Compound

Abstract

Compounds of Formula I [Formula 1] Disclosed is JPEG2024544019000034.jpg4156, wherein Y, n, R1, R2 and R3 have the meanings set forth herein, or a pharma- ceutically acceptable solvate or salt thereof. The compounds are useful as inhibitors of protein or lipid kinases, particularly as inhibitors of members of the PIM family of kinases, such as PIM-1, PIM-2 or PIM-3, and can be used to treat many conditions, particularly cancer.

Description

[Technical field]

[0001] The present invention relates to novel pharma- ceutically useful compounds, which are useful as inhibitors of protein or lipid kinases (e.g., inhibitors of members of the PIM family of kinases, e.g., PIM-1, PIM-2 or PIM-3). The invention also relates to the use of such compounds as medicines, to the use of such compounds for the in vitro, in situ and in vivo diagnosis or treatment of mammalian cells (or associated pathological conditions), pharmaceutical compositions containing them, and synthetic routes for their production. [Background technology]

[0002] Dysfunction of protein kinases (PKs) is a hallmark of many diseases. The majority of oncogenes and proto-oncogenes involved in human cancers encode PKs. Increased activity of PKs is also involved in many non-malignant diseases, such as benign prostatic hyperplasia, familial adenomatous polyposis, neurofibromatosis, psoriasis, vascular smooth cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthritis, glomerulonephritis, and postoperative stenosis and restenosis. PKs ​​are also involved in inflammatory conditions and the proliferation of viruses and parasites. PKs ​​may also play a major role in the pathogenesis and development of neurodegenerative disorders.

[0003] For a general discussion of PK dysfunction or dysregulation, see, for example, Current Opinion in Chemical Biology 1999, 3, 459-465.

[0004] PIM-1 is a proto-oncogene activated by a murine leukemia virus (the proviral integration site of Moloney murine leukemia virus - MoMuLV) that induces T-cell lymphomas [Cuypers, HT, et. al. Cell, 1984, 37, 141-150].

[0005] Expression of the proto-oncogene produces a 313-residue non-transmembrane serine / threonine kinase containing a 253-amino acid kinase domain. Two isoforms are known that are expressed via alternative transcription initiation (p44 and p33) [Saris, CJM et al. EMBO J. 1991, 10, 655-664].

[0006] PIM-1, PIM-2, and PIM-3 phosphorylate protein substrates important in cancer initiation and progression. For example, PIM-1 phosphorylates p21, Bad, c-myb, Cdc25A, and eIF4B, among others (see, e.g., Quian, KC et al, J. Biol. Chem. 2005, 280(7), 6130-6137, and references cited therein).

[0007] Two PIM-1 homologues have been described [Baytel, D. Biochem. Biophys. Acta 1998, 1442, 274-285;Feldman, J. et al. J. Biol. Chem. 1998, 273, 16535.16543]. PIM-2 and PIM-3 are 58% and 69% identical to PIM-1 at the amino acid level, respectively. PIM-1 is expressed primarily in the thymus, testis, and cells of the hematopoietic system [Mikkers, H.;Nawijn, M.;Allen, J.;Brouwers, C.;Verhoeven, E.;Jonkers, J.;Berns, Mol. Cell. Biol. 2004, 24, 6104;Bachmann, M.;Moroy, T. Int. J. Biochem. Cell Biol. 2005, 37, 726-730. 6115]. PIM-1 expression is directly induced by STAT (Signal Transducers and Activators of Transcription) transcription factors, and PIM-1 expression is induced by many cytokine signaling pathways, including interleukins (ILs), granulocyte-macrophage colony-stimulating factor (GM-CSF), α- and γ-interferons, erythropoietin, and prolactin [Wang, Z et al. J. Vet. Sci. 2001, 2, 167-179].

[0008] PIM-1 has been suggested to be involved in lymphoma development. Induced expression of PIM-1 and the proto-oncogene c-myc synergistically increases the incidence of lymphoma formation [Breuer, M. et al. Nature 1989, 340, 61-63;van Lohuizen M. et al. Cell, 1991, 65, 737-752]. PIM-1 has been shown to function in cytokine signaling pathways and play a role in T cell development [Schmidt, T. et al. EMBO J. 1998, 17, 5349-5359;Jacobs, H. et al. JEM 1999, 190, 1059-1068]. Signaling through gp130, a common subunit of the IL-6 cytokine family of receptors, can activate the transcription factor STAT3, leading to proliferation of hematopoietic cells [Hirano, T. et al. Oncogene 2000, 19, 2548-2556]. Kinase-active PIM-1 appears to be essential for gp130-mediated STAT3 proliferation signals. PIM-1 can cooperate with c-myc to promote STAT3-mediated cell cycle progression and anti-apoptosis [Shirogane, T. et al., Immunity, 1999, 11, 709-719]. PIM-1 also appears to be required for IL-3-stimulated growth of bone marrow-derived mast cells [Domen, J. et al., Blood, 1993, 82, 1445-1452] and for survival of FDCP1 cells after IL-3 withdrawal [Lilly, M. et al., Oncogene, 1999, 18, 4022-4031].

[0009] Furthermore, control of cell proliferation and survival by PIM-1 can be influenced by phosphorylation of cdc25, a well-established cell cycle regulator [Mochizuki, T. et al., J. Biol. Chem. 1999, 274, 18659-18666] and / or p21(Cip1 / WAF1) [Wang Z. et al. Biochim. Biophys. Acta 2002, 1593, 45-55], or by phosphorylation of heterochromatin protein 1, a molecule involved in chromatin structure and transcriptional regulation [Koike, N. et al, FEBS Lett. 2000, 467, 17-21].

[0010] Mice lacking all three PIM genes exhibited impaired responses to hematopoietic growth factors, demonstrating that PIM proteins are required for efficient proliferation of peripheral T lymphocytes. In particular, PIM function was shown to be required for efficient cell cycle induction of T cells in response to synergistic T cell receptor and IL-2 signaling. Numerous interacting partners and substrates of PIM-1 have been identified, suggesting an important role for PIM-1 in cell cycle control, proliferation, and cell survival.

[0011] The oncogenic potential of this kinase was first demonstrated in Eμ PIM-1 transgenic mice, in which overexpression of PIM-1 targets the B cell lineage and leads to the formation of B cell tumors [van Lohuizen, M.et al.;Cell 1989, 56, 673-682. PIM-1 was subsequently reported to be overexpressed in multiple prostate cancers, erythroleukemias, and several other types of human leukemia [Roh, M.et al.;. Cancer Res. 2003, 63, 8079-8084;Valdman, A. et al;Prostate 2004, 60, 367-371].

[0012] For example, chromosomal translocations of PIM-1 lead to overexpression of PIM-1 in diffuse large cell lymphoma [Akasaka, H.et al.;Cancer Res. 2000, 60, 2335-2341]. Furthermore, multiple missense mutations of PIM-1 have been reported in lymphomas of the nervous system and AIDS-induced non-Hodgkin's lymphomas, which probably affect the activity or stability of PIM-1 kinase [Pasqualucci, L. et al, Nature 2001, 412, 341-346;Montesinos-Rongen, M. et al., Blood 2004, 103, 1869-1875;Gaidano, G. et al., Blood 2003, 102, 1833-184]. Thus, the strong association between the reported overexpression data and the occurrence of PIM-1 mutations in cancer suggests a major role for PIM-1 in tumorigenesis.

[0013] Overexpression of PIM1 is associated with poor response to radiation therapy and various forms of chemotherapy, including platinum- and taxane-based treatments, in part because drug transporters induce PIMs. In addition, PIMs confer resistance to targeted therapies such as PI3K, PI3K / mTOR, AKT, pyruvate dehydrogenase, and mTOR inhibitors. On the other hand, the PIM pathway has been shown to be activated after TKI treatment, such as EGFR, MET, and ALK inhibitors. PIM kinases are also involved in resistance to angiogenic treatment with VEGF-A-targeted and VEGFR-targeted agents. (Reviewed by Toth RK, Warfel NA. Mol Cancer Ther. 2021 Jan;20(1):3-10.).

[0014] Furthermore, PIM-1 is associated with drug resistance through interaction with and phosphorylation of various targets in cancer, including breast cancer resistance protein (BRCP), Etk4, P-glycoprotein (P-gp), and FMS-like tyrosine kinase 3 (FLT3), making PIM-1 a promising target for cancer therapy (Toth RK and Warfel NA, supra).

[0015] PIM kinases are expressed following TCR and cytokine signaling in CD4+ T cells and play a role in CD4+ T proliferation and full activation and differentiation of naive CD4+ T cells as well as effector CD4+ T cell responses, thus PIM inhibition confers therapeutic benefit in T cell mediated diseases such as inflammatory bowel disease (IBD). Jackson et al. Cell Immunol. 2012;272(2):200-13;Shen Y, et al. Biomed Res. 2017;28:8267-70.

[0016] Indeed, in two different mouse models of inflammatory bowel disease, Pim-1 kinase inhibition attenuates IBD by promoting T cell differentiation into Foxp3+ regulatory T cells, as well as by downregulating excessive Th1 and Th17-type immune responses and inhibiting macrophage hyperactivation. Yue-Ming Shen et al., Dig Dis Sci 2012 Jul;57(7):1822-31;Yueming Shen, Clin Res Hepatol Gastroenterol. 2018 Sep;42(4):382-386.

[0017] Furthermore, PIM-1 upregulated by IL6 inhibits FOXP3 and thus suppresses the suppressive activity of Tregs in vitro, so targeting PIM-1 can improve the efficacy of antitumor immunotherapy (Z. Li, et al., J. Biol. Chem. 289 (2014) 26872-26881).

[0018] Similarly, PIM kinases exhibited lymphocyte- and NK cell-mediated immunoregulatory responses through cytokine production and activation of the NF-κB, MYC, and mTOR pathways (Z. Liu, et al. Am. J. Cancer Res. 10 (2020) 4085-4097).

[0019] Furthermore, the long form of PIM-1 kinase can transduce inflammation to the B cell survival program by associating with CD180, so PIM inhibition may provide a novel therapeutic option in autoimmune diseases associated with increased B cell activity, Egli N,. PLoS One 2015;10: e0142741.

[0020] All these data suggest that PIMs may represent new potential therapeutic targets in the prevention and treatment of human-specific autoimmune diseases.

[0021] PIM-1 is upregulated in PBMCs of systemic lupus erythematosus (SLE) patients with active disease and in the kidneys of lupus mouse models. Mechanistically, PIM-1 activates NFATc1 expression and upregulates intracellular Ca2+, which induces glomerular injury. 2+ PIM regulates NLRP3 inflammasome activation via IL-1. Furthermore, PIM inhibition attenuates renal disease and mortality in a lupus mouse model, positioning PIM as a therapeutic target for human lupus nephritis. Rong Fu et al. Arthritis Rheumatol. 2019 Aug;71(8):1308-1318.

[0022] Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic inflammation in multiple joints. PIM-1 has been found to be upregulated in RA synovial tissue and is induced in RA fibroblast-like synoviocytes (RA-FLS) by TNF-α, IL-6, or S100A4. Furthermore, PIM inhibition significantly reduced proinflammatory cytokine-induced proliferation migration and MMP production of RA-FLS in vitro. You-Jung Ha, Rheumatology (Oxford) . 2019 Jan 1;58(1):154-164.

[0023] On the other hand, PIM kinase inhibition reduces the pro-inflammatory effector function of CD4+ T cells from early RA patients who show high expression of PIM1, significantly inhibits the progression of RA-like arthritis models, and reduces cartilage destruction. Nicola J Maney et al. Arthritis Rheumatol . 2021 Oct;73(10):1820-1830. These results suggest that PIM-1 may be a potential therapeutic target for RA.

[0024] An integrative biology approach combining network analysis of psoriasis transcriptome datasets with clinically relevant preclinical models allows elucidation of IL-22 function in psoriasis and identification of PIM1 as a potential therapeutic target for the disease. Gayathri K Perera et al. Sci Transl Med. 2014 Feb 12;6(223):223ra22.

[0025] PIM kinases are also involved in neurodegenerative disorders such as Alzheimer's disease (AD). In patients, phosphorylated PARS40 correlates with Aβ and tau pathology, as well as cognitive impairment. PIM1 is the kinase responsible for PARS40 in the brain. In mouse models of AD, inhibition of PIM1 reduces PRAS40 phosphorylation, which correlates with reduced Aβ and tau pathology, as well as rescue of cognitive impairment by increasing proteasome function. Ramon Velazquez et al. Mol Neurodegener. 2016 Jul 13;11(1):52.

[0026] For efficient viral replication, human immunodeficiency virus type 2 utilizes viral protein X (Vpx) to suppress the host innate immune system. PIM kinases phosphorylate lentiviral Vpx and modulate its function to downregulate SAMHD1, reducing viral infectivity, implying that PIM kinases may be potential therapeutic targets for lentiviral infection. Kei Miyakawa et al. Nat Commun. 2019 Apr 23;10(1):1844.

[0027] Several other protein kinases have been described in the literature, and the activity and / or increased activity of such protein kinases, as well as PIM-1, PIM-2, and PIM-3, have been implicated in diseases such as cancer.

[0028] There is a continuing need to provide alternative and / or more effective inhibitors of protein kinases, particularly inhibitors of PIM-1, PIM-2 and / or PIM-3. Such modulators are expected to provide alternative and / or improved approaches for the management of disease conditions associated with activity and / or elevated activity of PIM-1, PIM-2 and / or PIM-3 protein kinases.

[0029] WO 2011 / 080510 describes generally tricyclic compounds having activity as kinase inhibitors, particularly as PIM family kinase inhibitors, as well as intermediates and processes for their preparation, but it does not disclose the types of compounds, particularly the specific compounds, described and claimed herein.

[0030] The listing or discussion of an apparently prior-published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the prior art or is common general knowledge. Summary of the Invention

[0031] In one aspect of the invention, a compound of formula I

[0032] [ka] (In the formula, Y is C(R a )(R b ) and NR c selected from the group consisting of; R a , R b , and R care each independently H and C 1~6 selected from the group consisting of alkyl; n is 1 to 3; Each R1 is halogen, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, and C 1~6 haloalkoxy; R2 is C 1~4 is alkyl; and R3 is H and C 1~3 alkyl), or a pharma- ceutically acceptable solvate or salt thereof.

[0033] In another aspect of the invention, there is provided a pharmaceutical formulation comprising a compound of formula I as defined herein, or a pharma- ceutically acceptable solvate or salt thereof, in admixture with a pharma- ceutically acceptable adjuvant, diluent or carrier.

[0034] In another aspect of the invention there is provided a compound of formula I, or a pharma- ceutically acceptable solvate or salt thereof, as defined herein, for use as a medicament.

[0035] In another aspect of the invention there is provided a compound of formula I, or a pharma- ceutically acceptable solvate or salt thereof, as defined herein, for use in the treatment of a disorder in which a protein or lipid kinase (e.g. a PIM family kinase such as PIM-1, PIM-2 and / or PIM-3) is known to play a role.

[0036] In another aspect of the invention there is provided the use of a compound of formula I, or a pharma- ceutically acceptable solvate or salt thereof, as defined herein, in the manufacture of a medicament for use in the treatment of a disorder in which a protein or lipid kinase (e.g. a PIM family kinase such as PIM-1, PIM-2 and / or PIM-3) is known to play a role.

