Use of 4-thiazole-N-(pyridin-2-yl)pyrimidin-2-amine derivatives in combination therapy against cancer

Abstract

Administering to a subject a compound of Formula I (or a pharma- ceutically acceptable salt, solvate, or prodrug thereof), as shown below: [Formula 1] and a method of treating a proliferative disease or condition in said subject, comprising co-administering TIFF2025509577000012.tif37165 with an immunotherapeutic agent, e.g., an immune checkpoint inhibitor, e.g., capable of inhibiting PD-1, PD-L1 / 2, CTLA-4, BTLA, or Tim-3 and / or one or more of their ligands. Pharmaceutical compositions and kits are also disclosed.

Description

[Technical field]

[0001] The present disclosure relates to combination therapies for treating proliferative cell diseases and conditions. In one particular application, the present disclosure provides a method comprising administering to a subject, such as a cancer patient, an effective amount of a particular thiazole-pyrimidine type anti-proliferative compound(s) in combination with an immune checkpoint inhibitor(s), such as an anti-PD-1 antibody.

[0002] Priority document This application claims priority to Australian Provisional Patent Application No. 2022900659, entitled "USE OF 4-THIAZOL-N-(PYRIDIN-2-YL)PYRIMIDIN-2-AMINE DERIVATIVES IN COMBINATION THERAPIES FOR CANCER," filed on March 17, 2022, the contents of which are incorporated herein by reference in their entirety. [Background technology]

[0003] Cancer immunotherapy methods have been developed in recent years to strengthen a patient's immune system to target tumors (see, e.g., Rizvi NA et al., Science 348:124-8, 2015, and Pardoll DM., Nat Rev Cancer 12:252-64, 2012). One class of such methods arose with the discovery of immune checkpoint receptors, e.g., PD-1 (programmed cell death protein 1, CD279) and CTLA-4 (cytotoxic T-lymphocyte-associated protein 4), which suppress the activity of antitumor (cytotoxic) T cells. In particular, this discovery has led to the development of blocking antibodies against certain instances of these receptors (or their ligands), such as pembrolizumab (a humanized antibody against PD-1), nivolumab (another anti-PD-1 antibody), atezolizumab (a monoclonal antibody against the PD-1 ligand, i.e., PD-L1, which blocks the interaction between PD-1 and PD-L1), durvalumab (another anti-PD-L1 antibody), and ipilimumab (a monoclonal antibody against CTLA-4). Some patients treated with checkpoint inhibitors such as these experience sustained tumor regression (Sharma P et al., Cell 161:205-14, 2015). However, despite promising clinical results, treatment with checkpoint inhibitor(s) (i.e., referred to as "checkpoint inhibitor therapy" or "checkpoint blockade therapy") has so far only proven successful in a small subset(s) of patients (Havel JJ et al., Nat Rev Cancer 19(3):133-150, 2019). Furthermore, there is growing evidence that tumors can acquire resistance to immunotherapies such as checkpoint inhibitor therapy (Koyama S, et al. Nat Commun 7:10501, 2016). It is therefore desirable to develop new therapeutic strategies that may broaden the range of tumors and / or patients that respond to immunotherapy or that may otherwise improve the specificity and / or efficacy of existing immunotherapies such as those mentioned above.

[0004] One potential new strategy is to identify and develop small molecule kinase inhibitors that can enhance or complement immunotherapy. Small molecule inhibitors have many advantages compared to antibody-based biologics, such as higher exposure in the tumor microenvironment and access to intracellular targets (Petroni G et al., Nat Review Immunol 20:669-679, 2020). In addition, there is some evidence that signaling from oncogenic kinase drivers can alter the tumor microenvironment to promote immune suppression (Ahn R and J Ursini-Siegel, Int J Mol Sci 22(5):2608-2631, 2021), and inhibiting these oncogenes using small molecule kinase inhibitors could potentially contribute to immune reactivation. In addition, small molecule kinase inhibitors can directly alter immune cell function and contribute to antitumor immunity (Ahn and Ursini-Siegel, 2021, see above). Therefore, combining small molecule kinase inhibitors, which can induce dramatic but short-lived tumor regression, with immunotherapies, such as checkpoint inhibitor therapy, which provide slower but potentially more durable responses, is an attractive potential new therapeutic strategy.

[0005] The present applicant has identified and developed a variety of novel small molecule kinase inhibitors, particularly targeting cyclin-dependent kinases (CDKs). CDKs are known to associate with various cyclin subunits and play a central role in regulating a variety of important regulatory pathways in cells, including cell cycle regulation, apoptosis, neurophysiology, differentiation and transcription. Thus, abnormal CDK expression and / or activity may, among other things, cause or contribute to abnormal cell cycle control, resulting in endless cell cycle resumption and progression, a hallmark of human cancer. To date, at least 20 CDKs and 30 cyclins have been identified. They can be classified into two major groups, cell cycle regulator CDKs and transcription regulator CDKs, reflecting their functions (Wang S et al., Trends Pharmacol Sci 29(6):302-313, 2008; Diab S et al., J Med Chem 63(14):7458-7474, 2020). The cell cycle regulator CDK class includes CDK1, 2, 3, 4, 5, 6, and 7, which function with their cyclin partners (e.g., cyclin A, B, C, D1, D2, D3, E, and F) to regulate cell cycle promotion. The transcription regulator CDK class includes CDK7, 8, 9, and 11, which function with cyclin C, H, K, L1, L2, T1, and T2. Given the function of these CDK classes, it is not surprising that CDKs are involved in cell proliferation diseases and conditions, particularly cancer. Cell proliferation is the result of direct or indirect deregulation of the cell division cycle, and CDKs play a key role in regulating the various stages of this cycle. Thus, CDK inhibitors are useful targets for cancer therapy, and CDK4 / 6 inhibitors, such as palbociclib, ribociclib, and abemaciclib, are approved by the U.S. Food and Drug Administration (FDA) as single agents or in combination for the treatment of patients with advanced or metastatic breast cancer.Although best known for their ability to block cell cycle progression, growing evidence indicates that their anticancer effects also result from a variety of immune activating effects, as these and other CDK4 / 6 inhibitors interact with immune cell populations in malignant cells and the tumor microenvironment (Petroni G et al., 2020, see above).

[0006] Applicants have identified a group of thiazole-pyrimidine type CDK inhibitor compounds that show remarkable potential to enhance the specificity and / or efficacy of various agents for cancer immunotherapy, such as those used in checkpoint inhibitor therapy (e.g. anti-PD-1 blocking antibodies), and thus may form the basis of useful novel combination therapies. Summary of the Invention

[0007] In a first aspect, the disclosure provides a method of treating a proliferative disease or condition in a subject, comprising co-administering to the subject a compound of formula I, as shown below (or a pharma- ceutically acceptable salt, solvate, or prodrug thereof), together with an immunotherapeutic agent: [ka] During the ceremony, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7are each independently selected from the group consisting of H, alkyl, aryl, aralkyl, halogen, NO2, CN, CF3, OH, O-alkyl, O-aryl, NH2, NH-alkyl, NH-aryl, N-(alkyl)2, N-(aryl)2, N-(alkyl)(aryl), COOH, CONH2, CONH-alkyl, CONH-aryl, SO3H, SO2-alkyl, SO2-aryl, SO2NH2, CF3, CO-alkyl, CO-aryl, wherein the alkyl, aryl and aralkyl groups are optionally substituted with one or more groups selected from halogen, CN, OH, O-methyl, NH2, COOH, CONH2 and CF3, and heterocyclic groups optionally substituted with one or more groups selected from alkyl, NH2, NH-alkyl, N(alkyl)2, COH and CO-alkyl; The compound is not 5-(2-((5-(4-(dimethylamino)piperidin-1-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-N,4-dimethylthiazol-2-amine.

[0008] The immunotherapeutic agent may be selected, for example, from agents known to those skilled in the art as being capable of promoting an immune response against cancer cells, for example, immune checkpoint inhibitors.

[0009] In a second aspect, the disclosure provides a pharmaceutical composition comprising a compound of formula I (or a pharma- ceutical acceptable salt, solvate, or prodrug thereof) as de?ned in the ?rst aspect and an immunotherapeutic agent for treating a proliferative disease or condition in a subject.

[0010] In a third aspect, the disclosure provides the use of a compound of formula I (or a pharma- ceutically acceptable salt, solvate, or prodrug thereof) as defined in the first aspect and an immunotherapeutic agent for treating a proliferative disease or condition in a subject.

[0011] In a fourth aspect, the disclosure provides the use of a compound of formula I (or a pharma- ceutically acceptable salt, solvate, or prodrug thereof) as defined in the first aspect and an immunotherapeutic agent in the manufacture of a medicament for treating a proliferative disease or condition in a subject.

