TW202005967A - Selective inhibitors of clinically important mutants of the EGFR tyrosine kinase - Google Patents

Abstract

The present invention provides compounds of Formula (I) or a subgeneric structure or species thereof, or a pharmaceutically acceptable salt, ester, solvate, and/or prodrug thereof, and methods and compositions for treating or ameliorating abnormal cell proliferative disorders, such as cancer, wherein A, R², R³, R¹⁰, E¹, E², E³, Y, and Z are as defined herein.

Description

Selective inhibitor of clinically important mutants of EGFR tyrosine kinase

The present invention relates to a compound of formula (I) or a subgenus structure or substance or a pharmaceutically acceptable salt ester, solvate and/or prodrug thereof, and includes such compound or a pharmaceutically acceptable salt thereof Pharmaceutical compositions of esters, solvates and/or prodrugs. The compounds and salts of the present invention inhibit kinases, especially epidermal growth factor receptor EGFR, and their specific mutants that are essential for the development of treatment resistance by EGFR inhibition therapy, and are suitable for the treatment or improvement of abnormal cell proliferative disorders, such as cancer.

The present invention relates to biarylamino compounds suitable as highly selective inhibitors of certain protein tyrosine kinases PTK, which are one of the subclasses of protein kinase PK. PK is an extremely important signaling entity in intracellular communication, in which it modifies a variety of proteins by catalyzing the transfer of the phosphate group from ATP acting as a phosphate donor to the phenolic hydroxyl group on the tyrosine side chain of the protein. Tyrosine kinase is often incorporated into the intracellular domain of a very large transmembrane protein, which has a homologous ligand binding domain in the extracellular domain, whereby ligand binding activates tyrosine in the cell Kinase. These molecules are receptor tyrosine kinases (RTK).

Structurally, these kinases are fully understood. There is a kinase domain, which can be a complete protein or only a domain of a much larger modular protein, and this domain has a basic conserved structure of about 35 kD, consisting of two leaflets, and the N-terminal leaflet is mainly composed of β-sheets The larger C-terminal domain is mainly composed of α-helix. There is a deep split between the two leaflets that binds both ATP and substrate. The substrate binding domain is extremely large and quite variable, and is used to distinguish substrates of different proteins and maintain phosphorylation specificity. This specificity can be extremely variable, with some enzymes such as MEK having only one known substrate, and other enzymes capable of phosphorylating hundreds of different hydroxyl groups in proteins.

Phosphorylation often changes the configuration of the modified protein, usually converting the enzyme from the inactive form to the active form, or vice versa, or tightly associates the protein with the specific binding partner, or may dissociate from it, Causes changes in cell positioning of functional multiprotein complexes, or assembly, or disassembly. The various transducers of signals that enter the cell and enter the nucleus from the cell surface are PK, or are controlled by PK, especially RTK. Therefore, inhibitors of kinase activity of PK can have extremely violent effects on cell signaling, alleviate normal responses to external signals, and improper overreactions usually caused by mutations or abnormal performance levels of one or more signaling molecules themselves. Although these pathways are extremely common in the body and are involved in one way or another in most body functions and diseases that can be caused by dysfunction, PK inhibitors are particularly suitable for the treatment of cancer and immune disorders. The overactivity of PK, especially RTK, in disease categories has been widely proven, and among them it usually plays a vital role in driving the disease process itself.

Kinases have been shown to be extremely important effectors in various disease processes, especially cancer. Cell proliferation is controlled by kinases at various levels, and under normal conditions of cell proliferation, signals must be sent from outside the cell, where it binds to receptors and activates these receptors. Various important receptors in cell signaling are kinases, especially RTK, or directly coupled to kinases that are activated by themselves through activated receptors. Once these kinases have been activated, they activate the signaling cascade, which usually involves several other kinases in the amplified wave of phosphorylation, which ultimately results in translocation to transcription factors in the nucleus and these transcriptions Factor activation. The activation of transcription factors leads to the production of proteins that perform multiple programs in the cell, including those that cause the cell to enter the hyperplastic cycle. Generally, once this process has continued for several hours, the newly synthesized protein will continue the process without further extracellular input. If the proliferative cell cycle is initiated, the first set of synthesized proteins includes other transcription factors, and its activators that drive later stages of the cell cycle, and effectors that begin the process of replicating and dividing cells. Kinase is the main control factor for each step in the process. When this process is not properly controlled and the cell can perform the cell cycle without proper external control, it is transformed, and if the immune system cannot eradicate these cells, it can form a tumor.

When examining transformed cells, one of their invariant features is hyperphosphorylation, showing that these cells have an overall excess of kinase activity, especially in the absence of any growth factors. Hyperphosphorylation can be caused by various mutations in the cell. For example, caused by a cell targeting a receptor-linked kinase that inappropriately produces its own ligand. Alternatively, one of these kinases may be severely over-expressed due to inability to properly control its performance, or due to multiple additional copies of the genes present in the cell. Another extremely common genetic defect is a mutation in the coding region of the kinase, which produces a constitutively active kinase and does not require an appropriate signal to activate it. Sometimes, the kinase may not have inappropriate activity, but the phosphatase is not activated by mutation or deletion, and it is speculated that the phosphatase limits its signaling by removing the phosphate from the target molecule. Examination of both cell culture tumors and isolates from clinical tumors will almost always find this type of defect in the phosphorylation system of tumor cells.

In the late 1980s, several small molecule kinase inhibitors were discovered. These molecules bind to the catalytic crack of the kinase almost unchanged and compete with ATP for their binding site. Therefore, it is ATP competitive, and most inhibitors found since then belong to this category. However, occasionally it has been found that kinase inhibitors compete with protein substrates (substrate competition), or more commonly with both ATP and substrate (dual inhibitors), or neither with receptors nor substrates ( Non-competitive inhibitors). After taking into account the difference in cell penetration, it was found that there is an extremely good relationship between the effectiveness of these compounds in the assay of isolated kinase enzyme inhibition and the inhibition of kinases in cells. Regarding multiple kinases, there is also an excellent relationship between the phosphorylation loss of downstream targets and the inhibitory effect of cell proliferation. Since this relationship has been shown thousands of times by a variety of different kinases, it is clearly demonstrated that abnormal kinase signaling can cause uncontrolled proliferation in transformed cells, and in many cases, blocking of overactivated kinase can stop the proliferation. In many cases, kinase inhibitors alone can actually induce apoptosis in transformed cells, leading to tumor shrinkage. This can happen because multiple genetic damage in the cell has been detected by the cell-corrected reading system, and the result usually activates several pro-apoptotic mechanisms in these cells, but abnormal phosphorylation can be fully involved in inhibiting The process of apoptosis. Some kinase inhibitors, especially those that target the kinases involved later in the cell cycle, are inherently cytotoxic because cells that are interrupted during mitosis tend to apoptosis very easily. Although good evidence that these capabilities in cells may prevent tumors growing as xenografts in nude mice initially appeared slowly, when the reagents were modified, it was shown that kinase inhibitors may slow the performance of targeted oncogenes The growth of tumors becomes routine, and better reagents return the size of the tumor, usually to a point where it is not measurable, and occasionally, these tumors will not regenerate after stopping the administration, indicating that the animal may have cured the tumor. In addition, after one of the in vivo efficacy and cell and enzyme activity has been correlated with tumor exposure, the in vivo efficacy is correlated with cell and enzyme activity.

Clinically proven to appear slowly, partly because clinical tumors are usually much more complicated than tumors grown under carefully controlled conditions, and partly because mice are much stronger in biochemistry than humans and can tolerate larger relative doses Drugs, and mainly because it is often extremely difficult to know which are the appropriate kinases to inhibit in any given random human tumor. However, imatinib was approved in 2000 for chronic myelogenous leukemia (CML), which is a fairly effective inhibitor of fusion tumorigenic TK BCR-ABL. This kinase inhibitor provides an extremely convincing clinical proof of the theoretical concept, because about two-thirds of CML patients (whose tumor actually contains one of the two forms of BCR-ABL) respond very well to treatment, and usually Leukemia cells disappear almost completely from the circulation. Surprisingly, blocking the surrounding mutations seems extremely slow, and the drug is still effective in 80% of patients even after 10 years of treatment. This has not been proven to be a general condition, partly because most tumors are found much later than CML in their biological history and take longer to become genetically heterogeneous, and partly because very few tumors are like CML Dependence on BCR-ABL is generally dependent on an oncogene.

Epidermal growth factor receptor tyrosine kinase inhibitor

The two 4-anilinoquinazoline inhibitors gefitinib and erlotinib of the epidermal growth factor RTK (EGFR, erbB-1) were approved for lung cancer about 10 years ago. EGFR is one of the most common dysregulated kinases seen in solid tumors, of which overexpression or mutation is usually seen in 50% or more of tumor types including non-small cell lung cancer (NSCLC). Although these inhibitors have excellent activity against multiple xenografts that have overexpressed EGFR, very limited activity can be seen in NSCLC, of which only about 10% of patients respond to the drug, and the average response lasts only about one year, but occasionally found Responders who lasted much longer. Surprisingly, in other tumor types known to have expressed EGFR, especially colorectal cancer (CRC), no targeted activity has been demonstrated, but the anti-EGFR monoclonal antibody Erbitux has shown comparable in CRC that has approved the use of this antibody Good clinical activity.

When scrutinizing NSCLC responders, it is found that most good responders have one of several EGFR single mutations (sm-EGFR), and those responders with wild-type receptor (wt-EGFR) usually do not respond significantly , Regardless of performance level. These mutations are extremely rare in CRC, which tends to over-express wt-EGFR, or over-express autocrine ligand expression. When analyzing these mutants, especially EGFR L858R and EGFR del746-750, it was found that they had intrinsically activated properties, which means that they drive proliferation without external signals and are also weaker than wt EGFR Binds ATP (higher K _m ), and has similar affinity to wt EGFR for these inhibitors. This means that because these inhibitors are ATP-competitive, it is easier to compete for ATP from the enzyme than in wt and turn off the kinase activity in susceptible mutants, in fact promoting the efficacy of inhibitors in these mutants. At the same time, these tumors have become more dependent on EGFR signaling for hyperplasia and survival than most tumors because the signals have been indeed too active since the initial mutation event.

As mentioned earlier, solid tumors, such as lung cancer, usually take quite a long time to be discovered, and their discovery may be an average of 6-12 years later than the appearance of the initial transformed cells. One of the characteristics of transformed cells is that they lose control of the quality control of their DNA replication, so their spontaneous mutation rate is much higher than that of untransformed cells. Since mutations are most likely to occur during DNA replication, and these cells replicate extremely rapidly, this further increases the mutation rate. The result is that as the tumor grows older, it will pick up a growing number of mutations, and it will pick it up in a random manner, so that the pure line of the tumor appears over time, with genetics that are slightly different from the original tumor and each other. These sub-pure lines not only involve competing for survival with the subject itself, but also competing with each other for survival because they compete with each other for the limited resources available to them. If the environment of the dominant tumor pure line is changed so that it becomes relatively unsuitable for its new environment (for example, by adding an effective inhibitor to it), the secondary pure line that was not previously successful may be able to receive the vacant Niche, as long as it is not affected by the inhibitor. Or, unless the pure line is killed completely, or the hyperplasia is completely turned off, it will continue to produce mutations, and if the mutation avoids the inhibitory effect, this sub-pure line will now proliferate arbitrarily, without the inhibitor or the suppressed Obstruction of the pure line of the parents. Therefore, natural selection predicts that cancer (like an infectious disease) should be able to develop drug resistance, and because the selection process is mainly driven by competition among tumor sub-branches within a single quality, the overall effect is to promote more aggressive sub-branches , And tumors generally become more deadly as they develop.

When following gefitinib and erlotinib responders, it was found that the onset of resistance may be associated with several different genetic changes. In rare cases, the tumor appears to pick up completely different signaling systems to drive the tumor, but usually, this resistance involves adjustment of the initial system. EGFR, together with erbB-2, erbB-3 and erbB-4, is a member of the erbB (type I) subfamily of RTK. These receptors are activated by ligands that induce their dimerization, and although EGFR-EGFR homodimers are quite commonly used for signaling, a more common process in this family is to induce ligands to induce heterodimerization, So that the signaling entity will be, for example, EGFR: erbB-2 or erb-B2: erbB-3 and appropriate ligands. The simplest way to reactivate the system is to increase the performance of one of the other erbBs, and this is frequently seen, even before treatment, and may help explain why multiple wt EGFR over-expressing tumors do not respond to EGFR inhibition. Slightly related mechanisms involve RTK HGFR, although not a member of the erbB family, RTK HGFR has been shown to form carcinogenic heterodimers with erbB family members, especially erbB-3 when overexpressed, and overexpression of HGFR is a common resistance to EGFR inhibitors mechanism. At least in laboratory settings, adding HGFR inhibitors to these cells will restore sensitivity to EGFR inhibitors. The third and most common pattern of resistance is further mutation in EGFR, resulting in a double mutant receptor (dm-EGFR), which reduces its sensitivity to EGFR inhibitors. The most common of these is the so-called "gatekeeper" mutation T790M, and NSCLCs with double mutants such as L858R/T790M are usually visible in the initial responders, who have subsequently developed resistance to EGFR inhibitors. It is impossible to know that the homozygote is always present, or that it only appears after treatment, but it seems most likely that the mutation is already present in short-term responders and can be used as a renewal in long-term responders who later develop resistance The mutation appears.

Initially, Xianxin's mutations blocked the inhibitor from spatially binding to the mutant enzyme, thus reducing its affinity and efficacy. However, recent studies have shown that these most common mutations have very little effect on the affinity of inhibitors, but may cause the ATP binding affinity to return to the affinity of wt EGFR, or may be as high as 10 times larger. The result is that these inhibitors can The achieved concentration is no longer high enough to turn off signaling to a therapeutically useful level. In principle, it is only necessary to improve the affinity of these inhibitors so that it is sufficient to overcome the increased ATP affinity, but in fact this is extremely difficult to perform, because gefitinib and erlotinib are already extremely effective with good PK properties , Sub-anamol concentrations, EGFR inhibitors, and still have general activity against tumors driven by wt EGFR. In addition, although the T790M mutant does not reduce the affinity of EGFR for erlotinib and gefitinib, it does limit the ways in which the affinity of the two inhibitors in the anilinoquinazoline chemical form may be increased. Therefore, in order to discover a greater affinity for T790M type mutants, new chemical templates have been examined, and some templates, especially U-type inhibitors of the type discussed later, seem to have considerable hope in this field.

EGFR receptors play an important role in the body, especially in the entire gastrointestinal epithelium and skin. The entire gastrointestinal epithelium and skin are hyperactive tissues. As two major toxicities, the dose-limiting toxicity of EGFR inhibitors is rash and severe GI disorder, which is almost certainly mainly mechanism-based toxicity. As long as the tumor is driven by wt EGFR, this is extremely difficult to avoid by rational design, especially for oral agents, where GI tract exposure is specific, but if the tumor is driven by mutant EGFR, it may be able to reduce the use of approved drugs Visible toxicity. Regarding NSCLC responding to EGFR inhibitors, the initial target is not wt-EGFR, but one of a limited number of sm-EGFR, and later the target is dm-EGFR, at least in principle, the two should have different from wt-EGFR The structure-activity relationship (SAR) at least gives the theoretical possibility to reduce side effects by discovering inhibitors with significantly better affinity for sm- and/or dm-EGFR than wt-EGFR. Attributed to the similarity between EGFR and mutant EGFR, and in fact the initial inhibitor only worked because it was already a sm-EGFR inhibitor superior to wt-EGFR, not due to intrinsic affinity (but ATP Competition), this is expected to be a difficult feat. Unfortunately, clinical observations indicate that the abnormal EGFR system that drives tumors needs to be extremely severely suppressed to produce targeted efficacy, while inhibiting wt-EGFR signaling in normal tissues at a high level sufficient to induce restrictive toxicity is relatively easy to achieve. However, EGFR inhibitors with enhanced affinity for EGFR mutants, especially T790M dm-EGFR have been found and examples of many of them are in the literature, several of which are currently in clinical trials. This patent application describes compounds that meet one of these criteria.

EGFR inhibitors with a significantly higher affinity for mutant EGFR than wt EGFR should be able to inhibit hyperplasia in tumors driven by the mutant at the optimal dose, and if they have any effect on EGFR signaling in untransformed tissues , The effect is relatively small, and wt EGFR is responsible for EGFR signaling in these untransformed tissues. This should allow the administration of significantly larger doses of mutant selective EGFR inhibitors, thereby increasing the efficacy and therapeutic index against mutant-driven tumors. It should be noted that due to the effect of the mutant on ATP binding, this is basically a situation already encountered by erlotinib and gefitinib responders, where the responding mutant is actually more sensitive to these inhibitors than wt EGFR, This is mainly due to its weakened affinity for the competitive ligand ATP. Several third-generation EGFR inhibitors have been revealed, some of which are in clinical practice. These compounds are generally irreversible inhibitors, originally based on the U-shaped diphenylaminopyrimidine skeleton, but this skeleton has been extended to several related skeletons, but all skeletons are bound to diphenylaminopyrimidine in a similar pattern. In general, these compounds are extremely effective inhibitors of mutant EGFR containing the T790M mutation, and are slightly less effective against wt EGFR and some other mutations. Because of this type, the mechanism-based toxicity of Xianxin wt EGFR inhibition should be significantly reduced, while maintaining extremely strong inhibitory efficacy against tumors driven by appropriate EGFR mutations. Therefore, this type of compound may be particularly suitable as a second-line therapy after patients previously susceptible to first-line erlotinib or gefitinib therapy have developed resistance. Not only will these inhibitors allow the appropriate mutant receptor to be strongly inhibited as before, but it should not itself induce toxicity via EGFR inhibition through a perceptible mechanism when doing so. The inhibitors of the present invention are irreversible inhibitors of EFGR. These agents have a similarly selective type against the mutant wt EGFR inhibition, and have excellent pharmacokinetic properties, and therefore will be proven to be used in NSCLC and by mutants An excellent agent for second-line treatment of any other tumor driven by this subfamily of EGFR kinases.

In the mid-1990s, another method was developed that particularly increased the efficacy of EGFR inhibitors. Multiple sites on the protein are quite nucleophilic because they are nucleophilic in nature, with cysteine thiol as an example in principle, of which lysine, histidine imidazole and serine , Threonine and tyrosine hydroxyl groups are also less likely to be effective, or because they have been intentionally activated, such as in the catalytic hydroxyl group in various amidases. These residues can usually be targeted by electrophiles, which modify the protein under fairly mild conditions. Depending on the function of the modified residue and its position on the protein, this may or may not result in loss of enzyme function. It is recognized that a subset of TK uses cysteine residues on the edge of the ATP binding gap to form hydrogen bonds with the ribose of ATP, and most TK uses threonine for this purpose. The EGFR family contains this cysteine (C ^{797 in} EGFR). It is speculated that this cysteine may be partially alkylated by an alkylation attached to an inhibitor that binds to the ATP binding site and provides an electrophile near the cysteine sulfur. In fact, many first-generation EGFR inhibitors are effective electrophiles, which may have fully targeted Cys ⁷⁹⁷ or other nucleophiles on EGFR. Unfortunately, this inhibitory effect neither produces extremely effective inhibitors nor extremely sensitive inhibitors, indicating that these electrophiles are sufficiently reactive and sufficiently indistinguishable to interact with multiple proteins, especially Kinase reactions, and in many of these cases, alkylation occurs in the catalytic domain or the control "switching zone" of the enzyme. For this concept to be useful, the alkylated part must have low inherent reactivity, because for potential PK and toxicity reasons, we do not want it to react with various nucleophiles in the body without distinction. In order for the alkylating agent to react with this very selective, very weak electrophilic reagent, it is shown that the compound itself must have a high (non-covalent) affinity for the binding site, and it will preferably have the following configuration In combination, the configuration places the electrophile in close proximity to the weak electrophile. Finally, it was also found that the reaction needs to be faster than the plasma half-life of the inhibitor, or most of them wash out from the body without ever reacting with the vital cysteine. These irreversible inhibitory compounds were found, and not only were they much more effective EGFR inhibitors in vivo than theoretically equivalent reversible inhibitors, but they also enabled (at least in anilinoquinazoline and related 3-cyano In the case of quinoline), the very poor erbB-2 and erbB-4 inhibition templates become extremely effective inhibitors of all erbB, proving that if the binding mode is very good in the placement of its alkylated part, it is extremely targeted at the target. High non-covalent affinity may not be important. Most of the second-generation EGFR inhibitors that enter the clinic are irreversible inhibitors of EFGR, which use acrylamide derivatives as electrophiles, and they appear to be more active in clinical practice than reversible inhibitors, but they also tend Because of its high toxicity, only one inhibitor, afatinib, has been shown to be in good form for approval.

Many different classes of kinase inhibitors have been developed, and several have been successfully approved and sold. It appears that one of the molecular skeletons that produces effective inhibition of a large number of kinases is a series of three-cascade rings, two of which and often all three rings are aromatic. These three-cascade rings can form when bound to kinases U-shaped structure. The two distal rings can be directly connected to the central ring by bonds or via various linkers consisting of a chain of 1-3 atoms. The central ring is almost unchanged as a nitrogen-containing heteroaromatic system with an NH group adjacent to the ring nitrogen, in the hinge domain of the kinase, between the N-terminal and C-terminal leaflets, just before the so-called DFG ring Forming 1-3 hydrogen bonds with the residue backbone, the DFG loop is an invariant structure in the kinase, which must be placed appropriately for the active configuration of the enzyme to be achieved. This end of the inhibitor also occupies part of the adenine-binding region of the kinase, which tends to be very hydrophobic, while the two loops that generate the "stem" of U occupy a wide channel, which is often filled with the remainder usually composed of ATP molecules Part of the space occupied by part. Although much of the affinity for specific kinases comes from decorating these core loops with the selected substituents, these substituents have a favorable interaction with the promising unique structural determinants in the target kinase, and/or not with the kinase It is desirable to inhibit the unfavorable interaction, but a large amount of affinity and selectivity for multiple kinases comes from various torsion and bending angles between the three loops, and some substituents that optimize the affinity for the target kinase cannot themselves directly It interacts with the protein and can control the most stable configuration of the three loops with respect to each other. Therefore, the purpose of some substituents may be to affect the overall internal energy of the inhibitory molecule in order to stabilize the favorable configuration for binding rather than directly interacting with the kinase.

The first-generation and second-generation EGFR/erbB-2 inhibitors that entered the clinic did not show a U-shaped binding mode. Having bound to (or extend the 4-anilino group) in the 4-anilino-gap between the collapsed and β4 αC- helix, the important groups L ⁷⁴⁵ -D ⁸⁵⁵ as part of a salt bridge and the D ⁸⁵⁵ Behind the DFG ring.

The present invention partially provides novel compounds and pharmaceutically acceptable salts, solvates, esters and/or prodrugs thereof, which can selectively modulate protein kinases, especially type I receptor tyrosine kinase (RTK) family Or the activity of the erbB family and most specifically certain mutant forms of the EGFR receptor that provide resistance to current EGFR-based inhibitor therapy. This inhibitory activity affects biological functions, including but not limited to cell proliferation and cell invasion, inhibiting metastasis, inducing apoptosis, or inhibiting angiogenesis. Also provided are pharmaceutical compositions and medicaments which comprise the compounds or salts of the present invention alone or in combination with other therapeutic or relieving agents.

In one embodiment, the present invention relates to a compound of formula (I) or its stereoisomer or pharmaceutically acceptable salt, solvate, ester or prodrug as disclosed herein.

或其立體異構體或醫藥學上可接受之鹽、溶劑合物、酯或前藥；其中，Z為CH或N；Y為

在Y¹及Y²中，R^5a為H、F、Cl、CF₃、CHF₂、CF₂C_1-6烷基、CF₂CH₂NR⁸R⁹、CH₂NR⁸R⁹、CN或C_1-6烷基；在Y¹及Y²中，R^6e為R¹⁰、H、F、芳基、雜芳基、環烷基、雜環烷基(CH₂)_mCHR¹⁰R⁷、CF₂(CH₂)_mCHR¹⁰R⁷或C(R¹⁰)₂R⁷；在Y⁴及Y⁵中，R^6t為C_1-6烷基、C_3-6環烷基、芳基、雜芳基、雜環烷基、(CH₂)_mCHR¹⁰R⁷、C(R¹⁰)₂R⁷；在Y¹及Y²中，R^6z為H、F、Cl、CF₃、CHF₂、CF₂C_1-6烷基或C_1-6烷基；或或者在Y¹及Y²中，R^6e及R^6z合起來形成=CR^6e'R^6z'(丙二烯)，其中R^6e'為R¹⁰、H、F、芳基、雜芳基、環烷基、雜環烷基、(CH₂)_mCHR¹⁰R⁷、CF₂(CH₂)_mCHR¹⁰R⁷或C(R¹⁰)₂R⁷且其中R^6z'為H、F、Cl、CF₃、CHF₂、CF₂C_1-6烷基或C_1-6烷基；或 或者在Y¹及Y²中，R^6e及R^6z與該兩者同時附接之sp²碳原子合起來形成4至7個成員之脂環族環，其中環原子之一視情況由NR⁸、O、S(O)_x、S(=O)(=NR⁸)、P=O、P(=O)(OR⁸)、OP(=O)(OR⁸)O置換，且該脂環族環視情況經選自由鹵素、側氧基、OH、OR⁸及NR⁸R⁹組成之群之一或多個取代基取代；R¹獨立地選自氫、氟、氯、溴、甲基、乙基、羥基、甲氧基、乙氧基、異丙氧基、環丙氧基、-OCF₃、-OCH₂CF₃、-OCH₂CHF₂、乙烯基、乙炔基、-CF₃、-CHF₂、-CHO、-CH₂OH、-CONH₂、-CO₂Me、-CONHMe、-CONMe₂及氰基；R²為-OCF₃、-OCHF₂、-OCF₂CF₃、-OCH₂CHF₂、-OCH₂CF₃、環丙基、環丙氧基、甲氧基、-OCD₃、乙氧基或異丙氧基；R³為-N(R¹⁰)C_2-6烷基-NR¹⁰R¹⁰、-N(R¹⁰)C_2-6烷基-R⁷、-O(CH₂)_pR⁷、-N(R¹⁰)C(=O)(CH₂)_pR⁷或R⁷；R^4a、R^4b及R^4c各自獨立地為H、氰基、硝基、鹵基、-C_1-6烷基、-C_1-6鹵烷基、-羧基-C_1-6烷基、-C_1-6羥基烷基、R⁸R⁹N-C_1-6烷基-、-C_2-6烯基、-C_2-6炔基、C_1-6醯基-、R⁷-(CH₂)_pC(=O)-、C_1-6羥基烷基-C(=O)-、羧基、-C_1-6烷氧基羰基、-C(=O)NR⁸R⁹、羥基、-C_1-6烷氧基、-C_1-6醯氧基、-NR⁸R⁹、C_1-6醯基-N(R¹⁰)-、吡唑、1,2,3-三唑、四唑、(C_1-6烷基)SO₂-或R⁷SO₂-；R⁷為OH、NR⁸R⁹、O(CH₂)_qNR⁸R⁹、C_1-6烷氧基、C_1-6烷氧基-C_1-6烷氧基、C_2-6羥基烷氧基、氧雜環丁烷基、氧雜環丁烷基氧基、氧雜環丁烷基胺基、氧雜環戊烷基、氧雜環戊烷基氧基、氧雜環戊烷基胺基、氧雜環己烷基、氧雜環己烷基氧基、氧雜環己烷基胺基、氧雜環庚烷基、氧雜環庚烷基氧基、氧雜環庚烷基胺基、氮雜環丁烷基、氮雜環丁烷基氧基、氮雜環丁烷基胺基、吡咯啶基、吡咯啶基氧基、吡咯啶基胺基、六氫吡啶基、六氫吡啶基氧基、六氫吡啶基胺基、氮雜環庚烷基、氮雜環庚烷基氧基、氮雜環庚烷基胺基、二氧雜環戊烷基、二噁烷基、嗎啉基、硫代嗎啉基、硫代嗎啉基-S,S-二氧化物、六氫吡嗪基、二氧 雜環庚烷基、二氧雜環庚烷基氧基、二氧雜環庚烷基胺基、氧氮雜環庚烷基、氧氮雜環庚烷基氧基、氧氮雜環庚烷基胺基、二氮雜庚烷基、二氮雜庚烷基氧基、二氮雜庚烷基胺基、(3R)-3-(二甲基胺基)吡咯啶-1-基、(3S)-3-(二甲基胺基)吡咯啶-1-基、3-(二甲基胺基)氮雜環丁烷-1-基、[2-(二甲基胺基)乙基](甲基)胺基、[2-(甲基胺基)乙基](甲基)胺基、5-甲基-2,5二氮雜螺[3.4]辛-2-基、(3aR,6aR)-5-甲基六-氫-吡咯并[3,4-b]吡咯-1(2H)-基、I-甲基-1,2,3,6-四氫吡啶-4-基、4-甲基六氫吡嗪-1-基、4-[2(二甲基胺基)-2-側氧基乙基]六氫吡嗪-1-基、甲基[2-(4-甲基六氫吡嗪-1基)乙基]胺基、甲基[2-(嗎啉-4-基)乙基]胺基、1-胺基-1,2,3,6四氫吡啶-4-基、4-[(2S)-2-胺基丙醯基]六氫吡嗪-1-基，其均可視情況經OH、OR¹⁰、側氧基、鹵素、R¹⁰、CH₂OR¹⁰或CH₂NR⁸R⁹取代；R⁸及R⁹各自獨立地為H、-CD₃、C_1-6烷基、C_3-6烯基、C_3-6炔基、C_3-8環烷基、-(C_1-3烷基)-(C_3-8環烷基)、C_3-8環烯基、C_1-C₆醯基、4-12員單環或二環雜環基、4-12員單環或二環雜環基-C₁-C₆烷基-、C_6-C₁₂芳基、5-12員雜芳基；其中R⁸及R⁹可進一步獨立地經多達三個選自羥基、C_1-6烷氧基、C_1-6羥基烷基、C_1-6烷氧基-C_1-6烷基、C_1-6烷氧基-C_1-6烷氧基、C_2-6羥基烷氧基、側氧基、硫羰基、氰基或鹵基之取代基取代；或或者，R⁸及R⁹與其同時附接之N原子合起來形成4-7個成員之雜環，該雜環含有多達一個選自O、S或NR¹¹之其他雜原子，或形成7-12個成員之雜雙環，該雜雙環可為稠合、橋接或螺環，且含有多達兩個選自O、S(O)_x或NR¹¹之其他雜原子，且此等雜環視情況經多達三個選自羥基、C_1-6烷氧基、C_1-6羥基烷基、C_1-6烷氧基-C_1-6烷基、C_1-6烷氧基-C_1-6烷氧基、C_2-6羥基烷氧基、側氧基、硫羰基、氰基或鹵基之取代基取代；R¹⁰各自獨立地為H、-CD₃、C_1-6烷基、C_3-6環烷基、C_2-6羥基烷基、C_1-6烷氧基-C_1-6烷基或C_2-6烷基-NR⁸R⁹； 或者，同時附接之同一N原子上的兩個R¹⁰形成5-6個成員之雜環，該雜環含有多達一個選自O、S或NR¹¹之其他雜原子；R¹¹各自獨立地為氫或C_1-C₆烷基，其視情況經多達三個選自羥基、側氧基、硫羰基、氰基或鹵基之取代基取代；m為0、1、2或3；n為1、2或3；q為2、3或4；p為0、1、2、3或4；且x為0、1或2。 In one embodiment, the invention relates to compounds of formula (A) or (B):

Or its stereoisomer or pharmaceutically acceptable salt, solvate, ester or prodrug; where Z is CH or N; Y is

In Y ¹ and Y ² , R ^5a is H, F, Cl, CF ₃ , CHF ₂ , CF ₂ C _1-6 alkyl, CF ₂ CH ₂ NR ⁸ R ⁹ , CH ₂ NR ⁸ R ⁹ , CN or C _1-6 alkyl; in Y ¹ and Y ² , R ^6e is R ¹⁰ , H, F, aryl, heteroaryl, cycloalkyl, heterocycloalkyl (CH ₂ ) _m CHR ¹⁰ R ⁷ , CF ₂ (CH ₂ ) _m CHR ¹⁰ R ⁷ or C(R ¹⁰ ) ₂ R ⁷ ; in Y ⁴ and Y ⁵ , R ^6t is C _1-6 alkyl, C _3-6 cycloalkyl, aryl, Heteroaryl, heterocycloalkyl, (CH ₂ ) _m CHR ¹⁰ R ⁷ , C(R ¹⁰ ) ₂ R ⁷ ; in Y ¹ and Y ² , R ^6z is H, F, Cl, CF ₃ , CHF ₂ , CF ₂ C _1-6 alkyl or C _1-6 alkyl; or alternatively in Y ¹ and Y ² , R ^6e and R ^6z combine to form =CR ^6e' R ^6z' (propadiene), where R ^6e' is R ¹⁰ , H, F, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, (CH ₂ ) _m CHR ¹⁰ R ⁷ , CF ₂ (CH ₂ ) _m CHR ¹⁰ R ⁷ or C( R ¹⁰ ) ₂ R ⁷ and wherein R ^6z′ is H, F, Cl, CF ₃ , CHF ₂ , CF ₂ C _1-6 alkyl or C _1-6 alkyl; or alternatively in Y ¹ and Y ² , R ^6e and R ^6z together with the sp ² carbon atoms to which they are attached together form an alicyclic ring of 4 to 7 members, one of the ring atoms is optionally composed of NR ⁸ , O, S(O) _x , S(=O)(=NR ⁸ ), P=O, P(=O)(OR ⁸ ), OP(=O)(OR ⁸ )O, and the alicyclic ring is selected from halogen, side One or more substituents in the group consisting of oxy, OH, OR ⁸ and NR ⁸ R ⁹ ; R ^{1 is} independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, hydroxyl, methoxy, Ethoxy, isopropoxy, cyclopropoxy, -OCF ₃ , -OCH ₂ CF ₃ , -OCH ₂ CHF ₂ , vinyl, ethynyl, -CF ₃ , -CHF ₂ , -CHO, -CH ₂ OH, -CONH ₂ , -CO ₂ Me, -CONHMe, -CONMe ₂ and cyano; R ² is -OCF ₃ , -OCHF ₂ , -OCF ₂ CF ₃ , -OCH ₂ CHF ₂ , -OCH ₂ CF ₃ , Cyclopropyl, cyclopropoxy, methoxy, -OCD ₃ , ethoxy or isopropoxy; R ³ is -N(R ¹⁰ )C _2-6 alkyl-NR ¹⁰ R ¹⁰ , -N( R ¹⁰ )C _{2- 6} alkyl-R ⁷ , -O(CH ₂ ) _p R ⁷ , -N(R ¹⁰ )C(=O)(CH ₂ ) _p R ⁷ or R ⁷ ; R ^4a , R ^4b and R ^4c are each independently H, cyano, nitro, halo, -C _1-6 alkyl, -C _1-6 haloalkyl, -carboxy-C _1-6 alkyl, -C _1-6 hydroxyalkyl, R ⁸ R ⁹ NC _1-6 alkyl-, -C _2-6 alkenyl, -C _2-6 alkynyl, C _1-6 acetyl-, R ⁷ -(CH ₂ ) _p C(=O)-, C _1-6 hydroxyalkyl -C(=O)-, carboxyl, -C _1-6 alkoxycarbonyl, -C(=O)NR ⁸ R ⁹ , hydroxy, -C _1-6 alkoxy, -C _1-6 Acyloxy, -NR ⁸ R ⁹ , C _1-6 Acyl-N(R ¹⁰ )-, pyrazole, 1,2,3-triazole, tetrazole, (C _1-6 alkyl) SO ₂ -or R ⁷ SO ₂ -; R ⁷ is OH, NR ⁸ R ⁹ , O(CH ₂ ) _q NR ⁸ R ⁹ , C _1-6 alkoxy, C _1-6 alkoxy-C _{1- 6} alkoxy, C _2-6 hydroxyalkoxy, oxetanyl, oxetanyloxy, oxetanylamino, oxetanyl, oxetan Alkyloxy, oxetanylamino, oxetanyl, oxetanyloxy, oxetanylamino, oxepanyl, oxepanyl Alkyloxy, oxetanylamino, azetidinyl, azetidinyloxy, azetidinylamino, pyrrolidinyl, pyrrolidinyloxy, pyrrole Pyridylamino, hexahydropyridyl, hexahydropyridyloxy, hexahydropyridylamino, azepanyl, azepanyloxy, azepanylamino, di Oxetanyl, dioxanyl, morpholinyl, thiomorpholinyl, thiomorpholinyl-S,S-dioxide, hexahydropyrazinyl, dioxepane, Dioxepanyloxy, dioxepanylamino, oxazepanyl, oxazepanyloxy, oxazepanylamino, diaza heteroalkyl heptanyl, diazepino alkyloxy, diazepino alkylamino, (3R) - 3 - (dimethylamino) pyrrolidin-l-yl, (3S) -3- ( Dimethylamino)pyrrolidin-1-yl, 3-(dimethylamino)azetidin-1-yl, [2-(dimethylamino)ethyl](methyl)amine Group, [2-(methylamino)ethyl](methyl)amino, 5-methyl-2,5diazaspiro[3.4]octan-2-yl, (3aR,6aR)-5- Methylhexa-hydro-pyrrolo[3,4-b]pyrrole-1(2H)-yl, 1-methyl-1,2,3,6-tetrahydropyridin-4-yl, 4-methylhexa Hydropyrazin-1-yl, 4-[2(dimethylamino)-2-oxoethyl]hexahydropyrazin-1-yl, methyl[2-(4-methylhexahydropyridine Azine-1yl)ethyl]amine, methyl[2-(morpholine- 4-yl)ethyl]amino, 1-amino-1,2,3,6 tetrahydropyridin-4-yl, 4-[(2S)-2-aminopropionyl]hexahydropyrazine- 1- group, which can be optionally substituted by OH, OR ¹⁰ , pendant, halogen, R ¹⁰ , CH ₂ OR ¹⁰ or CH ₂ NR ⁸ R ⁹ ; R ⁸ and R ⁹ are each independently H, -CD ₃ , C _1-6 alkyl, C _3-6 alkenyl, C _3-6 alkynyl, C _3-8 cycloalkyl, -(C _1-3 alkyl)-(C _3-8 cycloalkyl), C _3-8 cycloalkenyl, C _1- C ₆ acetyl, 4-12 membered monocyclic or bicyclic heterocyclyl, 4-12 membered monocyclic or bicyclic heterocyclyl-C ₁ -C ₆ alkyl- , C _6- C ₁₂ aryl, 5-12 member heteroaryl; wherein R ⁸ and R ⁹ can be further independently selected from up to three hydroxy, C _1-6 alkoxy, C _1-6 hydroxyalkyl , C _1-6 alkoxy-C _1-6 alkyl, C _1-6 alkoxy-C _1-6 alkoxy, C _2-6 hydroxyalkoxy, pendant, thiocarbonyl, cyano Or a substituent of a halogen group; or alternatively, R ⁸ and R ⁹ together with the N atom to which they are simultaneously attached form a heterocyclic ring of 4-7 members, the heterocyclic ring containing up to one selected from O, S or NR ¹¹ Other heteroatoms, or form a heterobicyclic ring of 7-12 members, the heterobicyclic ring may be fused, bridged or spirocyclic, and contain up to two other heterocycles selected from O, S(O) _x or NR ¹¹ Atoms, and these heterocycles are optionally selected from up to three hydroxyl groups, C _1-6 alkoxy groups, C _1-6 hydroxyalkyl groups, C _1-6 alkoxy-C _1-6 alkyl groups, C _{1- 6} alkoxy-C _1-6 alkoxy, C _2-6 hydroxyalkoxy, pendant, thiocarbonyl, cyano or halo substituent substitution; R ^{10 is} each independently H, -CD ₃ , C _1-6 alkyl, C _3-6 cycloalkyl, C _2-6 hydroxyalkyl, C _1-6 alkoxy-C _1-6 alkyl or C _2-6 alkyl-NR ⁸ R ⁹ Or, two R ¹⁰ on the same N atom attached at the same time form a heterocycle of 5-6 members, the heterocycle contains up to one other heteroatom selected from O, S or NR ¹¹ ; R ^{11 is} independent of each other is hydrogen or C _1- C ₆ alkyl, which is optionally substituted with up to three substituents selected from hydroxy, oxo, thiocarbonyl group, a cyano group or a halogen group substituted with the substituents; m is 2 or 3; n is 1, 2 or 3; q is 2, 3 or 4; p is 0, 1, 2, 3 or 4; and x is 0, 1 or 2.

或其立體異構體或醫藥學上可接受之鹽、溶劑合物、酯或前藥；其中，Z為CH或N；R¹係選自氫、氟、氯、溴、甲基、CF₃、CHF₂及氰基；R²為-OCF₃、-OCHF₂、-OCF₂CF₃、-OCH₂CHF₂、-OCH₂CF₃、環丙基、環丙氧基、甲氧基、-OCD₃、乙氧基或異丙氧基；R³為N(R¹⁰)C_2-6烷基-NR¹⁰R¹⁰； R^4a、R^4b及R^4c各自獨立地為H、氰基、鹵基、-C_1-6烷基、-C_1-6鹵烷基、羧基-C_1-6烷基、-C_1-6羥基烷基、R⁸R⁹N-C_1-6烷基-、-C_2-6烯基、-C_2-6炔基、C_1-6醯基-、R⁷-(CH₂)_pC(=O)-、C_1-6羥基烷基-C(=O)-、羧基、-C_1-6烷氧基羰基、-C(=O)NR⁸R⁹、羥基、烷氧基、C_1-6醯氧基、-NR⁸R⁹、C_1-6醯基-N(R¹⁰)-、R⁷SO₂-，R⁷為OH、NR⁸R⁹、O(CH₂)_qNR⁸R⁹、C_1-6烷氧基或C_2-6羥基烷氧基；R⁸及R⁹獨立地為H、-CD₃、C_1-6烷基、C_3-6烯基、C_3-6炔基、C_3-8環烷基、C_3-8環烯基、C_1-C₆醯基、4-12員單環或二環雜環基、4-12員單環或二環雜環基-C₁-C₆烷基-、C_6-C₁₂芳基、5-12員雜芳基；且R⁸及R⁹可進一步獨立地經多達三個選自羥基、C_1-6烷氧基、C_1-6羥基烷基、C_2-6羥基烷氧基、側氧基、硫羰基、氰基或鹵基之取代基取代；或或者，R⁸及R⁹與其同時附接之N原子合起來形成4-7個成員之雜環，該雜環含有多達一個選自O、S或NR¹¹之其他雜原子，或形成7-12個成員之雜雙環，該雜雙環可為稠合、橋接或螺環，且含有多達兩個選自O、S(O)_x或NR¹¹之其他雜原子，且此等雜環視情況經多達三個選自羥基、C_1-6烷氧基、C_1-6羥基烷基、C_1-6烷氧基-C_1-6烷基、C_1-6烷氧基-C_1-6烷氧基、C_2-6羥基烷氧基、側氧基、硫羰基、氰基或鹵基之取代基取代；R¹⁰各自獨立地為H、-CD₃、C_1-6烷基、C_3-6環烷基、C_2-6羥基烷基、C_1-6烷氧基-C_1-6烷基或C_2-6烷基-NR⁸R⁹；或p為0、1、2、3或4；q為2、3或4；且x為0、1或2。 In one embodiment, the present invention relates to compounds having the structure of formula (A):

Or its stereoisomer or pharmaceutically acceptable salt, solvate, ester or prodrug; wherein, Z is CH or N; R ¹ is selected from hydrogen, fluorine, chlorine, bromine, methyl, CF ₃ , CHF ₂ and cyano; R ² is -OCF ₃ , -OCHF ₂ , -OCF ₂ CF ₃ , -OCH ₂ CHF ₂ , -OCH ₂ CF ₃ , cyclopropyl, cyclopropoxy, methoxy,- OCD ₃ , ethoxy or isopropoxy; R ³ is N(R ¹⁰ )C _2-6 alkyl-NR ¹⁰ R ¹⁰ ; R ^4a , R ^4b and R ^4c are each independently H, cyano, halogen Group, -C _1-6 alkyl, -C _1-6 haloalkyl, carboxy -C _1-6 alkyl, -C _1-6 hydroxyalkyl, R ⁸ R ⁹ NC _1-6 alkyl-,- C _2-6 alkenyl, -C _2-6 alkynyl, C _1-6 acetyl-, R ⁷ -(CH ₂ ) _p C(=O)-, C _1-6 hydroxyalkyl-C(=O )-, carboxyl, -C _1-6 alkoxycarbonyl, -C(=O)NR ⁸ R ⁹ , hydroxy, alkoxy, C _1-6 acetyl, -NR ⁸ R ⁹ , C _1-6 Acyl-N(R ¹⁰ )-, R ⁷ SO ₂ -, R ⁷ is OH, NR ⁸ R ⁹ , O(CH ₂ ) _q NR ⁸ R ⁹ , C _1-6 alkoxy or C _2-6 hydroxy Alkoxy; R ⁸ and R ^{9 are} independently H, -CD ₃ , C _1-6 alkyl, C _3-6 alkenyl, C _3-6 alkynyl, C _3-8 cycloalkyl, C _{3- 8} cycloalkenyl, C ₁ -C ₆ acetyl, 4-12 membered monocyclic or bicyclic heterocyclyl, 4-12 membered monocyclic or bicyclic heterocyclyl-C ₁ -C ₆ alkyl-, C _{6 -} C ₁₂ aryl, 5-12 membered heteroaryl; and R ⁸ and R ⁹ may be further independently substituted with up to three substituents selected from hydroxy, C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _{2 -6} hydroxyalkoxy, pendant, thiocarbonyl, cyano or halo substituents; or alternatively, R ⁸ and R ⁹ together with the N atom to which they are attached together form a 4-7 member heterocycle , The heterocyclic ring contains up to one other heteroatom selected from O, S or NR ¹¹ , or forms a heterobicyclic ring of 7-12 members, the heterobicyclic ring may be fused, bridged or spirocyclic, and contains up to two Other heteroatoms selected from O, S(O) _x or NR ¹¹ , and these heterocycles may optionally be selected from up to three hydroxy groups, C _1-6 alkoxy groups, C _1-6 hydroxyalkyl groups, C _{1 -6} alkoxy-C _1-6 alkyl, C _1-6 alkoxy-C _1-6 alkoxy, C _2-6 hydroxyalkoxy, pendant, thiocarbonyl, cyano or halo Substituted by substituents; R ^{10 is} independently H, -CD ₃ , C _1-6 alkyl, C _3-6 cycloalkyl, C _2-6 hydroxyalkyl, C _1-6 alkoxy-C _{1 -6} alkyl or C _2-6 alkyl-N R ⁸ R ⁹ ; or p is 0, 1, 2, 3, or 4; q is 2, 3, or 4; and x is 0, 1, or 2.

In one embodiment, R ³ of formula (A) or (B) is -N(CH ₃ )CH ₂ CH ₂ NR ¹⁰ R ¹⁰ .

In one embodiment, R ^{10 of} formula (A) or (B) is each independently H, -CD ₃ , C _1-6 alkyl, C _3-6 cycloalkyl, or C _2-6 hydroxyalkyl. In other embodiments, each R ^{10 is} independently H, —CD ₃ , methyl, ethyl, or isopropyl.

。在一實施例中，R^5a、 R^6e及R^6z各自為H。 In one embodiment, Y in formula (A) or (B) is

. In one embodiment, R ^5a , R ^6e and R ^6z are each H.

In one embodiment, R ^4a of formula (A) or (B) is H, —C _1-6 alkyl, or —NR ⁸ R ⁹ .

In one embodiment, R ⁸ and R ^{9 of} formula (A) or (B) are independently H, -CD ₃ or C _1-6 alkyl.

In one embodiment, R ^4b and R ^{4c of} formula (A) or (B) are each independently H, cyano, F, Cl, Br, -C _1-6 alkyl, CF ₃ , CHF ₂ , CONH ₂ or C(=O)NR ⁸ R ⁹ . In one embodiment, R ^4b and R ^{4c of} formula (A) or (B) are each independently H, cyano, F, Cl, Br, CH ₃ , CF ₃ , CHF ₂ , CONH ₂ or C (= O)NR ⁸ R ⁹ .

或其立體異構體或醫藥學上可接受之鹽、溶劑合物、酯或前藥；其中，R¹為氫、氟、氯或甲基； R²為-OCF₃、-OCHF₂、-OCF₂CF₃、-OCH₂CHF₂、-OCH₂CF₃、環丙基、環丙氧基、甲氧基、-OCD₃、乙氧基或異丙氧基；R^4a為H或-NR⁸R⁹；R^4b及R^4c各自獨立地為H、氰基、F、Cl、Br、CH₃、CF₃、CHF₂、CONH₂或C(=O)NR⁸R⁹；R⁸及R⁹各自獨立地為H、-CD₃或C_1-6烷基；且R¹⁰各自獨立地為H、-CD₃、C_1-6烷基、C_3-6環烷基或C_2-6羥基烷基。在一實施例中，式(C)化合物包含：R¹為氫；R²為甲氧基、-OCD₃、乙氧基或異丙氧基；R^4a為NR⁸R⁹；R^4b為H或CH₃；R^4c為H、F、Cl、Br或CH₃；R⁸及R⁹各自獨立地為H、-CD₃、-CH₃、-CH₂CH₃或-CH(CH₃)₂；且R¹⁰各自獨立地為H、-CD₃、-CH₃、-CH₂CH₃或-CH(CH₃)₂。 In one embodiment, the present invention relates to compounds having the structure of formula (C):

Or its stereoisomer or pharmaceutically acceptable salt, solvate, ester or prodrug; wherein R ¹ is hydrogen, fluorine, chlorine or methyl; R ² is -OCF ₃ , -OCHF ₂ ,- OCF ₂ CF ₃ , -OCH ₂ CHF ₂ , -OCH ₂ CF ₃ , cyclopropyl, cyclopropoxy, methoxy, -OCD ₃ , ethoxy, or isopropoxy; R ^4a is H or -NR ⁸ R ⁹ ; R ^4b and R ^4c are each independently H, cyano, F, Cl, Br, CH ₃ , CF ₃ , CHF ₂ , CONH ₂ or C(=O)NR ⁸ R ⁹ ; R ⁸ and R ⁹ are each independently H, -CD ₃ or C _1-6 alkyl; and R ¹⁰ are each independently H, -CD ₃ , C _1-6 alkyl, C _3-6 cycloalkyl or C _2-6 Hydroxyalkyl. In one embodiment, the compound of formula (C) comprises: R ¹ is hydrogen; R ² is methoxy, -OCD ₃ , ethoxy, or isopropoxy; R ^4a is NR ⁸ R ⁹ ; R ^4b is H Or CH ₃ ; R ^4c is H, F, Cl, Br or CH ₃ ; R ⁸ and R ⁹ are each independently H, -CD ₃ , -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ ; And R ¹⁰ are each independently H, -CD ₃ , -CH ₃ , -CH ₂ CH _3, or -CH(CH ₃ ) ₂ .

或其立體異構體或醫藥學上可接受之鹽、溶劑合物、酯或前藥；其中， R¹為氫、氟、氯或甲基；R²為-OCF₃、-OCHF₂、-OCF₂CF₃、-OCH₂CHF₂、-OCH₂CF₃、環丙基、環丙氧基、甲氧基、-OCD₃、乙氧基或異丙氧基；R^4a為H或-NR⁸R⁹；R^4b及R^4c各自獨立地為H、氰基、F、Cl、Br、-C_1-6烷基、-CF₃、-CHF₂、-CONH₂或-C(=O)NR⁸R⁹；R⁸及R⁹各自獨立地為H、-CD₃或-C_1-6烷基；且R¹⁰各自獨立地為H、-CD₃、-C_1-6烷基、-C_3-6環烷基或-C_2-6羥基烷基。 In one embodiment, the compound of the present invention has a (CI) structure:

Or its stereoisomer or pharmaceutically acceptable salt, solvate, ester or prodrug; wherein R ¹ is hydrogen, fluorine, chlorine or methyl; R ² is -OCF ₃ , -OCHF ₂ ,- OCF ₂ CF ₃ , -OCH ₂ CHF ₂ , -OCH ₂ CF ₃ , cyclopropyl, cyclopropoxy, methoxy, -OCD ₃ , ethoxy, or isopropoxy; R ^4a is H or -NR ⁸ R ⁹ ; R ^4b and R ^4c are each independently H, cyano, F, Cl, Br, -C _1-6 alkyl, -CF ₃ , -CHF ₂ , -CONH ₂ or -C (=O) NR ⁸ R ⁹ ; R ⁸ and R ⁹ are each independently H, -CD ₃ or -C _1-6 alkyl; and R ¹⁰ are each independently H, -CD ₃ , -C _1-6 alkyl,- C _3-6 cycloalkyl or -C _2-6 hydroxyalkyl.

In another embodiment, the compound of formula (CI) comprises: R ¹ is hydrogen; R ² is methoxy, -OCD ₃ , ethoxy, or isopropoxy; R ^4a is NR ⁸ R ⁹ ; R ^4b is H or CH ₃ ; R ^4c is H, F, Cl, Br, -CF ₃ , -CH ₃ or -CH ₂ CH ₃ ; R ⁸ and R ⁹ are each independently H, -CD ₃ , -CH ₃ ,- CH ₂ CH ₃ or -CH(CH ₃ ) ₂ ; and R ¹⁰ are each independently H, -CD ₃ , -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ .

或其立體異構體或醫藥學上可接受之鹽、溶劑合物、酯或前藥。 In one embodiment, the compound of formula (A), (B) or (C) is:

Or its stereoisomers or pharmaceutically acceptable salts, solvates, esters or prodrugs.

或其立體異構體或醫藥學上可接受之鹽、溶劑合物、酯或前藥。 In one embodiment, the compound of formula (A), (B), (C) or (CI) is:

Or its stereoisomers or pharmaceutically acceptable salts, solvates, esters or prodrugs.

或其立體異構體或醫藥學上可接受之鹽、溶劑合物、酯或前藥；其中，Z為CH或N； X²及X⁷各自為CH、CR⁴或N；R¹為氫、氟、氯、溴、甲基、乙基、羥基、甲氧基、乙氧基、異丙氧基、環丙氧基、-OCF₃、-OCH₂CF₃、-OCH₂CHF₂、乙烯基、乙炔基、CF₃、CHF₂、CHO、CH₂OH、CONH₂、CO₂Me、CONHMe、CONMe₂或氰基；R²為-OCF₃、-OCHF₂、-OCF₂CF₃、-OCH₂CHF₂、-OCH₂CF₃、環丙基、環丙氧基、甲氧基、-OCD₃、乙氧基或異丙氧基；R³為N(R¹⁰)C_2-6烷基-NR¹⁰R¹⁰；R⁴各自獨立地為H、氰基、鹵基、-C_1-6烷基、-C_1-6鹵烷基、羧基-C_1-6烷基、-C_1-6羥基烷基、R⁸R⁹N-C_1-6烷基-、-C_2-6烯基、-C_2-6炔基、C_1-6醯基-、R⁷-(CH₂)_pC(=O)-、C_1-6羥基烷基-C(=O)-、羧基、-C_1-6烷氧基羰基、-C(=O)NR⁸R⁹、羥基、烷氧基、C_1-6醯氧基、-NR⁸R⁹、C_1-6醯基-N(R¹⁰)-或R⁷SO₂-；且R⁸及R⁹獨立地為H、-CD₃、C_1-6烷基、C_3-6烯基、C_3-6炔基、C_3-8環烷基、C_3-8環烯基、C_1-C₆醯基、4-12員單環或二環雜環基、4-12員單環或二環雜環基-C₁-C₆烷基-、C_6-C₁₂芳基、5-12員雜芳基；且R⁸及R⁹可進一步獨立地經多達三個選自羥基、C_1-6烷氧基、C_1-6羥基烷基、C_2-6羥基烷氧基、側氧基、硫羰基、氰基或鹵基之取代基取代；或或者，R⁸及R⁹與其同時附接之N原子合起來形成4-7個成員之雜環，該雜環含有多達一個選自O、S或NR¹¹之其他雜原子，或形成7-12個成員之雜雙環，該雜雙環可為稠合、橋接或螺環，且含有多達兩個選自O、S(O)_x或NR¹¹之其他雜原子，且此等雜環視情況經多達三個選自羥基、C_1-6烷氧基、C_1-6羥基烷基、C_1-6烷氧基-C_1-6烷基、C_1-6烷氧基-C_1-6烷氧基、C_2-6羥基烷氧基、側氧基、硫羰基、氰基或鹵基之取代基取代；R^4b為H、鹵基、-C_1-6烷基或-C_1-6鹵烷基；R^4c為氰基、C_1-6醯基-、-C(=O)NR⁸R⁹、羥基、烷氧基或F； R^4N為H、-CD₃或-C_1-6烷基；R⁷為OH、NR⁸R⁹、-O(CH₂)_qNR⁸R⁹、C_1-6烷氧基或C_2-6羥基烷氧基；R¹⁰各自獨立地為H、-CD₃、C_1-6烷基、C_3-6環烷基、C_2-6羥基烷基、C_1-6烷氧基-C_1-6烷基或C_2-6烷基-NR⁸R⁹；p=0、1、2、3或4；q=2、3或4；且x=0、1或2。 In one embodiment, the invention relates to compounds of formula (D):

Or its stereoisomers or pharmaceutically acceptable salts, solvates, esters or prodrugs; where Z is CH or N; X ² and X ⁷ are each CH, CR ⁴ or N; R ¹ is hydrogen , Fluorine, chlorine, bromine, methyl, ethyl, hydroxyl, methoxy, ethoxy, isopropoxy, cyclopropoxy, -OCF ₃ , -OCH ₂ CF ₃ , -OCH ₂ CHF ₂ , ethylene Group, ethynyl, CF ₃ , CHF ₂ , CHO, CH ₂ OH, CONH ₂ , CO ₂ Me, CONHMe, CONMe ₂ or cyano group; R ² is -OCF ₃ , -OCHF ₂ , -OCF ₂ CF ₃ ,- OCH ₂ CHF ₂ , -OCH ₂ CF ₃ , cyclopropyl, cyclopropoxy, methoxy, -OCD ₃ , ethoxy, or isopropoxy; R ³ is N(R ¹⁰ )C _2-6 alkane Radical -NR ¹⁰ R ¹⁰ ; R ^{4 is} each independently H, cyano, halo, -C _1-6 alkyl, -C _1-6 haloalkyl, carboxy -C _1-6 alkyl, -C _{1 -6} hydroxyalkyl, R ⁸ R ⁹ NC _1-6 alkyl-, -C _2-6 alkenyl, -C _2-6 alkynyl, C _1-6 acetyl-, R ⁷ -(CH ₂ ) _p C(=O)-, C _1-6 hydroxyalkyl-C(=O)-, carboxyl, -C _1-6 alkoxycarbonyl, -C(=O)NR ⁸ R ⁹ , hydroxyl, alkoxy , C _1-6 acyloxy, -NR ⁸ R ⁹ , C _1-6 acyl-N(R ¹⁰ )- or R ⁷ SO ₂ -; and R ⁸ and R ^{9 are} independently H, -CD ₃ , C _1-6 alkyl, C _3-6 alkenyl, C _3-6 alkynyl, C _3-8 cycloalkyl, C _3-8 cycloalkenyl, C _1- C ₆ acetyl, 4-12 member single Ring or bicyclic heterocyclyl, 4-12 membered monocyclic or bicyclic heterocyclyl-C ₁ -C ₆ alkyl-, C _6- C ₁₂ aryl, 5-12 membered heteroaryl; and R ⁸ and R ⁹ can further independently be selected from up to three groups selected from hydroxyl, C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _2-6 hydroxyalkoxy, pendant, thiocarbonyl, cyano or halo Substituted by a substituent of the group; or alternatively, R ⁸ and R ⁹ together with the N atom to which they are simultaneously attached form a heterocyclic ring of 4-7 members, the heterocyclic ring containing up to one other selected from O, S or NR ¹¹ A heteroatom, or a heterobicyclic ring of 7-12 members, which may be fused, bridged or spirocyclic, and contain up to two other heteroatoms selected from O, S(O) _x or NR ¹¹ , And these heterocycles may be selected from up to three hydroxy, C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _1-6 alkoxy-C _1-6 alkyl, C _1-6 alkyl Oxygen-C _1-6 alkoxy, C _2-6 hydroxyalkoxy, pendant, thiocarbonyl, cyano or halo substituent substitution; R ^4b is H, halo, -C _1-6 alkyl or -C _1-6 haloalkyl; R ^4c is cyano, C _1-6 acetyl-, -C(=O)NR ⁸ R ⁹ , hydroxy, alkoxy or F; R ^4N Is H, -CD ₃ or -C _1-6 alkyl; R ⁷ is OH, NR ⁸ R ⁹ , -O(CH ₂ ) _q NR ⁸ R ⁹ , C _1-6 alkoxy or C _2-6 hydroxy Alkoxy; R ^{10 is} each independently H, -CD ₃ , C _1-6 alkyl, C _3-6 cycloalkyl, C _2-6 hydroxyalkyl, C _1-6 alkoxy-C _{1- 6} alkyl or C _2-6 alkyl-NR ⁸ R ⁹ ; p=0, 1, 2, 3 or 4; q=2, 3 or 4; and x=0, 1 or 2.

或其立體異構體或醫藥學上可接受之鹽、溶劑合物、N-氧化物、酯或前藥；其中，Z為CH或N；X²及X⁷各自為CH、CR⁴或N；R¹為氫、氟、氯、溴、甲基、乙基、羥基、甲氧基、乙氧基、異丙氧基、環丙氧基、-OCF₃、-OCH₂CF₃、-OCH₂CHF₂、乙烯基、乙炔基、CF₃、CHF₂、CHO、CH₂OH、CONH₂、CO₂Me、CONHMe、CONMe₂或氰基； R²為-OCF₃、-OCHF₂、-OCF₂CF₃、-OCH₂CHF₂、-OCH₂CF₃、環丙基、環丙氧基、甲氧基、-OCD₃、乙氧基或異丙氧基；R³為-N(R¹⁰)(C_2-6烷基)-NR¹⁰R¹⁰或-N(R¹⁰)(C_3-10環烷基烷基)-NR¹⁰R¹⁰；R⁴各自獨立地為H、氰基、鹵基、-C_1-6烷基、-C_1-6鹵烷基、羧基-C_1-6烷基、-C_1-6羥基烷基、R⁸R⁹N-C_1-6烷基-、-C_2-6烯基、-C_2-6炔基、C_1-6醯基-、R⁷-(CH₂)_pC(=O)-、C_1-6羥基烷基-C(=O)-、羧基、-C_1-6烷氧基羰基、-C(=O)NR⁸R⁹、羥基、烷氧基、C_1-6醯氧基、-NR⁸R⁹、C_1-6醯基-N(R¹⁰)-或R⁷SO₂-；且R⁸及R⁹獨立地為H、-CD₃、C_1-6烷基、C_3-6烯基、C_3-6炔基、C_3-8環烷基、C_3-8環烯基、C_1-C₆醯基、4-12員單環或二環雜環基、4-12員單環或二環雜環基-C₁-C₆烷基-、C_6-C₁₂芳基、5-12員雜芳基；且R⁸及R⁹可進一步獨立地經多達三個選自羥基、C_1-6烷氧基、C_1-6羥基烷基、C_2-6羥基烷氧基、側氧基、硫羰基、氰基或鹵基之取代基取代；或或者，R⁸及R⁹與其同時附接之N原子合起來形成4-7個成員之雜環，該雜環含有多達一個選自O、S或NR¹¹之其他雜原子，或形成7-12個成員之雜雙環，該雜雙環可為稠合、橋接或螺環，且含有多達兩個選自O、S(O)_x或NR¹¹之其他雜原子，且此等雜環視情況經多達三個選自羥基、C_1-6烷氧基、C_1-6羥基烷基、C_1-6烷氧基-C_1-6烷基、C_1-6烷氧基-C_1-6烷氧基、C_2-6羥基烷氧基、側氧基、硫羰基、氰基或鹵基之取代基取代；R^4b為H、鹵基、-C_1-6烷基或-C_1-6鹵烷基；R^4c為H、氰基、羥基、烷氧基、-C_1-6烷基或-C_1-6鹵烷基、Cl或F，其限制條件在於當R^4c為H時，R^4b為鹵基、-C_1-6烷基或-C_1-6鹵烷基；R^4N為H、-CD₃或-C_1-6烷基；R⁷為OH、NR⁸R⁹、-O(CH₂)_qNR⁸R⁹、C_1-6烷氧基或C_2-6羥基烷氧基； R¹⁰各自獨立地為H、-CD₃、C_1-6烷基、C_3-6環烷基、C_2-6羥基烷基、C_1-6烷氧基-C_1-6烷基或C_2-6烷基-NR⁸R⁹；或或者，同一N原子上之兩個R¹⁰合起來形成3-7個成員之雜環，該雜環視情況經多達三個選自羥基、C_1-6烷氧基、C_1-6羥基烷基、C_1-6烷氧基-C_1-6烷基、C_1-6烷氧基-C_1-6烷氧基、C_2-6羥基烷氧基、側氧基、硫羰基、氰基或鹵基之取代基取代；p=0、1、2、3或4；q=2、3或4；且x=0、1或2。 In one embodiment, the invention relates to compounds of formula (DI):

Or its stereoisomers or pharmaceutically acceptable salts, solvates, N-oxides, esters or prodrugs; where Z is CH or N; X ² and X ⁷ are each CH, CR ⁴ or N ; R ¹ is hydrogen, fluorine, chlorine, bromine, methyl, ethyl, hydroxyl, methoxy, ethoxy, isopropoxy, cyclopropoxy, -OCF ₃ , -OCH ₂ CF ₃ , -OCH ₂ CHF ₂ , vinyl, ethynyl, CF ₃ , CHF ₂ , CHO, CH ₂ OH, CONH ₂ , CO ₂ Me, CONHMe, CONMe ₂ or cyano; R ² is -OCF ₃ , -OCHF ₂ , -OCF ₂ CF ₃ , -OCH ₂ CHF ₂ , -OCH ₂ CF ₃ , cyclopropyl, cyclopropoxy, methoxy, -OCD ₃ , ethoxy, or isopropoxy; R ³ is -N(R ¹⁰ )(C _2-6 alkyl)-NR ¹⁰ R ¹⁰ or -N(R ¹⁰ )(C _3-10 cycloalkylalkyl)-NR ¹⁰ R ¹⁰ ; R ^{4 is} independently H, cyano, halogen Group, -C _1-6 alkyl, -C _1-6 haloalkyl, carboxy -C _1-6 alkyl, -C _1-6 hydroxyalkyl, R ⁸ R ⁹ NC _1-6 alkyl-,- C _2-6 alkenyl, -C _2-6 alkynyl, C _1-6 acetyl-, R ⁷ -(CH ₂ ) _p C(=O)-, C _1-6 hydroxyalkyl-C(=O )-, carboxyl, -C _1-6 alkoxycarbonyl, -C(=O)NR ⁸ R ⁹ , hydroxy, alkoxy, C _1-6 acetyl, -NR ⁸ R ⁹ , C _1-6 Acyl-N(R ¹⁰ )- or R ⁷ SO ₂ -; and R ⁸ and R ^{9 are} independently H, -CD ₃ , C _1-6 alkyl, C _3-6 alkenyl, C _3-6 alkyne Group, C _3-8 cycloalkyl group, C _3-8 cycloalkenyl group, C ₁ -C ₆ acetyl group, 4-12 membered monocyclic or bicyclic heterocyclic group, 4-12 membered monocyclic or bicyclic heterocyclic group -C ₁ -C ₆ alkyl-, C _6- C ₁₂ aryl, 5-12 membered heteroaryl; and R ⁸ and R ⁹ can be further independently selected from up to three hydroxy, C _1-6 alkyl Oxygen, C _1-6 hydroxyalkyl, C _2-6 hydroxyalkoxy, pendant, thiocarbonyl, cyano or halo substituents; or alternatively, R ⁸ and R ⁹ are simultaneously attached to N atoms combine to form a 4-7 member heterocycle, the heterocycle contains up to one other heteroatom selected from O, S, or NR ¹¹ , or forms a 7-12 member heterobicycle, which may be Condensed, bridged or spiro ring, and containing up to two other heteroatoms selected from O, S(O) _x or NR ¹¹ , and these heterocycles are optionally selected from up to three hydroxyl groups, C _1-6 alkanes Oxy, C _1-6 hydroxyalkyl, C _1-6 alkoxy-C _1-6 alkyl, C _1-6 alkoxy-C _1-6 alkoxy, C _2-6 hydroxyalkoxy, pendant, thiocarbonyl, cyano or halo substituent substitution; R ^4b is H, halo, -C _1-6 alkyl or -C _1-6 haloalkyl ; R ^4c is H, cyano, hydroxy, alkoxy, -C _1-6 alkyl or -C _1-6 haloalkyl, Cl or F, the restriction is that when R ^4c is H, R ^4b is Halo, -C _1-6 alkyl or -C _1-6 haloalkyl; R ^4N is H, -CD ₃ or -C _1-6 alkyl; R ⁷ is OH, NR ⁸ R ⁹ , -O( CH ₂ ) _q NR ⁸ R ⁹ , C _1-6 alkoxy or C _2-6 hydroxyalkoxy; R ^{10 is} each independently H, -CD ₃ , C _1-6 alkyl, C _3-6 ring Alkyl, C _2-6 hydroxyalkyl, C _1-6 alkoxy-C _1-6 alkyl or C _2-6 alkyl-NR ⁸ R ⁹ ; or alternatively, two R ¹⁰ on the same N atom Taken together to form a heterocycle of 3-7 members, the heterocycle may optionally be up to three selected from hydroxyl, C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _1-6 alkoxy-C _{1 -6} alkyl, C _1-6 alkoxy-C _1-6 alkoxy, C _2-6 hydroxyalkoxy, pendant, thiocarbonyl, cyano or halo substituent substitution; p=0 , 1, 2, 3 or 4; q=2, 3 or 4; and x=0, 1 or 2.

In one embodiment of the compound of formula (DI), X ² is CH or CR ⁴ ; R ⁴ is methyl, ethyl, or isopropyl; R ^4c is cyano, -CF ₃ , Cl, or F; R ^4N is -CD ₃ , methyl, ethyl or isopropyl; and R ^4b is H, halo, methyl, ethyl or isopropyl.

In one embodiment of the compound of formula (DI), X ² is N; R ^4c is cyano, -CF ₃ , Cl, or F; R ^4N is -CD ₃ , methyl, ethyl, or isopropyl; and R ^4b is H, halo, methyl, ethyl or isopropyl.

或其立體異構體或醫藥學上可接受之鹽、溶劑合物、N-氧化物、 酯或前藥。 In one embodiment of the compound of formula (DI), the compound is

Or its stereoisomers or pharmaceutically acceptable salts, solvates, N-oxides, esters or prodrugs.

或其立體異構體或醫藥學上可接受之鹽、溶劑合物、酯或前藥；其中，Z為CH或N；X²、X³、X⁶及X⁷各自為CH、CR⁴或N；R¹為氫、氟、氯、溴、甲基、乙基、羥基、甲氧基、乙氧基、異丙氧基、環丙氧基、-OCF₃、-OCH₂CF₃、-OCH₂CHF₂、乙烯基、乙炔基、CF₃、CHF₂、CHO、CH₂OH、CONH₂、CO₂Me、CONHMe、CONMe₂或氰基；R²為-OCF₃、-OCHF₂、-OCF₂CF₃、-OCH₂CHF₂、-OCH₂CF₃、環丙基、環丙氧基、甲氧基、-OCD₃、乙氧基或異丙氧基；R³為N(R¹⁰)C_2-6烷基-NR¹⁰R¹⁰； R⁴各自獨立地為H、氰基、鹵基、-C_1-6烷基、-C_1-6鹵烷基、羧基-C_1-6烷基、-C_1-6羥基烷基、R⁸R⁹N-C_1-6烷基-、-C_2-6烯基、-C_2-6炔基、C_1-6醯基-、R⁷-(CH₂)_pC(=O)-、C_1-6羥基烷基-C(=O)-、羧基、-C_1-6烷氧基羰基、-C(=O)NR⁸R⁹、羥基、烷氧基、C_1-6醯氧基、-NR⁸R⁹、C_1-6醯基-N(R¹⁰)-或R⁷SO₂-；且R⁸及R⁹獨立地為H、-CD₃、C_1-6烷基、C_3-6烯基、C_3-6炔基、C_3-8環烷基、C_3-8環烯基、C_1-C₆醯基、4-12員單環或二環雜環基、4-12員單環或二環雜環基-C₁-C₆烷基-、C_6-C₁₂芳基、5-12員雜芳基；且R⁸及R⁹可進一步獨立地經多達三個選自羥基、C_1-6烷氧基、C_1-6羥基烷基、C_2-6羥基烷氧基、側氧基、硫羰基、氰基或鹵基之取代基取代；或或者，R⁸及R⁹與其同時附接之N原子合起來形成4-7個成員之雜環，該雜環含有多達一個選自O、S或NR¹¹之其他雜原子，或形成7-12個成員之雜雙環，該雜雙環可為稠合、橋接或螺環，且含有多達兩個選自O、S(O)_x或NR¹¹之其他雜原子，且此等雜環視情況經多達三個選自羥基、C_1-6烷氧基、C_1-6羥基烷基、C_1-6烷氧基-C_1-6烷基、C_1-6烷氧基-C_1-6烷氧基、C_2-6羥基烷氧基、側氧基、硫羰基、氰基或鹵基之取代基取代；R^4N為H、-CD₃或-C_1-6烷基；R⁷為OH、NR⁸R⁹、-O(CH₂)_qNR⁸R⁹、C_1-6烷氧基或C_2-6羥基烷氧基；R¹⁰各自獨立地為H、-CD₃、C_1-6烷基、C_3-6環烷基、C_2-6羥基烷基、C_1-6烷氧基-C_1-6烷基或C_2-6烷基-NR⁸R⁹；p=0、1、2、3或4；q=2、3或4；且x=0、1或2。 In one embodiment, the invention relates to compounds of formula (E):

Or its stereoisomers or pharmaceutically acceptable salts, solvates, esters or prodrugs; where Z is CH or N; X ² , X ³ , X ⁶ and X ⁷ are each CH, CR ⁴ or N; R ¹ is hydrogen, fluorine, chlorine, bromine, methyl, ethyl, hydroxy, methoxy, ethoxy, isopropoxy, cyclopropoxy, -OCF ₃ , -OCH ₂ CF ₃ ,- OCH ₂ CHF ₂ , vinyl, ethynyl, CF ₃ , CHF ₂ , CHO, CH ₂ OH, CONH ₂ , CO ₂ Me, CONHMe, CONMe ₂ or cyano; R ² is -OCF ₃ , -OCHF ₂ ,- OCF ₂ CF ₃ , -OCH ₂ CHF ₂ , -OCH ₂ CF ₃ , cyclopropyl, cyclopropoxy, methoxy, -OCD ₃ , ethoxy, or isopropoxy; R ³ is N(R ¹⁰ ) C _2-6 alkyl-NR ¹⁰ R ¹⁰ ; R ^{4 is} independently H, cyano, halo, -C _1-6 alkyl, -C _1-6 haloalkyl, carboxy-C _1-6 Alkyl, -C _1-6 hydroxyalkyl, R ⁸ R ⁹ NC _1-6 alkyl-, -C _2-6 alkenyl, -C _2-6 alkynyl, C _1-6 acetyl-, R ⁷ -(CH ₂ ) _p C(=O)-, C _1-6 hydroxyalkyl-C(=O)-, carboxyl, -C _1-6 alkoxycarbonyl, -C(=O)NR ⁸ R ⁹ , Hydroxy, alkoxy, C _1-6 acetyl, -NR ⁸ R ⁹ , C _1-6 acetyl-N(R ¹⁰ )- or R ⁷ SO ₂ -; and R ⁸ and R ^{9 are} independently H, -CD ₃ , C _1-6 alkyl, C _3-6 alkenyl, C _3-6 alkynyl, C _3-8 cycloalkyl, C _3-8 cycloalkenyl, C _1- C ₆ acetyl , 4-12 membered monocyclic or bicyclic heterocyclyl, 4-12 membered monocyclic or bicyclic heterocyclyl-C ₁ -C ₆ alkyl-, C _6- C ₁₂ aryl, 5-12 membered heteroaryl Radicals; and R ⁸ and R ⁹ can be further independently selected by up to three hydroxy, C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _2-6 hydroxyalkoxy, pendant, sulfur Carbonyl, cyano or halo substituent substitution; or alternatively, R ⁸ and R ⁹ together with the N atom to which they are simultaneously attached form a heterocyclic ring of 4-7 members, the heterocyclic ring containing up to one selected from O, S or NR ¹¹ other heteroatom, or form a heterobicyclic ring of 7-12 members, the heterobicyclic ring may be fused, bridged or spiro ring, and contains up to two selected from O, S (O) _x or NR ¹¹ other heteroatoms, and these heterocycles may optionally be selected from up to three hydroxy, C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _1-6 alkoxy-C _1-6 alkyl , C _1-6 alkoxy-C _1-6 alkoxy, C _2-6 hydroxyalkoxy, pendant, thiocarbonyl, cyano or halo substituent substitution; R ^4N is H, -CD ₃ or -C _1-6 alkyl; R ⁷ is OH, NR ⁸ R ⁹ , -O(CH ₂ ) _q NR ⁸ R ⁹ , C _1-6 alkoxy or C _2-6 Hydroxyalkoxy; R ^{10 is} each independently H, -CD ₃ , C _1-6 alkyl, C _3-6 cycloalkyl, C _2-6 hydroxyalkyl, C _1-6 alkoxy-C _{1 -6} alkyl or C _2-6 alkyl-NR ⁸ R ⁹ ; p=0, 1, 2, 3 or 4; q=2, 3 or 4; and x=0, 1 or 2.

或其立體異構體或醫藥學上可接受之鹽、溶劑合物、酯或前藥；其中，Z為CH或N；X⁶及X⁷各自為CH、CR⁴或N；R¹獨立地選自氫、氟、氯、溴、甲基、乙基、羥基、甲氧基、乙氧基、異丙氧基、環丙氧基、-OCF₃、-OCH₂CF₃、-OCH₂CHF₂、乙烯基、乙炔基、CF₃、CHF₂、CHO、CH₂OH、CONH₂、CO₂Me、CONHMe、CONMe₂及氰基；R²為-OCF₃、-OCHF₂、-OCF₂CF₃、-OCH₂CHF₂、-OCH₂CF₃、環丙基、環丙氧基、甲氧基、-OCD₃、乙氧基或異丙氧基；R³為N(R¹⁰)C_2-6烷基-NR¹⁰R¹⁰；R⁴各自獨立地為H、氰基、鹵基、-C_1-6烷基、-C_1-6鹵烷基、羧基-C_1-6烷基、-C_1-6羥基烷基、R⁸R⁹N-C_1-6烷基-、-C_2-6烯基、-C_2-6炔基、C_1-6醯基-、R⁷-(CH₂)_pC(=O)-、C_1-6羥基烷基-C(=O)-、羧基、-C_1-6烷氧基羰基、-C(=O)NR⁸R⁹、羥基、烷氧基、C_1-6醯氧基、-NR⁸R⁹、C_1-6醯基-N(R¹⁰)-、R⁷SO₂-，R^4a及R^4b各自獨立地為H、鹵基、-C_1-6烷基或-C_1-6鹵烷基； R^4c為氰基、C_1-6醯基-、-C(=O)NR⁸R⁹、羥基、烷氧基或F；R^4N為H、-CD₃、-C_1-6烷基或-C_1-6鹵烷基；R⁷為OH、NR⁸R⁹、O(CH₂)_qNR⁸R⁹、C_1-6烷氧基或C_2-6羥基烷氧基；R⁸及R⁹獨立地為H、-CD₃、C_1-6烷基、C_3-6烯基、C_3-6炔基、C_3-8環烷基、C_3-8環烯基、C_1-C₆醯基、4-12員單環或二環雜環基、4-12員單環或二環雜環基-C₁-C₆烷基-、C_6-C₁₂芳基、5-12員雜芳基；且R⁸及R⁹可進一步獨立地經多達三個選自羥基、C_1-6烷氧基、C_1-6羥基烷基、C_2-6羥基烷氧基、側氧基、硫羰基、氰基或鹵基之取代基取代；或R¹⁰各自獨立地為H、-CD₃、C_1-6烷基、C_3-6環烷基、C_2-6羥基烷基、C_1-6烷氧基-C_1-6烷基或C_2-6烷基-NR⁸R⁹；或p=0、1、2、3或4；且q=2、3或4。 In one embodiment, the invention relates to compounds of formula (F) or (G):

Or its stereoisomer or pharmaceutically acceptable salt, solvate, ester or prodrug; where Z is CH or N; X ⁶ and X ⁷ are each CH, CR ⁴ or N; R ^{1 is} independently Selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, hydroxyl, methoxy, ethoxy, isopropoxy, cyclopropoxy, -OCF ₃ , -OCH ₂ CF ₃ , -OCH ₂ CHF _2. Vinyl, ethynyl, CF ₃ , CHF ₂ , CHO, CH ₂ OH, CONH ₂ , CO ₂ Me, CONHMe, CONMe ₂ and cyano; R ² is -OCF ₃ , -OCHF ₂ , -OCF ₂ CF ₃ , -OCH ₂ CHF ₂ , -OCH ₂ CF ₃ , cyclopropyl, cyclopropoxy, methoxy, -OCD ₃ , ethoxy, or isopropoxy; R ³ is N(R ¹⁰ )C _{2 -6} alkyl-NR ¹⁰ R ¹⁰ ; R ^{4 is} independently H, cyano, halo, -C _1-6 alkyl, -C _1-6 haloalkyl, carboxy-C _1-6 alkyl, -C _1-6 hydroxyalkyl, R ⁸ R ⁹ NC _1-6 alkyl-, -C _2-6 alkenyl, -C _2-6 alkynyl, C _1-6 acetyl-, R ⁷ -(CH ₂ ) _p C(=O)-, C _1-6 hydroxyalkyl-C(=O)-, carboxyl, -C _1-6 alkoxycarbonyl, -C(=O)NR ⁸ R ⁹ , hydroxyl, Alkoxy, C _1-6 acetyloxy, -NR ⁸ R ⁹ , C _1-6 acetyl-N(R ¹⁰ )-, R ⁷ SO ₂ -, R ^4a and R ^4b are each independently H, halogen Group, -C _1-6 alkyl or -C _1-6 haloalkyl; R ^4c is cyano, C _1-6 acetyl-, -C(=O)NR ⁸ R ⁹ , hydroxyl, alkoxy or F; R ^4N is H, -CD ₃ , -C _1-6 alkyl or -C _1-6 haloalkyl; R ⁷ is OH, NR ⁸ R ⁹ , O(CH ₂ ) _q NR ⁸ R ⁹ , C _1-6 alkoxy or C _2-6 hydroxyalkoxy; R ⁸ and R ^{9 are} independently H, -CD ₃ , C _1-6 alkyl, C _3-6 alkenyl, C _3-6 alkynyl , C _3-8 cycloalkyl, C _3-8 cycloalkenyl, C _1- C ₆ acetyl, 4-12 membered monocyclic or bicyclic heterocyclic group, 4-12 membered monocyclic or bicyclic heterocyclic group -C ₁ -C ₆ alkyl-, C _6- C ₁₂ aryl, 5-12 membered heteroaryl; and R ⁸ and R ⁹ can be further independently selected from up to three hydroxy, C _1-6 alkoxy Group, C _1-6 hydroxyalkyl, C _2-6 hydroxyalkoxy, pendant, thiocarbonyl, cyano or halo substituents; or R ¹⁰ are each independently H, -CD ₃ , C _1-6 alkyl, C _3-6 cycloalkyl, C _2-6 hydroxyalkyl, C _1-6 alkoxy-C _1-6 alkyl Or C _2-6 alkyl-NR ⁸ R ⁹ ; or p=0, 1, 2, 3, or 4; and q=2, 3, or 4.

，或其立體異構體或醫藥學上可接受之鹽、溶劑合物、 酯或前藥。 In one embodiment, the compound of formula (D), (DI), (E), (EI), (F) or (G) is not:

, Or its stereoisomers or pharmaceutically acceptable salts, solvates, esters or prodrugs.

或其立體異構體或醫藥學上可接受之鹽、溶劑合物、酯或前 藥。 In one embodiment, the compound of formula (D), (DI), (E), (EI), (F) or (G) is:

Or its stereoisomers or pharmaceutically acceptable salts, solvates, esters or prodrugs.

或

或其立體異構體或醫藥學上可接受之鹽、溶 劑合物、N-氧化物、酯或前藥。 In one embodiment, the compound of formula (D), (DI), (E), (EI), (F) or (G) is:

or

Or its stereoisomers or pharmaceutically acceptable salts, solvates, N-oxides, esters or prodrugs.

