Tubulin polymerization inhibitors

Abstract

The present invention relates to a compound of formula (I) [Formula 1] TIFF2026501703000102.tif54159 (wherein B is aryl or 5- or 6-membered heteroaryl, R 1 -R 5 , V, W, Y and Z may be various groups), or a pharmaceutically acceptable salt and / or solvate thereof. The compounds according to the present invention are useful as tubulin polymerization inhibitors, and are particularly useful for use in the treatment of hematological and / or proliferative disorders.

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present invention relates to novel polycyclic compounds. The compounds according to the present invention are useful as tubulin polymerization inhibitors, and are particularly useful for the treatment of hematological and / or proliferative disorders. [Background technology]

[0002] The microtubule cytoskeleton regulates many important functions in eukaryotic cells, from cell division to cell motility and vesicle transport. The main structural component of microtubules is the αβ-tubulin heterodimer protein. Microtubule-targeting drugs (MTAs) inhibit microtubule function, disrupting mitotic spindle formation and ultimately causing mitotic arrest at the metaphase / interphase transition. Based on their effects on microtubule dynamics, MTAs are generally classified into two categories: microtubule-stabilizing agents (MSAs) or microtubule-destabilizing agents (MDAs). MSAs, such as epothilones, ixabepilone, and paclitaxel, promote microtubule assembly and are widely used as standard of care (SOC) for the treatment of breast cancer, as well as ovarian, prostate, and lung cancer. Meanwhile, MDAs, such as colchicine and vinca alkaloids, disassemble microtubules into tubulin dimers and small molecule oligomers. The vinca alkaloids vincristine and vinblastine were the first MTAs approved over half a century ago and are still widely used today for hematological disorders such as leukemia, particularly acute myeloid leukemia (AML). Colchicine was the first compound identified as an MTA and is the most widely used drug for the treatment of gout. However, colchicine is not used in cancer therapy due to its high toxicity at the doses required for cancer indications.

[0003] The clinical success of MTAs has been significantly limited by their toxicity and the emergence of drug resistance. Drug resistance, acquired during the course of treatment, has become a significant clinical problem. The most common mechanism of multidrug resistance (MDR) is conferred by ATP-binding cassettes (ABCs), such as the P-glycoprotein (Pgp) transporter, which actively transports drug molecules out of cells. There is also evidence that the expression of certain tubulin isotypes, such as class III β-tubulin, can reduce cellular sensitivity to microtubule-modifying agents. Taxanes and vinca alkaloids are particularly sensitive to Pgp-mediated efflux and therefore less effective against cells overexpressing the β-III tubulin isotype.

[0004] Among the different classes of MTAs, colchicine site ligands have perhaps been the most extensively studied. The colchicine site is buried in the middomain of β-tubulin, located near the intradimer interface between α- and β-tubulin subunits. In contrast, taxane site ligands bind to a pocket in β-tubulin on the luminal side of microtubules, while vinca site-targeting ligands bind at the interdimer interface between two longitudinally aligned tubulin dimers. Preclinical studies strongly suggest that CBSis are effective in suppressing the overexpression of tubulin isotypes and overcoming drug resistance mediated by ABC family members. Over the past few decades, many colchicine binding site inhibitors (CBSis), such as pranavirin, ABT751, combretastatin, lexibulin, Veru-111, and PTC596, have been reported; however, these compounds have yet to reach the commercialization stage for cancer treatment.

[0005] Therefore, there remains a need for small molecule compounds that have strong antiproliferative potency, exhibit broad antiproliferative activity against different cancer cell lines, and / or prevent antiproliferative drug resistance (e.g., drug resistance mechanisms associated with overexpression of efflux transporters such as Pgp, aberrant expression of β3-tubulin, or expression of mutant P53).

[0006] The applicant has unexpectedly discovered that the compound of formula (I) is a potent tubulin polymerization inhibitor. The compound of the present invention has also been found to induce mitotic arrest at the G2 / M phase, followed by apoptosis. Furthermore, the compound of the present invention has also been found to have a broad range of antiproliferative activity against different cancer cell lines. Therefore, the compound of the present invention is extremely useful in treating hematological and / or proliferative disorders, particularly in overcoming drug resistance. Summary of the Invention

[0007] Thus, the present invention provides a compound of formula (I) [ka] (In the formula, R 1 -R 5 , B, V, W, Y and Z are each independently as defined herein) or a pharmaceutically acceptable salt and / or solvate thereof.

[0008] In some embodiments, the compound has formula (II): [ka] (In the formula, R 1 , R 2 , R 3 , B and Y are each independently as defined herein) or a pharmaceutically acceptable salt and / or solvate thereof.

[0009] In some embodiments, B is selected from phenyl, thiazole, oxazole, oxadiazole, isoxazole, thiadiazole, pyrazole, pyridine, and pyrimidine, wherein the phenyl, thiazole, oxazole, oxadiazole, isoxazole, thiadiazole, pyrazole, pyridine, or pyrimidine may be optionally substituted with at least one methyl. In some embodiments, B is a 5-membered heteroaryl or a 6-membered heteroaryl.

[0010] In some embodiments, the compound has formula (III) [ka] (In the formula, R 1 , R 2 , R 3 and Y are each independently as defined herein) or a pharmaceutically acceptable salt and / or solvate thereof.

[0011] In some embodiments, Y is CR 9 and R 9 is hydrogen, C1-C 10 In some embodiments, R is selected from alkyl and halogen. 1 is C1-C 10 In some embodiments, R 2 is hydrogen. In some embodiments, R 1 is C1-C 10 Alkyl and / or R 2 is hydrogen. In some embodiments, R 3 is C1-C 10 alkyl group, C1-C 10 Alkyl is OR 7 and R 7 is C1-C 10 In some embodiments, the compound is selected from the compounds in Table 1 herein, and pharmaceutically acceptable salts and / or solvates thereof.

[0012] The present invention also relates to pharmaceutical compositions comprising a compound according to the present invention and at least one pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition comprises a compound according to the present invention as the only active pharmaceutical ingredient. In some embodiments, the pharmaceutical composition further comprises another active pharmaceutical ingredient.

[0013] The present invention also relates to a compound according to the present invention or a pharmaceutical composition according to the present invention for use as a medicament. The present invention also relates to a compound according to the present invention or a pharmaceutical composition according to the present invention for use in treating a hematological and / or proliferative disorder. In some embodiments, the hematological disorder is selected from lymphoma, leukemia (acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), or chronic myeloid leukemia (CML)), multiple myeloma (MM), myelodysplastic syndrome (MDS), and myelodysplasia with myelofibrosis. In some embodiments, the proliferative disorder is cancer, such as head and neck cancer, melanoma, renal cancer, gastric cancer, liver cancer, colorectal cancer, pancreatic cancer, laryngeal cancer, lung cancer, neuronal carcinoma, glioblastoma multiforme, osteosarcoma, fibrosarcoma, ovarian sarcoma, liposarcoma, Ewing's sarcoma, breast cancer, ovarian cancer, or prostate cancer. In some embodiments, the compound or pharmaceutical composition is administered with at least another active pharmaceutical ingredient.

[0014] definition In the present invention, the following terms have the following meanings:

[0015] chemical definition When a chemical substituent is a combination of chemical groups, the point of attachment of the substituent to the molecule is by the last chemical group listed to the right of the substituent's name. For example, an arylalkyl substituent is attached to the rest of the molecule through the alkyl moiety and may be represented as: "aryl-alkyl-". Unless otherwise noted, compounds are named using ChemBioDraw® Ultra 13.0.2 (PerkinElmer).

[0016] "Alkoxy" refers to an alkyl-O- group.

[0017] "Alkyl" refers to a saturated, straight or branched hydrocarbon chain, typically containing 1 to 16 carbon atoms, preferably 1 to 12 carbon atoms, more preferably 1 to 8 carbon atoms, and even more preferably 1 to 6 carbon atoms. Alkyl groups can be monovalent or polyvalent (i.e., "alkylene" groups (divalent alkyl groups) are included in the definition of "alkyl"). Alkyl groups can be optionally substituted with one or more substituents (e.g., 1 to 4 substituents, or e.g., 1, 2, 3, or 4 substituents) selected from oxo, halogen, hydroxyl, nitro, amino, cyano, alkylamino, dialkylamino, alkoxy, haloalkyl, acyl, carbamoyl, alkylsulfoxide, sulfamoyl, alkylthio, and carboxyl. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, and t-butyl, pentyl and its isomers (e.g., n-pentyl, isopentyl), and hexyl and its isomers (e.g., n-hexyl, isohexyl). Particular examples of alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, and t-butyl (including methylene, ethylene, n-propylene, n-butylene, and n-butylene).

[0018] "Amine" refers to a derivative of ammonia (NH3) in which one or more hydrogen atoms have been replaced with a substituent such as, for example, alkyl or aryl. "Amino" refers to the group -NH2.

[0019] "Aryl" refers to a cyclic, polyunsaturated, aromatic hydrocarbyl group containing at least one aromatic ring and 5 to 12 carbon atoms, preferably 6 to 10 carbon atoms. Aryl groups may be monovalent or polyvalent (e.g., divalent). Aryl groups can have a single ring (e.g., phenyl) or multiple fused or covalently linked aromatic rings (e.g., naphthyl). The aromatic ring may optionally contain one to two additional rings (cycloalkyl, heterocycloalkyl, or heteroaryl) fused thereto. This definition of "aryl" includes partially hydrogenated derivatives of the carbocyclic ring systems enumerated herein, so long as at least one ring is aromatic. Aryl groups may be optionally substituted with one or more substituents (e.g., 1 to 4 substituents, or e.g., 1, 2, 3, or 4 substituents) selected from oxo, halogen, hydroxyl, nitro, amino, cyano, alkyl (e.g., methyl), alkylamino, dialkylamino, alkoxy, haloalkyl, acyl, carbamoyl, alkylsulfoxide, sulfamoyl, alkylthio, and carboxyl. Non-limiting examples of aryl groups include phenyl, biphenyl, biphenylenyl, 5- or 6-tetralinyl, naphthalen-1- or 2-yl, 4-, 5-, 6- or 7-indenyl, 1-, 2-, 3-, 4- or 5-acenaphthylenyl, 3-, 4- or 5-acenaphthenyl, 1- or 2-pentalenyl, 4- or 5-indanyl, 5-, 6-, 7- or 8-tetrahydronaphthyl, 1,2,3,4-tetrahydronaphthyl, 1,4-dihydronaphthyl, and 1-, 2-, 3-, 4- or 5-pyrenyl. A particular example of an aryl group is phenyl.

[0020] "Azido" refers to the -N3 group, i.e., the azido functional group.

[0021] "Cyano" refers to the radical -CN.

[0022] "Cycloalkyl" refers to a cyclic alkyl group typically containing 3 to 15 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 8 carbon atoms, and even more preferably 3 to 6 carbon atoms. Cycloalkyl groups can be monovalent or polyvalent (e.g., divalent). Included within this definition of "cycloalkyl" are polycyclic cycloalkyls (e.g., bicyclos) and bridged cycloalkyl structures (e.g., containing rings joined through one atom ("spiro") or rings joined through two atoms). Cycloalkyl groups can be optionally substituted with one or more substituents (e.g., 1 to 4 substituents, or e.g., 1, 2, 3, or 4 substituents) selected from oxo, halogen, hydroxyl, nitro, amino, cyano, alkyl (e.g., methyl), alkylamino, dialkylamino, alkoxy, haloalkyl, acyl, carbamoyl, alkylsulfoxide, sulfamoyl, alkylthio, and carboxyl. Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopropyl, cyclohexyl, cycloheptyl, cyclooctanyl, cyclononanyl, cyclodecanyl, norbornyl, adamantyl, bicyclo[2.2.2]octanyl, bicyclo[4.4.0]decanyl, bicyclo[3.2.1]octanyl, bicyclo[3.3.1]nonanyl, bicyclo[2.1.1]hexane, 2,3-dihydro-1H-indenyl, 1,2,3,4-tetrahydronaphthalenyl, decahydronaphthalenyl, 1,2,3,4-tetrahydronaphthalenyl, and octahydropentalenyl.

[0023] "C x -C y " or "(C x -C y )" before the name of a group means, according to common usage in the chemical arts, that the group contains x to y carbon atoms.

[0024] "Halogen" refers to a fluorine, chlorine, bromine, or iodine atom.

[0025] "Heteroaryl" refers to an aromatic ring or ring system containing 5 to 15 carbon atoms, preferably 4 to 12 carbon atoms, and more preferably 3 to 10 carbon atoms, where one or two rings are fused or covalently linked, at least one ring is aromatic, and one or more carbon atoms within one or more of the rings are substituted with oxygen, nitrogen, and / or sulfur atoms. Heteroaryl groups may be monovalent or polyvalent (e.g., divalent). The nitrogen and sulfur heteroatoms are optionally oxidized, and the nitrogen heteroatom may be optionally quaternized (e.g., sulfur may be oxidized as SO or SO). This definition of "heteroaryl" includes partially hydrogenated derivatives of the carbocyclo systems enumerated herein and ring systems containing one or more fused non-aromatic cycloalkyl and / or heterocycloalkyl rings, so long as at least one ring is aromatic. In one embodiment, a heteroaryl is attached to another group or molecule through a carbon atom, i.e., the attaching atom is not selected from among the heteroatoms contained therein. In one embodiment, a heteroaryl is attached to another group or molecule through any of the heteroatoms (e.g., nitrogen) contained therein. When substituted with one or more other groups, a heteroaryl can be substituted through a carbon atom or a heteroatom (e.g., nitrogen), unless otherwise specified. A heteroaryl group can be optionally substituted with one or more substituents (e.g., 1 to 4 substituents, or, for example, 1, 2, 3, or 4 substituents) selected from oxo, halogen, hydroxyl, nitro, amino, cyano, alkyl (e.g., methyl), alkylamino, dialkylamino, alkoxy, haloalkyl, acyl, carbamoyl, alkylsulfoxide, sulfamoyl, alkylthio, and carboxyl.Non-limiting examples of heteroaryl groups include pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridinyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazinyl, dioxinyl, thiazinyl, triazinyl, tetrazinyl, imidazo[2,1-b][1,3]thiazolyl, thieno[3,2-b]furanyl, thieno[3,2-b]thiophenyl, thieno[2,3-d][1,3]thiazolyl, thieno[2,3-d]imidazolyl, tetrazolo[1,5-a]pyridinyl, indolyl, indolizinyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, isobenzothiophene, and the like. nyl, indazolyl, benzimidazolyl, 1,3-benzoxazolyl, 1,2-benzisoxazolyl, 2,1-benzisoxazolyl, 1,3-benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, 1,2,3-benzoxadiazolyl, 2,1,3-benzoxadiazolyl, 1,2,3-benzothiadiazolyl, 2,1,3-benzisothiazolyl Examples include benzothiadiazolyl, thienopyridinyl, purinyl, imidazo[1,2-a]pyridinyl, 6-oxo-pyridazin-1(6H)-yl, 2-oxopyridin-1(2H)-yl, 6-oxo-pyridazin-1(6H)-yl, 2-oxopyridin-1(2H)-yl, 1,3-benzodioxolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl and quinoxalinyl. Non-limiting examples of heteroaryl groups containing at least one fused non-aromatic ring include 2,3-dihydrobenzofuranyl, benzo[d][1,3]dioxolyl, indolinyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, 3,4-dihydro-2H-benzo[b][1,4]oxazinyl, 1,2,3,4-tetrahydroquinoxaline, 3,4-dihydro-2H-benzo[b][1,4]thiazine, and 2,3-dihydrobenzo[b][1,4]oxathiin.

