Halogenated heteroaryl and other heterocyclic kinase inhibitors, and their applications

Abstract

The present invention relates to kinase inhibitors that are structurally similar to dasatinib but contain a specific class of halogenated heteroaryls of the present invention. Such kinase inhibitors may exhibit one or more specific properties that are distinct from dasatinib and other structurally similar kinase inhibitors. The kinase inhibitors of the present invention, or pharmaceutical compositions containing them, can be used to treat proliferative disorders or conditions. The kinase inhibitors can be used to treat proliferative disorders such as mixed phenotype acute leukemia (MPAL), which is characterized by a human chromosomal translocation at 11q23 and / or the presence of the MEF2C protein in the KMT2A fusion oncoprotein. The kinase inhibitors and pharmaceutical compositions can be used topically to regulate skin pigmentation in a subject, for example, to provide UV protection and reduce the risk of skin cancer.

Description

[Technical Field]

[0001] The present invention relates to kinase inhibitors, particularly those of protein kinases including the SIK family, CSF1R, ABL / BCR-ABL, SRC, HCK, PDGFR, KIT, and / or their variants. While structurally similar to dasatinib, the kinase inhibitors of the present invention are unique and possess a specific class of halogenated heteroaryls. Such kinase inhibitors may exhibit one or more specific properties that differentiate them from dasatinib and other structurally similar kinase inhibitors. The kinase inhibitors of the present invention, or pharmaceutical compositions containing them, can be used to treat proliferative disorders, such as leukemia or solid tumors, or other disorders or conditions. In particular, these and other structurally similar kinase inhibitors may be used to treat proliferative disorders such as mixed phenotypic acute leukemia (MPAL), characterized by a human chromosomal translocation at 11q23 and / or the presence of the MEF2C protein of the KMT2A fusion oncoprotein. Kinase inhibitors or pharmaceutical compositions disclosed herein may be used topically to modulate skin pigmentation in a subject, for example, to provide UV protection and to reduce the risk of skin cancer.

[0002] Kinase inhibitors are enzyme inhibitors that inhibit the action of kinases. A partial, non-exclusive list of kinases includes 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 and have been shown to be important regulators in most cellular functions, including cell signaling, proliferation, differentiation, metabolism, survival, apoptosis, motility, and DNA damage repair. Phosphorylation, particularly dysregulated signaling due to dysregulation of protein phosphorylation, is associated with a wide range of diseases, including those related to abnormal kinase activity (e.g., increased activity). Such diseases include, but are not limited to, proliferative disorders (e.g., cancer, benign neoplasms, pathological angiogenesis, inflammatory diseases, and autoimmune diseases), as well as allergic and CNS disorders.

[0003] Protein tyrosine kinases (PTKs) are enzymes that phosphorylate tyrosine residues of peptides and proteins in conjunction with ATP as a substrate. PTKs include receptor protein tyrosine kinases (RPTKs), particularly those belonging to 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), as well as 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 oxygen atoms in the serine or threonine side chains of peptides and proteins. STKs include, among others, AKT1, Aurora kinase, BRAF, MAP kinases, PLK1, SIK1, SIK2, and SIK3.

[0004] Inhibition of protein kinases, and therefore phosphorylation of substrate peptides or proteins, has been shown to be useful in the treatment of many diseases. For example, the ERBB inhibitor afatinib is useful in the treatment of non-small cell lung cancer; the VEGFR, PDGFR, and c-KIT inhibitor axitinib is useful in the treatment of renal cell carcinoma; the ABL / BCR-ABL inhibitor bosutinib is useful in the treatment of chronic myeloid leukemia; the c-MET and VEGFR2 inhibitor cabozantinib is useful in the treatment of thyroid cancer; the ALK, HGFR, and c-MET inhibitor crizotinib is useful in the treatment of non-small cell lung cancer; the ABL / BCR-ABL, SRC, and c-KIT inhibitor dasatinib is useful in the treatment of chronic myeloid leukemia; and the EGFR inhibitor erlotinib is useful in the treatment of non-small cell lung cancer and pancreatic cancer. Imatinib, an ABL / BCR-ABL inhibitor, is useful in the treatment of chronic myeloid leukemia; lapatinib, a HER2 inhibitor, is useful in the treatment of breast cancer; nilotinib, an ABL / BCR-ABL inhibitor, is useful in the treatment of breast cancer; pazopanib is useful in the treatment of chronic myeloid leukemia; pazopanib is useful in the treatment of renal cell carcinoma and soft tissue sarcoma; palbociclib is a CDK4 and CDK6 inhibitor; ABL / BCR-ABL, BEGFR, FGFR, EPH, c-KIT, RET, TIE2 and FLT3 inhibitors are useful in the treatment of chronic myeloid leukemia; regorafenib, RET, VEGFR and PDGFR inhibitors are useful in the treatment of colorectal cancer and gastrointestinal stromal tumors; ribo Cyclib, cyclin D1 / CDK4, and CDK6 inhibitors are useful for HR-positive, HER2-negative advanced or metastatic breast cancer; the JAK inhibitor ruxolitinib is useful for the treatment of myelofibrosis; sorafenib, VEGFR, PDGFR, BRAF, and c-KIT inhibitors are useful for the treatment of renal cell carcinoma and hepatocellular carcinoma; the VEGFR and PDGFR inhibitor sunitinib is useful for the treatment of renal cell carcinoma, gastrointestinal stromal tumors, and pancreatic neuroendocrine tumors; the JAK inhibitor tofacitinib is useful for the treatment of rheumatoid arthritis; the VEGFR, EGFR, RET, BRK inhibitor vandatanib is useful for the treatment of thyroid cancer; and the BRAF inhibitor vemurafenib is useful for the treatment of malignant melanoma.

[0005] Given the numerous kinases and associated diseases, there is an existing need for novel, selective inhibitors of various kinases that may be useful in treating the associated diseases; in particular, there remains a need for novel kinase inhibitors, pharmaceutical compositions / formulations and their use (including use in therapeutic regimens) for the treatment of diseases associated with the abnormal activity of one or more kinases; in particular, (a) the presence of myocyte enhancer factor 2C (MEF2C) protein, human chromosomal translocation at 11q23, and / or lysine-methyltransferase 2A (KMT2A) fusion oncoproteins for use in the treatment of proliferative disorders such as mixed phenotypic acute leukemia (MPAL); or (b) there remains a need for novel kinase inhibitors as alternatives to existing kinase inhibitors such as dasatinib.

[0006] One specific kinase inhibitor is dasatinib (N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide, monohydrate; Figure 1A), which is marketed by Bristol-MyersSquibb as "SPRYCEL". It is indicated for the treatment of adult patients with (i) newly diagnosed Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in the chronic phase, (ii) chronic, transitional, or (myeloid or lymphoid) acute (Ph+) CML that is resistant to or intolerant of prior treatment including imatinib, and (iii) Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) that is resistant to or intolerant of prior treatment. In the EU, dasatinib is also indicated for the treatment of pediatric patients with chronic, newly diagnosed Ph+ CML (Ph+ CML-CP), or Ph+ CML-CP who are resistant to or intolerant of prior treatment including imatinib. In the US, it is also indicated for pediatric patients with chronic, Ph+ CML.

[0007] In particular, despite numerous trials being conducted, dasatinib has not been approved for use in cancers other than CML and Ph+ ALL in the United States and Europe. As of September 2018, dasatinib does not have an indication for solid tumors. In fact, many clinical trials that investigated the potential use of dasatinib for the treatment of solid tumors were either discontinued early (due to toxicity issues, etc.) or did not report strong or promising results. For example, according to information from clinicaltrials.gov as of September 2018, dasatinib has only reached one phase 3 trial for solid tumors: a single trial in combination with docetaxel for castration-resistant prostate cancer, which was a "READY" trial (NCT00744497). However, despite an early trial suggesting efficacy in chemotherapy-naive castration-resistant prostate cancer (Araujo et al., 2013, Lancet Oncol 14:13017), dasatinib failed to improve overall survival compared to docetaxel alone (e.g., Araujo et al. 2012, Cancer 118:63). Despite several trials for other cancers such as breast cancer, skin cancer, pancreatic cancer, brain cancer, or lung cancer, dasatinib has not demonstrated satisfactory efficacy or tolerability and has not progressed to phase 3 trials for any of these cancers. In particular, in a recent double-blind phase 2 trial in patients with locally advanced, unresectable pancreat, dasatinib failed to demonstrate an extension of overall survival when used in combination with gemcitabine compared to gemcitabine alone (Evens et al. 2017, Annal. Onc. 28:354). However, several recent specialized trials aimed at “targeted” therapies selected for patients with specific cancers (including solid tumors) expressing specific drug targets may potentially test dasatinib depending on the patient’s target profile.The TAPUR trial ("The Targeted Agent and Profiling Utilization Registry", https: / / www.tapur.org, NCT02693535) includes dasatinib as one possible treatment group based on one or more of the following targets: BCR-ABL, SRC, KIT, PDGFRB, EPHA2, FYN, LCK, YES1; and (ii) the Melanoma Institute Australia trial (NCT02645149) for patients with unresectable stage III or IV metastatic melanoma of BRAF and NRAS wild type who have progressed to or are unable to receive standard treatment (generally immunotherapy) includes dasatinib as one possible treatment depending on the KIT mutation found in the patient's cancer. Dasatinib is also one of the treatment groups in BMS's "FRACTION-lung" Phase 2 trial (NCT02750514), which may involve a combination study with the immunotumor nivolumab in patients with advanced non-small cell lung cancer. Other treatment groups in this trial are using nivolumab with other immunotumor drugs.

[0008] Therefore, there is a particular need for novel kinase inhibitors useful in treating cancer, especially solid tumors for which dasatinib is not indicated and / or cancers for which dasatinib has not shown promising results. In particular, there is a need for novel kinase inhibitors useful in treating one or more cancers, such as melanoma, breast cancer, lung cancer (e.g., non-small cell carcinoma), pancreatic or prostate cancer (e.g., castrated or hormone-resistant cancer).

[0009] Furthermore, there is a particular need for new kinase inhibitors useful for treating proliferative disorders such as mixed phenotypic acute leukemia (MPAL, also known as mixed cell lineage leukemia "MLL"), which are (particularly) characterized by the presence of human chromosomal translocation at 11q23 and / or the presence of MEF2C protein (phosphorylated MEF2C protein and / or active transcription factors such as MEF2C protein) as a KMT2A fusion oncoprotein.

[0010] Mixed phenotypic acute leukemia (MPAL), also known as "Mixed lineage leukaemia" (MLL), is a highly aggressive hematological cancer that primarily occurs in pediatric patients and, unlike other types of pediatric acute leukemia, has a poor prognosis (reviewed by Slany 2009, Haematologica 94:984). One form of MPAL is characterized by a BCR / ABL rearrangement. MPAL with t(9;22)(q34;q11.2) (or BCR / ABL1 rearrangement) is considered a distinct entity (Arber et al 2016, Blood 127:2391). The t(9;22)(q34;q11.2 rearrangement) results in a BCR / ABL1 fusion gene located on the Philadelphia chromosome (Ph), leading to constitutively active 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), which is the result of a chromosomal translocation affecting the KMT2A gene (also known as the MLL1 gene) at 11q23. This KMT2A / MLL translocation is the second most common genetic lesion in MPAL (MPAL MLL+). These 11q23 translation events result in the coexistence of the amino terminus of histone methyltransferase KMT2A with various different (translocation) fusion partners, disrupting the normal histone methyltransferase function of KMT2A and replacing it with heterogeneous functions contributed by the (translocation) fusion partners. The resulting protein chimeras are transcription factors that are regulated by other genes normally controlled by KMT2A. In particular, the transcription factor MEF2C is regulated by KMT2A and has been described as an oncogene in pediatric acute leukemia. MEF2C expression is associated with KMT2A fusion gene rearrangement in AML (Schw et al. 2009, Blood 114:2476), and MEF2C expression is associated with a subset of AML patients with poor survival outcomes (Lazlo et al. 2015, J Hematol & Oncol 8:115).

[0011] Tarumoto and co-workers (2018, Mol Cell 69:1017) showed that MEF2C activity in AML is driven by SIK3-phosphorylation of HDAC4, and that SIK3 knockout or chemical inhibition with the small molecule tool compound HG-9-91-01 potently reduces the viability of several MPAL-associated AML cell lines (including MOLM-13 and MV4-11); cytoplasmic retention of SIK3-phosphorylated HDAC4 modulates MEF2C activity, thus regulating nuclear (unphosphorylated) HDAC4, which acts as an inhibitory cofactor of MEF2C, a transcription factor of tumor survival / maintenance genes associated with AML proliferation (Figure 19). Indeed, recent studies have demonstrated that SIK3 inhibition by intraperitoneal administration of the small molecule tool compound YKL-05-099- suppresses AML progression in vivo (Tarumoto et al 2020, Blood 135:56). However, there is a need for further SIK3 inhibitors, particularly those with drug-like properties, and especially those that can be administered orally, for use in treating proliferative disorders (such as MPAL), and particularly those related to the expression of cancer survival genes regulated by SIK3-driven MEF2C.

[0012] Furthermore, there is still a need for novel kinase inhibitors useful in treating myeloid or lymphoblastic cancers such as leukemia, preferably useful in treating one or more Ph+ leukemias such as CML and / or ALL.

[0013] Dasatinib is described as a drug that inhibits the following kinases at nanomolar concentrations: BCR-ABL, SRCfamily (SRC, LCK, YES, FYN), c-KIT, EPHA2, and PDGFR-beta; its inhibition of the hybrid protein kinase BCR-ABL is particularly relevant to the indication of dasatinib for Ph+ leukemia.

[0014] BCR-ABL kinase is directly linked to the presence of a specific genetic abnormality on chromosome 22 in leukemia cancer cells (particularly CML cells) known as the "Philadelphia chromosome" (or Philadelphia translocation). This reciprocal translocation of genetic material between chromosome 9 and chromosome 22 places the ABL1 gene on chromosome 9 in parallel with the BCR gene on chromosome 22, creating a coding sequence for a hybrid protein known as "BCR-ABL" (protein-tyrosine kinase, constitutively on), which causes uncontrolled cell division. The majority of CML cases and 20-30% of ALL cases are Ph+. Imatinib (STI571), the first selective BRC-ABL inhibitor marketed by Novartis as "GLEEVEC / GLIVEC," was considered a breakthrough for the treatment of Ph+ leukemia. However, despite the extension of overall survival, the drug resistance that emerged during imatinib treatment has led scientists to discover that most such resistances result from the emergence of BCR-ABL mutations, particularly amino acid substitutions within the ABL-derived kinase domain (see Rossari & Orciuolo. 2018, J. Hemat. Oncol. 11:84, all of which are incorporated herein by reference).

[0015] Analysis of BCR-ABL mutation status and survival rates in patients treated with imatinib revealed that mutations within the phosphatase loop (P-loop) at the ABL position of the BCR-ABL kinase were the most frequent. However, (rare) mutations outside the P-loop (particularly within the kinase domain) were associated with a shortened overall survival in CML patients treated with imatinib (Jabbour et al., 2006, Leukemia 20:1767). Numerous emerging BCR-ABL mutations have been previously identified and described (see Table 1 in Biochem. Biophys. Acta 1754:3, Manley et al., 2005; and Table 1 in Rossari & Orciuolo 2018; this also describes mutations in other kinase targets of dasatinib; both such tables are specifically incorporated herein by reference). In particular, the following mutations are observed in the ATP-binding region of BCR-ABL (located in the positions shown in the 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 become resistant to imatinib, which is presumed to have occurred due to the emergence of one or more of these mutations. Based on modeling studies, dasatinib is predicted to bind to multiple conformations of the ABL kinase, which is thought to explain why some conformational mutations of ABL are inhibited by dasatinib but not by imatinib. Indeed, a retrospective analysis comparing mutagenesis during first-line treatment with dasatinib versus imatinib revealed that fewer different mutation sites appeared with dasatinib treatment (4 different sites) compared with imatinib treatment (12 different sites) (Hughes et al. 2015, Leukemia 29:1832, in particular Figure 1). However, importantly, (i) the overall proportion of patients with any type of mutation was almost the same (17 out of 259 patients with dasatinib and 18 out of 260 patients with imatinib), (ii) the majority of mutation sites that appeared during dasatinib treatment were in the ATP binding region (3 / 4 of the mutation sites), and (iii) the mutations that appeared during dasatinib treatment (11 / 17) were T315i mutations in the so-called "gatekeeper" residue, and even then, inhibition with dasatinib gave resistance to BCR-ABL kinase. A specific set of BCR-ABL mutants that can be tested against kinase inhibitors is provided by ProQinase ABL1 kinase "Wildtype and Mutant Panel," which includes the wild-type ABL1 protein (amino acids P118-S525) and mutants representing the most common imatinib-resistant mutants of BCR-ABL: G250E, Q252H, Y253F, E255K, T315I, F317I, M351T, and H396P (www.proqinase.com).

[0016] The T315I mutation is one of the most frequently occurring BCR-ABL mutations: it occurs in 2–20% of CML cases (Nicolini et al. 2009, Blood 114:5271). The resistance of such mutations to dasatinib inhibition is a potential drawback of dasatinib as a kinase inhibitor and has spurred the development of "third-generation" BCR-ABL inhibitors, known as ponatinib (marketed as ICLUSIG by Incyte & Takeda). However, while ponatinib certainly strongly inhibited the T315I mutation of the BCR-ABL kinase (in vitro IC50 of 2.0 nM), it is known to be a more promising kinase inhibitor than dasatinib, and it also inhibits many other kinases, with in vitro IC50 concentrations between 0.1 and 20 nM, for at least VEGFR, PDGFR, FGFR, EPH receptor and SRC family kinases, KIT, RET, TIE2, and FLT3, or at least members of those kinases. Furthermore, in the United States, sales of ponatinib were temporarily suspended in October 2013 due to the "risk of life-threatening blood clots and significant vascular narrowing." In December 2013, this suspension was partially lifted, and ponatinib was reintroduced with revised prescribing information, a new "black box warning," and "risk assessment and reduced prescribing" guidelines, which better assessed the risks and benefits of drug use. In addition, the price of ponatinib in the United States (which can cost up to $138,000 per year) has been criticized. Therefore, ponatinib has a substantial drawback: there is still a need for novel kinase inhibitors that have the potential to treat Ph+ leukemia (or other cancers) more effectively, safely, easily, and / or inexpensively, and / or novel kinase inhibitors that have the potential to be more selective to SRC, ABL / BCR-ABL, and / or LCK than other kinase inhibitors such as dasatinib or ponatinib.

[0017] However, compared to imatinib, dasatinib is not particularly specific to BCR-ABL and binds to and / or inhibits a significant number of other kinases (see Figure 3 in Bantscheff et al. 2007, Nat. Biotech. 25:1035; Supplementary Figure 2 in Anastassiadis et al. 2012, Nat. Biotech. 29:1039). In particular, dasatinib has been described as binding and / or inhibiting a large number of other kinases, including BTK, CSK, EPHB2, EPHB4, FYN, GAK, KIT, LYN, QIK, QSK, RIPK2, SRC, TEC, TESK2, YES, and ZAK, more significantly than imatinib. More specifically, dasatinib has been shown to be a significant inhibitor of salt-inducible kinases with IC50 values ​​of <3nM, <3nM, and 18nM for three family members SIK1, SIK2, and SIK3, respectively (Ozanne et al., 2015, Biochem. J. 465:271; also described in concurrently pending PCT / EP2018 / 060172). In fact, given that dasatinib is a low-selectivity kinase inhibitor, there is another potential drawback, which is thought to be causally related to the non-serious toxicological challenges faced when treating patients with dasatinib, particularly the increased incidence of thrombocytopenia (Wei et al. 2010, J. Hemat. Oncol. 3:47).

[0018] As described above, dasatinib is a potent inhibitor of KIT, and this receptor tyrosine kinase is becoming an increasingly interesting target for the treatment of certain cancers, not because mutations in the KIT gene have been detected in cancers such as leukemia, ovarian cancer, and melanoma (Babei et al. 2016, Drug Des. Dev. Thera., 10:2443). Dasatinib is also known to inhibit at least the most common KIT mutations in melanoma (Woodman et al. 2009, J. Clin. Onc. 27:9019). However, inhibition of KIT, particularly the relative activity of certain tyrosine kinase inhibitors on FLT3 and KIT, is associated with other side effects such as myelosuppression and hair pigment loss (Galanis and Levis 2015: Haematologica100: e89). In fact, treatment with dasatinib is associated with severe myelosuppression (see below).

[0019] Salt-inducible kinases (SIKs) constitute a serine-tyrosine kinase subfamily belonging to the adenosine-phosphate-activated kinase (AMPK) family. Three members (SIK1, 2-3) have been identified to date. The amino acid homology of SIK1 to SIK2 and SIK3 is 78% and 68%, respectively, in the kinase domain. Cloning of SIK1 (also known as SIK and SNF1LK), which is abundantly expressed in the adrenal glands of high-salt-feeding rats, led to the subsequent cloning of SIK2 (also known as QIK, KIAA781, and SNF1LK2), which is mainly expressed in adipose tissue, and SIK3 (also known as QSK, KIAA999, or L19), which is rather ubiquitous (Katoh et al. 2004, Mol. Cell. Endocrinol. 217:109). The three types of SIKs have similar structures and possess an N-terminal kinase domain (catalytic domain), a middle ubiquitin-related domain (thought to be important for phosphorylation by LKB1), and a long C-terminal sequence (thought to be a site for further phosphorylation by PKA). However, various SIKs have a wide range of roles to play. For example, various SIKs are involved in diverse biological processes such as the osteocytic response to parathyroid hormone in response to gastrin-induced induction of SIK1 and inhibition of gastric adenocarcinoma cell migration (Wein et al., 2016, Nature Commun. 7:13176) (Selvik et al., 2014, PLoS ONE 9:e112485). Other potential roles of salt-induced kinases (particularly SIK3) are described in WO2018 / 193084A1 (the present applicant), which further announced that SIK3 is a gene involved in the oral cell response to TNF, especially in oral cell resistance (October 25, 2018). Recently, it has been demonstrated that SIK (particularly SIK3) also regulates TGFβ-mediated transcriptional activity and apoptosis, and Hutchinson et al. (2010, Cell Death and Disease 11:49) have shown that SIK3 expression or activity confers resistance to TGFβ-mediated apoptosis.

[0020] In particular, it has been known since 2011 that inhibition of SIK2 promotes melanogenesis in B16F10 melanoma cells, as well as its role in various inflammatory responses (Clark et al., 2014; Sundberg et al., 2016) and oncology [especially the sensitization of tumor cells to immune responses (WO2018 / 193084A1)] (Kumagai et al., 2011, PLoS ONE6(10):e26148). Subsequently, it was described that pigmentation pathways, including those structurally related to YKL-05-099, can be effectively induced by (topical) treatment with SIK inhibitors (Mujahid et al., 2017, Cell Reports 19:2177). In fact, using such results, ongoing efforts have been made to develop methods to increase (or increase) skin pigmentation in a subject by topically administering an effective amount of a kinase inhibitor (WO2016 / 023014) that has been previously known to be an SIK inhibitor (WO2018 / 160774).

[0021] The kinase known as the 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 important for the differentiation of macrophages into the more repressive M2 phenotype (Lenzo et al 2012, Immunol Cell Bio90:429). In fact, the presence of CSF1R+ macrophages in tumors correlates with poor survival rates in various indications, including intestinal cancer, breast cancer, retinal cancer, and urological diseases (Zhang et al 2012, PLoS One 7:e50946t). Therefore, targeting CSF1R with either antibodies or small molecule inhibitors is attracting attention in cancer treatment by eliminating or re-educating repressive M2 macrophages. PLX3397 is one such inhibitor that targets CSF1R and is in clinical development for melanoma, glioblastoma, AML, and others (Cannarile et al 2017, J Immunotherapy Cancer 5:53).

[0022] Hematopoietic cell kinases (HCKs) are members of the SRC family of cytoplasmic tyrosine kinases (SFKs) and are expressed in myeloid and B lymphocyte cells. Excessive HCK activation is associated with several types of leukemia and enhances cell proliferation and survival through physical association with oncogenic fusion proteins and functional interactions with receptor tyrosine kinases. Elevated HCK activity is also observed in many solid malignancies, including breast and colon cancer, and correlates with reduced patient survival. HCKs enhance the secretion of growth factors and pro-inflammatory cytokines from myeloid cells and promote wound healing and macrophage polarization into a pro-tumor-promoting surrogate activation phenotype. Within tumor-associated macrophages, HCK stimulates the formation of podosomes that promote the degradation of the extracellular matrix, thereby enhancing immune and epithelial cell invasion. Thanks to the functional cooperation between HCK and true oncogenic tyrosine kinases, excessive HCK activation can reduce drug efficacy and contribute to chemoresistance, while genetic removal of HCK yields minimal physiological consequences in healthy mice. Because HCK has a known crystalline structure, it can directly inhibit cancer cell proliferation and indirectly suppress the source of tumor promotion changes in the tumor microenvironment, making it an attractive therapeutic target for both (Poh et al 2015, Oncotarget6:15742).

[0023] Therefore, there is still a need for novel kinase inhibitors that exhibit drug-like properties (especially those suitable for oral administration) and inhibit one or more kinases, including those selected from SIK3, ABL / BCR-ABL, SRC, HCK, PDGFR, KIT and / or CSF1R, and / or those exhibiting different kinase profiles with respect to kinases inhibited by dasatinib in particular. Examples include (i) novel kinase inhibitors that are more specific to important disease-related kinases (e.g., ABL / BCR-ABL, SRC, LCK, HCK, PDGFR CSFR1 and / or EPHA2, EPHA4, ACK1 and / or KIT) compared to other kinases; (ii) inhibitors that inhibit important disease or side effect-related kinases with a different profile than dasatinib (e.g., against KIT and / or FLT3); and (iii) inhibitors that inhibit one or more variants of disease-related kinases, particularly variants of ABL / BCR-ABL or KIT that are resistant to one or more kinase inhibitors.

[0024] Furthermore, while dasatinib is primarily metabolized by cytochrome P450 enzyme 3A4 (CYP3A4) in humans, it is also a time-dependent inhibitor of CYP3A4. In fact, if a patient is concomitantly taking a potent CYP3A4 inhibitor (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole), the plasma concentration of dasatinib may rise to dangerous levels, requiring a significant reduction in the dasatinib dose (e.g., from 100 mg / day to 20 mg / day). Grapefruit juice should also be avoided as it may increase the plasma concentration of dasatinib. Therefore, there is still a need for new kinase inhibitors that exhibit a different cytochrome P450 inhibition pattern (e.g., inhibition pattern against CYP3A4) than dasatinib.

[0025] Importantly, the dosage and administration of dasatinib should be discontinued (or reduced) if myelosuppression occurs. In fact, because treatment with dasatinib is associated with severe (NCI CTC grade 3 or 4) thrombocytopenia, neutropenia, and anemia, myelosuppression is listed as one of the "Warnings and Precautions" in the US prescribing information for dasatinib. In addition to causing thrombocytopenia in human subjects, clinical trials of dasatinib have shown the following: (i) Severe central nervous system (CNS) bleeding (including fatalities) occurred in 1% of patients. (ii) Severe gastrointestinal bleeding, including fatalities, occurred in 4% of patients and generally required treatment interruption and blood transfusions. (iii) Other severe bleeding occurred in 2% of patients.

[0026] However, further warnings and precautions for dasatinib include: (x) it is associated with fluid retention, with severe fluid retention reported in up to 10% of patients in clinical trials; (y) it may prolong ventricular repolarization (QT interval), with QT prolongation observed in up to 1% of CML patients in clinical trials; and (z) cardiac side effects were reported in 5.8% of 258 patients taking dasatinib, including cardiomyopathy, congestive heart failure, diastolic dysfunction, fatal myocardial infarction, and 1.6% of patients with left ventricular dysfunction. In fact, dasatinib is known to be an inhibitor of hERGs (Pharmacological / toxicological review and evaluation in NDA 21-986, p. 31). hERGs (human "Ether-a-go-go-Related Genes") are ion channels that contribute to the electrical activity of the heart and regulate heartbeat. If the ability of these channels to conduct electric currents across cell membranes is inhibited or impaired (e.g., by drug administration), it can lead to a potentially fatal condition called "long QT syndrome." Therefore, there is still a need for novel kinase inhibitors that exhibit hERG inhibition different from that of dasatinib. For example, it would be advantageous to provide a novel kinase inhibitor that exhibits an IC50 against hERGs greater than the IC50 of dasatinib.

[0027] In fact, the main metabolic pathway for dasatinib includes modifications to the chloro / methylphenyl or piperazinyl group of dasatinib (e.g., Christopher et al 2008, Drug Metab & Disp 36:1357, particularly Figure 4). In particular, CYP3A4-mediated reactive epoxide and quinone imine intermediates can form as reactive metabolites of dasatinib that covalently bind to biomolecules such as CYP proteins (Duckett & Cameron 2010, Expert Opin Drug Metab Toxicol 6:1175), which may contribute to the observed toxicity of dasatinib in humans and / or lead to drug-drug interactions with other CYP substrates (e.g., symbastine).

[0028] Therefore, there is still a need for further kinase inhibitors that exhibit a different metabolite profile from dasatinib (e.g., in humans), particularly those with one or more different primary metabolic pathways than dasatinib (especially those of dasatinib modified with chloro / methylphenyl and / or piperazinyl groups).

[0029] Compared to other BCR-ABL inhibitors, dasatinib has an extremely short half-life, with an overall mean terminal half-life of only 3–5 hours (see section 12.3, Pharmacokinetics, in the full package insert). In contrast, the elimination half-life of imatinib is approximately 18 hours. The mean terminal elimination half-life of bosutinib is 22.5 hours. The apparent elimination half-life of nilotinib is approximately 17 hours. The geometric mean terminal elimination half-life of ponatinib is approximately 24 hours. While not bound by theory, dasatinib's short half-life (suitable for once-daily dosing) may explain the limited activity associated with lower in vivo drug concentrations later in the day, and / or side effects associated with peak / higher in vivo drug concentrations immediately after dosing. Therefore, there is still a need for novel kinase inhibitors exhibiting longer half-life characteristics (e.g., longer than those shown by dasatinib). For example, a favorable kinase inhibitor may be more stable than dasatinib, for instance, by exhibiting a longer half-life in plasma and / or liver microsome stability assays.

[0030] Further precautions, adverse events, and other prescribing information for dasatinib can be found in the respective Product Characteristics Summary (SmPC) of the complete prescribing information, as can be found on the respective EMA and FDA websites (listed below, accessed August 20, 2018, and their entire contents incorporated herein by reference): (i) http: / / www.ema.europa.eu / docs / en_GB / docμMent_library / EPAR_Product_Information / hμMan / 000709 / WC500056998.pdf; and (ii) https: / / www.accessdata.fda.gov / drugsatfda_docs / label / 2010 / 021986s7s8lbl.pdf.

[0031] Numerous variants of dasatinib have been synthesized and demonstrated to possess in-vitro biochemical inhibitory activity against one or more kinases and / or antiproliferative effects on cells. In particular, such variants were synthesized (i) to understand and explain 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) to provide alternative kinase inhibitors and / or drug candidates (e.g., WO 2006 / 081172 and WO2008 / 033746). The variants of dasatinib described therein have phenyl moiety in carboxamide. These disclosures demonstrate other positions and a substantial range of substituents that may be substituted therein, providing compounds that are kinase inhibitors and / or have cell antiproliferative activity (Figure 8).

[0032] International Publication No. 2018 / 193084 (published by the applicant on October 25, 2018) discloses dasatinib variants having pyridinyl moiety and their use. The concurrently pending application PCT / EP2019 / 078751 (the present applicant) discloses further dasatinib variants having other heterocyclic moieties, particularly those having thiazolyl moieties. Beutner et al. (2018, Org Lett 20:4218) describe methods for forming challenging amide bonds, including those for specific pyridinepyrazines and pyrimidines. Pennington et al. (2017, J Med Chem 60:3552) describe how substitution of CH groups with N atoms in aromatic and heteroaromatic ring systems can affect molecular and physiological properties. However, empirically, such substitutions have been shown to yield improved potency that is not statistically superior to mere chance: Matched molecular pair analysis (MMPA) of internal data in Illinois (Hajduk & Sauer 2008, J MedChem 51:553) found that, as with most substituent substitutions, there is an almost equal probability of increasing or decreasing potency by exchanging the CH group and N atom. In fact, this analysis further revealed that the probability of achieving a tenfold increase in potency with such substitutions is less than 1 in 10, and the probability of achieving a 100fold increase is less than 1 in 100; similar to the probabilities observed when investigating the effect of such substitutions on improving binding affinity (Hu et al 2014, F1000 Research 3:36; de la Vega de Leon et al 2014, Med Chem Comm 5:64). [Overview of the project] [Problems that the invention aims to solve]

[0033] 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 demonstrated by in vitro and / or in vivo assays) that address one or more of these or other problems. Another object is that the present invention provides alternative and / or improved kinase inhibitors to dasatinib (or one or more kinase inhibitors such as those described herein). For example, kinase inhibitors that can exhibit one or more functional groups (e.g., kinase selectivity), ADMET, PK, and / or pharmacological properties that are different from and / or improved compared to dasatinib (or one or more kinase inhibitors such as those described herein) would be advantageous. In particular, it would be advantageous to provide inhibitors of one or more SIK family kinases having drug-like properties, and especially those that are orally administered, for use in the treatment of proliferative disorders (such as MPAL) particularly characterized by the presence of MEF2C protein (such as phosphorylated MEF2C protein and / or MEF2C protein as an active transcription factor), human chromosomal translocation at 11q23, and / or KMT2A fusion oncoprotein. The fundamental object of the present invention is resolved by subject matter disclosed or defined anywhere herein, for example, by subject matter of the appended claims. [Means for solving the problem]

[0034] In general, the main features of the present invention can be summarized in a brief description as follows:

[0035] In a first aspect, the present invention provides compounds selected from the group consisting of kinase inhibitors of formula Ia, solvates thereof, salts thereof, N-oxides thereof, complexes thereof, polymorphs thereof, crystalline forms thereof, racemic mixtures thereof, diastereomers thereof, enantiomers thereof, tautomers thereof, conformational isomers thereof, isotope-labeled forms thereof, prodrugs thereof, and combinations thereof: [ka] Here, Hy, R 2 , R 3 , R 4 , R 5 A, E, and A are defined as follows:

[0036] In a second embodiment, the present invention provides a pharmaceutical composition comprising the compound of the first embodiment, or a pharmaceutical composition comprising the compound of the first embodiment and a pharmaceutically acceptable excipient.

[0037] In a third embodiment, the present invention provides a compound of the first embodiment or a pharmaceutical composition of the second embodiment that is therapeutic.

[0038] In a related embodiment, the present invention provides a method for treating a disease, disorder, or condition, comprising administering to a subject a compound of the first embodiment or a pharmaceutical composition of the second embodiment, or a disease, disorder, or condition, wherein the disease, disorder, or condition is related to a kinase, comprising administering to a subject a compound of the first embodiment or a pharmaceutical composition of the second embodiment.

[0039] In a fourth embodiment, the present invention provides a compound of a first embodiment for use, or a pharmaceutical composition of a second embodiment for use, in the treatment of proliferative disorders in a subject, particularly in a human patient.

[0040] In a related embodiment, the present invention provides a method for treating proliferative disorders in a subject, comprising administering to the subject a compound of the first embodiment or a pharmaceutical composition of the second embodiment.

