Purine ring-containing compound and use thereof

Abstract

Provided are a compound for treating or preventing hypersensitivity or autoimmune inflammation-related diseases, and the use and a method for treating or preventing the hypersensitivity or autoimmune inflammation-related diseases in a subject. The compound is a compound of formula (I) or a pharmaceutically acceptable salt, solvate, isomer, ester, acid, metabolite or prodrug thereof.

Description

Compounds containing purine ring and uses thereof Technical Field

[0001] The present invention relates to the field of medicine, and in particular to a compound for treating hypersensitivity reaction or autoimmune inflammatory-related diseases, and its use and treatment method. Technical Background

[0002] Inflammatory bowel disease (IBD) is a chronic, relapsing inflammatory disease, the most common of which include ulcerative colitis (UC) and Crohn's disease (CD). According to 2014 data from the Chinese Center for Disease Control and Prevention, the number of IBD patients in China between 2005 and 2014 was approximately 350,000, and by 2025, the number of IBD patients in China is expected to reach 1.5 million.

[0003] Macrophages are the body's first line of defense against foreign antigens and play a crucial role in maintaining homeostasis and regulating inflammation. In a healthy intestine, M2 macrophages, or circulating monocytes, are recruited to the intestine and clear apoptotic epithelial cells and infiltrating bacteria, thereby maintaining intestinal homeostasis. In models of inflammatory bowel disease, peripheral circulating monocytes infiltrating the inflamed intestinal mucosa differentiate into M1 macrophages, secreting inflammatory cytokines that enhance the immune response and exacerbate the inflammatory symptoms of colitis. Phosphoglyceraldehyde kinase 1 (PGK1) is a key enzyme in glycolysis. It catalyzes the transfer of the 1-phosphate of 1,3-bisphosphoglycerate (1,3-BPG) to adenosine diphosphate (ADP), generating adenosine triphosphate (ATP), the first step in ATP production. PGK1 plays a crucial role in maintaining normal intracellular metabolism, redox balance, and DNA repair and replication. Studies have shown that PGK1 can regulate the expression of pro-inflammatory factors: IL-1β and IL-6 in macrophages. Inhibiting PGK1 can reduce the accumulation of NRF2 (nuclear factor-erythroid factor 2-related factor 2, NFE2L2) in the cytoplasm. NRF2 translocates to the nucleus and binds to the proximal region of the IL-1β and IL-6 genes, thereby inhibiting the secretion of inflammatory factors IL-1β and IL-6 (A potent PGK1 antagonist reveals PGK1 regulates the production of IL-1βand IL-6, Liping Liao et al., Acta Pharm Sin B, Vol. 12, Issue 11, 4180-4192, 2022). Therefore, PGK1 is a potential target for the treatment of inflammatory bowel disease.

[0004] Current treatments for inflammatory bowel disease include non-targeted therapies (such as aminosalicylic acid, glucocorticoids, and immunomodulators) and targeted therapies (such as anti-TNF, anti-IL-12 / IL-23, and anti-α4β7 integrin). Although biological targeted therapies are effective for many patients, up to 30% of patients still do not respond to initial treatment, and up to 50% of patients lose their response over time. Currently, the latest advances in molecular biology and the understanding of IBD immune pathways have opened up new possibilities for innovative drug therapies. Therefore, finding new targets and effective drugs is expected to break the bottleneck of IBD treatment and bring good news to patients with IBD. Summary of the Invention

[0005] The present disclosure provides novel PGK1 protein inhibitors and their use in treating and / or preventing diseases regulated by or affected by PGK1 protein activity or involving PGK1 protein activity or overexpression. The present disclosure provides a series of compounds with promising therapeutic effects and application prospects for hypersensitivity reactions or autoimmune inflammatory disorders.

[0006] In one aspect of the present invention, there is provided a compound of formula (I) or a pharmaceutically acceptable salt, solvate, isomer, ester, acid, metabolite or prodrug thereof,

[0007] in,

[0008] X is carbon or nitrogen,

[0009] R 1 Each is independently selected from amino, hydroxy, nitrile, halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, and C1-6 alkylsulfonyl, wherein n is 2 or 3;

[0010] R 2 Selected from C1-6 alkyl, C3-6 cycloalkyl, C3-6 cycloalkylC1-4 alkyl, C1-4 alkoxyC1-4 alkyl, C1-6 haloalkyl, C3-6 halocycloalkylC1-4 alkyl, C1-4 alkylaminoacylC1-C4 alkyl, and C2-6 dialkylaminoacylC1-C4 alkyl;

[0011] Y is selected from C1-6 alkyl, C3-6 cycloalkyl, C3-6 cycloalkylC1-4 alkyl, C3-6 cycloalkenyl, phenyl, four to six membered heterocyclyl, and four to six membered heterocyclylC1-4 alkyl;

[0012] R 3 each independently selected from hydroxy, amino, nitrile, oxo, carboxyl, aminoacyl, halogen, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 hydroxyalkylamino, C1-6 alkylamido, C1-6 alkylaminoacyl, C1-4 alkoxyC1-4 alkylamino, C1-4 hydroxyalkoxyC1-4 alkylamino, C1-6 alkylsulfonylamino, phenylC1-4 alkylamino, and four to six-membered heterocyclyl, wherein m is 0, 1, 2 or 3;

[0013] wherein the four to six-membered heterocyclic groups are each independently selected from piperidinyl, morpholinyl, piperazinyl, tetrahydrofuranyl, oxetanyl, and imidazolidinyl.

[0014] In a preferred embodiment, X is carbon, and relative to the amino linking group of the benzene ring, R 1 The position on the benzene ring is meta and / or para.

[0015] More preferably, relative to the amino linking group of the benzene ring, the para position of the benzene ring has no substituent or the R 1 is selected from halogen and C1-3 alkoxy. In addition, preferably, relative to the amino linking group of the benzene ring, R 1 Each is independently selected from nitrile, halogen, C1-3 alkoxy, C1-3 haloalkyl, and C1-3 haloalkoxy.

[0016] In another preferred embodiment, R 2 is selected from C3-6 alkyl, C3-6 cycloalkyl, C3-6 cycloalkylC1-3 alkyl, C1-3 alkoxyC1-3 alkyl, C1-3 haloalkyl, C1-3 alkylaminoacylC1-C3 alkyl, and C2-4 dialkylaminoacylC1-C3 alkyl. Particularly preferably, R 2 Selected from isopropyl and cyclopropyl.

[0017] In a further embodiment, Y is C2-5 alkyl, and R 3 Each is independently selected from hydroxy, amino, carboxyl, halogen, C1-3 alkyl, and C1-3 alkylaminoacyl, and m is 1 or 2.

[0018] In another embodiment, the compound of the present invention has the structure of Formula (II):

[0019] Among them, R 1 、R 2 、R 3 , m and n are as defined above.

[0020] Preferably, m is 1 or 2, more preferably 1.

[0021] In addition, preferably, R 3 Each is independently selected from hydroxyl, amino, nitrile, oxo, carboxyl, C1-3 alkyl, C1-3 hydroxyalkyl, C1-3 hydroxyalkylamino, C1-3 alkylamide, C1-3 alkoxy C1-3 alkylamino, C1-3 hydroxyalkoxy C1-3 alkylamino, C1-3 alkylsulfonylamino, phenyl C1-3 alkylamino, morpholinyl, and piperidinyl. Further preferably, R 3 Each is independently selected from hydroxy, amino, C1-3 alkyl, C1-3 hydroxyalkyl, C1-3 hydroxyalkylamino, and C1-3 alkoxy C1-3 alkylamino.

[0022] In another aspect, the present disclosure relates to a pharmaceutical composition comprising a compound of the present invention, or a pharmaceutically acceptable salt, solvate, isomer, ester, acid, metabolite or prodrug thereof, and a pharmaceutically acceptable carrier or excipient, and optionally other therapeutic agents.

[0023] In other aspects, the present disclosure relates to the use of the aforementioned PGK1 protein inhibitors in the preparation of medicaments for treating or preventing hypersensitivity reactions or autoimmune inflammatory diseases, particularly diseases regulated or affected by PGK1 protein activity or in which PGK1 protein activity or overexpression is involved, more preferably diseases associated with high expression and / or overactivation of PGK1. Preferably, hypersensitivity reactions or autoimmune inflammatory diseases include, but are not limited to, allergic rhinitis, asthma, atopic dermatitis, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, psoriasis, immune thrombocytopenic purpura, inflammatory bowel disease, chronic obstructive pulmonary disease, Sjögren's syndrome, pemphigus vulgaris, idiopathic plasmacytoid lymphadenopathy, atherosclerosis, myocardial infarction and thrombosis, and combinations thereof.

[0024] In another aspect, the present disclosure relates to a method for treating or preventing hypersensitivity reactions or autoimmune inflammatory-related diseases, comprising administering to a subject a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, solvate, isomer, ester, acid, metabolite or prodrug thereof, or a pharmaceutical composition of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] FIG1 shows the changes in body weight of mice in the blank group, vehicle group and drug group during the drug administration period in the enteritis model.

[0026] FIG2 shows the results of measuring the colon length of mice in the blank group, vehicle group, and drug group after administration in the enteritis model.

[0027] FIG3 shows the results of colon DAI scores of mice in the blank group, vehicle group, and drug group after administration in the enteritis model.

[0028] FIG4 shows the results of testing the levels of inflammatory factor IL-1β in the serum of mice in the blank group, vehicle group, and drug group after administration in the enteritis model.

[0029] FIG5 shows the results of testing the content of inflammatory factor IL-6 in the serum of mice in the blank group, vehicle group and drug group after administration in the enteritis model. DETAILED DESCRIPTION

[0030] the term

[0031] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs.

[0032] The term "alkyl" refers to an aliphatic hydrocarbon group, which can be a branched or straight chain alkyl group. Depending on the structure, the alkyl group can be a monovalent group or a divalent group (i.e., an alkylidene group). In the present invention, the alkyl group is preferably an alkyl group having 1 to 8 carbon atoms, more preferably a "low alkyl group" having 1 to 6 carbon atoms, and even more preferably an alkyl group having 1 to 4 carbon atoms. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, amyl, hexyl, etc. It should be understood that "alkyl" mentioned herein includes all possible configurations and conformations of the alkyl group, for example, "propyl" mentioned herein includes n-propyl and isopropyl, "butyl" includes n-butyl, isobutyl and tert-butyl, and "pentyl" includes n-pentyl, isopentyl, neopentyl, tert-pentyl, and penta-3-yl, etc.

[0033] The term "alkoxy" refers to an -O-alkyl group, wherein alkyl is as defined herein. Typical alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, and the like.

[0034] The term "alkoxyalkyl" refers to an alkyl group, as defined herein, substituted by an alkoxy group, as defined herein.

[0035] The term "cycloalkyl" refers to a monocyclic or polycyclic radical containing only carbon and hydrogen. Cycloalkyl includes a group having 3-12 ring atoms. According to structure, cycloalkyl can be a monovalent group or a divalent group (e.g., cycloalkylidene). In the present invention, cycloalkyl is preferably a cycloalkyl having 3-8 carbon atoms, more preferably a "low cycloalkyl" having 3-6 carbon atoms. The example of cycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and adamantyl.

[0036] The term "alkyl (cycloalkyl)" or "cycloalkylalkyl" refers to an alkyl group as defined herein substituted with a cycloalkyl group as defined herein. Non-limiting examples of cycloalkylalkyl include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, and the like.

[0037] The term "aromatic" refers to a planar ring having a delocalized π electron system and containing 4n+2 π electrons, where n is an integer. The aromatic ring can be composed of five, six, seven, eight, nine, or more than nine atoms. The aromatic group can be optionally substituted. The term "aromatic" includes carbocyclic aromatic groups (e.g., phenyl) and heterocyclic aromatic (or "heteroaryl" or "heteroaromatic") groups (e.g., pyridine). The term includes monocyclic or fused-ring polycyclic (i.e., rings that share adjacent pairs of carbon atoms) groups.

[0038] As used herein, the term "aryl" refers to an aromatic ring in which each of the atoms forming the ring is a carbon atom. The aryl ring can be composed of five, six, seven, eight, nine, or more than nine atoms. An aryl group can be optionally substituted. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, phenanthrenyl, anthracenyl, fluorenyl, and indenyl. Depending on the structure, an aryl group can be a monovalent group or a divalent group (i.e., an arylene group).

[0039] The term "aryloxy" refers to an -O-aryl group, wherein aryl is as defined herein.

[0040] The term "heteroaryl" refers to an aromatic group that includes one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur. The N-containing "heteroaryl" moiety refers to an aromatic group in which at least one skeletal atom on the ring is a nitrogen atom. Depending on the structure, a heteroaryl group can be a monovalent group or a divalent group (i.e., a heteroarylidene group). Examples of heteroaryl groups include, but are not limited to, pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolyl, isoquinolyl, indolyl, benzimidazolyl, benzofuranyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, isoindole, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl, naphthyridinyl, and furopyridinyl.

[0041] The term "alkyl (aryl)" or "aralkyl" refers to an alkyl group as defined herein substituted with an aryl group as defined herein. Non-limiting examples of alkyl (aryl) groups include benzyl, phenethyl, and the like.

[0042] The term "alkyl(heteroaryl)" or "heteroarylalkyl" means an alkyl group, as defined herein, substituted with a heteroaryl group, as defined herein.

[0043] As used herein, the term "heteroalkyl" refers to an alkyl group as defined herein where one or more of the backbone chain atoms is a heteroatom, such as oxygen, nitrogen, sulfur, silicon, phosphorus, or a combination thereof. The heteroatom(s) may be located at any position within the heteroalkyl group or at the position where the heteroalkyl group is attached to the rest of the molecule.

[0044] As used herein, the term "heterocycloalkyl" or "heterocyclyl" refers to a non-aromatic ring in which one or more of the atoms forming the ring are heteroatoms selected from nitrogen, oxygen, and sulfur. The heterocycloalkyl ring can be a monocyclic or polycyclic ring consisting of three, four, five, six, seven, eight, nine, or more than nine atoms. The heterocycloalkyl ring can be optionally substituted. Examples of heterocycloalkyls include, but are not limited to, lactams, lactones, cyclic imines, cyclic thioimides, cyclic carbamates, tetrahydrothiopyran, 4H-pyran, tetrahydropyran, piperidine, 1,3-dioxin, 1,3-dioxane, 1,4-dioxin, 1,4-dioxane, piperazine, 1,3-oxathiinane, 1,4-oxathiinane, 1,4-oxathiinane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbital Acid, dioxopiperazine, hydantoin, dihydrouracil, morpholine, trioxane, hexahydro-1,3,5-triazine, tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine, imidazolidine, pyrrolidone, pyrazoline, pyrazolidine, imidazolidine, imidazolidine, 1,3-dioxole, 1,3-dioxolane, 1,3-dithiole, 1,3-dithiolane, isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine and 1,3-oxathiolane. Depending on the structure, the heterocycloalkyl group can be a monovalent group or a divalent group (i.e., a heterocycloalkylene group).

[0045] The term "alkyl(heterocycloalkyl)" or "heterocycloalkylalkyl" means an alkyl group, as defined herein, substituted with a heterocycloalkyl group, as defined herein.

[0046] The term "alkoxy(heterocycloalkyl)" or "heterocycloalkylalkoxy" means an alkoxy group, as defined herein, substituted with a heterocycloalkyl group, as defined herein.

[0047] The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

[0048] The terms "haloalkyl," "haloalkoxy," and "haloheteroalkyl" include structures of alkyl, alkoxy, or heteroalkyl groups in which at least one hydrogen atom is replaced by a halogen atom. In certain embodiments, if two or more hydrogen atoms are replaced by halogen atoms, the halogen atoms may be the same or different from one another.

[0049] The term "hydroxy" refers to an -OH group.

[0050] The term "cyano" refers to a -CN group.

[0051] The term "ester group" refers to a chemical moiety having the formula -COOR, where R is selected from alkyl, cycloalkyl, aryl, heteroaryl (attached through a ring carbon), and heterocyclyl (attached through a ring carbon).

[0052] The term "amino" refers to a -NH2 group.

[0053] The term "aminoacyl" refers to a -CO-NH2 group.

[0054] The term "alkylaminoacyl" means a -CO-NH-R group, wherein R is alkyl as defined herein.

[0055] The term "amido" or "amido" refers to a -NR-CO-R' group, wherein R and R' are each independently hydrogen or alkyl.

[0056] The term "alkylamino" refers to an amino substituent further substituted with one or two alkyl groups, and specifically refers to the group -NRR', wherein R and R' are each independently selected from hydrogen or lower alkyl, with the proviso that -NRR' is not -NH2. "Alkylamino" includes radicals of compounds wherein the nitrogen of -NH2 is attached to at least one alkyl group. Examples of alkylamino groups include, but are not limited to, methylamino, ethylamino, and the like. "Dialkylamino" includes radicals wherein the nitrogen of -NH2 is attached to at least two other alkyl groups. Examples of dialkylamino groups include, but are not limited to, dimethylamino, diethylamino, and the like.

[0057] The terms "arylamino" and "diarylamino" refer to amino substituents further substituted with one or two aryl groups, specifically the group -NRR', where R and R' are each independently selected from hydrogen, lower alkyl, or aryl, wherein N is attached to at least one or two aryl groups, respectively.

[0058] The term "cycloalkylamino" refers to an amino substituent further substituted with one or two cycloalkyl groups as defined herein.

[0059] The term "heteroalkylamino" refers to an amino substituent further substituted with one or two heteroalkyl groups as defined herein.

[0060] The term "aralkylamino" herein refers to the group -NRR' wherein R is lower aralkyl and R' is hydrogen, lower alkyl, aryl or lower aralkyl.

[0061] The term "heteroarylamino" refers to an amino substituent further substituted with one or two heteroaryl groups as defined herein.

[0062] The term "heterocycloalkylamino" refers to an amino group, as defined herein, substituted with a heterocycloalkyl group, as defined herein.

[0063] The term "alkylaminoalkyl" means an alkyl group, as defined herein, substituted with an alkylamino group, as defined herein.

[0064] The term "aminoalkyl" refers to an alkyl substituent further substituted with one or more amino groups.

[0065] The term "aminoalkoxy" refers to an alkoxy substituent further substituted with one or more amino groups.

[0066] The term "hydroxyalkyl" or "hydroxyalkyl" refers to an alkyl substituent further substituted with one or more hydroxy groups.

[0067] The term "cyanoalkyl" refers to an alkyl substituent further substituted with one or more cyano groups.

[0068] The term "acyl" refers to a monovalent atomic group remaining after removing a hydroxyl group from an organic or inorganic oxygen-containing acid, and has the general formula RM(O)-, where M is usually C.

[0069] The term "carbonyl" refers to an organic functional group composed of two atoms, carbon and oxygen, connected by a double bond (C=O).

[0070] The term "alkanoyl" or "alkylcarbonyl" refers to a carbonyl group further substituted with an alkyl group. Typical alkanoyl groups include, but are not limited to, acetyl, propionyl, butyryl, valeryl, hexanoyl, and the like.

[0071] The term "arylcarbonyl" means a carbonyl group, as defined herein, substituted with an aryl group, as defined herein.

[0072] The term "alkoxycarbonyl" refers to a carbonyl group further substituted with an alkoxy group.

[0073] The term "heterocycloalkylcarbonyl" refers to a carbonyl group further substituted with a heterocycloalkyl group.

[0074] The terms "alkylaminocarbonyl," "cycloalkylaminocarbonyl," "arylaminocarbonyl," "aralkylaminocarbonyl," and "heteroarylaminocarbonyl" refer to a carbonyl group, as defined herein, substituted with an alkylamino group, a cycloalkylamino group, an arylamino group, an aralkylamino group, or a heteroarylamino group, as defined herein, respectively.

[0075] The term "alkylcarbonylalkyl" or "alkanoylalkyl" refers to an alkyl group further substituted with an alkylcarbonyl group.

[0076] The term "alkylcarbonylalkoxy" or "alkanoylalkoxy" refers to an alkoxy group further substituted with an alkylcarbonyl group.

[0077] The term "heterocycloalkylcarbonylalkyl" refers to an alkyl group further substituted with a heterocycloalkylcarbonyl group.

[0078] The term "mercapto" refers to a -SH group. The term "alkylthio" refers to a mercapto group, as defined herein, substituted with an alkyl group, as defined herein.

[0079] The term "sulfone" or "sulfonyl" refers to the functional group of sulfonic acid after losing the hydroxyl group, specifically refers to the -S(=O)2- group.

[0080] The term "sulfoxide" or "sulfinyl" refers to -S(=O)-.

[0081] The term "aminosulfonyl" or "aminosulfonyl" refers to the -S(=O)2-NH2 group.

[0082] The term "alkylsulfoxide" or "alkylsulfinyl" refers to an alkyl-S(=O)- group.

[0083] The term "alkylsulfonyl" or "alkylsulfonyl" refers to -S(=O)2-R, where R is alkyl.

[0084] The term "alkylaminosulfonyl" refers to a sulfone group, as defined herein, substituted with an alkylamino group, as defined herein.

[0085] The term "alkylsulfonylamino(amine) group" or "alkylsulfonylamino(amine) group", and "cycloalkylsulfonylamino(amine) group" or "cycloalkylsulfonylamino(amine) group" means that an amino group as defined herein is substituted by an alkylsulfonyl or cycloalkylsulfonyl group as defined herein, i.e. -NH-S(=O)2-R, wherein R is an alkyl group and a cycloalkyl group, respectively.

[0086] The terms "cycloalkylsulfonyl" and "cycloalkylsulfonyl" refer to -S(=O)2-R, where R is cycloalkyl.

[0087] The term "quaternary ammonium group" refers to -N + RR'R", wherein R, R' and R" are each independently selected from an alkyl group having 1 to 8 carbon atoms.

[0088] The term "optionally" refers to one or more events described later that may or may not occur, and includes both events that occur and events that do not occur. The term "optionally substituted" or "substituted" refers to that the group mentioned can be substituted by one or more additional groups, each of which is independently selected from alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, hydroxyl, alkoxy, cyano, halogen, amide, nitro, haloalkyl, amino, methylsulfonyl, alkylcarbonyl, alkoxycarbonyl, heteroarylalkyl, heterocycloalkylalkyl, aminoacyl, amino protecting group, etc. Among them, the amino protecting group is preferably selected from pivaloyl, tert-butyloxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, benzyl, p-methoxybenzyl, allyloxycarbonyl, and trifluoroacetyl, etc.

[0089] As used herein, "pharmaceutically acceptable forms" of the disclosed compounds include, but are not limited to, pharmaceutically acceptable salts, hydrates, solvates, polymorphs, esters, acids, isomers, metabolites, prodrugs, and isotopically labeled derivatives of the disclosed compounds.

[0090] The term "pharmaceutically acceptable salt" herein refers to a salt that retains the desired biological activity of the subject compound and exhibits minimal undesirable toxicological effects, i.e., is suitable for use in contact with the tissues of a subject without excessive toxicity, irritation, allergic reaction, etc., within the scope of reasonable medical judgment, and is consistent with a reasonable benefit / risk ratio. These pharmaceutically acceptable salts can be prepared in situ during the final isolation and purification of the compound, or by reacting the free acid or free base form of the purified compound with a suitable base or acid, respectively. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66: 1-19. Pharmaceutically acceptable salts of the compounds provided herein include salts derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid, or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionic acid salt, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, naphthalene-m,n-disulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc.

[0091] "Solvate" or "solvate" refers to a solvent addition form containing either a stoichiometric or non-stoichiometric amount of solvent. Some compounds tend to trap fixed molar ratios of solvent molecules in their crystalline solid state, thereby forming solvates. If the solvent is water, the solvate formed is a hydrate; if the solvent is an alcohol, the solvate formed is an alcoholate. Hydrates are formed by the association of one or more water molecules with one molecule of the substance, where the water remains in its molecular form as HO.

[0092] A "metabolite" of a compound disclosed herein is a derivative of the compound formed when the compound is metabolized. The term "active metabolite" refers to a biologically active derivative of a compound formed when the compound is metabolized. The term "metabolized," as used herein, refers to the sum of processes by which a particular substance is altered by an organism (including, but not limited to, hydrolysis reactions and reactions catalyzed by enzymes, such as oxidation reactions). Thus, an enzyme can produce a specific structural transformation into a compound. For example, cytochrome P450 catalyzes various oxidation and reduction reactions, while diphosphoglucosyltransferase catalyzes the conversion of activated glucuronic acid molecules to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines, and free sulfhydryl groups. Further information on metabolism can be obtained from "The Pharmacological Basis of Therapeutics," 9th edition, McGraw-Hill (1996). Metabolites of the compounds disclosed herein can be identified by administering the compound to a host and analyzing tissue samples from the host, or by incubating the compound with hepatocytes in vitro and analyzing the resulting compounds. Both methods are known in the art. In some embodiments, metabolites of the compound are formed by an oxidation process and correspond to the corresponding hydroxyl-containing compound. In some embodiments, the compound is metabolized to a pharmaceutically active metabolite.

[0093] As used herein, the term "modulate" refers to interacting directly or indirectly with a target to change the activity of the target, including, by way of example only, enhancing the activity of the target, inhibiting the activity of the target, limiting the activity of the target, or prolonging the activity of the target.

[0094] The term "prodrug" or "prodrug" refers to a derivative that may not be pharmacologically active but, in certain circumstances, can be administered orally or parenterally and thereafter metabolized in vivo to form a pharmacologically active compound of the present invention. Non-limiting examples of prodrugs include esters, carbonates, half-esters, phosphates, nitroesters, sulfates, sulfoxides, amides, carbamates, nitrogen-containing compounds, phosphoramides, glycosides, ethers, acetals, and ketals, among others.

[0095] An "effective amount" refers to an amount of a drug or pharmaceutical formulation that will elicit the biological or medical response of a tissue, system, animal, or human being, for example, that is being studied by a researcher or physician. Furthermore, the term "therapeutically effective amount" refers to any amount that results in treatment, cure, prevention, or alleviation of a disease, disorder, or side effect, or a reduction in the rate of progression of a disease or disorder, compared to a corresponding subject that has not received that amount. Also included within the scope of the term is an amount effective to enhance normal physiological function.

[0096] As used herein, the term "treating" refers to alleviating at least one symptom of a disease, disorder, or condition. The term includes administering and / or applying one or more compounds described herein to a subject to provide management or treatment of a condition. "Treatment" for the purposes of this disclosure may, but does not necessarily, provide a cure; rather, it is meant that "treatment" can be a form of management of a condition. When the compounds described herein are used to treat harmful proliferating cells (including cancer), "treatment" includes partial or complete destruction of the harmful proliferating cells with minimal damage to normal cells. The desired treatment mechanism for harmful rapidly proliferating cells (including cancer cells) at the cellular level is apoptosis.

[0097] As used herein, the term "prevention" includes both preventing or slowing the onset of clinically significant disease development or preventing or slowing the onset of a preclinically significant disease stage in an at-risk individual. This includes prophylactic treatment of individuals at risk of developing disease.

[0098] The term "subject" or "patient" includes organisms that can suffer from a disorder or a disorder associated with reduced or insufficient programmed cell death (apoptosis) or that can otherwise benefit from the administration of the compounds of the invention, such as humans and non-human animals. Preferred humans include human patients suffering from or prone to suffering from a disorder or related condition as described herein. The term "non-human animal" includes vertebrates, such as mammals, such as non-human primates, sheep, cattle, dogs, cats, and rodents such as mice, as well as non-mammals, such as chickens, amphibians, reptiles, etc.

[0099] The GI used in this paper 50 It refers to the drug concentration required to inhibit 50% of cell growth, that is, the drug concentration when the growth of 50% of cells (such as cancer cells) is inhibited or controlled.

[0100] IC used in this article 50 It refers to the amount, concentration, or dose of a particular test compound that achieves 50% inhibition of the maximal effect in the assay in which the effect is measured.

[0101] The EC used in this paper 50 It refers to the dose, concentration or amount of a test compound that elicits a dose-dependent response that elicits 50% of the maximal expression of a specific response induced, stimulated or potentiated by the particular test compound.

[0102] Unless otherwise indicated, the present invention employs conventional methods such as mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA technology, and pharmacology within the skill of the art. Unless specific definitions are provided, the nomenclature and laboratory procedures and techniques associated with analytical chemistry, synthetic organic chemistry, and medical and pharmaceutical chemistry described herein are those known to those skilled in the art. In general, the aforementioned techniques and steps can be implemented by conventional methods well known in the art and described in various general and more specific literature, which are cited and discussed in this specification.

[0103] Active compound

[0104] The present disclosure relates to a PGK1 protein inhibitor, which is a compound of formula (I) or a pharmaceutically acceptable salt, solvate, isomer, ester, acid, metabolite or prodrug thereof,

[0105] in,

[0106] X is carbon or nitrogen,

[0107] R 1 Each is independently selected from amino, hydroxy, nitrile, halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, and C1-6 alkylsulfonyl, wherein n is 2 or 3;

[0108] R 2 Selected from C1-6 alkyl, C3-6 cycloalkyl, C3-6 cycloalkylC1-4 alkyl, C1-4 alkoxyC1-4 alkyl, C1-6 haloalkyl, C3-6 halocycloalkylC1-4 alkyl, C1-4 alkylaminoacylC1-C4 alkyl, and C2-6 dialkylaminoacylC1-C4 alkyl;

[0109] Y is selected from C1-6 alkyl, C3-6 cycloalkyl, C3-6 cycloalkylC1-4 alkyl, C3-6 cycloalkenyl, phenyl, four to six membered heterocyclyl, and four to six membered heterocyclylC1-4 alkyl;

[0110] R 3 each independently selected from hydroxy, amino, nitrile, oxo, carboxyl, aminoacyl, halogen, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 hydroxyalkylamino, C1-6 alkylamido, C1-6 alkylaminoacyl, C1-4 alkoxyC1-4 alkylamino, C1-4 hydroxyalkoxyC1-4 alkylamino, C1-6 alkylsulfonylamino, phenylC1-4 alkylamino, and four to six-membered heterocyclyl, wherein m is 0, 1, 2 or 3;

[0111] The four to six-membered heterocyclic groups are each independently selected from four to six-membered heterocyclic alkyl groups containing 1 or 2 heteroatoms independently selected from N and O, more preferably selected from piperidinyl, morpholinyl, piperazinyl, tetrahydrofuranyl, oxetanyl, and imidazolidinyl.

[0112] In a preferred embodiment, X is carbon, and relative to the amino linking group of the benzene ring, R 1 The position on the benzene ring is meta and / or para.

[0113] More preferably, relative to the amino linking group of the benzene ring, the para position of the benzene ring has no substituent or the R 1 is selected from halogen and C1-3 alkoxy. In addition, preferably, relative to the amino linking group of the benzene ring, R 1 Each is independently selected from nitrile, halogen, C1-3 alkoxy, C1-3 haloalkyl, and C1-3 haloalkoxy.

[0114] In another preferred embodiment, R 2 is selected from C3-6 alkyl, C3-6 cycloalkyl, C3-6 cycloalkylC1-3 alkyl, C1-3 alkoxyC1-3 alkyl, C1-3 haloalkyl, C1-3 alkylaminoacylC1-C3 alkyl, and C2-4 dialkylaminoacylC1-C3 alkyl. Particularly preferably, R 2 Selected from isopropyl and cyclopropyl.

[0115] In a further embodiment, Y is C2-5 alkyl, and R 3 Each is independently selected from hydroxy, amino, carboxyl, halogen, C1-3 alkyl, and C1-3 alkylaminoacyl, and m is 1 or 2.

[0116] In another embodiment, the compound of the present invention has the structure of Formula (II):

[0117] Among them, R 1 、R 2 、R 3 , m and n are as defined above.

[0118] Preferably, m is 1 or 2, more preferably 1.

[0119] In addition, preferably, R 3 Each is independently selected from hydroxyl, amino, nitrile, oxo, carboxyl, C1-3 alkyl, C1-3 hydroxyalkyl, C1-3 hydroxyalkylamino, C1-3 alkylamide, C1-3 alkoxy C1-3 alkylamino, C1-3 hydroxyalkoxy C1-3 alkylamino, C1-3 alkylsulfonylamino, phenyl C1-3 alkylamino, morpholinyl, and piperidinyl. Further preferably, R 3Each is independently selected from hydroxy, amino, C1-3 alkyl, C1-3 hydroxyalkyl, C1-3 hydroxyalkylamino, and C1-3 alkoxy C1-3 alkylamino.

[0120] In a preferred embodiment, the PGK1 protein inhibitor of the present invention is selected from the following compounds or pharmaceutically acceptable salts, solvates, isomers, esters, acids, metabolites or prodrugs thereof:

[0121] For each variable, any combination of the above groups is also contemplated herein. It will be appreciated that substituents and substitution patterns on the compounds provided herein can be selected by one skilled in the art to provide chemically stable compounds that can be synthesized using techniques known in the art and those described herein.

[0122] Also described herein are pharmaceutically acceptable salts, solvates, isomers, esters, acids, metabolites, or prodrugs of this compound.

[0123] In particular, the compounds described herein can be made and / or used as pharmaceutically acceptable salts. Types of pharmaceutically acceptable salts include, but are not limited to: (1) acid addition salts, formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, or the like; or with an organic acid, such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, malic acid, citric acid, succinic acid, maleic acid, tartaric acid, fumaric acid, trifluoroacetic acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-1- -formic acid, 2-naphthalenesulfonic acid, tert-butylacetic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, dodecylsulfuric acid, gluconic acid, glutamic acid, salicylic acid, hydroxynaphthoic acid, stearic acid, muconic acid, etc.; (2) base addition salts, which are formed when the acidic protons in the parent compound are replaced by metal ions, such as alkali metal ions (such as lithium, sodium, potassium), alkaline earth metal ions (such as magnesium or calcium) or aluminum ions; or coordinated with organic bases or inorganic bases, acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, trimethylamine, N-methylglucamine, etc.; acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, etc.

[0124] The corresponding counter ion of the pharmaceutically acceptable salt can be analyzed and identified using various methods including, but not limited to, ion exchange chromatography, ion chromatography, capillary electrophoresis, inductively coupled plasma, atomic absorption spectroscopy, mass spectrometry, or any combination thereof.

[0125] The salt is recovered using at least one of the following techniques: filtration, precipitation with a non-solvent followed by filtration, evaporation of the solvent, or, in the case of aqueous solutions, lyophilization.

[0126] Screening and characterizing pharmaceutically acceptable salts, polymorphs and / or solvates can be accomplished using a variety of techniques including, but not limited to, thermal analysis, X-ray diffraction, spectroscopy, microscopy, elemental analysis. The various spectroscopic techniques used include, but are not limited to, Raman, FTIR, UVIS, and NMR (liquid and solid state). Various microscopic techniques include, but are not limited to, IR microscopy and Raman microscopy.

[0127] Drug uses

[0128] The PGK1 protein inhibitors disclosed herein can be used to treat or prevent hypersensitivity reactions or autoimmune inflammatory diseases, particularly diseases regulated or affected by PGK1 protein activity or in which PGK1 protein activity or overexpression is involved, more preferably diseases associated with high PGK1 expression and / or overactivation. Preferably, hypersensitivity reactions or autoimmune inflammatory diseases include, but are not limited to, allergic rhinitis, asthma, atopic dermatitis, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, psoriasis, immune thrombocytopenic purpura, inflammatory bowel disease, chronic obstructive pulmonary disease, Sjögren's syndrome, pemphigus vulgaris, idiopathic plasmacytoid lymphadenopathy, atherosclerosis, myocardial infarction and thrombosis, and combinations thereof.

[0129] In an embodiment of the present invention, the medicine comprising the compounds of this invention can be administered to the patient by at least one of injection, oral administration, inhalation, rectal administration and transdermal administration. When the patient is treated according to the present invention, the amount of a given drug depends on many factors, such as specific dosage regimen, disease or disease type and severity thereof, the uniqueness (such as body weight) of the patient or host for treatment, but, according to specific surrounding circumstances, including, for example, the specific drug, route of administration, disease for treatment and the patient or host for treatment, the dosage can be conventionally determined by methods known in the art. Usually, for the dosage used in adult treatment, the dosage is typically 0.02-5000mg / days, such as the scope of about 1-1500mg / days. The desired dose can be conveniently expressed as a dose or simultaneously administered (or in a short time) or at appropriate intervals, such as two, three, four or more doses per day. It will be appreciated by those skilled in the art that, although the above-mentioned dosage range has been given, specific effective amount can be appropriately adjusted according to the patient's situation and in conjunction with a physician's diagnosis.

[0130] In some embodiments of the methods or uses disclosed herein, a compound as described herein, any one of the compounds, is administered to a subject at a dosage (e.g., a therapeutically effective dose) of about 2 mg, 1-3 mg, 1-5 mg, 1-10 mg, 0.5-20 mg, or 0.1-50 mg. In some embodiments, the dosage (e.g., a therapeutically effective dose) is about 2 mg, 1-3 mg, 1-5 mg, 1-10 mg, 0.5-20 mg, 0.1-50 mg, 0.1-75 mg, 0.5-75 mg, 1-75 mg, 0.1-100 mg, 0.5-100 mg, or 1-100 mg. In some embodiments, the dosage is about 1-10 mg. In some embodiments, the dosage is about 1-50 mg. In some embodiments, the dosage is about 1-100 mg.

[0131] Preparation of compounds

[0132] Compounds of formula (I) and (II) can be synthesized using standard synthetic techniques known to those skilled in the art or using methods known in the art in combination with the methods described herein. In addition, the solvents, temperatures and other reaction conditions given herein can be varied according to the art.

[0133] In certain embodiments, provided herein are methods for preparing the kinase inhibitor compounds described herein and methods for using the same. In certain embodiments, the compounds described herein can be synthesized using the following synthetic schemes. Compounds can be synthesized using methods similar to those described below using appropriate alternative starting materials.

[0134] The starting materials used to synthesize the compounds described herein can be synthesized or obtained from commercial sources. The compounds described herein and other related compounds having different substituents can be synthesized using techniques and raw materials known to those skilled in the art. The reactions for preparing the compounds disclosed herein can be modified by reagents and conditions deemed appropriate by those skilled in the art to introduce various moieties into the molecules provided herein.

[0135] If desired, the reaction products can be isolated and purified using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography, etc. These products can be characterized using conventional methods, including physical constants and spectral data.

[0136] Example

[0137] The following specific non-limiting examples are to be interpreted as merely illustrative and not limiting of the present disclosure in any way. Although no further detailed description is required, it is believed that one skilled in the art can fully utilize the present disclosure based on the description herein.

[0138] Example 1: 3-Bromo-5-((2-((4-hydroxycyclohexyl)amino)-9-isopropyl-9H-purin-6-yl)amino)benzonitrile

[0139] To a solution of 2,6-dichloro-9-isopropyl-9H-purine (0.115 g, 0.5 mmol) in sec-butanol (1.5 mL) was added 3-amino-5-bromobenzonitrile (128 g, 0.65 mmol) and heated at 110°C for 12 hours. The mixture was cooled to room temperature and quenched by addition of saturated sodium bicarbonate solution. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography (eluent CH2Cl2 / MeOH=100 / 1) afforded 87 mg (yield 45%) of 3-bromo-5-((2-chloro-9-isopropyl-9H-purin-6-yl)amino)benzonitrile. MS m / z (ESI): 391.01 [M+H] + .

[0140] To a solution of 3-bromo-5-((2-chloro-9-isopropyl-9H-purin-6-yl)amino)benzonitrile (20 mg, 0.05 mmol) in sec-butanol (3 mL) were added trans-4-aminocyclohexan-1-ol (57 mg, 0.5 mmol) and triethylamine (0.14 mL, 1 mmol). After heating at 130° C. for 24 hours, the mixture was cooled to room temperature and quenched with water. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 50 / 1) to give 13 mg of the product (55% yield). 1 H NMR(500MHz,DMSO)δ10.12(s,1H),8.67(s,1H),8.41(s,1H),8.15(s,1H),7.69(s,1H),6.79(s,1H), 4.63-4.58(m,1H),3.68(s,1H),1.95(s,2H),1.84(s,2H),1.51(d,J=5.0Hz,6H),1.34-1.28(m,4H). MS m / z(ESI):470.13[M+H] + .

[0141] Example 2: 3-Bromo-5-((9-cyclopentyl-2-((4-hydroxycyclohexyl)amino)-9H-purin-6-yl)amino)benzonitrile

[0142] 2,6-Dichloropurine (187 mg, 1 mmol), triphenylphosphine (341 mg, 1.3 mmol), and cyclopentanol were dissolved in dry tetrahydrofuran (5 mL) and cooled to 0°C. Diisopropyl azodicarboxylate (263 mg, 1.3 mmol) was then added and the mixture was allowed to warm to room temperature and stirred for 12 hours. The solvent was removed under reduced pressure, water was added, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain 155 mg of 2,6-dichloro-9-cyclopentyl-9H-purine (yield 60%). MS m / z (ESI): 257.04 [M+H] + .

[0143] 2,6-Dichloro-9-cyclopentyl-9H-purine (129 mg, 0.5 mmol) and 3-amino-5-bromobenzonitrile (128 mg, 0.65 mmol) were dissolved in dry sec-butanol (5 mL) and heated at 110°C for 12 hours. The mixture was cooled to room temperature and quenched by addition of saturated sodium bicarbonate solution. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 100 / 1) to afford 134 mg (yield: 65%) of 3-bromo-5-((2-chloro-9-cyclopentyl-9H-purin-6-yl)amino)benzonitrile. MS m / z (ESI): 417.02 [M+H] + .

