Compounds and compositions for inhibiting EZH2

Abstract

The present invention relates to compounds and compositions for inhibiting EZH2. The present invention relates to aza-quinoline compounds of formula (I), # imgabs0, pharmaceutical compositions comprising such compounds; and the use of such compounds for the treatment of diseases or conditions mediated by Zeste homolog enhancer 2 (EZH2), Polycomb Suppression Complex 2 (PRC2), or a combination thereof.

Description

[0001] This application is a divisional application of Chinese patent application No. 2021800059037, with an application date of August 10, 2021, and the invention name is “Compounds and Compositions for Inhibiting EZH2”. Technical Field

[0002] The present invention relates to compounds, compositions and methods for inhibiting Enhancer of Zeste Homolog (EZH2), Polycomb Repressive Complex 2 (PRC2), or a combination thereof. Background Art

[0003] Site-specific lysine methylation on histones is one of the important epigenetic mechanisms that control and mediate many fundamental biological processes. The polycomb repressive complex 2 (PRC2) represses gene transcription by methylating histone H3 lysine 27 (H3K27) in the genomic regions of target genes. PRC2 requires a minimum of three core subunits, including SUZ12 (suppressor of zeste12), EED (embryonic ectoderm development), and the catalytic subunits EZH1 or EZH2 (Enhancer of Zeste homolog 1 / 2). EZH1 and EZH2 are homologous proteins that can be integrated into PRC2 separately despite having different tissue and temporal distributions. In PRC2, EZH2 can directly bind to the cofactor S-adenosylmethionine (SAM) and transfer the methyl group to the histone H3K27 site to form monomethylated lysine, dimethylated lysine and trimethylated lysine (H3K27me1, H3K27me2 and H3K27me3), thereby inhibiting gene transcription. PRC2-EZH2 has higher activity than PRC2-EZH1, mainly catalyzing the generation of H3K27me1 and some H3K27me2. EED can bind to H3K27me2 / 3 and allosterically activate the enzymatic activity of PRC2 to promote the spread of inhibitory marks.

[0004] EZH2 plays an important role in development and adult tissue homeostasis and is closely associated with a variety of diseases. EZH2, SUZ12, and EED are overexpressed in many cancers, including but not limited to breast cancer, prostate cancer, and hepatocellular carcinoma. Activating mutations of EZH2 have been found in patients with DLBCL (diffuse large B-cell lymphoma), FL (follicular lymphoma), melanoma, and parathyroid carcinoma. In DLBCL, compounds inhibited the activity of PRC2 methyltransferase by competing with the cofactor SAM or directly binding to EED, reversing the high H3K27me3 state, reactivating the expression of target genes, and inhibiting tumor growth / proliferation. In addition, EZH2 inhibitors can release the suppression of Th1 chemokines in tumor cells and enhance T cell infiltration in ovarian and colorectal cancers.

[0005] Therefore, EZH2 provides a pharmacological target for DLBCL and other cancers. In addition, EZH2 also plays an important role in autoimmune diseases and other disorders. In conclusion, there is a great need for small molecules that inhibit EZH2 activity. Summary of the invention

[0006] The present invention provides compounds that inhibit EZH2; and compositions and methods for treating or preventing diseases or conditions mediated by EZH2, PRC2, or a combination thereof.

[0007] In one aspect, the present invention provides a compound having formula (I) or a stereoisomer, enantiomer, mixture of enantiomers or a pharmaceutically acceptable salt thereof:

[0008]

[0009] or a stereoisomer, enantiomer, mixture of enantiomers or a pharmaceutically acceptable salt thereof;

[0010] in:

[0011] Y is N or CR a ;

[0012] R a , R 1 , R 3 , R 5 , R 6 , R 7 , R 8 and R 9 are independently H, halogen or -C1-C4 alkyl;

[0013] R 2 is -CN, -C1-C6 alkyl, -hydroxyC1-C4 alkylene, -C1-C4 alkoxy, -C2-C4 alkoxy substituted with 1-2 hydroxy groups;

[0014] -(CR 13 R 14 ) n C(=O)NR 11 R 12 、-(CR 13 R 14 ) n C(=O)NR 11 R 15 ;

[0015] -(CR 13 R 14 ) n C(=O)R 15 ;

[0016] -(CR2)n NR 11 C(=O)R 15 , -(CR2) n NR 11 (CR2)2C(=O)R 15 ;

[0017] -(CR2) n NR-C(=O)OR 11 , -(CR2) n NR-C(=O)O-(CR2)-R 15 ;

[0018] -NR-C(=O)(CR2)2C(=O)R 15 、-NR-C(=O)R 11 ;

[0019] -(CR2) n NR 11 R 12 , -(CR2) n NR 11 (CR2) n R 15 ;

[0020] -(CR2) n OR 15 , -(CR2) n R 15 ;

[0021] or a 5- to 6-membered heteroaryl group having 1 to 4 heteroatoms independently selected from O, S and N;

[0022] R 4a , R 4b , R 4c and R 4d are independently H or -C1-C4 alkyl;

[0023] R 10 is H, halogen, -C1-C4 alkyl, -C1-C4 alkoxy, -C1-C4 haloalkoxy or -NH(C1-C4 alkyl);

[0024] R 11 is H, -C1-C4 alkyl, -hydroxyC1-C4 alkylene, -cyanoC1-C4 alkylene, or -C1-C4 alkyl substituted by -C1-C4 alkoxy;

[0025] R 12 is H or -C1-C4 alkyl;

[0026] R 13is H, halogen, -CN, -OH, -C1-C4 alkyl or -hydroxyC1-C4 alkylene;

[0027] R 14 is H, halogen or -C1-C4 alkyl;

[0028] R 15 yes -C3-C6 cycloalkyl or 4- to 6-membered heterocycloalkyl having 1-2 heteroatoms independently selected from O, S, S(=O)2 and N; wherein R 15 The -C3-C6 cycloalkyl or 4- to 6-membered heterocycloalkyl is unsubstituted or substituted with 1-2 substituents selected from -OH, -C1-C4 alkyl, -hydroxyC1-C4 alkylene, -C1-C4 alkoxy, -SO2(C1-C4 alkyl) and -N(C1-C4 alkyl)2;

[0029] R 16 , if present, is a substituent selected from halogen, -CN, -OH, -C1-C4 alkyl and -hydroxyC1-C4 alkylene;

[0030] Each R is independently H or -C1-C4 alkyl;

[0031] m is 0, 1, or 2; and

[0032] Each n is independently selected from 0, 1 and 2.

[0033] In another aspect, the present invention provides a pharmaceutical composition comprising a compound having formula (I) or its subformula or a stereoisomer, enantiomer, enantiomeric mixture or pharmaceutically acceptable salt thereof; and one or more pharmaceutically acceptable carriers.

[0034] In yet another aspect, the present invention provides a combination, in particular a pharmaceutical combination, comprising a compound having formula (I) or its subformulae or a stereoisomer, enantiomer, enantiomeric mixture or pharmaceutically acceptable salt thereof; and one or more therapeutically active agents.

[0035] The compounds of the invention, alone or in combination with one or more therapeutically active agents, are useful for treating or preventing a disease or condition mediated by EZH2, PRC2, or a combination thereof. DETAILED DESCRIPTION

[0036] The present invention provides compositions and methods for treating or preventing diseases or conditions mediated by EZH2, PRC2, or a combination thereof.

[0037] definition

[0038] For the purpose of interpreting this specification, the following definitions shall apply and, where appropriate, terms used in the singular shall also include the plural and vice versa.

[0039] As used herein, the term "-C 1- C6 alkyl" or "-C 1-6 "Alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, having no unsaturation, having from one to six carbon atoms, and attached to the rest of the molecule by a single bond. 1- C4 alkyl" or "-C 1-4 "Alkyl" is also interpreted accordingly. -C 1- Examples of C6 alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, and 1,1-dimethylethyl (tert-butyl).

[0040] As used herein, the term "-C 1- "C4 alkoxy" refers to a group having the formula -OR a A group in which R a is C as generally defined above 1-4 Alkyl group. 1-6 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentyloxy, and hexyloxy.

[0041] As used herein, the term "cycloalkyl" refers to a saturated, monocyclic, fused bicyclic, fused tricyclic or bridged polycyclic ring system. Non-limiting examples of fused bicyclic or bridged polycyclic ring systems include bicyclo[1.1.1]pentane, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane, bicyclo[3.2.1]octane, bicyclo[2.2.2]octane and adamantyl. As used herein, the term "C3-C6 cycloalkyl" refers to a saturated monocyclic group having at least 3 and at most 6 carbon atoms. Non-limiting examples of the "C3-C6 cycloalkyl" group include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups.

[0042] "Halo" or "halogen" refers to bromo, chloro, fluoro or iodo.

[0043] As used herein, the term "-hydroxy C 1-4 "Alkylene" refers to a -C 1-4 Alkyl groups, where C 1-4 Any hydrogen atom of the alkyl group is replaced by OH. 1-4 Examples of alkyl groups include, but are not limited to, 1-ethanol, 2-methylpropan-1-ol, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, and 3-hydroxypropyl.

[0044] As used herein, the term "-cyano C 1-4 "Alkylene" refers to a -C 1-4 Alkyl groups, where -C 1-4 Any hydrogen atom of the alkyl group is replaced by CN.

[0045] As used herein, the term "haloalkoxy" refers to a haloalkyl group connected to oxygen, and can also be represented as -O-R', where R' represents a haloalkyl group. "C1-C4 haloalkoxy" is a haloalkoxy group including C1, C2, C3 and C4. Examples of haloalkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, trichloromethoxy, pentafluoroethoxy, pentachloroethoxy, 2,2,2-trifluoroethoxy, heptafluoropropoxy, heptachloropropoxy, difluorochloromethoxy, dichlorofluoromethoxy, difluoroethoxy, trifluoroethoxy, difluoropropoxy, dichloroethoxy and dichloropropoxy.

[0046] As used herein, the term "heterocyclyl" or "heterocyclic" refers to a stable 4-7 membered non-aromatic monocyclic group comprising 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur. The heterocyclic group may be connected by a carbon atom or a heteroatom. The term "5-6 membered heterocyclyl" is also interpreted accordingly. Examples of heterocyclyls include, but are not limited to, azetidinyl, oxetanyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, piperazinyl, tetrahydropyranyl or morpholinyl or perhydroazepine.

[0047] As used herein, the term "heterocyclyl C 0-6 "Alkyl" refers to a heterocyclic ring as defined above, which is separated by a single bond or by a C 1-6 The alkyl group is attached to the rest of the molecule.

[0048] As used herein, the term "heteroaryl" refers to a group of 5-9 membered aromatic monocyclic or condensed rings including 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur. The heteroaryl group can be connected by carbon atoms or heteroatoms. The term "5-6 membered heteroaryl" is also explained accordingly. Examples of 5-6 membered monocyclic heteroaryls include, but are not limited to, furanyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, piperazinyl, pyridazinyl, pyrimidinyl or pyridyl. Examples of fused heteroaryl groups include, but are not limited to, 9-membered heteroaryl groups such as benzofuranyl; 2,3-dihydrobenzofuranyl, 1,3-dihydroisobenzofuranyl; benzo[d][1,3]dioxol-5-yl; imidazo[1,2-a]pyridinyl; pyrazolo[1,5-a]pyridinyl; 1H-indazolyl and 1H-benzo[d]-imidazolyl.

[0049] "EZH2" refers to Enhancer of Zeste homolog 2.

[0050] "PRC2" refers to polycomb repressive complex 2.

[0051] The term "PRC2-mediated disease or condition" refers to a disease or condition that is directly or indirectly regulated by PRC2, including but not limited to any disease or condition that is directly or indirectly regulated by EZH2.

[0052] The term "disease or condition mediated by Enhancer of Zeste homolog (EZH2), Polycomb repressive complex 2 (PRC2), or a combination of Enhancer of Zeste homolog 2 (EZH2) and Polycomb repressive complex 2 (PRC2)" or the term "disease or condition mediated by EZH2, PRC2, or EZH2 / PRC2" refers to a disease or condition that is directly or indirectly regulated by EZH2, PRC2, or EZH2 and PRC2.

