give cyclophosphamide 100 mg / kg at 1 day before infection, and immunosuppress the mice.

[1059] 3.2 Establishment of immunocompromised mouse lung infection model

[1060] Preparation of bacterial solution: Take the Streptococcus pneumoniae strain and inoculate it on a 5% defibrillated sheep blood nutrient agar medium slope, incubate at 37°C for 16 h, then inoculate it into 100 mL of 5% lysed horse blood M-H II broth medium, incubate at 37°C in a 5% CO2 environment for 16 h, and determine the bacterial concentration by viable cell count.

[1061] 100mL bacteria solution was divided into sterile 10mL test tubes, centrifuged at 3000rpm / min for 5min, the supernatant was discarded, and then the same amount of sterile normal saline was added for resuspension, centrifuged again, the supernatant was discarded, and the normal saline was gradient diluted to the concentration of the model bacteria.

[1062] 3.3 Drug preparation

[1063] Drug solvent: sterile water, pH 3.0 (adjusted with hydrochloric acid) (sterile water is dissolved, and if it is clear, hydrochloric acid is not added for adjustment).

[1064] 3.4 Experimental content

[1065] 3.4.1 Infection and administration

[1066] On the day of infection, except for the Negative control, the rest of the groups were infected with bacterial suspension by nasal instillation, and 50μL of bacteria was used for infection. Each administration group was given the designed dose by gavage 2h after infection, and the Vehicle group and Negative control group were given the corresponding volume of solvent, and the volume of drug given to each mouse was 10mL / kg, and the drug was given once a day on the 2nd / 3rd day after infection.

[1067] 3.4.2 Sample collection

[1068] After 24h of pulmonary infection, the mice were sacrificed, and the alveolar lavage fluid and lung tissue were taken, weighed, and immediately placed in 5mL of sterile normal saline for homogenization.

[1069] 3.4.3 Tissue homogenate colony count

[1070] After weighing the tissue, it was placed in the pre-prepared 5mL sterile pre-cooled normal saline for tissue homogenization, and the homogenate was diluted with sterile normal saline by 10 times, and 1mL of the appropriate dilution concentration of the homogenate was taken in a sterile plate, and 9mL of agar medium was added, and mixed well. Each concentration prepared 2 plates, and placed in a 5% CO2 environment at 37℃ for 36-48h, and then the colony count was performed.

[1071] 3.4.4 Detection index

[1072] The animal bacterial load in the alveolar lavage fluid or tissue homogenate was detected by qPCR, or the solid culture count after lung tissue homogenization, and the bacterial load was calculated.

[1073] Experimental results: the tested compounds showed significant antibacterial or mycoplasma resistance in the animal model infected with the pathogen, and could effectively reduce the bacterial load of the model animals.

Claims

1. A compound represented by Formula I, a solvate thereof, a crystalline form thereof, a deuterated form thereof, a pharmaceutically acceptable salt thereof, or a solvate of a pharmaceutically acceptable salt thereof, Formula I wherein L is alkylene or alkenylene; said alkylene and said alkenylene are optionally substituted with one or more deuterium; X is CR 1 R 2 or The optionally substituted with one or two deuterium; Ring A is heteroaryl; said heteroaryl is a heteroaryl having one or more heteroatoms selected from the group consisting of N, O, and S; said heteroaryl is optionally substituted with one or more deuterium; R 1 and R 2 independently H, deuterium, OH, NH2, CN, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, O-alkyl, O-cycloalkyl, or heteroaryl; said alkyl, said alkenyl, said alkynyl, said cycloalkyl, said cycloalkenyl, said O-alkyl, said O-cycloalkyl, and said heteroaryl are optionally substituted with any substituent; said heteroaryl is a heteroaromatic group having one or more heteroatoms selected from N, O, and S; Or, R 1 R 2 Together with the carbon atom attached thereto, a heterocyclic group is formed; the heterocyclic group is a heteroatom selected from one or more of N, O and S, and the number of heteroatoms is independently one or more; the heterocyclic group may be optionally substituted by any substituent; R is R 3 is H, deuterium, CN, CONR 3-1 R 3-2 , COOR 3-3 , alkyl, alkenyl, alkynyl, cycloalkyl, aryl or heteroaryl; the alkyl, the alkenyl, the alkynyl, the cycloalkyl, the aryl and the heteroaryl are optionally substituted with any substituent; R 3-1 , R 3-2 , and R 3-3 are independently H or alkyl; said alkyl is optionally substituted with any substituent; R 4 is H or alkyl; said alkyl is optionally substituted with any substituent; R 5 is H, deuterium, alkyl, aryl, heteroaryl or heterocyclyl; said alkyl, said aryl, said heteroaryl and said heterocyclyl are optionally substituted with any substituent; said heteroaryl is a heteroaryl group having one or more heteroatoms selected from the group consisting of N, O and S, the number of heteroatoms being one or more; said heterocyclyl is a heterocyclyl group having one or more heteroatoms selected from the group consisting of N, O and S, the number of heteroatoms being one or more; R 6 is H, deuterium or methyl.

