Cell cycle regulation kinase inhibitor as well as preparation method and application thereof

Abstract

The invention relates to a cell cycle regulation kinase inhibitor as well as a preparation method and application thereof, in particular to a compound shown in a formula I, a pharmaceutical composition containing the compound, a preparation method of the pharmaceutical composition and application of the pharmaceutical composition to prevention or treatment of MASTL activity related diseases or conditions.

Description

Technical Field

[0001] This invention relates to a class of cell cycle-regulated kinase inhibitor compounds, pharmaceutical compositions comprising the same, methods for their preparation, and their use for the prevention or treatment of diseases or conditions associated with MASTL activity. Background Technology

[0002] Microtubule-associated serine / threonine kinase-like (MASTL) is a human homologue of Greatwall kinase and an atypical member of the AGC kinase family. MASTL possesses a unique non-conserved middle region (NCMR) located between the DFG and APE motifs of the kinase domain, which is crucial for target recognition and regulation of kinase activity. MASTL is primarily located in the nucleus, expressed in various cell types including monocytes, highly expressed in the tonsils, moderately expressed in the cerebral cortex, salivary glands, breast, cardiac muscle, smooth muscle, skeletal muscle, appendix, lymph nodes, and bone marrow, and lowly expressed or absent in the caudate nucleus, testis, skin, colon, and other tissues.

[0003] Both the absence and overexpression of MASTL can cause cell cycle abnormalities. MASTL deficiency / inhibition can lead to chromosome segregation errors (polyploidy), cytokinesis failure, cell cycle arrest, and ultimately, apoptosis. Some studies suggest that the necessity of MASTL for the cell cycle is limited to the embryonic and early developmental stages of an organism. However, the cell cycle control mechanisms of certain cancer cells are similar to those of embryonic cells, making tumor cells more sensitive to MASTL inhibition. Theoretically, tumor cells rely more on MASTL to promote cell proliferation, and tumor cells often contain checkpoint defects such as p53 mutations, while normal cells possess complete cell cycle checkpoint protection mechanisms. Therefore, compared to normal cells, tumor cells may be more sensitive to MASTL inhibitors.

[0004] Overexpression of MASTL promotes various tumor phenotypes, such as promoting tumor proliferation, invasion, metastasis, and chemotherapy resistance, leading to low patient survival and poor prognosis. The exact mechanism of tumor promotion is still under investigation. Current research indicates that, on the one hand, overexpressed MASTL excessively inhibits the PP2A / B55 complex through the Arpp19 / ENSA axis, causing delays or disruption of the correct timing of mitotic exit, resulting in chromosome bridges and micronuclei, leading to chromosomal instability and promoting tumor progression (Oncogene. 2018 Aug; 37(33):4518-4533.). It also promotes chemotherapy resistance by facilitating cell cycle recovery after DNA damage. On the other hand, overexpressed MASTL promotes tumor proliferation, invasion, and migration by activating the Wnt / β-catenin and PI3K / AKT / mTOR signaling pathways.

[0005] In summary, MASTL can serve as a potential target for cancer therapy. Currently, there are no marketed inhibitors targeting MASTL. Therefore, there is a need to develop new, highly effective, and low-toxicity MASTL inhibitors to meet clinical needs. Summary of the Invention

[0006] This invention provides a class of novel MASTL inhibitor compounds or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, isotopically labeled compounds, polymorphs, solvates, N-oxides, metabolites or prodrugs thereof.

[0007] Specifically, one aspect of the present invention provides compounds of Formula I or thereof, or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, isotopically labeled compounds, polymorphs, solvates, N-oxides, metabolites, or prodrugs thereof:

[0008]

[0009] in:

[0010] X 1 X 2 and X 3 Each is independently selected from N and CR 3 ;

[0011] Ring A is selected from C 6-10 Aryl, 5-10 membered heteroaryl and 5-8 membered heterocyclic;

[0012] L is selected from bond, -C(=O)-, -S(=O)-, -S(=O)2- and -(CR 4 R 5 ) n -;

[0013] R 1 Selected from C 3-8Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10-membered heteroaryl groups, wherein the cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each optionally selected independently from one or more halogens, D, -OH, -CN, -NR. 6 R 7 -CD3, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Substitution of cycloalkoxy groups and 3-8 membered heterocyclic groups;

[0014] R 2 Each occurrence is independently selected from H, D, halogen, -OH, -CN, -NR. 6 R 7 -C(=O)NR 6 R 7 -C(=O)R 8 -NHC(=O)R 8 -S(=O)R 8 -S(=O)2R 8 C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 2-6 Heteroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl groups, wherein the alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heteroalkyl, hydroxyalkyl, hydroxyalkoxy, cycloalkyl, cycloalkoxy, heterocyclic, aryl, and heteroaryl groups are each optionally bound by one or more R groups. a replace;

[0015] R 3 Each occurrence is independently selected from H, D, halogen, -OH, -CN, -NH2, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-6 Hydroxyalkyl, C 3-8Cycloalkyl and 3-6 membered heterocyclic groups, wherein the alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, cycloalkyl and heterocyclic groups are each optionally selected independently by one or more halogens, D, OH, CN, -NH2 and C. 1-6 Alkyl substituents;

[0016] R 4 and R 5 Each time it appears, it is independently selected from H, D, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 2-6 Heteroalkyl, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups, or R 4 and R 5 Together with the carbon atom to which it is attached, it forms a 3-8 membered cycloalkyl or a 4-8 membered heterocyclic group, wherein the alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heteroalkyl, hydroxyalkyl, cycloalkyl, and heterocyclic group are each optionally selected independently by one or more halogens, D, OH, CN, -NH2, C. 1-6 Alkyl and C 1-6 Substituents of haloalkyl groups;

[0017] R 6 and R 7 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups, or R 6 and R 7 Together with the nitrogen atom it is attached to, it forms a 3-8 membered heterocyclic group;

[0018] R 8 Each occurrence is independently selected from H, -OH, -NH2, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl and 3-6 membered heterocyclic groups, wherein the alkyl, haloalkyl, cycloalkyl and heterocyclic groups are each optionally selected independently from one or more halogens, D, OH, CN, -NH2 and C. 1-6 Alkyl substituents;

[0019] R a Each occurrence is independently selected from H, D, halogen, =O, -OH, -CN, -NR. 6 R 7-C(=O)NR 6 R 7 C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl and 3-6 membered heterocyclic groups, wherein the alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, cycloalkyl and heterocyclic groups are each optionally selected independently by one or more halogens, D, OH, CN, -NH2 and C. 1-6 Alkyl substituents;

[0020] m can be 0, 1, 2, or 3;

[0021] n can be 0, 1, 2, or 3, provided that L is a bond or n is 0, and X 1 X 2 and X 3 When both are CH: (1) at least one R 2 Selected from D, -OH, -CN, -NR 6 R 7 -C(=O)NR 6 R 7 -C(=O)R 8 -NHC(=O)R 8 -S(=O)R 8 -S(=O)2R 8 C 2-4 alkenyl, C 2-4 alkynyl group, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 Heteroalkyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl groups, wherein the alkenyl, alkynyl, hydroxyalkyl, hydroxyalkoxy, haloalkoxy, heteroalkyl, cycloalkoxy, heterocyclic, aryl, and heteroaryl groups are each optionally surrounded by one or more R groups. a Replacement; preferably, at least one R 2 Selected from D, -OH, -CN, -NR 6 R 7 -C(=O)NR 6 R 7 -C(=O)R 8 -NHC(=O)R 8 -S(=O)R 8 -S(=O)2R 8 C 2-4 alkenyl, C2-4 alkynyl group, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl groups, wherein the alkenyl, alkynyl, hydroxyalkoxy, haloalkoxy, cycloalkoxy, heterocyclic, aryl, and heteroaryl groups are each optionally surrounded by one or more R groups. a Replace; and / or (2)R 1 C 3-8 cycloalkyl or C 6-10 The aryl group, wherein the cycloalkyl group and the aryl group are each optionally composed of one or more elements independently selected from halogen, D, -OH, -CN, -NR. 6 R 7 -CD3, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Substitution of cycloalkoxy groups and 3-8 membered heterocyclic groups; and / or (3)R 1 It is a 3-8 membered heterocyclic group or a 5-10 membered heteroaryl group, wherein each heterocyclic group and heteroaryl group is independently separated by at least one group selected from D, -OH, -CN, -NR. 6 R 7 -CD3, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-8 Substitution with cycloalkoxy groups and 3-8 membered heterocyclic groups.

[0022] Another aspect of the present invention provides a pharmaceutical composition comprising a preventive or therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite or prodrug, and one or more pharmaceutically acceptable carriers.

[0023] Another aspect of the invention provides the use of the compounds of the invention or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, isotopically labeled compounds, polymorphs, solvates, N-oxides, metabolites or prodrugs of the invention, or pharmaceutical compositions of the invention, in the preparation of medicaments, particularly medicaments for the prevention or treatment of diseases or conditions associated with MASTL activity.

[0024] Another aspect of the invention provides the compounds of the invention or their pharmaceutically acceptable salts, esters, stereoisomers, tautomers, isotopically labeled compounds, polymorphs, solvates, N-oxides, metabolites or prodrugs, or pharmaceutical compositions of the invention, which are used as pharmaceuticals.

[0025] Another aspect of the invention provides compounds of the invention or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, isotopically labeled compounds, polymorphs, solvates, N-oxides, metabolites or prodrugs thereof, or pharmaceutical compositions of the invention, for the prevention or treatment of diseases or conditions associated with MASTL activity.

[0026] Another aspect of the invention provides a method for preventing or treating diseases or conditions associated with MASTL activity, the method comprising administering to an individual in need an effective amount of the compound of the invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite or prodrug of the invention, or a pharmaceutical composition of the invention.

[0027] Another aspect of the present invention provides a method for preparing the compounds of the present invention, which is selected from the following methods:

[0028] Method 1 includes one or more of the following steps:

[0029] Step 1: Compound IB-1 reacts with (Boc)2O under the action of a base to generate compound IB-2;

[0030]

[0031] Step 2: Compound IB-2 reacts with benzophenone imine via a Buchwald coupling reaction to generate compound IB-3;

[0032]

[0033] Step 3: Compound IB-3 undergoes a reduction reaction to generate compound IB-4;

[0034]

[0035] Step 4: Compound IB-4 undergoes a condensation reaction to generate compound IB-5;

[0036]

[0037] Step 5: Compound IB-5 undergoes deprotection under acidic conditions to generate compound IB;

[0038]

[0039] Method 2 includes the following steps: compound IB-1 undergoes a Buchwald coupling reaction to generate compound IC;

[0040]

[0041] Method 3 includes one or more of the following steps:

[0042] Step 1: Compound IC-1 undergoes a Buchwald coupling reaction to generate compound IC-2;

[0043] Step 2: Compound IC-2 undergoes a Buchwald coupling reaction to generate compound IC-3;

[0044] Step 3: Compound IC-3 undergoes a deprotection reaction to generate compound IC;

[0045]

[0046] Method four includes one or more of the following steps:

[0047] In the first step, compound IC-1 undergoes a Buchwald coupling reaction to generate compound IC-1-2;

[0048] In the second step, compound IC-1-2 undergoes a substitution reaction to generate compound IB-3;

[0049]

[0050] Method 5 includes one or more of the following steps:

[0051] In the first step, compound IB-2 undergoes a Buchwald coupling reaction to generate compound I-1;

[0052] In the second step, compound I-1 undergoes a deprotection reaction to generate compound I.

[0053]

[0054] Method six includes the following steps:

[0055] In the first step, compound IB-4 undergoes a Buchwald coupling reaction to generate compound I-1.

[0056]

[0057] Among them, R 2a R is optionally protected by a protecting group (e.g., an amino protecting group). 2 ;X 1 X 2X 3 R 1 R 2 , m, ring A and L are as defined above; Y 1 and Y 2 Each is independently a halogen, such as fluorine, chlorine, bromine, or iodine, preferably chlorine; PG1 and PG2 are each independently an H or amino protecting group, such as alkoxycarbonyl amino protecting groups, for example benzyloxycarbonyl (Cbz), tert-butyloxycarbonyl (Boc), methoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilylethoxycarbonyl (Teoc), or methoxycarbonyl (or ethoxycarbonyl); acyl amino protecting groups, such as phthaloyl (Pht), p-toluenesulfonyl (Tos). ), trifluoroacetyl (Tfa), o-(p-)nitrobenzenesulfonyl (Ns), p-pentanoyl, benzoyl, tert-butoxycarbonyl, 9-fluorenmethoxycarbonyl, allyloxycarbonyl, trichloroethoxycarbonyl, trimethylsilylethoxycarbonyl, benzyloxycarbonyl, p-methylbenzenesulfonyl, p-nitrobenzenesulfonyl, tert-butyl, trifluoroacetyl, methoxycarbonyl or ethoxycarbonyl; alkyl amino protecting groups, such as triphenylmethyl (Trt), 2,4-dimethoxybenzyl (Dmb), 4-methoxybenzyl (PMB) or benzyl (Bn). Detailed Implementation

[0058] definition

[0059] Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art. References to technical terms herein refer to techniques commonly understood in the art, including variations or equivalent substitutions of techniques that are obvious to one of ordinary skill in the art. While it is believed that the following terms will be well understood by one of ordinary skill in the art, the following definitions are set forth to better explain the invention.

[0060] The terms “comprising,” “including,” “having,” “containing,” or “involving,” and their other variations herein, are inclusive or open-ended and do not exclude other unlisted elements or method steps, although such other unlisted elements or method steps may not necessarily exist (i.e., these terms also cover the terms “consistently made up of” and “composed of”).

[0061] As used herein, the term "alkyl" is defined as a linear or branched saturated aliphatic hydrocarbon. In some embodiments, the alkyl group has 1 to 12 carbon atoms (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12), such as 1 to 6 carbon atoms or 1 to 4 carbon atoms. For example, as used herein, the term "C" is used to refer to... 1-6"Alkyl" refers to a linear or branched group having 1-6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, or n-hexyl), optionally substituted with one or more (such as 1, 2, or 3) suitable substituents such as halogens (in which case the group is called "haloalkyl") (e.g., CH2F, CHF2, CF3, CCl3, C2F5, C2Cl5, CH2CF3, CH2Cl, or -CH2CH2CF3, etc.). The term "C" 1-4 "Alkyl" refers to a linear or branched aliphatic hydrocarbon chain having 1 to 4 carbon atoms (i.e., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl).

[0062] As used herein, the term "heteroalkyl" refers to an alkyl group having one or more skeletal chain atoms in its main chain that are independently selected from atoms other than carbon, such as oxygen, nitrogen, sulfur, phosphorus, or combinations thereof. Numerical ranges (e.g., C) can be given. 2-6 A heteroalkyl group (C3-CH2OCH2CH3) refers to the number of carbon atoms in the chain, which in this example includes 2-6 carbon atoms. For example, the -CH2OCH2CH3 group is called a C3 heteroalkyl group, and the -CH2OCH2CH2NHCH3 group is called a C4 heteroalkyl group. Connection to the rest of the molecule can be made via heteroatoms or carbon atoms in the heteroalkyl chain.

[0063] As used herein, the term "haloalkyl" refers to an alkyl group substituted with one or more (such as 1, 2, or 3) identical or different halogen atoms, such as C2. 1-8 Haloalkyl, C 1-6 Haloalkyl, C 1-4 Halogenated alkyl groups, etc. The term "C" 1-8 "Halogenated alkyl", "C" 1-6 "Halogenated alkyl" and "C" 1-4 "Halogenated alkyl" refers to alkyl halogens having 1 to 8 (e.g., 1, 2, 3, 4, 5, 6, 7, 8) carbon atoms, 1 to 6 carbon atoms, and 1 to 4 carbon atoms, such as -CF3, -C2F5, -CHF2, -CH2F, -CH2CF3, -CH2Cl, or -CH2CH2CF3, etc.

[0064] As used herein, the term "hydroxyalkyl" refers to a group formed by replacing one or more hydrogen atoms in an alkyl group with hydroxyl groups, such as C10. 1-6 Hydroxyalkyl or C 1-4 Hydroxyalkyl groups, examples of which include, but are not limited to, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, -CH(OH)CH3, etc.

[0065] As used herein, the term "alkoxy" means -O-alkyl, where the alkyl group is as defined above, for example, C... 1-8Alkoxy, C 1-6 Alkoxy, C 1-4 Alkoxy or C 1-3 Alkyl group. C 1-6 Representative examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentoxy, hexoxy, etc., wherein the alkoxy group is optionally substituted by one or more (such as 1, 2, or 3) identical or different substituents. The term "haloalkoxy" refers to an alkoxy group in which the hydrogen atom is substituted by one or more (such as 1, 2, or 3) identical or different halogen atoms.

[0066] As used herein, the term "hydroxyalkoxy" refers to a group formed by replacing a hydrogen atom in an alkoxy group with one or more hydroxyl groups, such as C. 1-6 hydroxyalkoxy or C 1-4 Hydroxyalkoxy compounds, examples of which include, but are not limited to, hydroxymethoxy, hydroxyethoxy, hydroxypropoxy, hydroxybutoxy, -OCH2CH(OH)(CH3)2, etc.

[0067] As used herein, the terms “fused ring,” “dense ring,” or “fused together” refer to a ring system formed by two or more ring structures sharing two adjacent atoms.

[0068] As used herein, the term "spiroring" refers to a ring system consisting of two or more ring structures that share a single ring atom.

[0069] As used in this article, the term "bridged ring" refers to a ring system formed by two or more ring structures sharing two atoms that are not directly connected to each other.

[0070] As used herein, the term "cycloalkyl" refers to a saturated or unsaturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon cycloalkyl group, including but not limited to monocyclic alkyl groups (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, etc.) and bicyclic alkyl groups, including spirocyclic, fused-ring (fused-ring) or bridged-ring systems (i.e., spirocyclic alkyl, fused-ring (fused-ring) alkyl, and bridged-ring alkyl groups, such as bicyclic [1.1.1]pentyl, bicyclic [2.2.1]heptyl, etc.). In this invention, the cycloalkyl group is optionally substituted with one or more (such as 1, 2, or 3) identical or different substituents. The carbon atom on the cycloalkyl group is optionally substituted with an oxo group (i.e., forming C=O). The term "C 3-8 "Cycloalkyl" refers to a cycloalkyl group having 3 to 8 (e.g., 3, 4, 5, 6, 7, 8) cyclic carbon atoms, such as C10. 3-6 Cycloalkyl groups can be monocycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, or they can be bicycloalkyl, such as C10, C20, C30, C40, C50, C60, C7 ... 5-8 Spirocycloalkyl, C5-8 Bridged cycloalkyl, C 5-8 Polycyclic alkyl, C 5-6 Spirocycloalkyl, C 5-6 Bridged cycloalkyl or C 5-6 Fused cycloalkyl groups.

[0071] As used herein, the term "cycloalkoxy" refers to -O-cycloalkyl, where the cycloalkyl group is as defined above. Representative examples of cycloalkoxy groups include, but are not limited to, cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexoxy.

[0072] As used herein, the terms “heterocyclic group” and “heterocycle” are used interchangeably, specifically referring to an aliphatic monocyclic or polycyclic (e.g., fused, spirocyclic, or bridged) group having two or more (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14) carbon atoms and one or more (e.g., 1, 2, 3, or 4) heteroatoms, said heteroatoms including, but not limited to, oxygen, nitrogen, and sulfur atoms, wherein the carbon atoms and heteroatoms on said heterocyclic group are optionally substituted with oxo groups (e.g., forming C(=O), S(=O), or S(=O)2), or optionally with one or more (such as 1, 2, or 3) independently selected from halogens and C. 1-3Alkyl substituents. The term "saturated heterocycle" refers to a fully saturated heterocycle, including 5-8 membered saturated heterocycles and 5-6 membered saturated heterocycles, such as tetrahydropyrrole ring, tetrahydrofuran ring, tetrahydrothiophene ring, piperidine ring, morpholine ring, tetrahydropyran ring, piperazine ring, piperazine ketone ring, etc. The term "partially saturated heterocycle" refers to a heterocycle that contains both saturated single bonds and unsaturated double bonds, including 5-8 membered partially saturated heterocycles and 5-6 membered partially saturated heterocycles, such as 3,4-dihydro-2H-pyran, 1,2,3,4-tetrahydropyridine, 4,5-dihydroisoxazolyl, 4,5-dihydrooxazolyl, 2,5-dihydrooxazolyl, 2,3-dihydrooxazolyl, etc. As used herein, the term "heterocyclic group" includes, but is not limited to, 4-11 membered heterocyclic groups, 4-10 membered heterocyclic groups, 4-9 membered heterocyclic groups, 4-8 membered heterocyclic groups, 4-7 membered heterocyclic groups, 5-6 membered heterocyclic groups, 3-8 membered heterocyclic groups, 3-7 membered heterocyclic groups, 4-7 membered nitrogen-containing heterocyclic groups, 4-7 membered oxygen-containing heterocyclic groups, 4-7 membered sulfur-containing heterocyclic groups, 5-6 membered nitrogen-containing heterocyclic groups, 5-6 membered oxygen-containing heterocyclic groups, and 5-6 membered sulfur-containing heterocyclic groups. Each of the "nitrogen-containing heterocyclic group," "oxygen-containing heterocyclic group," and "sulfur-containing heterocyclic group" may also optionally contain one or more other heteroatoms independently selected from oxygen, nitrogen, and sulfur. As used herein, the term "3-8 membered heterocyclic group" refers to a heterocyclic group containing 3-8 ring atoms, including but not limited to 3-8 membered heterocyclic groups, 3-7 membered heterocyclic groups, 3-6 membered heterocyclic groups, 4-8 membered heterocyclic groups, 4-7 membered heterocyclic groups, 4-6 membered heterocyclic groups, 5-6 membered heterocyclic groups, 5-8 membered heterocyclic groups (e.g., 5-8 membered saturated or partially saturated heterocycles), 6-8 membered heterocyclic groups, 4-7 membered nitrogen-containing heterocyclic groups, 4-7 membered oxygen-containing heterocyclic groups, 4-7 membered sulfur-containing heterocyclic groups, 5-6 membered nitrogen-containing heterocyclic groups, 5-6 membered oxygen-containing heterocyclic groups, 5-6 membered sulfur-containing heterocyclic groups, etc. Examples of 3-8 membered heterocyclic groups include but are not limited to ethylene oxide, aziridinyl, aziridine, oxobutyl, tetrahydrofuranyl, pyrrolylalkyl, pyrrolidone (e.g.) ), imidazoalkyl, pyrazolalkyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, piperazinone (e.g.) ), trithianyl. Examples of “3-8 membered nitrogen-containing heterocyclic groups” include the aforementioned 3-8 membered heterocyclic groups containing nitrogen atoms.

[0073] In this invention, the heterocyclic group can form a fused ring structure with a heterocyclic group or a cycloalkyl group. The connection point of the fused ring structure with other groups can be on any heterocyclic group or on a cycloalkyl group. Therefore, the heterocyclic group of this invention also includes (but is not limited to) heterocyclic fused heterocyclic groups, heterocyclic fused cycloalkyl groups, monoheterocyclic fused monoheterocyclic groups, and monoheterocyclic fused monocycloalkyl groups, such as 3-7 membered (mono)heterocyclic fused 3-7 membered (mono)heterocyclic groups, 3-7 membered (mono)heterocyclic fused (mono)cycloalkyl groups, and 3-7 membered (mono)heterocyclic fused C4-6 (Mono)cycloalkyl groups, examples of which include, but are not limited to, pyrrolidinylcyclopropyl, cyclopentylazirylpropyl, pyrrolidinylcyclobutyl, pyrrolidinylpyrrolidinyl, pyrrolidinylpiperidinyl, pyrrolidinylpiperazinyl, and piperidinylmorpholinyl.

[0074] In this invention, the heterocyclic group also includes bridged heterocyclic groups and spiroheterocyclic groups.

[0075] As used herein, the term "bridged heterocycle" refers to a ring structure containing one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, nitrogen, and / or sulfur atoms) formed by two rings sharing two non-directly connected ring atoms. This includes, but is not limited to, 7-10 membered bridged heterocycles, 8-10 membered bridged heterocycles, 7-10 membered nitrogen-containing bridged heterocycles, 7-10 membered oxygen-containing bridged heterocycles, 7-10 membered sulfur-containing bridged heterocycles, etc., for example... The "nitrogen-bridged heterocycle", "oxygen-bridged heterocycle", and "sulfur-bridged heterocycle" may optionally also contain one or more other heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0076] As used herein, the term "spiroheterocycle" refers to a ring structure consisting of two or more rings sharing a single ring atom and containing one or more heteroatoms (e.g., oxygen, nitrogen, sulfur), including but not limited to 5-10 membered spiroheterocycles, 6-10 membered spiroheterocycles, 6-10 membered nitrogen-containing spiroheterocycles, 6-10 membered oxygen-containing spiroheterocycles, 6-10 membered sulfur-containing spiroheterocycles, etc. The "nitrogen-containing spiroheterocycle", "oxygen-containing spiroheterocycle", and "sulfur-containing spiroheterocycle" may optionally also contain one or more other heteroatoms independently selected from oxygen, nitrogen, and sulfur. The term "6-10-membered nitrogen-containing spiroheterocycle group" refers to a spiroheterocycle group containing a total of 6-10 ring atoms, of which at least one ring atom is a nitrogen atom.

[0077] Examples of groups obtained by fusion of heterocyclic groups and aryl groups include, but are not limited to:

[0078] As used herein, the terms "aryl," "phenyl," or "aromatic ring" refer to an all-carbon monocyclic or fused polycyclic aromatic group having a conjugated π-electron system. As used herein, the term "C" refers to a carbon-based monocyclic or fused polycyclic aromatic group. 6-10"Aryl (aromatic ring)" means an aryl (aromatic ring) containing 6 to 10 (e.g., 6, 7, 8, 9, 10) carbon atoms, preferably phenyl (benzene ring) or naphthyl (naphthalene ring). The aryl group is optionally substituted by one or more (e.g., 1, 2 or 3) identical or different substituents (e.g., halogen, OH, CN, NO2, C1-C6 alkyl, etc.).

[0079] As used herein, the term "heteroaryl" or "heteroaromatic ring" refers to a monocyclic or polycyclic aromatic group containing one or more identical or different heteroatoms, including monocyclic heteroaryl and bicyclic or polycyclic ring systems containing at least one heteroaromatic ring (an aromatic ring system containing at least one heteroatom), which may have 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, for example 5, 6, 7, 8, 9 or 10 ring atoms, and in each case may additionally be benzofused. The heteroatom may be oxygen, nitrogen or sulfur. The carbon atom and heteroatom on the heteroaryl group are optionally substituted with an oxo group (e.g., forming C(=O), S(=O) or S(=O)2).

[0080] As used herein, the terms "5-10-membered heteroaryl" or "5-10-membered heteroaryl ring" refer to a heteroaryl (heteroaryl ring) containing 5 to 10 (e.g., 5, 6, 7, 8, 9, 10) ring atoms, including 5-10-membered nitrogen-containing heteroaryl, 5-10-membered oxygen-containing heteroaryl, 5-10-membered sulfur-containing heteroaryl, 5-6-membered nitrogen-containing heteroaryl, 5-6-membered oxygen-containing heteroaryl, 5-6-membered sulfur-containing heteroaryl, etc. Each of the "nitrogen-containing heteroaryl," "oxygen-containing heteroaryl," and "sulfur-containing heteroaryl" optionally contains one or more other heteroatoms independently selected from oxygen, nitrogen, and sulfur. Examples of 5-10 membered heteroaryl groups (e.g., 5-6 membered heteroaryl groups) include, but are not limited to, thiophene, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, and benzo[a] derivatives of these groups or 5-10 membered fused-ring groups composed of these groups. The term "5-membered heteroaryl" refers to a heteroaryl group containing 5 ring atoms, such as those heteroaryl groups with 5 ring atoms mentioned above.