[0012] In a fifth aspect, the disclosure provides a kit comprising first and second containers (e.g., vials), the first container comprising a compound of Formula I (or a pharma- ceutically acceptable salt, solvate, or prodrug thereof) as defined in the first aspect, and the second container comprising an immunotherapeutic agent, optionally packaged with instructions for use of the kit in a method according to the first aspect. [Brief description of the drawings]

[0013] [Figure 1] The graph shows the in vivo antitumor activity of compound 1 (N-cyclopentyl-5-(2-((5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-4-methylthiazol-2-amine) against syngeneic EMT6 triple-negative breast cancer cells in mice (A). The treatment reduced phosphorylation of RB (B) and the level of immune checkpoint protein ligand PD-L1 (C) in the tumor tissue, indicating that the compound provides the effects of CDK4 / 6 inhibition and immunotherapy, respectively. [Diagram 2] Further results are graphically depicted showing the in vivo antitumor activity of Compound 1 against CT26.WT syngeneic colorectal cancer cells in mice. Animals were treated with vehicle or Compound 1 alone (A), or with a combination of Compound 1 and an anti-PD1 antibody (B). The antitumor effect translated into increased survival of the animals (C), and [Diagram 3]Further results are shown graphically to demonstrate the in vivo antitumor effect of Compound 1 through immune activation in the CT26.WT syngeneic mouse model. Animals were treated with vehicle or Compound 1 (A), anti-PD1 antibody (B), or a combination of Compound 1 and anti-PD1 antibody (C). Increased T cell populations were detected in the spleens of treated mice (D-G). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] The applicant has identified a group of 4-thiazole-N-(pyridin-2-yl)pyrimidin-2-amine derivatives suitable for enhancing the activity and / or efficacy of cancer immunotherapy (e.g., therapy involving administration of immunotherapeutic agents that promote an immune response against cancer cells, such as those used in checkpoint inhibitor therapy (e.g., anti-PD-1 antibodies)). As shown in Example 2, a representative compound, (N-cyclopentyl-5-(2-((5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-4-methylthiazol-2-amine) ("Compound 1"), was found to be capable of anti-proliferative effects via inhibition of CDK4 / 6 and related immunotherapeutic mechanism(s) of action (e.g., modulation of regulatory T cells and / or PD-1 / PD-1 ligand).

[0015] In a first aspect, the disclosure provides a method of treating a proliferative disease or condition in a subject, comprising co-administering to the subject a compound of formula I, as shown below (or a pharma- ceutically acceptable salt, solvate, or prodrug thereof), together with an immunotherapeutic agent: [ka] During the ceremony, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7are each independently selected from the group consisting of H, alkyl, aryl, aralkyl, halogen, NO2, CN, CF3, OH, O-alkyl, O-aryl, NH2, NH-alkyl, NH-aryl, N-(alkyl)2, N-(aryl)2, N-(alkyl)(aryl), COOH, CONH2, CONH-alkyl, CONH-aryl, SO3H, SO2-alkyl, SO2-aryl, SO2NH2, CF3, CO-alkyl, CO-aryl, wherein the alkyl, aryl and aralkyl groups are optionally substituted with one or more groups selected from halogen, CN, OH, O-methyl, NH2, COOH, CONH2 and CF3, and heterocyclic groups optionally substituted with one or more groups selected from alkyl, NH2, NH-alkyl, N(alkyl)2, COH and CO-alkyl; The compound is not 5-(2-((5-(4-(dimethylamino)piperidin-1-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-N,4-dimethylthiazol-2-amine.

[0016] The compounds of formula I have been found to have antiproliferative activity (e.g., anticancer effect). These compounds are believed to block tumor cell proliferation by inhibiting the activity of CDK4 and CDK6. In particular, the compounds of formula I have been found to inhibit cell proliferation, for example, in cancer cell lines both in vitro and in vivo, and are believed to be useful alone in the treatment of proliferative cell diseases and conditions.

[0017] Additionally, compounds of formula I have been found to have previously unrecognized antiproliferative (e.g., anticancer) activity via immunotherapeutic effects. In particular, compounds of formula I may inhibit the proliferation of cancer cells in vivo, for example, by promoting an immune response against the cancer cells.

[0018] Thus, the compounds of formula I are believed to have excellent potential to act as additional immunotherapeutic agents for the treatment of proliferative cell diseases and conditions, particularly when used in combination with another immunotherapeutic agent, such as those used in checkpoint inhibitor therapy (e.g., anti-PD-1 blocking antibodies).

[0019] In particular, as shown in the Examples below, co-administration of a compound of Formula I and another immunotherapeutic agent (particularly an immune checkpoint inhibitor) to a mouse model bearing syngeneic allografts of cancer cell lines achieved enhanced anti-proliferative effects and increased survival rates (i.e., compared to the use of the compound of Formula I or another immunotherapeutic agent alone).

[0020] In preferred embodiments, the enhanced antiproliferative effect represents synergy between the compound of formula I and the other immunotherapeutic agent, as can be assessed by determining a combination index (CI) value according to any method known to those skilled in the art, including, for example, the Chou-Talaly method (Chou TC et al., Trends Pharmacol Sci 4:450-454, 1983), where a CI value of <1 indicates a synergistic interaction between the compound of formula I and the other immunotherapeutic agent. In some embodiments, the CI value is determined based on the reduction in the level of tumor volume achieved by combination treatment in an in vivo mouse model, as described in the Examples below.

[0021] In this specification, a number of terms and expressions are used that are well known to those skilled in the art. Nonetheless, for the sake of clarity, some of these terms and expressions are defined below.

[0022] As used herein, anti-proliferative activity or effect within the scope of the present disclosure may be demonstrated by the ability to inhibit cell proliferation in whole cell assays in vitro and / or the ability to reduce tumor volume in vivo. Example(s) of a suitable assay for such activity, including methods of carrying it out, are described in the Examples below.

[0023] As used herein, the term "treating" includes the prevention of disease or condition and the alleviation of existing symptoms thereof.Accordingly, the action of "treating" a disease or condition includes (1) preventing or delaying the appearance of the clinical symptoms of the disease or condition that develop in a subject suffering from or susceptible to the disease or condition, (2) inhibiting the disease or condition (i.e., arresting, reducing, or delaying the onset of the disease or condition or its recurrence (in the case of maintenance treatment)), or inhibiting at least one clinical or subclinical symptom thereof, and (3) relieving or attenuating the disease or condition (i.e., causing the regression of the disease or condition or at least one clinical or subclinical symptom thereof).

[0024] As used herein, the term "alkyl" includes straight chain, branched, and cyclic alkyl groups having from 1 to 8 carbon atoms (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, and the like).

[0025] As used herein, the term "aryl" refers to a substituted (mono or poly) or unsubstituted monocyclic or polycyclic aromatic group, which may be fused or non-fused. The term therefore includes groups having 6 to 10 carbon atoms (e.g., phenyl, naphthyl, etc.). It is also understood that the term "aryl" is synonymous with the term "aromatic".

[0026] As used herein, the term "aralkyl" is used as a combination of the terms alkyl and aryl as defined above.

[0027] The term "aliphatic" has its ordinary meaning in the art and includes non-aromatic groups, such as alkanes, alkenes, and alkynes, and substituted derivatives thereof.

[0028] As used herein, the term "alicyclic" refers to a cyclic aliphatic group.

[0029] The term "halogen" refers to fluoro, chloro, bromo, and iodo.

[0030] As used herein, the term "heterocyclic" refers to a saturated or unsaturated cyclic group that contains one or more heteroatoms (e.g., N) in the ring system (e.g., a system that contains one or more rings (mono or poly), where multiple rings are present, the rings can be fused and / or non-fused). Thus, the term includes saturated heterocyclic groups, such as pyrrolidinyl, morpholinyl, aziridine, and piperazine, as well as unsaturated heterocyclic groups ("heteroaryl" groups, such as 2-pyridyl, 3-pyridyl, 4-pyridyl, 4-pyrimidyl, 5-indolyl, furan, thiophene, and thiazole), where at least one ring of the ring system contains from 1 to 4 heteroatoms selected from N, O, and S as ring members (i.e., it comprises at least one heterocyclic ring), and the nitrogen and sulfur atoms may be oxidized and the nitrogen atom(s) may be quaternized. Heterocyclic groups can be attached to the remainder of the molecule through a ring carbon or ring heteroatom, or, if the ring system is a polycyclic ring system, e.g., a bicyclic, tricyclic, or fused ring system, through any ring of the ring system.

[0031] As used herein, the term "derivative" includes any chemical modification of an entity. Examples of such chemical modifications are replacement of hydrogen with a halogen, alkyl, acyl, or amino group.

[0032] As used herein, the phrase "manufacturing a medicament" includes using a compound of Formula I and / or an immunotherapeutic agent directly as a medicament or using it at any stage in the manufacture of a medicament comprising said compound of Formula I and / or said immunotherapeutic agent.

[0033] Some of the compounds of formula I may exist as single stereoisomers, racemates, and / or mixtures of enantiomers and / or diastereomers. All such single stereoisomers, racemates, and mixtures thereof are included within the scope of the present disclosure. Such isomers, e.g., diastereomers, enantiomers, and geometric isomers, can be separated by physical and / or chemical methods known to those skilled in the art.

[0034] As used herein, the term "pharmaceutical acceptable salt" refers to a salt that retains the desired biological activity of the compound of formula I, including pharmaceutical acceptable acid addition salts and base addition salts. Suitable pharmaceutical acceptable acid addition salts of the compound of formula I can be prepared from inorganic acids or from organic acids. Examples of such inorganic acids are hydrochloric acid, sulfuric acid, and phosphoric acid. Suitable organic acids can be selected from aliphatic, alicyclic, aromatic, heterocyclic carboxylic, and sulfonic classes of organic acids. Examples of these are formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, fumaric acid, maleic acid, alkylsulfonic acid, and arylsulfonic acid. Further information on pharmaceutical acceptable salts can be found in Remington's Pharmaceutical Sciences, 19th Edition, Mack Publishing Co, Easton PA 1995.

[0035] The term "solvate" refers to any form of a compound of formula I resulting from solvation with a suitable solvent. Such forms may be, for example, crystalline solvates or complexes that may be formed between a solvent and a dissolved compound.

