Quinoline compounds and compositions for inhibiting EZH2

Abstract

The invention disclosed herein relates to azaquinoline compounds of formula (I), pharmaceutical compositions containing such compounds; and the use of such compounds to treat diseases or conditions mediated by Enhancer of Zeste Homolog 2 (EZH2), Polycomb Repressive Complex 2 (PRC2), or a combination thereof. [Case 1] TIFF2023538159000045.tif2859

Description

[Technical Field]

[0001] 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 technology]

[0002] Site-specific lysine methylation of histones is a key epigenetic mechanism in regulating and mediating many fundamental biological processes. Polycomb repressive complex 2 (PRC2) methylates histone H3 lysine 27 (H3K27) at genomic regions of target genes, thereby repressing gene transcription. 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, and both can be integrated into PRC2, but they have different tissue and temporal distributions. In PRC2, EZH2 can directly bind the cofactor S-adenosylmethionine (SAM) and transfer methyl groups to histone H3K27 sites to form mono-, di-, and trimethylated lysines (H3K27me1, H3K27me2, and H3K27me3), thereby repressing gene transcription. PRC2-EZH2 has higher activity than PRC2-EZH1, which primarily catalyzes the formation of H3K27me1 and some H3K27me2. EED binds to H3K27me2 / 3 and allosterically activates the enzymatic activity of PRC2, which can promote the spreading of repressive marks.

[0003] EZH2 plays a crucial role in developmental and adult tissue homeostasis and is closely associated with many diseases. EZH2, SUZ12, and EED are overexpressed in many cancers, including but not limited to breast cancer, prostate cancer, and hepatocellular carcinoma. EZH2-activating mutations leading to increased H3K27me3 have been identified in patients with DLBCL (diffuse large B-cell lymphoma), FL (follicular lymphoma), melanoma, and parathyroid adenocarcinoma. Inhibition of PRC2 methyltransferase activity by compounds that compete with the cofactor SAM or directly bind EED in DLBCL reverses the elevated H3K27me3 state, reactivates target gene expression, and inhibits tumor growth / proliferation. Furthermore, EZH2 inhibitors can release the suppression of Th1 chemokines in tumor cells and enhance T cell infiltration in ovarian and colorectal cancer. Summary of the Invention

[0004] 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 summary, there is a great need for small molecules that inhibit the activity of EZH2.

[0005] 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.

[0006] In one aspect, the present invention provides a compound of formula (I), or a stereoisomer, enantiomer, enantiomeric mixture or pharmaceutically acceptable salt thereof:

[0007] [ka] [In the formula, Y is N or CR a and; R a , R 1 , R 3 , R 5 , R6 , R 7 , R 8 and R 9 are independently H, halogen, or -C1-C4 alkyl; R 2 represents -CN, -C1-C6 alkyl, -hydroxyC1-C4 alkylene, -C1-C4 alkoxy, -C2-C4 alkoxy substituted with 1 or 2 hydroxyl 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 ;

[0008] [ka] or a 5- to 6-membered heteroaryl 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 with -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 teeth,

[0009] [ka] , -C3-C6 cycloalkyl or 4- to 6-membered heterocycloalkyl having 1 to 2 heteroatoms independently selected from O, S, S(=O)2 and N; R 15 wherein said -C3-C6 cycloalkyl or 4- to 6-membered heterocycloalkyl is unsubstituted or substituted with 1 to 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 16is, if present, 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; each n is independently selected from 0, 1, and 2. to provide.

[0010] In another aspect, the present invention provides pharmaceutical compositions comprising a compound of formula (I) or a subformula thereof, or a stereoisomer, enantiomer, enantiomeric mixture, or pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

[0011] In yet another aspect, the present invention provides combinations, particularly pharmaceutical combinations, comprising a compound of formula (I) or a sub-formula thereof, or a stereoisomer, enantiomer, enantiomeric mixture or pharmaceutically acceptable salt thereof, and one or more therapeutically active agents.

[0012] The compounds of the present invention can be used alone or in combination with one or more therapeutically active agents to treat or prevent diseases or conditions mediated by EZH2, PRC2, or a combination thereof. DETAILED DESCRIPTION OF THE INVENTION

[0013] The present invention provides compositions and methods for treating or preventing diseases or conditions mediated by EZH2, PRC2, or a combination thereof.

[0014] definition For the purposes of interpreting this specification, the following definitions shall apply and wherever appropriate, terms used in the singular shall also include the plural and vice versa.

[0015] As used herein, the terms "-C1-C6 alkyl" or "-C 1~6"Alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from 1 to 6 carbon atoms and attached to the rest of the molecule by a single bond. The terms "-C1-C4 alkyl" or "-C 1~4 "Alkyl" shall be construed accordingly. Examples of -C1-C6 alkyl include, but are not limited to, methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl), n-butyl, n-pentyl, and 1,1-dimethylethyl (t-butyl).

[0016] As used herein, the term "-C1-C4 alkoxy" refers to a group of the formula -OR a [In the formula, R a is generally C as defined above 1~4 It refers to the radical of the alkyl radical. 1~6 Examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentoxy, and hexoxy.

[0017] The term "cycloalkyl" as used herein 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 adamantanyl. As used herein, the term "C3-C6 cycloalkyl" refers to a saturated monocyclic group having at least three and at most six carbon atoms. Non-limiting examples of such "C3-C6 cycloalkyl" groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups.

[0018] "Halo" or "halogen" refers to bromo, chloro, fluoro, or iodo.

[0019] As used herein, the term "-hydroxyC1~4 "Alkylene" means a -C alkylene group as defined above. 1~4 refers to alkyl radicals, C 1~4 One of the hydrogen atoms in the alkyl radical is replaced by OH. Hydroxy C 1~4 Examples of alkyl include, but are not limited to, ethane-1-olyl, 2-methylpropan-1-olyl, hydroxy-methyl, 2-hydroxy-ethyl, 2-hydroxy-propyl, and 3-hydroxy-propyl.

[0020] As used herein, the term "-cyanoC 1~4 "Alkylene" means a -C alkylene group as defined above. 1~4 Alkyl radicals, -C 1~4 This refers to an alkyl radical in which one of the hydrogen atoms is replaced by CN.

[0021] The term "haloalkoxy," as used herein, refers to a haloalkyl linked to oxygen, which may also be represented as -O-R', where R' represents a haloalkyl group. "C1-C4 haloalkoxy" is intended to include C1, C2, C3, and C4 haloalkoxy groups. 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.

[0022] As used herein, the term "heterocyclyl" or "heterocyclic" refers to a stable 4- to 7-membered non-aromatic monocyclic ring radical containing one, two, or three heteroatoms individually selected from nitrogen, oxygen, and sulfur. The heterocyclyl radical can be attached via a carbon atom or a heteroatom. The term "5- to 6-membered heterocyclyl" should be interpreted accordingly. Examples of heterocyclyl include, but are not limited to, azetidinyl, oxetanyl, pyrrolinyl, pyrrolidyl, tetrahydrofuryl, tetrahydrothienyl, piperidyl, piperazinyl, tetrahydropyranyl, or morpholinyl or perhydroazepinyl.

[0023] As used herein, the term "heterocyclyl 0~6 "Alkyl" refers to a group consisting of a single bond or a C as defined above. 1~6 It refers to a heterocyclic ring, as defined above, attached to the rest of the molecule by an alkyl radical.

[0024] As used herein, the term "heteroaryl" refers to a 5- to 9-membered aromatic monocyclic or fused ring radical containing 1, 2, 3, or 4 heteroatoms individually selected from nitrogen, oxygen, and sulfur. The heteroaryl radical can be bonded via a carbon atom or a heteroatom. The term "5- to 6-membered heteroaryl" should be interpreted accordingly. Examples of 5- to 6-membered monocyclic heteroaryls include, but are not limited to, furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazinyl, pyridazinyl, pyrimidyl, or pyridyl. Examples of fused heteroaryls include, but are not limited to, 9-membered heteroaryls 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]pyridineyl; 1H-indazolyl, and 1H-benzo[d]-imidazolyl.

[0025] "EZH2" refers to enhancer of Zeste homolog 2.

[0026] "PRC2" refers to polycomb repressive complex 2.

[0027] 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.

[0028] The term "disease or condition mediated by Enhancer of Zeste homolog (EZH2), Polycomb repressive complex 2 (PRC2), or the 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.

[0029] 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 yet other embodiments, the subject is a human.

[0030] As used herein, the terms "inhibit," "inhibition," or "inhibiting" refer to the reduction or abrogation of a given condition, symptom, or disorder or disease, or a significant decrease in the baseline activity of a biological activity or process.

[0031] As used herein, the terms "treat," "treating," or "treatment" of any disease or disorder refers to alleviating or ameliorating the disease or disorder (i.e., slowing or halting the development of the disease or at least one of its clinical symptoms), or alleviating or ameliorating at least one physical parameter or biomarker associated with the disease or disorder, including those that may not be discernible to the patient.