[0053] As used herein, the term "subject" refers to mammals, primates (e.g., humans (male or female)), dogs, rabbits, guinea pigs, pigs, rats, and mice. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.

[0054] As used herein, the term "inhibit" refers to the reduction or suppression of a given condition, symptom or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.

[0055] As used herein, the term "treatment" or "treating" of any disease or disorder refers to alleviating or ameliorating the disease or disorder (i.e., slowing or arresting the progression of the disease or at least one clinical symptom thereof); or alleviating or ameliorating at least one physical parameter or biomarker associated with the disease or disorder, including physical parameters or biomarkers that may not be discernible by the patient.

[0056] As used herein, the term "prevention" of any disease or disorder refers to prophylactic treatment of the disease or disorder; or delaying the onset or progression of the disease or disorder.

[0057] As used herein, a subject is "in need of" a treatment if the subject would benefit biologically, medically, or in quality of life from the treatment.

[0058] As used herein, the term "therapeutically effective amount" of a compound of the present invention refers to an amount of the compound of the present invention that will induce a biological or medical response in a subject (e.g., reduction or inhibition of enzyme or protein activity, or improvement of symptoms, alleviation of symptoms, slowing or delaying disease progression, or prevention of disease, etc.).

[0059] As used herein, the term "pharmaceutical composition" refers to a compound of the present invention, or a pharmaceutically acceptable salt thereof, suitable for oral or enteral administration, and at least one pharmaceutically acceptable carrier.

[0060] As used herein, the term "pharmaceutically acceptable carrier" refers to substances that can be used to prepare or use pharmaceutical compositions, including, for example, suitable diluents, solvents, dispersion media, surfactants, antioxidants, preservatives, isotonic agents, buffers, emulsifiers, absorption delaying agents, salts, drug stabilizers, binders, excipients, disintegrants, lubricants, wetting agents, sweeteners, flavorings, dyes, and combinations thereof, as known to those skilled in the art (see, for example, Remington The Science and Practice of Pharmacy, 22nd edition, Pharmaceutical Press 2013, pp. 1049-1070).

[0061] As used herein, the terms "a", "an", "the" and similar terms used in the context of the invention (especially in the context of the claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

[0062] Description of the preferred embodiment

[0063] The present invention provides compounds that inhibit EZH2; and also provides compositions and methods for treating or preventing diseases mediated by EZH2, PRC2 or a combination thereof.

[0064] Various enumerated embodiments of the present invention are described herein. The features specified in each embodiment can be combined with other specified features to provide other embodiments of the present invention.

[0065] Embodiment 1. A compound having formula (I) or a stereoisomer, enantiomer, mixture of enantiomers or pharmaceutically acceptable salt thereof; as described above.

[0066] Embodiment 2. A compound according to embodiment 1, wherein the compound has formula (I-1), or a stereoisomer, enantiomer, enantiomeric mixture or pharmaceutically acceptable salt thereof;

[0067]

[0068] Where R 1 , R 2 , R 3 , R 4a , R 4b , R 4c , R4d R 5 , R 6 , R 7 , R 8 , R 9 and R 10 As defined in formula (1).

[0069] Embodiment 3. A compound according to embodiment 1, wherein the compound has formula (I-2), or a stereoisomer, enantiomer, enantiomeric mixture or pharmaceutically acceptable salt thereof;

[0070]

[0071] Among them, Y, R 2 and R 10 As defined in formula (1).

[0072] Embodiment 4. A compound according to embodiment 1, wherein the compound has formula (I-3), or a stereoisomer, enantiomer, enantiomeric mixture or pharmaceutically acceptable salt thereof;

[0073]

[0074] Among them, Y, R 2 and R 10 As defined in formula (1).

[0075] Embodiment 5. A compound according to embodiment 1, wherein the compound has formula (I-4), or a stereoisomer, enantiomer, enantiomeric mixture or pharmaceutically acceptable salt thereof;

[0076]

[0077] Where Y and R 2 As defined in formula (1).

[0078] Embodiment 6. The compound according to embodiment 1, wherein the compound has formula (I-5), or a stereoisomer, enantiomer, enantiomeric mixture or pharmaceutically acceptable salt thereof;

[0079]

[0080] Where Y and R 2 As defined in formula (1).

[0081] Embodiment 7. A compound according to embodiment 1, wherein the compound has formula (I-6), or a stereoisomer, enantiomer, enantiomeric mixture or pharmaceutically acceptable salt thereof;

[0082]

[0083] Where R 2 As defined in formula (1).

[0084] Embodiment 8. A compound according to embodiment 1, wherein the compound has formula (I-7), or a stereoisomer, enantiomer, enantiomeric mixture or pharmaceutically acceptable salt thereof;

[0085]

[0086] Where R 2 As defined in formula (1).

[0087] Embodiment 9. A compound according to any one of Embodiments 1-8, or a stereoisomer, enantiomer, enantiomeric mixture, or pharmaceutically acceptable salt thereof; wherein R 2 is -CN, -NH2, -C(=O)NH2, triazolyl,

[0088]

[0089]

[0090] Embodiment 10. A compound according to any one of Embodiments 1-8, or a stereoisomer, enantiomer, enantiomeric mixture, or pharmaceutically acceptable salt thereof; wherein R 2 Yes - (CH2) 1-2 C(=O)NR 11 R 15 or -(CR 13 R 14 )-C(=O)NR 11 R 15 .

[0091] Embodiment 11. The compound according to embodiment 10 or its stereoisomer, enantiomer, enantiomeric mixture or pharmaceutically acceptable salt; wherein R 15 Refers to a 4- to 6-membered heterocycloalkyl group having 1-2 heteroatoms independently selected from O, S and N; wherein the 4- to 6-membered heterocycloalkyl group is unsubstituted or substituted with 1-2 substituents selected from -OH, -C1-C4 alkyl, -hydroxyC1-C4 alkylene, -C1-C4 alkoxy, -SO2(C1-C4 alkyl) and -N(C1-C4 alkyl)2;

[0092] Embodiment 12. A compound according to Embodiment 10 or 11, or a stereoisomer, enantiomer, enantiomeric mixture, or pharmaceutically acceptable salt thereof; wherein R15 yes In certain embodiments, R 15 yes

[0093] Embodiment 13. A compound according to embodiment 12, wherein m is 1; and R 16 It is a -C1-C4 alkyl group.

[0094] Embodiment 14. A compound according to any one of Embodiments 1-13, or a stereoisomer, enantiomer, enantiomeric mixture, or pharmaceutically acceptable salt thereof; wherein R 2 yes

[0095]

[0096] Embodiment 15. The compound of embodiment 1, wherein the compound has formula (II), or a stereoisomer, enantiomer, mixture of enantiomers, or a pharmaceutically acceptable salt thereof;

[0097]

[0098] in:

[0099] Y is CH or N;

[0100] R 1 , R 3 , R 4a , R 4b , R 4c , R 4d and R 11 are independently H or C1-C4 alkyl;

[0101] R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are independently H, halogen or C1-C4 alkyl;

[0102] R 13 is H, halogen, -CN, -OH, -C1-C4 alkyl or -hydroxyC1-C4 alkylene;

[0103] R 14 is H, halogen or -C1-C4 alkyl;

[0104] R 15 is a 4- to 6-membered heterocycloalkyl group having 1-2 heteroatoms independently selected from O, S and N; and wherein R 15It is unsubstituted or substituted with 1-2 substituents selected from -OH, -C1-C4 alkyl, -hydroxyC1-C4 alkylene, -C1-C4 alkoxy, -SO2(C1-C4 alkyl) and -N(C1-C4 alkyl)2.

[0105] Embodiment 16. The compound according to embodiment 15, wherein the compound has formula (II-1), or a stereoisomer, enantiomer, enantiomeric mixture or pharmaceutically acceptable salt thereof;

[0106]

[0107] Embodiment 17. The compound according to embodiment 15, wherein the compound has formula (II-2), or a stereoisomer, enantiomer, enantiomeric mixture or pharmaceutically acceptable salt thereof;

[0108]

[0109] Embodiment 18. The compound according to embodiment 15, wherein the compound has formula (II-3), or a stereoisomer, enantiomer, enantiomeric mixture or pharmaceutically acceptable salt thereof;

[0110]

[0111] Embodiment 19. A compound according to any one of Embodiments 15-18, or a stereoisomer, enantiomer, enantiomeric mixture, or pharmaceutically acceptable salt thereof; wherein R 15 is azetidinyl or oxetanyl, wherein each azetidinyl or oxetanyl is unsubstituted or substituted with -OH, -C1-C4 alkyl or -hydroxyC1-C4 alkylene.

[0112] Embodiment 20. The compound according to embodiment 19 or a stereoisomer, enantiomer, enantiomeric mixture or pharmaceutically acceptable salt thereof; wherein R 15 yes In certain embodiments, R 15 yes

[0113] Embodiment 21. A compound according to embodiment 20, wherein m is 1; and R 16 It is a -C1-C4 alkyl group.

[0114] Embodiment 22. A compound according to embodiment 1, wherein the compound is selected from:

[0115] 2-(2-(((4-((8-chloro-7-methylquinolin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-methyl-N-(oxetan-3-yl)acetamide;

[0116] 2-(2-(((4-((8-chloro-7-methylquinolin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-2,2-difluoro-N-(oxetan-3-yl)acetamide;

[0117] 2-(2-(((4-((8-chloro-7-methylquinolin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-2-hydroxy-N-(oxetan-3-yl)propanamide;

[0118] 2-(2-(((4-((8-chloro-7-methylquinolin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-2-cyano-N-(oxetan-3-yl)acetamide;

[0119] 2-(2-(((4-((8-chloro-7-methylquinolin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-3-hydroxy-N-(oxetan-3-yl)propanamide;

[0120] 2-(2-(((4-((8-chloro-7-methylquinolin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-2-hydroxy-N-(oxetan-3-yl)acetamide;

[0121] 2-(2-(((4-((8-chloro-7-methylquinolin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-(oxetan-3-yl)propanamide; and

[0122] 2-(6-(((4-((8-chloro-7-methylquinolin-2-yl)amino)cyclohexyl)methyl)amino)pyridin-3-yl)-N-(oxetan-3-yl)acetamide;

[0123] or a stereoisomer, an enantiomer, a mixture of enantiomers or a pharmaceutically acceptable salt thereof.

[0124] Embodiment 23. A compound according to embodiment 1, wherein the compound is selected from:

[0125] 2-(2-((((1r,4r)-4-((8-chloro-7-methylquinolin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-methyl-N-(oxetan-3-yl)acetamide;

[0126] 2-(2-((((1r,4r)-4-((8-chloro-7-methylquinolin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-2,2-difluoro-N-(oxetan-3-yl)acetamide;

[0127] 2-(2-((((1r,4r)-4-((8-chloro-7-methylquinolin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-2-hydroxy-N-(oxetan-3-yl)propanamide;

[0128] 2-(2-((((1r,4r)-4-((8-chloro-7-methylquinolin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-2-cyano-N-(oxetan-3-yl)acetamide;

[0129] 2-(2-((((1r,4r)-4-((8-chloro-7-methylquinolin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-3-hydroxy-N-(oxetan-3-yl)propanamide;

[0130] (S)-2-(2-((((1r,4S)-4-((8-chloro-7-methylquinolin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-3-hydroxy-N-(oxetan-3-yl)propanamide;

[0131] (R)-2-(2-((((1r,4R)-4-((8-chloro-7-methylquinolin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-3-hydroxy-N-(oxetan-3-yl)propanamide;

[0132] 2-(2-((((1r,4r)-4-((8-chloro-7-methylquinolin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-2-hydroxy-N-(oxetan-3-yl)acetamide;

[0133] (S)-2-(2-((((1r,4S)-4-((8-chloro-7-methylquinolin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-2-hydroxy-N-(oxetan-3-yl)acetamide;

[0134] (R)-2-(2-((((1r,4R)-4-((8-chloro-7-methylquinolin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-2-hydroxy-N-(oxetan-3-yl)acetamide;

[0135] 2-(2-((((1r,4r)-4-((8-chloro-7-methylquinolin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-(oxetan-3-yl)propanamide;

[0136] (S)-2-(2-((((1r,4S)-4-((8-chloro-7-methylquinolin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-(oxetan-3-yl)propanamide;

[0137] (R)-2-(2-((((1r,4R)-4-((8-chloro-7-methylquinolin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-(oxetan-3-yl)propanamide; and

[0138] 2-(6-((((1r,4r)-4-((8-chloro-7-methylquinolin-2-yl)amino)cyclohexyl)methyl)amino)pyridin-3-yl)-N-(oxetan-3-yl)acetamide;

[0139] or a mixture of enantiomers or a pharmaceutically acceptable salt thereof.

