Azaquinoline compounds and uses thereof

Abstract

Provided are azaquinoline compounds of formula (I), pharmaceutical compositions comprising such compounds; and uses of such compounds for treating diseases or conditions mediated by Enhancer of Zeste Homolog 2 (EZH2), Polycomb Repressive Complex 2 (PRC2), or a combination thereof. [Formula 1] JPEG2022550353000174.jpg3165

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of WO 2019 / 108296, filed September 26, 2019, which is incorporated herein by reference in its entirety.

[0002] FIELD OF THE INVENTION 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]

[0003] 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.

[0004] 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

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

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

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

[0008] [ka] [In the formula, Y is N or CR 4 and; R 1 , R 3 and R 4are independently H, halogen, or -C1-C4 alkyl; R 2 is -CN, -C1-C6 alkyl, -hydroxyC1-C4 alkylene, -C1-C6 alkyl substituted with -N(C1-C4 alkyl)2; -C1-C4 alkoxy, -C2-C4 alkoxy substituted with 1 or 2 hydroxyl or cyano groups; -NH2, -NR 11 C(=O)R 15 , -C(=O)NH2, -(CH2) n R 15 , -R 15 , -NHC(=O)R 11 , -NR 12 C(=O)OR 11 , -C(=O)NR 11 R 12 , -(CH2) n C(=O)NR 11 R 12 , -(CH2) n NR 11 R 15 , -(CH2) n C(=O)NR 11 R 15 , -C(=O)NR 11 R 15 , -CR 13 R 14 C(=O)NR 11 R 15 , -OCR 11 R 12 R 13 , -(CH2) n C(=O)R 15 , -C(=O)R 15 , -CR 13 R 14 C(=O)R 15 , -(CH2) n NR 11 C(=O)R 15 , -(CH2) n NR 11 (CH2)2C(=O)R 15 , -NR 12 C(=O)(CH2)2C(=O)R 15 , -(CH2) n OR 15 , -(CH2) n NR11 C(=O)OCH2R 15 , -NR 11 C(=O)OCH2R 15 , -(CH2) n NR 11 (CH2) n R 15 ,

[0009] [ka] , or O, S, N and -NR c is a 5- to 6-membered heteroaryl having 1 to 4 ring members independently selected from: R 5a , R 5b , R 5c , R 5d and R c are independently H or -C1-C4 alkyl; R 6 , R 7 , R 8 and R 9 are independently H, halogen, 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, -SO2(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,

[0010] [ka] , -C3-C6 cycloalkyl, or O, S, S(=O)2, N and -NR 11 wherein the —C3-C6 cycloalkyl and the 4- to 6-membered heterocycloalkyl are independently unsubstituted or substituted with 1 to 2 substituents selected from —OH, —C1-C4 alkyl, -hydroxyC1-C4 alkylene, —C1-C4 alkoxy, and —N(C1-C4 alkyl); R 16 if present, is halogen, —CN, —OH, —C1-C4 alkyl, or -hydroxyC1-C4 alkylene; m is 0, 1 or 2; each n is independently selected from 1 and 2] with the proviso that the compound of formula (I) is not (2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)(4-methylpiperazin-1-yl)methanone, or a stereoisomer, enantiomer, enantiomeric mixture, or pharmaceutically acceptable salt thereof.

[0011] 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.

[0012] 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.

[0013] 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

[0014] The present invention provides compositions and methods for treating or preventing diseases or conditions mediated by EZH2, PRC2, or a combination thereof.

[0015] 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.

[0016] 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).

[0017] 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.

[0018] 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.

[0019] "Halo" or "halogen" refers to bromo, chloro, fluoro, or iodo.

[0020] As used herein, the term "-hydroxyC 1~4 "Alkylene" means a -C alkylene group as defined above. 1~4 refers to alkyl radicals, C 1~4 One or more hydrogen atoms of the alkyl radical are replaced by OH. HydroxyC 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.

[0021] 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.

[0022] 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. The term "-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.

[0023] 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.

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

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

[0039] 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.

[0040] 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.

[0041] Embodiment 1. A compound of formula (I), or a stereoisomer, enantiomer, enantiomeric mixture, or pharmaceutically acceptable salt thereof, as described above.

[0042] Embodiment 2. R 2 -CN, -NH2, -NR 11 C(=O)R 15 , -C(=O)NH2, -(CH2) n R 15 , -R 15 , -NHC(=O)R 11 , -NR 12 C(=O)OR 11 , -C(=O)NR 11 R 12 , -(CH2) n C(=O)NR 11 R 12 , -(CH2) n NR 11 R 15 , -(CH2) n C(=O)NR 11 R 15, -C(=O)NR 11 R 15 , -CR 13 R 14 C(=O)NR 11 R 15 , -OCR 11 R 12 R 13 , -(CH2) n C(=O)R 15 , -C(=O)R 15 , -CR 13 R 14 C(=O)R 15 , -(CH2) n NR 11 C(=O)R 15 , -(CH2) n NR 11 (CH2)2C(=O)R 15 , -NR 12 C(=O)(CH2)2C(=O)R 15 , -(CH2) n OR 15 , -(CH2) n NR 11 C(=O)OCH2R 15 , -NR 11 C(=O)OCH2R 15 , -(CH2) n NR 11 (CH2) n R 15 ,

[0043] [ka] , 1 R a -C1-C6 alkyl substituted with one R b -C1-C4 alkoxy substituted with, or O, S, N and NR c and R is a 5- to 6-membered heteroaryl having 1 to 4 ring members independently selected from c is H or -C1-C4 alkyl; R 11 is H, -C1-C4 alkyl, -SO2(C1-C4 alkyl), or one R b -C1-C4 alkyl substituted with; Each R13 are independently selected from H, halogen, CN, —OH, and —C1-C4 alkyl substituted with 0-1 —OH groups; R 15 but,

[0044] [ka] , 0 to 1 R a C3-C6 cycloalkyl substituted with groups, or O, S, S(=O)2, N and NR 11 and R is a 4- to 6-membered heterocycloalkyl having 1 to 2 ring members independently selected from 15 The heterocycloalkyl may be selected from 0 to 1 R a substituted with a group; R a is -OH, -CH2OH, C1-C4 alkyl, C1-C4 alkoxy, or -N(C1-C4 alkyl)2; R b are independently selected from -CN, -OH, and C1-C4 alkoxy; m is 0, 1 or 2; each n is independently selected from 1 and 2; A compound of formula (I) or a stereoisomer, enantiomer, enantiomeric mixture or pharmaceutically acceptable salt thereof.

[0045] Embodiment 3. A compound according to embodiment 1 or embodiment 2 having formula (I-2), or a stereoisomer, enantiomer, enantiomeric mixture or pharmaceutically acceptable salt thereof.

[0046] [ka]

[0047] Embodiment 4. A compound according to embodiment 1 or embodiment 2 having formula (I-3), or a stereoisomer, enantiomer, enantiomeric mixture or pharmaceutically acceptable salt thereof.

[0048] [ka]

[0049] Embodiment 5. A compound according to embodiment 1 or embodiment 2 having formula (I-4), or a stereoisomer, enantiomer, enantiomeric mixture or pharmaceutically acceptable salt thereof.

[0050] [ka]

[0051] Embodiment 6. A compound according to embodiment 1 or embodiment 2 having formula (I-5), or a stereoisomer, enantiomer, enantiomeric mixture, or pharmaceutically acceptable salt thereof.

[0052] [ka]

[0053] Embodiment 7. A compound according to embodiment 1 or embodiment 2 having formula (I-6), or a stereoisomer, enantiomer, enantiomeric mixture, or pharmaceutically acceptable salt thereof.

[0054] [ka]

[0055] Embodiment 8. A compound according to embodiment 1 or embodiment 2 having formula (I-7), or a stereoisomer, enantiomer, enantiomeric mixture, or pharmaceutically acceptable salt thereof.

[0056] [ka]

[0057] Embodiment 9. R 2 but, -CN, -NH2, -C(=O)NH2, -NHC(=O)R 11, -NR 12 C(=O)OR 11 , -C(=O)NR 11 R 12 , -(CH2) n C(=O)NR 11 R 12 , -(CH2) n NR 11 R 15 , -(CH2) n C(=O)NR 11 R 15 , -C(=O)NR 11 R 15 , -CR 13 R 14 C(=O)NR 11 R 15 , -OCR 11 R 12 R 13 , -(CH2) n R 15 , -NR 12 C(=O)(CH2)2C(=O)R 15 , -(CH2) n NR 11 C(=O)OCH2R 15 , -NR 11 C(=O)OCH2R 15 , -(CH2) n NR 11 (CH2) n R 15 , -(CH2) n C(=O)R 15 , -C(=O)R 15 , -CR 13 R 14 C(=O)R 15 , -(CH2) n NR 11 C(=O)R 15 , -NR 11 C(=O)R 15 , -(CH2) n NR 11 (CH2)2C(=O)R 15 , -(CH2) n OR 15 ,

[0058]

Chem.

[0059] Embodiment 10. R 2 but, -CN, -NH2, -C(=O)NH2, -NHC(=O)R 11 , -NR 12 C(=O)OR 11 , -C(=O)NR 11 R 12 , -(CH2) n C(=O)NR 11 R 12 , -(CH2) n NR 11 R 15 , -(CH2) n C(=O)NR 11 R 15 , -C(=O)NR 11 R 15 , -CR 13 R 14 C(=O)NR 11 R 15 , -OCR 11 R 12 R 13 , -(CH2) n R 15 , -NR 12 C(=O)(CH2)2C(=O)R 15 , -(CH2) n NR 11 C(=O)OCH2R 15 , -NR 11 C(=O)OCH2R 15 , -(CH2) n NR11 (CH2) n R 15 , -(CH2) n C(=O)R 15 , -CR 13 R 14 C(=O)R 15 , -(CH2) n NR 11 C(=O)R 15 , -NR 11 C(=O)R 15 , -(CH2) n NR 11 (CH2)2C(=O)R 15 , -(CH2) n OR 15 ,

[0060] [ka] , 1 R a -C1-C6 alkyl substituted with one R b -C1-C4 alkoxy substituted with, or N and -NR c is a 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from: R a , R b and R c is as defined in embodiment 2. A compound according to any one of embodiments 1 to 8, or a stereoisomer, enantiomer, enantiomeric mixture or pharmaceutically acceptable salt thereof.

[0061] Embodiment 11. R 2 but, -CN, -NH2, -C(=O)NH2, -NHC(=O)R 11 , -NR 12 C(=O)OR 11 , -C(=O)NR 11 R 12 , -CH2C(=O)NR 11 R 12 , triazolyl,

[0062] [ka] , 1 R a -C1-C6 alkyl substituted with a group, or one R b -C1-C4 alkoxy substituted with a group; R a and R b is as defined in embodiment 2. A compound according to any one of embodiments 1 to 8, or a stereoisomer, enantiomer, enantiomeric mixture or pharmaceutically acceptable salt thereof.

[0063] Embodiment 12. R 2 but, -CH2C(=O)NR 11 R 12 ,

[0064] [ka] or one R a C1-C6 alkyl substituted with; R a is as defined in embodiment 2. A compound according to any one of embodiments 1 to 8, or a stereoisomer, enantiomer, enantiomeric mixture or pharmaceutically acceptable salt thereof.

[0065] Embodiment 13. R 12 is H or —CH 3 , or a stereoisomer, enantiomer, enantiomeric mixture, or pharmaceutically acceptable salt thereof.

[0066] Embodiment 14. R 2 but,

[0067] [ka] and; R a is as defined in embodiment 2. A compound according to any one of embodiments 1 to 13, or a stereoisomer, enantiomer, enantiomeric mixture or pharmaceutically acceptable salt thereof.

[0068] Embodiment 15. R a The compound according to any one of embodiments 2 to 14, or a stereoisomer, enantiomer, enantiomeric mixture, or pharmaceutically acceptable salt thereof, wherein is —OH or —OCH 3 .

[0069] Embodiment 16. 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:

[0070] Embodiment 17. 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 substituent selected from —OH, —CHOH, —C1-C4 alkyl, —C1-C4 alkoxy, and —N(C1-C4 alkyl)2, or a stereoisomer, enantiomer, enantiomeric mixture, or a pharmaceutically acceptable salt thereof.

[0071] Embodiment 18. R 15 but,

[0072] [ka] and; R 16 when present, is halogen, —CN, —OH, —C1-C4 alkyl, or -hydroxyC1-C4 alkylene; m is 0, 1 or 2; A compound according to embodiment 16, or a stereoisomer, enantiomer, enantiomeric mixture, or pharmaceutically acceptable salt thereof.

[0073] Embodiment 19. R 15 but,

[0074] [ka] 17. The compound according to embodiment 16, wherein:

[0075] Embodiment 20. R 2 -CN, -NH2, -C(=O)NH2, triazolyl,

[0076] [ka] 20. The compound according to any one of embodiments 1 to 19, wherein:

[0077] Embodiment 21. R 2 but,

[0078] [ka] 20. The compound according to any one of embodiments 1 to 19, wherein:

[0079] Embodiment 22. A compound according to embodiment 1, having formula (II), or a stereoisomer, enantiomer, enantiomeric mixture, or pharmaceutically acceptable salt thereof.

[0080] [ka] [In the formula, Y is CH or N; R 1 , R3 , R 5a , R 5b , R 5c and R 5d are independently H or -C1-C4 alkyl; R 6 , R 7 , R 8 and R 9 are independently H, halogen, or -C1-C4 alkyl; R 10 is halogen or -C1-C4 alkoxy; R 11 is H, C1-C4 alkyl, -hydroxyC1-C4 alkylene or -cyanoC1-C4 alkylene; R 13 is H, halogen, —OH, —C1-C4 alkyl, or -hydroxyC1-C4 alkylene; R 14 is H, halogen or -C1-C4 alkyl; 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, and -N(C1-C4 alkyl).

[0081] Embodiment 23. A compound according to embodiment 22, having formula (II-1), or a stereoisomer, enantiomer, enantiomeric mixture, or pharmaceutically acceptable salt thereof.

[0082] [ka]

[0083] Embodiment 24. A compound according to embodiment 22, having formula (II-2), or a stereoisomer, enantiomer, enantiomeric mixture, or pharmaceutically acceptable salt thereof.

[0084] [ka]

[0085] Embodiment 25. A compound according to embodiment 22, having the formula (II-3), or a stereoisomer, enantiomer, enantiomeric mixture, or pharmaceutically acceptable salt thereof.

[0086] [ka]

[0087] Embodiment 26. R 11 is H, -C1-C4 alkyl, or one R b -C1-C4 alkyl substituted with R b is —CN, —OH, or —OCH3, or a stereoisomer, enantiomer, enantiomeric mixture, or pharmaceutically acceptable salt thereof.

[0088] Embodiment 27. R 13 is H, F, —CN, —OH, —CH or —CHOH, or a stereoisomer, enantiomer, enantiomeric mixture, or pharmaceutically acceptable salt thereof.

[0089] Embodiment 28. R 14 is H, F, or —CH 3 , or a stereoisomer, enantiomer, enantiomeric mixture, or pharmaceutically acceptable salt thereof.

[0090] Embodiment 29. 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.

[0091] Embodiment 30. R 15 but,

[0092] [ka] and; R 16 The compound according to embodiment 29, or a stereoisomer, enantiomer, enantiomeric mixture, or pharmaceutically acceptable salt thereof, wherein, if present, is -C1-C4 alkyl; and m is 0 to 1. In certain embodiments, R 15 teeth,

[0093] [ka] is.

[0094] Embodiment 31. A compound according to embodiment 1 selected from Examples C1 to C22 and Examples C24 to C77; or a pharmaceutically acceptable salt thereof.

[0095] Embodiment 32. N 2 -(((1,4-trans)-4-((8-methoxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)pyrimidine-2,5-diamine; N-(2-((((1,4-trans)-4-((8-methoxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)azetidine-3-carboxamide; N-(2-((((1,4-trans)-4-((8-methoxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-1-methylazetidine-3-carboxamide; 2-((((1,4-trans)-4-((8-methoxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidine-5-carbonitrile; 2-((((1,4-trans)-4-((8-methoxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidine-5-carboxamide; N-(2-((((1,4-trans)-4-((8-methoxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)acetamide; 2-hydroxy-N-(2-((((1,4-trans)-4-((8-methoxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)acetamide; (2-((((1,4-trans)-4-((8-methoxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)(piperazin-1-yl)methanone; N-(2-hydroxypropyl)-2-((((1,4-trans)-4-((8-methoxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidine-5-carboxamide; (2-((((1,4-trans)-4-((8-methoxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)(morpholino)methanone; (2-((((1,4-trans)-4-((8-methoxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)(4-methylpiperazin-1-yl)methanone; N-((1,4-trans)-4-(((5-(1H-1,2,4-triazol-5-yl)pyrimidin-2-yl)amino)methyl)cyclohexyl)-8-methoxy-1,7-naphthyridin-2-amine; 2-(2-((((1,4-trans)-4-((8-methoxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-(oxetan-3-yl)acetamide; N 2 -(((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)pyrimidine-2,5-diamine; Methyl (2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)carbamate; 2-Methoxyethyl(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)carbamate; 2-Hydroxyethyl(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)carbamate; Oxetan-3-ylmethyl(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)carbamate; N-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-2-hydroxyacetamide; N-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-4-morpholino-4-oxobutanamide; 2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidine-5-carbonitrile; (2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)(morpholino)methanone; (2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)(piperazin-1-yl)methanone; 2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)-N-(oxetan-3-yl)pyrimidine-5-carboxamide; 8-chloro-N-((1,4-trans)-4-(((5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyrimidin-2-yl)amino)methyl)cyclohexyl)-1,7-naphthyridin-2-amine; 8-chloro-N-((1,4-trans)-4-(((5-((oxetan-3-ylamino)methyl)pyrimidin-2-yl)amino)methyl)cyclohexyl)-1,7-naphthyridin-2-amine; 8-chloro-N-((1,4-trans)-4-(((5-(((3-methyloxetan-3-yl)amino)methyl)pyrimidin-2-yl)amino)methyl)cyclohexyl)-1,7-naphthyridin-2-amine; 1-((2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)methyl)azetidin-3-ol; 4-((2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)methyl)thiomorpholine 1,1-dioxide; 8-chloro-N-((1,4-trans)-4-(((5-(((oxetan-3-ylmethyl)amino)methyl)pyrimidin-2-yl)amino)methyl)cyclohexyl)-1,7-naphthyridin-2-amine; 8-chloro-N-((1,4-trans)-4-(((5-(((3-methoxycyclobutyl)amino)methyl)pyrimidin-2-yl)amino)methyl)cyclohexyl)-1,7-naphthyridin-2-amine; 3-(((2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)methyl)amino)cyclobutan-1-ol; (2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-1,3-dioxan-5-yl)methanol; 8-chloro-N-((1,4-trans)-4-(((5-((oxetan-3-yloxy)methyl)pyrimidin-2-yl)amino)methyl)cyclohexyl)-1,7-naphthyridin-2-amine; 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-(oxetan-3-yl)acetamide; 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-methyl-N-(oxetan-3-yl)acetamide; 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-1-(3-hydroxyazetidin-1-yl)ethan-1-one; 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-1-(3-(dimethylamino)pyrrolidin-1-yl)ethan-1-one; 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-1-(4-(2-hydroxyethyl)piperazin-1-yl)ethan-1-one; 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-1-(piperazin-1-yl)ethan-1-one; 2-(6-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyridin-3-yl)-N-(oxetan-3-yl)acetamide; 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-1-(4-methylpiperazin-1-yl)ethan-1-one; 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-cyclobutylacetamide; 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-1-(4-(2-methoxyethyl)piperazin-1-yl)ethan-1-one; 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)ethan-1-ol; 8-chloro-N-((1,4-trans)-4-(((5-(2-((3-methyloxetan-3-yl)amino)ethyl)pyrimidin-2-yl)amino)methyl)cyclohexyl)-1,7-naphthyridin-2-amine; 8-chloro-N-((1,4-trans)-4-(((5-(2-(oxetan-3-ylamino)ethyl)pyrimidin-2-yl)amino)methyl)cyclohexyl)-1,7-naphthyridin-2-amine; 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-(2-cyanoethyl)-N-(oxetan-3-yl)acetamide; 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-(2-cyanoethyl)-N-ethylacetamide; 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-(2-hydroxyethyl)-N-(oxetan-3-yl)acetamide; 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-(oxetan-3-yl)propanamide; (S)-2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-(oxetan-3-yl)propanamide; (R)-2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-(oxetan-3-yl)propanamide; 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-methyl-N-(oxetan-3-yl)propanamide; (S)-2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-methyl-N-(oxetan-3-yl)propanamide; (R)-2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-methyl-N-(oxetan-3-yl)propanamide; N-((2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)methyl)azetidine-2-carboxamide; N-((2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)methyl)oxetane-3-carboxamide; 2-((((1,4-trans)-4-((8-(methylamino)-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidine-5-carbonitrile; 2-((((1,4-trans)-4-((8-(methylamino)-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidine-5-carboxamide; N 2 -((1,4-trans)-4-(((5-aminopyrimidin-2-yl)amino)methyl)cyclohexyl)-N 8 -methyl-1,7-naphthyridine-2,8-diamine; N-(2-((((1,4-trans)-4-((8-(methylamino)-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)acetamide; 3-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)oxazolidin-2-one; Methyl(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)(methyl)carbamate; N 2 -(((1,4-trans)-4-((8-(difluoromethoxy)-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)pyrimidine-2,5-diamine; N-((1,4-trans)-4-(((5-(4H-1,2,4-triazol-3-yl)pyrimidin-2-yl)amino)methyl)cyclohexyl)-8-chloro-1,7-naphthyridin-2-amine; 2-((2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)oxy)propan-1-ol; 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-1-(3-hydroxyazetidin-1-yl)propan-1-one; (S)-2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-1-(3-hydroxyazetidin-1-yl)propan-1-one; (R)-2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-1-(3-hydroxyazetidin-1-yl)propan-1-one; 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-3-hydroxy-N-(oxetan-3-yl)propanamide; (R)-2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-3-hydroxy-N-(oxetan-3-yl)propanamide; (S)-2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-3-hydroxy-N-(oxetan-3-yl)propanamide; (S)-2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-2-hydroxy-N-(oxetan-3-yl)acetamide; (R)-2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-2-hydroxy-N-(oxetan-3-yl)acetamide, and 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-2,2-difluoro-N-(oxetan-3-yl)acetamide; or a pharmaceutically acceptable salt thereof.

[0096] Embodiment 33. A compound according to embodiment 1 selected from Examples C1 to C7, C9, C12 to C21 and Examples C25 to C77; or a pharmaceutically acceptable salt thereof.

[0097] Embodiment 34. A compound according to embodiment 1 or embodiment 22 selected from examples C13, C36-C37, C42, C49, C51-57 and C72-C77; or a pharmaceutically acceptable salt thereof.

[0098] Embodiment 35. A compound according to embodiment 1 or embodiment 22 which is 2-(2-(((4-((8-chloro-1,7-naphthyridin-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.

[0099] Embodiment 36. A compound according to embodiment 1 or embodiment 22 which is 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-(oxetan-3-yl)acetamide; or a pharmaceutically acceptable salt thereof. The compound is also known as 2-(2-((((1r,4r)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-(oxetan-3-yl)acetamide (Example C36).

[0100] Embodiment 37. A compound according to embodiment 1 or embodiment 22 which is 2-(2-(((4-((8-chloro-1,7-naphthyridin-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.

[0101] Embodiment 38. A compound according to embodiment 1 or embodiment 22 which is 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-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. The compound is also known as 2-(2-((((1r,4r)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-(oxetan-3-yl)propanamide (Example C52).

[0102] Embodiment 39. A compound according to embodiment 1 or embodiment 22 which is (S)-2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-(oxetan-3-yl)propanamide; or a pharmaceutically acceptable salt thereof. The compound is also known as (S)-2-(2-((((1r,4S)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-(oxetan-3-yl)propanamide (Example C53).

[0103] Embodiment 40. A compound according to embodiment 1 or embodiment 22 which is (R)-2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-(oxetan-3-yl)propanamide; or a pharmaceutically acceptable salt thereof. The compound is also known as (R)-2-(2-((((1r,4R)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-(oxetan-3-yl)propanamide (Example C54).

[0104] Embodiment 41. A pharmaceutical composition comprising a compound according to any one of embodiments 1 to 40 and one or more pharmaceutically acceptable carriers.

[0105] Embodiment 42. A combination comprising a compound according to any one of embodiments 1 to 40 and one or more additional therapeutically active agents.

[0106] Embodiment 43. The combination according to embodiment 42, 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.

[0107] Embodiment 44 A compound according to any one of embodiments 1 to 40, optionally in combination with a second therapeutic agent, for use in treating a disease or condition mediated by EZH2, PRC2 or EZH2 / PRC2.

[0108] Embodiment 45. The compound according to embodiment 44, wherein the second therapeutic agent is an anti-cancer agent, an analgesic, an anti-inflammatory agent, or a combination thereof.

[0109] Embodiment 46 Use of a compound according to any one of embodiments 1 to 40, 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.

[0110] Embodiment 47. 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 to 40, optionally in combination with a second therapeutic agent, thereby treating said disease or condition mediated by EZH2, PRC2 or EZH2 / PRC2.

[0111] Embodiment 48. 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 to 40, 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.

[0112] Embodiment 49. The use of a compound according to embodiment 46, or the method according to embodiment 47 or 48, 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.

[0113] Embodiment 50. The use of a compound according to embodiment 46, or a method according to embodiment 47 or 48, 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, and hepatocellular carcinoma.