[0036] The term "prodrug" refers to a compound that undergoes conversion to a compound of formula I in a biological system, usually by metabolic means (e.g., by hydrolysis, reduction, or oxidation). For example, an ester prodrug of a compound of formula I that contains a hydroxyl group can be converted to a compound of formula I in vivo by hydrolysis. Suitable esters of a compound of formula I that contains a hydroxyl group can be, for example, acetate, citrate, lactate, tartrate, malonate, oxalate, salicylate, propionate, succinate, fumarate, maleate, methylene-bis-p-hydroxynaphthoate, gestisate, isethionate, di-p-toluoyltartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate, and quinate. As another example, ester prodrugs of compounds of formula I that contain a carboxy group can be converted to compounds of formula I in vivo by hydrolysis. Examples of ester prodrugs include those described by Leinweber FJ, Drug Metab Rev 18:379-439 (1987). Similarly, acyl prodrugs of compounds of formula I that contain an amino group can be converted to compounds of formula I in vivo by hydrolysis. Examples of prodrugs for these and other functional groups, including amines, are given in Prodrugs: challenges and rewards, Valentino J Stella (ed), Springer, 2007.

[0037] For compounds of formula I that are solids, one of ordinary skill in the art will recognize that the compound (or a pharma- ceutically acceptable salt, solvate or prodrug thereof) may exist in different crystalline forms or polymorphs, all of which are encompassed within the scope of the present disclosure.

[0038] The term "therapeutically effective amount" or "effective amount" is an amount sufficient to produce a beneficial or desired clinical result. A therapeutically effective amount may be administered in one or more administrations. Typically, a therapeutically effective amount is sufficient to treat a disease or condition or otherwise palliate, ameliorate, stabilize, reverse, slow, or delay the progression of a disease or condition, such as, for example, cancer or another proliferative cell disease or condition. By way of example only, a therapeutically effective amount of a compound of formula I, or a pharma- ceutically acceptable salt, solvate, or prodrug thereof, may be comprised between about 0.1 and about 250 mg / kg body weight per day, more preferably between about 0.1 and about 100 mg / kg body weight per day, and even more preferably between about 0.1 and about 25 mg / kg body weight per day. For other immunotherapeutic agents, the therapeutically effective amount may be expected to vary considerably depending on the particular immunotherapeutic agent, but may similarly comprise from about 0.1 to about 250 mg / kg body weight every 1-3 weeks, more preferably from about 0.1 to about 100 mg / kg body weight every 1-3 weeks, and even more preferably from about 0.1 to about 25 mg / kg body weight every 1-3 weeks. However, notwithstanding the above, those skilled in the art will understand that the therapeutically effective amount of a compound / agent may vary and may depend on a variety of factors, including the activity of the particular compound / agent, the metabolic stability and length of action of the particular compound / agent, age, body weight, sex, health status, route and time of administration, excretion rate of the particular compound / agent, and, for example, the severity of the cancer or other proliferative cell disease or condition being treated.

[0039] In some embodiments, R 1 is H, alkyl (e.g., C 1-6 Alkyl or preferably C 1-3 Alkyl, such as methyl, ethyl, and C(CH) or C 3-6 cycloalkyl, e.g., cyclopentyl), or NH-C 1-6 Alkyl (e.g., NH-C 1-3 Alkyl, such as NH-methyl and NH-ethyl, or NH-C 3-6cycloalkyl, e.g., NH-cyclopentyl). Most preferably, R 1 NH-C 1-6 Alkyl (e.g., NH-C 1-3 Alkyl, such as NH-methyl and NH-ethyl, or NH-C 3-6 cycloalkyl, for example, NH-cyclopentyl.

[0040] In some embodiments, R 2 is H, alkyl (e.g., C 1-6 Alkyl or preferably C 1-3 Alkyl, for example methyl or ethyl), CN or halogen (preferably F).

[0041] In some embodiments, R 3 is H, alkyl (e.g., C 1-6 alkyl), CN or halogen (preferably F).

[0042] In some embodiments, R 4 and R 7 One or both of are (independently) H, OC 1-6 alkyl, or halogen.

[0043] In some embodiments, R 5 and R 6 is (independently) a heterocyclic group (preferably a saturated or unsaturated 5- or 6-membered cyclic group containing one or two N heteroatoms), and optionally an alkyl (e.g., C 1-6 Alkyl, or preferably C 1-3 Alkyl, such as methyl, ethyl, or C(CH3)2), NH2, NH-alkyl, such as NH-methyl and NH-ethyl, N(alkyl)2, such as N(C 1-3 alkyl)2 (e.g., N(CH3)2, N(CH2CH3)2 and N(CH3)(CH2CH3)), COH and CO-(C 1-3The heterocyclic group(s) may be provided with an alkyl bridge (e.g., -CH2- or -CH2CH2- bridge) linking the group to the 4 / 5 carbon atom of the pyridine ring.

[0044] Most preferably, R 5 and R 6 is independently selected from: [ka]

[0045] In some embodiments, R 4 , R 6 and R 7 are all H.

[0046] In one particularly preferred embodiment, the compound of formula I is N-cyclopentyl-5-(2-((5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-4-methylthiazol-2-amine, N-cyclopentyl-4-methyl-5-(2-((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)thiazol-2-amine, N-cyclopentyl-5-(2-((5-(4-ethylpiperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-4-methylthiazol-2-amine, 2-((5-(4-acetylpiperazin-1-yl)pyridin-2-yl)amino)-4-(4-methyl-2-(methylamino)thiazol-5-yl)pyrimidine-5-carbonitrile, N-cyclopentyl-5-(2-((5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-yl)amino)pyrimidin-4-yl)-4-methylthiazol-2-amine, 5-(2-((5-(4-aminopiperidin-1-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-N,4-dimethylthiazol-2-amine, 5-(2-((5-(4-aminopiperidin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-N-cyclopentyl-4-methylthiazol-2-amine, N-cyclopentyl-5-(5-fluoro-2-((5-morpholinopyridin-2-yl)amino)pyrimidin-4-yl)-4-methylthiazol-2-amine, 5-(2-((5-(4-(ethylamino)piperidin-1-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-N,4-dimethylthiazol-2-amine, 5-(2-((5-(4-(ethyl(methyl)amino)piperidin-1-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-N,4-dimethylthiazol-2-amine, 5-(5-fluoro-2-((5-((4-methylpiperazin-1-yl)methyl)pyridin-2-yl)amino)pyrimidin-4-yl)-N,4-dimethylthiazol-2-amine, 5-(5-fluoro-2-((5-((4-isopropylpiperazin-1-yl)methyl)pyridin-2-yl)amino)pyrimidin-4-yl)-N,4-dimethylthiazol-2-amine, or 5-(2-((5-(4-(diethylamino)piperidin-1-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-N,4-dimethylthiazol-2-amine.

[0047] In another particularly preferred embodiment, the compound of formula I is N-cyclopentyl-5-(2-((5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-4-methylthiazol-2-amine, N-cyclopentyl-4-methyl-5-(2-((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)thiazol-2-amine, N-cyclopentyl-5-(2-((5-(4-ethylpiperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-4-methylthiazol-2-amine, 2-((5-(4-acetylpiperazin-1-yl)pyridin-2-yl)amino)-4-(4-methyl-2-(methylamino)thiazol-5-yl)pyrimidine-5-carbonitrile, or N-cyclopentyl-5-(2-((5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-yl)amino)pyrimidin-4-yl)-4-methylthiazol-2-amine.

[0048] In yet another preferred embodiment, the compound of formula I is N-cyclopentyl-5-(2-((5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-4-methylthiazol-2-amine.

[0049] In some preferred embodiments, the compounds of formula I exhibit antiproliferative activity in human cell lines as measured by standard cytotoxicity assays. Preferably, the compounds exhibit an IC 50 More preferably, the compound exhibits an IC value of less than 5 μM, and even more preferably, less than 1 μM. 50 Values ​​below 0.5 μM are shown.

[0050] In some preferred embodiments, the compounds of formula I inhibit CDK4 and / or CDK6 as measured by any standard assay known to one of skill in the art. Preferably, the compounds inhibit CDK4 and / or CDK6 at or below an IC50 level as measured by any standard kinase assay known to one of skill in the art. 50 Values ​​below 1 μM or below 0.5 μM, more preferably even below 0.1 μM, are indicated.

[0051] Specific examples of compounds of formula I for use in the method according to the first aspect are shown in Table 1 below. [Table 1-1] [Table 1-2]

[0052] The other immunotherapeutic agent may be selected, for example, from agents known to those skilled in the art as capable of promoting an immune response against cancer cells. For example, the other immunotherapeutic agent may be selected from immune checkpoint inhibitors, for example, any agent (which may be, for example, a protein, peptide, antibody or antibody fragment, or a combination thereof) capable of inhibiting (for example, by blocking) the interaction between one or more immune checkpoint receptors and their ligand(s). As will be appreciated by those skilled in the art, among the immune checkpoint inhibitors suitable for use in the method according to the first aspect are agents capable of inhibiting PD-1 (for example, anti-PD-1 blocking antibodies, for example, pembrolizumab, lambrolizumab, cemiplimab, spartalizumab, and nivolumab, or anti-PD-L1 antibodies, for example, atezolizumab, avelumab, and durvalumab, or anti-PD-L2 antibodies), agents capable of inhibiting PD-L1, agents capable of inhibiting PD-L2, agents capable of inhibiting CTLA-4, and agents capable of inhibiting CTLA-4. These include drugs that can inhibit B and T lymphocyte attenuator (BTLA, CD272) (e.g. anti-BTLA antibodies), drugs that can inhibit T cell immunoglobulin and mucin domain-3 (Tim-3, CD366) (e.g. anti-Tim-3 antibodies) or so-called intracellular checkpoints, such as E3 ubiquitin-protein ligase (CBL-B) and CISH (cytokine-inducible SH2-containing protein).

[0053] In the method according to the first aspect, it will be appreciated that the method may include co-administration of one or more compounds of formula I (or a pharma- ceutically acceptable salt, solvate, or prodrug thereof) and one or more other immunotherapeutic agents.