[0140] Embodiment 24. A compound according to embodiment 1, wherein the compound is 2-(2-(((4-((8-chloro-7-methylquinolin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-(oxetan-3-yl)acetamide; or a stereoisomer, enantiomer, mixture of enantiomers, or a pharmaceutically acceptable salt thereof.

[0141] Embodiment 25. A compound according to embodiment 24, wherein the compound is 2-(2-((((1R,4R)-4-((8-chloro-7-methylquinolin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-(oxetan-3-yl)acetamide; or an enantiomeric mixture or a pharmaceutically acceptable salt thereof.

[0142] Embodiment 26. A compound according to embodiment 1, wherein the compound is 2-(2-(((4-((8-chloro-7-methylquinolin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-(oxetan-3-yl)propanamide; or a stereoisomer, enantiomer, mixture of enantiomers, or a pharmaceutically acceptable salt thereof.

[0143] Embodiment 27. A compound according to embodiment 26, wherein the compound is (S)-2-(2-((((1r,4S)-4-((8-chloro-7-methylquinolin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-(oxetan-3-yl)propanamide or (R)-2-(2-((((1r,4R)-4-((8-chloro-7-methylquinolin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-(oxetan-3-yl)propanamide; or an enantiomeric mixture or a pharmaceutically acceptable salt thereof.

[0144] Embodiment 28. A compound according to embodiment 1, wherein the compound is 2-(6-(((4-((8-chloro-7-methylquinolin-2-yl)amino)cyclohexyl)methyl)amino)pyridin-3-yl)-N-(oxetan-3-yl)acetamide; or a stereoisomer, enantiomer, mixture of enantiomers, or a pharmaceutically acceptable salt thereof.

[0145] Embodiment 29. A compound according to embodiment 25, wherein the compound is 2-(6-((((1r,4r)-4-((8-chloro-7-methylquinolin-2-yl)amino)cyclohexyl)methyl)amino)pyridin-3-yl)-N-(oxetane-3-yl)acetamide; or an enantiomeric mixture or a pharmaceutically acceptable salt thereof.

[0146] Embodiment 30. A pharmaceutical composition comprising a compound according to any one of embodiments 1-29, and one or more pharmaceutically acceptable carriers.

[0147] Embodiment 31. A combination comprising a compound according to any one of embodiments 1-29, and one or more additional therapeutically active agents.

[0148] Embodiment 32. The combination according to embodiment 31, wherein the one or more other therapeutically active agents are anti-cancer agents, analgesics, anti-inflammatory agents, immunomodulators, or combinations thereof.

[0149] Embodiment 33. A compound according to any one of embodiments 1-29, optionally in combination with a second therapeutic agent, for use in treating a disease or condition mediated by EZH2, PRC2 or EZH2 / PRC2.

[0150] Embodiment 34. The compound of embodiment 33, wherein the second therapeutic agent is an anticancer agent, an analgesic, an anti-inflammatory agent, or a combination thereof.

[0151] Embodiment 35. Use of a compound according to any one of Embodiments 1-29, optionally in combination with a second therapeutic agent, in the preparation of a medicament for treating a disease or condition mediated by EZH2, PRC2 or EZH2 / PRC2.

[0152] Embodiment 36. A method for treating a disease or condition mediated by EZH2, PRC2 or EZH2 / PRC2, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of embodiments 1-29, optionally in combination with a second therapeutic agent; thereby treating the above-mentioned disease or condition mediated by EZH2, PRC2 or EZH2 / PRC2.

[0153] Embodiment 37. A method for treating a disease or condition that may benefit or be treated by inhibiting EZH2, PRC2 or EZH2 / PRC2, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of embodiments 1-29, optionally in combination with a second therapeutic agent; thereby treating the above-mentioned disease or condition that may benefit or be treated by inhibiting EZH2, PRC2 or EZH2 / PRC2.

[0154] Embodiment 38. The use of a compound according to embodiment 35, or the method according to embodiment 36 or 37, wherein the disease or condition mediated by EZH2, PRC2 or EZH2 / PRC2, or the disease or condition that may benefit or be treated by inhibiting EZH2, PRC2 or EZH2 / PRC2 is diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, leukemia, multiple myeloma, gastric cancer, malignant rhabdoid tumor, hepatocellular carcinoma, prostate cancer, breast cancer, bile duct and gallbladder cancer, bladder cancer, neuroblastoma, glioma, glioblastoma and astrocytoma, cervical cancer, colorectal cancer, melanoma, endometrial cancer, esophageal cancer, head and neck cancer, lung cancer, nasopharyngeal cancer, ovarian cancer, pancreatic cancer, renal cell carcinoma, rectal cancer, thyroid cancer, parathyroid tumors, uterine tumors, rhabdomyosarcoma, Kaposi's sarcoma, synovial sarcoma, osteosarcoma and Ewing's sarcoma.

[0155] Embodiment 39. The use of a compound according to embodiment 35, or the method according to embodiment 36 or 37, wherein the disease or condition mediated by EZH2, PRC2 or EZH2 / PRC2, or the disease or condition that may benefit or be treated by inhibiting EZH2, PRC2 or EZH2 / PRC2 is diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, leukemia, multiple myeloma, gastric cancer, malignant rhabdoid tumor and hepatocellular carcinoma.

[0156] Embodiment 40. A method for inhibiting EZH2, PRC2 or EZH2 / PRC2, the method comprising administering a compound as described in any one of embodiments 1-29; thereby inhibiting EZH2, PRC2 or EZH2 / PRC2.

[0157] Unless otherwise indicated, the term "compounds of the present invention" refers to compounds of formula (I), compounds having subformulas thereof and exemplary compounds, and salts thereof, as well as all stereoisomers (including diastereomers and enantiomers), rotational isomers, tautomers and isotopically labeled compounds (including deuterium substitutions) and inherently formed moieties."Compounds of the present invention" further include N-oxide derivatives of such compounds.

[0158] Depending on the choice of starting materials and procedures, the compound can exist in the form of possible stereoisomers or as mixtures thereof, for example as pure optical isomers or as mixtures of stereoisomers, such as racemates and diastereomeric mixtures, depending on the number of asymmetric carbon atoms. The present invention is intended to include all such possible stereoisomers, including racemic mixtures, diastereomeric mixtures and optically pure forms. Optically active (R)- and (S)-stereoisomers can be prepared by chiral synthesis or using chiral reagents, or resolved using conventional techniques. If possible, substituents on atoms with unsaturated double bonds can exist in cis-(Z)- or trans-(E)-form. If the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituent can have a cis- or trans-configuration.

[0159] Any asymmetric atom (e.g., carbon, etc.) of one or more compounds of the invention may exist in a racemic or enantiomerically enriched form, e.g., (R)-, (S)-, or (R,S)-configuration. In some embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess of the (R)- or (S)-configuration.

[0160] Thus, as used herein, the compounds of the invention can exist in the form of one of the possible stereoisomers, rotamers, atropisomers, tautomers or mixtures thereof, for example, as substantially pure geometric (cis or trans) stereoisomers, diastereomers, optical isomers (enantiomers), racemates or mixtures thereof.

[0161] Any resulting mixtures of stereoisomers can be separated on the basis of the physicochemical differences of the components, into the pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and / or fractional crystallization.

[0162] The racemate of any compound or intermediate obtained by the present invention can be split into optical antipodes by known methods, for example, by separating its diastereoisomeric salts, obtaining optically active acids or bases, and releasing optically active acidic or basic compounds. In particular, the compound of the present invention can be split into their optical antipodes using basic groups, for example, the fractional crystallization of the salt formed by optically active acids can be used, and the optically active acid can be tartaric acid, dibenzoyltartaric acid, diacetyltartaric acid, di-O,O'-p-toluoyltartaric acid, mandelic acid, malic acid or camphor-10-sulfonic acid. The racemic compound of the present invention or racemic intermediate can also be split by chiral chromatography (for example, using high performance liquid chromatography (HPLC) including a chiral adsorbent).

[0163] Any chemical formula described herein represents an unlabeled form of a compound as well as an isotopically labeled form. An isotopically labeled compound has the structure of the chemical formula described herein except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Isotopes that can be incorporated into the compounds of the invention include isotopes of hydrogen.

[0164] In addition, the incorporation of certain isotopes, especially deuterium (i.e. 2 H or D) can provide certain therapeutic advantages by improving metabolic stability, such as increasing half-life in vivo or reducing dosage requirements or improving therapeutic index and tolerance. It should be understood that deuterium in this context is considered to be a substituent of a compound of formula (I) or its subformula. The concentration of deuterium can be defined by an isotopic enrichment factor. As described in the present invention, the term "isotopic enrichment factor" refers to the ratio between the isotopic abundance and the natural abundance of a specified isotope. If a substituent in a compound of the invention is deuterium, such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation on each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). It should be understood that the term "isotopic enrichment factor" can be applied to any isotope in the same manner as described for deuterium.

[0165] Examples of other isotopes that may be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, respectively 3 H. 11 C. 13 C. 14 C. 15 N. 18 F. 31 P. 32 P. 35 S. 36 Cl, 123 I. 124 I. 125 I. Thus, it should be understood that the present invention includes compounds incorporating any one or more of the above isotopes, including radioactive isotopes, such as 3 H and 14 C, or also including the incorporation of non-radioactive isotopes 2 H and 13 C. Such isotope-labeled compounds can be used for metabolic studies (using 14 C) reaction kinetics studies (e.g. 2 H or 3 H), detection or imaging techniques (such as positron emission tomography (PET) or single photon emission computed tomography (SPECT) including drug or substrate tissue distribution determination), or radiotherapy for patients. In particular, PET or SPECT studies are useful for 18 F or labeled compounds are in great demand. Isotope-labeled compounds of formula (I) or its subformulae can generally be prepared by those skilled in the art by conventional techniques known to those skilled in the art or by methods analogous to those described in the examples, using appropriate isotope-labeled reagents instead of unlabeled reagents.

[0166] The compounds of the present invention are obtained in free form or in the form of their salts. As described herein, the term "salt" refers to an acid addition salt or a base addition salt of the compounds of the present invention. "Salt" particularly includes "pharmaceutically acceptable salts". The term "pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness and properties of the compounds of the present invention and does not generally refer to a salt that is biologically or otherwise undesirable. In many cases, the compounds of the present invention are capable of forming acid salts and / or base salts due to the presence of amino and / or carboxyl groups or groups similar thereto.

[0167] Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids that can form the salts include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. Organic acids that can form the salts include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, etc.