[0081] In this invention, a heteroaryl group (e.g., a monoheteroaryl group) can share two adjacent atoms with an aryl group (e.g., a monocyclic aryl group, such as a phenyl group), a heterocyclic group (e.g., a monoheterocyclic group), a cycloalkyl group (e.g., a monocycloalkyl group), or another heteroaryl group (e.g., another monoheteroaryl group) to form a fused ring structure. The connection point can be on any heteroaryl ring or other rings, including but not limited to (mono)heteroaryl fused (mono)heteroaryl, (mono)heteroaryl fused (monocyclic) aryl, (mono)heteroaryl fused (mono)heterocyclic, and (mono)heteroaryl fused (mono)cycloalkyl, such as 5-6 membered (mono)heteroaryl fused 5-6 membered (mono)heteroaryl, 5-6 membered (mono)heteroaryl fused phenyl, 5-6 membered (mono)heteroaryl fused 5-6 membered (mono)heterocyclic, or 5-6 membered (mono)heteroaryl fused C 4-6 (Mono)cycloalkyl groups (e.g., 5-6-membered heteroarylcyclobutyl, 5-6-membered heteroarylcyclopentyl, or 5-6-membered heteroarylcyclohexyl), examples of which include, but are not limited to, benzothiazolyl, indolyl, isoyindolyl, indolyl, benzimidazole, quinolinyl, isoquinolinyl, wait.

[0082] As used herein, the term “halogenated” or “halogenated” is defined as including F, Cl, Br, or I.

[0083] As used in this article when describing functional groups, “CO” and “C(=O)” are interchangeable, “SO” and “S(=O)” are interchangeable, and “SO2” and “S(=O)2” are interchangeable.

[0084] The term "substitution" refers to the selective replacement of one or more (e.g., one, two, three, or four) hydrogen atoms on a specified atom by a designated group, provided that the substitution does not exceed the normal valence of the specified atom in the present case and that the substitution forms a stable compound. Combinations of substituents and / or variables are permitted only if such combinations form a stable compound.

[0085] If a substituent is described as “optionally substituted by one or more…”, then the substituent may be (1) unsubstituted or (2) substituted. If the carbon of the substituent is described as being optionally substituted by one or more of the substituents in the list, then one or more hydrogens on the carbon (to the extent that any hydrogens are present) may be substituted individually and / or together by independently selected optional substituents. If the nitrogen of the substituent is described as being optionally substituted by one or more of the substituents in the list, then one or more hydrogens on the nitrogen (to the extent that any hydrogens are present) may each be substituted by independently selected optional substituents.

[0086] If a substituent is described as being “independently selected” from a group, then each substituent is selected independently of the others. Therefore, each substituent may be the same as or different from another (other) substituent.

[0087] As used herein, the term "one or more" means one or more under reasonable conditions, such as two, three, four, five, six, seven, eight, nine, or ten.

[0088] Unless otherwise specified, as used herein, the connection point of a substituent may be located at any suitable position of the substituent.

[0089] When the bond of a substituent is such that it passes through the ring and connects two atoms, then such a substituent can be bonded to any cyclic atom in the substituted ring.

[0090] This invention also includes all pharmaceutically acceptable isotopically labeled compounds that are identical to the compounds of this invention, except that one or more atoms are replaced by atoms having the same atomic number but a different atomic mass or mass number than the dominant atomic mass or mass number found in nature. Examples of isotopes suitable for inclusion in the compounds of this invention include (but are not limited to) isotopes of hydrogen (e.g., deuterium). 2 H), tritium ( 3 H); carbon isotopes (e.g., H); 11 C 13 C and 14 C); isotopes of chlorine (e.g. 36 Cl); isotopes of fluorine (e.g., Cl); 18 F); isotopes of iodine (e.g., F); 123 I and 125 I); nitrogen isotopes (e.g.) 13 N and 15 N); isotopes of oxygen (e.g., N); 15 O、 17 O and 18 O); isotopes of phosphorus (e.g., O); phosphorus isotopes (e.g., O); 32 P); and isotopes of sulfur (e.g., ... 35 S). Certain isotope-labeled compounds of the present invention (e.g., those doped with radioactive isotopes) can be used in drug and / or substrate tissue distribution studies (e.g., analysis). Radioactive isotope tritium (i.e. 3 H) and carbon-14 (i.e. 14 C) It is particularly suitable for this purpose due to its ease of incorporation and detection. Using positron-emitting isotopes (e.g.) 11 C 18 F, 15 O and 13Substitution of N) can be used in positron emission tomography (PET) studies to examine substrate acceptor occupancy. The isotopically labeled compounds of the present invention can be prepared by methods similar to those described in the accompanying routes and / or examples and preparations, by using a suitable isotopically labeled reagent instead of the previously used unlabeled reagent. Pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent can be isotopically substituted, for example, D2O, acetone-d6, or DMSO-d6.

[0091] The term "stereoisomer" refers to an isomer formed due to at least one asymmetric center. In compounds having one or more (e.g., one, two, three, or four) asymmetric centers, racemic mixtures, single enantiomers, diastereomer mixtures, and single diastereomers can be produced. Specific individual molecules can also exist as geometric isomers (cis / trans). Similarly, the compounds of the present invention can exist as mixtures of two or more structurally different forms in rapid equilibrium (commonly referred to as tautomers). Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, etc. For example, nitroso-oximes can exist in equilibrium in solution in the following tautomer forms:

[0092]

[0093] It should be understood that the scope of this application covers all such isomers or mixtures thereof in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).

[0094] Solid lines may be used in this article. solid wedge Or virtual wedge The chemical bonds of the compounds of the present invention are depicted. Solid lines are used to depict bonds to asymmetric carbon atoms to indicate all possible stereoisomers (e.g., specific enantiomers, racemic mixtures, etc.) at that carbon atom. Solid or dashed wedges are used to depict bonds to asymmetric carbon atoms to indicate the presence of the indicated stereoisomers. When present in racemic mixtures, solid and dashed wedges are used to define relative stereochemistry, not absolute stereochemistry. Unless otherwise specified, the compounds of the present invention are intended to exist as stereoisomers (including cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotational isomers, conformational isomers, trans-blocking isomers, and mixtures thereof). The compounds of the present invention may exhibit more than one type of isomerism and may consist of mixtures thereof (e.g., racemic mixtures and diastereomer pairs).

[0095] This invention covers all possible crystalline forms or polymorphs of the compounds of this invention, which may be a single polymorph or a mixture of more than one polymorph in any proportion.

[0096] Cocrystal refers to the combination of active pharmaceutical molecules and other physiologically acceptable acids, bases, salts, and nonionic compound molecules in the same crystal lattice via hydrogen bonds, π-π stacking interactions, van der Waals forces, and other non-covalent bonds.

[0097] It should also be understood that certain compounds of the present invention may exist in their free form for therapeutic purposes, or, where appropriate, in their pharmaceutically acceptable derivative forms. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, N-oxides, metabolites, or prodrugs, which, upon administration to a patient in need, can directly or indirectly provide the compounds of the present invention or their metabolites or residues. Therefore, when referring to "compounds of the present invention" herein, it is also intended to encompass the various derivative forms of the compounds described above.

[0098] Pharmaceutically acceptable salts of the compounds of the present invention include their acid addition salts and base addition salts.

[0099] Pharmaceutically acceptable salts of the compounds of the present invention include their acid addition salts and base addition salts. For a review of suitable salts, see Stahl and Wermuth, “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” (Wiley-VCH, 2002).

[0100] As used herein, the term "ester" means an ester derived from the various general formula compounds of this application, including physiologically hydrolyzable esters (the compounds of the present invention that can be hydrolyzed under physiological conditions to release free acids or alcohols). The compounds of the present invention may themselves also be esters.

[0101] The compounds of the present invention can exist as solvates (preferably hydrates), wherein the compounds of the present invention contain a polar solvent, particularly, for example, water, methanol, or ethanol, as a structural element of the lattice of the compound. The amount of the polar solvent, particularly water, can be stoichiometric or non-stoichiometric.

[0102] Those skilled in the art will understand that not all nitrogen-containing heterocycles can form N-oxides because nitrogen requires available lone pairs of electrons to be oxidized to oxides. Those skilled in the art will identify nitrogen-containing heterocycles capable of forming N-oxides. Those skilled in the art will also recognize that tertiary amines can form N-oxides. Synthetic methods for preparing N-oxides of heterocycles and tertiary amines are well known to those skilled in the art, including but not limited to the oxidation of heterocycles and tertiary amines using peroxy acids such as peracetic acid and m-chloroperoxybenzoic acid (MCPBA), hydrogen peroxide, alkyl peroxides such as tert-butyl peroxide, sodium perborate, and dioxiranes such as dimethyldioxirane. These methods for preparing N-oxides have been extensively described and reviewed in the literature, see, for example: T.L. Gilchrist, Comprehensive Organic Synthesis, vol. 7, pp. 748-750; A.R. Katritzky and A.J. Boulton, Eds., Academic Press; and G.W. H. Heeseman and E.S. G. Wierstiuk, Advances in Heterocyclic Chemistry, vol. 22, pp. 390-392, A.R. Katritzky and A.J. Boulton, Eds., Academic Press.

[0103] The scope of this invention also includes metabolites of the compounds of this invention, i.e., substances formed in the body when the compounds of this invention are administered. Such products can be generated, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, etc., of the administered compound. Therefore, this invention includes metabolites of the compounds of this invention, including compounds obtained by methods that expose the compounds of this invention to mammals for a time sufficient to produce their metabolites.

[0104] This invention further includes, within its scope, prodrugs of the compounds of this invention, which are certain derivatives of the compounds of this invention that may themselves have little or no pharmacological activity, and which, when administered to or onto the body, can be converted, for example, by hydrolysis and cleavage into the compounds of this invention having the desired activity. Typically, such prodrugs are functional group derivatives of the compounds that are readily converted in vivo into the compounds with the desired therapeutic activity. Further information regarding the use of prodrugs can be found in “Pro-drugs as Novel Delivery Systems,” Vol. 14, ACS Symposium Series (T. Higuchi and V. Stella). The prodrugs of this invention can be prepared, for example, by replacing suitable functional groups present in the compounds of this invention with certain portions known to those skilled in the art as “pro-moiety” (e.g., as described in “Design of Prodrugs,” H. Bundgaard (Elsevier, 1985)).

[0105] This invention also covers compounds of the invention containing protecting groups. In any process of preparing the compounds of the invention, protection of sensitive or reactive groups on any relevant molecule may be necessary and / or desired, thereby forming a form of chemical protection for the compounds of the invention. This can be achieved by conventional protecting groups, for example, those described in T.W. Greene & P. ​​G. W. M. Uts, *Protective Groups in Organic Synthesis*, John Wiley & Sons, 1991, which are incorporated herein by reference. Protecting groups can be removed at appropriate subsequent stages using methods known in the art.

[0106] The term “about” means within ±10% of the stated value, preferably within ±5%, and more preferably within ±2%.

[0107] compound

[0108] In some embodiments, the present invention provides compounds of Formula I or thereof, or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, isotopically labeled compounds, polymorphs, solvates, N-oxides, metabolites, or prodrugs thereof:

[0109]

[0110] in:

[0111] X 1 X 2 and X 3 Each is independently selected from N and CR 3 ;

[0112] Ring A is selected from C 6-10 Aryl, 5-10 membered heteroaryl and 5-8 membered heterocyclic;

[0113] L is selected from bond, -C(=O)-, -S(=O)-, -S(=O)2- and -(CR 4 R 5 ) n -;

[0114] R 1 Selected from C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10-membered heteroaryl groups, wherein the cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each optionally selected independently from one or more halogens, D, -OH, -CN, -NR. 6 R 7 -CD3, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Substitution of cycloalkoxy groups and 3-8 membered heterocyclic groups;

[0115] R 2 Each occurrence is independently selected from H, D, halogen, -OH, -CN, -NR. 6 R 7 -C(=O)NR 6 R 7 -C(=O)R 8 -NHC(=O)R 8 -S(=O)R 8 -S(=O)2R 8 C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 2-6 Heteroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl groups, wherein the alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heteroalkyl, hydroxyalkyl, hydroxyalkoxy, cycloalkyl, cycloalkoxy, heterocyclic, aryl, and heteroaryl groups are each optionally bound by one or more R groups.a replace;

[0116] R 3 Each occurrence is independently selected from H, D, halogen, -OH, -CN, -NH2, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl and 3-6 membered heterocyclic groups, wherein the alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, cycloalkyl and heterocyclic groups are each optionally selected independently by one or more halogens, D, OH, CN, -NH2 and C. 1-6 Alkyl substituents;

[0117] R 4 and R 5 Each time it appears, it is independently selected from H, D, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 2-6 Heteroalkyl, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups, or R 4 and R 5 Together with the carbon atom to which it is attached, it forms a 3-8 membered cycloalkyl or a 4-8 membered heterocyclic group, wherein the alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heteroalkyl, hydroxyalkyl, cycloalkyl, and heterocyclic group are each optionally selected independently by one or more halogens, D, OH, CN, -NH2, C. 1-6 Alkyl and C 1-6 Substituents of haloalkyl groups;

[0118] R 6 and R 7 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups, or R 6 and R 7 Together with the nitrogen atom it is attached to, it forms a 3-8 membered heterocyclic group;

[0119] R 8 Each occurrence is independently selected from H, -OH, -NH2, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8Cycloalkyl and 3-6 membered heterocyclic groups, wherein the alkyl, haloalkyl, cycloalkyl and heterocyclic groups are each optionally selected independently from one or more halogens, D, OH, CN, -NH2 and C. 1-6 Alkyl substituents;

[0120] R a Each occurrence is independently selected from H, D, halogen, =O, -OH, -CN, -NR. 6 R 7 -C(=O)NR 6 R 7 C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl and 3-6 membered heterocyclic groups, wherein the alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, cycloalkyl and heterocyclic groups are each optionally selected independently by one or more halogens, D, OH, CN, -NH2 and C. 1-6 Alkyl substituents;

[0121] m can be 0, 1, 2, or 3;

[0122] n can be 0, 1, 2, or 3, provided that L is a bond or n is 0, and X 1 X 2 and X 3 When both are CH: (1) at least one R 2 Selected from D, -OH, -CN, -NR 6 R 7 -C(=O)NR 6 R 7 -C(=O)R 8 -NHC(=O)R 8 -S(=O)R 8 -S(=O)2R 8 C 2-4 alkenyl, C 2-4 alkynyl group, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 Heteroalkyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl groups, wherein the alkenyl, alkynyl, hydroxyalkyl, hydroxyalkoxy, haloalkoxy, heteroalkyl, cycloalkoxy, heterocyclic, aryl, and heteroaryl groups are each optionally surrounded by one or more R groups. a Replacement; preferably, at least one R 2Selected from D, -OH, -CN, -NR 6 R 7 -C(=O)NR 6 R 7 -C(=O)R 8 -NHC(=O)R 8 -S(=O)R 8 -S(=O)2R 8 C 2-4 alkenyl, C 2-4 alkynyl group, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl groups, wherein the alkenyl, alkynyl, hydroxyalkoxy, haloalkoxy, cycloalkoxy, heterocyclic, aryl, and heteroaryl groups are each optionally surrounded by one or more R groups. a Replace; and / or (2)R 1 C 3-8 cycloalkyl or C 6-10 The aryl group, wherein the cycloalkyl group and the aryl group are each optionally composed of one or more elements independently selected from halogen, D, -OH, -CN, -NR. 6 R 7 -CD3, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Substitution of cycloalkoxy groups and 3-8 membered heterocyclic groups; and / or (3)R 1 It is a 3-8 membered heterocyclic group or a 5-10 membered heteroaryl group, wherein each heterocyclic group and heteroaryl group is independently separated by at least one group selected from D, -OH, -CN, -NR. 6 R 7 -CD3, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-8 Substitution with cycloalkoxy groups and 3-8 membered heterocyclic groups.

[0123] In some embodiments, the compound of formula I provided by the present invention,

[0124] X 1 X 2 and X 3 Each is independently selected from N and CR 3 ;

[0125] Ring A is selected from C 6-10Aryl, 5-10 membered heteroaryl and 5-8 membered heterocyclic;

[0126] L is selected from bond, -C(=O)-, -S(=O)-, -S(=O)2- and -(CR 4 R 5 ) n -;

[0127] R 1 Selected from C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10-membered heteroaryl groups, wherein the cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each optionally selected independently from one or more halogens, D, -OH, -CN, -NR. 6 R 7 -CD3, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Substitution of cycloalkoxy groups and 3-8 membered heterocyclic groups;

[0128] R 2 Each occurrence is independently selected from H, D, halogen, -OH, -CN, -NR. 6 R 7 -C(=O)NR 6 R 7 -C(=O)R 8 -NHC(=O)R 8 -S(=O)R 8 -S(=O)2R 8 C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 2-6 Heteroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl groups, wherein the alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heteroalkyl, hydroxyalkyl, hydroxyalkoxy, cycloalkyl, cycloalkoxy, heterocyclic, aryl, and heteroaryl groups are each optionally bound by one or more R groups. a replace;

[0129] R3 Each occurrence is independently selected from H, D, halogen, -OH, -CN, -NH2, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl and 3-6 membered heterocyclic groups, wherein the alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, cycloalkyl and heterocyclic groups are each optionally selected independently by one or more halogens, D, OH, CN, -NH2 and C. 1-6 Alkyl substituents;

[0130] R 4 and R 5 Each time it appears, it is independently selected from H, D, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 2-6 Heteroalkyl, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups, or R 4 and R 5 Together with the carbon atom to which it is attached, it forms a 3-8 membered cycloalkyl or a 4-8 membered heterocyclic group, wherein the alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heteroalkyl, hydroxyalkyl, cycloalkyl, and heterocyclic group are each optionally selected independently by one or more halogens, D, OH, CN, -NH2, C. 1-6 Alkyl and C 1-6 Substituents of haloalkyl groups;

[0131] R 6 and R 7 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups, or R 6 and R 7 Together with the nitrogen atom it is attached to, it forms a 3-8 membered heterocyclic group;

[0132] R 8 Each occurrence is independently selected from H, -OH, -NH2, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8Cycloalkyl and 3-6 membered heterocyclic groups, wherein the alkyl, haloalkyl, cycloalkyl and heterocyclic groups are each optionally selected independently from one or more halogens, D, OH, CN, -NH2 and C. 1-6 Alkyl substituents;

[0133] R a Each occurrence is independently selected from H, D, halogen, =O, -OH, -CN, -NR. 6 R 7 C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl and 3-6 membered heterocyclic groups, wherein the alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, cycloalkyl and heterocyclic groups are each optionally selected independently by one or more halogens, D, OH, CN, -NH2 and C. 1-6 Alkyl substituents;

[0134] m can be 0, 1, 2, or 3;

[0135] n can be 0, 1, 2, or 3, provided that L is a bond or n is 0, and X 1 X 2 and X 3 When both are CH: (1) at least one R 2 Selected from D, -OH, -CN, -NR 6 R 7 -C(=O)NR 6 R 7 -C(=O)R 8 -NHC(=O)R 8 -S(=O)R 8 -S(=O)2R 8 C 2-4 alkenyl, C 2-4 alkynyl group, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 Heteroalkyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl groups, wherein the alkenyl, alkynyl, hydroxyalkyl, hydroxyalkoxy, haloalkoxy, heteroalkyl, cycloalkoxy, heterocyclic, aryl, and heteroaryl groups are each optionally surrounded by one or more R groups. a Replacement; preferably, at least one R 2 Selected from D, -OH, -CN, -NR 6 R 7-C(=O)NR 6 R 7 -C(=O)R 8 -NHC(=O)R 8 -S(=O)R 8 -S(=O)2R 8 C 2-4 alkenyl, C 2-4 alkynyl group, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl groups, wherein the alkenyl, alkynyl, hydroxyalkoxy, haloalkoxy, cycloalkoxy, heterocyclic, aryl, and heteroaryl groups are each optionally surrounded by one or more R groups. a Replace; and / or (2)R 1 C 3-8 cycloalkyl or C 6-10 The aryl group, wherein the cycloalkyl group and the aryl group are each independently and optionally separated by one or more elements selected from halogen, D, -OH, -CN, -NR. 6 R 7 -CD3, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Substitution of cycloalkoxy groups and 3-8 membered heterocyclic groups; and / or (3)R 1 It is a 3-8 membered heterocyclic group or a 5-10 membered heteroaryl group, wherein each heterocyclic group and heteroaryl group is independently separated by at least one group selected from D, -OH, -CN, -NR. 6 R 7 -CD3, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-8 Substitution with cycloalkoxy groups and 3-8 membered heterocyclic groups.

[0136] In some embodiments, in the compound of formula I provided by the present invention, R 3 Each occurrence is independently selected from H, D, halogen, -OH, -CN, -NH2, and C. 1-4 Alkyl, C 3-6 Cycloalkyl and 3-6 membered heterocyclic groups, wherein each alkyl, cycloalkyl and heterocyclic group is optionally selected independently from one or more halogens, D, OH, CN, -NH2 and C. 1-6 Alkyl substituents.

[0137] In some embodiments, in the compound of formula I provided by the present invention, R 3 Each time it appears, it is independently selected from H, D, halogen, -OH, -CN, -NH2, and C. 1-4 Alkyl group, which is optionally substituted with one or more substituents selected independently from halogens, D, OH, CN and NH2.

[0138] In some embodiments, in the compound of formula I provided by the present invention, R 3 Each of these elements is independently selected from H, D, halogens, -OH, and -NH2 each time it appears.

[0139] In some embodiments, in the compound of formula I provided by the present invention, R 3 Each of them is independently selected from H, -OH, and -NH2 each time it appears.

[0140] In some embodiments, in the compound of formula I provided by the present invention, R 3 Each occurrence is independently represented by H.

[0141] In some embodiments, in the compound of formula I provided by the present invention, X 1 X 2 and X 3 Each is independently selected from CH and N.

[0142] In some embodiments, in the compound of formula I provided by the present invention, X 1 Selected from CH and N.

[0143] In some embodiments, in the compound of formula I provided by the present invention, X 1 For CH.

[0144] In some embodiments, in the compound of formula I provided by the present invention, X 1 Let N be the number of elements in the array.

[0145] In some embodiments, in the compound of formula I provided by the present invention, X 2 Selected from CH and N.

[0146] In some embodiments, in the compound of formula I provided by the present invention, X 2 For CH.

[0147] In some embodiments, in the compound of formula I provided by the present invention, X 2 Let N be the number of elements in the array.

[0148] In some embodiments, in the compound of formula I provided by the present invention, X 3 Selected from CH and N.

[0149] In some embodiments, in the compound of formula I provided by the present invention, X 3 For CH.

[0150] In some embodiments, in the compound of formula I provided by the present invention, X 3 Let N be the number of elements in the array.

[0151] In some embodiments, in the compound of formula I provided by the present invention, X 1 X 2 and X 3 All are CH.

[0152] In some embodiments, in the compound of formula I provided by the present invention, X 1 For CH, X 2 Let N be the number of elements, and X be the number of elements. 3 For CH.

[0153] In some embodiments, in the compound of formula I provided by the present invention, ring A is selected from C 6-10 Aryl, 5-10 membered heteroaryl, and 5-8 membered saturated or partially saturated heterocyclic groups. In some embodiments, the 5-8 membered saturated or partially saturated heterocyclic groups do not contain an aromatic ring.

[0154] In some embodiments, in the compound of formula I provided by the present invention, ring A is selected from C 6-10 The heteroaryl group, 5-10 membered heteroaryl group, and 5-8 membered saturated or partially saturated heterocyclic group may each optionally contain one, two, or three heteroatoms independently selected from O, N, and S. In some embodiments, the 5-8 membered saturated or partially saturated heterocyclic group herein does not contain an aromatic ring.

[0155] In some embodiments, in the compound of formula I provided by the present invention, ring A is selected from C 6-10 Aryl, 5-10 membered heteroaryl and 5-8 membered saturated heterocyclic group, wherein each heteroaryl and heterocyclic group optionally comprises one, two or three heteroatoms independently selected from O, N and S.

[0156] In some embodiments, in the compound of formula I provided by the present invention, ring A is selected from C 6-10 The aryl group, 5-10 membered heteroaryl group, and 5-8 membered saturated heterocyclic group, wherein each heteroaryl group and heterocyclic group optionally comprises one, two, or three heteroatoms independently selected from O and N.

[0157] In some embodiments, in the compound of formula I provided by the present invention, ring A is a 5-10 membered heteroaryl or a 5-8 membered saturated heterocyclic group, wherein the heteroaryl and heterocyclic group optionally each comprises one, two or three heteroatoms each independently selected from O and N.

[0158] In some embodiments, in the compound of formula I provided by the present invention, ring A is C. 6-10 Aryl or 5-10 heteroaryl compounds.

[0159] In some embodiments, in the compound of formula I provided by the present invention, ring A is a 5-6 membered heteroaryl group.

[0160] In some embodiments, in the Formula I compound provided by the present invention, ring A is a 5-8 member saturated heterocyclic group.

[0161] In some embodiments, in the compound of formula I provided by the present invention, ring A is a 5-6 member saturated heterocyclic group.

[0162] In some embodiments, in the compound of formula I provided by the present invention, ring A is a 5-6 membered heteroaryl or a 5-6 membered saturated heterocyclic group, each of which contains one, two or three heteroatoms independently selected from O, N and S.

[0163] In some embodiments, in the Formula I compound provided by the present invention, ring A is selected from pyrazolyl, pyridinyl, oxazolyl, thiazolyl, pyrimidinyl, and tetrahydropyrroleyl.

[0164] In some embodiments, in the Formula I compound provided by the present invention, ring A is selected from pyrazolyl, pyridinyl, oxazolyl, and thiazolyl.

[0165] In some embodiments, in the compound of formula I provided by the present invention, ring A is selected from... Where * represents the connection site with L.

[0166] In some embodiments, in the compound of formula I provided by the present invention, ring A is selected from... Where * represents the connection site with L.

[0167] In some embodiments, in the compounds of formula I provided by the present invention, L is selected from bonds, -C(=O)-, -S(=O)2- and -(CR 4 R 5 )-.

[0168] In some embodiments, in the compounds of formula I provided by the present invention, L is selected from bonds, -C(=O)- and -(CR-). 4 R 5 )-.

[0169] In some embodiments, in the compound of formula I provided by the present invention, L is selected from -C(=O)-, -S(=O)2- and -(CR 4 R 5 )-.

[0170] In some embodiments, in the compound of formula I provided by the present invention, L is -C(=O)-, and ring A is a 5-6 membered heteroaryl or a 5-6 membered saturated heterocyclic group.

[0171] In some embodiments, in the compound of formula I provided by the present invention, L is -(CR 4 R 5 )-, ring A is a 5-6 membered heteroaryl group (e.g., pyrazole).

[0172] In some embodiments, in the Formula I compounds provided by the present invention, L is a bond and ring A is a 5-6 membered heteroaryl group (e.g., pyridine or pyrimidine).

[0173] In some embodiments, the compound of formula I provided by the present invention, Selected from

[0174] In some embodiments, the compound of formula I provided by the present invention, Selected from

[0175] In some embodiments, in the compound of formula I provided by the present invention, R 4 and R 5 Each time it appears, it is independently selected from H, D, and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

[0176] In some embodiments, in the compound of formula I provided by the present invention, R 4 and R 5 Each occurrence is independently assigned the value C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups.

[0177] In some embodiments, in the compound of formula I provided by the present invention, R 4 and R 5 Each occurrence is independently assigned the value C. 1-6 Alkyl, for example, methyl.

[0178] In some embodiments, in the compound of formula I provided by the present invention, R 1 Selected from 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 membered heteroaryl, wherein each of the heterocyclic group, aryl group and heteroaryl group is optionally selected independently from one or more halogens, D, -OH, -CN, -NR. 6 R 7 -CD3, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Substitution with cycloalkoxy groups and 3-8 membered heterocyclic groups.