[0026] "Heterocycloalkyl" refers to a non-aromatic, fully saturated or partially unsaturated cyclic group (e.g., a 3- to 7-membered monocyclic group, a 7- to 11-membered bicyclic group, or a group containing a total of 3 to 10 ring atoms) having at least one heteroatom in a ring containing at least one carbon atom. Heterocycloalkyl groups can be particularly 3- to 7-membered rings, preferably 5- or 6-membered rings. Heterocycloalkyl groups can be particularly monocyclic or bicyclic, preferably monocyclic. Each heteroatom-containing ring of a heterocycloalkyl group has 1, 2, 3, or 4 heteroatoms selected from nitrogen, oxygen, and / or sulfur atoms, where the nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized. In one embodiment, a heterocycloalkyl is bonded to another group or molecule through a carbon atom, i.e., the bond atom is not selected from among the heteroatoms contained therein. In one embodiment, a heterocycloalkyl is bonded to another group or molecule through one of the heteroatoms contained therein. When substituted with one or more other groups, heterocycloalkyls can be substituted through a carbon atom or a heteroatom (e.g., nitrogen), unless otherwise specified. The rings of polycyclic heterocycloalkyl groups can be fused, bridged, and / or joined through one or more spiro atoms. This definition includes polycyclic heterocycloalkyl (e.g., bicyclo) and bridged heterocycloalkyl structures (containing rings joined through one atom ("spiro") or two atoms). Heterocycloalkyl groups can be optionally substituted with one or more substituents (e.g., 1 to 4 substituents, or, for example, 1, 2, 3, or 4 substituents) selected from oxo, halogen, hydroxyl, nitro, amino, cyano, alkyl (e.g., methyl), alkylamino, dialkylamino, alkoxy, haloalkyl, acyl, carbamoyl, alkylsulfoxide, sulfamoyl, alkylthio, and carboxyl.Non-limiting examples of heterocycloalkyl groups include aziridinyl, oxiranyl, thiiranyl, piperidinyl, azetidinyl, 2-imidazolinyl, pyrazolidinyl, imidazolidinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, succinimidyl, 3H-indolyl, indolinyl, isoindolinyl, tetrahydropyran, 2-methyl- ... H-pyrrolyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, 4H-quinolidinyl, 2-oxopiperazinyl, piperazinyl, homopiperazinyl, 2-pyrazolinyl, 3-pyrazolinyl, tetrahydro-2H-pyranyl, 2H-pyranyl, 4H-pyranyl, 3,4-dihydro-2H-pyranyl, oxetanyl, thietanyl, 3-dioxolanyl, 1,4-dioxanyl, 2,5-dioxy These include midazolidinyl, 2-oxopiperidinyl, 2-oxopyrrololidinyl, indolinyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl (e.g., tetrahydroisoquinolin-1-yl, tetrahydroisoquinolin-2-yl, tetrahydroisoquinolin-3-yl, or tetrahydroisoquinolin-4-yl), thiomorpholinyl (e.g., thiomorpholin-4-yl), thiomorpholin-4-yl sulfoxide, thiomorpholin-4-yl sulfone, 1,3-dioxolanyl, 1,4-oxathianyl, 1,4-dithianyl, 1,3,5-trioxanyl, 1H-pyrrolidinyl, tetrahydro-1,1-dioxothiophenyl, N-formylpiperazinyl, and morpholinyl (e.g., morpholin-4-yl).

[0027] "Hydroxy" refers to the group --OH.

[0028] A "prodrug" refers to a pharmacologically acceptable derivative of a therapeutic agent (e.g., a compound according to the present invention), the in vivo biotransformation product of which is a therapeutic agent (active drug). Prodrugs are typically characterized by high bioavailability and being easily metabolized in vivo to the active compound. Non-limiting examples of prodrugs include amide prodrugs and carboxylic acid ester prodrugs.

[0029] "Solvate" refers to a molecular complex comprising a compound of the invention that contains one or more pharmaceutically acceptable solvent molecules, such as, for example, ethanol, in a stoichiometric or substoichiometric amount. The term "hydrate" refers to when the solvent is water.

[0030] general definition "About" as used herein means approximately, roughly, in the region of, or in the vicinity thereof. When "about" precedes a numerical value, it means ±10% of that numerical value. When "about" is used in conjunction with a numerical range, it extends the limits of that numerical range by 10%.

[0031] "Active pharmaceutical ingredient," "active ingredient," or "therapeutic agent" refers to a compound used for treatment and related to health. In particular, a therapeutic agent (e.g., a compound according to the present invention) may be indicated for the treatment of a disease (e.g., a blood disease and / or a proliferative disease). An active agent may also be indicated to improve the therapeutic activity of another therapeutic agent.

[0032] "Administration" or variations thereof (e.g., "administering") means administering a therapeutic agent, alone or as part of a pharmaceutically acceptable composition, to a patient having a condition, symptom, or disease to be treated.

[0033] The word "comprise" and variations thereof (e.g., "comprises," "comprising") are used herein in accordance with standard patent drafting terminology. Thus, when "comprise" precedes an object followed by an element, it means that the element is required to be present in the object (usually as a component of a composition), but does not exclude the presence of other elements in the object. Furthermore, throughout the specification, "comprise" and variations thereof encompass the narrower expression "consists essentially of" and the even narrower expression "consist of" and variations thereof (e.g., "consists of," "consisting of").

[0034] "Human" refers to a male or female human subject at any stage of development, including a neonate, infant, child, adolescent, and adult.

[0035] "Patient" means a person awaiting medical care, receiving medical care, or being or to be the subject of a medical procedure, or a subject being monitored for the development of a target disease or target condition.

[0036] By "pharmaceutically acceptable" it is meant that the components of the composition are compatible with each other and not harmful to the subject to which they are administered.

[0037] A "pharmaceutically acceptable carrier" refers to an excipient that does not produce an adverse, allergic, or other untoward reaction when administered to an animal, preferably a human. This includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, etc. For human administration, formulations should meet sterility, pyrogenicity, general safety, and purity standards as required by regulatory authorities, such as, for example, the Office of the FDA or the EMA. Examples of pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, salts or electrolytes such as zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances (e.g., sodium carboxymethylcellulose), polyethylene glycol, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and mutton tallow.

[0038] A "pharmaceutical composition" refers to a composition comprising at least one therapeutic agent (eg, a compound according to the present invention) and at least one pharmaceutically acceptable carrier.

[0039] "Subject" refers to an animal, typically a warm-blooded animal, preferably a mammal, more preferably a primate, and even more preferably a human. In one embodiment, a "subject" is a "patient" as defined herein. In one embodiment, the subject is suffering from a disease, and preferably has been diagnosed with the disease. In one embodiment, the subject is at risk of developing the disease. Examples of risk factors include, but are not limited to, a genetic predisposition or a family history of the disease.

[0040] A "therapeutically effective amount" (abbreviated "effective amount") refers to an amount of a therapeutic agent (e.g., a compound according to the present invention) sufficient to exert a desired therapeutic, prophylactic, or preventative effect on a patient when administered to the patient without causing significant negative or harmful side effects to the patient. A therapeutically effective amount may be administered prior to the onset of disease as a preventative or preventative measure. Alternatively, or in addition, a therapeutically effective amount may be administered after the onset of disease as a therapeutic measure.

[0041] "Treating," "treatment," or "alleviation" refers to both therapeutic treatment and prophylactic or preventative measures, the purpose of which is to prevent or slow (alleviate) the onset of a targeted condition or disorder (hereinafter "disease") (e.g., a blood disorder and / or a proliferative disorder). Those in need of treatment include those already with the disease, those prone to developing the disease, or those in whom the onset of the disease is to be prevented. After administration of a therapeutic amount of a therapeutic agent (e.g., a compound according to the present invention), a patient is successfully "treated" for a disease if the patient shows an observable and / or measurable reduction or elimination of one or more of the following: a reduction in the number of pathogens; a reduction in the proportion of pathogenic cells to the total cell count; and / or a reduction in the severity of one or more symptoms associated with the specific disease; a reduction in morbidity and mortality; and an improvement in quality of life. The above parameters for assessing successful treatment and improvement of a disease can be readily measured by routine laboratory procedures familiar to physicians. DETAILED DESCRIPTION OF THE INVENTION

[0042] compound The object of the present invention is to provide a compound of formula (I) [ka] (In the formula, R 1 -R 5, B, X, Y, V and W are as defined herein) or a pharmaceutically acceptable salt and / or solvate thereof.

[0043] In formula (I) herein, R 1 is hydrogen, C1-C 10 Alkyl, cyano, CF3, hydroxy, C1-C 10 In some embodiments, R is selected from alkoxy and halogen. 1 is C1-C 10 In some embodiments, R 1 is hydrogen. In some preferred embodiments, R 1 is selected from hydrogen, CH3, CF3, OCH3 and Cl.

[0044] In formula (I) herein, R 2 is hydrogen, C1-C 10 Alkyl, cyano, CF3, hydroxy, C1-C 10 In some embodiments, R is selected from alkoxy and halogen. 2 is hydrogen. In some preferred embodiments, R 2 is selected from hydrogen and CH3.

[0045] In formula (I) herein, R 3 is hydrogen, C1-C 10 Alkyl, C3-C 10 Cycloalkyl and C2-C 11 heterocycloalkyl, C-C 10 Alkyl is azido, cyano, -C(O)OR 6 , OR 7 , halogen, C3-C 10 Cycloalkyl, C2-C 11 C-C, optionally substituted with at least one group selected from heterocycloalkyl, aryl, and heteroaryl; 10 Cycloalkyl, C2-C 11 Heterocycloalkyl, aryl or heteroaryl is C1-C 10alkyl, at least one OR 7 , hydroxy, C1-C 10 Alkoxy, -C(O)OR 6 and halogen-substituted C1-C 10 alkyl, and R 6 and R 7 are each independently hydrogen and C1-C 10 alkyl.

[0046] In this specification, the above-mentioned R 3 In the definition of "R 3 is selected from (...) and C3-C 10 Cycloalkyl, C2-C 11 The statement "heterocycloalkyl, aryl, or heteroaryl may be optionally substituted (...)" is 3 When cycloalkyl or heterocycloalkyl is present in R 3 is the "principal group" of (e.g., R 3 C3-C 10 cycloalkyl) or R 3 is a substituent of the "main group" of (e.g., R 3 is C1-C 10 alkyl, and the C1-C 10 C3-C with at least one alkyl 10 cycloalkyl) or may be substituted as indicated.

[0047] In some embodiments, R 3 is C1-C 10 alkyl group, C1-C 10 Alkyl is hydroxyl or OR 7 and R 7 is C1-C 10 In some embodiments, R 3 is C1-C 10 alkyl group, C1-C 10 Alkyl is OR 7and R 7 is C1-C 10 It is alkyl.

[0048] In formula (I) herein, R 4 is hydrogen, hydroxy, C1-C 10 Alkyl and C1-C 10 In some embodiments, R 4 is hydrogen. In some preferred embodiments, R 4 is hydrogen and CH 3 is selected from.

[0049] In formula (I) herein, R 5 is hydrogen, hydroxy, C1-C 10 Alkyl and C1-C 10 In some embodiments, R 5 is hydrogen. In some preferred embodiments, R 5 is selected from hydrogen and CH3.

[0050] In Formula (I) herein, B is aryl, 5-membered heteroaryl, or 6-membered heteroaryl. In some embodiments, B is aryl. In some embodiments, B is 5-membered heteroaryl. In some embodiments, B is 6-membered heteroaryl. In some preferred embodiments, B is 5-membered heteroaryl or 6-membered heteroaryl. In some embodiments, B is selected from phenyl, thiazole, oxazole, oxadiazole, isoxazole, thiadiazole, pyrazole, pyridine, and pyrimidine, where phenyl, thiazole, oxazole, oxadiazole, isoxazole, thiadiazole, pyrazole, pyridine, or pyrimidine may be optionally substituted with at least one methyl. In some embodiments, B is phenyl. In some embodiments, B is selected from thiazole, oxazole, oxadiazole, isoxazole, thiadiazole, pyrazole, pyridine, and pyrimidine. In some preferred embodiments, B is selected from phenyl, thiazole, methylthiazole, oxazole, thiadiazole, pyrazole, pyridine, and pyrimidine. In some further preferred embodiments, B is thiazole.

[0051] In formula (I) herein, X is nitrogen or CR 8 and R 8 is hydrogen, C1-C 10 Alkyl, Cyano, CF3, C1-C 10 In some embodiments, X is selected from CR 8 In some preferred embodiments, X is selected from N, CH, and CF. In some embodiments, X is CH.

[0052] In formula (I) herein, Y is nitrogen or CR 9 and R 9 is hydrogen, C1-C 10 Alkyl, Cyano, CF3, C1-C 10 In some embodiments, Y is selected from CR 9In some embodiments, Y is CR 9 and R 9 is hydrogen, C1-C 10 In some preferred embodiments, Y is selected from N, CH, C-CH, C-OCH, C-CF, C-OCH(CH), C-Cl, and CF. In some embodiments, Y is CH.

[0053] In formula (I) herein, V is NR 10 , C.R. 11 R 12 or oxygen, R 10 , R 11 and R 12 are each independently hydrogen and C1-C 10 In some embodiments, V is selected from alkyl. 10 In some preferred embodiments, V is NH, CH 2 and O. In some embodiments, V is NH.

[0054] In formula (I) herein, W is C=O or CR 13 R 14 and R 13 and R 14 are each independently hydrogen and C1-C 10 In some embodiments, W is selected from CR alkyl. 13 R 14 In some embodiments, W is CHR 14 In some preferred embodiments, W is selected from C=O, CH2, and CH-CH3. In some embodiments, W is CH2.

[0055] In some embodiments, Y is CR 9 and R 9 is hydrogen, C1-C 10 R is selected from alkyl and halogen; 1 is C1-C 10 alkyl; R 2 is hydrogen; R 3 is C1-C10 alkyl group, C1-C 10 Alkyl is hydroxyl or OR 7 and R 7 is C1-C 10 In some embodiments, R 3 is C1-C 10 alkyl group, C1-C 10 Alkyl is OR 7 and R 7 is C1-C 10 It is alkyl.

[0056] In some embodiments, the compound of formula (I) is a compound of formula (II): [ka] (In the formula, R 1 , R 2 , R 3 , B and Y are each independently as defined in formula (I) herein, or a pharmaceutically acceptable salt and / or solvate thereof.

[0057] In some embodiments, the compound of formula (I) has formula (III): [ka] (In the formula, R 1 , R 2 , R 3 and Y are each independently as defined in formula (I) herein, or a pharmaceutically acceptable salt and / or solvate thereof.

