Heterocyclic kinase inhibitors and uses thereof

Abstract

The present invention relates to kinase inhibitors, particularly inhibitors of protein kinases including those of the protein tyrosine kinase LCH, ABL, SRC, KIT, and SIK families and / or mutants thereof. While structurally similar to dasatinib, the kinase inhibitors of the present invention may exhibit one or more distinct properties. The present invention also relates to pharmaceutical compositions comprising one or more kinase inhibitors. The kinase inhibitors of the present invention or pharmaceutical compositions thereof can be used to treat diseases or conditions, such as proliferative disorders, e.g., leukemia or solid tumors. The kinase inhibitors of the present invention or pharmaceutical compositions thereof can be used in the same or different therapeutic regimens as those used with dasatinib for the corresponding diseases. In particular, they can be used in combination therapeutic regimens with one or more additional therapeutic agents, such as immune checkpoint inhibitors.

Description

[Technical Field]

[0001] The present invention relates to kinase inhibitors, particularly inhibitors of protein kinases including those of the protein tyrosine kinase LCK, ABL, SRC, KIT, and SIK families and / or mutants thereof. While structurally similar to dasatinib, the kinase inhibitors of the present invention may exhibit one or more specific properties distinct from dasatinib. The present invention also 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 disorders or conditions, such as proliferative disorders, e.g., leukemia or solid tumors. The kinase inhibitors or pharmaceutical compositions can be used in treatment regimens corresponding to, similar to, or different from those used with dasatinib for the corresponding disorder, particularly in combination treatment regimens with one or more additional therapeutic agents, such as immune checkpoint inhibitors.

[0002] Kinase inhibitors are enzyme inhibitors that block the action of kinases. A partial, non-limiting list of such kinases includes ABlAKT, BCR-ABL, BLK, BRK, c-KIT, c-MET, CDKl, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDKlO, cRAFI, CSK, EGFR, ERBB2, ERBB3, ERBB4, ERK, PAK, FES, FGFRl, 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, SIKl, SIK2, SIK3, SRC, TIE, TIE2, TRK, and ZAP70. Kinases are enzymes that add phosphate groups to proteins or other organic molecules and have been shown to be important regulators of most cellular functions, including cell signaling, proliferation, differentiation, metabolism, survival, cell death, motility, and DNA damage repair. Deregulated signaling due to defective control of phosphorylation, particularly protein phosphorylation, has been implicated in a wide range of diseases, including those associated with abnormal (e.g., increased) activity of kinases. Such diseases include, but are not limited to, proliferative diseases (e.g., cancer, benign neoplasms, pathological angiogenesis, inflammatory diseases, and autoimmune diseases), as well as allergies and CNS disorders.

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

[0004] Inhibition of protein kinases, and therefore phosphorylation of substrate peptides or proteins, has been shown to be useful in the treatment of many diseases. for example, Afatinib, an ERBB inhibitor, is useful in the treatment of non-small cell lung cancer; Axitinib, a VEGFR, PDGFR, and c-KIT inhibitor, is useful in the treatment of renal cell carcinoma; Bosutinib, an ABL / BCR-ABL inhibitor, is useful in the treatment of chronic myeloid leukemia; Cabozantinib, a c-MET and VEGFR2 inhibitor, is useful in the treatment of thyroid cancer; Crizotinib, an ALK, HGFR, and c-MET inhibitor, is useful in the treatment of non-small cell lung cancer; Dasatinib, an ABL / BCR-ABL, SRC, and c-KIT inhibitor, is useful in the treatment of chronic myeloid leukemia; The EGFR inhibitor erlotinib is useful in the treatment of non-small cell lung cancer and pancreatic cancer; Gefitinib, an EGFR inhibitor, is useful in the treatment of non-small cell lung cancer; Imatinib, an ABL / BCR-ABL inhibitor, is useful in the treatment of chronic myeloid leukemia; The HER2 inhibitor lapatinib is useful in treating breast cancer; Nilotinib, an ABL / BCR-ABL inhibitor, is useful in the treatment of chronic myeloid leukemia; Pazopanib, a VEGFR, PDGFR, and c-KIT inhibitor, is useful in the treatment of renal cell carcinoma and soft tissue sarcoma; Palbociclib, an inhibitor of CDK4 and CDK6, is useful in the treatment of ER-positive and HER2-negative breast cancer; Ponatinib, an ABL / BCR-ABL, BEGFR, PDGFR, FGFR, EPH, SRC, c-KIT, RET, TIE2, and FLT3 inhibitor, is effective in treating chronic myeloid leukemia and acute lymphoblastic leukemia; Regorafenib, a RET, VEGFR, and PDGFR inhibitor, is useful in the treatment of rectal cancer and gastrointestinal stromal tumors; Ribociclib, an inhibitor of cyclin D1 / CDK4 and CDK6, is useful in the treatment of HR-positive, HER2-negative advanced or metastatic breast cancer; The JAK inhibitor ruxolitinib is useful in treating myelofibrosis; Sorafenib, a VEGFR, PDGFR, BRAF, and c-KIT inhibitor, is useful in treating renal cell carcinoma and hepatocellular carcinoma; Sunitinib, a VEGFR and PDGFR inhibitor, is useful in the treatment of renal cell carcinoma, gastrointestinal stromal tumors, and pancreatic neuroendocrine tumors; The JAK inhibitor tofacitinib is useful in treating rheumatoid arthritis; Vandetanib, a VEGFR, EGFR, RET, and BRK inhibitor, is useful in the treatment of thyroid cancer; and vemurafenib, a BRAF inhibitor, is useful in the treatment of melanoma.

[0005] Given the large number of kinases and associated diseases, there is an existing need for new inhibitors that are selective for various kinases that may be useful in treating the associated diseases; in particular, there remains a need for new kinase inhibitors, pharmaceutical compositions / formulations and their uses for treating diseases associated with the abnormal activity of one or more kinases; in particular, there remains a need for new inhibitors that are alternatives to existing kinase inhibitors such as dasatinib.

[0006] One particular kinase inhibitor is dasatinib (N-(2-chloro-6-methylphenyl)-2-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide, monohydrate (Figure 1(A)), marketed as "SPRYCEL" by Bristol-Myers Squibb, and is indicated for the treatment of adult patients with: (i) newly diagnosed, chronically-occurring, Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML); (ii) chronic, accelerated, or myeloid or lymphoid acute phase (Ph+) CML that has shown resistance or intolerance to prior imatinib-containing therapy; and (iii) Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) that has shown resistance or intolerance to prior therapy. In the EU, dasatinib is also indicated for the treatment of pediatric patients with newly diagnosed Ph+ CML in the chronic phase (Ph+ CML-CP) or Ph+ CML-CP that is resistant or intolerant to prior imatinib-containing therapy, and in the US, it is also indicated for pediatric patients with Ph+ CML in the chronic phase.

[0007] Notably, despite extensive testing of dasatinib, it is not approved for use in any cancer other than CML and Ph+ ALL in the United States or Europe, and as of September 2018, dasatinib is not indicated for solid tumors. Indeed, numerous clinical trials investigating the potential use of dasatinib in the treatment of solid tumors have either been terminated early (due to toxicity issues, for example) or have not reported strong or even promising results. For example, according to information on clinicaltrials.gov from September 2018 to September 2019, dasatinib has only reached one Phase 3 trial for solid tumors: Although dasatinib has suggested activity in chemotherapy-naive castration-resistant prostate cancer in early-phase clinical trials (e.g., Araujo et al., 2012, Cancer 118:63), a single trial in combination with docetaxel for castration-resistant prostate cancer, the "READY" trial (NCT00744497), failed to improve overall survival over docetaxel alone in such trials (Araujo et al., 2013, Cancer Oncol. 14:13017). Despite several trials in other cancers, such as breast, skin, pancreatic, brain, or lung cancer, dasatinib has not demonstrated satisfactory efficacy or tolerability and has not progressed to phase 3 trials for any of these cancers. Notably, a recent double-blind phase 2 trial in patients with locally advanced, unresectable pancreatic cancer failed to demonstrate an improvement in overall survival when combined with gemcitabine compared with gemcitabine alone (Evens et al. 2017, Annal. Onc. 28:354). However, several specialized trials aimed at selected "targeted" treatments for patients with specific cancers (including solid tumors) expressing specific drug targets may test dasatinib depending on the patient's target profile. For example, (i) the "tapur" trial ("Targeted Agent and Profiling Access Registry," https: / / www.tapur.org, NCT02693535) includes dasatinib in one possible treatment arm based on one or more of the following targets: BCR-ABL, SRC, KIT, PDGFRB, EPHA2, FYN, LCK, YES1; and (ii) the Melanoma Institute Australia trial (NCT02645149) in patients with BRAF and NRAS wild-type unresectable stage III or IV metastatic melanoma who have progressed on or are unable to receive standard therapy (typically immunotherapy), includes dasatinib as one possible treatment depending on the KIT mutation present in the patient's cancer. Dasatinib is also in one arm of BMS's "FRACTION-lung" Phase 2 trial (NCT02750514) and may be tested in combination with the immuno-oncology agent nivolumab in patients with advanced non-small cell lung cancer. Other arms of the trial are using nivolumab in combination with other immuno-oncology agents.

[0008] Thus, there is a particular need for new kinase inhibitors useful in the treatment of cancer, especially solid tumors for which dasatinib is not indicated and / or cancers for which dasatinib has not shown promising results. In particular, there remains a need for new kinase inhibitors useful in the treatment of one or more cancers, such as breast cancer, lung cancer (e.g., non-small cell carcinoma), pancreatic or prostate cancer (e.g., castrated or hormone-refractory), as well as melanoma. There also remains a need for new kinase inhibitors useful in the treatment of myeloid or lymphoblastic cancers, such as leukemia, preferably useful in the treatment of one or more Ph+ leukemias, such as CML and / or ALL.

[0009] Dasatinib has been described as an inhibitor of the following kinases at nanomolar concentrations: BCR-ABL, SRC family (SRC, LCK, YES, FYN), c-KIT, EPHA2, and PDGFR-β; however, what is particularly relevant to dasatinib's application in Ph+ leukemia is its inhibition of the hybrid protein kinase BCR-ABL.

[0010] The BC1ABL kinase is directly linked to a specific genetic abnormality on chromosome 22 in leukemic cancer cells (particularly CML cells) known as the "Philadelphia chromosome" (or Philadelphia translocation). This reciprocal translocation of genetic material between chromosomes 9 and 22 juxtaposes the ABL1 gene on chromosome 9 onto the BCR gene on chromosome 22, resulting in the coding sequence for a hybrid protein known as "BCR-ABL," a protein tyrosine kinase that is "always on," causing cells to divide uncontrollably. The majority of CML cases and 20-30% of ALL cases are Ph+. Imatinib (STI571), the first selective BCR-ABL inhibitor marketed by Novartis as "GLEEVEC / GLIVEC," was considered a breakthrough in the treatment of Ph+ leukemia. However, despite increased overall survival, drug resistance that developed during imatinib treatment led scientists to discover that a large proportion of such resistance arises due to the emergence of BCR-ABL mutations, particularly amino acid substitutions within the ABL-derived kinase domain (for review, see Rossari & Orciuolo. 2018, J. Hemat. Oncol. 11:84, incorporated herein by reference in its entirety).

[0011] Analysis of BCR-ABL mutation status and survival probability in patients treated with imatinib showed that mutations within the phosphatase loop (P-loop) of the ABL locus of the BCR-ABL kinase are the most frequent, but (rare) mutations outside the P-loop (especially within the kinase domain) are associated with decreased overall survival in CML patients treated with imatinib (Jabbour et al., 2006, Leukemia 20: 1767). A number of emerging BCR-ABL mutations have been previously identified and described (see Table 1 in Manley et al. 2005, Biochem. Biophys. Acta 1754:3; and Table 1 in Rossari & Orciuolo 2018, which also describes mutations in other kinase targets of dasatinib; both such tables are specifically incorporated herein by reference). In particular, in the ATP binding domain of BCR-ABL (with positions shown in the wild-type ABL protein), the following mutations are found: 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 that had become resistant to imatinib, presumably due to the emergence of one or other of these mutations. Based on modeling studies, dasatinib is predicted to bind to multiple conformations of the ABL kinase, which may explain why some conformational-changing mutations of ABL are inhibited by dasatinib but not by imatinib. Indeed, a retrospective analysis comparing mutation occurrence during first-line treatment with dasatinib or imatinib found that fewer distinct mutation sites emerged with dasatinib treatment (four distinct sites) compared with imatinib treatment (12 distinct sites) (Hughes et al. 2015, Leukemia 29: 1832, especially Figure 1). Importantly, however, (i) the overall proportion of patients who developed any type of mutation was similar (17 of 259 patients treated with dasatinib and 18 of 260 patients treated with imatinib), (ii) the majority of mutations that developed during dasatinib treatment were in the ATP-binding domain (3 / 4 mutation sites), and (iii) the most common mutation that developed during dasatinib treatment was the T315 mutation in the so-called "gate-keeper" residue, which still conferred resistance to dasatinib's inhibition of the BCR-ABL kinase. The ProQinase ABL1 Kinase "Wildtype and Mutant Panel" provides a specific set of BCR-ABL mutants that can be tested against kinase inhibitors, including the ABL1 wild-type protein (amino acids P118-S525) and the most common mutations of BCR-ABL: G250E, Q252H, Y253F, E255K, T315i, M351T, and H396P (www.proqinase.com).

[0012] The T315I mutation is one of the most frequent BCR-ABL mutations, occurring in 2-20% of CML cases (Nicolini et al. 2009, Blood 114:5271). The resistance of these mutations to dasatinib inhibition is one of dasatinib's shortcomings as a kinase inhibitor, prompting the development of a "third-generation" BCR-ABL inhibitor known as ponatinib (marketed as ICLUSIG by Incyte and Takeda). Ponatinib does indeed potently inhibit the T315I mutation in BCR-ABL kinase (in vitro IC50 of 2.0 nM), making it a more promising kinase inhibitor than dasatinib. It also inhibits many other kinases, including at least members of the VEGFR, PDGFR, FGFR, EPH receptor and SRC family of kinases, as well as KIT, RET, TIE2, and FLT3, with in vitro IC50 concentrations between 0.1 and 20 nM. Additionally, sales of ponatinib in the United States were suspended in October 2013 due to "risk of life-threatening blood clots and severe blood vessel narrowing," but this was partially lifted in December 2013, and revised prescribing information, a new Back Box Warning, and a Risk Evaluation and Mitigation Strategy were issued to better evaluate the risks and benefits of using the drug. Furthermore, the price of ponatinib in the United States (which costs $138,000 per year) has been criticized. Thus, substantial drawbacks are exhibited by ponatinib such that there remains a need for novel kinase inhibitors that have the potential to treat Ph+ leukemia (or other cancers) more effectively, safely, easily, and / or inexpensively, and / or that have the potential to be more selective for SRC, ABL / BCR-ABL, and / or LCK than other kinase inhibitors such as dasatinib or ponatinib.

[0013] However, compared to imatinib, dasatinib is not particularly specific for BCR-ABL and binds to and / or inhibits a significant number of other kinases (see Figure 3 in Bantscheff et al. 2007, Nat. Biotech. 25: 1035; Supplementary Figure 2 in Anastassiadis et al. 2012 Nat. Biotech. 29: 1039). In particular, dasatinib has been described to bind to and / or inhibit significantly more than imatinib 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 has been 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, dasatinib has yet another potential drawback, given that it is a poorly selective kinase inhibitor, and this reduction may be causally related to the increased incidence of non-serious toxicity challenges, particularly thrombocytopenia, encountered when treating patients with dasatinib (Wei et al. 2010, J. Hemat. Oncol. 3:47).

[0014] As mentioned above, dasatinib is a potent inhibitor of KIT, a receptor tyrosine kinase that is becoming an increasingly interesting target for the treatment of certain cancers, not least because mutations in the KIT gene have been detected in cancers such as leukemia, ovarian cancer, and melanoma (Babei et al. 2016, Drug Des. Dev. Thera., 10:2443). Dasatinib is also known to inhibit at least the most common KIT mutants in melanoma (Woodman et al. 2009, J. Clin. One. 27:9019). However, inhibition of KIT, particularly the relative activity of certain tyrosine kinase inhibitors against FLT3 and KIT, is associated with other side effects such as myelosuppression and hair depigmentation (Galanis and Levis 2015: Haematologica 100:e89). Indeed, treatment with dasatinib is associated with severe bone marrow suppression (see below).

[0015] Salt-inducible kinases (SIKs) constitute a serine tyrosine kinase subfamily within the adenosine monophosphate-activated kinase (AMPK) family. Three members (SIK1-2, -3) have been identified to date. SIK1 shares 78% and 68% amino acid identity with SIK2 and SIK3 in the kinase domain, respectively. Cloning of SIK1 (also known as SIK and SNF1LK), which is abundantly expressed in the adrenal gland of high-salt-fed rats, led to the subsequent cloning of SIK2 (QIK, also known as KIAA781 and SNF1LK2), which is expressed primarily in adipose tissue, and the rather ubiquitous SIK3 (QSK, also known as KIAA999 or L19) (Katoh et al. 2004, Mol. Cell. Endocrinol. 217: 109). The three SIKs share a similar structure, possessing an N-terminal kinase domain (catalytic domain), a middle ubiquitin-associated domain (thought to be important for phosphorylation by LKB1), and a long C-terminal sequence (thought to be a site for further phosphorylation by PKA). However, highly diverse roles have been implicated in the various SIKs. For example, various SIKs have been implicated in diverse biological processes, such as the induction of SIK1 by gastrin and the response of bone cells to parathyroid hormone (Wein et al., 2016, Nature Commun. 7: 13176) and the inhibition of gastric adenocarcinoma cell migration (Selvik et al., 2014, PLoS ONE 9: ell2485). Other potential roles of salt-inducible kinases (particularly SIK3) have been described in PCT / EP2018 / 060172, and SIK3 has been implicated in tumor cell cellular immune responses, particularly tumor necrosis factor (TNF) resistance.

[0016] Therefore, there remains a need for new kinase inhibitors, particularly those that exhibit a different profile of kinases relative to those inhibited by dasatinib. For example, (i) new kinase inhibitors that are more specific for important disease-related kinases (e.g., ABL / BCR-ABL, SRC, LCK, and / or EPHA2, EPHA4, CSF-R1, HCK, ACK1, and / or KIT) than for other kinases; (ii) inhibit important disease- or side-effect-related kinases with a different profile than dasatinib (e.g., for KIT and / or FLT3); and / or (iii) inhibit one or more mutants of disease-related kinases, particularly mutants that are resistant to one or other kinase inhibitors, such as mutants of ABL / BCR-ABL or KIT.

[0017] Furthermore, dasatinib is primarily metabolized by the cytochrome P450 enzyme 3A4 (CYP3A4) in humans and is also a time-dependent inhibitor of CYP3A4. Indeed, if patients are concurrently receiving strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole), dasatinib plasma concentrations may increase to dangerous levels, and the dasatinib dose must be significantly reduced (e.g., from 1 mg daily to 20 mg daily). Grapefruit juice may also increase dasatinib plasma concentrations and should be avoided. Therefore, there remains a need for new kinase inhibitors that exhibit different cytochrome P450 inhibition patterns (e.g., CYP3A4 inhibition patterns) from dasatinib.

[0018] Importantly, dasatinib should be discontinued (or its dosage reduced) if bone marrow suppression occurs. In fact, treatment with dasatinib is associated with severe (NCI CTC grade 3 or 4) thrombocytopenia, neutropenia, and anemia, and bone marrow suppression is listed as a single "Warnings and Precautions" in the dasatinib US prescribing information. In clinical trials of dasatinib, in addition to causing thrombocytopenia in human subjects, the following studies were conducted: (i) severe central nervous system (CNS) hemorrhage (including fatalities) occurred in 1% of patients; (ii) severe gastrointestinal bleeding, including fatalities, occurred in 4% of patients, generally requiring treatment interruption and transfusion; and (iii) other severe bleeding events occurred in 2% of patients.

[0019] However, the additional "warnings and precautions" for dasatinib include the following: (x) it is associated with fluid retention, with severe fluid retention having been reported in up to 10% of patients in clinical trials; (y) it may prolong ventricular repolarization (QT interval), with QT prolongation observed in up to 1% of CML patients in clinical trials; and (z) cardiac side effects were reported in 5.8% of 258 patients taking dasatinib, including cardiomyopathy, congestive heart failure, diastolic dysfunction, fatal myocardial infarction, and left ventricular dysfunction in 1.6% of patients. In fact, dasatinib is known to be an inhibitor of hERG (Pharmacology / Toxicity Review and Evaluation of NDA 21-986, p. 31). hERG (human "Ether-a-go-go-Related Gene") is an ion channel that contributes to the electrical activity of the heart and regulates heartbeat. Blocking or impairing the ability of this channel to conduct current across the cell membrane (e.g., by administration of drugs) can lead to potentially fatal "long QT syndrome." Therefore, there remains a need for new kinase inhibitors that exhibit hERG inhibition distinct from dasatinib. For example, it would be advantageous to provide novel kinase inhibitors that exhibit an IC50 for hERG that is higher than the IC50 of dasatinib.

[0020] Compared to other BCR-ABL inhibitors, dasatinib has an extremely short half-life, with an overall mean terminal half-life of only 3-5 hours (see "12.3. Pharmacokinetics" in the full package insert). In contrast, the elimination half-life of imatinib is approximately 18 hours. The mean terminal elimination half-life of bosutinib is 22.5 hours. The apparent elimination half-life of nilotinib is approximately 17 hours. The geometric mean terminal elimination half-life of ponatinib is approximately 24 hours. Without being bound by theory, the short half-life of dasatinib (suitable for once-daily dosing) may explain the limited activity associated with lower in vivo drug concentrations later in the day and / or side effects associated with peak / higher in vivo drug concentrations shortly after dosing. Thus, there remains a need for novel kinase inhibitors that exhibit longer half-life characteristics (e.g., than those exhibited by dasatinib). For example, advantageous kinase inhibitors may be more stable than dasatinib, e.g., by exhibiting a longer half-life in plasma and / or liver microsomal stability assays.

[0021] Further precautions, adverse events and other prescribing information for dasatinib can be found in the respective Summary of Product Characteristics (SmPC) in the full prescribing information, which can be found on the EMA's and FDA's respective websites (each shown below, accessed on August 20, 2018, the contents of each of which are incorporated herein by reference in their entirety): (i) http: / / www.ema.europa.eu / docs / en_GB / document_library / EPAR__Product_Information / human / 000709 / WC500056998.pdf, and (ii) https: / / www.accessdata.fda.gov / drugsatfda_docs / 1abel / 2010 / 021986s7s8lbl.pdf.

[0022] Numerous variants of dasatinib have been synthesized and demonstrated to have in vitro biochemical inhibitory activity against one or more kinases and / or antiproliferative activity against cells. In particular, such variants were synthesized (i) during the discovery phase of dasatinib to understand and explain its structure-activity relationship (SAR) (Lombardo et al., 2004, J Med Chem 47:6658; Das et al., 2006, J Med Chem 49:6819); and (ii) to provide alternative kinase inhibitors and / or drug candidates (e.g., WO 2006 / 081172 and WO 2008 / 033746). The dasatinib variants described therein have a phenyl moiety at the carboxamide. These disclosures demonstrate a substantial range of substituents that can be substituted at other positions and therein to provide compounds that are kinase inhibitors and / or have cellular antiproliferative activity (Figure 8).

[0023] International Publication No. WO 2018 / 193084 (published October 25, 2018) discloses dasatinib variants having a pyridinyl moiety. Beutner et al. (2018, Org Lett 20:4218) describe methods for forming challenging amide bonds, including those for certain pyridines, pyrazines, and pyrimidines. Pennington et al. (2017, J Med Chem 60:3552) describe how replacing C—H groups with N atoms in aromatic and heteroaromatic ring systems can affect molecular and physiological properties. However, it is known empirically that making such substitutions results in statistically no better improvement than chance: matched molecular pair analysis (MMPA) of internal data at Abbott (Hajduk & Sauer 2008, J Med Chem 51:553) found that, as with most substituent substitutions, there is a roughly equal probability of increasing or decreasing potency by exchanging C-H groups and N atoms. Indeed, this analysis further revealed that such substitutions have a less than 10-fold probability of achieving a 10-fold increase in potency and a less than 100-fold probability of achieving a 100-fold increase in potency; similar probabilities observed when investigating the effect of such substitutions on improving binding affinity (Hu et al., 2014, F1000 Research 3:36; de la Vega de Leon et al., 2014, Med Chem Comm 5:64).

[0024] Accordingly, one object of the present invention is to provide one or more kinase inhibitors having one or more properties (e.g., properties as demonstrated by in vitro and / or in vivo assays) that address one or more of these or other problems. Another object is to provide alternative and / or improved kinase inhibitors to dasatinib (or one or other kinase inhibitors such as those described herein). For example, kinase inhibitors that can exhibit one or more functional (e.g., kinase selectivity) and / or ADMET properties that are different from and / or improved compared to dasatinib (or one or other kinase inhibitors such as those described herein) would be particularly advantageous. The object underlying the present invention is solved by the subject matter disclosed or defined elsewhere herein, for example, by the subject matter of the accompanying claims. Summary of the Invention

[0025] Generally, as a brief description, the main aspects of the present invention can be summarized as follows:

[0026] In a first aspect, the present invention provides a compound selected from the group consisting of kinase inhibitors of the formula: [ka] and solvates, salts, N-oxides, complexes, polymorphs, crystalline forms, racemic mixtures, diastereomers, enantiomers, tautomers, conformers, isotopic labeling, prodrugs, and combinations thereof; where R 1a , R 1b , R 1c , R 2 , R 3 , R 4 , R 5 , A, B, and E are as defined herein.

[0027] In a second aspect, the present application provides a pharmaceutical composition comprising a compound of the first aspect, and optionally a pharmaceutically acceptable carrier.

[0028] In a third aspect, the application provides a compound of the first aspect or a pharmaceutical composition of the second aspect for use in therapy.

[0029] In a fourth aspect, the application provides a compound of the first aspect or a pharmaceutical composition of the second aspect for use in a method for the treatment of a disease, disorder or condition in an individual (particularly a human patient), wherein the disease or condition is associated with a kinase.

[0030] Further aspects of the invention are disclosed herein. [Brief explanation of the drawings]

[0031] The diagram shows:

[0032] [Figure 1-1] FIG. 1 shows the chemical structures of (A) dasatinib (compound A8), N-(2-chloro-6-methylphenyl)-2-((6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-yl)amino)thiazole-5-carboxamide; (B) kinase inhibitor B3, N-(4-chloro-2-methylpyridin-3-yl)-2-((6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-yl)amino)thiazole-5-carboxamide; (C) certain other kinase inhibitors of formula (I)C1-C13; and (D) certain other kinase inhibitors of formula (I)D1-D10. [Figure 1-2] Same as above

[0033] [Figure 2-1]FIG. 2 depicts the kinase inhibitory activity of (A-E) kinase inhibitors of formula (I) (B3, left column) against kinases (A) ABL1, (B) SRC, (C) SIK1, (D) SIK2, and (E) SIK3, relative to dasatinib, and the kinase inhibitory activity of (F-J) other kinase inhibitors of formula (I) (C3, left column, C12, right column) against kinases (F) ABL1, (G) SRC, (F-I) SIK1, (F-I) SIK2, and (J) SIK3, respectively—X-axis is compound concentration (M) and Y-axis is kinase activity (%). [Figure 2-2] Same as above

[0034] [Figure 3-1] Figure 3 shows the selectivity of kinase inhibition by the % residual activity (at 1 μM compound) of B3 (a kinase inhibitor of Formula (I)), dasatinib (A8), and C7 (another kinase inhibitor of Formula (I)): ****<25% residual activity; ***25% to <50% residual activity; **50% to <75% residual activity; *>75% residual activity. Protein kinase family classification (Manning et al., Science, 6 December 2002: Vol. 298, no. 5600, pp. 1912-1934): AGC: includes the PKA, PKG, and PKC families; CAMK: calcium / calmodulin-dependent protein kinase; CK1: casein kinase-like; CMGC: CDK, MAPK, GSK3, and CLK families; TK: tyrosine kinase; TKL: tyrosine kinase-like; STE: homolog of yeast Sterile 7, Sterile 11, and Sterile 20 kinases. ## constitutively active kinases. [Figure 3-2] Same as above [Figure 3-3] Same as above [Figure 3-4] Same as above [Figure 3-5] Same as above [Figure 3-6] Same as above [Figure 3-7] Same as above [Figure 3-8] Same as above

[0035] [Figure 4]Figure 4 shows the selectivity of kinase inhibition (by % residual activity at 1 μM compound) by kinase inhibitor B3 of Formula (I) (X-axis) compared to dasatinib (A8; Y-axis): (A) axis showing full range of residual activity; and (B) axis showing range of 0-50% residual activity.

[0036] [Figure 5] Figure 5: Kinase inhibitory activity of the kinase inhibitor of formula (I) (B3, left column) compared to dasatinib (A8, right column) against the kinases (A) FLT3, (B) SYK, (C) KIT, and (D) LCK. X-axis represents compound concentration (M), and Y-axis represents kinase activity (%).

[0037] [Figure 6] Figure 6: Sensitization of tumor cells to in vitro TNF challenge with (A) kinase inhibitor B3 and (B) A8 (dasatinib). Circles: compound (concentration indicated) + rHuTNF (10 ng / mL); squares: compound alone (concentration indicated) without rHuTNF.

[0038] [Figure 7] Figure 7: Relative tumor cell viability (normalized RLU by cytotoxicity / viability) of selected kinase inhibitors described in PCT / EP2018 / 060172 at various concentrations, alone (squares) or in combination with 10 ng / mL TNF (circles), in an assay using M579-A2-luc as described in Example 9. The inhibitory activity of these compounds against SIK family members and the related kinases ABL1 and SRC is also shown, with the metrics used listed in Table 3. (A) pan-SIK and ABL1 & SRC inhibitor, Compound B1; (B) ABL1 & SRC inhibitor, Compound B8; (C) SIK1, SIK2, and ABL1 & SRC inhibitor, Compound B4.

[0039] [Figure 8]Figure 8 shows (A) the potency of various derivatives of dasatinib against the indicated cell lines. The cellular antiproliferative activity of dasatinib variants was determined based on tetrazolium dye conversion after 72 hours of compound exposure. IC values ​​are reported as the average of at least three independent measurements, or individual IC values ​​if fewer than three measurements were performed. Variability around the mean is indicated by SE values ​​in parentheses and was <50% unless otherwise indicated. ; and (B) the biochemical and cellular antiproliferative activity of dasatinib variants was shown in Table 4 of Das et al., 2006 (J Med Chem 49:6819). an = 3, variation of individual values, <20%. bn = 3, variation of individual values, <30%.

[0040] [Figure 9] Figure 9 shows the selectivity of kinase inhibition (by % residual activity at 1 μM compound) by kinase inhibitors of Formula (I), C7 (Y-axis) compared to (A) dasatinib (A8; -X-axis); and (B) another kinase inhibitor of Formula (I), B3 (X-axis). The dashed area highlights groups of kinases that are substantially differentially inhibited between the applicable compounds.