或其立體異構體或醫藥學上可接受之鹽、溶劑合物、N-氧化物、酯或前藥，其中Z為CH或N；R¹為氫、氟、氯、溴、甲基、乙基、羥基、甲氧基、乙氧基、異丙氧基、環丙氧基、-OCF₃、-OCH₂CF₃、-OCH₂CHF₂、乙烯基、乙炔基、CF₃、CHF₂、CHO、CH₂OH、CONH₂、CO₂Me、CONHMe、CONMe₂或氰基；R²為-OCF₃、-OCHF₂、-OCF₂CF₃、-OCH₂CHF₂、-OCH₂CF₃、環丙基、環丙氧基、甲氧基、-OCD₃、乙氧基或異丙氧基；R³為N(R¹⁰)C_2-6烷基-NR¹⁰R¹⁰或-N(R¹⁰)(C_3-10環烷基烷基)-NR¹⁰R¹⁰；R⁴各自獨立地為H、氰基、鹵基、-C_1-6烷基、-C_1-6鹵烷基、羧基-C_1-6烷基、-C_1-6羥基烷基、R⁸R⁹N-C_1-6烷基-、-C_2-6烯基、-C_2-6炔基、C_1-6醯基-、R⁷-(CH₂)_pC(=O)-、C_1-6羥基烷基-C(=O)-、羧基、-C_1-6烷氧基羰基、-C(=O)NR⁸R⁹、羥基、烷氧基、C_1-6醯氧基、-NR⁸R⁹、C_1-6醯基-N(R¹⁰)-或R⁷SO₂-；且R⁸及R⁹獨立地為H、-CD₃、C_1-6烷基、C_3-6烯基、C_3-6炔基、C_3-8環烷基、C_3-8環烯基、C_1-C₆醯基、4-12員單環或二環雜環基、4-12員單環或二環雜環基-C₁-C₆烷基-、C_6-C₁₂芳基、5-12員雜芳基；且R⁸及R⁹可進一步獨立地經多達三個選自 羥基、C_1-6烷氧基、C_1-6羥基烷基、C_2-6羥基烷氧基、側氧基、硫羰基、氰基或鹵基之取代基取代；或或者，R⁸及R⁹與其同時附接之N原子合起來形成4-7個成員之雜環，該雜環含有多達一個選自O、S或NR¹¹之其他雜原子，或形成7-12個成員之雜雙環，該雜雙環可為稠合、橋接或螺環，且含有多達兩個選自O、S(O)_x或NR¹¹之其他雜原子，且此等雜環視情況經多達三個選自羥基、C_1-6烷氧基、C_1-6羥基烷基、C_1-6烷氧基-C_1-6烷基、C_1-6烷氧基-C_1-6烷氧基、C_2-6羥基烷氧基、側氧基、硫羰基、氰基或鹵基之取代基取代；R^4N為H、-CD₃或-C_1-6烷基；R⁷為OH、-NR⁸R⁹、-O(CH₂)_qNR⁸R⁹、C_1-6烷氧基或C_2-6羥基烷氧基；R¹⁰各自獨立地為H、-CD₃、C_1-6烷基、C_3-6環烷基、C_2-6羥基烷基、C_1-6烷氧基-C_1-6烷基或C_2-6烷基-NR⁸R⁹；或者，同一N原子上之兩個R¹⁰合起來形成3-7個成員之雜環，該雜環視情況經多達三個選自羥基、C_1-6烷氧基、C_1-6羥基烷基、C_1-6烷氧基-C_1-6烷基、C_1-6烷氧基-C_1-6烷氧基、C_2-6羥基烷氧基、側氧基、硫羰基、氰基或鹵基之取代基取代；p=0、1、2、3或4；q=2、3或4；且x=0、1或2。 In one embodiment, the invention relates to compounds of formula (EI):

Or its stereoisomer or pharmaceutically acceptable salt, solvate, N-oxide, ester or prodrug, wherein Z is CH or N; R ¹ is hydrogen, fluorine, chlorine, bromine, methyl, Ethyl, hydroxyl, methoxy, ethoxy, isopropoxy, cyclopropoxy, -OCF ₃ , -OCH ₂ CF ₃ , -OCH ₂ CHF ₂ , vinyl, ethynyl, CF ₃ , CHF ₂ , CHO, CH ₂ OH, CONH ₂ , CO ₂ Me, CONHMe, CONMe ₂ or cyano group; R ² is -OCF ₃ , -OCHF ₂ , -OCF ₂ CF ₃ , -OCH ₂ CHF ₂ , -OCH ₂ CF ₃ , Cyclopropyl, cyclopropoxy, methoxy, -OCD ₃ , ethoxy or isopropoxy; R ³ is N(R ¹⁰ )C _2-6 alkyl-NR ¹⁰ R ¹⁰ or -N( R ¹⁰ )(C _3-10 cycloalkylalkyl)-NR ¹⁰ R ¹⁰ ; R ^{4 is} each independently H, cyano, halo, -C _1-6 alkyl, -C _1-6 haloalkyl , Carboxy-C _1-6 alkyl, -C _1-6 hydroxyalkyl, R ⁸ R ⁹ NC _1-6 alkyl-, -C _2-6 alkenyl, -C _2-6 alkynyl, C _{1- 6} acetyl-, R ⁷ -(CH ₂ ) _p C(=O)-, C _1-6 hydroxyalkyl-C(=O)-, carboxyl, -C _1-6 alkoxycarbonyl, -C( =O) NR ⁸ R ⁹ , hydroxy, alkoxy, C _1-6 acetyl, -NR ⁸ R ⁹ , C _1-6 acetyl -N(R ¹⁰ )- or R ⁷ SO ₂ -; and R ⁸ and R ^{9 are} independently H, -CD ₃ , C _1-6 alkyl, C _3-6 alkenyl, C _3-6 alkynyl, C _3-8 cycloalkyl, C _3-8 cycloalkenyl, C _1- C ₆ acetyl, 4-12 membered monocyclic or bicyclic heterocyclyl, 4-12 membered monocyclic or bicyclic heterocyclyl-C ₁ -C ₆ alkyl-, C _6- C ₁₂ aryl , 5-12 membered heteroaryl; and R ⁸ and R ⁹ can be further independently selected from up to three selected from hydroxy, C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _2-6 hydroxyalkoxy Group, pendant, thiocarbonyl, cyano or halo; or alternatively, R ⁸ and R ⁹ together with the N atom to which they are attached at the same time form a heterocyclic ring of 4-7 members, the heterocyclic ring containing Up to one other heteroatom selected from O, S or NR ¹¹ , or forming a heterobicyclic ring of 7-12 members, the heterobicyclic ring may be fused, bridged or spiro ring, and contains up to two selected from O, S(O) _x or other hetero atoms of NR ¹¹ , and these heterocycles may optionally be selected from up to three hydroxy, C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _1-6 alkoxy -C _1-6 alkyl, C _1-6 alkoxy-C _1-6 alkoxy, C _2-6 hydroxyalkoxy, pendant, thiocarbonyl, cyano or halo Substituent substitution; R ^4N is H, -CD ₃ or -C _1-6 alkyl; R ⁷ is OH, -NR ⁸ R ⁹ , -O(CH ₂ ) _q NR ⁸ R ⁹ , C _1-6 alkoxy Group or C _2-6 hydroxyalkoxy; R ^{10 is} each independently H, -CD ₃ , C _1-6 alkyl, C _3-6 cycloalkyl, C _2-6 hydroxyalkyl, C _1-6 Alkoxy-C _1-6 alkyl or C _2-6 alkyl-NR ⁸ R ⁹ ; alternatively, two R ¹⁰ on the same N atom combine to form a heterocyclic ring of 3-7 members, the heterocyclic ring is optional Up to three selected from hydroxy, C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _1-6 alkoxy-C _1-6 alkyl, C _1-6 alkoxy-C _{1- 6} alkoxy, C _2-6 hydroxyalkoxy, pendant, thiocarbonyl, cyano or halo substituent substitution; p=0, 1, 2, 3 or 4; q=2, 3 or 4 ; And x=0, 1, or 2.

In some embodiments of the compound of formula (EI), R ³ is N(R ¹⁰ )C _2-6 alkyl-NR ¹⁰ R ¹⁰ or -N(R ¹⁰ )(C _3-10 cycloalkylalkyl)- NR ¹⁰ R ¹⁰ ; R ^{4 is} independently H, cyano, halo, -C _1-6 alkyl or -C _1-6 haloalkyl; and R ^4N is H, -CD ₃ or -C _{1- 6} alkyl; and R ^{10 is} each independently H, -CD ₃ or -C _1-6 alkyl.

或其 立體異構體或醫藥學上可接受之鹽、溶劑合物、N-氧化物、酯或前藥。 In some embodiments of the compound of formula (EI), the compound is

Or its stereoisomers or pharmaceutically acceptable salts, solvates, N-oxides, esters or prodrugs.

或其立體異構體或醫藥學上可接受之鹽、溶劑合物、酯或前藥；其中，X⁷為CH或N；X²獨立地為CH、CCH₃或N；R²為甲氧基、-OCD₃、乙氧基或異丙氧基；R^4b為H、F、Cl或CH₃；R^4N為H、-CD₃、CH₃、Et或CH(CH₃)₂；且R¹⁰各自獨立地為H、-CD₃、-CH₃、-CH₂CH₃或-CH(CH₃)₂。 In some embodiments, the present invention relates to compounds of formula (H):

Or its stereoisomer or pharmaceutically acceptable salt, solvate, ester or prodrug; where X ⁷ is CH or N; X ^{2 is} independently CH, CCH ₃ or N; R ² is methoxy Radical, -OCD ₃ , ethoxy or isopropoxy; R ^4b is H, F, Cl or CH ₃ ; R ^4N is H, -CD ₃ , CH ₃ , Et or CH(CH ₃ ) ₂ ; and R ¹⁰ are each independently H, -CD ₃ , -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ .

In one embodiment, the compound of structure (H) comprises: X ⁷ is CH or N; X ^{2 is} independently CH or CCH ₃ ; R ² is methoxy, -OCD ₃ , ethoxy or isopropoxy; R ^4b is H, F, Cl, or CH ₃ ; R ^4N is H, -CD ₃ , CH ₃ , Et, or CH(CH ₃ ) ₂ ; and R ^{10 is} independently H, -CD ₃ , -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ .

或其立體異構體或醫藥學上可接受之鹽、溶劑合物、酯或前藥；其中，X⁷為CH或N；X²獨立地為CH、CCH₃或N；R²為甲氧基、-OCD₃、乙氧基或異丙氧基；R^4b為H、F、Cl或CH₃；R^4N為H、-CD₃、CH₃、Et或CH(CH₃)₂；且R¹⁰各自獨立地為-CD₃、-CH₃、-CH₂CH₃或-CH(CH₃)₂。 In one embodiment, the compound of the present invention has the structure of formula (HI)

Or its stereoisomer or pharmaceutically acceptable salt, solvate, ester or prodrug; where X ⁷ is CH or N; X ^{2 is} independently CH, CCH ₃ or N; R ² is methoxy Radical, -OCD ₃ , ethoxy or isopropoxy; R ^4b is H, F, Cl or CH ₃ ; R ^4N is H, -CD ₃ , CH ₃ , Et or CH(CH ₃ ) ₂ ; and R ¹⁰ are each independently -CD ₃ , -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ .

In one embodiment, the compound of formula (HI) comprises: X ⁷ is CH; X ^{2 is} independently CH or CCH ₃ ; R ² is methoxy, -OCD ₃ , ethoxy, or isopropoxy; R ^4b Is H, F, Cl or CH ₃ ; R ^4N is H, -CD ₃ , CH ₃ , Et or CH(CH ₃ ) ₂ ; and R ^{10 is} independently -CD ₃ , -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ .

、

、

或

；或其立體異構 體或醫藥學上可接受之鹽、溶劑合物、酯或前藥。 In one embodiment, the compound of structure (H) is

,

,

or

; Or its stereoisomers or pharmaceutically acceptable salts, solvates, esters or prodrugs.

或

；或其立體異構體或醫藥學上可接受之鹽、 溶劑合物、酯或前藥。在一實施例中，結構(H)或(H-I)化合物為：

In one embodiment, the compound of structure (H) or (HI) is:

or

; Or its stereoisomers or pharmaceutically acceptable salts, solvates, esters or prodrugs. In one embodiment, the compound of structure (H) or (HI) is:

或其立體異構體或醫藥學上可接受之鹽、溶劑合物、酯或前藥；其中，X⁶為N或C-R⁴，其中R⁴為H、氰基、CONH₂、CONHCH₃、CON(CH₃)₂、COCH₃；X²獨立地為C-H、C-CH₃或N；X³獨立地為C-H、C-CH₃、C-CF₃、C-CHF₂、C-F、C-Cl或N；R^4N為H、-CD₃、-CH₃、-CH₂CH₃或-CH(CH₃)₂；R²為-OCF₃、-OCHF₂、-OCF₂CF₃、-OCH₂CHF₂、-OCH₂CF₃、環丙基、環丙氧基、甲氧基、-OCD₃、乙氧基或異丙氧基；R¹⁰各自獨立地為H、-CD₃、C_1-6烷基、C_3-6環烷基、C_2-6羥基烷基、C_1-6烷氧基-C_1-6烷基或C_2-6烷基-NR⁸R⁹；且R⁸及R⁹獨立地為H、-CD₃、C_1-6烷基、C_3-6烯基、C_3-6炔基、C_3-8環烷基、C_3-8環烯基、C_1-C₆醯基、4-12員單環或二環雜環基、4-12員單環或二環雜環基-C₁-C₆烷基-、C_6-C₁₂芳基、5-12員雜芳基；且R⁸及R⁹可進一步獨立地經多達三個選自羥基、C_1-6烷氧基、C_1-6羥基烷基、C_2-6羥基烷氧基、側氧基、硫羰基、氰基或鹵基之取代基取代。 In another embodiment, the invention relates to compounds of formula (J):

Or its stereoisomers or pharmaceutically acceptable salts, solvates, esters or prodrugs; where X ⁶ is N or CR ⁴ , where R ⁴ is H, cyano, CONH ₂ , CONHCH ₃ , CON (CH ₃ ) ₂ , COCH ₃ ; X ^{2 is} independently CH, C-CH ₃ or N; X ^{3 is} independently CH, C-CH ₃ , C-CF ₃ , C-CHF ₂ , CF, C-Cl Or N; R ^4N is H, -CD ₃ , -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ ; R ² is -OCF ₃ , -OCHF ₂ , -OCF ₂ CF ₃ , -OCH ₂ CHF ₂ , -OCH ₂ CF ₃ , cyclopropyl, cyclopropoxy, methoxy, -OCD ₃ , ethoxy, or isopropoxy; R ^{10 is} each independently H, -CD ₃ , C _{1- 6} alkyl, C _3-6 cycloalkyl, C _2-6 hydroxyalkyl, C _1-6 alkoxy-C _1-6 alkyl or C _2-6 alkyl-NR ⁸ R ⁹ ; and R ⁸ And R ^{9 is} independently H, -CD ₃ , C _1-6 alkyl, C _3-6 alkenyl, C _3-6 alkynyl, C _3-8 cycloalkyl, C _3-8 cycloalkenyl, C _1- C ₆ acetyl, 4-12 membered monocyclic or bicyclic heterocyclyl, 4-12 membered monocyclic or bicyclic heterocyclyl-C ₁ -C ₆ alkyl-, C _6- C ₁₂ aryl, 5-12 membered heteroaryl groups; and R ⁸ and R ⁹ may be independently selected from up to three further selected from hydroxy, C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _2-6 hydroxyalkoxy , Pendant, thiocarbonyl, cyano or halo substituents.

In one embodiment, the compound of formula (J) comprises: X ⁶ is C-CN; X ² is CH or C-CH ₃ ; X ³ is CH or C-CH ₃ ; R ^4N is H, -CD ₃ ,- CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ ; R ² is methoxy, -OCD ₃ , ethoxy or isopropoxy; R ^{10 is} independently H, -CD ₃ ,- CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ .

或其立體異構體或醫藥學上可接受之鹽、溶劑合 物、酯或前藥。在一實施例中，式(J)化合物為：

或其立體異構體或醫藥學上可接受之鹽、溶劑合物、酯或前藥。 In one embodiment, the compound of formula (J) is:

Or its stereoisomers or pharmaceutically acceptable salts, solvates, esters or prodrugs. In one embodiment, the compound of formula (J) is:

Or its stereoisomers or pharmaceutically acceptable salts, solvates, esters or prodrugs.

或其立體異構體或醫藥學上可接受之鹽、溶劑合物、酯或前藥；其中，Z為CH或N；X²為CR^4a或N；X⁶為CR^4b或N；X⁸為CH或N；R¹為氫、甲基、氟、氯、溴、CF₃或氰基；R²為-OCF₃、-OCHF₂、-OCF₂CF₃、-OCH₂CHF₂、-OCH₂CF₃、環丙氧基、甲氧基、-OCD₃、乙氧基或異丙氧基；R³為N(R¹⁰)C_2-6烷基-NR¹⁰R¹⁰；R^4a為H、氰基、鹵基、-C_1-6烷基或-C_1-6鹵烷基；R^4b為H、氰基、硝基、鹵基、-C_1-6烷基、-C_1-6鹵烷基、羧基-C_1-6烷基、-C_1-6羥基烷基、R⁸R⁹N-C_1-6烷基-、-C_2-6烯基、-C_2-6炔基、C_1-6醯基-、R⁷-(CH₂)_pC(=O)-、C_1-6羥基烷基-C(=O)-、羧基、-C_1-6烷氧基羰基、-C(=O)NR⁸R⁹、羥基、烷氧基、-OCD₃、C_1-6醯氧基、-NR⁸R⁹、C_1-6醯基-N(R¹⁰)-或R⁷SO₂-；R^4N為H、-C_1-6烷基或-CD₃；R⁸及R⁹獨立地為H、-CD₃、C_1-6烷基、C_3-8環烷基、C_3-8環烷基-(C_1-3烷基)-、C_1-C₆醯基、苯基、單環雜芳基或單環雜環基；且R⁸及R⁹可進一步獨立地經多達三個選自羥基、C_1-6烷氧基、側氧基、硫羰基、氰基或鹵基之取代基取代；或或者，R⁸及R⁹與其同時附接之N原子合起來形成4-7個成員之雜環，該雜環含有多達一個選自O、S或NR¹¹之其他雜原子，或形成7-12個成員之雜雙環，該雜雙環可為稠合、橋接或螺環，且含有多達兩個選自O、S(O)_x或NR¹¹之其他雜原子，且此等雜環視情況經多達三個選自羥基、C_1-6烷氧基、C_1-6羥基烷基、C_1-6 烷氧基-C_1-6烷基、C_1-6烷氧基-C_1-6烷氧基、C_2-6羥基烷氧基、側氧基、硫羰基、氰基或鹵基之取代基取代；R¹⁰各自獨立地為H、-CD₃、C_1-6烷基、C_3-6環烷基、C_2-6羥基烷基、C_1-6烷氧基-C_1-6烷基或C_2-6烷基-NR⁸R⁹；p=0、1、2、3或4；q=2、3或4；且x=0、1或2。 In one embodiment, the invention relates to compounds of formula (K):

Or its stereoisomer or pharmaceutically acceptable salt, solvate, ester or prodrug; where Z is CH or N; X ² is CR ^4a or N; X ⁶ is CR ^4b or N; X ⁸ CH or N; R ¹ is hydrogen, methyl, fluorine, chlorine, bromine, CF ₃ or cyano; R ² is -OCF ₃ , -OCHF ₂ , -OCF ₂ CF ₃ , -OCH ₂ CHF ₂ , -OCH ₂ CF ₃ , cyclopropoxy, methoxy, -OCD ₃ , ethoxy or isopropoxy; R ³ is N(R ¹⁰ )C _2-6 alkyl-NR ¹⁰ R ¹⁰ ; R ^4a is H , Cyano, halo, -C _1-6 alkyl or -C _1-6 haloalkyl; R ^4b is H, cyano, nitro, halo, -C _1-6 alkyl, -C _{1- 6} haloalkyl, carboxy-C _1-6 alkyl, -C _1-6 hydroxyalkyl, R ⁸ R ⁹ NC _1-6 alkyl-, -C _2-6 alkenyl, -C _2-6 alkynyl , C _1-6 acetyl-, R ⁷ -(CH ₂ ) _p C(=O)-, C _1-6 hydroxyalkyl-C(=O)-, carboxyl, -C _1-6 alkoxycarbonyl , -C(=O)NR ⁸ R ⁹ , hydroxyl, alkoxy, -OCD ₃ , C _1-6 acetyloxy, -NR ⁸ R ⁹ , C _1-6 acetyl-N(R ¹⁰ )- or R ⁷ SO ₂ -; R ^4N is H, -C _1-6 alkyl or -CD ₃ ; R ⁸ and R ^{9 are} independently H, -CD ₃ , C _1-6 alkyl, C _3-8 cycloalkane Group, C _3-8 cycloalkyl-(C _1-3 alkyl)-, C _1- C ₆ acetyl, phenyl, monocyclic heteroaryl or monocyclic heterocyclic group; and R ⁸ and R ⁹ may be Further independently substituted with up to three substituents selected from the group consisting of hydroxy, C _1-6 alkoxy, pendant, thiocarbonyl, cyano or halo; or alternatively, R ⁸ and R ⁹ are simultaneously attached to N Together, the atoms form a 4-7 member heterocycle, which contains up to one other heteroatom selected from O, S, or NR ¹¹ , or a 7-12 member heterobicycle, which may be fused Combined, bridged or spiro ring, and containing up to two other heteroatoms selected from O, S(O) _x or NR ¹¹ , and these heterocycles may optionally be selected from up to three selected from hydroxyl, C _1-6 alkoxy Group, C _1-6 hydroxyalkyl, C _1-6 alkoxy-C _1-6 alkyl, C _1-6 alkoxy-C _1-6 alkoxy, C _2-6 hydroxyalkoxy, Substitution of pendant, thiocarbonyl, cyano or halo groups; R ^{10 is} each independently H, -CD ₃ , C _1-6 alkyl, C _3-6 cycloalkyl, C _2-6 hydroxyalkane Group, C _1-6 alkoxy-C _1-6 alkyl or C _2-6 alkyl-NR ⁸ R ⁹ ; p=0, 1, 2, 3 or 4; q=2, 3 or 4; and x=0, 1 or 2.

或其立體異構體或醫藥學上可接受之鹽、溶劑合物、酯或前藥；其中，X²為CR^4a或N；X⁶為CR^4b或N；X⁸為CH或N；R²為甲氧基、-OCD₃、乙氧基或異丙氧基；R^4a為H、氰基、鹵基、-C_1-6烷基或-C_1-6鹵烷基； R^4b為H、氰基、硝基、鹵基、-C_1-6烷基、-C_1-6鹵烷基、羧基-C_1-6烷基、-C_1-6羥基烷基、R⁸R⁹N-C_1-6烷基-、-C_2-6烯基、-C_2-6炔基、C_1-6醯基-、R⁷-(CH₂)_pC(=O)-、C_1-6羥基烷基-C(=O)-、羧基、-C_1-6烷氧基羰基、-C(=O)NR⁸R⁹、羥基、烷氧基、-OCD₃、C_1-6醯氧基、-NR⁸R⁹、C_1-6醯基-N(R¹⁰)-、R⁷SO₂-；R^4N為H、-CH₃、Et、CH(CH3)2或-CD₃；R⁸及R⁹獨立地為H、-CD₃、C_1-6烷基、C_3-8環烷基、C_3-8環烷基-(C_1-3烷基)-、C_1-C₆醯基、苯基、單環雜芳基或單環雜環基；且R⁸及R⁹可進一步獨立地經多達三個選自羥基、C_1-6烷氧基、側氧基、硫羰基、氰基或鹵基之取代基取代；或或者，R⁸及R⁹與其同時附接之N原子合起來形成4-7個成員之雜環，該雜環含有多達一個選自O、S或NR¹¹之其他雜原子，或形成7-12個成員之雜雙環，該雜雙環可為稠合、橋接或螺環，且含有多達兩個選自O、S(O)_x或NR¹¹之其他雜原子，且此等雜環視情況經多達三個選自羥基、C_1-6烷氧基、C_1-6羥基烷基、C_1-6烷氧基-C_1-6烷基、C_1-6烷氧基-C_1-6烷氧基、C_2-6羥基烷氧基、側氧基、硫羰基、氰基或鹵基之取代基取代；R¹⁰各自獨立地為H、-CD₃、C_1-6烷基、C_3-6環烷基、C_2-6羥基烷基、C_1-6烷氧基-C_1-6烷基或C_2-6烷基-NR⁸R⁹；p=0、1、2、3或4；q=2、3或4；且x=0、1或2。在另一實施例中，式(L)化合物包含：X²為CR^4a或N；X⁶為CR^4b或N；X⁸為CH或N；R²為甲氧基、-OCD₃、乙氧基或異丙氧基； R^4a為H、F、Cl、CH₃、CF₃或CHF₂；R^4b為H、氰基、硝基、鹵基、-C_1-6烷基或-C_1-6鹵烷基；R^4N為H、-CD₃、-CH₃、-CH₂CH₃或-CH(CH₃)₂；且R¹⁰各自獨立地為H、-CD₃、-CH₃、-CH₂CH₃或-CH(CH₃)₂。在一些實施例中，式(L)化合物包含：X²為CR^4a或N；X⁶為CR^4b；X⁸為CH；R²為甲氧基、-OCD₃、乙氧基或異丙氧基；R^4a為H、F、CH₃、CF₃或CHF₂；R^4b為H、CH₃、F、Cl、CF₃或CHF₂；R^4N為H、-CD₃、-CH₃、-CH₂CH₃或-CH(CH₃)₂；R¹⁰各自獨立地為H、-CD₃、-CH₃、-CH₂CH₃或-CH(CH₃)₂。 In another embodiment, the invention relates to compounds of formula (L):

Or its stereoisomer or pharmaceutically acceptable salt, solvate, ester or prodrug; wherein X ² is CR ^4a or N; X ⁶ is CR ^4b or N; X ⁸ is CH or N; R ² is methoxy, -OCD ₃ , ethoxy or isopropoxy; R ^4a is H, cyano, halo, -C _1-6 alkyl or -C _1-6 haloalkyl; R ^4b is H, cyano, nitro, halo, -C _1-6 alkyl, -C _1-6 haloalkyl, carboxy -C _1-6 alkyl, -C _1-6 hydroxyalkyl, R ⁸ R ⁹ NC _1-6 alkyl-, -C _2-6 alkenyl, -C _2-6 alkynyl, C _1-6 acetyl-, R ⁷ -(CH ₂ ) _p C(=O)-, C _{1- 6} -hydroxyalkyl-C(=O)-, carboxyl, -C _1-6 alkoxycarbonyl, -C(=O)NR ⁸ R ⁹ , hydroxy, alkoxy, -OCD ₃ , C _1-6 acetyl Oxygen, -NR ⁸ R ⁹ , C _1-6 acetyl-N(R ¹⁰ )-, R ⁷ SO ₂ -; R ^4N is H, -CH ₃ , Et, CH(CH3) 2 or -CD ₃ ; R ⁸ and R ^{9 are} independently H, -CD ₃ , C _1-6 alkyl, C _3-8 cycloalkyl, C _3-8 cycloalkyl-(C _1-3 alkyl)-, C _1- C ₆ acetyl, phenyl, monocyclic heteroaryl or monocyclic heterocyclic group; and R ⁸ and R ⁹ may be independently independently selected by up to three from hydroxyl, C _1-6 alkoxy, pendant, Thiocarbonyl, cyano or halo substituent substitution; or alternatively, R ⁸ and R ⁹ together with the N atom to which they are simultaneously attached form a heterocyclic ring of 4-7 members, the heterocyclic ring containing up to one selected from O , S or NR ¹¹ other hetero atoms, or form a heterobicyclic ring of 7-12 members, the heterobicyclic ring may be fused, bridged or spiro ring, and contains up to two selected from O, S (O) _x or NR ¹¹ other heteroatoms, and these heterocycles are optionally selected from up to three hydroxy, C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _1-6 alkoxy-C _1-6 alkyl Group, C _1-6 alkoxy-C _1-6 alkoxy, C _2-6 hydroxyalkoxy, pendant, thiocarbonyl, cyano or halo substituents; R ^{10 is} each independently H, -CD ₃ , C _1-6 alkyl, C _3-6 cycloalkyl, C _2-6 hydroxyalkyl, C _1-6 alkoxy-C _1-6 alkyl, or C _2-6 alkyl -NR ⁸ R ⁹ ; p=0, 1, 2, 3 or 4; q=2, 3 or 4; and x=0, 1 or 2. In another embodiment, the compound of formula (L) comprises: X ² is CR ^4a or N; X ⁶ is CR ^4b or N; X ⁸ is CH or N; R ² is methoxy, -OCD ₃ , ethoxy Group or isopropoxy; R ^4a is H, F, Cl, CH ₃ , CF ₃ or CHF ₂ ; R ^4b is H, cyano, nitro, halo, -C _1-6 alkyl or -C _{1 -6} haloalkyl; R ^4N is H, -CD ₃ , -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ ; and R ^{10 is} each independently H, -CD ₃ , -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ . In some embodiments, the compound of formula (L) comprises: X ² is CR ^4a or N; X ⁶ is CR ^4b ; X ⁸ is CH; R ² is methoxy, -OCD ₃ , ethoxy, or isopropoxy Radical; R ^4a is H, F, CH ₃ , CF ₃ or CHF ₂ ; R ^4b is H, CH ₃ , F, Cl, CF ₃ or CHF ₂ ; R ^4N is H, -CD ₃ , -CH ₃ ,- CH ₂ CH ₃ or -CH(CH ₃ ) ₂ ; each R ^{10 is} independently H, -CD ₃ , -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ .

或其立體異構體或醫藥學上可接受之鹽、溶劑合物、酯或前藥。 In one embodiment, the compound of formula (L) is:

Or its stereoisomers or pharmaceutically acceptable salts, solvates, esters or prodrugs.

或其立體異構體或醫藥學上可接受之鹽、溶劑合物、酯或前藥；其中，Z為CH或N；R¹為氫、甲基、氟、氯、溴、-CF₃或氰基；R²為-OCF₃、-OCHF₂、-OCF₂CF₃、-OCH₂CHF₂、-OCH₂CF₃、環丙氧基、甲氧基、-OCD₃、乙氧基或異丙氧基；R³為N(R¹⁰)C_2-6烷基-NR¹⁰R¹⁰；R^4a為氰基、-C_1-6羥基烷基、C_1-6醯基-、吡唑、1,2,3-三唑、四唑、-C(=O)NR⁸R⁹、-NR⁸R⁹、C_1-6醯基-N(R¹⁰)-、(C_1-3烷基)SO₂NH-、(C_1-6烷基)SO₂-或R⁷SO₂-；R^4b為H、氰基、鹵基、-C_1-6烷基或-C_1-6鹵烷基；R⁷為-OH或-NR⁸R⁹；R⁸及R⁹獨立地為H、-CD₃、C_1-6烷基、C_3-8環烷基、C_3-8環烷基-(C_1-3烷基)-、C_1-C₆醯基、苯基、單環雜芳基或單環雜環基；且R⁸及R⁹可進一步獨立地經多達三個選自羥基、C_1-6烷氧基、側氧基、硫羰基、氰基或鹵基之取代基取代；或或者，R⁸及R⁹與其同時附接之N原子合起來形成4-7個成員之雜環，該雜環含有多達一個選自O、S或NR¹¹之其他雜原子；R¹⁰各自獨立地為H、-CD₃、C_1-6烷基、C_3-6環烷基、C_2-6羥基烷基、C_2-6烷基-NR⁸R⁹； 或者，同時附接之同一N原子上的兩個R¹⁰形成5-6個成員之雜環，該雜環含有多達一個選自O、S或NR¹¹之其他雜原子；且R¹¹各自獨立地為氫或C_1-C₆烷基，其視情況經多達三個選自羥基、側氧基、硫羰基、氰基及鹵基之取代基取代。 In some embodiments, the present invention relates to compounds of formula (M):

Or its stereoisomer or pharmaceutically acceptable salt, solvate, ester or prodrug; where Z is CH or N; R ¹ is hydrogen, methyl, fluorine, chlorine, bromine, -CF ₃ or Cyano; R ² is -OCF ₃ , -OCHF ₂ , -OCF ₂ CF ₃ , -OCH ₂ CHF ₂ , -OCH ₂ CF ₃ , cyclopropoxy, methoxy, -OCD ₃ , ethoxy, or iso Propoxy; R ³ is N(R ¹⁰ )C _2-6 alkyl-NR ¹⁰ R ¹⁰ ; R ^4a is cyano, -C _1-6 hydroxyalkyl, C _1-6 acetyl-, pyrazole, 1,2,3-triazole, tetrazole, -C(=O)NR ⁸ R ⁹ , -NR ⁸ R ⁹ , C _1-6 acetyl-N(R ¹⁰ )-, (C _1-3 alkyl )SO ₂ NH-, (C _1-6 alkyl)SO ₂ -or R ⁷ SO ₂ -; R ^4b is H, cyano, halo, -C _1-6 alkyl or -C _1-6 haloalkane Group; R ⁷ is -OH or -NR ⁸ R ⁹ ; R ⁸ and R ^{9 are} independently H, -CD ₃ , C _1-6 alkyl, C _3-8 cycloalkyl, C _3-8 cycloalkyl -(C _1-3 alkyl)-, C _1- C ₆ acetyl, phenyl, monocyclic heteroaryl or monocyclic heterocyclic group; and R ⁸ and R ⁹ may be independently selected from up to three Hydroxy, C _1-6 alkoxy, pendant, thiocarbonyl, cyano or halo substituents; or alternatively, R ⁸ and R ⁹ together with the N atom to which they are attached together form 4-7 members Heterocyclic ring, the heterocyclic ring contains up to one other heteroatom selected from O, S or NR ¹¹ ; R ^{10 is} each independently H, -CD ₃ , C _1-6 alkyl, C _3-6 cycloalkyl , C _2-6 hydroxyalkyl, C _2-6 alkyl-NR ⁸ R ⁹ ; or, two R ¹⁰ on the same N atom attached at the same time form a heterocycle of 5-6 members, the heterocycle contains Up to one other heteroatom selected from O, S or NR ¹¹ ; and R ¹¹ are each independently hydrogen or C ₁ -C ₆ alkyl, which may optionally be selected from hydroxyl, pendant, thiocarbonyl , Cyano and halogen substituents.

In another embodiment, the compound of formula (M) comprises: Z is CH; R ¹ is hydrogen, methyl, fluorine, chlorine, bromine, -CF ₃ or cyano; R ² is methoxy, -OCD ₃ , Ethoxy or isopropoxy; R ³ is -N(CH ₃ )CH ₂ CH ₂ NR ¹⁰ R ¹⁰ ; R ^4a is -NR ⁸ R ⁹ ; R ^4b is H, CH ₃ , F, Cl, CF ₃ Or CHF ₂ ; R ⁸ and R ^{9 are} independently H, -CD ₃ , C _1-6 alkyl, C _3-8 cycloalkyl, C _3-8 cycloalkyl-(C _1-3 alkyl)- , C _1- C ₆ acyl, phenyl, monocyclic heteroaryl or monocyclic heterocyclyl group; and R ⁸ and R ⁹ may be further independently substituted with up to three substituents selected from hydroxy, C _1-6 alkoxy, A substituent of a pendant oxygen group, a thiocarbonyl group, a cyano group or a halogen group; and R ¹⁰ are each independently H, -CD ₃ , -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ .

或其立體異構體或醫藥學上可接受之鹽、溶劑合物、酯或前藥。 In one embodiment, the compound of formula (M) is:

Or its stereoisomers or pharmaceutically acceptable salts, solvates, esters or prodrugs.

或其立體異構體或醫藥學上可接受之鹽、溶劑合物、酯或前藥；其中，X²為CH、CCH₃或N；X⁶為CR⁴或N；Z為CH或N；R¹為氫、甲基、氟、氯、溴、-CF₃或氰基；R²為-OCF₃、-OCHF₂、-OCF₂CF₃、-OCH₂CHF₂或-OCH₂CF₃；R³為N(R¹⁰)C_2-6烷基-NR¹⁰R¹⁰；R⁴為H、氰基、鹵基、-C_1-6烷基、-C_1-6鹵烷基；R^4a獨立地為氰基、-C_1-6羥基烷基、C_1-6醯基-、吡唑、1,2,3-三唑、四唑、-C(=O)NR⁸R⁹、-NR⁸R⁹、C_1-6醯基-N(R¹⁰)-、(C_1-3烷基)SO₂NH-、(C_1-6烷基)SO₂-或R⁷SO₂-；R⁷為-OH或-NR⁸R⁹；R⁸及R⁹獨立地為H、-CD₃、C_1-6烷基、C_3-8環烷基、C_3-8環烷基-(C_1-3烷基)-、C_1-C₆醯基、苯基、單環雜芳基或單環雜環基；且R⁸及R⁹可進一步獨立地經多達三個選自羥基、C_1-6烷氧基、側氧基、硫羰基、氰基或鹵基之取代基取代；R¹⁰各自獨立地為H、-CD₃、C_1-6烷基、C_3-6環烷基、C_2-6羥基烷基、C_2-6烷基-NR⁸R⁹。 In another embodiment, the invention relates to compounds of formula (N):

Or its stereoisomer or pharmaceutically acceptable salt, solvate, ester or prodrug; wherein, X ² is CH, CCH ₃ or N; X ⁶ is CR ⁴ or N; Z is CH or N; R ¹ is hydrogen, methyl, fluorine, chlorine, bromine, -CF ₃ or cyano; R ² is -OCF ₃ , -OCHF ₂ , -OCF ₂ CF ₃ , -OCH ₂ CHF ₂ or -OCH ₂ CF ₃ ; R ³ is N(R ¹⁰ )C _2-6 alkyl-NR ¹⁰ R ¹⁰ ; R ⁴ is H, cyano, halo, -C _1-6 alkyl, -C _1-6 haloalkyl; R ^4a Independently cyano, -C _1-6 hydroxyalkyl, C _1-6 acetyl-, pyrazole, 1,2,3-triazole, tetrazole, -C(=O)NR ⁸ R ⁹ ,- NR ⁸ R ⁹ , C _1-6 acetyl-N(R ¹⁰ )-, (C _1-3 alkyl)SO ₂ NH-, (C _1-6 alkyl)SO ₂ -or R ⁷ SO ₂ -; R ⁷ is -OH or -NR ⁸ R ⁹ ; R ⁸ and R ^{9 are} independently H, -CD ₃ , C _1-6 alkyl, C _3-8 cycloalkyl, C _3-8 cycloalkyl-( C _1-3 alkyl)-, C _1- C ₆ acetyl, phenyl, monocyclic heteroaryl or monocyclic heterocyclic group; and R ⁸ and R ⁹ may be further independently selected by up to three from hydroxyl, C _1-6 alkoxy, pendant, thiocarbonyl, cyano or halo substituent substitution; R ^{10 is} each independently H, -CD ₃ , C _1-6 alkyl, C _3-6 cycloalkane Group, C _2-6 hydroxyalkyl, C _2-6 alkyl-NR ⁸ R ⁹ .

或其立體異構體或醫藥學上可接受之鹽、溶劑合物、酯或前藥；其中，X⁶為CH、CCH₃或N；R²為-OCF₃、-OCHF₂、-OCF₂CF₃、-OCH₂CHF₂或-OCH₂CF₃；R⁸及R⁹各自獨立地為H、-CD₃、-CH₃、-CH₂CH₃或-CH(CH₃)₂；且R¹⁰各自獨立地為H、-CD₃、-CH₃、-CH₂CH₃或-CH(CH₃)₂。 In one embodiment, the compound of formula (N) has the structure of formula (O):

Or its stereoisomers or pharmaceutically acceptable salts, solvates, esters or prodrugs; where X ⁶ is CH, CCH ₃ or N; R ² is -OCF ₃ , -OCHF ₂ , -OCF ₂ CF ₃ , -OCH ₂ CHF ₂ or -OCH ₂ CF ₃ ; R ⁸ and R ⁹ are each independently H, -CD ₃ , -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ ; and R ¹⁰ are each independently H, -CD ₃ , -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ .

或其立體異構體或醫藥學上可接受之鹽、溶劑合物、酯或前藥。 In other embodiments, the compound of formula (N) or (O) is:

Or its stereoisomers or pharmaceutically acceptable salts, solvates, esters or prodrugs.

或其立體異構體或醫藥學上可接受之鹽、溶劑合物、酯、互變異構體或前藥；其中：Z為CH或N；R¹獨立地選自氫、氟、氯、溴、甲基、乙基、羥基、甲氧基、乙氧基、異丙氧基、環丙氧基、-OCF₃、-OCH₂CF₃、-OCH₂CHF₂、乙烯基、乙炔基、CF₃、CHF₂、CHO、CH₂OH、CONH₂、CO₂Me、CONHMe、CONMe₂或氰基；R²為-OCF₃、-OCHF₂、-OCF₂CF₃、-OCH₂CHF₂、-OCH₂CF₃、環丙基、環丙氧基、甲氧基、-OCD₃、乙氧基或異丙氧基；R³為N(R¹⁰)C_2-6烷基-NR¹⁰R¹⁰、N(R¹⁰)C_2-6烷基-R⁷、O(CH₂)_pR⁷、N(R¹⁰)C(=O)(CH₂)_pR⁷或R⁷；R⁴各自獨立地為H、氰基、硝基、鹵基、-C_1-6烷基、-C_1-6鹵烷基、羧基-C_1-6烷基、-C_1-6羥基烷基、R⁸R⁹N-C_1-6烷基-、-C_2-6烯基、-C_2-6炔基、C_1-6醯基-、R⁷-(CH₂)_pC(=O)-、C_1-6羥基烷基-C(=O)-、羧基、-C_1-6烷氧基羰基、-C(=O)NR⁸R⁹、羥基、烷氧基、C_1-6醯氧基、-NR⁸R⁹、C_1-6醯基-N(R¹⁰)-或R⁷SO₂-； R^4a獨立地為H、氰基、硝基、鹵基、-C_1-6烷基、-C_1-6鹵烷基、-C_1-6烷氧基、-C_1-6鹵烷氧基、-C_1-6羥基烷基、C_1-6醯基-、吡唑、1,2,3-三唑、四唑、-C(=O)NR⁸R⁹、-NR⁸R⁹、C_1-6醯基-N(R¹⁰)-、(C_1-3烷基)SO₂NH-、(C_1-6烷基)SO₂-或R⁷SO₂-；R⁷為OH、NR⁸R⁹、O(CH₂)_qNR⁸R⁹、C_1-6烷氧基或C_2-6羥基烷氧基；R⁸及R⁹獨立地為H、-CD₃、C_1-6烷基、C_3-6烯基、C_3-6炔基、C_3-8環烷基、C_3-8環烯基、C_1-C₆醯基、4-12員單環或二環雜環基、4-12員單環或二環雜環基-C₁-C₆烷基-、C_6-C₁₂芳基、5-12員雜芳基；且R⁸及R⁹可進一步獨立地經多達三個選自羥基、C_1-6烷氧基、C_1-6羥基烷基、C_2-6羥基烷氧基、側氧基、硫羰基、氰基或鹵基之取代基取代；或或者，R⁸及R⁹與其同時附接之N原子合起來形成4-7個成員之雜環，該雜環含有多達一個選自O、S或NR¹¹之其他雜原子，或形成7-12個成員之雜雙環，該雜雙環可為稠合、橋接或螺環，且含有多達兩個選自O、S(O)_x或NR¹¹之其他雜原子，且此等雜環視情況經多達三個選自羥基、C_1-6烷氧基、C_1-6羥基烷基、C_1-6烷氧基-C_1-6烷基、C_1-6烷氧基-C_1-6烷氧基、C_2-6羥基烷氧基、側氧基、硫羰基、氰基或鹵基之取代基取代；R¹⁰各自獨立地為H、-CD₃、C_1-6烷基、C_3-6環烷基、C_2-6羥基烷基、C_1-6烷氧基-C_1-6烷基或C_2-6烷基-NR⁸R⁹；或或者，同時附接之同一N原子上的兩個R¹⁰形成5-6個成員之雜環，該雜環含有多達一個選自O、S或NR¹¹之其他雜原子；且R¹¹各自獨立地為氫或C_1-C₆烷基，其視情況經多達三個選自羥基、側氧基、硫羰基、氰基及鹵基之取代基取代；p=0、1、2、3或4；q=2、3或4；且x=0、1或2。 In one embodiment, the invention relates to compounds of formula (P):

Or its stereoisomer or pharmaceutically acceptable salt, solvate, ester, tautomer or prodrug; where: Z is CH or N; R ^{1 is} independently selected from hydrogen, fluorine, chlorine, bromine , Methyl, ethyl, hydroxy, methoxy, ethoxy, isopropoxy, cyclopropoxy, -OCF ₃ , -OCH ₂ CF ₃ , -OCH ₂ CHF ₂ , vinyl, ethynyl, CF ₃ , CHF ₂ , CHO, CH ₂ OH, CONH ₂ , CO ₂ Me, CONHMe, CONMe ₂ or cyano group; R ² is -OCF ₃ , -OCHF ₂ , -OCF ₂ CF ₃ , -OCH ₂ CHF ₂ ,- OCH ₂ CF ₃ , cyclopropyl, cyclopropoxy, methoxy, -OCD ₃ , ethoxy, or isopropoxy; R ³ is N(R ¹⁰ )C _2-6 alkyl-NR ¹⁰ R ¹⁰ , N(R ¹⁰ )C _2-6 alkyl-R ⁷ , O(CH ₂ ) _p R ⁷ , N(R ¹⁰ )C(=O)(CH ₂ ) _p R ⁷ or R ⁷ ; R ^{4 is} independent Ground is H, cyano, nitro, halo, -C _1-6 alkyl, -C _1-6 haloalkyl, carboxy -C _1-6 alkyl, -C _1-6 hydroxyalkyl, R ⁸ R ⁹ NC _1-6 alkyl-, -C _2-6 alkenyl, -C _2-6 alkynyl, C _1-6 acetyl-, R ⁷ -(CH ₂ ) _p C(=O)-, C _1-6 hydroxyalkyl -C(=O)-, carboxyl, -C _1-6 alkoxycarbonyl, -C(=O)NR ⁸ R ⁹ , hydroxy, alkoxy, C _1-6 acetyloxy , -NR ⁸ R ⁹ , C _1-6 acetyl-N(R ¹⁰ )- or R ⁷ SO ₂ -; R ^{4a is} independently H, cyano, nitro, halo, -C _1-6 alkyl , -C _1-6 haloalkyl, -C _1-6 alkoxy, -C _1-6 haloalkoxy, -C _1-6 hydroxyalkyl, C _1-6 acetyl-, pyrazole, 1 , 2,3-triazole, tetrazole, -C(=O)NR ⁸ R ⁹ , -NR ⁸ R ⁹ , C _1-6 acetyl-N(R ¹⁰ )-, (C _1-3 alkyl) SO ₂ NH-, (C _1-6 alkyl)SO ₂ -or R ⁷ SO ₂ -; R ⁷ is OH, NR ⁸ R ⁹ , O(CH ₂ ) _q NR ⁸ R ⁹ , C _1-6 alkoxy Group or C _2-6 hydroxyalkoxy; R ⁸ and R ^{9 are} independently H, -CD ₃ , C _1-6 alkyl, C _3-6 alkenyl, C _3-6 alkynyl, C _3-8 Cycloalkyl, C _3-8 cycloalkenyl, C _1- C ₆ acetyl, 4-12 membered monocyclic or bicyclic heterocyclyl, 4-12 membered monocyclic or bicyclic heterocyclyl-C ₁ -C ₆ alkyl-, C _6- C ₁₂ aryl, 5-12 member heteroaryl; and R ⁸ and R ⁹ can be One-step independent substitution by up to three selected from hydroxy, C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _2-6 hydroxyalkoxy, pendant, thiocarbonyl, cyano or halo Radical substitution; or alternatively, R ⁸ and R ⁹ together with the N atom to which they are simultaneously attached form a heterocyclic ring of 4-7 members, the heterocyclic ring containing up to one other heteroatom selected from O, S or NR ¹¹ , Or form a heterobicyclic ring of 7-12 members, which may be fused, bridged or spirocyclic, and contain up to two other heteroatoms selected from O, S(O) _x or NR ¹¹ , and such The heterocyclic ring may be selected from up to three hydroxy, C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _1-6 alkoxy-C _1-6 alkyl, C _1-6 alkoxy- C _1-6 alkoxy, C _2-6 hydroxyalkoxy, pendant, thiocarbonyl, cyano or halo substituent substitution; R ^{10 is} each independently H, -CD ₃ , C _1-6 Alkyl, C _3-6 cycloalkyl, C _2-6 hydroxyalkyl, C _1-6 alkoxy-C _1-6 alkyl, or C _2-6 alkyl-NR ⁸ R ⁹ ; or alternatively, Two R ¹⁰ on the same N atom attached to form a heterocycle of 5-6 members, the heterocycle contains up to one other heteroatom selected from O, S or NR ¹¹ ; and each R ^{11 is} independently hydrogen or C _1- C ₆ alkyl, which is optionally substituted with up to three substituents selected from hydroxy, oxo, thiocarbonyl, cyano, and halo group of substituents; p = 0,1,2,3 or 4; q = 2, 3 or 4; and x = 0, 1 or 2.

In one embodiment, the compound of formula (P) comprises: Z is CH or N; R ¹ is hydrogen, methyl, fluorine, chlorine, bromine, -CF ₃ or cyano; R ³ is N(R ¹⁰ )C _{2 -6} alkyl-NR ¹⁰ R ¹⁰ ; R ^{4 is} independently H, cyano, halo, -C _1-6 alkyl, -C _1-6 haloalkyl; R ^{4a is} independently H, cyano , Nitro, halo, -C _1-6 alkyl, -C _1-6 haloalkyl, -C _1-6 alkoxy, -C _1-6 haloalkoxy, -C(=O)NR ⁸ R ⁹ or -NR ⁸ R ⁹ ; R ⁸ and R ^{9 are} independently H, -CD ₃ , -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ ; and R ^{10 is} each independently H , -CD ₃ , -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ .

或其立體異構體或醫藥學上可接受之鹽、溶劑合物、酯、互變 異構體或前藥。 In some embodiments, the compound of formula (P) is:

Or its stereoisomers or pharmaceutically acceptable salts, solvates, esters, tautomers or prodrugs.

In one embodiment, the invention relates to compounds having the following structure:

In one embodiment, the present invention relates to a pharmaceutical comprising any of the compounds disclosed herein or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof and a pharmaceutically acceptable carrier combination. In one embodiment, the present invention relates to formulas (I), (A), (B), (C), (CI), (D), (DI), (E), (( EI), (F), (G), (H), (HI), (J), (K), (L), (M), (N), (O) and/or (P) compounds Pharmaceutical composition of any one or a pharmaceutically acceptable salt, solvate, N-oxide, ester or prodrug and a pharmaceutically acceptable carrier.

In some embodiments, the present invention relates to a method for treating cancer in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of any of the compounds disclosed herein or its pharmacological Acceptable salts, solvates, esters or prodrugs. In one embodiment, the cancer is selected from lung cancer, colorectal cancer, pancreatic cancer, head and neck cancer, breast cancer, ovarian cancer, uterine cancer, liver cancer, and gastric cancer. In other embodiments, the cancer is non-small cell lung cancer (NSCLC).

In some embodiments, the present invention relates to a method for treating cancer in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of any of the compounds disclosed herein or its pharmacological Acceptable salts, solvates, esters or prodrugs. In one embodiment, the cancer is caused by mutations in the exon 20 domain of EGFR. In some embodiments, the mutation in the exon 20 domain of EGFR is selected from NPG, ASV, or T790M. In another embodiment, the mutation in the exon 20 domain of EGFR is T790M in parallel with the insertion mutation of exon 19 or the 21 point mutation of exon.

In one embodiment of any of the methods disclosed herein, the patient resists a compound other than any of the compounds disclosed herein or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof Kinase inhibitors other than drugs. In one embodiment, the kinase inhibitor is an EGFR inhibitor.

In one embodiment, the invention relates to a method for inhibiting EGFR or a mutation in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of any of the compounds disclosed herein Compounds or their pharmaceutically acceptable salts, solvates, esters or prodrugs. In one embodiment, the mutation is in the exon 20 domain of EGFR.

In one embodiment, the invention relates to a pharmaceutical composition comprising a compound of the invention or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, and a pharmaceutically acceptable carrier.

In one embodiment, the invention relates to a method for treating cancer in a patient in need, the method comprising administering to the patient a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt, solvent Compound, ester or prodrug.

In one embodiment, the method disclosed herein is suitable for treating cancer selected from lung cancer, colorectal cancer, pancreatic cancer, head and neck cancer, breast cancer, ovarian cancer, uterine cancer, liver cancer, and gastric cancer. In another embodiment, the cancer is non-small cell lung cancer (NSCLC).

In one embodiment, the method disclosed herein relates to cancer treatment, where the cancer is caused by mutations in the exon 20 domain of EGFR. In some embodiments, the mutation in the exon 20 domain of EGFR is selected from NPG, ASV, or T790M. In one embodiment, the mutation in the exon 20 domain of EGFR is T790M in parallel with the insertion mutation of exon 19 or the 21 point mutation of exon.

In one embodiment, the method disclosed herein relates to cancer treatment, wherein the patient is resistant to kinase inhibitors other than the compound of the present invention or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof. In another embodiment, the kinase inhibitor is an EGFR inhibitor.

The present invention also relates to a method for inhibiting EGFR or a mutation in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt or solvate thereof , Esters or prodrugs. In one embodiment, the mutation is in the exon 20 domain of EGFR.

In one embodiment, compounds suitable for any of the methods as disclosed herein are formulas (I), (A), (B), (C), (CI), (D ), (DI), (E), (EI), (F), (G), (H), (HI), (J), (K), (L), (M), (N), (O) and/or (P) compounds or their pharmaceutically acceptable salts, solvates, N-oxides, esters or prodrugs.

Cross-reference of related applications

This application claims the rights and interests of US Provisional Patent Application No. 62/528,697 filed on July 5, 2017. The disclosure content of this US Provisional Patent Application is incorporated herein by reference in its entirety for all purposes.

definition

The term "alkyl" refers to a saturated, monovalent aliphatic hydrocarbon group, including straight chain and branched chain groups having a specified number of carbon atoms. The term "C _1-6 alkyl" or "C ₁ -C ₆ alkyl" refers to straight or branched chain alkyl groups containing 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl Group, n-butyl, isobutyl, second butyl, third butyl, pentyl, hexyl and similar groups. Similarly, the term "C _1-4 alkyl" or "C ₁ -C ₄ alkyl" refers to straight or branched chain alkyl groups containing 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, Isopropyl, n-butyl, isobutyl, second butyl, third butyl and similar groups.

As used herein, the term "halogen" or "halo" refers to fluorine, chlorine, bromine, or iodine (F, Cl, Br, I), and in some cases, substituted alkyl groups may be specifically named with respect to substituents. For example, "haloalkyl" refers to an alkyl group having a specified number of carbon atoms, which is substituted with one or more halogen substituents, and typically contains 1-6 carbon atoms and 1, 2 or 3 halogen atoms (That is, "C ₁ -C ₆ haloalkyl"). Therefore, C ₁ -C ₆ haloalkyl includes trifluoromethyl (-CF ₃ ) and difluoromethyl (-CF ₂ H).

Similarly, "hydroxyalkyl" refers to an alkyl group having a specified number of carbon atoms, which is substituted with one or more hydroxy substituents, and typically contains 1-6 carbon atoms and 1, 2 or 3 hydroxyl groups (also That is, "C ₁ -C ₆ hydroxyalkyl"). Therefore, C ₁ -C ₆ hydroxyalkyl includes hydroxymethyl (-CH ₂ OH) and 2-hydroxyethyl (-CH ₂ CH ₂ OH).

The terms "C _1-6 alkoxy", "C ₁ -C ₆ alkoxy" or "OC _1-6 alkyl" refer to straight or branched chain alkoxy groups containing 1 to 6 carbon atoms, such as Methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, second butoxy, third butoxy, pentyloxy, hexyloxy and the like Group. The terms "C _1-4 alkoxy", "C ₁ -C ₄ alkoxy", "OC _1-4 alkyl" refer to straight or branched chain alkoxy groups containing 1 to 4 carbon atoms, such as Methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, second butoxy, third butoxy and the like.

The terms "C _3-6 cycloalkoxy", "C ₃ -C ₆ cycloalkoxy" or "OC _3-6 cycloalkyl" refer to cyclic alkoxy groups containing 3 to 6 carbon atoms, such as Cyclopropoxy, cyclobutoxy, cyclopentyloxy and similar groups.

"Alkoxyalkyl" refers to an alkyl group having a specified number of carbon atoms, which is substituted with one or more alkoxy substituents. Alkoxyalkyl groups typically contain 1-6 carbon atoms in the alkyl portion and are substituted with 1, 2 or 3 C ₁ -C ₄ alkoxy substituents. Such groups are sometimes described herein as C ₁ -C ₄ alkoxy-C ₁ -C ₆ alkyl. "Aminoalkyl" refers to an alkyl group having a specified number of carbon atoms, which is substituted with one or more substituted or unsubstituted amine groups, which groups are further defined herein.

Aminoalkyls typically contain 1-6 carbon atoms in the alkyl portion and are substituted with 1, 2 or 3 amine substituents. Therefore, C ₁ -C ₆ aminoalkyl includes, for example, aminomethyl (-CH ₂ NH ₂ ), N,N-dimethylamino-ethyl (-CH ₂ CH ₂ N(CH ₃ ) ₂ ) , 3- (N -cyclopropylamino) propyl (-CH ₂ CH ₂ CH ₂ NH- ^C Pr) and N -pyrrolidyl ethyl (-CH ₂ CH ₂ N -pyrrolidinyl).

"Alkenyl" refers to an alkyl group as defined herein, which consists of at least two carbon atoms and at least one carbon-carbon double bond. Typically, an alkenyl group has 2 to 20 carbon atoms ("C ₂ -C ₂₀ alkenyl"), preferably 2 to 12 carbon atoms ("C ₂ -C ₁₂ alkenyl"), more preferably 2 to 8 carbon atoms (“C ₂ -C ₈ alkenyl”) or 2 to 6 carbon atoms (“C ₂ -C ₆ alkenyl”) or 2 to 4 carbon atoms (“C ₂ -4 alkenyl”) . Representative examples include vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, and the like. "C ₂ -C ₆ alkenyl" means a straight or branched chain group containing 2 to 6 carbon atoms and at least one double bond between two sp ² hybrid carbon atoms. This definition also applies if it carries a substituent or exists as a substituent for other groups, for example in O-(C ₂ -C ₆ )alkenyl. Examples of suitable C ₂ -C ₆ alkenyl groups are n-propenyl, isopropenyl, n-butenyl, isobutenyl, n-pentenyl, second pentenyl, n-hexenyl, second hexenyl and the like Group. The alkenyl group can be unsubstituted or substituted by the same groups described herein as suitable for alkyl groups.

"Alkynyl" refers to an alkyl group as defined herein, which consists of at least two carbon atoms and at least one carbon-carbon triple bond. The alkynyl group has 2 to 20 carbon atoms ("C ₂ -C ₂₀ alkynyl group"), preferably 2 to 12 carbon atoms ("C ₂ -C ₁₂ alkynyl group"), more preferably 2 to 8 carbon atoms Atom ("C ₂ -C ₈ alkynyl") or 2 to 6 carbon atoms ("C ₂ -C ₆ alkynyl") or 2 to 4 carbon atoms ("C ₂ -C ₄ alkynyl"). Representative examples include, but are not limited to, ethynyl, 1-propynyl, 3-propynyl, 1-, 3-, or 4-butynyl, and the like. The alkynyl group can be unsubstituted or substituted by the same groups described herein as suitable for alkyl groups. "C ₂ -C ₆ alkynyl" means a straight or branched chain group containing 2 to 6 carbon atoms and at least one triple bond between two sp hybridized carbon atoms. This definition also applies if it carries a substituent or exists as a substituent for other groups, for example in O-(C ₂ -C ₆ ) alkynyl. Examples of suitable C ₂ -C ₆ alkynyl groups are propynyl, butynyl, pentynyl, hexynyl and the like.

As used herein, "alkylene" refers to a divalent hydrocarbon group having a specified number of carbon atoms, which can connect two other groups together. Sometimes, it refers to -(CH ₂ )n-, where n is 1-8, and preferably n is 1-4. Likewise, as used herein, m, q, and p may each be 1-8 or 0, with 0 indicating the absence of methylene units. Under specified circumstances, the alkylene group may also be substituted with other groups and may include one or more unsaturations (ie, alkenyl or alkynyl moieties) or rings. The open valence of alkylene need not be at the opposite end of the chain. Therefore, -CH(Me)- and -C(Me) ₂ -are also included in the scope of the term "alkylene", cyclic groups such as cyclopropane-1,1-diyl and such as ethylidene ( -CH=CH-) or propyl (-CH ₂ CH=CH-) unsaturated groups are also included. Where the alkylene group is described as optionally substituted, the substituents include those substituents that are typically present on alkyl groups as described herein.

"Heteroalkylene" refers to alkylene as described above, wherein one or more non-adjacent carbon atoms of the alkylene chain are replaced by -N-, -O-, -P- or -S- Forms such as -N(R)-, -P(=O)(R)-, -S(O) _x -or -S(=O)(=NR)- where R is H or C ₁ -C ₄ Alkyl and x is 0-2. For example, the group -O-(CH ₂ ) _1-4 -is a "C ₂ -C ₅ "extended heteroalkyl group, in which one of the carbon atoms of the corresponding alkylene group is replaced by O.

"Aryl" or "aromatic" means an all-carbon monocyclic or fused-ring polycyclic ring with a fully conjugated π-electron system and aromaticity. The term "C ₆ -C ₁₂ aryl group" and "C ₆ - ₁₂ aryl group" includes and encompasses within this term having 6 to 12 carbons and containing no hetero aromatic ring system atoms in the ring system. Examples of aryl groups are phenyl and naphthyl. The aryl group may be substituted or unsubstituted. The substituents on the adjacent ring carbon atoms of the C ₆ -C ₁₂ aryl group can be combined to form one or more substituents (such as pendant, C ₁ -C ₆ alkyl, hydroxyl, amine, and halogen) as appropriate Substituted 5- or 6-membered carbocycle, or optionally substituted with one or more substituents (such as pendant, C ₁ -C ₆ alkyl, hydroxy, amine and halogen) containing one, two or three 5 or 6 membered heterocyclic ring selected from ring heteroatoms of N, O and S(O) _x (where x is 0, 1 or 2). Examples of aryl groups include phenyl, biphenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, and tetrahydronaphthyl. The aryl group can be unsubstituted or substituted as described further herein.

"Heteroaryl" or "heteroaromatic" refers to a monocyclic or fused bicyclic or polycyclic system with well-known aromatic characteristics, which contains a specified number of ring atoms and includes at least one selected from N, O, and S The heteroatom serves as a ring member in the aromatic ring. The inclusion of heteroatoms allows the aromaticity of 5-membered rings and 6-membered rings. Typically, the heteroaryl group contains 5 to 20 ring atoms ("5-20 member heteroaryl"), preferably 5 to 14 ring atoms ("5-14 member heteroaryl"), and more preferably 5 to 12 ring atoms ("5-12 member heteroaryl") or 5 to 6 ring atoms ("5-6 member heteroaryl"). The heteroaryl ring is attached to the base molecule through the ring atoms of the heteroaryl ring, so that the aromaticity is maintained. Thus, a 6-membered heteroaryl ring can be attached to the base molecule via a ring C atom, and a 5-membered heteroaryl ring can be attached to the base molecule via a ring C or N atom. Heteroaryl groups can be unsubstituted or substituted as described further herein. As used herein, "5-6 membered heteroaryl" refers to a monocyclic group of 5 or 6 ring atoms that contains one, two, or three ring heteroatoms selected from N, O, and S, but includes It has a tetrazolyl group of 4 nitrogens, the remaining ring atom is C, and additionally has a fully conjugated π-electron system. The substituents on adjacent ring atoms of 5 or 6 membered heteroaryl groups can be combined to form a thick group optionally substituted by one or more substituents (such as pendant, C1-C6 alkyl, hydroxyl, amine and halogen) A 5- or 6-membered carbocycle, or optionally substituted with one or more substituents (such as pendant, C1-C6 alkyl, hydroxyl, amine, and halogen) containing one, two, or three selected from N , O and S(O)x (where x is 0, 1 or 2) are fused 5 or 6 membered heterocyclic rings. If the fused ring itself is aromatic, regardless of whether the second ring contains a heteroatom, it is called a fused (bicyclic) heteroaromatic substance. A pharmaceutically acceptable heteroaryl group is a heteroaryl group that is sufficiently stable to be attached to the compound of the present invention, formulated into a pharmaceutical composition, and then administered to patients in need.

Examples of 5-membered heteroaryl rings containing 1, 2 or 3 heteroatoms independently selected from O, N and S include pyrrolyl, thienyl, furyl, pyrazolyl, imidazolyl, oxazolyl, iso Oxazolyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, oxadiazolyl and thiadiazolyl. Preferably the 6-membered heteroaryl ring contains 1 or 2 nitrogen atoms. Examples of 6-membered heteroaryl groups are pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl. Examples of the fused heteroaryl ring include benzofuran, benzothiophene, indole, benzimidazole, indazole, quinolinone, isoquinoline, purine, pyrrolopyrimidine, naphthyridine, and carbazole.

As used herein, "arylene" refers to a divalent group produced by an aromatic hydrocarbon by removing a hydrogen atom from each of the two carbon atoms of the core. In frequent embodiments, the arylidene ring is 1,2-disubstituted or 1,3-disubstituted arylidene. The aryl ring of the aryl extension moiety may be substituted with a group suitable for the aryl ring at an open valence position as the case may indicate to the extent of the substitution. Preferably, the arylidene ring is a C6-C12 arylidene ring, such as 1,2-phenylene or 1,3-phenylene moiety.

Similarly, as used herein, "heteroaryl" refers to a divalent group produced by a heteroaromatic ring by removing a hydrogen atom from each of two carbons or one carbon atom and one nitrogen atom of the core . In frequent embodiments, the heteroaryl ring is 1,2-disubstituted or 1,3-disubstituted heteroaryl. The heteroaryl ring extending the heteroaryl moiety is optionally substituted with a group suitable for the heteroaryl ring to indicate the degree of the substitution. Preferably, the extended heteroaryl ring is a 5-12 membered, possibly fused extended heteroaryl ring, more preferably a 5-6 membered extended heteroaryl ring, each of which is optionally substituted.

The terms "heteroalicyclic", "heterocyclic" or "heterocyclic" are used interchangeably herein to refer to a non-aromatic, saturated or partially unsaturated ring system that contains a specified number of ring atoms, including at least one selected from The hetero atoms of N, O, and S serve as ring members, wherein the hetero ring is connected to the base molecule via the ring atom, which may be C or N. The heteroalicyclic ring may be fused to one or more other heteroalicyclic or carbocyclic rings, and these fused rings may be saturated, partially unsaturated, or aromatic. Preferably, the heteroalicyclic ring contains 1 to 4 heteroatoms selected from N, O, and S as ring members, and more preferably 1 or 2 ring heteroatoms, with the restriction that these heteroalicyclic rings do not contain two Adjacent oxygen atoms. Heteroalicyclic groups can be unsubstituted or substituted by the same groups described herein as suitable for alkyl, aryl or heteroaryl groups.

As defined herein, preferred heteroalicyclic groups include 3-12 membered heteroalicyclic groups, 5-8 membered heterocyclic groups (or heteroalicyclic groups), 4-12 membered heteroalicyclic monocyclics and 6 -12 member heteroalicyclic bicyclic. As used herein, "3-12 membered heteroalicyclic ring" refers to a monocyclic or bicyclic group having 3 to 12 ring atoms, wherein one, two, three, or four ring atoms are selected from N, O , P(O), S(O)x (where x is 0, 1, 2) and S(=O)(=NR) heteroatom, the remaining ring atom is C. The ring may also have one or more double bonds. However, this ring does not have a completely conjugated π-electron system. The substituents on the two ring carbon atoms can be combined to form a 5- or 6-membered bridging ring containing one, two or three selected from N, O and S(O)x (where x is 0, 1 Or the carbocyclic ring or heteroalicyclic ring of the ring heteroatom of 2). Heteroalicyclic groups are optionally substituted with pendant, hydroxy, amine, C1-C6 alkyl and similar groups.

In frequent embodiments, heteroalicyclic groups contain 3-12 ring members, including carbon and non-carbon heteroatoms, and preferably 4-6 ring members. In certain preferred embodiments, the substituents constituting the 3-12 membered heteroalicyclic group are selected from azetidinyl, pyrrolidinyl, hexahydropyridinyl, hexahydropyrazinyl, morpholinyl And thiomorpholinyl rings, each of which is optionally substituted to such an extent that the substitution has chemical significance.

It should be understood that up to two N, O, P, or S atoms are usually connected sequentially, except at the pendant or aza group at a higher than their basic state (eg, N ⁵⁺ , P ⁵⁺ , S ⁶⁺ ) The oxidation state is attached to N, P, or S to form groups such as, but not limited to, nitro, phosphinyl, phosphamidyl, sulfoximino, and sulfonyl, or in the In the case of certain heteroaromatic rings of azine, tetrazole, tetrazole, oxadiazole, thiadiazole, and the like.

"Cycloalkyl" means a non-aromatic, saturated or partially unsaturated carbocyclic ring system containing a specified number of carbon atoms, which can be a single ring, bridged, fused to the base molecule via the carbon atoms of the cycloalkyl ring Or spiral two-ring or multi-ring system. Typically, the cycloalkyl group of the present invention contains 3 to 12 carbon atoms ("C3-C12 cycloalkyl group"), preferably 3 to 8 carbon atoms ("C3-C8 cycloalkyl group"). Other cycloalkyl groups include partially unsaturated moieties of 4 to 7 carbons ("C4-C7 cycloalkenyl"). Representative examples include, for example, cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexene, cyclohexadiene, cycloheptane, cycloheptatriene, adamantane, and the like. The cycloalkyl group can be unsubstituted or substituted by the same groups described herein as suitable for alkyl groups. As used herein, "C3-C6 cycloalkyl" refers to an all-carbon, monocyclic or fused ring polycyclic group of 3 to 6 carbon atoms.

"Cycloalkylalkyl" can be used to describe a cycloalkyl ring, typically a C3-C8 cycloalkyl, which is connected to the base molecule via an alkylene linker, typically C1-C4 alkylene. Cycloalkylalkyl is described by the total number of carbon atoms in the carbocycle and the linker, and typically contains 4-12 carbon atoms ("C4-C12 cycloalkylalkyl"). Therefore, cyclopropylmethyl is C4-cycloalkylalkyl and cyclohexylethyl is C8-cycloalkylalkyl. The cycloalkylalkyl group can be unsubstituted or substituted on the cycloalkyl and/or alkylene moiety by the same groups described herein as suitable for alkyl groups.

"Aralkyl" refers to an aryl group obtained as described herein, which is attached to the base molecule via an alkylene or similar linker. Aralkyl is described by the total number of carbon atoms in the ring and the linker. Therefore, benzyl is C7-aralkyl and phenylethyl is C8-aralkyl. Typically, aralkyl groups contain 7-16 carbon atoms ("C7-C16 aralkyl"), wherein the aryl moiety contains 6-12 carbon atoms and the alkylene moiety contains 1-4 carbon atoms. These groups may also be represented as -C1-C4 alkylene-C6-C12 aryl.

"Heteroaralkyl" refers to a heteroaryl group as described above attached to the base molecule via an alkylene linker, and differs from "aralkyl" in that at least one ring atom of the aromatic moiety is Hetero atom selected from N, O and S. Heteroaralkyl groups are sometimes described herein in terms of the total number of non-hydrogen atoms (ie, C, N, S, and O atoms) in the combined ring and linker (excluding substituents). Thus, for example, pyridylmethyl may be referred to as "C7" heteroaralkyl. Typically, unsubstituted heteroaralkyl contains 6-20 non-hydrogen atoms (including C, N, S, and O atoms), wherein the heteroaryl moiety typically contains 5-12 carbons and the alkylene moiety typically Contains 1-4 carbon atoms. These groups may also be represented as -C1-C4 alkylidene-5-12-membered heteroaryl.

Similarly, "arylalkoxy" and "heteroarylalkoxy" refer to aryl and heteroaryl attached to the base molecule via a heteroalkyl linker (ie, -O-alkylene-) Groups, where these groups are described in terms of the total number of non-hydrogen atoms (ie, C, N, S, and O atoms) in the combined ring and linker. Therefore, -O-CH ₂ -phenyl and -O-CH ₂ -pyridyl will be referred to as C8-arylalkoxy and C8-heteroarylalkoxy, respectively.

Where aralkyl, arylalkoxy, heteroaralkyl or heteroarylalkoxy is described as optionally substituted, the substituent may be on the divalent linker part or on the aromatic group of the group Base or heteroaryl. The substituents present on the alkylene or heteroalkylene moiety, as appropriate, are generally the same as those described above for the alkyl or alkoxy groups, and optionally on the aryl or heteroaryl moiety The substituents are generally the same as those described above for aryl or heteroaryl.

"Hydroxy" refers to the -OH group.

"Acyl" means a monovalent group -C(O)alkyl, in which the alkyl portion has a specified number of carbon atoms (typically C1-C8, preferably C1-C6 or C1-C4) and can be applied to The alkyl group is substituted. Thus, C1-C4 acetyl groups include -C(O)C1-C4 alkyl substituents, such as -C(O)CH ₃ . Similarly, "acyloxy" refers to a monovalent group -OC(O)alkyl, in which the alkyl portion has a specified number of carbon atoms (typically C1-C8, preferably C1-C6 or C1-C4) and may Substituted by a group suitable for alkyl. Thus, C1-C4 acyl groups include -OC (O) C1-C4 alkyl substituents, e.g. -OC (O) CH _3.

The term "monocyclic or bicyclic ring system" refers to an aromatic, saturated or partially unsaturated ring system containing a specified number of ring atoms, and optionally includes one or more heteroatoms selected from N, O and S as ring members , Wherein the heterocycle is connected to the base molecule via a ring atom, which may be C or N. This term includes the terms "cycloalkyl", "aryl", "heterocyclic" and "heteroaryl". Typically, the monocyclic or bicyclic system of the present invention contains 4 to 12 member atoms ("4-12 membered monocyclic or bicyclic system"). The two-ring system can be connected via 1,1-fusion (snail), 1,2-fusion (fusion) or 1,>2-fusion (bridgehead). Representative examples include cyclopentane, cyclopentene, cyclohexane, norbornyl, spiro[2.3]hexane, phenyl, biphenyl, naphthyl, anthracenyl, phenanthrenyl, pyrrolyl, thienyl, furan Group, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, azetyl, pyrrolidinyl, hexahydropyridyl, hexahydropyrazinyl, benzothienyl, indole Radicals and similar groups.

The following describes representative examples of central azine systems, but the invention is not limited to these examples:

The following description can be taken as representative examples of 5,6-bicyclic azaaromatics of A ¹ , but the present invention is not limited to these examples:

The following description can be used as representative examples of 5.X bicyclic azaaromatics as A ¹ , A ² , A ³ or A ⁶ , but the present invention is not limited to these examples:

The following description can be used as a representative example of A ³ of 5.5 bicyclic azaaromatics, but the present invention is not limited to these examples:

The following is a representative example of the 6.5 bicyclic azaaromatics as A ^4a or A ^4b , but the present invention is not limited to these examples:

The following describes representative examples of A ⁵ , but the present invention is not limited to these examples:

As used herein, the term "displacement" in the case such as "the methylene unit is replaced by C=O" refers to the exchange of functional groups, for example, -CH ₂ -(methylene unit) uses -C(O)- (Carbonyl) exchange.

All alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, monocyclic and bicyclic heterocyclic, aryl (monocyclic and bicyclic), heteroaryl (monocyclic and bicyclic), cycloalkyl Alkyl, aralkyl, arylalkoxy, heteroaralkyl or heteroarylalkoxy (which includes any C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 ring Alkyl, C4-6 cycloalkenyl, C6-12 bicycloalkyl, 4-12 atom saturated monocyclic heterocycle or 6-12 atom saturated bicyclic heterocycle, all C6-12 aryl monocyclic Or bicyclic and 6-12 atom heteroaryl monocyclic or bicyclic) can be independently selected from halogen, hydroxyl, pendant, hydroxylamine, oxime, hydrazide, hydrazide, cyanide Group, nitro group, azido group, NR ⁸ R ⁹ , OC1-6 alkyl group, OC3-6 alkenyl group, OC3-6 alkynyl group, C1-6 alkyl group, OC3-8 cycloalkyl group, OC3-8 cycloalkene Group, C1-6 acetyl group, C1-6 oxy group, N(R ⁸ )COR ⁴ , CO ₂ R ⁴ , CONR ⁸ R ⁹ , NR ⁸ CONR ⁸ R ⁹ , NR ⁸ CO2R ⁴ , OCO2R ⁴ , OCONR ⁸ R ⁹ , S(O) _x R ⁴ , S(R ⁴ )(=O)=NR ⁸ , S(=O)(=NR ⁸ ) NR ⁸ R ⁹ , SO2NR ⁸ R ⁹ , NR ⁸ SO2R ⁴ , NR ⁸ SO2NR ⁸ R ⁹ , -NR ⁸ S(=O)(=NR ⁸ )R ⁴ , -N=S(=O)(R ⁴ )R ⁴ , -N=S(=O)(NR ⁸ R ⁹ ) R ⁴ , ONR ⁸ R ⁹ , ON(R ⁸ )COR ⁴ , ONR ⁸ CONR ⁸ R ⁹ , ONR ⁸ CO2R ⁴ , ONR ⁸ SO2R ⁴ , ONR ⁸ SO2NR ⁸ R ^{9 are} substituted by multiple substituents.