[0041] In a fifth embodiment, the present invention provides a compound or a pharmaceutical composition for use in the treatment of proliferative disorders in a subject, the treatment comprising administering the compound or the pharmaceutical composition to the subject, wherein the compound is selected from the following group of compounds: (a) to (c), or a pharmaceutical composition comprising such a compound and a pharmaceutical composition comprising such a compound and a pharmaceutically acceptable excipient: (a) Compounds of the first embodiment; (b) Compounds having the following formula: [ka] and, Compounds selected from the group consisting of the solvate, salt, N-oxide, complex, polymorph, crystalline form, racemic mixture, diastereomer, enantiomer, tautomer, conformator, isotope-labeled form, prodrug, and combinations thereof. Here, Hy, R 2 , R 3 , R 4 , R 5, A, and E are as defined herein; and (c) A compound having the following formula Ic: [Chemical formula] and, a compound selected from the group consisting of its solvate, its salt, its N-oxide, its complex, its polymorph, its crystalline form, its racemic mixture, its diastereomer, its enantiomer, its tautomer, its conformational isomer, its isotope-labeled form, its prodrug, and combinations thereof; where: R 1a , R 1b , R 1c , R 2 , R 3 , R 4 , R 5 , A, B, and E are as defined herein; and where the proliferative disorder is selected from one or more of (α)-(γ): (α) A proliferative disorder characterized by the presence of myocyte enhancer factor 2C (MEF2C) protein, such as phosphorylated MEF2C protein and / or MEF2C protein as an active transcription factor (or by cells involved in the proliferative disorder); preferably, the proliferative disorder is further characterized by the presence of phosphorylated histone deacetylase 4 (HDAC4) protein, such as HDAC4 protein phosphorylated by SIK3; and / or (β) A proliferative disorder characterized by or by cells involved in a proliferative disorder characterized by: (i) The presence of a human chromosomal translocation at 11q23; (ii) The presence of a rearrangement of the lysine-methyltransferase 2A (KMT2A) gene; (iii) The presence of a KMT - 2A fusion cancer protein; and / or (iv) The presence of a mutation in the K - RAS proto - oncogene GTPase (KRAS) gene and / or in the RUNX family transcription factor 1 (RUNX1) gene; and / or ? (γ) Mixed phenotype acute leukemia (MPAL).

[0042] In a related embodiment, the present invention provides a method for treating proliferative disorders in a subject, the method comprising administering a compound or pharmaceutical composition to the subject as defined in the fifth embodiment, where proliferative disorder is defined in the fifth embodiment.

[0043] In a further embodiment, the present invention provides a method for determining whether a subject suffering from a proliferative disorder is suitable for treatment with a compound or pharmaceutical composition as defined in a fifth embodiment, the method comprising determining the following in a biological sample obtained from the subject: (X) The presence of MEF2C protein, e.g., phosphorylated MEF2C protein and / or MEF2C protein as an active transcription factor; preferably, herein the proliferative impairment is further characterized by the presence of phosphorylated HDAC4 protein, e.g., HDAC4 protein phosphorylated by SIK3; and / or (Y) (i) The presence of a human chromosome translocation at 11q23; (ii) The presence of a rearrangement of the KMT2A gene; (iii) The presence of KMT2A fusion oncoprotein; and / or (iv) The presence of mutations in the KRAS gene and / or the RUNX1 gene, Here, the presence of the aforementioned proteins, translocations, rearrangements, oncoproteins, and / or mutations in a biological sample indicates that the subject is suitable for treatment with the compound or pharmaceutical composition.

[0044] In another embodiment, the present invention relates to a method for increasing (or increasing the appearance of) skin pigmentation in a subject, the method comprising the step of administering (e.g., an effective) amount of a kinase inhibitor (or a pharmaceutical composition comprising such a compound) used in the fifth embodiment to the subject.

[0045] In a further embodiment, the present application provides intermediates selected from compounds having formula (Id): [ka] And, Compounds selected from the group consisting of the solvate, salt, complex, polymorph, crystalline form, racemic mixture, diastereomer, enantiomer, tautomer, conformator, isotope-labeled form, and combinations thereof, Here, R 40 and R 41 This is defined herein.

[0046] In a further embodiment, the present application provides a method for producing a compound containing an amide moiety, the method comprising reacting an intermediate of the present invention with a corresponding carboxylic acid and optionally removing the amino protecting group.

[0047] Further aspects of the present invention are disclosed herein. [Brief explanation of the drawing]

[0048] The drawing shows the following:

[0049] [Figure 1-1]Figure 1 shows the following chemical structures: (A) Dasatinib (compound A8), N-(2-chloro-6-methylphenyl)-2-((6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-yl)amino)thiazole-5-carboxamide; (B) Kinase inhibitor B3, N-(4-chloro-2-methylpyridin-3-yl)-2-((6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-yl)amino)thiazole-5-carboxamide; (C) Other identified kinase inhibitors of formula (Ib) / (Ic) C1 to C13; (D) Further identified kinase inhibitors of formula (Ib) / (Ic) D1 to D10; and (E) Further identified kinase inhibitors of formula (Ia) E1 to E16. [Figure 1-2] Same as above [Figure 1-3] Same as above

[0050] [Figure 2-1] Figure 2 shows the inhibitory activity of kinase inhibitors of formula (Ib) / (Ic) (B3, left column) against kinases (A) ABL1; (B) SRC; (C) SIK1; (D) SIK2; and (E) SIK3 (A-E) compared to dasatinib (A8, right column), and the inhibitory activity 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 (F-J). The X-axis represents compound concentration (M), and the Y-axis represents kinase activity (%). [Figure 2-2] Same as above

[0051] [Figure 3-1]Figure 3 shows the selectivity of kinase inhibitors by their % residual activity (at 1 μM compound): B3 (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; ** 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. 191, 2-1934): AGC: Includes PKA, PKG, and PKC families; CAMK: Calcium-calmodulin-dependent protein kinase; CK1: Casein kinase-like; CMGC: Includes CDK, MAPK, GSK3, and CLK families; TK: Tyrosine kinase; TKL: Tyrosine kinase-like; STE: Homologs of yeast sterile (bactericidal) 7, sterile (bactericidal) 11, and sterile (bactericidal) 20 kinases. ## Constitutively active kinases. [Figure 3-2] Same as above [Figure 3-3] Same as above [Figure 3-4] Same as above [Figure 3-5] Same as above [Figure 3-6] Same as above [Figure 3-7] Same as above [Figure 3-8] Same as above

[0052] [Figure 4] Figure 4 shows the selectivity of kinase inhibitors of formula (Ib) / (Ic) and B3 (X-axis) compared to dasatinib (A8; Y-axis), based on the percentage of residual activity at 1 μM: the (A) axis shows the entire range of residual activity, and the (B) axis shows the residual activity in the 0-50% range.

[0053] [Figure 5]Figure 5 shows the inhibitory activity of 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). The X-axis represents compound concentration (M), and the Y-axis represents kinase activity (%).

[0054] [Figure 6] Figure 6 shows the sensitization of tumor cells to in vitro TNF-attack by (A) kinase inhibitor B3 and (B) A8 (dasatinib). Circles: compound (indicated concentration) + rHuTNF (10 ng / mL); Squares: compound alone without rHuTNF (indicated concentration).

[0055] [Figure 7] Figure 7 shows the relative tumor cell viability (normalized RLU by cytotoxicity / viability) of specific kinase inhibitors described in PCT / EP2018 / 060172 in assays using M579-A2-luc as described in Example 9, either alone (square) or in combination with 10 ng / mL of TNF (circle). It also shows the inhibitory activity of the compounds against SIK family members and related kinases ABL1 and SRC, and the indices used are shown 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.

[0056] [Figure 8]Figure 8 shows the cellular antiproliferative activity of dasatinib variants obtained from Table 1 of (A) Lombardo et al 2004 (J Med Chem 47: 6658), and the efficacy of various derivatives of dasatinib against the indicated cell lines. Antiproliferative activity was determined based on tetrazolium dye conversion after 72 hours of compound exposure. IC50 values ​​are reported as the average of at least three individual measurements, or as individual IC50 values ​​if fewer than three measurements were taken. Unless otherwise indicated by the SE values ​​in parentheses, variability around the mean was <50%; and (B) biochemical and cellular antiproliferative activity of dasatinib variants from Table 4 of Das et al 2006 (J Med Chem 49: 6819). an = 3, variability of individual values, <20%; bn = 3, individual values, <30%.

[0057] [Figure 9] Figure 9 shows the selectivity of kinase inhibition (by % residual activity at 1 μM compound) by the kinase inhibitor of formula (Ib) / (Ic), C7 (Y axis) compared with (A) dasatinib (A8; X axis) and another kinase inhibitor of formula (Ib) / (Ic), B3 (X axis). The dashed line region highlights the group of kinases that are substantially differentially inhibited among the applicable compounds.

[0058] [Figure 10] Figure 10 shows the body weight of female C57Bl / 6 mice after forced oral administration of different concentrations of C7, 33 mg / kg (black squares) and 100 mg / kg (gray diamonds), once daily (QD = A) and twice daily (BID = B), compared to control animals (gray squares). X axis: Days after administration; Y axis: Body weight change (%). (C) Plasma levels of C7 measured 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).

[0059] [Figure 11]Figure 11: (A) Tumor growth dynamics in mice transplanted with MC38 cells treated with vehicle (black square), C7 100 mg / kg QD (gray hexagon), C7 100 mg / kg BID (gray triangle), and A8 (dasatinib) 30 mg / kg QD A8 (gray circle). Y axis = mean tumor volume (mm3). Error bars are SEM. X axis: days. Statistical significance was calculated using two-way ANOVA analysis including Tukey's multiple comparison analysis. ***p<0.001; (B) Weight dynamics of mice in (A). Y axis: mean weight change (%).

[0060] [Figure 12] Figure 12 shows the immuno-oncological effects of C7, a compound of formula (Ib) / (Ic), on immune cells present in the tumor microenvironment. Intratumor immune infiltration was calculated as the percentage of CD45+ cells within the tumor. Statistical significance was calculated using one-way ANOVA analysis, including Tukey's multiple comparison analysis. (A) Y-axis: Ratio of CTLs to Treg cells. (B) Activated CTLs (CD25+CD69+); Y-axis: % of CD45+ cells. (C) Activated CTLs (Granzyme B+); Y-axis: % of CD45+ cells. (D) Immunosuppressed M2-like tumor-associated macrophages (TAMs) (CD206+MHC-II+); Y-axis: % of CD45+ cells; * p<0.05; ** p<0.01; *** p<0.00.

[0061] [Figure 13]Figure 13 shows TNF-induced cell death sensitized with compound C7. (A) TNF-induced apoptosis of PANC-1 cells. PANC-1 cells were treated with 370 nM ("rhomboid") and 3333 nM ("square") of C7, and DMSO alone ("star") for 120 h before adding 100 ng / ml of rHuTNF (+rHuTNF = open shapes; -rHuTNF = solid shapes; open circles 10 ng / mL rHuTNF control). Cell death was evaluated using real-time live-cell microscopy, and nuclear uptake of YOYO-1 dye (YOYO-1 + cell area / well) was measured. Y axis = tumor cell death (μm² / well). X-axis = Time (h); (B) Effect of C7 on TNF induction (100 ng / ml rMuTNF) in mouse MC38 apoptosis (+rMuTNF = "diamond"; -rMuTNF = "circle"). Cell viability was measured after 72 hours using the CellTiter-Glo assay. Luciferase levels were normalized to cells treated with rMuTNF (DMSO only) without the inhibitor. Y-axis = Viability (%). X-axis = Compound concentration (nM).

[0062] [Figure 14]Figure 14 shows (A) the effect of compound C7 on NFKB activity. Reporter PANC-1 cells expressing luciferase under the control of the NFKB promoter were treated with different concentrations of C7, followed by the addition of 10 ng / ml rHuTNF for 8 hours (+rHuTNF = "diamond"; -rHuTNF = "circle"). Luciferase activity was normalized to PANC-1 cells treated with rHuTNF (DMSO only) without the inhibitor. Y axis = NFKB activity (%). X axis = compound concentration (nM); (B) effect of compound C7 on HDAC4 phosphorylation. PANC-1 cells were treated with C7 at various concentrations (in the presence of 10 ng / mL rHuTNF) for 3 hours. Total cell lysates were analyzed by Meso Scale Discovery (MSD) assays using anti-HDAC4 capture and anti-pHDAC4 detection antibodies. HDAC4 phosphorylation was normalized to untreated PANC-1 cells (DMSO only). Y-axis = HDAC4 phosphorylation (%). X-axis = Compound concentration (nM).

[0063] [Figure 15] Figure 15 shows the inhibition of cell proliferation in WSU-NHL(A) and DOHH-2(B) cell lines by compound C7, with GI50 values ​​of approximately 8 nM and 9 nM, respectively. X axis: compound concentration (M); Y axis: percentage of cell proliferation inhibition (GI) at 96 hours.

[0064] [Figure 16] Figure 16 shows the selectivity of kinase inhibition (by residual activity % at 0.1 μM compound) by (A) the kinase inhibitor of formula (Ia)E9 (X axis) compared with E10 (Y axis), and by C7 (X axis) compared with the kinase inhibitor of formula (Ia)E4 (Y axis).

[0065] [Figure 17] Figure 17 shows the differential inhibition of MAP3K11 and NEK11 kinases between compound C7 (X-axis) and the kinase inhibitor of formula (Ia)E10 (Y-axis: % residual activity) at (A) a 1 μM compound concentration and (B) a 0.1 μM compound concentration.

[0066] [Figure 18-1] Figure 18 shows the activity of the SIK3 inhibitors disclosed herein against MEF2C-expressing AML cell lines: (A) Compound C7 against a panel of AML cell lines (showing potent lysis of such cell lines having phosphorylated MEF2C protein); (B) very potent cytotoxicity of Compound C7 against pMEF2C-positive KASMI-1 cell lines; and (C) low cytotoxicity of Compound C7 against pMEF2C-negative HEL cell lines. [Figure 18-2] Same as above

[0067] [Figure 19] Figure 19 shows a schematic diagram of SIK3-mediated regulation of the expression of a survival / maintenance gene (a) by the phosphorylated myocyte enhancer factor 2C (MEF2C) transcription factor. Overexpression of MEF2C is typically associated with the presence of a fusion of the lysine-methyltransferase 2A (KMT2A) protein (formerly known as "MLL"; (b)), which is brought about by a human chromosomal translocation at 11q23. MEF2C activity is regulated by the nuclear presence of HDAC4, which acts as an inhibitory cofactor, and its cytoplasmic retention is brought about by its phosphorylation by SIK3. Nuclear entry and presence of unphosphorylated HDAC4 (c) (and thus the reduction in the expression of tumor survival / maintenance genes due to inhibition of MEF2c transcription factor activity (a)) can be brought about by inhibition of SIK3 by compounds disclosed herein (d).

[0068] [Figure 20-1]Figure 20 shows (A) tumor growth dynamics in mice transplanted with MC38 cells, (1) control: rat IgG2A 10 mg / kg (black filled square), aPD-1 10 mg / kg 3q7d (light gray open crossed circle), and vehicle (light gray filled inverted triangle); and compound E10 30 mg / kg BID (gray open inverted triangle), E4 40 mg / kg BID (dark gray filled circle), E9 25 mg / kg BID (light gray filled square), E9 50 mg / kg BID (dark gray filled triangle), and C7 100 mg / kg BID (light gray filled diamond). Y axis = mean tumor volume (mm3). Error bar SEM statistical significance was calculated using one-way ANOVA analysis including Tukey's multiple comparison analysis. X axis = days. (B) Probability that the tumor volume of mice in (A) is less than 1000 mm3. Y axis: Probability of tumor volume <= 1000 mm3 at administration. X axis: Days. For both (A) and (B), control: rat IgG2A (A), aPD-1 10 mg / kg (b), vehicle (solvent) (c); and compound: 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)~(H) Tumor growth curves of individual mice; Y axis: tumor volume (mm3), X axis: days. (C)E9 25mg / kg BID; (D)E9 50mg / kg BID; (E)C7 100mg / kg BID; (F)aPD-1 10mg / kg; (G)rat IgG2a 10mg / kg and (H)vehicle. [Figure 20-2] Same as above

[0069] [Figure 21-1]Figure 21 shows the cancer immunotherapy effect of the kinase inhibitor of formula (Ia) on immune cells present in the tumor microenvironment. Intratumor immune infiltration (infiltrate) was calculated as the percentage of CD45+ cells within the tumor. Statistical significance was calculated using one-way ANOVA analysis, including Tukey's multiple comparison analysis. (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-positive 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) mMDSC (Ly6C+); (J) gMDSC (Ly6G+). Y-axis: % of CD45-positive cells, * p<0.05; ** p<0.01; *** p<0.001. X-axis: A = Rat IgG2A (10 mg / kg, 3q7d); B = aPD-1 (10 mg / kg, 3q7d); C = Vehicle (BID); 1 = C7 (100 mg / kg, BID); 2 = E4 (40 mg / kg, BID); 3 = E9 (25 mg / kg, BID); 4 = E9 (50 mg / kg, BID); 5 = E10 (30 mg / kg). [Figure 21-2] Same as above

[0070] [Figure 22] Figure 22 shows TNF-mediated cell killing induced by either (A) compound E9 or (B) compound C7 in SIK3 knockout MC38 clones (triangles) or SIK3 wild-type MC38 clones (squares) in the presence of 5 ng / ml TNF. Y axis = viability, normalized to no TNF. X axis = inhibitor concentration (nM).

[0071] [Figure 23]Figure 23 shows the classification of all known KMT2A fusion translocation partner genes (TPGs) by disease (adapted from Figure 3, Meyer et al 2018). TPGs are all classified by the diagnosed disease type. Such genes are diagnosed in ALL, t-ALL, t-AML, AML, T-ALL, MLL, bilineal acute leukemia (BAL), MDS, t-MDS, chronic myeloid leukemia (CML), t-CML, juvenile myelomonocytic leukemia (JMML), and lymphoma. The crossover genes belong to two distinct groups. TPGs in bold are the most common.

[0072] [Figure 24] Figure 24 shows the pharmacokinetic curves of compounds E4 (circle), E9 (inverted triangle), and E10 (diamond) of formula (Ia) compared to the closely related compound C7 (square) after oral administration of 30 mg / kg. Y-axis = total plasma compound concentration (ng / ml); X-axis = time (h).

[0073] [Figure 25] Figure 25 shows the reproducibility of the compounds of formula (Ia) and C7 against MC38 tumor cells + TNF. Y axis = EC50 tumor cell lysis (nM).

[0074] [Figure 26] Figure 26 shows 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, and y = 100 ng / ml). Vertical bars: Survival rate normalized to the absence of the compound at the indicated rMuTNF concentration. Left column for compound E9, right column for compound C7: MC38(A); CT26(B); and EMT6(C). Y-axis = Survival rate (normalized to the absence of the compound); X-axis = Compound concentration (nM).

[0075] [Figure 27]Figure 27 shows that compound E9 (24 mg / kg BID) (A) demonstrated superior and more uniform tumor growth suppression compared to dasatinib (30 mg / kg QD) (B) in an MC38 syngeneic tumor model. Left column = compound treatment group; right column = vehicle treatment group. Y axis = tumor volume (mm3); X axis = days after inoculation.

[0076] [Figure 28] Figure 28 shows the effect of compound E9 on NFKB activity, with (A) and (B) being the same. MC38 cells (B) or reporter PANC-1 cells (A) expressing luciferase under the control of the NFKB promoter were treated with different concentrations of E9 before adding 10 ng / ml rHuTNF for 8 hours (+rHuTNF = "diamond", EC50s = 405 nM for PANC-1 and EC50s = 389 nM for MC38; -rHuTNF = "circle"). Luciferase activity was normalized against cells treated with rHuTNF (DMSO only) without the inhibitor. Y axis = NFKB activity (%). X axis = compound concentration (nM); bar "A" survival rate without compound and without TNF; bar "B" survival rate without compound and with 10 ng / ml TNF; and (C) effect of compound E9 on HDAC4 phosphorylation. PANC-1 cells were treated with various concentrations (in the presence of 10 ng / mL rHuTNF) at E9 for 3 hours. Total cell lysates were analyzed using a Meso Scale Discovery (MSD) assay with anti-HDAC4 capture and anti-pHDAC4 detection antibodies. HDAC4 phosphorylation was normalized relative to untreated PANC-1 cells (DMSO only). Y-axis = HDAC4 phosphorylation (%). X-axis = Compound concentration (nM).

[0077] [Figure 29-1]Figure 29 shows the effects of compound E9 and anti-PD-1 mAB (alone or in combination) on in vivo tumor growth (mean + / SEM) in an MC38 syngeneic tumor model. (A) Y-axis = Tumor volume (mm3); X-axis = Days after initiation of treatment. Vehicle + anti-PD-1 mAB (square), vehicle + mIgG1e ctr (circle), E9 + anti-PD-1 mAB (inverted triangle), and E9 + mIgG1e ctr (triangle). (B) Median overall survival. Y-axis = Probability of survival (%); X-axis = Days after initiation of treatment. Vehicle + anti-PD-1 mAB (gray / dashed line), vehicle + mIgG1e ctr (black / solid), E9 + anti-PD-1 mAB (gray / solid), and E9 + mIgG1e ctr (black / dashed line). (C)~(D) Tumor growth curves of individual mice; Y axis: Tumor volume (mm3), X axis: Days after initiation of treatment. (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) Vehicle. [Figure 29-2] Same as above

[0078] [Figure 30] Figure 30 shows the effect of compound E9 on in vivo tumor growth (mean + / SEM) in immune elimination tumor models (EMT6) (A) and (B). Y axis = tumor volume (mm3); X axis = days after initiation of treatment. (A) Vehicle BID (square), E9 25 mg / kg BID (triangle), E9 12.5 mg / kg BID (diamond), and E9 5 mg / kg BID (circle). (B) Vehicle BID (square), E9 25 mg / kg BID (triangle), E9 25 mg / kg QD (inverted triangle). [Modes for carrying out the invention]

[0079] The present invention, and certain non-limiting aspects and / or embodiments thereof, will be described in more detail below.

[0080] The present invention could be described in further detail, but it should be understood that the invention is not limited to the specific methodologies, protocols, and reagents described herein, as these may vary. Furthermore, it should be understood that the terms used herein are for the purpose of describing specific embodiments only and are not intended to limit the scope of the invention as described, defined, or otherwise disclosed herein, in particular, as limited solely by any itemized embodiments or appended claims.

[0081] This specification describes in more detail certain elements of the present invention. While these elements are listed with specific embodiments, it should be understood that they can be combined in any way and in any number to create additional embodiments. The various examples and preferred embodiments described are not to be construed as limiting the invention to only the expressly described embodiments. This description of the application should be understood as supporting and encompassing embodiments that combine the expressly described embodiments with any number of the disclosed and / or preferred elements. Furthermore, any substitution and combination of all elements described in this application should be considered disclosed by the description of this application unless the context indicates otherwise. For example, in one embodiment of the compound of the present invention, L is a bond, and in another embodiment of the compound of the present invention, R 3 When is H, in a preferred embodiment of the compound of the present invention, L is a bond, and R 3 is H, or in one embodiment of the use of the compound of the present invention, the subject is an adult, and in another embodiment of the use of the compound of the present invention, the proliferative disorder is prostate cancer, and then, in a preferred embodiment of the use of the compound of the present invention, the subject is an adult and the proliferative disorder is prostate cancer.

[0082] General definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art.

[0083] Preferably, the terms used herein are defined as described in "A multilingual glossary of biotechnological terms: (IUPAC Recommendations)" (HGW). Leuenberger, B. Nagel, and H. Klobl, Eds., Helvetica Chimica Acta, CH-4010 Basel, Switzerland, (1995).

[0084] The implementation of this invention will, unless otherwise specified, use conventional methods of chemistry, biochemistry, and recombinant DNA technology described in the literature in the art (see, for example, Molecular Cloning: A Laboratory Manual, 2nd edition, edited by J. Sambrook et al., Cold Spring Harbor Laboratory Press, Cold Spring Harbor 1989).

[0085] Unless otherwise required by context, throughout this specification and the subsequent claims, variations of the word "comprise," "comprises," and "comprising" shall be understood to mean including one described member, an integer or step or group of members, or a plurality of integers or steps, but not to exclude other members, an integer or step or group of members, or a plurality of integers or steps. The term "consisting essentially of" means excluding any other member, integer, or step of any essential meaning, or any group of multiple members, integers, or steps of any essential meaning. For example, a pharmaceutical composition consisting essentially of a member / component as defined herein (such as the compound defined in any aspect of the Invention and optionally one additional therapeutic agent) excludes further therapeutic agents (other than the compound defined in any aspect of the Invention and optionally one additional therapeutic agent), but does not exclude trace amounts of contaminants (e.g., from isolation and purification methods) [e.g., amounts of contaminants (preferably the total amount of all contaminants present in the composition) less than 5% by weight, e.g., less than 4% by weight, less than 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, 0.05% by weight, etc.] and / or pharmaceutically acceptable excipients (carriers, e.g., phosphate-buffered saline, preservatives, etc.). The term "consisting of" means excluding all other members, significant integers or steps, or groups of significant members, integers or steps. For example, a pharmaceutical composition consisting of the components / ingredients defined herein (such as a compound, one excipient, and optionally one additional therapeutic agent, as defined in any aspect of the present invention) excludes any other compound in amounts exceeding 2% by weight of the whole composition (excessively 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%, 0.01%, or 0.02%). The term "comprising" encompasses the term "consisting essentially of," which in turn encompasses the term "consisting of." Therefore, in each occurrence in this application, the term "comprising" can be replaced with the term "consisting essentially of" or "consisting of." Similarly, in each occurrence in this application, the term "consisting essentially of" can be replaced with the term "consisting of."

[0086] As used herein, “and / or” should be interpreted as a specific disclosure of each of the two designated features or components, with or without the other feature or component. For example, “X and / or Y” should be interpreted as (i) X, (ii) Y, and (iii) X and Y, each of which should be interpreted as a specific disclosure of X and Y, as if they were described separately herein.

[0087] In the context of this invention, the terms “about” and “approximately” are used interchangeably and indicate intervals of precision that a person skilled in the art will understand to still ensure the technical effect of the feature in question. The terms typically indicate deviations from the indicated numerical value as ±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%, and, for example, ±0.01%. As a person skilled in the art will understand, a particular deviation of a numerical value from a given technical effect depends on the nature of the technical effect. For example, natural or biological technical effects may generally have larger deviations than artificial or engineered technical effects.

[0088] The terms “a,” “an,” and “The,” as well as similar references used in the context describing the present invention (particularly in the context of the claims), should be construed as encompassing both singular and plural unless otherwise indicated herein or unless the context clearly contradicts this interpretation.

[0089] The descriptions of value ranges in this specification are intended solely as a concise way to refer individually to each distinct value that falls within that range. Unless otherwise specified herein, each individual value is incorporated herein as if it were individually listed.

[0090] All methods described herein may be carried out in any suitable order, unless otherwise indicated herein or unless the context clearly contradicts it.

[0091] Any and all examples or illustrative language provided herein (e.g., “such as”) is intended solely to better illustrate the invention and not to otherwise limit the scope of the claimed invention. No language herein should be construed as indicating any non-claimed element essential to the practice of the invention.

[0092] This specification contains references to several documents. Each of the documents referenced herein (including all patents, patent applications, scientific publications, manufacturer specifications, instructions, etc.) is incorporated herein by reference in its entirety, whether above or below. Nothing in this specification shall be construed as admitting that the present invention does not have prior rights to such disclosures on the basis of prior inventions.

[0093] Terms such as “of the present invention,” “according to the present invention,” and “by the present invention” are intended to refer to all aspects and embodiments of the present invention as described and / or claimed herein, as used herein.

[0094] It should be understood that the application of the teachings of the present invention to specific problems or environments, and the inclusion of variations of the present invention or additional features therein (such as further aspects and embodiments) are within the capabilities of those skilled in the art in light of the teachings contained herein.

[0095] Unless the context indicates otherwise, the descriptions and definitions of features set forth above or below are not limited to any particular aspect or embodiment of the present invention, but apply equally to all aspects and embodiments described herein.

[0096] The term "alkyl" refers to a monoradical of a saturated linear or branched hydrocarbon. Preferably, the alkyl group contains 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, e.g., 1 to 6 or 1 to 4 carbon atoms. Exemplary alkyl groups include: methyl (Me), ethyl (Et), propyl, iso-propyl (also called 2-propyl or 1-methylethyl), butyl, iso-butyl, tert-butyl, n-pentyl, iso-pentyl, sec-pentyl, neo-pentyl, 1,2-dimethyl-propyl, iso-amyl, n-hexyl, iso-hexyl, sec-hexyl, n-heptyl, iso-heptyl, n-octyl, 2-ethyl-hexyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, etc. "Substituting alkyl" means that one or more hydrogen atoms of the alkyl group (up to the maximum number of hydrogen atoms bonded to the alkyl group, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, e.g., 1-5, 1-4, or 1-3, or 1-2) are substituted with a substituent other than hydrogen (if two or more hydrogen atoms are substituted, the substituents may be the same or different). Preferably, the substituent other than hydrogen is a first-level substituent, second-level substituent, or third-level substituent as specified herein, such as a halogen, -OH, -NH2, -NHCH3, -N(CH3)2, -CN, -OCH3, -OCF3, or an aryl which may be optionally substituted. Examples of substituted alkyls include: trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trichloroethyl, 2-hydroxyethyl, 2-aminoethyl, 2-(dimethylamino)ethyl, arylalkyl (also called "aralkyl," e.g., benzyl, chloro(phenyl)methyl, 4-methylphenylmethyl, (2,4-dimethylphenyl)methyl, o-fluorophenylmethyl, 2-phenylpropyl, 2-, 3-, or 4-carboxyphenylalkyl), or heteroarylalkyl (also called "heteroaralkyl").

[0097] The term "alkylene" refers to a diradical of a saturated straight-chain or branched-chain hydrocarbon. Preferably, the alkylene contains 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, for example, 1 to 6 or 1 to 4 carbon atoms.Examples of alkylene groups include: methylene, ethylene (e.g., 1,1-ethylene, 1,2-ethylene), propylene (e.g., 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-iso-butylene, 1,2-iso-butylene, and 1,3-iso-butylene), pentylene isomers (e.g., 1,1-pentylene, 1,2-pentylene, 1,3-pentylene, 1,4-pentylene, 1,5-pentylene, 1,1-iso-pentylene, 1,1-sec-pentyl, 1,1-neo-pentyl), hexylene isomers (e.g., 1,1-hexylene, 1,2-hexylene, 1,3-hexylene, 1,4-hexylene, 1,5-hexylene, 1,6-hexylene, and 1,1-isohexylene), heptylene isomers (e.g., 1,1-heptylene, 1,2-heptylene, 1,3-heptylene, 1,4-heptylene, 1,5-heptylene, 1,6-heptylene, 1,7-heptylene, and 1,1-isoheptylene), octylene isomers (e.g., 1,1-octylene, 1,2-octylene, 1,3-octylene, 1,4-octylene, 1,5-octylene, 1,6-octylene, 1,7-octylene, (1,8-octylene, and 1,1-isooctylene), etc. A linear alkylene moiety having at least three carbon atoms and free valence at each end may also be designated as a multiple of methylene (for example, 1,4-butylene may also be called tetramethylene). In general, instead of using the terminal "ylene" for the alkylene moieties specified above, the terminal "diyl" may also be used (for example, 1,2-butylene may also be called butane-1,2-diyl). A "substituted alkylene" means that one or more hydrogen atoms of the alkylene group (for example, up to the maximum number of hydrogen atoms bonded to the alkylene group, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, e.g., 1-5, 1-4, or 1-3, or 1-2) are substituted with a substituent other than hydrogen (if two or more hydrogen atoms are substituted, the substituents may be the same or different). Preferably, the substituents other than hydrogen are first-level substituents, second-level substituents, or third-level substituents as specified herein, such as halogens or optionally substituted aryls. Examples of substituted alkylenes include chloromethylene, dichloromethylene, fluoromethylene, and difluoromethylene.

[0098] The term "alkenyl" refers to a monoradical of an unsaturated straight-chain or branched-chain hydrocarbon having at least one carbon-carbon double bond. Generally, the maximum number of carbon-carbon double bonds in the alkenyl group can be equal to an integer calculated by dividing the number of carbon atoms in the alkenyl group by 2, and if the number of carbon atoms in the alkenyl group is uneven, 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, e.g., 2 to 6 carbon atoms or 2 to 4 carbon atoms. Therefore, in a preferred embodiment, the alkenyl group contains 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 2 to 8 carbon atoms and 1, 2, 3, or 4 carbon-carbon double bonds (e.g., 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 bond may be in a cis (Z) or trans (E) configuration. Exemplary alkenyl groups include: ethen-1,2-diyl, vinylidene (also called ethenylidene), 1-propen-1,2-diyl, 1-propen-1,3-diyl, 1-propen-2,3-diyl, allylidene, 1-buten-1,2-diyl, 1-buten-1,3-diyl, 1-buten-1,4-diyl, 1-buten-2,3-diyl, 1-buten-2,4-diyl, 1-buten-3,4-diyl, 2-buten-1,2-diyl, 2-buten-1,3-diyl, 2-buten-1,4-diyl, 2-buten-2,3-diyl, 2-buten-2,4-diyl, 2-buten-3,4-diyl, etc. When an alkenyl group is bonded to a nitrogen atom, the double bond cannot be α relative to the nitrogen atom. "Substituted alkenyl" means that one or more hydrogen atoms of the alkenyl group (for example, one per the maximum number of hydrogen atoms bonded to the alkenyl group, e.g., up to 10, e.g., 1-5, 1-4, or 1-3, or 1 or 2) are substituted with a substituent other than hydrogen (if two or more hydrogen atoms are substituted, the substituents may be the same or different). Preferably, the substituent other than hydrogen is a first-level substituent, second-level substituent, or third-level substituent as specified herein, such as a halogen or an aryl which can be optionally substituted. A specific example of a substituted alkenyl is styryl (i.e., 2-phenylvinyl).

[0099] The term "alkenylene" refers to a diradical of an unsaturated straight-chain or branched-chain hydrocarbon having at least one carbon-carbon double bond. Generally, the maximum number of carbon-carbon double bonds in an alkenylene group can be equal to an integer calculated by dividing the number of carbon atoms in the alkenylene group by 2, and if the number of carbon atoms in the alkenylene group is non-uniform, the result of the division is rounded to the next integer. For example, for an alkenylene group having 9 carbon atoms, the maximum number of carbon-carbon double bonds is 4. Preferably, the alkenylene 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 alkenylene 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, e.g., 2 to 6 carbon atoms or 2 to 4 carbon atoms. Therefore, in a preferred embodiment, the alkenylene group contains 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 2 to 8 carbon atoms and 1, 2, 3, or 4 carbon-carbon double bonds (e.g., 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 bond may be in a cis (Z) or trans (E) configuration. Exemplary alkenylene groups include: ethen-1,2-diyl, vinylidene (also called ethenylidene), 1-propen-1,2-diyl, 1-propen-1,3-diyl, 1-propen-2,3-diyl, allylidene, 1-buten-1,2-diyl, 1-buten-1,3-diyl, 1-buten-1,4-diyl, 1-buten-2,3-diyl, 1-buten-2,4-diyl, 1-buten-3,4-diyl, 2-buten-1,2-diyl, 2-buten-1,3-diyl, 2-buten-1,4-diyl, 2-buten-2,3-diyl, 2-buten-2,4-diyl, 2-buten-3,4-diyl, etc. When an alkenylene group is bonded to a nitrogen atom, the double bond cannot be α relative to the nitrogen atom. "Substituted alkenylene" means that one or more hydrogen atoms of the alkenylene group (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, e.g., 1-5, 1-4, or 1-3, or 1-2) are substituted with a substituent other than hydrogen (if two or more hydrogen atoms are substituted, the substituents may be the same or different). Preferably, the substituent other than hydrogen is a first-level substituent, second-level substituent, or third-level substituent as specified herein, such as a halogen or an aryl which can be optionally substituted. Specific examples of substituted alkenylenes are 1-phenylethylene-1,2-diyl and 2-phenylethylene-1,2-diyl.