[0144] To a solution of 3-bromo-5-((2-chloro-9-cyclopentyl-9H-purin-6-yl)amino)benzonitrile (21 mg, 0.05 mmol) in n-butanol (3 mL) was added trans-4-aminocyclohexan-1-ol (57 mg, 0.5 mmol) and triethylamine (0.14 mL, 1 mmol). The mixture was heated at 130° C. for 24 hours and then cooled to room temperature. The reaction mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 50 / 1) to afford 13 mg of the product (55% yield). 1 H NMR(500MHz,DMSO)δ10.56(s,1H),8.69-8.27(m,3H),7.76(s,1H),7.16(s,1H) ,4.77(s,1H),3.67(s,1H),3.41(s,1H),2.17-1.68(m,12H),1.42-1.29(m,4H). MS m / z(ESI):496.15[M+H] + .

[0145] Example 3: 3-Bromo-5-((9-cyclobutyl-2-((4-hydroxycyclohexyl)amino)-9H-purin-6-yl)amino)benzonitrile

[0146] 2,6-Dichloropurine (187 mg, 1 mmol), triphenylphosphine (341 mg, 1.3 mmol) and cyclobutanol were dissolved in dry tetrahydrofuran (5 mL) and cooled to 0°C. Diisopropyl azodicarboxylate (263 mg, 1.3 mmol) was then added and the mixture was allowed to warm to room temperature and stirred for 12 hours. The solvent was removed under reduced pressure, water was added, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain 97 mg of 2,6-dichloro-9-cyclobutyl-9H-purine (yield 40%). MS m / z (ESI): 243.02 [M+H] + .

[0147] 2,6-Dichloro-9-cyclobutyl-9H-purine (72 mg, 0.3 mmol) and 3-amino-5-bromobenzonitrile (77 mg, 0.39 mmol) were dissolved in dry sec-butanol (3 mL) and heated at 110°C for 12 hours. The mixture was cooled to room temperature and quenched by adding saturated sodium bicarbonate solution. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography (eluent CH2Cl2 / MeOH=100 / 1) gave 78 mg of 3-bromo-5-((2-chloro-9-cyclobutyl-9H-purin-6-yl)amino)benzonitrile (yield 65%), MS m / z (ESI): 403.01 [M+H] + .

[0148] To a solution of 3-bromo-5-((2-chloro-9-cyclobutyl-9H-purin-6-yl)amino)benzonitrile (20 mg, 0.05 mmol) in n-butanol (3 mL) were added trans-4-aminocyclohexan-1-ol (57 mg, 0.5 mmol) and triethylamine (0.14 mL, 1 mmol), and the mixture was heated at 130° C. for 24 hours. After cooling to room temperature, the mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 50 / 1) to afford 14 mg of the product (60% yield). 1 H NMR (500MHz, DMSO) δ10.01(s,1H),8.72(s,1H),8.40(s,1H),8.11(s,1H),7.97(s,1H),7.67(s,1H),6.72(s,1H),4.53(d,J=5.0Hz,1H),3.87( d,J=10.0Hz,1H),3.69(d,J=5.0Hz,1H),3.39(s,1H),2.64(s,1H),2.40 -2.37(m,1H),2.01-1.84(m,6H),1.33-1.23(m,4H),0.53-0.43(m,2H). MS m / z(ESI):482.13[M+H] + .

[0149] Example 4: 3-Chloro-5-((9-cyclobutyl-2-((4-hydroxycyclohexyl)amino)-9H-purin-6-yl)amino)benzonitrile

[0150] 2,6-Dichloro-9-cyclobutyl-9H-purine (72 mg, 0.3 mmol) (see Example 3) and 3-amino-5-chlorobenzonitrile (59 mg, 0.39 mmol) were dissolved in dry sec-butanol (3 mL) and heated at 110°C for 12 hours. The mixture was cooled to room temperature and quenched by adding saturated sodium bicarbonate solution. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography (eluent CH2Cl2 / MeOH=100 / 1) gave 64 mg of 3-chloro-5-((2-chloro-9-cyclobutyl-9H-purin-6-yl)amino)benzonitrile (yield 60%). MS m / z (ESI): 359.06 [M+H] + .

[0151] To a solution of 3-chloro-5-((2-chloro-9-cyclobutyl-9H-purin-6-yl)amino)benzonitrile (18 mg, 0.05 mmol) in n-butanol (3 mL) was added trans-4-aminocyclohexan-1-ol (57 mg, 0.5 mmol) and triethylamine (0.14 mL, 1 mmol). The mixture was heated at 130° C. for 24 hours and then cooled to room temperature. The mixture was quenched with water and extracted three times with dichloromethane. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 50 / 1) to afford 13 mg of the product (65% yield). 1 H NMR (500MHz, DMSO) δ10.04(s,1H),8.57(s,1H),8.37(s,1H),8.11(s,1H),7.98(s,1H),7.56(s,1H),6.74(s,1H),4.55(d,J=5.0Hz,1H),3 .87(d,J=10.0Hz,1H),3.67(s,1H),3.40(s,1H),2.64(s,1H),2.41-2.37(m,1H),2.01-1.85(m,6H),1.32-1.23(m,4H),0.53-0.43(m,2H). MS m / z(ESI):438.18[M+H] + .

[0152] Example 5: 3-((2-((4-aminocyclohexyl)amino)-9-isopropyl-9H-purin-6-yl)amino)-5-bromobenzonitrile

[0153] To a solution of 3-bromo-5-((2-chloro-9-isopropyl-9H-purin-6-yl)amino)benzonitrile (19 mg, 0.05 mmol) (See Example 1) in n-butanol (3 mL) were added trans-cyclohexane-1,4-diamine (57 mg, 0.5 mmol) and triethylamine (0.14 mL, 1 mmol). The mixture was heated at 130°C for 24 hours and then cooled to room temperature. The reaction mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 10 / 1) to afford 10 mg of the product (45% yield). 1 H NMR(500MHz,DMSO)δ10.31(s,1H),8.30(s,1H),8.06-7.96m,3H),7.71(s,1H),6.98( s,1H),4.62(s,1H),3.69(s,1H),2.99(s,1H),2.07-2.00(m,4H),1.52-1.34(m,10H). MS m / z(ESI):469.15[M+H] + .

[0154] Example 6: 3-Bromo-5-((2-((4-hydroxycyclohexyl)amino)-9-methyl-9H-purin-6-yl)amino)benzonitrile

[0155] 2,6-Dichloro-9-methyl-9H-purine (110 mg, 0.5 mmol) was dissolved in dry sec-butanol (5 mL), and 3-amino-5-bromobenzonitrile (129 mg, 0.65 mmol) was added. The mixture was heated at 110°C for 12 hours. After cooling to room temperature, the reaction was quenched by adding saturated sodium bicarbonate solution. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 100 / 1) to give 126 mg (yield: 65%) of 3-bromo-5-((2-chloro-9-methyl-9H-purin-6-yl)amino)benzonitrile. MS m / z (ESI): 362.98 [M+H] + .

[0156] To a solution of 3-bromo-5-((2-chloro-9-methyl-9H-purin-6-yl)amino)benzonitrile (20 mg, 0.05 mmol) in n-butanol (3 mL) was added trans-4-aminocyclohexan-1-ol (57 mg, 0.5 mmol) and triethylamine (0.14 mL, 1 mmol). The mixture was heated at 130° C. for 24 hours and then cooled to room temperature. The mixture was quenched with water and extracted three times with dichloromethane. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 50 / 1) to afford 11 mg of the product (50% yield). 1H NMR(500MHz,DMSO)δ10.00(s,1H),8.71(s,1H),8.40(s,1H),7.88(s,1H),7.67(s,1H),6.74(d,J=10.0Hz,1H ), 4.52 (d, J = 5.0Hz, 1H), 3.70 (s, 1H), 3.60 (s, 1H), 3.42-3.37 (m, 1H), 1.94-1.83 (m, 4H), 1.34-1.23 (m, 4H). MS m / z(ESI):442.10[M+H] + .

[0157] Example 7: 3-Bromo-5-((9-(cyclopropylmethyl)-2-((4-hydroxycyclohexyl)amino)-9H-purin-6-yl)amino)benzonitrile

[0158] 2,6-Dichloropurine (187 mg, 1 mmol) was dissolved in dry N,N-dimethylformamide (5 mL), and bromomethylcyclopropane (268 g, 2 mmol) and potassium carbonate (690 mg, 5 mmol) were added. The mixture was allowed to react at room temperature for 24 hours. The reaction was quenched by adding saturated sodium bicarbonate solution, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography (eluent: petroleum ether / ethyl acetate = 4 / 1) afforded 121 mg (yield: 50%) of 2,6-dichloro-9-(cyclopropylmethyl)-9H-purine. MS m / z (ESI): 243.02 [M+H] + .

[0159] 2,6-Dichloro-9-(cyclopropylmethyl)-9H-purine (130 mg, 0.5 mmol) was dissolved in dry sec-butanol (5 mL), 3-amino-5-bromobenzonitrile (129 mg, 0.65 mmol) was added, and the mixture was heated at 110°C for 12 hours. After cooling to room temperature, the reaction was quenched by adding saturated sodium bicarbonate solution. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography (eluent CH2Cl2 / MeOH=100 / 1) gave 110 mg (yield 55%) of 3-bromo-5-((2-chloro-9-(cyclopropylmethyl)-9H-purin-6-yl)amino)benzonitrile. MS m / z (ESI): 403.01 [M+H] + .

[0160] To a solution of 3-bromo-5-((2-chloro-9-(cyclopropylmethyl)-9H-purin-6-yl)amino)benzonitrile (20 mg, 0.05 mmol) in n-butanol (3 mL) was added trans-4-aminocyclohexan-1-ol (57 mg, 0.5 mmol) and triethylamine (0.14 mL, 1 mmol). The mixture was heated at 130° C. for 24 hours and then cooled to room temperature. The mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 50 / 1) to afford 12 mg of the product (50% yield). 1 H NMR (500MHz, DMSO) δ10.01(s,1H),8.71(s,1H),8.41(s,1H),7.97(s,1H),7.67(s,1H),6.71(s,1H),4.52(d,J=5.0Hz,1H) ,3.87(d,J=10.0Hz,2H),3.70-3.66(s,1H),3.44-3.33(m,1H),2.01-1.84(m,4H),1.30-1.23(m,5H),0.54-0.43(m,4H).MS m / z(ESI):482.13[M+H] + .

[0161] Example 8: 3-Bromo-5-((9-ethyl-2-((4-hydroxycyclohexyl)amino)-9H-purin-6-yl)amino)benzonitrile

[0162] 2,6-Dichloro-9-ethyl-9H-purine (107 mg, 0.5 mmol) was dissolved in dry sec-butanol (5 mL), and 3-amino-5-bromobenzonitrile (129 mg, 0.65 mmol) was added. The mixture was heated at 110°C for 12 hours. The mixture was cooled to room temperature and quenched by adding saturated sodium bicarbonate solution. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography (eluent: CH2Cl2 / MeOH = 100 / 1) afforded 112 mg (yield: 60%) of 3-bromo-5-((2-chloro-9-ethyl-9H-purin-6-yl)amino)benzonitrile. MS m / z (ESI): 376.99 [M+H] + .

[0163] To a solution of 3-bromo-5-((2-chloro-9-ethyl-9H-purin-6-yl)amino)benzonitrile (19 mg, 0.05 mmol) in n-butanol (3 mL) was added trans-4-aminocyclohexan-1-ol (57 mg, 0.5 mmol) and triethylamine (0.14 mL, 1 mmol). The mixture was heated at 130° C. for 24 hours and then cooled to room temperature. The mixture was quenched with water and extracted three times with dichloromethane. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 50 / 1) to afford 12 mg of the product (53% yield). 1 H NMR (500MHz, DMSO) δ10.01(s,1H),8.71(s,1H),8.41(s,1H),7.95(s,1H),7.67(s,1H),6.73(d,J=10.0Hz,1H),4.52(d ,J=5.0Hz,1H),4.04(q,J=10.0Hz,1H),3.73-3.66(s,1H),3.44-3.37(m,1H),1.95-1.83(m,4H),1.39-1.27(m,7H).MS m / z(ESI):456.11[M+H] + .

[0164] Example 9: 3-Bromo-5-((9-(tert-butyl)-2-((4-hydroxycyclohexyl)amino)-9H-purin-6-yl)amino)benzonitrile

[0165] 2,6-dichloropurine (561 mg, 3 mmol) and anhydrous sodium sulfate (6.82 g, 48 mmol) were suspended in dry tert-butanol (30 mL), and concentrated sulfuric acid (1.47 g, 15 mmol) was then added dropwise. The reaction mixture was heated at 120 ° C for 12 hours. After cooling to room temperature, saturated sodium bicarbonate solution was added to quench the reaction. It was extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography (eluent petroleum ether / ethyl acetate = 4 / 1) gave 121 mg (yield 50%) of 2,6-dichloro-9-tert-butyl-9H-purine. MS m / z (ESI): 245.04 [M+H] + .

[0166] 2,6-Dichloro-9-tert-butyl-9H-purine (122 mg, 0.5 mmol) was dissolved in dry sec-butanol (5 mL), and 3-amino-5-bromobenzonitrile (129 mg, 0.65 mmol) was added. The mixture was heated at 110°C for 12 hours. The mixture was cooled to room temperature and quenched by adding saturated sodium bicarbonate solution. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography (eluent: CH2Cl2 / MeOH = 100 / 1) afforded 127 mg (yield: 63%) of 3-bromo-5-((2-chloro-9-tert-butyl-9H-purin-6-yl)amino)benzonitrile. MS m / z (ESI): 405.02 [M+H] + .

[0167] To a solution of 3-bromo-5-((2-chloro-9-tert-butyl-9H-purin-6-yl)amino)benzonitrile (10 mg, 0.05 mmol) in n-butanol (3 mL) was added trans-4-aminocyclohexan-1-ol (57 mg, 0.5 mmol) and triethylamine (0.14 mL, 1 mmol). The mixture was heated at 130° C. for 24 hours and then cooled to room temperature. The mixture was quenched with water and extracted three times with dichloromethane. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 50 / 1) to afford 12 mg of the product (50% yield). 1 H NMR(500MHz,DMSO)δ9.94(s,1H),8.57(br,2H),7.92(s,1H),7.66(s,1H),6.67(s,1H),4.53(d,J= 5.0Hz,1H),3.65(s,1H),3.45-3.37(m,1H),2.01-1.82(m,4H),1.70(s,1H),1.39-1.27(m,4H).MS m / z(ESI):484.15[M+H] + .

[0168] Example 10: 3-Bromo-5-((9-cyclopropyl-2-((4-hydroxycyclohexyl)amino)-9H-purin-6-yl)amino)benzonitrile

[0169] 2,6-Dichloropurine (935 mg, 5 mmol) and cyclopropylboronic acid (860 mg, 10 mmol) were dissolved in dry 1,2-dichloroethane (50 mL), followed by the addition of copper acetate (1.0 g, 5 mmol), 2,2'-bipyridine (780 mg, 5 mmol), and anhydrous sodium carbonate (1.06 g, 10 mmol). The mixture was refluxed for 12 hours. The mixture was cooled to room temperature and quenched by the addition of saturated sodium bicarbonate solution. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography (eluent petroleum ether / ethyl acetate = 4 / 1) afforded 228 mg (yield 20%) of 2,6-dichloro-9-cyclopropyl-9H-purine. MS m / z (ESI): 229.00 [M+H] + .

[0170] 2,6-Dichloro-9-cyclopropyl-9H-purine (115 mg, 0.5 mmol) was dissolved in dry sec-butanol (5 mL), 3-amino-5-bromobenzonitrile (129 mg, 0.65 mmol) was added, and the mixture was heated at 110°C for 12 hours. After cooling to room temperature, the reaction was quenched by adding saturated sodium bicarbonate solution. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography (eluent CH2Cl2 / MeOH=100 / 1) gave 123 mg (yield 64%) of 3-bromo-5-((2-chloro-9-cyclopropyl-9H-purin-6-yl)amino)benzonitrile. MS m / z (ESI): 388.99 [M+H] + .

[0171] To a solution of 3-bromo-5-((2-chloro-9-cyclopropyl-9H-purin-6-yl)amino)benzonitrile (19 mg, 0.05 mmol) in n-butanol (3 mL) was added trans-4-aminocyclohexan-1-ol (57 mg, 0.5 mmol) and triethylamine (0.14 mL, 1 mmol). The mixture was heated at 130°C for 24 hours and then cooled to room temperature. The mixture was quenched with water and extracted three times with dichloromethane. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 50 / 1) to afford 10 mg of the product (45% yield). 1 H NMR(500MHz,DMSO)δ9.97(s,1H),8.70(s,1H),8.40(s,1H),7.87(s,1H),7.66(s,1H),6.78(d,J=10.0Hz,1H),4.49 (d,J=5.0Hz,1H),3.72-3.66(m,1H),3.43-3.37(m,1H),1.95-1.83(m,4H),1.39-1.28(m,4H),1.06-0.97(m,4H).MS m / z(ESI):468.11[M+H]+ .

[0172] Example 11: 3-((2-((4-aminocyclohexyl)amino)-9-cyclopropyl-9H-purin-6-yl)amino)-5-bromobenzonitrile

[0173] To a solution of 3-bromo-5-((2-chloro-9-cyclopropyl-9H-purin-6-yl)amino)benzonitrile (19 mg, 0.05 mmol) (Reference Example 10) in n-butanol (3 mL) were added trans-cyclohexane-1,4-diamine (57 mg, 0.5 mmol) and triethylamine (0.14 mL, 1 mmol). The mixture was heated at 130°C for 24 hours and then cooled to room temperature. The reaction mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 10 / 1) to afford 16 mg of the product (70% yield). 1 H NMR(500MHz,DMSO)δ9.99(s,1H),8.85(s,1H),8.25(s,1H),7.89(s,1H),7.67(s,1H),6.88(d,J=5.0Hz ,1H),3.75-3.65(m,1H),2.93-2.84(m,1H),2.03-1.93(m,4H),1.47-1.32(m,4H),1.00-0.84(m,4H).MS m / z(ESI):467.13[M+H] + .

[0174] Example 12: 3-((2-((4-aminocyclohexyl)amino)-9-cyclopropyl-9H-purin-6-yl)amino)-5-chlorobenzonitrile

[0175] 2,6-Dichloro-9-cyclopropyl-9H-purine (115 mg, 0.5 mmol) was dissolved in dry sec-butanol (5 mL), and 3-amino-5-chlorobenzonitrile (129 mg, 0.65 mmol) was added. The mixture was heated at 110°C for 12 hours. The mixture was cooled to room temperature and quenched by adding saturated sodium bicarbonate solution. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography (eluent: CH2Cl2 / MeOH = 100 / 1) gave 115 mg (yield: 67%) of 3-chloro-5-((2-chloro-9-cyclopropyl-9H-purin-6-yl)amino)benzonitrile. MS m / z (ESI): 345.04 [M+H] + .

[0176] To a solution of 3-chloro-5-((2-chloro-9-cyclopropyl-9H-purin-6-yl)amino)benzonitrile (17 mg, 0.05 mmol) in n-butanol (3 mL) was added trans-cyclohexane-1,4-diamine (57 mg, 0.5 mmol) and triethylamine (0.14 mL, 1 mmol). The mixture was heated at 130°C for 24 hours and then cooled to room temperature. The reaction mixture was quenched with water and extracted three times with dichloromethane. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 10 / 1) to afford 14 mg of the product (65% yield). 1 H NMR(500MHz,DMSO)δ10.03(s,1H),8.70-7.84(m,3H),7.56(s,1H),6.91(d,J=5.0Hz,1H),3 .67(s,1H),3.01-2.92(m,1H),2.07-1.99(m,4H),1.50-1.35(m,4H),1.07-0.98(m,4H).MS m / z(ESI):423.18[M+H] + .

[0177] Example 13: 3-((2-((4-aminocyclohexyl)amino)-9-cyclobutyl-9H-purin-6-yl)amino)-5-chlorobenzonitrile

[0178] 2,6-Dichloropurine (187 mg, 1 mmol), triphenylphosphine (341 mg, 1.3 mmol) and cyclobutanol were dissolved in dry tetrahydrofuran (5 mL) and cooled to 0°C. Diisopropyl azodicarboxylate (263 mg, 1.3 mmol) was then added and the mixture was allowed to warm to room temperature and stirred for 12 hours. The solvent was removed under reduced pressure, water was added, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain 97 mg of 2,6-dichloro-9-cyclobutyl-9H-purine (yield 40%). MS m / z (ESI): 243.02 [M+H] + .

[0179] 2,6-Dichloro-9-cyclobutyl-9H-purine (72 mg, 0.3 mmol) and 3-amino-5-chlorobenzonitrile (59 mg, 0.39 mmol) were dissolved in dry sec-butanol (3 mL) and heated at 110°C for 12 hours. Cooled to room temperature, the reaction was quenched by adding saturated sodium bicarbonate solution. Extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography (eluent CH2Cl2 / MeOH=100 / 1) gave 64 mg of 3-chloro-5-((2-chloro-9-cyclobutyl-9H-purin-6-yl)amino)benzonitrile (yield 60%). MS m / z (ESI): 359.06 [M+H] + .

[0180] To a solution of 3-chloro-5-((2-chloro-9-cyclobutyl-9H-purin-6-yl)amino)benzonitrile (18 mg, 0.05 mmol) in n-butanol (3 mL) was added trans-cyclohexane-1,4-diamine (57 mg, 0.5 mmol) and triethylamine (0.14 mL, 1 mmol). The mixture was heated at 130°C for 24 hours and then cooled to room temperature. The reaction mixture was quenched with water and extracted three times with dichloromethane. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 10 / 1) to afford 13 mg of the product (60% yield). 1 H NMR(500MHz,DMSO)δ10.03(s,1H),8.71-7.7(m,3H),7.56(s,1H),6.81(s,1H),3.88(s,1H),3.68(s,1H) ,2.94(t,J=10.0Hz,1H),2.70-2.36(m,2H),2.66-1.86(m,5H),1.46-1.27(m,5H),0.54-0.43(m,2H).MS m / z(ESI):437.20[M+H] + .

[0181] Example 14: 3-((2-((4-aminocyclohexyl)amino)-9-cyclobutyl-9H-purin-6-yl)amino)-5-bromobenzonitrile

[0182] 2,6-Dichloro-9-cyclobutyl-9H-purine (72 mg, 0.3 mmol) (Reference Example 13) and 3-amino-5-bromobenzonitrile (77 mg, 0.39 mmol) were dissolved in dry sec-butanol (3 mL) and heated at 110°C for 12 hours. The mixture was cooled to room temperature and quenched by adding saturated sodium bicarbonate solution. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography (eluent CH2Cl2 / MeOH=100 / 1) gave 78 mg of 3-bromo-5-((2-chloro-9-cyclobutyl-9H-purin-6-yl)amino)benzonitrile (yield 65%), MS m / z (ESI): 403.01 [M+H] + .

[0183] To a solution of 3-bromo-5-((2-chloro-9-cyclobutyl-9H-purin-6-yl)amino)benzonitrile (20 mg, 0.05 mmol) in n-butanol (3 mL) was added trans-cyclohexane-1,4-diamine (57 mg, 0.5 mmol) and triethylamine (0.14 mL, 1 mmol). The mixture was heated at 130°C for 24 hours and then cooled to room temperature. The reaction mixture was quenched with water and extracted three times with dichloromethane. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 10 / 1) to afford 13 mg of the product (55% yield). 1 H NMR(500MHz,DMSO)δ10.01(s,1H),8.37-7.92(m,3H),7.66(s,1H),6.79(s,1H),3.88(s,1H),3.71-3.69(m, 1H),2.93(t,J=10.0Hz,1H),2.69-2.36(m,2H),2.02-1.86(m,5H),1.51-1.26(m,5H),0.55-0.43(m,2H).MS m / z(ESI):481.15[M+H] + .

[0184] Example 15: 3-((2-((2-aminoethyl)amino)-9-cyclobutyl-9H-purin-6-yl)amino)-5-bromobenzonitrile

[0185] To a solution of 3-bromo-5-((2-chloro-9-cyclobutyl-9H-purin-6-yl)amino)benzonitrile (20 mg, 0.05 mmol) (Reference Example 14) in n-butanol (3 mL) were added ethylenediamine (30 mg, 0.5 mmol) and triethylamine (0.14 mL, 1 mmol). The mixture was heated at 130° C. for 24 hours and then cooled to room temperature. The reaction mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 10 / 1) to give 13 mg of the product (60% yield). 1 H NMR (500MHz, DMSO) δ10.07(s,1H),8.58(s,1H),8.55(s,1H),7.83(m,1H),7.69(s,1H),7.05(s,1H),3.93(d,J=10.0Hz,1H),3.57- 3.54(m,2H),3.08-3.04(m,2H),2.67-2.63(m,1H),2.45-2.40(m,2H),1.90-1.83(m,1H),1.30-1.26(m,1H),0.54-0.43(m,2H).MS m / z(ESI):427.10[M+H]+ .

[0186] Example 16: 3-Bromo-5-((9-isopropyl-2-((1-methylpiperidin-4-yl)amino)-9H-purin-6-yl)aminobenzonitrile

[0187] To a solution of 3-bromo-5-((2-chloro-9-isopropyl-9H-purin-6-yl)amino)benzonitrile (100 mg, 0.25 mmol) (Reference Example 1) in n-butanol (10 mL) were added 1-methylpiperidin-4-amine (88 mg, 0.77 mmol) and triethylamine (0.18 mL, 1.28 mmol). The mixture was heated at 130° C. for 24 hours and then cooled to room temperature. The reaction mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 10 / 1) to give 27 mg of the product (22% yield). 1 H NMR (500MHz, DMSO-d6) δ10.05(s,1H),8.54(s,2H),8.07(s,1H),7.69(s,1H),7.03(d,J=6.0Hz,1H),4.61(p,J=6.6Hz,1H ),3.92(s,1H),3.41(s,2H),3.08-2.82(m,2H),2.67(s,3H),2.18-2.06(m,2H),1.83(s,2H),1.52(s,3H),1.50(s,3H).MS m / z(ESI):469.14[M+H] + .

[0188] Example 17: 3-Bromo-5-((2-((4-(hydroxymethyl)cyclohexyl)amino)-9-isopropyl-9H-purin-6-yl)amino)benzonitrile

[0189] To a solution of 3-bromo-5-((2-chloro-9-isopropyl-9H-purin-6-yl)amino)benzonitrile (100 mg, 0.25 mmol) (Reference Example 1) in n-butanol (10 mL) were added (4-aminocyclohexyl)methanol (166 mg, 0.77 mmol) and triethylamine (0.18 mL, 1.28 mmol). The mixture was heated at 130° C. for 24 hours and then cooled to room temperature. The mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 10 / 1) to give 24 mg of the product (19% yield). 1H NMR(500MHz,DMSO-d6)δ9.99(s,1H),8.67-8.47(m,2H),8.02(s,1H),7.66(s,1H),6.7 1(d,J=6.3Hz,1H),4.58(p,J=6.7Hz,1H),4.36(t,J=5.3Hz,1H),3.69(ddt,J=14.6,11. 1,5.5Hz,1H),3.23(t,J=5.8Hz,2H),2.03-1.95(m,2H),1.80(d,J=11.6Hz,2H),1.50( s,3H),1.49(s,3H),1.24(d,J=9.9Hz,2H),1.18(d,J=6.2Hz,1H),1.12-1.00(m,2H).MS m / z(ESI):484.14[M+H] + .

[0190] Example 18: 3-Bromo-5-((9-isopropyl-2-((4-oxocyclohexyl)amino)-9H-purin-6-yl)amino)benzonitrile

[0191] To a solution of 3-bromo-5-((2-chloro-9-isopropyl-9H-purin-6-yl)amino)benzonitrile (19 mg, 0.05 mmol) (Reference Example 1) in n-butanol (3 mL) were added 4-aminocyclohexane-1-one (30 mg, 0.5 mmol) and triethylamine (0.14 mL, 1 mmol). The mixture was heated at 130° C. for 24 hours and then cooled to room temperature. The reaction mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 10 / 1) to give 13 mg of the product (60% yield). 1 H NMR(500MHz,DMSO-d6)δ10.05(s,1H),8.62(s,1H),8.56(s,1H),8.06(s,1H),7.68(s,1H),6.96(d,J=5.0Hz,1H),4.6 5-4.58(m,1H),4.27-4.20(m,1H),2.54-2.48(m,2H),2.37-2.20(m,4H),1.86-1.78(m,2H),1.52(d,J=5.0Hz,,6H).MS m / z(ESI):468.11[M+H] + .

[0192] Example 19: N-(4-((6-((3-bromo-5-cyanophenyl)amino)-9-isopropyl-9H-purin-2-yl)amino)cyclohexyl)acetamide

[0193] To a solution of 3-bromo-5-((2-chloro-9-isopropyl-9H-purin-6-yl)amino)benzonitrile (39 mg, 0.1 mmol) (Reference Example 1) in n-butanol (3 mL) were added N-(4-aminocyclohexyl)acetamide (78 mg, 0.5 mmol) and triethylamine (0.14 mL, 1 mmol). The mixture was heated at 130° C. for 24 hours and then cooled to room temperature. The mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 10 / 1) to give 25 mg of the product (49% yield). 1 H NMR (500MHz, DMSO-d6) δ10.02(s,1H),8.91(s,1H),8.27(s,1H),8.03(s,1H),7.72(d,J=5.0Hz,1H),7.67(s,1H),6.73(s,1H),4 .63-4.57(m,1H),3.72(s,1H),3.52(s,1H),2.00(s,2H),1.83(s,2H),1.80(s,3H),1.52(d,J=5.0Hz,,6H);1.45-1.31(m,4H).MS m / z(ESI):511.16[M+H] + .

[0194] Example 20: 3-((2-((5-Aminopentyl)amino)-9-isopropyl-9H-purin-6-yl)amino-5-bromo-benzonitrile

[0195] To a solution of 3-bromo-5-((2-chloro-9-isopropyl-9H-purin-6-yl)amino)benzonitrile (100 mg, 0.25 mmol) (Reference Example 1) in sec-butanol (10 mL) were added pentane-1,5-diamine (40 mg, 0.39 mmol) and triethylamine (0.088 mL, 0.64 mmol). The mixture was heated at 130°C for 24 hours and then cooled to room temperature. The reaction mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 10 / 1) to afford 16 mg of the product (27% yield). 1H NMR (500MHz, DMSO-d6) δ9.94(s,1H),8.60(d,J=44.5Hz,2H),8.03(s,1H),7.66(t,J=1.6Hz,1H),6.98(d,J=6.4H z,1H),4.60(p,J=6.8Hz,1H),3.35(s,4H),2.76(t,J=7.0Hz,2H),1.67-1.57(m,4H),1.51(s,3H),1.50(s,3H).MS m / z(ESI):457.14[M+H] + .

[0196] Example 21: 3-Bromo-5-((2-((((1R,3S)-3-hydroxycyclohexyl)amino)-9-isopropyl-9H-purin-6-yl)amino)benzonitrile

[0197] To a solution of 3-bromo-5-((2-chloro-9-isopropyl-9H-purin-6-yl)amino)benzonitrile (100 mg, 0.25 mmol) (Reference Example 1) in sec-butanol (10 mL) were added cis-3-aminocyclohexan-1-ol (88 mg, 0.76 mmol) and triethylamine (0.18 mL, 1 mmol). The mixture was heated at 130° C. for 24 hours and then cooled to room temperature. The reaction mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 50 / 1) to give 20 mg of the product (17% yield). 1 H NMR(500MHz,DMSO-d6)δ9.99(s,1H),8.58(d,J=34.7Hz,2H),8.03(s,1H),7.66(d,J=1.7Hz,1H), 6.78(d,J=8.3Hz,1H),4.59(p,J=7.1Hz,2H),3.77(dtd,J=11.4,7.8,4.2Hz,1H),3.56(s,1H),3.1 7(d,J=3.5Hz,1H),2.10(d,J=11.5Hz,1H),1.89(d,J=11.7Hz,1H),1.85-1.77(m,1H),1.70(dt,J= 13.7,3.7Hz,1H),1.50(s,3H),1.49(s,3H),1.37(s,1H),1.20-1.12(m,1H),1.12-1.04(m,1H).MS m / z(ESI):470.13[M+H] + .

[0198] Example 22: 3-Bromo-5-((2-((((1R,3R)-3-hydroxycyclohexyl)amino)-9-isopropyl-9H-purin-6-yl)amino)benzonitrile

[0199] To a solution of 3-bromo-5-((2-chloro-9-isopropyl-9H-purin-6-yl)amino)benzonitrile (100 mg, 0.25 mmol) (Reference Example 1) in sec-butanol (3 mL) were added trans-3-aminocyclohexan-1-ol (88 mg, 0.76 mmol) and triethylamine (0.18 mL, 1 mmol). The mixture was heated at 130° C. for 24 hours and then cooled to room temperature. The mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 50 / 1) to give 12 mg of the product (10% yield). 1 H NMR (500MHz, DMSO-d6) δ9.93 (s, 1H), 8.57 (s, 2H), 8.01 (s, 1H), 7.65 (t, J = 1.6Hz, 1H), 6.62 (d, J = 7.9Hz, 1H), 4.60 (h, J = 7.7, 7.3Hz,1H),4.32(s,1H),3.96(s,1H),1.88(s,1H),1.71(s,3H),1.51(s,3H),1.50(s,3H),1.47(s,2H),1.38-1.29(m,2H).MS m / z(ESI):470.13[M+H] + .

[0200] Example 23: 3-Bromo-5-((2-((3-hydroxypropyl)amino)-9-isopropyl-9H-purin-6-yl)amino)benzonitrile

[0201] To a solution of 3-bromo-5-((2-chloro-9-isopropyl-9H-purin-6-yl)amino)benzonitrile (50 mg, 0.13 mmol) (Reference Example 1) in sec-butanol (3 mL) were added 3-aminopropan-1-ol (29 mg, 0.39 mmol) and triethylamine (0.088 mL, 0.64 mmol). The mixture was heated at 130° C. for 24 hours and then cooled to room temperature. The reaction mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 50 / 1) to give 18 mg of the product (33% yield). 1H NMR (500MHz, DMSO-d6) δ9.97 (s, 1H), 8.60 (d, J = 30.1Hz, 2H), 8.02 (s, 1H), 7.65 (t, J = 1.6Hz, 1H), 6.88 (s, 1H), 4.60 (h, J = 6.7Hz, 1 H),4.43(t,J=5.2Hz,1H),3.52(td,J=6.4,5.1Hz,2H),3.37(q,J=6.6Hz,2H),1.76(p,J=6.6Hz,2H),1.51(s,3H),1.50(s,3H).MS m / z(ESI):430.09[M+H] + .

[0202] Example 24: 3-Bromo-5-((2-((4-hydroxybutyl)amino)-9-isopropyl-9H-purin-6-yl)amino)benzonitrile

[0203] To a solution of 3-bromo-5-((2-chloro-9-isopropyl-9H-purin-6-yl)amino)benzonitrile (50 mg, 0.13 mmol) (Reference Example 1) in sec-butanol (3 mL) were added 4-aminobutan-1-ol (34 mg, 0.39 mmol) and triethylamine (0.088 mL, 0.64 mmol). The mixture was heated at 130° C. for 24 hours and then cooled to room temperature. The reaction mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 50 / 1) to give 32 mg of the product (56% yield). 1 H NMR (500MHz, DMSO-d6) δ9.97(s,1H),8.65(s,1H),8.56(s,1H),8.01(s,1H),7.65(s,1H),6.91(s,1H),4.61(h,J=6.8Hz,1H),4.33( t,J=5.1Hz,1H),3.42(td,J=6.5,5.0Hz,2H),3.35-3.31(m,2H),1.65-1.58(m,2H),1.55-1.52(m,2H),1.51(s,3H),1.50(s,3H).MS m / z(ESI):444.11[M+H] + .

[0204] Example 25: 3-Bromo-5-((9-cyclopropyl-2-((4-(hydroxymethyl)cyclohexyl)amino)-9H-purin-6-yl)amino)benzonitrile

[0205] To a solution of 3-bromo-5-((2-chloro-9-cyclopropyl-9H-purin-6-yl)amino)benzonitrile (50 mg, 0.13 mmol) (Reference Example 10) in sec-butanol (3 mL) were added (4-aminocyclohexyl)methanol (64 mg, 0.39 mmol) and triethylamine (0.090 mL, 0.64 mmol). The mixture was heated at 130° C. for 24 hours and then cooled to room temperature. The mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 50 / 1) to give 12 mg of the product (19% yield). 1 H NMR(500MHz,DMSO-d6)δ9.97(s,1H),8.60(s,1H),8.54(s,1H),8.02(d,J=8.2H z,1H),7.87(s,1H),7.66(t,J=1.6Hz,1H),6.82(d,J=8.2Hz,1H),4.36(dt,J=1 2.2,5.3Hz,2H),3.75-3.65(m,1H),3.39(d,J=50.0Hz,1H),3.22(d,J=4.9Hz,2 H),1.97(s,3H),1.90-1.72(m,4H),1.30(d,J=3.5Hz,2H),1.29-1.21(m,5H).MS m / z(ESI):482.12[M+H] + .

[0206] Example 26: 3-Bromo-5-((2-((5-hydroxypentyl)amino)-9-isopropyl-9H-purin-6-yl)aminobenzonitrile

[0207] To a solution of 3-bromo-5-((2-chloro-9-isopropyl-9H-purin-6-yl)amino)benzonitrile (50 mg, 0.13 mmol) (Reference Example 1) in sec-butanol (3 mL) were added 5-aminopentan-1-ol (40 mg, 0.39 mmol) and triethylamine (0.088 mL, 0.64 mmol). The mixture was heated at 130° C. for 24 hours and then cooled to room temperature. The mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 50 / 1) to give 27 mg of the product (48% yield). 1H NMR(500MHz,DMSO-d6)δ9.96(s,1H),8.60(d,J=40.1Hz,2H),8.01(s,1H),6.91(s,1H),4.59(h,J=6.8Hz,1H),4.30(t,J=5.1Hz,1H),3.38(td,J =6.4,5.0Hz,2H),3.33-3.31(m,2H),1.59(p,J=7.4Hz,2H),1.51(s,3H),1.50(s,3H),1.48-1.42(m,2H),1.38(ddt,J=14.0,8.8,5.0Hz,2H).MS m / z(ESI):458.12[M+H] + .

[0208] Example 27: 3-Bromo-5-((9-isopropyl-2-((trans-4-((3-methoxypropyl)amino)cyclohexyl)amino)-9H-purin-6-yl)amino)benzonitrile

[0209] To a solution of 3-bromo-5-((2-chloro-9-isopropyl-9H-purin-6-yl)amino)benzonitrile (150 mg, 0.38 mmol) (Reference Example 1) in sec-butanol (3 mL) were added trans-N-(3-methoxypropyl)cyclohexane-1,4-diamine (298 mg, 1.15 mmol) and triethylamine (0.27 mL, 1.92 mmol). The mixture was heated at 130°C for 24 hours and then cooled to room temperature. The mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 50 / 1) to afford 8 mg of the product (4% yield). 1 H NMR (500MHz, DMSO-d6) δ10.00(s,1H),8.93(s,1H),8.03(s,1H),7.66(t,J=1.6Hz,1H),6.79(s,1H),4.67-4.54(m,1H),3.40(s,3H),3.25(s, MS m / z(ESI):541.85[M+H] + .

[0210] Example 28: 3-Bromo-5-((9-isopropyl-2-(((tetrahydrofuran-2-yl)methyl)amino)-9H-purin-6-yl)amino)benzonitrile

[0211] To a solution of 3-bromo-5-((2-chloro-9-isopropyl-9H-purin-6-yl)amino)benzonitrile (50 mg, 0.13 mmol) (Reference Example 1) in sec-butanol (3 mL) were added (tetrahydrofuran-2-yl)methanamine (39 mg, 0.39 mmol) and triethylamine (0.088 mL, 0.64 mmol). The mixture was heated at 130°C for 24 hours and then cooled to room temperature. The mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 50 / 1) to afford 39 mg of the product (67% yield). 1 H NMR(500MHz,DMSO-d6)δ10.04-9.91(m,1H),8.58(s,2H),8.02(s,1H),7.66(t,J=1.6H z,1H),6.90(s,1H),4.61(hept,J=6.8Hz,1H),4.06(p,J=6.4Hz,1H),3.79(td,J=7.6, 5.9Hz, 1H), 3.62 (td, J=7.7, 6.3Hz, 1H), 3.38 (td, J=6.1, 1.8Hz, 2H), 1.93 (ddt, J=16. 4,9.9,3.6Hz,1H),1.89-1.74(m,2H),1.67-1.59(m,1H),1.51(s,3H),1.50(s,3H); MS m / z(ESI):456.66[M+H] + .

