Combination therapy based on PD-1 inhibitor and SIK3 inhibitor

Abstract

The present invention relates to the use of a combination of PD-1 inhibitor therapy with certain kinase inhibitors, in particular inhibitors of protein kinases including the SIK family, CSF1R, ABL / BCR-ABL, SRC, HCK, PDGFR, KIT and / or their mutants, to overcome resistance to PD-1 / PDL1 inhibitor therapy in tumors. A preferred tumor disease treatable according to the present invention is lung squamous cell carcinoma with a PD-1 inhibitor therapy-resistant phenotype.

Description

[Technical field]

[0001] The present invention relates to the use of a combination of PD-1 inhibitor therapy with certain kinase inhibitors, in particular inhibitors of protein kinases including the SIK family, CSF1R, ABL / BCR-ABL, SRC, HCK, PDGFR, KIT and / or mutants thereof, to overcome resistance to PD-1 / PD-L1 inhibitor therapy in tumors. Preferred tumor diseases treatable according to the present invention are selected from epithelial cancers such as renal cell carcinoma or lung cell carcinoma, and in one preferred embodiment is lung squamous cell carcinoma with a PD-1 inhibitor therapy-resistant phenotype. [Background technology]

[0002] PD-1 expression on T cells is rapidly induced following antigen exposure, following engagement of the T cell receptor (TCR) with its cognate epitope-loaded MHC molecule in the draining lymph node. In addition to TCR dependency, the presence of interleukin 2 (IL-2), IL-7, IL-15, vascular endothelial growth factor (VEGF), IL-6, and transforming growth factor β (TGF-β) in the local cytokine milieu in lymph nodes and diseased tissues also contributes to PD-1 upregulation on T cells. PD-1 interacts with its ligands, namely PD-L1 (PD-L1 / B7-H1 / CD274) and PD-L2 (PDL2 / B7-DC / CD273). PD-1 ligands are expressed on transformed cells, professional antigen-presenting cells (pAPC), and epithelial cells, as well as T cells. This interaction provides signals that tolerize T cells to their antigen targets and neutralize their effector functions. Type 1 interferons (IFN-a / b) and tumor necrosis factor alpha (TNF-α) can upregulate PD-L1 expression on T cells, B cells, natural killer (NK) cells, myeloid cells, and epithelial cells, whereas PD-L2 expression can be induced via interferon gamma (IFN-γ), granulocyte-macrophage colony-stimulating factor (GM-CSF), and IL-4 signaling. By targeting factors that promote the formation and maintenance of an immunosuppressive microenvironment, for example, within tumors, immunotherapy can release the brakes on the host's own immune system and achieve the killing of cancer cells.

[0003] In fact, checkpoint inhibitors targeting PD-1 or its ligand PD-L1 have demonstrated unprecedented clinical efficacy in more than 15 cancer types, including melanoma, non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), bladder cancer, and Hodgkin's lymphoma. Indeed, therapeutic mAbs targeting either PD-1 or PD-L1 disrupt the ligand / receptor interaction, liberating T cells from their exhausted phenotype and allowing the reactivation of tumor antigen-specific immunity (for review, see Non-Patent Document 1).

[0004] Nevertheless, primary resistance to anti-PD-1 therapy is a common phenomenon, affecting up to 80% of patients in some cancer types. Moreover, it is now becoming clear that the promising initial responses observed among some patients may be negated by the development of acquired resistance to anti-PD-1 therapy (hereafter referred to throughout as acquired resistance), leading to tumor recurrence or progression. Currently, great efforts are being made to fully elucidate the mechanisms by which anti-PD-1 / PD-L1 therapy exerts its effect, to understand the resistance mechanisms that exist and limit its activity in some patients, and to develop a priori combination therapy approaches to sensitize resistant patients. In fact, as reviewed in Non-Patent Document 1, various combination therapies have been proposed or developed to enhance the therapeutic activity of anti-PD-1 / PD-L1 antibodies, including, but not limited to, anti-CTLA4 therapy, anti-OX40 (CD134) therapy, anti-TIM3 therapy, anti-LAG3 therapy, and anti-TIGIT therapy, radiation therapy, chemotherapy such as cisplatin, BRAF / MEK inhibitors, cytokine therapy such as anti-VEGF mAb (bevacizumab), anti-CD40 antibody, anti-CD73 antibody, or anti-CD137 antibody, viral therapy using oncolytic viruses, and many others.

[0005] In particular, immunotherapy, including therapy with inhibitors of the PD-1 / PD-L1 axis, is now the preferred treatment for most lung cancer patients, either as monotherapy or in combination. Although this approach has been shown to improve survival, most patients who initially respond to immunotherapy develop resistance over time, limiting the durability of immunotherapy.

[0006] It is therefore an object of the present invention to provide therapeutic options to overcome the PD-1 / PD-L1 resistance phenotype in cancer therapy. [Prior art documents] [Non-patent literature]

[0007] [Non-Patent Document 1] O'Donnell et al., Cancer treatment Reviews 52 (2017), 71-81 Summary of the Invention

[0008] In general, by way of a brief description, the main aspects of the present invention can be summarized as follows.

[0009] In a first aspect, the present invention relates to a compound or composition for use in treating a tumour in a subject, wherein the subject or tumour is resistant to treatment with an inhibitor of PD-1 or its ligand, or the subject has previously been treated with an inhibitor of PD-1 or its ligand (and preferably the tumour is recurrent); The compound or composition comprises (i) a composition comprising an inhibitor of PD-1 or its ligand (a PD-1 inhibitor) and an inhibitor of salt-inducible kinase 3 (a SIK3 inhibitor); or (ii) a SIK3 inhibitor, wherein the treatment comprises the concomitant or sequential administration of an inhibitor of PD-1 or its ligand; or (iii) an inhibitor of PD-1 or its ligand, wherein the treatment comprises simultaneous, separate or sequential administration of a SIK3 inhibitor; The present invention provides a compound or composition for use in a pharmaceutical composition comprising:

[0010] In a second aspect, the present application provides a pharmaceutical composition comprising an inhibitor of PD-1 or its ligand (PD-1 inhibitor) and an inhibitor of salt-inducible kinase 3 (SIK3 inhibitor), together with a pharma- ceutically acceptable carrier and / or excipient.

[0011] In a third aspect, the present application provides a pharmaceutical kit comprising an inhibitor of PD-1 or its ligand and a SIK3 inhibitor, wherein the kit is prepared so as to allow simultaneous, separate or sequential administration of the PD-1 inhibitor and the SIK3 inhibitor in therapy to a subject.

[0012] In a related aspect, the invention provides a method of treating a neoplastic disease in a subject, wherein the subject or tumor is resistant to treatment with an inhibitor of PD-1 or its ligand, or the subject has previously been treated with an inhibitor of PD-1 or its ligand, and the tumor is recurrent; The method includes steps (i) or (ii): (i) administering to a subject a therapeutically effective amount of a composition comprising an inhibitor of PD-1 or its ligand (PD-1 inhibitor) and an inhibitor of salt-inducible kinase 3 (SIK3 inhibitor); or (ii) administering to the subject a therapeutically effective amount of a SIK3 inhibitor, wherein the treatment further comprises simultaneous, separate or sequential administration of an inhibitor of PD-1 or its ligand; The present invention provides a method comprising:

[0013] Further aspects of the invention are disclosed herein. [Brief description of the drawings]

[0014] [Figure 1] 1 shows the chemical structures of (A) dasatinib (compound A8), N-(2-chloro-6-methylphenyl)-2-((6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-yl)amino)thiazole-5-carboxamide; (B) kinase inhibitor B3, N-(4-chloro-2-methylpyridin-3-yl)-2-((6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-yl)amino)thiazole-5-carboxamide; (C) certain other kinase inhibitors of formula (Ib) / (Ic) C1-C13; (D) certain further kinase inhibitors of formula (Ib) / (Ic) D1-D10; and (E) certain kinase inhibitors of formula (Ia) E1-E16. [Diagram 2]Schematic diagram of the control of expression of survival / maintenance genes (a) via SIK3 by nuclear factor kappa B (NFKB) transcriptional regulation (b). NFKB activity is controlled by the presence of HDAC4 activity in the nucleus as an inhibitory cofactor, and its retention in the cytoplasm is brought about by its phosphorylation by SIK3. The entry and presence of unphosphorylated HDAC4 in the nucleus (c) (and thus the reduction in expression of tumor survival / maintenance genes (a) by inhibiting the transcription factor activity of NFKB) can be brought about by the inhibition of SIK3 by compounds (d) disclosed herein, such as compound E9, thereby enhancing apoptosis. [Diagram 3] (A) Mean tumor growth kinetics and overall survival monitored after initiation of treatment for the MC38 tumor model. Treatment regimens are numbered 1-4 in the figure, and represent (1) 10 ml / kg vehicle + 10 mg / kg mIgG1e control, (2) 10 ml / kg vehicle + 10 mg / kg α-muPD-1, (3) 25 mg / kg compound E9 + 10 mg / kg mIgG1e control, and (4) 25 mg / kg compound E9 + 10 mg / kg α-mu-PD-1. (B) Tumor-infiltrating cytotoxic T cells (CTLs), CTL to regulatory T cell ratios, tumor-associated M2-macrophages (M2-TAMs), and M2-like TAMs were analyzed by flow cytometry. [Figure 4](A) Mean tumor growth kinetics and overall survival monitored after initiation of treatment for the EMT6 tumor model. Complete tumor regression was demonstrated in 2 of 10 animals. Treatment regimens are numbered 1-4 in the figure and represent: (1) 10 ml / kg vehicle + 10 mg / kg mIgG1e control, (2) 10 ml / kg vehicle + 10 mg / kg α-mu-PD-1, (3) 12.5 mg / kg Compound E9 + 10 mg / kg mIgG1e control, and (4) 12.5 mg / kg Compound E9 + 10 mg / kg α-mu-PD-1. (B) Mean tumor growth kinetics at the start of therapy for the KLN205 tumor model; treatment regimens are numbered 1-4 in the figure and represent: (1) 10 ml / kg vehicle + 10 mg / kg mIgG1e control, (2) 10 ml / kg vehicle + 10 mg / kg α-mu-PD-1, (3) 25 mg / kg Compound E9 + 10 mg / kg mIgG1e control, and (4) 25 mg / kg Compound E9 + 10 mg / kg α-mu-PD-1. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] The present invention, as well as certain non-limiting aspects and / or embodiments thereof, can be described in more detail as follows.

[0016] The present invention may be further described in more detail, but it is understood that the invention is not limited to the specific methodology, protocols, and reagents described herein, as these may vary. It is also understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the invention, which is limited only by any specifically described embodiments or those described, defined, or otherwise disclosed in the appended claims.

[0017] Certain elements of the present invention will now be described in more detail. Although these elements are listed with specific embodiments, it should be understood that they can be combined in any manner and in any number to create additional embodiments. The various described examples and preferred embodiments should not be construed as limiting the present invention to only those embodiments explicitly described. The present specification should be understood to support and encompass embodiments combining the explicitly described embodiments with any number of the disclosed and / or preferred elements. Furthermore, unless otherwise indicated by the context, any permutations and combinations of all elements described herein should be considered to be disclosed by the present specification. For example, in one embodiment of the compound of the present invention, L is a bond, and in another embodiment of the compound of the present invention, R 3 is H, in preferred embodiments of the compounds of the invention, L is a bond and R 3 is H; or in one embodiment of the use of the compounds of the invention, the subject is an adult human, and in another embodiment of the use of the compounds of the invention, the proliferative disorder is prostate cancer; in a preferred embodiment of the use of the compounds of the invention, the subject is an adult human and the proliferative disorder is prostate cancer.

[0018] General definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0019] Preferably, the terms used herein are defined as set forth in "A multilingual glossary of biotechnological terms: (IUPAC Recommendations)", HGW Leuenberger, B. Nagel, and H. Koelbl, Eds., Helvetica Chimica Acta, CH-4010 Basel, Switzerland, (1995).

[0020] The practice of the present invention employs, unless otherwise indicated, conventional methods of chemistry, biochemistry, and recombinant DNA technology, which are described in the art (e.g., Molecular Cloning: A Laboratory Manual, 2 nd Edition, J. Sambrook et al. eds., Cold Spring Harbor Laboratory Press, Cold Spring Harbor 1989).