[0100] The term "alkynyl" refers to a monoradical of an unsaturated linear or branched hydrocarbon having at least one carbon-carbon triple bond. Generally, the maximum number of carbon-carbon triple bonds in the alkynyl group can be equal to an integer calculated by dividing the number of carbon atoms in the alkynyl group by 2, and if the number of carbon atoms in the alkynyl group is non-uniform, the result of the division is rounded to the next integer. For example, for an alkynyl group having 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), i.e., 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 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.Specific examples of alkynyl groups include: ethynyl, 1-propynyl, 2-propynyl, 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-heptynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 5-heptynyl, 6-heptynyl, 1-octynyl, 2-octynyl, 3-octynyl, 4-octynyl, 5-octynyl, 6-octynyl, 7-octynyl, 1-nonylyl, 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. When an alkynyl group is bonded to a nitrogen atom, the triple bond cannot be α relative to the nitrogen atom. "Substituted alkynyl" means that one or more hydrogen atoms of the alkynyl group (for example, up to the maximum number of hydrogen atoms bonded to the alkynyl group, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, e.g., 1-5, 1-4, or 1-3, or 1-2) are substituted with a substituent other than hydrogen (if two or more hydrogen atoms are substituted, the substituents may be the same or different). Preferably, the substituent other than hydrogen is a first-level substituent, second-level substituent, or third-level substituent as specified herein, such as a halogen or an aryl which can be optionally substituted.

[0101] The term "alkynylene" refers to a diradical of an unsaturated linear or branched hydrocarbon having at least one carbon-carbon triple bond. Generally, the maximum number of carbon-carbon triple bonds in an alkynylene group can be equal to an integer calculated by dividing the number of carbon atoms in the alkynylene group by 2, and if the number of carbon atoms in the alkynylene group is non-uniform, the result of the division is rounded to the next integer. For example, for an alkynylene group having 9 carbon atoms, the maximum number of carbon-carbon triple bonds is 4. Preferably, the alkynylene group has 1 to 6 (e.g., 1 to 4), i.e., 1, 2, 3, 4, 5, or 6 (e.g., 1, 2, 3, or 4), more preferably 1 or 2 carbon-carbon triple bonds. Preferably, the alkynylene 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 alkynylene group contains 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 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. Specific examples of alkynylene groups include: ethyn-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. When an alkylylene group is bonded to a nitrogen atom, the triple bond cannot be α relative to the nitrogen atom. "Substituted alkylylene" means that one or more hydrogen atoms of the alkylylene group (for example, up to 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, the maximum number of hydrogen atoms bonded to the alkylylene group, e.g., 1 to 5, 1 to 4, or 1 to 3, or 1 to 2) are substituted with a substituent other than hydrogen (if more than one hydrogen atom is substituted, the substituents may be the same or different). Preferably, the substituent other than hydrogen is a halogen or an aryl which can be optionally substituted, as specified herein, a first-level substituent, a second-level substituent, or a third-level substituent.

[0102] The terms "aryl" or "aromatic ring" refer to monoradicals of aromatic cyclic hydrocarbons. Preferably, the aryl group contains 3 to 14 (e.g., 5, 6, 7, 8, 9, or 10, e.g., 5, 6, or 10) carbon atoms that can be arranged in one ring (e.g., phenyl) or two or more fused rings (e.g., naphthyl). Exemplary aryl groups include cyclopropenilium, cyclopentadienyl, phenyl, indenyl, naphthyl, azlenyl, fluorenyl, anthryl, and phenanthryl. Preferably, "aryl" refers to a monocyclic system containing 6 carbon atoms or an aromatic bicyclic system containing 10 carbon atoms. Preferred examples are phenyl and naphthyl. The term aryl does not include fullerenes. "Substituting aryl" means that one or more hydrogen atoms of the aryl group (up to the maximum number of hydrogen atoms bonded to the aryl group, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, e.g., 1-5, 1-4, or 1-3, or 1-2) are substituted with a substituent other than hydrogen (if two or more hydrogen atoms are substituted, the substituents may be the same or different). Preferably, the substituent other than hydrogen is a first-level substituent, a second-level substituent, or a third-level substituent, such as halogens, -CN, Nitro, -OR as specified herein. 11 (For example, -OH), -SR 11(For example, -SH), -N(R 12 )(R 13 ) (e.g., -NH2), alkyl (e.g., C 1-6 alkyl), alkenyl (e.g., C 2-6 alkenyl), and alkynyl (e.g., C 2-6 alkynyl) is a substituted aryl group, and includes: biphenyl, 2-fluorophenyl, 2-chloro-6-methylphenyl, anilinyl, 3-nitrophenyl, 4-hydroxyphenyl, methoxyphenyl (e.g., 2-, 3-, or 4-methoxyphenyl), and 4-ethoxyphenyl, etc.

[0103] The terms “heteroaryl” or “heteroaromatic cyclic” refer to the aryl group as defined above, in which one or more carbon atoms in the aryl group are substituted with heteroatoms (such as O, S, or N). Preferably, the heteroaryl is a 5- or 6-membered aromatic monocycle in which one, two, or three carbon atoms are substituted with the same or different heteroatoms of O, N, or S. Alternatively, it refers to an aromatic bicyclic or tricyclic system in which one, two, three, four, or five carbon atoms are substituted with the same or different heteroatoms of O, N, or S. Preferably, in each ring of the heteroaryl group, 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 ring heteroaryls include: monocyclic heteroaryl (e.g., 5- or 6-membered rings), bicyclic heteroaryl (e.g., 9- or 10-membered rings), and tricyclic heteroaryl (e.g., 13- or 14-membered rings). Examples of heteroaryl groups include: furanyl, thienyl, 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 called pyridinyl), pyrimidinyl, pyrazinyl, triazinyl (1,2,3-, 1,2,4-, and 1,3-)5-) benzofuranyl (1- and 2-), indolyl, isoindolyl, benzothienyl (1- and 2-), 1H-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, benzodiazinyl, quinoxalinyl, quinazolinyl, benzotriazinyl (1,2,3- and 1,2,4-benzotriazinyl), pyridazinyl, phenoxazinyl, thiazolopyridinyl, pyrrolothiazolyl, phenothiazinyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathiinyl, pyrrolizinyl, indolizinyl, indazolyl, purinyl, quinolizinyl, phthalazinyl, naphthyridinyl (1,5-, 1,6-, 1,7-, 1,8-, and 2,6-), cinnolinyl, pteridinyl, carbazolyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl (1,7-, 1,8-, 1,10-, 3,8-, and 4,7-), phenazinyl, oxazolopyridinyl, isoxazolopyridinyl, pyrrolooxazolyl, and pyrrolopyrrolyl. Examples of 5- or 6-membered heteroaryl include: furanyl, thienyl, oxazolyl, isoxazolyl, oxadiazolyl (1,2,5- and 1,2,3-), pyrrolyl, 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. "Substituting heteroaryl" means that one or more hydrogen atoms of a heteroaryl group (for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, for example, 1-5, 1-4, or 1-3, or 1-2) are substituted with a substituent other than hydrogen (if two or more hydrogen atoms are substituted, the substituents may be the same or different). Preferably, the substituent other than hydrogen is a first-level substituent, a second-level substituent, or a third-level substituent, such as a halogen, -CN, Nitro, or -OR as specified herein. 11 (For example, -OH), -SR 11 (For example, -SH), -N(R 12 )(R 13 ) (e.g., -NH2), alkyl (e.g., C 1-6 alkyl), alkenyl (e.g., C 2-6 alkenyl), and alkynyl (e.g., C 2-6 alkynyl) is a specific example of a substituted heteroaryl. Specific examples of substituted heteroaryls are: 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-methyl-thien-3-yl, 1,3,5-trimethylpyrazol-4-yl, 3,5-dimethyl-1,2-dioxazol-4-yl, 1,2,4-trimethylpyrrol-3-yl, 3-phenylpyrrolyl, 2,3'-bifuryl, 4-methylpyridyl, 2- or 3-ethylindolyl.

[0104] The terms “cycloalkyl” or “alicyclic” preferably refer to cyclic non-aromatic versions of “alkyl” and “alkenyl” having 3 to 14 carbon atoms, for example 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 (for example 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms), more preferably 3 to 7 carbon atoms. Examples of cycloalkyl groups include: cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, cyclononyl, cyclononenyl, cylcodecyl, cylcodecenyl, and adamantyl. The term "cycloalkyl" also means that it includes its bicyclic and tricyclic versions. When bicyclic rings are formed, it is preferable that each ring is linked to one another by two adjacent carbon atoms; alternatively, the two rings may be linked via the same carbon atom, i.e., they form a spirocyclic system or a "bridged" ring system. Examples of suitable cycloalkyls include: C 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 include fullerenes. "Substituted cycloalkyl" means that one or more hydrogen atoms of a cycloalkyl group (for example, up to the maximum number of hydrogen atoms bonded to the cycloalkyl group, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, e.g., 1-5, 1-4, or 1-3, or 1-2) are substituted with a substituent other than hydrogen (if one or more hydrogen atoms are substituted, the substituents may be the same or different). Preferably, the substituent other than hydrogen is a first-level substituent, a second-level substituent, or a third-level substituent, such as halogens, -CN, Nitro, or -OR as specified herein. 11 (For example, -OH), -SR 11 (For example, -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., C 2-6 alkenyl), and alkynyl (e.g., C 2-6 It is alkynyl. Specific examples of substituted cycloalkyls are: oxocyclohexyl, oxocyclopentyl, fluorocyclohexyl, and oxocyclohexenyl.

[0105] The terms “heterocyclyl” or “heterocyclic” mean the cycloalkyl group as defined above, in which one, two, three, or four ring carbon atoms in the cycloalkyl group are substituted with heteroatoms (selected from the group consisting of O, S, S(O), S(O)2, N, B, Si, and P, preferably selected from the group consisting of O, S, S(O)2, and N). If the ring of the heterocyclyl group contains only one type of heteroatom, the maximum number of such heteroatoms in the ring of the heterocyclyl group may be as follows: 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 the ring of the heterocyclyl group contains two or more heteroatoms, the maximum number of heteroatoms in the ring of the heterocyclyl group may 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 (where the maximum total number of heteroatoms in the ring of the heterocyclyl group is 4, and the maximum total number of each heteroatom in the ring of the heterocyclyl group 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 heterocyclyl group are selected from the group consisting of O, S, and N. In this embodiment, preferably, in each ring of the heterocyclyl group, 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 heterocyclyl rings include monocyclic heterocyclyl rings (e.g., 3, 4, 5, 6, or 7 members, preferably 4- to 7 members), bicyclic heterocyclyl rings (e.g., 8, 9, or 10 members), and tricyclic heterocyclyl rings (e.g., 12, 13, or 14 members). If the heterocyclyl group contains two or more rings, these rings are either fused (e.g., in quinolinyl or prynyl), spiro moieties, bridging structures, linked via double bonds, or a combination thereof. In other words, an unsubstituted heterocyclyl group does not include two heterocyclyl groups linked via single bonds. The term "heterocyclyl" also means that the above heteroaryl groups are partially or completely hydrogenated (e.g., dihydro, tetrahydro, hexahydro, octahydro, decahydro, dodecahydro, etc., or perhydro forms). Examples of heterocyclyl groups are: azetidinyl, morpholino, isochromanyl, chromanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, indolinyl, isoindolinyl, triazininanyl (1,2,3-, 1,2,4-, and 1,3,5-), di- and tetrahydrofuranyl, di- and tetrahydrothienyl, di- and tetrahydrooxazolyl, di- and tetrahydroisoxazolyl, di- and tetrahydrooxadiazolyl (1,2,5- and 1,2,3-), dihydropyrrolyl, dihydroimidazolyl, dihydropyrazolyl, di- and tetrahydrotriazolyl (1,2,3- and 1,24-), di- and tetrahydrothiazolyl, di- and tetrahydrothiazolyl, di- and tetrahydrothiadiazolyl (1,2,3- and 1,2,5-), 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 octahydrobenzothienyl (1- and 2), di-, tetra-, hexa- and octahydro-1H-indazolyl, di-, tetra-, hexa- and octahydrobenzimidazolyl, di-, tetra-, hexa- and octahydrobenzoxazolyl, di-, tetra-, hexa- and octahydroindoxazinyl, di-, tetra-, hexa- and octahydrobenzisoxazolyl, di-, tetra-, hexa- and octahydrobenzothiazolyl, di-, tetra-, hexa- and octahydrobenzisothiazolyl, di-, tetra-, hexa- and octahydrobenzotriazolyl, di-, tetra-, hexa-, octa- and decahydroquinolinyl, di-, tetra-, hexa-, octa- and decahydroisoquinolinyl, di-, tetra-, hexa-, octa- and decahydrobenzodiazinyl, di-, tetra-, hexa-, octa- and decahydroquinoxalinyl, di-, tetra-, hexa-, octa- and decahydroquinazolinyl, di-, tetra-, hexa-, octa- and decahydrobenzotriazinyl (1,2,3- and 1,2,4-), di-, tetra-, and hexahydropyridazinyl, di-, tetra-, hexa-, octa-, deca-, and dodecahydrophenoxazinyl, di-, tetra-, hexa-, and octahydrothiazolopyridinyl (e.g., 4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridinyl or 4,5,6,7-tetrahydro[1,3]thiazolo[4,5-c]pyridinyl, e.g., 4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl or 4,5,6,7-tetrahydro[1,3]thiazolo[4,5-c]pyridin-2-yl), di-, tetra-, and hexahydropyrrolothiazolyl, di-, tetra-, hexa-, octa-, and decahydrophenothiazinyl, di-, tetra-, hexa-, and octahydroisobenzofuranyl, di-, tetra-, hexa-, and octahydrochromenyl, di-, tetra-, hexa-, octa-, deca-, and dodecahydroxanthenyl, di-, tetra-, hexa-, octa-, deca-, and dodecahydrophenoxathiinyl, di-, tetra-, and hexahydropyrrolizinyl, di-, tetra-, hexa-, and octahydroindolizinyl, di-, tetra-, hexa-, and octahydroindazolyl, di-, tetra-, hexa-, and octahydropurinyl, di-, tetra-, hexa-, and octahydroquinolizinyl, di-, tetra-, hexa-, octa-, and decahydrophthalazinyl, di-, tetra-, hexa-, octa-, and decahydronaphthyridinyl (1,5-, 1,6-, 1,7-, 1,8-, and 2,6-), di-, tetra-, hexa-, octa- and decahydrocinnolinyl, di-, tetra-, hexa-, octa-, and decahydropteridinyl, di-, tetra-, hexa-, octa-, deca- and dodecahydrocarbazolyl, di-, tetra-, hexa-, octa-, deca-, dodeca-, and tetradecahydrophenanthridinyl, di-, tetra-, hexa-, octa-, deca-, dodeca-, and tetradecahydroacridinyl, di-, tetra-, hexa-, octa-, deca- and dodecahydroperimidinyl, di-, tetra-, hexa-, octa-, deca-, dodeca-, and tetradecahydrophenanthrolinyl (1,7-, 1,8-, 1,10-, 3,8-, and 4,7-), di-, tetra-, hexa-, octa-, deca-, dodeca-, and tetradecahydrophenazinyl, di-, tetra-, hexa- and octahydrooxazolopyridinyl, di-, tetra-, hexa- and octahydroisoxazolopyridinyl, di-, tetra-, hexa- and octahydrocyclopentapyrrolyl, di-, tetra-, hexa- and octahydrocyclopentpyrazolyl, di-, tetra-, hexa- and octahydrocyclopentaimidazolyl, di-, tetra-, hexa- and octahydrocyclopentathiazolyl, di-, tetra-, hexa- and octahydrocyclopentaoxazolyl, di-, tetra-, hexa- and octahydropyrrolopyrrolyl, di-, tetra-, hexa- and octahydropyrrolopyrazolyl, di-, tetra-, hexa- and octahydropyrroloimidazolyl, di-, tetra-, hexa- and octahydropyrrolothiazolyl (5,6-dihydro-4H-pyrrolo[3,4-d][1,3) thiazolyl is an example), di-, tetra-, hexa- and octahydropyrrolooxazolyl, di-, tetra-, hexa- and octahydropyrazolopyrazolyl, di-, tetra-, hexa- and octahydropyrazoloimidazolyl, di-, tetra-, hexa- and octahydropyrazolothiazolyl, di-, tetra-, hexa- and octahydropyrazolooxazolyl, di-, tetra-, hexa- and octahydroimidazoimidazolyl, di-, tetra-, hexa- and octahydroimidazothiazolyl, di-, tetra-, hexa- and octahydroimidazooxazolyl, di-, tetra-, hexa- and octahydrothiazolothiazolyl, di-, tetra-, hexa- and octahydrothiazolooxazolyl, and di-, tetra-, hexa- and octahydrooxazolooxazolyl. Examples of 5- or 6-membered heterocyclyl groups include: morpholino, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, di- and tetrahydrofuranyl, di- and tetrahydrothienyl, di- and tetrahydrooxazolyl, di- and tetrahydroisoxazolyl, di- and tetrahydrooxadiazolyl (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 tetrahydroisothiazolyl, di- and tetrahydrothiadiazolyl (1,2,3- and 1,2,5-), di- and tetrahydropyridyl, di-, tetra-, and hexahydropyrimidinyl, di- and tetrahydropyrazinyl, di- and tetrahydrotriazinyl (1,2,3-, 1,2,4-, and 1,3,5-), and triazinanyl (1,2,3-, 1,2,4-, and 1,3,5-). "Substituted heterocyclyl" means that one or more hydrogen atoms of the heterocyclyl group (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, e.g., 1-5, 1-4, or 1-3, or 1-2) are substituted with a substituent other than hydrogen (if two or more hydrogen atoms are substituted, the substituents may be the same or different). Preferably, the substituent other than hydrogen is a first-level substituent, a second-level substituent, or a third-level substituent, such as halogens, -CN, Nitro, or -OR as specified herein. 11 (For example, -OH), -SR 11 (For example, -SH), -N(R 12 )(R13 ) (e.g., -NH2), =X (e.g., =O, =S, or =NH), alkyl (e.g., C 1-6 alkyl), alkenyl (e.g., C 2-6 alkenyl), and alkynyl (e.g., C 2-6 It is alkynyl.

[0106] As used herein, the expression “partially hydrogenated form” of an unsaturated compound or group means that some of the unsaturation has been removed by formally adding hydrogen to the unsaturated compound or group first, without removing all of the unsaturation. The phrase “fully hydrogenated form” of an unsaturated compound or group is used herein interchangeably with the term “perhydro” and means that all of the unsaturation has been removed by formally adding hydrogen to the unsaturated compound or group first. For example, a partially hydrogenated five-membered ring heteroaryl group (such as furan, which contains two double bonds in the ring) includes the dihydro form of the five-membered ring heteroaryl group (such as 2,3-dihydrofuran or 2,5-dihydrofuran), while the tetrahydro form of the five-membered ring heteroaryl group (e.g., tetrahydrofuran, i.e., THF) is the fully hydrogenated (or perhydro) form of the five-membered ring heteroaryl group. Similarly, for six-membered heteroaryl groups having three double bonds within the ring (such as pyridyl), the partially hydrogenated forms include the di and tetrahydro forms (such as di and tetrahydropyridyl), while the hexahydro form (such as piperidinyl in the case of heteroarylpyridyl) is a fully hydrogenated (or perhydro) derivative of the aforementioned six-membered heteroaryl group. As a result, the hexahydro form of an aryl or heteroaryl can be considered a partially hydrogenated form according to the present invention only if the aryl or heteroaryl contains at least four unsaturated moieties consisting of double and triple bonds between ring atoms.

[0107] The term "aromatic" as used in the context of hydrocarbons means that the entire molecule must be aromatic. For example, when a monocyclic aryl is hydrogenated (either partially or completely), the resulting hydrogenated cyclic structure is classified as a cycloalkyl for the purposes of this invention. Similarly, when a bicyclic or polycyclic aryl (e.g., naphthyl) is hydrogenated, the resulting hydrogenated bicyclic or polycyclic structure (e.g., 1,2-dihydronaphthyl) is classified as a cycloalkyl for the purposes of this invention (even if one ring remains aromatic, as in 1,2-dihydronaphthyl). A similar distinction is made between heteroaryls and heterocyclyls in this application. For example, indolinyl, i.e., a dihydro variant of indolyl, is classified as a heterocyclyl for the purposes of this invention because only one ring of the bicyclic structure is aromatic, and one of the cyclic atoms is a heteroatom.

[0108] As used herein, the term “polycyclic” means that a structure has two or more rings (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10), preferably 2, 3, 4, or 5, more preferably 2, 3, or 4. Accordingly, according to the present invention, the term “polycyclic” does not include monocyclic structures in which the structure contains only one ring. Examples of polycyclic groups include condensed structures (e.g., naphthyl or anthryl), spiro compounds, rings linked via single or double bonds (e.g., biphenyl), and crosslinked structures (e.g., bornyl). Exemplary polycyclic structures are the aryl, heteroaryl, cycloalkyl, and heterocyclyl groups specified above, having at least two rings.

[0109] The term "halogen" or "halo" or "hal" means fluoro, chloro, bromo, or iodine.

[0110] The term "azid" means -N3.

[0111] The term "N-oxide" refers to the functional group (R n )3N + -O- This means an amine oxide or amine-N-oxide, which is a compound containing an NO-coordinate covalent bond, where R n R is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl and heterocyclyl, where each of the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl and heterocyclyl groups is independently selected. 30 Preferably, R is a first-level substituent, a second-level substituent, or a third-level substituent as specified herein. 30 One or more of these (such as 1 to the maximum number of hydrogen atoms bonded to an alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl group, for example, 1 to 5, 1 to 4, or between 1 and 3, or 1 or 2, up to a maximum of 10, such as 1, 2, 3, 4, 5, 6, 7, 8, 9) can be optionally substituted.

[0112] As used herein, the term “carboxylic acid” refers to a compound containing at least one carboxyl group (-COOH) or thiocarboxyl group (-CSOH) [preferably a compound containing at least one carboxyl group (-COOH), and in the context of Examples 1.1 and 1.2, only a compound containing at least one carboxyl group (-COOH)]. As used herein, the term “corresponding carboxylic acid” refers to a (thio)carboxylic acid, which, when reacted with further compounds (e.g., intermediates, e.g., intermediates of the present invention), yields the desired compound (e.g., a compound having an amide or thioamide bond). For example, if it is desired to prepare the compound of formula (Ia) using the intermediate of formula (Id), the corresponding acid may have the following formula (Ie): [ka] In the formula, Hy, R 2 , R 3A and E are as defined herein (in particular with respect to formulas (Ia), (IIIa), (IVa), (Va), (VIa), (VIIa) and / or (VIIIa)). For example, if it is desired to prepare a compound of formula (Ia) where E is S, it is preferable to use the intermediate of formula (Id), and the corresponding acid may have the above formula (Ie) where E is S. In another embodiment, if it is desired to prepare a compound of formula (Ia) where E is O, it is preferable to use the intermediate of formula (Id), and the corresponding acid may have the above formula (Ie) where E is O.

[0113] The term “impurity” as used herein means any foreign substance (in particular a chemical substance) that may be present in a composition containing the desired compound (e.g., the compounds described herein, a composition containing such a compound of formula (Ia)). Impurities may be naturally occurring, added during the synthesis and / or purification of the desired compound, or 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 decomposition products of the aforementioned compounds or the desired compound, one or more residues of protecting groups after deprotection, and combinations thereof.

[0114] "R 7 At least one of them is F, and / or R 7 The expression "at least one of is substituted with one or more F atoms" (and similar expressions) is R 6This means that the molecule is substituted with a portion having (i) at least one F atom and / or (ii) one or more F atoms (e.g., up to 1-2, 3, 4, 5, 6, 7, 8, 9, or 10, e.g., 1-5, 1-4, or 1-3, or 1 or 2). An exemplary portion having one or more F atoms includes one or more F atoms (e.g., up to 1-2, 3, 4, 5, 6, 7, 8, 9, or 10, e.g., 1-5, 1-4, or 1-3, or 1 or 2 or 3), for example, an alkyl group having three -CH2F, -CHF2, or -CF atoms. Further exemplary molars having one or more F atoms include F-substituted alkoxy groups [i.e., -O(C 1-3 -O(alkyl) or F-substituted alkylamino groups [i.e., -NH(alkyl) or -N(alkyl)2, for example, -NH(C 1-3 Alkyl) or -N(C 1-3 Alkyl)2) is included, where the alkyl (for example, C) of the alkoxy and monoalkylamino groups. 1-3 The alkyl) portion and the alkyl (for example, C) of the dialkylamino group 1-3 At least one of the alkyl moieties is substituted with one or more fluorine atoms (for example, one for the maximum number of hydrogen atoms bonded to the alkyl moiety, e.g., up to 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or up to 7, e.g., 1-5, 1-4, or 1-3, or 2 or 3).

[0115] As described elsewhere in this specification, formula (Ic) R 5" -LR 6" And R 6" is a heteroaryl or heterocyclyl, each of which is one or more independently selected R 7' It may be optionally substituted with. In connection with this, the term "R" used herein 6" Any two R atoms bonded to the same atom 7' The expression " is R 6"When substitution occurs with a total of two hydrogen atoms bonded to only one ring atom, two monoradicals (i.e., R) 7' This means that it can form a diradical = O. For example, according to the present invention, [ka] R 6" (Here, the dashed line is R 6" (1)R represents a bond that attaches to the rest of the compound. 7' Each of the groups may be a monoradical independently selected from the specific moieties identified herein (e.g., methyl or Cl), as well as (2)R 6" Any two R atoms bonded to the same atom 7' It also includes the possibility of the elements bonding with each other, and that is, formula [ka] tr R 6'' It forms the basic diradical =O. Here, the remaining R 7' The base is a monoradical. Similarly, R 6'' There are 4 R 7' If it is a 3-tetrahydrothienyl substituted with such substitution R 6'' This includes the following formulas, etc.: [ka] . As used herein, "any two R groups bonded to the same carbon atom of a cycloalkyl or heterocyclyl group" 30 These are combined together, =X 1 Similar terms such as "may form" should be interpreted in a similar manner. In this regard, R 6'' Any two R atoms bonded to the same atom 7' However, in embodiments where they can be combined to form =O, the premise is (i.e., =O without modification)R 6'must be a complex ring (because in a complex aromatic ring, there is no carbocyclic atom with two free valences). Similarly, when any two Rs bonded to the same atom of a moiety can combine together to form =X1, this moiety must be an alicyclic or complex ring in the premise (i.e., =X1 without modification) [because in a (hetero)aromatic ring, there is no carbocyclic atom with two free valences]. 30 When any two Rs bonded to the same atom of a moiety can combine together to form =X1, this moiety must be an alicyclic or complex ring in the premise (i.e., =X1 without modification) [because in a (hetero)aromatic ring, there is no carbocyclic atom with two free valences].

[0116] "One R 7' group is bonded to the ring atom to which R 6' is bonded to the rest of the compound, and the R 6' at the 2-position of this ring atom" (and similar expressions), when used in this specification, means that at least one of the two ring atoms directly adjacent to the ring atom to which R 6' is bonded to the rest of the compound has one R 7' group. In other words, for the ring atom to which R 6' is bonded to the rest of the compound (i.e., the "yl position" of R 6' ), at least one of the ortho positions of R 6 ' has an R 7' group. For example, when R 6' is 3-pyridyl substituted with one R 7' (therefore, the ring carbon at the 3-position relative to the ring nitrogen atom), applying the above formula, this R 7' group will be at the 2-position or 4-position of the 3-pyridyl group as shown in the following formula:

Chemical Structure

[0117] As used herein, the term “k-membered ring” means that the ring has k ring atoms. For example, the k of pyrazolyl is 5, and therefore, with respect to the ring atom (yl position) to which the pyrazolyl group is attached to the rest of the compound, the ortho positions are 2 and 5, and the k-1 position is 4. Furthermore, if pyridinyl is a 6-membered heteroaryl, then, with respect to the ring atom (yl position) to which the pyridinyl group is attached to the rest of the compound, the ortho positions are 2 and 6, and the k-1 position is 5.

[0118] R 6 However, regarding the fact that it is a 5-membered monocyclic heteroaryl containing at least one S ring atom, the expression "one R7 However, as a result, R 6 The ring atom to which the rest of the compound is bonded, and the C ring atom bonded at position 2 (and similar expressions), preferably one R 7 The basis is (i) thereby, R 6 (ii)R is directly adjacent to the ring atom bonded to the rest of the compound. 6 When numbering the ring atoms, the lower the number (for example, for the S ring atom, start with the number "1", and so on, R 6 The number of ring atoms bonded to the rest of the compound (i.e., R 6 The position of "il" (continues as low as possible) 6 This means that it is bonded to the C ring atom of R. In other words, 6 With respect to the yl position, R 6 The two C ring atoms at the "ortho" positions are preferably, when considering the shortest path between the S ring atom and the yl position, the S ring atom and the R 6 R between the yl position 7 It has a group. For example, R 6 However, one R 7 Applying the above expression to a 3-thienyl substituted with (therefore, the yl position is the ring carbon at position 3 relative to the S ring atom), this R 7 The group will be located at the 2-position of the 3-thienyl group, as shown in the following equation: [ka] In the formula, the dashed line indicates that R 6 This represents a bond that connects to the rest of the compound. Similarly, R 6 However, regarding the fact that it is a 5-membered monocyclic heteroaryl containing at least one S ring atom, the expression "one R 7 However, as a result, R6 is bonded to the ring atom of the rest of the compound, while R6 is bonded to the C ring atom at position 5 (and similar expressions), preferably one R 7 The basis is (i) thereby, R 6 (ii) R is directly adjacent to the ring atom bonded to the rest of the compound, and 6When numbering the ring atoms (for example, starting with number "1" for the S ring atom, R 6 The number of Ill positions follows as low as possible, and the higher the number R 6 This means that it is bonded to the C ring atom of R. In other words, R 6 With respect to the yl position, the C ring atom is preferably considered to have the shortest path between the S ring atom and the yl position, and R 6 Not lying between the yl position and R 7 It has a base. For example, the above formula ("Therefore, R 6 One R is attached to the C ring atom at position 5, relative to the ring atom bonded to the rest of the compound. 7 The group is bonded to R 6 is one R 7 When applied to the case of a 3-thienyl substituted with (and therefore the ring carbon at position 3 relative to the S ring atom), this R 7 The group is located at the 4th position of the 3-thienyl group, as shown in the following equation: [ka] In the formula, the dashed line indicates that R 6 This represents a bond that connects to the rest of the compound. Furthermore, R 6 However, regarding the fact that it is a 5-membered monocyclic heteroaryl containing at least one S ring atom, "one R 7 Therefore, R 6 The ring atom to which is bonded to the rest of the compound, and the C ring atom at position 2, one R 7 Therefore, R 6 The expression "bonded to the C ring atom at position 5" (and similar expressions) is preferred, thereby R 6 R is directly adjacent to the ring atom to which the rest of the compound is bonded. 6 Each of the two C ring atoms has one R 7 This means that they are combined. For example, as shown in the following equation, R 6 at least 2 R 7When it is a 3-thienyl substituted with a group (and therefore the ring carbon at position 3 relative to the S ring atom), the above formula ("therefore, R 6 For the ring atom bonded to the rest of the compound, one R is attached to the C ring atom at position 2. 7 They combine, and as a result, R 6 For the ring atom bonded to the rest of the compound, one R is attached to the C ring atom at position 5. 7 When you apply the term "they are joined", these R 7 The group will be located at positions 2 and 4 of the 3-thienyl group: [ka] In the formula, the dashed line indicates that R 6 This represents a bond that connects to the rest of the compound.

[0119] “The wavy line means that R 6 The expression “represents a bond that binds to the rest of the compound” is used herein to mean “therefore, R 6 This refers to a bond that is attached to the rest of the compound (i.e., (i) L when L is not a bond, or (ii) the carboxy(thio)amide group of formula (Ia), (Ib), or (Ic) - C(=E)N(R) when L is a bond). 4 (It bonds to any of the nitrogen atoms of the ) For example, R 6 but [ka] And when L is (i) methylene or (ii) a bond, the compound of formula (Ia) has the following structures (A1) and (A2), respectively: [ka] "The wavy line thereby represents a bond in which Hy attaches to the rest of the compound," or "The wavy line thereby represents a bond in which R 1a Similar wording, such as “represents a bond that connects to the rest of the compound,” should be interpreted in a similar manner when used herein.

[0120] As used herein (for example, R 1a In relation to the above, the term “asymmetric” preferably means that the moiety, in particular an asymmetric cycloalkyl or heterocyclyl group, is asymmetric with respect to its binding site to the rest of the compound (e.g., 1,4-oxazepan-4-yl) and / or has an asymmetric substitution pattern (e.g., 3-oxopiperazin-1-yl or 3-methylpiperazin-1-yl). For example, with respect to its binding site to the rest of the compound, a symmetric group has a plane of symmetry (as in 4-methylpiperazinyl), while an asymmetric group does not. An asymmetric group may have a chiral atom (e.g., a chiral C atom), such as 2-methylmorpholine-4-yl, but does not necessarily have a chiral atom (such as 3-oxopiperazin-1-yl). Exemplary asymmetric groups include: [ka] In the formula, R 30 And X are as defined herein, and the wavy line indicates a bond in which the asymmetric group is attached to the rest of the compound.

[0121] Certain asymmetric groups include: [ka] In the formula, R 30 And X are as defined herein, and the wavy line indicates a bond in which the asymmetric group is attached to the rest of the compound.

[0122] When used herein, the expression “adjacent ring atoms” preferably means that these two ring atoms share a common bond and are therefore directly bonded to each other, as in “the C ring atom and the S ring atom are adjacent ring atoms.” For example, in the structure shown below (i.e., at position 4, R 7In a 3-thienyl group substituted with , the C and S ring atoms at position 2 are adjacent ring atoms, while the C and S ring atoms at position 4 are separated by the C ring atom: [ka] Here, the wavy line indicates that R 6 This represents a bond that connects to the rest of the compound.

[0123] Similarly, as used herein, "R bonded to a C ring atom adjacent to an S ring atom" 40 The expression " is preferably R 40 This means that the C ring atom and S ring atom to which R is bonded are adjacent atoms. For example, in the structure shown below, R is bonded to the C ring atom adjacent to the S ring atom. 40 (Since this C ring atom is adjacent to the S ring atom) the R bonded to the C ring atom at position 2 40 On the other hand, R bonded to the C ring atom at position 4 40 This is an R bonded to a C ring atom that is separated 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 by the C ring atom (at position 5):) [ka]

[0124] The term "R" as used herein 6 The S ring atom is thereby R 6 The expression "not adjacent to the ring atom to which the rest of the compound is bonded" is preferably used for R 6 The S ring atom of R 6 The rest of the compound (i.e., R 6 This means that a ring atom is separated from a ring atom that is bonded to it by at least one ring atom (from its position). For example, R 6 is one R 7 If it is a thienyl that can be optionally substituted by "R 6 The S ring atom is thereby R 6The expression "not adjacent to the ring atom that is bonded to the rest of the compound" includes the following structures: [ka] However, excluding the following structures in particular: [ka] Here, the wavy line indicates that R 6 This represents a bond that connects to the rest of the compound.