[0179] In some embodiments, in the compound of formula I provided by the present invention, R 1 Selected from 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 membered heteroaryl, wherein each of the heterocyclic group, aryl group and heteroaryl group is optionally selected independently from one or more halogens, D, -OH, -CN, -NH2, -CD3, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Substitution with cycloalkyl and 3-8 membered heterocyclic groups.

[0180] In some embodiments, in the compound of formula I provided by the present invention, R 1 Selected from C 6-10 Aryl and 5-10 heteroaryl groups, wherein each aryl and heteroaryl group is optionally selected independently from one or more halogens, D, -OH, -CN, -NR. 6 R 7 -CD3, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Substitution with cycloalkoxy groups and 3-8 membered heterocyclic groups.

[0181] In some embodiments, in the compound of formula I provided by the present invention, R 1 Selected from C 6-10 Aryl and 5-10 heteroaryl groups, wherein each of the aryl and heteroaryl groups is optionally selected independently from one or more halogens, D, -CD3, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Substitution with cycloalkyl and 3-8 membered heterocyclic groups.

[0182] In some embodiments, in the compound of formula I provided by the present invention, R 1 The heteroaryl group is 5-10 nucleotides, wherein the heteroaryl group is optionally selected by one or more elements, each independently selected from halogen, D, -CD3, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Substitution with cycloalkyl and 3-8 membered heterocyclic groups.

[0183] In some embodiments, in the compound of formula I provided by the present invention, R 1It is a 5-6 membered heteroaryl group (e.g., triazolyl, pyrazolyl, pyridinyl, oxazolyl, thiazolyl, and pyrimidinyl), wherein the heteroaryl group is optionally selected by one or more elements, each independently selected from halogen, D, -CD3, C. 1-6 Alkyl, C 1-6 Halogenated alkyl and C 3-6 Substitution of cycloalkyl groups.

[0184] In some embodiments, in the compound of formula I provided by the present invention, R 1 It is a 5-membered heteroaryl group, wherein the heteroaryl group is optionally composed of one or more components each independently selected from -CD3, C 1-6 Alkyl and C 1-6 Substitution of alkyl halogens.

[0185] In some embodiments, in the compound of formula I provided by the present invention, R 1 Selected from 5-membered heteroaryl groups, wherein the heteroaryl group is optionally surrounded by one or more C groups. 1-4 Alkyl substitution.

[0186] In some embodiments, in the compound of formula I provided by the present invention, R 1 for

[0187] In some embodiments, in the compound of formula I provided by the present invention, R 1 The heterocyclic group is a 3-8 membered heterocyclic group, wherein the heterocyclic group is optionally selected by one or more elements, each independently selected from halogen, D, -OH, -CN, -NR. 6 R 7 -CD3, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Substitution with cycloalkoxy groups and 3-8 membered heterocyclic groups.

[0188] In some embodiments, in the compound of formula I provided by the present invention, R 1 The heterocyclic group is a 3-8 membered heterocyclic group, wherein the heterocyclic group is optionally selected by one or more elements, each independently selected from halogen, D, -OH, -CN, -NH2, -CD3, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 cycloalkyl and C 3-8 Substituents of cycloalkoxy groups.

[0189] In some embodiments, in the compound of formula I provided by the present invention, R 1It is a 3-8 membered heterocyclic group, wherein the heterocyclic group comprises 1, 2 or 3 heteroatoms, and the heterocyclic group is optionally composed of one or more atoms independently selected from halogen, D, -OH, -CN, -NH2, -CD3, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 cycloalkyl and C 3-8 Substituents of cycloalkoxy groups.

[0190] In some embodiments, in the compound of formula I provided by the present invention, R 1 It is a 3-8 membered heterocyclic group, wherein the heterocyclic group contains one heteroatom, and the heterocyclic group is optionally composed of one or more elements independently selected from halogen, D, -OH, -CN, -NH2, -CD3, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 cycloalkyl and C 3-8 Substituents of cycloalkoxy groups.

[0191] In some embodiments, in the compound of formula I provided by the present invention, R 1 It is a 3-8 membered heterocyclic group, wherein the heterocyclic group contains one heteroatom, and the heterocyclic group is optionally composed of one or more elements independently selected from halogen, -OH, -CN, -NH2, C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 1-6 Substitution of alkoxy groups.

[0192] In some embodiments, in the compound of formula I provided by the present invention, R 1 The group is selected from tetrahydropyrrole, tetrahydrofuran, tetrahydrothiophene, and piperazinone, wherein each of the tetrahydropyrrole, tetrahydrofuran, tetrahydrothiophene, and piperazinone groups is optionally selected by one or more groups independently from halogen, -OH, -CN, -NH2, C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 1-6 Substitution of alkoxy groups.

[0193] In some embodiments, in the compound of formula I provided by the present invention, R 1 Selected from tetrahydropyrrole, tetrahydrofuran, and tetrahydrothiophene, wherein each of the tetrahydropyrrole, tetrahydrofuran, and tetrahydrothiophene groups is optionally selected by one or more elements independently selected from halogen, -OH, -CN, -NH2, C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 1-6Substitution of alkoxy groups.

[0194] In some embodiments, in the compound of formula I provided by the present invention, R 1 Selected from tetrahydropyrrole, tetrahydrofuran, and tetrahydrothiophene, wherein each of the tetrahydropyrrole, tetrahydrofuran, and tetrahydrothiophene groups is optionally selected by one or more elements independently selected from halogen, -OH, -CN, -NH2, C. 1-4 Alkyl and C 1-4 Substitution of alkoxy groups.

[0195] In some embodiments, in the compound of formula I provided by the present invention, R 1 for

[0196] In some embodiments, in the compound of formula I provided by the present invention, R 1 for

[0197] In some embodiments, in the compound of formula I provided by the present invention, R 1 It is a 5-6 membered heteroaryl or a 3-8 membered heterocyclic group, wherein each heteroaryl and heterocyclic group comprises one, two, or three heteroatoms independently selected from O, N, and S, and the heteroaryl group is optionally composed of one or more heteroatoms independently selected from halogens, D, -CD3, C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 3-6 The cycloalkyl group is substituted with a substituent, wherein the heterocyclic group is optionally replaced by one or more substituents selected from halogens, -OH, -CN, -NH2, C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 1-6 Substitution of alkoxy groups;

[0198] Preferably, the heterocyclic group is selected from tetrahydropyrrole, tetrahydrofuran, tetrahydrothiophene, and piperazinone.

[0199] The heteroaryl group is selected from triazolyl, pyrazolyl, pyridinyl, oxazolyl, thiazolyl, and pyrimidinyl.

[0200] In some embodiments, in the compound of formula I provided by the present invention, R 1 Selected from

[0201] In some embodiments, in the compound of formula I provided by the present invention, R 2 Each occurrence is independently selected from H, D, halogen, -OH, -CN, -NR. 6 R 7 -C(=O)NR 6 R 7-C(=O)R 8 -NHC(=O)R 8 -S(=O)R 8 -S(=O)2R 8 C 1-6 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 2-4 Heteroalkyl, C 1-4 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl groups, wherein the alkyl, haloalkyl, alkoxy, haloalkoxy, heteroalkyl, hydroxyalkyl, hydroxyalkoxy, cycloalkyl, cycloalkoxy, heterocyclic, aryl and heteroaryl groups are each optionally bound by one or more R groups. a replace.

[0202] In some embodiments, in the compound of formula I provided by the present invention, R 2 Each occurrence is independently selected from H, D, halogen, -CN, -NR. 6 R 7 -C(=O)NR 6 R 7 -C(=O)R 8 -NHC(=O)R 8 -S(=O)R 8 -S(=O)2R 8 C 1-6 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 2-4 Heteroalkyl, C 1-4 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic groups, C 6-10 aryl and 5-6-membered heteroaryl, wherein the alkyl, haloalkyl, alkoxy, haloalkoxy, heteroalkyl, hydroxyalkyl, hydroxyalkoxy, cycloalkyl, cycloalkoxy, heterocyclic, aryl and heteroaryl groups are each optionally bound by one or more R a replace.

[0203] In some embodiments, in the compound of formula I provided by the present invention, R 2Each time it appears, it is independently selected from H, D, halogen, -OH, -CN, -NH2, -NHCH3, -C(=O)NH2, -C(=O)CH3, -NHC(=O)CH3, -S(=O)2NH2, C 1-6 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 2-4 Heteroalkyl, C 1-4 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl groups, wherein the alkyl, haloalkyl, alkoxy, haloalkoxy, heteroalkyl, hydroxyalkyl, hydroxyalkoxy, cycloalkyl, cycloalkoxy, heterocyclic, aryl and heteroaryl groups are each optionally bound by one or more R groups. a replace.

[0204] In some embodiments, in the compound of formula I provided by the present invention, R 2 Each occurrence is independently selected from H, D, halogen, -CN, -NH2, -C(=O)NH2, -C(=O)CH3, -NHC(=O)CH3, -S(=O)2NH2, C 1-6 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 2-4 Heteroalkyl, C 1-4 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic groups, and 5-6 membered heteroaryl groups, wherein the alkyl, haloalkyl, alkoxy, haloalkoxy, heteroalkyl, hydroxyalkyl, hydroxyalkoxy, cycloalkyl, cycloalkoxy, heterocyclic, and heteroaryl groups are each optionally surrounded by one or more R groups. a replace.

[0205] In some embodiments, in the compound of formula I provided by the present invention, R 2 Each time it appears, it is independently selected from H, halogen, -OH, -CN, -NH2, -NHCH3, -C(=O)NH2, -C(=O)CH3, -NHC(=O)CH3, -S(=O)2NH2, C 1-6 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 2-4 Heteroalkyl, C 1-6 Hydroxyalkoxy, C3-8 cycloalkyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic groups, and 5-10 membered heteroaryl groups, wherein the alkyl, haloalkyl, alkoxy, heteroalkyl, hydroxyalkoxy, cycloalkyl, cycloalkoxy, heterocyclic, and heteroaryl groups are each optionally surrounded by one or more R groups. a replace.

[0206] In some embodiments, in the compound of formula I provided by the present invention, R 2 Each occurrence is independently selected from H, -OH, halogen, -CN, -NH2, -NHCH3, -C(=O)NH2, -C(=O)CH3, -S(=O)2NH2, C 1-6 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-6 Hydroxyalkoxy, C 2-4 Heteroalkyl, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic groups, and 5-6 membered heteroaryl groups, wherein the alkyl, haloalkyl, alkoxy, hydroxyalkoxy, heteroalkyl, cycloalkyl, cycloalkoxy, heterocyclic, and heteroaryl groups are each optionally surrounded by one or more R groups. a replace.

[0207] In some embodiments, in the compound of formula I provided by the present invention, R 2 Each occurrence is independently selected from H, halogens, -CN, -NH2, -C(=O)NH2, -S(=O)2NH2, C 1-6 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-6 Hydroxyalkoxy, C 2-4 Heteroalkyl, 3-8-membered heterocyclic and 5-6-membered heteroaryl, wherein the alkyl, haloalkyl, alkoxy, hydroxyalkoxy, heteroalkyl, heterocyclic and heteroaryl are each optionally surrounded by one or more R a replace.

[0208] In some embodiments, in the compound of formula I provided by the present invention, R a Each occurrence is independently selected from H, D, halogen, =O, -OH, -CN, -NR. 6 R 7 -C(=O)NR 6 R 7 C 1-6 Alkyl and C 1-6 The alkyl group and the haloalkyl group are each optionally composed of one or more elements independently selected from halogens, D, OH, CN, -NH2, and C. 1-6 Alkyl substituents.

[0209] In some embodiments, in the compound of formula I provided by the present invention, R a Each time it appears, it is independently selected from H, D, halogen, -OH, -NH2, -C(=O)NHCH3, C 1-4 Alkyl and C 1-4 The alkyl group and the haloalkyl group are each optionally composed of one or more elements independently selected from halogens, D, OH, CN, -NH2, and C. 1-4 Alkyl substituents.

[0210] In some embodiments, in the compound of formula I provided by the present invention, R a Each time it appears, it is independently selected from H, D, halogen, -OH, -NH2, C. 1-4 Alkyl and C 1-4 The alkyl group and the haloalkyl group are each optionally composed of one or more elements independently selected from halogens, D, OH, CN, -NH2, and C. 1-4 Alkyl substituents.

[0211] In some embodiments, in the compound of formula I provided by the present invention, R 6 and R 7 Each time it appears, it is independently selected from H and C. 1-6 Alkyl and C 1-6 Halogenated alkyl, or R 6 and R 7 Together with the nitrogen atom it is attached to, it forms a 3-8 member nitrogen-containing heterocyclic group.

[0212] In some embodiments, in the compound of formula I provided by the present invention, R 8 Each occurrence is independently selected from H, -OH, -NH2, and C. 1-6 Alkyl and C 1-6 The alkyl group and the haloalkyl group are each optionally composed of one or more elements independently selected from halogens, D, OH, CN, -NH2, and C. 1-6 Alkyl substituents.

[0213] In some embodiments, in the compound of formula I provided by the present invention, R 2 Each occurrence is independently selected from H, -OH, -CN, -NH2, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups (e.g., -CHF2 and -CH2CF3), -C(=O)NH2, -S(=O)2NH2, -NHCH3, -C(=O)CH3,

[0214] In some embodiments, in the Formula I compounds provided by the present invention, m is 0, 1, or 2.

[0215] In some embodiments, n is 0 or 1 in the compound of formula I provided by the present invention.

[0216] In some embodiments, the compound of formula I provided by the present invention is a compound of formula IA:

[0217]

[0218] Where X 1 X 2 X 3 R 1 R 2 R 4 R 5 , m, and ring A are as defined above for compounds of formula I.

[0219] In some embodiments, the compound of formula I provided by the present invention is a compound of formula I-A1:

[0220]

[0221] Where R 1 R 2 R 4 R 5 , m, and ring A are as defined above for compounds of formula I.

[0222] In some embodiments, the compound of formula I provided by the present invention is a compound of formula IB:

[0223]

[0224] Where X 1 X 2 X 3 R 1 R 2 , m, and ring A are as defined above for compounds of formula I.

[0225] In some embodiments, the compound of formula I provided by the present invention is a compound of formula I-B1:

[0226]

[0227] Where R 1 R 2 , m, and ring A are as defined above for compounds of formula I.

[0228] In some embodiments, the compound of formula I provided by the present invention is a compound of formula C:

[0229]

[0230] Where X 1 X 2 X 3 R 1 R 2 , m, and ring A are as defined above for compounds of formula I.

[0231] In some embodiments, the compound of formula I provided by the present invention is a compound of formula I-C1:

[0232]

[0233] Where R 1 R 2 , m, and ring A are as defined above for compounds of formula I.

[0234] In some embodiments, the compounds of formula I-C1 provided by this invention satisfy at least one or more of the following:

[0235] (1) At least one R 2 Selected from D, -OH, -CN, -NR 6 R 7 -C(=O)NR 6 R 7 -C(=O)R 8 -NHC(=O)R 8 -S(=O)R 8 -S(=O)2R 8 C 2-4 alkenyl, C 2-4 alkynyl group, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 Heteroalkyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic groups, C 6-10 Aryl groups and 5-10 heteroaryl groups, preferably selected from D, -OH, -CN, -NH2, -C(=O)NH2, -C(=O)CH3, -NHC(=O)CH3, -S(=O)2NH2, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 Heteroalkyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl groups, more preferably selected from -CN, -NH2, -C(=O)NH2, -S(=O)2NH2, C 1-6Hydroxyalkoxy, 3-8 membered heterocyclic group, 5-10 membered heteroaryl, wherein the alkenyl, alkynyl, hydroxyalkyl, hydroxyalkoxy, haloalkoxy, heteroalkyl, cycloalkoxy, heterocyclic, aryl, and heteroaryl groups are each optionally surrounded by one or more R a replace;

[0236] Preferably, at least one R 2 Selected from D, -OH, -CN, -NR 6 R 7 -C(=O)NR 6 R 7 -C(=O)R 8 -NHC(=O)R 8 -S(=O)R 8 -S(=O)2R 8 C 2-4 alkenyl, C 2-4 alkynyl group, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic groups, C 6-10 Aryl groups and 5-10 heteroaryl groups, preferably selected from D, -OH, -CN, -NH2, -C(=O)NH2, -C(=O)CH3, -NHC(=O)CH3, -S(=O)2NH2, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl groups, wherein the alkenyl, alkynyl, hydroxyalkoxy, haloalkoxy, cycloalkoxy, heterocyclic, aryl, and heteroaryl groups are each optionally surrounded by one or more R groups. a replace;

[0237] (2)R 1 C 3-8 cycloalkyl or C 6-10 The aryl group, wherein the cycloalkyl group and the aryl group are each optionally composed of one or more elements independently selected from halogen, D, -OH, -CN, -NR. 6 R 7 -CD3, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Substitution of cycloalkoxy groups and 3-8 membered heterocyclic groups;

[0238] (3)R1 It is a 3-8 membered heterocyclic group or a 5-10 membered heteroaryl group, wherein each heterocyclic group and heteroaryl group is independently separated by at least one group selected from D, -OH, -CN, -NR. 6 R 7 -CD3, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-8 Substitution with cycloalkoxy groups and 3-8 membered heterocyclic groups.

[0239] In some embodiments, in the compounds of formula I-C1 provided by the present invention, at least one R 2 Selected from -OH, -NHCH3, -CN, -NH2, -C(=O)NH2, -C(=O)CH3, -S(=O)2NH2, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic groups (e.g., piperazinyl, piperidinyl, tetrahydropyrrolyl, morpholinyl, azirrobutyl), and 5-10 membered heteroaryl groups (e.g., pyrazolyl, isothiazolyl, pyrazinyl), wherein each of the hydroxyalkoxy, cycloalkoxy, heterocyclic, and heteroaryl groups is optionally surrounded by one or more R a replace.

[0240] In some embodiments, in the compounds of formula I-C1 provided by the present invention, at least one R 2 Selected from -CN, -NH2, -C(=O)NH2, -C(=O)CH3, -S(=O)2NH2, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic groups (e.g., piperazinyl, piperidinyl, tetrahydropyrrolyl, morpholinyl, azirrobutyl), and 5-10 membered heteroaryl groups (e.g., pyrazolyl, isothiazolyl, pyrazinyl), wherein each of the hydroxyalkoxy, cycloalkoxy, heterocyclic, and heteroaryl groups is optionally surrounded by one or more R a replace.

[0241] In some embodiments, in the compounds of formula I-C1 provided by the present invention, at least one R 2 Selected from -CN, -NH2, -C(=O)NH2, -S(=O)2NH2, C 1-6 Hydroxyalkoxy, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic groups (e.g., piperazinyl, piperidinyl, tetrahydropyrrolyl, morpholinyl, azirrobutyl), and 5-10 membered heteroaryl groups (e.g., pyrazolyl, isothiazolyl, pyrazinyl), wherein each of the hydroxyalkoxy, cycloalkoxy, heterocyclic, and heteroaryl groups is optionally surrounded by one or more R a replace.

[0242] In some embodiments, in the compounds of formula I-C1 provided by the present invention, optionally one of R 2 for

[0243] In some embodiments, in the compounds of formula I-C1 provided by the present invention, at least one R 2 Selected from D, -OH, -CN, -NR 6 R 7 -C(=O)NR 6 R 7 -C(=O)R 8 -NHC(=O)R 8 -S(=O)R 8 -S(=O)2R 8 C 2-4 alkenyl, C 2-4 alkynyl group, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 Heteroalkyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl groups, wherein the alkenyl, alkynyl, hydroxyalkyl, hydroxyalkoxy, haloalkoxy, heteroalkyl, cycloalkoxy, heterocyclic, aryl, and heteroaryl groups are each optionally surrounded by one or more R groups. a Replace; optionally, the remaining R 2 One of them is

[0244] In some embodiments, in the compounds of formula I-C1 provided by the present invention, at least one R 2 Selected from D, -OH, -CN, -NR 6 R 7 -C(=O)NR 6 R 7 -C(=O)R 8 -NHC(=O)R 8 -S(=O)R 8 -S(=O)2R 8 C 2-4 alkenyl, C 2-4 alkynyl group, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic groups, C 6-10aryl and 5-10 heteroaryl groups, wherein the alkenyl, alkynyl, hydroxyalkoxy, haloalkoxy, cycloalkoxy, heterocyclic, aryl, and heteroaryl groups are each optionally surrounded by one or more R groups. a Replace; optionally, the remaining R 2 One of them is

[0245] In some embodiments, in the compounds of formula I-C1 provided by the present invention, R a Each time it appears, it is independently selected from D, halogen, -OH, -NH2, -C(=O)NHCH3, C 1-4 Alkyl and C 1-4 The alkyl group and the haloalkyl group are each optionally composed of one or more elements independently selected from halogens, D, OH, CN, -NH2, and C. 1-4 Alkyl substituents.

[0246] In some embodiments, in the compounds of formula I-C1 provided by the present invention, at least one R 2 Selected from -OH, -CN, -NH2, -C(=O)NH2, -S(=O)2NH2, -NHCH3, -C(=O)CH3,

[0247] In some embodiments, in the compounds of formula I-C1 provided by the present invention, R 1 It is a 3-8 membered heterocyclic group, wherein the heterocyclic group is at least composed of a component selected from D, -OH, -CN, or -NR. 6 R 7 -CD3, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-8 Substitution with cycloalkoxy groups and 3-8 membered heterocyclic groups.

[0248] In some embodiments, in the compounds of formula I-C1 provided by the present invention, R 1 It is a 6-8 membered heterocyclic group (e.g., piperazinone group), said heterocyclic group optionally being selected independently by one or more halogens, D, -OH, -CN, -NR. 6 R 7 -CD3, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Substitution with cycloalkoxy groups and 3-8 membered heterocyclic groups.

[0249] In some embodiments, in the compounds of formula I-C1 provided by the present invention, R 1 for

[0250] In some embodiments, in the compounds of formula I-C1 provided by the present invention, R 1 for

[0251] In some embodiments, in the compounds of formula I-C1 provided by the present invention, R 1 It is a 6-8 membered heterocyclic group (e.g., piperazinone group), said heterocyclic group optionally being selected independently by one or more halogens, D, -OH, -CN, -NR. 6 R 7 -CD3, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Substitution of cycloalkoxy groups and 3-8 membered heterocyclic groups;

[0252] Preferably, R 1 for R 2 R 6 R 7 m and ring A are as defined in any of the embodiments described herein.

[0253] In some embodiments, the compound of formula I provided by the present invention is a compound of formula I-C2:

[0254]

[0255] Where R 1 R 2 , m, and ring A are as defined above for compounds of formula I.

[0256] This invention covers any combination of the above embodiments.

[0257] In some embodiments, the compounds of the present invention include, but are not limited to:

[0258]

[0259]

[0260] Preparation method and intermediates

[0261] The compounds of the present invention can be prepared by any method known in the art. Reagents and starting materials are readily available to those skilled in the art. Individual isomers, enantiomers and diastereomers can be separated or resolved at any convenient point in the synthesis by methods such as selective crystallization techniques or chiral chromatography (see, for example, selective crystallization techniques or chiral chromatography (see for example, J. Jacques, et al., "Enantiomers, Racemates, and Resolutions", John Wiley and Sons, Inc., 1981, and E.L. Leel and S.H. Wilen).

[0262] In some embodiments, the present invention provides a method for preparing a compound of formula IB, comprising one or more of the following steps:

[0263] Step 1: Compound IB-1 reacts with (Boc)2O under the action of a base to generate compound IB-2;

[0264]

[0265] Step 2: Compound IB-2 reacts with benzophenone imine via a Buchwald coupling reaction to generate compound IB-3;

[0266]

[0267] Step 3: Compound IB-3 undergoes a reduction reaction to generate compound IB-4;

[0268]

[0269] Step 4: Compound IB-4 undergoes a condensation reaction to generate compound IB-5;

[0270]

[0271] Step 5: Compound IB-5 undergoes deprotection under acidic conditions to generate compound IB;

[0272]

[0273] Among them, R 2a R is arbitrarily protected by the protected base. 2 ;X 1 X 2 X 3 R 1R 2 m, ring A are defined as above; Y 1 It is a halogen, such as fluorine, chlorine, bromine, or iodine, with chlorine being preferred.

[0274] In some implementations, when R 2 When an amino group is present, the protecting group may be an amino protecting group. In some embodiments, the amino protecting group is an alkoxycarbonyl amino protecting group, such as benzyloxycarbonyl (Cbz), tert-butyloxycarbonyl (Boc), methoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilylethoxycarbonyl (Teoc), methoxycarbonyl (or ethoxycarbonyl); or an acyl amino protecting group, such as phthaloyl (Pht), p-toluenesulfonyl (Tos), tert-butylsulfinyl, trifluoroacetyl (Tfa), or o-(p-) Nitrobenzenesulfonyl (Ns), pivaloyl, benzoyl, tert-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, allyloxycarbonyl, trichloroethoxycarbonyl, trimethylsilylethoxycarbonyl, benzyloxycarbonyl, p-methylbenzenesulfonyl, p-nitrobenzenesulfonyl, tert-butyl, trifluoroacetyl, methoxycarbonyl, or ethoxycarbonyl; alkyl amino protecting groups, such as triphenylmethyl (Trt), 2,4-dimethoxybenzyl (Dmb), 4-methoxybenzyl (PMB), benzyl (Bn).

[0275] The reaction conditions for each step are as follows:

[0276] Step 1: Compound IB-1 reacts with (Boc)₂O under the action of a base to generate compound IB-2. The base can be selected from LiHMDS, NaHMDS, KHMDS, NaH, TEA, DIPEA, DMAP, TEA, or a combination of DIPEA and DMAP, etc.; the solvent that can be used is, for example, 1,4-dioxane, DME, DMF, DMAc, NMP, DMSO, THF, DCM, DCE, etc.; and the reaction temperature is from room temperature to 100°C.

[0277] Step 2: Compound IB-2 reacts with benzophenone imine via a Buchwald coupling reaction to generate compound IB-3. The catalysts used in this Buchwald coupling reaction include, for example, combinations of phosphorus ligands such as Pd2(dba)3 with BINAP, dppf, Ruphos, BrettPhos, and Xantphos, or palladium catalysts such as BrettPhos Pd G3 or cataCXiumA Pd G3; bases that can be used include, for example, NaOt-Bu, KOt-Bu, Cs2CO3, CsF, K3PO4, Na2CO3, KOAc, NaHCO3, or K2CO3; solvents that can be used include, for example, 1,4-dioxane or DME; and the reaction temperature is 100°C to 150°C.

[0278] Step 3: Compound IB-3 undergoes a reduction reaction to generate compound IB-4. The reduction conditions for the reduction reaction can be a combination of hydroxylamine hydrochloride and sodium acetate, a combination of Pd / C and hydrogen, etc.; solvents that can be used include, for example, methanol, ethanol, THF, etc.; the reaction temperature is room temperature to 60°C.

[0279] Step 4: Compound IB-4 undergoes a condensation reaction to generate compound IB-5. The condensation conditions can be selected from combinations of condensing agents such as HATU, BOP, PyBOP, CDI, TCFH, triphosgene, phenyl chloroformate, and DIPEA, TEA, NMI, and pyridine, or any combination of POCl3, SOCl2, pyridine, and NaH. Solvents that can be used include, for example, 1,4-dioxane, DME, DMF, DMAc, NMP, DMSO, THF, DCM, DCE, and pyridine. The reaction temperature is 20°C to 60°C, for example, room temperature to 60°C.

[0280] Step 5: Compound IB-5 undergoes deprotection under acidic conditions to generate compound IB; the acid may be an aqueous solution of hydrochloric acid, a 1,4-dioxane solution of 4M HCl, an ethyl acetate solution of 4M HCl, a methanol solution of 4M HCl, an ethanol solution of 4M HCl, trifluoroacetic acid, etc. The reaction temperature is from room temperature (e.g., 20–25°C) to 100°C, preferably from room temperature (e.g., 20–25°C) to 80°C.