[0041] [Figure 10] Figure 10: Body weights of female C57BI / 6 mice administered 33 mg / kg (black squares) and 100 mg / kg (gray diamonds) by oral gavage once daily (QD = A) and twice daily (BID = B) compared to control animals (gray squares). X-axis: days post-dose; Y-axis: % body weight change. (C) Plasma levels of C7 measured by LC-MS / MS. A = 33 mg / kg QD; B = 100 mg / kg QD; C = 33 mg / kg BID; D = 100 mg / kg BID. Y-axis: plasma concentration of C7 (nM).

[0042] [Figure 11]Figure 11 shows (A) tumor growth kinetics in mice implanted with MC38 cells when treated with vehicle (black squares), C7 100 mg / kg QD (gray hexagons), C7 100 mg / kg BID (gray triangles), and A8 (dasatinib) 30 mg / kg QD A8 (gray circles). Y-axis = mean tumor volume (mm). Errors are SEM - X-axis: days. Statistical significance was calculated by ANOVA analysis with Tukey's multiple comparison analysis. *** p<0.001; (B) body weight kinetics of mice in (A). Y-axis: mean body weight change (%).

[0043] [Figure 12] Figure 12 shows the immuno-oncological effect of C7, a compound 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 using ANOVA analysis with Tukey's multiple comparison analysis. (A) Y-axis: ratio of CTL to Treg cells. (B) Activated CTL (CD25+CD69+); Y-axis: % of CD45+ cells. (C) Activated CTL (Granzyme B+); Y-axis: % of CD45+ cells. (D) Immunosuppressive M2-like tumor-associated macrophages (TAM) (CD206+MHC-II+); Y-axis: % of CD45+ cells; * p<0.05; ** p<0.01; *** p<0.00.

[0044] [Figure 13]Figure 13 shows TNF-induced cell death sensitized by compound C7. (A) TNF-induced apoptosis of PANC-1 cells. PANC-1 cells were treated with 370 nM ("diamonds") and 3333 nM ("squares") of C7, and DMSO alone ("stars"), before adding 100 ng / ml HurTNF for 120 h (+rHuTNF = open shapes; -rHuTNF = solid shapes; open circles = 10 ng / mL HurTNF control). Cell death was assessed using real-time live-cell microscopy to measure nuclear uptake of YOYO-1 dye (area of ​​YOYO-1+ cells / well). Y-axis = tumor cell death (µm² / well). X-axis = time (h); (B) Effect of C7 on TNF-induced (100 ng / ml rMuTNF) cell death in murine MC38 (+rMuTNF = "diamond"; -rMuTNF = "circle"). Cell viability was measured after 72 hours 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).

[0045] [Figure 14] Figure 14 shows (A) the effect of compound C7 on NFKB activity. Reporter PANC-1 cells expressing luciferase under the control of the NFKB promoter were treated with different concentrations of C7 for 8 hours before the addition of 10 ng / ml rHuTNF (+rHuTNF = "diamond"; -rHuTNF = "circle"). Luciferase activity was normalized to PANC-1 cells treated with rHuTNF without inhibitor (DMSO only). Y-axis = NFKB activity (%). X-axis = compound concentration (nM). (B) The 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 using a Meso Scale Discovery (MSD) assay using anti-HDAC4 capture and anti-pHDAC4 detection antibodies. HDAC4 phosphorylation was normalized to untreated PANC-1 cells (DMSO only). Y-axis = HDAC4 phosphorylation (%). X-axis = compound concentration (nM).

[0046] [Figure 15] Figure 15 shows the growth inhibition of WSU-NHL (A) and DOHH-2 (B) cell lines by compound C7, showing a GI50 of approximately 8 nM and 9 nM, respectively. X-axis: compound concentration (M); Y-axis: percentage growth inhibition at 96 hours (GI). DETAILED DESCRIPTION OF THE INVENTION

[0047] The present invention, and certain non-limiting aspects and / or embodiments thereof, may be described in more detail below.

[0048] Although the present invention can be described in further detail, it is understood that the invention is not limited to the particular methodology, protocols, and reagents described herein, as these may vary. It is also understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the invention, which is limited only by what is described, defined, or otherwise disclosed herein, particularly any particular embodiment or the appended claims.

[0049] Certain elements of the invention are described in more detail herein. While these elements are listed with specific embodiments, 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 construed as limiting the invention to only those embodiments explicitly described. This description of the present application should be understood to support and encompass embodiments combining the explicitly described embodiments with any number of the disclosed and / or preferred elements. Furthermore, any permutation and combination of all elements described in this application should be considered to be disclosed by the description of this application, unless the context dictates otherwise. For example, in one embodiment of the compounds of the invention, L is a bond and in another embodiment of the compounds of the invention, R 3is H, in a preferred embodiment of the compounds of the invention, L is a bond and R 3 is H, or in one embodiment of the use of the compounds of the invention, the subject is an adult, and in another embodiment of the use of the compounds of the invention, the proliferation disorder is prostate cancer, and then in a preferred embodiment of the use of the compounds of the invention, the subject is an adult and the proliferation disorder is prostate cancer.

[0050] General / Definition Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0051] Preferably, the terms used herein are defined as set forth in "A multilingual glossary of biotechnological terms: (IUPAC Recommendations)", HGW. Leuenberger, B. Nagel and H. Kolbl, Eds., Helvetica Chimica Acta, CH-4010 Basel, Switzerland, (1995).

[0052] The practice of the present invention employs, unless otherwise indicated, conventional methods of chemistry, biochemistry, and recombinant DNA technology as described in the literature of the art (see, e.g., Molecular Cloning: A Laboratory Manual, 2nd Edition, J. Sambrook et al., eds., Cold Spring Harbor Laboratory Press, Cold Spring Harbor 1989).

[0053] Unless the context requires otherwise, throughout this specification and the claims that follow, the words "comprise" and variations such as "comprises" and "comprising" will be understood to mean the inclusion of a stated member, integer or step or group(s) of members, integers or steps, but not the exclusion of other members, integers or steps or groups of members, integers or steps, and the words "consisting essentially of" will mean the exclusion of any essential member, integer or step or group of members, integers or steps. For example, a pharmaceutical composition consisting essentially of a member / component as defined herein (e.g., a compound as defined in any of the aspects of the present invention and optionally one additional therapeutic agent) excludes further therapeutic agents (other than a compound as defined in any of the aspects of the present invention and optionally one additional therapeutic agent), but does not exclude trace amounts (e.g., the amount of contaminants (preferably the amount of all contaminants present in the composition) is less than 5% by weight, e.g., less than 4% by weight, less than 3% by weight, 2% by weight, 1% by weight, 0.5% by weight, 0.4% by weight, 0.3% by weight, 0.2% by weight, 0.1% by weight, 0.05% by weight, etc. (of the total composition) and / or contaminants (e.g., from the isolation and purification method) in pharmaceutically acceptable excipients (carriers, e.g., phosphate buffered saline, preservatives, etc.). The term "consisting of" means excluding all other members, significant integers, or steps, or groups of significant members, integers, or steps. For example, a pharmaceutical composition consisting of components / ingredients defined herein (such as a compound defined in any of the aspects of the invention, one excipient, and optionally one additional therapeutic agent) excludes more than 2% by weight of any other compound (more than 1%, more than 0.5%, more than 0.4%, more than 0.3%, more than 0.2%, more than 0.1%, more than 0.09%, more than 0.08%, more than 0.07%, more than 0.06%, more than 0.05%, more than 0.04%, more than 0.03%, more than 0.02%, more than 0.01% by weight) of the total composition. The term "comprising" includes the term "consisting essentially of," which in turn includes the term "consisting of." Thus, at each occurrence in this application, the term "comprising" can be replaced with the term "consisting essentially of" or "consisting of," and similarly, at each occurrence in this application, the term "consisting essentially of" can be replaced with the term "consisting of."

[0054] As used herein, "and / or" should be interpreted as a specific disclosure of each of the two specified features or components, with or without the other feature, for example, "X and / or Y" should be interpreted as a specific disclosure of (i) X, (ii) Y, and (iii) each of X and Y, as if each were individually set forth herein.

[0055] In the context of the present invention, the terms "about" and "approximately" are used interchangeably and indicate an interval of accuracy that a person skilled in the art would understand to still ensure the technical effect of the feature in question. The terms typically indicate deviations from the indicated numerical value of ±5%, ±4%, ±3%, ±2%, ±1%, ±0.9%, ±0.8%, ±0.7%, ±0.6%, ±0.5%, ±0.4%, ±0.3%, ±0.2%, ±0.1%, ±0.05%, e.g., ±0.01%. As will be understood by those skilled in the art, the specific deviation of a numerical value for a given technical effect depends on the nature of the technical effect. For example, a natural or biological technical effect may generally have a greater deviation than an artificial or engineered technical effect. As will be understood by those skilled in the art, the specific deviation of a numerical value for a given technical effect depends on the nature of the technical effect. For example, a natural or biological technical effect may generally have a greater deviation than an artificial or engineered technical effect.

[0056] The terms "a," "an," and "the," and similar references used in the context of describing the present invention (particularly in the context of the claims), should be construed to encompass both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

[0057] The recitation of ranges of values ​​herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, and unless otherwise indicated herein, each separate value is incorporated herein to the same extent as if it were individually recited herein.

[0058] All methods described herein can be performed in any suitable order unless otherwise indicated herein or clearly contradicted by context.

[0059] Any and all examples provided herein, or the use of exemplary language (e.g., "such"), are intended merely to better illustrate the invention and do not otherwise limit the scope of the claims. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.

[0060] Several documents are cited within the body of this specification. Each of the documents 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 shall be construed as an admission that the present invention is not inventive over such disclosure by virtue of prior invention.

[0061] The terms "of the present invention," "in accordance with the present invention," "according to the present invention," and the like, as used herein, are intended to refer to all aspects and embodiments of the present invention as described and / or claimed herein.

[0062] It will be understood that application of the teachings of the present invention to a particular problem or environment, and the inclusion of variations of the present invention or additional features thereto (such as further aspects and embodiments), are within the capabilities of those skilled in the art in light of the teachings contained herein.

[0063] Unless the context dictates otherwise, the feature descriptions and definitions set forth above or below are not limited to any particular aspect or embodiment of the invention, but apply equally to all aspects and embodiments described.

[0064] The term "alkyl" refers to a monoradical 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, iso-propyl (also called 2-propyl or 1-methylethyl), butyl, iso-butyl, tert-butyl, n-pentyl, iso-pentyl, sec-pentyl, neo-pentyl, 1,2-dimethyl-propyl, iso-amyl, n-hexyl, iso-hexyl, sec-hexyl, n-heptyl, iso-heptyl, n-octyl, 2-ethyl-hexyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, and the like. "Substituted alkyl" means that one or more (up to the maximum number of hydrogen atoms attached to the alkyl group, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, e.g., 1 to 5, 1 to 4, or 1 to 3, or 1 to 2) hydrogen atoms of the alkyl group are replaced with a non-hydrogen substituent (when two or more hydrogen atoms are replaced, the substituents can be the same or different). Preferably, the non-hydrogen substituent is a first-level substituent, a second-level substituent, or a third-level substituent as specified herein, such as halogen, -OH, -NH2, -NHCH3, -N(CH3)2, -CN, -OCH3, -OCF3, or an optionally substituted aryl. Examples of substituted alkyls include trifluoromethyl, 2,2,2-trichloroethyl, 2-hydroxyethyl, 2-aminoethyl, 2-(dimethylamino)ethyl, arylalkyl (also called "aralkyl"; e.g., benzyl, chloro(phenyl)methyl, 4-methylphenylmethyl, (2,4-dimethylphenyl)methyl, o-fluorophenylmethyl, 2-phenylpropyl, 2-, 3-, or 4-carboxyphenylalkyl), or heteroarylalkyl (also called "heteroaralkyl").

[0065] The term "alkylene" refers to a diradical of a saturated straight or branched chain hydrocarbon. Preferably, the alkylene comprises 1 to 12 (e.g., 1 to 10) carbon atoms, i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms), more preferably 1 to 8 carbon atoms, e.g., 1 to 6 or 1 to 4 carbon atoms. Exemplary alkylene groups include methylene, ethylene (e.g., 1,1-ethylene, 1,2-ethylene), propylene (e.g., 1,1-propylene, 1,2-propylene (-CH(CH3)CH2-), 2,2-propylene (-C(CH3)2-), and 1,3-propylene), butylene isomers (e.g., 1,1-butylene, 1,2-butylene, 2,2-butylene, 1,3-butylene, 2,3-butylene (cis or trans or mixtures thereof), 1,4-butylene, 1,1-isobutylene, 1,2-isobutylene, and 1,3-isobutylene), pentylene isomers (e.g., 1,1-pentylene, 1,2-pentylene, 1,3-pentylene, 1,4-pentylene, 1,5-pentylene, 1,1-isopentylene, 1,1-sec-pentyl, 1,1-neo-pentyl), hexylene isomers (e.g., 1,1-hexylene, 1,2-hexylene, 1,3-hexylene, 1,4-hexylene, 1,5-hexylene, 1,6-hexylene, and 1,1-isohexylene), heptylene isomers (e.g., 1,1-heptylene, 1,2-heptylene, 1,3-heptylene, 1,4-heptylene, 1,5-heptylene, 1,6-heptylene, 1,7-heptylene, and 1,1-isoheptylene), octylene isomers (e.g., 1,1-octylene, 1,2-octylene, 1,3-octylene, 1,4-octylene, 1,5-octylene, 1,6-octylene, 1,7-octylene, 1,8-octylene, and 1,1-isooctylene), etc. Straight-chain alkylene moieties having at least three carbon atoms and a free valence at each end can also be designated as multiples of methylene (e.g., 1,4-butylene can also be called tetramethylene).In general, instead of using the terminal "ylene" for the alkylene moieties specified above, the terminal "diyl" can also be used (e.g., 1,2-butylene can also be called butane-1,2-diyl), and "substituted alkylene" means that one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, e.g., between 1 and 5, 1 and 4, or 1 and 3, or 1 or 2) hydrogen atoms bonded to an alkylene group are replaced with non-hydrogen substituents (when one or more hydrogen atoms are replaced, the substituents can be the same or different. Preferably, the non-hydrogen substituents are first-level substituents, second-level substituents, or third-level substituents as specified herein, such as halogen or optionally substituted aryl). Examples of substituted alkylene include chloromethylene, dichloromethylene, fluoromethylene, and difluoromethylene.

[0066] The term "alkenyl" refers to a monoradical of an unsaturated straight-chain or branched-chain hydrocarbon having at least one carbon-carbon double bond. Generally, the maximum number of carbon-carbon double bonds in an alkenyl group can be equal to an integer calculated by dividing the number of carbon atoms in the alkenyl group by 2; if the number of carbon atoms in the alkenyl group is uneven, the result of the division is rounded up to the next integer. For example, for an alkenyl group having 9 carbon atoms, the maximum number of carbon-carbon double bonds is 4. Preferably, the alkenyl group has 1 to 6 (e.g., 1 to 4), i.e., 1, 2, 3, 4, 5, or 6 carbon-carbon double bonds. Preferably, the alkenyl group contains 2 to 12 (e.g., 2 to 10) carbon atoms, i.e., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms), more preferably 2 to 8 carbon atoms, e.g., 2 to 6 carbon atoms or 2 to 4 carbon atoms. Thus, in preferred embodiments, the alkenyl group contains 2 to 12 (e.g., 2 to 10) carbon atoms and 1, 2, 3, 4, 5, or 6 (e.g., 1, 2, 3, 4, or 5) carbon-carbon double bonds, and more preferably 2 to 8 carbon atoms and 1, 2, 3, or 4 carbon-carbon double bonds (e.g., 2 to 6 carbon atoms and 1, 2, or 3 carbon-carbon double bonds, or 2 to 4 carbon atoms and 1 or 2 carbon-carbon double bonds). The carbon-carbon double bond may be in the cis (Z) or trans (E) configuration. Exemplary alkenyl groups include vinyl, 1-propenyl, 2-propenyl (e.g., 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 and the like. When an 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., one, relative to the maximum number of hydrogen atoms attached to the alkenyl group, e.g., up to 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, e.g., 1-5, 1-4, or 1-3, or 1 or 2) hydrogen atoms of an alkenyl group have been replaced with a non-hydrogen substituent (when two or more hydrogen atoms are replaced, the substituents can be the same or different). Preferably, the non-hydrogen substituent is a first-level substituent, a second-level substituent, or a third-level substituent as specified herein, such as a halogen or an optionally substituted aryl. An example of a substituted alkenyl is styryl (i.e., 2-phenylvinyl).

[0067] The term "alkenylene" refers to an unsaturated straight-chain or branched-chain hydrocarbon diradical having at least one carbon-carbon double bond. Generally, the maximum number of carbon-carbon double bonds in an alkenylene group can be equal to an integer calculated by dividing the number of carbon atoms in the alkenylene group by 2; if the number of carbon atoms in the alkenylene group is uneven, the result of the division is rounded to the next integer. For example, for an alkenylene group having 9 carbon atoms, the maximum number of carbon-carbon double bonds is 4. Preferably, the alkenylene group has 1 to 6 (e.g., 1 to 4), i.e., 1, 2, 3, 4, 5, or 6 carbon-carbon double bonds. Preferably, the alkenylene group contains 2 to 12 (e.g., 2 to 10) carbon atoms, i.e., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms), more preferably 2 to 8 carbon atoms, e.g., 2 to 6 carbon atoms or 2 to 4 carbon atoms. Thus, in preferred embodiments, the alkenylene group contains 2 to 12 (e.g., 2 to 10) carbon atoms and 1, 2, 3, 4, 5, or 6 (e.g., 1, 2, 3, 4, or 5) carbon-carbon double bonds, and more preferably 2 to 8 carbon atoms and 1, 2, 3, or 4 carbon-carbon double bonds (e.g., 2 to 6 carbon atoms and 1, 2, or 3 carbon-carbon double bonds, or 2 to 4 carbon atoms and 1 or 2 carbon-carbon double bonds). The carbon-carbon double bonds may be in the cis (Z) or trans (E) configuration. Exemplary alkenylene groups include ethene-1,2-diyl, vinylidene (also called ethenylidene), 1-propene-1,2-diyl, 1-propene-1,3-diyl, 1-propene-2,3-diyl, allylidene, 1-butene-1,2-diyl, 1-butene-1,3-diyl, 1-butene-1,4-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, and the like. When an 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., 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 to 2, etc.) hydrogen atoms of an alkenylene group have been replaced with non-hydrogen substituents (when two or more hydrogen atoms have been replaced, the substituents can be the same or different). Preferably, the non-hydrogen substituents are first-level substituents, second-level substituents, or third-level substituents as specified herein, such as halogen or optionally substituted aryl. Examples of substituted alkenylenes are 1-phenyl-ethylene-1,2-diyl and 2-phenyl-ethylene-1,2-diyl.

[0068] The term "alkynyl" refers to a monoradical of an unsaturated straight-chain or branched-chain hydrocarbon having at least one carbon-carbon triple bond. Generally, the maximum number of carbon-carbon triple bonds in an alkynyl group can be equal to an integer calculated by dividing the number of carbon atoms in the alkynyl group by 2; if the number of carbon atoms in the alkynyl group is uneven, the result of the division is rounded up 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 contains 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, e.g., 2 to 6 carbon atoms or 2 to 4 carbon atoms. Thus, in a preferred embodiment, the alkynyl group contains 2 to 12 (e.g., 2 to 10) carbon atoms and 1, 2, 3, 4, 5, or 6 (e.g., 1, 2, 3, 4, or 5 (preferably 1, 2, or 3)) carbon-carbon triple bonds, more preferably 2 to 8 carbon atoms and 1, 2, 3, or 4 (preferably 1 or 2) carbon-carbon triple bonds, e.g., 2 to 6 carbon atoms and 1, 2, or 3 carbon-carbon triple bonds or 2 to 4 carbon atoms and 1 or 2 carbon-carbon triple bonds. Examples of alkynyl groups include: ethynyl, 1-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, 7-heptynyl, 8-heptynyl, 9-heptynyl, 10-heptynyl, 11-heptynyl, 12-heptynyl, 13-heptynyl, 14-heptynyl, 15-heptynyl, 16-heptynyl, 17-heptynyl, 18-heptynyl, 19-heptynyl, 20-heptynyl, 21-heptynyl, 22-heptynyl, 23-heptynyl, 24-heptynyl, 25-heptynyl, 26-heptynyl, 27-heptynyl, 28-heptynyl, 29-heptynyl, 30-heptynyl, 31-heptynyl, 32-heptynyl, 33-heptynyl, 34-heptynyl, 35-heptynyl, 36-heptynyl, 37-heptynyl, 38-heptynyl, 39-heptynyl, 40-heptynyl, 41-heptynyl, 42-heptynyl, 43-heptynyl, 44-heptynyl, 45-heptynyl, 46-heptynyl, butynyl, 1-octynyl, 2-octynyl, 3-octynyl, 4-octynyl, 5-octynyl, 6-octynyl, 7-octynyl, 1-nonyl, 2-nonyl, 3-nonyl, 4-nonyl, 5-nonyl, 6-nonyl, 7-nonyl, 8-nonyl, 1-decynyl, 2-decynyl, 3-decynyl, 4-decynyl, 5-decynyl, 6-decynyl, 7-decynyl, 8-decynyl and the like. In the event that the alkynyl group is attached to a nitrogen atom, the triple bond cannot be alpha to the nitrogen atom. "Substituted alkynyl" means that one or more (e.g., up to the maximum number of hydrogen atoms bonded to the alkynyl group, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, e.g., 1 to 5, 1 to 4, or 1 to 3, or 1 to 2) hydrogen atoms of an alkynyl group are replaced with a non-hydrogen substituent (when two or more hydrogen atoms are replaced, the substituents can be the same or different). Preferably, the non-hydrogen substituent is a first-level substituent, a second-level substituent, or a third-level substituent as specified herein, such as halogen or optionally substituted aryl.

[0069] The term "alkynylene" refers to a diradical of an unsaturated straight or branched chain hydrocarbon having at least one carbon-carbon triple bond. In general, the maximum number of carbon-carbon triple bonds in an alkynylene group can be equal to the integer calculated by dividing the number of carbon atoms in the alkynylene group by 2, and if the number of carbon atoms in the alkynylene group is uneven, the result of the division is rounded to the next integer. For example, for an alkynylene group having nine carbon atoms, the maximum number of carbon-carbon triple bonds is four. Preferably, the alkynylene group has 1 to 6 (such as 1 to 4), ie 1, 2, 3, 4, 5, or 6 (such as 1, 2, 3, or 4), more preferably 1 or 2 carbon-carbon triple bonds. Preferably, the alkynylene group comprises 2 to 12 (such as 2 to 10) carbon atoms, i.e. 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms (such as 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms), more preferably 2 to 8 carbon atoms, for example 2 to 6 carbon atoms or 2 to 4 carbon atoms. Thus, in preferred embodiments, the alkynylene group contains 2 to 12 (e.g., 2 to 10) carbon atoms and 1, 2, 3, 4, 5, or 6 (e.g., 1, 2, 3, 4, or 5 (preferably 1, 2, or 3) carbon-carbon triple bonds), more preferably 2 to 8 carbon atoms and 1, 2, 3, or 4 (preferably 1 or 2) carbon-carbon triple bonds, for example, 2 to 6 carbon atoms and 1, 2, or 3 carbon-carbon triple bonds or 2 to 4 carbon atoms and 1 or 2 carbon-carbon triple bonds. Exemplary alkynylene groups include ethyne-1,2-diyl, 1-propyne-1,3-diyl, 1-propyne-3,3-diyl, 1-butyne-1,3-diyl, 1-butyne-1,4-diyl, 1-butyne-3,4-diyl, 2-butyne-1,4-diyl, and the like. In the event that 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., up to 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, e.g., 1 to 5, 1 to 4, or 1 to 3, or 1 to 2, up to a maximum of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, of the maximum number of hydrogen atoms bonded to the alkynylene group) hydrogen atoms are replaced with a non-hydrogen substituent (when more than one hydrogen atom is replaced, the substituents can be the same or different). Preferably, the non-hydrogen substituent is a first-level substituent, a second-level substituent, or a third-level substituent as specified herein, such as halogen or optionally substituted aryl.

[0070] The term "aryl" or "aromatic ring" refers to a monoradical of an aromatic cyclic hydrocarbon. Preferably, an aryl group contains 3 to 14 (e.g., 5, 6, 9, or 10) carbon atoms, which can be arranged in a single ring (e.g., phenyl) or two or more fused rings (e.g., naphthyl). Exemplary aryl groups include cyclopropenylium, cyclopentadienyl, phenyl, indenyl, naphthyl, azulenyl, fluorenyl, anthryl, and phenanthryl. Preferably, "aryl" refers to a monocyclic ring containing 6 carbon atoms or an aromatic bicyclic ring system containing 10 carbon atoms. Preferred examples are phenyl and naphthyl. "Substituted aryl" means that one or more (1 to a maximum of 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, bonded to the aryl group) hydrogen atoms of the aryl group are replaced with a substituent other than hydrogen (when two or more hydrogen atoms are replaced, the substituents may be the same or different). Preferably, the substituents other than hydrogen are 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 The substituted aryl may be a first-level substituent, a second-level substituent, or a third-level substituent as specified herein, such as alkynyl. Examples of substituted aryl include biphenyl, 2-fluorophenyl, 2-chloro-6-methylphenyl, anilinyl, 3-nitrophenyl, 4-hydroxyphenyl, methoxyphenyl (i.e., 2-, 3-, or 4-methoxyphenyl), and 4-ethoxyphenyl.

[0071] The term "heteroaryl" or "heteroaromatic ring" refers to an aryl group, as defined above, in which 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 5- or 6-membered aromatic monocyclic ring in which 1, 2, or 3 carbon atoms are replaced by the same or different heteroatoms O, N, or S. Alternatively, heteroaryl 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 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, a 3- to 14-membered heteroaryl encompasses monocyclic heteroaryls (e.g., 5- or 6-membered), bicyclic heteroaryls (e.g., 9- or 10-membered), and tricyclic heteroaryls (e.g., 13- or 14-membered).Exemplary heteroaryl groups include furanyl, thienyl, oxazolyl, isoxazolyl, oxadiazolyl (1,2,5- and 1,2,3-), pyrrolyl, imidazolyl, pyrazolyl, triazolyl (1,2,3- and 1,2,4-), tetrazolyl, thiazolyl, isothiazolyl, thiadiazolyl (1,2,3- and 1,2,5-), pyridyl (also called pyridinyl), pyrimidinyl, pyrazinyl, triazinyl (1,2,3-, 1,2,4- and 1,3,5-), benzofuranyl (1- and 2-), indolyl, isoindolyl, benzothienyl (1- and 2-), 1H-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, benzisoxazolyl, benzisoxazolyl, benzo ... thiazolyl, benzisothiazolyl, benzotriazolinyl, quinolinyl, isoquinolinyl, benzodiazinyl, quinoxalinyl, quinazolinyl, benzotriazinyl (1,2,3- and 1,4-benzotriazinyl), pyridazinyl, phenoxazinyl, thiazolopyridinyl, pyrrolothiazolyl, phenothiazinyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathinyl, pyrrolidinyl, indolizinyl, indazolyl, purinyl, quinolizinyl, phthalazinyl, naphthyridinyl (1,5-, 1,6-, 1,7-, 1,8-, and 2,6-), cinnolinyl, pteridinyl, carbazolyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl (1,7-, 1,8-, 1,10-, 3,8-, and 4,7-), phenazinyl, oxazolopyridinyl, isoxazolopyridinyl, pyrrolooxazolyl, and pyrrolopyrrolyl. 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 (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 to 2, etc.) hydrogen atoms of a heteroaryl group are replaced with a non-hydrogen substituent (when two or more hydrogen atoms are replaced, the substituents can be the same or different). Preferably, the substituents other than hydrogen are 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 The heteroaryl may be a first level substituent, a second level substituent, or a third level substituent as specified herein, such as alkynyl. Examples of substituted heteroaryl 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-thien-3-yl, 1,3,5-trimethylpyrazol-4-yl, 3,5-dimethyl-1,2-dioxazol-4-yl, 1,2,4-trimethylpyrrol-3-yl, 3-phenylpyrrolyl, 2,3'-bifuryl, 4-methylpyridyl, and 2- or 3-ethylindolyl.

[0072] The terms "cycloalkyl" or "alicyclic" refer to cyclic, non-aromatic versions of "alkyl" and "alkenyl," preferably having 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, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, cyclononyl, cyclononenyl, cyclodecyl, cyclodecenyl, and adamantyl. The term "cycloalkyl" is meant to include bicyclic and tricyclic versions thereof, although it is preferred that each ring is joined to each other through two adjacent carbon atoms, or alternatively, two rings are joined through the same carbon atom, i.e., they form a spirocyclic system or a "bridged" ring. Preferred examples of cycloalkyl include C 3-8 -Cycloalkyl, 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. Hydrogen atoms attached to the cycloalkyl group, e.g., up to 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, e.g., 1 to 5, 1 to 4, or 1 to 3, or 1 to 2, hydrogen atoms of the cycloalkyl group, are replaced with non-hydrogen substituents (when more than one hydrogen atom is replaced, the substituents may be the same or different). Preferably, the substituents other than hydrogen are halogen, —CN, nitro, —OR 11 (e.g., -OH), -SR 11 (e.g., -SH), -N(R 12 )(R 13 ) (e.g., —NH), ═X (e.g., ═O, ═S, or ═NH), alkyl (e.g., C 1-6 alkyl), alkenyl (e.g., C 2-6 alkenyl), and alkynyl (e.g., C 2-6The substituted cycloalkyl may be a first-level substituent, a second-level substituent, or a third-level substituent as specified herein, such as alkynyl. Examples of substituted cycloalkyl include oxocyclohexyl, oxocyclopentyl, fluorocyclohexyl, and oxocyclohexenyl.