Chemical compound

或其立體異構體或醫藥學上可接受之鹽、溶劑合物、酯、互變異構體或前藥；其中， A為

，

，

，或A⁶； a、b、c、d、e、f、g、h、i及j各自獨立地為(形式)雙鍵或(形式)單鍵，且X¹、X²、X³、X⁴、X⁵、X⁶、X⁷、X⁸、X⁹、X¹⁰、X¹¹及X¹²均未具有附接之兩個(形式)雙鍵；X¹、X²、X³、X⁶、X⁷、X⁸、X⁹、X¹⁰、X¹¹及X¹²各自視情況經取代且獨立地為C或選自由N、S及O組成之群之雜原子；且視情況存在的取代基係選自由=O(側氧基)、=S、=NR¹³、(=O)₂、(O)(NR¹³)、R⁴及R¹³組成之群；或或者，X¹、X²、X³、X⁶、X⁷、X⁸、X⁹、X¹⁰、X¹¹及X¹²各自選自由以下組成之群：C、CH、CR⁴、C(R⁴)₂、CR¹³、CH₂、C=O、C=S、C=NR¹³、N、NR⁴、NR¹³、N(O)、S、S(O)、S(O)₂、S(=O)(=NR¹³)、S(=NR¹³)₂及O；在A¹、A²、A³、A^4a及A^4b中，X⁴及X⁵各自獨立地為C或N；X¹、X²、X³、X⁴、X⁵、X⁶、X⁷、X⁸、X⁹、X¹⁰、X¹¹及X¹²中之至少四者為C、CR⁴或C(R⁴)₂；在A¹、A²、A³及A⁵中，X¹為C、CH或N；在A^4a中，X⁹為C、CH或N； 在A^4b中，X⁸為C、CH或N；在A^4a及A^4b中，X¹為N、NR¹³、C(R⁴)₂、C(O)、S(O)_x、S(=O)(=NR¹³)、S(=NR¹³)₂或CR⁴；在A¹、A²、A³、A^4a及A^4b中，X³為N、NR¹³、C(R⁴)₂、S(O)_x、S(=O)(=NR¹³)、S(=NR¹³)₂、C(O)或CR⁴；在A¹、A²、A³、A^4a及A^4b中，X³為N、NR¹³、C(R⁴)₂、C(O)、S(O)_x、S(=O)(=NR¹³)、S(=NR¹³)₂或CR⁴；在A⁵中，X²、X³、X⁴、X⁵及X⁶中之至少三者為C、C=O、CR⁴或C(R⁴)₂；E¹及E²獨立地為C-R¹或N，其限制條件在於E¹及E²不同時為N；E³及Z獨立地為CH或N；Y為

R¹獨立地選自氫、氟、氯、溴、甲基、乙基、羥基、甲氧基、乙氧基、異丙氧基、-OCF₃、-OCH₂CF₃、-OCH₂CHF₂、乙烯基、乙炔基、CF₃、CHF₂、CHO、CH₂OH、CONH₂、CO₂Me、CONHMe、CONMe₂及氰基；R²為R¹⁰、-OCF₃、-OCHF₂、-OCF₂CF₃、-OCH₂CHF₂、-OCH₂CF₃、環丙基、環丙氧基、甲氧基、乙氧基或異丙氧基；R³為C_2-6烯基-R⁷、C_2-6炔基-R⁷、N(R¹⁰)C_2-6烷基-NR¹⁰R¹⁰、N(R¹⁰)C_2-6烷基-R⁷、O(CH₂)_pR⁷、N(R¹⁰)C(=O)(CH₂)_pR⁷、C(R⁵)=C(R⁵)(CH₂)_pR⁷或R⁷；R⁴各自獨立地為H、氰基、硝基、鹵基、-C_1-6烷基、-C_1-6鹵烷基、C_1-6醯基-C_1-6烷基-、R⁷-(CH₂)_pC(=O)-C_1-6烷基-、羧基-C_1-6烷基-、C_1-6烷氧基羰基-C_1-6烷基-、R⁷-(CH₂)_pO-C(=O)-C_1-6烷基-、R⁸R⁹N-C(=O)C_1-6烷基-、R⁷-C_2-6烷基 -N(R¹⁰)-C(=O)C_1-6烷基-、-C_1-6羥基烷基、C_1-6烷氧基-C_1-6烷基-、R⁷(CH₂)_pOC_1-6烷基-、C_1-6醯氧基-C_1-6烷基-、R⁷-(CH₂)_pC(=O)O-C_1-6烷基-、C_1-6烷氧基-C(=O)O-C_1-6烷基-、R⁷(CH₂)_pO-C(=O)-OC_1-6烷基-、R⁸R⁹N-C(=O)OC_1-6烷基-、C_1-6烷基-N(R¹⁰)C(=O)O-C_1-6烷基-、R⁷(CH₂)_pN(R¹⁰)-C(=O)O-C_1-6烷基-、R⁸R⁹N-C_1-6烷基-、R¹³R¹³N-C_1-6烷基-、R⁷-C_1-6烷基-、C_1-6醯基N(R¹⁰)-C_1-6烷基-、R⁷-C_1-6醯基N(R¹⁰)-C_1-6烷基-、R⁷-(CH₂)_pC(=O)(N(R¹⁰)-C_1-6烷基-、R⁷-C_0-6烷基C(=O)N(R¹⁰)-C_1-6烷基-、C_1-6烷氧基-C(=O)N(R¹⁰)-C_1-6烷基-、R⁷-(CH₂)_pOC(=O)N(R¹⁰)C_1-6烷基-、R⁸R⁹NC(=O)N(R¹⁰)C_1-6烷基-、R¹⁰SO₂-N(R¹⁰)-C_1-6烷基-、R⁷-SO₂-N(R¹⁰)-C_1-6烷基-、C_1-6烷基S(O)_x-C_1-6烷基-、R⁷-(CH₂)_pS(O)_xC_1-6烷基-、R⁷SO₂C_1-6烷基-、C_1-6烷基S(=O)(=NR¹³)-C_1-6烷基-、C_1-6鹵烷基S(=O)(=NR¹³)-C_1-6烷基-、C_1-6烷基S(=NR¹³)(=NR¹³)-C_1-6烷基-、C_1-6鹵烷基S(=NR¹³)(=NR¹³)-C_1-6烷基-、R⁷S(=O)(=NR¹³)C_1-6烷基-、R⁷S(=NR¹³)(=NR¹³)-C_1-6烷基-、-C_2-6烯基、-C_2-6鹵烯基、R⁷-C_3-6烯基-、C_1-6烷氧基-C_3-6烯基-、-C_2-6炔基、-C_2-6鹵炔基、R⁷-C_2-6炔基-、C_2-6炔基-、C_1-6醯基-、R⁷-(CH₂)_pC(=O)-、R7-C_1-6烷基-C(=O)-、C_1-6羥基烷基-C(=O)-、C_1-6烷氧基-C_1-6烷基-C(=O)-、C_1-6烷基S(O)_x-C_1-6烷基-C(=O)-、羧基、-C_1-6烷氧基羰基、R⁷-(CH₂)_p氧基羰基-、-C(=O)NR⁸R⁹、R⁷-(CH₂)_p-N(R¹⁰)-C(=O)-、羥基、-C_1-6烷氧基、-C_1-6鹵烷氧基、C_1-6烷基-N(R¹⁰)C(=O)-C_1-6烷氧基-、R⁷(CH₂)_pO-、R⁷(CH₂)_pOC(=O)OC_2-6烷氧基-、R⁷(CH₂)_pN(R¹⁰)-C(=O)O-C_2-6烷氧基-、R⁸R⁹N-C(=O)OC_2-6烷氧基-、C_1-6烷氧基-C(=O)N(R¹⁰)-C_2-6烷氧基-、R⁷-(CH₂)_pOC(=O)N(R¹⁰)C_2-6烷氧基-、R⁸R⁹NC(=O)N(R¹⁰)C_2-6烷氧基-、C_1-6烷氧基羰基C_1-6烷氧基-、R⁷(CH₂)_pOC(=O)C_1-6烷氧基-、C_1-6醯氧基、R⁷-(CH₂)_pC(=O)O-、-NR⁸R⁹、-NR¹³R¹³、R⁸R⁹N-C_2-6烷基-N(R¹⁰)-、R⁷-C_2-6烷基-N(R¹⁰)-、C_1-6醯基-N(R¹⁰)-、C_1-6烷氧基羰基-N(R¹⁰)-、R⁸R⁹ N-C(=O)-N(R¹⁰)-、R⁷-C_1-6醯基-N(R¹⁰)-、C_1-6烷基S(O)₂-N(R¹⁰)-、R¹⁰S(O)₂-N(R¹⁰)-、C_1-6鹵烷基S(O)₂-N(R¹⁰)-、R⁷SO₂-N(R¹⁰)-、硫 基、C_1-6烷基S(O)_x-、C_1-6鹵烷基S(O)_x-、R⁷-(CH₂)_pS(O)₂-、R⁷SO₂-、C_1-6烷基-S(=O)(=NR¹³)-、C_1-6鹵烷基-S(=O)(=NR¹³)-、C_1-6烷基S(=NR¹³)(=NR¹³)-、C_1-6鹵烷基-S(=NR¹³)(=NR¹³)-、R⁷S(=O)(=NR¹³)-、R⁷S(=NR¹³)(=NR¹³)-、C_6-12芳基、C_6-C₁₂芳基-C₁-C₆烷基-、5-12員雜芳基、5-12員雜芳基-C₁-C₆烷基-、C_3-8環烷基-、C_3-8環烷基-C₁-C₆烷基-、C_3-8環烯基-、C_3-8環烯基-C₁-C₆烷基-、4-12員單環或二環雜環基-或4-12員單環或二環雜環基-C₁-C₆烷基-；在R³中，R⁵為H、F、CF₃、CHF₂或C₁-C₆烷基；在Y¹及Y²中，R^5a為H、F、Cl、CF₃、CHF₂、CF₂C_1-6烷基、CF₂CH₂NR⁸R⁹、CH₂NR⁸R⁹、CN或C_1-6烷基；在Y¹及Y²中，R^6e為R¹⁰、H、F、芳基、雜芳基、環烷基、雜環烷基、(CH₂)_mCHR¹⁰R⁷、CF₂(CH₂)_mCHR¹⁰R⁷或C(R¹⁰)₂R⁷；在Y⁴及Y⁵中，R^6t為C_1-6烷基、C_3-6環烷基、芳基、雜芳基、雜環烷基、(CH₂)_mCHR¹⁰R⁷、C(R¹⁰)₂R⁷；在Y¹及Y²中，R^6z為H、F、Cl、CF₃、CHF₂、CF₂C_1-6烷基或C_1-6烷基；或或者在Y¹及Y²中，R^6e及R^6z合起來形成R^6eR^6zC=；或或者在Y¹及Y²中，R^6e及R^6z與該兩者同時附接之sp²碳原子合起來形成4至7個成員之脂環族環，其中環原子之一視情況由NR⁸、O、S(O)_x、S(=O)(=NR⁸)、P=O、P(=O)(OR⁸)、OP(=O)(OR⁸)O置換，且該脂環族環視情況經選自由鹵素、側氧基、OH、OR⁸及NR⁸R⁹組成之群之一或多個取代基取代；R⁷為OH、NR⁸R⁹、O(CH₂)_qNR⁸R⁹、C_1-6烷氧基、C_1-6烷氧基-C_1-6烷氧基、C_2-6羥基烷氧基、氧雜環丁烷基、氧雜環丁烷基氧基、氧雜環丁烷基胺基、氧雜環戊烷基、氧雜環戊烷基氧基、氧雜環戊烷基胺基、氧雜環己烷基、氧雜環己烷基氧基、氧雜環己烷基胺基、氧雜環庚烷基、氧雜環庚烷基氧基、氧雜環庚烷基胺基、氮雜環丁烷基、氮雜環丁烷基氧基、氮雜環丁烷基胺基、吡咯啶基、吡 咯啶基氧基、吡咯啶基胺基、六氫吡啶基、六氫吡啶基氧基、六氫吡啶基胺基、氮雜環庚烷基、氮雜環庚烷基氧基、氮雜環庚烷基胺基、二氧雜環戊烷基、二噁烷基、嗎啉基、硫代嗎啉基、硫代嗎啉基-S,S-二氧化物、六氫吡嗪基、二氧雜環庚烷基、二氧雜環庚烷基氧基、二氧雜環庚烷基胺基、氧氮雜環庚烷基、氧氮雜環庚烷基氧基、氧氮雜環庚烷基胺基、二氮雜庚烷基、二氮雜庚烷基氧基、二氮雜庚烷基胺基、(3R)-3-(二甲基胺基)吡咯啶-1-基、(3S)-3-(二甲基胺基)吡咯啶-1-基、3-(二甲基胺基)氮雜環丁烷-1-基、[2-(二甲基胺基)乙基](甲基)胺基、[2-(甲基胺基)乙基](甲基)胺基、5-甲基-2,5二氮雜螺[3.4]辛-2-基、(3aR,6aR)-5-甲基六-氫-吡咯并[3,4-b]吡咯-1(2H)-基、I-甲基-1,2,3,6-四氫吡啶-4-基、4-甲基六氫吡嗪-1-基、4-[2(二甲基胺基)-2-側氧基乙基]六氫吡嗪-1-基、甲基[2-(4-甲基六氫吡嗪-1基)乙基]胺基、甲基[2-(嗎啉-4-基)乙基]胺基、1-胺基-1,2,3,6四氫吡啶-4-基、4-[(2S)-2-胺基丙醯基]六氫吡嗪-1-基，其均可視情況經OH、OR¹⁰、側氧基、鹵素、R¹⁰、CH₂OR¹⁰或CH₂NR⁸R⁹取代；R⁸及R⁹獨立地為H、-CD₃、C_1-6烷基、C_1-6鹵烷基、C_3-6烯基、C_3-6鹵烯基、C_3-6炔基、C₃-C₆鹵炔基、C_3-8環烷基、C_3-8環烷基-C₁-C₆烷基-、C_3-8鹵環烷基、C_3-8鹵環烷基-C₁-C₆烷基-、C_3-8環烯基、C_3-8環烯基-C₁-C₆烷基-、C_3-8鹵環烯基、C_3-8鹵環烯基-C₁-C₆烷基-、C_1-C₆醯基、C_1-C₆醯基-C₁-C₆烷基-、4-12員單環或二環雜環基、4-12員單環或二環雜環基-C₁-C₆烷基-、C_6-C₁₂芳基、C_6-C₁₂芳基-C₁-C₆烷基-、5-12員雜芳基或5-12員雜芳基-C₁-C₆烷基-；且R⁸及R⁹可進一步獨立地經多達三個選自羥基、C_1-6烷氧基、C_1-6羥基烷基、C_1-6烷氧基-C_1-6烷基、C_1-6烷氧基-C_1-6烷氧基、C_2-6羥基烷氧基、側氧基、硫羰基、氰基或鹵基之取代基取代；或或者，R⁸及R⁹與其同時附接之N原子合起來形成4-7個成員之雜環，該雜環含有多達一個選自O、S或NR¹¹之其他雜原子，且該雜環視情況經多達三個選自 羥基、C_1-6烷氧基、C_1-6羥基烷基、C_1-6烷氧基-C_1-6烷基、C_1-6烷氧基-C_1-6烷氧基、C_2-6羥基烷氧基、側氧基、硫羰基、氰基或鹵基之取代基取代；R¹⁰各自獨立地為H、-CD₃、C_1-6烷基、C_3-6環烷基、C_2-6羥基烷基、C_1-6烷氧基-C_1-6烷基或C_2-6烷基-NR⁸R⁹；R¹¹各自獨立地為氫、C_1-C₆烷基、C_3-C₆烯基、C_3-C₆炔基、C_3-C₆環烷基、C_6-C₁₂芳基、4-12員雜環基或5-12原雜芳基；或或者，兩個R¹¹與附接於其之雜原子合起來形成5-8員雜環基環，該5-8員雜環基環視情況經多達三個選自羥基、C_1-6烷氧基、C_1-6羥基烷基、C_1-6烷氧基-C_1-6烷基、C_1-6烷氧基-C_1-6烷氧基、C_2-6羥基烷氧基、側氧基、硫羰基、氰基及鹵基之取代基取代；R¹³各自獨立地為H、-CD₃、氰基、-C_1-6烷基、-C_1-6鹵烷基、C_1-6醯基-C_1-6烷基-、R⁷-(CH₂)_pC(=O)-C_1-6烷基-、羧基-C_1-6烷基-、C_1-6烷氧基羰基-C_1-6烷基-、R⁷-(CH₂)_pO-C(=O)-C_1-6烷基-、R⁸R⁹N-C(=O)C_1-6烷基-、R⁷-C_2-6烷基-N(R¹⁰)-C(=O)C_1-6烷基-、-C_2-6羥基烷基、C_1-6烷氧基-C_2-6烷基-、R⁷(CH₂)_pOC_2-6烷基-、C_1-6醯氧基-C_2-6烷基-、R⁷-(CH₂)_pC(=O)O-C_2-6烷基-、C_1-6烷氧基-C(=O)O-C_2-6烷基-、R⁷(CH₂)_pO-C(=O)-OC_2-6烷基-、R⁸R⁹N-C(=O)OC_2-6烷基-、C_1-6烷基-N(R¹⁰)C(=O)O-C_2-6烷基-、R⁷(CH₂)_pN(R¹⁰)-C(=O)O-C_2-6烷基-、R⁸R⁹N-C_2-6烷基-、R⁷-C_2-6烷基-、C_1-6醯基N(R¹⁰)-C_2-6烷基-、R⁷-C_1-6醯基N(R¹⁰)-C_2-6烷基-、R⁷-(CH₂)_pC(=O)N(R¹⁰)-C_2-6烷基-、R⁷-C_0-6烷基C(=O)N(R¹⁰)-C_2-6烷基-、C_1-6烷氧基-C(=O)N(R¹⁰)-C_2-6烷基-、R⁷-(CH₂)_pOC(=O)N(R¹⁰)C_2-6烷基-、R⁸R⁹NC(=O)N(R¹⁰)C_2-6烷基-、R¹⁰SO_2-N(R¹⁰)-C_2-6烷基-、R⁷-SO_2-N(R¹⁰)-C_2-6烷基-、C_1-6烷基S(O)_x-C_2-6烷基-、R⁷-(CH₂)_pS(O)_xC_2-6烷基-、R⁷SO₂C_2-6烷基-、C_1-6烷基S(=O)(=NR¹⁰)-C_2-6烷基-、C_1-6鹵烷基S(=O)(=N R¹⁰)-C_2-6烷基-、C_1-6烷基S(=N R¹⁰)(=N R¹⁰)-C_2-6烷基-、C_1-6鹵烷基S(=N R¹⁰)(=N R¹⁰)-C_2-6烷基-、R⁷S(=O)(=N R¹⁰)C_2-6烷基-、R⁷S(=NR¹³)(=NR¹³)-C_2-6烷基-、-C_3-6烯基、-C_3-6鹵烯基、R⁷-C_4-6烯基-、C_1-6烷氧基-C_4-6烯基-、-C_2-6炔基、-C_2-6鹵炔基、R⁷-C_2-6炔基-、C_2-6炔基-、C_1-6醯基-、R⁷-(CH₂)_pC(=O)-、R⁷-C_1-6烷基-C(=O)-、C_1-6羥基烷基-C(=O)-、C_1-6烷氧基-C_1-6烷基-C(=O)-、C_1-6烷基S(O)_x-C_1-6烷基-C(=O)-、-C_1-6烷氧基羰基、R⁷-(CH₂)_p氧基羰基-、-C(=O)NR⁸R⁹、R⁷-(CH₂)_p-N(R¹⁰)-C(=O)-、羥基、-C_1-6烷氧基、-C_1-6鹵烷氧基、C_1-6烷基-N(R¹⁰)C(=O)-C_1-6烷氧基-、R⁷(CH₂)_pO-、R⁷(CH₂)_pOC(=O)OC_2-6烷氧基-、R⁷(CH₂)_pN(R¹⁰)-C(=O)O-C_2-6烷氧基-、R⁸R⁹N-C(=O)OC_2-6烷氧基-、C_1-6烷氧基-C(=O)N(R¹⁰)-C_2-6烷氧基-、R⁷-(CH₂)_pOC(=O)N(R¹⁰)C_2-6烷氧基-、R⁸R⁹NC(=O)N(R¹⁰)C_2-6烷氧基-、C_1-6烷氧基羰基C_1-6烷氧基-、R⁷(CH₂)_pOC(=O)C_1-6烷氧基-、-C_1-6醯氧基、R⁷-(CH₂)_pC(=O)O-、-NR⁸R⁹、R⁸R⁹N-C_2-6烷基-N(R¹⁰)-、R⁷-C_2-6烷基-N(R¹⁰)-、C_1-6醯基-N(R¹⁰)-、C_1-6烷氧基羰基-N(R¹⁰)-、R⁸R⁹ N-C(=O)-N(R¹⁰)-、R⁷-C_1-6醯基-N(R¹⁰)-、C_1-6烷基S(O)₂-N(R¹⁰)-、R¹⁰S(O)₂-N(R¹⁰)-、C_1-6鹵烷基S(O)₂-N(R¹⁰)-、R⁷SO₂-N(R¹⁰)-、C_1-6烷基S(O)_x-、C_1-6鹵烷基S(O)_x-、R⁷-(CH₂)_pS(O)₂、R⁷SO₂-、C_1-6烷基-S(=O)(=N R¹⁰)-、C_1-6鹵烷基-S(=O)(=N R¹⁰)-、C_6-12芳基、C_6-C₁₂芳基-C₁-C₆烷基-、5-12員雜芳基、5-12員雜芳基-C₁-C₆烷基-、C_3-8環烷基-、C_3-8環烷基-C₁-C₆烷基-、C_3-8環烯基-、C_3-8環烯基-C₁-C₆烷基-、4-12員單環或二環雜環基-或4-12員單環或二環雜環基-C₁-C₆烷基-；或或者，兩個R⁴、兩個R¹³或R¹³及R⁴與附接於其之原子合起來形成5-7個成員之環，該環可為芳族或部分飽和的，且該環可含有多達兩個選自N、O及S之雜原子；且該5-7員環視情況進一步經選自由=O(側氧基)、=S、=NR¹³、(=O)₂、(O)(NR¹³)、R⁴及R¹³組成之群者取代；A⁶係選自：

A²視情況經R⁴取代； m為0、1、2或3；n=1、2或3；p=0、1、2、3或4；q=2、3或4；且x=0、1或2。 In one embodiment, the invention relates to compounds of formula (I):

Or its stereoisomers or pharmaceutically acceptable salts, solvates, esters, tautomers or prodrugs; where, A is

,

,

, Or A ⁶ ; a, b, c, d, e, f, g, h, i, and j are each independently (form) double bond or (form) single bond, and X ¹ , X ² , X ³ , X ⁴ , X ⁵ , X ⁶ , X ⁷ , X ⁸ , X ⁹ , X ¹⁰ , X ¹¹ and X ^{12 do} not have two (form) double bonds attached; X ¹ , X ² , X ³ , X ⁶ , X ⁷ , X ⁸ , X ⁹ , X ¹⁰ , X ¹¹ and X ¹² are each optionally substituted and are independently C or a heteroatom selected from the group consisting of N, S and O; and optionally substituted The radical is selected from the group consisting of =O (pendant oxygen), =S, =NR ¹³ , (=O) ₂ , (O)(NR ¹³ ), R ⁴ and R ¹³ ; or alternatively, X ¹ , X ² , X ³ , X ⁶ , X ⁷ , X ⁸ , X ⁹ , X ¹⁰ , X ¹¹ and X ¹² are each selected from the group consisting of: C, CH, CR ⁴ , C(R ⁴ ) ₂ , CR ¹³ , CH ₂ , C=O, C=S, C=NR ¹³ , N, NR ⁴ , NR ¹³ , N(O), S, S(O), S(O) ₂ , S(=O)(=NR ¹³ ), S(=NR ¹³ ) ₂ and O; in A ¹ , A ² , A ³ , A ^4a and A ^4b , X ⁴ and X ⁵ are each independently C or N; X ¹ , X ² , X ³ , X ⁴ , X ⁵ , X ⁶ , X ⁷ , X ⁸ , X ⁹ , X ¹⁰ , X ¹¹ and X ¹² are at least four of C, CR ⁴ or C(R ⁴ ) ₂ ; in A ¹ , A ^{In 2} , A ³ and A ⁵ , X ¹ is C, CH or N; in A ^4a , X ⁹ is C, CH or N; in A ^4b , X ⁸ is C, CH or N; in A ^4a and In A ^4b , X ¹ is N, NR ¹³ , C(R ⁴ ) ₂ , C(O), S(O) _x , S(=O)(=NR ¹³ ), S(=NR ¹³ ) ₂ or CR ⁴ ; In A ¹ , A ² , A ³ , A ^4a and A ^4b , X ³ is N, NR ¹³ , C(R ⁴ ) ₂ , S(O) _x , S(=O)(=NR ¹³ ) , S(=NR ¹³ ) ₂ , C(O) or CR ⁴ ; in A ¹ , A ² , A ³ , A ^4a and A ^4b , X ³ is N, NR ¹³ , C(R ⁴ ) ₂ , C (O), S(O) _x , S(=O)(=NR ¹³ ), S(=NR ¹³ ) ₂ or CR ⁴ ; In A ⁵ , X ² , X ³ , X ⁴ , X ⁵ and X At least three of ⁶ are C, C=O, CR ⁴ or C(R ⁴ ) ₂ ; E ¹ and E ^{2 are} independently CR ¹ or N, the limitation is that E ¹ and E ^{2 are} not N at the same time; E ³ and Z are independently CH or N; Y is

R ^{1 is} independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, hydroxyl, methoxy, ethoxy, isopropoxy, -OCF ₃ , -OCH ₂ CF ₃ , -OCH ₂ CHF ₂ , Vinyl, ethynyl, CF ₃ , CHF ₂ , CHO, CH ₂ OH, CONH ₂ , CO ₂ Me, CONHMe, CONMe ₂ and cyano; R ² is R ¹⁰ , -OCF ₃ , -OCHF ₂ , -OCF ₂ CF ₃ , -OCH ₂ CHF ₂ , -OCH ₂ CF ₃ , cyclopropyl, cyclopropoxy, methoxy, ethoxy, or isopropoxy; R ³ is C _2-6 alkenyl-R ⁷ , C _2-6 alkynyl-R ⁷ , N(R ¹⁰ )C _2-6 alkyl-NR ¹⁰ R ¹⁰ , N(R ¹⁰ )C _2-6 alkyl-R ⁷ , O(CH ₂ ) _p R ⁷ , N(R ¹⁰ )C(=O)(CH ₂ ) _p R ⁷ , C(R ⁵ )=C(R ⁵ )(CH ₂ ) _p R ⁷ or R ⁷ ; R ^{4 is} independently H, Cyano, nitro, halo, -C _1-6 alkyl, -C _1-6 haloalkyl, C _1-6 acetyl-C _1-6 alkyl-, R ⁷ -(CH ₂ ) _p C (=O)-C _1-6 alkyl-, carboxy-C _1-6 alkyl-, C _1-6 alkoxycarbonyl-C _1-6 alkyl-, R ⁷ -(CH ₂ ) _p OC( =O)-C _1-6 alkyl-, R ⁸ R ⁹ NC(=O)C _1-6 alkyl-, R ⁷ -C _2-6 alkyl-N(R ¹⁰ )-C(=O) C _1-6 alkyl-, -C _1-6 hydroxyalkyl, C _1-6 alkoxy-C _1-6 alkyl-, R ⁷ (CH ₂ ) _p OC _1-6 alkyl-, C _{1 -6} Acyloxy-C _1-6 alkyl-, R ⁷ -(CH ₂ ) _p C(=O)OC _1-6 alkyl-, C _1-6 alkoxy-C(=O)OC _{1 -6} alkyl-, R ⁷ (CH ₂ ) _p OC(=O)-OC _1-6 alkyl-, R ⁸ R ⁹ NC(=O)OC _1-6 alkyl-, C _1-6 alkyl -N(R ¹⁰ )C(=O)OC _1-6 alkyl-, R ⁷ (CH ₂ ) _p N(R ¹⁰ )-C(=O)OC _1-6 alkyl-, R ⁸ R ⁹ NC _1-6 alkyl-, R ¹³ R ¹³ NC _1-6 alkyl-, R ⁷ -C _1-6 alkyl-, C _1-6 acetyl N(R ¹⁰ )-C _1-6 alkyl-, R ⁷ -C _1-6 acetyl N(R ¹⁰ )-C _1-6 alkyl-, R ⁷ -(CH ₂ ) _p C(=O)(N(R ¹⁰ )-C _1-6 alkyl- , R ⁷ -C _0-6 alkane Group C(=O)N(R ¹⁰ )-C _1-6 alkyl-, C _1-6 alkoxy-C(=O)N(R ¹⁰ )-C _1-6 alkyl-, R ^7- (CH ₂ ) _p OC(=O)N(R ¹⁰ )C _1-6 alkyl-, R ⁸ R ⁹ NC(=O)N(R ¹⁰ )C _1-6 alkyl-, R ¹⁰ SO _2- N(R ¹⁰ )-C _1-6 alkyl-, R ⁷ -SO ₂ -N(R ¹⁰ )-C _1-6 alkyl-, C _1-6 alkyl S(O) _x -C _1-6 Alkyl-, R ⁷ -(CH ₂ ) _p S(O) _x C _1-6 alkyl-, R ⁷ SO ₂ C _1-6 alkyl-, C _1-6 alkyl S(=O)(= NR ¹³ )-C _1-6 alkyl-, C _1-6 haloalkyl S(=O)(=NR ¹³ )-C _1-6 alkyl-, C _1-6 alkyl S(=NR ¹³ ) (=NR ¹³ )-C _1-6 alkyl-, C _1-6 haloalkyl S(=NR ¹³ )(=NR ¹³ )-C _1-6 alkyl-, R ⁷ S(=O)(= NR ¹³ )C _1-6 alkyl-, R ⁷ S(=NR ¹³ )(=NR ¹³ )-C _1-6 alkyl-, -C _2-6 alkenyl, -C _2-6 haloalkenyl, R ⁷ -C _3-6 alkenyl -, C _1-6 alkoxy -C _3-6 alkenyl -, - C _2-6 alkynyl, -C _2-6 haloalkynyl, R ⁷ -C _{2- 6} alkynyl-, C _2-6 alkynyl-, C _1-6 acetyl-, R ⁷ -(CH ₂ ) _p C(=O)-, R7-C _1-6 alkyl-C(=O) -, C _1-6 hydroxyalkyl-C(=O)-, C _1-6 alkoxy-C _1-6 alkyl-C(=O)-, C _1-6 alkyl S(O) _x -C _1-6 alkyl-C(=O)-, carboxyl, -C _1-6 alkoxycarbonyl, R ⁷ -(CH ₂ ) _{poxycarbonyl-} , -C(=O)NR ⁸ R ⁹ , R ⁷ -(CH ₂ ) _p -N(R ¹⁰ )-C(=O)-, hydroxyl, -C _1-6 alkoxy, -C _1-6 haloalkoxy, C _1-6 alkyl -N(R ¹⁰ )C(=O)-C _1-6 alkoxy-, R ⁷ (CH ₂ ) _p O-, R ⁷ (CH ₂ ) _p OC(=O)OC _2-6 alkoxy -, R ⁷ (CH ₂ ) _p N(R ¹⁰ )-C(=O)OC _2-6 alkoxy-, R ⁸ R ⁹ NC(=O)OC _2-6 alkoxy-, C _{1- 6} alkoxy-C(=O)N(R ¹⁰ )-C _2-6 alkoxy-, R ⁷ -(CH ₂ ) _p OC(=O)N(R ¹⁰ )C _2-6 alkoxy -、R ⁸ R ⁹ NC(= O)N(R ¹⁰ )C _2-6 alkoxy-, C _1-6 alkoxycarbonyl C _1-6 alkoxy-, R ⁷ (CH ₂ ) _p OC(=O)C _1-6 alkane Oxygen-, C _1-6 acetyloxy, R ⁷ -(CH ₂ ) _p C(=O)O-, -NR ⁸ R ⁹ , -NR ¹³ R ¹³ , R ⁸ R ⁹ NC _2-6 alkyl -N(R ¹⁰ )-, R ⁷ -C _2-6 alkyl-N(R ¹⁰ )-, C _1-6 acetyl-N(R ¹⁰ )-, C _1-6 alkoxycarbonyl-N( R ¹⁰ )-, R ⁸ R ⁹ NC(=O)-N(R ¹⁰ )-, R ⁷ -C _1-6 acetyl-N(R ¹⁰ )-, C _1-6 alkyl S(O) ₂ -N(R ¹⁰ )-, R ¹⁰ S(O) ₂ -N(R ¹⁰ )-, C _1-6 haloalkyl S(O) ₂ -N(R ¹⁰ )-, R ⁷ SO ₂ -N( R ¹⁰ )-, thio, C _1-6 alkyl S(O) _x -, C _1-6 haloalkyl S(O) _x -, R ⁷ -(CH ₂ ) _p S(O) ₂ -, R ⁷ SO ₂ -, C _1-6 alkyl-S(=O)(=NR ¹³ )-, C _1-6 haloalkyl-S(=O)(=NR ¹³ )-, C _1-6 alkane Radical S(=NR ¹³ )(=NR ¹³ )-, C _1-6 haloalkyl-S(=NR ¹³ )(=NR ¹³ )-, R ⁷ S(=O)(=NR ¹³ )-, R ⁷ S(=NR ¹³ )(=NR ¹³ )-, C _6-12 aryl, C _6- C ₁₂ aryl-C ₁ -C ₆ alkyl-, 5-12 member heteroaryl, 5-12 member Heteroaryl-C ₁ -C ₆ alkyl-, C _3-8 cycloalkyl-, C _3-8 cycloalkyl-C ₁ -C ₆ alkyl-, C _3-8 cycloalkenyl-, C _{3 -8} cycloalkenyl-C ₁ -C ₆ alkyl-, 4-12 member monocyclic or bicyclic heterocyclyl- or 4-12 member monocyclic or bicyclic heterocyclyl-C ₁ -C ₆ alkyl- ; In R ³ , R ⁵ is H, F, CF ₃ , CHF ₂ or C ₁ -C ₆ alkyl; in Y ¹ and Y ² , R ^5a is H, F, Cl, CF ₃ , CHF ₂ , CF ₂ C _1-6 alkyl, CF ₂ CH ₂ NR ⁸ R ⁹ , CH ₂ NR ⁸ R ⁹ , CN or C _1-6 alkyl; in Y ¹ and Y ² , R ^6e is R ¹⁰ , H, F, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, (CH ₂ ) _m CHR ¹⁰ R ⁷ , CF ₂ (CH ₂ ) _m CHR ¹⁰ R ⁷ or C(R ¹⁰ ) ₂ R ⁷ ; in In Y ⁴ and Y ⁵ , R ^6t is C _{1 -6} alkyl, C _3-6 cycloalkyl, aryl, heteroaryl, heterocycloalkyl, (CH ₂ ) _m CHR ¹⁰ R ⁷ , C(R ¹⁰ ) ₂ R ⁷ ; in Y ¹ and Y ^{2 Wherein} R ^6z is H, F, Cl, CF ₃ , CHF ₂ , CF ₂ C _1-6 alkyl or C _1-6 alkyl; or alternatively in Y ¹ and Y ² , R ^6e and R ^6z are combined Forming R ^6e R ^6z C=; or alternatively in Y ¹ and Y ² , R ^6e and R ^6z together with the sp ² carbon atoms to which they are attached together form an alicyclic ring of 4 to 7 members, in which One of the ring atoms depends on NR ⁸ , O, S(O) _x , S(=O)(=NR ⁸ ), P=O, P(=O)(OR ⁸ ), OP(=O)(OR ⁸ ) O substitution, and the alicyclic ring is optionally substituted with one or more substituents selected from the group consisting of halogen, pendant oxygen, OH, OR ⁸ and NR ⁸ R ⁹ ; R ⁷ is OH, NR ⁸ R ⁹ , O(CH ₂ ) _q NR ⁸ R ⁹ , C _1-6 alkoxy, C _1-6 alkoxy-C _1-6 alkoxy, C _2-6 hydroxyalkoxy, oxetane Alkyl, oxetanyloxy, oxetanylamino, oxetanyl, oxetanyloxy, oxetanylamino, oxetanyl Alkyl, oxetanyloxy, oxetanylamino, oxepanyl, oxepanyloxy, oxepanylamino, azetidine Alkyl, azetidinyloxy, azetidinylamino, pyrrolidinyl, pyrrolidinyloxy, pyrrolidinylamino, hexahydropyridinyl, hexahydropyridinyloxy, hexa Hydropyridylamino, azepanyl, azepanyloxy, azepanylamino, dioxolyl, dioxanyl, morpholinyl, thio Morpholinyl, thiomorpholinyl-S,S-dioxide, hexahydropyrazinyl, dioxepane, dioxepaneoxy, dioxepane amine Group, oxazepanyl, oxazepanyloxy, oxazepanylamino, diazaheptanyl, diazaheptanyloxy, diazepine alkylamino, (3R) - 3 - (dimethylamino) pyrrolidin-l-yl, (3S) -3- (dimethylamino) pyrrolidin-l-yl, 3- (dimethylamino Aminoamino) azetidine-1-yl, [2-(dimethylamino)ethyl](methyl)amino, [2-(methylamino)ethyl](methyl) Amino, 5-methyl-2,5-diazaspiro[3.4]octan-2-yl, (3aR,6aR)-5-methylhexa-hydro-pyrrolo[3,4-b]pyrrole-1 (2H)-yl, 1-methyl-1,2,3,6-tetrahydropyridin-4-yl, 4-methylhexahydropyrazin-1-yl, 4-[2(dimethylamino )-2-oxoethyl]hexahydropyrazin-1-yl, methyl[2-(4-methylhexahydropyrazin-1-yl)ethyl]amine, methyl[2-(mol Porphyrin-4 -Yl)ethyl]amino, 1-amino-1,2,3,6 tetrahydropyridin-4-yl, 4-[(2S)-2-aminopropionyl]hexahydropyrazine-1 -Radicals, which are optionally substituted by OH, OR ¹⁰ , pendant oxygen, halogen, R ¹⁰ , CH ₂ OR ¹⁰ or CH ₂ NR ⁸ R ⁹ ; R ⁸ and R ^{9 are} independently H, -CD ₃ , C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 alkenyl, C _3-6 haloalkenyl, C _3-6 alkynyl, C ₃ -C ₆ haloalkynyl, C _3-8 ring Alkyl, C _3-8 cycloalkyl-C ₁ -C ₆ alkyl-, C _3-8 halocycloalkyl, C _3-8 halocycloalkyl-C ₁ -C ₆ alkyl-, C _{3- 8} cycloalkenyl, C _3-8 cycloalkenyl-C ₁ -C ₆ alkyl-, C _3-8 halocycloalkenyl, C _3-8 halocycloalkenyl-C ₁ -C ₆ alkyl-, C _1- C ₆ acetyl, C _1- C ₆ acetyl-C ₁ -C ₆ alkyl-, 4-12 membered monocyclic or bicyclic heterocyclic group, 4-12 membered monocyclic or bicyclic heterocyclic group- C ₁ -C ₆ alkyl-, C _6- C ₁₂ aryl, C _6- C ₁₂ aryl-C ₁ -C ₆ alkyl-, 5-12 member heteroaryl or 5-12 member heteroaryl- C ₁ -C ₆ alkyl-; and R ⁸ and R ⁹ can further independently be selected from up to three hydroxy, C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _1-6 alkoxy -C _1-6 alkyl, C _1-6 alkoxy-C _1-6 alkoxy, C _2-6 hydroxyalkoxy, pendant oxygen, thiocarbonyl, cyano or halo substituent substitution; Or alternatively, R ⁸ and R ⁹ together with the N atom to which they are simultaneously attached form a heterocyclic ring of 4-7 members, the heterocyclic ring containing up to one other heteroatom selected from O, S or NR ¹¹ , and the heterocyclic Depending on the situation, up to three are selected from hydroxy, C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _1-6 alkoxy-C _1-6 alkyl, C _1-6 alkoxy-C _1-6 alkoxy, C _2-6 hydroxyalkoxy, pendant, thiocarbonyl, cyano or halo substituent substitution; R ^{10 is} each independently H, -CD ₃ , C _1-6 alkane Group, C _3-6 cycloalkyl, C _2-6 hydroxyalkyl, C _1-6 alkoxy-C _1-6 alkyl or C _2-6 alkyl-NR ⁸ R ⁹ ; R ^{11 is} each independently is hydrogen, C _1- C ₆ alkyl, C _3- C ₆ alkenyl, C _3- C ₆ alkynyl, C _3- C ₆ cycloalkyl, C _6- C ₁₂ aryl, 4-12 membered heterocycle Radical or 5-12 original heteroaryl; or alternatively, two R ¹¹ and the hetero atom attached to it form a 5-8 membered heterocyclyl ring, which may be up to three Selected from hydroxy, C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _1-6 alkoxy-C _1-6 alkyl, C _1-6 alkoxy-C _1-6 alkoxy Group, C _2-6 hydroxyalkoxy, pendant, thiocarbonyl, cyano and halo substituents; R ^{13 is} each independently H, -CD ₃ , cyano, -C _1-6 alkyl , -C _1-6 haloalkyl, C _1-6 acetyl-C _1-6 alkyl-, R ⁷ -(CH ₂ ) _p C(=O)-C _1-6 alkyl-, carboxy-C _1-6 alkyl-, C _1-6 alkoxycarbonyl-C _1-6 alkyl-, R ⁷ -(CH ₂ ) _p OC(=O)-C _1-6 alkyl-, R ⁸ R ⁹ NC(=O)C _1-6 alkyl-, R ⁷ -C _2-6 alkyl-N(R ¹⁰ )-C(=O)C _1-6 alkyl-, -C _2-6 hydroxyalkyl , C _1-6 alkoxy-C _2-6 alkyl-, R ⁷ (CH ₂ ) _p OC _2-6 alkyl-, C _1-6 acetyl-C _2-6 alkyl-, R ⁷ -(CH ₂ ) _p C(=O)OC _2-6 alkyl-, C _1-6 alkoxy-C(=O)OC _2-6 alkyl-, R ⁷ (CH ₂ ) _p OC(= O)-OC _2-6 alkyl-, R ⁸ R ⁹ NC(=O)OC _2-6 alkyl-, C _1-6 alkyl-N(R ¹⁰ )C(=O)OC _2-6 alkyl Group, R ⁷ (CH ₂ ) _p N(R ¹⁰ )-C(=O)OC _2-6 alkyl-, R ⁸ R ⁹ NC _2-6 alkyl-, R ⁷ -C _2-6 alkyl -, C _1-6 acyl N(R ¹⁰ )-C _2-6 alkyl-, R ⁷ -C _1-6 acyl N(R ¹⁰ )-C _2-6 alkyl-, R ⁷ -(CH ₂ ) _p C(=O)N(R ¹⁰ )-C _2-6 alkyl-, R ⁷ -C _0-6 alkyl C(=O)N(R ¹⁰ )-C _2-6 alkyl-, C _1-6 alkoxy-C(=O)N(R ¹⁰ )-C _2-6 alkyl-, R ⁷ -(CH ₂ ) _p OC(=O)N(R ¹⁰ )C _2-6 alkane Base-, R ⁸ R ⁹ NC(=O)N(R ¹⁰ )C _2-6 alkyl-, R ¹⁰ SO _2- N(R ¹⁰ )-C _2-6 alkyl-, R ⁷ -SO _2- N(R ¹⁰ )-C _2-6 alkyl-, C _1-6 alkyl S(O) _x -C _2-6 alkyl-, R ⁷ -(CH ₂ ) _p S(O) _x C _{2- 6} alkyl-, R ⁷ SO ₂ C _2-6 alkyl-, C _1-6 alkyl S(=O)(=NR ¹⁰ )-C _2-6 alkyl-, C _1-6 haloalkyl S (=O)(=NR ¹⁰ )-C _2-6 alkyl-, C _1-6 alkyl S (=NR ¹⁰ )(=NR ¹⁰ )-C _2-6 alkyl-, C _1-6 halo Base S (=NR ¹⁰ )(=NR ¹⁰ )-C _2-6 alkyl-, R ⁷ S(=O)(=NR ¹⁰ )C _2-6 alkyl-, R ⁷ S(=NR ¹³ )(=NR ¹³ )-C _2-6 alkyl-, -C _3-6 alkenyl, -C _3-6 haloalkenyl, R ⁷ -C _4-6 alkenyl-, C _1-6 alkoxy-C _4-6 alkenyl- , -C _2-6 alkynyl, -C _2-6 haloalkynyl, R ⁷ -C _2-6 alkynyl-, C _2-6 alkynyl-, C _1-6 alkynyl-, R ⁷ -(CH ₂ ) _p C(=O)-, R ⁷ -C _1-6 alkyl-C(=O)-, C _1-6 hydroxyalkyl-C(=O)-, C _1-6 alkoxy- C _1-6 alkyl-C(=O)-, C _1-6 alkyl S(O) _x -C _1-6 alkyl-C(=O)-, -C _1-6 alkoxycarbonyl, R ⁷ -(CH ₂ ) _{poxycarbonyl-} , -C(=O)NR ⁸ R ⁹ , R ⁷ -(CH ₂ ) _p -N(R ¹⁰ )-C(=O)-, hydroxyl, -C _1-6 alkoxy, -C _1-6 haloalkoxy, C _1-6 alkyl-N(R ¹⁰ )C(=O)-C _1-6alkoxy- , R ⁷ (CH ₂ ) _p O-, R ⁷ (CH ₂ ) _p OC(=O)OC _2-6 alkoxy-, R ⁷ (CH ₂ ) _p N(R ¹⁰ )-C(=O)OC _2-6 alkoxy -, R ⁸ R ⁹ NC(=O)OC _2-6 alkoxy-, C _1-6 alkoxy-C(=O)N(R ¹⁰ )-C _2-6 alkoxy-, R ⁷ -(CH ₂ ) _p OC(=O)N(R ¹⁰ )C _2-6 alkoxy-, R ⁸ R ⁹ NC(=O)N(R ¹⁰ )C _2-6 alkoxy-, C _{1 -6} alkoxycarbonyl C _1-6 alkoxy-, R ⁷ (CH ₂ ) _p OC(=O)C _1-6 alkoxy-, -C _1-6 acetyloxy, R ⁷ -(CH ₂ ) _p C(=O)O-, -NR ⁸ R ⁹ , R ⁸ R ⁹ NC _2-6 alkyl-N(R ¹⁰ )-, R ⁷ -C _2-6 alkyl-N(R ¹⁰ ) -, C _1-6 acetyl-N(R ¹⁰ )-, C _1-6 alkoxycarbonyl-N(R ¹⁰ )-, R ⁸ R ⁹ NC(=O)-N(R ¹⁰ )-, R ⁷ -C _1-6 acetyl-N(R ¹⁰ )-, C _1-6 alkyl S(O) ₂ -N(R ¹⁰ )-, R ¹⁰ S(O) ₂ -N(R ¹⁰ )-, C _1-6 haloalkyl S(O) ₂ -N(R ¹⁰ )-, R ⁷ SO ₂ -N(R ¹⁰ )-, C _1-6 alkyl S(O) _x -, C _1-6 halo Alkyl S(O) _x -, R ⁷ -(CH ₂ ) _p S(O) ₂ , R ⁷ SO ₂ -, C _1-6 alkyl-S(=O)(=NR ¹⁰ )-, C _1-6 haloalkyl- S(=O)(=NR ¹⁰ )-, C _6-12 aryl, C _6- C ₁₂ aryl-C ₁ -C ₆ alkyl-, 5-12 member heteroaryl, 5-12 member heteroaryl -C ₁ -C ₆ alkyl-, C _3-8 cycloalkyl-, C _3-8 cycloalkyl-C ₁ -C ₆ alkyl-, C _3-8 cycloalkenyl-, C _3-8 Cycloalkenyl-C ₁ -C ₆ alkyl-, 4-12 membered monocyclic or bicyclic heterocyclyl- or 4-12 membered monocyclic or bicyclic heterocyclyl-C ₁ -C ₆ alkyl-; or Alternatively, two R ⁴ , two R ¹³ or R ¹³ and R ⁴ together with the atoms attached to them form a ring of 5-7 members, the ring may be aromatic or partially saturated, and the ring may Contains up to two heteroatoms selected from N, O, and S; and the 5-7 member circumstance is further selected from =O (pendant oxygen), =S, =NR ¹³ , (=O) ₂ , ( O) (NR ¹³ ), R ⁴ and R ¹³ are substituted; A ⁶ is selected from:

A ^{2 is} replaced by R ⁴ as appropriate; m is 0, 1, 2 or 3; n=1, 2 or 3; p=0, 1, 2, 3 or 4; q=2, 3 or 4; and x= 0, 1, or 2.

In one embodiment of formula (I), X ¹ , X ² , X ³ , X ⁶ , X ⁷ , X ⁸ , X ⁹ , X ¹⁰ , X ¹¹ and X ¹² are each selected from the group consisting of: C, CH, CR ⁴ , C(R ⁴ ) ₂ , CR ¹³ , CH ₂ , C=O, C=S, C=NR ¹³ , N, NR ⁴ , NR ¹³ , N(O), S, S(O) , S(O) ₂ , S(=O)(=NR ¹³ ), S(=NR ¹³ ) ₂ and O.

In one embodiment of formula (I), if any of X ² , X ³ , X ⁶ , X ⁷ , X ⁸ , X ⁹ , X ¹⁰ , X ¹¹ and X ¹² is NR ¹³ , O, S, C=O, C=NR ¹³ , S=O or SO ₂ , then the above bond with the atom is not a (formal) double bond; and X ¹ , X ² , X ³ , X ⁴ , X ⁵ , X ⁶ , At least four of X ⁷ , X ⁸ , X ⁹ , X ¹⁰ , X ¹¹ and X ¹² are C, CR ⁴ or C(R ⁴ ) ₂ .

In one embodiment of formula (I), X ¹ , X ² , X ³ , X ⁶ , X ⁷ , X ⁸ , X ⁹ , X ¹⁰ , X ¹¹ and X ¹² are each optionally substituted and are independently C Or a heteroatom selected from the group consisting of N, S, O, and the substituent is C=O, C=NR ¹³ , SO ₂ or S(O)(NR ¹³ ); in one embodiment of formula (I) , In A ¹ A ² , A ³ , A ^4a and A ^4b , at most four of X ¹ , X ² , X ³ , X ⁴ and X ⁵ and at least two may be C, CR ⁴ or C(R ⁴ ) ₂ .

In one embodiment of formula (I), in A ¹ , A ² and A ³ , if X ¹ , X ⁴ and X ^{5 are} both C, then one of X ² and X ³ is O, C=O, SO ₂ , N, NR ¹³ or S.

In one embodiment of formula (I), in A ¹ , A ² and A ³ , if X ¹ is N, X ² is C=O, SO ₂ , C=NR ¹³ , NR ¹³ or C=S, And X ⁴ and X ^{5 are} both C, then X ³ is C(R ⁴ ) ₂ , O, NR ¹³ , C=O or S.

In one embodiment of formula (I), in A ¹ , A ² and A ³ , if X ¹ is C and X ² and X ³ are CR ⁴ or N, then one of X ⁴ and X ⁵ may be N, but if X ¹ is N, or if one of X ² or X ^{3 is} not N or CR ⁴ , then X ⁴ and X ^{5 are} both C.

In one embodiment of formula (I), in A ^4a and A ^4b , at least one of X ¹ , X ² and X ³ is CR ⁴ or N, and one of X ⁴ and X ⁵ is C or N And the other is C.

In one embodiment of formula (I), in A ² the methylene units in the non-aromatic ring are optionally substituted with up to three independent R ⁴ ; and up to two of these methylene units are considered The case is independently replaced by C=O, C(R ⁴ ) ₂ , NR ¹⁰ , O, or S(O) _x .

In one embodiment of formula (I), in A ¹ , X ⁶ , X ⁷ , X ⁸ and X ⁹ may be CR ⁴ , N, NR ¹³ , C(R ¹ ) ₂ , C(O) or S (O) _x , the limitation is that at least two of them are CR ⁴ , C(=O), C(=NR ¹³ ), or N.

In one embodiment of formula (I), in A ³ , if X ⁴ or X ⁵ is N, then X ¹⁰ , X ^11, and X ^{12 are} independently N or CR ⁴ , and the limitation is that X ¹⁰ , X ^At most two of ¹¹ and X ¹² are N.

In one embodiment of formula (I), in A ³ , if X ⁴ and X ⁵ are C, and one of X ¹⁰ , X ^11, and X ¹² is NR ¹⁰ , O, or S, the remaining two are independently CR ⁴ or N.

In one embodiment of formula (I), in A ^4a and A ^4b , X ⁶ and X ⁷ may be CR ⁴ , N, NR ¹³ , C(R ¹ ) ₂ , C(O) or S(O) _x , whose limitation is that at least two of them are CR ⁴ , C(=O), C(=NR ¹³ ), or N.

In one embodiment of formula (I), in A ^4a , X ⁹ is C, CH, or N.

In one embodiment of formula (I), in A ^4b , X ⁸ is C, CH, or N.

In one embodiment of formula (I), in A ⁵ , at least three of X ² , X ³ , X ⁴ , X ⁵ and X ⁶ are C, C=O, CR ⁴ or C(R ⁴ ) ₂ . In one embodiment of formula (I), in A ⁵ , X ¹ is C, CH, or N.

In one embodiment of formula (I), when Z is CH, then A is not 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl, 1H-ind Indol-3-yl, 1-methyl-1H-indol-3-yl or pyrazolo[1,5-a]pyridin-3-yl.

In one embodiment of formula (I), Z is N. In another embodiment, Z is CH.

In another embodiment of formula (I), R ³ is selected from (3R)-3-(dimethylamino)pyrrolidin-1-yl, (3S)-3-(dimethyl-amino )Pyrrolidin-1-yl, 3-(dimethylamino)azetidin-1-yl, [2-(dimethylamino)ethyl]-(methyl)amino, [2 -(Methylamino)ethyl](methyl)amino, 5-methyl-2,5-diazaspiro[3.4]octan-2-yl, (3aR,6aR)-5-methylhexa -Hydrogen-pyrrolo[3,4-b]pyrrole-1(2H)-yl, 1-methyl-1,2,3,6-tetrahydropyridin-4-yl, 4-methylhexahydropyrazine -1-yl, 4-[2-(dimethylamino)-2-oxoethyl]hexahydropyrazin-1-yl, methyl[2-(4-methylhexahydropyrazine- 1-yl)ethyl]amino, methyl[2-(morpholin-4-yl)ethyl]amino, 1-amino-1,2,3,6-tetrahydropyridin-4-yl and A group consisting of 4-[(2S)-2-aminopropionyl]hexahydropyrazin-1-yl.

In another embodiment of formula (I), R ³ is -N(R ¹⁰ )C _2-6 alkyl-NR ¹⁰ R ¹⁰ . In another embodiment, R ³ is -N(R ¹⁰ )C _2-6 alkyl-NR ¹⁰ R ¹⁰ , where R ^{10 is} not H.

In another embodiment of formula (I), R ¹ is selected from H, F, Cl, Br, CF ₃ , -CN, methyl, -CHF ₂ , ethynyl, methoxy, ethoxy, iso Propoxy, -OCF ₃ , -OCH ₂ CF ₃ , -OCH ₂ CHF ₂ , -CHO, -CONH ₂ , -CONHMe, or -CONMe ₂ .

In another embodiment of formula (I), E ³ is N.

In another embodiment of formula (I), E ¹ and E ² are each CH.

In one embodiment of formula (I), E ¹ , E ² and E ³ combine with the nitrogen and carbon atoms of the six-membered ring to form a heteroaromatic ring, the heteroaromatic ring is selected from the group consisting of

。 In another embodiment of formula (I), Y is

.

In one embodiment, the present invention relates to compounds of formula (I) and compositions thereof as disclosed herein. In one embodiment, the compound of formula (I) is excluded from CN 105085489 A, WO 2015/127872, WO2013/014448, CN 105001208 A, CN 104844580 A, WO 2015/175632, WO 2015/188777, WO 2016/105525, WO2016060443 , WO 2016/029839, WO 2016/054987, WO 2016/015453, WO 2016/070816 and/or compounds exemplified in WO 2015/195228. In one embodiment, compounds of formula (I) exclude compounds exemplified in CN 104761585 A and/or CN 104761544 A.

The various embodiments disclosed in Formula (I) herein can also be applied to the following Formulas (A), (B), (C), (CI), (D), (DI), (E), (EI) , (F), (G), (H), (HI), (J), (K), (L), (M), (N), (O) and/or (P).

或其立體異構體或醫藥學上可接受之鹽、溶劑合物、酯或前藥；其中，Z為CH或N；Y為

在Y¹及Y²中，R^5a為H、F、Cl、CF₃、CHF₂、CF₂C_1-6烷基、CF₂CH₂NR⁸R⁹、CH₂NR⁸R⁹、CN或C_1-6烷基；在Y¹及Y²中，R^6e為R¹⁰、H、F、芳基、雜芳基、環烷基、雜環烷基、(CH₂)_mCHR¹⁰R⁷、CF₂(CH₂)_mCHR¹⁰R⁷或C(R¹⁰)₂R⁷；在Y⁴及Y⁵中，R^6t為C_1-6烷基、C_3-6環烷基、芳基、雜芳基、雜環烷基、(CH₂)_mCHR¹⁰R⁷、C(R¹⁰)₂R⁷；在Y¹及Y²中，R^6z為H、F、Cl、CF₃、CHF₂、CF₂C_1-6烷基或C_1-6烷基；或或者在Y¹及Y²中，R^6e及R^6z合起來形成=CR^6e'R^6z'(丙二烯)，其中R^6e'為R¹⁰、H、F、芳基、雜芳基、環烷基、雜環烷基、(CH₂)_mCHR¹⁰R⁷、CF₂(CH₂)_mCHR¹⁰R⁷或C(R¹⁰)₂R⁷且其中R^6z'為H、F、Cl、CF₃、CHF₂、CF₂C_1-6烷基或C_1-6烷基；或 或者在Y¹及Y²中，R^6e及R^6z與該兩者同時附接之sp²碳原子合起來形成4至7個成員之脂環族環，其中環原子之一視情況由NR⁸、O、S(O)_x、S(=O)(=NR⁸)、P=O、P(=O)(OR⁸)、OP(=O)(OR⁸)O置換，且該脂環族環視情況經選自由鹵素、側氧基、OH、OR⁸及NR⁸R⁹組成之群之一或多個取代基取代；R¹獨立地選自氫、氟、氯、溴、甲基、乙基、羥基、甲氧基、乙氧基、異丙氧基、環丙氧基、-OCF₃、-OCH₂CF₃、-OCH₂CHF₂、乙烯基、乙炔基、-CF₃、-CHF₂、-CHO、-CH₂OH、-CONH₂、-CO₂Me、-CONHMe、-CONMe₂及氰基；R²為-OCF₃、-OCHF₂、-OCF₂CF₃、-OCH₂CHF₂、-OCH₂CF₃、環丙基、環丙氧基、甲氧基、-OCD₃、乙氧基或異丙氧基；R³為-N(R¹⁰)C_2-6烷基-NR¹⁰R¹⁰、-N(R¹⁰)C_2-6烷基-R⁷、-O(CH₂)_pR⁷、-N(R¹⁰)C(=O)(CH₂)_pR⁷或R⁷；R^4a、R^4b及R^4c各自獨立地為H、氰基、硝基、鹵基、-C_1-6烷基、-C_1-6鹵烷基、-羧基-C_1-6烷基、-C_1-6羥基烷基、R⁸R⁹N-C_1-6烷基-、-C_2-6烯基、-C_2-6炔基、C_1-6醯基-、R⁷-(CH₂)_pC(=O)-、C_1-6羥基烷基-C(=O)-、羧基、-C_1-6烷氧基羰基、-C(=O)NR⁸R⁹、羥基、-C_1-6烷氧基、-C_1-6醯氧基、-NR⁸R⁹、C_1-6醯基-N(R¹⁰)-、吡唑、1,2,3-三唑、四唑、(C_1-6烷基)SO₂-或R⁷SO₂-；R⁷為OH、NR⁸R⁹、O(CH₂)_qNR⁸R⁹、C_1-6烷氧基、C_1-6烷氧基-C_1-6烷氧基、C_2-6羥基烷氧基、氧雜環丁烷基、氧雜環丁烷基氧基、氧雜環丁烷基胺基、氧雜環戊烷基、氧雜環戊烷基氧基、氧雜環戊烷基胺基、氧雜環己烷基、氧雜環己烷基氧基、氧雜環己烷基胺基、氧雜環庚烷基、氧雜環庚烷基氧基、氧雜環庚烷基胺基、氮雜環丁烷基、氮雜環丁烷基氧基、氮雜環丁烷基胺基、吡咯啶基、吡咯啶基氧基、吡咯啶基胺基、六氫吡啶基、六氫吡啶基氧基、六氫吡啶基胺基、氮雜環庚烷基、氮雜環庚烷基氧基、氮雜環庚烷基胺基、二氧雜環戊烷基、二噁烷基、嗎啉基、硫代嗎啉基、硫代嗎啉基-S,S-二氧化物、六氫吡嗪基、二氧 雜環庚烷基、二氧雜環庚烷基氧基、二氧雜環庚烷基胺基、氧氮雜環庚烷基、氧氮雜環庚烷基氧基、氧氮雜環庚烷基胺基、二氮雜庚烷基、二氮雜庚烷基氧基、二氮雜庚烷基胺基、(3R)-3-(二甲基胺基)吡咯啶-1-基、(3S)-3-(二甲基胺基)吡咯啶-1-基、3-(二甲基胺基)氮雜環丁烷-1-基、[2-(二甲基胺基)乙基](甲基)胺基、[2-(甲基胺基)乙基](甲基)胺基、5-甲基-2,5二氮雜螺[3.4]辛-2-基、(3aR,6aR)-5-甲基六-氫-吡咯并[3,4-b]吡咯-1(2H)-基、I-甲基-1,2,3,6-四氫吡啶-4-基、4-甲基六氫吡嗪-1-基、4-[2(二甲基胺基)-2-側氧基乙基]六氫吡嗪-1-基、甲基[2-(4-甲基六氫吡嗪-1基)乙基]胺基、甲基[2-(嗎啉-4-基)乙基]胺基、1-胺基-1,2,3,6四氫吡啶-4-基、4-[(2S)-2-胺基丙醯基]六氫吡嗪-1-基，其均可視情況經OH、OR¹⁰、側氧基、鹵素、R¹⁰、CH₂OR¹⁰或CH₂NR⁸R⁹取代；R⁸及R⁹各自獨立地為H、-CD₃、C_1-6烷基、C_3-6烯基、C_3-6炔基、C_3-8環烷基、-(C_1-3烷基)-(C_3-8環烷基)、C_3-8環烯基、C_1-C₆醯基、4-12員單環或二環雜環基、4-12員單環或二環雜環基-C₁-C₆烷基-、C_6-C₁₂芳基、5-12員雜芳基；其中R⁸及R⁹可進一步獨立地經多達三個選自羥基、C_1-6烷氧基、C_1-6羥基烷基、C_1-6烷氧基-C_1-6烷基、C_1-6烷氧基-C_1-6烷氧基、C_2-6羥基烷氧基、側氧基、硫羰基、氰基或鹵基之取代基取代；或或者，R⁸及R⁹與其同時附接之N原子合起來形成4-7個成員之雜環，該雜環含有多達一個選自O、S或NR¹¹之其他雜原子，或形成7-12個成員之雜雙環，該雜雙環可為稠合、橋接或螺環，且含有多達兩個選自O、S(O)_x或NR¹¹之其他雜原子，且此等雜環視情況經多達三個選自羥基、C_1-6烷氧基、C_1-6羥基烷基、C_1-6烷氧基-C_1-6烷基、C_1-6烷氧基-C_1-6烷氧基、C_2-6羥基烷氧基、側氧基、硫羰基、氰基或鹵基之取代基取代；R¹⁰各自獨立地為H、-CD₃、C_1-6烷基、C_3-6環烷基、C_2-6羥基烷基、C_1-6烷氧基-C_1-6烷基或C_2-6烷基-NR⁸R⁹； 或者，同時附接之同一N原子上的兩個R¹⁰形成5-6個成員之雜環，該雜環含有多達一個選自O、S或NR¹¹之其他雜原子；R¹¹各自獨立地為氫或C_1-C₆烷基，其視情況經多達三個選自羥基、側氧基、硫羰基、氰基或鹵基之取代基取代；n為1、2或3；q為2、3或4；p為0、1、2、3或4；且x為0、1或2。 In one embodiment, the compound of the present invention relates to the compound of formula (A) or (B):

Or its stereoisomer or pharmaceutically acceptable salt, solvate, ester or prodrug; where Z is CH or N; Y is

In Y ¹ and Y ² , R ^5a is H, F, Cl, CF ₃ , CHF ₂ , CF ₂ C _1-6 alkyl, CF ₂ CH ₂ NR ⁸ R ⁹ , CH ₂ NR ⁸ R ⁹ , CN or C _1-6 alkyl; in Y ¹ and Y ² , R ^6e is R ¹⁰ , H, F, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, (CH ₂ ) _m CHR ¹⁰ R ⁷ , CF ₂ (CH ₂ ) _m CHR ¹⁰ R ⁷ or C(R ¹⁰ ) ₂ R ⁷ ; in Y ⁴ and Y ⁵ , R ^6t is C _1-6 alkyl, C _3-6 cycloalkyl, aryl , Heteroaryl, heterocycloalkyl, (CH ₂ ) _m CHR ¹⁰ R ⁷ , C(R ¹⁰ ) ₂ R ⁷ ; in Y ¹ and Y ² , R ^6z is H, F, Cl, CF ₃ , CHF ₂ , CF ₂ C _1-6 alkyl or C _1-6 alkyl; or alternatively in Y ¹ and Y ² , R ^6e and R ^{6z are} combined to form =CR ^6e' R ^6z' (propadiene), where R ^6e' is R ¹⁰ , H, F, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, (CH ₂ ) _m CHR ¹⁰ R ⁷ , CF ₂ (CH ₂ ) _m CHR ¹⁰ R ⁷ or C (R ¹⁰ ) ₂ R ⁷ and wherein R ^6z′ is H, F, Cl, CF ₃ , CHF ₂ , CF ₂ C _1-6 alkyl or C _1-6 alkyl; or alternatively in Y ¹ and Y ² , R ^6e and R ^6z together with the sp ² carbon atoms to which they are attached together form an alicyclic ring of 4 to 7 members, where one of the ring atoms is optionally composed of NR ⁸ , O, S(O) _x , S(=O)(=NR ⁸ ), P=O, P(=O)(OR ⁸ ), OP(=O)(OR ⁸ )O, and the alicyclic ring is selected from halogen, One or more substituents in the group consisting of pendant oxygen, OH, OR ⁸ and NR ⁸ R ⁹ ; R ^{1 is} independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, hydroxyl, methoxy , Ethoxy, isopropoxy, cyclopropoxy, -OCF ₃ , -OCH ₂ CF ₃ , -OCH ₂ CHF ₂ , vinyl, ethynyl, -CF ₃ , -CHF ₂ , -CHO, -CH ₂ OH, -CONH ₂ , -CO ₂ Me, -CONHMe, -CONMe ₂ and cyano group; R ² is -OCF ₃ , -OCHF ₂ , -OCF ₂ CF ₃ , -OCH ₂ CHF ₂ , -OCH ₂ CF ₃ , Cyclopropyl, cyclopropoxy, methoxy, -OCD ₃ , ethoxy or isopropoxy; R ³ is -N(R ¹⁰ )C _2-6 alkyl-NR ¹⁰ R ¹⁰ , -N (R ¹⁰ )C _{2 -6} alkyl-R ⁷ , -O(CH ₂ ) _p R ⁷ , -N(R ¹⁰ )C(=O)(CH ₂ ) _p R ⁷ or R ⁷ ; R ^4a , R ^4b and R ^4c are independent of each other Ground is H, cyano, nitro, halo, -C _1-6 alkyl, -C _1-6 haloalkyl, -carboxy-C _1-6 alkyl, -C _1-6 hydroxyalkyl, R ⁸ R ⁹ NC _1-6 alkyl-, -C _2-6 alkenyl, -C _2-6 alkynyl, C _1-6 acetyl-, R ⁷ -(CH ₂ ) _p C(=O)-, C _1-6 hydroxyalkyl-C(=O)-, carboxyl, -C _1-6 alkoxycarbonyl, -C(=O)NR ⁸ R ⁹ , hydroxy, -C _1-6 alkoxy,- C _1-6 acetyloxy, -NR ⁸ R ⁹ , C _1-6 acetyl-N(R ¹⁰ )-, pyrazole, 1,2,3-triazole, tetrazole, (C _1-6 alkyl ) SO ₂ -or R ⁷ SO ₂ -; R ⁷ is OH, NR ⁸ R ⁹ , O(CH ₂ ) _q NR ⁸ R ⁹ , C _1-6 alkoxy, C _1-6 alkoxy-C _{1 -6} alkoxy, C _2-6 hydroxyalkoxy, oxetanyl, oxetanyloxy, oxetanylamino, oxetanyl, oxetane Pentyloxy, oxetanylamino, oxetanyl, oxetanyloxy, oxetanylamino, oxepanyl, oxetanyl Heptyloxy, oxetanylamino, azetidinyl, azetidinyloxy, azetidinylamino, pyrrolidinyl, pyrrolidinyloxy, Pyrrolidinylamino, hexahydropyridyl, hexahydropyridyloxy, hexahydropyridylamino, azepanyl, azepanyloxy, azepanylamino, Dioxolyl, dioxanyl, morpholinyl, thiomorpholinyl, thiomorpholinyl-S,S-dioxide, hexahydropyrazinyl, dioxepane , Dioxepaneoxy, dioxepeptylamino, oxazacycloheptyl, oxazacycloheptyloxy, oxazacycloheptylamino, di diazepino alkyl, alkyloxy diazepino, diazepino alkylamino, (3R) - 3 - (dimethylamino) pyrrolidin-l-yl, (3S) -3- (Dimethylamino)pyrrolidin-1-yl, 3-(dimethylamino)azetidin-1-yl, [2-(dimethylamino)ethyl](methyl) Amino, [2-(methylamino)ethyl] (methyl)amino, 5-methyl-2,5 diazaspiro[3.4]octan-2-yl, (3aR,6aR)-5 -Methylhexa-hydro-pyrrolo[3,4-b]pyrrole-1(2H)-yl, 1-methyl-1,2,3,6-tetrahydropyridin-4-yl, 4-methyl Hexahydropyrazin-1-yl, 4-[2(dimethylamino)-2-oxoethyl]hexahydropyrazin-1-yl, methyl[2-(4-methylhexahydro Pyrazin-1-yl)ethyl]amine, methyl[2-(morpholine -4-yl)ethyl]amino, 1-amino-1,2,3,6 tetrahydropyridin-4-yl, 4-[(2S)-2-aminopropionyl]hexahydropyrazine -1-yl, which are optionally substituted by OH, OR ¹⁰ , pendant oxygen, halogen, R ¹⁰ , CH ₂ OR ¹⁰ or CH ₂ NR ⁸ R ⁹ ; R ⁸ and R ⁹ are each independently H, -CD ₃ , C _1-6 alkyl, C _3-6 alkenyl, C _3-6 alkynyl, C _3-8 cycloalkyl, -(C _1-3 alkyl)-(C _3-8 cycloalkyl) , C _3-8 cycloalkenyl, C _1- C ₆ acetyl, 4-12 membered monocyclic or bicyclic heterocyclyl, 4-12 membered monocyclic or bicyclic heterocyclyl-C ₁ -C ₆ alkyl -, C _6- C ₁₂ aryl, 5-12 member heteroaryl; wherein R ⁸ and R ⁹ can be further independently selected by up to three selected from hydroxyl, C _1-6 alkoxy, C _1-6 hydroxyalkyl Group, C _1-6 alkoxy-C _1-6 alkyl, C _1-6 alkoxy-C _1-6 alkoxy, C _2-6 hydroxyalkoxy, pendant oxy, thiocarbonyl, cyano Substituted by a substituent of a group or a halogen group; or alternatively, R ⁸ and R ⁹ together with the N atom to which they are simultaneously attached form a heterocyclic ring of 4-7 members, the heterocyclic ring containing up to one selected from O, S or NR ¹¹ other heteroatoms, or form a heterobicyclic ring of 7-12 members, the heterobicyclic ring may be fused, bridged or spiro ring, and contains up to two other selected from O, S (O) _x or NR ¹¹ Heteroatoms, and these heterocycles are optionally selected from up to three hydroxy, C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _1-6 alkoxy-C _1-6 alkyl, C _{1 -6} alkoxy-C _1-6 alkoxy, C _2-6 hydroxyalkoxy, pendant, thiocarbonyl, cyano or halo substituent substitution; R ^{10 is} each independently H, -CD ₃ , C _1-6 alkyl, C _3-6 cycloalkyl, C _2-6 hydroxyalkyl, C _1-6 alkoxy-C _1-6 alkyl or C _2-6 alkyl-NR ⁸ R ⁹ ; Or, two R ¹⁰ on the same N atom attached at the same time form a heterocycle of 5-6 members, the heterocycle contains up to one other heteroatom selected from O, S or NR ¹¹ ; R ¹¹ each is independently hydrogen or C _1- C ₆ alkyl, which is optionally substituted with up to three substituents selected from hydroxy, oxo, thiocarbonyl group, a cyano group or a halogen group of substituents; n is 1, 2 or 3; q Is 2, 3, or 4; p is 0, 1, 2, 3, or 4; and x is 0, 1, or 2.

或其立體異構體或醫藥學上可接受之鹽、溶劑合物、酯或前藥；其中，Z為CH或N；R¹係選自氫、氟、氯、溴、甲基、CF₃、CHF₂及氰基；R²為-OCF₃、-OCHF₂、-OCF₂CF₃、-OCH₂CHF₂、-OCH₂CF₃、環丙基、環丙氧基、甲氧基、-OCD₃、乙氧基或異丙氧基；R³為N(R¹⁰)C_2-6烷基-NR¹⁰R¹⁰； R^4a、R^4b及R^4c各自獨立地為H、氰基、鹵基、-C_1-6烷基、-C_1-6鹵烷基、羧基-C_1-6烷基、-C_1-6羥基烷基、R⁸R⁹N-C_1-6烷基-、-C_2-6烯基、-C_2-6炔基、C_1-6醯基-、R⁷-(CH₂)_pC(=O)-、C_1-6羥基烷基-C(=O)-、羧基、-C_1-6烷氧基羰基、-C(=O)NR⁸R⁹、羥基、烷氧基、C_1-6醯氧基、-NR⁸R⁹、C_1-6醯基-N(R¹⁰)-、R⁷SO₂-，R⁷為OH、NR⁸R⁹、O(CH₂)_qNR⁸R⁹、C_1-6烷氧基或C_2-6羥基烷氧基；R⁸及R⁹獨立地為H、-CD₃、C_1-6烷基、C_3-6烯基、C_3-6炔基、C_3-8環烷基、C_3-8環烯基、C_1-C₆醯基、4-12員單環或二環雜環基、4-12員單環或二環雜環基-C₁-C₆烷基-、C_6-C₁₂芳基、5-12員雜芳基；且R⁸及R⁹可進一步獨立地經多達三個選自羥基、C_1-6烷氧基、C_1-6羥基烷基、C_2-6羥基烷氧基、側氧基、硫羰基、氰基或鹵基之取代基取代；或或者，R⁸及R⁹與其同時附接之N原子合起來形成4-7個成員之雜環，該雜環含有多達一個選自O、S或NR¹¹之其他雜原子，或形成7-12個成員之雜雙環，該雜雙環可為稠合、橋接或螺環，且含有多達兩個選自O、S(O)_x或NR¹¹之其他雜原子，且此等雜環視情況經多達三個選自羥基、C_1-6烷氧基、C_1-6羥基烷基、C_1-6烷氧基-C_1-6烷基、C_1-6烷氧基-C_1-6烷氧基、C_2-6羥基烷氧基、側氧基、硫羰基、氰基或鹵基之取代基取代；R¹⁰各自獨立地為H、-CD₃、C_1-6烷基、C_3-6環烷基、C_2-6羥基烷基、C_1-6烷氧基-C_1-6烷基或C_2-6烷基-NR⁸R⁹；或p為0、1、2、3或4；q為2、3或4；且x為0、1或2。 In another embodiment, the present invention relates to compounds having the structure of formula (A):

Or its stereoisomer or pharmaceutically acceptable salt, solvate, ester or prodrug; wherein, Z is CH or N; R ¹ is selected from hydrogen, fluorine, chlorine, bromine, methyl, CF ₃ , CHF ₂ and cyano; R ² is -OCF ₃ , -OCHF ₂ , -OCF ₂ CF ₃ , -OCH ₂ CHF ₂ , -OCH ₂ CF ₃ , cyclopropyl, cyclopropoxy, methoxy,- OCD ₃ , ethoxy or isopropoxy; R ³ is N(R ¹⁰ )C _2-6 alkyl-NR ¹⁰ R ¹⁰ ; R ^4a , R ^4b and R ^4c are each independently H, cyano, halogen Group, -C _1-6 alkyl, -C _1-6 haloalkyl, carboxy -C _1-6 alkyl, -C _1-6 hydroxyalkyl, R ⁸ R ⁹ NC _1-6 alkyl-,- C _2-6 alkenyl, -C _2-6 alkynyl, C _1-6 acetyl-, R ⁷ -(CH ₂ ) _p C(=O)-, C _1-6 hydroxyalkyl-C(=O )-, carboxyl, -C _1-6 alkoxycarbonyl, -C(=O)NR ⁸ R ⁹ , hydroxy, alkoxy, C _1-6 acetyl, -NR ⁸ R ⁹ , C _1-6 Acyl-N(R ¹⁰ )-, R ⁷ SO ₂ -, R ⁷ is OH, NR ⁸ R ⁹ , O(CH ₂ ) _q NR ⁸ R ⁹ , C _1-6 alkoxy or C _2-6 hydroxy Alkoxy; R ⁸ and R ^{9 are} independently H, -CD ₃ , C _1-6 alkyl, C _3-6 alkenyl, C _3-6 alkynyl, C _3-8 cycloalkyl, C _{3- 8} cycloalkenyl, C ₁ -C ₆ acetyl, 4-12 membered monocyclic or bicyclic heterocyclyl, 4-12 membered monocyclic or bicyclic heterocyclyl-C ₁ -C ₆ alkyl-, C _{6 -} C ₁₂ aryl, 5-12 membered heteroaryl; and R ⁸ and R ⁹ may be further independently substituted with up to three substituents selected from hydroxy, C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _{2 -6} hydroxyalkoxy, pendant, thiocarbonyl, cyano or halo substituents; or alternatively, R ⁸ and R ⁹ together with the N atom to which they are attached together form a 4-7 member heterocycle , The heterocyclic ring contains up to one other heteroatom selected from O, S or NR ¹¹ , or forms a heterobicyclic ring of 7-12 members, the heterobicyclic ring may be fused, bridged or spirocyclic, and contains up to two Other heteroatoms selected from O, S(O) _x or NR ¹¹ , and these heterocycles may optionally be selected from up to three hydroxy groups, C _1-6 alkoxy groups, C _1-6 hydroxyalkyl groups, C _{1 -6} alkoxy-C _1-6 alkyl, C _1-6 alkoxy-C _1-6 alkoxy, C _2-6 hydroxyalkoxy, pendant, thiocarbonyl, cyano or halo Substituted by substituents; R ^{10 is} independently H, -CD ₃ , C _1-6 alkyl, C _3-6 cycloalkyl, C _2-6 hydroxyalkyl, C _1-6 alkoxy-C _{1 -6} alkyl or C _2-6 alkyl-N R ⁸ R ⁹ ; or p is 0, 1, 2, 3, or 4; q is 2, 3, or 4; and x is 0, 1, or 2.

In some embodiments, R ³ in formula (A) or (B) is —N(CH ₃ )CH ₂ CH ₂ NR ¹⁰ R ¹⁰ . In other embodiments, R ³ in formula (A) or (B) is -N(CH ₃ )CH ₂ CH ₂ NR ¹⁰ R ¹⁰ , where R ^{10 is} each independently -CD ₃ , C _1-6 alkyl Group, C _3-6 cycloalkyl, C _2-6 hydroxyalkyl, C _1-6 alkoxy-C _1-6 alkyl, or C _2-6 alkyl-NR ⁸ R ⁹ .

。在一些實施例中， R^5a、R^6e及R^6z各自獨立地為H。 In one embodiment, Y in formula (A) or (B) is

. In some embodiments, R ^5a , R ^6e and R ^6z are each independently H.

或其立體異構體或醫藥學上可接受之鹽、溶劑合物、酯或前藥；其中，R¹為氫、氟、氯或甲基；R²為-OCF₃、-OCHF₂、-OCF₂CF₃、-OCH₂CHF₂、-OCH₂CF₃、環丙基、環丙氧基、甲氧基、-OCD₃、乙氧基或異丙氧基；R^4a為H或-NR⁸R⁹；R^4b及R^4c各自獨立地為H、氰基、F、Cl、Br、CH₃、CF₃、CHF₂、CONH₂或C(=O)NR⁸R⁹；R⁸及R⁹各自獨立地為H、-CD₃或C_1-6烷基；且R¹⁰各自獨立地為H、-CD₃、C_1-6烷基、C_3-6環烷基或C_2-6羥基烷基。在一實施例中，R^4b及R^4c各自獨立地為H、氰基、F、Cl、Br、CH₃、CF₃或CHF₂。 在另一實施例中，式(C)化合物包含：R¹為氫；R²為甲氧基、-OCD₃、乙氧基或異丙氧基；R^4a為NR⁸R⁹；R^4b為H或CH₃；R^4c為H、F、Cl、Br或CH₃；R⁸及R⁹各自獨立地為H、-CD₃、-CH₃、-CH₂CH₃或-CH(CH₃)₂；且R¹⁰各自獨立地為H、-CD₃、-CH₃、-CH₂CH₃或-CH(CH₃)₂。 In one embodiment, the compound of the present invention has the structure of formula (C):

Or its stereoisomer or pharmaceutically acceptable salt, solvate, ester or prodrug; wherein R ¹ is hydrogen, fluorine, chlorine or methyl; R ² is -OCF ₃ , -OCHF ₂ ,- OCF ₂ CF ₃ , -OCH ₂ CHF ₂ , -OCH ₂ CF ₃ , cyclopropyl, cyclopropoxy, methoxy, -OCD ₃ , ethoxy, or isopropoxy; R ^4a is H or -NR ⁸ R ⁹ ; R ^4b and R ^4c are each independently H, cyano, F, Cl, Br, CH ₃ , CF ₃ , CHF ₂ , CONH ₂ or C(=O)NR ⁸ R ⁹ ; R ⁸ and R ⁹ are each independently H, -CD ₃ or C _1-6 alkyl; and R ¹⁰ are each independently H, -CD ₃ , C _1-6 alkyl, C _3-6 cycloalkyl or C _2-6 Hydroxyalkyl. In one embodiment, R ^4b and R ^4c are each independently H, cyano, F, Cl, Br, CH ₃ , CF ₃ or CHF ₂ . In another embodiment, the compound of formula (C) comprises: R ¹ is hydrogen; R ² is methoxy, -OCD ₃ , ethoxy, or isopropoxy; R ^4a is NR ⁸ R ⁹ ; R ^4b is H or CH ₃ ; R ^4c is H, F, Cl, Br or CH ₃ ; R ⁸ and R ⁹ are each independently H, -CD ₃ , -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ ; and R ¹⁰ are each independently H, -CD ₃ , -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ .

或其立體異構體或醫藥學上可接受之鹽、溶劑合物、酯或前藥；其中，R¹為氫、氟、氯或甲基；R²為-OCF₃、-OCHF₂、-OCF₂CF₃、-OCH₂CHF₂、-OCH₂CF₃、環丙基、環丙氧基、甲氧基、-OCD₃、乙氧基或異丙氧基；R^4a為H或-NR⁸R⁹；R^4b及R^4c各自獨立地為H、氰基、F、Cl、Br、-C_1-6烷基、-CF₃、-CHF₂、CONH₂或-C(=O)NR⁸R⁹； R⁸及R⁹各自獨立地為H、-CD₃或-C_1-6烷基；且R¹⁰各自獨立地為H、-CD₃、-C_1-6烷基、-C_3-6環烷基或-C_2-6羥基烷基。在另一實施例中，式(C-I)化合物包含：R¹為氫；R²為甲氧基、-OCD₃、乙氧基或異丙氧基；R^4a為NR⁸R⁹；R^4b為H或CH₃；R^4c為H、F、Cl、Br、-CF₃、-CH₃或-CH₂CH₃；R⁸及R⁹各自獨立地為H、-CD₃、-CH₃、-CH₂CH₃或-CH(CH₃)₂；且R¹⁰各自獨立地為H、-CD₃、-CH₃、-CH₂CH₃或-CH(CH₃)₂。 In one embodiment, the compound of the present invention has a (CI) structure:

Or its stereoisomer or pharmaceutically acceptable salt, solvate, ester or prodrug; wherein R ¹ is hydrogen, fluorine, chlorine or methyl; R ² is -OCF ₃ , -OCHF ₂ ,- OCF ₂ CF ₃ , -OCH ₂ CHF ₂ , -OCH ₂ CF ₃ , cyclopropyl, cyclopropoxy, methoxy, -OCD ₃ , ethoxy, or isopropoxy; R ^4a is H or -NR ⁸ R ⁹ ; R ^4b and R ^4c are each independently H, cyano, F, Cl, Br, -C _1-6 alkyl, -CF ₃ , -CHF ₂ , CONH ₂ or -C(=O)NR ⁸ R ⁹ ; R ⁸ and R ⁹ are each independently H, -CD ₃ or -C _1-6 alkyl; and R ¹⁰ are each independently H, -CD ₃ , -C _1-6 alkyl, -C _3-6 cycloalkyl or -C _2-6 hydroxyalkyl. In another embodiment, the compound of formula (CI) comprises: R ¹ is hydrogen; R ² is methoxy, -OCD ₃ , ethoxy, or isopropoxy; R ^4a is NR ⁸ R ⁹ ; R ^4b is H or CH ₃ ; R ^4c is H, F, Cl, Br, -CF ₃ , -CH ₃ or -CH ₂ CH ₃ ; R ⁸ and R ⁹ are each independently H, -CD ₃ , -CH ₃ ,- CH ₂ CH ₃ or -CH(CH ₃ ) ₂ ; and R ¹⁰ are each independently H, -CD ₃ , -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ .

In one embodiment, R ¹⁰ in formula (C) or (CI) is each -CD ₃ , C _1-6 alkyl, C _3-6 cycloalkyl, or C _2-6 hydroxyalkyl.

In another embodiment, R ¹⁰ in formulas (A), (B), (C), and/or (CI) are each independently H, -CD ₃ , C _1-6 alkyl, C _3-6 Cycloalkyl or C _2-6 hydroxyalkyl. In other embodiments, each R ^{10 is} independently H, —CD ₃ , methyl, ethyl, or isopropyl.

In another embodiment, R ¹⁰ in formulas (A), (B), (C), and/or (CI) are each independently -CD ₃ , C _1-6 alkyl, C _3-6 cycloalkane Radical or C _2-6 hydroxyalkyl. In other embodiments, each R ^{10 is} independently -CD ₃ , methyl, ethyl, or isopropyl.

In another embodiment, R ^4a in formulas (A), (B), (C), and/or (CI) are each independently H, -C _1-6 alkyl, or -NR ⁸ R ⁹ . In one embodiment, R ^4a is -NR ⁸ R ⁹ . In one embodiment, R ⁸ and R ^{9 are} independently H, -CD ₃ or C _1-6 alkyl. In another embodiment, R ^4a is -N(CH ₃ ) ₂ .

In some embodiments, R ^4b and R ^4c in formulas (A), (B), (C), and/or (CI) are each independently H, cyano, F, Cl, Br, CH ₃ , CF _3. CHF ₂ , C(=O)NR ⁸ R ⁹ or CONH ₂ . In other embodiments, R ^4b and R ^4c in formulas (A), (B), (C), and/or (CI) are each independently H, cyano, F, Cl, Br, CH ₃ , CF ₃ or CHF ₂ . In one embodiment, R ^4b is H. In other embodiments, R ^4c is H, F, Cl, or Br. In some embodiments, R ^4c is H or Cl.

或其立體異構體或醫藥學上可接受之鹽、溶劑合物、酯或前藥；其中，Z為CH或N；X²及X⁷各自為CH、CR⁴或N；R¹為氫、氟、氯、溴、甲基、乙基、羥基、甲氧基、乙氧基、異丙氧基、環丙氧基、-OCF₃、-OCH₂CF₃、-OCH₂CHF₂、乙烯基、乙炔基、CF₃、CHF₂、CHO、CH₂OH、CONH₂、CO₂Me、CONHMe、CONMe₂或氰基；R²為-OCF₃、-OCHF₂、-OCF₂CF₃、-OCH₂CHF₂、-OCH₂CF₃、環丙基、環丙氧基、甲氧基、-OCD₃、乙氧基或異丙氧基；R³為N(R¹⁰)C_2-6烷基-NR¹⁰R¹⁰；R⁴各自獨立地為H、氰基、鹵基、-C_1-6烷基、-C_1-6鹵烷基、羧基-C_1-6烷基、-C_1-6羥基烷基、R⁸R⁹N-C_1-6烷基-、-C_2-6烯基、-C_2-6炔基、C_1-6醯基-、R⁷-(CH₂)_pC(=O)-、 C_1-6羥基烷基-C(=O)-、羧基、-C_1-6烷氧基羰基、-C(=O)NR⁸R⁹、羥基、烷氧基、C_1-6醯氧基、-NR⁸R⁹、C_1-6醯基-N(R¹⁰)-或R⁷SO₂-；且R⁸及R⁹獨立地為H、-CD₃、C_1-6烷基、C_3-6烯基、C_3-6炔基、C_3-8環烷基、C_3-8環烯基、C_1-C₆醯基、4-12員單環或二環雜環基、4-12員單環或二環雜環基-C₁-C₆烷基-、C_6-C₁₂芳基、5-12員雜芳基；且R⁸及R⁹可進一步獨立地經多達三個選自羥基、C_1-6烷氧基、C_1-6羥基烷基、C_2-6羥基烷氧基、側氧基、硫羰基、氰基或鹵基之取代基取代；或或者，R⁸及R⁹與其同時附接之N原子合起來形成4-7個成員之雜環，該雜環含有多達一個選自O、S或NR¹¹之其他雜原子，或形成7-12個成員之雜雙環，該雜雙環可為稠合、橋接或螺環，且含有多達兩個選自O、S(O)_x或NR¹¹之其他雜原子，且此等雜環視情況經多達三個選自羥基、C_1-6烷氧基、C_1-6羥基烷基、C_1-6烷氧基-C_1-6烷基、C_1-6烷氧基-C_1-6烷氧基、C_2-6羥基烷氧基、側氧基、硫羰基、氰基或鹵基之取代基取代；R^4b為H、鹵基、-C_1-6烷基或-C_1-6鹵烷基；R^4c為氰基、C_1-6醯基-、-C(=O)NR⁸R⁹、羥基、烷氧基或F；R^4N為H、-CD₃或-C_1-6烷基；R⁷為OH、NR⁸R⁹、-O(CH₂)_qNR⁸R⁹、C_1-6烷氧基或C_2-6羥基烷氧基；R¹⁰各自獨立地為H、-CD₃、C_1-6烷基、C_3-6環烷基、C_2-6羥基烷基、C_1-6烷氧基-C_1-6烷基或C_2-6烷基-NR⁸R⁹；p=0、1、2、3或4；q=2、3或4；且x=0、1或2。 In one embodiment, the compound of the present invention has the structure of formula (D):

Or its stereoisomer or pharmaceutically acceptable salt, solvate, ester or prodrug; where Z is CH or N; X ² and X ⁷ are each CH, CR ⁴ or N; R ¹ is hydrogen , Fluorine, chlorine, bromine, methyl, ethyl, hydroxyl, methoxy, ethoxy, isopropoxy, cyclopropoxy, -OCF ₃ , -OCH ₂ CF ₃ , -OCH ₂ CHF ₂ , ethylene Group, ethynyl, CF ₃ , CHF ₂ , CHO, CH ₂ OH, CONH ₂ , CO ₂ Me, CONHMe, CONMe ₂ or cyano group; R ² is -OCF ₃ , -OCHF ₂ , -OCF ₂ CF ₃ ,- OCH ₂ CHF ₂ , -OCH ₂ CF ₃ , cyclopropyl, cyclopropoxy, methoxy, -OCD ₃ , ethoxy, or isopropoxy; R ³ is N(R ¹⁰ )C _2-6 alkane Radical -NR ¹⁰ R ¹⁰ ; R ^{4 is} each independently H, cyano, halo, -C _1-6 alkyl, -C _1-6 haloalkyl, carboxy -C _1-6 alkyl, -C _{1 -6} hydroxyalkyl, R ⁸ R ⁹ NC _1-6 alkyl-, -C _2-6 alkenyl, -C _2-6 alkynyl, C _1-6 acetyl-, R ⁷ -(CH ₂ ) _p C(=O)-, C _1-6 hydroxyalkyl-C(=O)-, carboxyl, -C _1-6 alkoxycarbonyl, -C(=O)NR ⁸ R ⁹ , hydroxyl, alkoxy , C _1-6 acyloxy, -NR ⁸ R ⁹ , C _1-6 acyl-N(R ¹⁰ )- or R ⁷ SO ₂ -; and R ⁸ and R ^{9 are} independently H, -CD ₃ , C _1-6 alkyl, C _3-6 alkenyl, C _3-6 alkynyl, C _3-8 cycloalkyl, C _3-8 cycloalkenyl, C _1- C ₆ acetyl, 4-12 member single Ring or bicyclic heterocyclyl, 4-12 membered monocyclic or bicyclic heterocyclyl-C ₁ -C ₆ alkyl-, C _6- C ₁₂ aryl, 5-12 membered heteroaryl; and R ⁸ and R ⁹ can further independently be selected from up to three groups selected from hydroxyl, C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _2-6 hydroxyalkoxy, pendant, thiocarbonyl, cyano or halo Substituted by a substituent of the group; or alternatively, R ⁸ and R ⁹ together with the N atom to which they are simultaneously attached form a heterocyclic ring of 4-7 members, the heterocyclic ring containing up to one other selected from O, S or NR ¹¹ A heteroatom, or a heterobicyclic ring of 7-12 members, which may be fused, bridged or spirocyclic, and contain up to two other heteroatoms selected from O, S(O) _x or NR ¹¹ , And these heterocycles may be selected from up to three hydroxy, C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _1-6 alkoxy-C _1-6 alkyl, C _1-6 alkyl Oxygen-C _1-6 alkoxy, C _2-6 hydroxyalkoxy, pendant, thiocarbonyl, cyano or halo substituent substitution; R ^4b is H, halo, -C _1-6 alkyl or -C _1-6 haloalkyl; R ^4c is cyano, C _1-6 acetyl-, -C(=O)NR ⁸ R ⁹ , hydroxy, alkoxy or F; R ^4N Is H, -CD ₃ or -C _1-6 alkyl; R ⁷ is OH, NR ⁸ R ⁹ , -O(CH ₂ ) _q NR ⁸ R ⁹ , C _1-6 alkoxy or C _2-6 hydroxy Alkoxy; R ^{10 is} each independently H, -CD ₃ , C _1-6 alkyl, C _3-6 cycloalkyl, C _2-6 hydroxyalkyl, C _1-6 alkoxy-C _{1- 6} alkyl or C _2-6 alkyl-NR ⁸ R ⁹ ; p=0, 1, 2, 3 or 4; q=2, 3 or 4; and x=0, 1 or 2.

In one embodiment, R ¹⁰ in formula (D) is each independently -CD ₃ , C _1-6 alkyl, C _3-6 cycloalkyl, C _2-6 hydroxyalkyl, C _1-6 alkyl Oxy-C _1-6 alkyl or C _2-6 alkyl-NR ⁸ R ⁹ .