[0032] As used herein, the terms "prevent," "preventing," or "prevention" of any disease or disorder refers to the protective treatment of a disease or disorder or the delay in the onset or progression of a disease or disorder.

[0033] As used herein, a subject is "in need of" a treatment if such subject would benefit biologically, medically, or in quality of life from such treatment.

[0034] As used herein, the term "therapeutically effective amount" of a compound of the invention refers to an amount of a compound of the invention that will elicit a biological or medical response in a subject, such as a reduction or inhibition of enzyme or protein activity, or that will ameliorate symptoms, alleviate a condition, slow or delay disease progression, or prevent disease, etc.

[0035] As used herein, the term "pharmaceutical composition" refers to a compound of the present invention or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable carrier, in a form suitable for oral or parenteral administration.

[0036] As used herein, the term "pharmaceutically acceptable carrier" refers to a substance useful in the preparation or use of a pharmaceutical composition, and includes, for example, suitable diluents, solvents, dispersion media, surfactants, antioxidants, preservatives, isotonicity agents, buffers, emulsifiers, absorption delaying agents, salts, drug stabilizers, binders, excipients, disintegrants, lubricants, wetting agents, sweeteners, flavoring agents, dyes, and combinations thereof, as would be known to those skilled in the art (see, e.g., Remington The Science and Practice of Pharmacy, 22 nd Ed. Pharmaceutical Press, 2013, pp. 1049-1070).

[0037] As used herein, the terms "a," "an," "the," and similar terms used in the context of the present invention (especially in the context of the claims) are to be construed as encompassing both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

[0038] Description of the Preferred Embodiments The present invention provides compounds that inhibit EZH2; and compositions and methods for treating or preventing conditions mediated by EZH2, PRC2, or a combination thereof.

[0039] Various enumerated embodiments of the present invention are described herein. The specified features in each embodiment may be combined with other specified features to provide further embodiments of the present invention.

[0040] Embodiment 1. A compound of formula (I), or a stereoisomer, enantiomer, enantiomeric mixture, or pharmaceutically acceptable salt thereof, as described above.

[0041] Embodiment 2. A compound according to embodiment 1 having formula (I-1), or a stereoisomer, enantiomer, enantiomeric mixture, or pharmaceutically acceptable salt thereof.

[0042] [ka] [In the formula, R 1 , R 2 , R 3 , R 4a , R 4b , R 4c , R 4d , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 is as defined in equation (1)].

[0043] Embodiment 3. A compound according to embodiment 1, having formula (I-2), or a stereoisomer, enantiomer, enantiomeric mixture, or pharmaceutically acceptable salt thereof.

[0044] [ka] [In the formula, Y, R 2 and R 10 is as defined in equation (1)].

[0045] Embodiment 4. A compound according to embodiment 1 having formula (I-3), or a stereoisomer, enantiomer, enantiomeric mixture, or pharmaceutically acceptable salt thereof.

[0046] [ka] [In the formula, Y, R 2 and R 10 is as defined in equation (1)].

[0047] Embodiment 5. A compound according to embodiment 1 having formula (I-4), or a stereoisomer, enantiomer, enantiomeric mixture, or pharmaceutically acceptable salt thereof.

[0048] [ka] [Wherein, Y and R 2 is as defined in equation (1)].

[0049] Embodiment 6. A compound according to embodiment 1 having formula (I-5), or a stereoisomer, enantiomer, enantiomeric mixture, or pharmaceutically acceptable salt thereof.

[0050] [ka] [Wherein, Y and R 2 is as defined in equation (1)].

[0051] Embodiment 7. A compound according to embodiment 1 having formula (I-6), or a stereoisomer, enantiomer, enantiomeric mixture, or pharmaceutically acceptable salt thereof.

[0052] [ka] [In the formula, R 2 is as defined in equation (1)].

[0053] Embodiment 8. A compound according to embodiment 1 having formula (I-7), or a stereoisomer, enantiomer, enantiomeric mixture, or pharmaceutically acceptable salt thereof.

[0054] [ka] [In the formula, R 2 is as defined in equation (1)].

[0055] Embodiment 9. R 2 -CN, -NH2, -C(=O)NH2, triazolyl,

[0056] [ka]

[0057] [ka] The compound according to any one of embodiments 1 to 8, wherein:

[0058] Embodiment 10. R 2 But -(CH2) 1~2 C(=O)NR 11 R 15 or -(CR 13 R 14 )-C(=O)NR 11 R 15 The compound according to any one of embodiments 1 to 8, wherein:

[0059] Embodiment 11. R 15 is a 4- to 6-membered heterocycloalkyl having 1-2 heteroatoms independently selected from O, S, and N; and said 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, or a stereoisomer, enantiomer, enantiomeric mixture, or a pharmaceutically acceptable salt thereof.

[0060] Embodiment 12. R 15 but,

[0061] [ka] 12. The compound according to embodiment 10 or 11, wherein R is 15 teeth,

[0062] [ka] is.

[0063] Embodiment 13. m is 1; R 16 The compound according to embodiment 12, wherein is -C1-C4 alkyl.

[0064] Embodiment 14. R 2 but,

[0065] [ka] 14. The compound according to any one of embodiments 1 to 13, wherein:

[0066] Embodiment 15. A compound according to embodiment 1, having formula (II), or a stereoisomer, enantiomer, enantiomeric mixture, or pharmaceutically acceptable salt thereof.

[0067] [ka] [In the formula, 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 -hydroxyC1-C4 alkylene; R 14 is H, halogen or -C1-C4 alkyl; R 15is a 4- to 6-membered heterocycloalkyl having 1-2 heteroatoms independently selected from O, S, and N; R 15 is unsubstituted or substituted with 1 to 2 substituents selected from -OH, -C1-C4 alkyl, -hydroxyC1-C4 alkylene, -C1-C4 alkoxy, -SO2(C1-C4 alkyl) and -N(C1-C4 alkyl)2.

[0068] Embodiment 16. A compound according to embodiment 15, having formula (II-1), or a stereoisomer, enantiomer, enantiomeric mixture, or pharmaceutically acceptable salt thereof.

[0069] [ka]

[0070] Embodiment 17. A compound according to embodiment 15, having formula (II-2), or a stereoisomer, enantiomer, enantiomeric mixture, or pharmaceutically acceptable salt thereof.

[0071] [ka]

[0072] Embodiment 18. A compound according to embodiment 15, having formula (II-3), or a stereoisomer, enantiomer, enantiomeric mixture, or pharmaceutically acceptable salt thereof.

[0073] [ka]

[0074] Embodiment 19. R 15is azetidinyl or oxetanyl, each of which is unsubstituted or substituted with —OH, —C1-C4 alkyl, or —hydroxyC1-C4 alkylene, or a stereoisomer, enantiomer, enantiomeric mixture, or pharmaceutically acceptable salt thereof.

[0075] Embodiment 20. R 15 but,

[0076] [ka] or a stereoisomer, enantiomer, enantiomeric mixture, or pharmaceutically acceptable salt thereof. In certain embodiments, R 15 teeth,

[0077] [ka] is.

[0078] Embodiment 21. m is 1; R 16 The compound according to embodiment 20, wherein is -C1-C4 alkyl.

[0079] Embodiment 22. 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)-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, enantiomer, enantiomeric mixture or pharmaceutically acceptable salt thereof, selected from:

[0080] Embodiment 23. 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; 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; 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; 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; 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; (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-(oxetan-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 an enantiomeric mixture or a pharmaceutically acceptable salt thereof.

[0081] Embodiment 24. A compound according to embodiment 1 which 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, enantiomeric mixture, or pharmaceutically acceptable salt thereof.

[0082] Embodiment 25. A compound according to embodiment 24 which 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.

[0083] Embodiment 26. A compound according to embodiment 1 which 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.

[0084] Embodiment 27. A compound according to embodiment 26, which 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.

[0085] Embodiment 28. A compound according to embodiment 1 which 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, enantiomeric mixture, or pharmaceutically acceptable salt thereof.

[0086] Embodiment 29. A compound according to embodiment 25 which 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.

[0087] Embodiment 30. A pharmaceutical composition comprising a compound according to any one of embodiments 1 to 29 and one or more pharmaceutically acceptable carriers.

[0088] Embodiment 31. A combination comprising a compound according to any one of embodiments 1 to 29 and one or more additional therapeutically active agents.

[0089] Embodiment 32. A combination according to embodiment 31, wherein the one or more additional therapeutically active agents is an anti-cancer agent, an analgesic, an anti-inflammatory agent, an immunomodulatory agent, or a combination thereof.

[0090] Embodiment 33 A compound according to any one of embodiments 1 to 29, optionally in combination with a second therapeutic agent, for use in treating a disease or condition mediated by EZH2, PRC2 or EZH2 / PRC2.

[0091] Embodiment 34 The compound according to embodiment 33, wherein the second therapeutic agent is an anti-cancer agent, an analgesic, an anti-inflammatory agent, or a combination thereof.