[0021] Throughout the remainder of this specification and the claims, unless otherwise required by context, the word "comprise", as well as variants such as "comprises" and "comprising", shall be interpreted as meaning the inclusion of a stated member, integer or step or group of members, integers or steps, but not the exclusion of any other member, integer or step or group of members, integers or steps. The term "consisting essentially of" means the exclusion of any other member, integer or step, or group of members, integers or steps, having any essential value. For example, a pharmaceutical composition consisting essentially of members / components as defined herein (e.g., a compound as defined in any of the aspects of the present invention and optionally one additional therapeutic agent) excludes further therapeutic agents (other than the compound as defined in any of the aspects of the present invention and optionally one additional therapeutic agent), but does not exclude trace amounts of contaminants (e.g., from isolation and purification methods) (e.g., the amount of contaminant (preferably the amount of all contaminants present in the composition) is less than 5% by weight of the total composition, e.g., 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.05% by weight) and / or pharma- ceutically acceptable excipients (e.g., carriers, e.g., phosphate buffered saline, preservatives, etc.). The term "consisting only of" means excluding all other significant members, integers, or steps or groups of significant members, integers, or steps. For example, a pharmaceutical composition consisting only of members / components defined herein (e.g., a compound defined in any of the aspects of the present invention, an excipient and optionally an additional therapeutic agent) excludes any other compound (including a second or further excipient) in an amount greater than 2% by weight of the total composition (e.g., greater than 1%, greater than 0.5%, greater than 0.4%, greater than 0.3%, greater than 0.2%, greater than 0.1%, greater than 0.09%, greater than 0.08%, greater than 0.07%, greater than 0.06%, greater than 0.05%, greater than 0.04%, greater than 0.03%, greater than 0.02%, greater than 0.01% by weight of any other compound).The term "comprising" includes the term "consisting essentially of," which in turn includes the term "consisting only of." Thus, at each occurrence in this application, the term "comprising" may be replaced with the term "consisting essentially of" or "consisting only of." Similarly, at each occurrence in this application, the term "consisting essentially of" may be replaced with the term "consisting only of."

[0022] As used herein, "and / or" is considered to specifically disclose each of the two specified features or components with or without the other. For example, "X and / or Y" is considered to specifically disclose (i) X, (ii) Y, and (iii) X and Y as if each were individually set forth herein.

[0023] In the context of the present invention, the terms "about" and "approximately" are used indistinguishably and indicate an interval of accuracy that a person skilled in the art would understand to still ensure the technical effect of the feature in question. This term typically indicates a deviation from the specified numerical value of ±5%, ±4%, ±3%, ±2%, ±1%, ±0.9%, ±0.8%, ±0.7%, ±0.6%, ±0.5%, ±0.4%, ±0.3%, ±0.2%, ±0.1%, ±0.05%, e.g. ±0.01%. As will be understood by a person skilled in the art, the specific such deviation of the numerical value for a given technical effect will depend on the nature of that technical effect. For example, a natural or biological technical effect may generally have a larger such deviation than an artificial or engineered technical effect.

[0024] As used in the context of describing the present invention (particularly in the context of the claims), the terms "a," "an," and "the," and similar referents, unless otherwise indicated in the specification or clearly contradicted by context, are intended to encompass both the singular and the plural.

[0025] Recitation of ranges of values ​​herein is intended to serve merely as a shorthand method of referring individually to each separate value falling within the range, and unless otherwise stated herein, each individual value is incorporated herein as if it were individually recited herein.

[0026] All methods described herein can be performed in any suitable order unless otherwise indicated herein or clearly contradicted by context.

[0027] The use of any examples or exemplary language (e.g., "etc.") presented herein is intended merely to better illustrate the invention and does not limit the scope of the otherwise claimed invention. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.

[0028] Several documents are cited throughout the text of this specification. Each document cited herein (including all patents, patent applications, scientific publications, manufacturer's specifications, instructions, etc.), whether supra or infra, is incorporated herein by reference in its entirety. Nothing herein should be construed as an admission that the present invention is not entitled to antedate such disclosure by virtue of prior invention.

[0029] As used herein, the terms "of the invention," "according to the invention," "according to the invention," and the like are intended to refer to all aspects and embodiments of the present invention as described and / or claimed herein.

[0030] It will be understood that adapting the teachings of the present invention to a particular problem or environment and incorporating variations of the present invention or additional features thereto (such as further aspects and embodiments) will be within the capabilities of one of ordinary skill in the art in light of the teachings contained herein.

[0031] Unless the context dictates otherwise, the feature descriptions and definitions set forth above or below are not limited to any particular aspect or embodiment of the invention, but apply equally to all aspects and embodiments described.

[0032] "Polymorphism" as referred to herein means that a solid substance (such as a compound) can exist in more than one form or crystal structure, i.e., "polymorphic modifications" or "polymorphic forms". In the present invention, the terms "polymorphic modifications", "polymorphic forms" and "polymorphs" are used interchangeably. According to the present invention, these "polymorphic modifications" include crystalline forms, amorphous forms, solvates, hydrates, etc. Primarily, the reason for the existence of different polymorphic forms is due to the use of different conditions during the crystallization process, such as: solvent effects (crystal packing may differ in polar and non-polar solvents); Certain impurities that disrupt the growth pattern and promote the growth of metastable polymorphs; the level of supersaturation at which a substance will crystallize (generally the higher the concentration above solubility, the greater the likelihood of metastable formation); The temperature at which crystallization takes place; the shape of the covalent bond (differences that lead to structural polymorphism); Changes in mixing conditions.

[0033] Polymorphic forms may have different chemical, physical, and / or pharmacological properties, including, but not limited to, melting point, X-ray crystallography and diffraction pattern, chemical reactivity, solubility, dissolution rate, vapor pressure, density, hygroscopicity, flowability, stability, compressibility, and bioavailability. Polymorphic forms may spontaneously transform from a metastable (unstable) form to a stable form at a particular temperature. According to Ostwald's rule, it is generally the most unstable polymorphic form, not the most stable, that crystallizes first. Thus, the quality, efficacy, safety, processability, and / or manufacture of chemical compounds, such as the compounds of the present invention, may be affected by polymorphism. In many cases, the most stable polymorph of a compound (such as the compounds of the present invention) is selected because it has the least chance of conversion to another polymorph. However, a polymorphic form that is not the most stable polymorphic form may be selected for reasons other than stability, e.g., solubility, dissolution rate, and / or bioavailability.

[0034] The term "crystalline form" of a substance as used herein means that the smallest components of said substance (i.e., atoms, molecules or ions) form a crystal structure. As referred to herein, "crystalline structure" means a unique three-dimensional arrangement of atoms or molecules in a crystalline liquid or solid, characterized by a pattern that is a collection of atoms arranged in a specific way and a lattice that exhibits long-range order and symmetry. A lattice is an array of points that repeats periodically in three dimensions, and the patterns are located on the points of the lattice. The subunit of a lattice is the unit cell. The lattice parameters are the lengths of the sides of the unit cell and the angles between them. The symmetry of a crystal is embodied in its space group. To describe a crystal structure, parameters such as the chemical formula, lattice constants, space group, coordinates of the atoms and the occupancy of the point positions are required.

[0035] The term "amorphous form" of a substance, as used herein, means that the smallest building blocks of said substance (i.e., atoms, molecules, or ions) are not arranged in a lattice, but are arranged randomly. Thus, unlike a crystal, where there is short-range order (constant distances to adjacent atoms) and long-range order (periodic repetition of a primitive lattice), there is only short-range order in the amorphous form.

[0036] As used herein, the term "complex of a compound" refers to a higher-order compound produced by association of a compound with one or more other molecules. Exemplary complexes of a compound include, but are not limited to, solvates, clusters, and chelates of the aforementioned compounds.

[0037] The term "solvate" as used herein refers to an addition complex of a substance dissolved in a solvent (such as an organic solvent (e.g., aliphatic alcohols (methanol, ethanol, n-propanol, isopropanol, etc.), acetone, acetonitrile, ether, and the like), water, or a mixture of two or more of these liquids), where the addition complex exists in a crystalline or mixed crystalline form. The amount of solvent contained in the addition complex can be stoichiometric or non-stoichiometric. A "hydrate" is a solvate where the solvent is water.

[0038] In an isotopically labeled compound, one or more atoms are replaced with a corresponding atom having the same number of protons but a different number of neutrons. For example, a hydrogen atom may be replaced with a deuterium atom. Exemplary isotopes that may be used in the compounds of the invention include deuterium, 11 C. 13 C. 14 C. 15 N, 18 F, 32 P, 32 S, 35 S, 36 Cl, and 125 Contains I.

[0039] The expression "amino protecting group" as used herein preferably refers to any group capable of transferring an amino group contained in a compound to a less reactive (i.e. protected) amino group. Preferably, the amino protecting group can be incorporated into the corresponding compound under mild conditions, chemoselectively and / or regioselectively, and / or in good yield. Furthermore, it is desirable that the amino protecting group is stable under the conditions to which the protected compound is exposed (e.g., the conditions of the desired reaction and / or the purification conditions). It is preferable that the amino protecting group minimizes the risk of racemization of the stereocenter when present in the compound. In one embodiment, it is desirable that the amino protecting group can be removed from the protected compound under mild conditions in a selective manner to give the deprotected compound in high yield. Exemplary amino protecting groups include tert-butyloxycarbonyl (BOC), 9-fluorenylmethoxycarbonyl (FMOC), benzyloxycarbonyl (Cbz), p-methoxybenzylcarbonyl (MOZ), acetyl (Ac), trifluoroacetyl, benzoyl (Bz), benzyl (Bn), p-methoxybenzyl (PMB), 3,4-dimethoxyphenyl (DMPM), p-methoxyphenyl (PMP), 2,2,2-trichloroethoxycarbonyl (Troc), triphenylmethyl (trityl; Tr), toluenesulfonyl (tosyl; Ts), para-bromophenylsulfonyl (brosyl), 4-nitrobenzenesulfonyl (nosyl), and 2-nitrophenylsulfenyl (Nps).

[0040] The term "half-life" refers to the period of time required to eliminate half of the activity, amount or number of molecules. In the context of the present invention, the half-life of a compound disclosed herein (e.g., a compound of formula (Ia), formula (Ib), or formula (Ic)) indicates the stability of the compound.

[0041] The term "subject", "patient", "individual" or "animal" refers to a multicellular animal, such as a vertebrate. For example, a vertebrate in the context of the present invention is a mammal, a bird (e.g., a poultry), a reptile, an amphibian, a bony fish, and a cartilaginous fish, in particular any of the domesticated animals mentioned above, as well as a captive animal (especially a vertebrate), such as a zoo animal (especially a vertebrate). Mammals in the context of the present invention include, but are not limited to, humans, non-human primates, domesticated mammals, such as dogs, cats, sheep, cows, goats, pigs, horses, etc., laboratory mammals, such as mice, rats, rabbits, guinea pigs, etc., as well as a captive mammal, such as a zoo mammal. The term "animal" as used herein also includes humans. Particular non-limiting examples of birds include domesticated poultry, such as chickens, turkeys, ducks, geese, guinea fowl, pigeons, pheasants, and other birds. On the other hand, specific non-limiting examples of bony or cartilaginous fish include fish suitable for farming by aquaculture, such as bony fishes such as salmon, trout, sea bass, carp, catfish, etc.

[0042] In a first aspect, the present invention relates to a compound or composition for use in treating a tumour in a subject, wherein the subject or tumour is resistant to treatment with an inhibitor of PD-1 or its ligand, or the subject has previously been treated with an inhibitor of PD-1 or its ligand and the tumour is recurrent; The compound or composition comprises: (i) to (iii): (i) a composition comprising an inhibitor of PD-1 or its ligand (a PD-1 inhibitor) and an inhibitor of salt-inducible kinase 3 (a SIK3 inhibitor); or (ii) a SIK3 inhibitor, where the treatment comprises simultaneous or sequential administration of an inhibitor of PD-1 or its ligand; or (iii) an inhibitor of PD-1 or its ligand, wherein the treatment comprises simultaneous, separate or sequential administration of a SIK3 inhibitor; The present invention provides a compound or composition for use in a pharmaceutical composition comprising:

[0043] In an alternative aspect thereof, the invention provides the use of a compound or composition as defined above for the manufacture of a medicament for the treatment of a tumour in a subject, wherein the subject or tumour is resistant to treatment with an inhibitor of PD-1 or its ligand, or the subject has previously been treated with an inhibitor of PD-1 or its ligand and the tumour is recurrent. In this alternative aspect, the compound or composition is as defined in the first aspect.

[0044] In yet an alternative embodiment, there is provided a method of treating a neoplastic disease in a subject, wherein the subject or tumor is resistant to treatment with an inhibitor of PD-1 or its ligand, or the subject has previously been treated with an inhibitor of PD-1 or its ligand, and the tumor is recurrent; The method comprises steps (i) or (ii): (i) administering to a subject a therapeutically effective amount of a composition comprising an inhibitor of PD-1 or its ligand (PD-1 inhibitor) and an inhibitor of salt-inducible kinase 3 (SIK3 inhibitor); or (ii) administering to the subject a therapeutically effective amount of a SIK3 inhibitor, wherein the treatment further comprises simultaneous, separate or sequential administration of an inhibitor of PD-1 or its ligand; A method is provided, comprising:

[0045] The present invention has surprisingly identified a strong synergistic therapeutic effect in certain clinical scenarios when a SIK3 inhibitor is combined with a PD-1 inhibitor according to the definition described herein. The present invention may relate to the co-administration of a SIK3 inhibitor and a PD-1 inhibitor. As used herein, the term "co-administration" refers to the process of administering a combination of a SIK3 inhibitor and a PD-1 inhibitor to the same patient. The SIK3 inhibitor and the PD-1 inhibitor can be administered simultaneously, substantially simultaneously, or sequentially. The SIK3 inhibitor and the PD-1 inhibitor do not have to be administered by the same vehicle. The SIK3 inhibitor and the PD-1 inhibitor can be administered one or more times, and the number of administrations of each component of the combination can be the same or different. Furthermore, the SIK3 inhibitor and the PD-1 inhibitor do not have to be administered at the same site or by the same route.