[0281] In some embodiments, the present invention provides a method for preparing a compound of formula IB-3, comprising the following steps:

[0282] In the first step, compound IC-1 undergoes a Buchwald coupling reaction to generate compound IC-1-2;

[0283] In the second step, compound IC-1-2 undergoes a substitution reaction to generate compound IB-3;

[0284]

[0285] The reaction conditions for each step are as follows: The catalysts required for the first and second steps can be a combination of phosphorus ligands such as Pd2(dba)3 and BINAP, dppf, Ruphos, BrettPhos, and Xantphos, or palladium catalysts such as BrettPhos Pd G3 or cataCXiumAPd G3; the bases that can be used are, for example, NaOt-Bu, KOt-Bu, Cs2CO3, CsF, K3PO4, Na2CO3, KOAc, NaHCO3, or K2CO3; the solvents that can be used are, for example, 1,4-dioxane or DME; the reaction temperature is 100℃ to 150℃.

[0286] In some embodiments, the present invention provides a method for preparing a compound of formula IC, comprising the following steps:

[0287] Compound IB-1 undergoes a Buchwald coupling reaction to generate compound IC;

[0288]

[0289] Where: Y 1 X 1 X 2 X 3 R 1 R 2 m and ring A are defined as above.

[0290] The conditions for the Buchwald coupling reaction are as follows: the catalyst may be a combination of Pd2(dba)3 with phosphorus ligands such as BINAP, dppf, Ruphos, BrettPhos, and Xantphos, or a palladium catalyst such as BrettPhos Pd G3 or cataCXiumA Pd G3; the base that can be used is, for example, NaOt-Bu, KOt-Bu, Cs2CO3, CsF, K3PO4, Na2CO3, KOAc, NaHCO3, or K2CO3; the solvent that can be used is, for example, 1,4-dioxane or DME; and the reaction temperature is 100°C to 150°C.

[0291] In some embodiments, the present invention provides a method for preparing a compound of formula IC, comprising one or more of the following steps:

[0292] Step 1: Compound IC-1 undergoes a Buchwald coupling reaction to generate compound IC-2;

[0293] Step 2: Compound IC-2 undergoes a Buchwald coupling reaction to generate compound IC-3;

[0294] Step 3: Compound IC-3 undergoes a deprotection reaction to generate compound IC;

[0295]

[0296] Among them, X 1 X 2 X 3 R 1 R 2 m, ring A are defined as above; Y 2The halogen is, for example, fluorine, chlorine, bromine, or iodine, preferably chlorine; PG1 and PG2 are each independently an H or amino protecting group, said amino protecting group being, for example, an alkoxycarbonyl amino protecting group, such as benzyloxycarbonyl (Cbz), tert-butyloxycarbonyl (Boc), methoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilylethoxycarbonyl (Teoc), methoxycarbonyl (or ethoxycarbonyl); acyl amino protecting groups, such as phthaloyl (Pht), p-toluenesulfonyl (Tos), trimethylsilyl (Pht), methoxycarbon ... Fluoroacetyl (Tfa), o-(p-)nitrobenzenesulfonyl (Ns), p-pentanoyl, benzoyl, tert-butoxycarbonyl, 9-fluorenmethoxycarbonyl, allyloxycarbonyl, trichloroethoxycarbonyl, trimethylsilylethoxycarbonyl, benzyloxycarbonyl, p-methylbenzenesulfonyl, p-nitrobenzenesulfonyl, tert-butyl, trifluoroacetyl, methoxycarbonyl, or ethoxycarbonyl; alkyl amino protecting groups, such as triphenylmethyl (Trt), 2,4-dimethoxybenzyl (Dmb), 4-methoxybenzyl (PMB), benzyl (Bn).

[0297] The reaction conditions for each step are as follows:

[0298] The catalysts required for the first and second steps of the reaction can be selected from combinations of phosphorus ligands such as Pd2(dba)3 and BINAP, dppf, Ruphos, BrettPhos, and Xantphos, or palladium catalysts such as BrettPhos Pd G3 or cataCXiumAPd G3; the bases that can be used are, for example, NaOt-Bu, KOt-Bu, Cs2CO3, CsF, K3PO4, Na2CO3, KOAc, NaHCO3, or K2CO3; the solvents that can be used are, for example, 1,4-dioxane or DME; the reaction temperature is 100℃ to 150℃.

[0299] The third step involves removing the protecting group under acidic conditions to generate compound IC. The acid can be an aqueous solution of hydrochloric acid, a 4M HCl solution of 1,4-dioxane, a 4M HCl solution of ethyl acetate, a 4M HCl solution of methanol, a 4M HCl solution of ethanol, trifluoroacetic acid, etc. The reaction temperature is from room temperature to 100°C.

[0300] Those skilled in the art should understand that, depending on the desired product structure, one or more steps in the above preparation method may be omitted, and the order of reaction steps may be appropriately adjusted, and protection / deprotection reaction steps may be added or omitted as needed.

[0301] In some embodiments, the present invention provides a method for preparing a compound of formula I, comprising one or two of the following steps:

[0302] In the first step, compound IB-2 undergoes a Buchwald coupling reaction to generate compound I-1;

[0303] In the second step, compound I-1 undergoes a deprotection reaction to generate compound I.

[0304]

[0305] Among them, X 1 X 2 X 3 R 1 R 2 R 2a m, ring A, L and Y 1 As defined above.

[0306] The catalyst required for the first step reaction can be a combination of phosphorus ligands such as Pd2(dba)3 and BINAP, dppf, Ruphos, BrettPhos, and Xantphos, or palladium catalysts such as BrettPhos Pd G3, cataCXiumA Pd G3, and Pd-PEPPSI-IHept; the bases that can be used are, for example, NaOt-Bu, KOt-Bu, Cs2CO3, CsF, K3PO4, Na2CO3, KOAc, NaHCO3, or K2CO3; the solvents that can be used are, for example, 1,4-dioxane, tert-amyl alcohol, or DME; the reaction temperature is 100℃ to 150℃.

[0307] The acid used for deprotection in the second step can be an aqueous solution of hydrochloric acid, a 4M HCl solution of 1,4-dioxane, a 4M HCl solution of ethyl acetate, a 4M HCl solution of methanol, a 4M HCl solution of ethanol, trifluoroacetic acid, etc. The reaction temperature is from room temperature (e.g., 20–25°C) to 100°C.

[0308] In some embodiments, compound IB-2 undergoes a Buchwald coupling reaction while simultaneously removing the protecting group to generate compound I.

[0309] In some embodiments, the present invention provides a method for preparing a compound of formula I, comprising the following steps: compound IB-4 undergoing a Buchwald coupling reaction to generate compound I-1.

[0310]

[0311] Among them, X 1 X 2 X 3 R 1 R 2 R 2a m, ring A, and L are as defined above.

[0312] The catalyst required for the coupling reaction can be a combination of Pd2(dba)3 with phosphorus ligands such as BINAP, dppf, Ruphos, BrettPhos, and Xantphos, or a palladium catalyst such as BrettPhos Pd G3 or cataCXiumAPd G3; the base that can be used is, for example, NaOt-Bu, KOt-Bu, Cs2CO3, CsF, K3PO4, Na2CO3, KOAc, NaHCO3, or K2CO3; the solvent that can be used is, for example, 1,4-dioxane or DME; the reaction temperature is 100℃ to 150℃.

[0313] In some embodiments, intermediate compounds, or their salts, esters, stereoisomers, tautomers, isotopically labeled compounds, polymorphs, solvates, and N-oxides are provided as follows: (for example) ), (for example) ), (for example) ), (for example) ),

[0314] Among them, Y 1 Y 2 PG1, PG2, X 1 X 2 X 3 R 1 R 2 R 2a m, ring A, and L are as defined above.

[0315] In some embodiments, the above-mentioned intermediate compound or its salt, ester, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, or N-oxide can be used to prepare the compound represented by the general formula herein or its pharmaceutically acceptable form.

[0316] Pharmaceutical compositions, formulations and treatments

[0317] In some embodiments, the present invention provides a pharmaceutical composition comprising a preventive or therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite or prodrug, and one or more pharmaceutically acceptable carriers.

[0318] In some embodiments, the present invention provides a pharmaceutical formulation comprising a preventive or therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug, and one or more pharmaceutically acceptable carriers. The pharmaceutical formulation is preferably a solid, semi-solid, liquid, or gaseous formulation.

[0319] In some embodiments, the pharmaceutical composition or pharmaceutical formulation may also contain one or more other therapeutic agents.

[0320] In some embodiments, the pharmaceutical composition or pharmaceutical preparation is preferably administered orally, intravenously, intra-arterially, subcutaneously, intraperitoneally, intramuscularly, or transdermally.

[0321] In some embodiments, the present invention provides a kit comprising a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, a pharmaceutical composition of the present invention, or a pharmaceutical formulation of the present invention, and optionally instructions for use of the compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, the pharmaceutical composition of the present invention, or the pharmaceutical formulation of the present invention.

[0322] In some embodiments, the present invention provides the use of the compounds of the present invention or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, isotopically labeled compounds, polymorphs, solvates, N-oxides, metabolites or prodrugs of the present invention, or pharmaceutical compositions or pharmaceutical preparations of the present invention, in the preparation of a medicament for the prevention or treatment of diseases or conditions associated with MASTL activity.

[0323] In some embodiments, the present invention provides the use of the compounds of the present invention or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, isotopically labeled compounds, polymorphs, solvates, N-oxides, metabolites or prodrugs of the present invention, or pharmaceutical compositions or pharmaceutical formulations of the present invention, in the preparation of a medicament for modulating (e.g., reducing or inhibiting) MASTL activity.

[0324] In some embodiments, the present invention provides the compounds of the present invention or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, isotopically labeled compounds, polymorphs, solvates, N-oxides, metabolites or prodrugs thereof, or pharmaceutical compositions of the present invention, or pharmaceutical formulations of the present invention, which are used as pharmaceuticals.

[0325] In some embodiments, the present invention provides compounds of the present invention or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, isotopically labeled compounds, polymorphs, solvates, N-oxides, metabolites or prodrugs thereof, or pharmaceutical compositions of the present invention, or pharmaceutical formulations of the present invention, for the prevention or treatment of diseases or conditions associated with MASTL activity.

[0326] In some embodiments, the present invention provides a method for preventing or treating diseases or conditions associated with MASTL activity, the method comprising administering to an individual in need an effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite or prodrug of the present invention, or a pharmaceutical composition of the present invention, or a pharmaceutical formulation of the present invention.

[0327] In some embodiments, the disease or condition associated with MASTL activity is cancer or tumor, preferably cancer or tumor with high MASTL expression.

[0328] In some implementations, the cancer or tumor is preferably lung cancer, pancreatic cancer, breast cancer, ovarian cancer, hepatocellular carcinoma, gastric cancer, colon cancer, head and neck squamous cell carcinoma, prostate cancer, etc.

[0329] In this invention, "pharmaceutically acceptable carrier" refers to a diluent, excipient, vehicle, or medium that is administered co-administered with a therapeutic agent and is suitable, to the extent of reasonable medical judgment, for contact with human and / or other animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications commensurate with a reasonable benefit / risk ratio.

[0330] Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, sterile liquids. Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (1990).

[0331] The pharmaceutical compositions of the present invention can act systemically and / or locally. For this purpose, they can be administered via suitable routes.

[0332] For these routes of administration, the pharmaceutical compositions of the present invention can be administered in suitable dosage forms.

[0333] As used in this article, the term "effective amount" refers to the amount of a compound that, when administered, will alleviate one or more symptoms of the treated condition to some extent.

[0334] The dosing regimen can be adjusted to provide the optimal required response. For example, a single bolus injection can be administered, several fractions can be administered over time, or the dose can be proportionally reduced or increased as indicated by the urgency of the treatment situation. It should be noted that dosage values ​​can vary depending on the type and severity of the condition to be alleviated, and may include single or multiple doses. To further understand, for any given individual, the specific dosing regimen should be adjusted over time based on individual needs and the professional judgment of the person administering the composition or supervising its administration.

[0335] The amount of the compound of the present invention administered will depend on the individual being treated, the severity of the condition or illness, the rate of administration, the disposal of the compound, and the judgment of the prescribing physician. Generally, the effective dose is from about 0.0001 to about 50 mg per kg of body weight per day. In some cases, dose levels not exceeding the upper limit of the foregoing range may be sufficient, while in other cases, larger doses may still be used without causing any harmful side effects, provided that the larger dose is first divided into several smaller doses for administration throughout the day.

[0336] The content or amount of the compound of the present invention in a pharmaceutical composition or pharmaceutical preparation may be from about 0.01 mg to about 1000 mg.

[0337] Unless otherwise stated, as used herein, the term “treating” means to reverse, alleviate, or inhibit the progression of a disease or condition or one or more symptoms of such a disease or condition to which such term is applied, or to prevent such a disease or condition or one or more symptoms of such a disease or condition.

[0338] As used herein, “individual” includes both human and non-human animals. Exemplary human individuals include human individuals suffering from a disease (such as the disease described herein) (referred to as patients) or normal individuals. In this invention, “non-human animals” includes all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock, and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0339] In some embodiments, the pharmaceutical composition or pharmaceutical preparation of the present invention may further comprise one or more additional therapeutic or preventative agents (e.g., other drugs for treating cancer or tumor diseases). In some embodiments, the treatment methods of the present invention may further include administering one or more additional therapeutic or preventative agents (e.g., other drugs for treating cancer or tumor diseases).

[0340] Example

[0341] The present invention is further described below with reference to embodiments, but these embodiments are not intended to limit the scope of the invention.

[0342] The abbreviations used in this article have the following meanings:

[0343]

[0344]

[0345] The compounds of this invention are separated and purified by preparative TLC, silica gel column chromatography, Prep-HPLC and / or fast column chromatography (Flash column chromatography), and their structures are determined by... 1 Confirmation was performed using 1H NMR and / or MS. Reaction monitoring was performed using TLC or LC-MS.

[0346] 1 The H NMR spectroscopy method was performed using a Bruker superconducting nuclear magnetic resonance spectrometer (model AVACE III HD 400MHz).

[0347] LC / MS uses Aglient 1260Infinity / Aglient 6120Quadrupole.

[0348] TLC uses silica gel GF 254 as the stationary phase.

[0349] Column chromatography typically uses 200-300 mesh silica gel (Qingdao Ocean) as the stationary phase.

[0350] The rapid column chromatography method uses the Biotage rapid column chromatograph.

[0351] Prep-HPLC was performed using an Agilent 1260 or Waters 2489 HPLC system, with a Waters SunFire Prep C column. 18 OBD(19mm×150mm×5.0μm), Waters Xbridge Prep C 18 OBD (19mm×150mm×5.0μm) or YMC Actus Triart C 18 (20mm×150mm×5.0μm), column temperature 25℃, detection wavelength 214nm, 254nm or 280nm, mobile phase A is acetonitrile, mobile phase B is 0.05% formic acid aqueous solution or 0.05% ammonium bicarbonate aqueous solution or 0.05% TFA aqueous solution, the volume ratio of the mobile phase is adjusted according to the polarity of the compound; the mobile phase flow rate is 28mL / min.

[0352] The microwave reaction was carried out using the BiotageInitiator microwave reactor.

[0353] In the following examples, unless otherwise specified, the reaction temperature is room temperature (15-30°C).

[0354] The reagents used in this application were purchased from Acros Organics, Aldrich Chemical Company, or TEB Chemicals, etc.

[0355] Synthesis Example:

[0356] Intermediate Int A: N-(3-(2-aminopyridin-4-yl)pent-3-yl)-2-methylpropane-2-sulfinamide

[0357]

[0358] Step 1: Synthesis of 2-methyl-N-(pentyl-3-yl)propane-2-sulfinamide (compound Int A-3)

[0359] Compound Int A-2 (10 g, 82.51 mmol), THF (75 mL), compound Int A-1 (7.11 g, 82.51 mmol), and Ti(OiPr)4 (37.64 g, 165.02 mmol) were added to a reaction flask. The mixture was reacted at 65 °C for 16 hours under nitrogen protection. The reaction solution was diluted with water, resulting in the precipitation of a large amount of solid. The mixture was filtered through a diatomaceous earth filter, and the filtrate was extracted with EA (30 mL x 3). The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (EA:PE = 20:80), and the collected product was evaporated to dryness to obtain compound Int A-3 (11.2 g). MS (ESI, m / z): 190.1 [M+H] + .

[0360] Step 2: Synthesis of N-(3-(2-bromopyridin-4-yl)pent-3-yl)-2-methylpropane-2-sulfinamide (compound IntA-5)

[0361] Compound Int A-4 (8.82 g, 37.24 mmol) and iPr₂O (200 mL) were added to a reaction flask. Under nitrogen protection, the mixture was cooled in a -78°C bath for 10 min. Then, n-BuLi (1.6 M, 23.27 mL) was slowly added dropwise, and the reaction was maintained at this low temperature for 15 min. Next, a THF solution of compound Int A-3 (4.7 g, 24.83 mmol) was added dropwise at low temperature. After the addition was complete, the mixture was allowed to rise to room temperature for 2 hours. The reaction solution was diluted with water and extracted with EA (30 mL x 3). The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (EA:PE = 40:60), and the collected product was evaporated to dryness to obtain compound Int A-5 (5 g). MS (ESI, m / z): 347.1 [M+H] + .

[0362] Step 3: Synthesis of N-(3-(2-((diphenylmethylene)amino)pyridin-4-yl)pentan-3-yl)-2-methylpropane-2-sulfinamide (compound Int A-7)

[0363] Compounds Int A-5 (5.03 g, 14.48 mmol), Int A-6 (3.15 g, 17.38 mmol), palladium acetate (325.15 mg, 1.45 mmol), BINAP (901.79 mg, 1.45 mmol), Cs₂CO₃ (14.16 g, 43.45 mmol), and Tol (120 mL) were added to a reaction flask. The reaction was carried out under nitrogen protection at 110 °C for 16 h. The reaction solution was directly filtered through a diatomaceous earth filter, and the filter cake was washed with EA. The combined filtrates were concentrated to obtain compound Int A-7. MS (ESI, m / z): 448.3 [M+H] + .

[0364] Step 4: Synthesis of N-(3-(2-aminopyridin-4-yl)pent-3-yl)-2-methylpropane-2-sulfinamide (compound IntA)

[0365] Compound Int A-7 (2 g, 3.13 mmol), THF (10 mL), and H₂O (10 mL) were added to a reaction flask. 1M HCl aqueous solution (6.26 mL) was added under ice-water bath conditions. The ice-water bath was then removed, and the reaction was carried out at 25°C for 1 hour. The reaction solution was diluted with water, and the pH was adjusted to 7-8 with sodium bicarbonate. Extraction was performed using EA. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (DCM:MeOH = 95:5), and the collected product was evaporated to dryness to obtain compound Int A (570 mg). MS (ESI, m / z): 284.2 [M+H] + .

[0366] Intermediate Int B: 6-chloro-3-(1-methyl-1H-1,2,3-triazol-5-yl)-2,7-naphthidium-1-amine

[0367]

[0368] Step 1: Synthesis of 6-chloro-4-methylnicotinonitrile (compound Int B-2)

[0369] Compound Int B-1 (5 g, 37.28 mmol), 1,4-dioxane (80 mL), and POCl3 (11.43 g, 74.55 mmol) were added to a reaction flask. The mixture was reacted at 100 °C for 16 h under nitrogen protection. The reaction solution was directly evaporated to dryness, diluted with saturated sodium bicarbonate solution, extracted with EA, and the organic phases were combined. The mixture was washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (EA:PE = 30:70), and the collected product was evaporated to dryness to obtain compound Int B-2 (3.75 g). MS (ESI, m / z): 153.0 [M+H] + .

[0370] Step 2: Synthesis of 6-chloro-4-(2-(1-methyl-1H-1,2,3-triazol-5-yl)-2-oxoethyl)nicotinonitrile (compound Int B-4)

[0371] Compound Int B-2 (500 mg, 3.28 mmol) and THF (10 mL) were added to a reaction flask, dissolved, and then cooled to -78 °C under nitrogen protection. LiHMDS (1 M THF solution, 11.47 mL) was slowly added dropwise. After the addition was complete, the reaction was maintained at low temperature for 30 min. Then, a THF solution of compound Int B-3 (462.47 mg, 3.28 mmol) (4 mL) was added dropwise. After the addition was complete, the temperature bath was removed, and the reaction was allowed to proceed at room temperature for 1 hour. No further treatment was required to obtain compound Int B-4. MS (ESI, m / z): 262.0 [M+H] + .

[0372] Step 3: Synthesis of 6-chloro-3-(1-methyl-1H-1,2,3-triazol-5-yl)-2,7-naphthidine-1-amine (compound Int B)

[0373] Compound Int B-4 (850 mg, 3.25 mmol) was added to a reaction flask, followed by a single addition of NH4OAc (2.50 g, 32.48 mmol). The system was then cooled in an ice-water bath, and AcOH (20 mL) was slowly added dropwise. After the addition was complete, the temperature was raised to 70 °C and the reaction proceeded for 3 hours. Most of the solvent was removed by rotary evaporation, the solution was diluted with water, and the pH was adjusted to 8-9 with Na2CO3. EA (10 mL) was added, and the mixture was stirred vigorously for 30 minutes. The mixture was filtered, and the filter cake was washed successively with water, DCM, and PE, and dried to obtain compound Int B (530 mg). MS (ESI, m / z): 261.1 [M+H] + .

[0374] Intermediate Int C:N-(6-amino-3-(3-methyltriazol-4-yl)-2,7-naphthid-1-yl)-N-tert-butoxycarbonyl-tert-butyl carbamate

[0375]

[0376] Step 1: Synthesis of N-tert-butoxycarbonyl-N-(6-chloro-3-(3-methyltriazol-4-yl)-2,7-naphthid-1-yl)carbamate tert-butyl ester (compound Int C-1)

[0377] Int B (200 mg, 767.22 μmol), DMAP (46.87 mg, 383.61 μmol), and DIEA (594.94 mg, 4.60 mmol) were dissolved in THF (10 mL), and Boc₂O (502.33 mg, 2.30 mmol) was added dropwise. The mixture was heated to 60 °C and reacted for 3 hours. The solvent was removed by vacuum distillation, and the mixture was purified by silica gel column chromatography (PE / EA = 1 / 1). The purified compound, Int C-1 (320 mg), was obtained by rotary evaporation. MS (ESI, m / z): 461.2 [M+H-56] + .

[0378] Step 2: Synthesis of N-(6-(diphenylmethyleneamino)-3-(3-methyltriazol-4-yl)-2,7-naphthid-1-yl)-N-tert-butoxycarbonyl-tert-butyl carbamate (compound Int C-2)

[0379] Compounds Int C-1 (320 mg, 694.27 μmol), Int A-6 (188.74 mg, 1.04 mmol), Xantphos (80.34 mg, 138.85 μmol), Cs₂CO₃ (678.62 mg, 2.08 mmol), and Pd₂(dba)₃ (63.58 mg, 69.43 μmol) were dissolved in 1,4-dioxane (2 mL) and reacted at 100 °C for 4 hours under nitrogen protection. The solvent was removed by vacuum distillation, and the mixture was purified by silica gel column chromatography (PE / EA = 1 / 1). The purified compound was then evaporated to dryness to give Int C-2 (400 mg). MS (ESI, m / z): 606.3 [M+H] + .

[0380] Step 3: Synthesis of N-(6-amino-3-(3-methyltriazol-4-yl)-2,7-naphthid-1-yl)-N-tert-butoxycarbonyl-tert-butyl carbamate (compound Int C)

[0381] Compound Int C-2 (360 mg, 493.33 μmol) was dissolved in methanol (10 mL), and NaOAc (202.35 mg, 2.47 mmol) and HONH2·HCl (137.12 mg, 1.97 mmol) were added. The reaction was carried out at 30 °C for 2 hours. The mixture was diluted with water, extracted with ethyl acetate, and the organic phases were combined. The solvent was removed by vacuum distillation, and the mixture was purified by silica gel column chromatography (PE / EA = 1 / 4). The purified compound Int C (180 mg) was obtained by rotary evaporation. MS (ESI, m / z): 442.2 [M+H] + .

[0382] Int D: 1-Methyl-1H-1,2,3-triazol-5-carboxylic acid

[0383]

[0384] Int D-1 (1.1 g, 7.79 mmol) was dissolved in THF (5 mL), and a solution of LiOH (373.35 mg, 15.59 mmol) in water (2.5 mL) was added dropwise at 0 °C. After the addition was complete, the reaction was carried out at 30 °C for 2 hours. The solution was adjusted to acidity with 2 M HCl aqueous solution, extracted with ethyl acetate, and the organic phases were combined. The organic phase was dried over sodium sulfate, and the solvent was removed by vacuum distillation to obtain Int D (0.92 g). MS (ESI, m / z): 128.2 [M+H] + .

[0385] Intermediate Int E: tert-butylN-(6-((6-bromo-4-(1-(tert-butylsulfinylamino)-1-ethyl-propyl)-2-pyridyl)amino)-3-(3-methyltriazol-4-yl)-2,7-naphthidium-1-yl)-N-tert-butoxycarbonyl-carbamate

[0386]

[0387] Step 1: Synthesis of 2,6-dibromo-N-methoxy-N-methylisonicotinamide (compound Int E-3)

[0388] Compounds Int E-1 (5 g, 17.80 mmol), Int E-2 (3.47 g, 35.60 mmol), and HATU (8.12 g, 21.36 mmol) were dissolved in DMF (50 mL). DIPEA (11.50 g, 89.00 mmol, 15.80 mL) was added, and the mixture was stirred at 25 °C for 5 hours. The reaction was monitored by LC-MS until complete and the target product was formed. The reaction was quenched with water, followed by extraction three times with saturated brine and ethyl acetate. The organic phases were combined, washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (PE / EA = 50 / 50). The purified compound was concentrated to give Int E-3 (5.7 g). MS (ESI, m / z): 324.9 [M+H] + .

[0389] Step 2: Synthesis of 1-(2,6-dibromopyridin-4-yl)prop-1-one (compound Int E-4)

[0390] Compound Int E-3 (5.5 g, 16.98 mmol) was dissolved in THF (50 mL), cooled to 0 °C in an ice bath, and then 13 mL of a 2 M EtMgBr tetrahydrofuran solution was slowly added dropwise. After the addition was complete, the mixture was stirred at 0 °C for 2 hours. LC-MS monitoring showed that the reaction was complete and the target product was formed. The reaction was quenched by adding saturated ammonium chloride aqueous solution, and the mixture was stirred at room temperature for 1 hour. The solution was then directly concentrated and purified by silica gel column chromatography (PE / EA = 80 / 20). The concentrated solution yielded compound Int E-4 (2.92 g), MS (ESI, m / z): 294.0 [M+H]. + .

[0391] Step 3: Synthesis of N-(1-(2,6-dibromopyridin-4-yl)propylidene)-2-methylpropane-2-sulfinamide (compound Int E-5)

[0392] Compounds Int E-4 (2.92 g, 8.47 mmol), Int A-2 (2.05 g, 16.94 mmol), and Ti(OiPr)4 (4.82 g, 16.94 mmol) were dissolved in THF (50 mL), purged with nitrogen, and the mixture was heated to 75 °C and reacted for 16 hours. The reaction was monitored by LC-MS until complete and the target product was formed. After quenching with water, the mixture was directly concentrated and purified by silica gel column chromatography (PE / EA = 50 / 50). The concentrated product yielded compound Int E-5 (1.94 g), MS (ESI, m / z): 396.9 [M+H]. + .

