Heterocyclic kinase inhibitors and uses thereof

Abstract

The present invention relates to kinase inhibitors, particularly inhibitors of protein kinases, including the protein tyrosine kinases LCK, ABL, SRC, KIT, SIK family, and / or mutants thereof. Although structurally similar to dasatinib, the kinase inhibitors of the present invention may exhibit one or more properties that differ from dasatinib. Similarly, the present invention relates to pharmaceutical compositions comprising one or more kinase inhibitors. The kinase inhibitors or pharmaceutical compositions of the present invention can be used to treat diseases or conditions, such as proliferative diseases, such as leukemia or solid tumors. The kinase inhibitors or pharmaceutical compositions can be used in treatment regimens that are similar to, similar to, or different from the treatment regimens used for the corresponding diseases with dasatinib, and in particular can be used in combination treatment regimens with one or more other therapeutic agents (e.g., immune checkpoint inhibitors).

Description

[0001] illustrate

[0002] The present invention relates to kinase inhibitors, in particular inhibitors of protein kinases, including protein tyrosine kinases LCK, ABL, SRC, KIT, SIK family and / or its mutants. Although structurally similar to dasatinib, the kinase inhibitors of the present invention may exhibit one or more certain characteristics different from dasatinib. Similarly, the present invention relates to pharmaceutical compositions comprising one or more of the kinase inhibitors. The kinase inhibitors or pharmaceutical compositions of the present invention can be used to treat diseases or conditions, such as proliferative diseases, such as leukemia or solid tumors. Kinase inhibitors or pharmaceutical compositions can be used for treatment regimens corresponding to, similar to, or different from the treatment regimens of dasatinib for the corresponding diseases, and in particular can be used in combination with one or more other therapeutic agents (e.g., immune checkpoint inhibitors).

[0003] 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, CSK, EGFR, ERBB2, ERBB3, ERBB4, ERK, PAK, FES, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, FGR, FIT-1, FPS, FRK, FYN, HCK, IGF-1R, INS-R, JAK, KDR, LCK, LYN, MEK, p38, PDGFR, PIK, PKC, PYK2, ROS, SIK1, SIK2, SIK3, SRC, TIE, TIE2, TRK, and ZAP70. Kinases are enzymes that add phosphate groups to proteins or other organic molecules and have been shown to be key regulators of most cellular functions, including cell signaling, proliferation, differentiation, metabolism, survival, apoptosis, motility, DNA damage repair, etc. Phosphorylation, particularly dysregulated signal transduction due to defects in protein phosphorylation control, is involved in a variety of diseases. For example, diseases related to abnormal activity (e.g., increased activity) of kinases. Such diseases include, but are not limited to, proliferative diseases (e.g., cancer, benign tumors, pathological angiogenesis, inflammatory diseases, and autoimmune diseases) as well as allergies and CNS diseases.

[0004] Protein tyrosine kinase (PTK) is an enzyme that binds to ATP as a substrate for tyrosine residues in phosphorylated peptides and proteins. PTK includes in particular receptor protein tyrosine kinases (RPTK), including members of the epidermal growth factor kinase family (such as HER1 and HER2), platelet-derived growth factor (PDGF), and kinases (such as TIE2 and KDR) that play a role in angiogenesis; in addition, non-receptor protein tyrosine kinases are also included, including members of the SYK, JAK, and SRC kinase families (such as SRC, FYN, LYN, LCK, and BLK kinases). Protein serine / threonine kinases (STK) are enzymes that phosphorylate the oxygen atoms of serine or threonine side chains in peptides and proteins. STK includes in particular AKT1, Aurora kinases, BRAF, MAP kinases, PLK1, SIK1, SIK2, and SIK3.

[0005] Inhibition of protein kinases, and therefore of substrate peptides or proteins, has been shown to be useful in treating many diseases. For example, afatinib is an ERBB inhibitor used in the treatment of non-small cell lung cancer; axitinib is a VEGFR, PDGFR, and c-KIT inhibitor used in the treatment of renal cell carcinoma; bosutinib is an ABL / BCR-ABL inhibitor used in the treatment of chronic myeloid leukemia; cabozantinib is a c-MET and VEGFR2 inhibitor used in the treatment of thyroid cancer; crizotinib is an ALK, HGFR, and c-MET inhibitor used in the treatment of non-small cell lung cancer; dasatinib is an ABL / BCR-ABL, SRC, and c-KIT inhibitor used in the treatment of chronic myeloid leukemia; and erlotinib is an EGFR inhibitor used in the treatment of non-small cell lung cancer and pancreatic cancer.Gefitinib is an EGFR inhibitor that can be used to treat non-small cell lung cancer; imatinib is an ABL / BCR-ABL inhibitor that can be used to treat chronic myeloid leukemia; lapatinib is a HER2 inhibitor that can be used to treat breast cancer; nilotinib is an ABL / BCR-ABL inhibitor that can be used to treat chronic myeloid leukemia; pazopanib is a VEGFR, PDGFR and c-KIT inhibitors, which can be used to treat renal cell carcinoma and soft tissue sarcoma; palbociclib, a CDK4 and CDK6 inhibitor, can be used to treat ER-positive and HER2-negative breast cancer; ponatinib, an ABL / BCR-ABL, BEGFR, PDGFR, FGFR, EPH, SRC, c-KIT, RET, TIE2, and FLT3 inhibitor, can be used to treat chronic myeloid leukemia and acute lymphoblastic leukemia; regorafenib, a b) is a RET, VEGFR, and PDGFR inhibitor used for the treatment of colorectal cancer and gastrointestinal stromal tumors; ribociclib is a cyclin D1 / CDK4 and CDK6 inhibitor used for the treatment of HR-positive, HER2-negative advanced or metastatic breast cancer; ruxolitinib is a JAK inhibitor used for the treatment of myelofibrosis; sorafenib is a VEGFR, PDGFR, BRAF, and c-KIT inhibitor used for the treatment of renal cell carcinoma and hepatocellular carcinoma; sunitinib is a VEGFR and PDGFR inhibitor used for the treatment of renal cell carcinoma, gastrointestinal stromal tumors, and pancreatic neuroendocrine tumors; tofacitinib is a JAK inhibitor used for the treatment of rheumatoid arthritis; vandetanib is a VEGFR, EGFR, RET, and BRK inhibitor used for the treatment of thyroid cancer; and vemurafenib is a BRAF inhibitor used for the treatment of malignant melanoma.

[0006] In view of the large number of kinases and related diseases, there is a continuing need for new inhibitors that are selective for various kinases, which may be useful in treating related diseases; in particular, there remains a need for new kinase inhibitors, pharmaceutical compositions / formulations, and their use in treating diseases associated with abnormal activity of one or more kinases; in particular, there remains a need for new inhibitors that can replace existing kinase inhibitors (e.g., dasatinib).

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

[0008] It is important to note that, despite extensive trials, dasatinib has no indication for the treatment of cancers other than CML or Ph+ ALL in the United States or Europe; in particular, dasatinib has not been specifically approved for use in any solid tumors as of September 2018. Indeed, many clinical trials investigating dasatinib for its potential use in the treatment of solid tumors have been terminated prematurely (for example, due to toxicity issues) or have failed to report robust or even encouraging results. For example, according to information on clinicaltrials.gov (September 9, 2018), dasatinib has only been tested in one phase 3 solid tumor trial: in a single study (the "READY" trial (NCT00744497)) in combination with docetaxel in castration-resistant prostate cancer, but in this trial, dasatinib failed to improve overall survival compared with docetaxel alone (Araujo et al. 2013, Lancet Oncol. 14:13017), although there was some suggestion of activity in chemotherapy-naive castration-resistant prostate cancer in earlier trials (e.g., Araujo et al. 2012, Cancer 118:63). Although it has been tested in multiple trials for other cancers (e.g., breast cancer, skin cancer, pancreatic cancer, brain cancer, or lung cancer), dasatinib has not shown satisfactory efficacy or tolerability, and no phase 3 trials have been conducted for any of these cancers. In particular, in a double-blind phase 2 trial of patients with locally advanced, unresectable pancreatic cancer, dasatinib did not show an improvement in overall survival when combined with gemcitabine compared with gemcitabine alone (Evens et al. 2017, Annal. Onc. 28:354). However, recently, specialized trials designed to select patients for “targeted” therapies that express specific drug targets, including solid tumors, may test dasatinib based on the patient’s target profile. For example, (i) the “TAPUR” trial (“The Targeted Agent and Profiling Utilization Registry,” https: / / www.tapur.org, NCT02693535) included dasatinib in one or more treatment regimens based on one or more of the following targets: BCR-ABL, SRC, KIT, PDGFRB, EPHA2, FYN, LCK, YES1; and (ii) a clinical trial (NCT02645149) from the Melanoma Institute of Australia involving patients with BRAF and NRAS wild-type, unresectable stage III or IV metastatic melanoma who had progressed on or were unable to receive standard therapy (typically immunotherapy), including dasatinib as a possible treatment option depending on the KIT mutation found in the patient’s cancer.Dasatinib is also a possible arm of BMS's Phase 2 "FRACTION-Lung" trial (NCT02750514), in which it may be combined with the immuno-oncology drug nivolumab in patients with advanced non-small cell lung cancer. Other parts of the trial are combining nivolumab with other immuno-oncology drugs.

[0009] Therefore, there is a particular need for novel kinase inhibitors that can be used to treat cancers (particularly solid tumors) for which dasatinib is not indicated for treatment and / or for which dasatinib has not shown promising results. In particular, there is a need for novel kinase inhibitors for the treatment of one or more cancers, such as breast cancer, lung cancer (e.g., non-small cell carcinoma), pancreatic cancer, or prostate cancer (e.g., castration- or hormone-resistant), as well as melanoma. There is also a need for novel kinase inhibitors for the treatment of myeloid or lymphoblastic cancers, such as leukemias, preferably for the treatment of one or more Ph+ leukemias, such as CML and / or ALL.

[0010] Dasatinib is described as a nanomolar inhibitor of the following kinases: BCR-ABL, SRC family (SRC, LCK, YES, FYN), c-KIT, EPHA2, and PDGFR-β; of particular relevance to dasatinib's indication for Ph+ leukemias is its inhibition of the hybrid protein kinase BCR-ABL.

[0011] The BCL-ABL kinase is directly linked to the presence of a specific genetic abnormality on chromosome 22, known as the "Philadelphia chromosome" (or Philadelphia translocation), in leukemic cancer cells, particularly CML cells. This reciprocal translocation of genetic material between chromosomes 9 and 22 juxtaposes the ABL1 gene on chromosome 9 with the BCR gene on chromosome 22, resulting in the coding sequence for a hybrid protein known as "BCR-ABL": an always-on protein tyrosine kinase that causes uncontrolled cell division. 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+ leukemias. However, despite this increase in overall survival, resistance that develops during imatinib treatment has led scientists to discover that most of this resistance is due to the emergence of BCR-ABL mutations, specifically amino acid substitutions within the ABL-derived kinase domain (for review, see Rossari & Orciuolo. 2018, J. Hemat. Oncol. 11:84, herein incorporated by reference in its entirety).

[0012] Analysis of BCR-ABL mutation status and survival likelihood in patients treated with imatinib showed that mutations within the phosphatase loop (P loop) of the BCR-ABL kinase ABL site were the most common, but (more rare) mutations outside the P loop (particularly mutations within the kinase domain) were associated with decreased overall survival in CML patients treated with imatinib (Jabbour et al. 2006, Leukemia 20: 1767). Since then, many emerging 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 mutations. The kinase target of dasatinib; both of which are specifically incorporated herein by reference). In particular, the following mutations were found in the ATP-binding region of BCR-ABL (positions indicated for wild-type ABL protein): V299L, F311L, T315I, T315A, F317L, and F317V. Indeed, dasatinib was initially developed as a "second-generation" BCR-ABL inhibitor for the second-line treatment of CML, a disease that has become resistant to imatinib, presumably due to the emergence of one or another of these mutations. Based on modeling studies, dasatinib is predicted to bind to multiple conformations of the ABL kinase, which is thought to explain why dasatinib inhibits several conformational-altering mutations of ABL, whereas imatinib does not. Indeed, a retrospective analysis comparing mutational development during first-line treatment with dasatinib or imatinib found that fewer distinct mutation sites emerged with dasatinib (4 distinct sites) compared with imatinib (12 distinct sites) (Hughes et al. 2015, Leukemia 29:1832, specifically its Figure 1Importantly, however, (i) the overall proportion of patients who developed any type of mutation was roughly the same (17 / 259 dasatinib patients and 18 / 260 imatinib patients); (ii) the majority of mutations that emerged after dasatinib treatment were in the ATP-binding region (3 / 4 mutations); and (iii) the most common mutation that emerged during dasatinib treatment (11 / 17) was the T315I mutation at the so-called “gatekeeper” residue, which still confers resistance to dasatinib inhibition of the BCR-ABL kinase. The ProQinase ABL1 Kinase "Wildtype and Mutant Panel" provides a panel of BCR-ABL mutants that can be tested against kinase inhibitors, including the ABL1 wild-type protein (amino acids P118-S525) and mutant forms representing the most common imatinib-resistant mutant forms of BCR-ABL: G250E, Q252H, Y253F, E255K, T315I, F317I, M351T, and H396P (www.proqinase.com).

[0013] The T315I mutation is one of the most frequently occurring BCR-ABL mutations: occurring in 2% to 20% of CML cases (Nicolini et al. 2009, Blood 114: 5271). This mutation is resistant to inhibition by dasatinib, a potential drawback of dasatinib as a kinase inhibitor, which has stimulated the development of a "third generation" BCR-ABL inhibitor known as "ponatinib" (sold by Incyte & Takeda as ICLUSIG). However, although ponatinib does indeed strongly inhibit the T315I mutation of BCR-ABL kinase (in vitro IC50 of 2.0 nM), it is a more promiscuous kinase inhibitor than dasatinib and also inhibits many other kinases, including at least VEGFR, PDGFR, FGFR, EPH receptor and SRC kinase family members, as well as KIT, RET, TIE2 and FLT3, with in vitro IC50 concentrations between 0.1 and 20 nM. In addition, sales of ponatinib in the United States were temporarily suspended in October 2013 due to the "risk of life-threatening blood clots and severely narrowed blood vessels." In December 2013, the suspension was partially lifted and revised prescribing information was issued for ponatinib, with a new "black box warning" and a "risk evaluation and mitigation strategy" to better assess the risks and benefits of using the drug. In addition, the price of ponatinib in the United States (which may cost $138,000 per year) has also been criticized. Therefore, ponatinib exhibits substantial shortcomings, and there remains a need for new kinase inhibitors, particularly those that have the potential to be more effective, safe, easy and / or inexpensive to treat Ph+ leukemias (or other cancers); and / or inhibitors that are more selective for SRC, ABL / BCR-ABL and / or LCK compared to other kinase inhibitors (such as dasatinib or ponatinib).

[0014] However, in contrast to imatinib, dasatinib is not particularly specific for BCR-ABL and binds to and / or inhibits a large number of other kinases (see: Bantscheff et al. 2007, Nat. Biotech. 25:1035). Figure 3 ; Supplement to Anastassiadis et al. 2012, Nat. Biotech. 29:1039 Figure 2). In particular, compared to imatinib, dasatinib is described as more potent in binding to and / or inhibiting a number of other kinases, including: BTK, CSK, EPHB2, EPHB4, FYN, GAK, KIT, LYN, QIK, QSK, RIPK2, SRC, TEC, TESK2, YES, and ZAK. More specifically, dasatinib was shown to be a significant inhibitor of salt-inducible kinases, with IC50 values ​​of <3 nM, <3 nM, and 18 nM for three family members, SIK1, SIK2, and SIK3, respectively (Ozanne et al. 2015, Biochem. J. 465:271; also described in co-pending PCT / EP2018 / 060172). Indeed, given that dasatinib is a less selective kinase inhibitor (another potential disadvantage), this reduced selectivity may be causally related to the non-trivial toxicity challenges faced by dasatinib treatment, especially the increased incidence of thrombocytopenia (Wei et al. 2010, J. Hemat. Oncol. 3:47).

[0015] As mentioned above, dasatinib is a potent inhibitor of KIT, a tyrosine kinase receptor that is becoming an increasingly interesting target for the treatment of certain cancers (Babei et al. 2016, Drug Des. Dev. Thera., 10: 2443), particularly because mutations in the KIT gene have been detected in cancers such as leukemia, ovarian cancer, and melanoma. Dasatinib is also known to inhibit at least the most common KIT mutation in melanoma (Woodman et al. 2009, J. Clin. Onc. 27: 9019). However, inhibition of KIT, and particularly inhibition of the relative activity of certain tyrosine kinase inhibitors against FLT3 and KIT, has been associated with bone marrow suppression and other side effects (e.g., hair loss) (Galanis and Levis 2015: Haematologica 100: e89). Indeed, dasatinib treatment is associated with severe bone marrow suppression (see below).

[0016] Salt-inducible kinases (SIKs) constitute a subfamily of serine tyrosine kinases and belong to the adenosine monophosphate-activated kinase (AMPK) family. So far, three members (SIK1, 2, and 3) have been identified. In the kinase domain, SIK1 shares 78% and 68% amino acid homology with SIK2 and SIK3, respectively. The cloning of SIK1 (also known as SIK and SNF1LK), which is 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), which is primarily expressed in adipose tissue, and the rather common SIK3 (also known as QSK, KIAA0999, or L19) (Katoh et al. 2004, Mol. Cell. Endocrinol. 217: 109). The three SIKs have a similar structure, with an N-terminal kinase domain (catalytic domain), an intermediate ubiquitin-associated domain (thought to be important for phosphorylation of LKB1), and a long C-terminal sequence (thought to be the site of further phosphorylation by PKA). However, the various SIKs are involved in many different roles. For example, various SIKs have been implicated in biological processes such as the response of bone cells to parathyroid hormone (Wein et al. 2016, Nature Commun. 7: 13176), induction of SIK1 in response to gastrin, and inhibition of gastric adenocarcinoma cell migration (Selvik et al. 2014, PLoS ONE 9: e112485). Other potential roles of salt-induced kinases, particularly SIK3, are further described in the co-pending PCT / EP2018 / 060172. SIK3 is a gene involved in tumor cell responses to cell-mediated immunity, particularly tumor cell resistance to TNF.

[0017] Thus, there remains a need for new kinase inhibitors, particularly those that exhibit different kinase properties than the kinases 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, and / or EPHA2, EPHA4, CSF-R1, HCK, ACK1, and / or KIT) relative to other kinases, and exhibit greater specificity than dasatinib exhibits for one or more of these other kinases; (ii) inhibit key disease- or side effect-associated kinases in a manner different from that of dasatinib (e.g., inhibition of KIT and / or FLT3); and / or (iii) inhibit one or more mutants of a disease-associated kinase, particularly mutants that are resistant to one or more kinase inhibitors, such as mutants of ABL / BCR-ABL or KIT.

[0018] Furthermore, although dasatinib is primarily metabolized by the cytochrome P450 enzyme 3A4 (CYP3A4) in humans, it is also a time-dependent inhibitor of CYP3A4. Indeed, if patients are taking strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole) concomitantly, the dasatinib dose must be significantly reduced (eg, from 100 mg daily to 20 mg daily) because they may increase dasatinib plasma concentrations 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 exhibit a different pattern of cytochrome P450 inhibition than dasatinib (eg, inhibition of CYP3A4).

[0019] Importantly, the dose and administration of dasatinib should be discontinued (or reduced) upon the development of myelosuppression. Indeed, myelosuppression is described only as a "Warnings and Precautions" in the U.S. prescribing information for dasatinib, as treatment with dasatinib has been associated with severe (NCI CTC Grade 3 or 4) thrombocytopenia, neutropenia, and anemia. In all clinical studies of dasatinib, in addition to causing thrombocytopenia in humans, (i) severe central nervous system (CNS) bleeding (including death) occurred in 1% of patients; (ii) severe gastrointestinal bleeding, including fatal events, often requiring treatment interruption and transfusion, occurred in 4% of patients; and (iii) other serious bleeding cases occurred in 2% of patients.

[0020] Other "Warnings and Precautions" for dasatinib include: (x) it is associated with fluid retention, with severe fluid retention reported in up to 10% of patients in clinical trials; (y) it has the potential to prolong ventricular repolarization (QT interval), with up to 1% of CML patients experiencing QT prolongation in clinical trials; and (z) cardiac adverse reactions occurred in 5.8% of 258 patients taking dasatinib, including cardiomyopathy, congestive heart failure, diastolic dysfunction, fatal myocardial infarction, and left ventricular dysfunction in 1.6%. In fact, dasatinib is known to be an inhibitor of hERG (Pharmacology / Toxicity Studies and Evaluation of NDA 21-986, page 31). hERG (human "ether-related gene") is an ion channel that promotes the heart's electrical activity and coordinates the heart's beating. When the channel's ability to conduct electrical current across the cell membrane is inhibited or impaired (for example, by drug administration), "long QT syndrome" can result, which can be fatal. Therefore, there remains a need for novel kinase inhibitors that exhibit inhibitory effects on hERG that differ from those of dasatinib. For example, it would be advantageous to provide novel kinase inhibitors that exhibit a greater IC50 for hERG than dasatinib.

[0021] Compared to other BCR-ABL inhibitors, dasatinib has an extremely short half-life: the overall mean terminal half-life is only 3-5 hours (Section 12.3, "Pharmacokinetics" in the full prescribing information). In stark contrast, imatinib has an elimination half-life of approximately 18 hours; bosutinib has a mean terminal elimination half-life of 22.5 hours; nilotinib has an apparent elimination half-life of approximately 17 hours; and ponatinib has a geometric mean terminal elimination half-life of approximately 24 hours. Without being bound by theory, dasatinib's short half-life—indicative of once-daily dosing—may explain limited activity due to lower drug concentrations later in the day and / or side effects associated with peak drug concentrations / higher doses shortly after administration. Therefore, there remains a need for new kinase inhibitors that exhibit longer half-life properties (e.g., longer half-lives than those exhibited by dasatinib). For example, an advantageous kinase inhibitor may be a kinase inhibitor that is more stable than dasatinib, for example by demonstrating a longer half-life in plasma and / or liver microsomal stability assays.

[0022] Additional precautions, adverse events and other prescribing information for dasatinib may be found in the individual Summary of Product Characteristics (SmPC) of the full prescribing information, as available on the respective websites of the EMA and FDA (individually shown below, accessed on 20 August 2018, and the entire contents of each of which are incorporated herein by reference): (i) http: / / www.ema.europa.eu / docs / en_GB / document_library / EPAR_-

[0023] _Product_Information / human / 000709 / WC500056998.pdf, and (ii) https: / / www.accessdata.fda.gov / drugsatfda_docs / label / 2010 / 021986s7s8lbl.pdf.

[0024] Many variants of dasatinib have been synthesized and demonstrated to have in vitro biochemical inhibitory activity against one or more kinases and / or antiproliferative effects on cells. In particular, such 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);

[0025] (ii) providing alternative kinase inhibitors and / or drug candidates (e.g., WO 2006 / 081172 and WO 2008 / 033746). The variants of dasatinib described therein carry a phenyl moiety on the carboxamide. These disclosures demonstrate a substantial range of other positions and substituents that can be substituted thereon, which provide compounds that are kinase inhibitors and / or have cell antiproliferative activity ( Figure 8 ).

[0026] WO 2018 / 193084 (to the present applicant and published on October 25, 2018) discloses a dasatinib variant bearing a pyridyl moiety. Beutner et al. (2018, Org Lett 20:4218) described a method for forming challenging amide bonds, including those of certain pyridines, pyrazines, and pyrimidines. Pennington et al. (2017, J Med Chem 60:3552) described the potential effects of replacing CH groups with N atoms in aromatic and heteroaromatic ring systems on molecular and physiological properties. However, empirical evidence suggests that making such substitutions increases statistical power beyond the potential for chance: matched molecule pair analysis (MMPA) of Abbott internal data (Hajduk & Sauer 2008, J Med Chem 51:553) found that, as with most substituent substitutions, the likelihood of increasing or decreasing potency by exchanging CH groups and N atoms was roughly the same. Indeed, the analysis further revealed that the probability of achieving a 10-fold potency improvement with such substitutions was less than 1 in 10, and the probability of achieving a 100-fold potency improvement was less than 1 in 100. These probabilities are similar to those observed when studying the effects of such substitutions on binding affinity (Hu et al. 2014, F1000Research 3:36; de la Vega de Leon et al2014, MedChemComm5:64).

[0027] Therefore, an object of the present invention is to provide one or more kinase inhibitors having one or more properties for one or more of these or other problems (e.g., those shown by in vitro and / or in vivo assays). Among other objects, the present invention provides alternative and / or improved kinase inhibitors of dasatinib (or one or other kinase inhibitors, such as those described herein). For example, a kinase inhibitor that can exhibit one or more functions (e.g., kinase selectivity) and / or ADMET properties that are different and / or improved from dasatinib (or one or other kinase inhibitors, such as those described herein) would be particularly advantageous. The objects underlying the present invention are solved by the subject matter as disclosed or defined anywhere herein, for example, by the subject matter of the appended claims. SUMMARY OF THE INVENTION

[0029] In general, the main aspects of the present invention can be summarized as follows through a brief description:

[0030] In a first aspect, the present invention provides a compound selected from the group consisting of kinase inhibitors of the formula:

[0031]

[0032] and solvates, salts, N-oxides, complexes, polymorphs, crystal forms, racemic mixtures, diastereomers, enantiomers, tautomers, conformers, isotopically labeled forms, prodrugs, and combinations thereof; wherein R 1a 、R 1b 、R 1c 、R 2 、R 3 、R 4 、R 5 , A, B and E are as defined herein.

[0033] In a second aspect, the present application provides a pharmaceutical composition comprising the compound of the first aspect and an optional pharmaceutically acceptable carrier.

[0034] In a third aspect, the present application provides the compound of the first aspect or the pharmaceutical composition of the second aspect for use in treatment.

[0035] In a fourth aspect, the present application provides the compound of the first aspect or the pharmaceutical composition of the second aspect for use in a method of treating a disease, disorder or condition in an individual (particularly a human patient), wherein the disease or condition is associated with a kinase.

[0036] Other aspects of the invention are disclosed herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0037] The accompanying drawings show:

[0038] Figure 1 : The chemical structures of the following compounds are described: (A) dasatinib (Compound A8), N-(2-chloro-6-methylphenyl)-2-((6-(4-(2-hydroxymethyl)piperazin-1-yl)-2-methylpyrimidin-4-yl)amino)thiazole-5-carboxamide; (B) kinase inhibitor B3, N-(4-chloro-2-methylpyridin-3-yl)-2-((6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-yl)amino)thiazole-5-carboxamide; (C) certain other kinase inhibitors of Formula (I) C1 to C13; and (D) certain other kinase inhibitors of Formula (I) D1 to D10.

[0039] Figure 2: (A to E) Depicted are the inhibitory activities of a kinase inhibitor of formula (I) (B3, left column) against the kinases (A) ABL1; (B) SRC; (C) SIK1; (D) SIK2; and (E) SIK3, compared to dasatinib (A8, right column); and (F to J) Depicted are the inhibitory activities of other kinase inhibitors of formula (I) (C3, left column; C12, right column) against the kinases (F) ABL1; (G) SRC; (H) SIK1; (I) SIK2; and (J) SIK3. X-axis: Compound concentration (M) and Y-axis: Kinase activity (%).

[0040] Figure 3 : Depicts the selectivity of B3 (a kinase inhibitor of Formula (I)), dasatinib (A8), and C7 (another kinase inhibitor of Formula (I)) for kinase inhibition as a percentage of residual activity (at 1 uM compound): ****<25% residual activity; ***25% to <50% residual activity; **50% to <75% residual activity; *>75% residual activity. Classification of protein kinase families (Manning et al. Science 6 December 2002: Vol. 298 no. 5600 pp. 1912-1934): AGC: encompasses the PKA, PKG, and PKC families; CAMK: calcium / calmodulin-dependent protein kinase; CK1: casein kinase-like; CMGC: encompasses the CDK, MAPK, GSK3, and CLK families; TK: tyrosine kinase; TKL: tyrosine kinase-like; STE: homologs of Yeast Sterile 7, Sterile 11, and Sterile 20 kinases. ##Constitutively active kinase.

[0041] Figure 4 : Depicts the selectivity of kinase inhibitor B3 of formula (I) (X-axis) for inhibiting kinases (as a percentage of residual activity at 1 uM of compound) compared to dasatinib (A8; Y-axis): the (A) axis shows the entire range of residual activity; and the (B) axis represents the range of 0 to 50% residual activity.

[0042] Figure 5 : Depicts the inhibitory activity of the kinase inhibitor of formula (I) (B3, left column) against the kinases (A) FLT3; (B) SYK; (C) KIT; and (D) LCK compared to dasatinib (A8, right column). X-axis: Compound concentration (M) and Y-axis: Kinase activity (%).

[0043] Figure 6: Depicts the sensitization of tumor cells to in vitro TNF challenge by (A) kinase inhibitors B3 and (B) A8 (dasatinib); circles: compound (at the concentrations indicated) plus rHuTNF (10 ng / mL); squares: compound alone (at the concentrations indicated) without rHuTNF.

[0044] Figure 7 : Depicts relative tumor cell viability (RLU normalized by cytotoxicity / viability) of certain kinase inhibitors described in PCT / EP2018 / 060172 using M579-A2-luc described in Example 9 at various concentrations alone (squares) or in combination with 10 ng / mL TNF (circles). Also shown are indicative inhibitory activities of the compounds against SIK family members and related kinases ABL1 and SRC, as indicated in Table 3. (A) Pan-SIK and ABL1 & SRC inhibitor, compound B1; (B) ABL1 & SRC inhibitor, compound B8. (C) SIK1, SIK2, ABL1 & SRC inhibitor, compound B4.

[0045] Figure 8 Depicted are: (A) cellular antiproliferative activity of dasatinib variants obtained from Table 1 of Lombardo et al 2004 (J Med Chem 47:6658), showing the potency of various dasatinib derivatives against the indicated cell lines. a Antiproliferative activity was determined based on tetrazolium dye conversion after 72 hours of compound exposure. IC50 values ​​are reported as the mean of at least three separate determinations or as individual IC50 values ​​when fewer than three measurements are available. Variability around the mean is <50% unless otherwise indicated by the SE value in parentheses; and (B) biochemical and cellular antiproliferative activity of dasatinib variants from Table 4 of Das et al 2006 (J Med Chem 49:6819). an = 3, variation of individual values, <20%. bn = 3, individual values, <30%.

[0046] Figure 9 : Depicts the selectivity (as percent residual activity at 1 uM compound) of kinase inhibitor C7 of Formula (I) (Y-axis) in inhibiting kinases compared to (A) dasatinib (A8; X-axis) and (B) another kinase inhibitor B3 of Formula (I) (X-axis). The dashed area highlights the group of kinases that are substantially differently inhibited between the applicable compounds.

[0047] Figure 10Figure 3: Body weights of female C57Bl / 6 mice administered C7 at various concentrations (33 mg / kg (black squares) and 100 mg / kg (gray diamonds) once daily (QD = A) and twice daily (BID = B) by gavage compared to control animals (gray squares). X-axis: Days post-dose; Y-axis: Change in body weight (%). (C) C7 plasma levels determined by LC-MS / MS. A = 33 mg / kg QD; B = 100 mg / kg QD; C = 33 mg / kg BID; D = 100 mg / kg BID. Y-axis: C7 plasma concentration (nM).

[0048] Figure 11 Figure 3: Depicts tumor growth kinetics in mice implanted with MC38 cells after (A) treatment with vehicle (black squares), C7 100 mg / kg QD (grey hexagons), C7 100 mg / kg BID (grey triangles), and A8 (dasatinib) 30 mg / kg QD A8 (grey circles); Y-axis = mean tumor volume (mm3). Error bars SEM. X-axis: days. Statistical significance was calculated by two-way ANOVA with Tukey's multiple comparison analysis. ***p < 0.001. (B) Body weight kinetics of mice in (A). Y-axis: mean body weight change (%).

[0049] Figure 12 : Depicts the immunotumor effects of compound C7 of formula (I) on immune cells present in the tumor microenvironment. Intratumoral immune infiltration was calculated as the percentage of intratumoral CD45+ cells. Statistical significance was calculated by one-way analysis of variance, including Tukey's multiple comparison analysis. (A) Y-axis: ratio of CTL to Treg cells. (B) Activated CTLs (CD25+CD69+); Y-axis: percentage of CD45+ cells. (C) Activated CTLs (granzyme B+); Y-axis: percentage of CD45+ cells. (D) Immunosuppressive M2-like tumor-associated macrophages (TAMs) (CD206+MHC-II+); Y-axis: percentage of CD45+ cells; *p<0.05; **p<0.01; ***p<0.00.

[0050] Figure 13: Depicts TNF-killing cells sensitized by compound C7. (A) TNF-induced apoptosis of PANC-1 cells. PANC-1 cells were treated with 370 nM ("diamonds"), 3333 nM ("squares"), and DMSO alone ("stars"), followed by the addition of 100 ng / ml rHuTNF for 120 h (+rHuTNF = open shapes; -rHuTNF = solid shapes; open circles = 10 ng / mL rHuTNF control). Cell death was assessed using real-time live cell microscopy, measuring nuclear incorporation of YOYO-1 dye (area of ​​YOYO-1+ cells / well). Y-axis = tumor cell death (um2 / well). X-axis = time (h); (B) Effect of C7 on apoptosis of murine MC38 cells induced by TNF (100 ng / ml rMuTNF) (+rMuTNF = "diamonds"; -rMuTNF = "circles"). After 72 h, cell viability was measured using the CellTiter-Glo assay. Luciferase values ​​were normalized to cells treated with rMuTNF without inhibitor (DMSO only). Y-axis = viability (%). X-axis = compound concentration (nM).

[0051] Figure 14 Depicted are: (A) Effect of Compound C7 on NFKB activity. Reporter PANC-1 cells expressing luciferase under the control of the NFKB promoter were treated with various concentrations of C7, followed by the addition of 10 ng / mL rHuTNF for 8 hours (+rHuTNF = "diamonds"; -rHuTNF = "circles"). Luciferase activity was normalized to that of PANC-1 cells treated with rHuTNF without the inhibitor (DMSO only). Y-axis = NFKB activity (%). X-axis = compound concentration (nM). (B) Effect of Compound C7 on HDAC4 phosphorylation. PANC-1 cells were treated with various concentrations of C7 (in the presence of 10 ng / mL rHuTNF) for 3 hours. Whole-cell lysates were analyzed in a Meso Scale Discovery (MSD) assay using anti-HDAC4 capture and anti-pHDAC4 detection antibodies. HDAC4 phosphorylation was normalized to that of untreated PANC-1 cells (DMSO only). Y-axis = HDAC4 phosphorylation (%). X-axis = compound concentration (nM).

[0052] Figure 15 : Depicted: Growth inhibition of WSU-NHL (A) and DOHH-2 (B) cell lines by compound C7, showing GI50s of approximately 8 nM and 9 nM, respectively. X-axis: compound concentration (M); Y-axis: percent growth inhibition (GI) at 96 hours.