[0114] 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.

[0115] 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.

[0116] 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.

[0117] 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.

[0118] 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.

[0119] 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.

[0120] 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.

[0121] 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.

[0122] 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.

[0123] 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.

[0124] 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.

[0125] 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.

[0126] Pharmacology and Usefulness EZH2 is the catalytic subunit of PRC2, and its other homolog, EZH1, is highly abundant in mice and is required for the maintenance of adult progenitor cells in EZH2-deficient states. Cofactor-competing or EED-binding PRC2 inhibitors have been identified and exhibit variable selectivity for EZH2 over EZH1. Given the role of EZH1 in adult tissue homeostasis, selectively targeting EZH2 in PRC2 may offer a novel and unique approach that is advantageous or complementary to directly targeting the SAM competition or EED mechanisms of PRC2. Therefore, selectively targeting EZH2 represents a highly attractive strategy for the development of novel therapies for cancer treatment.

[0127] The compounds of the present invention were evaluated in biochemical assays for their ability to inhibit PRC2 activity in the pentameric complex of EZH2 / EZH1, SUZ12, EED, Rbap48, and AEBP. The ability of the compounds of the present invention to inhibit PRC2 cellular activity was assessed by analyzing H3K27me3 in human cell lines. The ability of the compounds of the present invention to inhibit cancer was derived from their ability to modulate the growth of human cancer cell lines that possess a specific dependency on PRC2 activity to maintain cancerous growth. The compounds of the present invention selectively target EZH2 at a different MOI than SAM-competitive inhibitors and EED K27me3 pocket binders.

[0128] 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, such as cancers that depend on PRC2 activity to sustain cancerous growth.

[0129] 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.

[0130] 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.

[0131] 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.

[0132] 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.

[0133] 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.

[0134] 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®).

[0135] 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).

[0136] 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).

[0137] 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).

[0138] 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).

[0139] 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).

[0140] 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).

[0141] 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).

[0142] Aromatase inhibitors: (Pathiraja, T. et al., Sci. Transl. Med., 6(229):229 ra41 (2014)) exemestane (Aromasin®); letrozole (Femara®); and anastrozole (Arimidex®).

[0143] 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.

[0144] 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).

[0145] 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).

[0146] 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.

[0147] Demethylating agents: (Musch, T. et al., PLoS One, (5):e10726 (2010)) 5-azacytidine (Vidaza®); and decitabine (Dacogen®).

[0148] Antiestrogens: (Bhan, A. et al., J Mol Biol., S0022-2836(14)00373-8 (2014)) Tamoxifen (Novaldex®); Toremifene (Fareston®); and Fulvestrant (Faslodex®).

[0149] Immunomodulatory agents of particular interest 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.

[0150] 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.

[0151] 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%.

[0152] 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.

[0153] 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.

[0154] The pharmaceutical composition may optionally 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 active ingredient for a subject weighing about 50 to 70 kg.

[0155] 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.

[0156] 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.

[0157] 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.

[0158] 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®).

[0159] 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.

[0160] 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.

[0161] 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).

[0162] 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.

[0163] 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.

[0164] 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.

[0165] Schemes 1-8 illustrate the synthesis of compounds of formula (I-3):

[0166] [ka] Potential routes for producing the compounds of the invention are described, including:

[0167] Compounds of formula (I) that possess a chiral center may be made substantially optically pure either by using substantially optically pure starting materials or by preparative chromatography, recrystallization or other separation techniques well known in the art (see the Examples section below for a more detailed description).

[0168] [ka]

[0169] As depicted in Scheme 1, 2-cyano-3-methylpyridine 1 was oxidized with m-CPBA to the corresponding pyridine-N-oxide 2, which was treated with POCl to give chloro-pyridine 3. Subsequent hydrolysis afforded picolinamide 4, which can also be prepared via direct amidation of picolinic acid 1'. Compound 5 was generated upon treatment of 4 with 1,1-di-tert-butoxy-N,N-dimethylmethanamine, followed by treatment with t-BuOK to give cyclized compound 6. Subsequent O-alkylation with an appropriate reagent produced 7, which was reacted with tert-butyl (((1,4-trans)-4-aminocyclohexyl)methyl)carbamate to give Boc-protected amine 8. Substitution of the deprotected amine (9) with an appropriately substituted 2-chloropyrimidine afforded compound 10.

[0170] [ka]

[0171] As depicted in Scheme 2, removal of the O-methyl and NH-Boc groups in 8A (where R' in compound 8 is methyl) using concentrated HCl afforded amine 11, which upon treatment with POCl3 gave chloro-amine 12. Substitution reaction with an appropriately substituted 2-chloropyrimidine afforded compound 13.

[0172] [ka]

[0173] As depicted in Scheme 3, nitro intermediate 14 (prepared as in Scheme 1, where R' is methyl and R 2 is NO) was reacted with POCl to give chloro-azaquinoline 17, which, upon treatment with NHCH, afforded displacement product 20. Subsequent reduction of the nitro group in intermediates 14, 17, and 20 with palladium hydrogen on charcoal or NaBH plus NiCl hydrate gave the corresponding amines 15, 18, and 21, which were reacted with appropriate reagents to give the corresponding products 16, 19, and 22.

[0174] [ka]

[0175] As depicted in Scheme 4, ethyl ester 23 (prepared as in Scheme 1, where R' is methyl and R 2 is —C(═O)OEt) was hydrolyzed with KOH to give acid 24, which was treated with an appropriate amine or POCl to give compound 25 and acyl chloride 26, respectively. Subsequent reaction of acyl chloride 26 with an appropriate amine gave compound 27.

[0176] [ka]

[0177] As depicted in Scheme 5, ethyl ester 28 (prepared as in Scheme 2, where R 2 is —C(═O)OEt) was reduced with DIBAL-H to give alcohol 29, which was oxidized with MnO to aldehyde 30. Subsequent reductive amination with an appropriate amine gave compound 31.

[0178] [ka]

[0179] As depicted in Scheme 6, amine 9A (prepared from Scheme 1, where R' is methyl) was reacted with the appropriate pyridine or pyrimidine fluoride / chloride to give the corresponding bromo or iodo intermediate 32. Subsequent coupling with the appropriate bromide gave ester 33, which was demethylated with concentrated HCl to give hydroxyl azaquinoline 34. After treatment of 34 with POCl, the resulting chloroazaquinoline 35 was converted to acid 36 under acidic or basic conditions. Amide coupling with the appropriate amine gave compound 37.

[0180] [ka]

[0181] As depicted in Scheme 7, Negishi coupling of 2-chloro-5-iodopyrimidine with the corresponding bromoacetate gave tert-butyl 2-(2-chloropyrimidin-5-yl)acetate. Subsequent alkylation of tert-butyl 2-(2-chloropyrimidin-5-yl)acetate afforded III. Treatment of the acid with ester II (or III) revealed acid IV. Preparation of compound 37A was completed by amide coupling with acid IV to give V, followed by chloro substitution with amine 12.

[0182] [ka]

[0183] As depicted in Scheme 7, ester 35A (prepared from Scheme 6, where R is isopropyl and R 13 and R 14where each is H) was reduced with DIBAL-H to give the corresponding alcohol 38. Subsequent mesylation and substitution with the appropriate amine gave compound 40. [Example]

[0184] 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.

[0185] 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.

[0186] Purification of intermediates and final products was carried out via either normal-phase or reverse-phase chromatography. Normal-phase chromatography was carried out using prepacked SiO2 cartridges eluting with a gradient of either hexane and ethyl acetate or DCM and MeOH unless otherwise indicated. Reverse-phase preparative HPLC was carried out using a C18 column with UV detection at 214 nm and 254 nm, or preparative LC eluting with a gradient of solvent A (water with 0.1% TFA) and solvent B (acetonitrile with 0.1% TFA), or with a gradient of solvent A (water with 0.05% TFA) and solvent B (acetonitrile with 0.05% TFA), or with a gradient of solvent A (water with 0.05% ammonia) and solvent B (acetonitrile with 0.05% ammonia).

[0187] Nuclear magnetic resonance (NMR) spectra were obtained using a Bruker Fourier transform spectrometer operating at the following frequencies:1 H NMR: 400 MHz (Bruker). 13 C NMR: 100 MHz (Bruker). Spectral data are reported in the format: chemical shift (multiplicity, number of hydrogens). Chemical shifts are specified in ppm downfield from a tetramethylsilane internal standard (δ units, tetramethylsilane = 0 ppm) and / or referenced to the solvent peak, which is 1 In the H NMR spectrum, it appears at 2.49 ppm for CD3SOCD3, 3.30 ppm for CD3OD, 1.94 for CD3CN, and 7.24 ppm for CDCl3.

[0188] 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.

[0189] Compound names provided herein were obtained using ChemDraw Ultra version 14.0 (CambridgeSoft®).

[0190] 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.

[0191] The following abbreviations used herein have the corresponding meanings:

[0192] [Table A-1]

[0193] [Table A-2]

[0194] [Example 1] N 2 -(((1,4-trans)-4-((8-methoxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)pyrimidine-2,5-diamine (C1) Step 1: 2-cyano-3-methylpyridine 1-oxide (1-1)

[0195] [ka] To a solution of compound 3-methylpicolinonitrile (10 g, 84.6 mmol, 1.0 equiv.) in CHCl (180 mL) was added m-CPBA (29.2 g, 139.3 mmol, 2.0 equiv.). The mixture was then stirred at 30 °C for 12 h. The mixture was neutralized to pH 7-8 with saturated aqueous NaCO solution and extracted three times with CHCl / CHOH (5 / 1, v / v, 200 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was triturated with petroleum ether and EtOAc, then filtered to give 2-cyano-3-methylpyridine 1-oxide (1-1). 1 H-NMR (400 MHz, DMSO-d6) δ ppm 8.32 (d, J = 6.4 Hz, 1H), 7.60-7.57 (m, 1H), 7.41 (d, J = 8.0 Hz, 1H), 2.45 (s, 3H).

[0196] Step 2: 6-chloro-3-methylpicolinonitrile (1-2)

[0197] [ka] A mixture of (1-1) (4 g, 29.9 mmol, 1.0 equiv) in POCl (30 mL) was stirred at 110 °C for 2 h. The solvent was removed, and the residue was neutralized to pH 7-8 with saturated aqueous NaCO and extracted three times with EtOAc (200 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The crude product was purified by column chromatography (petroleum ether / EtOAc = 50 / 1) to give 6-chloro-3-methylpicolinonitrile (1-2). 1 H-NMR (400 MHz, CDCl3) δ ppm 7.65 (d, J = 8.4 Hz, 1H), 7.45 (d, J = 8.0 Hz, 1H), 2.55 (s, 3H). MS: [M+H] + = 152.8.

[0198] Step 3: 6-chloro-3-methylpicolinamide (1-3)

[0199] [ka] To a solution of (1-2) (1.19 g, 7.9 mmol, 1.0 equiv) in DMSO (5 mL) was added a solution of NaOH (0.38 g, 9.44 mmol, 1.2 equiv) in water (3 mL). HO (30% in water, 1.78 g, 15.8 mmol, 2.0 equiv) was added dropwise to the mixture at 0 °C. The mixture was stirred at 15 °C for 0.5 h, then poured into water, and the resulting white precipitate was collected by filtration to give 6-chloro-3-methylpicolinamide (1-3). 1 H NMR (400 MHz, CD3OD)δ ppm 7.73 (d, J = 8.4 Hz, 1H), 7.46 (d, J = 8.0 Hz, 1H), 2.59 (s, 3H). MS: [M+H] + = 171.0.

[0200] [ka] Alternatively, to a stirred solution of 6-chloro-3-methylpicolinic acid (23.94 g, 140 mmol, 1.0 equiv.) and (COCl) (35.28 g, 280 mmol, 2.0 equiv.) in CHCl (100 mL), dry DMF (2.0 mL) was added dropwise over 30 min, and the resulting solution was stirred at 2–5 °C for 2 h and then concentrated. The residue was dissolved in CHCl (200 mL), and the solution was added dropwise to NHOH (200 mL) over 30 min, and the resulting solution was stirred at 2–5 °C for 1 h. The mixture was extracted with CHCl (200 mL × 2), and the combined organic layers were dried over anhydrous sodium sulfate and concentrated to give 6-chloro-3-methylpicolinamide (1-3). 1 H NMR (400 MHz, CD3OD): δ ppm 7.73 (d, J = 8.4 Hz, 1H), 7.46 (d, J = 8.0 Hz, 1H), 2.59 (s, 3H). MS: [M+H] + = 171.0.

[0201] Step 4: (E)-6-chloro-N-((dimethylamino)methylene)-3-methylpicolinamide (1-4)

[0202] [ka] To a solution of (1-3) (2.0 g, 11.7 mmol, 1.0 equiv) in THF (400 mL) was added 1,1-di-tert-butoxy-N,N-dimethylmethanamine (20 mL) under N2. The mixture was then stirred at 85 °C for 0.5 h. The resulting solution was used in the next step without further purification. MS: [M+H] + =225.9.

[0203] Step 5: 2-Chloro-1,7-naphthyridin-8(7H)-one (1-5)

[0204] [ka] To the above solution of (1-4), t-BuOK (1.5 M in THF, 11.5 mL, 17.5 mmol, 1.5 equiv.) was added. The mixture was stirred at 80 °C for 15 min. The solvent was removed, ice was added, and the mixture was then adjusted to pH 7-8 with 1N HCl and extracted four times with CHCl / CHOH (5 / 1, 300 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was triturated with petroleum ether and EtOAc, then filtered to give 2-chloro-1,7-naphthyridin-8(7H)-one (1-5). 1 H NMR (400 MHz, DMSO-d6): δ ppm 11.74 (br s, 1H), 8.21 (d, J = 8.4 Hz, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.33-7.30 (m, 1H), 6.59 (d, J = 6.8 Hz, 1H).MS: [M+H] + = 181.1.

[0205] Step 6: 2-Chloro-8-methoxy-1,7-naphthyridine (1-6)

[0206] [ka] To a solution of (1-5) (1.2 g, 6.6 mmol, 1.0 equiv) in CHCl (120 mL) was added triethyloxonium tetrafluoroborate (1.97 g, 13.3 mmol, 2.0 equiv). The mixture was stirred at 65 °C for 12 h. The mixture was added to 1 N NaOH (40 mL). After stirring for 20 min, the mixture was extracted three times with CHCl (200 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The crude product was purified by column chromatography (petroleum ether / EtOAc 8 / 1 to 5 / 1) to give 2-chloro-8-methoxy-1,7-naphthyridine (1-6). 1H NMR (400 MHz, CDCl3): δ ppm 8.11 (d, J = 5.6 Hz, 1H), 8.04 (d, J = 8.8 Hz, 1H), 7.58 (d, J = 8.8 Hz, 1H), 7.21 (d, J = 5.6 Hz, 1H), 4.20 (s, 3H).MS: [M+H] + = 194.8.

[0207] Step 7: tert-Butyl (((1,4-trans)-4-((8-methoxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)carbamate (1-7)

[0208] [ka] To a solution of (1-6) (650 mg, 3.35 mmol, 1.0 equiv) and tert-butyl (((1,4-trans)-4-aminocyclohexyl)methyl)carbamate (993 mg, 4.36 mmol, 1.3 equiv) in anhydrous THF (50 mL) was added BINAP (625 mg, 1.0 mmol, 0.3 equiv), Pd(dba) (306 mg, 0.34 mmol, 0.1 equiv), and t-BuONa (322 mg, 3.35 mmol, 1.0 equiv), and the mixture was stirred at 65 °C for 1.5 h. The mixture was filtered, and the filtrate was added to HO (30 mL) and extracted twice with EtOAc (50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give the crude product, which was purified by silica gel column chromatography (petroleum ether / EtOAc 4 / 1 to 3 / 1) to give tert-butyl (((1,4-trans)-4-((8-methoxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)carbamate (1-7). 1H NMR (400 MHz, CDCl3): δ ppm 7.79-7.75 (m, 2H), 7.01 (d, J = 5.6 Hz, 1H), 6.81 (d, J = 8.8 Hz, 1H), 5.07 (d, J = 8.0 Hz, 1H), 4.62 (br s, 1H), 4.13 (s, 3H), 3.61-3.54 (m, 1H), 3.00 (t, J = 6.4 Hz, 2H), 2.16-2.13 (m, 2H), 1.85-1.80 (m, 2H), 1.51-1.39 (m, 10H), 1.25-1.08 (m, 4H). MS: [M+H] + = 387.2.

[0209] Step 8: N-((1,4-trans)-4-(aminomethyl)cyclohexyl)-8-methoxy-1,7-naphthyridin-2-amine (1-8)

[0210] [ka] To a solution of (1-7) (320 mg, 0.83 mmol, 1.0 equiv) in CHCl (5 mL) was added TFA (1 mL) and the mixture was stirred at 25° C. for 1.5 h. The mixture was concentrated to give crude N-((1,4-trans)-4-(aminomethyl)cyclohexyl)-8-methoxy-1,7-naphthyridin-2-amine (1-8), which was used without further purification. MS: [M+H] + =286.9.

[0211] Step 9: 8-Methoxy-N-((1,4-trans)-4-(((5-nitropyrimidin-2-yl)amino)methyl)cyclohexyl)-1,7-naphthyridin-2-amine (1-9)

[0212] [ka] To a solution of (1-8) (230 mg, 0.8 mmol, 1.0 equiv.) in acetonitrile (2 mL) and THF (2 mL), 2-chloro-5-nitropyrimidine (154 mg, 0.96 mmol, 1.20 equiv.) and DIPEA (310 mg, 2.4 mmol, 5.0 equiv.) were added, and the mixture was stirred at room temperature for 0.5 h. The mixture was concentrated to give the crude product, which was purified by silica gel column chromatography (CHCl / CHOH=30 / 1) to give 8-methoxy-N-((1,4-trans)-4-(((5-nitropyrimidin-2-yl)amino)methyl)cyclohexyl)-1,7-naphthyridin-2-amine (1-9). 1 H NMR (400 MHz, CDCl3): δ ppm 9.11 (d, J = 3.2 Hz, 1H), 9.03 (d, J = 3.6 Hz, 1H), 7.83-7.79 (m, 2H), 7.03 (d, J = 5.6 Hz, 1H), 6.84 (d, J = 8.8 Hz, 1H), 6.07 (t, J = 6.0 Hz, 1H), 5.05 (br s, 1H), 4.14 (s, 3H), 3.76-3.58 (m, 1H), 3.46 (t, J = 6.4 Hz, 2H), 2.21-2.18 (m, 2H), 1.94-1.91 (m, 2H), 1.71-1.67 (m, 1H), 1.28-1.20 (m, 4H). MS: [M+H] + = 410.1.

[0213] Step 10:N 2 -(((1,4-trans)-4-((8-methoxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)pyrimidine-2,5-diamine (1)

[0214] [ka] To a solution of (1-9) (230 mg, 0.56 mmol, 1.0 equiv) in CHOH (15 mL) and EtOAc (15 mL) was added Pd / C (10%, 40 mg). The suspension was degassed under vacuum and purged with H several times. The mixture was stirred under a H balloon at 20 °C for 3 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: Phenomenex Gemini C18 200 mm x 25 mm x 5 um, gradient: 20-50% B (A = 0.5% NHOH in water, B = acetonitrile)) to give a 20% HCl (20-50% B, 20-50% B). 2 -(((1,4-trans)-4-((8-methoxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)pyrimidine-2,5-diamine (C1) was obtained. 1 H NMR (400 MHz, DMSO-d6): δ ppm 7.79 (s, 2H), 7.77 (s, 1H), 7.68 (d, J = 5.2 Hz, 1H), 7.09 (d, J = 5.6 Hz, 1H), 7.06 (d, J = 8.0 Hz, 1H), 6.89 (d, J = 8.8 Hz, 1H), 6.25 (t, J = 6.0 Hz, 1H), 4.38 (s, 2H ), 3.94 (s, 3H), 3.87 (br s, 1H), 3.06 (t, J = 6.0 Hz, 2H), 2.03-2.00 (m, 2H), 1.82-1.79 (m, 2H), 1.52 (br s, 1H), 1.21-1.00 (m, 4H). MS: [M+H] + = 380.2.

[0215] [Example 2] N-(2-((((1,4-trans)-4-((8-methoxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)azetidine-3-carboxamide (C2) Step 1: tert-butyl 3-((2-((((1,4-trans)-4-((8-methoxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)carbamoyl)azetidine-1-carboxylate (2-1)

[0216] [ka] To a solution of compound (C1) (200 mg, 0.53 mmol, 1.0 equiv.) in DMF (5 mL) was added DIEA (204 mg, 1.58 mmol, 3.0 equiv.), HATU (603 mg, 1.58 mmol, 3.0 equiv.), and 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (106 mg, 0.53 mmol, 1.0 equiv.). The mixture was stirred at 22° C. for 1.0 h. The mixture was added to EtOAc (50 mL) and washed twice with brine (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by column chromatography (CH2Cl2 / CH3OH 50 / 1 to 20 / 1) to give tert-butyl 3-((2-((((1,4-trans)-4-((8-methoxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)carbamoyl)azetidine-1-carboxylate (2-1). 1 H NMR (400 MHz, CDCl3): δ ppm 8.41 (s, 2H), 7.87-7.85 (m, 2H), 7.40 (br s, 1H), 7.06 (d, J = 5.6 Hz, 1H), 6.94 (d, J = 9.2 Hz, 1H), 5.57 (br s, 1H), 4.18-4.10 (m, 7H), 3.63 (br s, 1H), 3.41-3.33 (m, 1H), 3.28 (t, J = 6.4 Hz, 2H), 2.15-2.12 (m, 2H), 1.92-1.89 (m, 2H), 1.67-1.60 (m, 1H), 1.44 (s, 9H), 1.30-1.10 (m, 4H). MS: [M+H] + = 563.3.

[0217] Step 2: N-(2-((((1,4-trans)-4-((8-methoxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)azetidine-3-carboxamide (C2)

[0218] [ka] To a solution of (2-1) (250 mg, 0.44 mmol, 1.0 equiv) in CHCl (6.0 mL) was added TFA (1 mL), and the reaction mixture was stirred at 22 °C for 1.0 h. The mixture was concentrated to give the crude product (200 mg). The crude product (100 mg) was purified by preparative HPLC (column: Phenomenex Gemini C18 250 mm × 21.2 mm × 5 μm, gradient: 20–50% B (A = water, B = acetonitrile), flow rate: 25 mL / min) to give N-(2-((((1,4-trans)-4-((8-methoxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)azetidine-3-carboxamide (2). 1 H NMR (400 MHz, DMSO-d6): δ ppm 9.62 (s, 1H), 8.39 (s, 2H), 7.79 (d, J = 9.2 Hz, 1H), 7.68 (d, J = 5.6 Hz, 1H), 7.15-7.08 (m, 2H), 7.05 (d, J = 8.0 Hz, 1H), 6.90 (d, J = 8.8 Hz, 1H), 3.95 (s, 3H), 3.88 (br s, 1H), 3.73-3.71 (m, 1H), 3.59-3.44 (m, 4H), 3.14 (t, J = 6.4 Hz, 2H), 2.06-1.98 (m, 2H), 1.86-1.76 (m, 2H), 1.54 (br s, 1H), 1.24-1.01 (m, 4H). MS: [M+H] + = 463.2.

[0219] [Example 3] N-(2-((((1,4-trans)-4-((8-methoxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-1-methylazetidine-3-carboxamide (C3)

[0220] [ka] A solution of compound (C2) (100 mg, 0.22 mmol, 1.0 equiv.) in CHOH (3.0 mL) was basified with DIPEA to pH 7-8, followed by addition of NaBHCN (42 mg, 0.66 mmol, 3.0 equiv.) and (HCHO) n (32 mg, 1.08 mmol, 5.0 equiv) was added. The reaction mixture was stirred at 25 °C for 40 min. The mixture was quenched with water (20 mL) and extracted twice with CHCl (50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by preparative HPLC (column: Phenomenex Gemini C18 250 mm × 21.2 mm × 5 um, gradient: 20-40% B (A = water, B = acetonitrile), flow rate: 25 mL / min) to give N-(2-((((1,4-trans)-4-((8-methoxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-1-methylazetidine-3-carboxamide (C3). 1H NMR (400 MHz, DMSO-d6): δ ppm 9.65 (s, 1H), 8.39 (s, 2H), 7.79 (d, J = 9.2 Hz, 1H), 7.69 (d, J = 5.6 Hz, 1H), 7.12-7.08 (m, 2H), 7.05 (d, J = 7.6 Hz, 1H), 6.90 (d, J = 9.2 Hz, 1H), 3.95 (s, 3H), 3.86 (br s, 1H), 3.40 (t, J = 6.8 Hz, 2H), 3.27-3.21 (m, 1H), 3.16-3.10 (m, 4H), 2.18 (s, 3H), 2.04-2.01 (m, 2H), 1.93-1.79 (m, 2H), 1.55 (br s, 1H), 1.22-1.03 (m, 4H). MS: [M+H] + = 477.3.