[0037] In another aspect of the invention, there is provided a method of treating a disorder in which a protein or lipid kinase (e.g., a PIM family kinase such as PIM-1, PIM-2 and / or PIM-3) is known to play a role in a subject in need thereof, comprising administering to the subject a compound of formula I, or a pharma- ceutically acceptable solvate or salt thereof, as defined herein.

[0038] In a further aspect of the invention there is provided the use of a compound of formula I as defined herein in the manufacture of a medicament for the treatment of cancer.

[0039] In a further aspect of the invention there is provided a method of treating cancer which comprises administering to a patient suffering from or susceptible to such a condition a therapeutically effective amount of a compound of formula I as defined herein.

[0040] In a further aspect of the invention there is provided a compound of formula I as defined herein for use in the treatment of cancer.

[0041] In another aspect of the invention, (A) a compound of formula I, as defined herein, or a pharma- ceutically acceptable solvate or salt thereof; and (B) other therapeutic agents; A combination comprising: [Brief description of the drawings]

[0042] [Figure 1] FIG. 1 shows the anti-proliferative activity of three example compounds of the present invention and illustrates cell viability in A549 (lung cancer) and MiaPaca (pancreatic cancer) cell lines 72 hours after treatment with the three example compounds and Comparative Example 1 (Example 19 of WO 2011 / 080510). [Diagram 2] FIG. 1 compares the fold change in GI50 for these cell lines upon treatment with three compounds of the invention and Comparative Example 1. [Diagram 3]FIG. 1 shows the pharmacokinetics of three example compounds of the present invention and Comparative Example 1 in a Balb / C mouse model, showing the concentration of each compound as a function of time when the compounds were administered intravenously at 5 mg / kg. [Figure 4] FIG. 1 shows the pharmacokinetics of three example compounds of the present invention and Comparative Example 1 in a Balb / C mouse model, showing the concentration of each compound as a function of time when the compounds were orally administered at 10 mg / kg. [Diagram 5] FIG. 1 shows the antiproliferative activity of three example compounds of the present invention and illustrates cell viability in MV4:11 (acute myeloid leukemia), HT-29 (colon cancer), Jeko1 (mantle cell lymphoma) and SKMEL19 (melanoma) cell lines after 72 hours of treatment with the three example compounds and Comparative Example 1. [Figure 6] FIG. 1 compares the fold change in GI50 for these cell lines upon treatment with three compounds of the invention and Comparative Example 1. [Figure 7] FIG. 1 shows tumor volumes 0-21 days after treatment with the compound of Example 1 at doses of 25, 50 and 100 mg / kg compared to control (vehicle). [Figure 8] FIG. 1 shows the % change in body weight from days 0 to 21 after treatment with the compound of Example 1 at doses of 25, 50 and 100 mg / kg compared to control (vehicle). [Figure 9-1] FIG. 1 shows the effect of the compound of Example 1 in inhibiting the generation of Th1 and Th17 responses. [Figure 9-2] Ibid. and [Figure 10] FIG. 1 demonstrates that the compound of Example 1 promotes the generation of an iTreg response. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0043] Benefits and Surprising Findings The inventors have found that the compounds of the present invention exhibit surprisingly improved activity, particularly anti-proliferative activity, against a wide variety of cancer cell lines compared to the most structurally similar compounds as disclosed in WO 2011 / 080510. Thus, these compounds have improved in vivo efficacy in patients compared to the most similar compounds disclosed in WO 2011 / 080510, and have the potential to be developed as pharmaceuticals for treating a range of indications, particularly cancer.

[0044] The inventors have also found that the compounds of the present invention exhibit a surprising improvement in pharmacokinetic activity compared to the most structurally similar compounds as disclosed in WO2011 / 080510.This therefore means that the compounds have greater exposure to the site of action in vivo compared to the most similar compounds as disclosed in WO2011 / 080510, providing the potential for development as pharmaceuticals with improved efficacy in vivo or equivalent efficacy in vivo at lower doses.

[0045] definition By itself, "alkyl" refers to a straight or branched chain saturated aliphatic radical having a chain of carbon atoms. Typically, X Alkyl and C X~Y Alkyl is used where X and Y indicate the number of carbon atoms in the chain. For example, C 1~6 Alkyl includes alkyl groups having a chain length of between 1 and 6 carbons (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-methylpentyl, and 2-ethylbutyl). In some embodiments, alkyl is C 1~4 Alkyl, C 1~3 Alkyl, or C 1~2 Alternatively, the alkyl may be a C1 alkyl, a C2 alkyl, or a C3 alkyl.

[0046] "Alkoxy" means "-O-alkyl", where "alkyl" is as defined above in either its broadest or preferred embodiment. For example, C 1~6 Alkoxy includes alkoxy groups having a chain length of between 1 and 6 carbons (e.g., methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, sec-butyloxy, isobutyloxy, tert-butyloxy, n-pentyloxy, 2-methylbutyloxy, neopentyloxy, n-hexyloxy, 2-methylpentyloxy, and 2-ethylbutyloxy). In some embodiments, alkoxy is C 1~4 Alkoxy, C 1~3 Alkoxy, or C 1~2 Alternatively, "alkoxy" can be a C1 alkoxy, a C2 alkoxy, or a C3 alkoxy.

[0047] "Halogen" means fluorine, chlorine, bromine, or iodine.

[0048] "Haloalkyl" in either its broadest or preferred aspects means an alkyl as defined above, substituted with one or more halogen atoms, preferably fluorine or chlorine, more preferably fluorine, as defined above. The number of halogen atoms is limited only by the number of substitutable positions on the alkyl group, but may be 1 to 5, particularly 1, 2 or 3. In one embodiment, "haloalkyl" includes perhaloalkyl (i.e., all hydrogen atoms are replaced with halogen atoms, particularly fluorine atoms). For example, C 1~6Haloalkyl includes alkyl groups having a chain of between 1 and 6 carbons substituted with one or more halogens (e.g., mono-, di-, or trifluoromethyl, mono-, di-, or trichloromethyl, mono-, di-, tri-, tetra-, or pentafluoroethyl, mono-, di-, tri-, tetra-, or pentafluoroethyl, 1-, 2-, or 3-fluoropropyl, 1-, or 2-fluoroisopropyl, 1, 2, 3-, or 4-fluoro n-butyl, 1, 2, 3-, 4-, or 5-fluoro-n-pentyl, 1, 2, 3, 4, 5, or 6-fluoro n-hexyl. In some embodiments, haloalkyl is C 1~4 Haloalkyl, C 1~3 Haloalkyl, or C 1~2 It can be haloalkyl. Alternatively, the haloalkyl can be a C1 haloalkyl, a C2 haloalkyl, or a C3 haloalkyl. In some embodiments, the haloalkyl can be trifluoromethyl.

[0049] "Haloalkoxy" in either its broadest or preferred aspects means an alkoxy as defined above, substituted with one or more halogen atoms, preferably fluorine or chlorine, more preferably fluorine, as defined above. The number of halogen atoms is limited only by the number of substitutable positions on the alkoxy group, but may be 1 to 5, particularly 1, 2 or 3. In one embodiment, "haloalkoxy" includes perhaloalkoxy (i.e., all hydrogen atoms are replaced with halogen atoms, particularly fluorine atoms). For example, C 1~6Haloalkoxy includes alkoxy groups having a chain of between 1 and 6 carbons substituted with one or more halogens (e.g., mono-, di-, or trifluoromethoxy, mono-, di-, or trichloromethoxy, mono-, di-, tri-, tetra-, or pentafluoroethoxy, mono-, di-, tri-, tetra-, or pentafluoroethoxy, 1-, 2-, or 3-fluoro-n-propyloxy, 1-, or 2-fluoroisopropyloxy, 1, 2, 3-, or 4-fluoro-n-butyloxy, 1, 2, 3-, 4, or 5-fluoro-n-pentyloxy, or 1, 2, 3, 4, 5, or 6-fluoro-n-hexyloxy. In some embodiments, haloalkoxy is C 1~4 Haloalkoxy, C 1~3 Haloalkoxy, or C 1~2 It can be a haloalkoxy. Alternatively, the haloalkoxy can be a C1 haloalkoxy, a C2 haloalkoxy, or a (C3) haloalkoxy. In some embodiments, the haloalkoxy can be trifluoromethoxy.

[0050] compound The compounds of the present invention are compounds of formula I

[0051] [ka] (In the formula, Y is C(R a )(R b ) and NR c selected from the group consisting of; R a , R b , and R c are each independently H and C 1~6 selected from the group consisting of alkyl; n is 1 to 3; Each R1 is halogen, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, and C 1~6 haloalkoxy; R2 is C1~4 is alkyl; and R3 is H and C 1~3 alkyl), or a pharma- ceutically acceptable solvate or salt thereof.

[0052] In the compounds of the present invention, Y is C(R a )(R b ) and NR c is selected from the group consisting of:

[0053] In one embodiment, R a and R b are each independently H and C 1~4 In one embodiment, R a and R b are each independently selected from the group consisting of H, methyl and ethyl. a and R b are each independently selected from the group consisting of H and methyl. a and R b are both H.

[0054] In one embodiment, R c H and C 1~4 In one embodiment, R c is selected from the group consisting of H, methyl and ethyl. In one embodiment, R c is selected from the group consisting of H and methyl. In one embodiment, R c is H. In one embodiment, R c is methyl.

[0055] In one embodiment, Y is selected from the group consisting of CH2 and N(CH3). In one embodiment, Y is CH2. In one embodiment, Y is N(CH3).

[0056] In the compounds of the present invention, n is the number of non-hydrogen substituents R1 on the phenyl ring that carry them. In the compounds of the present invention, n is 1, 2 or 3. In one embodiment, n is 1 or 2. In one embodiment, n is 1. In one embodiment, n is 2.

[0057] In the compounds of the present invention, each R1 is selected from the group consisting of halogen, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, and C 1~6 In one embodiment, each R is selected from the group consisting of halogen, C 1~6 Haloalkyl, and C 1~6 In one embodiment, each R is selected from the group consisting of F, Cl, C 1~4 Haloalkyl, and C 1~4 In one embodiment, each R is selected from the group consisting of F, Cl, C 1~2 Haloalkyl, and C 1~2 In one embodiment, each R1 is selected from the group consisting of F, mono-, di-, or trifluoromethyl, and mono-, di-, or trifluoromethoxy. In one embodiment, each R1 is selected from the group consisting of F, CF3, and OCF3.

[0058] In one embodiment, R1 is halogen. In one embodiment, R1 is F or Cl. In one embodiment, R1 is F. In one embodiment, R1 is CH3. In one embodiment, R1 is CH2F. In one embodiment, R1 is CHF2. In one embodiment, R1 is CF3. In one embodiment, R1 is OCH3. In one embodiment, R1 is OCH2F. In one embodiment, R1 is OCHF2. In one embodiment, R1 is OCF3.

[0059] In one embodiment, n is 1 and R1 is OCF3. In one embodiment, n is 2 and one R1 is F and the other is CF3.

[0060] In the compounds of the present invention, R2 is C 1~4 In one embodiment, R2 is alkyl. In one embodiment, R2 is methyl, ethyl, or n-propyl. In one embodiment, R2 is methyl or ethyl. In one embodiment, R2 is CH3.

[0061] In the compounds of the present invention, R3 is selected from H and C 1~3 In one embodiment, R3 is selected from the group consisting of alkyl, methyl, ethyl, or n-propyl. In one embodiment, R3 is H, methyl, or ethyl. In one embodiment, R3 is H or CH3. In one embodiment, R3 is H.

[0062] In one embodiment, the OH group on the cyclohexane moiety is in a cis relationship to the amino moiety that is bonded to the remainder of the molecule.In one embodiment, the OH group on the cyclohexane moiety is in a trans relationship to the amino moiety that is bonded to the remainder of the molecule.

[0063] In one embodiment, Y is selected from the group consisting of CH2 and N(CH3); n is 1 or 2; and each R1 is halogen, C 1~6 Haloalkyl, and C 1~6 haloalkoxy; R2 is methyl, ethyl, or n-propyl; and R3 is H, methyl, or ethyl.

[0064] In one embodiment, Y is selected from the group consisting of CH2 and N(CH3); n is 1 or 2; and each R1 is F, Cl, C 1~2 Haloalkyl, and C 1~2 haloalkoxy; R2 is methyl or ethyl; and R3 is H or methyl.

[0065] In one embodiment, Y is selected from the group consisting of CH2 and N(CH3); n is 1 or 2; each R1 is selected from the group consisting of F, mono-, di- or trifluoromethyl, and mono-, di- or trifluoromethoxy; R2 is methyl; and R3 is H.

[0066] In one embodiment, the formula:

[0067] [ka] or a pharma- ceutically acceptable solvate or salt thereof is provided.

[0068] In one embodiment, the formula:

[0069] [ka] or a pharma- ceutically acceptable solvate or salt thereof is provided.

[0070] In one embodiment, the formula:

[0071] [ka] or a pharma- ceutically acceptable solvate or salt thereof is provided.

[0072] General method Compounds of formula I can be synthesized according to Scheme 1.

[0073] [ka] In Scheme 1, Y, n, R1, R2 and R3 are as defined above, and LG1 represents a suitable leaving group such as an iodo, bromo, chloro or sulfonate group (e.g., -OS(O)2CF3, -OS(O)2CH3 or -OS(O)2-p-tolyl).

[0074] According to a further aspect of the present invention there is provided a process for preparing a compound of formula I as defined herein, comprising reacting a compound of formula II:

[0075] [ka] wherein LG represents a suitable leaving group such as an iodo, bromo, chloro or sulfonate group (e.g., -OS(O)CF, -OS(O)CH or -OS(O)-p-tolyl), and R and Y are as defined above. and Formula III:

[0076] [ka] (wherein R2 and R3 are as defined above). With a compound of the formula:

[0077] This process can be carried out under any conditions suitable for the displacement of a leaving group of an aromatic compound by an amino group.

[0078] In one embodiment, the reaction is carried out in the presence of a suitable metal catalyst (or a salt or complex thereof). There is no particular restriction on the nature of the catalyst, as long as it is capable of catalyzing the substitution of the leaving group of the aromatic compound by the amino group. Examples of suitable catalysts include Cu, Cu(OAc)2, CuI (or CuI / diamine complex), copper tris(triphenylphosphine) bromide, Pd(OAc)2, tris(dibenzylideneacetone)-dipalladium(0) (Pd2(dba)3) or NiCl2, and optional additives, such as triphenylphosphine (Ph3P), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (Xantphos), NaI or suitable crown ethers such as 18-crown-6-benzene. Xantphos is preferred.

[0079] In one embodiment, the reaction is carried out in the presence of a suitable base. The base is not particularly limited as long as it can act as a base. Examples of suitable bases include NaH, triethylamine, pyridine, N,N'-dimethylethylenediamine, Na2CO3, K2CO3, K3PO4, Cs2CO3, sodium or potassium tert-butoxide (or mixtures thereof), optionally in the presence of 4 Å molecular sieves. Sodium tert-butoxide is preferred.

[0080] In one embodiment, the reaction is carried out in a suitable solvent. The solvent is not particularly limited as long as it is inert to the reaction and can dissolve the reactants at least to some extent. Examples of suitable solvents include dichloromethane, dioxane, toluene, ethanol, isopropanol, dimethylformamide, ethylene glycol, ethylene glycol dimethyl ether, water, dimethyl sulfoxide, acetonitrile, dimethylacetamide, N-methylpyrrolidinone, tetrahydrofuran, or mixtures thereof. Dioxane is preferred.