[0125] According to IUPAC nomenclature, preferably, the numbering of substituted heterocyclyl groups begins with the ring heteroatom and continues to the fewest possible substituents. For example, the following compounds have the following numbering of the ring atom and the following names: [ka]

[0126] The phrase "may be optionally substituted, may be optionally substituted, may be optionally substituted" means that one or more hydrogen atoms (for example, between 1 and 5, 1 and 4, or 1 and 3, or between 1 and 2, etc., up to 10 groups, for example, 1 for the maximum number of hydrogen atoms bonded to 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10 groups) may be substituted by a group other than hydrogen (i.e., a first-level substituent) such as: [alkyl (preferably C 1~6 Alkyl), alkenyl (preferably C 2~6 Alkenyl), Alkinyl (preferably C 2~6 Alkynyl, aryl (preferably 6-14 membered aryl), heteroaryl (preferably 3-14 membered heteroaryl), cycloalkyl (preferably 3-14 membered cycloalkyl), heterocyclyl (preferably 3-14 membered heterocyclyl), halogen, -CN, azide, -NO2, -OR 71 , -N(R 72 )(R 73 ), -S(O) 0-2 R71 , -S(O) 1-2 Ure 71 , -OS(O) 1-2 R 71 , -OS(O) 1-2 Ure 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 Ure 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 first-level substituents bonded to the same carbon atom of a cycloalkyl or heterocyclyl group are bonded together, =X 1 This can form, where the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl substituent of the first level may itself be substituted by one or more substituents (e.g., one, two, or three) selected from the group below (i.e., a second level substituent): [C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, 6-14 member aryl, 3-14 member heteroaryl, 3-14 member cycloalkyl, 3-14 member heterocyclyl, halogen, -CF3, -CN, azide, -NO2, -OR 81, -N(R 82 )(R 83 ), -S(O) 0-2 R 81 , -S(O) 1-2 Ure 81 , -OS(O) 1-2 R 81 , -OS(O) 1-2 Ure 81 , -S(O) 1-2 N(R 82 )(R 83 ), -OS(O) 1-2 N(R 82 )(R 83 ), -N(R 81 )S(O) 1-2 R 81 , -NR 81 S(O) 1-2 Ure 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 second-level substituents bonded to the same carbon atom of the first-level substituent, a cycloalkyl or heterocyclyl group, = X 2 This can form a second-level substituent, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Each of the alkynyl, 6-14 member aryl, 3-14 member heteroaryl, 3-14 member cycloalkyl, and 3-14 member heterocyclyl may be optionally substituted with one or more substituents (i.e., tertiary substituents) selected from the group consisting of: [C 1~3Alkyl, halogen, -CF3, -CN, azide, -NO2, -OH, -O(C 1-3 Alkyl), -OCF3, -S(C 1-3 Alkyl), -NH2, -NH(C 1-3 Alkyl), -N(C 1-3 Alkyl)2, -NHS(O)2(C 1-3 Alkyl), -S(O)2NH 2-z (C 1-3 Alkyl) z -C(=O)OH, -C(=O)O(C 1-3 Alkyl), -C(=O)NH 2-z (C 1-3 Alkyl) z -NHC(=O)(C 1-3 Alkyl), -NHC(=NH)NH z-2 (C 1-3 Alkyl) z , and -N(C 1-3 Alkyl)C(=NH)NH 2-z (C 1-3 Alkyl) z ), Here, each z is independently 0, 1, or 2, and each C 1~3 Alkyl groups are independently methyl, ethyl, propyl, or isopropyl, and / or any two third-level substituents bonded to the same carbon atom of a 3- to 14-membered cycloalkyl or heterocyclyl group that are second-level substituents are bonded together to form =O, =S, =NH, or =N(C) 1~3 It can form alkyl groups; Here, R 71 , R 72 , and R 73 Each of these is H, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 A molecule independently selected from the group consisting of alkynyl, 3-7 membered cycloalkyl, 5- or 6- membered aryl, 5- or 6- membered heteroaryl, and 3-7 membered heterocyclyl, where C 1-6 Alkyl, C 2-6 Alkenil, C 2-6Each of the alkynyl, 3-7 membered cycloalkyl, 5- or 6- membered aryl, 5- or 6- membered heteroaryl, and 3-7 membered heterocyclyl groups is C 1-3 Alkyl, halogen, -CF3, -CN, azide, -NO2, -OH, -O(C 1-3 Alkyl), -OCF3, =O, -S(C 1-3 Alkyl), -NH2, -NH(C 1-3 Alkyl), -N(C 1-3 Alkyl)2, -NHS(O)2(C 1-3 Alkyl), -S(O)2NH 2-z (C 1-3 Alkyl) z -C(=O)(C 1-3 alkyl), -C(=O)OH, -C(=O)O(C 1-3 Alkyl), -C(=O)NH 2-z (C 1-3 Alkyl) z -NHC(=O)(C 1-3 Alkyl), -NHC(=NH)NH z-2 (C 1-3 Alkyl) z , and -N(C 1-3 Alkyl)C(=NH)NH 2-z (C 1-3 Alkyl) z One, two, or three substituents independently selected from the group consisting of , which may be optionally substituted, where each z is independently 0, 1, or 2, and each C 1~3 Alkyl compounds are independently methyl, ethyl, propyl, or isopropyl; R 81 , R 82 , and R 83 Each of these is H, C 1-4 Alkyl, C 2-4 Alkenil, C 2-4 A molecule independently selected from the group consisting of alkylyl, 3-6 membered cycloalkyl, 5- or 6- membered aryl, 5- or 6- membered heteroaryl, and 3- to 6- membered heterocyclyl, where C 1-4 Alkyl, C 2-4 Alkenil, C 2-4Each of the alkynyl, 3- to 6-membered cycloalkyl, 5- or 6-membered aryl, 5- or 6-membered heteroaryl, and 3- to 6-membered heterocyclyl groups is C 1-3 Alkyl, halogen, -CF3, -CN, azide, -NO2, -OH, -O(C 1-3 Alkyl), -OCF3, =O, -S(C 1-3 Alkyl), -NH2, -NH(C 1-3 Alkyl), -N(C 1-3 Alkyl)2, -NHS(O)2(C 1-3 Alkyl), -S(O)2NH 2-z (C 1-3 Alkyl) z -C(=O)(C 1-3 alkyl), -C(=O)OH, -C(=O)O(C 1-3 Alkyl), -C(=O)NH 2-z (C 1-3 Alkyl) z -NHC(=O)(C 1-3 Alkyl), -NHC(=NH)NH z-2 (C 1-3 Alkyl) z , and -N(C 1-3 Alkyl)C(=NH)NH 2-z (C 1-3 Alkyl) z The substituents may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of , where each z is independently 0, 1, or 2, and each C 1~3 Alkyl is independently methyl, ethyl, propyl, or isopropyl; and, X 1 and X 2 Each of these is independently O, S, and N(R) 84 ) will be selected from.

[0127] A typical first-level substituent is preferably C 1-4 Alkyl, C 2-4 Alkenil, C 2-4Alkynyl, 6-membered aryl, 5- or 6-membered heteroaryl, 3- to 7-membered cycloalkyl, 3- to 7-membered (such as 5- or 6-membered) heterocyclyl, halogen, -CF3, -CN, azide, -NO2, -OH, -O(C 1-3 Alkyl), -S(C 1-3 Alkyl), -NH2, -NH(C 1-3 Alkyl), -N(C 1-3 Alkyl)2,-NHS(O)2(C 1-3 Alkyl), -S(O)2NH 2-z (C 1-3 Alkyl) z -C(=O)OH, -C(=O)O(C 1-3 Alkyl), -C(=O)NH 2-z (C 1-3 Alkyl) z , -NHC(=O)(C 1-3 Alkyl), -NHC(=NH)NH z-2 (C 1-3 Alkyl) z , and -N(C 1-3 Alkyl)C(=NH)NH 2-z (C 1-3 Alkyl) z Like C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkynyl, 6-~14-membered (like 6-~10-membered) aryl, 3-~14-membered (like 5- or 6-membered) heteroaryl, 3-~14-membered (like 3-~7-membered) cycloalkyl, 3-~14-membered (like 3-~7-membered) heterocyclyl, halogen, -CN, azide, -NO2, -OR 71 , -N(R 72 )(R 73 ), -S(O) 0-2 R 71 , -S(O) 1-2 Ure 71 , -OS(O) 1-2 R 71 , -OS(O) 1-2 Ure 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 Ure 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 A group consisting of is selected, where each z is independently 0, 1, or 2, and each C 1-3 Alkyl is independently methyl, ethyl, propyl, or isopropyl; where X 1 Each R is independently selected from O, S, NH and N(CH3); and each R 71 , R 72 , and R 73 As defined above, or preferably H, C 1-4 Alkyl, C 2-4 Alkenil, C 2-4 A molecule is independently selected from the group consisting of alkynyl, 5- or 6-membered cycloalkyl, 5- or 6-membered aryl, 5- or 6-membered heteroaryl, and 5- or 6-membered heterocyclyl, where alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl are C 1-3 Alkyl, halogen, -CF3, -CN, azide, -NO2, -OH, -O(C 1-3 Alkyl), -S(C 1-3 Alkyl), -NH2, -NH(C 1-3 Alkyl), -N(C 1-3 Alkyl)2,-NHS(O)2(C 1-3 Alkyl), -S(O)2NH 2-z (C 1-3 Alkyl) z -C(=O)OH, -C(=O)O(C 1-3 Alkyl), -C(=O)NH 2-z (C1-3 Alkyl) z , -NHC(=O)(C 1-3 Alkyl), -NHC(=NH)NH z-2 (C 1-3 Alkyl) z , and -N(C 1-3 Alkyl)C(=NH)NH 2-z (C 1-3 Alkyl) z From the group consisting of, independently selected, 1, 2, or 3 substituents may be optionally substituted, where each z is independently 0, 1, or 2, and each C 1-3 Alkyl is independently methyl, ethyl, propyl, or isopropyl. Specific examples of first-level substituents are C 1-3 Alkyl, phenyl, imidazolyl, thiazolyl, cyclopentyl, cyclohexyl, dihydrothiazolyl, thiazolidinyl, halogen, -CF3, -CN, -OH, -O(C 1-3 Alkyl), -S(C 1-3 Alkyl), -NH2, -NH(C 1-3 Alkyl), -N(C 1-3 Alkyl)2,-NHS(O)2(C 1-3 Alkyl), -C(=O)OH, -C(=O)O(C 1-3 Alkyl), -C(=O)NH 2-z (C 1-3 Alkyl) z , -NHC(=O)(C 1-3 Alkyl), -NHC(=NH)NH z-2 (C 1-3 Alkyl) z , and -N(C 1-3 Alkyl)C(=NH)NH 2-z (C 1-3 Alkyl) z A group consisting of is independently selected, where 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 first-level substituents are C 1-3 Alkyl, phenyl, thiazolidinyl, halogen (such as F, Cl, or Br), -NH2, -NHS(O)2(C1-3 Alkyl), -NHC(=O)(C 1-3 Alkyl, and -NHC(=NH)NH z-2 (C 1-3 Alkyl) z From the group consisting of, independently selected, where z is independently 0, 1, or 2, and each C 1-3 Alkyl compounds are independently methyl, ethyl, propyl, or isopropyl.

[0128] A typical second-level substituent is preferably C 1-4 Alkyl, C 2-4 Alkenil, C 2-4 Alkynyl, 6- or 10-membered aryl, 5- or 6-membered heteroaryl, 5- or 6-membered cycloalkyl, 5- or 6-membered heterocyclyl, halogen, =O, =S, -CF3, -CN, azide, -NO2, -OH, -O(C 1-3 Alkyl), -S(C 1-3 Alkyl), -NH2, -NH(C 1-3 Alkyl), -N(C 1-3 Alkyl)2,-NHS(O)2(C 1-3 Alkyl), -S(O)2NH 2-z (C 1-3 Alkyl) z -C(=O)OH, -C(=O)O(C 1-3 Alkyl), -C(=O)NH 2-z (C 1-3 Alkyl) z , -NHC(=O)(C 1-3 Alkyl), -NHC(=NH)NH z-2 (C 1-3 Alkyl) z , and -N(C 1-3 Alkyl)C(=NH)NH 2-z (C 1-3 Alkyl) z A group consisting of is selected, where each z is independently 0, 1, or 2, and each C 1-3 Alkyl is independently methyl, ethyl, propyl, or isopropyl. Specific examples of second-level substituents are C 1-3Alkyl, phenyl, 5- or 6-membered heteroaryl, 5- or 6-membered cycloalkyl, 5- or 6-membered heterocyclyl, halogen, =O, =S, -CF3, -CN, -OH, -O(C 1-3 Alkyl), -S(C 1-3 Alkyl), -NH2, -NH(C 1-3 Alkyl), -N(C 1-3 Alkyl)2,-NHS(O)2(C 1-3 Alkyl), -C(=O)OH, -C(=O)O(C 1-3 Alkyl), -C(=O)NH 2-z (C 1-3 Alkyl) z , -NHC(=O)(C 1-3 Alkyl), -NHC(=NH)NH z-2 (C 1-3 Alkyl) z , and -N(C 1-3 Alkyl)C(=NH)NH 2-z (C 1-3 Alkyl) z From the group consisting of, independently selected, where 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 secondary substituents are independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, phenyl, =O, and =S.

[0129] A typical third-level substituent is preferably C 1-3 Alkyl, phenyl, halogen, -CF3, -OH, -OCH3, -SCH3, -NH 2-z (CH3) z Selected from the group consisting of -C(=O)OH and -C(=O)OCH3, where each z is 0, 1 or 2, and each C 1-3 The alkyl group is methyl, ethyl, propyl, or isopropyl. Particularly preferred third-level substituents are selected from the group consisting of methyl, ethyl, propyl, isopropyl, halogen (such as F, Cl, or Br), and -CF3, such as halogens (e.g., F, Cl, or Br) and -CF3.

[0130] In this specification, the terms “optional” or “selective” mean that the matters, conditions, or states described below may or may not apply. The descriptions include both cases where the matters, conditions, or states occur and cases where they do not.

[0131] "Isomers" are compounds that have the same molecular formula but differ in the structure of their functional groups and / or atoms ("structural isomers") or their geometric (spatial) positions ("stereoisomers"). "Enantiomers" are a pair of stereoisomers that are mirror images of each other and cannot be superimposed. A "racemic mixture" or "racemate" contains equal amounts of a pair of enantiomers and is indicated by the prefix (±). "Diastereomers" are stereoisomers that cannot be superimposed and are not mirror images of each other. "Tautomers" are structural isomers of the same chemical substance that interconvert spontaneously and reversibly, even when pure, due to the movement 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 keto-enol-tautomer isomer. "Conformational isomers" are stereoisomers that can only be interconverted by rotation around a formal single bond, and in particular include stereoisomers that result in different three-dimensional forms of a (heterocyclic) ring, such as the chair, half-chair, boat, and twist-boat forms of cyclohexane.

[0132] Where a structural formula shown in this application can be interpreted as encompassing two or more isomers, such structural formula encompasses all possible isomers, and therefore individual isomers, unless otherwise specified. For example, the compound of formula (Ia) has Hy as follows: [ka] Here, the wavy line represents the bond through which Hy bonds to the rest of the compound; and R 1a This is 3-methylpiperazinyl, and it encompasses both isomers, such as the isomer with formula (B1) and the isomer with formula (B2): [ka] Furthermore, the compound of formula (Ic) is R 6‘’ 1-azabicyclo[2.2.2]oct-3-yl(optionally 1 or more R 7‘ (which can be substituted by) and encompasses both isomers, such as the isomer having formula (B3) and the isomer having formula (B4) (where n1 is 0, 1, 2, 3 or greater): [ka]

[0133] As used herein, “polymorphism” means that a solid material (such as a compound) can exist in two or more forms or crystalline structures, i.e., “polymorphic modifications” or “polymorphic forms.” The terms “polymorphic modifications,” “polymorphic forms,” and “polymorph” are used interchangeably in this invention. According to this invention, these “polymorphic modifications” include crystalline forms, amorphous forms, solvates, and hydrates. The reason for the existence of different polymorphic forms is mainly due to the use of different states during the crystallization process, such as: Solvent effect (crystal packing can differ between polar and nonpolar solvents); Certain impurities inhibit the growth mode and are favorable for the growth of metastable polymorphs; The supersaturation level at which a substance crystallizes (generally, the higher the concentration above solubility, the more likely metastable formation is to occur); The temperature at which crystallization occurs; Covalent bond structure (geometry) (differences leading to conformational polymorphism); Changes under stirring conditions.

[0134] Polymorphs may have different chemical, physical, and / or pharmacological properties, including but not limited to melting point, X-ray crystallography and diffraction pattern, chemical reactivity, solubility, dissolution rate, vapor pressure, density, hygroscopicity, fluidity, stability, compressibility, and bioavailability. Polymorphs can spontaneously convert from a metastable (unstable) form to a stable form at a specific temperature. According to Ostwald's Law, generally, the least stable polymorph is the first to crystallize. Therefore, the quality, efficacy, safety, processability, and / or manufacture of compounds such as the compounds of the present invention may be influenced by polymorphism. The most stable polymorph of a compound (such as the compounds of the present invention) is often selected because it minimizes the possibility of conversion to other polymorphs. However, for reasons other than stability, such as solubility, dissolution rate, and / or bioavailability, a polymorph other than the most stable one may be selected.

[0135] As used herein, the term “crystalline form” of a material means that the smallest components of the material (i.e., atoms, molecules, or ions) form a crystalline structure. As used herein, “crystalline structure” refers to a unique three-dimensional arrangement of atoms or molecules in a crystalline liquid crystal or solid, characterized by a pattern, a set of atoms arranged in a particular manner, and a lattice exhibiting long-range order and symmetry. A lattice is an arrangement of points that repeats periodically in three dimensions, and the pattern lies on the points of the lattice. A subunit of the lattice is the unit cell. Lattice parameters are the lengths of the ends of the unit cell and the angles between them. The symmetry of a crystal is embodied in its space group. To describe a crystalline structure, parameters such as the chemical formula, lattice parameters, space group, atomic coordinates, and the number of occupancies of point positions are required.

[0136] As used herein, the term "amorphous form" of a material means that the smallest components of the material (i.e., atoms, molecules, or ions) are not arranged in a lattice but are randomly arranged. Thus, unlike crystals, which have both short-range order (constant distance to the next neighboring atom) and long-range order (periodic repetition of the basic lattice), only short-range order exists in an amorphous form.

[0137] 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.

[0138] As used herein, the term “solvate” refers to an adduct complex of a substance dissolved in a solvent (e.g., an organic solvent (e.g., aliphatic alcohols (e.g., methanol, ethanol, n-propanol, isopropanol), acetone, acetonitrile, ether, etc.), water, or a mixture of two or more of these liquids), where the adduct complex exists in crystalline or mixed crystal form. The amount of solvent contained in the adduct complex may be stoichiometric or nonstoichiometric. “Hydrate” is a solvate in which the solvent is water.

[0139] In isotope-labeled compounds, one or more atoms are substituted by corresponding atoms that have the same number of protons but different numbers of neutrons. For example, a hydrogen atom may be replaced with a deuterium atom. Exemplary isotopes that can be used in the compounds of the present invention include deuterium, 11 C, 13 C, 14 C, 15 N, 18 F, 32 P, 32 S, 35 S, 36 Cl, and 125 I is included.

[0140] As used herein, the term “amino protecting group” preferably refers to any group that can transfer an amino group in a compound to a less reactive (i.e., protected) amino group. Preferably, the amino protecting group can be incorporated into the corresponding compound under mild conditions, in a chemoselective and / or regioselective manner, and / or in good yield. Furthermore, the amino protecting group should be stable under the conditions to which the protected compound is exposed (e.g., the desired reaction and / or purification conditions). Preferably, when the amino protecting group is present in the compound, the risk of stereocenter racemization should be minimized. In one embodiment, the amino protecting group should be removable from the protected compound under mild conditions and in a selective manner such that the deprotected compound is obtained in high yield. Examples of amino protecting groups include: tert-butyloxycarbonyl (BOC), 9-fluorenylmethoxycarbonyl (FMOC), benzyloxycarbonyl (Cbz), p-methoxybenzylcarbonyl (MOZ), acetyl (Ac), trifluoroacetyl, benzoyl (Bz), benzyl (Bn), p-methoxybenzyl (PMB), 3,4-dimethoxyphenyl (DMPM), p-methoxyphenyl (PMP), 2,2,2-trichloroethoxycarbonyl (Troc), triphenylmethyl (trityl;Tr), toluenesulfonyl (tosyl;Ts), para-bromophenylsulfonyl (brosyl), 4-nitrobenzenesulfonyl (nosyl), and 2-nitrophenylsulfenyl (Nps).

[0141] The term "half-life" refers to the time required for half of a molecule's activity, quantity, or number to disappear. In the context of the present invention, the half-life of the compounds disclosed herein (for example, compounds of formula (Ia), (Ib), or (Ic)) indicates the stability of the compound.

[0142] The terms “subject,” “patient,” “individual,” or “animal” refer to multicellular animals such as vertebrates. For example, vertebrates in the context of the present invention include mammals, birds (e.g., poultry), reptiles, amphibians, bony fish, and cartilaginous fish, in particular any of the above domestic animals, as well as captive animals (in particular vertebrates), such as zoo animals (in particular vertebrates). Mammals in the context of the present invention include, but are not limited to, humans, non-human primates, domestic mammals such as dogs, cats, sheep, cattle, goats, pigs, and horses, laboratory mammals such as mice, rats, rabbits, and guinea pigs, as well as captive mammals such as zoo mammals. The term “animal” as used herein also includes humans. Specific non-specific examples of birds include poultry, such as chickens, turkeys, ducks, geese, guinea pigs, pigeons, and pheasants, while specific non-specific examples of bony or cartilaginous fish include those suitable for aquaculture, such as bony fish (such as salmon, trout, perch, carp, and rodents).

[0143] The compound dasatinib (also known as compound A8 in this specification) has the following structure: [ka]

[0144] compound In a first aspect, as further described, defined, claimed and otherwise disclosed herein, the present invention provides compounds selected from the group consisting of kinase inhibitors of the following formula Ia, their solvates, salts, N-oxides, complexes, polymorphs, crystalline forms, racemic mixtures, diastereomers, enantiomers, tautomers, conformatorisomers, isotope-labeled compounds, prodrugs, and combinations thereof: [ka] Here, Hy is one or more independently selected R 1eIt is a heteroaryl or heterocyclyl which may be optionally substituted with; Each R 1e R is independent of R 1a , R 1b , R 1c and R 1d Selected from the group consisting of; R 1a and R 1d Each is independently selected from the following groups: H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, 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 Ure 11 , -OS(O) 1-2 R 11 , -OS(O) 1-2 Ure 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 Ure 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 Here, each of alkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, aryl groups, heterocyclyl groups, and heteroaryl groups is independently selected from one or more R groups.30 It may be optionally replaced by; R 1b and R 1c Each is independently selected from the following groups: H, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-7 Cycloalkyl, C 6-10 Aryl, 3-~7-membered heteroaryl, 3-~7-membered heterocyclyl, -O(CH2) 0-2 (C 3-7 Cycloalkyl), -O(CH2) 0-2 (C 6-10 aryl), -O(CH2) 0-2 (3-~7-membered heteroaryl), -O(CH2) 0-2 (3-~7-membered heterocyclyl), -NH(CH2) 0-2 (C 3-7 Cycloalkyl), -NH(CH2) 0-2 (C 6-10 Aryl), -NH(CH2) 0-2 (3-~7-membered heteroaryl), -NH(CH2) 0-2 (3-~7-membered heterocyclyl), halogen, -CF3, -CN, azide, -NO2, -OH, -O(C) 1-6 Alkyl), -OCF3, -S(C 1-6 Alkyl), -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2,-NHS(O)2(C 1-6 Alkyl), -S(O)2NH 2-z (C 1-6 Alkyl) z -C(=O)(C 1-6 Alkyl), -C(=O)OH, -C(=O)O(C 1-6 Alkyl), -C(=O)NH 2-z (C 1-6 Alkyl) z , -NHC(=O)(C 1-6 Alkyl), -NHC(=NH)NH z-2 (C 1-6 Alkyl) z , and -N(C 1-6Alkyl)C(=NH)NH 2-z (C 1-6 Alkyl) z Here, z is 0, 1, or 2, and C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-7 Cycloalkyl, C 6-10 The groups of aryl, 3-~7-membered heteroaryl, and 3-~7-membered heterocyclyl are -OH, methyl, ethyl, -OCH3, -SCH3, and -NH3, respectively. 2-z (CH3) z One, two, or three moieties (parts) independently selected from the group consisting of the above, which may be optionally substituted; R 2 H; R 3 The group is selected from the following: H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, 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 Ure 11 , -OS(O) 1-2 R 11 , -OS(O) 1-2 Ure 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 Ure 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 Here, each of alkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, aryl groups, heterocyclyl groups, and heteroaryl groups is independently selected from one or more R groups. 30 It may be optionally replaced by; R 4 H; R 5 -LR 6 ; L is selected from the following group: combination, C 1-6 Alkilen, C 2-6 Alkenylene, C 2-6 Alkynylene 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 n is 0 and o is 1; Y is independently O, S, and -N(R 13 )- Selected from; and C 1-6 Alkilen, C 2-6 Alkenylene, C 2-6 Alkinylene, -(CH2) m -, and -(CH2) n - Each base of is independently selected from one or more R 30 It may be optionally replaced by; R 6 It is a 5-membered monocyclic heteroaryl, which contains at least one S ring atom, and it is independently selected from one or more R 7 It is replaced by R 7 The following groups are independently selected: alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, halogen, -CN, azide, -NO2, -OR 11 , -N(R 12 )(R 13 ), -N(R 11 )(OR11 ), -S(O) 0-2 R 11 , -S(O) 1-2 Ure 11 , -OS(O) 1-2 R 11 , -OS(O) 1-2 Ure 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 Ure 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 Here, each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl groups is one or more R groups independently selected. 30 It may be optionally replaced by; Here, R 7 At least one of them is F, and / or R 7 At least one of them is substituted with one or more F atoms; A is S, O, NR 8 , and C(R 9 ) Selected from the group consisting of 2; R 8The group is selected from the following: H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl, where each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl groups is independently selected from one or more R 30 It may be optionally replaced by; R 9 The following are independently selected from the group consisting of: alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, halogen, -CN, azide, -NO2, -OR 11 , -N(R 12 )(R 13 ), -S(O) 0-2 R 11 , -S(O) 1-2 Ure 11 , -OS(O) 1-2 R 11 , -OS(O) 1-2 Ure 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 Ure 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 Here, each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl groups is independently selected from one or more R 30 It may be optionally replaced by; X is independent of O, S, and N(R) 14 Selected from the group of ); E is either O or S; R 11 The following are independently selected from the group: H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl, where each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups is one or more R groups independently selected 30 It may be optionally replaced by; R 12 and R 13 Each of these is independently selected from the group consisting of: H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl, or R 12 and R 13 These combine to form the base -N=CR 15 R 16 It can be bonded with a nitrogen atom forming a , where each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups is one or more R groups independently selected 30 It may be optionally replaced by; R 14 The following are independently selected from the group consisting of: H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, and -OR 11 Here, each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups is one or more R groups independently selected. 30 It may be optionally replaced by; R 15 and R 16 Each of these is independently selected from the group consisting of: H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, and -NH y R 20 2-y , or R 15 and R 16 These are combined and one or more R selected independently.30 It can be bonded with atoms forming a ring which may be optionally substituted, where each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups is one or more R groups independently selected 30 It may be optionally replaced by; y is an integer between 0 and 2; R 20 The group is independently selected from the following: alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl, where each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups is independently selected from one or more R groups. 30 It may be optionally replaced by; and R 30 is a first-level substituent, and in each case, independently selected from the group consisting of: alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, halogen, -CN, azide, -NO2, -OR 71 , -N(R 72 )(R 73 ), -S(O) 0-2 R 71 , -S(O) 1-2 Ure 71 , -OS(O) 1-2 R 71 , -OS(O) 1-2 Ure 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 Ure 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 the cycloalkyl or heterocyclyl group 30 is, =X 1 They can be bonded together to form a structure where each of the first-level substituents, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl groups, may be optionally substituted by one or more second-level substituents, where in each case the second-level substituent is independently selected from the group consisting of: C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, 3-~14-membered aryl, 3-~14-membered heteroaryl, 3-~14-membered cycloalkyl, 3-~14-membered heterocyclyl, halogen, -CF3, -CN, azide, -NO2, -OR 81 , -N(R 82 )(R 83 ), -S(O) 0-2 R 81 , -S(O) 1-2 Ure 81 , -OS(O) 1-2 R 81 , -OS(O) 1-2 Ure 81 , -S(O) 1-2 N(R 82 )(R 83 ), -OS(O) 1-2 N(R 82 )(R 83 ), -N(R 81 )S(O) 1-2 R 81 , -NR 81 S(O) 1-2 Ure 81 , -NR 81 S(O) 1-2N(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 、及び -X 2 C(=X 2 )X 2 R 81 、及び / 又は、 a cycloalkyl or heterocyclyl group which is a first-level substituent, any two second-level substituents bonded to the same carbon atom of which may be joined together to form =X 2 wherein each of the second-level substituents of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3- to 14-membered aryl, 3- to 14-membered heteroaryl, 3- to 14-membered cycloalkyl, 3- to 14-membered heterocyclyl groups may be substituted with one or more third-level substituents, wherein the third-level substituents are, in each case, independently selected from the group consisting of: C 1-3 alkyl, halogen, -CF3, -CN, azide, -NO2, -OH, -O(C 1-3 alkyl), -OCF3, -S(C 1-3 alkyl), -NH2, -NH(C 1-3 alkyl), -N(C 1-3 alkyl)2, -NHS(O)2(C 1-3 alkyl), -S(O)2NH 2-z (C 1-3 alkyl) z , -C(=O)OH, -C(=O)(C 1-3 alkyl), -C(=O)NH 2-z (C 1-3 alkyl) z , -NHC(=O)(C 1-3 alkyl), -NHC(=NH)NH z-2 (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 alkyl is independently methyl, ethyl, propyl, or isopropyl, and / or any two third-level substituents bonded to the same carbon atom of a 3- to 14-member cycloalkyl or heterocyclyl group, which is a second-level substituent, may be joined together to form =O, =S, =NH, or =N(C 1-3 alkyl); where R 71 , R 72 , and R 73 each is independently selected from the group consisting of: H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3- to 7-member cycloalkyl, 5- or 6-member aryl, 5- or 6-member heteroaryl, and 3- to 7-member heterocyclyl, where each group of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3- to 7-member cycloalkyl, 5- or 6-member aryl, 5- or 6-member heteroaryl, and 3- to 7-member heterocyclyl may be optionally substituted with 1, 2, or 3 substituents independently selected from the following: C​​​​​​​​​​​​​​​​​​​​​​​​​​z , -NHC(=O)(C 1-3 Alkyl), -NHC(=NH)NH z-2 (C 1-3 Alkyl) z , and -N(C 1-3 Alkyl)C(=NH)NH 2-z (C 1-3 Alkyl) z Here, each z is independently 0, 1, or 2, and each C 1-3 Alkyl compounds are independently methyl, ethyl, propyl, or isopropyl; Each R 81 , R 82 , and R 83 These are independently selected from the following groups: H, C 1-4 Alkyl, C 2-4 Alkenil, C 2-4 Alkinyl, 3-~6-membered cycloalkyl, 5- or 6-membered aryl, 5- or 6-membered heteroaryl, and 3-~6-membered heterocyclyl, where C 1-4 Alkyl, C 2-4 Alkenil, C 2-4 Each of the alkynyl, 3-~6-membered cycloalkyl, 5- or 6-membered aryl, 5- or 6-membered heteroaryl, and 3-~6-membered heterocyclyl groups may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of:C 1-3 Alkyl, halogen, -CF3, -CN, azide, -NO2, -OH, -O(C 1-3 Alkyl), -OCF3, =O, -S(C 1-3 Alkyl), -NH2, -NH(C 1-3 Alkyl), -N(C 1-3 Alkyl)2,-NHS(O)2(C 1-3 Alkyl), -S(O)2NH 2-z (C 1-3 Alkyl) z -C(=O)(C 1-3 Alkyl), -C(=O)OH, -C(=O)O(C 1-3 Alkyl), -C(=O)NH 2-z (C 1-3 Alkyl) z, -NHC(=O)(C 1-3 alkyl), -NHC(=NH)NH z-2 (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 alkyl is independently methyl, ethyl, propyl, or isopropyl; and, each X 1 and X[[ID=Z3]] 2 is independently selected from O, S, and N(R 84 ), where R 84 is H or C 1-3 alkyl.

[0145] In one embodiment, the kinase inhibitor has the following formula (IIa): [Chemical formula] [[ID=Z9]]<000533K> where Hy, R 2 , R 3 , R 4 , A, and E are independently defined as above (particularly in formula Ia), or below (particularly in formulas IIIa, IVa, Va, VIa, VIIa, and / or VIIIa), and R[[ID=4K]] 5 is -L-R 6 , where L is defined as above (particularly in formula Ia) or below, and R 6 is a 5-membered monocyclic heteroaryl containing at least one S ring atom, which is substituted with one or more (such as 1, 2, or 3, preferably 2, relative to the maximum number of hydrogen atoms bonded to the 5-membered monocyclic heteroaryl group) of independently selected R 7 , where R 7 is independently selected from the following group: alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, 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 Ure 11 , -OS(O) 1-2 R 11 , -OS(O) 1-2 Ure 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 Ure 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 Here, each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl groups is independently selected from one or more R groups (1 for the maximum number of hydrogen atoms bonded to the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl groups, for example, 1-5, 1-4, or 1-3, or 1 or 2, up to 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) 30 It may be optionally replaced by; here, R 7 At least one of them is F and / or R 7 At least one of them is substituted with one or more F atoms.

[0146] In one embodiment, the kinase inhibitor of formula (IIa) is Hy, R 2 , R 3, R 4 , A, E, L, and R 7 R is defined independently as described above (especially in formula Ia) or below (especially in formulas IIIa, IVa, Va, VIa, VIIa, and / or VIIIa), 6 Each of them is independently selected R, such as 1, 2, or 3, where 1 is the maximum number of hydrogen atoms bonded to the 5-membered monocyclic heteroaryl group. 7 The substitution is selected from the group consisting of thienyl, thiazolyl, and thiadiazolyl. For example, R 6 Each of them is independently selected R, such as 1, 2, or 3, where 1 is the maximum number of hydrogen atoms bonded to the 5-membered monocyclic heteroaryl group. 7 The substitution is selected from the group consisting of thienyl and thiazolyl. Preferably, R 6 R is independently selected from 1 or more (for example, 1, 2, or 3, preferably 2, as 1 for the maximum number of hydrogen atoms bonded to a 5-membered monocyclic heteroaryl group). 7 And it is thienyl that is substituted.

[0147] In any of the above embodiments of a kinase inhibitor of formula (IIa) (including that of formula Ia), thereby, R 6 However, R binds to the rest of the compound. 6 The ring atom is preferably a carbon atom.

[0148] In any of the above embodiments of a kinase inhibitor of formula (IIa) (including that of formula Ia), R 6 However, it is preferable to select from the following group: [ka] Here, the wavy line indicates that R 6 However, this represents a bond that connects to the rest of the compound.

[0149] In any of the above embodiments of a kinase inhibitor of formula (IIa) (including that of formula Ia), R 6 The S ring atom is thereby R6 It is preferable that the ring atom is not adjacent to any ring atoms bonded to the rest of the compound.

[0150] In one embodiment, the kinase inhibitor of formula (IIa) is Hy, R 2 , R 3 , R 4 , A, E, L, and R 7(6?) R is defined independently as described above (especially in formula Ia) or below (especially in formulas IIIa, IVa, Va, VIa, VIIa, and / or VIIIa), 6 Each of them has at least two R 7 The substituted component is thienyl or thiazolyl, preferably thienyl; in this embodiment, R 6 These are two different R's. 7 Therefore, substitution is preferable.

[0151] In any of the above embodiments of the kinase inhibitor of formula (IIa) (including the kinase inhibitor of formula (Ia)), one R 7 (In particular, R is F) 7 and / or R substituted with one or more F atoms 7 ) However, as a result, R 6 It is preferable that the ring atom bonded to the rest of the compound is bonded to the C ring atom at position 2 or 5. 6 However, at least two R 7 If substituted with R 7 One of the elements (in particular, R which is F) 7 and / or R substituted with one or more F atoms 7 ) However, as a result, R 6 A ring atom is bonded to the rest of the compound, and R is bonded to one of the C ring atoms at positions 2 and 5. 7 One of the elements, thereby, R 6 It is preferable that the ring atom bonded to the rest of the compound is bonded to the other C ring atom at positions 2 and 5.