[0046] As used herein, the term "therapeutically effective" in the context of the combination of the present invention refers to a sufficient amount or dose of a SIK3 inhibitor together with a sufficient amount or dose of a PD-1 inhibitor to treat a disease, particularly cancer. More preferably, therapeutically effective in certain embodiments refers to an amount of a PD-1 inhibitor and an SIK3 inhibitor that causes a synergistic therapeutic effect. The amount of SIK3 inhibitor in a given therapeutically effective combination may vary for different individuals and different tumor types, and depends on the one or more additional agents or treatments included in the combination. A "therapeutically effective amount" is determined using procedures routinely employed by those skilled in the art to produce an "improved therapeutic outcome". However, it will be understood that the total daily usage of the compounds and compositions of the present invention will be determined by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular patient will depend on a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the particular compound employed; the specific composition employed, the age, weight, health, sex and diet of the patient; the time of administration, route of administration and excretion rate of the particular compound employed; duration of treatment; drugs used in combination or simultaneously with the particular polypeptide employed; and similar factors known in the medical arts. For example, it is well within the skill of the artisan to begin dosing the compound at a level lower than that required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. However, the daily dosage of the product may vary over a wide range, from 0.01 mg to 1000 mg per adult. Typically, the composition contains 0.01 mg, 0.05 mg, 0.1 mg, 0.5 mg, 1.0 mg, 2.5 mg, 5.0 mg, 10.0 mg, 15.0 mg, 25.0 mg, 50.0 mg, 100 mg, 250 mg, and 500 mg of active ingredient, so that the dosage can be adjusted to suit the symptoms of the patient being treated. The pharmaceutical product typically contains about 0.01 mg to about 500 mg of active ingredient, preferably 1 mg to about 100 mg of active ingredient. An effective amount of the drug is usually supplied at a dosage level of 0.0002 mg to about 20 mg per kg of body weight per day, particularly about 0.001 mg to 7 mg per kg of body weight per day.

[0047] Inhibitors of PD-1 and its ligands As used herein, the term "PD-1 inhibitor" refers to an agent that interferes with the activation or function of PD-1. Examples of PD-1 inhibitors include anti-PD-1 antibodies (e.g., PD-1, PD-L1 or PDL2 antibodies), small organic molecule PD-1 antagonists, and / or agents that bind to or interfere with the function of PD-1. Typically, PD-1 inhibitors are antibodies or small organic molecules that bind to the PD-1 receptor or its ligands PD-L1 or PDL2.

[0048] In some embodiments, the PD-1 inhibitor is a small organic molecule. As used herein, the term "small organic molecule" refers to a molecule of a size comparable to organic molecules commonly used in pharmaceuticals. This term excludes biopolymers (e.g., proteins, nucleic acids, etc.). Preferred small organic molecules are up to 2000 Da in size, and most preferably up to about 1000 Da in size.

[0049] Patent publications related to PD-1 / PD-L1 antibodies include WO 2018 / 204303, CN Patent Application Publication No. 108640992, WO 2018 / 036472, CN Patent Application Publication No. 107384933, WO 2015 / 035606, CN Patent No. 107043425, CN Patent No. 106939050, and CN Patent Application Publication No. 106749663.

[0050] A non-exhaustive list of PD1 / PDL1 antibodies includes pembrolizumab (KEYTRUDA™), nivolumab (OPDIVO™), BMS-936559 (MDX 1105), cemiplimab (REGN2810), cemiplimab-rwlc (LIBTAYO™), avelumab (MSB0010718C or BAVENCIO™), durvalumab (MEDI4736 or Imfinzi™), atezolizumab (MPDL3280A or Tecentriq™), spartalizumab (PDR 001), as well as combinations thereof.

[0051] Depending on the tumor to be treated according to the present invention, a specific PD-1 inhibitory compound can be selected in combination with SIK3 inhibitor.This includes atezolizumab or avelumab or durvalumab or pembrolizumab or nivolumab, which can be used to treat bladder cancer; pembrolizumab or nivolumab, which can be used to treat colorectal cancer or gastric cancer or head and neck cancer or Hodgkin's lymphoma; nivolumab, which can be used to treat hepatocellular carcinoma; nivolumab, pembrolizumab, ipilimumab and nivolumab, which can be used to treat melanoma; atezolizumab or durvalumab or pembrolizumab or nivolumab, which can be used to treat lung cancer; avelumab, which can be used to treat Merkel cell carcinoma; pembrolizumab, which can be used to treat tissue-agnostic cancer.

[0052] Thus, as used herein, the term "antibody" is used to refer to any antibody-like molecule having an antigen-binding region, and includes antibody fragments comprising an antigen-binding domain such as Fab', Fab, F(ab')2, single domain antibodies (DAB), TandAbs dimers, Fv, scFv (single-chain Fv), dsFv, ds-scFv, Fd, linear antibodies, minibodies, diabodies, bispecific antibody fragments, bibodies, tribodies (bispecific or trispecific scFv-Fab fusions, respectively); sc-diabodies; kappa (lambda) bodies (scFv-CL fusions); BiTEs (bispecific Examples of antibody-based constructs include heterologous T cell engagers, scFv-scFv tandems that attract T cells; DVD-Ig (dual variable domain antibodies, bispecific format); SIP (small immune protein, a type of minibody); SMIP ("small modular immunopharmaceutical", scFv-Fc dimers; DART (ds stabilized diabody "dual affinity retargeting"); small antibody mimetics containing one or more CDRs, and the like. Techniques for preparing and using various antibody-based constructs and fragments are known in the art (see Rabat, 2002, which is specifically incorporated herein by reference). (see, e.g., E. et al., 1991). Diabodies in particular are further described in European Patent Application Publication No. 404,097 and International Publication No. WO 93 / 11161, while linear antibodies are further described in Zapata et al. (1995). Antibodies can be fragmented using conventional techniques. For example, F(ab')2 fragments can be generated by treating antibodies with pepsin. The resulting F(ab')2 fragments can be treated to reduce disulfide bridges to generate Fab' fragments. Papain digestion can lead to the formation of Fab fragments. Fab, Fab', F(ab')2, scFv, Fv, dsFv, Fd, dAbs, TandAbs, ds-scFv, dimers, minibodies, diabodies, bispecific antibody fragments and other fragments can also be synthesized recombinantly or chemically. Techniques for generating antibody fragments are known and described in the art.For example, Beckman et al., 2006, Holliger & Hudson, 2005, Le Gall et al., 2004, Reff & Heard, 2001, Reiter et al., 1996, and Young et al., 1995 each further detail and enable the generation of effective antibody fragments. In some embodiments, the antibodies of the invention are single chain antibodies. As used herein, the term "single domain antibody" has its general meaning in the art and refers to a single heavy chain variable domain of the type of antibody found in camelid mammals that naturally lack light chains. Such single domain antibodies are also referred to as "Nanobodies™". For a general description of (single) domain antibodies, reference is made to the prior art documents cited above, as well as to EP 0368684, Ward et al. (Nature 1989 Oct 12; 341 (6242): 544-6), Holt et al., Trends Biotechnok, 2003, 21(11):484-490, and WO 06 / 030220, WO 06 / 003388. In some embodiments, the antibody is a humanized antibody. As used herein, "humanized" refers to an antibody in which some, most or all of the amino acids outside the CDR regions have been replaced with corresponding amino acids from human immunoglobulin molecules. Methods for humanization include, but are not limited to, those described in U.S. Pat. Nos. 4,816,567, 5,225,539, 5,585,089, 5,693,761, 5,693,762, and 5,859,205, which are incorporated herein by reference.

[0053] SIK3 inhibitor compounds "Salt-inducible kinase 3" or "SIK3" (synonyms QSK and KIAA0999) is a member of a subfamily of serine / threonine protein kinases that includes SIK1, SIK2, and SIK3, and belongs to the AMP-activated protein kinase (AMPK) family. The SIK3 protein in the context of the present invention is typically a protein kinase. Relevant information on the human SIK3 protein is available in UniProt: Q9Y2K2 (entry version 138 of March 15, 2017), and the SIK3 protein in the context of the present invention preferably has the amino acid sequence shown in SIK3, entry version 138 of March 15, 2017, or entry version 144 of March 28, 2018, which sequences are incorporated herein by reference. SIK3 is a cytoplasmic protein with serine / threonine kinase activity, which is regulated through phosphorylation of a conserved threonine residue (position 163) in the T-loop of the kinase domain by the LKB1 complex. This phosphorylation has been reported to be essential for the catalytic activity of SIK3 (Lizcano, JM et al.; EMBO J. 23, 833-843 (2004)). For the purposes of the present invention disclosed herein, the term "phosphorylated SIK3" refers to a SIK3 protein that is phosphorylated in substantially the same manner as the SIK3 protein can be phosphorylated (e.g., is phosphorylated) by LKB1, and preferably such phosphorylated SIK3 includes a phosphorylated threonine at amino acid position 163. Phosphorylated SIK3 in the context of the present invention is a SIK3 protein that is activated in its cell biological context. At least four protein isoforms (SIK3-001 to SIK3-004) are known that are generated by alternative splicing of the SIK3 gene product. The human SIK3 gene is located at chromosome location 11q23.3 (HGNC gene symbol Acc:HGNC:29165) and is conserved in many species, including chimpanzee, rhesus monkey, dog, cow, mouse, rat, chicken, zebrafish, and frog.The term SIK3 in some embodiments of the present invention may also refer to variants of human SIK3 proteins having amino acid sequences substantially identical to the above-mentioned SIK3 amino acid sequences or having at least 80%, preferably 85%, more preferably 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, as determined, for example, using the "Blast 2 sequences" algorithm described by Tatusova & Madden 1999 (FEMS Microbiol Lett 174: 247-250), and (preferably) retaining the same or substantially the same biological activity (e.g., phosphorylating one or more class II (e.g., IIa) HDACs, such as HDAC4) as the respective reference SIK3. Preferred variants of SIK3 proteins include sequence variants due to sequence polymorphisms between and within the respective species populations, as well as mutations relative to the wild-type sequence of SIK3 located in or near the activation loop or activation loop (T-loop) of SIK3. A preferred variant of the SIK3 protein is the SIK3 T163 mutation, such as a mutation that affects the activation of SIK3. In a preferred embodiment, the SIK3 protein of the present invention is not a SIK1 (synonyms: SIK and SNF1LK) protein and / or is not a SIK2 (synonyms: QIK, KIAA0781 and SNF1LK2) protein. The amino acid sequences of human SIK1 (UniProt: P57059; entry version 168 of March 15, 2017) and human SIK2 (UniProt: Q9H0K1; entry version 153 of March 15, 2017) are incorporated herein by reference. Depending on the context (unless more specifically indicated), the term SIK3 may refer to a SIK3 protein (such as those described above) or an mRNA molecule encoding such a SIK3 protein. The same meaning is understood for "SIK1" and "SIK2".