[0393] Step 4: Synthesis of N-(3-(2,6-dibromopyridin-4-yl)pent-3-yl)-2-methylpropane-2-sulfinamide (compound Int E-6)

[0394] Compound Int E-5 (1.94 g, 4.90 mmol) was dissolved in THF (20 mL), and a 2 MEtMgBr tetrahydrofuran solution (3.67 mL) was slowly added dropwise under ice bath conditions. After the addition was complete, the mixture was stirred at 0 °C for 3 hours. LC-MS monitoring showed that the reaction was complete and the target product was formed. The reaction was quenched by adding saturated ammonium chloride aqueous solution, and the mixture was stirred at room temperature for 1 hour. The solution was then directly concentrated and purified by silica gel column chromatography (PE / EA = 50 / 50). The concentrated solution yielded compound Int E-6 (1.6 g), MS (ESI, m / z): 427.0 [M+H]. + .

[0395] Step 5: Synthesis of tert-butyl N-(6-((6-bromo-4-(1-(tert-butylsulfinylamino)-1-ethyl-propyl)-2-pyridyl)amino)-3-(3-methyltriazol-4-yl)-2,7-naphthid-1-yl)-N-tert-butoxycarbonyl-carbamate (compound Int E)

[0396] Compounds Int E-6 (72.41 mg, 169.88 μmol), Int C (50 mg, 113.25 μmol), Cs₂CO₃ (110.70 mg, 339.76 μmol), and Brettphos Pd G₃ (10.27 mg, 11.33 μmol) were dissolved in 1,4-dioxane (5 mL). After purging with nitrogen, the mixture was heated to 120 °C and reacted for 3 hours. LC-MS analysis showed product formation. The mixture was cooled to room temperature, concentrated, and purified by silica gel column chromatography (DCM / MeOH = 95 / 5). The concentrated product yielded compound Int E (50 mg). MS (ESI, m / z): 786.2 [M+H] + .

[0397] Example 1: N 6 -(2-(1-(difluoromethyl)-1H-pyrazol-3-yl)propyl-2-yl)-3-(1-methyl-1H-1,2,3-triazol-5-yl)-2,7-naphthidium-1,6-diamine

[0398]

[0399] Step 1: Synthesis of 2-(1H-pyrazol-3-yl)prop-2-ol (compounds 1-2)

[0400] Compound 1-1 (3.5 g, 24.98 mmol) and THF (80 mL) were added to a reaction flask. After completely purging with nitrogen, the reaction solution was cooled to 0 °C using an ice bath. Then, ethyl magnesium bromide (1 M, 99.90 mL) was slowly added dropwise. After the addition was complete, the temperature was raised to 60 °C and stirred for 2 hours. After the reaction was complete, a saturated sodium bicarbonate aqueous solution was added to quench the reaction. The mixture was extracted with dichloromethane / methanol at a ratio of 10:1, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain compound 1-2 (2.8 g). MS (ESI, m / z): 127.1 [M+H] + .

[0401] Step 2: Synthesis of 2-(1-(difluoromethyl)-1H-pyrazol-3-yl)prop-2-ol (compounds 1-3)

[0402] Compounds 1-2 (2.3 g, 18.23 mmol) and CsF (2.41 g, 36.46 mmol) were dissolved in acetonitrile (17 mL), and compound 28-4 (4.87 g, 18.23 mmol, 3.24 mL) was added dropwise. After the addition was complete, the mixture was stirred at 25 °C for 16 h. After the reaction was complete, EA was added to dilute the reaction solution, followed by the addition of saturated NaHSO4 solution, washing with saturated brine, drying over anhydrous sodium sulfate, filtering, and evaporating to dryness to obtain compound 1-3 (2.3 g). MS (ESI, m / z): 177.1 [M+H] + .

[0403] Step 3: Synthesis of 2-chloro-N-(2-(1-(difluoromethyl)-1H-pyrazol-3-yl)propyl-2-yl)acetamide (compounds 1-4)

[0404] Compounds 1-3 (2.3 g, 13.06 mmol) were dissolved in TFA (10 mL), and chloroacetonitrile (1.97 g, 26.11 mmol, 1.65 mL) was added dropwise at room temperature. After the addition was complete, the mixture was heated to 50 °C and stirred for 16 hours. After the reaction was complete, the reaction solution was evaporated to dryness, diluted with water, adjusted to alkali with sodium bicarbonate, extracted three times with ethyl acetate, the solvent was removed by vacuum distillation, and column chromatography (DCM / MeOH = 5 / 1) was performed. The solution was then evaporated to dryness to give compounds 1-4 (2.2 g). MS (ESI, m / z): 252.1 [M+H] + .

[0405] Step 4: Synthesis of 2-(1-(difluoromethyl)-1H-pyrazol-3-yl)propyl-2-amine (compounds 1-5)

[0406] Compounds 1-4 (2.2 g, 8.74 mmol) were dissolved in ethanol (10 mL) and acetic acid (1 mL). Thiourea (798.52 mg, 10.49 mmol) was added at room temperature. After the addition was complete, the mixture was heated to 75 °C and stirred for 3 hours. After the reaction was complete, the reaction solution was evaporated to dryness. The solution was diluted with a DCM:MeOH mixture (10:1), and the organic phase was washed successively with saturated sodium bicarbonate aqueous solution and saturated brine. The solution was dried over anhydrous sodium sulfate, filtered, evaporated to dryness, purified by flash (base), extracted with a DCM:MeOH mixture (10:1), and the solvent was removed by vacuum distillation to obtain compounds 1-5 (0.7 g). MS (ESI, m / z): 176.1 [M+H] + .

[0407] Step 5: N 6 Synthesis of -(2-(1-(difluoromethyl)-1H-pyrazol-3-yl)propyl-2-yl)-3-(1-methyl-1H-1,2,3-triazol-5-yl)-2,7-naphthidine-1,6-diamine (compound 1)

[0408] Compounds Int C-1 (111.32 mg, 241.51 μmol) and 1-5 (110 mg, 627.93 μmol) were dissolved in tert-amyl alcohol (10 mL), and Pd-PEPPSI-IHept (23.49 mg, 24.15 μmol) and Cs₂CO₃ (236.07 mg, 724.53 μmol) were added. The reaction was carried out overnight at 120 °C under nitrogen protection. The solvent was removed by vacuum distillation, and the mixture was separated by TLC (DCM:MeOH = 200:16). Compound 1 (5 mg) was prepared and lyophilized. MS (ESI, m / z): 400.2 [M+H] + .

[0409] 1H NMR(400MHz, DMSO-d6)δ9.01(s,1H),8.08(s,1H),8.04(d,J=2.8Hz,1H),7.90–7.60(t,J=120Hz,1 H),7.15–7.08(m,3H),6.86(s,1H),6.32(d,J=2.8Hz,1H),6.20(s,1H),4.31(s,3H),1.69(s,6H).

[0410] Example 4: N-(8-amino-6-(1-methyl-1H-1,2,3-triazol-5-yl)-2,7-naphthidin-3-yl)-1-(difluoromethyl)-1H-pyrazole-3-carboxamide

[0411]

[0412] Step 1: Synthesis of N-(tert-butoxycarbonyl)(6-(1-(difluoromethyl)-1H-pyrazole-3-carboxamido)-3-(1-methyl-1H-1,2,3-triazol-5-yl)-2,7-naphthidin-1-yl)carbamate (compound 4-2)

[0413] Int C (30 mg, 67.95 μmol) and compound 4-1 (13.22 mg, 81.54 μmol) were dissolved in pyridine (0.5 mL), and phosphorus oxychloride (31.26 mg, 203.86 μmol) was added. The mixture was stirred at 25 °C for 4 hours. Post-treatment: Pyridine was removed by concentration, ethyl acetate was added, and the mixture was filtered. The filtrate was concentrated to give compound 4-2 (20 mg). MS (ESI, m / z): 586.3. [M+H] + .

[0414] Step 2: Synthesis of N-(8-amino-6-(1-methyl-1H-1,2,3-triazol-5-yl)-2,7-naphthidin-3-yl)-1-(difluoromethyl)-1H-pyrazole-3-carboxamide (compound 4)

[0415] Compound 4-2 (20 mg, 34.16 μmol) was dissolved in DCM (1 mL), and dioxane hydrochloride (4 M, 2 mL) was added. The mixture was stirred at 25 °C for 2 hours. The solvent was removed by concentration, and compound 4 (10 mg) was prepared by pre-HPLC and lyophilized. MS (ESI, m / z): 386.1 [M+H] + .

[0416] 1H NMR (400MHz, DMSO-d6) δ10.23(s,1H),9.45(s,1H),8.47(d,J=2.8Hz,1H),8.39(d,J=0.8Hz,1H),8 .25(s,1H),7.98(t,J=58.8Hz,1H),7.64(s,2H),7.47(s,1H),7.20(d,J=2.8Hz,1H),4.40(s,3H).

[0417] The following compounds were prepared by referring to the method and general steps described in Example 4. Other required raw materials can be purchased commercially or obtained by experienced synthesizers from commercially available reagents using conventional reactions.

[0418]

[0419] Example 7: 3-(1-methyl-1H-1,2,3-triazol-5-yl)-N 6 -(4-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)-2,7-naphthidium-1,6-diamine

[0420]

[0421] Step 1: Synthesis of 4-(1-methyl-1H-pyrazol-3-yl)pyridin-2-amine (compound 7-3)

[0422] Compound 7-1 (150 mg, 681.59 μmol), compound 7-2 (109.74 mg, 681.59 μmol), CataCXiumA Pd G3 (49.64 mg, 68.16 μmol), K2CO3 (282.60 mg, 2.04 mmol), 1,4-dioxane (3 mL), and H2O (0.5 mL) were added to a reaction flask. After completely purging with nitrogen, the mixture was heated to 100 °C and reacted for 16 hours. After the reaction was complete, the solvent was removed by vacuum distillation, followed by column chromatography (DCM / MeOH = 92 / 8), and the solution was evaporated to dryness to give compound 7-3 (89 mg). MS (ESI, m / z): 175.1 [M+H] + .

[0423] Step 2: 3-(1-Methyl-1H-1,2,3-triazol-5-yl)-N 6 Synthesis of -(4-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)-2,7-naphthidine-1,6-diamine (compound 7)

[0424] Compound 7-3 (21.05 mg, 120.84 μmol), Int B (35 mg, 120.84 μmol), BrettPhos PdG3 (10.95 mg, 12.08 μmol), Cs₂CO₃ (78.74 mg, 241.67 μmol), and 1,4-dioxane (3 mL) were added to a reaction flask. After purging with nitrogen, the mixture was heated to 100 °C and reacted for 16 hours. The solid in the reaction solution was filtered off, and the solvent was removed by vacuum distillation. Compound 7 (2.76 mg) was prepared and lyophilized. MS (ESI, m / z): 399.2 [M+H] + .

[0425] 1 H NMR (400MHz, DMSO-d6) δ9.94(s,1H),9.32(s,1H),8.31–8.28(m,2H),8.22(s,1H),7.82(d,J=2.2 Hz,1H),7.77(s,1H),7.34(s,2H),7.28(m,2H),6.75(d,J=2.3Hz,1H),4.39(s,3H),3.93(s,3H).

[0426] The following compounds were prepared by referring to the method and general steps described in Example 7. Other required raw materials can be purchased commercially or obtained by experienced synthesizers from commercially available reagents using conventional reactions.

[0427]

[0428]

[0429] Example 10: 2-((8-amino-6-(1-methyl-1H-1,2,3-triazol-5-yl)-2,7-naphthid-3-yl)amino)isonicotinamide

[0430]

[0431] Step 1: Synthesis of 2-((8-amino-6-(1-methyl-1H-1,2,3-triazol-5-yl)-2,7-naphthid-3-yl)amino)isonicotinonitrile (compound 10-2)

[0432] Compound 10⁻¹ (57.58 mg, 483.35 μmol), Int B (35 mg, 120.84 μmol), BrettPhos PdG₃ (10.95 mg, 12.08 μmol), Cs₂CO₃ (118.11 mg, 362.51 μmol), and 1,4-dioxane (3 mL) were added to a reaction flask. After purging with nitrogen, the mixture was heated to 100 °C and reacted for 16 hours. After the reaction was complete, the solvent (DCM / MeOH = 96 / 4) was removed by vacuum distillation, and the mixture was evaporated to dryness to give compound 10⁻² (40 mg). MS (ESI, m / z): 344.2 [M+H] + .

[0433] Step 2: Synthesis of 2-((8-amino-6-(1-methyl-1H-1,2,3-triazol-5-yl)-2,7-naphthid-3-yl)amino)isonicotinamide (compound 10)

[0434] Compound 10⁻² (35 mg, 92.15 μmol), methanol (2 mL), H₂O (2 mL), and K₂CO₃ (50.94 mg, 368.61 μmol) were added to a reaction flask, followed by dropwise addition of H₂O₂ (41.79 mg, 368.61 μmol). The reaction was carried out at 25 °C for 1 hour. After the reaction was complete, the solid in the reaction solution was filtered off, the solvent was removed by vacuum distillation, and the product was prepared and lyophilized to obtain compound 10 (8.6 mg). MS (ESI, m / z): 362.0 [M+H] + .

[0435] 1 H NMR (400MHz, DMSO-d6) δ10.16(s,1H),9.33(s,1H),8.39(d,J=5.2Hz,1H),8.24(d,J=5.6Hz,2H),8.13 (s,1H),7.77(s,1H),7.64(s,1H),7.38(s,2H),7.28(s,1H),7.26(dd,J=5.3,1.4Hz,1H),4.39(s,3H).

[0436] Example 11: 2-((8-amino-6-(1-methyl-1H-1,2,3-triazol-5-yl)-2,7-naphthid-3-yl)amino)pyridine-4-sulfonamide

[0437]

[0438] Step 1: Synthesis of tert-butyl (4-(benzylthio)pyridin-2-yl)carbamate (compound 11-3)

[0439] Compound 11-1 (0.5 g, 1.33 mmol), compound 11-2 (246.89 mg, 1.99 mmol), Pd2(dba)3 (121.35 mg, 132.52 μmol), Xantphos (153.36 mg, 265.04 μmol), DIPEA (342.54 mg, 2.65 mmol), and 1,4-dioxane (6 mL) were added to a reaction flask. After purging with nitrogen, the mixture was heated to 100 °C and reacted for 16 hours. After the reaction was complete, the solvent was removed by vacuum distillation, followed by column chromatography (PE / EA = 9 1 / 9), and the solution was evaporated to dryness to give the title compound 11-3 (340 mg). MS (ESI, m / z): 317.1 [M+H] + .

[0440] Step 2: Synthesis of (4-(chlorosulfonyl)pyridin-2-yl)carbamate tert-butyl ester (compound 11-4)

[0441] Compound 11-3 (280 mg, 884.91 μmol), AcOH (4 mL), H₂O (1 mL), and HCl (1 M, 2 mL) were added to a reaction flask, followed by NCS (614.44 mg, 4.60 mmol). The reaction was carried out at 25 °C for 1 hour. After the reaction was complete, the mixture was purified by column chromatography (PE:EA = 90 / 10) and evaporated to dryness to give the title compound 11-4 (145 mg). MS (ESI, m / z): 237.0 [M-55] + .

[0442] Step 3: Synthesis of (4-aminosulfonylpyridin-2-yl)tert-butyl carbamate (compounds 11-5)

[0443] Compound 11-4 (120 mg, 409.92 μmol) and ammonia (1 mL) were added to a reaction flask and reacted at 50 °C for 1 hour. After the reaction was complete, the solution was evaporated to dryness to give the title compound 11-5 (110 mg). MS (ESI, m / z): 274.1 [M+H] + .

[0444] Step 4: Synthesis of 2-aminopyridine-4-sulfonamide (compound 11-6)

[0445] Compound 11-5 (110 mg, 402.48 μmol) and a 1 mL solution of 1,4-dioxane in 4 M HCl were added to a reaction flask, and the mixture was reacted at 40 °C for 2 hours. After the reaction was complete, the reaction solution was filtered and evaporated to dryness to obtain the title compound (80 mg). MS (ESI, m / z): 174.0 [M+H] + .

[0446] Step 5: Synthesis of 2-((8-amino-6-(1-methyl-1H-1,2,3-triazol-5-yl)-2,7-naphthidin-3-yl)amino)pyridine-4-sulfonamide (compound 11)

[0447] Compound 11-6 (41.86 mg, 241.67 μmol), Int B (35 mg, 120.84 μmol), BrettPhos PdG3 (10.95 mg, 12.08 μmol), Cs₂CO₃ (196.85 mg, 604.18 μmol), and 1,4-dioxane (3 mL) were added to a reaction flask. After purging with nitrogen, the mixture was heated to 100 °C and reacted for 16 hours. After the reaction was complete, a 4 M HCl solution of 1,4-dioxane (2 mL) was added, and the reaction solution was diluted with methanol (10 mL). The insoluble solids were then filtered off, the organic phase was evaporated to dryness, and compound 11 (0.59 mg) was prepared by lyophilization. MS (ESI, m / z): 398.1 [M+H] + .

[0448] 1 H NMR (400MHz, DMSO-d6) δ10.41(s,1H),9.35(s,1H),8.50(d,J=5.3Hz,1H),8.34(s,2H),8.23(s,1H),8.2 0(s,1H),7.89(s,1H),7.66(s,2H),7.42(s,2H),7.30(s,1H),7.25(dd,J=5.3,1.4Hz,1H),4.39(s,3H).

[0449] Example 14: 1-(6-((8-amino-6-(1-methyl-1H-1,2,3-triazol-5-yl)-2,7-naphthidin-3-yl)amino)-4-(3-aminopentan-3-yl)pyridin-2-yl)-4-methylpiperidin-4-ol)

[0450]

[0451] Step 1: Synthesis of N-(3-(2-chloro-6-(4-hydroxy-4-methylpiperidin-1-yl)pyridin-4-yl)pent-3-yl)-2-methylpropane-2-sulfinamide (compound 14-2)

[0452] Compound 15-2 (500 mg, 1.48 mmol), compound 14-1 (187.80 mg, 1.63 mmol), and CsF (293.95 mg, 4.45 mmol) were dissolved in NMP (5 mL) and reacted overnight at 100 °C. The mixture was cooled, diluted with ethyl acetate, washed with dilute brine, dried over sodium sulfate, and the solvent was removed by vacuum distillation. The mixture was then subjected to column chromatography (DCM:MeOH = 93:7), and evaporated to dryness to give compound 14-2 (0.5 g). MS (ESI, m / z): 416.2 [M+H] + .

[0453] Step 2: Synthesis of N-(3-(2-((diphenylmethylene)amino)-6-(4-hydroxy-4-methylpiperidin-1-yl)pyridin-4-yl)pent-3-yl)-2-methylpropane-2-sulfinamide (compound 14-3)

[0454] Compound 14-2 (500 mg, 1.20 mmol) and compound Int A-6 (326.73 mg, 1.80 mmol) were dissolved in 1,4-dioxane (10 mL), and Cs₂CO₃ (1.17 g, 3.61 mmol), Pd₂(dba)₃ (110.06 mg, 120.19 μmol), and Xantphos (139.08 mg, 240.37 μmol) were added. The reaction was carried out at 120 °C for 6 hours under nitrogen protection. The solvent was removed by vacuum distillation, and the mixture was subjected to column chromatography (EA:PE = 70:30). The solution was evaporated to dryness to give compound 14-3 (600 mg). MS (ESI, m / z): 561.3 [M+H] + .

[0455] Step 3: Synthesis of N-(3-(2-amino-6-(4-hydroxy-4-methylpiperidin-1-yl)pyridin-4-yl)pent-3-yl)-2-methylpropane-2-sulfinamide (compound 14-4)

[0456] Compound 14-3 (0.6 g, 748.94 μmol) was dissolved in MeOH (6 mL), and sodium acetate (307.19 mg, 3.74 mmol) and hydroxylamine hydrochloride (208.18 mg, 3.00 mmol) were added. The reaction was carried out at room temperature for 1 hour. The solvent was removed by vacuum distillation, followed by column chromatography (EA:PE = 100:0), and the solution was evaporated to dryness to give compound 14-4 (280 mg). MS (ESI, m / z): 397.3 [M+H] + .

[0457] Step 4: Synthesis of N-(3-(2-((8-amino-6-(1-methyl-1H-1,2,3-triazol-5-yl)-2,7-naphthidin-3-yl)amino)-6-(4-hydroxy-4-methylpiperidin-1-yl)pyridin-4-yl)pent-3-yl)-2-methylpropane-2-sulfinamide (compound 14-5)

[0458] Compound Int B (59.16 mg, 226.94 μmol) and compound 14-4 (90 mg, 226.94 μmol) were dissolved in 1,4-dioxane (10 mL), and Cs₂CO₃ (221.82 mg, 680.81 μmol) and BrettPhos Pd G₃ (20.57 mg, 22.69 μmol) were added. The reaction was carried out overnight at 100 °C under nitrogen protection. The solvent was removed by vacuum distillation, and the mixture was subjected to column chromatography (DCM:MeOH = 90:10). The solution was evaporated to dryness to give compound 14-5 (21 mg). MS (ESI, m / z): 621.4 [M+H] + .

[0459] Step 5: Synthesis of 1-(6-((8-amino-6-(1-methyl-1H-1,2,3-triazol-5-yl)-2,7-naphthidin-3-yl)amino)-4-(3-aminopentan-3-yl)pyridin-2-yl)-4-methylpiperidin-4-ol (compound 14)

[0460] Compound 14-5 (21.00 mg, 33.83 μmol) was dissolved in DCM (3 mL), and a 1,4-dioxane solution of 4 M HCl (3 mL) was added dropwise. The reaction was carried out at room temperature for 2 hours. The solvent was removed by vacuum distillation, and the solution was adjusted to alkali with ammonia-methanol solution. Compound 14 (9 mg) was then lyophilized. MS (ESI, m / z): 517.3 [M+H] + .

[0461] 1 H NMR(400MHz,DMSO-d6)δ10.21(s,2H),9.53(s,1H),9.28(s,1H),8.20(d,J =2.8Hz,1H),8.16(s,1H),7.34(s,2H),7.00(s,1H),6.55(s,1H),6.40(s, 1H),4.36(s,3H),3.85(d,J=12.4Hz,2H),3.47(s,2H),1.81–1.74(m,2H), 1.70–1.62(m,2H),1.62–1.52(m,4H),1.18(s,3H),0.74(t,J=7.3Hz,6H).

[0462] Example 15: 2-((6-((8-amino-6-(1-methyl-1H-1,2,3-triazol-5-yl)-2,7-naphthid-3-yl)amino)-4-(3-aminopent-3-yl)pyridin-2-yl)oxy)ethanol-1-ol

[0463]

[0464] Step 1: Synthesis of N-(3-(2,6-dichloropyridin-4-yl)pent-3-yl)-2-methylpropane-2-sulfinamide (compound 15-2)

[0465] Compound 15-1 (7.77 g, 34.23 mmol) dissolved in MTBE (150 mL) was added to a reaction flask. Under nitrogen protection, n-BuLi (1.6 M, 21.39 mL) was slowly added dropwise in a -78 °C bath. The reaction was maintained at this low temperature for 20 minutes. Then, a THF solution of compound Int A-3 (5.4 g, 28.52 mmol) in 10 mL was added dropwise at low temperature. After the addition was complete, the mixture was allowed to rise to room temperature for 2 hours. The reaction solution was diluted with water and extracted with EA (200 mL x 3). The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (EA:PE = 60:40), and the collected product was evaporated to dryness to obtain compound 15-2 (5.58 g). MS (ESI, m / z): 337.0 [M+H] + .

[0466] Step 2: Synthesis of N-(3-(2-chloro-6-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridin-4-yl)pent-3-yl)-2-methylpropane-2-sulfinamide (compound 15-4)

[0467] Compound 15-3 (176.82 mg, 1.21 mmol) was dissolved in THF (5 mL), and NaH (64.51 mg, 1.61 mmol) was added in portions. After stirring for 10 minutes, compound 15-2 (340 mg, 1.01 mmol) was added, and the reaction was carried out overnight at 80 °C. The reaction was quenched with water, the solvent was removed by vacuum distillation, and the mixture was subjected to column chromatography (EA:PE = 60:40). The solution was evaporated to dryness to give compound 15-4 (430 mg). MS (ESI, m / z): 363.1 [M+H-THP] + .

[0468] Step 3: Synthesis of N-(3-(2-((diphenylmethylene)amino)-6-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridin-4-yl)pentan-3-yl)-2-methylpropane-2-sulfinamide (compound 15-5)

[0469] Compound 15-4 (0.4 g, 894.79 μmol) and compound Int A-6 (194.60 mg, 1.07 mmol) were dissolved in 1,4-dioxane (10 mL), and Xantphos (103.55 mg, 178.96 μmol), Pd2(dba)3 (81.94 mg, 89.48 μmol), and Cs2CO3 (583.08 mg, 1.79 mmol) were added. The reaction was carried out overnight at 110 °C under nitrogen protection. The solvent was removed by vacuum distillation, and the mixture was subjected to column chromatography (EA:PE = 60:40). The solution was evaporated to dryness to give compound 15-5 (440 mg). MS (ESI, m / z): 592.3 [M+H] + .

[0470] Step 4: Synthesis of N-(3-(2-amino-6-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridin-4-yl)pent-3-yl)-2-methylpropane-2-sulfinamide (compound 15-6)

[0471] Compound 15-5 (400 mg, 675.90 μmol) was dissolved in MeOH (10 mL), and sodium acetate (277.23 mg, 3.38 mmol) and hydroxylamine hydrochloride (187.88 mg, 2.70 mmol) were added. The reaction was carried out at room temperature for 1 hour. The solvent was removed by vacuum distillation, followed by column chromatography (EA:PE = 90:10), and the solution was evaporated to dryness to give compound 15-6 (200 mg). MS (ESI, m / z): 428.3 [M+H] + .

[0472] Step 5: Synthesis of N-(3-(2-((8-amino-6-(1-methyl-1H-1,2,3-triazol-5-yl)-2,7-naphthidin-3-yl)amino)-6-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridin-4-yl)pent-3-yl)-2-methylpropane-2-sulfinamide (compound 15-7)

[0473] Compound Int B (55.42 mg, 212.60 μmol) and compound 15-6 (100 mg, 233.86 μmol) were dissolved in 1,4-dioxane (5 mL), and Cs₂CO₃ (207.81 mg, 637.81 μmol) and BrettPhos Pd G₃ (19.27 mg, 21.26 μmol) were added. The reaction was carried out overnight at 100 °C under nitrogen protection. Post-treatment: The solvent was removed by vacuum distillation, followed by column chromatography (DCM:MeOH = 95:5), and the solution was evaporated to dryness to obtain compound 15-7 (30 mg). MS (ESI, m / z): 652.4 [M+H] + .

[0474] Step 6: Synthesis of 2-((6-((8-amino-6-(1-methyl-1H-1,2,3-triazol-5-yl)-2,7-naphthid-3-yl)amino)-4-(3-aminopent-3-yl)pyridin-2-yl)oxy)eth-1-ol (compound 15)

[0475] Compound 15-7 (30 mg, 46.02 μmol) was dissolved in DCM (3 mL), and a 1,4-dioxane solution of 4 M HCl (3 mL) was added dropwise. The reaction was carried out at room temperature for 2 hours. The solvent was removed by vacuum distillation, and the mixture was adjusted to a base with ammonia-methanol solution. The solution was then lyophilized to give compound 15 (10 mg). MS (ESI, m / z): 464.3 [M+H] + .

[0476] 1 H NMR (400MHz, DMSO-d6) δ9.74(s,1H),9.29(d,J=1.2Hz,1H),8.27(d,J=0.8Hz,1 H),8.15(s,1H),7.34(s,2H),7.17(d,J=0.8Hz,1H),6.90(d,J=1.2Hz,1H),6.4 0(d,J=1.2Hz,1H),4.89(t,J=5.2Hz,1H),4.38(t,J=5.2Hz,2H),4.36(s,3H),3 .84–3.84(m,2H),1.73–1.64(m,2H),1.60–1.51(m,2H),0.67(t,J=7.3Hz,6H).