[0168] Pharmaceutically acceptable base addition salts can be formed with inorganic bases and organic bases. Inorganic bases from which the salts can be formed include, for example, ammonium salts and metals from columns I to XII of the periodic table. In certain embodiments, the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; preferred salts include ammonium salts, potassium salts, sodium salts, calcium salts, and magnesium salts. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines; substituted amines (including naturally occurring substituted amines); cyclic amines; basic ion exchange resins, and the like. Certain organic amines include isopropylamine, benzathine, choline salts, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

[0169] In another aspect, the present invention provides compounds of the invention in the form of acetate, ascorbate, adipate, aspartate, benzoate, benzenesulfonate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camphorsulfonate, decanoate, chloride / hydrochloride, chlorophylline, citrate, edisylate, fumarate, glucuronate, gluconate, glucuronate, glutamate, glutarate, glycolate, hippurate, hydroiodide / iodide, isethionate, lactate, The invention can be in the form of a bisphosphonate, a bisphosphonate, a bisphosphonate, a bisphosphonate, a bisphosphonate, a bisphosphonate, a bisphosphonate, a bisphosphonate, a bisphosphonate, a bisphosphonate, a bisphosphonate, a bisphosphonate, a bisphosphonate, a bisphosphonate, a bisphosphonate, a bisphosphonate, a bisphosphonate, a bisphosphonate, a bisphosphonate, a bisphosphonate, a bisphosphonate, a bisphosphonate, a bisphosphonate, a bisphosphonate, a bisphosphonate, a bisphosphonate, a bisphosphonate, a bisphosphonate, a bisphosphonate, a bisphosphonate, a bisphosphonate, a bisphosphonate, a bisphosphonate, a bisphosphonate, a bisphosphonate, a bisphosphonate, a bisphosphonate

[0170] Pharmacology and efficacy

[0171] In one aspect, the present invention provides a compound or pharmaceutically acceptable salt of formula (I) or its subformulae that is effective for treatment; in particular, for treating or preventing a disease or condition mediated by EZH2, PRC2 or a combination thereof.

[0172] In another aspect, the present invention provides a compound or pharmaceutically acceptable salt of formula (I) or its subformula for use in treating a disease or condition that is beneficial or treatable by inhibiting EZH2, PRC2 or a combination thereof; and use in the preparation of a medicament for treating a disease or condition that is treatable by inhibiting EZH2, PRC2 or a combination thereof.

[0173] Diseases or conditions mediated by EZH2, PRC2 or EZH2 / PRC2, or diseases or conditions that may benefit or be treated by inhibiting EZH2, PRC2 or EZH2 / PRC2 include, but are not limited to, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, leukemia, multiple myeloma, gastric cancer, malignant rhabdoid tumor, hepatocellular carcinoma, prostate cancer, breast cancer, bile duct and gallbladder cancer, bladder cancer, neuroblastoma, glioma, glioblastoma and astrocytoma, cervical cancer, colorectal cancer, melanoma, endometrial cancer, esophageal cancer, head and neck cancer, lung cancer, nasopharyngeal cancer, ovarian cancer, pancreatic cancer, renal cell carcinoma, rectal cancer, thyroid cancer, parathyroid tumors, uterine tumors, rhabdomyosarcoma, Kaposi's sarcoma, synovial sarcoma, osteosarcoma and Ewing's sarcoma.

[0174] Pharmaceutical compositions, dosage forms and administration

[0175] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.

[0176] In other embodiments, the composition includes at least two pharmaceutically acceptable carriers as described in the present invention. The pharmaceutical composition can be formulated for specific routes of administration, such as oral administration, parenteral administration (e.g., by injection, instillation, transdermal or topical administration) and rectal administration. Topical administration also includes inhalation or intranasal administration. The pharmaceutical composition of the present invention can be made into solid form (including but not limited to capsules, tablets, pills, granules, powders or suppositories) or liquid form (including but not limited to solutions, suspensions or emulsions). Tablets can be added with film coatings or enteric coatings according to methods known in the art. Typically, the pharmaceutical composition is a tablet or gelatin capsule comprising an active ingredient and one or more of the following excipients:

[0177] a) diluents, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine;

[0178] b) lubricants, such as silicon dioxide, talc, stearic acid, its magnesium or calcium salts and / or polyethylene glycol; in the case of tablets, also

[0179] c) binders, such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone; if necessary

[0180] d) disintegrating agents, such as starch, agar, alginic acid or its sodium salt, or effervescent mixtures; and

[0181] e) Absorbents, colorants, flavorings and sweeteners.

[0182] In another aspect, the compounds of the invention are combined with other therapeutic agents, such as other anticancer agents, antiallergic agents, antiemetics (or antiemetics), analgesics, cytoprotective agents, immunomodulators, and combinations thereof.

[0183] In one embodiment, the additional therapeutic agent is an anticancer agent or a chemotherapeutic agent. General chemotherapeutic agents considered in combination therapy include anastrozole Bicalutamide Bleomycin sulfate Busulfan Busulfan Injection Capecitabine N4-pentyloxycarbonyl-5-deoxy-5-fluorocytidine, carboplatin Carmustine Chlorambucil Cisplatin Cladribine Cyclophosphamide ( or ), cytosine arabinoside, cytosine arabinoside Cytarabine liposome injection Dakar Dactinomycin (Actinomycin D, Cosmegan), daunorubicin hydrochloride Daunorubicin citrate liposome injection Dexamethasone, docetaxel Doxorubicin Hydrochloride Etoposide Fludarabine phosphate 5-Fluorouracil Flutamide Tezacitibine, gemcitabine (difluorodeoxycytidine), hydroxyurea Idabi Ephedrine Irinotecan L-Asparaginase Calcium folate, mycophenolate 6-Mercaptopurine Methotrexate Mitoxantrone Gemtuzumab (mylotarg), paclitaxel Albumin-bound paclitaxel Implants of phoenix (Yttrium90 / MX-DTPA), pentostatin, polifeprosan 20, and carmustine Tamoxifen citrate Teniposide 6-thioguanine, thiotepa, tirapazamine Topotecan Hydrochloride for Injection Vinblastine Vincristine Vinorelbine

[0184] Particularly promising anticancer agents for use in combination with the compounds of the present invention include:

[0185] Cyclin-dependent kinase (CDK) inhibitors: (Chen, S. et al., Nat Cell Biol., 12(11): 1108-14 (2010); Zeng, X. et al., Cell Cycle, 10(4): 579-83 (2011)) Aloisine A; Alvocidib (also known as flavonopyrido or HMR-1275, 2-(2-chlorophenyl)-5,7-dihydroxy-8-[(3S,4R)-3-hydroxy-1-methyl-4-piperidinyl]-4-chromanone, described in U.S. Pat. No. 5,621,002); Crizotinib (PF-02341066, CAS 877399-52-5); 2-(2-chlorophenyl)-5,7-dihydroxy-8-[(2R,3S)-2-(hydroxymethyl)-1-methyl-3-pyrrolidinyl]-4H-1-benzopyran-4-one hydrochloride (P276-00, CAS 920113-03-7); 1-methyl-5-[[2-[5-(trifluoromethyl)-1H-imidazol-2-yl]-4-pyridinyl]oxy]-N-[4-(trifluoromethyl)phenyl]-1H-benzimidazol-2-amine (RAF265, CAS 927880-90-8); Indisulam (E7070); Roscovitine (CYC202); 6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one hydrochloride (PD0332991); Dinaciclib (SCH727965); N-[5-[[(5-tert-butyloxazol-2-yl)methyl]thio]thiazol-2-yl]piperidine-4-carboxamide (B 387032, CAS 345627-80-7); 4-[[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepine-2-yl]amino]-benzoic acid (MLN8054, CAS 869363-13-3); 5-[3-(4,6-difluoro-1H-benzimidazol-2-yl)-1H-indazol-5-yl]-N-ethyl-4-methyl-3-pyridinemethanamine (AG-024322, CAS 837364-57-5); 4-(2,6-dichlorobenzamido)-1H-pyrazole-3-carboxylic acid N-(piperidin-4-yl)amide (AT7519, CAS 844442-38-2); 4-[2-methyl-1-(1-methylethyl)-1H-imidazol-5-yl]-N-[4-(methylsulfonyl)phenyl]-2-pyrimidinamine (AZD5438, CAS 602306-29-6);Palbociclib (PD-0332991); and (2R,3R)-3-[[2-[[3-[[S(R)]-S-cyclopropylsulfonyliminoyl]-phenyl]amino]-5-(trifluoromethyl)-4-pyrimidinyl]oxy]-2-butanol (BAY 10000394). ;

[0186] Checkpoint kinase (CHK) inhibitors: (Wu, Z. et al., Cell Death Differ., 18(11):1771-9 (2011)) 7-hydroxystaurosporine (UCN-01); 6-bromo-3-(1-methyl-1H-pyrazol-4-yl)-5-(3R)-3-piperidinyl-pyrazolo[1,5-a]pyrimidin-7-amine (SCH900776, CAS 891494-63-6); 5-(3-fluorophenyl)-3-ureidothiophene-2-carboxylic acid N-[(S)-piperidin-3-yl]amide (AZD7762, CAS 860352-01-8); 4-[((3S)-1-azabicyclo[2.2.2]octan-3-yl)amino]-3-(1H-benzimidazol-2-yl)-6-chloroquinolin-2(1H)-one (CHIR 124, CAS 405168-58-3); 7-aminodactinomycin (7-AAD), isogranulatimide, debromohymenialdisine; N-[5-bromo-4-methyl-2-[(2S)-2-morpholinylmethoxy]-phenyl]-N'-(5-methyl-2-pyrazinyl)urea (LY2603618, CAS 911222-45-2); sulforaphane (CAS 4478-93-7, 4-methylsulfinylbutyl isothiocyanate); 9,10,11,12-tetrahydro-9,12-epoxy-1H-diindolo[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-i][1,6]benzodiazocine-1,3(2H)-dione (SB-218078, CAS135897-06-2); and TAT-S216A (YGRKKRRQRR RLYRSPAMPENL), and CBP501 ((d-Bpa)sws(d-Phe-F5)(d-Cha)rrrqrr); and (αR)-α-amino-N-[5,6-dihydro-2-(1-methyl-1H-pyrazol-4-yl)-6-oxyl-1H-pyrrolo[4,3,2-ef][2,3]benzodiazepine-8-yl]-cyclohexaneacetamide (PF-0477736).

[0187] Protein kinase B (PKB) or AKT inhibitors: (Rojanasakul, Y., Cell Cycle, 12(2):202-3 (2013); Chen B. et al., Cell Cycle, 12(1):112-21 (2013)) 8-[4-(1-aminocyclobutyl)phenyl]-9-phenyl-1,2,4-triazolo[3,4-f][1,6]naphthyridin-3(2H)-one (MK-2206, CAS 1032349-93-1); Perifosine (KRX0401); 4-dodecyl-N-1,3,4-thiadiazol-2-yl-benzenesulfonamide (PHT-427, CAS 1191951-57-1); 4-[2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-7-[(3S)-3-piperidinylmethoxy]-1H-imidazo[4,5-c]pyridin-4-yl]-2-methyl-3-butyn-2-ol (GSK690693, CAS937174-76-0); 8-(1-hydroxyethyl)-2-methoxy-3-[(4-methoxyphenyl)methoxy]-6H-dibenzo[b,d]pyran-6-one (palomid 529, P529 or SG-00529); Tricirbine (6-amino-4-methyl-8-(β-D-ribofuranosyl)-4H,8H-pyrrolo[4,3,2-de]pyrimido[4,5-c]pyridazine); (αS)-α-[[[5-(3-methyl-1H-indazol-5-yl)-3-pyridinyl]oxy]methyl]-phenethylamine (A674563, CAS 552325-73-2); 4-[(4-chlorophenyl)methyl]-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinamine (CCT128930, CAS 885499-61-6); 4-(4-chlorophenyl)-4-[4-(1H-pyrazol-4-yl)phenyl]-piperidine (AT7867, CAS 857531-00-1); and Archexin (RX-0201, CAS 663232-27-7).

[0188] C-RAF inhibitors: (Chang, C. et al., Cancer Cell, 19(1):86-100 (2011)) Sorafenib 3-(Dimethylamino)-N-[3-[(4-hydroxybenzoyl)amino]-4-methylphenyl]-benzamide (ZM336372, CAS208260-29-1); and 3-(1-cyano-1-methylethyl)-N-[3-[(3,4-dihydro-3-methyl-4-oxo-6-quinazolinyl)amino]-4-methylphenyl]-benzamide (AZ628, CAS1007871-84-2).

