Halogenated-heteroaryl and other heterocyclic kinase inhibitors, and uses thereof

Abstract

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

Description

Technical field

[0001] The present invention relates to kinase inhibitors, especially protein kinase inhibitors including SIK family, CSF1R, ABL / BCR-ABL, SRC, HCK, PDGFR, KIT and / or their mutants. Although structurally similar to dasatinib, the kinase inhibitors of the present invention are unique; having a specific class of halogenated heteroaryls. Such kinase inhibitors may exhibit one or more of certain properties that differ from dasatinib and other structurally similar kinase inhibitors. The kinase inhibitors of the invention, or pharmaceutical compositions comprising them, may be used in the treatment of diseases or conditions, for example proliferative diseases such as leukemia or solid tumors. In particular, these and other structurally similar kinase inhibitors could be used in the treatment of proliferative diseases—such as mixed phenotype acute leukemia (MPAL)—that are characterized (among others) by the presence of the MEF2C protein, a human chromosomal translocation at 11q23 and / or KMT2A fusion oncoprotein. Kinase inhibitors or pharmaceutical compositions disclosed herein can be topically administered to modulate skin pigmentation in a subject, eg, impart UV protection and reduce skin cancer risk.

Prior Technology

[0002] A kinase inhibitor is an enzyme inhibitor that blocks the action of a kinase. A partial, non-limiting list of such 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, enzymes that add phosphate groups to proteins or other organic molecules, have been shown to be key regulators of most cellular functions, including cell signaling, proliferation, differentiation, metabolism, survival, apoptosis, motility, DNA damage repair wait. Phosphorylation, especially the dysregulation of signaling due to defects in the control of protein phosphorylation, is closely related to a variety of diseases; for example, diseases related to abnormal activity (eg, increased activity) of kinases. Such diseases include, but are not limited to, proliferative diseases (such as cancer, benign tumors, pathological angiogenesis, inflammatory diseases, and autoimmune diseases), as well as allergic and CNS diseases.

[0003] Protein tyrosine kinases (PTKs) are enzymes that bind ATP to phosphorylate tyrosine residues in peptides and proteins as substrates. PTKs include, inter alia, receptor protein tyrosine kinases (RPTKs), including members of the epidermal growth factor kinase family (eg, HER1 and HER2), platelet-derived growth factor (PDGF), and kinases that play a role in angiogenesis (eg, TIE2 and KDR); in addition, non-receptor protein tyrosine kinases, including members of the SYK, JAK, and SRC kinase families (eg, SRC, HCK, FYN, LYN, LCK, and BLK kinases). Protein serine / threonine kinases (STKs) are enzymes that phosphorylate the oxygen atoms of the side chains of serine or threonine in peptides and proteins. STKs include AKT1, Aurora kinase, BRAF, MAP kinase, PLK1, SIK1, SIK2 and SIK3, among others.

[0004] Inhibition of protein kinases, and thus of substrate peptide or protein phosphorylation, has been shown to be effective in the treatment of a number of diseases. For example, afatinib is an ERBB inhibitor that is effective in the treatment of non-small cell lung cancer; axitinib is a VEGFR, PDGFR and c-KIT inhibitor that is effective in the treatment of renal It is effective in cell carcinoma; bosutinib is an ABL / BCR-ABL inhibitor, which is effective in the treatment of chronic myelogenous leukemia; cabozantinib is a c-MET and VEGFR2 inhibitor, is effective in the treatment of thyroid cancer; crizotinib is an ALK, HGFR and c-MET inhibitor, is effective in the treatment of non-small cell lung cancer; dasatinib (dasatinib) ) is an ABL / BCR-ABL, SRC and c-KIT inhibitor, which is effective in the treatment of chronic myelogenous leukemia; Erlotinib is an EGFR inhibitor, which is effective in the treatment of non-small cell lung cancer and It is effective in pancreatic cancer; gefitinib is an EGFR inhibitor that is effective in the treatment of non-small cell lung cancer; imatinib is an ABL / BCR-ABL inhibitor, It is effective in the treatment of chronic myelogenous leukemia; lapatinib is a HER2 inhibitor and is effective in the treatment of breast cancer; nilotinib is an ABL / BCR-ABL inhibitor It is effective in the treatment of chronic myelogenous leukemia; pazopanib is a VEGFR, PDGFR and c-KIT inhibitor, which is effective in the treatment of renal cell carcinoma and soft tissue sarcoma; palbociclib (palbociclib) is an inhibitor of CDK4 and CDK6, which is effective in the treatment of ER-positive and HER2-negative breast cancer; ponatinib is an inhibitor of ABL / BCR-ABL, BEGFR, PDGFR, FGFR, EPH , SRC, c-KIT, RET, TIE2 and FLT3 inhibitors are effective in the treatment of chronic myelogenous leukemia and acute lymphoblastic leukemia; regorafenib is a RET, VEGFR and PDGFR inhibitor, in It is effective in the treatment of colorectal cancer and gastrointestinal stromal tumors; ribociclib is an inhibitor of cyclin D1 / CDK4 and CDK6, and is effective in the treatment of HR-positive, HER2-negative advanced or metastatic breast cancer Effective in cancer; ruxolitinib, a JAK inhibitor, is effective in the treatment of myelofibrosis; sorafenib, a VEGFR, PDGFR, BRAF and c-KIT inhibitor It is effective in the treatment of renal cell carcinoma and hepatocellular carcinoma; sunitinib is a VEGFR and PDGFR inhibitor, which is effective in the treatment of renal cell carcinoma, gastrointestinal stromal tumor and pancreatic neuroendocrine tumors. Effective; tofacitinib is a JAK inhibitor, which is effective in the treatment of rheumatoid arthritis; vandetanib is a VEGFR, EGFR, RET and BRK inhibitor, in is effective in the treatment of thyroid cancer; and vemurafenib, a BRAF inhibitor, is effective in the treatment of malignant melanoma.

[0005] Given the large number of kinases and associated diseases, there is an ongoing need for new inhibitors that are selective for a variety of kinases and that may be useful for the treatment of associated diseases; in particular, there remains a need for new kinase inhibitors, pharmaceutical compositions / formulations and their use (including in therapeutic regimens) to treat diseases associated with abnormal activity of one or more kinases; in particular, there remains a need for new kinase inhibitors: (a) for the treatment of proliferative diseases, such as mixed-expression acute leukemia (MPAL) characterized (among others) by the presence of myocyte enhancer factor 2C (MEF2C) protein, human chromosomal translocation at 11q23, and / or lysine methyltransferase 2A (KMT2A) fusion oncoprotein; or (b) Alternatives to existing kinase inhibitors (eg, dasatinib).

[0006] A specific kinase inhibitor is dasatinib (N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1- Piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide, a hydrate; Figure 1A), is marketed under the name "SPRYCEL" by Bristol-Myers Squibb and is suitable for For the treatment of adult patients with: (i) newly diagnosed Philadelphia chromosome positive (Ph+) chronic myelogenous leukemia (CML) in chronic phase; Treatment-resistant or intolerable chronic phase, accelerated phase, or (myeloid or lymphoid) blast phase (Ph+) CML; and (iii) Philadelphia chromosome-positive acute phase resistant or intolerant to prior therapy Lymphoblastic leukemia (Ph+ALL). In Europe, dasatinib is also indicated for patients with newly diagnosed Ph+ CML in chronic phase (Ph+ CML-CP) or Ph+ CML-CP who are resistant or intolerant to prior therapy including imatinib Treatment of pediatric patients; in the United States, the drug is indicated for pediatric patients with chronic phase Ph+ CML.

[0007] It is noteworthy that despite numerous trials with dasatinib, the drug has not been used in the United States or Europe for any cancer other than CML or Ph+ ALL; in particular, as of September 2018 Dasatinib was not used in any solid tumors. Indeed, many clinical trials using dasatinib to investigate its possible use in solid tumors were terminated early (for example, due to toxicity concerns) or failed to report robust or at least promising results. For example, dasatinib has only been tested once in phase 3 in solid tumors: in a single study in combination with docetaxel in castration-resistant prostate cancer (" READY" trial (NCT00744497)), although there were some signs of its activity in earlier trials against castration-resistant prostate cancer that had not received chemotherapy (e.g. Araujo et al. In this trial, dasatinib did not improve overall survival over docetaxel alone (Araujo et al. 2013, Lancet Oncol. 14:13017). Despite several trials in other cancers such as breast, skin, pancreas, brain or lung, dasatinib has not shown satisfactory efficacy or tolerability, nor has it progressed against these cancers phase 3 trial. In particular, a recent double-blind phase 2 trial of dasatinib plus gemcitabine in patients with locally advanced unresectable pancreatic cancer failed to show improved overall survival compared with gemcitabine alone (Evens et al. 2017, Annal. Onc. 28:354). More recently, however, several dedicated studies aimed at selecting "targeted" therapy for patients with specific cancers (including solid tumors) expressing specific drug targets may potentially test dasatinib according to the patient's targeting profile. For example (i) "TAPUR" test ("The Targeted Agent and Profiling Utilization Registry", https: / / www.tapur.org, NCT02693535) included dasatinib as a possible treatment based on one or more of the following targets In the group: BCR-ABL, SRC, KIT, PDGFRB, EPHA2, FYN, LCK, YES1; and (ii) a trial by Melanoma Institute of Australia (NCT02645149) involving patients with unresectable metastatic stage III or IV Patients with stage BRAF and NRAS wild-type melanoma who have progressed or are unable to receive standard treatment (generally immunotherapy), including dasatinib as a possible treatment, depending on the KIT mutation identified in the patient's cancer. Dasatinib is also a possible branch of the BMS "FRACTION-Lung" phase 2 trial (NCT02750514), which may be tested in combination with the tumor immunotherapy drug nivolumab in patients with advanced non-small cell lung cancer. The other arm of the trial combined nivolumab with other immuno-oncology drugs.

[0008] Thus, there is a particular need for new kinase inhibitors for the treatment of cancers not indicated for treatment with dasatinib (especially solid tumors), and / or cancers for which dasatinib has not shown favorable effects. In particular, there is a need for new kinase inhibitors for the treatment of one or more cancers, such as breast cancer, lung cancer (eg, non-small cell lung cancer), pancreatic cancer, or prostate cancer (eg, castration-resistant or hormone-resistant prostate cancer) and melanoma.

[0009] Furthermore, there is a particular need for new kinase inhibitors for the treatment of proliferative diseases such as mixed phenotype acute leukemia (MPAL, also known as mixed lineage leukemia "MLL"), which are characterized (among other things) by the presence of MEF2C protein (eg, phosphorylated MEF2C protein and / or MEF2C protein as an active transcription factor), human chromosomal translocation at 11q23, and / or KMT2A fusion oncoprotein.

[0010] Mixed phenotype acute leukemia (MPAL), also known as "mixed lineage leukemia" (MLL), is a very aggressive blood cancer that occurs primarily in pediatric patients, unlike other types of childhood acute leukemia , poor prognosis (reviewed from Slany 2009, Haematologica 94:984). One form of MPAL is a BCR / ABL rearrangement. MPAL with t(9;22)(q34;q11.2) (or BCR / ABL1 rearrangement) was considered a separate entity (Arber et al 2016, Blood 127:2391). The t(9;22)(q34;q11.2) translocation results in a BCR / ABL1 fusion gene located on the Philadelphia chromosome (Ph), resulting in a constitutively active BCR / ABL1 tyrosine kinase. Another form of MPAL is characterized by the presence of the lysine methyltransferase 2A (KMT2A) fusion protein (also known as the MLL1 fusion protein), a chromosomal translocation affecting the KMT2A gene (also known as the MLL1 gene) at 11q23 result. This KMT2A / MLL rearrangement is the second most common inherited lesion in MPAL (MPAL-MLL+). These 11q23 translation events juxtapose the amino terminus of the histone methyltransferase KMT2A with a variety of different (translocation) fusion partners that disrupt KMT2A's normal histone methyltransferase function and replace it with (Translocation) Heterologous functional substitution contributed by a fusion partner. The resulting protein chimeras are transcriptional regulators that control other genes normally controlled by KMT2A. In particular, the transcription factor MEF2C can be controlled by KMT2A and is considered an oncogene in childhood acute leukemia. MEF2C expression is associated with a KMT2A fusion gene rearrangement in AML (Schwieger et al 2009, Blood 114:2476), and MEF2C expression defines a subgroup of AML patients with poor survival (Lazlo et al 2015, J Hematol & Oncol 8:115).

[0011] Tarumoto and colleagues (2018, Mol Cell 69:1017) showed that MEF2C activity in AML is driven by SIK3 phosphorylation of HDAC4, and SIK3 gene knockout or small molecule tool compound HG-9-91-01 Chemical inhibition greatly reduced viability of several MPAL-associated AML cell lines, including MOLM-13 and MV4-11; cytoplasmic retention of HDAC4 phosphorylated by SIK3 by preventing nuclear localization (unphosphorylated) as a corepressor of MEF2C HDAC4 regulates the activity of the transcription factor MEF2C, a tumor survival / maintenance gene associated with AML proliferation (Fig. 19). Indeed, recent studies have shown that SIK3 inhibition by the small molecule tool compound YKL-05-099, administered intraperitoneally, inhibits AML progression in vivo (Tarumoto et al 2020, Blood 135:56). However, there is still a need for more SIK3 inhibitors, especially those with drug-like properties and especially those that can be administered orally, for the treatment of proliferative diseases (such as MPAL), especially those related to SIK3-driven MEF2C control Inhibitors involved in the expression of cancer survival genes.

[0012] There is also a need for new kinase inhibitors for the treatment of myeloid or lymphoblastic carcinomas such as leukemias, preferably for the treatment of one or more Ph+ leukemias such as CML and / or ALL.

[0013] Dasatinib is described as an inhibitor at nanomolar concentrations of the following kinases: BCR-ABL, SRC family (SRC, LCK, YES, FYN), c-KIT, EPHA2, and PDGFR-β; and Of particular relevance to the indication of dasatinib in Ph+ leukemia is its inhibition of the hybrid protein kinase BCR-ABL.

[0014] The BCR-ABL kinase is directly related to the presence of a specific genetic abnormality on chromosome 22 of leukemia cancer cells (especially CML cells); known as the "Philadelphia chromosome" (or Philadelphia translocation). This reciprocal translocation of genetic material between chromosome 9 and chromosome 22 juxtaposes the ABL1 gene of chromosome 9 to the BCR gene of chromosome 22, forming a hybrid protein called "BCR-ABL" The coding sequence for : an "always-on" protein tyrosine kinase that causes cells to divide uncontrollably. The vast majority of CML cases and 20-30% of ALL cases are Ph+. The first selective BRC-ABL inhibitor, imatinib (STI571), marketed by Novartis as "GLEEVEC / GLIVEC", is considered a breakthrough in the treatment of Ph+ leukemia. However, despite an increase in overall survival, the development of resistance during imatinib treatment led scientists to discover that most of this resistance is due to the emergence of mutations in BCR-ABL, specifically the ABL-derived kinase Amino acid substitutions within domains (for a review, see Rossari & Orciuolo. 2018, J. Hemat. Oncol. 11:84, hereby incorporated by reference in its entirety).

[0015] The analysis of the BCR-ABL mutation status and survival probability of patients treated with imatinib showed that mutations in the phosphatase loop (P loop) at the ABL position of the BCR-ABL kinase were the most frequent, but outside the P loop (especially (Rare) mutations within the kinase domain) are associated with reduced overall survival in imatinib-treated CML patients (Jabbour et al. 2006, Leukemia 20:1767). Many novel BCR-ABL mutations have been identified and described (see Table 1 of Manley et al. 2005, Biochem. Biophys. Acta 1754:3 and Table 1 of Rossari & Orciuolo 2018, which also describe other kinases of dasatinib Mutations of the targets; these two tables are hereby specifically incorporated by reference). In particular, the following mutations were found in the ATP-binding region of BCR-ABL (indicating the location of the wild-type ABL protein): V299L, F311L, T315I, T315A, F317L, and F317V. In fact, dasatinib was originally developed as a "second-generation" BCR-ABL inhibitor for the second-line treatment of CML that had become resistant to imatinib, presumably due to one of these mutations or arising from the emergence of other mutations. Based on modeling studies, dasatinib is predicted to bind to multiple conformations of ABL kinase, which is thought to explain why dasatinib inhibits several conformation-altering mutations of ABL, but imatinib does not. In fact, a retrospective analysis comparing mutation development during first-line treatment with dasatinib or imatinib showed that treatment with dasatinib (4 different sites) with fewer different mutation sites (Hughes et al. 2015, Leukemia 29:1832, especially its Figure 1). Importantly, however: (i) the overall proportion of patients with any type of mutation was approximately the same (17 / 259 patients on dasatinib and 18 / 260 patients on imatinib); The majority of mutations were in the ATP-binding region (3 / 4 mutations); and (iii) the most common mutations arising during dasatinib treatment (11 / 17) were in residues known as "gatekeepers" The T315I mutation at the base, which still confers resistance to dasatinib inhibition of the BCR-ABL kinase. A specific panel of BCR-ABL mutants that can be tested against kinase inhibitors is provided by the ProQinase ABL1 Kinase "Wild-Type and Mutant Panel", consisting of the ABL1 wild-type protein (amino acids P118-S525) and representing the most prevalent BCR-ABL The mutant forms of imatinib-resistant mutant forms: G250E, Q252H, Y253F, E255K, T315I, F317I, M351T and H396P (www.proqinase.com).

[0016] The T315I mutation is one of the most common BCR-ABL mutations: present in 2% to 20% of CML cases (Nicolini et al. 2009, Blood 114:5271). This mutation is resistant to dasatinib inhibition, a potential drawback of dasatinib as a kinase inhibitor that stimulates the " Development of the third generation of BCR-ABL inhibitors. However, although ponatinib did strongly inhibit the T315I mutation of the BCR-ABL kinase (in vitro IC50 of 2.0 nM), it is known to be a more promiscuous kinase inhibitor than dasatinib and was also known to be a more promiscuous kinase inhibitor in vitro. IC50 concentrations between 0.1 and 20 nM inhibit many other kinases including at least members of the SRC family of receptors and kinases including VEGFR, PDGFR, FGFR, EPH, as well as KIT, RET, TIE2 and FLT3. In addition, sales of ponatinib in the United States were suspended in October 2013 due to "the risk of life-threatening blood clots and severe narrowing of blood vessels." The moratorium came in December 2013 following the release of ponatinib with revised prescribing information, a new "Boxed Warning" and a "Risk Assessment and Mitigation Strategy" to better assess the risks and benefits of using the drug. partially lifted. In addition, the price of ponatinib in the United States, which can cost as much as $138,000 per year, has also been criticized. Ponatinib therefore shows substantial disadvantages, and thus there is still a need for new kinase inhibitors, especially those with more potential for effective, safe, easy and / or inexpensive treatment of Ph+ leukemia (or other cancers); And / or inhibitors that are more selective for SRC, ABL / BCR-ABL, and / or LCK than other kinase inhibitors such as dasatinib or ponatinib.

[0017] However, in contrast to imatinib, dasatinib is not particularly specific for BCR-ABL, but binds and / or inhibits a number of other kinases (see Bantscheff et al. 2007, Nat. Biotech. 25 : 1035 Figure 3; Anastassiadis et al. 2012, Nat. Biotech. 29:1039 Supplementary Figure 2). In particular, dasatinib has been described to bind and / or inhibit many other kinases more significantly than imatinib, including: BTK, CSK, EPHB2, EPHB4, FYN, GAK, KIT, LYN, QIK, QSK, RIPK2, SRC, TEC, TESK2, YES, and ZAK. More specifically, dasatinib is an important inhibitor of salt-induced kinases, and the IC50 values ​​of the three family members SIK1, SIK2 and SIK3 are <3nM, <3nM and 18nM, respectively (Ozanne et al. 2015, Biochem. J . 465:271; also as described in co-pending PCT / EP2018 / 060172). In fact, given that dasatinib is a less selective kinase inhibitor (another potential disadvantage), this reduced selectivity may be related to the insignificant toxicity faced by patients treated with dasatinib associated with challenges, particularly increased incidence of thrombocytopenia (Wei et al. 2010, J. Hemat. Oncol. 3:47).

[0018] As mentioned above, dasatinib is a potent KIT inhibitor, and this receptor tyrosine kinase is becoming an increasingly interesting target for the treatment of certain cancers (Babei et al. 2016, Drug Des. Dev. Thera., 10:2443), especially since mutations in the KIT gene have been detected in cancers such as leukemia, ovarian cancer and melanoma. Dasatinib is also known to suppress at least the most common KIT mutation in melanoma (Woodman et al. 2009, J. Clin. Onc. 27:9019). However, inhibition of KIT, particularly the relative activity of certain tyrosine kinase inhibitors against FLT3 and KIT, has been associated with myelosuppression and other side effects such as hair fading (Galanis and Levis 2015: Haematologica 100:e89). In fact, dasatinib treatment has been associated with severe myelosuppression (see below).

[0019] Salt-induced kinase (SIK) constitutes the serine tyrosine kinase subfamily and belongs to the adenosine monophosphate-activated kinase (AMPK) family. Three members (SIK1, -2 and -3) have been identified so far. The amino acid homology between SIK1 and SIK2 and SIK3 in the kinase domain is 78% and 68%, respectively. Cloning of SIK1 (also known as SIK and SNF1LK) abundantly expressed in the adrenal glands of rats fed a high-salt diet led to the subsequent cloning of SIK2 (also known as QIK, KIAA0781 and SNF1LK2) predominantly expressed in adipose tissue, and comparable Universal SIK3 (also known as QSK, KIAA0999 or L19) (Katoh et al. 2004, Mol. Cell. Endocrinol. 217:109). These three SIKs have similar structures, with an N-terminal kinase domain (catalytic domain), an intermediate ubiquitin-associated domain (thought to be important for phosphorylation by LKB1), and a long C-terminal sequence ( considered to be the site of further phosphorylation by PKA). However, the roles involved in the different SIKs are very different. For example, various SIKs are involved in different biological processes, such as the response of bone cells to parathyroid hormone (Wein et al. 2016, Nature Commun. 7:13176) to induce SIK1 by gastrin and inhibit the migration of gastric adenocarcinoma cells (elvik et al. 2014, PLoS ONE 9:e112485). Other potential roles of salt-induced kinases, especially SIK3, are described in WO2018 / 193084A1 (the applicant, and published on October 25, 2018), in addition, SIK3 is a protein involved in tumor cell-to-cell-mediated immune responses Resistance, especially the gene of tumor cell resistance to TNF. Recently, SIKs (especially SIK3) were shown to also regulate TGFβ-mediated transcriptional activity and apoptosis, and Hutchinson et al. (2010, Cell Death and Disease 11:49) showed that SIK3 expression or activity resulted in a response to TGFβ-mediated apoptosis resistance.

[0020] In particular, in addition to playing a role in various inflammatory responses (Clark et al 2014; Sundberg et al 2016) and oncology—especially the sensitivity of tumor cells to immune responses (WO2018 / 193084A1)—since 2011 Inhibition of SIK2 has been known for years to promote melanogenesis in B16F10 melanoma cells (Kumagai et al 2011, PLoS ONE 6(10): e26148). It was subsequently described that the hyperpigmentation pathway including human skin explants can be effectively induced by (topical) application of SIK inhibitors, including those structurally related to YKL-05-099 (Mujahid et al 2017, Cell Reports 19:2177 ). In fact, using these results, it was subsequently sought to increase (the appearance of) the number of subjects tested by topically applying to the skin of the subjects an effective amount of a SIK inhibitor, including the use of kinase inhibitors previously known as SIK inhibitors (WO2016 / 023014). A method for skin pigmentation of patients (WO2018 / 160774).

[0021] A kinase known as 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 towards the more suppressive M2 phenotype (Lenzo et al 2012, Immunol Cell Bio 90:429). In fact, the presence of CSF1R+ macrophages in tumors is associated with poor survival in various indications including gastric, breast, ovarian, and bladder cancers (Zhang et al 2012, PLoS One 7:e50946t). Therefore, targeting CSF1R with antibodies or small-molecule inhibitors by eliminating or re-cultivating suppressive M2 macrophages has become an important approach in the treatment of cancer. PLX3397 is such an inhibitor targeting CSF1R, which is in clinical development for melanoma, glioblastoma, AML, etc. (Cannarile et al 2017, J Immunotherapy Cancer 5:53).

[0022] The kinase known as hematopoietic kinase (HCK) is a member of the SRC family of cytoplasmic tyrosine kinases (SFK), expressed in cells of myeloid and B-lymphoid lineages. Excessive HCK activation is associated with multiple types of leukemia and promotes cell proliferation and survival through physical association with oncogenic fusion proteins and functional interactions with receptor tyrosine kinases. Elevated HCK activity is also seen in many solid malignancies, including breast and colon cancer, and is associated with reduced patient survival. HCK can promote the secretion of myeloid cell growth factors and pro-inflammatory cytokines, and promote the differentiation of macrophages into wound healing and tumor-promoting alternate activation phenotypes. In tumor-associated macrophages, HCK stimulates the formation of pseudopodia bodies that promote extracellular matrix degradation, thereby enhancing immunity and epithelial cell invasion. Excessive HCK activation also reduces drug efficacy and leads to chemotherapy resistance due to the functional cooperation between HCK and bona fide oncogenic tyrosine kinases, whereas genetic ablation of HCK resulted in minimal physiological consequences in healthy mice. Given its known crystal structure, HCK thus provides an attractive therapeutic target for both, directly inhibiting the growth of cancer cells and indirectly inhibiting sources of pro-tumor changes in the tumor microenvironment (Poh et al 2015, Oncotarget 6 :15742).

[0023] Thus, there remains a need for new kinase inhibitors, especially those that exhibit drug-like properties (especially those suitable for oral administration) and that inhibit one or more kinases (including from SIK3, ABL / BCR-ABL, Any one selected from SRC, HCK, PDGFR, KIT, and / or CSF1R), and / or specifically an inhibitor that exhibits a different kinase profile than the one inhibited by dasatinib. For example, new kinase inhibitors that: (i) are more specific for key disease-associated kinases (e.g., ABL / BCR-ABL, SRC, LCK, HCK, PDGFR CSFR1 and / or EPHA2, EPHA4, ACK1 and / or KIT) are more specific; (ii) inhibit key disease- or side-effect-associated kinases (e.g., KIT and / or FLT3) in a different manner than dasatinib ); and / or (iii) inhibit one or more mutants of a disease-associated kinase, in particular mutants resistant to one or other kinase inhibitors, such as mutants of ABL / BCR-ABL or KIT.

[0024] In addition, although dasatinib is mainly metabolized by cytochrome P450 enzyme 3A4 (CYP3A4) in humans, it is also a time-dependent inhibitor of CYP3A4. In fact, if patients are also taking strong CYP3A4 inhibitors (such as ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir ), nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin and voriconazole), zedaza The dose of tinib must be reduced significantly (eg, from 100 mg per day to 20 mg per day), as this may increase plasma concentrations of dasatinib to potentially unsafe levels. Grapefruit juice may also increase dasatinib plasma concentrations and should also be avoided. Therefore, there remains a need for new kinase inhibitors that display a different pattern of cytochrome P450 inhibition (eg, for CYP3A4) than dasatinib.

[0025] It is important that the dose and administration of dasatinib be stopped (or reduced) once myelosuppression occurs. In fact, in the U.S. prescribing information of dasatinib, myelosuppression is only described as a "warning and precaution", because dasatinib treatment is associated with severe (NCI CTC grade 3 or 4) thrombocytopenia, neutropenia, and neutropenia. Leukopenia is associated with anemia. In addition to causing thrombocytopenia in human subjects, in all dasatinib clinical studies: (i) severe central nervous system bleeding (including death) occurred in 1% of patients; (ii) severe gastrointestinal bleeding occurred in 4% of patients , including death, usually requiring interruption of treatment and transfusion; and (iii) other major bleeding occurred in 2% of patients.

[0026] Further "warning and precautions" for dasatinib include: (x) it is associated with fluid retention, which has been reported in up to 10% of patients in clinical trials; (y) it has the potential to prolong ventricular repolarization (QT interval), QT prolongation in up to 1% of CML patients in clinical trials; and (z) cardiac adverse reactions, including cardiomyopathy in 1.6% of 258 patients taking dasatinib , congestive heart failure, diastolic dysfunction, fatal myocardial infarction, and patients with left ventricular dysfunction. In fact, dasatinib is known to be an inhibitor of hERG (Pharmacological / Toxicity Review and Evaluation of NDA 21-986, page 31). hERG (human Ether-a-go-go related gene) is an ion channel that contributes to the electrical activity of the heart and coordinates the beating of the heart. When the channel's ability to conduct electrical current across cell membranes is inhibited or impaired (for example, by drug administration), it can result in the potentially fatal "long QT syndrome." Therefore, there remains a need for new kinase inhibitors that exhibit inhibitory effects on hERG other than dasatinib. For example, it would be advantageous to provide new kinase inhibitors with an IC50 for hERG greater than dasatinib.

[0027] In fact, the main metabolic pathway of dasatinib includes the metabolic pathway modified by chloro / methylphenyl or piperazinyl of dasatinib (for example, Christopher et al 2008, Drug Metab & Disp 36:1357 , especially in Figure 4). In particular, CYP3A4-mediated formation of reactive epoxides and quinoneimine intermediates can form the active metabolite of dasatinib, which can covalently bind 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 cause drug interactions with other CYP substrates such as simvastatin.

[0028] Therefore, there remains a need for other kinase inhibitors (e.g. in humans) that exhibit a different metabolite profile than dasatinib, especially other kinases that have one or more major metabolic pathways that differ from dasatinib Inhibitors (especially chloro / methylphenyl and / or piperazinyl modified dasatinib).

[0029] Dasatinib has a very short half-life compared to other BCR-ABL inhibitors: the overall mean terminal half-life is only 3-5 hours (Section 12.3 "Pharmacokinetics" of the full prescribing information). In stark contrast: imatinib has an elimination half-life of approximately 18 hours; bosutinib has a mean end-phase elimination half-life of 22.5 hours; nilotinib has an apparent elimination half-life of approximately 17 hours; The geometric mean terminal elimination half-life of tinib is approximately 24 hours. Without being bound by theory, the shorter half-life of dasatinib—suitable for a once-daily dose—may explain the limited activity associated with lower drug concentrations in the body later in the day and / or with Side effects associated with peak / higher drug concentrations in the body shortly after administration. Therefore, there remains a need for new kinase inhibitors with longer half-life properties (eg, longer half-life than that shown for dasatinib). For example, an advantageous kinase inhibitor may be one that is more stable than dasatinib, for example by exhibiting a longer half-life in plasma and / or liver microsomal stability assays.

[0030] Further precautions, adverse events and other prescribing information for dasatinib can be found in the Summary of Product Characteristics (SmPC) of the full prescribing information on the respective websites of EMA and FDA (as shown below respectively, August 20, 2018 Accessed, and incorporated herein by reference in its entirety): (i) http: / / www.ema.europa.eu / docs / en_GB / document_library / EPAR_Product_Information / human / 000709 / WC500056998.pdf and (ii) https: / / www.accessdata.fda.gov / drugsatfda_docs / label / 2010 / 021986s7s8lbl.pdf.

[0031] Various variants of dasatinib have been synthesized and demonstrated to have in vitro biochemical inhibitory activity against one or more kinases and / or have antiproliferative effects on cells. In particular, these variants were synthesized: (i) during the discovery phase of dasatinib to understand and characterize its structure-activity relationship (SAR) (Lombardo et al 2004, J Med Chem 47:6658; Das et al 2006, J Med Chem 49:6819); and (ii) providing alternative kinase inhibitors and / or drug candidates (eg WO 2006 / 081172 and WO 2008 / 033746). The dasatinib variants described therein bear a phenyl moiety at the formamide. These disclosures demonstrate other positions and a large number of substituents that can be substituted thereon, providing compounds that are kinase inhibitors and / or have cellular antiproliferative activity (Figure 8).

[0032] WO 2018 / 193084 (the applicant, and disclosed on October 25, 2018) discloses dasatinib variants carrying pyridyl moieties and uses thereof. Co-pending application PCT / EP2019 / 078751 (the Applicant) further discloses dasatinib variants bearing other heterocyclic moieties, especially variants bearing thiazolyl moieties. Beutner et al. (2018, Org Lett 20:4218) describe a method for forming challenging amide bonds, including those attached to certain pyridines, pyrazines, and pyrimidines. Pennington et al. (2017, J Med Chem 60:3552) described that the substitution of CH groups with N atoms in aromatic and heteroaromatic ring systems can have molecular and physiological properties. However, it has been empirically shown that making such substitutions does not statistically improve potency any better than mere chance: Matched Molecular Pair Analysis (MMPA) of Abbott internal data (Hajduk & Sauer 2008, J Med Chem 51:553) found , as with most substituents, the probability of increasing or decreasing potency by exchanging CH groups and N atoms is approximately equal. In fact, the analysis further showed that the probability of achieving a 10-fold increase in potency with this surrogate is less than one in 10, and the probability of achieving a 100-fold increase is less than 1 in 100; Probability observed when the effect is observed (Hu et al 2014, F1000Research 3:36; de la Vega de Leon et al 2014, MedChemComm 5:64).

[0033] It is therefore an object of the present invention to provide one or more kinase inhibitors (eg inhibitors of SIK3, ABL / BCR-ABL, SRC, HCK, PDGFR, KIT and / or CSF1R kinases) having a or more properties (such as those shown by in vitro and / or in vivo tests) that may address one or more of these or other issues. Among other objects, the present invention provides alternative and / or improved kinase inhibitors to dasatinib (or one or other kinase inhibitors, such as those described herein). For example, one or more functional (e.g., kinase selectivity), ADMET, PK, and / or pharmacological properties that are different from dasatinib (or one or other kinase inhibitors, such as those described here) And / or improved kinase inhibitors compared to dasatinib would be advantageous. In particular, it would be advantageous to provide one or more SIK family kinase inhibitors with similar pharmaceutical properties, especially those that can be administered orally, for the treatment of proliferative diseases (such as MPAL), characterized (among other things) by Presence of MEF2C protein (eg phosphorylated MEF2C protein and / or MEF2C protein as active transcription factor), human chromosomal translocation at 11q23, and / or KMT2A fusion oncoprotein. The objects upon which this invention is based are solved by the subject matter disclosed or defined anywhere herein, for example by that of the appended claims.

Content of invention

[0034] In general, by brief description, the main aspects of the present invention can be summarized as follows:

[0035] In a first aspect, the present invention provides a compound selected from a kinase inhibitor of the following formula: (Ia), and solvates, salts, N oxides, complexes, polymorphs, and crystal forms thereof , racemic mixtures, diastereomers, enantiomers, tautomers, conformers, isotopically labeled forms, prodrugs and combinations thereof; wherein Hy, R2, R3 , R4, R5, A and E are as defined herein.

[0036] In a second aspect, the present application provides a pharmaceutical composition comprising the compound of the first aspect and optionally a pharmaceutically acceptable excipient.

[0037] In a third aspect, the application provides the compound of the first aspect or the pharmaceutical composition of the second aspect for use in therapy.

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

[0039] In the fourth aspect, the present application provides the compound of the first aspect or the pharmaceutical composition of the second aspect for treating a proliferative disease of a subject (especially a human patient).

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

[0041] In a fifth aspect, the application provides a compound or a pharmaceutical composition for treating a proliferative disease of an object, the treatment comprising administering the compound or a pharmaceutical composition to the object, wherein the compound is selected from the following compounds: (a ) to (c), or the pharmaceutical composition comprising the compound and optionally a pharmaceutically acceptable excipient: (a) a compound of the first aspect; (b) a compound of the formula: (Ib) As well as solvates, salts, N-oxides, complexes, polymorphs, crystalline forms, racemic mixtures, diastereomers, enantiomers, tautomers, configurational isomers compounds, isotopically labeled forms, prodrugs, and combinations thereof; wherein Hy, R2, R3, R4, R5', A, and E are as defined herein; and (c) a compound having the following formula (Ic): (Ic) and a solvent Compounds, salts, N-oxides, complexes, polymorphs, crystalline forms, racemic mixtures, diastereomers, enantiomers, tautomers, conformational isomers, Isotopically labeled forms, prodrugs and combinations thereof; wherein R1a, R1b, R1c, R2, R3, R4, R5'', A, B and E are as defined herein; and wherein the proliferative disorder is selected from (α) to One or more of (γ): (α) A proliferative disorder characterized by (or cells associated with 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; preferably, wherein the proliferative disorder is also characterized by the presence of phosphorylated histone deacetylase 4 (HDAC4) protein, such as SIK3 phosphorylated HDAC4 protein; and / or ( β) A proliferative disorder characterized by (or cells associated with a proliferative disorder characterized by): (i) the presence of a human chromosomal translocation at 11q23; (ii) the presence of lysine methyltransferase 2A (KMT2A ) a rearrangement of the gene; (iii) the presence of the KMT2A fusion oncoprotein; 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 aspect, the present invention provides a method for treating a proliferative disease in a subject, comprising administering to said subject a compound or pharmaceutical composition as defined in the fifth aspect, wherein the proliferative disease is as defined in the fifth aspect aspect defined.

[0043] In another aspect, the application provides a method for determining that a subject suffering from a proliferative disease is suitable for treatment with a compound or a pharmaceutical composition as defined in the fifth aspect, the method comprising, from the In a biological sample obtained from a subject it is determined: (X) the presence of MEF2C protein, such as phosphorylated MEF2C protein and / or MEF2C protein as an active transcription factor; preferably, wherein the proliferative disorder is also characterized by the presence of phosphorylated HDAC4 protein, For example, HDAC4 protein phosphorylated by SIK3; and / or (Y) (i) presence of human chromosomal translocation at 11q23; (ii) presence of KMT2A gene rearrangement; (iii) presence of KMT2A fusion oncoprotein; and / or (iv ) the presence of a mutation in the KRAS gene and / or the RUNX1 gene, wherein the presence of said protein, translocation, rearrangement, oncoprotein and / or mutation in a biological sample indicates that said subject is suitable for use in said compound or pharmaceutical composition treatment.

[0044] In another aspect, the present invention relates to a method of increasing skin pigmentation (or increasing the appearance of skin pigmentation) in a subject, the method comprising administering to said subject (eg, an effective amount of) the pigment used in the fifth aspect. Kinase inhibitors (or pharmaceutical compositions comprising such compounds).

[0045] In another aspect, the application provides an intermediate selected from compounds having the formula (Id): (Id) and solvates, salts, complexes, polymorphs, crystalline forms, racemic Mixtures, diastereomers, enantiomers, tautomers, conformers, isotopically labeled forms and combinations thereof, wherein R40 and R41 are as defined herein.

[0046] In another aspect, the application provides a method of preparing a compound comprising an amide moiety, the method comprising the steps of reacting an intermediate of the invention with a corresponding carboxylic acid, and optionally deprotecting the amine group group.

[0047] Other aspects of the invention are also disclosed herein.

Implementation

[0048] The invention and certain non-limiting aspects and / or embodiments thereof can be described in more detail as follows.

[0049] While the present invention may be further described in greater detail, it is to be understood that this invention is not limited to the particular methodology, protocols and reagents described herein as these may vary. It should also 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 present invention, which shall be limited only by what is described, defined or otherwise disclosed herein. limitations, particularly in any detailed examples or appended claims.

[0050] Certain elements of the invention are described in greater detail herein. These elements are listed with specific embodiments, however, it should be understood that they may be combined in any way and in any number to create additional embodiments. The various described embodiments and preferred embodiments should not be construed to limit the invention to only the expressly described embodiments. The description of the present application should be understood to support and encompass the embodiments explicitly described in combination with any number of disclosed and / or preferred elements. Furthermore, unless the context dictates otherwise, any permutation and combination of all described elements in this application should be considered as disclosed in the specification of this application. For example, if in one embodiment of a compound of this invention L is a bond and in another embodiment of a compound of this invention R3 is H, then in a preferred embodiment of a compound of this invention L is a bond and R3 is H, or if in one embodiment of the use of the compound of the invention the subject is an adult and in another embodiment of the use of the compound of the invention the proliferative disease is prostate cancer, then in the use of the compound of the invention In preferred embodiments, the subject is an adult and the proliferative disease is prostate cancer.

[0051] general definition

[0052] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0053] Preferably, the terms used herein are as defined in "A Multilingual Glossary of Biotechnology Terms: (IUPAC Recommendations)", H.G.W. Leuenberger, B. Nagel, and H. Kölbl, Eds., Helvetica Chimica Acta , CH-4010 Basel, Switzerland, (1995).

[0054] The practice of the present invention will employ, unless otherwise indicated, conventional methods of chemistry, biochemistry, and recombinant DNA techniques as explained in the literature of the art (see, e.g., Molecular Cloning: A Laboratory Manual, 2nd Edition, J. Sambrook et al. eds., Cold Spring Harbor Laboratory Press, Cold Spring Harbor 1989).

[0055] In this specification and subsequent patent claims, unless the context requires otherwise, the word "comprises" and variations such as "comprises" and "comprises" will be understood to imply inclusion of said members, integers or A step or a member, an integer or a group of steps, but not excluding any other member, an integer or a step or a member, an integer or a group of steps. The term "consisting essentially of" means excluding other members, integers or steps or groups of members, integers or steps having any essential meaning. For example, a pharmaceutical composition consisting essentially of a member / part as defined herein (e.g. a compound as defined in any aspect of the invention and optionally an additional therapeutic agent), would exclude other therapeutic agents (except for any aspect of the invention In addition to the compound defined in and optionally an additional therapeutic agent), but does not exclude trace amounts (for example, the amount of contaminants (the amount of all contaminants present in the preferred compound) compared to the total components, less than by weight 5% by weight, for example less than 4% by weight, 3% by weight, 2% by weight, 1% by weight, 0.5% by weight, 0.4% by weight, 0.3% by weight, 0.2% by weight, 0.1% by weight, 0.1% by weight, 0.05% by weight) contaminants (such as those from isolation and purification methods) and / or pharmaceutically acceptable excipients (such as carriers, such as phosphoric acid saline buffer solution, preservatives, etc.). The term "consisting of" means excluding all other members, integers or significant steps or groups of members, integers or significant steps. For example, a pharmaceutical composition consisting of a member / part as defined herein (a compound as defined in any aspect of the invention, an excipient and optionally an additional therapeutic agent) does not include any other relative to the total Ingredient weight exceeding 2% (such as any other compound which is greater than 1% by weight, greater than 0.5% by weight, greater than 0.4% by weight, greater than 0.3% by weight, greater than 0.2% by weight, Greater than 0.1%, greater than 0.09% by weight, greater than 0.08% by weight, greater than 0.07% by weight, greater than 0.06% by weight, greater than 0.05% by weight, greater than 0.04% by weight, greater than 0.03%, greater than 0.02% by weight, greater than 0.01% by weight) of the compound (including the second or more excipients). The term "comprising" includes the term "consisting essentially of", which in turn includes the term "consisting of". Accordingly, the term "comprising" may be replaced by the term "consisting essentially of" or "consisting of" each time it occurs in this application. Likewise, the term "consisting essentially of" may be replaced by the term "consisting of" each time it occurs in this application.

[0056] As used herein, "and / or" will be considered as a specific disclosure of each of two specific features or elements, including or excluding the other. For example, "X and / or Y" would be considered a specific disclosure of each of (i) X, (ii) Y, and (iii) X and Y, as if each were individually listed herein.

[0057] In the context of the present invention, the terms "about" and "approximately" are used interchangeably to denote a precise interval that a person of ordinary skill will understand to still ensure the technical effect of the stated feature. This term usually means ±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%, eg ±0.01%. As understood by those of ordinary skill, for a given numerical value of a technical effect, such specific deviation will depend on the nature of the technical effect. For example, natural or biotechnological effects may often be more biased than man-made or engineered technological effects.

[0058] The terms "a", "an" and "the / said" and similar references used in the context of describing the present invention (especially in the context of claims) shall be construed to include both the singular and the plural , unless otherwise indicated herein or clearly contradicted by context.

[0059] Recitation of ranges of values ​​herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein.

[0060] All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context.

[0061] The use of any and all examples, or exemplary language (eg, "such as") provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.

[0062] Several documents are cited throughout this specification. Every document cited herein (including all patents, patent applications, scientific publications, manufacturer's specifications, specifications, etc.), whether supra or infra, is hereby incorporated by reference in its entirety. Nothing herein should be construed as an admission that the present invention is not entitled to prior disclosure by virtue of prior invention.