2. The compound of claim 1, solvate, crystal form, deuterated form, pharmaceutically acceptable salt or solvate of the pharmaceutically acceptable salt of Formula I, wherein, said compound of Formula I satisfies one or more of the following conditions: (1) each heteroaryl is independently a 5-14 membered heteroaryl, preferably a 5-10 membered heteroaryl, more preferably a 5-6 membered heteroaryl or an 8-10 membered heteroaryl; (2) each alkyl is independently C 1-10 alkyl, preferably C 1-6 alkyl, e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, or t-butyl; (3) each alkylene is independently C 1-10 alkylene, preferably C 1-6 alkylene, more preferably C 1-4 alkylene, for example, (4) each alkenyl is independently C 2-10 alkenyl, preferably C 2-6 alkenyl, more preferably C 2-4 alkenyl, for example, (5) each alkenylene is independently C 2-10 alkylene, preferably C 2-6 alkylene, more preferably C 2-4 alkylene, for example, (6) each alkynyl is independently C 2-10 alkynyl, preferably C 2-6 alkynyl, more preferably C 2-4 alkynyl, for example, (7) each cycloalkyl is independently C 3-14 cycloalkyl, preferably C 3-10 cycloalkyl, more preferably C 3-8 cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; (8) each cycloalkyl is independently monocycloalkyl, spirocycloalkyl, bridged cycloalkyl, or fused cycloalkyl, preferably C 3-14 monocycloalkyl, C 3-14 spirocycloalkyl, C 3-14 bridged cycloalkyl, or C 3-14 fused cycloalkyl, more preferably C 3-14 monocycloalkyl; (9) each alkyl in O-alkyl is independently C 1-10 alkyl, preferably C 1-6 alkyl, e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, or t-butyl; (10) each cycloalkyl in the O-cycloalkyl is independently C 3-14 cycloalkyl, preferably C 3-10 cycloalkyl, more preferably C 3-8 cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; (11) each cycloalkyl in the O-cycloalkyl is independently monocycloalkyl, spirocycloalkyl, bridged cycloalkyl, or fused cycloalkyl, preferably C 3-14 monocycloalkyl, C 3-14 spirocycloalkyl, C 3-14 bridged cycloalkyl, or C 3-14 fused cycloalkyl, more preferably C 3-14 monocycloalkyl; (12) each cycloalkenyl is independently C 3-14 cycloalkenyl, preferably C 3-10 cycloalkenyl, more preferably C 3-8 cycloalkenyl; (13) each cycloalkenyl is independently monocycloalkenyl, spirocycloalkenyl, bridged cycloalkenyl, or fused cycloalkenyl, preferably C 3-14 monocycloalkenyl, C 3-14 spirocycloalkenyl, C 3-14 bridged cycloalkenyl, or C 3-14 fused cycloalkenyl, more preferably C 3-14 monocycloalkenyl; (14) each heterocyclyl is independently a 3-14 membered heterocyclyl, preferably a 3-10 membered heterocyclyl, more preferably a 3-8 membered heterocyclyl, for example, oxiranyl or azacyclohexyl; (15) each heterocyclyl is independently a mono-heterocyclyl, a spiro-heterocyclyl, a fused-heterocyclyl, or a bridged-heterocyclyl; preferably a 3-14 membered mono-heterocyclyl, a 3-14 membered spiro-heterocyclyl, a 3-14 membered fused-heterocyclyl, or a 3-14 membered bridged-heterocyclyl, more preferably a 3-14 membered mono-heterocyclyl; (16) each aryl is independently C 6-14 aryl, preferably C 6-10 aryl, more preferably phenyl or naphthyl; Preferably, said compound of Formula I satisfies one or more of the following conditions: (1) each C 3-14 monocycloalkyl is independently C 3-10 monocycloalkyl, preferably C 3-8 monocycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; (2) each C 3-14 spirocycloalkyl is independently C 3-10 spirocycloalkyl, preferably C 3-8 spirocycloalkyl; (3) each C 3-14 bridged cycloalkyl is independently C 3-10 bridged cycloalkyl, preferably C 3-8 bridged cycloalkyl; (4) each C 3-14 and cycloalkyl is independently C 3-10 and cycloalkyl, preferably C 3-8 and cycloalkyl; (5) each C 3-14 monocyclic alkynyl is independently C 3-10 monocyclic alkynyl, preferably C 3-8 monocyclic alkynyl; (6) each C 3-14 spirocycloalkenyl is independently C 3-10 spirocycloalkenyl, preferably C 3-8 spirocycloalkenyl; (7) each C 3-14 cycloalkenyl is independently C 3-10 cycloalkenyl, preferably C 3-8 cycloalkenyl; (8) each C 3-14 and cycloalkenyl is independently C 3-10 and cycloalkenyl is independently C 3-8 and cycloalkenyl is independently C (9) each 3-14 membered mono-heterocyclyl is independently a 3-10 membered mono-heterocyclyl, preferably a 3-8 membered mono-heterocyclyl, for example, oxiranyl or azacyclohexyl; (10) each 3-14 membered spiro-heterocyclyl is independently a 3-10 membered spiro-heterocyclyl, preferably a 3-8 membered spiro-heterocyclyl; (11) each 3-14 membered fused-heterocyclyl is independently a 3-10 membered fused-heterocyclyl, preferably a 3-8 membered fused-heterocyclyl; (12) each 3-14 membered bridged-heterocyclyl is independently a 3-10 membered bridged-heterocyclyl, preferably a 3-8 membered bridged-heterocyclyl; (13) said 5-6 membered heteroaryl is independently a "5-6 membered heteroaryl having one or two heteroatoms selected from the group consisting of N, O, and S, the number of heteroatoms being one, two, three, or four", preferably pyridinyl, diazole, triazole, pyrimidinyl, thiazolyl, oxazolyl, tetrazole, 1,3,4-thiadiazole; (14) said 8-10 membered heteroaryl is independently a "8-10 membered heteroaryl having one or two heteroatoms being N or O, the number of heteroatoms being one, two, or three", preferably benzo[c][1,2,5]oxadiazolyl or benzopyridinyl.