[0054] In a first embodiment, as further described, defined, claimed or otherwise disclosed herein, the present invention provides, as a SIK3 inhibitor, a compound of the formula: [ka] and its solvates, salts, N-oxides, complexes, polymorphs, crystalline forms, racemic mixtures, diastereomers, enantiomers, tautomers, conformers, isotopically labeled forms, prodrugs, and combinations thereof, During the ceremony, Hy is one or more independently selected R 1e heteroaryl or heterocyclyl optionally substituted with Each R 1e are independently 1a , R 1b , R 1c and R 1d is selected from the group consisting of Each R 1a and R 1d are independently H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, halogen, -CN, azide, -NO2, -OR 11 , -N(R 12 )(R 13 ), -N(R 11 )(OR 11 ), -S(O) 0~2 R 11 , -S(O) 1~2 OR 11 , -OS(O) 1~2 R 11 , -OS(O) 1~2 OR 11 , -S(O) 1~2 N(R 12 )(R 13 ), -OS(O) 1~2 N(R 12 )(R 13 ), -N(R 11 )S(O) 1~2 R 11 , -NR 11 S(O) 1~2 OR 11 , -NR 11 S(O) 1~2 N(R 12 )(R 13 ), -P(O)(OR 11)2, -OP(O)(OR 11 )2, -C(=X)R 11 , -C(=X)XR 11 , -XC(=X)R 11 and -XC(=X)XR 11 wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl groups is selected from the group consisting of one or more independently selected R 30 and optionally substituted with R 1b and R 1c each independently represents H, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 Cycloalkyl, C 6~10 Aryl, 3- to 7-membered heteroaryl, 3- to 7-membered heterocyclyl, -O(CH2) 0~2 (C 3~7 Cycloalkyl), -O(CH2) 0~2 (C 6~10 Aryl), -O(CH2) 0~2 (3- to 7-membered heteroaryl), -O(CH2) 0~2 (3- to 7-membered heterocyclyl), -NH(CH2) 0~2 (C 3~7 Cycloalkyl), -NH(CH2) 0~2 (C 6~10 Aryl), -NH(CH2) 0~2 (3- to 7-membered heteroaryl), -NH(CH2) 0~2 (3- to 7-membered heterocyclyl), halogen, -CF3, -CN, azide, -NO2, -OH, -O(C 1~6 alkyl), -OCF3, -S(C 1~6 alkyl), -NH2, -NH(C 1~6 alkyl), -N(C 1~6 alkyl)2, -NHS(O)2(C 1~6 alkyl), -S(O)2NH 2~z (C 1~6 Alkyl) z , -C(=O)(C 1~6 alkyl), -C(=O)OH, -C(=O)O(C 1~6alkyl), -C(=O)NH 2~z (C 1~6 Alkyl) z , -NHC(=O)(C 1~6 alkyl), -NHC(=NH)NH z~2 (C 1~6 Alkyl) z , and -N(C 1~6 Alkyl)C(=NH)NH 2~z (C 1~6 Alkyl) z where z is 0, 1, or 2; 1~6 Alkyl group, C 2~6 Alkenyl group, C 2~6 Alkynyl group, C 3~7 Cycloalkyl groups, C 6~10 The aryl group, the 3- to 7-membered heteroaryl group, and the 3- to 7-membered heterocyclyl group each include -OH, methyl, ethyl, -OCH3, -SCH3, and -NH 2~z (CH3) z and optionally substituted with one, two, or three moieties independently selected from the group consisting of: R 2 is H, R 3 is H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, halogen, -CN, azide, -NO2, -OR 11 , -N(R 12 )(R 13 ), -N(R 11 )(OR 11 ), -S(O) 0~2 R 11 , -S(O) 1~2 OR 11 , -OS(O) 1~2 R 11 , -OS(O) 1~2 OR 11 , -S(O) 1~2 N(R 12 )(R 13 ), -OS(O) 1~2 N(R 12 )(R 13 ), -N(R 11 )S(O) 1~2 R11 , -NR 11 S(O) 1~2 OR 11 , -NR 11 S(O) 1~2 N(R 12 )(R 13 ), -P(O)(OR 11 )2, -OP(O)(OR 11 )2, -C(=X)R 11 , -C(=X)XR 11 , -XC(=X)R 11 , and -XC(=X)XR 11 wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl groups is selected from the group consisting of one or more independently selected R 30 and optionally substituted with R 4 is H, R 5 Ha-LR 6 and L is a bond, C 1~6 Alkylene, C 2~6 Alkenylene, C 2~6 Alkynylene, and -(CH2) m -[Y-(CH2) n ] o -, where m is an integer from 1 to 6, n is an integer from 0 to 3, o is an integer from 1 to 3, and when n is 0, o is 1; and Y is independently selected from the group consisting of O, S, and -N(R 13 )-, C 1~6 Alkylene group, C 2~6 Alkenylene group, C 2~6 Alkynylene group, -(CH2) m - group, and -(CH2) n Each of the - groups is selected from one or two independently selected R 30 and optionally substituted with R 6 contains at least one S ring atom and one or more independently selected R 7 is a 5-membered monocyclic heteroaryl substituted with R 7are independently alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, halogen, -CN, azide, -NO2, -OR 11 , -N(R 12 )(R 13 ), -N(R 11 )(OR 11 ), -S(O) 0~2 R 11 , -S(O) 1~2 OR 11 , -OS(O) 1~2 R 11 , -OS(O) 1~2 OR 11 , -S(O) 1~2 N(R 12 )(R 13 ), -OS(O) 1~2 N(R 12 )(R 13 ), -N(R 11 )S(O) 1~2 R 11 , -NR 11 S(O) 1~2 OR 11 , -NR 11 S(O) 1~2 N(R 12 )(R 13 ), -P(O)(OR 11 )2, -OP(O)(OR 11 )2, -C(=X)R 11 , -C(=X)XR 11 , -XC(=X)R 11 , and -XC(=X)XR 11 wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl groups is selected from the group consisting of one or more independently selected R 30 where R 7 At least one of is F, and / or R 7 at least one of is substituted with one or more F atoms, A is S, O, NR 8 , and C(R 9 ) 2 selected from the group consisting of R 8is selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl, where each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl groups is selected from one or more independently selected R 30 and optionally substituted with R 9 are independently alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, halogen, -CN, azide, -NO2, -OR 11 , -N(R 12 )(R 13 ), -S(O) 0~2 R 11 , -S(O) 1~2 OR 11 , -OS(O) 1~2 R 11 , -OS(O) 1~2 OR 11 , -S(O) 1~2 N(R 12 )(R 13 ), -OS(O) 1~2 N(R 12 )(R 13 ), -N(R 11 )S(O) 1~2 R 11 , -NR 11 S(O) 1~2 OR 11 , -NR 11 S(O) 1~2 N(R 12 )(R 13 ), -C(=X)R 11 , -C(=X)XR 11 , -XC(=X)R 11 , and -XC(=X)XR 11 wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl groups is selected from the group consisting of one or more independently selected R 30 and optionally substituted with X is independently O, S, or N(R 14 ) selected from the group consisting of E is O or S; R 11 is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl, where each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups is selected from one or more independently selected R 30 and optionally substituted with R 12 and R 13 each is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl, or R 12 and R 13 together with the nitrogen atom to which they are attached form -N=CR 15 R 16 group, where each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups can be selected from one or more independently selected R 30 and optionally substituted with R 14 are independently H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, and -OR 11 wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups is selected from the group consisting of one or more independently selected R 30 and optionally substituted with R 15 and R 16 each independently is H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, and -NH y R 20 2~y or R 15 and R 16 may be joined together with the atoms to which they are attached to form a ring, which may be formed by one or more independently selected R 30wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups is optionally substituted with one or more independently selected R 30 and optionally substituted with y is an integer from 0 to 2; R 20 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl, where each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups is selected from one or more independently selected R 30 and optionally substituted with R 30 are first level substituents, each independently being alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, halogen, -CN, azide, -NO2, -OR 71 , -N(R 72 )(R 73 ), -S(O) 0~2 R 71 , -S(O) 1~2 OR 71 , -OS(O) 1~2 R 71 , -OS(O) 1~2 OR 71 , -S(O) 1~2 N(R 72 )(R 73 ), -OS(O) 1~2 N(R 72 )(R 73 ), -N(R 71 )S(O) 1~2 R 71 , -NR 71 S(O) 1~2 OR 71 , -NR 71 S(O) 1~2 N(R 72 )(R 73 ), -OP(O)(OR 71 )2, -C(=X 1 )R 71 , -C(=X 1 )X1 R 71 , -X 1 C(=X 1 )R 71 , and -X 1 C(=X 1 )X 1 R 71 and / or any two R attached to the same carbon atom of a cycloalkyl or heterocyclyl group are selected from the group consisting of 30 Let's get together =X 1 wherein each of the first level substituent alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl groups is optionally substituted with one or more second level substituents, wherein each of said second level substituents is independently selected from the group consisting of: 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, 3- to 14-membered aryl, 3- to 14-membered heteroaryl, 3- to 14-membered cycloalkyl, 3- to 14-membered heterocyclyl, halogen, -CF3, -CN, azide, -NO2, -OR 81 , -N(R 82 )(R 83 ), -S(O) 0~2 R 81 , -S(O) 1~2 OR 81 , -OS(O) 1~2 R 81 , -OS(O) 1~2 OR 81 , -S(O) 1~2 N(R 82 )(R 83 ), -OS(O) 1~2 N(R 82 )(R 83 ), -N(R 81 )S(O) 1~2 R 81 , -NR 81 S(O) 1~2 OR 81 , -NR 81 S(O) 1~2 N(R 82 )(R 83 ), -OP(O)(OR 81 )2, -C(=X2 )R 81 , -C(=X 2 )X 2 R 81 , -X 2 C(=X 2 )R 81 , and -X 2 C(=X 2 )X 2 R 81 and / or any two second level substituents attached to the same carbon atom of a first level substituent cycloalkyl or heterocyclyl group are taken together to be =X. 2 where the second level substituent C 1~6 Alkyl group, C 2~6 Alkenyl group, C 2~6 Each of the alkynyl group, the 3- to 14-membered aryl group, the 3- to 14-membered heteroaryl group, the 3- to 14-membered cycloalkyl group, and the 3- to 14-membered heterocyclyl group is optionally substituted with one or more third level substituents, wherein each said third level substituent is independently selected from the group consisting of C 1~3 Alkyl, halogen, -CF3, -CN, azide, -NO2, -OH, -O(C 1~3 alkyl), -OCF3, -S(C 1~3 alkyl), -NH2, -NH(C 1~3 alkyl), -N(C 1~3 alkyl)2, -NHS(O)2(C 1~3 alkyl), -S(O)2NH 2~z (C 1~3 Alkyl) z , -C(=O)OH, -C(=O)O(C 1~3 alkyl), -C(=O)NH 2~z (C 1~3 Alkyl) z , -NHC(=O)(C 1~3 alkyl), -NHC(=NH)NH z~2 (C 1~3 Alkyl) z , and -N(C 1~3 Alkyl)C(=NH)NH 2~z (C 1~3 Alkyl) zwherein each z is independently 0, 1, or 2; and each C 1~3 Alkyl is independently methyl, ethyl, propyl, or isopropyl, and / or any two third level substituents attached to the same carbon atom of a 3- to 14-membered cycloalkyl or heterocyclyl group that is a second level substituent are taken together to be =O, =S, =NH, or =N(C 1~3 alkyl), Where: R 71 , R 72 , and R 73 each independently represents H, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 alkynyl, 3- to 7-membered cycloalkyl, 5- or 6-membered aryl, 5- or 6-membered heteroaryl, and 3- to 7-membered heterocyclyl, wherein C 1~6 Alkyl group, C 2~6 Alkenyl group, C 2~6 Each of the alkynyl group, the 3- to 7-membered cycloalkyl group, the 5- or 6-membered aryl group, the 5- or 6-membered heteroaryl group, and the 3- to 7-membered heterocyclyl group is 1~3 Alkyl, halogen, -CF3, -CN, azide, -NO2, -OH, -O(C 1~3 alkyl), -OCF3, =O, -S(C 1~3 alkyl), -NH2, -NH(C 1~3 alkyl), -N(C 1~3 alkyl)2, -NHS(O)2(C 1~3 alkyl), -S(O)2NH 2~z (C 1~3 Alkyl) z , -C(=O)(C 1~3 alkyl), -C(=O)OH, -C(=O)O(C 1~3 alkyl), -C(=O)NH 2~z (C 1~3 Alkyl) z , -NHC(=O)(C 1~3 alkyl), -NHC(=NH)NH z~2 (C 1~3 Alkyl) z , and -N(C1~3 Alkyl)C(=NH)NH 2~z (C 1~3 Alkyl) z where each z is independently 0, 1, or 2; and each C 1~3 alkyl is independently methyl, ethyl, propyl, or isopropyl; R 81 , R 82 , and R 83 each independently represents H, C 1~4 Alkyl, C 2~4 Alkenyl, C 2~4 alkynyl, 3- to 6-membered cycloalkyl, 5- or 6-membered aryl, 5- or 6-membered heteroaryl, and 3- to 6-membered heterocyclyl, wherein C 1~4 Alkyl group, C 2~4 Alkenyl group, C 2~4 Each of the alkynyl group, the 3- to 6-membered cycloalkyl group, the 5- or 6-membered aryl group, the 5- or 6-membered heteroaryl group, and the 3- to 6-membered heterocyclyl group is 1~3 Alkyl, halogen, -CF3, -CN, azide, -NO2, -OH, -O(C 1~3 alkyl), -OCF3, =O, -S(C 1~3 alkyl), -NH2, -NH(C 1~3 alkyl), -N(C 1~3 alkyl)2, -NHS(O)2(C 1~3 alkyl), -S(O)2NH 2~z (C 1~3 Alkyl) z , -C(=O)(C 1~3 alkyl), -C(=O)OH, -C(=O)O(C 1~3 alkyl), -C(=O)NH 2~z (C 1~3 Alkyl) z , -NHC(=O)(C 1~3 alkyl), -NHC(=NH)NH z~2 (C 1~3 Alkyl) z , and -N(C 1~3 Alkyl)C(=NH)NH 2~z (C1~3 Alkyl) z where each z is independently 0, 1, or 2; and each C 1~3 alkyl is independently methyl, ethyl, propyl, or isopropyl; X 1 and X 2 Each of R is independently O, S, and N(R 84 ), where R 84 is H or C 1~3 It is an alkyl.

[0055] Such compounds that are kinase inhibitors are defined and exemplified in detail in WO 2021 / 214117, which is incorporated herein by reference in its entirety for purposes of defining the SIK3 inhibitors of the present invention.

[0056] A selection of SIK3 inhibitor compounds, including those synthesized and tested for use within the disclosure or methods of WO 2021 / 214117, are listed in Table A below.

[0057] [Table 1] TIFF2025511852000003.tif254170TIFF2025511852000004.tif98170

[0058] In certain embodiments, the compound of the present invention is selected from the group consisting of E4, E9, E10, and E16, and also from the group consisting of solvates, salts, N-oxides, complexes, polymorphs, crystalline forms, racemic mixtures, diastereomers, enantiomers, tautomers, conformers, isotopically labeled forms, prodrugs, and combinations thereof.