[0092] Embodiment 35 Use of a compound according to any one of embodiments 1 to 29, optionally in combination with a second therapeutic agent, in the manufacture of a medicament for a disease or condition mediated by EZH2, PRC2 or EZH2 / PRC2.

[0093] Embodiment 36. A method for treating a disease or condition mediated by EZH2, PRC2 or EZH2 / PRC2, 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 disease or condition mediated by EZH2, PRC2 or EZH2 / PRC2.

[0094] Embodiment 37. A method for treating a disease or condition that would benefit from or be treatable by inhibition of EZH2, PRC2 or EZH2 / PRC2, 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 said disease or condition that would benefit from or be treatable by inhibition of EZH2, PRC2 or EZH2 / PRC2.

[0095] 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 would benefit from or be treatable by inhibition of 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, colon 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 tumor, uterine tumor, rhabdomyosarcoma, Kaposi's sarcoma, synovial sarcoma, osteosarcoma, and Ewing's sarcoma.

[0096] 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 would benefit from or is treatable by inhibition of 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.

[0097] Embodiment 40. A method for inhibiting EZH2, PRC2 or EHZ2 / PRC2, comprising administering a compound of any one of embodiments 1 to 29, thereby inhibiting EZH2, PRC2 or EZH2 / PRC2.

[0098] Unless otherwise specified, the term "compound(s) of the invention" refers to compounds of Formula (I), subformulas thereof, and exemplified compounds and salts thereof, and all stereoisomers (including diastereoisomers and enantiomers), rotamers, tautomers and isotopically labeled compounds (including deuterium substitution), and inherently formed moieties. "Compounds of the invention" further includes N-oxide derivatives of such compounds.

[0099] Depending on the selection of starting materials and procedures, the compounds may exist in one of the possible stereoisomers or as a mixture thereof, e.g., as pure optical isomers or as stereoisomeric mixtures, such as racemic and diastereomeric mixtures, depending on the number of asymmetric carbon atoms. The present invention is intended to encompass all such possible stereoisomers, including racemic mixtures, diastereomeric mixtures, and optically pure forms. Optically active (R)- and (S)-stereoisomers may be prepared using chiral synthons or chiral reagents or resolved using conventional techniques. Substituents at atoms bearing unsaturated double bonds may, where possible, exist in cis- (Z)- or trans- (E)-form. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis- or trans-configuration.

[0100] Any asymmetric atom (e.g., carbon, etc.) of the compounds of the present invention can be present in racemic or enantiomerically enriched, e.g., (R)-, (S)-, or (R,S)-configuration. In certain embodiments, each asymmetric atom is in the (R)- or (S)-configuration with 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.

[0101] Thus, as used herein, the compounds of the present invention can be in the form of one of the possible stereoisomers, rotamers, atropisomers, tautomers or mixtures thereof, for example as a substantially pure geometric (cis or trans) stereoisomer, diastereomer, optical isomer (enantiomer), racemate or mixture thereof.

[0102] Any resulting mixture of stereoisomers can be separated on the basis of the physical chemical differences of the components into pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and / or fractional crystallization.

[0103] Any resulting racemic forms of the compounds or intermediates of the present invention can be resolved into their optical antipodes by known methods, for example, by separation of their diastereomeric salts, which are obtained by liberating optically active acidic or basic compounds using optically active acids or bases. In particular, basic moieties can be used in this manner to resolve the compounds of the present invention into their optical antipodes by fractional crystallization of salts formed with optically active acids, such as tartaric acid, dibenzoyltartaric acid, diacetyltartaric acid, di-O,O'-p-toluoyltartaric acid, mandelic acid, malic acid, or camphor-10-sulfonic acid. The racemic compounds or racemic intermediates of the present invention can also be resolved by chiral chromatography, for example, high-pressure liquid chromatography (HPLC), using a chiral adsorbent.

[0104] Any formula described herein is also intended to represent the unlabeled form and isotopically labeled form of compound.Isotopically labeled compound has the structure described by the formula described herein, except that one or more atoms are replaced by atoms with selected atomic mass or mass number.The isotope that can be incorporated into the compound of the present invention includes, for example, hydrogen isotope.

[0105] Additionally, certain isotopes, particularly deuterium (i.e. 2Incorporation of H or D) may result in certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements or improved therapeutic index or tolerability. It is understood that deuterium in this context is considered a substituent of a compound of formula (I) or a subformula thereof. The concentration of deuterium can be defined by the isotopic enrichment factor. The term "isotopic enrichment factor" as used herein means the ratio between the isotopic abundance and the natural abundance of a particular isotope. When a substituent in a compound of the invention is designated as deuterium, such compounds have, for each designated deuterium atom, an isotopic enrichment factor of at least 3500 (52.5% deuterium incorporation at 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 apply to any isotope in the same manner as described for deuterium.

[0106] Other examples of isotopes that may be incorporated into the compounds of the present invention are: 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, etc., each include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine. Thus, the present invention includes, for example, 3 H and 14 Radioactive isotopes such as C, or 2 H and 13It should be understood to include compounds incorporating one or more of any of the foregoing isotopes, including those in which a non-radioactive isotope such as C is present. Such isotopically labeled compounds are useful for metabolic studies ( 14 C), reaction kinetic 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 assays, or in radiation treatment of patients. 18 F or labeled compounds are particularly desirable for PET or SPECT studies. Isotopically labeled compounds of Formula (I) or subformulas thereof may generally be prepared by conventional techniques known to those skilled in the art, or by processes analogous to those described in the accompanying Examples, substituting an appropriate isotopically labeled reagent for the previously used non-labeled reagent.

[0107] The compounds of the present invention are obtained either in free form or as their salts. As used herein, the term "salt(s)" refers to acid addition or base addition salts of the compounds of the present invention. "Salt" specifically includes "pharmaceutical acceptable salts." The term "pharmaceutical acceptable salts" refers to salts that retain the biological effectiveness and properties of the compounds of the present invention and are typically not biologically or otherwise undesirable. In many cases, the compounds of the present invention can form acid and / or base salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto.

[0108] Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. Organic acids from which salts can be derived 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.

[0109] Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from groups I to XII of the periodic table. In certain embodiments, salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper, with particularly preferred salts including ammonium, potassium, sodium, calcium, 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, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

[0110] In another aspect, the present invention provides a compound of the present invention in the form of acetate, ascorbate, adipate, aspartate, benzoate, besylate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camphorsulfonate, caprate, chloride / hydrochloride, chlorotheophylline, citrate, ethanedisulfonate, fumarate, gluceptate, gluconate, glucuronate, glutamate, glutarate, glycolate, hippurate, hydroiodide / iodide, isethionate, lactate, lactobiolate, or the like. and the like. The compounds may be provided in the salt form of phosphate, lauryl sulfate, malate, maleate, malonate, mandelate, mesylate, methylsulfate, mucate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, polygalacturonate, propionate, sebacate, stearate, succinate, sulfosalicylate, sulfate, tartrate, tosylate, triphenylacetate, trifluoroacetate or xinafoate.

[0111] Pharmacology and Usefulness In one aspect, the present invention provides compounds of formula (I) or a subformula thereof, or a pharmaceutically acceptable salt thereof, useful for therapy, particularly for treating or preventing diseases or conditions mediated by EZH2, PRC2, or a combination thereof.

[0112] In another aspect, the present invention provides the use of a compound of formula (I) or a subformula thereof, or a pharmaceutically acceptable salt thereof, for treating a disease or condition that would benefit from or is treatable by inhibition of EZH2, PRC2, or a combination thereof; and for the manufacture of a medicament for treating a disease or condition that is treatable by inhibition of EZH2, PRC2, or a combination thereof.

[0113] Examples of diseases or conditions that are mediated by EZH2, PRC2, or EZH2 / PRC2, or that would benefit from or be treatable by inhibition of 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, colon 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.

[0114] Pharmaceutical Compositions, Dosages and Administration In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0115] In further embodiments, the composition comprises at least two pharmaceutically acceptable carriers, such as those described herein. Pharmaceutical compositions can be formulated for specific routes of administration, such as oral administration, parenteral administration (e.g., by injection, infusion, transdermal or topical administration), and rectal administration. Topical administration can also involve inhalation or intranasal application. Pharmaceutical compositions of the present invention can be configured in solid form (including, but not limited to, capsules, tablets, pills, granules, powders, or suppositories) or in liquid form (including, but not limited to, solutions, suspensions, or emulsions). Tablets can be either film-coated or enteric-coated according to methods known in the art. Typically, pharmaceutical compositions are tablets or gelatin capsules containing the active ingredient together with one or more of the following: a) diluents, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine; b) lubricants, for example silica, talcum, stearic acid, its magnesium or calcium salts and / or polyethylene glycol; in tablets also c) binders, such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone; if desired, d) disintegrants, such as starch, agar, alginic acid or its sodium salt, or effervescent mixtures; and e) Absorbents, colorants, flavorings and sweetening agents.