3. The compound of claim 2, solvate thereof, crystalline form thereof, deuterated form thereof, pharmaceutically acceptable salt thereof, or solvate of a pharmaceutically acceptable salt thereof, wherein, said compound of Formula I satisfies one or more of the following conditions: (1) the pyrazolyl group is (2) the pyridyl group is (3) the 5-14 membered heteroaryl is independently pyridazinyl, pyrimidinyl or pyrazinyl, for example (4) the C 1-10 alkylene is (5) the type of heteroatom in each heterocyclyl is N, the number of heteroatoms being independently one or two; (6) each heterocyclyl is independently a partially saturated 3-14 membered heterocyclyl having one or two double bonds in the ring; preferably, the partially saturated 3-14 membered heterocyclyl is a partially saturated 5-6 membered heterocyclyl, for example For example (7) said halogen is fluorine, chlorine, bromine, or iodine, for example fluorine.

4. The compound of claim 2, solvate, crystalline form, deuteride, pharmaceutically acceptable salt, or solvate of a pharmaceutically acceptable salt of Formula I, wherein, The compound of Formula I satisfies one or more of the following conditions: L is C 1-10 alkylene or C 2-10 alkenylene; said C 1-10 alkylene and said C 2-10 alkenylene is optionally substituted with one or more deuterium; X is CR 1 R 2 or The optionally substituted with one or two deuterium; Ring A is a 5-14 membered heteroaryl; said 5-14 membered heteroaryl is a 5-14 membered heteroaryl having one, two, or three heteroatoms selected from the group consisting of N, O, and S, the number of heteroatoms being one, two, three, or four; said 5-14 membered heteroaryl is optionally substituted with one or more deuterium; R 1 and R 2 independently H, deuterium, OH, NH2, CN, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-14 cycloalkyl, C 5-14 cycloalkenyl, O-C 1-10 alkyl, O-C 3-14 cycloalkyl or 5-14 membered heteroaryl; said C 1-10 alkyl, said C 2-10 alkenyl, said C 2-10 alkynyl, said C 3-14 cycloalkyl, C 5-14 cycloalkenyl, said O-C 1-10 alkyl, said O-C 3-14 cycloalkyl and said 5-14 membered heteroaryl are optionally substituted with 1, 2, or 3 R 1-1 membered heteroaryl having 1, 2, 3, or 4 heteroatoms selected from N, O, and S; each R is independently deuterium, OH, halogen, SO3R 1-1 independently deuterium, OH, halogen, SO3R 1-1-1 or COOR 1-1-2 ; R 1-1-1 and R 1-1-2 independently H or C 1-10 alkyl; said C 1-10 alkyl is optionally substituted with one or more deuterium; Or, R 1 R 2 Together with the carbon atom attached thereto, a 3-14 membered heterocyclic group is formed; the 3-14 membered heterocyclic group is a 3-14 membered heterocyclic group in which the heteroatoms are selected from one or two of N, O and S, and the number of heteroatoms is independently one or two; the 3-14 membered heterocyclic group is optionally substituted by one or more deuteriums; R is R 3 is H, deuterium, CN, CONR 3-1 R 3-2 , COOR 3-3 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-14 cycloalkyl, C 6-14 aryl and 5-14 membered heteroaryl; said C 1-10 alkyl, said C 2-10 alkenyl, said C 2-10 alkynyl, said C 3-14 cycloalkyl, said C 6-14 aryl and said 5-14 membered heteroaryl are optionally substituted with 1, 2, or 3 R 3-4 ; said 5-14 membered heteroaryl is a 5-14 membered heteroaryl having 1, 2, or 3 heteroatoms selected from N, O, and S, and having 1, 2, 3, or 4 of said heteroatoms; R 3-1 , R 3-2 , and R 3-3 are independently H or C 1-10 alkyl; said C 1-10 alkyl is optionally substituted with one or more deuterium; each R is independently deuterium, OH, halogen, NR 3-4 independently deuterium, OH, halogen, NR 3-4-1 R 3-4-2 、 C 1-10 alkyl or 5-14 membered heteroaryl; said C 1-10 alkyl and said 5-14 membered heteroaryl are optionally substituted with 1, 2, or 3 R 3-4-4 substituents; said 5-14 membered heteroaryl is a 5-14 membered heteroaryl having 1, 2, or 3 heteroatoms selected from N, O, and S, and having 1, 2, 3, or 4 double bonds. R 3-4-1 and R 3-4-2 are independently H, or C 1-10 alkyl; said C 1-10 alkyl is optionally substituted with one or more deuterium; R 3-4-3 is C 1-10 alkyl; said C 1-10 alkyl is optionally substituted with one or more deuterium; each R 3-4-4 independently deuterium, OH, NR a R b or C 1-10 alkyl; said C 1-10 alkyl is optionally substituted with 1, 2, or 3 R 3-4-4-1 substituents; R a and R b are independently H, or C 1-10 alkyl; said C 1-10 alkyl is optionally substituted with one or more deuterium; each R 3-4-4-1 independently deuterium, OH, or NH2; R 4 is H or C 1-10 alkyl; said C 1-10 alkyl is optionally substituted with 1, 2, or 3 R 4-1 substituents; each R is independently deuterium, OH, CN, halogen, NR 4-1 is independently deuterium, OH, CN, halogen, NR a R b , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-14 cycloalkyl, or C 5-14 cycloalkenyl; said C 1-10 alkyl, said C 2-10 alkenyl, said C 2-10 alkynyl, said C 3-14 cycloalkyl, and said C 5-14 cycloalkenyl is optionally substituted with one or more deuterium; R a and R b are independently H, or C 1-10 alkyl; said C 1-10 alkyl is optionally substituted with 1, 2, or 3 deuterium; R 5 H, deuterium, C 1-10 alkyl, C 3-14 cycloalkyl, C 6-14 aryl, 5-14 membered heteroaryl, or 3-14 membered heterocyclyl; said C 1-10 alkyl, said C 6-14 aryl, said 5-14 membered heteroaryl, and said 3-14 membered heterocyclyl are optionally substituted with 1, 2, or 3 R 5-1 substituents; said 5-14 membered heteroaryl is a 5-14 membered heteroaryl having 1, 2, or 3 heteroatoms selected from N, O, and S, and having 1, 2, 3, or 4 of the heteroatoms; said 3-14 membered heterocyclyl is a 3-14 membered heterocyclyl having 1, 2, or 3 heteroatoms selected from N, O, and S, and having 1, 2, 3, or 4 of the heteroatoms. Each R 5-1 Independently deuterium, cyano, halogen, oxo, hydroxyl, NR 5-1-1 R 5-1-2 C 1-10 Alkyl, OC 1-10 Alkyl, C 3-6 cycloalkyl, -NH-CO-C 1- 10 Alkyl; the C 1-10 Alkyl, the OC 1-10 Alkyl groups and the -NH-CO-C 1-10 The alkyl group may be optionally substituted with one or more deuterium, halogen, or hydroxyl groups; R 5-1-1 and R 5-1-2 are independently H or C 1-10 alkyl; said C 1-10 alkyl is optionally substituted with 1, 2, or 3 R 5-1-1-1 substituents; Each R 5-1-1-1 Independently, it is either deuterium or a 5-14 heteroaryl group; the 5-14 heteroaryl group is a 5-14 heteroaryl group with one, two, or three heteroatoms selected from N, O, and S, and the number of heteroatoms is one, two, three, or four; the 5-14 heteroaryl group is optionally substituted with one or more deuterium groups; R 6 is H, deuterium or methyl; Ideally, each R 5-1 Independently deuterium, halogen, oxo, hydroxyl, NR 5-1-1 R 5-1-2 C 1-10 Alkyl, OC 1-10 Alkyl, C 3-6 cycloalkyl, -NH-CO-C 1-10 Alkyl; the C 1-10 Alkyl, the OC 1-10 Alkyl groups and the -NH-CO-C 1-10 The alkyl group may be optionally substituted with one or more deuterium, halogen, or hydroxyl groups.