[0081] In another embodiment, the reaction can be carried out under microwave irradiation reaction conditions, or the reaction can be carried out in the absence of other reagents such as catalysts, bases, or even solvents.

[0082] Y is NR c The compound of formula II, wherein: is disclosed in WO 2011 / 080510. By way of example, the compound of formula II, wherein LG is chloro, Y is N-CH and the substituent R on the phenyl moiety is meta-OCF, is disclosed as intermediate 18 in WO 2011 / 080510.

[0083] Compounds of formula III are commercially available.

[0084] Y is C(R a )(R b ), compounds of formula II (hereafter referred to as compounds of formula IIa), can be synthesized according to Scheme 2.

[0085] [ka] In Scheme 2, n, R1, and R a , and R b is as defined above, and LG1, LG2, and LG3 each independently represent a suitable leaving group such as an iodo, bromo, chloro, or sulfonate group (e.g., -OS(O)2CF3, -OS(O)2CH3, or -OS(O)2-p-tolyl).

[0086] Step (a) involves reacting a compound of formula IV with an allylic alcohol or alkoxide in the presence of a base to replace the leaving group LG3 with an allyloxy group to form a compound of formula V. This process can be carried out under any conditions suitable for the replacement of a leaving group of an aromatic compound with an alcohol or alkoxide.

[0087] The reaction is carried out in the presence of a suitable base. The base is not particularly limited as long as it can act as a base. Examples of suitable bases include NaH, triethylamine, pyridine, N,N'-dimethylethylenediamine, Na2CO3, K2CO3, K3PO4, Cs2CO3, sodium or potassium tert-butoxide (or mixtures thereof), optionally in the presence of 4 Å molecular sieves. Cs2CO3 is preferred.

[0088] In one embodiment, the reaction is carried out in a suitable solvent. The solvent is not particularly limited as long as it is inert to the reaction and can dissolve the reactants at least to some extent. Examples of suitable solvents include dichloromethane, dioxane, toluene, ethanol, isopropanol, dimethylformamide, ethylene glycol, ethylene glycol dimethyl ether, water, dimethyl sulfoxide, acetonitrile, dimethylacetamide, N-methylpyrrolidinone, tetrahydrofuran, or mixtures thereof. Acetonitrile is preferred.

[0089] Step (b) involves reacting a compound of formula V with a benzoic acid hydrazide of formula VI to close the ring and form a compound of formula VII. This process can be carried out under any conditions suitable for the displacement of a leaving group of an aromatic compound by an alcohol or an alkoxide.

[0090] Certain compounds of formula VI are commercially available. Other compounds of formula VI can be made by reacting the corresponding benzoic acid or acid halide with hydrazine.

[0091] In one embodiment, the reaction is carried out in the presence of a suitable acid. The acid is not particularly limited as long as it can act as an acid. Examples of suitable acids include strong mineral acids, such as hydrochloric acid, nitric acid, and sulfuric acid, and sulfonic acids, such as methanesulfonic acid, p-toluenesulfonic acid, and trifluoromethanesulfonic acid. p-toluenesulfonic acid is preferred.

[0092] In one embodiment, the reaction is carried out in a suitable solvent. The solvent is not particularly limited as long as it is inert to the reaction and can dissolve the reactants at least to some extent. Examples of suitable solvents include dichloromethane, dioxane, toluene, ethanol, isopropanol, dimethylformamide, ethylene glycol, ethylene glycol dimethyl ether, water, dimethyl sulfoxide, acetonitrile, dimethylacetamide, N-methylpyrrolidinone, tetrahydrofuran, or mixtures thereof. Dioxane is preferred.

[0093] Step (c) involves the allylic rearrangement of a compound of formula VII to form a compound of formula VIII. This process can be carried out under any conditions suitable for effecting such a rearrangement.

[0094] In one embodiment, the reaction is carried out under microwave irradiation reaction conditions. In one embodiment, the reaction is carried out by simply heating the compound of formula VII. Typical temperatures range from 50 to 200°C, preferably 130 to 180°C.

[0095] In one embodiment, the reaction is carried out in a suitable solvent. The solvent is not particularly limited as long as it is inert to the reaction and can dissolve the reactants at least to some extent. Examples of suitable solvents include dichloromethane, 1,2-dichloroethane, dioxane, toluene, ethanol, isopropanol, dimethylformamide, ethylene glycol, ethylene glycol dimethyl ether, water, dimethyl sulfoxide, acetonitrile, dimethylacetamide, N-methylpyrrolidinone, tetrahydrofuran, or mixtures thereof. 1,2-dichloroethane is preferred.

[0096] Step (d) involves hydrating an alkene of formula VIII to form a diol compound of formula IX. This process can be carried out under any conditions that can achieve the anti-Markovnikov addition of a water molecule to the alkene.

[0097] In one embodiment, the reaction is carried out by hydroboration of an alkene of formula VIII, followed by oxidation of the resulting alkylborane intermediate to form an alkene of formula IX.

[0098] Examples of suitable hydroboration reagents include borane (optionally complexed with an ether such as tetrahydrofuran, or a thioether such as dimethylsulfide), 9-borabicyclo(3.3.1)nonane (9-BBN), catecholborane, and disiamylborane. Borane dimethylsulfide is preferred.

[0099] The oxidizing agent is not particularly limited as long as it can oxidize the alkylborane while being inert to other groups on the molecule. Examples of suitable oxidizing agents include compounds containing a peroxy group, such as hydrogen peroxide, peracids and their salts. Sodium perborate is preferred.

[0100] In one embodiment, the reaction is carried out in a suitable solvent. The solvent is not particularly limited as long as it is inert to the reaction and can dissolve the reactants at least to some extent. Examples of suitable solvents include dichloromethane, dioxane, toluene, ethanol, isopropanol, dimethylformamide, ethylene glycol, ethylene glycol dimethyl ether, water, dimethyl sulfoxide, acetonitrile, dimethylacetamide, N-methylpyrrolidinone, tetrahydrofuran, or mixtures thereof. Tetrahydrofuran is preferred.

[0101] Step (e) involves dehydration and ring closure of the compound of formula IX to form a compound of formula IIa. This process can be carried out under any conditions suitable for carrying out such dehydration and ring closure. For example, dehydration can be carried out by treating the diol with an acid or base.

[0102] In one embodiment, the process is carried out by reacting the diol compound of formula IX with Vilsmeier reagent (1-chloro-N,N-dimethyliminium chloride).

[0103] In one embodiment, the reaction is carried out in the presence of a suitable acid. The acid is not particularly limited as long as it can act as an acid. Examples of suitable acids include strong mineral acids, such as hydrochloric acid, nitric acid, and sulfuric acid, and sulfonic acids, such as methanesulfonic acid, p-toluenesulfonic acid, and trifluoromethanesulfonic acid. p-toluenesulfonic acid is preferred.

[0104] In one embodiment, the reaction is carried out in the presence of a suitable base. The base is not particularly limited as long as it can act as a base. Examples of suitable bases include NaH, triethylamine, pyridine, N,N'-dimethylethylenediamine, Na2CO3, K2CO3, K3PO4, Cs2CO3, sodium or potassium tert-butoxide (or mixtures thereof), optionally in the presence of 4 Å molecular sieves. Triethylamine is preferred.

[0105] In one embodiment, the reaction is carried out in a suitable solvent. The solvent is not particularly limited as long as it is inert to the reaction and can dissolve the reactants at least to some extent. Examples of suitable solvents include dichloromethane, 1,2-dichloroethane, dioxane, toluene, ethanol, isopropanol, dimethylformamide, ethylene glycol, ethylene glycol dimethyl ether, water, dimethyl sulfoxide, acetonitrile, dimethylacetamide, N-methylpyrrolidinone, tetrahydrofuran, or mixtures thereof. 1,2-dichloroethane is preferred.

[0106] Salts, solvates, polymorphs, enantiomers, isotopically labeled derivatives Pharmaceutically acceptable salts of the compounds of formula I include the acid addition and base salts thereof.

[0107] Suitable acid addition salts are formed from acids which form non-toxic salts, examples of which include acetate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camphorsulfonate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hybenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, and the like. These salts include phosphate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate, and xinafoate.

[0108] Suitable base salts are formed from bases which form non-toxic salts, examples of which include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.

[0109] Hemi-salts of acids and bases can also be formed, such as hemisulfate and hemicalcium salts.

[0110] For a review on suitable salts, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, 2002).

[0111] Pharmaceutically acceptable salts of compounds of formula I can be prepared in three ways: (i) by reacting a compound of formula I with a desired acid or base; (ii) by removing an acid- or base-labile protecting group from a suitable precursor of a compound of formula (I) using a desired acid or base, or by ring-opening of a suitable cyclic precursor, such as a lactone or lactam; or (iii) converting one salt of the compound of formula (I) into another salt by reaction with an appropriate acid or base or by a suitable ion exchange column, The composition may be prepared by one or more of the following methods.

[0112] All three reactions are typically carried out in solution. The resulting salt may be precipitated and recovered by filtration or by evaporation of the solvent. The degree of ionization in the resulting salts can vary from completely ionized to almost non-ionized.

[0113] The compounds of the invention may exist in a continuum of solid states ranging from completely amorphous to completely crystalline. The term "amorphous" refers to a state in which a material lacks long-range order at the molecular level and may exhibit the physical properties of a solid or a liquid, depending on the temperature. Typically, such materials do not exhibit a characteristic X-ray diffraction pattern and exhibit the properties of a solid, but are formally described as a liquid. Upon heating, a change from solid to liquid properties occurs, which is usually characterized by a second order change of state ("glass transition").

[0114] The term "crystalline" refers to a solid phase in which a substance has an ordered internal structure at the molecular level and gives a characteristic X-ray diffraction pattern with defined peaks. Such substances when heated sufficiently will also exhibit the properties of a liquid, although the change from solid to liquid is usually characterized by a first-order phase change (the "melting point").

[0115] The compounds of the present invention can also exist in unsolvated and solvated forms.The term "solvate" is used herein to describe a molecular complex that comprises the compounds of the present invention and one or more pharma-ceutically acceptable solvent molecules, such as ethanol.The term "hydrate" is used when the solvent is water.

[0116] The currently accepted classification system for organic hydrates is one that defines isolated site hydrates, channel hydrates, or metal-ion coordinated hydrates - see Polymorphism in Pharmaceutical Solids by KR Morris (Ed. HG Brittain, Marcel Dekker, 1995). Isolated site hydrates are those in which the water molecules are isolated from direct contact with each other by intervening organic molecules. In channel hydrates, the water molecules lie in lattice channels where they are adjacent to other water molecules. In metal-ion coordinated hydrates, the water molecules are bound to the metal ion.

[0117] If the solvent or water is tightly bound, the complex will have a well-defined stoichiometry independent of humidity. However, if the solvent or water is weakly bound, as is the case for channel hydrates and hygroscopic compounds, the water / solvent content will depend on humidity and drying conditions. In such cases, non-stoichiometry will be the norm.

[0118] As used herein, all references to compounds of Formula I include references to the pharma- ceutically acceptable salts and solvates thereof.

[0119] Compounds of the invention include compounds of formula (I) as defined above, including all polymorphs thereof and their crystal habits, prodrugs thereof and isomers (including optical isomers, geometric isomers and tautomers) as defined below, as well as isotopically labelled compounds of formula (I).

[0120] Compounds of formula I containing one or more asymmetric carbon atoms can exist as two or more stereoisomers. When structural isomers can be interconverted via a low energy barrier, tautomeric isomerism ("tautomerism") can occur. This can take the form of proton tautomerism in compounds of formula I containing, for example, imino, keto, or oxime groups, or so-called valence tautomerism in compounds containing aromatic moieties. Thus, a single compound may exhibit more than one type of isomerism.

[0121] All stereoisomers, geometric isomers and tautomers of the compounds of formula (I) are included within the scope of the present invention, including compounds exhibiting more than one type of isomerism, and mixtures of one or more thereof. Acid addition or base salts in which the counterion is optically active, such as d-lactate or l-lysine, or racemic, such as d-tartrate or d / -arginine, are included within the scope of the present invention.

[0122] Cis / trans isomers may be separated by conventional techniques well known to those skilled in the art, such as chromatography and fractional crystallization.

[0123] Conventional techniques for preparing / isolating individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of the racemate (or a racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC).

[0124] Alternatively, the racemate (or racemic precursor) can be reacted with a suitable optically active compound, for example an alcohol, or, if the compound of formula (I) contains an acidic or basic moiety, with a base or acid, such as 1-phenylethylamine or tartaric acid. The resulting diastereomeric mixture can be separated by chromatography and / or fractional crystallization, and one or both of the diastereoisomers can be converted to the corresponding pure enantiomer by means well known to those skilled in the art.

[0125] The chiral compounds of the invention (and their chiral precursors) can be obtained in enantiomerically enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of 0-50% by volume isopropanol, typically 2% to 20% by volume, and a hydrocarbon, typically heptane or hexane, containing 0-5% by volume of an alkylamine, typically 0.1% diethylamine. The eluate is concentrated to give the enriched mixture.

[0126] When either racemate crystallizes, two different types of crystals are possible: the first type is the racemate (true racemate) mentioned above, in which one homogeneous form of crystal is produced containing both enantiomers in equimolar amounts; the second type is the racemic mixture or conglomerate, in which two forms of crystals are produced, each containing a single enantiomer, in equimolar amounts.

[0127] Both crystalline forms present in a racemic mixture have identical physical properties, but may have different physical properties compared to the true racemate. Racemic mixtures can be separated by conventional techniques known to those skilled in the art - see, for example, Stereochemistry of Organic Compounds by EL Eliel and SH Wilen (Wiley, 1994).

[0128] The present invention includes all pharma- ceutically acceptable isotopically labeled compounds of formula (I) in which one or more atoms are replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominant in nature.

[0129] Examples of isotopes suitable for inclusion in the compounds of the invention include hydrogen isotopes, e.g., 2 H and 3 H and other carbon isotopes, e.g. 11 C. 13 C and 14 Chlorine isotopes such as C, e.g. 36 Fluorine isotopes such as Cl, e.g. 18 Iodine isotopes such as F, e.g. 123 I and 125 I and other nitrogen isotopes, e.g. 13 N and 15 N, etc., as well as oxygen isotopes, e.g., 15 O. 17 O and 18 Examples include O.

[0130] Certain isotopically labeled compounds of Formula I, such as those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotope tritium, i.e. 3 H, and carbon-14, i.e. 14 C are particularly useful for this purpose in view of their ease of incorporation and rapid means of detection.

[0131] Heavier isotopes, e.g., deuterium, i.e. 2 Substitution such as with H can confer certain therapeutic advantages resulting from greater metabolic stability, e.g., increased half-life in vivo or reduced dosage requirements, and therefore may be preferred in some circumstances.

[0132] Positron emitting isotopes, e.g. 11 C. 18 F, 15 O and 13Substitutions such as with N may be useful in positron emission tomography (PET) experiments to examine substrate receptor occupancy.

[0133] Isotopically labeled compounds of formula I can generally be prepared by conventional techniques known to those skilled in the art, or by analogous processes described in the accompanying examples and intermediates, substituting the appropriate isotopically labeled reagents previously utilized.

[0134] Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, eg, D2O, d6-acetone, d6-DMS, etc.

[0135] Pharmaceutical Compositions Pharmaceutical compositions suitable for the delivery of the compounds of the present invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation can be found, for example, in Remington's Pharmaceutical Sciences. 19th Edition (Mack Publishing Company, 1995).