[0212] Example 29: 3-Bromo-5-((9-cyclopropyl-2-((4-((2-hydroxyethyl)amino)cyclohexyl)amino)-9H-purin-6-yl)amino)benzonitrile

[0213] 3-((2-(((trans-4-aminocyclohexyl)amino)-9-cyclopropyl-9H-purin-6-yl)amino)-5-bromobenzonitrile (23 mg, 0.10 mmol) (Reference Example 11) was dissolved in dry DMF (3 mL), and then triethylamine (20 mg, 0.20 mmol) and 2-bromoethan-1-ol (12 mg, 0.1 mmol) were added sequentially, and the reaction was carried out at room temperature for 12 hours. The mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent CH2Cl2 / MeOH=10 / 1) to give 5 mg of the product (yield 20%). 1H NMR(500MHz,DMSO)δ9.97(s,H),8.76(s,1H),8.34(s,1H),7.88(s,1H),6.84(d,J=5.0Hz,1H),4.79(s,1H),3.70(s ,2H),3.54(t,J=5.0Hz,2H),2.78(s,2H),2.64(s,1H),2.02-1.99(m,4H),1.42-1.30(m,4H),1.06-0.97(m,4H).MS m / z(ESI):511.16[M+H] + .

[0214] Example 30: 3-Bromo-5-((2-((4-((2-hydroxyethyl)amino)cyclohexyl)amino)-9-isopropyl-9H-purin-6-yl)amino)benzonitrile

[0215] To a solution of 3-bromo-5-((2-chloro-9-isopropyl-9H-purin-6-yl)amino)benzonitrile (39 mg, 0.1 mmol) (Reference Example 1) in sec-butanol (1 mL) were added trans-1,4-cyclohexanediamine (57 mg, 0.5 mmol) and triethylamine (101 mg, 1 mmol). The mixture was heated at 130°C for 24 hours and then cooled to room temperature. The mixture was quenched by addition of saturated sodium bicarbonate solution, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography (eluent: CHCl / MeOH = 10 / 1) afforded 16 mg (34% yield) of 3-((2-(((trans-4-aminocyclohexyl)amino)-9-isopropyl-9H-purin-6-yl)amino)-5-bromobenzonitrile. MS m / z (ESI): 469.15 [M+H] + .

[0216] 3-((2-(((trans-4-aminocyclohexyl)amino)-9-isopropyl-9H-purin-6-yl)amino)-5-bromobenzonitrile (23 mg, 0.10 mmol) was dissolved in dry DMF (3 mL), and then triethylamine (20 mg, 0.20 mmol) and 2-bromoethanol (12 mg, 0.1 mmol) were added sequentially and reacted at room temperature for 12 hours. The mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent CH2Cl2 / MeOH=10 / 1) to give 6 mg of the product (yield 23%). 1H NMR(500MHz,DMSO)δ9.97(s,1H),8.68(s,1H),8.01(s,1H),7.66(s,1H),6.70(s,1H),4.61-4.56(m,2H),3.75-3.65 (m,1H),3.49(t,J=5.0Hz,2H),2.70(t,J=5.0Hz,2H),2.01-1.94(m,4H),1.50(d,J=5.0Hz,6H),1.36-1.29(m,4H).MS m / z(ESI):513.17[M+H] + .

[0217] Example 31: N-(4-((6-((3-bromo-5-cyanophenyl)amino)-9-isopropyl-9H-purin-2-yl)amino)cyclohexyl)methanesulfonamide

[0218] Under ice bath, 3-((2-(((trans-4-aminocyclohexyl)amino)-9-isopropyl-9H-purin-6-yl)amino)-5-bromobenzonitrile (23 mg, 0.05 mmol) (Reference Example 30) was dissolved in dry dichloromethane (3 mL), and then triethylamine (10 mg, 0.10 mmol) and methanesulfonyl chloride (6 mg, 0.05 mmol) were added sequentially. After reacting for 12 hours, water was added to quench the reaction. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent CH2Cl2 / MeOH=10 / 1) to give 6 mg of the product (yield 23%). 1 H NMR(500MHz,DMSO)δ10.00(s,1H),8.03(s,1H),7.66(s,1H),7.03(s,1H),6.74(s,1H),5.68(d,J=10.0Hz,1H), 4.61-4.56(m,1H),3.73-3.63(m,1H),3.33-3.06(m,2H),2.92(s,3H),2.02-1.90(m,4H),1.51-1.34(m,10H).MS m / z(ESI):547.12[M+H] + .

[0219] Example 32: 2-(6-((3-bromo-5-cyanophenyl)amino)-2-((trans-4-hydroxycyclohexyl)amino)-9H-purin-9-yl)-N,N-dimethylacetamide

[0220] 2,6-Dichloropurine (1.89 g, 10 mmol) was dissolved in dry N,N-dimethylformamide (50 mL), and 2-bromo-N,N-dimethylacetamide (2.00 g, 12 mmol) and N,N-diisopropylethylamine (1.94 g, 15 mmol) were added and reacted at room temperature for 24 hours. The reaction was quenched by adding saturated sodium bicarbonate solution. The product was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography was performed to obtain 1.47 g (yield 54%) of 2-(2,6-dichloro-9H-purin-9-yl)-N,N-dimethylacetamide. MS m / z (ESI): 274.03 [M+H] + .

[0221] 2-(2,6-Dichloro-9H-purin-9-yl)-N,N-dimethylacetamide (1.47 g, 5.4 mmol) was dissolved in dry sec-butanol (50 mL), and 3-amino-5-bromobenzonitrile (1.4 g, 7.0 mmol) was added. The mixture was heated at 110°C for 12 hours. The mixture was cooled to room temperature and quenched by adding saturated sodium bicarbonate solution. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography (eluent: CH2Cl2 / MeOH = 100 / 1) afforded 550 mg (yield: 32%) of 2-(6-((3-bromo-5-cyanophenyl)amino)-2-chloro-9H-purin-9-yl)-N,N-dimethylacetamide. MS m / z (ESI): 434.01 [M+H] + .

[0222] To a solution of 2-(6-((3-bromo-5-cyanophenyl)amino)-2-chloro-9H-purin-9-yl)-N,N-dimethylacetamide (43 mg, 0.10 mmol) in sec-butanol (1 mL) were added trans-4-aminocyclohexane-1-ol (58 mg, 0.5 mmol) and triethylamine (0.14 mL, 1 mmol). The mixture was heated at 130°C for 24 hours and then cooled to room temperature. The reaction mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 50 / 1) to afford 20 mg of the product (39% yield). 1H NMR(500MHz,DMSO-d6)δ10.00(s,1H),8.71(s,1H),8.41(s,1H),7.79(s,1H) ,7.67(d,J=1.6Hz,1H),6.69(d,J=8.2Hz,1H),4.96(s,2H),4.48(d,J=4.3Hz ,1H),3.74-3.61(m,1H),3.39(d,J=4.1Hz,1H),3.09(s,3H),2.86(s,3H),1. 92(d,J=11.7Hz,2H),1.83(d,J=11.1Hz,2H),1.32(q,J=12.1,10.9Hz,4H).MS m / z(ESI):513.13[M+H] + .

[0223] Example 33: 2-(2-((((trans)-4-aminocyclohexyl)amino)-6-((3-bromo-5-cyanophenyl)amino)-9H-purin-9-yl)-N,N-dimethylacetamide

[0224] To a solution of 2-(6-((3-bromo-5-cyanophenyl)amino)-2-chloro-9H-purin-9-yl)-N,N-dimethylacetamide (43 mg, 0.10 mmol) (Reference Example 32) in sec-butanol (1 mL) were added trans-1,4-cyclohexane-diamine (58 mg, 0.5 mmol) and triethylamine (0.14 mL, 1 mmol). The mixture was heated at 130°C for 24 hours and then cooled to room temperature. The reaction mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 50 / 1) to give 29 mg of the product (yield 57%). 1 H NMR (500MHz, DMSO-d6) δ8.73(s,1H),8.41(s,1H),7.79(s,1H),7.67(s,1H),6.73(d,J=8.1Hz,1H),4.96(s,2H),3.67( s,1H),3.09(s,3H),2.86(s,3H),2.70-2.60(m,1H),1.94(d,J=6.9Hz,2H),1.84(d,J=8.9Hz,2H),1.42-1.16(m,4H).MS m / z(ESI):512.15[M+H] + .

[0225] Example 34: 2-(6-((3-bromo-5-cyanophenyl)amino)-2-((4-hydroxybutyl)amino)-9H-purin-9-yl)-N,N-dimethylacetamide

[0226] To a solution of 2-(6-((3-bromo-5-cyanophenyl)amino)-2-chloro-9H-purin-9-yl)-N,N-dimethylacetamide (43 mg, 0.10 mmol) (Reference Example 32) in sec-butanol (1 mL) were added 4-aminobutan-1-ol (45 mg, 0.5 mmol) and triethylamine (0.14 mL, 1 mmol). The mixture was heated at 130° C. for 24 hours and then cooled to room temperature. The reaction mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 50 / 1) to give 23 mg of the product (47% yield). 1 H NMR (500MHz, DMSO-d6) δ10.01(s,1H),8.69(s,1H),8.54(s,1H),7.79(s,1H),7.66(d,J=1.5Hz,1H),6.93(t,J=5.8Hz,1H),4.97(s,2 H),4.33(t,J=5.0Hz,1H),3.41(d,J=5.0Hz,2H),3.33(s,2H),3.10(s,3H),2.86(s,3H),1.66-1.55(m,2H),1.50(p,J=6.6Hz,2H).MS m / z(ESI):487.12[M+H] + .

[0227] Example 35: 2-(6-((3-bromo-5-cyanophenyl)amino)-2-((5-hydroxypentyl)amino)-9H-purin-9-yl)-N,N-dimethylacetamide

[0228] To a solution of 2-(6-((3-bromo-5-cyanophenyl)amino)-2-chloro-9H-purin-9-yl)-N,N-dimethylacetamide (43 mg, 0.10 mmol) (Reference Example 32) in sec-butanol (1 mL) were added 5-aminopentan-1-ol (52 mg, 0.5 mmol) and triethylamine (0.14 mL, 1 mmol). The mixture was heated at 130° C. for 24 hours and then cooled to room temperature. The reaction mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 50 / 1) to give 9 mg of the product (yield 18%). 1H NMR (500MHz, DMSO-d6) δ10.05(s,1H),8.66(s,1H),8.53(s,1H),7.83(s,1H),7.67(d,J=1.7Hz,1H),6.96(s,1H),4.98(s,2H),3.30(t,J=7. 1Hz,4H),3.10(s,3H),2.86(s,3H),1.57(p,J=7.3Hz,2H),1.45(p,J=6.6Hz,2H),1.37(dq,J=10.8,7.1,5.3Hz,2H),1.24(d,J=5.8Hz,1H).MS m / z(ESI):501.13[M+H] + .

[0229] Example 36: 3-Bromo-5-((9-cyclopropyl-2-((trans-4-((2-(2-hydroxyethoxy)ethyl)amino)cyclohexyl)amino)-9H-purin-6-yl)amino)benzonitrile

[0230] 3-((2-(((trans-4-aminocyclohexyl)amino)-9-cyclopropyl-9H-purin-6-yl)amino)-5-bromobenzonitrile (23 mg, 0.10 mmol) (Reference Example 11) was dissolved in dry DMF (3 mL), and then triethylamine (20 mg, 0.20 mmol) and 2-(2-bromoethoxy)ethane-1-ol (17 mg, 0.1 mmol) were added sequentially, and the reaction was carried out at room temperature for 12 hours. The mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent CH2Cl2 / MeOH=10 / 1) to give 9 mg of the product (yield 40%). 1 H NMR(500MHz,DMSO)δ9.99(s,1H),8.79(s,1H),8.23(s,1H),7.88(s,1H),7.66(s,1H),6.87(d,J=10.0Hz,1H),3.7 1-3.33(m,7H),3.07(s,2H),2.94(s,2H),274(s,1H),2.04-1.97(m,4H),1.41-1.30(m,4H),1.06-0.84(m,4H).MS m / z(ESI):555.18[M+H] + Example 37: 3-Bromo-5-((2-((trans-4-(2-(2-hydroxyethoxy)ethyl)amino)cyclohexyl)amino)-9-isopropyl-9H-purin-6-yl)amino)benzonitrile

[0231] 3-((2-(((trans-4-aminocyclohexyl)amino)-9-isopropyl-9H-purin-6-yl)amino)-5-bromobenzonitrile (23 mg, 0.10 mmol) (Reference Example 30) was dissolved in dry DMF (3 mL), and then triethylamine (20 mg, 0.20 mmol) and 2-(2-bromoethoxy)ethane-1-ol (17 mg, 0.1 mmol) were added sequentially, and the reaction was carried out at room temperature for 12 hours. The mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent CH2Cl2 / MeOH=10 / 1) to give 4 mg of the product (yield 20%). 1 H NMR(500MHz,DMSO)δ10.03(s,1H),8.85(s,2H),8.06(s,1H),7.66(s,1H),6.80(s,1H),4.74- 4.58(m,2H),3.73-3.49(m,7H),3.13-3.05(m,3H),2.16-2.09(m,4H),1.61-1.34(m,10H).MS m / z(ESI):557.20[M+H] + .

[0232] Example 38: 2-(6-((3-bromo-5-cyanophenyl)amino)-2-((trans-4-hydroxycyclohexyl)amino)-9H-purin-9-yl)-N-methylacetamide

[0233] 2,6-Dichloropurine (1.89 g, 10 mmol) was dissolved in dry N,N-dimethylformamide (50 mL), and 2-bromo-N-methylacetamide (1.8 g, 12 mmol) and N,N-diisopropylethylamine (1.94 g, 15 mmol) were added. The mixture was allowed to react at room temperature for 24 hours. The reaction was quenched by adding saturated sodium bicarbonate solution, and the mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain 1.5 g (yield 58%) of 2-(2,6-dichloro-9H-purin-9-yl)-N-methylacetamide. MS m / z (ESI): 260.01 [M+H] + .

[0234] 2-(2,6-dichloro-9H-purin-9-yl)-N-methylacetamide (1.5 g, 5.8 mmol) was dissolved in dry sec-butanol (50 mL), 3-amino-5-bromobenzonitrile (1.4 g, 7.0 mmol) was added, and the mixture was heated at 110°C for 12 hours. After cooling to room temperature, the reaction was quenched by adding saturated sodium bicarbonate solution. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain 700 mg of 2-(6-((3-bromo-5-cyanophenyl)amino)-2-chloro-9H-purin-9-yl)-N-methylacetamide (yield 35%). MS m / z (ESI): 420.00 [M+H] + .

[0235] To a solution of 2-(6-((3-bromo-5-cyanophenyl)amino)-2-chloro-9H-purin-9-yl)-N-methylacetamide (42 mg, 0.10 mmol) in sec-butanol (1 mL) were added trans-4-aminocyclohexane-1-ol (58 mg, 0.5 mmol) and triethylamine (0.14 mL, 1 mmol). The mixture was heated at 130° C. for 24 hours and then cooled to room temperature. The reaction mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 50 / 1) to give 15 mg of the product (30% yield). 1 H NMR(500MHz,DMSO-d6)δ10.03(s,1H),8.72(s,1H),8.40(s,1H),8.08(s,1 H),7.85(s,1H),7.67(t,J=1.6Hz,1H),6.77-6.66(m,1H),4.67(s,2H),4.5 0(d,J=4.2Hz,1H),3.69-3.62(m,1H),3.41-3.37(m,1H),2.62(d,J=4.6Hz ,3H),1.92(d,J=11.3Hz,2H),1.84(d,J=10.8Hz,2H),1.39-1.25(m,4H).MS m / z(ESI):499.13[M+H] + .

[0236] Example 39: 2-(2-(((trans-4-aminocyclohexyl)amino)-6-((3-bromo-5-cyanophenyl)amino)-9H-purin-9-yl)-N-methylacetamide

[0237] To a solution of 2-(6-((3-bromo-5-cyanophenyl)amino)-2-chloro-9H-purin-9-yl)-N-methylacetamide (42 mg, 0.10 mmol) (Reference Example 38) in sec-butanol (1 mL) were added trans-1,4-cyclohexane-diamine (58 mg, 0.5 mmol) and triethylamine (0.14 mL, 1 mmol). The mixture was heated at 130° C. for 24 hours and then cooled to room temperature. The reaction mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 50 / 1) to give 17 mg of the product (yield: 34%). 1 H NMR (500MHz, DMSO-d6) δ8.78(s,1H),8.36(s,1H),8.10(s,1H),7.86(s,1H),7.67(d,J=1.6Hz,1H),6.77(d,J=8.1Hz,1H),4.68(s,2 H),3.67(s,1H),2.69(s,1H),2.62(d,J=4.5Hz,3H),1.96(d,J=10.0Hz,2H),1.86(d,J=9.5Hz,2H),1.32(dd,J=14.7,5.5Hz,4H).MS m / z(ESI):498.14[M+H] + .

[0238] Example 40: (R)-3-Bromo-5-((2-((1-hydroxybutan-2-yl)amino)-9-isopropyl-9H-purin-6-yl)aminobenzonitrile

[0239] To a solution of 3-bromo-5-((2-chloro-9-isopropyl-9H-purin-6-yl)amino)benzonitrile (20 mg, 0.05 mmol) (Reference Example 1) in sec-butanol (1 mL) were added (R)-2-aminobutan-1-ol (45 mg, 0.5 mmol) and triethylamine (0.14 mL, 1 mmol). The mixture was heated at 130°C for 24 hours and then cooled to room temperature. The mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 50 / 1) to give 13 mg of the product (57% yield). 1H NMR(500MHz,DMSO)δ9.97(s,1H),8.57(s,1H),8.02(s,1H),7.66(s,1H),6.46(d,J=10.0Hz,1H),4.61- 4.57(m,2H),3.90-3.83(m,1H),3.55-3.47(m,2H),1.69-1.49(m,8H),0.93(dd,J=10.0,5.0Hz,3H).MS m / z(ESI):444.11[M+H] + .

[0240] Example 41: (R)-3-Bromo-5-((9-cyclopropyl-2-((1-hydroxybutan-2-yl)amino)-9H-purin-6-yl)aminobenzonitrile

[0241] To a solution of 3-bromo-5-((2-chloro-9-cyclopropyl-9H-purin-6-yl)amino)benzonitrile (20 mg, 0.05 mmol) (Reference Example 10) in sec-butanol (1 mL) were added (R)-2-aminobutan-1-ol (45 mg, 0.5 mmol) and triethylamine (0.14 mL, 1 mmol). The mixture was heated at 110°C for 12 hours and then cooled to room temperature. The reaction mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 50 / 1) to afford 8 mg of the product (40% yield). 1 H NMR(500MHz,DMSO)δ9.97(s,1H),8.59(s,1H),8.50(s,1H),7.88(s,1H),7.66(s,1H),6.56(d,J=10.0Hz,1H),4.58(s,1H),3.9 2-3.83(m,1H),3.51(d,J=10.0,5.0Hz,2H),3.36(s,1H),1.70-1.48(m,2H),1.07-0.98(m,4H),0.85(dd,J=10.0,5.0Hz,3H).MS m / z(ESI):442.10[M+H] + .

[0242] Example 42: 3-Bromo-5-((2-((cis-4-hydroxycyclohexyl)amino)-9-isopropyl-9H-purin-6-yl)amino)benzonitrile

[0243] To a solution of 3-bromo-5-((2-chloro-9-isopropyl-9H-purin-6-yl)amino)benzonitrile (20 mg, 0.05 mmol) (Reference Example 1) in sec-butanol (1 mL) were added cis-4-aminocyclohexan-1-ol (58 mg, 0.5 mmol) and triethylamine (0.140 mL, 1 mmol). The mixture was heated at 130°C for 24 hours and then cooled to room temperature. The reaction mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 50 / 1) to give 9 mg of the product (40% yield). 1 H NMR(500MHz,DMSO)δ9.98(s,1H),8.59(s,2H),8.02(s,1H),7.65(s,1H),6.71(d,J=10 .0Hz,1H),4.62-4.32(m,2H),3.76(s,2H),1.77-1.58(m,8H),1.50(d,J=5.0Hz,3H).MS m / z(ESI):470.13[M+H] + .

[0244] Example 43: 3-Bromo-5-((9-cyclopropyl-2-((cis-4-hydroxycyclohexyl)amino)-9H-purin-6-yl)amino)benzonitrile

[0245] To a solution of 3-bromo-5-((2-chloro-9-cyclopropyl-9H-purin-6-yl)amino)benzonitrile (20 mg, 0.05 mmol) (Reference Example 10) in sec-butanol (1 mL) were added cis-4-aminocyclohexan-1-ol (58 mg, 0.5 mmol) and triethylamine (0.140 mL, 1 mmol). The mixture was heated at 130°C for 24 hours and then cooled to room temperature. The reaction mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 50 / 1) to give 5 mg of the product (20% yield). 1 H NMR(500MHz,DMSO)δ9.97(s,1H),8.60(s,1H),8.55(s,1H),7.87(s,1H),7.66(s,1H),6.83(d,J =10.0Hz,1H),4.32(d,J=5.0Hz,1H),3.39-3.32(s,1H),1.77-1.56(m,8H),1.08-0.97(m,4H).MS m / z(ESI):468.11[M+H] + .

[0246] Example 44: 3-((2-(((trans-4-(benzylamino)cyclohexyl)amino)-9-isopropyl-9H-purin-6-yl)amino)-5-bromobenzonitrile

[0247] To a solution of 3-bromo-5-((2-chloro-9-isopropyl-9H-purin-6-yl)amino)benzonitrile (39 mg, 0.1 mmol) (Reference Example 1) in sec-butanol (1 mL) were added trans-N1-benzylcyclohexane-1,4-diamine (102 mg, 0.5 mmol) and triethylamine (0.140 mL, 1 mmol). The mixture was heated at 130°C for 24 hours and then cooled to room temperature. The reaction mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 50 / 1) to afford 10 mg of the product (18% yield). 1 H NMR(500MHz,DMSO-d6)δ10.02(s,1H),8.90(s,1H),8.25(s,1H),8.04(s,1H),7.67(d ,J=1.6Hz,1H),7.54(d,J=7.3Hz,2H),7.42(dt,J=14.4,7.2Hz,2H),6.77(s,1H),4.6 5-4.53(m,1H),4.11(s,2H),3.72(dtd,J=11.6,7.8,4.1Hz,1H),2.91(s,1H),2.17(d ,J=11.8Hz,2H),2.09(d,J=10.8Hz,2H),1.50(d,J=6.8Hz,8H),1.39-1.27(m,2H).MS m / z(ESI):559.20[M+H] + .

[0248] Example 45: (R)-3-Bromo-5-((2-((2,3-dihydroxypropyl)amino)-9-isopropyl-9H-purin-6-yl)aminobenzonitrile

[0249] To a solution of 3-bromo-5-((2-chloro-9-isopropyl-9H-purin-6-yl)amino)benzonitrile (39 mg, 0.1 mmol) (Reference Example 1) in sec-butanol (1 mL) was added (R)-3-aminopropane-1,2-diol (46 mg, 0.5 mmol) and triethylamine (0.140 mL, 1 mmol). The mixture was heated at 130°C for 24 hours and then cooled to room temperature. The mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 50 / 1) to afford 15 mg of the product (34% yield). 1H NMR(500MHz,DMSO-d6)δ9.99(s,1H),8.58(s,2H),8.03(s,1H),7.66(t,J=1.6Hz,1H),6.75(s,1H),4.80(s,1H),4.60(td, J=17.6,15.5,8.8Hz,1H),3.71(q,J=5.5Hz,1H),3.52-3.37(m,4H),3.26(dt,J=12.9,6.0Hz,1H),1.51(d,J=6.7Hz,6H).MS m / z(ESI):446.10[M+H] + .

[0250] Example 46: 3-Bromo-5-((9-cyclopropyl-2-(((cis-3-hydroxycyclobutyl)methyl)amino)-9H-purin-6-yl)amino)benzonitrile

[0251] To a solution of 3-bromo-5-((2-chloro-9-cyclopropyl-9H-purin-6-yl)amino)benzonitrile (39 mg, 0.1 mmol) (Reference Example 10) in sec-butanol (1 mL) were added cis-3-(aminomethyl)cyclobutan-1-ol (46 mg, 0.5 mmol) and triethylamine (0.140 mL, 1 mmol). The mixture was heated at 110°C for 12 hours and then cooled to room temperature. The reaction mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 50 / 1) to give 13 mg of the product (6% yield). 1 H NMR (500MHz, DMSO-d6) δ9.99(s,1H),8.60(d,J=66.6Hz,2H),7.88(s,1H),7.66(t,J=1.6Hz,1H),7.06(t,J=5.8Hz,1H),4.88(d,J=6.3Hz,1H),3.90(d ,J=7.3Hz,1H),3.51(s,1H),2.33-2.21(m,2H),2.09-1.95(m,1H),1.56(q d,J=8.7,2.9Hz,2H),1.06(d,J=4.2Hz,2H),1.01(dd,J=7.3,4.9Hz,2H).MS m / z(ESI):454.10[M+H] + .

[0252] Example 47: (S)-3-Bromo-5-((2-((2,3-dihydroxypropyl)amino)-9-isopropyl-9H-purin-6-yl)aminobenzonitrile

[0253] To a solution of 3-bromo-5-((2-chloro-9-isopropyl-9H-purin-6-yl)amino)benzonitrile (39 mg, 0.1 mmol) (Reference Example 1) in sec-butanol (1 mL) was added (S)-3-aminopropane-1,2-diol (46 mg, 0.5 mmol) and triethylamine (0.140 mL, 1 mmol). The mixture was heated at 130°C for 24 hours and then cooled to room temperature. The mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 50 / 1) to afford 7 mg of the product (16% yield). 1 H NMR (500MHz, DMSO-d6) δ9.99(s,1H),8.58(s,2H),8.03(s,1H),7.66(t,J=1.6Hz,1H),6.74(s,1H),4.79(s,1H),4.61(p,J=6.8Hz,1 H),4.55(s,1H),3.71(h,J=5.3Hz,1H),3.43(ddq,J=33.6,11.0,5.5Hz,4H),3.26(dt,J=12.9,6.1Hz,1H),1.51(d,J=6.7Hz,6H).MS m / z(ESI):446.09[M+H] + .

[0254] Example 48: (S)-3-Bromo-5-((9-cyclopropyl-2-((2,3-dihydroxypropyl)amino)-9H-purin-6-yl)amino)benzonitrile

[0255] To a solution of 3-bromo-5-((2-chloro-9-cyclopropyl-9H-purin-6-yl)amino)benzonitrile (39 mg, 0.1 mmol) (Reference Example 10) in sec-butanol (1 mL) was added (S)-3-aminopropane-1,2-diol (46 mg, 0.5 mmol) and triethylamine (0.140 mL, 1 mmol). The mixture was heated at 130°C for 24 hours and then cooled to room temperature. The reaction mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 50 / 1) to afford 9 mg of the product (20% yield). 1H NMR(500MHz,DMSO-d6)δ9.99(s,1H),8.57(s,2H),7.89(s,1H),7.66(t,J=1.6Hz,1H),6.81(s,1H),4.84(s,1H),4.59(s,1H),3.70 (dt,J=6.8,5.0Hz,1H),3.51-3.43(m,1H),3.42-3.35(m,3H),3.30-3.23(m,1H),1.07(dd,J=5.3,2.9Hz,2H),1.04-0.97(m,2H).MS m / z(ESI):444.08[M+H] + .

[0256] Example 49: 3-Bromo-5-((9-cyclopropyl-2-((3,4-dihydroxybutyl)amino)-9H-purin-6-yl)amino)benzonitrile

[0257] To a solution of 3-bromo-5-((2-chloro-9-cyclopropyl-9H-purin-6-yl)amino)benzonitrile (39 mg, 0.1 mmol) (Reference Example 10) in sec-butanol (1 mL) were added 3-aminopropane-1,2-diol (46 mg, 0.5 mmol) and triethylamine (0.140 mL, 1 mmol). The mixture was heated at 130°C for 24 hours and then cooled to room temperature. The reaction mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 50 / 1) to afford 10 mg of the product (22% yield). 1 H NMR(500MHz,DMSO-d6)δ9.97(s,1H),8.59(d,J=50.9Hz,2H),7.88(s,1H),7.65(t,J= 1.7Hz,1H),6.93(s,1H),4.52(s,1H),4.44(t,J=5.7Hz,1H),3.58(d,J=7.1Hz,2H),3. 43(q,J=6.5Hz,3H),3.39-3.33(m,2H),3.29(d,J=5.3Hz,1H),1.82(ddq,J=11.4,7.5 ,3.8Hz,1H),1.55-1.46(m,1H),1.07(d,J=4.1Hz,2H),1.01(dd,J=7.5,5.1Hz,2H).MS m / z(ESI):458.10[M+H] + .

[0258] Example 50: 3-Bromo-5-((9-isopropyl-2-((trans-4-morpholinocyclohexyl)amino)-9H-purin-6-yl)amino)benzonitrile

[0259] To a solution of 3-bromo-5-((2-chloro-9-isopropyl-9H-purin-6-yl)amino)benzonitrile (39 mg, 0.1 mmol) (Reference Example 1) in sec-butanol (1 mL) were added trans-4-morpholinocyclohexan-1-amine (46 mg, 0.5 mmol) and triethylamine (0.140 mL, 1 mmol). The mixture was heated at 110°C for 12 hours and then cooled to room temperature. The mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 50 / 1) to give 14 mg of the product (26% yield). 1 H NMR(500MHz,DMSO-d6)δ9.99(s,1H),8.78-8.43(m,2H),8.03(s,1H),7.66(d,J=1.7Hz,1H),6.75(s,1H),4.59(p,J=6.7Hz,1H) ,4.50-4.26(m,1H),3.96-3.54(m,5H),2.38-1.85(m,6H),1.78-1.52(m,2H),1.50(d,J=6.8Hz,6H),1.34(d,J=12.8Hz,2H).MS m / z(ESI):539.18[M+H] + .

[0260] Example 51: 4-((6-((3-Bromo-5-cyanophenyl)amino)-9-isopropyl-9H-purin-2-yl)amino)butanoic acid

[0261] To a solution of 3-bromo-5-((2-chloro-9-isopropyl-9H-purin-6-yl)amino)benzonitrile (78 mg, 0.2 mmol) (Reference Example 1) in sec-butanol (2 mL) were added 4-aminobutyric acid (103 mg, 1.0 mmol) and triethylamine (0.28 mL, 2 mmol). The mixture was heated at 130° C. for 24 hours and then cooled to room temperature. The reaction mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 50 / 1) to give 4 mg of the product (5% yield). 1H NMR(500MHz,DMSO-d6)δ9.97(s,1H),8.60(d,J=45.6Hz,2H),8.01(s,1H),7.64(s,1H),6.97(t,J=5.8Hz,1H ),4.60(p,J=6.8Hz,1H),2.24(t,J=7.6Hz,2H),1.83(q,J=7.2Hz,2H),1.50(d,J=6.8Hz,6H),1.23(s,2H).MS m / z(ESI):458.08[M+H] + .

[0262] Example 52: N6-(3-amino-5-bromophenyl)-N2-(trans-4-aminocyclohexyl)-9-isopropyl-9H-purine-2,6-diamine

[0263] 2,6-Dichloro-9-isopropyl-9H-purine (115 mg, 0.5 mmol) was dissolved in dry sec-butanol (5 mL), 5-bromobenzene-1,3-diamine (94 mg, 0.5 mmol) was added, and the mixture was heated at 110 ° C for 12 hours. After cooling to room temperature, saturated sodium bicarbonate solution was added to quench the reaction. It was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography was performed to obtain 70 mg (yield 30%) of 5-bromo-N1-(2-chloro-9-isopropyl-9H-purin-6-yl)benzene-1,3-diamine, MS m / z (ESI): 381.02 [M+H] + .

[0264] To a solution of 5-bromo-N1-(2-chloro-9-isopropyl-9H-purin-6-yl)benzene-1,3-diamine (19 mg, 0.05 mmol) in sec-butanol (1 mL) was added trans-1,4-cyclohexanediamine (58 mg, 0.5 mmol) and triethylamine (0.140 mL, 1 mmol). The mixture was heated at 130°C for 24 hours and then cooled to room temperature. The mixture was quenched with water and extracted three times with dichloromethane. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 50 / 1) to afford 5 mg of the product (25% yield). 1 H NMR(500MHz,DMSO)δ9.33(s,1H),8.05(s,4H),6.42(s,1H),4.61-4.55(m,1H),4.48(d,J=5 .0Hz,1H),3.74-3.66(m,1H),3.01-2.92(m,1H),2.07-1.99(m,4H),1.54-1.30(m,10H).MS m / z(ESI):459.16[M+H] + .

[0265] Example 53: trans-3-((6-((3-bromo-5-cyanophenyl)amino)-9-cyclopropyl-9H-purin-2-yl)amino)cyclohexane-1-carboxamide

[0266] To a solution of 3-bromo-5-((2-chloro-9-cyclopropyl-9H-purin-6-yl)amino)benzonitrile (100 mg, 0.26 mmol) (Reference Example 10) in sec-butanol (3 mL) were added trans-3-aminocyclohexane-1-carboxamide (110 mg, 0.77 mmol) and triethylamine (130 mg, 1.29 mmol). The mixture was heated at 110° C. for 12 hours and then cooled to room temperature. The mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to give 20 mg of the product (16% yield). 1 H NMR(500MHz,DMSO-d6)δ9.98(s,1H),8.68(s,1H),8.45(s,1H),7.87(s,1H),7.66 (t,J=1.5Hz,1H),7.14(s,1H),6.91(d,J=8.4Hz,1H),6.68-6.63(m,1H),3.86-3. 74(m,1H),2.29(d,J=12.6Hz,1H),2.01-1.94(m,2H),1.76(dd,J=25.4,13.1Hz,2 H),1.45-1.32(m,2H),1.17(d,J=10.6Hz,2H),1.06(s,2H),1.02-0.98(m,2H).MS m / z(ESI):495.13[M+H] + .

[0267] Example 54: trans-3-((6-((3-bromo-5-cyanophenyl)amino)-9-isopropyl-9H-purin-2-yl)amino)cyclohexane-1-carboxamide

[0268] To a solution of 3-bromo-5-((2-chloro-9-isopropyl-9H-purin-6-yl)amino)benzonitrile (100 mg, 0.26 mmol) (Reference Example 1) in sec-butanol (3 mL) were added trans-3-aminocyclohexane-1-carboxamide (110 mg, 0.77 mmol) and triethylamine (130 mg, 1.29 mmol). The mixture was heated at 130°C for 24 hours and then cooled to room temperature. The mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to give 22 mg of the product (17% yield). 1H NMR(500MHz,DMSO-d6)δ9.98(s,1H),8.66(s,1H),8.48(s,1H),8.02(s,1H),7.66(t,J =1.6Hz,1H),7.15(s,1H),6.78(d,J=8.1Hz,1H),6.65(s,1H),4.59(p,J=6.8Hz,1H),3. 79(dt,J=7.7,3.6Hz,1H),2.29(s,1H),1.99(d,J=11.7Hz,2H),1.76(dd,J=25.7,12.8 Hz,2H),1.51(s,3H),1.49(s,3H),1.45-1.31(m,2H),1.19(dd,J=21.2,10.5Hz,2H); MS m / z(ESI):497.15[M+H] + .

[0269] Example 55: N2-(trans-4-aminocyclohexyl)-N6-(3-bromo-5-methoxyphenyl)-9-cyclopropyl-9H-purine-2,6-diamine

[0270] 2,6-Dichloro-9-cyclopropyl-9H-purine (50 mg, 0.22 mmol) (Reference Example 10) was dissolved in dry sec-butanol (2 mL), 3-bromo-5-methoxyaniline (132 mL, 0.66 mmol) was added, and the mixture was heated at 110° C. for 12 hours. The mixture was cooled to room temperature, quenched by adding saturated sodium bicarbonate solution, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography (eluent: CH2Cl2 / MeOH=100 / 1) gave 56 mg (yield: 65%) of N-(3-bromo-5-methoxyphenyl)-2-chloro-9-cyclopropyl-9H-purin-6-amine. MS m / z (ESI): 394.01 [M+H]. + .

[0271] To a solution of N-(3-bromo-5-methoxyphenyl)-2-chloro-9-cyclopropyl-9H-purin-6-amine (50 mg, 0.13 mmol) in sec-butanol (1 mL) were added trans-1,4-cyclohexanediamine (44 mg, 0.38 mmol) and triethylamine (64 mg, 0.64 mmol). The mixture was heated at 130°C for 24 hours and then cooled to room temperature. The mixture was quenched with water and extracted three times with dichloromethane. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to afford 12 mg of the product (20% yield). 1H NMR(500MHz,DMSO-d6)δ9.53(s,1H),8.15(s,1H),7.83(s,1H),7.53(s,1H),6.74(t,J =2.0Hz,1H),6.68(s,1H),3.76(s,3H),3.70(ddd,J=11.5,7.9,4.1Hz,1H),2.86(td,J =10.6,9.2,5.4Hz,1H),2.02(d,J=12.3Hz,2H),1.94(d,J=11.7Hz,2H),1.55-1.39(m, 3H),1.40-1.28(m,3H),1.27-1.24(m,1H),1.05(s,2H),0.99(dd,J=7.4,5.0Hz,2H); MS m / z(ESI):472.15[M+H] + .

[0272] Example 56: N2-(trans-4-aminocyclohexyl)-N6-(3-bromo-5-methoxyphenyl)-9-isopropyl-9H-purine-2,6-diamine

[0273] 2,6-Dichloro-9-isopropyl-9H-purine (80 mg, 0.28 mmol) was dissolved in dry sec-butanol (2 mL), 3-bromo-5-methoxyaniline (167 mg, 0.83 mmol) was added, and the mixture was heated at 110°C for 12 hours. After cooling to room temperature, the reaction was quenched by adding saturated sodium bicarbonate solution. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography (eluent CH2Cl2 / MeOH=100 / 1) gave 82 mg (yield 73%) of N-(3-bromo-5-methoxyphenyl)-2-chloro-9-isopropyl-9H-purin-6-amine. MS m / z (ESI): 396.02 [M+H] + .

[0274] To a solution of N-(3-bromo-5-methoxyphenyl)-2-chloro-9-isopropyl-9H-purin-6-amine (40 mg, 0.10 mmol) in sec-butanol (1 mL) were added trans-1,4-cyclohexanediamine (35 mg, 0.30 mmol) and triethylamine (51 mg, 0.50 mmol). The mixture was heated at 130°C for 24 hours and then cooled to room temperature. The mixture was quenched with water and extracted three times with dichloromethane. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to afford 12 mg of the product (25% yield). 1H NMR(500MHz,DMSO-d6)δ9.54(s,1H),8.14(s,1H),7.98(s,1H),7.97-7.82(m,2H),7.55( s,1H),6.74(s,1H),6.56(d,J=7.9Hz,1H),4.57(p,J=6.8Hz,1H),3.77(s,3H),3.70(ddd, J=11.4,7.6,3.9Hz,1H),2.97(tt,J=11.4,3.7Hz,1H),2.10-2.03(m,2H),2.00(d,J=12. 3Hz,2H),1.53(s,1H),1.50(s,3H),1.49(s,3H),1.41-1.33(m,2H),1.31-1.25(m,1H); MS m / z(ESI):474.15[M+H] + .

[0275] Example 57: trans-4-((6-((3-bromo-5-methoxyphenyl)amino)-9-isopropyl-9H-purin-2-yl)amino)cyclohexan-1-ol

[0276] To a solution of N-(3-bromo-5-methoxyphenyl)-2-chloro-9-isopropyl-9H-purin-6-amine (40 mg, 0.10 mmol) (Reference Example 56) in sec-butanol (1 mL) were added trans-4-aminocyclohexan-1-ol (35 mg, 0.30 mmol) and triethylamine (51 mg, 0.50 mmol). The mixture was heated at 130° C. for 24 hours and then cooled to room temperature. The mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to give 10 mg of the product (yield 21%). 1 H NMR (500MHz, DMSO-d6) δ9.50(s,1H),7.96(s,1H),7.58(s,1H),6.74(t,J=2.0Hz,1H),6.45(d,J=8.1Hz,1H),4.57(p,J=6.8Hz,1H),4.48(d,J =4.4Hz,1H),3.76(s,3H),1.94(d,J=11.0Hz,2H),1.84(d,J=10.3Hz,2H),1.50(s,3H),1.48(s,3H),1.36-1.32(m,2H),1.32-1.28(m,2H); MS m / z(ESI):475.15[M+H] + .

[0277] Example 58: 3-((2-(((trans-4-aminocyclohexyl)amino)-9-cyclopropyl-9H-purin-6-yl)amino)-5-(trifluoromethyl)benzonitrile

[0278] 2,6-Dichloro-9-cyclopropyl-9H-purine (100 mg, 0.44 mmol) (Reference Example 10) was dissolved in dry sec-butanol (2 mL), 3-amino-5-(trifluoromethyl)benzonitrile (244 mg, 1.32 mmol) was added, and the mixture was heated at 110°C for 12 hours. After cooling to room temperature, the reaction was quenched by adding saturated sodium bicarbonate solution. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography (eluent: CH2Cl2 / MeOH = 100 / 1) gave 100 mg (yield: 60%) of 3-((2-chloro-9-cyclopropyl-9H-purin-6-yl)amino)-5-(trifluoromethyl)benzonitrile. MS m / z (ESI): 379.07 [M+H] + .