[0189] Phosphoinositide 3-kinase (PI3K) inhibitors: (Gonzalez, M. et al., Cancer Res., 71(6):2360-2370 (2011)) 4-[2-(1H-indazol-4-yl)-6-[[4-(methylsulfonyl)piperazin-1-yl]methyl]thieno[3,2-d]pyrimidin-4-yl]morpholine (also known as GDC 0941 and described in PCT Publication Nos. WO 09 / 036082 and WO 09 / 055730); 2-methyl-2-[4-[3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydroimidazo[4,5-c]quinolin-1-yl]phenyl]propionitrile (described in PCT Publication No. WO 06 / 122806, also known as dactolisib); 4-(trifluoromethyl)-5-(2,6-dimorpholinopyrimidin-4-yl)pyridin-2-amine (described in PCT Publication No. WO 2007 / 084786, also known as buparlisib); Tozasertib (VX680 or MK-0457, CAS 639089-54-6); (5Z)-5-[[4-(4-pyridinyl)-6-quinolyl]methylene]-2,4-thiazolidinedione (GSK1059615, CAS 958852-01-2); (1E,4S,4aR,5R,6aS,9aR)-5-(acetoxy)-1-[(di-2-propenylamino)methylene]-4,4a,5,6,6a,8,9,9a-octahydro-11-hydroxy-4-(methoxymethyl)-4a,6a-dimethyl-cyclopenta[5,6]naphtho[1,2-c]pyran-2,7,10(1H)-trione (PX866, CAS 502632-66-8); 8-phenyl-2-(morpholin-4-yl)-chromen-4-one (LY294002, CAS154447-36-6); 2-amino-8-ethyl-4-methyl-6-(1H-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (SAR 245409 or XL 765); 1,3-dihydro-8-(6-methoxy-3-pyridinyl)-3-methyl-1-[4-(1-piperazinyl)-3-(trifluoromethyl)phenyl]-2H-imidazo[4,5-c]quinolin-2-one, (2Z)-2-butenedioate (1:1) (BGT 226); 5-fluoro-3-phenyl-2-[(1S)-1-(9H-purin-6-ylamino)ethyl]-4(3H)-quinazolinone (CAL101); 2-amino-N-[3-[N-[3-[(2-chloro-5-methoxyphenyl)amino]quinoxalin-2-yl]sulfamoyl]phenyl]-2-methylpropanamide (SAR 245408 or XL 147);and (S)-pyrrolidine-1,2-dicarboxylic acid 2-amide 1-({4-methyl-5-[2-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-pyridin-4-yl]-thiazol-2-yl}-amide) (BYL719). ;

[0190] BCL-2 inhibitors: (Béguelin, W. et al., Cancer Cell, 23(5):677-92 (2013)) 4-[4-[[2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohexen-1-yl]methyl]-1-piperazinyl]-N-[[4-[[(1R)-3-(4-morpholinyl)-1-[(phenylthio)methyl]propyl]amino]-3-[(trifluoromethyl)sulfonyl]phenyl]sulfonyl]benzamide (also known as ABT-263 and described in PCT Publication No. WO 09 / 155386); tetrastatin A; antimycin; gossypol ((-) BL-193); obatoclax; ethyl-2-amino-6-cyclopentyl-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromone-3-carboxylate (HA14-1); oblimersen (G3139, ); Bak BH3 peptide; (-)-gossypol acetic acid (AT-101); 4-[4-[(4'-chloro[1,1'-diphenyl]-2-yl)methyl]-1-piperazinyl]-N-[[4-[[(1R)-3-(dimethylamino)-1-[(phenylthio)methyl]propyl]amino]-3-nitrophenyl]sulfonyl]-benzamide (ABT-737, CAS 852808-04-9); and Navitoclax (ABT-263, CAS 923564-51-6).

[0191] Mitogen-activated protein kinase (MEK) inhibitors: (Chang, CJ et al., Cancer Cell, 19(1):86-100 (2011)) XL-518 (also known as GDC-0973, CAS No. 1029872-29-4, available from ACC Corp.); Selumetinib (5-[(4-bromo-2-chlorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H-benzimidazole-6-carboxamide, also known as AZD6244 or ARRY 142886, described in PCT Publication No. WO 2003077914); Benimetinib (6-(4-bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzimidazole-5-carboxylic acid (2-hydroxyethoxy)-amide, also known as MEK162, CAS 1073666-70-2, described in PCT Publication No. WO 2003077914); 2-[(2-chloro-4-iodophenyl)amino]-N-(cyclopropylmethoxy)-3,4-difluoro-benzamide (also known as CI-1040 or PD184352, and described in PCT Publication No. WO 2000035436); N-[(2R)-2,3-dihydroxypropyloxy]-3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-benzamide (also known as PD0325901 and described in PCT Publication No. WO 2002006213); 2,3-bis[amino[(2-aminophenyl)thio]methylene]-succinonitrile (also known as U0126 and described in U.S. Pat. No. 2,779,780); N-[3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-6-methoxyphenyl]-1-[(2R)-2,3-dihydroxypropyl]-cyclopropanesulfonamide (also known as RDEA119 or BAY869766 and described in PCT Publication No. WO 2007014011); (3S,4R,5Z,8S,9S,11E)-14-(ethylamino)-8,9,16-trihydroxy-3,4-dimethyl-3,4,9,19-tetrahydro-1H-2-benzoxetrazolyl-1,7(8H)-dione] (also known as E6201 and described in PCT Publication No. WO 2003076424); 2'-amino-3'-methoxyflavone (also known as PD98059, available from Biaffin GmbH & Co.,KG)); vemurafenib (PLX-4032, CAS 918504-65-1); (R)-3-(2,3-dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (TAK-733, CAS1035555-63-5); Pimasertib (AS-703026, CAS1204531-26-9); dimethyl sulfoxide trametinib (GSK-1120212, CAS1204531-25-80); 2-(2-fluoro-4-iodophenylamino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide (AZD 8330); and 3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-N-(2-hydroxyethoxy)-5-[(3-oxy[1,2]oxazolidin-2-yl)methyl]benzamide (CH 4987655 or Ro 4987655). .

[0192] Aromatase inhibitors: (Pathiraja, T. et al., Sci. Transl. Med., 6(229):229ra41 (2014)) Exemestane Letrozole and anastrozole

[0193] Topoisomerase II inhibitors: (Bai, J. et al., Cell Prolif., 47(3):211-8 (2014)) etoposide (VP-16 and etoposide phosphate, and ); Teniposide (VM-26, ); and Tafluposide.

[0194] SRC inhibitors: (Hebbard, L., Oncogen, 30(3):301-12 (2011)) Dasatinib Saracatinib (AZD0530, CAS 379231-04-6); Bosutinib (SKI-606, CAS 380843-75-4); 5-[4-[2-(4-morpholinyl)ethoxy]phenyl]-N-(phenylmethyl)-2-pyridineacetamide (KX2-391, CAS 897016-82-9); and 4-(2-chloro-5-methoxyphenylamino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (AZM475271, CAS 476159-98-5).

[0195] Histone deacetylase (HDAC) inhibitors: (Yamaguchi, J. et al., Cancer Sci., 101(2):355-62 (2010)) Voninostat ); Romidepsin Treichostatin A (TSA); Oxamflatin; Vorinostat ( Suberoylanilide hydroxamic acid); Pyroxamide (syberoyl-3-aminopyridineamide hydroxamic acid); Trapoxin A (RF-1023A); Trapoxin B (RF-10238); Cyclo[(αS,2S)-α-amino-η-oxy-2-oxirane octanoyl-O-methyl-D-tyrosyl-L-isoleucyl-L-prolyl] (Cyl-1); Cyclo[(αS,2S)-α-amino-η-oxy-2-oxirane octanoyl-O-methyl-D-tyrosyl-L-isoleucyl-(2S)-2-piperidinylcarbonyl] (Cyl-2); Cyclo[L-alanyl-D-alanyl-(2S)-η-oxy-L-α-aminooxirane octanoyl-D-prolyl] (HC-toxin); Cyclo[(α S,2S)-α-amino-η-oxy-2-oxirane octanoyl-D-phenylalanyl-L-leucyl-(2S)-2-piperidine carbonyl] (WF-3161); Chlamydocin ((S)-cyclo(2-methylalanyl-L-phenylalanyl-D-prolyl-η-oxy-L-α-aminooxirane octanoyl); histone deacetylase inhibitor (Apicidin) (cyclo(8-oxo-L-2-aminodecanoyl-1-methoxy-L-tryptophanyl-L-isoleucyl-D-2-piperidine carbonyl); Lomidicin ( FR-901228); 4-phenylbutyrate; Spiruchostatin A; Mylproin (valproic acid); Entinostat (-275, N-(2-aminophenyl)-4-[N-(pyridin-3-yl-methoxycarbonyl)-amino-methyl]-benzamide); and Depudecin (4,5:8,9-dianhydride-1,2,6,7,11-pentadeoxy-D-threo-D-ido-undeca-1,6-dienol).

[0196] Antitumor antibiotics: (Bai, J. et al., Cell Prolif., 47(3):211-8 (2014)) Doxorubicin ( and ); Bleomycin Daunorubicin (daunorubicin hydrochloride, daunomycin and daunorubicin hydrochloride, ); daunorubicin liposomes (daunorubicin citrate liposomes, ); Mitoxantrone (DHAD, ); Ellence TM ); Idabit Mitomycin C Geldanamycin; herbimycin; ravidomycin; and desacetylravidomycin.

[0197] Demethylating agent: (Musch, T. et al., PLoS One, (5): e10726 (2010)) 5-azacitidine and decitabine

[0198] Antiestrogens: (Bhan, A. et al., J Mol Biol., S0022-2836(14)00373-8(2014)) Tamoxifen Toremifene Fulvestrant

[0199] Particularly potential immunomodulators for use in combination with the compounds of the present invention include one or more of the following: agonists of co-stimulatory molecules or inhibitors of immune checkpoint molecules (e.g., one or more inhibitors of PD-1, PD-L1, LAG-3, TIM-3 or CTLA4) or any combination thereof.

[0200] In some embodiments, the immunomodulator is an agonist of a co-stimulatory molecule. In one embodiment, the agonist of the co-stimulatory molecule is selected from OX40, CD2, CD27, CDS, ICAM-1, LFA-1 (CD11a / CD18), ICOS (CD278), 4-1BB (CD137), GITR, CD30, CD40, BAFFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD160, B7-H3 or CD83 ligands (e.g., agonist antibodies or their antigen binding fragments or soluble fusions).

[0201] In some embodiments, the immunomodulator is an inhibitor of an immune checkpoint molecule. In one embodiment, the immunomodulator is an inhibitor of PD-1, PD-L1, PD-L2, CTLA4, TIM3, LAG3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 and / or TGFRβ. In one embodiment, the inhibitor of the immune checkpoint molecule inhibits PD-1, PD-L1, LAG-3, TIM-3 or CTLA4, or any combination thereof. The term "inhibition" or "inhibitor" includes reducing certain parameters (e.g., activity) of a specified molecule (e.g., an immune checkpoint inhibitor). For example, the term includes inhibiting (e.g., PD-1 or PD-L1 activity) by at least 5%, 10%, 20%, 30%, 40% or more activity. Therefore, inhibition does not require inhibition of 100% activity.

[0202] In another aspect, the present invention provides a pharmaceutical composition comprising at least one compound of the present invention (e.g., a compound having formula (I) or a subformula thereof) or a pharmaceutically acceptable salt and a pharmaceutically acceptable carrier suitable for administration to a human or animal subject, alone or in combination with other anticancer agents.