[0059] In certain embodiments, the compound of the present invention is E9, or a solvate, salt, N-oxide, complex, polymorph, crystalline form, tautomer, conformer, isotopically labeled form, prodrug, or combination thereof.

[0060] In another particular embodiment, the compound of the present invention is E4, or a solvate, salt, N-oxide, complex, polymorph, crystalline form, tautomer, conformer, isotopically labeled form, prodrug, or combination thereof.

[0061] In another particular embodiment, the compound of the invention is E10, or a solvate, salt, N-oxide, complex, polymorph, crystalline form, tautomer, conformer, isotopically labeled form, prodrug, or combination thereof.

[0062] In another particular embodiment, the compound of the present invention is E16, or a solvate, salt, N-oxide, complex, polymorph, crystalline form, racemic mixture, diastereomer, enantiomer, tautomer, conformer, isotopically labeled form, prodrug, or combination thereof.

[0063] In certain embodiments, the invention may relate to solvates, salts, N-oxides, complexes, racemic mixtures, diastereomers, enantiomers, tautomers, conformers, isotopically labeled forms, prodrugs, or combinations thereof of any of the compounds of the invention or any of the compounds used in the invention, such as solvates, salts, complexes, racemic mixtures, diastereomers, enantiomers, tautomers, conformers, isotopically labeled forms, or combinations thereof of such compounds.

[0064] The SIK3 inhibitor compounds of the present invention (and / or compounds used in the present invention) may be in the form of prodrugs. A prodrug of a compound of the present invention (or a compound used in the present invention) is a compound that undergoes chemical conversion under physiological conditions to provide a compound of the present invention upon administration to an individual. Furthermore, a prodrug can be converted to a compound of the present invention (or a compound used in the present invention) by chemical or biochemical methods in an ex vivo environment. For example, a prodrug can be slowly converted to a compound of the present invention (or a compound used in the present invention) when placed, for example, in a transdermal patch reservoir with a suitable enzyme or chemical reagent. Exemplary prodrugs are in vivo hydrolyzable esters (using an alcohol or carboxy group contained in the kinase inhibitors of the present invention (or a compound used in the present invention)) or amides (using an amino or carboxy group contained in the kinase inhibitors of the present invention (or a compound used in the present invention)). In particular, any amino group contained in the kinase inhibitors of the present invention (or a compound used in the present invention) that has at least one hydrogen atom can be converted to a prodrug form.

[0065] In another embodiment, the compounds of the invention exhibit one or more pharmacological properties that differ from those of dasatinib, compound B3 (WO 2018 / 193084), and / or compound C7 (International Application PCT / EP2019 / 078751).

[0066] In addition to the small molecule kinase inhibitors described above, the present invention also includes other strategies for interfering with the cellular function of SIK3. Other compounds are known, for example, from WO 2021 / 219731, WO 2019 / 202160 and WO 2018 / 193084.

[0067] A compound that is an "inhibitor of SIK3" (or "SIK3 inhibitor") is any moiety that inhibits SIK3, which may mean inhibiting the activity of SIK3, particularly the SIK3 protein, particularly phosphorylated SIK3. A SIK3 inhibitor may reduce (e.g., induce a decrease or decrease) the efficiency, effectiveness, amount or rate of one or more activities of SIK3, such as one or more of the activities described herein, such as the activity of SIK3 phosphorylating class II (e.g., Ila) HDAC (e.g., HDAC4) and / or the activity of SIK3 sensitizing cells involved in a proliferative disorder to a cell-mediated immune response. Such a SIK3 inhibitory moiety can act directly, for example, by binding to SIK3 and reducing one or more of the properties of SIK3, such as its function, particularly the amount or rate of its ability to act as a kinase (e.g., phosphorylate HDAC4), e.g., by reducing the activity of phosphorylated SIK3 in a cell.

[0068] In certain embodiments of these combination aspects, the inhibitor or antagonist of said SIK3 kinase or variant is preferably an inhibitory or antagonistic small molecule as described herein. In other embodiments of these combination aspects, the inhibitor or antagonist of said SIK3 or variant is a compound selected from a polypeptide, a peptide, a glycoprotein, a peptidomimetic, an antibody or an antibody-like molecule; a nucleic acid such as DNA or RNA, for example, antisense DNA or RNA, a ribozyme, an RNA or DNA aptamer, siRNA, shRNA and the like (including variants or derivatives thereof, such as peptide nucleic acid (PNA)); a targeted gene editing construct, for example, a CRISPR / Cas9 construct, a carbohydrate such as polysaccharides or oligosaccharides and the like (including variants or derivatives thereof); a lipid such as fatty acid and the like (including variants or derivatives thereof); or a small organic molecule, including, but not limited to, a small molecule ligand, a small cell-permeable molecule, and a peptidomimetic compound.

[0069] Pharmaceutical Compositions The compounds described in the present invention (particularly the SIK3 inhibitor compounds described above, particularly those shown in Table A) or used in the present invention are preferably administered to a patient in need thereof via a pharmaceutical composition. Thus, in a second aspect, the present invention provides a pharmaceutical composition comprising a kinase inhibitor as defined under the heading "Compound" above (e.g., a SIK3 kinase inhibitor having general formula (Ia), a complex, a polymorph, a crystalline form, a racemic mixture, a diastereomer, an enantiomer, a tautomer, a conformer, an isotopically labeled form, a prodrug, or a combination thereof) and optionally one or more pharma- ceutically acceptable excipients.

[0070] Thus, in one embodiment, the pharmaceutical composition comprises a kinase inhibitor as defined under the heading "Compound" above (particularly a compound of the first aspect of the invention) and one or more pharma- ceutically acceptable excipients. Moreover, the pharmaceutical composition may further comprise one or more additional therapeutic agents. Thus, in certain embodiments, the pharmaceutical composition comprises (i) a kinase inhibitor as defined under the heading "Compound" above (particularly a compound of the first aspect of the invention) and one or more additional therapeutic agents, or (ii) a kinase inhibitor as defined under the heading "Compound" above (particularly a compound of the first aspect of the invention) and one or more additional therapeutic agents and one or more pharma- ceutically acceptable excipients.

[0071] The term "pharmaceutical acceptable" refers to the non-toxicity of a material that does not interact with the (e.g., therapeutic) action of the active ingredients of a pharmaceutical composition (e.g., a kinase inhibitor of the invention (or a compound used in the invention), either alone or in combination with one or more additional therapeutic agents).

[0072] The pharmaceutical compositions may be administered to an individual by any route, such as enterally or parenterally.

[0073] As used herein, the terms "enteral administration" and "administered enterally" mean that the administered drug is absorbed by the stomach and / or intestines. Examples of enteral administration include oral administration and rectal administration. As used herein, the terms "parenteral administration" and "administered parenterally" mean administration methods other than enteral administration, usually by injection or topical application, including, but not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraosseous, intraorbital, intracardiac, intradermal, intraperitoneal, intratracheal, subcutaneous, subcuticular, intraarticular, subcapsular, intracerebral, intraventricular, subarachnoid, intraspinal, epidural and intrasternal administration (such as injection and / or infusion), and topical administration (e.g., transdermal, inhalation, or via mucous membranes (e.g., buccal, sublingual, vaginal)).

[0074] Dosage forms for topical and / or transdermal administration of the compounds described herein may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, and / or patches. In general, the active ingredient is mixed under sterile conditions with a pharma- ceutically acceptable excipient (such as one or more pharmaceutical carriers) and / or any needed preservatives and / or buffers, as appropriate. In addition, the present disclosure contemplates the use of transdermal patches, which often have the added advantage of delivering the active ingredient to the body in a controlled manner. Such dosage forms can be prepared, for example, by dissolving and / or dispersing the active ingredient in a suitable medium. Alternatively or additionally, the rate can be controlled either by providing a rate-controlling membrane and / or by dispersing the active ingredient in a polymer matrix and / or gel.

[0075] Suitable devices for use in delivering the intradermal pharmaceutical compositions described herein include short needle devices. Intradermal compositions can be administered by devices that limit the effective penetration length of the needle into the skin. Alternatively, or in addition, a conventional syringe can be used in the classical Mantoux method of intradermal administration. Jet injection devices are suitable that deliver liquid formulations to the dermis via a liquid jet injector and / or via a needle that generates a jet that penetrates the stratum corneum and reaches the dermis. Ballistic powder / particle delivery devices are suitable that use compressed gas to accelerate powdered compounds from the outer layer of the skin to the dermis.

[0076] Formulations suitable for topical administration include, but are not limited to, liquid and / or semi-liquid preparations such as liniments, lotions, oil-in-water and / or water-in-oil emulsions, e.g., creams, ointments, and / or pastes, and / or solutions and / or suspensions. Topically administrable formulations may contain, for example, from about 1% (w / w) to about 10% (w / w) of the active ingredient, although the concentration of the active ingredient may be as high as the solubility limit of the active ingredient in the solvent. Formulations for topical administration may further include one or more of the additional ingredients described herein.

[0077] The compounds of the present invention (or compounds used in the present invention) are generally applied in "pharmaceutically acceptable amounts" and "pharmaceutically acceptable preparations". Such compositions may contain salts, buffers, preservatives, carriers, and optionally other therapeutic agents. "Pharmaceutically acceptable salts" include acid addition salts that may be formed, for example, by mixing a solution of the compound with a solution of a pharmaceutically acceptable acid, such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid, or phosphoric acid. In addition, when the compound has an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts (e.g., sodium or potassium salts); alkaline earth metal salts (e.g., calcium or magnesium salts); and salts formed with suitable organic ligands (e.g., ammonium, quaternary ammonium, and amine cations formed using counter anions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, alkylsulfonates, and arylsulfonates).Specific examples of pharma- ceutically acceptable salts include acetate, adipate, alginate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium edetate, camphorate, camphorsulfonate, camsylate, carbonate, chloride, citrate, clavulanate, cyclopentanepropionate, and diglucanate. Conate, dihydrochloride, dodecyl sulfate, edetate, edisylate, estolate, esylate, ethanesulfonate, formate, fumarate, galactate, galacturonate, gluceptate, glucoheptonate, gluconate, glutamate, glycerophosphate, glycolylarsanilate, hemisulfate, heptanoate, hexanoate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroiodide, 2-Hydroxyethanesulfonate, Hydroxynaphthoate, Iodide, Isobutyrate, Isethionate, Lactate, Lactobionate, Laurate, Lauryl Sulfate, Malate, Maleate, Malonate, Mandelate, Mesylate, Methanesulfonate, Methylsulfate, Mucate, 2-Naphthalenesulfonate, Napsylate, Nicotinate, Nitrate, N-Methylglucamine Ammonium Salt, Oleate, Oxalate, Pamoate (Embene Salts include, but are not limited to, salts of the following: phosphate, palmitate, pantothenate, pectinate, persulfate, 3-phenylpropionate, phosphate / diphosphate, phthalate, picrate, pivalate, polygalacturonate, propionate, salicylate, stearate, sulfate, suberate, succinate, tannate, tartrate, theoclate, tosylate, triethiodide, undecanoate, valerate, and the like (see, e.g., Berge et al., "Pharmaceutical Salts", J. Pharm. Sci., 66, pp. 1-19 (1977)).

[0078] The term "excipient" as used herein is intended to refer to any substance in a pharmaceutical composition that is not an active ingredient (e.g., a therapeutically inactive ingredient that does not have any therapeutic effect in the amount / concentration used), such as a carrier, binder, lubricant, thickener, surfactant, preservative, stabilizer, emulsifier, buffer, flavoring agent, coloring agent, or antioxidant.

[0079] The compositions described in the present invention may include a pharma- ceutically acceptable carrier. As used herein, "pharmaceutically acceptable carrier" includes any physiologically compatible solvent, dispersion medium, coating, isotonicity agent, absorption delaying agent, and the like. A "pharmaceutically acceptable carrier" may be in the form of a solid, semi-solid, liquid, or combinations thereof. Preferably, the carrier is suitable for enteral (e.g., oral) or parenteral (e.g., intravenous, intramuscular, subcutaneous, spinal or epidermal administration (e.g., by injection or infusion)). Depending on the route of administration, the active compound, e.g., the compound of the present invention (or the compound used in the present invention), alone or in combination with one or more additional therapeutic agents, may be coated with a material that protects the active compound(s) from the action of acids and other natural conditions that may inactivate the active compound.

[0080] Examples of suitable aqueous and non-aqueous carriers that can be employed in the pharmaceutical compositions according to the present invention include water (e.g., water for injection), ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, and the like), aqueous solutions of salts, carbohydrates, sugar alcohols, or amino acids (e.g., saline or aqueous amino acid solutions), and suitable mixtures thereof and / or buffered forms thereof, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate). Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0081] Pharmaceutically acceptable carriers include sterile aqueous solutions or dispersions and sterile powders for extemporaneous preparation of sterile injectable solutions or dispersions.The use of such media and agents for pharma-ceutically active compounds is known in the art.Except insofar as any conventional media or agent is incompatible with the active compound, its use in the pharmaceutical compositions according to the present invention is contemplated.