[0279] To a solution of 3-((2-chloro-9-cyclopropyl-9H-purin-6-yl)amino)-5-(trifluoromethyl)benzonitrile (50 mg, 0.13 mmol) in sec-butanol (1 mL) was added trans-1,4-cyclohexanediamine (45 mg, 0.40 mmol) and triethylamine (67 mg, 0.66 mmol). The mixture was heated at 130°C for 24 hours and then cooled to room temperature. The reaction mixture was quenched with water and extracted three times with dichloromethane. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to afford 8 mg of the product (13% yield). 1 H NMR (500MHz, DMSO-d6) δ10.12(s,1H),8.67(s,2H),7.90(s,1H),7.84(s,1H),6.83(d,J=8.0Hz,1H),3.69(s,1H),2.86(s,1H),2. 02(d,J=8.4Hz,2H),1.95(s,2H),1.36(q,J=7.5,5.0Hz,4H),1.27-1.21(m,2H),1.10-1.04(m,2H),1.01(dd,J=7.5,5.1Hz,2H); MS m / z(ESI):457.20[M+H] + .

[0280] Example 59: 3-((9-cyclopropyl-2-((trans-4-hydroxycyclohexyl)amino)-9H-purin-6-yl)amino)-5-(trifluoromethyl)benzonitrile

[0281] To a solution of 3-((2-chloro-9-cyclopropyl-9H-purin-6-yl)amino)-5-(trifluoromethyl)benzonitrile (50 mg, 0.13 mmol) (Reference Example 58) in sec-butanol (1 mL) were added trans-4-aminocyclohexan-1-ol (45 mg, 0.40 mmol) and triethylamine (67 mg, 0.66 mmol). The mixture was heated at 110° C. for 12 hours and then cooled to room temperature. The reaction mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to give 10 mg of the product (yield: 17%). 1 H NMR (500MHz, DMSO-d6) δ10.13(s,1H),8.73(s,2H),7.89(s,1H),7.84(s,1H),6.76(d,J=8.2Hz,1H),4.50(d,J=3.8Hz,1H),3.69(d,J =10.2Hz,1H),3.35(s,1H),1.92(s,2H),1.83(d,J=10.4Hz,2H),1.30(q,J=13.8Hz,4H),1.07(s,2H),1.00(dd,J=7.3,5.0Hz,2H); MS m / z(ESI):458.20[M+H] + .

[0282] Example 60: 3-Bromo-5-((9-isopropyl-2-((trans-4-(piperidin-1-yl)cyclohexyl)amino)-9H-purin-6-yl)amino)benzonitrile

[0283] To a solution of 3-bromo-5-((2-chloro-9-isopropyl-9H-purin-6-yl)amino)benzonitrile (39 mg, 0.10 mmol) (Reference Example 1) in sec-butanol (1 mL) were added trans-(piperidin-1-yl)cyclohexane-1-amine hydrochloride (109 mg, 0.50 mmol) and triethylamine (101 mg, 1 mmol). The mixture was heated at 130°C for 24 hours and then cooled to room temperature. The mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 10 / 1) to give 14 mg of the product (26% yield). 1H NMR (500MHz, DMSO-d6) δ10.03(s,1H),9.81(s,1H),8.57(s,2H),8.04(s,1H),7.67(s,1H),6.83(d,J=7.8Hz,1H),4.64-4.55(m,1H),3.73- 3.64(m,1H),3.15(s,1H),2.93(s,2H),2.13(d,J=12.0Hz,4H),1.79(s,3H),1.66(s,3H),1.50(d,J=6.8Hz,6H),1.38(q,J=12.3Hz,3H).MS m / z(ESI):537.22[M+H] + .

[0284] Example 61: 3-Bromo-5-((9-cyclopropyl-2-((trans-4-(piperidin-1-yl)cyclohexyl)amino)-9H-purin-6-yl)amino)benzonitrile

[0285] To a solution of 3-bromo-5-((2-chloro-9-cyclopropyl-9H-purin-6-yl)amino)benzonitrile (39 mg, 0.10 mmol) (Reference Example 10) in sec-butanol (1 mL) were added trans-(piperidin-1-yl)cyclohexane-1-amine hydrochloride (109 mg, 0.50 mmol) and triethylamine (101 mg, 1 mmol). The mixture was heated at 130°C for 24 hours and then cooled to room temperature. The reaction mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 10 / 1) to give 11 mg of the product (21% yield). 1 H NMR (500MHz, DMSO-d6) δ10.03(s,1H),9.80(s,1H),8.57(d,J=16.4Hz,2H),7.89(s,1H),7.68(d,J=1.6Hz,1H),6.97(s,1H),3.71(d,J=8.5Hz,1H) ,3.15(s,1H),2.92(s,2H),2.13(d,J=11.8Hz,4H),1.79(s,4H),1.66(d, J=12.9Hz,3H),1.38(q,J=12.1Hz,3H),1.06(s,2H),1.03-0.93(m,2H).MS m / z(ESI):535.20[M+H] + .

[0286] Example 62: 3-Bromo-5-((2-(((3-hydroxyoxetan-3-yl)methyl)amino)-9-isopropyl-9H-purin-6-yl)amino)benzonitrile

[0287] To a solution of 3-bromo-5-((2-chloro-9-isopropyl-9H-purin-6-yl)amino)benzonitrile (39 mg, 0.10 mmol) (Reference Example 1) in sec-butanol (1 mL) were added (3-(aminomethyl)oxetan-3-yl)methanol (59 mg, 0.50 mmol) and triethylamine (101 mg, 1 mmol). The mixture was heated at 130° C. for 24 hours and then cooled to room temperature. The mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to give 10 mg of the product (22% yield). 1 H NMR (500MHz, DMSO-d6) δ10.03(s,1H),8.58(d,J=18.9Hz,2H),8.04(s,1H),7.66(t,J=1.6Hz,1H),6.93(s,1H),5.95(s, 1H),4.61(p,J=6.8Hz,1H),4.51(d,J=6.2Hz,2H),4.41(d,J=6.2Hz,2H),3.70(d,J=6.1Hz,2H),1.51(d,J=6.8Hz,6H).MS m / z(ESI):458.09[M+H] + .

[0288] Example 63: 3-Bromo-5-((9-cyclopropyl-2-(((3-hydroxyoxetan-3-yl)methyl)amino)-9H-purin-6-yl)amino)benzonitrile

[0289] To a solution of 3-bromo-5-((2-chloro-9-cyclopropyl-9H-purin-6-yl)amino)benzonitrile (39 mg, 0.10 mmol) (Reference Example 10) in sec-butanol (1 mL) were added (3-(aminomethyl)oxetan-3-yl)methanol (59 mg, 0.50 mmol) and triethylamine (101 mg, 1 mmol). The mixture was heated at 130°C for 24 hours and then cooled to room temperature. The mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to give 9 mg of the product (22% yield). 1H NMR (500MHz, DMSO-d6) δ10.03(s,1H),8.57(s,2H),7.91(s,1H),7.66(t,J=1.5Hz,1H),7.02(s,1H),6.04(s,1H),4.51(d,J=6.2Hz,2H), 4.42(d,J=6.3Hz,2H),3.71(d,J=6.0Hz,2H),3.37(tt,J=7.3,3.9Hz,1H),1.09-1.04(m,2H),1.01(dddd,J=8.1,6.8,5.2,2.2Hz,2H).MS m / z(ESI):456.08[M+H] + .

[0290] Example 64: 3-Bromo-5-((9-isopropyl-2-((2-(4-methylpiperazin-1-yl)ethyl)amino)-9H-purin-6-yl)amino)benzonitrile

[0291] To a solution of 3-bromo-5-((2-chloro-9-isopropyl-9H-purin-6-yl)amino)benzonitrile (39 mg, 0.10 mmol) (Reference Example 1) in sec-butanol (1 mL) were added 2-(4-methylpiperazin-1-yl)ethan-1-amine (72 mg, 0.50 mmol) and triethylamine (101 mg, 1 mmol). The mixture was heated at 130°C for 24 hours and then cooled to room temperature. The mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to afford 5 mg of the product (21% yield). 1 H NMR(500MHz,DMSO-d6)δ9.97(s,1H),8.56(d,J=23.2Hz,2H),8.02(s,1H),7.66(s,1H),6.71(s,1H),4.61(p ,J=6.8Hz,1H),3.44(q,J=6.5Hz,2H),2.61-2.54(m,4H),2.44(s,4H),2.22(s,3H),1.51(d,J=6.7Hz,6H).MS m / z(ESI):498.15[M+H] + .

[0292] Example 65: 3-Bromo-5-((9-cyclopropyl-2-((2-(4-methylpiperazin-1-yl)ethyl)amino)-9H-purin-6-yl)amino)benzonitrile

[0293] To a solution of 3-bromo-5-((2-chloro-9-cyclopropyl-9H-purin-6-yl)amino)benzonitrile (39 mg, 0.10 mmol) (Reference Example 10) in sec-butanol (1 mL) were added 2-(4-methylpiperazin-1-yl)ethan-1-amine (72 mg, 0.50 mmol) and triethylamine (101 mg, 1 mmol). The mixture was heated at 130°C for 24 hours and then cooled to room temperature. The mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to afford 3 mg of the product (13% yield). 1 H NMR(500MHz,DMSO-d6)δ9.97(s,1H),8.55(d,J=36.3Hz,2H),7.89(s,1H),7.66(t,J=1.6Hz,1H),6.80(s,1H),3.45(q,J=6.5 Hz,2H),3.36(q,J=3.4Hz,1H),2.56(s,4H),2.45(s,4H),2.25(s,3H),1.07(q,J=4.3Hz,2H),1.01(dd,J=7.4,5.0Hz,2H).MS m / z(ESI):496.15[M+H] + .

[0294] Example 66: 3-Bromo-5-((9-isopropyl-2-((2-(2-oxoimidazolidin-1-yl)ethyl)amino)-9H-purin-6-yl)amino)benzonitrile

[0295] To a solution of 3-bromo-5-((2-chloro-9-isopropyl-9H-purin-6-yl)amino)benzonitrile (39 mg, 0.10 mmol) (Reference Example 1) in sec-butanol (1 mL) were added 1-(2-aminoethyl)imidazolidin-2-one (66 mg, 0.50 mmol) and triethylamine (101 mg, 1 mmol). The mixture was heated at 130°C for 24 hours and then cooled to room temperature. The mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to afford 11 mg of the product (23% yield). 1H NMR(500MHz,DMSO-d6)δ9.98(s,1H),8.57(d,J=28.5Hz,2H),8.03(s,1H),7.65(t,J=1.7Hz,1H),6.94(s,1H),6 .23(s,1H),4.62(p,J=6.7Hz,1H),3.47-3.39(m,4H),3.28(s,1H),3.24-3.17(m,2H),1.51(d,J=6.8Hz,6H).MS m / z(ESI):484.13[M+H] + .

[0296] Example 67: 3-((2-(((trans-4-aminocyclohexyl)amino)-9-isopropyl-9H-purin-6-yl)amino)-5-(trifluoromethyl)benzonitrile

[0297] 2,6-Dichloro-9-isopropyl-9H-purine (100 mg, 0.44 mmol) was dissolved in dry sec-butanol (2 mL), and 3-amino-5-(trifluoromethyl)benzonitrile (244 mg, 1.32 mmol) was added. The mixture was heated at 110°C for 12 hours. After cooling to room temperature, the reaction was quenched by adding saturated sodium bicarbonate solution. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography (eluent: CH2Cl2 / MeOH = 100 / 1) afforded 110 mg (yield: 63%) of 3-((2-chloro-9-isopropyl-9H-purin-6-yl)amino)-5-(trifluoromethyl)benzonitrile. MS m / z (ESI): 381.08 [M+H] + .

[0298] To a solution of 3-((2-chloro-9-isopropyl-9H-purin-6-yl)amino)-5-(trifluoromethyl)benzonitrile (50 mg, 0.13 mmol) in sec-butanol (1 mL) was added trans-1,4-cyclohexanediamine (45 mg, 0.40 mmol) and triethylamine (66 mg, 0.65 mmol). The mixture was heated at 130°C for 24 hours and then cooled to room temperature. The reaction mixture was quenched with water and extracted three times with dichloromethane. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 10 / 1) to afford 10 mg of the product (17% yield). 1H NMR (500MHz, DMSO-d6) δ10.14(s,1H),8.62(s,2H),8.04(s,1H),7.93(s,2H),7.84(s,1H),6.74(s,1H),4.60(p,J=6.8Hz,1H ),3.73-3.59(m,1H),2.97(s,1H),2.03(dd,J=23.7,11.2Hz,4H),1.52(s,3H),1.51(s,3H),1.40(pd,J=12.7,6.2Hz,4H); MS m / z(ESI):459.23[M+H] + .

[0299] Example 68: 3-Bromo-5-((2-((((trans)-4-cyanohexyl)amino)-9-cyclopropyl-9H-purin-6-yl)amino)benzonitrile

[0300] To a solution of 3-bromo-5-((2-chloro-9-cyclopropyl-9H-purin-6-yl)amino)benzonitrile (39 mg, 0.10 mmol) (Reference Example 10) in sec-butanol (1 mL) were added trans-4-aminocyclohexane-1-carbonitrile hydrochloride (80 mg, 0.50 mmol) and triethylamine (101 mg, 1 mmol). The mixture was heated at 130°C for 24 hours and then cooled to room temperature. The reaction mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to give 8 mg of the product (17% yield). 1 H NMR(500MHz,DMSO-d6)δ9.98(s,1H),8.54(d,J=15.3Hz,2H),7.88(s,1H),7.6 8(d,J=1.6Hz,1H),6.92(d,J=7.8Hz,1H),3.74(dt,J=14.7,5.5Hz,2H),2.68(t t,J=11.7,3.7Hz,1H),2.14-2.06(m,2H),2.04-1.96(m,2H),1.72-1.62(m,2H) ,1.42-1.30(m,2H),1.06(p,J=4.9,4.4Hz,2H),1.00(dd,J=7.3,5.0Hz,2H).MS m / z(ESI):477.11[M+H] + .

[0301] Example 69: 3-((2-(((trans-4-aminocyclohexyl)amino)-9-isopropyl-9H-purin-6-yl)amino)-5-methoxybenzonitrile

[0302] 2,6-Dichloro-9-isopropyl-9H-purine (100 mg, 0.44 mmol) was dissolved in dry sec-butanol (2 mL), and 3-amino-5-methoxybenzonitrile (153 mg, 1.03 mmol) was added. The mixture was heated at 110°C for 12 hours. After cooling to room temperature, the reaction was quenched by adding saturated sodium bicarbonate solution. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography (eluent: CH2Cl2 / MeOH = 100 / 1) afforded 120 mg (81% yield) of 3-((2-chloro-9-isopropyl-9H-purin-6-yl)amino)-5-methoxybenzonitrile. MS m / z (ESI): 343.11 [M+H] + .

[0303] To a solution of 3-((2-chloro-9-isopropyl-9H-purin-6-yl)amino)-5-methoxybenzonitrile (50 mg, 0.15 mmol) in sec-butanol (1 mL) was added trans-1,4-cyclohexanediamine (50 mg, 0.45 mmol) and triethylamine (73 mg, 0.73 mmol). The mixture was heated at 130°C for 24 hours and then cooled to room temperature. The reaction mixture was quenched with water and extracted three times with dichloromethane. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 10 / 1) to afford 11 mg of the product (18% yield). 1 H NMR (500MHz, DMSO-d6) δ9.72(s,1H),8.12(s,1H),7.98(s,1H),7.94(t,J=2. 2Hz,1H),7.01(t,J=1.8Hz,1H),6.63(d,J=7.7Hz,1H),4.58(p,J=6.7Hz,1H) ,3.82(s,3H),3.66(d,J=8.9Hz,1H),2.82(s,1H),2.03(d,J=9.7Hz,2H),1.9 3(d,J=9.6Hz,2H),1.51(s,3H),1.50(s,3H),1.36(q,J=10.4,9.6Hz,4H);MS m / z(ESI):421.25[M+H] + .

[0304] Example 70: 3-((2-(((trans-4-hydroxycyclohexyl)amino)-9-isopropyl-9H-purin-6-yl)amino)-5-methoxybenzonitrile

[0305] To a solution of 3-((2-chloro-9-isopropyl-9H-purin-6-yl)amino)-5-methoxybenzonitrile (50 mg, 0.15 mmol) (Reference Example 69) in sec-butanol (1 mL) were added trans-4-aminocyclohexan-1-ol (50 mg, 0.45 mmol) and triethylamine (73 mg, 0.73 mmol). The mixture was heated at 130°C for 24 hours and then cooled to room temperature. The reaction mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 10 / 1) to give 12 mg of the product (20% yield). 1 H NMR (500MHz, DMSO-d6) δ10.13(s,1H),8.71(s,2H),8.03(s,1H),7.83(s,1H),6.63(d,J=8.2Hz,1H),4.59(p,J=6.7Hz,1H),4.50(d,J= MS m / z(ESI):460.22[M+H] + .

[0306] Example 71: 3-((2-((trans-4-aminocyclohexyl)amino)-9-cyclopropyl-9H-purin-6-yl)amino)-5-methoxybenzonitrile

[0307] 2,6-Dichloro-9-cyclopropyl-9H-purine (100 mg, 0.44 mmol) was dissolved in dry sec-butanol (2 mL), and 3-amino-5-methoxybenzonitrile (195 mg, 1.32 mmol) was added. The mixture was heated at 110°C for 12 hours. The mixture was cooled to room temperature and quenched by adding saturated sodium bicarbonate solution. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography (eluent: CH2Cl2 / MeOH = 100 / 1) afforded 125 mg (yield: 84%) of 3-((2-chloro-9-cyclopropyl-9H-purin-6-yl)amino)-5-methoxybenzonitrile. MS m / z (ESI): 341.09 [M+H] + .

[0308] To a solution of 3-((2-chloro-9-cyclopropyl-9H-purin-6-yl)amino)-5-methoxybenzonitrile (50 mg, 0.15 mmol) in sec-butanol (1 mL) was added trans-1,4-cyclohexanediamine (50 mg, 0.45 mmol) and triethylamine (74 mg, 0.73 mmol). The mixture was heated at 130°C for 24 hours and then cooled to room temperature. The reaction mixture was quenched with water and extracted three times with dichloromethane. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 10 / 1) to afford 15 mg of the product (24% yield). 1 H NMR (500MHz, DMSO-d6) δ9.72(s,1H),8.09(s,1H),7.94(s,1H),7.85(s,1H),7.01(t,J=1.8Hz,1H),6.75(d,J=7.6Hz,1H),3.82(s,3H),3 MS m / z(ESI):419.23[M+H] + .

[0309] Example 72: 3-((9-Cyclopropyl-2-((trans-4-hydroxycyclohexyl)amino)-9H-purin-6-yl)amino)-5-methoxybenzonitrile

[0310] To a solution of 3-((2-chloro-9-cyclopropyl-9H-purin-6-yl)amino)-5-methoxybenzonitrile (50 mg, 0.15 mmol) (Reference Example 71) in sec-butanol (1 mL) were added trans-4-aminocyclohexan-1-ol (50 mg, 0.45 mmol) and triethylamine (74 mg, 0.73 mmol). The mixture was heated at 110°C for 24 hours and then cooled to room temperature. The reaction mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 10 / 1) to give 12 mg of the product (20% yield). 1H NMR (500MHz, DMSO-d6) δ9.70(s,1H),8.16(t,J=1.6Hz,1H),7.97(s,1H),7.92(t,J=2.2Hz,1H),7.01(dd,J=2.4,1.2Hz,1H),6.55(d,J=7.8Hz,1H),4. 58(p,J=6.7Hz,1H),4.49(d,J=4.1Hz,1H),3.81(s,3H),3.71-3.63(m,1H) ,1.95(s,2H),1.85(s,2H),1.51(s,3H),1.49(s,3H),1.33-1.28(m,4H).MS m / z(ESI):422.24[M+H] + .

[0311] Example 73: 3-((9-Cyclopropyl-2-((2-(4-methylpiperazin-1-yl)ethyl)amino)-9H-purin-6-yl)amino)-5-(trifluoromethyl)benzonitrile

[0312] 2,6-Dichloro-9-cyclopropyl-9H-purine (100 mg, 0.44 mmol) was dissolved in dry sec-butanol (2 mL), and 3-amino-5-(trifluoromethyl)benzonitrile (244 mg, 1.32 mmol) was added. The mixture was heated at 110°C for 12 hours. After cooling to room temperature, the reaction was quenched by adding saturated sodium bicarbonate solution. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography (eluent: CH2Cl2 / MeOH = 100 / 1) afforded 100 mg (yield: 60%) of 3-((2-chloro-9-cyclopropyl-9H-purin-6-yl)amino)-5-(trifluoromethyl)benzonitrile. MS m / z (ESI): 379.07 [M+H] + .

[0313] To a solution of 3-((2-chloro-9-cyclopropyl-9H-purin-6-yl)amino)-5-(trifluoromethyl)benzonitrile (50 mg, 0.13 mmol) in sec-butanol (1 mL) were added 2-(4-methylpiperazin-1-yl)ethan-1-amine (56 mg, 0.40 mmol) and triethylamine (67 mg, 0.66 mmol). The mixture was heated at 130° C. for 24 hours and then cooled to room temperature. The reaction mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to afford 16 mg of the product (25% yield). 1H NMR (500MHz, DMSO-d6) δ10.17(s,1H),8.77(d,J=28.7Hz,2H),7.91(s,1H),7.83(s,1H),6.78(t,J=5.7Hz,1H), 3.45(q,J=6.4Hz,3H),2.59-2.52(m,3H),2.44(s,5H),2.22(s,3H),1.07(q,J=4.3Hz,2H),1.04-0.98(m,2H).MS m / z(ESI):486.24[M+H] + .

[0314] Example 74: 3-((6-((3-Bromo-5-cyanophenyl)amino)-9-isopropyl-9H-purin-2-yl)amino)-N-methylpropanamide

[0315] To a solution of 3-bromo-5-((2-chloro-9-isopropyl-9H-purin-6-yl)amino)benzonitrile (20 mg, 0.05 mmol) (Reference Example 1) in sec-butanol (1 mL) were added 3-amino-N-methylpropionamide (51 mg, 0.50 mmol) and triethylamine (101 mg, 1 mmol). The mixture was heated at 130°C for 24 hours and then cooled to room temperature. The mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to give 7 mg of the product (31% yield). 1 H NMR(500MHz,DMSO)δ9.97(s,1H),8.60(s,1H),8.55(s,1H),8.03(s,1H),7.73(d,J=5.0Hz,1H),7.65(s,1H),4.6 5-4.59(m,1H),3.55-3.51(m,2H),2.57(d,J=5.0Hz,3H),2.42(dd,J=10.0,5.0Hz,2H),1.51(d,J=10.0Hz,1H).MS m / z(ESI):457.11[M+H] + .

[0316] Example 75: 3-((6-((3-Bromo-5-cyanophenyl)amino)-9-cyclopropyl-9H-purin-2-yl)amino)-N-methylpropanamide

[0317] To a solution of 3-bromo-5-((2-chloro-9-cyclopropyl-9H-purin-6-yl)amino)benzonitrile (20 mg, 0.05 mmol) (Reference Example 10) in sec-butanol (1 mL) were added 3-amino-N-methylpropionamide (51 mg, 0.50 mmol) and triethylamine (101 mg, 1 mmol). The mixture was heated at 130°C for 24 hours and then cooled to room temperature. The reaction mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to give 3 mg of the product (13% yield). 1 H NMR(500MHz,DMSO)δ9.97(s,1H),8.62(s,1H),8.52(s,1H),7.89(s,1H),7.73(d,J=5.0Hz,1H),7.65(s,1H ),356-3.51(m,2H),3.39(s,1H),2.58(d,J=5.0Hz,3H),2.43(dd,J=10.0,5.0Hz,2H),1.08-0.99(m,4H).MS m / z(ESI):455.09[M+H] + .

[0318] Example 76: 4-((6-((3-Bromo-5-cyanophenyl)amino)-9-isopropyl-9H-purin-2-yl)amino)cyclohexane-1-carboxylic acid

[0319] To a solution of 3-bromo-5-((2-chloro-9-isopropyl-9H-purin-6-yl)amino)benzonitrile (20 mg, 0.05 mmol) (Reference Example 1) in sec-butanol (1 mL) were added 4-aminocyclohexane-1-carboxylic acid (71 mg, 0.50 mmol) and triethylamine (101 mg, 1 mmol). The mixture was heated at 130°C for 24 hours and then cooled to room temperature. The reaction mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to give 5 mg of the product (20% yield). 1 H NMR(500MHz,DMSO)δ11.94(br,1H),9.97(s,1H),8.65(s,1H),8.44(s,1H),8.02(s,1H),7.65(s, 1H),6.72(s,1H),4.62-4.57(m,1H),3.74-3.66(s,1H),2.18-1.94(m,5H),1.55-1.27(m,10H).MS m / z(ESI):498.13[M+H] + .

[0320] Example 77: 3-Bromo-5-((9-cyclopropyl-2-((2-(4-hydroxypiperidin-1-yl)ethyl)amino)-9H-purin-6-yl)amino)benzonitrile

[0321] To a solution of 3-bromo-5-((2-chloro-9-cyclopropyl-9H-purin-6-yl)amino)benzonitrile (39 mg, 0.10 mmol) (Reference Example 10) in sec-butanol (1 mL) were added 1-(2-aminoethyl)piperidin-4-ol (72 mg, 0.50 mmol) and triethylamine (101 mg, 1 mmol). The mixture was heated at 110°C for 12 hours and then cooled to room temperature. The reaction mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to give 9 mg of the product (yield 18%). 1 H NMR (500MHz, DMSO-d6) δ9.99(s,1H),8.56(d,J=42.9Hz,2H),7.89(s,1H),7.66(t,J=1.6Hz,1H),6.81(s,1H),4.51(s,1H),3. 43(s,3H),3.37(s,1H),2.78(s,2H),2.07(s,2H),1.70(s,2H),1.39(s,2H),1.07(q,J=5.8,5.1Hz,2H),1.04-0.93(m,2H).MS m / z(ESI):497.14[M+H] + .

[0322] Example 78: 3-Bromo-5-((9-cyclopropyl-2-((2-(piperidin-2-yl)ethyl)amino)-9H-purin-6-yl)amino)benzonitrile

[0323] To a solution of 3-bromo-5-((2-chloro-9-cyclopropyl-9H-purin-6-yl)amino)benzonitrile (78 mg, 0.20 mmol) (Reference Example 10) in sec-butanol (2 mL) were added tert-butyl 2-(2-amino-ethyl)-piperidine-1-carboxylate (144 mg, 1 mmol) and triethylamine (202 mg, 2 mmol). The mixture was heated at 130° C. for 24 hours and then cooled to room temperature. The mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 50 / 1) to afford 63 mg (yield: 54%) of the intermediate tert-butyl 2-(2-((6-((3-bromo-5-cyanophenyl)amino)-9-cyclopropyl-9H-purin-2-yl)amino)ethyl)piperidine-1-carboxylate.

[0324] The intermediate tert-butyl 2-(2-((6-((3-bromo-5-cyanophenyl)amino)-9-cyclopropyl-9H-purin-2-yl)amino)ethyl)piperidine-1-carboxylate (63 mg, 0.11 mmol) was added to a 6N HCl solution in ethyl acetate (2 mL) and stirred at room temperature for 12 hours. The solvent was removed under reduced pressure, and saturated sodium bicarbonate solution was added to neutralize excess hydrochloric acid. The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to afford 23 mg of the product (68% yield). 1 H NMR (500MHz, DMSO-d6) δ9.98 (s, 1H), 8.58 (d, J = 43.3Hz, 2H), 7.88 (s, 1H), 7.6 6(t,J=1.6Hz,1H),7.03(s,1H),3.46-3.34(m,5H),2.88(d,J=11.8Hz,1H),2.4 5(td,J=11.6,2.8Hz,1H),1.73-1.67(m,1H),1.59(td,J=13.4,7.0Hz,3H),1.4 8-1.42(m,1H),1.30-1.22(m,2H),1.06(q,J=4.4Hz,2H),1.04-0.96(m,2H).MS m / z(ESI):481.15[M+H] + .

[0325] Example 79: 3-Bromo-5-((9-isopropyl-2-((2-oxopiperidin-3-yl)amino)-9H-purin-6-yl)aminobenzonitrile

[0326] To a solution of 3-bromo-5-((2-chloro-9-isopropyl-9H-purin-6-yl)amino)benzonitrile (39 mg, 0.1 mmol) (Reference Example 1) in sec-butanol (1 mL) were added 3-aminopiperidin-2-one (57 mg, 0.50 mmol) and triethylamine (101 mg, 1 mmol). The mixture was heated at 130°C for 24 hours and then cooled to room temperature. The reaction mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to give 6 mg of the product (13% yield). 1H NMR(500MHz,DMSO-d6)δ10.02(s,1H),8.55(t,J=1.9Hz,2H),8.04(s,1H),7.67(s,1H),7.58(s,1H),6.89( s,1H),4.61(p,J=6.7Hz,1H),4.30(s,1H),3.20(s,2H),2.17(s,1H),1.87(s,3H),1.51(d,J=6.7Hz,6H).MS m / z(ESI):469.11[M+H] + .

[0327] Example 80: 3-Bromo-5-((2-cis-4-hydroxytetrahydrofuran-3-yl)methyl)amino)-9-isopropyl-9H-purin-6-yl)amino)benzonitrile

[0328] To a solution of 3-bromo-5-((2-chloro-9-isopropyl-9H-purin-6-yl)amino)benzonitrile (39 mg, 0.1 mmol) (Reference Example 1) in sec-butanol (1 mL) were added cis-4-(aminomethyl)tetrahydrofuran-3-ol (59 mg, 0.50 mmol) and triethylamine (101 mg, 1 mmol). The mixture was heated at 130°C for 24 hours and then cooled to room temperature. The reaction mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to give 13 mg of the product (28% yield). 1 H NMR(500MHz,DMSO-d6)δ10.01(s,1H),8.57(s,2H),8.04(s,1H),7.67(t,J=1.6Hz ,1H),6.90(s,1H),5.02(s,1H),4.60(p,J=6.8Hz,1H),4.26(s,1H),3.85(t,J=7.8 Hz, 1H), 3.79 (dd, J=9.2, 3.9Hz, 1H), 3.61 (dd, J=9.3, 1.3Hz, 1H), 3.49 (ddd, J=11. 7,9.1,6.6Hz,2H),3.45-3.38(m,1H),2.48-2.39(m,1H),1.51(d,J=6.8Hz,6H).MS m / z(ESI):472.12[M+H] + .

[0329] Example 81: 3-Bromo-5-((9-cyclopropyl-2-(((cis-4-hydroxytetrahydrofuran-3-yl)methyl)amino)-9H-purin-6-yl)amino)benzonitrile

[0330] To a solution of 3-bromo-5-((2-chloro-9-cyclopropyl-9H-purin-6-yl)amino)benzonitrile (39 mg, 0.1 mmol) (Reference Example 10) in sec-butanol (1 mL) were added cis-4-(aminomethyl)tetrahydrofuran-3-ol (59 mg, 0.50 mmol) and triethylamine (101 mg, 1 mmol). The mixture was heated at 130°C for 24 hours and then cooled to room temperature. The reaction mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to give 11 mg of the product (23% yield). 1 H NMR (500MHz, DMSO-d6) δ10.01(s,1H),8.56(s,2H),7.90(s,1H),7.67(t,J=1.6Hz,1H),7.02(s,1H),4.26(s,1H),3.86(t,J=7.8Hz,1H),3.79(dd ,J=9.2,3.9Hz,1H),3.62(dd,J=9.2,1.1Hz,1H),3.54-3.46(m,2H),3.4 3-3.34(m,3H),2.44(s,1H),1.06(t,J=3.0Hz,2H),1.04-0.98(m,2H).MS m / z(ESI):470.10[M+H] + .

[0331] Example 82: 3-Bromo-5-((2-((cis-4-(hydroxymethyl)cyclopent-2-en-1-yl)amino)-9-isopropyl-9H-purin-6-yl)aminobenzonitrile

[0332] To a solution of 3-bromo-5-((2-chloro-9-isopropyl-9H-purin-6-yl)amino)benzonitrile (39 mg, 0.1 mmol) (Reference Example 1) in sec-butanol (1 mL) were added (cis-4-aminocyclopent-2-en-1-yl)methanol hydrochloride (75 mg, 0.50 mmol) and triethylamine (101 mg, 1 mmol). The mixture was heated at 110°C for 12 hours and then cooled to room temperature. The reaction mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to give 10 mg of the product (21% yield). 1H NMR (500MHz, DMSO-d6) δ10.01(s,1H),8.57(s,2H),8.04(s,1H),7.65(t,J=1.6Hz,1H),6.88(s,1H),5.86(s,2H),4.94(q,J=7.2Hz,1H),4.61 (t,J=5.3Hz,2H),3.39(t,J=5.9Hz,2H),2.76(h,J=7.1,6.6Hz,1H),2.49-2.42(m,1H),1.51(d,J=6.7Hz,6H),1.38(dt,J=13.1,6.6Hz,1H).MS m / z(ESI):468.12[M+H] + .

[0333] Example 83: 3-((2-((4-Aminophenyl)amino)-9-cyclopropyl-9H-purin-6-yl)amino)-5-(trifluoromethyl)benzonitrile

[0334] 3-((2-chloro-9-cyclopropyl-9H-purin-6-yl)amino)-5-(trifluoromethyl)benzonitrile (100 mg, 0.26 mmol) (Reference Example 73) and p-phenylenediamine (43 mg, 0.40 mmol) were dissolved in dry 1,4-dioxane (1 mL). Palladium acetate (6 mg, 0.026 mmol), Xanphos (16 mg, 0.026 mmol), and cesium carbonate (258 mg, 0.80 mmol) were then added sequentially. The mixture was heated at 120°C for 4 hours and then cooled to room temperature. The mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to obtain 5 mg of the product (4% yield). 1 H NMR (500MHz, DMSO-d6) δ10.17(s,1H),8.91(d,J=10.2Hz,2H),8.42(d,J=1.9Hz,1H),7.98(s,1H),7.84(s,1H),7.35(d, J=8.4Hz,2H),6.57-6.52(m,2H),4.67(s,2H),3.43(tt,J=7.3,3.8Hz,1H),1.12(q,J=4.1Hz,2H),1.07-1.02(m,2H).MS m / z(ESI):451.17[M+H] + .

[0335] Example 84: 3-((2-(((3-(Benzylamino)oxetan-3-yl)methyl)amino)-9-isopropyl-9H-purin-6-yl)amino)-5-bromobenzonitrile

[0336] To a solution of 3-bromo-5-((2-chloro-9-isopropyl-9H-purin-6-yl)amino)benzonitrile (39 mg, 0.1 mmol) (Reference Example 1) in sec-butanol (1 mL) were added 3-(aminomethyl)-N-benzyloxetane-3-amine (96 mg, 0.50 mmol) and triethylamine (101 mg, 1 mmol). The mixture was heated at 130°C for 24 hours and then cooled to room temperature. The reaction mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to give 13 mg of the product (28% yield). 1 H NMR(500MHz,DMSO-d6)δ10.05(s,1H),8.60(d,J=28.5Hz,2H),8.05(s,1H), 7.67(t,J=1.6Hz,1H),7.32(d,J=7.5Hz,2H),7.26(t,J=7.5Hz,2H),7.21-7 .14(m,1H),6.79(s,1H),4.59(q,J=6.8Hz,1H),4.51(d,J=6.1Hz,2H),4.39 (d,J=6.1Hz,2H),3.87-3.77(m,4H),2.78(s,1H),1.48(d,J=6.8Hz,6H).MS m / z(ESI):547.16[M+H] + .

[0337] Example 85: (S)-3-Bromo-5-((9-cyclopropyl-2-((2-fluoro-3-hydroxypropyl)amino)-9H-purin-6-yl)aminobenzonitrile

[0338] To a solution of 3-bromo-5-((2-chloro-9-cyclopropyl-9H-purin-6-yl)amino)benzonitrile (39 mg, 0.1 mmol) (Reference Example 10) in sec-butanol (1 mL) were added (S)-3-amino-2-fluoropropan-1-ol (47 mg, 0.50 mmol) and triethylamine (101 mg, 1 mmol). The mixture was heated at 130°C for 24 hours and then cooled to room temperature. The reaction mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to give 7 mg of the product (16% yield). 1H NMR (500MHz, DMSO-d6) δ10.02(s,1H),8.55(s,2H),7.92(s,1H),7.67(t,J=1.6Hz,1H),7.19(s,1H),4.96(s,1H),4. 70(d,J=49.3Hz,1H),3.74-3.60(m,2H),3.60-3.51(m,2H),3.38(s,1H),1.08(t,J=4.2Hz,2H),1.05-0.98(m,2H).MS m / z(ESI):446.07[M+H] + .

[0339] Example 86: (R)-3-Bromo-5-((2-((2-fluoro-3-hydroxypropyl)amino)-9-isopropyl-9H-purin-6-yl)aminobenzonitrile

[0340] To a solution of 3-bromo-5-((2-chloro-9-isopropyl-9H-purin-6-yl)amino)benzonitrile (39 mg, 0.1 mmol) (Reference Example 1) in sec-butanol (1 mL) were added (R)-3-amino-2-fluoropropan-1-ol (47 mg, 0.50 mmol) and triethylamine (101 mg, 1 mmol). The mixture was heated at 130°C for 24 hours and then cooled to room temperature. The mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to give 9 mg of the product (20% yield). 1 H NMR (500MHz, DMSO-d6) δ10.09-9.95(m,1H),8.55(s,2H),8.05(s,1H),7.67(t,J=1.6Hz,1H),7.12(s,1H),4.95(t,J=5.8Hz, 1H),4.71(d,J=51.0Hz,1H),4.62(p,J=6.8Hz,1H),3.75-3.59(m,2H),3.55(dt,J=20.0,6.5Hz,2H),1.51(d,J=6.8Hz,6H).MS m / z(ESI):448.08[M+H] + .

[0341] Example 87: (R)-3-Bromo-5-((9-cyclopropyl-2-((2-fluoro-3-hydroxypropyl)amino)-9H-purin-6-yl)aminobenzonitrile

[0342] To a solution of 3-bromo-5-((2-chloro-9-cyclopropyl-9H-purin-6-yl)amino)benzonitrile (39 mg, 0.1 mmol) (Reference Example 10) in sec-butanol (1 mL) were added (R)-3-amino-2-fluoropropan-1-ol (47 mg, 0.50 mmol) and triethylamine (101 mg, 1 mmol). The mixture was heated at 130°C for 24 hours and then cooled to room temperature. The reaction mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to give 9 mg of the product (20% yield). 1 H NMR(500MHz,DMSO-d6)δ10.01(s,1H),8.55(s,2H),7.92(s,1H),7.67(s,1H),7.19(s,1H),4.96(s,1H),4.70(d ,J=49.1Hz,1H),3.74-3.59(m,2H),3.59-3.52(m,2H),3.38(s,1H),1.08(q,J=4.2Hz,2H),1.04-0.99(m,2H).MS m / z(ESI):446.07[M+H] + .

[0343] Example 88: 3-Bromo-5-((2-(((3-(hydroxymethyl)oxetan-3-yl)methyl)amino)-9-isopropyl-9H-purin-6-yl)amino)benzonitrile

[0344] To a solution of 3-bromo-5-((2-chloro-9-isopropyl-9H-purin-6-yl)amino)benzonitrile (39 mg, 0.1 mmol) (Reference Example 1) in sec-butanol (1 mL) were added (3-(aminomethyl)oxetan-3-yl)methanol (59 mg, 0.50 mmol) and triethylamine (101 mg, 1 mmol). The mixture was heated at 130° C. for 24 hours and then cooled to room temperature. The mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to give 10 mg of the product (21% yield). 1H NMR (500MHz, DMSO-d6) δ10.03(s,1H),8.57(s,2H),8.05(s,1H),7.67(q,J=1.5Hz,1H),7.08(s,1H),4.94(s,1H ),4.64-4.56(m,1H),4.43(d,J=5.8Hz,2H),4.33(d,J=5.8Hz,2H),3.68-3.61(m,4H),1.50(d,J=6.5Hz,6H).MS m / z(ESI):472.11[M+H] + .

[0345] Example 89: 3-Bromo-5-((9-cyclopropyl-2-(((3-(hydroxymethyl)oxetan-3-yl)methyl)amino)-9H-purin-6-yl)amino)benzonitrile

[0346] To a solution of 3-bromo-5-((2-chloro-9-cyclopropyl-9H-purin-6-yl)amino)benzonitrile (39 mg, 0.1 mmol) (Reference Example 10) in sec-butanol (1 mL) were added (3-(aminomethyl)oxetan-3-yl)methanol (59 mg, 0.50 mmol) and triethylamine (101 mg, 1 mmol). The mixture was heated at 130° C. for 24 hours and then cooled to room temperature. The mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to give 14 mg of the product (30% yield). 1 H NMR (500MHz, DMSO-d6) δ10.03(s,1H),8.56(s,2H),7.90(s,1H),7.67(t,J=1.6Hz,1H),7.18(s,1H),4.97(s,1H),4.43(d,J=5 .8Hz,2H),4.33(d,J=5.8Hz,2H),3.65(t,J=6.1Hz,4H),3.38-3.34(m,1H),1.06(dq,J=6.7,4.0Hz,2H),1.04-0.98(m,2H).MS m / z(ESI):470.10[M+H] + .