[0152] In one embodiment, the kinase inhibitor of formula (IIa) is Hy, R 2 , R 3, R 4 , A, E, L, and R 6 This is defined independently as described above (especially in formula Ia) or below (especially in formulas 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 alkyl, -OR 11 , and -N(R 12 )(R 13 Selected from the group consisting of ), where alkyl, R 11 Base and R 12 and R 13 Each of at least one of the groups is 1 or more (alkyl, R 11 Group, R 12 Or R 13 The atom is substituted with 1 F atom, such as 1 for the maximum number of hydrogen atoms bonded to the base, for example, 1-5, 1-4, or 1-3, or 1 or 2 (up to 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10).

[0153] In one embodiment, the kinase inhibitor of formula (IIa) is Hy, R 2 , R 3 , R 4 , A, E, L, and R 6 This is defined independently as described above (especially in formula Ia) or below (especially in formulas 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 the alkyl groups is selected from the group consisting of alkyl, -O(alkyl), -NH(alkyl), and -N(alkyl)2, where at least one of the alkyl groups of alkyl, -O(alkyl), and -NH(alkyl), and -N(alkyl)2 is substituted with one or more fluorine atoms (1 for the maximum number of hydrogen atoms bonded to the alkyl group, for example, 1-5, 1-4, or 1-3, or 1 or 2, up to 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10).

[0154] In one embodiment, the kinase inhibitor of formula (IIa) is Hy, R 2 , R 3 , R 4 , A, E, L, and R 6 This is defined independently as described above (especially in formula Ia) or below (especially in formulas 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 is C 1-3 Alkyl, -O(C 1-3 Alkyl), -NH(C 1-3 Alkyl) or -N(C 1-3 Selected from the group consisting of alkyl)2, where C 1-3 Alkyl, -NH(C 1-3 Alkyl), and -O(C 1-3 Alkyl) alkyl groups, and -N(C 1-3 At least one of the alkyl groups of alkyl)2 is 1 or more (C 1-3 The fluorine atoms are substituted with 1 of the maximum number of hydrogen atoms bonded to the alkyl group, for example, 1-5, 1-4, or 1-3, or 1 or 2 (up to 1, 2, 3, 4, 5, 6, 7, or 6).

[0155] In one embodiment, the kinase inhibitor of formula (IIa) is Hy, R 2 , R 3 , R 4 , A, E, L, and R 6 This is defined independently as described above (especially in formula Ia) or below (especially in formulas 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 is C 1-3 It is alkyl, and here, C 1-3 The alkyl group of an alkyl group is 1 or more (C 1-3 The fluorine atoms are substituted with 1 of the maximum number of hydrogen atoms bonded to the alkyl group, for example, 1-5, 1-4, or 1-3, or 1 or 2 (up to 1, 2, 3, 4, 5, 6, 7, or 6).

[0156] In one embodiment, the kinase inhibitor of formula (IIa) is Hy, R 2 , R 3 , R 4 , A, E, L, and R 6 This is defined independently as described above (especially in formula Ia) or below (especially in formulas 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 the members is selected from the group consisting of -CH2F, -CHF2, and -CF3, preferably selected from the group consisting of -CH2F and -CHF2.

[0157] In one embodiment, the kinase inhibitor of formula (IIa) is Hy, R 2 , R 3 , R 4 , A, E, L, and R 6 R is defined independently as described above (especially in formula Ia) or below (especially in formulas IIIa, IVa, Va, VIa, VIIa, and / or VIIIa), 6 Each of them has at least two R 7 Then it is replaced, and here, one R 7 It is selected from the group consisting of -CH2F, -CHF2, and -CF3, and one R 7 The is selected from the group consisting of halogens, -CH3, -CH2(hal), -CH(hal)2, and -C(hal)3, and more preferably from the group consisting of Cl, Br, F, CH3, -CH2F, -CHF2, and -CF3. For example, in one embodiment, one R 7 is selected from the group consisting of CH2F, -CHF2, and -CF3, preferably selected from the group consisting of -CH2F and -CHF2, and one R 7 It is Cl. In an alternative configuration, one R 7 is F, and one R 7The element is selected from the group consisting of halogens, CH3, -CH2(hal), -CH(hal)2, and -C(hal)3, more preferably from the group consisting of Cl, Br, F, CH3, -CH2F, -CHF2, and -CF3; even more preferably, one R 7 is F, and one R 7 It is Cl. In these embodiments, these two R 7 One of the elements is, by means of R 6 The ring atom to which the rest of the compound is bonded, and to one of the C ring atoms at positions 2 and 5, these two R 7 The other of the elements is thereby R 6 It is preferable that the ring atom to which the rest of the compound is bonded is bonded to the other C ring atom at positions 2 and 5.

[0158] In one embodiment, the kinase inhibitor of formula (IIa) is Hy, R 2 , R 3 , R 4 A, L, and E are defined independently above (especially in formula Ia) or below (especially in formulas IIIa, IVa, Va, VIa, VIIa, and / or VIIIa), and R 6 The following group is selected: [ka] More preferably, selected from the group consisting of the following: [ka] Alternatively, the following group is selected: [ka] Here, the wavy line in each case represents R 6 However, it exhibits bonding to the rest of the compound.

[0159] In any of the above embodiments of a kinase inhibitor of formula (IIa) (including that of formula Ia), L is bound to C1-6 Alkilen, C 2-6 Alkenylene, C 2-6 Alkynylene and -(CH2) m -[Y-(CH2) n ] o - can be selected from the group consisting of, where m is 1, 2, or 3, n is 0, 1, or 2, and o is 1, 2, or 3, where o is 1 when n is 0; Y is independently selected from O, S, and NH, where C 1-6 Alkilen, C 2-6 Alkenylene, C 2-6 Alkinylene, -(CH2) m -, and -(CH2) n -Each of the bases is arbitrarily and independently selected from 1 or 2 R 30 And it can be substituted. For example, in any of the above embodiments of a kinase inhibitor of formula (IIa) (including that of formula Ia), L is bound; one R 30 A C1 alkylene that can be optionally substituted; one R 30 C2 alkylenes (especially 1,2-ethylene or 1,1-ethylene) that can be optionally substituted; one R 30 C3 alkylenes (especially trimethylenes) that can be optionally substituted, one R 30 C4 alkylenes (especially tetramethylene or 2,4-butanediyl) that can be optionally substituted;-(CH2) m O-; and -(CH2) m NH-, where m is 1, 2, or 3, can be selected from the group. In particular, in any of the above embodiments of the kinase inhibitor of formula (IIa) (including that of formula Ia), L is a binding; one R 30 A C1 alkylene that can be optionally substituted; one R 30 The C2 alkylene (particularly 1,2-ethylene or 1,1-ethylene) which can be optionally substituted can be selected from the group consisting of -(CH2)O- and -(CH2)NH-; preferably, where L is selected from the group consisting of bond, -(CH2)- and -(CH2)2-.

[0160] More preferably, in any of the above embodiments of a kinase inhibitor of formula (IIa) (including that of formula Ia), L is a binding (e.g., R 5 is R 6 )

[0161] In one embodiment, a kinase inhibitor has formula (IIIa): [ka] Here, Hy, R 2 , R 3 , R 4 and R 5 E is defined independently as described above (especially in formulas Ia and / or IIa), or below (especially in formulas IVa, Va, VIa, VIIa, and / or VIIIa), where E is O or S (preferably O); and A is S, O, NH, N (C 1-6 Alkyl, and C(C 1-6 Selected from the group consisting of alkyl)2. In any of the above embodiments of the kinase inhibitor of formula (IIIa) (including those of formulas Ia and IIa), E may be O or S (preferably O); and A may be S, O, or N(CH3)2. In any of the above embodiments of the kinase inhibitor of formula (IIIa) (including those of formulas Ia and IIa), it is preferable that E is O or S (preferably O); and A is S. In any of the above embodiments of the kinase inhibitor of formula (IIIa) (including those of formulas Ia and IIa), it is preferable that E is O; and A is S.

[0162] In one embodiment, a kinase inhibitor has formula (IVa): [ka] Here, Hy, R 2 , R 4 , R 5 A and E are defined independently above (in particular in formulas Ia, IIa and / or IIIa), or below (in particular in formulas Va, VIa, VIIa and / or VIIIa), R 3The following group is selected: H, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-6 Cycloalkyl, phenyl, halogen, -CN, azide, -NO2, -O(C 1-6 Alkyl), -OCF3, -S(C 1-6 Alkyl), -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2,-NHS(O)2(C 1-6 Alkyl), -S(O)2NH 2-z (C 1-6 Alkyl) z -C(=O)(C 1-6 Alkyl), -C(=O)OH, -C(=O)O(C 1-6 Alkyl), -C(=O)NH 2-z (C 1-6 Alkyl) z , -NHC(=O)(C 1-6 Alkyl), -NHC(=NH)NH z-2 (C 1-6 Alkyl) z , and -N(C 1-6 Alkyl)C(=NH)NH 2-z (C 1-6 Alkyl) z Here, z is 0, 1, or 2, and here, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-6 Each of the cycloalkyl and phenyl groups can be independently one or more selected (e.g., C) 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-6 R (up to 10) is such that 1 is the maximum number of hydrogen atoms bonded to the cycloalkyl or phenyl group, for example, 1-5, 1-4, or 1-3, or 1 or 2. 30 It can be replaced by...

[0163] In one embodiment, a kinase inhibitor of formula (IVa) is used, Hy, R2 , R 4 , R 5 A and E are defined independently above (in particular in formulas Ia, IIa and / or IIIa), or below (in particular in formulas Va, VIa, VIIa and / or VIIIa), R 3 The following group is selected: H, C 1-4 Alkyl, C 3-6 Cycloalkyl, phenyl, halogen, -CN, -O(C 1-4 Alkyl), -OCF3, -S(C 1-4 Alkyl), -NH2, -NH(C 1-4 Alkyl), -N(C 1-4 Alkyl)2, -C(=O)(C 1-4 Alkyl), -C(=O)OH, -C(=O)O(C 1-4 Alkyl), -C(=O)NH 2-z (C 1-4 Alkyl) z , -NHC(=O)(C 1-4 Alkyl), -NHC(=NH)NH z-2 (C 1-4 Alkyl) z , and -N(C 1-4 Alkyl)C(=NH)NH 2-z (C 1-4 Alkyl) z Here, C 1-4 Alkyl, C 3-6 Each of the cycloalkyl and phenyl groups may be optionally substituted with 1, 2, or 3 independently selected from the group consisting of: 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), -C(=O)NH 2-z (C 1-3 Alkyl) z ,-(CH2) 1-3 NH2, -(CH2) 1-3 NH(C 1-3 Alkyl), -(CH2) 1-3 N(C 1-3 Alkyl)2,-(CH2) 1-3OH, and-(CH2) 1-3 O(C 1-3 Alkyl); and where z is 0, 1, or 2.

[0164] In one embodiment, a kinase inhibitor of formula (IVa) is used, Hy, R 2 , R 4 , R 5 A and E are defined independently above (in particular in formulas Ia, IIa and / or IIIa), or below (in particular in formulas Va, VIa, VIIa and / or VIIIa), R 3 The following group is selected: H, C 1-4 Alkyl, C 3-6 Cycloalkyl, phenyl, halogen, -CN, -O(C 1-4 Alkyl), -OCF3, -S(C 1-4 Alkyl), -NH2, -NH(C 1-4 Alkyl), -N(C 1-4 Alkyl)2, -C(=O)(C 1-4 Alkyl), -C(=O)OH, -C(=O)O(C 1-4 Alkyl), -C(=O)NH 2-z (C 1-4 Alkyl) z , -NHC(=O)(C 1-4 Alkyl), -NHC(=NH)NH z-2 (C 1-4 Alkyl) z , and -N(C 1-4 Alkyl)C(=NH)NH 2-z (C 1-4 Alkyl) z Here, the phenyl group may be optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of: 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), -C(=O)NH 2-z (C 1-3 Alkyl) z ,-(CH2) 1-3 NH2, -(CH2)1-3 NH(C 1-3 Alkyl), -(CH2) 1-3 N(C 1-3 Alkyl)2,-(CH2) 1-3 OH, and-(CH2) 1-3 O(C 1-3 Alkyl); and where z is 0, 1, or 2.

[0165] In one embodiment, a kinase inhibitor of formula (IVa) is used, Hy, R 2 , R 4 , R 5 A and E are defined independently above (in particular in formulas Ia, IIa and / or IIIa), or below (in particular in formulas Va, VIa, VIIa and / or VIIIa), R 3 The following group is selected: H, methyl, ethyl, propyl, isopropyl, phenyl, and halogens.

[0166] In one embodiment, a kinase inhibitor of formula (IVa) is used, Hy, R 2 , R 4 , R 5 A and E are defined independently above (in particular in formulas Ia, IIa and / or IIIa), or below (in particular in formulas Va, VIa, VIIa and / or VIIIa), R 3 H is H.

[0167] In one embodiment, a kinase inhibitor has formula (Va): [ka] Here, R 2 , R 3 , R 4 , R 5 A and E are defined independently above (in particular in formulas Ia, IIa, IIIa and / or IVa) or below (in particular in formulas VIa, VIIa and / or VIIIa), Hy is a 3-~10-membered heteroaryl or 3-~10-membered heterocyclyl, each of which is independently selected by R. 1eR can be optionally substituted with 1 or more (such as 1 for the maximum number of hydrogen atoms bonded to a 3-~10-membered heteroaryl or 3-~10-membered heterocyclyl group, for example, 1~5, 1~4, or 1~3, or 1 or 2, up to 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), where each R 1e These are independently selected from the following group: R 1a , R 1b , R 1c and R 1d ; and each R 1a , R 1b , R 1c and R 1d These are defined independently as above (with respect to formula (Ia)) or below (in particular, formulas (VIa), (VIIa), and / or (VIIIa)). For example, Hy can be selected from the following group: 5-~6-membered monocyclic heteroaryl, 5-~6-membered monocyclic heterocyclyl, 9-~10-membered bicyclic heteroaryl, and 8-~10-membered bicyclic heterocyclyl. Here, each of these can be independently selected R 1e R can be optionally substituted with 1 or more (for example, 1 for the maximum number of hydrogen atoms bonded to a 5-~6-membered monocyclic heteroaryl, 5-~6-membered monocyclic heterocyclyl, 9-~10-membered bicyclic heteroaryl, or 8-~10-membered bicyclic heterocyclyl group, such as 1~5, 1~4, or 1~3, or 1 or 2, up to 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10). Here, R 1e It can be independently selected from the following group: R 1a , R 1b , R 1c and R 1d ; and each R 1a , R 1b R 1c and R 1dR can be defined independently as described above (especially in formula Ia) or below (especially in formulas VIa, VIIa, and / or VIIIa). Preferably, Hy is a heteroaryl or heterocyclyl which comprises at least one N ring atom, and which is independently selected R 1e One or more of these (such as 1 for the maximum number of hydrogen atoms bonded to the heteroaryl or heterocyclyl group, for example, 1 to 5, 1 to 4, or 1 to 3, or 1 or 2, up to 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) can be optionally substituted.

[0168] In one embodiment of the kinase inhibitor of formula (Va), where R 2 , R 3 , R 4 , R 5 A and E are defined independently above (in particular in formulas Ia, IIa, IIIa and / or IVa) or below (in particular in formulas VIa, VIIa and / or VIIIa), Hy is as follows: [ka] Here, the wavy line represents a bond in which Hy binds to the rest of the compound, such that the kinase inhibitor of formula (Va) has the following formula (VIa). [ka] Here, R 1a , R 1b , and R 1c B is defined above (especially in formula Ia) or below (especially in formulas VIIa and / or VIIIa); B is N or CR 1d And here R 1d This is defined above (in particular in formula Ia) or below (in particular in formulas VIIa and / or VIIIa).

[0169] In one embodiment, the kinase inhibitor of formula (VIa) is R 1b , R 1c , R2 , R 3 , R 4 , R 5 A, B, and E are defined independently above [especially in formulas (Ia), (IIa), (IIIa), (IVa) and / or (Va)] or below [especially in formulas (VIIa) and / or (VIIIa)], and R 1a R is selected from the group consisting of: alkyl, -O(alkyl), -S(alkyl), -NH(alkyl), -N(alkyl)2, and heterocyclyl. Here, each of the alkyl and heterocyclyl groups is independently selected. 30 R can be optionally substituted with one or more (for example, 1 for the maximum number of hydrogen atoms bonded to the alkyl or heterocyclyl group, such as 1-5, 1-4, or 1-3, or 1 or 2, up to 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10). 1a One or more independently selected R(s) that can optionally replace R(s) 30 It is preferable that the substituents are independently selected from the first-level substituents, second-level substituents, and third-level substituents defined herein. 1a One or more independently selected R(s) that can optionally replace R(s) 30 More preferably, independently selected from the group consisting of: 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), -(CH2) 1-3 COOH and -NH 2-z (CH3)z Here, z is 0, 1, or 2; and C 1-3 Each alkyl group may be optionally substituted with one or two moieties independently selected from the following group: -OH, -OCH3, -SCH3, cyclopropyl, piperazinyl, 4-methyl-piperazinyl, 4-(2-hydroxyethyl)piperazinyl, 2-(N,N-dimethylamino)ethoxy, and -NH 2-z (CH3) z Here, z is 0, 1, or 2.

[0170] In one embodiment, the kinase inhibitor of formula (VIa) is R 1b , R 1c , R 2 , R 3 , R 4 , R 5 A, B, and E are defined independently above [especially in formulas (Ia), (IIa), (IIIa), (IVa) and / or (Va)] or below [especially in formulas (VIIa) and / or (VIIIa)], and R 1a The following group is selected: 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-~11-membered heterocyclyl. Here, the 3-~11-membered heterocyclyl group is 1 or 2 independently selected R 30 R can be optionally replaced by either 1 or 2, which can be independently selected. 30 It is preferable that the substituents are independently selected from the first-level substituents, second-level substituents, and third-level substituents defined herein. 1a One or more independently selected R(s) that can optionally replace R(s) 30More preferably, independently selected from the group consisting of: 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), -(CH2) 1-3 COOH and -NH 2-z (CH3) z , where z is 0, 1, or 2; and C 1-3 Each alkyl group may be optionally substituted with one or two moieties independently selected from the following group: -OH, -OCH3, -SCH3, cyclopropyl, piperazinyl, 4-methyl-piperazinyl, 4-(2-hydroxyethyl)piperazinyl, 2-(N,N-dimethylamino)ethoxy, and -NH 2-z (CH3) z Here, z is 0, 1, or 2.

[0171] In one embodiment, the kinase inhibitor of formula (VIa) is R 1b , R 1c , R 2 , R 3 , R 4 , R 5 A, B, and E are defined independently above [especially in formulas (Ia), (IIa), (IIIa), (IVa) and / or (Va)] or below [especially in formulas (VIIa) and / or (VIIIa)], and R 1a The following group is selected: C 1-3 Alkyl, -O(C 1-3 Alkyl), -S(C1-3 Alkyl), -NH(C 1-3 Alkyl), piperazinyl, piperidinyl, hexahydropyrimidinyl, hexahydropyridadinyl, morpholinyl, 1,2-oxadinyl, 1,3-oxadinyl, pyrrololidinyl, imidazolidinyl, pyrazolidinyl, diazepanyl, oxazepanyl, azaspirononanyl, diazaspirononanyl, azaspirodecanil, diazaspirodecanil, azaspironodecanil, and diazaspironodecanil. Here, each of the piperazinyl, piperidinyl, hexahydropyrimidinyl, hexahydropyridazinyl, morpholinyl, 1,2-oxadinanyl, 1,3-oxadinanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, diazepanyl, oxazepanyl, azaspirononyl, diazaspirononyl, azaspirodecyl, diazaspirodecyl, azaspirondecyl, and diazaspirondecyl groups is one or two independently selected R 30 It can be optionally substituted with R 1a R, which can be optionally replaced by either 1 or 2, is independently selected. 30 It is preferable that the substituents are independently selected from the first-level substituents, second-level substituents, and third-level substituents defined herein. 1a One or more independently selected R(s) that can optionally replace R(s) 30 More preferably, independently selected from the group consisting of: 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), -(CH2)1-3 COOH and -NH 2-z (CH3) z , where z is 0, 1, or 2; and the C 1-3 Each alkyl group may be optionally substituted with one or two moieties independently selected from the following group: -OH, -OCH3, -SCH3, cyclopropyl, piperazinyl, 4-methyl-piperazinyl, 4-(2-hydroxyethyl)piperazinyl, 2-(N,N-dimethylamino)ethoxy, and -NH 2-z (CH3) z Here, z is 0, 1, or 2.

[0172] In one embodiment, the kinase inhibitor of formula (VIa) is R 1b , R 1c , R 2 , R 3 , R 4 , R 5 A, B, and E are defined independently above [especially in formulas (Ia), (IIa), (IIIa), (IVa) and / or (Va)] or below [especially in formulas (VIIa) and / or (VIIIa)], and R 1a The following group is selected: -NH(C 1-3 Alkyl), piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl, diazepanyl, oxazepanyl, and diazaspirononyl, where each piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl, diazepanyl, oxazepanyl, and diazaspirononyl group is one or two independently selected R 30 And it can be optionally substituted, R 1a One or two independently selected Rs can be optionally substituted for R. 30 The following are independently selected from the group consisting of: 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 1-3Alkyl, and -NH 2-z (CH3) z Here, z is 0, 1, or 2.

[0173] In one embodiment, the kinase inhibitor of formula (VIa) is R 1b , R 1c , R 2 , R 3 , R 4 , R 5 A, B, and E are defined independently above [especially in formulas (Ia), (IIa), (IIIa), (IVa) and / or (Va)] or below [especially in formulas (VIIa) and / or (VIIIa)], and R 1a The following are selected from the group: 4-(2-hydroxyethyl)piperazinyl, 4-methylpiperazinyl, 3,4-dimethylpiperazinyl, 4-methyl-1,4-diazepan-1-yl, 3-oxopiperazine-1-yl, 2-methylmorpholin-4-yl, 3-methylpiperazine-1-yl, 3-(2-hydroxyethyl)piperazine-1-yl, 3-(2-hydroxyethyl)-4-methylpiperazine-1-yl, 3-(dimethylamino)piperidine-1-yl, 3-(methoxy)piperidine-1-yl, 3-(hydroxy)piperidine n-1-yl, 3-(dimethylamino)pyrrolidine-1-yl, 3-(hydroxy)pyrrolidine-1-yl, 3-(2-methoxyethoxy)pyrrolidine-1-yl, 3-(acetylamino)pyrrolidine-1-yl, 3-(methylsulfonylamino)pyrrolidine-1-yl, 7-methyl-2,7-diazaspiro[4.4]non-2-yl, 4-[2-(dimethylamino)ethyl]-1,4-diazepane-1-yl, 4-(acetyl)-1,4-diazepane-1-yl, 5-oxo-1,4-diazepane-1-yl, and 1,4-oxazepane-4-yl.

[0174] In any of the above embodiments of the kinase inhibitor of formula (VIa) [including those of formula (Ia), (IIa), (IIIa), (IVa), and / or (Va)], R 1a It can be asymmetric. For example, R 1a The following groups may be selected: [ka] Here, R 30 And X is defined here; and the dashed line is thereby R 1a The group represents a bond that attaches to the rest of the compound. In one embodiment, R 1a It is asymmetric and selected from the following group: 3,4-dimethylpiperazinyl, 4-methyl-1,4-diazepane-1-yl, 3-oxopiperazine-1-yl, 2-methylmorpholin-4-yl, 3-methylpiperazine-1-yl, 3-(2-hydroxyethyl)piperazine-1-yl, 3-(2-hydroxyethyl)-4-methylpiperazine-1-yl, 3-(dimethylamino)piperidine-1-yl, 3-(methoxy)piperidine-1-yl, 3-(hydroxy)piperidine-1-yl, 3-(dimethyl Amino)pyrrolidine-1-yl, 3-(hydroxy)pyrrolidine-1-yl, 3-(2-methoxyethoxy)pyrrolidine-1-yl, 3-(acetylamino)pyrrolidine-1-yl, 3-(methylsulfonylamino)pyrrolidine-1-yl, 7-methyl-2,7-diazaspiro[4.4]non-2-yl, 4-[2-(dimethylamino)ethyl]-1,4-diazepane-1-yl, 4-(acetyl)-1,4-diazepane-1-yl, 5-oxo-1,4-diazepane-1-yl, and 1,4-oxazepane-4-yl.

[0175] In any of the above embodiments of the kinase inhibitor of formula (VIa) [including those of formula (Ia), (IIa), (IIIa), (IVa), and / or (Va)], thereby, R 1a However, the remaining R of the compound 1a The atoms may be atoms other than C, preferably thereafter R 1a However, the remaining R of the compound 1a The atom is a N atom. In this case, R 1a Preferably selected from the group consisting of: heterocyclyl, heteroaryl, -OR 11 , -N(R 12 )(R 13 ), -N(R11 )(OR 11 ), -S(O) 0-2 R 11 , -S(O) 1-2 Ure 11 , -OS(O) 1-2 R 11 , -OS(O) 1-2 Ure 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 Ure 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 Here, each heterocyclyl and heteroaryl group is bonded to the rest of the compound via an atom other than C, and one or more independently selected R atoms (for example, 1 for the maximum number of hydrogen atoms bonded to the heterocyclyl or heteroaryl group, such as 1-5, 1-4, or 1-3, or 1 or 2, up to 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) 30 And it can be replaced by any choice. For example, R 1a It can be a heterocycline, which contains at least one N-ring atom, and which is bonded to the rest of the compound via the N-ring atom.

[0176] In one embodiment, the kinase inhibitor of formula (VIa) is R 1b , R 1c , R 2 , R 3 , R 4 , R 5A, B, and E are defined independently above [especially in formulas (Ia), (IIa), (IIIa), (IVa) and / or (Va)] or below [especially in formulas (VIIa) and / or (VIIIa)], and R 1a The following group is selected: [ka] Here, the wavy line indicates that R 1a The group represents a bond that attaches to the rest of the compound. Preferably, R 1a The following group is selected: [ka] Here, the wavy line indicates that R 1a This represents the bond that the group forms with the rest of the compound.

[0177] In any of the above embodiments of the kinase inhibitor of formula (VIa) [including those of formula (Ia), (IIa), (IIIa), (IVa and / or (Va)], each R 1b R 1c The following can be independently selected from the group consisting of: 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, pyridinyl, pyrazolyl, phenoxy, pyridinyloxy, imidazolylamino, and tetrahydrofuranylmethoxy, where z is 0, 1, or 2; and each phenyl, pyridinyl, pyrazolyl, phenoxy, pyridinyloxy, imidazolylamino, and tetrahydrofuranylmethoxy group may be optionally substituted with 1, 2, or 3 moieties independently selected from the following: 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 Here, z is 0, 1, or 2. Preferably, R 1b and R 1c At least one of the following is selected from the group consisting of: 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, where z is 0, 1, or 2. In one embodiment, R 1b H; and R 1c is methyl, ethyl, propyl, isopropyl, or phenyl, preferably methyl. In an alternative embodiment, R 1b is methyl, ethyl, propyl, or isopropyl, preferably methyl; and R 1c H is H.

[0178] In any of the above embodiments of the kinase inhibitor of formula (VIa) [including those of formula (Ia), (IIa), (IIIa), (IVa), and / or (Va)], thereby, R 1c However, the remaining R of the compound 1c The atom can be a C atom. In this embodiment, R1c It is preferable that the following group be independently selected: C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, -CF3, -CN, -C(=O)(C 1-6 Alkyl), -C(=O)OH, -C(=O)O(C 1-6 Alkyl, and -C(=O)NH 2-z (C 1-6 Alkyl) z Here, z is 0, 1, or 2, and each C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 The alkynyl group can be optionally substituted with one, two, or three moieties independently selected from the following group: -OH, methyl, ethyl, -OCH3, -SCH3, and -NH 2-z (CH3) z .

[0179] In any of the above embodiments of the kinase inhibitor of formula (VIa) [including those of formulas (Ia), (IIa), (IIIa), (IVa), and / or (Va)], B is N or CR 1d And here, R 1d The following group can be selected: 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, where each C 1-3 The alkyl group may be optionally substituted with 1, 2, or 3 moieties independently selected from the following group: halogen, -OH, -OCH3, -SCH, and -NH 2-z (CH3) z Here, z is 0, 1, or 2. In any of the above embodiments of the kinase inhibitor of formula (VIa) [including those of formula (Ia), (IIa), (IIIa), (IVa) and / or (Va)], B is N or CR 1dAnd here, R 1d The following group can be selected: 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.

[0180] In any of the above embodiments of the kinase inhibitor of formula (VIa) [including those of formulas (Ia), (IIa), (IIIa), (IVa), and / or (Va)], it is preferable that B is N.

[0181] In one embodiment, the kinase inhibitor has formula (VIIa) or (VIIIa): [ka] Here, Hy, R 1a , R 1b , R 1c , R 2 , R 3 , R 4 , R 5 A, B, and E are defined above (in particular in formulas (Ia), (IIa), (IIIa), (IVa), (Va), and / or (VIa)) or below; L is a bond. In one preferred embodiment of the kinase inhibitor having formula (VIIa) or (VIIIa): (A) R 1a The group is selected from the following: alkyl, -O(alkyl), -S(alkyl), -NH(alkyl), -N(alkyl)2, and heterocyclyl, preferably heterocyclyl that is bonded to the remainder of the compound via an atom other than C, where each alkyl and heterocyclyl group is independently selected R 30 R can be optionally substituted with one or more (for example, 1 for the maximum number of hydrogen atoms bonded to the alkyl or heterocyclyl group, such as 1-5, 1-4, or 1-3, or 1 or 2, up to 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), where preferably each R30 The following are selected from the group: 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), -(CH2) 1-3 COOH and -NH 2-z (CH3) z Here, z is 0, 1, or 2; and each C 1-3 The alkyl group may be optionally substituted with one or two moieties selected from the group consisting of: -OH, -OCH3, -SCH3, cyclopropyl, piperazinyl, 4-methyl-piperazinyl, 4-(2-hydroxyethyl)piperazinyl, 2-(N,N-dimethylamino)ethoxy, and -NH 2-z (CH3) z , where z is 0, 1, or 2; and / or (B) Each R 1b and R 1c The following are independently selected from the group consisting of: 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, pyridinyl, pyrazolyl, phenoxy, pyridinyloxy, imidazolylamino, and tetrahydrofuranylmethoxy, where z is 0, 1, or 2; and each phenyl, pyridinyl, pyrazolyl, phenoxy, pyridinyloxy, imidazolylamino, and tetrahydrofuranylmethoxy group may be optionally substituted with one or two moieties selected from the group consisting of: 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 Here, z is 0, 1, or 2, preferably here R 1b and R 1c One of them is H; and R 1b and R 1c Other than these are methyl, ethyl, propyl, isopropyl, or phenyl, and more preferably R 1b and R 1c The others are methyl; and / or (C) R 3 The following group is selected: H, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-6 Cycloalkyl, phenyl, halogen, -CN, azide, -NO2, -O(C 1-6 Alkyl), -OCF3, -S(C 1-6 Alkyl), -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2,-NHS(O)2(C 1-6 Alkyl), -S(O)2NH 2-z (C 1-6 Alkyl) z -C(=O)(C 1-6 Alkyl), -C(=O)OH, -C(=O)O(C 1-6 Alkyl), -C(=O)NH 2-z (C 1-6Alkyl) z , -NHC(=O)(C 1-6 Alkyl), -NHC(=NH)NH z-2 (C 1-6 Alkyl) z , and -N(C 1-6 Alkyl)C(=NH)NH 2-z (C 1-6 Alkyl) z Here, z is 0, 1, or 2, and each C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-6 Cycloalkyl and phenyl groups are one or more independently selected R 30 Therefore, it can be optionally substituted, preferably R here 3 is H; and / or (D) at least one R 7 F, and / or at least one R 7 The following group is selected: alkyl, -OR 11 , and -N(R 12 )(R 13 ), where each alkyl and R 11 Base and R 12 and R 13 At least one of the groups is substituted with one or more F atoms; and / or (E) A is selected from the following group: S, O, NH, N(C 1-6 Alkyl, and C(C 1-6 Alkyl)2, preferably, where A is S; and / or (F) B is N or CR 1d , here, R 1d The following group is selected: 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, where each C 1-3The alkyl group may be optionally substituted with one or two moieties selected from the following group: halogen, -OH, -OCH3, -SCH, and -NH 2-z (CH3) z Here, z is 0, 1, or 2, preferably here, B is N; and / or (G) E is either O or S, preferably O.

[0182] In a preferred embodiment of a kinase inhibitor having formula (VIIa) or (VIIIa), R 1a It is defined as (A) above; R 1b and / or R 1c Defined as above (B); R 3 It is defined as (C) above; R 7 R is defined as shown in (D) above, where R 6 is defined above (particularly in relation to formula (IIa)); A is defined as in (E) above; B is defined as in (F) above; and E is defined as in (G) above.

[0183] In a more preferred embodiment of a kinase inhibitor having formula (VIIa) or (VIIIa): (A') R 1a The following group is selected: 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 3-11-membered heterocyclyl, preferably heterocyclyl bonded to the remainder of the compound via an atom other than C, where the 3-11-membered heterocyclyl group is independently selected R 30 If 1 or more, it can be optionally replaced, where R can be optionally replaced. 1a R can be independently selected to replace 30One or more of the following are independently selected from the group consisting of: 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), -(CH2) 1-3 COOH and -NH 2-z (CH3) z Here, z is 0, 1, or 2; and each C 1-3 The alkyl group may be optionally substituted with one or two moieties selected from the following group: -OH, -OCH3, -SCH3, cyclopropyl, piperazinyl, 4-methyl-piperazinyl, 4-(2-hydroxyethyl)piperazinyl, 2-(N,N-dimethylamino)ethoxy, and -NH 2-z (CH3) z , where z is 0, 1 or 2; and / or (B') R 1b and R 1c At least one of the following is selected from the group consisting of: 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, where z is 0, 1 or 2, and R 1b and R 1c Other than the above, (B) is defined, preferably, here R1b and R 1c One of them is H; and R 1b and R 1c Other than these are methyl, ethyl, propyl, isopropyl, or phenyl, and more preferably R 1b and R 1c The others are methyl; and / or (C') R 3 The following group is selected: H, C 1-4 Alkyl, C 3-6 Cycloalkyl, phenyl, halogen, -CN, -O(C 1-4 Alkyl), -OCF3, -S(C 1-4 Alkyl), -NH2, -NH(C 1-4 Alkyl), -N(C 1-4 Alkyl)2, -C(=O)(C 1-4 Alkyl), -C(=O)OH, -C(=O)O(C 1-4 Alkyl), -C(=O)NH 2-z (C 1-4 Alkyl) z , -NHC(=O)(C 1-4 Alkyl), -NHC(=NH)NH z-2 (C 1-4 Alkyl) z , and -N(C 1-4 Alkyl)C(=NH)NH 2-z (C 1-4 Alkyl) z Here, the phenyl group may be optionally substituted with one, two, or three groups independently selected from the following group: 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), -C(=O)NH 2-z (C 1-3 Alkyl) z ,-(CH2) 1-3 NH2, -(CH2) 1-3 NH(C 1-3 Alkyl), -(CH2) 1-3 N(C 1-3Alkyl)2,-(CH2) 1-3 OH and -(CH2) 1-3 O(C 1-3 alkyl); and where z is 0, 1 or 2, preferably where R 3 is H; and / or (D') R 7 At least one of them is F, and / or R 7 At least one of the following is selected from the group: C 1-3 Alkyl, -O(C 1-3 Alkyl), -NH(C 1-3 Alkyl) or -N(C 1-3 Alkyl)2, here, C 1-3 Alkyl, -NH(C 1-3 Alkyl), and -O(C 1-3 Alkyl) alkyl groups, and -N(C 1-3 At least one of the alkyl groups in alkyl)2 is substituted with one or more fluorine atoms; (E') A is S, O, or N(CH3)2, preferably where A is S; and / or (F') B is N or CR 1d And here R 1d The following group is selected: 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, preferably, where B is N; and / or (G') E is either O or S, preferably O.