[0116] In another embodiment, the compounds of the present invention are combined with other therapeutic agents, such as other anti-cancer agents, anti-allergy agents, anti-nausea agents (or antiemetic agents), analgesics, cytoprotective agents, immunomodulatory agents, and combinations thereof.

[0117] In one embodiment, the other therapeutic agent is an anti-cancer or chemotherapeutic agent. Common chemotherapeutic agents considered for use in combination therapy include anastrozole (Arimidex®), bicalutamide (Casodex®), bleomycin sulfate (Blenoxane®), busulfan (Myleran®), busulfan injection (Busulfex®), capecitabine (Xeloda®), N4-pentoxycarbonyl-5-deoxy-5-fluorocytidine, carboplatin (Paraplatin®), and carmustine. (BiCNU®), chlorambucil (Leukeran®), cisplatin (Platinol®), cladribine (Leustatin®), cyclophosphamide (Cytoxan® or Neosar®), cytarabine, cytosine arabinoside (Cytosar-U®), cytarabine liposome injection (DepoCyt®), dacarbazine (DTIC-Dome®), dactinomycin (actinomycin D, Cosmegen®), osmegan), daunorubicin hydrochloride (Cerubidine®), daunorubicin citrate liposome injection (DaunoXome®), dexamethasone, docetaxel (Taxotere®), doxorubicin hydrochloride (Adriamycin®, Rubex®), etoposide (Vepesid®), fludarabine phosphate (Fludara®), 5-fluorouracil (Adrucil®, Efudex®), flutamivir phosphate (Fludara®), 5-fluorouracil (Adrucil®, Efudex®), (Eulexin®), tezacitibine, gemcitabine (difluorodeoxycytidine), hydroxyurea (Hydrea®), idarubicin (Idamycin®), ifosfamide (IFEX®), irinotecan (Camptosar®), L-asparaginase (ELSPAR®), leucovorin calcium, melphalan (Alkeran®), 6-mercaptopurine (Purinethol®),These include methotrexate (Folex®), mitoxantrone (Novantrone®), Mylotarg, paclitaxel (Taxol®), nab-paclitaxel (Abraxane®), Phoenix (Yttrium 90 / MX-DTPA), pentostatin, polifeprosan 20 with carmustine implant (Gliadel®), tamoxifen citrate (Nolvadex®), teniposide (Vumon®), 6-thioguanine, thiotepa, tirapazamine (Tirazone®), injectable topotecan hydrochloride (Hycamptin®), vinblastine (Velban®), vincristine (Oncovin®), and vinorelbine (Navelbine®).

[0118] Anti-cancer agents of particular interest for combination with the compounds of the invention include: 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)); alvocidib (also known as flavopiridol or HMR-1275, 2-(2-chlorophenyl)-5,7-dihydroxy-8-[(3S,4R)-3-hydroxy-1-methyl-4-piperidinyl]-4-chromenone and 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); Indisla (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 (B387032, CA S345627-80-7; 4-[[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino]-benzoic acid (MLN8054, CAS869363-13-3); 5-[3-(4,6-difluoro-1H-benzimidazol-2-yl)-1H-indazol-5-yl]-N-ethyl-4-methyl-3-pyridinemethanamine (AG-024322, CAS837364-57-5);4-(2,6-Dichlorobenzoylamino)-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-cyclopropylsulfonimidoyl]-phenyl]amino]-5-(trifluoromethyl)-4-pyrimidinyl]oxy]-2-butanol (BAY10000394).

[0119] 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, CAS891494-63-6); 5-(3-fluorophenyl)-3-ureidothiophene-2-carboxylic acid N-[(S)-piperidin-3-yl]amide (AZD7762, CAS860352-01- 8);4-[((3S)-1-azabicyclo[2.2.2]oct-3-yl)amino]-3-(1H-benzimidazol-2-yl)-6-chloroquinolin-2(1H)-one (CHIR124, 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]benzodiazocin-1,3(2H)-dione (SB-218078, CAS 135897-06-2 ); and TAT-S216A (YGRKKRRQRRRLYRSPAMPENL) 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-oxo-1H-pyrrolo[4,3,2-ef][2,3]benzodiazepin-8-yl]-cyclohexaneacetamide (PF-0477736).

[0120] 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-aminocyclobutyl)phenyl]-9-phenyl-1,2,4-triazolo[3,4-f][1,6]naphthyridin-3(2H)-one (MK-2206, CAS 1032349-93-1); (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; Triciribine (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]-benzeneethanamine (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).

[0121] C-RAF inhibitors: (Chang, C. et al., Cancer Cell, 19(1):86-100 (2011)) sorafenib (Nexavar®); 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).

[0122] 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 GDC0941 and described in 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 WO 06 / 122806 and also known as dactolisib); 4-(trifluoromethyl)-5-(2,6-dimorpholinopyrimidin-4-yl)pyridin-2-amine (described in WO 2007 / 084786 and also known as buparisib); tozasertib (VX680 or MK-0457, CAS 6 39089-54-6;(5Z)-5-[[4-(4-pyridinyl)-6-quinolinyl]methylene]-2,4-thiazolidinedione (GSK1059615, CAS958852-01-2);(1E,4S,4aR,5R,6aS,9aR)-5-(acetyloxy)-1-[(di-2-propenylamino)methylene]-4,4a,5,6,6a,8,9,9a-octahydro-11-hydroxy-4-(methoxymethyl)-4a,6a-dimethicone thyl-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, CAS 154447-36-6); 2-amino-8-ethyl-4-methyl-6-(1H-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (SAR245409 or XL765);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-butanedioate (1:1) (BGT226); 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 (SAR245408 or XL147); 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).

[0123] BCL-2 inhibitors: (Beguelin, 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 WO 09 / 155386); tetrocarcin A; antimycin; gossypol ((-)BL-193); obatoclax; ethyl-2-amino-6-cyclopentyl-4-(1-cyano-2-ethoxy-2-oxoethyl)-4Hchromone-3-carboxylate (HA14-1); oblimersen (G3139, Genasense®); Bak BH3 peptides; (-)-gossypol acetic acid (AT-101); 4-[4-[(4'-chloro[1,1'-biphenyl]-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).

[0124] Mitogen-activated protein kinase (MEK) inhibitor: (Chang, CJ et al., Cancer Cell, 19(1):86-100 (2011)) XL-518 (also known as GDC-0973, Cas number 1029872-29-4, ACC Corp.available from Pharmacia; selumetinib (5-[(4-bromo-2-chlorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H-benzimidazole-6-carboxamide, also known as AZD6244 or ARRY142886, and described in WO 2003077914); Benimetinib (6-(4-bromo-2-fluorophenyl)amino)-7-fluoro-3-methyl-3H-benzimidazole-5-carboxylic acid (2-hydroxyethoxy(h hydroxyethyoxy))-amide, also known as MEK162, CAS 1073666-70-2, described in WO 2003077914; 2-[(2-chloro-4-iodophenyl)amino]-N-(cyclopropylmethoxy)-3,4-difluoro-benzamide (also known as CI-1040 or PD184352, described in WO 2000035436); N-[(2R)-2,3-dihydroxypropoxy]-3,4-difluoro-2-[(2- [fluoro-4-iodophenyl)amino]-benzamide (also known as PD0325901 and described in WO 2002006213); 2,3-bis[amino[(2-aminophenyl)thio]methylene]-butanedinitrile (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]-cyclopropanesulfonyl] flavoneamide (also known as RDEA119 or BAY869766 and described in WO 2007014011); (3S,4R,5Z,8S,9S,11E)-14-(ethylamino)-8,9,16-trihydroxy-3,4-dimethyl-3,4,9,19-tetrahydro-1H-2-benzoxacyclotetradecine-1,7(8H)-dione (also known as E6201 and described in WO 2003076424); 2'-amino-3'-methoxyflavone (Biaffin GmbH & Co. KG);, also known as PD98059, available from Pharmacia Biosciences, KG, Germany; 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, CAS 1035555-63-5); pimasertib (AS-703026, CAS 1204531-26-9); trametinib dimethyl sulfoxide (GSK-1120212, CAS1204531-25-80); 2-(2-fluoro-4-iodophenylamino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide (AZD8330); and 3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-N-(2-hydroxyethoxy)-5-[(3-oxo-[1,2]oxazinan-2-yl)methyl]benzamide (CH4987655 or Ro4987655).

[0125] Aromatase inhibitors: (Pathiraja, T. et al., Sci. Transl. Med., 6(229):229 ra41 (2014)) exemestane (Aromasin®); letrozole (Femara®); and anastrozole (Arimidex®).

[0126] Topoisomerase II inhibitors: (Bai, J. et al., Cell Prolif., 47(3):211-8 (2014)) etoposide (VP-16 and etoposide phosphate, Toposar®, VePesid®, and Etopophos®); teniposide (VM-26, Vumon®); and tafluposide.