[0477] Example 16: 1-((6-((8-amino-6-(1-methyl-1H-1,2,3-triazol-5-yl)-2,7-naphthid-3-yl)amino)-4-(3-aminopent-3-yl)pyridin-2-yl)oxy)-2-methylprop-2-ol

[0478]

[0479] Step 1: Preparation of methyl 2-((4-methoxybenzyl)oxy)-2-methylpropionate (compound 16-3)

[0480] Compound 16-1 (1 g, 8.47 mmol) was dissolved in DMF (4 mL), and after complete purging with nitrogen, the solution was cooled to 0 °C. Then, NaH (372.47 mg, 9.31 mmol) was added in portions, and the reaction was allowed to proceed for 0.5 hours. Next, compound 16-2 (1.33 g, 8.47 mmol, 1.15 mL) was added, and after the addition was complete, the mixture was heated to 25 °C and reacted overnight. After the reaction was complete, the solution was purified by column chromatography (PE / EA = 95 / 5), and the solution was evaporated to dryness to give compound 16-3 (689 mg). MS (ESI, m / z): 256.2 [M+18] + .

[0481] Step 2: Preparation of 2-((4-methoxybenzyl)oxy)-2-methylprop-1-ol (compound 16-4)

[0482] Compound 16-3 (600 mg, 2.52 mmol) and tetrahydrofuran (5 mL) were added to a reaction flask. After cooling to 0 °C, lithium aluminum hydride (143.36 mg, 3.78 mmol) was added, and the mixture was gradually heated to room temperature and stirred for 2 hours. After the reaction was complete, tetrahydrofuran (10 mL) was added to dilute the reaction solution, followed by the addition of anhydrous sodium sulfate. Water was slowly added dropwise to quench the reaction until no more bubbles appeared. The reaction solution was then filtered through silica gel. The filtrate was evaporated to dryness, and the residue was diluted with EA, filtered through anhydrous sodium sulfate, and the solvent was removed by vacuum distillation to obtain compound 16-4 (550 mg). MS (ESI, m / z): 228.2 [M+18] + .

[0483] Step 3: Preparation of N-(3-(2-chloro-6-(2-((4-methoxybenzyl)oxy)-2-methylpropoxy)pyridin-4-yl)pent-3-yl)-2-methylpropane-2-sulfinamide (compound 16-5)

[0484] Compound 16-4 (479 mg, 2.28 mmol) and tetrahydrofuran (2 mL) were added to a reaction flask. After purging with nitrogen, NaH (121.43 mg, 3.04 mmol) was added under ice bath conditions, and the mixture was stirred for 0.5 hours. Then, compound 15-2 (640 mg, 1.90 mmol) was added, and the mixture was heated to 60 °C and reacted for 4.5 hours. After the reaction was complete, methanol was added to quench the reaction, and the mixture was then purified by column chromatography (PE / EA = 85 / 15). The solvent was removed by vacuum distillation to obtain compound 16-5 (500 mg). MS (ESI, m / z): 511.2 [M+H] + .

[0485] Step 4: Preparation of N-(3-(2-amino-6-(2-((4-methoxybenzyl)oxy)-2-methylpropoxy)pyridin-4-yl)pent-3-yl)-2-methylpropane-2-sulfinamide (compound 16-6)

[0486] Compound 16-5 (160 mg, 313.04 μmol), Pd2(dba)3 (28.67 mg, 31.30 μmol), BINAP (38.98 mg, 62.61 μmol), t-BuONa (90.25 mg, 939.12 μmol), compound Int A-6 (113.47 mg, 626.08 μmol), and 1,4-dioxane (8 mL) were added to a reaction flask. After purging with nitrogen, the mixture was heated to 120 °C and reacted for 16 hours. After the reaction was complete, the mixture was purified by column chromatography (PE / EA = 31 / 69), and the solvent was removed by vacuum distillation to obtain compound 16-6 (107 mg). MS (ESI, m / z): 492.3 [M+H] + .

[0487] Step 5: Preparation of N-(3-(2-((8-amino-6-(1-methyl-1H-1,2,3-triazol-5-yl)-2,7-naphthid-3-yl)amino)-6-(2-((4-methoxybenzyl)oxy)-2-methylpropoxy)pyridin-4-yl)pent-3-yl)-2-methylpropane-2-sulfinamide (compound 16-7)

[0488] Compound Int B (75 mg, 287.71 μmol), compound 16-6 (100 mg, 203.38 μmol), Cs₂CO₃ (198.80 mg, 610.15 μmol), BrettPhos Pd G₃ (36.87 mg, 40.68 μmol), and 1,4-dioxane (1.5 mL) were added to a microwave-safe tube. After purging with nitrogen, the tube was heated to 120 °C and reacted for 4 hours. After the reaction was complete, the mixture was purified by column chromatography (DCM / MeOH = 94 / 6), and the solvent was removed by vacuum distillation to obtain compound 16-7 (28 mg). MS (ESI, m / z): 716.4 [M+H] + .

[0489] Step 6: Preparation of N-(3-(2-((8-amino-6-(1-methyl-1H-1,2,3-triazol-5-yl)-2,7-naphthidin-3-yl)amino)-6-(2-hydroxy-2-methylpropoxy)pyridin-4-yl)pent-3-yl)-2-methylpropane-2-sulfinamide (compound 16-8)

[0490] Compound 16-7 (24 mg, 33.52 μmol), dichloromethane (1 mL), and trifluoroacetic acid (1 mL) were added to a reaction flask and stirred at 25 °C for 2 hours. After the reaction was complete, the pH was adjusted to alkaline by adding saturated sodium bicarbonate aqueous solution. The reaction mixture was then extracted multiple times with EA, and the organic phases were combined, washed with saturated brine, filtered through anhydrous sodium sulfate, and the solvent was removed by vacuum distillation to obtain compound 16-8 (20 mg). MS (ESI, m / z): 596.3 [M+H] + .

[0491] Step 7: Preparation of 1-((6-((8-amino-6-(1-methyl-1H-1,2,3-triazol-5-yl)-2,7-naphthidin-3-yl)amino)-4-(3-aminopent-3-yl)pyridin-2-yl)oxy)-2-methylprop-2-ol (compound 16)

[0492] Compound 16-8 (16 mg, 26.86 μmol) and a 4 M HCl solution of 1,4-dioxane (4 mL) were added to a reaction flask, and the mixture was heated to 60 °C and reacted for 1 hour. After the reaction was complete, the solvent was removed by vacuum distillation, the mixture was adjusted to a base with ammonia-methanol solution, and the solvent was removed by vacuum distillation. Compound 16 (8.96 mg) was then prepared and lyophilized. MS (ESI, m / z): 492.3 [M+H] + .

[0493] 1 H NMR (400MHz, DMSO-d6) δ9.77(s,1H),9.29(s,1H),8.33(s,1H),8.08(s,1H),7.37(s,2H),7.09(s,1H),6.91(s,1H),6.43(d,J=1.2H z,1H),4.70(s,1H),4.37(s,3H),4.16(s,2H),1.75-1.63(m,4H),1.56(dd,J=13.8,7.2Hz,2H),1.27(s,6H),0.68(t,J=7.4Hz,6H).

[0494] Example 19: N 6 -(4-(1H-pyrazol-3-yl)pyridin-2-yl)-3-(1-methyl-1H-1,2,3-triazol-5-yl)-2,7-naphthidium-1,6-diamine

[0495]

[0496] Step 1: Synthesis of 3-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (compound 19-3)

[0497] Compound 19-1 (1 g, 6.80 mmol), compound 19-2 (1.72 g, 20.41 mmol), TsOH·H₂O (129.42 mg, 680.40 μmol), and dichloromethane (15 mL) were added to a reaction flask and reacted at 25 °C for 4 hours. After the reaction was complete, the solvent was removed by vacuum distillation, and the mixture was subjected to C18 column chromatography (H₂O[0.05% NH₄HCO₃] / ACN = 78 / 22). The solution was evaporated to dryness to give compound 19-3 (628 mg). MS (ESI, m / z): 231.1 [M+H] + .

[0498] Step 2: Synthesis of 4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)pyridin-2-amine (compound 19-4)

[0499] Compound 7-1 (150 mg, 681.59 μmol), compound 19-3 (157.51 mg, 681.59 μmol), CataCXiumA Pd G3 (49.64 mg, 68.16 μmol), K2CO3 (282.60 mg, 2.04 mmol), 1,4-dioxane (3 mL), and H2O (0.5 mL) were added to a reaction flask. After completely purging with nitrogen, the mixture was heated to 100 °C and reacted for 16 hours. After the reaction was complete, the solvent was removed by vacuum distillation, followed by column chromatography (DCM / MeOH = 94 / 6), and the solution was evaporated to dryness to give compound 19-4 (89 mg). MS (ESI, m / z): 245.1 [M+H] + .

[0500] Step 3: 3-(1-Methyl-1H-1,2,3-triazol-5-yl)-N 6 Synthesis of -(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)pyridin-2-yl)-2,7-naphthidine-1,6-diamine (compound 19-5)

[0501] Compound 19-4 (32.47 mg, 132.92 μmol), Int B (35 mg, 120.84 μmol), BrettPhos PdG3 (10.95 mg, 12.08 μmol), Cs₂CO₃ (78.74 mg, 241.67 μmol), and 1,4-dioxane (3 mL) were added to a reaction flask. After completely purging with nitrogen, the mixture was heated to 110 °C and reacted for 16 hours. The solid in the reaction solution was filtered off, and the solvent was removed by vacuum distillation to obtain compound 19-5 (32 mg). MS (ESI, m / z): 469.2 [M+H] + .

[0502] Step 4: N 6Synthesis of -(4-(1H-pyrazol-3-yl)pyridin-2-yl)-3-(1-methyl-1H-1,2,3-triazol-5-yl)-2,7-naphthidine-1,6-diamine (compound 19)

[0503] Compound 19-5 (27 mg, 57.63 μmol), 4 M HCl / 1,4-dioxane (1 mL), and 1,4-dioxane (1 mL) were added to a reaction flask and reacted at 25 °C for 1 hour. After the reaction was complete, the solvent was removed by vacuum distillation, the mixture was adjusted to alkali with ammonia-methanol solution, and the solvent was removed by vacuum distillation. The prepared compound was lyophilized to give the title compound (4.36 mg). MS (ESI, m / z): 385.0 [M+H] + .

[0504] 1 H NMR (400MHz, DMSO-d6) δ13.16(s,1H),10.00(s,1H),9.33(s,1H),8.31(br,J=3.4Hz,2H),8.24(s,1H),7.8 8(s,1H),7.82(s,1H),7.37(s,2H),7.32(d,J=5.3Hz,1H),7.28(s,1H),6.77(d,J=2.0Hz,1H),4.40(s,3H).

[0505] Example 20: (R)-1-(1-amino-6-((4-(3-aminopent-3-yl)pyridin-2-yl)amino)-2,7-naphthidin-3-yl)pyrrolidine-3-ol

[0506]

[0507] Step 1: Synthesis of 1-(tert-butyl)-3-methyl-2-(2-chloro-5-(methoxycarbonyl)pyridin-4-yl)malonate (compound 20-3)

[0508] Compound 20-1 (10 g, 48.54 mmol), DMF (100 mL), compound 20-2 (12.68 g, 72.81 mmol), and Cs₂CO₃ (31.63 g, 97.08 mmol) were added to a reaction flask. The mixture was reacted at 40 °C for 3 hours under nitrogen protection. After the reaction was complete, the reaction solution was diluted with water, extracted with EA, and the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 20-3 (16 g). MS (ESI, m / z): 344.1 [M+H] + .

[0509] Step 2: Synthesis of methyl 6-chloro-4-(2-methoxy-2-oxoethyl)nicotinate (compound 20-4)

[0510] Compound 20-3 (16 g, 46.54 mmol), DCM (100 mL), and TFA (40 mL) were added to a reaction flask. The mixture was reacted at 25 °C for 2 hours under nitrogen protection. The reaction solution was directly evaporated to dryness, diluted with water, and the pH was adjusted to 7-8 with saturated NaHCO3 solution. Extraction was performed with EA, and the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 20-4 (10 g). MS (ESI, m / z): 244.0 [M+H] + .

[0511] Step 3: Synthesis of 6-chloro-2,7-naphthidine-1,3(2H,4H)-dione (compound 20-5)

[0512] Compound 20-4 (5.37 g, 22.04 mmol) and ammonia (25 mL) were added to an autoclave, which was then sealed and reacted at 120 °C for 16 hours. After the reaction was complete, a large amount of solid precipitated. The reaction solution was directly concentrated under reduced pressure to obtain compound 20-5 (4.1 g). MS (ESI, m / z): 197.0 [M+H] + .

[0513] Step 4: Synthesis of 1,3,6-trichloro-2,7-naphthidine (compound 20-6)

[0514] Compound 20-5 (1 g, 5.09 mmol), 1,4-dioxane (20 mL), and POCl3 (3.90 g, 25.43 mmol) were added to a reaction flask. The mixture was placed under nitrogen protection and reacted at 100 °C for 16 hours. After the reaction was complete, the reaction solution was directly evaporated to dryness, quenched with water, and the pH was adjusted to 8-9 with Na2CO3. The solution was extracted with EA, the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 20-6 (730 mg).

[0515] Step 5: Synthesis of 3,6-dichloro-N,N-bis(4-methoxybenzyl)-2,7-naphthidine-1-amine (compound 20-8)

[0516] Compound 20-6 (730 mg, 3.13 mmol), DIPEA (808.16 mg, 6.25 mmol), 1,4-dioxane (25 mL), and compound 20-7 (804.55 mg, 3.13 mmol) were added to a reaction flask. The mixture was reacted at 110 °C for 16 hours under nitrogen protection. The reaction solution was diluted with water and extracted with EA (30 mL x 3). The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (DCM:MeOH = 100:0), and the collected product was evaporated to dryness to obtain compound 20-8 (830 mg). MS (ESI, m / z): 455.2 [M+H] + .

[0517] Step 6: Synthesis of N-(3-(2-((8-(bis(4-methoxybenzyl)amino)-6-chloro-2,7-naphthidin-3-yl)amino)pyridin-4-yl)pentan-3-yl)-2-methylpropane-2-sulfinamide (compound 20-9)

[0518] Compound 20-8 (50 mg, 110.05 μmol), Int A (31.19 mg, 110.05 μmol), Pd2(dba)3 (10.08 mg, 11.00 μmol), XantPhos (12.74 mg, 22.01 μmol), Cs2CO3 (71.71 mg, 220.10 μmol), and 1,4-dioxane (2 mL) were added to a reaction flask. The mixture was reacted at 100 °C for 16 hours under nitrogen protection. The reaction solution was directly concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (DCM:MeOH = 98:2), and the collected product was evaporated to dryness to obtain compound 20-9 (70 mg). MS (ESI, m / z): 701.4 [M+H] + .

[0519] Step 7: Synthesis of N-(3-(2-((8-(bis(4-methoxybenzyl)amino)-6-((R)-3-hydroxypyrrolidone-1-yl)-2,7-naphthidin-3-yl)amino)pyridin-4-yl)pentan-3-yl)-2-methylpropane-2-sulfinamide (compound 20-11)

[0520] Compound 20-9 (70 mg, 99.81 μmol), compound 20-10 (24.67 mg, 199.62 μmol), BrettPhos Pd G3 (9.05 mg, 9.98 μmol), Cs₂CO₃ (97.56 mg, 299.44 μmol), and 1,4-dioxane (2 mL) were added to a reaction flask. The mixture was reacted at 100 °C for 16 h under nitrogen protection. The reaction solution was diluted with water, extracted with EA, and the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (DCM:MeOH = 95:5), and the collected product was evaporated to dryness to obtain compound 20-11 (35 mg). MS (ESI, m / z): 752.4 [M+H] + .

[0521] Step 8: Synthesis of (R)-1-(1-amino-6-((4-(3-aminopent-3-yl)pyridin-2-yl)amino)-2,7-naphthidin-3-yl)pyrrolidine-3-ol (compound 20)

[0522] Compound 20-11 (35 mg, 46.54 μmol) and TFA (3 mL) were added to a reaction flask. The mixture was reacted at 80 °C for 3 hours under nitrogen protection. The reaction mixture was directly concentrated under reduced pressure to obtain the crude product. The crude product was purified by pre-HPLC and lyophilized to obtain product compound 20. MS (ESI, m / z): 408.3 [M+H] + .

[0523] 1 H NMR (400MHz, DMSO-d6) δ9.31 (s, 1H), 8.89 (s, 1H), 8.25–8.21 (m, 1H), 8.19 (d, J = 5. 6Hz,1H),7.85(s,1H),7.33(s,1H),6.88(dd,J=5.6,1.6Hz,1H),6.77(s,2H),5.51 (s,1H),4.38–4.34(m,1H),3.49–3.47(m,2H),3.37–3.16(m,2H),2.02–1.94(m,1H ),1.90–1.83(m,1H),1.81–1.73(m,2H),1.69–1.60(m,2H),0.70(t,J=7.2Hz,6H).

[0524] Example 21: N 7 -(4-(3-aminopentan-3-yl)pyridin-2-yl)-2-(1-methyl-1H-1,2,3-triazol-5-yl)pyrido[4,3-d]pyrimidin-4,7-diamine

[0525]

[0526] Step 1: Synthesis of 4-amino-6-chloronicotinonitrile (compound 21-2)

[0527] Compound 21-1 (4 g, 15.72 mmol) was dissolved in DMF (30 mL), and CuCN (1.47 g, 15.72 mmol) was added. The reaction was carried out overnight at 120 °C under nitrogen protection. The mixture was cooled, diluted with water, extracted with ethyl acetate, and the organic phases were combined. The organic phase was dried over sodium sulfate, and the solvent was removed by vacuum distillation. The mixture was then subjected to column chromatography (PE / DCM = 1 / 9). The solution was evaporated to dryness to give compound 21-2 (1.16 g). MS (ESI, m / z): 154.1 [M+H] + .

[0528] Step 2: Synthesis of N-(2-chloro-5-cyanopyridin-4-yl)-1-methyl-1H-1,2,3-triazol-5-carboxamide (compound 21-3)

[0529] Int D (200 mg, 1.57 mmol) was dissolved in ACN (10 mL), NMI (284.23 mg, 3.46 mmol) was added, followed by fractional addition of TCFH (485.66 mg, 1.73 mmol). After stirring at room temperature for 10 minutes, compound 21-2 (241.65 mg, 1.57 mmol) was added, and the mixture was heated to 70 °C and reacted overnight. When half of the amine reaction was complete, NMI (284.23 mg, 3.46 mmol) was added again, followed by fractional addition of TCFH (485.66 mg, 1.73 mmol). The mixture was then heated to 70 °C and reacted for 4 hours. The solution was diluted with ammonium chloride aqueous solution, extracted with ethyl acetate, and the organic phases were combined. The organic phase was dried over sodium sulfate, and the solvent was removed by vacuum distillation. The column chromatography (DCM / EA = 7 / 3) was performed, and the solution was evaporated to dryness to obtain compound 21-3 (0.3 g). MS (ESI, m / z): 263.0 [M+H] + .

[0530] Step 3: Synthesis of 7-chloro-2-(1-methyl-1H-1,2,3-triazol-5-yl)pyrido[4,3-d]pyrimidin-4-amine (compound 21-4)

[0531] Compound 21-3 (230 mg, 875.67 μmol) was dissolved in sulfolane (3 mL), and PCl5 (729.40 mg, 3.50 mmol) was added. The mixture was heated to 100 °C and reacted overnight. After the reaction was complete, the solvent was removed by vacuum distillation, and the mixture was dissolved in ACN (2 mL). NH3·H2O (2 mL) was added dropwise in an ice bath, and the mixture was reacted at 50 °C for 1 hour. The solvent was removed by vacuum distillation, the mixture was diluted with water, filtered, and the solid was collected. The solid was evaporated to dryness to give compound 21-4 (110 mg). MS (ESI, m / z): 262.0 [M+H] +.

[0532] Step 4: Synthesis of N-(3-(2-((4-amino-2-(1-methyl-1H-1,2,3-triazol-5-yl))pyrido[4,3-d]pyrimidin-7-yl)amino)pyridin-4-yl)pentan-3-yl)-2-methylpropane-2-sulfinamide (compound 21-5)

[0533] Compound 21-4 (100 mg, 382.16 μmol), Int A (108.32 mg, 382.16 μmol), Brettphos Pd G3 (34.64 mg, 38.22 μmol), and Cs₂CO₃ (373.55 mg, 1.15 mmol) were dissolved in 1,4-dioxane (5 mL), and reacted at 110 °C for 4 hours under nitrogen protection. The solvent was removed by vacuum distillation, followed by column chromatography (MeOH / DCM = 15 / 85), and the solution was evaporated to dryness to give compound 21-5 (37 mg). MS (ESI, m / z): 509.2 [M+H] + .

[0534] Step 5: N 7 Synthesis of -(4-(3-aminopent-3-yl)pyridin-2-yl)-2-(1-methyl-1H-1,2,3-triazol-5-yl)pyrido[4,3-d]pyrimidine-4,7-diamine (compound 21)

[0535] Compound 21-5 (36 mg, 70.78 μmol) was dissolved in DCM (3 mL), and 4 M HCl / 1,4-dioxane (3 mL) was added dropwise. The reaction was carried out at room temperature for 2 hours. The solvent was removed by vacuum distillation, and the solution was adjusted to alkali with ammonia-methanol solution. The solvent was removed by vacuum distillation, followed by column chromatography (MeOH / DCM = 45 / 55). The solution was then prepared by pre-HPLC and lyophilized to obtain compound 21 (5 mg). MS (ESI, m / z): 405.2 [M+H] + .

[0536] 1 H NMR (400MHz, DMSO-d6) δ9.92(s,1H),9.29(s,1H),8.31(s,1H),8.25(d,J=5.6Hz,1H),8.23(s,1H),7.43(d,J=1. 6Hz,1H),7.00(dd,J=5.6,1.6Hz,1H),4.49(s,3H),1.78–1.69(m,2H),1.66–1.56(m,2H),0.68(t,J=7.4Hz,6H).

[0537] Example 22: 2-((8-amino-6-(1-methyl-1H-1,2,3-triazol-5-yl)-2,7-naphthidin-3-yl)amino)pyrimidine-4-carboxamide

[0538]

[0539] Step 1: Synthesis of N-tert-butoxycarbonyl-N-(6-((4-cyanopyrimidin-2-yl)amino)-3-(3-methyltriazol-4-yl)-2,7-naphthidin-1-yl)carbamate tert-butyl ester (compound 22-3)

[0540] Compound 22-1 (63.22 mg, 453.02 μmol), compound Int C (50 mg, 113.25 μmol), BrettPhos Pd G3 (10.27 mg, 11.33 μmol), Cs₂CO₃ (184.50 mg, 566.27 μmol), and 1,4-dioxane (3 mL) were added to a reaction flask. After purging with nitrogen, the mixture was heated to 100 °C and reacted for 16 hours. After the reaction was complete, the solvent was removed by vacuum distillation, followed by column chromatography (DCM / MeOH = 92 / 8). The solvent was evaporated to dryness to give compound 22-3 (24 mg). MS (ESI, m / z): 545.2 [M+H] + .

[0541] Step 2: Synthesis of 2-((8-amino-6-(1-methyl-1H-1,2,3-triazol-5-yl)-2,7-naphthidin-3-yl)amino)pyrimidine-4-carboxynitrile (compounds 22-4)

[0542] Compound 22-3 (24 mg, 44.15 μmol) was dissolved in 1 mL of 4 M HCl solution of 1,4-dioxane and reacted at 25 °C for 1 hour. After the reaction was complete, the solvent was evaporated to give compound 22-4 (17 mg). MS (ESI, m / z): 378.2 [M+34] + .

[0543] Step 3: Synthesis of 2-((8-amino-6-(1-methyl-1H-1,2,3-triazol-5-yl)-2,7-naphthidin-3-yl)amino)pyrimidine-4-carboxamide (compound 22)

[0544] Compound 22-4 (17 mg, 49.51 μmol) and K₂CO₃ (20.53 mg, 148.54 μmol) were added to a reaction flask and dissolved in a mixed solvent of MeOH (2 mL) and H₂O (0.5 mL). Then, H₂O₂ (112.28 mg, 990.26 μmol, 0.5 mL) was added, and the reaction was carried out at 20 °C for 1 hour. After the reaction was complete, the solid in the reaction solution was filtered off, the solvent was removed by vacuum distillation, and the product was prepared and lyophilized to obtain compound 22 (1.12 mg). MS (ESI, m / z): 363.2 [M+H] + .

[0545] 1 H NMR (400MHz, DMSO-d6) δ10.16 (s, 1H), 9.37 (s, 1H), 8.86 (d, J = 4.9Hz, 1H), 8.41 (s, 1H),8.20(s,1H),8.01(s,1H),7.96(s,1H),7.47(d,3H),7.38(s,1H),4.39(s,3H).

[0546] Example 24: (R)-1-(6-((8-amino-6-(1-methyl-1H-1,2,3-triazol-5-yl)-2,7-naphthidin-3-yl)amino)-4-(3-aminopent-3-yl)pyridin-2-yl)pyrrolidine-3-ol

[0547]

[0548] Step 1: Synthesis of N-(3-(2-chloro-6-((R)-3-hydroxypyrrolidone-1-yl)pyridin-4-yl)pent-3-yl)-2-methylpropane-2-sulfinamide (compound 24-2)

[0549] Compound 15-2 (200 mg, 592.93 μmol), 24-1 (51.66 mg, 592.93 μmol), DMSO (2 mL), and K₂CO₃ (245.84 mg, 1.78 mmol) were added to a reaction flask, and the reaction was carried out overnight at 100 °C. The mixture was cooled, diluted with water, extracted with ethyl acetate, and the organic phases were combined, washed with brine, dried over sodium sulfate, and the solvent was removed by vacuum distillation. The mixture was then subjected to column chromatography (PE / EA = 20 / 80), and evaporated to dryness to give compound 24-2 (70 mg). MS (ESI, m / z): 388.2 [M+H] + .

[0550] Step 2: Synthesis of N-tert-butoxycarbonyl-N-(6-((4-(1-(tert-butylsulfinylamino)-1-ethyl-propyl)-6-((3R)-3-hydroxypyrrolidone-1-yl)-2-pyridinyl)amino)-3-(3-methyltriazol-4-yl)-2,7-naphthidium-1-yl)carbamate (compound 24-3)

[0551] Compound 24-2 (25 mg, 64.44 μmol), compound Int C (28.45 mg, 64.44 μmol), Cs₂CO₃ (62.99 mg, 193.32 μmol), Brettphos Pd G₃ (5.84 mg, 6.44 μmol), and 1,4-dioxane (5 mL) were added to the reaction flask. The reaction was carried out overnight at 120 °C under nitrogen protection. The solvent was removed by vacuum distillation, followed by column chromatography (DCM / MeOH = 93 / 7), and the solution was evaporated to dryness to give compound 24-3 (35 mg). MS (ESI, m / z): 793.4 [M+H] + .

[0552] Step 3: Synthesis of (R)-1-(6-((8-amino-6-(1-methyl-1H-1,2,3-triazol-5-yl)-2,7-naphthidin-3-yl)amino)-4-(3-aminopent-3-yl)pyridin-2-yl)pyrrolidine-3-ol (compound 24)

[0553] Compound 24-3 (35 mg, 44.13 μmol) was dissolved in DCM (3 mL), and a 1,4-dioxane solution of 4 M HCl (3 mL) was added dropwise. The reaction was carried out at room temperature for 2 hours. The solvent was removed by vacuum distillation, and the product was prepared by lyophilization to give compound 24 (15 mg). MS (ESI, m / z): 489.3 [M+H] + .