[0063] As used herein, the terms "(of) the invention", "according to (the) invention", "according to (the) invention" and the like mean all aspects and implementations of the invention described and / or claimed herein. example.

[0064] It should be understood that applying the teachings of the present invention to a particular problem or circumstance, and including variations of the invention or additional features thereof (such as further aspects and embodiments), would be within the skill of the art in light of the teachings contained herein. within the ability of those with ordinary knowledge.

[0065] Unless the context dictates otherwise, descriptions and definitions of features listed above or below are not limited to any particular aspect or embodiment of the invention and apply equally to all aspects and embodiments described.

[0066] The term "alkyl" refers to a single radical of a saturated linear or branched chain hydrocarbon. Preferably, the alkyl group contains 1 to 12 (eg 1 to 10) carbon atoms, i.e. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms (eg 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. Exemplary alkyl groups include methyl (Me), ethyl (Et), propyl, isopropyl (also known as 2-propyl or 1-methylethyl), butyl, isobutyl, t-butyl Base, n-pentyl, isopentyl, sec-pentyl, neopentyl, 1,2-dimethylpropyl, isopentyl, n-hexyl, isohexyl, sec-hexyl, n-heptyl, isoheptyl, n- Octyl, 2-ethylhexyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, and the like. "Substituted alkyl" means one or more of an alkyl group (such as 1 to the maximum number of hydrogen atoms bound to the alkyl group, such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or up to 10 , eg 1 to 5, 1 to 4 or 1 to 3 or 1 or 2) hydrogen atoms are replaced by substituents other than hydrogen (when more than one hydrogen atom is substituted, the substituents may be the same or different). Preferably, substituents other than hydrogen are primary, secondary or tertiary substituents as defined herein, for example -OH, NH2, NHCH3, N(CH3)2, CN, OCH3, OCF3 , or optionally substituted aryl. Examples of substituted alkyl groups include trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trichloroethyl, 2-hydroxyethyl, 2-aminoethyl, 2-(dimethyl Amino) ethyl, aralkyl (also known as "aralkyl", e.g., benzyl, chloro(phenyl)methyl, 4-methylphenylmethyl, (2,4-dimethylbenzene base) methyl, o-fluorophenylmethyl (o-fluorophenylmethyl), 2-phenylpropyl, 2-, 3- or 4-carboxyphenylalkyl) or heteroaralkyl (also known as "heteroaryl alkyl").

[0067] The term "alkylene" refers to a diradical of a saturated linear or branched chain hydrocarbon. Preferably, the alkylene group comprises 1 to 12 (eg 1 to 10) carbon atoms, i.e. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms (eg 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms), more preferably 1 to 8 carbon atoms, such as 1 to 6 or 1 to 4 carbon atoms. Exemplary alkylene groups include methylene, ethylene (i.e. 1,1-ethylene, 1,2-ethylene), propylene (i.e. 1,1-propylene, 1,2- Propyl (-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 their mixture), 1,4-butylene, 1, 1-isobutylene, 1,2-isobutylene and 1,3-isobutylene), pentylene isomers (e.g. 1,1-pentylene, 1,2-pentylene, 1,3 -pentylene, 1,4-pentylene, 1,5-pentylene, 1,1-isopentylene, 1,1-sec-pentylene, 1,1-neopentyl), hexyleneiso Constructs (such as 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- Heptyl, 1,6-heptylene, 1,7-heptylene and 1,1-isoheptylene), octylene isomers (such as 1,1-octylene, 1,2- Octyl, 1,3-octyl, 1,4-octyl, 1,5-octyl, 1,6-octyl, 1,7-octyl, 1,8-octyl and 1,1-isooctylene) etc. Straight-chain alkylene moieties having at least 3 carbon atoms and a free valence at each end may also be designated as multiple methylene groups (for example, 1,4-butene may also be referred to as tetramethylene). Generally, instead of prefixing the alkylene moiety with "ylene" as described above, the suffix "diradical" can also be used (for example, 1,2-butylene may also be referred to as butane-1,2-diyl ). "Substituted alkylene" means one or more (for example, 1 to the maximum number of hydrogen atoms bonded to the alkylene group, such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or up to 10, such as 1 to 5, 1 to 4 or 1 to 3 or 1 or 2) hydrogen atoms are replaced by substituents other than hydrogen (when more than one hydrogen atom is replaced, the substituents may be the same or different ). Preferably, substituents other than hydrogen are primary, secondary or tertiary substituents as defined herein, eg halogen or optionally substituted aryl. Examples of substituted alkylene groups include chloromethylene, dichloromethylene, fluoromethylene and difluoromethylene.

[0068] The term "alkenyl" refers to a single radical of an unsaturated straight or branched chain hydrocarbon having at least one carbon-carbon double bond. In general, the maximum number of carbon-carbon double bonds in an alkenyl group can be equal to an integer calculated by dividing the number of carbon atoms in the alkenyl group by 2, and rounding the result of the division if the number of carbon atoms in the alkenyl group is uneven to the next integer. For example, for an alkenyl group having 9 carbon atoms, the maximum number of carbon-carbon double bonds is four. Preferably, the alkenyl group has 1 to 6 (eg 1 to 4), ie 1, 2, 3, 4, 5 or 6 carbon-carbon double bonds. Preferably, the alkenyl group contains 2 to 12 (eg 2 to 10) carbon atoms, i.e. 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms (eg 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. Thus, in preferred embodiments, the alkenyl group contains 2 to 12 (eg, 2 to 10) carbon atoms and 1, 2, 3, 4, 5 or 6 (eg, 1, 2, 3, 4 or 5) carbon-carbon double bonds, more preferably it contains 2 to 8 carbon atoms and 1, 2, 3 or 4 carbon-carbon double bonds, for example 2 to 6 carbon atoms and 1, 2 or 3 carbon-carbon double bonds Carbon double bond or 2 to 4 carbon atoms and 1 or 2 carbon-carbon double bonds. Carbon-carbon double bonds can be in either the cis (Z) or trans (E) configuration. Exemplary alkenyl groups include vinyl, 1-propenyl, 2-propenyl (i.e., allyl), 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2- Pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-heptene Base, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptyl, 1-octenyl, 2-octenyl, 3-octenyl, 4 -octenyl, 5-octenyl, 6-octenyl, 7-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 4-nonenyl, 5-nonenyl Alkenyl, 6-nonenyl, 7-nonenyl, 8-nonenyl, 1-decenyl, 2-decenyl, 3-decenyl, 4-decenyl, 5-decenyl , 6-decenyl, 7-decenyl, 8-decenyl, 9-decenyl, 1-undecenyl, 2-undecenyl, 3-undecenyl, 4-undecenyl Alkenyl, 5-undecenyl, 6-undecenyl, 7-undecenyl, 8-undecenyl, 9-undecenyl, 10-undecenyl, 1-dodecenyl Base, 2-dodecenyl, 3-dodecenyl, 4-dodecenyl, 5-dodecenyl, 6-dodecenyl, 7-dodecenyl, 8-dodecenyl , 9-dodecenyl, 10-dodecenyl, 11-dodecenyl, etc. If an alkenyl group is attached to a nitrogen atom, the double bond cannot be alpha to the nitrogen atom. "Substituted alkenyl" means one or more alkenyl groups (e.g., 1 to a maximum number of hydrogen atoms bound to the alkenyl group, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, eg 1 to 5, 1 to 4 or 1 to 3 or 1 or 2) hydrogen atoms are replaced by substituents other than hydrogen (when more than one hydrogen atom is replaced, the substituents may be the same or different). Preferably, substituents other than hydrogen are primary, secondary or tertiary substituents as defined herein, eg halogen or optionally substituted aryl. An example of a substituted alkenyl group is styryl (ie, 2-phenylethenyl).

[0069] The term "alkenylene" refers to a diradical of an unsaturated straight or branched chain hydrocarbon having at least one carbon-carbon double bond. In general, 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 not uniform, then Rounds the result of division to the next integer. For example, for an alkenylene group having 9 carbon atoms, the maximum number of carbon-carbon double bonds is four. Preferably, the alkenylene has 1 to 6 (eg 1 to 4), ie 1, 2, 3, 4, 5 or 6 carbon-carbon double bonds. Preferably, the alkenylene group contains 2 to 12 (eg 2 to 10) carbon atoms, i.e. 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms (eg 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. Thus, in preferred embodiments the alkenylene group contains 2 to 12 (eg 2 to 10 carbon) atoms and 1, 2, 3, 4, 5 or 6 (eg 1 , 2, 3, 4 or 5 a) carbon-carbon double bond, more preferably it contains 2 to 8 carbon atoms and 1, 2, 3 or 4 carbon-carbon double bonds, for example 2 to 6 carbon atoms and 1, 2, 3 or 4 carbon-carbon double bonds, or 3 carbon-carbon double bonds, or 2 to 4 carbon atoms and 1 or 2 carbon-carbon double bonds. Carbon-carbon double bonds can be in either the cis (Z) or trans (E) configuration. Exemplary alkenylene groups include ethylene-1,2-diyl, vinylidene (also known as vinylidene), 1-propene-1,2-diyl, 1-propene-1,3-diyl, 1 -propene-2,3-diyl, allyl, 1-butene-1,2-diyl, 1-butene-1,3-diyl, 1-butene-1,4-diyl , 1-butene-2,3-diyl, 1-butene-2,4-diyl, 1-butene-3,4-diyl, 2-butene-1,2-diyl, 2 -Butene-1,3-diyl, 2-butene-1,4-diyl, 2-butene-2,3-diyl, 2-butene-2,4-diyl, 2-butene Alkene-3,4-diyl, etc. If the alkenylene group is attached to a nitrogen atom, the double bond cannot be alpha to the nitrogen atom. "Substituted alkenylene" means one or more alkenylene groups (e.g., 1 to the maximum number of hydrogen atoms bonded to the alkenylene group, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or up to 10, such as 1 to 5, 1 to 4 or 1 to 3 or 1 or 2) hydrogen atoms are replaced by substituents other than hydrogen (when more than one hydrogen atom is replaced, the substituents may be the same or different ). Preferably, substituents other than hydrogen are primary, secondary or tertiary substituents as defined herein, eg halogen or optionally substituted aryl. Examples of substituted alkenylene groups are 1-phenyl-ethene-1,2-diyl and 2-phenyl-ethene-1,2-diyl.

[0070] The term "alkynyl" refers to a single radical of an unsaturated straight or branched chain hydrocarbon having at least one carbon-carbon triple bond. In general, the maximum number of carbon-carbon triple bonds in an 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 uneven, divide the The result of is rounded to the next whole number. For example, for an alkynyl group having 9 carbon atoms, the maximum number of carbon-carbon triple bonds is four. Preferably, the alkynyl group has 1 to 6 (eg 1 to 4), ie 1, 2, 3, 4, 5 or 6, more preferably 1 or 2 carbon-carbon triple bonds. Preferably, the alkynyl group contains 2 to 12 (eg 2 to 10) carbon atoms (eg 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms), ie 2, 3 , 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms, more preferably 2 to 8 carbon atoms, eg 2 to 6 carbon atoms or 2 to 4 carbon atoms. Thus, in preferred embodiments, the alkynyl group contains 2 to 12 (eg, 2 to 10) carbon atoms and 1, 2, 3, 4, 5 or 6 (eg, 1, 2, 3, 4 or 5 (preferably 1, 2 or 3)) carbon-carbon triple bonds, more preferably it contains 2 to 8 carbon atoms and 1, 2, 3 or 4 (preferably 1 or 2) carbon-carbon triple bonds, for example 2 to 6 carbon atoms and 1, 2 or 3 carbon-carbon triple bonds or 2 to 4 carbon atoms and 1 or 2 carbon-carbon triple bonds. Exemplary alkynyl groups include alkynyl, 1-alkynyl, 2-alkynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3- Pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-heptynyl, 2-heptynyl Base, 3-heptynyl, 4-heptynyl, 5-heptynyl, 6-heptynyl, 1-octynyl, 2-octynyl, 3-octynyl, 4-octynyl, 5-octynyl, 6-octynyl, 7-octynyl, 1-nonynyl, 2-nonynyl, 3-nonynyl, 4-nonynyl, 5-nonynyl, 6- Nonynyl, 7-nonynyl, 8-nonynyl, 1-decynyl, 2-decynyl, 3-decynyl, 4-decynyl, 5-decynyl, 6-decynyl base, 7-decynyl, 8-decynyl, 9-decynyl, etc. If an alkynyl group is attached to a nitrogen atom, the triple bond cannot be alpha to the nitrogen atom. "Substituted alkynyl" means one or more alkynyl groups (e.g., 1 to a maximum number of hydrogen atoms bound to the alkynyl group, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, eg 1 to 5, 1 to 4 or 1 to 3 or 1 or 2) hydrogen atoms are replaced by substituents other than hydrogen (when more than one hydrogen atom is replaced, the substituents may be the same or different). Preferably, substituents other than hydrogen are primary, secondary or tertiary substituents as defined herein, eg halogen or optionally substituted aryl.

[0071] The term "alkynylene" refers to a diradical of an unsaturated straight or branched chain hydrocarbon having at least one carbon-carbon triple bond. In general, the maximum number of carbon-carbon triple bonds in the alkynylene group can be equal to an integer calculated by dividing the number of carbon atoms in the alkynylene group by 2, if the number of carbon atoms in the alkynylene group is not uniform, then rounds the result of the division to the next integer. For example, for an alkynylene group having 9 carbon atoms, the maximum number of carbon-carbon triple bonds is four. Preferably, the alkynylene group has 1 to 6 (eg 1 to 4), ie 1, 2, 3, 4, 5 or 6, more preferably 1 or 2 carbon-carbon triple bonds. Preferably, the alkynylene group contains 2 to 12 (eg 2 to 10) carbon atoms (eg 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms), ie 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms, more preferably 2 to 8 carbon atoms, eg 2 to 6 carbon atoms or 2 to 4 carbon atoms. Thus, in preferred embodiments, the alkynylene group contains 2 to 12 (eg, 2 to 10) carbon atoms and 1, 2, 3, 4, 5 or 6 (eg, 1, 2, 3, 4 or 5 (more Preferably 1, 2 or 3)) carbon-carbon triple bonds, more preferably it comprises 2 to 8 carbon atoms and 1, 2, 3 or 4 (preferably 1 or 2) carbon-carbon triple bonds, for example 2 to 6 carbon atoms and 1, 2 or 3 carbon-carbon triple bonds or 2 to 4 carbon atoms and 1 or 2 carbon-carbon triple bonds. Exemplary alkynylene groups include ethyn-1,2-diyl, 1-propyne-1,3-diyl, 1-propyne-3,3-diyl, 1-butyne-1,3-diyl , 1-butyne-1,4-diyl, 1-butyne-3,4-diyl, 2-butyne-1,4-diyl, etc. If the alkynylene group is attached to the nitrogen atom, the double bond cannot be alpha to the nitrogen atom. "Substituted alkynylene" means one or more alkynylene groups (e.g., 1 to the maximum number of hydrogen atoms bonded to the alkynylene group, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or up to 10, such as 1 to 5, 1 to 4 or 1 to 3 or 1 or 2) hydrogen atoms are replaced by substituents other than hydrogen (when more than one hydrogen atom is replaced, the substituents may be the same or different ). Preferably, substituents other than hydrogen are primary, secondary or tertiary substituents as defined herein, eg halogen or optionally substituted aryl.

[0072] The term "aryl" or "aromatic ring" refers to a single radical of an aromatic cyclic hydrocarbon. Preferably, the aryl group contains 3 to 14 (for example, 5, 6, 7, 8, 9 or 10, for example 5, 6 or 10) carbon atoms which may be arranged in a ring (for example, benzene group) or two or more fused rings (for example, naphthyl). Exemplary aryl groups include cyclopropenyl, cyclopentadienyl, phenyl, indenyl, naphthyl, azulenyl, fluorenyl, anthryl, and phenanthryl Base (phenanthryl). Preferably, "aryl" refers to a monocyclic ring containing 6 carbon atoms or an aromatic bicyclic ring system containing 10 carbon atoms. Preferred examples are phenyl and naphthyl. Aryl groups do not contain fullerenes. "Substituted aryl" means one or more aryl groups (e.g., 1 to a maximum number of hydrogen atoms bonded to the aryl group, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, eg 1 to 5, 1 to 4 or 1 to 3 or 1 or 2) hydrogen atoms are replaced by substituents other than hydrogen (when more than one hydrogen atom is replaced, the substituents may be the same or different). Preferably, substituents other than hydrogen are primary, secondary or tertiary substituents as defined herein, such as halogen, -CN, nitro, -OR11 (eg, -OH), - SR11 (for example, -SH), -N(R12)(R13) (for example, -NH2), alkyl (for example, C1-6 alkyl), alkenyl (for example, C2-6 alkenyl) and alkynyl (for example, C2 - 6 alkynyl). Examples of substituted aryl groups include biphenyl, 2-fluorophenyl, 2-chloro-6-methylphenyl, anilino, 3-nitrophenyl, 4-hydroxyphenyl, methoxyphenyl (i.e. , 2-, 3- or 4-methoxyphenyl) and 4-ethoxyphenyl.

[0073] The term "heteroaryl" or "heteroaryl ring" refers to an aryl group as defined above, wherein one or more carbon atoms in the aryl group are replaced by a heteroatom (eg, O, S or N). Preferably, heteroaryl refers to a 5- or 6-membered aromatic monocyclic ring, wherein 1, 2 or 3 carbon atoms are substituted by the same or different O, N or S heteroatoms. Alternatively, it refers to an aromatic bicyclic or tricyclic ring system in which 1, 2, 3, 4 or 5 carbon atoms are replaced by the same or different O, N or S heteroatoms. 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 heteroaryls include monocyclic heteroaryls (eg, 5 or 6 members), bicyclic heteroaryls (eg, 9 or 10 members), and tricyclic heteroaryls (eg, 13 or 14 members) . Exemplary 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 (tetrazolyl), thiazolyl, isothiazolyl, thiadiazolyl (1,2,3- and 1,2,5-), pyridyl (pyridyl) (also known as pyridine base (pyridinyl)), pyrimidinyl (pyrimidinyl), pyrazinyl (pyrazinyl), triazinyl (triazinyl) (1,2,3-, 1,2,4- and 1,3,5-), benzo Furanyl (benzofuranyl) (1- and 2), indolyl (indolyl), isoindolyl (isoindolyl), benzothienyl (benzothienyl) (1- and 2-), 1H-indazolyl (1H- indazolyl), benzimidazolyl, benzoxazolyl, indoxazinyl, benzisoxazolyl, benzothiazolyl, benziso Benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, benzodiazinyl, quinoxalinyl, quinazoline quinazolinyl, benzotriazinyl (1,2,3- and 1,2,4-benzotriazinyl), pyridazinyl, phenoxazinyl, thiazole Thiazolopyridinyl, pyrrolothiazolyl, phenothiazinyl, isobenzofuranyl, chromenyl, xanthenyl, phenanthene Phenoxathiinyl, pyrrolizinyl, indolizinyl, indazolyl, purinyl, quinolizinyl, phthalazinyl , naphthyridinyl (naphthyridinyl) (1,5-, 1,6-, 1,7-, 1,8- and 2,6-), [octyl] cinnolinyl (cinnolinyl), pteridinyl (pteridinyl) , carbazolyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl (1,7-, 1,8-, 1,10- , 3,8- and 4,7-), phenazinyl, oxazolopyridinyl, isoxazolopyridinyl, pyrrolooxazolyl and pyrrolopyrrole base (pyrrolopyrrolyl). Exemplary 5- or 6-membered heteroaryl groups include furyl, 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. "Substituted heteroaryl" means one or more heteroaryl groups (e.g., 1 to the maximum number of hydrogen atoms bonded to the heteroaryl group, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or up to 10, such as 1 to 5, 1 to 4 or 1 to 3 or 1 or 2) hydrogen atoms are replaced by substituents other than hydrogen (when more than one hydrogen atom is replaced, the substituents may be the same or different ). Preferably, substituents other than hydrogen are primary, secondary or tertiary substituents as defined herein, such as halogen, -CN, nitro, -OR11 (eg, -OH), - SR11 (for example, -SH), -N(R12)(R13) (for example, -NH2), alkyl (for example, C1-6 alkyl), alkenyl (for example, C2-6 alkenyl) and alkynyl (for example, C2 - 6 alkynyl). Examples of substituted heteroaryl groups include 2,4-dimethylpyridin-3-yl, 2-methyl-4-bromopyridin-3-yl, 3-methyl-2-pyridin-2-yl, 3- Chloro-5-methylpyridin-4-yl, 4-chloro-2-methylpyridin-3-yl, 3,5-dimethylpyridin-4-yl, 2-methylpyridin-3-yl, 2 -Chloro-4-methylthiophen-3-yl, 1,3,5-trimethylpyrazol-4-yl, 3,5-dimethyl-1,2-two oxazol-4-yl, 1 , 2,4-trimethylpyrrol-3-yl, 3-phenylpyrrolyl, 2,3'-dithiol, 4-methylpyridyl, 2- or 3-ethylindolyl.

[0074] The term "cycloalkyl" or "cycloaliphatic" denotes cyclic non-aromatic versions of "alkyl" and "alkenyl" having preferably 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 (e.g. 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms), more preferably 3 to 7 carbon atoms. Exemplary cycloalkyl groups include cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclo Octyl, cyclooctenyl, cyclononyl, cyclononenyl, cyclododecyl and adamantyl. The term "cycloalkyl" is also meant to include bicyclic and tricyclic forms thereof. If bicyclic rings are formed, it is preferred that the rings are joined to each other at two adjacent carbon atoms, however, either the two rings are joined through the same carbon atom, ie they form a spiro ring system or they form a "bridged" ring system. Preferred examples of cycloalkyl include C3-8-cycloalkyl, especially cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, spiro[3,3]heptyl , spiro[3,4]octyl, spiro[4,3]octyl, bicyclo[4.1.0]heptyl, bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl, bicyclo[ 2.2.2] octyl, bicyclo[5.1.0]octyl and bicyclo[4.2.0]octyl. Cycloalkyl does not contain fullerenes. "Substituted cycloalkyl" means one or more cycloalkyl groups (e.g. 1 to the maximum number of hydrogen atoms bonded to the cycloalkyl group, e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9 or up to 10, such as 1 to 5, 1 to 4 or 1 to 3 or 1 or 2) hydrogen atoms are replaced by substituents other than hydrogen (when more than one hydrogen atom is replaced, the substituents may be the same or different) . Preferably, substituents other than hydrogen are primary, secondary or tertiary substituents as defined herein, such as halogen, -CN, nitro, -OR11 (eg, -OH), - SR11 (eg, -SH), -N(R12)(R13) (eg, -NH2), =X (eg, =O, =S, or =NH), alkyl (eg, C1-6 alkyl), alkenyl (eg C2-6 alkenyl) and alkynyl (eg C2-6 alkynyl). Examples of substituted cycloalkyl groups include oxocyclohexyl, oxocyclopentyl, fluorocyclohexyl and oxocyclohexyl.

[0075] The term "heterocyclyl" or "heterocycle" means a cycloalkyl group as defined above, wherein 1, 2, 3 or 4 ring carbon atoms in the cycloalkyl group are replaced by heteroatoms (for example selected from O, S, S(O), S(O)2, N, B, Si and P, preferably selected from O, S, S(O)2 and N, more preferably selected from O, S and N ). If the heterocyclyl ring contains only one type of heteroatom, the maximum number of said heteroatoms in the heterocyclyl ring may be: 2 O atoms (preferably 1 O atom); 2 S atom (preferably 1 S atom); 4 N atoms (eg 1, 2 or 3 N atoms); 2 B atoms (preferably 1 B atom); 1 Si atom and / or 1 P atom. If one ring of the heterocyclyl group contains two or more heteroatoms, the maximum number of said 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, wherein the maximum total number of heteroatoms in the heterocyclyl ring is 4, and in the heterocyclyl ring The maximum total number of each heteroatom is as follows: 1 O atom; 1 S atom; 1 or 2 N atoms; 1 B atom (preferably 0 B atom); 1 Si atom (preferably 0 Si atom). atom) and / or 1 P atom (preferably 0 P atom). In one embodiment, the heteroatoms of the heterocyclyl are selected from O, S and N. In this embodiment, preferably, in each ring of the heterocyclic 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 heterocyclyls include monocyclic heterocyclyls (for example, 3, 4, 5, 6 or 7 members, preferably 4 to 7 members), bicyclic heterocyclyls (for example, 8, 9 or 10 members ) and tricyclic heterocyclyl (eg, 12, 13 or 14 members). If the heterocyclyl group contains two or more rings, these rings are either fused (as in quinolinyl or purinyl), or are part of a spirocyclic ring, or have a bridged structure, or Linked by a double bond, or a combination thereof. In other words, an unsubstituted heterocyclyl group does not contain two heterocyclyl groups connected by a single bond. The term "heterocyclyl" is also meant to include partially or fully hydrogenated forms (eg, dihydro, tetrahydro, hexahydro, octahydro, decahydro, dodecahydro, etc. or perhydro forms) of the aforementioned heteroaryl groups. Exemplary heterocyclic groups include 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 tetrahydrofuranyl, di- and tetrahydrofuranyl 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 tetrahydrothiazolyl, di- and tetrahydrothiadiazolyl (1,2,3- and 1,2,5-), di- and tetrahydropyridyl (di- and tetrahydropyridyl), di-, tetra- and hexahydropyrimidinyl (di-, tetra- and hexahydropyrimidinyl), di- and tetrahydropyrazinyl (di- and tetrahydropyrazinyl), di- and tetrahydrotriazinyl (1,2,3-, 1,2,4- and 1,3,5-), di-, tetrahydropyrazinyl, and octahydrobenzo Furanyl (di-, tetra-, hexa- and octahydrobenzofuranyl) (1- and 2-), di-, tetra-, hexa- and octahydroindolyl (di-, tetra-, hexa- and octahydroindolyl), di, tetra, Di-, tetra-, hexa- and octahydroisoindolyl (di-, tetra-, hexa- and octahydroisoindolyl,), di-, tetra-, hexa- and octahydrobenzothienyl (di-, tetra-, hexa- and octahydrobenzothienyl) (1- and 2 -), di-, tetra-, hexa- and octahydro-1H-indazolyl (di-, tetra-, hexa- and octahydro-1H-indazolyl), di-, tetra-, hexa-, octahydro-1H-indazolyl (di-, tetra-, hexa- and octahydrobenzoxazolyl), di-, tetra-, hexa- and octahydrobenzoxazolyl, di-, tetra-, hexa- and octahydrobenzoxazolyl (tetra - , hexa- and octahydroindoxazinyl), di-, tetra-, hexa- and octahydrobenzisoxazinyl (di-, tetra-, hexa- and octahydrobenzisoxazolyl), di-, tetra-, hexa-, octahydrobenzisoxazinyl (di- , tetra-, hexa- and octahydrobenzothiazolyl), di-, tetra-, hexa-, octahydrobenzothiazolyl (di-, tetra-, hexa- and octahydrobenzisothiazolyl), di-, tetra-, hexa-, octahydrobenzothiazolyl ( di -, tetra-, hexa- and octahydrobenzotriazolyl), di, tetra, hexa, octahydroquinolinyl, di, tetra, hexa, octahydroquinolinyl Hydroxyisoquinolinyl (di-, tetra-, hexa-, octa- and decahydroisoquinolinyl), di-, tetra-, hexa-, octa- and decahydrobenzodiazinyl ), two, four, six, eight, decahydroquinazolinyl (di-, tetra-, hexa-, octa- and decahydroquinoxalinyl), two, four, six, eight, decahydroquinazolinyl (di-, tetra-, hexa-, octa- and decahydroquinazolinyl), di-, tetra-, hexa-, octa- and decahydrobenzotriazinyl (1,2,3- and 1 ,2,4-), two, four, hexahydropyridazinyl (di-, tetra-, and hexahydropyridazinyl), two, four, six, eight, dodecahydrophenazinyl (di-, tetra-, hexa-, octa-, deca- and dodecahydrophenoxazinyl), di-, tetra-, hexa-, and octahydrothiazolopyridinyl (e.g. 4,5,6-7-tetrahydro[ 1,3]thiazolyl[5,4-c]pyridyl or 4,5,6-7-tetrahydro[1,3]thiazolyl[4,5-c]pyridyl, for example 4,5,6- 7-tetrahydro[1,3]-thiazolyl[5,4-c]pyridin-2-yl or 4,5,6-7-tetrahydro[1,3]thiazolyl[4,5-c]pyridine -2-yl), di-, tetra-, and hexahydropyrrolothiazolyl (di-, tetra-, and hexahydropyrrolothiazolyl) octa- and decahydrophenothiazinyl), di-, tetra-, hexa-, and octahydroisobenzofuranyl, di-, tetra-, hexa-, and octahydroisobenzofuranyl (di-, tetra- , hexa-, and octahydrochromenyl), di-, tetra-, hexa-, octa-, deca- , and dodecahydroxanthenyl), two, four, Hexa, octa, deca and dodecahydrophenoxathiinyl (di-, tetra-, hexa-, octa-, deca-, and dodecahydrophenoxathiinyl), di, tetra, hexahydropyrrolinazinyl (di-, tetra-, and hexahydropyrrolizinyl), two, four, six, octahydroindolinazinyl (di-, tetra-, hexa-, and octahydroindolizinyl), two, four, six, octahydroindolinyl (di-, tetra-, hexa - , and octahydroindazolyl), two, four, six, octahydropurinyl (di-, tetra-, hexa-, and octahydropurinyl), two, four, six, octahydroquinolyl (di-, tetra-, hexa- , and octahydroquinolizinyl), di-, tetra-, hexa-, octa- and decahydroquinolizinyl), di-, tetra-, hexa-, octahydroquinolizinyl (di-, tetra-, hexa-, octa- and decahydrophthalazinyl), di- , tetra-, hexa-, octa- and decahydronaphthyridinyl) (1,5-, 1,6-, 1,7-, 1,8-, 2,6-), two, four, six, eight, decahydro[ Octa] Linyl (di-, tetra-, hexa-, octa- and decahydrocinnolinyl), two, four, six, eight, ten hydropteridinyl (di-, tetra-, hexa-, octa-, and decahydropteridinyl ), di, tetra, hexa, octa, deca and dodecahydrocarbazolyl (di-, tetra-, hexa-, octa-, deca- and dodecahydrocarbazolyl), di, tetra, hexa, octa, ten, twelve and tetradecahydrophenanthridinyl (di-, tetra-, hexa-, octa-, deca-, dodeca-, and tetradecahydrophenanthridinyl), di, tetra, hexa, octa, deca, dodeca and tetrahydroacridinyl (di - , tetra-, hexa-, octa-, deca-, dodeca-, and tetradecahydroacridinyl), di, tetra, hexa, octa, deca, dodecahydroacridinyl (di-, tetra-, hexa-, octa-, deca - and dodecahydroperimidinyl), two, four, six, eight, ten, twelve, tetrahydrophenanthroline (di-,tetra-, hexa-, octa-, deca-, dodeca-, and tetradecahydrophenanthrolinyl) (1,7-, 1,8-, 1,10-, 3,8-, 4,7-), two, four, six , octa, deca, dodeca and tetradecahydrophenazinyl (di-, tetra-, hexa-, octa-, deca-, dodeca-, and tetradecahydrophenazinyl), di, tetra, hexa and octahydrooxazolopyridyl (di-, tetra-, hexa- and octahydrooxazolopyridinyl), di, tetra, hexa and octahydroisoxazolopyridinyl (di-, tetra-, hexa- and octahydroisoxazolopyridinyl), di, tetra, hexa and octahydrocyclopenta Pyrrolyl (di-, tetra-, hexa- and octahydrocyclopentapyrrolyl), di-, tetra-, hexa- and octahydrocyclopentapyrazolyl (di-, tetra-, hexa- and octahydrocyclopentpyrazolyl), di, tetra, hexa and octahydrocyclopentapyrazolyl Pentahydrocyclopentamidazolyl (di-, tetra-, hexa- and octahydrocyclopentaimidazolyl), di-, tetra-, hexa- and octahydrocyclopentathiazolyl, di-, tetra-, hexa- and octahydrocyclopentathiazolyl pentazolyl (di-, tetra-, hexa- and octahydrocyclopentaoxazolyl), di-, tetra-, hexa- and octahydropyrrolopyrrolyl (di-, tetra-, hexa- and octahydropyrrolopyrrolyl), di-, tetra-, hexa- and octahydro Pyrrolopyrazolyl (di-, tetra-, hexa- and octahydropyrrolopyrazolyl), di-, tetra-, hexa- and octahydropyrroloimidazolyl (di-, tetra-, hexa- and octahydropyrroloimidazolyl), di, tetra, hexa, and octahydro Hydropyrrolothiazolyl (di-, tetra-, hexa- and octahydropyrrolothiazolyl) (such as 5,6-dihydro-4H-pyrrolo[3,4-d][1,3]thiazolyl), di, tetra, Di-, tetra-, hexa- and octahydropyrrolooxazolyl, di-, tetra-, hexa- and octahydropyrazolopyrazolyl, di-, tetra-, hexa- and octahydropyrazolopyrazolyl , four, six, octahydropyrazoloimidazolyl (di-, tetra-, hexa- and octahydropyrazoloimidazolyl) , di-, tetra-, hexa-, octahydropyrazolooxazolyl (di-, tetra-, hexa- and octahydropyrazolooxazolyl), di-, tetra-, hexahydroimidazolooxazolyl (di-, tetra-, hexa- and octahydroimidazoimidazolyl), di-, tetra-, hexa- and octahydroimidazothiazolyl), di-, tetra-, hexa- and octahydroimidazooxazolyl), di-, tetra-, hexa- and octahydrothiazolothiazolyl, di-, tetra-, hexa- and octahydrothiazolothiazolyl), di-, tetra-, hexa - and octahydrothiazolooxazolyl), and di-, tetra-, hexa- and octahydrooxazolooxazolyl. Exemplary 5- or 6-membered heterocyclic groups include morpholinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, di- and tetrahydrofuranyl, di- and tetrahydrothienyl, di- and tetrahydrothienyl, Hydroxazolyl, di- and tetrahydroisoxazolyl, di- and tetrahydroxazolyl (1,2,5- and 1,2,3-), dihydroimidazolyl, dihydropyrazolyl, di- and Tetrahydrotriazolyl (1,2,3- and 1,2,4-), di- and tetrahydrothiazolyl, di- and tetrahydroisothiazolyl, di- and tetrahydrothiadiazolyl (1,2,3 - and 1,2,5), di and tetrahydropyridyl, di, tetrahydropyrimidinyl, di and tetrahydropyrazinyl, di and tetrahydrotriazinyl (1,2,3-, 1, 2,4- and 1,3,5) and triazinyl (1,2,3-, 1,2,4- and 1,3,5). "Substituted heterocyclic group" refers to one or more heterocyclic groups (such as 1 to the maximum number of hydrogen atoms bonded to the heterocyclic group, such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or up to 10, such as 1 to 5, 1 to 4 or 1 to 3 or 1 or 2) hydrogen atoms are replaced by substituents other than hydrogen (when more than one hydrogen atom is replaced, the substituents may be the same or different ). Preferably, substituents other than hydrogen are primary, secondary or tertiary substituents as defined herein, such as halogen, -CN, nitro, -OR11 (eg, -OH), - SR11 (eg, -SH), -N(R12)(R13) (eg, -NH2), =X (eg, =O, =S, or =NH), alkyl (eg, C1-6 alkyl), alkenyl (eg C2-6 alkenyl) and alkynyl (eg C2-6 alkynyl). ,

[0076] The expression "partially hydrogenated form" of an unsaturated compound or group as used herein means removal of Partially unsaturated. The phrase "fully hydrogenated form" of an unsaturated compound or group is used herein interchangeably with the term "perhydro" and means that all unsaturation is removed by the formal addition of hydrogen to the originally unsaturated compound or group. For example, partially hydrogenated forms of 5-membered heteroaryls (with 2 double bonds in the ring, eg, furan) include dihydrogenated forms of said 5-membered heteroaryls (eg, 2,3-dihydrofuran or 2,5-dihydrofuran or 2,5-di Hydrofuran), while the tetrahydro form of the five-membered heteroaryl (eg tetrahydrofuran, ie THF) is the fully hydrogenated (or perhydro) form of the five-membered heteroaryl. Likewise, for 6-membered heteroaryls with 3 double bonds in the ring (such as pyridyl), the partially hydrogenated forms include the dihydro and tetrahydro forms (such as dihydro and tetrahydropyridyl), while the hexahydro forms (such as in Heteroarylpyridyl in the case of piperidinyl) is a fully hydrogenated (or perhydro) derivative of said 6-membered heteroaryl. Thus, the hexahydro form of an aryl or heteroaryl group can only be considered according to the invention if the aryl or heteroaryl group contains at least 4 unsaturations consisting of double and triple bonds between ring atoms Partially hydrogenated form.

[0077] The term "aromatic" in the context of hydrocarbons means that the entire molecule must be aromatic. For example, if a monocyclic aryl group is hydrogenated (partially or fully), the resulting hydrogenated ring structure is classified as cycloalkyl for the purposes of this invention. Likewise, if a bicyclic or polycyclic aryl group (such as naphthyl) is hydrogenated, the resulting hydrogenated bicyclic or polycyclic structure (such as 1,2-dihydronaphthyl) is classified as cycloalkyl for the purposes of this invention ( Even if there is only one ring, as in 1,2-dihydronaphthyl, it is still aromatic). A similar distinction is made in this application between heteroaryl and heterocyclyl. For example, indolinyl, the dihydro variant of indolyl, is classified as a heterocyclyl for the purposes of this invention because only one ring in the bicyclic structure is aromatic and one of the ring atoms is a heteroatom.

[0078] The term "polycyclic" as used herein means that the structure has two or more (eg 2, 3, 4, 5, 6, 7, 8, 9 or 10) rings, preferably 2, 3 , 4 or 5 rings, more preferably 2, 3 or 4 rings. Thus, according to the present invention, the term "polycyclic" does not include monocyclic structures, wherein said structures contain only one ring. Examples of polycyclic groups are condensed structures (such as naphthyl or anthracenyl), spiro compounds, rings connected by single or double bonds (such as biphenyl), and bridged structures (such as bornyl). Exemplary polycyclic structures are the aryl, heteroaryl, cycloalkyl and heterocyclyl groups specified above having at least two rings.

[0079] The term "halogen" or "halogen element" refers to fluorine, chlorine, bromine or iodine.

[0080] The term "azido" refers to -N3.

[0081] The term "N-oxide" refers to amine oxide or amine-N-oxide, which is a compound containing a functional group (Rn)3N+-O- (i.e. N-O coordination covalent bond), wherein Rn is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl and heterocyclyl, wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl and each of the heterocyclyl is optionally replaced by one or more (eg, 1 to a maximum of hydrogen atoms bonded to an alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl or heterocyclyl number, such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or up to 10, such as 1 to 5, 1 to 4 or 1 to 3 or 1 or 2) independently selected R30 substitution, said R30 Preferred are primary substituents, secondary substituents or tertiary substituents as defined herein.

[0082] The term "carboxylic acid" used herein 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 examples In the context of 1.1 and 1.2, only compounds containing at least one carboxyl group (COOH)). The term "corresponding carboxylic acid" as used herein refers to a (sulfur acid) that yields the desired compound (e.g., a compound having an amide or sulfamide linkage) when reacted with another compound (e.g., an intermediate, such as an intermediate of the present invention). generation) carboxylic acid. For example, if it is desired to use an intermediate of formula (Id) to prepare a compound of formula (Ia), the corresponding acid may have the following formula (Ie): (Ie) wherein Hy, R2, R3, A and E are as defined herein (particularly with respect to formulas (Ia), (IIa), (IVa), (Va), (VIa), (VIIa) and / or (VIIIa)) For example, if it is desired to prepare a compound of formula (Ia) wherein E is S, then Intermediates of formula (Id) are preferably used and the corresponding acids may be of formula (Ie) above where E is S. If, in another example, it is desired to prepare compounds of formula (Ia) where E is O, intermediates of formula (Id) are preferably used and the corresponding acids may have formula (Ie) above where E is O.

[0083] The term "impurity" as used herein refers to any impurity (especially chemical substance). Impurities can occur naturally, can be added during the synthesis and / or purification of the desired compound, or can be generated during the synthesis and / or purification of the desired compound. Exemplary impurities include one or more starting materials, one or more solvents, one or more intermediates or reactants, one or more degradation products of any of the above or the desired compound, deprotected One or more residues of post protecting groups and combinations thereof.

[0084] As used herein, the expression "at least one of R7 is F and / or at least one of R7 is substituted by one or more F atoms" (and similar expressions) means that R6 is replaced by (i) at least one F atom and / or (ii) contain one or more (for example, 1 to the maximum number of hydrogen atoms bound to the moiety, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10 , such as 1 to 5, 1 to 4, or 1 to 3, or 1 or 2) partial substitution of F atoms. Exemplary moieties with one or more F atoms include those with one or more (e.g., 1 to the maximum number of hydrogen atoms bonded to an alkyl group, e.g., 1, 2, 3, 4, 5, 6, 7 , 8, 9 or up to 10, such as 1 to 5, 1 to 4 or 1 to 3, or 1 or 2 or 3) F atoms, for example containing one or more (for example, 1 to 1 to 3) in combination with an alkyl group the maximum number of hydrogen atoms, for example, 1, 2, 3, 4, 5, 6 or 7, or up to 6, for example 1 to 5, 1 to 4, or 1 to 3, or 1 or 2 or 3) F Atomic C1-3 alkyl, such as -CH2F, -CHF2 or -CF3. Further exemplary moieties containing one or more F atoms include F-substituted alkoxy groups (i.e. -O(alkyl), such as -O(C1-3alkyl)) or F-substituted alkylamine groups (i.e.- NH(alkyl) or -N(alkyl)2, such as -NH(C1-3alkyl) or -N(C1-3alkyl)2), where the alkyl of alkoxy and monoalkylamino (for example, C1-3 alkyl) moiety and at least one alkyl (for example, C1-3 alkyl) part of the dialkylamine group is replaced by one or more (for example, 1 to Maximum number, such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or up to 10 or up to 7, such as 1 to 5, 1 to 4 or 1 to 3, or 1 or 2 or 3) F atoms replace.

[0085] As described elsewhere herein, for formula (Ic), R5" is -L-R6", and R6" is heteroaryl or heterocyclyl, each optionally represented by one or more independently selected R7 ' substitution. In this regard, the expression "any two R7' bonded to the same atom of R6" as used herein may be bonded together to form =O" means that two single radicals (i.e., R7') in total When replacing 2 hydrogen atoms, only one ring atom of R6" can be combined to form a diradical =O. For example, according to the present invention, R6'' (where R6" is the bond to the rest of the compound) includes not only (1) each of the R7' groups is independently selected from the specific moieties specified herein (such as methyl or The possibility of a single radical of Cl) also includes (2) the possibility of any two R7' groups combining with the same atom of R6" to form a diradical = O. The result is that the R6" group has the following Formula, or wherein the remaining R7' group is a single radical. Likewise, if R6'' is 3-tetrahydrothiophene substituted by four R7', such substituted R6'' contains the formula: ,,, , etc. As used herein, similar terms such as "any two R30 bonded to the same carbon atom of a cycloalkyl or heterocyclyl group may be taken together to form =X1" will be interpreted in a similar manner. In this regard, it should be understood that in those embodiments where any two R7' bonded to the same atom of R6'' may join together to form =0, R6'' initially (i.e., unmodified =0) must is a heterocycle (since there are no two free valence carbon ring atoms in a heterocycle). Similarly, if any two R30 bound to the same atom of a moiety can join together to form =X1, that moiety must initially (i.e., unmodified =X1) be alicyclic or heterocyclic (because in (hetero)aromatic There are no carbon ring atoms with two free valences in the ring).