[0136] The compounds of the present invention can be administered orally, which may involve swallowing, so that the compound enters the gastrointestinal tract, and / or buccal, lingual, or sublingual administration by which the compound enters the blood stream directly from the mouth.

[0137] Formulations suitable for oral administration include solid, semi-solid, and liquid systems, such as tablets; soft or hard capsules containing multiparticulates or nanoparticles, liquids, or powders; troches (including liquid-filled); chews; gels; fast dispersing dosage forms; films; ovules; sprays; and buccal / mucoadhesive patches.

[0138] Liquid formulations include suspensions, solutions, syrups and elixirs.Such formulations can be used as fillers for soft or hard capsules (e.g., made of gelatin or hydroxypropylmethylcellulose), and typically contain carriers such as water, ethanol, polyethylene glycol, propylene glycol, methylcellulose or suitable oils, and one or more emulsifiers and / or suspending agents.Liquid formulations can also be prepared by reconstitution of solids, for example, from sachets.

[0139] The compounds of the present invention may also be used in fast dissolving, fast disintegrating dosage forms as described in Expert Opinion in Therapeutic Patents, H (6), 981-986, by Liang and Chen (2001).

[0140] For tablet dosage forms, depending on the dose, the drug may comprise 1% to 80% by weight of the dosage form, more typically 5% to 60% by weight of the dosage form. In addition to the drug, tablets generally contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, lower alkyl substituted hydroxypropylcellulose, starch, pregelatinized starch, and sodium alginate. Generally, the disintegrant will comprise 1% to 25% by weight of the dosage form, preferably 5% to 20% by weight.

[0141] Binders are generally used to give tablet formulations adhesion.Suitable binders include microcrystalline cellulose, gelatin, sugar, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose.Tablets can also contain diluents such as lactose (monohydrate, spray-dried monohydrate, anhydrous, etc.), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch, and dibasic calcium phosphate dihydrate.

[0142] Tablets may also optionally include surfactants, such as sodium lauryl sulfate and polysorbate 80, and glidants, such as silicon dioxide and talc. If present, the surfactants may constitute 0.2% to 5% by weight of the tablet, and the glidants may constitute 0.2% to 1% by weight of the tablet.

[0143] Tablets also generally contain a lubricant such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulfate. Lubricants generally comprise from 0.25% to 10% by weight of the tablet, preferably from 0.5% to 3% by weight.

[0144] Other possible ingredients include antioxidants, colorants, flavorants, preservatives, and taste-masking agents.

[0145] Exemplary tablets contain up to about 80% drug, about 10% to about 90% binder, about 0% to about 85% diluent, about 2% to about 10% disintegrant, and about 0.25% to about 10% lubricant. Tablet blends may be compressed directly or by roller to form tablets. Tablet blends or portions of blends may alternatively be wet granulated, dry granulated, or melt granulated, melt congealed, or extruded prior to tableting. The final formulation may include one or more layers, may be coated or uncoated, and may further be encapsulated.

[0146] Tablet formulations are discussed in Pharmaceutical Dosage Forms: Tablets. Vol. 1, by H. Lieberman and L. Lachman (Marcel Dekker, New York, 1980).

[0147] Solid formulations for oral administration may be formulated to be immediate and / or modified release, including delayed-, sustained-, pulsed-, controlled-, targeted- and programmed-release.

[0148] Suitable modified release formulations for the purposes of the present invention are described in U.S. Patent No. 6,106,864. Details of other suitable release technologies, such as high energy dispersions, and osmotic and coated particles, can be found in Pharmaceutical Technology On-line. 25(2), 1-14, by Verma et al (2001). The use of chewing gum to achieve controlled release is described in WO 00 / 35298.

[0149] The compound of the present invention can also be administered parenterally, i.e. directly into bloodstream, muscle or internal organs.Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, ​​intrasternal, intracranial, intramuscular, intrasynovial and subcutaneous administration.Suitable devices for parenteral administration include needle (including microneedle) injector, needle-free injector and infusion technology.

[0150] Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably at a pH of 3 to 9), although for some applications parenteral formulations may be more suitably formulated as sterile nonaqueous solutions or as a dry form for use with a suitable vehicle such as sterile pyrogen-free water.

[0151] The preparation of parenteral formulations under sterile conditions, for example, by lyophilization, may be readily accomplished using standard pharmaceutical techniques well known to those skilled in the art.

[0152] The solubility of compounds of formula I used in the preparation of parenteral solutions may be increased by the use of appropriate formulation techniques, such as the incorporation of solubility-enhancing agents.

[0153] The preparation for parenteral administration may be formulated to be immediate and / or modified release.Modified release preparations include delayed release, sustained release, pulsed release, controlled release, targeted release and programmed release.Accordingly, the compound of the present invention can be formulated as a suspension or as a solid, semi-solid or thixotropic solution to be administered as an implanted depot that provides modified release of active compound.Examples of such preparations include drug-coated stents, and semi-solids and suspensions that contain drug-loaded poly([alpha]7-lactic-coglycolic)acid (PGLA) microspheres.

[0154] The compounds of the present invention can also be administered topically, (intra)dermally, or transdermally to the skin or mucosa. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages, and microemulsions. Liposomes can also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol, and propylene glycol. Penetration enhancers can also be incorporated--see, for example, J. Pharm. Sci., 88 (10), 955-958, by Finnin and Morgan (October 1999).

[0155] Other means of local administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free (eg Powderject™, Bioject™, etc.) injection.

[0156] Formulations for topical administration may be formulated to be immediate and / or modified release, including delayed-, sustained-, pulsed-, controlled-, targeted- and programmed release.

[0157] The compound of the present invention may be administered intranasally or by inhalation, typically in the form of dry powder from a dry powder inhaler (alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle mixed with phospholipids, such as phosphatidylcholine), as an aerosol spray from a pressurized container, pump, spray, atomizer (preferably an atomizer that uses electrohydrodynamics to generate a fine mist) or nebulizer, with or without a suitable propellant, such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane, or as nasal drops.For intranasal use, the powder may contain a bioadhesive agent, such as chitosan or cyclodextrin.

[0158] The pressurized container, pump, spray, atomizer, or nebulizer contains a solution or suspension of a compound of the invention, for example, with ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilizing, or sustained-release of the active agent, a propellant as a solvent, and an optional surfactant, e.g., sorbitan trioleate, oleic acid, or oligolactic acid.

[0159] Before use in a dry powder or suspension formulation, the drug is micronized to a size suitable for delivery by inhalation (typically less than 5 microns). This can be accomplished by any suitable comminuting method, such as spiral jet milling, fluidized bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization, or spray drying.

[0160] Capsules (e.g., made of gelatin or hydroxypropylmethylcellulose), blisters, and cartridges for use in inhalers or insufflators can be formulated to contain a powder mix of the compound of the present invention, a suitable powder base such as lactose or starch, and a performance modifier such as l-leucine, mannitol, or magnesium stearate.Lactose can be anhydrous or in the form of monohydrate, preferably the latter.Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose.

[0161] Suitable solution formulations for use in atomizers that use electrohydrodynamics to generate a fine mist can contain 1 μg to 20 mg of the compound of the invention per actuation, and actuation volumes can vary from 1 μl to 100 μl. A typical formulation can include a compound of formula I, propylene glycol, sterile water, ethanol, and sodium chloride. Alternative solvents that can be used in place of propylene glycol include glycerol and polyethylene glycol.

[0162] Suitable flavours, such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium, may be added to those formulations of the invention intended for inhaled / intranasal administration.

[0163] Formulations for inhaled / intranasal administration can be formulated to be immediate and / or modified release using, for example, PGLA. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted- and programmed-release.

[0164] The compounds of the invention may be administered rectally or vaginally, for example, in the form of a suppository, pessary, or enema. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate.

[0165] Formulations for rectal / vaginal administration may be formulated to be immediate and / or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted- and programmed release.

[0166] The compounds of the present invention may also be administered directly to the eye or ear, typically in the form of drops of micronized suspension or solution in isotonic pH-adjusted sterile saline.Other formulations suitable for eye and ear drops include ointments, gels, biodegradable (e.g., absorbent gel sponges, collagen, etc.) and non-biodegradable (e.g., silicone) implants, wafers, lenses, and microparticle or vesicular systems such as niosomes or liposomes.Polymers, such as crosslinked polyacrylic acid, poly(vinyl alcohol), hyaluronic acid, cellulose polymers, such as hydroxypropylmethylcellulose, hydroxyethylcellulose, or methylcellulose, or heteropolysaccharide polymers, such as gellan gum, can be incorporated with preservatives, such as benzalkonium chloride.Such formulations can also be delivered by iontophoresis.

[0167] Eye / ear drop formulations may be formulated to be immediate and / or modified release, including delayed-, sustained-, pulsed-, controlled-, targeted-, or programmed-release.

[0168] The compounds of the present invention may be combined with soluble polymeric substances, such as cyclodextrin and suitable derivatives thereof or polyethylene glycol-containing polymers, to improve their solubility, dissolution rate, taste masking, bioavailability and / or stability for use in any of the aforementioned modes of administration.

[0169] For example, drug-cyclodextrin complexes have been found to be generally useful for most dosage forms and routes of administration. Both inclusion and non-inclusion complexes can be used. As an alternative to direct complexation with drugs, cyclodextrins can be used as auxiliary additives, i.e., carriers, diluents, or solubilizers. The most commonly used for these purposes are α-, β-, and γ-cyclodextrins, examples of which can be found in WO 91 / 11172, WO 94 / 02518, and WO 98 / 55148.

[0170] Dosage For administration to human patients, the total daily dose of the compounds of the invention will typically range from 1 mg to 5000 mg, preferably from 10 mg to 2000 mg, more preferably from 50 mg to 1500 mg, even more preferably from 100 to 500 mg, depending, of course, on the mode of administration. The total daily dose can be administered in single or divided doses and, at the physician's discretion, may fall outside the typical ranges given herein.

[0171] These dosages are based on an average human subject weighing approximately 60 kg to 70 kg. Physicians can readily determine dosages for subjects whose weight falls outside this range, such as infants and the elderly.

[0172] For the avoidance of doubt, references herein to "treatment" include references to curative, palliative and prophylactic treatment.

[0173] combination According to another aspect of the present invention, (A) a compound of formula I, as defined herein, or a pharma- ceutically acceptable solvate or salt thereof; and (B) other therapeutic agents; A combination comprising:

[0174] The compounds of the invention can be combined with other therapeutic agents which are active against the disease or condition which they are intended to treat.

[0175] In one embodiment, the compounds of the invention are inhibitors of protein or lipid kinases (e.g., PIM family kinases such as PIM-1, PIM-2 and / or PIM-3) and / or may be combined with other therapeutic agents that are useful in the treatment of cancer and / or proliferative diseases. The compounds of the invention may also be combined with other therapies (e.g., radiation).

[0176] For example, the compounds of the present invention may be combined with one or more treatments independently selected from surgery, one or more anti-cancer / anti-neoplastic / anti-tumor agents, one or more hormonal therapeutic agents, one or more antibodies, one or more immunotherapeutic agents, radioactive iodine therapeutic agents, and radiation therapy.

[0177] More specifically, the compounds of the invention may be combined with agents that modulate the Ras / Raf / Mek pathway (e.g., inhibitors of MEK), the Jak / Stat pathway (e.g., inhibitors of Jak), the PI3K / Akt pathway (e.g., inhibitors of Akt, PI3K, mTOR), the DNA damage response mechanisms (e.g., inhibitors of ATM or ATR), or the stress signaling pathways (inhibitors of p38 or NF-κB).

[0178] For example, the compounds of the invention may be combined with: (i) targeted kinase inhibitors; (ii) tyrosine kinase inhibitors, such as acalabrutinib, adavosertib, afatinib, aflibercept, axitinib, bafetinib, bosutinib, crizotinib, dasatinib, erlotinib, evobrutinib, fenebrutinib, gefitinib, ibrutinib, imatinib, lapatinib, larotrectinib, nilotinib, pazopanib, ponatinib, pirtobrutinib, regorafenib, ruxolitinib, sorafenib, spebrutinib, sunitinib, tepotinib, tirabrutinib, trebrutinib, vandenatinib, or zanubrutinib; (iii) Akt or PI3-K inhibitors, e.g. pictilisib, dactolisib (BEZ235), copanlisib, duvelisib, ambralisib, alpelisib, zandelisib, parsaclisib or buparlisib; (iv) Flt-3 inhibitors; (v) BCL-2 inhibitors, such as oblimersen, navitoclax, or venetoclax; (vi) Therapeutic monoclonal antibodies, such as adalimumab, alemtuzumab, atezolizumab, AMP-224, AMP-514, AUNP12, avelumab, bevacizumab, BMS-986169, CA-170, camrelizumab, certolizumab pegol, cemiplimab, cetuximab, cosibelimab, denosumab, dostallimab, durubralumab, gemtuzamab ozogamicin, golimumab, ibritumomab tiuxetan (ibritumomab tiuexetan, ilipimumab, infliximab, nivolumab, ofatunumab, panitumumab, pembrolizumab, pertuzumab, rituximab, sintilimab, spartalizumab, tiselizumab, toripalimab, tositumomab or trastuzumab; (vii) MEK inhibitors, e.g., cobimetinib, selumetinib, mirdametinib (PD-0325901), trametinib, binimetinib, or TAK-733; (vii) BRaf inhibitors, e.g., encorafenib, dabrafenib, vemurafenib, or GDC-0879; (viii) Anthracyclines, such as daunorubicin, doxorubicin, epirubicin, idarubicin, mitoxantrone, or valrubicin; (ix) Taxanes, such as cabazitaxel, paclitaxel or docetaxel; (x) a platin, e.g., carboplatin, cisplatin, nedaplatin, or oxaliplatin; (xi) Nucleotide analogues, such as azacitidine, capecitabine, carmofur, cladribine, clofarabine, cytarabine, decitabine, floxuridine, 5-fluorouracil, gemcitabine, mercaptopurine, nelarabine, pentostatin, tegafur or thioguanine; (xii) Alkylating agents, such as bendamustine, busulfan, carmustine, chlorambucil, chlormethine, cyclophosphamide, dacarbazine, folemustine, ifosfamide, lomustine, melphalan, streptozotocin or temozolomide; (xiii) Hormonal therapeutic agents, for example estrogen receptor antagonists, such as tamoxifen; (xiv) antitumor compounds with potential radiosensitizing and / or chemosensitizing effects, such as chloroquine; (xv) mTOR inhibitors, such as sirolimus (rapamycin), everolimus, ridaforolimus, or temsirolimus; (xvi) JAK inhibitors, such as ruxolitinib, itacitinib, tofacitinib, oclacitinib, barictinib, peficitinib, fedratinib, upadacitinib, filgotinib, deglocitinib, celduratinib, gandotinib, lestaurtinib, momelotinib, pacritinib, abrocitinib, deuclavacitinib, CHZ868 or cucurbitacin; (xvii) a cyclin-dependent kinase inhibitor, e.g., a CDK6 or CDK4 inhibitor, such as palbociclib (PD-0332991), ribociclib, abemaciclib, or trilaciclib; (xviii) agents that modulate DNA damage response mechanisms and / or stress signaling pathways, e.g., inhibitors of ATM or ATR, inhibitors of p38 and / or NF-κB; (xix) MCL-1 inhibitors, such as omacetaxine mepecate or seliclilib; (xx) KRAS inhibitors, such as sotorasib (AMG510), adagrasib (MRTX849) or ARS-3248; (xxi) Antiandrogens, such as cyproterone acetate, flutinamide, nilutamide, bicalutamide or enzalutamide; (xxii) TNF inhibitors, such as some of the monoclonal antibodies listed above, as well as etanercept, pentoxifylline and bupropion; or (xxiii) Steroids, such as prednisolone, methylprednisolone, dexamethasone or hydrocortisone.