[0053] Detailed description of the invention

[0054] The present invention and certain non-limiting aspects and / or embodiments thereof may be described in further detail as follows.

[0055] Although the present invention may be further described in greater detail, it should be understood that the invention is not limited to the specific methodology, protocols, and reagents described herein, as these may vary. It should also be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the present invention, which will be limited only by what is described herein, defined herein, or otherwise disclosed, particularly in any sub-examples or appended claims.

[0056] Here, certain elements of the present invention are described in more detail. These elements are listed together with specific embodiments, however, it should be understood that they can be combined in any manner and in any number to create additional embodiments. The various described examples and preferred embodiments should not be interpreted as limiting the present invention to only the embodiments explicitly described. It should be understood that the description of this application supports and includes embodiments that combine the explicitly described embodiments with any number of disclosed and / or preferred elements. In addition, unless the context indicates otherwise, any arrangement and combination of all described elements in this application should be considered to be disclosed in the description of this application. For example, if in one embodiment of the compounds of the present invention L is a bond, and in another embodiment of the compounds of the present invention R 3 is H, then in a preferred embodiment of the compounds of the present invention, L is a bond and R 3 is H, or if in one embodiment of the use of the compounds of the present invention the subject is an adult human and in another embodiment of the use of the compounds of the present invention the proliferative disease is prostate cancer, then in a preferred embodiment of the use of the compounds of the present invention the subject is an adult human and the proliferative disease is prostate cancer.

[0057] General Definition

[0058] Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art.

[0059] Preferably, the terms used herein are as described in "A multilingual glossary of biotechnological terms: (IUPAC Recommendations)", HGW Leuenberger, B. Nagel, and H. As defined in Eds., Helvetica Chimica Acta, CH-4010 Basel, Switzerland, (1995).

[0060] The practice of the present invention will employ, unless otherwise indicated, conventional methods of chemistry, biochemistry and recombinant DNA techniques, which are explained in the literature in the art (see, for example, Molecular Cloning: A Laboratory Manual, 2 nd Edition, J. Sambrook et al. eds., Cold Spring Harbor Laboratory Press, Cold Spring Harbor 1989).

[0061] Throughout this specification and the claims that follow, unless the context requires otherwise, the word "comprise" and variations such as "comprises" and "comprising" will be understood to imply the inclusion of a stated member, integer or step or group of members, integers or steps but not the exclusion of any other member, integer or step or group of members, integers or steps. The term "consisting essentially of means excluding any other member, integer or step or group of members, integers or steps of any significance. For example, a pharmaceutical composition consisting essentially of the members / components defined herein (e.g., a compound defined in any aspect of the invention and optionally one additional therapeutic agent) will exclude other therapeutic agents (in addition to the compound defined in any aspect of the invention and optionally one additional therapeutic agent), but will not exclude trace amounts of contaminants (e.g., contaminants from isolation and purification processes) (e.g., the amount of contaminants (preferably the amount of all contaminants present in the composition) relative to the entire composition is less than 5% by weight, e.g., 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, 0.05% by weight) and / or pharmaceutically acceptable excipients (e.g., carriers, e.g., phosphate buffered saline, preservatives, etc.). The term "consisting of is intended to exclude all other members, integers, or steps or groups of members, integers, or steps of significance. For example, a pharmaceutical composition consisting of members / components as defined herein (e.g., compounds as defined in any aspect of the invention, an excipient, and optionally, an additional therapeutic agent) will exclude any other compound (including a second agent or further excipient) in an amount exceeding 2% by weight relative to the total composition (e.g., an amount of any other compound 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% by weight, 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% by weight, greater than 0.02% by weight, greater than 0.01% by weight). The term "comprising" encompasses the term "consisting essentially of," which in turn encompasses the term "consisting of." Therefore, each time it occurs in this application, the term "comprising" may be replaced by the term "consisting essentially of" or "consisting of. Likewise, each time it occurs in this application, the term "consisting essentially of" may be replaced by the term "consisting of.

[0062] As used herein, "and / or" should be taken as specific disclosure of either or both of the two specified features or components. For example, "X and / or Y" would be taken as specific disclosure of each of (i) X, (ii) Y, and (iii) X and Y, as if they were individually listed herein.

[0063] In the context of the present invention, the terms "approximately" and "approximately" are used interchangeably and represent an accuracy interval that a person of ordinary skill will understand to still ensure the technical effect of the feature in question. The term generally means a difference of ±5%, ±4%, ±3%, ±2%, ±1%, ±0.9%, ±0.8%, ±0.7%, ±0.6%, ±0.5%, ±0.4%, ±0.3%, ±0.2%, ±0.1%, ±0.05%, for example, ±0.01% from the indicated numerical value. As those skilled in the art will understand, for a given technical effect, this specific deviation of the numerical value will depend on the nature of the technical effect. For example, compared to man-made or engineered technical effects, natural or biotechnological effects may generally have a greater deviation. As those skilled in the art will understand, for a given technical effect, this specific deviation of the numerical value will depend on the nature of the technical effect. For example, compared to man-made or engineered technical effects, natural or biotechnological effects may generally have a greater deviation.

[0064] The use of the terms "a," "an," and "the" and similar referents in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

[0065] 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 separate value is incorporated into the specification as if it were individually recited herein.

[0066] All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context.

[0067] The use of any and all examples or exemplary language (e.g., "such as" or "for example") provided herein is intended merely to better illustrate the invention and does not limit the scope of the invention otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.

[0068] Throughout this specification, several documents are cited. Each document cited herein (including all patents, patent applications, scientific publications, manufacturer's specifications, instructions, 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 antedate such disclosure by virtue of prior invention.

[0069] As used herein, the terms "of the present invention," "according to the present invention," "in accordance with the present invention," etc. are intended to refer to all aspects and embodiments of the invention described and / or claimed herein.

[0070] It will be understood that applying the teachings of the present invention to a particular problem or situation, and incorporating variations of the invention or additional features thereof (such as further aspects and embodiments) will be within the capabilities of those skilled in the art based on the teachings contained herein.

[0071] Unless the context indicates otherwise, the descriptions and definitions of the 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.

[0072] The term "alkyl" refers to a monovalent radical of a saturated straight or branched chain hydrocarbon. Preferably, the alkyl group contains 1 to 12 (e.g., 1 to 10) carbon atoms, i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms), more preferably 1 to 8 carbon atoms, e.g., 1 to 6 or 1 to 4 carbon atoms. Exemplary alkyl groups include methyl, ethyl, propyl, isopropyl (also known as 2-propyl or 1-methylethyl), butyl, butyl, butyl, butyl, butyl, butyl, butyl, butyl, butyl, butyl, butyl, butyl, butyl, butyl, butyl, butyl, butyl, butyl, butyl, butyl, butyl, butyl, butyl, butyl, alkyl, isobutyl, tert-butyl, 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" refers to an alkyl group in which one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10) hydrogen atoms are bonded to the alkyl group. , e.g., 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, the substituents other than hydrogen are primary, secondary, or tertiary substituents as specified herein, e.g., halogen, -OH, -NH2, -NHCH3, -N(CH3)2, -CN, -OCH3, -OCF3, or optionally substituted aryl. Examples of substituted alkyl groups include trifluoromethyl, 2,2,2-trichloroethyl, 2-hydroxyethyl, 2-aminoethyl, 2-(dimethylamino)ethyl, arylalkyl (also referred to as "aralkyl", e.g., benzyl, chloro(phenyl)methyl, 4-methylphenylmethyl, (2,4-dimethylphenyl)methyl, o-fluorophenylmethyl, 2-phenylpropyl, 2-, 3-, or 4-carboxyphenylalkyl), or heteroarylalkyl (also referred to as "heteroaralkyl").

[0073] The term "alkylene" refers to a diradical of a saturated straight or branched hydrocarbon. Preferably, the alkylene group contains 1 to 12 (e.g., 1 to 10) carbon atoms, i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms), more preferably 1 to 8 carbon atoms, e.g., 1 to 6 or 1 to 4 carbon atoms. Exemplary alkylene groups include methylene, ethylene (i.e., 1,1-ethylene, 1,2-ethylene), propylene (i.e., 1,1-propylene, 1,2-propylene (-CH(CH3)CH2-), 2,2-propylene (-C(CH3)2-), and 1,3-propylene), butylene isomers (e.g., 1,1-butylene, 1,2-butylene, 2,2-butylene, 1,3-butylene, 2,3-butylene (cis or trans or mixtures thereof), 1,4-butylene, 1,1-isobutylene, 1,2-isobutylene, and 1,3-isobutylene), pentylene isomers (e.g., 1,1-pentylene, 1,2-pentylene, 1,3-pentylene, 1,4-pentylene, 1,5-pentylene, 1,1

[0014] In some embodiments, the present invention includes but is not limited to 1,1-diaminobenzene, ... A linear alkylene moiety having at least 3 carbon atoms and free valences at each end may also be designated as a polymethylene group (e.g., 1,4-butylene may also be referred to as a tetramethylene group). Typically, instead of using the prefix "methylene" for the alkylene moieties specified above, the suffix "diyl" may also be used (e.g., 1,2-butene may also be referred to as butenyl 1,2-diyl). "Substituted alkylene" refers to an alkylene group in which one or more (e.g., 1 to a maximum of 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, of the number of hydrogen atoms bound to the alkylene group) hydrogen atoms are replaced by a substituent other than hydrogen (when multiple hydrogen atoms are replaced, the substituents may be the same or different). Preferably, the substituent other than hydrogen is a primary substituent, a secondary substituent, or a tertiary substituent as specified herein, such as a halogen or an optionally substituted aryl group. Examples of substituted alkylene groups include chloromethylene, dichloromethylene, fluoromethylene, and difluoromethylene.

[0074] The term "alkenyl" refers to a monovalent group of an unsaturated straight or branched hydrocarbon with at least one carbon-carbon double bond. Typically, the maximum number of carbon-carbon double bonds in the alkenyl group can be equal to an integer, and this integer is obtained by such as calculating: the number of carbon atoms in the alkenyl group is divided by 2, and if the number of carbon atoms in the alkenyl group is an odd number, the division result is rounded down to the next integer. For example, for the alkenyl group with 9 carbon atoms, the maximum number of carbon-carbon double bonds is 4. Preferably, the alkenyl group has 1 to 6 (e.g., 1 to 4), i.e., 1, 2, 3, 4, 5 or 6 carbon-carbon double bonds. Preferably, the alkenyl group comprises 2 to 12 (e.g., 2 to 10) carbon atoms, i.e., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms (e.g., 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms), more preferably 2 to 8 carbon atoms, such as 2 to 6 carbon atoms or 2 to 4 carbon atoms. Thus, in a preferred embodiment, the alkenyl group comprises 2 to 12 (e.g., 2 to 10) carbon atoms and 1, 2, 3, 4, 5, or 6 (e.g., 1, 2, 3, 4, or 5) carbon-carbon double bonds, more preferably it comprises 2 to 8 carbon atoms and 1, 2, 3, or 4 carbon-carbon double bonds, e.g., 2 to 6 carbon atoms and 1, 2, or 3 carbon-carbon double bonds or 2 to 4 carbon atoms and 1 or 2 carbon-carbon double bonds. The carbon-carbon double bonds may be in the cis (Z) or trans (E) configuration. Exemplary alkenyl groups include ethenyl, 1-propenyl, 2-propenyl (i.e., allyl), 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 1-octenyl, 2-octenyl, 3-octenyl, 4-octenyl, 5-octenyl, 6-octenyl, 7-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 4-nonenyl, 5-nonenyl, 6-nonenyl, 7-nonenyl, 8-nonenyl, , 1-decenyl, 2-decenyl, 3-decenyl, 4-decenyl, 5-decenyl, 6-decenyl, 7-decenyl, 8-decenyl, 9-decenyl, 1-undecenyl, 2-undecenyl, 3-undecenyl, 4-undecenyl, 5-undecenyl, 6-undecenyl, 7-undecenyl, 8-undecenyl, 9-undecenyl, 10-undecenyl, 1-dodecenyl, 2-dodecenyl, 3-dodecenyl, 4-dodecenyl, 5-dodecenyl, 6-dodecenyl, 7-dodecenyl, 8-dodecenyl, 9-dodecenyl, 10-dodecenyl, 11-dodecenyl, etc. If the alkenyl group is attached to a nitrogen atom, the double bond cannot be alpha to the nitrogen atom."Substituted alkenyl" means that one or more (e.g., from 1 to the maximum number of hydrogen atoms bound to the alkenyl, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, e.g., 1 to 5, 1 to 4, or 1 to 3, or 1 or 2) hydrogen atoms in the alkenyl group are replaced by a substituent other than hydrogen (when replacing more than one hydrogen atom, the substituents may be the same or different). Preferably, the substituent other than hydrogen is a primary substituent, a secondary substituent, or a tertiary substituent as specified herein, e.g., a halogen or an optionally substituted aryl group. An example of a substituted alkenyl group is styryl (i.e., 2-phenylvinyl).

[0075] The term "alkenylene" refers to a diradical of an unsaturated straight or branched hydrocarbon having at least one carbon-carbon double bond. Typically, the maximum number of carbon-carbon double bonds in an alkenylene group can be equal to an integer, which is 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 an odd number, rounding the result of the division down to the next integer. For example, for an alkenylene group having 9 carbon atoms, the maximum number of carbon-carbon double bonds is 4. Preferably, the alkenylene group has 1 to 6 (e.g., 1 to 4), i.e., 1, 2, 3, 4, 5 or 6 carbon-carbon double bonds. Preferably, the alkenylene group comprises 2 to 12 (e.g. 2 to 10) carbon atoms, i.e. 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms (e.g. 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms), more preferably 2 to 8 carbon atoms, for example 2 to 6 carbon atoms or 2 to 4 carbon atoms. Therefore, in a preferred embodiment, the alkenylene group comprises 2 to 12 (e.g. 2 to 10 carbon) atoms and 1, 2, 3, 4, 5 or 6 (e.g. 1, 2, 3, 4 or 5) carbon-carbon double bonds, more preferably it comprises 2 to 8 carbon atoms and 1, 2, 3 or 4 carbon-carbon double bonds, for example 2 to 6 carbon atoms and 1, 2 or 3 carbon-carbon double bonds or 2 to 4 carbon atoms and 1 or 2 carbon-carbon double bonds. The carbon-carbon double bond can be in cis (Z) or trans (E) configuration. Exemplary alkenylene groups include ethene-1,2-diyl, vinylene (also known as vinylene), 1-propylene-1,2-diyl, 1-propylene-1,3-diyl, 1-propylene-2,3-diyl, arylene, 1-butene-1,2-diyl, 1-butene-1,3-diyl, 1-butene-1,4-diyl, 1-butene-2,3-diyl, 1-butene-2,4-diyl, 1-butene-3,4-diyl, 2-butene-1,2-diyl, 2-butene-1,3-diyl, 2-butene-1,4-diyl, 2-butene-2,3-diyl, 2-butene-2,4-diyl, 2-butene-3,4-diyl, etc. If the alkenylene group is attached to a nitrogen atom, the double bond cannot be alpha to the nitrogen atom. "Substituted alkenylene" means that one or more (e.g., from 1 to the maximum number of hydrogen atoms bound to the alkenylene, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or up to 10, e.g., 1 to 5, 1 to 4, or 1 to 3 or 1 or 2) hydrogen atoms of the alkenylene group are replaced by a substituent other than hydrogen (when replacing more than one hydrogen atom, the substituents may be the same or different). Preferably, the substituent other than hydrogen is a primary substituent, a secondary substituent, or a tertiary substituent as specified herein, e.g., a halogen or an optionally substituted aryl. Examples of substituted alkenylene are 1-phenyl-ethylene-1,2-diyl and 2-phenyl-ethylene-1,2-diyl.

[0076] The term "alkynyl" refers to a monoradical of an unsaturated straight or branched hydrocarbon having at least one carbon-carbon triple bond. Typically, the maximum number of carbon-carbon triple bonds in an alkynyl group can be equal to an integer, which is 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 an odd number, rounding the division result down to the next integer. For example, for an alkynyl group having 9 carbon atoms, the maximum number of carbon-carbon triple bonds is 4. Preferably, the alkynyl group has 1 to 6 (e.g., 1 to 4), i.e., 1, 2, 3, 4, 5 or 6, more preferably 1 or 2 carbon-carbon triple bonds. Preferably, the alkynyl group comprises 2 to 12 (e.g. 2 to 10) carbon atoms (e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms), i.e. 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms, more preferably 2 to 8 carbon atoms, for example 2 to 6 carbon atoms or 2 to 4 carbon atoms. Thus, in a preferred embodiment, the alkynyl group comprises 2 to 12 (e.g. 2 to 10) carbon atoms and 1, 2, 3, 4, 5 or 6 (e.g. 1, 2, 3, 4 or 5 (preferably 1, 2 or 3)) carbon-carbon triple bonds, more preferably it comprises 2 to 8 carbon atoms and 1, 2, 3 or 4 (preferably 1 or 2) carbon-carbon triple bonds, for example 2 to 6 carbon atoms and 1, 2 or 3 carbon-carbon triple bonds or 2-4 carbon atoms and 1 or 2 carbon-carbon triple bonds. Examples of alkynyl groups include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-heptynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 5-heptynyl, 6-heptynyl, 1-octynyl, 2-octynyl, 3-octynyl, 4-octynyl, 5-octynyl, 6-octynyl, 7-octynyl, 1-nonyl, 2-nonynyl, 3-nonynyl, 4-nonynyl, 5-nonynyl, 6-nonynyl, 7-nonynyl, 8-nonynyl, 1-decynyl, 2-decynyl, 3-decynyl, 4-decynyl, 5-decynyl, 6-decynyl, 7-decynyl, 8-decynyl, 9-decynyl, etc. If the alkynyl group is attached to a nitrogen atom, the triple bond cannot be alpha to the nitrogen atom. "Substituted alkynyl" means an alkynyl group in which one or more (e.g., from 1 to the 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, e.g., 1-5, 1-4, or 1-3, or 1 or 2) hydrogen atoms are replaced by a substituent other than hydrogen (when more than one hydrogen atom is replaced, the substituents may be the same or different). Preferably, the substituent other than hydrogen is a primary, secondary, or tertiary substituent as specified herein, e.g., a halogen or an optionally substituted aryl group.

[0077] The term "alkynylene" refers to a diradical of an unsaturated straight or branched hydrocarbon having at least one carbon-carbon triple bond. Typically, the maximum number of carbon-carbon triple bonds in an alkynylene group can be equal to an integer, which is calculated by dividing the number of carbon atoms in the alkynylene group by 2, and if the number of carbon atoms in the alkynylene group is an odd number, rounding the result of the division down to the next integer. For example, for an alkynylene group having 9 carbon atoms, the maximum number of carbon-carbon triple bonds is 4. Preferably, the alkynylene group has 1 to 6 (e.g., 1 to 4), i.e., 1, 2, 3, 4, 5 or 6 (e.g., 1, 2, 3 or 4), more preferably 1 or 2 carbon-carbon triple bonds. Preferably, the alkynylene group comprises 2 to 12 (e.g., 2 to 10) carbon atoms, i.e., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms (e.g., 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, more preferably 2 to 8 carbon atoms, such as 2 to 6 carbon atoms or 2 to 4 carbon atoms. Thus, in preferred embodiments, the alkynylene group comprises 2 to 12 (e.g., 2 to 10) carbon atoms and 1, 2, 3, 4, 5 or 6 (e.g., 1, 2, 3, 4 or 5 (preferably 1, 2 or 3)) carbon-carbon triple bonds, more preferably it comprises 2 to 8 carbon atoms and 1, 2, 3 or 4 (preferably 1 or 2) carbon-carbon triple bonds, such as 2 to 6 carbon atoms and 1, 2 or 3 carbon-carbon triple bonds or 2-4 carbon atoms and 1 or 2 carbon-carbon triple bonds. Exemplary alkynylene groups include ethynyl 1,2-diol alkyl, 1-propynyl-1,3-diyl, 1-propynyl-3,3-diyl, 1-butynyl-1,3-diyl, 1-butynyl-1,4-diyl, 1-butyl-3,4-diyl, 2-butyl-1,4-diyl, and the like. If the alkynylene group is attached to a nitrogen atom, the triple bond cannot be alpha to the nitrogen atom. "Substituted alkynylene" means that one or more (e.g., 1 to a maximum of the number of hydrogen atoms bound to the alkynylene group, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, e.g., 1 to 5, 1 to 4, or 1 to 3 or 1 or 2) hydrogen atoms of the alkynylene group are substituted with a substituent other than hydrogen (when more than one hydrogen atom is replaced, the substituents may be the same or different). Preferably, the substituent other than hydrogen is a first-level substituent, a second-level substituent, or a third-level substituent as specified herein, e.g., a halogen or an optionally substituted aryl group.

[0078] The term "aryl" or "aromatic ring" refers to a single radical of an aromatic cyclic hydrocarbon. Preferably, the aryl group contains 3 to 14 (e.g., 5, 6, 7, 8, 9, or 10, such as 5, 6, or 10) carbon atoms, which can be arranged in one ring (e.g., phenyl) or two rings. Or more condensed rings (e.g., naphthyl). Exemplary aryl groups include cyclopropenyl, cyclopentadienyl, phenyl, indenyl, naphthyl, azulenyl, fluorenyl, anthracenyl, and phenanthrenyl. 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 include fullerenes. "Substituted aryl" means that one or more (e.g., from 1 to the maximum number of hydrogen atoms bound to the aryl group, such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or up to 10, such as 1-5, 1-4, or 1-3, or 1 or 2) hydrogen atoms in the aryl group are replaced by a substituent other than hydrogen (when replacing more than one hydrogen atom, the substituents may be the same or different). Preferably, the substituent other than hydrogen is a primary substituent, a secondary substituent, or a tertiary substituent as specified herein, such as halogen, -CN, nitro, OR 11 (e.g., -OH), -SR 11 (e.g., -SH), -N(R 12 )(R 13 )(e.g. -NH2), alkyl (e.g. C 1-6 Alkyl), alkenyl (e.g. C 2-6 alkenyl) and alkynyl (e.g. C 2-6 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.

[0079] The term "heteroaryl" or "heteroaromatic ring" refers to an aryl group as defined above, wherein one or more carbon atoms in the aryl group are replaced by a heteroatom (e.g., O, S, or N). Preferably, heteroaryl refers to a five- or six-membered aromatic monocyclic ring in which 1, 2, or 3 carbon atoms are replaced by the same or different heteroatoms of O, N, or S. 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 heteroatoms of O, N, or S. Preferably, in each ring of the heteroaryl group, the maximum number of O atoms is 1, the maximum number of S atoms is 1, and the maximum total number of O and S atoms is 2. For example, 3- to 14-membered heteroaryl groups include monocyclic heteroaryl groups (e.g., 5- or 6-membered), bicyclic heteroaryl groups (e.g., 9- or 10-membered), and tricyclic heteroaryl groups (e.g., 13- or 14-membered). 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, thiazolyl, isothiazolyl, thiadiazolyl (1,2,3- and 1,2,5-), pyridyl (also known as pyridyl), pyrimidinyl, pyrazinyl, triazinyl (1,2,3-, 1,2,4- and 1,3,5-), benzofuranyl (1- and 2-), indolyl, isoindolyl, benzothiophenyl (1- and 2-), 1H-indazolyl, benzimidazolyl, benzoxazolyl, indoloxazinyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, quinoline benzothiophene, isothienothiphenyl, isobenzofuranyl, indazolyl, purinyl, quinolinyl, phthaloyl, naphthyridinyl (1,5-, 1,6-, 1,7-, 1,8-, and 2,6-), cinnamyl, pteridinyl, carbazolyl, phenanthridinyl, pyridinyl, piperidinyl, phenylethynylphthaloyl (1,7-, 1,8-, 1,10-, 3,8-, and 4,7-), phenazinyl, oxazolopyridinyl, isoxazolopyridinyl, pyrrolooxazolyl, and pyrrolopyrrolyl. Exemplary 5- or 6-membered 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-), thiazolyl, isothiazolyl, thiadiazolyl (1,2,3- and 1,2,5), pyridyl, pyrimidinyl, pyrazinyl, triazinyl (1,2,3-, 1,2,4- and 1,3,5-), and pyridazinyl."Substituted heteroaryl" means that one or more hydrogen atoms (e.g., from 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, e.g., 1-5, 1-4, or 1-3, or 1 or 2) of the hydrogen atoms in the heteroaryl group are replaced by a substituent other than hydrogen (when replacing more than one hydrogen atom, the substituents may be the same or different). Preferably, the substituent other than hydrogen is a primary substituent, a secondary substituent, or a tertiary substituent as specified herein, e.g., halogen, -CN, nitro, or OR. 11 (e.g., -OH), -SR 11 (e.g., -SH), -N(R 12 )(R 13 )(e.g. -NH2), alkyl (e.g. C 1-6 Alkyl), alkenyl (e.g. C 2-6 alkenyl) and alkynyl (e.g. C 2-6 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-methyl-thiazol-3-yl, 1,3,5-trimethylpyrazol-4-yl, 3,5-dimethyl-1,2-dioxazol-4-yl, 1,2,4-trimethylpyrrol-3-yl, 3-phenylpyrrolyl, 2,3'-difuranyl, 4-methylpyridinyl, and 2- or 3-ethylindolyl.

[0080] The term "cycloalkyl" or "cycloaliphatic" refers to cyclic, non-aromatic forms of "alkyl" and "alkenyl" groups having preferably 3 to 14 carbon atoms, e.g., 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, cyclopent ... The term "cycloalkyl" is also intended to include bicyclic and tricyclic forms thereof. If a bicyclic ring is formed, it is preferred that the individual rings are linked to each other at two adjacent carbon atoms, but, alternatively, the two rings are linked via the same carbon atom, i.e., they form a spirocyclic ring system or they form a "bridged" ring system. Preferred examples of cycloalkyl include C 3-8Cycloalkyl groups, in particular 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 groups do not include fullerenes. "Substituted cycloalkyl" refers to a cycloalkyl group in which one or more (e.g., from 1 to a 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, e.g., 1-5, 1-4, or 1-3, or 1 or 2) hydrogen atoms are replaced by a substituent other than hydrogen (when more than one hydrogen atom is replaced, the substituents may be the same or different). Preferably, the substituent other than hydrogen is a primary substituent, a secondary substituent or a tertiary substituent as specified herein, for example, halogen, -CN, nitro, OR 11 (e.g., -OH), -SR 11 (e.g., -SH), -N(R 12 )(R 13 )(e.g. -NH2), alkyl (e.g. C 1-6 Alkyl), alkenyl (e.g. C 2-6 alkenyl) and alkynyl (e.g. C 2-6 Examples of the substituted cycloalkyl group include an oxocyclohexyl group, an oxocyclopentyl group, a fluorocyclohexyl group, and an oxocyclohexenyl group.

[0081] The term "heterocyclyl" or "heterocycle" refers to a cycloalkyl group as defined above, wherein 1, 2, 3 or 4 of the ring carbon atoms in the cycloalkyl group are replaced by heteroatoms (e.g., selected from O, S, S(O), S(O)2, N, B, Si and P, preferably selected from O, S, S(O)2 and N, more preferably selected from O, S and N). If the ring of the heterocyclyl group contains only one type of heteroatom, the maximum number of heteroatoms in the ring of the heterocyclyl group can be as follows: 2 O atoms (preferably 1 O atom); 2 S atoms (preferably 1 S atom); 4 N atoms (e.g., 1, 2 or 3 N atoms); 2 B atoms (preferably 1 B atom); 1 Si atom; and / or 1 P atom. If the ring of the heterocyclyl group contains two or more types of heteroatoms, the maximum number of heteroatoms in the ring of the heterocyclyl group may be as follows: 1 O atom; 1 S atom; 2 N atoms (preferably 1 N atom); 1 B atom; 1 Si atom; and / or 1 P atom, wherein the maximum total number of heteroatoms in the ring of the heterocyclyl group is 4, and the maximum total number of heteroatoms in each ring of the heterocyclyl group is as follows: 1 O atom; 1 S atom; 1 or 2 N atoms; 1 B atom (preferably 0 B atoms); 1 Si atom (preferably 0 Si atoms); and / or 1 P atom (preferably 0 P atoms). In one embodiment, the heteroatoms of the heterocyclyl group are selected from O, S, and N. In this embodiment, preferably, in each ring of the heterocyclyl group, the maximum number of O atoms is 1, the maximum number of S atoms is 1, and the maximum total number of O and S atoms is 2. For example, 3 to 14 yuan of heterocyclic radicals encompass monocyclic heterocyclic radicals (e.g., 3, 4, 5, 6 or 7 yuan of heterocyclic radicals, preferably 4 to 7 yuan), bicyclic heterocyclic radicals (e.g., 8, 9 or 10 yuan) and tricyclic heterocyclic radicals (e.g., 12, 13 or 14 yuan). If the heterocyclic radical comprises two or more rings, these rings are fused (e.g., in quinolyl or purinyl), are spirocyclic moieties, are bridged structures, are connected by double bonds, or a combination thereof. In other words, unsubstituted heterocyclic radicals do not include two heterocyclic radicals connected by a single bond. The term "heterocyclic radical" also means a partially or completely hydrogenated form (e.g., dihydro, tetrahydro, hexahydro, octahydro, decahydro, dodecahydro, etc., or a perhydro form) of the above-mentioned heteroaryl. Exemplary heterocyclic groups include azetidinyl, morpholino, isotriphenylenyl, benzopyranyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, indolyl, isoindolyl, triazinyl (1,2,3-, 1,2,4-, and 1,3,5-), di- and tetrahydrofuranyl, di- and tetrahydrothiophenyl, 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 tetrahydrothiadiazolyl (1,2,3- and 1,2,5-), di- and tetrahydropyridinyl, di-, tetra- and hexahydropyrimidinyl, di- and tetrahydropyrazinyl, di- and tetrahydrotriazinyl (1,2,3-, 1,2,4- and 1,3,5-), di-, tetra-, hexa- and octahydrobenzofuranyl (1- and 2-), di-, tetra-, hexa- and octahydroindolyl, di-, tetra-, hexa- and octahydroisoindolyl, di-, tetra-, hexa- and octahydrobenzothiophenyl (1- and 2-), di-, tetra-, hexa- and octahydro-1H-indazolebutyl, di-, tetra-, hexa- and octahydrobenzimidazolyl, di-, tetra-, hexa- and octahydrobenzoxazolyl, di-, tetra-, hexa- and octahydrobenzoxazolyl, di-, tetra-, hexa- and octahydrobenzothiazolyl, di-, tetra-, hexa- , and octahydrobenzothiazolyl, di-, tetra-, hexa- and octahydrobenzotriazolyl, di-, tetra-, hexa-, octa-, and decahydro-quinolinyl, di-, tetra-, hexa-, octa- and decahydroisoquinolinyl, di-, tetra-, hexa-, octa-, and decahydrobenzodiazinyl, di-, tetra-, hexa-, octa-, and decahydroquinolinyl, di-, tetra-, hexa-, hexa-, octa- and decahydroquinazolinyl, di-, tetra-, hexa-, octa- and decahydrobenzotriazinyl (1,2,3- and 1,2,4-), di-, tetra- and hexahydropyridazinyl, di-, tetra-, hexa-, octa-, deca- and dodecahydrobenzoxazinyl, di-, tetra-, hexa-, and octahydrothiazolopyridinyl (e.g., 4,5,6-7-tetrahydro[1,3]thiazolo[5,4-c]pyridinyl or 4,5,6-7-tetrahydro[1 ,3]thiazolo[4,5-c]pyridinyl, for example 4,5,6-7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl or 4,5,6-7-tetrahydro[1,3]thiazolo[4,5-c]pyridin-2-yl), di-, tetra- and hexahydropyrrolothiazolyl, di-, tetra-, hexa-, octa- and decahydrophenothiazinyl, di-, tetra-, hexa-, and octahydroisobenzofuranyl, di-, tetra-, hexa-, and octahydrobenzodihydro, di-, tetra-, hexa-, hexa-, octa-, deca- and dodecahydrophenothiazinyl, di-, tetra-, hexa-, octa-, dodeca- and dodecahydropyrrolidinyl, di-, tetra- and hexahydropyrrolinyl, di-, tetra-, hexa- and octahydroindolyl, di-, tetra-, hexa- and octahydroindolyl, Purinyl, di-, tetra-, hexa- and octahydroquinolinazinyl, di-, tetra-, hexa-, octa-, octahydro and decahydronaphthazinyl, di-, tetra-, hexa-, hexa-, octahydronaphthyridinyl (1,5-, 1,6-, 1,7, 1,8- and 2,6-), di-, tetra-, hexa-, octa- and decahydrocinnamyl, di-, tetra-, hexa-, octa- and dodecahydropyridinyl, di-, tetra-, hexa-, octa-, deca- and dodecahydrocarbazolyl, di-, tetra-, hexa-, octa-, deca- and dodecahydrobenzophenanthrenyl, di-, tetra-, hexa-, octa-, deca-, dodeca- and tetradecahydroacridinyl, di-, tetra-, hexa-, octa-, deca- and dodecahydrobenzylidene, di-, tetra-, hexa-, octa-, deca-, dodeca- and tetradecahydrophenanthrolinyl (1,7-, 1,8-, 1,10-, 3,8- and 4,7-), di-, tetra-, hexa-, octa-, deca-, dodeca-, and tetra-hydrophenazinyl, di-, tetra-, hexa-, and octahydrooxazolopyridinyl, di-, tetra-, hexa-, and octahydroisoxazolopyridinyl, di-, tetra-, hexa-, and octahydrocyclopentapyrrolyl, di-, tetra-, hexa-, and octahydrocyclopentapyrazolyl, di-, tetra-, hexa-, and octahydrocyclopentaimidazolyl, di-, tetra-, hexa-, and octahydrocyclopentathiazolyl, di-, tetra-, hexa-, and octahydrocyclopentazolyl, di-, tetra-, hexa-, and octahydropyrrolopyrrolyl, di-, tetra-, hexa-, and octahydropyrazolopyrrolyl, di-, tetra-, hexa-, and octahydropyrroloimidazolyl, di-, tetra-, hexa-, and octahydropyrrolothiazolyl (e.g., 5,6-dihydrophenazinyl, di-, tetra-, hexa-, and octahydrooxazolopyridinyl, di-, tetra-, hexa-, and octahydroisoxazolopyridinyl, di-, tetra-, hexa-, and octahydrocyclopentapyrazolyl, di-, tetra-, hexa-, and octahydroisoxazolopyridin ... , and octahydropyrrolo[3,4-d][1,3]thiazolyl), di-, tetra-, hexa-, and octahydropyrrolooxazolyl, di-, tetra-, hexa-, and octahydropyrazolopyrazolyl, di-, tetra-, hexa-, and octahydropyrazoloimidazolyl, di-, tetra-, hexa-, and octahydropyrazolothiazolyl, di-, tetra-, hexa-, and octahydropyrazolooxazolyl, di-, tetra-, hexa-, and octahydroimidazoimidazolyl, di-, tetra-, hexa-, and octahydroimidazothiazolyl, di-, tetra-, hexa-, and octahydroimidazooxazolyl, di-, tetra-, hexa-, and octahydrothiazolothiazolyl, di-, tetra-, hexa-, and octahydrothiazolooxazolyl, and di-, tetra-, hexa-, and octahydrooxazolooxazolyl. Exemplary 5- or 6-membered heterocyclic groups include morpholino, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, di- and tetrahydrofuranyl, di- and tetrahydrothiophenyl, 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 and 1,2,4-). "Substituted heterocyclyl" means that one or more (e.g., from 1 to the maximum number of hydrogen atoms bonded to the heterocyclyl, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or up to 10, e.g., 1-5, 1-4, or 1-3, or 1 or 2) hydrogen atoms of the heterocyclyl group are replaced by a substituent other than hydrogen (when replacing more than one hydrogen atom, the substituents may be the same or different). Preferably, the substituent other than hydrogen is a primary substituent, a secondary substituent or a tertiary substituent as specified herein, for example, halogen, -CN, nitro, OR, 11 (e.g., -OH), -SR 11 (e.g., -SH), -N(R 12 )(R 13 )(e.g. -NH2), alkyl (e.g. C 1-6 Alkyl), alkenyl (e.g. C 2-6 alkenyl) and alkynyl (e.g. C 2-6 alkynyl).