或其立體異構體或醫藥學上可接受之鹽、溶劑合物、N-氧化物、酯或前藥；其中，Z為CH或N；X²及X⁷各自為CH、CR⁴或N；R¹為氫、氟、氯、溴、甲基、乙基、羥基、甲氧基、乙氧基、異丙氧基、環丙氧基、-OCF₃、-OCH₂CF₃、-OCH₂CHF₂、乙烯基、乙炔基、CF₃、CHF₂、CHO、CH₂OH、CONH₂、CO₂Me、CONHMe、CONMe₂或氰基；R²為-OCF₃、-OCHF₂、-OCF₂CF₃、-OCH₂CHF₂、-OCH₂CF₃、環丙基、環丙氧基、甲氧基、-OCD₃、乙氧基或異丙氧基；R³為-N(R¹⁰)(C_2-6烷基)-NR¹⁰R¹⁰或-N(R¹⁰)(C_3-10環烷基烷基)-NR¹⁰R¹⁰；R⁴各自獨立地為H、氰基、鹵基、-C_1-6烷基、-C_1-6鹵烷基、羧基-C_1-6烷基、-C_1-6羥基烷基、R⁸R⁹N-C_1-6烷基-、-C_2-6烯基、-C_2-6炔基、C_1-6醯基-、R⁷-(CH₂)_pC(=O)-、C_1-6羥基烷基-C(=O)-、羧基、-C_1-6烷氧基羰基、-C(=O)NR⁸R⁹、羥基、烷氧基、C_1-6醯氧基、-NR⁸R⁹、C_1-6醯基-N(R¹⁰)-或R⁷SO₂-；且 R⁸及R⁹獨立地為H、-CD₃、C_1-6烷基、C_3-6烯基、C_3-6炔基、C_3-8環烷基、C_3-8環烯基、C_1-C₆醯基、4-12員單環或二環雜環基、4-12員單環或二環雜環基-C₁-C₆烷基-、C_6-C₁₂芳基、5-12員雜芳基；且R⁸及R⁹可進一步獨立地經多達三個選自羥基、C_1-6烷氧基、C_1-6羥基烷基、C_2-6羥基烷氧基、側氧基、硫羰基、氰基或鹵基之取代基取代；或或者，R⁸及R⁹與其同時附接之N原子合起來形成4-7個成員之雜環，該雜環含有多達一個選自O、S或NR¹¹之其他雜原子，或形成7-12個成員之雜雙環，該雜雙環可為稠合、橋接或螺環，且含有多達兩個選自O、S(O)_x或NR¹¹之其他雜原子，且此等雜環視情況經多達三個選自羥基、C_1-6烷氧基、C_1-6羥基烷基、C_1-6烷氧基-C_1-6烷基、C_1-6烷氧基-C_1-6烷氧基、C_2-6羥基烷氧基、側氧基、硫羰基、氰基或鹵基之取代基取代；R^4b為H、鹵基、-C_1-6烷基或-C_1-6鹵烷基；R^4c為H、氰基、羥基、烷氧基、-C_1-6烷基或-C_1-6鹵烷基、Cl或F，其限制條件在於當R^4c為H時，R^4b為鹵基、-C_1-6烷基或-C_1-6鹵烷基；R^4N為H、-CD₃或-C_1-6烷基；R⁷為OH、NR⁸R⁹、-O(CH₂)_qNR⁸R⁹、C_1-6烷氧基或C_2-6羥基烷氧基；R¹⁰各自獨立地為H、-CD₃、C_1-6烷基、C_3-6環烷基、C_2-6羥基烷基、C_1-6烷氧基-C_1-6烷基或C_2-6烷基-NR⁸R⁹；或或者，同一N原子上之兩個R¹⁰合起來形成3-7個成員之雜環，該雜環視情況經多達三個選自羥基、C_1-6烷氧基、C_1-6羥基烷基、C_1-6烷氧基-C_1-6烷基、C_1-6烷氧基-C_1-6烷氧基、C_2-6羥基烷氧基、側氧基、硫羰基、氰基或鹵基之取代基取代；p=0、1、2、3或4；q=2、3或4；且x=0、1或2。 In one embodiment, the invention relates to compounds of formula (DI):

Or its stereoisomers or pharmaceutically acceptable salts, solvates, N-oxides, esters or prodrugs; where Z is CH or N; X ² and X ⁷ are each CH, CR ⁴ or N ; R ¹ is hydrogen, fluorine, chlorine, bromine, methyl, ethyl, hydroxyl, methoxy, ethoxy, isopropoxy, cyclopropoxy, -OCF ₃ , -OCH ₂ CF ₃ , -OCH ₂ CHF ₂ , vinyl, ethynyl, CF ₃ , CHF ₂ , CHO, CH ₂ OH, CONH ₂ , CO ₂ Me, CONHMe, CONMe ₂ or cyano; R ² is -OCF ₃ , -OCHF ₂ , -OCF ₂ CF ₃ , -OCH ₂ CHF ₂ , -OCH ₂ CF ₃ , cyclopropyl, cyclopropoxy, methoxy, -OCD ₃ , ethoxy, or isopropoxy; R ³ is -N(R ¹⁰ )(C _2-6 alkyl)-NR ¹⁰ R ¹⁰ or -N(R ¹⁰ )(C _3-10 cycloalkylalkyl)-NR ¹⁰ R ¹⁰ ; R ^{4 is} independently H, cyano, halogen Group, -C _1-6 alkyl, -C _1-6 haloalkyl, carboxy -C _1-6 alkyl, -C _1-6 hydroxyalkyl, R ⁸ R ⁹ NC _1-6 alkyl-,- C _2-6 alkenyl, -C _2-6 alkynyl, C _1-6 acetyl-, R ⁷ -(CH ₂ ) _p C(=O)-, C _1-6 hydroxyalkyl-C(=O )-, carboxyl, -C _1-6 alkoxycarbonyl, -C(=O)NR ⁸ R ⁹ , hydroxy, alkoxy, C _1-6 acetyl, -NR ⁸ R ⁹ , C _1-6 Acyl-N(R ¹⁰ )- or R ⁷ SO ₂ -; and R ⁸ and R ^{9 are} independently H, -CD ₃ , C _1-6 alkyl, C _3-6 alkenyl, C _3-6 alkyne Group, C _3-8 cycloalkyl group, C _3-8 cycloalkenyl group, C ₁ -C ₆ acetyl group, 4-12 membered monocyclic or bicyclic heterocyclic group, 4-12 membered monocyclic or bicyclic heterocyclic group -C ₁ -C ₆ alkyl-, C _6- C ₁₂ aryl, 5-12 membered heteroaryl; and R ⁸ and R ⁹ can be further independently selected from up to three hydroxy, C _1-6 alkyl Oxygen, C _1-6 hydroxyalkyl, C _2-6 hydroxyalkoxy, pendant, thiocarbonyl, cyano or halo substituents; or alternatively, R ⁸ and R ⁹ are simultaneously attached to N atoms combine to form a 4-7 member heterocycle, the heterocycle contains up to one other heteroatom selected from O, S, or NR ¹¹ , or forms a 7-12 member heterobicycle, which may be Condensed, bridged or spiro ring, and containing up to two other heteroatoms selected from O, S(O) _x or NR ¹¹ , and these heterocycles are optionally selected from up to three hydroxyl groups, C _1-6 alkanes Oxy, C _1-6 hydroxyalkyl, C _1-6 alkoxy-C _1-6 alkyl, C _1-6 alkoxy-C _1-6 alkoxy, C _2-6 hydroxyalkoxy, pendant, thiocarbonyl, cyano or halo substituent substitution; R ^4b is H, halo, -C _1-6 alkyl or -C _1-6 haloalkyl; R ^4c is H, cyano, hydroxy, alkoxy, -C _1-6 alkyl or -C _1-6 haloalkyl, Cl or F, the limitation is that when R ^4c is H, R ^4b is halogen Group, -C _1-6 alkyl or -C _1-6 haloalkyl; R ^4N is H, -CD ₃ or -C _1-6 alkyl; R ⁷ is OH, NR ⁸ R ⁹ , -O(CH ₂ ) _q NR ⁸ R ⁹ , C _1-6 alkoxy or C _2-6 hydroxyalkoxy; R ^{10 is} independently H, -CD ₃ , C _1-6 alkyl, C _3-6 cycloalkane Group, C _2-6 hydroxyalkyl, C _1-6 alkoxy-C _1-6 alkyl or C _2-6 alkyl-NR ⁸ R ⁹ ; or alternatively, two R ¹⁰ groups on the same N atom Together, they form a heterocycle of 3-7 members. The heterocycle is optionally selected from up to three hydroxy, C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _1-6 alkoxy-C _{1- 6} alkyl, C _1-6 alkoxy-C _1-6 alkoxy, C _2-6 hydroxyalkoxy, pendant, thiocarbonyl, cyano or halo substituent substitution; p=0, 1, 2, 3 or 4; q=2, 3 or 4; and x=0, 1 or 2.

In one embodiment of the compound of formula (DI), X ² is CH or CR ⁴ ; R ⁴ is methyl, ethyl, or isopropyl; R ^4c is cyano, -CF ₃ , Cl, or F; R ^4N is -CD ₃ , methyl, ethyl or isopropyl; and R ^4b is H, halo, methyl, ethyl or isopropyl.

或

，其中w為1、 2、3、4或5。在式(D-I)化合物之一實施例中，R³為-N(R¹⁰)(C_2-6烷基)-NR¹⁰R¹⁰，其中同一N原子上之兩個R¹⁰合起來形成3-7個成員之雜環，該雜環視情況經多達三個選自羥基、C_1-6烷氧基、C_1-6羥基烷基、C_1-6烷氧基-C_1-6烷基、C_1-6烷氧基-C_1-6烷氧基、C_2-6羥基烷氧基、側氧基、硫羰基、氰基或鹵基之取代基取代。在 式(D-I)化合物之一實施例中，R³為

，其中w為1、2、3、4或5。 在式(D-I)化合物之一實施例中，R³為

，其中w為1、2、3、4或5 且R¹⁰為H、-CD₃、甲基、乙基、丙基或異丙基。在式(D-I)化合物之一實施例中，R³為-N(R¹⁰)(C_2-6烷基)-NR¹⁰R¹⁰，其中C_2-6烷基為直鏈或分支鏈。在式(D-I)化合物之一實施例中，R³為-N(R¹⁰)(C_2-6烷基)-NR¹⁰R¹⁰，其中C_2-6烷基為分支鏈。 In one embodiment of the compound of formula (DI), R ³ is -N(R ¹⁰ )(C _3-10 cycloalkylalkyl)-NR ¹⁰ R ¹⁰ , where C _3-10 cycloalkylalkyl is selected from:

or

, Where w is 1, 2, 3, 4, or 5. In one embodiment of the compound of formula (DI), R ³ is -N(R ¹⁰ )(C _2-6 alkyl)-NR ¹⁰ R ¹⁰ , where two R ¹⁰ on the same N atom are combined to form 3- 7-membered heterocyclic ring, the heterocyclic ring is optionally selected from hydroxy, C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _1-6 alkoxy-C _1-6 alkyl, C _1-6 alkoxy-C _1-6 alkoxy, C _2-6 hydroxyalkoxy, pendant, thiocarbonyl, cyano or halo substituent substitution. In one embodiment of the compounds of formula (DI), R ³ is

, Where w is 1, 2, 3, 4, or 5. In one embodiment of the compounds of formula (DI), R ³ is

, Where w is 1, 2, 3, 4 or 5 and R ¹⁰ is H, -CD ₃ , methyl, ethyl, propyl or isopropyl. In one embodiment of the compound of formula (DI), R ³ is -N(R ¹⁰ )(C _2-6 alkyl)-NR ¹⁰ R ¹⁰ , where C _2-6 alkyl is a linear or branched chain. In one embodiment of the compound of formula (DI), R ³ is -N(R ¹⁰ )(C _2-6 alkyl)-NR ¹⁰ R ¹⁰ , where C _2-6 alkyl is a branched chain.

In one embodiment of the compound of formula (DI), R ¹⁰ is H, —CD ₃ , methyl, ethyl, propyl, or isopropyl.

In one embodiment of the compound of formula (DI), X ² is N; R ^4c is cyano, -CF ₃ , Cl, or F; R ^4N is -CD ₃ , methyl, ethyl, or isopropyl; and R ^4b is H, halo, methyl, ethyl or isopropyl.

In one embodiment of the compounds of formula (DI), X ² is N and X ⁷ is CH.

或其立體異構體或醫藥學上可接受之鹽、溶劑合物、酯或前藥；其中，Z為CH或N；X²、X³、X⁶及X⁷各自為CH、CR⁴或N；R¹為氫、氟、氯、溴、甲基、乙基、羥基、甲氧基、乙氧基、異丙氧基、環丙氧基、-OCF₃、-OCH₂CF₃、-OCH₂CHF₂、乙烯基、乙炔基、CF₃、CHF₂、CHO、CH₂OH、CONH₂、CO₂Me、CONHMe、CONMe₂或氰基；R²為-OCF₃、-OCHF₂、-OCF₂CF₃、-OCH₂CHF₂、-OCH₂CF₃、環丙基、環丙氧基、甲氧基、-OCD₃、乙氧基或異丙氧基；R³為N(R¹⁰)C_2-6烷基-NR¹⁰R¹⁰；R⁴各自獨立地為H、氰基、鹵基、-C_1-6烷基、-C_1-6鹵烷基、羧基-C_1-6烷基、-C_1-6羥基烷基、R⁸R⁹N-C_1-6烷基-、-C_2-6烯基、-C_2-6炔基、C_1-6醯基-、R⁷-(CH₂)_pC(=O)-、 C_1-6羥基烷基-C(=O)-、羧基、-C_1-6烷氧基羰基、-C(=O)NR⁸R⁹、羥基、烷氧基、C_1-6醯氧基、-NR⁸R⁹、C_1-6醯基-N(R¹⁰)-或R⁷SO₂-；且R⁸及R⁹獨立地為H、-CD₃、C_1-6烷基、C_3-6烯基、C_3-6炔基、C_3-8環烷基、C_3-8環烯基、C_1-C₆醯基、4-12員單環或二環雜環基、4-12員單環或二環雜環基-C₁-C₆烷基-、C_6-C₁₂芳基、5-12員雜芳基；且R⁸及R⁹可進一步獨立地經多達三個選自羥基、C_1-6烷氧基、C_1-6羥基烷基、C_2-6羥基烷氧基、側氧基、硫羰基、氰基或鹵基之取代基取代；或或者，R⁸及R⁹與其同時附接之N原子合起來形成4-7個成員之雜環，該雜環含有多達一個選自O、S或NR¹¹之其他雜原子，或形成7-12個成員之雜雙環，該雜雙環可為稠合、橋接或螺環，且含有多達兩個選自O、S(O)_x或NR¹¹之其他雜原子，且此等雜環視情況經多達三個選自羥基、C_1-6烷氧基、C_1-6羥基烷基、C_1-6烷氧基-C_1-6烷基、C_1-6烷氧基-C_1-6烷氧基、C_2-6羥基烷氧基、側氧基、硫羰基、氰基或鹵基之取代基取代；R^4N為H、-CD₃或-C_1-6烷基；R⁷為OH、NR⁸R⁹、-O(CH₂)_qNR⁸R⁹、C_1-6烷氧基或C_2-6羥基烷氧基；R¹⁰各自獨立地為H、-CD₃、C_1-6烷基、C_3-6環烷基、C_2-6羥基烷基、C_1-6烷氧基-C_1-6烷基或C_2-6烷基-NR⁸R⁹；p=0、1、2、3或4；q=2、3或4；且x=0、1或2。 In one embodiment, the compound of the present invention has the structure of formula (E):

Or its stereoisomers or pharmaceutically acceptable salts, solvates, esters or prodrugs; where Z is CH or N; X ² , X ³ , X ⁶ and X ⁷ are each CH, CR ⁴ or N; R ¹ is hydrogen, fluorine, chlorine, bromine, methyl, ethyl, hydroxy, methoxy, ethoxy, isopropoxy, cyclopropoxy, -OCF ₃ , -OCH ₂ CF ₃ ,- OCH ₂ CHF ₂ , vinyl, ethynyl, CF ₃ , CHF ₂ , CHO, CH ₂ OH, CONH ₂ , CO ₂ Me, CONHMe, CONMe ₂ or cyano; R ² is -OCF ₃ , -OCHF ₂ ,- OCF ₂ CF ₃ , -OCH ₂ CHF ₂ , -OCH ₂ CF ₃ , cyclopropyl, cyclopropoxy, methoxy, -OCD ₃ , ethoxy, or isopropoxy; R ³ is N(R ¹⁰ ) C _2-6 alkyl-NR ¹⁰ R ¹⁰ ; R ^{4 is} independently H, cyano, halo, -C _1-6 alkyl, -C _1-6 haloalkyl, carboxy-C _1-6 Alkyl, -C _1-6 hydroxyalkyl, R ⁸ R ⁹ NC _1-6 alkyl-, -C _2-6 alkenyl, -C _2-6 alkynyl, C _1-6 acetyl-, R ⁷ -(CH ₂ ) _p C(=O)-, C _1-6 hydroxyalkyl-C(=O)-, carboxyl, -C _1-6 alkoxycarbonyl, -C(=O)NR ⁸ R ⁹ , Hydroxy, alkoxy, C _1-6 acetyl, -NR ⁸ R ⁹ , C _1-6 acetyl-N(R ¹⁰ )- or R ⁷ SO ₂ -; and R ⁸ and R ^{9 are} independently H, -CD ₃ , C _1-6 alkyl, C _3-6 alkenyl, C _3-6 alkynyl, C _3-8 cycloalkyl, C _3-8 cycloalkenyl, C _1- C ₆ acetyl , 4-12 membered monocyclic or bicyclic heterocyclyl, 4-12 membered monocyclic or bicyclic heterocyclyl-C ₁ -C ₆ alkyl-, C _6- C ₁₂ aryl, 5-12 membered heteroaryl Radicals; and R ⁸ and R ⁹ can be further independently selected by up to three hydroxy, C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _2-6 hydroxyalkoxy, pendant, sulfur Carbonyl, cyano or halo substituent substitution; or alternatively, R ⁸ and R ⁹ together with the N atom to which they are simultaneously attached form a heterocyclic ring of 4-7 members, the heterocyclic ring containing up to one selected from O, S or NR ¹¹ other heteroatom, or form a heterobicyclic ring of 7-12 members, the heterobicyclic ring may be fused, bridged or spiro ring, and contains up to two selected from O, S (O) _x or NR ¹¹ other heteroatoms, and these heterocycles are optionally selected from up to three hydroxy, C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _1-6 alkoxy-C _1-6 alkyl , C _1-6 alkoxy-C _1-6 alkoxy, C _2-6 hydroxyalkoxy, pendant, thiocarbonyl, cyano or halo substituent substitution; R ^4N is H, -CD ₃ or -C _1-6 alkyl; R ⁷ is OH, NR ⁸ R ⁹ , -O(CH ₂ ) _q NR ⁸ R ⁹ , C _1-6 alkoxy or C _2-6 Hydroxyalkoxy; R ^{10 is} each independently H, -CD ₃ , C _1-6 alkyl, C _3-6 cycloalkyl, C _2-6 hydroxyalkyl, C _1-6 alkoxy-C _{1 -6} alkyl or C _2-6 alkyl-NR ⁸ R ⁹ ; p=0, 1, 2, 3 or 4; q=2, 3 or 4; and x=0, 1 or 2.

In one embodiment, R ¹⁰ in formula (E) is independently -CD ₃ , C _1-6 alkyl, C _3-6 cycloalkyl, C _2-6 hydroxyalkyl, C _1-6 alkoxy Group -C _1-6 alkyl or C _2-6 alkyl-NR ⁸ R ⁹ .

或其立體異構體或醫藥學上可接受之鹽、溶劑合物、酯或前藥；其中，Z為CH或N；X⁶及X⁷各自為CH、CR⁴或N；R¹獨立地選自氫、氟、氯、溴、甲基、乙基、羥基、甲氧基、乙氧基、異丙氧基、環丙氧基、-OCF₃、-OCH₂CF₃、-OCH₂CHF₂、乙烯基、乙炔基、CF₃、CHF₂、CHO、CH₂OH、CONH₂、CO₂Me、CONHMe、CONMe₂及氰基；R²為-OCF₃、-OCHF₂、-OCF₂CF₃、-OCH₂CHF₂、-OCH₂CF₃、環丙基、環丙氧基、甲氧基、-OCD₃、乙氧基或異丙氧基；R³為N(R¹⁰)C_2-6烷基-NR¹⁰R¹⁰；R⁴各自獨立地為H、氰基、鹵基、-C_1-6烷基、-C_1-6鹵烷基、羧基-C_1-6烷基、-C_1-6羥基烷基、R⁸R⁹N-C_1-6烷基-、-C_2-6烯基、-C_2-6炔基、C_1-6醯基-、R⁷-(CH₂)_pC(=O)-、C_1-6羥基烷基-C(=O)-、羧基、-C_1-6烷氧基羰基、-C(=O)NR⁸R⁹、羥基、烷氧基、C_1-6醯氧基、-NR⁸R⁹、C_1-6醯基-N(R¹⁰)-、R⁷SO₂-，R^4a及R^4b各自獨立地為H、鹵基、-C_1-6烷基或-C_1-6鹵烷基； R^4c為氰基、C_1-6醯基-、-C(=O)NR⁸R⁹、羥基、烷氧基或F；R^4N為H、-CD₃、-C_1-6烷基或-C_1-6鹵烷基；R⁷為OH、NR⁸R⁹、O(CH₂)_qNR⁸R⁹、C_1-6烷氧基或C_2-6羥基烷氧基；R⁸及R⁹獨立地為H、-CD₃、C_1-6烷基、C_3-6烯基、C_3-6炔基、C_3-8環烷基、C_3-8環烯基、C_1-C₆醯基、4-12員單環或二環雜環基、4-12員單環或二環雜環基-C₁-C₆烷基-、C_6-C₁₂芳基、5-12員雜芳基；且R⁸及R⁹可進一步獨立地經多達三個選自羥基、C_1-6烷氧基、C_1-6羥基烷基、C_2-6羥基烷氧基、側氧基、硫羰基、氰基或鹵基之取代基取代；或R¹⁰各自獨立地為H、-CD₃、C_1-6烷基、C_3-6環烷基、C_2-6羥基烷基、C_1-6烷氧基-C_1-6烷基或C_2-6烷基-NR⁸R⁹；或p=0、1、2、3或4；且q=2、3或4。 In one embodiment, the compound of the present invention has the structure of formula (F) or (G):

Or its stereoisomer or pharmaceutically acceptable salt, solvate, ester or prodrug; where Z is CH or N; X ⁶ and X ⁷ are each CH, CR ⁴ or N; R ^{1 is} independently Selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, hydroxyl, methoxy, ethoxy, isopropoxy, cyclopropoxy, -OCF ₃ , -OCH ₂ CF ₃ , -OCH ₂ CHF _2. Vinyl, ethynyl, CF ₃ , CHF ₂ , CHO, CH ₂ OH, CONH ₂ , CO ₂ Me, CONHMe, CONMe ₂ and cyano; R ² is -OCF ₃ , -OCHF ₂ , -OCF ₂ CF ₃ , -OCH ₂ CHF ₂ , -OCH ₂ CF ₃ , cyclopropyl, cyclopropoxy, methoxy, -OCD ₃ , ethoxy, or isopropoxy; R ³ is N(R ¹⁰ )C _{2 -6} alkyl-NR ¹⁰ R ¹⁰ ; R ^{4 is} independently H, cyano, halo, -C _1-6 alkyl, -C _1-6 haloalkyl, carboxy-C _1-6 alkyl, -C _1-6 hydroxyalkyl, R ⁸ R ⁹ NC _1-6 alkyl-, -C _2-6 alkenyl, -C _2-6 alkynyl, C _1-6 acetyl-, R ⁷ -(CH ₂ ) _p C(=O)-, C _1-6 hydroxyalkyl-C(=O)-, carboxyl, -C _1-6 alkoxycarbonyl, -C(=O)NR ⁸ R ⁹ , hydroxyl, Alkoxy, C _1-6 acetyloxy, -NR ⁸ R ⁹ , C _1-6 acetyl-N(R ¹⁰ )-, R ⁷ SO ₂ -, R ^4a and R ^4b are each independently H, halogen Group, -C _1-6 alkyl or -C _1-6 haloalkyl; R ^4c is cyano, C _1-6 acetyl-, -C(=O)NR ⁸ R ⁹ , hydroxyl, alkoxy or F; R ^4N is H, -CD ₃ , -C _1-6 alkyl or -C _1-6 haloalkyl; R ⁷ is OH, NR ⁸ R ⁹ , O(CH ₂ ) _q NR ⁸ R ⁹ , C _1-6 alkoxy or C _2-6 hydroxyalkoxy; R ⁸ and R ^{9 are} independently H, -CD ₃ , C _1-6 alkyl, C _3-6 alkenyl, C _3-6 alkynyl , C _3-8 cycloalkyl, C _3-8 cycloalkenyl, C _1- C ₆ acetyl, 4-12 membered monocyclic or bicyclic heterocyclic group, 4-12 membered monocyclic or bicyclic heterocyclic group -C ₁ -C ₆ alkyl-, C _6- C ₁₂ aryl, 5-12 membered heteroaryl; and R ⁸ and R ⁹ can be further independently selected from up to three hydroxy, C _1-6 alkoxy Group, C _1-6 hydroxyalkyl, C _2-6 hydroxyalkoxy, pendant, thiocarbonyl, cyano or halo substituents; or R ¹⁰ are each independently H, -CD ₃ , C _1-6 alkyl, C _3-6 cycloalkyl, C _2-6 hydroxyalkyl, C _1-6 alkoxy-C _1-6 alkyl Or C _2-6 alkyl-NR ⁸ R ⁹ ; or p=0, 1, 2, 3, or 4; and q=2, 3, or 4.

In one embodiment, R ¹⁰ in formula (F) and/or (G) are each independently -CD ₃ , C _1-6 alkyl, C _3-6 cycloalkyl, C _2-6 hydroxyalkyl , C _1-6 alkoxy-C _1-6 alkyl or C _2-6 alkyl-NR ⁸ R ⁹ .

In one embodiment, Formula (D), (DI), (E), (EI), (F) and / or (G) R ³ is in the N (R ¹⁰⁾ C _2-6 alkyl -NR ¹⁰ R ¹⁰ . In one embodiment, R ³ is -N(CH ₃ )CH ₂ CH ₂ NR ¹⁰ R ¹⁰ .

In another embodiment, R ¹⁰ in formulas (D), (DI), (E), (EI), (F), and/or (G) are each independently H, -CD ₃ , C _{1- 6} alkyl, C _3-6 cycloalkyl or C _2-6 hydroxyalkyl. In other embodiments, each R ^{10 is} independently H, —CD ₃ , methyl, ethyl, or isopropyl.

In another embodiment, R ¹⁰ in formulas (D), (DI), (E), (EI), (F), and/or (G) are each independently -CD ₃ , C _1-6 alkyl Group, C _3-6 cycloalkyl or C _2-6 hydroxyalkyl. In other embodiments, each R ^{10 is} independently -CD ₃ , methyl, ethyl, or isopropyl.

In one embodiment, Formula (D), (DI), (E), (EI), (F) and / or (G) in the R ¹ is hydrogen, methyl, fluoro, chloro, bromo, CF ₃ Or cyano. In another embodiment, R ¹ is H.

In one embodiment, R ^4c in formulas (D), (DI) and/or (F) is -CN.

In one embodiment, the compounds of formula (D), (DI), (E), (EI), (F) and/or (G) are not

。在另一實施例中，式(D)、(D-I)、(E)、(E-I)、(F)及/或(G)化 合物為

、

、

、

或

或其立體異構體或醫藥學上可接受之鹽、溶 劑合物、酯或前藥。 In another embodiment, the compound of formula (D), (DI), (E), (EI), (F) and/or (G) is

. In another embodiment, the compound of formula (D), (DI), (E), (EI), (F) and/or (G) is

,

,

,

or

Or its stereoisomers or pharmaceutically acceptable salts, solvates, esters or prodrugs.

或其立體異構體或醫藥學上可接受之鹽、溶劑合物、酯或前 藥。在另一實施例中，該化合物為

。 In another embodiment, the compound of formula (D), (DI), (E), (EI), (F) and/or (G) is

Or its stereoisomers or pharmaceutically acceptable salts, solvates, esters or prodrugs. In another embodiment, the compound is

.

或其立體異構體或醫藥學上可接受之鹽、溶劑合物、N-氧化物、酯或前藥，其中Z為CH或N；R¹為氫、氟、氯、溴、甲基、乙基、羥基、甲氧基、乙氧基、異丙氧基、環丙氧基、-OCF₃、-OCH₂CF₃、-OCH₂CHF₂、乙烯基、乙炔基、CF₃、CHF₂、CHO、CH₂OH、CONH₂、CO₂Me、CONHMe、CONMe₂或氰基；R²為-OCF₃、-OCHF₂、-OCF₂CF₃、-OCH₂CHF₂、-OCH₂CF₃、環丙基、環丙氧基、甲氧基、-OCD₃、乙氧基或異丙氧基；R³為N(R¹⁰)C_2-6烷基-NR¹⁰R¹⁰或-N(R¹⁰)(C_3-10環烷基烷基)-NR¹⁰R¹⁰；R⁴各自獨立地為H、氰基、鹵基、-C_1-6烷基、-C_1-6鹵烷基、羧基-C_1-6烷基、-C_1-6羥基烷基、R⁸R⁹N-C_1-6烷基-、-C_2-6烯基、-C_2-6炔基、C_1-6醯基-、R⁷-(CH₂)_pC(=O)-、C_1-6羥基烷基-C(=O)-、羧基、-C_1-6烷氧基羰基、-C(=O)NR⁸R⁹、羥基、烷氧基、C_1-6醯氧基、-NR⁸R⁹、C_1-6醯基-N(R¹⁰)-或R⁷SO₂-；且R⁸及R⁹獨立地為H、-CD₃、C_1-6烷基、C_3-6烯基、C_3-6炔基、C_3-8環烷基、C_3-8環烯基、C_1-C₆醯基、4-12員單環或二環雜環基、4-12員單環或二環雜環基-C₁-C₆烷基-、C_6-C₁₂芳基、5-12員雜芳基；且R⁸及R⁹可進一步獨立地經多達三個選自 羥基、C_1-6烷氧基、C_1-6羥基烷基、C_2-6羥基烷氧基、側氧基、硫羰基、氰基或鹵基之取代基取代；或或者，R⁸及R⁹與其同時附接之N原子合起來形成4-7個成員之雜環，該雜環含有多達一個選自O、S或NR¹¹之其他雜原子，或形成7-12個成員之雜雙環，該雜雙環可為稠合、橋接或螺環，且含有多達兩個選自O、S(O)_x或NR¹¹之其他雜原子，且此等雜環視情況經多達三個選自羥基、C_1-6烷氧基、C_1-6羥基烷基、C_1-6烷氧基-C_1-6烷基、C_1-6烷氧基-C_1-6烷氧基、C_2-6羥基烷氧基、側氧基、硫羰基、氰基或鹵基之取代基取代；R^4N為H、-CD₃或-C_1-6烷基；R⁷為OH、-NR⁸R⁹、-O(CH₂)_qNR⁸R⁹、C_1-6烷氧基或C_2-6羥基烷氧基；R¹⁰各自獨立地為H、-CD₃、C_1-6烷基、C_3-6環烷基、C_2-6羥基烷基、C_1-6烷氧基-C_1-6烷基或C_2-6烷基-NR⁸R⁹；或者，同一N原子上之兩個R¹⁰合起來形成3-7個成員之雜環，該雜環視情況經多達三個選自羥基、C_1-6烷氧基、C_1-6羥基烷基、C_1-6烷氧基-C_1-6烷基、C_1-6烷氧基-C_1-6烷氧基、C_2-6羥基烷氧基、側氧基、硫羰基、氰基或鹵基之取代基取代；p=0、1、2、3或4；q=2、3或4；且x=0、1或2。 In one embodiment, the invention relates to compounds of formula (EI):

Or its stereoisomer or pharmaceutically acceptable salt, solvate, N-oxide, ester or prodrug, wherein Z is CH or N; R ¹ is hydrogen, fluorine, chlorine, bromine, methyl, Ethyl, hydroxyl, methoxy, ethoxy, isopropoxy, cyclopropoxy, -OCF ₃ , -OCH ₂ CF ₃ , -OCH ₂ CHF ₂ , vinyl, ethynyl, CF ₃ , CHF ₂ , CHO, CH ₂ OH, CONH ₂ , CO ₂ Me, CONHMe, CONMe ₂ or cyano group; R ² is -OCF ₃ , -OCHF ₂ , -OCF ₂ CF ₃ , -OCH ₂ CHF ₂ , -OCH ₂ CF ₃ , Cyclopropyl, cyclopropoxy, methoxy, -OCD ₃ , ethoxy or isopropoxy; R ³ is N(R ¹⁰ )C _2-6 alkyl-NR ¹⁰ R ¹⁰ or -N( R ¹⁰ )(C _3-10 cycloalkylalkyl)-NR ¹⁰ R ¹⁰ ; R ^{4 is} each independently H, cyano, halo, -C _1-6 alkyl, -C _1-6 haloalkyl , Carboxy-C _1-6 alkyl, -C _1-6 hydroxyalkyl, R ⁸ R ⁹ NC _1-6 alkyl-, -C _2-6 alkenyl, -C _2-6 alkynyl, C _{1- 6} acetyl-, R ⁷ -(CH ₂ ) _p C(=O)-, C _1-6 hydroxyalkyl-C(=O)-, carboxyl, -C _1-6 alkoxycarbonyl, -C( =O) NR ⁸ R ⁹ , hydroxy, alkoxy, C _1-6 acetyl, -NR ⁸ R ⁹ , C _1-6 acetyl -N(R ¹⁰ )- or R ⁷ SO ₂ -; and R ⁸ and R ^{9 are} independently H, -CD ₃ , C _1-6 alkyl, C _3-6 alkenyl, C _3-6 alkynyl, C _3-8 cycloalkyl, C _3-8 cycloalkenyl, C _1- C ₆ acetyl, 4-12 membered monocyclic or bicyclic heterocyclyl, 4-12 membered monocyclic or bicyclic heterocyclyl-C ₁ -C ₆ alkyl-, C _6- C ₁₂ aryl , 5-12 membered heteroaryl; and R ⁸ and R ⁹ can be further independently selected from up to three selected from hydroxy, C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _2-6 hydroxyalkoxy Group, pendant, thiocarbonyl, cyano or halo; or alternatively, R ⁸ and R ⁹ together with the N atom to which they are attached at the same time form a heterocyclic ring of 4-7 members, the heterocyclic ring containing Up to one other heteroatom selected from O, S or NR ¹¹ , or forming a heterobicyclic ring of 7-12 members, the heterobicyclic ring may be fused, bridged or spiro ring, and contains up to two selected from O, S(O) _x or other hetero atoms of NR ¹¹ , and these heterocycles may optionally be selected from up to three hydroxy, C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _1-6 alkoxy -C _1-6 alkyl, C _1-6 alkoxy-C _1-6 alkoxy, C _2-6 hydroxyalkoxy, pendant, thiocarbonyl, cyano or halo Substituent substitution; R ^4N is H, -CD ₃ or -C _1-6 alkyl; R ⁷ is OH, -NR ⁸ R ⁹ , -O(CH ₂ ) _q NR ⁸ R ⁹ , C _1-6 alkoxy Group or C _2-6 hydroxyalkoxy; R ^{10 is} each independently H, -CD ₃ , C _1-6 alkyl, C _3-6 cycloalkyl, C _2-6 hydroxyalkyl, C _1-6 Alkoxy-C _1-6 alkyl or C _2-6 alkyl-NR ⁸ R ⁹ ; alternatively, two R ¹⁰ on the same N atom combine to form a heterocyclic ring of 3-7 members, the heterocyclic ring is optional Up to three selected from hydroxy, C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _1-6 alkoxy-C _1-6 alkyl, C _1-6 alkoxy-C _{1- 6} alkoxy, C _2-6 hydroxyalkoxy, pendant, thiocarbonyl, cyano or halo substituent substitution; p=0, 1, 2, 3 or 4; q=2, 3 or 4 ; And x=0, 1, or 2.

In some embodiments of the compound of formula (EI), R ³ is N(R ¹⁰ )C _2-6 alkyl-NR ¹⁰ R ¹⁰ or -N(R ¹⁰ )(C _3-10 cycloalkylalkyl)- NR ¹⁰ R ¹⁰ ; R ^{4 is} independently H, cyano, halo, -C _1-6 alkyl or -C _1-6 haloalkyl; and R ^4N is H, -CD ₃ or -C _{1- 6} alkyl; and R ^{10 is} each independently H, -CD ₃ or -C _1-6 alkyl.

或其 立體異構體或醫藥學上可接受之鹽、溶劑合物、N-氧化物、酯或前藥。 In some embodiments of the compound of formula (EI), the compound is

Or its stereoisomers or pharmaceutically acceptable salts, solvates, N-oxides, esters or prodrugs.

或其立體異構體或醫藥學上可接受之鹽、溶劑合物、酯或前藥；其中，X⁷為CH或N；X²獨立地為CH、CCH₃或N；R²為甲氧基、-OCD₃、乙氧基或異丙氧基；R^4b為H、F、Cl或CH₃；R^4N為H、-CD₃、CH₃、Et或CH(CH₃)₂；且R¹⁰各自獨立地為H、-CD₃、-CH₃、-CH₂CH₃或-CH(CH₃)₂。 In one embodiment, the compound of the present invention has the structure of formula (H)

Or its stereoisomer or pharmaceutically acceptable salt, solvate, ester or prodrug; where X ⁷ is CH or N; X ^{2 is} independently CH, CCH ₃ or N; R ² is methoxy Radical, -OCD ₃ , ethoxy or isopropoxy; R ^4b is H, F, Cl or CH ₃ ; R ^4N is H, -CD ₃ , CH ₃ , Et or CH(CH ₃ ) ₂ ; and R ¹⁰ are each independently H, -CD ₃ , -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ .

In one embodiment, the compound of structure (H) comprises: X ⁷ is CH or N; X ^{2 is} independently CH or CCH ₃ ; R ² is methoxy, -OCD ₃ , ethoxy or isopropoxy; R ^4b is H, F, Cl, or CH ₃ ; R ^4N is H, -CD ₃ , CH ₃ , Et, or CH(CH ₃ ) ₂ ; and R ^{10 is} independently H, -CD ₃ , -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ .

或其立體異構體或醫藥學上可接受之鹽、溶劑合物、酯或前藥；其中，X⁷為CH或N；X²獨立地為CH、CCH₃或N；R²為甲氧基、-OCD₃、乙氧基或異丙氧基；R^4b為H、F、Cl或CH₃；R^4N為H、-CD₃、CH₃、Et或CH(CH₃)₂；且R¹⁰各自獨立地為-CD₃、-CH₃、-CH₂CH₃或-CH(CH₃)₂。 In one embodiment, the compound of the present invention has the structure of formula (HI)

Or its stereoisomer or pharmaceutically acceptable salt, solvate, ester or prodrug; where X ⁷ is CH or N; X ^{2 is} independently CH, CCH ₃ or N; R ² is methoxy Radical, -OCD ₃ , ethoxy or isopropoxy; R ^4b is H, F, Cl or CH ₃ ; R ^4N is H, -CD ₃ , CH ₃ , Et or CH(CH ₃ ) ₂ ; and R ¹⁰ are each independently -CD ₃ , -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ .

In one embodiment, the compound of structure (H) comprises: X ⁷ is CH or N; X ^{2 is} independently CH or CCH ₃ ; R ² is methoxy, -OCD ₃ , ethoxy, or isopropoxy; R ^4b is H, F, Cl, or CH ₃ ; R ^4N is H, -CD ₃ , CH ₃ , Et, or CH(CH ₃ ) ₂ ; and R ^{10 is} independently H, -CD ₃ , -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ .

In one embodiment, Formula (D), (DI), (E), (EI), (F), (G) and / or (H), the R ¹⁰ is H, -CD ₃ or -CH ₃ . In some embodiments, Formula (D), (DI), (E), (EI), (F), (G), (H) and / or (HI) in the -CD ₃ or R ¹⁰ is - CH ₃ . In another embodiment, Formula (D), (DI), (E), (EI), (F), in the (G), (H) and / or (HI) R ¹⁰ is -CH _3.

In one embodiment, Formula (D), (DI), (E), (EI), (F), (G), (H) and / or (HI) in the R ² is methoxy, - OCD ₃ , ethoxy or isopropoxy. In another embodiment, R ² is methoxy.

In one embodiment, R ^4b in formulas (D), (DI), (E), (EI), (F), (G), (H), and/or (HI) is H or CH ₃ . In another embodiment, R ^4N in formulas (D), (DI), (E), (EI), (F), (G), (H), and/or (HI) is H or CH ₃ .

In one embodiment, X ⁷ in formulas (D), (DI), (E), (EI), (F), (G), (H), and/or (HI) is CH. In another embodiment, X ⁷ is N.

In one embodiment, X ² in formulas (D), (DI), (E), (EI), (F), (G), (H), and/or (HI) is CH. In another embodiment, X ² is N.

In one embodiment, X ² in formula (H) and/or (HI) is CH or CCH ₃ .

In one embodiment, R ¹⁰ in formula (H) is H, -CD ₃ or -CH ₃ . In some embodiments, R ¹⁰ in formula (H) and/or (HI) is -CD ₃ or -CH ₃ . In another embodiment, R ¹⁰ in formula (H) and/or (HI) is -CH ₃ .

In one embodiment, R ² in formula (H) and/or (HI) is methoxy, -OCD ₃ , ethoxy, or isopropoxy. In another embodiment, R ² is methoxy.

In one embodiment, R ^4b in formula (H) and/or (HI) is H or CH ₃ . In another embodiment, R ^4N in formula (H) and/or (HI) is H or CH ₃ .

In one embodiment, X ⁷ in formula (H) and/or (HI) is CH. In another embodiment, X ⁷ is N.

In one embodiment, X ² in formula (H) and/or (HI) is CH. In another embodiment, X ² is N.

In one embodiment of formula (H), X ⁷ is CH or N; X ^{2 is} independently CH or CCH ₃ ; R ² is methoxy, -OCD ₃ , ethoxy, or isopropoxy; R ^4b Is H, F, Cl or CH ₃ ; R ^4N is H, -CD ₃ , CH ₃ , Et or CH(CH ₃ ) ₂ ; and R ^{10 is} each independently H, -CD ₃ , -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ .

In one embodiment of the compounds of formula (H) and/or (HI), X ⁷ is CH; X ² is CH; R ² is methoxy, -OCD ₃ , ethoxy, or isopropoxy; R ^4b Is H, F, Cl, or CH ₃ ; R ^4N is H, -CD ₃ , CH ₃ , Et, or CH(CH ₃ ) ₂ ; and R ^{10 is} independently -CD ₃ , -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ .

In one embodiment of the compounds of formula (H) and/or (HI), X ⁷ is CH; X ² is CH; R ² is methoxy, -OCD ₃ , ethoxy, or isopropoxy; R ^4b Is F, Cl, or CH ₃ ; R ^4N is -CD ₃ , CH ₃ , Et, or CH(CH ₃ ) ₂ ; and R ^{10 is} independently -CD ₃ , -CH ₃ , -CH ₂ CH _3, or -CH (CH ₃ ) ₂ .

或其立體異構體或醫藥學上可接受之鹽、溶劑合物、酯或前藥；其中，X⁶為N或C-R⁴，其中R⁴為H、氰基、CONH₂、CONHCH₃、CON(CH₃)₂、COCH₃；X²獨立地為C-H、C-CH₃或N；X³獨立地為C-H、C-CH₃、C-CF₃、C-CHF₂、C-F、C-Cl或N；R^4N為H、-CD₃、-CH₃、-CH₂CH₃或-CH(CH₃)₂；R²為-OCF₃、-OCHF₂、-OCF₂CF₃、-OCH₂CHF₂、-OCH₂CF₃、環丙基、環丙氧基、甲氧基、-OCD₃、乙氧基或異丙氧基；R¹⁰各自獨立地為H、-CD₃、C_1-6烷基、C_3-6環烷基、C_2-6羥基烷基、C_1-6烷氧基-C_1-6烷基或C_2-6烷基-NR⁸R⁹；且 R⁸及R⁹獨立地為H、-CD₃、C_1-6烷基、C_3-6烯基、C_3-6炔基、C_3-8環烷基、C_3-8環烯基、C_1-C₆醯基、4-12員單環或二環雜環基、4-12員單環或二環雜環基-C₁-C₆烷基-、C_6-C₁₂芳基、5-12員雜芳基；且R⁸及R⁹可進一步獨立地經多達三個選自羥基、C_1-6烷氧基、C_1-6羥基烷基、C_2-6羥基烷氧基、側氧基、硫羰基、氰基或鹵基之取代基取代。 In one embodiment, the compound of the present invention has the structure of formula (J):

Or its stereoisomers or pharmaceutically acceptable salts, solvates, esters or prodrugs; where X ⁶ is N or CR ⁴ , where R ⁴ is H, cyano, CONH ₂ , CONHCH ₃ , CON (CH ₃ ) ₂ , COCH ₃ ; X ^{2 is} independently CH, C-CH ₃ or N; X ^{3 is} independently CH, C-CH ₃ , C-CF ₃ , C-CHF ₂ , CF, C-Cl Or N; R ^4N is H, -CD ₃ , -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ ; R ² is -OCF ₃ , -OCHF ₂ , -OCF ₂ CF ₃ , -OCH ₂ CHF ₂ , -OCH ₂ CF ₃ , cyclopropyl, cyclopropoxy, methoxy, -OCD ₃ , ethoxy, or isopropoxy; R ^{10 is} each independently H, -CD ₃ , C _{1- 6} alkyl, C _3-6 cycloalkyl, C _2-6 hydroxyalkyl, C _1-6 alkoxy-C _1-6 alkyl or C _2-6 alkyl-NR ⁸ R ⁹ ; and R ⁸ And R ^{9 is} independently H, -CD ₃ , C _1-6 alkyl, C _3-6 alkenyl, C _3-6 alkynyl, C _3-8 cycloalkyl, C _3-8 cycloalkenyl, C _1- C ₆ acetyl, 4-12 membered monocyclic or bicyclic heterocyclyl, 4-12 membered monocyclic or bicyclic heterocyclyl-C ₁ -C ₆ alkyl-, C _6- C ₁₂ aryl, 5-12 membered heteroaryl groups; and R ⁸ and R ⁹ may be independently selected from up to three further selected from hydroxy, C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _2-6 hydroxyalkoxy , Pendant, thiocarbonyl, cyano or halo substituents.

In one embodiment, R ¹⁰ in formula (J) is each -CD ₃ , C _1-6 alkyl, C _3-6 cycloalkyl, C _2-6 hydroxyalkyl, C _1-6 alkoxy -C _1-6 alkyl or C _2-6 alkyl-NR ⁸ R ⁹ .

In one embodiment, the compound of formula (J) comprises: X ⁶ is C-CN; X ² is CH or C-CH ₃ ; X ³ is CH or C-CH ₃ ; R ^4N is H, -CD ₃ ,- CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ ; R ² is methoxy, -OCD ₃ , ethoxy or isopropoxy; and R ^{10 is} each independently H, -CD ₃ , -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ .

In one embodiment, X ⁶ in formula (J) is C-CN. In another embodiment, X ² in formula (J) is CH or C-CH ₃ . In another embodiment, X ³ in formula (J) is CH or C-CH ₃ .

In some embodiments, R ^4N in formula (J) is H, —CD ₃ , —CH ₃ , —CH ₂ CH ₃ or —CH(CH ₃ ) ₂ . In other embodiments, R ^4N is H or -CH ₃ .

In one embodiment, R ² in formula (J) is methoxy, -OCD ₃ , ethoxy, or isopropoxy. In another embodiment, R ² is methoxy.

In some embodiments, R ¹⁰ in formula (J) is each independently H, -CD ₃ , -CH ₃ , -CH ₂ CH _3, or -CH(CH ₃ ) ₂ . In another embodiment, R ¹⁰ is -CD ₃ , -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ . In other embodiments, R ¹⁰ is -CH ₃ .

或其立體異構體或醫藥學上可接受之鹽、溶劑合物、酯或前藥；其中，Z為CH或N；X²為CR^4a或N；X⁶為CR^4b或N；X⁸為CH或N；R¹為氫、甲基、氟、氯、溴、CF₃或氰基；R²為-OCF₃、-OCHF₂、-OCF₂CF₃、-OCH₂CHF₂、-OCH₂CF₃、環丙氧基、甲氧基、-OCD₃、乙氧基或異丙氧基；R³為N(R¹⁰)C_2-6烷基-NR¹⁰R¹⁰；R^4a為H、氰基、鹵基、-C_1-6烷基或-C_1-6鹵烷基；R^4b為H、氰基、硝基、鹵基、-C_1-6烷基、-C_1-6鹵烷基、羧基-C_1-6烷基、-C_1-6羥基烷基、R⁸R⁹N-C_1-6烷基-、-C_2-6烯基、-C_2-6炔基、C_1-6醯基-、R⁷-(CH₂)_pC(=O)-、C_1-6羥基烷基-C(=O)-、羧基、-C_1-6烷氧基羰基、-C(=O)NR⁸R⁹、羥基、烷氧基、-OCD₃、C_1-6醯氧基、-NR⁸R⁹、C_1-6醯基-N(R¹⁰)-或R⁷SO₂-；R^4N為H、-C_1-6烷基或-CD₃； R⁸及R⁹獨立地為H、-CD₃、C_1-6烷基、C_3-8環烷基、C_3-8環烷基-(C_1-3烷基)-、C_1-C₆醯基、苯基、單環雜芳基或單環雜環基；且R⁸及R⁹可進一步獨立地經多達三個選自羥基、C_1-6烷氧基、側氧基、硫羰基、氰基或鹵基之取代基取代；或或者，R⁸及R⁹與其同時附接之N原子合起來形成4-7個成員之雜環，該雜環含有多達一個選自O、S或NR¹¹之其他雜原子，或形成7-12個成員之雜雙環，該雜雙環可為稠合、橋接或螺環，且含有多達兩個選自O、S(O)_x或NR¹¹之其他雜原子，且此等雜環視情況經多達三個選自羥基、C_1-6烷氧基、C_1-6羥基烷基、C_1-6烷氧基-C_1-6烷基、C_1-6烷氧基-C_1-6烷氧基、C_2-6羥基烷氧基、側氧基、硫羰基、氰基或鹵基之取代基取代；R¹⁰各自獨立地為H、-CD₃、C_1-6烷基、C_3-6環烷基、C_2-6羥基烷基、C_1-6烷氧基-C_1-6烷基或C_2-6烷基-NR⁸R⁹；p=0、1、2、3或4；q=2、3或4；且x=0、1或2。 In one embodiment, the compound of the present invention has the structure of formula (K):

Or its stereoisomer or pharmaceutically acceptable salt, solvate, ester or prodrug; where Z is CH or N; X ² is CR ^4a or N; X ⁶ is CR ^4b or N; X ⁸ CH or N; R ¹ is hydrogen, methyl, fluorine, chlorine, bromine, CF ₃ or cyano; R ² is -OCF ₃ , -OCHF ₂ , -OCF ₂ CF ₃ , -OCH ₂ CHF ₂ , -OCH ₂ CF ₃ , cyclopropoxy, methoxy, -OCD ₃ , ethoxy or isopropoxy; R ³ is N(R ¹⁰ )C _2-6 alkyl-NR ¹⁰ R ¹⁰ ; R ^4a is H , Cyano, halo, -C _1-6 alkyl or -C _1-6 haloalkyl; R ^4b is H, cyano, nitro, halo, -C _1-6 alkyl, -C _{1- 6} haloalkyl, carboxy-C _1-6 alkyl, -C _1-6 hydroxyalkyl, R ⁸ R ⁹ NC _1-6 alkyl-, -C _2-6 alkenyl, -C _2-6 alkynyl , C _1-6 acetyl-, R ⁷ -(CH ₂ ) _p C(=O)-, C _1-6 hydroxyalkyl-C(=O)-, carboxyl, -C _1-6 alkoxycarbonyl , -C(=O)NR ⁸ R ⁹ , hydroxyl, alkoxy, -OCD ₃ , C _1-6 acetyloxy, -NR ⁸ R ⁹ , C _1-6 acetyl-N(R ¹⁰ )- or R ⁷ SO ₂ -; R ^4N is H, -C _1-6 alkyl or -CD ₃ ; R ⁸ and R ^{9 are} independently H, -CD ₃ , C _1-6 alkyl, C _3-8 cycloalkane Group, C _3-8 cycloalkyl-(C _1-3 alkyl)-, C _1- C ₆ acetyl, phenyl, monocyclic heteroaryl or monocyclic heterocyclic group; and R ⁸ and R ⁹ may be Further independently substituted with up to three substituents selected from the group consisting of hydroxy, C _1-6 alkoxy, pendant, thiocarbonyl, cyano or halo; or alternatively, R ⁸ and R ⁹ are simultaneously attached to N Together, the atoms form a 4-7 member heterocycle, which contains up to one other heteroatom selected from O, S, or NR ¹¹ , or a 7-12 member heterobicycle, which may be fused Combined, bridged or spiro ring, and containing up to two other heteroatoms selected from O, S(O) _x or NR ¹¹ , and these heterocycles may optionally be selected from up to three selected from hydroxyl, C _1-6 alkoxy Group, C _1-6 hydroxyalkyl, C _1-6 alkoxy-C _1-6 alkyl, C _1-6 alkoxy-C _1-6 alkoxy, C _2-6 hydroxyalkoxy, Substitution of pendant, thiocarbonyl, cyano or halo groups; R ^{10 is} each independently H, -CD ₃ , C _1-6 alkyl, C _3-6 cycloalkyl, C _2-6 hydroxyalkane Group, C _1-6 alkoxy-C _1-6 alkyl or C _2-6 alkyl-NR ⁸ R ⁹ ; p=0, 1, 2, 3 or 4; q=2, 3 or 4; and x=0, 1 or 2.

In one embodiment, R ³ in formula (K) is N(R ¹⁰ )C _2-6 alkyl-NR ¹⁰ R ¹⁰ . In one embodiment, R ³ in formula (K) is N(R ¹⁰ )C _2-6 alkyl-NR ¹⁰ R ¹⁰ , where R ¹⁰ is -CD ₃ , C _1-6 alkyl, C _{3- 6} cycloalkyl, C _2-6 hydroxyalkyl, C _1-6 alkoxy-C _1-6 alkyl, or C _2-6 alkyl-NR ⁸ R ⁹ . In one embodiment, R ³ is -N(CH ₃ )CH ₂ CH ₂ NR ¹⁰ R ¹⁰ . In one embodiment, R ³ is -N(CH ₃ )CH ₂ CH ₂ NR ¹⁰ R ¹⁰ , where R ¹⁰ is -CD ₃ , C _1-6 alkyl, C _3-6 cycloalkyl, C _{2- 6} hydroxyalkyl, C _1-6 alkoxy-C _1-6 alkyl or C _2-6 alkyl-NR ⁸ R ⁹ .

或其立體異構體或醫藥學上可接受之鹽、溶劑合物、酯或前藥；其中，X²為CR^4a或N；X⁶為CR^4b或N；X⁸為CH或N；R²為甲氧基、-OCD₃、乙氧基或異丙氧基；R^4a為H、氰基、鹵基、-C_1-6烷基或-C_1-6鹵烷基；R^4b為H、氰基、硝基、鹵基、-C_1-6烷基、-C_1-6鹵烷基、羧基-C_1-6烷基、-C_1-6羥基烷基、R⁸R⁹N-C_1-6烷基-、-C_2-6烯基、-C_2-6炔基、C_1-6醯基-、R⁷-(CH₂)_pC(=O)-、C_1-6羥基烷基-C(=O)-、羧基、-C_1-6烷氧基羰基、-C(=O)NR⁸R⁹、羥基、烷氧基、-OCD₃、C_1-6醯氧基、-NR⁸R⁹、C_1-6醯基-N(R¹⁰)-、R⁷SO₂-；R^4N為H、-CH₃、Et、CH(CH₃)₂或-CD₃；R⁸及R⁹獨立地為H、-CD₃、C_1-6烷基、C_3-8環烷基、C_3-8環烷基-(C_1-3烷基)-、C_1-C₆醯基、苯基、單環雜芳基或單環雜環基；且R⁸及R⁹可進一步獨立地經多達三個選自羥基、C_1-6烷氧基、側氧基、硫羰基、氰基或鹵基之取代基取代；或 或者，R⁸及R⁹與其同時附接之N原子合起來形成4-7個成員之雜環，該雜環含有多達一個選自O、S或NR¹¹之其他雜原子，或形成7-12個成員之雜雙環，該雜雙環可為稠合、橋接或螺環，且含有多達兩個選自O、S(O)_x或NR¹¹之其他雜原子，且此等雜環視情況經多達三個選自羥基、C_1-6烷氧基、C_1-6羥基烷基、C_1-6烷氧基-C_1-6烷基、C_1-6烷氧基-C_1-6烷氧基、C_2-6羥基烷氧基、側氧基、硫羰基、氰基或鹵基之取代基取代；R¹⁰各自獨立地為H、-CD₃、C_1-6烷基、C_3-6環烷基、C_2-6羥基烷基、C_1-6烷氧基-C_1-6烷基或C_2-6烷基-NR⁸R⁹；p=0、1、2、3或4；q=2、3或4；且x=0、1或2。 In one embodiment, the compound of the present invention has the structure of formula (L):

Or its stereoisomer or pharmaceutically acceptable salt, solvate, ester or prodrug; wherein X ² is CR ^4a or N; X ⁶ is CR ^4b or N; X ⁸ is CH or N; R ² is methoxy, -OCD ₃ , ethoxy or isopropoxy; R ^4a is H, cyano, halo, -C _1-6 alkyl or -C _1-6 haloalkyl; R ^4b is H, cyano, nitro, halo, -C _1-6 alkyl, -C _1-6 haloalkyl, carboxy -C _1-6 alkyl, -C _1-6 hydroxyalkyl, R ⁸ R ⁹ NC _1-6 alkyl-, -C _2-6 alkenyl, -C _2-6 alkynyl, C _1-6 acetyl-, R ⁷ -(CH ₂ ) _p C(=O)-, C _{1- 6} -hydroxyalkyl-C(=O)-, carboxyl, -C _1-6 alkoxycarbonyl, -C(=O)NR ⁸ R ⁹ , hydroxy, alkoxy, -OCD ₃ , C _1-6 acetyl Oxygen, -NR ⁸ R ⁹ , C _1-6 acetyl-N(R ¹⁰ )-, R ⁷ SO ₂ -; R ^4N is H, -CH ₃ , Et, CH(CH ₃ ) ₂ or -CD ₃ ; R ⁸ and R ^{9 are} independently H, -CD ₃ , C _1-6 alkyl, C _3-8 cycloalkyl, C _3-8 cycloalkyl-(C _1-3 alkyl)-, C _{1 -} C ₆ acyl, phenyl, monocyclic heteroaryl or monocyclic heterocyclyl group; and R ⁸ and R ⁹ may be further independently substituted with up to three substituents selected from hydroxy, C _1-6 alkoxy, oxo , Thiocarbonyl, cyano or halo substituents; or alternatively, R ⁸ and R ⁹ together with the N atom to which they are attached at the same time form a heterocyclic ring of 4-7 members, the heterocyclic ring containing up to one selected from O, S or NR ¹¹ other hetero atoms, or form a heterobicyclic ring of 7-12 members, the heterobicyclic ring may be fused, bridged or spiro ring, and contains up to two selected from O, S (O) _x Or other heteroatoms of NR ¹¹ , and these heterocycles are optionally selected from up to three hydroxyl groups, C _1-6 alkoxy groups, C _1-6 hydroxyalkyl groups, C _1-6 alkoxy-C _1-6 Substitution of alkyl, C _1-6 alkoxy-C _1-6 alkoxy, C _2-6 hydroxyalkoxy, pendant, thiocarbonyl, cyano or halo; R ^{10 is} independently Is H, -CD ₃ , C _1-6 alkyl, C _3-6 cycloalkyl, C _2-6 hydroxyalkyl, C _1-6 alkoxy-C _1-6 alkyl, or C _2-6 alkyl Radical -NR ⁸ R ⁹ ; p=0, 1, 2, 3 or 4; q=2, 3 or 4; and x=0, 1 or 2.

In one embodiment, the compound of formula (L) comprises: X ² is CR ^4a or N; X ⁶ is CR ^4b or N; X ⁸ is CH or N; R ² is methoxy, -OCD ₃ , ethoxy Or isopropoxy; R ^4a is H, F, Cl, CH ₃ , CF ₃ or CHF ₂ ; R ^4b is H, cyano, nitro, halo, -C _1-6 alkyl or -C _{1- 6} haloalkyl; R ^4N is H, -CD ₃ , -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ ; and R ^{10 is} each independently H, -CD ₃ , -CH ₃ ,- CH ₂ CH ₃ or -CH(CH ₃ ) ₂ .

In another embodiment, the compound of formula (L) comprises: X ² is CR ^4a or N; X ⁶ is CR ^4b ; X ⁸ is CH; R ² is methoxy, -OCD ₃ , ethoxy or isopropyl Oxygen; R ^4a is H, F, CH ₃ , CF ₃ or CHF ₂ ; R ^{4b is} independently H, CH ₃ , F, Cl, CF ₃ or CHF ₂ ; R ^4N is H, -CD ₃ , -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ ; R ^{10 is} each independently H, -CD ₃ , -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ .

In one embodiment, R ¹⁰ in formula (L) is independently -CD ₃ , C _1-6 alkyl, C _3-6 cycloalkyl, C _2-6 hydroxyalkyl, C _1-6 alkyl Oxy-C _1-6 alkyl or C _2-6 alkyl-NR ⁸ R ⁹ . In another embodiment, R ¹⁰ is -CD ₃ , -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ .

In one embodiment, X ² in formula (K) and/or (L) is CH or N.

In one embodiment, X ⁶ in formula (K) and/or (L) is CH or N. In some embodiments, X ⁶ is CH.

In one embodiment, X ⁸ in formula (K) and/or (L) is CH or N. In some embodiments, X ⁸ is CH.

In one embodiment, R ^4N in formula (K) and/or (L) is H, -CD ₃ or -CH ₃ .

In one embodiment, R ² in formula (K) and/or (L) is methoxy, -OCD ₃ , ethoxy, or isopropoxy. In another embodiment, R ² is methoxy.

In some embodiments, R ¹⁰ in formulas (K) and/or (L) are each independently H, -CD ₃ , -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ . In other embodiments, R ^{10 is} each independently -CD ₃ , -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ . In other embodiments, R ¹⁰ is -CH ₃ .

或其立體異構體或醫藥學上可接受之鹽、溶劑合物、酯或前藥；其中，Z為CH或N；R¹為氫、甲基、氟、氯、溴、-CF₃或氰基；R²為-OCF₃、-OCHF₂、-OCF₂CF₃、-OCH₂CHF₂、-OCH₂CF₃、環丙氧基、甲氧基、-OCD₃、乙氧基或異丙氧基；R³為N(R¹⁰)C_2-6烷基-NR¹⁰R¹⁰；R^4a為氰基、-C_1-6羥基烷基、C_1-6醯基-、吡唑、1,2,3-三唑、四唑、-C(=O)NR⁸R⁹、-NR⁸R⁹、C_1-6醯基-N(R¹⁰)-、(C_1-3烷基)SO₂NH-、(C_1-6烷基)SO₂-或R⁷SO₂-；R^4b為H、氰基、鹵基、-C_1-6烷基或-C_1-6鹵烷基；R⁷為-OH或-NR⁸R⁹；R⁸及R⁹獨立地為H、-CD₃、C_1-6烷基、C_3-8環烷基、C_3-8環烷基-(C_1-3烷基)-、C_1-C₆醯基、苯基、單環雜芳基或單環雜環基；且R⁸及R⁹可進一步獨立地經多達三個選自羥基、C_1-6烷氧基、側氧基、硫羰基、氰基或鹵基之取代基取代；或或者，R⁸及R⁹與其同時附接之N原子合起來形成4-7個成員之雜環，該雜環含有多達一個選自O、S或NR¹¹之其他雜原子；R¹⁰各自獨立地為H、-CD₃、C_1-6烷基、C_3-6環烷基、C_2-6羥基烷基、C_2-6烷基-NR⁸R⁹； 或者，同時附接之同一N原子上的兩個R¹⁰形成5-6個成員之雜環，該雜環含有多達一個選自O、S或NR¹¹之其他雜原子；且R¹¹各自獨立地為氫或C_1-C₆烷基，其視情況經多達三個選自羥基、側氧基、硫羰基、氰基及鹵基之取代基取代。 In one embodiment, the compound of the present invention has the structure of formula (M):

Or its stereoisomer or pharmaceutically acceptable salt, solvate, ester or prodrug; where Z is CH or N; R ¹ is hydrogen, methyl, fluorine, chlorine, bromine, -CF ₃ or Cyano; R ² is -OCF ₃ , -OCHF ₂ , -OCF ₂ CF ₃ , -OCH ₂ CHF ₂ , -OCH ₂ CF ₃ , cyclopropoxy, methoxy, -OCD ₃ , ethoxy, or iso Propoxy; R ³ is N(R ¹⁰ )C _2-6 alkyl-NR ¹⁰ R ¹⁰ ; R ^4a is cyano, -C _1-6 hydroxyalkyl, C _1-6 acetyl-, pyrazole, 1,2,3-triazole, tetrazole, -C(=O)NR ⁸ R ⁹ , -NR ⁸ R ⁹ , C _1-6 acetyl-N(R ¹⁰ )-, (C _1-3 alkyl )SO ₂ NH-, (C _1-6 alkyl)SO ₂ -or R ⁷ SO ₂ -; R ^4b is H, cyano, halo, -C _1-6 alkyl or -C _1-6 haloalkane Group; R ⁷ is -OH or -NR ⁸ R ⁹ ; R ⁸ and R ^{9 are} independently H, -CD ₃ , C _1-6 alkyl, C _3-8 cycloalkyl, C _3-8 cycloalkyl -(C _1-3 alkyl)-, C _1- C ₆ acetyl, phenyl, monocyclic heteroaryl or monocyclic heterocyclic group; and R ⁸ and R ⁹ may be independently selected from up to three Hydroxy, C _1-6 alkoxy, pendant, thiocarbonyl, cyano or halo substituents; or alternatively, R ⁸ and R ⁹ together with the N atom to which they are attached together form 4-7 members Heterocyclic ring, the heterocyclic ring contains up to one other heteroatom selected from O, S or NR ¹¹ ; R ^{10 is} each independently H, -CD ₃ , C _1-6 alkyl, C _3-6 cycloalkyl , C _2-6 hydroxyalkyl, C _2-6 alkyl-NR ⁸ R ⁹ ; or, two R ¹⁰ on the same N atom attached at the same time form a heterocycle of 5-6 members, the heterocycle contains Up to one other heteroatom selected from O, S or NR ¹¹ ; and R ¹¹ are each independently hydrogen or C ₁ -C ₆ alkyl, which may optionally be selected from hydroxyl, pendant, thiocarbonyl , Cyano and halogen substituents.

In one embodiment, the compound of formula (M) comprises: Z is CH; R ¹ is hydrogen, methyl, fluorine, chlorine, bromine, -CF ₃ or cyano; R ² is methoxy, -OCD ₃ , ethyl Oxy or isopropoxy; R ³ is -N(CH ₃ )CH ₂ CH ₂ NR ¹⁰ R ¹⁰ ; R ^4a is -NR ⁸ R ⁹ ; R ^4b is H, CH ₃ , F, Cl, CF ₃ or CHF ₂ ; R ⁸ and R ^{9 are} independently H, -CD ₃ , C _1-6 alkyl, C _3-8 cycloalkyl, C _3-8 cycloalkyl-(C _1-3 alkyl)-, C _1- C ₆ acetyl, phenyl, monocyclic heteroaryl or monocyclic heterocyclic group; and R ⁸ and R ⁹ may be further independently selected by up to three from hydroxyl, C _1-6 alkoxy, pendant Oxygen, thiocarbonyl, cyano or halo substituents; and R ^{10 is} each independently H, -CD ₃ , -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ .

In one embodiment, R ¹⁰ in formula (M) is independently -CD ₃ , C _1-6 alkyl, C _3-6 cycloalkyl, C _2-6 hydroxyalkyl, C _2-6 alkyl Radical -NR ⁸ R ⁹ . In another embodiment, R ¹⁰ in formula (M) is each independently H, -CD ₃ , -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ . In other embodiments, R ^{10 is} each independently -CD ₃ , -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ . In other embodiments, each R ^{10 is} independently H, —CD ₃ , methyl, ethyl, or isopropyl. In some embodiments, each R ^{10 is} independently -CD ₃ , methyl, ethyl, or isopropyl. In some embodiments, each R ^{10 is} independently H, -CD _3, or methyl. In other embodiments, each R ^{10 is} independently -CD ₃ or methyl.

In another embodiment, R ^4a in formula (M) is each independently H, -C _1-6 alkyl, or -NR ⁸ R ⁹ . In one embodiment, R ^4a is -NR ⁸ R ⁹ . In one embodiment, R ⁸ and R ^{9 are} independently H, -CD ₃ or C _1-6 alkyl. In another embodiment, R ^4a is -N(CH ₃ ) ₂ .

In some embodiments, R ^4b in formula (M) is each independently H, cyano, F, Cl, Br, CH ₃ , CF _3, or CHF ₂ . In one embodiment, R ^4b is H, CH ₃ or CF ₃ .

In one embodiment, R ² in formula (M) is methoxy, -OCD ₃ , ethoxy, or isopropoxy. In another embodiment, R ² is methoxy.

In one embodiment, R ¹ in formula (M) is H.

或其立體異構體或醫藥學上可接受之鹽、溶劑合物、酯或前藥；其中，X²為CH、CCH₃或N；X⁶為CR⁴或N；Z為CH或N；R¹為氫、甲基、氟、氯、溴、-CF₃或氰基；R²為-OCF₃、-OCHF₂、-OCF₂CF₃、-OCH₂CHF₂或-OCH₂CF₃；R³為N(R¹⁰)C_2-6烷基-NR¹⁰R¹⁰；R⁴為H、氰基、鹵基、-C_1-6烷基、-C_1-6鹵烷基； R^4a獨立地為氰基、-C_1-6羥基烷基、C_1-6醯基-、吡唑、1,2,3-三唑、四唑、-C(=O)NR⁸R⁹、-NR⁸R⁹、C_1-6醯基-N(R¹⁰)-、(C_1-3烷基)SO₂NH-、(C_1-6烷基)SO₂-或R⁷SO₂-；R⁷為-OH或-NR⁸R⁹；R⁸及R⁹獨立地為H、-CD₃、C_1-6烷基、C_3-8環烷基、C_3-8環烷基-(C_1-3烷基)-、C_1-C₆醯基、苯基、單環雜芳基或單環雜環基；且R⁸及R⁹可進一步獨立地經多達三個選自羥基、C_1-6烷氧基、側氧基、硫羰基、氰基或鹵基之取代基取代；R¹⁰各自獨立地為H、-CD₃、C_1-6烷基、C_3-6環烷基、C_2-6羥基烷基、C_2-6烷基-NR⁸R⁹。 In one embodiment, the compound of the present invention has the structure of formula (N):

Or its stereoisomer or pharmaceutically acceptable salt, solvate, ester or prodrug; wherein, X ² is CH, CCH ₃ or N; X ⁶ is CR ⁴ or N; Z is CH or N; R ¹ is hydrogen, methyl, fluorine, chlorine, bromine, -CF ₃ or cyano; R ² is -OCF ₃ , -OCHF ₂ , -OCF ₂ CF ₃ , -OCH ₂ CHF ₂ or -OCH ₂ CF ₃ ; R ³ is N(R ¹⁰ )C _2-6 alkyl-NR ¹⁰ R ¹⁰ ; R ⁴ is H, cyano, halo, -C _1-6 alkyl, -C _1-6 haloalkyl; R ^4a Independently cyano, -C _1-6 hydroxyalkyl, C _1-6 acetyl-, pyrazole, 1,2,3-triazole, tetrazole, -C(=O)NR ⁸ R ⁹ ,- NR ⁸ R ⁹ , C _1-6 acetyl-N(R ¹⁰ )-, (C _1-3 alkyl)SO ₂ NH-, (C _1-6 alkyl)SO ₂ -or R ⁷ SO ₂ -; R ⁷ is -OH or -NR ⁸ R ⁹ ; R ⁸ and R ^{9 are} independently H, -CD ₃ , C _1-6 alkyl, C _3-8 cycloalkyl, C _3-8 cycloalkyl-( C _1-3 alkyl)-, C _1- C ₆ acetyl, phenyl, monocyclic heteroaryl or monocyclic heterocyclic group; and R ⁸ and R ⁹ may be further independently selected by up to three from hydroxyl, C _1-6 alkoxy, pendant, thiocarbonyl, cyano or halo substituent substitution; R ^{10 is} each independently H, -CD ₃ , C _1-6 alkyl, C _3-6 cycloalkane Group, C _2-6 hydroxyalkyl, C _2-6 alkyl-NR ⁸ R ⁹ .

In one embodiment, R ³ in formula (N) is -N(CH ₃ )CH ₂ CH ₂ NR ¹⁰ R ¹⁰ . In one embodiment, R ³ in formula (N) is -N(CH ₃ )CH ₂ CH ₂ NR ¹⁰ R ¹⁰ , where R ^{10 is} independently -CD ₃ , C _1-6 alkyl, C _{3- 6} cycloalkyl, C _2-6 hydroxyalkyl or C _2-6 alkyl-NR ⁸ R ⁹ .

In one embodiment, R ^4a in formula (N) is -NR ⁸ R ⁹ .

In one embodiment, R ¹ in formula (N) is H.

或其立體異構體或醫藥學上可接受之鹽、溶劑合物、酯或前藥；其中，X⁶為CH、CCH₃或N； R²為-OCF₃、-OCHF₂、-OCF₂CF₃、-OCH₂CHF₂或-OCH₂CF₃；R⁸及R⁹各自獨立地為H、-CD₃、-CH₃、-CH₂CH₃或-CH(CH₃)₂；且R¹⁰各自獨立地為H、-CD₃、-CH₃、-CH₂CH₃或-CH(CH₃)₂。 In one embodiment, the compound of the present invention has the structure of formula (O):

Or its stereoisomer or pharmaceutically acceptable salt, solvate, ester or prodrug; wherein, X ⁶ is CH, CCH ₃ or N; R ² is -OCF ₃ , -OCHF ₂ , -OCF ₂ CF ₃ , -OCH ₂ CHF ₂ or -OCH ₂ CF ₃ ; R ⁸ and R ⁹ are each independently H, -CD ₃ , -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ ; and R ¹⁰ are each independently H, -CD ₃ , -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ .

In another embodiment, R ¹⁰ in formulas (N) and/or (O) are each independently H, -CD ₃ , -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ . In other embodiments, each R ^{10 is} independently H, —CD ₃ , methyl, ethyl, or isopropyl. In some embodiments, each R ^{10 is} independently H, -CD _3, or methyl.

In another embodiment, R ¹⁰ in formulas (N) and/or (O) are each independently -CD ₃ , -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ . In other embodiments, each R ^{10 is} independently -CD ₃ , methyl, ethyl, or isopropyl. In some embodiments, each R ^{10 is} independently -CD ₃ or methyl.

In one embodiment, R ⁸ and R ⁹ in formula (N) and/or (O) are each independently H, -CD ₃ or C _1-6 alkyl. In another embodiment, R ⁸ and R ⁹ are each H, methyl, or ethyl.

In one embodiment, R ² in formula (N) and/or (O) is -OCF ₃ , -OCHF ₂ , -OCF ₂ CF ₃ , -OCH ₂ CHF ₂ or -OCH ₂ CF ₃ . In another embodiment, R ² is -OCF ₃ or -OCH ₂ CHF ₂ .

或其立體異構體或醫藥學上可接受之鹽、溶劑合物、酯、互變異構體或前藥； 其中：Z為CH或N；R¹獨立地選自氫、氟、氯、溴、甲基、乙基、羥基、甲氧基、乙氧基、異丙氧基、環丙氧基、-OCF₃、-OCH₂CF₃、-OCH₂CHF₂、乙烯基、乙炔基、CF₃、CHF₂、CHO、CH₂OH、CONH₂、CO₂Me、CONHMe、CONMe₂或氰基；R²為-OCF₃、-OCHF₂、-OCF₂CF₃、-OCH₂CHF₂、-OCH₂CF₃、環丙基、環丙氧基、甲氧基、-OCD₃、乙氧基或異丙氧基；R³為N(R¹⁰)C_2-6烷基-NR¹⁰R¹⁰、N(R¹⁰)C_2-6烷基-R⁷、O(CH₂)_pR⁷、N(R¹⁰)C(=O)(CH₂)_pR⁷或R⁷；R⁴各自獨立地為H、氰基、硝基、鹵基、-C_1-6烷基、-C_1-6鹵烷基、羧基-C_1-6烷基、-C_1-6羥基烷基、R⁸R⁹N-C_1-6烷基-、-C_2-6烯基、-C_2-6炔基、C_1-6醯基-、R⁷-(CH₂)_pC(=O)-、C_1-6羥基烷基-C(=O)-、羧基、-C_1-6烷氧基羰基、-C(=O)NR⁸R⁹、羥基、烷氧基、C_1-6醯氧基、-NR⁸R⁹、C_1-6醯基-N(R¹⁰)-或R⁷SO₂-；R^4a獨立地為H、氰基、硝基、鹵基、-C_1-6烷基、-C_1-6鹵烷基、-C_1-6烷氧基、-C_1-6鹵烷氧基、-C_1-6羥基烷基、C_1-6醯基-、吡唑、1,2,3-三唑、四唑、-C(=O)NR⁸R⁹、-NR⁸R⁹、C_1-6醯基-N(R¹⁰)-、(C_1-3烷基)SO₂NH-、(C_1-6烷基)SO₂-或R⁷SO₂-；R⁷為OH、NR⁸R⁹、O(CH₂)_qNR⁸R⁹、C_1-6烷氧基或C_2-6羥基烷氧基；R⁸及R⁹獨立地為H、-CD₃、C_1-6烷基、C_3-6烯基、C_3-6炔基、C_3-8環烷基、C_3-8環烯基、C_1-C₆醯基、4-12員單環或二環雜環基、4-12員單環或二環雜環基-C₁-C₆烷基-、C_6-C₁₂芳基、5-12員雜芳基；且R⁸及R⁹可進一步獨立地經多達三個選自羥基、C_1-6烷氧基、C_1-6羥基烷基、C_2-6羥基烷氧基、側氧基、硫羰基、氰基或鹵基之取代基取代；或或者，R⁸及R⁹與其同時附接之N原子合起來形成4-7個成員之雜環，該雜環含有多達一個選自O、S或NR¹¹之其他雜原子，或形成7-12個成員之雜雙環，該 雜雙環可為稠合、橋接或螺環，且含有多達兩個選自O、S(O)_x或NR¹¹之其他雜原子，且此等雜環視情況經多達三個選自羥基、C_1-6烷氧基、C_1-6羥基烷基、C_1-6烷氧基-C_1-6烷基、C_1-6烷氧基-C_1-6烷氧基、C_2-6羥基烷氧基、側氧基、硫羰基、氰基或鹵基之取代基取代；R¹⁰各自獨立地為H、-CD₃、C_1-6烷基、C_3-6環烷基、C_2-6羥基烷基、C_1-6烷氧基-C_1-6烷基或C_2-6烷基-NR⁸R⁹；或或者，同時附接之同一N原子上的兩個R¹⁰形成5-6個成員之雜環，該雜環含有多達一個選自O、S或NR¹¹之其他雜原子；且R¹¹各自獨立地為氫或C_1-C₆烷基，其視情況經多達三個選自羥基、側氧基、硫羰基、氰基及鹵基之取代基取代；p=0、1、2、3或4；q=2、3或4；且x=0、1或2。 In one embodiment, the compound of the present invention has the structure of formula (P):

Or its stereoisomer or pharmaceutically acceptable salt, solvate, ester, tautomer or prodrug; wherein: Z is CH or N; R ^{1 is} independently selected from hydrogen, fluorine, chlorine, bromine , Methyl, ethyl, hydroxyl, methoxy, ethoxy, isopropoxy, cyclopropoxy, -OCF ₃ , -OCH ₂ CF ₃ , -OCH ₂ CHF ₂ , vinyl, ethynyl, CF _{3, CHF 2, CHO, CH} 2 OH, CONH 2, CO 2 Me, CONHMe, CONMe 2 , or a cyano group; R ² is _{-OCF 3, -OCHF 2, -OCF 2} CF 3, -OCH 2 CHF 2, - OCH ₂ CF ₃ , cyclopropyl, cyclopropoxy, methoxy, -OCD ₃ , ethoxy, or isopropoxy; R ³ is N(R ¹⁰ )C _2-6 alkyl-NR ¹⁰ R ¹⁰ , N(R ¹⁰ )C _2-6 alkyl-R ⁷ , O(CH ₂ ) _p R ⁷ , N(R ¹⁰ )C(=O)(CH ₂ ) _p R ⁷ or R ⁷ ; R ^{4 is} independent of each other Ground is H, cyano, nitro, halo, -C _1-6 alkyl, -C _1-6 haloalkyl, carboxy -C _1-6 alkyl, -C _1-6 hydroxyalkyl, R ⁸ R ⁹ NC _1-6 alkyl-, -C _2-6 alkenyl, -C _2-6 alkynyl, C _1-6 acetyl-, R ⁷ -(CH ₂ ) _p C(=O)-, C _1-6 hydroxyalkyl -C(=O)-, carboxyl, -C _1-6 alkoxycarbonyl, -C(=O)NR ⁸ R ⁹ , hydroxy, alkoxy, C _1-6 acetyloxy , -NR ⁸ R ⁹ , C _1-6 acetyl-N(R ¹⁰ )- or R ⁷ SO ₂ -; R ^{4a is} independently H, cyano, nitro, halo, -C _1-6 alkyl , -C _1-6 haloalkyl, -C _1-6 alkoxy, -C _1-6 haloalkoxy, -C _1-6 hydroxyalkyl, C _1-6 acetyl-, pyrazole, 1 , 2,3-triazole, tetrazole, -C(=O)NR ⁸ R ⁹ , -NR ⁸ R ⁹ , C _1-6 acetyl-N(R ¹⁰ )-, (C _1-3 alkyl) SO ₂ NH-, (C _1-6 alkyl)SO ₂ -or R ⁷ SO ₂ -; R ⁷ is OH, NR ⁸ R ⁹ , O(CH ₂ ) _q NR ⁸ R ⁹ , C _1-6 alkoxy Group or C _2-6 hydroxyalkoxy; R ⁸ and R ^{9 are} independently H, -CD ₃ , C _1-6 alkyl, C _3-6 alkenyl, C _3-6 alkynyl, C _3-8 Cycloalkyl, C _3-8 cycloalkenyl, C _1- C ₆ acetyl, 4-12 membered monocyclic or bicyclic heterocyclyl, 4-12 membered monocyclic or bicyclic heterocyclyl-C ₁ -C ₆ alkyl-, C _6- C ₁₂ aryl, 5-12 member heteroaryl; and R ⁸ and R ⁹ can be One-step independent substitution by up to three selected from hydroxy, C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _2-6 hydroxyalkoxy, pendant, thiocarbonyl, cyano or halo Radical substitution; or alternatively, R ⁸ and R ⁹ together with the N atom to which they are simultaneously attached form a heterocyclic ring of 4-7 members, the heterocyclic ring containing up to one other heteroatom selected from O, S or NR ¹¹ , Or form a heterobicyclic ring of 7-12 members, which may be fused, bridged or spirocyclic, and contain up to two other heteroatoms selected from O, S(O) _x or NR ¹¹ , and such The heterocyclic ring may be selected from up to three hydroxy, C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _1-6 alkoxy-C _1-6 alkyl, C _1-6 alkoxy- C _1-6 alkoxy, C _2-6 hydroxyalkoxy, pendant, thiocarbonyl, cyano or halo substituent substitution; R ^{10 is} each independently H, -CD ₃ , C _1-6 Alkyl, C _3-6 cycloalkyl, C _2-6 hydroxyalkyl, C _1-6 alkoxy-C _1-6 alkyl, or C _2-6 alkyl-NR ⁸ R ⁹ ; or alternatively, Two R ¹⁰ on the same N atom attached to form a heterocycle of 5-6 members, the heterocycle contains up to one other heteroatom selected from O, S or NR ¹¹ ; and each R ^{11 is} independently hydrogen or C _1- C ₆ alkyl, which is optionally substituted with up to three substituents selected from hydroxy, oxo, thiocarbonyl, cyano, and halo group of substituents; p = 0,1,2,3 or 4; q = 2, 3 or 4; and x = 0, 1 or 2.

In one embodiment, the compound of formula (P) comprises: Z is CH or N; R ¹ is hydrogen, methyl, fluorine, chlorine, bromine, -CF ₃ or cyano; R ³ is N(R ¹⁰ )C _{2 -6} alkyl-NR ¹⁰ R ¹⁰ ; R ^{4 is} independently H, cyano, halo, -C _1-6 alkyl, -C _1-6 haloalkyl; R ^{4a is} independently H, cyano , Nitro, halo, -C _1-6 alkyl, -C _1-6 haloalkyl, -C _1-6 alkoxy, -C _1-6 haloalkoxy, -C(=O)NR ⁸ R ⁹ or -NR ⁸ R ⁹ ; R ⁸ and R ^{9 are} independently H, -CD ₃ , -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ ; and R ^{10 is} each independently H , -CD ₃ , -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ .

In one embodiment, R ¹ in formula (P) is hydrogen, methyl, fluorine, chlorine, bromine, —CF ₃ or cyano. In one embodiment, R ¹ is H.

In one embodiment, R ³ in formula (P) is N(R ¹⁰ )C _2-6 alkyl-NR ¹⁰ R ¹⁰ . In one embodiment, R ³ in formula (P) is N(R ¹⁰ )C _2-6 alkyl-NR ¹⁰ R ¹⁰ , where R ^{10 is} each independently -CD ₃ , C _1-6 alkyl, C _3-6 cycloalkyl, C _2-6 hydroxyalkyl, C _1-6 alkoxy-C _1-6 alkyl, or C _2-6 alkyl-NR ⁸ R ⁹ ; in another embodiment, R ³ is -N(CH ₃ )CH ₂ CH ₂ NR ¹⁰ R ¹⁰ . In another embodiment, R ³ is -N(CH ₃ )CH ₂ CH ₂ NR ¹⁰ R ¹⁰ , where R ^{10 is} each independently -CD ₃ , C _1-6 alkyl, C _3-6 cycloalkyl , C _2-6 hydroxyalkyl, C _1-6 alkoxy-C _1-6 alkyl or C _2-6 alkyl-NR ⁸ R ⁹ ; in another embodiment, R in formula (P) ⁴ Each independently represents H, cyano, halo, -C _1-6 alkyl, and -C _1-6 haloalkyl. In one embodiment, R ^{4 is} each independently H, cyano, halo or methyl.