[0184] In a more preferred embodiment of a kinase inhibitor having formula (VIIa) or (VIIIa), R 1a is defined in (A') above; R 1b and R 1c is defined in (B') above; R 3 is defined in (C') above; R7 is defined in (D') above, where R 6 is defined above (particularly in relation to (IIa)); A is defined above in (E'); B is defined above in (F'); and E is defined above in (G').

[0185] In a more preferred embodiment of a kinase inhibitor having formula (VIIa) or (VIIIa): (A'') R 1a R is a heterocyclyl that is bonded to the rest of the compound via an atom other than C, where the 3-~11-membered heterocyclyl group is optionally one or two independently selected R groups. 30 So, it is replaced, and here, R 1a One or two independently selected Rs that can optionally replace R 30 The following are selected from the group: 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), -(CH2) 1-3 COOH and -NH 2-z (CH3) z Here, z is 0, 1, or 2; and each C 1-3The alkyl group may be optionally substituted with one or two moieties independently selected from the following group: -OH, -OCH3, -SCH3, cyclopropyl, piperazinyl, 4-methyl-piperazinyl, 4-(2-hydroxyethyl)piperazinyl, 2-(N,N-dimethylamino)ethoxy, and -NH 2-z (CH3) z , where z is 0, 1 or 2; and / or (B'') R 1b and R 1c One of them is H; and R 1b and R 1c Other than these are methyl, ethyl, propyl, isopropyl, or phenyl, and more preferably R 1b and R 1c The others are methyl; and / or (C'') R 3 is H; and / or (D'') R 7 At least one of them is F, and / or R 7 At least one of the following is selected from the group: C 1-3 Alkyl, -O(C 1-3 Alkyl), -NH(C 1-3 Alkyl) or -N(C 1-3 Alkyl)2, here, C 1-3 Alkyl, -NH(C 1-3 Alkyl), and -O(C 1-3 Alkyl) alkyl groups, and -N(C 1-3 At least one of the alkyl groups in alkyl)2 is substituted with one or more fluorine atoms; (E'') A is S; and / or (F'') B is N; and / or (G'') E is O.

[0186] In a preferred embodiment of a kinase inhibitor having formula (VIIa) or (VIIIa), R1a is defined in (A'') above; R 1b and R 1c is defined in (B'') above; R 3 This is defined in (C'') above; R 7 is defined in (D'') above, where R 6 is defined above (in particular in relation to formula (IIa)); A is defined above in (E''); B is defined above in (F''); and E is defined above in (G'').

[0187] In a more preferred embodiment of a kinase inhibitor having formula (VIIa) or (VIIIa), [in particular, R 1a , R 1b , R 1c , R 3 [when A, B, and E are defined in (A), (B), (C), (E), (F), and / or (G) above, or (A'), (B'), (C'), (E'), (F'), and / or (G') above, or (A''), (B''), (C''), (E''), (F''), and / or (G'') above, one R 7 The group is selected from -CH2F, -CHF2, and -CF3, and preferably selected from -CH2F and -CHF2.

[0188] In a more preferred embodiment of a kinase inhibitor having formula (VIIa) or (VIIIa), [in particular, R 1a , R 1b , R 1c , R 3 [when A, B, and E are defined in (A), (B), (C), (E), (F), and / or (G) above, or (A'), (B'), (C'), (E'), (F'), and / or (G') above, or (A''), (B''), (C''), (E''), (F''), and / or (G'') above, one R 7 (Preferably R is F) 7 , and / or R substituted with one or more F atoms 7 ) thereafter, R 6However, it bonds to the C ring atom at position 2 or 5 relative to the ring atom bonded to the rest of the compound.

[0189] In a more preferred embodiment of a kinase inhibitor having formula (VIIa) or (VIIIa), [in particular, R 1a , R 1b , R 1c , R 3 [When A, B, and E are defined in (A), (B), (C), (E), (F), and / or (G) above, or (A'), (B'), (C'), (E'), (F'), and / or (G') above, or (A''), (B''), (C''), (E''), (F''), and / or (G'') above, R 6 is at least two R 7 It is replaced by R. 6 These are two different Rs 7 It can be replaced by...

[0190] In a more preferred embodiment of a kinase inhibitor having formula (VIIa) or (VIIIa), [in particular, R 1a , R 1b , R 1c , R 3 [When A, B, and E are defined in (A), (B), (C), (E), (F), and / or (G) above, or (A'), (B'), (C'), (E'), (F'), and / or (G') above, or (A''), (B''), (C''), (E''), (F''), and / or (G'') above, R 6 is at least two R 7 It is replaced by, here, one R 7 (Preferably R is F) 7 , and / or R substituted with one or more F atoms 7 ) thereafter, R 6 However, it is bonded to one of the C ring atoms at position 2 or 5 relative to the ring atom bonded to the rest of the compound, and one R 7 Therefore, R 6 However, it bonds to the ring atoms that are bonded to the rest of the compound, in addition to the C ring atoms at the 2nd or 5th position.

[0191] In a more preferred embodiment of a kinase inhibitor having formula (VIIa) or (VIIIa), [in particular, R 1a , R 1b , R 1c , R 3 [When A, B, and E are defined in (A), (B), (C), (E), (F), and / or (G) above, or (A'), (B'), (C'), (E'), (F'), and / or (G') above, or (A''), (B''), (C''), (E''), (F''), and / or (G'') above, R 6 is at least two R 7 Then it is replaced, and here one R 7 It is selected from the group consisting of -CH2F, -CHF2, and -CF3, and one R 7 The is selected from the group consisting of halogens, -CH3, -CH2(hal), -CH(hal)2, and -C(hal)3, and more preferably from the group consisting of Cl, Br, F, -CH3, -CH2F, -CHF2, and -CF3. In one embodiment, one R 7 is selected from the group consisting of -CH2F, -CHF2, and -CF3, preferably selected from the group consisting of -CH2F and -CHF2, and one R 7 is Cl. In an alternative embodiment, one R 7 is F, and one R 7 The is selected from the group consisting of halogens, CH3, -CH2(hal), -CH(hal)2, and -C(hal)3, more preferably from the group consisting of Cl, Br, F, CH3, -CH2F, -CHF2, and -CF3. Alternatively, in this embodiment, one R 7 is F, and one R 7 It is preferable that the component is Cl.

[0192] In a more preferred embodiment of a kinase inhibitor having formula (VIIa) or (VIIIa), [in particular, R 1a , R 1b , R 1c , R 3[When A, B, and E are defined in (A), (B), (C), (E), (F), and / or (G) above, or (A'), (B'), (C'), (E'), (F'), and / or (G') above, or (A''), (B''), (C''), (E''), (F''), and / or (G'') above, R 6 is selected from the group consisting of thienyl, thiazolyl, and thiadiazolyl, preferably selected from the group consisting of thienyl and thiazolyl, more preferably R 6 R is thienyl, where each thienyl, thiazolyl, and thiadiazolyl group is independently selected from 1 or more (for example, 1 for the maximum number of hydrogen atoms bonded to the thienyl, thiazolyl, or thiadiazolyl group, such as 1 or 2, or 1, 2 or 3) 7 And it gets replaced.

[0193] In a more preferred embodiment of a kinase inhibitor having formula (VIIa) or (VIIIa), [in particular, R 1a , R 1b , R 1c , R 3 [when A, B, and E are defined in (A), (B), (C), (E), (F), and / or (G) above, or (A'), (B'), (C'), (E'), (F'), and / or (G') above, or (A''), (B''), (C''), (E''), (F''), and / or (G'') above, therefor R 6 However, R binds to the rest of the compound. 6 The ring atom is a carbon atom.

[0194] In a more preferred embodiment of a kinase inhibitor having formula (VIIa) or (VIIIa), [in particular, R 1a , R 1b , R 1c , R 3[When A, B, and E are defined in (A), (B), (C), (E), (F), and / or (G) above, or (A'), (B'), (C'), (E'), (F'), and / or (G') above, or (A''), (B''), (C''), (E''), (F''), and / or (G'') above, R 6 The S ring atom is thereby R 6 However, it is not adjacent to the ring atom bonded to the rest of the compound.

[0195] In a more preferred embodiment of a kinase inhibitor having formula (VIIa) or (VIIIa), [in particular, R 1a , R 1b , R 1c , R 3 [When A, B, and E are defined in (A), (B), (C), (E), (F), and / or (G) above, or (A'), (B'), (C'), (E'), (F'), and / or (G') above, or (A''), (B''), (C''), (E''), (F''), and / or (G'') above, R 6 The following group is selected: [ka] More preferably, the following group is selected: [ka] Here, the wavy line indicates that R 6 This represents a bond that forms on the rest of the compound.

[0196] In any of the above embodiments of the kinase inhibitor of formula (VIIa) or (VIIIa) [including those of formula (Ia), (IIa), (IIIa), (IVa), (Va), and / or (VIa)], R 1a The following group can be selected: -NH(C 1-3Alkyl), piperazinyl, piperidinyl, morpholinyl, pyrrololidinyl, diazepanyl, oxazepanyl, and diazaspirononyl, where each piperazinyl, piperidinyl, morpholinyl, pyrrololidinyl, diazepanyl, oxazepanyl, and diazaspirononyl group is optionally one or two independently selected R 30 So, it is replaced, and here, R 1a R, which can be optionally replaced by either 1 or 2, is independently selected. 30 The following are independently selected from the group consisting of: 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 Here, z is 0, 1, or 2. For example, R 1a The following can be selected from the group: 4-(2-hydroxyethyl)piperazinyl, 4-methylpiperazinyl, 3,4-dimethylpiperazinyl, 4-methyl-1,4-diazepan-1-yl, 3-oxopiperazine-1-yl, 2-methylmorpholin-4-yl, 3-methylpiperazine-1-yl, 3-(2-hydroxyethyl)piperazine-1-yl, 3-(2-hydroxyethyl)-4-methylpiperazine-1-yl, 3-(dimethylamino)piperidine-1-yl, 3-(methoxy)piperidine-1-yl, 3-(hydroxy)piperidine -1-yl, 3-(dimethylamino)pyrrolidine-1-yl, 3-(hydroxy)pyrrolidine-1-yl, 3-(2-methoxyethoxy)pyrrolidine-1-yl, 3-(acetylamino)pyrrolidine-1-yl, 3-(methylsulfonylamino)pyrrolidine-1-yl, 7-methyl-2,7-diazaspiro[4.4]non-2-yl, 4-[2-(dimethylamino)ethyl]-1,4-diazepane-1-yl, 4-(acetyl)-1,4-diazepane-1-yl, 5-oxo-1,4-diazepane-1-yl, and 1,4-oxazepane-4-yl.

[0197] Formula (VIIa) or (VIIIa) [including those of formulas (Ia), (IIa), (IIIa), (IVa), (Va) and / or (VIa), in particular R 1a , R 1b , R 1c , R 3 , R 7 In any of the above embodiments of the kinase inhibitor, when A, B, and E are defined by (A), (B), (C), (D), (E), (F), and / or (G), or by (A'), (B'), (C'), (D'), (E'), (F'), and / or (G'), or by (A''), (B''), (C''), (D''), (E''), (F''), and / or (G''), R 1a It can be asymmetrical.

[0198] Formula (VIIa) or (VIIIa) [including those of formulas (Ia), (IIa), (IIIa), (IVa), (Va) and / or (VIa), in particular R 1a , R 1b , R 1c , R 3 , R 7 In any of the above embodiments of the kinase inhibitor, where A, B, and E are defined by (A), (B), (C), (D), (E), (F), and / or (G), or by (A'), (B'), (C'), (D'), (E'), (F'), and / or (G'), or by (A''), (B''), (C''), (D''), (E''), (F''), and / or (G''), thereby R 1a However, R binds to the rest of the compound. 1a The atom may be an atom other than C; preferably, R 1a However, R binds to the rest of the compound. 1a The atom is a nitrogen atom.

[0199] Formula (VIIa) or (VIIIa) [including those of formulas (Ia), (IIa), (IIIa), (IVa), (Va) and / or (VIa), in particular R 1a , R 1b , R 1c , R3 , R 7 In any of the above embodiments of the kinase inhibitor, where A, B, and E are defined by (A), (B), (C), (D), (E), (F), and / or (G), or by (A'), (B'), (C'), (D'), (E'), (F'), and / or (G'), or by (A''), (B''), (C''), (D''), (E''), (F''), and / or (G''), thereby R 1a However, R binds to the rest of the compound. 1a The atom could be a carbon atom.

[0200] In any of the above embodiments of the kinase inhibitor of formula (VIIa) or (VIIIa) [including those of formula (Ia), (IIa), (IIIa), (IVa), (Va), and / or (VIa)], R 1b H is; and R 1c The compound is methyl, ethyl, propyl, isopropyl, or phenyl, and is preferably methyl.

[0201] In any of the above embodiments of the kinase inhibitor of formula (VIIa) or (VIIIa) [including those of formula (Ia), (IIa), (IIIa), (IVa), (Va), and / or (VIa)], it is preferable that A is S; B is N; and / or E is O.

[0202] More preferably, in any of the above embodiments of the kinase inhibitor of formula (VIIa) or (VIIIa) [including those of formula (Ia), (IIa), (IIIa), (IVa), (Va), and / or (VIa)], A is S; B is N; and E is O.

[0203] In any of the above embodiments of the kinase inhibitor of formula (VIIa) or (VIIIa) [including those of formula (Ia), (IIa), (IIIa), (IVa), (Va), and / or (VIa)], R 3Preferably selected from the group consisting of: H, methyl, ethyl, propyl, isopropyl, phenyl, and halogen; more preferably R 3 H is H.

[0204] In one embodiment, the compound of the present invention is selected from the compounds shown in Figure 1E.

[0205] In the fifth aspect of the present invention, the present invention provides a compound or pharmaceutical composition for use in a treatment of proliferative impairment in a subject, a treatment comprising administering the compound or pharmaceutical composition to the subject, wherein the compound is selected from (a) the compound of the first aspect; (b) the compound of formula (Ib); and (c) the compound of formula (Ic), or a pharmaceutical composition that may contain such a compound and optionally pharmaceutically acceptable excipients: Formula (Ib) [ka] and its solvates, salts, N-oxides, complexes, polymorphs, crystalline forms, racemic mixtures, diastereomers, enantiomers, tautomers, conformatorisomers, isotope-labeled compounds, prodrugs, and combinations thereof. Here, Hy, R 2 , R 3 , R 4 A, and E are defined above [in particular in formulas (Ia), (IIa), (IIIa), (IVa), (Va), (VIa), (VIIa) and / or (VIIIa)] or below; R 5' -LR 6' L is a combination; R is a combination. 6' R is one or more independently selected values. 7' And it is a 5- or 6-membered heteroaryl that can be optionally substituted; R 7' The following group is independently selected: R 7 Alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, 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 Ure 11 , -OS(O) 1-2 R 11 , -OS(O) 1-2 Ure 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 Ure 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 Here, each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl group is one or more independently selected R 30 And it can be optionally substituted; and R 11 , R 12 , R 13 , X, and R 30 It is defined independently as described above (especially with respect to (Ia)); [ka] and its solvates, salts, N-oxides, complexes, polymorphs, crystalline forms, racemic mixtures, diastereomers, enantiomers, tautomers, conformatorisomers, isotope-labeled compounds, prodrugs, and combinations thereof. Here, R 1a , R 1b , R 1c , R 2 , R 3 , R 4 A, B, and E are defined independently above [in particular with respect to formulas (Ia), (IIIa), (IVa), (VIa), (VIIa) and / or (VIIIa)] or below; R 5'' -LR 6'' And; L is defined above [particularly with respect to formulas (Ia) and / or (IIa)]; R 6'' is a heteroaryl or heterocyclyl, each of which is one or more independently selected R 7' And it can be optionally replaced; R 7' The following group is independently selected: R 7 Alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, 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 Ure 11 , -OS(O) 1-2 R 11 , -OS(O) 1-2 Ure 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 Ure 11 , -NR 11 S(O) 1-2 N(R 12 )(R 13 ), -P(O)(OR 11 )2, -OP(O)(OR11 )2, -C(=X)R 11 -C(=X)XR 11 -XC(=X)R 11 , and -XC(=X)XR 11 , and / or R is a heterocyclyl group 6'' Any two R atoms bonded to the same atom 7' These groups can bond together to form =O, where each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl group can optionally be one or more independently selected R groups. 30 And it can be substituted; and R 11 , R 12 , R 13 , X, and R 30 These are defined independently, with respect to the above definition [especially equation (Ia)].

[0206] In one embodiment, the compound of formula (Ib) for use in a fifth aspect is the following general formula (IIb): [ka] Here, Hy, R 2 , R 3 , R 4 A, and E are defined above [in particular with respect to formulas (Ib), (IIIa), (IVa), (Va), (VIa), (VIIa) and / or (VIIIa)] or below [in particular with respect to formula (IIIb)], and R 6' The R selected independently 7' A 5- or 6-membered heteroaryl that can be optionally substituted with one or more of the following (e.g., 1 to 4, or 1 to 3, or 1 or 2, such as 1, 2, 3, 4, 5) such as 1 for the maximum number of hydrogen atoms bonded to the 5- or 6-membered heteroaryl group.

[0207] In one embodiment of the compound of formula (IIb) for use in a fifth aspect, Hy, R 2 , R 3 , R 4A, E, and R are defined independently as above [in particular with respect to formulas (Ib), (IIIa), (IVa), (Va), (VIa), (VIIa) and / or (VIIIa)] or below [in particular with respect to formula (IIIb)], and R 6' The following R 6'' Therefore, it is a 5- or 6-membered heteroaryl group as defined [in particular with respect to formula (Vc)].

[0208] In one embodiment of the compound of formula (IIb) for use in a fifth aspect, Hy, R 2 , R 3 , R 4 A, E, and R are defined independently as above [in particular with respect to formulas (Ib), (IIIa), (IVa), (Va), (VIa), (VIIa) and / or (VIIIa)] or below [in particular with respect to formula (IIIb)], and R 6' is a 5- or 6-membered heteroaryl (in particular, a 5-~6-membered monocyclic heteroaryl) comprising at least one ring heteroatom selected from the group consisting of N, O, and S, where the 5- or 6-membered heteroaryl is independently selected R 7' One or more of the following (e.g., 1-4, or 1-3, or 1 or 2, such as 1, 2, 3, 4, 5) can be optionally substituted (e.g., 1 for the maximum number of hydrogen atoms bonded to a 5- or 6-membered heteroaryl group). For example, R 6' This is a 5- or 6-membered heteroaryl compound containing at least one ring heteroatom selected from the group consisting of N and O [for example, the heteroaryl does not contain S as a ring heteroatom; and, in some embodiments, does not contain O as a ring heteroatom, for example, R]. 6' may by be an N-heteroaryl group, where the 5- or 6-membered heteroaryl group is independently selected R 7' It may be optionally substituted with 1, 2, or 3 of [as defined in this specification, for example, with respect to the following formula (Vc)].

[0209] In one embodiment of the compound of formula (IIb) for use in a fifth aspect, Hy, R 2 , R 3 , R 4 A, E, and R are defined independently as above [in particular with respect to formulas (Ib), (IIIa), (IVa), (Va), (VIa), (VIIa) and / or (VIIIa)] or below [in particular with respect to formula (IIIb)], and R 6' The following are selected from the group consisting of: pyridinyl, thienyl, pyridazinyl, pyrimidinyl, pyrazinyl, furanyl, pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl, and oxadiazolyl, each of which is independently selected from 1, 2, or 3 R 7' [In particular, with respect to formula (Vc) below, as defined herein] may be optionally substituted, preferably R 6' The following group is selected: pyridinyl, thienyl, pyrazolyl, isoxazolyl, and pyrrolyl, each of which is independently selected from 1, 2, or 3 R 7' [In particular, as defined herein, for example with respect to the following formula (Vc)] can be optionally substituted.

[0210] In any of the above embodiments of the compound of formula (IIb) for use in the fifth aspect [including that of formula (Ib)], R 7' The following group is independently selected: R 7 , C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkynyl, halogen, -CN, -O(C) 1-6 Alkyl), -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2,-NHS(O) 1-2 (C 1-6 Alkyl), -NHS(O) 1-2 O(C 1-6 Alkyl), -C(=O)(C 1-6 Alkyl), and -OC(=O)(C 1-6 Alkyl), where each C 1-6 Alkyl, C 2-6Alkenyl and C 2-6 The alkynyl group is one or more (for example, C 1-6 Alkyl, C 2-6 Alkenil, or C 2-6 R is independently selected from the maximum number of hydrogen atoms bonded to the alkynyl group, such as 1 for 1-5, 1-4, or 1-3, or 1 or 2 (up to 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), 30 And it can be replaced by any choice (where each R 30 ( Preferably selected from the first-level substituents, second-level substituents, and third-level substituents as defined herein). For example, R 7' The following group is independently selected: C 1-3 Alkyl, halogen, -CN, -O(C 1-3 Alkyl), -NH(C 1-3 Alkyl), and -N(C 1-3 Alkyl)2, where each C 1-3 The alkyl group must be one or more (for example, C 1-3 R is independently selected from the maximum number of hydrogen atoms bonded to the alkyl group, such as 1 for 1-5, 1-4, or 1-3, or 1 or 2 (up to 1, 2, 3, 4, 5, 6, 7, or 6), 30 And it can be replaced by any choice (where each R 30 ( Preferably selected from the first-level substituent, second-level substituent and third-level substituent as defined herein). In any of the above embodiments of the compound of formula (IIb) for use in the fifth aspect [including that of formula (Ib)], R 7' R is independently selected from the group consisting of Cl, Br, methyl, and ethyl, such as from the group consisting of Cl, Br, and methyl. In any other embodiment of the compound of formula (IIb) described above [including that of formula (Ib)], R 7' is any R that can be defined in relation to equation (Ia). 7 Like, independently, R 7 It is possible.

[0211] In any of the above embodiments of the compound of formula (IIb) for use in the fifth aspect [including that of formula (Ib)], R 6' It has been substituted, and one R 7' The basis is, by that, R 6' However, at the 2nd position, relative to the ring atom that is bonded to the rest of the compound, R 6' It is preferable to bond to the ring atom of (for example, R 6' OrthoR 7' (It is preferable to have a group). In any of the above embodiments of the compound of formula (IIb) for use in the fifth aspect [including that of formula (Ib)], R 6' R is 2 or more (such as 2, 3, or 4) 7' Substituted with a group, and 2 or more R 7' One of the bases is, by that, R 6' However, R is attached to the rest of the compound at the 2nd position in relation to the ring atom. 6' Bonded to the ring atom (for example, R 6' OrthoR 7' (having a base), and the remaining R 7' The base (singular or plural) is in a position other than the 2nd position, R 6' It is preferable that it bond to one or more ring atoms of . For example, in any of the above embodiments of the compound of formula (IIb) for use in the fifth aspect [including that of formula (Ib)], R 6' is R 2 or greater 7' A k-membered ring substituted with a group, and containing 2 or more R groups. 7' One of the bases is, by that, R 6' However, in relation to the regurgitated atom bonded to the rest of the compound, at position 2, R 6' Bonded to the ring atom (e.g., related to the yl position), and the remaining R 7' The base (singular or plural) is in a position other than the 2nd position, for example, the 3rd, 4th, 5th, ..., kth position, R 6' It is preferable to bond to one or more ring atoms of R. For example, R 6' In the case of a 5-membered ring, 2 or more R 7' One of the groups is R at position 2 (relative to the yl position). 6' Bonded to the ring atom, and the remaining R 7'The base (singular or plural) is at the 3rd, 4th, or 5th position (relative to the yl position), R 6' It is preferable that it bond to the ring atoms (or more) of . Furthermore, in any of the above embodiments of the compound of formula (IIb) for use in the fifth aspect [including that of formula (Ib)], R 6' R is 2 or more (such as 2, 3, or 4) 7' It is substituted with a group, and thereafter, R 6' However, each of the two ring atoms directly adjacent to the ring atom bonded to the rest of the compound has one R 7' It is preferable to have a group (for example, a k-membered ring R 6' Therefore, R 6' However, in relation to the ring atom bonded to the rest of the compound, one R is present at each of the 2 and k positions. 7' It has a base. For example, R 6' (is substituted at both ortho positions). In addition, in any of the above embodiments of the compound of formula (IIb) for use in the fifth aspect [including that of formula (Ib)], R 6' R is 2 or more (such as 3 or 4) 7' It is substituted with a group, and thereafter, R 6' However, each of the two ring atoms directly adjacent to the ring atom bonded to the rest of the compound has one R 7' Having a group (for example, a k-membered ring R) 6' Therefore, R 6' However, in relation to the ring atom bonded to the rest of the compound, one R is present at each of the 2 and k positions. 7' It has a base. For example, R 6' (is substituted in both of its ortho positions), and the third R 7' The group is directly adjacent to one of the ortho ring atoms. 6' It bonds to the ring atom, but that is how R 6' However, it is not a ring atom that is bonded to the rest of the compound (for example, a k-membered ring R). 6' Therefore, R 6' However, in relation to the ring atom bonded to the rest of the compound, a third R is located at one of the 3rd and k-1st positions. 7' It is preferable that it has a base.

[0212] In one embodiment of the compound of formula (IIb) for use in a fifth aspect, Hy, R 2 , R 3 , R 4 A, E, and R are defined independently above [particularly in terms of formulas (Ib), (IIIa), (IVa), (Va), (VIa), (VIIa), and / or (VIIIa)] or below [particularly in terms of formula (IIIb)], and R 6' It is selected from the following formula: [ka] Here, the wavy line indicates that R 6' However, this represents a bond that connects to the rest of the compound.

[0213] In one embodiment of the compound of formula (IIb) for use in a fifth aspect, Hy, R 2 , R 3 , R 4 A, E, and R are defined independently above [particularly in terms of formulas (Ib), (IIIa), (IVa), (Va), (VIa), (VIIa), and / or (VIIIa)] or below [particularly in terms of formula (IIIb)], and R 6' It is selected from the following formula: [ka] Here, the wavy line indicates that R 6' However, this represents a bond that connects to the rest of the compound.

[0214] In one embodiment of the compound of formula (IIb) for use in a fifth aspect, Hy, R 2 , R 3 , R 4 A, E, and R are defined independently above [particularly in terms of formulas (Ib), (IIIa), (IVa), (Va), (VIa), (VIIa), and / or (VIIIa)] or below [particularly in terms of formula (IIIb)], and R 6' It is selected from the following formula: [ka] Here, the wavy line indicates that R 6' This indicates a bond, specifically a bonding that occurs when a molecule binds to the rest of the compound.

[0215] In one embodiment of the compound of formula (IIb) for use in a fifth aspect [including the compound of formula (Ib)], R 6' R is a 5- or 6-membered heteroaryl containing an N atom as a ring heteroatom, 6' It can bond to the rest of the compound via the N ring atom of the heteroaryl group.

[0216] In one embodiment, for use in a fifth aspect, the compound of formula (Ib) has general formula (IIIb): [ka] Here, R 2 , R 3 , R 4 , R 5' A, E, and Hy are defined 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 independently selected R 1e A heteroaryl or heterocycline that can be optionally substituted with one or more of (such as 1 for the maximum number of hydrogen atoms bonded to the heteroaryl or heterocycline group, for example, 1-5, 1-4, or 1-3, or 1 or 2, up to 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10); each R 1e R 1a , R 1b , R 1c and R 1d Independently selected from the group consisting of; and each R 1a , R 1b R 1c and R 1dThese are defined independently as described above [in particular with respect to formulas (Ia), (IVa), (VIIa) and / or (VIIIa)] or below [in particular with respect to formulas (IIc), (IIIc), (VIIc) and / or (VIIIc)].

[0217] In one embodiment of the compound of formula (IIIb), R 2 , R 3 , R 4 , R 5' A, E, and Hy are defined independently as described above [in particular with respect to formulas (Ib), (IIb), (IIIa), (IVa), (VIIa), and / or (VIIIa)] or as described below [in particular with respect to formulas (IVc), (VIc), and / or (VIIc)], and Hy is defined as described above [in particular with respect to formulas (Va), (VIa), (VIIa), and / or (VIIIa)].

[0218] In one embodiment of the compound of formula (IIIb), R 2 , R 3 , R 4 , R 5' A, E, and Hy are independently defined 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-membered heteroaryl or 3-~10-membered heterocyclil, each of which is optionally selected from 1, 2, 3, 4, 5, or 6, independently as defined herein. 1e [In particular with respect to formulas (Ib), (IIIb), (Ia), and / or (Va)] these can be substituted.

[0219] In one embodiment of the compound of formula (IIIb), R 2 , R 3 , R 4 , R 5'A, E, and R are independently defined 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 bi-cyclic heteroaryl or mono- or bi-cyclic heterocyclil, each of which is optionally selected independently from 1, 2, 3, 4, 5, or 6 as defined herein [particularly with respect to formulas (Ib), (IIIb), (Ia), and / or (Va)]. 1e And it can be replaced.

[0220] In one embodiment of the compound of formula (IIIb), R 2 , R 3 , R 4 , R 5' A, E, and Hy are independently defined 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 the group consisting of: 5-~6-membered monocyclic heteroaryls, 5-~6-membered monocyclic heterocyclines, 9-~10-membered bicyclic heteroaryls, and 8-~10-membered bicyclic heterocyclines, each of which is optionally independently selected from 1, 2, 3, 4, 5, or 6 R 1e These can be substituted [in particular with respect to formulas (Ib), (IIIb), (Ia), and / or (Va)].

[0221] In one embodiment of the compound of formula (IIIb), R 2 , R 3 , R 4 , R 5'A, E, and Hy are independently defined 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 the group consisting of: pyridinyl, pyrimidinyl, pyrazinyl, pyridadinyl, triazinyl (e.g., 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl), pyrazolyl, oxadiazolyl, thiazolyl, triazolyl, thiadi Azolyl, cyclopentapyrimidinyl, dihydrocyclopentapyrimidinyl, pyrrolopyrimidinyl, indolidinyl, dihydroindolidinyl, tetrahydroindolidinyl, quinazolinyl, dihydroquinazolinyl, tetrahydroquinazolinyl, pyridopyrimidinyl, pyranopyrimidinyl, dihydropyranopyrimidinyl, tetrahydropyranopyrimidinyl, piperidinyl, tetrahydropyranyl, and 1,1-dioxidetetrahydrothiopyranyl, each of which can be optionally selected from 1, 2, 3, 4, 5, or 6 independently. 1e These can be substituted [in particular with respect to formulas (Ib), (IIIb), (Ia), and / or (Va)].

[0222] In one embodiment of the compound of formula (IIIb), R 2 , R 3 , R 4 , R 5' A, E, and E are independently defined 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 selected from the group consisting of the following: [ka] Here, each of the groups identified by a), b), c), d), e), f), and g) above is independently selected from R 1, 2, 3, 4, 5, or 6. 1e[Especially with respect to equations (Ib), (IIIb), (Ia), and / or (Va)], which can be optionally substituted, and where the tilde indicates that Hy is replaced by NR in equation (IIIb). 2 This represents the bond to the nitrogen atom of a moiety. If Hy contains NH as a ring member, the hydrogen atom is C 1-6 Or C 1-3 It is preferable to be substituted with an alkyl, more preferably methyl (forming an alkyl-substituted N ring atom), and Hy is independently selected from R 1, 2, 3, 4, or 5. 1e And, optionally, further substitutions are possible. Examples of such N-alkyl-substituted Hy groups include: [ka] Here, the dashed line indicates that Hy is, thereby, NR in equation (Ib). 2 This shows the bond that connects to the nitrogen atom of moiety.

[0223] In any of the above embodiments of the compound of formula (IIIb), Hy is one R 1b , one R 1c , and R between 1 and 4, such as 1, 2 or 3 1a Or R 1d Therefore, it can be optionally substituted; for example, Hy is R 1 (or 2). 1a [As defined above, particularly with respect to formulas (VIa), (VIIa) and / or (VIIIa), or hereafter, particularly with respect to formulas (IIc) and / or (VIIIc)], and R of 1 (or 2) 1b Or R 1c [As defined above, particularly with respect to formulas (VIa), (VIIa) and / or (VIIIa), or hereafter, particularly with respect to formulas (IIIc) and / or (VIIIc)], may be substituted, and all other R 1e H is H.

[0224] In any of the above embodiments of the compounds of formulas (Ib), (IIb), and (IIIb), it is preferable that A is S and / or E is O.

[0225] In any of the above embodiments of the compounds of formula (Ib), (IIb), and (IIIb), R 3 It is preferable that it be H.

[0226] In any of the above embodiments of the compounds of formulas (Ib), (IIb), and (IIIb), A is S and / or E is O and / or R 3 It is preferable that is H. For example, in one embodiment of the compounds of formulas (Ib), (IIb), and (IIIb), A is S; E is O; and R 3 H is H.

[0227] In one embodiment, a compound of formula (Ic) for use in a fifth aspect has the general formula (IIc): [ka] Here, R 1b , R 1c , R 2 , R 3 , R 4 , R 5'' A, B, and E are defined above [in particular with respect to formulas (Ic), (IIIa), (IVa), (VIa), (VIIa) and / or (VIIIa)] or below [in particular with respect to formulas (IIIc), (IVc), (Vc), (VIc), (VIIc) and / or (VIIIc)], and R 1a R is selected from the group consisting of: alkyl, -O(alkyl), -S(alkyl), -NH(alkyl), -N(alkyl)2, and heterocyclyl, where each alkyl and heterocyclyl group is optionally selected from one or more (e.g., 1, 2, or 3) independently selected groups. 30 And it can be substituted. Preferably, each R 30These are independently first-level substituents, second-level substituents, or third-level substituents, such as: alkyl (e.g., C 1-6 Alkyl), -(CH2) 1-3 OH, alkenyl (for example, C 2-6 Alkenyl), Alkinyl (for example, C 2-6 Alkynyl, halogen, -CN, nitro, -OR 11 (For example, -OH), -SR 11 (For example, -SH), -N(R 12 )(R 13 )(e.g., -NH2), and -C(=O)R 11 (For example, -C(=O)(C 1-3 Alkyl)).

[0228] 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 defined above [in particular with respect to formulas (Ic), (IIIa), (IVa), (VIa), (VIIa) and / or (VIIIa)] or below [in particular with respect to formulas (IIIc), (IVc), (Vc), (VIc), (VIIc) and / or (VIIIc)], and R 1a The following group is selected: 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-~7-membered heterocyclyl, where the 3-~7-membered heterocyclyl group may be optionally substituted with 1 or 2 moieties independently selected from the group consisting of: 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 1-3Alkyl), -(CH2) 1-3 COOH and -NH 2-z (CH3) z Here, z is 0, 1, or 2; and each C 1-3 The alkyl group may be optionally substituted with one or two moieties independently selected from the following group: -OH, -OCH3, -SCH3, cyclopropyl, piperazinyl, 4-methyl-piperazinyl, 4-(2-hydroxyethyl)piperazinyl, 2-(N,N-dimethylamino)ethoxy, and -NH 2-z (CH3) z Here, z is 0, 1, or 2.