[0127] SRC inhibitors: (Hebbard, L., Oncogene, 30(3):301-12 (2011)) dasatinib (Sprycel®); saracatinib (AZD0530, CAS379231-04-6); bosutinib (SKI-606, CAS380843-75-4); 5-[4-[2-(4-morpholinyl)ethoxy]phenyl]-N-(phenylmethyl)-2-pyridineacetamide (KX2-391, CAS897016-82-9); and 4-(2-chloro-5-methoxyanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (AZM475271, CAS476159-98-5).

[0128] Histone deacetylase (HDAC) inhibitors: (Yamaguchi, J. et al., Cancer Sci., 101(2):355-62 (2010)) vorinostat (Zolinza®); romidepsin (Istodax®); Treichostatin A (TSA); oxamflatin; vorinostat (Zolinza®, suberoylanilide hydroxamic acid); pyroxamide (suberoylsyberoyl-3-aminopyridineamide hydroxamic acid); trapoxin A (RF-1023A); trapoxin B (RF-10238); Cyclo[(αS,2S)-α-amino-η-oxo-2-oxiraneoctanoyl-O-methyl-D-tyrosyl-L-isoleucyl-L-prolyl] (Cyl-1); Cyclo[(αS,2S)-α-amino-η-oxo-2-oxiraneoctanoyl-O-methyl-D-tyrosyl-L-isoleucyl-(2S)-2-piperidinecarbonyl] (Cyl-2); Cyclo[L-alanyl-D-alanyl-(2S)-η-oxo-L-α-aminooxiraneoctanoyl-D-prolyl] (HC toxin );cyclo[(αS,2S)-α-amino-η-oxo-2-oxiraneoctanoyl-D-phenylalanyl-L-leucyl-(2S)-2-piperidinecarbonyl] (WF-3161); chlamydocin ((S)-cyclic(2-methylalanyl-L-phenylalanyl-D-prolyl-η-oxo-L-α-aminooxiraneoctanoyl); apicidin (cyclo(8-oxo-L-2-aminodecanoyl-1-methoxy-L-tryptophyl-L-isoleucyl-D-2-piperidinecarbonyl) ol); romidepsin (Istodax®, 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-dianhydro-1,2,6,7,11-pentadeoxy-D-threo-D-ido-undeca-1,6-dienitol).

[0129] Antitumor antibiotics: (Bai, J. et al., Cell Prolif., 47(3):211-8 (2014)) doxorubicin (Adriamycin® and Rubex®); bleomycin (lenoxane®); daunorubicin (daunorubicin hydrochloride, daunomycin and rubidomycin hydrochloride, Cerubidine®); daunorubicin liposomal (daunorubicin citrate liposomal, DaunoXome®); mitoxantrone (DHAD, Novantrone®); epirubicin (Ellence™); idarubicin (Idamycin®, Idamycin PFS®); mitomycin C (Mutamycin®); geldanamycin; herbimycin; rubidomycin; and desacetyl rubidomycin.

[0130] Demethylating agents: (Musch, T. et al., PLoS One, (5):e10726 (2010)) 5-azacytidine (Vidaza®); and decitabine (Dacogen®).

[0131] Antiestrogens: (Bhan, A. et al., J Mol Biol., S0022-2836(14)00373-8 (2014)) Tamoxifen (Novaldex®); Toremifene (Fareston®); and Fulvestrant (Faslodex®).

[0132] Particularly interesting immunomodulatory agents for combination with the compounds of the invention include one or more activators of costimulatory 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.

[0133] In certain embodiments, the immunomodulatory agent is an activator of a costimulatory molecule. In one embodiment, the costimulatory molecule agonist is selected from an agonist (e.g., an agonistic antibody or antigen-binding fragment thereof, or a soluble fusion) of 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 ligand.

[0134] In certain embodiments, the immunomodulatory agent is an inhibitor of an immune checkpoint molecule. In one embodiment, the immunomodulatory agent is an inhibitor of PD-1, PD-L1, PD-L2, CTLA4, TIM3, LAG3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4, and / or TGFRbeta. In one embodiment, the inhibitor of an immune checkpoint molecule inhibits PD-1, PD-L1, LAG-3, TIM-3, or CTLA4, or any combination thereof. The term "inhibition" or "inhibitor" includes a reduction in a particular parameter, e.g., activity, of a given molecule, e.g., an immune checkpoint inhibitor. For example, inhibition of at least 5%, 10%, 20%, 30%, 40% or more of activity, e.g., PD-1 or PD-L1 activity, is encompassed by this term. Thus, inhibition need not be 100%.

[0135] In another aspect, the present invention provides pharmaceutical compositions comprising at least one compound of the present invention (e.g., a compound of Formula (I) or a subformula thereof) or a pharmaceutically acceptable salt thereof, either alone or together with other anti-cancer agents, together with a pharmaceutically acceptable carrier suitable for administration to a human or animal subject.

[0136] In combination therapy, the compositions will be formulated either together as a combined therapeutic agent or as separate compositions. The compounds of the present invention and other therapeutic agents may be manufactured and / or formulated by the same or different manufacturers. The structures of therapeutic agents identified by code numbers, generic names, or trade names can be taken from the current edition of the standard compendium "The Merck Index" or from databases such as international patents (e.g., IMS World Publications). Other therapeutic agents that can be used in combination with the compounds of the present invention can be prepared and administered as described in the art, such as in the documents cited above.

[0137] Optionally, the pharmaceutical composition may contain a pharmaceutically acceptable carrier as described above. The pharmaceutical composition or combination of the present invention may be, for example, in a unit dosage of about 0.5 mg to 1000 mg of the active ingredient for a subject weighing about 50 to 70 kg.

[0138] In another aspect, the present invention provides a method for treating a human or animal subject suffering from a cell proliferative disease such as cancer, comprising administering to the subject a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, either alone or in combination with other anticancer drugs.In combination therapy, the compound of the present invention and other anticancer drugs can be administered simultaneously, concurrently, or sequentially without specific time restrictions, and such administration provides therapeutically effective levels of the two compounds in the patient's body.In addition, the compound of the present invention and other therapeutic drugs can be combined into a combination therapy (i) before the release of a combination product to a physician (for example, in the case of a kit containing the compound of the present invention and other therapeutic drugs); (ii) by the physician (or under the physician's guidance) immediately before administration; (iii) by the patient himself, for example, during the sequential administration of the compound of the present invention and other therapeutic drugs.

[0139] In one embodiment, the compound of the present invention and other anticancer drugs are generally administered sequentially by injection or orally in any order.Dosage regimen can vary according to the stage of disease, patient's physical condition, the safety profile and tolerance of each drug, and other criteria that are well known to the doctor and practitioner who administers the combination.The compound of the present invention and other anticancer drugs can be administered within minutes, hours, days, or even weeks apart, depending on the specific cycle used in treatment.In addition, cycle can include administering one drug more frequently than the other during treatment cycle, and administering each drug at different doses.

[0140] In yet another embodiment, the compounds of the present invention may be combined with other anti-cancer agents, anti-allergy agents, anti-nausea agents (or antiemetic agents), analgesics, cytoprotective agents, and combinations thereof.

[0141] In some cases, patients may experience allergic reactions to the compounds of the present invention and / or other anti-cancer agents during or after administration. Therefore, to minimize the risk of allergic reactions, anti-allergic agents may be administered. Suitable anti-allergic agents include corticosteroids, such as dexamethasone (e.g., DECADRON®), beclomethasone (e.g., BECLOVENT®), hydrocortisone (also known as cortisone, hydrocortisone sodium succinate, hydrocortisone sodium phosphate; e.g., ALA-CORT®, hydrocortisone phosphate, Solu-CORTEF®, HYDROCORT Acetate®, and LANACORT®), prednisolone (e.g., DELTA-Cortel®, ORAPRED®, PEDIAPRED®, and PRELONE®), prednisone (e.g., DELTASONE®, LIQUID TRIMETHYL PHOSPHATE), and the like. RED®, METICORTEN®, and ORASONE®), methylprednisolone (also known as 6-methylprednisolone, methylprednisolone acetate, methylprednisolone sodium succinate; e.g., DURALONE®, MEDRALONE®, MEDROL®, M-PREDNISOL®, and SOLU-MEDROL®); antihistamines, such as diphenhydramine (e.g., BENADRYL®), hydroxyzine, and cyproheptadine; and bronchodilators, such as the beta-adrenergic receptor agonists albuterol (e.g., PROVENTIL®) and terbutaline (BRETHINE®).

[0142] In other cases, patients may experience nausea during and after administration of the compounds of the present invention and / or other anticancer agents. Therefore, antiemetic drugs may be administered to prevent nausea (upper abdominal) and vomiting. Suitable antiemetic drugs include aprepitant (EMEND®), ondansetron (ZOFRAN®), granisetron HCl (KYTRIL®), lorazepam (ATIVAN®), dexamethasone (DECADRON®), prochlorperazine (COMPAZINE®), casopitant (REZONIC® and Zunrisa®), and combinations thereof.