In another embodiment, R ^4a in formula (P) is H, cyano, nitro, halo, -C _1-6 alkyl, -C _1-6 haloalkyl, -C _1-6 alkyl Oxy, -C _1-6 haloalkoxy, -C(=O)NR ⁸ R ⁹ or -NR ⁸ R ⁹ . In another embodiment, R ^4a is H, -C _1-6 alkyl, or -NR ⁸ R ⁹ . In one embodiment, R ^4a is -NR ⁸ R ⁹ . In one embodiment, R ⁸ and R ^{9 are} independently H, -CD ₃ , -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ . In another embodiment, R ^4a is -N(CH ₃ ) ₂ .

In another embodiment, R ¹⁰ in formula (P) is each independently H, -CD ₃ , -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ . In other embodiments, each R ^{10 is} independently H, —CD ₃ , methyl, ethyl, or isopropyl. In some embodiments, each R ^{10 is} independently H, -CD _3, or methyl.

In another embodiment, R ¹⁰ in formula (P) is independently -CD ₃ , -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ . In other embodiments, each R ^{10 is} independently -CD ₃ , methyl, ethyl, or isopropyl. In some embodiments, each R ^{10 is} independently -CD ₃ or methyl.

；

；及/或

； 或其醫藥學上可接受之鹽。 In one embodiment, the invention relates to one or more of the following compounds selected from:

;

; And/or

; Or its pharmaceutically acceptable salts.

；

；

；及/或

或其醫藥學上可接受之鹽。 In one embodiment, the invention relates to one or more of the following compounds selected from:

;

;

; And/or

Or its pharmaceutically acceptable salts.

In one embodiment, the invention relates to one or more of the following compounds selected from:

；及/或

；或其醫藥學上可接受 之鹽。 In one embodiment, the invention relates to one or more of the following compounds selected from:

; And/or

; Or its pharmaceutically acceptable salts.

；及/或

；或其醫藥學上可接受之鹽。 In another embodiment, the invention relates to one or more of the following compounds selected from:

; And/or

; Or its pharmaceutically acceptable salts.

In formulas (I), (A), (B), (C), (CI), (D), (DI), (E), (EI), (F), (G), (H), In one embodiment of (HI), (J), (K), (L), (M), (N), (O) and/or (P), R ^{10 is} not H. In formulas (I), (A), (B), (C), (CI), (D), (DI), (E), (EI), (F), (G), (H), In one embodiment of (HI), (J), (K), (L), (M), (N), (O) and/or (P), R ¹⁰ is -CD ₃ or C ₁ -C ₆ alkyl. In formulas (I), (A), (B), (C), (CI), (D), (DI), (E), (EI), (F), (G), (H), In one embodiment of (HI), (J), (K), (L), (M), (N), (O) and/or (P), R ¹⁰ is -CD ₃ , -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ .

In formulas (I), (A), (B), (C), (CI), (D), (DI), (E), (EI), (F), (G), (H), In one embodiment of (HI), (J), (K), (L), (M), (N), (O) and/or (P), the compound may be in the form of an N-oxide.

In one embodiment, the compounds of the present invention are excluded from CN 105085489 A, WO 2015/127872, WO2013/014448, CN 105001208 A, CN 104844580 A, WO 2015/175632, WO 2015/188777, WO 2016/105525, WO2016060443, WO Compounds exemplified in 2016/029839, WO 2016/054987, WO 2016/015453, WO 2016/070816 and/or WO 2015/195228.

In one embodiment, the compounds of the present invention exclude compounds exemplified in CN 104761585 A and/or CN 104761544 A.

In an embodiment of formula (A) or any of its subgenus of formula (I); R ^4a , R ^4b , R ^4c and R ^4d are embodiments of R ⁴ .

R'為視情況經取代之烷基。 The compounds of the present invention may also exist in several tautomeric forms, and one tautomer is described herein for convenience only, and should also be understood to encompass other tautomers in the form shown. Therefore, the chemical structure depicted herein encompasses all possible tautomeric forms of the illustrated compounds. As used herein, the term "tautomer" refers to isomers that are easily changed from each other so that they can exist in equilibrium together. For example, ketone and enol are two tautomeric forms of a compound. In another example, substituted 1,2,4-triazole derivatives can exist in at least three tautomeric forms as shown below:

R'is optionally substituted alkyl.

Those skilled in the art should realize that formulas (I), (A), (B), (C), (CI), (D), (DI), (E), (EI), (F), (G), (H), (HI), (J), (K), (L), (M), (N), (O) and/or (P) compounds or their subgenus structures or substances The substituents, variables and other parts should be selected so as to provide a compound that is sufficiently stable to provide a pharmaceutically acceptable compound that can be formulated into an acceptable stable pharmaceutical composition. In addition, those skilled in the art should realize that formulas (I), (A), (B), (C), (CI), (D), (DI), (E), (EI), (F ), (G), (H), (HI), (J), (K), (L), (M), (N), (O) and/or (P) compounds, their subgenus structures or Substituents, variables and other parts of a substance should be selected so that it will not produce any compounds with structural characteristics that violate the fundamental principles of chemical technology. For example, in an embodiment of formula (I) or one of its subgenus structures or substances, the two bonds of a, b, c, d, and e are (form) double bonds and the remaining bonds are (form) single bonds, so that The atoms X ¹ , X ² , X ³ , X ⁴ and X ^{5 do} not have two double bonds attached. In another embodiment of formula (I), in A ¹ , A ² and A ³ , when X ¹ is N, X ² is C=O, C=NR ¹⁰ or C=S, X ³ is O, When S or NR ¹⁰ and X ⁴ and X ⁵ are C, only e is a formal double bond. In another embodiment of formula (I), in A ¹ and A ³ , when one of X ¹ and X ⁴ and X ⁵ is N, then only b will be a (form) double bond. In another embodiment of formula (I), in A ³ , when X ¹ is C, and X ³ is O, S, or NR ¹⁰ , and one of X ⁴ and X ⁵ is N, then only c will be It is a (form) double bond.

In one embodiment, the invention relates to one or more of the compounds disclosed in Examples 1-30.

、

及

；或其醫藥學上可 接受之鹽。 In one embodiment, the compounds of the present invention include but are not limited to:

,

and

; Or its pharmaceutically acceptable salts.

Regarding EGFR targets, the compounds listed above will show similar activity and selectivity compared to the compounds listed as examples.

Pharmaceutical composition

In one embodiment, the invention relates to a pharmaceutical composition comprising a compound of the invention or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, and a pharmaceutically acceptable carrier.

As used in the preparation and examples, the following terms have the meanings indicated; "ng" refers to nanograms; "μg" refers to micrograms; "mg" refers to milligrams; "g" refers to grams; "kg" refers to kilograms ; "Nmole" or "nmol" refers to nanomolar; "mmol" refers to millimolar; "mol" refers to molar; "M" refers to molar concentration, "mM" refers to nanomolar concentration, "ΜM" means micromolar concentration, "nM" means nanomolar concentration, "L" means liter, "mL" means milliliter, and "μL" means microliter.

The pharmaceutically acceptable salts of the compounds of the present invention include acid addition and alkali salts (including disalts).

Suitable acid addition salts are formed from acids that form non-toxic salts. Examples include acetate, aspartate, benzoate, benzenesulfonate, bicarbonate/carbonate, bisulfate/sulfate, borate, d-camphorsulfonate, citrate, ethyl acetate Disulfonate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hydrobenzoate, hydrochloric acid Salt/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, methanesulfonic acid Salt, methyl sulfate, naphthalate, 2-naphthalene sulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate Salt/dihydrogen phosphate, glycosylate, stearate, succinate, tartrate, tosylate and trifluoroacetate.

Suitable base salts are formed from bases that form non-toxic salts. Examples include aluminum, arginine, benzathine, calcium, choline, diethylamine, diethanolamine, glycine, lysine, magnesium, meglumine, ethanolamine, potassium, sodium, tromethamine, and zinc salts .

For a review of suitable salts, see "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

The pharmaceutically acceptable salts of the compounds of the present invention can be easily prepared by mixing together the solution of the compound and the appropriate desired acid or base. The salt can precipitate from the solution and be collected by filtration or can be recovered by evaporation of the solvent. The degree of ionization of the salt can vary from fully ionized to almost non-ionized.

The compounds of the present invention containing one or more asymmetric carbon atoms can exist as two or more stereoisomers. In the case where the compounds of the present invention contain alkenyl or alkenyl groups, geometric cis/trans (or Z/E) isomers are possible. In the case where the compound contains, for example, a ketone or oxime group or an aromatic moiety, tautomer isomerization ("tautomerization") can occur. This shows that a single compound can exhibit more than one type of isomerization.

The claimed scope of the compounds of the invention includes all stereoisomers, geometric isomers and tautomeric forms of the compounds of the invention, including compounds exhibiting more than one type of isomerization and mixtures of one or more of them . Also included are acid additions or alkali salts, where the relative ion has optical activity, such as D-lactate or L-lysine, or racemicity, such as DL-tartrate or DL-arginine.

The cis/trans isomers can be separated by conventional techniques well known to those skilled in the art, such as chromatography and step crystallization.

The compounds of the present invention can also exhibit rotational enantiomerization, in which restricted rotation (especially around the bond joining the two aryl rings in the biaryl group) makes different rotational isomers incompatible with each other at normal ambient temperature, and It is possible that the molecules cannot be converted into each other at a temperature where the overall thermal stability of the molecule remains. In these cases, the different stereoisomers attributed to rotational enantiomerization are also advocated.

Conventional techniques for the preparation/separation of individual enantiomers include the palmitic synthesis from suitable optically pure precursors or the resolution of racemates (or salts) using, for example, palmitic high pressure liquid chromatography (HPLC) Or racemic derivatives), especially in a simulated moving bed (SMB) configuration.

Alternatively, the racemate (or racemic precursor) can be combined with a suitable optically active compound (eg, alcohol) or in the case where the compound of the present invention contains an acidic or basic moiety, such as tartaric acid or 1-phenylethyl Amine acid or alkali reaction. The resulting mixture of diastereomers can be separated by chromatography and/or fractional crystallization and one or both of these diastereomers can be converted into the corresponding pure pair by means well known to the skilled person Enantiomer.

The palmitic compounds of the present invention (and their palmitic precursors) can be obtained in the form of enantiomerically enriched forms on a partially symmetric resin with a mobile phase using chromatography (typically HPLC) It consists of a hydrocarbon (typically heptane or hexane) containing 0-50% isopropanol (typically 2-20%) and 0-5% alkylamine (typically 0.1% diethylamine). The concentration of dissolved species provides a thickened mixture.

The mixture of stereoisomers can be separated by conventional techniques known to those skilled in the art. [See, for example, "Stereochemistry of Organic Compounds" EL Eliel (Wiley, New York, 1994). ]

The present invention includes all pharmaceutically acceptable isotopically-labeled compounds of the present invention in which one or more atoms are composed of atoms having the same atomic number but atomic mass or mass number different from the atomic mass or mass number usually found in nature Replace.

Examples of isotopes suitable for inclusion in the compounds of the present invention include isotopes of hydrogen, such as ² H and ³ H; carbon, such as ¹¹ C, ¹³ C, and ¹⁴ C; chlorine, such as ³⁶ Cl; fluorine, such as ¹⁸ F; iodine, such as ¹²³ I and ¹²⁵ I; nitrogen, such as ¹³ N and ¹⁵ N; oxygen, such as ¹⁵ O, ¹⁷ O, and ¹⁸ O; phosphorus, such as ³² P; and sulfur, such as ³⁵ S.

Certain compounds of the invention labeled with isotopes are suitable for the study of the distribution of drugs and/or substrate tissues, such as those compounds incorporating radioisotopes. The radioisotopes tritium (that is, ³ H) and carbon-14 (that is, ¹⁴ C) are particularly suitable for this purpose in view of their easy incorporation and ready detection methods.

Substitution with heavier isotopes such as deuterium (ie, 2H) can provide certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dose requirements, and can therefore be Good.

Substitution with positron emitting isotopes such as ¹¹ C, ¹⁸ F, ¹⁵ O, and ¹³ N can be applied to positron emission tomography (PET) studies to check the acceptor occupancy of the substrate.

Isotope-labeled compounds of the present invention can generally be substituted for previously used appropriate isotopically-labeled reagents by conventional techniques known to those skilled in the art or by processes similar to their processes described in the accompanying examples and preparations Prepared without labeled reagents.

The compound of the present invention can be administered as a prodrug. Therefore, certain derivatives of the compounds of the present invention, which may themselves have little or no pharmacological activity, when administered into or onto the body, can be converted to Formula 1 (or disclosed herein, for example) by hydrolytic cleavage, such as by hydrolytic cleavage Of other formulas). These derivatives are called "prodrugs". Further information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems, Volume 14, ACS Symposium Series (T Higuchi and W Stella) and "Bioreversible Carriers in Drug Design", Pergamon Press, 1987 (Edited by EB Roche , American Pharmaceutical Association).

Prodrugs can be suitably present in the compounds of the present invention, for example, by replacing certain portions of the "pro-portion" described in "Design of Prodrugs" by those skilled in the art as, for example, H Bundgaard (Elsevier, 1985) in "Design of Prodrugs" Functional groups.

Some examples of such prodrugs include: when the compound contains a carboxylic acid functional group (-COOH), its ester, for example, replaces hydrogen with a C1-C6 alkyl group; when the compound contains an alcohol functional group (--OH), The ether, for example, replaces hydrogen with C ₁ -C ₆ alkoxymethyl (-C ₁ -C ₆ oxymethyl); and the compound contains a primary or secondary amino functional group (-NH ₂ or -NHR, where R is not H), its amide, for example, replacing one or two hydrogens with (C ₁ -C ₁₀ )alkanoyl (-C ₁ -C ₁₀ acetyl).

Further examples of replacement groups according to the aforementioned examples and examples of other prodrug types can be found in the aforementioned references.

Finally, certain compounds of the present invention may themselves act as prodrugs of other compounds of the present invention.

treatment method

In one embodiment, the invention relates to a method suitable for treating cancer selected from the group consisting of lung cancer, colorectal cancer, pancreatic cancer, head and neck cancer, breast cancer, ovarian cancer, uterine cancer, liver cancer, and gastric cancer. In another embodiment, the cancer is non-small cell lung cancer (NSCLC).

In one embodiment, the method disclosed herein relates to cancer treatment, where the cancer is caused by mutations in the exon 20 domain of EGFR. In some embodiments, the mutation in the exon 20 domain of EGFR is selected from NPG, ASV, or T790M. In one embodiment, the mutation in the exon 20 domain of EGFR is T790M in parallel with the insertion mutation of exon 19 or the 21 point mutation of exon.

In one embodiment, the cancer treatment method is particularly suitable for patients who are resistant to kinase inhibitors other than the compound of the present invention or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof. In another embodiment, the kinase inhibitor is an EGFR inhibitor.

The present invention also relates to a method for inhibiting EGFR or a mutation in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt or solvate thereof , Esters or prodrugs. In one embodiment, the mutation is in the exon 20 domain of EGFR.

The present invention further relates to therapeutic methods and uses, which include administering the compound of the present invention or a pharmaceutically acceptable salt thereof alone or in combination with other therapeutic agents or relieving agents.

In one embodiment, the present invention relates to a method for treating or inhibiting cell proliferation, cell invasiveness, metastasis, apoptosis or angiogenesis in a mammal, which comprises administering to the mammal a therapeutically effective amount The compound of the present invention or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention relates to a method for treating or inhibiting cell proliferation, cell invasiveness, metastasis, apoptosis or angiogenesis in a mammal, which comprises combining with a second therapeutic agent to the lactation The animal is administered a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof, wherein the combined amount of the compound of the present invention and the second therapeutic agent is effective to treat or inhibit the cell proliferation, cell invasiveness, metastasis, and cell apoptosis Death or angiogenesis.

In one embodiment, the second therapeutic agent is an antitumor agent selected from the group consisting of mitotic inhibitors, alkylating agents, antimetabolites, embedded antibiotics, growth factor inhibitors, radiation, cell cycle inhibitors, enzymes, and topology Isomerase inhibitors, biological response modifiers, antibodies, cytotoxic agents, antihormones and antiandrogens.

In other embodiments, the cell proliferation, cell invasiveness, metastasis, apoptosis or angiogenesis is mediated by members of the RTK erbB family, primarily EGFR and most likely the T790M mutant form of EGFR.

In another embodiment, the cell proliferation, cell invasiveness, metastasis, apoptosis or angiogenesis are associated with cancer selected from the group consisting of glioblastoma, lung cancer (eg, squamous cell carcinoma, non-small cell lung cancer , Adenocarcinoma, bronchioloalveolar carcinoma (BAC), BAC with focal invasion, adenocarcinoma and large cell carcinoma with BAC characteristics), pancreatic cancer, head and neck cancer (eg, squamous cell carcinoma), breast cancer, Colorectal cancer, epithelial cancer (eg, squamous cell carcinoma), ovarian and prostate cancer, and members of the overexpressing erbB family or carcinogenic fully activated mutants containing the erbB family (regardless of whether their proteins are overexpressing in the tumor) Any other group of cancers.

Another embodiment of the present invention relates to a compound of the present invention used as a medicament and specifically for treating a disease in which the inhibitory activity of EGFR and/or mutant EGFR protein (eg, L858R/T790M EGFR) can be Inducing benefits, such as cancer. Another embodiment of the present invention relates to the use of the compound of the present invention or a pharmaceutically acceptable salt thereof for the manufacture of EGFR-mediated diseases and/or pathologies, specifically listed above Drugs with EGFR inhibitory activity for diseases and/or pathologies.

The term "therapeutically effective amount" refers to the amount of the compound administered, which will reduce to some extent one or more symptoms of the condition being treated. With regard to the treatment of cancer, a therapeutically effective amount means that the amount has the effect of reducing the size of the tumor, inhibiting (ie, slowing or stopping) tumor metastasis, inhibiting (ie, slowing or stopping) tumor growth, or tumor aggressiveness and/or To some extent alleviates the effects of one or more signs or symptoms associated with the cancer.

The therapeutically effective amount can be easily determined by an attending diagnostician who is familiar with this technique by using conventional techniques and by observing the results obtained under similar circumstances. When determining the therapeutically effective dose and dose, the attending diagnostician will consider various factors, including but not limited to: the species of mammal; its size, age and general health status; the specific disease involved; the extent or severity of the disease ; Individual patient response; specific compound administered; mode of administration; bioavailability characteristics of the administered agent; selected dosage regimen; use of concomitant drug treatment; and other relevant conditions.

Unless otherwise indicated, as used herein, the term "treating" means reversing, relieving, inhibiting progression, or preventing a disorder or condition to which the term is applied, or one or more symptoms of the disorder or disorder. The term "treatment" also refers to the "treating" treatment behavior as just defined above. The term "treating" also includes adjuvant therapy for mammals.

As used herein, "cancer" refers to any malignant and/or aggressive growth or tumor caused by abnormal cell growth, including solid tumors (named for the type of cells that form these solid tumors), blood, bone marrow, or lymphatic system cancer. Examples of solid tumors include but are not limited to sarcoma and carcinoma. Examples of blood cancers include, but are not limited to leukemia, lymphoma, and myeloma. The term "cancer" includes, but is not limited to, primary cancer that starts at a specific site in the body, metastatic cancer that has spread from its starting location to other parts of the body, recurrence from the original primary cancer after remission, and Among people with different types of previous cancer history as the second primary cancer of the new primary cancer.

In another embodiment, the present invention provides a method for inhibiting cell proliferation, which comprises contacting a cell with an amount of a compound of the present invention or a pharmaceutically acceptable salt thereof in an amount effective to inhibit cell proliferation. In another embodiment, the present invention provides a method for inducing apoptosis, which comprises contacting a cell with an amount of a compound described herein effective to induce apoptosis of the cell.

"Contact" refers to the collection of a cell of the compound of the present invention or a pharmaceutically acceptable salt and one of the other target kinases that exhibits mutant EGFR or a transformation effect in a specific cell type, in a manner such that the compound can directly or Indirectly affects the activity of EGFR or the other kinase. Contacting can be achieved in vitro (that is, in an artificial environment, such as but not limited to in a test tube or medium) or in vivo (that is, in a living organism, such as but not limited to a mouse, rat, or rabbit).

In some embodiments, the cells are in cell lines such as cancer cell lines. In other embodiments, the cells are in a tissue or tumor, and the tissue or tumor may be in mammals including humans.

The administration of the compounds of the present invention can be achieved by any method that enables the delivery of these compounds to the site of action. Such methods include oral route, intraduodenal route, parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion), and superficial and rectal administration.

The dosage regimen can be adjusted to provide the best desired response. For example, a single bolus can be administered, several divided doses can be administered over time, or the dose can be reduced or increased proportionally as indicated by the urgency of the treatment situation. It is particularly advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage.

As used herein, a dosage unit form refers to a physical individual unit suitable as a unit dose for the mammal to be treated; each unit contains a predetermined amount of active compound, the predetermined amount is calculated to produce a place relevant to the required pharmaceutical carrier Need treatment effect. The specification of the dosage unit form of the present invention is indicated by and directly depends on the following: (a) the unique characteristics of the chemotherapeutic agent and the specific therapeutic or preventive effects pre-implemented, and (b) the limitations inherent in the compounding technology, Active compounds such as those used to treat the sensitivity of individuals.

The appropriate dose may vary with the type and severity of the condition to be treated and may include single or multiple doses. The attending diagnostician should understand that with regard to any specific mammal, the specific dosing regimen should be adjusted over time based on individual needs and the professional judgment of the person administering or supervising the administration of these compositions, and the dosage ranges stated herein are examples only It is sexual and is not intended to limit the scope or practice of the claimed composition. For example, the dosage may be adjusted based on pharmacokinetic or pharmacodynamic parameters, which may include clinical effects such as toxic effects and/or laboratory values. Therefore, the present invention encompasses escalation of doses in patients as determined by skilled artisans. Determination of appropriate dosages and protocols for administration of chemotherapeutic agents is well known in the relevant art and it should be understood that once the teachings disclosed herein are provided, they will be covered by the skilled artisan.

The suitable dosage of the compound of the present invention can be determined by comparing its in vitro activity and in vivo activity in animal models. The amount of the compound or its active salt or derivative required for treatment will vary not only with the specific salt selected, but also with the route of administration, the nature of the condition being treated and the age and condition of the patient, and The final decision will be made by the visiting physician or clinician.

The compounds of the present invention can be administered to patients at dosage levels ranging from about 0.1 to about 2,000 mg per day. For normal adults with a body weight of about 70 kg, a dose in the range of about 0.01 to about 10 mg/kg body weight/day is preferred. However, the specific dose used may vary. For example, the dosage may depend on various factors, including the patient's needs, the severity of the condition being treated, and the pharmacological activity of the compound used. The determination of the optimal dose for a particular patient is well known to those skilled in the art. In some cases, the dose level below the lower limit of the above range may be more than sufficient, while in other cases, larger doses can be used without causing harmful side effects, the limitation is that these larger doses are first divided into several smaller doses So as to give it all day.

The pharmaceutical composition of the present invention can be prepared, packaged, or sold in bulk, in a single unit dosage form, or in multiple single unit dosage forms. As used herein, "unit dose" is an individual amount of a pharmaceutical composition containing a predetermined amount of active ingredient. The amount of active ingredient is generally equal to the dose of active ingredient to be administered to the individual, or a convenient part of the dose, such as the general or one-third of the dose.

The relative amounts of the active ingredient, pharmaceutically acceptable carrier and any additional ingredients in the pharmaceutical composition of the invention will vary depending on the identity, size and condition of the individual being treated and further depending on the route of administration of the composition . For example, the composition may comprise between 0.1% and 100% (w/w) active members.

Pharmaceutical compositions suitable for the delivery of the compounds of the present invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation can be found in, for example, "Remington's Pharmaceutical Sciences", 19th Edition (Mack Publishing Company, 1995), the disclosure of which is incorporated herein by reference in its entirety.

The compound of the present invention can be administered orally. Oral administration may involve swallowing, allowing the compound to enter the gastrointestinal tract, or may be administered via the buccal or sublingual administration that allows the compound to enter the bloodstream directly from the oral cavity. Suitable formulations for oral administration include solid formulations (such as lozenges), capsules containing microparticles, liquids or powders, oral lozenges (including liquid-filled), chewables, multiparticulate and nanoparticulates, gels , Solid solutions, liposomes, membranes (including mucoadhesives), ovules, sprays and liquid formulations.

Liquid formulations include suspensions, solutions, syrups and elixirs. These formulations can be used as fillers in soft or hard capsules and typically include carriers (such as water, ethanol, polyethylene glycol, propylene glycol, methyl cellulose or suitable oils), and one or more emulsifiers and /Or suspending agent. Liquid formulations can also be prepared by solid recovery.

The compounds of the present invention can also be used in rapidly dissolving and rapidly disintegrating dosage forms, such as those described in Expert Opinion in Therapeutic Patents, 11(6), 981986 by Liang and Chen (2001), the disclosure content of which is incorporated by reference in its entirety Incorporated in this article.

With regard to lozenge dosage forms, depending on the dose, the drug may constitute 1 wt% to 80 wt% of the dosage form, more typically 5 wt% to 60 wt% of the dosage form. In addition to the drug, lozenges generally contain disintegrants. Examples of disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, Microcrystalline cellulose, hydroxypropyl cellulose substituted with lower alkyl, starch, pregelatinized starch and sodium alginate. Generally speaking, the disintegrant will comprise 1 wt% to 25 wt% of the dosage form, preferably 5 wt% to 20 wt%.

Binders are generally used to impart cohesive qualities to tablet formulations. Suitable binders include microcrystalline cellulose, gelatin, sugar, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose and hydroxypropyl methyl cellulose. Lozenges may also contain diluents such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline Cellulose, starch and calcium hydrogen phosphate dihydrate.

The lozenges may optionally include surfactants (such as sodium lauryl sulfate and polysorbate 80), and glidants (such as silica and talc). When present, the surfactant may constitute 0.2% to 5% by weight of the lozenge, and the glidant may constitute 0.2% to 1% by weight of the lozenge.

Lozenges generally also contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and a mixture of magnesium stearate and sodium lauryl sulfate. The lubricant generally accounts for 0.25% to 10% by weight of the tablet, preferably 0.5% to 3% by weight.

Other possible ingredients include antioxidants, colorants, flavoring agents, preservatives and taste masking agents.

Lozenge blends can be compressed directly or by roller to form lozenges. The tablet blend or part of the blend may alternatively be wet, dry or melt granulated, melt coagulated, or extruded prior to tablet making. The final formulation may include one or more layers and may be coated or uncoated; it may even be encapsulated.

The formulation of lozenges is discussed in "Pharmaceutical Dosage Forms: Tablets, Volume 1", H. Lieberman and L. Lachman, Marcel Dekker, N.Y., N.Y., 1980 (ISBN 0-8247-6918-X).

The aforementioned formulations for the various types of administration discussed above can be formulated for immediate and/or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, targeted, and programmed release. Suitable modified release formulations for the purpose of costing inventions are described in US Patent No. 6,106,864. Details of other suitable release technologies such as high energy dispersions and osmotic and coated particles will be found in Verma et al., Pharmaceutical Technology On-line, 25(2), 1-14 (2001). The use of chewing gum to achieve controlled release is described in WO 00/35298.

The compounds of the present invention can also be administered directly into the bloodstream, muscles, or internal organs. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) syringes, needle-free syringes, and infusion techniques.

Parenteral formulations are typically aqueous solutions (preferably to pH 3-9) that may contain excipients such as salts, carbohydrates, and buffers, but for some applications, they can be more suitably formulated to be combined Sterile non-aqueous solutions or dried forms used in suitable vehicles such as sterile, pyrogen-free water.

The preparation of parenteral formulations under sterile conditions, for example by lyophilization, can be easily achieved using standard pharmaceutical techniques well known to those skilled in the art.

The solubility of the compounds of the present invention for preparing parenteral solutions can be increased by using appropriate formulation techniques, such as the incorporation of solubility enhancers.

The formulations for parenteral administration can be formulated for immediate and/or modified release. Thus, the compounds of the present invention can be formulated as solid, semi-solid, or thixotropic liquids for administration in the form of implanted reservoirs that provide modified release of the active compound. Examples of such formulations include drug-coated stents and poly(glycolide-co-dl-lactide) or PGLA microspheres.

The compounds of the present invention can be combined with soluble macromolecular entities (such as cyclodextrin and its suitable derivatives or polyethylene glycol-containing polymers) in order to improve its solubility, dissolution rate, taste masking, biological properties for any of the above administration modes Availability and/or stability. For example, it has been found that drug-cyclodextrin complexes are generally suitable for most dosage forms and routes of administration. Both inclusion and non-inclusion complexes can be used. As an alternative to compounding directly with the drug, cyclodextrin can be used as an auxiliary additive, that is, as a carrier, diluent or solubilizer. α-, β- and γ-cyclodextrin are most commonly used for these purposes, examples of which can be found in International Patent Application Nos. WO 91/11172, WO 94/02518 and WO 98/55148.

The term "combination therapy" means that the compound of the present invention is administered sequentially or simultaneously with at least one additional medicament or pharmaceutical agent. Combination therapy encompasses the use of compounds of the invention and other therapeutic agents in individual dosage forms or in the same pharmaceutical formulation. The compounds of the present invention can be used in combination with one or more therapeutic agents (administered simultaneously, sequentially or separately).

In one embodiment of the present invention, the anticancer agent used in combination with the compound of the present invention and the pharmaceutical composition described herein is an antiangiogenic agent (eg, an agent that stops tumors from developing new blood vessels). Examples of anti-angiogenic agents include, for example, VEGF inhibitors, VEGFR inhibitors, TIE-2 inhibitors, PDGFR inhibitors, angiogenin inhibitors, PKCI3 inhibitors, CQX-2 (cyclooxygenase II) inhibitors, integration (Α-v/β-3), MMP-2 (matrix-metalloproteinase 2) inhibitors and MMP-9 (matrix metalloproteinase 9) inhibitors. Preferred anti-angiogenic agents include sunitinib (SutenFM), bevacizumab (Avastin ^™ ) and axitinib (AG 13736).

Additional anti-angiogenic agents include vatalanib (CGP 79787), sorafenib (Nexavar ^TM ), pegastanil octasodium (Macugen ^TM ), vandetanib (Zactima ^TM ), PF-0337210 (Pfizer) , SU 14843 (Pfizer), AZD 2171 (AstraZeneca), ranibizumab (Lucentis TM), Neovastat ^TM (AE 941), tetrathiomolybdate (Coprexa ^TM ), AMG 706 (Amgen), VEGF Trap (AVE 0005), CEP 7055 (Sanofi-Aventis), XL 880 (Exelixis), tilatinib (BAY 57-9352) and CP-868,596 (Pfizer).

Other examples of anti-angiogenic agents that can be used in combination with the compounds of the present invention and the pharmaceutical compositions described herein include celecoxib (Celebrex ^™ ), parecoxib (Dynastat ^™ ), delacoxib (SC 59046), Rumicoxib (Preige ^TM ), valdecoxib (Bextra ^TM ), rofecoxib (Vioxx ^TM ), eramimod (Careram ^TM ), IP 751 (lnvedus), SC-58125 (Pharmacia) and etoricoxib ( Arcoxia TM). Other anti-angiogenic agents include epoxifen (Aptosyn TM), disalicylate (Amigesic ^TM ), diflunisal (Dolobid ^TM ), ibuprofen (Motrin ^TM ), ketoprofen (Orudis ^TM ), naphthalene Butamethone (Relafen ^TM ), Piroxicam (FeldeneTM), Naproxen (AIeveTM, Naprosyn TM), Diclofenac (Voltaren TM), Indomethacin (Indocin ^TM ), Sulindac (ClinoriI ^TM ), Tol Metotin (Tolectin ^™ ), etodolac (Lodine ^™ ), ketorolac (ToradoI ^™ ) and oxaprozin (Daypro ^™ ). Other anti-angiogenic agents include ABT 510 (Abbott), Alestat (TMI 005), AZD 8955 (AstraZeneca), Incoside (Metastat ^™ ), and PCK 3145 (Procyon). Other anti-angiogenic agents include avid A (Neotigason TM), pritilidine (aplidine TM), slantide (EMD 121974), combretastatin A4 (CA4P), retinophenamine (4 HPR) , Haloflavone (Tempostatin ^TM ), Panzem ^TM (2-methoxyestradiol), PF-03446962 (Pfizer), Rimastat ( BMS 275291), catumaxomab (Removab ^TM ), Nalidomide (Revlimid ^™ ), squalamine (EVIZON ^™ ), thalidomide (Thalomid ^™ ), Ukrain ^™ (NSC 631570), Vitaxin ^™ (MEDI 522) and zoledronic acid (Zometa™).

In another embodiment, the anticancer agent is a so-called signal transduction inhibitor (e.g., a method of inhibiting intracellular communication of regulatory molecules that regulate the basic processes of cell growth, differentiation, and survival). Signal transduction inhibitors include small molecules, antibodies and antisense molecules. Signal transduction inhibitors include, for example, kinase inhibitors (eg, tyrosine kinase inhibitors or serine/threonine kinase inhibitors) and cell cycle inhibitors. More specifically, signal transduction inhibitors include, for example, farnesyl protein transferase inhibitors, EGF inhibitors, ErbB-1 (EGFR), ErbB-2, pan erb, IGF1 R inhibitors, MEK, c-Kit inhibition Agent, FLT-3 inhibitor, K-Ras inhibitor, Pl3 kinase inhibitor, JAK inhibitor, STAT inhibitor, Raf kinase inhibitor, Akt inhibitor, mTOR inhibitor, P70S6 kinase inhibitor, WNT pathway inhibitor and So-called multi-targeted kinase inhibitors. Preferred signal transduction inhibitors include gefitinib (Iressa ^TM ), cetuximab (Erbitux ^TM ), erlotinib (Tarceva ^TM ), trastuzumab (Herceptin ^TM ), sunitinib (Sutent ^™ ) and Imatinib (Gleevec ^™ ).

Additional examples of signal transduction inhibitors that can be used in combination with the compounds of the present invention and the pharmaceutical compositions described herein include BMS 214662 (Bristol-Myers Squibb), Lonafani (Sarasar ^™ ), Piritrexol (AG 2037) , Matuzumab (EMO 7200), nimotuzumab (TheraCIM h-R3 ^TM ), panitumumab (Vectibix ^TM ), vandetanib (Zactima ^TM ), pazopanib (SB 786034) , ALT 110 (Alteris Therapeutics), BIBW 2992 (Boehringer Ingelheim) and Cervene ^™ (TP 38). Other examples of signal transduction inhibitors include PF-2341 066 (Pfizer), PF-299804 (Pfizer), Carnetinib, Pertuzumab (Omnitarg ^TM ), Lapatinib (Tycerb ^TM ), Peliv Tinib (EKB 569), Miltefosin (Miltefosin ^TM ), BMS 599626 (Bristol-Myers Squibb), Lapuleucel-T (Neuvenge ^TM ), NeuVax ^TM (E75 cancer vaccine), Osidem ^TM , Muritinib (TAK) -165), panitumumab (Vectibix ^™ ), lapatinib (Tycerb ^™ ), peritinib (EKB 569) and pertuzumab (Omnitarg ^™ ). Other examples of signal transduction inhibitors include ARRY 142886 (Array Biopharm), everolimus (Certican ^™ ), zotarolimus (Endeavor ^™ ), tamsirolimus (ToriseI ^™ ), and AP 23573 (ARIAO). In addition, other signal transduction inhibitors include XL 647 (Exelixis), sorafenib (Nexavar ^™ ), LE-AON (Georgetown University) and GI-4000 (Globelmmune). Other signal transduction inhibitors include ABT 751 (Abbott), flapine (alvocidib/flavopiridol), BMS 387032 (Bristol Myers), EM 1421 (Erimos), N-(3-chloro-1H-indol-7-yl )-1,4-benzenedisulfonamide (E 7070), celecicily (CYC 200), BIO 112 (One Bio), BMS 387032 (Bristol-Myers Squibb), PO 0332991 (Pfizer) and AG 024322 (Pfizer ).

Among the signal transduction inhibitors suitable for combination with the agent of the present invention, it is considered that erlotinib, gefitinib, lapatinib, icotinib, afatinib, nalatinib, Peletinib and other erbB family inhibitors exemplified by dacomitinib are of particular interest. All of these compounds have sufficient wild-type erbB kinase inhibitory activity to have mechanism-based dose limiting toxicity, but all can be administered at tolerable levels and have demonstrated good clinical activity. One of its main weaknesses is that tumors that respond adequately to these drug treatments tend to have erbB mutations. These mutations make the tumors rarely susceptible to this inhibitor, but when combined with a second mutation, they tend to make the Tumors are very resistant to these agents. The selection pressure to accelerate this process has been discussed above. The compounds of the present invention target major resistance mutants, and because they have very little activity against wild-type enzymes, they will not significantly increase the mechanism-based toxicity. However, it will put the developing double mutant at the same selection disadvantage as the original susceptible mutant, and therefore will greatly slow down or possibly completely prevent the emergence of resistant cell lines. Therefore, this combination will prove extremely clinically applicable.

The present invention contemplates the use of the compounds of the present invention together with classic antitumor agents. Classic anti-neoplastic agents include hormone modulators (such as hormones, antihormones, androgen agonists, androgen antagonists, and anti-estrogen therapeutic agents), histone deacetylase (HOAC) inhibitors, gene silencing agents or genes Activator, ribonuclease, protein mimetics, topoisomerase I inhibitors, camptothecin derivatives, topoisomerase II inhibitors, alkylating agents, antimetabolites, poly(AOP-ribose) polymerase -1 (PARP-1) inhibitors, tubulin inhibitors, antibiotics, plant-derived spindle inhibitors, platinum coordination compounds, gene therapy agents, antisense oligonucleotides, vascular targeting agents (VTA) and Statin.

Examples of antitumor agents used in combination with the compounds of the present invention include Velcade (bortezomib), 9-aminocamptothecin, belonotecan, camptothecin, diflutecan, edotroline, etha Teichican (Daiichi), Gimatacan, 10-Hydroxycamptothecin, Irinotecan HCI (Camptosar), Letotecan, Orathecin (Supergen), Topotecan, Camptothecin, 10-hydroxy Camptothecin, 9-aminocamptothecin, irinotecan, edotecline, topotecan, arubicin, doxorubicin, aminafilte, amrubicin, anthanamycin, doxorubicin Novomycin, doxorubicin, ixaloxacin, epirubicin, etoposide, idamycin, carbrubicin, hydroxycarbamide diamine, nemorubicin, normectin (rice (Toranthraquinone), Zoxorubicin, Pixartron, Procarbazine, Phlebromycin, Sobuzocin, Tafluposide, Pentarubicin, Zinecard (dexpropylimine), Nitrogen mustard N-oxide, Cyclophosphamide, hexamelamine, AP-5280, Apazone, Brotaxine, bendamustine, busulfan, carboquinone, carmustine, chlorambucil, dacarbaba Azine, estramustine, formustine, glufosfamide, ifosfamide, lomustine, malafilamide, dichloromethyldiethylamine, melphalan, dibromomannitol, Dibromomantelol, mitomycin C, mitoxantrone, nimustine, ramustine, temozolomide, titipipe and platinum coordination alkylated compounds (such as cisplatin, Paraplatin (carboplatin) , Etaplatin, leproplatin, nedaplatin, Eloxatin (oxaliplatin, Sanofi), streptozotocin, saplatin, and combinations thereof).

The present invention also covers the use of the compounds of the present invention together with the following: dihydrofolate reductase inhibitors (such as methotrexate and trimetrexate glucuronate), purine antagonists (such as 6-mercaptopurine riboside , Mercaptopurine, 6-thioguanine, cladribine, clofarabine (Clolar), fludarabine, nairabine and raltitrexed), pyrimidine antagonists (such as 5-fluorouracil), Alimta (pemetrex) Tracetin disodium), capecitabine (Xeloda TM), cytosine cytarabine, Gemzar ^TM (gemcitabine), Tegafur, deoxyfluridine, carmofluor, cytarabine (including alkane phosphate, (Phosphate, stearate, sustained release and liposome forms), enoxitabine, 5-azacitidine (Vidaza), decitabine and ethynylcytosine nucleosides) and other antimetabolites (such as Eflornithine, hydroxyurea, methyltetrahydrofolate, Thymitaq, triamcinolone, trimetrisa and N-(5-[N-(3,4-dihydro-2-methyl -4-oxoquinazoline-6-ylmethyl)-N-methylamino]-2 thiophenemethylthiophenemethyl)-L-glutamic acid and combinations thereof).

Other examples of classic anti-tumor cytotoxic agents used in combination therapy using the compound of the present invention and optionally one or more other agents include Abraxane (Abraxis BioScience, Inc.), Batabrine (Amgen), and vinflunine (Bristol-Myers Squibb Company), actinomycin D, bleomycin, mitomycin C, Zinostatin, vinblastine, vincristine, vindesine, navelbine , Docetaxel (Taxotere), Otaxel, Pacific paclitaxel (including Taxoprexin, a DHA/paclitaxel conjugate), cisplatin, carboplatin, nedaplatin, oxaliplatin (Eloxatin), saplatin, Camptosar , Capecitabine (Xeloda), oxaliplatin (Eloxatin), taxotere alleviate A-acid, camphoramide (Telcyta ^TM ), DMXAA (Antisoma), ibandronic acid, L-aspartame Enzymes, Pegasparase (Oncaspar ^TM ), Efaproxiral (Efaproxyn ^TM -Radiation Therapy)), Bexarotene (Targretin ^TM ), Telmilifene, Theratope ^TM (Biomira), Tretinoin (Vesanoid ^TM ), Tirapaza Trizaone ^™ , Xcytrin ^™ Cotara ^™ (mAb) and NBI-3001 (Protoxb Therapeutics), polyglutamine-paclitaxel (Xyotax ^™ ) and combinations thereof.

Examples experiment Synthesis of compounds of the invention

The compounds of the present invention can be prepared by various processes known to those skilled in the art, and some synthetic schemes for preparing these compounds are described below.

The compound of the present invention can be regarded as composed of four cascade components; ring A (A'), which can be monocyclic or bicyclic; central azine ring (B'), which is usually 2,4,(5 )-Substituted pyrimidine (or bicyclic homologue); aniline (C') or 3-aminopyridine moieties; and affinity on the other C'ring to form a cascade A'-B'-C'-D' structure Electronic side chain (D'). This allows each of the four components to be used in combination with the other three components, thereby allowing a large number of analogs to be synthesized from relatively few structural units in a frugal and effective manner.

Several of the synthesis described in this document start by preparing the A'subunit and then attaching it to the B'subunit to form the A'-B' part through various chemical methods known to those skilled in the art, Many of these chemical methods are exemplified below. The C-unit is now attached by replacing the halogen atom on the B'-ring with a free primary amine of the C-unit to form the A'-B'-C' entity. The C-entity has an initial primary amine that is not masked by reducing a precursor group such as nitro or azide or by deprotecting the protected primary amine, and then the D-subunit is acylated Or the sulfonation reaction is attached to this free amine.

In many cases, despite acting as an electrophile in vivo, the D-subunit is actually a very weak electrophile and can withstand a reasonable variety of chemical reaction conditions, which appears to be particularly consistent with acrylamide and acetamide Based on D'substance. In addition, once incorporated into a larger entity, the A'-subunit can have quite different chemical reactivity from each other, sometimes making it modified later in the synthesis, and other times making it generally inert in subsequent reactions . The azine ring in the A'-B'-C' cascade entity tends to have low chemical reactivity. This allows the use of other reaction sequences. For example, if the A'moiety is sometimes slightly chemically reactive, it can be after A'-B' coupling, or after the A'-B'-C' entity is assembled, or sometimes even at A'-B' -After the complete assembly of the C'-D' entity, final chemical modification of the A'- part. Or the A'-B'-C' entity can be assembled, and then the C-ring can be modified, for example, by replacing the ortho-electrophilic fluorine of the nitro group with an R ³ amine, thiol, or alkoxide nucleophile. Those skilled in the art may find multiple opportunities to produce such deviations in "canonical" linear AD assembly, and several such reaction sequences are illustrated in the following reactions. See also PCT/US2017/012466.

A'-B' coupling

The central azine ring of the present invention can be obtained commercially with two halogen atoms (Q ¹ and Q ² ) in a 1,3-relationship with each other, and one of these halogens can always be preferentially replaced by the other ( Even if the original azine is symmetrical). Generally, the more reactive Q group (which is 4-chloro in the case of 2,4-dichloropyrimidine) can be replaced by nitrogen or carbon nucleophiles in good yield, leaving another group later Replaced by amine nucleophiles under potentially drastic conditions. In the case of pyrimidine, the A'-B' biaryl moiety is usually 4-substituted-2-chloropyrimidine, and most of the synthesis disclosed in this patent uses these intermediates. It is listed as an A intermediate in the experimental section.

The biaryl groups described herein can be linked together to the C atom of the central B'azine through the C or N atom on A'. If the A'moiety is connected via a 6-membered ring, the biaryl group must be prepared by carbon-carbon bond formation. Such synthesis is well known to those skilled in the art, and may involve Stille, Negishi Ullmann or Suzuki type catalytic reactions, or a variety of variations thereof, along with several other reaction sequences, which are known to those skilled in the art . If the connecting part of the A'- moiety is a five-membered aromatic ring containing an N atom, the ring can usually be attached via a C atom or an N atom. Proton extraction can drive toward C or N alkylation, depending on the precise system and the nature of the relative ions and catalyst present, and especially in the case of indole-like aromatics, N-to-C alkylation is usually familiar This technician has full control.

In addition, once the A'-B' biaryl group has been formed, it is usually possible to selectively react on the A'- portion of the molecule because the second halogen usually has a relatively low reactivity. Several such examples are illustrated in the experimental disclosure below. See also PCT/US2017/012466.

The C'-subunit contains a primary amine which will be used to replace the second Q substance. This can be carried out under acid catalysis (the most common method) or basic catalysis conditions or with transition metal catalysis, and such catalysis is fully exemplified in the prior art (eg, Buchwald reaction), and in some of the following examples. Although not specifically discussed above or exemplified below, it is also possible to replace the halogen with a primary amine of aniline, and the second Q group with ammonia or a suitable precursor (azide, trifluoroacetamide, sulfonamide, etc.) Group, modified if necessary, and then replacing the halogen on the C-unit under transition metal catalyzed conditions, then if an activating group is used, the activating group is removed from the nitrogen. The C'-portion also contains an amine precursor for attaching electrophilic D'-portions, especially nitro or in the form of a protected amine, especially a third Boc amine group. 3-Nitro has the advantage that it can activate its ortho-leaving group at the 4-position for nucleophilic substitution, thereby easily introducing multiple R ³ side chains, especially amines, at that position. Having a 4-substituent on the C'-partial fluorine is particularly beneficial for promoting this reaction, but other side chains (including carbon-linked side chains) can be obtained by having other halogens at the 4-position and then performing a transition metal coupling reaction (such as Stille, Suzuki, Sonogashira and Buchwald reaction).

The A'-B'-C' entity can be easily constructed to facilitate modification on the A'or C'part. Since the amine on the C'aromatic ring to be connected to the D'-electrophile is a primary amine, which needs to be protected during the B'-C' coupling, the reaction at this position is almost always required, and disclosed herein Most of the synthesis has this reaction. However, if the 3-amine precursor is highly activated, in order to replace the 4-halogen (for example, nitro), (A'-)B'-C' coupling can be performed before introducing R ³ and R ^{3 is} introduced into A Some examples of'-B'-C' entities are disclosed below. See also PCT/US2017/012466.

Generally, the electrophilic D'moiety is added at the end of the synthesis to produce the completed compound of the invention. However, as mentioned above, several D'-groups have sufficiently low chemical reactivity, especially when present as relatively weak electron-withdrawing amides, to allow for the completion of A'-B-'C'-D 'Physically undergo various transformations, especially when certain groups are introduced onto the A'-part, these groups may have interfered with some early chemistry, and some of these examples are also disclosed below. See also PCT/US2017/012466.

In principle, the B'-C' coupling should cooperate with the preformed complete C'-D' fragment, because the aniline/3-aminopyridine fragment with the attached D'unit will have at least the majority of the " The "monomer" C'part is also nucleophilic and is a primary amine for B'-C' coupling. Here, the same C'part starting material can be used as before, but the 1-amine needs to be protected, the 3-amine is not masked, it is acylated or sulfonated, and then the 1-amine is deprotected. Then, this C'-D' fragment can be used to couple to a suitable A'-B' fragment to form the final A'-B'-C'-D' entity, and several such synthesises are disclosed below. See also PCT/US2017/012466.

Therefore, the reactions described in this patent application make it possible not only to prepare the exemplified compounds of the present invention, but also to use the reactions described herein, and the variations in the chemical literature available to those skilled in the art that are readily available, allowing the production of multiple Other compounds, including those claimed in this patent application, are not specifically exemplified. In addition, as mentioned earlier, due to the modular nature of the compounds of the present invention, and the ability to prepare several examples of each module, a large number of compounds can be produced using the chemical methods achieved by the disclosure in this application. See also PCT/US2017/012466. For example, using the reaction conditions discussed in this application, one can use 3-aminopyridyl C'moieties instead of 3-anilino C'moieties in combination with most A'-B' moieties disclosed in this patent. As another example, the replacement of the 4-fluoro group on the nitroaniline of the precursor to the C'- moiety can be replaced by a variety of amines using the conditions disclosed in this document. See also PCT/US2017/012466.

Scheme 1 shows a general scheme for preparing the compounds of the present invention, and the description is as follows. A is A ¹ , which is connected to the 6,5-bicyclic system of the five-membered ring via the 1-(3-) position of the central azine ring, and Y It is α,β-unsaturated enamine. The synthesis involves the preparation of five components: appropriately substituted azine 1A , which contains leaving groups Q ¹ and Q ² , and usually but not necessarily halogens in the ortho and para positions of the specific nitrogen; suitable A group 2A ( In this case A ¹ ), where T ¹ represents a group that is a suitable coupling partner for Q ¹ ; a suitable m-nitroaniline or 3-amino-5-nitrate with a leaving group Q ³ (possibly halogen) Pyridine 4A ; the appropriate side chain R ³ T ² , that is 5 A , where T ² (usually hydrogen) is the appropriate leaving group for coupling via Q ³ substitution; and finally, the appropriate electrophile 9A , here by Enil chloride shows that Q ⁴ is a suitable leaving group for coupling with aromatic amines. Some of components 1A , 2A , 4A , 5A, and 9A are commercially available, and if they are not available, they can be prepared by methods known to those of ordinary skill.

This synthetic scheme describes a commonly used strategy, which basically has an A'connected sequentially to B', which is then attached to the C'part, which already has an attached R ³ side chain, and Then after reducing the nitro group, D'is attached to complete the synthesis. In the first step of Scheme 1, the azine 1A as the B'moiety is coupled to the A'moiety [6.5]-bicyclic 2A (at its 1- or 3-position) at its 4-position, with Q ¹ T ¹ The total loss is to form intermediate 3A . These couplings will frequently replace halide ions by nitrogen or nitrogen-based anions, but may also involve methods familiar to those skilled in the art (such as Stille, Negishi or Suzuki coupling, or Freidel-Crafts aryl substitution) Form a carbon-carbon bond. In step 2, Q ³ on 4A is replaced by 5A with a loss of Q ³ T ² to form intermediate 6A , the complete C'part. These couplings will frequently replace halide ions with nitrogen or nitrogen-based anions, but may also involve the formation of carbon-carbon bonds by methods familiar to those skilled in the art, such as Stille, Negishi, or Suzuki couplings.

In step 3, 6A amine nitrogen is used, and Q ^{2 is} replaced from the A'-B' part (intermediate 3A ) using methods known to those skilled in the art to form the A'-B'-C' cascade intermediate Body 7A . The nitro group of 7A is then reduced to the amine group of intermediate 8A using methods well known to those of ordinary skill, such as iron/acetic acid or catalytic hydrogenation. The synthesis of the complete A'-B'-C'-D' final product (in this illustrative general case 10A ¹ Y ¹ ) is accomplished by coupling the amine 8A with the amide of the appropriate enoic acid derivative 9A , in which the leaving group Q ⁴ may be a halide, activated ester, acid plus coupling agent or other activated acid derivatives known to those skilled in the art to be suitable for peptide coupling. Other compounds of the invention are prepared by similar processes, have different A and Y groups, use appropriate starting materials and coupling reactions, which are well known to those skilled in the art.

In Flow 2, one of the alternative strategies is described, using components similar to those in Flow 1. In this case, the illustrative A ¹ (A′) component is a 5-linked 6,5-azaaromatic system. The first step is the same as previously in Scheme 1, in which A'part 2B is coupled to B'azine 1A by the same type of reaction as previously described to form 3B , the A'-B' entity. Two alternative pathways 2A and 2B are described here to form a C'-D' fragment, which will be coupled with A'-B' later or at the end of the sequence because of the best chemistry It must be very different from the requirements for aniline and pyrimidine in Scheme 1.

In Scheme 2A, the starting nitroaniline 4B is similar to 4A , except that the amine is properly protected. The R ³ portion was introduced by substitution of Q ³ as before, and then the nitro group was reduced to an unprotected amine to generate the appropriate C′ fragment 6B . This fragment is then acylated with the D'moiety 9A on the free amine, and the coupling-ready C'D' entity 11B is completed by removing the protecting group from the original amine. In Scheme 2B, the high and selective reactivity of halonitropyridine allows simple preparation of the 4C moiety, where W is a group that can easily become an amine later. It can even be a proton, because after R ³ has been introduced by the 5A substitution of Q ³ , the 5-position of the pyridine is quite highly activated for electrophilic aromatic substitution. Substitution with free amine under non-reducing conditions will generate the C'entity as nitroaniline 6C , where the free amine is acetylated by the D'entity 9A at the correct position. Moderate reduction of 3-nitro to amine will complete the preparation of this C'-D' part 11C in a form ready for final coupling.

In many cases, the step that will be the final step of the synthesis, the Q2 fragment on 3A is replaced with a free amine on 11B or 11C , using the same kind of coupling, which is used to make A'as described in Scheme 1 The B'fragment is coupled to the C'part to produce entities 12A ¹ Y ¹ and 13A ¹ Y ¹ . Many of the same conditions can be used here, because the acrylamide D'moiety is particularly generally robust enough to withstand the amine replacement reaction used here. Alternatively, we can use the precursor of the final D'electrophile in this reaction and activate the final electrophile after this coupling is complete.

For examples of synthesis, see International Application No. PCT/US2017/012466, the disclosure of which is incorporated herein in its entirety for all intended purposes.

Intermediate A1. 2-chloro-4-(3-( N , N -dimethylamino)-6-methyl-pyrazolo[4,3-c]pyridin-1-yl)pyrimidine

4-Hydroxy-6-methylnicotinic acid methyl ester. A solution of 4-hydroxy-6-methylnicotinic acid (50.0 g, 261.4 mmol, 1.0 eq) in methanol (750 mL) was cooled to 0° C. and washed with SOCl ₂ (205.0 g, 1533 mmol, 5.0 eq) over 20 minutes. Drop treatment. The reaction mixture was warmed to 25°C, heated at 70°C for 20 hours, and concentrated. The resulting residue was washed with methanol (50 mL), filtered and dried to provide the product 4-hydroxy-6-methylnicotinic acid methyl ester (54.0 g, 99%). ¹ H NMR (300 MHz, CDCl ₃ ): δ 9.05 (s, 1H), 7.13 (s, 1H), 4.09 (s, 3H), 2.90 (s, 3H). ESI-MS (m/z): 168.0 (M+H) ⁺ .

4-Hydroxy-6-methylnicotinamide. A suspension of the product methyl 4-hydroxy-6-methylnicotinate (25.0 g, 149 mmol, 1.0 eq) in ammonia water (500 mL) was heated at 50° C. for 20 hours. The reaction mass was then concentrated, and the resulting residue was washed with a mixture of diethyl ether and DCM (100 mL, 8:2). The resulting solid was collected and dried under reduced pressure to provide the product 4-hydroxy-6-methylnicotinamide (20.0 g, 88%) as an off-white solid. ESI-MS (m/z): 151.0 (MH) ^- .

4-chloro-6-methylnicotinonitrile. A suspension of the product 4-hydroxy-6-methylnicotinamide (20.0 g, 131.5 mmol, 1.0 eq) in POCl ₃ (62 mL, 580 mmol, 4.4 eq) was heated at 110° C. for 5 hours. The mixture was cooled to 10°C and quenched with aqueous Na ₂ CO ₃ solution (200 ml). The mixture was then extracted with EtOAc (250 mL×3), and the combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified by chromatography (silica gel; 4-5% EtOAc in petroleum ether as the dissolving solvent) to provide the product 4-chloro-6-methylnicotinic acid nitrile (8.0 g, 40 %). ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 8.96 (s, 1H), 7.79 (s, 1H), 2.50 (s, 3H). ESI-MS (m/z): 153.0 (M+H) ⁺ .

3-amino-6-methyl- 1H -pyrazolo[4,3-c]pyridine. To a mixture of compound 4-chloro-6-methylnicotinic acid nitrile (8.0 g, 52.6 mmol, 1.0 eq) in n-butanol (80 mL) was added hydrazine hydrate (7.9 g, 158 mmol, 3.0 eq). Heat to reflux under nitrogen for 12h. The reaction mixture was allowed to cool to room temperature, and the solid was collected by filtration and washed with ethyl acetate (30 mL×2). Dry to produce compound 3-amino-6-methyl- 1H -pyrazolo[4,3-c]pyridine (5.0 g, 64%). ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 11.61 (br, 1H), 8.80 (s, 1H), 6.97 (s, 1H), 5.69 (s, 2H), 2.46 (s, 3H). ESI-MS (m/z): 149.0 (M+H) ⁺ .

2-chloro-4-(3-amino-6-methyl-pyrazolo[4,3-c]pyridin-1-yl)pyrimidine. t- BuOK (4.16g, 37.1mmol, 1.1eq) was carefully added to 3-amino-6-methyl- 1H -pyrazolo[4,3-c]pyridine (5.0g, 33.7) at 0°C mmol, 1.0 eq) in a solution in DMF (50 mL). The mixture was stirred at this temperature for 10 minutes. Then a solution of 2,4-dichloropyrimidine (5.53 g, 37.1 mmol, 1.1 eq) in DMF (25 mL) was added dropwise. The mixture was stirred at RT for 2h. After completion, the mixture was diluted with water (250 mL), filtered, and washed with water (20 mL×2). The filter cake is then dried and purified by silica gel column chromatography to produce the desired product 2-chloro-4-(3-amino-6-methyl-pyrazolo[4,3-c]pyridine-1- Base) pyrimidine (2.5g, 28%). ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 9.04 (s, 1H), 8.59 (d, J = 5.7 Hz, 1H), 8.13 (s, 1H), 7.53 (d, J = 5.7 Hz, 1H) , 2.63 (s, 3H). ESI-MS (m/z): 260.9 (M+H) ⁺ .

2-chloro-4-(3-( N , N -dimethylamino)-6-methyl-pyrazolo[4,3-c]pyridin-1-yl)pyrimidine. NaH (0.84g, 21.1mmol, 2.2eq) was carefully added to 2-chloro-4-(3-amino-6-methyl-pyrazolo[4,3-c]pyridine-1- at 0°C Yl)pyrimidine (2.5 g, 9.6 mmol, 1.0 eq) in a solution in DMF (25 mL), and the mixture was stirred at this temperature for 30 minutes. Then MeI (2.98 g, 21.1 mmol, 2.2 eq) was added dropwise. After the addition, the mixture was warmed to RT and stirring continued for 2 hours until completion. The mixture was poured into water (100 mL), and extracted with EA (50 mL×3). The combined organic layer was washed twice with brine, dried over sodium sulfate, concentrated and purified by silica column chromatography to produce the desired product 2-chloro-(3-( N , N -dimethylamino )-6-methyl-pyrazolo[4,3-c]pyridin-1-yl)pyrimidine (0.2 g, 7%). ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 9.26 (s, 1H), 8.70 (d, J = 5.7 Hz, 1H), 8.34 (s, 1H), 7.77 (d, J = 5.7 Hz, 1H) , 3.32 (s, 6H), 2.70 (s, 3H). ESI-MS (m/z): 288.9 (M+H) ⁺ .

A2. 2-chloro-4-(7-cyano-1,3-dimethyl- 1H -indol-5-yl)pyrimidine

5-Bromo-7-cyano-1,3-dimethyl- 1H -indole. To a stirred solution of 3-methyl-5-bromo-7-cyanoindole (1.17 g, 5 mmol) in THF (20 mL) was carefully added NaH (260 mg, 6.5 mmol) in portions at 0°C. The mixture was stirred at 0 °C for 30 min, and then MeI (781 mg, 5.5 mmol) was added dropwise. After the addition, the reaction mixture was stirred at room temperature for 2 h and quenched with water, the solution was extracted with EtOAc (20 mL×3) and dried over sodium sulfate, filtered and concentrated in vacuo to generate a crude residue, which was a crude residue The material was purified by silica gel chromatography to produce 5-bromo-7-cyano-1,3-dimethyl- 1H -indole (694 mg, 56%). ¹ H NMR(300MHz,CDCl ₃ ): δ 7.87(d, J =1.5Hz,1H),7.60(d, J =1.5Hz,1H),6.88(s,1H),4.06(s,3H),2.28 (s,3H).

7-cyano-1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 H- Indole. To a solution of 5-bromo-7-cyano-1,3-dimethyl- 1H -indole (523mg, 2.1mmol, 1.0eq) in dioxane (5mL) was added bis(pinacolyl group ) Diboron (592 mg, 2.3 mmol, 1.1 eq), KOAc (125 mg, 6.3 mmol, 3.0 eq) and Pd(dppf)Cl ₂ (124 mg, 0.168 mmol, 0.08 eq). The mixture was purged with nitrogen three times, followed by heating at 85°C under nitrogen for 6 hours. After TLC and LCMS indicated completion, the mixture was filtered, the filtrate was concentrated and purified by silica column to provide 7-cyano-1,3-dimethyl-5-(4,4,5,5-tetramethyl Yl-1,3,2-dioxaborolan-2-yl)-1 H -indole (350 mg, 56%). ¹ H NMR(300MHz,CDCl ₃ ): δ 8.23(s,1H),7.99(s,1H),6.85(s,1H),4.09(s,3H),2.33(s,3H),1.39(s, 12H).

2-chloro-4-(7-cyano-1,3-dimethyl- 1H -indol-5-yl)pyrimidine. To 7-cyano-1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 H -Indole (296mg, 1.0mmol, 1.0eq) in dioxane (5mL) and water (1mL) was added 2,4-dichloropyrimidine (162mg, 1.1mmol, 1.1eq), Pd (PPh ₃ ) ₄ (115 mg, 0.1 mmol, 0.1 eq) and K ₂ CO ₃ (411 mg, 3.0 mmol, 3.0 eq). The mixture was purged with nitrogen three times, followed by heating at 100°C under nitrogen for 3 hours. After TLC and LCMS indicated completion, the mixture was filtered, the filtrate was concentrated and purified by silica column to produce 2-chloro-4-(7-cyano-1,3-dimethyl- 1H -indole- 5-yl)pyrimidine (164mg, 58%). ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 8.65 (d, J =5.1 Hz, 1H), 8.55 (s, 1H), 8.29 (s, 1H), 7.70 (d, J = 5.1 Hz, 1H) , 6.95 (s, 1H), 4.13 (s, 3H), 2.35 (s, 3H).

A3. 2-chloro-4-(1, N -(third butoxycarbonyl)-7-cyano-3-methyl-pyrrolo[2,3-c]pyridin-4-yl)pyrimidine

3-amino-2-cyanopyridine. A solution of 2-cyano-3-fluoropyridine (5.0 g, 41 mmol, 1.0 eq) in DMSO (50 mL) was bubbled with ammonia gas at 70° C. for 6 h. After completion and cooling to room temperature, water (80 mL) was added, extracted with EA (100 mL×3), the combined organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to produce a crude residue, the The crude residue was purified by silica column to produce 3-amino-2-cyanopyridine (3.0 g, 61%). ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 7.85 (d, J = 3.0 Hz, 1H), 7.33-7.30 (m, 1H), 7.21-7.19 (m, 1H), 6.30 (br, 2H).

3-amino-4,6-dibromo-2-cyanopyridine. 3-Amino-2-cyanopyridine (3.0 g, 25.2 mmol, 1.0 eq) was dissolved in DMF (30 mL) and N-bromosuccinimide (10.1 g, 56.7 mmol, 2.3 eq) was added. The solution was stirred at room temperature for 20 h, then water (40 mL) was added. The mixture was extracted with EA (50 mL×3), the combined organic layer was washed with water and brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography to provide 3-amino-4,6-dibromo-2-cyanopyridine (4.0 g, 57%). ¹ H NMR (300 MHz, CDCl ₃ ): δ 7.74 (s, 1H), 4.95 (br, 2H). ESI-MS (m/z): 275.6 (MH) ^- .

3-(allylamino)-4,6-dibromo-2-cyano-pyridine. To a solution of 3-amino-4,6-dibromo-2-cyanopyridine (4.0 g, 14.4 mmol, 1.0 eq) in THF (40 mL) at 0°C was added dropwise t- BuOK (2.4 g , 21.6 mmol, 1.5 eq) in THF. The mixture was kept at this temperature for 10 min. Then 3-bromoprop-1-ene (1.7 g, 14.4 mmol, 1.0 eq) was added dropwise and the mixture was stirred at RT for 2 h. After TLC and LCMS indicated completion, the mixture was quenched with water (50 mL) and extracted with EA (50 mL×3). The combined organic layer was washed with brine (100 mL), dried over sodium sulfate, and concentrated to provide a crude residue, which was purified by column chromatography to provide 3-(allylamino)-4, 6-dibromo-2-cyano-pyridine (1.2g, 26%). ¹ H NMR(300MHz,CDCl ₃ ): δ 7.72(s,1H),6.02-5.86(m,1H),5.36-5.25(m,1H),4.88-4.86(m,1H),4.41-4.31(m , 2H), 4.04 (br, 1H).

5-Bromo-7-cyano-3-methyl-1 H -pyrrolo[2,3-c]pyridine. To a solution of 3-(allylamino)-4,6-dibromo-2-cyano-pyridine (8.0 g, 25.2 mmol, 1.0 eq) in MeCN (80 mL) was added TEA (7.64 g, 75.7 mmol, 3.0 eq), Pd(OAc) ₂ (610 mg, 2.52 mmol, 0.1 eq) and tri-o-tolylphosphine (1.53 g, 5.04 mmol, 0.2 eq). The mixture was purged with nitrogen three times, followed by reflux for 2 hours. After TLC and LCMS indicated completion, the mixture was diluted with water (150 mL), MeCN was removed under reduced pressure, and extracted with EA (100 mL×3). The combined organic layer was washed with saturated NH ₄ Cl (100 mL), dried over sodium sulfate, concentrated and purified on a silica column to provide 5-bromo-7-cyano-3-methyl-1 H -pyrrolo [2,3-c]pyridine (2.5g, 42%). ESI-MS (m/z): 235.8 (M+H) ⁺ .

1, N -(third butoxycarbonyl)-7-cyano-3-methyl-1 H -pyrrolo[2,3-c]pyridine. To a solution of 5-bromo-7-cyano-3-methyl- 1H -pyrrolo[2,3-c]pyridine (2.5g, 10.6mmol, 1.0eq) in DCM (30mL) was added DMAP ( 130 mg, 1.06 mmol, 0.1 eq) and TEA (2.1 g, 21.2 mmol, 2.0 eq). A solution of Boc ₂ O (2.77 g, 12.7 mmol, 1.2 eq) in DCM (10 mL) was added dropwise. After the addition, the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo to produce a crude residue, which was purified by silica gel chromatography to produce 1, N -(third butoxycarbonyl)-7-cyano-3-methyl-1 H -pyrrolo[2,3-c]pyridine (1.5 g, 42%). ¹ H NMR (300 MHz, CDCl ₃ ): δ 7.80 (s, 1H), 7.59 (s, 1H), 2.25 (s, 3H), 1.70 (s, 9H). ESI-MS (m/z): 279.8 (M+H-56) ⁺ .

酸。向1,N-(第三丁氧基羰基)-7-氰基-3-甲基-1H-吡咯并[2,3-c]吡啶(672mg，2.0mmol，1.0eq)於二噁烷(6mL)中之溶液中添加雙(頻那醇基)二硼(609.6mg，2.4mmol，1.2eq)、KOAc(588mg，6.0mmol，3.0eq)及Pd(dppf)Cl₂DCM(73mg，0.1mmol，0.05eq)。該混合物用氮氣淨化三次，接著在氮氣下在85℃下加熱持續6小時。在TLC及LCMS指示完成之後，過濾該混合物，濃縮濾液且在矽石管柱上純化，提供(1,N-(第三丁氧基羰基)-7-氰基-3-甲基-1H-吡咯并[2,3-c]吡啶-5-基)

酸(200mg，33%)。¹H NMR(300MHz,DMSO-d ₆ )：δ8.18(s,1H),7.82(s,1H),7.51(br,2H),2.28(s,3H),1.63(s,9H)。ESI-MS(m/z)：245.9(M+H-56)⁺。 (1, N -(third butoxycarbonyl)-7-cyano-3-methyl-1 H -pyrrolo[2,3-c]pyridin-5-yl)

acid. To 1, N -(third butoxycarbonyl)-7-cyano-3-methyl-1 H -pyrrolo[2,3-c]pyridine (672 mg, 2.0 mmol, 1.0 eq) in dioxane To the solution in (6mL) was added bis(pinacolyl) diboron (609.6mg, 2.4mmol, 1.2eq), KOAc (588mg, 6.0mmol, 3.0eq) and Pd(dppf)Cl ₂ DCM (73mg, 0.1 mmol, 0.05eq). The mixture was purged with nitrogen three times, followed by heating at 85°C under nitrogen for 6 hours. After TLC and LCMS indicated completion, the mixture was filtered, the filtrate was concentrated and purified on a silica column to provide (1, N- (third butoxycarbonyl)-7-cyano-3-methyl-1 H -Pyrrolo[2,3-c]pyridin-5-yl)

Acid (200mg, 33%). ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 8.18 (s, 1H), 7.82 (s, 1H), 7.51 (br, 2H), 2.28 (s, 3H), 1.63 (s, 9H). ESI-MS (m/z): 245.9 (M+H-56) ⁺ .

酸(200mg，0.66mmol，1.0eq)於二噁烷(5mL)及水(1mL)中之溶液中添加2,4-二氯嘧啶(109mg，0.73mmol，1.1eq)、Pd(PPh₃)₄(76mg，0.066mmol，0.1eq)及K₂CO₃(273mg，1.98mmol，3.0eq)。該混合物用氮氣淨化三次，接著在氮氣 下在100℃下加熱持續3小時。在TLC及LCMS指示完成之後，過濾該混合物，濃縮濾液且在矽石管柱上純化，提供2-氯-4-(1,N-(第三丁氧基羰基)-7-氰基-3-甲基-吡咯并[2,3-c]吡啶-4-基)嘧啶(90mg，36%)。ESI-MS(m/z)：269.9(M+H-100)⁺。 2-chloro-4-(1, N- (third butoxycarbonyl)-7-cyano-3-methyl-pyrrolo[2,3-c]pyridin-4-yl)pyrimidine. To (1, N- (third butoxycarbonyl)-7-cyano-3-methyl-1 H -pyrrolo[2,3-c]pyridin-5-yl)

Acid (200mg, 0.66mmol, 1.0eq) was added 2,4-dichloropyrimidine (109mg, 0.73mmol, 1.1eq) in dioxane (5mL) and water (1mL) in the solution, Pd (PPh _{3) 4} (76 mg, 0.066 mmol, 0.1 eq) and K ₂ CO ₃ (273 mg, 1.98 mmol, 3.0 eq). The mixture was purged with nitrogen three times, followed by heating at 100°C under nitrogen for 3 hours. After TLC and LCMS indicated completion, the mixture was filtered, the filtrate was concentrated and purified on a silica column to provide 2-chloro-4-(1, N- (third butoxycarbonyl)-7-cyano-3 -Methyl-pyrrolo[2,3-c]pyridin-4-yl)pyrimidine (90 mg, 36%). ESI-MS (m/z): 269.9 (M+H-100) ⁺ .

A4. 2-chloro-4-(6-cyano-1-methyl-1 H -indol-4-yl)pyrimidine

3-bromo-4-methyl-5-nitrobenzoic acid. To a mixture of 4-methyl-3-nitrobenzoic acid (25.0 g, 138 mmol, 1.0 eq) in concentrated H ₂ SO ₄ (100 mL) at room temperature was added 1,3-dibromo-5, 5-Dimethylimidazolidine-2,4-dione (39.4 g, 152 mmol, 1.1 eq). When the addition was complete, the reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into ice water (500 g) with stirring to form a white solid, filtered and dried in vacuo to produce 3-bromo-4-methyl-5-nitrobenzoic acid (32 g, 89%). ¹ HNMR (300 MHz, DMSO-d ₆ ): δ 8.33-8.31 (m, 2H), 2.72 (s, 3H). ESI-MS (m/z): 257.7 (MH) ^- .

3-Bromo-4-methyl-5-nitrobenzoic acid methyl ester. To a solution of 3-bromo-4-methyl-5-nitrobenzoic acid (32.0 g, 123 mmol, 1.0 eq) in MeOH (1.2 L) was added concentrated H ₂ SO ₄ (5 mL) at room temperature. The mixture was heated to reflux and stirred for 8h. After TLC and LCMS indicated completion, the mixture was concentrated under reduced pressure to remove most of MeOH, diluted with EtOAc (200 mL), washed with saturated NaHCO ₃ (100 mL×2), the organic layer was dried over Na ₂ SO ₄ , at Concentrate in vacuo to obtain methyl 3-bromo-4-methyl-5-nitrobenzoate, which was used as a white solid in the next step without further purification (30 g, crude material). ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 8.36 (s, 2H), 3.90 (s, 3H), 2.54 (s, 3H).

4-Bromo-1 H -indole-6-carboxylic acid methyl ester. A solution of 3-bromo-4-methyl-5-nitrobenzoic acid methyl ester (20.0g, 73.0mmol, 1.0eq) and DMF-DMA (19.5mL, 146.0mmol, 2.0eq) in anhydrous DMF (100ml) Heat to 120°C and stir for 6h. After cooling to 25°C, the reaction was concentrated to dryness under reduced pressure. The residue was dissolved in AcOH (250 mL), and Fe powder (82 g) was added to the mixture with stirring. The mixture was heated to 100 °C and stirred overnight, cooled to room temperature, diluted with EtOAc and filtered through celite, extracted with EtOAc (500 mL), and washed sequentially with saturated NaHCO ₃ , water and brine. The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated to produce an orange solid. Further purified by column chromatography (SiO ₂ , 100-200m, by n-hexane/EtOAc=20: 1-10: 1 dissociation) to provide methyl 4-bromo- 1H -indole-6-carboxylate . (8.0g, 42%, two steps), as a yellow solid. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 11.92 (br, 1H), 8.08 (s, 1H), 7.80-7.70 (m, 2H), 6.50 (sl br s, 1H), 3.87 (s, 3H ). ESI-MS (m/z): 253.7 (M+H) ⁺ .

4-Bromo-1-methyl-1 H -indole-6-carboxylic acid. To a solution of methyl 4-bromo- 1H -indole-6-carboxylate (8.06g, 30.6mmol, 1.0eq) in DMF (50mL) was added NaH (60% in mineral oil) at 0°C in portions , 1.8g, 45.9mmol, 1.5eq). The stirred mixture was warmed to room temperature and stirred for 10 min. Cool to 0 °C again and then add MeI (6.5 g, 45.9 mmol, 1.5 eq) dropwise. The reaction mixture was stirred at room temperature for 1 h, poured into 0.5N HCl (30 mL), extracted with EtOAc (50 mL×2), washed with water (50 mL), brine (50 mL) and dried over sodium sulfate. After filtering and removing the solvent, the residue was dissolved in MeOH (30 mL) and THF (30 mL). NaOH (3M, 30 mL) was added, the mixture was stirred at room temperature for 2 h, LCMS showed no starting material left, the residue was diluted with H ₂ O (50 mL), washed with EtOAc (25 mL×1), the aqueous layer was borrowed Neutralize to pH 3~4 with 1N HCl, filter the solid formed and dry to provide 4-bromo-1-methyl- 1H -indole-6-carboxylic acid (7.5g, 57%) as a white solid . ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 13.1-12.8 (brs, 1H), 8.11 (s, 1H), 7.78 (s, 1H), 7.69 (d, J = 2.1 Hz, 1H), 6.47 ( sl brs, 1H), 3.89 (s, 3H).

4-Bromo-1-methyl-1 H -indole-6-carboxamide. To a solution of 4-bromo-1-methyl- 1H -indole-6-carboxylic acid (3.5 g, 13.8 mmol, 1.0 eq) and a drop of DMF (catalyst) in DCM (50 mL) at 0°C dropwise Oxalyl chloride (2.4 mL, 27.6 mmol, 2.0 eq) was added. When the addition was complete, the reaction mixture was warmed to room temperature with stirring for 3 h, and concentrated to dryness in vacuo. The crude material acetyl chloride was dissolved in anhydrous THF (20 mL) and added dropwise to a mixture of concentrated aqueous ammonia (10 mL) and THF (20 mL) at 0°C. When the addition was complete, the reaction mixture was stirred at rt for 1 h, extracted with EtOAc, washed with brine, dried over Na ₂ SO ₄ , filtered and purified by column chromatography to provide 4 as a white solid -Bromo-1-methyl- 1H -indole-6-carboxamide (2.5g, 71.4%). ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 8.11(s, 1H), 8.03(brs, 1H), 7.81(s, 1H), 7.62(s, 1H), 7.37(brs, 1H), 6.43( s, 1H), 3.87 (s, 3H). ESI-MS (m/z): 252.8 (M+H) ⁺ .

4-Bromo-6-cyano-1-methyl-1 H -indole. 4-bromo-1-methyl -1 H - indol-6-acyl-amine (2.5g, 9.8mmol, 1.0eq)) in toluene (50mL) in the solution was added dropwise POCl ₃ (0.8mL) . When the addition was complete, the reaction mixture was heated to reflux and stirred for 3h. Cool to room temperature, slowly pour into ice water, extract with EtOAc (50 mL×2), wash with saturated NaHCO ₃ (20 mL) and brine, and concentrate in vacuo to provide the crude product. It was further purified by column chromatography to produce 4-bromo-6-cyano-1-methyl- 1H -indole (1.4 g, 60%) as a yellow solid. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 8.18 (s, 1H), 7.78 (sl brs, 1H), 7.67 (s, 1H), 6.53 (sl br s, 1H), 3.89 (s, 3H) .

6-cyano-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 H -indole.

4-Bromo-6-cyano-1-methyl-1 H -indole (1.4g, 6.0mmol, 1.0eq), bis(pinacolyl) diboron (2.28g, 9mmol, 1.5eq), Pd (dppf) Cl ₂ (219 mg, 0.3 mmol, 0.05 eq)) and KOAc (1.18 g, 12 mmol, 2.0 eq) in dioxane (25 mL) were heated to reflux and stirred under N ₂ atmosphere for 1 h. When LCMS showed that no starting material remained, the reaction mixture was filtered through celite and purified by column chromatography to provide 1-methyl-6-cyano-4-(4 , 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 H -indole (1.5 g, 89%). ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 8.25 (s, 1H), 7.78 (sl br s, 1H), 7.67 (s, 1H), 6.86 (sl br s, 1H), 3.89 (s, 3H ), 1.30 (s, 12H).

2-chloro-4-(6-cyano-1-methyl- 1H -indol-4-yl)pyrimidine. 1-methyl-6-cyano-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 H -indole( 1.5g, 5.3mmol, 1.0eq), 2,4-dichloropyrimidine (790mg, 5.3mmol, 1.0eq), Pd(dppf)Cl ₂ (193mg, 0.26mmol, 0.05eq) and K ₂ CO ₃ (1.45g , 10.6 mmol, 2.0 eq) in dioxane (25 mL) and H ₂ O (5 mL) was heated to 80° C. and stirred under N ₂ atmosphere for 2 h. When LCMS showed no starting material left, the reaction mixture was filtered through celite, concentrated in vacuo to provide the crude product, and further purified by column chromatography to provide 2-chloro- as a yellow solid 4-(6-cyano-1-methyl- 1H -indol-4-yl)pyrimidine (800 mg, 56%). ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 8.87 (d, J = 5.1 Hz, 1H), 8.36 (s, 1H), 8.26 (d, J = 5.1 Hz, 1H), 8.19 (s, 1H) , 7.87 (s, 1H), 7.26 (s, 1H), 3.95 (s, 3H). ESI-MS (m/z): 268.9 (M+H) ⁺ .

A5. 2-chloro-4-(3-( N , N -dimethylamino)-1 H -thieno[2,3-c]pyrazol-1-yl)pyrimidine

N' -(2-Bromothiophene-3-carbonyl)-4-methylbenzenesulfonyl hydrazide. 2-Bromothiophene-3-carboxylic acid (10.3 g, 50 mmol, 1.0 eq) was stirred in DCM (125 mL) with a drop of NMP. Thionyl chloride (7.1 g, 60 mmol, 1.2 eq) was added and the reaction was heated to reflux for 2 hours. The solvent was removed under reduced pressure to provide a crude residue (11 g). The residue was dissolved in toluene (250 mL) and 4-methylbenzenesulfonylhydrazine (18.6 g, 100 mmol, 2.0 eq) was added, and the mixture was heated to 100° C. for 2 hours. The reaction mixture was allowed to cool to room temperature and the suspension was filtered. The solid was slurried with 1N HCl and the suspension was filtered. The solid was washed with water and dried overnight under vacuum at 40°C to provide N' -(2-bromothiophene-3-carbonyl)-4-methylbenzenesulfonamide (11.0 g, 73%). ¹ HNMR(300MHz, DMSO- d ₆ ): δ 10.48(s,1H),9.97(s,1H),7.75(d, J =8.1Hz,2H),7.62(d, J =5.4Hz,1H), 7.35 (d, J = 8.1 Hz, 2H), 7.06 (d, J = 5.4 Hz, 1H), 2.36 (s, 3H). ESI-MS (m/z): 374.7 (M+H) ⁺ .

2-Bromo- N , N -dimethyl- N' -toluenesulfonylthiophene-3-aminomethylhydrazone. N' -(2-Bromothiophene-3-carbonyl)-4-methylbenzenesulfonamide hydrazide (10g, 26.7mmol, 1.0eq) was heated to 80 in sulfenyl dichloride (18.9g, 160mmol, 6.0eq) ℃ for 1 hour. The reaction mixture was cooled to room temperature and concentrated in vacuo to produce a crude residue. The residue was dissolved in THF (150 mL) at 0° C. and DABCO (5.98 g, 53.4 mmol, 2.0 eq) was added, followed by a solution of dimethylamine in THF (53.4 mL) dropwise. The reaction was warmed to room temperature and stirred overnight. The reaction was concentrated in vacuo to remove the solvent and water (200 mL) was added, extracted with DCM (150 mL×3). The combined organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to produce a crude residue, which was purified by silica gel chromatography to produce 2-bromo- N , N -dimethyl as a yellow solid - N '- toluene sulfonic acyl hydrazone urethane thiophene-3 (4g, 37%). ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 8.75 (s, 1H), 7.71-7.68 (m, 3H), 7.37 (d, J = 7.5 Hz, 2H), 6.85 (d, J = 5.1 Hz, 1H), 2.68 (s, 6H), 2.38 (s, 3H). ESI-MS (m/z): 401.7 (M+H) ⁺ .

3-( N , N -dimethylamino)-1-tosyl- 1H -thieno[2,3-c]pyrazole. 2-Bromo- N , N -dimethyl- N' -tosylthiophene-3-aminomethylhydrazone (1.0g, 2.5mmol, 1.0eq), CuI (95mg, 0.5mmol, 0.2eq), K A mixture of ₂ CO ₃ (690 mg, 5 mmol, 2.0 eq) in NMP (10 mL) was heated to 110° C. in the microwave for 20 min. After LCMS indicated completion, the reaction mixture was poured onto water (10 mL) and filtered, the filter cake was washed with water, and dried to produce the title 3-( N , N -dimethylamino)-1-tosyl sulfonamide Yl- 1H -thieno[2,3-c]pyrazole (410 mg, 51%). ¹ H NMR(300MHz, DMSO- d ₆ ): δ 7.67(d, J =8.1Hz, 2H), 7.37(2H, d J=8.1Hz-7.33(d, J=5.1Hz, 1H), 7.18(d , J = 5.1 Hz, 1H), 2.95 (s, 6H), 2.33 (s, 3H). ESI-MS (m/z): 321.8 (M+H) ⁺ .

3-( N , N -dimethylamino)-1 H -thieno[2,3-c]pyrazole. 3-( N , N -dimethylamino)-1-tosyl-1- H -thieno[2,3-c]pyrazole (1.28g, 4mmol, 1.0eq) and potassium hydroxide (1.12 g, 20 mmol, 5.0 eq) were combined in methanol (40 mL) and heated to reflux for 30 minutes. The solvent was removed under reduced pressure. The resulting residue was dissolved in DCM (400 mL), washed with water (250 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography to produce 3- (N, N - dimethylamino) -1 H - thieno [2,3-c] pyrazole (180mg, 27%). ¹ H NMR (300 MHz, CDCl ₃ ): δ 8.83 (br, 1H), 6.95 (d, J = 2.4 Hz, 1H), 6.74 (d, J = 2.4 Hz, 1H), 3.08 (s, 6H). ESI-MS (m/z): 167.9 (M+H) ⁺ .

2-chloro -4- (3- (N, N - dimethylamino) -1 H - thieno [2,3-c] pyrazol-1-yl) pyrimidine. 3- at 0 ℃ (N, N - dimethylamino) -1 H - thieno [2,3-c] pyrazole (180mg, 1.08mmol, 1.0eq) in DMF (2mL) solution of the T- BuOK (181 mg, 1.62 mmol, 1.5 eq) was added. The mixture was stirred at this temperature for 30 minutes, and then a solution of 2,4-dichloropyrimidine (192 mg, 1.3 mmol, 1.2 eq) was added. The mixture was stirred at RT overnight. After completion, the mixture was quenched with saturated aqueous NH ₄ Cl (4 mL) and then diluted with water (4 mL), extracted with EA (5 mL×3). The combined organic layers were washed with water (10 mL), dried and concentrated and purified by column chromatography Silica to yield 2-chloro -4- (3- (N, N - dimethylamino) -1 H - thieno And [2,3-c]pyrazol-1-yl)pyrimidine (80 mg, 27%). ¹ H NMR(300MHz,CDCl ₃ ): δ 8.41(d, J =4.2Hz,1H),7.52(d, J =4.2Hz,1H),7.15-7.00(m,2H),3.18(s,6H) . ESI-MS (m/z): 279.8 (M+H) ⁺ .