[0073] The term "heterocyclyl" or "heterocycle" refers to a cycloalkyl group as defined above in which one, two, three, or four ring carbon atoms in the cycloalkyl group are replaced by a heteroatom (such as one selected from the group consisting of O, S, S(O), S(O), N, B, Si, and P, preferably selected from the group consisting of O, S, S(O), and N). If the ring of a heterocyclyl group contains only one type of heteroatom, the maximum number of said heteroatoms in the ring of said heterocyclyl group may be as follows: 2 O atoms (preferably 1 O atom); 2 S atoms (preferably 1 S atom); 4 N atoms (e.g., 1, 2, or 3 N atoms); 2 B atoms (preferably 1 B atom); 1 Si atom; and / or 1 P atom. When the ring of a heterocyclyl group contains two or more heteroatoms, the maximum number of heteroatoms in the ring of the heterocyclyl group can be as follows: 1 O atom; 1 S atom; 2 N atoms (preferably 1 N atom); 1 B atom; 1 Si atom; and / or 1 P atom (wherein the maximum total number of heteroatoms in the ring of the heterocyclyl group is 4, and the maximum total number of each heteroatom in the ring of the heterocyclyl group is as follows: 1 O atom; 1 S atom; 1 or 2 N atoms; 1 B atom (preferably 0 B atoms); 1 Si atom (preferably 0 Si atoms); and / or 1 P atom (preferably 0 P atoms). In one embodiment, the heteroatoms of a heterocyclyl group are selected from the group consisting of O, S, and N. In this embodiment, preferably, 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 in each ring of the heterocyclyl group. For example, a 3- to 14-membered heterocyclyl includes a monocyclic heterocyclyl (e.g., 3-, 4-, 5-, 6-, or 7-membered, preferably 4- to 7-membered), a bicyclic heterocyclyl (e.g., 8-, 9-, or 10-membered), and a tricyclic heterocyclyl (e.g., 12-, 13-, or 14-membered). When a heterocyclyl group contains two or more rings, these rings are either fused (as in quinolinyl or purinyl), spiro moieties, bridged structures, linked via double bonds, or combinations thereof. In other words, an unsubstituted heterocyclyl group does not include two heterocyclyl groups linked via a single bond. The term "heterocyclyl" is also meant to include partially or fully hydrogenated forms (eg, dihydro, tetrahydro, hexahydro, octahydro, decahydro, dodecahydro, etc., or perhydro forms) of the above heteroaryl groups. Exemplary heterocyclyl groups include azetidinyl, morpholino, isochromanyl, chromanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, indolinyl, isoindolinyl, triazinanyl (1,2,3-, 1,2,4-, and 1,3,5-), di- and tetrahydrothienyl, di- and tetrahydrofuranyl, di- and tetrahydrothielyl, di- and tetrahydrooxazolyl, di- and tetrahydroisoxazolyl (1,2,5- and 1,2,3-), dihydropyrrolyl, dihydroimidazolyl, dihydropyrazolyl, di- and tetrahydrotriazolyl (1,2,3-, 1,2,4-), di- and tetrahydrothiazolyl, di- and tetrahydrothiadiazolyl (1,2,3- and 1,2,5-), di- and tetrahydropyridyl, di-, tetra- and hexahydropyrimidinyl, di- and tetrahydropyrazinyl, di- and tetrahydrotriazinyl (1,2,3-, 1,2,4- and 1,3,5-), di-, tetra-, hexa- and octahydrobenzofuranyl (1- and 2-), di-, tetra-, hexa- and octahydroindolyl, di-, tetra-, hexa- and octahydroisoindolyl, di-, tetra-, hexa- and octahydrobenzothienyl (1- and 2), di-, tetra-, hexa- and octahydro-1H-indazolyl, di-, tetra-, hexa- and octahydrobenzimidazolyl, di-, tetra-, hexa- and octahydrobenzoxazolyl, di-, tetra-, hexa- and octahydroindoxazinyl, di-, tetra-, hexa- and octahydrobenzisooxazolyl, di-, tetra-, hexa- and octahydrobenzothiazolyl, di-, tetra-, hexa- and octahydrobenzisothiazolyl, di-, tetra-, hexa- and octahydrobenzotriazolyl, di-, tetra-, hexa-, octa- and decahydroquinolinyl, di-, tetra-, hexa-, octa- and decahydroisoquinolinyl, di-, tetra-, hexa-, octa- and decahydrobenzodiazinyl, di-, tetra-, hexa-, octa- and decahydroquinoxalinyl, di-, tetra-, hexa-, octa- and decahydroquinazolinyl, di-, tetra-, hexa-, octa- and decahydrobenzotriazinyl (1,2,3-, 1,2,4-), Di-, tetra-, hexahydropyridazinyl, Di-, tetra-, hexa-, octa-, deca- and dodecahydrophenoxazinyl di-, tetra-, hexa-, octahydrothiazolopyridinyl (e.g., 4,5,6-7-tetrahydro[1,3]thiazolo[5,4-c]pyridinyl or 4,5,6-7-tetrahydro[1,3]-thiazolo[4,5-c]pyridinyl, e.g., 4,5,6-7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl or 4,5,6-7-tetrahydro[1,3]-thiazolo[4,5-c]pyridin-2-yl, di-, tetra- and hexahydropyrrolothiazolyl, di-, tetra-, hexa-, octa- and decahydrophenothiazinyl, di-, tetra-, hexa- and octahydroisobenzofuranyl, di-, tetra-, hexa- and octahydrochromenyl, di-, tetra-, hexa-, octa-, deca- and dodecahydroxanthenyl, di-, tetra-, hexa-, octa-, deca- and dodecahydrophenoxathiinyl, di-, tetra- and hexahydropyrrolidinyl, di-, tetra-, hexa- and octahydroindolizinyl, di-, tetra-, hexa- and octahydroindazolyl, di-, tetra-, hexa- and octahydropurinyl, di-, tetra-, hexa- and octahydroquinolidinyl, di-, tetra-, hexa-, octa- and decahydrophthalazinyl, di-, tetra-, hexa-, octa- and decahydronaphthalidinyl (1,5-, 1,6-, 1,7-, 1,8-, 2,6-), di-, tetra-, hexa-, octa- and decahydrocinnolinyl, di-, tetra-, hexa-, octa- and decahydropteridinyl, di-, tetra-, hexa-, octa-, deca- and dodecahydrocarbazolyl, di-, tetra-, hexa-, octa-, deca-, dodeca- and tetradecahydrophenanthridinyl, di-, tetra-, hexa-, octa-, deca-, dodeca- and tetradecahydroacridinyl, di-, tetra-, hexa-, octa-, deca- and dodecahydroperimidinyl, di-, tetra-, hexa-, octa-, deca-, dodeca- and tetradecahydrophenanthrolinyl (1,7-, 1,8-, 1,10-, 3,8- and 4,7-), di-, tetra-, hexa-, octa-, deca-, dodeca- and tetradecahydrophenazinyl, di-, tetra-, hexa- and octahydrooxazolopyridinyl, di-, tetra-, hexa- and octahydroisoxazolopyridinyl, di-, tetra-, hexa- and octahydrocyclopentapyrrolyl, di-, tetra-, hexa- and octahydrocyclopentopyrazolyl, di-, tetra-, hexa- and octahydrocyclopentaimidazolyl, di-, tetra-, hexa- and octahydrocyclopentathiazolyl, di-, tetra-, hexa- and octahydrocyclopentaoxazolyl, di-, tetra-, hexa- and octahydropyrrolopyrrolyl, di-, tetra-, hexa- and octahydropyrrolopyrazolyl, di-, tetra-, hexa- and octahydropyrroloimidazolyl, Di-, tetra-, hexa- and octahydropyrrolothiazolyl (5,6-dihydro-4H-pyrrolo[3,4-d][1,3]thiazolyl, 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 and the like. Exemplary 5- or 6-membered heterocyclyl groups include morpholino, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, di- and tetrahydrofuranyl, di- and tetrahydrothienyl, di- and tetrahydrooxazolyl, di- and tetrahydroisoxazolyl, di- and tetrahydrooxadiazolyl (1,2,5- and 1,2,3-), dihydropyrrolyl, dihydroimidazolyl, dihydropyrazolyl, di- and tetrahydrotriazolyl, and the like. di- and tetrahydrothiazolyl (1,2,3- and 1,2,4-), di- and tetrahydrothiazolyl, di- and tetrahydroisothiazolyl, di- and tetrahydrothiadiazolyl (1,2,3- and 1,2,5-), di- and tetrahydropyridyl, di-, tetra- and hexahydropyrimidinyl, di- and tetrahydropyrazinyl, di- and tetrahydrotriazinyl (1,2,3-, 1,2,4-, 1,3,5-), and triazinanyl (1,2,3-, 1,2,4-, 1,3,5-). "Substituted heterocyclyl" means that one or more (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 to 2, etc.) hydrogen atoms of a heterocyclyl group are replaced with non-hydrogen substituents (when two or more hydrogen atoms are replaced, the substituents can be the same or different). Preferably, the substituents other than hydrogen are halogen, —CN, nitro, —OR 11 (e.g., -OH), -SR 11 (e.g., -SH), -N(R 12 )(R 13) (e.g., —NH), ═X (e.g., ═O, ═S, or ═NH), alkyl (e.g., C 1-6 alkyl), alkenyl (e.g., C 2-6 alkenyl), and alkynyl (e.g., C 2-6 The substituent may be a first-level substituent, a second-level substituent, or a third-level substituent as specified herein, such as alkynyl.

[0074] The phrase "partially hydrogenated form" of an unsaturated compound or group, as used herein, means that a portion of the unsaturation is eliminated by formally adding hydrogen to the original unsaturated compound or group without eliminating all of the unsaturation. The phrase "fully hydrogenated form" is used interchangeably herein with the term "perhydro" and means that all unsaturation has been removed by first formally adding hydrogen to the unsaturated compound or group. For example, partially hydrogenated forms of a 5-membered heteroaryl group (containing two double bonds in the ring, such as furan) include dihydro forms of the 5-membered heteroaryl group (such as 2,3-dihydrofuran or 2,5-dihydrofuran), while tetrahydro forms of the 5-membered heteroaryl group (e.g., tetrahydrofuran, i.e., THF) are fully hydrogenated (or perhydro) forms of the 5-membered heteroaryl group. Similarly, for 6-membered heteroaryl groups having three double bonds in the ring (such as pyridyl), the partially hydrogenated forms include the di- and tetrahydro forms (such as di- and tetrahydropyridyl), while the hexahydro forms (such as piperidinyl in the case of heteroarylpyridyl) are fully hydrogenated (or perhydro) derivatives of said 6-membered heteroaryl groups. As a result, hexahydro forms of an aryl or heteroaryl can be considered partially hydrogenated forms according to the present invention only if the aryl or heteroaryl contains at least four unsaturated moieties consisting of double and triple bonds between ring atoms.

[0075] The term "aromatic" used in the context of hydrocarbons means that the entire molecule must be aromatic. For example, if a monocyclic aryl is hydrogenated (either partially or fully), the resulting hydrogenated ring structure is classified as a cycloalkyl for the purposes of this invention. Similarly, if a bicyclic or polycyclic aryl (e.g., naphthyl) is hydrogenated, the resulting hydrogenated bicyclic or polycyclic structure (e.g., 1,2-dihydronaphthyl) is classified as a cycloalkyl for purposes of this invention (even if one ring, such as in 1,2-dihydronaphthyl, is still aromatic). In the present invention, a similar distinction is made between heteroaryl and heterocyclyl. For example, indolinyl, a dihydro variant of indolyl, is classified as a heterocyclyl for purposes of this invention because only one ring of the bicyclic structure is aromatic and one of the ring atoms is a heteroatom.

[0076] As used herein, the term "polycyclic" means that the structure has 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; therefore, according to the present invention, the term "polycyclic" does not encompass monocyclic structures in which the structure contains only one ring. Examples of polycyclic groups are fused structures (e.g., naphthyl or anthryl), spiro compounds, rings connected via single or double bonds (e.g., biphenyl), and bridged structures (e.g., bornyl). Exemplary polycyclic structures are the aryl, heteroaryl, cycloalkyl, and heterocyclyl groups identified above that have at least two rings.

[0077] The term "halogen" or "halo" means fluoro, chloro, bromo, or iodo.

[0078] The term "azido" refers to -N3.

[0079] The term "N-oxide" refers to a functional group (Rn )3N + -O - means an amine oxide or amine-N-oxide, which is a chemical compound containing a coordinate covalent bond, i.e., NO, n are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, cycloalkyl, and heterocyclyl, wherein each of the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl groups optionally contains one or more (up to the maximum number of hydrogen atoms bonded to the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl group, e.g., 1-5, 1-4, or 1-3, or 1 or 2, such as, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, such as 1) independently selected R 30 can be substituted with R 30 is preferably a first level substituent, a second level substituent, or a third level substituent as specified herein.

[0080] As described elsewhere herein, R 5 Ha-LR 6 and R 6 is heteroaryl or heterocyclyl, each of which is selected from one or more independently selected R 7 may be optionally substituted with In this context, as used herein, "R 6 Any two R bonded to the same atom of 7 can bond together to form =O" is R 6 When replacing a total of two hydrogen atoms bonded to only one ring atom of 7 ) can form the diradical =O. For example, according to the present invention, [ka] (In the formula, the wavy line represents R 6represents the bond that connects it to the rest of the compound) is R 6 (1)R 7 (2) R 6 Any two R bonded to the same atom of 7 The groups bond together to form the diradical =O, [ka] R with the formula 6 group (where the remaining R 7 The group is a monoradical). Similarly, R 6 is 3-tetrahydrothienyl substituted with four R7, then such substituted R 6 contains The following formula: [ka] etc. "Any two R's bonded to the same carbon atom of a cycloalkyl group or a heterocyclyl group 30 are joined together to form =X 1 Similar terms such as "forming" and "forming" as used herein should be construed in an analogous manner. In this regard, R 6 Any two R bonded to the same atom of 7 can be taken together to form =O, first (i.e., without modification, =O)R 6 It should be understood that must be a heterocyclic ring (because in a heteroaromatic ring there are no carbon ring atoms with two free valences).

[0081] "One R 7 The group is R 6 R in the 2nd position relative to the ring atom that bonds to the rest of the compound 6 As used herein, the phrase "bonded to a ring atom of R 6At least one of the two ring atoms directly adjacent to the ring atom to which is attached to the remainder of the compound is one R 7 It means that the group is present. In other words, R 6 is the remainder of the compound (i.e., R 6 For the ring atom bonded to the "yl position" of 6 At least one of the ortho positions of 7 It has a group. For example, R 6 But one R 7 When the above formula is applied to a 3-pyridyl substituted with (i.e., the ring carbon atom is 3-positioned relative to the ring nitrogen atom), this R 7 The group will be at the 2- or 4-position of the 3-pyridyl group, as shown in the formula below: [ka] In the formula, the wavy line represents R 6 represents the bond that connects it to the rest of the compound. Furthermore, R 6 However, there are two or more (two or three, etc.) R 7 When substituted with a group, "R 6 R is in the 2 position relative to the ring atom that is attached to the rest of the compound 6 One R on a ring atom of 7 The expression "group is bonded" is used to 6 is attached to the remainder of the compound, and each of the two ring atoms directly adjacent to the ring atom is bonded to one R 7 This includes situations where the compound has a group (i.e., R 6 is one R at each of the 2nd and kth positions. 7 is a k-membered ring having a group, R 6 One R for the ring atom that is attached to the rest of the compound 7 having a group, i.e., R 6 is substituted at both of its ortho positions). For example, R 6 If the ring carbon is 3-pyrrolyl (so the ring carbon is in the yl position relative to the ring nitrogen atom), then "one R 7 The group is R 6R at the 2nd position relative to the ring atom that is attached to the rest of the compound 6 The phrase "bonded to a ring atom of" encompasses the following structures: [ka] However, the following structures are excluded: [ka]

[0082] As used herein, the term "k-membered ring" means that the ring has k ring atoms. For example, k in pyrazolyl is 5, so the ortho positions are the 2 and 5 positions, and the k-1 position is the 4 position, relative to the ring atom where the pyrazolyl group is attached to the rest of the compound (the yl position). Additionally, when pyridinyl is a 6-membered heteroaryl, the ortho positions are 2 and 6 and position k-1 is 5 relative to the ring atom at which the pyridinyl group is attached to the remainder of the compound (the yl position).

[0083] The expression "wavy line", as used herein, is R 6 represents the bond connecting it to the rest of the compound, and R 6 refers to the bond that connects L to the rest of the compound (i.e., (i) to L when L is not a bond, or (ii) to the carboxy(thio)amide group -C(E)N(R 4 )(R 5 ) attached to the nitrogen atom of For example, R 6 but, [ka] and L is (i) methylene or (ii) a bond, the compounds of formula (I) have the following structures (A1) and (A2): [ka]

[0084] The term "optionally substituted" means that one or more (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 may be replaced with the following groups: first-level substituents different from hydrogen; For example, alkyl (preferably C 1-6 alkyl), 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, azide, —NO2, —OR 71 , -N(R 72 )(R 73 ), -S(O) 0-2 R 71 ,-S(O) 1-2 OR 71 , -OS(O) 1-2 R 71 , -OS(O) 1-2 OR 71 , -S(O) 1-2 N(R 72 )(R 73 ), -OS(O) 1-2 N(R 72 )(R 73 ), -N(R 71 )S(O) 1-2 R 71 , -NR 71 S(O) 1-2 OR 71 , -NR 71 S(O) 1-2 N(R 72 )(R 73 ), -OP(O)(OR 71 )2, -C(=X 1 )R 71 , -C(=X 1 )X 1 R 71 , -X 1 C(=X 1 )R 71 , and X 1C(=X 1 )X 1 R 71 , and / or Any two first level substituents that together form =X 1 wherein each of the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl groups of the first level substituents is optionally substituted with one or more (e.g., 1, 2, or 3) substituents (i.e., second level substituents) selected from the following: 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, azide, -NO 2、 -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 , -N(R 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 )X 81 , -C(=X 2 )X2 R 81 , -X 2 C(=X 2 )R 81 , and X 2 C(=X 2 )X 2 R 81 , and / or Any two second level substituents that together form =X 2 and a second-level substituent C 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 may itself be optionally substituted with one or more (e.g., 1, 2, or 3) substituents (i.e., third-level substituents) selected from the following: C 1-3 Alkyl, halogen, -CF3, -CN, azide, -NO 2、 -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(wherein each z is independently 0, 1, or 2; and C 1-3 alkyl is independently methyl, ethyl, propyl or isopropyl; and / or Any two third level substituents, which together are =O, =S, =NH, =N(C 1-3 are attached to the same carbon atom of a second-level substituent, a 3- to 14-membered cycloalkyl or heterocyclyl group, which can form an alkyl group, R 71 , R 72 and R 73 are independently 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 Alkynyl, 3- to 7-membered cycloalkyl, 5- or 6-membered aryl, 5- or 6-membered heteroaryl, and 3- to 7-membered heterocyclyl groups are each independently C 1-3 Alkyl, halogen, -CF3, -CN, azide, -NO 2、 -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 wherein each z is independently 0, 1, or 2; and C 1-3 Alkyl is independently methyl, ethyl, propyl, or isopropyl; R81, R82, and R83 are each H, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 independently selected from the group consisting of 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 Alkynyl, 3- to 6-membered cycloalkyl, 5- or 6-membered aryl, 5- or 6-membered heteroaryl, and 3- to 6-membered heterocyclyl are each independently selected from the group consisting of C 1-3 Alkyl, halogen, -CF3, -CN, azide, -NO 2、 -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(C1-3 alkyl)C(=NH)NH 2-Z (C 1-3 alkyl) z wherein each z is independently 0, 1, or 2; and C 1-3 alkyl is independently methyl, ethyl, propyl, or isopropyl; and X 1 and X 2 are independently O, S and N(R 84 ), where R 84 is hydrogen or C 1-3 It is alkyl.

[0085] Typical primary substituents are 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) 1-2 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 , -C(=X 1 )R 71 , -C(=X1 )X 1 R 71 , -X 1 C(=X 1 )R 71 and X 1 C(=X 1 )X 1 R 71 , e.g., C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 6-membered aryl, 5- or 6-membered heteroaryl, 3- to 7-membered cycloalkyl, 3- or 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 each z is independently 0, 1, or 2; and each C 1-3 alkyl is independently methyl, ethyl, propyl, or isopropyl, and -X1 is independently selected from O, S, NH, and N(CH3); 71 , R 72 , and R 73 are as defined above, and each independently represents H, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4Preferably, the alkynyl, alkenyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups are selected from the group consisting of alkynyl, 5- or 6-membered cycloalkyl, aryl, heteroaryl, and heterocyclyl, wherein each alkynyl, alkenyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl group is selected from the group consisting of C 1-3 Alkyl, halogen, -CF3, -CN, azide, -NO2, -OH, -O(C 1-3 alkyl), -S(C 1-3 alkyl), -NH2, -NH(C 1-3 alkyl), -N(C 1-3 alkyl)2, NHS(O)2(C 1-3 alkyl), -S(O)2NH 2-X (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. Specific examples of first level substituents are C 1-3 Alkyl, phenyl, imidazolyl, thiazolyl, cyclopentyl, cyclohexyl, dihydrothiazolyl, thiazolidinyl, halogen, -CF3, -CN, -OH, -O(C 1-3 alkyl), -S(C 1-3 alkyl), -NH2, -NH(C 1-3 alkyl), -N(C 1-3 alkyl)2, -NHS(O)2(C 1-3alkyl), -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 Alkyl is independently methyl, ethyl, propyl, or isopropyl. Particularly preferred first level substituents are C 1-3 Alkyl, phenyl, thiazolidinyl, halogen (such as F, Cl, or Br), -NH2, -NHS(O)2(C 1-3 alkyl), -NHC(=O)(C 1-3 alkyl), and NHC(=NH)NH 2-Z (C 1-3 alkyl) z where z is 0, 1, or 2; and each C 1-3 Alkyl is independently methyl, ethyl, propyl, or isopropyl.

[0086] Typical second level substituents are preferably 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 1-3alkyl) 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. Specific examples of secondary substituents are 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 C1-3 alkyl is independently methyl, ethyl, propyl, or isopropyl. Particularly preferred second level substituents are independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, phenyl, ═O, and ═S.

[0087] Typical third level substituents are preferably C 1-3 Alkyl, phenyl, halogen, -CF3, -OH, -OCH3, -SCH3, -NH 2-Z (CH3) z , —C(═O)OH, and C(═O)OCH3, where z is 0, 1, or 2; 1-3 Alkyl is methyl, ethyl, propyl or isopropyl. Particularly preferred third level substituents are selected from the group consisting of methyl, ethyl, propyl, isopropyl, halogen (such as F, Cl, or Br), and halogen (such as F, Cl, or Br), -CF3, and CF3.

[0088] As used herein, the term "optional" or "optionally" means that the subsequently described event, circumstance, or symptom may or may not occur, and that the description includes instances in which said event, circumstance, or symptom occurs as well as instances in which it does not occur.

[0089] "Isomers" refer to compounds that have the same molecular formula but differ in structure (structural isomers) or in the geometric (spatial) location of functional groups and / or atoms (stereoisomers). "Enantiomers" are a pair of non-superimposable stereoisomers. A "racemic mixture" or "racemate" contains a pair of enantiomers in equal amounts and is designated by the prefix (±). "Diastereomers" are non-superimposable stereoisomers that are not mirror images of each other. "Tautomers" are structural isomers of the same chemical substance that spontaneously and reversibly interconvert, even in pure form, due to the migration of individual atoms or groups of atoms. For example, tautomers (tautomers) are in dynamic chemical equilibrium with each other. An example of a tautomer is keto-enol tautomer. Conformers are stereoisomers that can be formally interconverted simply by rotation about a single bond, in particular leading to different three-dimensional configurations of (hetero)cyclic rings, such as chair, half-chair, boat, and twist-boat forms of cyclohexane.

[0090] Where a structural formula shown in this application can be interpreted as including two or more isomers, said structural formula includes all possible isomers, and therefore individual isomers, unless otherwise specified. For example, R 6 1-azabocyclo[2.2.2]oct-3-yl (one or more R 7 The compounds of formula (I), which are optionally substituted with a group, include both isomers, for example, isomers having the following formula (B1) and isomers having the following formula (B2), where n1 is 0, 1, 2, 3 or more: [ka]

[0091] As used herein, "polymorphism" means that a solid material (e.g., a compound) can exist in two or more forms or crystalline structures, i.e., "polymorphic modifications" or "polymorphic forms." In the present invention, the terms "polymorphic modifications," "polymorphic forms," ​​and "polymorphs" are used interchangeably. According to the present invention, these "polymorphic modifications" include crystalline forms, amorphous forms, solvates, and hydrates. The existence of different polymorphic forms is primarily due to the use of different conditions during the crystallization process, such as: - Solvent effects (crystal packing may differ in polar and non-polar solvents); - Certain impurities that inhibit the growth pattern and favor the growth of metastable polymorphs; - the level of supersaturation at which the material will crystallize (generally, the higher the concentration above solubility, the more likely metastable formation is); - the temperature at which crystallization takes place; - Geometry of covalent bonds (differences leading to conformational polymorphism); - Changed the mixing conditions.

[0092] Polymorphs may have different chemical, physical, and / or pharmacological properties, including, but not limited to, melting point, X-ray crystallography and diffraction pattern, chemical reactivity, solubility, dissolution rate, vapor pressure, density, hygroscopicity, flowability, stability, compressibility, and bioavailability. Polymorphs can spontaneously transform from a metastable form (unstable form) to a stable form at a specific temperature. According to Ostwald's rule, it is generally the least stable polymorph that crystallizes first. Therefore, the quality, efficacy, safety, processability, and / or manufacture of compounds, such as the compounds of the present invention, can be affected by polymorphism. The most stable polymorph of a compound (such as the compounds of the present invention) is often selected because it minimizes the possibility of conversion to other polymorphs. However, polymorphs other than the most stable polymorph can be selected for reasons other than stability, such as solubility, dissolution rate, and / or bioavailability.

[0093] As used herein, the term "crystalline form" of a material means that the smallest components (i.e., atoms, molecules, or ions) of the material have a crystalline structure. As used herein, "crystalline structure" refers to a unique three-dimensional arrangement of atoms or molecules in a crystalline liquid or solid, characterized by a pattern, a set of atoms arranged in a specific manner, and a lattice that exhibits long-range order and symmetry. A lattice is an arrangement of points that repeats periodically in three dimensions, and patterns are located on the lattice points. A subunit of a lattice is the unit cell. Lattice parameters are the edge lengths of the unit cell and the angles between them. The symmetry of a crystal is embodied in its space group. To describe a crystal structure, parameters such as the chemical formula, lattice constants, space group, atomic coordinates, and the occupancy of point positions are required.

[0094] As used herein, the term "amorphous form" of a material means that the smallest components of the material (i.e., atoms, molecules, or ions) are not arranged in a lattice, but are arranged randomly. Thus, unlike a crystal, where there is short-range order (constant distance to the next neighbor atom) and long-range order (periodic repetition of the base lattice), only short-range order exists in an amorphous formation.

[0095] As used herein, the term "compound complex" refers to a higher-order compound produced by association of a compound with one or more other molecules. Exemplary compound complexes include, but are not limited to, solvates, clusters, and chelates of the compound.

[0096] The term "solvate" refers to an addition complex of a substance dissolved in a solvent (e.g., an organic solvent (e.g., an aliphatic alcohol (e.g., methanol, ethanol, n-propanol, isopropanol), acetone, acetonitrile, ether, etc.), water, or a mixture of two or more of these liquids), which exists in the form of a crystal or mixed crystal, and the amount of solvent contained in the addition complex may be stoichiometric or non-stoichiometric.

[0097] 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 with a deuterium atom. Exemplary isotopes that can be used in the compounds of the invention include deuterium, 11 C. 13 C. 14 C. 15 N, 18 F, 32 P, 32 S, 35 S, 36 CI, and 125 Contains I.

[0098] The term "half-life" relates to the period of time required to eliminate half of the activity, amount, or number of molecules. In the context of the present invention, the half-life of a compound of formula (I) or (Ia) indicates the stability of said compound.

[0099] The terms "subject," "patient," "individual," or "animal" refer to multicellular animals such as vertebrates. For example, vertebrates in the context of the present invention are captive animals (especially vertebrates) such as mammals, birds (e.g., poultry), reptiles, amphibians, bony fish, and cartilaginous fish, particularly domestic animals of any of the above, and zoo animals (especially vertebrates). Mammals in the context of the present invention include, but are not limited to, humans, non-human primates, domestic mammals such as dogs, cats, sheep, cows, goats, pigs, and horses, laboratory mammals such as mice, rats, rabbits, and guinea pigs, and captive mammals such as zoo mammals. As used herein, the term "animal" also includes humans. Specific non-limiting examples of birds include poultry, including birds (e.g., chickens, turkeys, ducks, geese, guinea pigs, pigeons, pheasants, etc.), while specific non-limiting examples of bony or cartilaginous fish include those suitable for cultivation by aquaculture, including bony fish (e.g., salmon, trout, perch, carp, catfish, etc.).