5. The compound of claim 1 or 4, solvate, crystal form, deuterated form, pharmaceutically acceptable salt, or solvate of the pharmaceutically acceptable salt of Formula I, wherein, said compound of Formula I satisfies one or more of the following conditions: ​ (1) in ring A, the 5-14 membered heteroaryl is a nitrogen heteroatom number of 2, 3 or 4 nitrogen heteroazolyl 5-14 membered heteroaryl, preferably a nitrogen heteroatom number of 2, 3 or 4 nitrogen heteroazolyl 5-6 membered heteroaryl, more preferably imidazolyl, 1,2,3-triazole, 1,2,4-triazole or tetrazole, for example (2) In L, the C 1-10 alkylene is C 1-6 alkylene, preferably C 1-4 alkylene, for example (3) In L, the C 2-10 alkylene is C 2-6 alkylene, preferably C 2-4 alkylene, for example (4) R 1 (4) R 2 (4) R 3 (4) R 4 (4) R 5 (4) R 3-1 (4) R 3-2 (4) R 3-3 (4) R 3-4 (4) R 5-1 (4) R 1-1-1 (4) R 1-1-2 (4) R 3-4-1 (4) R 3-4-2 (4) R 3-4-3 (4) R 3-4-4 (4) R 5-1-1 (4) R 5-1-2 (4) R a (4) R b (4) R 1-10 (4) R 1-6 (4) R (4) R (4) R (4) R (4) R (4) R (4) R (4) R (4) R (4) R (4) R (4) R (4) R (4) R (4) R (4) R (4) R (4) R (4) R (4) R (4) R (4) R (4) R (4) R (4) R (4) R (4) R (4) R (4) R (4) R (4) R (4) R (4) R (4) R (4) R (4) R (4) R (4) R (4) R (4) R (4) R (4) R (4) R (4) R (4) R (4) R (5) R 1 (6) R 2 (7) R 3 (8) R 2-10 (9) R 2-6 (10) R 2-4 (11) R (6) R 1 (7) R 2 (8) R 3 (9) R 2-10 (10) R 2-6 (11) R 2-4 (12) R (7) R 3 and R 5 , said C 3-14 cycloalkyl is independently C 3-10 cycloalkyl, preferably C 3-8 cycloalkyl, more preferably C 3-8 monocycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; (8)R 1 R 2 and R 5-1 In the OC 1-10 C in alkyl 1-10 Alkyl groups are independently C 1-6 Alkyl groups, preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; (9) R 1 (9) R 2 (9) R 3 (9) R 5 (9) R 3-4 (9) R 5-1-1-1 wherein the 5-14 membered heteroaryl is independently a 5-6 membered heteroaryl or an 8-10 membered heteroaryl; Preferably, the 5-6 membered heteroaryl can be independently "a 5-6 membered heteroaryl having 1, 2, 3, or 4 heteroatoms selected from N, O, and S", preferably pyridyl (e.g. ), a diazole (e.g., pyrazole or imidazole, also e.g. ), triazole (e.g. 1,2,3-triazole or 1,2,4-triazole, also for example ), pyrimidinyl (e.g., ), thiazolyl (e.g.) ), oxazolyl (e.g., oxazolyl ), tetrazole (e.g., ) or 1,3,4-thiadiazole; and / or, the 8-10 membered heteroaryl can be independently "8-10 membered heteroaryl having 1 or 2 of N or O as a heteroatom, and having 1, 2, or 3 heteroatoms in total", preferably benzo[c][l,2,5]oxadiazolyl (e.g. ) or benzopyridyl (e.g. quinolinyl or isoquinolinyl, again for example )； (10) R 1 (11) R 2 and together with the carbon atom to which they are attached form a 3-14 membered heterocyclyl, preferably a 3-8 membered heterocyclyl, more preferably a 3-6 membered heterocyclyl, for example, oxiranyl; (11) R 3 and R 5 , said C 6-14 aryl is independently C 6-10 aryl, preferably phenyl or naphthyl; (12) R 5 In particular, the 3-14 membered heterocyclyl group is a 3-10 membered heterocyclyl group, preferably a 3-8 membered heterocyclyl group, more preferably a 3-8 membered nitrogen heterocyclyl group or a 3-8 membered oxygen heterocyclyl group, for example, piperidinyl.