[0221] [Example 4] 2-((((1,4-trans)-4-((8-methoxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidine-5-carbonitrile (C4)

[0222] [ka] The title compound was prepared using a procedure similar to that in Step 9 of Example 1, except that 2-chloro-5-nitropyrimidine was replaced with 2-chloropyrimidine-5-carbonitrile, and the product was purified by preparative HPLC (Column: Phenomenex Gemini C18 200 mm × 25 mm × 5 μm, Gradient: 33-63% B (A = water, B = acetonitrile)) to give 2-((((1,4-trans)-4-((8-methoxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidine-5-carbonitrile (C4). 1H NMR (400 MHz, DMSO-d6): δ ppm 8.71 (d, J = 3.2 Hz, 1H), 8.63 (d, J = 3.2 Hz, 1H), 8.41 (t, J = 6.0 Hz, 1H), 7.79 (d, J = 9.2 Hz, 1H), 7.68 (d, J = 5.2 Hz, 1H), 7.09 (d, J = 5.6 Hz, 1H), 7.05 (d, J = 8.0 Hz, 1H), 6.90 (d, J = 9.2 Hz, 1H), 3.94 (s, 3H), 3.87 (br s, 1H), 3.23 (t, J = 6.4 Hz, 2H), 2.04-2.01 (m, 2H), 1.81-1.77 (m, 2H), 1.58 (br s, 1H), 1.23-1.05 (m, 4H). MS: [M+H] + = 390.1.

[0223] [Example 5] 2-((((1,4-trans)-4-((8-methoxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidine-5-carboxamide (C5)

[0224] [ka] To a solution of compound (C4) (60 mg, 0.15 mmol, 1.0 equiv) in DMSO (3 mL) was added KCO (64 mg, 0.46 mmol, 3.0 equiv) and water (0.5 mL). HO (30% aqueous solution, 52 mg, 0.46 mmol, 3.0 equiv) was added dropwise to the mixture at 0 °C. The mixture was stirred at 30 °C for 0.5 h. The reaction mixture was added to EtOAc (50 mL), washed twice with brine (20 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by preparative HPLC (column: Phenomenex Gemini C18 200 mm x 25 mm x 5 um, gradient: 11-48% B (A = water, B = acetonitrile)) to give 2-((((1,4-trans)-4-((8-methoxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidine-5-carboxamide (C5). 1 H NMR (400 MHz, DMSO-d6): δ ppm 8.73 (s, 1H), 8.69 (s, 1H), 7.85 (t, J = 6.0 Hz, 1H), 7.80 (d, J = 8.8 Hz, 1H), 7.69 (d, J = 5.6 Hz, 1H), 7.23 (br s, 1H), 7.10 (d, J = 5.2 Hz, 1H), 7.06 (d, J = 8.0 Hz, 1H), 6.91 (d, J = 8.8 Hz, 1H), 3.96 (s, 3H), 3.89 (br s, 1H), 3.24 (t, J = 6.4 Hz, 2H), 2.05-2.02 (m, 2H), 1.83-1.80 (m, 2H), 1.58 (br s, 1H), 1.23-1.06 (m, 4H). MS: [M+H] + = 408.2.

[0225] [Example 6] N-(2-((((1,4-trans)-4-((8-methoxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)acetamide (C6)

[0226] [ka] The title compound was prepared using a procedure similar to that in Step 1 of Example 2, except that 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid was replaced with acetic acid, and the product was purified by preparative HPLC (Column: Phenomenex Gemini C18 200 mm × 25 mm × 5 μm, Gradient: 19-49% B (A = water, B = acetonitrile)) to give N-(2-((((1,4-trans)-4-((8-methoxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)acetamide (C6). 1 H NMR (400 MHz, DMSO-d6): δ ppm 9.73 (s, 1H), 8.36 (s, 2H), 7.78 (d, J = 8.8 Hz, 1H), 7.68 (d, J = 5.6 Hz, 1H), 7.12-7.04 (m, 3H), 6.90 (d, J = 8.8 Hz, 1H), 3.94 (s, 3H), 3.88 (br s, 1H), 3.14 (t, J = 6.0 Hz, 2H), 2.03-2.00 (m, 2H), 1.99 (s, 3H), 1.82-1.79 (m, 2H), 1.55 (br s, 1H), 1.21-1.02 (m, 4H). MS: [M+H] + = 422.2.

[0227] [Example 7] 2-Hydroxy-N-(2-((((1,4-trans)-4-((8-methoxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)acetamide (C7)

[0228] [ka] The title compound was prepared using a procedure similar to that in Step 1 of Example 2, except that 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid was replaced with 2-hydroxyacetic acid. 1H NMR (400 MHz, DMSO-d6): δ ppm 9.59 (s, 1H), 8.46 (s, 2H), 7.79 (d, J = 8.8 Hz, 1H), 7.68 (d, J = 5.2 Hz, 1H), 7.13 (t, J = 6.0 Hz, 1H), 7.09 (d, J = 5.6 Hz, 1H), 7.06 (d, J = 8.0 Hz, 1H), 6.90 (d, J = 8.8 Hz, 1H), 5.75 (t, J = 6.0 Hz, 1H), 3.97 (d, J = 5.6 Hz, 2H), 3.95 (s, 3H), 3.87 (br s, 1H), 3.14 (t, MS: [M+H] + = 438.2.

[0229] [Example 8] (2-((((1,4-trans)-4-((8-methoxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)(piperazin-1-yl)methanone (C8) Step 1: Ethyl 2-((((1,4-trans)-4-((8-methoxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidine-5-carboxylate (8-1)

[0230] [ka] To a solution of (1-8) (2.2 g, 7.7 mmol, 1.0 equiv.) in DMF (30 mL) was added ethyl 2-chloropyrimidine-5-carboxylate (1.6 g, 8.4 mmol, 1.1 equiv.) and DIPEA (4.9 g, 38.5 mmol, 5.0 equiv.), and the mixture was stirred at 100 °C for 2.5 h. The mixture was added to EtOAc (100 mL), washed three times with brine (30 mL), dried over anhydrous NaSO, and concentrated. The crude product was purified by column chromatography (petroleum ether / EtOAc 2 / 1 to 1 / 1) to give ethyl 2-((((1,4-trans)-4-((8-methoxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidine-5-carboxylate (8-1). 1 H NMR (400 MHz, CDCl3): δ ppm 8.87 (s, 1H), 8.78 (s, 1H), 7.80-7.76 (m, 2H), 7.01 (d, J = 5.6 Hz, 1H), 6.82 (d, J = 9.2 Hz, 1H), 5.81 (br s, 1H), 5.07 (d, J = 7.6 Hz, 1H), 4.33 (q, J = 6.8 Hz, 1H), 4.13 (s, 3H), 3.62 (br s, 1H), 3.40 (t, J = 6.4 Hz, 2H), 2.18-2.16 (m, 2H), 1.92-1.90 (m, 2H), 1.65 (br s, 1H), 1.36 (t, J = 6.8 Hz, 3H), 1.24-1.20 (m, 4H). MS: [M+H] + = 437.2.

[0231] Step 2: 2-((((1,4-trans)-4-((8-methoxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidine-5-carboxylic acid (8-2)

[0232] [ka] To a solution of (8-1) (2.2 g, 5.0 mmol, 1.0 equiv) in MeOH (20 mL) was added HO (4 mL) and KOH (1.12 g, 20 mmol, 4.0 equiv), and the reaction mixture was stirred at 50 °C for 2.5 h. The mixture was concentrated and adjusted to pH 5-6 with 1 N HCl. The formed precipitate was collected by filtration to give 2-((((1,4-trans)-4-((8-methoxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidine-5-carboxylic acid (8-2). 1 H NMR (400 MHz, DMSO-d6): δ ppm 12.72 (br s, 1H), 8.73 (d, J = 2.8 Hz, 1H), 8.66 (d, J = 3.2 Hz, 1H), 8.13 (t, J = 6.0 Hz, 1H), 7.79 (d, J = 9.2 Hz, 1H), 7.68 (d, J = 5.2 Hz, 1H), 7.10-7.06 (m, 2H), 6.90 (d, J = 9.2 Hz, 1H), 3.94 (s, 3H), 3.88 (br s, 1H), 3.24 (t, J = 6.4 Hz, 2H), 2.04-2.01 (m, 2H), 1.82-1.79 (m, 2H), 1.59 (br s, 1H), 1.20-1.08 (m, 4H).

[0233] Step 3: (2-((((1,4-trans)-4-((8-methoxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)(piperazin-1-yl)methanone (C8)

[0234] [ka] To a solution of compound (8-2) (2.5 g, 6.1 mmol, 1.0 equiv.) in DMF (20 mL) was added piperazine (10 g, 123 mmol, 20.0 equiv.), DIEA (2.4 g, 18.3 mmol, 3.0 equiv.), and HATU (7.0 g, 18.3 mmol, 3.0 equiv.). The mixture was stirred at 15 °C for 0.5 h. The mixture was quenched with HO (50 mL) and extracted with EtOAc (100 mL × 4). The combined organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (CH2Cl2 / CH3OH=50 / 1) to give the crude product, which was triturated with petroleum ether / EtOAc (5 / 1, 100 mL), filtered and dried to give (2-((((1,4-trans)-4-((8-methoxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)(piperazin-1-yl)methanone (C8). 1 H NMR (400 MHz, DMSO-d6): δ ppm 8.36 (s, 1H), 8.32 (s, 1H), 7.79 (d, J = 8.8 Hz, 1H), 7.75 (t, J = 6.0 Hz, 1H), 7.68 (d, J = 5.6 Hz, 1H), 7.09 (d, J = 5.6 Hz, 1H), 7.06 (d, J = 7.6 Hz, 1H), 6.90 (d, J = 9.2 Hz, 1H), 3.95 (s, 3H), 3.88 (br s, 1H), 3.49-3.40 (m, 4H), 3.20 (t, J = 6.4 Hz, 2H), 2.72-2.66 (m, 4H), 2.04-2.01 (m, 2H), 1.83-1.80 (m, 2H), 1.58 (br s, 1H), 1.22-1.04 (m, 4H). MS: [M+H] + = 477.3.

[0235] [Example 9] N-(2-hydroxypropyl)-2-((((1,4-trans)-4-((8-methoxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidine-5-carboxamide (C9)

[0236] [ka] The title compound was prepared by using a procedure similar to that in Example 8, except that piperazine was replaced with 1-aminopropan-2-ol. 1 H NMR (400 MHz, DMSO-d6): δ ppm 8.71 (s, 1H), 8.68 (s, 1H), 8.24 (t, J = 5.6 Hz, 1H), 7.83-7.77 (m, 2H), 7.68 (d, J = 5.6 Hz, 1H), 7.09 (d, J = 5.6 Hz, 1H), 7.05 (d, J = 8.0 Hz, 1H), 6.90 (d, J = 9.2 Hz, 1H), 4.74 (d, J = 4.8 Hz, 1H), 3.95 (s, 3H), 3.87 (br s, 1H), 3.76-3.71 (m, 1H), 3.23 (t, J = 6.4 Hz, 2H), 3.19-3.11 (m, 2H), 2.04-2.01 (m, 2H), 1.83-1.79 (m, 2H), 1.58 (br s, 1H), 1.19-1.08 (m, 4H), 1.05 (d, J = 6.4 Hz, 3H). MS: [M+H] + = 466.2.

[0237] [Example 10] (2-((((1,4-trans)-4-((8-methoxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)(morpholino)methanone (C10)

[0238] [ka] The title compound was prepared by using a procedure similar to that in Example 8, except that piperazine was replaced with morpholine. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.40 (s, 1H), 8.36 (s, 1H), 7. 81-7.77 (m, 2H), 7.68 (d, J = 5.2 Hz, 1H), 7.09 (d, J = 5.2 Hz, 1H), 7.06 (d, J = 8.0 Hz, 1H), 6.90 (d, J = 8.8 Hz, 1H), 3.95 (s, 3H), 3.89 (br s, 1H), 3.68-3.58 (m, 4H), 3.58-3.49 (m, 4H), 3.21 (t, J = 6.4 Hz, 2H), 2.04-2.02 (m, 2H), 1.83-1.80 (m, 2H), 1.58 (br s, 1H), 1.22-1.05 (m, 4H). MS: [M+H] + = 478.2.

[0239] [Example 11] (2-((((1,4-trans)-4-((8-methoxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)(4-methylpiperazin-1-yl)methanone (C11)

[0240] [ka] The title compound was prepared by using a procedure similar to that in Example 8, except that piperazine was replaced with 1-methylpiperazine. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.37 (s, 1H), 8.33 (s, 1H), 7.80-7.76 (m, 2H), 7.68 (d, J = 5.2 Hz, 1H), 7.09 (d, J = 5.2 Hz, 1H), 7.06 (d, J = 7.6 Hz, 1H), 6.90 (d, J = 8.8 Hz, 1H), 3.95 (s, 3H), 3.86 (br s, 1H), 3.59 (br s, 4H), 3.21 (t, J = 6.4 Hz, 2H), 2.38-2.29 (m, 4H), 2.20 (s, 3H), 2.05-2.02 (m, 2H), 1.84-1.80 (m, 2H), 1.58 (br s, 1H), 1.22-1.04 (m, 4H). MS: [M+H] + = 491.3.

[0241] [Example 12] N-((1,4-trans)-4-(((5-(1H-1,2,4-triazol-5-yl)pyrimidin-2-yl)amino)methyl)cyclohexyl)-8-methoxy-1,7-naphthyridin-2-amine (C12) Step 1: N-((E)-(dimethylamino)methylene)-2-((((1,4-trans)-4-((8-methoxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidine-5-carboxamide (12-1)

[0242] [ka] To a solution of compound (C5) (55 mg, 0.13 mmol, 1.0 equiv) in THF (5 mL) was added DMFDMA (0.3 mL). The mixture was heated at 60° C. for 30 minutes. The mixture was concentrated in vacuo to give N-((E)-(dimethylamino)methylene)-2-((((1,4-trans)-4-((8-methoxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidine-5-carboxamide (12-1), which was used directly in the next step. MS: [M+H] + =463.2.

[0243] Step 2: N-((1,4-trans)-4-(((5-(1H-1,2,4-triazol-5-yl)pyrimidin-2-yl)amino)methyl)cyclohexyl)-8-methoxy-1,7-naphthyridin-2-amine (C12)

[0244] [ka] To a solution of (12-1) (50 mg, 0.11 mmol, 1.0 equiv) in AcOH (5 mL) was added hydrazine hydrate (127 mg, 2.16 mmol, 20 equiv). The reaction was heated at 85° C. for 0.5 h. The AcOH was then removed under vacuum, and the residue was basified by the addition of ammonia. The reaction mixture was extracted with EtOAc (30 mL×2), and the organic solvent was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC (Column: Waters Exselect C18 150 mm × 30 mm × 5 μm, Gradient: 22–37% B (A = 0.05% NH3HO in water, B = acetonitrile)) to give N-((1,4-trans)-4-(((5-(1H-1,2,4-triazol-5-yl)pyrimidin-2-yl)amino)methyl)cyclohexyl)-8-methoxy-1,7-naphthyridin-2-amine (C12). 1H NMR (400 MHz, DMSO-d6): δ ppm 8.81 (s, 2H), 8.39 (br s, 1H), 7.79 (d, J = 8.8 Hz, 1H), 7.70-7.60 (m, 2H), 7.11-7.06 (m, 2H), 6.90 (d, J = 8.4 Hz, 1H), 3.95 (s, 3H), 3.88 (br s, 1H), 3.24 (t, J = 5.6 Hz, 2H), 2.06-2.02 (m, 2H), 1.86-1.82 (m, 2H), 1.60 (br s, 1H), 1.21-1.09 (m, 4H). MS: [M+H] + = 432.2.

[0245] [Example 13] 2-(2-((((1,4-trans)-4-((8-methoxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-(oxetan-3-yl)acetamide (C13) Step 1: N-((1,4-trans)-4-(((5-iodopyrimidin-2-yl)amino)methyl)cyclohexyl)-8-methoxy-1,7-naphthyridin-2-amine (13-1)

[0246] [ka] The title compound was prepared using a procedure similar to that in Step 1 of Example 8, except that ethyl 2-chloropyrimidine-5-carboxylate was replaced with 2-chloro-5-iodopyrimidine, and the product was purified by column chromatography on silica gel (petroleum ether / EtOAc 5 / 1 to 1 / 1) to give N-((1,4-trans)-4-(((5-iodopyrimidin-2-yl)amino)methyl)cyclohexyl)-8-methoxy-1,7-naphthyridin-2-amine (13-1). 1H NMR (400 MHz, DMSO-d6): δ ppm 8.39 (s, 2H), 7.78 (d, J = 9.2 Hz, 1H), 7.68 (d, J = 5.6 Hz, 1H), 7.50 (t, J = 6.0 Hz, 1H), 7.09 (d, J = 5.6 Hz, 1H), 7.05 (d, J = 8.0 Hz, 1H), 6.89 (d, J = 8.8 Hz, 1H), 3.95 (s, 3H), 3.88 (br s, 1H), 3.13 (t, J = 6.0 Hz, 2H), 2.03-2.00 (m, 2H), 1.81-1.77 (m, 2H), 1.54 (br s, 1H), 1.15-1.05 (m, 4H). MS: [M+H] + = 491.1.

[0247] Step 2: tert-Butyl 2-(2-((((1,4-trans)-4-((8-methoxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)acetate (13-2)

[0248] [ka] To a mixture of zinc powder (346.7 mg, 5.30 mmol, 20 equiv.) in THF (8 mL) was added TMSCl (0.1 mL), and the mixture was stirred under N protection at 17 °C for 0.5 h. Subsequently, tert-butyl 2-bromoacetate (930.8 mg, 4.77 mmol, 18 equiv.) was added dropwise over 10 min. The resulting mixture was stirred under nitrogen at 17 °C for another hour. To the above mixture was then added (13-1) (130 mg, 0.27 mmol, 1.0 equiv.), X-phos (31.6 mg, 0.066 mmol, 0.25 equiv.), and Pd(dba) (48.6 mg, 0.053 mmol, 0.2 equiv.). The reaction mixture was stirred under N at 60 °C for 12 h. The mixture was quenched with saturated NH4Cl solution (5 mL) and extracted three times with EtOAc (10 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography on silica gel (petroleum ether / EtOAc 3 / 1 to 1 / 2) to give tert-butyl 2-(2-((((1,4-trans)-4-((8-methoxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)acetate (13-2)). 1 H NMR (400 MHz, DMSO-d6): δ ppm 8.13 (s, 2H), 7.78 (d, J = 8.8 Hz, 1H), 7.68 (d, J = 5.6 Hz, 1H), 7.16 (d, J = 6.0 Hz, 1H), 7.09 (d, J = 5.2 Hz, 1H), 7.05 (d, J = 8.0 Hz, 1H), 6.89 (d, J = 9.2 Hz, 1H), 3.95 (s, 3H), 3.88 (br s, 1H), 3.38 (s, 2H), 3.15 (t, J = 6.4 Hz, 2H), 2.04-2.01 (m, 2H), 1.83-1.80 (m, 2H), 1.56 (br s, 1H), 1.40 (s, 9H), 1.19-1.06 (m, 4H).

[0249] Step 3: 2-(2-((((1,4-trans)-4-((8-methoxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)acetic acid (13-3)

[0250] [ka] To a solution of 13-2 (100 mg, 0.21 mmol, 1.0 equiv) in CHCl (4 mL) was added TFA (1.0 mL) portionwise over 5 min. The reaction mixture was stirred at 19 °C for 1.5 h. The mixture was concentrated to give 2-(2-((((1,4-trans)-4-((8-methoxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)acetic acid (13-3). MS: [M+H] + =423.0.

[0251] Step 4: 2-(2-((((1,4-trans)-4-((8-methoxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-(oxetan-3-yl)acetamide (C13)

[0252] [ka] To a mixture of (13-3) (80 mg, 0.19 mmol, 1.0 equiv) in DMF (4 mL) was added DIEA (97.89 mg, 0.76 mmol, 4.0 equiv), followed by oxetan-3-amine (27.68 mg, 0.38 mmol, 2.0 equiv) and HATU (144.0 mg, 0.38 mmol, 2.0 equiv). The resulting mixture was stirred at 19 °C for 1.0 h. The mixture was diluted with water (5 mL) and extracted three times with EtOAc (10 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by preparative HPLC (Column: Durashell 150 mm x 25 mm x 5 um: 22-52% B (A = 0.5% NHOH in water, B = acetonitrile)) to give 2-(2-((((1,4-trans)-4-((8-methoxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-(oxetan-3-yl)acetamide (C13). 1 H NMR (400 MHz, DMSO-d6): δ ppm 8.80 (d, J = 6.4 Hz, 1H), 8.12 (s, 2H), 7.78 (d, J = 8.8 Hz, 1H), 7.68 (d, J = 5.6 Hz, 1H), 7.12 (d, J = 6.0 Hz, 1H), 7.09 (d, J = 5.6 Hz, 1H), 7.05 (d, J = 7.6 Hz, 1H), 6.89 (d, J = 8.8 Hz, 1H), 4.80-4.74 (m, 1H), 4.70 (t, J = 6.0 Hz, 2H), 4.41 (t, J = 6.4 Hz, 2H), 3.95 (s, 3H), 3.87 (br s, 1H), 3.24 (s, 2H), 3.15 (t, J = 6.4 Hz, 2H), 2.04-2.01 (m, 2H), 1.83-1.79 (m, 2H), 1.55 (br s, 1H), 1.22-1.02 (m, 4H). MS: [M+H] + = 478.1.

[0253] [Example 14] N 2-(((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)pyrimidine-2,5-diamine(C14) Step 1: 8-chloro-N-((1,4-trans)-4-(((5-nitropyrimidin-2-yl)amino)methyl)cyclohexyl)-1,7-naphthyridin-2-amine (14-1)

[0254] [ka] A mixture of (1-9) (160 mg, 0.39 mmol, 1.0 equiv) in POCl (5 mL) was stirred at 110 °C for 1.5 h. The solvent was removed, and the residue was basified with saturated NaHCO solution to pH 7-8 and extracted twice with EtOAc (50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give 8-chloro-N-((1,4-trans)-4-(((5-nitropyrimidin-2-yl)amino)methyl)cyclohexyl)-1,7-naphthyridin-2-amine (14-1). MS: [M+H] + =414.0.

[0255] Step 2:N 2 -(((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)pyrimidine-2,5-diamine(C14)

[0256] [ka] To a solution of (14-1) (100 mg, 0.24 mmol, 1.0 equiv) in CHOH (4 mL) and CHCl (1.5 mL) was added NiCl·6H0 (114 mg, 0.48 mmol, 2.0 equiv) and NaBH (36 mg, 0.96 mmol, 4.0 equiv). The mixture was stirred at 25 °C for 10 min. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: Phenomenex Gemini C18 250 mm × 21.2 mm × 5 μm, gradient: 32–47% B (A = water, B = acetonitrile)) and purified by N 2 -(((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)pyrimidine-2,5-diamine (C14) was obtained. 1 H NMR (400 MHz, DMSO-d6): δ ppm 7.95 (d, J = 5.2 Hz, 1H), 7.91 (d, J = 9.2 Hz, 1H), 7.79 (s, 2H), 7.55 (d, J = 5.2 Hz, 1H), 7.50 (d, J = 7.2 Hz, 1H), 6.99 (d, J = 9.2 Hz, 1H), 6.24 (t, J = 5.6 Hz, 1H), 4.37 (s, 2H), 3.90 (br s, 1H), 3.07 (t, J = 6.4 Hz, 2H), 2.12-2.09 (m, 2H), 1.84-1.80 (m, 2H), 1.55 (br s, 1H), 1.22-1.00 (m, 4H). MS: [M+H] + = 384.1.

[0257] [Example 15] Methyl (2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)carbamate (C15)

[0258] [ka] To a solution of (C14) (100 mg, 0.26 mmol, 1.0 equiv) in CHCl (5 mL) was added CDI (carbonyldiimidazole, 168 mg, 1.04 mmol, 5.0 equiv) and DIEA (134 mg, 1.04 mmol, 5.0 equiv). The mixture was stirred at 25° C. for 2 hours. CHOH (5 mL) was then added and stirred at 25° C. for 20 minutes. The reaction mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC (Column: Waters Crossbridge Prep OBD C18 150 mm x 30 mm x 5 um, Gradient: 31-61% B (A = 0.5% NH4HCO3 in water, B = acetonitrile)) to give methyl (2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)carbamate (C15). 1 H NMR (400 MHz, DMSO-d6): δ ppm 9.27 (s, 1H), 8.27 (s, 2H), 7.96 (d, J = 5.2 Hz, 1H), 7.91 (d, J = 8.8 Hz, 1H), 7.56-7.52 (m. 2H), 7.11 (br s, 1H), 6.99 (d, J = 9.2 Hz, 1H), 3.91 (br s, 1H), 3.63 (s, 3H), 3.14 (t, J = 6.4 Hz, 2H), 2.13-2.11 (m. 2H), 1.85-1.82 (m. 2H), 1.57 (br s, 1H), 1.24-1.15 (m, 2H), 1.14-1.03 (m, 2H). MS: [M+H] + = 442.2.

[0259] [Example 16] 2-Methoxyethyl (2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)carbamate (C16)

[0260] [ka] The title compound was prepared by using a procedure similar to that in Example 15, except that methanol was replaced with 2-methoxyethan-1-ol. 1 H NMR (400 MHz, DMSO-d6): δ ppm 9.36 (s, 1H), 8.27 (s, 2H), 7.95 (d, J = 5.2 Hz, 1H), 7.91 (d, J = 9.2 Hz, 1H), 7.55 (d, J = 5.2 Hz, 1H), 7.50 (d, J = 7.2 Hz, 1H), 7.08 (br s, 1H), 6.99 (d, J = 8.8 Hz, 1H), 4.17 (t, J = 4.8 Hz, 2H), 3.90 (br s, 1H), 3.54 (t, J = 4.8 Hz, 2H), 3.27 (s, 3H), 3.14 (t, J = 6.4 MS: [M+H] + = 486.2.