[0143] In still other cases, medications to alleviate pain experienced during the procedure are prescribed to make the patient more comfortable. Common over-the-counter pain relievers, such as TYLENOL®, are often used. Opioid analgesics, such as hydrocodone / paracetamol or hydrocodone / acetaminophen (e.g., VICODIN®), morphine (e.g., ASTRAMORPH® or AVINZA®), oxycodone (e.g., OXYCONTIN® or PERCOCET®), oxymorphone hydrochloride (OPANA®), and fentanyl (e.g., DURAGESIC®), are also useful for moderate or severe pain.

[0144] Additionally, cytoprotective agents (e.g., neuroprotectants, free radical scavengers, cardioprotectants, anthracycline extravasation neutralizers, nutrients, etc.) may be used as adjunctive therapy to protect normal cells from treatment toxicity and limit organ toxicity. Suitable cytoprotective agents include amifostine (ETHYOL®), glutamine, dimesna (TAVOCEPT®), mesna (MESNEX®), dexrazoxane (ZINECARD® or TOTECT®), xaliproden (XAPRILA®), and leucovorin (also known as calcium leucovorin, citrovorum factor, and folinic acid).

[0145] In another embodiment, the compounds of the present invention can be used in combination with known therapeutic processes, for example, with the administration of hormones or during radiation therapy. In certain cases, the compounds of the present invention can be used as radiosensitizers, especially for the treatment of tumors that exhibit poor sensitivity to radiation therapy.

[0146] In yet another aspect, the present invention provides kits comprising one or more compounds of the present invention and another therapeutic agent, as described above. Exemplary kits include (a) a compound of Formula (I) or a subformula thereof or a pharmaceutically acceptable salt thereof; and (b) at least one other therapeutic agent, such as those indicated above, whereby such kits may further include a package insert or other labeling containing administration instructions. Kits of the present invention may be used to administer different dosage forms, e.g., oral and parenteral, to administer two or more separate pharmaceutical compositions at different dosage intervals, or to titrate separate compositions relative to one another, wherein at least one pharmaceutical composition comprises a compound of Formula (I) or a subformula thereof.

[0147] Processes for Making the Compounds of the Invention The compounds of the invention can be prepared using the methods described below, or by variations thereon as will be appreciated by those skilled in the art of organic synthesis. Compounds of formula (I) that possess chiral centers can be made substantially optically pure by using substantially optically pure starting materials, or by preparative chromatography, recrystallization, or other separation techniques well known in the art.

[0148] [ka]

[0149] As depicted in Scheme 1, compounds of formula (I) can be prepared from a substitution reaction of the corresponding amine (INT-1) with an appropriately substituted 2-halo substituted pyrimidine or pyridine.

[0150] [ka]

[0151] As depicted in Scheme 2, reaction of amine INT-1 with an appropriate pyridine or pyrimidine halide provides the corresponding halo intermediate INT-2. Subsequent coupling of halo intermediate INT-2 with an appropriate bromide provides ester intermediate INT-3, which can be hydrolyzed to acid intermediate INT-4 under acidic or basic conditions. Compounds of formula (I) can be prepared by coupling acid intermediate INT-4 with an appropriately substituted amine.

[0152] [ka]

[0153] As depicted in Scheme 3, Negishi coupling of 2-chloro-5-iodopyrimidine / pyridine with the corresponding bromoacetate followed by alkylation affords intermediate INT-5. Hydrolysis of INT-5 and coupling with the corresponding amine affords the corresponding chloro-pyrimidine or pyridine amide intermediate INT-6. Compounds of formula (II) can be prepared from the substitution reaction of the corresponding amine (INT-1) with the appropriately substituted chloro-pyrimidine or pyridine amide intermediate INT-6. [Example]

[0154] Temperatures are given in degrees Celsius. The structure of final products, intermediates, and starting materials is confirmed by standard analytical methods, e.g., microanalysis and spectroscopic characteristics, e.g., MS, IR, NMR. Abbreviations used are those conventional in the art.

[0155] All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents, and catalysts utilized to synthesize the compounds of the present invention are either commercially available or can be produced by organic synthesis methods known to those skilled in the art (Houben-Weyl 4th Ed. 1952, Methods of Organic Synthesis, Thieme, Volume 21). Unless otherwise specified, starting materials are generally available from commercial sources.

[0156] The examples herein are merely illustrative of the invention and do not limit the scope of the invention as otherwise claimed. Furthermore, the compounds of the invention can be produced by organic synthesis methods known to those skilled in the art, as shown in the examples below. Where desired, conventional protecting groups are used in accordance with standard practice to protect reactive functional groups; see, for example, TW Greene and PGM Wuts in "Protecting Groups in Organic Synthesis", John Wiley and Sons, 1991.

[0157] Abbreviation Abbreviations, as used herein, are defined as follows: "1x" stands for 1 time, "2x" stands for 2 times, "3x" stands for 3 times, "°C" stands for degrees Celsius, "aq" stands for aqueous solution, "FCC" stands for flash column chromatography, "eq" stands for equivalent(s), "g" stands for gram(s), "mg" stands for milligram(s), "L" stands for liter(s), "mL" stands for milliliter(s), "μL" stands for microliter(s), "N" stands for normal, and "M" stands for molar. where "nM" stands for nanomolar, "mol" stands for mole(s), "mmol" stands for millimole(s), "min" stands for minute(s), "h" or "hrs" stands for hour(s), "RT" stands for room temperature, "ON" stands for overnight, "atm" stands for atmosphere, "psi" stands for pounds per square inch, "conc." stands for concentrated, "sat" or "sat'd" stands for saturated, "MW" stands for molecular weight, "mw" or "μ wave" stands for microwave, "mp" stands for melting point, "Wt" stands for weight, "MS" or "Mass "Spec" stands for mass spectrometry, "ESI" stands for electrospray ionization mass spectrometry, "HR" stands for high resolution, "HRMS" stands for high resolution mass spectrometry, "LCMS" or "LC-MS" stands for liquid chromatography mass spectrometry, "HPLC" stands for high pressure liquid chromatography, "RP HPLC" stands for reversed phase HPLC, "TLC" or "tlc" stands for thin layer chromatography, "NMR" stands for nuclear magnetic resonance spectroscopy, "nOe" stands for nuclear Overhauser effect spectroscopy, and " 1 "H" represents proton, "δ" represents delta, "s" represents singlet, "d" represents doublet, "t" represents triplet, "q" represents quartet, "m" represents multiplet, "br" represents broadband, "Hz" represents Hertz, "ee" represents "enantiomeric excess", and "α", "β", "R", "r", "S", "s", "E", and "Z" are stereochemical designations familiar to those skilled in the art.

[0158] The following abbreviations used herein have the corresponding meanings:

[0159] [Table 1]

[0160] Nuclear magnetic resonance (NMR) analysis was performed using a Bruker 400 MHz NMR. The spectral reference was either TMS or solvent of known chemical shift.

[0161] Intermediates Intermediate 1. tert-Butyl (((1R,4R)-4-((8-chloro-7-methylquinolin-2-yl)amino)cyclohexyl)methyl)carbamate

[0162] [ka] 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) was added K2CO3 (3.82 g, 27.7 mmol). 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 x 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. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.97 - 1.09 (m, 2 H), 1.14 - 1.22 (m, 2 H), 1.39 (s, 9 H), 1.45 (br. s., 1 H), 1.75 (d, J=11.80 Hz, 2 H), 2.13 (d, J=11.04 Hz, 2 H), 2.46 (s, 3 H), 2.82 (t, J=6.02 Hz, 2 H), 3.83 - 3.96 (m, 1 H), 6.72 (d, J=8.78 Hz, 1 H), 6.87 (br. s., 1 H), 7.08 (d, J=8.03 Hz, 2 H), 7.46 (d, J=8.28 Hz, 1 H), 7.81 (d, J=8.78 Hz, 1 H). LCMS:404.2

[0163] Intermediate 2. (1R,4R)-N1-(8-chloro-7-methylquinolin-2-yl)cyclohexane-1,4-diamine

[0164] [ka] 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, the residue was dissolved in DCM / i-PrOH (3:1, 50 mL), and the pH was adjusted to 9 with aqueous NaHCO. The aqueous phase was extracted with DCM / i-PrOH (3:1, 3×20 mL). The combined organic layers were washed with brine, dried (NaSO), 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.

[0165] Intermediate 3. 8-chloro-N-((1R,4R)-4-(((5-iodopyrimidin-2-yl)amino)methyl)cyclohexyl)-7-methylquinolin-2-amine

[0166] [ka] 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) were added 2-chloro-5-iodopyrimidine (CAS: 32779-38-7, 702 mg, 2.92 mmol) and DIPEA (1.08 g, 8.34 mmol). 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.

[0167] Intermediate 4. tert-Butyl 2-(2-((((1R,4R)-4-((8-chloro-7-methylquinolin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)acetate

[0168] [ka] 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 minutes, 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 hour 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), Pd(dba) (260 mg, 0.28 mmol), and X-Phos (266 mg, 0.56 mmol) at room temperature, then heated at 60 °C under N under N overnight. The mixture was quenched with NH Cl (100 mL). The aqueous phase was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine, dried (Na SO ), 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.