[0347] Example 90: 3-Bromo-5-((9-cyclopropyl-2-(((3,3-difluoro-1-(hydroxymethyl)cyclobutyl)methyl)amino)-9H-purin-6-yl)amino)benzonitrile

[0348] To a solution of 3-bromo-5-((2-chloro-9-cyclopropyl-9H-purin-6-yl)amino)benzonitrile (39 mg, 0.1 mmol) (Reference Example 10) in sec-butanol (1 mL) were added (1-(aminomethyl)-3,3-difluorocyclobutyl)methanol (76 mg, 0.50 mmol) and triethylamine (101 mg, 1 mmol). The mixture was heated at 130°C for 24 hours and then cooled to room temperature. The mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to give 12 mg of the product (24% yield). 1 H NMR (500MHz, DMSO-d6) δ10.02(s,1H),8.55(s,2H),7.91(s,1H),7.67(t,J=1.6Hz,1H),7.18(s,1H),5.04(s,1H),3.56(d,J=6.3 Hz,2H),3.47(s,2H),3.36(dt,J=7.4,3.9Hz,2H),2.52(s,1H),2.41(q,J=13.5Hz,2H),1.10-1.04(m,2H),1.04-0.97(m,2H).MS m / z(ESI):504.09[M+H] + .

[0349] Example 91: trans-4-((6-((3,5-dimethoxyphenyl)amino)-9-isopropyl-9H-purin-2-yl)amino)cyclohexan-1-ol

[0350] 2,6-Dichloro-9-isopropyl-9H-purine (1.4 g, 6 mmol) was dissolved in dry sec-butanol (10 mL), 3,5-dimethoxyaniline (1.2 g, 7.8 mmol) was added, and the mixture was heated at 110°C for 12 hours. After cooling to room temperature, the reaction was quenched by adding saturated sodium bicarbonate solution. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography (eluent CH2Cl2 / MeOH=100 / 1) gave 1.1 g (yield 52%) of 2-chloro-N-(3,5-dimethoxyphenyl)-9-isopropyl-9H-purine-6-amine. MS m / z (ESI): 348.12 [M+H] + .

[0351] To a solution of 2-chloro-N-(3,5-dimethoxyphenyl)-9-isopropyl-9H-purin-6-amine (35 mg, 0.1 mmol) in sec-butanol (1 mL) was added trans-4-aminocyclohexane-1-ol (58 mg, 0.50 mmol) and triethylamine (101 mg, 1 mmol). The mixture was heated at 130°C for 24 hours and then cooled to room temperature. The mixture was quenched with water and extracted three times with dichloromethane. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to afford 5 mg of the product (12% yield). 1 H NMR (500MHz, DMSO-d6) δ9.20(s,1H),7.93(s,1H),7.30(d,J=2.2Hz,2H),6.36(d,J=7.9Hz,1H),6.14(t,J=2.3Hz,1H),4.57(p,J=6.7Hz,1H),4 .50(d,J=4.4Hz,1H),3.74(s,6H),3.43-3.36(m,1H),1.94(d,J=9.7Hz,2H),1.83(d,J=9.4Hz,2H),1.49(d,J=6.7Hz,6H),1.35-1.20(m,5H).MS m / z(ESI):427.22[M+H] + .

[0352] Example 92: N2-((trans)-4-aminocyclohexyl)-N6-(3,5-dimethoxyphenyl)-9-isopropyl-9H-purine-2,6-diamine

[0353] To a solution of 2-chloro-N-(3,5-dimethoxyphenyl)-9-isopropyl-9H-purin-6-amine (35 mg, 0.1 mmol) (Reference Example 91) in sec-butanol (1 mL) were added trans-1,4-cyclohexanediamine (58 mg, 0.50 mmol) and triethylamine (101 mg, 1 mmol). The mixture was heated at 130°C for 24 hours and then cooled to room temperature. The mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 10 / 1) to afford 8 mg of the product (19% yield). 1H NMR (500MHz, DMSO-d6) δ9.21(s,1H),7.93(s,1H),7.30(d,J=2.3Hz,2H),6.38(d,J=7.9Hz,1H),6.14(t,J=2.3Hz,1H),4.57(p,J=6.8 Hz,1H),3.74(s,6H),2.62(tt,J=10.7,3.9Hz,1H),2.02-1.94(m,2H),1.88-1.77(m,2H),1.49(d,J=6.8Hz,6H),1.37-1.10(m,5H).MS m / z(ESI):426.24[M+H] + .

[0354] Example 93: 4-((6-((3,5-Dimethoxyphenyl)amino)-9-isopropyl-9H-purin-2-yl)amino)butan-1-ol

[0355] To a solution of 2-chloro-N-(3,5-dimethoxyphenyl)-9-isopropyl-9H-purin-6-amine (35 mg, 0.1 mmol) (Reference Example 91) in sec-butanol (1 mL) were added 4-aminobutan-1-ol (45 mg, 0.50 mmol) and triethylamine (101 mg, 1 mmol). The mixture was heated at 130°C for 24 hours and then cooled to room temperature. The mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to give 7 mg of the product (yield 18%). 1 H NMR (500MHz, DMSO-d6) δ9.21 (s, 1H), 7.93 (s, 1H), 7.35 (d, J = 2.3Hz, 2H), 6.60 (t, J = 5.8Hz, 1H), 6.12 (t, J = 2.3Hz, 1H), 4.58 (p, J = 6.8Hz, 1H),4.34(t,J=5.1Hz,1H),3.73(s,6H),3.41(td,J=6.5,5.1Hz,2H),1.67-1.54(m,2H),1.50(d,J=6.8Hz,6H),1.46(d,J=6.6Hz,2H).MS m / z(ESI):401.22[M+H] + .

[0356] Example 94: trans-4-((9-cyclopropyl-6-((3,5-dimethoxyphenyl)amino)-9H-purin-2-yl)amino)cyclohexan-1-ol

[0357] 2,6-Dichloro-9-cyclopropyl-9H-purine (500 mg, 2.2 mmol) was dissolved in dry sec-butanol (10 mL), 3,5-dimethoxyaniline (478 mg, 2.86 mmol) was added, and the mixture was heated at 110°C for 12 hours. After cooling to room temperature, the reaction was quenched by adding saturated sodium bicarbonate solution. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography (eluent CH2Cl2 / MeOH=100 / 1) gave 300 mg (yield 40%) of 2-chloro-N-(3,5-dimethoxyphenyl)-9-cyclopropyl-9H-purin-6-amine. MS m / z (ESI): 346.11 [M+H] + .

[0358] To a solution of 2-chloro-N-(3,5-dimethoxyphenyl)-9-cyclopropyl-9H-purin-6-amine (35 mg, 0.1 mmol) in sec-butanol (1 mL) was added trans-4-aminocyclohexane-1-ol (58 mg, 0.50 mmol) and triethylamine (101 mg, 1 mmol). The mixture was heated at 130°C for 24 hours and then cooled to room temperature. The mixture was quenched with water and extracted three times with dichloromethane. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to afford 7 mg of the product (17% yield). 1 H NMR (500MHz, DMSO-d6) δ9.20(s,1H),7.79(s,1H),7.30(d,J=2.2Hz,2H),6.51(s,1H),6.15(t,J=2.2Hz,1H),4.50(d,J=4.4Hz,1H),3.73 (s,6H),3.38(dd,J=9.9,4.6Hz,2H),1.93(d,J=8.8Hz,2H),1.83(s,2H),1.27(p,J=10.3Hz,5H),1.09-1.03(m,2H),1.02-0.95(m,2H).MS m / z(ESI):425.22[M+H] + .

[0359] Example 95: trans-4-((6-((3-bromo-5-(difluoromethoxy)phenyl)amino)-9-isopropyl-9H-purin-2-yl)amino)cyclohexan-1-ol

[0360] 2,6-Dichloro-9-isopropyl-9H-purine (100 mg, 0.44 mmol) was dissolved in dry sec-butanol (2 mL), 3-bromo-5-(difluoromethoxy)aniline (312 mg, 1.32 mmol) was added, and the mixture was heated at 110°C for 12 hours. After cooling to room temperature, the reaction was quenched by adding saturated sodium bicarbonate solution. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography (eluent: CH2Cl2 / MeOH = 100 / 1) gave 130 mg (yield: 69%) of N-(3-bromo-5-(difluoromethoxy)phenyl)-2-chloro-9-isopropyl-9H-purin-6-amine. MS m / z (ESI): 432.00 [M+H] + .

[0361] To a solution of N-(3-bromo-5-(difluoromethoxy)phenyl)-2-chloro-9-isopropyl-9H-purin-6-amine (100 mg, 0.23 mmol) in sec-butanol (1 mL) were added trans-4-aminocyclohexane-1-ol (80 mg, 0.70 mmol) and triethylamine (117 mg, 1.16 mmol). The mixture was heated at 130° C. for 24 hours and then cooled to room temperature. The mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to give 22 mg of the product (yield 11%). 1 H NMR(500MHz,DMSO-d6)δ9.81(s,1H),8.34(s,1H),7.99(s,1H),7.87(s,1H), 7.26(s,1H),6.99(t,J=2.0Hz,1H),6.55(d,J=8.1Hz,1H),4.58(p,J=6.8Hz, 1H),4.49(d,J=4.3Hz,1H),3.75-3.65(m,1H),1.94(d,J=11.0Hz,2H),1.84( d,J=10.2Hz,2H),1.50(s,3H),1.49(s,3H),1.31(dd,J=16.7,6.5Hz,4H).MS m / z(ESI):511.15[M+H] + .

[0362] Example 96: trans-4-((6-((3-bromo-5-(difluoromethoxy)phenyl)amino)-9-cyclopropyl-9H-purin-2-yl)amino)cyclohexan-1-ol

[0363] 2,6-Dichloro-9-cyclopropyl-9H-purine (100 mg, 0.44 mmol) was dissolved in dry sec-butanol (2 mL), 3-bromo-5-(difluoromethoxy)aniline (312 mg, 1.32 mmol) was added, and the mixture was heated at 110°C for 12 hours. After cooling to room temperature, the reaction was quenched by adding saturated sodium bicarbonate solution. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography (eluent: CH2Cl2 / MeOH = 100 / 1) afforded 140 mg (yield: 75%) of N-(3-bromo-5-(difluoromethoxy)phenyl)-2-chloro-9-cyclopropyl-9H-purin-6-amine. MS m / z (ESI): 429.99 [M+H] + .

[0364] To a solution of N-(3-bromo-5-(difluoromethoxy)phenyl)-2-chloro-9-cyclopropyl-9H-purin-6-amine (50 mg, 0.12 mmol) in sec-butanol (1 mL) were added trans-4-aminocyclohexane-1-ol (40 mg, 0.35 mmol) and triethylamine (59 mg, 0.58 mmol). The mixture was heated at 130° C. for 24 hours and then cooled to room temperature. The mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to afford 12 mg of the product (20% yield). 1 H NMR (500MHz, DMSO-d6) δ9.80(s,1H),8.36(s,1H),7.85(s,2H),7.25(t,J=73.7Hz,1H),7.00(t,J=1.9Hz,1H),6.69(s,1H),4.50(d,J=4.3Hz,1H),3 .39(q,J=8.4,7.0Hz,1H),1.93(d,J=11.4Hz,2H),1.84(d,J=10.7Hz,2H) ,1.42-1.29(m,4H),1.05(d,J=4.2Hz,2H),0.99(dd,J=7.3,5.1Hz,2H).MS m / z(ESI):509.11[M+H] + .

[0365] Example 97: N2-(trans-4-aminocyclohexyl)-9-cyclopropyl-N6-(3,5-dimethoxyphenyl)-9H-purine-2,6-diamine

[0366] To a solution of 2-chloro-N-(3,5-dimethoxyphenyl)-9-cyclopropyl-9H-purin-6-amine (35 mg, 0.1 mmol) (Reference Example 94) in sec-butanol (1 mL) were added trans-1,4-cyclohexanediamine (58 mg, 0.50 mmol) and triethylamine (101 mg, 1 mmol). The mixture was heated at 110°C for 12 hours and then cooled to room temperature. The mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to give 14 mg of the product (33% yield). 1 H NMR(500MHz,DMSO-d6)δ9.21(s,1H),7.79(s,1H),7.30(d,J=2.2Hz,2H),6.53(s,1H),6.14(t,J=2.3Hz,1H),3.74(s,6H),3.70(td,J=7.7,4.0Hz,1H ),2.61(tt,J=10.6,3.5Hz,1H),1.99-1.93(m,2H),1.81(d,J=12.2Hz,2H) ,1.36-1.13(m,5H),1.05(t,J=3.8Hz,2H),0.98(dd,J=7.4,5.1Hz,2H).MS m / z(ESI):424.24[M+H] + .

[0367] Example 98: N2-(trans-4-aminocyclohexyl)-N6-(3-bromo-5-(trifluoromethoxy)phenyl)-9-isopropyl-9H-purine-2,6-diamine

[0368] 2,6-Dichloro-9-isopropyl-9H-purine (462 mg, 2 mmol) was dissolved in dry sec-butanol (5 mL), 3-bromo-5-(trifluoromethoxy)aniline (660 mg, 2.6 mmol) was added, and the mixture was heated at 110°C for 12 hours. After cooling to room temperature, the reaction was quenched by adding saturated sodium bicarbonate solution. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography (eluent CH2Cl2 / MeOH=100 / 1) gave 600 mg (yield 67%) of N-(3-bromo-5-(trifluoromethoxy)phenyl)-2-chloro-9-isopropyl-9H-purin-6-amine. MS m / z (ESI): 449.99 [M+H] + .

[0369] To a solution of N-(3-bromo-5-(trifluoromethoxy)phenyl)-2-chloro-9-isopropyl-9H-purin-6-amine (45 mg, 0.1 mmol) in sec-butanol (1 mL) was added trans-1,4-cyclohexanediamine (58 mg, 0.50 mmol) and triethylamine (101 mg, 1 mmol). The mixture was heated at 110°C for 12 hours and then cooled to room temperature. The mixture was quenched with water and extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 10 / 1) to afford 8 mg of the product (15% yield). 1 H NMR(500MHz,DMSO-d6)δ9.92(s,1H),8.44(s,1H),8.15(s,1H),8.01(s,1H), 7.17(s,1H),6.59(d,J=8.2Hz,1H),4.58(p,J=6.8Hz,1H),3.68(tdt,J=11.7, 8.1,4.0Hz,1H),2.57-2.52(m,1H),1.93(d,J=11.6Hz,2H),1.82-1.76(m,2H ),1.49(d,J=6.8Hz,6H),1.37-1.26(m,2H),1.20(dd,J=24.4,12.0Hz,2H).MS m / z(ESI):528.13[M+H] + .

[0370] Example 99: N2-(trans-4-aminocyclohexyl)-N6-(3-bromo-5-(trifluoromethoxy)phenyl)-9-cyclopropyl-9H-purine-2,6-diamine

[0371] 2,6-Dichloro-9-cyclopropyl-9H-purine (229 mg, 1 mmol) (Reference Example 10) was dissolved in dry sec-butanol (2 mL), 3-bromo-5-(trifluoromethoxy)aniline (330 mg, 1.3 mmol) was added, and the mixture was heated at 110°C for 12 hours. The mixture was cooled to room temperature and quenched by adding saturated sodium bicarbonate solution. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography (eluent CH2Cl2 / MeOH=100 / 1) gave 160 mg (yield 32%) of N-(3-bromo-5-(trifluoromethoxy)phenyl)-2-chloro-9-cyclopropyl-9H-purin-6-amine. MS m / z (ESI): 447.98 [M+H] + .

[0372] To a solution of N-(3-bromo-5-(trifluoromethoxy)phenyl)-2-chloro-9-cyclopropyl-9H-purin-6-amine (45 mg, 0.1 mmol) in sec-butanol (1 mL) was added trans-1,4-cyclohexanediamine (58 mg, 0.50 mmol) and triethylamine (101 mg, 1 mmol). The mixture was heated at 110°C for 12 hours and then cooled to room temperature. The mixture was quenched with water and extracted three times with dichloromethane. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 10 / 1) to afford 10 mg of the product (19% yield). 1 H NMR(500MHz,DMSO-d6)δ9.93(s,1H),8.45(s,1H),8.13(s,1H),7.86(s,1H) ,7.17(s,1H),6.74(s,1H),3.69(dtd,J=11.3,7.5,4.0Hz,1H),3.51(s,1H) ,2.55(dt,J=10.9,3.9Hz,1H),2.00-1.89(m,2H),1.86-1.74(m,2H),1.38- 1.27(m,2H),1.26-1.16(m,2H),1.06(t,J=4.2Hz,2H),1.03-0.95(m,2H).MS m / z(ESI):526.12[M+H] + .

[0373] Example 100: trans-N2-(4-aminocyclohexyl)-N6-(3-bromo-5-(difluoromethoxy)phenyl)-9-isopropyl-9H-purine-2,6-diamine

[0374] To a solution of N-(3-bromo-5-(difluoromethoxy)phenyl)-2-chloro-9-isopropyl-9H-purin-6-amine (50 mg, 0.12 mmol) (Reference Example 95) in sec-butanol (1 mL) were added trans-1,4-cyclohexanediamine (40 mg, 0.35 mmol) and triethylamine (59 mg, 0.58 mmol). The mixture was heated at 110°C for 12 hours and then cooled to room temperature. The mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 10 / 1) to give 11 mg of the product (19% yield). 1H NMR(500MHz,DMSO-d6)δ9.83(s,1H),8.45(s,1H),8.01(s,1H),7.80(s,1H),6.99( d,J=1.9Hz,1H),6.63(d,J=8.0Hz,1H),4.58(p,J=6.7Hz,1H),3.70(dtt,J=11.6,8 .0,4.2Hz,1H),2.83(ddt,J=11.4,8.0,3.8Hz,1H),2.02(d,J=12.2Hz,2H),1.94(d ,J=12.0Hz,2H),1.50(s,3H),1.49(s,3H),1.47-1.38(m,2H),1.37-1.29(m,2H).MS m / z(ESI):510.10[M+H] + .

[0375] Example 101: trans-4-((6-((3-chloro-5-methoxyphenyl)amino)-9-isopropyl-9H-purin-2-yl)amino)cyclohexan-1-ol

[0376] 2,6-Dichloro-9-isopropyl-9H-purine (230 mg, 1 mmol) was dissolved in dry sec-butanol (5 mL), 3-chloro-5-methoxyaniline (204 mg, 1.3 mmol) was added, and the mixture was heated at 110°C for 12 hours. After cooling to room temperature, the reaction was quenched by adding saturated sodium bicarbonate solution. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography (eluent CH2Cl2 / MeOH=100 / 1) gave 226 mg (yield 64%) of 2-chloro-N-(3-chloro-5-methoxyphenyl)-9-isopropyl-9H-purin-6-amine. MS m / z (ESI): 352.07 [M+H] + .

[0377] To a solution of 2-chloro-N-(3-chloro-5-methoxyphenyl)-9-isopropyl-9H-purin-6-amine (35 mg, 0.10 mmol) in sec-butanol (1 mL) were added trans-4-aminocyclohexane-1-ol (58 mg, 0.50 mmol) and triethylamine (101 mg, 1 mmol). The mixture was heated at 130° C. for 24 hours and then cooled to room temperature. The mixture was quenched with water and extracted three times with dichloromethane. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to afford 13 mg of the product (30% yield). 1H NMR (500MHz, DMSO) δ9.53 (s, 1H), 7.96 (s, 2H), 7.53 (s, 1H), 6.62 (d, J = 5.0Hz, 1H), 6.48 (d, J = 10.0Hz, 1H), 4. 60-4.50(m,2H),3.73-3.65(m,1H),3.44-3.36(m,1H),1.99-1.83(m,4H),1.49(s,3H),1.37-1.26(m,4H).MS m / z(ESI):431.20[M+H] + .

[0378] Example 102: trans-4-((6-((3-chloro-5-methoxyphenyl)amino)-9-cyclopropyl-9H-purin-2-yl)amino)cyclohexan-1-ol

[0379] 2,6-Dichloro-9-cyclopropyl-9H-purine (230 mg, 1 mmol) was dissolved in dry sec-butanol (5 mL), 3-chloro-5-methoxyaniline (204 mg, 1.3 mmol) was added, and the mixture was heated at 110°C for 12 hours. After cooling to room temperature, the reaction was quenched by adding saturated sodium bicarbonate solution. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography (eluent CH2Cl2 / MeOH=100 / 1) gave 176 mg (yield 51%) of 2-chloro-N-(3-chloro-5-methoxyphenyl)-9-cyclopropyl-9H-purin-6-amine. MS m / z (ESI): 350.06 [M+H] + .

[0380] To a solution of 2-chloro-N-(3-chloro-5-methoxyphenyl)-9-cyclopropyl-9H-purin-6-amine (35 mg, 0.10 mmol) in sec-butanol (1 mL) were added trans-4-aminocyclohexane-1-ol (58 mg, 0.50 mmol) and triethylamine (101 mg, 1 mmol). The mixture was heated at 130° C. for 24 hours and then cooled to room temperature. The mixture was quenched with water and extracted three times with dichloromethane. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to afford 14 mg of the product (32% yield). 1H NMR(500MHz,DMSO)δ9.53(s,1H),7.98(s,2H),7.82(s,1H),7.50(s,1H),6.62(s,1H),4.51(d,J=5.0Hz,,1H), 3.76(s,3H),3.73-3.68(m,1H),3.44-3.36(m,1H),1.95-1.83(m,4H),1.34-1.26(m,4H),1.05-0.96(m,4H).MS m / z(ESI):429.18[M+H] + .

[0381] Example 103: trans-4-((6-((3-bromo-4-chloro-5-methoxyphenyl)amino)-9-isopropyl-9H-purin-2-yl)amino)cyclohexan-1-ol

[0382] 2,6-Dichloro-9-isopropyl-9H-purine (230 mg, 1 mmol) was dissolved in dry sec-butanol (5 mL), 3-bromo-4-chloro-5-methoxyaniline (306 mg, 1.3 mmol) was added, and the mixture was heated at 110°C for 12 hours. After cooling to room temperature, the reaction was quenched by adding saturated sodium bicarbonate solution. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography (eluent CH2Cl2 / MeOH=100 / 1) gave 226 mg (yield 64%) of N-(3-bromo-4-chloro-5-methoxyphenyl)-2-chloro-9-isopropyl-9H-purin-6-amine. MS m / z (ESI): 429.98 [M+H] + .

[0383] To a solution of N-(3-bromo-4-chloro-5-methoxyphenyl)-2-chloro-9-isopropyl-9H-purin-6-amine (43 mg, 0.10 mmol) in sec-butanol (1 mL) were added trans-4-aminocyclohexane-1-ol (58 mg, 0.50 mmol) and triethylamine (101 mg, 1 mmol). The mixture was heated at 130° C. for 24 hours and then cooled to room temperature. The mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to afford 15 mg of the product (30% yield). 1H NMR (500MHz, DMSO) δ9.63 (s, 1H), 8.41 (s, 1H), 7.98 (s, 1H), 7.70 (s, 1H), 6.49 (d, J = 10.0Hz, 1H), 4.60-4.55 (m, 1H), 4.49 (d, J = 5. 0Hz,1H),3.76-3.68(m,1H),3.44-3.37(m,1H),1.99-1.84(m,4H),1.50(d,J=5.0Hz,6H),1.34-1.27(m,4H),1.05-0.96(m,4H).MS m / z(ESI):509.11[M+H] + .

[0384] Example 104: trans-4-((6-((3-bromo-4-chloro-5-methoxyphenyl)amino)-9-cyclopropyl-9H-purin-2-yl)amino)cyclohexan-1-ol

[0385] 2,6-Dichloro-9-cyclopropyl-9H-purine (230 mg, 1 mmol) was dissolved in dry sec-butanol (5 mL), and 3-bromo-4-chloro-5-methoxyaniline (306 mg, 1.3 mmol) was added. The mixture was heated at 110°C for 12 hours. The mixture was cooled to room temperature and quenched by adding saturated sodium bicarbonate solution. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography (eluent: CH2Cl2 / MeOH = 100 / 1) afforded 256 mg (yield: 60%) of N-(3-bromo-4-chloro-5-methoxyphenyl)-2-chloro-9-cyclopropyl-9H-purin-6-amine. MS m / z (ESI): 427.97 [M+H] + .

[0386] To a solution of N-(3-bromo-4-chloro-5-methoxyphenyl)-2-chloro-9-cyclopropyl-9H-purin-6-amine (43 mg, 0.10 mmol) in sec-butanol (1 mL) were added trans-4-aminocyclohexane-1-ol (58 mg, 0.50 mmol) and triethylamine (101 mg, 1 mmol). The mixture was heated at 130° C. for 24 hours and then cooled to room temperature. The mixture was quenched with water and extracted three times with dichloromethane. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to afford 17 mg of the product (34% yield). 1H NMR(500MHz,DMSO)δ9.62(s,1H),8.46(s,1H),7.84(s,1H),7.66(s,1H),6.64(s,1H),4.48(d,J=10.0Hz ,1H),3.78-3.70(m,1H),3.43-3.37(m,1H),1.94-1.83(m,4H),1.38-1.27(m,4H),1.06-0.97(m,4H).MS m / z(ESI):507.09[M+H] + .

[0387] Example 105: trans-4-((6-((3,5-dimethoxyphenyl)amino)-9-isopropyl-9H-purin-2-yl)amino)-1-methylcyclohexan-1-ol

[0388] To a solution of 2-chloro-N-(3,5-dimethoxyphenyl)-9-isopropyl-9H-purin-6-amine (35 mg, 0.10 mmol) (Reference Example 91) in sec-butanol (1 mL) were added trans-4-amino-1-methylcyclohexane-1-ol (65 mg, 0.50 mmol) and triethylamine (101 mg, 1 mmol). The mixture was heated at 130°C for 24 hours and then cooled to room temperature. The mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to give 8 mg of the product (yield 18%). 1 H NMR (500MHz, DMSO-d6) δ9.19(s,1H),7.93(s,1H),7.31(d,J=2.3Hz,2H),6.35(d,J=8.0Hz,1H),6.14(s,1H),4.57(p,J=6.8Hz,1H),4.19(s,1 H),3.82(s,1H),3.74(s,6H),1.85(d,J=10.6Hz,2H),1.58(q,J=5.6,5.2Hz,2H),1.49(d,J=6.8Hz,6H),1.45(d,J=8.4Hz,4H),1.15(s,3H).MS m / z(ESI):441.23[M+H] + .

[0389] Example 106: trans-4-((9-cyclopropyl-6-((3,5-dimethoxyphenyl)amino)-9H-purin-2-yl)amino)-1-methylcyclohexan-1-ol

[0390] To a solution of 2-chloro-N-(3,5-dimethoxyphenyl)-9-cyclopropyl-9H-purin-6-amine (35 mg, 0.10 mmol) (Reference Example 94) in sec-butanol (1 mL) were added trans-4-amino-1-methylcyclohexane-1-ol (65 mg, 0.50 mmol) and triethylamine (101 mg, 1 mmol). The mixture was heated at 130°C for 24 hours and then cooled to room temperature. The mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to give 9 mg of the product (20% yield). 1 H NMR(500MHz,DMSO-d6)δ9.19(s,1H),7.79(s,1H),7.30(d,J=2.2Hz,2H),6.47(s,1H),6.14(s,1H),4.19(s,1H),3.84(s,1H),3.73(s,6H),1 .85(q,J=7.6,6.0Hz,2H),1.59(dd,J=8.7,5.4Hz,2H),1.45(q,J=8.0,5.2Hz,4H),1.15(s,3H),1.05(p,J=4.0Hz,2H),1.02-0.94(m,2H).MS m / z(ESI):439.24[M+H] + .

[0391] Example 107: trans-4-((6-((3-bromo-5-(methylsulfonyl)phenyl)amino)-9-isopropyl-9H-purin-2-yl)amino)cyclohexan-1-ol

[0392] 2,6-Dichloro-9-isopropyl-9H-purine (100 mg, 0.44 mmol) was dissolved in dry sec-butanol (2 mL), and 3-bromo-5-(methylsulfonyl)aniline (196 mg, 0.44 mmol) was added. The mixture was heated at 110°C for 12 hours. After cooling to room temperature, the reaction was quenched by adding saturated sodium bicarbonate solution. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography (eluent: CH2Cl2 / MeOH = 100 / 1) afforded 102 mg (yield: 53%) of N-(3-bromo-5-(methylsulfonyl)phenyl)-2-chloro-9-isopropyl-9H-purin-6-amine. MS m / z (ESI): 443.99 [M+H] + .

[0393] To a solution of N-(3-bromo-5-(methylsulfonyl)phenyl)-2-chloro-9-isopropyl-9H-purin-6-amine (50 mg, 0.11 mmol) in sec-butanol (1 mL) were added trans-4-aminocyclohexane-1-ol (39 mg, 0.34 mmol) and triethylamine (57 mg, 0.57 mmol). The mixture was heated at 130° C. for 24 hours and then cooled to room temperature. The mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to afford 13 mg of the product (22% yield). 1 H NMR(500MHz,DMSO-d6)δ10.05(s,1H),8.82(s,1H),8.46(s,1H),8.01(s,1H),7.64 (t,J=1.7Hz,1H),6.51(d,J=8.1Hz,1H),4.58(h,J=6.8Hz,1H),4.46(d,J=4.4Hz,1H ),3.76(s,1H),3.40(s,1H),3.27(s,3H),1.93(d,J=11.9Hz,2H),1.82(d,J=11.5H z,2H),1.50(s,3H),1.49(s,3H),1.40(d,J=11.6Hz,2H),1.32(t,J=12.2Hz,2H); MS m / z(ESI):523.10[M+H] + .

[0394] Example 108: trans-4-((6-((3-bromo-5-(methylsulfonyl)phenyl)amino)-9-cyclopropyl-9H-purin-2-yl)amino)cyclohexan-1-ol

[0395] 2,6-Dichloro-9-cyclopropyl-9H-purine (100 mg, 0.44 mmol) (Reference Example 10) was dissolved in dry sec-butanol (2 mL), 3-bromo-5-(methylsulfonyl)aniline (196 mg, 0.44 mmol) was added, and the mixture was heated at 110°C for 12 hours. The mixture was cooled to room temperature and quenched by adding saturated sodium bicarbonate solution. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography (eluent: CH2Cl2 / MeOH=100 / 1) afforded 108 mg (yield: 56%) of N-(3-bromo-5-(methylsulfonyl)phenyl)-2-chloro-9-cyclopropyl-9H-purin-6-amine. MS m / z (ESI): 441.97 [M+H] + .

[0396] To a solution of N-(3-bromo-5-(methylsulfonyl)phenyl)-2-chloro-9-isopropyl-9H-purin-6-amine (50 mg, 0.11 mmol) in sec-butanol (1 mL) were added trans-4-aminocyclohexane-1-ol (39 mg, 0.34 mmol) and triethylamine (57 mg, 0.57 mmol). The mixture was heated at 130° C. for 24 hours and then cooled to room temperature. The reaction mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to afford 12 mg of the product (20% yield). 1 H NMR (500MHz, DMSO-d6) δ10.04(s,1H),8.82(s,1H),8.46(t,J=1.9Hz,1H),7. 87(s,1H),7.64(t,J=1.6Hz,1H),6.66(s,1H),4.47(d,J=4.4Hz,1H),3.42-3. 37(m,1H),3.26(s,3H),1.92(d,J=11.9Hz,2H),1.85-1.77(m,2H),1.46-1.3 6(m,2H),1.36-1.29(m,2H),1.05(q,J=5.5,4.8Hz,2H),1.02-0.97(m,2H);MS m / z(ESI):521.08[M+H] + .

[0397] Example 109: trans-4-((9-cyclopentyl-6-((3,5-dimethoxyphenyl)amino)-9H-purin-2-yl)amino)cyclohexan-1-ol

[0398] 2,6-Dichloro-9-cyclopentyl-9H-purine (300 mg, 1.17 mmol) (Reference Example 2) was dissolved in dry sec-butanol (5 mL), 3,5-dimethoxyaniline (233 mg, 1.52 mmol) was added, and the mixture was heated at 110 ° C for 12 hours. Cooled to room temperature, saturated sodium bicarbonate solution was added to quench the reaction. Extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography (eluent CH2Cl2 / MeOH=100 / 1) gave 2-chloro-9-cyclopentyl-N-(3,5-dimethoxyphenyl)-9H-purine-6-amine 160 mg (yield 36%), MS m / z (ESI): 374.14 [M+H] + .

[0399] To a solution of 2-chloro-9-cyclopentyl-N-(3,5-dimethoxyphenyl)-9H-purin-6-amine (37 mg, 0.10 mmol) in sec-butanol (1 mL) was added trans-4-aminocyclohexane-1-ol (58 mg, 0.50 mmol) and triethylamine (101 mg, 1.0 mmol). The mixture was heated at 130°C for 24 hours and then cooled to room temperature. The mixture was quenched with water and extracted three times with dichloromethane. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to afford 9 mg of the product (20% yield). 1 H NMR (500MHz, DMSO-d6) δ9.18 (s, 1H), 7.88 (s, 1H), 7.30 (d, J = 2.3Hz, 2H), 6.35 (d, J=7.9Hz,1H),6.14(t,J=2.3Hz,1H),4.69(p,J=7.6Hz,1H),4.49(d,J=4.3Hz,1H), 3.73(s,6H),3.69(s,1H),3.40(dt,J=9.9,5.4Hz,1H),2.09(p,J=5.8Hz,2H),2.03 -1.79(m,8H),1.69(ddd,J=16.9,8.9,4.6Hz,2H),1.28(q,J=10.9,10.1Hz,4H).MS m / z(ESI):453.26[M+H] + .

[0400] Example 110: cis-3-(((9-cyclopentyl-6-((3,5-dimethoxyphenyl)amino)-9H-purin-2-yl)amino)methyl)cyclobutan-1-ol

[0401] To a solution of 2-chloro-9-cyclopentyl-N-(3,5-dimethoxyphenyl)-9H-purin-6-amine (37 mg, 0.10 mmol) (Reference Example 109) in sec-butanol (1 mL) were added cis-3-(aminomethyl)cyclobutane-1-ol (50 mg, 0.50 mmol) and triethylamine (101 mg, 1.0 mmol). The mixture was heated at 130°C for 24 hours and then cooled to room temperature. The mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to give 10 mg of the product (yield 23%). 1H NMR(500MHz,DMSO-d6)δ9.19(s,1H),7.89(s,1H),7.35(d,J=2.3Hz,2H),6.60(t,J=5.7Hz,1H) ,6.12(t,J=2.2Hz,1H),4.86(d,J=6.5Hz,1H),4.69(p,J=7.5Hz,1H),3.88(h,J=7.4Hz,1H),3.7 3(s,6H),3.33(d,J=6.3Hz,1H),2.29-2.20(m,2H),2.10(dt,J=11.7,6.7Hz,2H),1.99(dtd,J= 14.3,7.1,4.7Hz,3H),1.89(d,J=8.4Hz,2H),1.69(qt,J=6.5,2.8Hz,2H),1.56-1.48(m,2H).MS m / z(ESI):439.24[M+H] + .

[0402] Example 111: trans-4-((9-cyclohexyl-6-((3,5-dimethoxyphenyl)amino)-9H-purin-2-yl)amino)cyclohexan-1-ol

[0403] 2,6-dichloro-9-cyclohexyl-9H-purine (300 mg, 1.11 mmol, synthesized by a method similar to Example 2) was dissolved in dry sec-butanol (5 mL), 3,5-dimethoxyaniline (220 mg, 1.44 mmol) was added, and the mixture was heated at 110 ° C for 12 hours. Cooled to room temperature, saturated sodium bicarbonate solution was added to quench the reaction. Extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography (eluent CH2Cl2 / MeOH=100 / 1) gave 80 mg of 2-chloro-9-cyclohexyl-N-(3,5-dimethoxyphenyl)-9H-purine-6-amine (yield 19%), MS m / z (ESI): 388.15 [M+H] + .

[0404] To a solution of 2-chloro-9-cyclohexyl-N-(3,5-dimethoxyphenyl)-9H-purin-6-amine (39 mg, 0.10 mmol) in sec-butanol (1 mL) was added trans-4-aminocyclohexane-1-ol (58 mg, 0.50 mmol) and triethylamine (101 mg, 1.0 mmol). The mixture was heated at 130°C for 24 hours and then cooled to room temperature. The mixture was quenched with water and extracted three times with dichloromethane. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to afford 11 mg of the product (24% yield). 1H NMR (500MHz, DMSO-d6) δ9.20(s,1H),7.91(s,1H),7.30(d,J=2.2Hz,2H),6.40(d,J=7.9Hz,1H),6.14(t,J=2.2Hz,1H),4.49(d,J=4.4Hz ,1H),4.21-4.12(m,1H),3.74(s,6H),3.71(s,1H),3.45-3.36(m,1H),2.05-1.80(m,9H),1.70(d,J=12.9Hz,1H),1.44-1.18(m,8H).MS m / z(ESI):467.27[M+H] + .

[0405] Example 112: cis-4-((6-((3,5-dimethoxyphenyl)amino)-9-isopropyl-H-purin-2-yl)amino)cyclohexan-1-ol

[0406] To a solution of 2-chloro-N-(3,5-dimethoxyphenyl)-9-isopropyl-9H-purin-6-amine (39 mg, 0.10 mmol) (Reference Example 91) in sec-butanol (1 mL) were added cis-4-aminocyclohexane-1-ol (58 mg, 0.50 mmol) and triethylamine (101 mg, 1.0 mmol). The mixture was heated at 130°C for 24 hours and then cooled to room temperature. The mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to give 9 mg of the product (yield 21%). 1 H NMR (500MHz, DMSO-d6) δ9.19(s,1H),7.93(s,1H),7.32(d,J=2.2Hz,2H),6.35(d,J=7.5Hz,1H),6.14(t,J=2.3Hz,1H),4.58(hept,J =6.8Hz,1H),4.30(d,J=3.1Hz,1H),3.83-3.76(m,1H),3.73(s,6H),1.78-1.60(m,6H),1.56-1.51(m,2H),1.49(d,J=6.7Hz,6H).MS m / z(ESI):427.25[M+H] + .

[0407] Example 113: trans-4-((6-((4-chloro-3,5-dimethoxyphenyl)amino)-9-isopropyl-9H-purin-2-yl)amino)cyclohexan-1-ol

[0408] 2,6-Dichloro-9-isopropyl-9H-purine (115 mg, 0.5 mmol) was dissolved in dry sec-butanol (5 mL), 4-chloro-3,5-dimethoxyaniline (122 mg, 0.65 mmol) was added, and the mixture was heated at 110°C for 12 hours. After cooling to room temperature, the reaction was quenched by adding saturated sodium bicarbonate solution. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography (eluent CH2Cl2 / MeOH=100 / 1) gave 95 mg (yield 50%) of 2-chloro-N-(4-chloro-3,5-dimethoxyphenyl)-9-isopropyl-9H-purin-6-amine. MS m / z (ESI): 382.08 [M+H] + .

[0409] To a solution of 2-chloro-N-(4-chloro-3,5-dimethoxyphenyl)-9-isopropyl-9H-purin-6-amine (38 mg, 0.10 mmol) in sec-butanol (1 mL) was added trans-4-aminocyclohexane-1-ol (58 mg, 0.50 mmol) and triethylamine (101 mg, 1 mmol). The mixture was heated at 130°C for 24 hours and then cooled to room temperature. The mixture was quenched with water and extracted three times with dichloromethane. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to afford 16 mg of the product (35% yield). 1 H NMR (500MHz, DMSO) δ9.79 (s, 1H), 8.36 (s, 2H), 8.00 (s, 1H), 7.35 (d, J = 5.0Hz, 1H), 6.56 (d, J = 5.0Hz, 1H), 4.60-4. 48(m,2H),3.75-3.66(m,1H),3.42-3.37(m,1H),1.94-1.83(m,4H),1.49(d,J=10.0Hz,1H),1.40-1.25(m,4H).MS m / z(ESI):461.21[M+H] + .

[0410] Example 114: trans-4-((6-((4-chloro-3,5-dimethoxyphenyl)amino)-9-cyclopropyl-9H-purin-2-yl)amino)cyclohexan-1-ol

[0411] 2,6-Dichloro-9-cyclopropyl-9H-purine (115 mg, 0.5 mmol) was dissolved in dry sec-butanol (5 mL), 4-chloro-3,5-dimethoxyaniline (122 mg, 0.65 mmol) was added, and the mixture was heated at 110°C for 12 hours. After cooling to room temperature, the reaction was quenched by adding saturated sodium bicarbonate solution. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography (eluent CH2Cl2 / MeOH=100 / 1) gave 102 mg (yield 54%) of 2-chloro-N-(4-chloro-3,5-dimethoxyphenyl)-9-cyclopropyl-9H-purin-6-amine. MS m / z (ESI): 380.07 [M+H] + .

