Halogenated heteroaryl and other heterocyclic kinase inhibitors and their uses

Abstract

This invention relates to kinase inhibitors, particularly inhibitors of protein kinases including the SIK family CSF1R, ABL / BCR-ABL, SRC, HCK, PDGFR, KIT, and / or mutants thereof. Although structurally similar to dasatinib, the kinase inhibitors of this invention are distinctive, possessing a specific class of halogenated heteroaryl groups. Such kinase inhibitors may exhibit one or more properties that differ from dasatinib and other structurally similar kinase inhibitors. The kinase inhibitors of this invention, or pharmaceutical compositions comprising them, can be used to treat diseases or conditions such as proliferative disorders, such as leukemia or solid tumors. In particular, these and other structurally similar kinase inhibitors can be used to treat proliferative disorders—such as mixed phenotype acute leukemia (MPAL)—characterized, in particular, by the presence of the MEF2C protein, a human chromosomal translocation at 11q23, and / or the KMT2A fusion oncoprotein. The kinase inhibitors or pharmaceutical compositions disclosed herein can be used topically to modulate skin pigmentation in a subject, for example, to confer UV protection and reduce the risk of skin cancer.

Description

[0001] manual

[0002] This invention relates to kinase inhibitors, particularly protein kinase inhibitors comprising the SIK family, CSF1R, ABL / BCR-ABL, SRC, HCK, PDGFR, KIT, and / or mutants thereof. Although structurally similar to dasatinib, the kinase inhibitors of this invention are unique; they possess a specific class of halogenated heteroaryl groups. Such kinase inhibitors may exhibit one or more properties that differ from dasatinib and other structurally similar kinase inhibitors. The kinase inhibitors of this invention, or pharmaceutical compositions comprising them, can be used to treat diseases or conditions, such as proliferative disorders, like leukemia or solid tumors. In particular, these and other structurally similar kinase inhibitors can be used to treat proliferative disorders—such as mixed phenotype acute leukemia (MPAL)—characterized (especially) by the presence of MEF2C protein, human chromosomal translocation at 11q23, and / or KMT2A fusion oncoprotein. The kinase inhibitors or pharmaceutical compositions disclosed in this invention can be topically applied to modulate skin pigmentation in subjects, for example, to provide ultraviolet protection and reduce the risk of skin cancer.

[0003] Kinase inhibitors are enzyme inhibitors that block the action of kinases. Some non-limiting examples of such kinases include ABL, AKT, BCR-ABL, BLK, BRK, c-KIT, c-MET, CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, cRAF1, CSF1R, CSK, EGFR, ERBB2, ERBB3, ERBB4, ERK, PAK, FES, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, FGR, FIT-1, FPS, FRK, FYN, HCK, IGF-1R, INS-R, JAK, KDR, LCK, LYN, MEK, p38, PDGFR, PIK, PKC, PYK2, ROS, SIK1, SIK2, SIK3, SRC, TIE, TIE2, TRK, and ZAP70. Kinases are enzymes that add phosphate groups to proteins or other organic molecules. They have been shown to be key regulators of most cellular functions, including cell signaling, proliferation, differentiation, metabolism, survival, apoptosis, movement, and DNA damage repair. Phosphorylation, particularly signaling dysregulation due to defects in protein phosphorylation control, is closely associated with a variety of diseases, such as those related to abnormal kinase activity (e.g., increased activity). These diseases include, but are not limited to, proliferative disorders (e.g., cancer, benign tumors, pathological angiogenesis, inflammatory diseases, and autoimmune diseases) as well as allergies and CNS diseases.

[0004] Protein tyrosine kinases (PTKs) are enzymes that phosphorylate tyrosine residues in peptide chains and proteins by binding to ATP as a substrate. PTKs particularly include receptor protein tyrosine kinases (RPTKs), including members of the epidermal growth factor kinase family (e.g., HER1 and HER2), platelet-derived growth factor (PDGF), and kinases that play a role in angiogenesis (e.g., TIE2 and KDR); in addition, they include non-receptor protein tyrosine kinases, including members of the SYK, JAK, and SRC kinase families (e.g., SRC, HCK, FYN, LYN, LCK, and BLK kinases). Protein serine / threonine kinases (STKs) are enzymes that phosphorylate the oxygen atom of the serine or threonine side chain in peptide chains and proteins. STKs particularly include AKT1, Aurora kinase, BRAF, MAP kinase, PLK1, SIK1, SIK2, and SIK3.

[0005] Inhibiting protein kinases, and thus inhibiting the phosphorylation of their substrates into peptides or proteins, has proven effective in treating many diseases. For example, afatinib, an ERBB inhibitor, is effective in treating non-small cell lung cancer; axitinib, a VEGFR, PDGFR, and c-KIT inhibitor, is effective in treating renal cell carcinoma; bosutinib, an ABL / BCR-ABL inhibitor, is effective in treating chronic myeloid leukemia; cabozantinib, a c-MET and VEGFR2 inhibitor, is effective in treating thyroid cancer; and crizotinib, an ALK, HGFR, and c-MET inhibitor... It is effective in treating non-small cell lung cancer; dasatinib is an ABL / BCR-ABL, SRC, and c-KIT inhibitor that is effective in treating chronic myeloid leukemia; erlotinib is an EGFR inhibitor that is effective in treating non-small cell lung cancer and pancreatic cancer; gefitinib is an EGFR inhibitor that is effective in treating non-small cell lung cancer; imatinib is an ABL / BCR-ABL inhibitor that is effective in treating chronic myeloid leukemia; lapatinib is an H... ER2 inhibitors are effective in treating breast cancer; nilotinib, an ABL / BCR-ABL inhibitor, is effective in treating chronic myeloid leukemia; pazopanib, a VEGFR, PDGFR, and c-KIT inhibitor, is effective in treating renal cell carcinoma and soft tissue sarcoma; palbociclib, a CDK4 and CDK6 inhibitor, is effective in treating ER-positive and HER2-negative breast cancer; and ponatinib, an ABL / BCR-ABL, BEGFR, PDGFR, and FGFR inhibitor, is effective in treating ER-positive and HER2-negative breast cancer. EPH, SRC, c-KIT, RET, TIE2, and FLT3 inhibitors are effective in treating chronic myeloid leukemia and acute lymphoblastic leukemia; regorafenib, a RET, VEGFR, and PDGFR inhibitor, is effective in treating colorectal cancer and gastrointestinal stromal tumors; ribociclib, a cyclin D1 / CDK4 and CDK6 inhibitor, is effective in treating HR-positive, HER2-negative advanced or metastatic breast cancer; ruxolitinib, a JAK inhibitor, is effective in treating myelofibrosis.Sorafenib is a VEGFR, PDGFR, BRAF, and c-KIT inhibitor that is effective in treating renal cell carcinoma and hepatocellular carcinoma; sunitinib is a VEGFR and PDGFR inhibitor that is effective in treating renal cell carcinoma, gastrointestinal stromal tumors, and pancreatic neuroendocrine tumors; tofacitinib is a JAK inhibitor that is effective in treating rheumatoid arthritis; vandetanib is a VEGFR, EGFR, RET, and BRK inhibitor that is effective in treating thyroid cancer; and vemurafenib is a BRAF inhibitor that is effective in treating malignant melanoma.

[0006] Given the large number of kinases and related diseases, there is a persistent need for new inhibitors with multiple kinase selectivity that may be useful for the treatment of related diseases; in particular, there is still a need for new kinase inhibitors, pharmaceutical compositions / formulations and their uses (including in treatment regimens) to treat diseases associated with abnormal activity of one or more kinases; in particular, there is still a need for new kinase inhibitors: (a) for the treatment of proliferative diseases, such as mixed phenotype acute leukemia (MPAL) characterized (in particular) by the presence of myocyte enhancer factor 2C (MEF2C) protein, human chromosomal translocation at 11q23 and / or lysine methyltransferase 2A (KMT2A) fusion oncoprotein; or (b) alternatives to existing kinase inhibitors (e.g., dasatinib).

[0007] One specific kinase inhibitor is dasatinib (N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolylcarboxamide, a hydrate; Figure 1 A) Dasatinib is marketed by Bristol-Myers Squibb under the name “SPRYCEL” and is indicated for the treatment of adult patients with: (i) newly diagnosed chronic-phase Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML); (ii) chronic-phase, accelerated-phase, or (myeloid or lymphoid) blast crisis (Ph+) CML that is resistant to or intolerant of prior therapy, including imatinib; and (iii) Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) that is resistant to or intolerant of prior therapy. In Europe, dasatinib is also indicated for the treatment of pediatric patients newly diagnosed with chronic-phase Ph+CML (Ph+CML-CP) or Ph+CML-CP who are resistant to or intolerant of prior therapy, including imatinib; and in the United States, it is indicated for pediatric patients with chronic-phase Ph+CML.

[0008] It is worth noting that despite extensive trials with dasatinib, the drug has not been used in the United States or Europe for any cancer other than CML or Ph+ALL; in particular, as of September 2018, dasatinib had not been used for any solid tumors. In fact, many clinical trials using dasatinib to investigate its potential use in treating solid tumors have been terminated prematurely (e.g., due to toxicity issues) or have failed to report strong or at least promising results. For example, according to information on clinicaltrials.gov dated September 9, 2018, dasatinib has only been tested once in a phase 3 trial for solid tumors: in a single study of castration-resistant prostate cancer in combination with docetaxel (the “READY” trial (NCT00744497)). Although there were some indications of its activity in earlier trials suggesting resistance to chemotherapy-naïve castration-resistant prostate cancer (e.g., Araujo et al. 2012, Cancer 118:63), dasatinib did not improve overall survival compared to docetaxel alone in that trial (Araujo et al. 2013, Lancet Oncol. 14:13017). Despite several trials in other cancers such as breast cancer, skin cancer, pancreatic cancer, brain cancer, or lung cancer, dasatinib has not shown satisfactory efficacy or tolerability and has not progressed to phase 3 trials for these cancers. In particular, in a recent double-blind phase 2 trial of patients with locally advanced unresectable pancreatic cancer, dasatinib in combination with gemcitabine failed to demonstrate a higher overall survival than gemcitabine alone (Evens et al. 2017, Annal. Onc. 28:354). However, recently, some dedicated studies have aimed to select “targeted” therapies for patients with specific cancers (including solid tumors) expressing specific drug targets, potentially testing dasatinib based on the patient’s target profile. For example, (i) the “TAPUR” test (“The Targeted Agent and Profiling Utilization Registry”, https: / / www.tapur.org, NCT02693535) includes dasatinib in a potential treatment group based on one or more of the following targets: BCR-ABL, SRC, KIT, PDGFRB, EPHA2, FYN, LCK, YES1; and (ii) a trial at the Australian Melanoma Research Institute (NCT02645149) involving patients with unresectable metastatic stage III or IV BRAF and NRAS wild-type melanoma who have progressed or are ineligible for standard treatment (generally immunotherapy) included dasatinib as a potential treatment option, depending on the KIT mutation found in the patient’s cancer.Dasatinib is also a potential arm of the BMS “FRACTION-Lung” phase 2 trial (NCT02750514), which may be tested in combination with the immuno-oncology drug nivolumab in patients with advanced non-small cell lung cancer. Other arms of this trial will use nivolumab in combination with other immuno-oncology drugs.

[0009] Therefore, there is a particular need for new kinase inhibitors to treat cancers not specifically treated with dasatinib (especially solid tumors) and / or cancers for which dasatinib has not shown good efficacy. In particular, there is a need for new kinase inhibitors to treat one or more types of cancer, such as breast cancer, lung cancer (e.g., non-small cell lung cancer), pancreatic cancer, or prostate cancer (e.g., castration or hormone-resistant prostate cancer), and melanoma.

[0010] In addition, there is a particular need for novel kinase inhibitors for the treatment of proliferative disorders such as mixed phenotype acute leukemia (MPAL, also known as mixed lineage leukemia "MLL"), characterized (in particular) in the presence of MEF2C proteins (such as phosphorylated MEF2C proteins and / or MEF2C proteins as active transcription factors), 11q23 human chromosomal translocations, and / or KMT2A fusion oncoproteins.

[0011] Mixed phenotype acute leukemia (MPAL), also known as “mixed lineage leukemia” (MLL), is a highly aggressive blood cancer that primarily occurs in pediatric patients and has a poor prognosis, unlike other types of childhood acute leukemia (reviewed from Slany 2009, Haematologica 94:984). One form of MPAL is the BCR / ABL rearrangement. MPAL with t(9;22)(q34;q11.2) (or BCR / ABL1 rearrangement) is considered a separate entity (Arber et al 2016, Blood127:2391). The t(9;22)(q34;q11.2) translocation results in a BCR / ABL1 fusion gene located on the Philadelphia chromosome (Ph), leading to constitutively activated BCR / ABL1 tyrosine kinase. Another form of MPAL is characterized by the presence of a lysine methyltransferase 2A (KMT2A) fusion protein (also known as the MLL1 fusion protein), resulting from a chromosomal translocation affecting the KMT2A gene (also known as the MLL1 gene) at 11q23. This KMT2A / MLL rearrangement is the second most common inherited lesion in MPAL (MPAL-MLL+). These 11q23 translational activities juxtapose the N-terminus of the histone methyltransferase KMT2A with several different (translocation) fusion partners that disrupt the normal histone methyltransferase function of KMT2A and replace it with heterologous functions contributed by the (translocation) fusion partners. The resulting protein chimera is a transcriptional regulator that controls other genes normally controlled by KMT2A. In particular, the transcription factor MEF2C can be controlled by KMT2A and is considered an oncogene for childhood acute leukemia. MEF2C expression is associated with KMT2A fusion gene rearrangement in AML (Schwieger et al 2009, Blood 114:2476), and MEF2C expression defines a subset of AML patients with low survival (Lazlo et al 2015, J Hematol & Oncol 8:115).

[0012] Tarumoto et al. (2018, Mol Cell 69:1017) showed that MEF2C activity in AML is driven by SIK3 phosphorylation of HDAC4, and that SIK3 gene knockout or chemical inhibition by the small molecule tool compound HG-9-91-01 significantly reduced the survival of several MPAL-associated AML cell lines (including MOLM-13 and MV4-11); this is because cytoplasmic retention of SIK3-phosphorylated HDAC4 regulates the activity of MEF2C, a transcription factor associated with tumor survival / maintenance genes related to AML proliferation, by blocking nuclear localization (non-phosphorylated) HDAC4, which acts as a co-inhibitor of MEF2C. Figure 19In fact, recent studies have shown that SIK3 inhibition by the intraperitoneally administered small molecule tool compound YKL-05-099 inhibits the progression of AML in vivo (Tarumoto et al 2020, Blood 135:56). However, more SIK3 inhibitors are still needed, especially those with drug-like properties and particularly those that can be administered orally for the treatment of proliferative diseases (e.g., MPAL), particularly those inhibitors related to the expression of cancer survival genes controlled by SIK3-driven MEF2C.

[0013] There is also a need for novel kinase inhibitors for the treatment of myeloid or lymphoblastic carcinoma, such as leukemia, preferably for the treatment of one or more Ph+ leukemias, such as CML and / or ALL.

[0014] Dasatinib is described as an inhibitor of the following kinases at nanomolar concentrations: BCR-ABL, SRC family (SRC, LCK, YES, FYN), c-KIT, EPHA2, and PDGFR-β; its inhibitory effect on the heterozygous protein kinase BCR-ABL is particularly relevant to the indication of dasatinib in Ph+ leukemia.

[0015] BCR-ABL kinase is directly associated with a specific genetic abnormality on chromosome 22 in leukemia cancer cells, particularly CML cells; this is known as the "Philadelphia chromosome" (or Philadelphia translocation). This translocation of genetic material between chromosomes 9 and 22 places the ABL1 gene from chromosome 9 onto the BCR gene on chromosome 22, creating a sequence that encodes a heterozygous protein called "BCR-ABL": a "perpetually active" tyrosine kinase that causes cells to divide uncontrollably. The vast majority of CML cases and 20-30% of ALL cases are Ph+. The first selective BCR-ABL inhibitor, imatinib (STI571), marketed by Novartis as "GLEEVEC / GLIVEC," was considered a breakthrough in the treatment of Ph+ leukemia. However, despite the increase in overall survival, the resistance that develops during imatinib treatment has led scientists to discover that most of this resistance is due to the emergence of BCR-ABL mutations, particularly amino acid substitutions within the ABL-derived kinase domain (for the review, see Rossari & Orciuolo. 2018, J. Hemat. Oncol. 11:84, which is incorporated herein by reference in its entirety).

[0016] Analysis of BCR-ABL mutation status and survival probability in imatinib-treated patients showed that mutations within the phosphatase loop (P loop) of the ABL site of the BCR-ABL kinase were most frequent, but mutations outside the P loop (especially within the kinase domain) were (less common) associated with decreased overall survival in CML patients treated with imatinib (Jabbour et al. 2006, Leukemia 20:1767). Many new BCR-ABL mutations have been identified and described (see Table 1 in Manley et al. 2005, Biochem. Biophys. Acta 1754:3 and Table 1 in Rossari & Orciuolo 2018, which also describes mutations at other kinase targets of dasatinib; these tables are incorporated herein by reference). Specifically, the following mutations were found in the ATP-binding region of BCR-ABL (indicating the location of wild-type ABL protein): V299L, F311L, T315I, T315A, F317L, and F317V. In fact, dasatinib was initially developed as a "second-generation" BCR-ABL inhibitor for second-line treatment of CML that had developed resistance to imatinib, presumably due to the presence of one or more of these mutations. Based on model studies, dasatinib was predicted to bind to multiple conformations of ABL kinases, which was thought to explain why dasatinib inhibits several conformational mutations in ABL, while imatinib does not. Indeed, a retrospective analysis comparing mutation development during first-line treatment with dasatinib or imatinib showed fewer distinct mutation sites with dasatinib treatment (4 distinct sites) compared to imatinib treatment (12 distinct sites) (Hughes et al. 2015, Leukemia 29:1832, particularly its…). Figure 1 However, it is important to note that: (i) the overall proportion of patients with any type of mutation was roughly the same (17 / 259 patients with dasatinib and 18 / 260 patients with imatinib); (ii) most mutation sites that appeared after dasatinib treatment were located in the ATP-binding region (3 / 4 mutation sites); and (iii) the most common mutation that appeared during dasatinib treatment (11 / 17) was the T315I mutation at a residue known as the “gatekeeper”, which still makes BCR-ABL kinase resistant to dasatinib inhibition. A specific set of BCR-ABL mutants that can be tested against kinase inhibitors is provided by the ProQinase ABL1 kinase “wild-type and mutant set”, including the wild-type ABL1 protein (amino acids P118-S525) and mutant forms representing the most common imatinib-resistant mutant forms of BCR-ABL: G250E, Q252H, Y253F, E255K, T315I, F317I, M351T, and H396P (www.proqinase.com).

[0017] The T315I mutation is one of the most common BCR-ABL mutations, occurring in 2% to 20% of CML cases (Nicolini et al. 2009, Blood 114:5271). This mutation is resistant to dasatinib inhibition, a potential drawback of dasatinib as a kinase inhibitor, which spurred the development of a “third-generation” BCR-ABL inhibitor called ponatinib (marketed as ICLUSIG by Incyte & Takeda). However, while ponatinib does strongly inhibit the T315I mutation of BCR-ABL kinase (in vitro IC50 of 2.0 nM), it is known to be a more heterogeneous kinase inhibitor than dasatinib and also inhibits many other kinases in vitro at concentrations with IC50s between 0.1 and 20 nM, including at least VEGFR, PDGFR, FGFR, EPH receptor, and members of the SRC family of kinases, as well as KIT, RET, TIE2, and FLT3. Furthermore, ponatinib's sales in the United States were suspended in October 2013 due to the "risk of life-threatening thrombosis and severe vascular stenosis." This suspension was partially lifted in December 2013, following the release of revised prescribing information, a new "black box warning," and "risk assessment and mitigation strategies" to better assess the risks and benefits of using the drug. Additionally, ponatinib's price in the United States (potentially $138,000 per year) has also drawn criticism. Therefore, ponatinib has demonstrated substantial drawbacks, and new kinase inhibitors remain needed, particularly those that are more likely to be effective, safe, readily available, and / or inexpensive for treating Ph+ leukemia (or other cancers); and / or inhibitors that are more selective for SRC, ABL / BCR-ABL, and / or LCK than other kinase inhibitors (such as dasatinib or ponatinib).

[0018] However, compared to imatinib, dasatinib is not particularly specific to BCR-ABL, but rather binds to and / or inhibits a large number of other kinases (see Bantscheff et al. 2007, Nat. Biotech. 25:1035). Figure 3 ; Anastassiadiset al. 2012, Nat. Biotech. 29:1039 (supplement) Figure 2In particular, compared with imatinib, dasatinib has been described as binding to and / or inhibiting many other kinases more significantly, including BTK, CSK, EPHB2, EPHB4, FYN, GAK, KIT, LYN, QIK, QSK, RIPK2, SRC, TEC, TESK2, YES, and ZAK. More specifically, dasatinib is an important inhibitor of salt-induced kinases, with IC50 values ​​of <3 nM, <3 nM, and 18 nM for members of the three families SIK1, SIK2, and SIK3, respectively (Ozanne et al. 2015, Biochem. J. 465:271; also as described in the concurrently pending PCT / EP2018 / 060172). In fact, considering that dasatinib is a less selective kinase inhibitor (which is another potential drawback), this reduced selectivity may be related to the insignificant toxicity challenges faced when treating patients with dasatinib, particularly the increased incidence of thrombocytopenia (Wei et al. 2010, J. Hemat. Oncol. 3:47).

[0019] As mentioned above, dasatinib is a potent KIT inhibitor, and this receptor tyrosine kinase is becoming an increasingly interesting target for the treatment of certain cancers (Babei et al. 2016, Drug Des.Dev.Thera., 10:2443), especially since mutations in the KIT gene have been detected in cancers such as leukemia, ovarian cancer, and melanoma. Dasatinib is known to also inhibit at least the most common KIT mutations in melanoma (Woodman et al. 2009, J.Clin.Onc. 27:9019). However, KIT inhibition, particularly the relative activity of certain tyrosine kinase inhibitors against FLT3 and KIT, is associated with myelosuppression and other side effects such as hair discoloration (Galanis and Levis 2015:Haematologica 100:e89). In fact, dasatinib treatment has been associated with severe myelosuppression (see below).

[0020] Salt-inducible kinases (SIKs) constitute the serine tyrosine kinase subfamily, belonging to the adenosine monophosphate activated kinase (AMPK) family. Three members (SIK1, -2, and -3) have been identified to date. SIK1 shares 78% and 68% amino acid homology with SIK2 and SIK3 in the kinase domain, respectively. Cloning of SIK1 (also known as SIK and SNF1LK), which is highly expressed in the adrenal glands of rats fed a high-salt diet, led to subsequent cloning of SIK2 (also known as QIK, KIAA0781, and SNF1LK2), which is predominantly expressed in adipose tissue, as well as the fairly common SIK3 (also known as QSK, KIAA0999, or L19) (Katohe et al. 2004, Mol. Cell. Endocrinol. 217:109). These three SIKs share similar structures, possessing an N-terminal kinase domain (catalytic domain), an intermediate ubiquitin-associated domain (considered important for phosphorylation via LKB1), and a long C-terminal sequence (considered a site for further phosphorylation via PKA). However, the different SIKs are involved in very different roles. For example, various SIKs are involved in different biological processes, such as the response of osteocytes to parathyroid hormone (Weine et al. 2016, Nature Commun. 7:13176), SIK1 induction via gastrin, and inhibition of gastric adenocarcinoma cell migration (elvik et al. 2014, PLoS ONE 9:e112485). Other potential roles of salt-induced kinases (especially SIK3) are described in WO2018 / 193084A1 (published by the applicant on October 25, 2018). Furthermore, SIK3 is a gene involved in tumor cell resistance to cell-mediated immune responses, particularly tumor cell resistance to TNF. Recently, SIK (especially SIK3) has been shown to regulate TGFβ-mediated transcriptional activity and apoptosis. Hutchinson et al. (2010, Cell Death and Disease 11:49) showed that expression or activity of SIK3 leads to resistance to TGFβ-mediated apoptosis.

[0021] In particular, in addition to its role in various inflammatory responses (Clark et al 2014; Sundberg et al 2016) and oncology—especially in the sensitivity of tumor cells to immune responses (WO2018 / 193084A1)—it has been known since 2011 that inhibition of SIK2 promotes melanin production in B16F10 melanoma cells (Kumagai et al 2011, PLoS ONE 6(10):e26148). Subsequently, the effective induction of pigmentation pathways, including those in human skin explants, by (topical) application of SIK inhibitors, including those associated with the structure of YKL-05-099, has been described (Mujahid et al 2017, Cell Reports 19:2177). In fact, based on these results, a method was subsequently sought to increase (the occurrence) of skin pigmentation in subjects by topically applying an effective amount of SIK inhibitors to the skin of subjects, including the use of kinase inhibitors previously known as SIK inhibitors (WO2016 / 023014) (WO2018 / 160774).

[0022] A kinase called colony-stimulating factor 1 receptor (CSF1R) binds to its ligand CSF1, and the resulting downstream signaling leads to the differentiation and survival of myeloid cells expressing the CSF1R receptor. In particular, CSF1-CSF1R signaling is crucial for macrophage differentiation into the more repressive M2 phenotype (Lenzo et al 2012, Immunol Cell Bio 90:429). Indeed, the presence of CSF1R+ macrophages in tumors is associated with low survival rates in various indications, including gastric cancer, breast cancer, ovarian cancer, and bladder cancer (Zhang et al 2012, PLoS One 7:e50946t). Therefore, targeting CSF1R with antibodies or small molecule inhibitors by eliminating or reculturing repressive M2 macrophages has become an important approach to cancer treatment. PLX3397 is an inhibitor that targets CSF1R and is currently in clinical development for melanoma, glioblastoma, AML, etc. (Cannarile et al 2017, J Immunotherapy Cancer 5:53).

[0023] Hematopoietic cell kinase (HCK) is a member of the cytoplasmic tyrosine kinase (SFK) SRC family and is expressed in myeloid and B-lymphocyte cell lines. Excessive HCK activation is associated with multiple types of leukemia and promotes cell proliferation and survival through physical interactions with oncogenic fusion proteins and functional interactions with receptor tyrosine kinases. Elevated HCK activity is also seen in many solid malignancies, including breast and colon cancer, and is associated with reduced patient survival. HCK promotes the secretion of myeloid cell growth factors and pro-inflammatory cytokines and promotes macrophage differentiation into a wound-healing and tumor-promoting alternating activation phenotype. In tumor-associated macrophages, HCK stimulation promotes the formation of pseudopodia bodies that degrade the extracellular matrix, thereby enhancing immunity and epithelial cell invasion. Due to the functional cooperation between HCK and true oncogenic tyrosine kinases, excessive HCK activation also reduces drug efficacy and leads to chemotherapy resistance, while HCK gene ablation results in minimal physiological consequences in healthy mice. Given its known crystal structure, HCK provides an attractive therapeutic target for both, directly inhibiting cancer cell growth and indirectly suppressing the source of tumor-promoting changes in the tumor microenvironment (Poh et al 2015, Oncotarget 6:15742).

[0024] Therefore, there remains a need for new kinase inhibitors, particularly those exhibiting drug-like properties (especially those suitable for oral administration) and inhibiting one or more kinases (including any selected from SIK3, ABL / BCR-ABL, SRC, HCK, PDGFR, KIT, and / or CSF1R), and / or particularly exhibiting a kinase spectrum different from that inhibited by dasatinib. For example, new kinase inhibitors that: (i) have stronger specificity for key disease-related kinases (e.g., ABL / BCR-ABL, SRC, LCK, HCK, PDGFR, CSFR1, and / or EPHA2, EPHA4, ACK1, and / or KIT) compared to dasatinib's specificity for one or more other kinases; (ii) inhibit key disease or side-effect-related kinases (e.g., KIT and / or FLT3) in a manner different from dasatinib; and / or (iii) inhibit one or more mutants of disease-related kinases, particularly mutants resistant to one or more other kinase inhibitors, such as mutants of ABL / BCR-ABL or KIT.

[0025] Furthermore, although dasatinib is primarily metabolized by the cytochrome P450 enzyme 3A4 (CYP3A4) in the human body, it is also a time-dependent inhibitor of CYP3A4. In fact, if a patient is concurrently taking a potent CYP3A4 inhibitor (such as ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole), the dose of dasatinib must be significantly reduced (e.g., from 100 mg daily to 20 mg daily), as this may increase plasma concentrations of dasatinib to potentially unsafe levels. Grapefruit juice may also increase plasma concentrations of dasatinib and should also be avoided. Therefore, there is still a need for novel kinase inhibitors that exhibit a different cytochrome P450 inhibition pattern than dasatinib (e.g., against CYP3A4).

[0026] Importantly, once myelosuppression occurs, the dosage and administration of dasatinib should be discontinued (or reduced). In fact, in the US prescribing information for dasatinib, myelosuppression is only described as a “warning and precaution” because dasatinib treatment has been associated with severe (NCI CTC grade 3 or 4) thrombocytopenia, neutropenia, and anemia. In addition to causing thrombocytopenia in human subjects, in all dasatinib clinical studies: (i) 1% of patients experienced severe central nervous system bleeding (including death); (ii) 4% of patients experienced severe gastrointestinal bleeding, including death, which usually required interruption of treatment and transfusion; and (iii) 2% of patients experienced other serious bleeding.

[0027] Further “warnings and precautions” for dasatinib include: (x) its association with fluid retention, with severe fluid retention observed in up to 10% of patients in clinical trials; (y) its potential to prolong ventricular repolarization (QT interval), with QT prolongation observed in up to 1% of CML patients in clinical trials; and (z) in 258 patients taking dasatinib, 5.8% experienced cardiac adverse events, including cardiomyopathy, congestive heart failure, diastolic dysfunction, fatal myocardial infarction, and left ventricular dysfunction in 1.6%. In fact, dasatinib is known to be an inhibitor of hERG (Pharmacological / Toxicity Review and Evaluation of NDA 21-986, page 31). hERG (human Ether-a-go-go related gene) is an ion channel that contributes to the electrical activity of the heart and coordinates its beating. When the ability of this channel to conduct current across the cell membrane is inhibited or impaired (e.g., through drug administration), it can lead to potentially fatal “long QT syndrome.” Therefore, there remains a need for novel kinase inhibitors that exhibit inhibitory activity against hERG, distinct from dasatinib. For example, novel kinase inhibitors offering a higher IC50 for hERG than dasatinib would be advantageous.

[0028] In fact, the main metabolic pathway of dasatinib includes the metabolic pathway following its chloro / methylphenyl or piperazine modification (e.g., Christopher et al. 2008, Drug Metab & Disp 36:1357, particularly the one involving...). Figure 4 In particular, the formation of CYP3A4-mediated reactive epoxide and quinone imine intermediates can form the active metabolite of dasatinib, which can covalently bind to biomolecules such as CYP proteins (Duckett & Cameron 2010, Expert OpinDrug Metab Toxicol 6:1175), promoting the toxicity of dasatinib observed in humans and / or causing drug interactions with other CYP substrates (such as simvastatin).

[0029] Therefore, there is still a need for other kinase inhibitors (e.g. in humans) that exhibit a different metabolite profile than dasatinib, especially those with one or more major metabolic pathways that differ from dasatinib (particularly dasatinib modified with chloro / methylphenyl and / or piperazine).

[0030] Compared to other BCR-ABL inhibitors, dasatinib has a very short half-life: the overall mean terminal half-life is only 3–5 hours (see Section 12.3, “Pharmacokinetics,” for full prescribing information). This contrasts sharply with imatinib, which has an elimination half-life of approximately 18 hours; bosutinib, with a mean terminal elimination half-life of 22.5 hours; nilotinib, with an apparent elimination half-life of approximately 17 hours; and ponatinib, with a geometric mean terminal elimination half-life of approximately 24 hours. Without theoretical constraints, dasatinib's shorter half-life—applicable to a once-daily dose—may explain the limited activity associated with lower drug concentrations later in the day and / or the side effects associated with peak / higher drug concentrations shortly after administration. Therefore, there remains a need for new kinase inhibitors with longer half-lives (e.g., longer than the half-life shown by dasatinib). For example, a favorable kinase inhibitor could be a more stable inhibitor than dasatinib, for instance, by exhibiting a longer half-life in plasma and / or liver microsomal stability assays.

[0031] Further precautions, adverse events, and other prescribing information for dasatinib can be found in the Summary of Product Characteristics (SmPC) of the complete prescribing information on the respective websites of the EMA and FDA (accessed August 20, 2018, and whose entire contents are incorporated herein by reference): (i) http: / / www.ema.europa.eu / docs / en_GB / document_library / EPAR_Product_Information / human / 000709 / WC500056998.pdf and (ii) https: / / www.accessdata.fda.gov / drugsatfda_docs / label / 2010 / 021986s7s8lbl.pdf.

[0032] Several variants of dasatinib have been synthesized and demonstrated to possess in vitro biochemical inhibitory activity against one or more kinases and / or antiproliferative activity against cells. Specifically, these variants have been synthesized to: (i) understand and characterize the structure-activity relationship (SAR) of dasatinib during its discovery phase (Lombardo et al 2004, J Med Chem 47:6658; Das et al 2006, J Med Chem 49:6819); and (ii) provide alternative kinase inhibitors and / or drug candidates (e.g., WO 2006 / 081172 and WO 2008 / 033746). The dasatinib variants described herein carry a phenyl moiety at the formamide site. These disclosures demonstrate that other positions and a large number of substituents that can be substituted thereto provide compounds that are kinase inhibitors and / or possess antiproliferative activity against cells. Figure 8).

[0033] WO 2018 / 193084 (the applicant, published on October 25, 2018) discloses dasatinib variants carrying a pyridyl moiety and their uses. The pending application PCT / EP2019 / 078751 (the applicant) further discloses dasatinib variants carrying other heterocyclic moieties, particularly variants carrying a thiazolyl moiety. Beutner et al. (2018, OrgLett 20:4218) describe a method for forming challenging amide bonds, including amide bonds linked to certain pyridines, pyrazines, and pyrimidines. Pennington et al. (2017, J Med Chem 60:3552) describe the effects of substituting a CH group with an N atom in aromatic and heteroaromatic ring systems on molecular and physiological properties. However, empirical evidence suggests that such substitutions do not statistically improve potency better than mere chance: Matched molecular pair analysis (MMPA) of Abbott's internal data (Hajduk & Sauer 2008, J Med Chem 51:553) found that, as with most substituents, the probability of increasing or decreasing potency by exchanging the CH group and the N atom is roughly equal. In fact, the analysis further indicates that the probability of achieving a 10-fold increase in potency with such a substitution is less than one in ten, and the probability of achieving a 100-fold increase is less than one in hundred; similar to the probabilities observed when studying the effects of such substitutions on improving binding affinity (Hu et al 2014, F1000Research 3:36; de la Vega de Leon et al 2014, MedChemComm 5:64).

[0034] Therefore, one object of the present invention is to provide one or more kinase inhibitors (e.g., inhibitors of SIK3, ABL / BCR-ABL, SRC, HCK, PDGFR, KIT, and / or CSF1R kinases) having one or more properties (e.g., properties shown in in vitro and / or in vivo studies) that address one or more of these or other problems. Among other objects, the present invention provides alternatives to and / or improvements to dasatinib (or one or more other kinase inhibitors, such as those described herein). For example, kinase inhibitors that differ from and / or are improved compared to dasatinib (or one or more other kinase inhibitors, such as those described herein) in terms of one or more functionalities (e.g., kinase selectivity), ADMET, PK, and / or pharmacological properties would be advantageous. In particular, it would be advantageous to provide one or more SIK family kinase inhibitors with similar pharmaceutical properties, especially those that can be administered orally for the treatment of proliferative disorders (e.g., MPAL), characterized (in particular) by the presence of MEF2C protein (e.g., phosphorylated MEF2C protein and / or MEF2C protein as an active transcription factor), human chromosomal translocation at 11q23, and / or KMT2A fusion oncoprotein. The objectives upon which this invention is based are addressed by the subject matter disclosed or defined anywhere herein, such as by the subject matter of the appended claims. Invention Overview

[0036] Generally, the main aspects of the present invention can be summarized as follows through a brief description:

[0037] In a first aspect, the present invention provides a compound selected from kinase inhibitors of the following formula:

[0038]

[0039] And its solvates, salts, nitrogen oxides, complexes, polymorphs, crystalline forms, racemic mixtures, diastereomers, enantiomers, tautomers, conformational isomers, isotopic labeled forms, prodrugs, and combinations thereof; among which Hy and R 2 R 3 R 4 R 5 A and E are as defined in this article.

[0040] In a second aspect, this application provides a pharmaceutical composition comprising the compound of the first aspect and optionally a pharmaceutically acceptable excipient.

[0041] In a third aspect, this application provides a compound for treatment in the first aspect or a pharmaceutical composition for treatment in the second aspect.

[0042] In a related aspect, the present invention provides a method for treating a disease, symptom, or condition of a subject, comprising administering a compound of the first aspect or a pharmaceutical composition of the second aspect to the subject, optionally wherein the disease, symptom, or condition is related to a kinase.

[0043] In a fourth aspect, this application provides a compound of the first aspect or a pharmaceutical composition of the second aspect for use in treating proliferative diseases in subjects (especially human patients).

[0044] In a related aspect, the present invention provides a method for treating a proliferative disease in a subject, comprising administering a compound of the first aspect or a pharmaceutical composition of the second aspect to the subject.

[0045] In a fifth aspect, this application provides a compound or pharmaceutical composition for treating a proliferative disease in a subject, the treatment comprising administering the compound or pharmaceutical composition to the subject, wherein the compound is selected from the group consisting of (a) to (c), or the pharmaceutical composition comprises the compound and optionally a pharmaceutically acceptable excipient:

[0046] (a) The compound of the first aspect;

[0047] (b) Compounds having the following formula:

[0048]

[0049] And solvates, salts, nitrogen oxides, complexes, polymorphs, crystalline forms, racemic mixtures, diastereomers, enantiomers, tautomers, conformational isomers, isotopic labeled forms, prodrugs and combinations thereof; among which Hy and R 2 R 3 R 4 R 5 ', A and E are as defined herein; and

[0050] (c) Compounds having the following formula (Ic):

[0051]

[0052] And solvates, salts, nitrogen oxides, complexes, polymorphs, crystalline forms, racemic mixtures, diastereomers, enantiomers, tautomers, conformational isomers, isotopic labeled forms, prodrugs, and combinations thereof; wherein R 1a R 1b R 1c R 2 R 3 R 4 R 5” A, B, and E are as defined in this paper;

[0053] And the proliferative disease mentioned therein is selected from one or more of (α) to (γ):

[0054] (α) A proliferative disease, characterized (or characterized in cells associated with a proliferative disease by) the presence of myocyte enhancement factor 2C (MEF2C) protein, such as phosphorylated MEF2C protein and / or MEF2C protein as an active transcription factor; preferably, the proliferative disease is further characterized by the presence of phosphorylated histone deacetylase 4 (HDAC4) protein, such as SIK3 phosphorylated HDAC4 protein; and / or

[0055] (β) Proliferative disorders, characterized (or cells associated with proliferative disorders, characterized) by: (i) a human chromosomal translocation at 11q23; (ii) a rearrangement of the lysine methyltransferase 2A (KMT2A) gene; (iii) the presence of a KMT2A fusion oncoprotein; and / or (iv) mutations in the K-RAS proto-oncogene GTPase (KRAS) gene and / or in the RUNX family transcription factor 1 (RUNX1) gene; and / or

[0056] (γ) Mixed phenotype acute leukemia (MPAL).

[0057] In a related aspect, the present invention provides a method for treating a proliferative disease in a subject, comprising administering to the subject a compound or pharmaceutical composition as defined in the fifth aspect, wherein the proliferative disease is as defined in the fifth aspect.