[0261] [Example 17] 2-Hydroxyethyl (2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)carbamate (C17)

[0262] [ka] The title compound was prepared by using a procedure similar to that in Example 15, except that methanol was replaced with ethane-1,2-diol. 1H NMR (400 MHz, DMSO-d6): δ ppm 9.31 (s, 1H), 8.27 (s, 2H), 7.96 (d, J = 4.8 Hz, 1H), 7.91 (d, J = 8.8 Hz, 1H), 7.55 (d, J = 5.2 Hz, 1H), 7.51 (d, J = 7.2 Hz, 1H), 7.08 (d, J = 5.6 Hz, 1H), 6.99 (d, J = 9.2 Hz, 1H), 4.83 (t, J = 5.2 Hz, 1H), 4.07 (t, J = 5.2 Hz, 2H), 3.90 (br s, 1H), 3.61-3.58 (m, 2H), 3.14 (t, J = 6.4 Hz, 2H), 2.13-2.10 (m, 2H), 1.85-1.82 (m, 2H), 1.57 (br s, 1H), 1.29-1.15 (m, 2H), 1.13-1.03 (m, 2H). MS: [M+H] + = 472.1.

[0263] [Example 18] Oxetan-3-ylmethyl (2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)carbamate (C18)

[0264] [ka] The title compound was prepared by using a procedure similar to that in Example 15, except that methanol was replaced with oxetan-3-ylmethanol. 1H NMR (400 MHz, DMSO-d6): δ ppm 9.35 (s, 1H), 8.28 (s, 2H), 7.96 (d, J = 5.2 Hz, 1H), 7.91 (d, J = 8.8 Hz, 1H), 7.56 (d, J = 5.2 Hz, 1H), 7.51 (d, J = 7.2 Hz, 1H), 7.10 (t, J = 6.0 Hz, 1H), 6.99 (d, J = 8.4 Hz, 1H), 4.66 (t, J = 6.0 Hz, 2H), 4.38 (t, J = 6.0 Hz, 2H), 4.27 (d, J = 6.4 Hz, 2H), 3.91 (br s, 1H), 3.29-3.24 (m, 1H), 3.14 (t, J = 6.0 Hz, 2H), 2.13-2.11 (m, 2H), 1.85-1.82 (m, 2H), 1.57 (br s, 1H), 1.25-1.19 (m, 2H), 1.16-1.06 (m, 2H). MS: [M+H] + = 498.2.

[0265] [Example 19] N-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-2-hydroxyacetamide (C19)

[0266] [ka] The title compound was prepared using a procedure similar to that in Step 1 of Example 2, except that (C1) was replaced with (C14) and 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid was replaced with 2-hydroxyacetic acid. The product was purified by preparative HPLC (column: Phenomenex Gemini C18 250 mm × 21.2 mm × 5 um, gradient: 20-50% B (A = 0.5% NH4HCO3 in water, B = acetonitrile)) to give N-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-2-hydroxyacetamide (C19). 1 H NMR (400 MHz, DMSO-d6): δ ppm 9.59 (s, 1H), 8.45 (s, 2H), 7.96 (d, J = 5.2 Hz, 1H), 7.91 (d, J = 8.8 Hz, 1H), 7.56-7.51 (m, 2H), 7.13 (t, J = 6.0 Hz, 1H), 7.00 (d, J = 8.4 Hz, 1H), 5.74 (t, J = 6.4 Hz, 1H), 3.96 (d, J = 6.0 Hz, 2H), 3.90 (br s, 1H), 3.15 (t, J = 6.4 Hz, 2H), 2.14-2.11 (m, 2H), 1.85-1.82 (m, 2H), 1.58 (br s, 1H), 1.25-1.03 (m, 4H). MS: [M+H] + = 442.1.

[0267] [Example 20] N-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-4-morpholino-4-oxobutanamide (C20) Step 1: 4-((2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)amino)-4-oxobutanoic acid (20-1)

[0268] [ka] To a solution of (C14) (20 mg, 0.05 mmol, 1.0 equiv) in toluene (4 mL) was added dihydrofuran-2,5-dione (11 mg, 0.1 mmol, 2.0 equiv). The mixture was stirred at 110° C. for 30 minutes. The reaction mixture was concentrated under reduced pressure to give 4-((2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)amino)-4-oxobutanoic acid (20-1). MS: [M+H] + =484.2.

[0269] Step 2: N-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-4-morpholino-4-oxobutanamide (C20)

[0270] [ka] The title compound was prepared by using a procedure similar to that in Step 4 of Example 13, except that 13-3 was replaced with 20-1 and oxetan-3-amine was replaced with morpholine. The product was purified by preparative HPLC (Column: Waters Crossbridge Prep OBD C18 150 mm × 30 mm × 5 um, Gradient: 25-55% B (A = 0.5% NH4HCO3 in water, B = acetonitrile)) to give N-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-4-morpholino-4-oxobutanamide (C20). 1H NMR (400 MHz, DMSO-d6): δ ppm 9.76 (s, 1H), 8.39 (s, 2H), 7.96 (d, J = 5.2 Hz, 1H), 7.91 (d, J = 8.8 Hz, 1H), 7.56 (d, J = 5.2 Hz, 1Hz), 7.51 (d, J = 7.6 Hz, 1Hz), 7.08 (t, J = 5.6 Hz, 1H), 6.99 (d, J = 8.8 Hz, 1H), 3.91 (br s, 1H), 3.59-3.52 (m, 4H), 3.47-3.42 (m, 4H), 3.15 (t, J = 6.0 Hz, 2H), 2.61 (t, J = 6.0 Hz, 2H), 2.53 (t, J = 6.0 Hz, 2H), 2.13-2.11 (m, 2H), 1.85-1.82 (m, 2H), 1.57 (br s, 1H), 1.23-1.16 (m, 2H), 1.13-1.07 (m, 2H). MS: [M+H] + = 553.1.

[0271] [Example 21] 2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidine-5-carbonitrile (C21) Step 1: 2-(((1,4-trans)-4-(aminomethyl)cyclohexyl)amino)-1,7-naphthyridin-8-ol (21-1)

[0272] [ka] To a solution of (1-7) (350 mg, 0.90 mmol, 1.0 equiv) in EtOAc (5 mL) was added HCl / EtOAc (5 mL, 4N) and the mixture was stirred at 25° C. for 1 h. The mixture was concentrated to give 2-(((1,4-trans)-4-(aminomethyl)cyclohexyl)amino)-1,7-naphthyridin-8-ol (21-1), which was used in the next step without further purification. MS: [M+H] +=273.3.

[0273] Step 2: 2-((((1,4-trans)-4-((8-hydroxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidine-5-carbonitrile (21-2)

[0274] [ka] The title compound was prepared by using a procedure similar to that in Step 9 of Example 1, except that (1-8) was replaced with (21-1) and 2-chloro-5-nitropyrimidine was replaced with 2-chloropyrimidine-5-carbonitrile. The product was purified by column chromatography (petroleum ether / EtOAc 1 / 1 to 0 / 100, then CHCl / CHOH 20 / 1) to give 2-((((1,4-trans)-4-((8-hydroxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidine-5-carbonitrile (21-2). 1 H NMR (400 MHz, DMSO-d6): δ ppm 11.17 (d, J = 4.4 Hz, 1H), 8.71 (d, J = 2.8 Hz, 1H), 8.63 (d, J = 3.2 Hz, 1H), 8.42 (t, J = 6.0 Hz, 1H), 7.62 (d, J = 8.8 Hz, 1H), 6.87 (t, J = 6.4 Hz, 1H), 6.82 (d, J = 8.0 Hz, 1H), 6.79 (d, J = 8.8 Hz, 1H), 6.29 (d, J = 6.4 Hz, 1H), 3.86 (br s, 1H), 3.22 (t, J = 6.4 Hz, 2H), 2.01-1.98 (m, 2H), 1.88-1.70 (m, 2H), 1.57 (br s, 1H), 1.18-1.03 (m, 4H). MS: [M+H] + = 376.0.

[0275] Step 3: 2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidine-5-carbonitrile (C21)

[0276] [ka] A mixture of (21-2) (350 mg, 0.93 mmol, 1.0 equiv) in POCl (5 mL) was stirred at 110 °C for 2 h. The solvent was removed, and the residue was basified with saturated NaHCO solution to pH 7-8 and extracted twice with EtOAc (50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give the crude product (280 mg). The crude product (40 mg) was purified by preparative HPLC (column: Phenomenex Gemini C18 200 mm × 21.2 mm × 5 um, gradient: 40-70% B (A = water, B = acetonitrile)) to give 2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidine-5-carbonitrile (C21). 1 H NMR (400 MHz, DMSO-d6): δ ppm 8.71 (d, J = 2.8 Hz, 1H), 8.63 (d, J = 3.2 Hz, 1H), 8.42 (t, J = 6.0 Hz, 1H), 7.96 (d, J = 5.2 Hz, 1H), 7.91 (d, J = 9.2 Hz, 1H), 7.56 (d, J = 5.2 Hz, 1H), 7.52 (d, J = 7.2 Hz, 1H), 6.99 (d, J = 8.8 Hz, 1H), 3.90 (br s, 1H), 3.24 (t, J = 6.4 Hz, 2H), 2.14-2.11 (m, 2H), 1.83-1.80 (m, 2H), 1.59 (br s, 1H), 1.25-1.06 (m, 4H). MS: [M+H] + = 394.1.

[0277] [Example 22] (2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)(morpholino)methanone (C22) Step 1: 2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidine-5-carbonyl chloride (22-1)

[0278] [ka] A solution of (8-2) (140 mg, 0.34 mmol, 1.0 equiv) in POCl (3 mL) was stirred at 110° C. for 2 h. The mixture was concentrated to give 2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidine-5-carbonyl chloride (22-1), which was used in the next step without further purification.

[0279] Step 2: (2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)(morpholino)methanone (C22)

[0280] [ka] To a solution of morpholine (2 mL) in THF (10 mL) was added a suspension of (22-1) (70 mg, 0.16 mmol, 1.0 equiv) in THF (10 mL) dropwise over 10 min. The reaction mixture was stirred at 15 °C for 10 min. The mixture was then concentrated to give the crude product, which was purified by preparative HPLC (Column: Phenomenex Gemini C18 250 mm × 21.2 mm × 5 μm: 29-59% B (A = 0.5% NH4HCO3 in water, B = acetonitrile)) to give (2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)(morpholino)methanone (C22). 1 H NMR (400 MHz, DMSO-d6): δ ppm 8.40 (s, 1H), 8.36 (s, 1H), 7.96 (d, J = 5.2 Hz, 1H), 7.91 (d, J = 8.8 Hz, 1H), 7.80 (t, J = 6.0 Hz, 1H), 7.56 (d, J = 5.2 Hz, 1H), 7.52 (d, J = 7.2 Hz, 1H), 7.00 (d, J = 8.4 Hz, 1H), 3.91 (br s, 1H), 3.60-3.59 (m, 4H), 3.53-3.52 (m, 4H), 3.21 (t, J = 6.4 Hz, 2H), 2.14-2.12 (m, 2H), 1.86-1.83 (m, 2H), 1.59 (br s, 1H), 1.26-1.06 (m, 4H). MS: [M+H] + = 482.1.

[0281] [Example 23] (2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)(4-methylpiperazin-1-yl)methanone (C23)

[0282] [ka] The title compound was prepared by using a procedure similar to that in Step 2 of Example 22, except that morpholine was replaced with 1-methylpiperazine. 1 H NMR (400 MHz, DMSO-d6): δ ppm 8.37 (s, 1H), 8.33 (s, 1H), 7.96 (d, J = 5.2 Hz, 1H), 7.91 (d, J = 8.8 Hz, 1H), 7.78 (t, J = 6.0 Hz, 1H), 7.56 (d, J = 5.2 Hz, 1H), 7.52 (d, J = 7.2 Hz, 1H), 7.00 (d, J = 8.8 Hz, 1H), 3.91 (br s, 1H), 3.60-3.46 (m, 4H), 3.21 (t, J = 6.4 Hz, 2H), 2.35-2.30 (m, 4H), 2.19 (s, 3H), 2.15-2.12 (m, 2H), 1.86-1.83 (m, 2H), 1.60 (br s, 1H), 1.26-1.06 (m, 4H). MS: [M+H] + = 495.1. IC in EZH2 50 Values ​​(a) LC certification were above 100 μM.

[0283] [Example 24] (2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)(piperazin-1-yl)methanone (C24)

[0284] [ka] The title compound was prepared by using a procedure similar to that in Step 2 of Example 22, except that morpholine was replaced with piperazine. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.36 (s, 1H), 8.32 (s, 1H), 7.96 (d, J = 5.2 Hz, 1H), 7.91 (d, J = 8.8 Hz, 1H), 7.76 (t, J = 5.6 Hz, 1H), 7.56-7.52 (m, 2H), 7.00 (d, J = 8.8 Hz, 1H), 3.90 (br s, 1H), 3.43 (br s, 4H), 3.21 (t, J = 6.4 Hz, 2H), 2.75-2.65 (m, 4H), 2.14-2.12 (m, 2H), 1.86-1.83 (m, 2H), 1.61 (br s, 1H), 1.28-1.05 (m, 4H). MS: [M+H] + = 481.1.

[0285] [Example 25] 2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)-N-(oxetan-3-yl)pyrimidine-5-carboxamide (C25)

[0286] [ka] The title compound was prepared by using a procedure similar to that in Step 2 of Example 22, except that morpholine was replaced with oxetan-3-amine. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.88 (d, J = 6.8 Hz, 1H), 8.71 (d, J = 9.2 Hz, 2H), 7.97-7.90 (m, 3H), 7.56-7.51 (m, 2H), 6.99 (d, J = 9.2 Hz, 1H), 5.00-4.95 (m, 1H), 4.76 (t, J = 6.4 Hz, 2H), 4.55 (t, J = 6.4 Hz, 2H), 3.90 (br s, 1H), 3.24 (t, J = 6.4 Hz, 2H), 2.14-2.12 (m, 2H), 1.85-1.82 (m, 2H), 1.60 (br s, 1H), 1.26-1.07 (m, 4H). MS: [M+H] + = 468.0.

[0287] [Example 26] 8-chloro-N-((1,4-trans)-4-(((5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyrimidin-2-yl)amino)methyl)cyclohexyl)-1,7-naphthyridin-2-amine (C26) Step 1: N-((1,4-trans)-4-(aminomethyl)cyclohexyl)-8-chloro-1,7-naphthyridin-2-amine (26-1)

[0288] [ka] A solution of 21-1 (290 mg, 1.081 mmol, 1.0 equiv) in POCl (8 mL) was stirred at 110 °C for 5 h. The mixture was then concentrated, and the residue was basified with NH-H0 to pH 7-8. The crude product was purified by preparative HPLC (Column: Phenomenex Gemini C18 250 mm x 21.2 mm x 5 um: 45-75% B (A = 0.5% NHOH in water, B = methanol)) to give N-((1,4-trans)-4-(aminomethyl)cyclohexyl)-8-chloro-1,7-naphthyridin-2-amine (26-1). MS: [M+H] + =290.9.

[0289] Step 2: Ethyl 2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidine-5-carboxylate (26-2)

[0290] [ka] The title compound was prepared by using a procedure similar to that in Step 1 of Example 8 and purified by column chromatography on silica gel (petroleum ether / EtOAc 3 / 1 to 3 / 2) to give ethyl 2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidine-5-carboxylate (26-2). 1 H NMR (400 MHz, DMSO-d6): δ ppm 8.75 (d, J = 2.8 Hz, 1H), 8.69 (d, J = 2.8 Hz, 1H), 8.20 (t, J = 6.0 Hz, 1H), 7.96 (d, J = 5.2 Hz, 1H), 7.91 (d, J = 9.2 Hz, 1H), 7.55 (d, J = 5.2 Hz, 1H), 7.51 (d, J = 7.2 Hz, 1H), 6.99 (d, J = 9.2 Hz, 1H), 4.25 (q, J = 7.2 Hz, 2H), 3.91 (br s, 1H), 3.26 (t, J = 6.4 Hz, 2H), MS: [M+H] + = 441.1.

[0291] Step 3: (2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)methanol (26-3)

[0292] [ka] To a solution of (26-2) (40 mg, 0.09 mmol, 1.0 equiv) in THF (5 mL) was added DIBAL-H (0.45 mL, 0.45 mmol, 5.0 equiv) dropwise at −78° C. The reaction mixture was stirred at 20° C. for 2 h. The mixture was then quenched with aqueous NH4Cl (10 mL), filtered, and the filtrate was extracted three times with EtOAc (20 mL). The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to give (2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)methanol (26-3). MS: [M+H] + =399.1.

[0293] Step 4: 2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidine-5-carbaldehyde (26-4)

[0294] [ka] To a solution of 26-3 (33 mg, 0.08 mmol, 1.0 equiv) in CHCl (5 mL) was added MnO (72 mg, 0.8 mmol, 10.0 equiv). The reaction mixture was stirred at 45 °C for 2 h. It was then filtered, and the filtrate was concentrated to give 2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidine-5-carbaldehyde (26-4). MS: [M+H] + =397.2.

[0295] Step 5: 8-chloro-N-((1,4-trans)-4-(((5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyrimidin-2-yl)amino)methyl)cyclohexyl)-1,7-naphthyridin-2-amine (C26)

[0296] [ka] To a solution of (26-4) (50 mg, 0.126 mmol, 1.0 equiv) in MeOH (3 mL) was added 1-(methylsulfonyl)piperazine (41 mg, 0.252 mmol, 2.0 equiv) and NaBHCN (40 mg, 0.63 mmol, 5.0 equiv). The mixture was stirred at 25 °C for 4 h. The reaction mixture was quenched with aqueous NaHCO (10 mL) and extracted three times with CHCl (20 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to give the crude product, which was purified by preparative HPLC (Column: Durashell 150 mm × 25 mm × 5 um: 33-63% B (A = 0.05% ammonia hydroxide in water, B = acetonitrile)) to give 8-chloro-N-((1,4-trans)-4-(((5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyrimidin-2-yl)amino)methyl)cyclohexyl)-1,7-naphthyridin-2-amine (C26). 1H NMR (400 MHz, DMSO-d6): δ ppm 8.16 (s, 2H), 7.96 (d, J = 5.2 Hz, 1H), 7.91 (d, J = 9.2 Hz, 1H), 7.56 (d, J = 5.2 Hz, 1H), 7.51 (d, J = 6.8 Hz, 1H), 7.22 (t, J = 6.0 Hz, 1H), 6.99 (d, J = 9.2 Hz, 1H), 3.90 (br s, 1H), 3.32 (s, 2H), 3.16 (t, J = 6.4 Hz, 2H), 3.11-3.08 (m, 4H), 2.86 (s, 3H), 2.44-2.42 (m, 4H), 2.14-2.11 (m, 2H), 1.85-1.82 (m, 2H), 1.58 (br s, 1H), 1.25-1.16 (m, 2H), 1.13-1.04 (m, 2H). + = 545.3.

[0297] The following compounds were prepared using the general procedures and procedures from the examples described above, using the appropriate starting materials and reagents, as identified in Table 1.

[0298] [Table 1-1]

[0299] [Table 1-2]

[0300] [Example 34] (2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-1,3-dioxan-5-yl)methanol (C34)

[0301] [ka] To a solution of 26-4 (50 mg, 0.126 mmol, 1.0 equiv) and CSA (1 mg, 0.005 mmol, 0.05 equiv) in CHCl (3 mL) was added 2-(hydroxymethyl)propane-1,3-diol (11 mg, 0.106 mmol, 0.84 equiv). The mixture was stirred at 30 °C for 2 h. The reaction mixture was concentrated to give the crude product, which was purified by preparative HPLC (Column: Durashell 150 mm × 25 mm × 5 μm: 38-68% B (A = 10 mM NHOH, B = acetonitrile) to give (2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-1,3-dioxan-5-yl)methanol (C34). 1 H NMR (400 MHz, DMSO-d6), cis / trans mixture: δ ppm 8.23 ​​(d, J = 5.6 Hz, 2H), 7.96 (d, J = 5.2 Hz, 1H), 7.91 (d, J = 8.8 Hz, 1H), 7.55 (d, J = 5.2 Hz, 1H), 7.51 (d, J = 7.2 Hz, 1H), 7.39-7.35 (m, 1H), 6.99 (d, J = 9.2 Hz, 1H), 5.42 (s, 0.5H), 5.33 (s, 0.5H), 4.71 (t, J = 5.2 Hz, 0.5H), 4.60 (t, J = 5.2 Hz, 0.5H), 4.12 (dd, J = 4.4 Hz, 7.6 Hz, 1H), 4.06-4.03 (m, 1H), 3.96-4.00 (m, 1H), 3.92-3.88 (m, 1H), 3.71 (dd, J = 5.2 Hz, 7.6 Hz, 1H), 3.60 (t, J = 11.6 Hz, 1H), 3.26 (t, J = 5.6 Hz, 1H), 3.18 (t, J = 6.4 Hz, 2H), 2.13-2.07 (m, 2.5H), 1.84-1.81 (m, 2H), 1.58-1.48 (m, 1.5H), 1.25-1.16 (m, 2H), 1.13-1.04 (m, 2H). MS: [M+H] += 485.2.

[0302] [Example 35] 8-chloro-N-((1,4-trans)-4-(((5-((oxetan-3-yloxy)methyl)pyrimidin-2-yl)amino)methyl)cyclohexyl)-1,7-naphthyridin-2-amine (C35) Step 1: Oxetan-3-yl 4-methylbenzenesulfonate (35-1)

[0303] [ka] To a solution of oxetan-3-ol (300 mg, 4 mmol, 1.0 equiv) in CHCl (10 mL) was added EtN (1.62 g, 16 mmol, 4.0 equiv) and TsCl (1.52 g, 2 mmol, 2.0 equiv), and the reaction mixture was stirred at 23–31 °C for 16 h. The mixture was quenched with aqueous NaHCO (20 mL) and extracted three times with CHCl (20 mL). The organic layer was dried over NaSO, filtered, and concentrated to give the crude product, which was purified by column chromatography on silica gel (petroleum ether / EtOAc 50 / 1 to 10 / 1) to give oxetan-3-yl 4-methylbenzenesulfonate (35-1). 1 H NMR (400 MHz, CDCl3): δ ppm 7.78 (d, J = 8.4 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 5.32-5.26 (m, 1H), 4.73-4.64 (m, 4H), 2.45 (s, 3H).

[0304] Step 2: 8-chloro-N-((1,4-trans)-4-(((5-((oxetan-3-yloxy)methyl)pyrimidin-2-yl)amino)methyl)cyclohexyl)-1,7-naphthyridin-2-amine (C35)

[0305] [ka] To a solution of 26-3 (50 mg, 0.126 mmol, 1.0 equiv) and 35-1 (29 mg, 0.126 mmol, 1.0 equiv) in DMF (2 mL) was added NaH (60% in mineral oil, 6 mg, 0.15 mmol, 1.2 equiv) portionwise at 0° C. The mixture was stirred at 25° C. for 4 h. The reaction mixture was quenched with HO (20 mL), extracted with EtOAc (3 × 20 mL), and the organic layer was dried over NaSO, filtered, and concentrated to give the crude product, which was purified by preparative HPLC (Column: Waters crossbridge prep OBD C18 100 mm × 19 mm × 5 um: 30-45% B (A = 0.05% NHOH in water, B = acetonitrile)) to give 8-chloro-N-((1,4-trans)-4-(((5-((oxetan-3-yloxy)methyl)pyrimidin-2-yl)amino)methyl)cyclohexyl)-1,7-naphthyridin-2-amine (C35). 1 H NMR (400 MHz, DMSO-d6): δ ppm 8.25 (s, 2H), 7.96 (d, J = 5.2 Hz, 1H), 7.91 (d, J = 8.8 Hz, 1H), 7.55 (d, J = 5.2 Hz, 1H), 7.50 (t, J = 8.0 Hz, 1H), 7.33 (t, J = 6.0 Hz, 1H), 6.99 (d, J = 8.8 Hz, 1H), 4.67-4.59 (m, 3H), 4.40-4.38 (m, 2H), 4.21 (s, 2H), 3.90 (br s, 1H), 3.18 (t, J = 6.4 Hz, 2H), 2.13-2.11 (m, 2H), 1.85-1.81 (m, 2H), 1.58 (br s, 1H), 1.22-1.16 (m, 2H), 1.13-1.07 (m, 2H). MS: [M+H] + = 455.2.

[0306] [Example 36] 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-(oxetan-3-yl)acetamide (C36) Step 1: Ethyl 2-(2-((((1,4-trans)-4-((8-hydroxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)acetate (36-1)

[0307] [ka] To a solution of (13-2) (43 g, 89.8 mmol, 1.0 equiv) in EtOAc (20 mL) was added dropwise 4N HCl solution in EtOAc (40 mL). The reaction mixture was stirred at 40° C. for 20 hours. EtOH (40 mL) was then added to the above solution, and the mixture was stirred at 90° C. for 20 hours. The solution was then concentrated to give ethyl 2-(2-((((1,4-trans)-4-((8-hydroxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)acetate (36-1), which was used in the next step without further purification. MS: [M+H] + =437.2.

[0308] Step 2: Ethyl 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)acetate (36-2)

[0309] [ka] A solution of 36-1 (45 g, 103.09 mmol, 1.0 equiv) in POCl (390 mL) was stirred at 110 °C for 1.5 h. The mixture was then concentrated under reduced pressure, and the residue was diluted with ethyl acetate (450 mL) and then basified to pH 8-9 with aqueous NaHCO at 0 °C. The organic layer was separated, and the aqueous layer was extracted twice with ethyl acetate (400 mL). The combined organic layers were washed with brine (400 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give ethyl 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)acetate (36-2). MS: [M+H] + =455.2.