[0054] In some embodiments, the method of the first aspect may further comprise administering one or more additional compound(s) having antiproliferative activity, for example, one or more compound(s) of the following categories: Antitumor drugs and their combinations used in medical oncology, such as alkylating agents (e.g., cisplatin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulfan, temozolamide, and nitrosoureas), antimetabolites (e.g., gemcitabine and antifolates, such as fluoropyrimidines, e.g., 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, antitumor antibiotics (e.g., anthracyclines such as adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin, and mithramycin), antimitotic agents (e.g., vinca alkaloids such as vincristine, vinblastine, vindesine, and vinorelbine, and taxoids such as taxol and taxotere, and polokinase inhibitors), and topoisomerase inhibitors (e.g., epipodophyllotoxins such as etoposide and teniposide, amsacrine, topotecan, and camptothecin), Cytostatics, such as antiestrogens (e.g. tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene, and iodoxyfene), antiandrogens (e.g. bicalutamide, flutamide, nilutamide, and cyproterone acetate), LHRH antagonists or agonists (e.g. goserelin, leuprorelin, and buserelin), progestogens (e.g. megestrol acetate), aromatase inhibitors (e.g. anastrozole, letrozole, vorazole, and exemestane), and 5α-reductase inhibitors, such as finasteride, anti-nociceptive agents (e.g. c-Src kinase family inhibitors, such as 4-(6-chloro-2,3-methylenedioxyanilino)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-tetrahydropyran-4-yloxyquinazoline (AZD0530, International Patent Publication No. WO 01 / 94341), N-(2-chloro-6-methylphenyl)-2-{6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-ylamino}thiazole-5-carboxamide (dasatinib) and bosutinib (SKI-606)), as well as metalloproteinase inhibitors, including marimastat, inhibitors of urokinase-type plasminogen activator receptor function, or antibodies against heparanase, Inhibitors of growth factor function (e.g., growth factor antibodies and growth factor receptor antibodies, such as the anti-erbB2 antibody trastuzumab (Herceptin™), the anti-EGFR antibody panitumumab, the anti-erbB1 antibody cetuximab (Erbitux, C225), and any of the growth factor or growth factor receptor antibodies disclosed by Stern et al., Crit Rev Oncol Hematol 54:11-29, 2005).Such inhibitors also include tyrosine kinase inhibitors, for example inhibitors of the epidermal growth factor family (e.g., EGFR family tyrosine kinase inhibitors, for example, N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (gefitinib, ZD1839), N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) and 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-quinazolin-4-amine (CI 1033), erbB2 tyrosine kinase inhibitors, e.g., lapatinib), inhibitors of the hepatocyte growth factor family, inhibitors of the insulin growth factor family, inhibitors of the platelet-derived growth factor family, e.g., imatinib and / or nilotinib (AMN107), inhibitors of serine / threonine kinases (e.g., Ras / Raf signaling inhibitors, e.g., farnesyltransferase inhibitors, including sorafenib (BAY 43-9006), tipifarnib (R115777) and lonafarnib (SCH66336), and rapamycin (mTOR) inhibitors, e.g., everolimus, sirolimus and temsirolimus), inhibitors of cell signaling via MEK and / or AKT kinases (e.g., selumetinib, and trametinib), c-kit inhibitors, abl kinase inhibitors, phosphoinositide-3-kinase (PI3K) inhibitors (e.g., abl kinase inhibitors, rupelisib and duvelisib), Plt3 kinase inhibitors, CSF-1R kinase inhibitors, IGF receptor (insulin-like growth factor) kinase inhibitors, inhibitors of PARP (e.g., olaparib and rucaparib), Aurora kinase inhibitors (e.g., AZD1152, PH739358, VX-680, MLN8054, R763, MP235, MP529, VX-528 and AX39459) and cyclin-dependent kinase inhibitors, such as CDK2 and / or CDK9 inhibitors. angiogenesis inhibitors, such as those that inhibit the effects of vascular endothelial growth factor (e.g., the anti-vascular endothelial growth factor antibody bevacizumab (Avastin™)), as well as VEGF receptor tyrosine kinase inhibitors, such as vandetanib (ZD6474), vatalanib (PTK787), sunitinib (SU11248), axitinib (AG-013736), pazopanib (GW 786034), and 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline (AZD2171, Example 240 of International Patent Publication No. WO 00 / 47212), International Patent Publication Nos. WO 97 / 22596, WO 97 / 30035, WO compounds such as those disclosed in WO 97 / 32856, and WO 98 / 13354, as well as compounds that act by other mechanisms (e.g., linomide, an inhibitor of integrin αvβ3 function, and angiostatin); Antiproliferative / antineoplastic drugs and their combinations used in medical oncology, such as alkylating agents (e.g. carmustine, procarbazine, lomustine, vincristine, and TMZ), antimetabolites (e.g. gemcitabine and antifolates, such as fluoropyrimidines, e.g. 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, fludarabine, and hydroxyurea), antitumor antibiotics (e.g. anthracyclines, e.g. adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin, and mithramycin), antimitotics (e.g. vinca alkaloids, e.g. vincristine, vinblastine, vindesine, and vinorelbine, and taxoids, e.g. taxol and taxotere, and polokinase inhibitors inhibitors), and topoisomerase inhibitors (e.g., epipodophyllotoxins such as etoposide and teniposide, amsacrine, topotecan, and camptothecin); Cytostatics, such as antiestrogens (e.g. tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene, and iodoxyfene), antiandrogens (e.g. bicalutamide, flutamide, nilutamide, and cyproterone acetate), LHRH antagonists or agonists (e.g. goserelin, leuprorelin, and buserelin), progestogens (e.g. megestrol acetate), aromatase inhibitors (e.g. anastrozole, letrozole, vorazole, and exemestane), and 5α-reductase inhibitors, such as finasteride, Vascular damaging agents, such as combretastatin A4 and the compounds disclosed in International Patent Publication Nos. WO 99 / 02166, WO 00 / 40529, WO 00 / 41669, WO 01 / 92224, WO 02 / 04434, and WO 02 / 08213; Endothelin receptor antagonists, such as zibotentan (ZD4054) or atrasentan, and Antisense therapy, for example directed to the targets mentioned above, e.g. ISIS 2503, anti-ras antisense.

[0055] The method according to the first aspect is typically applied to the treatment of cancer or another proliferative cell disease or condition in a human subject. However, the subject may also be selected from, for example, livestock animals (e.g., cows, horses, pigs, sheep, and goats), companion animals (e.g., dogs and cats), and exotic animals (e.g., non-human primates, tigers, elephants, etc.).

[0056] Cancers and other proliferative cell diseases and conditions that may be treated according to the method of the first aspect include biliary tract cancer, brain tumors and other cancers of the central nervous system (CNS) (including glioblastoma and medulloblastoma), neuroblastoma, breast cancer, cervical cancer, ovarian cancer (including those arising from epithelial, stromal, germ cells, and mesenchymal cells), choriocarcinoma, colorectal cancer, uterine cancer, liver cancer, lung cancer, esophageal cancer, gastric cancer, hematological tumors (acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL) and chronic myeloid leukemia (CML), as well as acute myeloid leukemia (AML), multiple myeloma, AIDS-related leukemia, and adult T-cell leukemia. lymphomas, including non-Hodgkin's lymphoma, Hodgkin's disease, and lymphocytic lymphomas, intraepithelial neoplasia (including Bowen's disease and Paget's disease), oral cancer (including squamous cell carcinoma), pancreatic cancer, prostate cancer, sarcomas (including leiomyosarcoma, rhabdomyosarcoma, liposarcoma, fibrosarcoma, and osteosarcoma), skin cancer (including melanoma, Kaposi's sarcoma, basal cell carcinoma, and squamous cell carcinoma), testicular cancer (including germ cell tumors, e.g., seminoma, nonseminomatous teratoma, and choriocarcinoma), stromal tumors, germ cell tumors, thyroid cancer (including thyroid adenocarcinoma and medullary carcinoma), and renal cancer (including adenocarcinoma and Wilms' tumor).

[0057] In some embodiments, the cancers and other proliferative cell diseases and conditions treated according to the methods of the first aspect are characterized by overexpression of CDK4 and / or cyclin D, including, for example, lung cancer (Wu et al., J Transl Med 9:38(2011)), breast cancer (An et al., Am J Pathol 154(1):113-118(1999)), brain tumors and other cancers of the CNS (e.g., glioblastoma), and colorectal cancer (Ikeda et al., Jap J Clin Med 54(4):1054-1059(1996)). Overexpression of CDK4 and / or cyclin D can be identified by assessing the amount of mRNA encoding CDK4 and / or cyclin D in a suitable sample, for example, using any of the techniques well known to those of skill in the art (e.g., quantitative amplification techniques, e.g., qPCR).

[0058] In some embodiments, the cancers and other proliferative cell diseases and conditions treated according to the methods of the first aspect are characterized by overexpression of CDK6 and / or cyclin D, including, for example, T-cell acute lymphoblastic leukemia (ALL), brain tumors and other cancers of the CNS (e.g., medulloblastoma), and colorectal cancer (reviewed in Tadesse et al., Cell Cycle 14(20):3220-30 (2015)). Overexpression of CDK6 and / or cyclin D may be identified by assessing the amount of mRNA encoding CDK6 and / or cyclin D in a suitable sample, for example, using any of the techniques well known to those of skill in the art (e.g., quantitative amplification techniques, e.g., qPCR).

[0059] As will be appreciated by one of skill in the art, co-administration of a compound of Formula I with another immunotherapeutic agent can involve administering the compound and agent to a subject simultaneously, or can involve administering the compound and agent sequentially in any order (e.g., within seconds or minutes (e.g., 10, 60, or 90 minutes), or even within a few hours (e.g., within 2-48 hours)). Thus, the compound of Formula I and the other immunotherapeutic agent can be administered, for example, in the same pharmaceutical composition (i.e., for simultaneous administration) or in separate pharmaceutical compositions.