[0058] In one embodiment, the compound of formula (I) is selected from the compounds in Table 1 below, and pharmaceutically acceptable salts and / or solvates thereof. [Table 1] TIFF2026501703000009.tif215142TIFF2026501703000010.tif205139TIFF2026501703000011.tif199131TIFF2026501703000012.tif221142TIFF2026501703000013.tif213143TIFF2026501703000014.tif254159TIFF2026501703000015.tif220140TIFF2026501703000016.tif239159TIFF2026501703000017.tif220159TIFF2026501703000018.tif249159TIFF2026501703000019.tif240159TIFF2026501703000020.tif238159TIFF2026501703000021.tif252159TIFF2026501703000022.tif237159TIFF2026501703000023.tif231159TIFF2026501703000024.tif255159TIFF2026501703000025.tif225159TIFF2026501703000026.tif228159TIFF2026501703000027.tif255159TIFF2026501703000028.tif230159TIFF2026501703000029.tif220159TIFF2026501703000030.tif237159TIFF2026501703000031.tif241159TIFF2026501703000032.tif237159TIFF2026501703000033.tif230139TIFF2026501703000034.tif252159TIFF2026501703000035.tif255159TIFF2026501703000036.tif235159TIFF2026501703000037.tif86159

[0059] All references to compounds of Formula (I) include references to salts, solvates, multi-component complexes, and / or liquid crystals thereof. All references to compounds of Formula (I) include references to polymorphs and / or crystalline forms thereof. All references to compounds of Formula (I) include references to pharmaceutically acceptable prodrugs thereof. All references to compounds of Formula (I) include references to isotopically labeled compounds of Formula (I), including deuterated compounds of Formula (I). Compounds of Formula (I) and subformulas thereof may contain at least one asymmetric center and therefore may exist as different stereoisomers. Accordingly, all references to compounds of Formula (I) include references to all possible stereoisomers, and include not only racemates but also individual enantiomers and non-racemic mixtures thereof. When a compound is desired as a single enantiomer, such single enantiomer can be obtained by stereospecific synthesis, separation of the final product or any suitable intermediate, or chiral chromatographic methods known in the art. Resolution of the final product, an intermediate, or a starting material may be effected by any suitable method known in the art.

[0060] The compounds of the present invention may be in the form of pharmaceutically acceptable solvates. Pharmaceutically acceptable solvates of the compounds of formula (I) include hydrates thereof.

[0061] The compounds of the present invention may be in the form of pharmaceutically acceptable salts. Pharmaceutically acceptable salts of the compounds of formula (I) include their acid addition salts and base salts. Suitable acid addition salts are formed from acids that form non-toxic salts. Examples include acetate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hybenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, and isethione. Acid salts include hydroxysulfate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-naphthylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate, and xinafoate. Suitable base salts are formed from bases that form non-toxic salts. Examples include aluminum, arginine, benzathine, calcium, choline, diethylamine, 2-(diethylamino)ethanol, diolamine, ethanolamine, glycine, 4-(2-hydroxyethyl)-morpholine, lysine, magnesium, meglumine, morpholine, olamine, potassium, sodium, tromethamine, and zinc salts. Hemisalts of acids and bases, such as hemisulfate and hemicalcium salts, can also be formed. When the compound of formula (I) contains both an acidic group and a basic group, the compound of the present invention can also form an internal salt. Such compounds are also included in the scope of the present invention. When the compound of the present invention contains a hydrogen-donating heteroatom (e.g., NH), the present invention also includes salts and / or isomers formed by transferring the hydrogen atom to a basic group or atom within the molecule.Pharmaceutically acceptable salts of compounds of formula (I) can be prepared by one or more of the following methods: (i) reacting a compound of formula (I) with a desired acid; (ii) reacting a compound of formula (I) with a desired base; (iii) removing an acid- or base-labile protecting group from a suitable precursor of the compound of formula (I) or ring-opening a suitable cyclic precursor (e.g., a lactone or lactam) with a desired acid; and / or (iv) converting one salt of a compound of formula (I) to another salt by reaction with a suitable acid or using a suitable ion exchange column. All of these reactions are usually carried out in solution. The salt precipitates from the solution and can be recovered by filtration or by evaporation of the solvent. The degree of ionization of the salt can vary from completely ionized to nearly non-ionized.

[0062] Pharmaceutical Composition Another object of the present invention is a composition comprising a compound according to the present invention as described herein. In some embodiments, the composition further comprises at least one pharmaceutically acceptable carrier, making the composition a "pharmaceutical composition" as defined herein.

[0063] In some embodiments, the pharmaceutical composition comprises a compound according to the present invention as the only active pharmaceutical ingredient. In other embodiments, the pharmaceutical composition further comprises at least another active pharmaceutical ingredient (i.e., an active pharmaceutical ingredient that is not a compound according to the present invention). In some embodiments, the at least another active pharmaceutical ingredient is suitable for treating a hematological and / or proliferative disorder.

[0064] Another object of the present invention is a drug comprising a compound according to the invention as described herein.

[0065] kit Another object of the present invention is a kit of parts (abbreviated "kit") comprising a compound or composition according to the present invention as described herein. In some embodiments, the kit comprises an article of manufacture, such as, for example, a package or container. In some embodiments, the kit comprises instructions for use. The kit may be promoted, distributed, or sold as a unit for carrying out the medical uses of the present invention.

[0066] In some embodiments, the kit comprises a pharmaceutical composition comprising a compound according to the present invention and another pharmaceutical composition comprising at least another active pharmaceutical ingredient, in some embodiments, the at least another active pharmaceutical ingredient is suitable for treating a hematological and / or proliferative disorder.

[0067] Medical Use Another object of the invention is a compound or composition according to the invention as described herein (in particular a pharmaceutical composition) for use as a medicament.

[0068] Another object of the present invention is a compound or composition according to the invention as described herein for use in the treatment of hematological and / or proliferative disorders.

[0069] Another object of the present invention is a method of treating a hematological and / or proliferative disorder in a subject in need thereof. Another object of the present invention is the use of a compound or composition according to the present invention as described herein for the manufacture of a medicament for the treatment of a hematological and / or proliferative disorder. Another object of the present invention is the use of a compound or composition according to the present invention as described herein for the treatment of a hematological and / or proliferative disorder.

[0070] In one embodiment, the method or use comprises the step of administering to a subject a therapeutically effective amount of a compound, composition or drug according to the invention described herein.

[0071] In some embodiments, the hematological disease treated by the method or use of the present invention is lymphoma, leukemia, multiple myeloma (MM), myelodysplastic syndrome (MDS), or myelodysplasia with myelofibrosis. In some embodiments, the leukemia is acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), or chronic myelogenous leukemia (CML). In some embodiments, the proliferative disease treated by the method or use of the present invention is cancer. In some embodiments, the cancer is a solid cancer. In some embodiments, the cancer is head and neck cancer, melanoma, renal cancer, gastric cancer, liver cancer, colorectal cancer, pancreatic cancer, laryngeal cancer, lung cancer, neuronal carcinoma, glioblastoma multiforme, osteosarcoma, fibrosarcoma, ovarian sarcoma, liposarcoma, Ewing's sarcoma, breast cancer, ovarian cancer, or prostate cancer.

[0072] In one embodiment, the compounds, compositions, or drugs according to the present invention described herein are administered to a subject and can be formulated using methods known in the art.Non-limiting examples of forms suitable for administration include solutions (e.g., sterile aqueous solutions), gels, dispersions, emulsions, suspensions, and solid forms (e.g., powders or liposome forms) suitable for preparing solutions or suspensions by adding liquid before use.The compounds, compositions, or drugs according to the present invention described herein can be administered using administration routes well known in the art, such as parenteral, oral, inhalation, nebulization, rectal, nasal, or via implanted reservoirs.

[0073] However, it should be understood that the total daily dose of a compound, composition, or drug is determined by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose for a particular patient depends on various factors, including the disease being treated and its severity; the activity of the compound used; the age, weight, overall health, sex, and diet of the subject; the time of administration, the route of administration, the excretion rate of the specific therapeutic agent used; the duration of treatment; and drugs used in combination or co-administration with the specific therapeutic agent used, as well as similar factors well known in the medical field. For example, it is within the skill of a person skilled in the art to start administering a compound at a dose lower than that required to achieve the desired therapeutic effect and gradually increase the dose until the desired effect is achieved. The total dose required for each treatment can be administered in multiple divided doses or in a single dose.

[0074] In one embodiment, the dosage of the compound is about 0.01 to 500 mg / kg of patient body weight per day, which can be administered in single or multiple doses. Preferably, the dosage is about 0.1 to about 250 mg / kg per day, more preferably about 0.5 to about 100 mg / kg per day. Suitable dosages are about 0.01 to 250 mg / kg / day, about 0.05 to 100 mg / kg / day, or about 0.1 to 50 mg / kg / day. Within this range, the dosage may be about 0.05 to 0.5, about 0.5 to 5, or about 5 to 50 mg / kg / day. For oral administration, the compositions are preferably provided in the form of tablets containing about 1.0 to 1000 milligrams of active ingredient, particularly about 1.0, about 5.0, about 10.0, about 15.0, about 20.0, about 25.0, about 50.0, about 75.0, about 100.0, about 150.0, about 200.0, about 250.0, about 300.0, about 400.0, about 500.0, about 600.0, about 750.0, about 800.0, about 900.0, and about 1000.0 milligrams of active ingredient, with dosage adjusted according to the condition of the patient being treated. These compounds may be administered on a regimen of one to four times daily, preferably once or twice daily. It will be understood, however, that the specific dosage and frequency of administration for a particular patient may vary and will depend on a variety of factors, including the activity of the particular compound used, the metabolic stability and duration of action of that compound, the patient's age, weight, general health, sex, diet, method and time of administration, rate of excretion, concomitant drug use, the severity of the particular disease, and the patient being treated.

[0075] In some embodiments, a compound, composition, or drug according to the invention described herein is administered as the sole active pharmaceutical ingredient. In other embodiments, a compound, composition, or drug according to the invention described herein is administered with at least another active pharmaceutical ingredient. In other embodiments, a compound, composition, or drug according to the invention described herein is administered before, simultaneously with, and / or after at least another active pharmaceutical ingredient. In some embodiments, a composition or drug according to the invention described herein is a combined preparation for sequential, simultaneous, or separate use in the treatment of a hematological and / or proliferative disorder. In some embodiments, the at least another active pharmaceutical ingredient is suitable for the treatment of a hematological and / or proliferative disorder.

[0076] Manufacturing method The compounds according to the invention described herein may be prepared by synthetic methods well known to those skilled in the art.

[0077] Another object of the present invention is a method for preparing the compounds of the present invention. The compounds of the present invention can be prepared by several methods, including those outlined in Schemes 1-7 herein below, wherein the substituents in the schemes are defined in formula (I) herein, and A is the following moiety: [ka] However, unless otherwise specified.

[0078] Thus, the synthesis of aminooxazole derivatives of Formula Ia can be carried out by first reacting aromatic aldehyde V with p-toluenesulfonylmethyl isocyanide (TosMIC) to prepare the corresponding oxazole derivative II using the method of Van Leusen et al. (Tetrahedron Lett., 1972, 23, 2369) (Scheme 1). Non-commercial aldehydes can be prepared using literature methods by introducing the aldehyde group from the corresponding brominated aromatic compound using organometallic reagents and DMF, or by introducing the aldehyde group from the oxidation of the corresponding toluene according to the method of Frey et al. (Tetrahedron Lett., 2001, 39, 6815), or by introducing the aldehyde group from a reaction employing the dibromination of bromopicoline followed by hydrolysis with aqueous calcium carbonate, as used in the method of Bombrun et al. (Tetrahedron Lett., 2005, 36, 6033). Compounds of structure II can then be further functionalized by deprotonation of the oxazole group with a suitable organic base followed by electrophilic chlorination to give 2-chlorooxazole compounds III. Direct nucleophilic substitution with aminopyrazole compounds IV in the presence of a suitable solvent such as an alcohol (e.g., ethanol) upon heating at elevated temperatures can be used to give the final target aminooxazole compounds of formula Ia. [ka]

[0079] The aminothiazole derivatives of formula Ib can be prepared by the Hantzsch reaction of 2-bromoketone VII with thiourea derivative VI in the presence of a suitable solvent such as an alcohol (e.g., ethanol) under basic conditions and at elevated temperatures (Scheme 2). [ka]

[0080] Compounds of formula Ic can alternatively be prepared by reacting compound IX with an optionally substituted heterocycle A (Q is I, Br, or Cl) via a copper or palladium catalyzed coupling reaction according to the following Scheme 3. Those skilled in the art will appreciate that compound IX can be prepared according to the protocols shown in Scheme 1 and Scheme 2 above. [ka]

[0081] Alternatively, compounds of formula Id can also be prepared in two steps by aromatic nucleophilic substitution reaction of substituted pyrazole compounds IV with dihalogeno heteroaryl compounds (QBQ) to give intermediates XI (Scheme 4). Non-commercial aminopyrazoles IV can be prepared by N-alkylation of the corresponding 4-nitropyrazole compounds followed by reduction of the nitro group (see, for example, WO2015 / 089337 or WO2012 / 061337). Intermediate compounds XI can be further functionalized by Suzuki coupling with boronic acid pinacol ester intermediates XII (V = NH, O, or N-Tr) to give compounds of formula Id. [ka]

[0082] Analogs of intermediate XII with V=NH can be prepared in a two-step reaction, for example, by reacting the corresponding p-aminoboronic ester XIII with 2-chloroethyl isocyanate followed by cyclization in the presence of base, as described in Example 225 of EP 2857400 (2015) (Scheme 5). Further analogs of intermediate XII (V=O or N-Tr) can be prepared by the palladium-catalyzed Suzuki coupling reaction of the corresponding brominated aromatic boronic ester XIV with the corresponding cyclic compound XV (Scheme 5). In the case of N-trityl compound XVI, an additional deprotection step by TFA treatment is required to obtain compounds of formula Ie (V=NH) (Scheme 6). [ka] [ka]

[0083] Furthermore, other analogs can be obtained by changing the order of the above steps. In these compounds, dihalogeno heteroaryl compounds (QBQ) can be reacted with boronate ester compounds XII (V = N-Tr) under classical Suzuki coupling conditions to give intermediates XVII (Scheme 7). These intermediates XVII can be coupled with 4-aminopyrazole IV to give N-trityl-protected compounds of formula If (V = N-Tr), all of which can be deprotected with TFA as in Scheme 6 above. [ka]

[0084] Example The present invention is further illustrated by the following examples.

[0085] Example 1: Synthesis of compounds Example 1-1: General synthesis procedure The compounds of the present invention were prepared by several methods, including the synthetic methods disclosed in the detailed description above, and in particular similar to those shown in Schemes 1-7 herein. However, the synthetic methods described above are merely exemplary, and the compounds of the present invention may be synthesized by alternative routes that will be appreciated by those of skill in the art.

[0086] Example 1-2: Example of compound synthesis The present invention will be more fully understood by reference to the following preparative examples, which should not be construed as limiting the scope of the invention.

[0087] material and method General: All chemicals used were commercially available reagent-grade products. Solvents were of anhydrous commercial grade and were used without further purification. Reaction progress was monitored by thin-layer chromatography using Merck TLC plates (precoated silica gel 60F 254) visualized under UV light. 1 Multiplicities in H NMR spectra are indicated by singlet (s), broad singlet (br s), doublet (d), triplet (t), quartet (q), double doublet (dd), and multiplet (m). NMR spectra were measured on a Bruker Avance 300, 360, or 400 MHz spectrometer. Mass spectra were measured by electrospray ionization mass spectrometry (ESI MS) in positive mode or atmospheric pressure chemical ionization mass spectrometry (APCI MS) in positive mode.