[0310] Step 3: 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)acetic acid (36-3)

[0311] [ka] To a solution of 36-2 (40 g, 88.1 mmol, 1.0 equiv) in MeOH (300 mL) and THF (300 mL) was added NaOH (17.6 g, 441 mmol, 5.0 equiv) in HO (200 mL). The mixture was stirred at 20 °C for 2 h. The mixture was then acidified with 2 N HCl to pH 6-7 and extracted with CHCl (200 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)acetic acid (36-3), which was used in the next step without further purification. MS: [M+H] + =427.2.

[0312] Step 4: 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-(oxetan-3-yl)acetamide (C36)

[0313] [ka] To a solution of 36-3 (40.9 g, 0.096 mol, 1.0 equiv.) in DMF (200 mL) and CHCl (400 mL) was added oxetan-3-amine (8.4 g, 0.115 mol, 1.2 equiv.), HATU (54.7 g, 0.144 mol, 1.5 equiv.), and DIEA (37 g, 0.288 mol, 2.0 equiv.). The mixture was stirred at 15 °C for 3 h. The mixture was then diluted with HO (300 mL) and extracted three times with CHCl (300 mL), and the organic layer was dried over NaSO, filtered, and concentrated to give the crude product, which was purified by column chromatography on silica gel (CHCl / MeOH 100 / 1 to 40 / 1) to give the crude compound, which was triturated with EtOAc, filtered, and dried to give 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-(oxetan-3-yl)acetamide (C36). 1H NMR (400MHz, DMSO-d6): δ ppm 8.79 (d, J = 6.4 Hz, 1H), 8.12 (s, 2H), 7.96 (d, J = 5.2 Hz, 1H), 7.91 (d, J = 9.2 Hz, 1H), 7.55 (d, J = 5.2 Hz, 1H), 7.51 (d, J = 6.8 Hz, 1H), 7.13 (t, J = 6.0 Hz, 1H), 6.99 (d, J = 9.2 Hz, 1H), 4.79-4.73 (m, 1H), 4.69 (t, J = 6.4 Hz, 2H), 4.41 (t, J = 6.0 Hz, 2H), 3.90 (br s, 1H), 3.24 (s, 2H), 3.15 (t, J = 6.4 Hz, 2H), 2.13-2.11 (m, 2H), 1.85-1.82 (m, 2H), 1.57 (br s, 1H), 1.24-1.12 (m, 2H), 1.09-1.03 (m, 2H). MS: [M+H] + = 482.2.

[0314] The following compounds were prepared using the general procedures and procedures from the examples described above, with the appropriate starting materials and reagents, as identified in Table 2.

[0315] [Table 2-1]

[0316] [Table 2-2]

[0317] [Table 2-3]

[0318] [Example 46] 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)ethan-1-ol (C46) Step 1: Isopropyl 2-(2-((((1,4-trans)-4-((8-methoxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)acetate (46-1)

[0319] [ka] The title compound was prepared by using a procedure similar to that in Step 2 of Example 13, intermediate (13-2), except that tert-butyl 2-bromoacetate was replaced with isopropyl 2-bromoacetate, and the product was purified by column chromatography on silica gel (petroleum ether / EtOAc 3 / 1 to 1 / 2) to give isopropyl 2-(2-((((1,4-trans)-4-((8-methoxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)acetate (46-1). 1 H NMR (400MHz, DMSO-d6): δ 8.14 (s, 2H), 7.78 (d, J = 8.8 Hz, 1H), 7.68 (d, J = 5.6 Hz, 1H), 7.17 (t, J = 6.0 Hz, 1H), 7.09 (d, J = 5.6 Hz, 1H), 7.05 (d, J = 7.6 Hz, 1H), 6.89 (d, J = 9.2 Hz, 1H), 4.93-4.86 (m, 1H), 3.95 (s, 3H), 3.87 (br s, 1H), 3.45 (s, 2H), 3.15 (t, J = 6.0 Hz, 2H), 2.04-2.01 (m, 2H), 1.83-1.80 (m, 2H), 1.56 (brs, 1H), 1.20-1.03 (m, 10H). MS: [M+H] + = 465.2.

[0320] Step 2: Isopropyl 2-(2-((((1,4-trans)-4-((8-hydroxy-1,7-naphthyridin-2yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)acetate (46-2)

[0321] [ka] To a solution of 46-1 (720 mg, 1.55 mmol, 1.0 equiv) in 5 mL of EtOAc was added HCl / EtOAc (10 mL, 4N). The reaction mixture was stirred at 35° C. for 3 h. The reaction mixture was concentrated under reduced pressure to give isopropyl 2-(2-((((1,4-trans)-4-((8-hydroxy-1,7-naphthyridin-2yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)acetate 46-2, which was used without further purification. MS: [M+H] + =451.2.

[0322] Step 3: Isopropyl 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)acetate (46-3)

[0323] [ka] A solution of compound (46-2) (850 mg, 1.88 mmol, 1.0 equiv) in POCl (10 mL) was stirred at 110 °C for 1.5 h. The mixture was then concentrated under reduced pressure. The crude product was dissolved in EtOAc (100 mL), and the organic phase was washed with saturated aqueous NaHCO (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give isopropyl 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)acetate (46-3), which was used without further purification. MS: [M+H] + =469.2.

[0324] Step 4: 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)ethan-1-ol (C46)

[0325] [ka] To a solution of (46-3) (310 mg, 0.66 mmol, 1.0 equiv) in anhydrous THF (10 mL), DIBAL-H (3.3 mL, 3.30 mmol, 5.0 equiv, 1.0 M in toluene) was added dropwise over 10 min at −78 °C under N protection. After the addition was complete, the reaction mixture was stirred at 19–22 °C for 2 h. The reaction mixture was then diluted with EtOAc (50 mL) and quenched with saturated aqueous NH4Cl (3.5 mL). After stirring at 19-22° C. for 30 minutes, the mixture was filtered, and the filtrate was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)ethan-1-ol (C46). 1H NMR (400 MHz, DMSO-d6): δ ppm 8.12 (s, 2H), 7.96 (d, J = 5.2 Hz, 1H), 7.91 (d, J = 8.8 Hz, 1H), 7.56 (d, J = 5.2 Hz, 1H), 7.51 (d, J = 7.2 Hz, 1H), 7.03-6.99 (m, 2H), 4.65 (t, J = 5.2 Hz, 1H), 3.90 (br s, 1H), 3.51 (dd, J = 12.0, 6.8 Hz, 2H), 3.14 (t, J = 6.4 Hz, 2H), 2.49-2.47 (m, 2H), 2.13-2.11 (m, MS: [M+H] + = 413.2.

[0326] [Example 47] 8-chloro-N-((1,4-trans)-4-(((5-(2-((3-methyloxetan-3-yl)amino)ethyl)pyrimidin-2-yl)amino)methyl)cyclohexyl)-1,7-naphthyridin-2-amine (C47) Step 1: 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)ethyl methanesulfonate (47-1)

[0327] [ka] To a solution of compound (C46) (50 mg, 0.12 mmol, 1.0 equiv) in anhydrous CHCl (5 mL) was added DIPEA (46.5 mg, 0.36 mmol, 3.0 equiv) and MsCl (20.6 mg, 0.18 mmol, 1.5 equiv). The resulting mixture was stirred at 28-38 °C for 4 h. The mixture was then poured into water (60 mL) and extracted with CHCl (30 mL × 2). The combined organic phase was washed with brine (30 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)ethyl methanesulfonate (47-1), which was used without further purification. MS: [M+H] + =491.1.

[0328] Step 2: 8-chloro-N-((1,4-trans)-4-(((5-(2-((3-methyloxetan-3-yl)amino)ethyl)pyrimidin-2-yl)amino)methyl)cyclohexyl)-1,7-naphthyridin-2-amine (C47)

[0329] [ka] To a solution of (47-1) (65 mg, 0.13 mmol, 1.0 equiv) in DMF (5 mL) was added 3-methyloxetan-3-amine (23 mg, 0.26 mmol, 2.0 equiv), KCO (90 mg, 0.65 mmol, 5.0 equiv), and NaI (97.4 mg, 0.65 mmol, 5.0 equiv). The reaction mixture was heated at 80° C. for 18 h. The reaction mixture was then cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC (Column: Durashell 150 mm x 25 mm x 5 um: 24-54% B (A = 0.05% NH4OH in water, B = acetonitrile)) to give the synthesis of 8-chloro-N-((1,4-trans)-4-(((5-(2-((3-methyloxetan-3-yl)amino)ethyl)pyrimidin-2-yl)amino)methyl)cyclohexyl)-1,7-naphthyridin-2-amine (C47). 1 H NMR (400 MHz, DMSO-d6): δ ppm 8.15 (s, 2H), 7.96 (d, J = 4.8 Hz, 1H), 7.91 (d, J = 8.8 Hz, 1H), 7.56 (d, J = 5.2 Hz, 1H), 7.51 (d, J = 6.8 Hz, 1H), 7.02-6.99 (m, 2H), 4.41 (d, J = 5.2 Hz, 2H), 4.16 (d, J = 5.6 Hz, 2H), 3.91 (br s, 1H), 3.15 (t, J = 6.4 Hz, 2H), 2.64 (t, J = 7.2 Hz, 2H), 2.46 (t, J = 7.2 Hz, 2H), 2.24 (br s, 1H), 2.14-2.11 (m, 2H), 1.85-1.82 (m, 2H), 1.57 (br s, 1H), 1.33 (s, 3H), 1.25-1.19 (m, 2H), 1.12-1.03 (m, 2H). MS: [M+H] + = 482.3.

[0330] [Example 48] 8-chloro-N-((1,4-trans)-4-(((5-(2-(oxetan-3-ylamino)ethyl)pyrimidin-2-yl)amino)methyl)cyclohexyl)-1,7-naphthyridin-2-amine (C48)

[0331] [ka] The title compound was prepared by using a procedure similar to that in Step 2 of Example 47, except that 3-methyloxetan-3-amine was replaced with oxetan-3-amine. 1 H NMR (400 MHz, DMSO-d6): δ ppm 8.12 (s, 2H), 7.96 (d, J = 5.2 Hz, 1H), 7.91 (d, J = 9.2 Hz, 1H), 7.56 (d, J = 5.2 Hz, 1H), 7.51 (d, J = 7.2 Hz, 1H), 7.03-6.98 (m, 2H), 4.60 (t, J = 6.4 Hz, 2H), 4.31 (t, J = 6.0 Hz, 2H), 3.88-3.85 (m, 2H), 3.14 (t, J = 6.4 Hz, 2H), 2.60 (t, J = 7.2 Hz, 2H), 2.44 (t, J = MS: [M+H] + = 468.2.

[0332] [Example 49] 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-(2-cyanoethyl)-N-(oxetan-3-yl)acetamide (C49) Step 1: 3-(oxetan-3-ylamino)propanenitrile (49-1)

[0333] [ka] To a solution of 3-aminopropanenitrile (280 mg, 4.00 mmol, 1.0 equiv) in DCE (25 mL) was added oxetan-3-one (432.4 mg, 6.00 mmol, 1.5 equiv) and AcOH (720.6 mg, 12.00 mmol, 3.0 equiv). After stirring for 10 min, NaB(OAc)H (2.54 g, 12.00 mmol, 3.0 equiv) was added to the reaction mixture. The resulting mixture was stirred at 23–31 °C for 18 h. The reaction mixture was then diluted with CHCl (100 mL), and the organic phase was washed with saturated aqueous NaHCO (100 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 3-(oxetan-3-ylamino)propanenitrile (49-1), which was used directly in the next step.

[0334] Step 2: 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-(2-cyanoethyl)-N-(oxetan-3-yl)acetamide (C49)

[0335] [ka] To a solution of 36-5 (50 mg, 0.12 mmol, 1.0 equiv) in DMF (5 mL) was added 49-1 (23 mg, 0.18 mmol, 1.5 equiv), DIPEA (77.5 mg, 0.60 mmol, 5.0 equiv), and HATU (91 mg, 0.24 mmol, 2.0 equiv). The resulting mixture was stirred at 25-32 °C for 2 h. The mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC (Column: Durashell 150 mm x 25 mm x 5 um: 29-39% B (A = 0.05% NHOH in water, B = acetonitrile)) to give 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-(2-cyanoethyl)-N-(oxetan-3-yl)acetamide (C49). 1 H NMR (400 MHz, DMSO-d6), rotamers present: δ ppm 8.06 (d, J = 9.6 Hz, 2H), 7.96 (d, J = 5.2 Hz, 1H), 7.91 (d, J = 9.2 Hz, 1H), 7.56 (d, J = 5.2 Hz, 1H), 7.51 (d, J = 6.8 Hz, 1H), 7.12 (t, J = 6.4 Hz, 1H), 7.00 (d, J = 8.8 Hz, 1H), 5.33-5.29 (m, 0.5H), 4.84-4.80 (m, 0.5H), 4.73-4.70 (m, 2H), 4.61-4.59 (m, 2H), 3.91 (br s, 1H), 3.81-3.74 (m, 2H), 3.61 (s, 1H), 3.49 (s, 1H), 3.16 (t, J = 6.0 Hz, 2H), 2.84-2.78 (m, 2H), 2.14-2.11 (m, 2H), 1.85-1.82 (m, 2H), 1.58 (br s, 1H), 1.25-1.16 (m, 2H), 1.13-1.04 (m, 2H). MS: [M+H] + = 535.2.

[0336] [Example 50] 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-(2-cyanoethyl)-N-ethylacetamide (C50)

[0337] [ka] The title compound was prepared by using a procedure similar to that in Step 2 of Example 49, except that 3-(oxetan-3-ylamino)propanenitrile (49-1) was replaced with 3-(ethylamino)propanenitrile. 1 H NMR (400 MHz, DMSO-d6): δ ppm 8.08 (d, J = 8.4 Hz, 2H), 7.96 (d, J = 5.2 Hz, 1H), 7.91 (d, J = 8.8 Hz, 1H), 7.56 (d, J = 4.8 Hz, 1H), 7.52 (d, J = 7.2 Hz, 1H), 7.12 (t, J = 5.6 Hz, 1H), 7.00 (d, J = 8.8 Hz, 1H), 3.91 (br s, 1H), 3.69 (t, J = 6.8 Hz, 1H), 3.56-3.44 (m, 5H), 3.15 (t, J = 6.0 Hz, 2H), 2.87 (t, J = 6.8 Hz, 1H), 2.72 (t, J = 6.8 Hz, 1H), 2.14-2.11 (m, 2H), 1.86-1.83 (m, 2H), 1.58 (br s, 1H), 1.25-1.19 (m, 2H), 1.17-1.00 (m, 5H). MS: [M+H] + = 507.4.

[0338] [Example 51] 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-(2-hydroxyethyl)-N-(oxetan-3-yl)acetamide (C51)

[0339] [ka] The title compound was prepared by using a procedure similar to that in Step 2 of Example 49, except that 3-(oxetan-3-ylamino)propanenitrile (49-1) was replaced with 2-(oxetan-3-ylamino)ethan-1-ol. 1 H NMR (400 MHz, DMSO-d6, T = 80 o C): δ ppm 8.09 (s, 2H), 7.95 (d, J = 5.6 Hz, 1H), 7.88 (d, J = 9.2 Hz, 1H), 7.52 (d, J = 4.8 Hz, 1H), 7.18 (d, J = 7.2 Hz, 1H), 7.02 (d, J = 9.2 Hz, 1H), 6.66 (t, J = 5.6 Hz, 1H), 4.98 (br s, 1H), 4.65-4.63 (m, 4H), 3.89 (br s, 1H), 3.57-3.52 (m, 6H), 3.22 (t, J = 6.0 Hz, 2H), 2.17-2.14 (m, 2H), 1.89-1.86 (m, 2H), 1.63 (br s, 1H), 1.33-1.23 (m, 2H), 1.19-1.09 (m, 2H). MS: [M+H] + = 526.2.

[0340] [Example 52] 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-(oxetan-3-yl)propanamide (C52)

[0341] [ka] The title compound was prepared from (13-2) using a procedure similar to that in Step 2 of Example 13.

[0342] [ka] Prepared by using a procedure similar to that of Example 36, except that tert-butyl 2-bromoacetate was replaced with tert-butyl 2-bromopropanoate. The product was purified by preparative HPLC (Column: Durashell 150 mm × 25 mm × 5 μm: 35-65% B (A = 0.5% NHOH in water, B = acetonitrile)) to give 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-(oxetan-3-yl)propanamide (C52). 1 H NMR (400 MHz, DMSO-d6): δ ppm 8.73 (d, J = 6.8 Hz, 1H), 8.17 (s, 2H), 7.96 (d, J = 5.2 Hz, 1H), 7.91 (d, J = 8.8 Hz, 1H), 7.55 (d, J = 5.2 Hz, 1H), 7.50 (d, J = 6.8 Hz, 1H), 7.15 (t, J = 6.0 Hz, 1H), 7.00 (d, J = 8.8 Hz, 1H), 4.76-4.65 (m, 3H), 4.41 (t, J = 6.0 Hz, 1H), 4.35 (t, J = 6.0 Hz, 1H), 3.91 (br s, 1H), 3.41 (q, J = 6.8 Hz, 1H), 3.15 (t, J = 6.0 Hz, 2H), 2.13-2.11 (m, 2H), 1.85-1.82 (m, 2H), 1.57 (br s, 1H), 1.29 (d, J = 7.2 Hz, 3H), 1.25-1.16 (m, 2H), 1.13-1.03 (m, 2H). MS: [M+H] + = 496.2.

[0343] [Example 53 and Example 54] (S)-2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-(oxetan-3-yl)propanamide (C53) and (R)-2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-(oxetan-3-yl)propanamide (C54)

[0344] [ka] Compound (C52) (32 mg, 0.0645 mmol) was separated by SFC (Chiralpak AD-3 100 × 4.6 mm ID, 3 μm; 40% ethanol in CO (0.05% DEA), flow rate: 2.8 mL / min) to obtain peak 1 (t R = 3.61 min) and Peak 2 (t R = 4.22 min). Peak 1 (C53 or C54): 1H NMR (400 MHz, DMSO-d6): δ ppm 8.74 (d, J = 6.4 Hz, 1H), 8.17 (s, 2H), 7.96 (d, J = 5.2 Hz, 1H), 7.91 (d, J = 9.2 Hz, 1H), 7.55 (d, J = 5.6 Hz, 1H), 7.51 (d, J = 6.8 Hz, 1H), 7.15 (t, J = 5.6 Hz, 1H), 6.99 (d, J = 9.2 Hz, 1H), 4.77-4.65 (m, 3H), 4.41 (t, J = 5.6 Hz, 1H), 4.35 (t, J = 6.0 Hz, 1H), 3.90 (br s, 1H), 3.41 (q, J = 7.2 Hz, 1H), 3.15 (t, J = 6.0 Hz, 2H), 2.13-2.10 (m, 2H), 1.84-1.81 (m, 2H), 1.57 (br s, 1H), 1.30 (d, J = 7.2 Hz, 3H), 1.22-1.16 (m, 2H), 1.12-1.06 (m, 2H). MS: [M+H] + = 496.2. ピーク2(C53またはC54): 1H NMR (400 MHz, DMSO-d6): δ ppm 8.74 (d, J = 5.6 Hz, 1H), 8.17 (s, 2H), 7.96 (d, J = 5.2 Hz, 1H), 7.91 (d, J = 8.8 Hz, 1H), 7.55 (d, J = 5.6 Hz, 1H), 7.51 (d, J = 7.2 Hz, 1H), 7.15 (t, J = 6.0 Hz, 1H), 6.99 (d, J = 8.8 Hz, 1H), 4.77-4.65 (m, 3H), 4.41 (t, J = 5.6 Hz, 1H), 4.35 (t, J = 5.6 Hz, 1H), 3.90 (br s, 1H), 3.41 (q, J = 7.2 Hz, 1H), 3.15 (t, J = 6.0 Hz, 2H), 2.13-2.11 (m, 2H), 1.85-1.82 (m, 2H), 1.57 (br s, 1H), 1.30 (d, J = 7.2 Hz, 3H), 1.21-1.16 (m, 2H), 1.11-1.05 (m, 2H). MS: [M+H] + = 496.2.

[0345] [Example 55] 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-methyl-N-(oxetan-3-yl)propanamide (C55)

[0346] [ka] The title compound was prepared by using a procedure similar to that of Example 52, except that in Step 4 of Example 36, oxetan-3-amine was replaced with N-methyloxetan-3-amine. The product was purified by preparative HPLC (Column: Waters crossbridge preparative OBD C18 150 mm × 30 mm × 5 um: 22-52% B (A = NH4OH 0.5%, B = acetonitrile)) to give 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-methyl-N-(oxetan-3-yl)propanamide (C55). 1 H NMR (400 MHz, DMSO-d6, T = 80 o C): δ ppm 8.16 (s, 2H), 7.95 (d, J = 5.2 Hz, 1H), 7.88 (d, J = 9.2 Hz, 1H), 7.51 (d, J = 5.2 Hz, 1H), 7.18 (d, J = 6.8 Hz, 1H), 7.02 (d, J = 9.2 Hz, 1H), 6.73 (t, J = 6.0 Hz, 1H), 5.21-5.18 (m, 1H), 4.69-4.67 (m, 1H), 4.60-4.55 (m, 3H), 3.95-3.89 (m, 2H), 3.21 (t, J = 6.4 Hz, 2H), 3.05 (s, 3H), 2.16-2.14 (m, 2H), 1.88-1.85 (m, 2H), 1.56 (br s, 1H), 1.33-1.26 (m, 5H), 1.16-1.12 (m, 2H). MS: [M+H] + = 510.2.

[0347] [Example 56 and Example 57] (S)-2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-methyl-N-(oxetan-3-yl)propanamide (C56) and (R)-2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-methyl-N-(oxetan-3-yl)propanamide (C57)

[0348] [ka] Compound (C55) was separated by SFC (Chiralpak AD-3 100×4.6 mm ID, 3 μm; 40% ethanol in CO2 (0.05% DEA); flow rate: 2.8 mL / min) to obtain peak 1 (t R = 3.61 min) and Peak 2 (t R = 4.22 min). Peak 1 (C56 or C57): 1 H NMR (400 MHz, DMSO-d6), present as rotamers: δ ppm 8.16 (s, 1.2H), 8.12 (s, 0.8H), 7.96 (d, J = 5.1 Hz, 1H), 7.91 (d, J = 8.9 Hz, 1H), 7.56 (d, J = 5.2 Hz, 1H), 7.53 (d, J = 7.0 Hz, 1H), 7.24 - 7.17 (m, 1H), 6.99 (d, J = 8.6 Hz, 1H), 5.38-5.15 (m, 1H), 4. 78 - 4.33 (m, 4H), 3.96-3.88 (m, 2H), 3.14 (t, J = 6.3 MS: [M+H] + = 510.0. Peak 2 (C56 or C57): 1H NMR (400 MHz, DMSO-d6), present as rotamers: δ ppm 8.16 (s, 1.3H), 8.12 (s, 0.8H), 7.96 (d, J = 5.1 Hz, 1H), 7.91 (d, J = 8.9 Hz, 1H), 7.56 (d, J = 5.2 Hz, 1H), 7.53 (d, J = 7.1 Hz, 1H), 7.24 - 7.14 (m, 1H), 6.99 (d, J = 8.6 Hz, 1H), 5.34-5.15 (m, 1H), 4.78 - 4.33 (m, 4H), 3.94-3.90 (m, 2H), 3.15 (t, J = 6.2 MS: [M+H] + = 510.0.

[0349] [Example 58] N-((2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)methyl)azetidine-2-carboxamide (C58) Step 1: 2-((2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)methyl)isoindoline-1,3-dione (58-1)

[0350] [ka] To a solution of (26-1) (75 mg, 0.26 mmol, 1.0 equiv) in NMP (3 mL) was added DIEA (168 mg, 1.3 mmol, 5.0 equiv) and 2-((2-chloropyrimidin-5-yl)methyl)isoindoline-1,3-dione (78 mg, 0.28 mmol, 1.1 equiv). The reaction mixture was heated at 100° C. for 4 h. The mixture was diluted with EtOAc (10 mL) and washed three times with brine (20 mL). The organic phase was dried over anhydrous NaSO, filtered, and concentrated. The crude product was purified by column chromatography on silica gel (petroleum ether / EtOAc=1 / 1) to give 2-((2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)methyl)isoindoline-1,3-dione (58-1). MS: [M+H] + =528.3.

[0351] Step 2: N-((1,4-trans)-4-(((5-(aminomethyl)pyrimidin-2-yl)amino)methyl)cyclohexyl)-8-chloro-1,7-naphthyridin-2-amine (58-2)

[0352] [ka] To a solution of 58-1 (100 mg, 0.185 mmol, 1.0 equiv) in EtOH (4 mL) was added NH-HO (1 mL, 85%). The reaction mixture was stirred at 25 °C for 1 h. The mixture was lyophilized to give N-((1,4-trans)-4-(((5-(aminomethyl)pyrimidin-2-yl)amino)methyl)cyclohexyl)-8-chloro-1,7-naphthyridin-2-amine (58-2).