[0060] In a second aspect, the disclosure provides a pharmaceutical composition comprising a compound of formula I (or a pharma- ceutically acceptable salt, solvate, or prodrug thereof) as de?ned in the ?rst aspect and an immunotherapeutic agent, optionally in combination With a pharma- ceutically acceptable carrier, diluent, and / or excipient, for treating a proliferative disease or condition in a subject.

[0061] The compound of formula I and the other immunotherapeutic agents can be formulated into pharmaceutical compositions with pharma- ceutically acceptable carriers, diluents, and / or excipients in a therapeutically effective amount (which can be less than the amount that the compound can be used in a treatment in which it is used alone). Examples of suitable carriers and diluents are well known to those skilled in the art and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA 1995. Examples of excipients suitable for the various different forms of pharmaceutical compositions described herein can be found in Handbook of Pharmaceutical Excipients, 2000, pp. 211-215, 1995. nd Edition, (1994), Edited by A Wade and PJ Weller. Examples of suitable carriers include lactose, starch, glucose, methylcellulose, magnesium stearate, mannitol, sorbitol, and the like. Examples of suitable diluents include ethanol, glycerol, and water. The selection of carriers, diluents, and / or excipients can be made according to the intended route of administration and standard pharmaceutical practice.

[0062] The pharmaceutical composition comprising the compound of formula I and the other immunotherapeutic agent may further comprise any suitable binder, lubricant, suspending agent, coating agent, and solubilizing agent. Examples of suitable binders include starch, gelatin, natural sugars such as glucose, anhydrous lactose, liquid lactose, beta-lactose, corn syrup, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose and polyethylene glycol. Examples of suitable lubricants include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, etc. Preservatives, stabilizers, dyes, and even flavoring agents may be provided in the pharmaceutical composition. Examples of preservatives include sodium benzoate, sorbic acid, and esters of p-hydroxybenzoic acid. Antioxidants and suspending agents may also be used.

[0063] The pharmaceutical composition comprising the compound of formula I and the immunotherapeutic agent may be adapted for oral, rectal, intravaginal, parenteral, intramuscular, intraperitoneal, intraarterial, intrathecal, intrabronchial, subcutaneous, intradermal, intravenous, nasal, buccal, or sublingual administration routes. For oral administration, compressed tablets, pills, tablets, gellules, drops, and capsules may be used in particular. In other forms of administration, the pharmaceutical composition may comprise a solution or emulsion that may be injected intravenously, intraarterially, intrathecal, subcutaneous, intradermal, intraperitoneally, or intramuscularly, which are prepared from a sterile or sterilizable solution. The pharmaceutical composition comprising the compound of formula I and the immunotherapeutic agent may be in the form of a suppository, pessary, suspension, emulsion, lotion, ointment, cream, gel, spray, solution, or dusting powder. The pharmaceutical composition may be formulated into unit dosage form (i.e., in the form of a unit dose, or in the form of a discrete portion that contains a multiple or subunit of a unit dose).

[0064] The compounds of formula I and / or the immunotherapeutic agents may be provided as pharma- ceutically acceptable salts, including, for example, suitable acid addition or base salts thereof. A review of suitable pharmaceutical salts may be found in Berge et al., J Pharm Sci 66:1-19 (1977). Salts are formed, for example, with strong inorganic acids, such as mineral acids (e.g., sulfuric acid, phosphoric acid, or hydrohalic acid), strong organic carboxylic acids, such as unsubstituted or substituted (e.g., by halogen) alkane carboxylic acids having 1 to 4 carbon atoms, such as acetic acid, saturated or unsaturated dicarboxylic acids (e.g., oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, phthalic acid, or tetraphthalic acid), hydroxycarboxylic acids (e.g., ascorbic acid, glycolic acid, lactic acid, malic acid, tartaric acid, or citric acid), amino acids (e.g., aspartic acid or glutamic acid), benzoic acid, or organic sulfonic acids (e.g., (C1-C4)-alkyl or aryl sulfonic acids unsubstituted or substituted, for example, by halogen), such as methanesulfonic acid or p-toluenesulfonic acid. Furthermore, the compounds of formula I and / or the other immunotherapeutic agents may be provided in their various crystalline forms, polymorphs, and (an)hydrated forms. In this regard, it will be known to those skilled in the art that compounds may be isolated in any of these forms by slight variations in the purification and / or isolation methods from the solvents used in the synthetic preparation of such compounds.

[0065] In a third aspect, the disclosure provides the use of a compound of formula I (or a pharma- ceutically acceptable salt, solvate, or prodrug thereof) as defined in the first aspect and an immunotherapeutic agent for treating a proliferative disease or condition in a subject.

[0066] In a fourth aspect, the disclosure provides the use of a compound of formula I (or a pharma- ceutically acceptable salt, solvate, or prodrug thereof) as defined in the first aspect and an immunotherapeutic agent in the manufacture of a medicament for treating a proliferative disease or condition in a subject.

[0067] In a fifth aspect, the disclosure provides a kit comprising first and second containers (e.g., vials), the first container comprising a compound of Formula I (or a pharma- ceutically acceptable salt, solvate, or prodrug thereof) as defined in the first aspect, and the second container comprising an immunotherapeutic agent, optionally packaged with instructions for use of the kit in a method according to the first aspect.

[0068] Methods for synthesizing compounds of formula I have been previously described (see, for example, International (PCT) Patent Publication No. WO2017 / 020065, the contents of which are incorporated herein by reference in their entirety). In some embodiments, compounds of formula I can be synthesized by adapting the following general synthetic scheme: [ka] Here, typical reaction conditions are: (a) DMF-DMA or Bredereck's reagent, reflux; (b) Selectfluor, MeOH; (c) Et3N, HgCl2, DCM; (d) TFA / DCM (1:1), reflux; (e) A, B, NaOH, 2-methoxyethanol, microwave; and (f) Pd2dba3, xantphose, t-BuONa, dioxane, microwave.

[0069] With respect to the description of the synthetic methods in Scheme 1 above, one skilled in the art will understand that all proposed reaction conditions, including the choice of solvent, reaction atmosphere, reaction temperature, duration of experiment, and work-up procedures, can be readily selected. Furthermore, one skilled in the art will understand that the functional groups present on various portions of the molecule must be compatible with the reagents and reaction conditions used.

[0070] The necessary starting materials may be obtained by standard organic chemistry procedures. The preparation of such starting materials is illustrated in conjunction with the following representative process variants and in the following examples. Alternatively, the necessary starting materials may be obtained by analogous procedures that are within the ordinary skill of one of ordinary skill in the art. Furthermore, it will be understood that during the synthesis of the compound, or during the synthesis of a particular starting material, it may be desirable to protect certain substituents to prevent them from undesired reactions. Those skilled in the art will readily recognize when such protection is necessary and how such protecting groups can be introduced and subsequently removed. Examples of protecting groups are described, for example, in Protective Groups in Organic Synthesis by Theodora Green (publisher: John Wiley & Sons). Protecting groups can be removed by any convenient method known to those skilled in the art as being suitable for the removal of the protecting group in question. Such methods are selected to remove the protecting group with minimal disturbance to groups elsewhere in the molecule. Thus, if a reactant contains a group such as, for example, amino, carboxyl, or hydroxyl, it may be desirable to protect the group in some of the reactions mentioned herein.

[0071] Moreover, one skilled in the art would be able to select suitable reaction conditions for use in the coupling reaction of the compound of formula A or formula B shown in Scheme 1. However, typically, the reaction is carried out under anhydrous conditions and in the presence of an inert atmosphere, such as argon or nitrogen. The reaction may also be carried out at elevated temperatures, such as within the range of 80-180° C., for a suitable period of time, such as 20 minutes to 48 hours. Suitably, the reaction is carried out under microwave heating, such as at 80-180° C., for 20 minutes to 1.5 hours.

[0072] The resulting compounds may be isolated and purified using techniques well known to those of skill in the art.

[0073] The methods and uses of the present disclosure are further described below with reference to the following non-limiting examples and accompanying drawings. EXAMPLES

[0074] Example 1 Synthesis of Representative Compounds General 1 H and 13 C NMR spectra were recorded on a Bruker AVANCE III 500 spectrometer ( 1 H was 500MHz and recorded at 300K. 1 The H NMR spectrum shows that the residual non-deuterated solvent (or tetramethylsilane) 1 The H signal was referenced. High-resolution mass spectra were recorded on an AB SCIEX TripleTOF® 5600 mass spectrometer and ionization of all samples was performed using ESI. Purity of compounds was determined by analytical HPLC and was greater than 95%. Analytical HPLC was performed on a Shimadzu Prominence UFLC (UltraFast Liquid Chromatograph) system equipped with a CBM-20A communication bus module, DGU-20A 5R Degasser, LC-20AD Liquid Chromatograph Pump, SIL-20A HT The instrument was equipped with an autosampler, SPD-M20A photodiode array detector, CTO-20A column oven, and a Phenomenex Kinetex 5u C18 100A 250 mm x 4.60 mm column and was run using Method A (5-95% gradient of MeOH with 0.1% FA over 7 min, followed by 95% MeOH with 0.1% FA for 13 min, flow rate 1 mL / min), Method B (5-95% gradient of MeCN with 0.1% FA over 7 min, followed by 95% MeCN with 0.1% FA for 13 min, flow rate 1 mL / min).