[0179] According to a further aspect of the present invention, (A) a compound of the invention as defined above; and (B) another therapeutic agent useful in the treatment of cancer and / or proliferative diseases, Combination products are provided in which each of components (A) and (B) is formulated in admixture with a pharma- ceutically acceptable adjuvant, diluent or carrier.

[0180] Such combination products administer a compound of the invention in combination with another therapeutic agent and thus may be provided as separate formulations, at least one of which contains a compound of the invention and at least one of which contains the other therapeutic agent, or may be provided (i.e., formulated) as a combined preparation (i.e., provided as a single formulation containing a compound of the invention and the other therapeutic agent).

[0181] Therefore, it is further provided that: (1) a pharmaceutical formulation comprising a compound of the invention as defined above, another therapeutic agent useful in the treatment of cancer and / or a proliferative disease, and a pharma- ceutically acceptable adjuvant, diluent or carrier; and (2) A kit of parts comprising: (a) a pharmaceutical formulation comprising a compound of the invention as defined above, in admixture with a pharma- ceutically acceptable adjuvant, diluent or carrier; and (b) a pharmaceutical formulation comprising another therapeutic agent useful in the treatment of cancer and / or a proliferative disease in admixture with a pharma- ceutically acceptable adjuvant, diluent or carrier; A kit-of-parts, in which each of these components (a) and (b) is provided in a form suitable for administration in combination with the other.

[0182] In particularly preferred aspects of the invention, the compounds of the invention can be combined with other therapeutic agents (e.g., chemotherapeutic agents) for use as medicines (e.g., for use in the treatment of diseases or conditions described herein, such as those in mammals, particularly humans, where inhibition of cancer cell growth is necessary and / or desirable, e.g., for treating hyperproliferative disorders such as cancer (e.g., certain cancers that may be mentioned herein, e.g., in the Examples). Combining such active ingredients may produce synergistic effects.

[0183] The present invention further provides a process for preparing a combination product as defined above, which comprises bringing into association a compound of the invention as defined above, or a pharma- ceutically acceptable ester, amide, solvate or salt thereof, with other therapeutic agents useful in the treatment of cancer and / or proliferative diseases, and at least one pharma- ceutically acceptable adjuvant, diluent or carrier.

[0184] By "associated" it is meant that two components are combined with one another in a manner suitable for administration.

[0185] Thus, with respect to the above-defined process for preparing a kit-of-parts, by "associating" two components with each other, the two components of the kit-of-parts are (i) may be provided as separate formulations (i.e., independent of each other) and then combined for use with each other in a combination therapy; or (ii) may be packaged and provided together as separate components of a "combination pack" for use with each other in a combination therapy This includes:

[0186] The compounds of the present invention can also be combined with other therapeutic agents useful for treating diseases other than cancer. For example, in the treatment of autoimmune or inflammatory diseases, the compounds of the present invention can also be combined with other therapeutic agents useful for treating such diseases.

[0187] According to a further aspect of the present invention, (A) a compound of the invention as defined above; and (B) another therapeutic agent useful in the treatment of inflammatory and / or autoimmune diseases, Combination products are provided in which each of components (A) and (B) is formulated in admixture with a pharma- ceutically acceptable adjuvant, diluent or carrier.

[0188] Therefore, it is further provided that: (1) a pharmaceutical formulation comprising a compound of the invention as defined above, another therapeutic agent useful in the treatment of inflammatory and / or autoimmune diseases, and a pharma- ceutically acceptable adjuvant, diluent or carrier; and (2) A kit of parts comprising: (a) a pharmaceutical formulation comprising a compound of the invention as defined above, in admixture with a pharma- ceutically acceptable adjuvant, diluent or carrier; and (b) a pharmaceutical formulation comprising another therapeutic agent useful in the treatment of inflammatory and / or autoimmune diseases in admixture with a pharma- ceutically acceptable adjuvant, diluent or carrier; A kit-of-parts, in which each of these components (a) and (b) is provided in a form suitable for administration in combination with the other.

[0189] Examples of therapeutic agents useful in the treatment of autoimmune diseases include: (i) Nonsteroidal anti-inflammatory drugs (NSAIDs). Examples include salicylates, such as aspirin (acetylsalicylic acid), diflunisal (Dolobid), salicylic acid and its salts, salsalate (Disalcid); propionic acid derivatives, such as ibuprofen, dexbuprofen, naproxen, fenoprofen, ketoprofen, dexketoprofen, flurbiprofen, oxaprozin, loxoprofen, perbiprofen, and zaltoprofen; acetic acid derivatives, such as indomethacin, tolmetin, sulindac; ethanol. dolac; ketorolac; diclofenac; aceclofenac; bromfenac and nabumetone; enolic acid (oxicam) derivatives, such as piroxicam; meloxicam; tenoxicam; droxicam; lornoxicam or phenylbutazone; anthranilic acid derivatives (fenamates), such as mefenamic acid, meclofenamic acid, flufenamic acid, and tolfenamic acid; or selective COX-2 inhibitors (coxibs), such as celecoxib, parecoxib, lumiracoxib, or etoricoxib; (ii) glucocorticoids, e.g., prednisone, hydrocortisone, and budesonide; (iii) Disease-modifying antirheumatic drugs (DMARDs), such as abatacept, adalimumab, alefacept, anakinra, apremilast, azathioprine, baricitinib, certolizumab pegol, chloroquine, cyclosporine, D-penicillamine, efalizumab, etanercept, filgotinib, golimumab, guselkumab, hydroxychloroquine, infliximab, leflunomide, methotrexate, 6-mercaptopurine, rituximab, sariluman, sulfasalazine, tocilizumab, tofacitinib, and ustekinumab; (iv) cyclosporine; (v) topical calcineurin inhibitors, e.g., tacrolimus, and pimecrolimus; (vi) anti-CD20 antibodies, such as rituximab, ocrelizumab, obinutuzumab, ofatumumab, ibritumomab tiuxetan, tositumomab, and ublituximab; (vii) interleukin-17 inhibitors, e.g., secukinumab, ixekizumab, and brodalumab; (vii) IFN receptor agonists, e.g., emapalumab; (viii) B-cell activating factor inhibitors, e.g., belimumab; (ix) Gold compounds, such as sodium aurothiomalate.

[0190] Examples of therapeutic agents useful for treating inflammatory diseases include those listed above for treating autoimmune diseases, as well as immunoselective anti-inflammatory derivatives (ImSAIDS), such as the tripeptide FEG (Phe-Glu-Gly) and its D-isomer form feG.

[0191] The compounds of the invention may have the advantage of being effective inhibitors of protein or lipid kinases (e.g., PIM family kinases such as PIM-1, PIM-2, and / or PIM-3). Advantageously, when the compounds of the invention are used in combination with known chemotherapeutic agents (such as those described herein), the components of the combination may act synergistically.

[0192] The compounds of the invention, whether used for the above indications or not, may also have the advantage that they are more effective, less toxic, have a longer duration of action, are more potent, have fewer side effects, are more easily absorbed, and / or have a more favorable pharmacokinetic profile (e.g., higher oral bioavailability and / or lower clearance), and / or have other useful pharmacological, physical, or chemical properties than compounds known in the prior art.

[0193] Medical Uses and Methods of Treatment The compounds of the invention are indicated as medicaments. According to a further aspect of the invention there is provided a compound of the invention as defined above for use as a medicament.

[0194] The compounds of the invention are capable of inhibiting protein or lipid kinases, such as PIM family kinases, such as PIM-1, PIM-2, and / or PIM-3, for example, as can be shown in the tests described below and / or known to those skilled in the art. Thus, the compounds of the invention may be useful in treating disorders in individuals in which inhibition of such protein or lipid kinases (e.g., PIM family kinases, such as PIM-1, PIM-2, and / or PIM-3) is desired and / or required.

[0195] The term "inhibition" may refer to a measurable reduction and / or disruption of catalytic kinase (e.g., PIM family kinases such as PIM-1, PIM-2, and / or PIM-3) activity. Reduction and / or disruption of kinase activity can be measured by comparing the kinase activity of a sample containing a compound of the invention to an equivalent sample of the kinase (e.g., PIM family kinases such as PIM-1, PIM-2, and / or PIM-3) in the absence of a compound of the invention, as will be apparent to one of skill in the art. A measurable change can be objective (e.g., measurable by some test or marker, e.g., in an in vitro or in vivo assay or test as described below, or in another suitable assay or test known to one of skill in the art) or subjective (e.g., the subject shows an indication of or feels an effect).

[0196] Compounds of the invention may be found to exhibit 50% inhibition of protein or lipid kinases (e.g. PIM family kinases such as PIM-1, PIM-2 and / or PIM-3) at concentrations of 100 μM or less (e.g. less than 50 μM, or even less than 10 μM, for example less than 1 μM) when tested, for example, in an assay (or other test) as described below or in another suitable assay or test known to the skilled artisan.

[0197] Thus, the compounds of the invention are expected to be useful in treating disorders characterized by or associated with an increase in the overall activity of a protein or lipid kinase (e.g., a PIM family kinase such as PIM-1, PIM-2, and / or PIM-3) in which a protein or lipid kinase is known to play a role (e.g., by increasing the amount of the kinase or increasing the catalytic activity of the kinase). The compounds of the invention (alone or in combination with other active agents) may be shown to be active, for example, in a biochemical assay described herein, may be shown to have predictive activity, for example, based on a phosphorylation assay described herein, and / or may reduce the rate of cell proliferation, as may be shown, for example, in a cell proliferation assay described herein (e.g., using a cancer cell line (e.g., a commercially known one) such as those described herein).

[0198] Thus, the compounds of the invention are expected to be useful in treating diseases / disorders resulting from abnormal cell growth, function, or behavior associated with protein or lipid kinases (e.g., PIM family kinases such as PIM-1, PIM-2, and / or PIM-3), including cancer, immune disorders, cardiovascular disease, viral infections, inflammation, metabolic / endocrine dysfunction, and neurological disorders.

[0199] Thus, disorders / conditions which the compounds of the invention may be useful in treating include cancer (such as lymphoma, solid tumors, or cancers described below), obstructive airways disease, allergic diseases, inflammatory diseases (such as asthma, allergies, and inflammatory bowel diseases such as colitis and Crohn's disease), immunosuppression (such as transplant rejection), inflammatory and autoimmune diseases, e.g., rheumatoid arthritis, psoriasis, psoriatic arthritis, osteoarthritis, ankylosing spondylitis, atopic dermatitis, inflammatory bowel diseases such as ulcerative colitis and Crohn's disease, systemic lupus erythematosus, lupus nephritis, multiple sclerosis, peanut allergy, asthma, and celiac disease), disorders commonly associated with organ transplants, AIDS-related diseases, and other related diseases. Other relevant diseases that may be mentioned (especially due to the important role of kinases in regulating cell proliferation) include other cell proliferation disorders and / or non-malignant diseases, such as benign prostatic hyperplasia, familial adenomatous polyposis, neurofibromatosis, bone disorders, atherosclerosis, vascular smooth cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthritis, glomerulonephritis, postoperative stenosis and restenosis. Other disease states that may be mentioned include cardiovascular diseases, stroke, diabetes, hepatomegaly, Alzheimer's disease, cystic fibrosis, hormone-related diseases, immune deficiency disorders, destructive bone disorders, infections, conditions associated with cell death, thrombin-induced platelet aggregation, chronic myeloid leukemia, liver diseases, pathological immune conditions with T-cell activation and CNS disorders, pulmonary arterial hypertension (PAH), chronic obstructive pulmonary disease (COPD), sepsis, systemic sclerosis (scleroderma), type 1 diabetes, and hidradenitis suppurativa.

[0200] According to a further aspect of the invention there is provided a compound of the invention as defined above for use in the treatment of cancer.

[0201] According to a further aspect of the invention there is provided the use of a compound of the invention as defined above in the manufacture of a medicament for the treatment of cancer.

[0202] According to a further aspect of the present invention there is provided a method of treating cancer which comprises administering to a patient suffering from or susceptible to such a condition a therapeutically effective amount of a compound of the present invention as defined above.

[0203] According to a further aspect of the invention there is provided a compound of the invention as defined above for use in the treatment of cancer.

[0204] As mentioned above, the compounds of the present invention may be useful in the treatment of cancer. More specifically, the compounds of the present invention may therefore be useful in the treatment of a variety of cancers, including, but not limited to, the following cancers: bladder, breast, colon, kidney, liver, lung (including non-small cell and small cell lung), esophageal, gallbladder, ovarian, pancreatic, stomach, cervical, thyroid, prostate, skin, squamous cell carcinoma, testicular, genitourinary tract, laryngeal, glioblastoma, neuroblastoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, bone, adenoma, adenocarcinoma, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder, liver and biliary tract, kidney, bone marrow disorders, lymphatic disorders, hairy cell, buccal cavity and pharynx (oral cavity), lips, tongue, oral , pharynx, small intestine, colorectum, large intestine, rectum, brain and central nervous system, Hodgkin's disease and leukemia; hematopoietic tumors of the lymphatic system, such as leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, mantle cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma and Burkitt's lymphoma; hematopoietic tumors of the myeloid system, such as acute and chronic myeloid leukemia, myelodysplastic syndromes, and promyelocytic leukemia; mesenchymal tumors, such as fibrosarcoma and rhabdomyosarcoma; tumors of the central and peripheral nervous system, such as astrocytoma, neuroblastoma, glioma, and neurilemmoma; and other tumors, such as melanoma, seminoma, teratoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma, follicular thyroid carcinoma, and Kaposi's sarcoma.

[0205] According to a further aspect of the invention there is provided the use of a compound of the invention as defined above in the manufacture of a medicament for the treatment of an autoimmune or inflammatory disease.

[0206] According to a further aspect of the invention there is provided a method for the treatment of an autoimmune or inflammatory disease which comprises administering to a patient suffering from or susceptible to such a condition a therapeutically effective amount of a compound of the invention as defined above.

[0207] According to a further aspect of the invention there is provided a compound of the invention as defined above for use in the treatment of an autoimmune or inflammatory disease.

[0208] Examples of autoimmune and / or inflammatory diseases include, but are not limited to, celiac disease, psoriasis, inflammatory bowel disease, such as colitis and Crohn's disease, multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, aplastic anemia, myocarditis, autoimmune hepatitis, primary biliary cholangitis, alopecia areata, autoimmune urticaria, pemphigus vulgaris, and the like. vulgaris), autoimmune polyendocrine syndrome (APS), autoimmune pancreatitis, type 1 diabetes mellitus, autoimmune thyroiditis, Sjögren's syndrome, autoimmune hemolytic anemia, gastritis vasculitis, polyangiitis granulomatosis, autoimmune uveitis, myasthenia gravis, acute disseminated encephalomyelitis, relapsing polychondritis, Lambert-Eaton myasthenic syndrome, Hashimoto's encephalopathy, Felty's syndrome, autoimmune thyroiditis, Graves' disease, nephritis, bullous pemphigoid, dermatitis, epidermolysis bullosa acquisita, linear IgA disease, autoimmune lymphoproliferative syndrome, autoimmune neutropenia, autoimmune thrombocytopenic purpura, cold agglutinin disease, Evans' syndrome, pernicious anemia, Still's disease, psoriatic arthritis, rheumatic fever, Guillain-Barré syndrome, Ord's thyroiditis thyroiditis, ankylosing spondylitis, atopic dermatitis, systemic sclerosis (scleroderma), hidradenitis suppurativa, lupus nephritis, peanut allergy, and asthma.