[0353] Step 3: N-((2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)methyl)azetidine-2-carboxamide (C58)

[0354] [ka] To a solution of (58-2) (37 mg, 0.09 mmol, 1.0 equiv) in DMF (3 mL) was added 1-(tert-butoxycarbonyl)azetidine-2-carboxylic acid (20 mg, 0.09 mmol, 1.0 equiv), DIEA (35 mg, 0.27 mmol, 3.0 equiv), and HATU (89 mg, 0.27 mmol, 3.0 equiv). The resulting mixture was stirred at 25 °C for 1 h. The mixture was diluted with EtOAc (50 mL) and washed three times with brine (30 mL). The organic phase was dried over anhydrous NaSO, filtered, and concentrated. The residue was dissolved in ClCH (2 mL) and TFA (0.4 mL). The mixture was stirred at 25 °C for 1.5 h. The mixture was concentrated to give the crude product, which was purified by preparative HPLC (Column: Waters crossbridge 150 mm × 25 mm × 5 um: 20-50% B (A = 10 mM NH4HCO3 in water, B = acetonitrile)) to give N-((2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)methyl)azetidine-2-carboxamide (C58). 1H NMR (400 MHz, DMSO-d6): δ ppm 8.30 (t, J = 6.0 Hz, 1H), 8.18 (s, 2H), 7.95 (d, J = 5.2 Hz, 1H), 7.91 (d, J = 9.2 Hz, 1H), 7.55 (d, J = 5.2 Hz, 1H), 7.50 (d, J = 7.2 Hz, 1H), 7.17 (t, J = 6.0 Hz, 1H), 6.99 (d, J = 9.2 Hz, 1H), 4.12-4.09 (m, 3H), 3.90 (br s, 1H), 3.52 (q, J = 8.0 Hz, 2H), 3.17-3.14 (m, MS: [M+H] + = 481.3.

[0355] [Example 59] N-((2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)methyl)oxetane-3-carboxamide (C59)

[0356] [ka] The title compound was prepared by using a procedure similar to that in Step 3 of Example 58, except that 1-(tert-butoxycarbonyl)azetidine-2-carboxylic acid was replaced with oxetane-3-carboxylic acid. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.27 (t, J = 5.2 Hz, 1H), 8.17 (s, 2H), 7.95 (d, J = 5.2 Hz, 1H), 7.91 (d, J = 8.8 Hz, 1H), 7.55 (d, J = 5.2 Hz, 1H), 7.50 (d, J = 7.2 Hz, 1H), 7.20 (t, J = 5.6 Hz, 1H), 6.99 (d, J = 8.0 Hz, 1H), 4.63-4.57 (m, 4H), 4.07 (d, J = 5.2 Hz, 2H), 3.89 (br s, 1H), 3.76-3.69 (m, MS: [M+H] + = 482.2.

[0357] [Example 60] 2-((((1,4-trans)-4-((8-(methylamino)-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidine-5-carbonitrile (C60)

[0358] [ka] To a solution of compound (C21) (140 mg, 0.36 mmol, 1.0 equiv.) in THF (2 mL), t-BuONa (48 mg, 0.5 mmol, 1.4 equiv.), Pd(dba) (33 mg, 0.036 mmol, 0.1 equiv.), t-BuXphos (15 mg, 0.036 mmol, 0.1 equiv.), and MeNH (2 mL, 2 M in THF) were added under N protection. The mixture was stirred at 70 °C for 12 h. The mixture was filtered, and the filtrate was added to HO (20 mL) and extracted twice with EtOAc (50 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by column chromatography (petroleum ether / EtOAc 3 / 1 to EtOAc) to give 2-((((1,4-trans)-4-((8-(methylamino)-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidine-5-carbonitrile (C60), which was re-purified by preparative HPLC (column: YMC-Actas Triate C18 150 mm x 30 mm x 5 um, gradient: 50-80% B (A = 0.05% NH4OH in water, B = acetonitrile)) to give (C60). 1 H NMR (400 MHz, DMSO-d6): δ ppm 8.71 (d, J = 2.8 Hz, 1H), 8.63 (d, J = 2.8 Hz, 1H), 8.42 (t, J = 6.0 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.58 (d, J = 5.6 Hz, 1H), 6.89 (d, J = 8.0 Hz, 1H), 6.80 (d, J = 9.2 Hz, 1H), 6.70 (d, J = 4.8 Hz, 1H), 6.61 (d, J = 5.6 Hz, 1H), 3.98 (br s, 1H), 3.24 (t, J = 6.4 Hz, 2H), 2.97 (d, J = 5.2 Hz, 3H), 2.04-2.01 (m, 2H), 1.79-1.77 (m, 2H), 1.57 (br s, 1H), 1.23-1.09 (m, 4H). MS: [M+H] + = 389.2.

[0359] [Example 61] 2-((((1,4-trans)-4-((8-(methylamino)-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidine-5-carboxamide (C61)

[0360] [ka] The title compound was prepared by using a procedure similar to that in Example 5, except that compound (C4) was replaced with compound (C60), and the product was purified by preparative HPLC (Column: YMC-Actastriat C18 150 mm x 30 mm x 5 um, Gradient: 38-68% B (A = 0.05% NH4OH in water, B = acetonitrile)) to give 2-((((1,4-trans)-4-((8-(methylamino)-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidine-5-carboxamide (C61). 1 H NMR (400 MHz, DMSO-d6): δ ppm 8.72 (s, 1H), 8.68 (s, 1H), 7.84 (t, J = 6.0 Hz, 1H), 7.78 (br s, 1H), 7.64 (d, J = 9.2 Hz, 1H), 7.58 (d, J = 5.6 Hz, 1H), 7.22 (br s, 1H), 6.89 (d, J = 8.0 Hz, 1H), 6.70 (q, J = 5.2 Hz, 1H), 6.61 (d, J = 5.6 Hz, 1H), 3.99 (br s, 1H), 3.24 (t, J = 6.4 Hz, 2H), 2.98 (d, J = MS: [M+H] + = 407.2.

[0361] [Example 62] N 2-((1,4-trans)-4-(((5-aminopyrimidin-2-yl)amino)methyl)cyclohexyl)-N 8 -Methyl-1,7-naphthyridine-2,8-diamine (C62) Step 1:N 8 -methyl-N 2 -((1,4-trans)-4-(((5-nitropyrimidin-2-yl)amino)methyl)cyclohexyl)-1,7-naphthyridine-2,8-diamine (62-1)

[0362] [ka] The title compound was prepared by using a procedure similar to that in Example 60, except that compound (C21) was replaced with (14-1). The product was purified by column chromatography (petroleum ether / EtOAc 1 / 1 to 0 / 1) to give N 8 -methyl-N 2 -((1,4-trans)-4-(((5-nitropyrimidin-2-yl)amino)methyl)cyclohexyl)-1,7-naphthyridine-2,8-diamine (62-1) was obtained. 1 H NMR (400 MHz, CDCl3): δ ppm 9.11 (d, J = 3.2 Hz, 1H), 9.03 (d, J = 3.2 Hz, 1H), 7.78 (d, J = 6.0 Hz, 1H), 7.65 (d, J = 8.8 Hz, 1H), 6.69 (t, J = 6.0 Hz, 1H), 6.55 (br s, 1H), 6.09 (br s, 1H), 4.60 (d, J = 6.0 Hz, 1H), 3.88 (br s, 1H), 3.49 (t, J = 6.4 Hz, 2H), 3.24 (d, J = 4.8 Hz, 3H), 2.23-2.21 (m, 2H), 1.95-1.93 (m, 2H), 1.26-1.23 (m, 5H). MS: [M+H] + = 409.1.

[0363] Step 2:N 2-((1,4-trans)-4-(((5-aminopyrimidin-2-yl)amino)methyl)cyclohexyl)-N 8 -Methyl-1,7-naphthyridine-2,8-diamine (C62)

[0364] [ka] To a solution of (62-1) (50 mg, 0.12 mmol, 1.0 equiv) in CHOH (10 mL) was added Pd / C (10%, 10 mg). The suspension was degassed and then purged with H several times. The mixture was stirred under a H balloon at 30 °C for 1 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: Phenomenex Gemini C18 200 mm × 25 mm × 5 um, gradient: 29-49% B (A = 0.05% NH4HCO3 in water, B = acetonitrile)) to give a 29% to 49% B (A = 0.05% NH4HCO3 in water, B = acetonitrile) eluate. 2 -((1,4-trans)-4-(((5-aminopyrimidin-2-yl)amino)methyl)cyclohexyl)-N 8 -methyl-1,7-naphthyridine-2,8-diamine (C62) was obtained. 1 H NMR (400 MHz, DMSO-d6): δ ppm 7.79 (s, 2H), 7.64 (d, J = 8.8 Hz, 1H), 7.58 (d, J = 5.6 Hz, 1H), 6.88 (d, J = 8.0 Hz, 1H), 6.80 (d, J = 9.2 Hz, 1H), 6.68 (q, J = 4.8 Hz, 1H), 6.61 (d, J = 5.6 Hz, 1H), 6.22 (t, J = 6.4 Hz, 1H), 4.36 (s, 2H), 3.97 (br s, 1H), 3.08 (t, J = 6.4 Hz, 2H), 2.98 (d, J = 4.8 Hz, 3H), 2.02 (br s, 2H), 1.79 (br s, 2H), 1.53 (br s, 1H), 1.19-1.08 (m, 4H). + = 379.2.

[0365] [Example 63] N-(2-((((1,4-trans)-4-((8-(methylamino)-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)acetamide (C63)

[0366] [ka] The title compound was prepared by using a procedure similar to that of intermediate (2-1), except that compound (C1) was replaced with compound (C62), and the product was purified by preparative HPLC (column: Phenomenex Gemini C18 200 mm × 25 mm × 5 um, gradient: 24-44% B (A = 0.05% NH4CO3 in water, B = acetonitrile)) to give N-(2-((((1,4-trans)-4-((8-(methylamino)-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)acetamide (C63). 1 H NMR (400 MHz, DMSO-d6): δ ppm 9.72 (s, 1H), 8.36 (s, 2H), 7.64 (d, J = 8.8 Hz, 1H), 7.57 (d, J = 5.6 Hz, 1H), 7.09 (t, J = 6.0 Hz, 1H), 6.89 (d, J = 7.6 Hz, 1H), 6.80 (d, J = 8.8 Hz, 1H), 6.71 (d, J = 4.8 Hz, 1H), 6.61 (d, J = 5.6 Hz, 1H), 3.98 (br s, 1H), 3.15 (t, J = 6.4 Hz, 2H), 2.98 (d, J = 4.8 Hz, MS: [M+H] + = 421.2.

[0367] [Example 64] 3-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)oxazolidin-2-one (C64) Step 1: N-((1,4-trans)-4-(((5-bromopyrimidin-2-yl)amino)methyl)cyclohexyl)-8-methoxy-1,7-naphthyridin-2-amine (64-1)

[0368] [ka] To a solution of (1-8) (518 mg, 1.81 mmol, 1.0 equiv) in DMA (5 mL) was added 5-bromo-2-chloropyrimidine (454 mg, 2.35 mmol, 1.3 equiv) and DIPEA (1167 mg, 9.05 mmol, 5.0 equiv), and the mixture was stirred at 100 °C for 8 h. The mixture was diluted with EtOAc (50 mL) and washed twice with brine (30 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography on silica gel (petroleum ether / EtOAc 2 / 1 to 1 / 1) to give N-((1,4-trans)-4-(((5-bromopyrimidin-2-yl)amino)methyl)cyclohexyl)-8-methoxy-1,7-naphthyridin-2-amine (64-1). MS: [M+H] + =443.1 / 445.1.

[0369] Step 2: 3-(2-((((1,4-trans)-4-((8-methoxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)oxazolidin-2-one (64-2)

[0370] [ka] To a solution of (64-1) (100 mg, 0.23 mmol, 1.0 equiv) in dioxane (2.5 mL), oxazolidin-2-one (98 mg, 1.13 mmol, 5.0 equiv), (1S,2S)-cyclohexane-1,2-diamine (26 mg, 0.23 mmol, 1.0 equiv), CuI (13 mg, 0.07 mmol, 0.3 equiv), and KCO (63 mg, 0.46 mmol, 2.0 equiv) were added. The reaction mixture was stirred under microwave irradiation at 120 °C for 2 h. The mixture was filtered, and the filtrate was concentrated. The crude product was purified by column chromatography on silica gel (petroleum ether / EtOAc 1 / 1 to 0 / 100) to give 3-(2-((((1,4-trans)-4-((8-methoxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)oxazolidin-2-one (64-2). 1 H NMR (400 MHz, CDCl3): δ ppm 8.45 (s, 2H), 7.81-7.78 (m, 2H), 7.02 (d, J = 5.6 Hz, 1H), 6.84 (d, J = 8.8 Hz, 1H), 5.26 (t, J = 6.0 Hz, 1H), 5.09 (br s, 1H), 4.52 (t, J = 8.4 Hz, 2H), 4.14 (s, 3H), 3.98 (t, J = 8.0 Hz, 2H), 3.69-3.56 (m, 1H), 3.32 (t, J = 6.4 Hz, 2H), 2.19-2.17 (m, 2H), 1.94-1.92 (m, 2H), 1.60 (br s, 1H), 1.27-1.17 (m, 4H). MS: [M+H] + = 450.1.

[0371] Step 3: 3-(2-((((1,4-trans)-4-((8-hydroxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)oxazolidin-2-one (64-3)

[0372] [ka] To a solution of 64-2 (80 mg, 0.178 mmol, 1.0 equiv) in 5 mL of EtOAc was added HCl / EtOAc (10 mL, 4N), and the mixture was stirred at 35° C. for 2.5 h, then concentrated to give 3-(2-((((1,4-trans)-4-((8-hydroxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)oxazolidin-2-one 64-3. MS: [M+H] + =436.3.

[0373] Step 4: 3-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)oxazolidin-2-one (C64)

[0374] [ka] A solution of (64-3) (75 mg, 0.17 mmol, 1.0 equiv) in POCl (5 mL) was stirred at 110 °C for 1.5 h. The reaction mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: Durashell 150 × 25 mm × 5 um, gradient: 34–64% B (A = 0.5% NH4HCO3 in water, B = acetonitrile)) to give 3-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)oxazolidin-2-one (C64). 1H NMR (400 MHz, DMSO-d6): δ ppm 8.42 (s, 2H), 7.95 (d, J = 4.8 Hz, 1H), 7.91 (d, J = 9.2 Hz, 1H), 7.55 (d, J = 5.2 Hz, 1H), 7.51 (d, J = 7.2 Hz, 1H), 7.31 (t, J = 6.0 Hz, 1H), 6.99 (d, J = 9.2 Hz, 1H), 4.45-4.41 (m, 2H), 3.97 (t, J = 8.0 Hz, 2H), 3.91 (br s, 1H), 3.17 (t, J = 6.4 Hz, 2H), 2.14-2.11 (m, 2H), 1.85-1.82 (m, 2H), 1.58 (br s, 1H), 1.25-1.04 (m, 4H). MS: [M+H] + = 454.1.

[0375] [Example 65] Methyl (2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)(methyl)carbamate (C65) Step 1:N 2 -(((1,4-trans)-4-((8-methoxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)-N 5 -Methylpyrimidine-2,5-diamine (65-1)

[0376] [ka] The title compound was prepared by using a procedure similar to that in Example 60, except that compound (C21) was replaced with (64-1), and the product was purified by column chromatography (petroleum ether / EtOAc 1 / 1 to 0 / 100) to give N 2 -(((1,4-trans)-4-((8-methoxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)-N 5 -methylpyrimidine-2,5-diamine (65-1) was obtained.1 H NMR (400 MHz, CDCl3): δ ppm 7.87 (s, 2H), 7.80-7.78 (m, 2H), 7.02 (d, J = 5.6 Hz, 1H), 6.84 (d, J = 9.2 Hz, 1H), 5.11 (br s, 1H), 4.76 (t, J = 5.6 Hz, 1H), 4.14 (s, 3H), 3.79-3.52 (m, 1H), 3.27 (t, J = 6.4 Hz, 2H), 2.81 (s, 3H), 2.18-2.16 (m, 2H), 1.96-1.93 (m, 2H), 1.50 (br s, 1H), 1.27-1.16 (m, 4H). MS: [M+H] + = 394.1.

[0377] Step 2: Methyl (2-((((1,4-trans)-4-((8-methoxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)(methyl)carbamate (65-2)

[0378] [ka] To a solution of (65-1) (130 mg, 0.33 mmol, 1.0 equiv) in Cl2CH2 (5 mL) was added CDI (430 mg, 2.64 mmol, 8.0 equiv) and DIPEA (426 mg, 2.64 mmol, 8.0 equiv). The mixture was stirred at 40 °C for 1.5 h. Then CH3OH (10 mL) was added and stirred at 50 °C for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (50 mL) and washed three times with brine (30 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography on silica gel (petroleum ether / EtOAc 1 / 1 to 0 / 100) to give methyl (2-((((1,4-trans)-4-((8-methoxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)(methyl)carbamate (65-2).1 H NMR (400 MHz, CDCl3): δ ppm 8.15 (br s, 2H), 7.81-7.78 (m, 2H), 7.02 (d, J = 5.6 Hz, 1H), 6.84 (d, J = 9.2 Hz, 1H), 5.29 (br s, 1H), 5.07 (br s, 1H), 4.14 (s, 3H), 3.82-3.52 (m, 4H), 3.32 (t, J = 6.4 Hz, 2H), 3.24 (s, 3H), 2.20-2.17 (m, 2H), 1.96-1.93 (m, 2H), 1.66 (br s, 1H), 1.27-1.21 (m, 4H). MS: [M+H] + = 452.2.

[0379] Step 3: Methyl (2-((((1,4-trans)-4-((8-hydroxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)(methyl)carbamate (65-3)

[0380] [ka] The title compound was prepared by using a procedure similar to that of (64-3), except that (64-2) was replaced with (65-2). MS: [M+H] + =438.2.

[0381] Step 3: Methyl (2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)(methyl)carbamate (C65)

[0382] [ka] The title compound was prepared by using a procedure similar to that in Step 4 of Example 64, except that (64-3) was replaced with (65-3). The product was purified by preparative HPLC (Column: Durashell 150 mm × 25 mm × 5 μm, Gradient: 35-65% B (A = 0.05% ammonia hydroxide in water, B = acetonitrile)) to give methyl (2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)(methyl)carbamate (C65). 1 H NMR (400 MHz, DMSO-d6): δ ppm 8.22 (s, 2H), 7.95 (d, J = 5.2 Hz, 1H), 7.91 (d, J = 8.8 Hz, 1H), 7.55 (d, J = 5.2 Hz, 1H), 7.51 (d, J = 6.8 Hz, 1H), 7.38 (br s, 1H), 6.99 (d, J = 8.8 Hz, 1H), 3.91 (br s, 1H), 3.56 (br s, 3H), 3.17-3.14 (m, 5H), 2.14-2.11 (m, 2H), 1.86-1.83 (m, 2H), 1.59 (br s, 1H), 1.26-1.04 (m, 4H). MS: [M+H] + = 456.2.

[0383] [Example 66] N 2 -(((1,4-trans)-4-((8-(difluoromethoxy)-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)pyrimidine-2,5-diamine (C66) Step 1: 2-chloro-8-(difluoromethoxy)-1,7-naphthyridine (66-1)

[0384] [ka] To a solution of (1-6) (300 mg, 1.66 mmol, 1.0 equiv) in CHCN (70 mL) was added ClCFCOONa (303 mg, 1.99 mmol, 1.2 equiv). The mixture was stirred at 90 °C for 15 h. The mixture was added to saturated aqueous NHCl (30 mL) and extracted twice with EtOAc (50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The crude product was purified by column chromatography (petroleum ether / EtOAc = 3 / 1) to give 2-chloro-8-(difluoromethoxy)-1,7-naphthyridine (66-1). 1 H NMR (400 MHz, DMSO-d6): δ ppm 8.55 (d, J = 8.8 Hz, 1H), 8.24 (d, J = 5.6 Hz, 1H), 7.96 (t, J = 72 Hz, 1H), 7.94 (d, J = 4.0 Hz, 1H), 7.81 (d, J = 5.6 Hz, 1H). MS: [M+H] + = 230.8.

[0385] Step 2: tert-Butyl (((1,4-trans)-4-((8-(difluoromethoxy)-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)carbamate (66-2)

[0386] [ka] The title compound was prepared using a procedure similar to that in Step 7 of Example 1, replacing (1-6) with (66-1), and the product was purified by column chromatography (petroleum ether / EtOAc 5 / 1 to 3 / 1) to give tert-butyl (((1,4-trans)-4-((8-(difluoromethoxy)-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)carbamate (66-2). MS: [M+H] + =423.1.

[0387] Step 3: N-((1,4-trans)-4-(aminomethyl)cyclohexyl)-8-(difluoromethoxy)-1,7-naphthyridin-2-amine (66-3)

[0388] [ka] To a solution of 66-2 (160 mg, 0.38 mmol, 1.0 equiv) in CHCl (5 mL) was added TFA (1 mL) and the mixture was stirred at 15° C. for 2 h. The mixture was concentrated to give N-((1,4-trans)-4-(aminomethyl)cyclohexyl)-8-(difluoromethoxy)-1,7-naphthyridin-2-amine (66-3), which was used without further purification. MS: [M+H] + =323.1.

[0389] Step 4: 8-(Difluoromethoxy)-N-((1,4-trans)-4-(((5-nitropyrimidin-2-yl)amino)methyl)cyclohexyl)-1,7-naphthyridin-2-amine (66-4)

[0390] [ka] The title compound was prepared by using a procedure similar to that in Step 9 of Example 1, except that (1-8) was replaced with (66-3), and the product was purified by column chromatography (petroleum ether / EtOAc 3 / 1 to 1 / 1) to give 8-(difluoromethoxy)-N-((1,4-trans)-4-(((5-nitropyrimidin-2-yl)amino)methyl)cyclohexyl)-1,7-naphthyridin-2-amine (66-4). 1H NMR (400 MHz, DMSO-d6): δ ppm 9.10 (d, J = 3.2 Hz, 1H), 9.02 (d, J = 3.2 Hz, 1H), 8.91 (t, J = 5.6 Hz, 1H), 7.89 (d, J = 8.8 Hz, 1H), 7.79 (t, J = 73.2 Hz, 1H), 7.76 (d, J = 4.8 Hz, 1H), 7.41-7.36 (m, 2H), 6.99 (d, J = 8.4 Hz, 1H), 3.87 (br s, 1H), 3.31 (t, J = 6.4 Hz, 2H), 2.08-2.06 (m, 2H), 1.83-1.80 (m, 2H), 1.62 (br s, 1H), 1.22-1.11 (m, 4H). MS: [M+H] + = 446.2.

[0391] Step 4:N 2 -(((1,4-trans)-4-((8-(difluoromethoxy)-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)pyrimidine-2,5-diamine (C66)

[0392] [ka] To a solution of (66-4) (100 mg, 0.22 mmol, 1.0 equiv) in CHOH (20 mL) and EtOAc (20 mL) was added Pd / C (10%, 80 mg). The suspension was degassed under vacuum and purged with H several times. The mixture was stirred under a H balloon at 15 °C for 1.5 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: Phenomenex Gemini C18 200 mm × 25 mm × 5 um, gradient: 29-39% B (A = 0.5% NH4HCO3 in water, B = acetonitrile)) to give a 29% to 39% B (A = 0.5% NH4HCO3 in water, B = acetonitrile) eluate. 2 -(((1,4-trans)-4-((8-(difluoromethoxy)-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)pyrimidine-2,5-diamine (C66) was obtained. 1H NMR (400 MHz, DMSO-d6): δ ppm 7.89 (d, J = 8.8 Hz, 1H), 7.80 (t, J = 73.6 Hz, 1H), 7.79 (s, 2H), 7.75 (d, J = 5.2 Hz, 1H), 7.40 (d, J = 5.2 Hz, 1H), 7.36 (d, J = 7.6 Hz, 1H), 6.99 (d, J = 8.4 Hz, 1H), 4.37 (s, 2H), 3.86 (br s, 1H), 3.06 (t, J = 6.4 Hz, 2H), 2.06-2.04 (m, 2H), 1.83-1.81 (m, 2H), 1.52 (br s, 1H), 1.22-1.00 (m, 4H). 19 F NMR (400 MHz, DMSO-d6): δ ppm -86.34, -86.50. MS: [M+H] + = 416.1.

[0393] [Example 67] N-((1,4-trans)-4-(((5-(4H-1,2,4-triazol-3-yl)pyrimidin-2-yl)amino)methyl)cyclohexyl)-8-chloro-1,7-naphthyridin-2-amine (C67)

[0394] [ka] A solution of compound (C12) (100 mg, 0.23 mmol, 1.0 equiv.) in POCl3 (10 g) was heated at 110 °C for 5 h. POCl3 was then removed under vacuum, and the residue was basified by the addition of ammonia. The reaction mixture was extracted twice with EtOAc (50 mL), and the organic solvent was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC (Waters Excellect C18 150 mm × 30 mm × 5 μm column, gradient: 22–37% B (A = 0.05% NH3HO in water, B = acetonitrile)) to give N-((1,4-trans)-4-(((5-(4H-1,2,4-triazol-3-yl)pyrimidin-2-yl)amino)methyl)cyclohexyl)-8-chloro-1,7-naphthyridin-2-amine (C67). 1 H NMR (400 MHz, DMSO-d6): δ ppm 13.91 (br s, 1H), 8.81 (s, 2H), 8.39 (br s, 1H), 7.96 (d, J = 5.2 Hz, 1H), 7.91 (d, J = 9.2 Hz, 1H), 7.69-7.66 (m, 1H), 7.56 (d, J = 5.6 Hz, 1H), 7.52 (d, J = 7.6 Hz, 1H), 7.00 (d, J = 9.2 Hz, 1H), 3.91 (br s, 1H), 3.24 (t, J = 6.0 Hz, 2H), 2.15-2.13 (m, 2H), 1.87-1.84 (m, 2H), 1.58 (br s, 1H), 1.24-1.10 (m, 4H). MS: [M+H] + = 436.2.