[0100] The compound dasatinib (also referred to herein as compound A8) has the following structure: [ka]

[0101] Compounds 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: [ka] and solvates, salts, N-oxides, complexes, polymorphs, crystalline forms, racemic mixtures, diastereomers, enantiomers, tautomers, conformers, isotopically labeled forms, prodrugs, and combinations thereof; where: R 1a is H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, halogen, -CN, azide, -NO2, -OR 11 , -N(R 12 )(R 13 ), -N(R 11 )(OR 11 ) 、 -S(O) 0-2 R 11 , -S(O) 1-2 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 , -N(R 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)(OR11 )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 selected from the group consisting of one or more independently selected R 30 optionally substituted with; R 1b and R 1c each independently represents 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 heterocyclyl, -O(CH2) 0-2 (C 3-7 Cycloalkyl), -O(CH2) O-2 (C 6-10 aryl), -O(CH2) O-2 (3- to 7-membered heteroaryl), -O(CH2) O-2 (3- to 7-membered heterocyclyl), -NH(CH2) 0-2 (C 3-7 cycloalkyl), -NH(CH2) O-2 (C 6-10 aryl), -NH(CH2) O-2 (3- to 7-membered heteroaryl), -NH(CH2) O-2 (3- to 7-membered heterocyclyl), halogen, -CF3, -CN, azide, -NO2, -OH, -O(C 1-6 alkyl), -OCF3, -S(C 1-6 alkyl), -NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, -NHS(O)2(C 1-6 alkyl), -S(O)2NH 2-Z (C 1-6 alkyl) Z , -C(=O)(C 1-6 alkyl), -C(=O)OH, -C(=O)O(C1-6 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 wherein Z is 0, 1, or 2; and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 6-1O Aryl, 3- to 7-membered heteroaryl, and 3- to 7-membered heterocyclyl groups include OH, methyl, ethyl, -OCH3, -SCH3, and NH 2-Z (CH3) Z optionally substituted with 1, 2, or 3 moieties independently selected from the group consisting of: R 2 is H; R 3 is H, alkyl, alkynyl, alkenyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, halogen, -CN, azide, -NO2, -OR 11 , -N(R 12 )(R 13 ), -N(R 11 )(OR 11 ), -S(O) 0-2 R 11 , -S(O) 1-2 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 wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl groups is selected from the group consisting of one or more independently selected R 30 optionally substituted with; R 4 is H; R 5 -LR 6 is; L is a bond, C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylene, and (CH2) m -[Y-(CH2) n ] o wherein m is an integer between 1 and 6, n is an integer between 0 and 3, 0 is an integer between 1 and 3, and n is 0; o is 1; Y is O, S, and N(R 13 )- are independently selected from C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylene, -(CH2) m - and -(CH2) n Each of the - groups is selected from one or two independently selected R 30 optionally substituted with; R 6 is heteroaryl or heterocyclyl, each of which is selected from one or more independently selected R 7optionally substituted with; R 7 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, halogen, -CN, azide, -NO2, -OR 11 , -N(R 12 )(R 13 ), -N(R 11 )(OR 11 ), -S(O) 0-2 R 11 , -S(O) 1-2 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 R is a heterocyclyl group. 6 Any two R bonded to the same atom of 7 can be joined together to form =O, where each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl groups can be selected from one or more independently selected R 30 optionally substituted with; A is S, O, NR 8 , and C(R9 )2; R 8 is selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl groups is selected from one or more independently selected R 30 optionally substituted with; R 9 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, halogen, -CN, azide, -NO2, -OR 11 , -N(R 12 )(R 13 ), -S(O) 0-2 R 11 , -S(O) 1-2 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 ), -C(=X)R 11 , -C(=X)XR 11 , -XC(=X)R 11 , and -XC(=X)XR 11 wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl groups are independently selected from the group consisting of one or more independently selected R 30 may be optionally substituted with X is independently O, S, and N(R 14 ) selected from the group consisting of; E is O or S; B is N or CR 1d is; R 1d is H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, halogen, -CN, azide, -NO2, -OR 11 , -N(R 12 )(R 13 ), -N(R 11 )(OR 11 ), -S(O) 0-2 R 11 , -S(O) 1-2 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 wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl groups is independently selected from the group consisting of one or more independently selected R 30 optionally substituted with; R11 is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups is selected from one or more independently selected R 30 optionally substituted with; R 12 and R 13 each is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl, or R 12 and R 13 are bonded 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 can be selected from one or more independently selected R 30 optionally substituted with; R 14 is 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 independently selected from the group consisting of one or more independently selected R 30 optionally substituted with; R 15 and R 16 each of which is selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, and NH y R 20 2-y or R 15 and R 16 are bonded together with the atoms to which they are attached to one or more independently selected R 30wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups can be optionally substituted with one or more independently selected R 30 optionally substituted with; y is an integer between 0 and 2; R 20 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups is selected from one or more independently selected R 30 and R 30 are first-level substituents, which, in each case independently, are alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, halogen, -CN, azide, -NO2, -OR 71 , -N(R 72 )(R 73 ), -S(O) 0-2 R 71 , -S(O) 1-2 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 )R71 , -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 attached to the same carbon atom of a cycloalkyl or heterocyclyl group. 30 are bonded together, =X 1 wherein the first-level substituent alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl groups are optionally substituted by one or more second-level substituents, which in each case are selected from the group consisting of: 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, azide, -NO2, -OR 81 , -N(R 82 )(R 83 ), -S(O) 0-2 R 81 , -S(O) 1-2 OR 81 , -OS(O) 1-2 R 81 , -OS(O) 1-2 OR 81 , -S(O) 1-2 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 )(R83 ), -OP(O)(OR 81 )2, -C(=X 2 )R 81 , -C(=X 2 )X 2 R 81 , -X 2 C(=X 2 )R 81 , and -X 2 C(=X 2 )X 2 R 81 and / or any two second-level substituents attached to the same carbon atom of a cycloalkyl or heterocyclyl group are joined together and are represented by ═X 2 can be formed. Here, the second-level substituent C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 The alkynyl, 6- to 14-membered aryl, 3- to 14-membered heteroaryl, 3- to 14-membered cycloalkyl, and 3- to 14-membered heterocyclyl groups may be optionally substituted by one or more third-level substituents, wherein the third-level substituents, in each case, are selected from the group consisting of: C 1-3 Alkyl, halogen, -CF3, -CN, azide, -NO2, -OH, -O(C 1-3 alkyl), -OCF3, -S(C 1-3 alkyl), -NH2, -NH(C 1-3 alkyl), -N(C 1-3 alkyl)2, -NHS(O)2(C 1-3 alkyl), -S(O)2NH 2-Z (C 1-3 alkyl) z , -C(=O)OH, -C(=O)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 1-3alkyl)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. And / or any two third-level substituents attached to the same carbon atom of a 3- to 14-membered cycloalkyl or heterocyclyl group that is a second-level substituent may be joined together to form =O, =S, =NH, or =N(C 1-3 alkyl); R 71 , R 72 and R 73 are independently H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, 5- to 6-membered aryl, 5- to 6-membered heteroaryl, 3- to 7-membered cycloalkyl, and 3- to 7-membered heterocyclyl groups, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 5- to 6-membered aryl, 5- to 6-membered heteroaryl, 3- to 7-membered cycloalkyl, and 3- to 7-membered heterocyclyl groups are each independently C 1-3 Alkyl, halogen, -CF3, -CN, azide, -NO2, -OH, -O(C 1-3 alkyl), -OCF3, =O, -S(C 1-3 alkyl), -NH2, -NH(C 1-3 alkyl), -N(C 1-3 alkyl)2, -NHS(O)2(C 1-3 alkyl), -S(O)2NH 2-Z (C 1-3 alkyl) z , -C(=O)(C 1-3 alkyl), -C(=O)OH, -C(=O)O(C 1-3 alkyl), -C(=O)NH 2-Z (C 1-3 alkyl) z , -NHC(=O)(C 1-3 alkyl), -NHC(=NH)NH2-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; R 81 , R 82 , and R 83 are independently H, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 independently selected from the group consisting of alkynyl, 5- to 6-membered aryl, 5- to 6-membered heteroaryl, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocyclyl groups, wherein C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 The alkynyl, 5- to 6-membered aryl, 5- to 6-membered heteroaryl, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocyclyl groups may be optionally substituted with one, two, or three substituents independently selected from the group consisting of: 1-3 Alkyl, halogen, -CF3, -CN, azide, -NO2, -OH, -O(C 1-3 alkyl), -OCF3, =O, -S(C 1-3 alkyl), -NH2, -NH(C 1-3 alkyl), -N(C 1-3 alkyl)2, -NHS(O)2(C 1-3 alkyl), -S(O)2NH 2-Z (C 1-3 alkyl) z , -C(=O)(C 1-3 alkyl), -C(=O)OH, -C(=O)O(C 1-3 alkyl), -C(=O)NH 2-Z (C 1-3 alkyl) z , -NHC(=O)(C 1-3alkyl), -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 alkyl is independently methyl, ethyl, propyl, or isopropyl; and X 1 and X 2 each independently represents O, S, and N(R 84) where R 84 is H or C 1-3 It is alkyl.

[0102] In one embodiment, the kinase inhibitor has the formula (II): [ka] In the formula, 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 the group consisting of alkyl, —O(alkyl), —S(alkyl), —NH(alkyl), —N(alkyl), and heterocyclyl, wherein each of the alkyl and heterocyclyl groups is selected from one or more (e.g., 1, 2, or 3) independently selected R 30 Preferably, each R 30 are independently a first level substituent, a second level substituent, or a third level substituent as specified herein, such as alkyl (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).

[0103] 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, and R 1a is C 1-3 Alkyl, -O(C 1-3 alkyl), -S(C 1-3 alkyl), -NH(C 1-3 alkyl), -N(C 1-3 alkyl), and 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl group is selected from the group consisting of methyl, ethyl, —OH, —OCH3, —SCH3, cyclopropyl, 2-hydroxyethyl, 2-(N,N-dimethylamino)ethyl, 2-(N,N-dimethylamino)ethoxy, 2-aminoethyl, 2-(N-methylamino)ethyl, 2-(methoxyethyl), 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 C 1-3 Each of the alkyl groups is selected from -OH, -OCH3, -SCH3, cyclopropyl, piperazinyl, 4-methylpiperazinyl, 4-(2-hydroxyethyl)piperazinyl, 2-(N,N-dimethylamino)ethoxy, and NH 2-Z (CH3) Z wherein z is 0, 1, or 2.

[0104] 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, and R 1a is 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 the piperazinyl, morpholinyl, piperidinyl and pyrrolidinyl groups are selected from the group consisting of methyl, ethyl, -OH, -OCH3, -SCH3, cyclopropyl, 2-hydroxyethyl, 2-(N,N-dimethylamino)ethyl, 2-(N,N-dimethylamino)ethoxy, 2-aminoethyl, 2-(N-methylamino)ethyl, 2-(methoxyethyl), 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 C 1-3 Each of the alkyl groups is selected from -OH, -OCH3, -SCH3, cyclopropyl, piperazinyl, 4-methylpiperazinyl, 4-(2-hydroxyethyl)piperazinyl, 2-(N,N-dimethylamino)ethoxy, and NH 2-Z (CH3) Z wherein z is 0, 1, or 2.

[0105] 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, and R 1a is -NH(C 1-3 alkyl), piperazinyl, piperidinyl, and pyrrolidinyl, wherein the piperazinyl group is optionally substituted with one or two moieties independently selected from the group consisting of 2-hydroxyethyl, methyl, —CHCOOH, and —C(═O)CH; the piperidinyl group is optionally substituted with one or two moieties independently selected from the group consisting of —NH and 4-methylpiperazinyl; the pyrrolidinyl is optionally substituted with one or two OH; and C 1-3 Each of the alkyl groups is selected from the group consisting of -OH, -OCH3 and NH 2-Z (CH3) z wherein z is 0, 1, or 2.

[0106] 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 formula (I)) or below, and R 1a is selected from the group consisting of 4-(2-hydroxyethyl)piperazinyl, 4-methylpiperazinyl, 4-acetylpiperazinyl, (2-hydroxyethyl)amino, 4-aminopiperidinyl, 4-(4-methylpiperazinyl)piperidinyl, (4-carboxymethylpiperazinyl), and 3-hydroxypyrrolidinyl, for example, selected from the group consisting of 4-(2-hydroxyethyl)piperazinyl, 4-methylpiperazinyl, 4-acetylpiperazinyl, and (2-hydroxyethyl)amino.

[0107] In an alternative embodiment of the kinase inhibitor of formula (II), R 1b , R 1c , R 2 , R3 , R 4 , R 5 , A, B, and E are as defined above (particularly with respect to formula (I)) or as defined below, and R 1a is a leaving group (e.g., a halogen such as Cl, Br, or F), nitro, benzotriazol-1-yloxy, C1-C 10 Alkyl sulfonates, C1-C 10 haloalkylsulfonates, nonaflate (CFCFCFCFSO-), CFC(=O)O-, phenylsulfonate (wherein phenyl is optionally substituted with 1, 2, or 3 groups each independently selected from halogen and C-C alkyl), or a group of formula -[N(R x )(R y )(R z )] + [G] - (In the formula, R x , R y , and R z are independently hydrogen or alkyl), and G is the conjugate base of a strong acid (e.g., G - is Cl - )).

[0108] In one embodiment, the kinase inhibitor has the general formula (III): [ka] where R 1a , R 2 , R 3 , R 4 , R 5 , A, B, and E are as defined above (particularly in formula (I) and / or formula (II)) or as defined below, and R 1b and R 1c Each of these is H, methyl, ethyl, -OH, -OCH3, -SCH3, cyclopropyl, 2-hydroxyethyl, 2-(N,N-dimethylamino)ethyl, 2-(N,N-dimethylamino)ethoxy, 2-aminoethyl, 2-(N-methylamino)ethyl, 2-(methoxy)ethyl, -NH 2-Z (CH3) z, phenyl, pyridinyl, pyrazolyl, phenoxy, pyridinyloxy, imidazolylamino, and tetrahydrofuranylmethoxy, where z is 0, 1, or 2; and phenyl, pyridinyl, pyrazolyl, phenoxy, pyridinyloxy, imidazolylamino, and tetrahydrofuranylmethoxy are independently selected from the group consisting of methyl, ethyl, —OH, —OCH3, —SCH3, cyclopropyl, 2-hydroxyethyl, 2-(N,N-dimethylamino)ethyl, 2-(N,N-dimethylamino)ethoxy, 2-aminoethyl, 2-(N-methylamino)ethyl, 2-(methoxy)ethyl, and NH 2-Z (CH3) Z wherein z is 0, 1, or 2.

[0109] In one embodiment of the kinase inhibitor of Formula (III), R 1a , R 2 , R 3 , R 4 , R 5 , A, B, and E are defined above (particularly in formula (I) and / or (II)) or below, and R 1b and R 1c At least one of is H, methyl, ethyl, -OH, -OCH3, -SCH3, cyclopropyl, 2-hydroxyethyl, 2-(N,N-dimethylamino)ethyl, 2-(N,N-dimethylamino)ethoxy, 2-aminoethyl, 2-(N-methylamino)ethyl, 2-(methoxy)ethyl, -NH 2-Z (CH3) Z and phenyl, where z is 0, 1, or 2. In this embodiment, R 1b and R 1c may be as defined above (particularly with respect to formula (I), (II) and / or (III)), e.g., R 1b and R 1cOther than these, H, methyl, -OH, -OCH3, -SCH3, cyclopropyl, 2-hydroxyethyl, 2-(N,N-dimethylamino)ethyl, 2-(N,N-dimethylamino)ethoxy, 2-aminoethyl, 2-(N-methylamino)ethyl, 2-(methoxy)ethyl, -NH 2-Z (CH3) z , phenyl, pyridinyl, pyrazolyl, phenoxy, pyridinyloxy, imidazolylamino, and tetrahydrofuranylmethoxy, where z is 0, 1, or 2; and the phenyl, pyridinyl, pyrazolyl, phenoxy, pyridinyloxy, imidazolylamino, and tetrahydrofuranylmethoxy groups may be selected from the group consisting of methyl, ethyl, —OH, —OCH3, —SCH3, cyclopropyl, 2-hydroxyethyl, 2-(N,N-dimethylamino)ethyl, 2-(N,N-dimethylamino)ethoxy, 2-aminoethyl, 2-(N-methylamino)ethyl, 2-(methoxy)ethyl, and NH 2-Z (CH3) z wherein z is 0, 1, or 2. Alternatively, R 1b and R 1c each independently represents H, methyl, ethyl, -OH, -OCH3, -SCH3, cyclopropyl, 2-hydroxyethyl, 2-(N,N-dimethylamino)ethyl, 2-(N,N-dimethylamino)ethoxy, 2-aminoethyl, 2-(N-methylamino)ethyl, 2-(methoxy)ethyl, -NH 2-Z (CH3) Z and phenyl, where z is 0, 1, or 2.

[0110] In one embodiment of the kinase inhibitor of Formula (III), R 1a , R 2 , R 3 , R 4 , R 5 , A, B, and E are defined above (particularly in formula (I) and / or (II)) or below, and R 1bis methyl, ethyl, propyl, or isopropyl, preferably methyl; R 1c is H, and in an alternative embodiment, R 1b is H and R 1c is methyl, ethyl, propyl, isopropyl, or phenyl, preferably methyl.

[0111] In a related embodiment, the present invention provides a compound selected from the group consisting of kinase inhibitors of formula (Ia): [ka] and solvates, salts, N-oxides, complexes, polymorphs, crystalline forms, racemic mixtures, diastereomers, enantiomers, tautomers, conformers, isotopically labeled forms, prodrugs, and combinations thereof; where 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 formulas (IV), (VI), (VII), and / or (VIII)); R 5 is -L-R6, where L is a bond and R 6 is one or more independently selected R 7 and 5- or 6-membered heteroaryl optionally substituted with (particularly R 6 is one or more independently selected R as defined with respect to formula (V) below: 7 and optionally substituted 5- or 6-membered heteroaryl; Hy is one or more (e.g., up to the maximum number of hydrogen atoms bonded to the heteroaryl or heterocyclyl group, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 or less, e.g., 1 to 5, 1 to 4, or 1 to 3, or 1 or 2) independently selected R 1e and optionally substituted heteroaryl or heterocyclyl; each R 1e is R 1a , R 1b , R1c and R 1d independently selected from the group consisting of: R 1a , R 1b , R 1c and R 1d each independently as defined above (particularly with respect to formulas (I), (II), and / or (III)) or below (particularly with respect to formulas (VII) and / or (VIII)).

[0112] 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 as defined below (particularly with respect to formulas (IV), (VI), (VII), and / or (VIII)), and R 6 is a 5- or 6-membered heteroaryl optionally substituted with one or more independently selected R7 (particularly, R 6 is one or more independently selected R as defined with respect to formula (V) below: 7 and optionally substituted 5- or 6-membered heteroaryl), and Hy is each independently selected from 1, 2, 3, 4, 5, or 6 R 1e and 3- to 10-membered heteroaryl or 3- to 10-membered heterocyclyl optionally substituted with 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 formulas (IV), (VI), (VII), and / or (VIII)), and R 6 is one or more independently selected R 7 and optionally substituted 5- or 6-membered heteroaryl (particularly R 6 is one or more independently selected R as defined with respect to formula (V) below 7and Hy is each 1, 2, 3, 4, 5, or 6 independently selected R 1e and optionally substituted monocyclic or bicyclic heteroaryl, monocyclic or bicyclic heterocyclyl. 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 formulas (IV), (VI), (VII), and / or (VIII)), and R 6 is one or more independently selected R 7 and optionally substituted 5- or 6-membered heteroaryl (particularly R 6 is one or more independently selected R as defined with respect to formula (V) below 7 and Hy is 1, 2, 3, 4, 5, or 6 independently selected R 1e is selected from the group consisting of 5- or 6-membered monocyclic heteroaryl, 5- or 6-membered monocyclic heterocyclyl, 9- to 10-membered bicyclic heteroaryl, and 8- to 10-membered bicyclic heterocyclyl, optionally substituted with 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 formulas (IV), (VI), (VII), and / or (VIII)), and R 6 is one or more independently selected R 7 and optionally substituted 5- or 6-membered heteroaryl (particularly R 6 is one or more independently selected R as defined with respect to formula (V) below 7and Hy is selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl (e.g., 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl), pyrazolyl, oxadiazolyl, thiazolyl, triazolyl, thiadiazolyl, cyclopentapyrimidinyl, dihydrocyclopentapyrimidinyl, pyrrolopyrimidinyl, indole, and 1,1-dioxidetetrahydrothiopyranyl, each of which is selected from the group consisting of 1, 2, 3, 4, 5, or 6 independently selected R 1e (optionally substituted with). 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 formulas (IV), (VI), (VII), and / or (VIII)), and R 6 is one or more independently selected R 7 and optionally substituted 5- or 6-membered heteroaryl (particularly R 6 is one or more independently selected R as defined with respect to formula (V) below 7 and Hy is selected from the group consisting of: [ka] Each of the above groups a), b), c), d), e), f), and g) is composed of 1, 2, 3, 4, 5, or 6 independently selected R 1e where the wavy line indicates that in formula (Ia), Hy is NR 2represents the bond attached to the nitrogen atom of the moiety. When Hy contains an NH moiety as a ring member, the hydrogen atom is 1-6 or C 1-3 Preferably, Hy is optionally substituted with alkyl, such as alkyl, more preferably methyl (resulting in an alkyl-substituted N ring atom), and Hy is selected from 1, 2, 3, 4, or 5 independently selected R 1e may be further optionally substituted with Examples of such N-alkyl substituted Hy groups include: [ka] In the formula, the wavy line indicates that Hy is NR in formula (Ia). 2 represents the bond attached to the nitrogen atom of the moiety.

[0113] In any of the above embodiments of the kinase inhibitor of Formula (Ia), Hy is selected from the group consisting of one R 1b , 1 R 1c and R between 1 and 4, for example, 1, 2, or 3 1a or R 1d and optionally substituted with; for example, Hy may be substituted with one (or two) R 1a (as defined above or as defined below, in particular with respect to formula (II)), and one (or two) R 1b or R 1c (as defined above, particularly with respect to formula (III), or as defined below), and all other R 1e is H.

[0114] In any of the above embodiments of kinase inhibitors of formula (Ia), A is preferably S and / or E is preferably O.

[0115] In one embodiment, the kinase inhibitor has the general formula (IV): [ka] where R1a , R 1b , R 1c , R 2 , R 4 , R 5 , A, B, and E are defined above (especially with respect to formula (I), (II), and / or (III)) or below, and R 3 is H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, phenyl, halogen, -CN, azide, -NO2, -O(C 1-6 alkyl), -OCF3, -S(C 1-6 alkyl), -NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, -NHS(O)2(C 1-6 alkyl), -S(O)2NH 2-Z (C 1-6 alkyl) z , -C(=O)(C 1-6 alkyl), -C(=O)OH, -C(=O)O(C 1-6 alkyl), -C(=O)NH 2-Z (C 1-6 alkyl), -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、 (wherein z is 0, 1, or 2; C 1-6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Each of the cycloalkyl and phenyl groups may be selected from one or more independently selected R 30 and optionally substituted with

[0116] 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 defined above (particularly with respect to formula (I), (II), and / or (III)) or as follows, and R 3 is 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 the phenyl group is selected from the group consisting of halogen, methyl, isopropyl, -CN, -CF3, -OCF3, -OH, -NH2, -NH(C 1-3 alkyl), -N(C 1-3 alkyl)2, -NHC(=O)(C 1-3 alkyl), -C(=O)NH 2-Z (C 1-3 alkyl) Z , -(CH2) 1-3 NH2, -(CH2) 1-3 NH(C 1-3 alkyl), -(CH2) 1-3 N(C 1-3 alkyl)2, -(CH2) 1-3 OH, and (CH2) 1-3 O(C 1-3 and Z is 0, 1, or 2.

[0117] 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 formulas (I), (II), and / or (III)) or below, and R3 is selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, phenyl, and halogen.

[0118] 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 as defined below, and R 3 is H.

[0119] In one embodiment, the kinase inhibitor has the general formula (V): [ka] In the formula, R 1a , R 1b , R 1c , R 2 , R 3 , R 4 , A, B, and E are as defined above (particularly with respect to formulae (I), (II), (III), and / or (IV)) or as defined below, and R 5 -LR 6 where R 6 is a heteroaryl containing at least one ring heteroatom selected from the group consisting of N, O, and S, or a heterocyclyl containing at least one ring heteroatom selected from the group consisting of N, O, and S, and each of the heteroaryl and heterocyclyl groups is selected from one, two, three, or four independently selected R 7 and optionally substituted with, for example, R6 can be a heteroaryl containing at least one ring heteroatom selected from the group consisting of N and O (i.e., the heteroaryl does not contain S as a ring heteroatom; and, in some embodiments, does not contain O as a ring heteroatom, i.e., R 6 is N-heteroaryl), or heterocyclyl containing at least one ring heteroatom selected from the group consisting of N and O (i.e., 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 and R may be N-heterocyclyl, wherein each of the heteroaryl and heterocyclyl groups is selected from 1, 2, or 3 independently selected R 7 and optionally substituted with

[0120] 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 formulae (I), (II), (III), and / or (IV)) or below, and R 6 is a 3- to 10-membered heteroaryl (e.g., containing at least one ring heteroatom selected from the group consisting of N, O, and S, such as selected from the group consisting of N and O), or a 3- to 10-membered heterocyclyl (e.g., containing at least one ring heteroatom selected from the group consisting of N, O, and S, such as selected from the group consisting of N and O), each of which is selected from 1, 2, or 3 independently selected R 7 and optionally substituted with

[0121] 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 formulae (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 the group consisting of N, O, and S, such as selected from the group of N and O), or a monocyclic or bicyclic heterocyclyl (e.g., containing at least one ring heteroatom selected from the group consisting of N, O, and S, such as selected from the group of N and O), each of which is selected from one, two, or three independently selected R 7 and optionally substituted with

[0122] 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 formulae (I), (II), (III), and / or (IV)) or below, and R 6 is selected from the group consisting of 5- to 6-membered monocyclic heteroaryl (e.g., containing at least one ring heteroatom selected from the group consisting of N, O, and S, such as selected from the group of N and O), 4- to 6-membered monocyclic heterocyclyl (e.g., containing at least one ring heteroatom selected from the group consisting of N, O, and S, such as selected from the group of N and O), 4- to 6-membered monocyclic heterocyclyl (e.g., containing at least one ring heteroatom selected from the group consisting of N, O, and S, such as selected from the group of N and O), and 7- to 9-membered bicyclic heteroaryl (e.g., containing at least one ring heteroatom selected from the group consisting of N, O, and S, such as selected from the group of N and O), and 7- to 9-membered bicyclic heterocyclyl (e.g., containing at least one ring heteroatom selected from the group consisting of N, O, and S, such as selected from the group of N and O), each of which is selected from the group consisting of 1, 2, or 3 independently selected R 7 and optionally substituted with

[0123] 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 formulae (I), (II), (III), and / or (IV)) or below, and R 6 is a 5- to 6-membered monocyclic heteroaryl (e.g., containing at least one ring heteroatom selected from the group consisting of N, O, and S, such as selected from the group of N and O), which is selected from one, two, or three independently selected R 7 and optionally substituted with

[0124] 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 formulae (I), (II), (III), and / or (IV)) or below, and R 6 is a 7- to 9-membered bicyclic heterocyclyl (e.g., containing at least one ring heteroatom selected from the group consisting of N, O, and S, such as selected from the group of N and O), which is selected from one, two, or three independently selected R 7 and optionally substituted with

[0125] 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 formulae (I), (II), (III), and / or (IV)) or below, and R 6is selected from the group consisting of pyridinyl, thienyl, pyridazinyl, furanyl, pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazoimidazolyl, indolyl, naphthyridinyl, thienopyridinyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, azetidinyl, azabicycloheptanyl, azabicyclooctanyl, azapentacyclooctanyl, piperazinyl, morpholinyl, and tetrahydrothiophenyl, each of which is independently selected from R 7 Preferably, R 6 is selected from the group consisting of pyridinyl, thienyl, pyrazolyl, isoxazolyl, pyrrolyl, piperidinyl, pyrrolidinyl, azetidinyl, and azabicyclooctanyl, each of which is independently selected from R 7 may be optionally substituted with one, two, or three of:

[0126] In one embodiment of the kinase inhibitors of Formula (V) (including those of Formulas (I), (II), (III), and (IV)), R 7 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, -CN, -O(C 1-6 alkyl), -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, -NHS(O) 1-2 (C 1-6 alkyl), -NHS(O) 1-2 O(C 1-6 alkyl), -C(=O)(C 1-6 alkyl), and OC(=O)(C 1-6 alkyl), and / or R is a heterocyclyl group. 6 Any two Rs bonded to the same atom of 7 are bonded together to form =O, where C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl group may be selected from one or more independently selected R30 and optionally substituted with For example, R 7 is C 1-3 Alkyl, halogen, -CN, -O(C 1-3 alkyl), -NH(C 1-3 alkyl), and N(C 1-3 alkyl), and / or R is a heterocyclyl group. 6 Any two R bonded to the same atom of 7 can be bonded to each other to form =O, where C 1-3 Each alkyl group may be selected from one or more independently selected R 30 and optionally substituted with In any of the above embodiments of the kinase inhibitors of Formula (V) (including those of Formulas (I), (II), (III), and (IV)), R 7 may be independently selected from the group consisting of Cl, Br, methyl, and ethyl, for example, from the group consisting of Cl, Br, and methyl.

[0127] In any of the above embodiments of kinase inhibitors of Formula (V) (including kinase inhibitors of Formulas (I), (II), (III), and (IV)), R 6 If is substituted, R 6 is at the 2-position relative to the ring atom that is attached to the rest of the compound, R 6 One R on a ring atom of 7 It is preferred that the groups are linked (i.e., R 6 Ortho R 7 It is preferred that the aryl group has a hydroxyl group. In any of the above embodiments of kinase inhibitors of Formula (V) (including those of Formulas (I), (II), (III), and (IV)), R 6 Two or more (e.g., two, three, or four) R 7 When substituted with a group, two or more R 7 One of the groups is R 6 is attached to the rest of the compound (i.e., R 6 Ortho R 7R at the 2nd position relative to the ring atom (bearing a group) 6 are bonded to the ring atoms of the remaining R 7 The group is R at a position other than the 2-position. 6 It is preferred that the ring atom(s) of For example, a kinase inhibitor of formula (V) (including kinase inhibitors of formulas (I), (II), (III), and (IV)) 6 is two or more R 7 In any of the above embodiments of the k-membered ring substituted with a group, two or more R 7 One of the groups is R 6 R is in the 2 position relative to the ring atom that is attached to the rest of the compound 6 (i.e., to the yl position) and the remaining R 7 The R group is at a position other than the 2-position (e.g., the 3-, 4-, 5-, or k-position). 6 It is preferred that the ring atom of For example, R 6 When R is a 5-membered ring, two or more R 7 One of the groups is R at the 2-position 6 bonded to the ring atom (relative to the yl position) of 7 The group R 6 It is preferred that the ring atom (relative to the yl position) of Furthermore, in any of the above embodiments of the kinase inhibitors of formula (V) (including formulas (I), (II), (III), and (IV)), wherein R 6 two or more (e.g., two, three, or four) R 7 When substituted with a group, R 6 Each of the two ring atoms immediately adjacent to the ring atom to which is attached to the remainder of the compound is bonded to one R 7 It is preferable to have a group (for example, a k-membered ring R 6 is R 6 one R at each of positions 2 and k relative to the ring atom where 7 having a group, e.g., R 6 is substituted at both of its ortho positions). Furthermore, in any of the above embodiments of the kinase inhibitors of formula (V) (including those of formulas (I), (II), (III) and (IV)), R 6 Three or more (e.g., three or four) R 7 When substituted with a group, R 6 However, each of the two ring atoms immediately adjacent to the ring atom that is bonded to the remainder of the compound is bonded to one R 7 It is preferable to have a group (for example, a k-membered ring R 6 is R 6 one R at each of positions 2 and k relative to the ring atom where 7 having a group, e.g., R 6 is substituted at both its ortho positions), and a third R 7 The group is directly adjacent to one of the ortho ring atoms, but 6 is not a ring atom attached to the rest of the compound, R 6 (e.g., k-membered ring R 6 is the rest of the compound 6 a third R at the 3-position and the k-1-position relative to the ring atom to which 7 It is preferred that the aryl group is a aryl group.

[0128] 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 formulae (I), (II), (III), and / or (IV)) or below, and R 6 is selected from the following formula: [ka] In the formula, the wavy line represents R 6 represents the bond that connects it to the rest of the compound.

[0129] In one embodiment of the kinase inhibitor of Formula (V), R 1a , R 1b , R 1c , R2 , R 3 , R 4 , A, B, and E are as defined above (particularly with respect to formulae (I), (II), (III), and / or (IV)) or below, and R 6 is selected from the following formulas: [ka] In the formula, the wavy line represents R 6 represents the bond that connects it to the rest of the compound.

[0130] 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 formulae (I), (II), (III), and / or (IV)) or below, and R 6 is selected from the following formulas: [ka] In the formula, the wavy line represents R 6 represents the bond that connects it to the rest of the compound.

[0131] 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 formulae (I), (II), (III), and / or (IV)) or below, and R 6 is selected from the following formulas: [ka] In the formula, the wavy line represents R 6 represents the bond that connects it to the rest of the compound.

[0132] In any of the above embodiments of the kinase inhibitors of formula (V) (including those of formulas (I), (II), (III), and (IV)), L is a bond, C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylene, and (CH2) m -[Y-(CH2) n ] O -, wherein m is 1, 2, or 3; n is 0, 1, or 2; 0 is 1, 2, or 3; and when n is 0, 0 is 1; and Y is independently selected from O, S, and NH; and wherein C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylene, -(CH2) m - and -(CH2) n Each of the -groups may be one or more independently selected R 30 and optionally substituted with For example, in any of the above embodiments of the kinase inhibitors of formula (V) (including those of formulas (I), (II), (III), and (IV)), L is a bond; one R 30 and optionally substituted C alkylene; optionally one R 30 C2 alkylene (especially 1,2-ethylene or 1,1-ethylene) optionally substituted with 30 C alkylene (especially trimethylene) optionally substituted with one R 30 C4 alkylene (especially tetramethylene or 2,4-butanediyl) optionally substituted with -(CH2) m O-; and (CH2) m NH-, where m is 1, 2, or 3). In particular, in any of the above embodiments of kinase inhibitors of formula (V), (including those of formulas (I), (II), (III), and (IV)), L may be a bond.