[0169] Intermediate 5. 8-chloro-N-((1R,4R)-4-(((5-iodopyrimidin-2-yl)amino)methyl)cyclohexyl)-7-methylquinolin-2-amine

[0170] [ka] A solution of 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) in DCM (20 mL) and TFA (20 mL) was 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 (MgSO), 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. 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.00 - 1.25 (m, 4 H), 1.50 - 1.65 (m, 1 H), 1.75-1.90 (m, 2 H), 2.10-2.20 (m, 2 H), 2.45 (s, 3 H), 3.10-3.20 (m, 2 H), 3.25-3.35 (m, 2 H), 3.9 (m, 1 H), 6.7 (d, 1 H), 7.05 (d, 2 H), 7.15 (m, 1 H), 7.45 (d, 1 H), 7.80 (d, 1 H), 8.15 (s, 2 H), 12.25.12.50 (br. S, 1H). MS: [M+H] + = 440, 442

[0171] Example [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

[0172] [ka] 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), oxetan-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 × 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%, then with solvent A (2N NH 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. 1 H NMR (500 MHz, DMSO-d6) δ ppm 1.05 - 1.25 (m, 4 H), 1.55 - 1.65 (m, 1 H), 1.80-1.85 (m, 2 H), 2.10-2.15 (m, 2 H), 2.45 (s, 3 H), 3.15 (t, 2 H), 3.25 (s, 2 H), 3.85-3.95 (br s, 1 H), 4.40 (t, 2 H), 4.70 (t, 2 H), 4.75.4.80 (m, 1 H), 6.75 (d, 1 H), 7.05 (d, 2 H), 7.15 (t, 1 H), 7.45 (d, 1H), 7.80 (d, 1H), 8.12 (s, 2H), 8.72 (d, 1H). MS: [M+H] + = 495, 497.

[0173] The following compounds can be prepared from the corresponding intermediates by the following procedures analogous to Example 1 or from the methods described in Schemes 1-3.

[0174] [Table 2-1]

[0175] [Table 2-2]

[0176] [Table 2-3]

[0177] Assay The utility of the compounds of the present invention may be demonstrated using any one of the following test procedures.

[0178] EZH2 LC-MS assay Representative compounds of the present invention were serially and separately diluted 3-fold in DMSO to obtain 12 concentrations. Then, each concentration of test compound (120 nL each) was transferred to a 384-well Perkin Elmer ProxyPlate 384 Plus plate using a mosquito. A solution (6 μL) of 80 nM wild-type PRC2 (wtPRC2) complex and 60 μM SAM in reaction buffer (20 mM Tris, pH 8.0, 0.1% BSA, 0.01% Triton, 0.5 mM DTT) was added to the wells and then incubated with the test compound for 20 minutes. Each reaction was initiated by adding 6 μL of a solution of 3 μM substrate peptide H3K27me1 (histone H3[21-44]-K27me1-biotin) and 6 μM regulatory peptide H3K27me3 (histone H3[21-44]-K27me3) in reaction buffer. The final components of the reaction solution included 40 nM wtPRC2 complex, 30 μM SAM, 1.5 μM H3K27me1, and 3 μM H3K27me3 peptide, along with various concentrations of compounds. The positive control consisted of 40 nM enzyme, 30 μM SAM, 1.5 μM H3K27me1, and 3 μM H3K27me3 in the absence of test compound, while the negative control consisted of 30 μM SAM, 1.5 μM H3K27me1, and 3 μM H3K27me3 alone. Each reaction was incubated at room temperature for 120 minutes and then stopped by adding 3 μL of quenching solution (2.5% TFA with 320 nM d4-SAH). The reaction mixture was centrifuged (Eppendorf centrifuge 5810, rotor A-4-62) at 2000 rpm for 2 minutes and read on an API4000 triple quadrupole mass spectrometer equipped with a Turbulon Spray (Applied Biosystems) coupled to a Prominence UFLC (Shimadzu Corporation). The level of SAH production was normalized based on the values ​​derived from the positive and negative controls to obtain percent enzyme activity. The data were fitted to a dose-response equation using the program Helios to obtain the IC of the test compound. 50 got the value.

[0179] ELISA (H3K27 methylation) assay Representative compounds of the present invention were serially and separately diluted 3-fold in DO to obtain a total of 8 or 12 concentrations. Compounds were then added to G401 cells cultured in 384-well plates at a 1:500 dilution to obtain a maximum concentration of 20 μM. Cells were further cultured for 48 hours before the ELISA procedure.

[0180] Histone extraction: Cells in 384-well plates were washed with PBS (10x PBS buffer (80 g NaCl (Sigma, S3014), 2 g KCl (Sigma, 60128), 14.4 g NaHPO (Sigma, S5136), 2.4 g KHPO (Sigma, P9791) in 1 L of water, to pH 7.4) and lysed by the addition of lysis buffer (0.4 N HCl; 45 μL per well). Plates were gently agitated for 30 min at 4 °C. Cell lysates were neutralized with neutralization buffer (0.5 M dibasic sodium phosphate, pH 12.5, 1 mM DTT; 36 μL per well). Prior to the ELISA protocol, plates were agitated to ensure the lysates were well mixed.

[0181] ELISA protocol: Cell lysates were transferred to wells of a 384-well plate and the final volume was adjusted to 50 μL per well with PBS. The plates were sealed, centrifuged at 2,000 rpm for 2 minutes, and incubated at 4°C for approximately 16 hours. The plates were washed with TBST buffer (1x TBS (10x TBS: 24.2 g Tris (Sigma, T6066), 80 g NaCl (Sigma, S3014) in 1 L water, pH adjusted to 7.6 with HCl), plus 0.1% Tween-20). Blocking buffer (TBST, 5% BSA; 50 μL per well) was added, and the plates were incubated at room temperature for 1 hour. The blocking buffer was removed, and primary antibody was added (30 μL per well). The following dilutions were made in blocking buffer: anti-H3K27me3 antibody (Cell Signaling Technology, #9733) at a dilution of 1:1000, anti-H3K27me2 antibody (Cell Signaling Technology, #9288) at a dilution of 1:100, and anti-H3 antibody (Abcam, Cat. No. 24834) at a dilution of 1:1000. The primary antibodies were incubated in the plate at room temperature for 1 hour. The wells were washed with TBST and incubated with the secondary antibody at room temperature for 1 hour. The following dilutions were made in blocking buffer for the secondary antibodies: anti-rabbit antibody (Jackson ImmunoResearch, #111-035-003) at a dilution of 1:2000, and anti-mouse antibody (Cell signaling technology, #7076) at a dilution of 1:1000.

[0182] After 1 hour of incubation at room temperature, the wells were washed with TBST. ECL substrate (Pierce, #34080) was added at 30 μL per well, and the plate was centrifuged at 2,000 rpm for 2 minutes. Signals were read using a PerkinElmer Envision reader. H3 signal was used to normalize H3K27 methylation readouts, and then percentage inhibition was calculated relative to the DO-treated sample. Data were fitted to a dose-response curve using the program Helios to determine the IC of test compounds. 50 got the value.

[0183] Analysis of cell proliferation B-cell lymphoma cells, KARPAS422, were cultured using standard cell culture conditions in RPMI-1640 (Invitrogen, Cat. No. 11875) supplemented with 15% FBS (Invitrogen, Cat. No. 10099-141) at 37°C in a humidified incubator with 5% CO. To assess the effect of PRC2 inhibition on cell proliferation, exponentially growing cells were cultured at 1 × 10 in 12-well plates (Corning, Cat. No. CLS3513). 5 Cells were seeded at a density of 1 × 10 cells / mL. After cell seeding, compounds of the present invention were added to the cell culture medium (at concentrations ranging from 0 to 100 μM, in a 3-fold dilution series). Viable cell numbers were determined using a Vi-CELL (Beckman Coulter) every 3-4 days for up to 14 days. Cell counting days were replenished with fresh growth medium and compounds, and cells were split to 1 × 10 cells / mL. 5 The cells were then returned to a density of 1000 cells / mL. Total cell numbers are expressed as aliquot-adjusted viable cells per mL. Prism was used to generate dose-response curves and IC 50 Generated a value.

[0184] The exemplified examples disclosed below were tested in the EZH2 LC and / or EZH2 ELISA assays described above and found to have EZH2 inhibitory activity.

[0185] Table 3 below shows the IC's in EZH2 (a) LC-qualified and / or (b) ELISA-qualified assays measured for the following examples: 50 Enter the value.