6. The compound of claim 1 or 4, solvate, crystalline form, deuteride, pharmaceutically acceptable salt, or solvate of a pharmaceutically acceptable salt of Formula I, wherein, said compound of Formula I satisfies one or more of the following conditions: (1) L is C 1-10 alkylene or C 2-10 alkylene; preferably C 1-6 alkylene or C 2-6 alkylene; more preferably C 1-6 alkylene; (2) X is CR 1 R 2 or (3) ring A is a 5-10 membered heteroaryl, preferably a 5-6 membered heteroaryl, for example diazole, triazole or tetrazole; (4) R 1 and R 2 independently H, deuterium, OH, CN, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, O-C 1-10 alkyl, or 5-14 membered heteroaryl; said C 1-10 alkyl, said C 2-10 alkenyl, said C 2-10 alkynyl, said O-C 1-10 alkyl, and said 5-14 membered heteroaryl are optionally substituted with 1, 2, or 3 R 1-1 membered heteroaryl having 1, 2, 3, or 4 heteroatoms selected from N, O, and S; Preferably, R 1 and R 2 are independently H, OH, halogen or C 1-10 alkyl; For example, R 1 is C 1-6 alkyl, R 2 is H, OH or halogen; or R 1 is C 1-6 alkyl, R 2 is H or halogen; (5) each R 1-1 independently OH, halogen, SO3R 1-1-1 or COOR 1-1-2 ; (6) R 1-1-1 and R 1-1-2 are independently H or C 1-10 alkyl; preferably H or C 1-6 alkyl; (7) R 1 (8) R 2 and the carbon atom to which they are attached form a 3-14 membered heterocyclyl; the 3-14 membered heterocyclyl is a 3-14 membered heterocyclyl having 1 or 2 heteroatoms selected from N, O, and S, the number of heteroatoms being independently 1 or 2; Preferably, R 1 R 2 Together with the carbon atom attached to it, they form 3-6 membered oxoheterocyclic groups; (8)R 3 is H, deuterium, CN, CONR 3-1 R 3-2 , COOR 3-3 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-14 cycloalkyl, C 6-14 aryl or 5-14 membered heteroaryl; said C 1-10 alkyl, said C 2-10 alkenyl, said C 2-10 alkynyl, said C 3-14 cycloalkyl, said C 6-14 aryl and said 5-14 membered heteroaryl are optionally substituted with 1, 2, or 3 R 3-4 ; said 5-14 membered heteroaryl is a 5-14 membered heteroaryl having 1, 2, or 3 heteroatoms selected from N, O, and S, and having 1, 2, 3, or 4 of said heteroatoms; Preferably, R 3 is H, C 1-10 alkyl or 5-14 membered heteroaryl; the 5-6 membered heteroaryl is a 5-6 membered heteroaryl having 1, 2, or 3 heteroatoms selected from N, O, and S, and having 1, 2, 3, or 4 of the heteroatoms; For example, R 3 is H, C 1-6 alkyl or 5-6 membered heteroaryl; yet for example R 3 is H or C 1-6 alkyl, again for example H or C 1-4 alkyl, more for example H; (9) R 3-1 , R 3-2 , and R 3-3 are independently H or C 1-10 alkyl; preferably H or C 1-6 alkyl; (10) each R 3-4 independently OH, halogen, NR 3-4-1 R 3-4-2 , C 1-10 alkyl or 5-14 membered heteroaryl; said C 1-10 alkyl and said 5-14 membered heteroaryl are optionally substituted with 1, 2, or 3 R 3-4-4 substituents; said 5-14 membered heteroaryl is a 5-14 membered heteroaryl having 1, 2, or 3 heteroatoms selected from N, O, and S, and having 1, 2, 3, or 4 double bonds. Preferably, each R 3-4 independently is OH, NR 3-4-1 R 3-4-2 , C 1-10 alkyl or 5-14 membered heteroaryl; More preferably, each R 3-4 independently OH, NR 3-4-1 R 3-4-2 , C 1-6 alkyl or 5-6 membered heteroaryl; (11) R 3-4-1 and R 3-4-2 independently H, or C 1-10 alkyl; preferably, R 3-4-1 and R 3-4-2 are independently H, or C 1-6 alkyl; (12) R 3-4-3 is C 1-10 alkyl; preferably C 1-6 alkyl; (13) each R 3-4-4 independently OH, NR a R b or C 1-10 alkyl; preferably OH, NR a R b or C 1-6 alkyl; (14) R a and R b independently H, or C 1-10 alkyl; preferably H, or C 1-6 alkyl; (15) each R 3-4-4-1 independently OH or NR a R b ; preferably OH or NH2; (16) R 4 H or C 1-10 alkyl; preferably H or C 1-6 alkyl; more preferably H or C 1-4 alkyl; (17) R 5 H, C 6-14 aryl or 5-14 membered heteroaryl; said C 6-14 aryl and said 5-14 membered heteroaryl are optionally substituted with 1, 2, or 3 R 5-1 membered heteroaryl having 1, 2, 3, or 4 heteroatoms selected from N, O, and S; Preferably, R 5 is H, C 6-14 or 5-10 membered heteroaryl; said C 6-14 or 5-10 membered heteroaryl is optionally substituted with 1, 2, or 3 R 5 - 1 said 5-10 membered heteroaryl is a 5-10 membered heteroaryl having 1, 2, 3, or 4 heteroatoms selected from N, O, and S; More preferably, R 5 is C 6-14 aryl; said C 6-14 aryl is optionally substituted with 1, 2, or 3 R 5-1 substituents; (18) when R 5 substituents, R 5-1 substituents, R 5-1 may be bonded to the 5-14 membered heteroaryl group through a heteroatom (e.g., N) or carbon atom; for example, (19) each R 5-1 independently halogen, oxo, hydroxyl, NR 5-1-1 R 5-1-2 , C 1-10 alkyl, O-C 1-10 alkyl, C 3-6 cycloalkyl; R is independently oxo, NR 5-1 R is independently oxo, NR 5-1-1 R 5-1-2 , C 1-6 alkyl or O-C 1-6 alkyl; More preferably, each R 5-1 independently is NR 5-1-1 R 5-1-2 ; For example, each R 5-1 is independently NH2; (20) R 5-1-1 and R 5-1-2 independently H or C 1-10 alkyl; preferably H or C 1-6 alkyl; (21) each R 5-1-1-1 is independently 5-14 membered heteroaryl; the 5-14 membered heteroaryl is a 5-14 membered heteroaryl having 1, 2, or 3 heteroatoms selected from N, O, and S, and having 1, 2, 3, or 4 of the heteroatoms; Preferably, each R 5-1-1-1 is independently 5-10 membered heteroaryl; More preferably, each R 5-1-1-1 is independently 5-6 membered heteroaryl; (22) R 6 is H or methyl, for example H.