[0133] In any of the above embodiments of the kinase inhibitor of Formula (V) (including those of Formulas (I), (II), (III), and (IV)), wherein R 6 is a heterocyclyl or heteroaryl containing an N atom as a ring heteroatom (e.g., a 5-membered heteroaryl), L may be linked to R via the N ring atom of the heterocyclyl or heteroaryl group. 6 can be combined with

[0134] In one embodiment, the kinase inhibitor has the general formula (VI): [ka]

[0135] In the formula, 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 S, O, NH, N(C 1-6 alkyl), and C(C 1-6 alkyl)2. In any of the above embodiments of the kinase inhibitor of formula (VI) (including kinase inhibitors of formulas (I), (II), (III), (IV), and (V)), A is S, O, or N(CH 3)2 It could be. In any of the above embodiments of kinase inhibitors of formula (VI) (including kinase inhibitors of formulas (I), (II), (III), (IV) and (V)), A is preferably S.

[0136] In one embodiment, the kinase inhibitor has the general formula (VII): [ka]

[0137] where R 1a , R1b , 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) and / or (V)) or E is O or S (preferably O), and B is N or CR 1d where R 1d is 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 the C 1-3 Each alkyl is selected from the group consisting of halogen, -OH, -OCH3, -SCH and -NH 2-Z (CH3) Z wherein z is 0, 1, or 2, and optionally substituted with one or two moieties independently selected from the group consisting of: In any of the above embodiments of the kinase inhibitors of formula (VII) (including those of formulas (I), (II), (III), (IV), (V), and (VI)), E is O or S (preferably O) and B is N or CR 1d where R 1d is C 1-3 Alkyl, halogen, -O(C 1-3 alkyl), -S(C 1-3 alkyl), -NH(C 1-3 alkyl), and N(C 1-3 alkyl)2. In any of the above embodiments of kinase inhibitors of Formula (VII) (including kinase inhibitors of Formulas (I), (II), (III), (IV), (V) and (VI)), it is preferred that B is N, and more preferred that E is O and B is N.

[0138] In one embodiment, the kinase inhibitor has the general formula (VIII): [ka] In the formula, R 1a , R 1b , R 1c , R 2 , R 3 , R 4 , R 5 , A, B, and E are as defined above (particularly with respect to formulas (I), (II), (III), (IV), (V), (VI), and / or (VII)) or as defined below, and L is a bond. In a preferred embodiment of the kinase inhibitor having the general formula (VIII): (A) R 1a is selected from the group consisting of alkyl, —O(alkyl), —S(alkyl), —NH(alkyl), —N(alkyl), and heterocyclyl, wherein each of the alkyl and heterocyclyl groups is selected from one or more (e.g., 1, 2, or 3) independently selected R 30 may be optionally substituted with Preferably, each R 30 are independently a first level substituent, a second level substituent, or a third level substituent, as specified herein, for example, alkyl (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); (B) R 1b and R 1cEach of these is H, methyl, -OH, -OCH3, -SCH3, cyclopropyl, 2-hydroxyethyl, 2-(N,N-dimethylamino)ethyl, 2-(N,N-dimethylaminoethyl)ethoxy, 2-aminoethyl, 2-(N-methylamino)ethyl, 2-(methoxy)ethyl, -NH 2-Z (CH3) z , phenyl, pyridinyl, pyrazolyl, phenoxy, pyridinyloxy, imidazolylamino, and tetrahydrofuranylmethoxy, where z is 0, 1, or 2; each of the phenyl, pyridinyl, pyrazolyl, phenoxy, pyridinyloxy, imidazolylamino, and tetrahydrofuranylmethoxy groups is independently selected from the group consisting of methyl, ethyl, —OH, —OCH3, —SCH3, cyclopropyl, 2-hydroxyethyl, 2-(N,N-dimethylamino)ethyl, 2-(N,N-dimethylamino)ethoxy, 2-aminoethyl, 2-(N-methylamino)ethyl, 2-(methoxy)ethyl, and NH 2-Z (CH3) z wherein z is 0, 1, or 2; (C) R 3 is H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, phenyl, halogen, -CN, azide, -NO2, -O(C 1-6 alkyl), -OCF3, -S(C 1-6 alkyl), -NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, -NHS(O)2(C 1-6 alkyl), -S(O)2NH 2-Z (C 1-6 alkyl) z , -C(=O)(C 1-6 alkyl), C(=O)OH, -C(=O)O(C 1-6 alkyl), -C(=O)NH 2-Z (C 1-6 alkyl) z , -NHC(=O)(C 1-6alkyl), -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 wherein z is 0, 1, or 2; 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Each of the cycloalkyl and phenyl groups may be selected from one or more independently selected R 30 and optionally substituted]; (D) R 6 is as defined above (particularly with respect to formula (V)), and is preferably a 3- to 10-membered heteroaryl (e.g., containing at least one ring heteroatom selected from the group consisting of N, O, and S, such as from the group consisting of N, and O), or a 3- to 10-membered heterocyclyl (e.g., containing at least one ring heteroatom selected from the group consisting of N, O, and S, such as from the group consisting of N, and O), each of which is independently selected from 1, 2, or 3 R 7 and optionally substituted with; (E) A is S, O, NH, N(C 1-6 alkyl), and C(C 1-6 alkyl)2; (F) B is N or CR 1d where R 1d is 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 may be selected from the group consisting of halogen, -OH, -OCH3, -SCH, and NH 2-Z (CH3) zwhere z is 0, 1, or 2; and / or (G) E is O or S, preferably O.

[0139] In a preferred embodiment of the kinase inhibitor having the general formula (VIII), R 1a is as specified in (A) above, and R 1b and R 1c is as defined in (B), and R 3 is as specified in (C), and R 6 is as defined above (particularly with respect to formula (V)), and is preferably a 3- to 10-membered heteroaryl (e.g., containing at least one ring heteroatom selected from the group consisting of N, O, and S, such as the group consisting of N and O) or a 3- to 10-membered heterocyclyl (e.g., containing at least one ring heteroatom selected from the group consisting of N, O, and S, such as the group consisting of N and O), each of which is selected from 1, 2, or 3 independently selected R 7 and optionally substituted; A is as specified in (E), B is as specified in (F) above, and E is as specified in (G).

[0140] In a further preferred embodiment of the kinase inhibitor having the general formula (VIII): (A') R 1a is C 1-3 Alkyl, -O(C 1-3 alkyl), -S(C 1-3 alkyl), -NH(C 1-3 alkyl), -N(C 1-3alkyl)2, and 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl group is selected from the group consisting of methyl, ethyl, -OH, -OCH3, -SCH3, cyclopropyl, 2-hydroxyethyl, 2-(N,N-dimethylamino)ethyl, 2-(N,N-dimethylamino)ethoxy, 2-aminoethyl, 2-(N-methylamino)ethyl, 2-(methoxy)ethyl, 4-methylpiperazinyl, -C(=O)(C 1-3 alkyl), -(CH2) 1-3 COOH and NH 2-Z (CH3) z wherein z is 0, 1, or 2; and C 1-3 Each of the alkyl groups is 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; (B') R 1b and R 1c At least one of is H, methyl, ethyl, -OH, -OCH3, -SCH3, cyclopropyl, 2-hydroxyethyl, 2-(N,N-dimethylamino)ethyl, 2-(N,N-dimethylamino)ethoxy, 2-aminoethyl, 2-(N-methylamino)ethyl, 2-(methoxy)ethyl, -NH 2-Z (CH3) z and phenyl, where z is 0, 1, or 2; R 1b and R 1c otherwise as defined in (B) above; (C') R 3 is H, C 1-4 Alkyl, C 3-6 Cycloalkyl, phenyl, halogen, -CN, -O(C 1-4 alkyl), -OCF3, -S(C 1-4alkyl), -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 the phenyl group is selected from the group consisting of halogen, methyl, isopropyl, -CN, -CF3, -OCF3, -OH, -NH2, NH(C 1-3 alkyl), -N(C 1-3 alkyl)2, -NHC(=O)(C 1-3 alkyl), -C(=O)NH 2-Z (C 1-3 alkyl) Z , -(CH2) 1-3 NH2, -(CH2) 1-3 NH(C 1-3 alkyl), -(CH2) 1-3 N(C 1-3 alkyl)2, -(CH2) 1-3 OH and -(CH2) 1-3 O(C 1-3 alkyl), and z is 0, 1, or 2; (D') R 6are as defined above (particularly with respect to formula (V)), and are preferably 3- to 10-membered heteroaryl (e.g., containing at least one ring heteroatom selected from the group consisting of N, O, and S, such as the group consisting of N and O), or 3- to 10-membered heterocyclyl (e.g., containing at least one ring heteroatom selected from the group consisting of N, O, and S, such as the group consisting of N and O), each of which is selected from 1, 2, or 3 independently selected R 7 and optionally substituted, more preferably R 6 is a monocyclic or bicyclic heteroaryl or a monocyclic or bicyclic heterocyclyl, each of which is independently selected from 1, 2, or 3 R 7 and optionally substituted with; (E') A is S, O, or N(CH3)2; and / or (F') B is N or CR 1d where R 1d is 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 and / or (G') E is O or S, preferably O.

[0141] In a preferred embodiment of the kinase inhibitor having the general formula (VIII), R 1a is as specified above in (A'), and R 1b and R 1c is as defined in (B'), and R 3 is as specified in (C'), and R 6is as defined above (particularly with respect to formula (V)), and is preferably a 3- to 10-membered heteroaryl (e.g., containing at least one ring heteroatom selected from the group consisting of N, O, and S, such as the group consisting of N and O) or a 3- to 10-membered heterocyclyl (e.g., containing at least one ring heteroatom selected from the group consisting of N, O, and S, such as the group consisting of N and O), each of which is selected from 1, 2, or 3 independently selected R 7 and optionally substituted with, more preferably R 6 is a monocyclic or bicyclic heteroaryl (e.g., containing at least one ring heteroatom selected from the group consisting of N, O, and S, such as the group consisting of N and O) or a monocyclic or bicyclic heterocyclyl (e.g., containing at least one ring heteroatom selected from the group consisting of N, O, and S, such as the group consisting of N and O), each of which is independently selected from 1, 2, or 3 R 7 and optionally substituted; A is as specified in (E'), B is as specified in (F'), and E is as specified in (G').

[0142] In a further preferred embodiment of the kinase inhibitor having the general formula (VIII): (A") R 1a is -NH(C 1-3 alkyl), piperazinyl, piperidinyl, and pyrrolidinyl, wherein the piperazinyl group is optionally substituted with one or two moieties independently selected from the group consisting of 2-hydroxyethyl, methyl, —CHCOOH, and C(═O)CH; the piperidinyl group is optionally substituted with one or two moieties independently selected from the group consisting of —NH and 4-methyl-piperazinyl; the pyrrolidinyl is optionally substituted with one or two OH; 1-3 Each of the alkyl groups is -OH, -OCH3, and NH 2-Z (CH3) zwherein z is 0, 1, or 2; (B") (a)R 1b is methyl, ethyl, propyl, or isopropyl, preferably methyl; R 1c is H; or (b) R 1b is H; R 1c is methyl, ethyl, propyl, isopropyl, or phenyl, preferably methyl; (C") R 3 is selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, phenyl, and halogen; (D") R 6 are the same as above (particularly with respect to formula (V)), and are preferably 3- to 10-membered heteroaryl (e.g., containing at least one ring heteroatom selected from the group consisting of N, O, and S, such as the group consisting of N and O), or 3- to 10-membered heterocyclyl (e.g., containing at least one ring heteroatom selected from the group consisting of N, O, and S, such as the group consisting of N and O), and each is 1, 2, or 3 independently selected R 7 and optionally substituted More preferably, R 6 is a monocyclic or bicyclic heteroaryl (e.g., containing at least one ring heteroatom selected from the group consisting of N, O, and S, such as the group consisting of N and O), or a monocyclic or bicyclic heterocyclyl (e.g., containing at least one ring heteroatom selected from the group consisting of N, O, and S, such as the group consisting of N and O), each independently containing 1, 2, or 3 R 7 and optionally substituted with More preferably, R 6is selected from 5- to 6-membered monocyclic heteroaryl (e.g., containing at least one ring heteroatom selected from the group consisting of N, O, and S, such as the group consisting of N and O), 4- to 6-membered monocyclic heterocyclyl (e.g., containing at least one ring heteroatom selected from the group consisting of N, O, and S, such as the group consisting of N and O), 7- to 9-membered bicyclic heteroaryl (e.g., containing at least one ring heteroatom selected from the group consisting of N, O, and S, such as the group consisting of N and O), and 7- to 9-membered bicyclic heterocyclyl (e.g., containing at least one ring heteroatom selected from the group consisting of N, O, and S, such as the group consisting of N and O), each of which is selected from one, two, or three independently selected R 7 and optionally substituted More preferably, R 6 is a 5- to 6-membered monocyclic heteroaryl (e.g., containing at least one ring heteroatom selected from the group consisting of N, O, and S, such as the group consisting of N and O) or a 7- to 9-membered bicyclic heterocyclyl (e.g., containing at least one ring heteroatom selected from the group consisting of N, O, and S, such as the group consisting of N and O), each of which is independently selected from 1, 2, or 3 R 7 and optionally substituted with; (E") A is S; (F") B is N; and / or (G") E is O.

[0143] In a preferred embodiment of the kinase inhibitor having the general formula (VIII), R 1a is as specified above in (A"), and R 1b and R 1c is as defined in (B"), and R 3 is as specified in (C), and R 6is as defined above (particularly with respect to formula (V)), and is preferably a 3- to 10-membered heteroaryl (e.g., containing at least one ring heteroatom selected from the group consisting of N, O, and S, such as the group consisting of N and O) or a 3- to 10-membered heterocyclyl (e.g., containing at least one ring heteroatom selected from the group consisting of N, O, and S, such as the group consisting of N and O), each of which is selected from 1, 2, or 3 independently selected R 7 and optionally substituted, more preferably R 6 is a monocyclic or bicyclic heteroaryl (e.g., containing at least one ring heteroatom selected from the group consisting of N, O, and S, such as the group consisting of N and O) or a monocyclic or bicyclic heterocyclyl (e.g., containing at least one ring heteroatom selected from the group consisting of N, O, and S, such as the group consisting of N and O), each of which is selected from one, two, or three independently selected R 7 and optionally substituted with More preferably, R 6 is selected from the group of 5- to 6-membered monocyclic heteroaryl (e.g., containing at least one ring heteroatom selected from the group consisting of N, O, and S, such as the group consisting of N and O), 4- to 6-membered monocyclic heterocyclyl (e.g., containing at least one ring heteroatom selected from the group consisting of N, O, and S, such as the group consisting of N and O), 7- to 9-membered bicyclic heteroaryl (e.g., containing at least one ring heteroatom selected from the group consisting of N, O, and S, such as the group consisting of N and O), and 7- to 9-membered bicyclic heterocyclyl (e.g., containing at least one ring heteroatom selected from the group consisting of N, O, and S, such as the group consisting of N and O), each of which is selected from the group consisting of 1, 2, or 3 R 7 and optionally substituted with More preferably, R 6is a 5- to 6-membered monocyclic heteroaryl (e.g., containing at least one ring heteroatom selected from the group consisting of N, O, and S, such as the group consisting of N and O), or a 7- to 9-membered bicyclic heterocyclyl (e.g., containing at least one ring heteroatom selected from the group consisting of N, O, and S, such as the group consisting of N and O), each of which contains 1, 2, or 3 independently selected R 7 A is as specified above in (E"); B is as specified above in (F"); and E is as specified above in (G").

[0144] In one embodiment, the compound of the invention is selected from the compounds shown in Table A and / or Table B.

[0145] The compounds of the present invention (particularly, compounds of any one of formulae (I), (Ia), (II), (III), (IV), (V), (VI), (VII), and (VIII) as shown in Table A and / or Table B below) include not only the compounds shown therein, but also solvates (e.g., hydrates), salts (particularly, pharmaceutically acceptable salts), N-oxides (particularly, R 1a and / or R 6 or N-oxides thereof), complexes, polymorphs, crystalline forms, non-crystalline forms, amorphous forms, amorphous forms, racemic mixtures, non-racemic mixtures, diastereomers, enantiomers, tautomers, conformers, isotopically labeled forms, prodrugs, and any combination thereof.

[0146] Various exemplary or preferred R compounds, including compounds that have been synthesized and tested within or for use within the methods of the present invention, are provided. 1a substituent, R 1b substituent, R 1c substituent, R 2 substituent, R 3 substituent, R 4 substituent, R 5A selection of compounds representing examples of moieties A, A, and / or B, each individually or in any combination, are listed in Tables A and / or B below. Table A: Kinase inhibitors of formula (I). Compound name, structure, name [Table A-1] [Table A-2] "Compound B3 is included in Table 1 of co-pending PCT / EP2018 / 060172. Table B: Further kinase inhibitors of formula (I) Compound name, structure, name [Table B-1] [Table B-2] [Table B-3]

[0147] In certain embodiments, the compound of the present invention is selected from the group consisting of C7 and C8 and / or D1 and / or D9, or in certain embodiments, the compound of the present invention is B3; also solvates, salts, N-oxides, complexes, polymorphs, crystalline forms, tautomers, conformers, isotopically labeled forms, prodrugs, and combinations thereof.

[0148] In another particular embodiment, the compound of the invention is C12, or a solvate, salt, N-oxide, complex, polymorph, crystalline form, racemic mixture, diastereomer, enantiomer, tautomer, conformer, isotopically labeled form, prodrug, or combination thereof.

[0149] In certain embodiments, the present invention relates to solvates, salts, N-oxides, complexes, racemic mixtures, diastereomers, enantiomers, tautomers, conformers, isotopically labeled forms, prodrugs, or combinations thereof of any of the compounds of the present invention; to solvates, salts, complexes, racemic mixtures, diastereomers, enantiomers, tautomers, conformers, isotopically labeled forms, or combinations thereof of such compounds.

[0150] In one embodiment, the compounds of the present invention do not include one or more of the following groups (1) to (5) of formula (I) (in groups (1) to (5), a moiety (e.g., methyl) is unsubstituted unless the moiety is explicitly specified as substituted): (1) R 1a is 4-(2-hydroxyethyl)piperazin-1-yl or Cl, and R 1b is H and R 1c is methyl, B is N, E is O, and R 3 is H, A is S, and L is a bond, then R 6 is not 4-chloro-2-methylpyridin-3-yl. (2) R 1a is methoxy and R 1b is H and R 1c is methoxy, B is N, E is O, and R 3 is H, A is S, and L is a bond, then R 6 is not 2,2-difluoro-5H-1,3-dioxolo[4,5-f]benzimidazol-6-yl; (3) R 3 is H, A is S, L is a bond, R 6 is 1-methyl-4-piperidinyl and R 1B is H, B is N, E is O, and (i) R 1a is methyl, R 1c is not N-tert-butoxycarbonylpiperidin-4-yl; or (ii) R 1c is methyl, R 1ais not N-tert-butoxycarbonylpiperidin-4-yl or N-tert-butoxycarbonylpiperidin-3-yl; (4) E is O and B is CR 1d and R 1d is H, F, Cl or Br, R 1a is not H; and (5) R 1a is methyl, R 1b and R 1c is H, B is CH, E is O, A is S, R 3 is methyl, R 5 is not 1,3-benzodioxol-5-ylmethyl, 2-furanylmethyl, 1,3-benzodioxol-5-yl, 2-(2-thienyl)ethyl, 2-(4-morpholinyl)ethyl, 2-(2-pyridinyl)ethyl, 2-pyridinylmethyl, or tetrahydro-2-furanylmethyl.

[0151] In one embodiment, the compounds of the present invention do not include one or more of the following groups (6)-(8) of compounds having formula (Ia) (in which a moiety (e.g., methyl) is unsubstituted unless it is expressly specified that the moiety is substituted): (6) If Hy is: [ka] and (i) R 1a is 4-(2-hydroxyethyl)piperazin-1-yl or Cl, and R 1b is H and R 1c is methyl, B is N, E is O, and R 2 is H and R 3 is H and R 4 If is H and A is S, then R 6 is not 4-chloro-2-methylpyridin-3-yl; (ii) R 1a is methoxy and R 1b is H and R 1c is methoxy, B is N, E is O, and R2 is H and R 3 is H and R 4 If is H and A is S, then R 6 is not 2,2-difluoro-5H-1,3-dioxolo[4,5-f]benzimidazol-6-yl; (7) Hy is 1-{(2E)-4-[(2-methoxyethyl)amino]-1-oxo-2-buten-1-yl}piperidin-4-yl; R 2 is H; R 3 is H; R 4 is H; A is O; and E is O, then R 6 is not 5-methyl-pyridin-2-yl; (8) R 2 is H and R 3 is trifluoromethyl, and R 4 is H, A is O, E is O, and (i) R 6 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 (ii) When Hy is 1-(phenylmethyl)piperidin-4-yl, R 6 is not 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 (iii) When Hy is 1-(phenylmethyl)pyrrolidin-3-yl, 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.

[0152] In certain other embodiments, the compound is not selected from the group consisting of: * 5-Thiazolecarboxamide, 2-[(6-chloro-2-methyl-4-pyrimidinyl)amino]-N-[(2-[4-(2-hydroxyethyl)-1-piperazinyl]-6-methylphenyl]-(CAS Registry Number: 2048106-50-7), * 5-Thiazolecarboxamide, 2-[[7-[4-cyano-3-(trifluoromethyl)phenyl]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4yl]amino]-N-[(1R)-1-(1,3,4-oxadiazol-2-yl)ethyl]-4-(trifluoromethyl) (CAS Registry Number: 1831086-00-0), * 5-Thiazolecarboxamide, 2-[[6-methoxy-7-[3-(4-morpholinyl)propoxy]-4-quinazolinyl]amino]-N-(2-pyrazinylmethyl)-(CAS Registry Number: 385780-87-0), * 5-Thiazolecarboxamide, 2-[[6-methoxy-7-[3-(4-morpholinyl)propoxy]-4-quinazolinyl]amino]-N-(2-(3-pyridinyl)ethyl]-(CAS Registry Number: 385780-82-5), * 5-Thiazolecarboxamide, N-1H-indol-5-yl-2-[[6-methoxy-7-[3-(4-morpholinyl)propoxy]-4-quinazolinyl]amino]- (CAS Registry Number: 385780-79-0) * 5-Thiazolecarboxamide, 2-[[6-methoxy-7-[3-(4-morpholinyl)propoxy]-4-quinazolinyl]amino]-N-(2-thienylmethyl]-(CAS Registry Number: 385780-69-8), * 5-Thiazolecarboxamide, N-(2-furanylmethyl)-2-[[6-methoxy-7-[3-(4-morpholinyl)propoxy]-4-quinazolinyl]amino]-(CAS Registry Number: 385780-66-5), * 5-Thiazolecarboxamide, 2-[[6-methoxy-7-[3-(4-morpholinyl)propoxy]-4-quinazolinyl]amino]-N-2-pyridinyl-(CAS Registry Number: 385780-57-4) and * 5-Thiazolecarboxamide, 2-[[6-methoxy-7-[3-(4-morpholinyl)propoxy]-4-quinazolinyl]amino]-N-4-pyridinyl- (CAS Registry Number: 385779-93-1).

[0153] In certain other embodiments, the compound is not selected from the group consisting of: * Imidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide, N,N-dicyclopropyl-6-ethyl-1,6-dihydro-1-methyl-4-[[4methyl-5-[[(tetrahydro-2H-pyran-4-yl)amino]carbonyl]-2-thiazolyl]amino]- (CAS Registry Number: 1271022-78-6), * Imidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide, N,N-dicyclopropyl-6-ethyl-1,6-dihydro-1-methyl-4-[[4-methyl-5-[[(tetrahydro-1,1-dioxido-3-thienyl)amino]carbonyl]-2-thiazolyl]amino]- (CAS Registry Number: 1271022-57-1), * Imidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide, N,N-dicyclopropyl-6-ethyl-1,6-dihydro-1-methyl-4-[[4-methyl-5-[[[2-(4-morpholinyl)ethyl]amino]carbonyl]-2-thiazolyl]amino] (CAS Registry Number: 1271022-45-7), and * Imidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide, N,N-dicyclopropyl-6-ethyl-l,6-dihydro-1-methyl-4-[[5-[[methyl(tetrahydro-l,1-dioxido-3-thienyl)amino]carbonyl]-2-thiazolyl]amino]- (CAS Registry Number: 1271021-43-2) * 2-[(6-[(3-(1H-imidazol-1-yl)propyl)amino}pyridin-2-yl)amino]-4-methyl-N-[1-(phenylmethyl)-1H-indazol-5-yl]-l,3-thiazole-5-carboxamide (CAS Registry Number 302963-64-0) * 2-[(6-{(3-(1H-imidazol-1-yl)propyl)amino}-pyridin-2-yl)amino]-N-[1-(phenylmethyl)-1H-indazol-5-yl]-1,3-thiazole-5-carboxamide (CAS Registry Number 302963-55-9)

[0154] In a particular alternative of one or more embodiments 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).

[0155] Compounds of the present invention that contain a basic functional group can form salts with a variety of inorganic or organic acids. Compounds of the present invention that contain an acidic functional group can form salts with a variety of inorganic or organic bases. Exemplary inorganic and organic acids / bases and exemplary acid / base addition salts of compounds of the present invention are set forth in the definition of "Pharmaceutically Acceptable Salts" in the "Pharmaceutical Compositions" section below. Compounds of the present invention that contain both basic and acidic functional groups can be converted into either base or acid addition salts. Neutral forms of compounds of the present invention can be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.

[0156] The compounds of the present invention may also be in the form of N-oxides, i.e., functional groups [ka] (e.g., (R n )3N + -O - , i.e., a NO coordinate covalent bond, where R nare independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl, wherein each of the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl groups is selected from one or more (e.g., 1 to 5, 1 to 4, or 1 to 3, 1 or 2, up to 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) independently selected R 30 and optionally substituted, R 30 is preferably a first level substituent, second level substituent, or third level substituent as specified herein). Specific examples of N-oxides of the compounds of the invention are 1a and / or R 6 is a functional group [ka] Includes. R can occur as an N-oxide 1a Non-limiting examples of substituents include: [ka] Here, the wavy line indicates R 1a Represents the bond that attaches a substituent to the remainder of the compound. R can occur as an N-oxide 6 Non-limiting examples of substituents include: [ka] Here, the wavy line indicates R 6 Represents the bond by which a substituent is attached to the remainder of the compound.

[0157] The compounds of the present invention may be in prodrug form. A prodrug of a compound of the present invention is a compound that undergoes chemical conversion under physiological conditions to provide a compound of the present invention upon administration to an individual. Furthermore, prodrugs can be converted to a compound of the present invention by chemical or biochemical methods in an ex vivo environment. For example, a prodrug can be slowly converted to a compound of the present invention when placed in a transdermal patch reservoir with, for example, a suitable enzyme or chemical reagent. Exemplary prodrugs are in vivo hydrolyzable esters (using an alcohol or carboxy group contained in the kinase inhibitor of the present invention) or amides (using an amino or carboxy group contained in the kinase inhibitor of the present invention). Specifically, any amino group contained in the kinase inhibitor of the present invention that has at least one hydrogen atom can be converted to a prodrug form. Exemplary N-prodrug forms include carbamates (1), Mannich bases (2), enamines (3), and enaminones (4). [ka] where R 18 is selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups has one or more (up to 1, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, e.g., between 1 and 5, 1 and 4, or 1 and 3, or 1 or 2, relative to the maximum number of hydrogen atoms bonded to the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl group) independently selected R 30 (Preferably, each R 30 are independently as defined herein) and may be optionally substituted with The prodrug properties (solubility, permeability, stability, cleavage rate, site and conditions of cleavage in the body, target specificity, etc.) are determined by R 18 can be fine-tuned by modifying

[0158] Particular prodrug forms of the compounds of the present invention are those having the formula (IXa), (IXb), (IXc), or (IXd) (prodrugs): [ka] and solvates, salts, N-oxides, complexes, polymorphs, crystalline forms, racemic mixtures, diastereomers, enantiomers, tautomers, conformers, isotopically labeled forms, and any combination thereof (wherein R 1a , R 1b , R 1c , R 3 , R 5 , A, B, E and Hy are defined above (particularly with respect to formulae (I), (Ia), (II), (III), (IV), (V), (VI), and / or (VIII)) or as defined below). And R 2 and R 4 Each of R 2 and R 4 H, -P(O)(OR 11a )2, -(CH2) 1-3 -R 19 , -C(=X a )R 11a , and C(=X a )X a R 11a are independently selected from the group consisting of: where R 11a is selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups is independently selected from one or more (up to 1, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, e.g., between 1-5, 1-4, or 1-3, or 1 or 2, etc.) R 30 and optionally substituted; R 19is -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-dioxol-4-yl; a is independently selected from O, S, and NH; and —(CH) 1-3 The group is selected from one or two independently selected R 30 where R 30 are as defined herein (preferably each R 30 are independently selected from the group consisting of: first level substituents, second level substituents, and third level substituents as specified herein. In one embodiment of the prodrug form of Formula (IXa), (IXb), (IXc), or (IXd), R 1a , R 1b , R 1c , R 3 , R 5 , A, B, E, and Hy (particularly with respect to formulae (I), (Ia), (II), (III), (IV), (V), (VI), and / or (VIII)) or are as defined below. 2 and R 4 Each of these is H, -P(O)(OR 11a )2, -(CH2) 1-3 -R 19 , -C(=O)R 11a , and C(=O)OR 11a independently selected from the group consisting of: 2 and R 4 and are not both H. Here, R 11a is H and C 1-6 Alkyl (preferably C 1-3 alkyl), wherein the alkyl groups are selected from the group consisting of halogen, —OH, —OCH3, —SCH3, -2-(N,N-dimethylamino)ethoxy, and NH 2-Z (CH3) z(where z is 0, 1, or 2), and R 19 -OP(O)(OR 11a )2, -OC(=O)R 11a , -OC(=O)OR 11a , and 5-(C 1-3 -(CH2) 1-3 The groups include halogen, -OH, -OCH3, -SCH3, -2-(N,N-dimethylamino)ethoxy, and NH 2-Z (CH3) z wherein z is 0, 1, or 2.

[0159] For compounds of the invention having any one of formulas (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (IXa), (IXb), (IXc), and (IXd) and having one or more hydroxyl (i.e., -OH) groups, further specific prodrug forms are those in which at least one of the two or more hydroxyl groups is -OP(O)(OR 11a )2, -O(CH2) 1-3 -R 19 , -OC(=X a )R 11a , and OC(=X a )X a R 11a is a moiety selected from the group consisting of where R 11a is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl, and wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is independently selected from one or more (up to 1, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, e.g., between 1-5, 1-4, or 1-3, or 1 or 2, etc.) R relative to the maximum number of hydrogen atoms bonded to the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl group. 30and optionally substituted; R 19 is 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-dioxol-4-yl; a is independently selected from O, S, and NH; and -(CH) 1-3 The group may be one or two independently selected R 30 and optionally substituted, where R 30 as defined herein, are preferably independently selected from the group consisting of first level substituents, second level substituents, and third level substituents as specified herein. In one embodiment of the compounds of the invention, at least one derivatized hydroxyl group is —OP(O)(OR 11a )2, -O(CH2) 1-3 -R 19 , -OC(=O)R 11a , and OC(O)OR 11a wherein R 11a is H and C 1-6 Alkyl (preferably C 1-3 alkyl), where the alkyl groups are selected from the group consisting of halogen, —OH, —OCH3, —SCH3, -2-(N,N-dimethylamino)ethoxy, and NH 2-Z (CH3) z wherein z is 0, 1, or 2; R 19 is -OP(O)(OR 11a )2, -OC(=O)R 11a , -OC(=O)OR 11a , and 5-(C 1-3 -(alkyl)-2-oxo-1,3-dioxo-4-yl; and -(CH) 1-3The groups include halogen, -OH, -OCH3, -SCH3, 2-(N,N-dimethylamino)ethoxy, and NH 2-Z (CH3) z wherein z is 0, 1, or 2.