[0086] As used herein, the expression "one R7' group is bound to the ring atom of R6' at position 2 relative to the ring atom that R6' is bound to the rest of the compound" (and similar expressions) means directly with At least one of the two ring atoms adjacent to the ring atom to which R6' is attached to the remainder of the compound has an R7' group. In other words, at least one ortho position of R6' bears an R7' group relative to the ring atom to which R6' is bound to the rest of the compound (i.e. the "radical position" of R6'). For example, applying the above expression to the case of a 3-pyridyl group where R6' is substituted by one R7' (thus, the base position is the ring carbon at position 3 relative to the ring nitrogen atom), it follows that the R7' group is at Position 2 or 4 of the 3-pyridyl group is shown in the following formula: and where represents the bond of R6' to the rest of the compound. In addition, if R6' is substituted by more than one (eg two or three) R7' groups, as used herein the expression "one R7' group is at a position relative to the ring atom to which R6' is bound to the rest of the compound 2 bonded to a ring atom of R6'" (and similar expressions) include cases where two ring atoms immediately adjacent to the ring atom to which R6' is attached to the rest of the compound each carry an R7' group (i.e., R6' being a k-membered ring has one R7' group at each of positions 2 and k, relative to the ring atoms to which R6' is bound to the rest of the compound, i.e., R6' at its two ortho is superseded). For example, if R6' is 3-pyrrolyl (thus, the radical position is the ring carbon at position 3 relative to the ring nitrogen atom), then it is substituted by two R7' groups, expressing "one R7' group in position relative to R6' is bound to a ring atom of R6' at position 2 of the ring atom bound to the rest of the compound" includes the following structures: , , , and but does not include the following structures: .

[0087] The term "k-membered ring" as used herein means that the ring has k ring atoms. For example, for pyrazolyl k is 5; thus, the ortho positions are positions 2 and 5, and position k-1 is position 4, relative to the ring atom to which the pyrazolyl is bound (the radical position) to the rest of the compound. Furthermore, pyridyl is a 6-membered heteroaryl, and relative to the ring atom (base position) where the pyridyl is bound to the rest of the compound, the ortho positions are positions 2 and 6, and position k-1 is position 5.

[0088] With regard to R6 being a 5-membered monocyclic heteroaryl group containing at least one S ring atom, as used herein the expression "one R7 is attached to C at position 2 relative to the ring atom to which R6 is bound to the rest of the compound "Ring atom" (and similar expressions) preferably means that an R7 group is bonded to a C ring atom of R6 that is (i) directly adjacent to the ring atom through which R6 is attached to the rest of the compound and ( ii) Receive a lower number when numbering the ring atoms of R6 (e.g., start with the number "1" of the S ring atom and make the number of the ring atom that binds R6 to the rest of the compound (i.e. the "group" of R6 ” position) as low as possible to continue). In other words, relative to the base position of R6, when considering the shortest path between the S ring atom and the yl position, the C ring atoms at the two "ortho" positions of R6 preferably have the S ring atom and the base position of R6 R7 group between positions. For example, applying the above expression to the case where R6 is 3-thienyl substituted by one R7 (thus, the radical position is the 3rd ring carbon relative to the S ring atom) yields that the R7 group is at the 3rd position of 2 - Thienyl, as shown in the following formula: where R6 is represented as a bond to the rest of the compound. Likewise, with respect to R6 being a 5-membered monocyclic heteroaryl group comprising at least one S ring atom, as used herein the expression "one R7 is attached to C at position 5 relative to the ring atom to which R6 is bound to the remainder of the compound "Ring atom" (and similar expressions) preferably means that an R7 group is bonded to a C ring atom of R6 which is (i) directly adjacent to the ring atom through which R6 is attached to the rest of the compound and (ii ) receive higher numbers when numbering the ring atoms of R6 (eg, start with the number "1" for the S ring atoms and continue in such a way that the numbers for the base positions of R6 are as low as possible). In other words, relative to the radical position of R6, when considering the shortest path between the S ring atom and the radical position, the C ring atom preferably has an R7 group that is not located between the S ring atom and the radical position of R6. For example, applying the above expression ("an R7 group is attached to the C ring atom at position 5 relative to the ring atom to which R6 is bound to the rest of the compound") applies to a 3-thienyl group where R6 is substituted with an R7 situation (therefore, the radical position is the ring carbon at position 3 relative to the S ring atom), it can be seen that the R7 group is located at position 4 of the 3-thienyl group, as shown in the following formula: where R6 and the rest of the compound Partially bound keys. Furthermore, with respect to R6 being a 5-membered monocyclic heterocyclic heterocycle comprising at least one S ring atom, as used herein the expression "one R7 is attached to the C ring at position 2 relative to the ring atom to which R6 is bound to the rest of the compound atom, one R7 is attached to the C ring atom at position 5 relative to the ring atom to which R6 is bound to the rest of the compound" (and similar expressions) preferably means that for two C ring atoms of R6 directly adjacent to the ring atom Each of the ring atoms is connected to the ring atom to which R6 is connected to the rest of the compound to which R7 is connected. For example, the above expression ("one R7 is attached to the C ring atom at position 2 relative to the ring atom to which R6 is bound to the remainder of the compound, one R7 is attached at position 5 relative to the ring atom to which R6 is bound to the remainder of the compound to the C ring atom") applied to the case where R6 is 3-thienyl substituted by at least two R7 groups (thus, the radical position is the ring carbon at position 3 relative to the S ring atom), it follows that these R7 The groups are located at positions 2 and 4 of the 3-thienyl group as shown in the following formula: where R6 is the bond to the rest of the compound.

[0089] As used herein, the expression "representing the bond through which R6 is bound to the remainder of the compound" refers to the bond through which R6 is attached to the remainder of the compound (i.e., to (i) L if L is not a bond; if L is bond, then attached to (ii) the nitrogen atom of the carboxyl (thio)amido-C(=e)N(R4) of formula (Ia), (Ib) or (Ic)). For example, where R6 is and L is (i) methylene or (ii) a bond, compounds of formula (Ia) have the following structures (A1) and (A2), respectively: (A1) (A2) Similar terms such as "Represents a bond to the bond of Hy to the rest of the compound" or "represents a bond to the bond of Rla to the rest of the compound", as used herein, will be interpreted in a similar manner.

[0090] As used herein, the term "asymmetric" (for example, in conjunction with R1a) preferably means that the relevant moiety (especially an asymmetric cycloalkyl or heterocyclyl) is relative to its point of attachment to the rest of the compound , are asymmetric per se (e.g., 1,4-azazin-4-yl) and / or have an asymmetric substitution pattern (e.g., 3-azine-1-yl or 3-methylguanidine azin-1-yl). For example, a symmetrical group has a plane of symmetry relative to its point of attachment to the rest of the compound (eg, 4-methylpiperazinyl), while an asymmetric group has no plane of symmetry. An asymmetric group may have an asymmetric atom (e.g., a chiral C atom), as in 2-methylmorpholin-4-yl, but need not have an asymmetric atom (e.g., in 3- base). Exemplary asymmetric groups include the following groups: , , , , , , and, wherein R30 and X are as defined herein; and represent the linkage of the asymmetric group to the rest of the compound.

[0091] Asymmetric specific groups include the following groups: ,,,,,,,,,,,,,,,,,, and, wherein R30 and X are as defined herein; represent the asymmetric group and the rest of the compound Partially bound keys.

[0092] The expression "adjacent ring atoms" as used herein, as in "the C ring atom and the S ring atom are adjacent ring atoms", preferably means that the two ring atoms share a common keys, therefore, they bond directly to each other. For example, in the structure shown below (i.e., 3-thienyl substituted with R7 at position 4), the C ring atom and the S ring atom at position 2 are adjacent ring atoms, while the C ring atom at position 4 Atom and S ring atom are separated by C ring atom: where indicates the bond of R6 to the rest of the compound.

[0093] Likewise, the expression "R40 bonded to a C ring atom adjacent to an S ring atom" as used herein preferably means that the C ring atom and the S ring atom to which R40 is attached are adjacent atoms. For example, in the structure shown below, the R40 bound to the C ring atom adjacent to the S ring atom is the R40 bound to the C ring atom at position 2 (because the C ring atom is adjacent to the S ring atom), while The R40 bound to the C ring atom at position 4 is the R40 bound to the C ring atom separated from (or not adjacent to) the S ring atom (i.e. the C ring atom and the S ring atom at position 4 are separated by the C ring atom (in position 5 places) separation):.

[0094] The expression "the S ring atom of R6 is not adjacent to the ring atom to which R6 binds the rest of the compound" as used herein preferably means that the S ring atom of R6 is not adjacent to the ring atom which binds R6 to the compound through at least one ring atom. The remainder (i.e., from the base position of R6) of the ring atoms are separated. For example, if R6 is thienyl optionally substituted by one R7, the expression "the S ring atom of R6 is not adjacent to the ring atom to which R6 binds the rest of the compound" includes the following structures: , , and but especially, The following structures are not included: , , , and where a bond representing R6 is bound to the rest of the compound.

[0095] According to IUPAC nomenclature, preferably, the numbering of substituted heterocyclyl groups begins with the ring heteroatom and continues in such a way that the number of substituents is as low as possible. For example, the compound shown below has the following ring atom numbers and names: N-(2-fluoro-4-methylthiophen-3-yl)-2,5-dihydro-1H-imidazol-2-amine

[0096] The term "optionally substituted" means one or more (for example 1 to the maximum number of hydrogen atoms bound to a group, for example 1, 2, 3, 4, 5, 6, 7, 8, 9 or Up to 10, such as 1 to 5, 1 to 4, 1 to 3 or 1 or 2) hydrogen atoms may be substituted by groups other than hydrogen (i.e., primary substituents), such as alkyl (preferably, C1- 6 alkyl), alkenyl (preferably, C2-6 alkenyl), alkynyl (preferably, C2-6 alkynyl), aryl (preferably, 6 to 14 membered aryl), heteroaryl radical (preferably, 3 to 14 membered heteroaryl), cycloalkyl (preferably, 3 to 14 membered cycloalkyl), heterocyclyl (preferably, 3 to 14 membered heterocyclic), halogen, - CN, azido, -NO2, -OR71, -N(R72)(R73), -S(O)0-2R71, -S(O)1-2OR71, -OS(O)1-2R71, - OS(O)1-2OR71, -S(O)1-2N(R72)(R73), -OS(O)1-2N(R72)(R73), -N(R71)S(O)1-2R71 , -NR71S(O)1-2OR71, -NR71S(O)1-2N(R72)(R73), -OP(O)(OR71)2, -C(=X1)R71, -C(=X1)X1R71 , -X1C(=X1)R71 and -X1C(=X1)X1R71, and / or any two primary substituents bonded to the same carbon atom of a cycloalkyl or heterocyclyl group may be combined to form =X1, where , each of the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl and heterocyclyl groups of the primary substituent may itself be replaced by one or more (for example, one, two or three ) substituent (i.e., secondary substituent) which is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 6 to 14 membered aryl, 3 to 14 membered hetero Aryl, 3 to 14 membered cycloalkyl, 3 to 14 membered heterocyclyl, halogen, -CF3, -CN, azido, -NO2, -OR81, -N(R82)(R83), -S(O )0 -2R81, -S(O)1-2OR81, -OS(O)1-2R81, -OS(O)1-2OR81, -S(O)1-2N(R82)(R83), -OS( O) 1-2N(R82)(R83), -N(R81)S(O)1-2R81, -NR81S(O)1-2OR81, -NR81S(O)1-2N(R82)(R83), - OP( O)(OR81)2, -C(=X2)R81, -C(=X2)X2R81, -X2C(=X2)R81 and -X2C(=X2)X2R81, and / or with Any two secondary substituents bonded to the same carbon atom of the cycloalkyl or heterocyclic group can be combined to form = X2, wherein, the C1-6 alkyl, C2-6 alkenyl, C2- Each of the 6-alkynyl, 6- to 14-membered aryl, 3- to 14-membered heteroaryl, 3- to 14-membered cycloalkyl, and 3- to 14-membered heterocyclyl is optionally replaced by one or more (for example, one , two or three) substituents (ie, tertiary substituents) substituted independently selected from C1-3 alkyl, halogen, -CF3, -CN, azido, -NO2, -OH, -O (C1-3 alkyl), -OCF3, -S (C1-3 alkyl), -NH2, -NH (C1-3 alkyl), -N (C1-3 alkyl) 2, -NHS ( O)2 (C1-3 alkyl), -S(O)2NH2-z(C1-3 alkyl)z, -C(=O)OH, -C(=O)O(C1-3 alkyl) , -C (=O)NH2-z(C1-3 alkyl)z, -NHC(=O)(C1-3 alkyl), -NHC(=NH)NHz-2(C1-3 alkyl)z and -N (C1-3 alkyl) C (=NH) NH2-z (C1-3 alkyl) z, wherein each z is independently 0, 1 or 2, and each C1-3 alkyl is independently is methyl, ethyl, propyl or isopropyl, and / or any two tertiary substituents bonded to the same carbon atom of a 3- to 14-membered cycloalkyl or heterocyclyl as secondary substituents may be bonded together form =O, =S, =NH or =N(C1-3 alkyl); wherein each of R71, R72 and R73 is independently selected from H, C1-6 alkyl, C2-6 alkenyl , C2-6 alkynyl, 3 to 7 membered cycloalkyl, 5 or 6 membered aryl, 5 or 6 membered heterocyclic group and 3 to 7 membered heterocyclic group, wherein the C1-6 alkyl, C2- Each of 6 alkenyl, C2-6 alkynyl, 3 to 7 membered cycloalkyl, 5 or 6 membered aryl, 5 or 6 membered heteroaryl and 3 to 7 membered heterocyclyl is optionally replaced by one, Two or three substituents independently selected from the following substituents: C1-3 alkyl, halogen, -CF3, -CN, azido, -NO2, -OH, -O(C1-3 alkyl), - OCF3, = O, -S (C1-3 alkyl), -NH2, -NH (C1-3 alkyl), -N (C1-3 alkyl) 2, -NHS (O) 2 (C1-3 alkyl base), -S(O)2NH2-z(C1-3 alkyl) z, -C(=O)(C1-3 alkyl), -C(=O)OH, -C(=O)O( C1-3 alkyl), -C(=O)NH2-z(C1-3 alkyl)z, -NHC(=O)(C1-3 alkyl), -NHC(=NH)NHz-2(C1 -3 alkyl) z and -N (C1-3 alkyl) C (=NH) NH2-z (C1-3 alkyl) z, wherein each z is independently 0, 1 or 2, and each C1 -3 alkyl is independently methyl, ethyl, propyl or isopropyl; each of R81, R82 and R83 is independently selected from H, C1-4 alkyl, C2-4 alkenyl, C2-4 Alkynyl, 3 to 6 membered cycloalkyl, 5 or 6 membered aryl, 5 or 6 membered heteroaryl and 3 to 6 membered heterocyclic group, wherein C1-4 alkyl, C2-4 alkenyl, C2-4 Each of the alkynyl, 3 to 6 membered cycloalkyl, 5 or 6 membered aryl, 5 or 6 membered heteroaryl and 3 to 6 membered heterocyclyl is optionally replaced by one, two or three independently Substituents selected from the following substituents: C1-3 alkyl, halogen, -CF3, -CN, azido, -NO2, -OH, -O(C1-3 alkyl), -OCF3, =O, -S (C1-3 alkyl), -NH2, -NH (C1-3 alkyl), -N (C1-3 alkyl) 2, -NHS (O) 2 (C1-3 alkyl), -S (O )2NH2- z(C1-3 alkyl) z, -C(=O)(C1-3 alkyl), -C(=O)OH, -C(=O)O(C1-3 alkyl), -C(=O)NH2-z(C1-3 alkyl)z, -NHC(=O)(C1-3 alkyl), -NHC(=NH)NHz-2(C1-3 alkyl)z and -N(C1-3 alkyl)C(=NH)NH2-z(C1-3 alkyl)z, wherein each z is independently 0, 1 or 2, and each C1-3 alkyl is independently methyl, ethyl, propyl or isopropyl; and each of X1 and X2 is independently selected from O, S and N(R84), wherein R84 is H or C1-3 alkyl.

[0097] Typical primary substituents are preferably selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 6 to 14 members (such as 6 to 10 members) aryl, 3 to 14 members (eg 5 to 6 membered) heteroaryl, 3 to 14 membered (eg 3 to 7 membered) cycloalkyl, 3 to 14 membered (eg 3 to 7 membered) heterocyclyl, halogen, -CN, azido, - NO2, -OR71, -N(R72)(R73), -S(O)0-2R71, -S(O)1-2OR71, -OS(O)1-2R71, -OS(O)1-2OR71 , -S(O)1-2N(R72)(R73), -OS(O)1-2N(R72)(R73), -N(R71)S(O)1-2R71, -NR71S(O)1 - 2OR71, -C(=X1)R71, -C(=X1)X1R71, -X1C(=X1)R71 and -X1C(=X1)X1R71, such as C1-4 alkyl, C2-4 alkenyl, C2- 4-alkynyl, 6-membered aryl, 5- or 6-membered heteroaryl, 3- to 7-membered cycloalkyl, 3- to 7-membered (eg 5 or 6-membered) heterocyclyl, halogen, -CF3, -CN, azide group, -NO2, -OH, -O(C1-3 alkyl), -S(C1-3 alkyl), -NH2, -NH(C1-3 alkyl), -N(C1-3 alkyl) 2. -NHS(O)2(C1-3 alkyl), -S(O)2NH2-z(C1-3 alkyl)z, -C(=O)OH, -C(=O)O(C1 -3 alkyl), -C(=O)NH2-z(C1-3 alkyl)z, -NHC(=O)(C1-3 alkyl), -NHC(=NH)NHz-2(C1- 3 alkyl) z and -N (C1-3 alkyl) C (=NH) NH2-z (C1-3 alkyl) z, wherein each z is independently 0, 1 or 2, and each C1- 3 Alkyl is independently methyl, ethyl, propyl or isopropyl; wherein X1 is independently selected from O, S, NH and N (CH3); and each of R71, R72 and R73 is as defined above , or preferably, independently selected from H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, 5 or 6 membered cycloalkyl, 5 or 6 membered aryl, 5 or 6 membered hetero Aryl and 5- or 6-membered heterocyclyl, wherein each of said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is optionally replaced by one, two Or three substituents independently selected from the following substituents: C1-3 alkyl, halogen, -CF3, -CN, azido, -NO2, -OH, -O(C1-3 alkyl), -S( C1-3 alkyl), -NH2, -NH(C1-3 alkyl), -N(C1-3 alkyl)2, -NHS(O)2(C1-3 alkyl), -S(O) 2NH2 -z(C1-3 alkyl)z, -C(=O)OH, -C(=O)O(C1-3 alkyl), -C(=O)NH2-z(C1-3 alkyl ) z, -NHC(=O)(C1-3 alkyl), -NHC(=NH)NHz-2(C1-3 alkyl)z and -N(C1-3 alkyl)C(=NH)NH2 - z(C1-3 alkyl)z, wherein each z is independently 0, 1 or 2 and each C1-3 alkyl is independently methyl, ethyl, propyl or isopropyl. Specific examples of primary substituents are independently selected from C1-3 alkyl, phenyl, imidazolyl, thiazolyl, cyclopentyl, cyclohexyl, dihydrothiazolyl, thiazolidinyl, halogen, -CF3, -CN, -OH, -O(C1-3 alkyl), -S(C1-3 alkyl), -NH2, -NH(C1-3 alkyl), -N(C1-3 alkyl) 2, -NHS( O )2(C1-3 alkyl), -C(=O)OH, -C(=O)O(C1-3 alkyl), -C(=O)NH2-z(C1-3 alkyl) z, -NHC(=O)(C1-3 alkyl), -NHC(=NH)NHz-2(C1-3 alkyl)z and -N(C1-3 alkyl)C(=NH)NH2- z(C1-3 alkyl)z, wherein each z is independently 0, 1 or 2 and each C1-3 alkyl is independently methyl, ethyl, propyl or isopropyl. Particularly preferred primary substituents are independently selected from C1-3 alkyl, phenyl, thiazolidinyl, halogen (such as F, Cl or Br), -NH2, -NHS(O)2(C1-3 alkyl ), -NHC(=O)(C1-3 alkyl) and -NHC(=NH)NHz-2(C1-3 alkyl)z, where z is 0, 1 or 2, and each C1-3 alkane The radicals are methyl, ethyl, propyl or isopropyl, respectively.

[0098] Typical secondary substituents are preferably selected from C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, 6 or 10 membered aryl, 5 or 6 membered heteroaryl, 5 or 6 Member cycloalkyl, 5 or 6 member heterocyclyl, halogen, =O, =S, -CF3, -CN, azido, -NO2, -OH, -O(C1-3 alkyl), -S( C1-3 alkyl), -NH2, -NH(C1-3 alkyl), -N(C1-3 alkyl)2, -NHS(O)2(C1-3 alkyl), -S(O) 2NH2-z(C1-3 alkyl)z, -C(=O)OH, -C(=O)O(C1-3 alkyl), -C(=O)NH2-z(C1-3 alkyl )z, -NHC(=O)(C1-3 alkyl), -NHC(=NH)NHz-2(C1-3 alkyl)z and -N(C1-3 alkyl)C(=NH)NH2 -z(C1-3 alkyl)z, wherein each z is independently 0, 1 or 2 and each C1-3 alkyl is independently methyl, ethyl, propyl or isopropyl. Specific examples of secondary substituents are independently selected from C1-3 alkyl, phenyl, 5 or 6 membered heteroaryl, 5 or 6 membered cycloalkyl, 5 or 6 membered heterocyclyl, halogen, =O, = S, -CF3, -CN, -OH, -O(C1-3 alkyl), -S(C1-3 alkyl), -NH2, -NH(C1-3 alkyl), -N(C1-3 Alkyl)2, -NHS(O)2(C1-3alkyl), -C(=O)OH, -C(=O)O(C1-3alkyl), -C(=O)NH2- z(C1-3 alkyl)z, -NHC(=O)(C1-3 alkyl), -NHC(=NH)NHz-2(C1-3 alkyl)z and -N(C1-3 alkyl )C(=NH)NH2-z(C1-3 alkyl)z, wherein each z is independently 0, 1 or 2 and each C1-3 alkyl is independently methyl, ethyl, propyl or Isopropyl. Particularly preferred secondary substituents are independently selected from methyl, ethyl, propyl, isopropyl, phenyl, =O and =S.

[0099] Typical tertiary substituents are preferably selected from C1-3 alkyl, phenyl, halogen, -CF3, -OH, -OCH3, -SCH3, -NH2-z(CH3)z, -C(= O)OH and -C(=O)OCH3, where z is 0, 1 or 2 and C1-3alkyl is methyl, ethyl, propyl or isopropyl. Particularly preferred tertiary substituents are selected from methyl, ethyl, propyl, isopropyl, halogen (eg F, Cl or Br) and -CF3, eg halogen (eg F, Cl or Br) and -CF3.

[0100] As used herein, the term "optional" or "optional" means that the subsequently described event, circumstance or condition may or may not occur, and that the description includes instances and instances in which said event, circumstance or condition occurs and what happened.

[0101] "Isomers" are compounds that have the same molecular formula but differ in structure ("structural isomers") or in the geometric (spatial) position of functional groups and / or atoms ("stereoisomers"). "Enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of each other. A "racemic mixture" or "racemate" comprises a pair of enantiomers in equal amounts and is indicated by a prefix (±). "Diastereoisomers" are stereoisomers that are not superimposable, nor are they mirror images of each other. "Tautomers" are structural isomers of the same chemical substance that spontaneously and reversibly interconvert, even in pure form, as a result of migration of single atoms or groups of atoms; in a state of dynamic chemical equilibrium. An example of a tautomer is the keto-enol tautomeric isomer. "Conformational isomers" are stereoisomers that are interconvertible by rotation about a formal single bond, and include (especially) those that result in a difference in the three-dimensional shape of a (heterocyclic) ring, such as ring Chair, Half Chair, Boat and Twist Boat in Hexane.

[0102] If a formula shown in this application can be construed as including more than one isomer, unless expressly stated otherwise, the formula includes all possible isomers and therefore includes each individual isomer . For example, a compound of formula (Ia), wherein Hy is: wherein represents the bond between Hy and the rest of the compound; R1a is 3-methylpiperazinyl, including two isomers, for example, the isomer having the following formula (B1) Conformers and isomers having the following formula (B2): (B1) (B2). Furthermore, compounds of formula (Ic) wherein R6'' is 1-azabicyclo[2.2.2]oct-3-yl (optionally substituted by one or more R7' groups) contain two isomers, for example , an isomer having the following formula (B3) and an isomer having the following formula (B4) (where n1 is 0, 1, 2, 3 or greater): (B3) (B4).

[0103] As referred to herein, "polymorphism" means that a solid material (eg, a compound) can exist in more than one form or crystal structure, ie, "polymorphic variants" or "polymorphic forms." The terms "polymorphic variant" or "polymorphic form" and "polymorph" are used interchangeably herein. According to the present invention, these "polymorphic modifications" include crystalline forms, amorphous forms, solvates and hydrates. The reasons for the existence of different crystal forms are mainly due to the different conditions used in the crystallization process, such as: l solvent effect (packing of crystals may be different in polar and non-polar solvents); l certain impurities inhibit the growth mode and favor metastable l the supersaturation level at which the material crystallizes (generally, the higher the concentration above solubility, the more likely metastable states are formed); l the temperature at which crystallization occurs; l the geometry of the covalent bonds (resulting in differences in conformational polymorphism); l changes in stirring conditions.

[0104] Polymorphs may have different chemical, physical and / or pharmacological properties, including but not limited to: melting points, X-ray crystallography and diffraction patterns, chemical reactivity, solubility, dissolution rate, vapor pressure, density, absorption Wetness, flow, stability, firmness and bioavailability. Polymorphs can spontaneously change from metastable (unstable) to stable forms at specific temperatures. According to Ostwald's law, generally speaking, it is not the most stable polymorph that crystallizes first, but the least stable polymorph. Thus, for example, the quality, efficacy, safety, processability and / or manufacture of compounds of the present invention can be affected by polymorphism. In general, the most stable polymorphic form of a compound (eg, a compound of the invention) is selected because it is least likely to convert into another polymorphic form. However, polymorphic forms that are not the most stable may be selected for reasons other than stability, such as solubility, dissolution rate and / or bioavailability.

[0105] The term "crystalline form" of a material as used herein means that the smallest components (ie, atoms, molecules or ions) of the material form a crystalline structure. "Crystal structure" as used herein refers to a unique three-dimensional arrangement of atoms or molecules in a crystalline liquid or solid, characterized by a pattern arranged in a specific way, a group of atoms and a lattice exhibiting long-range order and symmetry. A lattice is an array of points that repeats periodically in three-dimensional space, and the pattern lies on the points of the lattice. The subunit of a lattice is the unit cell. Lattice parameters are the lengths of an element's sides and the angles between them. The symmetry of a crystal is reflected in its space group. To describe a crystal structure, the following parameters are required: chemical formula, lattice parameters, space group, atomic coordinates, and occupancy of sites.

[0106] The term "amorphous form" of a material as used herein means that the smallest components (ie, atoms, molecules or ions) of the material are not arranged in a crystal lattice but randomly. Thus, unlike crystals where there is both short-range order (constant distance to the next neighboring atom) and long-range order (periodic repetition of the fundamental lattice), only short-range order exists in amorphous form.

[0107] As used herein, the term "complex of a compound" refers to a higher order compound produced by the association of a compound with one or more other molecules. Exemplary complexes of compounds include, but are not limited to, solvates, clusters, and chelates of the compounds.

[0108] The term "solvate" as used herein refers to the dissolution of material in a solvent (e.g., an organic solvent (e.g., a fatty alcohol (e.g., methanol, ethanol, n-propanol, isopropanol), acetone, acetonitrile, diethyl ether, etc.), water or Addition complexes in mixtures of two or more of these liquids), wherein the addition complexes exist in the form of crystals or mixed crystals. The amount of solvent contained in the addition complex may be stoichiometric or non-stoichiometric. "Hydrate" is a solvate wherein the solvent is water.

[0109] In isotopically labeled compounds, one or more atoms are replaced by corresponding atoms having the same number of protons but a different number of neutrons. For example, a hydrogen atom may be replaced by a deuterium atom. Exemplary isotopes useful in compounds of the invention include deuterium, 11C, 13C, 14C, 15N, 18F, 32P, 32S, 35S, 36Cl, and 125I.

[0110] The expression "amino group protecting group" as used herein preferably refers to any group by which an amine group contained in a compound can be transferred to a less reactive (ie, protected) amine group. Preferably, amine protecting groups can be incorporated into the corresponding compounds under mild conditions in a chemoselective and / or regioselective manner and / or in good yields. Furthermore, amine protecting groups should be stable under the conditions to which the protected compound is subjected (eg, those of the desired reaction and / or purification). Preferably, the amine protecting group should minimize the risk of stereogenic center racemization when present in the compound. In one embodiment, the amine protecting group should be removed from the protected compound in a selective manner under mild conditions in order to obtain the deprotected compound in high yield. Exemplary amine protecting groups include tert-butoxycarbonyl (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-trichloromethoxycarbonyl (Troc), triphenylmethyl (trityl; Tr), tosyl (tosyl; Ts), p-bromobenzenesulfonyl (brosyl), 4-nitrobenzenesulfonyl (nosyl) and 2-nitrobenzenesulfonyl (Nps).

[0111] The term "half-life" relates to the period of time required to eliminate half of the activity, amount or quantity of molecules. In the context of the present invention, the half-life of a compound disclosed herein (eg, a compound of formula (Ia), (Ib) or (Ic)) is indicative of the stability of the compound.

[0112] The terms "subject", "patient", "individual" or "animal" relate to multicellular animals, such as vertebrates. For example, vertebrates in the context of the present invention are mammals, birds (e.g. poultry), reptiles, amphibians, bony fishes and cartilaginous fishes, especially any of the above-mentioned domestic animals as well as captive animals (especially vertebrate animals), such as zoo animals (especially vertebrates). Mammals involved in the present invention include but are not limited to humans, non-human primates, domesticated mammals (such as dogs, cats, sheep, cows, goats, pigs, horses, etc.), laboratory mammals (such as mice, rats, etc.) rats, rabbits, guinea pigs, etc.), and captive mammals (such as zoo mammals). The term "animal" as used herein also includes humans. Specific non-limiting examples of birds include domestic poultry, and include birds such as chickens, turkeys, ducks, geese, guinea fowl, pigeons, pheasants, etc.; while specific non-limiting examples of teleost or cartilaginous fish include suitable For fish cultured through aquaculture, and includes bony fishes such as salmon, trout, perch, carp, catfish, etc.

[0113] Compound Dasatinib (also referred to herein as Compound A8) has the following structure: .

[0114] compound

[0115] In a first aspect, as may be further described, defined, claimed or otherwise disclosed herein, the present invention provides a compound selected from the group consisting of kinase inhibitors of the following formula: (Ia) and solvates, salts , N-oxides, complexes, polymorphs, crystal forms, racemic mixtures, diastereomers, enantiomers, tautomers, conformers, isotopic labels forms, prodrugs, and combinations thereof; wherein: Hy is heteroaryl or heterocyclyl optionally substituted by one or more independently selected R1e; each R1e is independently selected from R1a, R1b, R1c, and R1d; R1a and each of R1d is independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, halogen, -CN, azido, -NO2, -OR11 , -N(R12)(R13), -N(R11)(OR11), -S(O)0-2R11, -S(O)1-2OR11, -OS(O)1-2R11, -OS(O )1 -2OR11, -S(O)1-2N(R12)(R13), -OS(O)1-2N(R12)(R13), -N(R11)S(O)1-2R11, -NR11S (O )1-2OR11, -NR11S(O)1-2N(R12)(R13), -P(O)(OR11)2, -OP(O)(OR11)2, -C(=X)R11, -C (=X)XR11, -XC(=X)R11 and -XC(=X)XR11, wherein in alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl and heteroaryl Each is optionally substituted by one or more independently selected R30; each of R1b and R1c is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 Cycloalkyl, C6-10 aryl, 3 to 7 membered heteroaryl, 3 to 7 membered heterocyclyl, -O(CH2)0-2(C3-7cycloalkyl), -O(CH2)0- 2(C6-10 aryl), -O(CH2)0-2(3 to 7 membered heteroaryl), -O(CH2)0-2(3 to 7 membered heterocyclyl), -NH(CH2) 0- 2(C3-7 cycloalkyl), -NH(CH2)0-2(C6-10 aryl), -NH(CH2)0-2(3 to 7 membered heterocyclyl), -NH(CH2 )0 -2(3 to 7-membered heterocyclic group), halogen, -CF3, -CN, azido, -NO2, -OH, -O(C1-6 alkyl), -OCF3, -S(C1- 6 alkyl), -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, -NHS(O)2(C1-6 alkyl), -S(O)2NH2- z(C1-6 alkyl)z, -C(=O)(C1-6 alkyl), -C(=O)OH, -C(=O)O(C1-6 alkyl), -C( =O )NH2-z(C1-6 alkyl) z, -NHC(=O)(C1-6 alkyl), -NHC(=NH)NHz-2(C1-6 alkyl)z and -N( C1-6 alkyl) C (= NH) NH2-z (C1-6 alkyl) z, wherein z is 0, 1 or 2, and C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl , C3-7 cycloalkyl, C6-10 aryl, 3 to 7 membered heteroaryl and 3 to 7 membered heterocyclyl groups are optionally 1, 2 or 3 independently selected from - Partial substitution of OH, methyl, ethyl, -OCH3, -SCH3 and -NH2-z(CH3)z; R2 is H; R3 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, hetero Cyclic, heteroaryl, halogen, -CN, azido, -NO2, -OR11, -N(R12)(R13), -N(R11)(OR11), -S(O)0-2R11, - S(O)1-2OR11, -OS(O)1-2R11, -OS(O)1-2OR11, -S(O)1-2N(R12)(R13), -OS(O)1-2N( R12) (R13), -N(R11)S(O)1-2R11, -NR11S(O)1-2OR11, -NR11S(O)1-2N(R12)(R13), -P(O)(OR11 )2, -OP(O)(OR11)2, -C(=X)R11, -C(=X)XR11, -XC(=X)R11 and -XC(=X)XR11, where alkyl, alkene Each of radical, alkynyl, cycloalkyl, aryl, heterocyclyl and heteroaryl is optionally substituted by one or more independently selected R30; R4 is H; R5 is -L-R6; L is selected Self-bonding, C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, and -(CH2)m-[Y-(CH2)n]o-, where m is between 1 and 6 An integer between , n is an integer between 0 and 3, o is an integer between 1 and 3, wherein, if n is 0, then o is 1; Y is independently selected from O, S and - N(R13)-; each of the C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, -(CH2)m- and -(CH2)n- groups is optional is substituted by one or two independently selected R30; R6 is a 5-membered monocyclic heteroaryl group containing at least one S ring atom and substituted by one or more independently selected R7; R7 is independently selected from alkyl, alkenyl , alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, halogen, -CN, azido, -NO2, -OR11, -N(R12)(R13), -N(R11)(OR11 ), -S(O)0-2R11, -S(O)1-2OR11, -OS(O)1-2R11, -OS(O)1-2OR11, -S(O)1-2N(R12)( R13), -OS(O)1-2N(R12)(R13), -N(R11)S(O)1-2R11, -NR11S(O)1-2OR11, -NR11S(O)1-2N(R12 )( R13), -P(O)(OR11)2, -OP(O)(OR11)2, -C(=X)R11, -C(=X)XR11, -XC(=X)R11, and - XC(=X)XR11, wherein each of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl and heteroaryl is optionally substituted by one or more independently selected R30, wherein At least one of R7 is F and / or at least one of R7 is substituted by one or more F atoms; A is selected from S, O, NR8 and C(R9)2; R8 is selected from H, alkyl, alkenyl, Alkynyl, cycloalkyl, aryl, heterocyclyl and heterocyclyl, wherein each of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl and heteroaryl is optionally replaced by One or more independently selected R30 is substituted; R9 is independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, halogen, -CN, azido, -NO2 , -OR11, -N(R12)(R13), -S(O)0-2R11, -S(O)1-2OR11, -OS(O)1-2R1, -OS(O)1-2OR11, - S(O)1-2N(R12)(R13), -OS(O)1-2N(R12)(R13), -N(R11)S(O)1-2R11, -NR11S(O)1-2OR11 , -NR11S(O)1-2N(R12)(R13), -C(=X)R11, -C(=X)XR11, -XC(=X)R11 and -XC(=X)XR11, where alkane Each of radical, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl and heteroaryl is optionally substituted by one or more independently selected R30; X is independently selected from O, S and N (R14); E is O or S; R11 is independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl, wherein alkyl, alkenyl, alkynyl , cycloalkyl, aryl, heteroaryl and heterocyclyl are optionally substituted by one or more independently selected R30; each of R12 and R13 is independently selected from H, alkyl, alkenyl group, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl, or R12 and R13 can be combined with the nitrogen atom to which they are attached to form a group -N=CR15R16, wherein alkyl, alkenyl, alkynyl , cycloalkyl, aryl, heteroaryl and heterocyclyl are optionally substituted by one or more independently selected R30; R14 are independently selected from H, alkyl, alkenyl, alkynyl, ring Alkyl, aryl, heteroaryl, heterocyclyl and -OR, wherein each of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is optionally replaced by one or a plurality of independently selected R30 substitutions; each of R15 and R16 is independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heterocyclyl, and -NHyR202- y, or R15 and R16 may be joined together with the atoms to which they are attached to form a ring which may be substituted by one or more independently selected R30, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl Each of , heteroaryl and heterocyclyl is optionally substituted by one or more independently selected R30; y is an integer from 0 to 2; R20 is independently selected from alkyl, alkenyl, alkynyl, cycloalkane radical, aryl, heteroaryl and heterocyclyl, wherein each of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is optionally replaced by one or more independently and R30 is a primary substituent, and each instance is independently selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, halogen, -CN, azido, -NO2, -OR71, -N(R72)(R73), -S(O)0-2R71, -S(O)1-2OR71, -OS(O)1-2R71, - OS(O)1-2OR71, -S(O)1-2N(R72)(R73), -OS(O)1-2N(R72)(R73), -N(R71)S(O)1-2R71 , -NR71S(O)1-2OR71, -NR71S(O)1-2N(R72)(R73), -OP(O)(OR71)2, -C(=X1)R71, -C(=X1)X1R71 , -X1C (=X1)R71 and -X1C(=X1)X1R71, and / or any two R30 bonded to the same carbon atom of a cycloalkyl or heterocyclyl group can be combined to form =X1, wherein, as a Each of the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl groups of the secondary substituents is optionally substituted with one or more secondary substituents, wherein, in each In some cases, the secondary substituents are independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3 to 14 membered aryl, 3 to 14 membered heteroaryl, 3 to 14 membered Cycloalkyl, 3 to 14 membered heterocyclyl, halogen, -CF3, -CN, azido, -NO2, -OR81, -N(R82)(R83), -S(O)0-2R81, -S (O)1 -2OR81, -OS(O)1-2R81, -OS(O)1-2OR81, -S(O)1-2N(R82)(R83), -OS(O)1-2N(R82 )(R83), -N(R81)S(O)1-2R81, -NR81S(O)1-2OR81, -NR81S(O)1-2N(R82)(R83), -OP(O)(OR81) 2. -C (=X2)R81, -C(=X2)X2R81, -X2C(=X2)R81 and -X2C(=X2)X2R81, and / or with cycloalkyl or heterocycle as the primary substituent Any two secondary substituents bonded to the same carbon atom of the group can be combined to form =X2, wherein, as a secondary substituent, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3 to Each of the 14-membered aryl, 3-14-membered heteroaryl, 3-14-membered cycloalkyl, and 3-14-membered heterocyclyl is optionally substituted by one or more tertiary substituents, wherein, in each In this case, the tertiary substituents are independently selected from C1-3 alkyl, halogen, -CF3, -CN, azido, -NO2, -OH, -O(C1-3 alkyl), -OCF3 , -S (C1-3 alkyl), -NH2, -NH (C1-3 alkyl), -N (C1-3 alkyl) 2, -NHS (O) 2 (C1-3 alkyl), - S(O)2NH2- z(C1-3 alkyl)z, -C(=O)OH, -C(=O)O(C1-3 alkyl), -C(=O)NH2-z(C1 -3 alkyl)z, -NHC(=O)(C1-3 alkyl), -NHC(=NH)NHz-2(C1-3 alkyl)z and -N(C1-3 alkyl)C( =NH)NH2-z (C1-3 alkyl) z, wherein each z is independently 0, 1 or 2 and each C1-3 alkyl is independently methyl, ethyl, propyl or isopropyl , and / or any two tertiary substituents bonded to the same carbon atom of a 3 to 14 membered cycloalkyl or heterocyclyl as a secondary substituent may be combined to form =O, =S, =NH or = N(C1-3 alkyl); WhereinEach of R71, R72 and R73 is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3 to 7 membered cycloalkyl, 5 or 6 membered aryl, 5 or 6-membered heterocycloalkyl and 3 to 7-membered heterocyclyl, wherein, the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3 to 7-membered cycloalkyl, 5 or 6-membered aromatic Each of the 5- or 6-membered heterocycloalkyl and the 3- to 7-membered heterocyclyl is optionally substituted by one, two or three substituents independently selected from the group consisting of C1-3 alkyl, halogen , -CF3, -CN, azido, -NO2, -OH, -O(C1-3 alkyl), -OCF3, =O, -S(C1-3 alkyl), -NH2, -NH(C1 -3 alkyl), -N(C1-3 alkyl)2, -NHS(O)2(C1-3 alkyl), -S(O)2NH2-z(C1-3 alkyl)z, -C (=O)(C1-3 alkyl), -C(=O)OH, -C(=O)O(C1-3 alkyl), -C(=O)NH2-z(C1-3 alkyl )z, -NHC(=O)(C1-3 alkyl), -NHC(=NH)NHz-2(C1-3 alkyl)z and -N(C1-3 alkyl)C(=NH)NH2 -z(C1-3 alkyl) z, wherein each z is independently 0, 1 or 2, and each C1-3 alkyl is independently methyl, ethyl, propyl or isopropyl; R81, Each of R82 and R83 is independently selected from H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, 3 to 6 membered cycloalkyl, 5 or 6 membered aryl, 5 or 6 membered Heterocycloalkyl and 3 to 6-membered heterocyclic group, wherein, the C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, 3 to 6 membered cycloalkyl, 5 or 6 membered aryl, Each of the 5 or 6 membered heterocycloalkyl and the 3 to 6 membered heterocyclyl is optionally substituted by one, two or three substituents independently selected from: C1-3 alkyl, halogen, - CF3, -CN, azido, -NO2, -OH, -O(C1-3 alkyl), -OCF3, =O, -S(C1-3 alkyl), -NH2, -NH(C1-3 Alkyl), -N(C1-3 alkyl)2, -NHS(O)2(C1-3 alkyl), -S(O)2NH2-z(C1-3 alkyl)z, -C(= O)(C1-3 alkyl), -C(=O)OH, -C(=O)O(C1-3 alkyl), -C(=O)NH2-z(C1-3 alkyl)z , -NHC(=O)(C1-3 alkyl), -NHC(=NH)NHz-2(C1-3 alkyl)z and -N(C1-3 alkyl)C(=NH)NH2-z (C1-3 alkyl) z, wherein each z is independently 0, 1 or 2, and each C1-3 alkyl is independently methyl, ethyl, propyl or isopropyl; and X1 and X2 Each of is independently selected from O, S and N(R84), wherein R84 is H or C1-3 alkyl.

[0116] In one embodiment, the kinase inhibitor has the formula (IIa): (IIa) wherein Hy, R2, R3, R4, A and E are independently as above (especially with respect to formula (Ia)) or hereinafter (especially is defined with respect to formula (IIIa), (IVa), (Va), (VIa), (VIIa) and / or (VIIIa)), and R5 is -L-R6, wherein L is as above (especially with respect to formula ( Ia)) or as defined below and R6 is a 5-membered monocyclic heteroaryl containing at least one S ring atom, replaced by one or more (eg 1 to the maximum number of hydrogen atoms bonded to the 5-membered monocyclic heteroaryl, For example 1, 2 or 3, preferably 2) independently selected R7 substitution, wherein R7 is independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, halogen, - CN, azido, -NO2, -OR11, -N(R12)(R13), -N(R11)(OR11), -S(O)0-2R11, -S(O)1-2OR11, -OS (O)1-2R11, -OS(O)1-2OR11, -S(O)1-2N(R12)(R13), -OS(O)1-2N(R12)(R13), -N(R11 )S(O)1-2R11, -NR11S(O)1-2OR11, -NR11S(O)1-2N(R12)(R13), -P(O)(OR11)2, -OP(O)(OR11 )2, -C(=X)R11, -C(=X)XR11, -XC(=X)R11 and -XC(=X)XR11, where alkyl, alkenyl, alkynyl, cycloalkyl, aryl Each of radical, heterocyclyl and heteroaryl is optionally replaced by one or more (for example, 1 to the maximum number of hydrogen atoms with alkyl, alkenyl, alkyne, cycloalkyl, aryl, heterocyclic group or heterocyclyl group, such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or up to 10, such as 1 to 5, 1 to 4, or 1 to 3 or 1 or 2) independently selected R30 is substituted, wherein at least one of R7 is F and / or at least one of R7 is substituted by one or more F atoms.