[0229] 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 defined above [in particular with respect to formulas (Ic), (IIIa), (IVa), (VIa), (VIIa) and / or (VIIIa)] or below [in particular with respect to formulas (IIIc), (IVc), (Vc), (VIc), (VIIc) and / or (VIIIc)], and R 1a The following group is selected: C 1-3 Alkyl, -O(C 1-3 Alkyl), -S(C 1-3 Alkyl), -NH(C 1-3 Alkyl), piperazinyl, morpholinyl, piperidinyl, and pyrrolidinyl, where each piperazinyl, morpholinyl, piperidinyl, and pyrrolidinyl group may be optionally substituted with one or two moieties independently selected from the group consisting of: 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 1-3Alkyl), -(CH2) 1-3 COOH and -NH 2-z (CH3) z Here, z is 0, 1, or 2; and each C 1-3 The alkyl group may be optionally substituted with one or two moieties independently selected from the following group: -OH, -OCH3, -SCH3, cyclopropyl, piperazinyl, 4-methyl-piperazinyl, 4-(2-hydroxyethyl)piperazinyl, 2-(N,N-dimethylamino)ethoxy, and -NH 2-z (CH3) z Here, z is 0, 1, or 2.

[0230] 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 defined above [in particular with respect to formulas (Ic), (IIIa), (IVa), (VIa), (VIIa) and / or (VIIIa)] or below [in particular with respect to formulas (IIIc), (IVc), (Vc), (VIc), (VIIc) and / or (VIIIc)], and R 1a The following group is selected: -NH(C 1-3 Alkyl), piperazinyl, piperidinyl, and pyrrolidinyl, where the piperazinyl group may be optionally substituted with 1 or 2 moieties independently selected from the group consisting of: 2-hydroxyethyl, methyl, -CH2COOH, and -C(=O)CH3; the piperidinyl group may be optionally substituted with 1 or 2 moieties independently selected from the group consisting of: -NH2 and 4-methylpiperazinyl; the pyrrolidinyl may be optionally substituted with 1 or 2 -OH groups; and each C 1-3The alkyl group may be optionally substituted with one or two moieties independently selected from the following group: -OH, -OCH3, and -NH 2-z (CH3) z Here, z is 0, 1, or 2.

[0231] 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 defined above [in particular with respect to formulas (Ic), (IIIa), (IVa), (VIa), (VIIa) and / or (VIIIa)] or below [in particular with respect to formulas (IIIc), (IVc), (Vc), (VIc), (VIIc) and / or (VIIIc)], and R 1a The following are selected from the group consisting of: 4-(2-hydroxyethyl)piperazinyl, 4-methylpiperazinyl, 4-acetylpiperazinyl, and (2-hydroxyethyl)amino, such as 4-(2-hydroxyethyl)piperazinyl, 4-methylpiperazinyl, 4-acetylpiperazinyl, (2-hydroxyethyl)amino, 4-aminopiperidinyl, 4-(4-methylpiperazinyl)piperidinyl, (4-carboxymethylpiperazinyl), and 3-hydroxypyrrolidinyl.

[0232] In an interchangeable embodiment of the compound of formula (IIc), R 1b , R 1c , R 2 , R 3 , R 4 , R 5'' A, B, and E are defined above [in particular with respect to formulas (Ic), (IIIa), (IVa), (VIa), (VIIa) and / or (VIIIa)] or below [in particular with respect to formulas (IIIc), (IVc), (Vc), (VIc), (VIIc) and / or (VIIIc)], and R 1aThis is a leaving group [for example, halogens (such as Cl, Br, or F), nitro, benzotriazole 1-yloxy, C1-C]. 10 Alkyl sulfonate, C1-C 10 Haloalkyl sulfonates, nonaflates (CF3CF2CF2CF2SO3-), CF3C(=O)O-, phenyl sulfonates (wherein the phenyl group can be optionally substituted with 1, 2, or 3 groups independently selected from halogens and C1-C4 alkyl groups), or formula -[N(R x )(R y )(R z )] + [G] - The ammonium salt of, where R x , R y , and R z G is independently hydrogen or alkyl, and G is a conjugate base of a strong acid (for example, G - Cl - (It is)

[0233] In one embodiment, a compound of formula (Ic) for use in a fifth aspect has the general formula (IIIc): [ka] Here R 1a , R 2 , R 3 , R 4 , R 5'' A, B, and E are defined above [in particular with respect to formulas (Ic), (IIc), (IIIa), (IVa), (VIa), (VIIa) and / or (VIIIa)] or below [in particular with respect to formulas (IVc), (Vc), (VIc), (VIIc) and / or (VIIIc)], and each R 1b and R 1c The following are independently selected from the group consisting of: 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, -NH2-z (CH3) z ,phenyl, pyridinyl, pyrazolyl, phenoxy, pyridinyloxy, iminidazolylamino, and tetrahydrofuranylmethoxy, where z is 0, 1, or 2; and each of the phenyl, pyridinyl, pyrazolyl, phenoxy, pyridinyloxy, iminidazolylamino, and tetrahydrofuranylmethoxy groups may be optionally substituted with 1, 2, or 3 moieties independently selected from the following: 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 Here, z is 0, 1, or 2.

[0234] In one embodiment of the compound of formula (IIIc), R 1a , R 2 , R 3 , R 4 , R 5'' A, B, and E are defined above [in particular with respect to formulas (Ic), (IIc), (IIIa), (IVa), (VIa), (VIIa), and / or (VIIIa)] or below [in particular with respect to formulas (IVc), (Vc), (VIc), (VIIc), and / or (VIIIc)], and at least one R 1b and R 1c The following are selected from the group: 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. In this embodiment, other R 1b and R 1cThis may be defined as described above [in particular with respect to formulas (Ia), (IIa), and / or (IIIa)], for example, the other R 1b and R 1c The following can be selected from the group: 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 , phenyl, pyridinyl, pyrazolyl, phenoxy, pyridinyloxy, iminidazolylamino, and tetrahydrofuranylmethoxy, where z is 0, 1, or 2; and where each of the phenyl, pyridinyl, pyrazolyl, phenoxy, pyridinyloxy, iminidazolylamino, and tetrahydrofuranylmethoxy groups may be optionally substituted with 1, 2, or 3 moieties independently selected from the following: 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 Here, z is 0, 1, or 2. Interchangeably, each R 1b and R 1c The following are independently selected from the group consisting of: 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.

[0235] In one embodiment of the compound of formula (IIIc), R 1a , R 2 , R 3 , R 4, R 5'' A, B, and E are defined above [in particular with respect to formulas (Ic), (IIc), (IIIa), (IVa), (VIa), (VIIa) and / or (VIIIa)], or below [in particular with respect to formulas (IVc), (Vc), (VIc), (VIIc) and / or (VIIIc)], and R 1b is methyl, ethyl, propyl, or isopropyl, preferably methyl; and R 1c is H. In an alternative embodiment, R 1b H is; and R 1c The compound is methyl, ethyl, propyl, isopropyl, or phenyl, preferably methyl.

[0236] In one embodiment, the compound of formula (Ic) for use in a fifth aspect has general formula (IVc). [ka] Here, R 1a , R 1b , R 1c , R 2 , R 4 , R 5'' A, B, and E are defined above [in particular with respect to formulas (Ic), (IIc), (IIIc), (IIIa), (VIa), (VIIa) and / or (VIIIa)], or below [in particular with respect to formulas (Vc), (VIc), (VIIc) and / or (VIIIc)], and R 3 The following group is selected: H, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-6 Cycloalkyl, phenyl, halogen, -CN, azide, -NO2, -O(C 1-6 Alkyl), -OCF3, -S(C 1-6 Alkyl), -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2,-NHS(O)2(C 1-6 Alkyl), -S(O)2NH 2-z (C 1-6 Alkyl) z-C(=O)(C 1-6 Alkyl), -C(=O)OH, -C(=O)O(C 1-6 Alkyl), -C(=O)NH 2-z (C 1-6 Alkyl) z , -NHC(=O)(C 1-6 Alkyl), -NHC(=NH)NH z-2 (C 1-6 Alkyl) z , and -N(C 1-6 Alkyl)C(=NH)NH 2-z (C 1-6 Alkyl) z Here, z is 0, 1, or 2, and here, each C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-6 Cycloalkyl and phenyl groups are optionally selected from one or more independently chosen R groups. 30 It can be replaced by this.

[0237] 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 defined above [in particular with respect to formulas (Ic), (IIc), (IIIc), (IIIa), (VIa), (VIIa), and / or (VIIIa)], or below [in particular with respect to formulas (Vc), (VIc), (VIIc), and / or (VIIIc)], and R 3 The following group is selected: H, C 1-4 Alkyl, C 3-6 Cycloalkyl, phenyl, halogen, -CN, -O(C 1-4 Alkyl), -OCF3, -S(C 1-4 Alkyl), -NH2, -NH(C 1-4 Alkyl), -N(C 1-4 Alkyl)2, -C(=O)(C 1-4 Alkyl), -C(=O)OH, -C(=O)O(C 1-4 Alkyl), -C(=O)NH 2-z (C1-4 Alkyl) z , -NHC(=O)(C 1-4 Alkyl), -NHC(=NH)NH z-2 (C 1-4 Alkyl) z , and -N(C 1-4 Alkyl)C(=NH)NH 2-z (C 1-4 Alkyl) z Here, the phenyl group may be optionally substituted with 1, 2, or any other group independently selected from the following group: 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), -C(=O)NH 2-z (C 1-3 Alkyl) z ,-(CH2) 1-3 NH2, -(CH2) 1-3 NH(C 1-3 Alkyl), -(CH2) 1-3 N(C 1-3 Alkyl)2,-(CH2) 1-3 OH and -(CH2) 1-3 O(C 1-3 Alkyl); and where z is 0, 1, or 2.

[0238] 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 defined above [in particular with respect to formulas (Ic), (IIc), (IIIc), (IIIa), (VIa), (VIIa), and / or (VIIIa)], or below [in particular with respect to formulas (Vc), (VIc), (VIIc), and / or (VIIIc)], and R 3 The following are selected from the group consisting of: H, methyl, ethyl, propyl, isopropyl, phenyl, and halogen.

[0239] 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 defined above [in particular with respect to formulas (Ic), (IIc), (IIIc), (IIIa), (VIa), (VIIa), and / or (VIIIa)], or below [in particular with respect to formulas (Vc), (VIc), (VIIc), and / or (VIIIc)], and R 3 H is H.

[0240] In one embodiment, a compound of formula (Ic) for use in a fifth aspect has the general formula (Vc): [ka] Here, R 1a , R 1b , R 1c , R 2 , R 3 , R 4 A, B, and E are defined above [in particular with respect to formulas (Ic), (IIc), (IIIc), (IVc), (IIIa), (IVa), (VIa), (VIIa), and / or (VIIIa)], or below [in particular with respect to formulas (VIc), (VIIc), and / or (VIIIc)], and R 5'' -LR 6'' And here, R 6'' is a heteroaryl containing at least one ring heteroatom selected from the group consisting of N, O, and S, or a heterocyclyl containing at least one ring heteroatom selected from the group consisting of N, O, and S, where each heteroaryl and heterocyclyl group may be optionally substituted with one or more independently selected R7' groups, such as 1, 2, or 3. For example, R 6'' It can be a heteroaryl comprising at least one ring heteroatom selected from the group consisting of N and O (for example, the heteroaryl does not contain S as a ring heteroatom; and in some embodiments, it does not contain O as a ring heteroatom, for example, R 6''(may be) an N-heteroaryl, or a heterocycline comprising at least one ring heteroatom selected from the group consisting of N and O (for example, the heterocycline does not contain S as a ring heteroatom; and in some embodiments does not contain O as a ring heteroatom, for example, R 6'' (may by) is an N-heterocyclyl, where each heteroaryl and heterocyclyl group may be optionally substituted with one or more independently selected R7' groups, such as 1, 2, or 3.

[0241] 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 defined above [in particular with respect to formulas (Ic), (IIc), (IIIc), (IVc), (IIIa), (IVa), (VIa), (VIIa), and / or (VIIIa)], or below [in particular with respect to formulas (VIc), (VIIc), and / or (VIIIc)], and R 6'' is a 3-~10-membered heteroaryl (containing at least one ring heteroatom selected from the group consisting of N, O, and S, such as from the group consisting of N and O) or a 3-~10-membered heterocyclil (containing at least one ring heteroatom selected from the group consisting of N, O, and S, such as from the group consisting of N and O), each of which may be optionally substituted with one or more independently selected R7' such as 1, 2, or 3.

[0242] 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 defined above [in particular with respect to formulas (Ic), (IIc), (IIIc), (IVc), (IIIa), (IVa), (VIa), (VIIa), and / or (VIIIa)], or below [in particular with respect to formulas (VIc), (VIIc), and / or (VIIIc)], and R 6'' The compound is a mono- or bi-cyclic heteroaryl (for example, containing at least one ring heteroatom selected from the group consisting of N, O, and S, such as from the group consisting of N and O), or a mono- or bi-cyclic heterocyclil (for example, containing at least one ring heteroatom selected from the group consisting of N, O, and S, such as from the group consisting of N and O), each of which may be optionally substituted with one or more independently selected R7' such as 1, 2, or 3.

[0243] 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 defined above [in particular with respect to formulas (Ic), (IIc), (IIIc), (IVc), (IIIa), (IVa), (VIa), (VIIa), and / or (VIIIa)], or below [in particular with respect to formulas (VIc), (VIIc), and / or (VIIIc)], and R 6''The group is selected from the following: 5-~6-membered monocyclic heteroaryls (e.g., containing at least one ring heteroatom selected from the group consisting of N, O, and S, such as from the group consisting of N and O), 4-~6-membered monocyclic heterocyclines (e.g., containing at least one ring heteroatom selected from the group consisting of N, O, and S, such as from the group consisting of N and O), 7-~9-membered biscyclic heteroaryls (e.g., containing at least one ring heteroatom selected from the group consisting of N, O, and S, such as from the group consisting of N and O), and 7-~9-membered biscyclic heterocyclines (e.g., containing at least one ring heteroatom selected from the group consisting of N, O, and S, such as from the group consisting of N and O), each of which may be optionally substituted with one or more independently selected R7' such as 1, 2, or 3.

[0244] 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 defined above [in particular with respect to formulas (Ic), (IIc), (IIIc), (IVc), (IIIa), (IVa), (VIa), (VIIa), and / or (VIIIa)], or below [in particular with respect to formulas (VIc), (VIIc), and / or (VIIIc)], and R 6'' is a 5- to 6-membered monocyclic heteroaryl (containing at least one ring heteroatom selected from the group consisting of N, O, and S, such as from the group consisting of N and O), which can be optionally substituted with one or more independently selected R7' such as 1, 2, or 3.

[0245] 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 defined above [in particular with respect to formulas (Ic), (IIc), (IIIc), (IVc), (IIIa), (IVa), (VIa), (VIIa), and / or (VIIIa)], or below [in particular with respect to formulas (VIc), (VIIc), and / or (VIIIc)], and R 6'' is a 7- to 9-membered biscyclic heterocycline (containing at least one ring heteroatom selected from the group consisting of N, O, and S, such as from the group consisting of N and O), which can be optionally substituted with one or more independently selected R7' such as 1, 2, or 3.

[0246] 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 defined above [in particular with respect to formulas (Ic), (IIc), (IIIc), (IVc), (IIIa), (IVa), (VIa), (VIIa), and / or (VIIIa)], or below [in particular with respect to formulas (VIc), (VIIc), and / or (VIIIc)], and R 6'' The following are selected from the group consisting of: pyridinyl, thienyl, pyridadinyl, furanyl, pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazoimidazolyl, indolyl, naphthilidinyl, thienopyridinyl, tetrahydropyranil, piperidinyl, pyrrolidinyl, azetidinyl, azabicycloheptanil, azabicyclooctanil, azapentacyclooctanil, piperazinyl, morpholinil, and tetrahydrothiophenyl, each of which is optionally selected from 1, 2, or 3 independently. 7' It can be replaced with, preferably R 6''The following groups may be selected: pyridinyl, thienyl, pyrazolyl, isoxazolyl, pyrrolyl, piperidinyl, pyrrolidinyl, azetidinyl, and azabicyclooctanil, each of which may be optionally substituted with one or more independently selected R7' such as 1, 2, or 3.

[0247] In any of the above embodiments of the compound of formula (Vc) [including the following compounds: (Ic), (IIc), (IIIc), and (IVc)], R 7' The following group can be independently and arbitrarily selected: R 7 , C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkynyl, halogen, -CN, -O(C) 1-6 Alkyl), -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2,-NHS(O) 1-2 (C 1-6 Alkyl), -NHS(O) 1-2 O(C 1-6 Alkyl), -C(=O)(C 1-6 Alkyl), and -OC(=O)(C 1-6 Alkyl), and / or any two R 7' , it is a heterocyclyl group R 6'' They bond to the same atom, and can bond together to form =O, where each C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 The alkynyl group is optionally selected from one or more independently selected R groups. 30 And it can be substituted. For example, R 7' The following group can be independently selected: 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 R 7' , it is a heterocyclyl group R 6''They bond to the same atom, and can bond together to form =O, where each C 1-3 The alkyl group is optionally selected from one or more independently selected R 30 And it can be substituted. In any of the above embodiments of the compound of formula (Vc) [including those of formula (Ic), (IIc), (IIIc), and (IVc)], R 7' The compounds can be independently and arbitrarily selected from the group consisting of: Cl, Br, and methyl, such as Cl, Br, methyl, and ethyl. In any other embodiment of the above embodiments of the compounds of formula (Vc) [including those of formulas (Ic), (IIc), (IIIc), and (IVc)], R 7' This is an independent R 7 R that can be defined in association with equation (Ia) 7 It's something like that.

[0248] In any of the above embodiments of the compound of formula (Vc) [including those of formula (Ic), (IIc), (IIIc), and (IVc)], where R 6'' It is replaced, and it is preferably one R 7' The base, by which, R 6'' However, at the 2nd position with respect to the ring atom that is bonded to the rest of the compound, R 6'' Bonding to the ring atom (for example, it is preferable to R 6'' However, OrthoR 7' (Retains the group). In any of the above embodiments of the compound of formula (Vc) [including those of formula (Ic), (IIc), (IIIc), and (IVc)], where R 6'' R is 2 or more (such as 2, 3, or 4) 7' It is substituted with a group, preferably with 2 or more R groups. 7' One of the elements, by which, R 6'' However, it bonds to the ring atom at position 2 with respect to the rest of the compound (for example, R 6'' However, R 7' (retains the group), and the remaining R 7' Moto is in a position other than 2nd place R 6'' It bonds to (or multiple) ring atoms of the atom. For example, in any of the above embodiments of the compound of formula (Vc) [including those of formula (Ic), (IIc), (IIIc), and (IVc)], where R 6'' is R 2 or greater 7' It is a k-membered ring substituted with a group, preferably with 2 or more R groups. 7' One of the elements, by which, R 6'' However, the remaining R atoms bond to the ring atom at position 2 (for example, with respect to the yl position) and the remaining R 7' The base is in a position other than 2nd place, for example, 3rd, 4th, 5th, ... kth place R 6'' A ring atom (or multiple ring atoms) is bonded to, for example, R 6'' However, if it is a 5-membered ring, it preferably has 2 or more R 7' One of the bases was in 2nd place with R 6'' Bonding to the ring atom (relative to the yl position) and the remaining R 7' The base is in 3rd, 4th, or 5th place, R 6'' It bonds to the ring atoms (including multiple atoms) (relative to the yl position). Furthermore, in any of the above embodiments of the compound of formula (Vc) [including those of formula (Ic), (IIc), (IIIc), and (IVc)], where R 6'' R is 2 or more (such as 2, 3, or 4) 7' It is substituted with the group, preferably by which R 6'' However, each of the two ring atoms directly adjacent to the ring atom bonded to the rest of the compound has one R 7' The group that retains the group [for example, a k-membered ring, R 6'' Therefore, R 6'' However, one R is bonded to the rest of the compound, in relation to the ring atom, at positions 2 and k, respectively. 7' It retains the base. For example, R 6'' It is replaced at both of its ortho-positions. In addition, in any of the above embodiments of the compound of formula (Vc) [including those of formula (Ic), (IIc), (IIIc), and (IVc)], where R 6'' R is 3 or higher (such as 3 or 4) 7' It is substituted with the group, preferably by which R 6''However, each of the two ring atoms directly adjacent to the ring atom bonded to the rest of the compound has one R 7' The group that retains the group [for example, a k-membered ring, R 6'' Therefore, R 6'' However, one R is bonded to the rest of the compound, in relation to the ring atom, at positions 2 and k, respectively. 7' It retains the base. For example, R 6'' It is replaced at both of its orthoracic positions. ] and the third R 7' The base, by which, R 6'' However, although it is not a ring atom bonded to the rest of the compound, it is directly adjacent to one of the orthoracic ring atoms, R 6'' Bonding to a ring atom (for example, a k-membered ring R 6'' Therefore, R 6'' However, a third R atom is attached to one of the ring atoms at positions 3 and k-1, relative to the rest of the compound. 7' (It retains the base.)

[0249] 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 defined above [in particular with respect to formulas (Ic), (IIc), (IIIc), (IVc), (IIIa), (IVa), (VIa), (VIIa), and / or (VIIIa)], or below [in particular with respect to formulas (VIc), (VIIc), and / or (VIIIc)], and R 6'' The answer is selected from the following formulas: [ka] Here, the wavy line indicates that R 6'' However, this represents a bond that connects to the rest of the compound.

[0250] 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 defined above [in particular with respect to formulas (Ic), (IIc), (IIIc), (IVc), (IIIa), (IVa), (VIa), (VIIa), and / or (VIIIa)] or below [in particular with respect to formulas (VIc), (VIIc), and / or (VIIIc)], and R 6'' The answer is selected from the following formulas: [ka] Here, the wavy line indicates that R 6'' However, this represents a bond that connects to the rest of the compound.

[0251] 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 defined above [in particular with respect to formulas (Ic), (IIc), (IIIc), (IVc), (IIIa), (IVa), (VIa), (VIIa), and / or (VIIIa)], or below [in particular with respect to formulas (VIc), (VIIc), and / or (VIIIc)], and R 6'' The answer is selected from the following formulas: [ka] Here, the wavy line indicates that R 6'' This indicates a bond, specifically a bonding that occurs when a molecule binds to the rest of the compound.

[0252] 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 defined above [in particular with respect to formulas (Ic), (IIc), (IIIc), (IVc), (IIIa), (IVa), (VIa), (VIIa), and / or (VIIIa)], or below [in particular with respect to formulas (VIc), (VIIc), and / or (VIIIc)], and R 6''The answer is selected from the following formulas: [ka] Here, the wavy line indicates that R 6'' However, this represents a bond that connects to the rest of the compound.

[0253] In any of the above embodiments of the compound of formula (Vc) [including those of formulas (Ic), (IIc), (IIIc), and (IVc)], L may be selected from the group consisting of: bond, C 1-6 Alkilen, C 2-6 Alkenylene, C 2-6 Alkynylene 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 if n is 0, then o is 1; Y is independently selected from: O, S, and NH, where each C 1-6 Alkilen, C 2-6 Alkenylene, C 2-6 Alkinylene, -(CH2) m -, and -(CH2) n - The base is one or more independently selected R 30 And it can be substituted. For example, in any of the above embodiments of the compound of formula (Vc) [including those of formula (Ic), (IIc), (IIIc), and (IVc)], L can be selected from the group consisting of: a bond; optionally, one R 30 And a C1 alkylene that can be substituted; optionally, one R 30 C2 alkylenes that can be substituted with [especially 1,2-ethylene or 1,1-ethylene]; optionally, one R 30 C3 alkylenes that can be substituted with [especially trimethylene]; optionally, one R 30 C4 alkylenes that can be substituted with (especially tetramethylene or 2,4-butanediyl);-(CH2) m O-; and -(CH2) mNH-, where m is 1, 2, or 3. In particular, in any of the above embodiments of the compound of formula (Vc) [including those of formula (Ic), (IIc), (IIIc), and (IVc)], L is a bond.

[0254] In any of the above embodiments of the compound of formula (Vc) [including those of formula (Ic), (IIc), (IIIc), and (IVc)], where R 6'' is a heterocyclyl or heteroaryl (e.g., a 5-membered heteroaryl) containing an N atom as a ring heteroatom, and L is R via the N ring atom of the heterocyclyl or heteroaryl group. 6'' It can be combined with other things.

[0255] In one embodiment, the compound of formula (Ic) for use in a fifth aspect is general formula (VIc): [ka]

[0256] Here, R 1a , R 1b , R 1c , R 2 , R 3 , R 4 , R 5'' B, and E are defined above [in particular with respect to formulas (Ic), (IIc), (IIIc), (IVc), (Vc), (IIIa), (IVa), (VIa), (VIIa) and / or (VIIIa)] or below [in particular with respect to formula (VIIc) and / or (VIIIc)], and A is selected from the group consisting of: 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 formula (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 formula (Ic), (IIc), (IIIc), (IVc), and (Vc)], it is preferably A that is S.

[0257] In one embodiment, the compound of formula (Ic) for use in a fifth aspect is general formula (VIIc): [ka]

[0258] Here, R 1a , R 1b , R 1c , R 2 , R 3 , R 4 , R 5'' , and A is defined above [especially with respect to formulas (Ic), (IIc), (IIIc), (IVc), (Vc), (VIc), (IIIa), (IVa), (VIa), (VIIa) and / or (VIIIa)] or below [especially with respect to formula (VIIIc)], E is O or S (preferably O), and B is N or CR 1d Therefore, here, R 1d The following group is selected: 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, where each C 1-3 The alkyl group may be optionally substituted with one or two moieties independently selected from the following group: halogen, -OH, -OCH3, -SCH, and -NH. 2-z (CH3) z Here, z is 0, 1, or 2. In any of the above embodiments of the compound of formula (VIIc) [including formulas (Ic), (IIc), (IIIc), (IVc), (Vc), and (VIc)], E is O or S (preferably O), and B is N or CR 1d Therefore, here, R 1d The following group can be selected: C 1-3 Alkyl, halogen, -O(C 1-3Alkyl), -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 formulas (Ic), (IIc), (IIIc), (IVc), (Vc), and (VIc)], it is preferably B is N, and more preferably E is O, and B is N.

[0259] In one embodiment, the compound of formula (Ic) for use in a fifth aspect is general formula (VIIIc): [ka] Here, R 1a , R 1b , R 1c , R 2 , R 3 , R 4 , R 5'' A, B, and E are defined above [particularly with respect to formulas (Ic), (IIc), (IIIc), (IVc), (Vc), (VIc), (VIIc), (IIIa), (IVa), (VIa), (VIIa) and / or (VIIIa)] or below, and L is a bond. Preferred embodiments of compounds having general formula (VIIIc): (A) R 1a R is selected from the group consisting of: alkyl, -O(alkyl), -S(alkyl), -NH(alkyl), -N(alkyl)2, and heterocyclyl, where each alkyl and heterocyclyl group is optionally selected from one or more (e.g., 1, 2, or 3) independently selected R 30 It can be replaced by. Preferably, each R 30 These are, independently, alkyl (e.g., C) as defined herein. 1-6 Alkyl), -(CH2) 1-3 OH, alkenyl (for example, C 2-6 Alkenyl), Alkinyl (for example, C 2-6 Alkynyl, halogen, -CN, nitro, -OR 11 (For example, -OH), -SR11 (For example, -SH), -N(R 12 )(R 13 )(e.g., -NH2), and -C(=O)R 11 [For example, -C(=O)(C 1-3 It is a first-level substituent, second-level substituent, or third-level substituent, such as alkyl; (B) Each R 1b and R 1c The following are independently selected from the group consisting of: 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 ,phenyl, pyridinyl, pyrazolyl, phenoxy, pyridinyloxy, imidazolylamino, and tetrahydrofuranylmethoxy, where z is 0, 1, or 2; and each phenyl, pyridinyl, pyrazolyl, phenoxy, pyridinyloxy, imidazolylamino, and tetrahydrofuranylmethoxy group may be optionally substituted with 1, 2, or 3 moieties independently selected from the following: 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 Here, z is 0, 1, or 2; (C) R 3 The following group is selected: H, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-6 Cycloalkyl, phenyl, halogen, -CN, azide, -NO2, -O(C 1-6 Alkyl), -OCF3, -S(C1-6 Alkyl), -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2,-NHS(O)2(C 1-6 Alkyl), -S(O)2NH 2-z (C 1-6 Alkyl) z -C(=O)(C 1-6 Alkyl), -C(=O)OH, -C(=O)O(C 1-6 Alkyl), -C(=O)NH 2-z (C 1-6 Alkyl) z , -NHC(=O)(C 1-6 Alkyl), -NHC(=NH)NH z-2 (C 1-6 Alkyl) z , and, -N(C 1-6 Alkyl)C(=NH)NH 2-z (C 1-6 Alkyl) z Here, z is 0, 1, or 2, and here, each C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-6 Cycloalkyl and phenyl groups are optionally selected from one or more independently chosen R groups. 30 And it can be replaced; (D) R 6'' This is defined above [particularly with respect to formula (Vc)], and preferably a 3-~10-membered heteroaryl (containing at least one ring heteroatom selected from the group consisting of N, O, and S, such as from the group consisting of N and O) or a 3-~10-membered heterocyclyl (containing at least one ring heteroatom selected from the group consisting of N, O, and S, such as from the group consisting of N and O), each of which may be optionally substituted with one or more independently selected R7' such as 1, 2, or 3; (E) A is selected from the following group: S, O, NH, N(C 1-6 Alkyl), and C(C 1-6 Alkyl)2; (F) B is N or CR 1d , here, R 1d The following group is selected: 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, where each C 1-3 The alkyl group may be independently and optionally substituted with one or two moieties selected from the group consisting of: halogen, -OH, -OCH3, -SCH, and -NH. 2-z (CH3) z , where z is 0, 1, or 2; and / or (G) E is either O or S, preferably O.

[0260] In a preferred embodiment of a compound having general formula (VIIIc), R 1a is defined as (A) above; R 1b and R 1c is defined in (B) above; R 3 is defined in (C) above; R 6'' A is defined above [in particular with respect to formula (Vc)], and preferably a 3-~10-membered heteroaryl (containing at least one ring heteroatom selected from the group consisting of N, O, and S, such as from the group consisting of N and O) or a 3-~10-membered heterocyclyl (containing at least one ring heteroatom selected from the group consisting of N, O, and S, such as from the group consisting of N and O), each of which may be optionally substituted with one or more independently selected R7' such as 1, 2, or 3; A is defined above in (E); B is defined above in (F); and E is defined above in (G).

[0261] In a more preferred embodiment of a compound having general formula (VIIIc): (A') R 1aThe following group is selected: 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-~7-membered heterocyclyl, where the 3-~7-membered heterocyclyl group may be optionally substituted independently with one or two moieties selected from the group consisting of: 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), -(CH2) 1-3 COOH and -NH 2-z (CH3) z Here, z is 0, 1, or 2; and each C 1-3 The alkyl group may be independently and optionally substituted with one or two moieties selected from the group consisting of: -OH, -OCH3, -SCH3, cyclopropyl, piperazinyl, 4-methyl-piperazinyl, 4-(2-hydroxyethyl)piperazinyl, 2-(N,N-dimethylamino)ethoxy, and -NH 2-z (CH3) z Here, z is 0, 1, or 2; (B') At least one R 1b and R 1c The following are selected from the group: 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 other R 1band R 1c is defined in (B) above; (C') R 3 The following group is selected: H, C 1-4 Alkyl, C 3-6 Cycloalkyl, phenyl, halogen, -CN, -O(C 1-4 Alkyl), -OCF3, -S(C 1-4 Alkyl), -NH2, -NH(C 1-4 Alkyl), -N(C 1-4 Alkyl)2, -C(=O)(C 1-4 Alkyl), -C(=O)OH, -C(=O)O(C 1-4 Alkyl), -C(=O)NH 2-z (C 1-4 Alkyl) z , -NHC(=O)(C 1-4 Alkyl), NHC(=NH)NH z-2 (C 1-4 Alkyl) z , and, -N(C 1-4 Alkyl)C(=NH)NH 2-z (C 1-4 Alkyl) z Here, the phenyl group may be independently and optionally substituted with one, two, or more groups selected from the group consisting of: 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), -C(=O)NH 2-z (C 1-3 Alkyl) z ,-(CH2) 1-3 NH2, -(CH2) 1-3 NH(C 1-3 Alkyl), -(CH2) 1-3 N(C 1-3 Alkyl)2,-(CH2) 1-3 OH and -(CH2) 1-3 O(C 1-3 alkyl); and where z is 0, 1, or 2; (D') R6'' R7' is defined above [in particular with respect to formula (Vc)], and is preferably a 3-~10-membered heteroaryl (containing at least one ring heteroatom selected from the group consisting of N, O, and S, such as from the group consisting of N and O) or a 3-~10-membered heterocyclil (containing at least one ring heteroatom selected from the group consisting of N, O, and S, such as from the group consisting of N and O), each of which may be optionally substituted with one or more independently selected R7' such as 1, 2, or 3, and more preferably R 6'' is a mono- or bi-cyclic heteroaryl or mono- or bi-cyclic heterocyclil, each of which may be optionally substituted with one or more independently selected R7' such as 1, 2, or 3; (E') A is S, O, or N(CH3)2; and / or (F') B is N or CR 1d , here, R 1d The following group is selected: 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 (G') E is either O or S, preferably O.

[0262] In a preferred embodiment of a compound having general formula (VIIIc), R 1a This is specified in (A') above; R 1b and R 1c This is specified in (B') above; R 3 This is specified in (C') above; R 6''R7' is defined above [in particular with respect to formula (Vc)], and is preferably a 3-~10-membered heteroaryl (containing at least one ring heteroatom selected from the group consisting of N, O, and S, such as from the group consisting of N and O) or a 3-~10-membered heterocyclil (containing at least one ring heteroatom selected from the group consisting of N, O, and S, such as from the group consisting of N and O), each of which may be optionally substituted with one or more independently selected R7' such as 1, 2, or 3, and more preferably R 6'' is a mono- or bi-cyclic heteroaryl (containing at least one ring heteroatom selected from the group consisting of N, O, and S, such as from the group consisting of N and O) or a mono- or bi-cyclic heterocyclil (containing at least one ring heteroatom selected from the group consisting of N, O, and S, such as from the group consisting of N and O), each of which may be optionally substituted with one or more independently selected R7' such as 1, 2, or 3; A is specified in (E') above; B is specified in (F') above; and E is specified in (G') above.