[0412] To a solution of 2-chloro-N-(4-chloro-3,5-dimethoxyphenyl)-9-cyclopropyl-9H-purin-6-amine (38 mg, 0.10 mmol) in sec-butanol (1 mL) was added trans-4-aminocyclohexane-1-ol (58 mg, 0.50 mmol) and triethylamine (101 mg, 1 mmol). The mixture was heated at 130°C for 24 hours and then cooled to room temperature. The mixture was quenched with water and extracted three times with dichloromethane. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to afford 14 mg of the product (31% yield). 1 H NMR(500MHz,DMSO)δ9.36(s,1H),7.82(s,1H),7.53(s,2H),6.49(d,J=10.0Hz,1H),4.51(d,J=5.0H z,1H),3.85(s,6H),3.82-3.74(m,1H),3.42-3.34(m,1H),1.93-1.83(m,4H),1.35-0.97(m,8H).MS m / z(ESI):459.19[M+H] + .

[0413] Example 115: trans-4-((6-((3,5-dibromophenyl)amino)-9-isopropyl-9H-purin-2-yl)amino)cyclohexan-1-ol

[0414] 2,6-Dichloro-9-isopropyl-9H-purine (115 mg, 0.5 mmol) was dissolved in dry sec-butanol (5 mL), 3,5-dibromoaniline (160 mg, 0.65 mmol) was added, and the mixture was heated at 110°C for 12 hours. After cooling to room temperature, the reaction was quenched by adding saturated sodium bicarbonate solution. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography (eluent CH2Cl2 / MeOH=100 / 1) gave 135 mg (yield 61%) of 2-chloro-N-(3,5-dibromophenyl)-9-isopropyl-9H-purin-6-amine. MS m / z (ESI): 443.92 [M+H] + .

[0415] To a solution of 2-chloro-N-(3,5-dibromophenyl)-9-isopropyl-9H-purin-6-amine (44 mg, 0.10 mmol) in sec-butanol (1 mL) was added trans-4-aminocyclohexane-1-ol (58 mg, 0.50 mmol) and triethylamine (101 mg, 1 mmol). The mixture was heated at 130°C for 24 hours and then cooled to room temperature. The mixture was quenched with water and extracted three times with dichloromethane. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to afford 17 mg of the product (33% yield). 1 H NMR (500MHz, DMSO) δ9.79 (s, 1H), 8.36 (s, 2H), 8.00 (s, 1H), 7.36 (d, J = 5.0Hz, 1H), 6.56 (d, J = 5.0Hz, 1H), 4.60-4. 48(m,2H),3.74-3.68(m,1H),3.42-3.37(m,1H),2.01-1.83(m,4H),1.49(d,J=10.0Hz,1H),1.40-1.25(m,4H).MS m / z(ESI):523.05[M+H] + .

[0416] Example 116: trans-4-((9-cyclopropyl-6-((3,5-dibromophenyl)amino)-9H-purin-2-yl)amino)cyclohexan-1-ol

[0417] 2,6-Dichloro-9-cyclopropyl-9H-purine (115 mg, 0.5 mmol) (Reference Example 10) was dissolved in dry sec-butanol (5 mL), 3,5-dibromoaniline (160 mg, 0.65 mmol) was added, and the mixture was heated at 110 ° C for 12 hours. Cooled to room temperature, saturated sodium bicarbonate solution was added to quench the reaction. Extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography (eluent CH2Cl2 / MeOH=100 / 1) gave 2-chloro-N-(3,5-dibromophenyl)-9-cyclopropyl-9H-purine-6-amine 110 mg (yield 50%), MS m / z (ESI): 441.91 [M+H] + .

[0418] To a solution of 2-chloro-N-(3,5-dibromophenyl)-9-cyclopropyl-9H-purin-6-amine (44 mg, 0.10 mmol) in sec-butanol (1 mL) was added trans-4-aminocyclohexane-1-ol (58 mg, 0.50 mmol) and triethylamine (101 mg, 1 mmol). The mixture was heated at 130°C for 24 hours and then cooled to room temperature. The mixture was quenched with water and extracted three times with dichloromethane. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to afford 20 mg of the product (37% yield). 1 H NMR (500MHz, DMSO) δ9.78 (s, 1H), 8.35 (s, 2H), 7.85 (s, 1H), 7.36 (d, J = 5.0Hz, 1H), 6.71 (d, J = 5.0Hz, 1H), 4. 80(s,1H),3.75-3.69(m,1H),3.42-3.36(m,1H),1.94-1.83(m,4H),1.41-1.25(m,4H),1.05-0.96(m,4H).MS m / z(ESI):521.03[M+H] + .

[0419] Example 117: cis-4-((9-cyclopentyl-6-((3,5-dimethoxyphenyl)amino)-9H-purin-2-yl)amino)-1-methylcyclohexan-1-ol

[0420] To a solution of 2-chloro-9-cyclopentyl-N-(3,5-dimethoxyphenyl)-9H-purin-6-amine (37 mg, 0.10 mmol) (Reference Example 109) in sec-butanol (1 mL) were added cis-4-amino-1-methylcyclohexane-1-ol (65 mg, 0.50 mmol) and triethylamine (101 mg, 1.0 mmol). The mixture was heated at 130°C for 24 hours and then cooled to room temperature. The mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to give 7 mg of the product (yield 15%). 1 H NMR(500MHz,DMSO-d6)δ9.18(s,1H),7.88(s,1H),7.32(d,J=2.3Hz,2H),6.37(d ,J=7.6Hz,1H),6.14(t,J=2.3Hz,1H),4.69(p,J=7.6Hz,1H),3.95(s,1H),3.73(s ,6H),3.68(s,1H),2.09(dt,J=12.2,6.4Hz,2H),1.98(d,J=6.5Hz,2H),1.88(s,2 H),1.74-1.61(m,6H),1.61-1.55(m,2H),1.40(t,J=12.7Hz,2H),1.13(s,3H).MS m / z(ESI):467.27[M+H] + .

[0421] Example 118: trans-4-((9-cyclopentyl-6-((3,5-dimethoxyphenyl)amino)-9H-purin-2-yl)amino)-1-methylcyclohexan-1-ol

[0422] To a solution of 2-chloro-9-cyclopentyl-N-(3,5-dimethoxyphenyl)-9H-purin-6-amine (37 mg, 0.10 mmol) (Reference Example 109) in sec-butanol (1 mL) were added trans-4-amino-1-methylcyclohexane-1-ol (65 mg, 0.50 mmol) and triethylamine (101 mg, 1.0 mmol). The mixture was heated at 130°C for 24 hours and then cooled to room temperature. The mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to give 7 mg of the product (15% yield). 1H NMR(500MHz,DMSO-d6)δ9.18(s,1H),7.88(s,1H),7.30(d,J=2.3Hz,2H),6.34(d,J=7 .9Hz,1H),6.14(t,J=2.3Hz,1H),4.69(p,J=7.6Hz,1H),4.20(s,1H),3.80(s,1H),3.7 4(s,6H),2.15-2.06(m,2H),2.03-1.95(m,2H),1.92-1.82(m,4H),1.69(ddd,J=16.4 ,8.7,4.5Hz,2H),1.58(t,J=7.1Hz,2H),1.45(dd,J=11.4,8.5Hz,4H),1.15(s,3H).MS m / z(ESI):467.27[M+H] + .

[0423] Example 119: cis-4-((9-cyclopentyl-6-((3,5-dimethoxyphenyl)amino)-9H-purin-2-yl)amino)cyclohexan-1-ol

[0424] To a solution of 2-chloro-9-cyclopentyl-N-(3,5-dimethoxyphenyl)-9H-purin-6-amine (37 mg, 0.10 mmol) (Reference Example 109) in sec-butanol (1 mL) were added cis-4-aminocyclohexan-1-ol (58 mg, 0.50 mmol) and triethylamine (101 mg, 1.0 mmol). The mixture was heated at 130°C for 24 hours and then cooled to room temperature. The mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to give 6 mg of the product (13% yield). 1 H NMR(500MHz,DMSO-d6)δ9.18(s,1H),7.89(d,J=2.9Hz,1H),7.32(t,J=2.7Hz ,2H),6.36(d,J=7.5Hz,1H),6.14(q,J=2.6Hz,1H),4.69(tt,J=9.3,4.6Hz,1 H),4.30(s,1H),3.75(s,2H),3.73(d,J=2.8Hz,6H),2.15-2.03(m,2H),2.00 (d,J=9.9Hz,2H),1.89(s,2H),1.77-1.61(m,8H),1.53(d,J=14.8Hz,2H).MS m / z(ESI):453.26[M+H] + .

[0425] Example 120: trans-4-((6-((4-bromo-3-methoxyphenyl)amino)-9-cyclopropyl-9H-purin-2-yl)amino)cyclohexan-1-ol

[0426] 2,6-Dichloro-9-cyclopropyl-9H-purine (115 mg, 0.5 mmol) was dissolved in dry sec-butanol (5 mL), 4-bromo-3-methoxyaniline (131 mg, 0.65 mmol) was added, and the mixture was heated at 110°C for 12 hours. After cooling to room temperature, the reaction was quenched by adding saturated sodium bicarbonate solution. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography (eluent CH2Cl2 / MeOH=100 / 1) gave 61 mg (yield 31%) of N-(4-bromo-3-methoxyphenyl)-2-chloro-9-cyclopropyl-9H-purine-6-amine. MS m / z (ESI): 394.01 [M+H] + .

[0427] To a solution of N-(4-bromo-3-methoxyphenyl)-2-chloro-9-cyclopropyl-9H-purin-6-amine (40 mg, 0.10 mmol) in sec-butanol (1 mL) were added trans-4-aminocyclohexane-1-ol (58 mg, 0.50 mmol) and triethylamine (101 mg, 1 mmol). The mixture was heated at 130° C. for 24 hours and then cooled to room temperature. The mixture was quenched with water and extracted three times with dichloromethane. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to afford 16 mg of the product (34% yield). 1 H NMR (500MHz, DMSO) δ9.47(s,1H),7.82(d,J=5.0Hz,1H),7.81(s,1H),7.70(s,1H),7.39(d,J=5.0Hz,1H),6.51(s,1H),4.41(d ,J=5.0Hz,1H),3.85(s,3H),3.72-3.65(m,1H),3.43-3.37(m,1H),1.96-1.85(m,4H),1.33-1.21(m,4H),1.06-0.97(m,4H).MS m / z(ESI):473.13[M+H] + .

[0428] Example 121: trans-4-((6-((3-bromo-4-methoxyphenyl)amino)-9-isopropyl-9H-purin-2-yl)amino)cyclohexan-1-ol

[0429] 2,6-Dichloro-9-isopropyl-9H-purine (115 mg, 0.5 mmol) was dissolved in dry sec-butanol (5 mL), 3-bromo-4-methoxyaniline (132 mg, 0.65 mmol) was added, and the mixture was heated at 110°C for 12 hours. After cooling to room temperature, the reaction was quenched by adding saturated sodium bicarbonate solution. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography (eluent CH2Cl2 / MeOH=100 / 1) gave 105 mg (yield 53%) of N-(3-bromo-4-methoxyphenyl)-2-chloro-9-isopropyl-9H-purin-6-amine. MS m / z (ESI): 396.02 [M+H] + .

[0430] To a solution of N-(3-bromo-4-methoxyphenyl)-2-chloro-9-isopropyl-9H-purin-6-amine (40 mg, 0.10 mmol) in sec-butanol (1 mL) were added trans-4-aminocyclohexane-1-ol (58 mg, 0.50 mmol) and triethylamine (101 mg, 1 mmol). The mixture was heated at 130° C. for 24 hours and then cooled to room temperature. The mixture was quenched with water and extracted three times with dichloromethane. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to afford 19 mg of the product (40% yield). 1 H NMR (500MHz, DMSO) δ9.39(s,1H),8.44(s,1H),7.92(s,1H),7.83(s,1H),7.03(d,J=10.0Hz,1H),6.36(d,J=10.0Hz,1H),4.59- 4.48(m,2H),3.82(s,3H),3.72-3.64(m,1H),3.42-3.37(m,1H),1.95-1.83(m,4H),1.49(d,J=5.0Hz,6H),1.35-1.27(m,4H).MS m / z(ESI):475.15[M+H] + .

[0431] Example 122: trans-4-((6-((3-bromo-4-methoxyphenyl)amino)-9-cyclopropyl-9H-purin-2-yl)amino)cyclohexan-1-ol

[0432] 2,6-Dichloro-9-cyclopropyl-9H-purine (115 mg, 0.5 mmol) was dissolved in dry sec-butanol (5 mL), 3-bromo-4-methoxyaniline (132 mg, 0.65 mmol) was added, and the mixture was heated at 110°C for 12 hours. After cooling to room temperature, the reaction was quenched by adding saturated sodium bicarbonate solution. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography (eluent CH2Cl2 / MeOH=100 / 1) gave 105 mg (yield 53%) of N-(3-bromo-4-methoxyphenyl)-2-chloro-9-cyclopropyl-9H-purin-6-amine. MS m / z (ESI): 394.01 [M+H] + .

[0433] To a solution of N-(3-bromo-4-methoxyphenyl)-2-chloro-9-cyclopropyl-9H-purin-6-amine (40 mg, 0.10 mmol) in sec-butanol (1 mL) were added trans-4-aminocyclohexane-1-ol (58 mg, 0.50 mmol) and triethylamine (101 mg, 1 mmol). The mixture was heated at 130° C. for 24 hours and then cooled to room temperature. The mixture was quenched with water and extracted three times with dichloromethane. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to afford 14 mg of the product (30% yield). 1 H NMR (500MHz, DMSO) δ9.38 (s, 1H), 8.46 (s, 1H), 7.78 (s, 2H), 7.03 (d, J = 10.0Hz, 1H), 6.51 (s, 1H), 4.49 (d, J = 5.0Hz, 1H),3.81(s,3H),3.72-3.67(m,1H),3.42-3.36(m,1H),1.98-1.83(m,4H),1.36-1.27(m,4H),1.04-0.96(m,4H).MS m / z(ESI):473.13[M+H] + .

[0434] Example 123: trans-4-((6-((4-bromo-3-methoxyphenyl)amino)-9-isopropyl-9H-purin-2-yl)amino)cyclohexan-1-ol

[0435] 2,6-Dichloro-9-isopropyl-9H-purine (115 mg, 0.5 mmol) was dissolved in dry sec-butanol (5 mL), 4-bromo-3-methoxyaniline (132 mg, 0.65 mmol) was added, and the mixture was heated at 110°C for 12 hours. After cooling to room temperature, the reaction was quenched by adding saturated sodium bicarbonate solution. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography (eluent CH2Cl2 / MeOH=100 / 1) gave 105 mg (yield 53%) of N-(4-bromo-3-methoxyphenyl)-2-chloro-9-isopropyl-9H-purin-6-amine. MS m / z (ESI): 396.02 [M+H] + .

[0436] To a solution of N-(4-bromo-3-methoxyphenyl)-2-chloro-9-isopropyl-9H-purin-6-amine (40 mg, 0.10 mmol) in sec-butanol (1 mL) were added trans-4-aminocyclohexane-1-ol (58 mg, 0.50 mmol) and triethylamine (101 mg, 1 mmol). The mixture was heated at 130° C. for 24 hours and then cooled to room temperature. The mixture was quenched with water and extracted three times with dichloromethane. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to afford 16 mg of the product (34% yield). 1 H NMR (500MHz, DMSO) δ9.47(s,1H),7.95(s,1H),7.82(dd,J=10.0,5.0Hz,1H),7.72(s,1H),7.39(d,J=5.0Hz,1H),6.45(d,J=5.0Hz,1H) ,4.60-4.50(m,2H),3.85(s,3H),3.70-3.66(m,1H),3.42-3.38(m,1H),2.01-1.85(m,4H),1.50(d,J=5.0Hz,6H),1.33-1.23(m,4H).MS m / z(ESI):475.15[M+H] + .

[0437] Example 124: trans-4-((6-((2-bromo-3-methoxyphenyl)amino)-9-isopropyl-9H-purin-2-yl)amino)cyclohexan-1-ol

[0438] 2,6-Dichloro-9-isopropyl-9H-purine (115 mg, 0.5 mmol) was dissolved in dry sec-butanol (5 mL), 2-bromo-3-methoxyaniline (130 mg, 0.65 mmol) was added, and the mixture was heated at 110°C for 12 hours. After cooling to room temperature, the reaction was quenched by adding saturated sodium bicarbonate solution. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography (eluent CH2Cl2 / MeOH=100 / 1) gave 99 mg (yield 50%) of N-(2-bromo-3-methoxyphenyl)-2-chloro-9-isopropyl-9H-purin-6-amine. MS m / z (ESI): 396.02 [M+H] + .

[0439] To a solution of N-(2-bromo-3-methoxyphenyl)-2-chloro-9-isopropyl-9H-purin-6-amine (40 mg, 0.10 mmol) in sec-butanol (1 mL) were added trans-4-aminocyclohexane-1-ol (58 mg, 0.50 mmol) and triethylamine (101 mg, 1 mmol). The mixture was heated at 130° C. for 24 hours and then cooled to room temperature. The mixture was quenched with water and extracted three times with dichloromethane. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to afford 19 mg of the product (40% yield). 1 H NMR (500MHz, DMSO) δ9.47(s,1H),7.95(s,1H),7.82(dd,J=10.0,5.0Hz,1H),7.72(s,1H),7.39(d,J=5.0Hz,1H),6.45(d,J=5.0Hz,1H) ,4.60-4.48(m,2H),3.85(s,3H),3.70-3.64(m,1H),3.43-3.38(m,1H),1.97-1.85(m,4H),1.50(d,J=5.0Hz,6H),1.33-1.23(m,4H).MS m / z(ESI):475.15[M+H] + .

[0440] Example 125: trans-4-((6-((2-bromo-5-methoxyphenyl)amino)-9-isopropyl-9H-purin-2-yl)amino)cyclohexan-1-ol

[0441] 2,6-Dichloro-9-isopropyl-9H-purine (115 mg, 0.5 mmol) was dissolved in dry sec-butanol (5 mL), 2-bromo-4-methoxyaniline (130 mg, 0.65 mmol) was added, and the mixture was heated at 110°C for 12 hours. After cooling to room temperature, the reaction was quenched by adding saturated sodium bicarbonate solution. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography (eluent CH2Cl2 / MeOH=100 / 1) gave 113 mg (yield 57%) of N-(2-bromo-4-methoxyphenyl)-2-chloro-9-isopropyl-9H-purin-6-amine. MS m / z (ESI): 396.02 [M+H] + .

[0442] To a solution of N-(2-bromo-4-methoxyphenyl)-2-chloro-9-isopropyl-9H-purin-6-amine (40 mg, 0.10 mmol) in sec-butanol (1 mL) were added trans-4-aminocyclohexane-1-ol (58 mg, 0.50 mmol) and triethylamine (101 mg, 1 mmol). The mixture was heated at 130° C. for 24 hours and then cooled to room temperature. The mixture was quenched with water and extracted three times with dichloromethane. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to afford 12 mg of the product (25% yield). 1 H NMR (500MHz, DMSO) δ9.47(s,1H),7.95(s,1H),7.82(dd,J=10.0,5.0Hz,1H),7.72(s,1H),7.39(d,J=5.0Hz,1H),6.45(d,J=5.0Hz,1H) ,4.60-4.50(m,2H),3.85(s,3H),3.70-3.66(m,1H),3.42-3.37(m,1H),1.97-1.85(m,4H),1.50(d,J=5.0Hz,6H),1.33-1.23(m,4H).MS m / z(ESI):475.15[M+H] + .

[0443] Example 126: trans-4-((9-cyclopropyl-6-((2,6-dimethoxypyridin-4-yl)amino)-9H-purin-2-yl)amino)-1-methylcyclohexan-1-ol

[0444] 2,6-Dichloro-9-cyclopropyl-9H-purine (1 g, 4.4 mmol) was dissolved in dry sec-butanol (10 mL), 2,6-dimethoxypyridin-4-amine (880 mg, 5.72 mmol) was added, and the mixture was heated at 110 ° C for 12 hours. After cooling to room temperature, saturated sodium bicarbonate solution was added to quench the reaction. It was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography (eluent CH2Cl2 / MeOH=100 / 1) gave 2-chloro-9-cyclopropyl-N-(2,6-dimethoxypyridin-4-yl)-9H-purine-6-amine 150 mg (yield 13%), MS m / z (ESI): 347.10 [M+H] + .

[0445] To a solution of 2-chloro-9-cyclopropyl-N-(2,6-dimethoxypyridin-4-yl)-9H-purin-6-amine (35 mg, 0.10 mmol) in sec-butanol (1 mL) was added trans-4-amino-1-methylcyclohexane-1-ol (65 mg, 0.50 mmol) and triethylamine (101 mg, 1.0 mmol). The mixture was heated at 130°C for 24 hours and then cooled to room temperature. The mixture was quenched with water and extracted three times with dichloromethane. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to afford 11 mg of the product (25% yield). 1 H NMR(500MHz,DMSO-d6)δ9.67(s,1H),7.85(s,1H),7.15(s,2H),6.69(d,J=7.5Hz,1H),4.22(s,1H),3.82(s,6H),3.78(s,1H),3.35(s,1H ),1.88(d,J=10.5Hz,2H),1.66-1.56(m,2H),1.46(t,J=12.4Hz,4H),1.16(s,3H),1.06(d,J=3.8Hz,2H),0.99(td,J=7.4,5.3Hz,2H).MS m / z(ESI):440.24[M+H] + .

[0446] Example 127: cis-4-((9-cyclopropyl-6-((2,6-dimethoxypyridin-4-yl)amino)-9H-purin-2-yl)amino)-1-methylcyclohexan-1-ol

[0447] To a solution of 2-chloro-9-cyclopropyl-N-(2,6-dimethoxypyridin-4-yl)-9H-purin-6-amine (35 mg, 0.10 mmol) (Reference Example 126) in sec-butanol (1 mL) were added cis-4-amino-1-methylcyclohexane-1-ol (65 mg, 0.50 mmol) and triethylamine (101 mg, 1.0 mmol). The mixture was heated at 130°C for 24 hours and then cooled to room temperature. The mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to give 11 mg of the product (25% yield). 1 H NMR(500MHz,DMSO-d6)δ9.69(s,1H),7.84(s,1H),7.17(s,2H),6.78(s,1H),3.97(s,1H),3.81(s,6H),3.66(d,J= 6.8Hz,1H),2.07(s,1H),1.75-1.56(m,6H),1.47(s,2H),1.14(s,3H),1.06(s,2H),0.99(dt,J=6.6,3.1Hz,2H).MS m / z(ESI):440.24[M+H] + .

[0448] Example 128: trans-4-((6-((3,5-dimethoxyphenyl)amino)-9-(2-ethoxyethyl)-9H-purin-2-yl)amino)cyclohexan-1-ol

[0449] 2,6-Dichloropurine (945 mg, 5 mmol) was dissolved in dry N,N-dimethylformamide (50 mL), 1-bromo-2-ethoxyethane (918 mg, 6 mmol) and N,N-diisopropylethylamine (968 mg, 7.5 mmol) were added, and the mixture was heated at 80 ° C for 12 hours. The reaction was quenched by adding saturated sodium bicarbonate solution. It was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography to obtain 510 mg of 2,6-dichloro-9-(2-ethoxyethyl)-9H-purine (yield 39%), MS m / z (ESI): 261.03 [M+H] + .

[0450] 2,6-Dichloro-9-(2-ethoxyethyl)-9H-purine (510 mg, 1.96 mmol) was dissolved in dry sec-butanol (10 mL), 3,5-dimethoxyaniline (390 mg, 2.55 mmol) was added, and the mixture was heated at 100°C for 12 hours. After cooling to room temperature, the reaction was quenched by adding saturated sodium bicarbonate solution. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography (eluent CH2Cl2 / MeOH=100 / 1) gave 390 mg (yield 54%) of 2-chloro-N-(3,5-dimethoxyphenyl)-9-(2-ethoxyethyl)-9H-purin-6-amine. MS m / z (ESI): 378.13 [M+H] + .

[0451] To a solution of 2-chloro-N-(3,5-dimethoxyphenyl)-9-(2-ethoxyethyl)-9H-purin-6-amine (40 mg, 0.10 mmol) in sec-butanol (1 mL) was added trans-4-aminocyclohexane-1-ol (58 mg, 0.50 mmol) and triethylamine (101 mg, 1 mmol). The mixture was heated at 130°C for 24 hours and then cooled to room temperature. The mixture was quenched with water and extracted three times with dichloromethane. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to afford 15 mg of the product (33% yield). 1 H NMR (500MHz, DMSO-d6) δ9.24 (s, 1H), 7.79 (s, 1H), 7.30 (d, J = 2.2Hz, 2H), 6.44 ( s,1H),6.15(t,J=2.2Hz,1H),4.51(d,J=4.3Hz,1H),4.15(t,J=5.6Hz,2H),3.7 4(s,6H),3.73-3.66(m,2H),3.44(q,J=7.0Hz,2H),3.39(d,J=4.5Hz,1H),1.93 (d,J=9.2Hz,2H),1.83(s,2H),1.28(q,J=10.4Hz,4H),1.06(t,J=7.0Hz,3H).MS m / z(ESI):457.26[M+H] + .

[0452] Example 129: cis-4-((6-((3,5-dimethoxyphenyl)amino)-9-(2-ethoxyethyl)-9H-purin-2-yl)amino)-1-methylcyclohexan-1-ol

[0453] To a solution of 2-chloro-N-(3,5-dimethoxyphenyl)-9-(2-ethoxyethyl)-9H-purin-6-amine (40 mg, 0.10 mmol) (Reference Example 128) in sec-butanol (1 mL) were added cis-4-amino-1-methylcyclohexane-1-ol (65 mg, 0.50 mmol) and triethylamine (101 mg, 1 mmol). The mixture was heated at 130° C. for 24 hours and then cooled to room temperature. The reaction mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to give 15 mg of the product (yield 21%). 1 H NMR (500MHz, DMSO-d6) δ9.24(s,1H),7.79(s,1H),7.33(d,J=2.2Hz,2H),6.47(s,1H),6.14(t,J=2.2Hz,1H),4.14(t,J=5.6Hz,2H),3.97(s,1H ),3.73(s,6H),3.70(d,J=5.2Hz,2H),3.44(q,J=7.0Hz,2H),1.72-1.54(m,6H),1.41(t,J=12.7Hz,2H),1.13(s,3H),1.06(t,J=7.0Hz,3H).MS m / z(ESI):471.27[M+H] + .

[0454] Example 130: trans-4-((9-(cyclopropylmethyl)-6-((3,5-dimethoxyphenyl)amino)-9H-purin-2-yl)amino)cyclohexan-1-ol

[0455] 2,6-Dichloro-9-(cyclopropylmethyl)-9H-purine (500 mg, 2.07 mmol) (Reference Example 7) was dissolved in dry sec-butanol (10 mL), 3,5-dimethoxyaniline (412 mg, 2.69 mmol) was added, and the mixture was heated at 95 ° C for 12 hours. After cooling to room temperature, saturated sodium bicarbonate solution was added to quench the reaction. It was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography (eluent CH2Cl2 / MeOH=100 / 1) gave 2-chloro-9-(cyclopropylmethyl)-N-(3,5-dimethoxyphenyl)-9H-purin-6-amine 223 mg (yield 29%), MS m / z (ESI): 360.12 [M+H] + .

[0456] To a solution of 2-chloro-9-(cyclopropylmethyl)-N-(3,5-dimethoxyphenyl)-9H-purin-6-amine (36 mg, 0.10 mmol) in sec-butanol (1 mL) were added trans-4-aminocyclohexane-1-ol (58 mg, 0.50 mmol) and triethylamine (101 mg, 1 mmol). The mixture was heated at 130°C for 24 hours and then cooled to room temperature. The mixture was quenched with water and extracted three times with dichloromethane. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to afford 7 mg of the product (32% yield). 1 H NMR(500MHz,DMSO-d6)δ9.22(s,1H),7.88(s,1H),7.31(d,J=2.3Hz,2H),6.39(s,1 H),6.15(t,J=2.3Hz,1H),4.50(d,J=4.4Hz,1H),3.85(d,J=7.1Hz,2H),3.74(s,6H) ,3.72-3.68(m,1H),3.39(q,J=4.4Hz,1H),1.93(d,J=8.9Hz,2H),1.83(d,J=6.8Hz ,2H),1.28(qd,J=9.0,7.0,2.9Hz,5H),0.57-0.49(m,2H),0.42(d,J=4.9Hz,2H).MS m / z(ESI):439.24[M+H] + .

[0457] Example 131: trans-4-((6-((3,5-dimethoxyphenyl)amino)-9-propyl-9H-purin-2-yl)amino)cyclohexan-1-ol

[0458] 2,6-Dichloropurine (1.89 g, 10 mmol) was dissolved in dry N,N-dimethylformamide (50 mL), 1-iodopropane (2.04 g, 12 mmol) and potassium carbonate (2.07 g, 15 mmol) were added, and the mixture was stirred at room temperature for 12 hours. Saturated sodium bicarbonate solution was added to quench the reaction. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography was performed to obtain 920 mg of 2,6-dichloro-9-propyl-9H-purine (yield 40%). MS m / z (ESI): 231.02 [M+H] + .

[0459] 2,6-Dichloro-9-propyl-9H-purine (400 mg, 1.74 mmol) was dissolved in dry sec-butanol (10 mL), 3,5-dimethoxyaniline (266 mg, 1.74 mmol) was added, and the mixture was heated at 95°C for 12 hours. After cooling to room temperature, saturated sodium bicarbonate solution was added to quench the reaction. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography (eluent CH2Cl2 / MeOH=100 / 1) gave 243 mg (yield 41%) of 2-chloro-N-(3,5-dimethoxyphenyl)-9-propyl-9H-purine-6-amine. MS m / z (ESI): 348.12 [M+H] + .

[0460] To a solution of 2-chloro-N-(3,5-dimethoxyphenyl)-9-propyl-9H-purin-6-amine (35 mg, 0.10 mmol) in sec-butanol (1 mL) was added trans-4-aminocyclohexane-1-ol (58 mg, 0.50 mmol) and triethylamine (101 mg, 1 mmol). The mixture was heated at 130°C for 24 hours and then cooled to room temperature. The mixture was quenched with water and extracted three times with dichloromethane. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to afford 13 mg of the product (30% yield). 1 H NMR (500MHz, DMSO-d6) δ9.22 (s, 1H), 7.84 (s, 1H), 7.30 (d, J = 2.2Hz, 2H), 6.42 (s,1H),6.15(t,J=2.2Hz,1H),4.50(d,J=4.3Hz,1H),3.96(t,J=7.0Hz,2H),3. 74(s,6H),3.71-3.66(m,1H),3.39(q,J=5.2,4.8Hz,1H),1.93(d,J=8.5Hz,2H) ,1.80(dt,J=21.7,5.9Hz,4H),1.28(q,J=9.3Hz,4H),0.85(t,J=7.4Hz,3H).MS m / z(ESI):427.24[M+H] + .

[0461] Example 132: (trans)-(4-((6-((3,5-dimethoxyphenyl)amino)-9-isopropyl-9H-purin-2-yl)amino)cyclohexyl)methanol

[0462] To a solution of 2-chloro-N-(3,5-dimethoxyphenyl)-9-isopropyl-9H-purin-6-amine (35 mg, 0.10 mmol) (Reference Example 91) in sec-butanol (1 mL) were added trans-(4-aminocyclohexyl)methanol (65 mg, 0.50 mmol) and triethylamine (101 mg, 1.0 mmol). The mixture was heated at 130°C for 24 hours and then cooled to room temperature. The mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to give 10 mg of the product (yield 23%). 1 H NMR (500MHz, DMSO-d6) δ9.21 (s, 1H), 7.93 (s, 1H), 7.32 (d, J = 2.3Hz, 2H), 6.40 ( s,1H),6.14(t,J=2.2Hz,1H),4.57(p,J=6.7Hz,1H),4.38(t,J=5.3Hz,1H),3.7 3(s,6H),3.71-3.67(m,1H),3.24(t,J=5.8Hz,2H),1.99(d,J=12.2Hz,2H),1.8 1-1.70(m,2H),1.49(d,J=6.7Hz,6H),1.37-1.17(m,4H),1.09-0.94(m,2H).MS m / z(ESI):441.26[M+H] + .

[0463] Example 133: (cis)-4-((6-((3,5-dimethoxyphenyl)amino)-9-isopropyl-9H-purin-2-yl)amino)cyclohexyl)methanol

[0464] To a solution of 2-chloro-N-(3,5-dimethoxyphenyl)-9-isopropyl-9H-purin-6-amine (35 mg, 0.10 mmol) (Reference Example 91) in sec-butanol (1 mL) were added cis-(4-aminocyclohexyl)methanol (65 mg, 0.50 mmol) and triethylamine (101 mg, 1.0 mmol). The mixture was heated at 130°C for 24 hours and then cooled to room temperature. The mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to give 12 mg of the product (yield 27%). 1H NMR (500MHz, DMSO-d6) δ9.21 (s, 1H), 7.93 (s, 1H), 7.32 (d, J = 2.2Hz, 2H), 6.40 ( s,1H),6.14(t,J=2.2Hz,1H),4.57(p,J=6.7Hz,1H),4.38(t,J=5.3Hz,1H),3.7 3(s,6H),3.71-3.64(m,1H),3.24(t,J=5.8Hz,2H),2.02-1.96(m,2H),1.77(d, J=12.8Hz,2H),1.49(d,J=6.7Hz,6H),1.37-1.19(m,4H),1.07-0.95(m,2H).MS m / z(ESI):441.26[M+H] + .

[0465] Example 134: ((trans)-4-((9-cyclopropyl-6-((3,5-dimethoxyphenyl)amino)-9H-purin-2-yl)amino)cyclohexyl)methanol

[0466] To a solution of 2-chloro-N-(3,5-dimethoxyphenyl)-9-cyclopropyl-9H-purin-6-amine (35 mg, 0.10 mmol) (Reference Example 94) in sec-butanol (1 mL) were added trans-(4-aminocyclohexyl)methanol (65 mg, 0.50 mmol) and triethylamine (101 mg, 1.0 mmol). The mixture was heated at 130°C for 24 hours and then cooled to room temperature. The mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to give 10 mg of the product (25% yield). 1 H NMR (500MHz, DMSO-d6) δ9.21(s,1H),7.79(s,1H),7.31(d,J=2.3Hz,2H),6.54(d,J=15.6Hz,1H),6.14(t,J=2.3Hz,1H),4.38(t,J=5.3Hz,1H ),3.73(s,6H),3.24(t,J=5.8Hz,2H),2.03-1.94(m,2H),1.77(d,J=12.9Hz,2H),1.39-1.29(m,1H),1.30-1.19(m,2H),1.10-0.95(m,6H).MS m / z(ESI):439.24[M+H] + .

[0467] Example 135: (cis)-4-((9-cyclopropyl-6-((3,5-dimethoxyphenyl)amino)-9H-purin-2-yl)amino)cyclohexyl)methanol

[0468] To a solution of 2-chloro-N-(3,5-dimethoxyphenyl)-9-cyclopropyl-9H-purin-6-amine (35 mg, 0.10 mmol) (Reference Example 94) in sec-butanol (1 mL) were added cis-(4-aminocyclohexyl)methanol (65 mg, 0.50 mmol) and triethylamine (101 mg, 1.0 mmol). The mixture was heated at 130°C for 24 hours and then cooled to room temperature. The mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to give 6 mg of the product (14% yield). 1 H NMR (500MHz, DMSO-d6) δ9.21(s,1H),7.79(s,1H),7.31(d,J=2.3Hz,2H),6.55(s,1H),6.14(t,J=2.3Hz,1H),4.38(t,J=5.3Hz,1H),3.73( s,6H),3.24(t,J=5.8Hz,2H),2.01-1.94(m,2H),1.85-1.70(m,2H),1.38-1.29(m,1H),1.25(q,J=13.4,12.6Hz,2H),1.09-0.94(m,6H).MS m / z(ESI):439.24[M+H] + .

[0469] Example 136: ((trans)-4-((6-((3-bromo-4-chloro-5-methoxyphenyl)amino)-9-isopropyl-9H-purin-2-yl)amino)cyclohexyl)methanol

[0470] To a solution of N-(3-bromo-4-chloro-5-methoxyphenyl)-2-chloro-9-isopropyl-9H-purin-6-amine (22 mg, 0.05 mmol) (Reference Example 103) in sec-butanol (1 mL) were added trans-(4-aminocyclohexyl)methanol (65 mg, 0.50 mmol) and triethylamine (101 mg, 1.0 mmol). The mixture was heated at 130° C. for 24 hours and then cooled to room temperature. The mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to give 6 mg of the product (yield 23%). 1H NMR(500MHz,DMSO-d6)δ9.64(s,1H),8.48(s,1H),7.98(s,1H),7.68(s,1H), 6.59-6.50(m,1H),4.58(p,J=6.8Hz,1H),4.38(t,J=5.3Hz,1H),3.86(s,3H) ,3.74(d,J=12.3Hz,1H),3.24(t,J=5.8Hz,2H),2.01-1.95(m,2H),1.81-1.7 4(m,2H),1.49(d,J=6.7Hz,6H),1.29-1.21(m,4H),1.07(d,J=13.1Hz,1H).MS m / z(ESI):523.12[M+H] + .

[0471] Example 137: cis-4-((6-((3-bromo-4-chloro-5-methoxyphenyl)amino)-9-isopropyl-9H-purin-2-yl)amino)cyclohexyl)methanol

[0472] To a solution of N-(3-bromo-4-chloro-5-methoxyphenyl)-2-chloro-9-isopropyl-9H-purin-6-amine (22 mg, 0.05 mmol) (Reference Example 103) in sec-butanol (1 mL) were added cis-(4-aminocyclohexyl)methanol (65 mg, 0.50 mmol) and triethylamine (101 mg, 1.0 mmol). The mixture was heated at 130° C. for 24 hours and then cooled to room temperature. The mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to give 5 mg of the product (yield 19%). 1 H NMR(500MHz,DMSO-d6)δ9.64(s,1H),8.49(s,1H),7.98(s,1H),7.68(s,1H),6 .69-6.32(m,1H),4.58(p,J=6.8Hz,1H),4.38(t,J=5.4Hz,1H),3.86(s,3H),3 .73(d,J=10.6Hz,1H),3.24(t,J=5.8Hz,2H),2.03-1.93(m,2H),1.77(d,J=12 .7Hz,2H),1.49(d,J=6.7Hz,6H),1.29-1.20(m,4H),1.09(t,J=12.9Hz,1H).MS m / z(ESI):523.12[M+H] +Example 138: ((trans)-4-((6-((3-bromo-4-chloro-5-methoxyphenyl)amino)-9-cyclopropyl-9H-purin-2-yl)amino)cyclohexyl)methanol

[0473] To a solution of N-(3-bromo-4-chloro-5-methoxyphenyl)-2-chloro-9-cyclopropyl-9H-purin-6-amine (22 mg, 0.05 mmol) (Reference Example 104) in sec-butanol (1 mL) were added trans-(4-aminocyclohexyl)methanol (65 mg, 0.50 mmol) and triethylamine (101 mg, 1.0 mmol). The mixture was heated at 130° C. for 24 hours and then cooled to room temperature. The mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to give 4 mg of the product (yield 15%). 1 H NMR(500MHz,DMSO-d6)δ9.64(s,1H),8.50(s,1H),7.84(s,1H),7.65(s,1H),6.70 (s,1H),4.38(t,J=5.4Hz,1H),3.86(s,3H),3.79-3.68(m,1H),3.23(t,J=5.8Hz, 2H),1.97(d,J=12.0Hz,2H),1.77(d,J=12.7Hz,2H),1.27(dd,J=24.4,10.9Hz,5H ),1.11(d,J=12.9Hz,1H),1.07-1.04(m,2H),0.99(ddd,J=6.4,3.7,2.4Hz,2H).MS m / z(ESI):521.11[M+H] + .

[0474] Example 139: cis-4-((6-((3-bromo-4-chloro-5-methoxyphenyl)amino)-9-cyclopropyl-9H-purin-2-yl)amino)cyclohexyl)methanol

[0475] To a solution of N-(3-bromo-4-chloro-5-methoxyphenyl)-2-chloro-9-cyclopropyl-9H-purin-6-amine (22 mg, 0.05 mmol) (Reference Example 104) in sec-butanol (1 mL) were added cis-(4-aminocyclohexyl)methanol (65 mg, 0.50 mmol) and triethylamine (101 mg, 1.0 mmol). The mixture was heated at 130° C. for 24 hours and then cooled to room temperature. The mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to give 4 mg of the product (yield 15%). 1H NMR(500MHz,DMSO-d6)δ9.64(s,1H),8.50(s,1H),7.84(s,1H),7.65(s,1H),6.70( s,1H),4.38(t,J=5.4Hz,1H),3.86(s,3H),3.74(td,J=11.0,9.2,5.6Hz,1H),3.23( t,J=5.8Hz,2H),1.98(t,J=7.5Hz,2H),1.77(d,J=12.7Hz,2H),1.36-1.20(m,5H), 1.11(d,J=12.9Hz,1H),1.05(d,J=5.0Hz,2H),0.99(ddd,J=6.6,3.8,2.5Hz,2H).MS m / z(ESI):521.11[M+H] + .