[0186] [Table 3-1]

[0187] [Table 3-2]

[0188] [Table 4]

[0189] It is understood that the examples and embodiments described herein are for illustrative purposes only, and that various modifications or changes in light thereof will be suggested to those skilled in the art and are to be included within the spirit and purview of this application and the scope of the appended claims. All publications, patents, and patent applications cited herein are incorporated herein by reference for all purposes. The inventions described in the original claims of this application are set forth below. [1] A compound having the structure of formula (I) or a stereoisomer, enantiomer, enantiomeric mixture, or pharmaceutically acceptable salt thereof: [ka] [In the formula, Y is N or CR a and; R a 、R 1 、R 3 、R 5 、R 6 、R 7 、R 8 and R9 are independently H, halogen or -C 1 ~C 4 is alkyl; R 2 -CN, -C 1 ~C 6 Alkyl, -hydroxyC 1 ~C 4 Alkylene, -C 1 ~C 4 Alkoxy, 1-2 hydroxyl substituted -C 2 ~C 4 Alkoxy; -(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 ; -(CR 2 ) n NR 11 C(=O)R 15 , -(CR 2 ) n NR 11 (CR 2 ) 2 C(=O)R 15 ; -(CR 2 ) n NR-C(=O)OR 11 , -(CR 2 ) n NR-C(=O)O-(CR 2 )-R 15 ; -NR-C(=O)(CR 2 ) 2 C(=O)R 15 , -NR-C(=O)R 11 ; -(CR 2 ) n NR 11 R 12 , -(CR 2 ) n NR 11 (CR 2 ) n R 15 ; -(CR 2 ) n OR 15 , -(CR 2 ) n R 15 ;

change

change

change

change

change

[10] The compound according to [1], which 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 according to [1], which 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 [1], which 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 according to [1], which 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, enantiomeric mixture, or pharmaceutically acceptable salt thereof.

[14] The compound according to [1], which 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 a compound according to any one of [1] to

[14] and a pharmaceutically acceptable carrier.

[16] A combination comprising a compound according to any one of [1] to

[14] and one or more therapeutically active agents.

[17] The combination according to

[16] , wherein the one or more therapeutically active agents are selected from anti-cancer agents, immunomodulatory agents, anti-allergic agents, anti-nausea agents, 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), comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound described in any of [1] to

[14] .

[19] The method of

[18] , wherein the disease or condition 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, colon 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 tumor, uterine tumor, rhabdomyosarcoma, Kaposi's sarcoma, synovial sarcoma, osteosarcoma, or Ewing's sarcoma.

[20] Use of a compound according to any one of [1] to

[14] , optionally in combination with a second therapeutic agent, in the manufacture of a medicament for 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).

Claims

1. A compound having the structure of formula (I) or a stereoisomer, enantiomer, enantiomeric mixture, or pharmaceutically acceptable salt thereof: 【Chemistry 1】 [In the formula, Y is N or CR ａ and R ａ , R １ , R ３ , R ５ , R ６ , R ７ , R ８ and R ９ are independently H, halogen or —C １ ~C ４ is alkyl; R ２ is —(CH 2 ) 1-2 C(═O)NR 11 R 15 or —(CR 13 R 14 )—C(═O)NR 11 R 15 ; R ４ａ , R ４ｂ , R ４ｃ and R ４ｄ are independently H or —C １ ~C ４ is alkyl; R １０ is H, halogen, -C １ ~C ４ Alkyl, —C １ ~C ４ Alkoxy, -C １ ~C ４ haloalkoxy or —NH(C １ ~C ４ alkyl); R １１ is H, -C １ ~C ４ Alkyl, -hydroxy C １ ~C ４ Alkylene, -cyano C １ ~C ４ Alkylene, or -C １ ~C ４ Alkoxy-substituted —C １ ~C ４ is alkyl; R １３ is H, halogen, -CN, -OH, -C １ ~C ４ Alkyl or -hydroxy C １ ~C ４ alkylene; R １４ is H, halogen or —C １ ~C ４ is alkyl; R １５ teeth, 【Chemistry 2】 , -C ３ ~C ６ Cycloalkyl, or O, S, S(=O) ２ and N; R １５ The above-C ３ ~C ６ The cycloalkyl or 4- to 6-membered heterocycloalkyl is unsubstituted or is selected from the group consisting of —OH, —C １ ~C ４ Alkyl, -hydroxy C １ ~C ４ Alkylene, -C １ ~C ４ Alkoxy, —SO ２ (C １ ~C ４ alkyl) and —N(C １ ~C ４ alkyl) ２ substituted with 1 to 2 substituents selected from: R １６ When present, it is a halogen, —CN, —OH, —C １ ~C ４ Alkyl and -hydroxy C １ ~C ４ the substituents being selected from alkylene; m is 0, 1 or 2.

2. 10. A compound according to claim 1, or a stereoisomer, enantiomer, enantiomeric mixture, or pharmaceutically acceptable salt thereof. [In the formula, R ２ teeth, 【Transformation 3】 is.

3. 2. The compound of claim 1, represented by formula (II), or a stereoisomer, enantiomer, enantiomeric mixture, or pharmaceutically acceptable salt thereof: 【Chemistry 4】 [In the formula, Y is CH or N; R １ , R ３ , R ４ａ , R ４ｂ , R ４ｃ , R ４ｄ and R １１ are independently H or C １ ~C ４ is alkyl; R ５ , R ６ , R ７ , R ８ , R ９ and R １０ are independently H, halogen or C １ ~C ４ is alkyl; R １３ is H, halogen, -CN, -OH, -C １ ~C ４ Alkyl or -hydroxy C １ ~C ４ alkylene; R １４ is H, halogen or —C １ ~C ４ is alkyl; R １５ is a 4- to 6-membered heterocycloalkyl having 1-2 heteroatoms independently selected from O, S, and N; R １５ is unsubstituted or is —OH, —C １ ~C ４ Alkyl, -hydroxy C １ ~C ４ Alkylene, -C １ ~C ４ Alkoxy, —SO ２ (C １ ~C ４ alkyl) and —N(C １ ~C ４ alkyl) ２ and is substituted with 1 to 2 substituents selected from:

4. R １５ but, 【Transformation 5】 2. The compound of claim 1, wherein R 16 and m are as defined in claim 1, or a stereoisomer, enantiomer, enantiomeric mixture or pharmaceutically acceptable salt thereof.

5. m is 1, and R １６ Ga-C １ ~C ４ 5. The compound of claim 4, or a stereoisomer, enantiomer, enantiomeric mixture, or pharmaceutically acceptable salt thereof, wherein R is alkyl.

6. 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)-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; 2. The compound of claim 1, or a stereoisomer, enantiomer, enantiomeric mixture, or pharmaceutically acceptable salt thereof, selected from:

7. 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; 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; 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; 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; 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; (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-(oxetan-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; 2. The compound of claim 1 selected from: or an enantiomeric mixture or a pharmaceutically acceptable salt thereof.

8. 2. The compound of claim 1, which 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, enantiomeric mixture, or pharmaceutically acceptable salt thereof.

9. 2. The compound of claim 1, which 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.

10. 2. The compound of claim 1, which 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.

11. 2. The compound of claim 1, which 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.

12. 2. The compound of claim 1, which 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, enantiomeric mixture, or pharmaceutically acceptable salt thereof.

13. 2. The compound of claim 1, which 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.

14. 14. A pharmaceutical composition comprising a compound of any one of claims 1 to 13 or a stereoisomer, enantiomer, enantiomeric mixture or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

15. 14. A combination comprising a compound according to any one of claims 1 to 13 or a stereoisomer, enantiomer, enantiomeric mixture or pharmaceutically acceptable salt thereof, and one or more therapeutically active agents.

16. 16. The combination of claim 15, wherein the one or more therapeutically active agents are selected from anti-cancer agents, immunomodulatory agents, anti-allergic agents, anti-nausea agents, analgesics and cytoprotective agents.

17. 14. A pharmaceutical composition comprising a compound of any one of claims 1 to 13, or a stereoisomer, enantiomer, enantiomeric mixture, or pharmaceutically acceptable salt thereof, 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).

18. 18. The pharmaceutical composition of claim 17, wherein the disease or condition 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, colon 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 tumor, uterine tumor, rhabdomyosarcoma, Kaposi's sarcoma, synovial sarcoma, osteosarcoma, or Ewing's sarcoma.

19. 14. Use of a compound of any one of claims 1 to 13, or a stereoisomer, enantiomer, enantiomeric mixture or pharmaceutically acceptable salt thereof, optionally in combination with a second therapeutic agent, in the manufacture of a medicament for 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).

20. 14. A compound according to any one of claims 1 to 13, or a stereoisomer, enantiomer, enantiomeric mixture, or pharmaceutically acceptable salt thereof, for use in 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).

21. 21. The compound of claim 20, or a stereoisomer, enantiomer, enantiomeric mixture, or pharmaceutically acceptable salt thereof, wherein the disease or condition 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, colon 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 tumor, uterine tumor, rhabdomyosarcoma, Kaposi's sarcoma, synovial sarcoma, osteosarcoma, or Ewing's sarcoma.

22. 21. The compound of claim 20, or a stereoisomer, enantiomer, enantiomeric mixture, or pharmaceutically acceptable salt thereof, optionally administered in combination with a second therapeutic agent.

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