[0160] In certain embodiments, the present invention relates to solvates, salts, N-oxides, complexes, racemic mixtures, diastereomers, enantiomers, tautomers, conformers, isotopically labeled forms, or combinations thereof, of prodrugs having Formula (IXa), (IXb), (IXc), or (IXd); for example, the present invention can relate to solvates, salts, complexes, racemic mixtures, diastereomers, enantiomers, tautomers, conformers, isotopically labeled forms, or combinations thereof, of such prodrugs.

[0161] In one particular embodiment, the compounds of the invention are hydrates, preferably monohydrates or dihydrates of the kinase inhibitors identified under the heading "Compounds" (e.g., kinase inhibitors having general formula (I), (Ia), (II), (III), (IV), (V), (VI), (VII), or (VIII), or solvates, salts (especially pharmaceutically acceptable salts), N-oxides (especially R 1a and / or R 6 or a solvate, salt, N-oxide, complex, polymorph, crystalline form, racemic mixture, diastereomer, enantiomer, tautomer, conformer, isotopically labeled form, prodrug (particularly a prodrug of formula (IXa), (IXb), (IXc), or (IXd) and / or having at least one derivatized hydroxyl group as specified above, or a solvate, salt, N-oxide, complex, polymorph, crystalline form, racemic mixture, diastereomer, enantiomer, tautomer, conformer, isotopically labeled form or combination thereof), or combination thereof). In another suitable embodiment, the compound of the invention is a semihydrate of such kinase inhibitor.

[0162] In certain embodiments, compounds of the present invention (e.g., as identified under the heading "Compounds") can be (e.g., provided) in purified or (e.g., substantially) pure form. For example, the compounds may be greater than about 50% pure, such as greater than about 60%, 70%, or 80% pure, suitably greater than about 90% pure (particularly about 95%, 97%, 98%, or even 99%). That is, in certain such embodiments, such compounds are present with limited amounts of impurities (e.g., those introduced during manufacture), such that only small amounts of impurities are present, including embodiments in which the compounds are present in a substantially impurity-free state. The purity of a compound (e.g., the absence of impurities, or the extent to which impurities are present) can be determined by routine procedures (e.g., HLPC).

[0163] In one embodiment, the present invention provides such compounds containing total impurities in the range of about 50%, 40%, 30%, and suitably less than 10% or 5% by HPLC, preferably in the range of about 3% and less than 2% by HPLC, more preferably less than 1% by HPLC. As used herein, "% coverage by HPLC" refers to the coverage of one or more peaks in an HPLC chromatogram compared to the coverage of all peaks in the HPLC chromatogram expressed as a percentage of the total coverage; further, the purity of a compound may be expressed herein as "HPLC" purity. Thus, "HPLC purity" is the area coverage under the compound peaks divided by the total area under the curve in the HPLC chromatogram. Suitably, the compound contains less than about 10% coverage of total impurities by HPLC. More preferably, the HPLC coverage of total impurities is less than about 5%.

[0164] In a related aspect, and as further described, claimed, or otherwise disclosed herein, the present invention provides one or more containers, wherein the containers (each independently or all) contain a kinase inhibitor of the first aspect (e.g., a compound represented by 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 a combination thereof, in an amount greater than about 10 mg; particularly an amount greater than about 50 mg or 100 mg; an amount greater than about 1 g, 10 g, 50 g or 100 g; or an amount greater than about 500 g or 1 kg.

[0165] In a further aspect, the present invention provides a compound of the invention (particularly those identified above with respect to any of formulas (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 compound of the invention has formula (I) as described above and does not include compounds belonging to one or more of groups (1), (2), (3), (4), and / or (5) of compounds (e.g., does not include one or more compounds of group (1) (particularly compounds of group (2) 1ais 4-(2-hydroxyethyl)piperazin-1-yl], (2) and / or (4) (in particular 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 invention have formula (Ia) and belong to one or more of group (6) (e.g., in particular, R 1a As specified above, this does not include compounds of group (6)(i), (7) and / or (8) in the case of 4-(2-hydroxyethyl)piperazin-1-yl).

[0166] As is evident from the examples, the inventors have found that the compounds of the present invention, as well as other structurally similar compounds, inhibit one or more protein-tyrosine kinases selected from the group consisting of 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, dosing, patient compliance, compatibility, stability, half-life, etc.) that are superior in at least one aspect to those exhibited by dasatinib.

[0167] Pharmaceutical Composition The compounds described in the present invention (particularly compounds of formula (I), (Ia), (II), (III), (IV), (V), (VI), (VII), or (VIII), particularly compounds set out in Table A and / or Table B) are preferably prepared into pharmaceutical compositions and administered to a patient in need thereof. Accordingly, in a second aspect, the present invention provides a kinase inhibitor as identified above under the heading "Compound" (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 a pharmaceutically acceptable salt), N-oxide (particularly a pharmaceutically acceptable salt), or N-oxide (particularly a pharmaceutically acceptable salt) of R 1a and / or R 6 and optionally one or more pharmaceutically acceptable excipients.

[0168] Thus, in one embodiment, a pharmaceutical composition comprises a kinase inhibitor identified above under the heading "Compound" and one or more pharmaceutically acceptable excipients. Additionally, the pharmaceutical composition may further comprise one or more additional therapeutic agents. Thus, in certain embodiments, a pharmaceutical composition comprises (i) a kinase inhibitor identified above under the heading "Compound" and one or more additional therapeutic agents; or (ii) a kinase inhibitor identified above under the heading "Compound," one or more additional therapeutic agents, and one or more pharmaceutically acceptable excipients.

[0169] The term "pharmaceutically acceptable" refers to the non-toxicity of a substance (alone or in combination with one or more additional therapeutic agents) that does not interact with the (e.g., therapeutic) action of the active ingredient (e.g., a kinase inhibitor of the present invention) of the pharmaceutical composition.

[0170] The pharmaceutical composition can be administered to an individual by any route, such as enterally or parenterally.

[0171] As used herein, the terms "enteral administration" and "administered enterally" mean that the administered drug is taken up by the stomach and / or intestines. Examples of enteral administration include oral and rectal administration. The terms "parenteral administration" and "administered parenterally," when used herein, refer to modes of administration other than enteral administration, usually by injection or topical administration, and include, but are not limited to, topical administration (e.g., epicutaneous, inhalation, or through mucous membranes (such as buccal, sublingual, or vaginal)), as well as intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraosseous, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, intracerebral, intraventricular, subarachnoid, intraspinal, epidural, and intrasternal administration (such as by injection and / or infusion).

[0172] The compounds of the present invention are generally applied in "pharmaceutically acceptable amounts" and "pharmaceutically acceptable preparations." Such compositions may contain salts, buffers, preservatives, carriers, and optionally other therapeutic agents. "Pharmaceutically acceptable salts" may include, for example, acid addition salts that may be formed by mixing a solution of the compound with a solution of a pharmaceutically acceptable acid, such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid, or phosphoric acid. Furthermore, if the compound contains 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, quaternary ammonium, and amine cations formed using counteranions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, alkylsulfonates, and arylsulfonates). Examples of pharmaceutically acceptable salts include acetate, adipate, alginate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium edetate, camphorate, camphosulfonate, camsylate, carbonate, chloride, citrate, clavulanate, cyclopentapropionate, digluconate, dihydrochloride, and dehydrogenase. Decylsulfonate, edetate, edisylate, estolate, esylate, ethanesulfonate, formate, fumarate, galactate, galacturonate, gluceptonate, glucoheptonate, gluconate, glutamate, glycerophosphate, glycolilal sanilate, hemisulfate, heptanoate, hexanoate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydrogen iodide, 2-hydroxyethanesulfonate Sodium benzoate, hydroxynaphthate, iodide, isobutyrate, isothionate, lactate, lactobionate, laurate, lactate, lauryl sulfate, maleate, maleate, malonate, mandelate, mesylate, methanesulfonate, methylsulfate, mucate, 2-naphthalenesulfonate, napsylate, nicotinate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, pamoate (embonate), palmitate Examples of suitable salts include, but are not limited to, mitate, pantothenate, pectinate, persulfate, 3-phenylpropionate, phosphate / diphosphate, phthalate, picrate, pivalate, polygalacturonate, propionate, salicylate, stearate, sulfate, suberate, succinate, tannate, tartrate, theoclate, tosylate, triethiodate, undecanoate, valerate, and the like (see, for example, Berge et al., "Pharmaceutical Salts," J. Pharm. Sci., 66, pp. 1-19 (1977)).

[0173] The term "excipient," as used herein, is intended to refer to all substances in a pharmaceutical composition that are not active ingredients (e.g., therapeutically inactive ingredients that exhibit no therapeutic effect in the amounts / concentrations used), such as, for example, carriers, binders, lubricants, thickeners, surfactants, preservatives, stabilizers, emulsifiers, buffers, flavoring agents, coloring agents, or antioxidants.

[0174] The compositions according to the present invention may contain a pharmaceutically acceptable carrier. As used herein, "pharmaceutically acceptable carrier" includes any and all physiologically compatible solvents, dispersion media, coatings, isotonic and absorption delaying agents, etc. The "pharmaceutically acceptable carrier" may be in the form of a solid, semi-solid, 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), alone or in combination with one or more additional therapeutic agents, may be coated in a material to protect the active compound from the action of acids and other natural conditions that may inactivate the active compound.

[0175] Examples of suitable aqueous and non-aqueous carriers that can be used in pharmaceutical compositions according to the present invention include water (e.g., water for injection), ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.), aqueous solutions of salts, carbohydrates, sugar alcohols, or amino acids (e.g., saline or aqueous amino acid solutions), and suitable mixtures and / or buffered forms thereof, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate). Proper fluidity can be maintained, for example, by the use of coating materials, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0176] 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 well known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, its use in the pharmaceutical compositions according to the present invention is contemplated.

[0177] The additional therapeutic agent may be administered together with, before, or after, or incorporated into a composition, a compound of the invention (particularly those identified above, such as those of 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 as described above, for example, 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 N-oxide), complex, polymorph, crystalline form, racemic mixture, diastereomer, enantiomer, tautomer, conformer, isotopically labeled form, prodrug (particularly of formula (IXa), (IXb), (IXc), or (IXd) and / or having at least one derivatized hydroxyl group as specified above, or a solvate, salt, N-oxide, complex, polymorph, crystalline form, racemic mixture, diastereomer, enantiomer, tautomer, conformer, isotopically labeled form, or combinations thereof), or combinations thereof, and at least one additional therapeutic agent, and one or more pharmaceutically acceptable excipients.

[0178] The "additional therapeutic agent" (which in one embodiment is not a kinase inhibitor of Formula (I) or (Ia), or in another embodiment may be a different kinase inhibitor of Formula (I) or (Ia)) can be used to treat a disease, disorder, or condition of a proliferative disorder (such as, for example, a cancer as described, defined, or disclosed elsewhere herein) and / or can be selected from any relevant optional compound that can be used to treat a disease, disorder, or condition associated with or caused by (i) the (e.g., aberrant) expression and / or activity of kinases such as SRC, ABL / BCR-ABL, LCK, SIK1, SIK2, SIK3, FLT3, and / or KIT; and / or PHA2, EPHA4, CSF-R1, HCK, and / or ACK1; and / or kinases such as 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, CT1A-4, 1AG3, or IDO1, and in particular, nivolumab, leratolimab, ipilimumab, and BMS-986205), agonists of TNF or TNFR1 or TNFR2 signaling, adoptive cell therapy, including CAR T cells against tumor antigens, vaccines, including dendritic cell (DC)-based vaccines, or agents that induce or can induce exposure of cells involved in the proliferative disorder to agonists of TNF or TNFR1 signaling, which are administered to a subject. The additional therapeutic agent can induce an additive or synergistic therapeutic effect.

[0179] The pharmaceutical compositions described herein may include, in addition to a kinase inhibitor of the present invention, at least one additional therapeutic agent, e.g., 1, 2, 3, 4, 5, 6, 7, or 8. In accordance with the present teachings, the at least one additional therapeutic agent can be formulated together with the kinase inhibitor of the present invention in a single pharmaceutical composition. Alternatively, the pharmaceutical composition can be configured as a kit of parts, where the kinase inhibitor of the present invention is provided in a first formulation and at least one additional therapeutic agent is provided in a second formulation, i.e., a second pharmaceutical composition. The first and second pharmaceutical compositions can be combined prior to use. In other words, a formulation containing an additional therapeutic agent can be added to the first pharmaceutical composition containing the kinase inhibitor of the present invention before administering the pharmaceutical composition. Alternatively, the present teachings contemplate administering the kinase inhibitor of the present invention formulated in a first pharmaceutical composition and administering at least one additional therapeutic agent formulated in a second pharmaceutical composition. The pharmaceutical compositions can be administered simultaneously or sequentially. For example, a first pharmaceutical composition may be administered at a first time point and a second pharmaceutical composition may be administered at a second time point, which may be, for example, 0, or up to 1, 2, 3, 4, 5, or 10 minutes, up to 1, 2, 3, 4, 5, or 10 hours, up to 1, 2, 3, 4, 5, or 10 days, up to 1, 2, 3, 4, 5, or 10 weeks, up to 1, 2, 3, 4, 5, or 10 months, or up to 1, 2, 3, 4, 5, or 10 years.

[0180] The compositions may also contain adjuvants such as preservatives, stabilizers, wetting agents, emulsifying agents, pH buffering agents, and dispersing agents. Prevention of the presence of microorganisms can be ensured by sterilization procedures and / or by the inclusion of various antibacterial and antifungal agents (e.g., parabens, chlorobutanol, phenol sorbic acid, and the like). It may also be desirable to include isotonic agents in the compositions, such as sugars, sodium chloride, and the like. Furthermore, prolonged absorption of the injectable dosage form may be achieved by including agents that slow absorption, such as aluminum monostearate and gelatin.

[0181] Regardless of the route of administration selected, the active compounds, which may be used in a suitable hydrated form, and / or pharmaceutical compositions according to the present invention are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those skilled in the art (see, e.g., Remington, "The Science and Practice of Pharmacy" (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).

[0182] Pharmaceutical compositions can be administered by various methods known in the art. As will be understood by those skilled in the art, the route and / or mode of administration will vary depending on the desired results. Pharmaceutical compositions containing one or more active compounds can be prepared using a carrier that protects one or more active compounds from rapid release, for example, controlled-release formulations, including implants, transdermal patches, and microencapsulated 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.

[0183] To administer the compounds of the present invention by certain administration routes, it may be necessary to coat the compound with a material to prevent its inactivation or to administer it simultaneously with the compound.For example, the compound can be administered to an individual in a suitable carrier (e.g., liposomes, or diluents).Pharmaceutically acceptable diluents include saline and aqueous buffer solutions.Liposomes include water-in-oil-in-water CGF emulsions and conventional liposomes (Strejan et al., J. Neuroimmunol. 7:27 (1984)).

[0184] Pharmaceutical compositions are typically sterile and stable under the conditions of manufacture and storage. The compositions may be formulated as a solution, microemulsion, liposome, or other suitable structure suitable to high drug concentration. The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyol, and suitable mixtures thereof. Proper fluidity is maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. In many cases, it is preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition. Prolonged absorption of injectable compositions can be achieved by including in the composition an agent that delays absorption, such as monostearate salts or gelatin.

[0185] Injectable compositions should be sterile and fluid to the extent that the composition can be delivered by syringe.In addition to water, carriers can be isotonic buffered saline solution, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, etc.), and suitable mixtures thereof.Sterile injectable solutions can be prepared by incorporating the required amount of active compound into a suitable solvent, optionally with one or a combination of the above-listed ingredients, followed by sterilization microfiltration.

[0186] Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle which contains the dispersion medium and the required other ingredients from those enumerated 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) to produce a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

[0187] The method of administration is adjusted to provide the optimum desired response (e.g., therapeutic response). For example, a single bolus can be administered, several divided doses can be administered over time, or the dose can be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. For ease of administration and uniformity of dosage, it is particularly useful to formulate the ingredients into dosage unit form. As used herein, dosage unit form refers to physically discrete units suitable as unitary dosages for the individual to be treated, each unit containing a predetermined amount of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specifications for the dosage unit forms to be used in accordance with the present invention are dictated by and directly dependent on (a) the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the technology of compounding such active compounds for treatment of susceptibility in an individual.

[0188] Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, and sodium sulfite; (2) oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, and α-tocopherol; and (3) metal chelating agents such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, and phosphoric acid.

[0189] For therapeutic / pharmaceutical formulations, compositions according to the present invention include those suitable for enteral administration (such as oral or rectal) or injection (such as 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 art of pharmacy. The amount of active ingredient (particularly the amount of a compound according to the present invention) that can be combined with a carrier material to produce a pharmaceutical composition (such as a single dosage form) will vary depending on the individual treated and the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be the amount of the composition that produces a therapeutic effect.

[0190] Generally, out of 100% (of the pharmaceutical formulation / composition), the amount of active ingredient (in particular the amount of a compound according to the present invention, optionally together with other therapeutically active ingredients, if present in the pharmaceutical formulation / 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 remaining components preferably consisting of one or more pharmaceutically acceptable excipients.

[0191] The amount of active ingredient (e.g., a compound of the invention) in unit dosage form and / or administered to an individual or used in therapy can range from about 0.1 mg to about 1000 mg (e.g., about 1 mg to about 500 mg, e.g., about 10 mg to about 200 mg) per unit, administration, or treatment. In certain embodiments, an appropriate amount of such active ingredient can be calculated using the mass or body surface area of ​​the individual, including between about 1 mg / kg and 10 mg / kg (e.g., between about 2 mg / kg and 5 mg / kg), or about 1 mg / m 2 and approximately 400 mg / m 2 and (e.g., about 3 mg / m 2 and approximately 350 mg / m 2 Between or about 10 mg / m 2 and approximately 200 mg / m 2 The amount of (between and) is included.

[0192] Actual dosage levels of the active ingredients in 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 mode of administration without being toxic to the patient. The selected dose level will depend upon various 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 treatment, other drugs, compounds and / or materials used in combination 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.

[0193] A physician or veterinarian skilled in the art can easily determine and prescribe the required (e.g., therapeutically) effective amount of the pharmaceutical composition. For example, the physician or veterinarian can start with a dose of the compound of the present invention at a level lower than required to achieve the desired therapeutic effect, and gradually increase the dose until the desired effect is achieved. Generally, a suitable daily dose of the composition according to the present invention will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend on the factors described above. Administration is preferably oral, intravenous, intramuscular, intraperitoneal, or subcutaneous, preferably administered proximal to the target site. If desired, a (e.g., therapeutically) effective daily dose of the pharmaceutical composition can be administered as two, three, four, five, six, or more subdoses, administered separately at appropriate intervals throughout the day, optionally in unit dosage form. While it is possible to administer the compounds according to the present invention alone, it is preferable to administer them as a pharmaceutical formulation / composition.

[0194] For oral administration, pharmaceutical compositions according to the invention can take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binders (e.g., pregelatinized maize starch, polyvinylpyrrolidone, hydroxypropyl methylcellulose), fillers (e.g., lactose, microcrystalline cellulose, calcium hydrogen phosphate), lubricants (e.g., magnesium stearate, talc, silica), disintegrants (e.g., potato starch, sodium starch glycolate), or wetting agents (e.g., sodium lauryl sulfate). Liquid preparations for oral administration can be in the form of, for example, solutions, syrups, or suspensions, or can be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations can be prepared by conventional means using pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol, syrup, cellulose derivatives, hydrogenated edible fats), emulsifying agents (e.g., lecithin, acacia), non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol, fractionated vegetable oils), preservatives (e.g., methyl or propyl-p-hydroxycarbonate, sorbic acid), and the like. The preparations may also contain buffer salts, flavoring agents, coloring agents, and sweetening agents as deemed appropriate. Preparations for oral administration can be suitably formulated to give controlled release of the pharmaceutical composition of the present invention.

[0195] In one embodiment, the compound is administered orally at a concentration of, for example, 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).

[0196] 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).

[0197] The pharmaceutical composition can be formulated as a suppository, with traditional binders and carriers such as triglycerides. Oral formulations can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, etc.

[0198] For administration by inhalation, the pharmaceutical compositions according to the invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a 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 dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, for example, gelatin for use in an inhaler or insufflator can be formulated containing a powder mix of a pharmaceutical composition according to the invention and a suitable powder base such as lactose or starch.

[0199] The pharmaceutical compositions according to the present invention can be formulated for parenteral administration by injection, e.g., bolus injection or continuous infusion. In one embodiment, the compounds or compositions according to the present invention can be administered by slow continuous infusion over an extended period (e.g., more than 24 hours) to reduce toxic side effects. Administration can also be carried out by continuous infusion over a period of 2 to 24 hours, e.g., 2 to 12 hours. Such a regimen can be repeated one or more times as needed, e.g., after 6 or 12 months.

[0200] In yet another embodiment, the compound or composition of this invention is administered by maintenance therapy (eg, once a week for a period of 6 months or more).

[0201] Injectable formulations can be provided in unit dosage form (e.g., pharmacopoeia, multi-dose containers) and with added preservatives. Pharmaceutical compositions according to the present invention can take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles and can contain formulatory agents such as suspending, stabilizing, or dispersing agents. Alternatively, the agent can be in powder form for constitution with a suitable vehicle (e.g., sterile, pyrogen-free water) before use. Typically, compositions for intravenous administration are solutions in sterile isotonic aqueous buffer. Where necessary, the composition may also contain a solubilizing agent and a local anesthetic (e.g., lignocaine) to alleviate pain at the injection site. Generally, the ingredients are supplied in unit-dose form, either individually or mixed together, for example, as a vacuum-dried lyophilized powder or water-free concentrate in a hermetically sealed container, such as an ampoule or small container indicating the quantity of active agent. When the composition is administered by infusion, it can be dispensed with an infusion bottle containing sterile pharmaceutical 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 may be mixed prior to administration.

[0202] Compositions according to the present invention that are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams, or spray formulations containing such carriers as are known in the art to be appropriate. Dosage forms for topical or transdermal administration of compositions according to the present invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that may be required.

[0203] Therapeutic / pharmaceutical compositions can be administered with medical devices known in the art. For example, in a preferred embodiment, therapeutic / pharmaceutical compositions according to the present invention can be administered with a needleless hypodermic injection device, such as those disclosed in U.S. Patent Nos. 5,399,163; 5,383,851; 5,312,335; 5,064,413; 4,941,880; 4,790,824; or 4,596,556. Examples of known implants and modules useful in the present invention include those described in U.S. Pat. No. 4,487,603, which discloses an implantable microinfusion pump for administering drugs at a controlled rate; U.S. Pat. No. 4,486,194, which discloses a therapeutic device for administering drugs through the skin; U.S. Pat. No. 4,447,233, which discloses an infusion pump for delivering drugs at precise infusion rates; U.S. Pat. No. 4,447,224, which discloses a variable flow rate implantable infusion device for continuous drug delivery; U.S. Pat. No. 4,439,196, which discloses an osmotic drug delivery system having multi-chamber compartments; and U.S. Pat. No. 4,475,916, which discloses an osmotic drug delivery system.

[0204] Many other such implants, delivery systems, and modules are known to those skilled in the art. In certain embodiments, the compounds according to the present invention can be formulated to ensure proper distribution in vivo. For example, the blood-brain barrier (BBB) ​​excludes many highly hydrophilic compounds. To ensure that the compounds of the present invention can cross the BBB (if desired), they can be formulated, for example, in liposomes. For methods of producing liposomes, see, for example, US 4,522,811; US ​​5,374,548; and US 5,399,331. Liposomes can contain one or more moieties that selectively transport to specific cells or organs, thereby enhancing targeted drug delivery (see, for example, V. V. Ranade (1989) J. Clin. Pharmacol 29: 685). Exemplary targeting moieties include folic acid or biotin (see, e.g., U.S. Patent No. 5,416,016 to Lou); 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 1-233: 134)).

[0205] In one embodiment, the compound according to the present invention is formulated in liposomes. In a more preferred embodiment, the liposomes contain a targeting moiety. In the most preferred embodiment, the compound in the liposomes is delivered by bolus injection to a site proximal to the desired area. Such liposome-based compositions should be fluid to the extent that they are easily injectable, stable under the conditions of manufacture and storage, and resistant to the contaminating action of microorganisms (e.g., bacteria and fungi).

[0206] A "therapeutically effective dose" for therapy / treatment can be measured by an objective response, which may be complete or partial. A complete response (CR) is defined as the absence of clinical, radiological, or other evidence of pathology, injury, or disease. A partial response (PR) is a greater than 50% reduction in disease. The median time to progression is an index that characterizes the durability of objective tumor regression.

[0207] A "therapeutically effective dosage" for treatment can also be measured by its ability to stabilize the progression of a symptom, disorder, or disease. The ability of a compound to inhibit one or more protein kinases or reduce the viability of cells associated with a proliferative disorder (e.g., cancer cells) can be assessed by using a suitable in vitro assay known to those skilled in the art, such as those described herein (particularly in the Examples below). Alternatively, the properties of compounds described in the present invention can be assessed by testing the compound's ability in a suitable animal model system known to those skilled in the art, such as those described herein (particularly in the Examples below). A therapeutically effective amount of a compound according to the present invention can cure, heal, alleviate, mitigate, alter, ameliorate, improve, or affect a physical condition, disorder, or disease, or a symptom of a physical condition, disorder, or disease, or a predisposition to a physical condition, disorder, or disease, in an individual. One skilled in the art can determine such amounts based on factors such as the size of the individual, the severity of the individual's symptoms, and the particular composition or route of administration selected.

[0208] Pharmaceutical compositions according to the invention may also, if desired, be presented in a pack or dispenser device which may contain one or more (e.g., unit) dosage forms containing the active compound. The pack may, for example, comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by a leaflet or other information describing (either to the patient and / or the administering physician) prominent information or details concerning the pharmaceutical composition contained in the package, such as how to administer, recommended dosages, safety and / or side effect information, among others.

[0209] In certain embodiments, pharmaceutical compositions of the present invention are formulated for oral administration, and in alternative certain embodiments, pharmaceutical compositions of the present invention are formulated for intravenous administration.

[0210] In one embodiment, the pharmaceutical compositions of the present invention are in unit dosage form and are particularly formulated for oral administration.

[0211] Each such unit dosage form contains 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 The composition may contain 1 to 950 mg of a compound such as a prodrug of Formula (IXa), (IXb), (IXc), or (IXd) and / or 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, prodrug (particularly having a prodrug of Formula (IXa), (IXb), (IXc), or (IXd) and / or having at least one derivatized hydroxyl group as described above, or having a solvate, salt, N-oxide, complex, polymorph, crystalline form, racemic mixture, diastereomer, enantiomer, tautomer, conformer, isotopically labeled form, or combinations thereof), or combinations thereof). In particular, such unit dosage forms (eg each) may comprise (eg contain) 2 to 150 mg of such compound; suitably 10 to 150 mg of such compound.

[0212] In such embodiments, pharmaceutical compositions of the invention that are unit dose forms (and particularly unit dose forms formulated for oral administration) may comprise (e.g., contain) an amount of such compound selected from the list of amounts consisting of 2 mg, 5 mg, 15 mg, 20 mg, 50 mg, 70 mg, 80 mg, 100 mg, and 140 mg per unit dose form; particularly, an amount of about 20 mg, 50 mg, 70 mg, or 100 mg of a compound of the invention.

[0213] In one particular embodiment, the pharmaceutical composition of the invention is (e.g., is formed as) a tablet, caplet, or capsule, and 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 described, for example, elsewhere herein.

[0214] Suitable excipients for pharmaceutical compositions of the invention, particularly when formulated as tablets or caplets, include those that further comprise one or more (e.g., all) excipients selected from the list consisting of lactose (e.g., lactose monohydrate), microcrystalline cellulose, croscarmellose sodium, hydroxypropyl cellulose, and magnesium stearate, and certain embodiments of such pharmaceutical compositions of the invention do so.

[0215] Therapeutic and Other Uses In a third aspect, the present application provides a compound as identified above under the heading "Compound", or a pharmaceutical composition as identified above under the heading "Pharmaceutical Composition", for use as a medicament, e.g., for use in therapy. In one embodiment of these aspects, the compounds of the invention have formula (I) and do not include compounds belonging to one or more of groups (1), (2), (3), (4) and (5), compounds identified above under the heading "Compounds" (particularly, one or more compounds of group (1) (particularly, R 1a is 4-(2-hydroxyethyl)piperazin-1-yl), compounds of group (1), (2) and / or (4) (in particular 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 compound of the invention is a compound having formula (Ia) and belonging to one or more of group (6) (e.g., particularly as specified above under the heading "Compounds"), wherein R 1a is 4-(2-hydroxyethyl)piperazin-1-yl, the compounds of group (6)(i), (7) and / or (8)) are not included.

[0216] It is contemplated that the compounds identified above under the heading "Compounds" may be used for (i) inhibition of kinases (e.g., those 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) inhibition of cellular resistance to an (e.g., cell-mediated) immune response. For example, the compounds may be used in methods for the treatment of a disease, disorder, or condition in an individual (e.g., a human patient), wherein the disease or condition is associated with such kinases.

[0217] The compounds of the invention may be used for therapy, alone or in combination with one or more further therapeutic agents, for example in combination as defined or disclosed elsewhere herein, including EGFR inhibitors, gemcitabine, docetaxel, and immune checkpoint inhibitors (such as inhibitors of PD1, PDLL, CT1A-4, 1AG3 or IDO1, and in particular immune checkpoint inhibitors selected from the list consisting of nivolumab, leratolimab, ipilimumab and BMS-986205), TNF, or agonists of TNFR1- or TNFR2-signaling, and are administered to a subject in an agent that induces or can induce the induction of TNFR1-signaling or exposure of cells involved in the proliferation disorder to TNF or an agonist of TNFR1-signaling.

[0218] Treatments containing or utilizing such compounds can be provided at home, in a doctor's office, clinic, outpatient department of a hospital, or in a hospital. Treatment is generally initiated under medical supervision so that a medical professional can closely monitor the effectiveness of the treatment and make any necessary adjustments. The duration of treatment will vary depending on the patient's age, symptoms, response to treatment, etc.

[0219] A person who is at greater risk of developing a condition (also called a physical abnormality), disorder, or disease may receive prophylactic treatment to inhibit or delay the symptoms of the condition, disorder, or disease.