[0117] In one embodiment of the kinase inhibitor of formula (IIa), Hy, R2, R3, R4, A, E, L and R7 are independently as above (especially with respect to formula (Ia)) or hereinafter (especially As defined with respect to formulas (IIIa), (IVa), (Va), (VIa), (VIIa) and / or (VIIIa)), R6 is selected from thienyl, thiazolyl and thiadiazolyl, each of which is replaced by a or a plurality (eg 1 to the maximum number of hydrogen atoms bound to a 5-membered monocyclic heteroaryl, eg 1, 2 or 3) independently selected R7 substitutions. For example, R6 may be selected from thiophene and thiazolyl, each of which is independently selected by one or more (e.g., 1 to the maximum number of hydrogen atoms bound to a 5-membered monocyclic heteroaryl, e.g., 1, 2 or 3) R7 replaced. Preferably, R6 is thienyl substituted by one or more (eg 1 to the maximum number of hydrogen atoms bound to a 5-membered monocyclic heteroaryl, eg 1, 2 or 3, preferably 2) independently selected R7 .

[0118] In any of the above embodiments of the kinase inhibitor of formula (IIa), including kinase inhibitors of formula (la), preferably R6 the ring atom through which R6 is bound to the rest of the compound is a C atom.

[0119] In any of the above embodiments of the kinase inhibitor of formula (IIa) (including the kinase inhibitor of formula (Ia), preferably R6 is selected from: ,,,,,,,,,,,,,, , , , , , , , , , , , , , , , , , , , , , , etc., where R6 is bound to the rest of the compound.

[0120] In any of the above embodiments of the kinase inhibitor of formula (IIa), including the kinase inhibitor of formula (Ia), it is preferred that the S ring atom of R6 is not connected to the ring atom through which R6 is bound to the remainder of the compound adjacent.

[0121] In one embodiment of the kinase inhibitor of formula (IIa), Hy, R2, R3, R4, A, E, L and R7 are independently as above (especially with respect to formula (Ia)) or hereinafter (especially As defined with respect to formulas (IIIa), (IVa), (Va), (VIa), (VIIa) and / or (VIIIa)), R6 is thienyl or thiazolyl, preferably thienyl, each of which is replaced by at least Two R7s are substituted; in this embodiment, R6 is more preferably replaced by two R7s different from each other.

[0122] In any of the above embodiments of the kinase inhibitor of formula (IIa) (including the kinase inhibitor of formula (Ia), preferably one R7 (in particular, R7 is F and / or R7 is replaced by one or more F atom substitution) is attached to the C ring atom at position 2 or 5 relative to the ring atom to which R6 is bound to the remainder of the compound. In those cases where R6 is substituted by at least two R7 groups, preferably one of the R7 groups (especially R7 is F and / or R7 is substituted by one or more F atoms) is bound to R6 relative to The remainder of the compound is bound to one of the C ring atoms at positions 2 and 5 of the ring atom, and one of the R7 groups is bound to the other at positions 2 and 5 relative to the R6 bound to the ring atom of the remainder of the compound C ring atom.

[0123] In one embodiment of the kinase inhibitor of formula (IIa), Hy, R2, R3, R4, A, E, L and R6 are independently as above (especially with respect to formula (Ia)) or below (especially defined with respect to formulas (IIIa), (IVa), (Va), (VIa), (VIIa) and / or (VIIIa)), and at least one of R7 is F and / or at least one of R7 is selected from: Alkyl, -OR11 and -N(R12)(R13), wherein each of said alkyl and R11 groups and at least one of said R12 and R13 groups are replaced by one or more (for example, 1 to The maximum number of hydrogen atoms bound to an alkyl, R11, R12 or R13 group, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9 or up to 10, for example 1 to 5, 1 to 4 or 1 to 3 or 1 or 2) F atom substitution.

[0124] In one embodiment of the kinase inhibitor of formula (IIa), Hy, R2, R3, R4, A, E, L and R6 are independently as above (especially with respect to formula (Ia)) or below (especially defined with respect to formulas (IIIa), (IVa), (Va), (VIa), (VIIa) and / or (VIIIa)), and at least one of R7 is F and / or at least one of R7 is selected from: Alkyl, -O(alkyl), -NH(alkyl) and -N(alkyl)2, wherein, alkyl, -O(alkyl), -NH(alkyl) and -N( Alkyl) At least one alkyl group of 2 is replaced by one or more (for example, 1 to the maximum number of hydrogen atoms bonded to the alkyl group, such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or at most 10, eg 1 to 5, 1 to 4 or 1 to 3, or 1 or 2) F atom substitution.

[0125] In one embodiment of the kinase inhibitor of formula (IIa), Hy, R2, R3, R4, A, E, L and R6 are independently as above (especially with respect to formula (Ia)) or hereinafter (especially Defined with respect to formulas (IIIa), (IVa), (Va), (VIa), (VIIa) and / or (VIIIa)), and at least one of R7 is F and / or at least one of R7 is selected from C1 -3 alkyl, -O(C1-3 alkyl), -NH(C1-3 alkyl) or -N(C1-3 alkyl)2, wherein, C1-3 alkyl, -O(C1-3 Alkyl) and -NH(C1-3 alkyl) and at least one alkyl of -N(C1-3 alkyl)2 is replaced by one or more (for example, 1 to combined with C1-3 alkyl Maximum number of hydrogen atoms, eg 1, 2, 3, 4, 5, 6, 7 or up to 6, eg 1 to 5, 1 to 4 or 1 to 3 or 1 or 2) F atom substitution.

[0126] In one embodiment of the kinase inhibitor of formula (IIa), Hy, R2, R3, R4, A, E, L and R6 are independently as above (especially with respect to formula (Ia)) or hereinafter (especially defined with respect to formulas (IIIa), (IVa), (Va), (VIa), (VIIa) and / or (VIIIa)), and at least one of R7 is F and / or at least one of R7 is C1- 3 alkyl, wherein the alkyl of C1-3 alkyl is replaced by one or more (for example, 1 to the maximum number of hydrogen atoms combined with C1-3 alkyl, such as 1, 2, 3, 4, 5, 6, 7 or up to 6, eg 1 to 5, 1 to 4 or 1 to 3 or 1 or 2) F atom substitution.

[0127] In one embodiment of the kinase inhibitor of formula (IIa), Hy, R2, R3, R4, A, E, L and R6 are independently as above (especially with respect to formula (Ia)) or hereinafter (especially Defined with respect to formulas (IIIa), (IVa), (Va), (VIa), (VIIa) and / or (VIIIa)), and at least one of R7 is F and / or at least one of R7 is selected from - CH2F, -CHF2 and -CF3 are preferably selected from -CH2F and -CHF2.

[0128] In one embodiment of the kinase inhibitor of formula (IIa), Hy, R2, R3, R4, A, E, L and R6 are independently as above (especially with respect to formula (Ia)) or hereinafter especially with respect to defined by formula (IIIa), (IVa), (Va), (VIa), (VIIa) and / or (VIIIa)), and R6 is substituted by at least two R7, wherein one R7 is selected from -CH2F, -CHF2 and -CF3, one R7 is selected from halogen, -CH3, -CH2(hal), -CH(hal)2 and -C(hal)3, more preferably selected from Cl, Br, F, CH3, -CH2F, -CHF2 and -CF3. For example, in one embodiment, one R7 is selected from -CH2F, -CHF2 and -CF3, preferably selected from -CH2F and -CHF2, and one R7 is Cl. In an alternative embodiment, one R7 is F and one R7 is selected from halogen, -CH3, -CH2(hal), -CH(hal)2 and -C(hal)3, more preferably selected from Cl, Br, F , CH3, -CH2F, -CHF2 and -CF3; more preferably, one R7 is F and one R7 is Cl. In these embodiments, preferably one of the two R7 groups is attached to one of the C ring atoms at positions 2 and 5 relative to the ring atom to which R6 is bound to the remainder of the compound, and The other of these two R7 groups is attached to another C ring atom at positions 2 and 5 relative to the ring atom to which R6 is bound to the rest of the compound.

[0129] In one embodiment of the kinase inhibitor of formula (IIa), Hy, R2, R3, R4, A, L, and E are independently as above (especially with respect to formula (Ia)) or hereinafter (especially with respect to formula (IIIa), (IVa), (Va), (VIa), (VIIa) and / or (VIIIa)), and R6 is selected from: ,,,,,,, and, more preferably selected from: and, Or selected from: and, wherein in each case represents the bond of R6 to the rest of the compound.

[0130] In any of the above embodiments of the kinase inhibitor of formula (IIa) (including the kinase inhibitor of formula (Ia), L can be selected from the group consisting of a bond, C1-6 alkylene, C2-6 alkenylene, C2 -6 alkynylene and -(CH2)m-[Y-(CH2)n]o-, wherein m is 1, 2 or 3, n is 0, 1 or 2, and o is 1, 2 or 3, wherein, If n is 0, then o is 1; Y is independently selected from O, S and NH, wherein, C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, -(CH2)m- Each of the and -(CH2)n- groups is optionally substituted with one or two independently selected R30. For example, in any of the above embodiments of the kinase inhibitor of formula (IIa), including the kinase inhibitor of formula (la), L can be selected from: a bond; C1 alkylene, optionally substituted with one R30; C2 alkylene (especially 1,2-ethylene or 1,1-ethylene), optionally substituted by one R30; C3 alkylene (especially trimethylene), optionally substituted by one R30 ; C4 alkylene (especially tetramethylene or 2,4-butanediyl), optionally substituted by one R30, -(CH2)mO- and -(CH2)mNH-, where m is 1, 2 or 3. In particular, in any of the above embodiments of the kinase inhibitors of formula (IIa), including kinase inhibitors of formula (Ia), L can be selected from the group consisting of: a bond, C1 alkylene, optionally substituted with one R30; C2 Alkylene (especially 1,2-ethylene or 1,1-ethylene), optionally substituted by one R30, -(CH2)mO- and -(CH2)mNH-; preferably, L Can be selected from: bond, -(CH2)-, -(CH2)2-.

[0131] Optimally, in any of the above embodiments of the kinase inhibitor of formula (IIa), including kinase inhibitors of formula (la), L is a bond (ie, R5 is R6).

[0132] In one embodiment, the kinase inhibitor has the formula (IIIa): (IIIa) wherein in one embodiment of the kinase inhibitor of formula (IIa), Hy, R2, R3, R4, and R5 are independently as above (especially with respect to formula (Ia) and / or (IIa)) or as defined below (especially with respect to formula (IIIa), (IVa), (Va), (VIa), (VIIa) and / or (VIIIa)) , E is O or S (preferably O); and A is selected from S, O, NH, N(C1-6 alkyl) and C(C1-6 alkyl)2. In any of the above embodiments of the kinase inhibitor of formula (IIIa) (including the kinase inhibitors of formula (Ia) and formula (IIa), E is O or S (preferably O); A can be S, O or N(CH3)2. In any of the above embodiments of the kinase inhibitor of formula (IIIa), including kinase inhibitors of formula (Ia) and formula (IIa), preferably E is O or S (preferably O); and A is S . In any of the above embodiments of the kinase inhibitor of formula (Ilia), including kinase inhibitors of formula (Ia) and formula (IIa), preferably E is O; and A is S.

[0133] In one embodiment, the kinase inhibitor has the formula (IVa): (IVa) wherein Hy, R2, R4, R5, A and E are independently as above (especially with respect to formulas (Ia), (IIa) and / or (IIIa)) or as defined below (in particular with respect to formulas (IIIa), (IVa), (Va), (VIa), (VIIa) and / or (VIIIa)), and R3 is selected from H, C1- 6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, phenyl, halogen, -CN, azido, -NO2, -O(C1-6 alkyl), -OCF3 , -S (C1-6 alkyl), -NH2, -NH (C1-6 alkyl), -N (C1-6 alkyl) 2, -NHS (O) 2 (C1-6 alkyl), - S(O)2NH2-z(C1-6 alkyl) z, -C(=O)(C1-6 alkyl), -C(=O)OH, -C(=O)O(C1-6 alkane base), -C(=O)NH2-z(C1-6 alkyl)z, -NHC(=O)(C1-6 alkyl), -NHC(=NH)NHz-2(C1-6 alkyl ) z and -N (C1-6 alkyl) C (=NH) NH2-z (C1-6 alkyl) z, wherein z is 0, 1 or 2, and wherein C1-6 alkyl, C2-6 alkene Each of C2-6 alkynyl, C3-6 cycloalkyl and phenyl is optionally replaced by one or more (for example, 1 to C1-6 alkyl, C2-6 alkenyl, C2-6 The maximum number of hydrogen atoms bound to alkynyl, C3-6 cycloalkyl and phenyl, for example 1, 2, 3, 4, 5, 6, 7, 8, 9 or up to 10, for example 1 to 5, 1 to 4 or 1 to 3 or 1 or 2) independently selected R30 replacement.

[0134] In one embodiment of the kinase inhibitor of formula (IVa), Hy, R2, R4, R5, A and E are independently as above (especially with respect to formulas (Ia), (IIa) and / or (IIIa) ) or as defined below (especially with respect to formulas (IIIa), (IVa), (Va), (VIa), (VIIa) and / or (VIIIa)), and R3 is selected from H, C1-4 alkyl, C3 -6 cycloalkyl, phenyl, halogen, -CN, -O(C1-4 alkyl), -OCF3, -S(C1-4 alkyl), -NH2, -NH(C1-4 alkyl), -N(C1-4alkyl)2, -C(=O)(C1-4alkyl), -C(=O)OH, -C(=O)O(C1-4alkyl), -C (=O)NH2-z(C1-4 alkyl)z, -NHC(=O)(C1-4 alkyl), -NHC(=NH)NHz-2(C1-4 alkyl)z and -N (C1-4 alkyl) C (=NH) NH2-z (C1-4 alkyl) z, wherein, each of said C1-4 alkyl, C3-6 cycloalkyl and phenyl optionally One, two or three independently selected from halogen, methyl, isopropyl, -CN, -CF3, -OCF3, -OH, -NH2, -NH(C1-3 alkyl), -N(C1 -3 alkyl) 2, -NHC(=O)(C1-3 alkyl), -C(=O)NH2-z(C1-3 alkyl)z, -(CH2)1-3NH2, -(CH2 )1-3NH(C1-3 alkyl), -(CH2)1-3N(C1-3 alkyl)2, -(CH2)1-3OH and (CH2)1-3O(C1-3 alkyl) Group substitution; where z is 0, 1 or 2.

[0135] In one embodiment of the kinase inhibitor of formula (IVa), Hy, R2, R4, R5, A and E are independently as above (especially with respect to formulas (Ia), (IIa) and / or (IIIa) ) or (defined below in particular with respect to formulas (IIIa), (IVa), (Va), (VIa), (VIIa) and / or (VIIIa)), and R3 is selected from H, C1-4 alkyl, C3 -6 cycloalkyl, phenyl, halogen, -CN, -O(C1-4 alkyl), -OCF3, -S(C1-4 alkyl), -NH2, -NH(C1-4 alkyl), -N(C1-4alkyl)2, -C(=O)(C1-4alkyl), -C(=O)OH, -C(=O)O(C1-4alkyl), -C (=O)NH2-z(C1-4 alkyl)z, -NHC(=O)(C1-4 alkyl), -NHC(=NH)NHz-2(C1-4 alkyl)z and -N (C1-4alkyl)C(=NH)NH2-z(C1-4alkyl)z, wherein the phenyl is optionally substituted by one, two or three groups independently selected from: Halogen, methyl, isopropyl, -CN, -CF3, -OCF3, -OH, -NH2, -NH (C1-3 alkyl), -N (C1-3 alkyl) 2, -NHC (=O )(C1-3 alkyl), -C(=O)NH2-z(C1-3 alkyl)z, -(CH2)1-3NH2, -(CH2)1-3NH(C1-3 alkyl), -(CH2)1-3N(C1-3 alkyl)2, -(CH2)1-3OH and CH2)1-3O(C1-3 alkyl);

[0136] In one embodiment of the kinase inhibitor of formula (IVa), Hy, R2, R4, R5, A and E are independently as above (especially with respect to formulas (Ia), (IIa) and / or (IIIa) ) or as defined below (in particular with respect to formulas (IIIa), (IVa), (Va), (VIa), (VIIa) and / or (VIIIa)), and R3 is selected from H, methyl, ethyl, propyl radical, isopropyl, phenyl and halogen.

[0137] In one embodiment of the kinase inhibitor of formula (IVa), Hy, R2, R4, R5, A and E are independently as above (especially with respect to formulas (Ia), (IIa) and / or (IIIa) ) or as defined below (in particular with respect to formulas (IIIa), (IVa), (Va), (VIa), (VIIa) and / or (VIIIa)), and R3 is H.

[0138] In one embodiment, the kinase inhibitor has the formula (Va): (Va) wherein R2, R3, R4, R5, A and E are independently as above (in particular with respect to formulas (Ia), (IIa), (IIIa)) or as defined below (in particular with respect to formulas (IIIa), (IVa), (Va), (VIa), (VIIa) and / or (VIIIa)), Hy is a 3 to 10 membered heteroaryl or 3 to 10 membered heterocyclic groups, each of which is optionally replaced by one or more (for example, 1 to the maximum number of hydrogen atoms combined with a 3 to 10 membered heteroaryl group or a 3 to 10 membered heterocyclic group, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9 or up to 10, such as 1 to 5, 1 to 4, 1 to 3 or 1 or 2) independently selected R1e substitutions, wherein each R1e is independently is selected from R1a, R1b, R1c and R1d; and each of R1a, R1b, R1c and R1d is independently as above (especially with respect to formula (Ia)) or below (especially with respect to formula (IIIa), (IVa), (Va), (VIa), (VIIa) and / or (VIIIa)). For example, Hy may be selected from: 5 to 6 membered monocyclic heterocyclyl, 5 to 6 membered monocyclic heterocyclyl, 9 to 10 membered bicyclic heterocyclyl, and 8 to 10 membered bicyclic heterocyclyl, each of which is optionally ground by one or more (for example, 1 to 5 to 6 membered monocyclic heterocyclyl, 5 to 6 membered monocyclic heterocyclyl, 9 to 10 membered bicyclic heterocyclyl or 8 to 10 membered bicyclic heterocyclyl The maximum number of hydrogen atoms, such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, such as 1 to 5, 1 to 4, 1 to 3 or 1 or 2) independently selected R1e substitution , wherein each R1e is independently selected from R1a, R1b, R1c and R1d; and each of R1a, R1b, R1c and R1d is independently as above (especially with respect to formula (Ia)) or below especially with respect to formula (IIIa ), (IVa), (Va), (VIa), (VIIa) and / or (VIIIa)). Preferably, Hy is a heteroaryl or heterocyclyl comprising at least one N ring atom and optionally replaced by one or more (for example, 1 to the maximum number of hydrogen atoms bound to the heteroaryl or heterocyclyl , eg 1, 2, 3, 4, 5, 6, 7, 8, 9 or up to 10, eg 1 to 5, 1 to 4 or 1 to 3 or 1 or 2) independently selected R1e substitutions.

[0139] In one embodiment of the kinase inhibitor of formula (Va), R2, R3, R4, R5, A and E are independently as above (especially with respect to formulas (Ia), (IIa), (IIIa)) or as defined below (in particular with respect to formulas (IIIa), (IVa), (Va), (VIa), (VIIa) and / or (VIIIa)), and Hy is: wherein denotes the bond of Hy to the remainder of the compound, Thus the kinase inhibitor of formula (Va) has the formula (VIa): (VIa) wherein R1a, R1b and R1c are independently as above (especially with respect to formulas (Ia), (IIa), (IIIa)) or hereinafter especially defined with respect to formulas (IIIa), (IVa), (Va), (VIa), (VIIa) and / or (VIIIa)); and B is N or CR1d, wherein R1d is as above (in particular with respect to formula (Ia) ) or as defined below in particular with respect to formulas (IIIa), (IVa), (Va), (VIa), (VIIa) and / or (VIIIa)).

[0140] In one embodiment of the kinase inhibitor of formula (VIa), R1b, R1c, R2, R3, R4, R5, A, B and E are independently as above (especially with respect to formulas (Ia), (IIa) , (IIIa), (IVa) and / or (Va)) or as defined below (especially with respect to formulas (IIIa), (IVa), (Va), (VIa), (VIIa) and / or (VIIIa)) , and R1a is selected from alkyl, -O (alkyl), -S (alkyl), -NH (alkyl), -N (alkyl) 2 and heterocyclyl, wherein in alkyl and heterocyclyl Each is optionally represented by one or more (e.g., 1 to the maximum number of hydrogen atoms bonded to the alkyl or heterocyclyl group, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or at most 10, eg 1 to 5, 1 to 4 or 1 to 3 or 1 or 2) independently selected R30 substitutions. Preferably, one or more independently selected R30 optionally substituted for R1a are independently selected from primary substituents, secondary substituents and tertiary substituents specified herein; more preferably, R1a optionally substituted One or more independently selected R30 are independently selected from methyl, ethyl, -OH, =O, -OCH3, -SCH3, cyclopropyl, 2-hydroxyethyl, 2-(N,N-dimethylamine base) ethyl, 2-(N,N-dimethylamino)ethoxy, 2-(methoxy)ethoxy, 2-aminoethyl, 2-(N-methylamino)ethyl , 2-(methoxy) ethyl, 4-methyl piperazinyl, -C(=O)(C1-3 alkyl), -NHC(=O)(C1-3 alkyl), -N( C1 -3 alkyl)C(=O)(C1-3 alkyl), -NHS(O)2(C1-3 alkyl), -N(C1-3 alkyl)S(O)2(C1- 3 alkyl), -(CH2)1-3COOH and -NH2-z(CH3)z, wherein z is 0, 1 or 2; each of said C1-3 alkyl is optionally replaced by one or two Partial substitution independently selected from the following: -OH, -OCH3, -SCH3, cyclopropyl, piperazinyl, 4-methylpiperazinyl, 4-(2-hydroxyethyl)piperazinyl, 2-( N,N-Dimethylamino)ethoxy and -NH2-z(CH3)z, where z is 0, 1 or 2.

[0141] In one embodiment of the kinase inhibitor of formula (VIa), R1b, R1c, R2, R3, R4, R5, A, B and E are independently as above (especially with respect to formulas (Ia), (IIa) , (IIIa), (IVa) and / or (Va)) or as defined below (especially with respect to formulas (IIIa), (IVa), (Va), (VIa), (VIIa) and / or (VIIIa)) , and R1a is selected from C1-3 alkyl, -O (C1-3 alkyl), -S (C1-3 alkyl), -NH (C1-3 alkyl), -N (C1-3 alkyl) 2 and 3 to 11 membered heterocyclyl, wherein said 3 to 11 membered heterocyclyl is optionally substituted by one or two independently selected R30, wherein one or two independently selected R30 of R1a is optionally substituted independently selected from the primary substituents, secondary substituents and tertiary substituents specified herein; more preferably, one or more independently selected R30 optionally substituted for R1a are independently selected from methyl, ethyl, -OH, =O, -OCH3, -SCH3, cyclopropyl, 2-hydroxyethyl, 2-(N,N-dimethylamino)ethyl, 2-(N,N-dimethylamino)ethyl Oxy, 2-(methoxy)ethoxy, 2-aminoethyl, 2-(N-methylamino)ethyl, 2-(methoxy)ethyl, 4-methylpiperazinyl , -C(=O)(C1-3 alkyl), -NHC(=O)(C1-3 alkyl), -N(C1-3 alkyl)C(=O)(C1-3 alkyl) , -NHS(O)2(C1-3 alkyl), -N(C1-3 alkyl)S(O)2(C1-3 alkyl), -(CH2)1-3COOH and -NH2-z( CH3)z, wherein z is 0, 1 or 2; each of said C1-3 alkyl groups is optionally substituted by one or two moieties independently selected from: -OH, -OCH3, -SCH3, Cyclopropyl, piperazinyl, 4-methylpiperazinyl, 4-(2-hydroxyethyl)piperazinyl, 2-(N,N-dimethylamino)ethoxy and -NH2-z( CH3 )z, wherein z is 0,1 or 2.

[0142] In one embodiment of the kinase inhibitor of formula (VIa), R1b, R1c, R2, R3, R4, R5, A, B and E are independently as above (especially with respect to formulas (Ia), (IIa) , (IIIa), (IVa) and / or (Va)) or as defined below (especially with respect to formulas (IIIa), (IVa), (Va), (VIa), (VIIa) and / or (VIIIa)) , and R1a is selected from C1-3 alkyl, -O (C1-3 alkyl), -S (C1-3 alkyl), -NH (C1-3 alkyl), piperazinyl, piperidinyl, hexa Hexahydropyrimidinyl, hexahydropyridazinyl, morpholinyl, 1,2-oxazinyl, 1,3-oxazinyl, pyrrolidinyl, imidazole Pyridyl, pyrazolidinyl, diazepanyl, oxazepanyl, azaspirononyl, diazaspirononanyl, Azaspirodecyl, diazaspirodecyl, azaspiroundecyl and diazaspiroundecyl, of which piperazinyl, guanidine Pyridyl, hexahydropyrimidinyl, hexahydropyrimidinyl, morpholinyl, 1,2-oxazinyl, 1,3-oxazinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, diazepam Heptyl, Oxazepanyl, Azaspironyl, Diazaspironyl, Azaspirodecyl, Diazaspirodecyl, Azaspiroundecyl and diazaspiroundecyl are optionally substituted with one or two independently selected R30, wherein one or two independently selected R30 optionally substituting R1a are independently selected from the primary substituents specified herein, Secondary substituents and tertiary substituents; more preferably, one or more independently selected R30 optionally substituted for R1a are independently selected from methyl, ethyl, -OH, =O, -OCH3, -SCH3, Cyclopropyl, 2-hydroxyethyl, 2-(N,N-dimethylamino)ethyl, 2-(N,N-dimethylamino)ethoxy, 2-(methoxy)ethoxy Base, 2-aminoethyl, 2-(N-methylamino)ethyl, 2-(methoxy)ethyl, 4-methylpiperazinyl, -C(=O)(C1-3 alkane base), -NHC(=O)(C1-3 alkyl), -N(C1-3 alkyl)C(=O)(C1-3 alkyl), -NHS(O)2(C1-3 alkyl base), -N(C1-3 alkyl)S(O)2(C1-3 alkyl), -(CH2)1-3COOH and -NH2-z(CH3)z, where z is 0, 1 or 2 ; each of said C1-3 alkyl groups is optionally substituted by one or two moieties independently selected from: -OH, -OCH3, -SCH3, cyclopropyl, piperazinyl, 4-methyl Piperazinyl, 4-(2-hydroxyethyl)piperazinyl, 2-(N,N-dimethylamino)ethoxy and -NH2-z(CH3)z, where z is 0, 1 or 2 .

[0143] In one embodiment of the kinase inhibitor of formula (VIa), R1b, R1c, R2, R3, R4, R5, A, B and E are independently as above (especially with respect to formulas (Ia), (IIa) , (IIIa), (IVa) and / or (Va)) or as defined below (especially with respect to formulas (IIIa), (IVa), (Va), (VIa), (VIIa) and / or (VIIIa)) , and R1a is selected from -NH (C1-3 alkyl), piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl, diazepanyl, oxazepanyl and diazepine Zaspironyl, wherein each of piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl, diazepanyl, oxazepanyl and diazaspironyl is optionally substituted by one or two independently selected R30, wherein one or two independently selected R30 optionally substituting R1a are independently selected from methyl, -OH, =O, -OCH3, 2-hydroxyethyl, 2-(N,N-dimethylamino)ethyl, 2-(methoxy)ethoxy, -C(=O)(C1-3 alkyl), -NHC(=O)(C1-3 alkyl), -NHS(O)2(C1-3 alkyl) and -NH2-z(CH3)z, where z is 0, 1 or 2.

[0144] In one embodiment of the kinase inhibitor of formula (VIa), R1b, R1c, R2, R3, R4, R5, A, B and E are independently as above (especially with respect to formulas (Ia), (IIa) , (IIIa), (IVa) and / or (Va)) or as defined below (especially with respect to formulas (IIIa), (IVa), (Va), (VIa), (VIIa) and / or (VIIIa)) , and R1a is selected from 4-(2-hydroxyethyl)piperazinyl (4-(2-hydroxyethyl)piperazinyl), 4-methylpiperazinyl (4-methylpiperazinyl), 3,4-dimethylpiperazinyl Base (3,4-dimethylpiperazinyl), 4-methyl-1,4-diazepan-1-yl (4-methyl-1,4-diazepan-1-yl), 3-oxopiperazin-1- Base (3-oxopiperazin-1-yl), 2-methylmorpholin-4-yl (2-methylmorpholin-4-yl), 3-methylpiperazin-1-yl (3-methylpiperazin-1-yl) , 3-(2-hydroxyethyl)piperazin-1-yl (3-(2-hydroxyethyl)piperazin-1-yl), 3-(2-hydroxyethyl)-4-methylpiperazin-1- Base (3-(2-hydroxyethyl)-4-methylpiperazin-1-yl), 3-(dimethylamino) piperidin-1-yl (3-(dimethylamino)piperidin-1-yl), 3-(methylpiperazin-1-yl), 3-(methylpiperazin-1-yl) Oxy)piperidin-1-yl (3-(methoxy)piperidin-1-yl), 3-(hydroxy)piperidin-1-yl (3-(hydroxy)piperidin-1-yl), 3-(two Methylamino)pyrrolidin-1-yl (3-(dimethylamino)pyrrolidin-1-yl), 3-(hydroxy)pyrrolidin-1-yl (3-(hydroxy)pyrrolidin-1-yl), 3-( 2-methoxyethoxy)pyrrolidin-1-yl (3-(2-methoxyethoxy)pyrrolidin-1-yl), 3-(acetylamino)pyrrolidin-1-yl (3-(acetylamino) pyrrolidin-1-yl), 3-(methylsulfonylamino)pyrrolidin-1-yl (3-(methylsulfonylamino)pyrrolidin-1-yl), 7-methyl-2,7-diazaspiro [4.4] Keto-2-yl (7-methyl-2,7-diazaspiro[4.4]non-2-yl), 4-[2-(dimethylamino)ethyl]-1,4-diazaspiro Hepan-1-yl (4-[2-(dimethylamino)ethyl]-1,4-diazepan-1-yl), 4-(acetyl)-1,4-diazepan- 1-yl (4-(acetyl)-1,4-diazepan-1-yl), 5-oxo-1,4-diazepan-1-yl (5-oxo-1,4-diazepan -1-yl) and 1,4-oxazepan-4-yl (1,4-oxazepan-4-yl).

[0145] In any of the above embodiments of the kinase inhibitor of formula (VIa), including kinase inhibitors of formula (Ia), (IIa), (IIa), (IVa) and / or (Va), R1a Can be asymmetric. For example, R1a may be selected from the group consisting of: , , , , , , and, wherein R30 and X are as defined herein; and represent the bond by which the R1a group is bound to the rest of the compound. In one embodiment, R1a is asymmetric and is selected from 3,4-dimethylpiperazinyl, 4-methyl-1,4-diazepin-1-yl, 3-oxopiperazine-1 -yl, 2-methylmorpholin-4-yl, 3-methylpiperazin-1-yl, 3-(2-hydroxyethyl)piperazin-1-yl, 3-(2-hydroxyethyl) -4-Methylpiperazin-1-yl, 3-(dimethylamino)piperidin-1-yl, 3-(methoxy)piperidin-1-yl, 3-(hydroxyl)piperidin-1 -yl, 3-(dimethylamino)pyrrolidin-1-yl, 3-(hydroxyl)pyrrolidin-1-yl, 3-(2-methoxyethoxy)pyrrolidin-1-yl, 3 -(Acetamido)pyrrolidin-1-yl, 3-(methylsulfonamido)pyrrolidin-1-yl, 7-methyl-2,7-diazaspiro[4.4]one-2- Base, 4-[2-(dimethylamino)ethyl]-1,4-azepan-1-yl, 4-(acetyl)-1,4-diazepan- 1-yl, 5-oxo-1,4-diazepan-1-yl, and 1,4-oxazepan-4-yl.

[0146] In any of the above embodiments of the kinase inhibitors of formula (VIa) (including kinase inhibitors of formula (Ia), (IIa), (IIa), (IVa) and / or (Va), R1a and the compound The R1a atom combined with the rest of the compound may be an atom other than C; preferably, the R1a atom combined with the rest of the compound is an N atom. In this embodiment, R1a is preferably selected from heterocyclic group, heterocyclic aryl group, -OR11, -N(R12)(R13), -N(R11)(OR11), -S(O)0-2R11 , -S(O)1-2OR11, -OS(O)1-2R11, -OS(O)1-2OR11, -S(O)1-2N(R12)(R13), -OS(O)1- 2N(R12)(R13), -N(R11)S(O)1-2R11, -NR11S(O)1-2OR11, -NR11S(O)1-2N(R12)(R13), -P(O) (OR11)2, -OP(O)(OR11)2, -XC(=X)R11, and -XC(=X)XR11, where each of the heterocyclyl and heteroaryl passes through an atom other than C Combined with the rest of the compound, and optionally replaced by one or more (for example, 1 to the maximum number of hydrogen atoms bound to the heterocyclyl or heteroaryl, such as 1, 2, 3, 4, 5, 6, 7 , 8, 9 or up to 10, eg 1 to 5, 1 to 4, or 1 to 3, or 1 or 2) independently selected R30 substitutions. For example, Rla can be a heterocyclyl group that contains at least one N ring atom and is bonded to the remainder of the compound via the N ring atom.

[0147] In one embodiment of the kinase inhibitor of formula (VIa), R1b, R1c, R2, R3, R4, R5, A, B and E are independently as above (especially with respect to formulas (Ia), (IIa) , (IIIa), (IVa) and / or (Va)) or as defined below, and R1a is selected from: ,,,,,,,,,,,,,,,,,,,,,,, and, where R1a A bond that binds to the rest of the compound. Preferably R1a is selected from the group consisting of: , , , , and , wherein it represents the bond of R1a to the rest of the compound.

[0148] In any of the above embodiments of the kinase inhibitors of formula (VIa), including kinase inhibitors of formula (Ia), (IIa), (IIa), (IVa) and / or (Va), R1b and R1c Can be independently selected from H, methyl, ethyl, propyl, isopropyl, -OH, -OCH3, -SCH3, cyclopropyl, 2-hydroxyethyl, 2-(N,N-dimethylamino ) ethyl, 2-(N,N-dimethylamino)ethoxy, 2-aminoethyl, 2-(N-methylamino)ethyl, 2-(methoxy)ethyl,- NH2-z(CH3)z, phenyl, pyridyl, pyrazolyl, phenoxy, pyridyloxy, imidazolylamine and tetrahydrofuranmethoxy, wherein z is 0, 1 or 2; and phenyl, pyridine Each of pyrazolyl, phenoxy, pyridyloxy, imidazolylamino and tetrahydrofuranmethoxy is optionally substituted with one, two or three 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)ethyl Oxy, 2-aminoethyl, 2-(N-methylamino)ethyl, 2-(methoxy)ethyl, and -NH2-z(CH3)z, where z is 0, 1 or 2. Preferably, at least one of R1b and R1c is selected from H, methyl, ethyl, propyl, isopropyl, -OH, -OCH3, -SCH3, cyclopropyl, 2-hydroxyethyl, 2-( N,N-dimethylamino)ethyl, 2-(N,N-dimethylamino)ethoxy, 2-aminoethyl, 2-(N-methylamino)ethyl, 2-( methoxy)ethyl, -NH2-z(CH3)z and phenyl, wherein z is 0, 1 or 2; in one embodiment, R1b is H; R1c is methyl, ethyl, propyl, iso Propyl or phenyl, preferably methyl. In another embodiment, R1b is methyl, ethyl, propyl or isopropyl, preferably methyl; R1c is H.

[0149] In any of the above embodiments of the kinase inhibitor of formula (VIa), including kinase inhibitors of formula (Ia), (IIa), (IIa), (IVa) and / or (Va), wherein The R1C atom to which R1C is bound to the rest of the compound may be a C atom. In this embodiment, preferably R1c is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -CF3, -CN, -C(=O)(C1-6 alkyl) , -C(=O)OH, -C(=O)O(C1-6 alkyl) and -C(=O)NH2-z(C1-6 alkyl)z, where z is 0, 1 or 2 And each of C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl is optionally substituted by one, two or three moieties independently selected from: -OH, methyl, ethyl , -OCH3, -SCH3 and -NH2-z(CH3)z.

[0150] In any of the above embodiments of the kinase inhibitor of formula (VIa), including kinase inhibitors of formula (Ia), (IIa), (IIa), (IVa) and / or (Va), B is N or CR1d, wherein R1d can be selected from C1-3 alkyl, halogen, -O(C1-3 alkyl), -S(C1-3 alkyl), -NH(C1-3 alkyl) and -N (C1-3 alkyl)2, wherein C1-3 alkyl is optionally substituted by one or two moieties independently selected from: halogen, -OH, -OCH3, -SCH and -NH2-z(CH3) z, where z is 0, 1 or 2. In any of the above embodiments of the kinase inhibitor of formula (VIa), including kinase inhibitors of formula (Ia), (IIa), (IIa), (IVa) and / or (Va), B is N or CR1d, wherein R1d can be selected from: C1-3 alkyl, halogen, -O(C1-3 alkyl), -S(C1-3 alkyl), -NH(C1-3 alkyl) and -N(C1 -3 alkyl) 2.

[0151] In any of the above embodiments of the kinase inhibitor of formula (VIa), including kinase inhibitors of formula (Ia), (IIa), (IIa), (IVa) and / or (Va), the most Good B is N.

[0152] In one embodiment, the kinase inhibitor has the general formula (VIIa) or (VIIIa): (VIIa) (VIIIa) wherein Hy, R1a, R1b, R1c, R2, R3, R4, R5, A, B and E is independently as defined above (in particular with respect to formulas (Ia), (IIa), (Ilia), (IVa), (Va) and / or (VIa)) or below and L is a bond. In a preferred embodiment of the kinase inhibitor having general formula (VIIa) or (VIIIa): (A) R1a is selected from the group consisting of alkyl, -O(alkyl), -S(alkyl), -NH(alkyl ), -N(alkyl)2 and heterocyclyl, preferably a heterocyclyl bonded to the rest of the compound through an atom other than C, wherein each of the alkyl and heterocyclyl is optionally replaced by one or more (for example, 1 to the maximum number of hydrogen atoms bonded to an alkyl or heterocyclic group, such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or up to 10, such as 1 to 5, 1 to 4. 1 to 3 or 1 or 2) independently selected R30 substitutions, wherein, preferably, R30 is independently selected from methyl, ethyl, -OH, =O, -OCH3, -SCH3, cyclopropyl, 2 -Hydroxyethyl, 2-(N,N-dimethylamino)ethyl, 2-(N,N-dimethylamino)ethoxy, 2-(methoxy)ethoxy, 2-amine Ethyl, 2-(N-methylamino)ethyl, 2-(methoxy)ethyl, 4-methylpiperazinyl, -C(=O)(C1-3 alkyl), -NHC (=O)(C1-3 alkyl), -N(C1-3 alkyl)C(=O)(C1-3 alkyl), -NHS(O)2(C1-3 alkyl), -N (C1-3 alkyl) S (O) 2 (C1-3 alkyl), - (CH2) 1-3COOH and -NH2-z (CH3) z, wherein z is 0, 1 or 2; The C1- Each of the 3 alkyl groups is optionally substituted with one or two moieties independently selected from the group consisting of -OH, -OCH3, -SCH3, cyclopropyl, piperazinyl, 4-methylpiperazinyl, 4 -(2-hydroxyethyl)piperazinyl, 2-(N,N-dimethylamino)ethoxy and -NH2-z(CH3)z, wherein z is 0, 1 or 2; and / or ( B) Each of R1b and R1c is independently selected from: H, methyl, ethyl, propyl, isopropyl, -OH, -OCH3, -SCH3, cyclopropyl, 2-hydroxyethyl, 2- (N,N-Dimethylamino)ethoxy, 2-aminoethyl, 2-(N-methylamino)ethyl, 2-(methoxy)ethyl, -NH2-z(CH3) z, phenyl, pyridyl, pyrazolyl, phenoxy, pyridyloxy, imidazolylamino and tetrahydrofuranmethoxy, wherein z is 0, 1 or 2; said phenyl, pyridyl, pyrazolyl Each of , phenoxy, pyridyloxy, imidazolylamino and tetrahydrofuranmethoxy is optionally substituted with one, two or three 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 and -NH2-z(CH3)z, wherein z is 0, 1 or 2; preferably, wherein One of R1b and R1c is H; and the other of R1b and R1c is methyl, ethyl, propyl, isopropyl or phenyl, more preferably, the other of R1b and R1c is methyl; and / or (C) R3 is selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, phenyl, halogen, -CN, azido, -NO2, -O (C1-6 alkyl), -OCF3, -S (C1-6 alkyl), -NH2, -NH (C1-6 alkyl), -N (C1-6 alkyl) 2, -NHS ( O)2(C1-6 alkyl), -S(O)2NH2-z(C1-6 alkyl)z, -C(=O)(C1-6 alkyl), -C(=O)OH, -C(=O)O(C1-6 alkyl), -C(=O)NH2-z(C1-6 alkyl)z, -NHC(=O)(C1-6 alkyl), -NHC( =NH)NHz-2(C1-6 alkyl)z and -N(C1-6 alkyl)C(=NH)NH2-z(C1-6 alkyl)z, wherein z is 0, 1 or 2; And wherein each of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl and phenyl is optionally substituted by one or more independently selected R30, preferably , wherein R3 is H; and / or (D) at least one of R7 is F and / or at least one of R7 is selected from alkyl, OR11 and -N(R12)(R13), wherein said alkyl and R11 Each of the groups and at least one of the R12 and R12 groups are substituted by one or more F atoms; and / or (E) A is selected from S, O, NH, N(C1-6 alkyl) and C(C1-6 alkyl)2, wherein preferably A is S; and / or (F) B is N or CR1d, wherein R1d is selected from C1-3 alkyl, halogen, -O(C1-3 alkane group), -S(C1-3 alkyl), -NH(C1-3 alkyl) and -N(C1-3 alkyl) 2, wherein each of the C1-3 alkyl is optionally replaced by one or Two partial substitutions independently selected from: halogen, -OH, -OCH3, -SCH and -NH2-z(CH3)z, wherein z is 0, 1 or 2, preferably B is N; and / or (G) E is O or S, preferably O.

[0153] In a preferred embodiment of the kinase inhibitor having general formula (VIIa) or (VIIIa), R1a is as described above in (A); R1b and R1c are as defined above in (B); R3 is as above (C); R7 is as defined above in (D), wherein R6 is as defined above (especially with respect to formula (IIa)); A is as described above in (E); B is as described above in (F); E As described in (G) above.