7. The compound of claim 1 or 4, solvate, crystalline form, deuteride, pharmaceutically acceptable salt thereof, or solvate of a pharmaceutically acceptable salt thereof, characterized in that, satisfies one or more of the following conditions: (1) L is C 4-6 alkylene; said C 4-6 alkylene is optionally substituted with one or more deuterium; preferably, L is C 4-6 alkylene; more preferably, L is "1" position to ring A, R L independently H, D or -CH3, preferably one R L is H, the other R L is H, D or -CH3; (2) X is CR 1 R 2 ; (3) R 1 and R 2 independently are halo or C 1-6 alkyl; alternatively, R 1 is H or halo; R 2 is C 1-6 alkyl; preferably, R 1 is halo; R 2 is C 1-6 alkyl; (4) ring A is a 5 membered heteroaryl, the heteroatom species in the 5 membered heteroaryl is selected from one, two or three of N, O and S, the number of heteroatoms is 1, 2 or 3; (5) R is Preferably, R 6 is H, R 3 is C 1-6 alkyl; (6) R 4 is C 1-6 alkyl; for example C 1-4 alkyl; (7) R 5 is 5-6 membered heteroaryl, a kind of heteroatom in the 5-6 membered heteroaryl is N, and the number of heteroatoms is 1 or 2; the 5-6 membered heteroaryl is optionally substituted by 1, 2 or 3 R 5-1 ; preferably, the number of heteroatoms is 2; preferably, R 5 is pyridazinyl; the pyridazinyl is optionally substituted by 1, 2 or 3 R 5-1 ; (8) R 5-1 independently -NH2, deuterium, halogen, oxo, or C 1-6 alkyl; for example, -NH2, deuterium, halogen, or C 1-6 alkyl; for example, -NH2; or, R 5 - 1 independently deuterium, halogen, oxo, or C 1-6 alkyl; for example, independently deuterium, halogen, or C 1-6 alkyl; or, R 5-1 independently -NH2, deuterium, halogen, hydroxyl, or C 1-6 alkyl; for example, R 5-1 independently deuterium, halogen, hydroxyl, or C 1-6 alkyl; or R 5-1 independently deuterium, halogen, hydroxyl, -NH2, -NH-C 1-4 alkyl, C 1-4 alkyl, or O-C 1-4 alkyl; or each R 5-1 is cyano.