[0058] On the other hand, this application provides a method for determining whether a subject suffering from a proliferative disease is suitable for treatment with a compound or pharmaceutical composition as defined in the fifth aspect, the method comprising determining, in a biological sample obtained from said subject:

[0059] (X) The presence of MEF2C protein, such as phosphorylated MEF2C protein and / or MEF2C protein as an active transcription factor; preferably, the proliferative disease is further characterized by the presence of phosphorylated HDAC4 protein, such as HDAC4 protein phosphorylated by SIK3; and / or

[0060] (Y)(i) the presence of a human chromosomal translocation at 11q23; (ii) the presence of a KMT2A gene rearrangement; (iii) the presence of a KMT2A fusion oncoprotein; and / or (iv) the presence of a mutation in the KRAS gene and / or the RUNX1 gene, wherein the presence of the protein, translocation, rearrangement, oncoprotein, and / or mutation in the biological sample indicates that the object is suitable for the treatment of the compound or pharmaceutical composition.

[0061] In another aspect, the present invention relates to a method for increasing skin pigmentation (or increasing the appearance of skin pigmentation) in a subject, the method comprising administering to the subject (e.g., an effective amount) a kinase inhibitor (or a pharmaceutical composition comprising the compound) used in the fifth aspect.

[0062] On the other hand, this application provides an intermediate selected from compounds having formula (Id):

[0063]

[0064] And solvates, salts, complexes, polymorphs, crystalline forms, racemic mixtures, diastereomers, enantiomers, tautomers, conformational isomers, isotopic labeling forms and combinations thereof, wherein R 40 and R 41 As defined in this article.

[0065] On the other hand, this application provides a method for preparing a compound comprising an amide moiety, the method comprising reacting an intermediate of the invention with a corresponding carboxylic acid, and optionally removing an amino protecting group.

[0066] Other aspects of the invention are also disclosed herein.

[0067] Brief description of the attached figures

[0068] The attached image shows:

[0069] Figure 1 Describe the chemical structures of the following compounds: (A) dasatinib (compound A8), N-(2-chloro-6-methylphenyl)-2-((6-(4-(2-hydroxyethyl)-1-piperazinyl)-2-methyl-4-pyrimidinyl)amino)-5-thiazolecarboxamide; (B) kinase inhibitor B3, N-(4-chloro-2-methylpyridin-3-yl)-2-((6-(4-(2-hydroxyethyl)-1-piperazinyl)-2-methyl-4-pyrimidinyl)amino)-5-thiazolecarboxamide; (C) certain other kinase inhibitors of formula (Ib) / (Ic) C1 to C13; (D) certain further kinase inhibitors of formula (Ib) / (Ic) D1 to D10; and (E) certain kinase inhibitors of formula (Ia) E1 to E16.

[0070] Figure 2The inhibitory activities of the kinase inhibitors of formula (Ib) / (Ic) (B3, left column) against kinases (A)ABL1, (B)SRC, (C)SIK1, (D)SIK2, and (E)SIK3, compared to dasatinib (A8, right column), are described (in A through E). The inhibitory activities of other kinase inhibitors of formula (Ib) / (Ic) (C3, left column; C12, right column) against kinases (F)ABL1, (G)SRC, (H)SIK1, (I)SIK2, and (J)SIK3, are also described (in F through J). X-axis: compound concentration (M); Y-axis: kinase activity (%).

[0071] Figure 3 : Describe the selectivity of kinase inhibition by percentage of residual activity (at 1 μM of compound) for B3 (a kinase inhibitor of formula (Ib) / (Ic), dasatinib (A8), and C7 (another kinase inhibitor of formula (Ib) / (Ic)): **** <25% residual activity; ***25% to <50% residual activity;

[0072] **50% to <75% residual activity; *>75% residual activity. Classification of protein kinase families (Manning et al. Science 6 December 2002: Vol.298 no.5600 pp.1912-1934): AGC: includes the PKA, PKG, and PKC families; CAMK: calcium / calmodulin-dependent protein kinase; CK1: casein kinase-like; CMGC: includes the CDK, MAPK, GSK3, and CLK families; TK: tyrosine kinase; TKL: tyrosine kinase-like; STE: homologues of yeast kinases 7, 11, and 20. ## Constitutive active kinases.

[0073] Figure 4 : Describe the selectivity of the kinase inhibitor B3 of formula (Ib) / (Ic) (X-axis) for kinase inhibition compared with dasatinib (A8; Y-axis) (as a percentage of residual activity of 1 μM compound): (A) axis shows the full range of residual activity; (B) axis shows the range of residual activity from 0 to 50%.

[0074] Figure 5 Description of the inhibitory activities of the kinase inhibitors of formula (Ib) / (Ic) (B3, left column) against kinases (A) FLT3, (B) SYK, (C) KIT, and (D) LCK, compared to dasatinib (A8, right column). X-axis: compound concentration (M) and Y-axis: kinase activity (%).

[0075] Figure 6The figures describe the sensitivity of tumor cells to in vitro TNF attack by (A) kinase inhibitors B3 and (B) A8 (dasatinib); circles: compounds (concentrations shown in the figure) with rHuTNF (10 ng / mL); squares: compounds alone (concentrations shown in the figure) without rHuTNF.

[0076] Figure 7 The relative tumor cell viability (RLU normalized by cytotoxicity / viability) in assays using certain kinase inhibitors described in PCT / EP2018 / 060172 at different concentrations of M579-A2-luc as described in Example 9, alone (squares) or in combination with 10 ng / mL TNF (circles), is described. Indicative inhibitory activity of the compound against SIK family members and related kinases ABL1 and SRC is also shown, along with the indicators used in Table 3. (A) Pan-SIK and ABL1 & SRC inhibitor, compound B1; (B) ABL1 & SRC inhibitor, compound B8; (C) SIK1, SIK2, and ABL1 & SRC inhibitor, compound B4.

[0077] Figure 8 Description: (A) Cellular antiproliferative activity of dasatinib variants taken from Table 1 of Lombardo et al 2004 (J Med Chem 47:6658), showing the potency of various derivatives of dasatinib against the cell lines shown. Antiproliferative activity was determined based on tetrazolium dye conversion after 72 h of compound exposure. IC50 values ​​are reported as the average of at least three individual measurements, or as individual IC50 values ​​in cases of fewer than three measurements. Variance around the average is <50% unless the SE value in parentheses indicates otherwise; (B) Biochemical and cellular antiproliferative activity of dasatinib variants from Table 4 of Das et al 2006 (J Med Chem 49:6819). an = 3, variation in individual values, <20%. bn = 3, individual values, <30%.

[0078] Figure 9 The description shows the selectivity of the kinase inhibitor C7 (Y-axis) of formula (Ib) / (Ic) for kinase inhibition compared to (A) dasatinib (A8; X-axis) and (B) another kinase inhibitor B3 (X-axis) of formula (Ib) / (Ic), which is the percentage of residual activity of the compound at 1 μM. The dashed areas highlight the kinase groups that are significantly inhibited among the applicable compounds.

[0079] Figure 10Description of body weight in female C57Bl / 6 mice after administration of C7 at different concentrations (33 mg / kg, black squares) and 100 mg / kg, twice daily (BID, gray squares) via tube feeding, compared to control animals (gray squares). X-axis: Number of days after administration; Y-axis: Change in body weight (%). (C) Plasma levels of C7 were determined by LC-MS / MS. A = 33 mg / kg QD; B = 100 mg / kg QD; C = 33 mg / kg BID; D = 100 mg / kg BID. Y-axis: Plasma concentration of C7 (nM).

[0080] Figure 11 (A) Description of tumor growth kinetics in mice treated with excipients (black squares), C7 100 mg / kg QD (gray hexagons), C7 100 mg / kg BID (gray triangles), and A8 (dasatinib) 30 mg / kg QD A8 (gray circles); Y-axis = mean tumor volume (mm3). Error bars were observed using SEM. X-axis: number of days. Statistical significance was calculated using two-way ANOVA, including Tukey multiple comparisons. ***p < 0.001; (B) Description of mouse body weight kinetics in (A). Y-axis: mean body weight change (%).

[0081] Figure 12 The immuno-oncological effects of compound C7 (Ib) / (Ic) on immune cells present in the tumor microenvironment were described. Intratumoral immune infiltration was calculated as the percentage of CD45+ cells within the tumor. Statistical significance was calculated using one-way ANOVA, including Tukey multiple comparisons analysis. (A) Y-axis: Ratio of CTLs to Treg cells. (B) Activated CTLs (CD25+CD69+); Y-axis: Percentage of CD45+ cells. (C) Activated CTLs (granzyme B+); Y-axis: Percentage of CD45+ cells. (D) Immunosuppressive M2-like tumor-associated macrophages (TAMs) (CD206+MHC-II+); Y-axis: Percentage of CD45+ cells; *p<0.05; **p<0.01; ***p<0.00.

[0082] Figure 13Describe the killing effect of TNF on cells sensitive to compound C7. (A) TNF-induced apoptosis in PANC-1 cells. PANC-1 cells were treated with 370 nM (“rhombus”), 3333 nM (“square”) of C7 and DMSO alone (“star”) for 120 h, followed by the addition of 100 ng / ml rHuTNF (+rHuTNF = hollow shape; -rHuTNF = solid shape; hollow circle 10 ng / ml rHuTNF control group). Cell death was assessed using real-time live-cell microscopy, measuring nuclear incorporation of YOYO-1 dye (area of ​​YOYO-1+ cells / well). Y-axis = tumor cell death (µm² / well). X-axis = time (h); (B) Effect of C7 on TNF-induced (100 ng / ml rMuTNF) apoptosis in mouse MC38 cells (+rMuTNF = “rhombus”; -rMuTNF = “circle”). Cell viability was determined by CellTiter-Glo after 72 h. Luciferase values ​​were normalized to cells treated with inhibitor-free rHuTNF (DMSO only). Y-axis = viability (%). X-axis = compound concentration (nM).

[0083] Figure 14 Description: (A) Effect of compound C7 on NFKB activity. PANC-1 reporter cells expressing luciferase under the control of the NFKB promoter were treated with different concentrations of C7 for 8 hours, followed by the addition of 10 ng / mL rHuTNF (+rMuTNF = "diamond"; -rMuTNF = "circle"). Luciferase activity was normalized to PANC-1 cells treated with inhibitor-free rHuTNF (DMSO only). Y-axis = NFKB activity (%). X-axis = compound concentration (nM); (B) Effect of compound C7 on HDAC4 phosphorylation. PANC-1 cells were treated with different concentrations of C7 (in the presence of 10 ng / mL rHuTNF) for 3 hours. Whole-cell lysates were analyzed in a Meso Scale Discovery (MSD) assay using an anti-HDAC4 capture antibody and an anti-pHDAC4 detection antibody. HDAC4 phosphorylation was normalized to untreated PANC-1 cells (DMSO only). Y-axis = HDAC4 phosphorylation (%). X-axis = compound concentration (nM).

[0084] Figure 15 Description: The growth-inhibiting effect of compound C7 on WSU-NHL(A) and DOHH-2(B) cell lines is shown with GI50 values ​​of approximately 8 nM and 9 nM, respectively. X-axis: compound concentration (M); Y-axis: percentage of growth inhibition (GI) at 96 hours.

[0085] Figure 16Description of kinase inhibitory selectivity (based on % residual activity of 0.1 μM compounds): (A) kinase inhibitor E9 (X-axis) of formula (Ia) compared to E10 (Y-axis); and (B) C7 (X-axis) compared to kinase inhibitor E4 (Y-axis) of formula (Ia).

[0086] Figure 17 Describe the differential inhibition of MAP3K11 and NEK11 kinases by compound C7 (X-axis) and the kinase inhibitor E10 of formula (Ia) (Y-axis: % residual activity) at: (A) 1 μM compound concentration; and (B) 0.1 μM compound concentration.

[0087] Figure 18 The activity of the SIK3 inhibitors disclosed herein against MEF2C-expressing AML cell lines is described as follows: (A) Compound C7 exhibits strong lysis of a group of AML cell lines containing phosphorylated MEF2C protein; (B) Compound C7 shows highly efficient cytotoxicity against pMEF2C-positive KASUMI-1 cell lines; and (C) Compound C7 shows low cytotoxicity against pMEF2C-negative HEL cell lines.

[0088] Figure 19 : A schematic diagram illustrating SIK3-mediated control of survival / maintenance gene (a) expression via phosphorylation of the cardiomyocyte enhancer factor 2C (MEF2C) transcription factor. MEF2C overexpression is associated with the presence of a lysine methyltransferase 2A (KMT2A) protein (formerly known as “MLL”; (b)) fusion, typically caused by a human chromosomal translocation at 11q23. MEF2C activity is controlled by the presence of HDAC4 in the nucleus, which acts as an inhibitory cofactor, and its retention in the cytoplasm is induced by SIK3 phosphorylation. Nuclear entry and presence of unphosphorylated HDAC4 (c) (thus reducing tumor survival / maintenance gene (a) expression by inhibiting MEF2C transcription factor activity) can be achieved by inhibiting SIK3 with the compound (d) disclosed herein.

[0089] Figure 20: Describe the tumor growth kinetics of mice implanted with MC38 cells in (A) and treated with the following methods: (1) Controls: ratIgG2a 10 mg / kg (black solid square), aPD-1 10 mg / kg 3q7d (light gray hollow cross circle) and excipient (light gray solid inverted triangle); compounds E10 30 mg / kg BID (gray hollow inverted triangle), E4 40 mg / kg BID (dark gray solid circle), E9 25 mg / kg BID (light gray solid square), E9 50 mg / kg BID (dark gray solid triangle) and C7 100 mg / kg BID (light gray solid rhombus). Y-axis = mean tumor volume (mm3). One-way ANOVA, including Tukey multiple comparison analysis, was used to calculate the statistical significance of error bars SEM. X-axis = number of days. (B) The probability of tumor volume <1000 mm3 in mice in (A). Y-axis: Probability of tumor volume <= 1000 mm3 after treatment. X-axis: Number of days. For (A) and (B), controls: ratIgG2a (a), aPD-1 10 mg / kg (b), and excipient (c); and compounds: C7 100 mg / kg (d) BID, E4 40 mg / kg BID (e), E9 25 mg / kg BID (f), E9 50 mg / kg BID (g), and E10 30 mg / kg BID (h). (C) to (H) Mouse tumor growth curves; Y-axis: tumor volume (mm3), X-axis: number of days. (C) E9 25 mg / kg BID; (D) E9 50 mg / kg BID; (E) C7 100 mg / kg BID; (F) aPD-1 10 mg / kg; (G) ratIgG2a 10 mg / kg and (H) excipient.

[0090] Figure 21: Descriptive (Ia) kinase inhibitors on the immuno-oncological effects of immune cells present in the tumor microenvironment. Intratumoral immune infiltration was calculated as the percentage of CD45+ cells within the tumor. Statistical significance was calculated using one-way ANOVA, including Tukey multiple comparisons. (A) CD3+ T cells; (B) CD8+ T cells; (C) Activated CTLs (CD8+CD25+); (D) Activated CTLs (CD8+granzyme B+); (E) Regulatory T cells (CD25+, FoxP3+). Y-axis: Percentage of CD45+ cells. (F) CD11b+ myeloid cells; (G) Antitumor M1 tumor-associated macrophages (TAM) (CD206-MHC-II+); (H) Immunosuppressive M2 tumor-associated macrophages (TAM) (CD206+MHC-II-); (I) mMDSCs (Ly6C+); (J) gMDSCs (Ly6G+). Y-axis: percentage of CD45+ cells, *p<0.05; **p<0.01; ***p<0.001. X-axis: A = ratIgG2a (10mg / kg, 3q7d); B = aPD-1 (10mg / kg, 3q7d); C = excipient (BID); 1 = C7 (100mg / kg, BID); 2 = E4 (40mg / kg, BID); 3 = E9 (25mg / kg, BID); 4 = E9 (50mg / kg, BID); 5 = E10 (30mg / kg, BID).

[0091] Figure 22 Describes TNF-mediated cell killing induced by (A) compound E9 or (B) compound C7 in the presence of 5 ng / ml TNF in either the SIK3 knockout MC38 clone (triangle) or the SIK3 wild-type MC38 clone (square). Y-axis = activity, normalized to TNF-free. X-axis = inhibitor concentration, in nM.

[0092] Figure 23 Disease classification describing all known KMT2A fusion translocation partner genes (TPG) (adapted from Meyer et al 2018) Figure 3 All TPGs are grouped according to the type of disease they have diagnosed. These genes have been diagnosed with ALL, t-ALL, t-AML, AML, t-ALL, MLL, acute biphenotypic leukemia (BAL), MDS, t-MDS, chronic myeloid leukemia (CML), t-CML, juvenile myelomonocytic leukemia (JMML), and lymphoma. Genes at the crossover point belong to two different groups. TPGs marked in bold are the most common.

[0093] Figure 24This describes the pharmacokinetic curves of compounds E4 (circular), E9 (inverted triangle), and E10 (diamond) of formula (Ia) after administration of 30 mg / kg po, compared with the closely related compound C7 (square). Y-axis = total plasma compound concentration (ng / ml); X-axis = time (h).

[0094] Figure 25 Reproducibility of experiments using the descriptive formula (Ia) and compound C7 against MC38 tumor cells and TNF. Y-axis = EC50 tumor cell lysis (nM).

[0095] Figure 26 This section describes exemplary TNF-dependent dose-response curves for compound E9 compared to closely related compound C7, tested against various mouse tumor cell lines at different (mouse) TNF concentrations (rMuTNF concentrations: x = 0 ng / ml, y = 10 ng / ml, y = 100 ng / ml). Vertical bars: Normalized survival of the compound at the indicated rMuTNF concentrations. Left column: Compound E9; Right column: Compound C7, against: MC38 (A); CT26 (B); and EMT6 (C). Y-axis = survival (normalized to no compound); X-axis = compound concentration (nM).

[0096] Figure 27 This study describes the superior and more uniform tumor growth inhibition of compound E9 (24 mg / kg BID) in the MC38 syngeneic tumor model compared to dasatinib (30 mg / kg QD) (B). Left column = compound treatment group; Right column = excipient treatment group. Y-axis = tumor volume (mm3); X-axis = days post-inoculation.

[0097] Figure 28Description: Effects of compound E9 on NFKB activity (A) and (B). Reporter PANC-1 cells (A) or MC38 cells (B) expressing luciferase under the control of the NFKB promoter were treated with different concentrations of E9 for 8 hours, followed by the addition of 10 ng / ml rHuTNF (+rHuTNF = "diamond", EC50s = 405 nM for PANC-1 and 389 nM for MC38; -rHuTNF = "circle"). Luciferase activity was normalized to cells treated with rHuTNF without the inhibitor (DMSO only). Y-axis = NFKB activity (%). X-axis = compound concentration (nM); bar "A": viability without the compound and without TNF; bar "B": viability without the compound and with 10 ng / ml TNF; and (C) Effect of compound E9 on HDAC4 phosphorylation. PANC-1 cells were treated with different concentrations of E9 (in the presence of 10 ng / ml rHuTNF) for 3 hours. Whole-cell lysates were analyzed in a specific protein analyzer (MSD) using anti-HDAC4 capture antibody and anti-pHDAC4 detection antibody. HDAC4 phosphorylation was normalized for untreated PANC-1 cells (DMSO only). Y-axis = HDAC4 phosphorylation (%). X-axis = compound concentration (nM).

[0098] Figure 29 Describes the effects of compounds E9 and anti-PD-1mAB (alone or in combination) on in vivo tumor growth (mean + / - SEM) in the MC38 syngeneic tumor model. (A) Y-axis = tumor volume (mm3); X-axis = days after treatment initiation. Excipient + anti-PD-1mAB (square), excipient + mIgG1ectr (circle), E9 + anti-PD-1mAB (inverted triangle), and E9 + mIgG1ectr (triangle). (B) Median overall survival. Y-axis = survival probability (%); X-axis = days after treatment initiation. Excipient + anti-PD-1mAB (gray / dashed line), excipient + mIgG1ectr (black / solid line), E9 + anti-PD-1mAB (gray / solid line), and E9 + mIgG1ectr (black / dashed line). (C) to (D) Mouse tumor growth curves; Y-axis: tumor volume (mm3), X-axis: days after treatment initiation. (C) E9 25 mg / kg BID; (D) aPD-1 2.5 mg / kg; (E) E9 50 mg / kg BID + aPD-1 2.5 mg / kg and (F) excipients.

[0099] Figure 30Describe the effects of compound E9 (A) and (B) on in vivo tumor growth in an immune-exempt tumor model (EMT6) (mean + / - SEM). Y-axis = tumor volume (mm3); X-axis = days after treatment initiation. (A) Excipient BID (square), E9 25 mg / kg BID (triangle), E9 12.5 mg / kg BID (rhombus), and E9 5 mg / kg BID (circle). (B) Excipient BID (square), E9 25 mg / kg BID (triangle), and E9 25 mg / kg QD (inverted triangle).

[0100] Detailed Description of the Invention

[0101] The present invention and its specific non-limiting aspects and / or embodiments can be described in more detail below.

[0102] While the invention can be described in more detail, it should be understood that the invention is not limited to the specific methods, schemes, and reagents described herein, as they can vary. It should also be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the invention, which will be limited to the content described, defined, or otherwise disclosed herein, particularly in any detailed embodiments or appended claims.

[0103] Certain elements of the invention are described herein in more detail. These elements are set forth with particular embodiments; however, it should be understood that they can be combined in any manner and in any number to create additional embodiments. The various described embodiments and preferred embodiments should not be construed as limiting the invention to the explicitly described embodiments. The description of this application should be understood to support and include embodiments that combine the explicitly described embodiments with any number of disclosed and / or preferred elements. Furthermore, unless the context otherwise indicates, any permutation and combination of all elements described herein should be considered as disclosed in the specification of this application. For example, if in one embodiment of the compound of the invention L is a bond, while in another embodiment of the compound of the invention R 3 If H is present, then in the preferred embodiment of the compound of the present invention, L is a bond and R is a bond. 3 Yes, or if in one embodiment of the use of the compound of the present invention the subject is an adult, and in another embodiment the proliferative disease is prostate cancer, then in the preferred embodiment of the use of the compound of the present invention the subject is an adult and the proliferative disease is prostate cancer.

[0104] General definition

[0105] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0106] Preferably, the terms used herein are as defined in the “Multilingual Glossary of Biotechnology Terms: (IUPAC Recommendation)”, H.G. Leuenberger, B. Nagel, and H. Eds., Helvetica Chimica Acta, CH-4010 Basel, Switzerland, (1995).

[0107] Unless otherwise stated, the practice of this invention will employ conventional methods of chemical, biochemical, and recombinant DNA techniques, which are explained in the literature in this field (see, for example, Molecular Cloning: A Laboratory Manual, 2nd Edition, J. Sambrook et al. eds., Cold Spring Harbor Laboratory Press, Cold Spring Harbor 1989).

[0108] In this specification and the following claims, unless the context otherwise requires, the word “comprising” and variations such as “comprising” and “including” will be understood to imply the inclusion of the stated member, integer, or step, or member, integer, or group of steps, but not to exclude any other member, integer, or step, or member, integer, or group of steps. The term “consistently of” means excluding other members, integers, or steps, or members, integers, or groups of steps with any essential meaning. For example, a pharmaceutical composition substantially consisting of members / parts as defined herein (e.g., compounds as defined in any aspect of the invention and optionally an additional therapeutic agent) will exclude other therapeutic agents (other than compounds as defined in any aspect of the invention and optionally an additional therapeutic agent), but will not exclude trace amounts (e.g., the amount of contaminants (preferably all contaminants present in the compound) relative to the total composition, less than 5% by weight, such as less than 4% by weight, 3% by weight, 2% by weight, 1% by weight, 0.5% by weight, 0.4% by weight, 0.3% by weight, 0.2% by weight, 0.1% by weight, 0.1% by weight, 0.05% by weight) of contaminants (e.g., those derived from separation and purification methods) and / or pharmaceutically acceptable excipients (e.g., carriers, such as phosphate buffer solutions, preservatives, etc.). The term "consisting of" means excluding all other members, integers or significant steps, or groups of members, integers or significant steps. For example, a pharmaceutical composition comprising members / parts as defined herein (such as compounds, excipients, and optionally an additional therapeutic agent as defined in any aspect of the invention) does not include any other compound (including a second or more excipients) comprising more than 2% by weight of the total ingredients (such as any other compound, which is greater than 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, or 0.01% by weight) relative to the total ingredients. The term “comprising” includes the term “consistently composed of,” which in turn includes the term “composed of.” Therefore, whenever the term "comprising" appears in this application, it may be replaced with the terms "substantially composed of" or "composed of". Similarly, whenever the term "substantially composed of" appears in this application, it may be replaced with the terms "composed of".

[0109] When used herein, “and / or” will be considered as a specific disclosure of each of two particular features or elements, including or excluding the other. For example, “X and / or Y” will be considered as a specific disclosure of each of (i) X, (ii) Y, and (iii) X and Y, as if each were listed separately herein.

[0110] In the context of this invention, the terms "about" and "approximately" are used interchangeably to indicate a precise range that a person skilled in the art would understand to still ensure the technical effect of the stated feature. This term typically indicates a deviation from the indicated value of ±5%, ±4%, ±3%, ±2%, ±1%, ±0.9%, ±0.8%, ±0.7%, ±0.6%, ±0.5%, ±0.4%, ±0.3%, ±0.2%, ±0.1%, ±0.05%, for example, ±0.01%. As will be understood by a person skilled in the art, for a given numerical value of technical effect, this specific deviation will depend on the nature of the technical effect. For example, natural or biotechnological effects may generally have a larger deviation than artificial or engineered effects.

[0111] The terms “a,” “an,” and “the,” as well as similar references used in the context of describing the invention (particularly in the context of the claims), should be interpreted as including both the singular and plural forms, unless otherwise stated herein or clearly contradicted by the context.

[0112] References to ranges of values ​​in this document are intended only as a shorthand for individually referring to each individual value falling within that range. Unless otherwise stated herein, each individual value is incorporated into the specification as if it were described separately herein.

[0113] All methods described herein may be performed in any appropriate order unless otherwise stated herein or clearly contradicted by the context.

[0114] The use of any and all examples or exemplary language (e.g., "for example") provided herein is intended only to better illustrate the invention and does not constitute a limitation on the scope of the otherwise claimed invention. No language in the specification should be construed as representing any unclaimed element essential to the implementation of the invention.

[0115] This specification incorporates numerous references. Each of these references (including all patents, patent applications, scientific publications, manufacturer's specifications, instructions, etc.) is incorporated herein by reference in its entirety, whether preceding or following. Nothing herein should be construed as an admission that the invention is not entitled to prior disclosure based on prior invention.

[0116] As used herein, the terms “(this) invention,” “in accordance with (this) invention,” “based on (this) invention,” etc., refer to all aspects and embodiments of the invention described and / or claimed herein.

[0117] It should be understood that applying the teachings of this invention to a particular problem or situation, as well as including variations of the invention or additional features thereof (e.g., further aspects and embodiments), in accordance with the teachings contained herein, will be within the capabilities of those skilled in the art.

[0118] Unless the context otherwise indicates, the description and definition of the features listed above or below are not limited to any particular aspect or embodiment of the invention, and are equally applicable to all aspects and embodiments described.

[0119] The term "alkyl" refers to a single radical of a saturated straight-chain or branched hydrocarbon. Preferably, the alkyl group comprises 1 to 12 (e.g., 1 to 10) carbon atoms, i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms), more preferably 1 to 8 carbon atoms, such as 1 to 6 or 1 to 4 carbon atoms. Exemplary alkyl groups include methyl (Me), ethyl (Et), propyl, isopropyl (also known as 2-propyl or 1-methylethyl), butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, secondary pentyl, neopentyl, 1,2-dimethylpropyl, isopentyl, n-hexyl, isohexyl, secondary hexyl, n-heptyl, isoheptyl, n-octyl, 2-ethylhexyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, and the like. "Substituted alkyl" means that one or more hydrogen atoms of an alkyl group (such as 1 to the maximum number of hydrogen atoms bonded to the alkyl group, such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or up to 10, such as 1 to 5, 1 to 4, 1 to 3 or 1 or 2) are replaced by substituents other than hydrogen (when more than one hydrogen atom is replaced, the substituents may be the same or different). Preferably, the substituents other than hydrogen are primary, secondary or tertiary substituents as defined herein, such as -OH, NH2, NHCH3, N(CH3)2, CN, OCH3, OCF3, or optionally substituted aryl groups. Examples of substituted alkyl groups include trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trichloroethyl, 2-hydroxyethyl, 2-aminoethyl, 2-(dimethylamino)ethyl, aralkyl (also known as "aralkyl", e.g., benzyl, chloro(phenyl)methyl, 4-methylphenylmethyl, (2,4-dimethylphenyl)methyl, o-fluorophenylmethyl, 2-phenylpropyl, 2-, 3- or 4-carboxyphenylalkyl) or heteroaryl (also known as "heteroaryl").

[0120] The term "alkylene" refers to a diradical of a saturated straight-chain or branched hydrocarbon. Preferably, the alkylene comprises 1 to 12 (e.g., 1 to 10) carbon atoms, that is, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms), more preferably comprising 1 to 8 carbon atoms, such as 1 to 6 or 1 to 4 carbon atoms. Exemplary alkylenes include methylene, ethylene (i.e., 1,1-ethylene, 1,2-ethylene), propylene (i.e., 1,1-propylene, 1,2-propylene (-CH(CH3)CH2-), 2,2-propylene (-C(CH3)2-), and 1,3-propylene), butylene isomers (e.g., 1,1-butylene, 1,2-butylene, 2,2-butylene, 1,3-butylene, 2,3-butylene (cis or trans or mixtures thereof), 1,4-butylene, 1,1-isobutylene, 1,2-isobutylene, and 1,3-isobutylene), and pentylene isomers (e.g., 1,1-pentylene, 1,2-pentylene, 1,3-pentylene, 1,4-pentylene, 1,5-pentylene, 1,1... -Isopentyl, 1,1-secpentyl, 1,1-neopentyl), hexane isomers (e.g., 1,1-hexane, 1,2-hexane, 1,3-hexane, 1,4-hexane, 1,5-hexane, 1,6-hexane and 1,1-isohexane), heptyl isomers (e.g., 1,1-heptyl, 1,2-heptyl, 1,3-heptyl, 1,4-heptyl, 1,5-heptyl, 1,6-heptyl, 1,7-heptyl and 1,1-isoheptyl), octyl isomers (e.g., 1,1-octyl, 1,2-octyl, 1,3-octyl, 1,4-octyl, 1,5-octyl, 1,6-octyl, 1,7-octyl and 1,8-octyl and 1,1-isooctyl), etc. A straight-chain alkylene moiety having at least three carbon atoms and free valences at each end may also be designated as multiple methylene groups (e.g., 1,4-butene may also be referred to as tetramethylene). Generally, instead of the prefix "alkylene" as described above, the suffix "diyl" may also be used (e.g., 1,2-butylene may also be referred to as butane-1,2-diyl). "Substituted alkylene" refers to one or more hydrogen atoms of an alkylene moiety (e.g., one to a maximum number of hydrogen atoms bonded to the alkylene moiety, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, such as 1 to 5, 1 to 4, 1 to 3, or 1 or 2) being substituted with a substituent other than hydrogen (when more than one hydrogen atom is substituted, the substituents may be the same or different). Preferably, the substituent other than hydrogen is a primary, secondary, or tertiary substituent as defined herein, such as a halogen or optionally a substituted aryl group. Examples of substituted alkylene moieties include chloromethylene, dichloromethylene, fluoromethylene, and difluoromethylene.

[0121] The term "alkenyl" refers to a single radical of an unsaturated straight-chain or branched hydrocarbon having at least one carbon-carbon double bond. Typically, the maximum number of carbon-carbon double bonds in an alkenyl group can be an integer, calculated by dividing the number of carbon atoms in the alkenyl group by 2. If the number of carbon atoms in the alkenyl group is not uniform, the result of the division is rounded to the next integer. For example, for an alkenyl group having 9 carbon atoms, the maximum number of carbon-carbon double bonds is 4. Preferably, the alkenyl group has 1 to 6 (e.g., 1 to 4), i.e., 1, 2, 3, 4, 5, or 6 carbon-carbon double bonds. Preferably, the alkenyl group contains 2 to 12 (e.g., 2 to 10) carbon atoms, i.e., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms), more preferably 2 to 8 carbon atoms, for example, 2 to 6 carbon atoms or 2 to 4 carbon atoms. Therefore, in a preferred embodiment, the alkenyl group comprises 2 to 12 (e.g., 2 to 10) carbon atoms and 1, 2, 3, 4, 5, or 6 (e.g., 1, 2, 3, 4, or 5) carbon-carbon double bonds. More preferably, it comprises 2 to 8 carbon atoms and 1, 2, 3, or 4 carbon-carbon double bonds, for example, 2 to 6 carbon atoms and 1, 2, or 3 carbon-carbon double bonds, or 2 to 4 carbon atoms and 1 or 2 carbon-carbon double bonds. The carbon-carbon double bonds can be cis (Z) or trans (E) configurations. Exemplary alkenyl groups include vinyl, 1-propenyl, 2-propenyl (i.e., allyl), 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptyl, 1-octenyl, 2-octenyl, 3-octenyl, 4-octenyl, 5-octenyl, 6-octenyl, 7-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 4-nonenyl, 5-nonenyl, 6-nonenyl, 7 -Nonenyl, 8-nonenyl, 1-decenyl, 2-decenyl, 3-decenyl, 4-decenyl, 5-decenyl, 6-decenyl, 7-decenyl, 8-decenyl, 9-decenyl, 1-undecenyl, 2-undecenyl, 3-undecenyl, 4-undecenyl, 5-undecenyl, 6-undecenyl, 7-undecenyl, 8-undecenyl, 9-undecenyl, 10-undecenyl, 1-dodecenyl, 2-dodecenyl, 3-dodecenyl, 4-dodecenyl, 5-dodecenyl, 6-dodecenyl, 7-dodecenyl, 8-dodecenyl, 9-dodecenyl, 10-dodecenyl, 11-dodecenyl, etc. If the alkenyl group is bonded to a nitrogen atom, the double bond cannot be an α-bond of the nitrogen atom."Substituted alkenyl" refers to an alkenyl group in which one or more hydrogen atoms (e.g., 1 to a maximum number of hydrogen atoms bonded to the alkenyl group, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, such as 1 to 5, 1 to 4, 1 to 3, or 1 or 2) are replaced by substituents other than hydrogen (when more than one hydrogen atom is replaced, the substituents may be the same or different). Preferably, the substituents other than hydrogen are primary, secondary, or tertiary substituents as defined herein, such as halogens or optionally substituted aryl groups. An example of a substituted alkenyl group is a styryl (i.e., 2-phenylvinyl).

[0122] The term "alkenyl" refers to a diradical of an unsaturated straight-chain or branched hydrocarbon having at least one carbon-carbon double bond. Typically, the maximum number of carbon-carbon double bonds in an alkenyl can be an integer, calculated by dividing the number of carbon atoms in the alkenyl by 2. If the number of carbon atoms in the alkenyl is not uniform, the result is rounded to the next integer. For example, for an alkenyl with 9 carbon atoms, the maximum number of carbon-carbon double bonds is 4. Preferably, the alkenyl has 1 to 6 (e.g., 1 to 4), i.e., 1, 2, 3, 4, 5, or 6 carbon-carbon double bonds. Preferably, the alkenyl contains 2 to 12 (e.g., 2 to 10) carbon atoms, i.e., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms), more preferably 2 to 8 carbon atoms, e.g., 2 to 6 carbon atoms or 2 to 4 carbon atoms. Therefore, in a preferred embodiment, the alkenyl group comprises 2 to 12 (e.g., 2 to 10 carbon) atoms and 1, 2, 3, 4, 5, or 6 (e.g., 1, 2, 3, 4, or 5) carbon-carbon double bonds. More preferably, it comprises 2 to 8 carbon atoms and 1, 2, 3, or 4 carbon-carbon double bonds, for example, 2 to 6 carbon atoms and 1, 2, 3, or 4 carbon-carbon double bonds, or 3 carbon-carbon double bonds, or 2 to 4 carbon atoms and 1 or 2 carbon-carbon double bonds. The carbon-carbon double bonds can be cis (Z) or trans (E) configurations. Exemplary alkenyl groups include ethylene-1,2-diyl, vinylidene (also known as vinylidene), 1-propen-1,2-diyl, 1-propen-1,3-diyl, 1-propen-2,3-diyl, allyl, 1-butene-1,2-diyl, 1-butene-1,3-diyl, 1-butene-1,4-diyl, 1-butene-2,3-diyl, 1-butene-2,4-diyl, 1-butene-3,4-diyl, 2-butene-1,2-diyl, 2-butene-1,3-diyl, 2-butene-1,4-diyl, 2-butene-2,3-diyl, 2-butene-2,4-diyl, 2-butene-3,4-diyl, etc. If the alkenyl group is attached to a nitrogen atom, the double bond cannot be an α-bond of the nitrogen atom. "Substituted alkenyl" refers to one or more hydrogen atoms of an alkenyl group (e.g., 1 to a maximum number of hydrogen atoms bonded to the alkenyl group, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, such as 1 to 5, 1 to 4, 1 to 3, or 1 or 2) being substituted with substituents other than hydrogen (when more than one hydrogen atom is substituted, the substituents may be the same or different). Preferably, the substituents other than hydrogen are primary, secondary, or tertiary substituents as defined herein, such as halogens or optionally substituted aryl groups. Examples of substituted alkenyl groups are 1-phenyl-vinyl-1,2-diyl and 2-phenyl-vinyl-1,2-diyl.

[0123] The term "alkynyl" refers to a single radical of an unsaturated straight-chain or branched hydrocarbon having at least one carbon-carbon triple bond. Typically, the maximum number of carbon-carbon triple bonds in an alkynyl group can be an integer, calculated by dividing the number of carbon atoms in the alkynyl group by 2. If the number of carbon atoms in the alkynyl group is not uniform, the result of the division is rounded to the next integer. For example, for an alkynyl group with 9 carbon atoms, the maximum number of carbon-carbon triple bonds is 4. Preferably, the alkynyl group has 1 to 6 (e.g., 1 to 4), i.e., 1, 2, 3, 4, 5, or 6, more preferably 1 or 2 carbon-carbon triple bonds. Preferably, the alkynyl group comprises 2 to 12 (e.g., 2 to 10) carbon atoms (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms), that is, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms, more preferably 2 to 8 carbon atoms, for example 2 to 6 carbon atoms or 2 to 4 carbon atoms. Therefore, in a preferred embodiment, the alkynyl group comprises 2 to 12 (e.g., 2 to 10) carbon atoms and 1, 2, 3, 4, 5, or 6 (e.g., 1, 2, 3, 4, or 5 (preferably 1, 2, or 3)) carbon-carbon triple bonds, more preferably it comprises 2 to 8 carbon atoms and 1, 2, 3, or 4 (preferably 1 or 2) carbon-carbon triple bonds, for example 2 to 6 carbon atoms and 1, 2, or 3 carbon-carbon triple bonds or 2 to 4 carbon atoms and 1 or 2 carbon-carbon triple bonds. Exemplary alkynyl groups include alkynyl, 1-alkynyl, 2-alkynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-hepynyl, 2-hepynyl, 3-hepynyl, 4-hepynyl, 5-hepynyl, 6-hepynyl, 1-octyynyl, 2- Octynyl, 3-octyynyl, 4-octyynyl, 5-octyynyl, 6-octyynyl, 7-octyynyl, 1-nonynyl, 2-nonynyl, 3-nonynyl, 4-nonynyl, 5-nonynyl, 6-nonynyl, 7-nonynyl, 8-nonynyl, 1-decynyl, 2-decynyl, 3-decynyl, 4-decynyl, 5-decynyl, 6-decynyl, 7-decynyl, 8-decynyl, 9-decynyl, etc. If the ynyl group is attached to a nitrogen atom, the triple bond cannot be an α bond of the nitrogen atom. "Substituted alkynyl" means that one or more hydrogen atoms of the alkynyl group (e.g., 1 to a maximum number of hydrogen atoms bonded to the alkynyl group, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, such as 1 to 5, 1 to 4, 1 to 3, or 1 or 2) are substituted with substituents other than hydrogen (when more than one hydrogen atom is substituted, the substituents may be the same or different). Preferably, the substituents other than hydrogen are primary, secondary, or tertiary substituents as defined herein, such as halogens or optionally substituted aryl groups.