[0154] In a further preferred embodiment, the kinase inhibitor has the general formula (VIIa) or (VIIIa): (A') R1a is selected from C1-3 alkyl, -O(C1-3 alkyl), -S (C1-3 alkyl), -NH(C1-3 alkyl), -N(C1-3 alkyl)2 and 3 to 11 membered heterocyclyl, preferably bonded to the rest of the compound through an atom other than C wherein the 3 to 11 membered heterocyclyl is optionally substituted by one or two independently selected R30, wherein one or two independently selected R30 optionally substituting R1a are independently selected from methyl, Ethyl, -OH, =O, -OCH3, -SCH3, cyclopropyl, 2-hydroxyethyl, 2-(N,N-dimethylamino)ethyl, 2-(N,N-dimethylamine base) ethoxy, 2-(methoxy)ethoxy, 2-aminoethyl, 2-(N-methylamino)ethyl, 2-(methoxy)ethyl, 4-methyl Piperazinyl, -C(=O)(C1-3 alkyl), -NHC(=O)(C1-3 alkyl), -N(C1-3 alkyl)C(=O)(C1-3 Alkyl), -NHS(O)2(C1-3alkyl), -N(C1-3alkyl)S(O)2(C1-3alkyl), -(CH2)1-3COOH and -NH2 -z(CH3)z, wherein z is 0, 1 or 2; each of said C1-3 alkyl groups is optionally substituted by one or two moieties independently selected from: -OH, -OCH3, -SCH3, cyclopropyl, piperazinyl, 4-methylpiperazinyl, 4-(2-hydroxyethyl)piperazinyl, 2-(N,N-dimethylamino)ethoxy and -NH2 -z(CH3)z, wherein z is 0, 1 or 2; and / or (B') at least one of R1b and R1c is selected from: H, methyl, ethyl, propyl, isopropyl, -OH , -OCH3, -SCH3, cyclopropyl, 2-hydroxyethyl, 2-(N,N-dimethylamino)ethoxy, 2-aminoethyl, 2-(N-methylamino)ethyl radical, 2-(methoxy)ethyl, -NH2-z(CH3)z and phenyl, wherein z is 0, 1 or 2, and the other of R1b and R1c is as defined in (B) above, relatively Preferably one of R1b and R1c is H; and the other of R1b and R1c is methyl, ethyl, propyl, isopropyl or phenyl, more preferably, the other of R1b and R1c is methyl and / or (C') R3 is selected from H, C1-4 alkyl, C3-6 cycloalkyl, phenyl, halogen, -CN, -O(C1-4 alkyl), -OCF3, -S (C1-4 alkyl), -NH2, -NH (C1-4 alkyl), -N (C1-4 alkyl) 2, -C (=O) (C1-4 alkyl), -C (= O)OH, -C(=O)O(C1-4 alkyl), -C(=O)NH2-z(C1-4 alkyl)z, -NHC(=O)(C1-4 alkyl) , -NHC(=NH)NHz-2(C1-4 alkyl)z and -N(C1-4 alkyl)C(=NH)NH2-z(C1-4 alkyl)z, wherein the phenyl Optionally substituted with one, two or three groups independently selected from the group consisting of halogen, methyl, isopropyl, -CN, -CF3, -OCF3, -OH, -NH2, -NH(C1- 3 alkyl), -N(C1-3 alkyl) 2, -NHC(=O)(C1-3 alkyl), -C(=O)NH2-z(C1-3 alkyl), -(CH2 )1-3NH2, -(CH2)1-3NH(C1-3 alkyl), -(CH2)1-3N(C1-3 alkyl)2, -(CH2)1-3OH and -(CH2)1- 3O(C1-3 alkyl); wherein z is 0, 1 or 2, wherein preferably R3 is H; and / or (D') at least one of R7 is F and / or at least one of R7 is selected From C1-3 alkyl, -O (C1-3 alkyl), -NH (C1-3 alkyl) or -N (C1-3 alkyl) 2, wherein C1-3 alkyl, -NH (C1- 3 alkyl) and -O(C1-3 alkyl) and at least one alkyl of -N(C1-3 alkyl)2 is substituted by one or more F atoms; (E') A is S, O or N(CH3)2, wherein preferably A is S; and / or (F')B is N or CR1d, wherein R1d is selected from C1-3 alkyl, halogen, -O(C1-3 alkyl) , -S(C1-3 alkyl), -NH(C1-3 alkyl) and -N(C1-3 alkyl)2, preferably B is N; and / or (G') E is O or S, preferably O.

[0155] In preferred embodiments of the kinase inhibitor of general formula (VIIa) or (VIIIa), R1a is as described above in (A'); R1b and R1c are as defined above in (B'); R3 As described above in (C'); R7 as defined above in (D'), wherein R6 is as defined above (especially with respect to formula (IIa)); A as described above in (E'); B as described above in (F ') as described above; E as described above (G').

[0156] In a further preferred embodiment, the kinase inhibitor has the general formula (VIIa) or (VIIIa): (A'') R1a is a heterocyclic group bonded to the rest of the compound through an atom other than C, wherein The 3- to 11-membered heterocyclyl is optionally substituted by one or two independently selected R30, wherein one or two independently selected R30 optionally substituting R1a are independently selected from methyl, ethyl, -OH, =O, -OCH3, -SCH3, cyclopropyl, 2-hydroxyethyl, 2-(N,N-dimethylamino)ethyl, 2-(N,N-dimethylamino)ethoxy, 2-(methoxy)ethoxy, 2-aminoethyl, 2-(N-methylamino)ethyl, 2-(methoxy)ethyl, 4-methylpiperazinyl, -C (=O)(C1-3 alkyl), -NHC(=O)(C1-3 alkyl), -N(C1-3 alkyl)C(=O)(C1-3 alkyl), -NHS (O)2(C1-3 alkyl), -N(C1-3 alkyl)S(O)2(C1-3 alkyl), -(CH2)1-3COOH and -NH2-z(CH3)z , wherein z is 0, 1 or 2; and each of the C1-3 alkyl groups is optionally substituted by one or two moieties independently selected from: -OH, -OCH3, -SCH3, cyclopropyl, Piperazinyl, 4-methylpiperazinyl, 4-(2-hydroxyethyl)piperazinyl, 2-(N,N-dimethylamino)ethoxy and -NH2-z(CH3)z, wherein z is 0, 1 or 2; and / or (B'') one of R1b and R1c is H; the other of R1b and R1c is methyl, ethyl, propyl, isopropyl or phenyl, More preferably the other of R1b and R1c is methyl; and / or (C'') R3 is H; and / or (D'') at least one of R7 is F and / or at least one of R7 is selected from C1-3 alkyl, -O(C1-3 alkyl), -NH(C1-3 alkyl) or -N(C1-3 alkyl)2, wherein C1-3 alkyl, -NH(C1-3 Alkyl) and -O(C1-3 alkyl) and at least one alkyl of -N(C1-3 alkyl)2 is substituted by one or more F atoms; (E'') A is S; and / or (F'') B is N; and / or (G'') E is O.

[0157] In a preferred embodiment of the kinase inhibitor of general formula (VIIa) or (VIIIa), R1a is as described above in (A''); R1b and R1c are as defined in (B'') above ; R3 is as above (C''); R7 is as above (D''), wherein R6 is as above (especially with respect to formula (IIa)); A is as above (E''); B is as described above (F''); E is as described above (G'').

[0158] In a further preferred embodiment, the kinase inhibitor has general formula (VIIa) or (VIIIa) (especially when R1a, R1b, R1c, R3, A, B and E are as above (A), (B) , (C), (E), (F) and / or (G), or (A'), (B'), (C'), (E'), (F') and / or ( G'), or (A''), (B''), (C''), (E''), (F'') and / or (G'')), a R7 is selected from -CH2F, -CHF2 and -CF3, preferably selected from -CH2F and -CHF2.

[0159] In a further preferred embodiment, the kinase inhibitor has general formula (VIIa) or (VIIIa) (especially when R1a, R1b, R1c, R3, A, B and E are as above (A), (B) , (C), (E), (F) and / or (G), or (A'), (B'), (C'), (E'), (F') and / or ( G'), or (A''), (B''), (C''), (E''), (F'') and / or (G'')), a R7 (preferably R7 of F and / or R7 substituted by one or more F atoms) is attached to the C ring atom at position 2 or 5 relative to the ring atom to which R6 is bound to the remainder of the compound.

[0160] In a further preferred embodiment, the kinase inhibitor has general formula (VIIa) or (VIIIa) (especially when R1a, R1b, R1c, R3, A, B and E are as above (A), (B) , (C), (E), (F) and / or (G), or (A'), (B'), (C'), (E'), (F') and / or ( G'), or (A''), (B''), (C''), (E''), (F'') and / or (G'')), R6 Replaced by at least two R7. For example, R6 may be replaced by two R7 different from each other.

[0161] In a further preferred embodiment, the kinase inhibitor has general formula (VIIa) or (VIIIa) (especially when R1a, R1b, R1c, R3, A, B and E are as above (A), (B) , (C), (E), (F) and / or (G), or (A'), (B'), (C'), (E'), (F') and / or ( G'), or (A''), (B''), (C''), (E''), (F'') and / or (G'')), R6 Substituted by at least two R7, of which one R7 (preferably R7 of F and / or R7 substituted by one or more F atoms) at positions 2 and 5 relative to the ring atom to which R6 is bound to the remainder of the compound Attached to one C ring atom, one R7 is attached to another C ring atom at positions 2 and 5 relative to the ring atom to which R6 is bound to the remainder of the compound.

[0162] In a further preferred embodiment, the kinase inhibitor has general formula (VIIa) or (VIIIa) (especially when R1a, R1b, R1c, R3, A, B and E are as above (A), (B) , (C), (E), (F) and / or (G), or (A'), (B'), (C'), (E'), (F') and / or ( G'), or (A''), (B''), (C''), (E''), (F'') and / or (G'')), R6 Substituted by at least two R7, wherein one R7 is selected from -CH2F, -CHF2 and -CF3, and one R7 is selected from halogen, -CH3, -CH2(hal), -CH(hal)2 and -C(hal)3 , more preferably selected from Cl, Br, F, -CH3, -CH2F, -CHF2 and -CF3. In one embodiment, one R7 is selected from -CH2F, -CHF2 and -CF3, preferably selected from -CH2F and -CHF2, and one R7 is Cl. In an alternative embodiment, one R7 is F, and one R7 is selected from halogen, -CH3, -CH2(hal), -CH(hal)2 and -C(hal)3, more preferably selected from Cl, Br, F, -CH3, -CH2F, -CHF2, and -CF3. In this alternative embodiment, preferably one R7 is F and one R7 is Cl.

[0163] In a further preferred embodiment, the kinase inhibitor has general formula (VIIa) or (VIIIa) (especially when R1a, R1b, R1c, R3, A, B and E are as above (A), (B) , (C), (E), (F) and / or (G), or (A'), (B'), (C'), (E'), (F') and / or ( G'), or (A''), (B''), (C''), (E''), (F'') and / or (G'')), R6 Selected from thienyl, thiazolyl and thiadiazolyl, preferably selected from thienyl and thiazolyl, more preferably R6 is thienyl, wherein each of thienyl, thiazolyl and thiadiazolyl is replaced by one or more (eg, 1 to the maximum number of hydrogen atoms bound to thienyl, thiazolyl or thiadiazolyl, eg 1, 2 or 3, eg 1 or 2) independently selected R7 substitutions.

[0164] In a further preferred embodiment, the kinase inhibitor has general formula (VIIa) or (VIIIa) (especially when R1a, R1b, R1c, R3, A, B and E are as above (A), (B) , (C), (E), (F) and / or (G), or (A'), (B'), (C'), (E'), (F') and / or ( G'), or (A''), (B''), (C''), (E''), (F'') and / or (G'')), R6 The R6 ring atom bound to the rest of the compound is a C atom.

[0165] In a further preferred embodiment, the kinase inhibitor has general formula (VIIa) or (VIIIa) (especially when R1a, R1b, R1c, R3, A, B and E are as above (A), (B) , (C), (E), (F) and / or (G), or (A'), (B'), (C'), (E'), (F') and / or ( G'), or (A''), (B''), (C''), (E''), (F'') and / or (G'')), R6 The S ring atom of is not adjacent to the ring atom to which R6 is bound to the rest of the compound.

[0166] In a further preferred embodiment, the kinase inhibitor has general formula (VIIa) or (VIIIa) (especially when R1a, R1b, R1c, R3, A, B and E are as above (A), (B) , (C), (E), (F) and / or (G), or (A'), (B'), (C'), (E'), (F') and / or ( G'), or (A''), (B''), (C''), (E''), (F'') and / or (G'')), where R6 is selected from: , , , , , , and, preferably selected from: and, wherein it represents the bond between R6 and the rest of the compound. Any of the kinase inhibitors of formula (VIIa) or (VIIIa) above (including those of formula (Ia), (IIa), (IIIa), (IVa), (Va) and / or (VIa)) In an embodiment, R1a can be selected from -NH (C1-3 alkyl), piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl, diazepanyl, oxazepanyl and diazaspirone groups, of which piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl, diazepanyl, oxazepanyl and diazaspironyl Each is optionally substituted with one or two independently selected R30, wherein one or two independently selected R30 optionally substituting R1a are independently selected from methyl, -OH, =O, -OCH3, 2-hydroxy Ethyl, 2-(N,N-dimethylamino)ethyl, 2-(methoxy)ethoxy, -C(=O)(C1-3 alkyl), -NHC(=O)( C1-3 alkyl), -NHS(O)2(C1-3 alkyl), and -NH2-z(CH3)z, where z is 0, 1 or 2. For example, R1a may be selected from 4-(2-hydroxyethyl)piperazinyl, 4-methylpiperazinyl, 3,4-dimethylpiperazinyl, 4-methyl-1,4-diazepine Nitrogen-1-yl, 3-oxopiperazin-1-yl, 2-methylmorpholin-4-yl, 3-methylpiperazin-1-yl, 3-(2-hydroxyethyl)piperazine- 1-yl, 3-(2-hydroxyethyl)-4-methylpiperazin-1-yl, 3-(dimethylamino)piperidin-1-yl, 3-(methoxy)piperidine- 1-yl, 3-(hydroxy)piperidin-1-yl, 3-(dimethylamino)pyrrolidin-1-yl, 3-(hydroxyl)pyrrolidin-1-yl, 3-(2-methoxy ethoxy)pyrrolidin-1-yl, 3-(acetylamino)pyrrolidin-1-yl, 3-(methylsulfonamido)pyrrolidin-1-yl, 7-methyl-2 ,7-diazaspiro[4.4]keto-2-yl, 4-[2-(dimethylamino)ethyl]-1,4-diazepan-1-yl, 4-( Acetyl)-1,4-diazepan-1-yl, 5-oxo-1,4-diazepan-1-yl and 1,4-oxazepan-1-yl Alk-4-yl.

[0168] In the above formula (VIIa) or (VIIIa) (including those of formula (Ia), (IIa), (IIIa), (IVa), (Va) and / or (VIa), especially when R1a, R1b , R1c, R3, A, B and E are as described above in (A), (B), (C), (E), (F) and / or (G), or (A'), (B') , (C'), (E'), (F') and / or (G'), or (A''), (B''), (C''), (E''), In any embodiment of the kinase inhibitor described in (F'') and / or (G''), R1a may be asymmetric.

[0169] In the above formula (VIIa) or (VIIIa) (including those of formula (Ia), (IIa), (IIIa), (IVa), (Va) and / or (VIa), especially when R1a, R1b , R1c, R3, A, B and E are as described above in (A), (B), (C), (E), (F) and / or (G), or (A'), (B') , (C'), (E'), (F') and / or (G'), or (A''), (B''), (C''), (E''), (F'') and / or (G'') In any embodiment of the kinase inhibitor, the R1a atom that binds R1a to the rest of the compound may be an atom other than C; preferably, make The atom of R1a to which R1a is bound to the rest of the compound is an N atom.

[0170] In the above formula (VIIa) or (VIIIa) (including those of formula (Ia), (IIa), (IIIa), (IVa), (Va) and / or (VIa), especially when R1a, R1b , R1c, R3, A, B and E are as described above in (A), (B), (C), (E), (F) and / or (G), or (A'), (B') , (C'), (E'), (F') and / or (G'), or (A''), (B''), (C''), (E''), In any embodiment of the kinase inhibitor described in (F'') and / or (G''), the R1c atom that binds R1c to the rest of the compound may be a C atom.

[0171] In the above formula (VIIa) or (VIIIa) (including those of formula (Ia), (IIa), (IIIa), (IVa), (Va) and / or (VIa)), preferably R1b ​​is H; and R1c is methyl, ethyl, propyl, isopropyl or phenyl, preferably methyl.

[0172] In the above formula (VIIa) or (VIIIa) (including those of formula (Ia), (IIa), (IIIa), (IVa), (Va) and / or (VIa)), preferably A is S; B is N; and / or E is O.

[0173] More preferably, the above 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.

[0174] In the above formula (VIIa) or (VIIIa) (including those of formula (Ia), (IIa), (IIIa), (IVa), (Va) and / or (VIa)), R3 is preferably selected from From the following: H, methyl, ethyl, propyl, isopropyl, phenyl and halogen; more preferably, R3 is H.

[0175] In one embodiment, the compound of the invention is selected from the compounds shown in Figure IE.

[0176] In the context of the fifth aspect, the application provides a compound or a pharmaceutical composition for treating a proliferative disease in a subject, the treatment comprising administering the compound or the pharmaceutical composition to the subject, wherein the compound (a) a compound of the first aspect; (b) a compound of formula (Ib) below; and (c) a compound of formula (Ic) below, or, the pharmaceutical composition comprises said compound and optionally a pharmaceutical Acceptable excipients above: (Ib) and solvates, salts, N-oxides, complexes, polymorphs, crystal forms, racemic mixtures, diastereoisomers, enantiomers Compounds, tautomers, conformers, isotopically labeled forms, prodrugs, and combinations thereof, wherein Hy, R2, R3, R4, A and E are independently as above (especially with respect to formula (Ia), ( IIIa), (IVa), (Va), (VIa), (VIIa) and / or (VIIIa)) or as defined below; R5' is -L-R6'; L is a bond; R6' is optionally 5- or 6-membered heteroaryl substituted by one or more independently selected R7'; R7' independently selected from R7, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl , Halogen, -CN, Azido, -NO2, -OR11, -N(R12)(R13), -N(R11)(OR11), -S(O)0-2R11, -S(O)1- 2OR11, -OS(O)1-2R11, -OS(O)1-2OR11, -S(O)1-2N(R12)(R13), -OS(O)1-2N(R12)(R13), - N(R11)S(O)1-2R11, -NR11S(O)1-2OR11, -NR11S(O)1-2N(R12)(R13), -P(O)(OR11)2, -OP( O )(OR11)2, -C(=X)R11, -C(=X)XR11, -XC(=X)R11 and -XC(=X)XR11, where alkyl, alkenyl, alkynyl, ring Each of alkyl, aryl, heterocyclyl and heteroaryl is optionally substituted by one or more independently selected R30; and R11, R12, R13, X and R30 are independently as defined above (in particular With respect to formula (Ia)); (Ic) and solvates, salts, N-oxides, complexes, polymorphs, crystal forms, racemic mixtures, diastereomers, enantiomers , tautomers, conformers, isotopically labeled forms, prodrugs, and combinations thereof, wherein R1a, R1b, R1c, R2, R3, R4, A, B and E are independently as above (especially with respect to formula (Ia), (IIIa), (IVa), (Va), (VIa), (VIIa) and / or (VIIIa)) or as defined below; R5' is -L-R6'; L is as above (especially with respect to formula (Ia) and / or (IIa)); R6' is heteroaryl or heterocyclyl optionally substituted by one or more independently selected R7'; R7' is independently selected from R7, alkyl , alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, halogen, -CN, azido, -NO2, -OR11, -N(R12)(R13), -N(R11 )( OR11), -S(O)0-2R11, -S(O)1-2OR11, -OS(O)1-2R11, -OS(O)1-2OR11, -S(O)1-2N( R12) (R13), -OS(O)1-2N(R12)(R13), -N(R11)S(O)1-2R11, -NR11S(O)1-2OR11, -NR11S(O)1- 2N(R12)(R13), -P(O)(OR11)2, -OP(O)(OR11)2, -C(=X)R11, -C(=X)XR11, -XC(=X) R11 and -XC(=X)XR11, and / or any two R7' bonded to the same atom of R6'' as a heterocyclyl group can be combined to form =O, where alkyl, alkenyl, alkynyl , cycloalkyl, aryl, heterocyclyl and heteroaryl are optionally substituted by one or more independently selected R30; and R11, R12, R13, X and R30 are independently as defined above ( Especially with respect to formula (Ia)).

[0177] In one embodiment, the compound of formula (Ib) according to the particular use of the fifth aspect has the general formula (IIb) (IIb) wherein Hy, R2, R3, R4, A and E are independently as above (in particular With respect to formula (Ib), (IIIa), (IVa), (Va), (VIa), (VIIa) and / or (VIIIa)) or as defined below (especially with respect to formula (IIIb)); R6' is any Optionally replaced by one or more (for example 1 to the maximum number of hydrogen atoms bonded to a 5 or 6 membered heteroaryl, for example 1, 2, 3, 4, 5, for example 1 to 4, or 1 to 3, or 1 or 2) 5- or 6-membered heteroaryl substituted by independently selected R7' (in particular as defined herein, as with respect to formula (Vc) below).

[0178] In one embodiment of the compound of formula (IIb) used according to the fifth aspect, Hy, R2, R3, R4, A and E are independently as above (especially with respect to formula (Ib), (IIIa), ( IVa), (Va), (VIa), (VIIa) and / or (VIIIa)) or as defined below (especially with respect to formula (IIIb)); and R6' is as defined below (especially with respect to formula (Vc)) 5 or 6 membered heteroaryl as defined for R6''.

[0179] In an embodiment of the compound of formula (IIb) according to the special use of the fifth aspect, Hy, R2, R3, R4, A and E are independently as above (especially with respect to formula (Ib), (IIIa) , (IVa), (Va), (VIa), (VIIa) and / or (VIIIa)) or as defined below (especially with respect to formula (IIIb)); and R6' is a 5- or 6-membered heteroaryl (especially is a 5 to 6 membered monocyclic heteroaryl) containing at least one ring heteroatom selected from N, O and S, wherein the 5 or 6 membered heteroaryl is optionally replaced by one or more (for example 1 to 5 or the maximum number of hydrogen atoms bonded to a 6-membered heteroaryl, such as 1, 2, 3, 4, 5, such as 1 to 4, or 1 to 3, or 1 or 2) independently selected R7' (especially as herein defined, as with respect to formula (Vc) below) substitution. For example, R6' can be a 5- or 6-membered heteroaryl containing at least one ring heteroatom selected from N and O (i.e., the heteroaryl does not contain S as a ring heteroatom; and in some embodiments does not contain O as a ring heteroatom; Ring heteroatoms, i.e. R6' may consist of N-heteroaryl), wherein 5- or 6-membered heteroaryl is optionally substituted by one, two or three independently selected R7' (in particular as defined herein, e.g. Regarding the following formula (Vc)).

[0180] In an embodiment of the compound of formula (IIb) according to the special use of the fifth aspect, Hy, R2, R3, R4, A and E are independently as above (especially with respect to formula (Ib), (IIIa) , (IVa), (Va), (VIa), (VIIa) and / or (VIIIa)) or as defined below (especially with respect to formula (IIIb)); and R6' is selected from pyridyl, thiophene, pyrazinyl , pyrimidinyl, pyrazinyl, furyl, pyrrole, pyrazolyl, oxazolyl, isoxazolyl and oxadiazolyl, each of which is optionally replaced by one, two or three independently selected R7' (in particular as defined herein, for example with respect to formula (Vc) below), preferably R6' is selected from pyridyl, thienyl, pyrazolyl, isoxazolyl and pyrrolyl, each of which is optionally replaced by One, two or three independently selected R7' (in particular as defined herein, for example with respect to formula (Vc) below) substitution.

[0181] In any of the above embodiments of the compound of formula (IIb) (including the compound of formula (Ib)) according to the specific use of the fifth aspect, R7' can be independently selected from R7, C1-6 alkyl, C2-6 Alkenyl, C2-6 alkynyl, halogen, -CN, -O(C1-6 alkyl), -NH(C1-6 alkyl), -N(C1-6 alkyl)2, -NHS(O) 1-2(C1-6 alkyl), -NHS(O)1-2O, (C1-6 alkyl), -C(=O)(C1-6 alkyl) and -OC(=O)(C1 -6 alkyl), wherein each of C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl is optionally replaced by one or more (for example, 1 to C1-6 alkyl, C2- The maximum number of hydrogen atoms bound to a 6 alkenyl or a C2-6 alkynyl group, for example 1, 2, 3, 4, 5, 6, 7, 8, 9 or up to 10, for example 1 to 5, 1 to 4 or 1 to 3 or 1 or 2) independently selected R30 (wherein each R30 is preferably selected from primary substituents, secondary substituents and tertiary substituents as defined herein). For example, R7' can be independently selected from C1-3 alkyl, halogen, -CN, -O(C1-3 alkyl), -NH(C1-3 alkyl) and -N(C1-3 alkyl)2 , wherein each of the C1-3 alkyl groups is optionally replaced by one or more (for example, 1 to the maximum number of hydrogen atoms combined with the C1-3 alkyl group, such as 1, 2, 3, 4, 5, 6, 7 or up to 6, for example 1 to 5, 1 to 4, or 1 to 3, or 1 or 2) independently selected R30 (wherein each R30 is preferably selected from primary substituents as defined herein , secondary substituents and tertiary substituents) substitutions. In any of the above embodiments of compounds of formula (IIb) (including compounds of formula (Ib)) according to the specific use of the fifth aspect, R7' can be independently selected from Cl, Br, methyl and ethyl, for example selected from Cl , Br and methyl. In another embodiment of any of the above embodiments of the compound of formula (IIb) (including the compound of formula (Ib)) according to the specific use of the fifth aspect, R7' can be independently R7, such as defined in formula (Ia) any R7.

[0182] In any of the above embodiments of the compound of formula (IIb) (including the compound of formula (Ib)) according to the special use of the fifth aspect, when R6' is substituted, preferably one R7' group is in relation to R6 'bound to the R6' ring atom at position 2 of the ring atom bound to the remainder of the compound (ie preferably R6' has an ortho R7' group). In any of the above embodiments of compounds of formula (IIb) (including compounds of formula (Ib)) according to the special use of the fifth aspect, wherein R6' is replaced by two or more (eg two, three or four) R7 ' group substitution, preferably one of the two or more R7' groups is bound to the ring atom of R6' at position 2 relative to the ring atom to which R6' is bound to the rest of the compound (i.e. R6 'with an ortho R7' group), and the remaining R7' group is attached to the ring atom of R6' at a position other than position 2. For example, in any of the above embodiments of compounds of formula (IIb) (including compounds of formula (Ib)) according to the particular use of the fifth aspect, wherein R6' is a k-membered ring substituted with two or more R7' groups , preferably one of the two or more R7' groups is bound to the ring atom of R6' at position 2 relative to the ring atom that R6' is bound to the remainder of the compound (ie, relative to the base position) , and the remaining R7' group is bonded to the ring atom of R6' at a position other than position 2 (eg, position 3, 4, 5, ...k). For example, where R6' is a 5-membered ring, preferably one of the two or more R7' groups is attached to the ring atom of R6' at position 2 (relative to the yl position), and the remaining R7 The 'group is bonded to the ring atom of R6' at position 3, 4 or 5 (relative to the base position). Furthermore, in any of the above embodiments of compounds of formula (IIb) (including compounds of formula (Ib)) for specific use according to the fifth aspect, wherein R6' is replaced by two or more (eg two, three or four ) R7' group substitution, preferably, each of the two ring atoms directly adjacent to the ring atom to which R6' is attached to the rest of the compound bears an R7' group (for example, relative to the compound R6' ring atoms bound to the remainder of the ring, R6' as a k-membered ring has one R7' group at each of positions 2 and k, e.g. R6' is substituted at its two ortho positions). Additionally, in any of the above embodiments of compounds of formula (IIb) (including compounds of formula (Ib)) for specific use according to the fifth aspect, wherein R6' is replaced by three or more (eg three or four) R7' Group substitution, preferably, each of the two ring atoms directly adjacent to the ring atom to which R6 is attached to the rest of the compound bears an R7' group (e.g., relative to the The R6' ring atom of the k-membered ring has one R7' group at each of positions 2 and k, for example R6' is substituted at its two ortho positions), and the third R7' group group is bonded to a ring atom of R6' that is directly adjacent to an adjacent ring atom, but not to which R6' is bonded to the rest of the compound (e.g., R6' is a k-membered ring, relative to R6' A ring atom bound to the rest of the compound, bearing a third R7' group in one of the positions 3 to k-1).

[0183] In an embodiment of the compound of formula (IIb) according to the special use of the fifth aspect, Hy, R2, R3, R4, A and E are independently as above (especially with respect to formula (Ib), (IIIa) , (IVa), (Va), (VIa), (VIIa) and / or (VIIIa)) or as defined below (especially with respect to formula (IIIb)), R6' is selected from the following formulae: ,,,,,, , , , , , , , , and , where R6' represents the bond to the rest of the compound.

[0184] In an embodiment of the compound of formula (IIb) according to the special use of the fifth aspect, Hy, R2, R3, R4, A and E are independently as above (especially with respect to formula (Ib), (IIIa) , (IVa), (Va), (VIa), (VIIa) and / or (VIIIa)) or as defined below (especially with respect to formula (IIIb)), R6' is selected from the following formulae: ,,,,,, , , and , wherein represent the bond of R6' to the rest of the compound.

[0185] In an embodiment of the compound of formula (IIb) according to the specific use of the fifth aspect, Hy, R2, R3, R4, A and E are independently as above (especially with respect to formula (Ib), (IIIa) , (IVa), (Va), (VIa), (VIIa) and / or (VIIIa)) or as defined below (especially with respect to formula (IIIb)), R6' is selected from the following formulae: ,,,,, and , where represents the bond of R6' to the rest of the compound.

[0186] In any of the above-mentioned embodiments of the compound of formula (IIb) (including the compound of formula (Ib)) according to the special use of the fifth aspect, wherein R6' is a 5 or 6 membered heteroaryl group containing as ring hetero Atomic N atom, R6' can be connected to the rest of the compound via the N ring atom of the 5- or 6-membered heteroaryl.

[0187] In one embodiment, the compound of formula (Ib) according to the particular use of the fifth aspect has the general formula (IIIb) (IIIb) wherein R2, R3, R4, R5, A and E are independently as above (in particular with respect to formula (Ib), (IIb), (IIIa), (IVa), (VIIa) and / or (VIIIa)) or hereinafter (in particular with respect to formula (IVc), (VIc) and / or (VIIc)) and Hy is optionally replaced by one or more (for example 1 to the maximum number of hydrogen atoms bonded to a heteroaryl or heterocyclyl, for example 1, 2, 3, 4, 5, 6, 7, 8, 9 or up to 10, eg 1 to 5, 1 to 4 or 1 to 3 or 1 or 2) independently selected R1e substituted heteroaryl or heterocyclyl; each R1e is independently selected from R1a, R1b, R1c and R1d and each of R1a, R1b, R1c and R1d is independently as above (especially with respect to formula (Ia), (VIa), (VIIa) and / or (VIIIa)) or below (especially with respect to formula (IIc) , (IIc), (VIIc) and / or (VIIIc)).

[0188] In one embodiment of the compound of formula (IIIb), R2, R3, R4, R5, A and E are independently as above (especially with respect to formulas (Ib), (IIb), (IIIa), (IVa) , (VIIa) and / or (VIIIa)) or as defined below (especially with respect to formula (IVc), (VIc) and / or (VIIc)), Hy is as defined above (especially with respect to formula (Va), ( VIIa) and / or (VIIIa)).

[0189] In one embodiment of the compound of formula (IIIb), R2, R3, R4, R5, A and E are independently as above (especially with respect to formulas (Ib), (IIb), (IIIa), (IVa) , (VIIa) and / or (VIIIa)) or as defined below (especially with respect to formulas (IVc), (VIc) and / or (VIIc)), and Hy is a 3-10 membered heterocyclyl or a 3-10 membered Heterocyclyl, each of which is optionally substituted by one, two, three, four, five or six independently selected R1e as defined herein (especially with respect to formulas (Ib), (IIIb), (Ia) and / or (Va)).

[0190] In one embodiment of the compound of formula (IIIb), R2, R3, R4, R5, A and E are independently as above (especially with respect to formulas (Ib), (IIb), (IIIa), (IVa) , (VIIa) and / or (VIIIa)) or as defined below (especially with respect to formulas (IVc), (VIc) and / or (VIIc)), and Hy is a mono- or bicyclic heteroaryl or a mono- or bicyclic heterocycle each of which is optionally substituted by one, two, three, four, five or six independently selected R1e (especially with respect to formulas (Ib), (IIIb), (Ia) and / or ( Va)).

[0191] In one embodiment of the compound of formula (IIIb), R2, R3, R4, R5, A and E are independently as above (especially with respect to formulas (Ib), (IIb), (IIIa), (IVa) , (VIIa) and / or (VIIIa)) or as defined below (especially with respect to formulas (IVc), (VIc) and / or (VIIc)), and Hy is selected from the group consisting of 5-6 membered monocyclic heterocyclyl , 5-6 membered monocyclic heterocyclyl, 9-10 membered bicyclic heterocyclyl and 8-10 membered bicyclic heterocyclyl groups, each of which is optionally composed of one, two, three, four, Five or six independently selected R1e substitutions (especially with respect to formulas (Ib), (IIIb), (Ia) and / or (Va)).

[0192] In one embodiment of the compound of formula (IIIb), R2, R3, R4, R5, A and E are independently as above (especially with respect to formulas (Ib), (IIb), (IIIa), (IVa) , (VIIa) and / or (VIIIa)) or as defined below (especially with respect to formulas (IVc), (VIc) and / or (VIIc)), and Hy is selected from pyridyl, pyrimidinyl, pyrazinyl, pyridyl Azinyl, triazinyl (e.g., 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl), pyrazolyl, oxadiazolyl, thiazole base, triazolyl, thiadiazolyl, pentapyrimidinyl, dihydrocyclopentapyrimidinyl, pyrropyrimidinyl, indorazinyl, indorazinyl, tetrahydroindorazinyl, quinazolinyl , dihydroquinazolinyl, tetrahydroquinazolinyl, pyridyl pyrimidinyl, pyranyl pyrimidinyl, dihydropyranyl pyrimidinyl, tetrahydropyranyl pyrimidinyl, piperidinyl, tetrahydropyranyl and 1, 1-Dioxytetrahydrothiopyranyl, each of which is optionally substituted by one, two, three, four, five or six independently selected R1e (especially with respect to formula (Ib), (IIIb), (Ia) and / or (Va)).

[0193] In one embodiment of the compound of formula (IIIb), R2, R3, R4, R5', A and E are independently as above (especially with respect to formula (Ib), (IIb), (IIIa), ( IVa) and / or (VIIIa)) or as defined below ((IVc) (VIc) and / or (VIIc)), and Hy is selected from: a), and; b), and; c),, and; d), and; e),,,,, and; f),, and; and / or g),,, and, each of which is in a), b), c), d), e ), f), and g) are optionally represented by one, two, three, four, five or six independently selected R1e (especially with respect to formulas (Ib), (IIIb) , (Ia), and / or (Va)), and wherein represents the bond between Hy and the nitrogen atom of the NR2 part in formula (IIIb). If Hy contains an NH moiety as a member of the ring, then preferably a hydrogen atom is substituted by an alkyl group, such as a C1-6 or C1-3 alkyl group, further preferably a methyl group (resulting in an alkyl group replacing an N ring atom), and Hy is optionally further substituted with one, two, three, four or five independently selected R1e. Examples of such Nalkyl substituted Hy groups include , , , and , wherein represents the bond of Hy to the nitrogen atom of the NR2 moiety in formula (Ib).

[0194] In the compound of formula (IIIb) in any of the above embodiments, Hy can be substituted by one R1b, one R1c, and 1 to 4 (eg 1, 2 or 3) R1a or R1d; for example, Hy can Substituted by one (or two) R1a (as defined above, especially with respect to formulas (VIa), (VIIa) and / or (VIIIa), or as follows, especially with respect to formulas (IIc) and / or (VIIIc)), and by one (or both) R1b or R1c (as defined above, especially with respect to formula (VIa) (VIIa) and / or (VIIIa), or as follows, especially with respect to formula (IIIc) and / or (VIIIc)) substituted, and all other R1e are H.

[0195] In the compounds of formula (Ib), (IIb) and (IIIb) in any of the above embodiments, preferably A is S and / or E is O.

[0196] In compounds of formula (Ib), (IIb) and (IIIb) of any of the above embodiments, preferably R3 is H.

[0197] In the compounds of formula (Ib), (IIb) and (IIIb) in any of the above embodiments, preferably A is S and / or E is O and / or R3 is H. For example, in one embodiment of formulas (Ib), (IIb) and (IIIb), A is S; E is O; and R3 is H.

[0198] In one embodiment, the compound for specific use according to the fifth aspect formula (Ic) has the general formula (IIc) (IIc) wherein R1b, R1c, R2, R3, R4, R5'', A, B and E is as above (especially with respect to formulas (Ic), (IIIa), (IVa), (VIa), (VIIa) and / or (VIIIa)) or as follows (especially with respect to formulas (IIIc), (IVc), (Vc ), (VIc), (VIIc) and / or (VIIIc)), and R1a is selected from the group consisting of alkyl, -O(alkyl), -S(alkyl), -NH(alkyl), -N( Alkyl)2 and heterocyclyl, wherein each alkyl and heterocyclyl group is optionally substituted by one or more (eg, one, two or three) independently selected R30. Preferably, each R30 is independently a primary substituent, secondary substituent, or tertiary substituent as described herein, such as alkyl (eg, C1-6 alkyl), -(CH2)1- 3OH, alkenyl (eg, C2-6 alkenyl), alkynyl (eg, C2-6 alkynyl), halogen, -CN, nitro, -OR11 (eg, -OH), -SR11 (eg, -SH ), -N(R12)(R13) (eg, -NH2) and C(=O)R11 (eg, -C(=O)(C1-3 alkyl)).

[0199] In one embodiment of the compound of formula (IIc), R1b, R1c, R2, R3, R4, R5'', A, B and E are as above (especially with respect to formula (Ic), (IIIa), ( IVa), (VIa), (VIIa) and / or (VIIIa)) or as follows (especially with respect to formulas (IIIc), (IVc), (Vc), (VIc), (VIIc) and / or (VIIIc)) Defined, and R1a is selected from C1-3 alkyl, -O (C1-3 alkyl), -S (C1-3 alkyl), -NH (C1-3 alkyl), -N (C1-3 alkyl base) 2 and 3 to 7 membered heterocyclyl, wherein the 3 to 7 membered heterocyclyl groups are optionally independently selected from methyl, ethyl, -OH, -OCH3, -SCH3, cyclopropyl, 2- Hydroxyethyl, 2-(N, N-dimethylamino)ethyl, 2-(N, N-dimethylamino)ethoxy, 2-aminoethyl, 2-(N-methylamine Base) ethyl, 2-(methoxy) ethyl, 4-methylpiperazinyl, -C(=O)(C1-3 alkyl), -(CH2)1-3COOH and -NH2-z( One or two moieties of CH3)z, wherein z is 0, 1 or 2; and each C1-3 alkyl group is optionally independently selected from -OH, -OCH3, -SCH3, cyclopropyl, Piperazinyl, 4-methyl-piperazinyl, 4-(2-hydroxyethyl)piperazinyl, 2-(N,N-dimethylamino)ethoxy and -NH2-z(CH3)z One or two moieties of where z is 0, 1 or 2 are substituted.

[0200] In one embodiment of the compound of formula (IIc), R1b, R1c, R2, R3, R4, R5'', A, B and E are as above (especially with respect to formula (Ic), (IIIa), ( IVa), (VIa), (VIIa) and / or (VIIIa)) or as follows (especially with respect to formulas (IIIc), (IVc), (Vc), (VIc), (VIIc) and / or (VIIIc)) Defined, and R1a is selected from C1-3 alkyl, -O (C1-3 alkyl), -S (C1-3 alkyl), -NH (C1-3 alkyl), piperazinyl, morpholinyl , piperidinyl and pyrrolidinyl, wherein each piperazinyl, morpholinyl, piperidinyl and pyrrolidinyl groups are optionally independently selected from methyl, ethyl, -OH, -OCH3, -SCH3 , cyclopropyl, 2-hydroxyethyl, 2-(N, N-dimethylamino)ethyl, 2-(N, N-dimethylamino)ethoxy, 2-aminoethyl, 2 -(N-methylamino)ethyl, 2-(methoxy)ethyl, 4-methylpiperazinyl, -C(=O)(C1-3alkyl), -(CH2)1-3COOH , and one or two moieties of -NH2-z(CH3)z, wherein z is 0, 1 or 2; and each C1-3 alkyl group is optionally independently selected from -OH, -OCH3, -SCH3, cyclopropyl, piperazinyl, 4-methyl-piperazinyl, 4-(2-hydroxyethyl)piperazinyl, 2-(N, N-dimethylamino)ethoxy, and One or two moieties of -NH2-z(CH3)z, where z is 0, 1 or 2.

[0201] In one embodiment of the compound of formula (IIc), R1b, R1c, R2, R3, R4, R5'', A, B and E are as above (especially with respect to formula (Ic), (IIIa), ( IVa), (VIa), (VIIa) and / or (VIIIa)) or as follows (especially with respect to formulas (IIIc), (IVc), (Vc), (VIc), (VIIc) and / or (VIIIc)) defined, and R1a is selected from -NH(C1-3 alkyl), piperazinyl, piperidinyl and pyrrolidinyl, wherein the piperazinyl group is optionally independently selected from 2-hydroxyethyl, methyl , -CH2COOH and -C(=O)CH3 are substituted by one or two moieties; piperidinyl groups are optionally substituted by one or two moieties independently selected from -NH2 and 4-methylpiperazinyl; pyrrole The pyridyl group is optionally substituted with one or two -OH; and each of the C1-3 alkyl groups is optionally independently selected from -OH, -OCH3, and -NH2-z(CH3) One or both moieties of z, where z is 0, 1 or 2, are substituted.

[0202] In one embodiment of the compound of formula (IIc), R1b, R1c, R2, R3, R4, R5'', A, B and E are as above (especially with respect to formula (Ic), (IIIa), ( IVa), (VIa), (VIIa) and / or (VIIIa)) or as follows (especially with respect to formulas (IIIc), (IVc), (Vc), (VIc), (VIIc) and / or (VIIIc)) Defined, and R1a is selected from 4-(2-hydroxyethyl)piperazinyl, 4-methylpiperazinyl, 4-acetylpiperazinyl, (2-hydroxyethyl)amino, 4-amine Piperidinyl, 4-(4-methylpiperazinyl)piperidinyl, (4-carboxymethylpiperazinyl) and 3-hydroxypyrrolidinyl, for example selected from 4-(2-hydroxyethyl) Piperazinyl, 4-methylpiperazinyl, 4-acetylpiperazinyl and (2-hydroxyethyl)amine.

[0203] In an alternative embodiment of the compound of formula (IIc), R1b, R1c, R2, R3, R4, R5'', A, B and E are as above (especially with respect to formulas (Ic), (IIIa), (IVa), (VIa), (VIIa) and / or (VIIIa)) or as follows (especially with respect to formulas (Ic), (IIIa), (IVa), (VIa), (VIIa) and / or (VIIIa) ), and R1a is a leaving group (for example, halogen (such as Cl, Br or F), nitro, benzotriazol-1-yloxy, C1-C10 alkylsulfonate, C1-C10 Haloalkylsulfonate, perfluorobutanesulfonate (CF3CF2CF2CF2SO3-), CF3C(=O)O-, benzenesulfonate (wherein phenyl is optionally selected from one, two or three independently halogen and C1-C4 alkyl groups), or ammonium salts of the formula -[N(Rx)(Ry)(Rz)]+[G]-, where Rx, Ry and Rz are all independently hydrogen or alkane group, and G is the conjugate base of a strong acid (for example, G- is Cl-)).