[0082] As used herein, a "partially hydrogenated form" of an unsaturated compound or group refers to a group in which some of the unsaturated groups have been removed by formally adding hydrogen to the original unsaturated compound or group without removing all unsaturated groups. The term "fully hydrogenated form of an unsaturated compound or group" is used interchangeably with the term "perhydro" herein and refers to a group in which all unsaturated bonds have been removed by formally adding hydrogen to the original unsaturated compound or group. For example, a partially hydrogenated form of a 5-membered heteroaryl (containing 2 double bonds in the ring, such as furan) includes a dihydro form of the 5-membered heteroaryl (e.g., 2,3-dihydrofuran or 2,5-dihydrofuran), while a tetrahydro form of the 5-membered heteroaryl (e.g., tetrahydrofuran, i.e., THF) is a fully hydrogenated (or perhydro) form of the 5-membered heteroaryl. Similarly, for a 6-membered heteroaryl having 3 double bonds in the ring (e.g., pyridyl), partially hydrogenated forms include dihydro and tetrahydro forms (e.g., dihydro and tetrahydropyridyl), while hexahydro forms (e.g., heteroarylpyridyl, such as piperidinyl) are fully hydrogenated (or perhydro) derivatives of the 6-membered heteroaryl. Thus, if a hexahydro form of an aryl or heteroaryl is considered only as a partially hydrogenated form, the aryl or heteroaryl contains at least four unsaturated moieties consisting of double and triple bonds between ring atoms.

[0083] The term "aromatic" as used in the context of hydrocarbons means that the entire molecule must be aromatic. For example, if a monocyclic aromatic group is hydrogenated (partially or completely), the resulting hydrogenated cyclic structure is classified as a cycloalkyl for the purposes of this invention. Similarly, if a bicyclic or polycyclic aromatic group (e.g., naphthyl) is hydrogenated, the resulting hydrogenated bicyclic or polycyclic structure (e.g., 1,2-dihydronaphthyl) is classified as a cycloalkyl for the purposes of this invention (even though one ring, such as 1,2-dihydronaphthyl, is still aromatic). In this application, a similar distinction is made between heteroaryl and heterocyclyl. For example, indolyl, 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.

[0084] As used herein, the term "polycyclic" refers to a structure having two or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10), preferably 2, 3, 4, or 5, more preferably 2, 3, or 4 rings. Thus, according to the present invention, the term "polycyclic" does not include monocyclic structures, wherein the structure comprises only one ring. Examples of polycyclic groups are fused structures (e.g., naphthyl or anthracenyl), spirocyclic compounds, rings connected by single or double bonds (e.g., biphenyl), and bridged structures (e.g., bornyl). Exemplary polycyclic structures are the above-mentioned aryl, heteroaryl, cycloalkyl, and heterocyclyl groups having at least two rings.

[0085] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0086] The term "azido" refers to -N3.

[0087] The term "N-oxide" refers to an amine oxide or amine-N-oxide, which is a amine containing a functional group (R n )3N + -O - (i.e., NO coordinated covalent bond) compound, wherein R n R is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl, wherein each of the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl is optionally replaced by one or more (e.g., from 1 to a maximum, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, e.g., 1 to 5, 1 to 4, or 1 to 3, or 1 or 2, based on the number of hydrogen atoms bonded to the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl) independently selected R 30 Replacement, R 30 Preferred are the first-stage substituents, second-stage substituents or third-stage substituents specified herein.

[0088] As described elsewhere in this paper, R 5 -LR 6 , and R 6 is heteroaryl or heterocyclyl, each of which is optionally replaced by one or more independently selected R 7 In this connection, the expression "bonded to R 6 Any two R on the same atom 7 Can be linked together to form =O" means that when two monovalent groups (i.e. R 7 ) is combined with only one R 6 When a total of 2 hydrogen atoms of the ring atoms of substituted, a diradical =O can be formed. For example, according to the present invention, R 6 for (in Represents R 6 bonds to the rest of the compound) encompasses not only (1) each R 7 The possibility that the group is a monovalent group independently selected from the specific moieties specified herein (e.g., methyl or Cl) also encompasses (2) being bound to R 6 Any two R of the same atom 7 The groups are linked together to form a diradical =O, giving the general formula R 6 group, where the remaining R 7 The group is a single radical. Similarly, in R 6 It is the four R 7 In the case of substituted 3-tetrahydrothienyl, such substituted R 6 Including the following: Etc. Similar terms, such as "any two R 30 Can be linked together to form =X 1 ” will be interpreted in a similar manner. In this regard, it should be understood that in those embodiments, 6 Any two R 7 Can be connected together to form =O, R 6 Originally (ie, without the modification =0) it must be a heterocycle (since there are no carbon ring atoms with two free valences in a heteroaromatic ring).

[0089] As used herein, the expression "an R 7 Group relative to R 6 Position 2 of the ring atom bound to the rest of the compound is R 6 "Bound to the ring atoms" means the 6 At least one of the two ring atoms directly adjacent to the ring atom attached to the rest of the compound bears an R 7 In other words, relative to R 6 The ring atom to which it is attached to the rest of the compound (i.e., R 6 In terms of the “base position” of 6 At least one adjacent position of 7 For example, applying the above expression to R 6 To be an R 7 In the case of a substituted 3-pyridyl group (thus, the radical position is the ring carbon at position 3 relative to the ring nitrogen atom), then the R 7 The group is located at the 2 or 4 position of the 3-pyridyl group, as shown in the following formula:

[0090]

[0091] in Represents R 6 The bond that binds the compound to the rest of the compound. 6 By more than one (for example, two or three) R 7 In the case of group substitution, the expression "one R 7 Group relative to R 6 Position 2 of the ring atom bound to the rest of the compound is R 6 "Bound to a ring atom of R" includes the case where 6 Each of the two ring atoms directly adjacent to the ring atom that is connected to the rest of the compound carries an R 7 Group (ie R 6 is a k-membered ring, relative to R 6Each of the 2 and k positions of the ring atom bound to the rest of the compound carries an R 7 Group (ie R 6 is substituted at both of its ortho positions). For example, if R 6 It is two R 7 substituted 3-pyrrolyl radical (thus, the radical position is the ring carbon 3 relative to the ring nitrogen atom), then the expression "one R 7 Group relative to R 6 Position 2 of the ring atom bound to the rest of the compound is R 6 The ring atoms are combined" include the following structures:

[0092]

[0093] But exclude the following structures:

[0094]

[0095] As used herein, the term "k-membered ring" means that the ring has k ring atoms. For example, for pyrazolyl, k is 5; thus, relative to the ring atom to which the pyrazolyl is attached to the rest of the compound (base position), the ortho positions are positions 2 and 5, and position k-1 is position 4. Furthermore, for pyridinyl being a 6-membered heteroaryl, relative to the ring atom to which the pyridinyl is attached to the rest of the compound (base position), the ortho positions are positions 2 and 6, and position k-1 is position 5.

[0096] As used herein, the expression “ Represents R 6 The bond to the rest of the compound is R 6 through its bond to the rest of the compound (i.e., (i) to L, if L is not a bond, or (ii) to the carboxy(thio)amido group -C(E)N(R) of formula (I), if L is a bond). 4 )(R 5 ) is connected to the nitrogen atom of 6 for When L is (i) a methylene group or (ii) a bond, the compound of formula (I) has the following structures (A1) and (A2), respectively:

[0097]

[0098] The term "optionally substituted" means that one or more (e.g., 1 to the maximum number of hydrogen atoms bonded to the 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 may be replaced by a group other than hydrogen (i.e., a primary substituent), such as an alkyl group (preferably C 1-6Alkyl), alkenyl (preferably C 2-6 Alkenyl), alkynyl (preferably C 2-6 alkynyl), aryl (preferably 6- to 14-membered aryl), heteroaryl (preferably 3- to 14-membered heteroaryl), cycloalkyl (preferably 3- to 14-membered cycloalkyl), heterocyclyl (preferably 3- to 14-membered heterocyclyl), halogen, -CN, azido, -NO2, -OR 71 、-N(R 72 )(R 73 ),-S(O) 0-2 R 71 、-S(O) 1-2 OR 71 、-OS(O) 1-2 R 71 、-OS(O) 1-2 OR 71 、-S(O) 1-2 N(R 72 )(R 73 ),-OS(O) 1-2 N(R 72 )(R 73 )、-N(R 71 )S(O) 1-2 R 71 、-NR 71 S(O) 1-2 OR 71 、-NR 71 S(O) 1-2 N(R 72 )(R 73 )、-OP(O)(OR 71 )2、-C(=X 1 )R 71 、-C(=X 1 )X 1 R 71 、-X 1 C(=X 1 )R 71 , and / or any two first-level substituents bound to the same carbon atom of a cycloalkyl or heterocyclyl group may be linked together to form =X 1 , wherein each of the first-level substituents of alkyl, alkenyl, alkynyl, aryl, cycloalkyl and heterocyclyl can itself be substituted by one or more (e.g., one, two or three) substituents (i.e., second-level substituents), wherein the second-level substituents are selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 6- to 14-membered aryl, 3- to 14-membered heteroaryl, 3- to 14-membered cycloalkyl, 3- to 14-membered heterocyclyl, halogen, -CF3, -CN, azido, -NO2, -OR 81、-N(R 82 )(R 83 ),-S(O) 0-2 R 81 、-S(O) 1-2 OR 81 、-OS(O) 1-2 R 81 、-OS(O) 1-2 OR 81 、-S(O) 1-2 N(R 82 )(R 83 ),-OS(O) 1-2 N(R 82 )(R 83 )、-N(R 81 )S(O) 1-2 R 81 、-NR 81 S(O) 1-2 OR 81 、-NR 81 S(O) 1-2 N(R 82 )(R 83 )、-OP(O)(OR 81 )2、-C(=X 2 )R 81 、-C(=X 2 )X 2 R 81 、-X 2 C(=X 2 )R 81 and -X 2 C(=X 2 )X 2 R 81 , and / or any two second-stage substituents bonded to the same carbon atom of the cycloalkyl or heterocyclic group as the first-stage substituent may be bonded together to form =X 2 , where the C of the second substituent 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Each of the alkynyl, 6- to 14-membered aryl, 3- to 14-membered heteroaryl, 3- to 14-membered cycloalkyl, and 3- to 14-membered heterocyclyl groups is optionally substituted by one or more (e.g., one, two, or three) substituents (i.e., tertiary substituents) independently selected from C 1-3 Alkyl, halogen, -CF3, -CN, azido, -NO2, -OH, -O(C 1-3 alkyl), -OCF3, -S(C 1-3 alkyl), -NH2, -NH(C 1-3 Alkyl), -N(C1-3 Alkyl)2, -NHS(O)2(C 1-3 Alkyl), -S(O)2NH 2-z (C 1-3 alkyl) z 、-C(=O)OH、-C(=O)O(C 1-3 alkyl), -C(=O)NH 2-z (C 1-3 alkyl) z 、-NHC(=O)(C 1-3 alkyl), -NHC(=NH)NH 2-z (C 1-3 alkyl) z and -N(C 1-3 alkyl)C(=NH)NH 2-z (C 1-3 alkyl) z , where each z is independently 0, 1, or 2, and each C 1-3 The alkyl group is independently methyl, ethyl, propyl or isopropyl, and / or any two tertiary substituents bonded to the same carbon atom of the 3 to 14-membered cycloalkyl or heterocyclic group as the second substituent may be linked together in the form of =O, =S, =NH or =N(C 1-3 alkyl);

[0099] in

[0100] R 71 、R 72 and R 73 Each of which is independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3 to 7 membered cycloalkyl, 5 or 6 membered aryl, 5 or 6 membered heteroaryl and 3 to 7 membered heterocyclyl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Each of alkynyl, 3 to 7 membered cycloalkyl, 5 or 6 membered aryl, 5 or 6 membered heteroaryl and 3 to 7 membered heterocyclyl is optionally substituted by one, two or three independently selected from C 1-3 Alkyl, halogen, -CF3, -CN, azido, -NO2, -OH, -O(C 1-3 alkyl), -OCF3, =O, -S(C 1-3 alkyl), -NH2, -NH(C 1-3 Alkyl), -N(C 1-3 Alkyl)2, -NHS(O)2(C 1-3 Alkyl), -S(O)2NH 2-z (C 1-3 alkyl) z 、-C(=O)(C1-3 alkyl), -C(=O)OH, -C(=O)O(C 1-3 alkyl), -C(=O)NH 2-z (C 1-3 alkyl) z 、-NHC(=O)(C 1-3 alkyl), -NHC(=NH)NH 2-z (C 1-3 alkyl) z and -N(C 1-3 alkyl)C(=NH)NH 2-z (C 1-3 alkyl) z substituted with a substituent, wherein each z is independently 0, 1 or 2, and each C 1-3 Alkyl is independently methyl, ethyl, propyl or isopropyl;

[0101] R 81 、R 82 and R 83 Each of which is independently selected from H, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 3 to 6-membered cycloalkyl, 5 or 6-membered aryl, 5 or 6-membered heteroaryl and 3 to 6-membered heterocyclyl, wherein each C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 3 to 6 membered cycloalkyl, 5 or 6 membered aryl, 5 or 6 membered heteroaryl and 3 to 6 membered heterocyclyl are optionally substituted by one, two or three independently selected from C 1-3 Alkyl, halogen, -CF3, -CN, azido, -NO2, -OH, -O(C 1-3 alkyl), -OCF3, =O, -S(C 1-3 alkyl), -NH2, -NH(C 1-3 Alkyl), -N(C 1-3 Alkyl)2, -NHS(O)2(C 1-3 Alkyl), -S(O)2NH 2-z (C 1-3 alkyl) z 、-C(=O)(C 1-3 alkyl), -C(=O)OH, -C(=O)O(C 1-3 alkyl), -C(=O)NH 2-z (C 1-3 alkyl) z 、-NHC(=O)(C 1-3 alkyl), -NHC(=NH)NH 2-z (C 1-3 alkyl) zand -N(C 1-3 alkyl)C(=NH)NH 2-z (C 1-3 alkyl) z substituted with a substituent, wherein each z is independently 0, 1 or 2, and each C 1-3 Alkyl is independently methyl, ethyl, propyl or isopropyl; and

[0102] X 1 and X 2 Each of which is independently selected from O, S and N(R 84 ), where R 84 H or C 1-3 alkyl.

[0103] Typical first-stage substituents are preferably selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, 6- to 14-membered (e.g., 6- to 10-membered) aryl, 3- to 14-membered (e.g., 5- or 6-membered) heteroaryl, 3- to 14-membered (e.g., 3- to 7-membered) cycloalkyl, 3- to 14-membered (e.g., 3- to 7-membered) heterocyclyl, halogen, -CN, azido, -NO2, -OR 71 、-N(R 72 )(R 73 ),-S(O) 0-2 R 71 、-S(O) 1-2 OR 71 、-OS(O) 1- 2R 71 、-OS(O) 1-2 OR 71 、-S(O) 1-2 N(R 72 )(R 73 ),-OS(O) 1-2 N(R 72 )(R 73 )、-N(R 71 )S(O) 1-2 R 71 、-NR 71 S(O) 1-2 OR 71 、-NR 71 S(O) 1-2 N(R 72 )(R 73 )、-OP(O)(OR 71 )2、-C(=X 1 )R 71 、-C(=X 1 )X 1 R 71 、-X1 C(=X 1 )R 71 and -X 1 C(=X 1 )X 1 R 71 , for example C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 6-membered aryl, 5-membered or 6-membered heteroaryl, 3- to 7-membered cycloalkyl, 3- to 7-membered (e.g., 5- or 6-membered) heterocyclyl, halogen, -CF3, -CN, azido, -NO2, -OH, -O(C 1-3 Alkyl), -S(C 1-3 alkyl), -NH2, -NH(C 1-3 Alkyl), -N(C 1-3 Alkyl)2, -NHS(O)2(C 1-3 Alkyl), -S(O)2NH 2-z (C 1-3 alkyl) z 、-C(=O)OH、-C(=O)O(C 1-3 alkyl), -C(=O)NH 2-z (C 1-3 alkyl) z 、-NHC(=O)(C 1-3 alkyl), -NHC(=NH)NH 2-z (C 1-3 alkyl) z and -N(C 1-3 alkyl)C(=NH)NH 2-z (C 1-3 alkyl) z , wherein each z is independently 0, 1 or 2, and each C 1-3 Alkyl is independently methyl, ethyl, propyl or isopropyl; wherein X1 is independently selected from O, S, NH and N(CH3); and R 71 、R 72 and R 73 Each of which is as defined above, or is preferably independently selected from H, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 alkynyl, 5 or 6 membered cycloalkyl, 5 or 6 membered aryl, 5 or 6 membered heteroaryl and 5 or 6 membered heterocyclyl, wherein each of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is optionally substituted with one, two or three substituents independently selected from C 1-3 Alkyl, halogen, -CF3, -CN, azido, -NO2, -OH, -O(C 1-3 Alkyl), -S(C 1-3alkyl), -NH2, -NH(C 1-3 Alkyl), -N(C 1-3 Alkyl)2, -NHS(O)2(C 1-3 Alkyl), -S(O)2NH 2-z (C 1-3 alkyl) z 、-C(=O)OH、-C(=O)O(C 1-3 alkyl), -C(=O)NH 2-z (C 1-3 alkyl) z 、-NHC(=O)(C 1-3 alkyl), -NHC(=NH)NH 2-z (C 1-3 alkyl) z and -N(C 1-3 alkyl)C(=NH)NH 2-z (C 1-3 alkyl) z , wherein each z is independently 0, 1 or 2, and each C 1-3 Alkyl is independently methyl, ethyl, propyl or isopropyl. Particularly preferred first-level substituents are independently selected from C 1-3 Alkyl, phenyl, thiazolidinyl, halogen (such as F, Cl or Br), -NH2, -NHS(O)2(C 1-3 alkyl), -NHC(=O)(C 1-3 alkyl) and -NHC(=NH)NH 2-z (C 1-3 alkyl) z , where z is 0, 1, 2 and each C 1-3 Alkyl groups are independently methyl, ethyl, propyl or isopropyl.

[0104] Typical second-stage substituents are preferably selected from C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 6 or 10-membered aryl, 5 or 6-membered heteroaryl, 5 or 6-membered cycloalkyl, 5 or 6-membered heterocyclyl, halogen, =O, =S, -CF3, -CN, azido, -NO2, -OH, -O(C 1-3 Alkyl), -S(C 1-3 alkyl), -NH2, -NH(C 1-3 Alkyl), -N(C 1-3 Alkyl)2, -NHS(O)2(C 1-3 Alkyl), -S(O)2NH 2-z (C 1-3 alkyl) z 、-C(=O)OH、-C(=O)O(C 1-3alkyl), -C(=O)NH 2-z (C 1-3 alkyl) z 、-NHC(=O)(C 1-3 alkyl), -NHC(=NH)NH 2-z (C 1-3 alkyl) z and -N(C 1-3 alkyl)C(=NH)NH 2-z (C 1-3 alkyl) z , wherein each z is independently 0, 1 or 2, and each C 1-3 Alkyl is independently methyl, ethyl, propyl or isopropyl. Specific examples of the second-level substituent are independently selected from C 1-3 Alkyl, phenyl, 5- or 6-membered heteroaryl, 5- or 6-membered cycloalkyl, 5- or 6-membered heterocyclyl, halogen, =O, =S, -CF3, -CN, -OH, -O(C 1-3 Alkyl), -S(C 1-3 alkyl), -NH2, -NH(C 1-3 Alkyl), -N(C 1-3 Alkyl)2, -NHS(O)2(C 1-3 alkyl), -C(=O)OH, -C(=O)O(C 1-3 alkyl), -C(=O)NH 2-z (C 1-3 alkyl) z 、-NHC(=O)(C 1-3 alkyl), -NHC(=NH)NH 2-z (C 1-3 alkyl) z and -N(C 1-3 alkyl)C(=NH)NH 2-z (C 1-3 alkyl) z , wherein each z is independently 0, 1 or 2, and each C 1-3 The alkyl group is independently methyl, ethyl, propyl or isopropyl. Particularly preferred secondary substituents are independently selected from methyl, ethyl, propyl, isopropyl, phenyl, =O and =S.

[0105] Typical tertiary substituents are preferably selected from C 1-3 Alkyl, phenyl, halogen, -CF3, -OH, -OCH3, -SCH3, -NH 2-z (CH3) z , -C(=O)OH and -C(=O)OCH3, wherein z is 0, 1 or 2 and C 1-3Alkyl is methyl, ethyl, propyl or isopropyl. Particularly preferred tertiary substituents are selected from methyl, ethyl, propyl, isopropyl, halogen (e.g. F, Cl or Br) and -CF3, such as halogen (e.g. F, Cl or Br) and -CF3.

[0106] As used herein, the term "optional" or "optionally" means that the subsequently described event, situation or circumstance may or may not occur, and that the description includes instances where said event, situation or circumstance occurs and instances where it does not.

[0107] "Isomers" are compounds that have the same molecular formula but differ in structure ("structural isomers") or in the geometric (spatial) positions 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" contains equal amounts of a pair of enantiomers and is denoted by the prefix (±). "Diastereomers" are stereoisomers that are non-superimposable and are not mirror images of each other. "Tautomers" are structural isomers of the same chemical substance that can spontaneously and reversibly convert into each other (even if pure) due to the migration of a single atom or group of atoms. That is, tautomers are in dynamic chemical equilibrium with each other. Examples of tautomers are keto-enol-tautomer isomers. "Conformational isomers" are stereoisomers that are interconvertible solely by rotation about a formal single bond, and include especially those that result in different 3-dimensional forms of the (heterocyclic) ring, e.g., the chair, half-chair, boat, and twisted-boat forms of cyclohexane.

[0108] Where a structural formula shown in this application can be interpreted as comprising more than one isomer, unless expressly stated otherwise, the structural formula includes all possible isomers and therefore includes each individual isomer. 6 is 1-azabicyclo[2.2.2]oct-3-yl (optionally replaced by one or more R 7 The compound of formula (I) substituted with a group includes two isomers, for example, an isomer having the following formula (B1) and an isomer having the following formula (B2) (wherein n1 is 0, 1, 2, 3 or greater):

[0109]

[0110] As used herein, "polymorphism" refers to the ability of a solid material (e.g., a compound) to exist in more than one form or crystal structure, i.e., a "polymorphic modification" or "polymorphic form." The terms "polymorphic modification," "polymorphic form," and "polymorph" are used interchangeably herein. According to the present invention, these "polymorphic modifications" include crystalline forms, amorphous forms, solvates, and hydrates. Primarily, the existence of different polymorphic forms is due to the different conditions used during the crystallization process, such as the following:

[0111] Solvent effects (crystals may pack differently in polar and nonpolar solvents);

[0112] Certain impurities can inhibit the growth pattern and favor the growth of metastable polymorphs;

[0113] The supersaturation from which the material crystallizes (generally, the higher the concentration above solubility, the greater the likelihood of a metastable state);

[0114] The temperature at which crystallization is carried out;

[0115] Covalent bond geometry (leading to differences in conformational polymorphism);

[0116] Change stirring conditions.

[0117] Polymorphs may have different chemical, physical and / or pharmacological properties, including but not limited to melting point, X-ray crystals and diffraction patterns, chemical reactivity, solubility, dissolution rate, vapor pressure, density, hygroscopicity, fluidity, stability, compactness and bioavailability. At a specific temperature, a polymorph can spontaneously change from a metastable form (unstable form) to a stable form. According to Ostwald's rule, it is usually not the most stable, but the most unstable polymorph that is first crystallized. Therefore, the quality, efficacy, safety, processability and / or manufacture of a compound (such as a compound of the present invention) are affected by polymorphism. Generally, due to the minimum possibility of being converted into another polymorph, the most stable polymorph of a compound (such as a compound of the present invention) is selected. However, due to reasons other than stability, such as solubility, dissolution rate and / or bioavailability, a polymorph that is not the most stable polymorph may be selected.

[0118] As used herein, the term "crystalline form" of a material refers to the formation of a crystal structure by the smallest components (i.e., atoms, molecules, or ions) of the material. "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, a group of atoms arranged in a particular way, and a lattice that exhibits long-range order and symmetry. A lattice is an array of points that repeat periodically in three dimensions, and the pattern is located at these points of the lattice. The subunit of the lattice is the unit cell. The lattice parameters are the lengths of the edges of the unit cell and the angles between them. The symmetry of a crystal is reflected in its space group. In order to describe the crystal structure, the following parameters are required: chemical formula, lattice parameters, space group, atomic coordinates, and occupancy numbers of point positions.

[0119] As used herein, the term "amorphous form of a material" means that the smallest components of the material (i.e., atoms, molecules, or ions) are not arranged in a crystalline lattice but are arranged randomly. Thus, unlike crystals, where both short-range order (constant distance to the next neighboring atom) and long-range order (periodic repetition of the basic lattice) exist, only short-range order exists in an amorphous form.

[0120] As used herein, the term "complex of a compound" refers to a higher order compound formed by associating the compound with one or more other molecules. Exemplary complexes of a compound include, but are not limited to, solvates, clusters, and chelates of the compound.

[0121] As used herein, the term "solvate" refers to an addition complex of a dissolved material in a solvent (e.g., an organic solvent (e.g., aliphatic alcohols (e.g., methanol, ethanol, n-propanol, isopropanol), acetone, acetonitrile, diethyl ether, etc.), water, or a mixture of two or more thereof), wherein the addition complex exists in the form of crystals or mixed crystals. The amount of solvent contained in the addition complex can be stoichiometric or non-stoichiometric. "Hydrate" is a solvate in which the solvent is water.

[0122] In an isotopically labeled compound, 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 the compounds of the present invention include deuterium, 11 C. 13 C. 14 C. 15 N. 18 F. 32 P. 32 S. 35 S. 36 Cl and 125 I.

[0123] The term "half-life" refers to the time required to eliminate half of the activity, amount or number of a molecule. In the context of the present invention, the half-life of a compound of formula (I) or (Ia) is an indication of the stability of said compound.

[0124] The terms "subject", "patient", "individual" or "animal" refer to multicellular animals, such as vertebrates. For example, in the context of the present invention, vertebrates are mammals, birds (e.g., poultry), reptiles, amphibians, bony fish and cartilaginous fish, in particular domesticated animals of any of the foregoing, and captive animals (in particular vertebrates), such as zoo animals (in particular vertebrates). In the context of the present invention, mammals include, but are not limited to, humans, non-human primates, domesticated mammals (e.g., dogs, cats, sheep, cattle, goats, pigs, horses, etc.), laboratory mammals (e.g., mice, rats, rabbits, guinea pigs, etc.), and captive mammals (e.g., zoo mammals). The term "animal" as used herein also includes humans. Specific non-limiting examples of birds include domesticated poultry, and include birds, such as chickens, turkeys, ducks, geese, guinea fowls, pigeons, pheasants, etc. Specific non-limiting examples of bony or cartilaginous fish include those suitable for breeding by aquaculture, and include bony fish, such as salmon, trout, perch, carp, catfish, etc.

[0125] The compound dasatinib (also referred to herein as Compound A8) has the following structure:

[0126]

[0127] Compound

[0128] In a first aspect, and 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 formula:

[0129]

[0130] and solvates, salts, N-oxides, complexes, polymorphs, crystal forms, racemic mixtures, diastereomers, enantiomers, tautomers, conformers, isotopically labeled forms, prodrugs, and combinations thereof;

[0131] in:

[0132] R 1a Selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, halogen, -CN, azido, -NO2, -OR 11 、-N(R 12 )(R 13 )、-N(R11 )(OR 11 ),-S(O) 0-2 R 11 、-S(O) 1-2 OR 11 、-OS(O) 1-2 R 11 、-OS(O) 1- 2OR 11 、-S(O) 1-2 N(R 12 )(R 13 ),-OS(O) 1-2 N(R 12 )(R 13 )、-N(R 11 )S(O) 1-2 R 11 、-NR 11 S(O) 1-2 OR 11 、-NR 11 S(O) 1-2 N(R 12 )(R 13 )、-P(O)(OR 11 )2、-OP(O)(OR 11 )2, -C(=X)R 11 、-C(=X)XR 11 、-XC(=X)R 11 and -XC(=X)XR 11 , wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl groups is optionally replaced by one or more independently selected R 30 replace;

[0133] R 1b and R 1c Each of which is independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 6-10 aryl, 3- to 7-membered heteroaryl, 3- to 7-membered heterocyclic group, -O(CH2) 0-2 (C 3-7 Cycloalkyl), -O(CH2) 0-2 (C 6-10 Aryl), -O(CH2) 0-2 (3- to 7-membered heteroaryl), -O(CH2) 0-2 (3 to 7 membered heterocyclic group), -NH(CH2) 0-2 (C 3-7 Cycloalkyl), -NH(CH2)0-2 (C 6-10 Aryl), -NH(CH2) 0-2 (3- to 7-membered heteroaryl), -NH(CH2) 0-2 (3 to 7 membered heterocyclic group), halogen, -CF3, -CN, azido, -NO2, -OH, -O(C 1-6 alkyl), -OCF3, -S(C 1-6 alkyl), -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, -NHS(O)2(C 1-6 Alkyl), -S(O)2NH 2-z (C 1-6 alkyl) z 、-C(=O)(C 1-6 alkyl), -C(=O)OH, -C(=O)O(C 1-6 alkyl), -C(=O)NH 2-z (C 1-6 alkyl) z 、-NHC(=O)(C 1-6 alkyl), -NHC(=NH)NH 2-z (C 1-6 alkyl) z and -N(C 1-6 alkyl)C(=NH)NH 2-z (C 1-6 alkyl) z , where z is 0, 1, or 2, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 6-10 Each of the aryl, 3 to 7 membered heteroaryl and 3 to 7 membered heterocyclyl groups is optionally substituted by 1, 2 or 3 groups independently selected from -OH, methyl, ethyl, -OCH3, -SCH3 and -NH 2-z (CH3) z Partial replacement of

[0134] R 2 It is H;

[0135] R 3 Selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, halogen, -CN, azido, -NO2, -OR 11 、-N(R 12 )(R 13 )、-N(R 11 )(OR 11 ),-S(O) 0-2 R11 、-S(O) 1-2 OR 11 、-OS(O) 1-2 R 11 、-OS(O) 1- 2OR 11 、-S(O) 1-2 N(R 12 )(R 13 ),-OS(O) 1-2 N(R 12 )(R 13 )、-N(R 11 )S(O) 1-2 R 11 、-NR 11 S(O) 1-2 OR 11 、-NR 11 S(O) 1-2 N(R 12 )(R 13 )、-P(O)(OR 11 )2、-OP(O)(OR 11 )2, -C(=X)R 11 、-C(=X)XR 11 、-XC(=X)R 11 and -XC(=X)XR 11 , wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl groups is optionally replaced by one or more independently selected R 30 replace;

[0136] R 4 It is H;

[0137] R 5 Yes-LR 6 ;

[0138] L is selected from a bond, C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene and -(CH2) m -[Y-(CH2) n ] o -, wherein m is an integer between 1 and 6, 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(R 13 )-; and C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, -(CH2) m - and -(CH2)n - groups, each of which is optionally replaced by one or two independently selected R 30 replace;

[0139] R 6 is heteroaryl or heterocyclyl, each of which is optionally substituted by one or more independently selected R 7 replace;

[0140] R 7 independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, halogen, -CN, azido, -NO2, -OR 11 、-N(R 12 )(R 13 )、-N(R 11 )(OR 11 ),-S(O) 0-2 R 11 、-S(O) 1-2 OR 11 、-OS(O) 1-2 R 11 、-OS(O) 1-2 OR 11 、-S(O) 1-2 N(R 12 )(R 13 ),-OS(O) 1-2 N(R 12 )(R 13 )、-N(R 11 )S(O) 1-2 R 11 、-NR 11 S(O) 1-2 OR 11 、-NR 11 S(O) 1-2 N(R 12 )(R 13 )、-P(O)(OR 11 )2、-OP(O)(OR 11 )2, -C(=X)R 11 、-C(=X)XR 11 、-XC(=X)R 11 and -XC(=X)XR 11 , and / or with R as a heterocyclic group 6 Any two R 7 can be linked together to form =0, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl and heteroaryl groups is optionally replaced by one or more independently selected R 30 replace;

[0141] A is selected from S, O, NR 8 and C(R 9 )2;

[0142] R 8 is selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl and heteroaryl groups is optionally replaced by one or more independently selected R 30 replace;

[0143] R 9 independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, halogen, -CN, azido, -NO2, -OR 11 、-N(R 12 )(R 13 ),-S(O) 0-2 R 11 、-S(O) 1-2 OR 11 、-OS(O) 1-2 R 11 、-OS(O) 1-2 OR 11 、-S(O) 1- 2N(R 12 )(R 13 ),-OS(O) 1-2 N(R 12 )(R 13 )、-N(R 11 )S(O) 1-2 R 11 、-NR 11 S(O) 1-2 OR 11 、-NR 11 S(O) 1-2 N(R 12 )(R 13 ),-C(=X)R 11 、-C(=X)XR 11 、-XC(=X)R 11 and -XC(=X)XR 11 , wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl groups is optionally replaced by one or more independently selected R 30 replace;

[0144] X is independently selected from O, S and N (R 14 );

[0145] E is O or S;

[0146] B is N or CR1d ;

[0147] R 1d Selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, halogen, -CN, azido, -NO2, -OR 11 、-N(R 12 )(R 13 )、-N(R 11 )(OR 11 ),-S(O) 0-2 R 11 、-S(O) 1-2 OR 11 、-OS(O) 1-2 R 11 、-OS(O) 1- 2OR 11 、-S(O) 1-2 N(R 12 )(R 13 ),-OS(O) 1-2 N(R 12 )(R 13 )、-N(R 11 )S(O) 1-2 R 11 、-NR 11 S(O) 1-2 OR 11 、-NR 11 S(O) 1-2 N(R 12 )(R 13 )、-P(O)(OR 11 )2、-OP(O)(OR 11 )2, -C(=X)R 11 、-C(=X)XR 11 、-XC(=X)R 11 and -XC(=X)XR 11 , wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl groups is optionally replaced by one or more independently selected R 30 replace;