[0476] Example 140: trans-4-((9-cyclopropyl-6-((4-fluoro-3,5-dimethoxyphenyl)amino)-9H-purin-2-yl)amino)cyclohexan-1-ol

[0477] 2,6-Dichloro-9-cyclopropyl-9H-purine (115 mg, 0.5 mmol) was dissolved in dry sec-butanol (5 mL), 4-fluoro-3,5-dimethoxyaniline (111 mg, 0.65 mmol) was added, and the mixture was heated at 110°C for 12 hours. After cooling to room temperature, the reaction was quenched by adding saturated sodium bicarbonate solution. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography (eluent CH2Cl2 / MeOH=100 / 1) gave 109 mg (yield 60%) of 2-chloro-N-(4-fluoro-3,5-dimethoxyphenyl)-9-cyclopropyl-9H-purin-6-amine. MS m / z (ESI): 364.10 [M+H] + .

[0478] To a solution of 2-chloro-N-(4-fluoro-3,5-dimethoxyphenyl)-9-isopropyl-9H-purin-6-amine (73 mg, 0.20 mmol) in sec-butanol (1 mL) was added trans-4-aminocyclohexane-1-ol (115 mg, 1.0 mmol) and triethylamine (202 mg, 2.0 mmol). The mixture was heated at 130°C for 24 hours and then cooled to room temperature. The mixture was quenched with water and extracted three times with dichloromethane. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to afford 4 mg of the product (15% yield). 1H NMR (500MHz, DMSO) δ9.30(s,1H),7.82(s,1H),7.49(d,J=5.0Hz,2H),6.56(s,1H),4.57(d,J=5.0H z,1H),3.84(s,6H),3.79-3.72(m,1H),3.41-3.31(m,1H),1.91-1.82(m,4H),1.34-0.97(m,8H).MS m / z(ESI):443.22[M+H] + .

[0479] Example 141: trans-4-((6-((4-fluoro-3,5-dimethoxyphenyl)amino)-9-isopropyl-9H-purin-2-yl)amino)cyclohexan-1-ol

[0480] 2,6-Dichloro-9-isopropyl-9H-purine (115 mg, 0.5 mmol) was dissolved in dry sec-butanol (5 mL), 4-fluoro-3,5-dimethoxyaniline (111 mg, 0.65 mmol) was added, and the mixture was heated at 110°C for 12 hours. After cooling to room temperature, the reaction was quenched by adding saturated sodium bicarbonate solution. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography (eluent CH2Cl2 / MeOH=100 / 1) gave 111 mg (yield 61%) of 2-chloro-N-(4-fluoro-3,5-dimethoxyphenyl)-9-isopropyl-9H-purin-6-amine. MS m / z (ESI): 366.11 [M+H] + .

[0481] To a solution of 2-chloro-N-(4-fluoro-3,5-dimethoxyphenyl)-9-isopropyl-9H-purin-6-amine (73 mg, 0.20 mmol) in sec-butanol (1 mL) was added trans-4-aminocyclohexane-1-ol (115 mg, 1.0 mmol) and triethylamine (202 mg, 2.0 mmol). The mixture was heated at 130°C for 24 hours and then cooled to room temperature. The mixture was quenched with water and extracted three times with dichloromethane. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to afford 4 mg of the product (15% yield). 1H NMR (500MHz, DMSO) δ9.31 (s, 1H), 7.96 (s, 1H), 7.50 (d, J = 5.0Hz, 2H), 6.42 (s, 1H), 4.59-4.55 (m, 1H), 3.84 ( s,6H),3.77-3.69(m,1H),3.41-3.36(m,1H),1.93-1.83(m,4H),1.50(d,J=5.0Hz,1H),1.34-1.15(m,4H).MS m / z(ESI):445.24[M+H] + .

[0482] Example 142: ((trans)-4-((6-((3,5-dimethoxyphenyl)amino)-9-propyl-9H-purin-2-yl)amino)cyclohexyl)methanol

[0483] To a solution of 2-chloro-N-(3,5-dimethoxyphenyl)-9-propyl-9H-purin-6-amine (35 mg, 0.10 mmol) (Reference Example 131) in sec-butanol (1 mL) were added trans-(4-aminocyclohexyl)methanol (65 mg, 0.50 mmol) and triethylamine (101 mg, 1.0 mmol). The mixture was heated at 130°C for 24 hours and then cooled to room temperature. The mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to give 4 mg of the product (9% yield). 1 H NMR(500MHz,DMSO-d6)δ9.29(s,1H),7.85(s,1H),7.33(d,J=2.2Hz,2H),6.5 4(s,1H),6.14(t,J=2.2Hz,1H),4.43(t,J=5.3Hz,1H),3.96(t,J=7.1Hz,2H) ,3.73(s,6H),3.23(t,J=5.8Hz,2H),1.98(d,J=12.2Hz,2H),1.77(t,J=11.6 Hz,4H),1.38-1.17(m,4H),1.01(q,J=12.6Hz,2H),0.85(t,J=7.4Hz,3H).MS m / z(ESI):441.26[M+H] + .

[0484] Example 143: cis-4-((6-((3,5-Dibromophenyl)amino)-9-isopropyl-9H-purin-2-yl)amino)cyclohexyl)methanol

[0485] To a solution of 2-chloro-N-(3,5-dibromophenyl)-9-isopropyl-9H-purin-6-amine (22 mg, 0.05 mmol) (Reference Example 115) in sec-butanol (1 mL) were added cis-(4-aminocyclohexyl)methanol (65 mg, 0.50 mmol) and triethylamine (101 mg, 1.0 mmol). The mixture was heated at 130° C. for 24 hours and then cooled to room temperature. The mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to give 5 mg of the product (yield 19%). 1 H NMR(500MHz,DMSO-d6)δ9.87(s,1H),8.37(s,2H),8.02(s,1H),7.36(t,J=1 .7Hz,1H),6.68(d,J=8.3Hz,1H),4.62-4.53(m,1H),4.42(t,J=5.3Hz,1H),3 .71(s,1H),3.23(t,J=5.8Hz,2H),1.97(d,J=10.9Hz,2H),1.78(d,J=12.5H z,2H),1.49(d,J=6.8Hz,6H),1.26(dd,J=24.4,11.1Hz,4H),1.13(s,1H).MS m / z(ESI):537.06[M+H] + .

[0486] Example 144: ((trans)-4-((9-cyclopropyl-6-((3,5-dibromophenyl)amino)-9H-purin-2-yl)amino)cyclohexyl)methanol

[0487] To a solution of 2-chloro-N-(3,5-dibromophenyl)-9-cyclopropyl-9H-purin-6-amine (22 mg, 0.05 mmol) (Reference Example 116) in sec-butanol (1 mL) were added trans-(4-aminocyclohexyl)methanol (65 mg, 0.50 mmol) and triethylamine (101 mg, 1.0 mmol). The mixture was heated at 130° C. for 24 hours and then cooled to room temperature. The mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to give 5 mg of the product (yield 19%). 1H NMR(500MHz,DMSO-d6)δ9.86(s,1H),8.36(s,2H),7.87(s,1H),7.36(d,J=1.8 Hz,1H),6.84(s,1H),4.42(t,J=5.3Hz,1H),3.79-3.58(m,1H),3.33(d,J=9.9H z,1H),3.23(t,J=5.9Hz,2H),1.96(d,J=11.8Hz,2H),1.78(d,J=12.5Hz,2H), 1.27(dt,J=22.5,11.7Hz,4H),1.13(s,1H),1.05(s,2H),1.01-0.95(m,2H).MS m / z(ESI):535.05[M+H] + .

[0488] Example 145: cis-4-((9-cyclopropyl-6-((3,5-dibromophenyl)amino)-9H-purin-2-yl)amino)cyclohexyl)methanol

[0489] To a solution of 2-chloro-N-(3,5-dibromophenyl)-9-cyclopropyl-9H-purin-6-amine (22 mg, 0.05 mmol) (Reference Example 116) in sec-butanol (1 mL) were added cis-(4-aminocyclohexyl)methanol (65 mg, 0.50 mmol) and triethylamine (101 mg, 1.0 mmol). The mixture was heated at 130° C. for 24 hours and then cooled to room temperature. The mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to give 4 mg of the product (yield 15%). 1 H NMR(500MHz,DMSO-d6)δ9.86(s,1H),8.36(s,2H),7.87(s,1H),7.36(t,J=1.7 Hz,1H),6.84(s,1H),4.42(t,J=5.3Hz,1H),3.83-3.58(m,1H),3.33(d,J=11.5 Hz,1H),3.23(t,J=5.9Hz,2H),1.96(d,J=11.9Hz,2H),1.78(d,J=12.5Hz,2H), 1.27(dt,J=22.1,11.6Hz,4H),1.13(s,1H),1.05(s,2H),1.01-0.97(m,2H).MS m / z(ESI):535.04[M+H] + .

[0490] Example 146: cis-4-((6-((4-chloro-3,5-dimethoxyphenyl)amino)-9-cyclopropyl-9H-purin-2-yl)amino)cyclohexyl)methanol

[0491] To a solution of 2-chloro-N-(4-chloro-3,5-dimethoxyphenyl)-9-cyclopropyl-9H-purin-6-amine (19 mg, 0.05 mmol) (Reference Example 114) in sec-butanol (1 mL) were added cis-(4-aminocyclohexyl)methanol (65 mg, 0.50 mmol) and triethylamine (101 mg, 1.0 mmol). The mixture was heated at 130° C. for 24 hours and then cooled to room temperature. The reaction mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to give 4 mg of the product (yield 17%). 1 H NMR(500MHz,DMSO-d6)δ9.41(s,1H),7.84(s,1H),7.56(s,2H),6.61(s,1H ),4.44(t,J=5.3Hz,1H),3.85(s,6H),3.78(s,1H),3.23(t,J=5.8Hz,2H), 1.97(s,2H),1.76(d,J=12.7Hz,2H),1.30(s,1H),1.28(s,1H),1.26(d,J= 4.2Hz,2H),1.06(s,2H),0.99(q,J=7.4,6.5Hz,2H),0.96-0.90(m,1H).MS m / z(ESI):473.17[M+H] + .

[0492] Example 147: cis-4-((6-((4-chloro-3,5-dimethoxyphenyl)amino)-9-isopropyl-9H-purin-2-yl)amino)cyclohexyl)methanol

[0493] To a solution of 2-chloro-N-(4-chloro-3,5-dimethoxyphenyl)-9-isopropyl-9H-purin-6-amine (19 mg, 0.05 mmol) (Reference Example 113) in sec-butanol (1 mL) were added cis-(4-aminocyclohexyl)methanol (65 mg, 0.50 mmol) and triethylamine (101 mg, 1.0 mmol). The mixture was heated at 130° C. for 24 hours and then cooled to room temperature. The mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to give 4 mg of the product (yield 17%). 1H NMR(500MHz,DMSO-d6)δ9.42(s,1H),7.97(s,1H),7.57(s,2H),6.46(s,1H) ,4.61-4.53(m,1H),4.43(t,J=5.3Hz,1H),3.85(s,6H),3.75(s,1H),3.23( t,J=5.8Hz,2H),1.98(d,J=11.6Hz,2H),1.76(d,J=12.7Hz,2H),1.50(d,J= 6.8Hz,6H),1.30(s,1H),1.28(s,1H),1.26(d,J=4.3Hz,1H),0.94(s,1H).MS m / z(ESI):475.22[M+H] + .

[0494] Example 148: cis-4-((6-((3,5-dimethoxyphenyl)amino)-9-(3-methoxypropyl)-9H-purin-2-yl)amino)cyclohexyl)methanol

[0495] 2,6-Dichloropurine (1.89 g, 10 mmol) was dissolved in dry N,N-dimethylformamide (50 mL), 1-iodo-3-methoxypropane (2.4 g, 12 mmol) and N,N-diisopropylethylamine (1.9 g, 15 mmol) were added, and the mixture was stirred at room temperature for 12 hours. Saturated sodium bicarbonate solution was added to quench the reaction. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography was performed to obtain 1.12 g (yield 43%) of 2,6-dichloro-9-(3-methoxypropyl)-9H-purine. MS m / z (ESI): 261.03 [M+H] + .

[0496] 2,6-Dichloro-9-(3-methoxypropyl)-9H-purine (130 mg, 0.5 mmol) was dissolved in dry sec-butanol (5 mL), 3,5-dimethoxyaniline (153 mg, 1 mmol) was added, and the mixture was heated at 100°C for 12 hours. After cooling to room temperature, the reaction was quenched by adding saturated sodium bicarbonate solution. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography (eluent CH2Cl2 / MeOH=100 / 1) gave 100 mg (yield 53%) of 2-chloro-N-(3,5-dimethoxyphenyl)-9-(3-methoxypropyl)-9H-purin-6-amine. MS m / z (ESI): 378.13 [M+H] + .

[0497] To a solution of 2-chloro-N-(3,5-dimethoxyphenyl)-9-(3-methoxypropyl)-9H-purin-6-amine (38 mg, 0.10 mmol) in sec-butanol (1 mL) was added cis-(4-aminocyclohexyl)methanol (65 mg, 0.50 mmol) and triethylamine (101 mg, 1.0 mmol). The mixture was heated at 130°C for 24 hours and then cooled to room temperature. The mixture was quenched with water and extracted three times with dichloromethane. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to afford 9 mg of the product (28% yield). 1 H NMR (500MHz, DMSO-d6) δ9.25 (s, 1H), 7.81 (s, 1H), 7.32 (d, J = 2.3Hz, 2H), 6.50 (s,1H),6.14(t,J=2.3Hz,1H),4.40(t,J=5.3Hz,1H),4.05(t,J=7.1Hz,2H),3. 73(s,6H),3.31(t,J=6.1Hz,2H),3.23(s,4H),2.00(td,J=15.5,14.3,8.1Hz,4 H),1.76(d,J=12.8Hz,2H),1.40-1.18(m,5H),1.01(q,J=12.8,12.4Hz,2H).MS m / z(ESI):471.27[M+H] + .

[0498] Example 149: cis-4-((9-(cyclobutylmethyl)-6-((3,5-dimethoxyphenyl)amino)-9H-purin-2-yl)amino)cyclohexyl)methanol

[0499] 2,6-Dichloropurine (1.89 g, 10 mmol) was dissolved in dry N,N-dimethylformamide (50 mL), (iodomethyl)cyclobutane (2.35 g, 12 mmol) and potassium carbonate (2.07 g, 15 mmol) were added, and stirred at room temperature for 12 hours. The reaction was quenched by adding saturated sodium bicarbonate solution. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography was performed to obtain 1.02 g (yield 40%) of 2,6-dichloro-9-(cyclobutylmethyl)-9H-purine. MS m / z (ESI): 257.04 [M+H] + .

[0500] 2,6-Dichloro-9-(cyclobutylmethyl)-9H-purine (300 mg, 1.17 mmol) was dissolved in dry sec-butanol (10 mL), and 3,5-dimethoxyaniline (179 mg, 1.17 mmol) was added. The mixture was heated at 100°C for 12 hours. After cooling to room temperature, the reaction was quenched by adding saturated sodium bicarbonate solution. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 100 / 1) to give 218 mg (yield: 50%) of 2-chloro-9-(cyclobutylmethyl)-N-(3,5-dimethoxyphenyl)-9H-purin-6-amine. MS m / z (ESI): 374.14 [M+H] + .

[0501] To a solution of 2-chloro-9-(cyclobutylmethyl)-N-(3,5-dimethoxyphenyl)-9H-purin-6-amine (37 mg, 0.10 mmol) in sec-butanol (1 mL) was added cis-(4-aminocyclohexyl)methanol (65 mg, 0.50 mmol) and triethylamine (101 mg, 1.0 mmol). The mixture was heated at 130°C for 24 hours and then cooled to room temperature. The mixture was quenched with water and extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to afford 9 mg of the product (19% yield). 1 H NMR (500MHz, DMSO-d6) δ9.25(s,1H),7.83(s,1H),7.32(d,J=2.2Hz,2H),6.50(s,1H),6.14(t,J=2.3Hz,1H),4.40(t,J=5.3Hz,1H),4.02(d,J=7.4 Hz,2H),3.73(s,6H),3.23(t,J=5.8Hz,2H),2.78(p,J=7.5Hz,1H),2.03- 1.92(m,4H),1.89-1.72(m,6H),1.38-1.21(m,4H),1.07-0.95(m,2H).MS m / z(ESI):467.27[M+H] + .

[0502] Example 150: ((trans-4-((9-(cyclobutylmethyl)-6-((3,5-dimethoxyphenyl)amino)-9H-purin-2-yl)amino)cyclohexyl)methanol

[0503] To a solution of 2-chloro-9-(cyclobutylmethyl)-N-(3,5-dimethoxyphenyl)-9H-purin-6-amine (37 mg, 0.10 mmol) (Reference Example 149) in sec-butanol (1 mL) were added trans-(4-aminocyclohexyl)methanol (65 mg, 0.50 mmol) and triethylamine (101 mg, 1.0 mmol). The mixture was heated at 130° C. for 24 hours and then cooled to room temperature. The mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to give 11 mg of the product (24% yield). 1 H NMR (500MHz, DMSO-d6) δ9.25 (s, 1H), 7.83 (s, 1H), 7.32 (d, J = 2.3Hz, 2H), 6.5 0(s,1H),6.14(t,J=2.3Hz,1H),4.40(t,J=5.3Hz,1H),4.02(d,J=7.4Hz,2H) ,3.73(s,6H),3.23(t,J=5.8Hz,2H),2.78(hept,J=7.7Hz,1H),2.02-1.92(m ,4H),1.89-1.67(m,6H),1.37-1.17(m,4H),1.01(dt,J=13.5,10.7Hz,2H).MS m / z(ESI):467.28[M+H] + .

[0504] Example 151: ((trans)-4-((6-((3,5-dimethoxyphenyl)amino)-9-(3-methoxypropyl)-9H-purin-2-yl)amino)cyclohexyl)methanol

[0505] To a solution of 2-chloro-N-(3,5-dimethoxyphenyl)-9-(3-methoxypropyl)-9H-purin-6-amine (70 mg, 0.19 mmol) (Reference Example 148) in sec-butanol (1 mL) were added trans-(4-aminocyclohexyl)methanol (65 mg, 0.50 mmol) and triethylamine (101 mg, 1.0 mmol). The mixture was heated at 130° C. for 24 hours and then cooled to room temperature. The mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to give 32 mg of the product (yield: 37%). 1H NMR (500MHz, DMSO-d6) δ9.25(s,1H),7.81(s,1H),7.32(d,J=2.3Hz,2H),6.50(s,1H),6.14(t,J=2.2Hz,1H),4.40(t,J=5.3Hz,1H),4.05(t,J=7.1Hz ,2H),3.73(s,6H),3.31(t,J=6.1Hz,2H),3.23(s,5H),2.00(tt,J=12.6,5 .2Hz,4H),1.76(d,J=12.7Hz,2H),1.39-1.17(m,4H),1.07-0.95(m,2H).MS m / z(ESI):471.27[M+H] + .

[0506] Example 152: trans-4-((6-((3-bromo-4-chloro-5-methoxyphenyl)amino)-9-(3-methoxypropyl)-9H-purin-2-yl)amino)cyclohexan-1-ol

[0507] 2,6-Dichloro-9-(3-methoxypropyl)-9H-purine (188 mg, 0.72 mmol) (Reference Example 148) was dissolved in dry sec-butanol (5 mL), 3-bromo-4-chloro-5-methoxyaniline (170 mg, 0.72 mmol) was added, and the mixture was heated at 90°C for 12 hours. After cooling to room temperature, saturated sodium bicarbonate solution was added to quench the reaction. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography (eluent CH2Cl2 / MeOH=100 / 1) gave 180 mg (yield 57%) of N-(3-bromo-4-chloro-5-methoxyphenyl)-2-chloro-9-(3-methoxypropyl)-9H-purin-6-amine, MS m / z (ESI): 459.99 [M+H] + .

[0508] To a solution of N-(3-bromo-4-chloro-5-methoxyphenyl)-2-chloro-9-(3-methoxypropyl)-9H-purin-6-amine (46 mg, 0.10 mmol) in sec-butanol (1 mL) were added trans-4-aminocyclohexan-1-ol (58 mg, 0.5 mmol) and triethylamine (101 mg, 1.0 mmol). The mixture was heated at 130° C. for 24 hours and then cooled to room temperature. The mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to afford 15 mg of the product (28% yield). 1H NMR(500MHz,DMSO-d6)δ9.67(s,1H),8.47(s,1H),7.86(s,1H),7.68(s,1H), 6.59(s,1H),4.51(d,J=4.7Hz,1H),4.06(t,J=7.1Hz,2H),3.87(s,3H),3.73 (s,1H),3.45-3.36(m,1H),3.31(d,J=6.1Hz,2H),3.23(s,3H),2.01(p,J=6. 6Hz,2H),1.92(d,J=9.9Hz,2H),1.84(d,J=9.4Hz,2H),1.40-1.27(m,4H).MS m / z(ESI):539.11[M+H] + .

[0509] Example 153: ((trans)-4-((6-((3-bromo-4-chloro-5-methoxyphenyl)amino)-9-(3-methoxypropyl)-9H-purin-2-yl)amino)cyclohexyl)methanol

[0510] To a solution of N-(3-bromo-4-chloro-5-methoxyphenyl)-2-chloro-9-(3-methoxypropyl)-9H-purin-6-amine (46 mg, 0.10 mmol) (Reference Example 152) in sec-butanol (1 mL) were added trans-(4-aminocyclohexyl)methanol (65 mg, 0.50 mmol) and triethylamine (101 mg, 1.0 mmol). The mixture was heated at 130° C. for 24 hours and then cooled to room temperature. The mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to give 11 mg of the product (yield 20%). 1 H NMR (500MHz, DMSO-d6) δ9.67(s,1H),8.50(s,1H),7.86(s,1H),7.66(s,1H),6.62(s,1H),4.39(t,J=5.3Hz,1H),4.06(t,J=7.2Hz,2H),3.86(s,3H ),3.78-3.67(m,1H),3.32(t,J=6.3Hz,2H),3.23(s,5H),2.05-1.93(m,4 H),1.77(d,J=12.6Hz,2H),1.38-1.23(m,3H),1.07(d,J=12.9Hz,2H).MS m / z(ESI):553.13[M+H] + .

[0511] Example 154: trans-4-((6-((4-chloro-3,5-dimethoxyphenyl)amino)-9-propyl-9H-purin-2-yl)amino)cyclohexan-1-ol

[0512] 2,6-Dichloro-9-propyl-9H-purine (164 mg, 0.7 mmol) (see Example 131) was dissolved in dry sec-butanol (5 mL), 4-chloro-3,5-dimethoxyaniline (131 mg, 0.7 mmol) was added, and the mixture was heated at 90°C for 12 hours. After cooling to room temperature, saturated sodium bicarbonate solution was added to quench the reaction. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography (eluent CH2Cl2 / MeOH=100 / 1) gave 156 mg of 2-chloro-N-(4-chloro-3,5-dimethoxyphenyl)-9-propyl-9H-purin-6-amine (yield 58%), MS m / z (ESI): 382.08 [M+H] + .

[0513] To a solution of 2-chloro-N-(4-chloro-3,5-dimethoxyphenyl)-9-propyl-9H-purin-6-amine (43 mg, 0.10 mmol) in sec-butanol (1 mL) was added trans-4-aminocyclohexane-1-ol (58 mg, 0.5 mmol) and triethylamine (101 mg, 1.0 mmol). The mixture was heated at 130°C for 24 hours and then cooled to room temperature. The mixture was quenched with water and extracted three times with dichloromethane. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to afford 12 mg of the product (26% yield). 1 H NMR (500MHz, DMSO-d6) δ9.38(s,1H),7.87(s,1H),7.54(s,2H),6.40(s,1H),4.51(d,J=4.6Hz,1H),3.97(t,J=7.1Hz,2H),3.85(s,6H),3. 76(s,1H),3.39(dq,J=10.3,5.2Hz,1H),1.91(d,J=12.3Hz,2H),1.82(td,J=14.5,5.7Hz,4H),1.37-1.19(m,4H),0.86(t,J=7.3Hz,3H).MS m / z(ESI):461.20[M+H] + .

[0514] Example 155: (trans-4-((6-((3-bromo-4-chloro-5-methoxyphenyl)amino)-9-cyclopropyl-9H-purin-2-yl)amino)cyclohexyl)methanol

[0515] To a solution of N-(3-bromo-4-chloro-5-methoxyphenyl)-2-chloro-9-cyclopropyl-9H-purin-6-amine (43 mg, 0.10 mmol) (Reference Example 104) in sec-butanol (1 mL) were added trans-(4-aminocyclohexyl)methanol (65 mg, 0.50 mmol) and triethylamine (101 mg, 1.0 mmol). The mixture was heated at 130° C. for 24 hours and then cooled to room temperature. The mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent CH2Cl2 / MeOH=20 / 1) to give 14 mg of the product (yield 27%). 1 H NMR(500MHz,DMSO-d6)δ9.62(s,1H),8.48(s,1H),7.84(s,1H),7.66(s,1H),6 .68(s,1H),4.37(t,J=5.3Hz,1H),3.86(s,3H),3.74(ddt,J=15.6,11.5,5.9Hz ,1H),3.24(t,J=5.8Hz,2H),1.98(d,J=12.1Hz,2H),1.77(d,J=12.7Hz,2H),1. 29(dd,J=25.1,11.8Hz,3H),1.14-1.03(m,4H),0.99(dd,J=7.3,5.1Hz,2H).MS m / z(ESI):521.11[M+H] + .

[0516] Example 156: trans-4-((6-((4-chloro-3,5-dimethoxyphenyl)amino)-9-(cyclopropylmethyl)-9H-purin-2-yl)amino)cyclohexan-1-ol

[0517] 2,6-Dichloro-9-(cyclopropylmethyl)-9H-purine (200 mg, 0.83 mmol) (Reference Example 7) was dissolved in dry sec-butanol (5 mL), 4-chloro-3,5-dimethoxyaniline (155 mg, 0.83 mmol) was added, and the mixture was heated at 90°C for 12 hours. After cooling to room temperature, saturated sodium bicarbonate solution was added to quench the reaction. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography (eluent CH2Cl2 / MeOH=100 / 1) gave 160 mg (yield 50%) of 2-chloro-N-(4-chloro-3,5-dimethoxyphenyl)-9-(cyclopropylmethyl)-9H-purin-6-amine. MS m / z (ESI): 394.08 [M+H] + .

[0518] To a solution of 2-chloro-N-(4-chloro-3,5-dimethoxyphenyl)-9-(cyclopropylmethyl)-9H-purin-6-amine (40 mg, 0.10 mmol) in sec-butanol (1 mL) was added trans-4-aminocyclohexane-1-ol (58 mg, 0.5 mmol) and triethylamine (101 mg, 1.0 mmol). The mixture was heated at 130°C for 24 hours and then cooled to room temperature. The mixture was quenched with water and extracted three times with dichloromethane. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to afford 10 mg of the product (21% yield). 1 H NMR(500MHz,DMSO-d6)δ9.38(s,1H),7.91(s,1H),7.55(s,2H),6.38(d,J= 8.3Hz,1H),4.51(d,J=4.6Hz,1H),3.88(s,1H),3.86(s,6H),3.77(d,J=10 .1Hz,1H),3.39(td,J=10.3,4.7Hz,1H),1.95-1.89(m,2H),1.87-1.80(m, 2H),1.36-1.16(m,6H),0.52(dt,J=7.9,2.9Hz,2H),0.46-0.42(m,2H).MS m / z(ESI):473.21[M+H] + .

[0519] Example 157: (trans-4-((6-((4-chloro-3,5-dimethoxyphenyl)amino)-9-(cyclopropylmethyl)-9H-purin-2-yl)amino)cyclohexyl)methanol

[0520] To a solution of 2-chloro-N-(4-chloro-3,5-dimethoxyphenyl)-9-(cyclopropylmethyl)-9H-purin-6-amine (46 mg, 0.10 mmol) (Reference Example 156) in sec-butanol (1 mL) were added trans-(4-aminocyclohexyl)methanol (65 mg, 0.50 mmol) and triethylamine (101 mg, 1.0 mmol). The mixture was heated at 130° C. for 24 hours and then cooled to room temperature. The mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to give 16 mg of the product (8% yield). 1H NMR(500MHz,DMSO-d6)δ9.37(s,1H),7.91(s,1H),7.57(s,2H),6.40(s,1H ),4.38(t,J=5.3Hz,1H),3.87(s,1H),3.86(d,J=3.1Hz,6H),3.80-3.72(m, 1H),3.24(t,J=5.8Hz,2H),2.01-1.94(m,2H),1.80-1.72(m,2H),1.36-1. 20(m,5H),0.96(t,J=13.0Hz,2H),0.55-0.50(m,2H),0.46-0.41(m,2H).MS m / z(ESI):487.22[M+H] + .

[0521] Example 158: trans-4-((6-((3-bromo-4-chloro-5-methoxyphenyl)amino)-9-(cyclopropylmethyl)-9H-purin-2-yl)amino)cyclohexan-1-ol

[0522] 2,6-Dichloro-9-(cyclopropylmethyl)-9H-purine (200 mg, 0.83 mmol) (Reference Example 7) was dissolved in dry sec-butanol (5 mL), 3-bromo-4-chloro-5-methoxyaniline (196 mg, 0.83 mmol) was added, and the mixture was heated at 90°C for 12 hours. After cooling to room temperature, saturated sodium bicarbonate solution was added to quench the reaction. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography (eluent CH2Cl2 / MeOH=100 / 1) gave 151 mg (yield 42%) of N-(3-bromo-4-chloro-5-methoxyphenyl)-2-chloro-9-(cyclopropylmethyl)-9H-purin-6-amine, MS m / z (ESI): 441.98 [M+H] + .

[0523] To a solution of N-(3-bromo-4-chloro-5-methoxyphenyl)-2-chloro-9-(cyclopropylmethyl)-9H-purin-6-amine (44 mg, 0.10 mmol) in sec-butanol (1 mL) were added trans-4-aminocyclohexane-1-ol (58 mg, 0.5 mmol) and triethylamine (101 mg, 1.0 mmol). The mixture was heated at 130° C. for 24 hours and then cooled to room temperature. The mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to afford 11 mg of the product (21% yield). 1H NMR(500MHz,DMSO-d6)δ9.64(s,1H),8.42(s,1H),7.93(s,1H),7.70(s,1H ),6.52(d,J=8.2Hz,1H),4.48(d,J=4.7Hz,1H),3.87(s,3H),3.86(s,1H),3 .73(s,1H),3.43-3.35(m,1H),1.93(d,J=9.8Hz,2H),1.84(d,J=9.3Hz,2H ),1.39-1.22(m,6H),0.52(dt,J=8.0,2.9Hz,2H),0.42(d,J=5.0Hz,2H).MS m / z(ESI):521.11[M+H] + .

[0524] Example 159: cis-4-((6-((4-chloro-3,5-dimethoxyphenyl)amino)-9-propyl-9H-purin-2-yl)amino)cyclohexyl)methanol

[0525] To a solution of 2-chloro-N-(4-chloro-3,5-dimethoxyphenyl)-9-propyl-9H-purin-6-amine (38 mg, 0.10 mmol) (Reference Example 154) in sec-butanol (1 mL) were added cis-(4-aminocyclohexyl)methanol (65 mg, 0.5 mmol) and triethylamine (101 mg, 1.0 mmol). The mixture was heated at 130° C. for 24 hours and then cooled to room temperature. The mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent CH2Cl2 / MeOH=20 / 1) to give 9 mg of the product (yield 20%). 1 H NMR (500MHz, DMSO-d6) δ9.36(s,1H),7.86(s,1H),7.56(s,2H),6.42(s,1H),4.38(t,J=5.4Hz,1H),3.97(t,J=7.1Hz,2H),3.85(s,6H),3.76(d,J= 10.2Hz,1H),3.23(t,J=5.8Hz,2H),1.97(d,J=12.4Hz,2H),1.85-1.70(m ,4H),1.33-1.20(m,3H),0.94(q,J=13.5Hz,2H),0.86(t,J=7.3Hz,3H).MS m / z(ESI):475.22[M+H] + .

[0526] Example 160: trans-4-((9-cyclopropyl-6-((3,4-difluoro-5-methoxyphenyl)amino)-9H-purin-2-yl)amino)cyclohexan-1-ol

[0527] 2,6-Dichloro-9-cyclopropyl-9H-purine (115 mg, 0.5 mmol) was dissolved in dry sec-butanol (5 mL), 3,4-difluoro-5-methoxyaniline (103 mg, 0.65 mmol) was added, and the mixture was heated at 110°C for 12 hours. After cooling to room temperature, saturated sodium bicarbonate solution was added to quench the reaction. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography (eluent CH2Cl2 / MeOH=100 / 1) gave 58 mg (yield 33%) of 2-chloro-9-cyclopropyl-N-(3,4-difluoro-5-methoxyphenyl)-9H-purin-6-amine. MS m / z (ESI): 352.08 [M+H] + .

[0528] To a solution of 2-chloro-9-cyclopropyl-N-(3,4-difluoro-5-methoxyphenyl)-9H-purin-6-amine (34 mg, 0.10 mmol) in sec-butanol (1 mL) was added trans-4-aminocyclohexane-1-ol (58 mg, 0.5 mmol) and triethylamine (101 mg, 1.0 mmol). The mixture was heated at 130°C for 24 hours and then cooled to room temperature. The mixture was quenched with water and extracted three times with dichloromethane. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to afford 10 mg of the product (24% yield). 1 H NMR(500MHz,DMSO)δ9.55(s,1H),8.10-8.06(m,1H),7.82(s,1H),7.48(s,1H),6.70(s,1H),4.45(d,J= 5.0Hz,1H),3.86(s,3H),3.71-3.61(m,1H),3.43-3.38(m,1H),1.97-1.85(m,4H),1.34-0.97(m,8H).MS m / z(ESI):431.20[M+H] + .

[0529] Example 161: trans-4-((6-((3,5-Dibromo-4-fluorophenyl)amino)-9-isopropyl-9H-purin-2-yl)amino)cyclohexan-1-ol

[0530] 2,6-Dichloro-9-isopropyl-9H-purine (115 mg, 0.5 mmol) was dissolved in dry sec-butanol (5 mL), 3,5-dibromo-4-fluoroaniline (175 mg, 0.65 mmol) was added, and the mixture was heated at 110°C for 12 hours. After cooling to room temperature, the reaction was quenched by adding saturated sodium bicarbonate solution. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography (eluent CH2Cl2 / MeOH=100 / 1) gave 123 mg (yield 53%) of 2-chloro-N-(3,5-dibromo-4-fluorophenyl)-9-isopropyl-9H-purin-6-amine. MS m / z (ESI): 459.90 [M+H] + .

[0531] To a solution of 2-chloro-N-(3,5-dibromo-4-fluorophenyl)-9-isopropyl-9H-purin-6-amine (23 mg, 0.05 mmol) in sec-butanol (1 mL) was added trans-4-aminocyclohexane-1-ol (58 mg, 0.5 mmol) and triethylamine (101 mg, 1.0 mmol). The mixture was heated at 130°C for 24 hours and then cooled to room temperature. The mixture was quenched with water and extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to afford 11 mg of the product (40% yield). 1 H NMR(500MHz,DMSO)δ9.78(s,1H),8.44(d,J=5.0Hz,2H)),8.00(s,1H),6.59(d,J=5.0Hz,1H)),4.60-4.48(m ,2H),3.73-3.64(m,1H),3.41-3.37(m,1H),1.94-1.84(m,4H),1.49(d,J=5.0Hz,6H),1.39-1.28(m,4H).MS m / z(ESI):541.04[M+H] + .

[0532] Example 162: trans-4-((9-cyclopropyl-6-((3,5-dibromo-4-fluorophenyl)amino)-9H-purin-2-yl)amino)cyclohexan-1-ol

[0533] 2,6-Dichloro-9-cyclopropyl-9H-purine (115 mg, 0.5 mmol) was dissolved in dry sec-butanol (5 mL), 3,5-dibromo-4-fluoroaniline (177 mg, 0.65 mmol) was added, and the mixture was heated at 110°C for 12 hours. After cooling to room temperature, the reaction was quenched by adding saturated sodium bicarbonate solution. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography (eluent CH2Cl2 / MeOH=100 / 1) gave 115 mg (yield 50%) of 2-chloro-N-(3,5-dibromo-4-fluorophenyl)-9-cyclopropyl-9H-purin-6-amine. MS m / z (ESI): 459.90 [M+H] + .

[0534] To a solution of 2-chloro-N-(3,5-dibromo-4-fluorophenyl)-9-cyclopropyl-9H-purin-6-amine (23 mg, 0.05 mmol) in sec-butanol (1 mL) was added trans-4-aminocyclohexane-1-ol (58 mg, 0.5 mmol) and triethylamine (101 mg, 1.0 mmol). The mixture was heated at 130°C for 24 hours and then cooled to room temperature. The mixture was quenched with water and extracted three times with dichloromethane. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to afford 10 mg of the product (36% yield). 1 H NMR (500MHz, DMSO) δ9.78(s,1H),8.44(d,J=5.0Hz,2H)),7.85(s,1H),6.73(d,J=5.0Hz,1H)),4.49(d,J=5. 0Hz,1H),3.74-3.67(m,1H),3.41-3.36(m,1H),1.93-1.84(m,4H),1.40-1.28(m,4H),1.05-0.96(m,4H).MS m / z(ESI):539.02[M+H] + .

[0535] Example 163: trans-4-((6-((3,5-dimethoxyphenyl)amino)-9-isobutyl-9H-purin-2-yl)amino)cyclohexan-1-ol

[0536] 2,6-Dichloropurine (1.89 g, 10 mmol) was dissolved in dry N,N-dimethylformamide (50 mL), 1-iodo-2-methylpropane (2.2 g, 12 mmol) and potassium carbonate (2.07 g, 15 mmol) were added, and the mixture was stirred at room temperature for 12 hours. The reaction was quenched by adding saturated sodium bicarbonate solution. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography was performed to obtain 1.1 g (yield 45%) of 2,6-dichloro-9-isobutyl-9H-purine. MS m / z (ESI): 245.04 [M+H] + .

[0537] 2,6-Dichloro-9-isobutyl-9H-purine (168 mg, 0.7 mmol) was dissolved in dry sec-butanol (10 mL), 3,5-dimethoxyaniline (107 mg, 0.7 mmol) was added, and the mixture was heated at 90°C for 12 hours. After cooling to room temperature, the reaction was quenched by adding saturated sodium bicarbonate solution. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography (eluent CH2Cl2 / MeOH=100 / 1) gave 125 mg (yield 51%) of 2-chloro-N-(3,5-dimethoxyphenyl)-9-isobutyl-9H-purin-6-amine. MS m / z (ESI): 362.14 [M+H] + .

[0538] To a solution of 2-chloro-N-(3,5-dimethoxyphenyl)-9-isobutyl-9H-purin-6-amine (36 mg, 0.1 mmol) in sec-butanol (1 mL) was added trans-4-aminocyclohexane-1-ol (58 mg, 0.5 mmol) and triethylamine (101 mg, 1.0 mmol). The mixture was heated at 130°C for 24 hours and then cooled to room temperature. The mixture was quenched with water and extracted three times with dichloromethane. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to afford 15 mg of the product (34% yield). 1H NMR (500MHz, DMSO-d6) δ9.24 (s, 1H), 7.82 (s, 1H), 7.30 (d, J = 2.3Hz, 2H), 6.4 4(s,1H),6.15(t,J=2.3Hz,1H),4.51(d,J=4.3Hz,1H),3.81(d,J=7.2Hz,2H), 3.74(s,6H),3.71(s,1H),3.43-3.36(m,1H),2.18(hept,J=6.8Hz,1H),1.95 -1.90(m,2H),1.87-1.81(m,2H),1.32-1.24(m,4H),0.86(d,J=6.7Hz,6H).MS m / z(ESI):441.26[M+H] + .

[0539] Example 164: ((trans)-4-((6-((3,5-dimethoxyphenyl)amino)-9-isobutyl-9H-purin-2-yl)amino)cyclohexyl)methanol

[0540] To a solution of 2-chloro-N-(3,5-dimethoxyphenyl)-9-isobutyl-9H-purin-6-amine (36 mg, 0.1 mmol) (Reference Example 163) in sec-butanol (1 mL) were added trans-(4-aminocyclohexyl)methanol (58 mg, 0.5 mmol) and triethylamine (101 mg, 1.0 mmol). The mixture was heated at 130°C for 24 hours and then cooled to room temperature. The mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to give 15 mg of the product (34% yield). 1 H NMR(500MHz,DMSO-d6)δ9.24(s,1H),7.81(s,1H),7.32(d,J=2.3Hz,2H),6.47(s ,1H),6.14(t,J=2.3Hz,1H),4.39(t,J=5.3Hz,1H),3.81(d,J=7.3Hz,2H),3.73(s ,6H),3.23(t,J=5.8Hz,2H),2.18(hept,J=6.8Hz,1H),2.01-1.94(m,2H),1.76( d,J=12.9Hz,2H),1.37-1.21(m,4H),1.06-0.94(m,2H),0.86(d,J=6.6Hz,6H).MS m / z(ESI):455.28[M+H] + .