[0204] In one embodiment, the compound for specific use according to the fifth aspect formula (Ic) has the general formula (IIIc) (IIIc) wherein R1a, R2, R3, R4, R5'', A, B and E are as above (especially with respect to formulas (Ic), (IIc), (IIIa), (IVa), (VIa), (VIIa) and / or (VIIIa)) or as follows (especially with respect to formulas (IVc), (Vc), (VIc), (VIIc) and / or (VIIIc)), and each R1b and R1c is independently selected from H, methyl, ethyl, -OH, -OCH3, -SCH3, cyclopropyl, 2- Hydroxyethyl, 2-(N, N-dimethylamino)ethyl, 2-(N, N-dimethylamino)ethoxy, 2-aminoethyl, 2-(N-methylamino ) ethyl, 2-(methoxy)ethyl, -NH2-z(CH3)z, phenyl, pyridyl, pyrazolyl, phenoxy, pyridyloxy, imidazolylamino and tetrahydrofurylmethyl Oxygen, wherein z is 0, 1 or 2; and each of phenyl, pyridyl, pyrazolyl, phenoxy, pyridyloxy, imidazolylamino and tetrahydrofuranylmethoxy is optionally independently selected from From methyl, ethyl, -OH, -OCH3, -SCH3, cyclopropyl, 2-hydroxyethyl, 2-(N, N-dimethylamino) ethyl, 2-(N, N-dimethyl One, two, or Three partial substitutions where z is 0, 1 or 2.

[0205] In an embodiment of the compound of formula (IIIc), R1a, R2, R3, R4, R5'', A, B and E are as above (especially with respect to formulas (Ic), (IIc), (IIIa) , (IVa), (VIa), (VIIa) and / or (VIIIa)) or as defined below (especially with respect to formulas (IVc), (Vc), (VIc), (VIIc) and / or (VIIIc)) , and at least one of R1b and R1c is selected from H, methyl, ethyl, -OH, -OCH3, -SCH3, cyclopropyl, 2-hydroxyethyl, 2-(N, N-dimethylamino) Ethyl, 2-(N, N-dimethylamino)ethoxy, 2-aminoethyl, 2-(N-methylamino)ethyl, 2-(methoxy)ethyl, -NH2 -z(CH3)z and phenyl, where z is 0, 1 or 2. In this embodiment, the other of R1b and R1c may be as defined above (especially with respect to formulas (Ia), (IIa) and / or (IIIa)), for example, the other of R1b and R1c may be selected from H, methyl, ethyl, -OH, -OCH3, -SCH3, cyclopropyl, 2-hydroxyethyl, 2-(N, N-dimethylamino) ethyl, 2-(N, N-di Methylamino)ethoxy, 2-aminoethyl, 2-(N-methylamino)ethyl, 2-(methoxy)ethyl, -NH2-z(CH3)z, phenyl, pyridine Base, pyrazolyl, phenoxy, pyridyloxy, imidazolylamino and tetrahydrofurylmethoxy, wherein z is 0, 1 or 2; and wherein phenyl, pyridyl, pyrazolyl, phenoxy, Each of the pyridyloxy, imidazolylamine and tetrahydrofurylmethoxy groups is optionally independently selected from methyl, ethyl, -OH, -OCH3, -SCH3, cyclopropyl, 2-hydroxy Ethyl, 2-(N, N-dimethylamino)ethyl, 2-(N, N-dimethylamino)ethoxy, 2-aminoethyl, 2-(N-methylamino) One, two or three moieties of ethyl, 2-(methoxy)ethyl and -NH2-z(CH3)z, where z is 0, 1 or 2. Alternatively, each of R1b and R1c is independently selected from H, methyl, ethyl, -OH, -OCH3, -SCH3, cyclopropyl, 2-hydroxyethyl, 2-(N, N-dimethyl Amino)ethyl, 2-(N, N-dimethylamino)ethoxy, 2-aminoethyl, 2-(N-methylamino)ethyl, 2-(methoxy)ethyl , -NH2-z(CH3)z and phenyl, wherein z is 0, 1 or 2.

[0206] In an embodiment of the compound of formula (IIIc), R1a, R2, R3, R4, R5'', A, B and E are as above (especially with respect to formulas (Ic), (IIc), (IIIa) , (IVa), (VIa), (VIIa) and / or (VIIIa)) or as defined below (especially with respect to formulas (IVc), (Vc), (VIc), (VIIc) and / or (VIIIc)) , and R1b is methyl, ethyl, propyl, or isopropyl, preferably methyl; and R1c is H. In an alternative embodiment, R1c is H; and R1c is methyl, ethyl, propyl, isopropyl or phenyl, preferably methyl.

[0207] In one embodiment, the compound for specific use according to the fifth aspect formula (Ic) has the general formula (IVc) (IVc) wherein R1a, R1b, R1c, R2, R4, R5'', A, B and E is as above (especially with respect to formulas (Ic), (IIc), (IIIc), (IIIa), (VIa), (VIIa) and / or (VIIIa)) or as follows (especially with respect to formulas (Vc), (VIc ), (VIIc) and / or (VIIIc)), and R3 is selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, phenyl, halogen , -CN, azido, -NO2, -O(C1-6 alkyl), -OCF3, -S(C1 -6 alkyl), -NH2, -NH(C1-6 alkyl), -N( C1-6 alkyl) 2, -NHS (O) 2 (C1-6 alkyl), -S (O) 2NH2-z (C1 -6 alkyl) z, -C (=O) (C1-6 alkyl base), -C(=O)OH, -C(=O)O(C1-6 alkyl), -C(=O)NH2-z(C1-6 alkyl)z, -NHC(=O) (C1-6 alkyl), -NHC(=NH)NHz-2(C1-6 alkyl)z and -N(C1-6 alkyl)C(=NH)NH2-z(C1-6 alkyl) z, wherein z is , 1 or 2 and wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl and phenyl are optionally replaced by one or more independently Select the R30 to replace.

[0208] In one embodiment of the compound of formula (IVc), R1a, R1b, R1c, R2, R4, R5'', A, B and E are as above (especially with respect to formulas (Ic), (IIc), ( IIIc), (IIIa), (VIa), (VIIa) and / or (VIIIa)) or as defined below (in particular with respect to formulas (Vc), (VIc), (VIIc) and / or (VIIIc)), and R3 is selected from H, C1-4 alkyl, C3-6 cycloalkyl, phenyl, halogen, -CN, -O (C1-4 alkyl), -OCF3, -S (C1-4 alkyl), - NH2, -NH(C1-4 alkyl), -N(C1-4 alkyl)2, -C(=O)(C1-4 alkyl), -C(=O)OH, -C(=O )O(C1-4 alkyl), -C(=O)NH2-z(C1-4 alkyl)z, -NHC(=O)(C1-4 alkyl), -NHC(=NH)NHz- 2 (C1-4 alkyl) z and -N (C1-4 alkyl) C (=NH) NH2-z (C1-4 alkyl) z, wherein phenyl is optionally selected by one, two or independently From halogen, methyl, isopropyl, -CN, -CF3, -OCF3, -OH, -NH2, -NH (C1-3 alkyl), -N (C1-3 alkyl) 2, -NHC (= O)(C1-3 alkyl), -C(=O)NH2-z(C1-3 alkyl)z, -(CH2)1-3NH2, -(CH2)1-3NH(C1-3 alkyl) , -(CH2)1-3N(C1-3 alkyl)2, -(CH2)1-3OH and -(CH2)1-3O(C1-3 alkyl) are substituted; and wherein z is 0, 1 or 2.

[0209] In one embodiment of the compound of formula (IVc), R1a, R1b, R1c, R2, R4, R5'', A, B and E are as above (especially with respect to formulas (Ic), (IIc), ( IIIc), (IIIa), (VIa), (VIIa) and / or (VIIIa)) or as defined below (in particular with respect to formulas (Vc), (VIc), (VIIc) and / or (VIIIc)), and R3 is selected from H, methyl, ethyl, propyl, isopropyl, phenyl and halogen.

[0210] In one embodiment of the compound of formula (IVc), R1a, R1b, R1c, R2, R4, R5'', A, B and E are as above (especially with respect to formula (Ic), (IIc), ( IIIc), (IIIa), (VIa), (VIIa) and / or (VIIIa)) or as defined below (in particular with respect to formulas (Vc), (VIc), (VIIc) and / or (VIIIc)), and R3 is H.

[0211] In one embodiment, the compound for specific use according to the fifth aspect formula (Ic) has the general formula (Vc) (Vc) wherein R1a, R1b, R1c, R2, R3, R4, A, B and E are as above (especially with respect to formulas (Ic), (IIc), (IIIc), (IVc), (IIIa), (IVa), (VIa), (VIIa) and / or (VIIIa)) or as follows (especially with respect to formula (VIc), (VIIc) and / or (VIIIc)), and R5'' is -L-R6'', wherein R6'' is a heteroatom comprising at least one ring heteroatom selected from N, O and S Aryl, or a heterocyclyl comprising at least one ring heteroatom selected from N, O, and S, wherein each heteroaryl and heterocyclyl group is optionally replaced by one or more (for example, one, two or three) independently selected R7' substitutions. For example, R6'' can be a heteroaryl group containing at least one ring heteroatom selected from N and O (e.g., the heteroaryl group does not contain S as a ring heteroatom; and in some embodiments does not contain O as a ring heteroatom , that is, R6'' may be N-heteroaryl), or may be a heterocyclyl containing at least one ring heteroatom selected from N and O (for example, the heterocyclyl does not contain S as a ring heteroatom; and in Some embodiments do not contain O as a ring heteroatom, i.e., R6'' can be N-heterocyclyl), wherein each heteroaryl and heterocyclyl group is optionally replaced by one or more (e.g., one , two or three) independently selected R7' substitutions.

[0212] In an embodiment of the compound of formula (Vc), R1a, R1b, R1c, R2, R3, R4, A, B and E are as above (especially with respect to formulas (Ic), (IIc), (IIIc) , (IVc), (IIIa), (IVa), (VIa), (VIIa) and / or (VIIIa)) or as defined below (especially with respect to formulas (VIc), (VIIc) and / or (VIIIc)) , and R6'' is a 3 to 10 membered heteroaryl group (eg, comprising at least one ring heteroatom selected from N, O, and S, eg, selected from N and O) or a 3 to 10 membered heterocyclic group (eg, comprising at least one ring heteroatom selected from N, O and S, eg selected from N and O), each of the above optionally substituted with one or more (eg one, two or three) independently selected R7' .

[0213] In an embodiment of the compound of formula (Vc), R1a, R1b, R1c, R2, R3, R4, A, B and E are as above (especially with respect to formulas (Ic), (IIc), (IIIc) , (IVc), (IIIa), (IVa), (VIa), (VIIa) and / or (VIIIa)) or as defined below (especially with respect to formulas (VIc), (VIIc) and / or (VIIIc)) , and R6'' is a monocyclic or bicyclic heteroaryl group (for example, comprising at least one ring heteroatom selected from N, O and S, such as selected from N and O) or a monocyclic or bicyclic heterocyclic group (for example, comprising at least one ring heteroatom selected from N, O and S, e.g. selected from N and O), each of which is optionally independently selected by one or more (e.g. one, two or three) R7' replace.

[0214] In an embodiment of the compound of formula (Vc), R1a, R1b, R1c, R2, R3, R4, A, B and E are as above (especially with respect to formulas (Ic), (IIc), (IIIc) , (IVc), (IIIa), (IVa), (VIa), (VIIa) and / or (VIIIa)) or as defined below (especially with respect to formulas (VIc), (VIIc) and / or (VIIIc)) , and R6'' is selected from 5 to 6 membered monocyclic heteroaryl (for example, containing at least one ring heteroatom selected from N, O and S, such as selected from N and O), 4 to 6 membered monocyclic heterocyclic group (e.g., containing at least one ring heteroatom selected from N, O, and S, e.g., selected from N and O), 7- to 9-membered bicyclic heteroaryl (e.g., containing at least one ring heteroatom selected from N, O, and S heteroatom, for example selected from N and O) and 7 to 9 membered bicyclic heterocyclyl (for example, comprising at least one ring heteroatom selected from N, O and S, for example selected from N and O), each of the above is optionally substituted by one or more (eg one, two or three) independently selected R7'.

[0215] In an embodiment of the compound of formula (Vc), R1a, R1b, R1c, R2, R3, R4, A, B and E are as above (especially with respect to formulas (Ic), (IIc), (IIIc) , (IVc), (IIIa), (IVa), (VIa), (VIIa) and / or (VIIIa)) or as defined below (especially with respect to formulas (VIc), (VIIc) and / or (VIIIc)) , and R6'' is a 5 to 6 membered monocyclic heteroaryl group (for example, containing at least one ring heteroatom selected from N, O and S, such as selected from N and O), which is optionally replaced by one or more (eg one, two or three) independently selected R7' substitutions.

[0216] In an embodiment of the compound of formula (Vc), R1a, R1b, R1c, R2, R3, R4, A, B and E are as above (especially with respect to formulas (Ic), (IIc), (IIIc) , (IVc), (IIIa), (IVa), (VIa), (VIIa) and / or (VIIIa)) or as defined below (especially with respect to formulas (VIc), (VIIc) and / or (VIIIc)) , and R6'' is a 7 to 9 membered bicyclic heterocyclyl group (for example, comprising at least one ring heteroatom selected from N, O and S, for example selected from N and O), which is replaced by one or more (for example, one, Two or three) independently selected R7' substitutions.

[0217] In an embodiment of the compound of formula (Vc), R1a, R1b, R1c, R2, R3, R4, A, B and E are as above (especially with respect to formulas (Ic), (IIc), (IIIc) , (IVc), (IIIa), (IVa), (VIa), (VIIa) and / or (VIIIa)) or as defined below (especially with respect to formulas (VIc), (VIIc) and / or (VIIIc)) , and R6'' is selected from pyridyl, thienyl, pyridazinyl, furyl, pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, indolyl, naphthalene Pyridyl, thienopyridine, tetrahydropyranyl, piperidinyl, pyrrolidinyl, azetidinyl, azabicycloheptyl, azabicyclooctyl, azapentacycloctyl, piperazinyl , morpholinyl and tetrahydrothienyl, each of the above is optionally substituted by one, two or three independently selected R7', preferably R6'' is selected from pyridyl, thienyl, pyrazolyl, Isoxazolyl, pyrrolyl, piperidinyl, pyrrolidinyl, azetidinyl and azabicyclooctyl, each of which is optionally replaced by one or more (for example, one, two or three ) independently selected R7' substitutions.

[0218] In any of the foregoing embodiments of compounds of formula (Vc) (including those of formulas (Ic), (IIc), (IIIc) and (IVc), R7' can be independently selected from R7, C1-6 alkane Base, C2-6 alkenyl, C2-6 alkynyl, halogen, -CN, -O(C1-6 alkyl), -NH(C1-6 alkyl), -N(C1-6 alkyl)2, -NHS (O) 1-2 (C1-6 alkyl), -NHS (O) 1-2O (C1-6 alkyl), -C (=O) (C1-6 alkyl) and -OC (= O) (C1-6 alkyl), and / or any two R7' bonded to the same atom of R6'' as the heterocyclic group can be linked together to form =O, wherein each C1-6 alkyl, C2 -6 alkenyl and C2-6 alkynyl groups are optionally substituted with one or more independently selected R30. For example R7' can be independently selected from R7, C1-3 alkyl, halogen, -CN, -O(C1-3 alkyl), -NH(C1-3 alkyl) and -N(C1-3 alkyl) 2, and / or any two R7' bonded to the same atom of R6'' as a heterocyclic group may be joined together to form =O, wherein the C1-3 alkyl group is optionally independently selected by one or more R30 replaced. In any of the above embodiments of the compound of formula (Vc), including those of (Ic), (IIc), (IIIc) and (IVc), R7' can be independently selected from Cl, Br, methyl and ethyl, For example selected from Cl, Br and methyl. In another of any of the above embodiments of the compound of formula (Vc), including those of (Ic), (IIc), (IIIc) and (IVc), R7' can independently be R7, for example in combination with formula ( Any R7 defined in Ia).

[0219] In any of the above embodiments of the compound of formula (Vc) (including those of (Ic), (IIc), (IIIc) and (IVc), where R6'' is substituted, preferably one The R7' group is attached to the ring atom of R6'' at position 2 relative to the ring atom to which R6'' is bound to the rest of the compound (ie, preferably R6'' bears an ortho R7' group). In any of the above embodiments of compounds of formula (Vc) (including those of formulas (Ic), (IIc), (IIIc) and (IVc), where R6'' is replaced by two or more (eg, two Where one, three or four) R7' groups are substituted, preferably one of the two or more R7' groups is combined with The ring atoms of R6'' are attached (ie, R6'' has an ortho R7' group), and the remaining R7' groups are attached to the ring atoms of R6'' at positions other than position 2. For example, in any of the foregoing embodiments of compounds of formula (Vc), including those of formulas (Ic), (IIc), (IIIc) and (IVc), where R6'' is replaced by two or more ( For example, in the case of k-membered rings substituted with two, three or four) R7' groups, it is preferred that one of the two or more R7' groups be at the point where R6'' is attached to the rest of the compound the ring atom is attached to the ring atom of R6'' at position 2 (i.e. relative to the base position), and the remaining R7' group is attached to (to) the ring atom of R6'' at a position other than position 2, For example, at positions 3, 4, 5...k. For example, where R6'' is a 5-membered ring, preferably one of the two or more R7' groups is attached to the ring atom of R6'' at position 2 (relative to the base position), and the remaining The R7' group is attached to the ring atom of R6'' at position 3, 4 or 5 (relative to the base position). Also, in any of the above embodiments of compounds of formula (Vc), including those of formulas (Ic), (IIc), (IIIc) and (IVc), where R6'' is replaced by two or more (eg , two, three or four) where the R7' group is substituted, preferably each of the two ring atoms directly adjacent to the ring atom to which R6'' is attached to the rest of the compound carries a The R7' group (e.g., R6'' is a k-membered ring with one R7' group at each of positions 2 and k relative to the ring atom to which R6'' is bound to the rest of the compound, e.g., R6 Both ortho positions of '' are replaced). Furthermore, in any of the above embodiments of compounds of formula (Vc), including those of formulas (Ic), (IIc), (IIIc) and (IVc), where R6'' is replaced by three or more (eg , three or four) where the R7' group is substituted, preferably each of the two ring atoms directly adjacent to the ring atom to which R6'' is attached to the rest of the compound bears an R7' group group (e.g., R6'' is a k-membered ring with an R7' group at each of positions 2 and k relative to the ring atom to which R6'' is attached, e.g., R6'' Both ortho positions are substituted) and the third R7' group is attached to a ring atom at R6'' that is directly adjacent to one of the ortho ring atoms, but not to which R6'' is attached to the rest of the compound Ring atoms (eg, R6'' is a k-membered ring with a third R7' group at one of position 3 and k-1 relative to the ring atom to which R6'' is bound to the rest of the compound).

[0220] In an embodiment of the compound of formula (Vc), R1a, R1b, R1c, R2, R3, R4, A, B and E are as above (especially with respect to formulas (Ic), (IIc), (IIIc) , (IVc), (IIIa), (IVa), (VIa), (VIIa) and / or (VIIIa) or as defined below (especially with respect to formulas (VIc), (VIIc) and / or (VIIIc)), And R6'' is selected from the following molecular formulas: ,,,,,,,,,,,,,,,,,,,,,, and, wherein it represents the bond between R6'' and the rest of the compound.

[0221] In an embodiment of the compound of formula (Vc), R1a, R1b, R1c, R2, R3, R4, A, B and E are as above (especially with respect to formulas (Ic), (IIc), (IIIc) , (IVc), (IIIa), (IVa), (VIa), (VIIa) and / or (VIIIa)) or as defined below (especially with respect to formulas (VIc), (VIIc) and / or (VIIIc)) , and R6'' is selected from the following molecular formulas: ,,,,,,,, and, wherein represents the bond connecting R6'' to the rest of the compound.

[0222] In an embodiment of the compound of formula (Vc), R1a, R1b, R1c, R2, R3, R4, A, B and E are as above (especially with respect to formulas (Ic), (IIc), (IIIc) , (IVc), (IIIa), (IVa), (VIa), (VIIa) and / or (VIIIa)) or as defined below (especially with respect to formulas (VIc), (VIIc) and / or (VIIIc)) , and R6'' is selected from the following molecular formulas: ,,,,, and, wherein represents the bond connecting R6'' to the rest of the compound.

[0223] In an embodiment of the compound of formula (Vc), R1a, R1b, R1c, R2, R3, R4, A, B and E are as above (especially with respect to formulas (Ic), (IIc), (IIIc) , (IVc), (IIIa), (IVa), (VIa), (VIIa) and / or (VIIIa)) or as defined below (especially with respect to formulas (VIc), (VIIc) and / or (VIIIc)) , and R6'' is selected from the following molecular formulas: ,,,, and, wherein represents the bond connecting R6'' to the rest of the compound.

[0224] In any of the foregoing embodiments of compounds of formula (Vc), including those of formulas (Ic), (IIc), (IIIc) and (IVc), L can be selected from a bond, C1-6 alkylene , C2-6 alkenylene, C2-6 alkynylene and -(CH2)m-[Y-(CH2)n]o-, wherein m is 1, 2 or 3, n is 0, 1 or 2, o is 1, 2 or 3, wherein o is 1 if n is 0; y is independently selected from O, S and NH, wherein each C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene , -(CH2)m- and -(CH2)n- groups are optionally substituted with one or more independently selected R30. For example, in any of the foregoing embodiments of compounds of formula (Vc), including those of formulas (Ic), (IIc), (IIIc), and (IVc), L can be selected from: a bond; C1 alkylene, any optionally substituted by one R30; C2 alkylene (especially 1,2-ethylene or 1,1-ethylene), optionally substituted by one R30; C3 alkylene (especially trimethylene) , optionally substituted by one R30; C4 alkylene (especially tetramethylene or 2,4-butanediyl), optionally substituted by one R30; -(CH2)mO- and -(CH2)mNH -, where m is 1, 2 or 3. In particular, in any of the above embodiments of compounds of formula (Vc), including those of formulas (Ic), (IIc), (IIIc) and (IVc), L can be a bond.

[0225] In any of the foregoing embodiments of compounds of formula (Vc) (including those of formulas (Ic), (IIc), (IIIc) and (IVc)), at R6'' is a ring heteroatom containing an N atom In the case of a heterocyclic group or a heteroaryl group (for example, a 5-membered heteroaryl group), L may be connected to R6'' through the N ring atom of the heterocyclic group or heteroaryl group.

[0226] In one embodiment, the compound for specific use according to the fifth aspect formula (Ic) has the general formula (VIc) (VIc) wherein R1a, R1b, R1c, R2, R3, R4, R5'', B and E as above (especially with respect to formulas (Ic), (IIc), (IIIc), (IVc), (Vc), (IIIa), (IVa), (VIa), (VIIa) and / or (VIIIa)) or is defined below (in particular with respect to formula (VIIc) and / or (VIIIc)), and A is selected from S, O, NH, N(C1-6alkyl) and C(C1-6alkyl)2. In any of the above embodiments of compounds of formula (VIc), including those of formulas (Ic), (IIc), (IIIc), (IVc) and (Vc), A can be S, O or N(CH3) 2. In any of the above embodiments of compounds of formula (VIc), including those of formulas (Ic), (IIc), (IIIc), (IVc) and (Vc), preferably A is S.

[0227] In one embodiment, the compound for specific use according to the fifth aspect formula (Ic) has the general formula (VIIc) (VIIc) wherein R1a, R1b, R1c, R2, R3, R4, R5'' and A are as above (especially with respect to formulas (Ic), (IIc), (IIIc), (IVc), (Vc), (VIc), (IIIa), (IVa), (VIa), (VIIa) and / or (VIIIa) ) or as defined below (especially with respect to formula (VIIIc)), E is O or S (preferably O) and B is N or CR1d, wherein R1d is selected from C1-3 alkyl, halogen, -O(C1- 3 alkyl), -S (C1-3 alkyl), -NH (C1-3 alkyl) and -N (C1-3 alkyl) 2, wherein each of the C1-3 alkyl groups is optionally is substituted with one or two moieties independently selected from halogen, -OH, -OCH3, -SCH and -NH2-z(CH3)z, where z is 0, 1 or 2. In any of the above embodiments of compounds of formula (VIIc), including those of formulas (Ic), (IIc), (IIIc), (IVc), (Vc) and (VIc), E is O or S (compared to preferably O) and B is N or CR1d, wherein R1d can be selected from C1-3 alkyl, halogen, -O(C1-3 alkyl), -S(C1-3 alkyl), -NH(C1-3 Alkyl) and -N(C1-3 alkyl)2. In any of the above embodiments of compounds of formula (VIIc), including those of formulas (Ic), (IIc), (IIIc), (IVc), (Vc) and (VIc), preferably B is N and more preferably Preferably E is O and B is N.

[0228] In one embodiment, the compound for specific use according to the fifth aspect formula (Ic) has the general formula (VIIIc) (VIIIc) wherein R1a, R1b, R1c, R2, R3, R4, R5'', A, B and E as above (especially with respect to formulas (Ic), (IIc), (IIIc), (IVc), (Vc), (VIc), (VIIc), (IIIa), (IVa), (VIa), ( VIIa) and / or (VIIIa)) or as defined below, and L is a bond. In a preferred embodiment of the compound having the general formula (VIIIc): (A) R1a is selected from the group consisting of alkyl, -O(alkyl), -S(alkyl), -NH(alkyl), -N(alk radical) 2 and heterocyclyl, wherein each alkyl and heterocyclyl group is optionally substituted with one or more (eg, one, two or three) independently selected R30. Preferably, each R30 is independently a primary substituent, secondary substituent or tertiary substituent as defined herein, such as alkyl (eg, C1-6 alkyl), -(CH2)1-3OH , alkenyl (eg, C2-6 alkenyl), alkynyl (eg, C2-6 alkynyl), halogen, -CN, nitro, -OR11 (eg, -OH), -SR11 (eg, -SH) , -N(R12)(R13) (eg, -NH2) and -C(=O)R11 (eg, -C(=O)(C1-3 alkyl)); (B) each of R1b and R1c One independently selected from H, methyl, ethyl, propyl, or isopropyl, -OH, -OCH3, -SCH3, cyclopropyl, 2-hydroxyethyl, 2-(N, N-dimethylamine base) ethyl, 2-(N, N-dimethylamino)ethoxy, 2-aminoethyl, 2-(N-methylamino)ethyl, 2-(methoxy)ethyl , -NH2-z(CH3)z, phenyl, pyridyl, pyrazolyl, phenoxy, pyridyloxy, imidazolylamine and tetrahydrofuranylmethoxy, wherein z is 0, 1 or 2; and benzene Each of the radical, pyridyl, pyrazolyl, phenoxy, pyridyloxy, imidazolylamine and tetrahydrofurylmethoxy groups is optionally independently selected from methyl, ethyl, -OH, - OCH3, -SCH3, cyclopropyl, 2-hydroxyethyl, 2-(N, N-dimethylamino)ethyl, 2-(N, N-dimethylamino)ethoxy, 2-amine One, two or three moieties substituted by ethyl, 2-(N-methylamino)ethyl, 2-(methoxy)ethyl and -NH2-z(CH3)z, where z is 0 , 1 or 2; (C) R3 is selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, phenyl halogen, -CN, azido, - NO2, -O(C1-6 alkyl), -OCF3, -S(C1-6 alkyl), -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, - NHS (O)2(C1-6 alkyl), -S(O)2NH2-z(C1-6 alkyl)z, -C(=O)(C1-6 alkyl), -C(=O) OH, -C(=O)O(C1-6 alkyl), -C(=O)NH2-z(C1-6 alkyl)z, -NHC(=O)(C1-6 alkyl), - NHC (=NH)NHz-2(C1-6alkyl)z and -N(C1-6alkyl)C(=NH)NH2-z(C1-6alkyl)z, where z is 0, 1 or 2 and wherein each of C1-6 alkyl, C2-6 alkenyl C2-6 alkynyl, C3-6 cycloalkyl and phenyl is optionally substituted by one or more independently selected R30; (D) R6'' is as defined above (particularly with respect to formula (Vc)), and is preferably a 3 to 10 membered heteroaryl group (for example comprising at least one ring heteroatom selected from N, O and S, for example selected from N and O ) or 3 to 10 membered heterocyclyl (eg, comprising at least one ring heteroatom selected from N, O, and S, eg, selected from N and O), each of the above optionally replaced by one or more ( For example one, two or three) independently selected R7' substitutions; (E) A is selected from S, O, NH, N(C1-6 alkyl) and C(C1-6 alkyl)2; (F) B is N or CR1d, wherein R1d is selected from C1-3 alkyl, halogen, -O (C1-3 alkyl), -S (C1-3 alkyl), -NH (C1-3 alkyl) and -N (C1-3 alkyl) 2, wherein each of the C1-3 alkyl groups is optionally independently selected from one of halogen, -OH, -OCH3, -SCH and -NH2-z(CH3)z or Two moieties are substituted, wherein z is 0, 1 or 2; and / or (G) E is O or S, preferably O.

[0229] In a preferred embodiment of the compound of general formula (VIIIc), R1a is as defined in item (A) above; R1b and R1c are as defined in item (B) above; R3 is as defined in item (C) above ; R6'' is as specified above (particularly with respect to formula (Vc)) and is preferably a 3 to 10 membered heteroaryl group (for example comprising at least one ring heteroatom selected from N, O and S, for example selected from N and O) or 3 to 10 membered heterocyclyl (eg, comprising at least one ring heteroatom selected from N, O, and S, eg, selected from N and O), each of the above optionally replaced by one or more (eg one, two or three) independently selected R7' substitutions; A is as specified in item (E) above; B is as specified in item (F) above; and E is as specified in item (G) above.

[0230] In a more preferred embodiment of the compound of formula (VIIIc): (A') R1a is selected from C1-3 alkyl, -O(C1-3 alkyl), -S(C1-3 alkyl) , -NH(C1-3 alkyl), -N(C1-3 alkyl)2 and 3 to 7 membered heterocyclyl, wherein the 3 to 7 membered heterocyclyl groups are optionally independently selected from methyl, Ethyl, -OH, -OCH3, -SCH3, cyclopropyl, 2-hydroxyethyl, 2-(N, N-dimethylamino)ethyl, 2-(N, N-dimethylamino)ethyl Oxygen, 2-aminoethyl, 2-(N-methylamino)ethyl, 2-(methoxy)ethyl, 4-methylpiperazinyl, -C(=O)(C1-3 alkyl), -(CH2)1-3COOH and -NH2-z(CH3)z, where z is 0, 1 or 2; and each of the C1-3 alkyl groups is optionally optionally independently selected from -OH, -OCH3, -SCH3, cyclopropyl, piperazinyl, 4-methyl-piperazinyl, 4-(2-hydroxyethyl)piperazinyl, 2-(N, N-dimethylamino) ethoxy and one or two moieties of -NH2-z(CH3)z are substituted, wherein z is 0, 1 or 2; (B') at least one of R1b and R1c is selected from H, Methyl, ethyl, propyl, or isopropyl, -OH, -OCH3, -SCH3, cyclopropyl, 2-hydroxyethyl, 2-(N, N-dimethylamino)ethyl, 2- (N, N-dimethylamino)ethoxy, 2-aminoethyl, 2-(N-methylamino)ethyl, 2-(methoxy)ethyl, -NH2-z(CH3 )z and phenyl, wherein z is 0, 1 or 2 and the other of R1b and R1c is as defined in item (B) above; (C') R3 is selected from H, C1-4 alkyl, C3-6 ring Alkyl, phenyl, halogen, -CN, -O(C1-4 alkyl), -OCF3, S(C1-4 alkyl), -NH2, -NH(C1-4 alkyl), -N(C1 -4alkyl)2, -C(=O)(C1-4alkyl), -C(=O)OH, -C(=O)O(C1-4alkyl), -C(=O) NH2-z(C1-4 alkyl) z, -NHC(=O)(C1-4 alkyl), -NHC(=NH)NHz-2(C1-4 alkyl)z and -N(C1-4 Alkyl)C(=NH)NH2-z(C1-4alkyl)z, wherein the phenyl group is optionally replaced by one, two or independently selected from halogen, methyl, isopropyl, -CN, - CF3, -OCF3, -OH, -NH2, -NH(C1-3 alkyl), -N(C1-3 alkyl)2, -NHC(=O)(C1-3 alkyl), -C(= O)NH2-z(C1-3 alkyl)z, -(CH2)1-3NH2, -(CH2)1-3NH(C1-3 alkyl), -(CH2)1-3N(C1-3 alkyl )2, -(CH2)1-3OH and -(CH2)1-3O(C1-3 alkyl); and z is 0, 1 or 2; (D') R6'' as defined above ( Especially with respect to formula (Vc)), and preferably 3 to 10 membered heteroaryl (for example, containing at least one ring heteroatom selected from N, O and S, for example selected from N and O) or 3 to 10 membered heteroaryl Heterocyclyl (e.g., comprising at least one ring heteroatom selected from N, O, and S, e.g., selected from N and O), each of the above optionally replaced by one or more (e.g., one, two or three a) independently selected R7' substituted, more preferably R6'' is monocyclic or bicyclic heteroaryl or monocyclic or bicyclic heterocyclyl, each of which is optionally replaced by one or more (e.g. one, two or Three) independently selected R7' substitutions; (E') A is S, O, or N(CH3)2; and / or (F') B is N or CR1d, where R1d is selected from C1-3 alkyl, halogen , -O(C1-3alkyl), -S(C1-3alkyl), -NH(C1-3alkyl), and -N(C1-3alkyl)2; and / or (G')E is O or S, preferably O.

[0231] In a preferred embodiment of the compound of general formula (VIIIc), R1a is as defined above in item (A'); R1b and R1c are as defined in item (B') above; R3 is as defined in item (C') above R6'' is as defined in the above item (especially with respect to formula (Vc)), and is preferably a 3 to 10 membered heteroaryl group (for example, containing at least one ring heteroatom selected from N, O and S, e.g. selected from N and O) or 3 to 10 membered heterocyclyl (e.g. comprising at least one ring heteroatom selected from N, O and S, e.g. selected from N and O), each of which is optionally One or more (for example one, two or three) independently selected R7' is substituted, more preferably R6'' is monocyclic or bicyclic heteroaryl (for example, containing at least one ring heteroaryl selected from N, O and S atoms, e.g. selected from N and O) or monocyclic or bicyclic heterocyclyl (e.g., comprising at least one ring heteroatom selected from N, O and S, e.g. selected from N and O), each of the above optionally is substituted by one or more (eg, one, two or three) independently selected R7'; A is as defined in item (E') above; B is as defined in item (F') above; and E is as in ( G') as defined in item.

[0232] In a more preferred embodiment of the compound of general formula (VIIIc): (A'') R1a is selected from -NH(C1-3 alkyl), piperazinyl, piperidinyl and pyrrolidinyl, wherein A piperazinyl group is optionally substituted with one or two moieties independently selected from 2-hydroxyethyl, methyl, -CH2COOH, and -C(=O)CH3; a piperidinyl group is optionally independently selected from One or two moieties from -NH2 and 4-methylpiperazinyl; the pyrrolidinyl group is optionally substituted by one or two -OH; and each of the C1-3 alkyl groups is optionally is substituted by one or two moieties independently selected from -OH, -OCH3 and -NH2-z(CH3)z, where z is 0, 1 or 2; (B'') (a) R1b is methyl, ethyl and R1c is H; or (b) R1b is H; and R1c is methyl, ethyl, propyl, isopropyl or phenyl, preferably Methyl; (C'') R3 selected from H, methyl, ethyl, propyl, isopropyl, phenyl and halogen; (D') R6'' as defined above (especially with respect to formula (Vc)) , and preferably a 3 to 10 membered heteroaryl group (for example, containing at least one ring heteroatom selected from N, O and S, such as selected from N and O) or a 3 to 10 membered heterocyclic group (for example, containing at least one ring heteroatom selected from N, O and S, e.g. selected from N and O), each of the above optionally substituted by one or more (e.g. one, two or three) independently selected R7' , more preferably R6'' is monocyclic or bicyclic heteroaryl (for example, comprising at least one ring heteroatom selected from N, O and S, for example selected from N and O) or monocyclic or bicyclic heterocyclic group (for example, comprising at least one ring heteroatom selected from N, O and S, e.g. selected from N and O), each of the above optionally selected by one or more (e.g. one, two or three) independently selected R7 'Substituted, more preferably R6'' is selected from 5 to 6 membered monocyclic heteroaryls (e.g. comprising at least one ring heteroatom selected from N, O and S, e.g. selected from N and O), 4 to 6 membered monocyclic heteroaryls Ring heterocyclyl (for example, comprising at least one ring heteroatom selected from N, O and S, for example selected from N and O), 7 to 9 membered bicyclic heteroaryl (for example, comprising at least one ring heteroatom selected from N, O and A ring heteroatom of S, for example selected from N and O) and a 7 to 9 membered bicyclic heterocyclyl group (for example, comprising at least one ring heteroatom selected from N, O and S, for example selected from N and O), in the above Each of is optionally substituted by one or more (eg, one, two or three) independently selected R7', more preferably R6'' is a 5 to 6 membered monocyclic heteroaryl group (eg, containing at least one selected Ring heteroatoms selected from N, O and S, e.g. selected from N and O) or 7 to 9 membered bicyclic heterocyclyl (e.g., comprising at least one ring heteroatom selected from N, O and S, e.g. selected from N and O), each of the above is optionally substituted by one or more (eg, one, two or three) independently selected R7'; (E'') A is S; (F'') B is N ; and / or (G'') E is O.

[0233] In a preferred embodiment of the compound of general formula (VIIIc), R1a is as specified in item (A'') above, R1b and R1c are as defined in item (B'') above; R3 is as defined in item (C') above ') as specified; R6'' is as defined above (especially with respect to formula (Vc)) and is preferably a 3 to 10 membered heteroaryl group (for example, comprising at least one ring heteroatom selected from N, O and S, e.g. selected from N and O) or 3 to 10 membered heterocyclyl (e.g. comprising at least one ring heteroatom selected from N, O and S, e.g. selected from N and O), each of which is optionally One or more (for example one, two or three) independently selected R7' is substituted, more preferably R6'' is monocyclic or bicyclic heteroaryl (for example, containing at least one ring heteroaryl selected from N, O and S atoms, e.g. selected from N and O) or monocyclic or bicyclic heterocyclyl (e.g., comprising at least one ring heteroatom selected from N, O and S, e.g. selected from N and O), each of the above optionally is substituted by one or more (for example one, two or three) independently selected R7', more preferably R6'' is selected from 5 to 6 membered monocyclic heteroaryl (for example, containing at least one member selected from N, O and S ring heteroatoms, e.g. selected from N and O), 4 to 6 membered monocyclic heterocyclyl (e.g., comprising at least one ring heteroatom selected from N, O and S, e.g. selected from N and O) , 7 to 9 membered bicyclic heteroaryl (for example, comprising at least one ring heteroatom selected from N, O and S, for example selected from N and O) and 7 to 9 membered bicyclic heterocyclyl (for example, comprising at least one Ring heteroatoms selected from N, O and S, e.g. selected from N and O), each of the above optionally substituted by one or more (e.g. one, two or three) independently selected R7', more Preferably R6'' is a 5 to 6 membered monocyclic heteroaryl group (e.g., comprising at least one ring heteroatom selected from N, O and S, e.g. selected from N and O) or a 7 to 9 membered bicyclic heterocyclic group (e.g. , comprising at least one ring heteroatom selected from N, O and S, e.g. selected from N and O), each of the above optionally independently selected by one or more (e.g. one, two or three) R7' is substituted; A is as specified in item (E'') above; B is as specified in item (F'') above; and E is as specified in item (G'') above.

[0234] In one embodiment, the compounds of the invention are selected from those shown in Table A and / or those shown in Figure IE.

[0235] In one embodiment, the compounds used in the invention (in particular, in the fifth aspect of the invention) are selected from those shown in Table A (and / or depicted in Figure 1E) and in Figure 1E. 1B, those compounds shown in Figure 1C and / or Figure 1D.

[0236] It is intended that the compound of the present invention (especially any one compound in formula (Ia), (IIa), (IIIa), (IVa), (Va), (VIa), (VIIa) and (VIIIa) , such as shown in Table A below; and / or compounds in Figure 1E) and / or compounds used in the present invention (especially formula (Ib), (IIb), (IIIb), (Ic), (IIc) , (IIIc) (IVc), (Vc), (VIc), (VIIc) and (VIIIc), any one of the compounds, such as those shown in Figure 1B, Figure 1C and / or Figure 1D) include not only The compounds shown also include their solvates (eg, hydrates), salts (especially pharmaceutically acceptable salts), N-oxides (especially N-oxides of R1a and / or R6'') , complexes, polymorphs, crystalline forms, non-crystalline forms, amorphous forms, racemic mixtures, non-racemic mixtures, diastereomers, enantiomers, tautomers compounds, conformers, isotopically labeled forms, prodrugs, and any combination thereof.

[0237] Selection of compounds within the scope of the invention or for use in the methods of the invention, including those that have been synthesized and tested - and / or represent various exemplary or preferred Hy substituents, R1a substituents , R1b substituent, R1c substituent, R1d substituent, R1e substituent, R2 substituent, R3 substituent, R4 substituent, R5 moiety, A moiety, B moiety, and / or E moiety, each alone or in any combination Other compounds useful in the synthesis of the present invention - are listed in Table A below. Table A: Kinase inhibitors of formula (Ia). compound serial number structure name E1 N-(2-Chloro-4-fluorothiophen-3-yl)-2-((6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-yl )amino)thiazole-5-carboxamide E2 N-(4-chloro-2-fluorothiophen-3-yl)-2-((6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-yl )amino)thiazole-5-carboxamide E3 N-(2-Chloro-4-(fluoromethyl)thiophen-3-yl)-2-((6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidine -4-yl)amino)thiazole-5-carboxamide E4 N-(2-Chloro-4-(difluoromethyl)thiophen-3-yl)-2-((6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methyl pyrimidin-4-yl)amino)thiazole-5-carboxamide E5 N-(2-Chloro-4-(trifluoromethyl)thiophen-3-yl)-2-((6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methyl pyrimidin-4-yl)amino)thiazole-5-carboxamide E6 N-(4-chloro-2-(fluoromethyl)thiophen-3-yl)-2-((6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidine -4-yl)amino)thiazole-5-carboxamide E7 N-(4-chloro-2-(difluoromethyl)thiophen-3-yl)-2-((6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methyl pyrimidin-4-yl)amino)thiazole-5-carboxamide E8 N-(4-chloro-2-(trifluoromethyl)thiophen-3-yl)-2-((6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methyl pyrimidin-4-yl)amino)thiazole-5-carboxamide E9 N-(2-chloro-4-(fluoromethyl)thiophen-3-yl)-2-((2-methyl-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl) Amino)thiazole-5-carboxamide E10 N-(2-chloro-4-(fluoromethyl)thiophen-3-yl)-2-((6-(3,4-dimethylpiperazin-1-yl)-2-methylpyrimidine-4 -yl)amino)thiazole-5-carboxamide E11 N-(2-Chloro-4-(fluoromethyl)thiophen-3-yl)-2-((2-methyl-6-(4-methyl-1,4-diazepam-1-yl) pyrimidin-4-yl)amino)thiazole-5-carboxamide E12 N-(2-Chloro-4-(fluoromethyl)thiophen-3-yl)-2-((2-methyl-6-(3-oxopiperazin-1-yl)pyrimidin-4-yl) Amino)thiazole-5-carboxamide E13 N-(2-chloro-4-(difluoromethyl)thiophen-3-yl)-2-((6-(3,4-dimethylpiperazin-1-yl)-2-methyl-pyrimidine -4-yl)amino)thiazole-5-carboxamide E14 N-(2-chloro-4-fluorothiophen-3-yl)-2-((2-methyl-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl)amino)thiazole -5-formamide E15 N-(4-chloro-2-fluorothiophen-3-yl)-2-((2-methyl-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl)amino)thiazole -5-formamide E16 N-(2-chloro-4-(difluoromethyl)thiophen-3-yl)-2-((2-methyl-6-(3,4-dimethylpiperazin-1-yl)pyrimidine- 4-yl)amino)thiazole-5-carboxamide

[0238] In particular embodiments, the compounds of the present invention are selected from E4, E9, E10 and E16; and their solvates, salts, N-oxides, complexes, polymorphs, crystalline forms, racemic Rotary mixtures, diastereomers, enantiomers, tautomers, conformers, isotopically labeled forms, prodrugs, and combinations thereof.

[0239] In certain embodiments, the compound of the invention is E9, or a solvate, salt, N-oxide, complex, polymorph, crystalline form, tautomer, conformational isomer, or Constructs, isotopically labeled forms, prodrugs, or combinations thereof.

[0240] In certain other embodiments, the compound of the invention is E4, or a solvate, salt, N-oxide, complex, polymorph, crystalline form, tautomer, configuration thereof Isomers, isotopically labeled forms, prodrugs, or combinations thereof.