[0148] R 11 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 independently selected R 30 replace;

[0149] R 12 and R 13Each of R is independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl, or R 12 and R 13 Can be linked together with the nitrogen atom to which they are attached to form the group -N=CR 15 R 16 , wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl groups is optionally replaced by one or more independently selected R 30 replace;

[0150] R 14 independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl and -OR 11 , wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl groups is optionally replaced by one or more independently selected R 30 replace;

[0151] R 15 and R 16 Each of the groups is independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, and -NH y R 20 2-y , or R 15 and R 16 capable of being joined together with the atoms to which they are attached to form one or more independently selected R 30 substituted rings wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups is optionally replaced by one or more independently selected R 30 replace;

[0152] y is an integer from 0 to 2;

[0153] R 20 independently selected from 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 independently selected R 30 replace; and

[0154] R 30 is a first-level substituent and is independently selected at each occurrence from alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, halogen, -CN, azido, -NO2, -OR 71 、-N(R 72 )(R 73 ),-S(O) 0-2 R 71 、-S(O) 1-2 OR71 、-OS(O) 1-2 R 71 、-OS(O) 1-2 OR 71 、-S(O) 1-2 N(R 72 )(R 73 ),-OS(O) 1-2 N(R 72 )(R 73 )、-N(R 71 )S(O) 1-2 R 71 、-NR 71 S(O) 1-2 OR 71 、-NR 71 S(O) 1-2 N(R 72 )(R 73 )、-OP(O)(OR 71 )2、-C(=X 1 )R 71 、-C(=X 1 )X 1 R 71 、-X 1 C(=X 1 )R 71 and -X 1 C(=X 1 )X 1 R 71 , and / or any two R bound to the same carbon atom of a cycloalkyl or heterocyclyl group 30 Can be connected together to form =X 1 , wherein each of the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl and heterocyclyl groups as first-stage substituents is optionally substituted with one or more second-stage substituents, wherein the second-stage substituents are independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3- to 14-membered aryl, 3- to 14-membered heteroaryl, 3- to 14-membered cycloalkyl, 3- to 14-membered heterocyclyl, halogen, -CF3, -CN, azido, -NO2, -OR 81 、-N(R 82 )(R 83 ),-S(O) 0- 2R 81 、-S(O) 1-2 OR 81 、-OS(O) 1-2 R 81 、-OS(O) 1-2 OR81 、-S(O) 1-2 N(R 82 )(R 83 ),-OS(O) 1-2 N(R 82 )(R 83 )、-N(R 81 )S(O) 1-2 R 81 、-NR 81 S(O) 1-2 OR 81 、-NR 81 S(O) 1-2 N(R 82 )(R 83 )、-OP(O)(OR 81 )2、-C(=X 2 )R 81 、-C(=X 2 )X 2 R 81 、-X 2 C(=X 2 )R 81 and -X 2 C(=X 2 )X 2 R 81 , and / or any two second-stage substituents bonded to the same carbon atom of a cycloalkyl or heterocyclyl group as a first-stage substituent can be linked together to form =X 2 , where C as the second substituent 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Each of the alkynyl, 3 to 14 membered aryl, 3 to 14 membered heteroaryl, 3 to 14 membered cycloalkyl, 3 to 14 membered heterocyclyl groups is optionally substituted with one or more tertiary substituents, wherein the tertiary substituents are independently selected from C 1-3 Alkyl, halogen, -CF3, -CN, azido, -NO2, -OH, -O(C 1-3 alkyl), -OCF3, -S(C 1-3 alkyl), -NH2, -NH(C 1-3 Alkyl), -N(C 1-3 Alkyl)2, -NHS(O)2(C 1-3 Alkyl), -S(O)2NH 2-z (C 1-3 alkyl) z 、-C(=O)OH、-C(=O)O(C 1-3 alkyl), -C(=O)NH 2-z (C 1-3 alkyl)z 、-NHC(=O)(C 1-3 alkyl), -NHC(=NH)NH 2-z (C 1-3 alkyl) z and -N(C 1-3 alkyl)C(=NH)NH 2-z (C 1-3 alkyl) z , where each z is independently 0, 1, or 2, and each C 1-3 The alkyl group is independently methyl, ethyl, propyl or isopropyl, and / or any two tertiary substituents bonded to the same carbon atom of a 3 to 14-membered cycloalkyl or heterocyclyl group as a secondary substituent can be linked together to form =0, =S, =NH or =N(C 1-3 alkyl);

[0155] in

[0156] R 71 、R 72 and R 73 Each of which is independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3 to 7 membered cycloalkyl, 5 or 6 membered aryl, 5 or 6 membered heteroaryl and 3 to 7 membered heterocyclyl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Each of the alkynyl, 3 to 7 membered cycloalkyl, 5 or 6 membered aryl, 5 or 6 membered heteroaryl and 3 to 7 membered heterocyclyl groups is optionally substituted by one, two or three independently selected radicals from C 1-3 Alkyl, halogen, -CF3, -CN, azido, -NO2, -OH, -O(C 1-3 alkyl), -OCF3, =O, -S(C 1-3 alkyl), -NH2, -NH(C 1-3 Alkyl), -N(C 1-3 Alkyl)2, -NHS(O)2(C 1-3 Alkyl), -S(O)2NH 2-z (C 1-3 alkyl) z 、-C(=O)(C 1-3 alkyl), -C(=O)OH, -C(=O)O(C 1-3 alkyl), -C(=O)NH 2-z (C 1-3 alkyl) z 、-NHC(=O)(C 1-3 alkyl), -NHC(=NH)NH 2-z (C1-3 alkyl) z and -N(C 1-3 alkyl)C(=NH)NH 2-z (C 1-3 alkyl) z substituted with a substituent, wherein each z is independently 0, 1 or 2, and each C 1-3 Alkyl is independently methyl, ethyl, propyl or isopropyl;

[0157] R 81 、R 82 and R 83 Each of which is independently selected from H, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 3 to 6-membered cycloalkyl, 5 or 6-membered aryl, 5 or 6-membered heteroaryl and 3 to 6-membered heterocyclyl, wherein C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Each of the alkynyl, 3 to 6 membered cycloalkyl, 5 or 6 membered aryl, 5 or 6 membered heteroaryl and 3 to 6 membered heterocyclyl groups is optionally substituted by one, two or three independently selected radicals from C 1-3 Alkyl, halogen, -CF3, -CN, azido, -NO2, -OH, -O(C 1-3 alkyl), -OCF3, =O, -S(C 1-3 alkyl), -NH2, -NH(C 1-3 Alkyl), -N(C 1-3 Alkyl)2, -NHS(O)2(C 1-3 Alkyl), -S(O)2NH 2-z (C 1-3 alkyl) z 、-C(=O)(C 1-3 alkyl), -C(=O)OH, -C(=O)O(C 1-3 alkyl), -C(=O)NH 2-z (C 1-3 alkyl) z 、-NHC(=O)(C 1-3 alkyl), -NHC(=NH)NH 2-z (C 1-3 alkyl) z and -N(C 1-3 alkyl)C(=NH)NH 2-z (C 1-3 alkyl) z substituted with a substituent, wherein each z is independently 0, 1 or 2, and each C 1-3 Alkyl is independently methyl, ethyl, propyl or isopropyl; and

[0158] X 1 and X 2 Each of which is independently selected from O, S and N(R 84 ), where R 84 H or C 1-3 alkyl.

[0159] In one embodiment, the kinase inhibitor has formula (II):

[0160]

[0161] where R 1b 、R 1c 、R 2 、R 3 、R 4 、R 5 , A, B and E are as defined above (particularly with respect to formula (I)) or below, and R 1a is selected from alkyl, -O(alkyl), -S(alkyl), -NH(alkyl), -N(alkyl)2 and heterocyclyl, wherein each alkyl and heterocyclyl is optionally substituted by one or more (e.g., one, two or three) independently selected R 30 Preferably, each R 30 is independently a first substituent, a second substituent, or a third substituent as specified herein, such as an alkyl group (e.g., C 1-6 alkyl), -(CH2) 1-3 OH, alkenyl (e.g., C 2-6 alkenyl), alkynyl (e.g. C 2-6 Alkynyl), halogen, -CN, nitro, -OR 11 (e.g. -OH), -SR 11 (e.g. -SH), -N(R 12 )(R 13 )(e.g., -NH2) and -C(=O)R 11 (For example, -C(=O)(C 1-3 alkyl)).

[0162] In one embodiment of the kinase inhibitor of formula (II), R 1b 、R 1c 、R 2 、R 3 、R 4 、R 5 , A, B and E are as defined above (particularly with respect to formula (I)) or below, R 1a Selected from C 1-3 Alkyl, -O(C 1-3 Alkyl), -S(C 1-3 Alkyl), -N(C 1-3Alkyl), -N(C 1-3 alkyl) 2 and 3 to 7 membered heterocyclyl, wherein the 3 to 7 membered heterocyclyl is optionally substituted with one or two moieties independently selected from methyl, ethyl, -OH, -OCH3, -SCH3, cyclopropyl, 2-hydroxyethyl, 2-(N,N-dimethylamino)ethyl, 2-(N,N-methylamino)ethoxy, 2-aminoethyl, 2-(N-methylamino)ethyl, 2-(methoxy)ethyl, 4-methylpiperazinyl, -C(=O)(C 1-3 alkyl), -(CH2)1-3COOH and -NH2-z(CH3)z, wherein z is 0, 1 or 2; and each C 1-3 The alkyl group is optionally substituted by one or two groups independently selected from -OH, -OCH 3 , -SCH 3 , cyclopropyl, piperazinyl, 4-methyl-piperazinyl, 4-(2-hydroxyethyl)piperazinyl, 2-(N,N-dimethylamino)ethoxy and -NH 2-z (CH3) z , where z is 0, 1, or 2.

[0163] In one embodiment of the kinase inhibitor of formula (II), R 1b 、R 1c 、R 2 、R 3 、R 4 、R 5 , A, B and E are as defined above (particularly with respect to formula (I)) or below, R 1a Selected from C 1-3 Alkyl, -O(C 1-3 Alkyl), -S(C 1-3 Alkyl), -NH(C 1-3 alkyl), piperazinyl, morpholinyl, piperidinyl and pyrrolidinyl, wherein piperazinyl, morpholinyl, piperidinyl and pyrrolidinyl are each optionally substituted by one or two independently selected from methyl, ethyl, -OH, -OCH3, -SCH3, cyclopropyl, 2-hydroxyethyl, 2-(N,N-dimethylamino)ethyl, 2-(N,N-dimethylamino)ethoxy, 2-aminoethyl, 2-(N-methylamino)ethyl, 2-(methoxy)ethyl, 4-methylpiperazinyl, -C(=O)(C 1-3 alkyl), -(CH2) 1-3 COOH and -NH 2-z (CH3) z wherein z is 0, 1 or 2; and each C 1-3 The alkyl group is optionally substituted by one or two groups independently selected from -OH, -OCH3, -SCH3, cyclopropyl, piperazinyl, 4-methyl-piperazinyl, 4-(2-hydroxyethyl)piperazinyl, 2-(N,N-dimethylamino)ethoxy and -NH 2-z(CH3) z wherein z is 0, 1 or 2.

[0164] In one embodiment of the kinase inhibitor of formula (II), R 1b 、R 1c 、R 2 、R 3 、R 4 、R 5 , A, B and E are as defined above (particularly with respect to formula (I)) or below, R 1a Selected from -NH(C 1-3 alkyl), piperazinyl, piperidinyl and pyrrolidinyl, wherein piperazinyl is optionally substituted with one or two moieties independently selected from 2-hydroxyethyl, methyl, -CH2COOH and -C(=O)CH3; piperidinyl is optionally substituted with one or two moieties independently selected from -NH2 and 4-methylpiperazinyl; pyrrolidinyl is optionally substituted with one or two -OH; and C 1-3 Each of the alkyl groups is optionally substituted with one or two moieties independently selected from: -OH, -OCH3, and -NH 2-z (CH3) z , where z is 0, 1, or 2.

[0165] In one embodiment of the kinase inhibitor of formula (II), R 1b 、R 1c 、R 2 、R 3 、R 4 、R 5 , A, B and E are as defined above (particularly with respect to formula (I)) or below, R 1a is selected from 4-(2-hydroxyethyl)piperazinyl, 4-methylpiperazinyl, 4-acetylpiperazinyl, (2-hydroxyethyl)amino, 4-aminopiperidinyl, 4-(4-methylpiperazinyl)piperidinyl, (4-carboxymethylpiperazinyl) and 3-hydroxypyrrolidinyl, for example 4-(2-hydroxyethyl)piperazinyl, 4-methylpiperazinyl, 4-acetylpiperazinyl and (2-hydroxyethyl)amino.

[0166] In another embodiment of the kinase inhibitor of formula (II), R 1b 、R 1c 、R 2 、R 3 、R 4 、R 5 , A, B and E are as defined above (particularly with respect to formula (I)) or below, R 1a is a leaving group (e.g., halogen (e.g., Cl, Br, or F), nitro, benzotriazol-1-yloxy, C1-C 10 Alkyl sulfonate, C1-C10 Halogenated alkylsulfonates, azelaic acid esters (CF3CF2CF2CF2SO3-), CF3C(=O)O-, benzenesulfonates (wherein the phenyl group is optionally substituted by 1, 2 or 3 groups, each of which is independently selected from halogen and C1-C4 alkyl), or compounds of the formula -[N(R x )(R y )(R z )] + [G] - ammonium salts, where R x 、R y and R z is independently hydrogen or alkyl, G is the conjugate base of a strong acid (e.g., G - Cl - )).

[0167] In one embodiment, the kinase inhibitor has the general formula (III)

[0168]

[0169] where R 1a 、R 2 、R 3 、R 4 、R 5 , A, B and E are as defined above (particularly with respect to formula (I) and / or (II)) or below, and R 1b and R 1c Each is independently selected from H, methyl, ethyl, -OH, -OCH3, -SCH3, cyclopropyl, 2-hydroxyethyl, 2-(N,N-dimethylamino)ethyl, 2-(N,N-dimethylamino)ethoxy, 2-aminoethyl, 2-(N-methylamino)ethyl, 2-(methoxy)ethyl, -NH 2-z (CH3) z , phenyl, pyridyl, pyrazolyl, phenoxy, pyridyloxy, imidazolylamino and tetrahydrofuranylmethoxy, wherein z is 0, 1 or 2; each of phenyl, pyridyl, pyrazolyl, phenoxy, pyridyloxy, imidazolylamino and tetrahydrofuranylmethoxy is optionally 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 -NH 2-z (CH3) z wherein z is 0, 1 or 2.

[0170] In one embodiment of the kinase inhibitor of formula (III), R 1a 、R2 、R 3 、R 4 、R 5 , A, B and E are as defined above (particularly with respect to formula (I) and / or (II)) or below, and R 1b and R 1c At least one of H, methyl, ethyl, -OH, -OCH3, -SCH3, cyclopropyl, 2-hydroxyethyl, 2-(N,N-dimethylamino)ethyl, 2-(N,N-dimethylamino)ethoxy, 2-aminoethyl, 2-(N-methylamino)ethyl, 2-(methoxy)ethyl, -NH 2-z (CH3) z and phenyl, wherein z is 0, 1 or 2. In this embodiment, R 1b and R 1c The other of may be as defined above (particularly with respect to formula (I), (II) and / or (III)), for example, R 1b and R 1c The other of the group may be selected from H, methyl, ethyl, -OH, -OCH3, -SCH3, cyclopropyl, 2-hydroxyethyl, 2-(N,N-dimethylamino)ethyl, 2-(N,N-dimethylamino)ethoxy, 2-aminoethyl, 2-(N-methylamino)ethyl, 2-(methoxy)ethyl, -NH 2-z (CH3) z , phenyl, pyridyl, pyrazolyl, phenoxy, pyridyloxy, imidazolylamino and tetrahydrofuranylmethoxy, wherein z is 0, 1 or 2; wherein each phenyl, pyridyl, pyrazolyl, phenoxy, pyridyloxy, imidazolylamino and tetrahydrofuranylmethoxy is optionally 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 -NH 2-z (CH3) z wherein z is 0, 1 or 2. Alternatively, R 1b and R 1c Each is independently selected from H, methyl, ethyl, -OH, -OCH3, -SCH3, cyclopropyl, 2-hydroxyethyl, 2-(N,N-dimethylamino)ethyl, 2-(N,N-dimethylamino)ethoxy, 2-aminoethyl, 2-(N-methylamino)ethyl, 2-(methoxy)ethyl, -NH 2-z (CH3) z and phenyl, wherein z is 0, 1 or 2.

[0171] In one embodiment of the kinase inhibitor of formula (III), R1a 、R 2 、R 3 、R 4 、R 5 , A, B and E are as defined above (particularly with respect to formula (I) and / or (II)) or below, and R 1b is methyl, ethyl, propyl or isopropyl, preferably methyl; and R 1c is H. In another embodiment, R 1b H; R 1c It is methyl, ethyl, propyl, isopropyl or phenyl, preferably methyl.

[0172] In a related aspect, the present invention provides a compound selected from the group consisting of kinase inhibitors of formula (Ia):

[0173]

[0174] and solvates, salts, N-oxides, complexes, polymorphs, crystal forms, racemic mixtures, diastereomers, enantiomers, tautomers, conformers, isotopically labeled forms, prodrugs, and combinations thereof; wherein R 2 、R 3 、R 4 , A and E are each independently as defined above (particularly with respect to formula (I)) or below (particularly with respect to formula (IV), (VI), (VII) and / or (VIII)); R 5 Yes-LR 6 , where L is a bond, and R 6 is optionally one or more independently selected R 7 Substituted 5- or 6-membered heteroaryl (particularly, R 6 is optionally replaced by one or more independently selected R as defined by formula (V) below 7 substituted 5- or 6-membered heteroaryl); Hy is optionally substituted by one or more (e.g., 1 to the maximum number of hydrogen atoms bound to the heteroaryl or heterocyclyl, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or up to 10, e.g., 1 to 5, 1 to 4 or 1 to 3 or 1 or 2) independently selected R 1e Substituted heteroaryl or heterocyclic group; each R 1e Independently selected from R 1a 、R 1b 、R 1c and R 1d ; and R 1a 、R 1b 、R 1c and R 1dEach independently as defined above (particularly with respect to formula (I), (II) and / or (III)) or below (particularly with respect to formula (VII) and / or (VIII)).

[0175] In one embodiment of the kinase inhibitor of Formula (Ia), R 2 、R 3 、R 4 , A and E are independently as defined above (particularly with respect to formula (I)) or below (particularly with respect to formula (I), (IV), (VI), (VII) and / or (VIII)), R 6 is a 5- or 6-membered heteroaryl group, which is optionally substituted by one or more independently selected R 7 Substitution (particularly, R 6 is optionally replaced by one or more independently selected R defined with respect to formula (V) below 7 or Hy is a 3- to 10-membered heteroaryl or a 3- to 10-membered heterocyclyl, each of which is optionally substituted by 1, 2, 3, 4, 5, or 6 independently selected R 1e In one embodiment of the kinase inhibitor of formula (Ia), R 2 、R 3 、R 4 , A and E are independently as defined above (particularly with respect to formula (I)) or below (particularly with respect to formula (I), (IV), (VI), (VII) and / or (VIII)), R 6 is optionally one or more independently selected R 7 Substituted 5- or 6-membered heteroaryl (particularly, R 6 is optionally replaced by one or more independently selected R defined with respect to formula (V) below 7 substituted 5 or 6 membered heteroaryl); Hy is a monocyclic or bicyclic heteroaryl or a monocyclic or bicyclic heterocyclyl, each of which is optionally substituted by 1, 2, 3, 4, 5 or 6 independently selected R 1e In one embodiment of the kinase inhibitor of formula (Ia), R 2 、R 3 、R 4 , A and E are independently as defined above (particularly with respect to formula (I)) or below (particularly with respect to formula (I), (IV), (VI), (VII) and / or (VIII)), R 6 is optionally one or more independently selected R 7 Substituted 5- or 6-membered heteroaryl (particularly, R 6 is optionally replaced by one or more independently selected R defined with respect to formula (V) below 7substituted 5- or 6-membered heteroaryl); Hy is selected from 5- to 6-membered monocyclic heteroaryl, 5- to 6-membered monocyclic heterocyclyl, 9- to 10-membered bicyclic heteroaryl, and 8- to 10-membered bicyclic heterocyclyl, each of which is optionally substituted by one, two, three, four, five, or six independently selected RR 1e In one embodiment of the kinase inhibitor of formula (Ia), R 2 、R 3 、R 4 , A and E are independently as defined above (particularly with respect to formula (I)) or below (particularly with respect to formula (I), (IV), (VI), (VII) and / or (VIII)), R 6 is optionally one or more independently selected R 7 Substituted 5- or 6-membered heteroaryl (particularly, R 6 is optionally replaced by one or more independently selected R defined with respect to formula (V) below 7 substituted 5- or 6-membered heteroaryl); Hy is selected from pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl (e.g., 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl), pyrazolyl, oxadiazolyl, thiazolyl, triazolyl, thiadiazolyl, cyclopentylpyrimidinyl, dihydrocyclopentylpyrimidinyl, pyrrolopyrimidinyl, indolizinyl, dihydroindolizine, tetrahydroindolizine, quinazolinyl, dihydroquinazolinyl, tetrahydroquinoline, pyridopyrimidinyl, pyranopyrimidinyl, dihydropyranopyrimidinyl, tetrahydropyranopyrimidinyl, piperidinyl, tetrahydropyranyl, and 1,1-dioxidotetrahydrothiopyranyl, each of which is optionally substituted by one, two, three, four, five, or six independently selected R 1e In one embodiment of the kinase inhibitor of formula (Ia), R 2 、R 3 、R 4 , A and E are independently as defined above (particularly with respect to formula (I)) or below (particularly with respect to formula (I), (IV), (VI), (VII) and / or (VIII)), R 6 is optionally one or more independently selected R 7 Substituted 5- or 6-membered heteroaryl (particularly, R 6 is optionally replaced by one or more independently selected R defined with respect to formula (V) below 7 substituted 5- or 6-membered heteroaryl); and Hy is selected from:

[0176] a)

[0177] b)

[0178] c)

[0179] d)

[0180] e)

[0181] f)

[0182] g)

[0183] wherein each group specified in a), b), c), d), e), f) and g) above is optionally replaced by one, two, three, four, five or six independently selected R 1e Replace, and where Represents Hy through its reaction with NR of formula (Ia) 2 In the case where Hy contains an NH moiety as a ring member, it is preferred that the hydrogen atom is replaced by an alkyl group, for example C 1-6 or C 1-3 Alkyl, more preferably methyl (resulting in an alkyl-substituted N ring atom), and Hy optionally further substituted by 1, 2, 3, 4 or 5 independently selected R 1e Examples of such N-alkyl-substituted Hy groups include in Represents Hy and NR of formula (Ia) 2 The bonds to which the nitrogen atoms of the moieties are attached.

[0184] In any of the above embodiments of the kinase inhibitors of Formula (Ia), Hy may be replaced by an R 1b , an R 1c and 1 to 4 substitutions, such as 1, 2 or 3, R 1a or R 1d ; For example, Hy can be represented by one (or two) R 1a and (as defined above, in particular with respect to formula (II) or as defined below), and by one (or two) R 1b or R 1c (as defined above, in particular with respect to formula (III) or below) substituted, all other R 1e For H.

[0185] In any of the above embodiments of the kinase inhibitor of formula (Ia), preferably A is S and / or E is O.

[0186] In one embodiment, the kinase inhibitor has the general formula (IV)

[0187]

[0188] where R 1a 、R 1b 、R 1c 、R 2 、R 4 、R 5 , A, B and E are as defined above (particularly with respect to formula (I), (II) and / or (III)) or below, and R 3 Selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, phenyl, halogen, -CN, azido, -NO2, -O(C 1-6 alkyl), -OCF3, -S(C 1-6 alkyl), -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, -NHS(O)2(C 1-6 Alkyl), -S(O)2NH 2-z (C 1-6 alkyl) z 、-C(=O)(C 1-6 alkyl), -C(=O)OH, -C(=O)O(C 1-6 alkyl), -C(=O)NH 2-z (C 1-6 alkyl) z 、-NHC(=O)(C 1-6 alkyl), -NHC(=NH)NH 2-z (C 1-6 alkyl) z and -N(C 1-6 alkyl)C(=NH)NH 2-z (C 1-6 alkyl) z , where z is 0, 1, or 2, and each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl and phenyl are optionally replaced by one or more independently selected R 30 replace.

[0189] In one embodiment of the kinase inhibitor of formula (IV), R 1a 、R 1b 、R 1c 、R 2 、R 4 、R 5 , A, B and E are as defined above (particularly with respect to formula (I), (II) and / or (III)) or below, and R 3 Selected from H, C1-4 Alkyl, C 3-6 Cycloalkyl, phenyl, halogen, -CN, -O(C 1-4 alkyl), -OCF3, -S(C 1-4 alkyl), -NH2, -NH(C 1-4 Alkyl), -N(C 1-4 alkyl)2, -C(=O)(C 1-4 alkyl), -C(=O)OH, -C(=O)O(C 1-4 alkyl), -C(=O)NH 2-z (C 1-4 alkyl) z 、-NHC(=O)(C 1-4 alkyl), -NHC(=NH)NH 2-z (C 1-4 alkyl) z and -N(C 1-4 alkyl)C(=NH)NH 2-z (C 1-4 alkyl) z , wherein phenyl is optionally substituted by one, two or more independently selected from halogen, methyl, isopropyl, -CN, -CF3, -OCF3, -OH, -NH2, -NH(C 1-3 Alkyl), -N(C 1-3 alkyl)2, -NHC(=O)(C 1-3 alkyl), -C(=O)NH 2-z (C 1-3 alkyl) z 、-(CH2) 1-3 NH2, -(CH2) 1-3 NH(C 1-3 alkyl), -(CH2) 1-3 N(C 1-3 alkyl)2, -(CH2) 1-3 OH and -(CH2) 1-3 O(C 1-3 wherein z is 0, 1 or 2.

[0190] In one embodiment of the kinase inhibitor of formula (IV), R 1a 、R 1b 、R 1c 、R 2 、R 4 、R 5 , A, B and E are as defined above (particularly with respect to formula (I), (II) and / or (III)) or below, and R 3 Selected from H, methyl, ethyl, propyl, isopropyl, phenyl and halogen.

[0191] In one embodiment of the kinase inhibitor of formula (IV), R 1a 、R 1b 、R 1c 、R 2 、R 4 、R 5 , A, B and E are as defined above (particularly with respect to formula (I), (II) and / or (III)) or below, and R 3 For H.

[0192] In one embodiment, the kinase inhibitor has the general formula (V)

[0193]

[0194] where R 1a 、R 1b 、R 1c 、R 2 、R 3 、R 4 , A, B and E are as defined above (particularly with respect to formula (I), (II), (III) and / or (IV)) or below, and R 5 Yes-LR 6 , where R 6 is a heteroaryl group containing at least one ring heteroatom selected from N, O and S, or a heterocyclyl group containing at least one ring heteroatom selected from N, O and S, wherein each heteroaryl group and heterocyclyl group is optionally substituted by one, two or three independently selected R 7 Replace. For example, R 6 can be a heteroaryl group containing at least one ring heteroatom selected from N and O (i.e., the heteroaryl group does not contain S as a ring heteroatom; and in some embodiments, does not contain O as a ring heteroatom, i.e., R 6 may be N-heteroaryl), or a heterocyclyl containing at least one ring heteroatom selected from N and O (i.e., the heterocyclyl does not contain S as a ring heteroatom; and in some embodiments, does not contain O as a ring heteroatom, i.e., R 6 may be N-heterocyclyl), wherein each heteroaryl and heterocyclyl is optionally substituted by one, two or three independently selected R 7 replace.

[0195] In one embodiment of the kinase inhibitor of Formula (V), R 1a 、R 1b 、R 1c 、R 2 、R 3 、R 4 , A, B and E are as defined above (particularly with respect to formula (I), (II), (III) and / or (IV)) or below, and R6 is a 3- to 10-membered heteroaryl (e.g., containing at least one ring heteroatom selected from N, O, and S, e.g., selected from N and O) or a 3- to 10-membered heterocyclyl (e.g., containing at least one ring heteroatom selected from N, O, and S, e.g., selected from N and O), each of which is optionally substituted by one, two, or three independently selected R 7 replace.

[0196] In one embodiment of the kinase inhibitor of Formula (V), R 1a 、R 1b 、R 1c 、R 2 、R 3 、R 4 , A, B and E are as defined above (particularly with respect to formula (I), (II), (III) and / or (IV)) or below, and R 6 is a monocyclic or bicyclic heteroaryl (e.g., containing at least one ring heteroatom selected from N, O and S, such as selected from N and O) or a monocyclic or bicyclic heterocyclyl (e.g., containing at least one ring heteroatom selected from N, O and S, such as selected from N and O), each of which is optionally substituted by one, two or three independently selected R 7 replace.

[0197] In one embodiment of the kinase inhibitor of Formula (V), R 1a 、R 1b 、R 1c 、R 2 、R 3 、R 4 , A, B and E are as defined above (particularly with respect to formula (I), (II), (III) and / or (IV)) or below, and R 6 is selected from 5- to 6-membered monocyclic heteroaryl (e.g., containing at least one ring heteroatom selected from N, O and S, for example, selected from N and O), 4- to 6-membered monocyclic heterocyclyl (e.g., containing at least one ring heteroatom selected from N, O and S, for example, 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, for example, selected from N and O) and 7- to 9-membered bicyclic heterocyclyl (e.g., containing at least one ring heteroatom selected from N, O and S, for example, selected from N and O), each of which is optionally substituted by one, two or three independently selected R 7 replace.

[0198] In one embodiment of the kinase inhibitor of Formula (V), R 1a 、R 1b 、R 1c 、R 2 、R 3 、R 4, A, B and E are as defined above (particularly with respect to formula (I), (II), (III) and / or (IV)) or below, and R 6 is a 5- to 6-membered monocyclic heteroaryl (eg, containing at least one ring heteroatom selected from N, O and S, eg, selected from N and O), which is optionally substituted by one, two or three independently selected R 7 replace.

[0199] In one embodiment of the kinase inhibitor of Formula (V), R 1a 、R 1b 、R 1c 、R 2 、R 3 、R 4 , A, B and E are as defined above (particularly with respect to formula (I), (II), (III) and / or (IV)) or below, and R 6 is a 7- to 9-membered bicyclic heterocyclyl (eg, containing at least one ring heteroatom selected from N, O, and S, eg, selected from N and O), which is optionally substituted by one, two, or three independently selected R 7 replace.

[0200] In one embodiment of the kinase inhibitor of Formula (V), R 1a 、R 1b 、R 1c 、R 2 、R 3 、R 4 , A, B and E are as defined above (particularly with respect to formula (I), (II), (III) and / or (IV)) or below, and R 6 is selected from the group consisting of pyridyl, thienyl, pyridazinyl, furanyl, pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazoimidazolyl, indolyl, naphthyridinyl, thienopyridinyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, azetidinyl, azabicycloheptyl, azabicyclooctyl, azapentacyclooctyl, piperazinyl, morpholinyl and tetrahydrothienyl, each of which is replaced by one, two or three independently selected R 7 Substituted, preferably R 6 is selected from pyridyl, thienyl, pyrazolyl, isoxazolyl, pyrrolyl, piperidinyl, pyrrolidinyl, azetidinyl and azabicyclooctanyl, each of which is optionally substituted by one, two or three independently selected R 7 replace.

[0201] In any of the above embodiments of the kinase inhibitor of Formula (V), including kinase inhibitors of Formulas (I), (II), (III), and (IV), R 7 Can be independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C2-6 Alkynyl, halogen, -CN, -O(C 1-6 Alkyl), -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, -NHS(O) 1-2 (C 1-6 Alkyl), -NHS(O) 1-2 O(C 1-6 alkyl), -C(=O)(C 1-6 alkyl) and -OC(=O)(C 1-6 alkyl), and / or with R as a heterocyclic group 6 Any two R 7 Can be linked together to form the form =O, where C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each of the alkynyl groups is optionally substituted with one or more independently selected R 30 Replace. For example, R 7 Can be independently selected from C 1-3 Alkyl, halogen, -CN, -O(C 1-3 Alkyl), -NH(C 1-3 alkyl) and -N(C 1-3 alkyl)2, and / or with R as a heterocyclic group 6 Any two R 7 Can be linked together to form =O, where each C 1-3 The alkyl group is optionally replaced by one or more independently selected R 30 In any of the above embodiments of the kinase inhibitor of formula (V), including kinase inhibitors of formula (I), (II), (III) and (IV), R 7 It may be independently selected from Cl, Br, methyl and ethyl, for example selected from Cl, Br and methyl.

[0202] In any of the above embodiments of the kinase inhibitor of Formula (V), including kinase inhibitors of Formulas (I), (II), (III), and (IV), wherein R 6 is substituted, preferably with one R 7 Group relative to R 6 Position 2 of the ring atom bound to the rest of the compound is R 6 The ring atoms of 6 With ortho R 7 In any of the above embodiments of the kinase inhibitor of formula (V), including kinase inhibitors of formula (I), (II), (III), and (IV), wherein R 6 By two or more (e.g. two, three or four) R7 Group substitution, preferably two or more R 7 One of the groups is relative to R 6 Position 2 of the ring atom bound to the rest of the compound is R 6 The ring atoms are combined (ie R 6 With ortho R 7 group), and the remaining R 7 The group is attached to R at a position other than position 2 6 For example, in any of the above embodiments of the kinase inhibitor of formula (V), including kinase inhibitors of formula (I), (II), (III), and (IV), wherein R 6 is formed by two or more R 7 The k-membered ring is substituted with a group, preferably two or more R 7 Group relative to R 6 The ring atom to which it is attached to the rest of the compound (ie, relative to the radical position) is located at position 2 and is connected to R 6 The ring atoms are bound, while the remaining R 7 The group is bound to a position other than position 2, such as position 3, 4, 5, ... k. For example, in R 6 In the case of a 5-membered ring, preferably two or more R 7 One of the groups is in position 2 (relative to the base position) with R 6 The ring atoms are combined, and the remaining R 7 The group is in the 3, 4 or 5 position (relative to the base position) with R 6 In addition, in any of the above embodiments of the kinase inhibitors of formula (V), including kinase inhibitors of formula (I), (II), (III) and (IV), wherein R 6 By two or more (for example, two, three or four) R 7 Group substitution, preferably, with R 6 Each of the two ring atoms directly adjacent to the ring atom directly attached to the rest of the compound carries an R 7 Groups (e.g., R 6 is a k-membered ring, relative to R 6 The ring atom bound to the rest of the compound has an R at positions 2 and k. 7 Groups, such as R 6 is substituted at both ortho positions). Additionally, in any of the above embodiments of the kinase inhibitor of Formula (V), including kinase inhibitors of Formulas (I), (II), (III), and (IV), wherein R 6 By three or more (e.g. three or four) R 7 Group substitution, preferably with R 6Each of the two ring atoms directly adjacent to the ring atom directly attached to the rest of the compound carries an R 7 Groups (e.g., R 6 is a k-membered ring, relative to R 6 A ring atom bound to the rest of the compound, with one R at each of positions 2 and k 7 Groups, such as R 6 are substituted at both ortho positions), and the third R 7 Group bonded to R 6 is directly adjacent to one of the adjacent ring atoms but is not R 6 The ring atom to which it is attached to the rest of the compound (e.g., R 6 is a k-membered ring, relative to R 6 Ring atoms bound to the rest of the compound, bearing a third R at positions 3 and k-1 7 group).