[0075] N-Cyclopentyl-5-(2-((5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-4-methylthiazol-2-amine (1): To a solution of 5-(2-amino-5-fluoropyrimidin-4-yl)-N-cyclopentyl-4-methylthiazol-2-amine (200 mg, 0.68 mmol) in dioxane (3 mL), 1-((6-bromopyridin-3-yl)methyl)-4-ethylpiperazine (233 mg, 0.82 mmol), Pd2dba3 (31 mg, 0.034 mmol), Xantphos (41 mg, 0.07 mmol) and t-BuONa (98 mg, 1.02 mmol) were added and heated at 150° C. for 1 h under microwave irradiation. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, gradient from DCM to DCM:MeOH=93:7) to give 1 as an orange solid (100 mg, 29%). 1 H NMR (DMSO-d6) δ0.99 (t, 3H, J7.0), 1.49-1.59 (m, 4H),1.64 - 1.72 (m,2H), 1.90 - 1.97(m, 2H), 2.38 (sbr, 10H), 2.48 (d,3H, J 2.5), 3.42 (s,2H), 3.95 - 3.98(m, 1H), 7.64 (dd,1H, J 8.5 &2.0), 8.10 (d, 1H,J 8.5), 8.16 (d,1H, J 2.0), 8.27 (d,1H, J 7.0), 8.46 (d,1H, J 3.5), 9.77 (s,1H). HRMS (ESI): m / z 497.2601[M+H] + .

[0076] N-Cyclopentyl-4-methyl-5-(2-((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)thiazol-2-amine (2): To a mixture of crude 1-(5-(piperazin-1-yl)pyridin-2-yl)guanidine trifluoroacetate (441 mg, 2.00 mmol) and (E)-1-(2-(cyclopentylamino)-4-methylthiazol-5-yl)-3-(dimethylamino)prop-2-en-1-one (279 mg, 1.00 mmol) in 2-methoxyethanol (3 mL) was added NaOH (80.0 mg, 2.00 mmol). The reaction mixture was heated at 180° C. for 1 h under microwave irradiation, cooled to room temperature, and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, gradient from DCM to DCM:MeOH=92:8) and recrystallized with DCM and MeOH to give 2 as a dark yellow solid (70.0 mg, 16%). mp 210-213° C. 1 H NMR (DMSO-d6) 1.49-1.68(m, 7H), 1.89-1.94 (m, 2H),2.46 (s, 3H), 2.85(t, 4H, J 4.5),3.02 (t, 4H, J5.0), 3.98 (m, 1H),6.90 (d, 1H, J5.5), 7.36 (dd, 1H,J 9.0 & 3.0),7.98 (d, 1H, J3.0), 8.07 (d, 1H,J 9.0), 8.18 (d,1H, J 7.0), 8.33 (d,1H, J 5.5), 9.33 (s,1H). HRMS (ESI): m / z 437.2222[M+H] + .

[0077] N-Cyclopentyl-5-(2-((5-(4-ethylpiperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-4-methylthiazol-2-amine (3): To a mixture of crude 1-(5-(4-ethylpiperazin-1-yl)pyridin-2-yl)guanidine trifluoroacetate (496 mg, 2.00 mmol) and (E)-1-(2-(cyclopentylamino)-4-methylthiazol-5-yl)-3-(dimethylamino)prop-2-en-1-one (279 mg, 1.00 mmol) in 2-methoxyethanol (3 mL) was added NaOH (80.0 mg, 2.00 mmol). The reaction mixture was heated at 180° C. under microwave irradiation for 1 h, cooled to room temperature, and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, gradient from DCM to DCM:MeOH=96:4) and recrystallized from MeOH to give 3 as a yellow solid (117 mg, 25%). 1 H NMR (CDCl3) δ1.14 (t, 3H, J7.0), 1.56-1.76 (m, 6H),2.06-2.12 (m, 2H), 2.49(q, 2H, J 7.5), 2.54 (s,3H), 2.64 (s, 3H),3.19 (t, 4H, J4.5), 3.14 (t, 4H,J 5.0), 3.86 (apps, 1H), 5.77 (s,1H), 6.84 (d, 1H,J 5.0), 7.34 (dd,1H, J 9.0 &3.0), 7.94 (d, 1H,J 3.0), 7.94 (s,1H), 8.01 (d, 1H,J 3.0), 8.26 (d,1H, J 9.0), 8.33 (d,1H, J 5.5). HRMS (ESI):m / z 465.2541 [M+H] + .

[0078] 2-((5-(4-acetylpiperazin-1-yl)pyridin-2-yl)amino)-4-(4-methyl-2-(methylamino)thiazol-5-yl)pyrimidine-5-carbonitrile (4): To a solution of crude 1-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)guanidine trifluoroacetate (315 mg, 1.20 mmol) in 2-methoxyethanol (4 mL) was added tert-butyl (E)-(5-(2-cyano-3-(dimethylamino)acryloyl)-4-methylthiazol-2-yl)(methyl)carbamate (350 mg, 1.00 mmol) and NaOH (82.0 mg, 2.40 mmol). The reaction mixture was heated at 180° C. for 90 min under microwave irradiation, cooled to room temperature, and then concentrated under reduced pressure. The residue was purified by chromatography (silica gel, gradient from DCM to DCM:MeOH=90:10, successive addition of 32% aqueous ammonia, up to 3%). The solid was washed with DCM and MeOH, then filtered to give 4 as a pale yellow solid (157 mg, 35%). 1 H NMR (DMSO-d6) δ2.04 (s, 3H), 2.40(s, 3H), 2.87 (s,3H), 3.10 (t, 2H,J 5.0), 3.16 (t,2H, J 5.0), 3.58 (t,4H, J 5.0), 7.46 (dd,1H, J 9.5 &3.0), 7.90 (d, 1H,J 9.0), 8.06 (d,1H, J 3.0), 8.26 (q,1H, J 3.0), 8.75 (s,1H), 10.33 (s, 1H).HRMS (ESI): m / z 450.1844[M+H] + .

[0079] N-Cyclopentyl-5-(2-((5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-yl)amino)pyrimidin-4-yl)-4-methylthiazol-2-amine (5): To a solution of 5-(2-aminopyrimidin-4-yl)-N-cyclopentyl-4-methylthiazol-2-amine (275 mg, 1.00 mmol) in dioxane (3 mL), 1-((6-bromopyridin-3-yl)methyl)-4-ethylpiperazine (341 mg, 1.2 mmol), Pd2dba3 (45.8 mg, 0.05 mmol), Xantphos (58 mg, 0.1 mmol) and t-BuONa (144 mg, 1.5 mmol) were added and heated at 150° C. for 1 h under microwave irradiation. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, gradient from DCM to DCM:MeOH:NH4OH=9:1:0.3) and recrystallized with DCM and MeOH to give 5 as a white solid (200 mg, 42%). 1 H NMR (CDCl3) δ1.09 (t, 3H, J7.0), 1.58 - 1.76(m, 6H), 2.08 -2.14 (m, 2H), 2.43(q, 2H, J 7.0,CH2CH3),2.55 (s br, 11H),3.48 (s, 2H), 3.86- 3.92 (m, 1H),5.42 (d, 2H, J7.0), 6.90(d, 1H, J5.5), 7.68 (dd, 1H,J 9.0 & 2.5),7.89 (s, 1H), 8.19(d, 1H, J 2.0),8.35 - 8.38 (m,2H). HRMS (ESI): m / z 479.2703[M+H] + .

[0080] 5-(2-((5-(4-aminopiperidin-1-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-N,4-dimethylthiazol-2-amine (6): Compound 7 was obtained by reacting 1-(5-(4-aminopiperidin-1-yl)pyridin-2-yl)guanidine trifluoroacetate (702 mg, 3.00 mmol) and (469 mg, 2.00 mmol) and ((E)-3-(dimethylamino)-2-fluoro-1-(4-methyl-2-(methylamino)thiazol-5-yl)prop-2-en-1-one (243 mg, 1.00 mmol) to give an orange solid (40.0 mg, 10%). 1 H NMR (DMSO-d6)δ 1.75-1.80 (m, 2H),2.45 (d, 3H, J2.0), 2.62 (t, 2H,J 6.0), 2.85 (t,2H, J 5.5), 3.45 (t,2H, J 5.0), 3.53 (t,2H, J HRMS (ESI): m / z 415.1821[M+H] + .

[0081] 5-(2-((5-(4-aminopiperidin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-N-cyclopentyl-4-methylthiazol-2-amine (7): To a mixture of 1-(5-(4-aminopiperidin-1-yl)pyridin-2-yl)guanidine trifluoroacetate (702 mg, 3.00 mmol) and (E)-1-(2-(cyclopentylamino)-4-methylthiazol-5-yl)-3-(dimethylamino)prop-2-en-1-one (558 mg, 2.00 mmol) in 2-methoxyethanol (5 mL) was added NaOH (160.0 mg, 4.00 mmol). The reaction mixture was heated at 180° C. under microwave irradiation for 2 h, cooled to room temperature, and concentrated under reduced pressure. The residue was purified by chromatography to give 7 as a yellow solid (90 mg, 10%). 1 H NMR (CDCl3) δ1.50-1.77 (m, 10H), 1.95 (d,2H, J 10.5), 2.07-2.13 (m, 2H),2.54 (s, 3H), 2.75-2.85(m, 3H), 3.53 -3.56 (m, 2H), 3.85- 3.91 (m, 1H),5.43 (d, J 5.0,1H), 6.84 (d, 1H,J 5.5), 7.34 (dd,1H, J 9.0 &3.0), 7.75 (s, 1H),8.00 (d, 1H, J3.0), 8.25 (d, 1H,J 9.0), 8.32 (d,1H, J 5.5).HRMS (ESI): m / z 451.2415 [M+H] + .