8. The compound of claim 1, solvate, crystalline form, deuteride, pharmaceutically acceptable salt, or solvate of a pharmaceutically acceptable salt of Formula I, wherein, the compound of formula I is any of the following schemes: Scheme 1 : The compound of Formula I is a compound of Formula I-X1: t is 0, 1, 2 or 3; R 5-1 independently deuterium, cyano, halogen, hydroxyl, -NH2, -NH-C 1-4 alkyl, C 1-4 alkyl or O-C 1-4 alkyl; ring A is a 5-6 membered heteroaryl, the heteroatom species in the 5-6 membered heteroaryl is selected from one, two or three of N, O and S, the number of heteroatoms is 1, 2, 3 or 4; R L independently H, D, or -CH3; X is CR 1 R 2 ; R 1 is H or halogen; R 2 is C 1-6 alkyl; R 6 is H, R 3 is H or C 1-6 alkyl; R 4 is H or C 1-6 alkyl; Scheme 2: The compound of Formula I is a compound of Formula I-X1: t is 0, 1, 2 or 3; R 5-1 independently deuterium, cyano, hydroxyl, halogen, -NH2, -NH-C 1-4 alkyl, C 1-4 alkyl or O-C 1-4 alkyl; ring A is a 5 membered heteroaryl, the heteroatom species in the 5 membered heteroaryl is selected from one, two or three of N, O and S, the number of heteroatoms is 1, 2, 3 or 4; R L independently H, D, or -CH3; X is CR 1 R 2 ; R 1 halogen; R 2 is C 1-4 alkyl; R 6 is H, R 3 is H; R 4 is H or C 1-4 alkyl; Scheme 3: The compound of Formula I is a compound of Formula I-X2: t is 0, 1 or 2; R 5-1 independently D, -CH3, halogen, -NH2, -O-CH3, hydroxyl, or -NH-CH3; R L is H, D, or -CH3; ring A is a 5 membered heteroaryl, the heteroatom species in the 5 membered heteroaryl is selected from one, two or three of N, O and S, the number of heteroatoms is 1, 2, 3 or 4; R4 is H, methyl, ethyl, propyl or isopropyl, preferably methyl; Scheme 4: the compound of formula I is any of the following schemes: R 5 is pyridazinyl; said pyridazinyl is optionally substituted with 1, 2, or 3 R 5-1 substituents; R 5-1 independently -NH2, deuterium, hydroxyl, NR 5-1-1 R 5-1-2 , -O-C 1-6 alkyl or C 1-6 alkyl; R 5-1-1 and R 5-1-2 are independently H or C 1-6 alkyl; ring A is a 5 membered heteroaryl, the heteroatom species in the 5 membered heteroaryl is selected from one, two or three of N, O and S, the number of heteroatoms is 1, 2 or 3; L is C 4-6 alkylene; said C 4-6 alkylene is optionally substituted with one or more deuterium; X is CR 1 R 2 ; R 1 R is halogen; R 2 is C 1-6 alkyl; R is R 6 is H, R 3 is C 1-6 alkyl; R 4 is C 1-6 alkyl; Preferably, the scheme 1, scheme 2, scheme 3 and scheme 4 independently satisfy one or two of the following conditions: (1) Ring A is imidazolyl, triazolyl, tetrazolyl, pyrazolyl, 1,3,4-thiadiazolyl, 1,3,4- oxadiazolyl, 1,2,4-oxadiazole, oxazolyl, isoxazolyl, or thiazolyl, preferably, For wherein "1" is attached to L and "2" is attached to R 5 ; preferably, For wherein "1 " is attached to L and "2" is attached to R 5 ; (2) X is For example 9. The compound of formula I as claimed in claim 8, its solvate, its crystal form, its deuterated derivative, its pharmaceutically acceptable salt, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that: The compound as shown in Formula I is a compound as shown in Formula I-X2-A, I-X2-B, I-X2-C, I-X2-D, I-X2-E, I-X2-F, I-X2-G, I-X1-1, or I-X1-2:

10. The compound of claim 1, solvate thereof, crystalline form thereof, deuterated form thereof, pharmaceutically acceptable salt thereof, or solvate of a pharmaceutically acceptable salt thereof, wherein, the compound of formula I is any of the following schemes: Scheme 1: The compound as shown in formula I is a compound as shown in formula I-3: wherein: R L selected from H, D, or -CH3; W 1 is 5-membered heteroaryl, the kind of heteroatom in the 5-membered heteroaryl being selected from one, two, or three of N, O, and S, the number of heteroatoms being one, two, or three; t is 0, 1 or 2; R 5-1 independently D, -CH3, halogen, -NH2, -O-CH3, hydroxyl, or -NH-CH3; Scheme 2: The compound of Formula I is a compound of Formula I-3-A: wherein: R L selected from H, D, or -CH3; W 1 is 5-membered heteroaryl, the kind of heteroatom in the 5-membered heteroaryl being selected from one, two, or three of N, O, and S, the number of heteroatoms being one, two, or three; t is 0, 1 or 2; R 5-1 independently D, -CH3, halogen, -NH2, -O-CH3, hydroxyl, or -NH-CH3; Scheme 3: The compound of Formula I is a compound of Formula I-3-B: wherein: R L selected from H, D, or -CH3; W 1 is a 5-membered heteroaryl, the kind of heteroatom in the 5-membered heteroaryl being selected from one, two, or three of N, O, and S, the number of heteroatoms being one, two, or three; t is 0, 1 or 2; R 5-1 independently D, -CH3, halogen, -NH2, -O-CH3, hydroxyl, or -NH-CH3; Preferably, in Scheme 1, Scheme 2 and Scheme 3, W 1 independently imidazolyl, triazolyl, tetrazolyl, pyrazolyl, 1,3,4-thiadiazolyl, 1,3,4- oxadiazolyl, 1,2,4-oxadiazolyl, oxazolyl, isoxazolyl or thiazolyl, preferably, For wherein "1" is attached to L and "2" is attached to R 5 ; preferably, For wherein "1 " is attached to L and "2" is attached to R 5 .