[0124] The term "acetylenic" refers to a diradical of an unsaturated straight-chain or branched hydrocarbon having at least one carbon-carbon triple bond. Typically, the maximum number of carbon-carbon triple bonds in an acetylenic group can be an integer, calculated by dividing the number of carbon atoms in the acetylenic group by 2. If the number of carbon atoms in the acetylenic group is not uniform, the result of the division is rounded to the next integer. For example, for an acetylenic group with 9 carbon atoms, the maximum number of carbon-carbon triple bonds is 4. Preferably, the acetylenic group has 1 to 6 (e.g., 1 to 4), i.e., 1, 2, 3, 4, 5, or 6, more preferably 1 or 2 carbon-carbon triple bonds. Preferably, the ynylene group comprises 2 to 12 (e.g., 2 to 10) carbon atoms (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms), that is, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms, more preferably 2 to 8 carbon atoms, for example 2 to 6 carbon atoms or 2 to 4 carbon atoms. Therefore, in a preferred embodiment, the ynylene group comprises 2 to 12 (e.g., 2 to 10) carbon atoms and 1, 2, 3, 4, 5, or 6 (e.g., 1, 2, 3, 4, or 5 (preferably 1, 2, or 3)) carbon-carbon triple bonds, more preferably it comprises 2 to 8 carbon atoms and 1, 2, 3, or 4 (preferably 1 or 2) carbon-carbon triple bonds, for example 2 to 6 carbon atoms and 1, 2, or 3 carbon-carbon triple bonds or 2 to 4 carbon atoms and 1 or 2 carbon-carbon triple bonds. Exemplary ynylene groups include acetylen-1,2-diyl, 1-propyn-1,3-diyl, 1-propyn-3,3-diyl, 1-butyn-1,3-diyl, 1-butyn-1,4-diyl, 1-butyn-3,4-diyl, 2-butyn-1,4-diyl, etc. If the ynylene group is attached to a nitrogen atom, the double bond cannot be an α-bond of the nitrogen atom. "Substituted ynylene group" means that one or more hydrogen atoms of the ynylene group (e.g., 1 to a maximum number of hydrogen atoms bonded to the ynylene group, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, such as 1 to 5, 1 to 4, 1 to 3, or 1 or 2) are substituted with substituents other than hydrogen (when more than one hydrogen atom is substituted, the substituents may be the same or different). Preferably, the substituents other than hydrogen are primary, secondary, or tertiary substituents as defined herein, such as halogens or optionally substituted aryl groups.

[0125] The term "aryl" or "aromatic ring" refers to a single radical of an aromatic cyclic hydrocarbon. Preferably, the aryl group comprises 3 to 14 (e.g., 5, 6, 7, 8, 9, or 10, such as 5, 6, or 10) carbon atoms, which may be arranged in a single ring (e.g., phenyl) or two or more fused rings (e.g., naphthyl). Exemplary aryl groups include cyclopropenyl, cyclopentadienyl, phenyl, indenyl, naphthyl, azuryl, fluorenyl, anthraceneyl, and phenanthryl. Preferably, "aryl" refers to a single ring containing 6 carbon atoms or an aromatic bicyclic system containing 10 carbon atoms. Preferred examples are phenyl and naphthyl. The aryl group does not contain fullerenes. "Substituted aryl" means that one or more hydrogen atoms of an aryl group (e.g., 1 to a maximum number of hydrogen atoms bonded to the aryl group, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, such as 1 to 5, 1 to 4, 1 to 3, or 1 or 2) are replaced by substituents other than hydrogen (when more than one hydrogen atom is replaced, the substituents may be the same or different). Preferably, the substituents other than hydrogen are primary, secondary, or tertiary substituents as defined herein, such as halogens, -CN, nitro, -OR. 11 (e.g., -OH), -SR 11 (e.g., -SH), -N(R) 12 (R) 13 (e.g., -NH2), alkyl (e.g., C) 1-6 alkyl), alkenyl (e.g., C10) 2-6 alkenyl) and ynyl) 2-6 (Alkyne group). Examples of substituted aryl groups include biphenyl, 2-fluorophenyl, 2-chloro-6-methylphenyl, aniline, 3-nitrophenyl, 4-hydroxyphenyl, methoxyphenyl (i.e., 2-, 3-, or 4-methoxyphenyl), and 4-ethoxyphenyl.

[0126] The term "heteroaryl" or "heteroary ring" refers to an aryl group as defined above, wherein one or more carbon atoms in the aryl group are substituted with heteroatoms (e.g., O, S, or N). Preferably, a heteroaryl refers to a 5- or 6-membered aromatic monocyclic ring, wherein 1, 2, or 3 carbon atoms are substituted with the same or different O, N, or S heteroatoms. Alternatively, it refers to an aromatic bicyclic or tricyclic system, wherein 1, 2, 3, 4, or 5 carbon atoms are substituted with the same or different O, N, or S heteroatoms. Preferably, in each ring of the heteroaryl, the maximum number of O atoms is 1, the maximum number of S atoms is 1, and the maximum total number of O and S atoms is 2. For example, 3- to 14-membered heteroaryls include monocyclic heteroaryls (e.g., 5- or 6-membered), bicyclic heteroaryls (e.g., 9- or 10-membered), and tricyclic heteroaryls (e.g., 13- or 14-membered). Exemplary heteroaryl groups include furanyl, thiophene, oxazolyl, isoxazolyl, oxadiazolyl (1,2,5- and 1,2,3-), pyrrolyl, imidazolyl, pyrazolyl, triazolyl (1,2,3- and 1,2,4-), tetrazolyl, thiazolyl, isothiazolyl, thiadiazolyl (1,2,3- and 1,2,5-), pyridyl (also known as pyridyl), pyrimidinyl, pyrazinyl, and others. Triazinyl (1,2,3-, 1,2,4- and 1,3,5-), benzofuranyl (1- and 2-), indoleyl, isoyindoleyl, benzothiopheneyl (1- and 2-), 1H-indoleyl, benzimidazolyl, benzoxazolyl, indoleoxazinyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, benzodiazinyl, quinolinyl Quinazolinyl, benzotriazinyl (1,2,3- and 1,2,4-benzotriazinyl), pyridazinyl, phenothiazinyl, thiazopyridyl, pyrrolothiazolyl, phenothiazinyl, isobenzofuranyl, chromenyl, flavinyl, phenothiazinyl, pyrrolizinyl, indoleazinyl, indoleazolyl, purinyl, quinazinyl, o-phenyldimethazinyl, naphridinyl (1,5-, 1,6-, 1,7-, 1,8- and 2,6-), cinnolinyl, pteridinyl, carbazolyl, phenanthrolinyl, acridineyl, piperidinyl, phenanthrolinyl (1,7-, 1,8-, 1,10-, 3,8- and 4,7-), phenanthrolinyl, oxazolopyridinyl, isoxazolopyridinyl, pyrroloxazolyl and pyrrolopyrroleyl. Exemplary 5- or 6-membered heteroaryl groups include furanyl, thiophene, oxazolyl, isoxazolyl, oxadiazolyl (1,2,5- and 1,2,3-), pyrrole, imidazolyl, pyrazolyl, triazolyl (1,2,3- and 1,2,4-), thiazolyl, isothiazolyl, thiadiazolyl (1,2,3- and 1,2,5-), pyridyl, pyrimidinyl, pyrazinyl, triazinyl (1,2,3-, 1,2,4- and 1,3,5-), and pyridazinyl."Substituted heteroaryl" means that one or more hydrogen atoms of a heteroaryl group (e.g., 1 to a maximum number of hydrogen atoms bonded to the heteroaryl group, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, such as 1 to 5, 1 to 4, 1 to 3, or 1 or 2) are substituted with substituents other than hydrogen (when more than one hydrogen atom is substituted, the substituents may be the same or different). Preferably, the substituents other than hydrogen are primary, secondary, or tertiary substituents as defined herein, such as halogens, -CN, nitro, -OR. 11 (e.g., -OH), -SR 11 (e.g., -SH), -N(R) 12 (R) 13 (e.g., -NH2), alkyl (e.g., C) 1-6 alkyl), alkenyl (e.g., C10) 2-6 alkenyl) and ynyl) 2-6 (Alkyne group). Examples of substituted heteroaryl groups include 2,4-dimethylpyridin-3-yl, 2-methyl-4-bromopyridin-3-yl, 3-methyl-2-pyridin-2-yl, 3-chloro-5-methylpyridin-4-yl, 4-chloro-2-methylpyridin-3-yl, 3,5-dimethylpyridin-4-yl, 2-methylpyridin-3-yl, 2-chloro-4-methylthiophene-3-yl, 1,3,5-trimethylpyrazol-4-yl, 3,5-dimethyl-1,2-dioxazol-4-yl, 1,2,4-trimethylpyrrole-3-yl, 3-phenylpyrrole, 2,3'-dithiol, 4-methylpyridinyl, 2- or 3-ethylindolyl.

[0127] The terms "cycloalkyl" or "cycloaliphatic" refer to cyclic non-aromatic versions of "alkyl" and "alkenyl" having preferably 3 to 14 carbon atoms, such as 3 to 12 or 3 to 10 carbon atoms, i.e., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 carbon atoms (e.g., 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms), more preferably 3 to 7 carbon atoms. Exemplary cycloalkyl groups include cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, cyclononyl, cyclononenyl, cyclododecyl, and adamantyl. The term "cycloalkyl" also means including its bicyclic and tricyclic forms. If a bicyclic ring is formed, it is preferable that the rings are connected to each other at two adjacent carbon atoms; however, the two rings may also be connected by the same carbon atom, i.e., they form a spirocyclic system or a "bridged" ring system. Preferred examples of cycloalkyl groups include C1. 3-8-Cycloalkyl, especially cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, spiro[3,3]heptyl, spiro[3,4]octyl, spiro[4,3]octyl, bicyclo[4.1.0]heptyl, bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl, and bicyclo[4.2.0]octyl. Cycloalkyl does not contain fullerenes. "Substituted cycloalkyl" means that one or more hydrogen atoms of the cycloalkyl group (e.g., 1 to a maximum number of hydrogen atoms bonded to the cycloalkyl group, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, such as 1 to 5, 1 to 4, 1 to 3, or 1 or 2) are substituted with substituents other than hydrogen (when more than one hydrogen atom is substituted, the substituents may be the same or different). Preferably, the substituents other than hydrogen are primary, secondary, or tertiary substituents as defined herein, such as halogens, -CN, nitro, -OR. 11 (e.g., -OH), -SR 11 (e.g., -SH), -N(R) 12 (R) 13 (e.g., -NH2), =X (e.g., =O, =S or =NH), alkyl (e.g., C) 1-6 alkyl), alkenyl (e.g., C10) 2-6 alkenyl) and ynyl) 2-6 (Alkyne group). Examples of substituted cycloalkyl groups include oxocyclohexyl, oxocyclopentyl, fluorocyclohexyl, and oxocyclohexyl.

[0128] The term "heterocyclic group" or "heterocycle" means a cycloalkyl group as defined above, wherein 1, 2, 3, or 4 ring carbon atoms in the cycloalkyl group are replaced by heteroatoms (e.g., selected from O, S, S(O), S(O)2, N, B, Si, and P, preferably selected from O, S, S(O)2, and N, more preferably selected from O, S, and N). If the ring of the heterocyclic group contains only one type of heteroatom, the maximum number of heteroatoms in the ring of the heterocyclic group may be: 2 O atoms (preferably 1 O atom); 2 S atoms (preferably 1 S atom); 4 N atoms (e.g., 1, 2, or 3 N atoms); 2 B atoms (preferably 1 B atom); 1 Si atom and / or 1 P atom. If one ring of the heterocyclic base contains two or more heteroatoms, the maximum number of heteroatoms in the ring of the heterocyclic base can be as follows: 1 O atom; 1 S atom; 2 N atoms (preferably 1 N atom); 1 B atom; 1 Si atom and / or 1 P atom, wherein the maximum total number of heteroatoms in the heterocyclic base ring is 4, and the maximum total number of each heteroatom in the heterocyclic base ring is as follows: 1 O atom; 1 S atom; 1 or 2 N atoms; 1 B atom (preferably 0 B atoms); 1 Si atom (preferably 0 Si atoms) and / or 1 P atom (preferably 0 P atoms). In one embodiment, the heteroatoms of the heterocyclic base are selected from O, S, and N. In this embodiment, preferably, in each ring of the heterocyclic base, the maximum number of O atoms is 1, the maximum number of S atoms is 1, and the maximum total number of O and S atoms is 2. For example, 3- to 14-membered heterocyclic groups include monocyclic heterocyclic groups (e.g., 3, 4, 5, 6, or 7-membered, preferably 4 to 7-membered), bicyclic heterocyclic groups (e.g., 8, 9, or 10-membered), and tricyclic heterocyclic groups (e.g., 12, 13, or 14-membered). If the heterocyclic group contains two or more rings, these rings are either fused (e.g., in a quinoline or purine group), spirocyclic, bridged, connected by double bonds, or a combination thereof. In other words, an unsubstituted heterocyclic group does not contain two heterocyclic groups connected by single bonds. The term "heterocyclic group" also means a partially or fully hydrogenated form (e.g., dihydro, tetrahydro, hexahydro, octahydro, decahydro, dodecahydro, etc., or all-hydrogen forms) containing the aforementioned heteroaryl groups. Exemplary heterocyclic groups include azacyclobutane, morpholino, isocyano, chromocyano, pyrrolyl, imidazolino, pyrazolyl, piperidinyl, piperazinyl, indolyl, isoyindolyl, triazinyl (1,2,3-, 1,2,4-, and 1,3,5-), di- and tetrahydrofuranyl, di- and tetrahydrothiopheneyl, di- and tetrahydrooxazolyl, di- and tetrahydroisooxazolyl, di- and tetrahydrooxazolyl (1,2,5-, and 1,2,3-), dihydropyrrolyl, dihydroimidazolyl, dihydropyrazolyl, di- and tetrahydrotriazolyl (1,2,3-, and 1,2,4-), di- and tetrahydrothiazolyl, di- and tetrahydrothiazolyl, di- and tetrahydrothiazolyl (1,2,3-, and 1,2,4-), ...5-), di- and tetrahydropyridyl, di, tetra, and hexahydropyrimidinyl, di- and tetrahydropyrazinyl, di- and tetrahydrotriazinyl (1,2,3-, 1,2,4- and 1,3,5-), di-, tetra, hexa, and octahydrobenzofuranyl (1- and 2-), di-, tetra, hexa, and octahydroindolyl, di-, tetra, hexa, and octahydroisoindolyl, di-, tetra, hexa, and octahydroisoindolyl, di-, tetra, hexa, and octahydroxyindoloxazinyl, di-, tetra, hexa, and octahydroxybenzoisooxazolyl, di-, tetra, hexa, and octahydroxybenzothiazolyl, di-, tetra, hexa, and octahydroxybenzoisothiazolyl, di-, tetra, hexa, and octahydroxybenzotriazolyl, di-, tetra, hexa, and octahydroxybenzotriazolyl 2,4,6,8 ... Groups, such as 4,5,6-7-tetrahydro[1,3]thiazolyl[5,4-c]pyridin-2-yl or 4,5,6-7-tetrahydro[1,3]thiazolyl[4,5-c]pyridin-2-yl), di, tetra, hexahydropyrrolithiazolyl, di, tetra, hexa, octa, and decahydrophenanthiazinyl, di, tetra, hexa, and octahydroisobenzofuranyl, di, tetra, hexa, and octahydrochromenyl, di, tetra, hexa, octa, deca, and dodecahydroxanthrayl, di, tetra, hexa, octa, deca, and dodecahydroxanthrayl, di, tetra, hexahydropyrrolylyl, di, tetra, hexa, octahydroindolazidyl, di, tetra, hexa, octahydroindolazidyl, di, tetra, hexa, octahydropurine, di, Tetra-, hexa-, octa-hydroquinolinyl, di, tetra, hexa-, octa- and deca-hydrophenazinyl, di, tetra, hexa-, octa-, deca-hydronaphthidyl (1,5-, 1,6-, 1,7-, 1,8-, 2,6-), di, tetra, hexa-, octa-, deca-hydroindenyl, di, tetra, hexa-, octa-, deca- and dodecylcarbazoyl, di, tetra, hexa-, octa-, deca- and tetradecylanthracene, di, tetra, hexa-, octa-, deca- and tetradecylacridyl, di, tetra, hexa-, octa-, deca-, dodecylpyrimidinyl, di, tetra, hexa-, octa-, deca-, dodecyl, tetradecyl, o-phenanthrolinel (1,7-, 1,8-, 1,10-, 3,8-, 4,7-), di, tetra, hexa, octa, deca, dodecyl and tetratetrahydrophenazinyl, di, tetra, hexa and octahydrooxazolopyridyl, di, tetra, hexa and octahydroisooxazolopyridyl, di, tetra, hexa and octahydrocyclopentapyrrolyl, di, tetra, hexa and octahydrocyclopentapyrazoleyl, di, tetra, hexa and octahydrocyclopentimidazolyl, di, tetra, hexa and octahydrocyclopentathiazoleyl, di, tetra, hexa and octahydrocyclopentoxazolyl, di, tetra, hexa and octahydropyrrolyl, di, tetra, hexa and octahydropyrrolyl, di, tetra, hexa and octahydropyrrolimizolyl, di, tetra, hexa and octahydropyrrolthiazoleyl (e.g. 5, 6-Dihydro-4H-pyrrolo[3,4-d][1,3]thiazolyl), di, tetra, hexa, and octahydropyrroloxazolyl, di, tetra, hexa, and octahydropyrroloazolyl, di, tetra, hexa, and octahydropyrazoleimidazolyl, di, tetra, hexa, and octahydropyrazolethiazolyl, di, tetra, hexa, and octahydropyrazoleoxazolyl, di, tetra, hexa, and octahydroimidazolyl, di, tetra, hexa, and octahydroimidazoxazolyl, di, tetra, hexa, and octahydrothiazolyl, di, tetra, hexa, and octahydrothiazolyl, and di, tetra, hexa, and octahydrooxazolyl. Exemplary 5- or 6-membered heterocyclic groups include morpholino, pyrrolyl, imidazolino, pyrazolyl, piperidinyl, piperazinyl, di- and tetrahydrofuranyl, di- and tetrahydrothiopheneyl, di- and tetrahydrooxazolyl, di- and tetrahydroisooxazolyl, di- and tetrahydrooxazolyl (1,2,5- and 1,2,3-), dihydroimidazolyl, dihydropyrazolyl, di- and tetrahydrotriazolyl (1,2,3- and 1,2,4-), di- and tetrahydrothiazolyl, di- and tetrahydroisothiazolyl, di- and tetrahydrothiadiazolyl (1,2,3- and 1,2,5), di- and tetrahydropyridinyl, di, tetra, and hexahydropyrimidinyl, di- and tetrahydropyrazinyl, di- and tetrahydrotriazinyl (1,2,3-, 1,2,4- and 1,3,5), and triazinyl (1,2,3-, 1,2,4- and 1,3,5). "Substituted heterocyclic group" refers to a heterocyclic group in which one or more hydrogen atoms (e.g., 1 to a maximum number of hydrogen atoms bonded to the heterocyclic group, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, such as 1 to 5, 1 to 4, 1 to 3, or 1 or 2) are replaced by substituents other than hydrogen (when more than one hydrogen atom is replaced, the substituents may be the same or different). Preferably, the substituents other than hydrogen are primary, secondary, or tertiary substituents as defined herein, such as halogen, -CN, nitro, -OR, etc. 11 (e.g., -OH), -SR 11 (e.g., -SH), -N(R) 12 (R) 13 (e.g., -NH2), =X (e.g., =O, =S or =NH), alkyl (e.g., C) 1-6 alkyl), alkenyl (e.g., C10) 2-6 alkenyl) and ynyl) 2-6 (Alkyne group).

[0129] As used herein, the expression “partially hydrogenated form” for an unsaturated compound or group means removing partial unsaturation by formally adding hydrogen to the original unsaturated compound or group without removing all unsaturated portions. The phrase “fully hydrogenated form” for an unsaturated compound or group is used interchangeably herein with the term “fully hydrogenated” and means removing all unsaturation by formally adding hydrogen to the original unsaturated compound or group. For example, a partially hydrogenated form of a 5-membered heteroaryl group (containing two double bonds in the ring, such as furan) includes the dihydrogen form of said 5-membered heteroaryl group (e.g., 2,3-dihydrofuran or 2,5-dihydrofuran), while the tetrahydrogen form of said 5-membered heteroaryl group (e.g., tetrahydrofuran, i.e., THF) is the fully hydrogenated (or fully hydrogenated) form of said 5-membered heteroaryl group. Similarly, for a 6-membered heteroaryl group (e.g., pyridyl) having three double bonds in the ring, the partially hydrogenated forms include dihydro and tetrahydroforms (e.g., dihydro and tetrahydropyridyl), while the hexahydroform (e.g., piperidyl in the case of heteroarylpyridyl) is a fully hydrogenated (or all-hydrogen) derivative of the 6-membered heteroaryl group. Therefore, if an aryl or heteroaryl group contains at least four unsaturated moieties consisting of double and triple bonds between ring atoms, the hexahydroform of the aryl or heteroaryl group can only be considered a partially hydrogenated form according to the invention.

[0130] In the context of hydrocarbons, the term "aromatic" implies that the entire molecule must be aromatic. For example, if a monocyclic aryl group is hydrogenated (partially or entirely), the resulting hydrogenated ring structure is classified as cycloalkyl for the purposes of this invention. Similarly, if a bicyclic or polycyclic aryl group (e.g., naphthyl) is hydrogenated, the resulting hydrogenated bicyclic or polycyclic structure (e.g., 1,2-dihydronaphthyl) is classified as cycloalkyl for the purposes of this invention (even if only one ring is present, such as the ring in 1,2-dihydronaphthyl, it is still aromatic). A similar distinction is made between heteroaryl and heterocyclic groups in this application. For example, indolyl, i.e., the dihydro variant of indolyl, is classified as a heterocyclic group for the purposes of this invention because only one ring in the bicyclic structure is aromatic, while one of the ring atoms is a heteroatom.

[0131] As used herein, the term "polycyclic" refers to a structure having two or more rings (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10), preferably 2, 3, 4, or 5 rings, more preferably 2, 3, or 4 rings. Therefore, according to the invention, the term "polycyclic" does not include monocyclic structures, which contain only one ring. Examples of polycyclic groups are fused structures (e.g., naphthyl or anthracene), spirocyclic compounds, rings linked by single or double bonds (e.g., biphenyl), and bridged structures (e.g., borneol). Exemplary polycyclic structures are aryl, heteroaryl, cycloalkyl, and heterocyclic groups having at least two rings, as specifically referred to above.

[0132] The term "halogen" or "halogenated elements" refers to fluorine, chlorine, bromine, or iodine.

[0133] The term "azido group" refers to -N3.

[0134] The term "N-oxide" refers to amine oxides or amine-N-oxides, which contain the functional group (R). n )3N + -O - Compounds containing NO (i.e., NO coordinated covalent bonds), where R n The R is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclic groups, wherein each of the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclic groups is optionally independently selected by one or more (e.g., 1 to a maximum number of hydrogen atoms combined with the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or heterocyclic group, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, e.g., 1 to 5, 1 to 4, 1 to 3, or 1 or 2). 30 Instead, the R 30 Preferably, it is a primary substituent, a secondary substituent, or a tertiary substituent as specified herein.

[0135] As used herein, the term "carboxylic acid" refers to a compound containing at least one carboxyl group (COOH) or a thiocarboxyl group (-CSOH) (preferably, a compound containing at least one carboxyl group (COOH), and in the context of Examples 1.1 and 1.2, a compound containing only at least one carboxyl group (COOH)). The term "corresponding carboxylic acid" as used herein refers to a (thio)carboxylic acid that, when reacted with another compound (e.g., an intermediate, such as the intermediate of the present invention), produces the desired compound (e.g., a compound having an amide or thioamide bond). For example, if it is desired to prepare a compound of formula (Ia) using an intermediate of formula (Id), the corresponding acid may have the following formula (Ie):

[0136]

[0137] Among them Hy, R 2 R 3 A and E are as defined herein (particularly with respect to formulas (Ia), (IIa), (IVa), (Va), (VIa), (VIIa), and / or (VIIIa)). For example, if it is desirable to prepare a compound of formula (Ia) where E is S, then an intermediate of formula (Id) is preferably used, and the corresponding acid may have the above formula (Ie), where E is S. If, in another embodiment, it is desirable to prepare a compound of formula (Ia) where E is O, then an intermediate of formula (Id) is preferably used, and the corresponding acid may have the above formula (Ie), where E is O.

[0138] As used herein, the term "impurity" refers to any impurity (especially a chemical substance) that may be present in a composition containing the desired compound (e.g., a composition containing the compound described herein, such as compound (Ia)). Impurities may arise naturally, may be added during the synthesis and / or purification of the desired compound, or may be generated during the synthesis and / or purification of the desired compound. Exemplary impurities include one or more starting materials, one or more solvents, one or more intermediates or reactants, one or more degradation products of any of the above or the desired compound, one or more residues of deprotected protecting groups, and combinations thereof.

[0139] As used in this article, “R” 7 At least one of them is F and / or R 7 At least one of the atoms in R is replaced by one or more F atoms (and similar expressions) meaning that R 6 The portion is replaced by (i) at least one F atom and / or (ii) a portion containing one or more F atoms (e.g., 1 to a maximum number of hydrogen atoms bonded to the portion, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, such as 1 to 5, 1 to 4, or 1 to 3, or 1 or 2). An exemplary portion with one or more F atoms includes an alkyl group containing one or more F atoms (e.g., 1 to a maximum number of hydrogen atoms bonded to the alkyl group, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, such as 1 to 5, 1 to 4, or 1 to 3, or 1 or 2 or 3), for example, a C group containing one or more F atoms (e.g., 1 to a maximum number of hydrogen atoms bonded to the alkyl group, such as 1, 2, 3, 4, 5, 6, or 7, or up to 6, such as 1 to 5, 1 to 4, or 1 to 3, or 1 or 2 or 3). 1-3 Alkyl groups, such as -CH2F, -CHF2, or -CF3. Further exemplary portions containing one or more F atoms include F-substituted alkoxy groups (i.e., -O (alkyl), such as -O (C)). 1-3 Alkyl or F-substituted alkylamino groups (i.e., -NH(alkyl) or -N(alkyl)2, for example -NH(C)2) 1-3 alkyl) or -N(C) 1-3 Alkyl)2), wherein the alkyl group of the alkoxy group and the monoalkylamino group (e.g., C) 1-3 At least one alkyl group (e.g., C10) of the alkyl group and the dialkylamino group. 1-3 The alkyl group is replaced by one or more F atoms (e.g., 1 to a maximum number of hydrogen atoms bonded to the alkyl group, such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or up to 10 or up to 7, such as 1 to 5, 1 to 4 or 1 to 3, or 1 or 2 or 3).

[0140] As described elsewhere in this article, for equation (Ic), R 5”For -LR 6” And R 6” It is a heteroaryl or heterocyclic group, each optionally constituting one or more independently selected R groups. 7’ Replacement. For this, as used in this paper, the expression "any two with R" is used. 6” R bonded to the same atom 7' The fact that they can combine to form =O means that there are two single radicals (i.e., R) 7’ When a total of 2 hydrogen atoms are replaced, it only interacts with R. 6” A single ring atom can combine to form a diradical =O. For example, according to the present invention, (in R represents 6” The bonds that bind to the rest of the compound include not only (1) R 7' The possibility that each of the groups is a single radical independently selected from a specific moiety (e.g., methyl or Cl) as specified herein, also includes (2) any two R groups 7' Group and R 6” The probability that the same atom can combine to form a diradical =O, the result is R 6” The group has the following molecular formula The remaining R 7' The group is a single free radical. Similarly, if R... 6” If it is 3-tetrahydrothiophene substituted with four R7', then this substitution of R... 6” It contains the following molecular formulas: etc. Similar terms as used herein, such as "any two R groups bonded to the same carbon atom of a cycloalkyl or heterocyclic group", are used to refer to this. 30 They can be combined to form =X 1 ", will be explained in a similar manner. In this regard, it should be understood that in those embodiments, where R is incorporated 6” Any two R atoms of the same type 7’ They can be combined to form =O,R 6” Initially (i.e., unmodified = O), it must be a heterocycle (because there are no two free-valence carbon ring atoms in a heterocycle). Similarly, if any two R atoms are bonded to the same atom in a portion of the ring, it must be a heterocycle. 30 They can be combined to form =X 1 Then that part is initially (i.e., unmodified = X) 1 It must be an alicyclic or heterocyclic ring (because there are no carbon ring atoms with two free valences in (hetero)aromatic rings).

[0141] As used in this article, "an R" 7’ Groups relative to R 6’ The ring atom bonded to the rest of the compound is located at position 2 with R.6’ "Ring atom bonding" (and similar expressions) means direct interaction with R 6’ At least one of two adjacent ring atoms connected to the rest of the compound has an R 7’ Group. In other words, R 6’ At least one neighboring position relative to R 6’ The ring atoms (i.e., R) that are bonded to the rest of the compound 6’ (base position), with R 7’ Groups. For example, applying the above expression to R 6' By an R 7' In the case of a substituted 3-pyridyl group (therefore, the group position is the ring carbon at position 3 relative to the ring nitrogen atom), the R can be derived. 7' The group is located at position 2 or 4 of the 3-pyridinyl group, as shown in the following formula:

[0142]

[0143] in R represents 6’ The bonds that bind to the rest of the compound. Furthermore, if R... 6’ By one or more (e.g., two or three) R 7’ Group substitution, as used in this paper to express "an R 7’ Groups relative to R 6’ The ring atom bonded to the rest of the compound is located at position 2 with R. 6’ The "ring atom binding" (and similar expressions) includes R 6’ Each of two directly adjacent ring atoms connected to the rest of the compound carries an R. 7’ The case of groups (i.e., R as a k-membered ring) 6’ Each of positions 2 and k has an R 7’ Group, relative to R 6’ The ring atoms that bind to the rest of the compound, i.e., R 6’ It is replaced at its two adjacent positions). For example, if R 6’ It is a 3-pyrrole group (therefore, the group position is the ring carbon at position 3 relative to the ring nitrogen atom), then it is affected by two R groups. 7’ Group substitution, expressing "an R 7’ Groups relative to R 6’ The ring atom bonded to the rest of the compound is located at position 2 with R. 6’ The "ring atom bonding" includes the following structures:

[0144]

[0145] However, the following structures are not included:

[0146]

[0147] As used herein, the term "k-membered ring" means that the ring has k ring atoms. For example, for a pyrazolium group, k is 5; therefore, the adjacent positions are positions 2 and 5 relative to the ring atoms (base positions) to which the pyrazolium group is bonded with the rest of the compound, and position k-1 is position 4. Furthermore, for a 6-membered heteroaryl group, the adjacent positions are positions 2 and 6 relative to the ring atoms (base positions) to which the pyridinium group is bonded with the rest of the compound, and position k-1 is position 5.

[0148] Regarding R 6 It is a 5-membered monocyclic heteroaryl group containing at least one S ring atom, as expressed in this paper as "an R 7 In relation to R 6 The phrase "the ring atom at position 2 of the remaining part of the compound is attached to a C ring atom" (and similar expressions) preferably means an R 7 Group and R 6 The C-ring atom is bonded to R, and this C-ring atom (i) is directly bonded to R. 6 The ring atoms connected to the remainder of the compound are adjacent and (ii) in relation to R 6 When numbering ring atoms, lower numbers are received (e.g., starting with the number "1" for S ring atoms and making R...). 6 The number of ring atoms (i.e., R) that bind with the remainder of the compound. 6 (Continue in the manner that the "base" position is as low as possible). In other words, relative to R 6 The base position, when considering the shortest path between the S-ring atom and the yl position, R 6 The two "adjacent" C ring atoms preferably have a position located at R 6 The R between the S ring atom and the base position 7 Groups. For example, applying the above expression to R 6 It was by an R 7 The case of a substituted 3-thiophene group (therefore, the group position is the 3rd ring carbon relative to the S ring atom) yields the R... 7 The group located at 2 is a 3-thiophene group, as shown in the following formula:

[0149]

[0150] in R represents 6 The bonds that bind with the remainder of the compound. Similarly, regarding R... 6 It is a 5-membered monocyclic heteroaryl group containing at least one S-ring atom, as expressed in this paper as "an R 7 In relation to R 6The phrase "the ring atom attached to the remaining part of the compound at position 5 is connected to the C ring atom" (and similar expressions) preferably means an R 7 Group and R 6 The C ring atom is bound to the C ring atom (i) directly with R. 6 The ring atoms connected to the remainder of the compound are adjacent and (ii) in relation to R 6 When numbering ring atoms, higher numbers are received (e.g., starting with the number "1" for the S ring atom, so that R...). 6 (Continue with the base position numbers as low as possible). In other words, relative to R... 6 When considering the shortest path between the S-ring atom and the base position, the C-ring atom preferably has a position not located between the S-ring atom and the R-ring atom. 6 R between the base positions 7 Groups. For example, the above expression ("an R group") 7 Groups relative to R 6 The ring atom at position 5 of the compound is attached to the C ring atom. This applies to R. 6 It uses an R 7 In the case of a substituted 3-thiophene group (therefore, the group position is the ring carbon at position 3 relative to the S ring atom), it can be seen that the R 7 The group is located at position 4 of the 3-thiophene group, as shown in the following formula:

[0151]

[0152] in R represents 6 The bonds bound to the remainder of the compound. Furthermore, regarding R... 6 It is a 5-membered monocyclic heterocyclic heterocycle containing at least one S-ring atom, as expressed in this paper as "an R 7 In relation to R 6 Position 2 of the ring atom, which binds to the remaining part of the compound, is attached to the C ring atom, an R 7 In relation to R 6 The phrase "position 5 of the ring atom bound to the remaining part of the compound is connected to the C ring atom" (and similar expressions) preferably means that, for R directly adjacent to the ring atom 6 Each of the two C-ring atoms is associated with R 6 With R 7 The remaining ring atoms of the linked compound are connected. For example, the above expression ("an R...") 7 In relation to R 6 Position 2 of the ring atom, which binds to the remaining part of the compound, is attached to the C ring atom, an R 7 In relation to R 6The position of the ring atom in the remaining part of the compound is connected to the C ring atom. This is applied to R. 6 It is by at least two Rs 7 In the case of substituted 3-thiophene groups (therefore, the group position is the ring carbon at position 3 relative to the S ring atom), these R groups can be derived. 7 The groups are located at positions 2 and 4 of the 3-thiophene group, as shown in the following formula:

[0153]

[0154] in R represents 6 Bonds that bind to the rest of the compound.

[0155] The expression used in this article is " R represents 6 The bond that binds to the remainder of the compound refers to R. 6 By attaching to the bonds of the remaining part of the compound (i.e., if L is not a bond, it is attached to (i)L; if L is a bond, it is attached to the nitrogen atom of the carboxyl (thio)amide group -C(=e)N(R4) of formula (Ia), (Ib), or (Ic). For example, in R 6 yes When L is a (i) methylene or (ii) bond, the compounds of formula (Ia) have the following structures (A1) and (A2), respectively:

[0156]

[0157] Similar terms, such as " "Indicates the bond that Hy is bonded to the rest of the compound" or " R represents 1a "Bonds that bind to the remainder of the compound," as used herein, will be explained in a similar manner.

[0158] The term “asymmetric” as used in this paper (e.g., in conjunction with R) 1a Preferably, this means that the relevant portion (particularly an asymmetric cycloalkyl or heterocyclic group) is itself asymmetric (e.g., 1,4-oxazine-4-yl) and / or has an asymmetric substitution pattern (e.g., 3-oxoperazin-1-yl or 3-methylpiperazin-1-yl) with respect to its attachment point to the rest of the compound. For example, a symmetric group has a plane of symmetry (e.g., 4-methylpiperazinyl) with respect to its attachment point to the rest of the compound, while an asymmetric group does not. An asymmetric group may have asymmetric atoms (e.g., chiral C atoms), such as in 2-methylmorpholino-4-yl, but does not necessarily have asymmetric atoms (e.g., in 3-oxoperazin-1-yl). Exemplary asymmetric groups include the following:

[0159]

[0160] Where R 30 And X as defined in this article; and This indicates a bond formed when an asymmetric group is bonded to the rest of the compound.

[0161] Asymmetric specific groups include the following groups:

[0162]

[0163] Where R 30 And X as defined in this article; This indicates a bond formed when an asymmetric group is bonded to the rest of the compound.

[0164] The expression "adjacent ring atoms" as used herein, such as in "C ring atoms and S ring atoms are adjacent ring atoms," preferably means that the two ring atoms share a common bond and therefore are directly bonded to each other. For example, in the structure shown below (i.e., R at position 4) 7 In the substituted 3-thiophene group, the C ring atom at position 2 and the S ring atom are adjacent ring atoms, while the C ring atom at position 4 and the S ring atom are separated by C ring atoms:

[0165]

[0166] in R represents 6 Bonds that bind to the remainder of the compound.

[0167] Similarly, the expression used in this paper, "R bonded to C ring atoms of neighboring S ring atoms", is used to express this concept. 40 "Preferred means R" 40 The attached C-ring atoms and S-ring atoms are adjacent atoms. For example, in the structure shown in the figure below, the C-ring atom adjacent to the S-ring atom is bonded to the R-ring atom. 40 R is bonded to the C ring atom at position 2. 40 (Because the C ring atom is adjacent to the S ring atom), while the R atom at position 4 is bonded to the C ring atom. 40 R is a C-ring atom bonded to an S-ring atom that is separate from (or not adjacent to) the S-ring atom. 40 (That is, the C ring atom and S ring atom at position 4 are separated from the C ring atom (at position 5):

[0168]

[0169] The expression “R” used in this article 6 S ring atoms and R 6 "The ring atoms bonded to the rest of the compound are not adjacent" preferably means R6 The S ring atom and R through at least one ring atom 6 The remainder of the compound (i.e., from R) 6 The ring atoms (at their base positions) are separated. For example, if R 6 It is arbitrarily assigned to an R 7 The substituted thiophene group expresses "R". 6 S ring atoms and R 6 The structure “the ring atoms bonded to the rest of the compound are not adjacent” includes the following structures:

[0170]

[0171] However, the following structures are excluded:

[0172]

[0173] in R represents 6 Bonds that bind to the rest of the compound.