[0088] LCMS Methods: Method A: This method was performed on a Waters AutoPurification high-performance liquid chromatography (HPLC) system coupled to an SQD mass spectrometer. The gradient used was a linear gradient starting at t = 0.0 min with 5% MeCN + 0.1% formic acid in water, reaching 100% MeCN + 0.1% formic acid by t = 5.0 min, and then maintained at this level from t = 5.0 min to t = 10.0 min. The column used was a Nucleoshell 5 μm RP18plus 4.6 x 150 mm. The detector was a single quadrupole mass spectrometer (SQD) using ESI positive mode. Method B: This method was performed on a Waters HPLC 2695 Alliance coupled to a ZMD mass spectrometer. The gradient used was a linear gradient starting from 0% MeCN + 0.04% formic acid in water at t = 0.0 min, then reaching 100% MeCN + 0.04% formic acid by t = 3.1 min, then maintained there until t = 3.8 min, decreasing to 0% MeCN + 0.04% formic acid in water at t = 4.8 min. The column used was a Sunfire 2.1 x 50 mm, dp: 3.5 μm.

[0089] Abbreviation aqu aqueous solution BINAP 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl n-Buli n-Butyllithium t-BuOH tert-butyl alcohol CaCO3 Calcium Carbonate CCl4 Carbon tetrachloride C2Cl6 hexachloroethane CDCl3 Deuterochloroform Cs2CO3 Cesium Carbonate CuI Copper(I) iodide DCC dicyclohexylcarbodiimide DCM dichloromethane DIPEA Diisopropylethylamine DIAD Diisopropyl azodicarboxylate DMA Dimethylacetamide DMAP 4-dimethylaminopyridine DMF Dimethylformamide DMSO-d6 hexadeuterodimethyl sulfoxide EDCI 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide EtOAc ethyl acetate EtOH ethanol Et2O diethyl ether Et3N Triethylamine h time HOBt Hydroxybenzotriazole iPrOH 2-propanol K2CO3 Potassium Carbonate KHCO3 Potassium bicarbonate KOtBu potassium tert-butoxide LiHMDS Lithium bis(trimethylsilyl)amide MeCN acetonitrile MeOH Methanol MgSO4 Magnesium Sulfate mins minutes NaCl Sodium chloride Na2CO3 Sodium Carbonate NaH sodium hydride NaHCO3 Sodium bicarbonate NaNO2 Sodium Nitrite NaOEt Sodium ethoxide NaOH Sodium hydroxide NBS N-Bromo-succinimide NH4Cl Ammonium chloride NH4SCN Ammonium thiocyanate NMP N-methyl-pyrrolidin-2-one NaOtBu Sodium tert-butoxide NMR nuclear magnetic resonance Pd / C Palladium Carbon Pd2(dba)3 tris(dibenzylideneacetone)dipalladium(0) Pd(OAc)2 Palladium(II) Acetate Pd(PPh3)4 tetrakis(triphenylphosphine)palladium(0) PE Petroleum Ether (PhCO)2O2 benzoyl peroxide RT room temperature sat.aqu saturated aqueous solution SnCl2·2H2O Tin(II) chloride dihydrate SiO2 Silica Gel TFA trifluoroacetic acid THF tetrahydrofuran TosMIC p-Toluenesulfonylmethyl isocyanide t R retention time XantPhos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

[0090] Synthesis of Compound 001 [ka]

[0091] Preparation of 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)imidazolidin-2-one (1b). Intermediate 1b was prepared in two steps using 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1a) with 2-chloroethyl isocyanate and EtN, followed by KOtBu, according to the method described in Example 225 of EP 2857400 (2015). The crude product was purified by SiO column chromatography (Puriflash) eluting with 2–5% EtOH in DCM to give 1b as a white solid (2.43 g, 59%). 1 H NMR (400MHz, DMSO-d6) δ7.68-7.44(m, 4H), 7.06(s, 1H), 3.97-3.75(m, 2H), 3.41(dd, J=9.2, 6.8Hz, 2H), 1.28(s, 12H).

[0092] Preparation of 1-(2-methoxyethyl)-4-nitro-1H-pyrazole (1d). Similar to the method described in WO 2015 / 089337 (pp. 125-6), a mixture of 4-nitro-1H-pyrazole (1c) (2.00 g, 17.6 mmol), 1-bromo-2-methoxyethane (1.66 mL, 17.6 mmol), and K2CO3 (5.47 g, 39.6 mmol) in MeCN (50 mL) was heated to 80 °C for 18 h. The cooled mixture was treated with water and extracted with DCM. The combined organic components were dried over MgSO4, filtered, evaporated, and then purified by SiO2 (Puriflash) column chromatography eluting with 0–5% EtOH in DCM to give 1d as a clear oil (2.77 g, 92%). 1 H NMR (400MHz, DMSO-d6) δ8.84(s, 1H), 8.26(s, 1H), 4.34(t, J=5.2Hz, 2H), 3.79-3.64(m, 2H), 3.23(s, 3H).

[0093] Preparation of 1-(2-methoxyethyl)-1H-pyrazol-4-amine (1e). A solution of intermediate 1d (2.75 g, mmol) in EtOH (50 ml) was treated with 10% Pd / C and stirred under an H atmosphere at ambient temperature and pressure for 18 hours. The mixture was filtered and evaporated to give crude product 1e as a red oil. 1 H NMR (400 MHz, chloroform-d) δ 7.16 (d, J = 1.0 Hz, 1H), 7.09 (d, J = 0.9 Hz, 1H), 4.16 (t, J = 5.3 Hz, 2H), 3.69 (t, J = 5.3 Hz, 2H), 3.33 (s, 3H).

[0094] Preparation of 2-chloro-N-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-amine (1g). A stirred solution of 2,4-dichloropyrimidine (1f) (500 mg, 3.36 mmol), 1e (474 ​​mg, 3.36 mmol), and EtN (515 μL, 3.70 mmol) in iPrOH (20 mL) was heated to reflux under argon for 18 h. The cooled mixture was treated with water and then extracted with DCM. The combined organic components were dried over MgSO, filtered, evaporated, and then purified by SiO column chromatography eluting with 0–2% EtOH in DCM to give 1g as a brown oil (464 mg, 54%) that solidified upon standing. 1 H NMR (400MHz, DMSO-d6) δ10.01(s, 1H), 8.05(d, J=5.9Hz, 1H), 7.93(s, 1H), 7.53(s, 1 H), 6.61(d, J=5.9Hz, 1H), 4.24(t, J=5.3Hz, 2H), 3.67(t, J=5.3Hz, 2H), 3.23(s, 3H).

[0095] Preparation of 1-(4-(4-((1-(2-Methoxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-2-yl)phenyl)imidazolidin-2-one (001). A sealed tube was charged with 1g (100 mg, 0.394 mmol), 1b (136 mg, 0.473 mmol), Pd(PPh3)4 (23 mg, 0.0197 mmol)K2CO3 (163 mg, 1.18 mmol), dioxane (5 mL), and water (1 mL) and degassed with a stream of argon for 5 minutes. The tube was sealed and heated with stirring at 100 °C for 18 hours, then cooled, treated with water, and extracted with a mixture of DCM and EtOH. The combined organic portions were dried over MgSO, filtered, evaporated, and then purified by SiO (Puriflash) column chromatography eluting with 5-15% EtOH in DCM and triturated with DCM containing pentane to give compound 001 as a white solid (46 mg, 31%). 1 H NMR (400MHz, DMSO-d6) δ9.50(s, 1H), 8.32-8.27(m, 2H), 8.25(d, J=5.8Hz, 1H), 8.10(s, 1H), 7.72-7.67(m, 2H), 7.59(s, 1H), 7.0 8(s, 1H), 6.52(d, J=5.9Hz, 1H), 4.30(t, J=5.2Hz, 2H), 3.95-3.88(m, 2H), 3.71(t, J=5.2Hz, 2H), 3.49-3.38(m, 2H), 3.28(s, 3H).

[0096] Synthesis of Compound 002 [ka]

[0097] Preparation of 2-chloro-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (2b). Intermediate 2b was prepared from 2,4-dichloropyrimidine (1f) and 1-methyl-1H-pyrazol-4-amine (2a) in a manner similar to that described for intermediate 1g above, and after purification by SiO (Puriflash) column chromatography eluting with 5% EtOH in DCM, 2b was obtained as a beige solid (1.70 g, 79%). 1H NMR (400MHz, DMSO-d6) δ10.01(s, 1H), 8.05(d, J=5.9Hz, 1H), 7.90(s, 1H), 7.49(s, 1H), 6.61(d, J=6.0Hz, 1H), 3.83(s, 3H).

[0098] Preparation of 1-(4-(4-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-2-yl)phenyl)imidazolidin-2-one (002). Compound 002 was prepared from 2b and 1b as described above for compound 001 to afford compound 002 as a beige solid (60 mg, 45%). 1 H NMR (400MHz, DMSO-d6) δ9.49(s, 1H), 8.31(d, J=8.9Hz, 2H), 8.25(d, J=5.8Hz, 1H), 8.03(s, 1H), 7.71(d, J=8.9Hz, 2H) , 7.59(s, 1H), 7.09(s, 1H), 6.53(d, J=5.8Hz, 1H), 3.97-3.90(m, 2H), 3.89(s, 3H), 3.45(t, J=7.9Hz, 2H), 3.33(s, 3H). Synthesis of Compound 003 [ka]

[0099] Preparation of 1-tritylimidazolidin-2-one (3b). A solution of imidazolidin-2-one (3a) (20.0 g, 230 mmol), triphenylmethyl chloride (65.0 g, 230 mmol), and EtN (65 mL, 460 mmol) in anhydrous DCM (200 mL) was stirred at room temperature for 42 hours. The mixture was diluted with water and extracted with DCM. The combined organic components were washed twice with brine, dried over MgSO, filtered, and evaporated to give 3b as a white solid (60.8 g, 80%). 1 H NMR (300MHz, DMSO-d6) δ7.47-7.32(m, 6H), 7.33-7.22(m, 6H), 7.22-7.12(m, 3H), 6.40(s, 1H), 3.32-3.09(m, 4H).

[0100] Preparation of 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-tritylimidazolidin-2-one (3d). A sealed tube was charged with Intermediate 3b (3.19 g, 9.71 mmol), 2-(4-bromophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3c) (2.50 g, 8.83 mmol), Pd(dba) (647 mg, 0.706 mmol), XantPhos (1.02 g, 1.77 mmol), CsCO (6.33 g, 19.4 mmol), and dioxane (30 mL) and degassed with a stream of argon for 5 minutes. The tube was sealed and heated with stirring at 100 °C for 18 hours. The cooled mixture was then diluted with water and extracted with EtOAc. The combined organic components were dried over MgSO, filtered, evaporated, and then purified by SiO (Puriflash) column chromatography eluting with 0–20% EtOAc in cyclohexane to give 3d as a yellow foam (4.00 g, 85%). 1 H NMR (400MHz, DMSO-d6) δ7.61-7.53(m, 2H), 7.50-7.36(m, 8H), 7.34-7.27(m, 6H), 7.24-7.19(m, 3H), 3.88-3.77(m, 2H), 3.44(t, J=7.5Hz, 2H), 1.37-1.19(m, 12H).

[0101] Preparation of 1-(4-(2-chloropyrimidin-4-yl)phenyl)-3-tritylimidazolidin-2-one (3e). A sealed tube was charged with 3d (3.82 g, 7.20 mmol), 2,4-dichloropyrimidine 1f (2.15 g, 14.4 mmol), Pd(PPh) (166 mg, 0.144 mmol), 0.4 M aqueous NaCO (43 mL, 17.3 mmol), and MeCN (53 mL) and degassed with a stream of argon for 5 minutes. The tube was sealed and heated with stirring at 100 °C for 18 hours. The cooled mixture was then diluted with water and extracted with EtOAc. The combined organic components were dried over MgSO4, filtered, evaporated, and the residue was purified by SiO2 (Puriflash) column chromatography eluting with 0–30% EtOAc in cyclohexane to give 3e as a yellow foam (3.08 g, 83%).1 H NMR (300MHz, DMSO-d6) δ8.72 (d, J=5.4Hz, 1H), 8.13 (d, J=8.9Hz, 2H), 8.05 (d, J=5.4Hz, 1H), 7.64 (d, J=9.0Hz) , 2H), 7.44-7.39(m, 6H), 7.36-7.29(m, 6H), 7.26-7.19(m, 3H), 3.90(t, J=7.5Hz, 2H), 3.48(t, J=7.5Hz, 2H).

[0102] Preparation of 1-(4-(2-((1-(2-Methoxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)phenyl)imidazolidin-2-one (003). A sealed tube was charged with 3e (200 mg, 0.387 mmol), 1e (55 mg, 0.387 mmol), Pd(dba) (30 mg, 0.031 mmol), XantPhos (47 mg, 0.077 mmol), CsCO (287 mg, 0.851 mmol), and dioxane (5 ml) and degassed with a stream of argon for 5 minutes. The tube was sealed and heated with stirring at 100 °C for 18 hours. The cooled mixture was treated with water and extracted with DCM. The combined organic fractions were dried over MgSO4, filtered, and evaporated, then purified by SiO2 (Puriflash) column chromatography eluting with 0-5% EtOH in DCM to give crude product 3f as a black gum. This gum was treated with 1.25 M HCl in EtOH (10 ml) and stirred at 50 °C for 2 h. The mixture was adjusted to pH 8 with saturated aqueous NaHCO3 and extracted with DCM. The combined organic fractions were dried over MgSO4, filtered, and evaporated. The residue was purified by SiO2 (Puriflash) column chromatography eluting with 0-15% EtOH in DCM to give compound 003 as a yellow solid (13 mg, 9%). 1H NMR (400MHz, DMSO-d6) δ9.41(s, 1H), 8.42(d, J=5.2Hz, 1H), 8.16-8.08(m, 2H), 7.99(s, 1H), 7.75-7.71(m, 2H), 7.57(s, 1H), 7.2 3(d, J=5.3Hz, 1H), 7.12(s, 1H), 4.25(t, J=5.3Hz, 2H), 3.96-3.89(m, 2H), 3.68(t, J=5.3Hz, 2H), 3.47-3.42(m, 2H), 3.26(s, 3H).

[0103] Synthesis of Compound 004 [ka]

[0104] Preparation of 1-(3,5-dimethylbenzyl)-1H-pyrazol-4-amine (4b). Intermediate 4b was prepared in two steps from 4-nitro-1H-pyrazole (1c) and 3,5-dimethylbenzyl bromide via 1-(3,5-dimethylbenzyl)-4-nitro-1H-pyrazole (4a), which was hydrogenated over palladium as described above for intermediate 1e to give 4b as a purple oil (641 mg, 78%). 1 H NMR (400MHz, DMSO-d6) δ7.03(s, 1H), 6.92(s, 1H), 6.89(s, 1H), 6.78(s, 2H), 5.02(s, 2H), 3.82(s, 2H), 2.22(s, 6H).