[0395] [Example 68] 2-((2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)oxy)propan-1-ol (C68) Step 1: Ethyl 2-((2-((((1,4-trans)-4-((8-hydroxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)oxy)propanoate (68-1)

[0396] [ka] The title compound was prepared by using a procedure similar to that in Step 9 in Example 1 by replacing 2-chloro-5-nitropyrimidine with ethyl 2-((2-chloropyrimidin-5-yl)oxy)propanoate. MS: [M+H] + =467.0.

[0397] Step 2: Ethyl 2-((2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)oxy)propanoate (68-2)

[0398] [ka] The title compound was prepared by using a procedure similar to that in Example 67, except that compound (C12) was replaced with (68-1). 1H NMR (400 MHz, DMSO-d6): δ ppm 8.09 (s, 2H), 7.97 (d, J = 5.3 Hz, 1H), 7.92 (d, J = 9.0 Hz, 1H), 7.56 (d, J = 5.3 Hz, 1H), 7.53 (d, J = 7.0 Hz, 1H), 7.00 (d, J = 6.0 Hz, 2H), 4.83 (q, J = 6.8 Hz, 1H), 4.14 (qd, J = 7.1, 2.3 Hz, 2H), 3.44-3.42 (m, 1H), 3.12 (t, J = 6.3 Hz, 2H), 2.12 (d, J = 11.0 Hz, 2H), 1.83 (d, J = 11.8 Hz, 2H), 1.61-1.53 ​​(m, 1H), 1.48 (d, J = 6.8 Hz, 3H), 1.25-1.16 (m, 5H), 1.13-1.02 (m, 2H). MS: [M+H] + = 485.0.

[0399] Step 3: 2-((2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)oxy)propan-1-ol (C68)

[0400] [ka] To a solution of (68-2) (18 mg, 0.037 mmol) in EtOH (2 mL) was added NaBH (42.1 mg, 1.113 mmol). The mixture was stirred at 0 °C for 10 minutes and then at room temperature for 4 hours. The mixture was purified by preparative HPLC to give 2-((2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)oxy)propan-1-ol (C68). 1H NMR (400 MHz, DMSO-d6): δ ppm 8.09 (s, 2H), 7.96 (d, J = 5.3 Hz, 1H), 7.92 (d, J = 9.0 Hz, 1H), 7.56 (d, J = 5.3 Hz, 1H), 7.53 (d, J = 7.3 Hz, 1H), 7.00 (d, J = 8.5 Hz, 1H), 6.89 (t, J = 5.8 Hz, 1H), 4.20-4.11 (m, 1H), 3.95 (br s, 1H), 3.57-3.25 (m, 2H), 3.12 (t, J = 6.4 Hz, 2H), 2.13-2.11 (m, 2H), 1.85-1.82 (m, 2H), 1.57 (br s, 1H), 1.25-1.06 (m, 7H). MS: [M+H] + = 443.0.

[0401] [Example 69] 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-1-(3-hydroxyazetidin-1-yl)propan-1-one (C69)

[0402] [ka] The title compound was prepared by using a procedure similar to that in Example 52, except that oxetan-3-amine was replaced with azetidin-3-ol. 1H NMR (400 MHz, DMSO-d6), rotamers present: δ ppm 8.17 (s, 1H), 8.16 (s, 1H), 7.96 (d, J = 5.2 Hz, 1H), 7.91 (d, J = 9.1 Hz, 1H), 7.55 (d, J = 5.2 Hz, 1H), 7.51 (d, J = 7.0 Hz, 1H), 7.21-7.13 (m, 1H), 7.00 (d, J = 9.2 Hz, 1H), 5.71 (d, J = 6.2 Hz, 0.5H), 5.67 (d, J = 6.3 Hz, 0.5H), 4.49-4.33 (m, 1.5H), 4.24 (t, J = 7.6 Hz, 0.5H), 4.07-3.82 (m, 2.5H), 3.74 (d, J = 5.1 Hz, 0.5H), 3.62-3.55 (m, 0.5H), 3.50 (q, J = 7.1 Hz, 1.5), 3.15 (br s, MS: [M+H] + = 496.2.

[0403] [Example 70 and Example 71] (S)-2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-1-(3-hydroxyazetidin-1-yl)propan-1-one (C70) and (R)-2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-1-(3-hydroxyazetidin-1-yl)propan-1-one (C71)

[0404] [ka] The racemate (C69) was separated by SFC (Chiralpak AD-3 id 50 x 4.6 mm, 3 um; 40% iso-propanol in CO2 (0.05% DEA); flow rate: 4 mL / min; 40 °C) to give peak 1 (t R =0.57 min) and Peak 2 (t R = 1.04 min). Peak 1 (C70 or C71): 1 H NMR (400 MHz, DMSO-d6), exists as rotamers: δ ppm 8.17 (s, 1H), 8.16 (s, 1H), 7.96 (d, J = 5.1 Hz, 1H), 7.91 (d, J = 8.9 Hz, 1H), 7.56 (d, J = 5.2 Hz, 1H), 7.51 (d, J = 7.1 Hz, 1H), 7.19 (q, J = 6.7 Hz, 1H), 7.00 (d, J = 8.7 Hz, 1H), 5.68 (br s, 1H), 4.50-4.34 (m, 1.5H), 4.24 (t, J = 7.8Hz, 0.5H), 4.08-3.82 (m, 2.5H), 3.75 (d, J = 4.9 Hz, 0.5H), 3.63-3.56 (m, 0.5H), 3.50 (q, J = 6.9 Hz, 1.5H), 3.15 (br s, 2H), 2.14-2.11 (m, 2H), 1.85-1.82 (m, 2H), 1.58 (br s, 1H), 1.26-1.04 (m,7H). MS: [M+H] + = 496.2. Peak 2 (C70 or C71): 1H NMR (400 MHz, DMSO-d6): δ ppm 8.19 (s, 1H), 8.18 (s, 1H), 7.96 (d, J = 5.1 Hz, 1H), 7.91 (d, J = 8.9 Hz, 1H), 7.56 (d, J = 5.2 Hz, 1H), 7.52 (d, J = 7.1 Hz, 1H), 7.29-7.19 (m, 1H), 7.00 (d, J = 9.0 Hz, 1H), 5.71 (br s, 1H), 4.48-4.35 (m, 1.5H), 4.25 (t, J = 7.9Hz, 0.5H), 4.08-3.93 (m, 2.5H), 3.78-3.72 (m, 0.5H), 3.58 (dd, J = 10.1, 4.4 Hz, 0.5H), 3.55-3.47 (m, 1.5H), 3.16 (br s, 2H), 2.14-2.11 (m, 2H), 1.85-1.82 (m, 2H), 1.57 (br s, 1H), 1.28-1.04 (m, 7H). MS: [M+H] + = 496.2.

[0405] [Example 72] 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-3-hydroxy-N-(oxetan-3-yl)propanamide (C72)

[0406] [ka] To a solution of compound (C36) (200 mg, 0.207 mmol, 1.0 equiv) in DMF (5 mL) was added KCO (172 mg, 0.621 mmol, 3.0 equiv) and paraformaldehyde (24 mg, 0.414 mmol, 2.0 equiv). The mixture was stirred at 30° C. for 4 h, then diluted with HO (20 mL) and extracted three times with CHCl (20 mL), and the organic layer was dried over NaSO, filtered, and concentrated to give a residue which was purified by column chromatography on silica gel (CHCl / MeOH 100 / 1 to 20 / 1) to give 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-3-hydroxy-N-(oxetan-3-yl)propanamide (C72). 1 H NMR (400 MHz, DMSO-d6): δ ppm 8.80 (d, J = 6.4 Hz, 1H), 8.15 (s, 2H), 7.96 (d, J = 5.2 Hz, 1H), 7.91 (d, J = 8.8 Hz, 1H), 7.55 (d, J = 5.2 Hz, 1H), 7.51 (d, J = 7.2 Hz, 1H), 7.16 (t, J = 6.0 Hz, 1H), 6.99 (d, J = 8.8 Hz, 1H), 4.88 (t, J = 5.2 Hz, 1H), 4.79-4.65 (m, 3H), 4.41 (t, J = 6.0 Hz, 1H), 4.34 (t, J = 6.0 Hz, 1H), 3.90-3.89 (m, 1H), 3.86-3.80 (m, 1H), 3.53-3.47 (m, 1H), 3.41-3.37 (m, 1H), 3.14 (t, J = 6.4 Hz, 2H), 2.13-2.10 (m, 2H), 1.84-1.81 (m, 2H), 1.56 (br s, 1H), 1.24-1.16 (m, 2H), 1.12-1.03 (m, 2H). MS: [M+H] + = 512.1.

[0407] [Example 73 and Example 74] (R)-2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-3-hydroxy-N-(oxetan-3-yl)propanamide (C73) and (S)-2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-3-hydroxy-N-(oxetan-3-yl)propanamide (C74)

[0408] [ka] Racemic Example 72 was separated by SFC (Chiralpak AS-H, 150×4.6 mm ID, 5 μm; mobile phase: A:CO B:ethanol (0.05% DEA); gradient: 5% hold over 0.5 min, then 5% to 40% B over 3.5 min and 40% hold over 2.5 min, then 5% B over 1.5 min; flow rate: 3 mL / min, column temperature: 40° C.) to give peak 1 (t R = 4.56 min) and Peak 2 (t R = 5.05 min). Peak 1 (C73 or C74): 1H NMR (400 MHz, DMSO-d6): δ ppm 8.80 (d, J = 6.4 Hz, 1H), 8.15 (s, 2H), 7.96 (d, J = 5.2 Hz, 1H), 7.91 (d, J = 8.8 Hz, 1H), 7.55 (d, J = 5.2 Hz, 1H), 7.51 (d, J = 6.8 Hz, 1H), 7.17 (t, J = 6.0 Hz, 1H), 6.99 (d, J = 9.2 Hz, 1H), 4.88 (t, J = 5.2 Hz, 1H), 4.77-4.65 (m, 3H), 4.41 (t, J = 6.0 Hz, 1H), 4.34 (t, J = 6.0 Hz, 1H), 3.90-3.89 (m, 1H), 3.86-3.82 (m, 1H), 3.51-3.47 (m, 1H), 3.41-3.33 (m, 1H), 3.14 (t, J = 6.4 Hz, 2H), 2.13-2.10 (m, 2H), 1.84-1.81 (m, 2H), 1.56 (br s, 1H), 1.22-1.16 (m, 2H), 1.12-1.03 (m, 2H). MS: [M+H] + = 512.1. ピーク2(C73またはC74): 1H NMR (400 MHz, DMSO-d6): δ ppm 8.80 (d, J = 6.4 Hz, 1H), 8.15 (s, 2H), 7.96 (d, J = 5.2 Hz, 1H), 7.91 (d, J = 8.8 Hz, 1H), 7.55 (d, J = 4.8 Hz, 1H), 7.51 (d, J = 7.2 Hz, 1H), 7.17 (t, J = 6.0 Hz, 1H), 6.99 (d, J = 8.8 Hz, 1H), 4.88 (t, J = 5.2 Hz, 1H), 4.77-4.65 (m, 3H), 4.41 (t, J = 6.0 Hz, 1H), 4.34 (t, J = 6.0 Hz, 1H), 3.90 (br s, 1H), 3.86-3.80 (m, 1H), 3.51-3.47 (m, 1H), 3.41-3.37 (m, 1H), 3.14 (t, J = 6.4 Hz, 2H), 2.13-2.10 (m, 2H), 1.84-1.81 (m, 2H), 1.56 (br s, 1H), 1.22-1.16 (m, 2H), 1.12-1.03 (m, 2H). MS: [M+H] + = 512.1.

[0409] [Example 75 and Example 76] (S)-2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-2-hydroxy-N-(oxetan-3-yl)acetamide (C75) and (R)-2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-2-hydroxy-N-(oxetan-3-yl)acetamide (C76) Step 1: 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-2-oxoacetic acid (75-1)

[0410] [ka] To a solution of compound (C36) (212 mg, 0.44 mmol, 1.0 equiv.) in anisole (15 mL) was added SeO (195.3 mg, 1.76 mmol, 4.0 equiv.). The reaction mixture was heated to 125° C. for 3 h. The mixture was then cooled to room temperature, filtered, and washed with CHCl / MeOH (100 mL, 10 / 1). The filtrate was concentrated under reduced pressure and the crude product was purified by preparative HPLC (Column: Extimate C18 150 mm x 25 mm x 5 um, Gradient: 21-51% B (A = 0.05% ammonia in water, B = acetonitrile)) to give 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-2-oxoacetic acid (75-1). MS: [M+H] + =441.0.

[0411] Step 2: Ethyl 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-2-oxoacetate (75-2)

[0412] [ka] To a solution of 75-1 (120 mg, 0.27 mmol) in anhydrous EtOH (10 mL) was added SOCl (161 mg, 1.35 mmol). The reaction mixture was stirred under N protection at 1-9 °C for 24 h. The reaction mixture was then diluted with ice / HO (30 mL), basified with saturated aqueous NaHCO to pH 8-9, and then extracted with CHCl (3 × 50 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give ethyl 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-2-oxoacetate (75-2). MS: [M+H]+ =469.1.

[0413] Step 3: Ethyl 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-2-hydroxyacetate (75-3)

[0414] [ka] To a solution of (75-2) (132 mg, 0.28 mmol, 1.0 equiv) in anhydrous MeOH (12 mL) was added NaBH (10.6 mg, 0.28 mmol, 1.0 equiv) under N protection at 0 °C. The reaction mixture was stirred at this temperature for 10 min. The reaction mixture was then quenched with HO (5 mL), diluted with brine (30 mL), and extracted three times with CHCl (50 mL). The combined organic layers were dried over anhydrous NaSO, filtered and concentrated under reduced pressure to give the crude compound, which was purified by column chromatography on silica gel (CHCl / MeOH 50 / 1 to 20 / 1) to give ethyl 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-2-hydroxyacetate (75-3). 1 H NMR (400 MHz, CDCl3): δ ppm 8.32 (s, 2H), 8.05 (d, J = 5.2 Hz, 1H), 7.77 (d, J = 9.2 Hz, 1H), 7.34 (d, J = 5.2 Hz, 1H), 6.81 (d, J = 8.8 Hz, 1H), 5.41-5.40 (m, 1H), 5.03 (s, 1H), 4.32-4.20 (m, 2H), 3.51-3.49 (m, 1H), 3.35 (t, J = 6.4 Hz, 2H), 2.27 (br s, 2H), 1.96-1.94 (m, 2H), 1.66-1.65 (m, 1H), 1.30-1.27 (m, 3H), 1.24-1.21 (m, 4H). MS: [M+H]+ = 471.2.

[0415] Step 4: 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-2-hydroxy-N-(oxetan-3-yl)acetamide (75-4)

[0416] [ka] A mixture of (75-3) (35 mg, 0.074 mmol, 1.0 equiv) in oxetan-3-amine (0.5 mL) was heated to 65 °C for 16 h. The mixture was then cooled to room temperature and purified by preparative HPLC (Column: Extimate C18 150 x 25 mm x 5 um, Gradient: 24-54% B (A = water / 0.05% ammonia hydroxide, B = acetonitrile)) to give 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-2-hydroxy-N-(oxetan-3-yl)acetamide (75-4). MS: [M+H] + =498.1.

[0417] Step 4: (S)-2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-2-hydroxy-N-(oxetan-3-yl)acetamide (C75) and (R)-2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)-amino)pyrimidin-5-yl)-2-hydroxy-N-(oxetan-3-yl)acetamide (C76)

[0418] [ka] (75-4) was purified by SFC separation (Chiralpak AD-3 50 × 4.6 mm ID, 3 μm; mobile phase: 40% ethanol (0.05% DEA) in CO2; flow rate: 4 mL / min; column temperature: 40 °C) to obtain peak 1 (t R = 1.40 min) and Peak 2 (t R = 4.80 min). Peak 1 (C75 or C76): 1 H NMR (400 MHz, DMSO-d6): δ ppm 8.77 (d, J = 6.4 Hz, 1H), 8.22 (s, 2H), 7.96 (d, J = 5.2 Hz, 1H), 7.91 (d, J = 8.8 Hz, 1H), 7.56 (d, J = 5.2 Hz, 1H), 7.51 (d, J = 6.8 Hz, 1H), 7.27 (t, J = 6.0 Hz, 1H), 6.99 (d, J = 8.4 Hz, 1H), 6.15 (d, J = 4.8 Hz, 1H), 4.84-4.78 (m, 2H), 4.67-4.65 (m, 2H), 4.55-4.52 (m, 2H), 3.90 (br s, 1H), 3.16 (t, J = 6.0 Hz, 2H), 2.13-2.11 (m, 2H), 1.85-1.81 (m, 2H), 1.57 (br s, 1H), 1.22-1.16 (m, 2H), 1.13-1.04 (m, 2H). MS: [M+H] + = 498.2. Peak 2 (C75 or C76): 1H NMR (400 MHz, DMSO-d6): δ ppm 8.77 (d, J = 6.8 Hz, 1H), 8.22 (s, 2H), 7.96 (d, J = 5.2 Hz, 1H), 7.91 (d, J = 8.8 Hz, 1H), 7.56 (d, J = 5.2 Hz, 1H), 7.51 (d, J = 6.8 Hz, 1H), 7.27 (t, J = 6.0 Hz, 1H), 6.99 (d, J = 9.2 Hz, 1H), 6.15 (d, J = 4.4 Hz, 1H), 4.84-4.78 (m, 2H), 4.68-4.65 (m, 2H), 4.55-4.52 (m, 2H), 3.90 (br s, 1H), 3.16 (t, J = 6.0 Hz, 2H), 2.13-2.11 (m, 2H), 1.84-1.81 (m, 2H), 1.57 (br s, 1H), 1.22-1.16 (m, 2H), 1.13-1.06 (m, 2H). MS: [M+H] + = 498.1.

[0419] [Example 77] 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-2,2-difluoro-N-(oxetan-3-yl)acetamide (C77) Step 1: Ethyl 2-(2-chloropyrimidin-5-yl)-2,2-difluoroacetate (77-1)

[0420] [ka] A mixture of 2-chloro-5-iodopyrimidine (4.0 g, 16.64 mmol, 1.0 equiv.), Cu (3.17 g, 49.91 mmol, 3.0 equiv.), and ethyl 2-bromo-2,2-difluoroacetate (4.05 g, 19.96 mmol, 1.2 equiv.) in dry DMSO (40 mL, dried over MgSO) was heated at 75° C. for 2 h under N protection. The mixture was quenched with saturated NH4Cl solution (20 mL) and extracted three times with EtOAc (40 mL). The organic phase was washed with water (100 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated. The crude was purified by column chromatography on silica gel (petroleum ether / EtOAc=40:1) to give ethyl 2-(2-chloropyrimidin-5-yl)-2,2-difluoroacetate (77-1). 1 H NMR (400 MHz, DMSO-d6): δ ppm 9.08 (s, 2H), 4.33 (q, J = 7.2 Hz, 2H), 1.25 (t, J = 7.2 Hz, 3H). MS: [M+H] + = 236.9.

[0421] Step 2: Ethyl 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-2,2-difluoroacetate (77-2)

[0422] [ka] To a mixture of 26-1 (150 mg, 0.46 mmol, 1.0 equiv) in DMF (5 mL) was added 77-1 (130 mg, 0.55 mmol, 1.2 equiv) and DIEA (355 mg, 2.75 mmol, 6.0 equiv). The resulting solution was heated at 100° C. for 4 h. It was then diluted with water (6 mL) and extracted three times with EtOAc (10 mL). The organic layer was washed three times with water (30 mL), dried over anhydrous NaSO, filtered, and concentrated. The crude product was purified by column chromatography on silica gel (petroleum ether / EtOAc 10:1 to 6:1) to give ethyl 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-2,2-difluoroacetate (77-2). 1 H NMR (400 MHz, DMSO-d6): δ ppm 8.48 (s, 1H), 8.43 (s, 1H), 8.03 (t, J = 5.6 Hz, 1H), 7.96 (d, J = 5.2 Hz, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.56 (d, J = 5.2 Hz, 1H), 7.52 (d, J = 7.2 Hz, 1H), 6.99 (d, J = 9.2 Hz, 1H), 4.33 (q, J = 6.8 Hz, 2H), 3.90 (br s, 1H), 3.22 (t, J = 6.8 Hz, 2H), 2.15-2.11 (m, 2H), 1.85-1.81 (m, 2H), 1.60 (br s, 1H), 1.26 (t, J = 7.2 Hz, 3H), 1.12-1.08 (m, 4H). MS: [M+H] + = 491.2.

[0423] Step 3: 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-2,2-difluoro-N-(oxetan-3-yl)acetamide (C77)

[0424] [ka] A mixture of (77-2) (50 mg, 0.10 mmol, 1.0 equiv) and oxetan-3-amine (372.22 mg, 5.09 mmol, 50 equiv) in a 50 mL round-bottom flask was stirred for 2 h at 15° C. The mixture was diluted with water (3 mL) and extracted three times with EtOAc (5 mL). The combined organic layers were concentrated and the crude product was purified by preparative HPLC (Column: Extimate C18 150 mm x 25 mm x 5 um, Gradient: 35-65% B (A = 0.05% ammonia in water, B = ACN), Flow rate: 25 mL / min) to give 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-2,2-difluoro-N-(oxetan-3-yl)acetamide (C77). 1 H NMR (400 MHz, DMSO-d6): δ ppm 9.65 (d, J = 6.4 Hz, 1H), 8.44-8.40 (m, 2H), 7.96 (d, J = 5.2 Hz, 1H), 7.94-7.90 (m, 1H), 7.55 (d, J = 5.2 Hz, 1H), 7.51 (d, J = 6.8 Hz, 1H), 6.99 (d, J = 8.8 Hz, 1H), 4.90-4.82 (m, 1H), 4.70 (t, J = 6.8 Hz, 2H), 4.55 (t, J = 6.8 Hz, 2H), 3.90 (br s, 1H), 3.21 (t, J = 6.8 Hz, 2H), 2.14-2.11 (m, 2H), 1.84-1.81 (m, 2H), 1.60 (br s, 1H), 1.26-1.05 (m, 4H). 19 F NMR (400 MHz, DMSO-d6): δ ppm -100.00. MS: [M+H] + = 518.1.

[0425] Biological assays Compounds of the invention can be evaluated for their ability to inhibit PRC2 using the assays described below and other assays known in the art.

[0426] 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.

[0427] 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.

[0428] 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.

[0429] 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.

[0430] 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.

[0431] 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.

[0432] 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.

[0433] 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.

[0434] [Table 3-1]

[0435] [Table 3-2]

[0436] Table 4 below shows the antiproliferative activity (IC) in B-cell lymphoma cells KARPAS422 after 14 days of treatment for the following examples: 50 Enter the value.

[0437] [Table 4]

[0438] 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 of formula (I), or a stereoisomer, enantiomer, enantiomeric mixture, or pharmaceutically acceptable salt thereof: [ka] [In the formula, Y is N or CR 4 and; R 1 、R 3 and R 4 are independently H, halogen or -C 1 ~C 4 is alkyl; R 2 -CN, -C 1 ~C 6 Alkyl, -hydroxyC 1 ~C 4 Alkylene, -N(C 1 ~C 4 alkyl) 2 -C replaced with 1 ~C 6 Alkyl;-C 1 ~C 4 Alkoxy, -C substituted with 1-2 hydroxyl or cyano 2 ~C 4 Alkoxy; -NH 2 , -NR 11 C(=O)R 15 , -C(=O)NH 2 , -(CH 2 ) n R 15 、-R 15 , -NHC(=O)R 11 , -NR 12 C(=O)OR 11 , -C(=O)NR 11 R 12 , -(CH 2 ) n C(=O)NR 11 R 12 , -(CH 2 ) n NR 11 R 15 , -(CH 2 ) n C(=O)NR 11 R 15 , -C(=O)NR 11 R 15 , -CR 13 R 14 C(=O)NR 11 R 15 , -OCR 11 R 12 R 13 , -(CH 2 ) n C(=O)R 15 , -C(=O)R 15 , -CR 13 R 14 C(=O)R 15 , -(CH 2 ) n NR 11 C(=O)R 15 , -(CH 2 ) n NR 11 (CH 2 ) 2 C(=O)R 15 , -NR 12 C(=O)(CH 2 ) 2 C(=O)R 15 , -(CH 2 ) n OR 15 , -(CH 2 ) n NR 11 C(=O)OCH 2 R 15 , -NR 11 C(=O)OCH 2 R 15 , -(CH 2 ) n NR 11 (CH 2 ) n R 15 、

change

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change

change

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change

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[10] The compound according to [6], which is represented by formula (II-2), or a stereoisomer, enantiomer, enantiomeric mixture, or pharmaceutically acceptable salt thereof.

change

[11] R 11 But, H, -C 1~C 4 Alkyl, or one R b -C replaced with 1 ~C 4 alkyl; R b -CN, -OH or -OCH 3 The compound according to any one of [1], [3] to [6] and [9] to

[10] , wherein:

[12] R 13 H, F, -CN, -OH, -CH 3 or -CH 2 1. The compound according to any one of [1], [3] to [6] and [9] to

[11] , wherein R is OH, or a stereoisomer, enantiomer, enantiomeric mixture or pharmaceutically acceptable salt thereof.