[0082] The pharmaceutical compositions described herein may contain at least one, for example one, two, three, four, five, six, seven or eight additional therapeutic agents in addition to the kinase inhibitors and PD-1 inhibitors of the present invention (and / or the compounds or compositions used in the present invention). According to the present teachings, the at least one additional therapeutic agent may be formulated together with the kinase inhibitors of the present invention (and / or the compounds used in the present invention) in a single pharmaceutical composition. Alternatively, the pharmaceutical composition may be configured as a kit of parts, where the kinase inhibitors of the present invention (or the compounds used in the present invention) are provided in a first formulation and the at least one additional therapeutic agent is provided in a second formulation, i.e., the second pharmaceutical composition. The first pharmaceutical composition and the second pharmaceutical composition may be combined before use. In other words, a formulation containing the additional therapeutic agent may be added to the first pharmaceutical composition containing the kinase inhibitors of the present invention (or the compounds used in the present invention) before administering the pharmaceutical composition. Alternatively, the present teachings also contemplate administering the kinase inhibitor of the present invention (or the compound used in the present invention) formulated in a first pharmaceutical composition and administering at least one additional therapeutic agent formulated in a second pharmaceutical composition. The pharmaceutical compositions can be administered in combination or sequentially. For example, the first pharmaceutical composition can be administered at a first time point and the second pharmaceutical composition can be administered at a second time point, where the time points can be separated by, for example, 0 minutes, or up to 1, 2, 3, 4, 5, or 10 minutes, up to 1, 2, 3, 4, 5, or 10 hours, up to 1, 2, 3, 4, 5, or 10 days, up to 1, 2, 3, 4, 5, or 10 weeks, up to 1, 2, 3, 4, 5, or 10 months, or up to 1, 2, 3, 4, 5, or 10 years.

[0083] The composition may contain auxiliary agents such as preservatives, stabilizers, wetting agents, emulsifiers, pH buffers, and dispersants. Prevention of the presence of microorganisms can be ensured by sterilization procedures and / or the inclusion of various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents in the composition, such as sugars, sodium chloride, and the like. In addition, the inclusion of agents that delay absorption, such as aluminum monostearate and gelatin, can prolong the absorption of the injectable preparation.

[0084] Regardless of the selected route of administration, the active compounds, which may be used in a suitable hydrated form, and / or the pharmaceutical compositions according to the present invention are formulated into pharma- ceutically acceptable dosage forms by conventional methods known to those skilled in the art (see, for example, Remington, "The Science and Practice of Pharmacy" edited by Allen, Loyd V., Jr., 22nd edition, Pharmaceutical Sciences, September 2012; Ansel et al., "Pharmaceutical Dosage Forms and Drug Delivery Systems", 7th edition, Lippincott Williams & Wilkins Publishers, 1999).

[0085] Pharmaceutical compositions can be administered in various ways known in the art. As will be appreciated by those skilled in the art, the route and / or mode of administration will vary depending on the desired results. Pharmaceutical compositions containing one or more active compounds can be prepared with a carrier that protects one or more active compounds from rapid release, such as controlled release formulations, including implants, transdermal patches, and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparing such compositions are generally known to those skilled in the art. For example, see Sustained and Controlled Release Drug Delivery Systems, JR Robinson, ed., Marcel Dekker, Inc., New York, 1978.

[0086] In order to administer the compound of the present invention (or the compound used in the present invention) by a certain route of administration, it may be necessary to coat the compound with a material that prevents its inactivation, or to co-administer the compound with the material.For example, the compound can be administered to an individual in a suitable carrier, such as liposome, or diluent.Pharmaceutically acceptable diluents include saline and aqueous buffers.Liposomes include water-in-oil-in-water CGF emulsions as well as conventional liposomes (Strejan et al., J. Neuroimmunol. 7: 27(1984)).

[0087] The pharmaceutical compositions are typically sterile and stable under the conditions of manufacture and storage. The compositions can be formulated as solutions, microemulsions, liposomes, or other ordered structures suitable for high drug concentrations. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion, and by the use of surfactants. In many cases, it is preferable to include an isotonic agent, for example, sugar, polyalcohol such as mannitol, sorbitol, or sodium chloride in the composition. Prolonged absorption of an injectable composition can be brought about by including an agent that delays absorption, for example, monostearate salts and gelatin in the composition.

[0088] Injectable composition should be sterile and fluid to the extent that composition can be delivered by syringe.Besides water, carrier can be isotonic buffered saline solution, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like) and their appropriate mixture.Sterile injectable solution can be prepared by incorporating active compound in the required amount in appropriate solvent, adding one or combination of the above-listed components as required, and then carrying out sterilization microfiltration.

[0089] Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle containing a basic dispersion medium and the necessary other ingredients listed above. In the case of sterile powders for preparing sterile injectable solutions, the preferred preparation method is vacuum drying and freeze-drying (lyophilization) to obtain a powder of the active ingredient plus any additional desired ingredients from the solution that has been previously sterile-filtered.

[0090] Dosage regimens are adjusted to provide the optimum desired response (e.g., therapeutic response). For example, a single bolus may be administered, multiple divided doses may be administered over time, or the dose may be proportionally reduced or increased according to the exigencies of the therapeutic situation. It is particularly advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suitable as unitary dosages for the individual to be treated, each unit containing a predetermined amount of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specifications for the dosage unit forms used according to the present invention are determined and directly dependent on (a) the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such active compounds for the treatment of susceptibility in an individual.

[0091] Examples of pharma- ceutically acceptable antioxidants include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

[0092] For therapeutic / pharmaceutical preparations, compositions according to the invention include those suitable for enteral administration (such as oral or rectal) or parenteral administration (e.g. nasal, topical (including vaginal, buccal and sublingual)). The compositions may conveniently be presented in unit dosage form and may be prepared by any method known in the art of pharmacy. The amount of active ingredient (particularly the amount of a compound according to the invention) that can be combined with a carrier material to produce a pharmaceutical composition (e.g. a single dosage form) will vary depending on the individual being treated and the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the composition that produces a therapeutic effect.

[0093] Generally, out of 100% (pharmaceutical formulation / composition), the amount of active ingredient (in particular the amount of a compound according to the invention (or a compound used in the present invention), optionally together with other therapeutically active agents, if present in the pharmaceutical formulation / composition) ranges from about 0.01% to about 99%, preferably from about 0.1% to about 70%, most preferably from about 1% to about 30%, where the remainder is preferably made up of one or more pharma- ceutically acceptable excipients.

[0094] The amount of active ingredient, e.g., a compound according to the invention (or a compound used in the present invention), in a unit dosage form and / or when administered to an individual or used in a treatment ranges from about 0.1 mg to about 1000 mg (e.g., about 1 mg to about 500 mg, e.g., about 10 mg to about 200 mg) per unit dose or treatment. In certain embodiments, an appropriate amount of such an active ingredient can be calculated using the body weight or body surface area of ​​the individual, and is between about 1 mg / kg to 10 mg / kg (e.g., about 2 mg / kg to 5 mg / kg), or about 1 mg / m 2 ~about 400mg / m 2 (For example, about 3 mg / m 2 ~about 350mg / m 2 or about 10 mg / m 2 ~about 200mg / m 2 ) amount.

[0095] The actual dosage level of the active ingredient in the pharmaceutical compositions according to the invention can be varied to obtain an effective amount of the active ingredient to achieve the desired therapeutic response for a particular patient, composition, and mode of administration without causing toxicity to the patient. The selected dosage level will depend on a variety of pharmacokinetic factors, including the activity of the particular composition employed, the route of administration, the time of administration, the rate of excretion of the particular compound employed, the duration of treatment, other drugs, compounds and / or substances used in combination with the particular composition employed, the age, sex, weight, condition, general health, and previous medical history of the patient being treated, and similar factors known in the medical arts.

[0096] A physician or veterinarian of ordinary skill in the art can easily determine and formulate the (e.g., therapeutically) effective amount of the pharmaceutical composition required. For example, the physician or veterinarian can start the dosage of the compound according to the invention (or the compound used in the present invention) at a level lower than that required to achieve the desired therapeutic effect, and gradually increase the dosage until the desired effect is achieved. In general, a suitable daily dose of the composition according to the invention is the amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend on the factors mentioned above. Administration is preferably oral, intravenous, intramuscular, intraperitoneal, or subcutaneous, and is preferably administered in close proximity to the target site. If desired, the (e.g., therapeutically) effective daily dose of the pharmaceutical composition may be administered as two, three, four, five, six or more separate doses administered at appropriate intervals throughout the day, optionally in unit dosage form. Although it is possible to administer the compound according to the invention (or the compound used in the present invention) alone, it is preferred to administer the compound as a pharmaceutical formulation / composition.

[0097] For oral administration, pharmaceutical compositions according to the invention can take the form of tablets or capsules prepared by conventional means with pharma- ceutically acceptable excipients, such as binding agents (e.g., pregelatinized maize starch, polyvinylpyrrolidone, hydroxypropylmethylcellulose), fillers (e.g., lactose, microcrystalline cellulose, calcium hydrogen phosphate), lubricants (e.g., magnesium stearate, talc, silica), disintegrants (e.g., potato starch, sodium starch glycolate), or wetting agents (e.g., sodium lauryl sulfate). Liquid preparations for oral administration can take the form, for example, of solutions, syrups, or suspensions, or can be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations can be prepared by conventional means using pharma- ceutically acceptable additives, such as suspending agents (e.g., sorbitol, syrups, cellulose derivatives, hydrogenated edible fats), emulsifying agents (e.g., lecithin, acacia), non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol, fractionated vegetable oils), preservatives (e.g., methyl- or propyl-p-hydroxycarbonate, sorbic acid), and the like. The preparations may also contain buffer salts, flavoring, coloring, and sweetening agents as deemed appropriate. Preparations for oral administration can be suitably formulated to provide controlled release of the pharmaceutical compositions of the present invention.

[0098] In one embodiment, the compound is administered orally at a concentration of, for example, up to 100 mg / kg body weight (e.g., up to 50 mg / kg body weight, up to 40 mg / kg body weight, up to 30 mg / kg body weight, up to 20 mg / kg body weight, up to 10 mg / kg body weight, up to 5 mg / kg body weight, up to 4 mg / kg body weight, up to 3 mg / kg body weight, up to 2 mg / kg body weight, up to 1 mg / kg body weight).

[0099] In one embodiment, the compound is administered parenterally (e.g., intravenously, intramuscularly, or subcutaneously) at a concentration of, for example, up to 10 mg / kg body weight (e.g., up to 5 mg / kg body weight, up to 4 mg / kg body weight, up to 3 mg / kg body weight, up to 2 mg / kg body weight, up to 1 mg / kg body weight, up to 0.5 mg / kg body weight, up to 0.4 mg / kg body weight, up to 0.3 mg / kg body weight, up to 0.2 mg / kg body weight, up to 0.1 mg / kg body weight).

[0100] The pharmaceutical composition can be formulated as a suppository, using traditional binders and carriers such as triglycerides. Oral formulations can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc.

[0101] For administration by inhalation, the pharmaceutical compositions according to the invention are conveniently delivered in the form of an aerosol spray from pressurized packs or nebulizers using a suitable propellant (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, nitrogen, or other suitable gas). In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, for example, gelatin for use in an inhaler or insufflator can be formulated to contain a powder mix of a pharmaceutical composition according to the invention and a suitable powder base such as lactose or starch.

[0102] The pharmaceutical compositions according to the invention can be formulated for parenteral administration, for example, by injection, either by bolus injection or continuous infusion. In one embodiment, the compounds or compositions according to the invention can be administered by slow continuous infusion over an extended period, such as more than 24 hours, to reduce toxic side effects. Administration can also be by continuous infusion over a period of 2 hours to 24 hours, for example, 2 hours to 12 hours. Such a regimen can be repeated one or more times as needed, for example, after 6 months or 12 months.

[0103] In yet another embodiment, a compound or composition according to the invention is administered in a maintenance therapy, such as, for example, once a week for a period of six months or more.

[0104] Preparations for injection can be presented in unit dosage form (e.g., vials, multi-dose containers) with added preservatives. Pharmaceutical compositions according to the invention can take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles and can contain formulatory agents such as suspending, stabilizing or dispersing agents. Alternatively, the agent can be in powder form for constitution with a suitable vehicle (e.g., sterile pyrogen-free water) before use. Typically, compositions for intravenous administration are solutions in sterile isotonic aqueous buffer. Where necessary, the composition can also include a solubilizing agent and a local anesthetic such as lignocaine to ease pain at the site of the injection. Generally, the ingredients are supplied, either separately or mixed together in unit dosage form, as a dry lyophilized powder or water-free concentrate in a hermetically sealed container such as an ampule or sachette indicating the quantity of active agent. When the composition is administered by infusion, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline. Where the composition is administered by injection, an ampoule of sterile water for injection or saline can be provided so that the ingredients may be mixed prior to administration.

[0105] Compositions according to the invention suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate. Dosage forms for topical or transdermal administration of compositions according to the invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under sterile conditions with a pharma- ceutically acceptable carrier and any preservatives, buffers or propellants as may be required.