[0105] Preparation of 2-chloro-N-(1-(3,5-dimethylbenzyl)-1H-pyrazol-4-yl)pyrimidin-4-amine (4c) and 4-chloro-N-(1-(3,5-dimethylbenzyl)-1H-pyrazol-4-yl)pyrimidin-2-amine (4d). A mixture of regioisomers 4c and 4d was prepared from 2,4-dichloropyrimidine (1f) and 1-(3,5-dimethylbenzyl)-1H-pyrazol-4-amine (4b) in a similar manner to intermediate 1g above. Purification by SiO2 (Puriflash) column chromatography eluting with 2–5% EtOH in DCM afforded 4d as a beige solid (104 mg, 10%; first elution) followed by 4c as a white solid (749 mg, 75%; last elution). 4c: 1 H NMR (400MHz, DMSO-d6) δ9.92(s, 1H), 8.05(d, J=5.9Hz, 1H), 7.96(s, 1H), 7.55(s , 1H), 6.92(s, 1H), 6.86(s, 2H), 6.61(d, J=5.9Hz, 1H), 5.23(s, 2H), 2.24(s, 6H). 4d: 1 H NMR (400MHz, DMSO-d6) δ9.82(s, 1H), 8.36(d, J=5.1Hz, 1H), 7.91(s, 1H), 7.54(s , 1H), 6.91(s, 1H), 6.85(s, 2H), 6.81(d, J=5.2Hz, 1H), 5.20(s, 2H), 2.23(s, 6H).

[0106] Preparation of 1-(4-(4-((1-(3,5-dimethylbenzyl)-1H-pyrazol-4-yl)amino)pyrimidin-2-yl)phenyl)imidazolidin-2-one (004). Compound 004 was prepared from 4c and 1b in a manner similar to the preparation of compound 001 above to afford 004 as a white solid (60 mg, 38%). 1H NMR (400MHz, DMSO-d6) δ9.53(s, 1H), 8.24(d, J=5.8Hz, 1H), 8.23-8.19(m, 2H), 8.09(s, 1H), 7.66(d, J=8.9Hz, 2H), 7.59(s, 1H), 7.09(s, 1H), 6.99-6.93(m, 3H), 6.52(d, J=5.9Hz, 1H), 5.27(s, 2H), 3.96-3.85(m, 2H), 3.48-3.42(m, 2H), 2.25(s, 6H).

[0107] Synthesis of Compound 005 [ka]

[0108] Preparation of 1-(4-(2-((1-(3,5-dimethylbenzyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)phenyl)imidazolidin-2-one (005). Compound 005 was prepared from 4d and 1b in a manner similar to the preparation of compound 001 above to afford 005 as a white solid (69 mg, 49%). 1 H NMR (400MHz, DMSO-d6) δ9.43(s, 1H), 8.41(d, J=5.2Hz, 1H), 8.06(d, J=8.5Hz, 2H), 7.99(s, 1H), 7.71(d, J=8.7Hz, 2H), 7.58(s, 1H), 7 .23(d, J=5.3Hz, 1H), 7.13(s, 1H), 6.95(s, 1H), 6.90(s, 2H), 5.22(s, 2H), 3.92(t, J=7.9Hz, 2H), 3.45(t, J=8.0Hz, 2H), 2.24(s, 6H).

[0109] Synthesis of Compound 006 [ka]

[0110] Preparation of 1-(2-ethoxyethyl)-4-nitro-1H-pyrazole (6a). A mixture of 4-nitropyrazole (1c) (2.00 g, 17.7 mmol), 1-bromo-2-ethoxyethane (1.99 mL, 17.7 mmol), and K2CO3 (5.50 g, 39.8 mmol) in MeCN (50 mL) was stirred at 80 °C for 3 h. Water was added, and the mixture was extracted with EtOAc. The combined organic components were then dried over MgSO4, filtered, and evaporated. The residue was purified by SiO2 (Puriflash) column chromatography eluting with 0–5% EtOH in DCM to give intermediate 6a as a clear, mobile oil (2.90 g, 88%). 1 H NMR (400MHz, DMSO-d6) δ8.84(s, 1H), 8.26(s, 1H), 4.33(t, J=5.3Hz, 2H), 3.76(t, J=5.3Hz, 2H), 3.42(q, J=7.0Hz, 2H), 1.04(t, J=7.0Hz, 3H).

[0111] Preparation of 1-(2-ethoxyethyl)-1H-pyrazol-4-amine (6b). To a solution of intermediate 6a (2.89 g, 15.6 mmol) in ethanol (35 mL) was added 10% Pd / C (289 mg, 10 wt%). The reaction mixture was stirred at room temperature and atmospheric pressure for 2 hours, after which the mixture was filtered and the filtrate was concentrated to give intermediate 6b as a red, mobile oil (2.43 g, quantitative). 1 H NMR (400MHz, DMSO-d6) δ7.02(s, 1H), 6.89(s, 1H), 4.04(t, J=5.6Hz, 2H), 3.7 7(s, 2H), 3.62(t, J=5.6Hz, 2H), 3.39(q, J=7.0Hz, 2H), 1.07(t, J=7.0Hz, 3H).

[0112] Preparation of 1-(4-(6-bromopyridin-2-yl)phenyl)-3-tritylimidazolidin-2-one (6d). Prepared from 3d and 2,6-dibromopyridine (6c) using Pd(PPh) and CsCO in dioxane / water in a manner similar to the synthesis of intermediate 3e above to give 6d as a beige solid (680 mg, 57%). 1H NMR (400MHz, DMSO-d6) δ8.02-7.92(m, 2H), 7.78(t, J=7.8Hz, 1H), 7.64-7.49(m, 4H), 7.46-7.39(m, 6H) ), 7.33(t, J=7.7Hz, 6H), 7.26-7.19(m, 3H), 3.89(dd, J=8.6, 6.5Hz, 2H), 3.47(dd, J=8.5, 6.6Hz, 2H).

[0113] Preparation of 1-(4-(6-((1-(2-ethoxyethyl)-1H-pyrazol-4-yl)amino)pyridin-2-yl)phenyl)imidazolidin-2-one (006). Compound 006 was then prepared from 6b and 6d in a manner similar to 3f above using Pd(dba), XantPhos, and NaOtBu in dioxane to give crude product 6e. Crude product 6e was treated with 1.25 N HCl solution in EtOH at 50° C. for 2 hours, as described in the preparation of compound 003 above, to give 006 as a beige powder (35 mg, 17%). 1 H NMR (300MHz, DMSO-d6) δ8.86(s, 1H), 8.09-7.95(m, 3H), 7.73-7.63(m, 2H), 7.59-7.47(m, 2H), 7.15(d, J=7.4Hz, 1H), 7.04(s, 1H), 6.58( d.

[0114] Synthesis of Compound 007 [ka]

[0115] Preparation of 5-(4-iodophenyl)oxazole (7b). To a solution of 4-iodobenzaldehyde (7a) (15.0 g, 64.7 mmol) in MeOH (150 ml) was added K2CO3 (26.8 g, 194 mmol) and TosMIC (15.2 g, 77.6 mmol). The reaction mixture was stirred at room temperature for 16 h. The mixture was evaporated to dryness, diluted with water, and extracted twice with EtOAc. The combined organic components were washed with water, followed by saturated aqueous NaCl, dried over MgSO4, filtered, and evaporated. The final product was purified by silica gel chromatography using 30% EtOAc / cyclohexane as the eluent to give intermediate 7b as a yellow solid (10.7 g, 61%). 1 H NMR (500MHz, DMSO-d6) δ8.47(s, 1H), 7.86(d, J=8.4Hz, 2H), 7.76(s, 1H), 7.54(d, J=8.4Hz, 2H).

[0116] Preparation of 5-(4-iodophenyl)-2-chlorooxazole (7c). To a stirred solution of intermediate 7b (5.40 g, 19.9 mmol) in anhydrous THF (55 mL) was added dropwise a 1 M solution of LiHMDS in THF (21.9 mL, 21.9 mmol) at -78 °C. The reaction mixture was stirred at -78 °C for 30 min, C2Cl6 (1.09 g, 4.62 mmol) was added, and the reaction mixture was stirred at room temperature for 16 h. The mixture was diluted with water and extracted twice with EtOAc. The combined organic components were washed with water, followed by saturated aqueous NaCl, dried over MgSO4, filtered, and evaporated. The final product was purified by silica gel chromatography using 0–20% EtOAc / cyclohexane as the eluent to give intermediate 7c (4.80 g, 79%). 1 H NMR (500MHz, DMSO-d6) δ7.87 (d, J=8.6Hz, 2H), 7.86 (s, 1H), 7.50 (d, J=8.5Hz, 2H).

[0117] Preparation of N-(1-(2-ethoxyethyl)-1H-pyrazol-4-yl)-5-(4-iodophenyl)oxazol-2-amine (7d). To a solution of intermediate 7c (512 mg, 1.68 mmol) in anhydrous iPrOH (6 mL) was added intermediate 6b (260 mg, 1.68 mmol) and 1 M aqueous hydrochloric acid (400 μL, 0.400 mmol), and the mixture was stirred at 80° C. for 5 h. The cooled mixture was evaporated to dryness, diluted with water, and extracted twice with EtOAc. The combined organic components were dried over MgSO4, filtered, and evaporated. The final product was purified by silica gel chromatography using EtOAc / MeOH as the eluent to give intermediate 7d (78 mg, 11%). 1 H NMR (500MHz, DMSO-d6) δ9.98(s, 1H), 7.83(s, 1H), 7.77(d, J=8.5Hz, 2H), 7.46(d, J=13.2Hz, 2H), 7.35(d, J=8.5Hz, 2H), 4.22(t, J=5.5Hz, 2H), 3.71(t, J=5.5Hz, 2H), 3.43(q, J=7.0Hz, 2H), 1.08(t, J=7.0Hz, 3H).

[0118] Preparation of 1-(4-(2-((1-(2-ethoxyethyl)-1H-pyrazol-4-yl)amino)oxazol-5-yl)phenyl)imidazolidin-2-one (007). To a solution of 7d (78 mg, 0.184 mmol) in anhydrous dioxane (2.3 mL) in a sealed tube, 2-imidazolidinone (3a) (159 mg, 1.84 mmol), cesium carbonate (132 mg, 0.405 mmol), and XantPhos (21 mg, 0.037 mmol) were added sequentially. The reaction mixture was degassed with nitrogen for 20 minutes, and then Pd(dba) (14 mg, 0.015 mmol) was added. The reaction mixture was stirred at 110 °C for 16 hours, after which the cooled mixture was diluted with water and extracted with EtOAc. The combined organic phase was washed with a saturated solution of NaHCO3, then brine, dried over MgSO4, filtered, and evaporated. The final product was purified by silica gel chromatography using 0-10% MeOH / EtOAc as the eluent to give compound 007 as a beige powder (9 mg, 13%). 1H NMR (500MHz, DMSO-d6) δ9.86(s, 1H), 7.83(s, 1H), 7.62(d, J=8.7Hz, 2H), 7.49(d, J=8.7Hz, 2H), 7.43(s, 1H), 7.25(s, 1H) , 7.00(s, 1H), 4.22(t, J=5.5Hz, 2H), 3.90-3.85(m, 2H), 3.71(t, J=5.5Hz, 2H), 3.46-3.35(m, 4H), 1.09(t, J=7.0Hz, 3H).

[0119] Synthesis of Compound 008 [ka]

[0120] Preparation of 1-(1-(2-ethoxyethyl)-1H-pyrazol-4-yl)thiourea (8a). To a solution of ammonium thiocyanate (497 mg, 6.53 mmol) in acetone (8 mL) was added dropwise at room temperature benzoyl chloride (690 μL, 5.94 mmol). The reaction mixture was stirred at 70° C. for 20 minutes, after which a solution of intermediate 6b (922 mg, 5.94 mmol) in acetone (9 mL) was added, and the reaction mixture was stirred at 70° C. for another 20 minutes. The mixture was evaporated, water was added, and the mixture was extracted with EtOAc. The combined organic components were washed with brine, dried over MgSO4, filtered, and evaporated. The residue was dissolved in MeOH (17 mL), treated with potassium carbonate (1.60 g, 11.9 mmol), and stirred at room temperature for 18 hours. Methanol was removed under reduced pressure, and the residue was treated with water and extracted with EtOAc. The combined organic portions were dried over MgSO4, filtered and evaporated to give intermediate 8a (151 mg, 12%). 1 H NMR (500MHz, DMSO-d6) δ9.32(s, 1H), 7.86(s, 2H), 7.41(s, 1H), 7.24(s, 1H), 4.18(t, J=5.5Hz, 2H), 3.70(t, J=5.5Hz, 2H), 3.42(q, J=7.0Hz, 2H), 1.08(t, J=7.0Hz, 3H).

[0121] Preparation of 4-(4-bromophenyl)-N-(1-(2-ethoxyethyl)-1H-pyrazol-4-yl)thiazol-2-amine (8b). To a solution of 2,4'-dibromoacetophenone (8c) (196 mg, 0.705 mmol) in EtOH (30 mL) was added intermediate 8a (151 mg, 0.75 mmol) and potassium bicarbonate (212 mg, 2.11 mmol). The reaction mixture was stirred at 80 °C for 16 h. The cooled mixture was evaporated, diluted with water, and extracted with EtOAc. The combined organic components were washed with brine, dried over MgSO, filtered, and evaporated. The residue was purified by silica gel chromatography using EtOAc as the eluent to give intermediate 8b as a beige powder (116 mg, 42%). 1 H NMR (500MHz, DMSO-d6) δ9.94(s, 1H), 8.01(s, 1H), 7.91-7.83(m, 2H), 7.63-7.58(m, 2H), 7.51(s, 1H), 7 .30(s, 1H), 4.26(t, J=5.4Hz, 2H), 3.73(t, J=5.4Hz, 2H), 3.45(q, J=7.0Hz, 2H), 1.10(t, J=7.0Hz, 3H).

[0122] Preparation of 1-(4-(2-((1-(2-ethoxyethyl)-1H-pyrazol-4-yl)amino)thiazol-4-yl)phenyl)imidazolidin-2-one (008). To a solution of 8b (116 mg, 0.295 mmol) in anhydrous dioxane (4 mL) in a sealed tube was added 2-imidazolidinone (3a) (254 mg, 2.95 mmol), cesium carbonate (211 mg, 0.649 mmol), and XantPhos (34 mg, 0.059 mmol) sequentially. The reaction mixture was degassed with nitrogen for 20 minutes, after which Pd(dba) (22 mg, 0.024 mmol) was added. The reaction mixture was stirred at 110 °C for 16 hours, after which the cooled mixture was diluted with water and extracted with EtOAc. The combined organic phase was washed with saturated aqueous NaHCO, then brine, dried over MgSO, filtered, and evaporated. The final product was purified by silica gel chromatography using 0-20% MeOH in EtOAc as the eluent to give intermediate 008 (38 mg, 32%).1 H NMR (500MHz, DMSO-d6) δ9.88(s, 1H), 8.04(s, 1H), 7.85(d, J=8.9Hz, 2H), 7.60(d, J=8.9Hz, 2H), 7.48(s, 1H), 7.07(s, 1H), 6. 97(s, 1H), 4.26(t, J=5.4Hz, 2H), 3.94-3.86(m, 2H), 3.73(t, J=5.4Hz, 2H), 3.44(p, J=8.0, 7.5Hz, 4H), 1.10(t, J=7.0Hz, 3H).