[0554] 1 H NMR(400MHz,DMSO-d6)δ9.50(s,1H),9.26(s,1H),8.48(s,1H),8.28(br,1H),8. 19(s,1H),7.33(br,2H),7.07(s,1H),6.43(s,1H),6.01(s,1H),4.46(s,1H),4.3 6(s,3H),3.65–3.61(m,1H),3.59–3.55(m,2H),3.44–3.38(m,2H),2.10–2.06(m, 1H),2.01–1.92(m,1H),1.82–1.73(m,2H),1.71–1.63(m,2H),0.76–0.68(m,6H).

[0555] The following compounds were prepared by the method and general steps described in Example 24. Other required raw materials can be purchased commercially or synthesized by experienced synthesizers using conventional reactions from commercially available reagents.

[0556]

[0557] Example 25: N-(8-amino-6-(1-methyl-1H-1,2,3-triazol-5-yl)-2,7-naphthid-3-yl)-6-cyclopropylnicotinamide

[0558]

[0559] Step 1: Synthesis of N-tert-butoxycarbonyl-(6-(6-cyclopropylnicotinamide)-3-(1-methyl-1H-1,2,3-triazol-5-yl)-2,7-naphthid-1-yl) tert-butyl carbamate (compound 25-2)

[0560] Compound Int C (30 mg, 67.95 μmol) and compound 25-1 (13.31 mg, 81.54 μmol) were dissolved in pyridine (0.5 mL), and POCl3 (31.26 mg, 203.86 μmol) was added. The mixture was stirred at 25 °C for 4 hours. The pyridine was removed by concentration, and the mixture was filtered after adding ethyl acetate. The filtrate was concentrated to give compound 25-2 (35 mg). MS (ESI, m / z): 587.3 [M+H] + .

[0561] Step 2: Synthesis of N-(8-amino-6-(1-methyl-1H-1,2,3-triazol-5-yl)-2,7-naphthid-3-yl)-6-cyclopropylnicotinamide (compound 25)

[0562] Compound 25-2 (35 mg, 59.66 7.3) was dissolved in dichloromethane (1 mL), and a 1,4-dioxane solution of 4 M HCl (0.5 mL) was added. The mixture was stirred at 25 °C for 1 hour. The solution was directly concentrated and sent to the preparation section. Lyophilization yielded compound 25 (6 mg). MS (ESI, m / z): 387.2 [M+H] + .

[0563] 1H NMR (400MHz, DMSO-d6) δ11.14(s,1H),9.45(s,1H),9.05–9.00(m,1H),8.45(s,1H),8.25(dd,J=8.0,2.4Hz,1H),8.23(s,1H ),7.56(s,2H),7.45(dd,J=8.0,0.8Hz,1H),7.43(s,1H),4.40(s,3H),2.22(ddd,J=8.0,5.2,3.2Hz,1H),1.09–0.98(m,4H).

[0564] Example 28: (S)-N-(8-amino-6-(1-methyl-1H-1,2,3-triazol-5-yl)-2,7-naphthidin-3-yl)-3-(methylamino)pyrrolidine-1-carboxamide

[0565]

[0566] Step 1: Synthesis of N-tert-butoxycarbonyl-N-(3-(3-methyltriazol-4-yl)-6-(((3S)-3-(tert-butoxycarbonyl(methyl)amino)pyrrolidine-1-carbonyl)amino)-2,7-naphthidium-1-yl)carbamate tert-butyl ester (compound 28-2)

[0567] Compound Int C (33.07 mg, 74.90 μmol), DIPEA (29.04 mg, 224.69 μmol), and DCM (5 mL) were added to a reaction flask. Triphosgene (26.67 mg, 89.88 μmol) was added, and the mixture was reacted at room temperature for 0.5 hours. Then, compound 28-1 (30 mg, 149.79 μmol) was added, and the mixture was stirred at room temperature for 2 hours. The solvent was removed by vacuum distillation, using a scraper (DCM / MeOH = 20 / 1), and the mixture was filtered. The solvent was removed by vacuum distillation to obtain compound 28-2 (25 mg). MS (ESI, m / z): 668.4 [M+H] + .

[0568] Step 2: Synthesis of (S)-N-(8-amino-6-(1-methyl-1H-1,2,3-triazol-5-yl)-2,7-naphthidin-3-yl)-3-(methylamino)pyrrolidine-1-carboxamide (compound 30)

[0569] Compound 28-2 (25 mg, 37.44 μmol) was dissolved in DCM (3 mL), and a 1,4-dioxane solution of 4 M HCl (3 mL) was added dropwise. The reaction was carried out at room temperature for 2 hours. The solvent was removed by vacuum distillation, and the solution was adjusted to alkali with ammonia-methanol solution. The solution was then lyophilized to give compound 28 (2 mg). MS (ESI, m / z): 368.2 [M+H] + .

[0570] 1 H NMR (400MHz, DMSO-d6) δ9.32(d,J=0.8Hz,1H),8.84(s,1H),8.19(s,1H),8.07(d,J=0.8Hz,1H),7.42(br,2H),7.27(s,1H) ,4.37(s,3H),3.57–3.42(m,4H),3.27–3.23(m,1H),3.17–3.11(m,1H),2.27(s,3H),1.99–1.94(m,1H),1.75–1.68(s,1H).

[0571] The following compounds were prepared by referring to the method and general steps described in Example 28. Other required raw materials can be purchased commercially or obtained by experienced synthesizers from commercially available reagents using conventional reactions.

[0572]

[0573]

[0574] Example 30: N 6 -(4-(3-aminopentan-3-yl)-6-morpholinopyridin-2-yl)-3-(1-methyl-1H-1,2,3-triazol-5-yl)-2,7-naphthidium-1,6-diamine

[0575]

[0576] Step 1: Synthesis of N-(3-(2-chloro-6-morpholinopyridin-4-yl)pentan-3-yl)-2-methylpropane-2-sulfinamide (compound 30-2)

[0577] Compound 15-2 (60 mg, 177.88 μmol), compound 30-1 (17.05 mg, 195.67 μmol), CsF (35.27 mg, 533.64 μmol), and DMF (2 mL) were added to a reaction flask and reacted at 100 °C for 16 hours. After the reaction was complete, the mixture was purified by column chromatography (PE / EA = 94 / 6) and evaporated to dryness to obtain compound 30-2 (35 mg). MS (ESI, m / z): 388.1 [M+H] + .

[0578] Step 2: Synthesis of tert-butyl(6-((4-(3-((tert-butylsulfinyl)amino)pentan-3-yl)-6-morpholinopyridin-2-yl)amino)-3-(1-methyl-1H-1,2,3-triazol-5-yl)-2,7-naphthidin-1-yl)carbamate (compound 30-3)

[0579] Compound 30-2 (25 mg, 64.44 μmol), compound Int C (29 mg, 64.44 μmol), Cs₂CO₃ (62.99 mg, 193.32 μmol), BrettPhos Pd G₃ (11.68 mg, 12.89 μmol), and 1,4-dioxane (5 mL) were added to a reaction flask. After purging with nitrogen, the mixture was heated to 120 °C and stirred for 16 hours. After the reaction was complete, the solid in the reaction solution was filtered off, and the solvent was removed by vacuum distillation to obtain compound 30-3 (51 mg). MS (ESI, m / z): 593.3 [M+H-Boc] + .

[0580] Step 3: N 6 Synthesis of -(4-(3-aminopentan-3-yl)-6-morpholinopyridin-2-yl)-3-(1-methyl-1H-1,2,3-triazol-5-yl)-2,7-naphthidine-1,6-diamine (compound 30)

[0581] Compound 30-3 (41 mg, 51.70 μmol) was dissolved in 2 mL of 4 M HCl in a 1,4-dioxane solution, and the mixture was heated to 60 °C and stirred for 2 hours. After the reaction was complete, the reaction solution was evaporated to dryness, and an alkali was adjusted with NH3-methanol solution. The solvent was removed by vacuum distillation, and the solution was sent for preparative purification. The purified solution was then lyophilized to give compound 30 (6.13 mg). MS (ESI, m / z): 489.3 [M+H] + .

[0582] 1 H NMR(400MHz,DMSO-d6)δ9.53(s,1H),9.27(s,1H),8.20(s,1H),8.19(s,1H),7.32(s,2H),7.09(s,1H),6.67(s, 1H), 6.43 (s, 1H), 4.36 (s, 3H), 3.79 (t, J = 4.8Hz, 4H), 3.49 (t, J = 4.8Hz, 4H), 1.62 (m, 6H), 0.68 (t, J = 7.3Hz, 6H).

[0583] Example 32: N 6-(4-(3-aminopentan-3-yl)-6-(3-fluoro-3-methylazacyclobutan-1-yl)pyridin-2-yl)-3-(1-methyl-1H-1,2,3-triazol-5-yl)-2,7-naphthidium-1,6-diamine

[0584]

[0585] The synthesis methods of compounds 32-1 to 32-3 are as described in steps one and two of the synthesis in Example 24.

[0586] Step 3: N 6 Synthesis of -(4-(3-aminopent-3-yl)-6-(3-fluoro-3-methylazacyclobutan-1-yl)pyridin-2-yl)-3-(1-methyl-1H-1,2,3-triazol-5-yl)-2,7-naphthidine-1,6-diamine (compound 32)

[0587] Compound 32-3 (30 mg, 37.74 μmol) was dissolved in 2 mL of TFA and reacted at 90 °C for 1 hour. After the reaction was complete, the solvent was removed by vacuum distillation, and the product was prepared by lyophilization to give compound 32 (5 mg). MS (ESI, m / z): 491.3 [M+H] + .

[0588] 1 H NMR(400MHz,DMSO-d6)δ9.56(s,1H),9.26(s,1H),8.37(s,1H),8.24(s,1H),7.31(s,2H),7.17(s,1H),6.65(d,J=1.2Hz,1H),6.05 (d,J=1.2Hz,1H),4.37(s,3H),4.18–4.03(m,4H),1.73–1.69(m,2H),1.68–1.63(m,3H),1.61–1.48(m,4H),0.68(t,J=7.6Hz,6H).

[0589] The following compounds were prepared by referring to the method and general steps described in Example 32. Other required raw materials can be purchased commercially or obtained by experienced synthesizers from commercially available reagents using conventional reactions.

[0590]

[0591] Example 36: 4-(1-amino-6-((4-(3-aminopent-3-yl)pyridin-2-yl)amino)-2,7-naphthidin-3-yl)piperazin-2-one

[0592]

[0593] Step 1: Synthesis of 3-chloro-6-((diphenylmethylene)amino)-N,N-bis(4-methoxybenzyl)-2,7-naphthidine-1-amine (compound 36-1)

[0594] Compound 20-8 (0.77 g, 1.69 mmol) and Int A-6 (322.50 mg, 1.78 mmol) were dissolved in 1,4-dioxane (15 mL), and Pd2(dba)3 (155.19 mg, 169.47 μmol), cesium carbonate (1.10 g, 3.39 mmol), and Xantphos (196.12 mg, 338.95 μmol) were added. The mixture was heated to 100 °C for 2 hours under nitrogen protection. Extraction was performed with water and ethyl acetate, and the solution was concentrated under reduced pressure and then loaded onto a normal-phase column (PE / EA = 87 / 13). The solution was evaporated to dryness to give compound 36-1 (0.27 g). MS (ESI, m / z): 599.1 [M+H] + .

[0595] Step 2: Synthesis of 4-(1-(bis(4-methoxybenzyl)amino)-6-((diphenylmethylene)amino)-2,7-naphthid-3-yl)piperazin-2-one (compound 36-3)

[0596] Compounds 36-1 (110 mg, 183.60 μmol) and 36-2 (36.76 mg, 367.21 μmol) were dissolved in 1,4-dioxane (10 mL), and Pd₂(dba)₃ (16.81 mg, 18.36 μmol), Cs₂CO₃ (179.46 mg, 550.81 μmol), and Ruphos (17.14 mg, 36.72 μmol) were added. The reaction was carried out overnight at 100 °C under nitrogen protection. The solvent was removed by vacuum distillation, and the mixture was subjected to column chromatography (DCM / MeOH = 70 / 30). The solution was evaporated to dryness to give compound 36-3 (90 mg). MS (ESI, m / z): 663.3 [M+H] + .

[0597] Step 3: Synthesis of 4-(6-amino-1-(bis(4-methoxybenzyl)amino)-2,7-naphthid-3-yl)piperazin-2-one (compound 36-4)

[0598] Compound 36-3 (90 mg, 135.79 μmol) was dissolved in MeOH (4 mL), and sodium acetate (55.70 mg, 678.96 μmol) and hydroxylamine hydrochloride (37.75 mg, 543.17 μmol) were added. The mixture was reacted overnight at room temperature. The solvent was removed by vacuum distillation, followed by column chromatography (DCM / MeOH = 90 / 10), and the solution was evaporated to dryness to give compound 36-4 (26.12 mg). MS (ESI, m / z): 499.3 [M+H]+ .

[0599] Step 4: Synthesis of N-(3-(2-((8-(bis(4-methoxybenzyl)amino)-6-(3-oxopiperazin-1-yl)-2,7-naphthidin-3-yl)amino)pyridin-4-yl)pent-3-yl)-2-methylpropane-2-sulfinamide (compound 36-5)

[0600] Int A-5 (26.12 mg, 75.21 μmol) and compound 36-4 (25 mg, 50.14 μmol) were dissolved in 1,4-dioxane (5 mL), and Brettphos Pd G3 (4.55 mg, 5.01 μmol) and Cs₂CO₃ (20.48 mg, 150.43 μmol) were added. The reaction was carried out overnight at 100 °C under nitrogen protection. The solvent was removed by vacuum distillation, and the mixture was subjected to column chromatography (DCM / MeOH = 90 / 10). The solution was evaporated to dryness to give compound 36-5 (15 mg). MS (ESI, m / z): 765.4 [M+H] + .

[0601] Step 5: Synthesis of 4-(1-amino-6-((4-(3-aminopent-3-yl)pyridin-2-yl)amino)-2,7-naphthidin-3-yl)piperazin-2-one (compound 36)

[0602] Compound 36-5 (15 mg, 19.61 μmol) was dissolved in TFA (3 mL) and reacted at 80 °C for 3 hours. The solvent was removed by vacuum distillation, and the mixture was adjusted to an alkali of ammonia-methanol solution. The solution was then lyophilized to give compound 36 (2.5 mg). MS (ESI, m / z): 421.3 [M+H] + .

[0603] 1 H NMR(400MHz,DMSO-d6)δ9.66(s,1H),9.21(s,1H),8.21–8.19(m,2H),7.37(s,1H),7.15(br,2H),7.09(s,1H),6.95–6.93( m,1H),3.84–3.77(m,2H),3.03–2.96(m,2H),1.76–1.67(m,2H),1.63–1.54(dd,J=13.8,7.2Hz,2H),0.67(t,J=7.2Hz,6H).

[0604] Example 37: 1-(6-((8-amino-6-(1-methyl-1H-1,2,3-triazol-5-yl)-2,7-naphthidin-3-yl)amino)-4-(3-aminopent-3-yl)pyridin-2-yl)-N-methylpiperidin-4-carboxamide

[0605]

[0606] Step 1: Synthesis of 1-(6-bromo-4-(3-((tert-butylsulfinyl)amino)pent-3-yl)pyridin-2-yl)-N-methylpiperidin-4-carboxamide (compound 37-2)

[0607] Compound 37-1 (27.25 mg, 152.51 μmol), compound Int E-6 (50 mg, 117.31 μmol), Cs₂CO₃ (152.89 mg, 469.25 μmol), and Brettphos Pd G₃ (10.63 mg, 11.73 μmol) were dissolved in 1,4-dioxane (5 mL), purged with nitrogen, and the mixture was heated to 120 °C and reacted for 3 hours. After the reaction was complete, the mixture was purified by column chromatography (DCM / MeOH = 90 / 10) and evaporated to dryness to give compound 37-2 (30 mg). MS (ESI, m / z): 487.2 [M+H] + .

[0608] Step 2: Synthesis of tert-butylN-tert-butoxycarbonyl-N-(6-((4-(1-(tert-butylsulfinylamino)-1-ethyl-propyl)-6-(4-(methylcarbamoyl)-1-piperidinyl)-2-pyridinyl)amino)-3-(3-methyltriazol-4-yl)-2,7-naphthidium-1-yl)carbamate (compound 37-3)

[0609] Compound 37-2 (90 mg, 184.62 μmol), compound Int C (97.81 mg, 221.54 μmol), Cs₂CO₃ (120.30 mg, 369.23 μmol), and Brettphos Pd G₃ (16.74 mg, 18.46 μmol) were dissolved in 1,4-dioxane (10 mL), and after purging with nitrogen, the mixture was heated to 120 °C and reacted for 3 hours. After the reaction was complete, the mixture was purified by column chromatography (DCM / MeOH = 90 / 10), and the solvent was removed by vacuum distillation to obtain compound 37-3 (50 mg). MS (ESI, m / z): 848.5 [M+H] + .

[0610] Step 3: Synthesis of 1-(6-((8-amino-6-(1-methyl-1H-1,2,3-triazol-5-yl)-2,7-naphthidin-3-yl)amino)-4-(3-aminopent-3-yl)pyridin-2-yl)-N-methylpiperidin-4-carboxamide (compound 37)

[0611] Compound 37-3 (50 mg, 58.96 μmol) was dissolved in 2 mL of 4 M HCl in a 1,4-dioxane solution and stirred at 20 °C for 2 hours. After the reaction was complete, the reaction solution was evaporated to dryness, and an alkali was adjusted with NH3-methanol solution. The solvent was removed by vacuum distillation, and the solution was sent for preparative purification. The purified solution was then lyophilized to give compound 37 (23 mg). MS (ESI, m / z): 544.3 [M+H] + .

[0612] 1 H NMR (400MHz, DMSO-d6) δ9.57(s,1H),9.28(s,1H),8.28(s,2H),8.18(s,1H),7.79(d,J=4.7Hz,1H),7.35(s,2H),7.02(s,1H),6.60(s, 1H), 6.43 (s, 1H), 4.36 (s, 3H), 2.98–2.87 (m, 2H), 2.57 (d, J = 4.5Hz, 3H), 1.83–1.75 (m, 4H), 1.73–1.55 (m, 6H), 0.74 (t, J = 7.4Hz, 6H).

[0613] Example 38: N 6 -(1-(1-(1-(difluoromethyl)-1H-pyrazol-3-yl)ethyl)-3-(1-methyl-1H-1,2,3-triazol-5-yl)-2,7-naphthidium-1,6-diamine

[0614]

[0615] Step 1: Synthesis of (E)-N-(1-(1H-pyrazol-3-yl)ethylene)-2-methylpropane-2-sulfinamide (compound 38-2)

[0616] Compound 38-1 (2.00 g, 18.16 mmol) and Int A-2 (2.20 g, 18.16 mmol) were dissolved in THF (20 mL), and tetraisopropyl titanate (10.32 g, 36.33 mmol) was added dropwise. The reaction was carried out overnight at 75 °C. The reaction was quenched with sodium bicarbonate aqueous solution, filtered, and the filtrate was collected. The filtrate was diluted with ethyl acetate, washed three times with dilute brine, dried over sodium sulfate, and the solvent was removed by vacuum distillation. The mixture was then subjected to column chromatography (PE / EA = 50 / 50) and evaporated to dryness to give compound 38-2 (2.2 g). MS (ESI, m / z): 214.2 [M+H] + .

[0617] Step 2: Synthesis of N-(1-(1H-pyrazol-3-yl)ethyl)-2-methylpropane-2-sulfinamide (compound 38-3)

[0618] Compound 38-2 (1 g, 4.69 mmol) was dissolved in THF (15 mL), and NaBH4 (709.47 mg, 18.75 mmol) was added in portions under ice bath conditions. The reaction was carried out under ice bath conditions for two hours. The reaction was quenched with water, extracted with ethyl acetate, and the organic phases were combined, dried over sodium sulfate, and the solvent was removed by vacuum distillation to give compound 38-3 (0.9 g). MS (ESI, m / z): 216.1 [M+H] + .

[0619] Step 3: Synthesis of N-(1-(1-(difluoromethyl)-1H-pyrazol-3-yl)ethyl)-2-methylpropane-2-sulfinamide (compound 38-5)

[0620] Compound 38-3 (0.92 g, 4.27 mmol) and CsF (564.87 mg, 8.55 mmol) were dissolved in acetonitrile (10 mL), and compound 28-4 (2.28 g, 8.55 mmol) was added dropwise. The reaction was allowed to proceed overnight at room temperature. The reaction was quenched with sodium sulfite aqueous solution, extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed with sodium bicarbonate aqueous solution, dried over sodium sulfate, and the solvent was removed by vacuum distillation. The mixture was flash-extracted, the aqueous phase was removed by vacuum distillation, and the solvent was removed by rotary evaporation to give compound 38-5 (0.4 g). MS (ESI, m / z): 266.1 [M+H] + .

[0621] Step 4: Synthesis of 1-(1-(difluoromethyl)-1H-pyrazol-3-yl)ethyl-1-amine (compound 38-6)

[0622] Compound 38-5 (0.39 g, 1.47 mmol) was dissolved in DCM (5 mL), and a 1,4-dioxane solution of 4 M HCl (1 mL) was added dropwise. The reaction was carried out at room temperature for 1 hour. The solvent was removed by vacuum distillation to give compound 38-6 (0.2 g). MS (ESI, m / z): 162.1 [M+H] + .

[0623] Step 5: Synthesis of tert-butylN-tert-butoxycarbonyl-N-(6-(1-(1-(difluoromethyl)pyrazol-3-yl)ethylamino)-3-(3-methyltriazol-4-yl)-2,7-naphthidium-1-yl)carbamate (compound 38-7)

[0624] Compound Int C-1 (40 mg, 86.78 μmol) and compound 38-6 (34.30 mg, 173.57 μmol) were dissolved in 1,4-dioxane (10 mL), and Pd-PEPPSI-IHept (8.44 mg, 8.68 μmol) and Cs₂CO₃ (84.83 mg, 260.35 μmol) were added. The reaction was carried out overnight at 120 °C under nitrogen protection. The solvent was removed by vacuum distillation, and the mixture was subjected to column chromatography (PE / EA = 40 / 60). The solution was evaporated to dryness to give compound 38-7 (16 mg). MS (ESI, m / z): 586.3 [M+H] + .

[0625] Step 6: N 6 Synthesis of -(1-(1-(difluoromethyl)-1H-pyrazol-3-yl)ethyl)-3-(1-methyl-1H-1,2,3-triazol-5-yl)-2,7-naphthidine-1,6-diamine (compound 38)

[0626] Compound 38-7 (16 mg, 27.32 μmol) was dissolved in DCM (3 mL), and a 1,4-dioxane solution of 4 M HCl (1 mL) was added dropwise. The reaction was carried out at room temperature for 2 hours. The solvent was removed by vacuum distillation, and the solution was adjusted to an ammonia-methanol base. The mixture was then lyophilized to give compound 38 (3 mg). MS (ESI, m / z): 386.2 [M+H] + .

[0627] 1 H NMR (400MHz, DMSO-d6) δ9.10 (s, 1H), 8.12–8.08 (m, 2H), 7.89–7.60 (t, J = 104Hz, 1H), 7.27 (d, J = 8.3Hz, 1H) ,7.16(br,2H),6.99(d,J=0.7Hz,1H),6.43–6.41(m,2H),5.16(br,1H),4.34(s,3H),1.51(d,J=6.8Hz,3H).

[0628] Example 39: 1-(6-((8-amino-6-(1-methyl-1H-1,2,3-triazol-5-yl)-2,7-naphthid-3-yl)amino)-4-(3-aminopentan-3-yl)pyridin-2-yl)ethane-1-one (compound 39) and 2-(6-((8-amino-6-(1-methyl-1H-1,2,3-triazol-5-yl)-2,7-naphthid-3-yl)amino)-4-(3-aminopentan-3-yl)pyridin-2-yl)prop-2-ol (compound 40)

[0629]

[0630] Step 1: Synthesis of methyl 6-((8-(bis(tert-butoxycarbonyl)amino)-6-(3-methyltriazol-4-yl)-2,7-naphthidium-3-yl)amino)-4-(1-(tert-butylsulfinylamino)-1-ethyl-propyl)pyridine-2-carboxylic acid ester (compound 39-1)

[0631] Compounds Int E (140 mg, 177.94 μmol), Pd(dppf)Cl2 (13.02 mg, 17.79 μmol), and TEA (90.03 mg, 889.70 μmol) were dissolved in MeOH (10 mL), carbon monoxide was displaced, and the mixture was heated to 120 °C for 3 hours. After the reaction was complete, the solution was evaporated to dryness to give compound 39-1 (136 mg). MS (ESI, m / z): 766.4 [M+H] + .

[0632] Step 2: Synthesis of methyl 6-((8-amino-6-(1-methyl-1H-1,2,3-triazol-5-yl)-2,7-naphthidin-3-yl)amino)-4-(3-aminopentan-3-yl)pyridinecarboxylic acid (compound 39-2)

[0633] Compound 39-1 (136 mg, 177.56 9 mol) was dissolved in 5 mL of 4 M HCl in a solution of 1,4-dioxane and stirred at 20 °C for 2 hours. After the reaction was complete, the solvent was removed by vacuum distillation to give compound 39-2 (81 mg). MS (ESI, m / z): 462.3 [M+H] + .

[0634] Step 3: Synthesis of 1-(6-((8-amino-6-(1-methyl-1H-1,2,3-triazol-5-yl)-2,7-naphthid-3-yl)amino)-4-(3-aminopentan-3-yl)pyridin-2-yl)ethane-1-one (compound 39) and 2-(6-((8-amino-6-(1-methyl-1H-1,2,3-triazol-5-yl)-2,7-naphthid-3-yl)amino)-4-(3-aminopentan-3-yl)pyridin-2-yl)prop-2-ol (compound 40)

[0635] Compound 39-2 (81.95 mg, 177.56 μmol) was dissolved in THF (10 mL), purged with nitrogen, and cooled to 0 °C. Then, MeMgBr (211.73 mg, 1.78 mmol) was slowly added dropwise. After the addition was complete, the reaction was maintained at 0 °C for 2 hours. After the reaction was complete, water was added to quench the reaction, the reaction solution was evaporated to dryness, and the solution was sent for preparative purification. The resulting compounds were lyophilized to obtain compound 39 (13 mg) and compound 40 (11 mg).

[0636] Compound 39: MS (ESI, m / z): 446.3 [M+H] +

[0637] 1 H NMR (400MHz, DMSO-d6) δ9.77(s,1H),9.30(s,1H),8.32(s,1H),8.21(s,1H),7.36(s,2H),7.24(dd,J=10.9,1. 4Hz, 2H), 7.06 (s, 1H), 4.36 (s, 3H), 1.75 (p, J = 7.2Hz, 2H), 1.64 (dq, J = 14.3, 7.3Hz, 2H), 0.70 (t, J = 7.3Hz, 6H).

[0638] Compound 40: MS (ESI, m / z): 462.3 [M+H] +

[0639] 1 H NMR (400MHz, DMSO-d6) δ9.77(s,1H),9.30(s,1H),8.32(s,1H),8.21(s,1H),7.36(s,2H),7.25(d,J=1.4Hz,1H),7.22(d,J= 1.4Hz,1H),7.06(s,1H),4.36(s,3H),1.75(dd,J=13.9,7.3Hz,2H),1.68–1.60(m,2H),1.53(s,6H),0.70(t,J=7.3Hz,6H).

[0640] Example 41: 2-Amino-N-(8-amino-6-(1-methyl-1H-1,2,3-triazol-5-yl)-2,7-naphthid-3-yl)isonicotinamide

[0641]

[0642] Step 1: Synthesis of methyl 2-(bis(4-methoxybenzyl)amino)isonicotinic acid (compound 41-2)

[0643] Compound 44-1 (2 g, 13.14 mmol), PMBCl (5.25 g, 32.86 mmol, 4.55 mL), TEA (6.65 g, 39.43 mmol, 9.14 mL), and acetonitrile (32 mL) were added to a reaction flask and reacted at 80 °C for 4 hours under nitrogen protection. After the reaction was complete, the mixture was purified by silica gel column chromatography (PE:DCM = 40:60), and the solvent was evaporated to dryness to give compound 41-2 (677 mg). MS (ESI, m / z): 393.2 [M+H] + .