[0203] In one embodiment of the kinase inhibitor of Formula (V), R 1a 、R 1b 、R 1c 、R 2 、R 3 、R 4 , A, B and E are as defined above (particularly with respect to formula (I), (II), (III) and / or (IV)) or below, and R 6 Selected from the following formula:

[0204]

[0205] in Represents R 6 The bond that binds it to the rest of the compound.

[0206] In one embodiment of the kinase inhibitor of Formula (V), R 1a 、R 1b 、R 1c 、R 2 、R 3 、R 4 , A, B and E are as defined above (particularly with respect to formula (I), (II), (III) and / or (IV)) or below, and R 6 Selected from the following formula:

[0207]

[0208] in Represents R 6 The bond that binds it to the rest of the compound.

[0209] In one embodiment of the kinase inhibitor of Formula (V), R 1a 、R 1b 、R 1c 、R 2 、R 3 、R 4 , A, B and E are as defined above (particularly with respect to formula (I), (II), (III) and / or (IV)) or below, and R 6 Selected from the following formula:

[0210]

[0211] in Represents R 6 The bond that binds it to the rest of the compound.

[0212] In one embodiment of the kinase inhibitor of Formula (V), R 1a 、R 1b 、R 1c 、R 2 、R 3 、R 4 , A, B and E are as defined above (particularly with respect to formula (I), (II), (III) and / or (IV)) or below, and R 6 Selected from the following formula:

[0213]

[0214] in Represents R 6 The bond that binds it to the rest of the compound.

[0215] In any of the above embodiments of the kinase inhibitor of formula (V), including kinase inhibitors of formula (I), (II), (III), and (IV), L can be selected from a bond, C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene 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 if n is 0, then o is 1; Y is independently selected from O, S and NH, wherein each C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, -(CH2) m - and -(CH2) n - group is optionally replaced by one or more independently selected R 30For example, in any of the above embodiments of the kinase inhibitor of formula (V), including the kinase inhibitors of formula (I), (II), (III) and (IV), L can be selected from: a bond; optionally replaced by one R 30 Substituted C1 alkylene; optionally substituted by one R 30 Substituted C2 alkylene (especially 1,2-ethylene or 1,1-ethylene); optionally substituted by one R 30 Substituted C3 alkylene (especially trimethylene); optionally substituted by one R 30 Substituted C4 alkylene (especially tetramethylene or 2,4-butanediyl); -(CH2) m O-; and -(CH2) m NH-, wherein m is 1, 2 or 3. In particular, in any of the above embodiments of the kinase inhibitor of formula (V), including kinase inhibitors of formula (I), (II), (III) and (IV), L can be a bond.

[0216] In any of the above embodiments of the kinase inhibitor of Formula (V), including kinase inhibitors of Formulas (I), (II), (III), and (IV), wherein R 6 is a heterocyclic group or heteroaryl group containing a N atom as a ring heteroatom (e.g., a 5-membered heteroaryl group), and L can be connected to R via the N ring atom of the heterocyclic group or heteroaryl group. 6 .

[0217] In one embodiment, the kinase inhibitor has the general formula (VI)

[0218]

[0219] where R 1a 、R 1b 、R 1c 、R 2 、R 3 、R 4 、R 5 , B and E are as defined above (particularly with respect to formula (I), (II), (III), (IV) and / or (V)) or below, and A is selected from S, O, NH, N(C 1-6 alkyl) and C(C 1-6 In any of the above embodiments of the kinase inhibitor of formula (VI), including those of formula (I), (II), (III), (IV), and (V), A may be S, O, or N(CH). In any of the above embodiments of the kinase inhibitor of formula (VI), including those of formula (I), (II), (III), (IV), and (V), preferably A is S.

[0220] In one embodiment, the kinase inhibitor has the general formula (VII)

[0221]

[0222] where R 1a 、R 1b 、R 1c 、R 2 、R 3 、R 4 、R 5 and A is as defined above (particularly with respect to formula (I), (II), (III), (IV), (V) and / or (VI)) or below, E is O or S (preferably O), and B is N or CR 1d , where R 1d Selected from C 1-3 Alkyl, halogen, -O(C 1-3 Alkyl), -S(C 1-3 Alkyl), -NH(C 1-3 alkyl) and -N(C 1-3 alkyl)2, wherein each C 1-3 The alkyl group is optionally substituted independently by one or two groups selected from halogen, -OH, OCH3, -SCH and -NH 2-z (CH3) z wherein z is 0, 1 or 2. In any of the above embodiments of the kinase inhibitor of formula (VII) (including kinase inhibitors of formula (I), (II), (III), (IV), (V) and (VI)), E is O or S (preferably O), B is N or CR 1d , where R 1d Can be selected from C 1-3 Alkyl, halogen, -O(C 1-3 Alkyl), -S(C 1-3 Alkyl), -NH(C 1-3 alkyl) and -N(C 1-3 In any of the above embodiments of the kinase inhibitor of formula (VII), including kinase inhibitors of formula (I), (II), (III), (IV), (V), and (VI), preferably B is N, more preferably E is O and B is N.

[0223] In one embodiment, the kinase inhibitor has the general formula (VIII)

[0224]

[0225] where R 1a 、R 1b 、R 1c 、R 2 、R 3 、R4 、R 5 , A, B and E are as defined above (particularly with respect to formula (I), (II), (III), (IV), (V), (VI) and / or (VII)) or below, and L is a bond. In a preferred embodiment of the kinase inhibitor having the general formula (VIII):

[0226] (A)R 1a is selected from alkyl, -O(alkyl), -S(alkyl), -NH(alkyl), -N(alkyl)2 and heterocyclyl, wherein each of alkyl and heterocyclyl is optionally replaced by one or more independently selected R 30 Preferably, each R 30 is independently a first substituent, a second substituent, or a third substituent as specified herein, such as an alkyl group (e.g., C 1-6 alkyl), -(CH2) 1-3 OH, alkenyl (e.g. C 2-6 alkenyl), alkynyl (e.g. C 2-6 alkynyl), halogen, -CN, nitro, -OR 11 (e.g. -OH), -SR 11 (e.g. -SH), -N(R 12 )(R 13 ) (e.g., -NH2) and -C(=O)R 11 (e.g. -C(=O)(C 1-3 alkyl));

[0227] (B)R 1b and R 1c Each of them is independently selected from H, methyl, ethyl, -OH, -OCH3, -SCH3, cyclopropyl, 2-hydroxyethyl, 2-(N,N-dimethylamino)ethoxy, 2-(N,N-dimethylamino)ethoxy, 2-aminoethyl, 2-(N-methylamino)ethyl, 2-(methoxy)ethyl, -NH 2-z (CH3) z , phenyl, pyridyl, pyrazolyl, phenoxy, pyridyloxy, imidazolylamino and tetrahydrofuranylmethoxy, wherein z is 0, 1 or 2; and each of phenyl, pyridyl, pyrazolyl, phenoxy, pyridyloxy, imidazolylamino and tetrahydrofuranylmethoxy is optionally 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 -NH 2-z (CH3) z Partial substitution, wherein z is 0, 1 or 2;

[0228] (C)R 3 Selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, phenyl, halogen, -CN, azido, -NO2, -O(C 1-6 alkyl), -OCF3, -S(C 1-6 alkyl), -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, -NHS(O)2(C 1-6 Alkyl), -S(O)2NH 2-z (C 1-6 alkyl) z 、-C(=O)(C 1-6 alkyl), -C(=O)OH, -C(=O)O(C 1-6 alkyl), -C(=O)NH 2-z (C 1-6 alkyl) z 、-NHC(=O)(C 1-6 alkyl), -NHC(=NH)NH 2-z (C 1-6 alkyl) z and -N(C 1-6 alkyl)C(=NH)NH 2-z (C 1-6 alkyl) z , where z is 0, 1, or 2, and where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Each of cycloalkyl and phenyl is optionally replaced by one or more independently selected R 30 replace;

[0229] (D)R 6 As defined above (particularly with respect to formula (V)), and preferably 3- to 10-membered heteroaryl (e.g., comprising at least one ring heteroatom selected from N, O, and S, such as 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, such as selected from N and O), each of which is optionally substituted by one, two or three independently selected R 7 replace;

[0230] (E)A is selected from S, O, NH, N(C 1-6 alkyl) and C(C 1-6 Alkyl)2;

[0231] (F)B is N or CR1d , where R 1d Selected from C 1-3 Alkyl, halogen, -O(C 1-3 Alkyl), -S(C 1-3 Alkyl), -NH(C 1-3 alkyl) and -N(C 1-3 Alkyl)2, wherein C 1-3 Each of the alkyl groups is optionally substituted by one or two groups independently selected from halogen, -OH, -OCH3, -SCH and -NH 2-z (CH3) z wherein z is 0, 1 or 2; and / or

[0232] (G) E is O or S, preferably O.

[0233] In a preferred embodiment of the kinase inhibitor having the general formula (VIII), R 1a As specified in (A) above; R 1b and R 1c As defined in (B) above; R 3 As specified in (C) above; R 6 As defined above (particularly with respect to formula (V)), and preferably 3- to 10-membered heteroaryl (e.g., comprising at least one ring heteroatom selected from N, O, and S, such as 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, such as selected from N and O), each of which is optionally substituted by one, two or three independently selected R 7 Substitution; A is as specified above in (E); B is as described above in (F); E is as described above in (G).

[0234] In a further preferred embodiment of the kinase inhibitors having the general formula (VIII):

[0235] (A')R 1a Selected from C 1-3 Alkyl, -O(C 1-3 Alkyl), -S(C 1-3 Alkyl), -NH(C 1-3 Alkyl), -N(C 1-3 alkyl) 2 and 3 to 7 membered heterocyclic groups, wherein the 3 to 7 membered heterocyclic groups are optionally replaced by one or two independently selected from methyl, ethyl, -OH, -OCH3, -SCH3, cyclopropyl, 2-hydroxyethyl, 2-(N,N-dimethylamino)ethoxy, 2-(N,N-dimethylamino)ethoxy, 2-aminoethyl, 2-(N-methylamino)ethyl, 2-(methoxy)ethyl, 4-methylpiperazinyl, -C(=O)(C 1-3 alkyl), -(CH2) 1-3COOH and -NH 2-z (CH3) z wherein z is 0, 1 or 2; and C 1-3 Each of the alkyl groups is optionally substituted by one or two groups independently selected from -OH, -OCH3, -SCH3, cyclopropyl, piperazinyl, 4-methyl-piperazinyl, 4-(2-hydroxyethyl)piperazinyl, 2-(N,N-dimethylamino)ethoxy and -NH 2-z (CH3) z Partial substitution, wherein z is 0, 1 or 2;

[0236] (B')R 1b and R 1c At least one of H, methyl, ethyl, -OH, -OCH3, -SCH3, cyclopropyl, 2-hydroxyethyl, 2-(N,N-dimethylamino)ethyl, 2-(N,N-dimethylamino)ethoxy, 2-aminoethyl, 2-(N-methylamino)ethyl, 2-(methoxy)ethyl, -NH 2-z (CH3) z and phenyl, wherein z is 0, 1 or 2, and R 1b and R 1c the other of which is as defined above in (B);

[0237] (C')R 3 Selected from H, C 1-4 Alkyl, C 3-6 Cycloalkyl, phenyl, halogen, -CN, -O(C 1-4 alkyl), -OCF3, -S(C 1-4 alkyl), -NH2, -NH(C 1-4 Alkyl), -N(C 1-4 alkyl)2, -C(=O)(C 1-4 alkyl), -C(=O)OH, -C(=O)O(C 1-4 alkyl), -C(=O)NH 2-z (C 1-4 alkyl) z 、-NHC(=O)(C 1-4 alkyl), -NHC(=NH)NH 2-z (C 1-4 alkyl) z and -N(C 1-4 alkyl)C(=NH)NH 2-z (C 1-4 alkyl) z , wherein phenyl is optionally substituted by one, two or more independently selected from halogen, methyl, isopropyl, -CN, -CF3, -OCF3, -OH, -NH2, -NH(C 1-3Alkyl), -N(C 1-3 alkyl)2, -NHC(=O)(C 1-3 alkyl), -C(=O)NH 2-z (C 1-3 alkyl) z 、-(CH2) 1-3 NH2, -(CH2) 1-3 NH(C 1-3 alkyl), -(CH2) 1-3 N(C 1-3 alkyl)2, -(CH2) 1-3 OH and -(CH2) 1-3 O(C 1-3 alkyl); and wherein z is 0, 1 or 2;

[0238] (D')R 6 As defined above (particularly with respect to formula (V)), and preferably 3- to 10-membered heteroaryl (e.g., comprising at least one ring heteroatom selected from N, O, and S, such as 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, such as selected from N and O), each of which is optionally substituted by one, two or three independently selected R 7 Substituted, more preferably R 6 is a monocyclic or bicyclic heteroaryl or a monocyclic or bicyclic heterocyclyl, each of which is optionally substituted by one, two or three independently selected R 7 replace;

[0239] (E')A is S, O or N(CH3)2; and / or

[0240] (F')B is N or CR 1d , where R 1d Selected from C 1-3 Alkyl, halogen, -O(C 1-3 Alkyl), -S(C 1-3 Alkyl), -NH(C 1-3 alkyl) and -N(C 1-3 alkyl)2; and / or

[0241] (G')E is O or S, preferably O.

[0242] In a preferred embodiment of the kinase inhibitor having the general formula (VIII), R 1a As specified above in (A'); R 1b and R 1c As defined above in (B'); R 3 As specified above in (C'); R 6As defined above (particularly with respect to formula (V)), and preferably 3- to 10-membered heteroaryl (e.g., comprising at least one ring heteroatom selected from N, O, and S, such as 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, such as selected from N and O), each of which is optionally substituted by one, two or three independently selected R 7 Substituted, more preferably R 6 is a monocyclic or bicyclic heteroaryl (e.g., containing at least one ring heteroatom selected from N, O and S, such as selected from N and O) or a monocyclic or bicyclic heterocyclyl (e.g., containing at least one ring heteroatom selected from N, O and S, such as selected from N and O), each of which is optionally substituted by one, two or three independently selected R 7 Substitution; A is as described above in (E'); B is as described above in (F'); E is as described above in (G').

[0243] In a further preferred embodiment of the kinase inhibitors having the general formula (VIII):

[0244] (A”)R 1a Selected from -NH(C 1-3 alkyl), piperazinyl, piperidinyl and pyrrolidinyl, wherein piperazinyl is optionally substituted with one or two moieties independently selected from 2-hydroxyethyl, methyl, -CH2COOH and -C(=O)CH3; piperidinyl is optionally substituted with one or two moieties independently selected from -NH2 and 4-methylpiperazinyl; pyrrolidinyl is optionally substituted with one or two -OH; and C 1-3 Each of the alkyl groups is optionally substituted with one or two moieties independently selected from: -OH, -OCH3, and -NH 2-z (CH3) z , where z is 0, 1, or 2;

[0245] (B”)(a)R 1b is methyl, ethyl, propyl or isopropyl, preferably methyl, R 1c is H; or (b) R 1b H, R 1c is methyl, ethyl, propyl, isopropyl or phenyl, preferably methyl;

[0246] (C”)R 3 is selected from H, methyl, ethyl, propyl, isopropyl, phenyl and halogen;

[0247] (D”)R 6As defined above (particularly with respect to formula (V)), and preferably 3- to 10-membered heteroaryl (e.g., comprising at least one ring heteroatom selected from N, O and S, such as 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, such as selected from N and O), each of which is optionally substituted by one, two or three independently selected R 7 Substituted, more preferably, R 6 is a monocyclic or bicyclic heteroaryl (e.g., containing at least one ring heteroatom selected from N, O and S, such as selected from N and O), or a monocyclic or bicyclic heterocyclyl (e.g., containing at least one ring heteroatom selected from N, O and S, such as selected from N and O), each of which is optionally substituted by one, two or three independently selected R 7 Substituted, more preferably R 6 is selected from 5- to 6-membered monocyclic heteroaryl (e.g., containing at least one ring heteroatom selected from N, O and S, for example, selected from N and O), 4- to 6-membered monocyclic heterocyclyl (e.g., containing at least one ring heteroatom selected from N, O and S, for example, 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, for example, selected from N and O) and 7- to 9-membered bicyclic heterocyclyl (e.g., containing at least one ring heteroatom selected from N, O and S, for example, selected from N and O), each of which is optionally substituted by one, two or three independently selected R 7 substituted, more preferably R 6 is a 5- to 6-membered monocyclic heteroaryl (e.g., containing at least one ring heteroatom selected from N, O, and S, such as selected from N and O) or a 7- to 9-membered bicyclic heterocyclyl (e.g., containing at least one ring heteroatom selected from N, O, and S, such as selected from N and O), each of which is optionally substituted by one, two, or three independently selected R 7 replace;

[0248] (E”)A is S;

[0249] (F”)B is N; and / or

[0250] (G”)E is O.

[0251] In a preferred embodiment of the kinase inhibitor having the general formula (VIII), R 1a As specified above in (A”); R 1b and R 1c As defined above in (B”); R 3 As specified above in (C”); R 6As defined above (particularly with respect to formula (V)), and preferably 3- to 10-membered heteroaryl (e.g., comprising at least one ring heteroatom selected from N, O and S, such as 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, such as selected from N and O), each of which is optionally substituted by one, two or three independently selected R 7 Substituted, more preferably, R 6 is a monocyclic or bicyclic heteroaryl (e.g., containing at least one ring heteroatom selected from N, O and S, such as selected from N and O), or a monocyclic or bicyclic heterocyclyl (e.g., containing at least one ring heteroatom selected from N, O and S, such as selected from N and O), each of which is optionally substituted by one, two or three independently selected R 7 substituted, more preferably R 6 is selected from 5- to 6-membered monocyclic heteroaryl (e.g., containing at least one ring heteroatom selected from N, O and S, for example, selected from N and O), 4- to 6-membered monocyclic heterocyclyl (e.g., containing at least one ring heteroatom selected from N, O and S, for example, 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, for example, selected from N and O) and 7- to 9-membered bicyclic heterocyclyl (e.g., containing at least one ring heteroatom selected from N, O and S, for example, selected from N and O), each of which is optionally substituted by one, two or three independently selected R 7 substituted, more preferably R 6 is a 5- to 6-membered monocyclic heteroaryl (e.g., containing at least one ring heteroatom selected from N, O, and S, such as selected from N and O) or a 7- to 9-membered bicyclic heterocyclyl (e.g., containing at least one ring heteroatom selected from N, O, and S, such as selected from N and O), each of which is optionally substituted by one, two, or three independently selected R 7 Substitution; A is as described above in (E”); B ​​is as described above in (F”); E is as described above in (G”).

[0252] In one embodiment, the compound of the present invention is selected from the compounds shown in Table A and / or Table B.

[0253] It is intended that the compounds of the present invention (particularly formula (I), (Ia), (II), (III), (IV), (V), (VI), (VII) and (VIII) (e.g., compounds described in Table A and / or Table B below) encompass not only the described compounds, but also their solvates (e.g., hydrates), salts (particularly pharmaceutically acceptable salts), N-oxides (particularly R 1a and / or R 6N-oxides), complexes, polymorphs, crystalline forms, amorphous forms, racemic mixtures, non-racemic mixtures, diastereomers, enantiomers, tautomers, conformers, isotopically labeled forms, prodrugs, and any combination thereof.

[0254] Selected compounds include compounds that have been synthesized and tested within the scope of the present invention or for use in the methods of the present invention, and / or compounds that represent various exemplary or preferred R 1a Substituent, R 1b Substituent, R 1c Substituent, R 2 Substituent, R 3 Substituent, R 4 Substituent, R 5 Examples of Parts A and / or B are listed in Table A and / or Table B below.

[0255] Table A: Kinase inhibitors of formula (I).

[0256]

[0257]

[0258] *Compound B3 is included in Table 1 of co-pending PCT / EP2018 / 060172. Table B: Other kinase inhibitors of formula (I)

[0259]

[0260]

[0261] In specific embodiments, the compound of the present invention is selected from C7 and C8 and / or D1 and / or D9, or in certain embodiments, the compound of the present invention is B3; and their solvates, salts, N-oxides, complexes, polymorphs, crystal forms, tautomers, conformers, isotopically labeled forms, prodrugs and combinations thereof.

[0262] In another specific embodiment, the compound of the present invention is C12 or a solvate, salt, N-oxide, complex, polymorph, crystalline form, racemic mixture, diastereomer, enantiomer, tautomer, conformer, isotopically labeled form, prodrug, or a combination thereof.

[0263] In certain embodiments, the present invention may relate to solvates, salts, N-oxides, complexes, racemic mixtures, diastereomers, enantiomers, tautomers, conformers, isotopically labeled forms, prodrugs, or combinations thereof of any compound of the present invention; for example, solvates, salts, complexes, racemic mixtures, diastereomers, enantiomers, tautomers, conformers, isotopically labeled forms, or combinations thereof of such compounds.

[0264] In one embodiment, the compounds of the present invention do not include compounds of one or more of the following groups (1) to (5) of formula (I) (in groups (1) to (5), one moiety (e.g., methyl) is unsubstituted unless it is explicitly stated that the moiety is substituted):

[0265] (1) When R 1a is 4-(2-hydroxyethyl)piperazine-1-yl or Cl, R 1b H, R 1c is methyl, B is N, E is O, R 3 is H, A is S, and L is a bond, then R 6 Not 4-chloro-2-methylpyridin-3-yl;

[0266] (2) When R 1a is methoxy, R 1b H, R 1c is methoxy, B is N, E is O, R 3 is H, A is S, and L is a bond, then R 6 Not 2,2-difluoro-5H-1,3-dioxa[4,5-f]benzimidazol-6-yl;

[0267] (3) When R 3 is H, A is S, L is a bond, R 6 is 1-methyl-4-piperidinyl, R 1b is H, B is N, E is O, and

[0268] (i)R 1a When it is methyl, then R 1c is not N-tert-butoxycarbonylpiperidin-4-yl; or

[0269] (ii)R 1c When it is methyl, then R 1a Not N-tert-butoxycarbonylpiperidin-4-yl or N-tert-butoxycarbonylpiperidin-3-yl;

[0270] (4) When E is O and B is CR 1d , and R 1d When it is H, F, Cl or Br, then R 1a is not H; and

[0271] (5) When R 1a is methyl, R 1b and R 1c Each of is H, B is CH, E is O, A is S, and R 3 When it is methyl, R5 is not 1,3-benzodioxazol-5-ylmethyl, 2-furylmethyl, 1,3-benzodioxazol-5-yl, 2-(2-thienyl)ethyl, 2-(4-morpholinyl)ethyl, 2-(2-pyridyl)ethyl, 2-pyridylmethyl, or tetrahydro-2-furylmethyl.

[0272] In one embodiment, the compounds of the present invention do not include one or more compounds of the following groups (6) to (8) having formula (Ia) (in groups (6) to (8), one moiety (e.g., methyl) is unsubstituted unless it is explicitly stated that the moiety is substituted):

[0273] (6) When Hy is

[0274] When and

[0275] (i)R 1a is 4-(2-hydroxyethyl)piperazine-1-yl or Cl, R 1b H, R 1c is methyl, B is N, E is O, R 2 H, R 3 H, R 4 When is H and A is S, then R 6 Not 4-chloro-2-methylphenyl-3-yl;

[0276] (ii) When R 1a is methoxy, R 1b H, R 1c is methoxy, B is N, E is O, R 2 H, R 3 H, R 4 When is H and A is S, then R 6 Not 2,2-difluoro-5H-1,3-dioxa[4,5-f]benzimidazol-6-yl;

[0277] (7) When Hy is 1-{(2E)-4-[(2-methoxyethyl)amino]-1-oxo-2-buten-1-yl}piperidin-4-yl, R 2 H, R 3 H, R 4 When it is H, A is O, and E is O, then R6 is not 5-methyl-naphthalen-2-yl;

[0278] (8) When R 2H, R 3 is trifluoromethyl, R 4 is H, A is O, E is O, and

[0279] (i)R 6 when it is 6-{4-[(2-fluorophenyl)carbamoyl]piperazin-1-yl}pyridin-3-yl, then Hy is not 1-(phenylmethyl)-piperidin-4-yl, 1-(phenylmethyl)pyrrolidin-3-yl or tetrahydro-2H-pyran-4-yl; or

[0280] (ii) When Hy is 1-(phenylmethyl)piperidin-4-yl, then R 6 other than 6-(3-{[(2-fluorophenyl)carbamoyl]amino}-pyrrolidin-1-yl)pyridin-3-yl or 6-({1-[(2-fluorophenyl)carbamoyl]piperidin-4-yl}amino)pyridin-3-yl; or

[0281] (iii) When Hy is 1-(phenylmethyl)pyrrolidin-3-yl, then R 6 is not 6-({(3S)-1-[(2-fluorophenyl)carbamoyl]-pyrrolidin-3-yl}amino)pyridin-3-yl or 6-({(3R)-1-[(2-fluorophenyl)carbamoyl]pyrrolidin-3-yl}-amino)pyridin-3-yl. In certain other embodiments, the compound is not one selected from:

[0282] 5-thiazolecarboxamide, 2-[(6-chloro-2-methyl-4-pyrimidinyl)amino]-N-[2-[4-(2-hydroxyethyl)-1-piperazinyl]-6-methylphenyl]-(CAS Reg. No. 2048106-50-7),

[0283] 5-thiazolecarboxamide, 2-[[7-[4-cyano-3-(trifluoromethyl)phenyl]-5,6,7,8-tetrahydropyridinyl[3,4-d]pyrimidin-4-yl]amino]-N-[(1R)-1-(1,3,4-oxadiazol-2-yl)ethyl]-4-(trifluoromethyl)-(CAS Reg. No. 1831086-00-0),

[0284] 5-thiazolecarboxamide, 2-[[6-methoxy-7-[3-(4-morpholinyl)propoxy]-4-quinazolinyl]amino]-N-(2-pyrazinylmethyl)-(CAS Reg. No.: 385780-87-0),

[0285] 5-thiazolecarboxamide, 2-[[6-methoxy-7-[3-(4-morpholinyl)propoxy]-4-quinazolinyl]amino]-N-[2-(3-pyridyl)ethyl]-(CAS Reg. No.: 385780-82-5),

[0286] 5-thiazolecarboxamide, N-1H-indol-5-yl-2-[[6-methoxy-7-[3-(4-morpholinyl)propoxy]-4-quinazolinyl]amino]-(CAS Reg. No.: 385780-79-0),

[0287] 5-thiazolecarboxamide, 2-[[6-methoxy-7-[3-(4-morpholinyl)propoxy]-4-quinazolinyl]amino]-N-(2-thienylmethyl)-(CAS Reg. No.: 385780-69-8),

[0288] 5-thiazolecarboxamide, N-(2-furylmethyl)-2-[[6-methoxy-7-[3-(4-morpholinyl)propoxy]-4-quinazolinyl]amino]-(CAS Reg. No.: 385780-66-5),

[0289] 5-thiazolecarboxamide, 2-[[6-methoxy-7-[3-(4-morpholinyl)propoxy]-4-quinazolinyl]amino]-N-2-pyridyl-(CAS Reg. No. 385780-57-4), and

[0290] 5-Thiazolecarboxamide, 2-[[6-methoxy-7-[3-(4-morpholinyl)propoxy]-4-quinazolinyl]amino]-N-4-pyridinyl-(CAS Reg. No.: 385779-93-1).

[0291] In certain other embodiments, the compound is not selected from one of:

[0292] Imidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide, N,N-dicyclopropyl-6-ethyl-1,6-dihydro-1-methyl-4-[[4-methyl-5-[[(tetrahydro-2H-pyran-4-yl)amino]carbonyl]-2-thiazolyl]amino]-(CAS Reg. No. 1271022-78-6),

[0293] Imidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide, N,N-dicyclopropyl-6-ethyl-1,6-dihydro-1-methyl-4-[[4-methyl-5-[[(tetrahydro-1,1-dioxo-3-thienyl)amino]carbonyl]-2-thiazolyl]amino]-(CAS Reg. No. 1271022-57-1),

[0294] imidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide, N,N-dicyclopropyl-6-ethyl-1,6-dihydro-1-methyl-4-[[4-methyl-5-[[[2-(4-morpholinyl)ethyl]amino]carbonyl]-2-thiazolyl]amino]-(CAS Reg. No. 1271022-45-7), and

[0295] Imidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide, N,N-dicyclopropyl-6-ethyl-1,6-dihydro-1-methyl-4-[[5-[[methyl(tetrahydro-1,1-dioxo-3-thienyl)amino]carbonyl]-2-thiazolyl]amino]-(CAS Reg. No. 1271021-43-2)

[0296] 2-[(6-{[3-(1H-imidazol-1-yl)propyl]amino}pyridin-2-yl)amino]-4-methyl-N-[1-(phenylmethyl)-1H-indazol-5-yl]-1,3-thiazole-5-carboxamide (CAS Reg. No.: 302963-64-0)

[0297] 2-[(6-{[3-(1H-imidazol-1-yl)propyl]amino}pyridin-2-yl)amino]-N-[1-(phenylmethyl)-1H-indazol-5-yl]-1,3-thiazole-5-carboxamide (CAS Reg. No.: 302963-55-9).

[0298] In certain alternatives of one or more aspects herein, the compound is N-(2-chloro-6-methylphenyl)-2-((6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-yl)amino)thiazole-5-carboxamide (dasatinib; A8).

[0299] Compounds of the invention containing basic functional groups can form salts with a variety of inorganic or organic acids. Compounds of the invention containing acidic functional groups can form salts with a variety of inorganic or organic bases. Exemplary inorganic and organic acid / base and exemplary acid / base addition salts of the compounds of the invention are given below in the definition of "Pharmaceutically Acceptable Salts" in the "Pharmaceutical Compositions" section. Compounds of the invention containing basic and acidic functional groups can be converted into base or acid addition salts. Neutral forms of the compounds of the invention can be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.

[0300] The compounds of the present invention may be in the form of N-oxides, ie they may contain a functional group ≡N + -O - (For example, (R n )3N + -O - , i.e., NO coordinate covalent bond, where Rn independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl, wherein each alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl group is optionally replaced by one or more (e.g., from 1 to a maximum, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, e.g., 1 to 5, 1 to 4, or 1 to 3, or 1 or 2, of the number of hydrogen atoms bonded to the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl group) independently selected R 30 Replacement, R 30 Specific examples of N-oxides of compounds of the present invention are those wherein R 1a and / or R 6 Contains functional group ≡N + -O - Those that can appear as N-oxides 1a Non-limiting examples of substituents include the following:

[0301] in Represents R 1a The bond that binds a substituent to the rest of the compound. R can occur as an N-oxide 6 Non-limiting examples include:

[0302] in Represents R 6 The bond that binds a substituent to the rest of the compound.

[0303] The compounds of the present invention may be in the form of prodrugs. Prodrugs of the compounds of the present invention are compounds that undergo chemical conversion under physiological conditions to provide the compounds of the present invention after administration to a subject. In addition, prodrugs may be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, when placed in a transdermal patch reservoir, for example, together with a suitable enzyme or chemical reagent, a prodrug may be slowly converted to the compounds of the present invention. Exemplary prodrugs are esters (using alcohol or carboxyl groups contained in the kinase inhibitors of the present invention) or amides (using amino or carboxyl groups contained in the kinase inhibitors of the present invention) that are hydrolyzable in vivo. Specifically, any amino group contained in the kinase inhibitors of the present invention and having at least one hydrogen atom can be converted to a prodrug form. Typical N-prodrug forms include carbamates (1), Mannich bases (2), enamines (3), and enaminones (4).

[0304]

[0305] where R18 R is 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., from 1 to the maximum number of hydrogen atoms bound to the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl group, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, e.g., 1 to 5, 1 to 4, or 1 to 3, or 1 or 2) independently selected R 30 Substituted, where R 30 As defined herein (preferably, each R 30 are independently a first substituent, a second substituent, or a third substituent as described herein). The R 18 The prodrug can be modified to fine-tune its properties (e.g., solubility, permeability, stability, cleavage rate, where and under what conditions it is cleaved in vivo, target specificity, etc.).

[0306] Particular prodrug forms of the compounds of the invention are those having the formula (IXa), (IXb), (IXc) or (IXd) (prodrugs):

[0307]

[0308]

[0309] and solvates, salts, N-oxides, complexes, polymorphs, crystal forms, racemic mixtures, diastereomers, enantiomers, tautomers, conformers, isotopically labeled forms, and combinations thereof, wherein R 1a 、R 1b 、R 1c 、R 3 、R 5 , A, B, E and Hy are as defined above (particularly with respect to formula (I), (Ia), (II), (III), (IV), (V), (VI) and / or (VIII)) or below, R 2 and R 4 Each independently selected from H, -P(O)(OR 11a )2、-(CH2) 1-3 -R 19 、-C(=X a )R 11a and -C(=X a )X a R 11a , provided that R 2 and R 4 Not all are H, among which R 11aR 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 is optionally replaced by one or more (e.g., from 1 to the maximum number of hydrogen atoms bound to the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, e.g., 1 to 5, 1 to 4, or 1 to 3, or 1 or 2) independently selected R 30 Replacement; R 19 are independently selected from -OP(O)(OR 11a )2. -X a C(=X a )R 11a 、-X a C(=X a )X a R 11a and 5-alkyl-2-oxo-1,3-dioxolan-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 R 30 Substituted, where R 30 As defined herein (preferably, each R 30 (IXa), (IXb), (IXc), or (IXd), wherein R 1a 、R 1b 、R 1c 、R 3 、R 5 , A, B, E and Hy are as defined above (especially for formula (I), (Ia), (II), (III), (IV), (V), (VI) and / or (VIII)) or below, and R 2 and R 4 Each is independently selected from H, -P(O)(OR 11a )2、-(CH2) 1-3 -R 19 、-C(=O)R 11a and -C(=O)OR 11a , provided that R 2 and R 4 Not all are H, among which R 11a Independently selected from H and C 1-6 Alkyl (preferably C 1-3 alkyl), wherein the alkyl is optionally substituted by one or two independently selected halogen radicals -OH, -OCH3, -SCH3, 2-(N,N-dimethylamino)ethoxy and -NH 2-z (CH3)z substituted by a substituent, wherein z is 0, 1 or 2; R 19 are independently selected from -OP(O)(OR 11a )2, -OC(=O)R 11a 、-OC(=O)OR 11a and 5-(C 1-3 alkyl)-2-oxo-1,3-dioxa-4-yl; and -(CH2) 1-3 - group is optionally substituted by one or two independently selected from halogen, -OH, -OCH3, -SCH3, 2-(N,N-dimethylamino)ethoxy and -NH 2-z (CH3) z wherein z is 0, 1 or 2.