A6. 2-chloro-4-(3-( N , N -dimethylamino)-5-chloro-1 H -thieno[2,3-c]pyrazol-1-yl)pyrimidine

2-chloro -4- (3- (N, N - dimethylamino) -1 H - thieno [2,3-c] pyrazol-1-yl) pyrimidine (140mg, 0.5mmol, 1.0eq ) NCS (73.4 mg, 0.55 mmol, 1.1 eq) was added to the solution in the mixed solution of benzene and acetic acid (1:1, 1.4 mL). The mixture was heated to 70°C and stirring continued for 2 hours. After completion, the mixture was poured into ice water (5 g), extracted with DCM (5 mL×2), the combined organic layer was washed with brine (5 mL), dried, concentrated and purified by silica column to generate 2 -Chloro-4-(3-( N , N -dimethylamino)-5-chloro-1 H -thieno[2,3-c]pyrazol-1-yl)pyrimidine (78.3 mg, 50% ). ¹ H NMR (300 MHz, CDCl ₃ ): δ 8.45 (d, J = 5.4 Hz, 1H), 7.52 (d, J = 5.4 Hz, 1H), 7.01 (s, 1H), 3.15 (s, 6H). ESI-MS (m/z): 314.0 (M+H) ⁺ .

A7. 2-chloro-4-(4-cyano-1-methyl-1 H -indol-6-yl)pyrimidine

5-Bromo-2-methyl-3-nitrobenzoic acid. 1,3-Dibromo-5,5-dimethylimidazolidine-2,4-dione (47.2g, 166mmol, 1.0eq) was added to 2-methyl-3-nitrobenzene in portions at room temperature Formic acid (30 g, 166 mmol, 1.0 eq) in a stirred mixture of concentrated H ₂ SO ₄ (100 mL). When the addition was complete, the reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into ice water (500 g) with stirring to form a white solid, which was filtered and dried in vacuo to give the desired product 5-bromo-2-methyl-3-nitrobenzoic acid (35 g , 81%). ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 8.30 (s, 1H), 8.14 (s, 1H), 2.44 (s, 3H).

Methyl 5-bromo-2-methyl-3-nitrobenzoate. To a solution of 5-bromo-2-methyl-3-nitrobenzoic acid (35 g, 135 mmol, 1.0 eq) in MeOH (1.2 L) was added concentrated H ₂ SO ₄ (5 mL) at room temperature, and the mixture Heat to reflux and stir for 8h. LCMS showed no starting material left. The mixture was concentrated under reduced pressure to remove most of MeOH, diluted with EtOAc (200 mL), washed with saturated NaHCO ₃ (100 mL×2), the organic layer was dried over Na ₂ SO ₄ and concentrated in vacuo to produce the desired The product methyl 5-bromo-2-methyl-3-nitrobenzoate (30 g, crude material) was used directly in the next step without further purification. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 8.14 (s, 1H), 8.00 (s, 1H), 3.96 (s, 3H), 2.58 (s, 3H).

6-Bromo-1 H -indole-4-carboxylic acid methyl ester. A solution of methyl 5-bromo-2-methyl-3-nitrobenzoate (40g, 146mmol, 1.0eq) and DMF-DMA (39mL, 292.0mmol, 2.0eq) in DMF (150ml) was heated to 120°C Lasts 6h. After cooling to 25°C, the reaction was concentrated to dryness under reduced pressure. The residue was dissolved in AcOH (350 mL), and Fe powder (164 g) was added to the mixture in portions with vigorous stirring. The mixture was heated to 100°C and stirred overnight. Cooled to room temperature, diluted with EtOAc and filtered through celite, extracted with EtOAc (500 mL), and washed sequentially with saturated NaHCO ₃ , water, and brine. The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated to produce an orange solid as a crude residue. Further purification by column chromatography (SiO ₂ , 100-200 m, by n-hexane/EtOAc=20:1-10:1 dissolution) provides 6-bromo-1 H -indole as a yellow solid Methyl 4-formate (22.0 g, 59%, two steps). ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 8.46 (br, 1H), 8.04 (s, 1H), 7.75 (s, 1H), 7.36 (s, 1H), 7.18 (s, 1H), 4.01 ( s,3H). ESI-MS (m/z): 253.8 (M+H) ⁺ .

6-Bromo-1-methyl-1 H -indole-4-carboxylic acid. To a solution of NaH (60% in mineral oil, 2.23 g, 56.9 mmol, 1.5 eq) in DMF (50 mL) was added methyl 6-bromo-1 H -indole-4-carboxylate (10.0 g, 37.9 mmol, 1.0 eq). The mixture was warmed to room temperature and stirred for 10 min. After cooling again to 0°C, MeI (8.06 g, 56.9 mmol, 1.5 eq) was added dropwise. The reaction mixture was stirred at room temperature for 1 h and quenched with 0.5N HCl (30 mL), extracted with EtOAc (70 mL×2), washed with water (1×50 mL), brine and dried over sodium sulfate. After filtering and removing the solvent, the residue was dissolved in MeOH (40 mL) and THF (40 mL), 3N NaOH (40 mL) was added, and the mixture was stirred at room temperature for 2 h, at which time LC-MS showed no starting Material left. The residue was diluted with H ₂ O (50 mL) and washed with EtOAc (35 mL). When by 1N HCl and the aqueous layer to pH = 3 to 4, to form a solid, the solid was filtered and dried in vacuo to provide the desired as a white solid of the product was 6-bromo-1-methyl -1 H - Indole-4-carboxylic acid (7.6 g, 79%). ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 8.00 (s, 1H), 7.78 (s, 1H), 7.51 (s, 1H), 6.92 (s, 1H), 3.37 (s, 3H).

6-Bromo-1-methyl-1 H -indole-4-carboxamide. To a solution of 6-bromo-1-methyl- 1H -indole-4-carboxylic acid (4.5g, 17.7mmol, 1.0eq) and a drop of DMF (catalyst) in DCM (60mL) at 0°C dropwise Oxalyl chloride (3.1 mL, 35.4 mmol, 2.0 eq) was added. When the addition was complete, the reaction mixture was warmed to room temperature and stirred for 3 h, then concentrated to dryness in vacuo. The residue was dissolved in anhydrous THF (30 mL) and added dropwise to a mixture of concentrated aqueous ammonia (15 mL) and THF (30 mL) at 0°C. When the addition was complete, the reaction mixture was stirred at room temperature for 1 h, extracted with EtOAc, washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to generate a crude residue, which was passed through the column layer It was purified by analysis to provide the desired product 6-bromo-1-methyl- 1H -indole-4-carboxamide (1.2 g, 22%) as a white solid. ¹ H NMR(300MHz,CDCL ₃ ): δ 8.76(d, J =3.0Hz,1H),8.50(d, J =8.4Hz,1H),8.37(s,1H),7.87(s,1H),7.51 -7.48 (m, 1H), 7.10 (s, 1H), 3.89 (s, 3H). ESI-MS (m/z): 253.0 (M+H) ⁺ .

6-Bromo-4-cyano-1-methyl-1 H -indole. 6-bromo-1-methyl -1 H - indole-4-acyl-amine (1.2g, 4.9mmol, 1.0eq) in toluene (50mL) in the solution was added dropwise POCl ₃ (0.4mL), When the addition was complete, the reaction mixture was heated to reflux and stirred for 3h. Cool to room temperature, slowly pour into ice cold water, extract with EtOAc (50 mL×2), wash with saturated NaHCO ₃ (20 mL) and brine, dry (Na ₂ SO ₄ ) and concentrate in vacuo to provide the crude product, the The crude product was further purified by column chromatography to give the desired product 6-bromo-4-cyano-1-methyl- 1H -indole (0.46 g, 41%) as a yellow solid. ESI-MS (m/z): 236.6 (M+H) ⁺ .

4-cyano-1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 H -indole. 6-Bromo-4-cyano-1-methyl-1 H -indole (0.46g, 2.0mmol, 1.0eq), bis(pinacolyl) diboron (0.75g, 3.0mmol, 1.5eq), A solution of Pd(dppf)Cl ₂ (72 mg, 0.09 mmol, 0.05 eq) and KOAc (0.39 g, 4.0 mmol, 2.0 eq) in dioxane (25 mL) was heated to reflux under N ₂ for 1 h, LCMS showed no Starting material remained, the reaction mixture was filtered through celite, concentrated under reduced pressure, and purified by column chromatography to provide the desired product 4-cyano-1-methyl- as a yellow solid 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1 H -indole (0.52 g, 93%). ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 8.02 (s, 1H), 7.94 (s, 1H), 7.28 (s, 1H), 6.71 (s, 1H), 3.90 (s, 3H), 1.40 ( s, 12H).

2-chloro-4-(4-cyano-1-methyl- 1H -indol-6-yl)pyrimidine. 4-cyano-1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 H -indole( 0.5g, 1.6mmol, 1.0eq), 2,4-dichloropyrimidine (263mg, 1.6mmol, 1.0eq), Pd(dppf)Cl ₂ (64mg, 0.09mmol, 0.05eq) and K ₂ CO ₃ (0.48g , 3.53 mmol, 2.0 eq) in dioxane (10 mL) and H ₂ O (2 mL) was heated to 80° C. and stirred under N ₂ for 2 h. LCMS showed that no starting material remained, so the reaction mixture was filtered through celite and concentrated in vacuo to provide the crude product. This crude product was further purified by column chromatography to provide the desired product as a yellow solid, 2-chloro-4-(4-cyano-1-methyl- 1H -indol-6-yl)pyrimidine (300mg, 70%). ESI-MS (m/z): 268.5 (M+H) ⁺ .

A8. 2-chloro-4-(3-methoxy- 1H -indazol-1-yl)pyrimidine

1- N -ethoxycarbonyl-3-hydroxy-1 H -indazole. Ethyl chloroformate (8.9g, 82mmol, 1.1eq) was slowly added to a suspension of 3-hydroxy- 1H -indazole (10g, 74.6mmol, 1.0eq) in pyrimidine (50mL), and the reaction mixture was heated To 100°C and stir for 5h. TLC, LC-MS indicated that the starting material disappeared and then poured into water (400 mL) and the precipitate was collected by filtration, washed with water (200 mL) and acetone (350 mL), and then air dried to generate 1- N -ethoxy Carbonyl-3-hydroxy-1 H -indazole (13.0 g, 86%). ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 12.19 (br, 1H), 8.04 (d, J = 8.4 Hz, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.61 (t, J = 7.8 Hz, 1H), 7.34 (t, J = 7.8Hz, 1H), 4.40 (q, J = 6.6Hz, 2H), 1.36 (t, J = 7.2Hz, 3H). ESI-MS (m/z): 207.1 (M+H) ⁺ .

1- N -ethoxycarbonyl-3-methoxy-1 H -indazole. To a solution of 1- N -ethoxycarbonyl-3-hydroxy- 1H -indazole (5.0 g, 24.2 mmol, 1.0 eq) in acetone (50 mL) was added Cs ₂ CO ₃ (9.5 g, 29.1 mmol, 1.2 eq) and iodomethane (4.13 g, 29.1 mmol, 1.2 eq), then heated to 70° C. and stirred for 2 h. LC-MS indicated that the starting material had disappeared. The reaction mixture was filtered, the precipitate was rinsed with EA (50 mL), and the combined filtrate was concentrated under reduced pressure to produce a crude residue, which was purified by silica gel column chromatography to produce 1- N -B Oxycarbonyl-3-methoxy- 1H -indazole (1.9 g, 34%). ¹ H NMR(300MHz,CDCl ₃ ): δ 8.20-8.05(m,1H),7.68(d, J =7.8Hz,1H),7.56(t, J =7.2Hz,1H),7.31(t, J = 7.2Hz, 1H), 4.58 (q, J = 7.2Hz, 2H), 4.21 (s, 3H), 1.52 (t, J = 7.2Hz, 3H). ESI-MS (m/z): 221.1 (M+H) ⁺ .

3-methoxy- 1H -indazole. To a solution of 1- N -ethoxycarbonyl-3-methoxy- 1H -indazole (1.9g, 8.6mmol, 1.0eq) in EtOH (50mL) was added 1N NaOH _(aq) (12.9mL) . The reaction was stirred at room temperature for 2h, at which time LC-MS indicated that the starting material was used up. The reaction mixture was extracted with EA (50 mL×3) and the organic extract was washed with brine (30 mL), dried over sodium sulfate, and concentrated under reduced pressure to provide the desired product 3-methoxy- 1H -indazole ( 1.2g, 93%). ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 11.91 (br, 1H), 7.58 (d, J = 7.5 Hz, 1H), 7.45-7.34 (m, 2H), 7.00 (t, J = 6.0 Hz, 1H ), 3.99 (s, 3H). ESI-MS (m/z): 149.1 (M+H) ⁺ .

2-chloro-4-(3-methoxy- 1H -indazol-1-yl)pyrimidine. A solution of 3-methoxy- 1H -indazole (1.2g, 8.1mmol, 1.0eq) in DMF (24mL) was cooled to 0°C, and t- BuOK (1.0g, 8.9mmol, 1.1eq) was carefully added ). The mixture was stirred at this temperature for 10 minutes. Then a solution of 2,4-dichloropyrimidine (1.27 g, 8.1 mmol, 1.0 eq) in DME (10 mL) was added dropwise. The mixture was stirred at RT for 2h. After completion, the mixture was diluted with water (80 mL), filtered, the filter cake was washed with water (10 mL×2), dried and then purified by silica column chromatography to produce 2-chloro-4-as an off-white solid (3-methoxy- 1H -indazol-1-yl)pyrimidine (1.2g, 57%). ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 8.63 (d, J = 5.4 Hz, 1H), 8.54 (d, J = 8.4 Hz, 1H), 7.83-7.67 (m, 3H), 7.41 (t, J =7.5Hz, 1H), 4.16(s, 3H). ESI-MS (m/z): 261.0 (M+H) ⁺ .

A9. 2-chloro-4-(6-cyano-1-methyl-1 H -indazol-4-yl)pyrimidine

3-bromo-4-methyl-5-nitrobenzoic acid. To a mixture of 4-methyl-3-nitrobenzoic acid (36.0 g, 200 mmol, 1.0 eq) in concentrated H ₂ SO ₄ (150 mL) at room temperature was added 1,3-dibromo-5, 5-Dimethylhydantoin (51.8 g, 200 mmol, 1.0 eq). When the addition was complete, the reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into ice water (500 g) with stirring, the white precipitate solid was filtered and dried in vacuo to give the desired product 3-bromo-4-methyl-5-nitrobenzoic acid (40 g, 77% ). ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 8.33 (s, 1H), 8.31 (s, 1H), 2.53 (s, 3H). ESI-MS (m/z): 257.9 (MH) ^- .

3-Bromo-4-methyl-5-nitrobenzoic acid methyl ester. To a solution of 3-bromo-4-methyl-5-nitrobenzoic acid (40.0 g, 153 mmol, 1.0 eq) in MeOH (1.2 L) was added concentrated H ₂ SO ₄ (10 mL) at room temperature. The mixture was heated to reflux and stirred for 8h. LCMS showed no starting material left. The mixture was concentrated under reduced pressure to remove most of MeOH, diluted with EtOAc (200 mL), washed with saturated NaHCO ₃ (100 mL×2), the organic layer was dried over Na ₂ SO ₄ and concentrated in vacuo to produce a white solid. The desired product, methyl 3-bromo-4-methyl-5-nitrobenzoate (40 g, 93%), was used in the next step without further purification. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 8.35 (s, 2H), 3.90 (s, 3H), 2.50 (s, 3H).

3-Amino-5-bromo-4-methylbenzoic acid methyl ester. To a solution of methyl 3-bromo-4-methyl-5-nitrobenzoate (20g, 73.0mmol, 1.0eq) in EtOH (150ml) and AcOH (50mL) was added Fe powder (16.3g, 292 mmol, 4.0 eq). The mixture was heated to reflux and stirred for 2h. LC-MS indicated disappearance of starting material, the reaction mixture was cooled to rt, diluted with EtOAc (200mL) and diatomaceous earth by filtration, washed with saturated NaHCO _3, water and brine. The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to produce methyl 3-amino-5-bromo-4-methylbenzoate (13 g, 73%) as a white solid. ESI-MS (m/z): 244.0 (M+H) ⁺ .

4-Bromo- 1H -indazole-6-carboxylic acid methyl ester. To a solution of methyl 3-amino-5-bromo-4-methylbenzoate (13 g, 53.5 mmol, 1.0 eq) in AcOH (150 mL) was added dropwise an aqueous solution of NaNO ₂ (3.7 g, 5mL, 53.5mmol, 1.0eq). The stirred mixture was allowed to warm to room temperature and stirred overnight, the reaction mixture was poured into ice water, the precipitated solid was filtered and dried to produce a crude residue, which was purified by column chromatography to produce 4-bromo- 1 H -Indazole-6-carboxylic acid methyl ester (4.5 g, 33%). ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 8.17 (s, 2H), 7.80 (s, 1H), 3.90 (s, 3H). ESI-MS (m/z): 255.0 (M+H) ⁺ .

4-Bromo-1-methyl-1 H -indazole-6-carboxylic acid methyl ester. To a solution of methyl 4-bromo- 1H -indazole-6-carboxylate (4.5g, 17.6mmol, 1.0eq) in DMF (50mL) was added NaH (60% in mineral oil) at 0°C in portions , 1.0g, 26.4mmol, 1.5eq). The stirred mixture was warmed to room temperature and stirred for 10 min. Cool to 0 °C again and then add MeI (3.7 g, 26.4 mmol, 1.5 eq) dropwise. The reaction mixture was stirred at room temperature for 1 h, poured into 0.5N HCl (30 mL), extracted with EtOAc (50 mL×2), washed with water (50 mL), brine (50 mL) and dried over sodium sulfate. The residue was purified by column chromatography to produce methyl 4-bromo-1-methyl- 1H -indazole-6-carboxylate (2.5 g, 53%). ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 8.36 (s, 1H), 8.15 (s, 1H), 7.83 (s, 1H), 4.17 (s, 3H), 3.92 (s, 3H). ESI-MS (m/z): 269.0 (M+H) ⁺ .

4-Bromo-1-methyl-1 H -indazole-6-carboxylic acid. To a solution of methyl 4-bromo-1-methyl- 1H -indazole-6-carboxylate (2.5 g, 9.3 mmol, 1.0 eq) in THF (15 mL) and MeOH (15 mL) was added aqueous NaOH ( 12 mL, 37 mmol, 3N), and the reaction mixture was stirred at room temperature for 1 h. LCMS showed no starting material left. The reaction mixture was concentrated under reduced pressure to remove most of THF and MeOH, the residue was diluted with H ₂ O, neutralized by 1N.HCl to pH=3~4, the solid precipitate was filtered and dried to provide the desired product 4-Bromo-1-methyl-1 H -indazole-6-carboxylic acid (1.8 g, 76%). ¹ HNMR (300 MHz, DMSO- d ₆ ): δ 8.32 (s, 1H), 8.12 (s, 1H), 7.82 (s, 1H), 4.15 (s, 3H). ESI-MS (m/z): 254.9 (M+H) ⁺ .

4-Bromo-1-methyl-1 H -indazole-6-carboxamide. To a solution of 4-bromo-1-methyl- 1H -indazole-6-carboxylic acid (1.8 g, 7.1 mmol, 1.0 eq) and a drop of DMF (catalyst) in DCM (50 mL) at 0°C dropwise Oxalyl chloride (1.5 mL, 17 mmol, 7.5 eq) was added, and when the addition was complete, the reaction mixture was heated to reflux for 3 h. The solution was cooled to room temperature, concentrated to dryness in vacuo, and the acetyl chloride was dissolved in anhydrous THF (20 mL) and added dropwise to a mixture of concentrated aqueous ammonia (10 mL) and THF (20 mL) at 0°C. . When the addition was complete, the reaction mixture was stirred at room temperature for 1 h, extracted with EtOAc, washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to provide the desired product as a white solid 4- Bromo-1-methyl-1 H -indazole-6-carboxamide (1.8 g, crude material). ESI-MS (m/z): 253.9 (M+H) ⁺ .

4-Bromo-6-cyano-1-methyl-1 H -indazole. To a mixture of 4-bromo-1-methyl- 1H -indazole-6-carboxamide (1.8 g, 7.1 mmol, 1.0 eq) in toluene (50 mL) was added POCl ₃ (0.8 mL) dropwise, When the addition was complete, the reaction mixture was heated to reflux and stirred for 3h. After cooling to room temperature, the reaction mixture was slowly poured into ice water, extracted with EtOAc (50 mL×2), the combined organic layer was washed with saturated NaHCO ₃ (20 mL) and brine, dried and concentrated in vacuo to provide The crude product was further purified by column chromatography to produce the desired product 4-bromo-6-cyano-1-methyl- 1H -indazole (1.0 g, 63%) as a yellow solid ). ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 8.48 (s, 1H), 8.20 (s, 1H), 7.80 (s, 1H), 4.14 (s, 3H). ESI-MS (m/z): 236.0 (M+H) ⁺ .

6-cyano-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 H -indazole. 4-bromo-6-cyano-1-methyl- 1H -indazole (1.0g, 4.2mmol, 1.0eq), bis(pinacolyl) diboron (2.1g, 8.4mmol, 2.0eq), A solution of Pd(dppf)Cl ₂ (154 mg, 0.21 mmol, 0.05 eq) and KOAc (0.8 g, 8.4 mmol, 2.0 eq) in dioxane (25 mL) was heated to reflux and stirred under N ₂ atmosphere for 1 h. When LCMS showed that no starting material remained, the reaction mixture was filtered through celite and purified by column chromatography to provide the desired product 6-cyano-1-methyl-4 as a yellow solid -(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 H -indazole (0.9 g, 75%). ¹ H NMR (300 MHz, CDCl ₃ ): δ 8.40 (s, 1H), 7.84 (s, 2H), 4.12 (s, 3H), 1.40 (s, 12H). ESI-MS (m/z): 284.0 (M+H) ⁺ .

2-chloro-4-(6-cyano-1-methyl- 1H -indazol-4-yl)pyrimidine. 6-cyano-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 H -indazole ( 1,1g, 4.2mmol, 1.0eq), 2,4-dichloropyrimidine (798mg, 4.2mmol, 1.0eq), Pd(dppf)Cl ₂ (154mg, 0.21mmol, 0.05eq) and K ₂ CO ₃ (1.73 g, 12.6 mmol, 3.0 eq) in dioxane (25 mL) and H ₂ O (5 mL) was heated to 80° C. and stirred under N ₂ for 2 h. LCMS showed no starting material left, the reaction mixture was filtered through celite and concentrated in vacuo to provide the crude product, which was further purified by column chromatography to provide the desired product 2 as a yellow solid -Chloro-4-(6-cyano-1-methyl- 1H -indazol-4-yl)pyrimidine (0.7 g, 62%). ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 8.95 (br s, 1H), 8.76 (s, 1H), 8.68 (s, 1H), 8.40-8.36 (m, 2H), 4.20 (s, 3H) . ESI-MS (m/z): 270.0 (M+H) ⁺ .

A10. 2-chloro-4-(1-methyl-1 H -indazol-4-yl)pyrimidine

4-bromo-1-methyl-1 H -indazole. Methylhydrazine (7.56 g, 69.6 mmol) was added to a solution of 2-bromo-6-fluorobenzaldehyde (2.0 g, 9.95 mmol, 1.0 eq) in DMSO (35 mL). The mixture was heated to 85°C and stirring continued for 24 hours. The mixture was then cooled to room temperature and diluted with water (50 mL). The solution was extracted with CH ₂ Cl ₂ (2×50 mL) and the combined organic layer was dried (Mg ₂ SO ₄ ), filtered, and concentrated under reduced pressure to produce a crude residue 4-bromo-1-methyl-1 H -indazole (1.5 g, crude material), this crude residue was used without further purification. ¹ H NMR (300 MHz, CDCl ₃ ): δ 8.01 (s, 1H), 7.35-7.28 (m, 3H), 4.10 (s, 3H). ESI-MS (m/z): 211.0 (M+H) ⁺ .

1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 H -indazole. A 100 mL three-necked flask was fed with 4-bromo-1-methyl-1 H -indazole (1.38 g, 6.57 mmol, 1.0 eq) and bis(pinacolyl) diboron (2.34 g, 8.54 mmol, 1.3 eq), KOAc (2.09 g, 19.71 mmol, 3.0 eq) and PdCl ₂ (dppf) CH ₂ Cl ₂ complex (0.29 g, 0.32 mmol, 0.05 eq). Anhydrous DMSO (22 mL) was added and the mixture was heated at 90 °C for 4h. The reaction mixture was cooled, filtered and the filter cake was washed with TBME (2×50 mL). The filtrate was washed with brine (3×50 mL), dried over Na ₂ SO ₄ , concentrated and purified by silica column to produce the desired product 1-methyl-4-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl)-1 H -indazole (1.0 g, 60%). ¹ H NMR (300 MHz, CDCl ₃ ): δ 8.37 (s, 1H), 7.67-7.66 (m, 1H), 7.51-7.50 (m, 1H), 7.42-7.40 (m, 1H), 4.10 (s, 3H ), 1.42 (s, 12H). ESI-MS (m/z): 259.1 (M+H) ⁺ .

2-chloro-4-(1-methyl- 1H -indazol-4-yl)pyrimidine. To 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 H -indazole under argon ( 774mg, 3.0mmol, 1.0eq) in a solution of 1,4-dioxane/water (5/1, 10mL) was added 2,4-dichloropyrimidine (542mg, 3.60mmol, 1.2eq), potassium carbonate ( 954 mg, 9.0 mmol, 3.0 eq) and (dppf) ₂ PdCl ₂ (108 mg, 0.15 mmol, 0.05 eq). The mixture was purged with argon at room temperature for 10 min and refilled with argon, heated to reflux and stirred for 4 h, at which time TLC indicated completion. The reaction mixture was concentrated to produce a crude residue, which was purified by silica column to produce the desired product 2-chloro-4-(1-methyl- 1H -indazole-4 as a yellow solid -Yl)pyrimidine (300 mg, 40%). ¹ H NMR (300 MHz, CDCl ₃ ): δ 8.73 (sl br s, 2H), 7.83-7.75 (m, 2H), 7.62-7.55 (m, 2 H), 4.19 (s, 3H). ESI-MS (m/z): 245.0 (M+H) ⁺ .

A11. 2-chloro-4-(1,3-dimethyl-1 H -pyrrolo[2,3-b]pyridin-5-yl)pyrimidine

5-Bromo-1,3-dimethyl- 1H -pyrrolo[2,3-b]pyridine. To a solution of 5-bromo-3-methyl- 1H -pyrrolo[2,3-b]pyridine (1.0 g, 4.74 mmol, 1 eq) in DMF (20 mL) was added NaH (0 0.21 g, 5.2 mmol, 1.1 eq), and the mixture was stirred at this temperature for 30 minutes. Then MeI (0.74 g, 5.2 mmol, 1.1 eq) was added dropwise. After the addition, the mixture was stirred at this temperature for 30 minutes until completion. The mixture was poured into water (70 mL), and extracted with EA (50 mL×3). The combined organic layer was washed twice with brine, dried over sodium sulfate, filtered and the filtrate was concentrated in vacuo to generate a residue, which was purified by silica gel column chromatography (EtOAc/hexane, 1/10) To provide 5-bromo-1,3-dimethyl- 1H -pyrrolo[2,3-b]pyridine (0.8 g, 75%). ¹ H NMR (300 MHz, CDCl ₃ ): δ 8.33 (s, 1H), 7.96 (s, 1H), 6.96 (s, 1H), 3.82 (s, 3H), 2.28 (s, 3H). ESI-MS (m/z): 225.0 (M+H) ⁺ .

1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 H -pyrrolo[2, 3-b]pyridine. Under a nitrogen atmosphere, add 5-bromo-1,3-dimethyl- 1H -pyrrolo[2,3-b]pyridine (0.8 g, 3.55 mmol, 1.0 eq) to 1,4-dioxane (8 mL ) Added bis(pinacolyl) diboron (1.17g, 4.62mmol, 1.3eq), KOAc (1.045g, 10.66mmol, 3.0eq) and Pd(dppf)Cl ₂ DCM (290mg, 0.355mmol) , 0.1eq). The mixture was purged with nitrogen 3 times and stirred at 90°C for 2 hours. After cooling to room temperature, the mixture was concentrated and the residue was purified by silica gel chromatography to produce 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2 -Dioxolane-2-yl)-1 H -pyrrolo[2,3-b]pyridine (0,79 g, 82%). ¹ H NMR(300MHz,CDCl ₃ ): δ 8.71(s,1H),8.33(s,1H),6.93(s,1H),3.86(s,3H),2.32(s,3H),1.39(s, 12 H). ESI-MS (m/z): 273.1 (M+H) ⁺ .

2-chloro-4-(1,3-dimethyl- 1H -pyrrolo[2,3-b]pyridin-5-yl)pyrimidine. To 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 H -pyrrole under nitrogen To a solution of [2,3-b]pyridine (0.8g, 2.94mmol, 1.0eq) in 1,4-dioxane (20mL) and water (4mL) was added 2,4-dichloropyrimidine (0.482g , 3.23 mmol, 1.1 eq), K ₂ CO ₃ (1.217 g, 8.82 mmol, 3.0 eq) and Pd(dppf)Cl ₂ DCM (240 mg, 0.294 mmol, 0.1 eq). The mixture was bubbled with nitrogen for 10 minutes, then purged with nitrogen 3 times and stirred at 60°C for 2.5 hours. After cooling, the mixture was concentrated and the residue was purified by silica gel chromatography to produce 2-chloro-4-(1,3-dimethyl- 1H -pyrrolo[2,3-b]pyridine-5- Base) pyrimidine (0.53g, 70%). ¹ H NMR(300MHz,CDCl ₃ ): δ 8.98(s,1 H),8.72-8.57(m,2 H),7.73(sl br s,1H),7.04(s,1 H),3.90(s, 3 H), 2.40 (s, 3 H). ESI-MS (m/z): 259.1 (M+H) ⁺ .

A12. 2-chloro-4-(1,3-dimethyl-1 H -indol-5-yl)pyrimidine

5-bromo-3-methyl-1 H -indole. To a solution of 5-bromo- 1H -indole-3-carbaldehyde (5.0 g, 22.4 mmol, 1.0 eq) in THF (100 mL) was added LiAlH ₄ (1.02 g, 26.9 mmol, 1.2 eq). The resulting solution was stirred at reflux for 2 h, then poured into 1N NaOH solution (300 mL), filtered and the filter cake was washed with EA, the aqueous layer was separated and extracted with ethyl acetate (3×150 mL), dried over anhydrous sodium sulfate and then at Concentrate under vacuum to produce a residue, which was purified by silica gel chromatography (petroleum ether containing 3% ethyl acetate) to provide 5-bromo-3-methyl- 1H -indole (2.5g, 53% ). ¹ H NMR(300MHz,CDCl ₃ ): δ 7.97(br,1 H),7.73(s,1 H),7.28-7.26(m,2 H),7.00(s,1 H),2.31(s,3 H).

5-bromo-1,3-dimethyl- 1H -indole. A solution of 5-bromo-3-methyl- 1H -indole (5.0 g, 23.8 mmol, 1.0 eq) in DMF (100 mL) was cooled to 0°C under nitrogen, and NaH (1.05 g, 26.2) was carefully added mmol, 1.1 eq) and the mixture was stirred at this temperature for 30 minutes. Then MeI (3.72 g, 26.2 mmol, 1.1 eq) was added dropwise. After the addition, the mixture was stirred at this temperature for 30 minutes until completion. The reaction was quenched with water (300 mL) and extracted with EA (150 mL×3). The combined organic layer was washed twice with brine, dried over sodium sulfate, filtered and the filtrate was concentrated in vacuo to generate a residue, which was purified by silica gel column chromatography (EtOAc/hexane, 1/10) To provide 5-bromo-1,3-dimethyl- 1H -indole (5.11 g, 95%). ¹ H NMR(300MHz,CDCl ₃ ): δ 7.71(s,1 H),7.30-7.29(m,1 H),7.17-7.15(m,1 H),6.84(s,1 H),3.73(s ,3 H),2.36(s,3 H).

1,3-Dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxolane-2-yl)-1 H -indole. To a solution of 5-bromo-1,3-dimethyl- 1H -indole (0.54g, 2.4mmol, 1.0eq) in 1,4-dioxane (10mL) under nitrogen was added That alcohol group) diboron (0.796 g, 3.13 mmol, 1.3 eq), KOAc (0.708 g, 7.23 mmol, 3.0 eq) and Pd(dppf)Cl ₂ DCM (196 mg, 0.24 mmol, 0.1 eq). The mixture was purged with nitrogen 3 times and stirred at 90°C for 2 hours. After cooling, the mixture was concentrated and the residue was purified by silica gel chromatography to produce 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-diox Heterocyclopentane-2-yl)-1 H -indole (520 mg, 79%). ¹ H NMR(300MHz,CDCl ₃ ): δ 8.12(s,1H),7.69-7.66(m,1H),7.28-7.26(m,1H),6.82(s,1H),3.75(s,3H), 2.36(s, 3H), 1.40(s, 12H).

2-chloro-4-(1,3-dimethyl- 1H -indol-5-yl)pyrimidine. To 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 H -ind under nitrogen Indole (0.52g, 1.92mmol, 1.0eq) in a solution of 1,4-dioxane (13mL) and water (2.6mL) was added 2,4-dichloropyrimidine (0.314g, 2.11mmol, 1.1eq) , K ₂ CO ₃ (0.794 g, 5.75 mmol, 3.0 eq) and Pd(dppf)Cl ₂ DCM (0.156 g, 0.192 mmol, 0.1 eq). The mixture was bubbled with nitrogen for 10 minutes, then purged with nitrogen 3 times and stirred at 60°C for 2.5 hours. After cooling, the mixture was concentrated and the residue was purified by silica gel chromatography to produce 2-chloro-4-(1,3-dimethyl- 1H -indol-5-yl)pyrimidine (0.3g, 60 %). ¹ H NMR(300MHz,CDCl ₃ ): δ 8.57(d, J =4.8Hz,1H),8.40(s,1H),7.99(d, J =8.1Hz,1H),7.74(d, J =4.2Hz , 1H), 7, 36 (d, J = 8.7Hz, 1H), 6.91 (s, 1H), 3.80 (s, 3H), 2.40 (s, 3H).

A13. 2-chloro-4-(3-chloro-1-methyl-1 H -pyrrolo[2,3-b]pyridin-5-yl)pyrimidine

5-bromo-3-chloro-1 H -pyrrolo[2,3-b]pyridine. To a solution of 5-bromo-1 H -pyrrolo[2,3-b]pyridine (5.0 g, 25.4 mmol, 1.0 eq) in THF (100 mL) was added N-chlorobutadiene imide (4.0 g, 30.4 mmol, 1.2 eq) and the mixture was stirred at room temperature for 24 h. Water (100 mL) was added to the reaction mixture, followed by extraction with EA (3×80 mL). The combined organic layer was dried over Mg ₂ SO ₄ , filtered and the filtrate was concentrated in vacuo to produce a crude residue, which was purified by silica gel column chromatography (EtOAc/hexane, 1/5) to provide 5-Bromo-3-chloro-1 H -pyrrolo[2,3-b]pyridine (5.0 g, 85%). ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 12.26 (br, 1H), 8.37 (s, 1H), 8.16 (s, 1H), 7.79 (s, 1H). ESI-MS (m/z): 232.9 (M+H) ⁺ .

5-bromo-3-chloro-1-methyl-1 H -pyrrolo[2,3-b]pyridine. To a cooled solution of 5-bromo-3-chloro-1 H -pyrrolo[2,3-b]pyridine (5.0 g, 21.6 mmol, 1.0 eq) in DMF (100 mL) under nitrogen was carefully added NaH ( 1.0 g, 26.0 mmol, 1.2 eq) and the mixture was stirred at 0°C for 30 minutes. Then MeI (3.7 g, 26.0 mmol, 1.2 eq) was added dropwise. After the addition, the mixture was stirred at this temperature for 30 minutes until completion. The mixture was poured into water (200 mL) and extracted with EA (150 mL×3). The combined organic layer was washed twice with brine, dried over sodium sulfate, filtered and the filtrate was concentrated in vacuo to generate a residue, which was purified by silica gel column chromatography (EtOAc/hexane, 1/10) To provide 5-bromo-3-chloro-1-methyl-1 H -pyrrolo[2,3-b]pyridine (3.8 g, 71%). ¹ H NMR (300 MHz, CDCl ₃ ): δ 8.40 (s, 1H), 8.05 (s, 1H), 7.19 (s, 1H), 3.87 (s, 3H). ESI-MS (m/z): 246.9 (M+H) ⁺ .

3-chloro-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 H -pyrrolo[2 ,3-b]pyridine. Under nitrogen, 5-bromo-3-chloro-1-methyl- 1H -pyrrolo[2,3-b]pyridine (0.2g, 0.82mmol, 1.0eq) in 1,4-dioxane (2mL ), bis(pinacolyl) diboron (0.269g, 1.06mmol, 1.3eq), KOAc (0.240g, 2.45mmol, 3eq) and Pd(dppf)Cl ₂ DCM (66mg, 0.08mmol, 0.1eq). The mixture was purged with nitrogen 3 times and stirred at 90°C for 2 hours. After cooling, the mixture was concentrated and the residue was purified by silica gel chromatography to produce 3-chloro-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-di Oxaborolan-2-yl)-1 H -pyrrolo[2,3-b]pyridine (0.2 g, 84%). ¹ H NMR (300 MHz, CDCl ₃ ): δ 8.74 (s, 1H), 8.39 (s, 1H), 7.15 (s, 1H), 3.89 (s, 3H), 1.40 (s, 12H). ESI-MS (m/z): 293.1 (M+H) ⁺ .

2-chloro-4-(3-chloro-1-methyl- 1H -pyrrolo[2,3-b]pyridin-5-yl)pyrimidine. Under nitrogen, 3-chloro-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 H- To a solution of pyrrolo[2,3-b]pyridine (0.2g, 0.685mmol, 1.0eq) in 1,4-dioxane (5mL) and water (1mL) was added 2,4-dichloropyrimidine (0.112 g, 0.753 mmol, 1.1 eq), K ₂ CO ₃ (0.284 g, 2.05 mmol, 3.0 eq) and Pd(dppf)Cl ₂ DCM (0.056 g, 0.068 mmol, 0.1 eq). The mixture was bubbled with nitrogen for 10 minutes, then purged with nitrogen 3 times and stirred at 60°C for 2.5 hours. After cooling, the mixture was concentrated and the residue was purified by silica gel chromatography to produce 2-chloro-4-(3-chloro-1-methyl- 1H -pyrrolo[2,3-b]pyridine-5 -Yl)pyrimidine (0.1 g, 62%). ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 9.17 (s, 1H), 8.85-8.75 (m, 1H), 8.71 (s, 1H), 8.37-8.29 (m, 1H), 7.90 (s, 1H ), 3.87 (s, 3H). ESI-MS (m/z): 279.0 (M+H) ⁺ .

A14. Acetic acid 2-(1-(2-chloropyrimidin-4-yl)-1 H -indol-3-yl)-2-oxoethyl ester

2-( 1H -Indol-3-yl)-2-oxoethyl acetate. To a solution of 1 H -indole (11.7 g, 100 mmol, 1.0 eq) in toluene (200 ml) was added pyridine (7.9 g, 100 mmol, 1.0 eq). The mixture was heated to 60° C. and then 2-chloro-2-oxoethyl acetate (13.6 g, 100 mmol, 1.0 eq) was slowly added dropwise. After the addition, the mixture was stirred at 60°C for 1 hour, cooled to room temperature and mixed with MeOH/H ₂ O (200 mL) and stirred for 1 hour. After completion, the mixture was filtered and purified by silica column chromatography to provide the desired product 2-( 1H -indol-3-yl)-2-oxoethyl acetate (1g, 5 %). ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 8.80 (br, 1H), 8.35-8.34 (m, 1H), 7.91 (s, 1H), 7.44-7.43 (m, 1H), 7.33-7.27 (m , 2H), 5.22 (s, 2H), 2.21 (s, 3H). ESI-MS (m/z): 217.9 (M+H) ⁺ .

Acetic acid 2-(1-(2-chloropyrimidin-4-yl)-1 H -indol-3-yl)-2-oxoethyl ester. To a solution of 2-( 1H -indol-3-yl)-2-oxoethyl acetate (1.08g, 5.0mmol, 1.0eq) in DMF (10mL) at 0°C over a period of 20min 60% NaH (300mg, 7.5mmol, 1.5eq). After the addition, the reaction was stirred at 0°C for 20 minutes, and then DMF (2 mL) containing 2,4-dichloropyrimidine (820 mg, 5.5 mmol, 1.1 eq) was added at 0°C. The reaction mixture was stirred at room temperature for 1 hour, quenched with H ₂ O (10 mL) and extracted with EA (20 mL). The organic layer was washed with brine, dried over Na ₂ SO ₄ , concentrated in vacuo and purified by silica column chromatography to provide the desired product acetic acid 2-(1-(2-chloropyrimidin-4-yl)- 1 H -Indol-3-yl)-2-oxoethyl ester (280 mg, 18%). ¹ H NMR(300MHz,CDCl ₃ ): δ 8.97(s,1H),8.78(d, J =7.5Hz,1H),8.67(d, J =5.1Hz,1H),8.42(d, J =7.8Hz , 1H), 7.54-7.44 (m, 2H), 7.26-7.25 (m, 1H), 5.31 (s, 2H), 2.28 (s, 3H). ESI-MS (m/z): 329.9 (M+H) ⁺ .

A15. N -(1-(2-chloropyrimidin-4-yl)-1 H -indazol-3-yl)methanesulfonamide

To a solution of 3-amino-1-(2-chloropyrimidin-4-yl)indazole (500 mg, 2.0 mmol, 1.0 eq) in DCM (10 mL) at 0°C was added DIPEA (310 mg, 2.4 mmol, 1.2 eq) and MsCl (275 mg, 2.4 mmol, 1.2 eq). The mixture was stirred at RT for 2h, and TLC indicated completion. The reaction was diluted with DCM (30 mL), washed with brine (30 mL×3), dried over sodium sulfate, concentrated and purified on silica column to provide N- (1-(2-chloropyrimidin-4-yl)- 1 H -indazol-3-yl)methanesulfonamide (290 mg, 44%). ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 11.55-11.30 (br, 1H), 8.69 (d, J=5.7Hz, 1H), 8.58 (t, J=8.2Hz, 1H), 8.06 (dd, J=8.411Hz, 1H), 7.82-7.66(m, 2H), 7.46-7.38(m, 1H) 3.48(d, J =6.3Hz, 3H). ESI-MS (m/z): 321.7 (MH) ^- .

A16. 2-chloro-4-(1-( N -methylamino)imidazo[1,5-a]pyridin-3-yl)pyrimidine

2-chloro- N- (pyridin-2-ylmethyl)pyrimidine-4-carboxamide. To a solution of 2-chloropyrimidine-4-carboxylic acid (14.0 g, 88.3 mmol, 1.0 eq) in DCM (100 mL) was added pyridin-2-ylmethylamine (11.4 g, 106 mmol, 1.2 eq), DIPEA (28.5 g , 221mmol, 2.5eq) and HATU (50.4g, 132.5mmol, 1.5eq), the mixture was stirred at 25 °C overnight. TLC and LCMS indicated completion. The mixture was cooled to 0 °C, quenched with water (100 mL), and extracted with DCM (50 mL x 3). The combined organic layer was dried over sodium sulfate, concentrated and purified by silica column to provide 2-chloro- N- (pyridin-2-ylmethyl)pyrimidine-4-carboxamide (5g, 23%). ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 9.56 (br, 1H), 9.03 (d, J = 4.8Hz, 1H), 8.52 (d, J = 3.9Hz, 1H), 8.05 (d, J = 4.5Hz, 1H), 7.78-7.73 (m, 1H), 7.34-7.25 (m, 2H), 4.61 (d, J = 5.7Hz, 2H). ESI-MS (m/z): 248.9 (M+H) ⁺ .

2-chloro-4-(imidazo[1,5-a]pyridin-3-yl)pyrimidine. A solution of 2-chloro- N- (pyridin-2-ylmethyl)pyrimidine-4-carboxamide (5.0 g, 20.2 mmol, 1.0 eq) in POCl ₃ (75 mL) was refluxed for 7 hours. After TLC and LCMS indicated completion, the mixture was cooled to RT and poured into ice water, extracted with EA (100 mL×3). The combined organic layer was washed with brine (100 mL×2), dried over sodium sulfate, and concentrated under reduced pressure to provide 2-chloro-4-(imidazo[1,5-a]pyridin-3-yl)pyrimidine (4g, 87%). ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 9.67 (d, J = 6.3 Hz, 1H), 8.69 (d, J = 4.8 Hz, 1H), 8.11 (d, J = 5.1 Hz, 1H), 7.91 -7.84(m,2H), 7.25-7.16(m,2H). ESI-MS (m/z): 230.9 (M+H) ⁺ .

2-chloro-4-(1-nitroimidazo[1,5-a]pyridin-3-yl)pyrimidine. To a solution of 2-chloro-4-(imidazo[1,5-a]pyridin-3-yl)pyrimidine (5.0g, 21.6mmol, 1.0eq) in AcOH (100mL) at 10-15°C A mixture of HOAc and HNO ₃ (1/1, 50 mL) was added dropwise. The mixture was stirred at RT for 30 min. After TLC and LCMS indicated completion, the mixture was diluted with water (50 mL), and the formed precipitate was collected by filtration, washed with water, and dried to give the desired product 2-chloro-4-(1-nitroimidazo[ 1,5-a]pyridin-3-yl)pyrimidine, which was used directly in the next step. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 9.92 (d, J = 6.9 Hz, 1H), 9.14 (d, J = 4.8 Hz, 1H), 8.47 (d, J = 9.0 Hz, 1H), 8.26 -8.18(m,1H), 7.92-7.88(m,1H),7.65-7.63(m,1H). ESI-MS (m/z): 275.8 (M+H) ⁺ .

2-chloro-4-(1-aminoimidazo[1,5-a]pyridin-3-yl)pyrimidine. To 2-chloro-4-(1-nitroimidazo[1,5-a]pyridine 3-yl) pyrimidine (5.0g, 18.1mmol, 1.0eq) in EtOH and water (10 / 1,100mL) was added in the _{NH 4 Cl (2.9g, 54.3mmol,} 3.0eq) and Fe powder (10.0g , 181mmol, 10.0eq). The mixture was stirred at RT for 5h. After TLC and LCMS indicated completion, the mixture was filtered. The filtrate was concentrated and purified by silica column to provide the desired product 2-chloro-4-(1-aminoimidazo[1,5-a]pyridin-3-yl)pyrimidine (600 mg, 13.6%). ESI-MS (m/z): 245.9 (M+H) ⁺ .

2-chloro-4-(1-(2,2,2-trifluoroacetamido)imidazo[1,5-a]pyridin-3-yl)pyrimidine. To a solution of 2-chloro-4-(1-aminoimidazo[1,5-a]pyridin-3-yl)pyrimidine (245 mg, 1.0 mmol, 1.0 eq) in DCM (4 mL) at 0°C TEA (303 mg, 3.0 mmol, 3.0 eq), DMAP (22 mg, 0.1 mmol, 0.1 eq) and trifluoroacetic anhydride (252 mg, 1.2 mmol, 1.2 eq) were added. The mixture was stirred at RT for 3h. After TLC and LCMS indicated completion, the mixture was concentrated and purified on a silica column, 2-chloro-4-(1-(2,2,2-trifluoroethylamido)imidazo[1,5- a] Pyridin-3-yl)pyrimidine (300 mg, 87%). ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 12.02 (s, 1H), 9.72 (d, J=5.1 Hz, 1H), 8.73 (d, J = 5.4 Hz, 1H), 8.05 (d, J = 5.1Hz, 1H), 7.76 (d, J = 6Hz, 1H), 7.29 (d, J = 5.4Hz, 2H). LCMS: (M+H) ⁺ : 341.8.

2-chloro-4-(1-( N -methyl-2,2,2-trifluoroacetamido)imidazo[1,5-a]pyridin-3-yl)pyrimidine. To 2-chloro-4-(1-(2,2,2-trifluoroethylamido)imidazo[1,5-a]pyridin-3-yl)pyrimidine (459 mg, 1.3 mmol, 1.0 eq) to a solution in DMF (5 mL) was added 60% NaH (65 mg, 1.6 mmol, 1.2 eq) in portions, and the mixture was kept at 0° C. for 30 minutes. Then MeI (203 mg, 1.4 mmol, 1.1 eq) was added dropwise. After the addition, the mixture was stirred at room temperature for 2h. The reaction mixture was poured into water (50 mL), extracted with DCM (50 mL×3), the combined organic layer was washed with brine (50 mL×3), dried over sodium sulfate, and concentrated to produce the desired product 2-chloro-4 -(1-( N -methyl-2,2,2-trifluoroacetamido)imidazo[1,5-a]pyridin-3-yl)pyrimidine (500 mg, crude material), the product does not require purification Used directly in the next step. ESI-MS (m/z): 355.8 (M+H) ⁺ .

2-chloro-4-(1-( N -methylamino)imidazo[1,5-a]pyridin-3-yl)pyrimidine. To 2-chloro-4-(1-( N -methyl-2,2,2-trifluoroacetamido)imidazo[1,5-a]pyridin-3-yl)pyrimidine (500mg, 0.95mmol , 1.0eq) to a solution in MeOH (10 mL) was added K ₂ CO ₃ (131 mg, 0.95 mmol, 1.0 eq). After stirring for 30 min, TLC indicated completion. The mixture was concentrated and diluted with water (50 mL) and extracted with DCM (50 mL×2). The organic layer was washed with brine (50 mL×2), dried over sodium sulfate, and purified on a silica column to provide 2-chloro-4-(1-( N -methylamino)imidazo[1,5-a ]Pyridin-3-yl)pyrimidine (148 mg, 40%). ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 9.54 (d, J = 7.2 Hz, 1H), 8.42 (d, J = 5.4 Hz, 1H), 7.84 (d, J = 8.1 Hz, 2H), & .77(d,J=5.7Hz,1H), 7.12(t,J=6.9Hz,1H),6.97-6.93(m,1H),6.40-6.38(m,1H),2.97(d,J=4.5 Hz, 3H). ESI-MS (m/z): 259.9 (M+H) ⁺ .

A17. Methyl 1-(2-chloropyrimidin-4-yl)-1 H -indole-3-carboxylate

To a 500 mL four-necked flask was added THF (300 mL) and methyl indole-3-carboxylate (28.0 g, 159 mmol, 1.0 eq). The solution was cooled to 0°C and t- BuOK (21.5 g, 191 mmol, 1.2 eq) was added portionwise. After stirring at this temperature for 1 h, 2,4-dichloropyrimidine (23.8 g, 159 mmol, 1.0 eq) was added and the mixture was warmed to RT and stirring continued for 2 h until completion. The reaction was quenched with saturated NH ₄ Cl (34 mL), diluted with water (500 mL) and then filtered and the filtrate was concentrated with DCM (100 mL×3). The combined organic layer was dried over Na ₂ SO ₄ , concentrated and purified by silica column chromatography to produce the product as a brown solid (7 g, 16%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.70-8.68 (m, 1H), 8.55-8.45 (m, 1H), 8.36-8.26 (m, 1H), 7.57-7.32 (m, 4H), 3.99 (s, 3H).

A18. 2-chloro-4-(3-( N , N -dimethylamino)-1 H -pyrazolo[4,3-b]pyridin-1-yl)pyrimidine

3-amino- 1H -pyrazolo[4,3-b]pyridine. A mixture of 2-cyano-3-fluoropyridine (40 g, 328 mmol, 1.0 eq) and hydrazine hydrate (47.8 mL, 984 mmol, 3.0 eq) in n-butanol (400 mL) was heated to reflux overnight under nitrogen. The reaction mixture was cooled to room temperature, water (300 mL) was added, the phases were separated, and the organic phase was concentrated under reduced pressure. The residual solid was collected by filtration and washed with water, and dried to give 3-amino- 1H -pyrazolo[4,3-b]pyridine (31 g, 73%) as a yellow solid. ¹ H NMR(300MHz,CDCl ₃ ): δ 11.64(s,1H),8.27(sl br s,1H),7.69(d, J =8.4Hz,1H),7.25-7.22(m,1H),5.37( br, 2H). ESI-MS (m/z): 135.0 (M+H) ⁺ .

2-chloro-4-(3-amino- 1H -pyrazolo[4,3-b]pyridin-1-yl)pyrimidine. To a solution of 3-amino- 1H -pyrazolo[4,3-b]pyridine (6.2g, 1.0eq) in DMF (95mL) at 0°C was added t- BuOK (6.2g, 1.2eq), after the addition, the mixture was stirred at 0°C for 30 min. A solution of 2,4-dichloropyrimidine (7.5 g, 1.1 eq) in DMF (50 mL) was added dropwise at 0°C. After the addition was complete, the reaction mixture was stirred at ft for 4 h, LCMS indicated that the starting material disappeared, H ₂ O (400 mL) was added, the precipitate was filtered and dried to provide the desired product 2-chloro-4 as a yellow solid -(3-amino- 1H -pyrazolo[4,3-b]pyridin-1-yl)pyrimidine (5.5 g, 48%). ¹ H NMR (300 MHz, CDCl ₃ ): δ 8.76 (d, J = 7.8 Hz, 1H), 8.62-8.57 (m, 2H), 7.67-7.55 (m, 2H), 6.76 (br, 2H). ESI-MS (m/z): 246.9 (M+H) ⁺ .

2-chloro -4- (3- (N, N - dimethylamino) -1 H - pyrazolo [4,3-b] pyridin-1-yl) pyrimidine. To 2-chloro-4-(3-amino- 1H -pyrazolo[4,3-b]pyridin-1-yl)pyrimidine (5.5g, 22.3mmol, 1.0eq) in anhydrous DMF at 0°C To the solution in (110 mL) was added NaH (1.78 g, 44.7 mmol, 60% dispersion in mineral oil, 2.2 eq) in portions. After stirring at 0°C for 30 minutes, methyl iodide (6.9 g, 48.5 mmol, 2.2 eq) was added dropwise, after which the reaction mixture was allowed to warm to room temperature, and LC-MS indicated that the starting material disappeared. H ₂ O (300 mL) was carefully added and the aqueous phase was extracted with EtOAc. The combined organic layer was washed with H ₂ O and saturated NaCl. Next, the combined organic layer was dried over Na ₂ SO ₄ and after filtration, the solvent was removed in vacuo to provide the crude product, which was further purified by column chromatography to provide 2-chloro-4-( 3- (N, N - dimethylamino) -1 H - pyrazolo [4,3-b] pyridin-1-yl) pyrimidine (500mg, 8%). ¹ HNMR(300MHz,CDCl ₃ ): δ 9.02(d, J =9.0Hz,1H),8.61(d, J =3.0Hz,1H),8.46(d, J =6.3Hz,1H),7.70(d, J = 5.7Hz, 1H), 7.50-7.45(m, 1H), 3.45(s, 6H). ESI-MS (m/z): 274.9 (M+H) ⁺ .

A19. 2-chloro-4-(3-(methylamino)-1 H -thieno[2,3-c]pyrazol-1-yl)pyrimidine

2-Bromo- N -methyl- N' -toluenesulfonylthiophene-3-aminomethylhydrazone. A mixture of N' -(2-bromothiophene-3-carbonyl)-4-methylbenzenesulfonylhydrazine (10g, 26.7mmol) in sulfenyl dichloride (18.9g, 160mmol) was heated to 80°C for 1 hour . The reaction mixture was cooled to room temperature and concentrated in vacuo to produce a crude residue. The residue was dissolved in THF (150 mL) at 0°C and DABCO (5.98 g, 53.4 mmol) was added, followed by dropwise addition of a solution of methylamine in THF (53.4 mL). The reaction was warmed to room temperature and stirred overnight. The reaction was concentrated in vacuo to remove the solvent and water (200 mL) was added, extracted with DCM (150 mL×3), the combined organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to generate a crude residue, which was a crude residue The material was purified by silica gel chromatography to produce 2-bromo- N -methyl- N' -tosylthiophene-3-aminomethylhydrazone (2g, 18%) as a yellow solid. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 7.87-7.84 (m, 2 H), 7.30-7.28 (m, 3 H), 6.84 (d, J = 5.7 Hz, 1 H), 2.67 (s, 3 H), 2.40 (s, 3 H). ESI-MS (m/z): 388.0 (M+H) ⁺ .

3-(methylamino)-1-tosyl- 1H -thieno[2,3-c]pyrazole. 2-Bromo- N -methyl- N' -tosylthiophene-3-aminomethylhydrazone (970mg, 2.5mmol), CuI (95mg, 0.5mmol) and K ₂ CO ₃ (690mg, 5mmol) in NMP The mixture in (10 mL) was heated to 110 °C in the microwave for 20 min. LC-MS indicated that the starting material disappeared. The reaction mixture was poured onto 10 mL of water and filtered, the filter cake was washed with water, and dried to produce 3-(methylamino)-1-tosyl- 1H -thieno[2,3-c]pyrazole ( 400mg, 52%). ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 7.65 (d, J = 8.0 Hz, 2 H), 7.35 (d, J = 8.0 Hz, 2 H), 7.28 (d, J = 5.6 Hz, 1 H ), 6.93 (d, J = 5.6 Hz, 1 H), 6.84 (br, 1 H), 2.72 (s, 3 H), 2.32 (s, 3 H). ESI-MS (m/z): 308.0 (M+H) ⁺ .

3-(methylamino)-1 H -thieno[2,3-c]pyrazole. To a solution of 3-methylamino-1-tosyl- 1H -thieno[2,3-c]pyrazole (1.23g, 4mmol) in methanol (40mL) was added magnesium powder (480mg, 20mmol). The mixture was stirred at rt for 30 minutes. The solvent was removed under reduced pressure. The resulting residue was dissolved in DCM (40 mL) and washed with water (25 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography to produce 3-(methylamino)-1 H -thieno[2,3-c]pyrazole (180 mg, 27%). ¹ H NMR(300MHz,CDCl ₃ ): δ 6.90-7.75(br,2 H),6.85(d, J =5.4Hz,1 H),6.72(d, J =5.4Hz,1 H),3.04(s , 3 H). ESI-MS (m/z): 154.1 (M+H) ⁺ .

2-chloro-4-(3-(methylamino)-1 H -thieno[2,3-c]pyrazol-1-yl)pyrimidine. To a solution of 3-(methylamino)-1 H -thieno[2,3-c]pyrazole (168 mg, 1.08 mmol) in THF (2 mL) at 0°C was added ^t BuOK (181 mg, 1.62 mmol). The mixture was stirred at this temperature for 30 minutes, and then a solution of 2,4-dichloropyrimidine (192 mg, 1.3 mmol) was added. The mixture was stirred at RT overnight. After completion, the mixture was quenched with saturated aqueous NH ₄ Cl (4 mL) and then diluted with water (4 mL), and extracted with DCM (5 mL×3). The combined organic layer was washed with water (10 mL), concentrated and purified by silica column chromatography to produce 2-chloro-4-(3-(methylamino)-1 H -thieno[2,3 -c]pyrazol-1-yl)pyrimidine (80 mg, 27%). ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.45 (d, J = 5.6 Hz, 1 H), 7.56 (d, J = 5.6 Hz, 1 H), 7.12 (d, J = 5.6 Hz, 1 H), 6.96 (d, J = 5.2 Hz, 1 H), 3.13 (s, 3 H). ESI-MS (m/z): 266.0 (M+H) ⁺ .

A20. 2-chloro-4-(5-chloro-3-(methylamino)-1 H -thieno[2,3-c]pyrazol-1-yl)pyrimidine

To 2-chloro-4-(3-(methylamino)-1 H -thieno[2,3-c]pyrazol-1-yl)pyrimidine (133mg, 0.5mmol, 1eq) in benzene and acetic acid NCS (73.4 mg, 0.55 mmol, 1.1 eq) was added to the solution in the mixed solution (1:1, 1.4 mL). The mixture was heated to 70°C and stirring continued for 2 hours. After completion, the mixture was poured into ice water (5 g), extracted with DCM (5 mL×2), the combined organic layer was washed with brine (5 mL), dried, concentrated and purified by silica column to generate the Product required (75mg, 50%). ¹ H NMR (300 MHz, CDCl ₃ ): δ 8.47 (d, J = 5.4 Hz, 1 H), 7.53 (d, J = 5.4 Hz, 1 H), 6.90 (s, 1 H), 3.10 (s, 3 H), 1.5-1.75 (brs, 1H). ESI-MS (m/z): 300.1 (M+H) ⁺ .

A21. 2-chloro-4-(1-methyl-1 H -indol-4-yl)pyrimidine

4-bromo-1-methyl-1 H -indole. NaH (1.22 g, 51.02 mmol, 2.0 eq) was added portionwise to a stirred solution of 4-bromo-1 H -indole (5.0 g, 25.51 mmol, 1.0 eq) in DMF (100 mL) at 0°C. The mixture was stirred for 30 min, and then DMF (20 mL) containing CH ₃ I (9.0 g, 63.77 mmol, 2.5 eq) was added at 0°C. The reaction mixture was stirred at 0°C for 3h. TLC and LC-MS indicated completion, water (50 mL) was added and the mixture was extracted with EtOAc (2×50 mL), dried over sodium sulfate, concentrated and purified by silica column to produce 4-bromo-1-methyl- 1 H -indole (3.2 g, 56%). ¹ H NMR (300 MHz, CDCl ₃ ): δ 7.31-7.27 (m, 2 H), 7.14-7.12 (m, 2 H), 6.56 (s, 1H, 3.82 (s, 3 H). ESI-MS (m /z): 210.0(M ⁺ H) ⁺ .

1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 H -indole. A 250 mL flask was fed 4-bromo-1-methyl-1 H -indole (3.5 g, 16.66 mmol, 1.0 eq) and bis(pinacolyl) diboron (6.3 g, 24.99 mmol) under argon. , 1.5eq), KOAc (4.9g, 49.98mmol, 3.0eq) and _{PdCl 2 (dppf) CH 2 Cl} 2 complex (1.36g, 1.66mmol, 0.1eq). Anhydrous 1,4-dioxane (70 mL) was added and the mixture was heated to 90 °C and stirred for 4 h. The reaction mixture was cooled, filtered through a silica gel plug and the plug was washed with TBME (2×50 mL). The combined filtrate was washed with brine (3×50 mL), dried (Na ₂ SO ₄ ), concentrated and purified by silica column to produce 1-methyl-4-(4,4,5,5-tetramethyl Yl-1,3,2-dioxaborolan-2-yl)-1 H -indole (3.0 g, 71%). ¹ H NMR(300MHz,CDCl ₃ ): δ 7.70(d, J =7.2Hz,1 H),7.48(d, J =8.1Hz,1 H),7.30-7.27(m,1 H),7.10(d , J = 3.0 Hz, 1 H), 7.04 (d, J = 2.7 Hz, 1 H), 3.83 (s, 3 H), 1.45 (s, 12 H). ESI-MS (m/z): 258.2 (M+H) ⁺ .

2-chloro-4-(1-methyl- 1H -indol-4-yl)pyrimidine. To 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 H -indole under argon 1,0g, 3.89mmol, 1.0eq) in a solution of 1,4-dioxane/water (5:1, 12mL) was added 2,4-dichloropyrimidine (700mg, 4.69mmol, 1.2eq), Na ₂ CO ₃ (1.23 g, 11.67 mmol, 3.0 eq) and (dppf) ₂ PdCl ₂ (140 mg, 0.19 mmol, 0.05 eq). The mixture was purged with argon at room temperature for 10 min, refilled with argon, and stirred at 100°C until TLC indicated completion. The reaction mixture was filtered through celite and concentrated to produce a crude residue, which was purified by silica gel chromatography to produce 2-chloro-4-(1-methyl- 1H -indol-4-yl ) Pyrimidine (500mg, 52%). ¹ H NMR (300 MHz, DMSO): δ 8.78 (d, J = 5.6 Hz, 1 H), 8.12 (d, J = 4.2 Hz, 1 H), 7.84 (d, J = 7.6 Hz, 1 H), 7.73 (d, J =8.4Hz,1 H),7.56(d, J =3.2Hz,1 H),7.34(t, J =8.0Hz,1 H),7.13(d, J =2,8Hz,1 H ), 3.88 (s, 1H). ESI-MS (m/z): 244.1 (M+H) ⁺ .

A22. 2-chloro-4-(7-cyano-1,3-dimethyl- 1H -indol-5-yl)pyrimidine

5-Bromo-7-cyano-1,3-dimethyl- 1H -indole. NaH (480 mg, 12 mmol, 1.2 eq) was carefully added to 5-bromo-7-cyano-3-methyl-1 H -indole (2.34 g, 10 mmol, 1.0 eq) in DMF (40 mL) with cooling In solution and the mixture was stirred at 0°C for 30 minutes. Then MeI (1.7 g, 12 mmol, 1.2 eq) was added dropwise. After the addition, the mixture was stirred at this temperature for 30 minutes until completion. The mixture was poured into water (100 mL) and extracted with EA (100 mL×3). The combined organic layer was washed twice with brine, dried over sodium sulfate, filtered and the filtrate was concentrated in vacuo to produce a residue, which was purified by silica gel column chromatography to provide 5-bromo-7-cyano -1,3-dimethyl- 1H -indole (1.6g, 64%). ¹ H NMR (300 MHz, CDCl ₃ ): δ 7.85 (s, 1H), 7.58 (s, 1H), 6.86 (s, 1H), 4.04 (s, 3H), 2.26 (s, 3H).

7-cyano-1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 H- Indole. To a solution of 5-bromo-7-cyano-1,3-dimethyl- 1H -indole (1.24g, 5.0mmol, 1.0eq) in 1,4-dioxane (20mL) under nitrogen Bis(pinacolyl) diboron (1.65 g, 6.5 mmol, 1.3 eq), KOAc (1.47 g, 15 mmol, 3.0 eq) and Pd(dppf)Cl ₂ DCM (412 mg, 0.5 mmol, 0.1 eq) were added. The mixture was purged with nitrogen 3 times and stirred at 90°C for 2 hours. After cooling, the mixture was concentrated and the residue was purified by silica gel chromatography to generate the title compound (940 mg, 63%). ¹ H NMR(300MHz,CDCl ₃ ): δ 8.15(s,1H),7.91(s,1H),6.76(s,1H),4.00(s,3H),2.25(s,3H),1.31(s, 12H). ESI-MS (m/z): 297.2 (M+H) ⁺ .

2-chloro-4-(7-cyano-1,3-dimethyl- 1H -indol-5-yl)pyrimidine. To 7-cyano-1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxolane-2-yl) under nitrogen -1 H -indole (592mg, 2.0mmol, 1.0eq) was added to a solution of 1,4-dioxane (10mL) and water (2mL) 2,4-dichloropyrimidine (325.6mg, 2.2mmol, 1.1 eq), K ₂ CO ₃ (828 mg, 6.0 mmol, 3.0 eq) and Pd(dppf)Cl ₂ DCM (164.7 mg, 0.068 mmol, 0.1 eq). The mixture was bubbled with nitrogen for 10 minutes, then purged with nitrogen 3 times and stirred at 80°C for 2.5 hours. After cooling, the mixture was concentrated and the residue was purified by silica gel chromatography to produce 2-chloro-4-(7-cyano-1,3-dimethyl- 1H -indol-5-yl)pyrimidine (310mg, 55%). ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 8.56 (d, J = 5.2 Hz, 1 H), 8.47 (s, 1 H), 8.20 (s, 1 H), 7.61 (d, J = 5.2 Hz ,1 H),6.87(s,1 H),4.04(s,3 H),2.31(s,3 H). ESI-MS (m/z): 283.1 (M+H) ⁺ .

B1. N -(5-Amino-4-(difluoromethoxy)-2-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)acrylamide

2-(difluoromethoxy)-4-fluoro-1-nitrobenzene. To a solution of 5-fluoro-2-nitrophenol (20 g, 127 mmol, 1.0 eq) in DMF (200 mL) was added sodium chlorodifluoroacetate (28 g, 184 mmol, 1.5 eq) portionwise, followed by K ₂ CO ₃ (32g, 254mmol, 2.0eq). The mixture was stirred at 90°C for 2 hours. After completion, the mixture was quenched with water (200 mL), extracted with MTBE (150 mL×3), the combined organic layer was dried, concentrated and purified by silica column to produce 2-(difluoromethoxy)- 4-fluoro-1-nitrobenzene (20g, 76%). ¹ H NMR (300 MHz, CDCl ₃ ): δ 8.06-8.01 (m, 1H), 7.27-7.08 (m, 2H), 6.66 (t, J = 72.3 Hz, 1H).

2-(difluoromethoxy)-4-fluoroaniline. To a solution of compound 2-(difluoromethoxy)-4-fluoro-1-nitrobenzene (20g, 96mmol, 1.0eq) in MeOH (200mL) was added Pd/C (4g), and the mixture was at 1 atm Stir overnight at room temperature under a hydrogen atmosphere. LC-MS indicated that the starting material disappeared. The reaction mixture was filtered through diatomaceous earth and the filtrate was concentrated in vacuo to give the crude product 2-(difluoromethoxy)-4-fluoroaniline (16g), which was directly used in the next step without further purification. ESI-MS (m/z): 177.9 (M+H) ⁺ .

2-(difluoromethoxy)-4-fluoro-5-nitroaniline. 2-(Difluoromethoxy)-4-fluoroaniline (16g, 8.5mmol, 1.0eq) was added portionwise to a cold solution (30mL) of concentrated sulfuric acid at 0°C, and after addition, potassium nitrate was added portionwise (10 g, 9.9 mmol, 1.1 eq). The mixture was stirred at 0°C for 2h, LC-MS indicated that the starting material had disappeared, the reaction mixture was poured into ice water and neutralized to pH 9 by aqueous sodium bicarbonate solution, extracted with MTBE (150mL×3), The combined organic layer was dried over sodium sulfate and concentrated to produce a crude residue, which was purified by silica gel column chromatography to produce the desired product 2-(difluoromethoxy)-4-fluoro-5- Nitroaniline (12g, 60%). ¹ H NMR(300MHz,CDCl ₃ ): δ 7.49(d, J =6.9Hz,1H),7.02(d, J =10.8Hz,1H),6.62(t, J =72.0Hz,1H),4.12(br , 2H). ESI-MS (m/z): 222.9 (M+H) ⁺ .

N -T-butoxycarbonyl-2-(difluoromethoxy)-4-fluoro-5-nitroaniline. To a solution of 2-(difluoromethoxy)-4-fluoro-5-nitroaniline (12g, 54mmol, 1.0eq) in DCM (120mL) was added DIPEA (10.4g, 81mmol, 1.5eq) and DMAP (0.56 g, 5.4 mmol, 0.1 eq), followed by the dropwise addition of a solution of (Boc) ₂ O (14.14 g, 64.8 mmol, 1.2 eq) in DCM (20 mL). The reaction was stirred at room temperature overnight, and LC-MS indicated that the starting material had disappeared. The solvent was removed under reduced pressure to produce a crude residue, which was purified by silica gel column chromatography to produce the desired product N -third butoxycarbonyl-2-(difluoromethoxy)- 4-fluoro-5-nitroaniline (8.7g, 50%). ESI-MS (m/z): 320.8 (MH) ^- .

N -T-butoxycarbonyl-2-(difluoromethoxy)-4-((2-(dimethylamino)ethyl)(methyl)amino)-5-nitroaniline. DIPEA was added to a solution of N -third butoxycarbonyl-2-(difluoromethoxy)-4-fluoro-5-nitroaniline (8.7g, 76.1mmol, 1.0eq) in EtOH (40mL) (11.8g, 91.4mmol, 1.2eq) and N,N,N' -trimethylethane-1,2-diamine (8.7g, 83.5mmol, 1.1eq), the mixture was heated to 60°C and stirred overnight . LC-MS and TLC indicated that the starting material had disappeared. The reaction was concentrated to produce a crude residue N -third butoxycarbonyl-2-(difluoromethoxy)-4-((2-(dimethylamino)ethyl)(methyl)amino) -5-Nitroaniline (14g), this crude residue was used directly in the next step without further purification. ESI-MS (m/z): 404.9 (M+H) ⁺ .

5-amino-(1, N -third-butoxycarbonyl)-2-(difluoromethoxy)-4-((2-(dimethylamino)ethyl)(methyl)amino )aniline. To N -third butoxycarbonyl-2-(difluoromethoxy)-4-((2-(dimethylamino)ethyl)(methyl)amino)-5-nitroaniline ( 14g, crude material) in MeOH (200mL) was added Pd/C (4g), and the mixture was stirred overnight at room temperature under 1 atm hydrogen atmosphere. LC-MS indicated that the starting material disappeared. The reaction mixture was filtered through diatomaceous earth and the filtrate was concentrated in vacuo to give the crude product 5-amino-(1, N -third butoxycarbonyl)-2-(difluoromethoxy)-4-(( 2-(Dimethylamino)ethyl)(methyl)amino)aniline (11 g), this crude product was used directly in the next step without further purification. ESI-MS (m/z): 374.9 (M+H) ⁺ .

5-propenylamino-(1, N -third butoxycarbonyl)-2-(difluoromethoxy)-4-((2-(dimethylamino)ethyl)(methyl) Amino group) aniline. Acryloyl chloride (690 mg, 7.6 mmol, 1.5 eq) was added dropwise to 5-amino-(1, N -third butoxycarbonyl)-2-(difluoromethoxy)-4 at 0°C -((2-(dimethylamino)ethyl)(methyl)amino)aniline (1.5g, 5mmol, 1.0eq) and DIPEA (780mg, 6mmol, 1.2eq) in THF (30mL) in. The resulting mixture was stirred for 1 h. The reaction mixture was quenched with saturated NaHCO ₃ (20 mL), extracted with EA (30 mL×3) and the organic extract was washed with brine (30 mL), dried over sodium sulfate, and concentrated to provide the desired product 5-propenylamino -(1, N -T-butoxycarbonyl)-2-(difluoromethoxy)-4-((2-(dimethylamino)ethyl)(methyl)amino)aniline (500mg , Crude material), which was used directly in the next step without further purification. ESI-MS (m/z): 428.9 (M+H) ⁺ .

N- (5-amino-4-(difluoromethoxy)-2-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)acrylamide. To 5-propenylamino-(1, N -third butoxycarbonyl)-2-(difluoromethoxy)-4-((2-(dimethylamino)ethyl)(methyl ) Amino)aniline (500 mg, crude material) in DCM (5 mL) was added TFA (3 mL) and the mixture was heated to reflux overnight. TLC, LC-MS indicated that the starting material had disappeared. The reaction mixture was neutralized to pH=9 by saturated NaHCO ₃ , extracted with DCM (10 mL×3) and the combined organic extracts were washed with brine (20 mL), dried over sodium sulfate, and concentrated to produce a crude residue, the The crude residue was purified by silica gel column chromatography to produce N- (5-amino-4-(difluoromethoxy)-2-((2-(dimethylamino)ethyl)(methyl Base) amino) phenyl) acrylamide (200 mg, 12.2%, 2 steps). ¹ H NMR(300MHz, DMSO- d ₆ ): δ 10.07(brs,1H),7.77(s,1H),6.97(s,1H),6.96(t,J=75Hz,1H),6.43-6.20(m , 2H), 5.77-5.74(m, 1H), 5.01(s, 2H), 2.80-2.75(m, 2H), 2.64(s, 3H), 2.34-2.30(m, 2H), 2.25(s, 6H ). ESI-MS (m/z): 328.9 (M+H) ⁺ .

B2. N -(5-amino-4-(2,2-difluoroethoxy)-2-((2-(dimethylamino)ethyl)(methyl)amino)phenyl) Acrylamide

2-(2,2-difluoroethoxy)-4-fluoro-1-nitrobenzene. After 30min, divide into several parts of 2,4-difluoro-1-nitrobenzene (30.0g, 1.89mmol, 1.0eq) and 2,2-difluoroethyl-1-ol (20.1g, 2.44mol, 1.3eq) Sodium hydroxide (9.0 g, 2.26 mmol, 1.2 eq) was added to the solution in toluene (60 mL) to keep the temperature between 30 and 40°C. The reaction was stirred at 45°C until 2,4-difluoro-1-nitrobenzene had disappeared. After cooling, water (60 mL) and 2.5NH ₂ SO ₄ (30 mL) were added to neutralize the pH to 5, and the organic layer was separated. The aqueous layer was extracted with EtOAc (30 mL×2). The combined organic layer was washed with saturated NaCl (10 mL), dried over Na ₂ SO ₄ , filtered and concentrated to produce a crude residue, which was purified by column chromatography to produce the desired as a yellow solid The product 2-(2,2-difluoroethoxy)-4-fluoro-1-nitrobenzene (32 g, 78%). ¹ H NMR(300MHz,CDCl ₃ ): δ 8.00(t, J =7.2Hz,1H),6.88-6.80(m,2H),6.19(t, J =54.6Hz,1H),4.36-4.12(m, 2H). ESI-MS (m/z): 221.8 (M+H) ⁺ .

2-(2,2-difluoroethoxy)-4-fluoroaniline. To a solution of 2-(2,2-difluoroethoxy)-4-fluoro-1-nitrobenzene (32g, 145mmol, 1.0eq) in MeOH (320mL) was added Pd/C (10%, 6.4 g, 0.4eq). The reaction was stirred at room temperature under a hydrogen atmosphere of 1 atm overnight. The reaction mixture was filtered through celite and concentrated to produce 2-(2,2-difluoroethoxy)-4-fluoroaniline (26.0 g, 95%) as a red solid. ¹ HNMR(300MHz,CDCl ₃ ): δ 7.01-6.97(m,1H),6.70-6.62(m,2H),6.20(tt, J _d =1.5Hz54.6Hz,1H),4.32(dt J _d =1.5 Hz, J _t =12.3Hz, 2H). ESI-MS (m/z): 191.9 (M+H) ⁺ .

2-(2,2-difluoroethoxy)-4-fluoro-5-nitroaniline. 2-(2,2-Difluoroethoxy)-4-fluoroaniline (26 g, 136 mmol, 1.0 eq) was added portionwise to concentrated H ₂ SO ₄ (60 mL) at 0°C. Then KNO ₃ (17.2 g, 164 mmol, 1.2 eq) was added in portions, and when the addition was complete, the reaction was warmed to rt. After LCMS indicated that the starting material disappeared, the reaction mixture was poured into ice water and neutralized by Na ₂ CO ₃ , extracted with MBTE, dried over Na ₂ SO ₄ , filtered, concentrated in vacuo, and then passed through the column Purified by chromatography to give the desired product 2-(2,2-difluoroethoxy)-4-fluoro-5-nitroaniline (15.2 g, 47%). ¹ H NMR(300MHz,CDCl ₃ ) δ 7.45(d, J =4.2Hz,1H),6.67(d, J =11.7Hz,1H),6.18(sl br t, J =54.3Hz,1H),4.29( sl br t, Jt = 12.6Hz, 1H), 4.10-3.85 (br, 2H). ESI-MS (m/z): 236.9 (M+H) ⁺ .

N -third butoxycarbonyl-2-(2,2-difluoroethoxy)-4-fluoro-5-nitroaniline. To 2-(2,2-difluoroethoxy)-4-fluoro-5-nitroaniline (15.2g, 64.4mmol, 1.0eq), DMAP (0.786g, 6.44mmol, 0.1eq) and DIPEA (12.45 g, 96.6 mmol, 1.5 eq) in DCM (150 mL) was added (Boc) ₂ O (15.45 g, 70.8 mmol, 1.1 eq), and the reaction mixture was stirred at room temperature overnight. TLC and LCMS indicated that no starting material remained, the reaction mixture was concentrated in vacuo and the residue was purified by column chromatography to provide N -third butoxycarbonyl-2-(2,2-difluoroethoxy Yl)-4-fluoro-5-nitroaniline (6.6 g, 21%). ¹ HNMR(300MHz,CDCl ₃ ) δ 8.98(br,1H),6.86(sl br s,1H),6.75(d, J =11.4Hz,1H),6.21(sl br t, J =55.2Hz,1H) , 4.34(dt, Jd=2.7Hz, Jt=12.3Hz, 2H), 1.56(s, 9H). ESI-MS (m/z): 334.8 (MH) ^- .

N -Third-butoxycarbonyl-2-(2,2-difluoroethoxy)-4-((2-(dimethylamino)ethyl)(methyl)amino)-5-nitro Aniline. To N -third butoxycarbonyl-2-(2,2-difluoroethoxy)-4-fluoro-5-nitroaniline (6.6g, 19.6mmol, 1.0eq) in EtOH (130mL) was added DIPEA (2.46g, 19.6mmol, 1.0eq) and ^{N 1, N 1, N 2} - trimethyl-1,2-diamine (2.5g, 23.5mmol, 1.2eq), and the reaction The mixture was heated to 60°C overnight. LCMS indicated that the reaction was complete, so the mixture was cooled to rt, and concentrated in vacuo to produce a crude residue, which was purified by column chromatography to produce the desired product N -Third as a red oil Butoxycarbonyl-2-(2,2-difluoroethoxy)-4-((2-(dimethylamino)ethyl)(methyl)amino)-5-nitroaniline (7.5 g, 90%). ¹ H NMR(300MHz,CDCl ₃ ) δ 8.60(br,1H),6.83(s,1H),6.80(1H,s),6.19sl br(t, J =54.6Hz,1H),4.34(sl br t J=13.2Hz, 2H), 3.52-3.31(m, 2H), 2.90(s, 3H), 2.84-2.67(m, 2H), 2.38(s, 6H), 1.54(s, 9H). ESI-MS (m/z): 418.8 (M+H) ⁺ .

5-amino-(1, N -third-butoxycarbonyl)-2-(2,2-difluoroethoxy)-4-((2-(dimethylamino)ethyl)(methyl Radical) amine) aniline. To N -third butoxycarbonyl-2-(2,2-difluoroethoxy)-4-((2-(dimethylamino)ethyl)(methyl)amino)-5- Nitroaniline (7.5 g, 17.9 mmol, 1.0 eq) in MeOH (80 mL) was added Pd/C (10 wt%, 5.6 g, 3.0 eq). The reaction was stirred overnight at rt under 1 atm hydrogen atmosphere. The reaction mixture was filtered through celite and concentrated to produce 5-amino-(1, N -third-butoxycarbonyl)-2-(2,2-difluoroethoxy)-4 as a red solid -((2-(dimethylamino)ethyl)(methyl)amino)aniline (6.6 g, 96%). ¹ H NMR(300MHz,CDCl ₃ ): δ 7.53(s,1H),6.86(s,1H),6.65(s,1H),6.08(t, J =54.0Hz,1H),4.14(t, J = 13.2Hz, 2H), 3.00-2.80 (m, 2H), 2.63 (s, 3H), 2.44-2.30 (m, 2H), 2.22 (s, 6H), 1.53 (s, 9H). ESI-MS (m/z): 388.9 (M+H) ⁺ .

5-propenylamino-(1, N -third-butoxycarbonyl)-2-(2,2-difluoroethoxy)-4-((2-(dimethylamino)ethyl) (Methyl)amino)aniline. 5-amino-(1, N -third butoxycarbonyl)-2-(2,2-difluoroethoxy)-4-((2-(dimethylamino)) Ethyl)(methyl)amino)aniline (6.6g, 17.0mmol, 1.0eq) and DIPEA (2.45g, 18.9mmol, 1.1eq) in THF (66mL) were added dropwise propylene acetyl chloride (1.69 g, 18.9 mmol, 1.1 eq) in THF (5 mL). After the addition, the mixture was stirred at 0 °C for 10 min and warmed to rt. LCMS indicated that the starting material disappeared, the reaction was quenched with water (30 mL), extracted with EA and washed with saturated NaHCO ₃ and brine, dried over Na ₂ SO ₄ , filtered and concentrated to produce a crude residue, which was passed by Column chromatography purification to produce the desired product 5-propenylamino-(1, N -third butoxycarbonyl)-2-(2,2-difluoroethoxy)-4-((2 -(Dimethylamino)ethyl) (methyl)amino)aniline (2.5 g, 33%). ESI-MS (m/z): 443.3 (M+H) ⁺ .

N -(5-amino-4-(2,2-difluoroethoxy)-2-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)acrylonitrile amine. To 5-propenamide-(1, N -third butoxycarbonyl)-2-(2,2-difluoroethoxy)-4-((2-(dimethylamino)ethyl ) (Methyl)amino)aniline (2.9 g, 6.56 mmol, 1.0 eq) in DCM (20 mL) was added TFA (10 mL), and then the mixture was heated to reflux. After TLC and LCMS indicated that the starting material disappeared, the reaction mixture was concentrated in vacuo at rt to remove most of TFA and DCM, neutralized by NaHCO ₃ to pH=7, by DCM/MeOH (10:1 ) Extraction, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to produce a crude residue, which was purified by column chromatography to provide the desired product N- (5-amine as a gray solid Yl-4-(2,2-difluoroethoxy)-2-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)acrylamide (1.4g, 64 %). ¹ H NMR(300MHz,CDCl ₃ ): δ 9.13(s,1H),6.78(s,1H),6.72(s,1H),6.47-6.42(m,1H),6.12(tt, J =55.2Hz, 3.9Hz, 1H), 5.72-5.67 (m, 1H), 4.21 (dt, J _d = 4.0Hz, J _t = 13.0Hz, 2H), 3.00-2.96 (m, 2H), 2.68 (s, 3H), 2.46-2.42 (m, 8H). ESI-MS (m/z): 343.2 (M+H) ⁺ .