[0203] In combination therapy, the composition will be formulated together as a combination therapeutic agent or as a separate composition. The compounds of the present invention and other therapeutic agents can be manufactured and / or formulated by the same or different manufacturers. The structure of the therapeutic agent named by number, common name or trade name can be taken from the standard compendium "The Merck Index" or database (e.g., International Patents (e.g., IMS World Publications)). Other therapeutic agents used in combination with the compounds of the present invention can be prepared and administered by methods described in the art (such as in the literature cited above).

[0204] Optionally, the pharmaceutical composition includes a pharmaceutically acceptable carrier as described above. The pharmaceutical composition or combination of the present invention can be administered, for example, to a subject of about 50-70 kg in a unit dose of 0.5 mg to 1000 mg of one or more active ingredients.

[0205] On the other hand, the present invention provides a method for treating a human or animal subject suffering from a cell proliferative disease (such as cancer), the method comprising administering to the subject a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt alone or in combination with other anticancer agents. In combination therapy, the compound of the present invention and one or more other anticancer agents can be administered simultaneously, concurrently or sequentially (without a specific time limit), wherein the administration method provides a therapeutically effective level of the two compounds in the patient's body. In addition, the compound of the present invention and other therapeutic agents can also be combined to form a combination therapy in the following manner: (i) before the combination product is given to a physician (e.g., in the case of a kit including the compound of the present invention and other therapeutic agents); (ii) shortly before administration, by the physician himself (or under the guidance of a physician); (iii) by the patient himself, for example, during the sequential administration of the compound of the present invention and other therapeutic agents.

[0206] In one embodiment, the compounds of this invention and one or more other anticancer agents are usually administered sequentially in any order by infusion or oral administration. The dosage regimen can be changed according to the stage of the disease, the patient's physical health, the safety of a single drug, the tolerance of a single drug, and other standards known to the attending physician and one or more practitioners who administer the combination. The compounds of this invention and one or more other anticancer agents can be administered within minutes, hours, days or even weeks of each other, depending on the specific cycle of treatment. In addition, the cycle includes during the treatment cycle, compared to a drug, more frequently giving another drug, and the drug dosage given each time may be different.

[0207] In another aspect, the compounds of the present invention may be combined with other anticancer agents, antiallergic agents, antiemetics (or antiemetics), analgesics, cytoprotective agents, and combinations thereof.

[0208] In some cases, some patients may develop an allergic reaction to the compounds of the invention and / or one or more other anticancer agents during or after administration. Therefore, an antiallergic agent may be administered to minimize the risk of an allergic reaction. Suitable antiallergic agents include corticosteroids, such as dexamethasone (e.g., ), beclomethasone (e.g. ), hydrocortisone (also known as cortisone, hydrocortisone sodium succinate, hydrocortisone sodium phosphate; for example, Hydrocortisone phosphate, HYDROCORT and ), prednisolone (e.g. and ), prednisone (e.g. LIQUID and ), methylprednisolone (also known as 6-methylprednisolone, methylprednisolone acetate, methylprednisolone sodium succinate; e.g., M- and ); antihistamines, such as diphenhydramine (e.g., ),hydroxyl and cyproheptadine; and bronchodilators, such as beta-adrenergic receptor agonists, albuterol (e.g., ), and terbutaline

[0209] In other cases, some patients may experience nausea during and after administration of the compounds of the invention and / or one or more other anticancer agents. Therefore, antiemetics may be administered to prevent nausea (upset stomach) and vomiting. Suitable antiemetics include aprepitant Antansito Granisetron HCl Lorazepam Dexamethasone Prochlorperazine casopitant and ), and combinations thereof.

[0210] In other cases, giving people medicine to relieve pain during treatment can make them more comfortable. Common over-the-counter pain relievers, such as Opioid analgesics such as hydrocodone / acetaminophen or hydrocodone / acetaminophen (e.g. ), morphine (e.g. or ), oxycodone (e.g., or ), morphone hydrochloride and fentanyl (e.g., ) can also be used for moderate or severe pain.

[0211] In addition, cytoprotectants (e.g., neuroprotectants, free radical scavengers, cardioprotectants, anthracycline extravasation neutralizers, nutrients, etc.) can be used as adjunctive therapy to protect normal cells from therapeutic toxicity and limit organ toxicity. Suitable cytoprotectants include amifostine Glutamyl acid, dimesna Mesna Dexrazoxane ( or ), xaliproden and folinic acid (also known as calcium folinic acid, citrovorum factor, and folinic acid).

[0212] In another aspect, the compounds of the invention can be used in combination with known treatment methods, for example, for hormone or radiation therapy. In certain cases, the compounds of the invention can be used as radiosensitizers, particularly useful for treating tumors that show low sensitivity to radiation therapy.

[0213] In another aspect, the present invention provides a kit comprising one or more compounds of the present invention and another therapeutic agent as described herein. Representative kits include (a) a compound or a pharmaceutically acceptable salt of formula (I) or a subformula thereof; and (b) at least one other therapeutic agent, for example, as described herein; the kit may further include a package insert or other labeling including instructions for administration. The kit of the present invention can be used to administer different drug forms, for example, oral and parenteral administration; for administering two or more separate pharmaceutical compositions at different dosage intervals; or for compositions titrated separately against each other; wherein at least one pharmaceutical composition includes a compound of formula (I) or a subformula thereof.

[0214] Process for preparing the compounds of the present invention

[0215] The compounds of the present invention can be prepared using the following methods or other similar methods understood by those skilled in the art of organic synthesis. Substantially optically pure compounds of formula (I) having chiral centers can be prepared by using substantially optically pure starting materials or by separation chromatography, recrystallization or other separation methods well known in the art.

[0216]

[0217] Solution 1

[0218] As depicted in Scheme 1, compounds of formula (I) can be prepared by displacement reaction of the corresponding amine (INT-1) with an appropriately substituted 2-halo-substituted pyrimidine or pyridine.

[0219]

[0220] Solution 2

[0221] As described in Scheme 2, the amine INT-1 is reacted with an appropriate pyridine or pyrimidine halide to give the corresponding halogenated intermediate INT-2. Subsequently, the halogenated intermediate INT-2 is coupled with an appropriate bromide to give the ester intermediate INT-3, which can be hydrolyzed under acidic or basic conditions to the acidic intermediate INT-4. Compounds having formula (I) can be prepared by coupling the acidic intermediate INT-4 with an appropriately substituted amine.

[0222]

[0223] Solution 3

[0224] As described in Scheme 3, 2-chloro-5-iodopyrimidine / pyridine is coupled with the corresponding bromoacetate Negishi and subsequently alkylated to give the intermediate INT-5. INT-5 is hydrolyzed and coupled with the corresponding amine to give the corresponding chloro-pyrimidine or pyridine amide intermediate INT-6. Compounds of formula (II) can be prepared by displacement reaction of the corresponding amine (INT-1) with the appropriately substituted chloro-pyrimidine or pyridine amide intermediate INT-6.

[0225] Example

[0226] Temperatures are expressed in degrees Celsius. The structures of final products, intermediates and starting materials are confirmed by standard analytical methods (e.g., microanalysis and spectroscopic characteristics (e.g., MS, IR, NMR)). Abbreviations used are conventional in the art.

[0227] All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents and catalysts used to synthesize the compounds of the present invention are commercially available or can be synthesized by known organic synthesis methods by technicians familiar with the technology (Houben-Weyl 4th edition 1952, Methods of Organic Synthesis, Thieme (Thieme Press) Volume 21). Unless otherwise stated, starting materials are generally available from commercial sources.

[0228] The following examples are merely illustrative of the present invention and do not limit the scope of the invention claimed in addition. In addition, the compounds of the present invention can be synthesized by known organic synthesis methods by technicians familiar with the technology, as shown in the following examples. When necessary, according to standard practice, conventional protecting groups are used to protect reactive functional groups, for example, referring to "Protecting Groups in Organic Synthesis" by TW Greene and PGM Wuts, John Wiley & Sons, 1991.

[0229] abbreviation

[0230] Abbreviations used herein are defined as follows: “1x” means once, “2x” means twice, “3x” means three times, “°C” means degrees Celsius, “aq” means aqueous, “FCC” means flash column chromatography, “eq” means equivalent or equivalents, “g” means gram or grams, “mg” means milligram or milligrams, “L” means liter or liters, “mL” means milliliter or milliliters, “μL” means microliter or microliters, “N” means normal, “M” means molar, “nM” means nanomole, “mol” means mole or moles, and “mmol” means millimole. "MS" or "MassSpec" means mass spectrometry, "ESI" means electrospray ionization mass spectrometry, "HR" means high resolution, "HRMS" means high resolution mass spectrometry, "LCMS" or "LC-MS" means liquid chromatography-mass spectrometry, "HPLC" means high performance liquid chromatography, "RP HPLC" means reverse phase HPLC, "TLC" or "tlc" means thin layer chromatography, "NMR" means nuclear magnetic resonance spectroscopy, "nOe" means nuclear Overhauser effect spectroscopy, 1 "H" means proton, "δ" means delta, "s" means singlet, "d" means doublet, "t" means triplet, "q" means quartet, "m" means multiplet, "br" means broad, "Hz" means Hertz, "ee" means "enantiomeric excess", and "α", "β", "R", "r", "S", "s", "E", and "Z" are stereochemical nomenclatures well known to those skilled in the art.

[0231] The abbreviations used below have the corresponding meanings:

[0232]

[0233]

[0234] Nuclear magnetic resonance (NMR) analysis was performed using a Bruker 400 MHz NMR. Spectra were referenced to the known chemical shifts of TMS or the solvent.

[0235] Intermediates Intermediate 1. tert-Butyl (((1R,4R)-4-((8-chloro-7-methylquinolin-2-yl)amino)cyclohexyl)methyl)carbamate

[0236]

[0237] K2CO3 (3.82 g, 27.7 mmol) was added to a solution of 2,8-dichloro-7-methylquinoline (CAS1690692-63-7, 1.95 g, 9.22 mmol) and tert-butyl (((1R, 4R)-4-aminocyclohexyl)methyl)carbamate (CAS192323-07-2, 2.07 g, 9.68 mmol) in NMP (20 mL). The mixture was stirred at 150 ° C for 5 h and cooled to room temperature. Water (30 mL) was added to the mixture and the aqueous phase was extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with petroleum ether / EtOAc (15% to 25%) to give tert-butyl (((1R,4R)-4-((8-chloro-7-methylquinolin-2-yl)amino)cyclohexyl)methyl)carbamate. 1 H NMR(400MHz,DMSO-d6)δppm 0.97-1.09(m,2H),1.14-1.22(m,2H),1.39(s,9H),1.45(br.s.,1H),1. 75(d,J=11.80Hz,2H),2.13(d,J=11.04Hz,2H),2.46(s,3H),2.82(t,J=6 .02Hz,2H),3.83-3.96(m,1H),6.72(d,J=8.78Hz,1H),6.87(br.s.,1H),7.08(d,J=8.03Hz,2H),7.46(d,J=8.28Hz,1H),7.81(d,J=8.78Hz,1H). LCMS: 404.2

[0238] Intermediate 2. (1R,4R)-N1-(8-chloro-7-methylquinolin-2-yl)cyclohexane-1,4-diamine

[0239]

[0240] To a solution of tert-butyl (((1R,4R)-4-((8-chloro-7-methylquinolin-2-yl)amino)cyclohexyl)methyl)carbamate (1.25 g, 3.22 mmol) in DCM (15 mL) was added TFA (5 mL). The mixture was stirred at 30°C for 2 h. The solvent was evaporated under reduced pressure and the residue was dissolved in DCM / i-PrOH (3:1, 50 mL) and the pH was adjusted to 9 with aqueous NaHCO3. The aqueous phase was extracted with DCM / i-PrOH (3:1, 3×20 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with petroleum ether / EtOAc (35% to 55%) to give (1R,4R)-N1-(8-chloro-7-methylquinolin-2-yl)cyclohexane-1,4-diamine.