[0209] In addition, protein kinases or lipid kinases (e.g., PIM family kinases such as PIM-1, PIM-2, and / or PIM-3) may also be involved in the proliferation of viruses and parasites. Protein kinases or lipid kinases may also play a key role in the pathogenesis and development of neurodegenerative disorders. Thus, the compounds of the present invention may also be useful in the treatment of viral conditions, parasitic conditions, and neurodegenerative disorders.

[0210] The compounds of the invention are indicated for both the therapeutic and / or prophylactic treatment of the above mentioned conditions.

[0211] According to a further aspect of the present invention, there is provided a method for treating a disease (e.g., a cancer or other disease as described herein) associated with desired and / or required inhibition of a protein or lipid kinase (e.g., a PIM family kinase such as PIM-1, PIM-2, and / or PIM-3) (e.g., a disease / disorder resulting from abnormal cell growth, function or behavior associated with a protein or lipid kinase (e.g., a PIM family kinase such as PIM-1, PIM-2, and / or PIM-3)), which comprises administering to a patient suffering from or susceptible to such a condition a therapeutically effective amount of a compound of the present invention as defined above.

[0212] A "patient" includes mammalian (including human) patients. Thus, the methods of treatment discussed above can include treatment of the human body or the animal body.

[0213] The term "effective amount" refers to that amount of a compound that confers a therapeutic effect on the treated patient. The effect may be objective (e.g., measurable by some test or marker) or subjective (e.g., the subject gives an indication of or feels an effect).

[0214] Abbreviation In the following sections, the following abbreviations are used: 1,2-DCE 1,2-dichloroethane ATP Adenosine Triphosphate DCM Dichloromethane EtOAc Ethyl acetate Et3N Triethylamine h time min HPLC High Performance Liquid Chromatography MeOH Methanol mw Microwave nBuOH n-Butanol NMR nuclear magnetic resonance AcCN Acetonitrile rt room temperature c-Hex Cyclohexane DMSO Dimethyl sulfoxide EtOH Ethanol AcOH Acetic acid Rt retention time LCMS Liquid Chromatography Mass Spectrometry ESI Electrospray Ionization p-TsOH p-Toluenesulfonic acid Et2O Diethyl ether THF Tetrahydrofuran Pd2dba3 Tris(dibenzylideneacetone)-dipalladium(0) Xantphos (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) HEPES 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid EGTA Ethylene glycol bis(β-aminoethyl ether)-N,N,N',N'-tetraacetic acid DMEM Dulbecco's modified Eagle's medium.

[0215] The following examples illustrate the invention. The preparation of intermediates is described in the Intermediates section below.

[0216] Intermediates Intermediate 1: 5-chloro-3-(4-fluoro-3-trifluoromethylphenyl)-6-methyl-7,8-dihydro-6H-9-oxa-1,2,3a,4,6-pentaazacyclopenta[a]naphthalene

[0217] [ka] 5,8-Dichloro-4-methyl-3,4-dihydro-2H-pyridazino[4,5-b][1,4]oxazine (intermediate 12 disclosed in WO 2011 / 080510) (9 g, 41 mmol) and 4-fluoro-3-trifluoromethylbenzoic acid hydrazide (intermediate 7) (13.6 g, 61 mmol) were heated in nBuOH (180 ml) at 170 °C for 20 h. The red-black mixture was concentrated in vacuo and the residue was purified by automated flash chromatography (SiO2, eluent c-Hex / EtOAc 75:25 to 0:100) to give the desired regioisomer intermediate 1 (2.51 g, 16% yield). LCMS1 (ESI): Rt = 5.7 min, m / z = 388.20 [M+ H] + . 1 H NMR (300 MHz, DMSO-d6) δ 8.72 (m, 2H), 7.89 (t, J = 9.6 Hz, 1H), 4.60 (t, J = 4.0 Hz, 2H), 3.34 (m, 3H), 2.91 (s, 3H).

[0218] Intermediate 2: 4-Allyloxy-3,6-dichloropyridazine

[0219] [ka] 3,4,6-Trichloropyridazine (7.5 g, 40.889 mmol) and Cs2CO3 (1.6 equiv., 69.51 mmol, 22.65 g) were mixed in acetonitrile (182 mL) and then heated at 65 °C. Allyl alcohol (1.5 equiv., 61.33 mmol, 4.171 mL) was added dropwise. The mixture was heated at 65 °C for 1 h, after which the solvent was concentrated under vacuum. The residue was taken up in DCM-water. The layers were separated and the organic phase was washed with brine, dried (Na2SO4) and concentrated under vacuum. The crude product was purified by flash chromatography (SiO2, eluent 0-50% EtOAc in cyclohexane) to give 4-allyloxy-3,6-dichloropyridazine, intermediate 2 (3.451 g, 41% yield), as a white solid. 1 H NMR (300 MHz, chloroform-d) δ 6.92 (s, 1H), 6.03 (ddt, J = 17.3, 10.5, 5.3 Hz, 1H), 5.59 - 5.37 (m, 2H), 4.72 (dt, J = 5.3, 1.5 Hz, 2H).

[0220] Intermediate 3: 8-Allyloxy-6-chloro-3-(3-trifluoromethoxyphenyl)-[1,2,4]triazolo[4,3-b]pyridazine

[0221] [ka] Intermediate 2 (3.451 g, 16.8 mmol) and 3-trifluoromethoxybenzoic acid hydrazide (CAS321195-88-4, available from Apollo Scientific as PC061) (4.076 g, 18.51 mmol, 1.1 mmol) were dissolved in dioxane (50 mL) and p-TsOH (3.201 g, 16.83 mmol, 1.0 equiv) was added. The mixture was refluxed for 4 h. Dioxane was removed in vacuo and the residue was taken up in DCM and a saturated aqueous solution of NaHCO3. The layers were separated and the organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, eluent c-Hex-EtOAc, 0-50% EtOAc) to give intermediate 3 (0.576 g, 9% yield) as a white solid. 1 H NMR (300 MHz, CDCl3) δ 8.44 (dt, J = 7.9, 1.3 Hz, 1H), 8.39 (m 1H), 7.59 (t, J = 8.1 Hz, 1H), 7.42 - 7.34 (m, 1H), 6.48 (s, 1H), 6.13 (ddt, J = 17.2, 10.9, 5.6 Hz, 1H), 5.64 - 5.43 (m, 2H), 5.02 (dt, J = 5.6 Hz, 0.9 Hz, 2H).

[0222] Intermediate 4: 7-Allyl-6-chloro-3-(3-trifluoromethoxyphenyl)-[1,2,4]triazolo[4,3-b]pyridazin-8-ol

[0223] [ka] Intermediate 3 (576 mg, 1.54 mmol) in 1,2-DCE (10 mL) in a microwave vial was heated at 165° C. under microwave irradiation for 1 h. A precipitate was observed in the reaction mixture. The solvent was removed under vacuum and the solid was filtered and washed with Et2O to give Intermediate 4 (0.329 g, 57% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ: 8.79 (dt, J = 7.9, 1.2 Hz, 1H), 8.41 (m, 1H), 7.64 (t, J = 8.1 Hz, 1H), 7.35 (m, 1H), 5.8 (m, 2H), 5.2-5.07 (m, 2H), 3.69 (m, 2H).

[0224] Intermediate 5: 6-chloro-7-(3-hydroxypropyl)-3-(3-trifluoromethoxyphenyl)-[1,2,4]triazolo[4,3-b]pyridazin-8-ol

[0225] [ka] Borane-dimethylsulfide complex (2M in THF, 1.84 mL) was added to a suspension of intermediate 4 (0.329 g, 0.887 mmol) in dry THF (20 mL) at 0° C., and the mixture was stirred overnight. The reaction was carefully quenched with water at 0° C., and sodium perborate (683 mg) was added. Stirring was continued at room temperature for 2.5 h. The mixture was acidified with 1 M aqueous HCl, then extracted with EtOAc. The organic layer was dried (Na2SO4) and concentrated to give the following product: a mixture of intermediate 5 and its isomer 6-chloro-7-(2-hydroxypropyl)-3-(3-trifluoromethoxyphenyl)-[1,2,4]triazolo[4,3-b]pyridazin-8-ol as a white solid (0.420 g), which was used as such in the next reaction step. LCMS (ESI): Rt = 4.98 and 5.1 min, m / z = 389.02 [M+H] + .

[0226] Intermediate 6: 5-chloro-3-(3-trifluoromethoxyphenyl)-7,8-dihydro-6H-9-oxa-1,2,3a,4-tetraaza-cyclopenta[a]naphthalene

[0227] [ka] To a suspension of the isomeric mixture containing intermediate 5 (0.420 g; 1.08 mmol, 1.0 equiv) in DCM (10 mL) was added Vilsmeier reagent (0.207 g, 1.62 mmol, 1.5 equiv) at room temperature. After 10 min, a solution was obtained, Et3N (0.753 mL) was added, and the mixture was stirred overnight. The solvent was removed under vacuum and the crude product was purified by column chromatography to separate both isomers (SiO2, eluent 0-4% MeOH in DCM) to give intermediate 6 (0.243 g, 60% yield) as a yellow solid. 1 H NMR (300 MHz, CDCl3) δ 8.42 (m, 1H), 8.38 (s, 1H), 7.57 (dd, t, J = 8.1 Hz, 1H), 7.35 (m, 1H), 4.55 (m, 2H), 2.80 (t, J = 6.4 Hz, 2H), 2.24 (m, 2H).

[0228] Intermediate 7: 4-Fluoro-3-trifluoromethylbenzoic acid hydrazide

[0229] [ka] A mixture of 4-fluoro-3-(trifluoromethyl)benzoic acid (15 g, 72 mmol) and SOCl2 (10.5 mL, 144 mmol) was heated to reflux for 2 h (80 °C). The reaction mixture was concentrated under vacuum; the residue was dissolved in toluene and evaporated under reduced pressure to give the crude product 4-fluoro-3-trifluoromethylbenzoyl chloride, which was dried under vacuum overnight and then used without further purification. 4-Fluoro-3-trifluoromethyl-benzoyl chloride dissolved in DCM (45 mL) was added dropwise to a solution of N2H4H2O (9.6 mL) in anhydrous DCM (45 mL) at 0 °C and the reaction temperature was allowed to reach room temperature over 2 h. The solvent was removed and the white residue was added with hot water to give a precipitate, which was filtered and washed with more hot water. The white solid was dried overnight in a fume hood to give a white solid. The water was extracted with DCM and the organic phase was dried over MgSO4, filtered and dried to give 4-fluoro-3-trifluoromethyl-benzoic acid hydrazide compound (1.34 g). Excess yield (2 steps) 61%. 1 H NMR (300 MHz, DMSO) δ 10.05 (s, 1H), 8.29 - 7.96 (m, 2H), 7.63 (t, J = 9.7 Hz, 1H), 4.62 (s, 2H). EXAMPLES

[0230] [Example 1] 1-Methyl-4-[6-methyl-3-(3-trifluoromethoxyphenyl)-7,8-dihydro-6H-9-oxa-1,2,3a,4,6-pentaazacyclopenta[a]naphthalen-5-ylamino]cyclohexanol

[0231] [ka] A deoxygenated solution of 5-chloro-6-methyl-3-(3-trifluoromethoxyphenyl)-7,8-dihydro-6H-9-oxa-1,2,3a,4,6-pentaazacyclopenta[a]naphthalene (disclosed as intermediate 18 in WO 2011 / 080510) (0.5 g; 1.296 mmol), cis-4-amino-1-methylcyclohexanol (0.251 g; 1.94 mmol), NaOtBu (0.224 g; 2.33 mmol), Xantphos (0.075 g; 0.13 mmol), and Pd2dba3 (0.059 g; 0.065 mmol) in dioxane (2.0 mL) was heated at 100° C. for 1 h under microwave conditions. The reaction was carried out in 9 batches of 500 mg of intermediate. The different batches were combined and the solvent was removed under vacuum. The crude product was purified by column chromatography (SiO2, eluent 0-8% MeOH-NH3 in DCM) and then triturated with EtOAc to give Example 1 (1.880 g, 34% yield) as a white solid. LCMS1 (ESI): Rt = 5.49 min, m / z = 479.02 [M+ H] + . 1 H NMR (300 MHz, CDCl3) δ 8.61 (s, 1H), 8.47 (d, J = 8.0 Hz, 1H), 7.52 (t, J = 8.1 Hz, 1H), 7.29 (m, 1H), 4.96 (d, J = 7.1 Hz, 1H), 4.47 (m, 2H), 3.80 (m, 1H), 3.20 (m, 2H), 2.73 (s, 3H), 2.07 (m, 2H), 1.71 (m, 6H), 1.31 (s, 3H).

[0232] [Example 2] 4-[3-(4-fluoro-3-trifluoromethylphenyl)-6-methyl-7,8-dihydro-6H-9-oxa-1,2,3a,4,6-pentaaza-cyclopenta[a]naphthalen-5-ylamino]-1-methylcyclohexanol

[0233] [ka] Intermediate 1 (1 g, 2.58 mmol) was dissolved in n-BuOH (12.5 mL) and Et3N (1.1 mL; 7.74 mmol) and cis-4-amino-1-methylcyclohexanol (1 g; 7.74 mmol) were added. The mixture was heated to 180 °C in a pressure tube. After stirring overnight, the reaction was stopped and the solvent was evaporated to give a residue which was purified by automated flash chromatography (SiO2, eluent DCM / MeOH 100-96:4) to give Example 2 as a white solid (444 mg, 36% yield). LCMS1 (ESI): Rt = 5.5 min, m / z =481.02 [M+ H] + . 1 H NMR (300 MHz, DMSO) δ 8.97 (d, J = 5.7 Hz, 1H), 8.67 (m, 1H), 7.71 (t, J = 12 Hz, 1H), 6.25 (d, J = 7.5 Hz, 1H), 4.43 (t, J = 3.9 Hz, 2H), 4.09 (s, 1H), 3.68 (m, 1H), 3.20 (m, 2H), 2.66 (s, 3H), 1.81 (m, 4H), 1.61 (m, 2H), 1.36 (m, 2H), 1.14 (s, 3H).

[0234] [Example 3] 1-Methyl-4-[3-(3-trifluoromethoxyphenyl)-7,8-dihydro-6H-9-oxa-1,2,3a,4-tetraaza-cyclopenta[a]naphthalen-5-ylamino]cyclohexanol

[0235] [ka] A solution of intermediate 6 (0.243 g; 0.655 mmol), cis-4-amino-1-methyl-cyclohexanol (0.254 g; 1.96 mmol, 3.0 equiv.) and Et3N (183 μl, 2.0 equiv.) in n-BuOH (8.0 mL) was heated to 185 °C in an oil bath. The solvent was removed under vacuum and the crude product was purified by column chromatography (SiO2, 0-6% MeOH-NH3 in DCM) to give the desired product of Example 3 (50 mg, 16% yield). LCMS1 (ESI): Rt = 5.547 min, m / z = 464.20 [M+ H] + . 1 H NMR (300 MHz, DMSO-d6) δ 8.67 (s, 1H), 8.42 (d, J = 8.1 Hz, 1H), 7.70 (t, J = 8.1 Hz, 1H), 7.50 (d, J = 8.2 Hz, 1H), 6.40 (d, J = 7.4 Hz, 1H), 4.40 (m, 2H), 4.12 (s, 1H), 3.70 (m, 1H), 2.08 (m, 2H), 1.79 (t, J = 7.4 Hz, 4H), 1.65 (m, 2H), 1.40 (m, 2H), 1.14 (s, 3H).