[0220] The term "treatment" is known to those skilled in the art and includes the administration or application of a therapeutic agent (e.g., a pharmaceutical composition containing said agent), or treatment for the administration or application of a therapeutic agent (e.g., a pharmaceutical composition containing said agent) to a patient, or treatment to cells, cell cultures, cell lines, samples, tissues, or organs isolated from a patient, with the purpose of curing, alleviating, altering, ameliorating, or preventing a physical abnormality, disorder, or disease, or a symptom of a physical abnormality, disorder, or disease, or a predisposition to a physical abnormality, disorder, or disease, wherein the patient has a physical abnormality, disorder, or disease, or a symptom of a physical abnormality, disorder, or disease, or a predisposition to a disorder, disease, or physical abnormality. Thus, the term "treatment" can include prophylactic treatment of a physical abnormality, disorder, or disease, or a symptom of a physical abnormality, disorder, or disease. Treatment agents, when used in treatment, include the kinase inhibitors of the present invention and include, but are not limited to, additional treatment agents, which can be small molecules, peptides, peptidomimetics, polypeptides / proteins, antibodies, nucleotides such as DNA or RNA, cells, viruses, ribozymes, siRNA, and antisense oligonucleotides.

[0221] Accordingly, in a fourth aspect, and as may be further described, defined, claimed, or disclosed herein, the present invention provides a compound (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 a pharmaceutically acceptable salt), N-oxide (particularly a pharmaceutically acceptable salt), N-aminopropyl methyl ... 1a and / or R 6 or a solvate, salt, N-oxide, complex, polymorph, crystalline form, diastereomer, enantiomer, tautomer, conformer, isotopically labeled form, prodrug (particularly having formula (IXa), (IXb), (IXc), or (IXd) and / or having at least one derivatized hydroxyl group as specified above, or a solvate, salt, N-oxide, complex, polymorph, crystalline form, diastereomer, enantiomer, tautomer, conformer, isotopically labeled form or combination thereof) or combination thereof).

[0222] In another fourth aspect, and as further described, defined, claimed or disclosed herein, the present invention provides a pharmaceutical composition as described above (e.g., a compound identified under the heading "Compound" [e.g., 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 ... 1a and / or R 6or N-oxides thereof), complexes, polymorphs, crystalline forms, racemic mixtures, diastereomers, enantiomers, tautomers, conformers, isotopically labeled forms, prodrugs (in particular prodrugs having formula (IXa), (IXb), (IXc), or (IXd) and / or prodrugs having at least one derivatized hydroxyl group as specified above, or solvates, oxides, complexes, polymorphs, crystalline forms, racemic mixtures, diastereomers, enantiomers, tautomers, conformers, isotopically labeled forms or combinations thereof) or combinations thereof).

[0223] In a related fourth aspect, and as further described, defined, claimed or disclosed herein, the invention provides a method for treating a proliferative disorder in a subject (e.g., a method for treating a proliferative disorder in a subject), comprising: (X) A compound identified in the title "Compound" (e.g., a kinase inhibitor of general formula (I), (Ia), (II), (III), (IV), (V), (VI), (VII), or (VIII), or a solvate, salt (especially a pharmaceutically acceptable salt), N-oxide (especially R 1a and / or R 6 N-oxides of), complexes, polymorphs, crystalline forms, racemic mixtures, diastereomers, enantiomers, tautomers, conformers, isotopically labeled forms, prodrugs (particularly prodrugs having formula (IXa), (IXb), (IXc), and / or (IXd), at least one derivatized hydroxyl group as specified above, salts, complexes, polymorphs, diastereomers, tautomers, conformers, or combinations thereof) or combinations thereof); or (Y) "The above-mentioned pharmaceutical compositions (e.g., those containing the compounds specified in the title "Compounds")" (e.g., kinase inhibitors of general formula (I), (Ia), (II), (IV), (VI), (VII), or (VIII), or solvates, salts (especially pharmaceutically acceptable salts), N-oxides (especially R 1a and / or R 6or a combination thereof, The present invention relates to a method for treating a proliferative disorder in a subject, comprising administering to a subject a compound comprising:

[0224] In another related fourth aspect, and as may be further described, defined, claimed or disclosed herein, the present invention provides compounds identified under the heading "Compounds" (e.g., compounds of general formula (I), (Ia), (II), (III), (IV), (V), (VI), (VII), or (VIII), or solvates, salts (particularly pharmaceutically acceptable salts), N-oxides (particularly R 1a and / or R 6 and / or having at least one derivatized hydroxyl group, or a solvate, salt, N-oxide, complex, polymorph, crystalline form, racemic mixture, diastereomer, enantiomer, tautomer, conformer, isotopically labeled form, prodrug (particularly having Formula (IXa), (IXb), (IXc), or (IXd), and / or having at least one derivatized hydroxyl group, or a solvate, salt, N-oxide, complex, polymorph, crystalline form, racemic mixture, diastereomer, enantiomer, tautomer, conformer, isotopically labeled form or combinations thereof) or combinations thereof) for the manufacture of a medicament for the treatment of a proliferative disorder in a subject.

[0225] In such fourth aspect, the treatment of such use or method comprises administering to the subject (eg, a therapeutically effective amount) a compound or pharmaceutical composition of the invention.

[0226] In one particular embodiment of such an aspect, the subject is a human, suitably an adult human, e.g., a human aged 18 (or 16) or older, e.g., a human aged between about 18 (or 16) and 90 years of age, or between 18 (or 16) and 80 years of age. In some such embodiments, the adult human 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 particular such embodiments, the adult human is a young adult (about 18 (or 16) to 45 (or 40), or about 30 to 45 (or 40)), middle-aged (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), or elderly (about 60 to 90 (or elderly, such as 92, 95, or 98), about 65 to 85, or about 70 to 88).

[0227] Alternatively within such an embodiment, the subject being treated is a pediatric human, such as one who is under about 18 (or 16). 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 (such as between about 2 months and about 2 years or years of age), a toddler (such as between about 2 and about 4 years of age), a child (such as between about 4 and about 9 years of age), a pre-adolescent (such as between about 9 and about 12 or 13 (or 11 or 14) years of age), or an adolescent (such as between about 12 or 13 (or 11 or 14) years of age and about 15 (or 16 or 17) years of age).

[0228] In one embodiment of such aspect, treatment comprises administering to an adult human subject in need thereof an amount of a compound of the invention (e.g., in a pharmaceutical composition) less than about 140 mg / day, e.g., optionally in the absence of a proliferative disorder, e.g., if the subject is afflicted with a proliferative disorder that is not chronic phase Ph+ CML. In an alternative embodiment of such aspect, treatment comprises administering to an adult human subject in need thereof an amount of such a compound (e.g., as in a pharmaceutical composition) greater than about 140 mg / day, e.g., greater than 150 mg / day.

[0229] In another embodiment of this aspect, the treatment comprises administering to an adult human subject in need thereof a compound of the invention (e.g., in a pharmaceutical composition) in an amount less than about 100 mg / day. For example, optionally, the proliferative disorder is (e.g., the subject is suffering from) chronic phase Ph+ CML. In an alternative embodiment of this aspect, the treatment comprises administering to an adult human subject in need thereof a compound of the invention (e.g., in a pharmaceutical composition) in an amount greater than about 100 mg / day, such as greater than 120 mg / day.

[0230] In an alternative embodiment, the treatment comprises administering to a pediatric human subject in need thereof an amount of a compound of the invention: *Less than 40 mg daily for pediatric patients weighing 10 kg or more but less than 20 kg; *Less than 60 mg daily for pediatric patients weighing 20 kg or more but less than 30 kg; *Less than approximately 70 mg per day for pediatric patients weighing 30 kg or more but less than 45 kg; or *Less than approximately 100 mg per day for pediatric patients weighing 45 kg or more.

[0231] In a further alternative embodiment, treatment comprises administering to a pediatric human subject in need thereof an amount of a compound of the invention: *More than approximately 40 mg daily in pediatric patients weighing 10 kg or more but less than 20 kg; *More than 60 mg daily for children weighing 20 kg or more but less than 30 kg; *More than approximately 70 mg per day in pediatric patients weighing 30 kg to less than 45 kg; or *More than about 100 mg / day in pediatric patients weighing 45 kg or more.

[0232] For embodiments in which an amount of such compound is administered (eg, administered) to a human subject, such amount may be administered less frequently than daily. For example, a predetermined amount of "less than 40 mg per day" may be achieved by administering, for example, 35, 30 or 20 mg per day, or 75, 65 or 40 mg every other day (or less frequently).

[0233] In certain embodiments, the subject is unlikely to have (or not suffer) an adverse reaction (such as, for example, myelosuppression) upon (or after) such administration of a compound of the invention (e.g., a therapeutically effective amount).

[0234] In one such particular embodiment, upon (or after) administration of such (e.g., therapeutically effective) amount of the compound to a subject, the subject is unlikely to have (or not suffer from) a non-hematological adverse reaction, such as a cardiac adverse reaction.

[0235] More particularly of such embodiments, upon (or after) such administration of such a compound (e.g., a therapeutically effective amount) to a subject, the subject is less likely to have (or not suffer from) QT prolongation.

[0236] In one embodiment, the subject is characterized by not concurrently using a strong CYP3A4 inhibitor, for example, not concomitantly using ketoconazole, itraconazole, erythromycin, clarithromycin, ritonavir, telithromycin, or consuming grapefruit juice.

[0237] A disease, disorder or (physical) condition, in the context of the invention described herein, is in a particular embodiment a proliferative disorder (including a condition or symptom associated with such a disorder).

[0238] "Proliferative disorder" refers to a disorder characterized by abnormal proliferation of cells. Proliferative disorder does not imply any limitation on the rate of proliferation of cells, but simply a loss of normal controls affecting growth and cell division. Thus, in some embodiments, cells of a proliferative disorder may have the same cell division rate as normal cells, but do not respond to signals that limit such proliferation. Within the scope of "proliferative disorder" is a neoplasm or tumor in which there is abnormal proliferation of tissue or cells. Cancer is understood in the art and includes any of a variety of malignant neoplasms characterized by proliferation of cells that 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 of the liver. Non-cancerous proliferative disorders also include hyperproliferation of cells in the skin, such as psoriasis and its various clinical forms, Reiter's syndrome, pityriasis rubra pilaris, and hyperproliferative variants of disorders of keratinization (e.g., actinic keratosis, senile keratosis), scleroderma, and the like.

[0239] In more particular implementations, the proliferative disorder is a cancer or tumor, particularly a solid tumor (including conditions or symptoms associated with such cancer or tumor). Such proliferative disorders 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, rhabdoid tumor of the kidney, Ewing's sarcoma, chondrosarcoma, any hematological malignancy (e.g., chronic lymphoblastic leukemia, chronic myelomonocytic leukemia, acute lymphoblastic leukemia, acute lymphocytic leukemia, acute myelogenous leukemia, acute myeloblastic leukemia, chronic myeloblastic leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, chronic lymphocytic leukemia, chronic myelogenous leukemia, myelodysplastic syndrome, hairy cell leukemia, mast cell leukemia, mast cell neoplasm, follicular lymphoma, diffuse large cell carcinoma) tumors of the central nervous system (e.g., brain tumor, glioblastoma, non-glioblastoma brain tumor, meningioma, pituitary adenoma, vestibular schwannoma, primitive neuroectodermal tumor, medulloblastoma, astrocytoma, anaplastic astrocytoma, oligodendroglioma, ependymoma, and choroid plexus papilloma), myeloproliferative disorders (e.g., polycythemia vera, thrombocythemia, idiopathic myelofibrosis), soft tissue sarcoma, thyroid cancer, endometrial cancer, carcinoid cancer, or liver cancer.

[0240] In certain embodiments, various aspects of the invention relate to treatments (eg, using compounds or pharmaceutical compositions of the invention) for proliferative disorders, including those described herein. Thus, in such embodiments, the proliferative disorder may be a cancer or tumor.

[0241] In one particular embodiment, the cancer is a hematopoietic or lymphoid cancer, and in one such embodiment, the proliferative disorder is afflicted with or suspected of afflicting Philadelphia chromosome positive leukemia; for example, Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) or Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL).

[0242] In certain embodiments, the proliferative disorder (e.g., afflicted by or suspected of afflicting a subject (e.g., an adult human subject)) is: * Newly diagnosed in chronic phase (Ph+ CML); * Chronic, accelerated, or acute phase CML resistant to or intolerant to prior therapy including imatinib (e.g., imatinib mesylate); or * Ph+ acute lymphoblastic leukemia (ALL) and lymphoblastic acute phase CML resistant or intolerant to prior therapy.

[0243] In another specific embodiment, the subject is a pediatric human and has (e.g., the subject is afflicted with or suspected of being afflicted with) the following proliferative disorders: *Newly diagnosed Ph+ CML in chronic phase (Ph+ CML-CP) or Ph+ CML-CP that is resistant or intolerant to prior therapy, including imatinib.

[0244] In another specific embodiment, the cancer is a solid tumor, and in one such embodiment, the proliferative disorder is (e.g., the subject has or is suspected of having) a solid tumor, such as one of those described elsewhere herein, including pancreatic cancer, breast cancer, lung, prostate, melanoma, ovarian cancer, esophageal cancer, sarcoma, and colorectal cancer. In certain such embodiments, the proliferative disorder is pancreatic cancer (e.g., the subject has or is suspected of having pancreatic cancer); in other such embodiments, the proliferative disorder is prostate cancer (e.g., the subject has or is suspected of having prostate cancer); in other such embodiments, the proliferative disorder is lung cancer (e.g., the subject has or is suspected of having lung cancer (e.g., non-small cell lung cancer)).

[0245] 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 treatment (e.g., an additional therapeutic agent, surgery, or radiation therapy as described elsewhere herein). Such a combination treatment regimen can then include embodiments in which such exposure / administration is concomitant. In alternative embodiments, such administration can be continuous, particularly in embodiments in which the compounds (or pharmaceutical compositions) of the present invention are administered prior to such other procedure. For example, the compounds (or pharmaceutical compositions) can be administered continuously within about 14 days (e.g., before) of the other procedure, such as within about 10, 7, 5, 2, or 1 day of the other procedure, further including cases in which the compounds (or pharmaceutical compositions) can be administered continuously 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 the other procedure.

[0246] Such combination regimens may include administering to a subject (e.g., additionally): * EGFR inhibitors and / or gemcitabine, particularly if the proliferative disorder is pancreatic cancer (e.g., if the subject has or is suspected of having pancreatic cancer); * docetaxel, particularly when the proliferative disorder is prostate cancer (e.g., when the subject has or is suspected of having prostate cancer); and / or * Immune checkpoint inhibitors, particularly when the proliferative disease is lung cancer (e.g., the subject has or is suspected of having lung cancer), such as non-small cell lung cancer.

[0247] Exemplary immune checkpoint inhibitors that may comprise such combination therapies or regimens are described elsewhere and include antibody or small molecule inhibitors of PD1, PDL1, CT1A-4, 1AG3 or IDO1, and in particular, such immune checkpoint inhibitors may be selected from the list consisting of nivolumab, leratolimab, ipilimumab and BMS-986205, in particular nivolumab.

[0248] In other embodiments, the combination regimen can include administering to the subject (e.g., in addition): * immune activator (e.g. agonist) antibodies, such as antibodies against OX40 (e.g. Yang et al. 2012, Blood 120:4533), 41BB, CD40 or ICOS (e.g. Denge et al. 2004, Hybrid Hybridomics 23: 176), in particular antibodies that stimulate / prime T cells, thereby increasing TNF levels, and / or * Dendritic cell (DC)-based vaccination (e.g., Lowe et al. 2014, Oncoimmunology 3:e27589).

[0249] In one particular embodiment, the proliferative disorder (e.g., in a subject) has progressed (e.g., despite standard therapy), or in another embodiment, the subject may not be able 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 on standard therapy or as not being able to receive (e.g., intolerant to) standard therapy.

[0250] Examples of standard therapies would be imatinib (e.g., for CML or ALL), docetaxel (e.g., for prostate cancer), or immunotherapy (e.g., for melanoma or lung cancer) such as immune checkpoint inhibitors described as Ehlein.

[0251] Sensitization of immune responses and kinase inhibition The compounds of the invention can sensitize cells involved in proliferative disorders to a cell-mediated immune response.

[0252] Thus, in one embodiment, a treatment comprising administering a compound (or pharmaceutical composition) of the invention to a subject comprises sensitizing cells involved in a proliferative disorder to (e.g., mediated or supported by) a cell-mediated immune response.

[0253] In an alternative embodiment, a treatment comprising administering a compound (or pharmaceutical composition) of the invention to a subject comprises inhibition of (e.g., mediated by or supported by) a kinase involved in resistance to a cell-mediated immune response, such as inhibition of SIK3.

[0254] In a related embodiment, a treatment comprising administering a compound (or pharmaceutical composition) of the invention to a subject comprises inhibiting a kinase involved in resistance to a cellular immune response (e.g., inhibiting SIK3), and (thereby) sensitizing cells involved in the proliferative disorder to (e.g., mediated or supported by) a cellular immune response.

[0255] In a further aspect, and as further described, defined, claimed, or disclosed herein, the invention relates to a method for sensitizing cells involved in a proliferative disorder to a cell-mediated immune response in the treatment of a proliferative disorder in a subject, comprising administering to the subject a compound (or pharmaceutical composition) of the invention; and in another further aspect, and as further described, defined, claimed, or disclosed herein, the invention relates to a method for inhibiting a kinase involved in resistance to a cell-mediated immune response in the treatment of a proliferative disorder in a subject (e.g., comprising administering to the subject a compound (or pharmaceutical composition) of the invention in the treatment of a proliferative disorder in the subject).

[0256] In a related further aspect, and as further described, defined, claimed or otherwise disclosed herein, the present invention relates to a compound (or pharmaceutical composition) of the present invention for use as a pharmaceutical (i) for sensitizing cells involved in a proliferative disorder to a cell-mediated immune response; and / or (ii) for inhibiting kinases involved in resistance to a cell-mediated immune response, such as inhibiting SIK.

[0257] In yet a further related aspect, and as further described, defined, claimed or otherwise disclosed herein, the invention relates to a compound (or pharmaceutical composition) of the invention for use as a medicament (e.g., an immuno-oncology medicament) for sensitizing cells involved in a proliferative disorder (e.g., a tumor or cancer) to a cell-mediated immune response (e.g., sensitizing cells involved in the proliferative disorder to killing (cell death) that can be induced by a cell-mediated immune response). Immuno-oncology pharmaceuticals are recognized by those skilled in the art and include agents intended (e.g., specifically designed) to enhance one or more components of an organism's (e.g., human) immune system against cancerous or neoplastic cells present in such organism. An immuno-oncology drug may be one (e.g., an antibody) that binds to an exogenous immune (inhibitory) checkpoint molecule (e.g., those described elsewhere herein) and suppresses (e.g., directly) T cell function against cancerous or neoplastic cells, or an immuno-oncology drug may inhibit an immune regulator (e.g., as in the present invention, SIK3) that is intrinsic to the cancerous or neoplastic cell; such endogenous immune regulator does not actively (e.g., directly) suppress T cells, but rather protects the tumor or cancer cell from the immune response via a resistance mechanism.

[0258] In certain embodiments of such aspects, cells involved in the proliferative disorder can be sensitized to killing (cell death) by (eg, induced by) a cell-mediated immune response.

[0259] "Salt-inducible kinase 3" or "SIK3" (synonyms QSK and KIAA999) is a member of a subfamily of serine / threonine protein kinases that includes SIK1, SIK2, and SIK3, which belong to the AMP-activated protein kinase (AMPK) family. The SIK3 protein in the context of the present invention is typically a protein kinase. Relevant information regarding the human SIK3 protein is accessible at UniProt: Q9Y2K2 (entry version 138 of March 15, 2017), and the SIK3 protein in the context of the present invention preferably has the amino acid sequence shown in SIK3, entry version 138 of March 15, 2017, or entry version 144 of March 28, 2018, which sequences are incorporated herein by reference. SIK3 is a cytoplasmic protein with serine / threonine kinase activity and is regulated through phosphorylation of a conserved threonine residue (position 163) in the T-loop of the kinase domain by the LKB1 complex; this phosphorylation has been reported to be essential for the catalytic activity of SIK3 (Lizcano, JMet al.; EMBO J. 23, 833-843 (2004)). For purposes of the present invention disclosed herein, the term "phosphorylated SIK3" refers to a SIK3 protein that is substantially phosphorylated when the SIK3 protein can be phosphorylated by LKB1 (for example), where such phosphorylated SIK3 preferably contains a phosphorylated threonine at amino acid position 163. Phosphorylated SIK3 in the context of the present invention is SIK3 protein that is activated in its cell biological context. At least four protein isoforms (SIK3-001 to SIK3-004) are known to be generated by alternative splicing of the SIK3 gene product. The human SIK3 gene is located at chromosome 11q23.3 (HGNC gene Symbo1acc: HGNC:29165) and is conserved in many species, including chimpanzees, rhesus monkeys, dogs, cattle, mice, rats, chickens, zebrafish, and frogs. In some embodiments of the present invention, the term SIK3 may also relate to variants of human SIK3 proteins that are substantially identical to the amino acid sequence of SIK3 as described above, or have at least 80%, preferably 85%, more preferably 90, 95, 96, 97, 98, 99, or 100% sequence identity, as determined, for example, using the "Blast2 sequence" algorithm described in Tatusova & Madden 1999 (FEMS Microbiol Lett 174: 247-250), and (preferably) have an amino acid sequence that is identical or substantially identical to the respective reference SIK3 (e.g., that phosphorylates one or more class II (e.g., IIa) HDACs such as HDAC4). Preferred variants of the SIK3 protein include sequence variants thereof resulting from sequence polymorphisms between and within populations of each species, as well as mutants compared to the wild-type sequence of SIK3 located in or near the activation loop or activation loop (T-loop) of SIK3. A preferred mutant of the SIK3 protein is the SIK3 T163 mutation, such as a mutation that affects the activation of SIK3. In a preferred embodiment, the SIK3 protein of the present invention is not a SIK1 (synonyms: SIK and SNF1LK) protein and / or is not a SIK2 (synonyms: QIK, KIAA0781 and SNF1LK2) protein. The amino acid sequences of human SIK1 (UniProt: P57059; entry 168 of 15-Mar-2017) and human SIK2 (UniProt: Q9H0K1; entry 153 of 15-Mar-2017) are incorporated herein by reference. The term SIK3 (unless more specifically indicated) may refer, as applicable in context, to a SIK3 protein (eg, as described above) or to an mRNA molecule encoding such a SIK3 protein. Similar meanings for "SIK1" and "SIK2" should be understood.

[0260] A compound that is an "inhibitor of SIK3" (or "SIK3 inhibitor") is any substance moiety that inhibits SIK3, which may mean inhibiting the activity of SIK3, particularly SIK3 protein, particularly phosphorylated SIK3. A SIK3 inhibitor may impair (e.g., decrease or induce a decrease in) the efficiency, effectiveness, amount, or rate of one or more activities of SIK3 (e.g., one or more of the activities described herein, e.g., the activity of SIK3 to phosphorylate class II (e.g., IIa) HDAC (e.g., HDAC4) and / or to sensitize cells involved in proliferative disorders to a cell-mediated immune response).

[0261] Such SIK3-inhibiting moieties can act directly, for example, by binding to SIK3 and decreasing the amount or rate of one or more of its functions, particularly its properties such as its ability to act as a kinase (e.g., its ability to phosphorylate HDAC4), e.g., by decreasing the activity of phosphorylated SIK3 in a cell.

[0262] Compounds that are SIK3 inhibitors are described elsewhere herein, including those that can be characterized by applicable functional groups and / or structural features described herein.

[0263] In preferred embodiments, "subject" is specifically meant to include all mammals, including, but not limited to, humans as well as 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 is understood that particularly preferred subjects according to the present invention are human subjects, e.g., humans suffering from (or at risk of suffering from) a disorder, disease, or condition, e.g., a human patient.

[0264] As used herein, "treatment" is synonymous with treating a disease, disorder or (abnormal physical) condition, which includes reducing the symptoms of the disease, disorder or (abnormal physical) condition, inhibiting the progression of the disease, disorder or (abnormal physical) condition, causing regression of the disease, disorder or (abnormal physical) condition, and / or curing the disease, disorder or condition.

[0265] In a preferred embodiment, "treatment" in the present invention is also meant to include, in particular, therapeutic treatment, as well as prophylactic or suppressive treatment for a disease (or disorder or (abnormal physical) condition); thus, for example, successful administration of a compound (or pharmaceutical composition) of the present invention before the onset of a disease results in treatment of the disease. "Treatment" also encompasses administration of a compound (or pharmaceutical composition) of the present invention after the onset of a disease to ameliorate or eradicate the disease (or its symptoms). Administration of a compound (or pharmaceutical composition) of the present invention, with possible alleviation of clinical symptoms and possibly improvement of the disease, also encompasses treatment of the disease. "In need of treatment" includes events in which a disease, disorder or (abnormal physical) condition must be prevented, and includes subjects (e.g., human subjects) already having a disease, disorder or (abnormal physical) condition, as well as subjects (including those below) who are prone to or suspected of having a disease, disorder or (abnormal physical) condition.

[0266] The cells sensitized to a cellular immune response are suitably cells involved in a proliferative disorder (e.g., cells associated with a proliferative disorder), and in certain embodiments, such cells are cells involved in a proliferative disorder (e.g., cells undergoing abnormal proliferation, such as hyperproliferative cells). For example, such cells can be cells characterized by a loss of normal controls affecting their growth and cell division (e.g., cells of a neoplasm or tumor). In certain embodiments, such cells can be cancerous cells or cells derived from cancer or tumor cells. In other embodiments, such cells can be skin cells (e.g., those exhibiting hyperproliferation, such as those involved in psoriasis, Reiter's syndrome, pityriasis rubra pilaris, or scleroderma).

[0267] A cell may be "involved in a proliferative disorder" if, for example, it is a causative agent in or affected by such proliferative disorder. In particular, cells are defined as "involved in a proliferative disorder" if they are characterized by abnormal proliferation, such as abnormal cell growth or cell division, and the abnormal cell growth or cell division is part of or causes the pathology of the proliferative disorder. In embodiments in which the proliferative disorder is a tumor or cancer, the cells "involved in the proliferative disorder" can be, by way of non-limiting example, tumor (or cancer) cells, or cells derived from (tissues of) such tumors or cancers, particularly cells of solid tumors.

[0268] In certain embodiments, compounds of the invention can inhibit SIK3 in cells involved in proliferative disorders (eg, tumor cells). In particular such embodiments, the compound is capable of preferentially inhibiting SIK3 in such cells relative to inhibition of SIK1 and / or SIK2 in such cells; and / or SIK1 and / or SIK2 and / or SIK3 can be inhibited in one or more types of immune cells, with SIK3 being preferentially inhibited in such cells. For example, compounds of the invention may inhibit SIK1 and / or SIK2 and / or SIK3 in macrophages and / or dendritic cells (particularly those capable of producing IL-10), and may preferentially inhibit SIK3 in cells involved in proliferative disorders (e.g., tumor cells).

[0269] The compounds (or pharmaceutical compositions) of the present invention can be administered to a subject in an amount (e.g., a dose) that is effective to, inter alia, inhibit SIK3 and / or sensitize cells involved in a proliferative disorder to a cell-mediated immune response. Suitable amounts, formulations and means for such administration are described elsewhere herein.

[0270] In certain embodiments, the compound (or pharmaceutical composition) of the invention is administered in an amount effective (such as a therapeutically effective amount) to reduce the activity of SIK3, preferably SIK3, in cells involved in a proliferative disorder. In such embodiments, a "therapeutically effective amount" of a compound (or pharmaceutical composition) can be an amount that can reduce the activity of SIK3 to an applicable level, but does not result in significant (e.g., intolerable) side effects or overdosing with respect to other activities of the compound (or pharmaceutical composition).

[0271] Preferably, the activity of SIK3 is effectively inhibited (reduced), preferably in relation to SIK3 kinase in cells involved in the proliferative disorder. For example, an "effective" inhibition (or reduction) can include a reduction in activity to an extent (or level) that has a physiological effect, such as about a 10%, 20%, 50%, or more than 50%, e.g., a 70% or 90% reduction in activity of the respective kinase. With respect to SIK3, one such reduction may be desirable to elicit a therapeutic response.

[0272] The term "immune cell" is art-recognized to describe any cell of an organism that participates in the immune system of such an organism, particularly a mammal such as a human. White blood cells (leukocytes) are the immune cells involved in the innate immune system, while the cells of the adaptive immune system are a specialized type of white blood cell known as lymphocytes. B cells and T cells are the major types of lymphocytes and are derived from hematopoietic stem cells in the bone marrow. B cells are involved in the humoral immune response, while T cells are involved in the cell-mediated immune response. In a preferred embodiment of the invention, the immune cell may be a myeloid cell, such as a T cell, and in particular (as in cases where an increased cellular immune response is required, such as for treating cancer), the T cell may be a cytotoxic T cell (TC, also known as cytotoxic T lymphocyte, CTL, T killer cell, cytotoxic T cell, CD8+ T cell or killer T cell). CTLs are T cells that are involved in killing cancer cells, infected cells (especially virally), or cells that have been damaged in other ways. Other preferred immune cells for such embodiments may include tumor-infiltrating lymphocytes (TILs). TILs are white blood cells that have left the bloodstream and migrated to tumors. Typically, TILs are a mixture of different cell types (e.g., T cells, B cells, NK cells, macrophages) in varying proportions, with T cells being the most abundant. TILs are often found in the stroma or tumor itself and are involved in killing tumor cells. The presence of lymphocytes in tumors is often associated with better clinical outcomes.

[0273] As used herein, the term "cellular immune response" includes responses in a host organism including the maturation, proliferation, activation, migration, infiltration and / or differentiation of T cells, and / or the activation, proliferation, activation, infiltration, and / or activation / regulation / infiltration of macrophages, natural killer cells, T lymphocytes (or T cells), helper T lymphocytes, memory T lymphocytes, suppressor T lymphocytes, regulator T lymphocytes, and / or cytotoxic T lymphocytes (CTLs), and / or combinations thereof, and / or the production, release, and / or effect of one or more cell-secreted or cell-secreted factors such as cytokines or autacoids (particularly inflammatory cytokines such as TNF), and / or one or more components of such processes (e.g., specific inflammatory cytokines such as cytokines or autacoids, specific inflammatory cytokines such as TNF). As used herein, the term "cell-mediated immune response" can include a cellular response involving genetically engineered, in vitro cultured, autologous, xenogeneic, modified, and / or transferred T lymphocytes, or it can include cell-secreted or cell-secreted factors (such as cytokines or autacoids, particularly inflammatory cytokines such as TNF) produced by genetic engineering. The cellular immune response is preferably not a humoral immune response, such as an immune response that involves the release of antibodies. In certain embodiments, particularly when the proliferative disorder is a cancer or tumor, the cell-mediated immune response is an anti-tumor cell-mediated immune response, such as a cytotoxic cell-mediated immune response (such as cytotoxic T cells and / or TNF exposure) that kills cancer or tumor cells, leading to a decrease in tumor (cell) growth.

[0274] In certain embodiments, the cell-mediated immune response may be mediated by cells, such as immune cells, capable of secreting (secreting) inflammatory cytokines, such as one 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].