[0644] Step 2: Synthesis of 2-(bis(4-methoxybenzyl)amino)isonicotinic acid (compound 41-3)

[0645] Compound 41-2 (200 mg, 509.62 μmol), LiOH (36.62 mg, 1.53 mmol), H₂O (0.5 mL), and methanol (2 mL) were added to a reaction flask and stirred at 60 °C for 16 hours. After the reaction was complete, the solution of 1,4-dioxane in 4 M HCl was added to adjust the acidity, the solvent was evaporated to dryness, the solid was dissolved in DCM and filtered, and the solvent was evaporated to dryness again to give compound 41-3 (190 mg). MS (ESI, m / z): 379.2 [M+H] + .

[0646] Step 3: Synthesis of 2-(bis(4-methoxybenzyl)amino)isonicotinamide chloride (compound 41-4)

[0647] Compound 41-3 (40 mg, 90.60 μmol) and SOCl2 (1 mL) were added to a reaction flask and stirred at 80 °C for 2 hours. After the reaction was complete, the solvent was evaporated to obtain compound 41-4 (84 mg). The sample was quenched with methanol and sent for analysis. MS (ESI, m / z): 393.2 [M+H] + .

[0648] Step 4: Synthesis of tert-butyl N-(6-((2-(bis((4-methoxyphenyl)methyl)amino)pyridine-4-carbonyl)amino)-3-(3-methyltriazol-4-yl)-2,7-naphthidin-1-yl)-N-tert-butoxycarbonyl-carbamate (compounds 41-5)

[0649] Compound Int C (15 mg, 33.98 μmol) was dissolved in DMF (1 mL), and after purging with nitrogen, NaH (4.08 mg, 101.93 μmol) was added. The mixture was stirred at room temperature for 0.5 hours, followed by the addition of a dichloromethane solution of compound 41-4 (84 mg, 211.59 μmol). The reaction was carried out at 25 °C for 4 hours. After the reaction was complete, the solution was evaporated to dryness to obtain compound 41-5 (20 mg). MS (ESI, m / z): 702.3 [M+H-100] + .

[0650] Step 5: Synthesis of 2-amino-N-(8-amino-6-(1-methyl-1H-1,2,3-triazol-5-yl)-2,7-naphthid-3-yl)isonicotinamide (compound 41)

[0651] Compound 41-5 (45 mg, 81.14 μmol) was dissolved in TFA (1 mL) and reacted at 80 °C for 2 hours. After the reaction was complete, the reaction solution was evaporated to dryness, and after adjusting the alkali with NH3-methanol solution, the solvent was evaporated to dryness again before being sent to the preparation section. The solution was then lyophilized to give compound 41 (0.7 mg). MS (ESI, m / z): 362.1 [M+H] + .

[0652] 1 H NMR (400MHz, DMSO-d6) δ10.99(s,1H),9.44(s,1H),8.41(s,1H),8.23(s,1H),8.06(d,J=4.9Hz,1 H),7.56(s,2H),7.44(s,1H),7.03(dd,J=5.3,1.6Hz,1H),6.95(s,1H),6.23(s,2H),4.40(s,3H).

[0653] Example 42: N 6 -(4-(3-aminopentan-3-yl)-6-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)-3-(1-methyl-1H-1,2,3-triazol-5-yl)-2,7-naphthidium-1,6-diamine

[0654]

[0655] Step 1: Synthesis of tert-butylN-tert-butoxycarbonyl-N-(6-((4-(1-(tert-butylsulfinylamino)-1-ethyl-propyl)-6-(1-methylpyrazol-3-yl)-2-pyridyl)amino)-3-(3-methyltriazol-4-yl)-2,7-naphthidium-1-yl]carbamate (compound 42-2)

[0656] Compound Int E (50 mg, 63.55 μmol), compound 42-1 (26.45 mg, 127.10 μmol), cataCXium A Pd G3 (9.26 mg, 12.71 μmol), and K3PO4 (40.47 mg, 190.65 μmol) were dissolved in a mixed solvent of 4-dioxane (5 mL) and water (1 mL). The mixture was heated to 120 °C for 3 hours under N2 protection. After the reaction was complete, the solvent was removed by vacuum distillation, and compound 42-2 (25 mg) was purified by column chromatography (DCM:MeOH = 95:5). MS (ESI, m / z): 788.4 [M+H] + .

[0657] Step 2: N 6Synthesis of -(4-(3-aminopent-3-yl)-6-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)-3-(1-methyl-1H-1,2,3-triazol-5-yl)-2,7-naphthidine-1,6-diamine (compound 42)

[0658] Compound 42-2 (25 mg, 31.73 μmol) was dissolved in DCM (3 mL), and a 1,4-dioxane solution of 4 M HCl (2 mL) was added dropwise. The reaction was carried out at room temperature for 2 hours. After the reaction was complete, the solvent was removed by vacuum distillation, and the product was prepared by lyophilization to give compound 42 (6 mg). MS (ESI, m / z): 484.3 [M+H] + .

[0659] 1 H NMR (400MHz, DMSO-d6) δ9.94(s,1H),9.34(s,1H),8.24(s,1H),8.15(s,1H),7.51(d,J=2.0Hz,1H),7.42(d,J=1.2Hz,1H),7.38(s,2H),7.36(d,J=1 .6Hz,1H),7.21(s,1H),6.77(d,J=2.0Hz,1H),4.37(s,3H),4.22(s,3H), 1.82–1.74(m,2H),1.73(s,2H),1.68–1.59(m,2H),0.72(t,J=7.2Hz,6H).

[0660] Example 43: (S)-N-(8-amino-6-(1-methyl-1H-1,2,3-triazol-5-yl)-2,7-naphthidin-3-yl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide

[0661]

[0662] Step 1: Synthesis of tert-butylN-tert-butoxycarbonyl-N-(3-(3-methyltriazol-4-yl)-6-(((S)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carbonyl)amino)-2,7-naphthidium-1-yl)carbamate (compound 43-2)

[0663] Compounds Int C (58.21 mg, 131.85 μmol) and Py (20.86 mg, 263.70 μmol) were added to a reaction flask and dissolved in DCM (5 mL). Phenyl chloroformate (30.97 mg, 197.78 μmol) was added dropwise under ice bath conditions, and the reaction was carried out at room temperature for 2 hours. The formation of the active ester was detected. The reaction was quenched with 1 M hydrochloric acid, extracted twice with dichloromethane, and the organic phases were combined. The organic phases were washed with sodium chloride aqueous solution and dried with sodium sulfate. The solvent was removed by vacuum distillation. Compound 43-1 (50 mg, 263.70 μmol) and DIEA (51.12 mg, 395.56 μmol) were dissolved in DMSO (5 mL) with the above-mentioned evaporated active ester and reacted overnight at 80 °C. The mixture was diluted with water, extracted with ethyl acetate, and the organic phases were combined. The mixture was washed three times with sodium chloride aqueous solution and dried with vacuum distillation. Column chromatography (DCM / MeOH = 95 / 5) was performed, and the collected organic phases were evaporated to dryness to obtain compound 43-2 (40 mg). MS(ESI, m / z): 621.3 [M+H] + .

[0664] Step 2: Synthesis of (S)-N-(8-amino-6-(1-methyl-1H-1,2,3-triazol-5-yl)-2,7-naphthidin-3-yl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (compound 43)

[0665] Compound 43-2 (40 mg, 64.45 μmol) was dissolved in DCM (4 mL), and a 1,4-dioxane solution of 4 M HCl (2 mL) was added dropwise. The reaction was carried out at room temperature for 1 hour. The solvent was removed by vacuum distillation, and the solution was adjusted to alkali with ammonia-methanol solution. The mixture was then lyophilized to give compound 43 (18 mg). MS (ESI, m / z): 421.3 [M+H] + .

[0666] 1 H NMR(400MHz,DMSO-d6)δ9.32(s,1H),8.93(br,1H),8.19(s,1H),8.06(s,1H),7.43(br,2H),7.28(s,1H),4.38(s,3H),3.80–3.72(s,1H),3.66–3 .60m,1H),3.44–3.37(m,1H),3.15–3.07(m,1H),2.48–2.46(m,1H),2.4 5–2.44(m,1H),2.43–2.41(m,1H),2.14–2.05(m,1H),1.73–1.65(m,1H).

[0667] The above synthesis examples are merely illustrative; other compounds in this application can be synthesized similarly with reference to the above synthesis examples.

[0668] Biological evaluation

[0669] Experimental Example 1: Testing the inhibitory effect of compounds on MASTL enzyme activity

[0670] Experimental method: Based on ADP-Glo TM The instructions for the Promega kinase assay kit are as follows: The method for determining the inhibitory effect of the compounds of this invention on MASTL enzyme activity is as follows:

[0671] After pre-incubating MASTL enzyme (SignalChem) with different concentrations of test compounds at 25°C for 30 min, the substrate ARPP19 (SignalChem) and adenosine triphosphate (ATP) were added to initiate the reaction. After incubation at 25°C for 2 h, ADP-Glo ​​was added. TM The reagents were incubated at 25°C for 60 minutes, and then the kinase detection reagent was added. The signal value was then detected after incubation at 25°C for 60 minutes.

[0672] Using the solvent group (DMSO) as a negative control and the buffer group (without MASTL enzyme) as a blank control, the percentage inhibition rate of different concentrations of the compound was calculated according to the following formula:

[0673] Percentage inhibition rate = (Negative control fluorescence signal ratio - Compound fluorescence signal ratio) / (Negative control fluorescence signal ratio - Blank control fluorescence signal ratio) × 100%.

[0674] Fit the detected signal value and calculate IC. 50 The inhibitory effect of the compound on MASTL enzyme activity was determined according to the above method, and the results are shown in Table 1.

[0675] Table 1. Inhibitory activity of the compounds of the present invention against MASTL

[0676]

[0677]

[0678] In addition, other compounds of the present invention, such as compounds 26-29 and compound 41, etc., IC 50 The value is also less than 120 nM.

[0679] Experimental results show that the compounds of this invention have a strong inhibitory effect on MASTL enzyme.

[0680] Experimental Example 2: Pharmacokinetic Test of Compounds in Balb / c Mice

[0681] The compound of this invention and control compound 1 (prepared according to patent application WO2024003773A1) were administered intravenously (1 mg / kg). The IV solvent was 5% DMSO + 5% Solutol + 90% physiological saline. Blood was collected via the submandibular vein at 0 h before administration and at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8 and 24 h after administration (intravenous). The plasma was placed in K2-EDTA anticoagulant tubes, centrifuged at 4000 rpm for 10 min (4℃), and stored at -80℃ for analysis. An appropriate amount of plasma sample was added to a precipitant containing an internal standard, shaken to mix, and centrifuged at 4000 rpm for 10 min at 4℃. The supernatant was analyzed by LC-MS / MS. Pharmacokinetic parameters were calculated using a non-compartmental model, and the results are shown in Table 2.

[0682] Table 2: Pharmacokinetic parameters of the compounds in mice

[0683]

[0684] in conclusion:

[0685] The above experimental results show that the compound of the present invention has a low in vivo clearance rate, high blood drug concentration, and high in vivo exposure.

[0686] Compare with the structure of compound 1:

[0687]

[0688] In addition to those described herein, various modifications of the invention will be apparent to those skilled in the art based on the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. All references cited in this application (including all patents, patent applications, journal articles, books, and any other disclosures) are incorporated herein by reference in their entirety.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof: in: X 1 X 2 and X 3 Each is independently selected from N and CR 3 ; Ring A is selected from C 6-10 Aryl, 5-10 membered heteroaryl and 5-8 membered heterocyclic; L is selected from bond, -C(=O)-, -S(=O)-, -S(=O)2- and -(CR 4 R 5 ) n -; R 1 Selected from C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10-membered heteroaryl groups, wherein the cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each optionally selected independently from one or more halogens, D, -OH, -CN, -NR. 6 R 7 -CD3, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Substitution of cycloalkoxy groups and 3-8 membered heterocyclic groups; R 2 Each occurrence is independently selected from H, D, halogen, -OH, -CN, -NR. 6 R 7 -C(=O)NR 6 R 7 -C(=O)R 8 -NHC(=O)R 8 -S(=O)R 8 -S(=O)2R 8 C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 2-6 Heteroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl groups, wherein the alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heteroalkyl, hydroxyalkyl, hydroxyalkoxy, cycloalkyl, cycloalkoxy, heterocyclic, aryl, and heteroaryl groups are each optionally bound by one or more R groups. a replace; R 3 Each occurrence is independently selected from H, D, halogen, -OH, -CN, -NH2, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl and 3-6 membered heterocyclic groups, wherein the alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, cycloalkyl and heterocyclic groups are each optionally selected independently by one or more halogens, D, OH, CN, -NH2 and C. 1-6 Alkyl substituents; R 4 and R 5 Each time it appears, it is independently selected from H, D, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 2-6 Heteroalkyl, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups, or R 4 and R 5 Together with the carbon atom to which it is attached, it forms a 3-8 membered cycloalkyl or a 4-8 membered heterocyclic group, wherein the alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heteroalkyl, hydroxyalkyl, cycloalkyl, and heterocyclic group are each optionally selected independently by one or more halogens, D, OH, CN, -NH2, C. 1-6 Alkyl and C 1-6 Substituents of haloalkyl groups; R 6 and R 7 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups, or R 6 and R 7 Together with the nitrogen atom it is attached to, it forms a 3-8 membered heterocyclic group; R 8 Each occurrence is independently selected from H, -OH, -NH2, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl and 3-6 membered heterocyclic groups, wherein the alkyl, haloalkyl, cycloalkyl and heterocyclic groups are each optionally selected independently from one or more halogens, D, OH, CN, -NH2 and C. 1-6 Alkyl substituents; R a Each occurrence is independently selected from H, D, halogen, =O, -OH, -CN, -NR. 6 R 7 -C(=O)NR 6 R 7 C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl and 3-6 membered heterocyclic groups, wherein the alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, cycloalkyl and heterocyclic groups are each optionally selected independently by one or more halogens, D, OH, CN, -NH2 and C. 1-6 Alkyl substituents; preferably, R a Each occurrence is independently selected from H, D, halogen, =O, -OH, -CN, -NR. 6 R 7 C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl and 3-6 membered heterocyclic groups, wherein the alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, cycloalkyl and heterocyclic groups are each optionally selected independently by one or more halogens, D, OH, CN, -NH2 and C. 1-6 Alkyl substituents; m can be 0, 1, 2, or 3; n is 0, 1, 2, or 3. The condition is that L is a key or n is 0, and X 1 X 2 and X 3 When both are CH: 1) At least one R 2 Selected from D, -OH, -CN, -NR 6 R 7 -C(=O)NR 6 R 7 -C(=O)R 8 -NHC(=O)R 8 -S(=O)R 8 -S(=O)2R 8 C 2-4 alkenyl, C 2-4 alkynyl group, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl groups, wherein the alkenyl, alkynyl, hydroxyalkoxy, haloalkoxy, cycloalkoxy, heterocyclic, aryl, and heteroaryl groups are each optionally surrounded by one or more R groups. a Replace; and / or 2)R 1 C 3-8 cycloalkyl or C 6-10 The aryl group, wherein the cycloalkyl group and the aryl group are each optionally composed of one or more elements independently selected from halogen, D, -OH, -CN, -NR. 6 R 7 -CD3, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Substitution of cycloalkoxy groups and 3-8 membered heterocyclic groups; and / or 3)R 1 It is a 3-8 membered heterocyclic group or a 5-10 membered heteroaryl group, wherein each heterocyclic group and heteroaryl group is independently separated by at least one group selected from D, -OH, -CN, -NR. 6 R 7 -CD3, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-8 Substitution with cycloalkoxy groups and 3-8 membered heterocyclic groups.

2. The compound of claim 1 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, satisfying one or more of the following conditions: 1)X 1 It is CH or N, preferably CH; 2)X 2 For CH or N; 3)X 3 It is CH or N, preferably CH; 4) Ring A is selected from C 6-10 Aryl, 5-10 membered heteroaryl and 5-8 membered saturated heterocyclic groups, preferably C 6-10 Aryl or 5-10 heteroaryl, more preferably 5-6 heteroaryl; 5) L is selected from bond, -C(=O)-, -S(=O)2- and -(CR 4 R 5 )-; 6)R 4 and R 5 Each time it appears, it is independently selected from H, D, and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups; 7)R 1 Selected from 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 membered heteroaryl, wherein each of the heterocyclic group, aryl group and heteroaryl group is optionally selected independently from one or more halogens, D, -OH, -CN, -NH2, -CD3, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Substitution with cycloalkyl groups and 3-8 membered heterocyclic groups; 8)R 2 Each time it appears, it is independently selected from H, D, halogen, -OH, -CN, -NH2, -NHCH3, -C(=O)NH2, -C(=O)CH3, -NHC(=O)CH3, -S(=O)2NH2, C 1-6 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 2-4 Heteroalkyl, C 1-4 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic groups, C 6-10 Aryl groups and 5-10 heteroaryl groups, preferably selected from H, D, halogens, -CN, -NH2, -C(=O)NH2, -C(=O)CH3, -NHC(=O)CH3, -S(=O)2NH2, C 1-6 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-6 Hydroxyalkoxy, C 2-4 Heteroalkyl, C 1-4 Hydroxyalkyl, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic groups, and 5-6 membered heteroaryl groups, wherein the alkyl, haloalkyl, alkoxy, haloalkoxy, heteroalkyl, hydroxyalkyl, hydroxyalkoxy, cycloalkyl, cycloalkoxy, heterocyclic, aryl, and heteroaryl groups are each optionally bound by one or more R groups. a replace; 9)R a Each occurrence is independently selected from H, D, halogen, =O, -OH, -CN, -NR. 6 R 7 -C(=O)NR 6 R 7 C 1-6 Alkyl and C 1-6 The alkyl group and the haloalkyl group are each optionally composed of one or more elements independently selected from halogens, D, OH, CN, -NH2, and C. 1-6 Alkyl substituents; Preferably, R a Each time it appears, it is independently selected from H, D, halogen, -OH, -NH2, C. 1-4 Alkyl and C 1-4 The alkyl group and the haloalkyl group are each optionally composed of one or more elements independently selected from halogens, D, OH, CN, -NH2, and C. 1-4 Alkyl substituents; 10)R 6 and R 7 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Halogenated alkyl, or R 6 and R 7 Together with the nitrogen atom it is attached to, it forms a 3-8 member nitrogen-containing heterocyclic group; 11)R 8 Each occurrence is independently selected from H, -OH, -NH2, and C. 1-6 Alkyl and C 1-6 The alkyl group and the haloalkyl group are each optionally composed of one or more elements independently selected from halogens, D, OH, CN, -NH2, and C. 1-6 Alkyl substituents; 12) m is 0, 1, or 2; 13) n is 0 or 1.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, wherein the compound is a compound of formula IA, IB, or IC, preferably a compound of formula I-A1, I-B1, I-C1, or I-C2. in, X 1 X 2 X 3 R 1 R 2 R 4 R 5 m, ring A as defined in claim 1 or 2.

4. The compound of any one of claims 1-3, or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug, satisfying one or more of the following conditions: 1) Ring A is a 5-6 membered heteroaryl or a 5-6 membered saturated heterocyclic group, wherein each of the heteroaryl or saturated heterocyclic group contains one, two or three heteroatoms independently selected from O, N and S; Preferably, ring A is selected from pyrazolyl, pyridinyl, oxazolyl, thiazolyl, pyrimidinyl, and tetrahydropyrroleyl. More preferably, ring A is selected from Where * represents the connection site with L; 2) Selected from 3)R 1 It is a 5-6 membered heteroaryl or a 3-8 membered heterocyclic group, wherein each heteroaryl and heterocyclic group comprises one, two, or three heteroatoms independently selected from O, N, and S, and the heteroaryl group is optionally composed of one or more heteroatoms independently selected from halogens, D, -CD3, C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 3-6 The cycloalkyl group is substituted with a substituent, wherein the heterocyclic group is optionally replaced by one or more substituents selected from halogens, -OH, -CN, -NH2, C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 1-6 Substitution of alkoxy groups; Preferably, the heterocyclic group is selected from tetrahydropyrrole, tetrahydrofuran, tetrahydrothiophene, and piperazinone, and the heteroaryl group is selected from triazolyl, pyrazolyl, pyridinyl, oxazolyl, thiazolyl, and pyrimidinyl; In particular, R 1 Selected from 4)R 2 Each occurrence is independently selected from H, -OH, halogen, -CN, -NH2, -NHCH3, -C(=O)NH2, -C(=O)CH3, -S(=O)2NH2, C 1-6 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-6 Hydroxyalkoxy, C 2-4 Heteroalkyl, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic groups, and 5-6 membered heteroaryl groups, wherein the alkyl, haloalkyl, alkoxy, hydroxyalkoxy, heteroalkyl, cycloalkyl, cycloalkoxy, heterocyclic, and heteroaryl groups are each optionally surrounded by one or more R groups. a replace; R a Each time it appears, it is independently selected from H, D, halogen, -OH, -NH2, -C(=O)NHCH3, C 1-4 Alkyl and C 1-4 The alkyl group and the haloalkyl group are each optionally composed of one or more elements independently selected from halogens, D, OH, CN, -NH2, and C. 1-4 Alkyl substituents; Preferably, R 2 Each occurrence is independently selected from H, -OH, -CN, -NH2, and C. 1-6 Alkyl, C 1-6 Haloalkyl, -C(=O)NH2, -S(=O)2NH2, -NHCH3, -C(=O)CH3, 5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, wherein it is a compound of formula I-C1 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, and satisfies one or more of the following conditions: 1) At least one R 2 Selected from -OH, -NHCH3, -CN, -NH2, -C(=O)NH2, -C(=O)CH3, -S(=O)2NH2, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic groups (e.g., piperazinyl, piperidinyl, tetrahydropyrrolyl, morpholinyl, azirrobutyl), and 5-10 membered heteroaryl groups (e.g., pyrazolyl, isothiazolyl, pyrazinyl), wherein each of the hydroxyalkoxy, cycloalkoxy, heterocyclic, and heteroaryl groups is optionally surrounded by one or more R a Replacement; for example, at least one R 2 Selected from -CN, -NH2, -C(=O)NH2, -C(=O)CH3, -S(=O)2NH2, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic groups (e.g., piperazinyl, piperidinyl, tetrahydropyrrolyl, morpholinyl, azirrobutyl), and 5-10 membered heteroaryl groups (e.g., pyrazolyl, isothiazolyl, pyrazinyl), wherein each of the hydroxyalkoxy, cycloalkoxy, heterocyclic, and heteroaryl groups is optionally surrounded by one or more R a replace; R a Each time it appears, it is independently selected from H, D, halogen, -OH, -NH2, -C(=O)NHCH3, C 1-4 Alkyl and C 1-4 The alkyl group and the haloalkyl group are each optionally composed of one or more elements independently selected from halogens, D, OH, CN, -NH2, and C. 1-4 Alkyl substituents; Preferably, at least one R 2 Selected from -OH, -CN, -NH2, -C(=O)NH2, -S(=O)2NH2, -NHCH3, -C(=O)CH3, 2) m and ring A are as defined in any one of claims 1-4.

6. A compound of formula I-C1 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof. in, R 1 It is a 6-8 membered heterocyclic group (e.g., piperazinone group), said heterocyclic group optionally being selected independently by one or more halogens, D, -OH, -CN, -NR. 6 R 7 -CD3, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Substitution of cycloalkoxy groups and 3-8 membered heterocyclic groups; Preferably, R 1 for R 2 R 6 R 7 m and ring A are as defined in any one of claims 1-5.

7. A compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, wherein the compound is selected from:

8. A pharmaceutical composition comprising the compound of any one of claims 1-7 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite or prodrug thereof, and one or more pharmaceutically acceptable carriers.

9. The use of the compound of any one of claims 1-7 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite or prodrug, or the pharmaceutical composition of claim 8 in the preparation of a medicament, particularly in the preparation of a medicament for the prevention or treatment of diseases or conditions associated with MASTL activity.

10. The use as claimed in claim 9, wherein the disease or condition associated with MASTL activity is cancer or tumor, preferably cancer or tumor with high MASTL expression, preferably lung cancer, pancreatic cancer, breast cancer, ovarian cancer, hepatocellular carcinoma, gastric cancer, colon cancer, head and neck squamous cell carcinoma, or prostate cancer.

11. A method for preparing the compound as described in any one of claims 1-7, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, selected from the following methods: Method 1 includes one or more of the following steps: Step 1: Compound IB-1 reacts with (Boc)2O under the action of a base to generate compound IB-2; Step 2: Compound IB-2 reacts with benzophenone imine via a Buchwald coupling reaction to generate compound IB-3: Step 3: Compound IB-3 undergoes a reduction reaction to generate compound IB-4; Step 4: Compound IB-4 undergoes a condensation reaction to generate compound IB-5; Step 5: Compound IB-5 undergoes deprotection under acidic conditions to generate compound IB; Method 2 includes the following steps: Compound IB-1 undergoes a Buchwald coupling reaction to generate compound IC; Method 3 includes one or more of the following steps: Step 1: Compound IC-1 undergoes a Buchwald coupling reaction to generate compound IC-2; Step 2: Compound IC-2 undergoes a Buchwald coupling reaction to generate compound IC-3; Step 3: Compound IC-3 undergoes a deprotection reaction to generate compound IC; Method four includes one or more of the following steps: In the first step, compound IC-1 undergoes a Buchwald coupling reaction to generate compound IC-1-2; In the second step, compound IC-1-2 undergoes a substitution reaction to generate compound IB-3; Method 5 includes one or more of the following steps: In the first step, compound IB-2 undergoes a Buchwald coupling reaction to generate compound I-1; In the second step, compound I-1 undergoes a deprotection reaction to generate compound I. Method six includes the following steps: compound IB-4 undergoes a Buchwald coupling reaction to generate compound I-1. Among them, R 2a R is optionally protected by a protecting group (e.g., an amino protecting group). 2 ;X 1 X 2 X 3 R 1 R 2 m, ring A and L are as defined in any one of claims 1-7; Y 1 and Y 2 Each is independently a halogen, such as fluorine, chlorine, bromine, or iodine, preferably chlorine; PG1 and PG2 are each independently an H or amino protecting group, such as alkoxycarbonyl amino protecting groups, for example benzyloxycarbonyl (Cbz), tert-butyloxycarbonyl (Boc), methoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilylethoxycarbonyl (Teoc), or methoxycarbonyl (or ethoxycarbonyl); acyl amino protecting groups, such as phthaloyl (Pht), p-toluenesulfonyl (Tos). ), trifluoroacetyl (Tfa), o-(p-)nitrobenzenesulfonyl (Ns), p-pentanoyl, benzoyl, tert-butoxycarbonyl, 9-fluorenmethoxycarbonyl, allyloxycarbonyl, trichloroethoxycarbonyl, trimethylsilylethoxycarbonyl, benzyloxycarbonyl, p-methylbenzenesulfonyl, p-nitrobenzenesulfonyl, tert-butyl, trifluoroacetyl, methoxycarbonyl or ethoxycarbonyl; alkyl amino protecting groups, such as triphenylmethyl (Trt), 2,4-dimethoxybenzyl (Dmb), 4-methoxybenzyl (PMB) or benzyl (Bn).

12. The following are compounds or their salts, esters, stereoisomers, tautomers, isotopically labeled compounds, polymorphs, solvates, or N-oxides: (for example) ), (for example) ), (for example) ), (for example) ), in: Y 1 Y 2 PG1, PG2, X 1 X 2 X 3 R 1 R 2 R 2a m, ring A, and L are as defined in claim 11.

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