[0174] According to the IUPAC nomenclature, preferably, the numbering of the substituted heterocyclic groups begins with the cyclic heteroatom and continues in a manner that minimizes the number of substituents. For example, the compounds shown below have the following cyclic atom numbers and names:

[0175]

[0176] N-(2-fluoro-4-methylthiophene-3-yl)-2,5-dihydro-1H-imidazol-2-amine

[0177] The term "optionally substituted" means that one or more hydrogen atoms (e.g., 1 to a maximum number of hydrogen atoms bonded to a group, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or up to 10, e.g., 1 to 5, 1 to 4, 1 to 3 or 1 or 2) can be substituted by a group other than hydrogen (i.e., a primary substituent), such as an alkyl group (preferably C10). 1-6 Alkyl), alkenyl (preferably, C 2-6 alkenyl), ynyl (preferably, C 2-6 Alkynyl, aryl (preferably 6 to 14-membered aryl), heteroaryl (preferably 3 to 14-membered heteroaryl), cycloalkyl (preferably 3 to 14-membered cycloalkyl), heterocyclic (preferably 3 to 14-membered heterocyclic), halogen, -CN, azide, -NO2, -OR 71 -N(R) 72 (R) 73 ), -S(O) 0-2 R 71 -S(O) 1-2 OR 71 -OS(O)1-2 R 71 -OS(O) 1-2 OR 71 -S(O) 1-2 N(R 72 (R) 73 ), -OS(O) 1-2 N(R 72 (R) 73 ), -N(R 71 S(O) 1-2 R 71 -NR 71 S(O) 1-2 OR 71 -NR 71 S(O) 1-2 N(R 72 (R) 73 ), -OP(O)(OR 71 )2、-C(=X 1 )R 71 -C(=X) 1 )X 1 R 71 -X 1 C(=X 1 )R 71 and -X 1 C(=X 1 )X 1 R 71 And / or any two primary substituents bonded to the same carbon atom of a cycloalkyl or heterocyclic group can combine to form =X 1 In this primary substituent, each of the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclic groups can be substituted by one or more (e.g., one, two, or three) substituents (i.e., secondary substituents), which are independently selected from C10. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, 6- to 14-membered aryl, 3- to 14-membered heteroaryl, 3- to 14-membered cycloalkyl, 3- to 14-membered heterocyclic, halogen, -CF3, -CN, azide, -NO2, -OR 81 -N(R) 82 (R) 83 ), -S(O) 0-2 R 81 -S(O) 1-2 OR 81 -OS(O) 1-2 R 81 -OS(O) 1-2 OR 81 -S(O) 1-2N(R 82 (R) 83 ), -OS(O) 1-2 N(R 82 (R) 83 ), -N(R 81 S(O) 1-2 R 81 -NR 81 S(O) 1-2 OR 81 -NR 81 S(O) 1-2 N(R 82 (R) 83 ), -OP(O)(OR 81 )2、-C(=X 2 )R 81 -C(=X) 2 )X 2 R 81 -X 2 C(=X 2 )R 81 and -X 2 C(=X 2 )X 2 R 81 And / or any two secondary substituents bonded to the same carbon atom of a cycloalkyl or heterocyclic group that is a primary substituent can combine to form =X 2 Among them, the C of the secondary substituent 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Each of the alkynyl, 6- to 14-membered aryl, 3- to 14-membered heteroaryl, 3- to 14-membered cycloalkyl, and 3- to 14-membered heterocyclic groups is optionally substituted by one or more (e.g., one, two, or three) substituents (i.e., tertiary substituents) independently selected from C10. 1-3 Alkyl, halogen, -CF3, -CN, azide, -NO2, -OH, -O(C) 1-3 Alkyl), -OCF3, -S(C 1-3 Alkyl groups, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl)2、-NHS(O)2(C 1-3 Alkyl group), -S(O)2NH 2-z (C 1-3 alkyl) z -C(=O)OH, -C(=O)O(C 1-3 Alkyl group), -C(=O)NH 2-z (C 1-3 alkyl) z -NHC(=O)(C1-3 Alkyl group), -NHC(=NH)NH 2-z (C 1-3 alkyl) z and -N(C 1-3 alkyl)C(=NH)NH 2-z (C 1-3 alkyl) z where each z is independently 0, 1, or 2, and each C 1-3 The alkyl group is independently methyl, ethyl, propyl, or isopropyl, and / or any two tertiary substituents attached to the same carbon atom of a 3- to 14-membered cycloalkyl or heterocyclic group as secondary substituents can combine to form =O, =S, =NH, or =N(C 1-3 alkyl);

[0178] in

[0179] R 71 R 72 and R 73 Each of them is independently selected from H, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, 3- to 7-membered cycloalkyl group, 5- or 6-membered aryl group, 5- or 6-membered heterocyclic group, and 3- to 7-membered heterocyclic group, wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Each of the alkynyl, 3- to 7-membered cycloalkyl, 5- or 6-membered aryl, 5- or 6-membered heteroaryl, and 3- to 7-membered heterocyclic groups is optionally substituted by one, two, or three independently selected from the following substituents: C 1-3 Alkyl, halogen, -CF3, -CN, azide, -NO2, -OH, -O(C) 1-3 Alkyl), -OCF3, =O, -S(C 1-3 Alkyl groups, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl)2、-NHS(O)2(C 1-3 Alkyl group), -S(O)2NH 2-z (C 1-3 alkyl) z -C(=O)(C 1-3 Alkyl group), -C(=O)OH, -C(=O)O(C 1-3 Alkyl group), -C(=O)NH 2-z (C 1-3 alkyl) z -NHC(=O)(C 1-3 Alkyl group), -NHC(=NH)NH 2-z (C 1-3 alkyl)z and -N(C 1-3 alkyl)C(=NH)NH 2-z (C 1-3 alkyl) z where each z is independently 0, 1, or 2, and each C 1-3 The alkyl group is independently methyl, ethyl, propyl, or isopropyl;

[0180] R 81 R 82 and R 83 Each of them is independently selected from H, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkynyl, 3- to 6-membered cycloalkyl, 5- or 6-membered aryl, 5- or 6-membered heteroaryl, and 3- to 6-membered heterocyclic, wherein C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Each of the alkynyl, 3- to 6-membered cycloalkyl, 5- or 6-membered aryl, 5- or 6-membered heteroaryl, and 3- to 6-membered heterocyclic groups is optionally substituted by one, two, or three independently selected from the following substituents: C 1-3 Alkyl, halogen, -CF3, -CN, azide, -NO2, -OH, -O(C) 1-3 Alkyl), -OCF3, =O, -S(C 1-3 Alkyl groups, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl)2、-NHS(O)2(C 1-3 Alkyl group), -S(O)2NH 2-z (C 1-3 alkyl) z -C(=O)(C 1-3 Alkyl group), -C(=O)OH, -C(=O)O(C 1-3 Alkyl group), -C(=O)NH 2-z (C 1-3 alkyl) z -NHC(=O)(C 1-3 Alkyl group), -NHC(=NH)NH 2-z (C 1-3 alkyl) z and -N(C 1-3 alkyl)C(=NH)NH 2-z (C 1-3 alkyl) z where each z is independently 0, 1, or 2, and each C 1-3 The alkyl group is independently methyl, ethyl, propyl, or isopropyl; and

[0181] X 1 and X2 Each of them is independently selected from O, S, and N(R) 84 ), where R 84 For H or C 1-3 alkyl.

[0182] Typical primary substituents are preferably selected from C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkynyl, 6 to 14 nucleotides (e.g., 6 to 10 nucleotides) aryl, 3 to 14 nucleotides (e.g., 5 to 6 nucleotides) heteroaryl, 3 to 14 nucleotides (e.g., 3 to 7 nucleotides) cycloalkyl, 3 to 14 nucleotides (e.g., 3 to 7 nucleotides) heterocyclic, halogen, -CN, azide, -NO2, -OR 71 -N(R) 72 (R) 73 ), -S(O) 0-2 R 71 -S(O) 1-2 OR 71 -OS(O) 1- 2R 71 -OS(O) 1-2 OR 71 -S(O) 1-2 N(R 72 (R) 73 ), -OS(O) 1-2 N(R 72 (R) 73 ), -N(R 71 S(O) 1-2 R 71 -NR 71 S(O) 1-2 OR 71 -C(=X) 1 )R 71 -C(=X) 1 )X 1 R 71 -X 1 C(=X 1 )R 71 and -X 1 C(=X 1 )X 1 R 71 For example, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne, 6-membered aryl, 5- or 6-membered heteroaryl, 3- to 7-membered cycloalkyl, 3- to 7-membered (e.g., 5- or 6-membered) heterocyclic, halogen, -CF3, -CN, azide, -NO2, -OH, -O(C 1-3 alkyl), -S(C 1-3Alkyl groups, -NH2, -NH(C 1-3 alkyl), -N(C) 1-3 Alkyl)2、-NHS(O)2(C 1-3 Alkyl group), -S(O)2NH 2-z (C 1-3 alkyl) z -C(=O)OH, -C(=O)O(C 1-3 Alkyl group), -C(=O)NH 2-z (C 1-3 alkyl) z -NHC(=O)(C 1-3 Alkyl group), -NHC(=NH)NH 2-z (C 1-3 alkyl) z and -N(C 1-3 alkyl)C(=NH)NH 2-z (C 1-3 alkyl) z where each z is independently 0, 1, or 2, and each C 1-3 The alkyl group is independently methyl, ethyl, propyl, or isopropyl; wherein X1 is independently selected from O, S, NH, and N(CH3); and R 71 R 72 and R 73 Each of them, as defined above, or preferably, is independently selected from H, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 The alkyl, 5- or 6-membered cycloalkyl, 5- or 6-membered aryl, 5- or 6-membered heteroaryl, and 5- or 6-membered heterocyclic groups, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclic groups is optionally substituted by one, two, or three independent substituents selected from the following: C 1-3 Alkyl, halogen, -CF3, -CN, azide, -NO2, -OH, -O(C) 1-3 alkyl), -S(C 1-3 Alkyl groups, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl)2、-NHS(O)2(C 1-3 Alkyl group), -S(O)2NH 2-z (C 1-3 alkyl) z -C(=O)OH,-C(=O)O(C 1-3 Alkyl group), -C(=O)NH 2-z (C 1-3 alkyl) z -NHC(=O)(C 1-3Alkyl group), -NHC(=NH)NH 2-z (C 1-3 alkyl) z and -N(C 1-3 alkyl)C(=NH)NH 2-z (C 1-3 alkyl) z Each z is independently 0, 1, or 2 and each C 1-3 The alkyl group is independently methyl, ethyl, propyl, or isopropyl. Specific examples of primary substituents are independently selected from C10. 1-3 Alkyl, phenyl, imidazolyl, thiazolyl, cyclopentyl, cyclohexyl, dihydrothiazolyl, thiazolylalkyl, halogen, -CF3, -CN, -OH, -O(C 1-3 alkyl), -S(C 1-3 Alkyl groups, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl)2、-NHS(O)2(C 1-3 Alkyl group), -C(=O)OH, -C(=O)O(C 1-3 Alkyl group), -C(=O)NH 2-z (C 1-3 alkyl) z -NHC(=O)(C 1-3 Alkyl group), -NHC(=NH)NH 2-z (C 1-3 alkyl) z and -N(C 1-3 alkyl)C(=NH)NH 2-z (C 1-3 alkyl) z Each z is independently 0, 1, or 2 and each C 1-3 The alkyl group is independently methyl, ethyl, propyl, or isopropyl. Particularly preferred primary substituents are independently selected from C10. 1-3 Alkyl, phenyl, thiazolyl, halogen (such as F, Cl or Br), -NH2, -NHS(O)2(C 1-3 Alkyl), -NHC(=O)(C 1-3 alkyl) and -NHC(=NH)NH 2-z (C 1-3 alkyl) z Where z is 0, 1, or 2, and each C 1-3 The alkyl groups are methyl, ethyl, propyl, or isopropyl.

[0183] Typical secondary substituents are preferably selected from C. 1-4 Alkyl, C 2-4 alkenyl, C 2-4Alkyne, 6 or 10 aryl, 5 or 6 heteroaryl, 5 or 6 cycloalkyl, 5 or 6 heterocyclic, halogen, =O, =S, -CF3, -CN, azide, -NO2, -OH, -O(C 1-3 alkyl), -S(C 1-3 Alkyl groups, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl)2、-NHS(O)2(C 1-3 Alkyl group), -S(O)2NH 2-z (C 1-3 alkyl) z -C(=O)OH, -C(=O)O(C 1-3 Alkyl group), -C(=O)NH 2-z (C 1-3 alkyl) z -NHC(=O)(C 1-3 Alkyl group), -NHC(=NH)NH 2-z (C 1-3 alkyl) z and -N(C 1-3 alkyl)C(=NH)NH 2-z (C 1-3 alkyl) z Each z is independently 0, 1, or 2 and each C 1-3 The alkyl group is independently methyl, ethyl, propyl, or isopropyl. Specific examples of secondary substituents are independently selected from C10. 1-3 Alkyl, phenyl, 5 or 6-membered heteroaryl, 5 or 6-membered cycloalkyl, 5 or 6-membered heterocyclic, halogen, =O, =S, -CF3, -CN, -OH, -O(C 1-3 alkyl), -S(C 1-3 Alkyl groups, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl)2、-NHS(O)2(C 1-3 Alkyl group), -C(=O)OH, -C(=O)O(C 1-3 Alkyl group), -C(=O)NH 2-z (C 1-3 alkyl) z -NHC(=O)(C 1-3 Alkyl group), -NHC(=NH)NH 2-z (C 1-3 alkyl) z and -N(C 1-3 alkyl)C(=NH)NH 2-z (C 1-3 alkyl) z Each z is independently 0, 1, or 2 and each C1-3 The alkyl group is independently methyl, ethyl, propyl, or isopropyl. Particularly preferred secondary substituents are independently selected from methyl, ethyl, propyl, isopropyl, phenyl, =O, and =S.

[0184] Typical tertiary substituents are preferably selected from C. 1-3 Alkyl, phenyl, halogen, -CF3, -OH, -OCH3, -SCH3, -NH 2-z (CH3) z -C(=O)OH and -C(=O)OCH3, where z is 0, 1 or 2 and C 1-3 The alkyl group is methyl, ethyl, propyl, or isopropyl. Particularly preferred tertiary substituents are selected from methyl, ethyl, propyl, isopropyl, halogens (e.g., F, Cl, or Br) and -CF3, such as halogens (e.g., F, Cl, or Br) and -CF3.

[0185] As used herein, the terms “optional” or “optional” mean that an event, situation, or condition described below may or may not occur, and the description includes both the possibility that the event, situation, or condition may occur and the possibility that it may not occur.

[0186] "Isomers" are compounds that have the same molecular formula but differ in structure ("structural isomers") or the geometric (spatial) positions of functional groups and / or atoms ("stereoisomers"). "Enantiomers" are a pair of stereoisomers, which are non-superimposable mirror images of each other. "Raceous mixtures" or "racemates" contain a pair of equal amounts of enantiomers and are indicated by the prefix (±). "Diarrhetomers" are stereoisomers that are non-superimposable and not mirror images of each other. "Tautomers" are structural isomers of the same chemical substance that can spontaneously and reversibly interconvert, even in their pure form, due to the migration of individual atoms or groups of atoms; that is, tautomers are in dynamic chemical equilibrium with each other. An example of a tautomer is the isomer of keto-enol tautomerism. "Conformation" refers to stereoisomers that can interconvert simply by rotating around a formal single bond, and (especially) includes isomers that result in different three-dimensional forms of (heterocyclic) rings, such as the chair, half-chair, boat, and torsion boat forms of cyclohexane.

[0187] If the structural formula shown in this application can be interpreted as including more than one isomer, unless otherwise expressly stated, the structural formula includes all possible isomers, and therefore includes each individual isomer. For example, a compound of formula (Ia), wherein Hy is:

[0188]

[0189] in Represents the bond between Hy and the remainder of the compound; R 1aIt is 3-methylpiperazinyl and comprises two isomers, for example, an isomer having the following formula (B1) and an isomer having the following formula (B2):

[0190]

[0191] Furthermore, in the compound of formula (Ic), where R 6” It is 1-azabicyclo[2.2.2]oct-3-yl (optionally replaced by one or more R 7' Group substitution) includes two isomers, for example, an isomer having the following formula (B3) and an isomer having the following formula (B4) (where n1 is 0, 1, 2, 3 or greater):

[0192]

[0193] As used herein, "polymorphism" refers to the ability of a solid material (e.g., a compound) to exist in more than one form or crystal structure, i.e., "polymorphic variant" or "polymorphic form." The terms "polymorphic variant" or "polymorphic form" and "polymorphism" are used interchangeably in this invention. According to the invention, these "polymorphic variants" include crystalline forms, amorphous forms, solvates, and hydrates. The existence of different crystalline forms is mainly due to the different conditions used during crystallization, such as:

[0194] • Solvent effect (crystal packing may differ in polar and nonpolar solvents);

[0195] • Certain impurities inhibit growth patterns, which is beneficial to the growth of metastable polymorphs;

[0196] • The level of supersaturation in material crystallization (generally, the higher the concentration above the solubility, the greater the likelihood of metastable state formation);

[0197] • The temperature at which crystallization occurs;

[0198] • The geometric structure of covalent bonds (leading to differences in conformational polymorphism);

[0199] • Changes in stirring conditions.

[0200] Polymorphs may possess different chemical, physical, and / or pharmacological properties, including but not limited to: melting point, X-ray crystallography and diffraction patterns, chemical reactivity, solubility, dissolution rate, vapor pressure, density, hygroscopicity, flowability, stability, compactness, and bioavailability. At specific temperatures, a polymorph can spontaneously transform from a metastable (unstable) form to a stable form. According to Ostwald's law, generally, the least stable polymorph is not the first to crystallize. Therefore, the quality, efficacy, safety, processability, and / or manufacture of compounds such as those of the present invention can be affected by polymorphism. Typically, the most stable polymorph of a compound (e.g., the compound of the present invention) is chosen because it has the lowest probability of transforming into another polymorph. However, for reasons other than stability, such as solubility, dissolution rate, and / or bioavailability, a less stable polymorphic form may be chosen.

[0201] The term "crystalline form" as used in this document refers to the smallest components of the material (i.e., atoms, molecules, or ions) forming a crystalline structure. "Crystal structure" as used herein refers to a unique three-dimensional arrangement of atoms or molecules in a crystalline liquid or solid, characterized by a pattern arranged in a specific manner, a set of atoms, and a lattice exhibiting long-range order and symmetry. A lattice is a periodically repeating array of points in three-dimensional space, with the pattern located at points on the lattice. The subunit of a lattice is the unit cell. Lattice parameters are the lengths of the edges of a single cell and the angles between them. The symmetry of a crystal is manifested in its space group. To describe a crystal structure, the following parameters are required: chemical formula, lattice parameters, space group, atomic coordinates, and the number of occupancy points.

[0202] The term "amorphous form" as used in this paper refers to the fact that the smallest components of the material (i.e., atoms, molecules, or ions) are not arranged in a crystal lattice but are arranged randomly. Therefore, unlike crystals, which exhibit both short-range order (constant distance from the next adjacent atom) and long-range order (periodic repetition of the basic lattice), only short-range order exists in an amorphous form.

[0203] As used herein, the term "complex of a compound" refers to a higher-order compound formed by the association of a compound with one or more other molecules. Exemplary complexes of a compound include, but are not limited to, solvates, clusters, and chelates of the compound.

[0204] As used herein, the term "solvent" refers to an addition complex of a dissolved material in a solvent (e.g., an organic solvent, such as a fatty alcohol (e.g., methanol, ethanol, n-propanol, isopropanol), acetone, acetonitrile, diethyl ether, etc.), water, or a mixture of two or more of these liquids), wherein the addition complex exists in crystalline or mixed crystalline form. The amount of solvent contained in the addition complex may be stoichiometric or non-stoichiometric. A "hydrate" is a solvate in which the solvent is water.

[0205] In isotopically labeled compounds, one or more atoms are replaced by corresponding atoms having the same number of protons but different numbers of neutrons. For example, a hydrogen atom can be replaced by a deuterium atom. Exemplary isotopes that can be used in the compounds of this invention include deuterium, 11 C 13 C 14 C 15 N. 18 F, 32 P, 32 S. 35 S. 36 Cl and 125 I.

[0206] As used herein, the expression "amino protecting group" preferably refers to any group in a compound through which an amino group can be transferred to a less reactive (i.e., protected) amino group. Preferably, the amino protecting group can be incorporated into the corresponding compound in a chemoselective and / or regioselective manner and / or in good yield under mild conditions. Furthermore, the amino protecting group should remain stable under the conditions experienced by the protected compound (e.g., the conditions of the desired reaction and / or purification conditions). Preferably, when present in the compound, the amino protecting group should minimize the risk of stereogenic racemization. In one embodiment, the amino protecting group should be selectively removed from the protected compound under mild conditions to obtain the deprotected compound in high yield. Exemplary amino protecting groups include tert-butoxycarbonyl (BOC), 9-fluorenmethoxycarbonyl (FMOC), benzyloxycarbonyl (Cbz), p-methoxybenzylcarbonyl (MOZ), acetyl (Ac), trifluoroacetyl, benzoyl (Bz), benzyl (Bn), p-methoxybenzyl (PMB), 3,4-dimethoxyphenyl (DMPM), p-methoxyphenyl (PMP), 2,2-trichloromethoxycarbonyl (Troc), triphenylmethyl (trityl; Tr), tosyl (tosyl; Ts), p-bromobenzenesulfonyl (brosyl), 4-nitrobenzenesulfonyl (nosyl), and 2-nitrobenzenesulfonyl (Nps).

[0207] The term "half-life" refers to the time period required to eliminate half of the activity, amount, or number of molecules. In the context of this invention, the half-life of the compounds disclosed herein (e.g., compounds of formula (Ia), (Ib), or (Ic)) indicates the stability of the compound.

[0208] The terms “subject / object,” “patient,” “individual,” or “animal” refer to multicellular animals, such as vertebrates. For example, in the context of this invention, vertebrates are mammals, birds (e.g., poultry), reptiles, amphibians, bony fishes, and cartilaginous fishes, especially any of the above-mentioned domesticated animals and captive animals (especially vertebrates), such as zoo animals (especially vertebrates). Mammals involved in this invention include, but are not limited to, humans, non-human primates, domesticated mammals (e.g., dogs, cats, sheep, cattle, goats, pigs, horses, etc.), laboratory mammals (e.g., mice, rats, rabbits, guinea pigs, etc.), and captive mammals (e.g., zoo mammals). The term “animal” as used herein also includes humans. Specific non-limiting examples of birds include domesticated poultry, and include birds such as chickens, turkeys, ducks, geese, guinea fowl, pigeons, pheasants, etc.; while specific non-limiting examples of bony or cartilaginous fishes include fish suitable for aquaculture, and include bony fishes such as salmon, trout, bass, carp, catfish, etc.

[0209] The compound dasatinib (also referred to herein as compound A8) has the following structure:

[0210]

[0211] compound

[0212] In a first aspect, as may be further described, defined, claimed or otherwise disclosed herein, the present invention provides a compound selected from kinase inhibitors of the following formula:

[0213]

[0214] And solvates, salts, N-oxides, complexes, polymorphs, crystalline forms, racemic mixtures, diastereomers, enantiomers, tautomers, conformational isomers, isotopic labeled forms, prodrugs and combinations thereof;

[0215] in:

[0216] Hy is an R that is arbitrarily chosen by one or more independent selections. 1e Substituted heteroaryl or heterocyclic groups;

[0217] Each R 1e Independently selected from R 1a R 1b R 1c and R 1d ;

[0218] R 1a and R 1dEach of these groups is independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, heteroaryl, halogen, -CN, azide, -NO2, -OR 11 -N(R) 12 (R) 13 ), -N(R 11 (OR) 11 ), -S(O) 0-2 R 11 -S(O) 1-2 OR 11 -OS(O) 1-2 R 11 -OS(O) 1-2 OR 11 -S(O) 1-2 N(R 12 (R) 13 ), -OS(O) 1-2 N(R 12 (R) 13 ), -N(R 11 S(O) 1-2 R 11 -NR 11 S(O) 1-2 OR 11 -NR 11 S(O) 1-2 N(R 12 (R) 13 -P(O)(OR) 11 )2、-OP(O)(OR 11 )2、-C(=X)R 11 -C(=X)XR 11 -XC(=X)R 11 and -XC(=X)XR 11 Each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, and heteroaryl groups is optionally represented by one or more independently selected R groups. 30 replace;

[0219] R 1b and R 1c Each of them is independently selected from H, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 cycloalkyl, C 6-10 Aryl, 3- to 7-membered heteroaryl, 3- to 7-membered heterocyclic, -O(CH2) 0-2 (C 3-7 cycloalkyl), -O(CH2) 0-2 (C 6-10 Aryl), -O(CH2)0-2 (3 to 7-membered heteroaryl groups), -O(CH2) 0-2 (3 to 7-membered heterocyclic groups), -NH(CH2) 0-2 (C 3-7 cycloalkyl), -NH(CH2) 0-2 (C 6-10 Aryl), -NH(CH2) 0-2 (3 to 7-membered heterocyclic groups), -NH(CH2) 0-2 (3- to 7-membered heterocyclic groups), halogens, -CF3, -CN, azide groups, -NO2, -OH, -O(C 1-6 Alkyl), -OCF3, -S(C 1-6 Alkyl groups, -NH2, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl)2、-NHS(O)2(C 1-6 Alkyl group), -S(O)2NH 2-z (C 1-6 alkyl) z -C(=O)(C 1-6 Alkyl group), -C(=O)OH, -C(=O)O(C 1-6 Alkyl group), -C(=O)NH 2-z (C 1-6 alkyl) z -NHC(=O)(C 1-6 Alkyl group), -NHC(=NH)NH 2-z (C 1-6 alkyl) z and -N(C 1-6 alkyl)C(=NH)NH 2-z (C 1-6 alkyl) z Where z is 0, 1, or 2, and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 cycloalkyl, C 6-10 Each of the aryl, 3- to 7-membered heteroaryl, and 3- to 7-membered heterocyclic groups is optionally composed of one, two, or three independently selected from -OH, methyl, ethyl, -OCH3, -SCH3, and -NH. 2-z (CH3) z Partial replacement;

[0220] R 2 It is H;

[0221] R 3 Selected from alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, heteroaryl, halogen, -CN, azide, -NO2, -OR 11-N(R) 12 (R) 13 ), -N(R 11 (OR) 11 ), -S(O) 0-2 R 11 -S(O) 1-2 OR 11 -OS(O) 1-2 R 11 -OS(O) 1-2 OR 11 -S(O) 1-2 N(R 12 (R) 13 ), -OS(O) 1-2 N(R 12 (R) 13 ), -N(R 11 S(O) 1-2 R 11 -NR 11 S(O) 1-2 OR 11 -NR 11 S(O) 1-2 N(R 12 (R) 13 -P(O)(OR) 11 )2、-OP(O)(OR 11 )2、-C(=X)R 11 -C(=X)XR 11 -XC(=X)R 11 and -XC(=X)XR 11 Each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, and heteroaryl groups is optionally represented by one or more independently selected R groups. 30 replace;

[0222] R 4 It is H;

[0223] R 5 Yes -LR 6 ;

[0224] L is selected from key, C 1-6 Alkylene, C 2-6 imidene group, C 2-6 Alynyl group and -(CH2) m -[Y-(CH2) n ] o - where m is an integer between 1 and 6, n is an integer between 0 and 3, and o is an integer between 1 and 3, where o is 1 if n is 0; Y is independently selected from O, S, and -N(R). 13-; The C 1-6 Alkylene, C 2-6 imidene group, C 2-6 Alynyl group, -(CH2) m - and -(CH2) n - Each of the groups is optionally represented by one or two independently selected R groups. 30 replace;

[0225] R 6 It is an R containing at least one S ring atom and selected by one or more independently chosen atoms. 7 Substituted 5-membered monocyclic heteroaryl group;

[0226] R 7 Independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, heteroaryl, halogen, -CN, azide, -NO2, -OR 11 -N(R) 12 (R) 13 ), -N(R 11 (OR) 11 ), -S(O) 0-2 R 11 -S(O) 1-2 OR 11 -OS(O) 1-2 R 11 -OS(O) 1-2 OR 11 -S(O) 1-2 N(R 12 (R) 13 ), -OS(O) 1-2 N(R 12 (R) 13 ), -N(R 11 S(O) 1-2 R 11 -NR 11 S(O) 1-2 OR 11 -NR 11 S(O) 1-2 N(R 12 (R) 13 -P(O)(OR) 11 )2、-OP(O)(OR 11 )2、-C(=X)R 11 -C(=X)XR 11 -XC(=X)R 11 and -XC(=X)XR 11 Each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, and heteroaryl groups is optionally represented by one or more independently selected R groups. 30Replace, where R 7 At least one of them is F and / or R 7 At least one of them is replaced by one or more F atoms;

[0227] A is selected from S, O, NR 8 and C(R) 9 )2;

[0228] R 8 Selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, and heterocyclic, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, and heteroaryl groups is optionally selected by one or more independently chosen R groups. 30 replace;

[0229] R 9 Independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, heteroaryl, halogen, -CN, azide, -NO2, -OR 11 -N(R) 12 (R) 13 ), -S(O) 0-2 R 11 -S(O) 1-2 OR 11 -OS(O) 1-2 R 1 -OS(O) 1-2 OR 11 -S(O) 1-2 N(R 12 (R) 13 ), -OS(O) 1-2 N(R 12 (R) 13 ), -N(R 11 S(O) 1-2 R 11 -NR 11 S(O) 1-2 OR 11 -NR 11 S(O) 1-2 N(R 12 (R) 13 -C(=X)R 11 -C(=X)XR 11 -XC(=X)R 11 and -XC(=X)XR 11 Each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, and heteroaryl groups is optionally represented by one or more independently selected R groups. 30 replace;

[0230] X is independently selected from O, S, and N(R)14 );

[0231] E is either O or S;

[0232] R 11 Independently selected from H, alkyl, alkenyl, ynyl, cycloalkyl, aryl, heteroaryl, and heterocyclic groups, wherein each of the alkyl, alkenyl, ynyl, cycloalkyl, aryl, heteroaryl, and heterocyclic groups is optionally selected by one or more independently chosen R groups. 30 replace;

[0233] R 12 and R 13 Each of these groups is independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclic groups, or R. 12 and R 13 They can combine with the nitrogen atoms they are attached to to form the group -N=CR. 15 R 16 Each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclic groups is optionally represented by one or more independently selected R groups. 30 replace;

[0234] R 14 Independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclic and -OR 11 Each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclic groups is optionally represented by one or more independently selected R groups. 30 replace;

[0235] R 15 and R 16 Each of these groups is independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, heterocyclic, and -NH. y R 20 2-y , or R 15 and R 16 They can be linked together with the atoms they are attached to to form a ring, which can be formed by one or more independently selected R atoms. 30 Substitution, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclic groups is optionally replaced by one or more independently selected R groups. 30 replace;

[0236] y is an integer from 0 to 2;

[0237] R 20 Independently selected from alkyl, alkenyl, ynyl, cycloalkyl, aryl, heteroaryl, and heterocyclic groups, wherein each of the alkyl, alkenyl, ynyl, cycloalkyl, aryl, heteroaryl, and heterocyclic groups is optionally selected by one or more independently chosen R groups. 30Replace; and

[0238] R 30 It is a primary substituent, and in each case, it is independently selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclic, halogen, -CN, azide, -NO2, -OR 71 -N(R) 72 (R) 73 ), -S(O) 0-2 R 71 -S(O) 1-2 OR 71 -OS(O) 1-2 R 71 -OS(O) 1-2 OR 71 -S(O) 1-2 N(R 72 (R) 73 ), -OS(O) 1-2 N(R 72 (R) 73 ), -N(R 71 S(O) 1-2 R 71 -NR 71 S(O) 1-2 OR 71 -NR 71 S(O) 1-2 N(R 72 (R) 73 ), -OP(O)(OR 71 )2、-C(=X 1 )R 71 -C(=X) 1 )X 1 R 71 -X 1 C(=X 1 )R 71 and -X 1 C(=X 1 )X 1 R 71 And / or any two R groups bonded to the same carbon atom of a cycloalkyl or heterocyclic group. 30 They can be combined to form =X 1 In this embodiment, each of the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclic groups that are primary substituents is optionally substituted by one or more secondary substituents, wherein, in each case, the secondary substituent is independently selected from C10. 1-6 Alkyl, C 2-6 alkenyl, C 2-6Alkyne, 3 to 14 aryl, 3 to 14 heteroaryl, 3 to 14 cycloalkyl, 3 to 14 heterocyclic, halogen, -CF3, -CN, azide, -NO2, -OR 81 -N(R) 82 (R) 83 ), -S(O) 0-2 R 81 -S(O) 1- 2OR 81 -OS(O) 1-2 R 81 -OS(O) 1-2 OR 81 -S(O) 1-2 N(R 82 (R) 83 ), -OS(O) 1-2 N(R 82 (R) 83 ), -N(R 81 S(O) 1- 2R 81 -NR 81 S(O) 1-2 OR 81 -NR 81 S(O) 1-2 N(R 82 (R) 83 ), -OP(O)(OR 81 )2、-C(=X 2 )R 81 -C(=X) 2 )X 2 R 81 -X 2 C(=X 2 )R 81 and -X 2 C(=X 2 )X 2 R 81 And / or any two secondary substituents bonded to the same carbon atom of a cycloalkyl or heterocyclic group that is a primary substituent can combine to form =X 2 Among them, C is a secondary substituent. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Each of the alkynyl, 3- to 14-membered aryl, 3- to 14-membered heteroaryl, 3- to 14-membered cycloalkyl, and 3- to 14-membered heterocyclic groups is optionally substituted by one or more tertiary substituents, wherein, in various cases, the tertiary substituents are independently selected from C1-3 alkyl, halogen, -CF3, -CN, azide, -NO2, -OH, -O(C 1-3 Alkyl), -OCF3, -S(C1-3 Alkyl groups, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl)2、-NHS(O)2(C 1-3 Alkyl group), -S(O)2NH 2-z (C 1-3 alkyl) z -C(=O)OH, -C(=O)O(C 1-3 Alkyl group), -C(=O)NH 2-z (C 1-3 alkyl) z -NHC(=O)(C 1-3 Alkyl group), -NHC(=NH)NH 2-z (C 1-3 alkyl) z and -N(C 1-3 alkyl)C(=NH)NH 2-z (C 1-3 alkyl) z Each z is independently 0, 1, or 2 and each C 1-3 The alkyl group is independently methyl, ethyl, propyl, or isopropyl, and / or any two tertiary substituents bonded to the same carbon atom of a 3- to 14-membered cycloalkyl or heterocyclic group as secondary substituents can combine to form =O, =S, =NH, or =N(C 1-3 alkyl);

[0239] in

[0240] R 71 R 72 and R 73 Each of them is independently selected from H, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, 3- to 7-membered cycloalkyl group, 5- or 6-membered aryl group, 5- or 6-membered heterocycloalkyl group and 3- to 7-membered heterocycloyl group, wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Each of the alkynyl, 3- to 7-membered cycloalkyl, 5- or 6-membered aryl, 5- or 6-membered heterocycloalkyl, and 3- to 7-membered heterocycloyl groups is optionally substituted by one, two, or three independent substituents selected from the following: C 1-3 Alkyl, halogen, -CF3, -CN, azide, -NO2, -OH, -O(C) 1-3 Alkyl), -OCF3, =O, -S(C 1-3 Alkyl groups, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl)2、-NHS(O)2(C 1-3Alkyl group), -S(O)2NH 2-z (C 1-3 alkyl) z -C(=O)(C 1-3 Alkyl group), -C(=O)OH, -C(=O)O(C 1-3 Alkyl group), -C(=O)NH 2-z (C 1-3 alkyl) z -NHC(=O)(C 1-3 Alkyl group), -NHC(=NH)NH 2-z (C 1-3 alkyl) z and -N(C 1-3 alkyl)C(=NH)NH 2-z (C 1-3 alkyl) z where each z is independently 0, 1, or 2, and each C 1-3 The alkyl group is independently methyl, ethyl, propyl, or isopropyl;

[0241] R 81 R 82 and R 83 Each of them is independently selected from H, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, 3- to 6-membered cycloalkyl group, 5- or 6-membered aryl group, 5- or 6-membered heterocycloalkyl group, and 3- to 6-membered heterocycloyl group, wherein the C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Each of the alkynyl, 3- to 6-membered cycloalkyl, 5- or 6-membered aryl, 5- or 6-membered heterocycloalkyl, and 3- to 6-membered heterocycloyl groups is optionally substituted by one, two, or three independently selected from the following substituents: C 1-3 Alkyl, halogen, -CF3, -CN, azide, -NO2, -OH, -O(C) 1-3 Alkyl), -OCF3, =O, -S(C 1-3 Alkyl groups, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl)2、-NHS(O)2(C 1-3 Alkyl group), -S(O)2NH 2-z (C 1-3 alkyl) z -C(=O)(C 1-3 Alkyl group), -C(=O)OH, -C(=O)O(C 1-3 Alkyl group), -C(=O)NH 2-z (C 1-3 alkyl) z-NHC(=O)(C 1-3 Alkyl group), -NHC(=NH)NH 2-z (C 1-3 alkyl) z and -N(C 1-3 alkyl)C(=NH)NH 2-z (C 1-3 alkyl) z where each z is independently 0, 1, or 2, and each C 1-3 The alkyl group is independently methyl, ethyl, propyl, or isopropyl; and

[0242] X 1 and X 2 Each of them is independently selected from O, S, and N(R) 84 ), where R 84 Is it H or C? 1-3 alkyl.

[0243] In one embodiment, the kinase inhibitor has formula (IIa):

[0244]

[0245] Among them Hy, R 2 R 3 R 4 A and E are independently defined as above (particularly with respect to equation (Ia)) or below (particularly with respect to equations (IIIa), (IVa), (Va), (VIa), (VIIa) and / or (VIIIa)), and R 5 Yes -LR 6 Where L is as defined above (especially with respect to equation (Ia)) or below and R 6 It is a 5-membered monocyclic heteroaryl group containing at least one S ring atom, and R is independently selected by one or more (e.g., from 1 to a maximum number of hydrogen atoms bonded to the 5-membered monocyclic heteroaryl group, e.g., 1, 2 or 3, preferably 2) 7 Replace, where R 7 Independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, heteroaryl, halogen, -CN, azide, -NO2, -OR 11 -N(R) 12 (R) 13 ), -N(R 11 (OR) 11 ), -S(O) 0-2 R 11 -S(O) 1-2 OR 11 -OS(O) 1-2 R 11 -OS(O) 1-2 OR11 -S(O) 1-2 N(R 12 (R) 13 ), -OS(O) 1-2 N(R 12 (R) 13 ), -N(R 11 S(O) 1-2 R 11 -NR 11 S(O) 1-2 OR 11 -NR 11 S(O) 1-2 N(R 12 (R) 13 -P(O)(OR) 11 )2、-OP(O)(OR 11 )2、-C(=X)R 11 -C(=X)XR 11 -XC(=X)R 11 and -XC(=X)XR 11 Each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, and heteroaryl groups is optionally combined with one or more (e.g., 1 to a maximum number of hydrogen atoms with the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, or heterocyclic group, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, e.g., 1 to 5, 1 to 4, or 1 to 3, or 1 or 2) independently selected R 30 Replace, where R 7 At least one of them is F and / or R 7 At least one of them is replaced by one or more F atoms.

[0246] In one embodiment of the formula (IIa) kinase inhibitor, Hy, R 2 R 3 R 4 A, E, L and R 7 Independently as defined above (especially with respect to equation (Ia)) or below (especially with respect to equations (IIIa), (IVa), (Va), (VIa), (VIIa) and / or (VIIIa)), R 6 The R group is selected from thienyl, thiazolyl, and thiadiazolyl groups, wherein each group is independently selected by one or more (e.g., from 1 to a maximum number of hydrogen atoms bonded to a 5-membered monocyclic heteroaryl group, e.g., 1, 2, or 3). 7 Replacement. For example, R 6 The R group can be selected from thiophene and thiazolyl groups, each of which is independently selected by one or more (e.g., from 1 to a maximum number of hydrogen atoms bonded to a 5-membered monocyclic heteroaryl group, e.g., 1, 2, or 3). 7Replacement. Preferably, R 6 R is independently selected by one or more (e.g., from 1 to a maximum number of hydrogen atoms bonded to a 5-membered monocyclic heteroaryl group, e.g., 1, 2 or 3, preferably 2). 7 Substituted thiophene group.

[0247] In any of the above embodiments of the formula (IIa) kinase inhibitor (including the formula (Ia) kinase inhibitor), R is preferred. 6 R 6 The ring atom that binds to the rest of the compound is a carbon atom.

[0248] In any of the above embodiments of the formula (IIa) kinase inhibitor (including the formula (Ia) kinase inhibitor), preferably R 6 Selected from:

[0249]

[0250]

[0251] in R represents 6 Bonds that bind to the rest of the compound.

[0252] In any of the above embodiments of the formula (IIa) kinase inhibitor (including the formula (Ia) kinase inhibitor), R is preferred. 6 The S ring atoms do not interact with R 6 The ring atoms are adjacent to it through its bond with the rest of the compound.

[0253] In one embodiment of the formula (IIa) kinase inhibitor, Hy, R 2 R 3 R 4 A, E, L and R 7 Independently as defined above (especially with respect to equation (Ia)) or below (especially with respect to equations (IIIa), (IVa), (Va), (VIa), (VIIa) and / or (VIIIa)), R 6 It is a thiophene group or a thiazole group, preferably a thiophene group, each of which is surrounded by at least two R groups. 7 Replacement; in this embodiment, it is more preferable to use two Rs that are different from each other. 7 Replace R 6 .