[0241] Intermediate 3. 8-Chloro-N-((1R,4R)-4-(((5-iodopyrimidin-2-yl)amino)methyl)cyclohexyl)-7-methylquinolin-2-amine

[0242]

[0243] 2-Chloro-5-iodopyrimidine (CAS: 32779-38-7, 702 mg, 2.92 mmol) and DIPEA (1.08 g, 8.34 mmol) were added to a solution of (1R, 4R)-N1-(8-chloro-7-methylquinolin-2-yl)cyclohexane-1,4-diamine (805 mg, 2.78 mmol) in EtOH (10 mL). The reaction mixture was stirred at 80 ° C overnight. The solvent was evaporated and the residue was dissolved in DCM (50 mL) and water (30 mL). The aqueous phase was extracted with DCM (3×30 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with petroleum ether / EtOAc (15% to 25%) to give 8-chloro-N-((1R,4R)-4-(((5-iodopyrimidin-2-yl)amino)methyl)cyclohexyl)-7-methylquinolin-2-amine.

[0244] Intermediate 4. tert-Butyl 2-(2-((((1R,4R)-4-((8-chloro-7-methylquinolin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)acetate

[0245]

[0246] TMSCl (0.03 mL, 0.29 mmol) was added to a suspension of zinc powder (11.3 g, 173 mmol) in dry THF (270 mL). After stirring at room temperature for 20 min, a solution of tert-butyl 2-bromoacetate (CAS: 5292-43-3, 16.8 mL, 115 mmol) was added. The mixture was stirred at 60 ° C for 1 h and then cooled to room temperature. The suspension was added to a mixture of 8-chloro-N-((1R, 4R)-4-(((5-iodopyrimidin-2-yl)amino)methyl)cyclohexyl)-7-methylquinolin-2-amine (2.93 g, 5.77 mmol), Pd2(dba)3 (260 mg, 0.28 mmol) and X-Phos (266 mg, 0.56 mmol) at room temperature and then heated at 60 ° C overnight under N2. The mixture was quenched with NH4Cl (100 mL). The aqueous phase was extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with petroleum ether / EtOAc (30% to 80%) to give tert-butyl 2-(2-((((1R,4R)-4-((8-chloro-7-methylquinolin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)acetate.

[0247] Intermediate 5. 8-Chloro-N-((1R,4R)-4-(((5-iodopyrimidin-2-yl)amino)methyl)cyclohexyl)-7-methylquinolin-2-amine

[0248]

[0249] Tert-butyl 2-(2-((((1R,4R)-4-((8-chloro-7-methylquinolin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)acetate (4.20 g, 8.46 mmol) was added to a solution of DCM (20 mL) and TFA (20 mL) and allowed to stand at room temperature for 1 h. The solvent was evaporated under reduced pressure, the residue was dissolved in DCM / iPrOH (3:1, 50 mL), and the pH was adjusted to between 5 and 6. The aqueous phase was extracted with DCM / iPrOH (3:1, 3×50 mL). The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure to give 8-chloro-N-((1R,4R)-4-(((5-iodopyrimidin-2-yl)amino)methyl)cyclohexyl)-7-methylquinolin-2-amine. 1H NMR(400MHz,DMSO-d6)δppm 1.00-1.25(m,4H),1.50-1.65(m,1H),1.75-1.90(m,2H),2.10-2.20(m,2H),2.45(s,3H),3.10-3.20(m,2H),3.25-3.35( m,2H),3.9(m,1H),6.7(d,1H),7.05(d,2H),7.15(m,1H),7.45(d,1H),7.80(d,1H),8.15(s,2H),12.25.12.50(br.S,1H). MS:[M+H] + =440,442

[0250] Example

[0251] Example 1. 2-(2-((((1R,4R)-4-((8-chloro-7-methylquinolin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-(oxetan-3-yl)acetamide

[0252]

[0253] A mixture of 8-chloro-N-((1R,4R)-4-(((5-iodopyrimidin-2-yl)amino)methyl)cyclohexyl)-7-methylquinolin-2-amine (Intermediate 5) (2.50 g, 5.68 mmol), oxetane-3-amine (CAS: 21635-88-1, 513 mg, 8.52 mmol), DMAP (693 mg, 5.68 mmol) and EDCI (2.17 g, 11.4 mmol) in DCM (40 mL) was stirred at 25 °C for 16 h. The mixture was adjusted to pH 6. The aqueous phase was extracted with DCM (3 x 30 mL). The combined organic layers were washed with NaHCO, washed with brine, dried (NaSO), filtered and concentrated under reduced pressure. The residue was purified by column chromatography, eluting first with petroleum ether / EtOAc (40% to 100%) and then with solvent A (2N NH3 in MeOH / MeOH / DCM 1:10:100) in DCM (20% to 40%) to give 2-(2-((((1R,4R)-4-((8-chloro-7-methylquinolin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-(oxetan-3-yl)acetamide. 1H NMR(500MHz,DMSO-d6)δppm1.05-1.25(m,4H),1.55-1.65(m,1H),1.80-1.85(m ,2H),2.10-2.15(m,2H),2.45(s,3H),3.15(t,2H),3.25(s,2H),3.85-3.95(br s,1H),4.40(t,2H),4.70(t,2H),4.75.4.80(m,1H),6.75(d,1H),7.05( d,2H),7.15(t,1H),7.45(d,1H),7.80(d,1H),8.12(s,2H),8.72(d,1H). MS:[M+H] + =495,497.

[0254] The following compounds can be prepared by methods similar to Example 1, or according to the methods described in Schemes 1-3, using corresponding intermediates.

[0255]

[0256]

[0257]

[0258]

[0259] test

[0260] Any of the following experimental procedures can be used to demonstrate the functionality of the compounds of the invention.

[0261] EZH2 LC-MS test

[0262] The representative compounds of the present invention were diluted 3 times in DMSO to obtain twelve concentrations. Then each concentration of the test compound (120nL each) was transferred by Mosquito to a 384-well PerkinElmer ProxiPlate 384plus plate. A reaction buffer (20mM Tris, pH 8.0, 0.1% BSA, 0.01% Triton, 0.5mM DTT) solution (6μL) containing 80nM wild-type PRC2 (wtPRC2) complex and 60μM SAM was added to each well and then incubated with the test compound for 20min. A 6μL reaction buffer solution containing 3μM substrate peptide H3K27me1 (histone H3[21-44]-K27me1-biotin) and 6μM regulatory peptide H3K27me3 (histone H3[21-44]-K27me3) was added to each well to trigger each reaction. The final components in the reaction solution included 40nM wtPRC2 complex, 30μM SAM, 1.5μM H3K27me1 peptide and 3μM H3K27me3 peptide with different concentrations of compounds. The positive control consisted of 40nM enzyme, 30μM SAM, 1.5μM H3K27me1 and 3μM H3K27me3, excluding the test compound, and the negative control consisted of 30μM SAM, 1.5μM H3K27me1 and 3μM H3K27me3 alone. Each reaction was incubated at room temperature for 120min and then terminated by adding 3μL quenching solution (2.5% TFA containing 320nM d4-SAH). The reaction mixture was centrifuged at 2000 rpm (Eppendorf centrifuge 5810, rotor A-4-62) for 2 min and read on an API 4000 triple quadrupole mass spectrometer equipped with a Turbulon Spray (Applied Biosystem) coupled to a Prominence UFLC (Shimadzu). SAH production levels were normalized based on the values ​​of the positive and negative controls to obtain percent enzyme activity. The data were fitted to a dose-response equation using the Helios program to obtain the IC of the test compound. 50 value.

[0263] ELISA (H3K27 methylation) assay

[0264] Representative compounds of the invention were serially and separately diluted 3-fold in DO to obtain a total of eight or twelve concentrations. Compounds were then added to G401 cells and cultured in 384-well plates at a 1:500 dilution to obtain a maximum concentration of 20 μM. Cells were further cultured for 48 h before the ELISA procedure.

[0265] Histone extraction: Cells in 384-well plates were washed with PBS (10×PBS buffer (80 g NaCl (Sigma, S3014), 2 g KCl (Sigma, 60128), 14.4 g Na2HPO4 (Sigma, S5136), 2.4 g KH2PO4 (Sigma, P9791) to 1 L water, pH to 7.4) and lysed by adding lysis buffer (0.4 N HCl; 45 μL / well). The plates were gently agitated for 30 min at 4°C. The cell lysate was neutralized with neutralization buffer (0.5 M disodium hydrogen phosphate, pH 12.5, 1 mM DTT; 36 μL / well). The plate was agitated to ensure that the lysate was thoroughly mixed before ELISA.

[0266] ELISA protocol: Cell lysate was transferred to each well of a 384-well plate and the final volume was adjusted to 50 μL per well with PBS. The plate was sealed, centrifuged at 2000 rpm for 2 min, and incubated at 4 °C for about 16 h. The plate was washed with TBST buffer (1×TBS containing 0.1% Tween 20 (10xTBS: 24.2 g Tris (Sigma, T6066), 80 g NaCl (Sigma, S3014) to 1 L water and pH adjusted to 7.6 with HCl)). Blocking buffer (TBST, 5% BSA; 50 μL / well) was added and the plate was incubated at room temperature for 1 h. The blocking buffer was removed and the primary antibody (30 μL / well) was added. The following dilutions were made in blocking buffer: 1:1000 for anti-H3K27me3 antibody (Cell Signaling Technology, #9733); 1:100 for anti-H3K27me2 antibody (Cell Signaling Technology, #9288); 1:100 for anti-H3 antibody (Abcam, catalog number 24834). The primary antibodies were incubated in the plate for 1 h at room temperature. The wells were washed with TBST and incubated with the secondary antibodies for 1 h at room temperature. For the secondary antibodies, the following dilutions were made in blocking buffer: 1:2000 for anti-rabbit antibody (Jackson ImmunoResearch, #111-035-003); 1:1000 for anti-mouse antibody (Cell Signaling Technology, #7076).

[0267] After incubation for 1 h at room temperature, the wells were washed with TBST. 30 μL of ECL substrate (Pierce, #34080) was added to each well, and the plate was centrifuged at 2000 rpm for 2 min. The signal was read using the Envision reader from PerkinElmer. The H3K27 methylation readings were normalized using the H3 signal, and the percentage inhibition of the DO-treated samples was then calculated. The data were fitted to a dose-response curve using the Helios program to obtain the IC of the test compound. 50 value.

[0268] Cell proliferation analysis

[0269] Using standard cell culture conditions, B cell lymphoma cells KARPAS422 were cultured in RPMI-1640 (Invitrogen, catalog number 11875) supplemented with 15% FBS (Invitrogen, catalog number 10099-141) at 37°C in a humidified incubator with 5% CO2. To assess the effect of PRC2 inhibition on cell proliferation, exponentially growing cells were plated at 1×10 5 Cells were plated at a density of 10 cells / mL in 12-well plates (Corning, catalog number CLS3513). After cell inoculation, the compounds of the invention were added to the cell culture medium (concentration range 0 to 100 μM, 3x dilution series). The number of viable cells was measured every 3-4 days using Vi-CELL (Beckman Coulter) for up to 14 days. On the day of cell counting, fresh growth medium and compounds were added to allow cell division to return to 1×10 5 The total cell number is expressed as division-adjusted viable cells per mL. Dose-response curves and IC were generated using Prism. 50 value.

[0270] The illustrative embodiments described below were tested in the EZH2 LC- and / or EZH2 ELISA assays described above and were found to have EZH2 inhibitory activity.

[0271] Table 3 lists the IC values ​​of the following examples in the EZH2 (a) LC qualification and / or (b) ELISA qualification assays. 50 value.

[0272] Table 3

[0273]

[0274]

[0275]

[0276] nd = not determined

[0277] Text description: "+++” "++” "+” LCMS <0.05μM 0.05-0.10μM >0.10μM ELISA H3K27 <0.01μM 0.01-0.1μM >0.1μM

[0278] It should be understood that the embodiments and implementations described herein are for illustrative purposes only, and various modifications or changes will be apparent to those skilled in the art, and these modifications are included within the spirit and purpose of the present application and the scope of the appended claims. All publications, patents, and patent applications cited herein are incorporated herein by reference for all purposes.