[0310] For compounds of the present invention having any one of Formula (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (IXa), (IXb), (IXc) and (IXd) and having one or more hydroxyl groups (i.e., -OH), another particular prodrug form is one in which at least one of the two or more hydroxyl groups is derivatized to a group selected from -OP(O)(OR 11a )2、-O(CH2) 1-3 -R 19 、-OC(=X a )R 11a and -OC(=X a )X a R 11a A group in which R 11a R is 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., from 1 to the maximum number of hydrogen atoms bound to the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl group, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, e.g., 1 to 5, 1 to 4, or 1 to 3, or 1 or 2) independently selected R 30 Replacement; R 19 are independently selected from -OP(O)(OR 11a )2. -X a C(=X a )R 11a 、-X a C(=X a )X a R 11a and 5-alkyl-2-oxo-1,3-dioxolan-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 R 30 Substituted, where R 30 As defined herein (preferably, each R 30 In one embodiment of this prodrug form of the compound of the invention having the following characteristics, at least one derivatized hydroxyl group is selected from -OP(O)(OR 11a )2、-O(CH2) 1-3 -R 19 、-OC(=O)R 11a and-OC(O)OR 11a , where R 11a Independently selected from H and C 1-6 Alkyl (preferably C 1-3 alkyl), wherein the alkyl group may be optionally substituted by one or two independently selected from halogen, -OH, -OCH3, -SCH3, 2-(N,N-dimethylamino)ethoxy and -NH 2-z (CH3) z substituted by a substituent, wherein z is 0, 1 or 2; R 19 are independently selected from -OP(O)(OR 11a )2, -OC(=O)R 11a 、-OC(=O)OR 11a and 5-(C 1-3 alkyl)-2-oxo-1,3-dioxetane-4-yl; and -(CH2) 1-3 - group is optionally substituted by one or two independently selected from halogen, -OH, -OCH3, -SCH3, 2-(N,N-dimethylamino)ethoxy and -NH 2-z (CH3) z wherein z is 0, 1 or 2.

[0311] In certain embodiments, the present invention may be directed to a solvate, salt, N-oxide, complex, racemic mixture, diastereomer, enantiomer, tautomer, conformer, isotopically labeled form, or combinations thereof of a prodrug having Formula (IXa), (IXb), (IXc), or (IXd); for example, a solvate, salt, complex, racemic mixture, diastereomer, enantiomer, tautomer, conformer, isotopically labeled form, or combinations thereof of such a prodrug.

[0312] In a particular embodiment, the compound of the invention is a hydrate, suitably a monohydrate or dihydrate, or a solvate, a salt (especially a pharmaceutically acceptable salt), an N-oxide (especially R 1a and / or R 6 N-oxides), complexes, polymorphs, crystal forms, racemic mixtures, diastereomers, enantiomers, tautomers, conformers, isotopically labeled forms, prodrugs (especially of formula (IXa), (IXb), (IXc) or (IXd) and / or a prodrug having at least one derivatized hydroxyl group as described above, or solvates, salts, N-oxides, complexes, polymorphs, crystal 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 is a hemihydrate of such a kinase inhibitor.

[0313] In certain embodiments, the compounds of the present invention (e.g., as specified under the title "Compound") can be purified or (e.g., substantially) pure form (e.g., provided therewith). For example, the purity of the compound can be greater than about 50%, for example, greater than about 60%, 70% or 80%, suitably greater than about 90% (particularly greater than about 95%, 97% 98% or even 99%). That is, in certain such embodiments, such compounds are present with only a limited amount of impurities (e.g., such as those introduced during manufacture), for example, only a small amount of impurities are present, including embodiments in which the compound is present in a place where impurities are substantially absent. The purity of the compound (e.g., absence or presence of impurities) can be determined by conventional methods, for example, by HLPC.

[0314] In one embodiment, the invention provides a compound having an HPLC area of ​​less than about 50%, 40%, 30% and suitably 10% or 5%, preferably an HPLC area of ​​less than about 3% and 2%, more preferably a total impurity area of ​​less than 1% by HPLC. As used herein, the term "% area of ​​HPLC" refers to the area of ​​one or more peaks in the HPLC chromatogram as a percentage of the total area compared to the total area of ​​all peaks in the HPLC chromatogram. Additionally, the purity of a compound may be expressed herein as "HPLC" purity. Thus, "HPLC purity" is the calculated value of the area under the compound peak divided by the total area under the curve in the HPLC chromatogram. Suitably, by HPLC, the compound comprises a total impurity area of ​​less than about 10%. More preferably, the total impurity area of ​​HPLC is less than about 5%.

[0315] In a related aspect and as will be further described, defined, claimed or disclosed, the invention provides one or more containers, wherein the containers (each independently or all collectively) comprise a kinase inhibitor of the first aspect (e.g., a kinase inhibitor having the general formula (I), (Ia), (II), (III), (IV), (V), (VI), (VII) or (VIII), or a solvate, salt (particularly a pharmaceutically acceptable salt), N-oxide (particularly R 1a and / or R 6 or combinations thereof) of Formula (IXa), (IXb), (IXc) or (IXd) and / or a prodrug having at least one hydroxyl group derivatized as described above, solvates, salts, N-oxides, complexes, polymorphs, crystal forms, racemic mixtures, diastereomers, enantiomers, tautomers, conformers, isotopically labeled forms, or combinations thereof) in an amount greater than about 10 mg; in particular, in an amount greater than about 50 mg or 100 mg; suitably, in an amount greater than about 1 g, 10 g, 50 g or 100 g; or in an amount greater than about 500 g or 1 Kg.

[0316] In another aspect, the present invention provides compounds of the invention (particularly as described above with respect to formula (I), (Ia), (II), (III), (IV), (V), (VI), (VII) and (VIII)) for use as a medicament, e.g. for use in therapy. In one embodiment of this aspect, the compounds of the invention do not include compounds having formula (I) and belonging to one or more of groups (1), (2), (3), (4) and / or (5) as described above (e.g. group (1) (particularly when R 1a is 4-(2-hydroxyethyl)piperazin-1-yl), (2) and / or (4) (particularly the compounds 2-[(6-{[3-(1H-imidazol-1-yl)propyl]amino}pyridin-2-yl)amino]-4-methyl-N-[1-(phenylmethyl)-1H-indazol-5-yl]-1,3-thiazole-5-carboxamide and 2-[(6-{[3-(1H-imidazol-1-yl)propyl]amino}pyridin-2-yl)amino]-N-[1-(phenylmethyl)-1H-indazol-5-yl]-1,3-thiazole-5-carboxamide). In one embodiment of this aspect, the compounds of the present invention do not include compounds having formula (Ia) and belonging to group (6) as described above (for example, when R 1a When it is 4-(2-hydroxyethyl)piperazin-1-yl, it is one or more of the compounds of (7) and / or (8).

[0317] As is apparent from the examples, the inventors have discovered that the compounds of the present invention and other structurally similar compounds inhibit one or more protein tyrosine kinases selected from ABL1 / BCR-ABL, SRC, LCK, KIT, FLT3 and mutants thereof, and / or SIK1, SIK2, and SIK3, and / or PHA2, EPHA4, CSF-R1, HCK, and ACK1; and / or NEK11, WEE1, WNK2, Aurora-A, Aurora-B, and TBK1. In one embodiment, the compounds of the present invention exhibit pharmacological properties (selectivity, bioavailability, toxicity, side effects, dosage, patient compliance, compatibility, stability, half-life, etc.) that are superior to those exhibited by sartinib in at least one aspect.

[0318] Pharmaceutical composition

[0319] The compounds described in the present invention (particularly the compounds specified above, e.g., compounds of formula (I), (Ia), (II), (III), (IV), (V), (VI), (VII)) or (VIII), in particular compounds of Table A and / or Table B) are preferably administered to a patient in need thereof via a pharmaceutical composition. Thus, in a second aspect, the present invention provides a pharmaceutical composition comprising a kinase inhibitor as specified above under the heading "Compounds" (e.g., a kinase inhibitor having the general formula (I), (Ia), (II), (III), (IV), (V), (VI), (VII) or (VIII)) or a solvate, salt (particularly a pharmaceutically acceptable salt), N-oxide (particularly R 1a and / or R 6 N-oxides), complexes, polymorphs, crystalline forms, racemic mixtures, diastereomers, enantiomers, tautomers, conformers, isotopically labeled forms, prodrugs (in particular prodrugs of formula (IXa), (IXb), (IXc)) or (IXd) and / or having at least one derivatized hydroxyl group as described above, or solvates, salts, N-oxides, complexes, polymorphs, crystalline forms, racemic mixtures, diastereomers, enantiomers, tautomers, conformers, isotopically labeled forms or combinations thereof) or combinations thereof) and optionally one or more pharmaceutically acceptable excipients.

[0320] Thus, in one embodiment, the pharmaceutical composition comprises a kinase inhibitor as specified above under the heading "Compounds" and one or more pharmaceutically acceptable excipients. In addition, the pharmaceutical composition may further comprise one or more other therapeutic agents. Thus, in specific embodiments, the pharmaceutical composition comprises (i) a kinase inhibitor as specified above under the heading "Compounds" and one or more other therapeutic agents; or (ii) a kinase inhibitor as specified above under the heading "Compounds," one or more other therapeutic agents, and one or more pharmaceutically acceptable excipients.

[0321] The term "pharmaceutically acceptable" refers to non-toxic materials that do not interact with the (eg, therapeutic) action of the active ingredients of the pharmaceutical composition (eg, a kinase inhibitor of the invention, alone or in combination with one or more other therapeutic agents).

[0322] The pharmaceutical composition can be administered to a subject by any route, eg, enteral or parenteral.

[0323] As used herein, the expressions "enteral administration" and "administered enterally" refer to administration that is absorbed by the stomach and / or intestines. 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, typically by injection or topical administration, 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 administration (e.g., by injection and / or infusion) as well as topical administration (e.g., epidermal, inhalation, or through a mucous membrane (e.g., buccal, sublingual, or vaginal)).

[0324] The compounds of the present invention are generally administered in a "pharmaceutically acceptable amount" and in a "pharmaceutically acceptable formulation". Such compositions may contain salts, buffers, preservatives, carriers and, optionally, other therapeutic agents. "Pharmaceutically acceptable salts" include, for example, acid addition salts, which can be formed, for example, by mixing a solution of the compound with a solution of a pharmaceutically acceptable acid (e.g., hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid). In addition, where the compound has an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts (e.g., sodium or potassium salts); alkaline earth metal salts (e.g., calcium or magnesium salts); and salts formed with suitable organic ligands (e.g., ammonium salts, quaternary ammonium salts and amine cations, which are formed using counter anions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, alkyl sulfonates and aryl sulfonates).Illustrative examples of pharmaceutically acceptable salts include, but are not limited to, acetate, adipate, alginate, arginine, ascorbate, aspartate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium edetate, camphorate, camphorsulfonate, camphorsulfonic acid, carbonate, chloride, citrate, clavulanate, cyclopentanepropionate, digluconate, dihydrochloride, lauryl sulfate, edetate, edisylate, estolate, esylate, ethanesulfonate, formate, fumarate, galactate, galacturonate, gluceptate, glucoheptonate, gluconate, glutamate, glycerophosphate, e), α-glycolylarsanilate, hemisulfate, heptanoate, hexanoate, hexylisophthalate, ammonium hydrobromide, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, hydroxynaphthoate, iodide, isobutyrate, isothioate, lactate, ethyl lactobionate, laurate, lauryl sulfate, malate, maleate, malonate, mandelate, methanesulfonate, methylsulfonate, dimethyl sulfate, mucate, 2-naphthalenesulfonate , naphthoate, nicotinate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, pamoate (inner acid salt), palmitate, pantothenate, pectinate, persulfate, 3-phenylpropionate, phosphate / diphosphate, phthalate, picrate, pivalate, polygalacturonate, propionate, salicylate, stearate, sulfate, suberate, succinate, tannate, tartrate, teoclate, tosylate, triethyl iodide, undecanoate, valerate, and the like (see, e.g., Berge et al., "Pharmaceutical Salts", J. Pharm. Sci., 66, pp. 1-19 (1977)).

[0325] As used herein, the term "excipient" is intended to mean all substances in a pharmaceutical composition that are not active ingredients (e.g., therapeutically inert ingredients that do not exhibit any therapeutic effect in the amounts / concentrations used), such as carriers, binders, lubricants, thickeners, surfactants, preservatives, stabilizers, emulsifiers, buffers, flavorings, colorants, or antioxidants.

[0326] The compositions described in the present invention may include a pharmaceutically acceptable carrier. As used herein, "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, etc. that are physiologically compatible. A "pharmaceutically acceptable carrier" can be in the form of a solid, semisolid, liquid, or a combination thereof. Preferably, the carrier is suitable for enteral (e.g., oral) or parenteral administration (e.g., intravenous, intramuscular, subcutaneous, spinal or epidermal administration (e.g., by injection or infusion)). Depending on the route of administration, the active compound (e.g., a compound of the present invention) can be coated in a material alone or in combination with one or more other therapeutic agents to protect the one or more active compounds from the effects of acids and other natural conditions that may inactivate the active compound.

[0327] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions according to the present invention include water (e.g., water for injection), ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.), salts, carbohydrates, aqueous solutions of sugar alcohols or amino acids (e.g., saline solutions or aqueous solutions of amino acids), and suitable mixtures and / or buffered forms thereof, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate). For example, appropriate fluidity can be maintained by using coating materials such as lecithin, by maintaining the desired particle size in the case of dispersions, and by using surfactants.

[0328] Pharmaceutically acceptable carriers include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. 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 compound, they may be considered for use in the pharmaceutical compositions according to the present invention.

[0329] The additional therapeutic agent may be administered with, before or after, or incorporated into the composition with the compounds of the invention (particularly those specified above, e.g., Formula (I), (Ia), (II), (III), (IV), (V), (VI), (VII) or (VIII)). In one embodiment, the pharmaceutical compositions described herein comprise a kinase inhibitor of the invention (e.g., having the general formula (I), (Ia), (II), (III), (IV), (V), (VI), (VII) or (VIII) or a solvate, salt (particularly a pharmaceutically acceptable salt), N-oxide (particularly R 1a and / or R 6N-oxides), complexes, polymorphs, crystalline forms, racemic mixtures, diastereomers, enantiomers, tautomers, conformers, isotopically labeled forms, prodrugs (especially prodrugs of formula (IXa), (IXb), (IXc) or (IXd) and / or having at least one hydroxyl group derivatized as described above, or solvates, salts, N-oxides, complexes, polymorphs, crystalline forms, racemic mixtures, diastereomers, enantiomers, tautomers, conformers, isotopically labeled forms or combinations thereof) or combinations of any of the foregoing), at least one additional therapeutic agent and one or more pharmaceutically acceptable excipients.

[0330] The "additional therapeutic agent" (which in one embodiment is not a kinase inhibitor of formula (I) or (Ia) as specified herein, or in another embodiment may be formula (I) or (Ia)) may be selected from any compound that is useful for treating a disorder, disease or condition that is a proliferative disease (e.g., cancer, e.g., a disease described, defined or disclosed elsewhere herein) and / or is caused by or associated with: (i) (e.g., mis-) expression and / or activity of a kinase (e.g., SRC, ABL / BCR-ABL, LCK, SIK1, SIK2, SIK3, FLT3 and / or KIT; and / or PHA2, EPHA4, CSF-R1, HCK and ACK1; and / or NEK11, WEE1, WNK2, Aurora-A, Aurora-B and TBK1); and / or (ii) cellular resistance to a (e.g., cell-mediated) immune response. Examples of suitable additional therapeutic agents are defined or disclosed elsewhere herein and include: EGFR inhibitors, gemcitabine, docetaxel and immune checkpoint inhibitors (e.g., inhibitors of PD1, PDL1, CTLA-4, LAG3 or IDO1, particularly immune checkpoint inhibitors selected from nivolumab, relatlimab, ipilimumab and BMS-986205), TNF or TNFR1- or TNFR2 signaling agonists, adoptive cell therapy, including CAR T cells directed against tumor antigens, vaccines, including dendritic cell-based vaccines, or agents that, when administered to a subject, can induce or induce exposure of cells associated with a proliferative disease to a TNF or TNFR1 signaling agonist. The additional therapeutic agent can induce an additive or synergistic therapeutic effect.

[0331] The pharmaceutical compositions described herein may further comprise at least one, e.g., 1, 2, 3, 4, 5, 6, 7, or 8, other therapeutic agents in addition to the kinase inhibitor of the present invention. According to the present teachings, the at least one additional therapeutic agent may be formulated together with the kinase inhibitor of the present invention in a single pharmaceutical composition. Alternatively, the pharmaceutical composition may be configured as a kit of parts, wherein the kinase inhibitor of the present invention is provided in the form of a first formulation and the at least one other therapeutic agent is provided in the form of a second formulation (i.e., a second pharmaceutical composition). The first and second pharmaceutical compositions may be combined prior to use. In other words, prior to administration of the pharmaceutical composition, the formulation comprising the additional therapeutic agent may be added to the first pharmaceutical composition comprising the kinase inhibitor of the present invention. Alternatively, the present teachings contemplate administration of a kinase inhibitor of the present invention formulated in a first pharmaceutical composition and administration of at least one other therapeutic agent formulated in a second pharmaceutical composition. The pharmaceutical compositions may be administered simultaneously or sequentially. For example, a first pharmaceutical composition can be administered at a first time point and a second pharmaceutical composition can be administered at a second time point, where the time points can be separated, for example, by 0 or at most 1, 2, 3, 4, 5, or 10 minutes, at most 1, 2, 3, 4, 5, or 10 hours, at most 1, 2, 3, 4, 5, or 10 days, at most 1, 2, 3, 4, 5, or 10 weeks, at most 1, 2, 3, 4, 5, or 10 months, or at most 1, 2, 3, 4, 5, or 10 years.

[0332] The composition can also include adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers, pH buffers and dispersants. Can be ensured to prevent the presence of microorganisms by sterilization procedures and / or by comprising various antibacterial and antifungal agents (such as parabens, chlorobutanol, phenol sorbic acid etc.). It may also be necessary to include isotonic agents in the composition, such as sugar, sodium chloride etc. In addition, the absorption of the injectable drug form can be extended by comprising an agent that delays absorption, such as aluminum monostearate and gelatin.

[0333] Regardless of the route of administration selected, the active compounds that can be used in a suitable hydrated form and / or the pharmaceutical compositions according to the present invention can be formulated into pharmaceutically acceptable dosage forms by conventional methods known to those skilled in the art (see, for example, Remington, "The Science and Practice of Pharmacy" edited by Allen, Loyd V., Jr., 22nd edition, Pharmaceutical Sciences, September 2012; Ansel et al., "Pharmaceutical Dosage Forms and Drug Delivery Systems", 7th edition, Lippincott Williams & Wilkins Publishers, 1999).

[0334] Pharmaceutical compositions can be administered by a variety of methods known in the art. As will be appreciated by those skilled in the art, routes of administration and / or modes will vary depending on the desired results. Pharmaceutical compositions comprising one or more active compounds can be prepared with a carrier that protects the one or more active compounds from rapid release, such as controlled release formulations, including implants, transdermal patches, and microcapsule delivery systems. Biodegradable biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid can be used. Methods for preparing such compositions are generally known to those skilled in the art. See, for example, Sustained and Controlled Release Drug Delivery Systems, JR Robinson, ed., Marcel Dekker, Inc., New York, 1978.

[0335] In order to administer the compounds of the present invention by certain routes of administration, it may be necessary to coat the compound with a material that prevents its inactivation or to co-administer the compound. For example, the compound can be administered to an individual in the form of an appropriate carrier (e.g., liposomes) or diluent. Pharmaceutically acceptable diluents include saline and aqueous buffered solutions. Liposomes include water-in-oil-in-water CGF emulsions as well as conventional liposomes (Strejan et al., J. Neuroimmunol. 7:27 (1984)).

[0336] Pharmaceutical composition is usually sterile and stable under production and storage conditions. Composition can be formulated as solution, microemulsion, liposome or other ordered structures suitable for high drug concentration. Carrier can be solvent or dispersion medium, and it comprises for example water, ethanol, polyol (for example glycerol, propylene glycol and liquid polyethylene glycol etc.) and suitable mixture thereof. Can for example by using coating such as lecithin, by maintaining required particle size and by using surfactant to maintain suitable fluidity in the case of dispersion. In many cases, preferably include isotonic agent in composition, for example sugar, polyol, as mannitol, sorbitol or sodium chloride. By including the reagent of delayed absorption in composition, for example monostearate and gelatin, the extended absorption of injectable composition can be realized.

[0337] The composition for injection should be sterile and its fluidity should be such that it can be delivered by syringe. In addition to water, the carrier can be an isotonic buffered saline solution, ethanol, a polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, etc.) and a suitable mixture thereof. Sterile injection solutions can be prepared by mixing the required amount of the active compound with the required one or a combination of the above ingredients in an appropriate solvent and then sterilizing and microfiltration.

[0338] Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients as described above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze drying (lyophilization), which yield a powder of the active ingredient and any additional desired ingredient from a previously sterile-filtered solution thereof.

[0339] The dosage regimen is adjusted to provide the optimal desired response (e.g., a therapeutic response). For example, a single bolus can be administered, several separate doses can be administered over time, or the dose can be proportionally reduced or increased depending on the urgency of the therapeutic situation. It is particularly advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniform dosage. As used herein, dosage unit form refers to physically discrete units suitable as unit doses for individuals to be treated; each unit contains a predetermined amount of active compound that is calculated to produce the desired therapeutic effect together with the desired pharmaceutical carrier. The specifications of the dosage unit form used in accordance with the present invention are determined by and directly depend on the following factors: (a) the unique characteristics of the active compound and the specific therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such active compounds to treat individual sensitivities.

[0340] Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, etc.; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol, etc.; and (3) metal chelators, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, etc.

[0341] For therapeutic / pharmaceutical formulations, the compositions according to the present invention include components suitable for enteral administration (e.g., oral or rectal) or parenteral administration (e.g., nasal, topical (including vaginal, buccal, and sublingual)). The compositions may conveniently be presented in unit dosage form and may be prepared by any method known in the pharmaceutical art. The amount of active ingredient (particularly the amount of the compound of the invention) that may be combined with a carrier material to produce a pharmaceutical composition (e.g., a single dosage form) will vary depending on the individual being treated and the particular mode of administration. The amount of active ingredient that may be combined with a carrier material to produce a single dosage form will generally be that amount of the composition that produces a therapeutic effect.

[0342] Typically, out of 100% (for a pharmaceutical preparation / composition), the amount of active ingredient (in particular the amount of the compound of the present invention, optionally together with other therapeutically active agents (if present in the pharmaceutical preparation / composition)) ranges from about 0.01% to about 99%, preferably from about 0.1% to about 70%, most preferably from about 1% to about 30%, with the remainder preferably consisting of one or more pharmaceutically acceptable excipients.

[0343] The amount of active ingredient (e.g., a compound of the invention) in unit dosage form and / or when administered to an individual or for treatment can be in the range of about 0.1 mg to about 1000 mg per unit, administration, or treatment (e.g., about 1 mg to about 500 mg, such as about 10 mg to about 200 mg). In certain embodiments, the mass or body surface area of ​​an individual can be used to calculate a suitable amount of such active ingredient, including about 1 mg / kg to 10 mg / kg (e.g., about 2 mg / kg to 5 mg / kg), or about 1 mg / m 2 to about 400 mg / m 2 (e.g. about 3 mg / m 2 Up to about 350 mg / m 2 or about 10 mg / m 2 to about 200 mg / m 2 ).

[0344] Actual dosage levels of the active ingredients in the pharmaceutical compositions according to the present invention may be varied to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and regimen, without being toxic to the patient. The selected dosage level will depend upon a variety of pharmacokinetic factors, including the activity of the particular composition employed, the route of administration, the time of administration, the rate of excretion of the particular compound employed, the duration of the treatment, other drugs, compounds, and / or materials used in conjunction with the particular composition employed, the age, sex, weight, condition, general health, and previous medical history of the patient being treated, and similar factors well known in the medical arts.

[0345] A doctor or veterinarian with ordinary skills in the art can easily determine and prescribe (for example, in treatment) the desired pharmaceutical composition of effective dose. For example, a doctor or veterinarian can start with a dosage of the compound of the present invention lower than the level required for obtaining the desired therapeutic effect, and gradually increase the dosage until the desired effect is obtained. Generally, the suitable daily dose of the composition according to the present invention will be the amount of the compound of the lowest dose that effectively produces the therapeutic effect. Such an effective dose will generally depend on the above-mentioned factors. Preferably, it is administered orally, intravenously, intramuscularly, intraperitoneally or subcutaneously, preferably near the target site. If necessary, the (for example, in treatment) effective daily dose of the pharmaceutical composition can be administered all day with two, three, four, five, six or more sub-doses at appropriate intervals, optionally in unit dosage form. Although the compound according to the present invention can be administered alone, it is preferably administered in the form of a pharmaceutical preparation / composition.

[0346] For oral administration, the pharmaceutical composition according to the present invention can be taken in the form of tablets or capsules prepared for example by conventional methods with pharmaceutically acceptable excipients, wherein the excipient is, for example, a binding agent (for example pregelatinized corn starch, polyvinyl pyrrolidone, hydroxypropyl methylcellulose), a filler (for example lactose, microcrystalline cellulose, calcium hydrogen phosphate), a lubricant (for example magnesium stearate, talc, silicon dioxide), a disintegrant (for example potato starch, sodium starch glycolate) or a wetting agent (for example sodium lauryl sulfate). Liquid preparations for oral administration can be in the form of, for example, solutions, syrups or suspensions, or can exist in the form of dry products, to be prepared with water or other suitable excipients before use. Such liquid preparation can be prepared by conventional methods together with pharmaceutically acceptable additives, such as suspending agents (such as sorbitol, syrup, cellulose derivatives, hydrogenated edible fats), emulsifiers (such as lecithin, gum arabic), non-aqueous vehicles (such as almond oil, oily esters, ethanol, fractionated vegetable oils), preservatives (such as methyl p-hydroxycarbonate or propyl p-hydroxybenzoate, sorbic acid). Such preparations can also optionally include buffer salts, flavorings, coloring agents and sweeteners. Orally administered preparations can be suitably formulated to control the release of the pharmaceutical composition of the present invention.

[0347] In one embodiment, the compound is administered orally at a concentration of, e.g., up to 100 mg / kg body weight (e.g., up to 50 mg / kg body weight, up to 40 mg / kg body weight, up to 30 mg / kg body weight, up to 20 mg / kg body weight, up to 10 mg / kg body weight, up to 5 mg / kg body weight, up to 4 mg / kg body weight, up to 3 mg / kg body weight, up to 2 mg / kg body weight, up to 1 mg / kg body weight).

[0348] In one embodiment, the compound is administered parenterally (e.g., intravenously, intramuscularly, or subcutaneously), for example, at a concentration of up to 10 mg / kg body weight (e.g., up to 5 mg / kg body weight, up to 4 mg / kg body weight, up to 3 mg / kg body weight, up to 2 mg / kg body weight, up to 1 mg / kg body weight, up to 0.5 mg / kg body weight, up to 0.4 mg / kg body weight, up to 0.3 mg / kg body weight, up to 0.2 mg / kg body weight, up to 0.1 mg / kg body weight).

[0349] The pharmaceutical composition can be formulated into a suppository with traditional binders and carriers (e.g., triglycerides). Oral formulations can include standard carriers such as pharmaceutical grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like.

[0350] For administration by inhalation, the pharmaceutical compositions according to the invention are conveniently delivered in the form of an aerosol from a pressurized pack or nebulizer using a suitable propellant (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, nitrogen or other suitable gas). In the case of a pressurized aerosol, the metering unit and thus the dosage unit can be determined by providing a valve. Capsules and cartridges of, for example, gelatin for use in an inhaler or insufflator can be formulated containing a powder mix of the pharmaceutical composition according to the invention and a suitable powder base (e.g., lactose or starch).

[0351] The pharmaceutical composition according to the present invention can be configured to be used for by injection, for example, by push injection or continuous infusion for parenteral administration. In one embodiment, the compound of the present invention or composition can be administered by slow continuous infusion for a long time (for example, more than 24 hours), to reduce toxic side effects. Administration can also be carried out by continuous infusion 2 to 24 hours (for example, 2 to 12 hours). The scheme can be repeated once or many times as needed, for example, after 6 months or 12 months.

[0352] In another embodiment, the compounds or compositions according to the invention are administered by maintenance therapy, for example once a week for 6 months or longer.

[0353] Injections can exist in unit dosage form (e.g., in glass bottles, in multi-dose containers) with added preservatives. Pharmaceutical compositions according to the present invention can take the form of suspensions, solutions or emulsions such as in oily or aqueous vehicles, and can include preparatons, such as suspending agents, stabilizers or dispersants. Alternatively, the reagent can be in powder form so that it can be formulated with a suitable vehicle (e.g., sterile pyrogen-free water) before use. Typically, compositions for intravenous administration are solutions in sterile isotonic aqueous buffers. If necessary, the composition may also include a solubilizer and a local anesthetic, such as lidocaine, to alleviate pain at the injection site. Typically, the ingredients are provided separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or anhydrous concentrate, placed in a sealed container indicating the active agent content, such as an ampoule or a sachet. When the composition is to be administered by infusion, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline. Where the composition is administered by injection, an ampoule of sterile water for injection or saline can be provided so that the ingredients can be mixed prior to administration.

[0354] Compositions according to the present invention that are suitable for vaginal administration also include pessaries, tampons, emulsifiable pastes, gels, pastes, foams or sprays containing suitable carriers known in the art. Dosage forms for topical or transdermal administration of compositions according to the present invention include powders, sprays, ointments, pastes, emulsifiable pastes, lotions, gels, solutions, patches and inhalants. Active compound can be mixed with pharmaceutically acceptable carriers and any preservatives, buffers or propellants that may be needed under aseptic conditions.

[0355] The therapeutic / pharmaceutical compositions can be administered with medical devices known in the art. For example, in a preferred embodiment, the therapeutic / pharmaceutical compositions according to the present invention can be administered with a needle-free subcutaneous injection device, such as those disclosed in US 5,399,163, US 5,383,851, US 5,312,335, US 5,064,413, US 4,941,880, US 4,790,824, or US 4,596,556. Examples of well-known implants and modules that can be used in the present invention include those described in the following documents: US 4,487,603, which discloses an implantable microinfusion pump for dispensing drugs at a controlled rate; US 4,486,194, which discloses a therapeutic device for administering drugs through the skin; US 4,447,233, which discloses a drug infusion pump for delivering drugs at a precise infusion rate; US 4,447,224, which discloses a variable flow implantable infusion device for continuous drug delivery; US 4,439,196, which discloses an osmotic drug delivery system with multiple chamber compartments; and US 4,475,916, which discloses an osmotic drug delivery system.

[0356] Many other such implants, delivery systems and modules are known to those skilled in the art. In certain embodiments, the compound according to the present invention can be formulated to ensure appropriate distribution in vivo. For example, the blood-brain barrier (BBB) ​​excludes many highly hydrophilic compounds. In order to ensure that the compounds of the present invention pass through the BBB (if necessary), they can be formulated into, for example, liposomes. For methods of making liposomes, see, for example, US 4,522,811, US 5,374,548 and US 5,399,331. Liposomes can include one or more parts that are selectively transported to specific cells or organs, and therefore enhance targeted drug delivery (see, for example, VVRanade (1989) J.Clin.Pharmacol.29:685). Exemplary targeting moieties include folic acid or biotin (see, e.g., US 5,416,016 to Low et al.); mannosides (Umezawa et al., (1988) Biochem. Biophys. Res. Commun. 153: 1038); antibodies (PG Bloeman et al. (1995) FEBS Lett. 357: 140; M. Owais et al. (1995) Antimicrob. Agents Chemother. 39: 180); and surfactant protein A receptor (Briscoe et al. (1995) Am. J. Physiol. 1233: 134).

[0357] In one embodiment, the compounds according to the present invention are formulated into liposomes. In a more preferred embodiment, the liposomes include a targeting moiety. In a most preferred embodiment, the compound in the liposomes is delivered to a site proximate to the desired area by bolus injection. Such liposome-based compositions should have fluidity to the extent that they are easy to inject, should be stable under manufacturing and storage conditions, and should be preserved to resist the contaminating effects of microorganisms such as bacteria and fungi.

[0358] A "therapeutically effective dose" for a treatment / therapy can be measured by an objective response, which can be complete or partial. A complete response (CR) is defined as the absence of any clinical, radiographic, or other evidence of disease, disorder, or illness. A partial response (PR) is defined as a greater than 50% reduction in disease. The median time to progression is a measure of the durability of the objective tumor response.

[0359] The "therapeutically effective dose" of treatment / therapy can also be measured by its ability to stabilize disease, illness or disease progression. The ability of the compound to inhibit one or more protein kinases or reduce the viability of cells (such as cancer cells) associated with proliferative diseases can be assessed by using suitable in vitro assays known to skilled practitioners, such as those described herein (especially in the following "Examples"). Alternatively, the performance of the compound described in the present invention can be assessed by examining the ability of the compound in suitable animal model systems known to those skilled in the art (such as those described herein) (especially in the following "Examples"). A therapeutically effective amount of the compound according to the present invention can cure, heal, alleviate, slow down, change, remedy, improve, improve or affect the condition, illness or disease or the symptom of the condition, illness or disease or the susceptibility individual's condition, illness or disease. Those of ordinary skill in the art will be able to determine these amounts based on factors such as the size of the individual, the severity of the individual's symptoms, and the specific composition or route of administration selected.

[0360] If desired, the pharmaceutical compositions according to the present invention may also be provided in the form of a package or dispenser, which may contain one or more dosage forms (e.g., units) containing the active compound. The package may, for example, comprise metal or plastic foil, such as a blister pack. The package or dispenser device may be accompanied by a leaflet or other information; in particular, describing (to the patient and / or attending physician) important information or details about the pharmaceutical composition contained in the package, such as how to administer the drug, recommended dosage, safety and / or side effect information.

[0361] In one specific embodiment, the pharmaceutical compositions of the present invention are formulated for oral administration. In another specific embodiment, the pharmaceutical compositions of the present invention are formulated for intravenous administration.

[0362] In one embodiment, the pharmaceutical composition of the invention is in unit dosage form, and in particular may be in unit dosage form formulated for oral administration.

[0363] Each such unit dosage form may contain (for example, may contain) 1 to 950 mg of a compound, for example, a kinase inhibitor of the first aspect (for example, a kinase inhibitor having general formula (I), (Ia), (II), (III), (IV), (V), (VI), (VII) or (VIII), or a solvate salt (particularly a pharmaceutically acceptable salt), N-oxide (particularly R 1a and / or R 6

[0014] The present invention also provides a compound of formula (IXa), (IXb), (IXc) or (IXd) and / or a compound having at least one derivatized hydroxyl group as described above, or a solvate, salt, N-oxide, complex, polymorph, crystalline form, racemic mixture, diastereomer, enantiomer, tautomer, conformer, isotopically labeled form or combination thereof). In particular, (e.g. each) such unit dosage form may comprise (e.g. may contain) 2 to 150 mg of such compound; suitably, 10 to 150 mg of the compound.