[0254] In any of the above embodiments of the formula (IIa) kinase inhibitor (including the formula (Ia) kinase inhibitor), a preferred R 7 (especially R) 7 For F and / or R 7 (replaced by one or more F atoms) in relation to R6 The ring atoms that bind to the remainder of the compound are attached to C ring atoms at positions 2 or 5. In these cases, where R 6 At least two R 7 Group substitution, preferably, one of the R groups 7 Groups (especially R) 7 For F and / or R 7 (replaced by one or more F atoms) in relation to R 6 The ring atoms at positions 2 and 5 of the remaining part of the compound are attached to one of the C ring atoms, and one of the R atoms is attached to the other. 7 Groups relative to R 6 The ring atoms at positions 2 and 5, which are bound to the remainder of the compound, are attached to another C ring atom.

[0255] In one embodiment of the formula (IIa) kinase inhibitor, Hy, R 2 R 3 R 4 A, E, L and R 6 Independently as defined above (especially with respect to equation (Ia)) or below (especially with respect to equations (IIIa), (IVa), (Va), (VIa), (VIIa) and / or (VIIIa)), and R 7 At least one of them is F and / or R 7 At least one of them is selected from: alkyl, -OR 11 and -N(R) 12 (R) 13 ), wherein the alkyl and R 11 Each of the groups and the R 12 and R 13 At least one of the groups is combined with one or more (e.g., 1 to alkyl, R) 11 R 12 Or R 13 The maximum number of hydrogen atoms bonded to the group, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9 or up to 10, for example 1 to 5, 1 to 4 or 1 to 3 or 1 or 2) F atom substitution.

[0256] In one embodiment of the formula (IIa) kinase inhibitor, Hy, R 2 R 3 R 4 A, E, L and R 6 Independently as defined above (especially with respect to equation (Ia)) or below (especially with respect to equations (IIIa), (IVa), (Va), (VIa), (VIIa) and / or (VIIIa)), and R 7 At least one of them is F and / or R 7At least one of them is selected from: alkyl, -O (alkyl), -NH (alkyl) and -N (alkyl)2, wherein the alkyl of alkyl, -O (alkyl), -NH (alkyl) and at least one alkyl of -N (alkyl)2 is substituted by one or more F atoms (e.g., 1 to the maximum number of hydrogen atoms combined with alkyl, such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or up to 10, such as 1 to 5, 1 to 4 or 1 to 3, or 1 or 2).

[0257] In one embodiment of the formula (IIa) kinase inhibitor, Hy, R 2 R 3 R 4 A, E, L and R 6 Independently as defined above (especially with respect to equation (Ia)) or below (especially with respect to equations (IIIa), (IVa), (Va), (VIa), (VIIa) and / or (VIIIa)), and R 7 At least one of them is F and / or R 7 At least one of them is selected from C 1-3 Alkyl, -O(C) 1-3 alkyl), -NH(C) 1-3 alkyl) or -N(C) 1-3 Alkyl)2, wherein, C 1-3 Alkyl, -O(C) 1-3 alkyl) and -NH(C 1-3 alkyl groups and -N(C) 1-3 At least one alkyl group of alkyl group 2 is contained in one or more (e.g., 1 to C) 1-3 The maximum number of hydrogen atoms in an alkyl group, for example 1, 2, 3, 4, 5, 6, 7 or up to 6, for example 1 to 5, 1 to 4 or 1 to 3 or 1 or 2) F atom substitution.

[0258] In one embodiment of the formula (IIa) kinase inhibitor, Hy, R 2 R 3 R 4 A, E, L and R 6 Independently as defined above (especially with respect to equation (Ia)) or below (especially with respect to equations (IIIa), (IVa), (Va), (VIa), (VIIa) and / or (VIIIa)), and R 7 At least one of them is F and / or R 7 At least one of them is C 1-3 Alkyl, wherein C 1-3 The alkyl group is composed of one or more (e.g., 1 to C) alkyl groups. 1-3The maximum number of hydrogen atoms in an alkyl group, for example 1, 2, 3, 4, 5, 6, 7 or up to 6, for example 1 to 5, 1 to 4 or 1 to 3 or 1 or 2) F atom substitution.

[0259] In one embodiment of the formula (IIa) kinase inhibitor, Hy, R 2 R 3 R 4 A, E, L and R 6 Independently as defined above (especially with respect to equation (Ia)) or below (especially with respect to equations (IIIa), (IVa), (Va), (VIa), (VIIa) and / or (VIIIa)), and R 7 At least one of them is F and / or R 7 At least one of them is selected from -CH2F, -CHF2 and -CF3, preferably selected from -CH2F and -CHF2.

[0260] In one embodiment of the formula (IIa) kinase inhibitor, Hy, R 2 R 3 R 4 A, E, L and R 6 Independently as defined above (particularly with respect to equation (Ia)) or below, particularly with respect to equations (IIIa), (IVa), (Va), (VIa), (VIIa) and / or (VIIIa)), and R 6 At least two R 7 The replacements include one R7 selected from -CH2F, -CHF2, and -CF3, and one R 7 The compounds are selected from halogens, -CH3, -CH2(hal), -CH(hal)2, and -C(hal)3, and more preferably from Cl, Br, F, CH3, -CH2F, -CHF2, and -CF3. For example, in one embodiment, an R 7 Selected from -CH2F, -CHF2 and -CF3, preferably selected from -CH2F and -CHF2, and one R 7 It is Cl. In an alternative embodiment, an R 7 It's F, and an R. 7 Selected from halogens, -CH3, -CH2(hal), -CH(hal)2 and -C(hal)3, more preferably selected from Cl, Br, F, CH3, -CH2F, -CHF2 and -CF3; more preferably, one R 7 It's F, and an R. 7 It is Cl. In these embodiments, preferably, the two Rs 7 One of the groups in the group is relative to R 6The ring atoms at positions 2 and 5, which bind to the remainder of the compound, are attached to one of the C ring atoms, and these two R atoms... 7 Another group in relation to R 6 The ring atoms that are bonded to the rest of the compound are attached to another C ring atom at positions 2 and 5.

[0261] In one embodiment of the formula (IIa) kinase inhibitor, Hy, R 2 R 3 R 4 A, L, and E are independently defined as above (particularly with respect to equation (Ia)) or below (particularly with respect to equations (IIIa), (IVa), (Va), (VIa), (VIIa), and / or (VIIIa)), and R 6 Selected from:

[0262]

[0263] More preferably selected from:

[0264] Or selected from:

[0265] in In each case, R is represented as 6 Bonds that bind to the remainder of the compound.

[0266] In any of the above embodiments of the (IIa) kinase inhibitor (including the (Ia) kinase inhibitor), L may be selected from the bond, C 1-6 Alkylene, C 2-6 imidene group, C 2-6 Alynyl group and -(CH2) m -[Y-(CH2) n ] o - where m is 1, 2, or 3, n is 0, 1, or 2, and o is 1, 2, or 3, where o is 1 if n is 0; Y is independently selected from O, S, and NH, where C 1-6 Alkylene, C 2-6 imidene group, C 2-6 Alynyl group, -(CH2) m - and -(CH2) n Each of the groups is optionally represented by one or two independently selected R groups. 30 Substitution. For example, in any of the above embodiments of the kinase inhibitor of formula (IIa) (including the kinase inhibitor of formula (Ia)), L may be selected from: bond; C1 alkylene, optionally with an R 30 Substitution; C2 alkylene (especially 1,2-ethylene or 1,1-ethylene), optionally with an R 30Substitution; C3 alkylene (especially trimethylene) is optionally replaced by an R 30 Substitution; C4 alkylene (especially tetramethylene or 2,4-butadiene), optionally with an R 30 -(CH2) m O- and -(CH2) m NH-substitution, where m is 1, 2, or 3. In particular, in any of the above embodiments of the formula (IIa) kinase inhibitor (including the formula (Ia) kinase inhibitor), L may be selected from: a bond, a C1 alkylene group, optionally separated by an R 30 Substitution; C2 alkylene (especially 1,2-ethylene or 1,1-ethylene), optionally with an R 30 -(CH2) m O- and -(CH2) m NH-substitution; preferably, L can be selected from: bond, -(CH2)-, -(CH2)2-.

[0267] Most preferably, in any of the above embodiments of the kinase inhibitor of formula (IIa) (including the kinase inhibitor of formula (Ia)), L is a bond (i.e., R 5 It is R 6 ).

[0268] In one embodiment, the kinase inhibitor has formula (IIIa):

[0269]

[0270] In one embodiment of the (IIa) kinase inhibitor, Hy, R 2 R 3 R 4 and R 5 Independently as defined above (particularly with respect to formulas (Ia) and / or (IIa)) or below (particularly with respect to formulas (IIIa), (IVa), (Va), (VIa), (VIIa) and / or (VIIIa)), E is O or S (preferably O); and A is selected from S, O, NH, N (C 1-6 alkyl) and C(C) 1-6 Alkyl)2. In any of the above embodiments of the kinase inhibitor of formula (IIIa) (including kinase inhibitors of formula (Ia) and (IIa)), E is O or S (preferably O); A may be S, O or N(CH3)2. In any of the above embodiments of the kinase inhibitor of formula (IIIa) (including kinase inhibitors of formula (Ia) and (IIa)), E is preferably O or S (preferably O); and A is S. In any of the above embodiments of the kinase inhibitor of formula (IIIa) (including kinase inhibitors of formula (Ia) and (IIa)), E is preferably O; and A is S.

[0271] In one embodiment, the kinase inhibitor has the formula (IVa):

[0272]

[0273] Among them Hy, R 2 R 4 R 5 A and E are independently defined as above (in particular with respect to equations (Ia), (IIa) and / or (IIIa)) or below (in particular with respect to equations (IIIa), (IVa), (Va), (VIa), (VIIa) and / or (VIIIa)), and R 3 Selected from H, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, phenyl, halogen, -CN, azide, -NO2, -O(C 1-6 Alkyl), -OCF3, -S(C 1-6 Alkyl groups, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2、-NHS(O)2(C 1-6 Alkyl group), -S(O)2NH 2-z (C 1-6 alkyl) z -C(=O)(C 1-6 Alkyl group), -C(=O)OH, -C(=O)O(C 1-6 Alkyl group), -C(=O)NH 2-z (C 1-6 alkyl) z -NHC(=O)(C 1-6 Alkyl group), -NHC(=NH)NH 2-z (C 1-6 alkyl) z and -N(C 1-6 alkyl)C(=NH)NH 2-z (C 1-6 alkyl) z Where z is 0, 1, or 2, and where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Each of the cycloalkyl and phenyl groups is optionally represented by one or more (e.g., 1 to C). 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6The maximum number of hydrogen atoms in the combination of cycloalkyl and phenyl groups, such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or up to 10, such as 1 to 5, 1 to 4, 1 to 3, or 1 or 2, is independently chosen by R. 30 replace.

[0274] In one embodiment of the (IVa) kinase inhibitor, Hy, R 2 R 4 R 5 A and E are independently defined as above (in particular with respect to equations (Ia), (IIa) and / or (IIIa)) or below (in particular with respect to equations (IIIa), (IVa), (Va), (VIa), (VIIa) and / or (VIIIa)), and R 3 Selected from H, C 1-4 Alkyl, C 3-6 Cycloalkyl, phenyl, halogen, -CN, -O(C) 1-4 Alkyl), -OCF3, -S(C 1-4 Alkyl groups, -NH2, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl)2、-C(=O)(C 1-4 Alkyl group), -C(=O)OH, -C(=O)O(C 1-4 Alkyl group), -C(=O)NH 2-z (C 1-4 alkyl) z -NHC(=O)(C 1-4 Alkyl group), -NHC(=NH)NH 2-z (C 1-4 alkyl) z and -N(C 1-4 alkyl)C(=NH)NH 2-z (C 1-4 alkyl) z , wherein, the C 1-4 Alkyl, C 3-6 Each of the cycloalkyl and phenyl groups is optionally selected independently by one, two, or three from halogen, methyl, isopropyl, -CN, -CF3, -OCF3, -OH, -NH2, -NH(C 1-3 alkyl), -N(C) 1-3 Alkyl)2、-NHC(=O)(C 1-3 Alkyl group), -C(=O)NH 2-z (C 1-3 alkyl) z -(CH2) 1-3 NH2、-(CH2) 1-3 NH(C 1-3 Alkyl group), -(CH2) 1-3N(C 1-3 Alkyl group 2, -(CH2) 1-3 OH and (CH2) 1-3 O(C 1-3 Alkyl groups are substituted; where z is 0, 1 or 2.

[0275] In one embodiment of the (IVa) kinase inhibitor, Hy, R 2 R 4 R 5 A and E are independently defined as above (particularly with respect to equations (Ia), (IIa) and / or (IIIa)) or (hereinafter particularly with respect to equations (IIIa), (IVa), (Va), (VIa), (VIIa) and / or (VIIIa)), and R 3 Selected from H, C 1-4 Alkyl, C 3-6 Cycloalkyl, phenyl, halogen, -CN, -O(C) 1-4 Alkyl), -OCF3, -S(C 1-4 Alkyl groups, -NH2, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl)2、-C(=O)(C 1-4 Alkyl group), -C(=O)OH, -C(=O)O(C 1-4 Alkyl group), -C(=O)NH 2-z (C 1-4 alkyl) z -NHC(=O)(C 1-4 Alkyl group), -NHC(=NH)NH 2-z (C 1-4 alkyl) z and -N(C 1-4 alkyl)C(=NH)NH 2-z (C 1-4 alkyl) z The phenyl group is optionally substituted with one, two, or three groups independently selected from the following: halogen, methyl, isopropyl, -CN, -CF3, -OCF3, -OH, -NH2, -NH(C 1-3 alkyl), -N(C) 1-3 Alkyl)2、-NHC(=O)(C 1-3 Alkyl group), -C(=O)NH 2-z (C 1-3 alkyl) z -(CH2) 1-3 NH2、-(CH2) 1-3 NH(C 1-3 Alkyl group), -(CH2) 1-3 N(C 1-3Alkyl group 2, -(CH2) 1-3 OH and CH2) 1-3 O(C 1-3 Alkyl); where z is 0, 1 or 2.

[0276] In one embodiment of the (IVa) kinase inhibitor, Hy, R 2 R 4 R 5 A and E are independently defined as above (in particular with respect to equations (Ia), (IIa) and / or (IIIa)) or below (in particular with respect to equations (IIIa), (IVa), (Va), (VIa), (VIIa) and / or (VIIIa)), and R 3 Selected from H, methyl, ethyl, propyl, isopropyl, phenyl and halogen.

[0277] In one embodiment of the (IVa) kinase inhibitor, Hy, R 2 R 4 R 5 A and E are independently defined as above (in particular with respect to equations (Ia), (IIa) and / or (IIIa)) or below (in particular with respect to equations (IIIa), (IVa), (Va), (VIa), (VIIa) and / or (VIIIa)), and R 3 It is H.

[0278] In one embodiment, the kinase inhibitor has the formula (Va):

[0279]

[0280] Where R 2 R 3 R 4 R 5 A and E are independently defined as above (particularly with respect to formulas (Ia), (IIa), (IIIa)) or below (particularly with respect to formulas (IIIa), (IVa), (Va), (VIa), (VIIa) and / or (VIIIa)), Hy is a 3 to 10-membered heteroaryl or a 3 to 10-membered heterocyclic group, wherein each is optionally independently selected by one or more R (e.g., 1 to a maximum number of hydrogen atoms bonded to the 3 to 10-membered heteroaryl or 3 to 10-membered heterocyclic group, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or up to 10, e.g., 1 to 5, 1 to 4, 1 to 3 or 1 or 2). 1e Replace, where each R 1e Independently selected from R 1a R 1b R 1c and R 1d And R 1a R1b R 1c and R 1d Each of these is independently defined as above (particularly with respect to formula (Ia)) or below (particularly with respect to formulas (IIIa), (IVa), (Va), (VIa), (VIIa) and / or (VIIIa)). For example, Hy may be selected from: 5- to 6-membered monocyclic heterocyclic groups, 5- to 6-membered monocyclic heterocyclic groups, 9- to 10-membered bicyclic heterocyclic groups, and 8- to 10-membered bicyclic heterocyclic groups, wherein each is optionally independently selected by one or more R (e.g., 1 to the maximum number of hydrogen atoms combined with 5- to 6-membered monocyclic heterocyclic groups, 5- to 6-membered monocyclic heterocyclic groups, 9- to 10-membered bicyclic heterocyclic groups, or 8- to 10-membered bicyclic heterocyclic groups, such as 1 to 5, 1 to 4, 1 to 3, or 1 or 2). 1e Replace, where each R 1e Independently selected from R 1a R 1b R 1c and R 1d And R 1a R 1b R 1c and R 1d Each of these is independently defined as above (particularly with respect to formula (Ia)) or below, particularly with respect to formulas (IIIa), (IVa), (Va), (VIa), (VIIa), and / or (VIIIa)). Preferably, Hy is a heteroaryl or heterocyclic group containing at least one N-ring atom and optionally independently selected by one or more R atoms (e.g., 1 to a maximum number of hydrogen atoms bonded to the heteroaryl or heterocyclic group, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, such as 1 to 5, 1 to 4, 1 to 3, or 1 or 2). 1e replace.

[0281] In one embodiment of the formula (Va) kinase inhibitor, R 2 R 3 R 4 R 5 A and E are independently defined as above (in particular with respect to equations (Ia), (IIa), (IIIa)) or below (in particular with respect to equations (IIIa), (IVa), (Va), (VIa), (VIIa) and / or (VIIIa)), and Hy is:

[0282]

[0283] in The bond representing the binding of Hy to the remainder of the compound gives the kinase inhibitor of formula (Va) the characteristic of formula (VIa):

[0284]

[0285] Where R 1a R 1b and R 1c Independently as defined above (particularly with respect to equations (Ia), (IIa), (IIIa)) or below, particularly with respect to equations (IIIa), (IVa), (Va), (VIa), (VIIa) and / or (VIIIa)); and B is N or CR 1d , where R 1d As defined above (especially with respect to formula (Ia)) or below (especially with respect to formulas (IIIa), (IVa), (Va), (VIa), (VIIa) and / or (VIIIa)).

[0286] In one embodiment of the formula (VIa) kinase inhibitor, R 1b R 1c R 2 R 3 R 4 R 5 A, B, and E are independently defined as above (in particular with respect to equations (Ia), (IIa), (IIIa), (IVa), and / or (Va)) or below (in particular with respect to equations (IIIa), (IVa), (Va), (VIa), (VIIa), and / or (VIIIa)), and R 1a The R is selected from alkyl, -O (alkyl), -S (alkyl), -NH (alkyl), -N (alkyl)2 and heterocyclic groups, wherein each of the alkyl and heterocyclic groups is optionally independently selected by one or more (e.g., 1 to a maximum number of hydrogen atoms combined with the alkyl or heterocyclic group, such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or up to 10, such as 1 to 5, 1 to 4 or 1 to 3 or 1 or 2). 30 Replacement. Preferably, R is optionally replaced. 1a One or more independent choices of R 30 Independently selected from the primary, secondary, and tertiary substituents specified herein; more preferably, R is optionally substituted. 1a One or more independent choices of R 30 Independently selected from methyl, ethyl, -OH, =O, -OCH3, -SCH3, cyclopropyl, 2-hydroxyethyl, 2-(N,N-dimethylamino)ethyl, 2-(N,N-dimethylamino)ethoxy, 2-(methoxy)ethoxy, 2-aminoethyl, 2-(N-methylamino)ethyl, 2-(methoxy)ethyl, 4-methylpiperazinyl, -C(=O)(C 1-3 Alkyl), -NHC(=O)(C 1-3 alkyl), -N(C) 1-3Alkyl)C(=O)(C 1-3 Alkyl), -NHS(O)2(C 1-3 alkyl), -N(C) 1-3 Alkyl)S(O)2(C 1-3 Alkyl group), -(CH2) 1-3 COOH and -NH 2-z (CH3) z Where z is 0, 1, or 2; the C 1-3 Each of the alkyl groups is optionally substituted by one or two independently selected from the following moieties: -OH, -OCH3, -SCH3, cyclopropyl, piperazinyl, 4-methylpiperazinyl, 4-(2-hydroxyethyl)piperazinyl, 2-(N,N-dimethylamino)ethoxy, and -NH. 2-z (CH3) z , where z is 0, 1 or 2.

[0287] In one embodiment of the formula (VIa) kinase inhibitor, R 1b R 1c R 2 R 3 R 4 R 5 A, B, and E are independently defined as above (in particular with respect to equations (Ia), (IIa), (IIIa), (IVa), and / or (Va)) or below (in particular with respect to equations (IIIa), (IVa), (Va), (VIa), (VIIa), and / or (VIIIa)), and R 1a Selected from C 1-3 Alkyl, -O(C) 1-3 alkyl), -S(C 1-3 alkyl), -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl)2 and 3 to 11-membered heterocyclic groups, wherein the 3 to 11-membered heterocyclic groups are optionally represented by one or two independently selected R 30 Replacement, wherein R is optionally replaced 1a One or two independent choices of R 30 Independently selected from the primary, secondary, and tertiary substituents specified herein; more preferably, R is optionally substituted. 1a One or more independent choices of R 30 Independently selected from methyl, ethyl, -OH, =O, -OCH3, -SCH3, cyclopropyl, 2-hydroxyethyl, 2-(N,N-dimethylamino)ethyl, 2-(N,N-dimethylamino)ethoxy, 2-(methoxy)ethoxy, 2-aminoethyl, 2-(N-methylamino)ethyl, 2-(methoxy)ethyl, 4-methylpiperazinyl, -C(=O)(C 1-3Alkyl), -NHC(=O)(C 1-3 alkyl), -N(C) 1-3 Alkyl)C(=O)(C 1-3 Alkyl), -NHS(O)2(C 1-3 alkyl), -N(C) 1-3 Alkyl)S(O)2(C 1-3 Alkyl group), -(CH2) 1- 3COOH and -NH 2-z (CH3) z Where z is 0, 1, or 2; the C 1-3 Each of the alkyl groups is optionally substituted by one or two independently selected from the following moieties: -OH, -OCH3, -SCH3, cyclopropyl, piperazinyl, 4-methylpiperazinyl, 4-(2-hydroxyethyl)piperazinyl, 2-(N,N-dimethylamino)ethoxy, and -NH. 2-z (CH3) z , where z is 0, 1 or 2.

[0288] In one embodiment of the formula (VIa) kinase inhibitor, R 1b R 1c R 2 R 3 R 4 R 5 A, B, and E are independently defined as above (in particular with respect to equations (Ia), (IIa), (IIIa), (IVa), and / or (Va)) or below (in particular with respect to equations (IIIa), (IVa), (Va), (VIa), (VIIa), and / or (VIIIa)), and R 1a Selected from C 1-3 Alkyl, -O(C) 1-3 alkyl), -S(C 1-3 alkyl), -NH(C) 1-3Alkyl), piperazinyl, piperidinyl, hexahydropyrimidinyl, hexahydropyrimidinyl, morpholinyl, 1,2-oxazinanyl, 1,3-oxazinanyl, pyrrolidinyl, imidazolinyl, pyrazolyl, diazepanyl, oxazepanyl, azaspirononyl, diaspirodecyl, diaspirodecane The compounds are aziraspiroundecyl and diazaspiroundecyl, wherein piperazinyl, piperidinyl, hexahydropyrimidinyl, hexahydropyrimidinyl, morpholinyl, 1,2-oxazinyl, 1,3-oxazinyl, pyrrolidinyl, imidazolinyl, pyrazolyl, diazacycloheptyl, oxazacycloheptyl, aziraspirone, diazaspirone, aziraspirodecyl, diazaspirodecyl, aziraspiroundecyl, and diazaspiroundecyl are optionally selected by one or two independently chosen R. 30 Replacement, wherein R is optionally replaced 1a One or two independent choices of R 30 Independently selected from the primary, secondary, and tertiary substituents specified herein; more preferably, R is optionally substituted. 1a One or more independent choices of R 30 Independently selected from methyl, ethyl, -OH, =O, -OCH3, -SCH3, cyclopropyl, 2-hydroxyethyl, 2-(N,N-dimethylamino)ethyl, 2-(N,N-dimethylamino)ethoxy, 2-(methoxy)ethoxy, 2-aminoethyl, 2-(N-methylamino)ethyl, 2-(methoxy)ethyl, 4-methylpiperazinyl, -C(=O)(C 1-3 Alkyl), -NHC(=O)(C 1-3 alkyl), -N(C) 1-3 Alkyl)C(=O)(C 1-3 Alkyl), -NHS(O)2(C 1-3 alkyl), -N(C) 1-3 Alkyl)S(O)2(C 1-3 Alkyl group), -(CH2) 1-3 COOH and -NH 2-z (CH3) z Where z is 0, 1, or 2; the C 1-3 Each of the alkyl groups is optionally substituted by one or two independently selected from the following moieties: -OH, -OCH3, -SCH3, cyclopropyl, piperazinyl, 4-methylpiperazinyl, 4-(2-hydroxyethyl)piperazinyl, 2-(N,N-dimethylamino)ethoxy, and -NH. 2-z (CH3) z , where z is 0, 1 or 2.

[0289] In one embodiment of the formula (VIa) kinase inhibitor, R 1b R 1c R 2 R 3 R 4 R 5 A, B, and E are independently defined as above (in particular with respect to equations (Ia), (IIa), (IIIa), (IVa), and / or (Va)) or below (in particular with respect to equations (IIIa), (IVa), (Va), (VIa), (VIIa), and / or (VIIIa)), and R 1a Selected from -NH(C 1-3 Alkyl), piperazine, piperidinyl, morpholinyl, pyrrolyl, diazacycloheptyl, oxazacycloheptyl, and diazaspirone, wherein each of piperazine, piperidinyl, morpholinyl, pyrrolyl, diazacycloheptyl, oxazacycloheptyl, and diazaspirone is optionally represented by one or two independently selected R. 30 Replacement, wherein R is optionally replaced 1a One or two independent choices of R 30 Independently selected from methyl, -OH, =O, -OCH3, 2-hydroxyethyl, 2-(N,N-dimethylamino)ethyl, 2-(methoxy)ethoxy, -C(=O)(C 1-3 Alkyl), -NHC(=O)(C 1-3 Alkyl), -NHS(O)2(C 1-3 alkyl) and -NH 2-z (CH3) z , where z is 0, 1 or 2.

[0290] In one embodiment of the formula (VIa) kinase inhibitor, R 1b R 1c R 2 R 3 R 4 R 5 A, B, and E are independently defined as above (in particular with respect to equations (Ia), (IIa), (IIIa), (IVa), and / or (Va)) or below (in particular with respect to equations (IIIa), (IVa), (Va), (VIa), (VIIa), and / or (VIIIa)), and R 1aSelected from 4-(2-hydroxyethyl)piperazinyl, 4-methylpiperazinyl, 3,4-dimethylpiperazinyl, 4-methyl-1,4-diaza-1-yl, 3-oxopiperazin-1-yl, 2-methylmorpholin-4-yl, 3-methylpiperazin-1-yl, 3-(2-hydroxyethyl)piperazin-1-yl, 3-(2-hydroxyethyl)-4-methylpiperazin-1-yl, 3-(dimethylamino)piperazin-1-yl, 3-(methoxy)piperidin-1-yl, 3-(hydroxy)piperidin-1-yl, 3-(dimethylamino)pyrrolidine-1-yl, 3- (hydroxy)pyrrolidine-1-yl, 3-(2-methoxyethoxy)pyrrolidine-1-yl, 3-(acetamido)pyrrolidine-1-yl, 3-(methanesulfonylamino))pyrrolidine-1-yl, 7-methyl-2,7-diazaspiro[4.4]one-2-yl, 4-[2-(dimethylamino)ethyl]-1,4-diazacycloheptane-1-yl, 4-(acetyl)-1,4-diazacycloheptane-1-yl, 5-oxo-1,4-diazacycloheptane-1-yl and 1,4-oxazacycloheptane-4-yl.

[0291] In any of the above embodiments of the kinase inhibitor of formula (VIa) (including kinase inhibitors of formulas (Ia), (IIa), (IIa), (IVa) and / or (Va)), R 1a It can be asymmetric. For example, R 1a You can choose from:

[0292]

[0293] Where R 30 And X as defined in this paper; and R represents 1a A bond that binds a group to the rest of the compound. In one embodiment, R 1a It is asymmetric and selected from 3,4-dimethylpiperazinyl, 4-methyl-1,4-diaza-1-yl, 3-oxopiperazin-1-yl, 2-methylmorpholin-4-yl, 3-methylpiperazin-1-yl, 3-(2-hydroxyethyl)piperazin-1-yl, 3-(2-hydroxyethyl)-4-methylpiperazin-1-yl, 3-(dimethylamino)piperidin-1-yl, 3-(methoxy)piperidin-1-yl, 3-(hydroxy)piperidin-1-yl, 3-(dimethylamino)pyrrolidine-1-yl, 3-(hydroxy)pyrrolidine-1-yl, 3-(hydroxy)pyrrolidine-1-yl, 3-(hydroxy)pyrrolidine-1-yl, 3-(hydroxy)pyrrolidine-1-yl, 3-dimethylamino ... Pyrrolidine-1-yl, 3-(2-methoxyethoxy)pyrrolidine-1-yl, 3-(acetamido)pyrrolidine-1-yl, 3-(methanesulfonylamino)pyrrolidine-1-yl, 7-methyl-2,7-diazaspiro[4.4]one-2-yl, 4-[2-(dimethylamino)ethyl]-1, 4-azacycloheptane-1-yl, 4-(acetyl)-1,4-diazacycloheptane-1-yl, 5-oxo-1,4-diazacycloheptane-1-yl, and 1,4-oxazacycloheptane-4-yl.

[0294] In any of the above embodiments of the (VIa) kinase inhibitor (including (Ia), (IIa), (IIa), (IVa) and / or (Va) kinase inhibitors), R 1a R that binds to the rest of the compound 1a The atom can be an atom other than C; preferably, R 1a R, which binds to the rest of the compound 1a The atom is a nitrogen atom. In this embodiment, R 1a Preferably selected from heterocyclic groups, heterocyclic aryl groups, and -OR groups. 11 -N(R) 12 (R) 13 ), -N(R 11 (OR) 11 ), -S(O) 0-2 R 11 -S(O) 1-2 OR 11 -OS(O) 1-2 R 11 -OS(O) 1-2 OR 11 -S(O) 1-2 N(R 12 (R) 13 ), -OS(O) 1-2 N(R 12 (R) 13 ), -N(R 11 S(O) 1-2 R 11 -NR 11 S(O) 1-2 OR 11 -NR 11 S(O) 1-2 N(R 12 (R) 13 -P(O)(OR) 11 )2、-OP(O)(OR 11 )2、-XC(=X)R 11 and -XC(=X)XR 11 Each of the heterocyclic and heteroaryl groups is bonded to the remainder of the compound by an atom other than C, and is optionally independently selected by one or more R groups (e.g., 1 to a maximum number of hydrogen atoms bonded to the heterocyclic or heteroaryl group, such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or up to 10, such as 1 to 5, 1 to 4, or 1 to 3, or 1 or 2). 30 Replacement. For example, R 1aIt can be a heterocyclic group, which contains at least one N-ring atom and is bonded to the remainder of the compound via the N-ring atom.

[0295] In one embodiment of the formula (VIa) kinase inhibitor, R 1b R 1c R 2 R 3 R 4 R 5 A, B, and E are independently as defined above (especially with respect to equations (Ia), (IIa), (IIIa), (IVa), and / or (Va)) or below, and R 1a Selected from:

[0296]

[0297] in R represents 1a Bonds that bind to the rest of the compound. Preferably R 1a Selected from:

[0298]

[0299] in R represents 1a Bonds that bind to the rest of the compound.

[0300] In any of the above embodiments of the (VIa) kinase inhibitor (including (Ia), (IIa), (IIa), (IVa) and / or (Va) kinase inhibitors), R 1b and R 1c It can be independently selected from H, methyl, ethyl, propyl, isopropyl, -OH, -OCH3, -SCH3, cyclopropyl, 2-hydroxyethyl, 2-(N,N-dimethylamino)ethyl, 2-(N,N-dimethylamino)ethoxy, 2-aminoethyl, 2-(N-methylamino)ethyl, 2-(methoxy)ethyl, -NH 2-z (CH3) z phenyl, pyridyl, pyrazolyl, phenoxy, pyridoxy, imidazolylamino, and tetrahydrofuranmethoxy, wherein z is 0, 1, or 2; and each of phenyl, pyridyl, pyrazolyl, phenoxy, pyridoxy, imidazolylamino, and tetrahydrofuranmethoxy is optionally substituted by one, two, or three independently selected from the following moieties: methyl, ethyl, -OH, -OCH3, -SCH3, cyclopropyl, 2-hydroxyethyl, 2-(N,N-dimethylamino)ethyl, 2-(N,N-dimethylamino)ethoxy, 2-aminoethyl, 2-(N-methylamino)ethyl, 2-(methoxy)ethyl, and -NH 2-z (CH3) z Where z is 0, 1, or 2. Preferably, R1b and R 1c At least one of the following is selected from H, methyl, ethyl, propyl, isopropyl, -OH, -OCH3, -SCH3, cyclopropyl, 2-hydroxyethyl, 2-(N,N-dimethylamino)ethyl, 2-(N,N-dimethylamino)ethoxy, 2-aminoethyl, 2-(N-methylamino)ethyl, 2-(methoxy)ethyl, -NH 2-z (CH3) z and phenyl, wherein z is 0, 1 or 2; in one embodiment, R 1b For H; R 1c It is methyl, ethyl, propyl, isopropyl, or phenyl, preferably methyl. In another embodiment, R 1b It is methyl, ethyl, propyl, or isopropyl, preferably methyl; R 1c For H.

[0301] In any of the above embodiments of the kinase inhibitor of formula (VIa) (including kinase inhibitors of formulas (Ia), (IIa), (IIa), (IVa) and / or (Va), wherein R 1C R that binds to the rest of the compound 1C The atom can be a carbon atom. In this embodiment, R is preferred. 1c Selected independently from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, -CF3, -CN, -C(=O)(C 1-6 Alkyl group), -C(=O)OH, -C(=O)O(C 1-6 alkyl) and -C(=O)NH 2-z (C 1-6 alkyl) z Where z is 0, 1 or 2 and C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Each of the alkynyl groups may optionally be substituted by one, two, or three independently selected from the following moieties: -OH, methyl, ethyl, -OCH3, -SCH3, and -NH. 2-z (CH3) z .

[0302] In any of the above embodiments of the kinase inhibitor of formula (VIa) (including kinase inhibitors of formulas (Ia), (IIa), (IIa), (IVa) and / or (Va)), B is N or CR. 1d , where R 1d Optional from C 1-3 Alkyl, halogen, -O(C) 1-3 alkyl), -S(C 1-3 alkyl), -NH(C) 1-3alkyl) and -N(C) 1-3 Alkyl)2, wherein C 1-3 The alkyl group is optionally substituted by one or two independently selected moieties from the following: halogen, -OH, -OCH3, -SCH and -NH. 2-z (CH3) z Where z is 0, 1, or 2. In any of the above embodiments of the kinase inhibitor of formula (VIa) (including kinase inhibitors of formulas (Ia), (IIa), (IIa), (IVa), and / or (Va)), B is N or CR. 1d , where R 1d Optional from: C 1-3 Alkyl, halogen, -O(C) 1-3 alkyl), -S(C 1-3 alkyl), -NH(C) 1-3 alkyl) and -N(C) 1-3 Alkyl)2.

[0303] In any of the above embodiments of the kinase inhibitor of formula (VIa) (including kinase inhibitors of formulas (Ia), (IIa), (IIa), (IVa) and / or (Va), B is most preferably N.

[0304] In one embodiment, the kinase inhibitor has the general formula (VIIa) or (VIIIa):

[0305]

[0306] Among them Hy, R 1a R 1b R 1c R 2 R 3 R 4 R 5 A, B, and E are independently as defined above (particularly with respect to formulas (Ia), (IIa), (IIIa), (IVa), (Va), and / or (VIa)) or below, and L is a bond. In a preferred embodiment of a kinase inhibitor having the general formula (VIIa) or (VIIIa):

[0307] (A)R 1a The R group is selected from alkyl, -O (alkyl), -S (alkyl), -NH (alkyl), -N (alkyl)2 and heterocyclic groups, preferably heterocyclic groups bonded to the remainder of the compound by atoms other than C, wherein each of the alkyl and heterocyclic groups is optionally independently selected by one or more (e.g., 1 to a maximum number of hydrogen atoms bonded to the alkyl or heterocyclic group, such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or up to 10, such as 1 to 5, 1 to 4, 1 to 3 or 1 or 2). 30 Replacement, wherein, preferably, R30 Independently selected from methyl, ethyl, -OH, =O, -OCH3, -SCH3, cyclopropyl, 2-hydroxyethyl, 2-(N,N-dimethylamino)ethyl, 2-(N,N-dimethylamino)ethoxy, 2-(methoxy)ethoxy, 2-aminoethyl, 2-(N-methylamino)ethyl, 2-(methoxy)ethyl, 4-methylpiperazinyl, -C(=O)(C 1-3 Alkyl), -NHC(=O)(C 1-3 alkyl), -N(C) 1-3 Alkyl)C(=O)(C 1-3 Alkyl), -NHS(O)2(C 1-3 alkyl),-

[0308] N(C 1-3 Alkyl)S(O)2(C 1-3 Alkyl group), -(CH2) 1-3 COOH and -NH 2-z (CH3) z Where z is 0, 1, or 2; the C 1-3 Each of the alkyl groups is optionally substituted by one or two independently selected from the following moieties: -OH, -OCH3, -SCH3, cyclopropyl, piperazinyl, 4-methylpiperazinyl, 4-(2-hydroxyethyl)piperazinyl, 2-(N,N-dimethylamino)ethoxy, and -NH. 2-z (CH3) z Where z is 0, 1, or 2; and / or

[0309] (B)R 1b and R 1c Each of these is independently selected from: H, methyl, ethyl, propyl, isopropyl, -OH, -OCH3, -SCH3, cyclopropyl, 2-hydroxyethyl, 2-(N,N-dimethylamino)ethoxy, 2-aminoethyl, 2-(N-methylamino)ethyl, 2-(methoxy)ethyl, -NH 2-z (CH3) z phenyl, pyridyl, pyrazolyl, phenoxy, pyridoxy, imidazolylamino, and tetrahydrofuranmethoxy, wherein z is 0, 1, or 2; each of the phenyl, pyridyl, pyrazolyl, phenoxy, pyridoxy, imidazolylamino, and tetrahydrofuranmethoxy groups is optionally substituted by one, two, or three independently selected portions from: methyl, ethyl, -OH, -OCH3, -SCH3, cyclopropyl, 2-hydroxyethyl, 2-(N,N-dimethylamino)ethyl, 2-(N,N-dimethylamino)ethoxy, 2-aminoethyl, 2-(N-methylamino)ethyl, 2-(methoxy)ethyl, and -NH 2-z (CH3) z Where z is 0, 1, or 2; preferably, where R 1band R 1c One of them is H; and R 1b and R 1c The other one is methyl, ethyl, propyl, isopropyl, or phenyl, more preferably, R 1b and R 1c The other one is methyl; and / or

[0310] (C)R 3 Selected from H, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, phenyl, halogen, -CN, azide, -NO2, -O(C 1-6 alkyl),-

[0311] OCF3, -S(C 1-6 Alkyl groups, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2、-NHS(O)2(C 1-6 Alkyl group), -S(O)2NH 2-z (C 1-6 alkyl) z -

[0312] C(=O)(C 1-6 Alkyl group), -C(=O)OH, -C(=O)O(C 1-6 Alkyl group), -C(=O)NH 2-z (C 1-6 alkyl) z -NHC(=O)(C 1-6 alkyl),-

[0313] NHC(=NH)NH 2-z (C 1-6 alkyl) z and -N(C 1-6 alkyl)C(=NH)NH 2-z (C 1-6 alkyl) z Where z is 0, 1, or 2; and where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Each of the cycloalkyl and phenyl groups is optionally selected by one or more independently chosen R groups. 30 Replacement, preferably, wherein R 3 It is H; and / or

[0314] (D)R 7 At least one of them is F and / or R 7At least one of them is selected from alkyl, OR 11 and -N(R) 12 (R) 13 ), wherein the alkyl and R 11 Each of the groups and the R 12 and R 12 At least one of the groups is substituted by one or more F atoms; and / or

[0315] (E)A is selected from S, O, NH, N(C 1-6 alkyl) and C(C) 1-6 Alkyl)2, wherein preferably A is S; and / or

[0316] (F)B is N or CR 1d , where R 1d Selected from C 1-3 Alkyl, halogen, -O(C) 1-3 alkyl), -S(C 1-3 alkyl), -NH(C) 1-3 alkyl) and -N(C) 1-3 Alkyl)2, wherein C 1-3 Each of the alkyl groups is optionally substituted by one or two independently selected from the following moieties: halogen, -OH, -OCH3, -SCH, and -NH. 2-

[0317] z (CH3) z Where z is 0, 1, or 2, preferably B is N; and / or

[0318] (G)E is O or S, with O being preferred.