[0123] Synthesis of Compound 009 [ka]

[0124] Preparation of 1-(2-ethoxyethyl)-4-isothiocyanato-1H-pyrazole (9a). A solution of intermediate 6b (800 mg, 5.1 mmol) and thiocarbonyldiimidazole (9b) (1.01 g, 5.6 mmol) in anhydrous DMF (15 mL) was stirred at room temperature for 16 hours. The solvent was evaporated, and the residue was purified by silica gel chromatography using 50% EtOAc in cyclohexane to give intermediate 9a (520 mg, 51%). 1 H NMR (500 MHz, chloroform-d) δ 7.54 (s, 2H), 4.28 (t, J = 5.7 Hz, 2H), 3.80 (t, J = 5.6 Hz, 2H), 3.49 (q, J = 7.0 Hz, 2H), 1.17 (t, J = 7.0 Hz, 3H).

[0125] Preparation of 3-(4-bromophenyl)-N-(1-(2-ethoxyethyl)-1H-pyrazol-4-yl)-1,2,4-thiadiazol-5-amine (9d). A solution of intermediate 9a (520 mg, 2.64 mmol), 4-bromobenzamidine hydrochloride (9c) (1.24 g, 5.27 mmol), and anhydrous EtN (767 μL, 5.27 mmol) in anhydrous DMF (15 mL) was stirred at room temperature for 16 hours. DIAD (572 μL, 2.90 mmol) was added, and the mixture was stirred at room temperature for another 16 hours. Water was added, and the crude product was extracted with EtOAc. The combined organic components were washed with saturated aqueous NaHCO, then water, then brine, dried over MgSO, filtered, and evaporated. The residue was purified by silica gel chromatography using 30-50% EtOAc / cyclohexane as the eluent to give intermediate 9d (500 mg, 48%). 1 H NMR (500MHz, chloroform-d) δ8.06(d, J=8.5Hz, 2H), 7.80(s, 2H), 7.59(d, J=8.5Hz, 2H), 4.3 6(t, J=5.7Hz, 2H), 3.86(t, J=5.7Hz, 2H), 3.52(q, J=7.0Hz, 2H), 1.19(t, J=7.0Hz, 3H).

[0126] Preparation of 1-(4-(5-((1-(2-ethoxyethyl)-1H-pyrazol-4-yl)amino)-1,2,4-thiadiazol-3-yl)phenyl)-3-tritylimidazolidin-2-one (9e). To a solution of intermediate 9d (500 mg, 1.27 mmol) in anhydrous dioxane (10 mL) in a sealed tube, intermediate 3b (500 mg, 1.52 mmol), cesium carbonate (828 mg, 2.54 mmol), and XantPhos (69 mg, 0.12 mmol) were added sequentially. The reaction mixture was degassed with nitrogen for 20 minutes, and then Pd2(dba)3 (5 mg, 0.06 mmol) was added. The tube was sealed, and the mixture was stirred at 110 °C for 16 hours. The cooled mixture was diluted with water and extracted twice with EtOAc. The combined organic phase was washed with water, then saturated NaCl solution, dried over MgSO, filtered, and evaporated. The residue was purified by silica gel chromatography using 60-90% EtOAc / cyclohexane as the eluent to give intermediate 9e (440 mg, 53%). 1 H NMR (500MHz, chloroform-d) δ8.09(d, J=8.8Hz, 2H), 7.78(s, 2H), 7.57(d, J=8.8Hz, 2H), 7.52-7.44(m, 8H), 7.35-7.28(m, 4H), 7 .26-7.20(m, 8H), 3.84(d, J=6.4Hz, 2H), 3.54(d, J=7.2Hz, 2H), 3.52-3.49(m, 4H), 3.41-3.35(m, 2H), 1.18(t, J=7.0Hz, 3H).

[0127] Preparation of 1-(4-(5-((1-(2-ethoxyethyl)-1H-pyrazol-4-yl)amino)-1,2,4-thiadiazol-3-yl)phenyl)imidazolidin-2-one (009). To a solution of intermediate 9e (440 mg, 0.69 mmol) in DCM (20 ml) was added TFA (5.0 ml) dropwise. The reaction mixture was stirred at room temperature for 16 hours. The solvent was evaporated, a saturated solution of NaHCO was added, and the crude product was extracted with DCM. The combined organic components were washed with water, then brine, dried over MgSO, filtered, and evaporated. The reaction mixture was triturated with DCM and filtered. The resulting solid was purified by silica gel chromatography using 5% methyl alcohol / DCM as the eluent to give compound 009 (110 mg, 40%). 1 H NMR (500MHz, chloroform-d) δ8.17(d, J=8.7Hz, 2H), 7.80(s, 2H), 7.67(d, J=8.7Hz, 2H), 4.36(t, J=5.6Hz, 2H), 4.05-4.00(m, 2H), 3.86(t, J=5.7Hz, 2H), 3.67-3.62(m, 2H), 3.51(q, J=7.0Hz, 2H), 1.19(t, J=7.0Hz, 3H).

[0128] Synthesis of Compound 010 [ka]

[0129] Preparation of 1-(2-methoxyethyl)-3-methyl-4-nitro-1H-pyrazole (10b). A solution of 4-nitro-3-methyl-1H-pyrazole (10a) (6.00 g, 47.2 mmol), 1-bromo-2-methoxyethane (6.66 mL, 70.8 mmol), and potassium carbonate (13.0 g, 94.4 mmol) in anhydrous butan-2-one (180 mL) was stirred at 80 °C for 16 h. The solvent was evaporated, water was added, and the crude product was extracted with EtOAc. The combined organic components were washed with water and brine, then dried over MgSO, filtered, and evaporated. The residue was purified by silica gel chromatography using 0–70% EtOAc / cyclohexane to give intermediate 10b as a colorless oil (8.30 g, 95%). 1 H NMR (400MHz, DMSO-d6) δ8.76 (s, 1H), 4.27 (t, J=5.2Hz, 2H), 3.73-3.66 (m, 2H), 3.24 (s, 3H), 2.43 (s, 3H).

[0130] Preparation of 1-(2-methoxyethyl)-3-methyl-1H-pyrazol-4-amine (10c). To a solution of intermediate 10b (8.30 g, 44.8 mmol) in EtOH (200 ml) was added 10% palladium on carbon (830 mg). Hydrazine monohydrate (5.40 ml, 111 mmol) was added dropwise at 0° C. The reaction mixture was stirred at room temperature for 2 hours and at 60° C. for 16 hours. The heated mixture was then filtered through Celite® and washed with ethanol. The filtrate was concentrated to give intermediate 10c as a red oil (7.10 g), which was used directly in the next step. 1 H NMR (400MHz, DMSO-d6) δ6.95(s, 1H), 3.98(t, J=5.5Hz, 2H), 3.56(td, J=5.5, 1.8Hz, 2H), 3.51(s, 2H), 3.22(s, 3H), 1.99(s, 3H).

[0131] Preparation of 4-iodo-N-((1-(2-methoxyethyl)-3-methyl-1H-pyrazol-4-yl)carbamothioyl)benzamide (10e). A solution of ammonium thiocyanate (3.83 g, 50.3 mmol) and 4-iodobenzoyl chloride (10d) (12.8 g, 48.0 mmol) in acetone (50 ml) was stirred at 70 °C for 30 minutes and then treated with a solution of Intermediate 10c (7.10 g, 45.8 mmol) in acetone (40 ml). After stirring at 70 °C for 1 hour, the mixture was evaporated, water was added, and the solid was filtered and washed with water and cyclohexane. The solid was dissolved in a small amount of DCM, and MTBE was added until a solid formed. The solid was filtered and dried under reduced pressure to give Intermediate 10e as a white powder (2.60 g, 13%). 1 H NMR (400MHz, DMSO-d6) δ12.57(s, 1H), 11.67(s, 1H), 8.43(s, 1H), 7.93(d, J=8.5Hz, 2H), 7. 75(d, J=8.5Hz, 2H), 4.19(t, J=5.3Hz, 2H), 3.66(t, J=5.3Hz, 2H), 3.24(s, 3H), 2.18(s, 3H).

[0132] Preparation of 1-(1-(2-methoxyethyl)-3-methyl-1H-pyrazol-4-yl)thiourea (10f). A solution of intermediate 10e (2.60 g, 5.85 mmol) in MeOH (15 ml) with potassium carbonate (1.62 g, 11.7 mmol) was stirred at room temperature for 3 hours. Methanol was removed under reduced pressure, and the residue was treated with water and extracted with EtOAc. The combined organic components were washed with brine, dried over MgSO, filtered, evaporated, and the residue was triturated with ether to give intermediate 10f as a white powder (1.10 g, 87%). 1 H NMR (500MHz, DMSO-d6) δ8.89(s, 1H), 7.68-7.56(m, 2H), 6.59(s, 1H), 4.11(t, J=5.5Hz, 2H), 3.64(t, J=5.5Hz, 2H), 3.23(s, 3H), 2.02(s, 3H).

[0133] Preparation of N-(1-(2-methoxyethyl)-3-methyl-1H-pyrazol-4-yl)-4-(4-nitrophenyl)thiazol-2-amine (10h). To a solution of 2-bromo-4'-nitroacetophenone (10g) (512 mg, 2.10 mmol) in EtOH (10 ml) was added Intermediate 10f (450 mg, 2.10 mmol) and potassium bicarbonate (631 mg, 6.30 mmol). The reaction mixture was stirred at 80 °C for 4 h. The cooled mixture was evaporated to dryness, diluted with water, and extracted with EtOAc. The combined organic portions were dried over MgSO, filtered, and evaporated to give Intermediate 10h as a brown solid (723 mg, 96%). 1 H NMR (400MHz, DMSO-d6) δ9.49(s, 1H), 8.27(d, J=9.0Hz, 2H), 8.14(d, J=9.0Hz, 2H), 8.07(s , 1H), 7.58(s, 1H), 4.20(t, J=5.4Hz, 2H), 3.68(t, J=5.4Hz, 2H), 3.27(s, 3H), 2.15(s, 3H).

[0134] Preparation of 4-(4-aminophenyl)-N-(1-(2-methoxyethyl)-3-methyl-1H-pyrazol-4-yl)thiazol-2-amine (10i). To a solution of intermediate 10h (723 mg, 2.01 mmol) in EtOH / DCM (18 / 9 ml) was added SnCl2·2H2O (2.60 g, 11.5 mmol), and the reaction mixture was stirred at room temperature for 16 h. Water was added, and the mixture was brought to basic pH by the addition of 2.5 M aqueous NaOH. The crude product was extracted with DCM, and the combined organic components were washed with water and brine, dried over MgSO4, filtered, and evaporated to give intermediate 10i as a red powder (612 mg, 92%). 1 H NMR (400MHz, DMSO-d6) δ9.19(s, 1H), 8.03(s, 1H), 7.55(d, J=8.5Hz, 2H), 6.73(s, 1H), 6.57(d, J= 8.6Hz, 2H), 5.18(s, 2H), 4.18(t, J=5.3Hz, 2H), 3.67(t, J=5.3Hz, 2H), 3.27(s, 3H), 2.13(s, 3H).

[0135] Preparation of 3-(4-(2-((1-(2-Methoxyethyl)-3-methyl-1H-pyrazol-4-yl)amino)thiazol-4-yl)phenyl)oxazolidin-2-one (010). To a solution of intermediate 10i (300 mg, 0.911 mmol) in anhydrous DCM (4.5 mL) was added triethylamine (380 μL, 2.73 mmol) at room temperature. Then, 2-chloroethyl chloroformate (10j) (850 μL, 0.819 mmol) was added dropwise at 0° C., and the reaction mixture was stirred at room temperature for 4 hours. Water was added, and the crude product was extracted with DCM. The combined organic components were dried over MgSO4, filtered, and evaporated. The resulting product was dissolved in anhydrous THF (4.5 mL), and KOtBu (307 mg, 2.73 mmol) was added portionwise, and the reaction mixture was stirred at room temperature for 1.5 hours. Water was added, and the crude product was extracted with EtOAc. The combined organic phase was washed with water and brine, then dried over MgSO, filtered, and evaporated. The residue was purified by silica gel chromatography using 0 / 60 / 40 to 10 / 90 / 0% methanol / EtOAc / cyclohexane to give compound 010 as a beige powder (80 mg, 22%). 1 H NMR (400MHz, DMSO-d6) δ9.34(s, 1H), 8.05(s, 1H), 7.90(d, J=8.8Hz, 2H), 7.61(d, J=8.8Hz, 2H), 7.12(s, 1H), 4.50-4.41(m, 2H), 4.19(t, J=5.3Hz, 2H), 4.14-4.05(m, 2H), 3.67(t, J=5.3Hz, 2H), 3.26(s, 3H), 2.14(s, 3H).

[0136] Synthesis of Compound 011 [ka]

[0137] Preparation of 1-(4-bromophenyl)-3-((1-(2-ethoxyethyl)-1H-pyrazol-4-yl)amino)-3-(methylthio)prop-2-en-1-one (11a). To a solution of intermediate 6b (580 mg, 3.74 mmol) in anhydrous DCM (30 mL) was added DIPEA (2.0 mL, 11.2 mmol) and thiophosgene (280 μL, 3.74 mmol) dropwise successively at 0° C. The reaction mixture was stirred at room temperature for 30 minutes, after which water was added and the crude product was extracted with DCM. The combined organic components were washed with water, dried over MgSO4, filtered, and evaporated. The residue was then dissolved in anhydrous DMF (17 mL) and added at 0 °C to a solution previously prepared by treating 4'-bromoacetophenone (11b) (744 mg, 3.74 mmol) with a solution of NaH (60% in oil) (179 mg, 4.48 mmol) in anhydrous DMF (10 mL). The reaction mixture was stirred at room temperature for 45 min, and iodomethane (230 μL, 3.74 mmol) was added dropwise at 0 °C. The reaction mixture was stirred at room temperature for 45 min. Water was added, and the crude product was extracted with EtOAc. The combined organic components were washed with saturated aqueous NaHCO3 and then brine, then dried over MgSO4, filtered, and evaporated. The product was purified by silica gel chromatography using 0–50% EtOAc / cyclohexane as the eluent to give intermediate 11a as a brown oil (374 mg, 25%). 1 H NMR (500MHz, DMSO-d6) δ13.15(s, 1H), 7.90(d, J=8.8Hz, 3H), 7.67(d, J=8.5Hz, 2H), 7.54(s, 1H), 5.94(s, 1 H), 4.24(t, J=5.4Hz, 2H), 3.73(t, J=5.4Hz, 2H), 3.42(q, J=7.0Hz, 2H), 2.53(s, 3H), 1.08(t, J=7.0Hz, 3H).

[0138] Preparation of 5-(4-bromophenyl)-N-(1-(2-ethoxyethyl)-1H-pyrazol-4-yl)-1H-pyrazol-3-amine (11c). To a solution of intermediate 11a (374 mg, 0.910 mmol) in isopropanol (9.5 mL) was added hydrazine monohydrate (50 μL, 1.03 mmol), and the mixture was stirred at 83° C. for 4 hours. The solvent was evaporated, and the product was purified by silica gel chromatography using 0-100% EtOAc / cyclohexane as the eluent to give intermediate 11c as a beige powder (291 mg, 85%). 1 H NMR (500MHz, DMSO-d6) δ12.18(s, 1H), 7.95(s, 1H), 7.70-7.66(m, 3H), 7.62(d, J=8.6Hz, 2H), 7.32(s, 1H) , 6.08(s, 1H), 4.17(t, J=5.5Hz, 2H), 3.70(t, J=5.5Hz, 2H), 3.43(q, J=7.0Hz, 2H), 1.09(t, J=7.0Hz, 3H).