Example 1. N -(5-((4-(3-(dimethylamino)-6-methyl-1 H -pyrazolo[4,3-c]pyridin-1-yl)pyrimidine-2 -Yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

2-chloro-4-( N , N ,6-trimethyl-pyrazolo[4,3-c]pyridin-3-amine-1-yl)pyrimidine (120mg, 0.42mmol, 1.0eq), N- (5-Amino-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (134mg, 0.46mmol, 1.1eq) And 2-pentanol (2mL) and p-TsOH ^. H ₂ O (87 mg, 0.46 mmol, 1.1 eq) was sealed in a 10 mL Schlenk tube. The mixture was stirred at 120°C for 2h. After completion, the mixture was cooled to RT and diluted with saturated NaHCO ₃ (10 mL) and DCM/MeOH (10/1, 20 mL), the organic layer was separated and the aqueous layer was extracted with DCM (5 mL×2). The combined organic layer was washed with NaHCO ₃ (20 mL×2) and brine (20 mL), dried, concentrated and purified by preparative HPLC to provide N- (5-((4-(3-(dimethylamino )-6-methyl- 1H -pyrazolo[4,3-c]pyridin-1-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl Group) (methyl)amino)-4-methoxyphenyl) acrylamide (6 mg, 2.7%). ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 9.76 (br, 1H), 9.44 (m, 1H), 8.99 (s, 1H), 8.42-8.40 (m, 2H), 7.50-7.33 (m, 2H ), 6.83-6.65 (m, 2H), 6.33-6.27 (m, 1H), 5.66-5.64 (m, 1H), 3.90 (s, 3H), 3.18 (s, 6H), 3.09-3.07 (m, 2H) ), 2.82-2.80 (m, 5H), 2.56 (s, 3H), 2.50 (s, 6H). ESI-MS (m/z): 544.8 (M+H) ⁺ .

Example 2. N- (5-((4-(7-cyano-1,3-dimethyl- 1H -indol-5-yl)pyrimidin-2-yl)amino)-2-(( 2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

To 2-chloro-4-(7-cyano-1,3-dimethyl- 1H -indol-5-yl)pyrimidine (164mg, 0.58mmol, 1.0eq) and N- (5-amino- 2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (170mg, 0.58mmol, 1.0eq) in 2-pentanol ( 4mL) was added p-toluenesulfonic acid monohydrate (123mg, 0.64mmol, 1.1eq). The mixture was heated to 120 °C in a 10 mL Schlenk tube for 5 h. After cooling to RT, the mixture was poured into water (10 mL), extracted with DCM/MeOH=10:1 (10 mL×3), the combined organic layer was washed with brine (10 mL), dried over sodium sulfate, concentrated and Purified by silica column to provide N- (5-((4-(7-cyano-1,3-dimethyl- 1H -indol-5-yl)pyrimidin-2-yl)amino )-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (48 mg, 15%). ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 10.19 (br, 1H), 9.07 (s, 1H), 8.71 (s, 1H), 8.51-8.49 (m, 2H), 8.20 (s, 1H), 7.59-7.57(m,1H), 7.32(s,1H), 7.04(s,1H), 6.40-6.34(m,1H), 6.27-6.21(m,1H),5.75-5.72(m,1H), 4.04(s, 3H), 3.85(s, 3H), 2.89-2.87(m, 2H), 2.71(s, 3H), 2.34-2.32(m, 2H), 2.23(s, 3H), 2.17(s, 6H). ESI-MS (m/z): 538.8 (M+H) ⁺ . HPLC: 94.8%.

Example 3. N- (5-((4-(7-cyano-3-methyl- 1H -pyrrolo[2,3-c]pyridin-5-yl)pyrimidin-2-yl)amino) -2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

Add 2-chloro-4-(1, N -(third butoxycarbonyl)-7-cyano-3-methyl-pyrrolo[2,3-c]pyridin-4-yl to a 10 mL microwave tube ) Pyrimidine (90 mg, 0.24 mmol, 1.0 eq), N -(5-amino-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxybenzene yl) acrylamide (78mg, 0.27mmol, 1.1eq), 2- pentanol (2mL) and ^p-TsOH. H ₂ O (51 mg, 0.27 mmol, 1.1 eq). The mixture was stirred at 170 °C under microwave for 1 h. After completion, the mixture was cooled to RT and diluted with saturated NaHCO ₃ (10 mL) and DCM/MeOH (10/1, 11 mL), the organic layer was separated and the aqueous layer was extracted with DCM/MeOH (5 mL×2). The combined organic layer was washed with NaHCO ₃ (10 mL) and brine (10 mL), dried, concentrated and purified by preparative HPLC to provide N-(5-((4-(7-cyano-3-methyl- 1 H -pyrrolo[2,3-c]pyridin-5-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino )-4-methoxyphenyl)acrylamide (6 mg, 4.8%). ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 12.48 (br, 1H), 10.20 (s, 1H), 9.21 (s, 1H), 9.01 (s, 1H), 8.56 (d, J = 4.8 Hz, 1H), 8.17(s, 1H), 7.72(d, J = 4.8Hz, 1H), 7.64(s, 1H), 7.05(s, 1H), 6.45-6.36(m, 1H), 6.20-6.14(m , 1H), 5.73(m, 1H), 3.87(s, 3H), 2.89-2.87(m, 2H), 2.72(s, 3H), 2.50-2.48(m, 2H), 2.30(s, 3H), 2.22 (s, 6H). ESI-MS (m/z): 526.2 (M+H) ⁺ . HPLC: 98.0%.

Example 4. N- (5-((4-(6-cyano-1-methyl-1H-indol-4-yl)pyrimidin-2-yl)amino)-2-((2-(di Methylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

Add 2-chloro-4-(6-cyano-1-methyl- 1H -indol-4-yl)pyrimidine (269mg, 1.0mmol, 1.0eq), N- (5-amine to a 10mL microwave tube 2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (321mg, 1.1mmol, 1.1eq) and 2-pentyl Alcohol (5mL) and p-TsOH ^. H ₂ O (175 mg, 1.0 mmol, 1.0 eq). The mixture was stirred in the microwave at 150°C for 2h. After completion, the mixture was cooled to RT and diluted with saturated NaHCO ₃ (10 mL) and DCM/MeOH (10/1, 20 mL), the organic layer was separated and the aqueous layer was extracted with DCM (5 mL×2). The combined organic layer was washed with NaHCO ₃ (20 mL×2) and brine (20 mL), dried, concentrated and purified by preparative HPLC to provide N- (5-((4-(6-cyano-1-methyl Yl-1H-indol-4-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy Phenyl) acrylamide (38mg, 5%). ¹ H NMR(300MHz, DMSO- d ₆ ): δ 10.11(br,1H),8.81(s,1H),8.51(d, J =4.8Hz,1H),8.39(s,1H),8.23(s, 1H), 8.11(s,1H),7.69(s,1H),7.42(d, J =4.5Hz,1H),7.10(s,1H),7.02(s,1H),6.24-6.38(m,2H ), 5.74 (d, J = 9.0Hz, 1H), 3.91 (s, 3H), 3.81 (s, 3H), 2.88-2.99 (m, 2H), 2.79 (s, 3H), 2.13-2.33 (m, 2H), 2.22 (s, 6H). ESI-MS (m/z): 525.3 (M+H) ⁺ .

Example 5. N -(5-((4-(3-(dimethylamino)-1 H -thieno[2,3-c]pyrazol-1-yl)pyrimidin-2-yl)amino )-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

To a 100 mL four-necked flask (10 mL Shlenk tube?), add 2-chloro-4-(3-( N , N -dimethylamino)-1 H -thieno[2,3-c]pyrazole-1 -Yl)pyrimidine (80mg, 0.287mmol, 1.0eq), N- (5-amino-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy Phenyl) acrylamide (92 mg, 0.315 mmol, 1.1 eq) and 2-pentanol (2 mL) and TsOH‧H ₂ O (54 mg, 0.315 mmol, 1.1 eq). The mixture was stirred at 120°C for 2h. After completion, the mixture was cooled to RT and diluted with water (3 mL) and DCM/MeOH (10/1, 4 mL), the organic layer was separated and the aqueous layer was extracted with DCM (5 mL×2). The combined organic layer was washed with NaHCO ₃ (5 mL×2) and brine (5 mL), the combined organic layer was dried, concentrated and purified by preparative HPLC to provide N-(5-((4-(3-( Dimethylamino)-1 H -thieno[2,3-c]pyrazol-1-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl Group) (methyl)amino)-4-methoxyphenyl) acrylamide (26 mg, 17%). ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 10.20 (s, 1H), 8.44 (s, 2H), 8.32 (d, J = 2.7 Hz, 1H), 7.21-7.10 (m, 1H), 7.08- 7.02 (m, 2H), 6.94 (d, J = 2.7Hz, 1H), 6.37-6.33 (m, 1H), 6.20-6.14 (m, 1H), 5.73-5.70 (m, 1H), 3.76 (s, 3H), 3.06 (s, 6H), 2.91-2.90 (m, 2H), 2.74 (s, 3H), 2.34-2.33 (m, 2H), 2.22 (s, 6H). ESI-MS (m/z): 535.8 (M+H) ⁺ .

Example 6. N -(5-((4-(5-chloro-3-(dimethylamino)-1 H -thieno[2,3-c]pyrazol-1-yl)pyrimidine-2- Yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

To 2-chloro-4-(3-( N , N -dimethylamino)-5-chloro- 1H -thieno[2,3-c]pyrazol-1-yl)pyrimidine (78.3mg, 0.25mmol, 1.0eq) and N- (5-amino-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (80.4mg, 0.275mmol, 1.1eq) in 2-pentanol (2mL) solution was added p-TsOH ^. H ₂ O (52.3 mg, 0.275 mmol, 1.1 eq). The mixture was heated in a Schlenk tube to 140° C. under microwave for 30 min. After completion, the mixture was cooled to RT and diluted with saturated NaHCO ₃ (10 mL) and DCM/MeOH (10/1, 20 mL), the organic layer was separated and the aqueous layer was extracted with DCM (5 mL×2). The combined organic layer was washed with NaHCO ₃ (20 mL×2) and brine (20 mL), dried, concentrated and purified by preparative HPLC to provide N-(5-((4-(5-chloro-3-(bis Methylamino)-1 H -thieno[2,3-c]pyrazol-1-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl ) (Methyl)amino)-4-methoxyphenyl) acrylamide (28 mg, 19%). ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 10.16 (br, 1H), 8.71 (s, 1H), 8.35 (m, 2H), 7.42 (s, 1H), 7.05 (s, 1H), 6.90 ( s,1H),6.38-6.35(m,1H),6.20-6.15(m,1H),5.77-5.70(m,1H),3.72(s,3H),3.03(s,6H),2.94-2.92( m, 2H), 2.75 (s, 3H), 2.40-2.35 (m, 2H), 2.24 (s, 6H). ESI-MS (m/z): 570.2 (M+H) ⁺ .

Example 7. N- (5-((4-(4-cyano-1-methyl- 1H -indol-6-yl)pyrimidin-2-yl)amino)-2-((2-( Dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

Add 2-chloro-4-(4-cyano-1-methyl- 1H -indol-6-yl)pyrimidine (269mg, 1.0mmol, 1.0eq), N- (5-amine to a 10mL microwave tube 2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (321mg, 1.1mmol, 1.1eq) and 2-pentyl Alcohol (5mL) and p-TsOH ^. H ₂ O (175 mg, 1.0 mmol, 1.0 eq). The mixture was stirred in the microwave at 150°C for 2h. After completion, the mixture was cooled to RT and diluted with saturated NaHCO ₃ (10 mL) and DCM/MeOH (10/1, 20 mL), the organic layer was separated and the aqueous layer was extracted with DCM (5 mL×2). The combined organic layer was washed with NaHCO ₃ (20 mL×2) and brine (20 mL), dried, concentrated and purified by preparative HPLC to provide N- (5-((4-(4-cyano-1-methyl Yl- 1H -indol-6-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy Phenyl) acrylamide (38mg, 5%). ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 10.21 (s, 1H), 9.18 (s, 1H), 8.70 (s, 1H), 8.49-8.54 (m, 2H), 8.17 (s, 1H), 7.79(s,1H),7.62(d, J =4.5Hz,1H),7.05(s,1H),6.64(s,1H),6.23-6.43(m,2H),5.75(d, J =9.0Hz , 1H), 3.94 (s, 3H), 3.87 (s, 3H), 2.88-2.86 (m, 2H), 2.71 (s, 3H), 2.32-3.30 (m, 2H), 2.22 (s, 6H). ESI-MS (m/z): 525.3 (M+H) ⁺ .

Example 8 (comparative). N -(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(3-methyl Oxy-1 H -indazol-1-yl)pyrimidin-2-yl)amino)phenyl)acrylamide

To a 10mL Schlenk tube, add 2-chloro-4-(3-methoxy- 1H -indazol-1-yl)pyrimidine (200mg, 0.77mmol, 1.0eq), N- (5-amino-2- ((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (248mg, 0.85mmol, 1.1eq) and 2-pentanol (3mL) And p-TsOH ^. H ₂ O (160 mg, 0.85 mmol, 1.1 eq). The mixture was stirred at 120°C for 2h. After completion, the mixture was cooled to RT and diluted with saturated NaHCO ₃ (10 mL) and DCM/MeOH (10/1, 20 mL), the organic layer was separated and the aqueous layer was extracted with DCM (5 mL×2). The combined organic layer was washed with NaHCO ₃ (20 mL×2) and brine (20 mL), dried, concentrated and purified by preparative HPLC to provide N- (2-((2-(dimethylamino)ethyl )(Methyl)amino)-4-methoxy-5-((4-(3-methoxy- 1H -indazol-1-yl)pyrimidin-2-yl)amino)phenyl) Acrylamide (53mg, 13%). ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 10.08 (br, 1H), 8.71 (s, 1H), 8.46-8.45 (m, 2H), 8.34 (d, J = 5.7 Hz, 1H), 7.69 ( d, J = 7.5Hz, 1H), 7.37-7.35(m, 1H), 7.28-7.26(m, 1H), 7.08-7.05(m, 2H), 6.47-6.42(m, 1H), 6.20-6.15( m,1H),5.74-5.71(m,1H),4.13(s,3H),3.76(s,3H),2.96-2.94(m,2H),2.75(s,3H),2.46-2.30(m, 2H), 2.28 (s, 6H). ESI-MS (m/z): 517.2 (M+H) ⁺ .

Example 9. N- (5-((4-(6-cyano-1-methyl- 1H -indazol-4-yl)pyrimidin-2-yl)amino)-2-((2-( Dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

Add 2-chloro-4-(6-cyano-1-methyl- 1H -indazol-4-yl)pyrimidine (269mg, 1.0mmol, 1.0eq), N- (5-amine to a 10mL microwave tube 2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (321mg, 1.1mmol, 1.1eq) and 2-pentyl Alcohol (5mL) and p-TsOH ^. H ₂ O (175 mg, 1.0 mmol, 1.0 eq). The mixture was stirred in the microwave at 150°C for 2h. After completion, the mixture was cooled to RT and diluted with saturated NaHCO ₃ (10 mL) and DCM/MeOH (10/1, 20 mL), the organic layer was separated and the aqueous layer was extracted with DCM (5 mL×2). The combined organic layer was washed with NaHCO ₃ (20 mL×2) and brine (20 mL), dried, concentrated and purified by preparative HPLC to provide N- (5-((4-(6-cyano-1-methyl Yl- 1H -indazol-4-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy Phenyl) acrylamide (16mg, 3%). ¹ H NMR(300MHz, DMSO- d ₆ ): δ 8.70(s,1H),8.61-8.54(m,4H),8.28(s,1H),7.58(d, J =5.1Hz,1H), 7.04( s,1H),6.45-6.31(m,1H),6.30-6.28(m,1H),6.25-6.19(m,1H),5.74-5.71(m,1H),4.12(s,3H),3.78( s, 3H), 2.98-2.92 (m, 2H), 2.73 (s, 3H), 2.40-2.22 (m, 8H). ESI-MS (m/z): 526.2 (M+H) ⁺ .

Example 10 (comparative). N -(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(1-methyl Yl- 1H -indazol-4-yl)pyrimidin-2-yl)amino)phenyl)acrylamide

2-chloro-4-(1-methyl- 1H -indazol-4-yl)pyrimidine (300mg, 1.22mmol, 1.0eq), N- (5-amino-2-((2-(dimethyl Aminoamino)ethyl) (methyl)amino)-4-methoxyphenyl) acrylamide (393mg, 1.34mmol, 1.1eq) and p-TsOH ^. A solution of H ₂ O (255 mg, 1.34 mmol, 1.1 eq) in 2-pentanol (12 mL) was heated in a microwave reactor at 150° C. for 1 h. After completion, the mixture was cooled to RT and diluted with MeOH/DCM=1:10 (20 mL) and saturated NaHCO ₃ (5 mL). The organic layer was separated, washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to produce a crude residue, which was purified by preparative HPLC to provide N- (2-((2-(dimethylamine Yl)ethyl)(methyl)amino)-4-methoxy-5-((4-(1-methyl- 1H -indazol-4-yl)pyrimidin-2-yl)amino) Phenyl) acrylamide (78mg, 12%). ¹ H NMR(300MHz,CDCl ₃ ): δ 10.06(br,1H),9.70(s,1H),8.63(d, J =5.1Hz,1H),8.54(s,1H),8.02(d, J = 5.7Hz, 1H), 7.73(s, 1H), 7.58-7.52(m, 2H), 7.29(m, 1H), 6.81(s, 1H), 6.49-6.44(m, 2H), 5.72-5.68(m , 1H), 4.14 (s, 3H), 3.91 (s, 3H), 2.94-2.93 (m, 2H), 2.73 (s, 3H), 2.34-2.32 (s, 8H). ESI-MS (m/z): 501.3 (M+H) ⁺ . HPLC: 99.1%.

Example 11. N -(5-((4-(1,3-dimethyl-1 H -pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)-2 -((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

Add 2-chloro-4-(1,3-dimethyl- 1H -pyrrolo[2,3-b]pyridin-5-yl)pyrimidine (300mg, 1.16mmol, 1.0eq) to the 10mL microwave reactor , N- (5-amino-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (115mg, 0.394mmol, 1.1eq), 2-pentanol (3mL) and p-TsOH ^. H ₂ O (243 mg, 1.28 mmol, 1.1 eq). The mixture was stirred in the microwave at 160°C for 40 min. After completion, the mixture was cooled to RT and diluted with saturated NaHCO ₃ (10 mL) and DCM/MeOH (10/1, 20 mL), the organic layer was separated and the aqueous layer was extracted with DCM/MeOH (10/1,2×5 mL) . The combined organic layer was washed with NaHCO ₃ (10 mL) and brine (10 mL), dried, concentrated and purified by preparative HPLC to provide N- (5-((4-(1,3-dimethyl- 1H -Pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)- 4-methoxyphenyl) acrylamide (63 mg, 11%). ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 10.16 (br, 1H), 9.11-9.07 (m, 2H), 8.79 (s, 1H), 8.47 (s, 1H), 8.13 (s, 1 H) , 7.51(s, 1H), 7.34(s, 1H), 7.04(s, 1H), 6.42-6.40(m, 1H), 6.25-6.19(m, 1H), 5.80-5.74(m, 1H), 3.86 (s,3H),3.79(s,3H),2.89-2.87(m,2H),2.72(s,3H),2.48-2.42(m,2H),2.28(s,3H),2.22(s,6H ). ESI-MS (m/z): 515.3 (M+H) ⁺ .

Example 12. N- (5-((4-(1,3-dimethyl- 1H -indol-5-yl)pyrimidin-2-yl)amino)-2-((2-(dimethyl Aminoamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

To a solution of 2-chloro-4-(1,3-dimethyl- 1H -indol-5-yl)pyrimidine (300mg, 1.16mmol, 1.0eq) in 2-pentanol (3mL) was added N -(5-amino-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (375mg, 1.28mmol, 1.1eq ) And p-TsOH ^. H ₂ O (244 mg, 1.28 mmol, 1.1 eq). The mixture was stirred in the microwave at 160°C for 40 minutes. After completion, the mixture was cooled to RT and diluted with saturated NaHCO ₃ (10 mL) and DCM/MeOH (10/1, 20 mL), the organic layer was separated and the aqueous layer was extracted with DCM/MeOH (10/1, 2×5 mL) . The combined organic layer was washed with NaHCO ₃ (10 mL) and brine (10 mL), dried, concentrated and purified by preparative HPLC to provide N- (5-((4-(1,3-dimethyl- 1H -Indazol-5-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl) Acrylamide (65mg, 10.8%). ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 10.14 (br, 1H), 9.11 (s, 1H), 8.41 (s, 2H), 8.08 (d, J = 7.8 Hz, 1H), 7.99 (s, 1H), 7.45-7.43(m, 2H), 7.13(s, 1H), 7.02(s, 1H), 6.46-6.37(m, 1H), 6.28-6.22(m, 1H), 5.77-5.74(m, 1H), 3.87(s, 3H), 3.75(s, 3H), 2.90-2.88(m, 2H), 2.71(s, 3H), 2.32-2.30(m, 2H), 2.28(s, 3H), 2.22 (s,6H). ESI-MS (m/z): 514.3 (M+H) ⁺ .

Example 13 (comparative). N -(5-((4-(3-chloro-1-methyl-1 H -pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl) Amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

Add 2-chloro-4-(3-chloro-1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidine (100mg, 0.358mmol, 1.0eq) to the 10mL microwave reactor , N- (5-amino-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (115mg, 0.394mmol, 1.1eq), 2-pentanol (1mL) and p-TsOH ^. H ₂ O (75 mg, 0.39 mmol, 1.1 eq). The mixture was stirred in the microwave at 160°C for 1 h. After completion, the mixture was cooled to RT and diluted with saturated NaHCO ₃ (10 mL), and extracted with DCM/MeOH (10/1, 10 mL, 5 mL 5 mL). The combined organic layer was washed with NaHCO ₃ (5 mL) and brine (5 mL), dried, concentrated and purified by preparative HPLC to provide N- (5-((4-(3-chloro-1-methyl-1 H -pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino) -4-methoxyphenyl) acrylamide (8 mg, 5%). ¹ HNMR (300 MHz, DMSO- d ₆ ): δ 10.13 (br, 1H), 9.16 (s, 1H), 8.97 (s, 1H), 8.73 (s, 1H), 8.49 (s, 1H), 8.26 (s ,1H),7.82(s,1H),7.56(s,1H),7.02(s,1H),6.39-6.36(m,1H),6.33-6.20(m,1H),5.76-5.74(m,1H ), 3.85 (s, 6H), 2.88-2.86 (m, 2H), 2.72 (s, 3H), 2.31-2.30 (m, 2H), 2.21 (s, 6H). ESI-MS (m/z): 535.2 (M+H) ⁺ .

Example 14. N -(2-((2-(Dimethylamino)ethyl)(methyl)amino)-5-((4-(3-(2-hydroxyethanoyl)-1 H -Indol-1-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide

Acetic acid 2-(1-(2-chloropyrimidin-4-yl)-1 H -indol-3-yl)-2-oxoethyl acetate (165mg, 0.5mmol, 1.0eq) and N -(5-amino-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (160mg, 0.55mmol, 1.1eq ) Add p-TsOH to the solution in 2-pentanol (3mL) ^. H ₂ O (105 mg, 0.55 mmol, 1.1 eq). The mixture was heated to 100°C for 2h. The mixture was poured into water (10 mL), then adjusted to pH=7 with saturated sodium bicarbonate solution, extracted with EA (10 mL×2), dried over sodium sulfate, and concentrated to provide the desired diarylamine (30 mg, 10 %). LCMS: (M+H) ⁺ : 585.8.

To a solution of the above diarylamine (30 mg, 0.05 mmol, 1.0 eq) in MeOH (3 mL) was added K ₂ CO ₃ (20 mg, 0.15 mmol, 3.0 eq). The reaction was stirred at room temperature for 1 hour. After completion, the mixture was filtered; the filtrate was concentrated in vacuo and purified by silica column chromatography to provide the desired product N- (2-((2-(dimethylamino)ethyl)(methyl yl) amino) -5 - ((4- (3- (2-hydroxy-acetyl yl) -1 H - indol-1-yl) pyrimidin-2-yl) amino) -4-methoxybenzene Base) acrylamide (2mg, 7%). ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 9.40 (s, 1H), 9.12 (s, 1H), 8.72-8.54 (m, 2H), 8.25-8.24 (m, 2H), 7.28-7.26 (m , 2H), 7.05-7.04 (m, 1H), 6.74-6.72 (m, 1H), 6.22-6.18 (m, 1H), 5.73-5.69 (m, 1H), 5.32 (br, 1H), 5.09 (s , 1H), 4.63 (s, 2H), 3.84 (s, 3H), 3.33-3.31 (m, 2H), 2.68 (s, 3H), 2.66-2.64 (m, 2H), 2.50 (s, 6H). ESI-MS (m/z): 543.8 (M+H) ⁺ . HPLC: 75.1%.

Example 15. N -(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(3-(methylsulfonamide Amino)-1 H -indazol-1-yl)pyrimidin-2-yl)amino)phenyl) acrylamide

N was added to 100mL four-necked flask - (1- (2-chloro-4-yl) -1 H - indazol-3-yl) methanesulfonamide Amides (290mg, 0.89mmol, 1.0eq), N - ( 5-amino-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (284mg, 0.98mmol, 1.1eq), 2-pentanol (5mL) and p-TsOH ^. H ₂ O (185 mg, 0.97 mmol, 1.1 eq). The mixture was stirred at 120°C for 2h. After completion, the mixture was cooled to RT and diluted with water (10 mL) and DCM/MeOH (10/1, 20 mL), the organic layer was separated and the aqueous layer was extracted with DCM (5 mL×2). The combined organic layer was washed with NaHCO ₃ (20 mL×2) and brine (20 mL), the combined organic layer was dried, concentrated and purified by preparative HPLC to provide N- (2-((2-(dimethyl Amino)ethyl)(methyl)amino)-4-methoxy-5-((4-(3-(methylsulfonamido)-1 H -indazol-1-yl)pyrimidine- 2-yl)amino)phenyl)acrylamide (20 mg, 4%). ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 9.96 (br, 1H), 8.67 (s, 1H), 8.42-8, 34 (m, 3H), 7.87 (d, J = 7.5 Hz, 1H), 7.36-7.33(m,1H),7.28-7.24(m,1H),7.12-7.04(m,2H),6.52-6.44(m,1H),6.22-6.17 (m,1H),5.73(d, J =10.8Hz, 1H), 3.77(s, 3H), 3.32(s, 3H), 3.03-3.00(m, 2H), 2.73(s, 3H), 2.61-2.58(m, 2H), 2.38(s, 6H). ESI-MS (m/z): 579.7 (MH) ^- . HPLC: 85.6%.

Example 16. N -(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(1-(methylamino )Imidazo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide

To 2-chloro-4-(1-( N -methylamino)imidazo[1,5-a]pyridin-3-yl)pyrimidine (128mg, 0.49mmol, 1.0eq) and N- (5-amine 2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (137mg, 0.49mmol, 1.0eq) in 2-pentane To a solution in alcohol (4 mL) was added PTSA (103 mg, 0.53 mmol, 1.1 eq). The reaction was stirred at 100°C for 2 hours. After cooling to RT, the mixture was diluted with water (50 mL), extracted with DCM (50 mL×3, washed with brine (50 mL), concentrated and the residue was purified by preparative HPLC to provide N- (2-((2- (Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(1-(methylamino)imidazo[1,5-a]pyridine- 3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide (12 mg, 5%). ESI-MS (m/z): 515.9 (M+H) ^+. HPLC: 66.1%.

Example 17. N -(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(3-(methoxymethoxy Group)-1 H -indol-1-yl)pyrimidin-2-yl)amino)phenyl)acrylamide

1-(2-((4-Fluoro-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)-1 H -indole-3-carboxylic acid methyl ester. To a 250 mL four-necked flask was added 1-(2-chloropyrimidin-4-yl)-1 H -indole-3-carboxylic acid methyl ester (6.0 g, 20.9 mmol, 1.0 eq), 4-fluoro-2-methoxy 5-Nitroaniline (4.6g, 24.7mmol, 1.2eq), 2-pentanol (110 mL) and p- TsOH ^. H ₂ O (5.4 g, 28.4 mmol, 1.4 eq). The mixture was refluxed for 2h. After completion, the precipitate was collected by filtration and the solid was redissolved in water (30 mL), and then adjusted to pH=8~9 with ammonia water. The solid was filtered, washed with water (100 mL×2) and dried to produce 1-(2-((4-fluoro-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)-1 H -indole-3-carboxylic acid methyl ester (6.3 g, 77%). ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 9.14 (s, 1H), 8.82 (s, 1H), 8.68 (d, J = 8.4 Hz, 1H), 8.58-8.56 (m, 2H), 8.11 (d , J = 7.8Hz, 1H), 7.51-7.28 (m, 4H), 3.98 (s, 3H), 3.88 (s, 3H).

1-(2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)pyrimidine-4 - yl) -1 H - indole-3-carboxylate. A 250 mL sealed tube was fed with 1-(2-((4-fluoro-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)-1H-indole-3-carboxylic acid methyl Ester (6.3g, 7.6mmol, 1.0eq), DIPEA (5.9g, 45mmol, 6.0eq), DMAc (70mL) and N,N,N' -trimethylethane-1,2-diamine (2.35g , 22.9mmol, 3.0eq). The mixture was heated to 120°C and monitored by TLC and LCMS. After completion, the mixture was poured into water (400 mL) and extracted with EA (3×200 mL). The combined organic layer was washed with brine (3×200 mL), dried over Na ₂ SO ₄ , concentrated and purified by column chromatography to give crude product 1-(2-((4-((2-(two Methylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)-1 H -indole-3-carboxylic acid methyl ester (12.0g, 56%).

1-(2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)pyrimidine-4 -Yl)-1 H -indol-3-yl)methanol. A 500 mL four-necked flask was fed with 1-(2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrobenzene yl) amino) pyrimidin-4-yl) -1 H - indole-3-carboxylate (12.0g, 23.1mmol, 1.0eq), and THF (100mL). The mixture was cooled to -78 °C and DIBAL-H (104 mL, 92.4 mmol, 4.0 eq) was added dropwise. After the addition, the mixture was stirred at this temperature for 30 minutes and then warmed to -40°C. The reaction was monitored by TLC. After completion, the reaction was quenched at -40°C by careful addition of Na ₂ SO ₄ .10H ₂ O (Gerberberg salt 50 g) in batches with vigorous stirring. After quenching was completed, the reaction mixture was slowly warmed to 0°C. When gas evolution has stopped and the precipitate has granulated, the slurry is vacuum filtered and the residue is rinsed with DCM (2×100 mL). The combined filtrate was dried, concentrated and purified by column chromatography to produce the product 1-(2-((4-((2-(dimethylamino)ethyl)(methyl)amino)- 2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)-1 H -indol-3-yl)methanol (6.0 g, 53%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 9.16 (s, 1H), 8.43 (d, J = 5.7 Hz, 1H), 8.17 (d, J = 8.7 Hz, 1H), 7.97 (s, 1H), 7.74 ( d, J = 7.5Hz, 1H), 7.54 (s, 1H), 7.37-7.27 (m, 3H), 6.94 (d, J = 5.7Hz, 1H), 6.66 (s, 1H), 4.96 (s, 2H ), 3.97 (s, 3H), 3.31 (t, J = 7.2Hz, 2H), 2.89 (s, 3H), 2.62 (t, J = 7.2Hz, 2H), 2.31 (s, 6H).

N ¹ -(2-(dimethylamino)ethyl)-5-methoxy- N ⁴ -(4-(3-(methoxymethyl)-1H-indol-1-yl)pyrimidine -2-yl) -N ¹ -methyl-2-nitrobenzene-1,4-diamine. Add (1-(2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrobenzene yl) amino) pyrimidin-4-yl) -1 H - indol-3-yl) methanol (3,2g, 6.5mmol, 1.0eq), and DMF (25mL). The mixture was cooled to -40°C and NaH (172 mg, 7.1 mmol, 1.1 eq) was added portionwise. After stirring at this temperature for 30 minutes, MeI (500 mg, 11.3 mmol, 1.7 eq) was added. The mixture was stirred for another 30 minutes and TLC showed the reaction was complete. The reaction mixture was poured into water (100 mL), and extracted with EA (100 mL×2). The combined organic layer was dried, concentrated and purified by column chromatography to produce the product N ¹ -(2-(dimethylamino)ethyl)-5-methoxy- N ⁴ -(4-( 3-(methoxymethyl)-1H-indol-1-yl)pyrimidin-2-yl) -N ¹ -methyl-2-nitrobenzene-1,4-diamine (700mg, 22%) . ¹ H NMR(300MHz,CDCl ₃ ) δ 8.29(s,1H),7.90(s,1H),7.72-7.54(m,3H),7.18-7.10(m,1H),6.78(s,1H),6.62 (d, J =5.4Hz, 1H), 4.82(s, 2H), 3.80(s, 3H), 3.61-3.58(m, 2H), 3.43(s, 3H), 3.10-3.02(m, 2H), 2.92 (s, 3H), 2.57 (s, 6H).

N ¹ -(2-(dimethylamino)ethyl)-5-methoxy- N ⁴ -(4-(3-(methoxymethyl)-1 H -indol-1-yl) Pyrimidin-2-yl) -N ¹ -methylbenzene-1,2,4-triamine. To a 100 mL three-necked flask was added N ¹ -(2-(dimethylamino)ethyl)-5-methoxy- N ⁴ -(4-(3-(methoxymethyl)-1H-ind Indole-1-yl)pyrimidin-2-yl) -N ¹ -methyl-2-nitrobenzene-1,4-diamine (700 mg, 1.3 mmol), 10% Pd/C (500 mg) and MeOH (5 mL ). The mixture was stirred under H ₂ atmosphere for 2 hours. After completion, the mixture was filtered and washed with MeOH. The filtrate was concentrated to produce the product N ¹ -(2-(dimethylamino)ethyl)-5-methoxy- N ⁴ -(4-(3-(methoxymethyl)-1 H -indole -1-yl)pyrimidin-2-yl) -N ¹ -methylbenzene-1,2,4-triamine (390 mg, crude material), this product was used in the next step without further purification. ESI-MS (m/z): 476 (M+H) ⁺ .

N -(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(3-(methoxymethyl)- 1 H -Indol-1-yl)pyrimidin-2-yl)amino)phenyl)acrylamide. To N ¹ -(2-(dimethylamino)ethyl)-5-methoxy- N ⁴ -(4-(3-(methoxymethyl)-1 H -Indol-1-yl)pyrimidin-2-yl) -N ¹ -methylbenzene-1,2,4-triamine (390 mg, 0.82 mmol) in DCM (4 mL) was added propylene acetyl chloride (4 38 mg, 0.5 mmol). The mixture was stirred at RT for 1 h. After completion, the mixture was diluted with DCM (10 mL), washed with saturated NaHCO ₃ (10 mL) and brine (10 mL). The organic layer was dried, concentrated and purified by preparative HPLC to produce N- (2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-( (4- (3- (methoxymethyl) -1 H - indol-1-yl) pyrimidin-2-yl) amino) phenyl) acrylamide (19mg, 3%, 2 steps). ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.11 (s, 1H), 8.46-8.41 (m, 1H), 8.27-8.22 (m, 1H), 7.93 (s, 1H), 7.74-7.71 (m, 1H), 7.57-7.52 (m, 1H), 7.23-7.01 (m, 3H), 6.80 (br, 1H), 6.45-6.36 (m, 1H), 6.21-6.15 (m, 1H), 5.74-5.71 ( m,1H),4.63(s,2H),3.69(s,3H),3.34(s,3H),2.94-2.90(m,2H),2.73(s,3H),2.42-2.39(m,2H) , 2.23 (s, 6H). ESI-MS (m/z): 530.3 (M+H) ⁺ .

Example 18. N -(4-(difluoromethoxy)-5-((4-(3-(dimethylamino)-1 H -indazol-1-yl)pyrimidin-2-yl)amine Group)-2-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)acrylamide

Add N- (5-amino-4-(difluoromethoxy)-2-((2-(dimethylamino)ethyl)(methyl)amino)phenyl) to a 10mL Schlenk tube acrylamide (151mg, 0.55mmol, 1.0eq), 1- (2- chloro-pyrimidin-4-yl) -3- (N, N - dimethylamino) -1 H - indazole (200mg, 0.61mmol , 1.1eq), 2-pentanol (3mL) and p-TsOH ^. H ₂ O (116 mg, 0.61 mmol, 1.1 eq). The mixture was stirred at 120°C for 2h. After completion, the mixture was cooled to RT and diluted with saturated NaHCO ₃ (10 mL) and DCM/MeOH (10/1, 20 mL), the organic layer was separated and the aqueous layer was extracted with DCM (5 mL×2). The combined organic layer was washed with NaHCO ₃ (20 mL×2) and brine (20 mL), dried (Na ₂ SO ₄ ), concentrated and purified by preparative HPLC to provide N- (4-(difluoromethoxy) -5-((4-(3-(dimethylamino)-1 H -indazol-1-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino ) Ethyl) (methyl) amino) phenyl) acrylamide (38 mg, 12%). ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 10.16 (br, 1H), 8.97 (s, 1H), 8.53-8.49 (m, 2H), 8.30 (d, J = 4.8 Hz, 1H), 7.97 ( d, J = 7.5Hz, 1H), 7.33-7.04(m, 5H), 6.56(m, 1H), 6.23-6.18(m, 1H), 5.77-5.74(m, 1H), 3.16(s, 6H) , 2.98-2.95 (m, 2H), 2.73 (s, 3H), 2.50-2.48 (m, 2H), 2.31 (s, 6H). ESI-MS (m/z): 566.2 (M+H) ⁺ . HPLC: 97.8%.

Example 19. N -(4-(difluoromethoxy)-5-((4-(3-(dimethylamino)-1 H -pyrazolo[4,3-b]pyridine-1- Yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)phenylacrylamide

2-chloro 10mL Schlenk tube -4- (3- (N, N - dimethylamino) -1 H - pyrazolo [4,3-b] pyridin-1-yl) pyrimidine (274mg, 1.0mmol, 1eq), N- (5-amino-4-(difluoromethoxy)-2-((2-(dimethylamino)ethyl)(methyl)amino)phenyl) Acrylamide (360mg, 1.1mmol, 1.1eq), 2-pentanol (5mL) and p- TsOH ^. H ₂ O (116 mg, 0.61 mmol, 0.61 eq). The mixture was stirred at 120°C for 2h. After completion, the mixture was cooled to RT and diluted with saturated NaHCO ₃ (10 mL) and DCM/MeOH (10/1, 20 mL), the organic layer was separated and the aqueous layer was extracted with DCM (5 mL×2). The combined organic layer was washed with NaHCO ₃ (20 mL×2) and brine (20 mL), dried (Na ₂ SO ₄ ), concentrated and purified by preparative HPLC to provide N- (4-(difluoromethoxy) -5-((4-(3-(dimethylamino)-1 H -pyrazolo[4,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-( (2-(Dimethylamino)ethyl)(methyl)amino)phenylacrylamide (55 mg, 9.7%). ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 10.24 (br, 1H ), 9.06 (s, 1H), 8.75 (br, 1H), 8.57-8.51 (m, 2H), 8.33 (d, J = 4.8Hz, 1H), 7.33-7.05 (m, 4H), 6.46-6.38 ( m,1H),6.23-6.17(m,1H),5.78-5.75(m,1H),3.42(s,6H),2.89(m,2H),2.74(s,3H),2.39(m,2H) , 2.22 (s, 6H). ESI-MS (m/z): 567.2 (M+H) ^+. HPLC: 95.0%.

Example 20. N- (4-(difluoromethoxy)-2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-(3-( Ethylamino)-1 H -pyrazolo[4,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)phenyl)acrylamide

Add 2-chloro-4-(3-( N -ethylamino)pyrazolo[4,3-b]pyridin-1-yl)pyrimidine (274mg, 1.0mmol, 1.0eq) to a 10mL Schlenk tube, N-(5-amino-4-(difluoromethoxy)-2-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)acrylamide (360mg, 1.1mmol, 1.1eq), 2-pentanol (5mL) and p- TsOH ^. H ₂ O (116 mg, 0.61 mmol, 0.61 eq). The mixture was stirred at 120°C for 2h. After completion, the mixture was cooled to RT and diluted with saturated NaHCO ₃ (10 mL) and DCM/MeOH (10/1, 20 mL), the organic layer was separated and the aqueous layer was extracted with DCM (5 mL×2). The combined organic layer was washed with NaHCO ₃ (20 mL×2) and brine (20 mL), dried, concentrated and purified by preparative HPLC to provide the desired product N- (4-(difluoromethoxy)-2- ((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-(3-(ethylamino)-1 H -pyrazolo[4,3-b ]Pyridin-1-yl)pyrimidin-2-yl)amino)phenyl)acrylamide (2 mg, 0.3%). ¹ H NMR(300MHz, DMSO- d ₆ ): δ 10.23(br,1H),8.98(s,1H),8.66-8.60(m,1H),8.58(s,1H),8.49(d, J =4.8 Hz, 1H), 8.30 (d, J = 4.8Hz, 1H), 7.31-7.30 (m, 1H), 7.20 (s, 1H), 7.05 (s, 1H), 6.94-6.90 (m, 1H), 6.42 -6.37(m,1H),6.23-6.17(m,1H),5.78-5.75(m,1H),3.43-3.42(m,2H),2.90-2.88(m,2H),2.74(s,3H) , 2.39-2.38 (m, 2H), 2.23 (s, 6H), 1.26-1.24 (m, 3H). ESI-MS (m/z): 567.2 (M+H) ⁺ .

Example 21. N -(4-(2,2-difluoroethoxy)-5-((4-(3-(dimethylamino)-1 H -pyrazolo[4,3-b] Pyridin-1-yl)pyrimidin-2-yl)amino)-2-( N -(2-(dimethylamino)ethyl)- N -methylamino)phenyl)acrylamide

N -(5-amino-4-(2,2-difluoroethoxy)-2-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)acrylonitrile amine (80mg, 0.23mmol, 1.0eq), 2- chloro -4- (3- (N, N - dimethylamino) -1 H - pyrazolo [4,3-b] pyridin-1-yl ) Pyrimidine (64mg, 0.23mmol, 1.0eq) and p-TsOH ^. A solution of H ₂ O (43 mg, 0.25 mmol, 1.1 eq) in 2-pentanol (2 mL) was heated at 140° C. in the microwave for 30 min. After completion, the mixture was cooled to RT and diluted with saturated NaHCO ₃ (10 mL) and DCM/MeOH (10/1, 20 mL), the organic layer was separated and the aqueous layer was extracted with DCM (5 mL×2). The combined organic layer was washed with NaHCO ₃ (20 mL×2) and brine (20 mL), dried, concentrated and purified by preparative HPLC to provide N- (4-(2,2-difluoroethoxy)-5 -((4-(3-(dimethylamino)-1 H -pyrazolo[4,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-( N- (2-(Dimethylamino)ethyl) -N -methylamino)phenyl)acrylamide (8 mg, 4.7%). ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 10.14 (br, 1H), 8.69-8.62 (m, 2H), 8.58-8.52 (m, 2H), 8.34-8.30 (m, 1H), 7.28-7.09 (m,3H),6.43-6.27(m,1H),6.24-6,13(m,2H), 5.76-5.72(m,1H),4.30-4.20(m,2H),3.32(s,6H) , 3.03-3.01 (m, 2H), 2.92 (s, 3H), 2.40-2.38 (m, 2H), 2.25 (s, 6H). ESI-MS (m/z): 581.3 (M+H) ⁺ . HPLC: 98.0%.

Example 22. N -(4-(2,2-difluoroethoxy)-2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4- (3-(ethylamino)-1 H -pyrazolo[4,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)phenyl)acrylamide

N -(5-amino-4-(2,2-difluoroethoxy)-2-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)acrylonitrile Amine (264mg, 0.77mmol, 1.1eq), 2-chloro-4-(3-( N -ethylamino)pyrazolo[4,3-b]pyridin-1-yl)pyrimidine (212mg, 0.77mmol , 1.0eq) and p-TsOH ^. A solution of H ₂ O (144 mg, 0.85 mmol, 1.1 eq) in 2-pentanol (2 mL) was heated to 140° C. in the microwave for 30 min. After completion, the mixture was cooled to RT and diluted with saturated NaHCO ₃ (10 mL) and DCM/MeOH (10/1, 20 mL), the organic layer was separated and the aqueous layer was extracted with DCM (5 mL×2). The combined organic layer was washed with NaHCO ₃ (10 mL×2) and brine (10 mL), dried, concentrated and purified by preparative HPLC to provide N- (4-(2,2-difluoroethoxy)-2 -((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-(3-(ethylamino)-1 H -pyrazolo[4,3- b] Pyridin-1-yl)pyrimidin-2-yl)amino)phenyl)acrylamide (38 mg, 8.5%). ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 10.16 (br, 1H), 8.62-8.41 (m, 3H), 8.40 (s, 1H), 8.32 (s, 1H), 7.29-7.27 (m, 1H ), 7.22 (s, 1H), 7.16-7.11 (m, 1H), 6.98-6.94 (m, 1H), 6.47-6.13 (m, 3H), 5.74-5.70 (m, 1H), 4.33-4.25 (m , 2H), 3.38-3.34(m, 2H), 2.91-2.90(m, 2H), 2.75(s, 3H), 2.37-2.35(m, 2H), 2.23(s, 6H), 1.26(t, J = 3.6Hz, 3H). ESI-MS (m/z): 581.3 (M+H) ⁺ .

Example 23. N -(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(3-(methylmethyl )-1 H -thieno[2,3-c]pyrazol-1-yl)pyrimidin-2-yl)amino)phenyl)acrylamide

2-chloro-4- (5-chloro-3- (methylamino) -1 H - thieno [2,3-c] pyrazol-1-yl) To a 10mL Schlenk tube pyrimidine (50mg, 0.189 mmol, 1.0eq), N- (5-amino-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl) acrylamide ( 60mg, 0.207mmol, 1.1eq) and 2-pentanol (1mL) and p- TsOH ^. H ₂ O (40 mg, 0.207 mmol, 1.1 eq). The mixture was stirred at 120°C for 2h. After completion, the mixture was cooled to RT and diluted with water (3 mL) and DCM/MeOH (10/1, 4 mL), the organic layer was separated and the aqueous layer was extracted with DCM (5 mL×2). The combined organic layer was washed with NaHCO ₃ (5 mL×2) and brine (5 mL), the combined organic layer was dried, concentrated and purified by preparative HPLC to provide N- (2-((2-(dimethyl Amino)ethyl)(methyl)amino)-4-methoxy-5-((4-(3-(methylamino)-1 H -thieno[2,3-c]pyrazole -1-yl)pyrimidin-2-yl)amino)phenyl)acrylamide (17 mg, 17%). ¹ H NMR(300MHz,CDCl ₃ ): δ 10.12(br,1 H),9.38(s,1 H),8.42(d, J =5.7Hz,1H),7.38(s,1 H),7.12(d , J =5.4Hz,1 H),6.94-6.89(m,2 H),6.80(s,1 H),6.39-6.36(m,2 H),5.68(t, J =5.7Hz,1 H) ,4.21(br,1 H),3.90(s,3 H),3.10(d, J =4.2Hz,3 H),2.95-2.92(m,2 H),2.74(s,3 H),2.35- 2.33(m,8 H). ESI-MS (m/z): 522.2 (M+H) ⁺ .

Example 24. N -(5-((4-(5-chloro-3-(methylamino)-1 H -thieno[2,3-c]pyrazol-1-yl)pyrimidin-2-yl )Amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

To 2-chloro-4-(5-chloro-3-(methylamino)-1 H -thieno[2,3-c]pyrazol-1-yl)pyrimidine (75 mg, 0.25 mmol, 1 eq) and N- (5-Amino-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl) acrylamide (80.4mg, 0.275mmol, 1.1eq) Add p-TsOH to the solution in 2-pentanol (2mL) ^. H ₂ O (52.3 mg, 0.275 mmol, 1.1 eq). The mixture was heated to 140°C under microwave for 30 min. After completion, the mixture was cooled to RT and diluted with saturated NaHCO ₃ (10 mL) and DCM/MeOH (10/1, 20 mL), the organic layer was separated and the aqueous layer was extracted with DCM (5 mL×2). The combined organic layer was washed with NaHCO ₃ (20 mL×2) and brine (20 mL), dried, concentrated and purified by preparative HPLC to provide N- (5-((4-(5-chloro-3-(A Aminoamino)-1 H -thieno[2,3-c]pyrazol-1-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl) (Methyl)amino)-4-methoxyphenyl)acrylamide (20 mg, 14%). ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 10.19 (br, 1H), 8.64 (br, 1 H), 8.38 (s, 1 H), 8.31 (d, J = 5.4 Hz, 1 H), 7.08 (s,1 H),7.05(s,1 H),6.85(d, J =5.4Hz,1 H),6.69-6.68(m,1 H),6.42-6.33(m,1 H),6.21- 6.15(m,1 H),5.74-5.70(m,1 H),3.72(s,3 H),2.93-2.90(m,2 H),2.86(d, J =4.5Hz,3 H),2.75 (s,3 H),2.36-2.32(m,2 H),2.22(s,6H). ESI-MS(m/z): 556.2(M+H) ⁺

Example 25 (comparative). N- (2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(1-methyl Yl- 1H -indol-4-yl)pyrimidin-2-yl)amino)phenyl)acrylamide

2-chloro-4-(1-methyl- 1H -indol-4-yl)pyrimidine (250mg, 1.02mmol, 1.0eq), N- (5-amino-2-((2-(dimethyl Aminoamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (325 mg, 1.11 mmol, 1.1 eq) and p-TsOH.H ₂ O (215 mg, 1.13 mmol, 1.1 eq) A solution in 2-pentanol (10 mL) was heated in the microwave to 150° C. for 1 h. After completion, the mixture was cooled to RT and diluted with MeOH: DCM=1:10 (20 mL) and saturated NaHCO ₃ (5 mL). The organic layer was separated, washed with brine, concentrated and purified by preparative HPLC to provide N- (2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy -5-((4-(1-methyl-1H-indol-4-yl)pyrimidin-2-yl)amino)phenyl)acrylamide (30 mg, 5.8%). ¹ H NMR(300MHz,CDCl ₃ ): δ 10.01(br,1 H),9.68(s,1 H),8.58(d, J =4.2Hz,1 H),7.87(d, J =7.2Hz,1 H), 7.70 (s, 1 H), 7.44 (d, J = 8.0Hz, 1 H), 7.37 (t, J = 7.6Hz, 1 H), 7.25 (d, J = 4.8Hz, 1 H), 7.16 (d, J = 3.2Hz, 1 H), 7.00 (d, J = 2.8Hz, 1 H), 6.77 (s, 1 H), 6.48-6.36 (m, 2 H), 5.68 (d, J = 11.2Hz, 1 H), 3.87(s, 3 H), 3.84(s, 3 H), 2.95-2.90(m, 2 H), 2.70(s, 3 H), 2.28-2.20(m, 8 H) . ESI-MS (m/z): 500.2 (M+H) ⁺ . HPLC: 96.8%.

Example 26. N- (5-((4-(7-cyano-1,3-dimethyl- 1H -indol-5-yl)pyrimidin-2-yl)amino)-2-(( 2-(ethyl(methyl)amino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

N -methyl- N- (2-(methylamino)ethyl)acetamide. To a solution of N ¹ , N ² -dimethylethane-1,2-diamine (8.8 g, 100 mmol, 1.0 eq) in DCM (100 mL) was added TEA (20.2 g, 200 mmol, 2.0 eq.), Cool to 0 °C and add AcCl (7.8 g, 100 mmol) dropwise. The mixture was stirred at 0°C for 2h. Water (100 mL) was added to the reaction mixture, followed by extraction with DCM (3×100 mL). The combined organic layer was washed with brine and dried over MgSO ₄ , filtered and the filtrate was concentrated in vacuo to generate a crude residue, which was directly used in the next step without further purification (9.2 g, crude material).

N ¹ -ethyl- N ¹ , N ² -dimethylethane-1,2-diamine. Was added LiAlH ₄ (in the (2- (methylamino) ethyl) acetyl amine (6.5g, 50mmol, 1eq) in THF (100mL) was carefully cooled - under nitrogen a solution of N - methyl - N 2.28 g, 60 mmol, 1.2 eq) and the mixture was stirred at 0°C for 30 minutes. Next, the mixture was stirred at room temperature until completion. The reaction mixture was quenched with water and extracted with EA (150 mL×3). The combined organic layer was washed with brine, dried over sodium sulfate, filtered and the filtrate was concentrated in vacuo to generate a residue, which was used directly in the subsequent reaction without further purification (3.8 g, crude material). ESI-MS (m/z): 117.2 (M+H) ⁺ .

5-(2-((4-fluoro-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)-1,3-dimethyl- 1H -indole-3- Nitrile. To the microwave reactor, add 2-chloro-4-(7-cyano-1,3-dimethyl- 1H -indol-5-yl)pyrimidine (1.3g, 4.6mmol, 1.0eq), 4- Fluoro-2-methoxy-5-nitroaniline (0.86 g, 4.6 mmol, 1.0 eq), 2-pentanol (26 mL) and p-toluenesulfonic acid monohydrate (0.96 g, 5.06 mmol, 1.1 eq). The mixture was heated to 140°C and stirring continued for 20 minutes. After cooling to RT, the reaction was filtered and the filtrate was washed with CH ₃ CN (10 mL). The residue was then dispersed in CH ₃ CN (25 mL, then filtered, washed with CH ₃ CN (10 mL) and dried to produce the desired product (1.6 g, 80%). ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 9.25 (d, J = 8.1 Hz, 1 H), 8.71 (s, 1 H), 8.59 (d, J = 5.4 Hz, 1 H), 8.54 (s, 1 H), 8.47 (s, 1 H), 7.72(d, J =5.7Hz,1 H),7.47(d, J =8.1Hz,1 H),7.11(d, J =8.4Hz,1 H),4.05(s,3 H),4.03(s , 3 H), 2.34 (s, 3 H). ESI-MS (m/z): 433.1 (M+H) ⁺ .

5-(2-((4-((2-(ethyl(methyl)amino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino) Pyrimidin-4-yl)-1,3-dimethyl- 1H -indole-7-carbonitrile. Add 5-(2-((4-fluoro-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)-1,3-dimethyl-1 H to a 50 mL sealed tube - indole-7-carbonitrile (0.5g, 1.16mmol, 1eq), DIPEA (0.45g, 3.47mmol, 1.0eq), DMAc (5mL) and N ¹ - ethyl - N ^1, N ² - dimethyl Ethane-1,2-diamine (202 mg, 1.74 mmol, 1.5 eq). The reaction was stirred at 120°C until completion. After cooling, the reaction was poured into water (20 mL) and extracted with EtOAc (20 mL×3). The combined organic layer was washed with water (20 mL×2) and brine (20 mL), dried, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to produce the desired product (320 mg, 52%). ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 8.81 (s, 1H), 8.65 (s, 1 H), 8.50 (d, J = 4.8 Hz, 1 H), 8.41 (s, 1 H), 8.23 (s,1 H),7.59(d, J =4.8Hz,1 H),7.31(s,1 H),6.82(s,1 H),4.03(s,3 H),3.98(s,3 H ), 3.26 (t, J = 6.0 Hz, 2 H), 2.95-2.85 (m, 2 H), 2.79 (s, 3 H), 2.38-2.36 (m, 5 H), 2.32 (s, 3 H) , 0.94 (t, J = 7.2 Hz, 3 H). ESI-MS (m/z): 529.2 (M+H) ⁺ .

5-(2-((5-amino-4-((2-(ethyl(methyl)amino)ethyl)(methyl)amino)-2-methoxyphenyl)amino) Pyrimidin-4-yl)-1,3-dimethyl- 1H -indole-7-carbonitrile. 5-(2-((4-((2-(ethyl(methyl)amino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino ) Pyrimidin-4-yl)-1,3-dimethyl-1 H -indole-7-carbonitrile (320 mg, crude material) in MeOH (5 mL) was added Pd/C (50 mg). The mixture was stirred under a hydrogen atmosphere of 1 atm for 1.5 hours. After completion, the reaction was filtered and washed with MeOH (5 mL×2). The filtrate was concentrated in vacuo to produce the desired product (240 mg, crude material), which was used in the next step without purification. ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 8.69 (s, 1 H), 8.46-8.43 (m, 2 H), 8.01 (s, 1 H), 7.55-8.53 (m, 2 H), 7.33 (s,1 H),6.75(s,1 H),4.05(s,3 H),3.76(s,3 H),2.95(s,3 H),2.89-2.85(m,2 H),2.79 (s, 3 H), 2.62-2.60 (m, 2 H), 2.48-2.45 (m, 2 H), 1.96 (s, 3 H), 1.00 (t, J = 6.8 Hz, 3 H). ESI-MS (m/z): 499.2 (M+H) ⁺ .

N -(5-((4-(7-cyano-1,3-dimethyl-1H-indol-5-yl)pyrimidin-2-yl)amino)-2-((2-(B (Methyl)amino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide. 5-(2-((5--amino-4-((2-(ethyl(methyl)amino)ethyl)(methyl)amino)-2- Methoxyphenyl)amino)pyrimidin-4-yl)-1,3-dimethyl- 1H -indole-7-carbonitrile (240 mg, crude material) in DCM (4 mL) Acryloyl chloride (102 g, 1.2 mmol, 1.5 eq) was added dropwise. After the addition, the reaction was warmed to RT and stirring continued for 1 hour. The reaction was diluted with DCM (10 mL) and washed with saturated NaHCO ₃ (5 mL), water (5 mL) and brine (5 mL). The combined organic layer was dried and concentrated to produce crude shipping, which was purified by preparative HPLC to produce N- (5-((4-(7-cyano-1,3-dimethyl-1H- Indol-5-yl)pyrimidin-2-yl)amino)-2-((2-(ethyl(methyl)amino)ethyl)(methyl)amino)-4-methoxybenzene Base) acrylamide (30mg, 11%). ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 9.91 (br, 1 H), 9.08 (s, 1 H), 8.71 (s, 1 H), 8.51-8.48 (m, 2 H), 8.15 (s ,1 H),7.57(d, J =5.2Hz,1 H),7.32(s,1 H),7.03(s,1 H),6.43-6.39(m,1 H),6.27-6.23(m, 1 H), 5.75-5.73 (m, 1 H), 4.05 (s, 3 H), 3.87 (s, 3 H), 2.88-2.87 (m, 2 H), 2.71 (s, 3 H), 2.48- 2.45 (m, 5 H), 2.34 (s, 3 H), 2.21-2.14 (m, 2 H), 1.01 (t, J = 7.2 Hz, 3 H). ESI-MS (m/z): 553.2 (M+H) ⁺ .

Example 27. N -(2-((2-(bis(methyl-d ₃ )Amino)ethyl)(methyl)amino)-5-((4-(7-cyano-1,3-dimethyl- 1H -indol-5-yl)pyrimidin-2-yl )Amino)-4-methoxyphenyl)acrylamide mesylate

(2-(bis(methyl-d3)amino)ethyl)(methyl)aminocarboxylic acid third butyl ester. Under a nitrogen atmosphere, deuterated dimethylamine hydrochloride (9.0 g, 102.7 mmol) was added to 200 mL of 1,2-dichloroethane in a 500 mL three-necked flask at room temperature, followed by the addition of N-methyl Tert-butyl N-(2-oxoethyl)carbamate (17.8 g, 102.9 mmol) was added to the reaction system. The reaction was stirred at room temperature for 2h. After the reaction system was cooled to 0°C, sodium triethoxyborohydride (32.6 g, 153.8 mmol) was added in portions and then the reaction was warmed to room temperature. The reaction mixture was stirred overnight. The reaction was quenched with 100 mL of saturated aqueous ammonium chloride solution, and the mixture was extracted twice with 200 mL of dichloromethane. The aqueous phase was collected, adjusted to pH 9 with saturated aqueous sodium carbonate, extracted twice with 150 mL of dichloromethane, and the organic phases were combined, washed twice with 100 mL of saturated brine, dried over anhydrous sodium sulfate and concentrated to dryness to produce 3.7 g (2-(bis(methyl-d ₃ )amino)ethyl)(methyl)aminocarboxylic acid third butyl ester (17.3%) as a yellow oil.

N ² -methyl-N ¹ ,N ¹ -bis(methyl-d ₃ )ethane-1,2-diamine trifluoroacetate. It will be used as raw material at room temperature (2-(bis(A -D ₃ )amino)ethyl)(methyl)carbamic acid tert-butyl ester (3.7g, 17.8mmol) was dissolved in 20mL anhydrous DCM in a 50mL single-necked flask, followed by the addition of 10mL TFA at room temperature Into the reaction system. The reaction mixture was stirred at room temperature for 4h. The reaction mixture was concentrated to produce an intermediate as a crude product, which was directly used in the next step without purification.

5-(2-((4-fluoro-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)-1,3-dimethyl-1H-indole-7-methyl Nitrile. In a 250mL single-necked flask, to 5-(2-chloropyrimidin-4-yl)-1,3-dimethyl-1H-indole-7-carbonitrile (5.0g, 17.7mmol, 1.0eq) To a solution of 4-fluoro-2-methoxy-5-nitroaniline (3.6g, 19.4mmol, 1.1eq) in 2-pentanol (100mL) was added p-toluenesulfonic acid monohydrate (3.3g, 19.2 mmol, 1.1 eq). The mixture was heated to 118°C for 8h, then cooled to 25°C, and filtered under reduced pressure. The filter cake was washed with ethyl acetate (200 mL×2). To the resulting filter cake was added sodium bicarbonate solution to adjust the pH to 8, and the precipitated solid was filtered under vacuum. The filter cake was dried to obtain the product (6.9 g, yield 90.2%).

5-(2-((4-((2-(bis(methyl-d3)amino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino )Pyrimidin-4-yl)-1,3-dimethyl-1H-indole-7-carbonitrile. In a 250 mL single-necked flask, the crude product N ² -methyl-N ¹ ,N ¹ -bis(methyl-d ₃ )ethane-1,2-diamine trifluoroacetate and potassium carbonate (8.8 g , 63.8mmol) added to 5-(2-((4-fluoro-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)-1,3-dimethyl- 1H -A solution of indole-7-carbonitrile (6.9 g, 16.0 mol) in 100 mL NMP. The resulting mixture was stirred at 85°C for 12 hours, then cooled to rt. Then water (100 mL) was added. The solid material was collected by filtration, washed with water (10 mL×2), and the filter cake was purified by silica gel column chromatography (DCM/MeOH/NH ₃ ‧H ₂ O=10/1/0.01) to produce the product (5.7 g, yield 68.4%).

5-(2-((5-amino-4-((2-(bis(methyl-d3)amino)ethyl)(methyl)amino)-2-methoxyphenyl)amino )Pyrimidin-4-yl)-1,3-dimethyl-1H-indole-7-carbonitrile. To 5-(2-((4-((2-(bis(methyl-d ₃ )amino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl) Amino)pyrimidin-4-yl)-1,3-dimethyl- 1H -indole-7-carbonitrile (5.6g, 10.8mmol) in THF (100mL) was added Pd/C (800mg ). The mixture was stirred in a 250 mL single-neck flask under a hydrogen atmosphere of 1 atm at 30° C. for 8 h. The reaction mixture was filtered through celite and the filter cake was washed with DCM (20 mL×2), and the filtrate was concentrated to dryness under reduced pressure to produce the product (4.5 g, 84.9% yield).

N-(2-((2-(bis(methyl-d3)amino)ethyl)(methyl)amino)-5-((4-(7-cyano-1,3-dimethyl -1H-indol-5-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide. In a 250 mL single-necked flask, triethylamine (1.23 g, 12.2 mmol) was added to 5-(2-((5-amino-4-((2-(bis(methyl-d3)amino)ethyl ) (Methyl)amino)-2-methoxyphenyl)amino)pyrimidin-4-yl)-1,3-dimethyl-1H-indole-7-carbonitrile (3.0g, 6.1mmol ) In a solution in 100 mL of THF. Acryloyl chloride (775 mg, 8.6 mmol) was then added dropwise at -5°C and stirring continued for 3 hours. The reaction was quenched with 5 mL of saturated sodium carbonate solution. Then water (100 mL) was added, and the mixture was extracted with dichloromethane (200 mL). The organic phase was concentrated and the residue was purified by medium pressure preparative chromatography (H ₂ O/CH ₃ CN=1/9) to produce the product (1.5 g, yield 45.1%).

N-(2-((2-(bis(methyl-d3)amino)ethyl)(methyl)amino)-5-((4-(7-cyano-1,3-dimethyl -1H-indol-5-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl) acrylamide mesylate. A solution of methanesulfonic acid (269 mg, 2.8 mmol) in purified water (2.7 mL) was added dropwise to N-(2-((2-(bis(methyl-d3)amino)ethyl )(Methyl)amino)-5-((4-(7-cyano-1,3-dimethyl- 1H -indol-5-yl)pyrimidin-2-yl)amino)-4 -A solution of methoxyphenyl) acrylamide (1.5 g, 2.8 mmol) in 15 mL of acetonitrile. The mixture was stirred for 1 hour, and then heated to 55°C with stirring for 2 hours. The solvent was removed and the residue was ground to obtain the product (1.73 g, yield 96.4%). ¹ H-NMR (400MHz, DMSO) δ : 9.53 (s, 1H), 9.16 (s, 1H), 8.77-8.68 (m, 2H), 8.53-8.48 (m, 2H), 8.30 (s, 1H), 7.61(d, J=5.2Hz, 1H), 7.34(s, 1H), 7.02(s, 1H), 6.72-6.60(m, 1H), 6.35-6.27(m, 1H), 5.81-5.76(m, 1H), 4.04(s, 3H), 3.90(s, 3H), 3.30-3.20(m, 4H), 2.61(s, 3H), 2.33-2.2(m, 6H). LC-MS (M/e): 545.4 (M-MSA+H ⁺ ).

Example 28. N- (5-((4-(7-cyano-1,3-dimethyl- 1H -indol-5-yl)pyrimidin-2-yl)amino)-2-(( 2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

5-(2-((4-((2-(dimethylamino)ethyl)amino)-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)- 1,3-dimethyl-1H-indole-7-carbonitrile. To a solution of N,N-dimethylethane-1,2-diamine (3.2 g, 36.0 mmol) in DMF (100 mL) was added 5-(2-((4-fluoro-2-methoxy -5-nitrophenyl)amino)pyrimidin-4-yl)-1,3-dimethyl-1H-indole-7-carbonitrile (10.0g, 24.0mmol) and potassium carbonate (6.6g, 48.0 mmol). The mixture was heated at 100° C. for 9 h, then poured into water (500 mL). After cooling, the solid product was collected by filtration and purified by column chromatography to produce the product (5.0 g, 43.2%). ESI-MS (m/z): 501.1 (M+H) ⁺ .

(4-((third butoxycarbonyl)(2-(dimethylamino)ethyl)amino)-2-methoxy-5-nitrophenyl)(4-(7-cyano -1,3-dimethyl-1H-indol-5-yl)pyrimidin-2-yl)aminocarboxylic acid third butyl ester. Add 5-(2-((4-((2-(dimethylamino)ethyl)amino)-2-methoxy-5-nitrophenyl)amino) to a 100-mL flask Pyrimidin-4-yl)-1,3-dimethyl-1H-indole-7-carbonitrile (5.0g, 0.01mol), Boc ₂ O (21.8g, 0.1mol), N,N-dimethyl Aminopyridine (12.2 g, 0.1 mol) and 1,4-dioxane (50 mL). The mixture was heated at reflux for 7h, then cooled to 25°C. After concentration, the residue was purified by column chromatography (dissolved with CH ₂ Cl ₂ /MeOH=25:1) to produce 2.7 g (38.6%) of the desired product. ESI-MS (m/z): 701.4 (M+H) ⁺ .

(5-amino-4-((third butoxycarbonyl)(2-(dimethylamino)ethyl)amino)-2-methoxyphenyl)(4-(7-cyano -1,3-dimethyl-1H-indol-5-yl)pyrimidin-2-yl)aminocarboxylic acid third butyl ester. To (4-((third butoxycarbonyl)(2-(dimethylamino)ethyl)amino)-2-methoxy-5-nitrophenyl)(4-(7-cyano -1,3-dimethyl-1H-indol-5-yl)pyrimidin-2-yl)aminocarboxylic acid tert-butyl ester (2.0g, 2.85mmol) in 20mL tetrahydrofuran was added 10% Pd /C (0.2g, 50% wet). The mixture was hydrogenated at 30°C and atmospheric pressure for 7 hours. After filtration and concentration, the desired product (1.7 g, 87.7%) was obtained. ESI-MS (m/z): 671.4 (M+H) ⁺ .

(5-propenylamino-4-((third butoxycarbonyl)(2-(dimethylamino)ethyl)amino)-2-methoxyphenyl)(4-(7- Cyanyl-1,3-dimethyl-1H-indol-5-yl)pyrimidin-2-yl)carbamic acid third butyl ester. At 0°C, (5-amino-4-((third butoxycarbonyl)(2-(dimethylamino)ethyl)amino)-2-methoxyphenyl)(4- (7-cyano-1,3-dimethyl-1H-indol-5-yl)pyrimidin-2-yl)aminocarboxylic acid tert-butyl ester (1.7 g, 2.5 mmol) in CH ₂ Cl ₂ (17 mL ) And tetrahydrofuran (17 mL) were added triethylamine (0.51 g, 5.0 mmol) and acryloyl chloride (0.34 g, 3.75 mmol). The mixture was stirred for 2 h, then poured into 100 mL of saturated NaHCO ₃ solution. The organic phase was separated and the aqueous phase was extracted with CH ₂ Cl ₂ (100 mL). The combined organic phase is concentrated. The residue was purified by chromatography to produce the desired product (1.01 g, 55%). ESI-MS (m/z): 725.5 (M+H) ⁺ .

N-(5-((4-(7-cyano-1,3-dimethyl-1H-indol-5-yl)pyrimidin-2-yl)amino)-2-((2-(di Methylamino)ethyl)amino)-4-methoxyphenyl)acrylamide. Trifluoroacetic acid (10mL) was added to (5-propenylamino-4-((third butoxycarbonyl)(2-(dimethylamino)ethyl)amino)) in a 25-mL flask 2-Methoxyphenyl)(4-(7-cyano-1,3-dimethyl-1H-indol-5-yl)pyrimidin-2-yl)aminocarboxylic acid third butyl ester (1.01g , 1.39mmol). After stirring for 1 h, the mixture was concentrated and dissolved in CH ₂ Cl ₂ (50 mL). The solution was washed with saturated sodium bicarbonate solution and dried over Na ₂ SO ₄ . Concentration provided the product (400 mg, 54.7%). ¹ HNMR (400 MHz, DMSO- d ₆ ): δ 9.42 (s, 1H), 8.62 (s, 1H), 8.38 (s, 1H), 8.37 (d, J = 5.2 Hz, 1H), 8.04 (s, 1H ), 7.75(s,1H),7.44(d, J =5.2Hz,1H),7.30(s,1H),6.48(m,1H),6.41(s,1H),6.19(dd, J ₁ =16.8 Hz, J ₂ =2.0Hz, 1H), 5.69 (dd, J ₁ = 10Hz, J ₂ = 2.0Hz, 1H), 4.75(m, 1H), 4.02(s, 3H), 3.82(s, 3H), 3.18 (m, 2H), 2.48 (bt, 2H), 2.28 (s, 3H), 2.17 (s, 3H). ESI-MS (m/z): 525.3 (M+H) ⁺ .

Example 29. N-(5-((4-(7-cyano-1,3-dimethyl-1H-indol-5-yl)pyrimidin-2-yl)amino)-4-methoxy -2-(methyl(2-(methylamino)ethyl)amino)phenyl)acrylamide

(2-((4-((4-(7-cyano-1,3-dimethyl-1H-indol-5-yl)pyrimidin-2-yl)amino)-5-methoxy- 2-Nitrophenyl)(methyl)amino)ethyl)(methyl)carbamic acid tert-butyl ester. To a solution of N-third butoxycarbonyl-N,N'-dimethylethane-1,2-diamine (6.5 g, 34.7 mmol) in DME (90 mL) was added 5-(2-( (4-fluoro-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)-1,3-dimethyl-1H-indole-7-carbonitrile (10.0g, 24.0 mmol) and potassium carbonate (9.6 g, 69.3 mmol). The mixture was heated at 80° C. for 6 h, then poured into water (600 mL). The solid product was collected by filtration and washed with water. After drying overnight at 40°C, the product (8.6 g, 61.9%) was obtained. ESI-MS (m/z): 601.4 (M+H) ⁺ .

(2-((2-amino-4-((4-(7-cyano-1,3-dimethyl-1H-indol-5-yl)pyrimidin-2-yl)amino)-5 -Methoxyphenyl)(methyl)amino)ethyl)(methyl)aminocarboxylic acid third butyl ester. To (2-((4-((4-(7-cyano-1,3-dimethyl-1H-indol-5-yl)pyrimidin-2-yl)amino)-5-methoxy (2-nitrophenyl) (methyl) amino) ethyl) (methyl) carbamic acid tert-butyl ester (8.6g, 14.3mmol) in 170mL tetrahydrofuran was added 10% Pd/C ( 1.72g, 50% wet). The mixture was hydrogenated at 30°C and atmospheric pressure for 15h. After filtration and concentration, the desired product (8.2 g, 100%) was obtained. ESI-MS (m/z): 571.4 (M+H) ⁺ .

(2-((2-propenylamino-4-((4-(7-cyano-1,3-dimethyl-1H-indol-5-yl)pyrimidin-2-yl)amino) -5-Methoxyphenyl)(methyl)amino)ethyl)(methyl)aminocarboxylic acid third butyl ester. At 0°C, (2-((2-amino-4-((4-(7-cyano-1,3-dimethyl-1H-indol-5-yl)pyrimidin-2-yl) Amino)-5-methoxyphenyl)(methyl)amino)ethyl)(methyl)aminocarboxylic acid tert-butyl ester (7.7g, 13.5mmol) and triethylamine (2.7g, 27.0mmol) ) To a solution of CH ₂ Cl ₂ (60 mL) and tetrahydrofuran (20 mL) was added 40 mL of tetrahydrofuran containing propylene acetyl chloride (1.7 g, 18.9 mmol). The mixture was stirred for 4 h, then poured into saturated NaHCO ₃ solution. The organic phase was separated and the aqueous phase was extracted with ethyl acetate. The combined organic phase is concentrated. The residue was purified by chromatography to produce the desired product (4.8 g, 56.9%). ESI-MS (m/z): 625.4 (M+H) ⁺ .

N-(5-((4-(7-cyano-1,3-dimethyl-1H-indol-5-yl)pyrimidin-2-yl)amino)-4-methoxy-2- (Methyl(2-(methylamino)ethyl)amino)phenyl)acrylamide. Trifluoroacetic acid (40mL) was added to (2-((2-propenylamino-4-((4-(7-cyano-1,3-dimethyl-1H-indol-5-yl)pyrimidine -2-yl)amino)-5-methoxyphenyl)(methyl)amino)ethyl)(methyl)aminocarboxylic acid tert-butyl ester (4.6g, 7.4mmol) in 80mL CH ₂ Cl ₂ in the solution. After stirring at 30 °C for 2 h, the mixture was concentrated and dissolved in CH ₂ Cl ₂ (200 mL). The solution was washed with saturated sodium bicarbonate solution until pH=9 and dried over Na ₂ SO ₄ . Concentrate and slurry with ethyl acetate to provide product (1.6 g, 41.5%). ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 9.36 (s, 1H), 8.84 (s, 1H), 8.66 (s, 1H), 8.48 (d, J = 5.2 Hz, 1H), 8.46 (s, 1H), 8.17(s, 1H), 7.57(d, J = 5.2Hz, 1H), 7.29(s, 1H), 6.97(s, 1H), 6.72(m, 1H), 6.29(dd, J ₁ = 16.8Hz, J ₂ =1.6Hz,1H),5.76(dd, J ₁ =6.0Hz, J ₂ =2.0Hz,1H),4.02(s,1H),3.84(s,1H),3.20(m,2H ), 3.11 (m, 2H), 2.67 (s, 3H), 2.60 (s, 3H), 2.28 (s, 1H). ESI-MS (m/z): 525.3 (M+H) ⁺ .

Example 30. N -(5-(4-(7-cyano-3-methyl-1H-indol-5-yl)pyrimidin-2-ylamino)-2-((2-(dimethyl (Amino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide.

To compounds 7-cyano-5-(2-chloropyrimidin-4-yl)-3-methyl-1H-indole (130mg, 0.48mmol, 1.0eq) and 5-( N -propenylamino)- 4-( N ,1-(2-( N,N -dimethylamino)ethyl)- N ,1-methyl)amino)-2-methoxyaniline (141 mg, 0.48 mmol, 1.0 eq ) To a solution in 2-pentanol (6.6 mL) was added p-toluenesulfonic acid monohydrate (101.6 mg, 0.528 mmol, 1.1 eq). The mixture was heated to 80°C for 5h. After cooling to rt, the mixture was poured into water (50 mL), extracted with DCM (50 mL×3), the combined organic layer was washed with brine (50 mL), dried over sodium sulfate, concentrated and passed through a silica column Purification to provide the desired product N- (5-(4-(7-cyano-3-methyl-1H-indol-5-yl)pyrimidin-2-ylamino)-2-((2-( Dimethylamino)ethyl) (methyl)amino)-4-methoxyphenyl)acrylamide (148 mg, 58%). ¹ HNMR (300 MHz, DMSO- d ₆ ): δ 11.90 (br, 1 H), 10.19 (br, 1 H), 9.14 (s, 1 H), 8.73 (s, 1 H), 8.52-8.49 (m, 2 H), 8.15(s,1 H),7.67(s,1 H),7.33(s,1 H),7.04(s,1 H),6.36-6.29(m,2 H),5.75-5.72( m, 1 H), 3.86 (s, 3 H), 2.86-2.84 (m, 2 H), 2.71 (s, 3 H), 2.31-2.29 (m, 5 H), 2.21 (s, 6 H). LCMS (M+H) ⁺ : 524.8. HPLC: 95.1%.

biology abbreviation

DMSO: dimethyl sulfoxide

DTT: dithiothreitol

ATP: adenosine triphosphate 34

EDTA: ethylenediaminetetraacetic acid

Ki: enzyme inhibition constant

DMEM: Du's modified Eagle's medium

NCS: newborn calf serum

PBS: phosphate buffered saline

PMSF; phenylmethanesulfonyl fluoride

ELISA: enzyme-linked immunosorbent analysis

IgG; immunoglobulin G

FBS: fetal bovine serum

BDNF; brain-derived neurotrophic factor

Kinase inhibition analysis

The inhibitory effect of the compounds of the present invention on kinases is measured using commercially available analytical kits and services well known to those of ordinary skill. These kits and services are used for measurement including but not limited to ALK, ABL, AXL, Aur B and C, BLK, erbB-2, erbB-4, EGFR, mutant EGFR, HPK, IRAK1, RON, ROS1, SLK , STK10, TIE2, TRK, c-Met, Lck, Lyn, Src, Fyn, Syk, Zap-70, Itk, Tec, Btk, EGFR, ErbB2, Kdr, Flt-1, Flt-3, Tek, c-Met , InsR and Atk inhibition of multiple kinases. Commercial suppliers of these analysis kits and services include Promega Corporation and Reaction Biology Corporation, EMD Millipore and CEREP. In addition to these commercially available analytical kits and services, the kinase inhibitory activity of compounds of formula (I-VIII) is also measured by the analysis described below.

Purification of epidermal growth factor receptor tyrosine kinase Human EGF receptor tyrosine kinase was isolated from A431 human epidermal carcinoma cells expressing EGF receptor by the following method. Cells were grown in 50% Dulbecco's modified Eagle in a roller bottle and 50% HAM F-12 nutrient medium (Gibco) containing 10% fetal bovine serum. Approximately ¹⁰⁹ cells were dissolved in two volumes of buffer containing 20 mM 2-(4N-[2-hydroxyethyl]hexahydropyrazin-1-yl)ethanesulfonic acid (hepes) (pH 7.4 ), 5mM ethylene glycol bis(2-aminoethyl ether) N,N,N',N'-tetraacetic acid, 1% Triton X-100, 10% glycerin, 0.1mM sodium orthovanadate, 5mM fluorinated Sodium, 4mM pyrophosphate, 4mM benzamide, 1mM dithiothreitol, 80μg/mL aprotinin, 40μg/mL leupeptin and 1mM phenylmethylsulfonyl fluoride. After centrifugation at 25,000xg for 10 minutes, the supernatant was equilibrated with 10 mL of wheat germ agglutinin agarose at 40° C. for 2 h. The wheat germ agglutinin agarose was previously mixed with 50 mM Hepes, 10% glycerol, 0.1% Triton X- 100 and 150 mM NaCI (pH 7.5) (equilibration buffer) were equilibrated. The contaminated protein was washed from the resin with 1M NaCl in equilibration buffer, and the enzyme was successively dissolved with 0.5M N-acetyl-1-D-glucosamine, 1 mM urea in equilibration buffer. The enzyme was dissolved with 0.1 mg/ml EGF. The receptor appears to be homogeneous, as analyzed by Coomassie blue stained polyacrylamide electrophoresis gel.

Using the same technique as described in the previous paragraph, multiple mutant forms of the epidermal growth factor receptor can be isolated from the appropriate cell line containing it. For example, the EGFR del746-750 mutant protein can be extracted from PC-9 cells, and the L858R/T790M double mutant EGFR protein can be isolated from H1975 cells.

Determination of IC50 value for single mutant EGFR_d746-750

Enzyme analysis for IC50 determination was performed in a total volume of 25 μL. All compounds were diluted to 500 μM stock solution in 100% DMSO and a series of 4-fold dilutions were prepared for 10 doses. The "Max" and "Min" control groups contain 100% DMSO. "Max" represents the DMSO control group without enzymes, and "Min" represents the low control group without compounds. Transfer 10 μl of compound to 90 μl 1x kinase base buffer to prepare an intermediate dilution. Transfer 5 μl of the intermediate dilution compound to a 384-well analysis plate, and then add 10 μl of 2.5x enzyme buffer containing (12.5 nM EGFR_d746-750, 5 mM DTT, 1 x kinase base buffer) to the analysis plate. Incubate at RT for 10 minutes and add 10 μl of 2.5 x substrate buffer containing (7.5 μM peptide, 35 μM ATP, 25 mM MgCl2, 1 x kinase base buffer) to start the reaction. Incubate for 1 h at RT and add 25 μl stop buffer to stop the reaction. Collect the conversion data from Caliper and the conversion data from the Caliper program. Fit the data in XLfit to obtain IC50 values.

Determination of IC50 value of double mutant EGFR (EGFR_T790M/L858R)

Enzyme analysis for IC50 determination was performed in a total volume of 25 μL. All compounds were diluted to 500 μM stock solution in 100% DMSO and a series of 4-fold dilutions were prepared for 10 doses. The "Max" and "Min" control groups contain 100% DMSO. "Max" represents the DMSO control group without enzymes, and "Min" represents the low control group without compounds. Transfer 10 μl of compound to 90 μl 1x kinase base buffer to prepare an intermediate dilution. Transfer 5 μl of the intermediate dilution compound to a 384-well analysis plate, and then add 10 μl of 2.5x enzyme buffer containing (25 nM EGFR_T790M/L858R, 5 mM DTT, 1 x kinase base buffer) to the analysis plate. Incubate for 10 minutes at RT and add 10 μl of 2.5 x substrate buffer containing (7.5 μM peptide, 47.5 μM ATP, 25 mM MgCl2, 1 x kinase base buffer) to start the reaction. Incubate for 1 h at RT and add 25 μl stop buffer to stop the reaction. Collect the conversion data from Caliper and the conversion data from the Caliper program. Data fitting to obtain _IC50 values XLfit IC.

Determination of IC50 value of wt EGFR

Enzyme analysis for IC50 determination was performed in a total volume of 25 μL. All compounds were diluted to 500 μM stock solution in 100% DMSO and a series of 4-fold dilutions were prepared for 10 doses. The "Max" and "Min" control groups contain 100% DMSO. "Max" represents the DMSO control group without enzymes, and "Min" represents the low control group without compounds. Transfer 10 μl of compound to 90 μl 1x kinase base buffer to prepare an intermediate dilution. Transfer 5 μl of the intermediate dilution compound to a 384-well assay plate, and then add 10 μl of 2.5x enzyme buffer containing (20 nM EGFR, 5 mM DTT, 1 x kinase base buffer) to the assay plate. Incubate at RT for 10 minutes and add 10 μl of 2.5x substrate buffer containing (7.5 μM peptide, 5.75 μM ATP, 25 mM MgCl2, 25 mM MnCl2, 1 x kinase base buffer) to start the reaction. Incubate for 1 h at RT and add 25 μl stop buffer to stop the reaction. Collect the conversion data from Caliper and the conversion data from the Caliper program. Fit the data in XLfit to obtain IC50 values.

Other kinase inhibition analysis

The analysis to determine the inhibitory effect of compounds of formula (I-VIII) on other kinases is performed according to procedures known to those of ordinary skill. These analyses include, but are not limited to, the inhibition of the following kinases:

Wild-type c-Met kinase. The inhibitory effect of wild-type c-Met kinase was determined as described in International Publication No. WO 2011/069761, the entire contents of which were incorporated by reference.

LCK and BLK kinases. The inhibitory effects of LCK and BLK kinases were determined as described in US Patent No. 7,125,875, the entire contents of the case are incorporated by reference.

The compounds described herein were screened in the following manner. Kinases suitable for the following assays to determine the kinase activity of the compounds described herein include, but are not limited to: Lck, Lyn, Src, Fyn, Syk, Zap-70, Itk, Tec, Btk, ErbB2, ErbB-4, Kdr, Flt -1, Flt-3, Tek, c-Met and Atk. Kinases are expressed in E. coli or baculovirus-High Five expression systems as fusion proteins fused to the kinase domain of glutathione S-transferase (GST) or full-length constructs or polyhistidine-tagged proteins. It is purified to near homogeneity by affinity chromatography as essentially previously described (Lehr et al., 1996; Gish et al., 1995). In some cases, the kinase is co-expressed or mixed with the purified or partially purified regulatory polypeptide before activity measurement. Kinase activity and inhibition are basically measured by established protocols (Braunwalder et al., 1996). Briefly, the transfer of ³² P0 ₄ from ATP to the bioactive surface attached to the microtiter plate is synthesized by poly (Glu-Tyr) 4:1 or poly (Arg-Ser) 3:1 as an evaluation enzyme activity basis. After the incubation period, the amount of phosphate ester transferred was measured by first washing the plate with 0.5% phosphoric acid, adding liquid scintillator, and then counting in a liquid scintillation detector. The IC _{50 was} determined by the concentration of the compound that caused a 50% reduction in the amount of ³² P incorporated into the substrate bound to the substrate. Phosphate alone, in combination or in combination with other amino acids, in a dissolved or fixed (i.e., solid phase) state is transferred to a peptide or polypeptide substrate containing tyrosine, serine, threonine or histidine Other similar methods are also applicable. For example, the transfer of phosphates to peptides or polypeptides can also use scintillation proximity (Wu et al., 2000), ELISA (Cleaveland et al., 1990), fluorescence polarization (Seethala and Menzel, 1998), and homogeneous time resolution fluorescence (HTRF, Kolb et al., 1998). Alternatively, kinase activity can be measured using an antibody-based method, whereby the antibody or polypeptide is used as a reagent to detect the phosphorylated target polypeptide.

references

Braunwalder et al. (1996). Anal. Biochem. 234(1):23-26.