[0082] N-Cyclopentyl-5-(2-((5-morpholinopyridin-2-yl)amino)pyrimidin-4-yl)-4-methylthiazol-2-amine (8): To a mixture of 1-(5-morpholinopyridin-2-yl)guanidine trifluoroacetate (442 mg, 2.00 mmol) and (E)-1-(2-(cyclopentylamino)-4-methylthiazol-5-yl)-3-(dimethylamino)-2-fluoroprop-2-en-1-one (297 mg, 1.00 mmol) in 2-methoxyethanol (3 mL) was added NaOH (80.0 mg, 2.00 mmol). The reaction mixture was heated at 180° C. under microwave irradiation for 1 h, cooled to room temperature, and concentrated under reduced pressure. The residue was purified by chromatography to give 8 as a brown solid (120 mg, 26%). 1 H NMR (DMSO-d6) δ1.50-1.57 (m, 4H), 1.66- 1.69 (m, 2H),1.90 - 1.95 (m,2H), 2.47 (d, 1H,J 2.5), 3.09 (t,4H, J 5.0), 3.75 (t,4H, J 5.0), 3.96 (m,1H), 7.42 (dd, 1H,J 9.0 & 3.0),7.96 (d, 1H, ,J 9.0), 7.98 (d,1H, J 3.0), 8.24 (d,1H, J 7.0), 8.41 (d,1H, J 7.0), 9.52(s, 1H).HRMS(ESI): m / z 456.1976 [M+H] + .

[0083] Example 2 Pharmacological activity of representative compounds Kinase assay Inhibition of CDKs and other kinases was measured by radiometric assay (RIA) using Eurofins Pharma Discovery or Reaction Biology Corporation's Kinase Profiler service. Inhibition of CDK4 / cyclin D1, CDK6 / cyclin D3, and CDK9 / cyclin T1 was also measured using the ADP Glo kinase assay (Promega Corporation, Madison WI, United States of America). Briefly, kinase reactions of CDK4 / cyclin D1 and CDK6 / cyclin D3 were performed with kinase reaction buffer (40 nM Tris base pH 7.5, 20 mM MgCl2, 0.4 mM DTT), 0.1 mg / ml BSA, and RB-CTF substrate (C-terminal fraction of retinoblastoma protein 1). For CDK9 / cyclin T1, kinase reactions were performed with standard assay buffer and kinase dilution buffer and RBER-IRStide substrate. Serial 1:3 dilutions were prepared for ten concentrations (10 μM-0.5 nM) of test compounds. Kinase reactions were initiated by the addition of ATP and incubated at 37°C for 40 min before being stopped by the addition of 10 μL of ADP Glo reagent. After 40 min of incubation in the dark at room temperature (RT), 20 μL / well of kinase detection reagent was added and incubated for 40 min. Luminescence was measured using an EnVision Multilabel plate reader (PerkinElmer, Buckinghamshire, United Kingdom). Positive and negative controls were run in the presence and absence of CDK kinases, respectively. Median inhibition (IC) was calculated using a four-parameter logistic nonlinear regression model using GraphPad prism (version 6.0). 50 ) values ​​were calculated. The apparent inhibition constant (K i ) values ​​for each kinase m (ATP) and IC 50 The results for representative compounds are shown in Table 2. Compound 1 was the most potent CDK4 / 6 inhibitor and was selected for further evaluation for its immunotherapeutic potential.

[0084] [Table 2]

[0085] cell culture Mouse triple-negative breast cancer EMT6 tumor cells (ATCC® CRL-2755™) and colorectal cancer CT26.WT cells (ATCC® CRL-2638™) were cultured and grown in RPMI-1640 medium (Roswell Park Memorial Institute Medium-1640) supplemented with 10% heat-inactivated fetal bovine serum (FBS) with L-glutamine and sodium bicarbonate (Sigma-Aldrich, Macquarie Park, NSW, Australia). Cells were cultured in a 5% CO2, 37°C incubator.

[0086] In vivo antitumor activity in mice bearing breast cancer cell syngeneic allografts EMT6 cells were harvested and resuspended in a 1:1 mixture of Matrigel™ (#354234, Corning Life Sciences, Corning, NY, United States of America) and serum-free RPMI-1640 medium, and then injected subcutaneously (sc) into the right flank of each female BALB / c mouse (7x10 5 (Volume of 100 μL containing 10 cells). 3After reaching a median age of 10 days, mice were randomized into two groups (n=4 / group) and were orally administered vehicle (1% CMC in water) or compound 1 (150 mg / kg) once daily (QD PO). Treatment with compound 12 resulted in 47% tumor growth inhibition (TGI%) on the final day of tumor measurement (Figure 1A). Levels of phosphorylated RB (p-S807 / 11) were also found to be decreased in EMT6 tumors harvested 2 hours after the final dose, confirming inhibition of CDK4 / 6 (Figure 1B). There was also a decrease in PDL-1, an immune checkpoint inhibitor, in spleen samples of mice isolated 2 hours after the final dose, indicating the immunotherapeutic potential of compound 1 (Figure 1C). No significant weight loss or obvious toxicity was observed in the compound 1-treated groups throughout the study.

[0087] In vivo antitumor activity in mice bearing colorectal cancer cell syngeneic allografts Similarly, mice bearing CT26.WT colorectal cancer cells were matched and randomized into vehicle or treatment groups (n=8 / group). Mean tumor volume was approximately 100 mm 3 Female BALB / c mice were treated with vehicle (distilled water QD PO), compound 1 (100 mg / kg QD PO), anti-PD1 antibody (RMP1-14 derived mouse monoclonal antibody, Assay Matrix Pty Ltd, Ivanhoe North, VIC, Australia), 200 μg / mouse / week intraperitoneally (ip), or compound 1 plus anti-PD-1 antibody. Compound 1 achieved significant tumor growth inhibition (TGI%) of 75% when used alone and 91% when used in combination with anti-PD-1 antibody, measured on day 21 of treatment (Figure 2A-B). Treatment with compound 1 was also found to significantly prolong mouse survival when administered as a single agent (p<0.001) and in combination with anti-PD-1 antibody (p<0.001, Figure 2C).

[0088] In another experiment, mice bearing CT26.WT colorectal cancer cells were treated with vehicle (distilled water QD PO), compound 1 (100 mg / kg QD PO), anti-PD-1 antibody (150 μg / mouse / week ip), or compound 1 plus anti-PD-1 antibody. Compound 1 resulted in a TGI of 77% when used alone and 91% in combination with anti-PD-1 antibody at day 15 of administration (Figures 3A and 3C). This combination approach was even more effective compared to anti-PD-1 alone (p=0.03, Figure 3B). The immune contribution to the improved anti-cancer efficacy by compound 1 was demonstrated by the increased levels of various immune markers, e.g., CD3+, CD4+, CDK8+, and CD45+ T cells (Figures 3D-G).

[0089] conclusion A representative compound of the compound group defined by formula I, namely compound 1 (N-cyclopentyl-5-(2-((5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-4-methylthiazol-2-amine), was found to inhibit CDK4 / 6 kinase (known to be involved in cell cycle regulation) and to have an antitumor effect on mice with an intact immune system, e.g. Balb / C mice, bearing EMT6 breast cancer or CT26.WT colorectal cancer syngeneic allografts. Furthermore, this representative compound was found to be able to increase the levels of various immune markers, indicating that the compounds of formula I have excellent potential to act as immunotherapeutic agents for the treatment of proliferative cell diseases and conditions, especially when used in combination with another immunotherapeutic agent, e.g. one used in checkpoint inhibitor therapy.

[0090] Throughout this specification and the claims which follow, unless the context requires otherwise, the words "comprise" and "include" and the variations "comprising" and "including" are understood to mean the inclusion of a stated whole or group of wholes but not the exclusion of any other whole or group of wholes.

[0091] The reference to any prior art in this specification is not, and should not be construed as, any form of admission that this prior art forms part of the common general knowledge.

[0092] Those skilled in the art will understand that the present disclosure is not limited to use for the specific applications described. The present disclosure is also not limited to its preferred embodiments with respect to the specific elements and / or features described or illustrated herein. It will also be understood that the present disclosure is not limited to the disclosed embodiment(s), but that various rearrangements, modifications, and substitutions are possible without departing from the scope of the present disclosure, as described and defined in the following claims.

Claims

1. An agent comprising a compound of formula I shown below, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, for treating a proliferative disorder or condition in a subject, and for co-administration to the subject together with an immunotherapy agent: 【Chemistry 1】 During the ceremony, R １ 、R ２ 、R ３ 、R ４ 、R ５ 、R ６ and R ７ are each independently selected from the group consisting of H, alkyl, aryl, aralkyl, halogen, NO ２ , CN, CF ３ , OH, O-alkyl, O-aryl, NH ２ , NH-alkyl, NH-aryl, N-(alkyl) ２ , N-(aryl) ２ , N-(alkyl)(aryl), COOH, CONH ２ , CONH-alkyl, CONH-aryl, SO ３ H, SO ２ -alkyl, SO ２ -aryl, SO ２ NH ２ , CF ３ , CO-alkyl, CO-aryl, and may be optionally substituted with one or more groups selected from the group consisting of the alkyl, aryl, and aralkyl groups optionally substituted with one or more groups selected from halogen, CN, OH, O-methyl, NH ２ , COOH, CONH ２ and CF ３ , and one or more groups selected from heterocyclic groups optionally substituted with one or more groups selected from alkyl, NH ２ , NH-alkyl, N(alkyl) ２ , COH and CO-alkyl, provided that The aforementioned compound is not 5-(2-((5-(4-(dimethylamino)piperidine-1-yl)pyridine-2-yl)amino)-5-fluoropyrimidine-4-yl)-N,4-dimethylthiazole-2-amine.