[0139] Preparation of 1-(4-(3-((1-(2-ethoxyethyl)-1H-pyrazol-4-yl)amino)-1H-pyrazol-5-yl)phenyl)-3-tritylimidazolidin-2-one (11d). To a solution of Intermediate 11c (291 mg, 0.773 mmol) in anhydrous NMP (7.5 mL) in a sealed tube, Intermediate 3b (762 mg, 2.32 mmol), cesium carbonate (630 mg, 1.93 mmol), and XantPhos (90 mg, 0.155 mmol) were added sequentially. The reaction mixture was degassed with nitrogen for 20 minutes, after which Pd(dba) (57 mg, 0.062 mmol) was added, the tube was sealed, and heated at 130 °C for 16 hours. The cooled mixture was diluted with water and extracted with EtOAc. The combined organic components were washed with water, dried over MgSO, filtered, and evaporated. The residue was purified by preparative silica gel plate chromatography using 100% EtOAc as the eluent to give intermediate 11d as a beige powder (35 mg, 7%). 1H NMR (500MHz, DMSO-d6) δ7.86(s, 1H), 7.66(s, 1H), 7.60(d, J=8.7Hz, 2H), 7.48(d, J=8.6Hz, 2H), 7.45-7.40(m, 7H), 7.35-7.29(m, 8H) , 7.24(d, J=7.3Hz, 3H), 4.16(t, J=5.5Hz, 2H), 3.85(t, J=7.6Hz, 2H), 3.69(t, J=5.5Hz, 2H), 3.48-3.39(m, 4H), 1.09(t, J=7.0Hz, 3H).

[0140] Preparation of 1-(4-(3-((1-(2-ethoxyethyl)-1H-pyrazol-4-yl)amino)-1H-pyrazol-5-yl)phenyl)imidazolidin-2-one (011). To a solution of intermediate 11d (35 mg, 0.056 mmol) in DCM (2 ml), TFA (100 μl) was added dropwise. The reaction mixture was stirred at room temperature for 4 hours. The mixture was made basic with 2.5 M aqueous NaOH, and the crude product was extracted with DCM. The combined organic components were washed with brine, then dried over MgSO4, filtered, and evaporated. The residue was purified by preparative silica gel plate chromatography using 10% MeOH / DCM as the eluent to give compound 011 as a white powder (3 mg, 14%). 1 H NMR (500MHz, DMSO-d6) δ12.08(s, 1H), 7.85(s, 1H), 7.71-7.59(m, 5H), 7.31(s, 1H), 7.00 (s, 1H), 5.97(s, 1H), 4.16(t, J=5.5Hz, 2H), 3.91-3.85(m, 2H), 3.70(t, J=5.8Hz, 2H), 3.45-3.41(m, 4H), 1.09(t, J=7.0Hz, 3H).

[0141] Synthesis of Compound 012 [ka]

[0142] Preparation of 1-(4-(2-((1-(2-Methoxyethyl)-3-methyl-1H-pyrazol-4-yl)amino)thiazol-4-yl)phenyl)pyrrolidin-2-one (012). To a solution of intermediate 10i (312 mg, 0.947 mmol) and HATU (360 mg, 0.947 mmol) in anhydrous DMF (10 ml) was added 4-chlorobutyric acid (12a) (100 μl, 0.947 mmol) and triethylamine (263 μl, 1.89 mmol) at room temperature. The reaction mixture was stirred at room temperature for 4 hours, after which water was added and the crude product was extracted with DCM. The combined organic components were washed twice with saturated NaHCO solution, then with water and brine, dried over MgSO, filtered and evaporated. The resulting product was dissolved in anhydrous THF (5 mL) and treated with KOtBu (319 mg, 2.84 mmol) in several portions, and the reaction mixture was stirred at room temperature for 1.5 hours. Water was added, and the crude product was extracted with EtOAc. The combined organic components were washed with brine, dried over MgSO, filtered, and evaporated. The residue was purified by silica gel chromatography using 0 / 60 / 40 to 10 / 90 / 0% MeOH / EtOAc / cyclohexane to give compound 012 as an orange solid (214 mg, 57%). 1 H NMR (400MHz, DMSO-d6) δ9.33(s, 1H), 8.05(s, 1H), 7.88(d, J=8.8Hz, 2H), 7.70(d, J=8.8Hz, 2H), 7.11(s, 1H), 4.1 9(t, J=5.3Hz, 2H), 3.87(t, J=7.0Hz, 2H), 3.67(t, J=5.3Hz, 2H), 3.26(s, 3H), 2.14(s, 3H), 2.09(q, J=7.4Hz, 2H).

[0143] Synthesis of Compound 013 [ka]

[0144] Preparation of 1-(3-methoxypropyl)-3-methyl-4-nitro-1H-pyrazole (13a). A solution of 4-nitro-3-methyl-1H-pyrazole (10a) (2.00 g, 15.7 mmol), 3-bromo-1-methoxypropane (2.60 mL, 23.1 mmol), and potassium carbonate (4.30 g, 31.1 mmol) in anhydrous butan-2-one (60 mL) was stirred at 80 °C for 16 h. The cooled mixture was evaporated, water was added, and the crude product was extracted with EtOAc. The combined organic components were washed with brine, dried over MgSO4, filtered, and evaporated. The final product was purified by silica gel chromatography using 0–60% EtOAc / cyclohexane to give a mixture of regioisomers 13a and 13b as a yellow oil (2.70 g, 86% overall yield). 13a: 1 H NMR (400MHz, DMSO-d6) δ8.78(s, 1H), 4.16(m, 2H), 3.30(m, 2H), 3.22(s, 3H), 2.42(s, 3H), 2.08-1.92(m, 2H).

[0145] Preparation of 1-(3-methoxypropyl)-3-methyl-1H-pyrazol-4-amine (13c). To a solution of a mixture of regioisomers 13a and 13b (2.70 g, 13.6 mmol) in EtOH (50 mL) was added 10% Pd / C (1.0 g) and then hydrazine monohydrate (1.80 mL, 36.6 mmol) dropwise at 0° C. The reaction mixture was stirred at 0° C. for 20 minutes and then at room temperature for 30 minutes. The mixture was filtered through a Celite® pad and washed with ethanol. The filtrate was concentrated to give a crude mixture of regioisomers 13c and 13d (2.40 g) as a colorless oil, which was used directly in the next step. 13c: 1 H NMR (400MHz, DMSO-d6) δ6.92(s, 1H), 3.86(m, 2H), 3.52(br s, 2H), 3.25(m, 2H), 3.21(s, 3H), 1.98(s, 3H), 1.87(m, 2H).

[0146] Preparation of 4-iodo-N-((1-(3-methoxypropyl)-3-methyl-1H-pyrazol-4-yl)carbamothioyl)benzamide (13e). A solution of ammonium thiocyanate (1.18 g, 15.8 mmol) and 4-iodobenzoyl chloride (10d) (3.97 g, 14.9 mmol) in acetone (18 ml) was stirred at 70 °C for 30 min. Then, a solution of a mixture of intermediates 13c and 13d (2.40 g, 14.2 mmol) in acetone (18 ml) was added, and the mixture was stirred at 70 °C for a further 30 min. The mixture was evaporated, water was added, and the mixture was extracted with EtOAc. The combined organic components were washed with brine, dried over MgSO, filtered, and evaporated. The final product was purified by silica gel chromatography using 0-50% EtOAc in cyclohexane as the eluent to give intermediate 13e as a white powder (1.90 g, 29%). 1 H NMR (400MHz, DMSO-d6) δ12.56(s, 1H), 11.56(s, 1H), 8.39(s, 1H), 7.93(m, 2H), 7.75(m , 2H), 4.08(t, J=6.7Hz, 2H), 3.28(m, 2H), 3.24(s, 3H), 2.18(s, 3H), 2.02-1.92(m, 2H).

[0147] Preparation of 1-(1-(3-methoxypropyl)-3-methyl-1H-pyrazol-4-yl)thiourea (13f). A solution of intermediate 13e (1.90 g, 4.15 mmol) and potassium carbonate (1.15 g, 8.29 mmol) in MeOH (50 ml) was stirred at room temperature for 18 h. The solvent was evaporated and the solid was treated with water and extracted with DCM. The combined organic components were dried over MgSO, filtered, evaporated, and then triturated with cyclohexane followed by trituration with ether to give intermediate 13f as a white powder (760 mg, 80%). 1 H NMR (400MHz, DMSO-d6) δ 8.90(s, 1H), 7.66(br s, 2H), 7.31(br s, 1H), 6.65(br s, 1H), 3.99(t, J=7.0Hz, 2H), 3.29(m, 2H), 3.23(s, 3H), 2.02(s, 3H), 1.99-1.91(m, 2H).

[0148] Preparation of 4-(4-bromo-2-fluorophenyl)-N-(1-(3-methoxypropyl)-3-methyl-1H-pyrazol-4-yl)thiazol-2-amine (13h). To a solution of 2-bromo-1-(4-bromo-2-fluorophenyl)ethan-1-one (13g) (259 mg, 0.876 mmol) in EtOH (20 ml) was added Intermediate 13f (200 mg, 0.876 mmol) and potassium bicarbonate (263 mg, 2.63 mmol). The reaction mixture was stirred at 80° C. for 18 h, after which the cooled mixture was evaporated to dryness, diluted with water, and extracted with EtOAc. The combined organic components were washed with brine, dried over MgSO4, filtered, and evaporated. The final product was purified by silica gel chromatography using 0-100% EtOAc as the eluent to give intermediate 13h as an oil (127 mg, 34%). 1 H NMR (400MHz, DMSO-d6) δ9.39(s, 1H), 8.03(t, J=8.5Hz, 1H), 7.98(s, 1H), 7.62(dd, J=11.2Hz, 2.0Hz, 1H), 7.50(dd, J=8.4Hz, 2. 0Hz, 1H), 7.14(d, J=2.6Hz, 1H), 4.07(t, J=6.9Hz, 2H), 3.29(t, J=6.0Hz, 2H), 3.24(s, 3H), 2.14(s, 3H), 1.18(t, J=7.1Hz, 2H).

[0149] Preparation of 1-(3-fluoro-4-(2-((1-(3-methoxypropyl)-3-methyl-1H-pyrazol-4-yl)amino)thiazol-4-yl)phenyl)-3-tritylimidazolidin-2-one (13i). To a solution of Intermediate 13h (127 mg, 0.299 mmol) in anhydrous NMP (3.5 mL) in a sealed tube, Intermediate 3b (108 mg, 0.328 mmol), cesium carbonate (243 mg, 0.748 mmol), and XantPhos (35 mg, 0.060 mmol) were added sequentially. The reaction mixture was degassed with nitrogen for 20 minutes, after which Pd(dba) (22 mg, 0.024 mmol) was added and the mixture was stirred at 130 °C for 18 hours. The cooled mixture was diluted with water and extracted with EtOAc. The combined organic phase was washed with water, dried over MgSO, filtered, and evaporated. The final product was purified by silica gel chromatography using 0-100% EtOAc in cyclohexane as the eluent to give intermediate 13i as a white powder (88 mg, 44%). 1H NMR (400MHz, DMSO-d6) δ9.33(s, 1H), 8.02-7.95(m, 2H), 7.42(d, J=7.9Hz, 6H), 7.34( t, J=7.4Hz, 7H), 7.24(t, J=7.2Hz, 4H), 6.95(d, J=2.2Hz, 1H), 4.06(t, J=6.6Hz, 2H), 3.87(t, J=7.4Hz, 2H), 3.47(t, J=7.5Hz, 2H), 3.29(s, 2H), 3.23(s, 3H), 2.13(s, 3H), 2.00-1.93(m, 2H).

[0150] Preparation of 1-(3-fluoro-4-(2-((1-(3-methoxypropyl)-3-methyl-1H-pyrazol-4-yl)amino)thiazol-4-yl)phenyl)imidazolidin-2-one (013). To a solution of intermediate 13i (88 mg, 0.131 mmol) in DCM (2 ml), TFA (110 μl, 1.44 mmol) was added dropwise and the mixture was stirred at room temperature for 3 h. The mixture was stirred with a saturated solution of NaHCO for 1 h, extracted with DCM, and washed with brine. The combined organic components were dried over MgSO, filtered, evaporated, and the residue was purified by preparative silica gel plate chromatography using 5 / 95% MeOH / DCM to give compound 013 as a beige powder (36 mg, 64%). 1 H NMR (400MHz, DMSO-d6) δ9.34(s, 1H), 8.04-7.97(m, 2H), 7.64(dd, J=15.0, 2.1Hz, 1H), 7.36(dd, J=8.8, 2.1Hz, 1H), 7.15(s, 1H), 6.95(d, J=2 .4Hz, 1H), 4.08(t, J=6.9Hz, 2H), 3.93-3.86(m, 2H), 3.47-3.40(m, 2H), 3.29(d, J=6.2Hz, 2H), 3.24(s, 3H), 2.14(s, 3H), 2.01-1.94(m, 2H).

[0151] Synthesis of Compound 014 [ka]

[0152] Preparation of 1-(3-methoxypropyl)-4-nitro-3-(trifluoromethyl)-1H-pyrazole (14b). A solution of 4-nitro-3-(trifluoromethyl)-1H-pyrazole (14a) (1.00 g, 5.52 mmol) in MeCN (20 mL) was treated with KCO (1.72 g, 12.4 mmol) and 1-bromo-3-methoxypropane (621 μL, 5.52 mmol) and heated at 80° C. for 4 h. Water was added, and the mixture was extracted with DCM. The combined organic components were dried over MgSO, filtered, and evaporated to give 14b as an orange oil (1.32 g, 94%). 1H NMR (400MHz, DMSO-d6) δ9.17(s, 1H), 4.31(t, J=7.1Hz, 2H), 3.34(t, J=6.0Hz, 2H), 3.21(s, 3H), 2.07(p, J=6.4Hz, 2H).

[0153] Preparation of 1-(3-methoxypropyl)-3-(trifluoromethyl)-1H-pyrazol-4-amine (14c). A solution of intermediate 14b (1.31 g, 5.17 mmol) in EtOH was treated with 10% palladium on carbon (130 mg) and stirred at room temperature under a hydrogen atmosphere overnight. The mixture was filtered and evaporated to give 14c as a black crystalline solid (979 mg, 85%). 1 H NMR (400MHz, DMSO-d6) δ7.21(s, 1H), 4.21(s, 2H), 4.04(t, J=7.0Hz, 2H), 3.26(t, J=6.2Hz, 2H), 3.22(s, 3H), 1.94(p, J=6.6Hz, 2H).

[0154] Preparation of 2-(4-bromophenyl)pyrimidin-4-ol (14e). A mixture of 4-bromobenzimidamide hydrochloride (9c) (5.00 g, 21.2 mmol) and K2CO3 (2.93 g, 21.2 mmol) in EtOH (100 mL) was treated with ethyl propiolate (14d) (2.16 mL, 21.2 mmol) and heated to reflux overnight. The mixture was cooled to room temperature, filtered, and the filtrate was concentrated to an orange slurry. Water (100 mL) and 1 M aqueous hydrochloric acid were added to the mixture to pH 2, and the solid was removed by filtration. The solid was treated with THF, the solvent was evaporated, and the procedure was repeated. The solid product was dried in a desiccator at 80 °C to give 14e as a pale orange solid (4.63 g, 87%). 1 H NMR (400MHz, DMSO-d6) δ8.13 (d, J=6.5Hz, 1H), 8.11-8.02 (m, 2H), 7.81-7.65 (m, 2H), 6.41 (d, J=6.5Hz, 1H).