[0106] The therapeutic / pharmaceutical compositions can be administered using medical devices known in the art. For example, in a preferred embodiment, the therapeutic / pharmaceutical compositions according to the present invention can be administered with a needleless subcutaneous injection device, such as the devices disclosed in U.S. Patent No. 5,399,163, U.S. Patent No. 5,383,851, U.S. Patent No. 5,312,335, U.S. Patent No. 5,064,413, U.S. Patent No. 4,941,880, U.S. Patent No. 4,790,824, or U.S. Patent No. 4,596,556. Examples of known implants and modules useful in the present invention include those described in U.S. Pat. No. 4,487,603, which discloses an implantable microinfusion pump for administering drugs at a controlled rate; U.S. Pat. No. 4,486,194, which discloses a therapeutic device for administering pharmaceutical agents through the skin; U.S. Pat. No. 4,447,233, which discloses a drug infusion pump for delivering drugs at precise infusion rates; U.S. Pat. No. 4,447,224, which discloses a variable flow rate implantable infusion device for continuous drug delivery; U.S. Pat. No. 4,439,196, which discloses an osmotic drug delivery system having multiple chamber compartments; and U.S. Pat. No. 4,475,916, which discloses an osmotic drug delivery system.

[0107] Many other such implants, delivery systems, and modules are known to those skilled in the art. In certain embodiments, the compounds according to the invention can be formulated to ensure proper distribution in vivo. For example, the blood-brain barrier (BBB) ​​excludes many highly hydrophilic compounds. To ensure that the compounds according to the invention cross the BBB (if desired), they can be formulated, for example, in liposomes. For methods of making liposomes, see, for example, U.S. Pat. Nos. 4,522,811, 5,374,548, and 5,399,331. Liposomes may contain one or more moieties that selectively transport to specific cells or organs, thus enhancing targeted drug delivery (see, for example, VV Ranade (1989) J. Clin. Pharmacol. 29: 685). Exemplary targeting moieties include folic acid or biotin (see, e.g., U.S. Patent No. 5,416,016 to Low et al.), mannosides (Umezawa et al., (1988) Biochem. Biophys. Res. Commun. 153: 1038), antibodies (PG Bloeman et al. (1995) FEBS Lett. 357: 140; M. Owais et al. (1995) Antimicrob. Agents Chemother. 39: 180), and surfactant protein A receptor (Briscoe et al. (1995) Am. J. Physiol. 1233: 134).

[0108] In one embodiment, the compound according to the present invention (or the compound used in the present invention) is formulated in liposomes. In a more preferred embodiment, the liposomes contain a targeting moiety. In a most preferred embodiment, the compound in the liposomes is delivered by bolus injection to a site close to the desired area. Such liposome-based compositions should be fluid enough to be easily syringable, stable under the conditions of manufacture and storage, and preserved against the contaminating action of microorganisms such as bacteria and fungi.

[0109] A "therapeutically effective dose" of a treatment / treatment can be measured by a complete or partial objective response. A complete response (CR) is defined as the absence of clinical, radiological or other evidence of pathology, injury or disease. A partial response (PR) results from a greater than 50% reduction in disease. Median time to progression is a measure that characterizes the durability of an objective tumor response.

[0110] A "therapeutically effective dosage" for treatment / treatment can also be measured by its ability to stabilize the progression of a condition, disorder or disease. The ability of a compound to inhibit one or more protein kinases or reduce the viability of cells associated with a proliferative disorder, such as cancer cells, can be evaluated using suitable in vitro assays known to those skilled in the art, such as those described herein (particularly in the Examples below). Alternatively, the properties of the compounds described in the present invention can be evaluated by examining the ability of the compounds in suitable animal model systems known to those skilled in the art, such as those described herein (particularly in the Examples below). A therapeutically effective amount of a compound according to the present invention can cure, ameliorate, alleviate, ameliorate, alter, correct, ameliorate, improve, or affect a condition, disorder or disease, or a symptom of a condition, disorder or disease, or a predisposition to a condition, disorder or disease in an individual. One skilled in the art can determine such amounts based on factors such as the size of the individual, the severity of the individual's symptoms, and the particular composition or route of administration selected.

[0111] The pharmaceutical compositions according to the invention may, if desired, be presented in a pack or dispenser device which may contain one or more (e.g., unit) dosage forms containing the active compound. The pack may, for example, comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by a leaflet or other information, in particular one which gives (either to the patient and / or the administering physician) important information or details concerning the pharmaceutical composition contained in the package, such as the mode of administration, the recommended dosage, safety and / or side effect information, etc.

[0112] In certain embodiments, the pharmaceutical compositions of the present invention are formulated for oral administration, and in alternative certain embodiments, the pharmaceutical compositions of the present invention are formulated for intravenous administration.

[0113] In one embodiment, the pharmaceutical composition of the invention is in unit dosage form, particularly a unit dosage form formulated for oral administration.

[0114] Each such unit dosage form may contain (e.g., may contain) 1 mg to 950 mg of a compound, such as a SIK3 kinase inhibitor of the first aspect or a compound used in the fifth aspect, complex, polymorph, crystalline form, racemic mixture, diastereomer, enantiomer, tautomer, conformer, isotopically labeled form, prodrug, or combinations thereof. In particular, such unit dosage forms (e.g., each) may contain (e.g., may contain) 2 mg to 150 mg of such compound, suitably 10 mg to 150 mg of such compound.

[0115] In specific such embodiments, a pharmaceutical composition of the invention in unit dosage form (particularly a unit dosage form formulated for oral administration) may comprise (e.g., contain) an amount of such a compound selected from the group consisting of 2 mg, 5 mg, 15 mg, 20 mg, 50 mg, 70 mg, 80 mg, 100 mg and 140 mg per unit dosage form, and in particular comprises (e.g., contains) an amount of a compound of the invention (or a compound used in the invention) of about 20 mg, 50 mg, 70 mg or 100 mg.

[0116] In a particular embodiment, the pharmaceutical composition of the invention is (e.g., is formed as) a tablet, caplet, or capsule, and suitably the pharmaceutical composition of the invention (e.g., its unit dosage form) is a caplet. Methods of forming (e.g., manufacturing) tablets and caplets are described, for example, elsewhere herein.

[0117] Suitable excipients for pharmaceutical compositions of the invention, particularly when formed as tablets or caplets, and specific embodiments of such pharmaceutical compositions of the invention include those that further comprise one or more (e.g., all) excipients selected from the group consisting of lactose (e.g., lactose monohydrate), microcrystalline cellulose, croscarmellose sodium, hydroxypropyl cellulose, and magnesium stearate.

[0118] Therapeutic and Other Uses The present application provides a compound or composition as defined under the heading of SIK3 inhibitors and / or PD-1 inhibitors above, or a pharmaceutical composition as defined under the heading of "Pharmaceutical Compositions" above, for use as a medicament, e.g. for use in therapy, co-administration or combination therapy of a subject suffering from a PD-1 therapy resistant tumour.

[0119] Treatments that include or utilize such compounds can be provided at home, in a doctor's office, clinic, hospital outpatient department, or hospital. Treatment is generally initiated under the supervision of a physician so that a medical professional can closely monitor the effectiveness of the treatment and make any necessary adjustments. The duration of treatment will vary depending on the age and condition of the patient, and how the patient responds to the treatment.

[0120] An individual who is at increased risk of developing a condition, disorder, or disease may receive prophylactic treatment to prevent or delay the symptoms of the condition, disorder, or disease.

[0121] The term "treatment" is known to those skilled in the art and includes the application or administration of a therapeutic agent (e.g., a pharmaceutical composition containing the aforementioned agent) or treatment to a patient having a condition, disorder or disease, a symptom of a condition, disorder or disease, or a predisposition to a condition, disorder or disease, or to a cell, cell culture, cell line, sample, tissue or organ isolated from the patient, with the purpose of curing, ameliorating, alleviating, mitigating, altering, correcting, ameliorating, affecting or preventing the condition, disorder or disease, a symptom of the condition, disorder or disease, or a predisposition to the condition, disorder or disease. Thus, the term "treatment" can include prophylactic treatment of a condition, disorder or disease, or prophylactic treatment of a symptom of a condition, disorder or disease. Therapeutic agents, when used therapeutically, include the kinase inhibitors of the present invention (or compounds used in the fifth aspect of the present invention) and include additional therapeutic agents which may be, but are not limited to, small molecules, peptides, peptidomimetics, polypeptides / proteins, antibodies, nucleotides such as DNA or RNA, cells, viruses, ribozymes, siRNAs, and antisense oligonucleotides.

[0122] A disease, disorder or condition in the context of the invention described herein is in certain embodiments a proliferative disorder (including a condition or symptom associated with such a disorder).

[0123] "Proliferative disorder" refers to a disorder characterized by abnormal proliferation of cells. Proliferative disorder does not imply any limitation on the rate of cell growth, but merely indicates a loss of normal controls affecting growth and cell division. Thus, in some embodiments, cells of a proliferative disorder may have the same cell division rate as normal cells, but do not respond to signals that limit such growth. Included within the scope of "proliferative disorder" is a neoplasm or tumor that is an abnormal growth of tissue or cells. Cancer is understood in the art and includes any of a variety of malignant neoplasms characterized by proliferation of cells with the ability to invade surrounding tissues and / or metastasize to new colonization sites. Proliferative disorders include cancer, atherosclerosis, rheumatoid arthritis, idiopathic pulmonary fibrosis, and liver cirrhosis. Non-cancerous proliferative disorders also include hyperproliferation of cells in the skin, such as psoriasis and its various clinical forms, Reiter's syndrome, pityriasis rubra pilaris, and hyperproliferative dysplastic changes in disorders of keratinization (e.g., actinic keratosis, senile keratosis), scleroderma, and the like.

[0124] The preferred tumor is a solid tumor. In another particular embodiment, the proliferative disorder is a solid tumor (e.g., the subject suffers from or is suspected to suffer from), which is one of those described elsewhere herein, such as pancreatic cancer, breast cancer, lung cancer, prostate cancer, melanoma, ovarian cancer, esophageal cancer, sarcoma and colon cancer. In certain such embodiments, the proliferative disorder is pancreatic cancer (e.g., the subject suffers from or is suspected to suffer from), in other such embodiments, the proliferative disorder is prostate cancer (e.g., the subject suffers from or is suspected to suffer from), and in yet other such embodiments, the proliferative disorder is lung cancer (e.g., non-small cell lung cancer) (e.g., the subject suffers from or is suspected to suffer from).

[0125] According to the present invention, the proliferative disorder or tumor treatable with the compounds / compositions of the present invention is preferably a tumor due to repolarization of the tumor microenvironment, e.g. by reducing regulatory T cells (Treg) and immunosuppressive myeloid cells in the tumor, activating cytotoxic T lymphocyte (CTL) activity and promoting the CTL to Treg ratio.

[0126] In a more specific embodiment, the proliferative disorder is a cancer or tumor, particularly a solid tumor, including a pathology or condition associated with such a cancer or tumor. Preferred tumors treatable by the present invention are tumors that are resistant to PD-1 inhibitor therapy, for example, tumors in patients who have previously received PD-1 inhibitor therapy, which tumors may be recurrent and require additional treatment. The present invention provides for overcoming PD-1 inhibitor therapy by providing a combination of SIK3 inhibitor therapy and PD-1 inhibitor therapy in accordance with the present invention.

[0127] According to a further aspect, and advantageously in relation to the treatment of cancer, the present invention relates to a composition comprising a SIK3 inhibitor for use in increasing the sensitivity of a subject to PD-1 inhibitor therapy. As used herein, the expression "resistant to PD-1 inhibitors" can refer to the fact that the majority of patients with a given disease do not respond to these treatments (PD-1 inhibitors) and / or have a poor prognosis. In that case, the disease is considered to be generally resistant to anti-PD-1 therapy, while other diseases are sensitive to said treatment. As an example, certain types of cancers are known to be more resistant to PD-1 inhibitors than other cancers, and / or a given patient with said disease may be resistant to anti-PD-1 therapy even if the disease is known to be generally sensitive to anti-PD-1 therapy.

[0128] According to another embodiment, a patient resistant to PD-1 inhibitor therapy may be a patient with rapid disease progression (HPD) after anti-PD-1 treatment, i.e. a patient whose disease accelerates during treatment with a PD-1 inhibitor. A further aspect of the present invention relates to a method of increasing the efficacy of a PD-1 inhibitor administered to a patient as part of a treatment regimen, comprising administering to the subject a pharmacologic effective amount of a SIK3 inhibitor in combination with a PD-1 inhibitor. In other words, the present invention relates to a composition comprising a SIK3 inhibitor for use in increasing the efficacy of treatment with a PD-1 inhibitor in a subject. Furthermore, the present invention relates to a method of treating a patient in need of treatment, comprising administering to the patient a therapeutically effective combination of a PD-1 inhibitor and a SIK3 inhibitor, wherein administration of the combination results in an enhanced therapeutic effect compared to administration of a PD-1 inhibitor alone.

[0129] PD-1 resistant cancers are known in the art, however preferred is PD-1 resistant squamous non-small cell lung cancer.