[0241] In certain other embodiments, the compound of the present invention is E10, or a solvate, salt, N-oxide, complex, polymorph, crystalline form, tautomer, configuration thereof Isomers, isotopically labeled forms, prodrugs, or combinations thereof.

[0242] In certain other embodiments, the compound of the invention is E16, or a solvate, salt, N-oxide, complex, polymorph, crystalline form, racemic mixture, diastereomeric Isomers, enantiomers, tautomers, conformers, isotopically labeled forms, prodrugs, or combinations thereof.

[0243] In certain embodiments, the present invention may relate to solvates, salts, N-oxides, complexes, racemic mixtures, diastereoisomeric enantiomers, tautomers, conformers, isotopically labeled forms, prodrugs or combinations thereof; such as solvates, salts, complexes, racemic mixtures, non- Enantiomers, enantiomers, tautomers, conformers, isotopically labeled forms, or combinations thereof.

[0244] In one embodiment, the compound used in the present invention does not comprise the compound of one or more of the following groups (1) to (6) of formula (Ic) (in groups (1) to (6), Moieties (such as methyl) are not substituted unless it is stated that said moieties are substituted): (1) When R1a is 4-(2-hydroxyethyl)piperazin-1-yl or Cl, R1b is H; R1c is Methyl; B is N; E is O; R3 is H; A is S; and L is a bond; then R6'' is not 4-chloro-2-methylpyridin-3-yl; (2) when R1a is R1b is H; R1c is methoxy; B is N; E is O; R3 is H; A is S; and L is a bond; then R6'' is not 2,2-difluoro-5H- 1,3-Diazol[4,5-f]benzimidazol-6-yl; (3) When R3 is H; A is S; L is a bond; R6'' is 1-methyl-4-crop R1b is H; B is N; E is O; and (i) R1a is methyl; then R1c is not N-tert-butoxycarbonylpiperidin-4-yl; or (ii) R1c is methyl when; then R1a is not N-tert-butoxycarbonylpiperidin-4-yl or N-tert-butoxycarbonylpiperidin-3-yl; (4) when E is O; B is CR1d and R1d is H, F , Cl or Br, then R1a is not H; (5) when R1a is methyl; R1b and R1c are both H; B is CH; E is O; A is S; and R3 is methyl; then R5'' Not 1,3-benzodioxol-5-ylmethyl, 2-furylmethyl, 1,3-benzodioxolan-5-yl, 2-(2-thienyl)ethyl, 2 -(4-morpholinyl)ethyl, 2-(2-pyridyl)ethyl, 2-pyridylmethyl, or tetrahydro-2-furylmethyl; and (6) when A is S; R3 is H; E is O; L is a bond; R6'' is 1-[2,4-bis(trifluoromethyl)benzyl]-1H-pyrazol-4-yl; R1a is H, R1b is H, R1c is H; and B is CR1d; then R1d is not H.

[0245] In one embodiment, the compound used in the present invention does not comprise the compound of one or more of the following groups (7) to (10) of formula (Ib) (in groups (7) to (10) A moiety (eg methyl) is unsubstituted unless it is stated that said moiety is substituted): (7) when Hy is: and (i) when R1a is 4-(2-hydroxyethyl)piperazin-1-yl or Cl; R1b is H; R1c is methyl; B is N; E is O; R2 is H; R3 is H; R4 is H; and A is S; then R6' is not 4-chloro-2-picoline -3-yl; or (ii) when E is O; B is CR1d and R1d is H, F, Cl or Br; then R1a is not H; (8) when Hy is 1-{(2E)-4-[ (2-methoxyethyl)amino]-1-oxo-2-buten-1-yl}piperidin-4-yl; R2 is H; R3 is H; R4 is H; A is O; When E is O; then R6' is not 5-methyl-pyridin-2-yl; (9) when R2 is H; R3 is trifluoromethyl; R4 is H; A is O; E is O; and (i ) R6' is 6-{4-[(2-fluorophenyl)aminoformyl]piperazin-1-yl}pyridin-3-yl; then Hy is not 1-(phenylmethyl)- Pyridin-4-yl, 1-(phenylmethyl)pyrrolidin-3-yl or tetrahydro-2H-pyran-4-yl; or (ii) Hy is 1-(phenylmethyl)pyrrolidinyl- 4-base; then R6' is not 6-(3-{[(2-fluorophenyl)aminoformyl]amino}-pyrrolidin-1-yl)pyridin-3-yl or 6-({1-[(2-fluorophenyl)aminoformyl]piperidin-4-yl}amino)pyridin-3-yl; or (iii) Hy is 1-(phenylmethyl)pyrrolidin-3 - radical; then R6' is not 6-({(3S)-1-[(2-fluorophenyl)aminoformyl]-pyrrolidin-3-yl}amino)pyridin-3-yl or 6 -({(3R)-1-[(2-fluorophenyl)aminoformyl]pyrrolidin-3-yl}-amino)pyridin-3-yl; (10) When A is S; R3 is H; E is O; and R6' is 1-[2,4-bis(trifluoromethyl)benzyl]-1H-pyrazol-4-yl; then Hy is not 2-pyridyl.

[0246] In certain other embodiments, the compound used in the present invention is not one selected from: 1 5-thiazole carboxamide, 2-[(6-chloro-2-methyl-4-pyrimidinyl) Amino]-N-[2-[4-(2-hydroxyethyl)-1-piperazinyl]-6-methylphenyl]- (CAS registry number: 2048106-50-7), l 5- Thiazole carboxamide, 2-[[7-[4-cyano-3-(trifluoromethyl)phenyl]-5,6,7,8-tetrahydropyridino[3,4-d]pyrimidine-4 -yl]amino]-N-[(1R)-1-(1,3,4-oxadiazol-2-yl)ethyl]-4-(trifluoromethyl)-(CAS registration number: 1831086 - 00-0), l 5-thiazole carboxamide, 2-[[6-methoxy-7-[3-(4-morpholinyl)propoxy]-4-quinazolinyl]amino ] -N-(2-pyrazinylmethyl)-(CAS registry number: 385780-87-0), l 5-thiazole carboxamide, 2-[[6-methoxy-7-[3-( 4-morpholinyl)propoxy]-4-quinazolinyl]amino]-N-[2-(3-pyridyl)ethyl]-(CAS registry number: 385780-82-5), l 5-Thiazolamide, N-1H-indol-5-yl-2-[[6-methoxy-7-[3-(4-morpholinyl)propoxy]-4-quinazoline Base]amino]-(CAS registration number: 385780-79-0), l 5-thiazole carboxamide, 2-[[6-methoxy-7-[3-(4-morpholinyl)propoxy base]-4-quinazolinyl]amino]-N-(2-thienylmethyl)-(CAS registration number: 385780-69-8), l 5-thiazoleformamide, N-(2-furan Methyl)-2-[[6-methoxy-7-[3-(4-morpholinyl)propoxy]-4-quinazolinyl]amino]-(CAS registry number: 385780-66 - 5), l 5-thiazole carboxamide, 2-[[6-methoxy-7-[3-(4-morpholinyl)propoxy]-4-quinazolinyl]amino]- N -2-pyridyl- (CAS registration number: 385780-57-4), and l 5-thiazole carboxamide, 2-[[6-methoxy-7-[3-(4-morpholinyl) Propoxy]-4-quinazolinyl]amino]-N-4-pyridyl- (CAS Reg. No.: 385779-93-1).

[0247] In other certain embodiments, the compound used in the present invention is not selected from the following one: 1 imidazoline[4,5-d]pyrrole[2,3-b]pyridine-7-carboxamide, N , N-dicyclopropyl-6-ethyl-1,6-dihydro-1-methyl-4-[[4-methyl-5-[[(tetrahydro-2H-pyran-4- base)amino]carbonyl]-2-thiazolyl]amino]-(CAS registration number: 1271022-78-6), l imidazoline[4,5-d]pyrrole[2,3-b]pyridine-7 -Formamide, N, N-dicyclopropyl-6-ethyl-1,6-dihydro-1-methyl-4-[[4-methyl-5-[[(tetrahydro-1, 1-dioxide-3-thiophene)amino]carbonyl]-2-thiazolyl]amino]-(CAS registry number: 1271022-57-1), l imidazoline[4,5-d]pyrrole[2, 3-b]pyridine-7-carboxamide, N, N-dicyclopropyl-6-ethyl-1,6-dihydro-1-methyl-4-[[4-methyl-5-[ [[2-(4-morpholinyl)ethyl]amino]carbonyl]-2-thiazolyl]amino]-(CAS registry number: 1271022-45-7) and l imidazoline[4,5-d ]pyrrole[2,3-b]pyridine-7-carboxamide, N, N-dicyclopropyl-6-ethyl-1,6-dihydro-1-methyl-4-[[5-[ [Methyl(tetrahydro-1,1-dioxide-3-thiophene)amino]carbonyl]-2-thiazolyl]amino]-(CAS registration number: 1271021-43-2) l 2-[(6 - {[3-(1H-imidazol-1-yl)propyl]amino}pyridin-2-yl)amino]-4-methyl-N-[1-(phenylmethyl)-1H-ind Azol-5-yl]-1,3-thiazole-5-carboxamide (CAS registration number: 302963-64-0) l 2-[(6-{[3-(1H-imidazol-1-yl)propane Base]amino}pyridin-2-yl)amino]-N-[1-(phenylmethyl)-1H-indazol-5-yl]-1,3-thiazole-5-carboxamide (CAS Registration number: 302963-55-9)

[0248] In certain alternatives of one or more aspects herein (particularly the fifth aspect of the invention), the compound is N-(2-chloro-6-methylphenyl)-2-((6 -(4-(2-Hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-yl)amino)thiazole-5-carboxamide (A8; Figure 1A), especially one of Hydrate (dasatinib).

[0249] In certain other alternatives of one or more aspects herein (particularly the fifth aspect of the invention), the compound is ARN-3261 (Vankayalapati et al 2017, AACR Cancer Res 77(13 Suppl): Abstract nr LB-296; US 9,260,426, US 9,890,153, US 9,951,062).

[0250] Compounds of the invention (and / or compounds used in accordance with the invention) containing basic functional groups can form salts with a variety of inorganic or organic acids. Compounds of the invention (and / or compounds used in the invention) containing acidic functional groups can form salts with a variety of inorganic or organic bases. Exemplary inorganic and organic acids / bases and exemplary acid / base addition salts of compounds of the invention (or compounds used in the invention) are given in the definition of "pharmaceutically acceptable salts" in the "Pharmaceutical Compositions" section below. out. Compounds of the invention (and / or compounds used in the invention) containing basic and acidic functional groups can be converted into base or acid addition salts. Neutral forms of compounds of the invention (or compounds used in the invention) can be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.

[0251] Compounds of the invention (and / or compounds used in the invention) may be in the form of N-oxides, i.e., they may contain functional groups Functional groups ≡N+-O- (for example, (Rn)3N+-O-, i.e. N-O Coordination covalent bond, wherein Rn is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl and heterocyclyl, wherein alkyl, alkenyl, alkynyl, aryl, Each of heteroaryl, cycloalkyl, and heterocyclyl is optionally replaced by one or more (for example, with alkyl, alkenyl, chloro, aryl, heteroaryl, cycloalkyl, or hetero The maximum number of hydrogen atoms bound by the cyclic group is from 1 to the maximum number, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9 or up to 10, such as between 1 to 5, 1 to 4, or 1 3, or 1 or 2) independently selected R30 substitution, R30 is preferably a primary substituent, secondary substituent, or tertiary substituent specified herein). Particular examples of N-oxides of compounds of the invention (or compounds used according to the invention) are those wherein R1a and / or R6 (or R6' or R6'') contain the functional group ≡N+-O-. Non-limiting examples of R1a substituents that can occur as N-oxides include the following: Partially bound keys. Non-limiting examples of R6'' substituents that can occur as N-oxides include the following: , , , , and , where represents the linkage of the R6'' substituent to the rest of the compound.

[0252] Compounds of the invention (and / or compounds used in the invention) may be in the form of prodrugs. Prodrugs of the compounds of the invention (or of the compounds used in the invention) are those compounds which, upon administration to a subject, are chemically transformed under physiological conditions to provide the compounds of the invention. In addition, prodrugs can be converted to compounds of the invention (or compounds used in the invention) by chemical or biochemical methods in an in vitro environment. For example, prodrugs can be slowly converted to compounds of the invention (or compounds used in the invention), eg, when placed in a transdermal patch reservoir with suitable enzymes or chemical reagents. Exemplary prodrugs are esters (using alcohol or carboxyl groups contained in the kinase inhibitors of the invention (or in the compounds used in the invention)) or amides (using the alcohols or carboxyl groups contained in the kinase inhibitors of the invention (or used in the invention) compounds)), which are hydrolyzed in vivo. In particular, any amine group contained in a kinase inhibitor of the invention (or in a compound used in the invention) and bearing at least one hydrogen atom can be converted into a prodrug form. Typical N-prodrug forms include carbamates (1), mannichons (2), enamines (3) and enaminones (4). (1) (2) (3) (4) wherein R18 is independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl, wherein alkyl, alkenyl, Each of the alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups is optionally replaced by one or more (e.g., with alkyl, alkenyl, plastic, cycloalkyl, aryl , heteroaryl, or heterocyclyl, the maximum number of hydrogen atoms bound is from 1 to the maximum number, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9 or up to 10, such as between 1 and 5 , 1 to 4, or 1 to 3, or 1 or 2) independently selected R30 substitutions, wherein R30 is as defined herein (preferably, each R30 is independently a primary substituent, a secondary substituent as described herein group or tertiary substituent). Prodrug properties (such as solubility, permeability, stability, cleavage speed, under what conditions are cleaved in vivo, target specificity, etc.) can be fine-tuned by modifying R18.

[0253] A particular prodrug form of a compound of the invention (or a compound for use in the invention) is one having the formula (IXa), (Xa), (XIa) or (XIIa) (or (IXb), (Xb), (IXc) or (Xc)) (prodrugs): (IXa) (Xa) (XIa) (XIIa) (IXb) (Xb) (IXc) (Xc) and solvates, salts, N-oxides, complexes , polymorphs, crystalline forms, racemic mixtures, diastereomers, enantiomers, tautomers, configurational isomers, isotopically labeled forms and combinations thereof, wherein R1a, R1b , R1c, R3, R5, R5', R5'', A, B, E and Hy as above (especially with respect to formulas (Ia), (IIa), (IIIa), (IVa), (Va), (VIa) , (VIIa), (VIIIa), (Ib), (IIb), (IIIb), (Ic), (IIc), (IIIc), (IVc), (Vc), (VIc), (VIIc) and / or or (VIIIc)) or as defined below, and each of R2 and R4 is independently selected from H, -P(O)(OR11a)2, -(CH2)1-3-R19, -C(=Xa) R11a and -C(=Xa)XaR11a, with the proviso that not both R2 and R4 are H, wherein R11a is independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl , wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl groups is optionally replaced by one or more (e.g. with alkyl, alkenyl, alkyne The maximum number of hydrogen atoms bound to a radical, cycloalkyl, aryl, heteroaryl or heterocyclyl group is from 1 to the maximum number, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9 or Up to 10, such as between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2) R30 substitutions independently selected; R19 independently selected from -OP(O)(OR11a)2, -XaC(=Xa) R11a , -XaC(=Xa)XaR11a and 5-alkyl-2-oxo-1,3-two oxazol-4-yl; Xa is independently selected from O, S and NH; and -(CH2)1-3- The group is optionally substituted with one or two independently selected R30, wherein R30 is as defined herein (preferably, each R30 is independently selected from primary substituents, secondary substituents and tertiary substituents as specified herein base). In one embodiment of the prodrug form of formula (IXa), (Xa), (XIa), (XIIa), (IXb), (Xb), (IXc) or (Xc), R1a, R1b, R1c, R3 , R5, R5', R5'', A, B, E and Hy as above (especially with respect to formulas (Ia), (IIa), (IIIa), (IVa), (Va), (VIa), (VIIa) , (VIIIa), (Ib), (IIb), (IIIb), (Ic), (IIc), (IIIc), (IVc), (Vc), (VIc), (VIIc) and / or (VIIIc) ) or as defined below, and each of R2 and R4 is independently selected from H, -P(O)(OR11a)2, -(CH2)1-3-R19, -C(=O)R11a and -C (=O)OR11a, with the proviso that not both R2 and R4 are H, wherein R11a is independently selected from H and C1-6 alkyl (preferably C1-3 alkyl), wherein the alkyl group is optionally selected from halogen , -OH, -OCH3, -SCH3, 2-(N, N-dimethylamino)ethoxy and -NH2-z(CH3)z groups where z is 0 , 1 or 2; R19 is independently selected from -OP(O)(OR11a)2, -OC(=O)R11a, -OC(=O)OR11a and 5-(C1-3 alkyl)-2-oxo-1 , 3-dioxazol-4-yl; and -(CH2)1-3-groups are optionally independently selected from halogen, -OH, -OCH3, -SCH3, 2-(N, N-dimethyl Amino)ethoxy and one or both moieties of -NH2-z(CH3)z, where z is 0, 1 or 2.

[0254] For any one of formula (Ia), (IIa), (IIIa), (IVa), (Va), (VIa), (VIIa), (VIIIa), (IXa), (Xa), (XIa ) and (XIIa) (or for compounds of the invention having any of the formulas (Ib), (IIb), (IIIb), (IXb), (Xb), (Ic), (IIc), (IIIc), (IVc ), (Vc), (VIc), (VIIc), (VIIIc), (IXc) and (Xc) compounds used in the present invention) and have one or more hydroxyl (ie -OH) groups, another A particular prodrug form is one in which at least one of the two or more hydroxyl groups is derivatized to be selected from the group consisting of -OP(O)(OR11a)2, -O(CH2)1-3-R19, -OC(=Xa) A moiety of R11a and -OC(=Xa)XaR11a, wherein R11a is independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl, wherein alkyl, alkenyl, Each of alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl is optionally replaced by one or more (such as with alkyl, alkenyl, plastic, cycloalkyl, aryl, heteroaryl 1 to the maximum number of hydrogen atoms bound to a radical or heterocyclyl group, for example 1, 2, 3, 4, 5, 6, 7, 8, 9 or up to 10, for example between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2) independently selected R30 substitution; R19 independently selected from -OP(O)(OR11a)2, -XaC(=Xa)R11a, -XaC(=Xa)XaR11a, and 5-alkyl -2-oxo-1,3-two oxazol-4-yl; Xa is independently selected from O, S and NH; and -(CH2)1-3-group is optionally replaced by one or two independently selected R30 Substitution, wherein R30 is as defined herein (preferably, each R30 is independently selected from primary substituents, secondary substituents and tertiary substituents specified herein). In one embodiment of this prodrug form of a compound of the invention (or a compound used in the invention), at least one derivatized hydroxyl group is selected from -OP(O)(OR11a)2, -O(CH2)1-3 -R19, -OC(=O)R11a and -OC(O)OR11a, wherein R11a is independently selected from H and C1-6 alkyl (preferably C1-3 alkyl), wherein the alkyl group is optionally One or two partial substitutions of groups independently selected from halogen, -OH, -OCH3, -SCH3, 2-(N,N-dimethylamino)ethoxy and -NH2-z(CH3)z, wherein z is 0, 1 or 2; R19 is independently selected from -OP(O)(OR11a)2, -OC(=O)R11a, -OC(=O)OR11a and 5-(C1-3 alkyl)-2 -Oxy-1,3-dioxazol-4-yl; and -(CH2)1-3-groups are optionally independently selected from halogen, -OH, -OCH3, -SCH3, 2-(N, N -Dimethylamino)ethoxy and one or both moieties of -NH2-z(CH3)z, where z is 0, 1 or 2.

[0255] In certain embodiments, the invention (or compounds used in the invention, such as used in the fifth aspect of the invention) may involve ) (or the solvates, salts, N-oxides, complexes, racemic mixtures, diastereomers, Enantiomers, tautomers, conformers, isotopically labeled forms or combinations thereof; such as solvates, salts, complexes, racemic mixtures, diastereoisomers of these prodrugs , enantiomers, tautomers, conformers, isotopically labeled forms, or combinations thereof.

[0256] In a particular embodiment, a compound of the invention (or a compound for use in the invention) is a hydrate, suitably a monohydrate or a dihydrate of a kinase inhibitor, as described under the heading "Compounds" (e.g., a kinase inhibitor of general formula (Ia), (IIa), (IIIa), (IVa), (Va), (VIa), (VIIa) or (VIIIa) (or of general formula (Ib) , (IIb), (IIIb), (Ic), (IIc), (IIIc), (IVc), (Vc), (VIc), (VIIc), or (VIIIc) compounds), or solvates, salts (especially pharmaceutically acceptable salts), N-oxides (especially N-oxides of R1a and / or R6''), complexes, polymorphs, crystalline forms, racemic mixtures, non- Enantiomers, enantiomers, tautomers, conformers, isotopically labeled forms, prodrugs (especially of formula (IXa), (Xa), (XIa) or (XIIa) ( or a prodrug of (IXb), (Xb), (IXc) or (Xc)) and / or having at least one derivatized hydroxyl group, as specified above, or a solvate, salt, N-oxide, complex polymorphs, crystalline forms, racemic mixtures, diastereomers, enantiomers, tautomers, conformers, isotopically labeled forms or combinations thereof) or combinations thereof ). In another suitable embodiment, the compound of the invention (or a compound for use in the invention) is the hemihydrate of such a kinase inhibitor.

[0257] In certain embodiments, compounds of the invention (eg, as specified under the heading "Compounds") can be (eg, provided as) purified or (eg, substantially) pure form. For example, the compound may have a purity of greater than about 50%, such as greater than about 60%, 70% or 80%, suitably greater than about 90% (especially greater than about 95%, 97% or 98%) or even 99%). That is, in certain such embodiments, such compounds are present only with limited amounts of impurities (e.g., those introduced during manufacturing), such as only small amounts of impurities, including where the compound is present substantially absent form of impurities. The purity (eg, the degree or absence of impurities) of a compound can be determined by routine procedures, eg, by HLPC.

[0258] In one embodiment, the present invention provides compounds that contain less than about 50%, 40%, 30%, and suitably 10% or 5% HPLC area, preferably less than about 3% and 2% HPLC area area, more preferably total impurities less than 1% HPLC area. The term "% HPLC area" as used herein refers to the area of ​​one or more peaks in an HPLC chromatogram compared to the total area of ​​all peaks in the HPLC chromatogram expressed as a percentage of the total area. Furthermore, the purity of a compound may be expressed herein as "HPLC" purity. Therefore, "HPLC purity" is a calculation of the area under the peak of the compound divided by the total area under the curve in the HPLC chromatogram. More suitably, the compound contains less than about 10% HPLC total impurity area. More preferably, the HPLC area of ​​total impurities is less than about 5%.

[0259] In related aspects, and as may be further described, defined, claimed or otherwise disclosed herein, the present invention provides one or more containers, wherein the containers (each independently or all collectively) comprise the first aspect Kinase inhibitors or compounds used in the fifth aspect (for example, having the general formula (Ia), (IIa), (IIIa), (IVa), (Va), (VIa), (VIIa), or (VIIIa) Kinase inhibitors (or compounds of formula (Ib), (IIb), (IIIb), (Ic), (IIc), (IIIc), (IVc), (Vc), (VIc), (VIIc) , or the compound of (VIIIc)), or solvates, salts (especially pharmaceutically acceptable salts), N-oxides (especially N-oxides of R1a and / or R6''), complexes, Polymorphs, crystalline forms, racemic mixtures, diastereomers, enantiomers, tautomers, conformers, isotopically labeled forms, prodrugs (especially of formula (IXa ), (Xa), (XIa) or (XIIa) (or a prodrug in (IXb), (Xb), (IXc), or (Xc) and / or having at least one derivatized hydroxyl group, as specified above , or solvates, salts, N-oxides, complexes, polymorphs, crystalline forms, racemic mixtures, diastereomers, enantiomers, tautomers, conformational isomers Constructs, isotope-labeled forms (or combinations thereof) in excess of about 10 mg; particularly in excess of about 50 mg or 100 mg; suitable amounts greater than about 1 g, 10 g, 50 g or 100 g; or greater than about 500 g or 1 Kg.

[0260] In another aspect, the present invention provides compounds of the invention (especially above with respect to formulas (Ia), (IIa), (IIIa), (IVa), (Va), (VIa), (VIIa) and (VIIIa)) for use as a medicament, for example in therapy. In one embodiment of the fifth aspect, the compounds for use in the present invention do not include the compounds having formula (Ic) belonging to groups (1), (2), (3), (4), (5) and / or one or more compounds in (6) (such as group (1) (especially when R1a is 4-(2-hydroxyethyl) piperazin-1-yl group (1) compound), ( 2) and / or (4) (especially the compound 2-[(6-{[3-(1H-imidazol-1-yl)propyl]amino}pyridin-2-yl)amino]-4-methyl Base-N-[1-(phenylmethyl)-1H-indazol-5-yl]-1, 3-thiazole-5-carboxamide and 2-[(6-{[3-(1H-imidazole -1-yl)propyl]amino}propyl-2-yl)amino]-N-[1-(phenylmethyl)-1H-indazol-5-yl]-1,3-thiazole- 5-Formamide) in one or more compounds. In one embodiment of this aspect, the compound used in the fifth aspect of the present invention does not include having formula (Ib) and belonging to group (7) as described above (for example, one of groups (7)(i), (8), (9) and / or (10) especially when R1a is 4-(2-hydroxyethyl)piperazin-1-yl or multiple compounds.

[0261] As is evident from the Examples, the inventors have discovered that the compounds of the present invention, as well as other structurally similar compounds, inhibit one or more protein tyrosine kinases, including those selected from the group consisting of SIK3, ABL / BCR-ABL and CSF1R , or selected from SRC, HCK, PDGFR and KIT, or selected from ABL1 / BCR-ABL, SRC, LCK, KIT, FLT3 and mutants thereof, and / or SIK1, SIK2 and SIK3, and / or PHA2, EPHA4, CSFR1 , HCK, and ACK1; and / or any of NEK11, WEE1, WNK2, Aurora-A, Aurora-B, and TBK1. In one embodiment, the pharmacological properties (selectivity, bioavailability, toxicity, side effects, dosage, patient compliance, compatibility, stability, half-life, etc.) exhibited by the compounds of the present invention are at least in one aspect superior to those of up to Pharmacological properties exhibited by satinib.

[0262] In one embodiment, the compounds of the invention exhibit, inter alia, a different kinase profile than the kinases inhibited by dasatinib and / or compound B3 (WO 2018 / 193084). In one embodiment, the compounds of the invention are kinase inhibitors that: (i) inhibit one or more key disease-associated kinases (e.g., ABL / BCR-ABL, SRC, HCK, PDGFR, KIT and / or CSF1R, and / or EPHA2, EPHA4, ACK1, and / or KIT, and / or LCK) specificity than dasatinib (and / or Compound B3) for one or more of these other kinases (ii) inhibit key disease- or side-effect-associated kinases with a different profile than dasatinib (e.g., KIT and / or FLT3) and / or Compound B3; and / or (iii) inhibit a Mutants of one or more disease-associated kinases, especially mutants resistant to one or other kinase inhibitors, such as mutants of ABL / BCR-ABL or KIT.

[0263] In another embodiment, the compounds of the present invention exhibit one or more pharmacological properties different from dasatinib, compound B3 (WO 2018 / 193084) and / or compound C7 (PCT / EP2019 / 078751) academic characteristics. This difference in pharmacological properties may result in the administration of the compounds of the invention in different treatment regimens than, for example, dasatinib. Such properties may be one or more improved DMPK properties such as those described in Example 5.2 (eg AUC, plasma concentration and / or free plasma concentration).

[0264] Pharmaceutical composition

[0265] Compounds of the present invention (especially those specified above as formula (Ia), (IIa), (IIIa), (IVa), (Va), (VIa), (VIIa) or (VIIIa) Compounds of those, especially those given in Table A) or compounds used in the present invention (especially those specified above as formulas (Ib), (IIb), (IIIb), (Ic), (IIc) , (IIIc), (IVc), (Vc), (VIc), (VIIc), or (VIIIc)) are preferably administered to a patient in need thereof via a pharmaceutical composition. Accordingly, in a second aspect, the present invention provides a pharmaceutical composition comprising a kinase inhibitor as specified above under the heading "Compounds" (for example, having the general formula (Ia), (IIa), (IIIa), (IVa), (Va), (VIa), (VIIa) or (VIIIa), or solvates, salts (especially pharmaceutically acceptable salts), N-oxides (especially N-oxides of R1a ), complexes, polymorphs, crystalline forms, racemic mixtures, diastereomers, enantiomers, tautomers, conformers, isotopically labeled forms, prodrugs (especially prodrugs of formula (IXa), (Xa), (XIa), or (XIIa) and / or having at least one derivatized hydroxyl group, as specified above, or solvates, salts, N-oxides, zirconium compounds, polymorphs, crystalline forms, racemic mixtures, diastereomers, enantiomers, tautomers, conformers, isotopically labeled forms or combinations thereof) or combination) and optionally one or more pharmaceutically acceptable excipients.

[0266] Accordingly, in one embodiment, the pharmaceutical composition comprises a kinase inhibitor as specified above under the heading "Compounds" (particularly a compound of the first aspect of the invention) and one or more pharmaceutically acceptable excipients Forming agent. In addition, pharmaceutical compositions may also contain one or more additional therapeutic agents. Thus, in a particular embodiment, the pharmaceutical composition comprises (i) a kinase inhibitor as specified above under the heading "Compounds" (in particular a compound of the first aspect of the invention) and one or more additional therapeutic agents; or (ii) a kinase inhibitor as specified above under the heading "Compounds" (in particular a compound of the first aspect of the invention), one or more additional therapeutic agents and one or more pharmaceutically acceptable excipients .

[0267] The term "pharmaceutically acceptable" means that it is not combined with a pharmaceutical composition (eg, a kinase inhibitor of the invention (or a compound for use in the invention), alone or in combination with one or more additional therapeutic agents) The (eg, therapeutic) action of the active ingredient interacts with the non-toxic substance of the material.

[0268] The pharmaceutical compositions may be administered to a subject by any route, eg enteral or parenteral.

[0269] As used herein, the expressions "enterally administered" and "administered enterally" mean that the administered drug is absorbed by the stomach and / or intestine. Examples of enteral administration include oral and rectal administration. As used herein, the expressions "parenteral administration" and "administered parenterally" refer to modes of administration other than enteral administration, usually by injection or topical application, including but not limited to intravenous, intramuscular, intraarterial, Intrathecal, intracapsular, intraosseous, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, intracerebral, intraventricular, subarachnoid, intraspinal, Epidural and intrasternal (eg, by injection and / or infusion) and topical (eg, subcutaneous, inhalation, or via mucous membranes (eg, buccal, sublingual, or vaginal)). Dosage forms for topical and / or transdermal administration of the compounds described herein may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants and / or or patches. Generally, the active ingredient is mixed under sterile conditions with a pharmaceutically acceptable excipient such as one or more pharmaceutically acceptable carriers and / or any required preservatives and / or buffers. Furthermore, the disclosure herein contemplates the use of transdermal patches, which generally have the added advantage of providing controlled delivery of active ingredients to the body. Such dosage forms can be prepared, for example, by dissolving and / or dispersing the active ingredient in the proper medium. Alternatively, or in addition, the rate may be controlled by providing a rate controlling membrane and / or by dispersing the active ingredient in a polymer matrix and / or gel.

[0271] Suitable devices for delivering the intradermal pharmaceutical compositions described herein include short needle devices. Intradermal compositions can be administered through devices that limit the effective penetration length of a needle into the skin. Alternatively, or in addition, conventional syringes can be used for the classic Manto method of intradermal administration. Jet injection devices that deliver liquid formulations to the dermis via a liquid jet injector and / or via a needle that pierces the stratum corneum and produces a jet that reaches the dermis are suitable. Ballistic powder / particle delivery devices that use compressed gas to accelerate the compound in powder form through the outer layers of the skin to the dermis are suitable. Formulations suitable for topical administration include, but are not limited to, liquid and / or semi-liquid formulations, such as liniments, lotions, oil-in-water and / or water-in-oil emulsions, such as creams, ointments, and / or pastes agents, and / or solutions and / or suspensions. Topically administrable formulations may, for example, contain from about 1% to about 10% (w / w) active ingredient, although the concentration of active ingredient may be as high as the solubility limit of the active ingredient in the solvent. Formulations for topical administration may also contain one or more additional ingredients as described herein.

[0273] The compound of the present invention (or the compound used in the present invention) is usually used in "pharmaceutically acceptable amount" and "pharmaceutically acceptable formulation". Such compositions may contain salts, buffers, preservatives, carriers and optionally other therapeutic agents. "Pharmaceutically acceptable salt" includes, for example, acid addition salts, which can be obtained, for example, by mixing a solution of the compound with a pharmaceutically acceptable acid (such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, etc.). (benzoic acid), citric acid, tartaric acid, carbonic acid or phosphoric acid). In addition, when the compound bears an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts (such as sodium or potassium salts); alkaline earth metal salts (such as calcium or magnesium salts); Ligand-formed salts (e.g., ammonium, quaternary ammonium, and amine cations using counteranions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, alkylsulfonates, and aryl sulfonate formation). Exemplary examples of pharmaceutically acceptable salts include, but are not limited to, acetate, adipate, alginate, arginate, ascorbate , aspartate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate (borate), bromide, butyrate, calcium edetate, camphorate, camphorsulfonate, dextrocamsylate, carbonate, chlorine compound, citrate, clavulanate, cyclopentanepropionate, digluconate, dihydrochloride, dodecylsulfate, edetate, edisylate, estolate, esylate, ethanesulfonate, formate, fumaric acid Salt (fumarate), galactate, galacturonate, gluceptate, glucoheptonate, gluconate, glutamine glutamate, glycerophosphate, glycolylarsanilate, hemisulfate, heptanoate, hexanoate, hexyl m-phenyl Hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, hydroxynaphthoate (hydroxynaphthoate), iodide, isobutyrate, isosulfurate, lactate, lactobionate, laurate, lauryl sulfate, apple Malate, maleate, malonate, mandelate, mesylate, methyl methanesulfonate, methyl sulfate, mucate (mucate), 2-naphthalenesulfonate, napsylate, nicotinate, nitrate, N-methylglucamine ammonium salt, oleate ), oxalate (oxalate), pamoate (pamoate) (pamoate) (embonate), palmitate (palmitate), pantothenate (pantothenate), pectate (pectinate), over Sulfate (persulfate), 3-cyclopropionate, phosphate / diphosphate, phthalate, picrate, pivalate, polygalacturonate ), propionate, salicylate, stearate, sulfate, suberate, succinate, tannate, tartrate, 8-chlorophylline Teoclate, tosylate, triethyl iodide, undecanoate, valerate, etc. (see, for example, Berge et al., "Pharmaceutical Salts", J. Pharm. Sci., 66, pp. . 1-19 (1977)).

[0274] The term "excipient" as used herein is intended to mean all substances in a pharmaceutical composition that are not active ingredients (eg, they are therapeutically inactive ingredients that do not exhibit any therapeutic effect in the amounts / concentrations used) , for example, carriers, binders, lubricants, thickeners, surfactants, preservatives, stabilizers, emulsifiers, buffers, flavoring agents, coloring agents or antioxidants.

[0275] The compositions described in this invention may comprise a pharmaceutically acceptable carrier. As used herein, "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, and the like that are physiologically compatible. A "pharmaceutically acceptable carrier" can be in the form of solid, semi-solid, liquid or a combination thereof. Preferably, the carrier is suitable for enteral (eg oral) or parenteral (eg intravenous, intramuscular, subcutaneous, spinal or epidermal administration (eg injection or infusion)) administration. Depending on the route of administration, an active compound, such as a compound of the invention (or a compound for use in the invention), alone or in combination with one or more additional therapeutic agents, may be coated in a material to protect the active compound from acid and other natural conditions that may inactivate the active compound.

[0276] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical composition according to the present invention include water (such as water for injection), ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.), salts Aqueous solutions, carbohydrates, sugar alcohols, or aqueous solutions of amino acids (such as saline or aqueous amino acids) and suitable mixtures thereof and / or buffered forms thereof, vegetable oils (such as olive oil) and injectable organic esters (such as oil ethyl acetate). Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by maintaining the desired particle size in the case of dispersions, and by the use of surfactants.

[0277] Pharmaceutically acceptable carriers include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. The use of such media and agents for pharmaceutically active compounds is known in the art. Unless any conventional media or agents are incompatible with the active compounds, their use in the pharmaceutical compositions according to the invention is contemplated.

[0278] The additional therapeutic agent may be with, before or after the compound of the present invention, or with the compound used in the present invention (particularly as specified above, such as formula (Ia), (IIa), (IIIa ), (IVa), (Va), (VIa), (VIIa), (VIIIa), (Ib), (IIb), (IIIb), (Ic), (IIc), (IIIc), (IVc), (Vc), (VIc), (VIIc), or (VIIIc)) together, before or after them, or incorporated into the composition. In one embodiment, the pharmaceutical compositions described herein comprise a kinase inhibitor of the invention (or a compound as used in the invention) as described above (eg, of general formula (Ia), (IIa), (IIIa) , (IVa), (Va), (VIa), (VIIa), (VIIIa), (Ib), (IIb), (IIIb), (Ic), (IIc), (IIIc), (IVc), ( Vc), (VIc), (VIIc), or (VIIIc) or solvates, salts (especially pharmaceutically acceptable salts), N-oxides (especially N of R1a, R6' and / or R6'' -oxides), complexes, polymorphs, crystalline forms, racemic mixtures, diastereomers, enantiomers, tautomers, conformers, isotopically labeled forms , prodrugs (especially of formula (IXa), (Xa), (XIa), (XIIa), (IXb), (Xb), (IXc), or (Xc) and / or prodrugs having at least one derivatized hydroxyl group , as specified above, or solvates, salts, N-oxides, complexes, polymorphs, crystalline forms, racemic mixtures, diastereomers, enantiomers, tautomers compound, conformer, isotopically labeled form, or a combination thereof), or a combination of any of the foregoing), at least one additional therapeutic agent, and one or more pharmaceutically acceptable excipients.

[0279] "Additional therapeutic agent" (which in one embodiment is not a kinase inhibitor of formula (Ia) as described herein, or in another embodiment (i) is not a kinase inhibitor of formula (Ia) as described herein ) is a kinase inhibitor; (ii) is not a compound of formula (Ib) as described herein; and (iii) is not a compound of formula (IIIa) as described herein, or may in another embodiment be of formula (Ia) Different kinase inhibitors, or in another embodiment may be different kinase inhibitors of formula (Ia), (Ib) and / or (Ic)) may be selected from those useful in the treatment as a proliferative disorder and / or by Any compound that causes or is associated with a disorder, disease or condition: (i) (e.g. erroneous) expression and / or activity of kinases such as SRC, ABL / BCR-ABL, HCK, PDGFR CSFR1, LCK, SIK1, SIK2, SIK3, FLT3, and / or KIT; and / or PHA2, EPHA4, and ACK1; and / or NEK11, WEE1, WNK2, Aurora-A, Aurora-B, and TBK1, and / or (ii) pairs (e.g., mediated induced) immune response to cellular resistance. Examples of suitable additional therapeutic agents are defined or disclosed elsewhere herein, including EGFR inhibitors, gemcitabine, docetaxel and immune checkpoint inhibitors (such as inhibitors of PD1, PDL1, CTLA-4, LAG3 or IDO1, In particular immune checkpoint inhibitors selected from the group consisting of nivolumab, rilarizumab, ipilimumab and BMS-986205), agonists of TNF or TNFR1- or TNFR2-signaling, adoptive cell therapy ( including CAR T cells targeting tumor antigens), vaccines (including dendritic cell (DC)-based vaccination), or agonists capable of inducing or exposing cells involved in proliferative diseases to TNF or TNFR1-signaling The medicament is administered to the subject. Additional therapeutic agents may induce additive or synergistic therapeutic effects.

[0280] In addition to the kinase inhibitors of the invention (and / or the compounds used in the invention), the pharmaceutical compositions described herein may comprise at least one of, for example, 1, 2, 3, 4, 5, 6, 7 or 8 additional therapeutic agents. In accordance with the teachings herein, at least one additional therapeutic agent can be formulated with a kinase inhibitor of the invention (and / or with a compound for use in the invention) in a single pharmaceutical composition. Alternatively, the pharmaceutical composition may be configured as a kit, wherein the kinase inhibitor of the invention (or a compound for use in the invention) is provided in a first formulation and at least one additional therapeutic agent is provided in a second formulation (i.e., provided in the second pharmaceutical composition). The first and second pharmaceutical compositions may be combined prior to use. In other words, a formulation comprising an additional therapeutic agent can be added to a first pharmaceutical composition comprising a kinase inhibitor of the invention (or a compound used in the invention) prior to administration of the pharmaceutical composition. Alternatively, the teachings herein contemplate the administration of a kinase inhibitor of the invention (or a compound for use in the invention) formulated in a first pharmaceutical composition and at least one additional therapeutic agent formulated in a second pharmaceutical composition . The pharmaceutical compositions can be administered simultaneously or sequentially. For example, a first pharmaceutical composition may be administered at a first time point and a second pharmaceutical composition may be administered at a second time point, wherein the time points may be separated by, f...