[0319] In a preferred embodiment of a kinase inhibitor having general formula (VIIa) or (VIIIa), R 1a As stated in (A) above; R 1b and R 1c As defined in (B) above; R 3 As stated in (C) above; R 7 As defined above (D), where R 6 As specified above (especially with respect to formula (IIa)); A is as stated above (E); B is as stated above (F); E is as stated above (G).

[0320] In a further preferred embodiment, the kinase inhibitor has the general formula (VIIa) or (VIIIa):

[0321] (A')R 1a Selected from C 1-3 Alkyl, -O(C) 1-3 alkyl), -S(C1-3 alkyl), -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl) 2- and 3- to 11-membered heterocyclic groups, preferably heterocyclic groups bonded to the remainder of the compound by atoms other than C, wherein the 3- to 11-membered heterocyclic group is optionally connected by one or two independently selected R 30 Replacement, wherein R is optionally replaced 1a One or two independent choices of R 30 Independently selected from methyl, ethyl, -OH, =O, -OCH3, -SCH3, cyclopropyl, 2-hydroxyethyl, 2-(N,N-dimethylamino)ethyl, 2-(N,N-dimethylamino)ethoxy, 2-(methoxy)ethoxy, 2-aminoethyl, 2-(N-methylamino)ethyl, 2-(methoxy)ethyl, 4-methylpiperazinyl, -C(=O)(C 1-3 Alkyl), -NHC(=O)(C 1-3 alkyl), -N(C) 1-3 Alkyl)C(=O)(C 1-3 alkyl),

[0322] -NHS(O)2(C 1-3 alkyl), -N(C) 1-3 Alkyl)S(O)2(C 1-3 Alkyl group), -(CH2) 1-3 COOH and -NH 2-z (CH3) z Where z is 0, 1, or 2; the C 1-3 Each of the alkyl groups is optionally substituted by one or two independently selected from the following moieties: -OH, -OCH3, -SCH3, cyclopropyl, piperazinyl, 4-methylpiperazinyl, 4-(2-hydroxyethyl)piperazinyl, 2-(N,N-dimethylamino)ethoxy, and -NH. 2-z (CH3) z Where z is 0, 1, or 2; and / or

[0323] (B')R 1b and R 1c At least one of them is selected from: H, methyl, ethyl, propyl, isopropyl, -OH, -OCH3, -SCH3, cyclopropyl, 2-hydroxyethyl, 2-

[0324] (N,N-Dimethylamino)ethoxy, 2-aminoethyl, 2-(N-methylamino)ethyl, 2-(methoxy)ethyl, -NH 2-z (CH3) z and phenyl, where z is 0, 1 or 2, R 1b and R 1c Another one, as defined in (B) above, preferably wherein R1b and R 1c One of them is H; and R 1b and R 1c The other one is methyl, ethyl, propyl, isopropyl, or phenyl, more preferably, R 1b and R 1c The other one is methyl; and / or

[0325] (C')R 3 Selected from H, C 1-4 Alkyl, C 3-6 Cycloalkyl, phenyl, halogen, -CN, -O(C) 1-4 Alkyl), -OCF3, -S(C 1-4 Alkyl groups, -NH2, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl)2、-C(=O)(C 1-4 Alkyl group), -C(=O)OH, -C(=O)O(C 1-4 Alkyl group), -C(=O)NH 2-z (C 1-4 alkyl) z -NHC(=O)(C 1-4 Alkyl group), -NHC(=NH)NH 2-z (C 1-4 alkyl) z and -N(C 1-4 alkyl)C(=NH)NH 2-z (C 1-4 alkyl) z The phenyl group is optionally substituted with one, two, or three groups independently selected from the following: halogen, methyl, isopropyl, -CN, -CF3, -OCF3, -OH, -NH2, -NH(C 1-3 alkyl),-

[0326] N(C 1-3 Alkyl)2、-NHC(=O)(C 1-3 Alkyl group), -C(=O)NH 2-z (C 1-3 Alkyl group), -(CH2) 1-3 NH2、-(CH2) 1-3 NH(C 1-3 Alkyl group), -(CH2) 1-3 N(C 1-3 Alkyl group 2, -(CH2) 1-3 OH and -(CH2) 1-3 O(C 1-3 Alkyl); wherein z is 0, 1 or 2, wherein preferably R 3 For H; and / or

[0327] (D')R 7 At least one of them is F and / or R 7 At least one of them is selected from C 1-3 Alkyl, -O(C) 1-3 alkyl), -NH(C) 1-3 alkyl) or -N(C) 1-3 Alkyl)2, wherein C 1-3 Alkyl, -NH(C) 1-3 alkyl) and -O(C 1-3 alkyl groups and -N(C) 1-3 At least one alkyl group of alkyl group (E')2 is substituted with one or more F atoms; (E')A is S, O or N(CH3)2, wherein preferably A is S; and / or

[0328] (F')B is N or CR 1d , where R 1d Selected from C 1-3 Alkyl, halogen, -O(C) 1-3 alkyl), -S(C 1-3 alkyl), -NH(C) 1-3 alkyl) and -N(C) 1-3 Alkyl group 2, preferably B is N; and / or

[0329] (G')E is either O or S, with O being preferred.

[0330] In a preferred embodiment of a kinase inhibitor having general formula (VIIa) or (VIIIa), R 1a As stated in (A') above; R 1b and R 1c As defined above (B'); R 3 As stated above (C'); R 7 As defined above (D'), where R 6 As specified above (especially with respect to formula (IIa)); A is as stated above (E'); B is as stated above (F'); E is as stated above (G').

[0331] In a further preferred embodiment, the kinase inhibitor has the general formula (VIIa) or (VIIIa):

[0332] (A”)R 1a It is a heterocyclic group that is bonded to the rest of the compound by atoms other than C, wherein the 3 to 11-membered heterocyclic group is optionally linked by one or two independently selected R atoms. 30 Replacement, wherein R is optionally replaced 1a One or two independent choices of R 30Independently selected from methyl, ethyl, -OH, =O, -OCH3,

[0333] -SCH3, cyclopropyl, 2-hydroxyethyl, 2-(N,N-dimethylamino)ethyl, 2-(N,N-dimethylamino)ethoxy, 2-(methoxy)ethoxy, 2-aminoethyl,

[0334] 2-(N-methylamino)ethyl, 2-(methoxy)ethyl, 4-methylpiperazinyl, -C(=O)(C 1-3 Alkyl), -NHC(=O)(C 1-3 alkyl), -N(C) 1-3 Alkyl)C(=O)(C 1-3 Alkyl), -NHS(O)2(C 1-3 alkyl), -N(C) 1-3 Alkyl)S(O)2(C 1-3 Alkyl group), -(CH2) 1-3 COOH and -NH 2-z (CH3) z Where z is 0, 1, or 2; and C 1-3 Each of the alkyl groups is optionally substituted by one or two independently selected from the following moieties: -OH, -OCH3, -SCH3,

[0335] Cyclopropyl, piperazinyl, 4-methylpiperazinyl, 4-(2-hydroxyethyl)piperazinyl, 2-(N,N-dimethylamino)ethoxy, and -NH 2-z (CH3) z Where z is 0, 1, or 2; and / or

[0336] (B”)R 1b and R 1c One of them is H; R 1b and R 1c The other one is methyl, ethyl, propyl, isopropyl, or phenyl, more preferably R. 1b and R 1c The other one is methyl; and / or

[0337] (C”)R 3 For H; and / or

[0338] (D”)R 7 At least one of them is F and / or R 7 At least one of them is selected from C 1-3 Alkyl, -O(C) 1-3 alkyl), -NH(C) 1-3 alkyl) or -N(C) 1-3 Alkyl)2, wherein C 1-3 Alkyl, -NH(C) 1-3 alkyl) and -O(C1-3 alkyl groups and -N(C) 1-3 At least one alkyl group of alkyl group 2 is substituted by one or more F atoms;

[0339] (E”)A is S; and / or

[0340] (F”)B is N; and / or

[0341] (G”)E is O.

[0342] In a preferred embodiment of a kinase inhibitor having general formula (VIIa) or (VIIIa), R 1a As stated in (A”) above; R 1b and R 1c As defined above (B”); R 3 As stated above (C”); R 7 As defined above (D”), where R 6 As specified above (especially with respect to formula (IIa)); A is as stated above (E”); B ​​is as stated above (F”); E is as stated above (G”).

[0343] In a further preferred embodiment, the kinase inhibitor has the general formula (VIIa) or (VIIIa) (especially when R 1a R 1b R 1c R 3 When A, B, and E are as described above in (A), (B), (C), (E), (F) and / or (G), or in (A'), (B'), (C'), (E'), (F') and / or (G'), or in (A”), (B”), (C”), (E”), (F”) and / or (G”), an R 7 It is selected from -CH2F, -CHF2 and -CF3, with a preference for -CH2F and -CHF2.

[0344] In a further preferred embodiment, the kinase inhibitor has the general formula (VIIa) or (VIIIa) (especially when R 1a R 1b R 1c R 3 When A, B, and E are as described above in (A), (B), (C), (E), (F) and / or (G), or in (A'), (B'), (C'), (E'), (F') and / or (G'), or in (A”), (B”), (C”), (E”), (F”) and / or (G”), an R 7 (preferably F of R) 7 and / or R7 substituted with one or more F atoms relative to R 6The ring atom at position 2 or 5 of the remaining part of the compound is attached to the C ring atom.

[0345] In a further preferred embodiment, the kinase inhibitor has the general formula (VIIa) or (VIIIa) (especially when R 1a R 1b R 1c R 3 When A, B, and E are as described above in (A), (B), (C), (E), (F), and / or (G), or in (A'), (B'), (C'), (E'), (F'), and / or (G'), or in (A”), (B”), (C”), (E”), (F”), and / or (G”), R 6 At least two R 7 Replacement. For example, R 6 It can be two different Rs 7 replace.

[0346] In a further preferred embodiment, the kinase inhibitor has the general formula (VIIa) or (VIIIa) (especially when R 1a R 1b R 1c R 3 When A, B, and E are as described above in (A), (B), (C), (E), (F), and / or (G), or in (A'), (B'), (C'), (E'), (F'), and / or (G'), or in (A”), (B”), (C”), (E”), (F”), and / or (G”), R 6 At least two R 7 Replace, one of the R 7 (preferably F of R) 7 and / or R substituted by one or more F atoms 7 In relation to R 6 At positions 2 and 5 of the ring atoms bound to the remainder of the compound, a C ring atom and an R ring atom are attached. 7 In relation to R 6 The ring atoms at positions 2 and 5, which are bound to the remainder of the compound, are attached to another C ring atom.

[0347] In a further preferred embodiment, the kinase inhibitor has the general formula (VIIa) or (VIIIa) (especially when R 1a R 1b R 1c R 3When A, B, and E are as described above in (A), (B), (C), (E), (F), and / or (G), or in (A'), (B'), (C'), (E'), (F'), and / or (G'), or in (A”), (B”), (C”), (E”), (F”), and / or (G”), R 6 At least two R 7 Replace, one of the R 7 Selected from -CH2F, -CHF2 and -CF3, and one R 7 The component is selected from halogens, -CH3, -CH2(hal), -CH(hal)2, and -C(hal)3, and more preferably from Cl, Br, F, -CH3, -CH2F, -CHF2, and -CF3. In one embodiment, an R 7 Selected from -CH2F, -CHF2 and -CF3, preferably selected from -CH2F and -CHF2, and one R 7 It is Cl. In an alternative embodiment, an R 7 It is F, and one R 7 The halogen is selected from halogens, -CH3, -CH2(hal), -CH(hal)2, and -C(hal)3, and more preferably from Cl, Br, F, -CH3, -CH2F, -CHF2, and -CF3. In this alternative embodiment, preferably one R 7 It is F and one R 7 It is Cl.

[0348] In a further preferred embodiment, the kinase inhibitor has the general formula (VIIa) or (VIIIa) (especially when R 1a R 1b R 1c R 3 When A, B, and E are as described above in (A), (B), (C), (E), (F), and / or (G), or in (A'), (B'), (C'), (E'), (F'), and / or (G'), or in (A”), (B”), (C”), (E”), (F”), and / or (G”), R 6 Selected from thienyl, thiazolyl, and thiadiazole, preferably from thienyl and thiazolyl, more preferably R 6 It is a thiophene group, wherein each of the thiophene, thiazolyl, and thiadiazolyl groups is independently selected by one or more (e.g., from 1 to a maximum number of hydrogen atoms bonded to the thiophene, thiazolyl, or thiadiazolyl group, e.g., 1, 2, or 3, e.g., 1 or 2) R. 7 replace.

[0349] In a further preferred embodiment, the kinase inhibitor has the general formula (VIIa) or (VIIIa) (especially when R 1a R1b R 1c R 3 When A, B, and E are as described above in (A), (B), (C), (E), (F), and / or (G), or in (A'), (B'), (C'), (E'), (F'), and / or (G'), or in (A”), (B”), (C”), (E”), (F”), and / or (G”), R 6 R that binds to the rest of the compound 6 The ring atom is a carbon atom.

[0350] In a further preferred embodiment, the kinase inhibitor has the general formula (VIIa) or (VIIIa) (especially when R 1a R 1b R 1c R 3 When A, B, and E are as described above in (A), (B), (C), (E), (F), and / or (G), or in (A'), (B'), (C'), (E'), (F'), and / or (G'), or in (A”), (B”), (C”), (E”), (F”), and / or (G”), R 6 S ring atoms and R 6 The ring atoms that bind to the rest of the compound are not adjacent.

[0351] In a further preferred embodiment, the kinase inhibitor has the general formula (VIIa) or (VIIIa) (especially when R 1a R 1b R 1c R 3 A, B, and E are as described above in (A), (B), (C), (E), (F), and / or (G), or in (A'), (B'), (C'), (E'), (F'), and / or (G'), or in (A”), (B”), (C”), (E”), (F”), and / or (G”), where R 6 Selected from:

[0352]

[0353] Preferably selected from:

[0354]

[0355] in R represents 6 Bonds that bind to the rest of the compound.

[0356] In any embodiment of the kinase inhibitor of formula (VIIa) or (VIIIa) (including those of formulas (Ia), (IIa), (IIIa), (IVa), (Va) and / or (VIa)), R 1a It can be selected from -NH(C) 1-3 Alkyl), piperazine, piperidinyl, morpholinyl, pyrrolyl, diazacycloheptyl, oxazacycloheptyl, and diazaspirone, wherein each of piperazine, piperidinyl, morpholinyl, pyrrolyl, diazacycloheptyl, oxazacycloheptyl, and diazaspirone is optionally represented by one or two independently selected R. 30 Replacement, wherein R is optionally replaced 1a One or two independent choices of R 30 Independently selected from methyl, -OH, =O, -OCH3, 2-hydroxyethyl, 2-(N,N-dimethylamino)ethyl, 2-(methoxy)ethoxy, -C(=O)(C 1-3 Alkyl), -NHC(=O)(C 1-3 Alkyl), -NHS(O)2(C 1-3 alkyl) and -NH 2-z (CH3) z , where z is 0, 1, or 2. For example, R 1a It can be selected from 4-(2-hydroxyethyl)piperazinyl, 4-methylpiperazinyl, 3,4-dimethylpiperazinyl, 4-methyl-1,4-diazazon-1-yl, 3-oxoperazin-1-yl, 2-methylmorpholino-4-yl, 3-methylpiperazin-1-yl, 3-(2-hydroxyethyl)piperazin-1-yl, 3-(2-hydroxyethyl)-4-methylpiperazin-1-yl, 3-(dimethylamino)piperidin-1-yl, 3-(methoxy)piperidin-1-yl, 3-(hydroxy)piperidin-1-yl, 3-(dimethylamino)pyrrolidine-1-yl, 3-(hydroxy)pyrrolidine-1-yl, 3-(2-methoxyethoxy)pyrrolidine-1-yl, 3-(acetamido)pyrrolidine-1-yl, 3-(methanesulfonamide)pyrrolidine-1-yl, 7-methyl-2,7-diazaspirocyclic[4,4]one-2-yl, 4-[2-(dimethylamino)ethyl]-1,4-diazacycloheptane-1-yl, 4-(acetyl)-1,4-diazacycloheptane-1-yl, 5-oxo-1,4-diazacycloheptane-1-yl and 1,4-oxazacycloheptane-4-yl.

[0357] In the above formulas (VIIa) or (VIIIa) (including formulas (Ia), (IIa), (IIIa), (IVa), (Va) and / or (VIa), especially when R 1a R 1b R 1c R 3In any embodiment of the kinase inhibitor as described in (A), (B), (C), (E), (F) and / or (G) above, or (A'), (B'), (C'), (E'), (F') and / or (G'), or (A”), (B”), (C”), (E”), (F”) and / or (G”), R 1a It can be asymmetrical.

[0358] In the above formulas (VIIa) or (VIIIa) (including formulas (Ia), (IIa), (IIIa), (IVa), (Va) and / or (VIa), especially when R 1a R 1b R 1c R 3 In any embodiment of the kinase inhibitor as described above in (A), (B), (C), (E), (F) and / or (G), or (A'), (B'), (C'), (E'), (F') and / or (G'), or (A”), (B”), (C”), (E”), (F”) and / or (G”), R is made 1a R that binds to the remainder of the compound 1a The atom can be an atom other than C; preferably, R 1a R that binds to the remainder of the compound 1a The atom is a nitrogen atom.

[0359] In the above formulas (VIIa) or (VIIIa) (including formulas (Ia), (IIa), (IIIa), (IVa), (Va) and / or (VIa), especially when R 1a R 1b R 1c R 3 In any embodiment of the kinase inhibitor as described in (A), (B), (C), (E), (F) and / or (G) above, or (A'), (B'), (C'), (E'), (F') and / or (G'), or (A”), (B”), (C”), (E”), (F”) and / or (G”), R 1c R binds to the rest of the compound 1c The atom can be a carbon atom.

[0360] In the above formula (VIIa) or (VIIIa) (including those formulas (Ia), (IIa), (IIIa), (IVa), (Va) and / or (VIa), R is preferred. 1b It is H; and R 1c It is methyl, ethyl, propyl, isopropyl, or phenyl, with methyl being preferred.

[0361] In the above formula (VIIa) or (VIIIa) (including those formulas (Ia), (IIa), (IIIa), (IVa), (Va) and / or (VIa), preferably A is S; B is N; and / or E is O.

[0362] More preferably, in the above formula (VIIa) or (VIIIa) (including those formulas (Ia), (IIa), (IIIa), (IVa), (Va) and / or (VIa), A is S; B is N; and E is O.

[0363] In the above formula (VIIa) or (VIIIa) (including those formulas (Ia), (IIa), (IIIa), (IVa), (Va) and / or (VIa), R 3 Preferably selected from the following: H, methyl, ethyl, propyl, isopropyl, phenyl, and halogen; more preferably, R 3 It is H.

[0364] In one embodiment, the compound of the present invention is selected from... Figure 1 Compound E is shown.

[0365] In the context of the fifth aspect, this application provides compounds or pharmaceutical compositions for treating a proliferative disease in a subject, the treatment comprising administering the compound or the pharmaceutical composition to the subject, wherein the compound is selected from (a) compounds of the first aspect; (b) compounds of formula (Ib); and (c) compounds of formula (Ic), or the pharmaceutical composition comprises the compound and optionally a pharmaceutically acceptable excipient:

[0366]

[0367] And solvates, salts, N-oxides, complexes, polymorphs, crystalline forms, racemic mixtures, diastereomers, enantiomers, tautomers, conformational isomers, isotopic labeled forms, prodrugs and combinations thereof, wherein Hy and R 2 R 3 R 4 A and E are independently defined as above (in particular with respect to equations (Ia), (IIIa), (IVa), (Va), (VIa), (VIIa) and / or (VIIIa)) or below; R 5’ Yes -LR 6’ L is a bond; R 6’ R is arbitrarily selected by one or more independent choices. 7’ Substituted 5- or 6-membered heteroaryl groups; R 7’ Independently selected from R 7Alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, heteroaryl, halogen, -CN, azide, -NO2, -OR 11 -N(R) 12 (R) 13 ), -N(R 11 (OR) 11 ), -S(O) 0-2 R 11 -S(O) 1-2 OR 11 -OS(O) 1- 2R 11 -OS(O) 1-2 OR 11 -S(O) 1-2 N(R 12 (R) 13 ), -OS(O) 1-2 N(R 12 (R) 13 ), -N(R 11 S(O) 1-2 R 11 -NR 11 S(O) 1-2 OR 11 -NR 11 S(O) 1-2 N(R 12 (R) 13 -P(O)(OR) 11 )2、-OP(O)(OR 11 )2、-C(=X)R 11 -C(=X)XR 11 -XC(=X)R 11 and -XC(=X)XR 11 Each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, and heteroaryl groups is optionally represented by one or more independently selected R groups. 30 Replace; and R 11 R 12 R 13 X and R 30 Independently as defined above (especially with respect to equation (Ia));

[0368]

[0369] And solvates, salts, N-oxides, complexes, polymorphs, crystalline forms, racemic mixtures, diastereomers, enantiomers, tautomers, conformational isomers, isotopic labeled forms, prodrugs and combinations thereof, wherein R 1a R 1b R1c R 2 R 3 R 4 A, B, and E are independently defined as above (especially with respect to equations (Ia), (IIIa), (IVa), (Va), (VIa), (VIIa), and / or (VIIIa)) or below; R 5’ Yes -LR 6’ ;L as described above (especially with respect to formulas (Ia) and / or (IIa));R 6’ R is arbitrarily selected by one or more independent choices. 7’ Substituted heteroaryl or heterocyclic group; R 7’ Independently selected from R 7 Alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, heteroaryl, halogen, -CN, azide, -NO2, -OR 11 -N(R) 12 (R) 13 ), -N(R 11 (OR) 11 ), -S(O) 0-2 R 11 -S(O) 1-2 OR 11 -OS(O) 1-2 R 11 -OS(O) 1-2 OR 11 -S(O) 1-2 N(R 12 (R) 13 ), -OS(O) 1-2 N(R 12 (R) 13 ), -N(R 11 S(O) 1-2 R 11 -NR 11 S(O) 1-2 OR 11 -NR 11 S(O) 1-2 N(R 12 (R) 13 -P(O)(OR) 11 )2、-OP(O)(OR 11 )2、-C(=X)R 11 -C(=X)XR 11 -XC(=X)R 11 and -XC(=X)XR 11 , and / or with R as a heterocyclic group 6” Any two R atoms bonded to the same atom 7’They can be combined to form =O, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, and heteroaryl groups is optionally accompanied by one or more independently selected R groups. 30 Replace; and R 11 R 12 R 13 X and R 30 Independently as defined above (especially with respect to formula (Ia)).

[0370] In one embodiment, the compound of formula (Ib) according to the specific use of the fifth aspect has the general formula (IIb).

[0371]

[0372] Among them Hy, R 2 R 3 R 4 A and E are independently defined as above (in particular with respect to equations (Ib), (IIIa), (IVa), (Va), (VIa), (VIIa) and / or (VIIIa)) or below (in particular with respect to equation (IIIb)); R 6’ R is optionally selected independently by one or more (e.g., 1 to a maximum number of hydrogen atoms bonded to 5 or 6 heteroaryl groups, e.g., 1, 2, 3, 4, 5, e.g., 1 to 4, or 1 to 3, or 1 or 2) 7' (In particular, as defined herein, such as with respect to the following formula (Vc)) substituted 5- or 6-membered heteroaryl groups.

[0373] In one embodiment of the compound of formula (IIb) used according to the fifth aspect, Hy, R 2 R 3 R 4 A and E are independently defined as above (in particular with respect to equations (Ib), (IIIa), (IVa), (Va), (VIa), (VIIa) and / or (VIIIa)) or below (in particular with respect to equation (IIIb)); and R 6’ The following text (especially regarding formula (Vc)) relates to R 6” The defined 5- or 6-membered heteroaryl group.

[0374] In one embodiment of the compound of formula (IIb) according to the specific use of the fifth aspect, Hy, R 2 R 3 R 4 A and E are independently defined as above (in particular with respect to equations (Ib), (IIIa), (IVa), (Va), (VIa), (VIIa) and / or (VIIIa)) or below (in particular with respect to equation (IIIb)); and R 6’It is a 5- or 6-membered heteroaryl group (especially a 5- or 6-membered monocyclic heteroaryl group) comprising at least one cyclic heteroatom selected from N, O, and S, wherein the 5- or 6-membered heteroaryl group is optionally independently selected by one or more R groups (e.g., 1 to a maximum number of hydrogen atoms bonded to the 5- or 6-membered heteroaryl group, e.g., 1, 2, 3, 4, 5, e.g., 1 to 4, or 1 to 3, or 1 or 2). 7’ (In particular, as defined in this paper, such as with respect to the following formula (Vc)) substitution. For example, R 6' It can be a 5- or 6-membered heteroaryl group, which contains at least one cyclic heteroatom selected from N and O (i.e., the heteroaryl group does not contain S as a cyclic heteroatom; and in some embodiments, it does not contain O as a cyclic heteroatom, i.e., R). 6' (may be composed of N-heteroaryl groups), wherein the 5- or 6-membered heteroaryl group is optionally separated by one, two, or three independently selected R groups. 7' Replace (especially as defined in this article, for example with respect to the following formula (Vc)).

[0375] In one embodiment of the compound of formula (IIb) according to the specific use of the fifth aspect, Hy, R 2 R 3 R 4 A and E are independently defined as above (in particular with respect to equations (Ib), (IIIa), (IVa), (Va), (VIa), (VIIa) and / or (VIIIa)) or below (in particular with respect to equation (IIIb)); and R 6’ The group is selected from pyridyl, thiophene, pyrazinyl, pyrimidinyl, pyrazinyl, furanyl, pyrrole, pyrazolyl, oxazolyl, isoxazolyl, and oxadiazolyl, wherein each is optionally selected by one, two, or three independently chosen R. 7’ (In particular, as defined herein, for example with respect to the following formula (Vc)) substitution, preferably R 6’ The group is selected from pyridyl, thiophene, pyrazolyl, isoxazolyl, and pyrroleyl, wherein each is optionally selected by one, two, or three independently chosen R. 7’ (In particular, as defined herein, for example with respect to the following formula (Vc)) substitution.

[0376] In any of the above embodiments of the compound of formula (IIb) (including the compound of formula (Ib)) for the specific use according to the fifth aspect, R 7’ Can be independently selected from R 7 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, -CN, -O(C) 1-6 alkyl), -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl group 2, -NHS(O) 1-2 (C1-6 Alkyl group), -NHS(O) 1-2 O、(C 1-6 Alkyl), -C(=O)(C 1-6 Alkyl) and -OC (=O)(C 1-6 Alkyl), wherein C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Each of the ynyl groups is optionally enclosed by one or more (e.g., 1 to C). 1-6 Alkyl, C 2-6 alkenyl or C 2-6 The maximum number of hydrogen atoms bonded to the alkynyl group, such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or up to 10, such as 1 to 5, 1 to 4, 1 to 3, or 1 or 2, is independently chosen by R. 30 (where each R) 30 Preferably, the substitution is selected from primary, secondary, and tertiary substituents as specified herein. For example, R 7' Can be independently selected from C 1-3 Alkyl, halogen, -CN, -O(C) 1-3 alkyl), -NH(C) 1-3 alkyl) and -N(C) 1-3 alkyl)2, wherein the C 1-3 Each of the alkyl groups is optionally composed of one or more (e.g., 1 to C). 1-3 The maximum number of hydrogen atoms in the alkyl group, for example 1, 2, 3, 4, 5, 6, 7 or at most 6, for example 1 to 5, 1 to 4, or 1 to 3, or 1 or 2) independently selected R 30 (where each R) 30 Preferably, the substitution is selected from primary, secondary, and tertiary substituents as defined herein. In any of the above-described embodiments of the compound of formula (IIb) (including the compound of formula (Ib)) for the specific use according to the fifth aspect, R 7' It can be independently selected from Cl, Br, methyl, and ethyl, for example, selected from Cl, Br, and methyl. In another embodiment of any of the above embodiments of the compound of formula (IIb) (including the compound of formula (Ib)) according to the specific use of the fifth aspect, R 7' Can be independently for R 7 For example, any R defined by equation (Ia) 7 .

[0377] In any of the above embodiments of the compound of formula (IIb) (including the compound of formula (Ib)) for the specific use according to the fifth aspect, when R 6' When replaced, one R is preferred. 7' Groups relative to R 6'The remaining ring atom of the compound binds to R at position 2. 6' Ring atoms (i.e., preferably R) 6’ Having a neighboring R 7’ (Group). In any of the above embodiments of the compound of formula (IIb) (including the compound of formula (Ib)) for the specific use according to the fifth aspect, wherein R 6' By two or more (e.g., two, three or four) R 7' Group substitution, preferably, two or more R groups 7' One of the groups is relative to R 6' The ring atom bonded to the remainder of the compound at position 2 is related to R. 6' The ring atoms are bonded (i.e., R) 6' Having adjacent R 7' (group), and the remaining R 7' The group is attached to R at a position other than position 2. 6' The ring atoms. For example, in any of the above embodiments of the compound of formula (IIb) (including the compound of formula (Ib)) for the specific use according to the fifth aspect, wherein R 6' Is it by two or more R 7' A group-substituted k-membered ring, preferably two or more R groups. 7' One of the groups is relative to R 6' The remaining ring atom of the compound binds to R at position 2. 6' The ring atoms (i.e., relative to the base position), and the remaining R 7' Groups at positions other than position 2 (e.g., positions 3, 4, 5, ... k) are related to R. 6' The ring atoms are bonded. For example, in R 6' In the case of a 5-membered ring, two or more R's are preferred. 7' One of the groups is attached to R at position 2. 6' The ring atoms (relative to the yl position), and the remaining R 7' Group and R 6' The ring atoms are bonded at positions 3, 4, or 5 (relative to the base position). Furthermore, in any of the above-described embodiments of the compound of formula (IIb) (including the compound of formula (Ib)) for the specific use according to the fifth aspect, wherein R... 6' By two or more (e.g., two, three or four) R 7' Group substitution, preferably, directly with R 6' Each of two adjacent ring atoms connected to the rest of the compound carries an R. 7' Groups (e.g., R groups relative to the rest of the compound) 6' Ring atoms, R as a k-membered ring 6'There is an R at each position 2 and k. 7' Groups, such as R 6' (Substituted at its two adjacent positions). Additionally, in any of the above embodiments of the compound of formula (IIb) (including the compound of formula (Ib)) for the specific use according to the fifth aspect, wherein R... 6' By three or more (e.g., three or four) R 7' Group substitution, preferably, directly with R 6 Each of two adjacent ring atoms connected to the rest of the compound carries an R. 7' Groups (e.g., R groups relative to the rest of the compound) 6' Ring atoms, R as a k-membered ring 6' There is an R at each position 2 and k. 7' Groups, such as R 6' (It is replaced at its two adjacent positions), and the third R 7' Group and R 6' A ring atom is bonded to a ring atom that is directly adjacent to a neighboring ring atom, but is not R. 6' Ring atoms (e.g., R) that are bonded to the rest of the compound 6' It is a k-element ring, relative to R 6' The ring atoms bonded to the rest of the compound have a third R at one of the positions between 3 and k-1. 7' (group).

[0378] In one embodiment of the compound of formula (IIb) according to the specific use of the fifth aspect, Hy, R 2 R 3 R 4 A and E are independently defined as above (in particular with respect to equations (Ib), (IIIa), (IVa), (Va), (VIa), (VIIa) and / or (VIIIa)) or below (in particular with respect to equation (IIIb)), R 6' Selected from the following formulas:

[0379]

[0380] in R represents 6' Bonds that bind to the rest of the compound.

[0381] In one embodiment of the compound of formula (IIb) according to the specific use of the fifth aspect, Hy, R 2 R 3 R 4A and E are independently defined as above (in particular with respect to equations (Ib), (IIIa), (IVa), (Va), (VIa), (VIIa) and / or (VIIIa)) or below (in particular with respect to equation (IIIb)), R 6' Selected from the following formulas:

[0382]

[0383] in R represents 6' Bonds that bind to the rest of the compound.

[0384] In one embodiment of the compound of formula (IIb) according to the specific use of the fifth aspect, Hy, R 2 R 3 R 4 A and E are independently defined as above (in particular with respect to equations (Ib), (IIIa), (IVa), (Va), (VIa), (VIIa) and / or (VIIIa)) or below (in particular with respect to equation (IIIb)), R 6' Selected from the following formulas:

[0385]

[0386] in R represents 6' Bonds that bind to the rest of the compound.

[0387] In any of the above embodiments of the compound of formula (IIb) (including the compound of formula (Ib)) for the specific use according to the fifth aspect, wherein R 6' It is a 5- or 6-membered heteroaryl group, containing an N atom as a cyclic heteroatom, and R 6' It can be attached to the rest of the compound via the N-ring atom of a 5- or 6-membered heteroaryl group.

[0388] In one embodiment, the compound of formula (Ib) according to the specific use of the fifth aspect has the general formula (IIIb).

[0389]

[0390] Where R 2 R 3 R 4 R 5A and E are independently defined as above (particularly with respect to formulas (Ib), (IIb), (IIIa), (IVa), (VIIa) and / or (VIIIa)) or below (particularly with respect to formulas (IVc), (VIc) and / or (VIIc)), and Hy is R, which is optionally independently selected by one or more (e.g., 1 to a maximum number of hydrogen atoms bonded to a heteroaryl or heterocyclic group, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or up to 10, e.g., 1 to 5, 1 to 4, or 1 to 3 or 1 or 2). 1e Substituted heteroaryl or heterocyclic groups; each R 1e Independently selected from R 1a R 1b R 1c and R 1d And R 1a R 1b R 1c and R 1d Each of them is defined independently as above (in particular with respect to equations (Ia), (VIa), (VIIa) and / or (VIIIa)) or below (in particular with respect to equations (IIc), (IIc), (VIIc) and / or (VIIIc)).

[0391] In one embodiment of the compound of formula (IIIb), R 2 R 3 R 4 R 5 A and E are defined independently as above (in particular with respect to formulas (Ib), (IIb), (IIIa), (IVa), (VIIa) and / or (VIIIa)) or below (in particular with respect to formulas (IVc), (VIc) and / or (VIIc)), and Hy is defined as above (in particular with respect to formulas (Va), (VIIa) and / or (VIIIa)).

[0392] In one embodiment of the compound of formula (IIIb), R 2 R 3 R 4 R 5 A and E are independently defined as above (particularly with respect to formulas (Ib), (IIb), (IIIa), (IVa), (VIIa) and / or (VIIIa)) or below (particularly with respect to formulas (IVc), (VIc) and / or (VIIc)), and Hy is a 3-10 member heterocyclic group or a 3-10 member heterocyclic group, wherein each is optionally composed of one, two, three, four, five or six independently selected R as defined herein. 1e Replacement (especially with respect to formulas (Ib), (IIIb), (Ia) and / or (Va)).

[0393] In one embodiment of the compound of formula (IIIb), R 2 R 3 R 4 R 5 A and E are independently defined as above (particularly with respect to formulas (Ib), (IIb), (IIIa), (IVa), (VIIa) and / or (VIIIa)) or below (particularly with respect to formulas (IVc), (VIc) and / or (VIIc)), and Hy is a mono- or bicyclic heteroaryl or a mono- or bicyclic heterocyclic group, wherein each is optionally composed of one, two, three, four, five or six independently selected R. 1e Replacement (especially with respect to formulas (Ib), (IIIb), (Ia) and / or (Va)).

[0394] In one embodiment of the compound of formula (IIIb), R 2 R 3 R 4 R 5 A and E are independently defined as above (particularly with respect to formulas (Ib), (IIb), (IIIa), (IVa), (VIIa) and / or (VIIIa)) or below (particularly with respect to formulas (IVc), (VIc) and / or (VIIc)), and Hy is a group selected from those containing 5-6 member monocyclic heterocyclic groups, 5-6 member monocyclic heterocyclic groups, 9-10 member bicyclic heterocyclic groups, and 8-10 member bicyclic heterocyclic groups, wherein each is optionally composed of one, two, three, four, five, or six independently selected R groups. 1e Replacement (especially with respect to formulas (Ib), (IIIb), (Ia) and / or (Va)).

[0395] In one embodiment of the compound of formula (IIIb), R 2 R 3 R 4 R 5A and E are independently defined as above (particularly with respect to formulas (Ib), (IIb), (IIIa), (IVa), (VIIa) and / or (VIIIa)) or below (particularly with respect to formulas (IVc), (VIc) and / or (VIIc)), and Hy is selected from pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl (e.g., 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl), pyrazolyl, oxadiazinyl, etc. Azolyl, thiazolyl, triazolyl, thiadiazolyl, cyclopentadiazinyl, dihydrocyclopentadiazinyl, pyrrolipidyl, indoleazinyl, dihydroindoleazinyl, tetrahydroindoleazinyl, quinazolinyl, dihydroquinazolinyl, tetrahydroquinazolinyl, pyridinepyrimidinyl, pyranpyrimidinyl, dihydropyranpyrimidinyl, tetrahydropyranpyrimidinyl, piperidinyl, tetrahydropyranyl, and 1,1-dioxytetrahydrothiopyranyl, wherein each is optionally represented by one, two, three, four, five, or six independently selected R groups. 1e Replacement (especially with respect to formulas (Ib), (IIIb), (Ia) and / or (Va)).

[0396] In one embodiment of the compound of formula (IIIb), R 2 R 3 R 4 R 5’ A and E are independent as defined above (especially with respect to equations (Ib), (IIb), (IIIa), (IVa) and / or (VIIIa)) or as follows ((IVc), (VIc) and / or (VIIc)), and Hy is selected from:

[0397]

[0398] Each of the groups specified under a), b), c), d), e), f), and g) is optionally represented by one, two, three, four, five, or six independently selected R groups. 1e (In particular, regarding the substitution of formulas (Ib), (IIIb), (Ia), and / or (Va)), and where Hy represents NR in equation (IIIb) 2 The bonds are partially linked by nitrogen atoms. If Hy contains an NH moiety as a member of the ring, then preferably the hydrogen atoms are replaced with alkyl groups, such as C. 1-6 Or C 1-3 Alkyl group, more preferably methyl group (resulting in alkyl substitution of N-ring atoms), and Hy optionally further selected by one, two, three, four or five independently chosen R groups. 1e Substitution. Examples of this N-alkyl-substituted Hy group include in Represents Hy and NR in equation (Ib) 2The bonds that connect some nitrogen atoms.

[0399] In the compounds of formula (IIIb) in any of the above embodiments, Hy can be converted by an R 1b An R 1c and 1 to 4 (e.g., 1, 2 or 3) R 1a Or R 1d Replacement; for example, Hy can be replaced by one (or two) R 1a (As defined above, particularly with respect to equations (VIa), (VIIa) and / or (VIIIa), or as follows, particularly with respect to equations (IIc) and / or (VIIIc)) are replaced and are replaced by one (or two) R 1b Or R 1c (As defined above, particularly with respect to equations (VIa), (VIIa), and / or (VIIIa), or as follows, particularly with respect to equations (IIIc) and / or (VIIIc)) substitution, and all other R 1e For H.

[0400] In the compounds of formulas (Ib), (IIb), and (IIIb) of any of the above embodiments, it is preferred that A is S and / or E is O.

[0401] In the compounds of formulas (Ib), (IIb), and (IIIb) of any of the above embodiments, R is preferred. 3 It is H.

[0402] In the compounds of formulas (Ib), (IIb), and (IIIb) of any of the above embodiments, it is preferred that A is S and / or E is O and / or R. 3 It is H. For example, in one embodiment of formulas (Ib), (IIb), and (IIIb), A is S; E is O; and R is H. 3 It is H.