[0263] In a more preferred embodiment of the compound having general formula (VIIIc): (A'') R 1a The following group is selected: -NH(C 1-3 Alkyl), piperazinyl, piperidinyl, and pyrrolidinyl, Here, the piperazinyl group may be independently and optionally substituted with one or two moieties selected from the group consisting of: 2-hydroxyethyl, methyl, -CH2COOH, and -C(=O)CH3; The piperidinyl group may be independently and optionally substituted with one or two moieties selected from the group consisting of: -NH2 and 4-methylpiperazinyl; The pyrrolidinyl can be optionally substituted with 1 or 2 -OH groups; and, Each C 1-3 The alkyl group may be optionally substituted with one or two moieties selected from the following group: -OH, -OCH3, and -NH 2-z (CH3) z Here, z is 0, 1, or 2; (B'') (a)R 1b is methyl, ethyl, propyl, or isopropyl, preferably methyl; and R 1c is H; or (b)R 1b H is; and R 1c This is methyl, ethyl, propyl, isopropyl, or phenyl, preferably methyl; (C'') R 3 The following are selected from the group consisting of: H, methyl, ethyl, propyl, isopropyl, phenyl, and halogen; (D'') R 6'' R is defined above [in particular with respect to formula (Vc)], and preferably a 3-~10-membered heteroaryl (containing at least one ring heteroatom selected from the group consisting of N, O, and S, such as from the group consisting of N and O) or a 3-~10-membered heterocyclyl (containing at least one ring heteroatom selected from the group consisting of N, O, and S, such as from the group consisting of N and O), each of which optionally comprises one or more independently selected R such as 1, 2, or 3. 7' And it can be replaced, More preferably, R 6'' or mono- or bi-cyclic heteroaryl (e.g., containing at least one ring heteroatom selected from the group consisting of N, O, and S, such as from the group consisting of N and O), or mono- or bi-cyclic heterocyclyl (e.g., containing at least one ring heteroatom selected from the group consisting of N, O, and S, such as from the group consisting of N and O), each of which is optionally composed of one or more independently selected R such as 1, 2, or 3. 7' And it can be replaced, More preferably, R 6'' The following groups are selected: 5-~6-membered monocyclic heteroaryls (e.g., including at least one ring heteroatom selected from the group consisting of N, O, and S, such as from the group consisting of N and O), 4-~6-membered monocyclic heterocyclines (e.g., including at least one ring heteroatom selected from the group consisting of N, O, and S, such as from the group consisting of N and O), 7-~9-membered bicyclic heteroaryls (e.g., including at least one ring heteroatom selected from the group consisting of N, O, and S, such as from the group consisting of N and O), and 7-~9-membered bicyclic heterocyclines (e.g., including at least one ring heteroatom selected from the group consisting of N, O, and S, such as from the group consisting of N and O), each of which is optionally selected from one or more independently selected R such as 1, 2, or 3. 7' And it can be replaced, More preferably, R 6'' is a 5- to 6-membered monocyclic heteroaryl (containing at least one ring heteroatom selected from the group consisting of N, O, and S, such as from the group consisting of N and O) or a 7- to 9-membered bicyclic heterocycline (containing at least one ring heteroatom selected from the group consisting of N, O, and S, such as from the group consisting of N and O), each of which may be optionally substituted with one or more independently selected R7' such as 1, 2, or 3; (E'') A is S; (F'') B is N; and / or (G'') E is O.

[0264] In a preferred embodiment of a compound having general formula (VIIIc), R 1a This is specified in (A'') above; R 1b and R 1c This is specified in (B'') above; R 3 This is specified in (C'') above; R 6''R is defined above [in particular with respect to formula (Vc)], and preferably a 3-~10-membered heteroaryl (containing at least one ring heteroatom selected from the group consisting of N, O, and S, such as from the group consisting of N and O) or a 3-~10-membered heterocyclyl (containing at least one ring heteroatom selected from the group consisting of N, O, and S, such as from the group consisting of N and O), each of which optionally comprises one or more independently selected R such as 1, 2, or 3. 7' It can be replaced by, More preferably, R 6'' However, the compound is a mono- or bi-cyclic heteroaryl (for example, containing at least one ring heteroatom selected from the group consisting of N, O, and S, such as from the group consisting of N and O) or a mono- or bi-cyclic heterocyclyl (for example, containing at least one ring heteroatom selected from the group consisting of N, O, and S, such as from the group consisting of N and O), each of which is optionally composed of one or more independently selected R such as 1, 2, or 3. 7' It can be replaced by, More preferably, R 6'' The following groups are selected: 5-~6-membered monocyclic heteroaryls (e.g., including at least one ring heteroatom selected from the group consisting of N, O, and S, such as from the group consisting of N and O), 4-~6-membered monocyclic heterocyclines (e.g., including at least one ring heteroatom selected from the group consisting of N, O, and S, such as from the group consisting of N and O), 7-~9-membered bicyclic heteroaryls (e.g., including at least one ring heteroatom selected from the group consisting of N, O, and S, such as from the group consisting of N and O), and 7-~9-membered bicyclic heterocyclines (e.g., including at least one ring heteroatom selected from the group consisting of N, O, and S, such as from the group consisting of N and O), each of which is optionally selected from one or more independently selected R such as 1, 2, or 3. 7' It can be replaced by, More preferably, R 6''This includes 5- to 6-membered monocyclic heteroaryls (e.g., containing at least one ring heteroatom selected from the group consisting of N, O, and S, such as from the group consisting of N and O) or 7- to 9-membered bicyclic heterocyclines (e.g., containing at least one ring heteroatom selected from the group consisting of N, O, and S, such as from the group consisting of N and O), each of which may optionally contain one or more independently selected R such as 1, 2, or 3. 7' Replaced by; A is identified in (E'') above; B is identified in (F'') above; and E is identified in (G'') above.

[0265] In one embodiment, the compounds of the present invention are selected from those shown in Table A and / or Figure 1E.

[0266] In one embodiment, the compounds of the present invention (particularly in the fifth aspect of the present invention) are selected from the following compounds: those shown in Table A (and / or Figure 1E), and those shown in Figures 1B, 1C, and / or 1D.

[0267] The compounds of the present invention [in particular, any one of the compounds of formulas (Ia), (IIa), (IIIa), (IVa), (Va), (VIa), (VIIa), and (VIIIa) as shown in Table A, hereafter, and / or in Figure 1E], and / or the compounds used in the present invention [in particular, any one of the compounds of formulas (Ib), (IIb), (IIIb), (Ic), (IIc), (IIIc), (IVc), (Vc), (VIc), (VIIc), and (VIIIc) as shown in Figures 1B, 1C, and / or 1D] include not only the compounds shown therein, but also their solvates (e.g., hydrates), salts (in particular, pharmaceutically acceptable salts), and N-oxides (in particular, R 1a and / or R 6''The term is intended to encompass compounds selected from the group consisting of N-oxides of , their complexes, their polymorphs, their crystalline forms, their amorphous forms, their racemic mixtures, their non-racemic mixtures, their diastereomers, their enantiomers, their tautomers, their conformational isomers, their isotope-labeled forms, their prodrugs, and combinations thereof.

[0268] This invention includes compounds synthesized and tested for use within the scope of the present invention or within the scope of the methods of the present invention, and / or various exemplary or preferred Hy substituents, R 1a substituent, R 1b substituent, R 1c substituent, R 1d substituent, R 1e substituent, R 2 substituent, R 3 substituent, R 4 substituent, R 5 Table A below lists examples of Moiety, A Moiety, B Moiety, and / or E Moiety, or selections of compounds that are useful for the synthesis of further compounds of the present invention, either individually or in any combination. Table A: Kinase inhibitors of formula (Ia) [Table A-1] [Table A-2] [Table A-3]

[0269] In a particular embodiment, the compounds of the present invention are selected from the group consisting of: E4, E9, E10, and E16; and also include: compounds selected from the group consisting of its solvates, salts, N-oxides, complexes, polymorphs, crystalline forms, racemic mixtures, diastereomers, enantiomers, tautomers, conformatorisomers, isotope-labeled compounds, prodrugs, and combinations thereof.

[0270] In one embodiment, the compound of the present invention is E9, or a compound selected from the group consisting of its solvate, its salt, its N-oxide, its complex, its polymorph, its crystalline form, its tautomer, its conformational isomer, its isotope-labeled form, its prodrug, and combinations thereof.

[0271] In another embodiment, the compound of the present invention is E4, or a compound selected from the group consisting of its solvate, its salt, its N-oxide, its complex, its polymorph, its crystalline form, its tautomer, its conformational isomer, its isotope-labeled form, its prodrug, and combinations thereof.

[0272] In another embodiment, the compound of the present invention is E10, or a compound selected from the group consisting of its solvate, its salt, its N-oxide, its complex, its polymorph, its crystalline form, its tautomer, its conformational isomer, its isotope-labeled form, its prodrug, and combinations thereof.

[0273] In another embodiment, the compound of the present invention is E16, or a compound selected from the group consisting of its solvate, its salt, its N-oxide, its complex, its polymorph, its crystalline form, its racemic mixture, its diastereomer, its enantiomer, its tautomer, its conformator, its isotope-labeled form, its prodrug, and combinations thereof.

[0274] In some aspects, the present invention may relate to compounds selected from the group consisting of any of the compounds of the present invention or any of the compounds used in the present invention, their solvates, salts, N-oxides, complexes, racemic mixtures, diastereomers, enantiomers, tautomers, conformosomers, isotopically labeled compounds, prodrugs, and combinations thereof; for example, compounds such as those selected from the group consisting of any of the compounds such as their solvates, salts, complexes, racemic mixtures, diastereomers, enantiomers, tautomers, conformosomers, isotopically labeled compounds, and combinations thereof.

[0275] In one embodiment, the compounds used in the present invention do not include one or more compounds of the following groups (1) to (6) of formula (Ic) [in groups (1) to (6), a moiety (such as methyl) is not substituted unless it is explicitly specified that the moiety is substituted]: (1) R 1a However, it is 4-(2-hydroxyethyl)piperazin-1-yl or Cl; R 1b However, H is; R 1c B is methyl; B is N; E is O; R 3 When is H; A is S; and L is a bond; in that case, R 6'' It is not 4-chloro-2-methylpyridin-3-yl; (2) R 1a However, it is methoxy; R 1b However, H;R 1c B is methoxy; B is N; E is O; R 3 However, when H is, A is S, and L is a bond; in that case, R 6'' It is not 2,2-difluoro-5H-1,3-dioxolo[4,5-f]benzimidazol-6-yl; (3) R 3 H is H; A is S; L is a bond; R 6'' However, it is 1-methyl-4-piperidinyl; R 1b H is; B is N; E is O; and (i) R 1a However, when it is methyl; in that case, R 1c It is not N-tert-butoxycarbonylpiperidin-4-yl; or, (ii) R 1c However, when it is methyl; in that case, R 1a It is not N-tert-butoxycarbonylpiperidin-4-yl or N-tert-butoxycarbonylpiperidin-3-yl; (4) E is O; B is CR 1d and R 1d However, if it is H, F, Cl, or Br, then R 1a It is not H; (5) R 1a However, each R is methyl; 1b and R 1c H is; B is CH; E is O; A is S; and R 3 However, when it is methyl; in that case, R 5'' is not 1,3-benzodioxol-5-ylmethyl, 2-furanylmethyl, 1,3-benzodioxol-5-yl, 2-(2-thienyl)ethyl, 2-(4-morpholinyl)ethyl, 2-(2-pyridinyl)ethyl, 2-pyridinylmethyl, or tetrahydro-2-furanylmethyl; and, (6) A is S; R 3 H is H; E is O; L is a bond; R 6'' However, it is 1-[2,4-bis(trifluoromethyl)benzyl]-1H-pyrazol-4-yl; R 1a However, H is R 1b However, H is R 1c However, H is; and B is CR 1d When that is the case; in that case, R 1d It is not H.

[0276] In one embodiment, the compounds used in the present invention do not include one or more compounds of the following groups (7) to (10) of formula (Ib) [in groups (7) to (10), a moiety (such as methyl) is not substituted unless it is explicitly specified that the moiety is substituted]: (7) Hy: [ka] and (i) R 1aHowever, it is 4-(2-hydroxyethyl)piperazin-1-yl or Cl; R 1b However, H is; R 1c B is methyl; B is N; E is O; R 2 However, H is; R 3 However, H is; R 4 However, H is true; and A is true, S is true; in that case, R 6' is not 4-chloro-2-methylpyridin-3-yl; or, (ii) E is O; B is CR 1d and R 1d However, when it is H, F, Cl, or Br; in that case, R 1a It is not H; (8) Hy is 1-{(2E)-4-[(2-methoxyethyl)amino]-1-oxo-2-buten-1-yl}piperidine-4-yl; R 2 However, H is; R 3 However, H is; R 4 However, when H is O, and A is O, and E is O, then R 6' It is not 5-methyl-pyridin-2-yl; (9) R 2 However, H is; R 3 However, it is trifluoromethyl; R 4 H is; A is O; E is O; and, (i) R 6' However, when it is 6-{4-[(2-fluorophenyl)carbamoyl]piperazin-1-yl}pyridine-3-yl; in that case, Hy is not 1-(phenylmethyl)-piperidine-4-yl, 1-(phenylmethyl)pyrrolidine-3-yl, or tetrahydro-2H-pyran-4-yl; or, (ii) When Hy is 1-(phenylmethyl)piperidine-4-yl; in that case, R 6'is not 6-(3-{[(2-fluorophenyl)carbamoyl]amino}-pyrrolidin-1-yl)pyridine-3-yl or 6-({1-[(2-fluorophenyl)carbamoyl]piperidin-4-yl}amino)pyridine-3-yl; or, (iii) When Hy is 1-(phenylmethyl)pyrrolidine-3-yl; in that case, R 6' It is not 6-({(3S)-1-[(2-fluorophenyl)carbamoyl]-pyrrolidin-3-yl}amino)pyridine-3-yl or 6-({(3R)-1-[(2-fluorophenyl)carbamoyl]pyrrolidin-3-yl}-amino)pyridine-3-yl; (10) A is S; R 3 H is; E is O; and R 6' However, when it is 1-[2,4-bis(trifluoromethyl)benzyl]-1H-pyrazol-4-yl, in which case Hy is not 2-pyrozyl.

[0277] In another embodiment, the compounds used in the present invention are not selected from the group consisting of: 5-Thiazolecarboxamide, 2-[(6-chloro-2-methyl-4-pyrimidinyl)amino]-N-[2-[4-(2-hydroxyethyl)-1-piperazinyl]-6-methylphenyl]-(CAS Registry No:2048106-50-7), 5-Thiazolecarboxamide、2-[[7-[4-cyano-3-(trifluoromethyl)phenyl]-5,6,7,8-tetrahydropyrido[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)、 5-Thiazolecarboxamide、2-[[6-mエトキシ-7-[3-(4-morpholinyl)propoxy]-4-quinazolinyl]amino]-N-(2-pyrazinylmethyl)-(CAS Registry No:385780-87-0)、 5-Thiazolecarboxamide、2-[[6-mエトキシ-7-[3-(4-morpholinyl)propoxy]-4-quinazolinyl]amino]-N-[2-(3-pyridinyl)ethyl]-(CAS Registry No:385780-82-5)、 5-Thiazolecarboxamide、N-1H-indol-5-yl-2-[[6-mエトキシ-7-[3-(4-morpholinyl)propoxy]-4-quinazolinyl]amino]-(CAS Registry No:385780-79-0)、 5-Thiazolecarboxamide、2-[[6-mエトキシ-7-[3-(4-morpholinyl)propoxy]-4-quinazolinyl]amino]-N-(2-thienylmethyl)-(CAS Registry No:385780-69-8)、 5-Thiazolecarboxamide、N-(2-furanylmethyl)-2-[[6-mエトキシ-7-[3-(4-morpholinyl)propoxy]-4-quinazolinyl]amino]-(CAS Registry No:385780-66-5)、 5-Thiazolecarboxamide, 2-[[6-m-ethoxy-7-[3-(4-morpholinyl)propoxy]-4-quinazolinyl]amino]-N-2-pyridinyl-(CAS Registry No:385780-57-4), and 5-Thiazolecarboxamide, 2-[[6-methoxy-7-[3-(4-morpholinyl)propoxy]-4-quinazolinyl]amino]-N-4-pyridinyl-(CAS Registry No:385779-93-1).

[0278] In another embodiment, the compounds used in the present invention are not selected from the group consisting of: Imidazo[4,5-d]pyrrolo[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), Imidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide, N,N-dicyclopropyl-6-ethyl-1,6-dihydro-1-methyl-4-[[4-methyl-5-[[(tetrahydro-1,1-dioxido-3-thienyl)amino]carbonyl]-2-thiazolyl]amino]-(CAS Registry No:1271022-57-1), Imidazo[4,5-d]pyrrolo[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 Imidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide, N,N-dicyclopropyl-6-ethyl-1,6-dihydro-1-methyl-4-[[5-[[methyl(tetrahydro-1,1-dioxido-3-thienyl)amino]carbonyl]-2-thiazolyl]amino]-(CAS Registry No: 1271021-43-2) 2-[(6-{[3-(1H-imidazol-1-yl)propyl]amino}pyridin-2-yl)amino]-4-methyl-N-[1-(phenylmethyl)-1H-indazol-5-yl]-1,3-thiazole-5-carboxamide (CAS Registry No: 302963-64-0) 2-[(6-{[3-(1H-imidazol-1-yl)propyl]amino}pyridin-2-yl)amino]-N-[1-(phenylmethyl)-1H-indazol-5-yl]-1,3-thiazole-5-carboxamide (CAS Registry No: 302963-55-9).

[0279] In one or more of the alternatives disclosed herein (in particular in the fifth aspect of the present 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 1A), in particular its monohydrate (dasatinib).

[0280] In one or more other alternatives to the aspects disclosed herein (in particular, in the fifth aspect of the present invention), the compound is ARN-3261 (Vankayalapati et al 2017, AACR Cancer Res 77(13Suppl):Abstract nr LB-296;US9260426,US9890153,US9951062).

[0281] Compounds of the present invention (and / or compounds used in the present invention) containing basic functional groups can form salts with a variety of inorganic or organic acids. Compounds of the present invention (and / or compounds used in the present invention) containing acidic functional groups can form salts with a variety of inorganic or organic acids. Exemplary inorganic and organic acids / bases, as well as exemplary acid / base addition salts of the compounds of the present invention (or compounds used in the present invention), are specified in the definition of pharmaceutically acceptable salts in the following section on pharmaceutical compositions. Compounds of the present invention (and / or compounds used in the present invention) containing both basic and acidic functional groups can be converted into base or acid addition salts. The neutral form of a compound of the present invention (or a compound used in the present invention) can be regenerated by contacting the salt with a base or acid and then isolating the parent compound by conventional means.

[0282] The compounds of the present invention (and / or compounds used in the present invention) may be in the form of N-oxides. That is, they may contain the following functional group: ≡N + -O - [For example, (R n )3N + -O- That is, an NO-coordinate covalent bond, where R n R is independently selected from the group consisting of: hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl, where each alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl group is independently selected from 1 or more (1 for the maximum number of hydrogen atoms bonded to the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl group, for example, 1-5, 1-4, 1-3, or 1 or 2, up to 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), 30 And R can be optionally replaced. 30 Preferably, these are first-level substituents, second-level substituents, or third-level substituents as defined herein. A special example of the N-oxide of the compound of the present invention (or the compound used in the present invention) is R 1a and / or R 6 (or R 6' Or R 6'' ) is a functional group ≡N + -O - It contains R, which can exist as an N-oxide. 1a Non-restrictive examples of substituents include: [ka] Here, the wavy line indicates that R 1a A substituent represents a bond to the rest of the compound. R can exist as an N-oxide 6'' Non-restrictive examples of substituents include: [ka] Here, the wavy line indicates that R 6'' A substituent represents a bond to the rest of the compound.

[0283] The compounds of the present invention (and / or compounds used in the present invention) may be in the form of prodrugs. A prodrug of a compound of the present invention (or a compound used in the present invention) is a compound that undergoes a chemical change under physiological conditions to provide the compound of the present invention upon administration to an individual. Additionally, a prodrug may be converted to a compound of the present invention (or a compound used in the present invention) in an ex vivo environment by chemical or biochemical means. For example, a prodrug may be slowly converted to a compound of the present invention (or a compound used in the present invention) when placed in a transdermal patch storage container with a suitable enzyme or chemical agent. Exemplary prodrugs are esters (using alcohols or carboxyl groups contained in the kinase inhibitor (or compound used in the present invention)) or amides (using aminos or carboxyl groups contained in the kinase inhibitor (or compound used in the present invention)) that can be hydrolyzed in vivo. In particular, any amino group contained in the kinase inhibitor (or compound used in the present invention) and having at least one hydrogen atom can be converted to a prodrug form. Typical N-prodrugs include carbamates (1), Mannich bases (2), enamines (3), and enaminones (4). [ka] Here, R 18 R is independently selected from the group consisting of: H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl, where each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl group is independently selected from 1 or more (1 for the maximum number of hydrogen atoms bonded to the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl group, for example, 1-5, 1-4, 1-3, or 1 or 2, up to 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), 30 And R can be optionally replaced.30 Herein, it is defined (preferably, the R 30 (These are independently first-level substituents, second-level substituents, or third-level substituents as defined herein). The properties of the prodrug (solubility; permeability; stability; degradation rate in living organisms, under what conditions, and due to target specificity, etc.) are as follows: 18 It can be fine-tuned through modification.

[0284] A special prodrug form of the compound of the present invention (or a compound used in the present invention) is a prodrug having the following formula (IXa), (Xa), (XIa), or (XIIa) [or (IXb), (Xb), (IXc), or (Xc)]: [ka] , and its solvates, salts, N-oxides, complexes, polymorphs, crystalline forms, racemic mixtures, diastereomers, enantiomers, tautomers, conformational isomers, isotopically labeled forms, and combinations thereof. Here, R 1a , R 1b , R 1c , R 3 , R 5 , R 5' , R 5'' A, B, E, and Hy are defined above [in particular with respect to formulas (Ia), (IIa), (IIIa), (IVa), (Va), (VIa), (VIIa), (VIIIa), (Ib), (IIb), (IIIb), (Ic), (IIc), (IIIc), (IVc), (Vc), (VIc), (V...

Claims

1. The following group: 【Chemistry 1】 and, Compounds selected from its solvates, salts, N-oxides, complexes, polymorphs, crystalline forms, racemic mixtures, diastereomers, enantiomers, tautomers, conformatorisomers, isotope-labeled compounds, and combinations thereof.

2. The compound according to claim 1, wherein the compound is a group consisting of the following: 【Chemistry 2】 and compounds selected from its solvates, salts, N-oxides, complexes, polymorphs, crystalline forms, tautomers, conformational isomers, isotopically labeled compounds, and combinations thereof.

3. The compound according to claim 1, wherein the compound is a group consisting of the following: 【Transformation 3】 and compounds selected from the solvates thereof, salts thereof, N-oxides thereof, complexes thereof, polymorphs thereof, crystalline forms thereof, tautomers thereof, conformational isomers thereof, isotope-labeled compounds thereof, and combinations thereof.

4. The compound according to claim 1, wherein the compound is a group consisting of the following: 【Chemistry 4】 and compounds selected from the solvates thereof, salts thereof, N-oxides thereof, complexes thereof, polymorphs thereof, crystalline forms thereof, racemic mixtures thereof, diastereomers thereof, enantiomers thereof, tautomers thereof, conformational isomers thereof, isotope-labeled compounds thereof, and combinations thereof.

5. The compound according to claim 1, wherein the compound is a group consisting of the following: 【Transformation 5】 and compounds selected from the solvates thereof, salts thereof, N-oxides thereof, complexes thereof, polymorphs thereof, crystalline forms thereof, racemic mixtures thereof, diastereomers thereof, enantiomers thereof, tautomers thereof, conformational isomers thereof, isotope-labeled compounds thereof, and combinations thereof.

6. The following group: 【Transformation 6】 and compounds selected from the solvates thereof, salts thereof, N-oxides thereof, complexes thereof, polymorphs thereof, crystalline forms thereof, tautomers thereof, conformational isomers thereof, isotope-labeled compounds thereof, and combinations thereof.

7. A compound according to any one of claims 1 to 6, wherein the compound has a purity of 90% or more, 95% or more, 98% or more, or 99% or more.

8. A compound according to any one of claims 1, 4, and 5, selected from the group consisting of the compound and its solvates, salts thereof, racemic mixtures thereof, diastereomers thereof, enantiomers thereof, tautomers thereof, conformational isomers thereof, and isotope-labeled compounds thereof.

9. A compound according to any one of claims 1, 2, 3, and 6, selected from the group consisting of the compound and its solvates, salts thereof, tautomers thereof, conformational isomers thereof, and isotopically labeled compounds thereof.

10. The compound according to claim 1, wherein the compound is the following compound: 【Transformation 7】 Or, its salt, or its solvate.

11. The following formula: 【Transformation 8】 A compound having the following properties.

12. A salt of a compound, where the compound is given by the following formula: 【Chemistry 9】 Salt, which contains salt.

13. The salt according to claim 12, which is a pharmaceutically acceptable salt.

14. The solvate of a compound, where the compound is given by the following formula: 【Chemistry 10】 A solvate having the properties of a solvate.

15. A pharmaceutical composition comprising the compound described in any one of claims 1 to 7 and a pharmaceutically acceptable excipient.

16. A pharmaceutical composition according to claim 15, wherein the pharmaceutical composition is formulated for oral administration.

17. The pharmaceutical composition according to claim 15 or 16, which is a unit-dose dosage form.

18. The pharmaceutical composition according to claim 15, comprising a pharmaceutically acceptable salt or solvate of the compound.

19. A pharmaceutical composition comprising the salt described in claim 13 or the solvate described in claim 14 and a pharmaceutically acceptable excipient.

20. A pharmaceutical product comprising the compound described in any one of claims 1 to 7 or the pharmaceutical composition described in claim 15.

21. The pharmaceutical product according to claim 20, comprising a pharmaceutically acceptable salt or solvate of the compound.

22. A pharmaceutical product for treating a target, kinase-related disease, disorder, or condition, comprising the compound according to any one of claims 1 to 7 or the pharmaceutical composition according to claim 15.

23. A pharmaceutical product comprising a compound or pharmaceutical composition for use in the treatment of proliferative disorders in a subject, wherein the treatment comprises administering the compound or pharmaceutical composition to the subject, wherein the compound is the compound according to any one of claims 1 to 7, and the pharmaceutical composition is the pharmaceutical composition according to claim 15.

24. A pharmaceutical product comprising a compound or pharmaceutical composition according to claim 23, wherein the proliferative disorder is cancer or a tumor.

25. A pharmaceutical product comprising a compound or pharmaceutical composition according to claim 24, wherein the cancer is a solid tumor.

26. A pharmaceutical product comprising a compound or pharmaceutical composition according to claim 24 or 25, wherein the treatment further comprises administering an immune checkpoint inhibitor to a subject.

27. A pharmaceutical product comprising the compound or pharmaceutical composition described in claim 26, wherein the immune checkpoint inhibitor is an antibody or small molecule inhibitor against PD1, PDL1, CTLA-4, LAG3, or IDO1.

28. A pharmaceutical product comprising the compound or pharmaceutical composition described in claim 27, wherein the immune checkpoint inhibitor is selected from the list consisting of nivolumab, relatirimab, ipilimumab, and BMS-986205.

29. A pharmaceutical product comprising the compound or pharmaceutical composition described in claim 28, wherein the immune checkpoint inhibitor is nivolumab.

30. A pharmaceutical product comprising the compound or pharmaceutical composition according to any one of claims 23 to 29, wherein (i) the subject has a proliferative disorder that has progressed with standard treatment; or (ii) the subject is unable to receive standard treatment.

31. A pharmaceutical product comprising a compound or pharmaceutical composition according to any one of claims 23 to 29, wherein the treatment comprises contacting cells associated with proliferative impairment in a subject with (i) TNF, aTNF variant, and / or a TNFR2 or TNFR1-signaling agonist, and (ii) the compound or pharmaceutical composition; and optionally, Here, the amount of TNF that comes into contact with cells associated with proliferative disorders in the target group is increased in the pharmaceutical product.

32. A pharmaceutical product comprising the compound or pharmaceutical composition described in claim 31, wherein (i) TNF, a TNF variant, or a TNFR1 or TNFR2-signaling agonist is administered to a subject; (ii) an agent capable of inducing or inducing contact of cells associated with proliferative impairment to TNF, a TNF variant, or a TNFR1- or TNFR2-signaling agonist is administered to the subject; or (iii) contact of cells associated with proliferative impairment to TNF is induced by a pharmaceutical, therapeutic or other method that increases the amount of TNF in the plasma of the subject and / or in the environment of such cells.

33. A pharmaceutical product comprising the compound or pharmaceutical composition according to claim 31 or 32, wherein contact of cells associated with proliferative impairment to TNF is induced by a pharmaceutical, therapeutic or other method that increases the amount of TNF in the plasma of the subject and / or in the environment of such cells.

34. A pharmaceutical product comprising a compound or pharmaceutical composition according to any one of claims 23 to 33, wherein the treatment comprises administering the pharmaceutical product twice a day (bis in die; BID).

35. A pharmaceutical product comprising a compound or pharmaceutical composition for use in the treatment of proliferative disorders in a subject, wherein the treatment comprises administering the pharmaceutical product, wherein the compound is selected from (a) below, and the pharmaceutical composition comprises such compound and pharmaceutically acceptable excipients: (a) The compound according to any one of claims 1 to 7; and Here, proliferative disorders are selected from one or more of (α) to (γ): (α) Proliferative disorders characterized by cells associated with proliferative disorders characterized by the following, or by the following: The presence of MEF2C proteins, such as phosphorylated myocyte enhancer factor 2C (MEF2C) protein and / or MEF2C protein as an active transcription factor. Or, Proliferative disorders characterized by, or by, cells associated with proliferative disorders characterized by: The presence of phosphated HDAC4 proteins, such as SIK3-phosphated histone deacetylase 4 (HDAC4) protein; and / or (β) Proliferative disorders characterized by cells associated with proliferative disorders characterized by the following: (i) the presence of a human chromosomal translocation at 11q23; (ii) the presence of rearrangement of the lysine methyltransferase 2A (KMT2A) gene; (iii) the presence of a KMT2A fusion oncoprotein; and / or (iv) the presence of mutations in the K-RAS proto-oncogene GTPase (KRAS) gene and / or the RUNX family transcription factor 1 (RUNX1) gene; and / or (γ) Mixed phenotype acute leukemia (MPAL).

36. A pharmaceutical product comprising the compound or pharmaceutical composition described in Claim 35, wherein the proliferative disorder is (i) myeloma or multiple myeloma; or (ii) leukemia, or acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL), or T-cell acute lymphoblastic leukemia (T-ALL), MLL-AML, or MLL-ALL.

37. A testing method for determining whether a subject with a proliferative disorder is suitable for the pharmaceutical treatment described in claim 35, the testing method comprising determining in a biological sample obtained from the subject or containing cells associated with the proliferative disorder: (X) The presence of MEF2C proteins, such as phosphorylated myocyte enhancer factor 2C (MEF2C) protein and / or MEF2C protein as an active transcription factor; and, Here, the proliferative disorder may be further characterized by the presence of a phosphated HDAC4 protein, such as a histone deacetylase 4 (HDAC4) protein phosphated by SIK3; and / or (Y) (i) presence of a human chromosomal translocation at 11q23; (ii) presence of a translocation of the lysine methyltransferase 2A (KMT2A) gene; (iii) presence of a KMT2A fusion oncoprotein; and / or (iv) presence of mutations in the K-RAS proto-oncogene GTPase (KRAS) gene and / or the RUNX family transcription factor 1 (RUNX1) gene. Here, the presence, translocation, rearrangement, tumor protein, and / or mutation of the protein in the biological sample indicates that the subject is suitable for treatment with the pharmaceutical.

38. A testing method according to claim 37, wherein the proliferative disorder is (i) myeloma or multiple myeloma; or (ii) leukemia, or acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL), or T-cell acute lymphoblastic leukemia (T-ALL), MLL-AML or MLL-ALL.

39. A pharmaceutical product comprising a compound or pharmaceutical composition according to any one of claims 22 to 36, wherein the subject is a human, or a testing method according to claim 37 or 38.

40. Intermediate selected from compounds having the following formula (Id): 【Chemistry 11】 And, The solvates, salts, complexes, polymorphs, crystalline forms, racemic mixtures, diastereomers, enantiomers, tautomers, conformatorisomers, isotope-labeled compounds, and combinations thereof, Here: One R 40 However, F, -CH 2 F, -CHF 2 , and -CF 3 Selected from the group consisting of, and other R 40 However, it is Cl, and R 41 The group is selected from the group consisting of H and an amino protecting group selected from the group consisting of: tert-butyloxycarbonyl (BOC), 9-fluorenylmethoxycarbonyl (FMOC), benzyloxycarbonyl (Cbz), p-methoxybenzylcarbonyl (MOZ), acetyl (Ac), trifluoroacetyl, benzoyl (Bz), benzyl (Bn), p-methoxybenzyl (PMB), 3,4-dimethoxyphenyl (DMPM), p-methoxyphenyl (PMP), 2,2,2-trichloroethoxycarbonyl (Troc), triphenylmethyl (trityl;Tr), toluenesulfonyl (tosyl;Ts), para-bromophenylsulfonyl (brosyl), 4-nitrobenzenesulfonyl (nosyl), and 2-nitrophenylsulfenyl (Nps).

41. The intermediate according to claim 40, wherein one R 40 is -CH 2 F and -CHF 2 is selected from the group consisting of, and the other R 40 is bonded to a C ring atom adjacent to the S ring atom and is Cl, the intermediate.

42. The intermediate according to claim 40, wherein the intermediate is the group consisting of: 【Chemistry 12】 And, The solvates, salts, complexes, polymorphs, crystalline forms, tautomers, conformational isomers, isotopically labeled compounds, and intermediates selected from combinations thereof.

43. The intermediate according to claim 40, wherein the intermediate is the group consisting of: 【Chemistry 13】 And, The solvates, salts, complexes, polymorphs, crystalline forms, tautomers, conformational isomers, isotopically labeled compounds, and intermediates selected from combinations thereof.

44. The intermediate according to claim 40, wherein the intermediate is the group consisting of: 【Chemistry 14】 And, The solvates, salts, complexes, polymorphs, crystalline forms, tautomers, conformational isomers, isotopically labeled compounds, and intermediates selected from combinations thereof.

45. An intermediate according to any one of claims 40 to 44, selected from the group consisting of the aforementioned intermediate and its solvate, salt thereof, tautomer thereof, conformational isomer thereof, and isotope-labeled compound thereof.

46. The intermediate according to claim 40, wherein the intermediate is 【Chemistry 15】 Alternatively, an intermediate which is a salt thereof, or a solvate thereof.

47. The intermediate according to claim 40, wherein the intermediate is 【Chemistry 16】 Or an intermediate, which is a salt thereof.

48. An intermediate according to claim 40, wherein the intermediate is 2-chloro-4-(fluoromethyl)thiophene-3-amine hydrochloride.

49. A method for producing a compound containing amide moiety, wherein the compound is the compound described in any of claims 1 to 6, and the production method comprises the step of reacting a corresponding carboxylic acid with an intermediate described in any of claims 40 to 48.

50. A manufacturing method according to claim 49, wherein R 41 The amino protecting group is selected from the following group: tert-butyloxycarbonyl (BOC), 9-fluorenylmethoxycarbonyl (FMOC), benzyloxycarbonyl (Cbz), p-methoxybenzylcarbonyl (MOZ), acetyl (Ac), trifluoroacetyl, benzoyl (Bz), benzyl (Bn), p-methoxybenzyl (PMB), 3,4-dimethoxyphenyl (DMPM), p-methoxyphenyl (PMP), 2,2,2-trichloroethoxycarbonyl (Troc), triphenylmethyl (trityl;Tr), toluenesulfonyl (tosyl;Ts), para-bromophenylsulfonyl (brosyl), 4-nitrobenzenesulfonyl (nosyl), and 2-nitrophenylsulfenyl (Nps). A manufacturing method comprising the step of removing an amino protecting group.

51. A method for preparing the compound according to claim 7, comprising the following steps: A compound according to any one of claims 1 to 6 is provided in a mixture having one or more impurities; and, At least the fraction of the impurity is removed from the mixture.

52. A method for producing a pharmaceutical composition, comprising the step of formulating a compound according to any one of claims 1 to 7 together with a pharmaceutically acceptable excipient.

53. A method for producing a pharmaceutical composition, comprising the step of formulating a compound according to any one of claims 1 to 5 together with a pharmaceutically acceptable excipient, or A method for producing a pharmaceutical composition, comprising performing or having performed the manufacturing method described in claim 49 for the production of a compound, and formulating the produced compound together with a pharmaceutically acceptable excipient.

54. A method for manufacturing a pharmaceutical package, including the following steps; The pharmaceutical composition according to claim 15 is loaded into a package, thereby preparing a package containing the pharmaceutical composition, wherein the package may optionally contain a woven print containing formulation information of the pharmaceutical composition.

55. A method according to claim 54, wherein the pharmaceutical composition is the final pharmaceutical form.

56. A pharmaceutical package comprising the pharmaceutical composition described in claim 15.

57. A pharmaceutical package according to claim 56, wherein the pharmaceutical composition is the final pharmaceutical dosage form.

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