Claims

1. A compound selected from the group consisting of a kinase inhibitor of the following formula: (Ia), and its solvates, salts, N-oxides, complexes, polymorphs, crystalline forms, racemic mixtures, diastereomers, enantiomers, tautomers, conformational isomers, isotopically labeled forms, prodrugs, and combinations thereof; wherein: Hy is a heteroaryl or heterocyclic group, optionally substituted by one or more independently selected R1e; each R1e is independently selected from R1a, R1b, R1c, and R1d; each of R1a and R1d is independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, heteroaryl, halogen, -CN, azide, -NO2, -OR11, -N(R12)(R13), -N(R11)(OR11), -S(O)0-2R11, -S(O)1-2OR11, -OS(O)1-2R11, -OS(O)1-2OR11, -S(O)1-2N(R12)(R13), -OS(O)1-2N(R12)(R13). -N(R11)S(O)1-2R11, -NR11S(O)1-2OR11, -NR11S(O)1-2N(R12)(R13), -P(O)(OR11)2, -OP(O)(OR11)2, -C(=X)R11, -C(=X)XR11, -XC(=X)R11 and -XC(=X)XR11, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic and heteroaryl groups is optionally substituted by one or more independently selected R30 groups; Each of R1b and R1c is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-7 cycloalkyl, C6-10 aryl, 3 to 7 membered heteroaryl, 3 to 7 membered heterocyclic, O(CH2)O-2 (C3-7 cycloalkyl), -O(CH2)O-2 (C6-10 aryl), -O(CH2)O-2 (3 to 7 membered heteroaryl), -O(CH2)O-2 (3 to 7 membered heterocyclic), -NH(CH2)O-2 (C3-7 cycloalkyl), -NH(CH2)O-2 (C6-10 aryl), -NH(CH2)O-2 (3 to 7 membered heteroaryl), -NH(CH2)O-2 (3 to 7 membered heterocyclic), halogen, -CF3, -CN, azide. The following are character groups: -NO2, -OH, -O(C1-6 alkyl), -OCF3, -S(C1-6 alkyl), -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, -NHS(O)2(C1-6 alkyl), -S(O)2NH2-z(C1-6 alkyl)z, -C(=O)(C1-6 alkyl), -C(=O)OH, -C(=O)O(C1-6 alkyl), -C(=O)NH2-z(C1-6 alkyl)z, -NHC(=O)(C1-6 alkyl), -NHC(=NH)NHz-2(C1-6 alkyl)z, and -N(C1-6 alkyl)C(=NH)NH2-z(C1-6 alkyl)z, where z is 0, 1, or 2.Furthermore, each of the C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-7 cycloalkyl, C6-10 aryl, 3- to 7-membered heteroaryl, and 3- to 7-membered heterocyclic groups is optionally partially substituted by one, two, or three independently selected from -OH, methyl, ethyl, -OCH3, -SCH3, and -NH2-z(CH3)z; R2 is H; R3 is selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, heteroaryl, halogen, -CN, azide, -NO2, -OR11, -N(R12)(R13), -N(R11)(OR11), -S(O)0-2R11, -S(O)1-2OR11, -OS(O)1-2R11, -OS(O)1-2OR11, -S(O)1-2N(R12)(R13), -OS(O)1-2N(R12)(R13), -N(R1 1) S(O)1-2R11, -NR11S(O)1-2OR11, -NR11S(O)1-2N(R12)(R13), -P(O)(OR11)2, -OP(O)(OR11)2, -C(=X)R11, -C(=X)XR11, -XC(=X)R11 and -XC(=X)XR11, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic and heteroaryl groups is optionally substituted by one or more independently selected R30; R4 is H; R5 is -L-R6; L is selected from bond, C1-6 alkylene, C2-6 alkenylene, C2-6 alkyneene, and -(CH2)m-[Y-(CH2)n]o-, where m is an integer from 1 to 6, n is an integer from 0 to 3, and o is an integer from 1 to 3, where o is 1 if n is 0; Y is independently selected from O, S, and -N(R13)-; and each of the C1-6 alkylene, C2-6 alkenylene, C2-6 alkyneene, -(CH2)m-, and -(CH2)n- groups is optionally substituted by one or two independently selected R30s; R6 is a 5-membered monocyclic heteroaryl group.It contains at least one S ring atom and is substituted by one or more independently selected R7 atoms; R7 is independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, heteroaryl, halogen, -CN, azide, -NO2, -OR11, -N(R12)(R13), -N(R11)(OR11), -S(O)0-2R11, -S(O)1-2OR11, -OS(O)1-2R11, -OS(O)1-2OR11, -S(O)1-2N(R12)(R13), -OS(O)1-2N(R12)(R13), -N(R11)S(O)1-2R11, -NR1 1S(O)1-2OR11, -NR11S(O)1-2N(R12)(R13), -P(O)(OR11)2, -OP(O)(OR11)2, -C(=X)R11, -C(=X)XR11, -XC(=X)R11 and -XC(=X)XR11, wherein each of the alkyl, alkenyl, ynyl, cycloalkyl, aryl, heterocyclic and heteroaryl groups is optionally substituted by one or more independently selected R30, wherein at least one of R7 is F and / or at least one of R7 is substituted by one or more F atoms; A is selected from S, O, NR8 and C(R9)2; R8 is selected from H, alkyl, alkenyl, ynyl, cycloalkyl, aryl, heterocyclic and heteroaryl groups, wherein each of the alkyl, alkenyl, ynyl, cycloalkyl, aryl, heterocyclic and heteroaryl groups is optionally substituted by one or more independently selected R30; R9 is independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, heteroaryl, halogen, -CN, azide, -NO2, -OR11, -N(R12)(R13), -S(O)0-2R11, -S(O)1-2OR11, -OS(O)1-2R11, -OS(O)1-2OR11, -S(O)1-2N(R12)(R13), -OS(O)1-2N(R12)(R13). -N(R11)S(O)1-2R11, -NR11S(O)1-2OR11, -NR11S(O)1-2N(R12)(R13), -C(=X)R11, -C(=X)XR11, -XC(=X)R11 and -XC(=X)XR11, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic and heteroaryl groups is optionally substituted by one or more independently selected R30s; X is independently selected from O, S, and N (R14); E is O or S; R11 is independently selected from H, alkyl, alkenyl, ynyl, cycloalkyl, aryl, heteroaryl, and heterocyclic groups, wherein each of the alkyl, alkenyl, ynyl, cycloalkyl, aryl, heteroaryl, and heterocyclic groups is optionally substituted by one or more independently selected R30 groups; each of R12 and R13 is independently selected from H, alkyl, alkenyl, ynyl, cycloalkyl, aryl, heteroaryl, and heterocyclic groups.Alternatively, R12 and R13 can be attached to the nitrogen atom to which they are attached to form the group -N=CR15R16, wherein each of the alkyl, alkenyl, ynyl, cycloalkyl, aryl, heteroaryl, and heterocyclic groups is optionally substituted by one or more independently selected R30s; R14 is independently selected from H, alkyl, alkenyl, ynyl, cycloalkyl, aryl, heteroaryl, heterocyclic, and -OR11, wherein each of the alkyl, alkenyl, ynyl, cycloalkyl, aryl, heteroaryl, and heterocyclic groups is optionally substituted by one or more independently selected R30s; Each of R15 and R16 is independently selected from H, alkyl, alkenyl, ynyl, cycloalkyl, aryl, heteroaryl, heterocyclic, and -NHyR202-y, or R15 and R16 can be linked together with the atoms to which they are attached to form a ring optionally substituted with one or more independently selected R30s, wherein each of the alkyl, alkenyl, ynyl, cycloalkyl, aryl, heteroaryl, and heterocyclic groups is optionally substituted with one or more independently selected R30s; y is an integer from 0 to 2; R20 is independently selected from alkyl, alkenyl, ynyl, cycloalkyl, aryl, heteroaryl, and heterocyclic groups, wherein each of the alkyl, alkenyl, ynyl, cycloalkyl, aryl, heteroaryl, and heterocyclic groups is optionally substituted by one or more independently selected R30 groups; and R30 is a primary substituent and in each case is independently selected from alkyl, alkenyl, ynyl, aryl, heteroaryl, cycloalkyl, heterocyclic, halogen, -CN, azide, -NO2, -OR71, -N(R72)(R73), -S(O)0-2R71, -S(O)1-2OR71, -OS(O)1-2R71, -OS(O)1-2OR71, -S(O)1-2N(R72)(R73), -O S(O)1-2N(R72)(R73), -N(R71)S(O)1-2R71, -NR71S(O)1-2OR71, -NR71S(O)1-2N(R72)(R73), -OP(O)(OR71)2, -C(=X1)R71, -C(=X1)X1R71, -X1C(=X1)R71 and -X1C(=X1)X1R71, and / or any two R30s bonded to the same carbon atom of a cycloalkyl or heterocyclic group can be linked together to form =X1, wherein each of the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl and heterocyclic groups that are primary substituents is optionally substituted by one or more secondary substituents.The secondary substituent is independently selected in each case from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3 to 14 aryl, 3 to 14 heteroaryl, 3 to 14 cycloalkyl, 3 to 14 heterocyclic, halogen, -CF3, -CN, azide, -NO2, -OR81, -N(R82)(R83), -S(O)0-2R81, -S(O)1-2OR81, -OS(O)1-2R81, -OS(O)1-2OR81, -S(O)1-2N(R82)(R83), -OS(O)1-2N(R82)(R83), -N(R81 =X2, -NR81S(O)1-2R81, -NR81S(O)1-2OR81, -NR81S(O)1-2N(R82)(R83), -OP(O)(OR81)2, -C(=X2)R81, -C(=X2)X2R81, -X2C(=X2)R81 and -X2C(=X2)X2R81, and / or any two secondary substituents bonded to the same carbon atom of a cycloalkyl or heterocyclic group as a primary substituent can be linked together to form =X2, wherein the secondary substituents are C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3 to 14 aryl, 3 to 14 Each of the membered heteroaryl, 3 to 14 membered cycloalkyl, and 3 to 14 membered heterocyclic groups is optionally substituted by one or more tertiary substituents, wherein the tertiary substituent is independently selected in each case from C1-3 alkyl, halogen, -CF3, -CN, azide, -NO2, -OH, -O(C1-3 alkyl), -OCF3, -S(C1-3 alkyl), -NH2, -NH(C1-3 alkyl), -N(C1-3 alkyl)2, -NHS(O)2(C1-3 alkyl), -S(O)2NH2-z(C1-3 alkyl)z, -C(=O)OH, -C(=O)O(C1-3 alkyl) =O, =S, =NH, or =N(C1-3 alkyl)z, -NHC(=O)(C1-3 alkyl), -NHC(=NH)NHz-2(C1-3 alkyl)z, and -N(C1-3 alkyl)C(=NH)NH2-z(C1-3 alkyl)z, wherein each z is independently 0, 1, or 2, and each C1-3 alkyl is independently methyl, ethyl, propyl, or isopropyl, and / or any two tertiary substituents bonded to the same carbon atom of a 3- to 14-membered cycloalkyl or heterocyclic group as a secondary substituent can be linked together to form =O, =S, =NH, or =N(C1-3 alkyl); wherein each of R71, R72, and R73 is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, 3 to 7-membered cycloalkyl, 5 or 6-membered aryl, 5 or 6-membered heteroaryl, and 3 to 7-membered heterocyclic.Each of the C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, 3- to 7-membered cycloalkyl, 5- or 6-membered aryl, 5- or 6-membered heteroaryl, and 3- to 7-membered heterocyclic groups is optionally selected by one, two, or three independently from C1-3 alkyl, halogen, -CF3, -CN, azide, -NO2, -OH, -O (C1-3 alkyl), -OCF3, =O, -S (C1-3 alkyl), -NH2, -NH (C1-3 alkyl), -N (C1-3 alkyl)2, -NHS(O)2 (C1-3 alkyl), -S(O)2NH The substituents of 2-z(C1-3 alkyl)z, -C(=O)(C1-3 alkyl), -C(=O)OH, -C(=O)O(C1-3 alkyl), -C(=O)NH2-z(C1-3 alkyl)z, -NHC(=O)(C1-3 alkyl), -NHC(=NH)NHz-2(C1-3 alkyl)z and -N(C1-3 alkyl)C(=NH)NH2-z(C1-3 alkyl)z are substituted, wherein each z is independently 0, 1 or 2, and each C1-3 alkyl group is independently methyl, ethyl, propyl or isopropyl; Each of R81, R82, and R83 is independently selected from H, C1-4 alkyl, C2-4 alkenyl, C2-4 ynyl, 3 to 6-membered cycloalkyl, 5 or 6-membered aryl, 5 or 6-membered heteroaryl, and 3 to 6-membered heterocyclic groups, wherein each of the C1-4 alkyl, C2-4 alkenyl, C2-4 ynyl, 3 to 6-membered cycloalkyl, 5 or 6-membered aryl, 5 or 6-membered heteroaryl, and 3 to 6-membered heterocyclic groups is optionally selected by one, two, or three independently selected from C1-3 alkyl, halogen, -CF3, -CN, azide, -NO2, -OH, -O (C1-3 alkyl), -OCF3, =O, -S (C1-3 alkyl), -NH2, -NH (C1-3 alkyl), -N (C1-3 alkyl)2, -NHS(O)2(C The substituents X1 and X2 are selected from O, S, and N (R84), wherein each Z is independently 0, 1, or 2, and each C1-3 alkyl group is independently methyl, ethyl, propyl, or isopropyl; and each of X1 and X2 is independently selected from O, S, and N (R84), wherein R84 is H or a C1-3 alkyl group.

2. The compound as claimed in claim 1, wherein at least one of R7 is F and / or at least one of R7 is selected from C1-3 alkyl, -O (C1-3 alkyl), -NH (C1-3 alkyl) or -N (C1-3 alkyl)2, wherein at least one of the alkyl groups of C1-3 alkyl, -NH (C1-3 alkyl) and -O (C1-3 alkyl) and the alkyl group of -N (C1-3 alkyl)2 is substituted by one or more F atoms.

3. The compound as claimed in claim 1 or 2, wherein at least one of R7 is F and / or at least one of R7 is a C1-3 alkyl group, wherein the alkyl group of the C1-3 alkyl group is substituted with one or more F atoms; and / or, wherein at least one of R7 is F and / or at least one of R7 is selected from -CH2F, -CHF2 and -CF3, preferably selected from -CH2F and -CHF2; and / or one of R7 is attached to a C ring atom at position 2 relative to the ring atom of R6 that is attached to the remainder of the compound, preferably wherein the R7 is F and / or the R7 is substituted with one or more F atoms; and / or one of R7 is attached to a C ring atom at position 5 relative to the ring atom of R6 that is attached to the remainder of the compound, preferably wherein the R7 is F and / or the R7 is substituted with one or more F atoms.

4. The compound of any one of claims 1 to 3, wherein R6 is selected from thienyl, thiazolyl and thiadiazolyl, each of which is substituted by one or more independently selected R7; and / or wherein R6 is selected from thienyl and thiazolyl, each of which is substituted by one or more independently selected R7.

5. The compound of any one of claims 1 to 4, wherein R6 is a thiophene group substituted by one or more independently selected R7 groups.

6. The compound of any one of claims 1 to 5, wherein the ring atom of R6, which is bonded to the remainder of the compound, is a C atom; and / or wherein the S ring atom of R6 is not adjacent to the ring atom of R6 bonded to the remainder of the compound.

7. The compound of any one of claims 1 to 6, wherein R6 is selected from: , , , , , , and , wherein the bond representing R6 is bonded to the remainder of the compound; and / or, wherein R6 is selected from: and , wherein the bond representing R6 is bonded to the remainder of the compound; or wherein R6 is selected from: and , wherein the bond representing R6 is bonded to the remainder of the compound.

8. The compound of any one of claims 1 to 7, wherein L is a bond; E is O; and / or A is selected from S, O, NH, N (C1-6 alkyl) and C (C1-6 alkyl)2.

9. The compound as claimed in any one of claims 1 to 8, wherein L is a bond; E is O; and A is S.

10. The compound of any one of claims 1 to 9, wherein Hy is selected from 5 to 6-membered monocyclic heteroaryl, 5 to 6-membered monocyclic heterocyclic, 9 to 10-membered bicyclic heteroaryl and 8 to 10-membered bicyclic heterocyclic, each optionally substituted by one or more independently selected R1e.

11. The compound of any one of claims 1 to 10, wherein Hy is: wherein a bond representing Hy is bonded to the remainder of the compound; R1a, R1b and R1c are as defined in claim 1; and B is N or CR1d.

12. The compound of any one of claims 1 to 11, wherein R1a is selected from C1-3 alkyl, -O (C1-3 alkyl), -S (C1-3 alkyl), -NH (C1-3 alkyl), pirazinyl, pirazinyl, hexahydropyrimidinyl, hexahydropyridazinyl, morpholinyl, 1,2-azinyl, 1,3-azinyl, pyrrolidinyl, imidazodinyl, pyrazolidinyl, diazacycloheptyl, oxazacycloheptyl, azaspironel, diazaspironel, azaspirodel, diazaspirodel, azaspiroundecyl, diazaspiroundecyl, azaspiroundecyl, and diazaspiroundecyl. Undecyl, wherein each of the following groups is optionally substituted by one or two independently selected R30s, wherein the one or two independently selected R30s optionally substituted by R1a are independently selected from methyl methacrylate (MCM). alkyl, 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)(C1-3 alkyl), -NHC(=O)(C1-3 alkyl), -N(C1-3 alkyl)C(=O)(C1-3 alkyl), -NHS(O)2(C1-3) The C1-3 alkyl groups are substituted with one or two independently selected from -OH, -OCH3, -SCH3, cyclopropyl, pizopyridine, 4-methyl-pizopyridine, 4-(2-hydroxyethyl)pizopyridine, 2-(N,N-dimethylamino)ethoxy and -NH2-z(CH3)z, where z is 0, 1 or 2.

13. The compound of any one of claims 1 to 12, wherein R1a is asymmetric; optionally, wherein R1a is selected from 3,4-dimethylpiperazinyl, 4-methyl-1,4-diazacycloheptane-1-yl, 3-oxopiperazin-1-yl, 2-methylmorpholino-4-yl, 3-methylpiperazin-1-yl, 3-(2-hydroxyethyl)piperazin-1-yl, 3-(2-hydroxyethyl)-4-methylpiperazin-1-yl, 3-(dimethylamino)piperidin-1-yl, 3-(methoxy)piperidin-1-yl, 3-(hydroxy)piperidin-1-yl, 3-(dimethylamino)pyrrolidin-1-yl, 3-(hydroxy ... Pyrrolidin-1-yl, 3-(2-methoxyethoxy)pyrrolidin-1-yl, 3-(acetamino)pyrrolidin-1-yl, 3-(methanesulfonylamino)pyrrolidin-1-yl, 7-methyl-2,7-diazaspiro[4.4]one-2-yl, 4-[2-(dimethylamino)ethyl]-1,4-diazacycloheptane-1-yl, 4-(acetamino)-1,4-diazacycloheptane-1-yl, 5-oxo-1,4-diazacycloheptane-1-yl and 1,4-oxazacycloheptane-4-yl.

14. The compound of any one of claims 1 to 13, wherein the atom of R1a, which is bonded to the remainder of the compound, is an atom other than C, preferably N; optionally, wherein R1a is selected from heterocyclic groups, heteroaryl groups, -OR11, -N(R12)(R13), -N(R11)(OR11), -S(O)0-2R11, -S(O)1-2OR11, -OS(O)1-2R11, -OS(O)1-2OR11, -S(O)1-2N(R12)(R13), -OS(O)1-2N(R12)(R13), -N(R11)S(O)1-2R11, -NR11S(O)1-2OR11, -N R11S(O)1-2N(R12)(R13), -P(O)(OR11)2, -OP(O)(OR11)2, -XC(=X)R11 and -XC(=X)XR11, wherein each of the heterocyclic and heteroaryl groups is bonded to the remainder of the compound by an atom other than C, and optionally substituted by one or more independently selected R30; and / or wherein R1a is a heterocyclic group containing at least one N ring atom and bonded to the remainder of the compound by an N ring atom.

15. The compound of claim 14, wherein R1a is selected from: , , , , , , , , , , , , , , , , , , and , wherein the bond representing R1a is bonded to the remainder of the compound; optionally, wherein R1a is selected from: , , , , and , wherein the bond representing R1a is bonded to the remainder of the compound.

16. The compound of any one of claims 1 to 15, wherein R1b is methyl, ethyl, propyl or isopropyl, preferably methyl; and R1c is H.

17. The compound of any one of claims 1 to 16, wherein B is N.

18. The compound of any one of claims 1 to 17, wherein R1b is H; R1c is methyl; B is N; and R3 is H.

19. The compound as claimed in claim 11, wherein: L is a bond; Furthermore, (A')R1a is selected from C1-3 alkyl, -O(C1-3 alkyl), -S(C1-3 alkyl), -NH(C1-3 alkyl), -N(C1-3 alkyl)2 and 3 to 11-membered heterocyclic groups, preferably heterocyclic groups bonded to the remainder of the compound by atoms other than C, wherein the 3 to 11-membered heterocyclic group is optionally substituted by one or two independently selected R30s, wherein the one or two independently selected R30s optionally substituting R1a are selected from methyl, ethyl, -OH, =O, -OCH3, -SCH3, cyclopropyl, 2-hydroxyethyl, 2-(N,N-dimethylamino)ethyl, 2-(N ,N-dimethylamino)ethoxy, 2-(methoxy)ethoxy, 2-aminoethyl, 2-(N-methylamino)ethyl, 2-(methoxy)ethyl, 4-methylpiperazinyl, -C(=O)(C1-3 alkyl), -NHC(=O)(C1-3 alkyl), -N(C1-3 alkyl)C(=O)(C1-3 alkyl), -NHS(O)2(C1-3 alkyl), -N(C1-3 alkyl)S(O)2(C1-3 alkyl), -(CH2)1-3COOH and -NH2-z(CH3)z, wherein z is 0, 1 or 2; and each of the C1-3 alkyl groups is optionally divided by a One or two of them are independently selected from -OH, -OCH3, -SCH3, cyclopropyl, pizobinyl, 4-methyl-pizobinyl, 4-(2-hydroxyethyl)pizobinyl, 2-(N,N-dimethylamino)ethoxy, and -NH2-z(CH3)z, wherein z is 0, 1, or 2; and at least one of (B')R1b and R1c is selected from H, methyl, ethyl, propyl, isopropyl, -OH, -OCH3, -SCH3, cyclopropyl, 2-hydroxyethyl, 2-(N,N-dimethylamino)ethyl, 2-(N,N-dimethylamino)ethoxy, 2-aminoethyl, 2-(N-methylamino)ethyl, 2 -(methoxy)ethyl, -NH2-z(CH3)z and phenyl, wherein z is 0, 1 or 2, and the other of R1b and R1c is independently selected from H, methyl, ethyl, propyl, isopropyl, -OH, -OCH3, -SCH3, cyclopropyl, 2-hydroxyethyl, 2-(N,N-dimethylamino)ethyl, 2-(N,N-dimethylamino)ethoxy, 2-aminoethyl, 2-(N-methylamino)ethyl, 2-(methoxy)ethyl, -NH2-z(CH3)z, phenyl, pyridyl, pyrazolyl, phenoxy, pyridyloxy, imidazoleamino and tetrahydrofuranylmethoxy, wherein z is 0, 1 or 2;Furthermore, each of the phenyl, pyridyl, pyrazolyl, phenoxy, pyridyloxy, imidazolylamino, and tetrahydrofuranylmethoxy groups is optionally partially substituted by one, two, or three independently selected from methyl, ethyl, -OH, -OCH3, -SCH3, cyclopropyl, 2-hydroxyethyl, 2-(N,N-dimethylamino)ethyl, 2-(N,N-dimethylamino)ethoxy, 2-aminoethyl, 2-(N-methylamino)ethyl, 2-(methoxy)ethyl, and -NH2-z(CH3)z, wherein z is 0, 1, or 2, preferably wherein one of R1b and R1c is H; and R1b and R1c The other is methyl, ethyl, propyl, isopropyl, or phenyl, preferably the other of R1b and R1c is methyl; and (C')R3 is selected from H, C1-4 alkyl, C3-6 cycloalkyl, phenyl, halogen, -CN, -O(C1-4 alkyl), -OCF3, -S(C1-4 alkyl), -NH2, -NH(C1-4 alkyl), -N(C1-4 alkyl)2, -C(=O)(C1-4 alkyl), -C(=O)OH, -C(=O)O(C1-4 alkyl), -C(=O)NH2-z(C1-4 alkyl)z, -NHC(=O)(C1-4 alkyl), - NHC(=NH)NHz-2(C1-4 alkyl)z and -N(C1-4 alkyl)C(=NH)NH2-z(C1-4 alkyl)z, wherein the phenyl group is optionally surrounded by one, two, or three independently selected from halogen, methyl, isopropyl, -CN, -CF3, -OCF3, -OH, -NH2, -NH(C1-3 alkyl), -N(C1-3 alkyl)2, -NHC(=O)(C1-3 alkyl), -C(=O)NH2-z(C1-3 alkyl)z, -(CH2)1-3NH2, -(CH2)1-3NH(C1-3 alkyl), -(CH2)1 The groups -3N(C1-3alkyl)2, -(CH2)1-3OH and -(CH2)1-3O(C1-3alkyl) are substituted; and z is 0, 1 or 2, preferably R3 is H; and at least one of (D')R7 is F and / or at least one of R7 is selected from C1-3alkyl, -O(C1-3alkyl), -NH(C1-3alkyl) or -N(C1-3alkyl)2, wherein at least one of the alkyl groups of C1-3alkyl, -NH(C1-3alkyl) and -O(C1-3alkyl) and the alkyl group of -N(C1-3alkyl)2 is substituted by one or more F atoms; (E')A is S, O, or N(CH3)2, preferably S; and (F')B is N or CR1d, wherein R1d is selected from C1-3 alkyl, halogen, -O (C1-3 alkyl), -S (C1-3 alkyl), -NH (C1-3 alkyl), and -N (C1-3 alkyl)2, preferably N; and (G')E is O or S, preferably O.

20. The compound of claim 19, wherein one of R7 is selected from -CH2F, -CHF2 and -CF3, preferably selected from -CH2F and -CHF2.

21. The compound as claimed in claim 19 or 20, wherein one of R7 is selected from -CH2F, -CHF2 and -CF3, preferably selected from -CH2F and -CHF2, and one of R7 is Cl.

22. The compound as claimed in claim 19, wherein one of R7 is F and the other of R7 is Cl.

23. The compound of claim 19, wherein R6 is selected from: , , , , , , and , wherein R6 represents a bond that binds R6 to the remainder of the compound; or wherein R6 is selected from: and , wherein R6 represents a bond that binds R6 to the remainder of the compound.

24. The compound of any one of claims 19 to 23, wherein R1a is selected from: 4-(2-hydroxyethyl)piperazinyl, 4-methylpiperazinyl, 3,4-dimethylpiperazinyl, 4-methyl-1,4-diazacycloheptane-1-yl, 3-oxopiperazin-1-yl, 2-methylmorpholino-4-yl, 3-methylpiperazin-1-yl, 3-(2-hydroxyethyl)piperazin-1-yl, 3-(2-hydroxyethyl)-4-methylpiperazin-1-yl, 3-(dimethylamino)piperazin-1-yl, 3-(methoxy)piperazin-1-yl, 3-(hydroxy)piperazin-1-yl, 3-( The following are listed: (dimethylamino)pyrrolidin-1-yl, 3-(hydroxy)pyrrolidin-1-yl, 3-(2-methoxyethoxy)pyrrolidin-1-yl, 3-(acetamino)pyrrolidin-1-yl, 3-(methanesulfonylamino)pyrrolidin-1-yl, 7-methyl-2,7-diazaspiro[4.4]one-2-yl, 4-[2-(dimethylamino)ethyl]-1,4-diazacycloheptane-1-yl, 4-(acetamino)-1,4-diazacycloheptane-1-yl, 5-oxo-1,4-diazacycloheptane-1-yl, and 1,4-oxazacycloheptane-4-yl.

25. The compound of any one of claims 19 to 24, wherein R1a is asymmetric.

26. The compound of any one of claims 19 to 25, wherein the atoms of R1a that are bonded to the remainder of the compound are atoms other than C, preferably N atoms.

27. The compound of any one of claims 19 to 26, wherein R1b is H; R1c is methyl; A is S; B is N; E is O; and R3 is H.

28. The compound of any one of claims 1 to 27, wherein the compound is selected from: , , , , , , , , and , and its solvates, salts, N-oxides, complexes, polymorphs, crystalline forms, racemic mixtures, diastereomers, enantiomers, tautomers, configurational isomers, isotopically labeled forms, prodrugs, and combinations thereof.

29. The compound of any one of claims 1 to 28, wherein the compound is selected from: [list of compounds], and its solvates, salts, N-oxides, complexes, polymorphs, crystalline forms, tautomers, conformational isomers, isotopically labeled forms, prodrugs, and combinations thereof; or wherein the compound is selected from: [list of compounds], and its solvates, salts, N-oxides, complexes, polymorphs, crystalline forms, tautomers, conformational isomers, isotopically labeled forms, prodrugs, and combinations thereof; or wherein the compound is selected from: [list of compounds], and its solvates, salts, N-oxides, complexes, polymorphs, crystalline forms, racemic mixtures, diastereomers, enantiomers, tautomers, conformational isomers, isotopically labeled forms, prodrugs, and combinations thereof; or wherein the compound is selected from: [list of compounds]. And its solvates, salts, N-oxides, complexes, polymorphs, crystalline forms, racemic mixtures, diastereomers, enantiomers, tautomers, configurational isomers, isotopic labeled forms, prodrugs and combinations thereof.

30. The compound of any one of claims 1 to 27, wherein the compound is selected from: , , , and , and solvates therewith, salts, N-oxides, complexes, polymorphs, crystalline forms, tautomers, conformational isomers, isotopically labeled forms, prodrugs, and combinations thereof.

31. The compound of any one of claims 1 to 30, wherein the compound is in a substantially pure form, particularly in a pure form of more than about 90%, 95%, 98% or 99%.

32. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 31, and optionally further comprising a pharmaceutically acceptable excipient; optionally, wherein the pharmaceutical composition is formulated for oral administration; and / or wherein the pharmaceutical composition is in unit dosage form.

33. The compound of any one of claims 1 to 31 or the pharmaceutical composition of claim 32, for the purpose of treatment.

34. A method for treating a disease, symptom, or condition of a subject, comprising administering to the subject a compound as described in any one of claims 1 to 31 or a pharmaceutical composition as described in claim 32, optionally wherein the disease, symptom, or condition is related to a kinase.

35. A compound or pharmaceutical composition for treating a proliferative disease in a subject, the treatment comprising administering the compound or pharmaceutical composition to the subject, wherein, The compound is the compound as described in any one of claims 1 to 31, and the pharmaceutical composition is the pharmaceutical composition as described in claim 32.

36. A compound or pharmaceutical composition for a specific purpose as described in claim 35, wherein the proliferative disease is cancer or a tumor; optionally, wherein the cancer is a solid tumor.

37. A compound or pharmaceutical composition for a specific purpose as described in claim 35 or 36, wherein the treatment further includes administration of an immune checkpoint inhibitor to the subject.

38. A compound or pharmaceutical composition for a specific purpose as claimed in any one of claims 35 to 37, the treatment comprising exposing cells in the subject associated with proliferative disorders to: (i) TNF, TNF variants, and / or agonists of TNFR12 or TNFR1 signaling; and (ii) the compound or pharmaceutical composition; optionally: wherein the amount of TNF exposed to cells in the subject associated with proliferative disorders is increased; and / or wherein: (i) administering to the subject a TNF, TNF variant, or TNFR1 or TNFR2 signaling agonist; (ii) administering to the subject an agent capable of inducing or inducing TNF, TNF variant, or TNFR1 or TNFR2 signaling agonist exposure to cells associated with proliferative diseases; or (iii) inducing TNF exposure to cells associated with proliferative diseases by increasing the amount of TNF in the subject's plasma and / or such cellular environment through a medicine, treatment, or other means; and / or inducing TNF exposure to cells associated with proliferative diseases by increasing the amount of TNF in the subject's plasma and / or such cellular environment through a medicine, treatment, or other means.

39. A compound or pharmaceutical composition for a specific purpose as claimed in any one of claims 35 to 38, wherein the treatment comprises administering the compound or pharmaceutical composition twice daily (bis in die; BID).

40. A compound or pharmaceutical composition for treating a proliferative disease of a subject, the treatment comprising administration of the compound or pharmaceutical composition, wherein the compound is selected from compounds (a) to (c), and the pharmaceutical composition comprises such a compound and optionally a pharmaceutically acceptable excipient: (a) a compound as described in any one of claims 1 to 31; and (b) a compound having the formula (Ib), and its solvates, salts, N-oxides, complexes, polymorphs, crystalline forms, racemic mixtures, diastereomers, enantiomers, tautomers, conformational isomers, isotopically labeled forms, prodrugs, and combinations thereof, wherein: Hy, R2, R3, A, E, and R4 are as defined in claim 1; R5' is -L-R6'; L is a bond; R6' is a 5- or 6-membered heteroaryl group, optionally substituted by one or more independently selected R7's; R7' is independently selected from R7, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, heteroaryl, halogen, -CN, azide, -NO2, -OR11, -N(R12)(R13), -N(R11)(OR11), -S(O)0-2R11, -S(O)1-2OR11, -OS(O)1-2R11, -OS(O)1-2OR11, -S(O)1-2N(R12)(R13), -OS(O)1-2N(R12)(R13), -N(R11)S(O)1-2R11 -NR11S(O)1-2OR11, -NR11S(O)1-2N(R12)(R13), -P(O)(OR11)2, -OP(O)(OR11)2, -C(=X)R11, -C(=X)XR11, -XC(=X)R11 and -XC(=X)XR11, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic and heteroaryl groups is optionally substituted by one or more independently selected R30 groups; and R11, R12, R13, X and R30 are as defined in claim 1. Optionally, with the condition that (I) when A is S, R3 is H, E is O, and R6' is 1-[2,4-bis(trifluoromethyl)benzyl]-1H-pyrazol-4-yl, then Hy is not 2-pyridinyl; (II) when Hy is 1-{(2E)-4-[(2-2-methoxyethyl)amino]-1-oxo-2-buten-1-yl}piperidin-4-yl, R3 is H, A is O, and E is O, then R6' is not 5-methyl-pyridin-2-yl; (III) When R3 is trifluoromethyl, A is O, E is O, and (i) R6' is 6-{4-[(2-fluorophenyl)aminomethyl]piperazin-1-yl}pyridin-3-yl, then Hy is not 1-(phenylmethyl)piperazin-4-yl, 1-(phenylmethyl)pyrrolidin-3-yl, or tetrahydro-2H-pyran-4-yl; or (ii) Hy is 1-(phenylmethyl)piperazin-4-yl, then R6' is not 6-(3-{[(2-fluorophenyl)aminomethyl]amino}pyrrolidin-3-yl}pyrrolidin-4-yl}. (iii) When Hy is 1-(benzyl)pyrrolidin-3-yl, then R6' is not 6-({(3S)-1-[(2-fluorophenyl)aminomethyl]pyrrolidin-3-yl}amino)pyrrolidin-3-yl or 6-({(3R)-1-[(2-fluorophenyl)aminomethyl]pyrrolidin-3-yl}amino)pyrrolidin-3-yl;And / or (IV) when Hy is, and (1) R1a is 4-(2-hydroxyethyl)piperazin-1-yl or Cl, R1b is H, R1c is methyl, B is N, E is O, R3 is H, and A is S, then R6' is not 4-chloro-2-methylpyridin-3-yl; (2) when E is O, B is CR1d, and R1d is H, F, Cl or Br, then R1a is not H; (c) compounds having the following formula (Ic): , and their solvates, salts, N-oxides, complexes, polymorphs, crystalline forms, racemic mixtures, diastereomers, enantiomers, tautomers, conformational isomers, isotopically labeled forms, prodrugs and combinations thereof, wherein: R1a, R1b, R1c, R2, R3, A, E and R4 are as defined in claim 1; B is N or CR1d, where R1d is as defined in Request 1; R5'' is -L-R6''; L is as defined in Request 1; R6'' is a heteroaryl or heterocyclic group, each of which is optionally replaced by one or more independently selected R7's; R7' is independently selected from R7, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, heteroaryl, halogen, -CN, azide, -NO2, -OR11, -N(R12)(R13), -N(R11)(OR11), -S(O)0-2R11, -S(O)1-2OR11, -OS(O)1-2R11, -OS(O)1-2OR11, -S(O)1-2N(R12)(R13), -OS(O)1-2N(R12)(R13), -N(R11)S(O)1-2R11, -NR11S(O)1-2OR11, -NR1 1S(O)1-2N(R12)(R13), -P(O)(OR11)2, -OP(O)(OR11)2, -C(=X)R11, -C(=X)XR11, -XC(=X)R11 and -XC(=X)XR11, and / or any two R7's bonded to the same atom of R6'' as a heterocyclic group can bond together to form =O, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic and heteroaryl groups is optionally substituted by one or more independently selected R30s; and R11, R12, R13, X and R30 are as defined in claim 1. Optionally, with the condition that (1) when R1a is 4-(2-hydroxyethyl)piperazin-1-yl or Cl, R1b is H, R1c is methyl, B is N, E is O, R3 is H, A is S, and L is a bond, then R6'' is not 4-chloro-2-methylpyridin-3-yl; (2) when R1a is methoxy, R1b is H, R1c is methoxy, B is N, E is O, R3 is H, A is S, and L is a bond, then R6'' is not 2,2-difluoro-5H-1,3-dioxa[4,5-f]benzimidazol-6-yl;(3) When R3 is H, A is S, L is a bond, R6'' is 1-methyl-4-piperidinyl, R1b is H, B is N, E is O, and (i) R1a is methyl, then R1c is not N-tert-butoxycarbonylpiperidin-4-yl; or (ii) R1c is methyl, then R1a is not N-tert-butoxycarbonylpiperidin-4-yl or N-tert-butoxycarbonylpiperidin-3-yl; (4) When E is O, B is CR1d, and R1d is H, F, Cl or Br, then R1a is not H; and / or (5) when R1a is methyl, R1b and R1c are each H, B is CH, E is O, A is S, and R3 is methyl, then R5'' is not 1,3-benzodiazol-5-ylmethyl, 2-furanylmethyl, 1,3-benzodiazol-5-yl, 2-(2-thienyl)ethyl, 2-(4-morpholinyl)ethyl, 2-(2-pyridyl)ethyl, 2-pyridylmethyl or tetrahydro-2-furanylmethyl; (6) When A is S, R3 is H, E is O, L is a bond, R6'' is 1-[2,4-bis(trifluoromethyl)benzyl]-1H-pyrazol-4-yl, R1a is H, R1b is H, R1c is H, and B is CR1d, then R1d is not H; and the proliferative disease is selected from one or more of (α) to (γ): (α) Cells with proliferative disorders or associated with such proliferative disorders are characterized by the presence of myocyte enhancer factor 2C (MEF2C) protein, such as phosphorylated MEF2C protein and / or the presence of MEF2C protein as an active transcription factor; preferably, the cells with such proliferative disorders or associated with such proliferative disorders are further characterized by the presence of phosphorylated histone deacetylases 4 (HDAC4) protein, such as HDAC4 protein phosphorylated by SIK3; and / or (β) cells with proliferative disorders or associated with such proliferative disorders are 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 KMT2A fusion oncoprotein; and / or (iv) 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).

41. A compound or pharmaceutical composition for a specific purpose as described in claim 40: wherein the compound is a compound as defined in claim 19(b), and R6' is a 5-membered monocyclic heteroaryl group containing at least one cyclic heteroatom selected from N, O, and S and optionally substituted by one, two, or three independently selected R7'; or wherein the compound is a compound as defined in claim 19(c), and R6'' is a 5- or 6-membered heteroaryl group containing at least one S ring atom and optionally substituted by one, two, or three independently selected R7'.

42. A compound or pharmaceutical composition for a specific purpose as claimed in claim 40 or 41, wherein the compound is selected from: , , , and , and its solvates, salts, N-oxides, complexes, polymorphs, crystalline forms, racemic mixtures, diastereomers, enantiomers, tautomers, configurational isomers, isotopically labeled forms, prodrugs, and combinations thereof.

43. A method for determining whether a subject suffering from a proliferative disease is suitable for treatment with a compound or pharmaceutical composition as defined in any one of claims 40 to 42, the method comprising: In a biological sample obtained from the subject and preferably containing cells associated with the proliferative disease, it is determined that: (X) MEF2C protein is present, for example, phosphorylated MEF2C protein and / or MEF2C protein as an active transcription factor; preferably, the proliferative disease is further characterized by the presence of phosphorylated HDAC4 protein, for example, HDAC4 protein phosphorylated by SIK3; and / or (Y) (i) human chromosomal translocation at 11q23; (ii) rearrangement of the KMT2A gene; (iii) KMT2A fusion oncoprotein; and / or (iv) mutation in the KRAS gene and / or RUNX1 gene, wherein the presence of the protein, translocation, rearrangement, oncoprotein, and / or mutation in the biological sample indicates that the subject is suitable for treatment with the compound or pharmaceutical composition.

44. A compound or pharmaceutical composition for a specific purpose as claimed in any one of claims 40 to 42, or the method as claimed in claim 43, wherein the proliferative disease or cells associated with the proliferative disease are characterized by: (i) the presence of a human chromosomal translocation at 11q23; (ii) the presence of a rearrangement of the KMT2A gene; and / or (iii) the presence of a KMT2A fusion oncoprotein, preferably wherein: (a) The human chromosomal translocation is selected from t(4,11), t(9,11), t(11,19), t(10,11), and t(6,11); and / or (b) the rearrangement of the KMT2A gene contains the following fusion or the KMT2A fusion oncoprotein is expressed from a rearrangement containing the following fusion: a fusion of the KMT2A gene with a translocation partner gene selected from AF4, AF9, ENL, AF10, ELL, and AF6.

45. A compound or pharmaceutical composition for a specific purpose as claimed in any one of claims 40 to 42 and 44, or the method as claimed in claim 43 or 44, wherein the proliferative disease is: (i) myeloma, preferably multiple myeloma; or (ii) leukemia, preferably acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL), more preferably T-cell acute lymphoblastic leukemia (T-ALL), MLL-AML, or MLL-ALL.

46. ​​A compound or pharmaceutical composition for a specific purpose as claimed in any one of claims 40 to 42, 44 and 45, or a method as claimed in any one of claims 43 to 45, wherein the object is an object carrying a KMT2A rearrangement (KMT2A-r); preferably wherein such an object is a patient suffering from KMT2A-r leukemia.

47. The method of claim 43, further comprising the step of administering to a subject a compound or pharmaceutical composition as defined in any one of claims 40 to 42, wherein the presence or amount of the protein, translocation, oncoprotein, and / or mutation has been determined in a biological sample obtained from the subject.

48. An intermediate selected from compounds having the formula (Id): , and its solvates, salts, complexes, polymorphs, crystalline forms, racemic mixtures, diastereomers, enantiomers, tautomers, configurational isomers, isotopic labels, and combinations thereof, wherein: One of R40 is F or selected from C1-3 alkyl, -O(C1-2 alkyl), -NH(C1-2 alkyl) and -N(C1-2 alkyl)2, wherein at least one of the alkyl groups of C1-3 alkyl, -O(C1-2 alkyl) and -NH(C1-2 alkyl) and the alkyl group of -N(C1-2 alkyl)2 is substituted by one, two or three F atoms, and the other R40 is selected from halogen, -Me, -OMe, -Et and -OEt; and R41 is selected from H and an amino protecting group, with the condition that (1) the intermediate is not 2-bromo-4-(trifluoromethyl)thiophene-3-amine; (2) When R40 connected to the C ring atom at the 4 position of the thiophene ring is -Me and the other R40 is -CHF2, then R41 is not (1-propylpiperidin-2-yl)carbonyl; and (3) when R40 connected to the C ring atom at the 4 position of the thiophene ring is -Me and the other R40 is F, then R41 is not 4,5-dihydro-1H-imidazol-2-yl.

49. The intermediate as claimed in claim 48, wherein one of R40 is selected from F, -CH2F, -CHF2 and -CF3, and the other R40 is selected from halogen, -Me, -OMe, -Et and -OEt, more preferably from Cl, Br, F and -Me; and / or one of R40 is selected from F, -CH2F, -CHF2 and -CF3, more preferably from -CH2F and -CHF2, and the other R40 is Cl, optionally the R40 bonded to the C ring atom adjacent to the S ring atom is Cl.

50. The intermediate as claimed in claim 48 or 49, wherein the amine protecting group is selected from: tert-butyloxycarbonyl (BOC), 9-fluorenylmethoxycarbonyl (FMOC), benzyloxycarbonyl (Cbz), p-methoxybenzyloxycarbonyl (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), tosyl (tosyl; Ts), p-bromobenzenesulfonyl (brosyl), 4-nitrobenzenesulfonyl (nosyl), and 2-nitrobenzenesulfonyl (Nps).

51. The intermediate as claimed in any one of claims 48 to 50, wherein the intermediate is selected from: , , , , , , and , and its solvates, salts, complexes, polymorphs, crystalline forms, tautomers, configurational isomers, isotopic-labeled forms, and combinations thereof; or wherein the intermediate is selected from: , , , , , , and , and its solvates, salts, complexes, polymorphs, crystalline forms, tautomers, configurational isomers, isotopic-labeled forms, and combinations thereof.

52. A method for preparing a compound comprising a amide moiety, the method comprising the steps of: reacting an intermediate as described in claim 48 or 49 with a corresponding carboxylic acid, and optionally removing an amino protecting group; optionally, wherein the compound is a kinase inhibitor, particularly an inhibitor of one or more protein kinases selected from: SIK (preferably SIK3), CSFR1, ABL, SRC, HCK, PDGFR and KIT; preferably selected from: SIK3, ABL / BCR-ABL, HCK and CSF1R kinases.

53. A method for preparing the compound as claimed in claim 31, comprising the following steps: l Provides a compound as claimed in any one of claims 1 to 30 in a mixture having one or more impurities; And l removes at least a portion of the impurities from the mixture.

54. A method for preparing a pharmaceutical composition, comprising the following steps: The compound as described in any one of claims 1 to 31 is formulated together with a pharmaceutically acceptable excipient.

55. A method for preparing a pharmaceutical composition, comprising the following steps: The compound as described in any one of claims 1 to 29 is formulated together with a pharmaceutically acceptable excipient; Or it may include: l Implementing or having implemented the method described in claim 52 to manufacture the compound; And l formulates the manufactured compound together with pharmaceutically acceptable excipients.

56. A method for preparing pharmaceutical packaging, comprising the following steps: l Insert the pharmaceutical composition (preferably in the form of a finished pharmaceutical product) as described in claim 32 into the packaging to form a package containing the pharmaceutical composition; And optionally, insert a leaflet containing prescription information for the pharmaceutical composition into the packaging.

57. A pharmaceutical package comprising the pharmaceutical composition as described in claim 32; preferably, wherein the pharmaceutical composition is in the form of a finished pharmaceutical product.