[0403] In one embodiment, the compound according to the fifth aspect (Ic) for a specific purpose has a general formula (IIc).

[0404]

[0405] Where R 1b R 1c R 2 R 3 R 4 R 5” A, B, and E are as defined above (particularly with respect to equations (Ic), (IIIa), (IVa), (VIa), (VIIa), and / or (VIIIa)) or as follows (particularly with respect to equations (IIIc), (IVc), (Vc), (VIc), (VIIc), and / or (VIIIc)), and R1a Selected from alkyl, -O (alkyl), -S (alkyl), -NH (alkyl), -N (alkyl)2 and heterocyclic groups, wherein each alkyl and heterocyclic group is optionally represented by one or more (e.g., one, two or three) independently selected R groups. 30 Replacement. Preferably, each R 30 Independently, it is a primary substituent, a secondary substituent, or a tertiary substituent as described herein, such as an alkyl group (e.g., C10). 1-6 Alkyl group), -(CH2) 1-3 OH, alkenyl (e.g., C) 2-6 alkenyl), ynyl (e.g., C10), alkynyl (e.g., C10), 2-6 Alkyne, halogen, -CN, nitro, -OR 11 (e.g., -OH), -SR 11 (e.g., -SH), -N(R) 12 (R) 13 (e.g., -NH2) and C(=O)R 11 (For example, -C(=O)(C) 1-3 alkyl)).

[0406] In one embodiment of the compound of formula (IIc), R 1b R 1c R 2 R 3 R 4 R 5” A, B, and E are as defined above (particularly with respect to equations (Ic), (IIIa), (IVa), (VIa), (VIIa), and / or (VIIIa)) or as follows (particularly with respect to equations (IIIc), (IVc), (Vc), (VIc), (VIIc), and / or (VIIIc)), and R 1a Selected from C 1-3 Alkyl, -O(C) 1-3 alkyl), -S(C 1-3 alkyl), -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl) 2 and 3 to 7-membered heterocyclic groups, wherein the 3 to 7-membered heterocyclic groups are optionally independently selected from methyl, ethyl, -OH, -OCH3, -SCH3, cyclopropyl, 2-hydroxyethyl, 2-(N,N-dimethylamino)ethyl, 2-(N,N-dimethylamino)ethoxy, 2-aminoethyl, 2-(N-methylamino)ethyl, 2-(methoxy)ethyl, 4-methylpiperazinyl, -C(=O)(C 1-3 Alkyl group), -(CH2) 1-3 COOH and -NH 2-z (CH3) zOne or both parts are replaced, where z is 0, 1, or 2; and each C 1-3 The alkyl group is optionally selected independently from -OH, -OCH3, -SCH3, cyclopropyl, piperazinyl, 4-methyl-piperazinyl, 4-(2-hydroxyethyl)piperazinyl, 2-(N,N-dimethylamino)ethoxy, and -NH 2-z (CH3) z One or both parts are replaced, where z is 0, 1 or 2.

[0407] In one embodiment of the compound of formula (IIc), R 1b R 1c R 2 R 3 R 4 R 5” A, B, and E are as defined above (particularly with respect to equations (Ic), (IIIa), (IVa), (VIa), (VIIa), and / or (VIIIa)) or as follows (particularly with respect to equations (IIIc), (IVc), (Vc), (VIc), (VIIc), and / or (VIIIc)), and R 1a Selected from C 1-3 Alkyl, -O(C) 1-3 alkyl), -S(C 1-3 alkyl), -NH(C) 1-3 Alkyl), piperazinyl, morpholinyl, piperidinyl, and pyrrolidinyl, wherein each piperazinyl, morpholinyl, piperidinyl, and pyrrolidinyl group is optionally independently selected from methyl, ethyl, -OH, -OCH3, -SCH3, cyclopropyl, 2-hydroxyethyl, 2-(N,N-dimethylamino)ethyl, 2-(N,N-dimethylamino)ethoxy, 2-aminoethyl, 2-(N-methylamino)ethyl, 2-(methoxy)ethyl, 4-methylpiperazinyl, -C(=O)(C 1-3 Alkyl group), -(CH2) 1-3 COOH and -NH 2-z (CH3) z One or both parts are replaced, where z is 0, 1, or 2; and each C 1-3 The alkyl group is optionally selected independently from -OH, -OCH3, -SCH3, cyclopropyl, piperazinyl, 4-methyl-piperazinyl, 4-(2-hydroxyethyl)piperazinyl, 2-(N,N-dimethylamino)ethoxy, and -NH 2-z (CH3) z One or both parts are replaced, where z is 0, 1 or 2.

[0408] In one embodiment of the compound of formula (IIc), R 1b R 1c R 2R 3 R 4 R 5” A, B, and E are as defined above (particularly with respect to equations (Ic), (IIIa), (IVa), (VIa), (VIIa), and / or (VIIIa)) or as follows (particularly with respect to equations (IIIc), (IVc), (Vc), (VIc), (VIIc), and / or (VIIIc)), and R 1a Selected from -NH(C 1-3 Alkyl), piperazine, piperidinyl, and pyrrolidinyl, wherein the piperazine group is optionally substituted by one or both moieties independently selected from 2-hydroxyethyl, methyl, -CH2COOH, and -C(=O)CH3; the piperidinyl group is optionally substituted by one or both moieties independently selected from -NH2 and 4-methylpiperazine; the pyrrolidinyl group is optionally substituted by one or two -OH groups; and C 1-3 Each group in the alkyl group is optionally and independently selected from -OH, -OCH3, and -NH. 2-z (CH3) z One or both parts are replaced, where z is 0, 1 or 2.

[0409] In one embodiment of the compound of formula (IIc), R 1b R 1c R 2 R 3 R 4 R 5” A, B, and E are as defined above (particularly with respect to equations (Ic), (IIIa), (IVa), (VIa), (VIIa), and / or (VIIIa)) or as follows (particularly with respect to equations (IIIc), (IVc), (Vc), (VIc), (VIIc), and / or (VIIIc)), and R 1a It is selected from 4-(2-hydroxyethyl)piperazinyl, 4-methylpiperazinyl, 4-acetylpiperazinyl, (2-hydroxyethyl)amino, 4-aminopiperidinyl, 4-(4-methylpiperazinyl)piperidinyl, (4-carboxymethylpiperazinyl) and 3-hydroxypyrrolidinyl, for example selected from 4-(2-hydroxyethyl)piperazinyl, 4-methylpiperazinyl, 4-acetylpiperazinyl and (2-hydroxyethyl)amino.

[0410] In an alternative embodiment of the compound of formula (IIc), R 1b R 1c R 2 R 3 R 4 R 5”A, B, and E are as defined above (especially with respect to equations (Ic), (IIIa), (IVa), (VIa), (VIIa), and / or (VIIIa)) or as follows (especially with respect to equations (Ic), (IIIa), (IVa), (VIa), (VIIa), and / or (VIIIa)), and R 1a It is a leaving group (e.g., halogen (e.g., Cl, Br, or F), nitro, benzotriazol-1-yloxy, C1-C). 10 Alkyl sulfonates, C1-C 10 Halogenated alkyl sulfonates, perfluorobutyl sulfonates (CF3CF2CF2CF2SO3-), CF3C(=O)O-, benzene sulfonates (wherein the phenyl group is optionally substituted by one, two, or three groups independently selected from halogens and C1-C4 alkyl groups), or of the formula -[N(R x (R) y (R) z )] + [G] - ammonium salts, of which R x R y and R z Both are independently hydrogen or alkyl, and G is the conjugate base of a strong acid (e.g., G...). - It is Cl - )).

[0411] In one embodiment, the compound for a specific application according to the fifth aspect (Ic) has the general formula (IIIc).

[0412]

[0413] Where R 1a R 2 R 3 R 4 R 5” A, B, and E are as defined above (especially with respect to equations (Ic), (IIc), (IIIa), (IVa), (VIa), (VIIa), and / or (VIIIa)) or as follows (especially with respect to equations (IVc), (Vc), (VIc), (VIIc), and / or (VIIIc)), and each R 1b and R 1c Independently selected from H, methyl, ethyl, -OH, -OCH3, -SCH3, cyclopropyl, 2-hydroxyethyl, 2-(N,N-dimethylamino)ethyl, 2-(N,N-dimethylamino)ethoxy, 2-aminoethyl, 2-(N-methylamino)ethyl, 2-(methoxy)ethyl, -NH 2-z (CH3) zphenyl, pyridyl, pyrazolyl, phenoxy, pyridyloxy, imidazoleylamino, and tetrahydrofuranylmethoxy, wherein z is 0, 1, or 2; and each phenyl, pyridyl, pyrazolyl, phenoxy, pyridyloxy, imidazoleylamino, and tetrahydrofuranylmethoxy is optionally independently selected from methyl, ethyl, -OH, -OCH3, -SCH3, cyclopropyl, 2-hydroxyethyl, 2-(N,N-dimethylamino)ethyl, 2-(N,N-dimethylamino)ethoxy, 2-aminoethyl, 2-(N-methylamino)ethyl, 2-(methoxy)ethyl, and -NH 2-z (CH3) z One, two, or three parts are replaced, where z is 0, 1, or 2.

[0414] In one embodiment of the compound of formula (IIIc), R 1a R 2 R 3 R 4 R 5” A, B, and E are as defined above (particularly with respect to equations (Ic), (IIc), (IIIa), (IVa), (VIa), (VIIa), and / or (VIIIa)) or as follows (particularly with respect to equations (IVc), (Vc), (VIc), (VIIc), and / or (VIIIc)), and R 1b and R 1c At least one of the following is selected from H, methyl, ethyl, -OH, -OCH3, -SCH3, cyclopropyl, 2-hydroxyethyl, 2-(N,N-dimethylamino)ethyl, 2-(N,N-dimethylamino)ethoxy, 2-aminoethyl, 2-(N-methylamino)ethyl, 2-(methoxy)ethyl, -NH 2-z (CH3) z And phenyl, wherein z is 0, 1, or 2. In this embodiment, R 1b and R 1c Another one in can be defined as above (especially with respect to equations (Ia), (IIa) and / or (IIIa)), for example, R 1b and R 1c The other can be selected from H, methyl, ethyl, -OH, -OCH3, -SCH3, cyclopropyl, 2-hydroxyethyl, 2-(N,N-dimethylamino)ethyl, 2-(N,N-dimethylamino)ethoxy, 2-aminoethyl, 2-(N-methylamino)ethyl, 2-(methoxy)ethyl, -NH 2-z (CH3) zThe groups z are phenyl, pyridyl, pyrazolyl, phenoxy, pyridoxy, imidazolylamino, and tetrahydrofuranylmethoxy, wherein z is 0, 1, or 2; and each of the phenyl, pyridyl, pyrazolyl, phenoxy, pyridoxy, imidazolylamino, and tetrahydrofuranylmethoxy groups is optionally independently selected from methyl, ethyl, -OH, -OCH3, -SCH3, cyclopropyl, 2-hydroxyethyl, 2-(N,N-dimethylamino)ethyl, 2-(N,N-dimethylamino)ethoxy, 2-aminoethyl, 2-(N-methylamino)ethyl, 2-(methoxy)ethyl, and -NH 2-z (CH3) z One, two, or three parts are replaced, where z is 0, 1, or 2. Alternatively, R 1b and R 1c Each of these is independently selected from H, methyl, ethyl, -OH, -OCH3, -SCH3, cyclopropyl, 2-hydroxyethyl, 2-(N,N-dimethylamino)ethyl, 2-(N,N-dimethylamino)ethoxy, 2-aminoethyl, 2-(N-methylamino)ethyl, 2-(methoxy)ethyl, -NH 2-z (CH3) z And phenyl, where z is 0, 1 or 2.

[0415] In one embodiment of the compound of formula (IIIc), R 1a R 2 R 3 R 4 R 5” A, B, and E are as defined above (particularly with respect to equations (Ic), (IIc), (IIIa), (IVa), (VIa), (VIIa), and / or (VIIIa)) or as follows (particularly with respect to equations (IVc), (Vc), (VIc), (VIIc), and / or (VIIIc)), and R 1b It is methyl, ethyl, propyl, or isopropyl, preferably methyl; and R 1c It is H. In an alternative embodiment, R 1c It is H; and R 1c It is methyl, ethyl, propyl, isopropyl, or phenyl, with methyl being preferred.

[0416] In one embodiment, the compound for a specific application according to the fifth aspect (Ic) has the general formula (IVc).

[0417]

[0418] Where R 1a R 1b R 1c R 2 R 4 R 5”A, B, and E are as defined above (especially with respect to equations (Ic), (IIc), (IIIc), (IIIa), (VIa), (VIIa), and / or (VIIIa)) or as follows (especially with respect to equations (Vc), (VIc), (VIIc), and / or (VIIIc)), and R 3 Selected from H, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, phenyl, halogen, -CN, azide, -NO2, -O(C 1-6 alkyl), -OCF3, -S(C1) -6 Alkyl groups, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2、-NHS(O)2(C 1-6 Alkyl group), -S(O)2NH 2-z (C1 -6 alkyl) z -C(=O)(C 1-6 Alkyl group), -C(=O)OH, -C(=O)O(C 1-6 Alkyl group), -C(=O)NH 2-z (C 1-6 alkyl) z -NHC(=O)(C 1-6 Alkyl group), -NHC(=NH)NH 2-z (C 1-6 alkyl) z and -N(C 1-6 alkyl)C(=NH)NH 2-z (C 1-6 alkyl) z Where z is 1 or 2 and each of C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Both cycloalkyl and phenyl groups are optionally separated by one or more independently selected R groups. 30 replace.

[0419] In one embodiment of the compound of formula (IVc), R 1a R 1b R 1c R 2 R 4 R 5”A, B, and E are as defined above (especially with respect to equations (Ic), (IIc), (IIIc), (IIIa), (VIa), (VIIa), and / or (VIIIa)) or as follows (especially with respect to equations (Vc), (VIc), (VIIc), and / or (VIIIc)), and R 3 Selected from H, C 1-4 Alkyl, C 3-6 Cycloalkyl, phenyl, halogen, -CN, -O(C) 1-4 Alkyl), -OCF3, -S(C 1-4 Alkyl groups, -NH2, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl)2、-C(=O)(C 1-4 Alkyl group), -C(=O)OH, -C(=O)O(C 1-4 Alkyl group), -C(=O)NH 2-z (C 1-4 alkyl) z -NHC(=O)(C 1-4 Alkyl group), -NHC(=NH)NH 2-z (C 1-4 alkyl) z and -N(C 1-4 alkyl)C(=NH)NH 2-z (C 1-4 alkyl) z The phenyl group is optionally surrounded by one, two, or independently selected from halogen, methyl, isopropyl, -CN, -CF3, -OCF3, -OH, -NH2, -NH(C 1-3 alkyl), -N(C) 1-3 Alkyl)2、-NHC(=O)(C 1-3 Alkyl group), -C(=O)NH 2-z (C 1-3 alkyl) z -(CH2) 1-3 NH2、-(CH2) 1-3 NH(C 1-3 Alkyl group), -(CH2) 1-3 N(C 1-3 Alkyl group 2, -(CH2) 1-3 OH and -(CH2) 1-3 O(C 1-3 The alkyl group is substituted; and z is 0, 1 or 2.

[0420] In one embodiment of the compound of formula (IVc), R 1a R 1b R 1c R 2 R4 R 5” A, B, and E are as defined above (especially with respect to equations (Ic), (IIc), (IIIc), (IIIa), (VIa), (VIIa), and / or (VIIIa)) or as follows (especially with respect to equations (Vc), (VIc), (VIIc), and / or (VIIIc)), and R 3 Selected from H, methyl, ethyl, propyl, isopropyl, phenyl and halogen.

[0421] In one embodiment of the compound of formula (IVc), R 1a R 1b R 1c R 2 R 4 R 5” A, B, and E are as defined above (especially with respect to equations (Ic), (IIc), (IIIc), (IIIa), (VIa), (VIIa), and / or (VIIIa)) or as follows (especially with respect to equations (Vc), (VIc), (VIIc), and / or (VIIIc)), and R 3 For H.

[0422] In one embodiment, the compound according to the fifth aspect (Ic) for a specific purpose has the general formula (Vc).

[0423]

[0424] Where R 1a R 1b R 1c R 2 R 3 R 4 A, B, and E are as defined above (especially with respect to equations (Ic), (IIc), (IIIc), (IVc), (IIIa), (IVa), (VIa), (VIIa), and / or (VIIIa)) or as follows (especially with respect to equations (VIc), (VIIc), and / or (VIIIc)), and R 5” For -LR 6” , where R 6” It is a heteroaryl group containing at least one cyclic heteroatom selected from N, O, and S, or a heterocyclic group containing at least one cyclic heteroatom selected from N, O, and S, wherein each heteroaryl and heterocyclic group is optionally represented by one or more (e.g., one, two, or three) independently selected R groups. 7' Replacement. For example, R 6” It can be a heteroaryl group containing at least one cyclic heteroatom selected from N and O (e.g., the heteroaryl group does not contain S as a cyclic heteroatom; and in some embodiments does not contain O as a cyclic heteroatom, i.e., R).6” It can be an N-heteroaryl group, or it can be a heterocyclic group containing at least one cyclic heteroatom selected from N and O (e.g., the heterocyclic group does not contain S as a cyclic heteroatom; and in some embodiments it does not contain O as a cyclic heteroatom, i.e., R). 6” (may be N-heterocyclic groups), wherein each heteroaryl and heterocyclic group is optionally surrounded by one or more (e.g., one, two, or three) independently selected R groups. 7' replace.

[0425] In one embodiment of the compound of formula (Vc), R 1a R 1b R 1c R 2 R 3 R 4 A, B, and E are as defined above (especially with respect to equations (Ic), (IIc), (IIIc), (IVc), (IIIa), (IVa), (VIa), (VIIa), and / or (VIIIa)) or as follows (especially with respect to equations (VIc), (VIIc), and / or (VIIIc)), and R 6” It is a 3- to 10-membered heteroaryl group (e.g., containing at least one cyclic heteroatom selected from N, O, and S, such as N and O) or a 3- to 10-membered heterocyclic group (e.g., containing at least one cyclic heteroatom selected from N, O, and S, such as N and O), each of which is optionally selected by one or more (e.g., one, two, or three) independently chosen R 7' replace.

[0426] In one embodiment of the compound of formula (Vc), R 1a R 1b R 1c R 2 R 3 R 4 A, B, and E are as defined above (especially with respect to equations (Ic), (IIc), (IIIc), (IVc), (IIIa), (IVa), (VIa), (VIIa), and / or (VIIIa)) or as follows (especially with respect to equations (VIc), (VIIc), and / or (VIIIc)), and R 6” It is a monocyclic or bicyclic heteroaryl group (e.g., containing at least one cyclic heteroatom selected from N, O, and S, such as N and O) or a monocyclic or bicyclic heterocyclic group (e.g., containing at least one cyclic heteroatom selected from N, O, and S, such as N and O), each of which is optionally independently selected by one or more (e.g., one, two, or three) R 7' replace.

[0427] In one embodiment of the compound of formula (Vc), R 1aR 1b R 1c R 2 R 3 R 4 A, B, and E are as defined above (especially with respect to equations (Ic), (IIc), (IIIc), (IVc), (IIIa), (IVa), (VIa), (VIIa), and / or (VIIIa)) or as follows (especially with respect to equations (VIc), (VIIc), and / or (VIIIc)), and R 6” The R group is selected from 5- to 6-membered monocyclic heteroaryl groups (e.g., containing at least one cyclic heteroatom selected from N, O, and S, such as N and O), 4- to 6-membered monocyclic heterocyclic groups (e.g., containing at least one cyclic heteroatom selected from N, O, and S, such as N and O), 7- to 9-membered bicyclic heteroaryl groups (e.g., containing at least one cyclic heteroatom selected from N, O, and S, such as N and O), and 7- to 9-membered bicyclic heterocyclic groups (e.g., containing at least one cyclic heteroatom selected from N, O, and S, such as N and O), each of which is optionally independently selected by one or more (e.g., one, two, or three) R groups. 7' replace.

[0428] In one embodiment of the compound of formula (Vc), R 1a R 1b R 1c R 2 R 3 R 4 A, B, and E are as defined above (especially with respect to equations (Ic), (IIc), (IIIc), (IVc), (IIIa), (IVa), (VIa), (VIIa), and / or (VIIIa)) or as follows (especially with respect to equations (VIc), (VIIc), and / or (VIIIc)), and R 6” It is a 5- to 6-membered monocyclic heteroaryl group (e.g., containing at least one cyclic heteroatom selected from N, O, and S, such as N and O), which is optionally composed of one or more (e.g., one, two, or three) independently selected R 7’ replace.

[0429] In one embodiment of the compound of formula (Vc), R 1a R 1b R 1c R 2 R 3 R 4A, B, and E are as defined above (especially with respect to equations (Ic), (IIc), (IIIc), (IVc), (IIIa), (IVa), (VIa), (VIIa), and / or (VIIIa)) or as follows (especially with respect to equations (VIc), (VIIc), and / or (VIIIc)), and R 6” It is a 7- to 9-membered bicyclic heterocyclic group (e.g., containing at least one cyclic heteroatom selected from N, O, and S, such as N and O), which is independently selected by one or more (e.g., one, two, or three) R 7’ replace.

[0430] In one embodiment of the compound of formula (Vc), R 1a R 1b R 1c R 2 R 3 R 4 A, B, and E are as defined above (especially with respect to equations (Ic), (IIc), (IIIc), (IVc), (IIIa), (IVa), (VIa), (VIIa), and / or (VIIIa)) or as follows (especially with respect to equations (VIc), (VIIc), and / or (VIIIc)), and R 6” Selected from pyridinyl, thiopheneyl, pyridazinyl, furanyl, pyrroleyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazoleimidazolyl, indolyl, naphridinyl, thiophenepyridine, tetrahydropyranyl, piperidinyl, pyrrolidinyl, azacyclobutane, azabicycloheptyl, azabicyclooctyl, azapentacyclooctyl, piperazinyl, morpholinyl, and tetrahydrothiopheneyl, each of which is optionally selected by one, two, or three independently chosen R 7' Replacement, preferably R 6” The R group is selected from pyridinyl, thiophene, pyrazolyl, isoxazolyl, pyrroleyl, piperidinyl, pyrrolidinyl, aziridine, and azirbicyclooctyl, each of which is optionally independently selected by one or more (e.g., one, two, or three). 7’ replace.

[0431] In any of the above embodiments of the compounds of formula (Vc) (including those of formulas (Ic), (IIc), (IIIc), and (IVc), R 7' Can be selected independently from R 7 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, -CN, -O(C) 1-6 alkyl), -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl group 2, -NHS(O) 1-2 (C1-6 Alkyl group), -NHS(O) 1-2 O(C 1-6 Alkyl), -C(=O)(C 1-6 Alkyl) and -OC (=O)(C 1-6 Alkyl group), and / or any two of R groups as heterocyclic groups 6” R of the same atoms 7' They can be connected together to form =O, where each C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 The alkynyl group is optionally replaced by one or more independently selected R groups. 30 Replacement. For example, R 7' It can be selected independently from R 7 C 1-3 Alkyl, halogen, -CN, -O(C) 1-3 alkyl), -NH(C) 1-3 alkyl) and -N(C) 1-3 alkyl)2, and / or any two of R as heterocyclic groups 6” R of the same atoms 7' They can be connected together to form =O, where C 1-3 The alkyl group is optionally replaced by one or more independently selected R groups. 30 Substitution. In any of the above embodiments of the compounds of formula (Vc) (including those of (Ic), (IIc), (IIIc) and (IVc), R 7' It can be independently selected from Cl, Br, methyl, and ethyl, for example, selected from Cl, Br, and methyl. In any other of the above embodiments of the compound of formula (Vc) (including those of (Ic), (IIc), (IIIc), and (IVc), R 7' It can be R independently 7 For example, it can be combined with any R defined in equation (Ia). 7 .

[0432] In any of the above embodiments of the compounds of formula (Vc) (including those of (Ic), (IIc), (IIIc) and (IVc), in R 6” In the case of replacement, one R is preferred. 7' Groups relative to R 6” The positions of the ring atoms bonded to the rest of the compound are 2 and R. 6” The ring atoms are connected (i.e., preferably R). 6” With adjacent R 7' Group). In any of the above embodiments of compounds of formula (Vc) (including those of formulas (Ic), (IIc), (IIIc) and (IVc), in R 6”By two or more (e.g., two, three, or four) R 7' In the case of group substitution, two or more R groups are preferred. 7' One of the groups is relative to R 6” The position 2 of the ring atom connected to the rest of the compound is related to R. 6” The ring atoms are connected (i.e., R) 6” With adjacent R 7' (group), and the remaining R 7' The positions of the group other than position 2 and R 6” The ring atoms are connected. For example, in any of the above embodiments of compounds of formula (Vc) (including those of formulas (Ic), (IIc), (IIIc) and (IVc), in R 6” It is by two or more (e.g., two, three, or four) R 7' In the case of a k-membered ring with substituted groups, two or more R groups are preferred. 7' One of the groups is relative to R 6” The position 2 of the ring atom connected to the rest of the compound is related to R. 6” The ring atoms are connected (i.e., relative to the base position), and the remaining R 7' The group at positions other than position 2 and (with) R 6” The ring atoms are connected, for example, at positions 3, 4, 5...k. For example, in R... 6” In the case of a 5-membered ring, two or more R's are preferred. 7' One of the groups is at position 2 (relative to the base position) with R. 6” The ring atoms are connected, and the remaining R 7' The group is at position 3, 4, or 5 (relative to the base position) with R 6” The ring atoms are connected. Furthermore, in any of the above-described embodiments of the compound of formula (Vc) (including those of formulas (Ic), (IIc), (IIIc), and (IVc), in R... 6” By two or more (e.g., two, three, or four) R 7' In the case of group substitution, it is preferred to use R. 6” Each of the two ring atoms directly adjacent to the ring atom bonded to the rest of the compound carries an R. 7' Groups (e.g., R) 6” It is a k-element ring, relative to R 6” The ring atoms that bind to the rest of the compound each have an R at positions 2 and k. 7' Groups, for example, R 6” Both adjacent positions are substituted). Furthermore, in any of the above-described embodiments of the compound of formula (Vc) (including those of formulas (Ic), (IIc), (IIIc), and (IVc), in R6” By three or more (e.g., three or four) R 7' In the case of group substitution, it is preferred to use R. 6” Each of the two ring atoms directly adjacent to the ring atom bonded to the rest of the compound carries an R. 7' Groups (e.g., R) 6” It is a k-element ring, relative to R 6” The ring atoms connected to the rest of the compound each have an R at positions 2 and k. 7' Groups, for example, R 6” Both adjacent positions are replaced) and the third R 7' Group and R 6” The ring atoms are connected, and this ring atom is directly adjacent to one of the neighboring ring atoms, but not R. 6” Ring atoms (e.g., R) attached to the rest of the compound 6” It is a k-element ring, relative to R 6” The ring atom bonded to the rest of the compound has a third R at position 3 and k-1. 7' (group).

[0433] In one embodiment of the compound of formula (Vc), R 1a R 1b R 1c R 2 R 3 R 4 A, B, and E are as defined above (especially with respect to equations (Ic), (IIc), (IIIc), (IVc), (IIIa), (IVa), (VIa), (VIIa) and / or (VIIIa) or as follows (especially with respect to equations (VIc), (VIIc) and / or (VIIIc)), and R 6” Selected from the following molecular formulas:

[0434]

[0435] in Represents R 6” Bonds that are attached to the rest of the compound.

[0436] In one embodiment of the compound of formula (Vc), R 1a R 1b R 1c R 2 R 3 R 4A, B, and E are as defined above (especially with respect to equations (Ic), (IIc), (IIIc), (IVc), (IIIa), (IVa), (VIa), (VIIa), and / or (VIIIa)) or as follows (especially with respect to equations (VIc), (VIIc), and / or (VIIIc)), and R 6” Selected from the following molecular formulas:

[0437]

[0438] in Represents R 6” Bonds that are attached to the rest of the compound.

[0439] In one embodiment of the compound of formula (Vc), R 1a R 1b R 1c R 2 R 3 R 4 A, B, and E are as defined above (especially with respect to equations (Ic), (IIc), (IIIc), (IVc), (IIIa), (IVa), (VIa), (VIIa), and / or (VIIIa)) or as follows (especially with respect to equations (VIc), (VIIc), and / or (VIIIc)), and R 6” Selected from the following molecular formulas:

[0440]

[0441] in Represents R 6” Bonds that are attached to the rest of the compound.

[0442] In one embodiment of the compound of formula (Vc), R 1a R 1b R 1c R 2 R 3 R 4 A, B, and E are as defined above (especially with respect to equations (Ic), (IIc), (IIIc), (IVc), (IIIa), (IVa), (VIa), (VIIa), and / or (VIIIa)) or as follows (especially with respect to equations (VIc), (VIIc), and / or (VIIIc)), and R 6” Selected from the following molecular formulas:

[0443]

[0444] in Represents R 6” Bonds that are attached to the rest of the compound.

[0445] In any of the above embodiments of compounds of formula (Vc) (including those of formulas (Ic), (IIc), (IIIc), and (IVc), L may be selected from the bond, C 1-6 Alkylene, C 2-6 imidene group, C 2-6 Alynyl group and -(CH2) m -[Y-(CH2) n ] o - where m is 1, 2, or 3, n is 0, 1, or 2, and o is 1, 2, or 3, where o is 1 if n is 0; y is independently selected from O, S, and NH, where each C 1-6 Alkylene, C 2-6 imidene group, C 2-6 Alynyl group, -(CH2) m - and -(CH2) n - The group is optionally selected by one or more independently chosen R 30 Substitution. For example, in any of the above embodiments of compounds of formula (Vc) (including those of formulas (Ic), (IIc), (IIIc), and (IVc), L may be selected from: bond; C1 alkylene, optionally with an R 30 Substitution; C2 alkylene (especially 1,2-ethylene or 1,1-ethylene), optionally with an R 30 Substitution; C3 alkylene (especially trimethylene), optionally with an R 30 Substitution; C4 alkylene (especially tetramethylene or 2,4-butadiene), optionally with an R 30 Substitution; -(CH2) m O- and -(CH2) m NH-, where m is 1, 2, or 3. In particular, in any of the above embodiments of compounds of formula (Vc) (including those of formulas (Ic), (IIc), (IIIc), and (IVc), L can be a bond.

[0446] In any of the above embodiments of the compounds of formula (Vc) (including those of formulas (Ic), (IIc), (IIIc), and (IVc), in R 6” In the case of a heterocyclic group or heteroaryl group (e.g., a 5-membered heteroaryl group) containing an N atom as a ring heteroatom, L can be attached to R through the N ring atom of the heterocyclic group or heteroaryl group. 6” .

[0447] In one embodiment, the compound according to the fifth aspect (Ic) for a specific purpose has the general formula (VIc).

[0448]

[0449] Where R 1a R 1b R 1c R 2 R 3 R 4 R 5” B and E are as defined above (especially with respect to formulas (Ic), (IIc), (IIIc), (IVc), (Vc), (IIIa), (IVa), (VIa), (VIIa) and / or (VIIIa)) or as follows (especially with respect to formulas (VIIc) and / or (VIIIc)), and A is selected from S, O, NH, N (C 1-6 alkyl) and C(C) 1-6 Alkyl)2. In any of the above embodiments of the compound of formula (VIc) (including those of formulas (Ic), (IIc), (IIIc), (IVc), and (Vc), A may be S, O, or N(CH3)2. In any of the above embodiments of the compound of formula (VIc) (including those of formulas (Ic), (IIc), (IIIc), (IVc), and (Vc), A is preferably S.

[0450] In one embodiment, the compound for a specific application according to the fifth aspect (Ic) has the general formula (VIIc).

[0451]

[0452] Where R 1a R 1b R 1c R 2 R 3 R 4 R 5” As defined above (especially with respect to formulas (Ic), (IIc), (IIIc), (IVc), (Vc), (VIc), (IIIa), (IVa), (VIa), (VIIa) and / or (VIIIa)) or as follows (especially with respect to formula (VIIIc)), E is O or S (preferably O) and B is N or CR. 1d , where R 1d Selected from C 1-3 Alkyl, halogen, -O(C) 1-3 alkyl), -S(C 1-3 alkyl), -NH(C) 1-3 alkyl) and -N(C) 1-3 Alkyl)2, wherein C 1-3 Each of the alkyl groups is optionally and independently selected from halogen, -OH, -OCH3, -SCH and -NH. 2-z (CH3) zOne or both parts are substituted, where z is 0, 1, or 2. In any of the above embodiments of the compounds of formula (VIIc) (including those of formulas (Ic), (IIc), (IIIc), (IVc), (Vc), and (VIc), E is O or S (preferably O) and B is N or C. 1d , where R 1d Can be selected from C 1-3 Alkyl, halogen, -O(C) 1-3 alkyl), -S(C 1-3 alkyl), -NH(C) 1-3 alkyl) and -N(C) 1-3 Alkyl)2. In any of the above embodiments of the compound of formula (VIIc) (including those of formulas (Ic), (IIc), (IIIc), (IVc), (Vc) and (VIc), B is preferably N and more preferably E is O and B is N.

[0453] In one embodiment, the compound for a specific application according to the fifth aspect (Ic) has the general formula (VIIIc).

[0454]

[0455] Where R 1a R 1b R 1c R 2 R 3 R 4 R 5” A, B, and E are as defined above (especially with respect to formulas (Ic), (IIc), (IIIc), (IVc), (Vc), (VIc), (VIIc), (IIIa), (IVa), (VIa), (VIIa), and / or (VIIIa)) or as follows, and L is a bond. In a preferred embodiment of a compound having the general formula (VIIIc):

[0456] (A)R 1a Selected from alkyl, -O (alkyl), -S (alkyl), -NH (alkyl), -N (alkyl)2 and heterocyclic groups, wherein each alkyl and heterocyclic group is optionally represented by one or more (e.g., one, two or three) independently selected R groups. 30 Replacement. Preferably, each R 30 Independently, it is a primary substituent, secondary substituent, or tertiary substituent as defined herein, such as an alkyl group (e.g., C10, 2000-2000). 1-6 Alkyl group), -(CH2) 1-3 OH, alkenyl (e.g., C) 2-6 alkenyl), ynyl (e.g., C10), alkynyl (e.g., C10), 2-6 Alkyne, halogen, -CN, nitro, -OR 11(e.g., -OH), -SR 11 (e.g., -SH), -N(R) 12 (R) 13 )(For example,-

[0457] NH2) and -C(=O)R 11 (For example, -C(=O)(C) 1-3 alkyl));

[0458] (B)R 1b and R 1c Each of these is independently selected from H, methyl, ethyl, propyl, or isopropyl, -OH, -OCH3, -SCH3, cyclopropyl, 2-hydroxyethyl,

[0459] 2-(N,N-dimethylamino)ethyl, 2-(N,N-dimethylamino)ethoxy, 2-aminoethyl, 2-(N-methylamino)ethyl, 2-(methoxy)ethyl, -NH 2-

[0460] z (CH3) z , phenyl, pyridyl, pyrazolyl, phenoxy, pyridoxy, imidazoleylamino and tetrahydrofuranylmethoxy, wherein z is 0, 1 or 2;

[0461] Furthermore, each of the following groups—phenyl, pyridyl, pyrazolyl, phenoxy, pyridyloxy, imidazolylamino, and tetrahydrofuranylmethoxy—is optionally independently selected from methyl, ethyl, -OH, -OCH3, -SCH3, cyclopropyl, 2-hydroxyethyl, 2-(N,N-dimethylamino)ethyl, 2-(N,N-dimethylamino)ethoxy, 2-aminoethyl, 2-(N-methylamino)ethyl, 2-(methoxy)ethyl, and -NH 2-z (CH3) z One, two, or three parts are replaced, where z is 0, 1, or 2;

[0462] (C)R 3 Selected from H, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, phenyl halogen, -CN, azide, -NO2, -O(C 1-6 Alkyl), -OCF3,

[0463] -S(C 1-6 Alkyl groups, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2、-NHS(O)2(C 1-6 Alkyl group), -S(O)2NH 2-z(C 1-6 alkyl) z -C(=O)(C 1-6 Alkyl group), -C(=O)OH, -C(=O)O(C 1-6 Alkyl group), -C(=O)NH 2-z (C 1-6 alkyl) z -NHC(=O)(C 1-6 Alkyl group), -NHC(=NH)NH 2-z (C 1-6 alkyl) z and -N(C 1-6 alkyl)C(=NH)NH 2-z (C 1-6 alkyl) z Where z is 0, 1 or 2 and where C 1-6 Alkyl, C 2-6 alkenyl C 2-6 alkynyl group, C 3-6 Each of the cycloalkyl and phenyl groups is optionally selected by one or more independently chosen R groups. 30 replace;

[0464] (D)R 6” As defined above (particularly with respect to formula (Vc)), and preferably a 3- to 10-membered heteroaryl group (e.g., containing at least one cyclic heteroatom selected from N, O, and S, such as N and O) or a 3- to 10-membered heterocyclic group (e.g., containing at least one cyclic heteroatom selected from N, O, and S, such as N and O), each of which is optionally selected by one or more (e.g., one, two, or three) independently chosen R 7’ replace;

[0465] (E)A is selected from S, O, NH, N(C 1-6 alkyl) and C(C) 1-6 Alkyl)2;

[0466] (F)B is N or CR 1d , where R 1d Selected from C 1-3 Alkyl, halogen, -O(C) 1-3 alkyl), -S(C 1-3 alkyl), -NH(C) 1-3 alkyl) and -N(C) 1-3 Alkyl)2, wherein C 1-3 Each of the alkyl groups is optionally selected independently from halogen, -OH, -OCH3, -SCH, and -NH. 2-z (CH3) z One or both parts are replaced, where z is 0, 1, or 2; and / or

[0467] (G)E is O or S, preferably O.

[0468] In a preferred embodiment of a compound having the general formula (VIIIc), R 1a As specified in section (A) above; R 1b and R 1c As defined in section (B) above; R 3 As defined in item (C) above; R 6” As specified above (particularly with respect to formula (Vc)) and preferably a 3- to 10-membered heteroaryl group (e.g., containing at least one cyclic heteroatom selected from N, O, and S, such as N and O) or a 3- to 10-membered heterocyclic group (e.g., containing at least one cyclic heteroatom selected from N, O, and S, such as N and O), each of the above is optionally selected by one or more (e.g., one, two, or three) independently chosen R 7’ Replace; A as specified in item (E) above; B as specified in item (F) above; and E as specified in item (G) above.