[0236] Biological Examples Biological Example 1 - Protein PIM Kinase Assay PIM kinase activity was measured using the commercially available ADP Hunter™ Plus assay (DiscoveRx ref. 33-016), a homogenous assay that measures ADP accumulation as a universal product of kinase activity. PIM-1 and PIM-2 proteins were obtained by purification as described in Martinez-Gonzalez et. al. Eur. J. Med Chem. 2019, 168, 87-109, and PIM-3 was obtained from Millipore (catalog no. 14-738). The assay was performed according to the general manufacturer's recommendations, with protein and substrate concentrations adapted to optimal conditions. The kinase buffer was 15 mM HEPES, pH 7.4, 20 mM NaCl, 1 mM EGTA, 0.02% Tween-20, 10 mM MgCl2, and 0.1 mg / mL LBGG (bovine gamma-globulin). All PIM kinase assays were performed with 100 μM PIM tide (ARKRRRHPSGPPTA) as peptide substrate, and 100 μM ATP. Protein concentrations were 50, 350, and 200 pg / μl for PIM-1, 2, and 3, respectively. IC values ​​for the compounds listed were 50 To calculate the β-actin concentration, serial 1:3 dilutions were prepared and the reaction was initiated by the addition of ATP. Incubation was carried out for 1 h at 25°C. Reagents A and B (DiscoveRx) were added sequentially to the wells and the plate was incubated at 37°C for 30 min. Fluorescence counts were read on a Victor instrument (Perkin Elmer) using the recommended settings (544 nm as excitation wavelength and 580 nm as emission wavelength, respectively). Values ​​were plotted against inhibitor concentration and fitted to a sigmoidal dose-response curve using ActivityBase software from IDBS.

[0237] The results are shown in Table 1. Comparative Example 1 is Example 19 of WO 2011 / 080510, which is believed to be the prior art compound most structurally similar to the compounds of the present invention. In Table 1, **** indicates an IC of less than 1 nM. 50 *** denotes IC between 1 and 5 nM 50** denotes IC between 5 and 10 nM 50 ** denotes IC between 10 and 50 nM 50 Represents.

[0238] [Table 1]

[0239] The results show that the activity of the compounds of the present invention against PIM-1, PIM-2, and PIM-3 kinases is at least comparable to that of the most similar prior art compounds, and therefore these compounds can be expected to be useful in the treatment of diseases mediated by these PIM kinases, as outlined herein.

[0240] Biological Example 2 - BAD S112 phosphorylation inhibition assay The efficacy of compounds of the invention in inhibiting BAD phosphorylation was measured by inCell ELISA.

[0241] Materials: H1299 cells overexpressing PIM-1 (H1299Pim1). DMSO plates: 96-well polystyrene, untreated, round bottom plates, from Costar (catalog no. 3797). Cell plates: 96-well flat bottom plates biocoated with poly-D-lysine, with lid, from Becton Dickinson (catalog no. 354651). Cell culture medium: DMEM high glucose, 10% fetal bovine serum, 2mM L-glutamine, P / S. Antibodies: phospho BAD S112 antibody, from Cell Signaling (catalog no. 9291S), peroxidase-conjugated anti-rabbit antibody, from Amersham (catalog no. 3619). Reagents: SuperSignal ELISA femto, from Pierce (catalog no. 1001110).

[0242] Procedure: Cells were seeded at 15,000 cells per 200 μl per well in 96-well plates and incubated for 16 hours at 37°C with 5% CO2. On day 2, nine serial 1:2 compound dilutions were made in DMSO in 96-well plates. Compounds were added to duplicate wells of 96-well cell plates using an FX BECKMAN robot (Beckman Coulter) and incubated at 37°C under CO2 in medium without fetal bovine serum (FBS). After 4 hours, relative levels of BAD S112 phosphorylation were measured by Cell ELISA using SuperSignal ELISA Femto substrate (Pierce) and read on a VICTOR (Perkin Elmer). EC 50 Values ​​were calculated using ActivityBase from IDBS.

[0243] The results are shown in Table 2. Comparative Example 1 is Example 19 of International Publication No. 2011 / 080510.

[0244] [Table 2]

[0245] From the above it can be concluded that the compounds of the examples improve cellular regulation of PIM biomarkers, thus offering the potential for the compounds to improve cellular responses to treatment with PIM inhibitors.

[0246] Biological Example 3 - Antiproliferative Assay The activity of the compounds of the present invention against the proliferation of the cancer cell lines A549 (used as a model for the study of lung cancer) and MiaPaca (used as a model for the study of pancreatic cancer) was tested and compared with the activity of the most similar prior art compound (Example 19 of WO 2011 / 080510).

[0247] Cells were harvested just before reaching confluence, counted in a hemocytometer, and diluted in culture medium. Cells were then seeded into 96-well microtiter plates at a density of 4,000 cells / well. Cells were incubated for 24 hours before compound addition.

[0248] Compounds were weighed and diluted in DMSO to a final concentration of 10 mM. From this, a "mother plate" was prepared with serial dilutions at 200-fold the final concentration in culture medium. The final concentration of DMSO in the tissue culture medium should not exceed 0.5%. An appropriate volume of compound solution (2 μl) was automatically added (Beckman FX96 tip) to 0.2 ml medium to give the final concentration of each drug.

[0249] Each concentration was assayed in duplicate. Cells were exposed to compounds for 72 hours and then processed for reading with the CellTiter-Glo® Luminescent Cell Viability Assay (Promega) according to the manufacturer's instructions and read on an EnVision (Perkin Elmer). GI 50 Values ​​were calculated using ActivityBase from IDBS.

[0250] The results are shown in Figures 1 and 2. Figure 1 shows the cell viability of each cell line after 72 hours for three example compounds and Comparative Example 1 (Example 19 in WO 2011 / 080510). Figure 2 shows the GI of three example compounds of the present invention against these cell lines. 50 The fold change is compared with Comparative Example 1.

[0251] The results show that all three example compounds of the present invention exhibit surprising improvements in antiproliferative activity against both cell lines compared to the structurally most similar compound of Comparative Example 1. Thus, these compounds have increased in vivo efficacy in patients compared to the most similar compound of Comparative Example 1 and have the potential to be developed as more potent pharmaceuticals for treating cancer, particularly lung and pancreatic cancer.

[0252] Biological Example 4 - Pharmacokinetics Ten-week-old female BALB / c mice were used for in vivo clearance determination (n=3 per time point). Compounds were formulated in 10% N-methylpyrrolidone (NMP) / 50% polyethylene glycol PEG300 / 40% NaCl 0.9% for intravenous injection (iv) and 10% NMP / 90% PEG300 for oral injection (PO). Plasma samples were collected after a single iv dose at 0.08, 0.25, 0.5, 1, and 4 hours, and after a single PO dose at 0.08, 0.16, 0.25, 0.5, 1, 4, 8, and 24 hours.

[0253] Extraction of compounds from plasma was achieved by solid-phase extraction followed by analysis by high-performance liquid chromatography / mass spectrometry (Agilent 1100, Applied Biosystems API 2000). The amount of inhibitor and internal standard in each mouse plasma sample was quantified based on a calibration curve generated using standards of known compound concentrations.

[0254] The results are shown in Figures 3 and 4. Figure 3 shows the concentration of each compound as a function of time when the compounds were administered intravenously at 5 mg / kg, and Figure 4 shows the concentration of each compound as a function of time when the compounds were administered orally at 10 mg / kg.

[0255] The results show that all three example compounds of the present invention exhibit surprising improvements in pharmacokinetic activity compared to the most structurally similar compound, Comparative Example 1. This therefore means that the compounds have greater exposure to the site of action in vivo compared to Comparative Example 1, providing the potential for development as pharmaceuticals with improved efficacy in vivo or equivalent efficacy in vivo at lower doses.

[0256] Biological Example 5 - Combination Antiproliferative Data The in vitro antiproliferative activity of the combination of the compound of Example 1 with several known anticancer compounds was measured using the same method outlined above for Biological Example 3. Combination index scores were calculated by the method of Chou and Talalay (CalcuSyn software, Biosoft).

[0257] The combination partner compounds were as follows: PI3K inhibitor pictisilib (GDC-0941) MEK inhibitor mirdametinib (PD-0325901) and the EGFR and ErbB2 inhibitor lapatinib.

[0258] The results are shown in Table 3. In this table, ++++ indicates very strong synergy; +++ indicates strong synergy; and ++ indicates synergy.

[0259] [Table 3]

[0260] The results show that the combination of the compound of Example 1 with these known anti-cancer compounds results in synergistic anti-proliferative activity.

[0261] Biological Example 6 - Further Antiproliferative Assays The activity of the compounds of the present invention against the proliferation of cancer cell lines MV4:11 (used as a research model for acute myeloid leukemia), HT-29 (used as a research model for colon cancer), Jeko1 (used as a research model for mantle cell lymphoma), and SKMEL19 (used as a research model for melanoma) was tested and compared with the activity of the most similar prior art compound Comparative Example 1 (Example 19 of WO2011 / 080510). The materials and methods used are the same as in Biological Example 3.

[0262] The results are shown in Figures 5 and 6. In particular, Figure 5 shows the anti-proliferative activity of three example compounds of the present invention, showing cell viability in MV4:11 (acute myeloid leukemia), HT-29 (colon cancer), Jeko1 (mantle cell lymphoma) and SKMEL19 (melanoma) cell lines after 72 hours of treatment with the three example compounds and Comparative Example 1, and Figure 6 compares the fold change in GI50 for these cell lines when treated with the three compounds of the present invention and Comparative Example 1.

[0263] The results show that all three example compounds of the present invention exhibit surprising improvements in antiproliferative activity against the four cell lines compared to the structurally most similar compound of Comparative Example 1. Thus, these compounds have increased in vivo efficacy in patients compared to the most similar compound of Comparative Example 1 and have the potential to be developed as more potent pharmaceutical agents for treating cancer, particularly acute myeloid leukemia, colon cancer, mantle cell lymphoma, and melanoma.

[0264] Biological Example 7 - In vitro efficacy against breast cancer cell lines The efficacy of the compound of Example 1 against various cell lines of breast cancer was evaluated. Staurosporine (STS) (Sigma, Cat. No. S4400-1MG, Lot No. #115M4047V) and dactolisib (BEZ-235) were used as references.

[0265] material RPMI 1640 (Invitrogen, Catalog No. 11875-093; Lot No. 1811359); Fetal Bovine Serum (FBS) (Invitrogen, Catalog No. 10099-141; Lot No. 1652792); Hybricare (ATCC, Catalog No. 46-X; Lot No. 61939036); Insulin, Human Recombinant Zinc (Cat. No. 12585-014; Lot No. 1758396); L-Glutamine (Invitrogen, Catalog No. 25030-081; Lot No. 1532081); 0.25% Trypsin-Ethylenediaminetetraacetic acid (EDTA) (Invitrogen, Catalog No. 25200-072, Lot #1806021); Penicillin-Streptomycin Solution (Hyclone Catalog #SV30010, Lot #J160016); Glutamax (Gibco Catalog #35050-061; Lot #1715705); DMSO (Sigma Catalog #276855-1L, Lot #STBD8882V); 96-well plate, white-walled, clear-bottom, tissue culture treated (Corning Catalog #CLS3903; Lot #16816002); 96-well, square-well V-bottom (Costar Catalog #3960; Lot #04914002); CellTiter Glo Assay Kit (Promega Catalog #G7571, Lot #0000126342). Staurosporine (Sigma, Catalog No. S4400-1MG, Lot No. #115M4047V)

[0266] Cell lines - as shown in Table 4 below.

[0267] [Table 4]

[0268] Experimental Method Celltiter Glo assay Cell seeding: To prepare complete medium, FBS and appropriate additives were added and mixed gently according to the information sheet provided by the vendor. The cell name and complete medium and passage number marked on the flask were identified, and the culture medium was removed and discarded using a vacuum pump. The cell layer was briefly rinsed with 0.25% (w / v) trypsin-0.038% (w / v) EDTA solution to remove all traces of serum containing trypsin inhibitors. 3.0 ml of trypsin-EDTA solution was added to the flask, and the cells were observed under an inverted microscope until the cell layer was dispersed. 8.0 ml of complete growth medium was added, and the cells were aspirated gently by pipetting. The cell suspension was transferred to a centrifuge tube and centrifuged at 800-1000 rpm for 3-5 min. The supernatant was discarded using a vacuum pump, and the appropriate amount of complete medium was added. The cell pellet was gently pipetted to suspend, the cell number was counted with a Vi-cell XR, and the cells were adjusted to the appropriate density. According to the planned plate layout, 100 μL of cell suspension was added to a 96-well opaque-walled, clear-bottom plate, and the plate was placed in a CO incubator overnight.

[0269] Preparation of compounds - shown in Table 5 below.

[0270] [Table 5]

[0271] Compound plate preparation and addition: Preparation of test article plates: 10 mM stock solutions were prepared in DMSO. Starting working solutions and 10-point 3-fold serial dilutions were prepared in DMSO according to Table 5. b. Preparation of staurosporine plates: 0.4 mM staurosporine was prepared at working concentration in DMSO. c. Compound addition: 0.5 μL of DMSO diluted compounds (200x) was transferred to wells containing 100 μL of culture medium while the day 0 plates were measured with CellTiter Glo as listed below. d. Cells were incubated with compounds for 72 hours at 37°C with 5% CO2.

[0272] Preparation of reagents: CellTiter-Glo Buffer was thawed and equilibrated to room temperature prior to use. Lyophilized CellTiter-Glo Substrate was equilibrated to room temperature prior to use. The appropriate amount of CellTiter-Glo Buffer was transferred to the amber bottle containing CellTiter-Glo Substrate to reconstitute the lyophilized enzyme / substrate mixture, thereby forming the CellTiter-Glo Reagent. Mixing was performed by gently vortexing, swirling, or inverting the contents to obtain a homogenous solution; CellTiter-Glo Substrate went into solution easily in less than a minute.

[0273] Assay Measurement After the corresponding treatment, cell morphology was observed under an inverted microscope. After the plate and its contents were equilibrated to room temperature for approximately 30 min, 100 μL of CellTiter-Glo reagent was added to the assay plate in a Multidrop Combi instrument, and the contents were mixed on an orbital shaker for 10 min to induce cell lysis. The plate was incubated at room temperature for 10 min to stabilize the luminescence signal, a white backing seal was attached to the clear bottom, and luminescence was recorded by Enspire with the settings: Luminescence, measurement time 0.1 ms.

[0274] The results are shown in Table 6, with data expressed as absolute IC in μM. 50 It is expressed as:

[0275] [Table 6]

[0276] The results show that the compound of Example 1 is potent against cell lines in vitro and therefore can be expected to exhibit efficacy against breast cancer in vivo.