Cleaveland et al. (1990). Anal Biochem. 190(2):249-53.

Gish et al. (1995). Protein Eng. 8(6):609-614.

Kolb et al. (1998). Drug Discov. Today. 3:333-342.

Lehr et al. (1996). Gene 169(2): 27527-9.

Seethala et al. (1998). Anal Biochem. 255(2):257-62.

Wu et al. (2000). Comb Chem High Throughput Screen. 3(1):27-36.

EGFR Cell Analysis Overview Protocol Cell proliferation analysis H1975 inhibition analysis (cell proliferation).

H1975 cells are cryopreserved in liquid nitrogen. Before thawing the cells, 15 mL of cell culture medium (RPMI 1640 medium supplemented with 10% fetal bovine serum and 1% penicillin/streptomycin) was placed in a T75 flask and kept in a humid 37°C/5% CO2 incubator The flask was pre-incubated for 15 minutes to allow the medium to equilibrate to the proper pH and temperature. Remove the vial from liquid nitrogen and quickly defrost by placing in a water bath at 37°C and gently stirring for 1-2 minutes, and then remove the contamination by wiping with 70% ethanol, then open to Class II organisms In a safety cabinet. Transfer the contents of the vial dropwise to 10 mL of cell culture medium in a sterile 15 mL conical tube. The tube was then centrifuged at 200 x g for 5 minutes and the supernatant was aspirated. The cell pellet was resuspended with 1 mL of fresh cell culture medium and transferred to a T75 flask containing cell culture medium.

In order to subculture H1975 cells, the adherent cells were first washed with trypsin/EDTA. Then trypsin/EDTA (3 mL, for T75 flask) was added to the flask and vortexed to ensure that the cells were completely trypsin coated. The flask was then incubated at 37°C until the cells detached. Add an equal volume of cell culture medium to stop the reaction. The detached cells were collected and centrifuged at 200 x g for 5 minutes, and then resuspended in fresh medium. Next, transfer the cells to a new T75 flask containing cell culture medium. The cells were subcultured in the medium at a ratio of 1:2 or 1:4 three times a week.

The test compound was dissolved in DMSO at 30 mM. 45 μL of compound was transferred to a 384-well compound source plate (LABCYTE catalog #P-05525) and serially diluted at a ratio of 1:3 to produce a 13-point dilution. The same volume of DMSO was used as the high control group. 20 nL of these compound DMSO dilutions (10 points, from 1.11 mM to 0.056 μM) were dispensed into new 384-well analysis plates by Echo 550.

The cells from the flask were collected into the cell culture medium as described above and the number of cells was counted using Automated Cell Counter (Thermo Fisher Scientific, Countess ^™ ). The cells were diluted to 25,000 cells/mL with culture medium and 40 μL of cell suspension was added to each well of the designated 384-well cell culture plate. The final concentration is 1,000 cells/well. Only medium was added as a low control group. The plates were covered with a lid and placed in a 37°C 5% CO2 incubator for 72 hours.

After 72 hours of incubation, the plates were removed from the incubator and equilibrated at room temperature for 15 minutes. Prior to the experiment, CellTiter Glo reagent (Promega, G9243) was incubated at 37°C. The buffer is equilibrated to room temperature and used to dissolve the substrate. To determine cell viability, add 40 μL of CellTiter-Glo reagent to each well to be detected (add 1:1 to the culture medium). Next, the plates were placed at room temperature for 30 min, and then read on EnSpire (PerkinElmer).

。接著藉由在XLFit中擬合為四參數邏輯曲線來計算IC₅₀。 Regarding the IC ₅₀ estimate, the luminescence readout is converted to% suppression by applying the following equation:

. Followed by fitting XLFit as the four parameter logistic curve to calculate the IC _50.

PC-9 growth inhibition analysis (cell proliferation).

The inhibition analysis of PC-9 cells was performed in the same manner as described above for H1975 cells.

A431 inhibition analysis (cell proliferation).

The medium for A431 cells is Du's modified Eagle's medium supplemented with 10% fetal bovine serum and 1% penicillin/streptomycin. The DMSO dilution used in the A431 analysis is 10 points from 30nM to 1.52uM. The remaining procedures were performed in the same manner as described above for H1975 cells.

Cellular EGFR autophosphorylation analysis. L858R/T790M double mutant H1975 autophosphorylation inhibition analysis (ELISA)

H1975 cells are cryopreserved in liquid nitrogen. Before thawing the cells, 15 mL of cell culture medium (RPMI 1640 medium supplemented with 10% fetal bovine serum and 1% penicillin/streptomycin) was placed in a T75 flask and incubated at a humid 37°C/5% CO ₂ The flask was pre-incubated in the vessel for 15 minutes to equilibrate the medium to the proper pH and temperature. Remove the vial from liquid nitrogen and quickly defrost by placing in a water bath at 37°C and gently stirring for 1-2 minutes, and then remove the contamination by wiping with 70% ethanol, then open to Class II organisms In a safety cabinet. Transfer the contents of the vial dropwise to 10 mL of cell culture medium in a sterile 15 mL conical tube. The tube was then centrifuged at 200 xg for 5 minutes and the supernatant was aspirated. The cell pellet was resuspended with 1 mL of fresh cell culture medium and transferred to a T75 flask containing cell culture medium.

In order to subculture H1975 cells, the adherent cells were first washed with trypsin/EDTA. Then trypsin/EDTA (3 mL, for T75 flask) was added to the flask and vortexed to ensure that the cells were completely trypsin coated. The flask was then incubated at 37°C until the cells detached. Add an equal volume of cell culture medium to stop the reaction. The detached cells were collected and centrifuged at 200 x g for 5 minutes, and then resuspended in fresh medium. Next, transfer the cells to a new T75 flask containing cell culture medium. The cells were subcultured in the medium at a ratio of 1:4 three times a week.

The cells from the flask were collected into cell culture medium and the number of cells was counted using an Automated Cell Counter (Thermo Fisher Scientific, Countess ^™ ). The cells were diluted to 250,000 cells/mL with medium and 40 μL of cell suspension was added to each well of the designated 384-well cell culture plate. The final concentration is 10,000 cells/well. The plates were covered with a lid and placed in a 37°C 5% CO ₂ incubator overnight for cell attachment.

The next day, the test compound was dissolved in DMSO at 10 mM. 45 uL of compound was transferred to a 384-well compound source plate (LABCYTE catalog #P-05525) and serially diluted at a ratio of 1:3 to produce a 13-point dilution. The same volume of DMSO was used as the high control group. 40 nL of these compound DMSO dilutions (11 points from 1.11 mM to 0.019 uM) were dispensed into H1975 cell plates by Echo 550.

The plate was placed back in a 37°C 5% CO ₂ incubator for 2 hours. The medium in each well was replaced with ice cold HBSS. The HBSS was then removed, 30 μL of cell lysis buffer was added to each well and the plates were shaken on a plate shaker for 30 min. Centrifuge at 1,000 rpm for 5 min to remove air bubbles and transfer 25 uL of lysate supernatant for p-EGFR analysis by using a commercial ELISA kit (R&D, DYC1095B-5).

。接著藉由在XLFit(IDBS,Guildford,Surrey)中擬合為四參 數邏輯曲線來計算IC₅₀。 Regarding the IC ₅₀ estimate, the absorption readout is converted to% relative activity by applying the following equation:

. Followed by fitting as XLFit (IDBS, Guildford, Surrey) in the four-parameter logistic curve to calculate the IC _50.

Wild type EGFR A431 autophosphorylation inhibition analysis (ELISA).

The medium for A431 cells is Du's modified Eagle's medium supplemented with 10% fetal bovine serum and 1% penicillin/streptomycin. The DMSO dilution used in the A431 analysis is 11 points from 10 mM to 0.17 uM. After 2 hours of treatment with the test compound, 4.5 μL of EGF (1 μg/mL) was added to each well and stimulation continued for 10 min. The rest of the procedure was performed in the same manner as described above for H1975 cells.

Exon 19 deletion EGFR (activated single mutant) PC-9 cell font phosphorylation analysis.

Human lung cell line PC9 (exon 19 deleted EGFR) was obtained from American type Culture Collection. PC9 cells were maintained in RPMI 1640 containing 10% fetal bovine serum and 2 mM glutamine. Cells were grown in a humidified incubator at 37°C and 5% CO ₂ . The analysis for measuring cell phosphorylation of endogenous p-EGFR in cell lysates was performed according to the protocol described in the R&D Systems DuoSet IC Human Phospho-EGF R ELISA (R&D Systems catalog number #DYCI095). 40 μL of cells were seeded (10,000 cells/well) in growth medium in a Coming black, clear bottom 384-well plate and incubated at 37° C. and 5% CO ₂ overnight. The cells were administered acoustically using Echo 555, where the compound was serially diluted in 100% DMSO. The plate was incubated for another 2h, then after aspirating the medium, 40 μL x lysis buffer was added to each well. Greiner black high-binding 384-well plates were coated with capture antibody and then blocked with 3% BSA. After removing the block, 15 μL of lysate was transferred to the Greiner black high-binding 384-well plates and incubated for 2 hours. After aspirating and washing the plates with PBS, 20 μL of detection antibody was added and incubated for 2 hours. After aspirating and washing the plates with PBS, 20 μL of QuantaBlu fluorescent generating peroxidase substrate (Thermo Fisher Scientific catalog number 15169) was added and incubated for 1 hour. 20 μL of QuantaBlu stop solution was added to the plate and fluorescence reading was performed on the Envision plate reader using excitation 352 nm wavelength and emission 460 nm wavelength. The data obtained with each compound is exported to a suitable software package (such as Origin) to perform curve fitting analysis. From this data, the IC ₅₀ value is determined by calculating the compound concentration required to produce a 50% effect.

IGF-1R inhibition analysis

The test compound was dissolved in DMSO at 30 mM. 45 μL of compound was transferred to a 384-well compound source plate (LABCYTE catalog #P-05525) and serially diluted at a ratio of 1:3 to produce a 12-point dilution. The same volume of DMSO was used as the high control group. Dispense 20 nL of these compound DMSO dilutions into a new 384-well analysis plate by Echo 550. Prepare IGF-1R protein (0.87nM, CARNA BIOSCIENCE, catalog # 08-141), fluorescent labeled substrate FLPeptide13 (2μM, PerkinElmer, catalog #760357) for kinase assay buffer (100mM HEPES (pH 7.5), 10mM MgCl _2. 0.05% Brij-35, 0.5mM DTT and 0.1mg/ml BSA). 15 μL of kinase assay buffer containing IGF-1R protein and substrate was transferred to the assay plate and incubated at RT for 30 minutes. Kinase analysis buffer supplemented with substrate peptides was used as a low control group to monitor background. 40 μM ATP was prepared for kinase analysis buffer and 5 μL ATP solution was added to each well to start the reaction. The assay plate was incubated at 25°C for 180 minutes and the reaction was stopped by adding 40 μL of 0.5M EDTA.

The separation was performed by using Caliper EZ Reader II to distinguish phosphorylated fluorescently labeled peptides from non-phosphorylated peptides and the detection was directly converted to conversion rate.

。接著藉由在XLFit(IDBS,Guildford,Surrey)中擬 合為四參數邏輯曲線來計算IC₅₀。 Regarding the IC ₅₀ estimate, the% mass conversion value is converted to% relative activity by applying the following equation:

. Followed by fitting as XLFit (IDBS, Guildford, Surrey) in the four-parameter logistic curve to calculate the IC _50.

INSR suppression analysis

The test compound was dissolved in DMSO at 30 mM. 45 uL of compound was transferred to a 384-well compound source plate (LABCYTE catalog #P-05525) and serially diluted at a 1:3 ratio to produce a 12-point dilution. The same volume of DMSO was used as the high control group. Dispense 20 nL of these compound DMSO dilutions into a new 384-well analysis plate by Echo 550. INSR protein preparation (0.73nM, CARNA BIOSCIENCE, catalog # 08-142), fluorescent marker by mass FLPeptide13 (2μM, PerkinElmer, catalog # 760357) for the kinase assay buffer (100mM HEPES (pH 7.5), 10mM MgCl 2, 0.05% Brij-35, 0.5mM DTT and 0.1mg/ml BSA). 15 μL of kinase analysis buffer containing INSR protein and substrate was transferred to the analysis plate and incubated at RT for 30 minutes. Kinase analysis buffer supplemented with substrate peptides was used as a low control group to monitor background. 40 μM ATP was prepared for kinase analysis buffer and 5 μL ATP solution was added to each well to start the reaction. The assay plate was incubated at 25°C for 180 minutes and the reaction was stopped by adding 40 μL of 0.5M EDTA.

The results were analyzed in the same way as IGF-IR. For the results of IGF-IR and INSR enzyme analysis, see Table 5.

Various other kinases. Including but not limited to Lck, Lyn, Src, Fyn, Syk, Zap-70, Itk, Tec, Btk, EGFR, ErbB2, Kdr, Flt-1, Flt-3, Tek, c-Met, InsR and Atk The inhibitory effect of kinases was determined as described in US Patent No. 6,881,737, the entire contents of which were incorporated by reference.

PK study in mice

In order to determine the drug concentration of the compound of the present invention in plasma, pharmacokinetic patterns and PK parameters were obtained after intravenous and oral administration in male CD1 mice.

Research plan:

Test animal: Healthy male CD1 mice (weight 20-30g, 18 mice, free access to food and water), provided by Sibeifu laboratory.

Dose level and route of administration: Respectively, Group IV is administered to animals via intravenous injection from the tail vein (1 mg/kg, 5 mL/kg, 10% DMSO/40% PEG400/50% water), and Group PO The animals were administered via oral tube (10 mg/kg, 10 mL/kg, (10% DMSO/40% PEG400/50% water).

Sample collection: Using healthy animals, weigh and mark the tail and cage card, and then administer the drug. Blood samples were collected from the dorsal metatarsal vein for the IV group at 0.083, 0.25, 0.5, 1, 2, 4, 8, 24h after dosing and for the PO group at 0.25, 0.5, 1, 2, 4, 8, 24h after dosing (0.03 mL per time point), collected from the heart at the end time point (approximately 0.3 mL). Five minutes after all samples were collected at each time point to obtain plasma, the blood samples were placed in a tube coated with heparin-Na and then placed on a cold box and centrifuged at 4000 g at 4°C. These plasma samples were stored in a freezer at -75±15°C before analysis.

The drug concentration was determined by the LC/MS/MS method, and the PK parameters were observed as follows.

給藥1mg/kg IV；10mg/kg PO；*關於實例2，給藥2mg/kg IV；10mg/kg PO

1 mg/kg IV administration; 10 mg/kg PO; *For Example 2, 2 mg/kg IV administration; 10 mg/kg PO

給藥1mg/kg IV，10mg/kg PO

Administration of 1mg/kg IV, 10mg/kg PO

Animal xenograft tumor model

General plan. From ATCC cell lines known to carry the oncogene of interest or from intentionally transfected appropriately transformed cells suspended in the appropriate medium, and 5×10 ⁶ or 1×10 ⁷ cells are injected into the side of nu/nu mice Belly. Alternatively, trocar placement of fragments (usually about 1 mm ³ ) of tumors passaged in vivo can be used to initiate such tumors. When the tumor has reached the appropriate size for the experiment (usually in the range of 100-300 mg), the animals are randomly divided into matching groups of 6-10 mice and the size of the tumor, and once a day or Give the vehicle or test object twice. A caliper gauge was used to determine tumor volume. The percentage increase in xenograft tumor volume on day n to day 0 (the day when the test compound is administered) is calculated as (tumor volume on day n-tumor volume on day 0/tumor volume on day 0) )×100. The average percentage of tumor growth inhibition in each drug-treated group relative to the vehicle-treated group was calculated as (1-the average percentage increase in tumor volume in the drug-treated group/the average percentage increase in tumor volume in the vehicle-treated group) ×100. One-sided t test was used to assess statistical significance.

Analysis of wild-type EGFR xenotransporters . For the measurement of the efficacy against tumors overexpressing wt EGFR, xenografts grown from A431 epidermal or LoVo colon cancer cells can be used.

EGFR del746-750 xenograft model . For the measurement of the efficacy against tumors overexpressing EGFR-del746-750, xenografts grown from PC9 NSCLC cells can be used.

EGFR L858R xenograft model . For the measurement of the efficacy against tumors overexpressing EGFR-L858R, xenografts grown from H3255 NSCLC cells can be used.

EGFR L858R/T790M double mutant xenograft model . For the measurement of the efficacy against tumors overexpressing the EGFR-L858R/T790M double mutant, a xenograft grown from H1975 NSCLC cells was used. The tumor size was measured on the 10th day after administration. Regarding the H1975 xenograft model, the effect of the compounds of the present invention on tumor size is shown in Table 8.

Pharmacodynamic analysis . Mice with any of the aforementioned tumors (preferably 200-300 mg in size) can be euthanized at appropriate intervals after oral administration of the drug. The tumor was excised, frozen quickly, and dispersed in a non-denaturing lysis buffer containing protease and phosphatase inhibitor using Qiagen Tissue-Lyser. The homogeneous solution was dissolved at 4°C for 1 h, clarified by centrifugation, and then analyzed for phosphor EGFR/erbB-2/3/4 and total receptor by quantitative immunoblotting. The phosphorus-RTK signal of each RTK band is standardized with its total RTK signal. Alternatively, the ratio of total ERK to phosphorus-ERK can be measured in tumors by similar techniques using appropriate eERK and phosphorus-ERK antibodies.

a. Mean, ±SEM, n=9.

b. Relative tumor volume T _RTV /C _RTV %=T _RTV /C _RTV ×100%, RTV=V _D10 /V _D0

c. Tumor growth inhibition: TGI%=[1-(T _D10 -T _D0 )/(V _D10 -V _D0 )]×100%

Patch clamp analysis on hERG inhibition

1. Cells. The HEK 293 cell line stably expressing the hERG channel (catalog # K1236) was purchased from Invitrogen. These cells were cultured in 85% DMEM, 10% dialyzed FBS, 0.1 mM NEAA, 25 mM HEPES, 100 U/mL penicillin-streptomycin, 5 μg/mL blasticidin and 400 μg/mL geneticin. The cells were split about three times a week using TrypLE ^™ Express and maintained between about 40% to about 80% confluent. Prior to this analysis, the cells were placed on a coverslip at 5×105 cells per 6 cm cell culture dish and induced with 1 μg/mL doxycycline for 48 hours.

2. Solution. Extracellular solution (mM): 132NaCl, 4KCl, 3CaCl2, 0.5MgCl2, 11.1 glucose and 10HEPES (pH adjusted to 7.35 with NaOH). Intracellular solution (mM): 140KCl, 2MgCl ₂ , 10EGTA, 5MgATP, 10HEPES (pH adjusted to 7.35 with KOH)

3. Test the compound. The test compound was initially prepared in DMSO as a stock solution with a final concentration of 30 mM. This stock solution was further diluted with DMSO to prepare intermediate solutions having concentrations of 10.0, 3.0, 1.0, and 0.3 mM, respectively. Before the experiment, the working solution was finally prepared by diluting the above-mentioned continuous solution 1000 times with extracellular solution to reach a final concentration of 30, 10, 3, 1, and 0.3 μM, and the final concentration of DMSO in the working solution was 0.1 %.

4. Ion channel current measurement. Place the cell culture dish in the infusion chamber on the microscope stage, and use the ×10 objective lens to locate the desired cells. The tip of the electrode is guided to the cell surface, and gentle suction through the side port of the electrode holder is used to establish a tight seal. Use the C _rapid elimination control to remove the capacitive current that cooperates with the voltage step, and obtain a whole cell configuration by applying repetitive, brief, intense suction until the diaphragm has ruptured. The membrane potential was set to -60mV at this point to ensure that the hERG channel was closed, and then the C _slow elimination control on the amplifier was used to eliminate the capacitive current spike. The holding potential was set to -90mV for 1 second, the recording current was set to 50kHz and the filter was set to 10kHz. The leakage current was tested for 500ms at -80mV. The hERG current was induced by depolarizing at +30mV for 4.8 seconds and then the voltage was returned to 50mV for 5.2 seconds to remove the inactivation and observe the deactivation tail current. The maximum amount of tail current is used to determine the hERG current amplitude. The current was recorded for 120 seconds to analyze the current stability. Only stable cells with recording parameters above the threshold should be used for drug administration. The vehicle control group was then applied to these cells to establish a baseline. Once the hERG current stabilization continued for 3 minutes, the test compound was applied. The hERG current in the presence of the test compound was recorded for approximately 5 minutes to reach steady state and then 5 scans were captured. Regarding the dose response test, five doses of compound from low concentration to high concentration were applied to cells. In order to ensure good performance of the cultured cells and operation, a positive control group with five dose concentrations of dofetilide was also used to test the same batch of cells.

5. Use a five-point dose curve for the hERG current IC ₅₀ determination. Use Patchmaster or Clampfit software to analyze the data, using the following expression: (peak tail current _compound ) peak current suppression = (1-peak tail current _agent ) × 100 Use Graphpad Prism 6.0 to fit the data to an S-shaped dose curve.

Enzyme assays for IC ₅₀ determination of the various enzymes under the procedures of the herein disclosed. In Tables 1-10, the example numbers correspond to the compounds prepared in the mentioned example numbers.

The patents and publications listed herein describe general techniques in this technology and are therefore incorporated by reference in their entirety for all purposes and to the extent they are incorporated as if they were individually and individually instructed to cite Merged into general. In the event of any conflict between the cited reference and this specification, this specification shall prevail. In describing embodiments of the present application, specific terminology is used for the sake of clarity. However, the invention is not intended to be limited to the specific terms so selected. This description should in no way be considered as limiting the scope of the invention. All examples provided are representative and not limiting. The above embodiments can be modified or changed without departing from the invention, as those skilled in the art will understand according to the above teachings. Therefore, it should be understood that within the scope of the patent application and its equivalents, the present invention may be implemented in ways different from the specific description.

Claims (65)

A compound of formula (A) or (B):

Or its stereoisomer or pharmaceutically acceptable salt, solvate, ester or prodrug; where Z is CH or N; Y is

In Y ¹ and Y ² , R ^5a is H, F, Cl, CF ₃ , CHF ₂ , CF ₂ C _1-6 alkyl, CF ₂ CH ₂ NR ⁸ R ⁹ , CH ₂ NR ⁸ R ⁹ , CN or C _1-6 alkyl; in Y ¹ and Y ² , R ^6e is R ¹⁰ , H, F, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, (CH ₂ ) _m CHR ¹⁰ R ⁷ , CF ₂ (CH ₂ ) _m CHR ¹⁰ R ⁷ or C(R ¹⁰ ) ₂ R ⁷ ; in Y ⁴ and Y ⁵ , R ^6t is C _1-6 alkyl, C _3-6 cycloalkyl, aryl , Heteroaryl, heterocycloalkyl, (CH ₂ ) _m CHR ¹⁰ R ⁷ , C(R ¹⁰ ) ₂ R ⁷ ; in Y ¹ and Y ² , R ^6z is H, F, Cl, CF ₃ , CHF ₂ , CF ₂ C _1-6 alkyl or C _1-6 alkyl; or alternatively in Y ¹ and Y ² , R ^6e and R ^{6z are} combined to form =CR ^6e' R ^6z' (propadiene), where R ^6e' is R ¹⁰ , H, F, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, (CH ₂ ) _m CHR ¹⁰ R ⁷ , CF ₂ (CH ₂ ) _m CHR ¹⁰ R ⁷ or C (R ¹⁰ ) ₂ R ⁷ and wherein R ^6z′ is H, F, Cl, CF ₃ , CHF ₂ , CF ₂ C _1-6 alkyl or C _1-6 alkyl; or alternatively in Y ¹ and Y ² , R ^6e and R ^6z together with the sp ² carbon atoms to which they are attached together form an alicyclic ring of 4 to 7 members, where one of these ring atoms is optionally composed of NR ⁸ , O, S(O ) _x , S(=O)(=NR ⁸ ), P=O, P(=O)(OR ⁸ ), OP(=O)(OR ⁸ )O, and the alicyclic ring is selected from One or more substituents of the group consisting of halogen, pendant oxygen, OH, OR ⁸ and NR ⁸ R ⁹ ; R ^{1 is} independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, hydroxyl, methyl Oxygen, ethoxy, isopropoxy, cyclopropoxy, -OCF ₃ , -OCH ₂ CF ₃ , -OCH ₂ CHF ₂ , vinyl, ethynyl, -CF ₃ , -CHF ₂ , -CHO, -CH ₂ OH, -CONH ₂ , -CO ₂ Me, -CONHMe, -CONMe ₂ and cyano group; R ² is -OCF ₃ , -OCHF ₂ , -OCF ₂ CF ₃ , -OCH ₂ CHF ₂ , -OCH ₂ CF ₃ , cyclopropyl, cyclopropoxy, methoxy, -OCD ₃ , ethoxy or isopropoxy; R ³ is -N(R ¹⁰ )C _2-6 alkyl-NR ¹⁰ R ¹⁰ , -N(R ¹⁰ )C _2-6 alkyl-R ⁷ , -O(CH ₂ ) _p R ⁷ , -N(R ¹⁰ )C(=O)(CH ₂ ) _p R ⁷ or R ⁷ ; each of R ^4a , R ^4b and R ^4c Independently H, cyano, nitro, halo, -C _1-6 alkyl, -C _1-6 haloalkyl, -carboxy-C _1-6 alkyl, -C _1-6 hydroxyalkyl, R ⁸ R ⁹ NC _1-6 alkyl-, -C _2-6 alkenyl, -C _2-6 alkynyl, C _1-6 acetyl-, R ⁷ -(CH ₂ ) _p C(=O)- , C _1-6 hydroxyalkyl-C(=O)-, carboxyl, -C _1-6 alkoxycarbonyl, -C(=O)NR ⁸ R ⁹ , hydroxyl, -C _1-6 alkoxy, -C _1-6 acetyloxy, -NR ⁸ R ⁹ , C _1-6 acetyl-N(R ¹⁰ )-, pyrazole, 1,2,3-triazole, tetrazole, (C _1-6 alkyl Radical) SO ₂ -or R ⁷ SO ₂ -; R ⁷ is -OH, -NR ⁸ R ⁹ , -O(CH ₂ ) _q NR ⁸ R ⁹ , C _1-6 alkoxy, C _1-6 alkoxy -C _1-6 alkoxy, C _2-6 hydroxyalkoxy, oxetanyl, oxetanyloxy, oxetanylamino, oxetanyl , Oxetanyloxy, oxetanylamino, oxetanyl, oxetanyloxy, oxetanylamino, oxepanyl , Oxetanyloxy, oxetanylamino, azetyl, azetyloxy, azetylamino, pyrrolidinyl, pyrrolidine Yloxy, pyrrolidinylamino, hexahydropyridinyl, hexahydropyridinyloxy, hexahydropyridinylamino, azepanyl, azepanyloxy, azepanyl Amino, dioxolyl, dioxan, morpholinyl, thiomorpholinyl, thiomorpholinyl-S,S-dioxide, hexahydropyrazinyl, dioxa Cycloheptanyl, dioxepaneoxy, dioxepanealkylamino, oxazacycloheptyl, oxazacycloheptyloxy, oxazacycloheptyloxy group, diazepino alkyl, alkyloxy diazepino, diazepino alkylamino, (3R) - 3 - (dimethylamino) pyrrolidin-l-yl, (3S )-3-(dimethylamino)pyrrolidin-1-yl, 3-(dimethylamino)azetidin-1-yl, [2-(dimethylamino)ethyl] (Methyl)amino, [2-(methylamino)ethyl](methyl)amino, 5-methyl-2,5diazaspiro[3.4]oct-2-yl, (3aR, 6aR)-5-methylhexa-hydro-pyrrolo[3,4-b]pyrrole-1(2H)-yl, 1-methyl-1,2,3,6-tetrahydropyridin-4-yl, 4-methylhexahydropyrazin-1-yl, 4-[2(dimethylamino)-2-oxoethyl]hexahydropyrazin-1-yl, methyl[2-(4- Methylhexahydropyrazine-1-yl)ethyl]amine, methyl[ 2-(morpholin-4-yl)ethyl]amino, 1-amino-1,2,3,6 tetrahydropyridin-4-yl, 4-[(2S)-2-aminopropionyl ] Hexahydropyrazin-1-yl, which may be optionally substituted with OH, OR ¹⁰ , pendant, halogen, R ¹⁰ , CH ₂ OR ¹⁰ or CH ₂ NR ⁸ R ⁹ ; R ⁸ and R ⁹ are each independently It is H, -CD ₃ , C _1-6 alkyl, C _3-6 alkenyl, C _3-6 alkynyl, C _3-8 cycloalkyl, -(C _1-3 alkyl)-(C _{3- 8} cycloalkyl), C _3-8 cycloalkenyl, C ₁ -C ₆ acetyl, 4-12 membered monocyclic or bicyclic heterocyclyl, 4-12 membered monocyclic or bicyclic heterocyclyl-C ₁ -C ₆ alkyl-, C _6- C ₁₂ aryl, 5-12 membered heteroaryl; wherein R ⁸ and R ⁹ can be further independently selected by up to three from hydroxyl, C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _1-6 alkoxy-C _1-6 alkyl, C _1-6 alkoxy-C _1-6 alkoxy, C _2-6 hydroxyalkoxy, pendant , Thiocarbonyl, cyano or halo substituents; or alternatively, R ⁸ and R ⁹ together with the N atom to which they are attached at the same time form a heterocyclic ring of 4-7 members, the heterocyclic ring containing up to one selected from O, S or NR ¹¹ other hetero atoms, or form a heterobicyclic ring of 7-12 members, the heterobicyclic ring may be fused, bridged or spiro ring, and contains up to two selected from O, S (O) _x Or other heteroatoms of NR ¹¹ , and these heterocycles may optionally be selected from up to three hydroxy, C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _1-6 alkoxy-C _1-6 Substitution of alkyl, C _1-6 alkoxy-C _1-6 alkoxy, C _2-6 hydroxyalkoxy, pendant oxy, thiocarbonyl, cyano or halo; R ^{10 is} each independently Is H, -CD ₃ , C _1-6 alkyl, C _3-6 cycloalkyl, C _2-6 hydroxyalkyl, C _1-6 alkoxy-C _1-6 alkyl, or C _2-6 alkyl Radical -NR ⁸ R ⁹ ; alternatively, two R ¹⁰ on the same N atom attached at the same time form a heterocyclic ring of 5-6 members, the heterocyclic ring contains up to one other hetero group selected from O, S or NR ¹¹ Atom; R ^{11 is} each independently hydrogen or C ₁ -C ₆ alkyl, which is optionally substituted with up to three substituents selected from hydroxyl, pendant, thiocarbonyl, cyano or halo; m is 0, 1, 2 or 3; n is 1, 2 or 3; q is 2, 3 or 4; p is 0, 1, 2, 3 or 4; and x is 0, 1 or 2. For example, the compound of patent application item 1, wherein the compound has the structure of formula (A):

Or its stereoisomer or pharmaceutically acceptable salt, solvate, ester or prodrug; wherein Z is CH or N; R ¹ is selected from hydrogen, fluorine, chlorine, bromine, methyl, CF ₃ , CHF ₂ and cyano; R ² is -OCF ₃ , -OCHF ₂ , -OCF ₂ CF ₃ , -OCH ₂ CHF ₂ , -OCH ₂ CF ₃ , cyclopropyl, cyclopropoxy, methoxy,- OCD ₃ , ethoxy or isopropoxy; R ³ is N(R ¹⁰ )C _2-6 alkyl-NR ¹⁰ R ¹⁰ ; R ^4a , R ^4b and R ^4c are each independently H, cyano, halogen Group, -C _1-6 alkyl, -C _1-6 haloalkyl, carboxy -C _1-6 alkyl, -C _1-6 hydroxyalkyl, R ⁸ R ⁹ NC _1-6 alkyl-,- C _2-6 alkenyl, -C _2-6 alkynyl, C _1-6 acetyl-, R ⁷ -(CH ₂ ) _p C(=O)-, C _1-6 hydroxyalkyl-C(=O )-, carboxyl, -C _1-6 alkoxycarbonyl, -C(=O)NR ⁸ R ⁹ , hydroxy, alkoxy, C _1-6 acetyl, -NR ⁸ R ⁹ , C _1-6 Acyl-N(R ¹⁰ )-, R ⁷ SO ₂ -, R ⁷ is OH, NR ⁸ R ⁹ , O(CH ₂ ) _q NR ⁸ R ⁹ , C _1-6 alkoxy or C _2-6 hydroxy Alkoxy; R ⁸ and R ^{9 are} independently H, -CD ₃ , C _1-6 alkyl, C _3-6 alkenyl, C _3-6 alkynyl, C _3-8 cycloalkyl, C _{3- 8} cycloalkenyl, C ₁ -C ₆ acetyl, 4-12 membered monocyclic or bicyclic heterocyclyl, 4-12 membered monocyclic or bicyclic heterocyclyl-C ₁ -C ₆ alkyl-, C _{6 -} C ₁₂ aryl, 5-12 membered heteroaryl; and R ⁸ and R ⁹ may be further independently substituted with up to three substituents selected from hydroxy, C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _{2 -6} hydroxyalkoxy, pendant, thiocarbonyl, cyano or halo substituents; or alternatively, R ⁸ and R ⁹ together with the N atom to which they are attached together form a 4-7 member heterocycle , The heterocyclic ring contains up to one other heteroatom selected from O, S or NR ¹¹ , or forms a heterobicyclic ring of 7-12 members, the heterobicyclic ring may be fused, bridged or spirocyclic, and contains up to two Other heteroatoms selected from O, S(O) _x or NR ¹¹ , and these heterocycles may optionally be selected from up to three hydroxy groups, C _1-6 alkoxy groups, C _1-6 hydroxyalkyl groups, C _{1 -6} alkoxy-C _1-6 alkyl, C _1-6 alkoxy-C _1-6 alkoxy, C _2-6 hydroxyalkoxy, pendant, thiocarbonyl, cyano or halo Substituted by substituents; R ^{10 is} independently H, -CD ₃ , C _1-6 alkyl, C _3-6 cycloalkyl, C _2-6 hydroxyalkyl, C _1-6 alkoxy-C _{1 -6} alkyl or C _2-6 alkyl-N R ⁸ R ⁹ ; or p is 0, 1, 2, 3, or 4; q is 2, 3, or 4; and x is 0, 1, or 2. For example, the compound of claim 1 or item 2, wherein R ³ is -N(CH ₃ )CH ₂ CH ₂ NR ¹⁰ R ¹⁰ . A compound as in any one of claims 1 to 3, wherein R ^{10 is} each independently H, -CD ₃ , C _1-6 alkyl, C _3-6 cycloalkyl, or C _2-6 Hydroxyalkyl. The compound according to any one of claims 1 to 3, wherein R ^{10 is} each independently H, -CD ₃ , methyl, ethyl or isopropyl. If the compound of any one of items 1 to 5 of the patent application scope, where Y is

For example, the compound of claim 6, wherein R ^5a , R ^6e and R ^6z are each H. A compound according to any one of claims 1 to 7, wherein R ^4a is H, -C _1-6 alkyl or -NR ⁸ R ⁹ . For example, the compound of claim 8, wherein R ⁸ and R ^{9 are} independently H, -CD ₃ or C _1-6 alkyl. For example, the compound of any one of items 1 to 9 of the patent application scope, wherein R ^4b and R ^4c are each independently H, cyano, F, Cl, Br, -C _1-6 alkyl, CF ₃ , CHF ₂ , CONH ₂ or C(=O)NR ⁸ R ⁹ . Compounds as in any one of the first to tenth patent applications, where R ^4b and R ^4c are each independently H, cyano, F, Cl, Br, CH ₃ , CF ₃ , CHF ₂ , CONH ₂ Or C(=O)NR ⁸ R ⁹ . For example, the compound of claim 1, wherein the compound has the structure of formula (C):

Or its stereoisomer or pharmaceutically acceptable salt, solvate, ester or prodrug; wherein R ¹ is hydrogen, fluorine, chlorine or methyl; R ² is -OCF ₃ , -OCHF ₂ ,- OCF ₂ CF ₃ , -OCH ₂ CHF ₂ , -OCH ₂ CF ₃ , cyclopropyl, cyclopropoxy, methoxy, -OCD ₃ , ethoxy, or isopropoxy; R ^4a is H or -NR ⁸ R ⁹ ; R ^4b and R ^4c are each independently H, cyano, F, Cl, Br, CH ₃ , CF ₃ , CHF ₂ , CONH ₂ or C(=O)NR ⁸ R ⁹ ; R ⁸ and R ⁹ are each independently H, -CD ₃ or C _1-6 alkyl; and R ¹⁰ are each independently H, -CD ₃ , C _1-6 alkyl, C _3-6 cycloalkyl or C _2-6 Hydroxyalkyl. For example, the compound of claim 12 of the patent scope, wherein: R ¹ is hydrogen; R ² is methoxy, -OCD ₃ , ethoxy or isopropoxy; R ^4a is NR ⁸ R ⁹ ; R ^4b is H or CH ₃ ; R ^4c is H, F, Cl, Br or CH ₃ ; R ⁸ and R ⁹ are each independently H, -CD ₃ , -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ ; And R ^{10 is} each independently H, -CD ₃ , -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ . For example, the compound of patent application item 1, wherein the compound has the structure of formula (CI):

Or its stereoisomer or pharmaceutically acceptable salt, solvate, ester or prodrug; where R ¹ is hydrogen, fluorine, chlorine or methyl; R ² is -OCF ₃ , -OCHF ₂ ,- OCF ₂ CF ₃ , -OCH ₂ CHF ₂ , -OCH ₂ CF ₃ , cyclopropyl, cyclopropoxy, methoxy, -OCD ₃ , ethoxy, or isopropoxy; R ^4a is H or -NR ⁸ R ⁹ ; R ^4b and R ^4c are each independently H, cyano, F, Cl, Br, -C _1-6 alkyl, -CF ₃ , -CHF ₂ , -CONH ₂ or -C (=O) NR ⁸ R ⁹ ; R ⁸ and R ⁹ are each independently H, -CD ₃ or -C _1-6 alkyl; and R ¹⁰ are each independently H, -CD ₃ , -C _1-6 alkyl,- C _3-6 cycloalkyl or -C _2-6 hydroxyalkyl. For example, the compound of claim 14 of the patent scope, wherein: R ¹ is hydrogen; R ² is methoxy, -OCD ₃ , ethoxy or isopropoxy; R ^4a is NR ⁸ R ⁹ ; R ^4b is H or CH ₃ ; R ^4c is H, F, Cl, Br, -CF ₃ , -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ ; R ⁸ and R ⁹ are each independently H, -CD ₃ , -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ ; and R ¹⁰ are each independently H, -CD ₃ , -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ . For example, the compound of any one of items 1 to 15 of the patent application scope, wherein the compound is:

Or its stereoisomers or pharmaceutically acceptable salts, solvates, esters or prodrugs. For example, the compound of any one of items 1 to 15 of the patent application scope, wherein the compound is:

; Or its stereoisomers or pharmaceutically acceptable salts, solvates, esters or prodrugs. A compound of formula (D):

Or its stereoisomer or pharmaceutically acceptable salt, solvate, ester or prodrug; where Z is CH or N; X ² and X ⁷ are each CH, CR ⁴ or N; R ¹ is hydrogen , Fluorine, chlorine, bromine, methyl, ethyl, hydroxyl, methoxy, ethoxy, isopropoxy, cyclopropoxy, -OCF ₃ , -OCH ₂ CF ₃ , -OCH ₂ CHF ₂ , ethylene Group, ethynyl, CF ₃ , CHF ₂ , CHO, CH ₂ OH, CONH ₂ , CO ₂ Me, CONHMe, CONMe ₂ or cyano group; R ² is -OCF ₃ , -OCHF ₂ , -OCF ₂ CF ₃ ,- OCH ₂ CHF ₂ , -OCH ₂ CF ₃ , cyclopropyl, cyclopropoxy, methoxy, -OCD ₃ , ethoxy, or isopropoxy; R ³ is N(R ¹⁰ )C _2-6 alkane Radical -NR ¹⁰ R ¹⁰ ; R ^{4 is} each independently H, cyano, halo, -C _1-6 alkyl, -C _1-6 haloalkyl, carboxy -C _1-6 alkyl, -C _{1 -6} hydroxyalkyl, R ⁸ R ⁹ NC _1-6 alkyl-, -C _2-6 alkenyl, -C _2-6 alkynyl, C _1-6 acetyl-, R ⁷ -(CH ₂ ) _p C(=O)-, C _1-6 hydroxyalkyl-C(=O)-, carboxyl, -C _1-6 alkoxycarbonyl, -C(=O)NR ⁸ R ⁹ , hydroxyl, alkoxy , C _1-6 acyloxy, -NR ⁸ R ⁹ , C _1-6 acyl-N(R ¹⁰ )- or R ⁷ SO ₂ -; and R ⁸ and R ^{9 are} independently H, -CD ₃ , C _1-6 alkyl, C _3-6 alkenyl, C _3-6 alkynyl, C _3-8 cycloalkyl, C _3-8 cycloalkenyl, C _1- C ₆ acetyl, 4-12 member single Ring or bicyclic heterocyclyl, 4-12 membered monocyclic or bicyclic heterocyclyl-C ₁ -C ₆ alkyl-, C _6- C ₁₂ aryl, 5-12 membered heteroaryl; and R ⁸ and R ⁹ can further independently be selected from up to three groups selected from hydroxyl, C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _2-6 hydroxyalkoxy, pendant, thiocarbonyl, cyano or halo Substituted by a substituent of the group; or alternatively, R ⁸ and R ⁹ together with the N atom to which they are simultaneously attached form a heterocyclic ring of 4-7 members, the heterocyclic ring containing up to one other selected from O, S or NR ¹¹ A heteroatom, or a heterobicyclic ring of 7-12 members, which may be fused, bridged or spirocyclic, and contain up to two other heteroatoms selected from O, S(O) _x or NR ¹¹ , And these heterocycles may be selected from up to three hydroxy, C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _1-6 alkoxy-C _1-6 alkyl, C _1-6 alkyl Oxygen-C _1-6 alkoxy, C _2-6 hydroxyalkoxy, pendant, thiocarbonyl, cyano or halo substituent substitution; R ^4b is H, halo, -C _1-6 alkyl or -C _1-6 haloalkyl; R ^4c is cyano, C _1-6 acetyl-, -C(=O)NR ⁸ R ⁹ , hydroxy, alkoxy or F; R ^4N Is H, -CD ₃ or -C _1-6 alkyl; R ⁷ is OH, NR ⁸ R ⁹ , -O(CH ₂ ) _q NR ⁸ R ⁹ , C _1-6 alkoxy or C _2-6 hydroxy Alkoxy; R ^{10 is} each independently H, -CD ₃ , C _1-6 alkyl, C _3-6 cycloalkyl, C _2-6 hydroxyalkyl, C _1-6 alkoxy-C _{1- 6} alkyl or C _2-6 alkyl-NR ⁸ R ⁹ ; p=0, 1, 2, 3 or 4; q=2, 3 or 4; and x=0, 1 or 2. A compound of formula (DI):

Or its stereoisomers or pharmaceutically acceptable salts, solvates, N-oxides, esters or prodrugs; where Z is CH or N; X ² and X ⁷ are each CH, CR ⁴ or N ; R ¹ is hydrogen, fluorine, chlorine, bromine, methyl, ethyl, hydroxyl, methoxy, ethoxy, isopropoxy, cyclopropoxy, -OCF ₃ , -OCH ₂ CF ₃ , -OCH ₂ CHF ₂ , vinyl, ethynyl, CF ₃ , CHF ₂ , CHO, CH ₂ OH, CONH ₂ , CO ₂ Me, CONHMe, CONMe ₂ or cyano; R ² is -OCF ₃ , -OCHF ₂ , -OCF ₂ CF ₃ , -OCH ₂ CHF ₂ , -OCH ₂ CF ₃ , cyclopropyl, cyclopropoxy, methoxy, -OCD ₃ , ethoxy, or isopropoxy; R ³ is -N(R ¹⁰ )(C _2-6 alkyl)-NR ¹⁰ R ¹⁰ or -N(R ¹⁰ )(C _3-10 cycloalkylalkyl)-NR ¹⁰ R ¹⁰ ; R ^{4 is} independently H, cyano, halogen Group, -C _1-6 alkyl, -C _1-6 haloalkyl, carboxy -C _1-6 alkyl, -C _1-6 hydroxyalkyl, R ⁸ R ⁹ NC _1-6 alkyl-,- C _2-6 alkenyl, -C _2-6 alkynyl, C _1-6 acetyl-, R ⁷ -(CH ₂ ) _p C(=O)-, C _1-6 hydroxyalkyl-C(=O )-, carboxyl, -C _1-6 alkoxycarbonyl, -C(=O)NR ⁸ R ⁹ , hydroxy, alkoxy, C _1-6 acetyl, -NR ⁸ R ⁹ , C _1-6 Acyl-N(R ¹⁰ )- or R ⁷ SO ₂ -; and R ⁸ and R ^{9 are} independently H, -CD ₃ , C _1-6 alkyl, C _3-6 alkenyl, C _3-6 alkyne Group, C _3-8 cycloalkyl group, C _3-8 cycloalkenyl group, C ₁ -C ₆ acetyl group, 4-12 membered monocyclic or bicyclic heterocyclic group, 4-12 membered monocyclic or bicyclic heterocyclic group -C ₁ -C ₆ alkyl-, C _6- C ₁₂ aryl, 5-12 membered heteroaryl; and R ⁸ and R ⁹ can be further independently selected from up to three hydroxy, C _1-6 alkyl Oxygen, C _1-6 hydroxyalkyl, C _2-6 hydroxyalkoxy, pendant, thiocarbonyl, cyano or halo substituents; or alternatively, R ⁸ and R ⁹ are simultaneously attached to N atoms combine to form a 4-7 member heterocycle, the heterocycle contains up to one other heteroatom selected from O, S, or NR ¹¹ , or forms a 7-12 member heterobicycle, which may be Condensed, bridged or spiro ring, and containing up to two other heteroatoms selected from O, S(O) _x or NR ¹¹ , and these heterocycles are optionally selected from up to three hydroxyl groups, C _1-6 alkanes Oxy, C _1-6 hydroxyalkyl, C _1-6 alkoxy-C _1-6 alkyl, C _1-6 alkoxy-C _1-6 alkoxy, C _2-6 hydroxyalkoxy, pendant, thiocarbonyl, cyano or halo substituent substitution; R ^4b is H, halo, -C _1-6 alkyl or -C _1-6 haloalkyl ; R ^4c is H, cyano, hydroxy, alkoxy, -C _1-6 alkyl or -C _1-6 haloalkyl, Cl or F, the restriction is that when R ^4c is H, R ^4b is Halo, -C _1-6 alkyl or -C _1-6 haloalkyl; R ^4N is H, -CD ₃ or -C _1-6 alkyl; R ⁷ is OH, NR ⁸ R ⁹ , -O( CH ₂ ) _q NR ⁸ R ⁹ , C _1-6 alkoxy or C _2-6 hydroxyalkoxy; R ^{10 is} each independently H, -CD ₃ , C _1-6 alkyl, C _3-6 ring Alkyl, C _2-6 hydroxyalkyl, C _1-6 alkoxy-C _1-6 alkyl or C _2-6 alkyl-NR ⁸ R ⁹ ; or alternatively, two R ¹⁰ on the same N atom Taken together to form a heterocycle of 3-7 members, the heterocycle may optionally be up to three selected from hydroxyl, C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _1-6 alkoxy-C _{1 -6} alkyl, C _1-6 alkoxy-C _1-6 alkoxy, C _2-6 hydroxyalkoxy, pendant, thiocarbonyl, cyano or halo substituent substitution; p=0 , 1, 2, 3 or 4; q=2, 3 or 4; and x=0, 1 or 2. A compound of formula (E):

Or its stereoisomers or pharmaceutically acceptable salts, solvates, esters or prodrugs; where Z is CH or N; X ² , X ³ , X ⁶ and X ⁷ are each CH, CR ⁴ or N; R ¹ is hydrogen, fluorine, chlorine, bromine, methyl, ethyl, hydroxyl, methoxy, ethoxy, isopropoxy, cyclopropoxy, -OCF ₃ , -OCH ₂ CF ₃ ,- OCH ₂ CHF ₂ , vinyl, ethynyl, CF ₃ , CHF ₂ , CHO, CH ₂ OH, CONH ₂ , CO ₂ Me, CONHMe, CONMe ₂ or cyano; R ² is -OCF ₃ , -OCHF ₂ ,- OCF ₂ CF ₃ , -OCH ₂ CHF ₂ , -OCH ₂ CF ₃ , cyclopropyl, cyclopropoxy, methoxy, -OCD ₃ , ethoxy, or isopropoxy; R ³ is N(R ¹⁰ ) C _2-6 alkyl-NR ¹⁰ R ¹⁰ ; R ^{4 is} independently H, cyano, halo, -C _1-6 alkyl, -C _1-6 haloalkyl, carboxy-C _1-6 Alkyl, -C _1-6 hydroxyalkyl, R ⁸ R ⁹ NC _1-6 alkyl-, -C _2-6 alkenyl, -C _2-6 alkynyl, C _1-6 acetyl-, R ⁷ -(CH ₂ ) _p C(=O)-, C _1-6 hydroxyalkyl-C(=O)-, carboxyl, -C _1-6 alkoxycarbonyl, -C(=O)NR ⁸ R ⁹ , Hydroxy, alkoxy, C _1-6 acetyl, -NR ⁸ R ⁹ , C _1-6 acetyl-N(R ¹⁰ )- or R ⁷ SO ₂ -; and R ⁸ and R ^{9 are} independently H, -CD ₃ , C _1-6 alkyl, C _3-6 alkenyl, C _3-6 alkynyl, C _3-8 cycloalkyl, C _3-8 cycloalkenyl, C _1- C ₆ acetyl , 4-12 membered monocyclic or bicyclic heterocyclyl, 4-12 membered monocyclic or bicyclic heterocyclyl-C ₁ -C ₆ alkyl-, C _6- C ₁₂ aryl, 5-12 membered heteroaryl Radicals; and R ⁸ and R ⁹ can be further independently selected by up to three hydroxy, C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _2-6 hydroxyalkoxy, pendant, sulfur Carbonyl, cyano or halo substituent substitution; or alternatively, R ⁸ and R ⁹ together with the N atom to which they are simultaneously attached form a heterocyclic ring of 4-7 members, the heterocyclic ring containing up to one selected from O, S or NR ¹¹ other heteroatom, or form a heterobicyclic ring of 7-12 members, the heterobicyclic ring may be fused, bridged or spiro ring, and contains up to two selected from O, S (O) _x or NR ¹¹ other heteroatoms, and these heterocycles are optionally selected from up to three hydroxy, C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _1-6 alkoxy-C _1-6 alkyl , C _1-6 alkoxy-C _1-6 alkoxy, C _2-6 hydroxyalkoxy, pendant, thiocarbonyl, cyano or halo substituent substitution; R ^4N is H, -CD ₃ or -C _1-6 alkyl; R ⁷ is OH, NR ⁸ R ⁹ , -O(CH ₂ ) _q NR ⁸ R ⁹ , C _1-6 alkoxy or C _2-6 Hydroxyalkoxy; R ^{10 is} each independently H, -CD ₃ , C _1-6 alkyl, C _3-6 cycloalkyl, C _2-6 hydroxyalkyl, C _1-6 alkoxy-C _{1 -6} alkyl or C _2-6 alkyl-NR ⁸ R ⁹ ; p=0, 1, 2, 3 or 4; q=2, 3 or 4; and x=0, 1 or 2. A compound of formula (F) or (G):

Or its stereoisomer or pharmaceutically acceptable salt, solvate, ester or prodrug; where Z is CH or N; X ⁶ and X ⁷ are each CH, CR ⁴ or N; R ^{1 is} independently Selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, hydroxyl, methoxy, ethoxy, isopropoxy, cyclopropoxy, -OCF ₃ , -OCH ₂ CF ₃ , -OCH ₂ CHF _2. Vinyl, ethynyl, CF ₃ , CHF ₂ , CHO, CH ₂ OH, CONH ₂ , CO ₂ Me, CONHMe, CONMe ₂ and cyano; R ² is -OCF ₃ , -OCHF ₂ , -OCF ₂ CF ₃ , -OCH ₂ CHF ₂ , -OCH ₂ CF ₃ , cyclopropyl, cyclopropoxy, methoxy, -OCD ₃ , ethoxy, or isopropoxy; R ³ is N(R ¹⁰ )C _{2 -6} alkyl-NR ¹⁰ R ¹⁰ ; R ^{4 is} independently H, cyano, halo, -C _1-6 alkyl, -C _1-6 haloalkyl, carboxy-C _1-6 alkyl, -C _1-6 hydroxyalkyl, R ⁸ R ⁹ NC _1-6 alkyl-, -C _2-6 alkenyl, -C _2-6 alkynyl, C _1-6 acetyl-, R ⁷ -(CH ₂ ) _p C(=O)-, C _1-6 hydroxyalkyl-C(=O)-, carboxyl, -C _1-6 alkoxycarbonyl, -C(=O)NR ⁸ R ⁹ , hydroxyl, Alkoxy, C _1-6 acetyloxy, -NR ⁸ R ⁹ , C _1-6 acetyl-N(R ¹⁰ )-, R ⁷ SO ₂ -, R ^4a and R ^4b are each independently H, halogen Group, -C _1-6 alkyl or -C _1-6 haloalkyl; R ^4c is cyano, C _1-6 acetyl-, -C(=O)NR ⁸ R ⁹ , hydroxyl, alkoxy or F; R ^4N is H, -CD ₃ , -C _1-6 alkyl or -C _1-6 haloalkyl; R ⁷ is OH, NR ⁸ R ⁹ , O(CH ₂ ) _q NR ⁸ R ⁹ , C _1-6 alkoxy or C _2-6 hydroxyalkoxy; R ⁸ and R ^{9 are} independently H, -CD ₃ , C _1-6 alkyl, C _3-6 alkenyl, C _3-6 alkynyl , C _3-8 cycloalkyl, C _3-8 cycloalkenyl, C _1- C ₆ acetyl, 4-12 membered monocyclic or bicyclic heterocyclic group, 4-12 membered monocyclic or bicyclic heterocyclic group -C ₁ -C ₆ alkyl-, C _6- C ₁₂ aryl, 5-12 membered heteroaryl; and R ⁸ and R ⁹ can be further independently selected from up to three hydroxy, C _1-6 alkoxy Group, C _1-6 hydroxyalkyl, C _2-6 hydroxyalkoxy, pendant, thiocarbonyl, cyano or halo substituents; or R ¹⁰ are each independently H, -CD ₃ , C _1-6 alkyl, C _3-6 cycloalkyl, C _2-6 hydroxyalkyl, C _1-6 alkoxy-C _1-6 alkyl Or C _2-6 alkyl-NR ⁸ R ⁹ ; or p=0, 1, 2, 3, or 4; and q=2, 3, or 4. If the compound of any one of the items 18 to 21 of the patent application range, the compound is not:

Or its stereoisomers or pharmaceutically acceptable salts, solvates, esters or prodrugs. For example, the compound of any one of items 18 to 21 of the patent application scope, wherein the compound is:

Or its stereoisomers or pharmaceutically acceptable salts, solvates, esters or prodrugs. For example, the compound of claim 19, wherein X ² is CH or CR ⁴ ; R ⁴ is methyl, ethyl or isopropyl; R ^4c is cyano, -CF ₃ , Cl or F; R ^{4N is-} CD ₃ , methyl, ethyl or isopropyl; and R ^4b is H, halo, methyl, ethyl or isopropyl. If the compound of claim 19 or 24 is applied for, the compound is:

,

or

, Or its stereoisomers or pharmaceutically acceptable salts, solvates, esters or prodrugs. For example, the compound of claim 19, wherein X ² is N; R ^4c is cyano, -CF ₃ , Cl or F; R ^4N is -CD ₃ , methyl, ethyl or isopropyl; and R ^4b It is H, halo, methyl, ethyl or isopropyl. If the compound of claim 26 is applied for, the compound is

Or its stereoisomers or pharmaceutically acceptable salts, solvates, esters or prodrugs. A compound of formula (EI):

Or its stereoisomers or pharmaceutically acceptable salts, solvates, esters or prodrugs; where Z is CH or N; R ¹ is hydrogen, fluorine, chlorine, bromine, methyl, ethyl, hydroxyl , Methoxy, ethoxy, isopropoxy, cyclopropoxy, -OCF ₃ , -OCH ₂ CF ₃ , -OCH ₂ CHF ₂ , vinyl, ethynyl, CF ₃ , CHF ₂ , CHO, CH ₂ OH, CONH ₂ , CO ₂ Me, CONHMe, CONMe ₂ or cyano group; R ² is -OCF ₃ , -OCHF ₂ , -OCF ₂ CF ₃ , -OCH ₂ CHF ₂ , -OCH ₂ CF ₃ , cyclopropyl , Cyclopropoxy, methoxy, -OCD ₃ , ethoxy or isopropoxy; R ³ is N(R ¹⁰ )C _2-6 alkyl-NR ¹⁰ R ¹⁰ or -N(R ¹⁰ )( C _3-10 cycloalkylalkyl)-NR ¹⁰ R ¹⁰ ; R ^{4 is} each independently H, cyano, halo, -C _1-6 alkyl, -C _1-6 haloalkyl, carboxy-C _1-6 alkyl, -C _1-6 hydroxyalkyl, R ⁸ R ⁹ NC _1-6 alkyl-, -C _2-6 alkenyl, -C _2-6 alkynyl, C _1-6 acetyl , R ⁷ -(CH ₂ ) _p C(=O)-, C _1-6 hydroxyalkyl-C(=O)-, carboxyl, -C _1-6 alkoxycarbonyl, -C(=O)NR ⁸ R ⁹ , hydroxy, alkoxy, C _1-6 acetyloxy, -NR ⁸ R ⁹ , C _1-6 acetyl-N(R ¹⁰ )- or R ⁷ SO ₂ -; and R ⁸ and R ⁹ Independently H, -CD ₃ , C _1-6 alkyl, C _3-6 alkenyl, C _3-6 alkynyl, C _3-8 cycloalkyl, C _3-8 cycloalkenyl, C _1- C _6- acyl, 4-12 membered monocyclic or bicyclic heterocyclyl, 4-12 membered monocyclic or bicyclic heterocyclyl-C ₁ -C ₆ alkyl-, C _6- C ₁₂ aryl, 5-12 Member heteroaryl; and R ⁸ and R ⁹ can be further independently selected from up to three hydroxy, C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _2-6 hydroxyalkoxy, pendant oxygen Group, thiocarbonyl, cyano or halo; or alternatively, R ⁸ and R ⁹ together with the N atom to which they are attached at the same time form a heterocyclic ring of 4-7 members, the heterocyclic ring containing up to one selected Other heteroatoms from O, S or NR ¹¹ , or form a heterobicyclic ring of 7-12 members, the heterobicyclic ring may be fused, bridged or spirocyclic and contain up to two selected from O, S(O) _x or other heteroatom of NR ¹¹ , and these heterocycles are optionally selected from up to three hydroxy, C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _1-6 alkoxy-C _{1- 6} alkyl, C _1-6 alkoxy-C _1-6 alkoxy, C _2-6 hydroxyalkoxy, pendant, thiocarbonyl, cyano or halo substituents Generation; R ^4N is H, -CD ₃ or -C _1-6 alkyl; R ⁷ is OH, -NR ⁸ R ⁹ , -O(CH ₂ ) _q NR ⁸ R ⁹ , C _1-6 alkoxy or C _2-6 hydroxyalkoxy; R ^{10 is} each independently H, -CD ₃ , C _1-6 alkyl, C _3-6 cycloalkyl, C _2-6 hydroxyalkyl, C _1-6 alkoxy -C _1-6 alkyl or C _2-6 alkyl-NR ⁸ R ⁹ ; or, two R ¹⁰ on the same N atom combine to form a heterocyclic ring of 3-7 members, the heterocyclic ring may Up to three selected from hydroxy, C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _1-6 alkoxy-C _1-6 alkyl, C _1-6 alkoxy-C _1-6 alkyl Oxygen, C _2-6 hydroxyalkoxy, pendant, thiocarbonyl, cyano or halo substituent substitution; p=0, 1, 2, 3 or 4; q=2, 3 or 4; and x=0, 1 or 2. For example, the compound of claim 28, wherein R ³ is N(R ¹⁰ )C _2-6 alkyl-NR ¹⁰ R ¹⁰ or -N(R ¹⁰ )(C _3-10 cycloalkylalkyl)-NR ¹⁰ R ¹⁰ ; R ^{4 is} independently H, cyano, halo, -C _1-6 alkyl or -C _1-6 haloalkyl; and R ^4N is H, -CD ₃ or -C _1-6 Alkyl; and R ^{10 is} each independently H, -CD ₃ or -C _1-6 alkyl. If the compound of claim 28 or 29 is applied for, the compound is

Or its stereoisomers or pharmaceutically acceptable salts, solvates, esters or prodrugs. For example, the compound of claim 18, wherein the compound has the structure of formula (H)

Or its stereoisomer or pharmaceutically acceptable salt, solvate, ester or prodrug; where X ⁷ is CH or N; X ^{2 is} independently CH, CCH ₃ or N; R ² is methoxy Radical, -OCD ₃ , ethoxy or isopropoxy; R ^4b is H, F, Cl or CH ₃ ; R ^4N is H, -CD ₃ , CH ₃ , Et or CH(CH ₃ ) ₂ ; and R ¹⁰ are each independently H, -CD ₃ , -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ . For example, the compound of claim 31, wherein X ⁷ is CH or N; X ^{2 is} independently CH or CCH ₃ ; R ² is methoxy, -OCD ₃ , ethoxy, or isopropoxy; R ^4b Is H, F, Cl or CH ₃ ; R ^4N is H, -CD ₃ , CH ₃ , Et or CH(CH ₃ ) ₂ ; and R ^{10 is} each independently H, -CD ₃ , -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ . For example, the compound of claim 31 or 32, wherein the compound is:

, Or its stereoisomers or pharmaceutically acceptable salts, solvates, esters or prodrugs. For example, the compound of claim 18, wherein the compound has the structure of formula (HI):

Or its stereoisomer or pharmaceutically acceptable salt, solvate, ester or prodrug; where X ⁷ is CH or N; X ^{2 is} independently CH, CCH ₃ or N; R ² is methoxy Radical, -OCD ₃ , ethoxy or isopropoxy; R ^4b is H, F, Cl or CH ₃ ; R ^4N is H, -CD ₃ , CH ₃ , Et or CH(CH ₃ ) ₂ ; and R ¹⁰ are each independently -CD ₃ , -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ . For example, the compound of claim 31, item 32 or item 34, wherein the compound is:

Or its stereoisomers or pharmaceutically acceptable salts, solvates, esters or prodrugs. For example, the compound of claim 20, wherein the compound has the structure of formula (J):

Or its stereoisomers or pharmaceutically acceptable salts, solvates, esters or prodrugs; where X ⁶ is N or CR ⁴ , where R ⁴ is H, cyano, CONH ₂ , CONHCH ₃ , CON (CH ₃ ) ₂ , COCH ₃ ; X ^{2 is} independently CH, C-CH ₃ or N; X ^{3 is} independently CH, C-CH ₃ , C-CF ₃ , C-CHF ₂ , CF, C-Cl Or N; R ^4N is H, -CD ₃ , -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ ; R ² is -OCF ₃ , -OCHF ₂ , -OCF ₂ CF ₃ , -OCH ₂ CHF ₂ , -OCH ₂ CF ₃ , cyclopropyl, cyclopropoxy, methoxy, -OCD ₃ , ethoxy, or isopropoxy; R ^{10 is} each independently H, -CD ₃ , C _{1- 6} alkyl, C _3-6 cycloalkyl, C _2-6 hydroxyalkyl, C _1-6 alkoxy-C _1-6 alkyl or C _2-6 alkyl-NR ⁸ R ⁹ ; and R ⁸ And R ^{9 is} independently H, -CD ₃ , C _1-6 alkyl, C _3-6 alkenyl, C _3-6 alkynyl, C _3-8 cycloalkyl, C _3-8 cycloalkenyl, C _1- C ₆ acetyl, 4-12 membered monocyclic or bicyclic heterocyclyl, 4-12 membered monocyclic or bicyclic heterocyclyl-C ₁ -C ₆ alkyl-, C _6- C ₁₂ aryl, 5-12 membered heteroaryl groups; and R ⁸ and R ⁹ may be independently selected from up to three further selected from hydroxy, C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _2-6 hydroxyalkoxy , Pendant, thiocarbonyl, cyano or halo substituents. For example, the compound of claim 36, wherein: X ⁶ is C-CN; X ² is CH or C-CH ₃ ; X ³ is CH or C-CH ₃ ; R ^4N is H, -CD ₃ , -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ ; R ² is methoxy, -OCD ₃ , ethoxy or isopropoxy; R ^{10 is} each independently H, -CD ₃ , -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ . For example, if the compound of patent application item 36 or 37, the compound is:

Or its stereoisomers or pharmaceutically acceptable salts, solvates, esters or prodrugs. For example, if the compound of patent application item 36 or 37, the compound is:

Or its stereoisomers or pharmaceutically acceptable salts, solvates, esters or prodrugs. A compound of formula (K):

Or its stereoisomer or pharmaceutically acceptable salt, solvate, ester or prodrug; where Z is CH or N; X ² is CR ^4a or N; X ⁶ is CR ^4b or N; X ⁸ CH or N; R ¹ is hydrogen, methyl, fluorine, chlorine, bromine, CF ₃ or cyano; R ² is -OCF ₃ , -OCHF ₂ , -OCF ₂ CF ₃ , -OCH ₂ CHF ₂ , -OCH ₂ CF ₃ , cyclopropoxy, methoxy, -OCD ₃ , ethoxy or isopropoxy; R ³ is N(R ¹⁰ )C _2-6 alkyl-NR ¹⁰ R ¹⁰ ; R ^4a is H , Cyano, halo, -C _1-6 alkyl or -C _1-6 haloalkyl; R ^4b is H, cyano, nitro, halo, -C _1-6 alkyl, -C _{1- 6} haloalkyl, carboxy-C _1-6 alkyl, -C _1-6 hydroxyalkyl, R ⁸ R ⁹ NC _1-6 alkyl-, -C _2-6 alkenyl, -C _2-6 alkynyl , C _1-6 acetyl-, R ⁷ -(CH ₂ ) _p C(=O)-, C _1-6 hydroxyalkyl-C(=O)-, carboxyl, -C _1-6 alkoxycarbonyl , -C(=O)NR ⁸ R ⁹ , hydroxyl, alkoxy, -OCD ₃ , C _1-6 acetyloxy, -NR ⁸ R ⁹ , C _1-6 acetyl-N(R ¹⁰ )- or R ⁷ SO ₂ -; R ^4N is H, -C _1-6 alkyl or -CD ₃ ; R ⁸ and R ^{9 are} independently H, -CD ₃ , C _1-6 alkyl, C _3-8 cycloalkane Group, C _3-8 cycloalkyl-(C _1-3 alkyl)-, C _1- C ₆ acetyl, phenyl, monocyclic heteroaryl or monocyclic heterocyclic group; and R ⁸ and R ⁹ may be Further independently substituted with up to three substituents selected from the group consisting of hydroxy, C _1-6 alkoxy, pendant, thiocarbonyl, cyano or halo; or alternatively, R ⁸ and R ⁹ are simultaneously attached to N Together, the atoms form a 4-7 member heterocycle, which contains up to one other heteroatom selected from O, S, or NR ¹¹ , or a 7-12 member heterobicycle, which may be fused Combined, bridged or spiro ring, and containing up to two other heteroatoms selected from O, S(O) _x or NR ¹¹ , and these heterocycles may optionally be selected from up to three selected from hydroxyl, C _1-6 alkoxy Group, C _1-6 hydroxyalkyl, C _1-6 alkoxy-C _1-6 alkyl, C _1-6 alkoxy-C _1-6 alkoxy, C _2-6 hydroxyalkoxy, Substitution of pendant, thiocarbonyl, cyano or halo groups; R ^{10 is} each independently H, -CD ₃ , C _1-6 alkyl, C _3-6 cycloalkyl, C _2-6 hydroxyalkane Group, C _1-6 alkoxy-C _1-6 alkyl or C _2-6 alkyl-NR ⁸ R ⁹ ; p=0, 1, 2, 3 or 4; q=2, 3 or 4; and x=0, 1 or 2. For example, the compound of claim 40, wherein the compound has the structure of formula (L):

Or its stereoisomer or pharmaceutically acceptable salt, solvate, ester or prodrug; wherein X ² is CR ^4a or N; X ⁶ is CR ^4b or N; X ⁸ is CH or N; R ² is methoxy, -OCD ₃ , ethoxy or isopropoxy; R ^4a is H, cyano, halo, -C _1-6 alkyl or -C _1-6 haloalkyl; R ^4b is H, cyano, nitro, halo, -C _1-6 alkyl, -C _1-6 haloalkyl, carboxy -C _1-6 alkyl, -C _1-6 hydroxyalkyl, R ⁸ R ⁹ NC _1-6 alkyl-, -C _2-6 alkenyl, -C _2-6 alkynyl, C _1-6 acetyl-, R ⁷ -(CH ₂ ) _p C(=O)-, C _{1- 6} -hydroxyalkyl-C(=O)-, carboxyl, -C _1-6 alkoxycarbonyl, -C(=O)NR ⁸ R ⁹ , hydroxy, alkoxy, -OCD ₃ , C _1-6 acetyl Oxygen, -NR ⁸ R ⁹ , C _1-6 acetyl-N(R ¹⁰ )-, R ⁷ SO ₂ -; R ^4N is H, -CH ₃ , Et, CH(CH3) 2 or -CD ₃ ; R ⁸ and R ^{9 are} independently H, -CD ₃ , C _1-6 alkyl, C _3-8 cycloalkyl, C _3-8 cycloalkyl-(C _1-3 alkyl)-, C _1- C ₆ acetyl, phenyl, monocyclic heteroaryl or monocyclic heterocyclic group; and R ⁸ and R ⁹ may be independently independently selected by up to three from hydroxyl, C _1-6 alkoxy, pendant, Thiocarbonyl, cyano or halo substituent substitution; or alternatively, R ⁸ and R ⁹ together with the N atom to which they are simultaneously attached form a heterocyclic ring of 4-7 members, the heterocyclic ring containing up to one selected from O , S or NR ¹¹ other hetero atoms, or form a heterobicyclic ring of 7-12 members, the heterobicyclic ring may be fused, bridged or spiro ring, and contains up to two selected from O, S (O) _x or NR ¹¹ other heteroatoms, and these heterocycles are optionally selected from up to three hydroxy, C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _1-6 alkoxy-C _1-6 alkyl Group, C _1-6 alkoxy-C _1-6 alkoxy, C _2-6 hydroxyalkoxy, pendant, thiocarbonyl, cyano or halo substituents; R ^{10 is} each independently H, -CD ₃ , C _1-6 alkyl, C _3-6 cycloalkyl, C _2-6 hydroxyalkyl, C _1-6 alkoxy-C _1-6 alkyl, or C _2-6 alkyl -NR ⁸ R ⁹ ; p=0, 1, 2, 3 or 4; q=2, 3 or 4; and x=0, 1 or 2. For example, the compound of claim 41, wherein: X ² is CR ^4a or N; X ⁶ is CR ^4b or N; X ⁸ is CH or N; R ² is methoxy, -OCD ₃ , ethoxy or Isopropoxy; R ^4a is H, F, Cl, CH ₃ , CF ₃ or CHF ₂ ; R ^4b is H, cyano, nitro, halo, -C _1-6 alkyl or -C _1-6 Haloalkyl; R ^4N is H, -CD ₃ , -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ ; and R ^{10 is} each independently H, -CD ₃ , -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ . For example, the compound of claim 41, wherein: X ² is CR ^4a or N; X ⁶ is CR ^4b ; X ⁸ is CH; R ² is methoxy, -OCD ₃ , ethoxy or isopropoxy ; R ^4a is H, F, CH ₃ , CF ₃ or CHF ₂ ; R ^4b is H, CH ₃ , F, Cl, CF ₃ or CHF ₂ ; R ^4N is H, -CD ₃ , -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ ; R ^{10 is} each independently H, -CD ₃ , -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ . For example, the compound of any one of items 41 to 43 of the patent application scope, wherein the compound is:

Or its stereoisomers or pharmaceutically acceptable salts, solvates, esters or prodrugs. A compound of formula (M):

Or its stereoisomer or pharmaceutically acceptable salt, solvate, ester or prodrug; where Z is CH or N; R ¹ is hydrogen, methyl, fluorine, chlorine, bromine, -CF ₃ or Cyano; R ² is -OCF ₃ , -OCHF ₂ , -OCF ₂ CF ₃ , -OCH ₂ CHF ₂ , -OCH ₂ CF ₃ , cyclopropoxy, methoxy, -OCD ₃ , ethoxy, or iso Propoxy; R ³ is N(R ¹⁰ )C _2-6 alkyl-NR ¹⁰ R ¹⁰ ; R ^4a is cyano, -C _1-6 hydroxyalkyl, C _1-6 acetyl-, pyrazole, 1,2,3-triazole, tetrazole, -C(=O)NR ⁸ R ⁹ , -NR ⁸ R ⁹ , C _1-6 acetyl-N(R ¹⁰ )-, (C _1-3 alkyl )SO ₂ NH-, (C _1-6 alkyl)SO ₂ -or R ⁷ SO ₂ -; R ^4b is H, cyano, halo, -C _1-6 alkyl or -C _1-6 haloalkane Group; R ⁷ is -OH or -NR ⁸ R ⁹ ; R ⁸ and R ^{9 are} independently H, -CD ₃ , C _1-6 alkyl, C _3-8 cycloalkyl, C _3-8 cycloalkyl -(C _1-3 alkyl)-, C _1- C ₆ acetyl, phenyl, monocyclic heteroaryl or monocyclic heterocyclic group; and R ⁸ and R ⁹ may be independently selected from up to three Hydroxy, C _1-6 alkoxy, pendant, thiocarbonyl, cyano or halo substituents; or alternatively, R ⁸ and R ⁹ together with the N atom to which they are attached together form 4-7 members Heterocyclic ring, the heterocyclic ring contains up to one other heteroatom selected from O, S or NR ¹¹ ; R ^{10 is} each independently H, -CD ₃ , C _1-6 alkyl, C _3-6 cycloalkyl , C _2-6 hydroxyalkyl, C _2-6 alkyl-NR ⁸ R ⁹ ; or, two R ¹⁰ on the same N atom attached at the same time form a heterocycle of 5-6 members, the heterocycle contains Up to one other heteroatom selected from O, S or NR ¹¹ ; and R ¹¹ are each independently hydrogen or C ₁ -C ₆ alkyl, which may optionally be selected from hydroxyl, pendant, thiocarbonyl , Cyano and halogen substituents. For example, the compound of claim 45, wherein: Z is CH; R ¹ is hydrogen, methyl, fluorine, chlorine, bromine, -CF ₃ or cyano; R ² is methoxy, -OCD ₃ , ethoxy Radical or isopropoxy; R ³ is -N(CH ₃ )CH ₂ CH ₂ NR ¹⁰ R ¹⁰ ; R ^4a is -NR ⁸ R ⁹ ; R ^4b is H, CH ₃ , F, Cl, CF ₃ or CHF ₂ ; R ⁸ and R ^{9 are} independently H, -CD ₃ , C _1-6 alkyl, C _3-8 cycloalkyl, C _3-8 cycloalkyl-(C _1-3 alkyl)-, C _1- C ₆ acetyl, phenyl, monocyclic heteroaryl or monocyclic heterocyclic group; and R ⁸ and R ⁹ can be further independently selected by up to three from hydroxyl, C _1-6 alkoxy, pendant oxygen Substituted by a substituent of a group, a thiocarbonyl group, a cyano group or a halogen group; and R ^{10 is} each independently H, -CD ₃ , -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ . If the compound of claim 45 or 46 is applied for, the compound is

Or its stereoisomers or pharmaceutically acceptable salts, solvates, esters or prodrugs. A compound of formula (N):

Or its stereoisomer or pharmaceutically acceptable salt, solvate, ester or prodrug; wherein, X ² is CH, CCH ₃ or N; X ⁶ is CR ⁴ or N; Z is CH or N; R ¹ is hydrogen, methyl, fluorine, chlorine, bromine, -CF ₃ or cyano; R ² is -OCF ₃ , -OCHF ₂ , -OCF ₂ CF ₃ , -OCH ₂ CHF ₂ or -OCH ₂ CF ₃ ; R ³ is N(R ¹⁰ )C _2-6 alkyl-NR ¹⁰ R ¹⁰ ; R ⁴ is H, cyano, halo, -C _1-6 alkyl, -C _1-6 haloalkyl; R ^4a Independently cyano, -C _1-6 hydroxyalkyl, C _1-6 acetyl-, pyrazole, 1,2,3-triazole, tetrazole, -C(=O)NR ⁸ R ⁹ ,- NR ⁸ R ⁹ , C _1-6 acetyl-N(R ¹⁰ )-, (C _1-3 alkyl)SO ₂ NH-, (C _1-6 alkyl)SO ₂ -or R ⁷ SO ₂ -; R ⁷ is -OH or -NR ⁸ R ⁹ ; R ⁸ and R ^{9 are} independently H, -CD ₃ , C _1-6 alkyl, C _3-8 cycloalkyl, C _3-8 cycloalkyl-( C _1-3 alkyl)-, C _1- C ₆ acetyl, phenyl, monocyclic heteroaryl or monocyclic heterocyclic group; and R ⁸ and R ⁹ may be further independently selected by up to three from hydroxyl, C _1-6 alkoxy, pendant, thiocarbonyl, cyano or halo substituent substitution; R ^{10 is} each independently H, -CD ₃ , C _1-6 alkyl, C _3-6 cycloalkane Group, C _2-6 hydroxyalkyl, C _2-6 alkyl-NR ⁸ R ⁹ . For example, the compound of claim 48, wherein the compound has the structure of formula (O):

Or its stereoisomers or pharmaceutically acceptable salts, solvates, esters or prodrugs; where X ⁶ is CH, CCH ₃ or N; R ² is -OCF ₃ , -OCHF ₂ , -OCF ₂ CF ₃ , -OCH ₂ CHF ₂ or -OCH ₂ CF ₃ ; R ⁸ and R ⁹ are each independently H, -CD ₃ , -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ ; and R ¹⁰ are each independently H, -CD ₃ , -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ . For example, the compound of claim 48 or 49, wherein the compound is:

Or its stereoisomers or pharmaceutically acceptable salts, solvates, esters or prodrugs. A compound of formula (P):

Or its stereoisomer or pharmaceutically acceptable salt, solvate, ester, tautomer or prodrug; wherein: Z is CH or N; R ^{1 is} independently selected from hydrogen, fluorine, chlorine, bromine , Methyl, ethyl, hydroxyl, methoxy, ethoxy, isopropoxy, cyclopropoxy, -OCF ₃ , -OCH ₂ CF ₃ , -OCH ₂ CHF ₂ , vinyl, ethynyl, CF ₃ , CHF ₂ , CHO, CH ₂ OH, CONH ₂ , CO ₂ Me, CONHMe, CONMe ₂ or cyano group; R ² is -OCF ₃ , -OCHF ₂ , -OCF ₂ CF ₃ , -OCH ₂ CHF ₂ ,- OCH ₂ CF ₃ , cyclopropyl, cyclopropoxy, methoxy, -OCD ₃ , ethoxy, or isopropoxy; R ³ is N(R ¹⁰ )C _2-6 alkyl-NR ¹⁰ R ¹⁰ , N(R ¹⁰ )C _2-6 alkyl-R ⁷ , O(CH ₂ ) _p R ⁷ , N(R ¹⁰ )C(=O)(CH ₂ ) _p R ⁷ or R ⁷ ; R ^{4 is} independent of each other Ground is H, cyano, nitro, halo, -C _1-6 alkyl, -C _1-6 haloalkyl, carboxy -C _1-6 alkyl, -C _1-6 hydroxyalkyl, R ⁸ R ⁹ NC _1-6 alkyl-, -C _2-6 alkenyl, -C _2-6 alkynyl, C _1-6 acetyl-, R ⁷ -(CH ₂ ) _p C(=O)-, C _1-6 hydroxyalkyl -C(=O)-, carboxyl, -C _1-6 alkoxycarbonyl, -C(=O)NR ⁸ R ⁹ , hydroxy, alkoxy, C _1-6 acetyloxy , -NR ⁸ R ⁹ , C _1-6 acetyl-N(R ¹⁰ )- or R ⁷ SO ₂ -; R ^{4a is} independently H, cyano, nitro, halo, -C _1-6 alkyl , -C _1-6 haloalkyl, -C _1-6 alkoxy, -C _1-6 haloalkoxy, -C _1-6 hydroxyalkyl, C _1-6 acetyl-, pyrazole, 1 , 2,3-triazole, tetrazole, -C(=O)NR ⁸ R ⁹ , -NR ⁸ R ⁹ , C _1-6 acetyl-N(R ¹⁰ )-, (C _1-3 alkyl) SO ₂ NH-, (C _1-6 alkyl)SO ₂ -or R ⁷ SO ₂ -; R ⁷ is OH, NR ⁸ R ⁹ , O(CH ₂ ) _q NR ⁸ R ⁹ , C _1-6 alkoxy Group or C _2-6 hydroxyalkoxy; R ⁸ and R ^{9 are} independently H, -CD ₃ , C _1-6 alkyl, C _3-6 alkenyl, C _3-6 alkynyl, C _3-8 Cycloalkyl, C _3-8 cycloalkenyl, C _1- C ₆ acetyl, 4-12 membered monocyclic or bicyclic heterocyclyl, 4-12 membered monocyclic or bicyclic heterocyclyl-C ₁ -C ₆ alkyl-, C _6- C ₁₂ aryl, 5-12 member heteroaryl; and R ⁸ and R ⁹ can be One-step independently hydroxyl up to three substitutions selected from hydroxyl, C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _2-6 hydroxyalkoxy, pendant, thiocarbonyl, cyano or halo Radical substitution; or alternatively, R ⁸ and R ⁹ together with the N atom to which they are simultaneously attached form a heterocyclic ring of 4-7 members, the heterocyclic ring containing up to one other heteroatom selected from O, S or NR ¹¹ , Or form a heterobicyclic ring of 7-12 members, which may be fused, bridged or spirocyclic, and contain up to two other heteroatoms selected from O, S(O) _x or NR ¹¹ , and such The heterocyclic ring may be selected from up to three hydroxy, C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _1-6 alkoxy-C _1-6 alkyl, C _1-6 alkoxy- C _1-6 alkoxy, C _2-6 hydroxyalkoxy, pendant, thiocarbonyl, cyano or halo substituent substitution; R ^{10 is} each independently H, -CD ₃ , C _1-6 Alkyl, C _3-6 cycloalkyl, C _2-6 hydroxyalkyl, C _1-6 alkoxy-C _1-6 alkyl, or C _2-6 alkyl-NR ⁸ R ⁹ ; or alternatively, Two R ¹⁰ on the same N atom attached to form a heterocycle of 5-6 members, the heterocycle contains up to one other heteroatom selected from O, S or NR ¹¹ ; and each R ^{11 is} independently hydrogen or C _1- C ₆ alkyl, which is optionally substituted with up to three substituents selected from hydroxy, oxo, thiocarbonyl, cyano, and halo group of substituents; p = 0,1,2,3 or 4; q = 2, 3, or 4; and x=0, 1, or 2. For example, the compound of claim 51, wherein: Z is CH or N; R ¹ is hydrogen, methyl, fluorine, chlorine, bromine, -CF ₃ or cyano; R ³ is N(R ¹⁰ )C _{2- 6} alkyl-NR ¹⁰ R ¹⁰ ; R ^{4 is} independently H, cyano, halo, -C _1-6 alkyl, -C _1-6 haloalkyl; R ^{4a is} independently H, cyano, Nitro, halo, -C _1-6 alkyl, -C _1-6 haloalkyl, -C _1-6 alkoxy, -C _1-6 haloalkoxy, -C(=O)NR ⁸ R ⁹ or -NR ⁸ R ⁹ ; R ⁸ and R ^{9 are} independently H, -CD ₃ , -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ ; and R ^{10 is} independently H, -CD ₃ , -CH ₃ , -CH ₂ CH ₃ or -CH(CH ₃ ) ₂ . For example, if the compound of claim 51 or 52 is applied for, the compound is:

Or its stereoisomers or pharmaceutically acceptable salts, solvates, esters, tautomers or prodrugs. A compound with the following structure:

A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 54 or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, and a pharmaceutically acceptable Carrier. A method for treating cancer in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound as described in any one of claims 1 to 54 or its pharmaceutically acceptable Salts, solvates, esters or prodrugs. For example, the method of claim 56, wherein the cancer is selected from lung cancer, colorectal cancer, pancreatic cancer, head and neck cancer, breast cancer, ovarian cancer, uterine cancer, liver cancer, and gastric cancer. For example, the method of claim 56 or 57 of the patent application, wherein the cancer is non-small cell lung cancer (NSCLC). For example, the method of claim 58, wherein the cancer is caused by a mutation in the exon 20 domain of EGFR. For example, the method of claim 59, wherein the mutation in the exon 20 domain of the EGFR is selected from NPG, ASV, or T790M. For example, the method of claim 60, wherein the mutation in the exon 20 domain of the EGFR is T790M in parallel with the insertion mutation of exon 19 or the mutation of exon 21 points. The method according to any one of the patent application items 56 to 61, wherein the patient is resistant to the compound or the pharmaceutically acceptable salt thereof according to any one of the patent application items 1 to 54, Kinase inhibitors other than solvates, esters or prodrugs. For example, the method of claim 62, wherein the kinase inhibitor is an EGFR inhibitor. A method for inhibiting EGFR or a mutation in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound as claimed in any one of claims 1 to 54 or a pharmaceutical Acceptable salts, solvates, esters or prodrugs. For example, the method of claim 64, wherein the mutation is in the exon 20 domain of the EGFR.