[0469] In a more preferred embodiment of the compound having formula (VIIIc):

[0470] (A')R 1a Selected from C 1-3 Alkyl, -O(C) 1-3 alkyl), -S(C 1-3 alkyl), -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl) 2 and 3 to 7-membered heterocyclic groups, wherein the 3 to 7-membered heterocyclic groups are optionally independently selected from methyl, ethyl, -OH, -OCH3, -SCH3, cyclopropyl, 2-hydroxyethyl, 2-(N,N-dimethylamino)ethyl,

[0471] 2-(N,N-dimethylamino)ethoxy, 2-aminoethyl, 2-(N-methylamino)ethyl, 2-(methoxy)ethyl, 4-methylpiperazinyl, -C(=O)(C 1-3 alkyl),

[0472] -(CH2) 1-3 COOH and -NH 2-z (CH3) z One or both parts are replaced, where z is 0, 1, or 2; and C 1-3 Each of the alkyl groups is optionally selected independently from -OH, -OCH3, -SCH3, cyclopropyl, piperazinyl, 4-methyl-piperazinyl, 4-(2-hydroxyethyl)piperazinyl, 2-(N,N-dimethylamino)ethoxy, and -NH 2-z (CH3) z One or both parts are replaced, where z is 0, 1 or 2;

[0473] (B')R 1b and R 1c At least one of the following is selected from H, methyl, ethyl, propyl, or isopropyl, -OH, -OCH3, -SCH3, cyclopropyl, 2-hydroxyethyl, 2-(N,N-dimethylamino)ethyl, 2-(N,N-dimethylamino)ethoxy, 2-aminoethyl, 2-(N-methylamino)ethyl, 2-(methoxy)ethyl, -NH 2-z (CH3) z and phenyl, where z is 0, 1 or 2 and R 1b and R 1c Another one is as defined in item (B) above;

[0474] (C')R 3 Selected from H, C 1-4 Alkyl, C 3-6 Cycloalkyl, phenyl, halogen, -CN, -O(C) 1-4 Alkyl), -OCF3, S(C 1-4 Alkyl groups, -NH2, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl)2、-C(=O)(C 1-4 Alkyl group), -C(=O)OH, -C(=O)O(C 1-4 Alkyl group), -C(=O)NH 2-z (C 1-4 alkyl) z -NHC(=O)(C 1-4 Alkyl group), -NHC(=NH)NH 2-z (C 1-4 alkyl) z and -N(C 1-4 alkyl)C(=NH)NH 2-z (C 1-4 alkyl) z The phenyl group is optionally surrounded by one, two, or independently selected from halogen, methyl, isopropyl, -CN, -CF3, -OCF3, -OH, -NH2, -NH(C 1-3 alkyl), -N(C) 1-3 alkyl)2、-

[0475] NHC(=O)(C 1-3 Alkyl group), -C(=O)NH 2-z (C 1-3 alkyl) z -(CH2) 1-3 NH2、-(CH2) 1-3 NH(C 1-3 Alkyl group), -(CH2) 1-3 N(C1-3 alkyl)2、-

[0476] (CH2) 1-3 OH and -(CH2) 1-3 O(C 1-3 The alkyl group is substituted; and z is 0, 1 or 2;

[0477] (D')R 6” As defined above (particularly with respect to formula (Vc)), and preferably a 3- to 10-membered heteroaryl group (e.g., containing at least one cyclic heteroatom selected from N, O, and S, such as N and O) or a 3- to 10-membered heterocyclic group (e.g., containing at least one cyclic heteroatom selected from N, O, and S, such as N and O), each of which is optionally selected by one or more (e.g., one, two, or three) independently chosen R 7’ Replacement, or better R 6” It is a monocyclic or bicyclic heteroaryl or a monocyclic or bicyclic heterocyclic group, each of which is optionally selected by one or more (e.g., one, two or three) independently chosen R 7’ replace;

[0478] (E')A is S, O, or N(CH3)2; and / or

[0479] (F')B is N or CR 1d , where R 1d Selected from C 1-3 Alkyl, halogen, -O(C) 1-3 alkyl), -S(C 1-3 alkyl), -NH(C) 1-3 alkyl) and -N(C) 1-3 Alkyl)2; and / or

[0480] or

[0481] (G')E is O or S, preferably O.

[0482] In a preferred embodiment of a compound having the general formula (VIIIc), R 1a As defined in item (A') above; R 1b and R 1c As defined in item (B') above; R 3 As defined in item (C') above; R 6” As defined above (particularly with respect to formula (Vc)), and preferably a 3- to 10-membered heteroaryl group (e.g., containing at least one cyclic heteroatom selected from N, O, and S, such as N and O) or a 3- to 10-membered heterocyclic group (e.g., containing at least one cyclic heteroatom selected from N, O, and S, such as N and O), each of which is optionally selected by one or more (e.g., one, two, or three) independently chosen R 7’Replacement, or better R 6” The R is a monocyclic or bicyclic heteroaryl group (e.g., containing at least one cyclic heteroatom selected from N, O, and S, such as N and O) or a monocyclic or bicyclic heterocyclic group (e.g., containing at least one cyclic heteroatom selected from N, O, and S, such as N and O), each of which is optionally selected by one or more (e.g., one, two, or three) independently chosen R 7’ Replace; A as defined above (E'); B as defined above (F'); and E as defined above (G').

[0483] In a more preferred embodiment of a compound having the general formula (VIIIc):

[0484] (A ” )R 1a Selected from -NH(C 1-3 Alkyl), piperazine, piperidinyl, and pyrrolidinyl, wherein the piperazine group is optionally independently selected from 2-hydroxyethyl, methyl, -

[0485] CH2COOH and -C(=O)CH3 are substituted with one or both moieties; the piperidinyl group is optionally substituted with one or both moieties independently selected from -NH2 and 4-methylpiperazinyl; the pyrrolidinyl group is optionally substituted with one or two -OH groups; and C 1-3 Each of the alkyl groups is optionally independently selected from -OH,

[0486] -OCH3 and -NH 2-z (CH3) z One or both parts are replaced, where z is 0, 1 or 2;

[0487] (B ” (a)R 1b It is methyl, ethyl, propyl, or isopropyl, preferably methyl; and R 1c It is H; or (b)R 1b It is H; and R 1c It is methyl, ethyl, propyl, isopropyl, or phenyl, preferably methyl;

[0488] (C ” )R 3 Selected from H, methyl, ethyl, propyl, isopropyl, phenyl, and halogens;

[0489] (D')R 6”As defined above (particularly with respect to formula (Vc)), and preferably a 3- to 10-membered heteroaryl group (e.g., containing at least one cyclic heteroatom selected from N, O, and S, such as N and O) or a 3- to 10-membered heterocyclic group (e.g., containing at least one cyclic heteroatom selected from N, O, and S, such as N and O), each of which is optionally selected by one or more (e.g., one, two, or three) independently chosen R 7’ Replacement, or better R 6” The R is a monocyclic or bicyclic heteroaryl group (e.g., containing at least one cyclic heteroatom selected from N, O, and S, such as N and O) or a monocyclic or bicyclic heterocyclic group (e.g., containing at least one cyclic heteroatom selected from N, O, and S, such as N and O), each of which is optionally selected by one or more (e.g., one, two, or three) independently chosen R 7’ Replacement, or better R 6” Selected from 5- to 6-membered monocyclic heteroaryl groups (e.g., containing at least one selected from N,

[0490] Cyclic heteroatoms of O and S, such as those selected from N and O), 4- to 6-membered monocyclic heterocyclic groups (e.g., containing at least one cyclic heteroatom selected from N, O, and S, such as those selected from N and O), 7- to 9-membered bicyclic heteroaryl groups (e.g., containing at least one cyclic heteroatom selected from N, O, and S, such as those selected from N and O), and 7- to 9-membered bicyclic heterocyclic groups (e.g., containing at least one cyclic heteroatom selected from N, O, and S, such as those selected from N and O), each of which is optionally surrounded by one or more (e.g., one, two, or three) independently selected R 7’ Replacement, or better R 6” The R is a 5- to 6-membered monocyclic heteroaryl group (e.g., containing at least one cyclic heteroatom selected from N, O, and S, such as N and O) or a 7- to 9-membered bicyclic heterocyclic group (e.g., containing at least one cyclic heteroatom selected from N, O, and S, such as N and O), each of which is optionally selected by one or more (e.g., one, two, or three) independently chosen R 7’ replace;

[0491] (E ” A is S;

[0492] (F ” B is N; and / or

[0493] (G ” E is O.

[0494] In a preferred embodiment of a compound having the general formula (VIIIc), R 1a As mentioned above (A) ” As specified in item ) R 1b and R 1c As above (B) ” As defined in item ); R3 As mentioned above (C) ” As specified in item ); R 6” As defined above (particularly with respect to formula (Vc)) and preferably 3 to 10-membered heteroaryl groups (e.g., containing at least one cyclic heteroatom selected from N, O, and S, such as N and O) or 3 to 10-membered heterocyclic groups (e.g., containing at least one cyclic heteroatom selected from N, O, and S, such as N and O), each of which is optionally selected by one or more (e.g., one, two, or three) independently chosen R 7’ Replacement, or better R 6” It is a monocyclic or bicyclic heteroaryl group (e.g., containing at least one cyclic heteroatom selected from N, O, and S, such as N and O) or a monocyclic or bicyclic heterocyclic group (e.g., containing at least one cyclic heteroatom selected from N, O, and S, such as N and O), each of which is optionally selected by one or more (e.g., one, two, or three) independently chosen R 7’ Replacement, or better R 6” The R is selected from 5- to 6-membered monocyclic heteroaryl groups (e.g., containing at least one cyclic heteroatom selected from N, O, and S, such as N and O), 4- to 6-membered monocyclic heterocyclic groups (e.g., containing at least one cyclic heteroatom selected from N, O, and S, such as N and O), 7- to 9-membered bicyclic heteroaryl groups (e.g., containing at least one cyclic heteroatom selected from N, O, and S, such as N and O), and 7- to 9-membered bicyclic heterocyclic groups (e.g., containing at least one cyclic heteroatom selected from N, O, and S, such as N and O), each of which is optionally selected by one or more (e.g., one, two, or three) independently chosen R. 7’ Replacement, or better R 6” It is a 5- to 6-membered monocyclic heteroaryl group (e.g., containing at least one cyclic heteroatom selected from N, O, and S, such as N and O) or a 7- to 9-membered bicyclic heterocyclic group (e.g., containing at least one cyclic heteroatom selected from N, O, and S, such as N and O), each of which is optionally selected by one or more (e.g., one, two, or three) independently chosen R 7’ Replace; A as above (E) ” As specified in item (F); B as stated above (F) ” As specified in item (G); and E as stated above (G) ” As specified in item ().

[0495] In one embodiment, the compounds of the present invention are selected from those shown in Table A and / or those such as Figure 1 The compound shown in E.

[0496] In one embodiment, the compounds used in this invention (particularly in the fifth aspect of this invention) are selected from those shown in Table A (and / or those listed in Table A). Figure 1 Those depicted in E) and in Figure 1 B. Figure 1 C and / or Figure 1 The compounds shown in D.

[0497] The intent is to use compounds of the present invention (particularly any one of formulas (Ia), (IIa), (IIIa), (IVa), (Va), (VIa), (VIIa) and (VIIIa), as shown in Table A below, for example; and / or in Figure 1 Compounds in E) and / or compounds used in this invention (especially any one of formulas (Ib), (IIb), (IIIb), (Ic), (IIc), (IIIc), (IVc), (Vc), (VIc), (VIIc), and (VIIIc), for example in Figure 1 B. Figure 1 C and / or Figure 1 The compounds shown in D include not only the compounds shown, but also their solvates (e.g., hydrates), salts (especially pharmaceutically acceptable salts), and N-oxides (especially R...). 1a and / or R 6” N-oxides, complexes, polymorphs, crystalline forms, amorphous forms, racemic mixtures, non-racemic mixtures, diastereomers, enantiomers, tautomers, conformational isomers, isotopically labeled forms, prodrugs, and any combination thereof.

[0498] The selection of compounds used within the scope of this invention or in the methods of this invention includes those that have been synthesized and tested—and / or those representing various exemplary or preferred Hy substituents, R 1a Substituents, R 1b Substituents, R 1c Substituents, R 1d Substituents, R 1e Substituents, R 2 Substituents, R 3 Substituents, R 4 Substituents, R 5 Parts A, B, and / or E, each individually or in any combination, can be used to synthesize other compounds of the present invention—listed in Table A below.

[0499] Table A: Kinase inhibitors of formula (Ia).

[0500]

[0501]

[0502]

[0503] In certain embodiments, the compounds of the present invention are selected from E4, E9, E10 and E16; as well as their solvates, salts, N-oxides, complexes, polymorphs, crystalline forms, racemic mixtures, diastereomers, enantiomers, tautomers, conformational isomers, isotopically labeled forms, prodrugs and combinations thereof.

[0504] In some embodiments, the compound of the present invention is E9, or a solvate, salt, N-oxide, complex, polymorph, crystalline form, tautomer, conformational isomer, isotopically labeled form, prodrug, or combination thereof.

[0505] In some other embodiments, the compound of the present invention is E4, or a solvate, salt, N-oxide, complex, polymorph, crystalline form, tautomer, conformational isomer, isotopically labeled form, prodrug, or combination thereof.

[0506] In some other embodiments, the compound of the present invention is E10, or a solvate, salt, N-oxide, complex, polymorph, crystalline form, tautomer, conformational isomer, isotopically labeled form, prodrug, or combination thereof.

[0507] In some other embodiments, the compound of the present invention is E16, or a solvate, salt, N-oxide, complex, polymorph, crystalline form, racemic mixture, diastereomer, enantiomer, tautomer, conformational isomer, isotopically labeled form, prodrug, or combination thereof.

[0508] In some embodiments, the invention may relate to any compound of the invention or any solvate, salt, N-oxide, complex, racemic mixture, diastereomer, enantiomer, tautomer, conformational isomer, isotopically labeled form, prodrug, or combination thereof; for example, solvates, salts, complexes, racemic mixtures, diastereomers, enantiomers, tautomers, conformational isomers, isotopically labeled forms, or combinations thereof.

[0509] In one embodiment, the compounds used in this invention do not contain one or more compounds of the following groups (1) to (6) of formula (Ic) (in groups (1) to (6), a portion (e.g., methyl) is not substituted unless explicitly stated that the portion is substituted):

[0510] (1) When R 1a It is 4-(2-hydroxyethyl)piperazin-1-yl or Cl,R 1b It is H; R 1c It is methyl; B is N; E is O; R 3 When H is H, A is S, and L is a bond, then R... 6”It is not 4-chloro-2-methylpyridin-3-yl;

[0511] (2) When R 1a It is a methoxy group; R 1b It is H; R 1c It is methoxy; B is N; E is O; R 3 When H is H, A is S, and L is a bond, then R... 6” It is not 2,2-difluoro-5H-1,3-dioxazole[4,5-f]benzimidazol-6-yl;

[0512] (3) When R 3 H is H; A is S; L is a bond; R is R 6” It is 1-methyl-4-piperidinyl; R 1b It is H; B is N; E is O; and

[0513] (i)R 1a When it is methyl; then R 1c Not N-tert-butoxycarbonylpiperidin-4-yl; or

[0514] (ii)R 1c When it is methyl; then R 1a Not N-tert-butoxycarbonylpiperidin-4-yl or N-tert-butoxycarbonylpiperidin-3-yl;

[0515] (4) When E is O; B is CR 1d and R 1d When it is H, F, Cl or Br, then R 1a Not H;

[0516] (5) When R 1a It is methyl; R 1b and R 1c All are H; B is CH; E is O; A is S; and R 3 When it is methyl; then R 5” It is not 1,3-benzodioxol-5-ylmethyl, 2-furanmethyl, 1,3-benzodioxane-5-yl, 2-(2-thienyl)ethyl, 2-(4-morpholinyl)ethyl, 2-(2-pyridyl)ethyl, 2-pyridylmethyl, or tetrahydro-2-furanylmethyl; and

[0517] (6) When A is S; R 3 H is H; E is O; L is a bond; R is R 6” It is 1-[2,4-bis(trifluoromethyl)benzyl]-1H-pyrazole-4-yl; R 1a It is H, R 1b It is H, R 1c It is H; and B is CR. 1d When; then R 1d Not H.

[0518] In one embodiment, the compounds used in this invention do not contain one or more of the following groups (7) to (10) of formula (Ib) (where the portion (e.g., methyl) in group (7) to (10) is not substituted unless explicitly stated that the portion is substituted):

[0519] (7) When Hy is:

[0520] and

[0521] (i) When R 1a It is 4-(2-hydroxyethyl)piperazin-1-yl or Cl; R 1b It is H; R 1c It is methyl; B is N; E is O; R 2 It is H; R 3 It is H; R 4 When H is S and A is S, then R 6' Not 4-chloro-2-methylpyridin-3-yl; or

[0522] (ii) When E is O; B is CR 1d And R 1d When it is H, F, Cl, or Br; then R 1a Not H;

[0523] (8) When Hy is 1-{(2E)-4-[(2-methoxyethyl)amino]-1-oxo-2-buten-1-yl}piperidin-4-yl; R 2 It is H; R 3 It is H; R 4 When H is O; A is O; E is O; then R 6' It is not 5-methyl-pyridin-2-yl;

[0524] (9) When R 2 It is H; R 3 It is trifluoromethyl; R 4 It is H; A is O; E is O; and

[0525] (i)R 6' When it is 6-{4-[(2-fluorophenyl)carbamoyl]piperazin-1-yl}pyridin-3-yl; then Hy is not 1-(phenylmethyl)piperidin-4-yl, 1-(phenylmethyl)pyrrolidine-3-yl, or tetrahydro-2H-pyran-4-yl; or

[0526] (ii) When Hy is 1-(phenylmethyl)piperidin-4-yl; then R 6'Not 6-(3-{[(2-fluorophenyl)carbamoyl]amino}-pyrrolidine-1-yl)pyridin-3-yl or 6-({1-[(2-fluorophenyl)carbamoyl]piperidin-4-yl}amino)pyridin-3-yl; or

[0527] (iii) When Hy is 1-(phenylmethyl)pyrrolidine-3-yl; then R 6' It is not 6-({(3S)-1-[(2-fluorophenyl)carbamoyl]-pyrrolidine-3-yl}amino)pyridine-3-yl or 6-({(3R)-1-[(2-fluorophenyl)carbamoyl]pyrrolidine-3-yl}-amino)pyridine-3-yl;

[0528] (10) When A is S; R 3 It is H; E is O; and R is... 6' If it is 1-[2,4-bis(trifluoromethyl)benzyl]-1H-pyrazole-4-yl, then Hy is not 2-pyridyl.

[0529] In some other embodiments, the compounds used in this invention are not selected from one of the following:

[0530] ·5-Thiazolylcarboxamide, 2-[(6-chloro-2-methyl-4-pyrimidinyl)amino]-N-[2-[4-(2-hydroxyethyl)-1-piperazinyl]-6-methylphenyl]- (CAS Registry No.: 2048106-50-7),

[0531] ·5-Thiazolyl carboxamide, 2-[[7-[4-cyano-3-(trifluoromethyl)phenyl]-5,6,7,8-tetrahydropyridin[3,4-d]pyrimidin-4-yl]amino]-N-[(1R)-1-(1,3,4-oxadiazol-2-yl)ethyl]-4-(trifluoromethyl)- (CAS Registry No.: 1831086-00-0),

[0532] ·5-Thiazolylcarboxamide, 2-[[6-methoxy-7-[3-(4-morpholinyl)propoxy]-4-quinazolinyl]amino]-N-(2-pyrazinylmethyl)- (CAS Registry No.: 385780-87-0),

[0533] ·5-Thiazolylcarboxamide, 2-[[6-methoxy-7-[3-(4-morpholinyl)propoxy]-4-quinazolinyl]amino]-N-[2-(3-pyridyl)ethyl]- (CAS Registry No.: 385780-82-5),

[0534] ·5-Thiazolylcarboxamide, N-1H-indol-5-yl-2-[[6-methoxy-7-[3-(4-morpholinyl)propoxy]-4-quinazolinyl]amino]- (CAS Registry No.: 385780-79-0),

[0535] ·5-Thiazolylcarboxamide, 2-[[6-methoxy-7-[3-(4-morpholinyl)propoxy]-4-quinazolinyl]amino]-N-(2-thiophenemethyl)- (CAS Registry No.: 385780-69-8),

[0536] ·5-Thiazolylcarboxamide, N-(2-furanmethyl)-2-[[6-methoxy-7-[3-(4-morpholinyl)propoxy]-4-quinazolinyl]amino]- (CAS Registry No.: 385780-66-5),

[0537] ·5-Thiazolylcarboxamide, 2-[[6-methoxy-7-[3-(4-morpholinyl)propoxy]-4-quinazolinyl]amino]-N-2-pyridyl- (CAS Registry No.: 385780-57-4) and

[0538] ·5-Thiazolylcarboxamide, 2-[[6-methoxy-7-[3-(4-morpholinyl)propoxy]-4-quinazolinyl]amino]-N-4-pyridinyl- (CAS Registry No.: 385779-93-1).

[0539] In some other embodiments, the compounds used in this invention are not selected from one of the following:

[0540] ·Imidazolino[4,5-d]pyrrole[2,3-b]pyridine-7-carboxamide, N,N-dicyclopropyl-6-ethyl-1,6-dihydro-1-methyl-4-[[4-methyl-5-[[(tetrahydro-2H-pyran-4-yl)amino]carbonyl]-2-thiazolyl]amino]- (CAS Registry No.: 1271022-78-6),

[0541] ·Imidazolino[4,5-d]pyrrole[2,3-b]pyridine-7-carboxamide, N,N-dicyclopropyl-6-ethyl-1,6-dihydro-1-methyl-4-[[4-methyl-5-[[(tetrahydro-1,1-dioxy-3-thiophene)amino]carbonyl]-2-thiazolyl]amino]- (CAS Registry No.: 1271022-57-1),

[0542] ·Imidazolino[4,5-d]pyrrole[2,3-b]pyridine-7-carboxamide, N,N-dicyclopropyl-6-ethyl-1,6-dihydro-1-methyl-4-[[4-methyl-5-[[[2-(4-morpholinyl)ethyl]amino]carbonyl]-2-thiazolyl]amino]-(CAS Registry No.: 1271022-45-7) and

[0543] • Imidazolino[4,5-d]pyrrole[2,3-b]pyridine-7-carboxamide, N,N-dicyclopropyl-6-ethyl-1,6-dihydro-1-methyl-4-[[5-[[methyl(tetrahydro-1,1-dioxy-3-thiophene)amino]carbonyl]-2-thiazolyl]amino]- (CAS Registry No.: 1271021-43-2)

[0544] ·2-[(6-{[3-(1H-imidazol-1-yl)propyl]amino}pyridin-2-yl)amino]-4-methyl-N-[1-(phenylmethyl)-1H-indazol-5-yl]-1,3-thiazolyl-5-carboxamide (CAS Registry No.: 302963-64-0)

[0545] ·2-[(6-{[3-(1H-imidazol-1-yl)propyl]amino}pyridin-2-yl)amino]-N-[1-(phenylmethyl)-1H-indazol-5-yl]-1,3-thiazolyl-5-carboxamide (CAS registered)

[0546] Number: 302963-55-9

[0547] In certain alternatives to one or more aspects of this document (particularly the fifth aspect of the invention), the compound is N-(2-chloro-6-methylphenyl)-2-((6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-yl)amino)thiazole-5-carboxamide (A8; Figure 1 A), especially its monohydrate (dasatinib).

[0548] In some other alternative examples of one or more aspects of this document (particularly the fifth aspect of the invention), the compound is ARN-3261 (Vankayalapati et al 2017, AACR Cancer Res 77(13Suppl):Abstract nrLB-296; US 9,260,426, US 9,890,153, US 9,951,062).

[0549] Compounds of the present invention containing basic functional groups (and / or compounds used in the present invention) can form salts with a variety of inorganic or organic acids. Compounds of the present invention containing acidic functional groups (and / or compounds used in the present invention) can form salts with a variety of inorganic or organic bases. Exemplary inorganic and organic acids / bases and exemplary acid / base addition salts of compounds of the present invention (or compounds used in the present invention) are given in the definition of "pharmaceutically acceptable salts" in the "Pharmaceutical Compositions" section below. Compounds of the present invention containing basic and acidic functional groups (and / or compounds used in the present invention) can be converted into base or acid addition salts. The neutral form of compounds of the present invention (or compounds used in the present invention) can be regenerated by contacting the salt with a base or acid and separating the parent compound in a conventional manner.

[0550] The compounds of this invention (and / or the compounds used in this invention) may be in the form of N-oxides, that is, they may contain the functional group ≡N. + -O - (For example, (R) n )3N + -O - That is, NO coordinate covalent bond, where R n The R group is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclic groups, wherein each of the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclic groups is optionally independently selected by one or more (e.g., the maximum number of hydrogen atoms combined with the alkyl, alkenyl, chloro, aryl, heteroaryl, cycloalkyl, or heterocyclic group is 1 to a maximum number, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, such as between 1 and 5, 1 and 4, or 1 and 3, or 1 or 2). 30 Replace, R 30 Preferably, it is a primary substituent, a secondary substituent, or a tertiary substituent as specified herein. Specific embodiments of the N-oxide of the compound of the present invention (or the compound used in the present invention) are those in which R... 1a and / or R 6 (or R) 6' Or R 6” ) Contains functional groups ≡N + -O - Those that can appear as N-oxides. 1a Non-limiting embodiments of the substituents include the following:

[0551]

[0552]

[0553] in Represents R 1aThe bond formed when a substituent binds to the rest of the compound. R can appear as an N-oxide. 6” Non-limiting embodiments of the substituents include the following: in Represents R 6” Substituents are bonds that bind to the rest of the compound.

[0554] The compounds of the present invention may be in prodrug form. Prodrugs of the compounds of the present invention are those compounds that undergo chemical transformation under physiological conditions after administration to provide the compounds of the present invention. Furthermore, prodrugs can be converted into the compounds of the present invention (or the compounds used in the present invention) in an in vitro environment by chemical or biochemical methods. For example, prodrugs can be slowly converted into the compounds of the present invention (or the compounds used in the present invention), for example, when placed in a transdermal patch reservoir containing suitable enzymes or chemical reagents. Exemplary prodrugs are esters (using an alcohol or carboxyl group contained in the kinase inhibitor of the present invention (or the compounds used in the present invention)) or amides (using a kinase inhibitor contained in the present invention (or the compounds used in the present invention)) that are hydrolyzable in vivo. Specifically, any amino group contained in the kinase inhibitor of the present invention (or the compounds used in the present invention) and having at least one hydrogen atom can be converted into a prodrug form. Typical N-prodrug forms include carbamates (1), Mannich bases (2), enamines (3), and enamine ketones (4).

[0555]

[0556] Where R 18 The R group is independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclic groups, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclic groups is optionally independently selected by one or more (e.g., the maximum number of hydrogen atoms combined with the alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group is 1 to a maximum number, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, such as between 1 and 5, 1 and 4, or 1 and 3, or 1 or 2). 30 Replace, where R 30 As defined herein (preferably, each R as described herein) 30 (Independently, it can be a primary, secondary, or tertiary substituent). Prodrug properties (such as solubility, permeability, stability, cleavage rate, cleavage conditions in vivo, target specificity, etc.) can be modified by R. 18 Make minor adjustments.

[0557] The specific prodrug form of the compounds of the present invention (or the compounds used in the present invention) is those having the formula (IXa), (Xa), (XIa) or (XIIa) (or (IXb), (Xb), (IXc) or (Xc)):

[0558]

[0559] And solvates, salts, N-oxides, complexes, polymorphs, crystalline forms, racemic mixtures, diastereomers, enantiomers, tautomers, conformational isomers, isotopic labeling forms and combinations thereof, wherein R 1a R 1b R 1c R 3 R 5 R 5' R 5” A, B, E, and Hy are as defined above (especially with respect to equations (Ia), (IIa), (IIIa), (IVa), (Va), (VIa), (VIIa), (VIIIa), (Ib), (IIb), (IIIb), (Ic), (IIc), (IIIc), (IVc), (Vc), (VIc), (VIIc), and / or (VIIIc)) or as defined below, and R 2 and R 4 Each of them is independently selected from H, -P(O)(OR) 11a 2、-(CH2) 1-3 -R 19 -C(=X) a )R 11a and -C(=X) a )X a R 11a The condition is that it is not R. 2 and R 4 Both are H, of which R 11a The R group is independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclic groups, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclic groups is optionally independently selected by one or more (e.g., the maximum number of hydrogen atoms combined with the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group is 1 to a maximum number, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, such as between 1 and 5, 1 and 4, or 1 and 3, or 1 or 2). 30 Replace; R 19 Independently selected from -OP(O)(OR 11a )2、-X a C(=X a )R 11a -Xa C(=X a )X a R 11a and 5-alkyl-2-oxo-1,3-dioxazol-4-yl; X a It is independently selected from O, S, and NH; and -(CH2) 1-3 -The group is optionally replaced by one or two independently selected R groups. 30 Replace, where R 30 As defined herein (preferably, each R...) 30 Independently selected from primary, secondary, and tertiary substituents as specified herein. In one embodiment of a prodrug form of formula (IXa), (Xa), (XIa), (XIIa), (IXb), (Xb), (IXc), or (Xc), R 1a R 1b R 1c R 3 R 5 R 5' R 5” A, B, E, and Hy are as defined above (especially with respect to equations (Ia), (IIa), (IIIa), (IVa), (Va), (VIa), (VIIa), (VIIIa), (Ib), (IIb), (IIIb), (Ic), (IIc), (IIIc), (IVc), (Vc), (VIc), (VIIc), and / or (VIIIc)) or as defined below, and R 2 and R 4 Each of them is independently selected from H, -P(O)(OR) 11a 2、-(CH2) 1-3 -R 19 -C(=O)R 11a and -C(=O)OR 11a The condition is that it is not R. 2 and R 4 Both are H, of which R 11a Independently selected from H and C 1-6 Alkyl (preferably C) 1-3 Alkyl group, wherein the alkyl group is optionally selected from halogen, -OH, -OCH3, -SCH3, 2-(N,N-dimethylamino)ethoxy and -NH 2-z (CH3) z One or both parts of the group are substituted, where z is 0, 1, or 2; R 19 Independently selected from -OP(O)(OR 11a )2、-OC(=O)R 11a -OC(=O)OR 11a and 5-(C 1-3(alkyl)-2-oxo-1,3-dioxazol-4-yl; and -(CH2) 1-3 The - group is optionally selected independently from halogen, -OH, -OCH3, -SCH3, 2-(N,N-dimethylamino)ethoxy, and -NH 2-z (CH3) z One or both parts are replaced, where z is 0, 1 or 2.

[0560] For compounds of the present invention having any of the formulas (Ia), (IIa), (IIIa), (IVa), (Va), (VIa), (VIIa), (VIIIa), (IXa), (Xa), (XIa), and (XIIa) (or for compounds used in the present invention having any of the formulas (Ib), (IIb), (IIIb), (IXb), (Xb), (Ic), (IIc), (IIIc), (IVc), (Vc), (VIc), (VIIc), (VIIIc), (IXc), and (Xc)) and containing one or more hydroxyl (i.e., -OH) groups, another specific prodrug form is wherein at least one of these two or more hydroxyl groups is derived from -OP(O)(OR) 11a 2、-O(CH2) 1-3 -R 19 -OC(=X) a )R 11a and -OC(=X) a )X a R 11a The part where R 11a The R group is independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclic groups, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclic groups is optionally independently selected by one or more hydrogen atoms (e.g., 1 to a maximum number, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, such as between 1 and 5, 1 to 4, or 1 to 3, or 1 or 2) independently selected. 30 Replace; R 19 Independently selected from -OP(O)(OR 11a )2、-X a C(=X a )R 11a -X a C(=X a )X a R 11a and 5-alkyl-2-oxo-1,3-dioxazol-4-yl; X a It is independently selected from O, S, and NH; and -(CH2) 1-3 -The group is optionally replaced by one or two independently selected R groups.30 Replace, where R 30 As defined herein (preferably, each R...) 30 Independently selected from primary, secondary, and tertiary substituents as specified herein. In one embodiment of this prodrug form of the compound of the present invention (or the compound used in the present invention), at least one derivatized hydroxyl group is selected from -OP(O)(OR). 11a 2、-O(CH2) 1-3 -R 19 -OC(=O)R 11a and -OC(O)OR 11a , where R 11a Independently selected from H and C 1-6 Alkyl (preferably C) 1-3 Alkyl group, wherein the alkyl group is optionally selected independently from halogen, -OH, -OCH3, -SCH3, 2-(N,N-dimethylamino)ethoxy and -NH 2-z (CH3) z One or both of the groups are substituted, where z is 0, 1, or 2; R 19 Independently selected from -OP(O)(OR 11a )2、-OC(=O)R 11a -OC(=O)OR 11a and 5-(C 1-3 (alkyl)-2-oxo-1,3-dioxazol-4-yl; and -(CH2) 1-3 The - group is optionally selected independently from halogen, -OH, -OCH3, -SCH3, 2-(N,N-dimethylamino)ethoxy, and -NH 2-z (CH3) z One or both parts are replaced, where z is 0, 1 or 2.

[0561] In some embodiments, the present invention (or the compounds used in the present invention, such as those used in the fifth aspect of the invention) may relate to solvates, salts, N-oxides, complexes, racemic mixtures, diastereomers, enantiomers, tautomers, conformational isomers, isotopically labeled forms, or combinations thereof of prodrugs having the formula (IXa), (Xa), (XIa), or (XIIa) (or (IXb), (Xb), (IXc), or (Xc)).

[0562] In a particular embodiment, the compound of the present invention (or the compound used in the present invention) is a hydrate, suitably a monohydrate or dihydrate of a kinase inhibitor, as described under the title “Compound” (e.g., a kinase inhibitor having the general formula (Ia), (IIa), (IIIa), (IVa), (Va), (VIa), (VIIa), or (VIIIa) (or a compound having the general formula (Ib), (IIb), (IIIb), (Ic), (IIc), (IIIc), (IVc), (Vc), (VIc), (VIIc), or (VIIIc)), or a solvate, salt (especially a pharmaceutically acceptable salt), N-oxide (especially R 1a and / or R 6” The compounds of the present invention (or compounds used in the present invention) are hemihydrates of such kinase inhibitors, including N-oxides, complexes, polymorphs, crystalline forms, racemic mixtures, diastereomers, enantiomers, tautomers, conformational isomers, isotopically labeled forms, prodrugs (especially prodrugs of formula (IXa), (Xa), (XIa) or (XIIa) (or (IXb), (Xb), (IXc) or (Xc)) and / or having at least one derivatized hydroxyl group as specified above, or solvates, salts, N-oxides, complexes, polymorphs, crystalline forms, racemic mixtures, diastereomers, enantiomers, tautomers, conformational isomers, isotopically labeled forms, or combinations thereof. In another suitable embodiment, the compound of the present invention (or the compound used in the present invention) is a hemihydrate of such kinase inhibitor.

[0563] In some embodiments, the compounds of the present invention (e.g., those specified under the title "Compounds") may be (e.g., provided as) purified or (e.g., substantially) pure. For example, the purity of the compound may be greater than about 50%, such as greater than about 60%, 70%, or 80%, suitably greater than about 90% (particularly greater than about 95%, 97%, or 98%) or even 99%. That is, in some such embodiments, such compounds are present only with limited amounts of impurities (e.g., those introduced during the manufacturing process), such as only small amounts of impurities, including where the compound exists in a form substantially free of impurities. The purity of the compound (e.g., the degree to which impurities are absent or present) can be determined by conventional procedures, such as by HLPC.

[0564] In one embodiment, the invention provides a compound containing less than about 50%, 40%, 30%, and suitably 10% or 5% HPLC area, preferably less than about 3% and 2% HPLC area, and more preferably less than 1% HPLC area of ​​total impurities. As used herein, the term "%HPLC area" refers to the area of ​​one or more peaks in an HPLC chromatogram as a percentage of the total area of ​​all peaks. Furthermore, the purity of a compound may be expressed herein as "HPLC" purity. Therefore, "HPLC purity" is a calculation by dividing the area under the compound peak by the total area under the curve in the HPLC chromatogram. More suitably, the compound contains less than about 10% HPLC total impurity area. More prefer...

Claims

1. A compound selected from the following kinase inhibitors: or its salt; in: Hy is in The bonds representing Hy's association with the remainder of the compound; B is N; R 1a Selected from in Represents R 1a Bonds that bind to the rest of the compound; R 1b It is H; R 1c It is methyl; R 2 For H; R 3 For H; R 4 is H; R 5 For -LR 6 ; L is a bond; R 6 Selected from in Represents R 6 Bonds that bind to the rest of the compound; A is S; and E is O.

2. The compound according to claim 1, wherein R 6 Selected from: in Represents R 6 Bonds that bind to the rest of the compound.

3. The compound according to claim 1, wherein R 6 Selected from: in Represents R 6 Bonds that bind to the rest of the compound.

4. The compound according to claim 1, wherein the compound is selected from: Or its salt.

5. The compound according to claim 1, wherein the compound is: Or its salt.

6. The compound according to claim 1, wherein the compound is: Or its salt.

7. The compound according to claim 1, wherein the compound is: Or its salt.

8. The compound according to claim 1, wherein the compound is: Or its salt.

9. The compound according to claim 1, wherein the compound is selected from: Or its salt.

10. The compound according to claim 1, wherein the compound is in substantially pure form.

11. The compound according to claim 2, wherein R 6 yes: in Represents R 6 Bonds that bind to the rest of the compound.

12. The compound according to claim 1, wherein R 1a yes: in Represents R 1a Bonds that bind to the rest of the compound.

13. A compound, wherein the compound is of formula [formula missing]. Kinase inhibitors.

14. A salt of a compound, wherein the compound is of the formula... Kinase inhibitors.

15. The salt according to claim 14, wherein the salt is a pharmaceutically acceptable salt.

16. A pharmaceutical composition comprising the compound of any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, and optionally further comprising a pharmaceutically acceptable excipient; optionally, The pharmaceutical composition is formulated for oral administration; and / or The pharmaceutical composition is a unit dosage form.

17. A pharmaceutical composition comprising the compound of claim 13 or the salt of claim 15, and optionally further comprising a pharmaceutically acceptable excipient; optionally, The pharmaceutical composition is formulated for oral administration; and / or The pharmaceutical composition is a unit dosage form.

18. An intermediate selected from compounds having the formula (Id): or its salt, in: An R 40 Selected from F, -CH2F, -CHF2, and -CF3, and another R 40 It is Cl; and R 41 Selected from H and amino protecting groups.

19. The intermediate according to claim 18, wherein one of R... 40 Selected from -CH2F and -CHF2, and another R 40 It is Cl.

20. The intermediate according to claim 18, wherein the R bonded to the C ring atom adjacent to the S ring atom 40 It is Cl.

21. The intermediate according to claim 18, wherein one of R... 40 It is -CH2F or -CHF2, and binds to another R atom of the C ring adjacent to the S ring atom. 40 It is Cl.

22. The intermediate according to claim 18 or 19, wherein the amino protecting group is selected from: tert-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, acetyl, trifluoroacetyl, benzoyl, benzyl, p-methoxybenzyl, 3,4-dimethoxyphenyl, p-methoxyphenyl, 2,2,2-trichloroethoxycarbonyl, triphenylmethyl, toluenesulfonyl, p-bromobenzenesulfonyl, 4-nitrobenzenesulfonyl, and 2-nitrobenzenesulfonyl.

23. The intermediate according to claim 18, wherein the intermediate is selected from: Or its salt.

24. The intermediate according to claim 18, wherein the intermediate is selected from: Or its salt.

25. The intermediate according to claim 18, wherein the intermediate is selected from: Or its salt.

26. The intermediate according to claim 18, wherein the intermediate is: Or its salt.

27. The intermediate according to claim 18, wherein the intermediate is: Or its salt.

28. The intermediate according to claim 18, wherein the intermediate is 2-chloro-4-(fluoromethyl)thiophene-3-amine hydrochloride.

29. A method for preparing a compound comprising an amide moiety, wherein the compound is a kinase inhibitor of claim 1, the method comprising the following steps: The intermediate of any one of claims 18 to 21 is reacted with the corresponding carboxylic acid.

30. The method according to claim 29, when R 41 When the protecting group is an amino group, the method further includes the following steps: Remove the amino protecting group.

31. A method for preparing the compound of claim 10, comprising the following steps: • Provides the compound of claim 1 in a mixture having one or more impurities, wherein the compound is provided by: synthesizing the compound in an impure form by implementing or having implemented the method of claim 29; and • Remove at least a portion of the impurities from the mixture.

32. The method of claim 31, wherein column chromatography, selective precipitation, grinding and elution of the impurities with a suitable solvent in which the desired compound is insoluble are used to remove at least a portion of the impurities from the mixture.

33. A method for preparing a pharmaceutical composition, comprising the following steps: The compound of any one of claims 1 to 10 is formulated together with a pharmaceutically acceptable excipient.

34. A method for preparing a pharmaceutical composition, comprising the following steps: The compound of any one of claims 1 to 8 is formulated together with a pharmaceutically acceptable excipient; or include: • The method of claim 29 has been implemented or has been implemented to manufacture the compound; as well as • Formulate the manufactured compound together with pharmaceutically acceptable excipients.

35. A method for preparing a drug package, comprising the following steps: • Inserting the pharmaceutical composition of claim 16 into a package to form a package containing the pharmaceutical composition; and optionally, • Insert a leaflet containing prescription information for the drug composition into the packaging.

36. The method of claim 35, wherein the pharmaceutical composition is in the form of a finished pharmaceutical product.

37. A pharmaceutical package comprising the pharmaceutical composition of claim 16.

38. The pharmaceutical packaging according to claim 37, wherein the pharmaceutical composition is in the form of a finished pharmaceutical product.

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