[0277] Biological Example 8 - In vivo efficacy in leukemia models The antitumor efficacy of the compound of Example 1 was measured in a human leukemia KG-1 subcutaneous xenograft model in CB-17 SCID mice. The groups and treatments for the in vivo efficacy study are shown in Table 7 below.

[0278] [Table 7]

[0279] Mice were divided into groups on day 0 (D0), with Example 1 25BID*21 group starting in the evening on day 0 (D0), and other groups starting in the morning on day 1 (D1). On the 21st day of treatment, 8 hours and 24 hours after the last administration, tumors were harvested from 4 mice each from the vehicle group, Example 1 25mg / kg BID group, and Example 1 50mg / kg group.

[0280] Animals: Female mice (Mus musculus), strain: CB-17 SCID; 6-8 weeks old, weight: 18-20 g, were obtained from Shanghai Lingchang BioTech Co., Ltd. Of the 59 mice obtained, 40 were grouped for efficacy studies. Mice were housed in individual ventilated cages with 5 animals each at constant temperature (20-26°C) and humidity (40-70%). The cages were made of polycarbonate and the bedding was corncob, which was changed twice a week. During the study period, animals had free access to radiation-sterilized dry granule diet and sterile drinking water.

[0281] Reagents: DMSO and PEG-400 were obtained from Sigma.

[0282] Preparation of formulations: Step 1: First, a 100 mg / mL solution of Example 1 in DMSO was prepared. 0.24 mL DMSO was dispensed into a volumetric vial (5 ml), then 5 mg of Example 1 compound was added and mixed until dissolved. An aliquot of Example 1 (approximately 5 mg) was taken from the resulting solution and mixed until dissolved and until 100 mg / mL was reached (a total of 24 mg of compound is required). The drug dissolved reasonably quickly, allowing ample time for preparation. Step 2: (10 mg / mL formulation): To a vial containing 100 mg / mL of Example 1 compound in DMSO solution prepared in Step 1, 2.0 mL of PEG 400 was added and mixed until a clear solution was obtained. An additional 2.4 mL of PEG 400 was added and mixed until homogenous.

[0283] Cell culture: KG-1 (leukemia, acute myeloid) cells were purchased from ATCC (ATCC® CCL-246™). The base medium for this cell line is ATCC formulation Iscove's modified Dulbecco's medium, catalog number 30-2005. To make the complete growth medium, the following components were added to the base medium: fetal bovine serum to a final concentration of 20%. Cultures were then maintained by adding fresh medium or replacing the medium, or centrifuged to remove 2×10 5 Cultures were established by resuspending at 2 × 10 viable cells / mL. 5 ~1×10 6 Viable cells / mL were maintained between 2 x 10 6 Do not exceed cells / mL. See: https: / / www.atcc.org / Products / All / CCL-246.aspx#culturemethod

[0284] Tumor inoculation: To develop tumors, inoculate KG-1 tumor cells (5 × 10) in a 0.2 mL mixture of basal medium and 50% Matrigel. 6 cells / mouse) were inoculated subcutaneously into the right flank of the mice.

[0285] All procedures related to the handling, care, and treatment of animals in this study were performed in accordance with the guidelines of the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC) and approved by Shanghai ChemPartner's Institutional Animal Care and Use Committee (IACUC). During regular monitoring, animals were checked for any effects on normal behavior, including mobility, food and water intake (visual observation only), weight gain / loss (weight was measured three times a week), eye / hair tangles, and other abnormal effects. Mortality and observed clinical signs were recorded.

[0286] Tumor measurements and endpoints: The primary endpoint was tumor growth delay or cure. Tumor size was measured three times a week in two dimensions using calipers and volume was calculated according to the following formula: V = 0.5a × b 2 where a and b were the long and short diameters of the tumor, respectively, to obtain the mean diameter in mm 3 Tumor size was measured in two dimensions using calipers, and volume was calculated using the following formula: V = 0.5 × a × b 2 (where a and b are the major and minor diameters, respectively) to obtain the diameter in mm 3 The tumor size was then used to calculate the TGI value. The TGI was calculated according to the following formula: TGI(%)=(1-(TV-treated / Dn-TV-treated / D1) / (TV-control / Dn-TV-control / D1))×100%.

[0287] Sample Collection: On the 21st day of treatment, tumors were collected from 4 mice each from the vehicle, Example 1 25 mg / kg BID, and Example 1 50 mg / kg groups, 8 and 24 hours after the last dose.

[0288] Statistical Analysis: Summary statistics including mean and standard error of the mean (SEM) were provided for tumor volume for each group at each time point. Statistical analysis of differences in tumor volume between groups was performed 21 days after the last dose. Statistical analysis of differences in tumor volume and tumor weight between groups was performed. All data were analyzed using GraphPad Prism software. P<0.05 was considered statistically significant. Tumor volumes were compared between vehicle and all treatment groups using two-way ANOVA combined with Bonferroni post-hoc tests. Tumor weights were compared between vehicle and all treatment groups using one-way ANOVA combined with Dunnett post-hoc tests.

[0289] The results are shown in Figures 7 and 8, where Figure 7 shows the tumor volume from days 0 to 21 after treatment with the compound of Example 1 at 25, 50 and 100 mg / kg compared to the control (vehicle), and Figure 8 shows the % change in body weight from days 0 to 21 after treatment with the compound of Example 1 at 25, 50 and 100 mg / kg compared to the control (vehicle).

[0290] The results show that this compound is effective in a mouse model of this leukemia and therefore may be predicted to show efficacy in vivo against human leukemia.

[0291] Biological Example 9 This biological example demonstrates that the compound of Example 1 enhances the generation of regulatory CD4+ T cells while suppressing pathogenic Th1 / Th17 CD4+ T cell responses.

[0292] In chronic inflammatory diseases such as psoriasis and IBD, effector T cell subsets known as Th1 cells (secreting IFNγ) and Th17 cells (secreting IL-17A) are established drivers of pathogenesis, whereas iTreg cells (inducible regulatory T cells) are thought to be key mediators of immune suppression and resolution (Hu, P et al. Front Immunol. 2021 Dec 15;12:788940 and Nussbaum, L. et al. Br. J. Dermatol. 2021 Jan;184(1):14-24).

[0293] We investigated the effect of PIM1 / 2 kinase inhibition on the development of these subsets in vitro at various concentrations and determined that at the optimal concentration (12.5 nM), the presence of the compound of Example 1 significantly suppressed "harmful" pro-inflammatory Th1 and Th17 responses, while promoting the generation of immunoregulatory iTreg cells.

[0294] method CD4 + T H Cell culture and differentiation Naive CD4 + T cells were purified from mouse spleens and lymph nodes using positive selection with magnetic beads (CD4 L3T4 kit, Miltenyi Biotec, UK). Purified T cells were activated with plate-bound αCD3ε (1 μg / ml; 2C11) and αCD28 (3 μg / ml; 37.51) in the presence or absence of the compound of Example 1 or cyclosporine A (Sigma Aldrich) and cultured at 37° C. for 72 h under Th1 conditions (IL-12 [20 ng / ml] + αIL-4 (11B1) [10 μg / ml]), 72 h under Th17 conditions (αIFNγ [10 μg / ml] + αIL-4 [5 μg / ml] + IL-6 [20 ng / nl] + TGFβ (5 ng / ml)), and 96 h under iTreg conditions (TGFβ (5 ng / ml)).

[0295] ELISA Mouse IFNγ and IL-17a ELISA kits were purchased from eBioscience (Thermo Fisher, UK) and performed according to the manufacturer's instructions using Corning® High Binding ELISA plates (Merck, CLS9018). All ELISAs were analyzed using a Synergy MX microplate reader (BioTek).

[0296] Flow cytometry Intracellular protein expression was assessed by first restimulating cells for 4–6 h at 37 °C with phorbol 12-myristate 13-acetate (PMA) (10 ng / ml) (Sigma Aldrich), ionomycin (1 μg / ml) (Sigma Aldrich), and brefeldin A (5 μg / ml) (eBioscience). Cells were fixed and permeabilized using a FOXP3 staining buffer set (eBiosciences / Thermo Fisher, UK) according to the manufacturer's instructions to facilitate detection of intracellular cytokines (IFNγ and IL-17a) and transcription factors (FoxP3). Initial gating was performed on live cells using the Live Dead fixable Aqua Dead Cell staining kit (Invitrogen). Fc block (93) and all fluorochrome-conjugated antibodies used, αCD4 (GK1.5), αIFNγ (XMG1.2), αIL-17a (17B7), and αFOXP3 (NRRF-30; FJK-16S), were purchased from eBiosciences (Thermo Fisher, UK). Multiparameter analyses were performed on an LSR / Fortessa (Becton Dickinson Biosciences (BD)) and analyzed using FlowJo software (Tree Star).

[0297] The results are shown in Figures 9 and 10. In particular, Figure 9 shows that the compound of Example 1 inhibits the generation of Th1 and Th17 responses. In vitro Th1 cell differentiation, as determined by the secretion of IFNγ, is inhibited by the presence of the compound of Example 1 over a range of concentrations as determined by (A) ELISA and (B) FACS analysis of IFNγ expression levels by CD4+ T cells. In vitro Th17 cell differentiation, as determined by the secretion of IL-17A, is inhibited by the presence of the compound of Example 1 over a range of concentrations as determined by (C) ELISA and (D) FACS analysis of IL-17A expression levels by CD4+ T cells. T cell immunosuppressive therapy was established with cyclosporine A (CsA) included as a control. The data shown are representative of two independent experiments that showed similar results: statistical analysis used an unpaired Student's t-test, where * represents P<0.05 and ** represents P<0.01.

[0298] Figure 10 further demonstrates that the compound of Example 1 promotes the generation of iTreg responses. Differentiation of iTreg cells in vitro, as determined by intracellular expression levels of the Treg marker FoxP3 by FACS analysis. T cell immunosuppressive therapy was established by cyclosporine A (CsA), which was included as a control. Data shown are representative of two independent experiments with similar results.

[0299] Furthermore, in contrast to CsA, the presence of the compound of Example 1 (12.5 nM) significantly increased the expression of the transcription factor FoxP3, which confers regulatory / suppressive T cell function, when CD4+ T cells were differentiated under inducible Treg (iTreg) conditions in vitro (Figure 10).

[0300] Taken together these data indicate that the compound of Example 1 modulates the development of effector CD4+ T cell subsets towards a more anti-inflammatory profile.

[0301] Biological Example 10 - In vitro potency against leukemia cell lines The efficacy of the compound of Example 1 against various cell lines of leukemia was evaluated. Staurosporine (STS) (Sigma, Cat. No. S4400-1MG, Lot No. #115M4047V) and dactolisib (BEZ-235) were used as references.

[0302] Materials: RPMI 1640 (Invitrogen, Catalog No. 11875-093; Lot No. 1811359), IMDM (Invitrogen, Catalog No. 12440-053; Lot No. 1806052), FBS (Invitrogen, Catalog No. 10099-141, Lot No. 1652792), Penicillin-Streptomycin Solution (Hyclone, Catalog No. SV30010, Lot No. J160016), Glut amax (Gibco, Catalog No. 35050-061; Lot No. 1715705), DMSO (Sigma, Catalog No. 276855-1L; Lot No. #STBD8882V), 96-well plate, white-walled, clear-bottom, tissue culture treated (Corning, Catalog No. CLS3903; Lot No. 16816002); 96-well, square-hole, V-bottom (Costar, Catalog No. 3960; Lot No. 04914002); CellTiter Glo Assay Kit (Promega, Catalog No. G7571; Lot No. 0000126342), staurosporine (sigma, Catalog No. S4400-1MG; Lot No. #115M4047V).

[0303] The cell lines are shown in Table 8. In all cases, the incubation time was 72 hours and the cell lines were grown as suspension. The seeding density was per well of a 96-well plate.

[0304] [Table 8]

[0305] Experimental Method The cell seeding method, compound preparation, compound plate preparation, reagent preparation, and assay measurement method were the same as in Biological Example 7 above.

[0306] The results are shown in Table 9, with data expressed as absolute IC in μM. 50 It is expressed as:

[0307] [Table 9]

[0308] The results show that the compound of Example 1 is potent against cell lines in vitro and therefore can be expected to exhibit efficacy against leukemia in vivo.

[0309] All publications mentioned in the above specification are incorporated herein by reference. Various modifications and variations of the present invention will be apparent to those skilled in the art without departing from the scope and spirit of the present invention. Although the present invention has been described in connection with specific preferred embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications and equivalents of the described modes for carrying out the invention that are apparent to those skilled in the art of chemistry, pharmacy, or related fields are intended to be within the scope of the following claims.

Claims

1. Compounds of Formula I 【Chemical 1】 (In the formula, Y is C(R ａ ) (R ｂ ) and NR ｃ selected from the group consisting of: R ａ , R ｂ , and R ｃ are each independently H and C １～６ selected from the group consisting of alkyl; n is 1 to 3; Each R １ is a halogen, C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxy, and C １～６ haloalkoxy; R ２ is C １～４ is alkyl; and R ３ is H and C １～３ alkyl), or a pharmaceutically acceptable solvate or salt thereof.

2. Y is CH ２ and N(CH ３ 2. The compound of claim 1, wherein the compound is selected from the group consisting of:

3. 3. The compound of claim 1 or claim 2, wherein n is 1 or 2.

4. Each R １ But F, CF ３ , and OCF ３ 2. The compound of claim 1 selected from the group consisting of:

5. n is 1 and R １ However, OCF ３ 2. The compound of claim 1, wherein:

6. n is 2, and one of R １ is F and the other is CF ３ 2. The compound of claim 1, wherein:

7. R ２ But CH ３ 2. The compound of claim 1, wherein:

8. R ３ The compound of claim 1 , wherein is H.

9. formula: 【Chemistry 2】 2. The compound of claim 1, or a pharmaceutically acceptable solvate or salt thereof.

10. formula: 【Chemistry 3】 2. The compound of claim 1, or a pharmaceutically acceptable solvate or salt thereof.

11. formula: 【Chemistry 4】 2. The compound of claim 1, or a pharmaceutically acceptable solvate or salt thereof.

12. 10. A pharmaceutical formulation comprising a compound of formula I according to claim 1, or a pharmaceutically acceptable solvate or salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.

13. 10. A medicament comprising a compound of formula I according to claim 1, or a pharmaceutically acceptable solvate or salt thereof.

14. A pharmaceutical composition for the treatment of a disease comprising a compound of formula I according to claim 1, or a pharmaceutically acceptable solvate or salt thereof, wherein the disease is selected from the group consisting of cancer, immune disorders, cardiovascular diseases, viral infections, inflammation, metabolic / endocrine dysfunction, neurological disorders, obstructive airway diseases, allergic diseases, inflammatory diseases, immunosuppression, disorders commonly associated with organ transplantation, AIDS-related diseases, benign prostatic hyperplasia, familial adenomatous polyposis, polyposis, neurofibromatosis, psoriasis, bone disorders, atherosclerosis, vascular smooth cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthritis, glomerulonephritis and postoperative stenosis, restenosis, stroke, diabetes, hepatomegaly, Alzheimer's disease, cystic fibrosis, hormone-related diseases, immunodeficiency disorders, destructive bone disorders, infectious diseases, conditions associated with cell death, thrombin-induced platelet aggregation, chronic myeloid leukemia, liver diseases, pathological immune conditions involving T-cell activation, CNS disorders, and other related diseases.

15. (A) a compound of formula I according to claim 1, or a pharmaceutically acceptable solvate or salt thereof; and (B) Other therapeutic agents A combination including:

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