[0364] In particular, in such embodiments, a pharmaceutical composition of the invention in unit dosage form (particularly a pharmaceutical composition in unit dosage form formulated for oral administration) may comprise (e.g., may contain) - for each unit dosage form - an amount of such compound approximately selected from the group consisting of: 2 mg, 5 mg, 15 mg, 20 mg, 50 mg, 70 mg, 80 mg, 100 mg and 140 mg; in particular, it comprises (e.g., contains) an amount of about 20 mg, 50 mg, 70 mg or 100 mg of a compound of the invention.

[0365] In a specific embodiment, the pharmaceutical composition of the invention is (e.g., formed into) a tablet, caplet, or capsule; suitably, the pharmaceutical composition of the invention (e.g., its unit dosage form) is a caplet. Methods of forming (e.g., manufacturing) tablets and caplets are, for example, described elsewhere herein.

[0366] Excipients suitable for use in the pharmaceutical compositions of the present invention, particularly when formulated in tablet or caplet form, include, and specific embodiments of such pharmaceutical compositions of the present invention include, those further comprising one or more (e.g., all) excipients selected from the group consisting of lactose (e.g., lactose monohydrate), microcrystalline cellulose, croscarmellose sodium, hydroxypropyl cellulose, and magnesium stearate.

[0367] Therapeutic and other applications

[0368] In a third aspect, the present application provides compounds as specified above under the heading "Compounds" or pharmaceutical compositions as specified above under the heading "Pharmaceutical Compositions" for use as medicaments, e.g., for use in therapy. In one embodiment of these aspects, the compounds of the invention do not include compounds as specified above under the heading "Compounds" having formula (I) and belonging to one or more of groups (1), (2), (3), (4) and / or (5) (e.g., group (1) (particularly when R 1a is 4-(2-hydroxyethyl)piperazin-1-yl), (2) and / or (4) (particularly the compounds 2-[(6-{[3-(1H-imidazol-1-yl)propyl]amino}pyridin-2-yl)amino]-4-methyl-N-[1-(phenylmethyl)-1H-indazol-5-yl]-1,3-thiazole-5-carboxamide and 2-[(6-{[3-(1H-imidazol-1-yl)propyl]amino}pyridin-2-yl)amino]-N-[1-(phenylmethyl)-1H-indazol-5-yl]-1,3-thiazole-5-carboxamide). In one embodiment of these aspects, the compounds of the invention do not include compounds of formula (Ia) as specified above under the heading "Compounds" and belonging to group (6) (e.g., particularly compounds). When (i) R 1a wherein the compound is a 4-(2-hydroxyethyl)piperazin-1-yl group, and one or more compounds of group (6) (7) and / or (8).

[0369] It is contemplated that the compounds described above under the heading "Compounds" may be used to inhibit: (i) kinases, such as the kinases described herein, particularly SRC, ABL, BCR-ABL, LCK, SIK1, SIK2, SIK3, FLT3 and / or KIT and / or PHA2, EPHA4, CSF-R1, HCK and ACK1 and / or NEK11, WEE1, WNK2, Aurora-A, Aurora-B and TBK1; and / or (ii) cellular resistance to (e.g., cell-mediated) immune responses. For example, the compounds may be used in a method of treating a disease, disorder or condition in a subject, particularly a human patient, wherein the disease or condition is associated with such a kinase.

[0370] The compounds of the present invention may be used alone or in combination with one or more other therapeutic agents, for example, in combination with a therapeutic agent as defined or disclosed elsewhere herein, including EGFR inhibitors, gemcitabine, docetaxel, immune checkpoint inhibitors (e.g., inhibitors of PD1, PDLL, CTLA-4, LAG3 or IDO1, in particular immune checkpoint inhibitors selected from nivolumab, relatlimab, ipilimumab and BMS-986205), TNF or TNFR1 or TNFR2 signaling agonists, adoptive cell therapy (including CAR T cells against tumor antigens), vaccines (including dendritic cell (DC)-based vaccination) or agents that, when administered to a subject, are capable of inducing or induce exposure of cells associated with a proliferative disease to a TNF or TNFR1 signaling agonist.

[0371] Treatments that include or use these compounds can be provided at home, in a doctor's office, at a clinic, in an outpatient department of a hospital, or in a hospital. Treatment is usually started under medical supervision so that medical staff can closely observe the effects of treatment and make necessary adjustments. The duration of treatment depends on the patient's age and condition, as well as how the patient responds to treatment.

[0372] People who are at increased risk for developing a disease, condition, or illness may receive preventive treatment to suppress or delay the symptoms of that disease, condition, or illness.

[0373] The term "treatment" is known to those skilled in the art and includes the application or administration of a therapeutic agent (e.g., a pharmaceutical composition comprising such an agent) to a patient or the treatment or application or administration of a therapy (e.g., a pharmaceutical composition comprising such an agent) to a patient or the procedure of isolating cells, cell cultures, cell lines, samples, tissues or organs from a patient suffering from a disease, condition or symptom of a disease or susceptibility to a disease, condition or disease, for the purpose of curing, healing, alleviating, mitigating, altering, remedying, improving, modifying, affecting or preventing the symptoms of the disease, condition or symptom or susceptibility to the disease, condition or disease. Thus, the term "treatment" can include prophylactic treatment of a disease, condition or disease or a symptom of a disease, condition or disease. When used in therapy, therapeutic agents include the kinase inhibitors of the present invention and include, but are not limited to, other therapeutic agents, which can be small molecules, peptides, peptidomimetics, polypeptides / proteins, antibodies, nucleotides (e.g., DNA or RNA), cells, viruses, ribozymes, siRNA and antisense oligonucleotides.

[0374] Thus, in a fourth aspect, and as may be further described, defined, claimed or otherwise disclosed herein, the present invention relates to compounds specified under the heading "Compounds" (e.g., having the general formula (I), (Ia), (II), (III), (IV), (V), (VI), (VII) or (VIII) or solvate salts (particularly pharmaceutically acceptable salts), N-oxides (particularly R 1a and / or R 6 N-oxides), complexes, polymorphs, crystal forms, racemic mixtures, diastereomers, enantiomers, tautomers, conformers, isotopically labeled forms, prodrugs (particularly having formula (IXa), (IXb), (IXc) or (IXd) and / or having at least one derivatized hydroxyl group as described above, or solvates, salts, N-oxides, complexes, polymorphs, crystal forms, racemic mixtures, diastereomers, enantiomers, tautomers, conformers, isotopically labeled forms or combinations thereof) or combinations thereof) for treating a proliferative disease in a subject.

[0375] In another fourth aspect, and as may be further described, defined, claimed or otherwise disclosed herein, the present invention relates to a pharmaceutical composition as described above (e.g., a pharmaceutical composition comprising a compound specified in the heading "Compounds" (e.g., having the general formula (I), (Ia), (II), (III), (IV), (V), (VI), (VII) or (VIII) or a solvate salt (particularly a pharmaceutically acceptable salt), N-oxide (particularly R 1a and / or R 6 N-oxides), complexes, polymorphs, crystal forms, racemic mixtures, diastereomers, enantiomers, tautomers, conformers, isotopically labeled forms, prodrugs (particularly having formula (IXa), (IXb), (IXc) or (IXd) and / or having at least one derivatized hydroxyl group as described above, or solvates, salts, N-oxides, complexes, polymorphs, crystal forms, racemic mixtures, diastereomers, enantiomers, tautomers, conformers, isotopically labeled forms or combinations thereof) or combinations thereof) for treating a proliferative disease in a subject.

[0376] In a related fourth aspect, and as may be further described, defined, claimed or otherwise disclosed herein, the present invention relates to a method for treating a proliferative disease in a subject, the method comprising administering to the subject (e.g., a therapeutically effective amount of): (X) a compound specified under the heading "Compound" (e.g., having the general formula (I), (Ia), (II), (III), (IV), (V), (VI), (VII) or (VIII) or a solvate salt (particularly a pharmaceutically acceptable salt), N-oxide (particularly R 1a and / or R 6 N-oxides), complexes, polymorphs, crystalline forms, racemic mixtures, diastereomers, enantiomers, tautomers, conformers, isotopically labeled forms, prodrugs (particularly having formula (IXa), (IXb), (IXc) or (IXd) and / or having at least one hydroxyl group derivatized as described above, or solvates, salts, N-oxides, complexes, polymorphs, crystalline forms, racemic mixtures, diastereomers, enantiomers, tautomers, conformers, isotopically labeled forms or combinations thereof) or combinations thereof); or (Y) a pharmaceutical composition as described above (e.g., a pharmaceutical composition comprising a compound designated under the heading "Compound" (e.g., having formula (I), (Ia), (II), (III), (IV), (V), (VI), (VII) or (VIII) or a solvate salt (particularly a pharmaceutically acceptable salt), N-oxide (particularly R 1a and / or R 6 N-oxides thereof), complexes, polymorphs, crystalline forms, racemic mixtures, diastereomers, enantiomers, tautomers, conformers, isotopically labeled forms, prodrugs (in particular having formula (IXa), (IXb), (IXc) or (IXd) and / or having at least one derivatized hydroxyl group as described above, or solvates, salts, N-oxides, complexes, polymorphs, crystalline forms, racemic mixtures, diastereomers, enantiomers, tautomers, conformers, isotopically labeled forms or combinations thereof) or combinations thereof).

[0377] In another related fourth aspect, and as may be further described, defined, claimed or otherwise disclosed herein, the present invention relates to compounds designated under the heading "Compounds" (e.g., having the general formula (I), (Ia), (II), (III), (IV), (V), (VI), (VII) or (VIII) or solvate salts (particularly pharmaceutically acceptable salts), N-oxides (particularly R 1a and / or R 6N-oxides), complexes, polymorphs, crystalline forms, racemic mixtures, diastereomers, enantiomers, tautomers, conformers, isotopically labeled forms, prodrugs (particularly having formula (IXa), (IXb), (IXc) or (IXd) and / or having at least one derivatized hydroxyl group as described above, or solvates, salts, N-oxides, complexes, polymorphs, crystalline forms, racemic mixtures, diastereomers, enantiomers, tautomers, conformers, isotopically labeled forms or combinations thereof) or combinations thereof), for the preparation of a medicament for treating a proliferative disease in a subject.

[0378] In such fourth aspect, the treatment of the use or method comprises administering to the subject (eg, a therapeutically effective amount) a compound or pharmaceutical composition of the invention.

[0379] In a specific embodiment of this aspect, the subject is a human, suitably an adult human. For example, a human aged 18 (or 16) or older, such as a human aged between 18 (or 16) and 90, or between 18 (or 16) and 80. In certain such embodiments, the adult is about 20 years of age or older, 30 years of age or older, 35 years of age or older, 40 years of age or older, 45 years of age or older, 50 years of age or older, or 55 years of age or older. In more specific embodiments of such embodiments, the adult is a young person (e.g., about 18 (or 16) to 45 (or 40), or about 30 to 45 (or 40) years old), a middle-aged person (e.g., about 45 (or 40) to 65 (or 60), or about 45 (or 40) to 55 (or 50), or about 55 (or 50) to 65 (or 60) years old), or an elderly person (e.g., about 60 to 90 (or older, such as 92, 95 or 98), about 65 to 85 to about 70 to 88).

[0380] As an alternative to such embodiments, the subject being treated is a pediatric patient, e.g., a patient younger than about 18 years (or 16 years). For example, such a human can be between about 3 and 18 (or 16), e.g., between about 5 and 16, or between about 10 and 16, or between 12 and 17. A pediatric human can be an infant (e.g., between about two months and about 2 years), a toddler (e.g., between about 2 years and about 4 years), a toddler (e.g., between about 4 years and about 9 years), a prepubertal patient (e.g., between about 9 years and about 12 or 13 years (or 11 or 14 years), or an adolescent (e.g., between about 12 or 13 years (or 11 or 14 years) and 15 years (or 16 or 17 years)).

[0381] In one embodiment of this aspect, the treatment comprises administering less than about 140 mg of a compound of the invention (e.g., contained in a pharmaceutical composition) per day to an adult subject in need thereof. For example, optionally, where the proliferative disease is not (e.g., the subject suffers from) chronic stage Ph+ CML. In an alternative embodiment of this aspect, the treatment comprises administering to an adult human subject in need thereof an amount of greater than about 140 mg per day (e.g., greater than 150 mg per day) of such a compound (e.g., contained in a pharmaceutical composition).

[0382] In another embodiment of this aspect, the treatment comprises administering less than about 100 mg of a compound of the invention (e.g., contained in a pharmaceutical composition) per day to an adult subject in need thereof. For example, optionally, in the case where the proliferative disease is not chronic stage Ph+ CML (e.g., which the subject suffers from). In an alternative embodiment of this aspect, the treatment comprises administering to an adult human subject in need thereof an amount of greater than about 100 mg per day (e.g., greater than 120 mg per day) of such a compound (e.g., contained in a pharmaceutical composition).

[0383] In an alternative embodiment, the treatment comprises administering to a pediatric human subject in need thereof an amount of a compound of the invention:

[0384] For pediatric patients weighing between 10 kg and 20 kg, less than 40 mg per day;

[0385] For pediatric patients weighing between 20 kg and 30 kg, less than 60 mg per day;

[0386] Less than 70 mg daily for pediatric patients weighing 30 kg to 45 kg; or

[0387] For pediatric patients weighing at least 45 kg, less than about 100 mg per day.

[0388] In another alternative embodiment, the treatment comprises administering to a pediatric human subject in need thereof an amount of a compound of the invention:

[0389] For pediatric patients weighing 10 kg to 20 kg, greater than approximately 40 mg per day;

[0390] For pediatric patients weighing 20 kg to 30 kg, greater than approximately 60 mg per day;

[0391] Greater than about 70 mg per day for pediatric patients weighing 30 kg to 45 kg; or

[0392] For pediatric patients weighing at least 45 kg, greater than about 100 mg per day.

[0393] For embodiments in which a certain amount of such a compound (e.g., to be administered) is administered to a human subject, the amount may be administered less frequently than daily. For example, a given amount "less than 40 mg per day" may be achieved by, for example, 35, 30, or 20 mg per day, or 75, 65, or 40 mg once every two days (or less frequently).

[0394] In a specific embodiment, upon (or following) administration of such (eg, therapeutically effective amount) compound of the invention, the subject is less likely to (eg, does not) develop (or suffer) an adverse effect, such as myelosuppression.

[0395] In one such specific embodiment, upon (or following) administration of such (e.g., therapeutically effective amount) compound of the invention, the subject is unlikely (e.g., does not) develop (or suffer) a non-hematologic adverse reaction, such as a cardiologic adverse reaction.

[0396] More specifically in such embodiments, upon (or after) administering a (eg, therapeutically effective) amount of the compound to a subject, the subject is unlikely (eg, does not) develop (or suffer) QT prolongation.

[0397] In one embodiment, the subject is characterized by not concurrently taking a strong CYP3A4 inhibitor, such as ketoconazole, itraconazole, erythromycin, clarithromycin, ritonavir, telithromycin, or consuming grapefruit juice.

[0398] In certain embodiments, in the context of the invention described herein, the disease, disorder or condition is a proliferative disease (including conditions or symptoms associated with such disorders).

[0399] "Proliferative disease" refers to a disease characterized by abnormal proliferation of cells. Proliferative disease does not mean any restriction on cell growth rate, but only represents the loss of normal controls that affect growth and cell division. Therefore, in some embodiments, the cells of the proliferative disease can have the same cell division rate as normal cells, but do not respond to signals that limit this growth. Within the scope of "proliferative disease" are tumors or tumors, which are abnormal growths of tissues or cells. Cancer is known in the art and includes any of the various malignant tumors characterized by cell proliferation, which have the ability to invade surrounding tissues and / or metastasize to new colonization sites. Proliferative diseases include cancer, atherosclerosis, rheumatoid arthritis, idiopathic pulmonary fibrosis and cirrhosis. Non-cancerous proliferative diseases also include excessive proliferation of skin cells, such as psoriasis and its various clinical forms, Reiter's syndrome, pityriasis erythematosus, hyperproliferative variants of keratinization disorders (such as actinic keratosis, senile keratosis), scleroderma, etc.

[0400] In more specific embodiments, the proliferative disease is a cancer or tumor, particularly a solid tumor (including conditions or symptoms associated with such a cancer or tumor). Such proliferative diseases include, but are not limited to, head and neck cancer, squamous cell carcinoma, multiple myeloma, solitary plasmacytoma, renal cell carcinoma, retinoblastoma, germ cell tumors, hepatoblastoma, hepatocellular carcinoma, melanoma, rhabdomyosarcoma of the kidney, Ewing's sarcoma, chondrosarcoma, any hematological malignancy (e.g., chronic lymphocytic leukemia, chronic myelomonocytic leukemia, acute lymphoblastic leukemia, acute lymphocytic leukemia, acute myeloid leukemia, acute myeloblastic leukemia, chronic myeloid leukemia, Hodgkin's disease, non-Hodgkin's leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, myelodysplastic syndrome, hairy cell leukemia, mast cell leukemia, mast cell tumors, follicular lymphoma , diffuse large cell lymphoma, mantle cell lymphoma, marginal zone lymphoma, Burkitt lymphoma, mycoses, mitotic syndromes, cutaneous T-cell lymphoma, peripheral T-cell lymphoma, chronic myeloproliferative disorders, granulomatous osteomyelitis, myeloid metaplasia, systemic mastocytosis) and central nervous system tumors (e.g., brain cancer, glioblastoma, non-glioblastic brain cancer, meningioma, pituitary adenoma, vestibular schwannoma, primitive neuroectodermal tumor, medulloblastoma, astrocytoma, mesenchymal astrocytoma, oligodendroglioma, ependymoma, and choroid plexus papilloma), myeloproliferative disorders (e.g., polycythemia vera, thrombocythemia, idiopathic myelofibrosis), soft tissue sarcoma, thyroid cancer, endometrial cancer, carcinoid tumor, or liver cancer.

[0401] In a specific embodiment, various aspects of the present invention relate (e.g., to the compounds or pharmaceutical compositions of the present invention) to the treatment of a proliferative disease, including those described herein. Thus, in such embodiments, the proliferative disease may be a cancer or tumor.

[0402] In a specific embodiment, the cancer is a hematopoietic or lymphoid cancer, and in one such embodiment, the proliferative disorder is (e.g., the subject has or is suspected of having) a Philadelphia chromosome-positive leukemia; e.g., Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL).

[0403] In certain embodiments, the proliferative disease is (eg, the subject (eg, an adult human subject) has or is suspected of having)

[0404] Newly diagnosed with chronic phase (Ph+ CML);

[0405] Chronic, accelerated, or blastic CML that is resistant or intolerant to prior therapy including imatinib (e.g., imatinib mesylate); or

[0406] Ph+ acute lymphoblastic leukemia (ALL) and lymphoblastic CML that are resistant or intolerant to previous therapy.

[0407] In another specific embodiment, the subject is a pediatric human and the proliferative disease is (eg, the subject has or is suspected of having):

[0408] Newly diagnosed chronic phase Ph+ CML (Ph+ CML-CP) or Ph+ CML-CP that is resistant or resistant to previous therapy (including imatinib).

[0409] In another specific embodiment, the cancer is a solid tumor, and in one such embodiment, the proliferative disease is (e.g., the subject suffers from or is suspected of having) a solid tumor of one of the solid tumors described elsewhere herein, such as pancreatic cancer, breast cancer, lung cancer, prostate cancer, melanoma, ovarian cancer, esophageal cancer, sarcoma, and colorectal cancer. In some such embodiments, the proliferative disease is (e.g., the subject suffers from or is suspected of having) pancreatic cancer; in another such embodiment, the proliferative disease is (e.g., the subject suffers from or is suspected of having) prostate cancer; in another such embodiment, the proliferative disease is (e.g., the subject suffers from or is suspected of having) lung cancer (e.g., non-small cell lung cancer).

[0410] As described elsewhere, the compounds (or pharmaceutical compositions) of the present invention can be administered to a subject (e.g., as a combination therapy or regimen) with another medical procedure (e.g., an additional therapeutic agent, such as surgery or radiation therapy as described elsewhere herein). Such combination therapy regimens can then include embodiments in which such exposure / administration occurs simultaneously. In alternative embodiments, such administration can be sequential; particularly in those embodiments in which the compounds (or pharmaceutical compositions) of the present invention are administered prior to such other procedures. For example, the compounds (or pharmaceutical compositions) can be administered sequentially within about 14 days of (e.g., prior to) the other procedure, such as within about 10 days, 7 days, 5 days, 2 days, or 1 day of (e.g., prior to) the other procedure; and further including those in which the compounds (or pharmaceutical compositions) can be administered sequentially within about 48 hours, 24 hours, 12 hours, 8 hours, 6 hours, 4 hours, 2 hours, 1 hour, 30 minutes, 15 minutes, or 5 minutes of (e.g., prior to) the other procedure.

[0411] Such a combination treatment regimen may comprise (e.g., further) administering to the subject:

[0412] EGFR inhibitors and / or gemcitabine—particularly when the proliferative disease is (eg, the subject has or is suspected of having) pancreatic cancer;

[0413] Docetaxel—particularly when the proliferative disorder is (eg, the subject has or is suspected of having) prostate cancer; and / or

[0414] • Immune checkpoint inhibitors—particularly when the proliferative disease is (eg, the subject has or is suspected of having) lung cancer (eg, non-small cell lung cancer).

[0415] Exemplary immune checkpoint inhibitors that may comprise such combination therapies or regimens are described elsewhere and include antibodies or small molecule inhibitors of PD1, PDL1, CTLA-4, LAG3, or IDO1, particularly such immune checkpoint inhibitors can be selected from the list consisting of nivolumab, relatlimab, ipilimumab, and BMS-986205, particularly nivolumab.

[0416] In other embodiments, the combination regimen may comprise (e.g., further) administering to the subject:

[0417] immune activator (e.g., agonist) antibodies, such as antibodies to OX40 (e.g., Yang et al 2012, Blood 120:4533), 41BB, CD40, or ICOS (e.g., Deng et al 2004, Hybrid Hybridomics 23:176), particularly to increase TNF levels by stimulating / stimulating T cells; and / or

[0418] Dendritic cell (DC)-based vaccination (e.g., Lowe et al 2014, Oncoimmunology 3:e27589).

[0419] In a particular embodiment, the proliferative disease (e.g., in a subject) has progressed under (e.g., despite) standard therapy, or in another embodiment, the subject may be unable to receive standard therapy, e.g., because the subject is intolerant to it. In any such embodiment, the subject can be characterized (e.g., stratified) as having progressed under standard therapy or being unable to receive (e.g., intolerant to) standard therapy.

[0420] Examples of standard therapies include imatinib (e.g., for CML or ALL), docetaxel (e.g., for prostate cancer), or immunotherapies such as the immune checkpoint inhibitors described as ehrein (e.g., for melanoma or lung cancer).

[0421] Sensitization to immune responses and kinase inhibition

[0422] The compounds of the present invention can sensitize cells associated with proliferative diseases to a cell-mediated immune response.

[0423] Thus, in one embodiment, a treatment comprising administering to a subject a compound (or pharmaceutical composition) of the invention involves (eg, mediates or supports) sensitizing cells associated with a proliferative disorder to a cell-mediated immune response.

[0424] In an alternative embodiment, the treatment comprising administering to a subject a compound (or pharmaceutical composition) of the invention involves (eg, mediated or supported by) inhibition of a kinase involved in resistance to a cell-mediated immune response (eg, inhibition of SIK3).

[0425] In a related embodiment, the treatment comprising administering a compound (or pharmaceutical composition) of the invention to a subject involves (e.g., mediated or supported by) inhibition of a kinase involved in resistance to a cell-mediated immune response (e.g., inhibition of SIK3) and (e.g., thereby) sensitizing cells associated with a proliferative disease to a cell-mediated immune response.

[0426] In another aspect, and as may be further described, defined, claimed, or otherwise disclosed herein, the present invention relates to a method for sensitizing cells associated with a proliferative disease to a cell-mediated immune response in the treatment of a proliferative disease in a subject, the method comprising administering to the subject a compound (or pharmaceutical composition) of the present invention; in another aspect, and as may be further described, defined, claimed, or otherwise disclosed herein, the present invention relates to a method for inhibiting a kinase associated with resistance to (e.g., inhibition of) a cell-mediated immune response in the treatment of a proliferative disease in a subject, the method comprising administering to the subject a compound (or pharmaceutical composition) of the present invention.

[0427] In a related further aspect, and as may be further described, defined, claimed or otherwise disclosed herein, the present invention relates to a compound of the invention (or pharmaceutical composition) for use as a medicament for: (i) sensitizing cells associated with a proliferative disease of a cell-mediated immune response; and / or (ii) inhibiting a kinase involved in resistance to a cell-mediated immune response, such as inhibiting SIK.

[0428] In yet another related further aspect, and as may be further described, defined, claimed or otherwise disclosed herein, the present invention relates to compounds of the present invention (or pharmaceutical compositions) for use as drugs (e.g., immuno-oncology drugs), which sensitize cells associated with proliferative diseases (e.g., tumors or cancers) to cell-mediated immune responses, such as sensitizing cells associated with proliferative diseases to killing (cell death) that may be induced by a cell-mediated immune response. "Immuno-oncology" drugs are drugs that one of ordinary skill in the art would recognize, and include one or more components of the immune system that are intended to (e.g., specifically designed for) enhance the ability of an organism (e.g., a human) to resist cancer cells or tumor cells present in the organism. Immuno-oncology drugs can be drugs (e.g., antibodies) that are combined with external immune (inhibitory) checkpoint molecules (e.g., as described elsewhere herein) and (e.g., directly) inhibit T cell function against cancer cells or tumor cells, or immuno-oncology drugs can be drugs that inhibit immunomodulators inherent to cancer cells or tumor cells (e.g., SIK3 in the present invention), wherein such intrinsic immunomodulators cannot actively (e.g., directly) inhibit T cells, but rather protect tumors or cancer cells from immune responses through resistance mechanisms.

[0429] In certain embodiments of these aspects, cells associated with a proliferative disease can be susceptible to killing (cell death) by (eg, induced by) a cell-mediated immune response.

[0430] "Salt-inducible kinase 3" or "SIK3" (synonyms QSK and KIAA0999) is a member of the serine / threonine protein kinase subfamily, including SIK1, SIK2 and SIK3, which belong to the AMP-activated protein kinase (AMPK) family. In the context of the present invention, a SIK3 protein is typically a protein kinase. Relevant information about human SIK3 protein is available at UniProt: Q9Y2K2 (entry version 138, March 15, 2017), and in the context of the present invention, the SIK3 protein preferably has the amino acid sequence shown in entry version 138 of SIK3, March 15, 2017, or entry version 144, March 28, 2018, which sequences are incorporated herein by reference. SIK3 is a cytoplasmic protein with serine / threonine kinase activity that is regulated by phosphorylation of a conserved threonine residue (position 163) in the T-loop of the kinase domain by the LKB1 complex. It is reported that phosphorylation is essential for SIK3 catalytic activity (Lizcano, JM et al.; EMBO J. 23, 833–843 (2004)). For the purposes of the invention disclosed herein, the term “phosphorylated SIK3” shall mean a substantially phosphorylated SIK3 protein, since the SIK3 protein can be phosphorylated by (e.g., by) LKB1, wherein preferably, such phosphorylated SIK3 comprises phosphothreonine at amino acid position 163. In the context of the present invention, phosphorylated SIK3 is a SIK3 protein that is activated in its cell biological environment. At least four protein isoforms (SIK3-001 to SIK3-004) produced by alternative splicing of the SIK3 gene product are known. The human SIK3 gene is located at chromosome position 11q23.3 (HGNC gene Symbol Acc: HGNC: 29165) and is conserved in many species, such as chimpanzees, rhesus monkeys, dogs, cows, mice, rats, chickens, zebrafish, and frogs. In some embodiments of the invention, the term SIK3 may also relate to a variant of a human SIK3 protein having an amino acid sequence that is substantially identical or at least 80%, preferably 85%, more preferably 90, 95, 96, 97, 98, 99 or 100% identical to the amino acid sequence of the above-mentioned SIK3, as determined using, for example, the "Blast 2 sequence" algorithm described by Tatusova & Madden 1999 (FEMS Microbiol Lett 174:247-250), and which (preferably) retains the same or substantially the same biological activity as the corresponding reference SIK3 (e.g., phosphorylating one or more class II (e.g., IIa) HDACs, such as HDAC4).Preferred variants of SIK3 protein include sequence variants thereof, which are due to sequence polymorphisms between and among populations of various species, and mutations (T loops) SIK3 located in or immediately adjacent to the active loop or activation loop compared to the wild-type sequence of SIK3. A preferred variant of SIK3 protein is a SIK3 T163 mutation, such as a mutation that affects SIK3 activation. In a preferred embodiment, the SIK3 protein of the present invention is not a SIK1 (synonymous: SIK and SNF1LK) protein and / or is not a SIK2 (synonymous: QIK, KIAA0781, and SNF1LK2) protein. The amino acid sequences of human SIK1 (UniProt: P57059; entry version 168 of March 15, 2017) and human SIK2 (UniProt: Q9H0K1; entry version 153 of March 15, 2017) are incorporated herein by reference. As applicable to the context (if not more specifically indicated), the term SIK3 may refer to a SIK3 protein (eg, one of the above) or an mRNA molecule encoding such a SIK3 protein. Similar meanings should be understood with respect to "SIK1" and "SIK2."

[0431] A compound that is an "inhibitor of SIK3" (or "SIK3 inhibitor") is one that inhibits any portion of SIK3, which may mean inhibiting the activity of SIK3, particularly the SIK3 protein, particularly the activity of phosphorylated SIK3. A SIK3 inhibitor may impair (e.g., induce or reduce) the efficiency, potency, amount, or rate of one or more activities of SIK3, such as one or more of the activities described herein, for example, the activity of SIK3 to phosphorylate a class II (e.g., IIa) HDAC (e.g., HDAC4) and / or sensitize cells associated with a proliferative disease to a cell-mediated immune response.

[0432] Such SIK3-inhibiting moieties can act directly, e.g., by binding to SIK3 and reducing the amount or rate of one or more properties of SIK3 (e.g., its function, particularly its ability to act as a kinase) (e.g., phosphorylating HDAC4), e.g., by reducing the activity of phosphorylated SIK3 in a cell.

[0433] Compounds that are SIK3 inhibitors are described elsewhere herein and include those that can be characterized by applicable functional and / or structural features listed herein.

[0434] In preferred embodiments, in particular, "subject" is also meant to include all mammals, including but not limited to humans, but also non-human primates, such as cynomolgus monkeys. It also includes dogs, cats, horses, sheep, goats, cows, rabbits, pigs, and rodents (such as mice and rats). It will be understood that particularly preferred subjects according to the present invention are human subjects, e.g., humans having a condition, disease, or illness (or humans at risk of having a condition, disease, or illness), e.g., human patients.

[0435] As used herein, "therapy" is synonymous with treating a disease, disorder or condition, which includes alleviating the symptoms of the disease, disorder or condition, inhibiting the progression of the disease, disorder or condition, causing regression of the disease, disorder or condition, and / or curing the disease, disorder or condition.

[0436] In a preferred embodiment, the "treatment" of the present invention particularly also includes, for example, therapy (e.g., therapeutic treatment) and prevention or inhibition of the disease (or disorder or condition). Thus, for example, successful administration of the compound of the present invention (or pharmaceutical composition) before the onset of the disease can result in the treatment of the disease. "Treatment" also encompasses administering the compound of the present invention (or pharmaceutical composition) after the onset of the disease to improve or eradicate the disease (or its symptoms). Administering the compound of the present invention (or pharmaceutical composition) after onset and after clinical symptoms may alleviate clinical symptoms and may improve the disease, also including the treatment of the disease. "Objects in need of treatment" include objects (e.g., human subjects) who already have the disease, disorder, or condition, as well as objects who are susceptible to or suspected of having the disease, disorder, or condition, including preventing objects in which the disease, disorder, or condition is present.

[0437] The cell that is sensitive to the cell-mediated immune response is suitably a cell associated with a proliferative disease (e.g., a cell associated with a proliferative disease), in certain embodiments, such a cell is a cell associated with a proliferative disease (e.g., a cell that proliferates abnormally, such as a cell that overproliferates). For example, such a cell can be a cell characterized by the loss of a normal control that affects its growth and cell division, such as a tumor or tumor cell. In specific embodiments, such a cell can be a cancer cell, or a cell derived from a cancer cell or tumor cell. In other embodiments, such a cell can be a skin cell, such as a cell that shows overproliferation, such as a skin cell involved in psoriasis, Reiter's syndrome, pityriasis versicolor, or scleroderma.

[0438] For example, a cell may be "associated with a cell proliferative disease" if it is associated with cell proliferation, e.g., it is a causative agent of the cell proliferative disease, or is affected by the cell proliferative disease. A cell is specifically "associated with a proliferative disease" if the cell is characterized by abnormal proliferation, such as abnormal cell growth or cell division, and if the abnormal cell growth or cell division is the pathology or causative factor of the proliferative disease. In embodiments where the proliferative disease is a tumor or cancer, non-limiting examples of cells "associated with a proliferative disease" can be tumor (or cancer cell) cells or cells (of a tissue) derived from such a tumor or cancer; in particular, solid tumors.

[0439] In certain embodiments, the compounds of the present invention can inhibit SIK3 in cells associated with proliferative diseases (e.g., tumor cells). In particular, in such embodiments, the compounds can inhibit SIK3 in such cells over inhibiting SIK1 and / or SIK2 in such cells; and / or can inhibit SIK3 in such cells over inhibiting SIK1 and / or SIK2 and / or SIK3 in one or more types of immune cells. For example, the compounds of the present invention can inhibit SIK3 in cells associated with proliferative diseases (e.g., tumor cells) over inhibiting SIK1 and / or SIK2 and / or SIK3 in macrophages and / or dendritic cells (particularly those capable of or producing IL-10).

[0440] The compounds (or pharmaceutical compositions) of the present invention can be administered to a subject in an amount effective to inhibit SIK3 and / or to sensitize cells associated with a proliferative disease to a cell-mediated immune response. Suitable amounts, formulations, and modes of administration are described elsewhere herein.

[0441] In certain embodiments, the compounds (or pharmaceutical compositions) of the present invention are administered in an amount (e.g., a therapeutically effective amount) effective to reduce SIK3 activity (preferably SIK3 in cells associated with a proliferative disease). In such embodiments, a "therapeutically effective amount" of a compound (or pharmaceutical composition) can be an amount that reduces SIK3 activity to a useful level, but does not result in significant (e.g., intolerable) side effects or overdose with respect to other activities of the compound (or pharmaceutical composition).