[13] R 14 is H, F or -CH 3 The compound according to any one of [1], [3] to [6] and [9] to

[12] , wherein:

[14] R 15 is azetidinyl or oxetanyl, each of which is unsubstituted or is selected from the group consisting of —OH, —C 1 ~C 4 Alkyl or -hydroxy C 1 ~C 4 A compound according to any one of [9] to

[13] , or a stereoisomer, enantiomer, enantiomeric mixture or pharmaceutically acceptable salt thereof, which is substituted with alkylene.

[15] R 15 but,

change

[14] The compound according to

[14] , or a stereoisomer, enantiomer, enantiomeric mixture or pharmaceutically acceptable salt thereof.

[16] R 15 but,

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[14] The compound according to

[14] , wherein:

[17] N 2 -(((1,4-trans)-4-((8-methoxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)pyrimidine-2,5-diamine; N-(2-((((1,4-trans)-4-((8-methoxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)azetidine-3-carboxamide; N-(2-((((1,4-trans)-4-((8-methoxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-1-methylazetidine-3-carboxamide; 2-((((1,4-trans)-4-((8-methoxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidine-5-carbonitrile; 2-((((1,4-trans)-4-((8-methoxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidine-5-carboxamide; N-(2-((((1,4-trans)-4-((8-methoxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)acetamide; 2-hydroxy-N-(2-((((1,4-trans)-4-((8-methoxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)acetamide; (2-((((1,4-trans)-4-((8-methoxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)(piperazin-1-yl)methanone; N-(2-hydroxypropyl)-2-((((1,4-trans)-4-((8-methoxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidine-5-carboxamide; (2-((((1,4-trans)-4-((8-methoxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)(morpholino)methanone; (2-((((1,4-trans)-4-((8-methoxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)(4-methylpiperazin-1-yl)methanone; N-((1,4-trans)-4-(((5-(1H-1,2,4-triazol-5-yl)pyrimidin-2-yl)amino)methyl)cyclohexyl)-8-methoxy-1,7-naphthyridin-2-amine; 2-(2-((((1,4-trans)-4-((8-methoxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-(oxetan-3-yl)acetamide; N 2 -(((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)pyrimidine-2,5-diamine; Methyl (2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)carbamate; 2-Methoxyethyl(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)carbamate; 2-Hydroxyethyl(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)carbamate; Oxetan-3-ylmethyl(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)carbamate; N-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-2-hydroxyacetamide; N-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-4-morpholino-4-oxobutanamide; 2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidine-5-carbonitrile; (2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)(morpholino)methanone; (2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)(piperazin-1-yl)methanone; 2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)-N-(oxetan-3-yl)pyrimidine-5-carboxamide; 8-chloro-N-((1,4-trans)-4-(((5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyrimidin-2-yl)amino)methyl)cyclohexyl)-1,7-naphthyridin-2-amine; 8-chloro-N-((1,4-trans)-4-(((5-((oxetan-3-ylamino)methyl)pyrimidin-2-yl)amino)methyl)cyclohexyl)-1,7-naphthyridin-2-amine; 8-chloro-N-((1,4-trans)-4-(((5-(((3-methyloxetan-3-yl)amino)methyl)pyrimidin-2-yl)amino)methyl)cyclohexyl)-1,7-naphthyridin-2-amine; 1-((2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)methyl)azetidin-3-ol; 4-((2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)methyl)thiomorpholine 1,1-dioxide; 8-chloro-N-((1,4-trans)-4-(((5-(((oxetan-3-ylmethyl)amino)methyl)pyrimidin-2-yl)amino)methyl)cyclohexyl)-1,7-naphthyridin-2-amine; 8-chloro-N-((1,4-trans)-4-(((5-(((3-methoxycyclobutyl)amino)methyl)pyrimidin-2-yl)amino)methyl)cyclohexyl)-1,7-naphthyridin-2-amine; 3-(((2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)methyl)amino)cyclobutan-1-ol; (2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-1,3-dioxan-5-yl)methanol; 8-chloro-N-((1,4-trans)-4-(((5-((oxetan-3-yloxy)methyl)pyrimidin-2-yl)amino)methyl)cyclohexyl)-1,7-naphthyridin-2-amine; 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-(oxetan-3-yl)acetamide; 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-methyl-N-(oxetan-3-yl)acetamide; 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-1-(3-hydroxyazetidin-1-yl)ethan-1-one; 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-1-(3-(dimethylamino)pyrrolidin-1-yl)ethan-1-one; 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-1-(4-(2-hydroxyethyl)piperazin-1-yl)ethan-1-one; 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-1-(piperazin-1-yl)ethan-1-one; 2-(6-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyridin-3-yl)-N-(oxetan-3-yl)acetamide; 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-1-(4-methylpiperazin-1-yl)ethan-1-one; 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-cyclobutylacetamide; 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-1-(4-(2-methoxyethyl)piperazin-1-yl)ethan-1-one; 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)ethan-1-ol; 8-chloro-N-((1,4-trans)-4-(((5-(2-((3-methyloxetan-3-yl)amino)ethyl)pyrimidin-2-yl)amino)methyl)cyclohexyl)-1,7-naphthyridin-2-amine; 8-chloro-N-((1,4-trans)-4-(((5-(2-(oxetan-3-ylamino)ethyl)pyrimidin-2-yl)amino)methyl)cyclohexyl)-1,7-naphthyridin-2-amine; 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-(2-cyanoethyl)-N-(oxetan-3-yl)acetamide; 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-(2-cyanoethyl)-N-ethylacetamide; 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-(2-hydroxyethyl)-N-(oxetan-3-yl)acetamide; 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-(oxetan-3-yl)propanamide; (S)-2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-(oxetan-3-yl)propanamide; (R)-2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-(oxetan-3-yl)propanamide; 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-methyl-N-(oxetan-3-yl)propanamide; (S)-2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-methyl-N-(oxetan-3-yl)propanamide; (R)-2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-methyl-N-(oxetan-3-yl)propanamide; N-((2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)methyl)azetidine-2-carboxamide; N-((2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)methyl)oxetane-3-carboxamide; 2-((((1,4-trans)-4-((8-(methylamino)-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidine-5-carbonitrile; 2-((((1,4-trans)-4-((8-(methylamino)-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidine-5-carboxamide; N 2 -((1,4-trans)-4-(((5-aminopyrimidin-2-yl)amino)methyl)cyclohexyl)-N 8 -methyl-1,7-naphthyridine-2,8-diamine; N-(2-((((1,4-trans)-4-((8-(methylamino)-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)acetamide; 3-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)oxazolidin-2-one; Methyl(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)(methyl)carbamate; N 2 -(((1,4-trans)-4-((8-(difluoromethoxy)-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)pyrimidine-2,5-diamine; N-((1,4-trans)-4-(((5-(4H-1,2,4-triazol-3-yl)pyrimidin-2-yl)amino)methyl)cyclohexyl)-8-chloro-1,7-naphthyridin-2-amine; 2-((2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)oxy)propan-1-ol; 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-1-(3-hydroxyazetidin-1-yl)propan-1-one; (S)-2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-1-(3-hydroxyazetidin-1-yl)propan-1-one; (R)-2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-1-(3-hydroxyazetidin-1-yl)propan-1-one; 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-3-hydroxy-N-(oxetan-3-yl)propanamide; (R)-2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-3-hydroxy-N-(oxetan-3-yl)propanamide; (S)-2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-3-hydroxy-N-(oxetan-3-yl)propanamide; (S)-2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-2-hydroxy-N-(oxetan-3-yl)acetamide; (R)-2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-2-hydroxy-N-(oxetan-3-yl)acetamide; and 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-2,2-difluoro-N-(oxetan-3-yl)acetamide; The compound according to [1], or a pharmaceutically acceptable salt thereof, selected from:

[18] A pharmaceutical composition comprising a compound according to any one of [1] to

[17] and a pharmaceutically acceptable carrier.

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

[17] and one or more therapeutically active agents.

[20] The combination according to

[19] , 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.

[21] 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

[17] .

[22] The method of

[21] , 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.

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

[17] , 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 of formula (I) or a stereoisomer, enantiomer, enantiomeric mixture or pharmaceutically acceptable salt thereof 【Chemistry 1】 [In the formula, Y is N or CR ４ and R １ , R ３ and R ４ are independently H, halogen or —C １ ~C ４ is alkyl; R ２ is -CN, -C １ ~C ６ Alkyl, -hydroxy C １ ~C ４ alkylene, —C substituted with one R a １ ~C ６ alkyl [wherein R a is —OH, —CH 2 OH, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, or —N(C 1 -C 4 alkyl) 2 ]; １ ~C ４ Alkoxy, —C substituted with 1 to 2 hydroxyl or cyano ２ ~C ４ Alkoxy; -NH ２ , -NR １１ C(=O)R １５ , —C(═O)NH ２ , -(CH ２ ) ｎ R １５ , -R １５ , -NHC(=O)R １１ , -NR １２ C(=O)OR １１ , —C(═O)NR １１ R １２ , -(CH ２ ) ｎ C(=O)NR １１ R １２ , -(CH ２ ) ｎ NR １１ R １５ , -(CH ２ ) ｎ C(=O)NR １１ R １５ , —C(═O)NR １１ R １５ , -CR １３ R １４ C(=O)NR １１ R １５ , -OCR １１ R １２ R １３ , -(CH ２ ) ｎ C(=O)R １５ , -C(=O)R １５ , -CR １３ R １４ C(=O)R １５ ,-(EH ２ ) ｎ NR １１ C(=O)R １５ ,-(EH ２ ) ｎ NR １１ (CH) ２ ) ２ C(=O)R １５ 、-NR １２ C(=O)(CH) ２ ) ２ C(=O)R １５ ,-(EH ２ ) ｎ OR １５ ,-(EH ２ ) ｎ NR １１ C(=O)OCH ２ R １５ 、-NR １１ C(=O)OCH ２ R １５ ,-(EH ２ ) ｎ NR １１ (CH) ２ ) ｎ R １５ 、 【Chemistry 2】 , or O, S, N and -NR ｃ is a 5- to 6-membered heteroaryl having 1 to 4 ring members independently selected from: R ５ａ , R ５ｂ , R ５ｃ , R ５ｄ and R ｃ are independently H or —C １ ~C ４ is alkyl; R ６ , R ７ , R ８ and R ９ are independently H, halogen 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, —SO ２ (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 １２ is H 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 teeth, 【Transformation 3】 , -C ３ ~C ６ Cycloalkyl, or O, S, S(=O) ２ , N and -NR １１ and -C is a 4- to 6-membered heterocycloalkyl having 1 to 2 ring members independently selected from ３ ~C ６ The cycloalkyl and 4- to 6-membered heterocycloalkyl are independently unsubstituted or are substituted with —OH, —C １ ~C ４ Alkyl, -hydroxy C １ ~C ４ Alkylene, -C １ ~C ４ Alkoxy 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 or -hydroxy C １ ~C ４ alkylene; m is 0, 1 or 2; each n is independently selected from 1 and 2; with the proviso that the compound of formula (I) is not (2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)(4-methylpiperazin-1-yl)methanone, or a stereoisomer, enantiomer, enantiomeric mixture, or pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, wherein the compound is represented by formula (I-4): or a stereoisomer, enantiomer, enantiomeric mixture, or pharmaceutically acceptable salt thereof. 【Chemistry 4】

3. R ２ が、-CN、-NH ２ 、-C(=O)NH ２ 、-NHC(=O)R １１ 、-NR １２ C(=O)OR １１ 、-C(=O)NR １１ R １２ ,-(EH ２ ) ｎ C(=O)NR １１ R １２ ,-(EH ２ ) ｎ NR １１ R １５ ,-(EH ２ ) ｎ C(=O)NR １１ R １５ 、-C(=O)NR １１ R １５ 、-CR １３ R １４ C(=O)NR １１ R １５ 、-OCR １１ R １２ R １３ ,-(EH ２ ) ｎ R １５ 、-NR １２ C(=O)(CH) ２ ) ２ C(=O)R １５ ,-(EH ２ ) ｎ NR １１ C(=O)OCH ２ R １５ 、-NR １１ C(=O)OCH ２ R １５ ,-(EH ２ ) ｎ NR １１ (CH) ２ ) ｎ R １５ ,-(EH ２ ) ｎ C(=O)R １５ 、-CR １３ R １４ C(=O)R １５ ,-(EH ２ ) ｎ NR １１ C(=O)R １５ 、-NR １１ C(=O)R １５ 、-(CH ２ ) ｎ NR １１ (CH ２ ) ２ C(=O)R １５ 、-(CH ２ ) ｎ OR １５ 、 【Transformation 5】 1 R ａ -C substituted with １ ~C ６ alkyl, one R ｂ -C substituted with １ ~C ４ Alkoxy, or N and —NR ｃ 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from ｃ is H or -C １ ~C ４ alkyl); R ａ But -OH, -CH ２ OH, C １ ~C ４ Alkyl, C １ ~C ４ Alkoxy or -N(C １ ~C ４ alkyl) ２ and R ｂ -CN, -OH and C １ ~C ４ independently selected from alkoxy; 3. A compound according to claim 1 or 2, or a stereoisomer, enantiomer, enantiomeric mixture or pharmaceutically acceptable salt thereof.

4. R ２ But -CN, -NH ２ , —C(═O)NH ２ , -NHC(=O)R １１ , -NR １２ C(=O)OR １１ , —C(═O)NR １１ R １２ , -CH ２ C(=O)NR １１ R １２ , triazolyl, 【Transformation 6】 1 R ａ C substituted with a group １ ~C ６ alkyl, or one R ｂ C substituted with a group １ ~C ４ is alkoxy; R ａ But -OH, -CH ２ OH, C １ ~C ４ Alkyl, C １ ~C ４ Alkoxy or -N(C １ ~C ４ alkyl) ２ and R ｂ -CN, -OH and C １ ~C ４ independently selected from alkoxy; 3. A compound according to claim 1 or 2, or a stereoisomer, enantiomer, enantiomeric mixture or pharmaceutically acceptable salt thereof.

5. R ２ But -CH ２ C(=O)NR １１ R １２ , 【Transformation 7】 or one R ａ C substituted with １ ~C ６ is alkyl; R ａ But -OH, -CH ２ OH, C １ ~C ４ Alkyl, C １ ~C ４ Alkoxy or -N(C １ ~C ４ alkyl) ２ That is, 3. A compound according to claim 1 or 2, or a stereoisomer, enantiomer, enantiomeric mixture or pharmaceutically acceptable salt thereof.

6. R ２ but, 【Transformation 8】 and R ａ But -OH, -CH ２ OH, C １ ~C ４ Alkyl, C １ ~C ４ Alkoxy or -N(C １ ~C ４ alkyl) ２ That is, 3. A compound according to claim 1 or 2, or a stereoisomer, enantiomer, enantiomeric mixture or pharmaceutically acceptable salt thereof.

7. R ２ But -CN, -NH ２ , —C(═O)NH ２ , triazolyl, 【Chemistry 9】 5. The compound of any one of claims 1 to 4, wherein:

8. R ２ but, 【Chemistry 10】 7. The compound of any one of claims 1 to 6, wherein:

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

10. The compound according to any one of claims 1, 2, 3 and 9, wherein the compound is represented by formula (II-2), or a stereoisomer, enantiomer, enantiomeric mixture or pharmaceutically acceptable salt thereof. 【Chemistry 12】

11. R １１ But H, -C １ ~C ４ alkyl, or one R ｂ -C substituted with １ ~C ４ alkyl; R ｂ is —CN, —OH or —OCH ３ 11. The compound of any one of claims 1, 3 to 6 and 9 to 10, wherein:

12. R １３ H, F, -CN, -OH, -CH ３ or -CH ２ 12. The compound of any one of claims 1, 3-6 and 9-11, or a stereoisomer, enantiomer, enantiomeric mixture or pharmaceutically acceptable salt thereof, wherein R is 0, 1 or 2;

13. R １４ is H, F or -CH ３ 13. The compound of any one of claims 1, 3 to 6 and 9 to 12, or a stereoisomer, enantiomer, enantiomeric mixture or pharmaceutically acceptable salt thereof, wherein:

14. R １５ is azetidinyl or oxetanyl, each of which is unsubstituted or is selected from the group consisting of —OH, —C １ ~C ４ Alkyl or -hydroxy C １ ~C ４ 11. The compound of claim 9 or 10, or a stereoisomer, enantiomer, enantiomeric mixture, or pharmaceutically acceptable salt thereof, which is substituted with alkylene.

15. R １５ but, 【Chemistry 13】 and R １６ If exists, -C １ ~C ４ alkyl; m is 0 to 1; 15. The compound of claim 14, or a stereoisomer, enantiomer, enantiomeric mixture, or pharmaceutically acceptable salt thereof.

16. R １５ but, 【Chemistry 14】 15. The compound of claim 14, wherein:

17. N ２ -(((1,4-trans)-4-((8-methoxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)pyrimidine-2,5-diamine; N-(2-((((1,4-trans)-4-((8-methoxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)azetidine-3-carboxamide; N-(2-((((1,4-trans)-4-((8-methoxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-1-methylazetidine-3-carboxamide; 2-((((1,4-trans)-4-((8-methoxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidine-5-carbonitrile; 2-((((1,4-trans)-4-((8-methoxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidine-5-carboxamide; N-(2-((((1,4-trans)-4-((8-methoxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)acetamide; 2-hydroxy-N-(2-((((1,4-trans)-4-((8-methoxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)acetamide; (2-((((1,4-trans)-4-((8-methoxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)(piperazin-1-yl)methanone; N-(2-hydroxypropyl)-2-((((1,4-trans)-4-((8-methoxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidine-5-carboxamide; (2-((((1,4-trans)-4-((8-methoxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)(morpholino)methanone; (2-((((1,4-trans)-4-((8-methoxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)(4-methylpiperazin-1-yl)methanone; N-((1,4-trans)-4-(((5-(1H-1,2,4-triazol-5-yl)pyrimidin-2-yl)amino)methyl)cyclohexyl)-8-methoxy-1,7-naphthyridin-2-amine; 2-(2-((((1,4-trans)-4-((8-methoxy-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-(oxetan-3-yl)acetamide; N ２ -(((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)pyrimidine-2,5-diamine; Methyl (2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)carbamate; 2-Methoxyethyl(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)carbamate; 2-hydroxyethyl(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)carbamate; Oxetan-3-ylmethyl(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)carbamate; N-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-2-hydroxyacetamide; N-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-4-morpholino-4-oxobutanamide; 2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidine-5-carbonitrile; (2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)(morpholino)methanone; (2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)(piperazin-1-yl)methanone; 2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)-N-(oxetan-3-yl)pyrimidine-5-carboxamide; 8-chloro-N-((1,4-trans)-4-(((5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyrimidin-2-yl)amino)methyl)cyclohexyl)-1,7-naphthyridin-2-amine; 8-chloro-N-((1,4-trans)-4-(((5-((oxetan-3-ylamino)methyl)pyrimidin-2-yl)amino)methyl)cyclohexyl)-1,7-naphthyridin-2-amine; 8-chloro-N-((1,4-trans)-4-(((5-(((3-methyloxetan-3-yl)amino)methyl)pyrimidin-2-yl)amino)methyl)cyclohexyl)-1,7-naphthyridin-2-amine; 1-((2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)methyl)azetidin-3-ol; 4-((2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)methyl)thiomorpholine 1,1-dioxide; 8-chloro-N-((1,4-trans)-4-(((5-(((oxetan-3-ylmethyl)amino)methyl)pyrimidin-2-yl)amino)methyl)cyclohexyl)-1,7-naphthyridin-2-amine; 8-chloro-N-((1,4-trans)-4-(((5-(((3-methoxycyclobutyl)amino)methyl)pyrimidin-2-yl)amino)methyl)cyclohexyl)-1,7-naphthyridin-2-amine; 3-(((2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)methyl)amino)cyclobutan-1-ol; (2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-1,3-dioxan-5-yl)methanol; 8-chloro-N-((1,4-trans)-4-(((5-((oxetan-3-yloxy)methyl)pyrimidin-2-yl)amino)methyl)cyclohexyl)-1,7-naphthyridin-2-amine; 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-(oxetan-3-yl)acetamide; 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-methyl-N-(oxetan-3-yl)acetamide; 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-1-(3-hydroxyazetidin-1-yl)ethan-1-one; 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-1-(3-(dimethylamino)pyrrolidin-1-yl)ethan-1-one; 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-1-(4-(2-hydroxyethyl)piperazin-1-yl)ethan-1-one; 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-1-(piperazin-1-yl)ethan-1-one; 2-(6-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyridin-3-yl)-N-(oxetan-3-yl)acetamide; 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-1-(4-methylpiperazin-1-yl)ethan-1-one; 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-cyclobutylacetamide; 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-1-(4-(2-methoxyethyl)piperazin-1-yl)ethan-1-one; 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)ethan-1-ol; 8-chloro-N-((1,4-trans)-4-(((5-(2-((3-methyloxetan-3-yl)amino)ethyl)pyrimidin-2-yl)amino)methyl)cyclohexyl)-1,7-naphthyridin-2-amine; 8-chloro-N-((1,4-trans)-4-(((5-(2-(oxetan-3-ylamino)ethyl)pyrimidin-2-yl)amino)methyl)cyclohexyl)-1,7-naphthyridin-2-amine; 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-(2-cyanoethyl)-N-(oxetan-3-yl)acetamide; 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-(2-cyanoethyl)-N-ethylacetamide; 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-(2-hydroxyethyl)-N-(oxetan-3-yl)acetamide; 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-(oxetan-3-yl)propanamide; (S)-2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-(oxetan-3-yl)propanamide; (R)-2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-(oxetan-3-yl)propanamide; 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-methyl-N-(oxetan-3-yl)propanamide; (S)-2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-methyl-N-(oxetan-3-yl)propanamide; (R)-2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-methyl-N-(oxetan-3-yl)propanamide; N-((2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)methyl)azetidine-2-carboxamide; N-((2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)methyl)oxetane-3-carboxamide; 2-((((1,4-trans)-4-((8-(methylamino)-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidine-5-carbonitrile; 2-((((1,4-trans)-4-((8-(methylamino)-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidine-5-carboxamide; N ２ -((1,4-trans)-4-(((5-aminopyrimidin-2-yl)amino)methyl)cyclohexyl)-N ８ -methyl-1,7-naphthyridine-2,8-diamine; N-(2-((((1,4-trans)-4-((8-(methylamino)-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)acetamide; 3-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)oxazolidin-2-one; Methyl (2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)(methyl)carbamate; N ２ -(((1,4-trans)-4-((8-(difluoromethoxy)-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)pyrimidine-2,5-diamine; N-((1,4-trans)-4-(((5-(4H-1,2,4-triazol-3-yl)pyrimidin-2-yl)amino)methyl)cyclohexyl)-8-chloro-1,7-naphthyridin-2-amine; 2-((2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)oxy)propan-1-ol; 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-1-(3-hydroxyazetidin-1-yl)propan-1-one; (S)-2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-1-(3-hydroxyazetidin-1-yl)propan-1-one; (R)-2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-1-(3-hydroxyazetidin-1-yl)propan-1-one; 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-3-hydroxy-N-(oxetan-3-yl)propanamide; (R)-2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-3-hydroxy-N-(oxetan-3-yl)propanamide; (S)-2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-3-hydroxy-N-(oxetan-3-yl)propanamide; (S)-2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-2-hydroxy-N-(oxetan-3-yl)acetamide; (R)-2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-2-hydroxy-N-(oxetan-3-yl)acetamide; and 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-2,2-difluoro-N-(oxetan-3-yl)acetamide; 2. The compound of claim 1 selected from:

18. (R)-2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-1-(3-hydroxyazetidin-1-yl)propan-1-one; 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-3-hydroxy-N-(oxetan-3-yl)propanamide; 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-(oxetan-3-yl)acetamide; 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-(oxetan-3-yl)propanamide; (S)-2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-(oxetan-3-yl)propanamide; (R)-2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-(oxetan-3-yl)propanamide; 18. The compound of claim 17 selected from: or a pharmaceutically acceptable salt thereof.

19. 19. The compound of claim 18, which is (R)-2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-1-(3-hydroxyazetidin-1-yl)propan-1-one, or a pharmaceutically acceptable salt thereof.

20. 19. The compound of claim 18, which is 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-3-hydroxy-N-(oxetan-3-yl)propanamide, or a pharmaceutically acceptable salt thereof.

21. 19. The compound of claim 18, which is 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-(oxetan-3-yl)acetamide, or a pharmaceutically acceptable salt thereof.

22. 19. The compound of claim 18, which is (S)-2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-(oxetan-3-yl)propanamide, or a pharmaceutically acceptable salt thereof.

23. 19. The compound of claim 18, which is (R)-2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-(oxetan-3-yl)propanamide, or a pharmaceutically acceptable salt thereof.

24. The compound of claim 18, which is 2-(2-((((1,4-trans)-4-((8-chloro-1,7-naphthyridin-2-yl)amino)cyclohexyl)methyl)amino)pyrimidin-5-yl)-N-(oxetan-3-yl)propanamide, or a pharmaceutically acceptable salt thereof.

25. 25. A pharmaceutical composition comprising a compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

26. 25. A combination comprising a compound according to any one of claims 1 to 24 or a pharmaceutically acceptable salt thereof and one or more therapeutically active agents.

27. 27. The combination of claim 26, 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.

28. 25. A pharmaceutical composition comprising a compound according to any one of claims 1 to 24 or a 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).

29. 29. The pharmaceutical composition of claim 28, 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.

30. 26. Use of a compound of any one of claims 1 to 24 or a 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).

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