11. The compound of claim 1 or 4, solvate, crystalline form, deuteride, pharmaceutically acceptable salt thereof, or solvate of a pharmaceutically acceptable salt thereof, characterized in that, the compound of formula I is any of the following schemes: (1) L is (2) ring A is diazole, triazole, tetrazole, 1,3,4-thiadiazole, 1,3,4-oxadiazole; wherein the diazole is preferably imidazole, the triazole is preferably 1,2,3-triazole; (3) Ring A is Preferably, For wherein "1 " is attached to L and "2" is attached to R 5 ; more preferably, For wherein "1 " is attached to L and "2" is attached to R 5 ; (4) R 1-1-2 is CH3; (5) R 1-1-1 is H; (6) R 1-1 is COOCH3or -SO3H; (7) R 1 is H, F, OH or CH3, for example R 1 is H or F, and for example F; (8) R 2 H, F, OH, CN, OCH3, CH3, CH2F, CH2OH, For example R 2 is methyl; (9) R 1 (9) R 2 and the carbon atom to which they are attached form (10) R a and R b independently H, or methyl; (11) R 3-4-3 independently CH3; (12) R 3-1 and R 3-2 is independently H; (13) R 3-3 independently CH2CH3; (14) R 3-4 independently OH, F, NH2, (15) R 3 H, methyl, cyano, for example H; (16) R 4 is H or methyl, for example methyl; (17) R 5-1-1-1 independently (18) R 5-1-1 and R 5-1-2 are independently H or (19) R 5-1 independently Cl, F, CH3, OCH3, NH2, OH, C2H5, -CH2F, -CF3, -CHF2, cyclopropyl, n-propyl, isopropyl, deuterium, -NH-COCH3, -NH-COCF3; (20) R 5 is H, Preferably, in the compound of formula I, X is For example, X is For example 12. The compound of claim 1 or 4, solvate, crystalline form, deuteride, pharmaceutically acceptable salt, or solvate of a pharmaceutically acceptable salt of Formula I, wherein, The compound of Formula I is any one of the following:

13. A pharmaceutical composition comprising (i) a compound of formula I, solvate thereof, crystal form thereof, deuterated derivative thereof, pharmaceutically acceptable salt thereof or solvate of the pharmaceutically acceptable salt thereof as claimed in any one of claims 1-12; and (ii) a pharmaceutically acceptable carrier.

14. Use of a compound of formula I, solvate thereof, crystal form thereof, deuterated derivative thereof, pharmaceutically acceptable salt thereof, solvate of the pharmaceutically acceptable salt thereof as claimed in any one of claims 1-12 or a pharmaceutical composition as claimed in claim 13 in the preparation of a medicament.

15. The use as claimed in claim 14, which satisfies one or more of the following conditions: (1) the medicament is an anti-pathogen medicament, preferably an anti-bacterial, mycoplasma or chlamydia medicament, for example an anti-mycoplasma medicament; More preferably, the bacteria are selected from one or more of Gram-positive bacteria, Gram-negative bacteria and anaerobic bacteria; for example Staphylococcus, Streptococcus, Enterococcus, Haemophilus, Moraxella, Legionella, Mycobacterium, Helicobacter, Clostridium, Bacteroides, Corynebacterium, Bacillus or Enterobacteriaceae; Further preferably, the Gram-positive bacteria are selected from one or more of Staphylococcus aureus, Streptococcus pneumoniae and Streptococcus pyogenes; the Gram-negative bacteria are Moraxella catarrhalis and / or Haemophilus influenzae; the bacteria are preferably Streptococcus pneumoniae and / or Streptococcus pyogenes; The Chlamydia is preferably Chlamydia pneumoniae; the Mycoplasma is preferably Mycoplasma pneumoniae; (2) the medicament is for treating upper respiratory tract infection, lower respiratory tract infection or soft tissue infection; for example lower respiratory tract infection, in turn for example pneumonia, again for example community-acquired pneumonia or hospital-acquired lung infection.

16. Use of a compound of Formula I, solvates thereof, crystalline forms thereof, deuterated forms thereof, pharmaceutically acceptable salts thereof, solvates of pharmaceutically acceptable salts thereof, or the pharmaceutical composition of claim 13 in the manufacture of a medicament for preventing and / or treating a disease associated with bacteria, Mycoplasma or Chlamydia.

17. The use according to claim 16, wherein The use meets one or more of the following conditions: (1) the bacteria are selected from one or more of Gram-positive bacteria, Gram-negative bacteria and anaerobic bacteria; for example Staphylococcus, Streptococcus, Enterococcus, Haemophilus, Moraxella, Legionella, Mycobacterium, Helicobacter, Clostridium, Bacteroides, Corynebacterium, Bacillus or Enterobacteriaceae; Preferably, the Gram-positive bacteria are selected from one or more of Staphylococcus aureus, Streptococcus pneumoniae and Streptococcus pyogenes; the Gram-negative bacteria are Moraxella catarrhalis and / or Haemophilus influenzae; the bacteria are preferably Streptococcus pneumoniae and / or Streptococcus pyogenes; (3) the Chlamydia is Chlamydia pneumoniae; (4) the Mycoplasma is Mycoplasma pneumoniae; (5) the disease associated with bacteria, Mycoplasma or Chlamydia is upper respiratory tract infection, lower respiratory tract infection or soft tissue infection, for example lower respiratory tract infection, in turn for example pneumonia, again for example community-acquired pneumonia or hospital-acquired lung infection.

Images