[0442] Preferably, the activity of SIK3 is effectively inhibited (reduced), preferably referring to SIK3 kinase in cells associated with a proliferative disease. For example, "effective" inhibition (or reduction) can include an action where the reduction in activity has a physiological effect (e.g., a reduction to a therapeutically effective level), such as a reduction of about 10%, 20%, 50%, or greater than 50%, such as 70% or 90%, of the activity of the respective kinase. With respect to SIK3, one of these reductions may be required to elicit a therapeutic response.

[0443] The term "immune cell" is a generally accepted description of any cell of an organism related to the immune system of the organism, particularly a cell of a mammal such as a human. Leukocytes (white blood cells) are immune cells involved in the innate immune system, while cells of the adaptive immune system are special types of leukocytes, referred to as lymphocytes. B cells and T cells are the main types of lymphocytes, which derive from hematopoietic stem cells in the bone marrow. B cells participate in humoral immune responses, while T cells participate in cell-mediated immune responses. In a preferred embodiment of the present invention, the immune cell can be a myeloid cell, such as a T cell, and particularly (such as when it is necessary to increase a cell-mediated immune response such as for the treatment of cancer), the T cell can be a cytotoxic T cell (also referred to as TC, cytotoxic T lymphocytes, CTL, T killer cells, cytolytic T cells, CD8+ T cells or killer T cells). CTL is a T cell that participates in killing cancer cells, infected cells (especially infected by viruses) or otherwise damaged cells. Other preferred immune cells for this type of embodiment may include tumor infiltrating lymphocytes (TIL). TIL is a leukocyte that has left the blood and migrated to the tumor. Typically, TILs are a mixture of different cell types (e.g., T cells, B cells, NK cells, macrophages) in variable proportions, with T cells being the most abundant cells. TILs can often be found in the stroma and in the tumor itself and are associated with killing tumor cells. The presence of lymphocytes in tumors is generally associated with better clinical outcomes.

[0444] As used herein, the term "cell-mediated immune response" may include, but is not limited to, a response in a host organism that involves, utilizes and / or promotes the maturation, proliferation, activation, migration, infiltration and / or differentiation of T cells, and / or the activation, migration, infiltration and / or differentiation of macrophages, natural killer cells, T lymphocytes (or T cells), helper T lymphocytes, memory T lymphocytes, suppressor T lymphocytes, regulatory T lymphocytes and / or cytotoxic T lymphocytes (CTLs), and / or the production, release and / or action of one or more cell-secretable or cell-secreted factors (e.g., cytokines or autoantibodies (particularly pro-inflammatory cytokines, such as TNF), and / or one or more components of any such processes (e.g., cytokines or autoantibodies, particularly pro-inflammatory cytokines, such as TNF). TNF). As used herein, the term "cell-mediated immune response" may include cellular responses involving genetically engineered, cultured in vitro, autologous, heterologous, modified and / or transferred T lymphocytes, or may include cell-secreted factors (e.g., cytokines or autoantibodies, particularly proinflammatory cytokines, such as TNF) that can be secreted by cells or produced by genetic engineering. The cell-mediated immune response is preferably not a humoral immune response, such as an immune response involving antibody release. In certain embodiments, particularly when the proliferative disease is cancer or a tumor, the cell-mediated immune response is an anti-tumor cell-mediated immune response. For example, a cytotoxic cell-mediated immune response (e.g., cytotoxic T cells and / or TNF exposure) that results in reduced tumor (cell) growth, such as killing cancer cells or tumors.

[0445] In certain embodiments, the cell-mediated immune response can be mediated by cells (e.g., immune cells) capable of secreting (e.g., secreting) proinflammatory cytokines, such as those selected from the group consisting of interleukin-1 (IL-1), IL-8, and IL-12, tumor necrosis factor (TNF), interferon gamma (IFN-γ), and granulocyte-macrophage colony stimulating factor. In particular, in such embodiments, the proinflammatory cytokine is tumor necrosis factor (TNF) α.

[0446] In other embodiments, the cell-mediated immune response can be a factor that can be secreted by a cell or secreted by a cell (e.g., a cytokine or autoantibody), in particular a factor that can be secreted or secreted by an immune cell. In particular, in such embodiments, the cell-mediated immune response is a proinflammatory cytokine, in particular tumor necrosis factor (TNF).

[0447] As used herein in the context of cells being sensitive to a cell-mediated immune response, the terms "sensitive to," "sensitized," and "sensitized" (and the like) will be understood by those skilled in the art to include the meaning that such cells may exhibit a higher sensitivity to a cell-mediated immune response for one or more effects (e.g., therapeutic effects) exhibited by such cells. In particular, when present (e.g., exposed to) a cell-mediated immune response, such sensitized cells can be killed more easily (e.g., more quickly, a greater proportion of cells die or are killed, and / or the number or exposure to a cell-mediated immune response is lower) than similar cells that have not yet been so "sensitized." For example, when exposed to a lower number of T cells or a lower concentration of TNF (e.g., about 10%, 20%, 30%, 40%, 50% or more than 50% fewer T cells or a lower concentration of TNF), such sensitized cells can be induced to undergo cell death (e.g., apoptosis). Methods for determining whether such cells have been sensitized to a cell-mediated immune response (and to what extent) are described herein, for example, in the Examples. Thus, in certain embodiments of the invention, cells associated with a proliferative disease may be sensitized to cell death / killing (eg, by entry into apoptosis) via a cell-mediated immune response (eg, CTL or proinflammatory cytokines, such as TNF).

[0448] In the context of the invention disclosed herein, the terms "tumor necrosis factor" and "TNF" (formerly and therefore alternatively referred to as tumor necrosis factor alpha and TNF-α) should be understood to refer to any protein known in the art by these names. In particular, the term TNF encompasses endogenous TNF of any organism in which it is present, and preferably includes endogenous TNF of an animal or mammal, such as a human. By way of example and not limitation, human TNF may encompass, in particular, the endogenous protein of Pennica et al. 1984 (Nature 312:724-9) and entry number P01375 in the UniProtKB / Swiss-Prot database (e.g., entry version 224 of March 15, 2017), as well as any sequence variants due to normal sequence polymorphisms between and within human populations. By way of further non-limiting example, the term encompasses endogenous TNF proteins annotated in the UniProtKB / Swiss-Prot databases of cow (Q06599), dog (P51742), goat (P13296), guinea pig (P51435), cat (P19101), horse (P29553), mouse (P06804), chimpanzee (Q8HZD9), pig (P23563), rabbit (P04924), rat (P16599), etc., as well as any sequence variants thereof due to sequence polymorphisms between and within populations of various species. Furthermore, the term TNF specifically encompasses soluble, secreted cytokine forms of TNF, including its monomeric form and, preferably, its generally more active trimeric form (see, e.g., Smith & Baglioni 1987. J Biol Chem 262:6951-4). The primary amino acid sequences of soluble forms of endogenous TNF are indicated for each exemplary organism in the above-mentioned UniProtKB / Swiss-Prot database entries. In addition, the term TNF may also include membrane-bound forms of TNF expressed on the surface of certain cell types (see, for example, Kriegler et al. 1988. Cell 53:45-53).Furthermore, the term TNF may also include synthetic or recombinant proteins whose primary amino acid sequence is identical or substantially identical to the sequence of an endogenous TNF ("substantially identical", as used throughout this specification, generally means ≥80%, such as ≥85%, preferably ≥90%, preferably ≥95%, even more preferably ≥98% or ≥99% sequence identity), as determined using, for example, the "Blast 2 sequence" algorithm described by Tatusova & Madden 1999 (FEMS Microbiol Lett 174:247-250), which (preferably) retain the same or substantially the same biological activity as the respective endogenous TNF, as determined using, for example, the cytotoxicity assay described by Flick & Gifford 1984 (J Immunol Methods 68:167-75). As will be clear from the context of the aspects and embodiments of the present invention, the term TNF herein may particularly refer to soluble and / or membrane-bound (preferably soluble) endogenous TNF produced by a cell, tissue, organ or organism, preferably a human. However, the term "TNF" also contemplates exogenous forms of tumor necrosis factor, particularly those produced by recombinant techniques, and which, in certain embodiments, can be administered to a subject, exposed to a cell, or contacted with a cell in accordance with various aspects and embodiments of the invention. In certain such embodiments, the TNF can be a recombinant TNF, such as BEROMUN, used as a therapeutic agent.

[0449] In certain embodiments, the cell-mediated immune response may be mediated by pro-inflammatory cytokine-secreting cells, such as lymphocytes (eg, T cells), particularly cytotoxic T lymphocytes (CTLs).

[0450] In certain embodiments, the cell-mediated immune response can induce killing (e.g., cell death, such as by apoptosis) of cells associated with a proliferative disease. For example, a treatment (method) can include (e.g., can involve) a cell-mediated immune response (or be mediated by) inducing such killing of cells associated with a proliferative disease.

[0451] Cells relevant to proliferative diseases can be killed (for example, induced to enter cell death) by one or more cytotoxic processes, particularly those endogenous to such cells, such as programmed cell death (PCD). Cell death processes may include, but are not limited to, necrosis (particularly necrotizing disease), apoptosis, neurasthenia, autophagy, hypertrophy, mitotic catastrophe, and activation-induced cell death. In certain preferred embodiments, cells relevant to proliferative diseases (such as tumor cells) are induced to apoptosis by a cell-mediated immune response (for example, by TNF). In another embodiment, in the absence of a cell-mediated immune response (for example, in the absence of TNF), the compounds of the present invention (or pharmaceutical compositions) are administered to not kill such cells. In particular, in such other embodiments, the compound (or pharmaceutical composition) can be administered in an amount (for example, a dosage) that does not effectively kill such cells in the absence of a cell-mediated immune response. The examples herein describe various assays by which the amount of the compound (or pharmaceutical composition) of the present invention can be determined, and this amount effectively kills such cells only or preferably in the presence of a cell-mediated immune response.

[0452] In other specific embodiments, the cell-mediated immune response may involve at least one immune cell effector molecule, in particular an effector molecule that can be secreted or secreted by an immune cell. In particular, in such embodiments, the effector molecule may be a proinflammatory cytokine, preferably tumor necrosis factor (TNF).

[0453] In certain embodiments, the effector molecule is not a cellular effector molecule selected from Fas ligand (FasL or CD95L) and TNF-related apoptosis-inducing ligand (TRAIL, CD253 or TNFSF10).

[0454] In a specific embodiment of the invention, the compounds (or pharmaceutical compositions) of the invention can be administered to a subject (e.g., in an effective amount or dosage) with the intention (or thereby) to (effectively) sensitize cells associated with a proliferative disease to killing by TNF. For example, the compounds (or pharmaceutical compositions) can be administered in a therapeutically effective amount, e.g., an amount effective to sensitize cells associated with a proliferative disease to killing (cell death) induced by TNF.

[0455] For example, a compound (or pharmaceutical composition) of the invention can be administered to a subject (e.g., in an effective amount or effective dose) to induce apoptosis of such cells mediated by TNF, e.g., when such cells are in the presence of or exposed to TNF. In a further embodiment, a compound (or pharmaceutical composition) of the invention can be administered to a subject (e.g., in an effective amount or dose) to induce a reduced amount of cytotoxicity (e.g., apoptosis)—e.g., not induce killing (e.g., apoptosis) of such cells—in the absence of TNF; for example, a compound (or pharmaceutical composition) can be administered in an amount or dose that is less effective (e.g., ineffective) in inducing such killing) of cytotoxicity (e.g., apoptosis) in the absence of TNF.

[0456] TNF can induce a pro-apoptotic process by binding to tumor necrosis factor receptor 1 (TNFR1) and / or tumor necrosis factor receptor 2 (TNFR2) and / or by signaling. Thus, in certain embodiments, the compounds (or pharmaceutical compositions) of the present invention can be administered to a subject (e.g., in an effective amount or dosage) to (effectively) sensitize cells associated with a proliferative disease to apoptosis mediated by tumor necrosis factor receptor 1 (TNFR1) signaling and / or tumor necrosis factor receptor 2 (TNFR2) signaling. Preferably, the compound (or pharmaceutical composition) can be administered to a subject (e.g., in an effective amount or dosage) to (effectively) sensitize cells associated with a proliferative disease to apoptosis mediated thereby, particularly apoptosis mediated by TNFR1. For example, the compound (or pharmaceutical composition) can be administered in a therapeutically effective amount that effectively mediates TNFR1- and / or TNFR2-signaling and / or apoptosis mediated thereby.

[0457] For example, in certain embodiments, a compound (or pharmaceutical composition) of the invention can be administered (e.g., in an amount or dose effective) to induce apoptosis in such cells via TNFR1 and / or TNFR2 signaling (e.g., in the presence of active TNFR1 signaling). In particular, in such embodiments, a compound (or pharmaceutical composition) can be administered to a subject (e.g., in an amount or dose, e.g., a therapeutically effective amount) to (effectively) induce a reduced amount of cytotoxicity (e.g., apoptosis)—e.g., not induce apoptosis in such cells—in the absence of TNFR1 and / or TNFR2 signaling, e.g., in the absence of active TNFR1 signaling. For example, a compound (or pharmaceutical composition) can be administered in an amount or dose that is less effective for cytotoxicity (e.g., apoptosis)—e.g., not effective in inducing such apoptosis—in the absence of such signaling.

[0458] Thus, in certain embodiments, a compound (or pharmaceutical composition) of the invention can be administered to a subject (e.g., in an amount or dosage) to induce a reduced amount of cytotoxicity (e.g., apoptosis), e.g., no cytotoxicity, to cells associated with a proliferative disease in the absence of a cell-mediated immune response.

[0459] In certain embodiments, even if the subject's tumor grows during treatment, the compound (or pharmaceutical composition) of the present invention can continue to be administered to the subject. Without being bound by theory, even if an increase in tumor size is observed during such treatment, it may indicate an (enhanced) immune response against the tumor cells (e.g., the cells have become sensitive to a cell-mediated immune response; and as a result of this immune response, the size of the tumor is increasing), and thus, in such embodiments, administration of the compound (or pharmaceutical composition) can continue to maintain this sensitivity and the associated (enhanced) immune response.

[0460] As described in PCT / EP2018 / 060172, inhibition of SIK3 is associated with a number of key biological processes or phenotypes, including, surprisingly, involvement in controlling and / or triggering cell-intrinsic cytotoxic processes, such as apoptosis. For example, by inhibiting SIK3, tumor cells can be sensitized to the apoptotic / cytotoxic effects of TNF through pathways and their components, including liver kinase B1 (LKB1, STK11, or NY-REN-19), histone deacetylase 4 (HDAC4), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB), and pro-apoptotic genes regulated by NF-kappaB, such as Caspase 8 and Caspase 9. c-Jun N-terminal kinase (JNK) is a signaling component associated with sensitization to the apoptotic / cytotoxic effects of TNF through inhibition of SIK3.

[0461] In the context of this embodiment (and other applicable embodiments), the term "associated with..." can mean that two components, variables, effects or phenotypes are interrelated and / or related to each other (e.g., associated), and / or that a causal relationship exists between the first and the second component, variable, effect or phenotype (e.g., the second is a response to the first, the second is a result of the first, or the second is caused by the first).

[0462] Thus, in one such embodiment, administration of a compound (or pharmaceutical composition) of the invention can be associated with impairment of NF-κB activity in cells associated with a proliferative disease (e.g., by enhancing or increasing NF-κB translocation from the nucleus).

[0463] In particular, in such embodiments, such impaired NF-κB activity (e.g., due to enhanced or translocation of NF-κB from the nucleus) may be associated with (activated) TNF- and / or TNFR1-mediated signaling (or TNFR2-mediated signaling) in these cells.

[0464] In certain embodiments, the compounds (or pharmaceutical compositions) of the present invention can be administered to a subject (e.g., in an effective amount or dose) to impair or inhibit NF-κB activity in cells associated with a proliferative disease, for example, to enhance or increase the translocation of NF-κB from the nucleus of such cells. For example, the compound (or pharmaceutical composition) can be administered to a subject in a specific (e.g., therapeutically effective) amount that effectively (efficiently) attenuates NF-κB activity in cells associated with a proliferative disease, particularly effectively (efficiently) enhancing or increasing the translocation of NF-κB from the nucleus of cells associated with a proliferative disease.

[0465] In alternative or further embodiments, administration of a compound (or pharmaceutical composition) of the invention can be associated with increasing the activity of class II (e.g., IIa) HDACs (e.g., HDAC4) in cells associated with a proliferative disease (e.g., administering the compound (or pharmaceutical composition) in an effective amount or dose to thereby increase), such as their translocation or localization in the nucleus of such cells or their activity in the nucleus; particularly when signaling is mediated by TNF and / or TNFR1 (or TNFR2-mediated signaling) in such cells.

[0466] In other alternative or further embodiments, administration of a compound (or pharmaceutical composition) of the invention can be associated with deacylation of nuclear NF-κB (e.g., deacylation at its p65 subunit) and / or reduced transactivation of one or more anti-apoptotic factors, particularly in cells associated with a proliferative disease mediated by TNF- and / or TNFR1 signaling (or TNFR2-mediated signaling). For example, a compound (or pharmaceutical composition) can be administered (e.g., in an effective amount or dose) to cause deacylation of nuclear NF-κB (e.g., at its p65 subunit) and / or reduce transactivation of one or more anti-apoptotic factors.

[0467] In another alternative or further embodiment, administration of a compound (or pharmaceutical composition) of the invention can be associated with increased cleavage of Caspase 8 and / or Caspase 9 in cells associated with a proliferative disease (e.g., administration of the compound (or pharmaceutical composition) in an effective amount or dose to thereby increase), particularly when TNF- and / or TNFR1-mediated (or TNFR2-mediated signaling) is involved in such cells.

[0468] In other alternative or further embodiments, administration of a compound (or pharmaceutical composition) of the invention can be associated with a decrease in the transcription of one or more anti-apoptotic factors, particularly in the context of TNF- and / or TNFR1-mediated signaling (or TNFR2-mediated signaling) in cells associated with a proliferative disease, such as a decrease in the transcription of one or more NF-κB target genes in such cells. In particular, a compound (or pharmaceutical composition) can be administered (e.g., at an effective dose) to decrease the transcription of one or more such anti-apoptotic factors, particularly in the context of TNF- and / or TNFR1-mediated signaling (or TNFR2-mediated signaling) in cells associated with a proliferative disease.

[0469] In one embodiment, administration of a compound (or pharmaceutical composition) of the invention can be associated with (e.g., administering the compound (or pharmaceutical composition) in an effective amount or dose to thereby increase) JNK activation (e.g., by phosphorylation) in cells associated with a proliferative disease, particularly when TNF- and / or TNFR1-mediated signaling (or TNFR2-mediated signaling) in such cells.

[0470] In another embodiment, administration of a compound (or pharmaceutical composition) of the invention may not be associated with significant changes in CREB pathway signaling and / or significant changes in expression of genes mediated by CREB and / or CREB regulation.

[0471] In a specific embodiment, TNF-(TNFR2-) and / or TNFR1-mediated signaling in cells associated with a proliferative disease may be associated with increased levels of pLKB1 in such cells.

[0472] As will now be apparent to one of ordinary skill in the art, given the knowledge of the present invention, the therapeutic aspects of the present invention may further comprise the step of administering one or more other moieties that appropriately modify the expression, activity, function, or stability of one or more of these other pathway components to additively or synergistically contribute to the therapeutic effect. For example, in one such embodiment, the therapeutic aspects of the present invention may further comprise the step of administering an LKB1 inhibitor. In another such embodiment, the therapeutic aspects of the present invention may further comprise the step of administering an agent that promotes, enhances, or increases the expression of one or more Class II (e.g., IIa) HDACs (histone deacetylases), such as HDAC4, in the nucleus of cells associated with a proliferative disease. In yet another such embodiment, the therapeutic aspects of the present invention may further comprise the step of administering an NF-κB inhibitor (activation). The present invention also contemplates the use of combinations of two or more such other moieties with the compounds (or pharmaceutical compositions) of the present invention and / or the use of other (e.g., anti-cancer) therapeutically active agents (e.g., additional therapeutic agents, such as those described elsewhere herein) with the compounds (or pharmaceutical compositions).

[0473] In another aspect, and as may be further described, defined, claimed or otherwise disclosed herein, the present invention relates to a method of sensitizing cells associated with a proliferative disease to a cell-mediated immune response, the method comprising exposing (e.g., contacting) cells associated with the proliferative disease to a compound (or pharmaceutical composition) of the present invention. This method can generally be practiced as an in vitro and / or ex vivo method.

[0474] In a specific embodiment, the cell-mediated immune response comprises killing cells associated with a proliferative disease, e.g., wherein the killing involves (e.g., is mediated by, or is supported by) TNF (TNF), TNFR2-, and / or TNFR1-mediated signaling. For example, killing such cells may involve apoptosis of such cells induced by TNF, TNFR2, and / or TNFR1-mediated signaling. In this embodiment and other applicable embodiments of the various aspects of the invention, TNFR2 and / or TNFR1-mediated signaling can be triggered (e.g., activated) by any suitable triggering molecule (e.g., TNF, a variant of TNF, and / or a TNFR2 or TNFR1 agonist); in particular, by exposing (e.g., contacting) cells associated with a proliferative disease to a triggering molecule (e.g., TNF, a TNF variant, or a TNFR1 agonist). Such exposure can result in binding of the triggering molecule (e.g., TNF, a TNF variant, or a TNFR1 agonist) to TNFR2 and / or TNFR1, particularly triggering (e.g., activating) TNFR1 signaling.

[0475] In another aspect, and as may be further described, defined, claimed, or otherwise disclosed herein, the present invention relates to a method of killing cells associated with a proliferative disease, comprising exposing (e.g., contacting) the cells. The cells associated with the proliferative disease: (i) a TNF variant and / or agonist of TNF, TNFR1, or TNFR2 signaling (preferably TNFR1 signaling); and exposing the cells associated with the proliferative disease to (ii) a compound (or pharmaceutical composition) of the present invention. As will be understood by one skilled in the art or of ordinary skill, this method can generally be practiced as an in vitro and / or ex vivo method.

[0476] In a related aspect, the invention relates to a compound (or pharmaceutical composition) of the invention for use in treating a proliferative disease involving killing of cells associated with the proliferative disease, said treatment comprising exposing said cells to (i) TNF, a TNF variant and / or a TNFR1 or TNFR2 agonist; and (ii) a compound (or pharmaceutical composition) of the invention.

[0477] In particular embodiments of these aspects, the killing of cells associated with a proliferative disease is mediated by sensitizing such cells to a cell-mediated immune response, particularly by inducing sensitivity to apoptosis involving (e.g., mediated by or supported by) TNF, TNFR2 and / or TNFR1-mediated signaling.

[0478] Cells associated with a proliferative disease can be exposed to TNF, a TNF variant, and / or a TNFR1 or TNFR2 agonist by contacting the cells with the trigger molecule; and / or the cells can be exposed to a compound (or pharmaceutical composition) of the invention by contacting such cells with (or introducing) a compound (or pharmaceutical composition) of the invention. The amount (or dose) of (i) TNF, a TNF variant, and / or a TNFR1 or TNFR2 agonist; and / or (ii) a compound (or pharmaceutical composition) of the invention is generally an effective amount; this is an amount (or dose) effective, for example, to sensitize cells to apoptosis induced by TNF, TNFR2, and / or TNFR1-mediated signaling (e.g., by killing the cells). Suitable amounts of these agents (or methods of determining them) that can be incorporated into these aspects of the invention are disclosed elsewhere, as are other specific features of the compounds (or pharmaceutical compositions) of the invention. Thus, in certain embodiments: (i) TNF, a TNF variant, and / or an agonist of TNFR1 or TNFR2; and (ii) a compound of the invention (or pharmaceutical composition) can be administered to a subject having a proliferative disease (e.g., treatment can include administering: (i) TNF, a TNF variant, and / or an agonist of TNFR1 or TNFR2; and (ii) a compound of the invention (or pharmaceutical composition) can be administered to a subject).

[0479] The cell associated with a proliferative disease may be a cell as described elsewhere herein, and in particular, such a cell may be a cancer cell or a tumor cell. For example, such a cell may be a solid tumor or a cell derived from a solid tumor.

[0480] In certain embodiments of these aspects, the method is an in vitro (and / or ex vivo) method. In alternative embodiments of such methods, cells associated with a proliferative disease (e.g., tumor cells) are present in such subjects, particularly in subjects in need of treatment thereof.

[0481] In other embodiments of the methods of these aspects, the (therapeutic) effect of the method (e.g., on cells associated with a proliferative disease) can be by (e.g., treatment can include, involve, or be mediated by) inhibiting SIK3; in particular, by inhibiting the function and / or activity of SIK3 or a protein (e.g., a phosphorylated SIK3 protein and / or as described elsewhere herein). In particular, in such embodiments, SIK3 activity is reduced (e.g., effectively), for example, to a therapeutically effective level.

[0482] In certain embodiments of such methods, cells associated with a proliferative disease (e.g., tumor cells) are not killed or induced into apoptosis (e.g., they proliferate) upon TNF-, TNFR2-, and / or TNFR1-mediated signaling and / or exposure to (e.g., an effective amount or dose of) a TNF, TNF variant, TNFR2, or TNFR1 agonist in the absence (e.g., an effective amount or dose) of a compound (or pharmaceutical composition) of the invention.

[0483] As described above, in certain embodiments of these methods, the compounds (or pharmaceutical compositions) of the present invention can inhibit SIK3 in cells associated with a proliferative disease (e.g., tumor cells). In particular, in such embodiments, the compounds (or pharmaceutical compositions) can inhibit SIK3 in such cells in preference to inhibiting SIK1 and / or SIK2 in such cells; and / or can inhibit SIK3 in such cells in preference to inhibiting SIK1 and / or SIK2 and / or SIK3 in one or more types of immune cells. For example, the compounds (or pharmaceutical compositions) of the present invention can inhibit SIK3 in cells associated with a proliferative disease (e.g., tumor cells) in preference to inhibiting SIK1 and / or SIK2 and / or SIK3 in macrophages and / or dendritic cells (particularly those capable of or producing IL-10). In certain embodiments, the (therapeutic) effect is mediated by (e.g., the treatment comprises, involves, is mediated by) inhibition of SIK3 in cells associated with a proliferative disease (e.g., tumor cells); and in further such embodiments, the (therapeutic) effect is not mediated by (or the effect is not mediated by) (e.g., the treatment does not comprise, does not involve, or is not mediated by) inhibition of SIK2, particularly SIK2 in / in other cells (e.g., cells associated with a proliferative disease or immune cells), and / or the (therapeutic) effect is not mediated by (or the effect is not mediated by) inhibition of SIK1 (e.g., the treatment does not comprise, does not involve, or is not mediated by inhibition of SIK1), particularly SIK1 in / in other cells (e.g., cells associated with a proliferative disease or immune cells).

[0484] Thus, in one embodiment, SIK3 is inhibited in (e.g., within) cells associated with a proliferative disease (e.g., by a compound or pharmaceutical composition of the invention). In another (or further) embodiment, another kinase (e.g., SIK2, particularly SIK2) is inhibited to a lesser extent than SIK3 (e.g., in cells implicated in a proliferative disease) in (e.g., within) immune cells (e.g., CTLs). In yet another (or further) embodiment, SIK1, particularly SIK1 in (e.g., within) immune cells (e.g., CTLs), is inhibited to a lesser extent than such SIK3.

[0485] In certain such embodiments, one or more of the kinases selected from the group consisting of SIK3, SIK1, SIK2, JAK1, RET, ERBB4 PDGFR-α, and EPHB2 are inhibited (e.g., by a compound or drug of the invention) to a lesser extent than one or more of the kinases selected from the group consisting of ABL1, SRC, BCR-ABL, LCK, LYN, YES, FYN, KIT, and FLT3.

[0486] In certain such embodiments, one or more of the kinases selected from the group consisting of PDGFR-α, TGFB-R1, B-RA, p38-β, ACV-R1, BMPR1A, and RET are inhibited (e.g., by a compound or drug of the invention) to a lesser extent than one or more of the kinases consisting of EPHA2, EPHA4, CSF1-R, HCK, and ACK1.

[0487] In certain such embodiments, one or more of the kinases selected from NEK11, WEE1, WNK2, Aurora-A, Aurora-B, and TBK1 are inhibited (e.g., by a compound or drug of the invention) to a lesser extent than one or more of the kinases selected from ABL1, SRC, BCR-ABL, LCK, LYN, YES, FYN, and KIT.

[0488] A given kinase (e.g., SIK1 or SIK2) is inhibited "to a lesser extent" than another kinase (e.g., SIK3) if, for example, the amount of inhibition of another kinase (e.g., SIK3) is greater than about 2 times that of a given kinase, e.g., the amount of inhibition is about 5, 10, 20, 50, 75, or 100 times greater than that of a given kinase. In particular, the amount of inhibition of the other kinase (e.g., SIK3) may be about 5 to 20 times, 20 to 50, or 50 to 100 times greater than that of a given kinase. For example, SIK3 (i.e., another kinase) may be inhibited by about 20 to 50 times relative to SIK1 and / or SIK2 (i.e., a given kinase). For example, a compound (or pharmaceutical composition) of the invention may inhibit another kinase (e.g., SIK3) by 80% (i.e., having only 20% of its uninhibited activity), but inhibit a given kinase (e.g., SIK1) by only 4% and SIK2 by only 8%. Thus, another kinase (e.g., SIK3) is inhibited about 20-fold more than a given kinase (e.g., SIK1) and about 10-fold more than another given kinase (e.g., SIK2). In certain embodiments, another kinase (e.g., SIK3) can be inhibited to the same extent as, e.g., SIK1 (e.g., between about 2 and 53-fold greater than each other), and SIK2, e.g., is inhibited to a lesser extent than either (or both) of, e.g., SIK3 and SIK1: for example, in such embodiments, inhibition of, e.g., SIK3 and SIK1 is about 20 to 50-fold greater than inhibition of SIK2 (e.g., in immune cells).

[0489] The compounds of the present invention are shown to be potent inhibitors of one or more kinases (as shown in the Examples, particularly Figure 3 In particular, Figure 3Any one of the kinases (or any combination thereof) having a residual activity of about 50% to about 25%, or less than about 25% (particularly, a kinase having a residual activity of less than 10%) is considered a "key kinase" inhibited by each compound of the present invention. Mutants of such kinases are also contemplated. As specific examples, key kinases include one or more kinases selected from the group consisting of SIK1, SIK2, SIK3, ABL1 / BCR-ABL, SRC, FLT3, KIT, YES, LYN, FYN, and LCK; and / or EPHA2, EPHA4, CSF1-R, HCK, ACK1; and / or PDGFR-α, TGFB-R1, B-RAF, and / or p38-β; and / or ACV-R1 and / or BMPR1A; and / or RET; and / or NEK11, WEE1, and / or WNK2; and / or Aurora-A and / or Aurora-B; and / or TBK1; in particular, ABL1 / BCR-ABL, ABL1 / BCR-ABL, and FLT3.

[0490] The inventors have discovered that, compared to other kinase inhibitors, the compounds of the present invention inhibit different groups of kinases and / or inhibit each kinase to varying degrees. For example, compounds B3 and A8 are equivalent inhibitors of ABL1 and SRC (and ABL1 mutants). However, as shown in the Examples, they inhibit SIK1, SIK2, SIK3, and particularly FLT3, KIT, and SYK to varying degrees.

[0491] It is also shown in the examples that the compounds of the invention have a higher selectivity for ABL1 and (in particular) for SRC kinase compared to dasatinib, and that this selectivity also applies to the class of protein-tyrosine kinases. ...

Claims

1. A compound selected from the group consisting of kinase inhibitors of the formula: and salts, N-oxides, and combinations thereof; in: R 1a for R 1b H, R 1c is methyl; R 2 It is H; R 3 is H; R 4 It is H; R 5 Yes-LR 6 ; L is a key; R 6 is chosen by two independently chosen R 7 substituted thienyl; R 7 One of them is halogen, R 7 The other of which is halogen or C optionally substituted with one, two or three independently selected halogens 1-2 alkyl; A is S; E is O; B is N.

2. The compound according to claim 1, wherein the halogen is Cl or Br, and the C 1-2 The alkyl group is methyl.

3. The compound according to claim 1, wherein one R 7 Group relative to R 6 The ring atom at position 2 that is bound to the rest of the compound is R 6 The ring atoms are combined.

4. The compound according to claim 1, wherein R 6 Selected from: in Represents R 6 A bond to the rest of the compound.

5. The compound according to claim 1, which is selected from: and salts, N-oxides, and combinations thereof.

6. The compound according to claim 1, which is selected from: and salts, N-oxides, and combinations thereof.

7. The compound according to claim 1, which is selected from: and salts, N-oxides, and combinations thereof.

8. The compound according to claim 1, which is selected from: and salts, N-oxides, and combinations thereof.

9. The compound according to claim 1, wherein the salt is a pharmaceutically acceptable salt.

10. The compound according to claim 1, wherein the compound is a kinase inhibitor of formula (I) or a pharmaceutically acceptable salt thereof.

11. A compound selected from the kinase inhibitors of formula (I) as defined in claim 1 or pharmaceutically acceptable salts thereof. 12 . A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof, and further comprising a pharmaceutically acceptable excipient.

13. The pharmaceutical composition of claim 12, formulated for oral administration.

14. The pharmaceutical composition according to claim 12 or 13, which is in unit dosage form.

15. Use of a compound according to any one of claims 1 to 5 or a pharmaceutical composition according to any one of claims 12 to 14 for the preparation of a medicament for treating a disease, disorder or condition associated with SIK kinase in a subject.

16. Use of the compound of any one of claims 1 to 5 or the pharmaceutical composition of any one of claims 12 to 14 in the preparation of a medicament for treating a proliferative disease or condition associated with SIK kinase in a subject.

17. Use of a compound according to any one of claims 1 to 5 or a pharmaceutical composition according to any one of claims 12 to 14 in the preparation of a medicament for treating a proliferative disease or condition in a subject, said treatment comprising administering said compound or pharmaceutical composition to said subject, wherein said proliferative disease is cancer or a tumor.

18. The use according to claim 17, wherein the cancer is a solid tumor.

19. Use according to any one of claims 16 and 17, wherein the subject is a human subject.

20. Use of an intermediate in the preparation of the compound according to claim 1, wherein the intermediate comprises a substituent R 6 or R 1a , or contain the following structure: in, R 6 、R 1a , A and B as defined in claim 1, It contains a substituent R 1a The intermediate is selected from 2-(piperazin-1-yl)ethan-1-ol, 1-methylpiperazine and 1-acetylpiperazine; and It contains a substituent R 6 The intermediate is selected from the group consisting of 6 amine or its hydrochloride.

21. The use according to claim 20, wherein the intermediate is 2-chloro-4-methylthiophene-3-amine.

22. The use of an intermediate in preparing a compound according to any one of claims 1 to 5, wherein the intermediate is selected from a compound having R as defined in any one of claims 1 to 5 1b 、R 1c 、R 2 、R 3 、R 4 、R 5 , A, B and E of formula (I), and wherein R 1a Is a leaving group.

23. Use according to claim 22, wherein the leaving group is a halogen.

24. Use according to claim 23, wherein the halogen is Cl.

25. The use according to claim 22, further comprising the following steps: providing a compound according to any one of claims 1 to 5 in a mixture with one or more impurities; and • Removing at least a portion of the impurities from the mixture.

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