2. R １ However, H, C １－６ Alkyl, or NH-C １－６ The agent according to claim 1, wherein it is alkyl.

3. R １ The agent according to claim 2, wherein the agent is NH-methyl or NH-cyclopentyl.

4. R ２ However, H, C １－６ The agent according to claim 1, wherein it is an alkyl, CN, or halogen.

5. R ３ However, H, C １－６ The agent according to claim 1, wherein it is an alkyl, CN, or halogen.

6. R ４ and R ７ However, independently, H, O-C １－６ The agent according to claim 1, selected from alkyl and halogen.

7. R ５ and R ６ However, independently selected from saturated or unsaturated five-membered or six-membered heterocyclic groups containing H and one or two N heteroatoms, the heterocyclic group optionally contains C １－６ Alkyl, NH ２ NH-C １－６ Alkyl, N(C) １－３ Alkyl) ２ , COH and CO-(C １－３ The agent according to claim 1, which is substituted with one or more groups selected from alkyl groups.

8. R ５ and R ６ However, independently selected from saturated or unsaturated five-membered or six-membered heterocyclic groups containing H and one or two N heteroatoms, the heterocyclic group may optionally be methyl, ethyl, or C(CH) ３ ) ２ ), NH ２ NH-methyl, NH-ethyl, N(CH ３ ) ２ , N (CH ２ CH ３ ) ２ , N (CH ３ ) (CH ２ CH ３ ), COH and COCH ３ The agent according to claim 7, which is substituted with one or more groups selected from the following.

9. R ５ and R ６ However, independently selected from the following, the agent according to claim 7: 【Chemistry 2】

10. R ６ H is R ５ The agent according to claim 7, wherein the agent is selected from the following: 【Transformation 3】

11. The compound of formula I is N-cyclopentyl-5-(2-((5-((4-ethylpiperazine-1-yl)methyl)pyridine-2-yl)amino)-5-fluoropyrimidine-4-yl)-4-methylthiazole-2-amine, N-cyclopentyl-4-methyl-5-(2-((5-(piperazine-1-yl)pyridine-2-yl)amino)pyrimidine-4-yl)thiazole-2-amine, N-cyclopentyl-5-(2-((5-(4-ethylpiperazine-1-yl)pyridine-2-yl)amino)pyrimidine-4-yl)-4-methylthiazole-2-amine, 2-((5-(4-acetylpiperazine-1-yl)pyridine-2-yl)amino)-4-(4-methyl-2-(methylamino)thiazole-5-yl)pyrimidine-5-carbonitrile, N-cyclopentyl-5-(2-((5-((4-ethylpiperazine-1-yl)methyl)pyridine-2-yl)amino)pyrimidine-4-yl)-4-methylthiazole-2-amine, 5-(2-((5-(4-aminopiperidine-1-yl)pyridine-2-yl)amino)-5-fluoropyrimidine-4-yl)-N,4-dimethylthiazole-2-amine, 5-(2-((5-(4-aminopiperidine-1-yl)pyridine-2-yl)amino)pyrimidine-4-yl)-N-cyclopentyl-4-methylthiazole-2-amine, N-cyclopentyl-5-(5-fluoro-2-((5-morpholinopyridine-2-yl)amino)pyrimidine-4-yl)-4-methylthiazole-2-amine, 5-(2-((5-(4-(ethylamino)piperidine-1-yl)pyridine-2-yl)amino)-5-fluoropyrimidine-4-yl)-N,4-dimethylthiazole-2-amine, 5-(2-((5-(4-(ethyl(methyl)amino)piperidine-1-yl)pyridine-2-yl)amino)-5-fluoropyrimidine-4-yl)-N,4-dimethylthiazole-2-amine, 5-(5-fluoro-2-((5-((4-methylpiperazine-1-yl)methyl)pyridine-2-yl)amino)pyrimidine-4-yl)-N,4-dimethylthiazole-2-amine, 5-(5-fluoro-2-((5-((4-isopropylpiperazine-1-yl)methyl)pyridine-2-yl)amino)pyrimidine-4-yl)-N,4-dimethylthiazole-2-amine, or The agent according to claim 1, wherein the agent is 5-(2-((5-(4-(diethylamino)piperidine-1-yl)pyridine-2-yl)amino)-5-fluoropyrimidine-4-yl)-N,4-dimethylthiazole-2-amine.

12. The compound of formula I is N-cyclopentyl-5-(2-((5-((4-ethylpiperazine-1-yl)methyl)pyridine-2-yl)amino)-5-fluoropyrimidine-4-yl)-4-methylthiazole-2-amine, N-cyclopentyl-4-methyl-5-(2-((5-(piperazine-1-yl)pyridine-2-yl)amino)pyrimidine-4-yl)thiazole-2-amine, N-cyclopentyl-5-(2-((5-(4-ethylpiperazine-1-yl)pyridine-2-yl)amino)pyrimidine-4-yl)-4-methylthiazole-2-amine, 2-((5-(4-acetylpiperazine-1-yl)pyridine-2-yl)amino)-4-(4-methyl-2-(methylamino)thiazole-5-yl)pyrimidine-5-carbonitrile, or The agent according to claim 11, wherein the agent is N-cyclopentyl-5-(2-((5-((4-ethylpiperazine-1-yl)methyl)pyridine-2-yl)amino)pyrimidine-4-yl)-4-methylthiazole-2-amine.

13. The agent according to claim 12, wherein the compound of formula I is N-cyclopentyl-5-(2-((5-((4-ethylpiperazine-1-yl)methyl)pyridine-2-yl)amino)-5-fluoropyrimidine-4-yl)-4-methylthiazole-2-amine.

14. The agent according to any one of claims 1 to 13, wherein the immunotherapy agent is selected from immune checkpoint inhibitors.

15. The agent according to claim 14, wherein the immunotherapy agent is selected from immune checkpoint inhibitors capable of inhibiting PD-1, PD-L1 / 2, CTLA-4, BTLA, or Tim-3 and / or one or more of their ligands.

16. The agent according to claim 15, wherein the immunotherapy agent is selected from pembrolizumab, lambrolizumab, semiprimab, spartalizumab, nivolumab, atezolizumab, avelumab, durvalumab, and ipilimumab.

17. The agent according to claim 15, wherein the immunotherapy agent is selected from immune checkpoint inhibitors that can inhibit PD-1 or its ligand, i.e., PD-L1 or PD-L2.

18. The agent according to any one of claims 1 to 13, wherein the proliferative disorder or condition is selected from the group consisting of biliary tract cancer, brain tumors and other cancers of the central nervous system (CNS), neuroblastoma, breast cancer, cervical cancer, ovarian cancer, choriocarcinoma, colorectal cancer, endometrial cancer, liver cancer, lung cancer, esophageal cancer, gastric cancer, hematological tumors, neoplasms in situ, oral cancer, pancreatic cancer, prostate cancer, sarcoma, skin cancer, testicular cancer, stromal tumors, germ cell tumors, thyroid cancer, and renal cancer.

19. A pharmaceutical composition for treating a proliferative disorder or condition in a subject, comprising optionally a compound of formula I as defined in any one of claims 1 to 13, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and an immunotherapy agent, in combination with a pharmaceutically acceptable carrier, diluent, and / or excipient.

20. The pharmaceutical composition according to claim 19, wherein the immunotherapy agent is selected from immune checkpoint inhibitors.

21. The pharmaceutical composition according to claim 20, wherein the immunotherapy agent is selected from immune checkpoint inhibitors capable of inhibiting PD-1, PD-L1 / 2, CTLA-4, BTLA, or Tim-3 and / or one or more of their ligands.

22. The pharmaceutical composition according to claim 21, wherein the immunotherapy agent is selected from pembrolizumab, lambrolizumab, semiprimab, spartalizumab, nivolumab, atezolizumab, avelumab, durvalumab, and ipilimumab.

23. The pharmaceutical composition according to claim 21, wherein the immunotherapy agent is selected from immune checkpoint inhibitors that can inhibit PD-1 or its ligand, i.e., PD-L1 or PD-L2.

24. Use of a compound of formula I as defined in any one of claims 1 to 13, or a pharmaceutically acceptable salt, solvate, or prodrug or immunotherapy agent thereof, in the manufacture of a drug for treating a proliferative disorder or condition in a subject.

25. The use according to claim 24, wherein the immunotherapy agent is selected from immune checkpoint inhibitors.

26. The use according to claim 25, wherein the immunotherapy agent is selected from immune checkpoint inhibitors capable of inhibiting PD-1, PD-L1 / 2, CTLA-4, BTLA, or Tim-3 and / or one or more of their ligands.

27. The use according to claim 26, wherein the immunotherapy agent is selected from pembrolizumab, lambrolizumab, semiprimab, spartalizumab, nivolumab, atezolizumab, avelumab, durvalumab, and ipilimumab.

28. The use according to claim 26, wherein the immunotherapy agent is selected from immune checkpoint inhibitors that can inhibit PD-1 or its ligand, i.e., PD-L1 or PD-L2.

29. A kit comprising a first and a second container, wherein the first container comprises a compound of formula I as defined in any one of claims 1 to 13, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and the second container comprises an immunotherapy agent, and optionally packaged together with instructions for use of the kit in the pharmaceutical product described in claim 1.

30. The kit according to claim 29, wherein the immunotherapy agent is selected from immune checkpoint inhibitors.

31. The kit according to claim 30, wherein the immunotherapy agent is selected from immune checkpoint inhibitors capable of inhibiting PD-1, PD-L1 / 2, CTLA-4, BTLA, or Tim-3 and / or one or more of their ligands.

32. The kit according to claim 31, wherein the immunotherapy agent is selected from pembrolizumab, lambrolizumab, semiprimab, spartalizumab, nivolumab, atezolizumab, avelumab, durvalumab, and ipilimumab.

33. The kit according to claim 31, wherein the immunotherapy agent is selected from immune checkpoint inhibitors that can inhibit PD-1 or its ligand, i.e., PD-L1 or PD-L2.

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