[0130] In certain aspects of the invention, in view of the foregoing and the following examples, the invention further relates to the following preferred itemized aspects and embodiments: Item 1: A compound or composition for use in treating a tumor in a subject, wherein the subject or tumor is resistant to treatment with an inhibitor of PD-1 or its ligand, or the subject has previously been treated with an inhibitor of PD-1 or its ligand and the tumor is recurrent; The compound or composition comprises: (i) to (iii): (i) a composition comprising an inhibitor of PD-1 or its ligand (a PD-1 inhibitor) and an inhibitor of salt-inducible kinase 3 (a SIK3 inhibitor); or (ii) a SIK3 inhibitor, wherein the treatment comprises the concomitant or sequential administration of an inhibitor of PD-1 or its ligand; or (iii) an inhibitor of PD-1 or its ligand, wherein the treatment comprises simultaneous, separate or sequential administration of a SIK3 inhibitor; The compound or composition for use is any one of the following: Item 2: The compound or composition for use according to item 1, wherein the tumor disease is a solid tumor or a liquid tumor. Item 3: The compound or composition for use according to item 1 or 2, wherein the tumor is a recurrent tumor and / or a metastatic tumor. Item 4: The compound or composition for use according to any one of items 1 to 3, wherein the treatment is for increasing the sensitivity of a subject to an inhibitor of PD-1 or its ligand. Item 5: The compound or composition for use according to any one of items 1 to 5, wherein the tumor is (i) a lung cancer of the squamous type, preferentially the tumor is a non-small cell lung cancer of the squamous type, or (ii) a lymphoma, such as mediastinal large B-cell lymphoma (PMBCL). Item 6: The compound or composition for use according to any one of items 1 to 5, wherein the inhibitor of PD-1 or its ligand is an inhibitor of PD-1 or PD-L1 or PDL2, preferentially an anti-PD-1 antibody or an anti-PD-L1 antibody. Item 7: The compound or composition for use according to item 6, wherein the inhibitor of PD-1 or its ligand is selected from the group consisting of pembrolizumab, nivolumab, BMS-936559, cemiplimab, avelumab, durvalumab, atezolizumab, dostallimab, spartalizumab, or a combination thereof. Item 8: A SIK3 inhibitor having the formula: [ka] and compounds selected from the group consisting of kinase inhibitors of the formula (I) and solvates, salts, N-oxides, complexes, polymorphs, crystalline forms, racemic mixtures, diastereomers, enantiomers, tautomers, conformers, isotopically labeled forms, prodrugs, and combinations thereof, wherein Hy, R 2 , R 3 , R 4 , R 58. The compound or composition for use according to any one of claims 1 to 7, wherein A, B, and E are as in WO 2021 / 214117. Item 9: The SIK3 inhibitor has the formula: [ka] 9. The compound or composition for use according to item 8, which is (N-(2-chloro-4-(fluoromethyl)thiophen-3-yl)-2-((2-methyl-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl)amino)thiazole-5-carboxamide), having the formula: Item 10: A compound or composition for use according to any one of the preceding items, in the form of a preparation for simultaneous, separate or sequential use in therapy in a subject. Item 11: The compound or composition for use according to item 10, wherein the preparation comprises an inhibitor of PD-1 or its ligand and an SIK3 inhibitor. Item 12: A pharmaceutical composition comprising an inhibitor of PD-1 or its ligand (PD-1 inhibitor) and an inhibitor of salt-inducible kinase 3 (SIK3 inhibitor), together with a pharma- ceutically acceptable carrier and / or excipient. Item 13: A pharmaceutical kit comprising an inhibitor of PD-1 or its ligand and a SIK3 inhibitor, wherein the kit is prepared so that the PD-1 inhibitor and the SIK3 inhibitor can be administered simultaneously, separately or sequentially in therapy to a subject. Item 14: The pharmaceutical composition according to item 12 or 14, or the pharmaceutical kit according to item 13 or 14, wherein the PD-1 inhibitor and / or the SIK3 inhibitor is as described in any one of items 1 to 11. Item 15: A pharmaceutical composition according to item 12, 14 or 15, or a pharmaceutical kit according to item 13, 14 or 15, for use in a treatment as described in any one of items 1 to 11. Item 16: A method of treating a tumor disease in a subject, wherein the subject or tumor is resistant to treatment with an inhibitor of PD-1 or its ligand, or the subject has previously been treated with an inhibitor of PD-1 or its ligand and the tumor is recurrent; The method comprises steps (i) or (ii): (i) administering to a subject a therapeutically effective amount of a composition comprising an inhibitor of PD-1 or its ligand (PD-1 inhibitor) and an inhibitor of salt-inducible kinase 3 (SIK3 inhibitor); or (ii) administering to the subject a therapeutically effective amount of a SIK3 inhibitor, wherein the treatment further comprises simultaneous, separate or sequential administration of an inhibitor of PD-1 or its ligand; A method comprising: Item 17: The method of item 16, wherein the tumor disease is a solid tumor. Item 18: The method according to item 16 or 17, wherein the tumor is a recurrent tumor and / or a metastatic tumor. Item 19: The method of any one of items 16 to 18, wherein the treatment is for increasing the subject's sensitivity to therapy with an inhibitor of PD-1 or its ligand. Item 20: The method according to any one of items 16 to 19, wherein the tumor is (i) a lung cancer of the squamous type, preferentially the tumor is a non-small cell lung cancer of the squamous type, or (ii) a lymphoma, such as mediastinal large B-cell lymphoma (PMBCL). Item 21: The method according to any one of items 16 to 20, wherein the inhibitor of PD-1 or its ligand is an inhibitor of PD-1 or PD-L1 or PDL2, preferentially an anti-PD-1 antibody or an anti-PD-L1 antibody. Item 22: The method of any one of items 16 to 21, wherein the inhibitor of PD-1 or its ligand is selected from the group consisting of pembrolizumab, nivolumab, BMS-936559, cemiplimab, avelumab, durvalumab, atezolizumab, spartalizumab, dostallimab, or a combination thereof. Item 23: A SIK3 inhibitor having the formula: [ka] and compounds selected from the group consisting of kinase inhibitors of the formula (I) and solvates, salts, N-oxides, complexes, polymorphs, crystalline forms, racemic mixtures, diastereomers, enantiomers, tautomers, conformers, isotopically labeled forms, prodrugs, and combinations thereof, wherein Hy, R 2 , R 3 , R 4 , R 5 23. The method according to any one of items 16 to 22, wherein A and E are as defined for compounds of formula (Ia) in WO 2021 / 214117. Item 24: The SIK3 inhibitor has the formula: [ka] and solvates, salts, N-oxides, complexes, polymorphs, crystalline forms, racemic mixtures, diastereomers, enantiomers, tautomers, conformers, isotopically labeled forms, prodrugs, and combinations thereof.

[0131] In view of the above, it will be appreciated that the present invention also relates to the following itemized embodiments: EXAMPLES

[0132] An example is given below:

[0133] Example 1: SIK3 inhibitor E9 repolarizes the tumor microenvironment and shows potent antitumor effects in monotherapy and in combination with PD-1 blockade MC38 tumor cells were implanted subcutaneously into C57Bl6 / N mice, with an average tumor volume of 100 mm 3The tumor-bearing mice were randomized to receive compound E9 at 25 mg / kg orally twice daily and anti-mouse PD-1 mAb (clone: ​​RMP1-14) or corresponding control at 10 mg / kg intraperitoneally twice weekly. The results are shown in Figures 3A and 3B.

[0134] Figure 3 shows that SIK3 inhibitor E9 demonstrated highly significant antitumor efficacy and survival extension in monotherapy in the MC38 tumor model. Furthermore, treatment with E9 repolarized the tumor microenvironment by reducing regulatory T cells (Treg) and immunosuppressive myeloid cells, activating cytotoxic T lymphocyte (CTL) activity, and promoting the CTL to Treg ratio. Combining SIK3 inhibitor E9 with anti-PD-1 maximized the potential of the antitumor immune environment.

[0135] Example 2: SIK3 inhibitor E9 acts synergistically with PD-1 inhibitors in immune checkpoint-resistant breast and lung cancer models EMT6 tumor cells were implanted in the mammary fat pad of BALB / c mice, resulting in a mean tumor volume of 65 mm 3 KLN205 tumor cells were implanted subcutaneously in DBA / 2 mice, with a mean tumor volume of 60 mm 3 Both animal models were treated with the indicated doses of compound E9 orally twice daily and with 10 mg / kg of anti-mouse PD-1 mAb (clone: ​​RMP1-14) or matched control intraperitoneally twice weekly. The results are shown in Figure 4A and Figure 4B.

[0136] Figure 4A shows that combination therapy of SIK3 inhibitor (E9) and PD-1 inhibitor acted synergistically in immune-exclusion breast cancer model EMT6 and immune checkpoint-resistant lung squamous cell carcinoma model KLN205. Remarkably, complete tumor regression and prolonged overall survival were achieved in EMT6 tumors, and tumor growth was significantly delayed in KLN205 lung cancer (Figure 4B). Notably, a surprising synergistic effect was observed when compound E9 was combined with anti-PD-1 antibody in the mouse lung squamous cell carcinoma cell line KLN205. Growth inhibition in monotherapy ranged from -6% TGI (compared to control) for PD-1 alone and 22% (compared to control) for E9 alone to a 44% TGI increase in the combination.

Claims

1. A compound or composition for use in treating a tumor in a subject, wherein the subject or the tumor is resistant to treatment with an inhibitor of PD-1 or its ligand, or the subject has previously been treated with an inhibitor of PD-1 or its ligand and the tumor is recurrent; The compound or composition comprises: (i) to (iii): (i) a composition comprising an inhibitor of PD-1 or its ligand (PD-1 inhibitor) and an inhibitor of salt-inducible kinase 3 (SIK3 inhibitor); or (ii) a SIK3 inhibitor, wherein the treatment comprises the concomitant or sequential administration of an inhibitor of PD-1 or its ligand; or (iii) an inhibitor of PD-1 or its ligand, wherein the treatment comprises the simultaneous, separate or sequential administration of a SIK3 inhibitor; 2. The compound or composition for use, which is any one of:

2. 2. The compound or composition for use according to claim 1, wherein the tumor disease is a solid tumor or a liquid tumor.

3. 3. The compound or composition for use according to claim 1 or 2, wherein the tumor is a recurrent tumor and / or a metastatic tumor.

4. The compound or composition for use according to any one of claims 1 to 3, wherein said treatment is for increasing the sensitivity of said subject to an inhibitor of said PD-1 or its ligand.

5. 6. The compound or composition for use according to any one of claims 1 to 5, wherein the tumour is (i) a lung cancer of the squamous type, preferentially the tumour is a non-small cell lung cancer of the squamous type, or (ii) a lymphoma, such as mediastinal large B-cell lymphoma (PMBCL).

6. 6. A compound or composition for use according to any one of claims 1 to 5, wherein said inhibitor of PD-1 or its ligand is an inhibitor of PD-1 or PD-L1 or PDL2, preferentially an anti-PD-1 antibody or an anti-PD-L1 antibody.

7. 7. The compound or composition for use according to claim 6, wherein the inhibitor of PD-1 or its ligand is selected from the group consisting of pembrolizumab, nivolumab, BMS-936559, cemiplimab, avelumab, durvalumab, atezolizumab, dostallimab, spartalizumab, or combinations thereof.

8. The SIK3 inhibitor has the formula: 【Chemistry 1】 and compounds selected from the group consisting of kinase inhibitors of the formula (I) and solvates, salts, N-oxides, complexes, polymorphs, crystalline forms, racemic mixtures, diastereomers, enantiomers, tautomers, conformers, isotopically labeled forms, prodrugs, and combinations thereof, wherein Hy, R ２ , R ３ , R ４ , R ５ 8. The compound or composition for use according to any one of claims 1 to 7, wherein A and E are as in WO 2021 / 214117.

9. The SIK3 inhibitor has the formula: 【Chemistry 2】 9. The compound or composition for use according to claim 8, which is (N-(2-chloro-4-(fluoromethyl)thiophen-3-yl)-2-((2-methyl-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl)amino)thiazole-5-carboxamide), which is a compound having the formula:

10. A compound or composition for use according to any one of claims 1 to 9, in the form of a preparation for simultaneous, separate or sequential use in therapy in said subject.

11. The compound or composition for use according to claim 10, wherein the preparation comprises an inhibitor of PD-1 or its ligand and an SIK3 inhibitor.

12. A pharmaceutical composition comprising an inhibitor of PD-1 or its ligand (PD-1 inhibitor) and an inhibitor of salt-inducible kinase 3 (SIK3 inhibitor) together with a pharma- ceutically acceptable carrier and / or excipient.

13. A pharmaceutical kit comprising an inhibitor of PD-1 or its ligand and an SIK3 inhibitor, wherein the kit is prepared so that the PD-1 inhibitor and the SIK3 inhibitor can be administered simultaneously, separately or sequentially in therapy to a subject.

14. The pharmaceutical composition according to claim 12 or 14, or the pharmaceutical kit according to claim 13 or 14, wherein the PD-1 inhibitor and / or the SIK3 inhibitor are as defined in any one of claims 1 to 11.

15. A pharmaceutical composition according to claim 12, 14 or 15, or a pharmaceutical kit according to claim 13, 14 or 15, for use in a treatment as defined in any one of claims 1 to 11.

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