[0275] In other embodiments, the cell-mediated immune response can be a cell-secreted or cell-secreted factor (such as a cytokine or autologous factor), particularly one that is secretable or secreted by immune cells. In particular such embodiments, the cell-mediated immune response is a pro-inflammatory cytokine, particularly tumor necrosis factor (TNF).

[0276] The terms "sensitize," "sensitization," and "sensitizing" (and the like), when used herein in the context of cells that are sensitized to a cell-mediated immune response, will be understood by those skilled in the art and include the meaning that such cells may exhibit increased susceptibility to one or more effects (e.g., treatment effects) that a cell-mediated immune response may have on such cells. In particular, highly sensitized cells may be killed more easily (e.g., die or kill a greater proportion of cells more rapidly and / or at a lower dose or exposure) in the presence (e.g., exposure) of a cell-mediated immune response than similar cells that are less "sensitized." For example, such highly sensitized cells can be induced to undergo cell death (e.g., apoptosis) when exposed to fewer T cells or lower concentrations of TNF (e.g., about 10%, 20%, 30%, 40%, 50% or less than 50% fewer T cells or lower concentrations of TNF). Methods for determining whether (and to what extent) such cells have been sensitized to a cell-mediated immune response are described herein (eg, in the Examples). Thus, in certain embodiments of the invention, cells involved in a proliferative disorder can be sensitized to cell death / killing (e.g., by apoptosis) by a cell-mediated immune response (e.g., CTLs or inflammatory cytokines (e.g., TNF)).

[0277] The terms "tumor necrosis factor" and "TNF" (previously and therefore alternatively known as tumor necrosis factor alpha and TNF-alpha) should be understood in the context of the invention disclosed herein to refer to any protein known under these designations in the art. In particular, the term TNF encompasses endogenous TNF in any living organism, preferably an animal or mammal, such as a human. By way of example and not limitation, human TNF can include, inter alia, the endogenous protein as disclosed in Pennica et al., 1984 (Nature 312: 724-9) and the UniProtKB / Swiss-Prot database having entry number P01375 (e.g., entry version 224 of 15-Mar-2017), as well as any sequence variants thereof resulting from normal sequence polymorphisms between and within human populations. By way of further non-limiting example, the term can encompass endogenous TNF proteins as annotated in the UniProtKB / Swiss-Prot database for bovine (Q06599), canine (P51742), goat (P13296), guinea pig (P51435), feline (P19101), equine (P29553), mouse (P06804), chimpanzee (Q8HZD9), porcine (P23563), rabbit (P04924), rat (P16599), and others, and any sequence variants thereof due to sequence polymorphism between and within populations of each species. Furthermore, the term TNF specifically includes soluble secreted cytokine forms of TNF (including monomeric forms), as well as, preferably, its typically more active component trimer forms (see, e.g., Smith & Baglioni 1987. J Biol Chem 262: 6951-4). The primary amino acid sequences of the soluble forms of endogenous TNF are shown in the above UniProtKB / Swiss-Prot database entries for each exemplified organism. In addition, the term TNF also encompasses membrane-bound forms of TNF that are expressed on the surface of several cell types (see, eg, Kriegler et al., 1988. Cell 53: 45-53). Furthermore, the term TNF may also encompass synthetic or recombinant proteins whose primary amino acid sequence is identical or substantially identical to that of endogenous TNF (as used throughout this specification, generally refers to 80% or more, e.g., 85% or more, preferably 90% or more, more preferably 95% or more, even more preferably 98% or more or 99% or more sequence identity), as determined, for example, using the "B1ast 2 sequence" algorithm described by Tatusova & Madden 1999 (FEMS Microbiol Lett 174: 247-250), and which (preferably) retain the same or substantially the same biological activity as the respective endogenous TNF, as determined, for example, using the cytotoxicity test 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 may particularly refer herein to endogenous TNF, soluble and / or membrane-bound (preferably soluble), produced by a cell, tissue, organ or organism (preferably human). Nevertheless, what is contemplated by the term "TNF" are exogenous forms of tumor necrosis factor, particularly those produced by recombinant techniques, which in certain embodiments may be administered to a subject or exposed to or contacted with cells in various aspects and embodiments of the invention. In certain such embodiments, the TNF can be recombinant TNF (eg, BEROMUN) used as a therapeutic agent.

[0278] In some embodiments, the cell-mediated immune response can be mediated by inflammatory cytokine-secreting cells such as lymphocytes (eg, T cells), particularly cytotoxic T lymphocytes (CTLs).

[0279] In certain embodiments, the cellular immune response can induce killing (e.g., cell death via apoptosis) of cells involved in the proliferative disorder. For example, a method of treatment can include inducing such killing (e.g., mediated by) a cell-mediated immune response of cells involved in the proliferative disorder.

[0280] Cells involved in a proliferative disorder may be killed (e.g., induced to undergo cell death) by one or more cytotoxic treatments, particularly processes that are endogenous to such cells, such as programmed cell death (PCD). Cell death processes include, but are not limited to, necrosis (particularly necroptosis), apoptosis, anoikis, autophagy, ferroptosis, mitotic catastrophe, and activation-induced cell death. In certain preferred embodiments, cells involved in a proliferative disorder (eg, tumor cells) are induced to cell death by a cell-mediated immune response (eg, by TNF). In further embodiments, the compounds (or pharmaceutical compositions) of the invention are administered in a manner that does not kill such cells in the absence of a cell-mediated immune response (eg, in the absence of TNF). In particular, in such further embodiments, the compound (or pharmaceutical composition) may be administered in an amount (e.g., a dose) that is ineffective to kill such cells in the absence of a cell-mediated immune response. The Examples herein describe various assays by which the amount of a compound (or pharmaceutical composition) of the invention effective to kill such cells only, or preferentially, in the presence of a cell-mediated immune response can be determined.

[0281] In other particular embodiments, the cell-mediated immune response may comprise at least one immune cell effector molecule, particularly an effector molecule secretable or secreted by an immune cell. In particular such embodiments, the effector molecule may be a proinflammatory cytokine, preferably tumor necrosis factor (TNF).

[0282] 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).

[0283] In certain embodiments of the invention, a compound (or pharmaceutical composition) of the invention can be administered to a subject (e.g., in an effective amount or dose) with the intent (or to) effectively sensitize cells involved in a proliferative disorder to TNF-induced killing. For example, the compound (or pharmaceutical composition) can be administered in a therapeutically effective amount, such as an amount effective to sensitize cells involved in a proliferative disorder to TNF-induced killing (cell death).

[0284] For example, a compound (or pharmaceutical composition) of the present invention can be administered to a subject (e.g., in an effective amount or dose) to induce TNF-mediated apoptosis of such cells, such as when the cells are in the presence of or contacted with TNF. In further embodiments, a compound (or pharmaceutical composition) of the present invention may be administered to a subject to induce a reduced amount of cytotoxicity (e.g., cell death) (e.g., so as not to induce killing (e.g., cell death) of such cells) such that it does not induce killing (e.g., cell death) of such cells in the absence of TNF; for example, the compound (or pharmaceutical composition) may be administered in an amount or dose that is ineffective in cytotoxicity (e.g., cell death) (e.g., ineffective to induce such killing) in the absence of TNF.

[0285] TNF can induce pro-apoptotic processes through binding to and / or signaling through tumor necrosis factor receptor 1 (TNFR1) and tumor necrosis factor receptor 2 (TNFR2). Thus, in certain embodiments, a compound (or pharmaceutical composition) of the present invention can be administered to a subject (e.g., in an effective amount or dose) to (effectively) sensitize cells involved in a proliferative disorder 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 dose) to (effectively) sensitize cells involved in a proliferative disorder, particularly to cell death mediated by TNFR1. For example, the compound (or pharmaceutical composition) can be administered in a therapeutically effective amount effective to mediate TNFR1- and / or TNFR2-signaling and / or cell death mediated thereby.

[0286] For example, in certain embodiments, a compound (or pharmaceutical composition) of the invention can be administered (e.g., in an effective amount or dose) to induce apoptosis of such cells by TNFR1- and / or TNFR2-signaling, such as upon active TNFR1 signaling. In particular, in such embodiments, the compound (or pharmaceutical composition) may be administered to a subject (e.g., in an amount or dose, such as a therapeutically effective amount) to (effectively) induce a reduced amount of cytotoxicity (e.g., apoptosis) in such cells in the absence of TNFR1- and / or TNFR2-signaling, e.g., in the absence of active TNFR1 signaling, so as not to induce apoptosis of such cells. For example, the compound (or pharmaceutical composition) may be administered in an amount or amounts that are ineffective in cytotoxicity (e.g., cell death) (e.g., ineffective to induce such cell death in the absence of such signaling).

[0287] Thus, in certain embodiments, a compound (or pharmaceutical composition) of the present invention can be administered to a subject (e.g., in an amount or dose) to induce a reduced amount of cytotoxicity (e.g., cell death) (e.g., not cytotoxicity) to cells involved in a proliferative disorder in the absence of a cell-mediated immune response.

[0288] In certain embodiments, a compound (or pharmaceutical composition) of the invention can continue to be administered to a subject even as the subject's tumor increases in size during treatment. Without being bound by theory, even if an increase in tumor size is observed during such treatment, this may indicate an (enhanced) immune response against the cells of the tumor (e.g., the cells have become sensitized to a cell-mediated immune response; and the tumor is increasing in size due to such an immune response), and therefore, treatment with the compound (or pharmaceutical composition) can continue in such embodiments to maintain such detection sensitivity and associated (enhanced) immune response.

[0289] As described in PCT / EP2018 / 060172, inhibition of SIK3 is surprisingly associated with several important biological processes or phenotypes, including those involved in the regulation and / or induction of cell-intrinsic cytotoxic processes, such as cell death. For example, tumor cells can be sensitized to the apoptotic / cytotoxic effects of TNF by inhibition of SIK3, acting 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-κB), and NF-κB-regulated pro-apoptotic genes such as caspase 8 and caspase 9. Additionally, c-Jun N-terminal kinase (JNK) is a signaling component involved in sensitizing to the apoptotic / toxic effects of TNF by inhibiting SIK3.

[0290] In the context of this embodiment (and other embodiments, if applicable), the term "associated" can mean that two components, variables, effects, or phenotypes are interconnected with each other and / or that they are related to each other (e.g., correlated) and / or that there is a causal relationship between a first component and a second component, variable, effect, or phenotype (e.g., the second component is responsive to the first component, the second component is a result of the first component, the second component is caused by the first component, or the second component is caused by the first component).

[0291] Thus, in one such embodiment, administration of a compound (or pharmaceutical composition) of the invention may be associated with impaired NF-κB activity (e.g., by enhancing or increasing translocation of NF-κB from the nucleus) in cells involved in a proliferative disorder.

[0292] In particular, in such embodiments, such impairment of NF-κB activity (e.g., by enhancement or translocation of NF-κB out of the nucleus) may be associated with (activated) TNF- and / or TNFR1-mediated signaling (or TNFR2-mediated signaling) in such cells.

[0293] In certain embodiments, a compound (or pharmaceutical composition) of the invention may be administered to a subject (e.g., in an effective amount or dose) to impair or inhibit NF-κB activity in cells involved in a proliferative disorder, e.g., to enhance or increase the translocation of NF-κB from the nuclei of such cells. For example, a compound (or pharmaceutical composition) can be administered to a subject in an amount effective to (effectively) impair NF-κB activity in cells involved in a proliferative disorder, in particular in an amount effective to (effectively) enhance or increase the translocation of NF-κB from the nucleus of cells involved in a proliferative disorder.

[0294] In alternative or further embodiments, administration of a compound (or pharmaceutical composition) of the invention may be associated with an increase in the activity of class II (e.g., IIa) HDAC, e.g., HDAC4, in cells involved in a proliferative disorder, e.g., its translocation or localization to the nucleus of the cell or its activity; in particular, to increase the activity of TNF and / or TNFR1-mediated signaling (or TNFR2-mediated signaling) in such cells (e.g., the compound (or pharmaceutical composition) is administered in an effective amount or dose, etc.).

[0295] In other alternative or further embodiments, administration of a compound (or pharmaceutical composition) of the present invention may be associated with deacylation of nuclear NF-κB (e.g., deacylation at its p65 subunit) and / or decreased transactivation of one or more anti-apoptotic factors, particularly TNF- and / or TNFR1-mediated signaling (or TNFR2-mediated signaling) in cells involved in proliferative disorders. 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 decreased transactivation of one or more anti-apoptotic factors.

[0296] In another alternative or further embodiment, administration of a compound (or pharmaceutical composition) of the invention may be associated with cleavage of caspase 8 and / or caspase 9 in cells involved in a proliferative disorder, particularly an increase (e.g., amount or dose effective, etc.) of TNF- and / or TNFR1-mediated (or TNFR2-mediated signaling) signaling in such cells.

[0297] In yet other alternative or additional embodiments, administration of a compound (or pharmaceutical composition) of the present invention may be associated with a decrease in transcription of one or more anti-apoptotic factors upon specific TNF- and / or TNFR1-mediated signaling (or TNFR2-mediated signaling) in cells involved in a proliferative disorder, e.g., a decrease in transcription of one or more NF-κB target genes in such cells. In particular, the compound (or pharmaceutical composition) can be administered (e.g., in a dose-effective amount) to reduce transcription of one or more such anti-apoptotic factors upon TNF- and / or TNFR1-mediated signaling (or TNFR2-mediated signaling) in cells involved in a proliferative disorder.

[0298] In one embodiment, administration of a compound (or pharmaceutical composition) of the invention may be associated with an increase (e.g., in an amount or dose effective to increase JNK activation (e.g., by phosphorylation) in cells involved in a proliferative disorder, particularly upon TNF- and / or TNFR1-mediated signaling (or TNFR2-mediated signaling) in such cells (e.g., to which the compound (or pharmaceutical composition) is administered).

[0299] In another embodiment, administration of a compound (or pharmaceutical composition) of the present invention may not be associated with significant changes in CREB-pathway signaling and / or significantly altered gene expression mediated by CREB- and / or CREB-regulation.

[0300] In certain embodiments, TNF-(TNFR2-) and / or TNFR1-mediated signaling in cells involved in a proliferative disorder may be associated with increased levels of pLKB1 in such cells.

[0301] As will be apparent to one skilled in the art armed with the knowledge of the present invention, the treatment aspects of the present invention may further comprise administering one or more other moieties that suitably modify the expression, activity, function or stability of one or more of these other pathway components so as to additively or synergistically contribute to the treatment effect. For example, in one such embodiment, the treatment aspect of the invention may further comprise administering an inhibitor of LKB1. In another such embodiment, the treatment aspect of the invention may further comprise administering a compound of the invention that promotes, enhances, or increases one or more class II (e.g., IIa) HDACs (histone deacetylases) (e.g., HDAC4) in the nuclei of cells involved in the proliferative disorder. In yet another aspect of such an embodiment, the treatment aspect of the invention may further comprise administering an inhibitor (activator) of NF-κB. The present invention also contemplates that combinations of two or more such other moieties may be used in treatment with the compounds (or pharmaceutical compositions) of the present invention, and / or using other (e.g., anti-cancer) therapeutically active ingredients (e.g., additional therapeutic agents as described elsewhere herein) together with the compounds (or pharmaceutical compositions).

[0302] In a further aspect, and as further described, defined, claimed, or otherwise disclosed herein, the present invention relates to a method for sensitizing cells involved in a proliferative disorder to a cell-mediated immune response, comprising exposing (e.g., contacting) cells involved in a proliferative disorder to a compound (or pharmaceutical composition) of the present invention. Such methods may typically be performed as in vitro and / or ex vivo methods.

[0303] In certain embodiments, the cell-mediated immune response comprises killing cells involved in the proliferative disorder, e.g., the killing comprises (e.g., mediated or supported by) TNF-, TNFR2-, and / or TNFR1-mediated signaling. For example, killing of such cells can include apoptosis of such cells induced by TNF-, TNFR2- and / or TNFR1-mediated signaling. In this and other applicable embodiments of various aspects of the invention, TNFR2- and / or TNFR1-mediated signaling can be triggered (e.g., activated) by any suitable trigger molecule (e.g., TNF, a TNF mutant, and / or a TNFR1- or TNFR2-agonist); in particular, by exposing (e.g., contacting) cells associated with a proliferative disorder to the trigger molecule (e.g., TNF, a TNF mutant, or a TNFR1 agonist). Such exposure may result in the binding of inducing molecules (eg, TNF, TNF variants, or TNFR1 agonists) to TNFR2 and / or TNFR1, in particular inducing (eg, activating) TNFR1 signaling.

[0304] In a further aspect, and as may be further described, defined, claimed or disclosed herein, the present invention relates to a method for killing cells involved in a proliferative disorder, comprising: (i) exposing (e.g., contacting) cells involved in a proliferative disorder to TNF, a TNF mutant and / or an agonist of TNFR1- or TNFR2-signaling (preferably TNFR1 signaling); and (ii) exposing (e.g., contacting) cells involved in a proliferative disorder to a compound (or pharmaceutical composition) of the present invention. As will be appreciated by those skilled in the art, such methods may typically be performed as in vitro and / or ex vivo methods.

[0305] In a related aspect, the invention relates to a compound (or pharmaceutical composition) of the invention for use in treating a proliferative disease involving death of cells involved in the proliferative disorder, the treatment comprising exposing such cells to (i) TNF, a TNF variant and / or a TNFR1- or TNFR2-agonist; and (ii) a compound (or pharmaceutical composition) of the invention.

[0306] In certain embodiments of such aspects, killing of cells involved in the proliferative disorder is mediated by sensitizing such cells to a cell-mediated immune response, particularly by inducing susceptibility of such cells to cell death involving (e.g., mediated by, or supported by) TNF-, TNFR2-, and / or TNFR1-mediated signaling.

[0307] Cells involved in a proliferation disorder may be exposed to TNF, TNF variants and / or TNFR1- or TNFR2-agonists by contacting the cells with such trigger molecules; and / or such cells may be exposed to compounds (or pharmaceutical compositions) of the invention by contacting such cells with (or introducing into) a compound (or pharmaceutical composition) of the invention. The amount (or dose) of (i) TNF, TNF variants and / or TNFR1- or TNFR2-agonists; and / or (ii) compounds (or pharmaceutical compositions) of the invention is typically an effective amount, i.e., an amount (or dose) effective to sensitize cells (e.g., kill such cells) to cell death induced by, for example, TNF-, TNFR2-, and / or TNFR1-mediated signaling. Suitable amounts of these active ingredients (or methods for determining them) that may be incorporated in these aspects of the invention are disclosed, as are further specific features of the compounds (or pharmaceutical compositions) of the invention. Thus, in certain embodiments: (i) a TNF, a TNF variant and / or a TNFR1- or TNFR2-agonist; and (ii) a compound (or pharmaceutical composition) of the present invention may be administered to a subject suffering from a proliferative disorder (e.g., treatment may include administration of (i) a TNF, a TNF variant and / or a TNFR1- or TNFR2-agonist; and (ii) a compound (or pharmaceutical composition) of the present invention may be administered to a subject).

[0308] The cells involved in the proliferative disorder may be those described elsewhere herein, and in particular such cells may be cancerous or tumor cells, for example such cells may be of or derived from a solid tumor.

[0309] In certain embodiments of these aspects, the method is an in vitro (and / or ex vivo) method. In alternative embodiments of such methods, the cells involved in the proliferative disorder (e.g., tumor cells) are present in such a subject (particularly a subject in need of such treatment).

[0310] In further embodiments of the methods of these aspects, the (treatment) effect of such methods (e.g., on cells involved in a proliferative disorder) may be mediated (e.g., the treatment may include, involve, or be mediated by inhibiting SIK3) by inhibiting SIK3 (e.g., the treatment may be by inhibiting the function and / or activity of SIK3 mRNA or protein (e.g., of phosphorylated SIK3 protein, and / or as described elsewhere herein). In particular, in such embodiments, SIK3 activity is (e.g., effectively) reduced, e.g., reduced to a therapeutically effective level.

[0311] In certain embodiments of such methods, in the absence (e.g., at such an effective amount or dose) of a compound (or pharmaceutical composition) of the invention, cells involved in a proliferative disorder (e.g., tumor cells) are not killed or induced to enter cell death (e.g., they proliferate) upon exposure to TNF, TNFR2- and / or TNFR1-mediated signaling and / or a TNF, TNF variant, TNFR2 or TNFR1 agonist (e.g., at an effective amount or dose).

[0312] As noted above, in certain embodiments of these methods, the compounds (or pharmaceutical compositions) of the invention may inhibit SIK3 in cells involved in a proliferative disorder (eg, tumor cells). In particular, in such embodiments, the compound (or pharmaceutical composition) may inhibit SIK3 in such cells in preference to inhibiting SIK1 and / or SIK2 in such cells, and / or may 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, a compound (or pharmaceutical composition) of the present invention may inhibit SIK3 in cells involved in a proliferation disorder (e.g., tumor cells) preferentially over inhibiting SIK1 and / or SIK2 and / or SIK3 in macrophages and / or dendritic cells (particularly those capable of producing IL-10). In certain embodiments, the (treatment) effect is mediated by (e.g., treatment includes, involves, is by, or is mediated by) inhibition of SIK3 in (a) cell(s) involved in a proliferative disorder (e.g., a tumor cell); In further aspects of such embodiments, the (treatment) effect is not mediated by inhibition of SIK2, particularly SIK2, in other cells involved in proliferative disorders or immune cells (or the (treatment) effect is mediated by not inhibiting SIK2 (e.g., the treatment does not involve, does not involve, or is not mediated by inhibiting SIK2)), and / or the (treatment) effect is not mediated by inhibition of SIK1, particularly SIK1, in other cells involved in proliferative disorders or immune cells (or the (treatment) effect is mediated by not inhibiting SIK1 (e.g., the treatment does not involve, does not involve, or is not mediated by inhibiting SIK1)).

[0313] Thus, in one embodiment, SIK3 of (eg, in) a cell involved in a proliferative disorder is inhibited (eg, by a compound or pharmaceutical composition of the invention). In another (or further) embodiment, another kinase (e.g., SIK2, particularly SIK2) in immune cells (e.g., CTLs) is inhibited less than SIK3 (e.g., cells involved in a proliferative disorder). In yet another (or further) embodiment, SIK1, particularly SIK1 in immune cells (eg, CTLs), is inhibited to a lesser extent than such SIK3.

[0314] In certain such embodiments, one or more of the kinases selected from the list consisting of SIK3, SIK1, SIK2, JAK1, RET, ERBB4 PDGFR-α, and EPHB2 are inhibited to a lesser extent than one or more of the kinases selected from the list consisting of ABL1, SRC, BCR-ABL, LCK, LYN, YES, FYN, KIT, and FLT3 (e.g., by a compound or pharmaceutical composition of the invention).

[0315] In certain such embodiments, one or more of the kinases selected from the list consisting of PDGFR-α, TGFB-R1, B-RA, p38-β, ACV-R1, BMPR1A, and RET are inhibited (e.g., by a compound or pharmaceutical composition of the invention) to a lesser extent than one or more of the kinases selected from the list consisting of EPHA2, EPHA4, CSF1-R, HCK, and ACK1.

[0316] In certain such embodiments, one or more of the kinases selected from the list consisting of NEK11, WEE1, WNK2, Aurora-A, Aurora-B, and TBK1 are inhibited (e.g., by a compound or pharmaceutical composition of the invention) to a lesser extent than one or more of the kinases selected from the list consisting of ABL1, SRC, BCR-ABL, LCK, LYN, YES, FYN, and KIT.

[0317] A given kinase (such as SIK1 or SIK2) can be inhibited "to a lesser extent" than another kinase (such as SIK3) if, for example, the other kinase (such as SIK3) is inhibited by about 2-fold more than the given kinase, e.g., by about 5-fold, 10-fold, 20-fold, 50-fold, 75-fold, or 100-fold more than the given kinase. In particular, other kinases (eg, SIK3) can be inhibited at amounts between about 5-20 fold, 20-50 fold, or 50-100 fold greater than the given kinase. For example, SIK3 (ie, the other kinase) can be inhibited about 20-50 times more than SIK1 and / or SIK2 (ie, the given kinase). By way of example, a compound (or pharmaceutical composition) of the present invention may inhibit a given kinase (e.g., SIK1) by only 4% and SIK2 by only 8%, while inhibiting other kinases (e.g., SIK3) by 80% (i.e., having only 20% of its uninhibited activity). Thus, the other kinase (e.g., SIK3) is inhibited approximately 20-fold more than a given kinase (e.g., SIK1) and 10-fold more than another kinase (e.g., SIK2). In certain embodiments, the other kinase (e.g., SIK3) may be inhibited, for example, to about the same extent as SIK1 (e.g., between about 2-53 fold of each other), and SIK2 may be inhibited, for example, to a lesser extent than either (or both) of SIK3 and SIK1; for example, in such embodiments, SIK3 and SIK1 may be inhibited, for example, about 20-50 fold more than SIK2 (e.g., in immune cells).

[0318] Compounds of the present invention have been shown t...

Claims

1. A compound selected from the group consisting of kinase inhibitors of the formula: 【Chemistry 1】 and solvates, salts, racemic mixtures, diastereomers, enantiomers, tautomers, conformers, and isotopically labeled compounds thereof; where: R 1a is selected from the group consisting of: -NH(C 1-3 alkyl), and 2-hydroxyethyl, methyl, -C(=O)CH 3 and -CH 2 piperazinyl optionally substituted with one moiety selected from the group consisting of COOH; R 1b is H and R 1c is methyl, or R 1b is methyl and R 1c is H; R 2 is H; R 3 is selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, phenyl, and halogen, wherein each of methyl, ethyl, propyl, isopropyl, and phenyl is selected from one or more independently selected R 30 is optionally substituted with; R 4 is H; R 5 -LR 6 is; L is a bond; R 6 is selected from the group consisting of pyridinyl, thienyl, pyrazolyl, isoxazolyl, and quinuclidinyl, each of which is independently selected from R 7 optionally substituted with one, two or three of; R 7 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, and halogen, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl groups is selected from one or more independently selected R 30 is optionally substituted with; A is S; E is O; B is N; R 30 is, at each occurrence, independently selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, halogen, -CN, azide, and -NO 2 and independently selected from the group consisting of: (1) R 1a is 4-(2-hydroxyethyl)piperazin-1-yl, and R 1b is H and R 1c is methyl, B is N, E is O, and R 3 is H, A is S, and L is a bond, then R 6 is not 4-chloro-2-methylpyridin-3-yl.

2. 2. The compound according to claim 1, selected from the group consisting of the kinase inhibitors of formula (I) and solvates and salts thereof, wherein said salts are pharma- ceutically acceptable salts.

3. R 1a 3. The compound according to claim 1 or 2, wherein is selected from the group consisting of (2-hydroxyethyl)amino, 4-(2-hydroxyethyl)piperazinyl, 4-methylpiperazinyl and 4-acetylpiperazinyl.

4. R 1a The compound of claim 3, wherein is 4-methylpiperazinyl.

5. R 1b is H and R 1c The compound according to any one of claims 1 to 4, wherein is methyl.

6. R 3 The compound according to any one of claims 1 to 5, wherein is H.

7. R 7 is C 1-3 is selected from the group consisting of alkyl and halogen, 1-3 The compound of any one of claims 1 to 6, wherein each alkyl is optionally substituted with one or more independently selected methyl or halogen.

8. R 6 is one or two independently selected R 7 The compound of any one of claims 1 to 7, which is pyridinyl substituted with

9. One R 7 The compound of claim 8 , wherein is attached to a ring atom of the pyridinyl at the 2-position relative to the ring atom to which the pyridinyl is attached to the remainder of the compound.

10. R 6 is one or two independently selected R 7 The compound according to any one of claims 1 to 7, wherein the thienyl is substituted with

11. One R 7 The compound of claim 10, wherein is attached to a ring atom of the thienyl at the 2-position relative to the ring atom to which the thienyl is attached to the remainder of the compound.

12. At least one R 7 The compound according to any one of claims 1 to 11, wherein is selected from the group consisting of Cl and Br.

13. R 6 However, two independently selected R 7 thienyl substituted with 7 is Cl attached to a ring atom of the thienyl at the 2-position relative to the ring atom to which the thienyl is attached to the remainder of the compound.

14. A compound according to any one of claims 1 to 7, wherein R 6 is a compound selected from the following formulas: 【Chemistry 2】 In the formula, the wavy line represents R 6 represents the bond that attaches it to the rest of the compound.

15. A compound according to claim 1, A compound selected from the group consisting of: 【Chemistry 3】 and solvates, salts, tautomers, conformers, and isotopically labeled compounds thereof; or A compound selected from the group consisting of: 【Chemistry 4】 and solvates, salts, tautomers, conformers, and isotopically labeled compounds thereof.

16. A compound according to claim 1, A compound selected from the group consisting of: 【Chemistry 5】 and solvates, salts, tautomers, conformers, and isotopically labeled compounds thereof; or A compound selected from the group consisting of: 【Chemistry 6】 and solvates, salts, tautomers, conformers, and isotopically labeled compounds thereof.

17. The compound of claim 1 selected from the group consisting of: 【Chemistry 7】 and solvates, salts, tautomers, conformers, and isotopically labeled compounds thereof.

18. 16. A pharmaceutical composition comprising a compound according to any one of claims 1 to 15, wherein said salt is a pharma- ceutically acceptable salt, optionally further comprising a pharma- ceutically acceptable excipient.

19. A medicament comprising a compound according to any one of claims 1 to 15, wherein said salt is a pharma- ceutically acceptable salt, or a pharmaceutical composition according to claim 18, for use in therapy.

20. 20. A medicament comprising a compound or pharmaceutical composition according to claim 19 for use in treating a proliferative disorder in a subject.

21. A medicament comprising a compound or a pharmaceutical composition for use in treating a proliferative disorder in a subject, the treatment comprising administering to the subject the compound or pharmaceutical composition, wherein the compound is a compound according to any one of claims 1 to 15, wherein said salt is a pharma- ceutical acceptable salt, or the pharmaceutical composition is a pharmaceutical composition according to claim 18.

22. 22. A medicament comprising the compound or pharmaceutical composition according to claim 20 or 21, wherein the proliferative disease is cancer or a tumor.

23. 23. A medicament comprising the compound or pharmaceutical composition according to claim 22, wherein the cancer is a solid tumor.

24. 24. A medicament comprising the compound or pharmaceutical composition of claim 22 or 23, wherein the treatment further involves administration of an immune checkpoint inhibitor.

25. A medicament comprising the compound or pharmaceutical composition according to any one of claims 20 to 24, wherein the subject is a human subject.

26. 18. A pharmaceutical composition comprising a compound according to claim 16 or 17, wherein said salt is a pharma- ceutically acceptable salt, optionally further comprising a pharma- ceutically acceptable excipient.

27. A medicament comprising a compound or pharmaceutical composition for use in treating a proliferative disorder in a human subject, the treatment comprising administering the compound or pharmaceutical composition to the subject, wherein the compound is a compound according to claim 16 or 17, wherein the salt is a pharma- ceutical acceptable salt, or the pharmaceutical composition is a pharmaceutical composition according to claim 26.

28. 28. A medicament comprising the compound or pharmaceutical composition according to claim 27, wherein the proliferative disease is cancer or a tumor.

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