[0155] Preparation of 2-(4-bromophenyl)-4-chloropyrimidine (14f). A mixture of intermediate 14e (4.60 g, 18.3 mmol) in POCl (50 mL) was heated to reflux for 1 h. The cooled mixture was evaporated, and the residue was treated with water and extracted with DCM. The combined organic components were dried over MgSO, filtered, evaporated, and purified by SiO column chromatography (Puriflash) eluting with 0–10% EtOAc in cyclohexane to give 14f as a yellow solid (3.06 g, 62%). 1 H NMR (400MHz, DMSO-d6) δ8.95-8.83(m, 1H), 8.31-8.20(m, 2H), 7.80-7.71(m, 2H), 7.71-7.59(m, 1H).

[0156] Preparation of 2-(4-bromophenyl)-N-(1-(3-methoxypropyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)pyrimidin-4-amine (14g). A mixture of intermediates 14f (300 mg, 1.11 mmol) and 14c (248 mg, 1.11 mmol) in iPrOH (10 mL) and concentrated hydrochloric acid (5 drops) was heated overnight in a sealed tube under an argon atmosphere. The cooled mixture was treated with saturated aqueous NaHCO3 and extracted with DCM. The combined organic components were dried over MgSO4, filtered, evaporated, and then purified by SiO2 column chromatography (Puriflash) eluting with 10–50% EtOAc in cyclohexane to give 14g as a pale yellow gum (332 mg, 66%). 1 H NMR (400MHz, DMSO-d6) δ9.07(s, 1H), 8.35(d, J=5.9Hz, 1H), 8.31(s, 1H), 8.25-8.15(m, 2H), 7.73-7.56 (m, 2H), 6.70(s, 1H), 4.28(t, J=7.0Hz, 2H), 3.35(t, J=6.1Hz, 2H), 3.23(s, 3H), 2.08(p, J=6.6Hz, 2H).

[0157] Preparation of 1-(4-(4-((1-(3-methoxypropyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)amino)pyrimidin-2-yl)phenyl)-3-tritylimidazolidin-2-one (14h). Intermediate 14h was prepared from 14g in a manner similar to intermediate 9e above, using intermediate 3b, Pd(dba), XantPhos, and CsCO in dioxane (409 mg, 83%). 1 H NMR (400MHz, DMSO-d6) δ8.96(s, 1H), 8.39-8.27(m, 2H), 8.25-8.09(m, 2H), 7.59-7.52(m, 2H), 7.45-7.38(m, 6H), 7.38-7.30(m, 6H), 7.30-7.14 (m, 4H), 4.27(t, J=6.9Hz, 2H), 3.87(dd, J=8.6, 6.5Hz, 2H), 3.46(dd, J=8.5, 6.5Hz, 2H), 3.33(t, J=6.1Hz, 2H), 3.21(s, 3H), 2.14-2.01(m, 2H).

[0158] Preparation of 1-(4-(4-((1-(3-methoxypropyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)amino)pyrimidin-2-yl)phenyl)imidazolidin-2-one (014). Compound 014 was prepared from 14h and TFA in DCM (158 mg, 60%) in the same manner as compound 013 above. 1 H NMR (400MHz, DMSO-d6) δ8.95(s, 1H), 8.34(s, 1H), 8.31(d, J=5.7Hz, 1H), 8.23(d, J=8.7Hz, 2H), 7.71-7.63(m, 2H), 7.06(s, 1H), 6.65(s, 1H), 4.29(t, J=6.9Hz, 2H), 3.90(dd, J=9.2, 6.7Hz, 2H), 3.43(t, J=8.0Hz, 2H), 3.35(t, J=6.1Hz, 2H), 3.24(s, 3H), 2.08(p, J=6.6Hz, 2H). By repeating the above method using appropriate starting materials and conditions, and general knowledge in the art, additional analog compounds shown in Table 1 hereinabove and listed in Table 2 below were prepared and characterized.

[0159] Examples 1-3: Analytical data of synthetic compounds Analytical data for the final compound is shown in Table 2 below. [Table 2] TIFF2026501703000061.tif253159TIFF2026501703000062.tif234139TIFF20265017030000 63.tif229134TIFF2026501703000064.tif231142TIFF2026501703000065.tif255159TIFF202 6501703000066.tif236142TIFF2026501703000067.tif237159TIFF2026501703000068.tif25 5159TIFF2026501703000069.tif229136TIFF2026501703000070.tif229141TIFF20265017030 00071.tif187159TIFF2026501703000072.tif185159TIFF2026501703000073.tif246159TIF F2026501703000074.tif235159TIFF2026501703000075.tif193159TIFF2026501703000076.t if251159TIFF2026501703000077.tif206159TIFF2026501703000078.tif243159TIFF2026501 703000079.tif254159TIFF2026501703000080.tif221136TIFF2026501703000081.tif124159

[0160] Example 2: Biological Assays Example 2-1: In vitro tubulin polymerization assay

[0161] material and method This assay was performed using a fluorescence-based tubulin polymerization assay kit (Cytoskeleton; catalog number BK011P) according to the manufacturer's instructions. Briefly, purified porcine brain tubulin was prepared at a concentration of 2 mg / ml in 80 mM PIPES pH 6.9, 2.0 mM MgCl2, 0.5 mM EGTA, 1.0 mM GTP (guanosine triphosphate), and 15% glycerol and stored on ice. The tubulin was then incubated with a 10 μM solution of each test compound or control compound in a PIPES-based polymerization buffer containing 1 mM GTP at 37°C. Polymerization was monitored by the increase in fluorescence due to the incorporation of the fluorescent reporter into microtubules (MTs) as polymerization proceeded. Experiments were performed in duplicate, and results are expressed as the percentage of MT polymerization inhibition at the end of the experiment relative to the DMSO control.

[0162] result The results of this assay are shown in Table 3 below. [Table 3]

[0163] It has therefore been observed that the compounds of formula (I) of the present invention are capable of inhibiting tubulin polymerization. The compounds listed in Table 3 are suitable representatives of the compounds of formula (I).

[0164] Example 2-2: Cell cycle analysis: G2 / M arrest after 24 hours of treatment with compounds material and method Human colon cancer cell line HCT116 cells were cultured in medium at a cell density of 10 5Cells were seeded into 24-well plates at 100 cells / mL / well. The following day, the medium was removed and replaced with medium containing 100 nM of test compound. After 24 hours of treatment, the medium was removed, the cells were washed once with PBS 1X, and trypsinized with 0.05% trypsin-EDTA solution (Lifetech catalog number 25300-054). The cells were then resuspended in medium and transferred to a 96-well plate. The plate was centrifuged, and the cell pellet was washed twice in cold PBS. The cell pellet was then resuspended in propidium iodide staining solution containing 0.1% NP40, 0.1% sodium citrate, 50 μg / mL propidium iodide, and 0.2 mg / mL RNase A. Cells were immediately analyzed for DNA content using an Accuri 6 hemocytometer. Results are expressed as the percentage of viable cells accumulated in the G2 / M phase of the cell cycle.

[0165] result The results of this assay are shown in Table 4 below. [Table 4]

[0166] Microtubules play a key role in determining cell shape and polarity, facilitating cell movement and intracellular transport, and segregating chromosomes during mitosis. During mitosis, interphase microtubules disappear and are replaced by a new microtubule network that interacts with the mitotic spindle to distribute chromatids evenly to the two daughter cells. Microtubule disruption arrests the cell division cycle at the G2 / M checkpoint, preventing cell division and inducing apoptosis.

[0167] Thus, it has been observed that the compounds of formula (I) of the present invention can induce G2 / M mitotic arrest. The compounds listed in Table 4 are suitable representatives of the compounds of formula (I).

[0168] Example 2-3: Cell-based proliferation screening of compounds material and method A CellTiter-Blue cell-based viability / proliferation assay (Promega G8080) was performed on tumor cell lines. 4 Cells were seeded in 96-well plates at 50 μl per well. The following day, treatment was initiated by adding 1 / 10 serial dilutions of test compounds ranging from 0 to 10 μM. Cells were grown for 48 hours at 37°C and then incubated with 10 μl per well of Promega CellTiter-Blue reagent at 37°C for 4 hours. The amount of resorufin dye formed was quantified by fluorescence emission at 590 nm using a scanning multiwell spectrophotometer (OPTIMA, BMG labtech, France). Blank wells without cells served as background controls for the spectrophotometer. The positive control for the assay corresponded to the cell growth obtained without drug treatment (100% growth), i.e., without test compound. Each sample was performed in duplicate, and experiments were repeated at least twice. The results presented below represent the IC 50 (i.e., the concentration required to obtain 50% inhibition of growth in the absence of treatment), and "++++" indicates the IC 50 ≦100nM, "+++" is 100 <IC 50 ≦500nM, "++" indicates 500 <IC 50 ≤1000nM, and "+" indicates IC 50 Equivalent to >1000 nM; ND: not determined.

[0169] The cell lines tested were: HL60, MOLM14, NOMO1, THP1, HUT78, CCRF_CEM, KARPAS 299, REC1, NALM6, A549, H1299, HEP2, HGC27, HRT18, PANC_1, PLC PRF5, U118, U87_MG, Tov21G, 786-O, ACHN, PC3, LnCaP, DU145, MCF7, MDA-MB-468, SW872, SK-N-MC, A4573, U2OS, WEHI164, and MESSA.

[0170] result The results of this assay are shown in Tables 5 and 6 below. [Table 5] JPEG2026501703000085.jpg233143 [Table 6] JPEG2026501703000087.jpg251159JPEG2026501703000088.jpg241159JPEG2026501703000089.jpg246159

[0171] IC shown in Tables 5 and 6 above 50 is expressed as follows:++++:IC 50 ≦100nM, +++:100 <IC 50 ≦500nM, ++:500 <IC 50 ≦1000nM, +:IC 50 >1000nM, ND: Not measured.

[0172] Therefore, it was observed that the compounds of formula (I) of the present invention exhibit highly effective antiproliferative activity against the above cell lines. The compounds listed in Tables 5 and 6 are suitable representatives of the compounds of formula (I).

Claims

1. Formula (I) 【Chemistry 1】 (In the formula, R １ and R ２ are each independently hydrogen, C １ -C １０ Alkyl, cyano, CF ３ , hydroxy, C １ -C １０ selected from alkoxy and halogen; R ３ is hydrogen, C １ -C １０ Alkyl, C ３ -C １０ Cycloalkyl and C ２ -C １１ heterocycloalkyl; Said C １ -C １０ Alkyl is azido, cyano, -C(O)OR ６ , OR ７ , halogen, C ３ -C １０ Cycloalkyl, C ２ -C １１ optionally substituted with at least one group selected from heterocycloalkyl, aryl, and heteroaryl; Said C ３ -C １０ cycloalkyl, the C ２ -C １１ Heterocycloalkyl, said aryl or said heteroaryl is C １ -C １０ Alkyl, and OR ７ , hydroxy, C １ -C １０ Alkoxy, —C(O)OR ６ and C substituted with at least one halogen １ -C １０ may be optionally substituted with at least one group selected from alkyl; R ６ and R ７ are each independently hydrogen and C １ -C １０ alkyl; R ４ and R ５ are each independently hydrogen, hydroxy, C １ -C １０ Alkyl and C １ -C １０ alkoxy; B is aryl, 5-membered heteroaryl, or 6-membered heteroaryl; X is nitrogen or CR ８ and R ８ is hydrogen, C １ -C １０ Alkyl, cyano, CF ３ , C １ -C １０ selected from alkoxy and halogen; Y is nitrogen or CR ９ and R ９ is hydrogen, C １ -C １０ Alkyl, cyano, CF ３ , C １ -C １０ selected from alkoxy and halogen; V is NR １０ , C.R. １１ R １２ or oxygen, R １０ , R １１ and R １２ are each independently hydrogen and C １ -C １０ alkyl; and W is C=O or CR １３ R １４ and R １３ and R １４ are each independently hydrogen and C １ -C １０ or a pharmaceutically acceptable salt and / or solvate thereof.

2. The compound has the formula (II) 【Chemistry 2】 (In the formula, R １ , R ２ , R ３ 10. The compound of claim 1, wherein B and Y are each independently as defined in claim 1, or a pharmaceutically acceptable salt and / or solvate thereof.

3. 3. The compound of claim 1 or claim 2, wherein B is selected from phenyl, thiazole, oxazole, oxadiazole, isoxazole, thiadiazole, pyrazole, pyridine and pyrimidine, wherein said phenyl, said thiazole, said oxazole, said oxadiazole, said isoxazole, said thiadiazole, said pyrazole, said pyridine or said pyrimidine is optionally substituted with at least one methyl.

4. The compound according to any one of claims 1 to 3, wherein B is a 5-membered heteroaryl or a 6-membered heteroaryl.

5. The compound has the formula (III) 【Transformation 3】 (In the formula, R １ , R ２ , R ３ and Y are each independently as defined in claim 1, or a pharmaceutically acceptable salt and / or solvate thereof.

6. Y is CR ９ and R ９ is hydrogen, C １ -C １０ The compound according to any one of claims 1 to 5, wherein the alkyl is selected from alkyl and halogen.

7. R １ is C １ -C １０ alkyl, and / or R ２ The compound according to any one of claims 1 to 6, wherein is hydrogen.

8. R ３ is C １ -C １０ is an alkyl group, １ -C １０ Alkyl is OR ７ and R ７ is C １ -C １０ The compound according to any one of claims 1 to 7, which is alkyl.

9. The compound of claim 1 selected from: Table 1 and pharmaceutically acceptable salts and / or solvates thereof.

10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9 and at least one pharmaceutically acceptable carrier.

11. The pharmaceutical composition according to claim 10, comprising the compound according to any one of claims 1 to 9 as the sole pharmaceutically active ingredient.

12. The pharmaceutical composition of claim 10, wherein the pharmaceutical composition further comprises another active pharmaceutical ingredient.

13. A compound according to any one of claims 1 to 9 or a pharmaceutical composition according to any one of claims 10 to 12 for use as a medicament.

14. A compound according to any one of claims 1 to 9 or a pharmaceutical composition according to any one of claims 10 to 12 for use in the treatment of hematological and / or proliferative disorders, Preferably, the hematological disorder is selected from lymphoma, leukemia (such as acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL) or chronic myelogenous leukemia (CML)), multiple myeloma (MM), myelodysplastic syndrome (MDS) and myelodysplasia with myelofibrosis; and / or The proliferative disease is cancer, for example, head and neck cancer, melanoma, renal cancer, gastric cancer, liver cancer, colorectal cancer, pancreatic cancer, laryngeal cancer, lung cancer, neuronal carcinoma, glioblastoma multiforme, osteosarcoma, fibrosarcoma, ovarian sarcoma, liposarcoma, Ewing's sarcoma, breast cancer, ovarian cancer, or prostate cancer; Compound or pharmaceutical composition.

15. 15. The compound or pharmaceutical composition for use according to claim 14, wherein said compound or said composition is administered in combination with at least another active pharmaceutical ingredient.

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