Claims

1. A compound having the structure of formula (I): or a stereoisomer, enantiomer, mixture of enantiomers or a pharmaceutically acceptable salt thereof; in: Y is N or CR a ; R a , R 1 , R 3 , R 5 , R 6 , R 7 , R 8 and R 9 are independently H, halogen or -C1-C4 alkyl; R 2 is -CN, -C1-C6 alkyl, -hydroxyC1-C4 alkylene, -C1-C4 alkoxy, -C2-C4 alkoxy substituted with 1-2 hydroxy groups; -(CR 13 R 14 ) n C(=O)NR 11 R 12 、-(CR 13 R 14 ) n C(=O)NR 11 R 15 ; -(CR 13 R 14 ) n C(=O)R 15 ; -(CR2) n NR 11 C(=O)R 15 、-(CR2) n NR 11 (CR2)2C(=O)R 15 ; -(CR2) n NR-C(=O)OR 11 、-(CR2) n NR-C(=O)O-(CR2)-R 15 ; -NR-C(=O)(CR2)2C(=O)R 15 、-NR-C(=O)R 11 ; -(CR2) n NR 11 R 12 、-(CR2) n NR 11 (CR2) n R 15 ; -(CR2) n OR 15 、-(CR2) n R 15 ; or a 5- to 6-membered heteroaryl group having 1 to 4 heteroatoms independently selected from O, S and N; R 4a , R 4b , R 4c and R 4d are independently H or -C1-C4 alkyl; R 10 is H, halogen, -C1-C4 alkyl, -C1-C4 alkoxy, -C1-C4 haloalkoxy or -NH(C1-C4 alkyl); R 11 is H, -C1-C4 alkyl, -hydroxyC1-C4 alkylene, -cyanoC1-C4 alkylene, or -C1-C4 alkyl substituted by -C1-C4 alkoxy; R 12 is H or -C1-C4 alkyl; R 13 is H, halogen, -CN, -OH, -C1-C4 alkyl or -hydroxyC1-C4 alkylene; R 14 is H, halogen or -C1-C4 alkyl; R 15 yes -C3-C6 cycloalkyl or 4- to 6-membered heterocycloalkyl having 1-2 heteroatoms independently selected from O, S, S(=O)2 and N; wherein R 15 The -C3-C6 cycloalkyl or 4- to 6-membered heterocycloalkyl is unsubstituted or substituted with 1-2 substituents selected from -OH, -C1-C4 alkyl, -hydroxyC1-C4 alkylene, -C1-C4 alkoxy, -SO2(C1-C4 alkyl) and -N(C1-C4 alkyl)2; R 16 , if present, is a substituent selected from halogen, -CN, -OH, -C1-C4 alkyl and -hydroxyC1-C4 alkylene; Each R is independently H or -C1-C4 alkyl; m is 0, 1, or 2; and Each n is independently selected from 0, 1 and 2.

2. The compound according to claim 1, or a stereoisomer, enantiomer, enantiomeric mixture or pharmaceutically acceptable salt thereof; wherein R 2 Yes - (CH2) 1-2 C(=O)NR 11 R 15 or -(CR 13 R 14 )-C(=O)NR 11 R 15 .

3. A compound according to claim 1 or claim 2, wherein the compound has formula (II), or a stereoisomer, enantiomer, enantiomeric mixture or pharmaceutically acceptable salt thereof; wherein, R 2 yes 4. The compound of claim 1, wherein the compound has formula (II), or a stereoisomer, enantiomer, mixture of enantiomers, or a pharmaceutically acceptable salt thereof; in: Y is CH or N; R 1 , R 3 , R 4a , R 4b , R 4c , R 4d and R 11 are independently H or C1-C4 alkyl; R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are independently H, halogen or C1-C4 alkyl; R 13 is H, halogen, -CN, -OH, -C1-C4 alkyl or -hydroxy 1- C4 alkylene; R 14 is H, halogen or -C1-C4 alkyl; and R 15 is a 4- to 6-membered heterocycloalkyl group having 1-2 heteroatoms independently selected from O, S and N; and wherein R 15 It is unsubstituted or substituted with 1-2 substituents selected from -OH, -C1-C4 alkyl, -hydroxyC1-C4 alkylene, -C1-C4 alkoxy, -SO2(C1-C4 alkyl) and -N(C1-C4 alkyl)2.

5. The compound according to claim 4, or a stereoisomer, enantiomer, enantiomeric mixture or pharmaceutically acceptable salt thereof; wherein, R 15 yes 6. The compound according to claim 5, or a stereoisomer, enantiomer, mixture of enantiomers or a pharmaceutically acceptable salt thereof; wherein m is 1 and R 16 It is a -C1-C4 alkyl group.

7. The compound according to claim 1, wherein the compound is selected from: 2-(2-(((4-((8-chloro-7-methylquinolin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-methyl-N-(oxetan-3-yl)acetamide; 2-(2-(((4-((8-chloro-7-methylquinolin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-2,2-difluoro-N-(oxetan-3-yl)acetamide; 2-(2-(((4-((8-chloro-7-methylquinolin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-2-hydroxy-N-(oxetan-3-yl)propanamide; 2-(2-(((4-((8-chloro-7-methylquinolin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-2-cyano-N-(oxetan-3-yl)acetamide; 2-(2-(((4-((8-chloro-7-methylquinolin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-3-hydroxy-N-(oxetan-3-yl)propanamide; 2-(2-(((4-((8-chloro-7-methylquinolin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-3-hydroxy-N-(oxetan-3-yl)propanamide; 2-(2-(((4-((8-chloro-7-methylquinolin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-2-hydroxy-N-(oxetan-3-yl)acetamide; 2-(2-(((4-((8-chloro-7-methylquinolin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-(oxetan-3-yl)propanamide; and 2-(6-(((4-((8-chloro-7-methylquinolin-2-yl)amino)cyclohexyl)methyl)amino)pyridin-3-yl)-N-(oxetan-3-yl)acetamide; or a stereoisomer, an enantiomer, a mixture of enantiomers or a pharmaceutically acceptable salt thereof.

8. The compound according to claim 1, wherein the compound is selected from: 2-(2-((((1r,4r)-4-((8-chloro-7-methylquinolin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-methyl- N-(Oxetane-3-yl)acetamide; 2-(2-((((1r,4r)-4-((8-chloro-7-methylquinolin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-2,2-difluoro- N-(Oxetane-3-yl)acetamide; 2-(2-((((1r,4r)-4-((8-chloro-7-methylquinolin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-2-hydroxy- N-(Oxetane-3-yl)propionamide; 2-(2-((((1r,4r)-4-((8-chloro-7-methylquinolin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-2-cyano- N-(Oxetane-3-yl)acetamide; 2-(2-((((1r,4r)-4-((8-chloro-7-methylquinolin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-3-hydroxy- N-(Oxetane-3-yl)propionamide; (S)-2-(2-((((1r,4S)-4-((8-chloro-7-methylquinolin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-3-hydroxy-N-(oxetan-3-yl)propanamide; (R)-2-(2-((((1r,4R)-4-((8-chloro-7-methylquinolin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-3-hydroxy-N-(oxetan-3-yl)propanamide; 2-(2-((((1r,4r)-4-((8-chloro-7-methylquinolin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-2-hydroxy- N-(Oxetane-3-yl)acetamide; (S)-2-(2-((((1r,4S)-4-((8-chloro-7-methylquinolin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-2-hydroxy-N-(oxetan-3-yl)acetamide; (R)-2-(2-((((1r,4R)-4-((8-chloro-7-methylquinolin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-2-hydroxy-N-(oxetan-3-yl)acetamide; 2-(2-((((1r,4r)-4-((8-chloro-7-methylquinolin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-(oxetan-3-yl)propanamide; (S)-2-(2-((((1r,4S)-4-((8-chloro-7-methylquinolin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-(oxetan-3-yl)propanamide; (R)-2-(2-((((1r,4R)-4-((8-chloro-7-methylquinolin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-(oxetan-3-yl)propanamide; and 2-(6-((((1r,4r)-4-((8-chloro-7-methylquinolin-2-yl)amino)cyclohexyl)methyl)amino)pyridin-3-yl)-N-(oxetan-3-yl)acetamide; or a mixture of enantiomers or a pharmaceutically acceptable salt thereof.

9. The compound of claim 1, wherein the compound is 2-(2-(((4-((8-chloro-7-methylquinolin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-(oxetan-3-yl)acetamide; or a stereoisomer, enantiomer, mixture of enantiomers, or a pharmaceutically acceptable salt thereof.

10. The compound according to claim 1, wherein the compound is 2-(2-((((1R,4R)-4-((8-chloro-7-methylquinolin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-(oxetan-3-yl)acetamide; or an enantiomeric mixture or a pharmaceutically acceptable salt thereof.

11. The compound of claim 1, wherein the compound is 2-(2-(((4-((8-chloro-7-methylquinolin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-(oxetan-3-yl)propanamide; or a stereoisomer, enantiomer, enantiomeric mixture, or pharmaceutically acceptable salt thereof.

12. The compound according to claim 1, wherein the compound is (S)-2-(2-((((1r,4S)-4-((8-chloro-7-methylquinolin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-(oxetan-3-yl)propanamide or (R)-2-(2-((((1r,4R)-4-((8-chloro-7-methylquinolin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-(oxetan-3-yl)propanamide; or an enantiomeric mixture or a pharmaceutically acceptable salt thereof.

13. The compound of claim 1, wherein the compound is 2-(6-(((4-((8-chloro-7-methylquinolin-2-yl)amino)cyclohexyl)methyl)amino)pyridin-3-yl)-N-(oxetan-3-yl)acetamide; or a stereoisomer, enantiomer, mixture of enantiomers, or a pharmaceutically acceptable salt thereof.

14. The compound according to claim 1, wherein the compound is 2-(6-((((1r,4r)-4-((8-chloro-7-methylquinolin-2-yl)amino)cyclohexyl)methyl)amino)pyridin-3-yl)-N-(oxetan-3-yl)acetamide; or an enantiomeric mixture or a pharmaceutically acceptable salt thereof.

15. A pharmaceutical composition comprising the compound according to any one of claims 1 to 14, and a pharmaceutically acceptable carrier.

16. A combination comprising a compound as claimed in any one of claims 1 to 14, and one or more therapeutically active agents.

17. The combination according to claim 16, wherein the one or more therapeutically active agents are selected from anticancer agents, immunomodulators, antiallergic agents, antiemetics, analgesics and cytoprotective agents.

18. A method for treating a disease or condition mediated by Enhancer of Zeste homolog 2 (EZH2), Polycomb repressive complex 2 (PRC2), or a combination of Enhancer of Zeste homolog 2 (EZH2) and Polycomb repressive complex 2 (PRC2), the method comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound as described in any one of claims 1-14.

19. The method of claim 18, wherein the disease or disorder is diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, leukemia, multiple myeloma, gastric cancer, malignant rhabdoid tumor, hepatocellular carcinoma, prostate cancer, breast cancer, bile duct and gallbladder cancer, bladder cancer, neuroblastoma, schwannoma, glioma, glioblastoma and astrocytoma, cervical cancer, colorectal cancer, melanoma, endometrial cancer, esophageal cancer, head and neck cancer, lung cancer, nasopharyngeal cancer, ovarian cancer, pancreatic cancer, renal cell carcinoma, rectal cancer, thyroid cancer, parathyroid tumors, uterine tumors, rhabdomyosarcoma, Kaposi's sarcoma, synovial sarcoma, osteosarcoma, or Ewing's sarcoma.

20. Use of a compound of any one of claims 1-14, optionally in combination with a second therapeutic agent, in the preparation of a medicament for treating a disease or condition mediated by Enhancer of Zeste homolog 2 (EZH2), Polycomb repressive complex 2 (PRC2), or a combination of Enhancer of Zeste homolog 2 (EZH2) and Polycomb repressive complex 2 (PRC2).

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