[0541] Example 165: trans-4-((6-((3-bromo-4-chloro-5-methoxyphenyl)amino)-9-isobutyl-9H-purin-2-yl)amino)cyclohexan-1-ol

[0542] 2,6-Dichloro-9-isobutyl-9H-purine (168 mg, 0.7 mmol) (Reference Example 163) was dissolved in dry sec-butanol (10 mL), 3-bromo-4-chloro-5-methoxyaniline (165 mg, 0.7 mmol) was added, and the mixture was heated at 90°C for 12 hours. After cooling to room temperature, saturated sodium bicarbonate solution was added to quench the reaction. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography (eluent CH2Cl2 / MeOH=100 / 1) gave 170 mg (yield 56%) of N-(3-bromo-4-chloro-5-methoxyphenyl)-2-chloro-9-isobutyl-9H-purin-6-amine. MS m / z (ESI): 444.00 [M+H] + .

[0543] To a solution of N-(3-bromo-4-chloro-5-methoxyphenyl)-2-chloro-9-isobutyl-9H-purin-6-amine (45 mg, 0.1 mmol) in sec-butanol (1 mL) were added trans-4-aminocyclohexane-1-ol (58 mg, 0.5 mmol) and triethylamine (101 mg, 1.0 mmol). The mixture was heated at 130° C. for 24 hours and then cooled to room temperature. The mixture was quenched with water and extracted three times with dichloromethane. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to afford 12 mg of the product (23% yield). 1 H NMR (500MHz, DMSO-d6) δ9.67(s,1H),8.45(s,1H),7.87(s,1H),7.68(s,1H),6.58(s,1H),4.50(s,1H),3.87(s,3H),3.82(d,J=7.3Hz,2H),3. 72(s,1H),3.38(s,1H),2.18(hept,J=6.8Hz,1H),1.92(d,J=10.5Hz,2H),1.84(d,J=9.7Hz,2H),1.37-1.28(m,4H),0.86(d,J=6.6Hz,6H).MS m / z(ESI):523.12[M+H] + .

[0544] Example 166: ((trans)-4-((6-((3-bromo-4-chloro-5-methoxyphenyl)amino)-9-isobutyl-9H-purin-2-yl)amino)cyclohexyl)methanol

[0545] To a solution of N-(3-bromo-4-chloro-5-methoxyphenyl)-2-chloro-9-isobutyl-9H-purin-6-amine (45 mg, 0.1 mmol) (Reference Example 165) in sec-butanol (1 mL) were added trans-(4-aminocyclohexyl)methanol (58 mg, 0.5 mmol) and triethylamine (101 mg, 1.0 mmol). The mixture was heated at 130° C. for 24 hours and then cooled to room temperature. The mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to give 13 mg of the product (yield 24%). 1 H NMR(500MHz,DMSO-d6)δ9.66(s,1H),8.49(s,1H),7.87(s,1H),7.67(s,1H),6.61(s ,1H),4.39(t,J=5.3Hz,1H),3.86(s,3H),3.82(d,J=7.3Hz,2H),3.72(d,J=9.7Hz,1 H),3.23(t,J=5.8Hz,2H),2.18(hept,J=6.9Hz,1H),1.97(d,J=12.0Hz,2H),1.77(d ,J=12.6Hz,2H),1.36-1.23(m,3H),1.08(t,J=12.8Hz,2H),0.86(d,J=6.7Hz,6H).MS m / z(ESI):537.14[M+H] + .

[0546] Example 167: cis-4-((6-((3-bromo-4-chloro-5-methoxyphenyl)amino)-9-isobutyl-9H-purin-2-yl)amino)cyclohexyl)methanol

[0547] To a solution of N-(3-bromo-4-chloro-5-methoxyphenyl)-2-chloro-9-isobutyl-9H-purin-6-amine (45 mg, 0.1 mmol) (Reference Example 165) in sec-butanol (1 mL) were added cis-(4-aminocyclohexyl)methanol (58 mg, 0.5 mmol) and triethylamine (101 mg, 1.0 mmol). The mixture was heated at 130° C. for 24 hours and then cooled to room temperature. The mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to give 13 mg of the product (yield 24%). 1H NMR(500MHz,DMSO-d6)δ9.66(s,1H),8.49(s,1H),7.87(s,1H),7.67(s,1H),6.61(s ,1H),4.39(t,J=5.3Hz,1H),3.86(s,3H),3.82(d,J=7.3Hz,2H),3.72(d,J=8.1Hz,1 H),3.23(t,J=5.8Hz,2H),2.18(hept,J=6.8Hz,1H),1.97(d,J=12.1Hz,2H),1.77(d ,J=12.7Hz,2H),1.34-1.22(m,3H),1.07(d,J=12.9Hz,2H),0.86(d,J=6.6Hz,6H).MS m / z(ESI):537.14[M+H] + .

[0548] Example 168: trans-4-((6-((3-bromo-4-chloro-5-methoxyphenyl)amino)-9-(3,3,3-trifluoropropyl)-9H-purin-2-yl)amino)cyclohexan-1-ol

[0549] 2,6-Dichloropurine (1.89 g, 10 mmol) was dissolved in dry N,N-dimethylformamide (50 mL), 1,1,1-trifluoro-3-iodopropane (2.7 g, 12 mmol) and potassium carbonate (2.07 g, 15 mmol) were added, and the mixture was stirred at room temperature for 12 hours. The reaction was quenched by adding saturated sodium bicarbonate solution. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography was performed to obtain 1.14 g (yield 40%) of 2,6-dichloro-9-(3,3,3-trifluoropropyl)-9H-purine. MS m / z (ESI): 284.99 [M+H] + .

[0550] 2,6-Dichloro-9-(3,3,3-trifluoropropyl)-9H-purine (200 mg, 0.7 mmol) was dissolved in dry sec-butanol (10 mL), and 3-bromo-4-chloro-5-methoxyaniline (165 mg, 0.7 mmol) was added. The mixture was heated at 90°C for 12 hours. After cooling to room temperature, the reaction was quenched by adding saturated sodium bicarbonate solution. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography (eluent: CH2Cl2 / MeOH = 100 / 1) afforded 101 mg (yield: 36%) of N-(3-bromo-4-chloro-5-methoxyphenyl)-2-chloro-9-(3,3,3-trifluoropropyl)-9H-purin-6-amine. MS m / z (ESI): 483.96 [M+H] + .

[0551] To a solution of N-(3-bromo-4-chloro-5-methoxyphenyl)-2-chloro-9-(3,3,3-trifluoropropyl)-9H-purin-6-amine (80 mg, 0.16 mmol) in sec-butanol (1 mL) was added trans-4-aminocyclohexane-1-ol (115 mg, 1.0 mmol) and triethylamine (202 mg, 2.0 mmol). The mixture was heated at 130°C for 24 hours and then cooled to room temperature. The mixture was quenched with water and extracted three times with dichloromethane. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to afford 45 mg of the product (40% yield). 1 H NMR (500MHz, DMSO-d6) δ9.70(s,1H),8.47(s,1H),7.94(s,1H),7.66(s,1H),6.65(d,J=8.0Hz,1H),4.51(d,J=4.7Hz,1H),4.29(t,J=7.1Hz, 2H),3.87(s,3H),3.73(s,1H),3.39(d,J=4.6Hz,1H),2.94(td,J=11.5,5.7Hz,2H),1.93(s,2H),1.84(d,J=9.6Hz,2H),1.39-1.29(m,4H).MS m / z(ESI):563.08[M+H] + .

[0552] Example 169: (trans-4-((6-((3-bromo-4-chloro-5-methoxyphenyl)amino)-9-(3,3,3-trifluoropropyl)-9H-purin-2-yl)amino)cyclohexyl)methanol

[0553] To a solution of N-(3-bromo-4-chloro-5-methoxyphenyl)-2-chloro-9-(3,3,3-trifluoropropyl)-9H-purin-6-amine (48 mg, 0.10 mmol) (Reference Example 168) in sec-butanol (1 mL) were added trans-(4-aminocyclohexyl)methanol (129 mg, 1.0 mmol) and triethylamine (202 mg, 2.0 mmol). The mixture was heated at 130° C. for 24 hours and then cooled to room temperature. The mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to give 17 mg of the product (30% yield). 1H NMR(500MHz,DMSO-d6)δ9.70(s,1H),8.51(s,1H),7.94(s,1H),7.64(s,1H) ,6.68(s,1H),4.39(t,J=5.4Hz,1H),4.29(t,J=7.0Hz,2H),3.86(s,3H),3.7 3(s,1H),3.23(t,J=5.8Hz,2H),2.94(dtd,J=17.9,11.1,8.8Hz,2H),1.98( d,J=12.0Hz,2H),1.77(d,J=12.7Hz,2H),1.35-1.24(m,3H),1.08(s,2H).MS m / z(ESI):577.10[M+H] + Example 170: trans-4-((6-((4-chloro-3,5-dimethoxyphenyl)amino)-9-(3,3,3-trifluoropropyl)-9H-purin-2-yl)amino)cyclohexan-1-ol

[0554] 2,6-Dichloro-9-(3,3,3-trifluoropropyl)-9H-purine (200 mg, 0.7 mmol) (Reference Example 168) was dissolved in dry sec-butanol (10 mL), 4-chloro-3,5-dimethoxyaniline (131 mg, 0.7 mmol) was added, and the mixture was heated at 90°C for 12 hours. After cooling to room temperature, saturated sodium bicarbonate solution was added to quench the reaction. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography (eluent CH2Cl2 / MeOH=100 / 1) gave 121 mg (yield 40%) of 2-chloro-N-(4-chloro-3,5-dimethoxyphenyl)-9-(3,3,3-trifluoropropyl)-9H-purin-6-amine, MS m / z (ESI): 436.06 [M+H] + .

[0555] To a solution of 2-chloro-N-(4-chloro-3,5-dimethoxyphenyl)-9-(3,3,3-trifluoropropyl)-9H-purin-6-amine (44 mg, 0.10 mmol) in sec-butanol (1 mL) was added trans-4-aminocyclohexane-1-ol (58 mg, 0.5 mmol) and triethylamine (101 mg, 1.0 mmol). The mixture was heated at 130°C for 24 hours and then cooled to room temperature. The mixture was quenched with water and extracted three times with dichloromethane. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to afford 14 mg of the product (27% yield). 1H NMR (500MHz, DMSO-d6) δ9.44(s,1H),7.92(s,1H),7.53(s,2H),6.49(s,1H),4.53(d,J=4.6Hz,1H),4.30(t,J=7.0Hz,2H),3.85(s,6H),3.75(s,1H ),3.39(h,J=5.2Hz,1H),2.94(ddt,J=18.2,11.5,6.8Hz,2H),1.92(d,J= 12.3Hz,2H),1.87-1.81(m,2H),1.36-1.26(m,2H),1.25-1.15(m,2H).MS m / z(ESI):515.18[M+H] + .

[0556] Example 171: ((trans)-4-((6-((4-chloro-3,5-dimethoxyphenyl)amino)-9-(3,3,3-trifluoropropyl)-9H-purin-2-yl)amino)cyclohexyl)methanol

[0557] To a solution of 2-chloro-N-(4-chloro-3,5-dimethoxyphenyl)-9-(3,3,3-trifluoropropyl)-9H-purin-6-amine (44 mg, 0.10 mmol) (Reference Example 170) in sec-butanol (1 mL) were added trans-(4-aminocyclohexyl)methanol (58 mg, 0.5 mmol) and triethylamine (101 mg, 1.0 mmol). The mixture was heated at 130° C. for 24 hours and then cooled to room temperature. The mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to give 13 mg of the product (yield 25%). 1 H NMR(500MHz,DMSO-d6)δ9.43(s,1H),7.92(s,1H),7.55(s,2H),6.51(s,1H) ,4.40(t,J=5.3Hz,1H),4.30(t,J=6.9Hz,2H),3.85(s,6H),3.75(s,1H),3. 23(t,J=5.7Hz,2H),2.95(dtd,J=18.2,11.3,7.0Hz,2H),1.98(d,J=12.0Hz ,2H),1.76(d,J=12.9Hz,2H),1.35-1.21(m,3H),0.93(d,J=13.1Hz,2H).MS m / z(ESI):529.20[M+H] +Example 172: cis-4-((6-((3-bromo-4-chloro-5-methoxyphenyl)amino)-9-(3,3,3-trifluoropropyl)-9H-purin-2-yl)amino)cyclohexyl)methanol

[0558] To a solution of N-(3-bromo-4-chloro-5-methoxyphenyl)-2-chloro-9-(3,3,3-trifluoropropyl)-9H-purin-6-amine (40 mg, 0.08 mmol) (Reference Example 168) in sec-butanol (1 mL) were added cis-(4-aminocyclohexyl)methanol (65 mg, 0.5 mmol) and triethylamine (101 mg, 1.0 mmol). The mixture was heated at 130° C. for 24 hours and then cooled to room temperature. The reaction mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to give 13 mg of the product (yield 22%). 1 H NMR(500MHz,DMSO-d6)δ9.68(s,1H),8.45(d,J=28.5Hz,1H),7.93(s,1H),7.6 6(s,1H),6.65(s,1H),4.38(t,J=5.4Hz,1H),4.29(t,J=7.1Hz,2H),3.87(s,3H ),3.73(d,J=11.3Hz,1H),3.24(t,J=5.8Hz,2H),2.99-2.88(m,2H),1.98(d,J =12.0Hz,2H),1.81-1.74(m,2H),1.36-1.25(m,3H),1.07(d,J=13.0Hz,2H).MS m / z(ESI):577.10[M+H] + .

[0559] Example 173: trans-4-((6-((3-bromo-5-methoxyphenyl)amino)-9-(2-fluoroethyl)-9H-purin-2-yl)amino)cyclohexan-1-ol

[0560] 2,6-Dichloropurine (1.89 g, 10 mmol) was dissolved in dry N,N-dimethylformamide (50 mL), 1-fluoro-2-iodoethane (2.09 g, 12 mmol) and potassium carbonate (2.07 g, 15 mmol) were added, and the mixture was stirred at room temperature for 12 hours. The reaction was quenched by adding saturated sodium bicarbonate solution. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography was performed to obtain 1.0 g (yield 43%) of 2,6-dichloro-9-(2-fluoroethyl)-9H-purine. MS m / z (ESI): 235.00 [M+H] + .

[0561] 2,6-Dichloro-9-(2-fluoroethyl)-9H-purine (200 mg, 0.85 mmol) was dissolved in dry sec-butanol (10 mL), 3-bromo-5-methoxyaniline (172 mg, 0.85 mmol) was added, and the mixture was heated at 90°C for 12 hours. After cooling to room temperature, the reaction was quenched by adding saturated sodium bicarbonate solution. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography (eluent CH2Cl2 / MeOH=100 / 1) gave 210 mg (yield 62%) of N-(3-bromo-5-methoxyphenyl)-2-chloro-9-(2-fluoroethyl)-9H-purin-6-amine. MS m / z (ESI): 400.00 [M+H] + .

[0562] To a solution of N-(3-bromo-5-methoxyphenyl)-2-chloro-9-(2-fluoroethyl)-9H-purin-6-amine (34 mg, 0.10 mmol) in sec-butanol (1 mL) were added trans-4-aminocyclohexane-1-ol (58 mg, 0.5 mmol) and triethylamine (101 mg, 1.0 mmol). The mixture was heated at 130° C. for 24 hours and then cooled to room temperature. The mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to afford 15 mg of the product (38% yield). 1 H NMR(500MHz,DMSO-d6)δ9.59(s,1H),8.11(s,1H),7.88(s,1H),7.57(s,1H),6.76(t,J=1.9H z,1H),6.56(d,J=8.1Hz,1H),4.83(t,J=5.0Hz,1H),4.74(t,J=4.9Hz,1H),4.50(d,J=4.4Hz ,1H),4.36(t,J=4.8Hz,1H),4.30(t,J=5.0Hz,1H),3.76(s,3H),3.74-3.67(m,1H),3.44-3. 35(m,1H),1.93(d,J=11.3Hz,2H),1.84(d,J=10.9Hz,2H),1.30(dd,J=24.3,11.9Hz,4H).MS m / z(ESI):479.13[M+H] + .

[0563] Example 174: trans-4-((6-((3-bromo-5-methoxyphenyl)amino)-9-(3-fluoropropyl)-9H-purin-2-yl)amino)cyclohexan-1-ol

[0564] 2,6-Dichloropurine (1.89 g, 10 mmol) was dissolved in dry N,N-dimethylformamide (50 mL), 1-fluoro-3-iodopropane (2.26 g, 12 mmol) and potassium carbonate (2.07 g, 15 mmol) were added, and the mixture was stirred at room temperature for 12 hours. The reaction was quenched by adding saturated sodium bicarbonate solution. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography was performed to obtain 1.14 g (yield 46%) of 2,6-dichloro-9-(3-fluoropropyl)-9H-purine. MS m / z (ESI): 249.01 [M+H] + .

[0565] 2,6-Dichloro-9-(3-fluoropropyl)-9H-purine (200 mg, 0.8 mmol) was dissolved in dry sec-butanol (10 mL), 3-bromo-5-methoxyaniline (161 mg, 0.8 mmol) was added, and the mixture was heated at 90°C for 12 hours. After cooling to room temperature, the reaction was quenched by adding saturated sodium bicarbonate solution. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography (eluent CH2Cl2 / MeOH=100 / 1) gave 211 mg (yield 62%) of N-(3-bromo-5-methoxyphenyl)-2-chloro-9-(3-fluoropropyl)-9H-purin-6-amine. MS m / z (ESI): 414.01 [M+H] + .

[0566] To a solution of N-(3-bromo-5-methoxyphenyl)-2-chloro-9-(3-fluoropropyl)-9H-purin-6-amine (41 mg, 0.10 mmol) in sec-butanol (1 mL) were added trans-4-aminocyclohexane-1-ol (58 mg, 0.5 mmol) and triethylamine (101 mg, 1.0 mmol). The mixture was heated at 130° C. for 24 hours and then cooled to room temperature. The mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to afford 17 mg of the product (35% yield). 1H NMR(500MHz,DMSO-d6)δ9.55(s,1H),8.10(s,1H),7.88(s,1H),7.57(s,1H),6.75(t,J=1.9H z,1H),6.54(d,J=8.0Hz,1H),4.53(t,J=5.6Hz,1H),4.49(d,J=4.4Hz,1H),4.44(t,J=5.7Hz ,1H),4.12(t,J=7.1Hz,2H),3.76(s,3H),3.72(d,J=10.4Hz,1H),3.43-3.35(m,1H),2.19(d p,J=26.3,6.3Hz,2H),1.93(d,J=11.3Hz,2H),1.83(d,J=10.7Hz,2H),1.41-1.25(m,4H).MS m / z(ESI):493.13[M+H] + .

[0567] Example 175: trans-4-((6-((3-bromo-5-(difluoromethoxy)phenyl)amino)-9-(2-fluoroethyl)-9H-purin-2-yl)amino)cyclohexan-1-ol

[0568] 2,6-Dichloro-9-(2-fluoroethyl)-9H-purine (200 mg, 0.85 mmol) (see Example 173) was dissolved in dry sec-butanol (10 mL), 3-bromo-5-(difluoromethoxy)aniline (202 mg, 0.85 mmol) was added, and the mixture was heated at 95°C for 12 hours. The mixture was cooled to room temperature and quenched by adding saturated sodium bicarbonate solution. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography (eluent: CH2Cl2 / MeOH = 100 / 1) afforded 201 mg (yield: 53%) of N-(3-bromo-5-(difluoromethoxy)phenyl)-2-chloro-9-(2-fluoroethyl)-9H-purin-6-amine. MS m / z (ESI): 435.98 [M+H] + .

[0569] To a solution of N-(3-bromo-5-(difluoromethoxy)phenyl)-2-chloro-9-(2-fluoroethyl)-9H-purin-6-amine (44 mg, 0.10 mmol) in sec-butanol (1 mL) were added trans-4-aminocyclohexane-1-ol (58 mg, 0.5 mmol) and triethylamine (101 mg, 1.0 mmol). The mixture was heated at 130° C. for 24 hours and then cooled to room temperature. The reaction mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to afford 19 mg of the product (10% yield). 1H NMR(500MHz,DMSO-d6)δ9.89-9.79(m,1H),8.35(s,1H),7.90(s,1H),7.86(s,1H),7.26(t,J=7 3.7Hz,1H),7.01(d,J=1.9Hz,1H),6.62(d,J=8.1Hz,1H),4.84(t,J=5.0Hz,1H),4.74(t,J=4.8 Hz,1H),4.49(d,J=4.3Hz,1H),4.37(t,J=4.9Hz,1H),4.31(t,J=5.0Hz,1H),3.71(d,J=11.3Hz ,1H),3.43-3.35(m,1H),1.93(d,J=11.1Hz,2H),1.84(d,J=10.4Hz,2H),1.38-1.27(m,4H).MS m / z(ESI):515.10[M+H] + .

[0570] Example 176: trans-4-((6-((4-bromo-3,5-dimethoxyphenyl)amino)-9-isopropyl-9H-purin-2-yl)amino)cyclohexan-1-ol

[0571] 2,6-Dichloro-9-isopropyl-9H-purine (115 mg, 0.5 mmol) was dissolved in dry sec-butanol (5 mL), 4-bromo-3,5-dimethoxyaniline (151 mg, 0.65 mmol) was added, and the mixture was heated at 110°C for 12 hours. After cooling to room temperature, the reaction was quenched by adding saturated sodium bicarbonate solution. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography (eluent: CH2Cl2 / MeOH = 100 / 1) gave 64 mg (yield: 30%) of N-(4-bromo-3,5-dimethoxyphenyl)-2-chloro-9-isopropyl-9H-purin-6-amine. MS m / z (ESI): 426.03 [M+H] + .

[0572] To a solution of N-(4-bromo-3,5-dimethoxyphenyl)-2-chloro-9-isopropyl-9H-purin-6-amine (43 mg, 0.10 mmol) in sec-butanol (1 mL) was added trans-4-aminocyclohexane-1-ol (58 mg, 0.5 mmol) and triethylamine (101 mg, 1.0 mmol). The mixture was heated at 130°C for 24 hours and then cooled to room temperature. The mixture was quenched with water and extracted three times with dichloromethane. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to afford 10 mg of the product (20% yield). 1H NMR(500MHz,DMSO)δ9.38(s,1H),7.96(s,1H),7.53(s,2H),6.57(s,1H),6.36(d,J=5.0Hz,1H),4.61-4.50(m,2H), 3.85(s,6H),3.80-3.70(m,1H),3.42-3.37(m,1H),1.94-1.83(m,4H),1.50(d,J=10.0Hz,6H),1.33-1.19(m,4H).MS m / z(ESI):505.16[M+H] + .

[0573] Example 177: trans-4-((6-((4-bromo-3,5-dimethoxyphenyl)amino)-9-cyclopropyl-9H-purin-2-yl)amino)cyclohexan-1-ol

[0574] 2,6-Dichloro-9-cyclopropyl-9H-purine (115 mg, 0.5 mmol) was dissolved in dry sec-butanol (5 mL), 4-bromo-3,5-dimethoxyaniline (151 mg, 0.65 mmol) was added, and the mixture was heated at 110°C for 12 hours. After cooling to room temperature, the reaction was quenched by adding saturated sodium bicarbonate solution. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography (eluent CH2Cl2 / MeOH=100 / 1) gave 70 mg (yield 33%) of N-(4-bromo-3,5-dimethoxyphenyl)-2-chloro-9-cyclopropyl-9H-purin-6-amine. MS m / z (ESI): 424.02 [M+H] + .

[0575] To a solution of N-(4-bromo-3,5-dimethoxyphenyl)-2-chloro-9-cyclopropyl-9H-purin-6-amine (43 mg, 0.10 mmol) in sec-butanol (1 mL) was added trans-4-aminocyclohexane-1-ol (58 mg, 0.5 mmol) and triethylamine (101 mg, 1.0 mmol). The mixture was heated at 130°C for 24 hours and then cooled to room temperature. The mixture was quenched with water and extracted three times with dichloromethane. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to afford 12 mg of the product (25% yield). 1H NMR(500MHz,DMSO)δ9.38(s,1H),7.82(s,1H),7.52(s,2H),6.48(s,1H),4.51(d,J=5.0Hz,1H ),3.85(s,6H),3.81-3.73(m,1H),3.41-3.35(m,1H),1.93-1.83(m,4H),1.35-0.97(m,8H).MS m / z(ESI):503.14[M+H] + .

[0576] Example 178: trans-4-((6-((4-chloro-3,5-dimethoxyphenyl)amino)-9-((3,3-difluorocyclobutyl)methyl)-9H-purin-2-yl)amino)cyclohexan-1-ol

[0577] 2,6-dichloropurine (1.89 g, 10 mmol) was dissolved in dry N,N-dimethylformamide (50 mL), 1,1-difluoro-3-(iodomethyl)cyclobutane (2.78 g, 12 mmol) and potassium carbonate (2.07 g, 15 mmol) were added, and the mixture was stirred at room temperature for 12 hours. Saturated sodium bicarbonate solution was added to quench the reaction. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography was performed to obtain 1.23 g (yield 41%) of 2,6-dichloro-9-((3,3-difluorocyclobutyl)methyl)-9H-purine. MS m / z (ESI): 293.02 [M+H] + .

[0578] 2,6-Dichloro-9-((3,3-difluorocyclobutyl)methyl)-9H-purine (155 mg, 0.53 mmol) was dissolved in dry sec-butanol (10 mL), 4-chloro-3,5-dimethoxyaniline (99 mg, 0.53 mmol) was added, and the mixture was heated at 90°C for 12 hours. After cooling to room temperature, the reaction was quenched by adding saturated sodium bicarbonate solution. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography (eluent CH2Cl2 / MeOH=100 / 1) gave 131 mg (yield 56%) of 2-chloro-N-(4-chloro-3,5-dimethoxyphenyl)-9-((3,3-difluorocyclobutyl)methyl)-9H-purin-6-amine, MS m / z (ESI): 444.08 [M+H] + .

[0579] To a solution of 2-chloro-N-(4-chloro-3,5-dimethoxyphenyl)-9-((3,3-difluorocyclobutyl)methyl)-9H-purin-6-amine (44 mg, 0.10 mmol) in sec-butanol (1 mL) was added trans-4-aminocyclohexane-1-ol (58 mg, 0.5 mmol) and triethylamine (101 mg, 1.0 mmol). The mixture was heated at 130°C for 24 hours and then cooled to room temperature. The reaction mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to afford 15 mg of the product (29% yield). 1 H NMR(500MHz,DMSO-d6)δ9.39(s,1H),7.91(s,1H),7.55(s,2H),6.45(s,1H),4.39(t,J=5.3Hz,1H),4.15(d,J=5.2Hz,2H),3.85(s,6H),3.78-3 .73(m,1H),3.23(t,J=5.7Hz,2H),2.70-2.62(m,3H),1.97(d,J=12.2Hz,2H),1.77(d,J=12.9Hz,2H),1.36-1.22(m,4H),1.00-0.89(m,2H).MS m / z(ESI):537.22[M+H] + .

[0580] Example 179: trans-4-((6-((4-chloro-3,5-dimethoxyphenyl)amino)-9-isobutyl-9H-purin-2-yl)amino)cyclohexan-1-ol

[0581] 2,6-Dichloro-9-isobutyl-9H-purine (200 mg, 0.82 mmol) (Reference Example 163) was dissolved in dry sec-butanol (5 mL), 4-chloro-3,5-dimethoxyaniline (153 mg, 0.82 mmol) was added, and the mixture was heated at 90°C for 12 hours. After cooling to room temperature, saturated sodium bicarbonate solution was added to quench the reaction. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography (eluent CH2Cl2 / MeOH=100 / 1) gave 161 mg (yield 50%) of 2-chloro-N-(4-chloro-3,5-dimethoxyphenyl)-9-isobutyl-9H-purin-6-amine. MS m / z (ESI): 396.10 [M+H] + .

[0582] To a solution of 2-chloro-N-(4-chloro-3,5-dimethoxyphenyl)-9-isobutyl-9H-purin-6-amine (40 mg, 0.10 mmol) in sec-butanol (1 mL) was added trans-4-aminocyclohexane-1-ol (58 mg, 0.5 mmol) and triethylamine (101 mg, 1.0 mmol). The mixture was heated at 130°C for 24 hours and then cooled to room temperature. The mixture was quenched with water and extracted three times with dichloromethane. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to afford 11 mg of the product (23% yield). 1 H NMR (500MHz, DMSO-d6) δ9.38(s,1H),7.84(s,1H),7.53(s,2H),6.40(s,1H),4.51(d,J=4.6Hz,1H),3.85(s,6H),3.83(d,J=7.3Hz,2H),3.75 (s,1H),3.43-3.36(m,1H),2.19(dp,J=13.9,7.0Hz,1H),1.94-1.88(m,2H),1.87-1.79(m,2H),1.37-1.14(m,4H),0.87(d,J=6.6Hz,6H).MS m / z(ESI):475.22[M+H] + .

[0583] Example 180: ((trans)-4-((6-((4-chloro-3,5-dimethoxyphenyl)amino)-9-isobutyl-9H-purin-2-yl)amino)cyclohexyl)methanol

[0584] To a solution of 2-chloro-N-(4-chloro-3,5-dimethoxyphenyl)-9-isobutyl-9H-purin-6-amine (40 mg, 0.10 mmol) (Reference Example 179) in sec-butanol (1 mL) were added trans-(4-aminocyclohexyl)methanol (65 mg, 0.5 mmol) and triethylamine (101 mg, 1.0 mmol). The mixture was heated at 130° C. for 24 hours and then cooled to room temperature. The mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to give 13 mg of the product (yield 27%). 1H NMR(500MHz,DMSO-d6)δ9.37(s,1H),7.84(s,1H),7.55(s,2H),6.42(s,1H),4.38 (t,J=5.3Hz,1H),3.85(s,6H),3.83(d,J=7.4Hz,2H),3.75(s,1H),3.23(t,J=5.7H z,2H),2.19(dq,J=13.5,6.8Hz,1H),1.97(d,J=12.3Hz,2H),1.76(d,J=12.9Hz,2 H),1.28(d,J=13.9Hz,3H),0.93(q,J=15.5,14.2Hz,2H),0.86(d,J=6.7Hz,6H).MS m / z(ESI):489.23[M+H] + .

[0585] Example 181: trans-4-((6-((3-bromo-4-chloro-5-methoxyphenyl)amino)-9-(2-fluoroethyl)-9H-purin-2-yl)amino)cyclohexan-1-ol

[0586] 2,6-Dichloro-9-(2-fluoroethyl)-9H-purine (200 mg, 0.85 mmol) (see Example 173) was dissolved in dry sec-butanol (5 mL), 3-bromo-4-chloro-5-methoxyaniline (201 mg, 0.85 mmol) was added, and the mixture was heated at 90°C for 12 hours. After cooling to room temperature, the reaction was quenched by adding saturated sodium bicarbonate solution. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography (eluent: CH2Cl2 / MeOH = 100 / 1) gave 170 mg (yield: 46%) of N-(3-bromo-4-chloro-5-methoxyphenyl)-2-chloro-9-(2-fluoroethyl)-9H-purin-6-amine. MS m / z (ESI): 433.96 [M+H] + .

[0587] To a solution of N-(3-bromo-4-chloro-5-methoxyphenyl)-2-chloro-9-(2-fluoroethyl)-9H-purin-6-amine (44 mg, 0.10 mmol) in sec-butanol (1 mL) were added trans-4-aminocyclohexane-1-ol (58 mg, 0.5 mmol) and triethylamine (101 mg, 1.0 mmol). The mixture was heated at 130° C. for 24 hours and then cooled to room temperature. The mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to afford 14 mg of the product (27% yield). 1H NMR(500MHz,DMSO-d6)δ9.69(s,1H),8.44(s,1H),7.89(s,1H),7.68(s,1H),6.58( d,J=7.9Hz,1H),4.84(t,J=4.9Hz,1H),4.74(t,J=4.8Hz,1H),4.49(d,J=4.7Hz,1H ),4.37(t,J=4.6Hz,1H),4.31(t,J=5.0Hz,1H),3.87(s,3H),3.74(s,1H),3.39(d, J=4.6Hz,1H),1.93(d,J=10.2Hz,2H),1.84(d,J=9.9Hz,2H),1.38-1.27(m,4H).MS m / z(ESI):513.08[M+H] + .

[0588] Example 182: trans-4-((6-((3-bromo-4-chloro-5-methoxyphenyl)amino)-9-(3-fluoropropyl)-9H-purin-2-yl)amino)cyclohexan-1-ol

[0589] 2,6-Dichloro-9-(3-fluoropropyl)-9H-purine (200 mg, 0.8 mmol) (see Example 174) was dissolved in dry sec-butanol (5 mL), 3-bromo-4-chloro-5-methoxyaniline (189 mg, 0.8 mmol) was added, and the mixture was heated at 90°C for 12 hours. After cooling to room temperature, the reaction was quenched by adding saturated sodium bicarbonate solution. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography (eluent: CH2Cl2 / MeOH = 100 / 1) afforded 127 mg (yield: 35%) of N-(3-bromo-4-chloro-5-methoxyphenyl)-2-chloro-9-(3-fluoropropyl)-9H-purin-6-amine. MS m / z (ESI): 447.97 [M+H] + .

[0590] To a solution of N-(3-bromo-4-chloro-5-methoxyphenyl)-2-chloro-9-(3-fluoropropyl)-9H-purin-6-amine (44 mg, 0.10 mmol) in sec-butanol (1 mL) were added trans-4-aminocyclohexane-1-ol (58 mg, 0.5 mmol) and triethylamine (101 mg, 1.0 mmol). The mixture was heated at 130° C. for 24 hours and then cooled to room temperature. The mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to afford 11 mg of the product (21% yield). 1H NMR(500MHz,DMSO-d6)δ9.66(s,1H),8.43(s,1H),7.90(s,1H),7.68(s,1H),6.57( d,J=8.1Hz,1H),4.53(t,J=5.6Hz,1H),4.49(d,J=4.7Hz,1H),4.44(t,J=5.7Hz,1H) ,4.13(t,J=7.0Hz,2H),3.87(s,3H),3.73(s,1H),3.42-3.35(m,1H),2.19(dp,J=2 6.2,6.3Hz,2H),1.93(d,J=9.9Hz,2H),1.84(d,J=9.5Hz,2H),1.38-1.28(m,4H).MS m / z(ESI):527.10[M+H] + .

[0591] Example 183: trans-4-((6-((3-bromo-5-(difluoromethoxy)phenyl)amino)-9-(cyclopropylmethyl)-9H-purin-2-yl)amino)cyclohexan-1-ol

[0592] 2,6-Dichloro-9-(cyclopropylmethyl)-9H-purine (200 mg, 0.87 mmol) (Reference Example 7) was dissolved in dry sec-butanol (5 mL), 3-bromo-5-(difluoromethoxy)aniline (207 mg, 0.87 mmol) was added, and the mixture was heated at 90°C for 12 hours. After cooling to room temperature, saturated sodium bicarbonate solution was added to quench the reaction. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography (eluent CH2Cl2 / MeOH=100 / 1) gave 165 mg (yield 43%) of N-(3-bromo-5-(difluoromethoxy)phenyl)-2-chloro-9-(cyclopropylmethyl)-9H-purin-6-amine, MS m / z (ESI): 444.00 [M+H] + .

[0593] To a solution of N-(3-bromo-5-(difluoromethoxy)phenyl)-2-chloro-9-(cyclopropylmethyl)-9H-purin-6-amine (44 mg, 0.10 mmol) in sec-butanol (1 mL) were added trans-4-aminocyclohexane-1-ol (58 mg, 0.5 mmol) and triethylamine (101 mg, 1.0 mmol). The mixture was heated at 130° C. for 24 hours and then cooled to room temperature. The reaction mixture was quenched with water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to afford 16 mg of the product (31% yield). 1H NMR(500MHz,DMSO-d6)δ9.82(s,1H),8.34(s,1H),7.94(s,1H),7.87(s,1H),7.26(t,J=73.8 Hz,1H),7.00(d,J=2.0Hz,1H),6.57(d,J=8.2Hz,1H),4.49(d,J=4.3Hz,1H),3.86(d,J=7.1Hz ,2H),3.73-3.66(m,1H),3.40(q,J=6.1,4.8Hz,1H),1.94(d,J=10.9Hz,2H),1.84(d,J=10.3 Hz,2H),1.30(dd,J=23.5,11.2Hz,5H),0.52(dt,J=8.1,3.0Hz,2H),0.42(d,J=5.0Hz,2H).MS m / z(ESI):523.13[M+H] + .

[0594] Example 184: In vitro inhibitory activity (enzyme activity) detection of compounds on PGK1 protein

[0595] Powdered solutions of the compound of the present invention and the comparative compound were dissolved in DMSO to a 1 mM stock solution. The stock solution was then serially diluted with DMSO in three-fold increments to eight concentrations, followed by a 25-fold dilution in reaction buffer (20 mM Tris, 100 mM NaCl, 0.1 mM MgCl2, 2 mM DTT, pH 8.6). To each 600 μL PE tube, 5 μL of a solution of PGK1 protein (recombinant human PGK1 protein, purchased from abcom, USA, Cat. No. ab211320) diluted to 0.2 ng / μL in reaction buffer was added, followed by 5 μL of the diluted compound. After incubation for 10 minutes, 10 μL of substrate 3-phosphoglycerate diluted to 0.4 μg / μL with reaction buffer (20 mM Tris, 100 mM NaCl, 0.1 mM MgCl2, 2 mM DTT, pH 8.6) and 20 μM ATP (purchased from Promega, Madison, WI) were added and reacted at room temperature for 30 minutes. Then, 20 μL of ADP Glo was added to each well. TMReagent (purchased from Promega, Madison, WI) and incubated for 40 minutes to stop the reaction and deplete the remaining ATP. Then, 40 μL of kinase assay reagent (purchased from Promega, Madison, WI) was added to convert ADP into ATP. The newly synthesized ATP was detected using a luciferase / luciferin system. The luminescence value was measured using a multifunctional microplate reader (Envision, PerkinElmer, MA, USA), and the data were fitted using Graph Pad Prim 9.0 to calculate the half-maximal inhibitory concentration (IC) of the test drug. 50 The data are shown in Table 2.

[0596] The test results showed that the compound of the present invention has a strong inhibitory activity on PGK1, and its IC 50 All were below 100 nM (see Table 2). Simultaneously, the inventors synthesized comparative compounds 1 and 2 and purchased compound NG52 from MedChem Express in China, the structure of which is shown in Table 1. The results showed that the compounds of the present invention exhibited significantly superior inhibitory activity against PGK1 to the comparative compounds, suggesting that the substituents on the five-membered ring of purine and the substituents and number on the benzene ring may affect the PGK1 inhibitory activity.

[0597] Table 1. Structures of comparative compounds

[0598] Table 2. In vitro inhibitory activity (enzyme activity) test results of PGK1 protein

[0599] Example 185: In vitro inhibitory activity (enzyme activity) detection of compound 1 on CDKs protein

[0600] CDK1 / CyclinA1 was purchased from Promega, Madison, catalog number: VA7399; CDK2 / CyclinA1 was purchased from Promega, Madison, catalog number: V2971; CDK6 / CyclinD3 was purchased from Promega, Madison, catalog number: V4510; CDK7 / CyclinH1 / MNAT1 was purchased from Promega, Madison, catalog number: VA7402; CDK9 / CyclinK was purchased from Promega, Madison, catalog number: V4104.

[0601] The powder of compound 1 of the present invention was dissolved in DMSO to prepare a mother solution with a concentration of 1 mM. The solution was then diluted to 8 concentrations in a three-fold gradient with DMSO and then diluted 25-fold with reaction buffer (20 mM Tris, 100 mM NaCl, 0.1 mM MgCl2, 2 mM DTT, pH 8.6). In a 600 μL PE tube, 5 μL of the above-mentioned CDKs protein solution diluted to 0.2-1 ng / μL (the specific amount was determined according to the protein instruction manual) was added to each tube, followed by the addition of 5 μL of the diluted compound 1. The mixture was incubated for 10 minutes, followed by the addition of 10 μL of substrate diluted to 0.4 μg / μL with reaction buffer (20 mM Tris, 100 mM NaCl, 0.1 mM MgCl2, 2 mM DTT, pH 8.6) and 50 μM ATP (purchased from Promega, Madison, WI), and the reaction was allowed to proceed at room temperature for 30 minutes. Then, 20 μL of ADP Glo™ reagent (purchased from Promega, Madison, WI) was added to each well and incubated for 40 minutes to stop the reaction and deplete the remaining ATP. Then, 40 μL of kinase assay reagent (purchased from Promega, Madison, WI) was added to convert ADP into ATP. The newly synthesized ATP was detected using a luciferase / luciferin system. The luminescence value was measured using a multifunctional microplate reader (Envision, PerkinElmer, MA, USA), and the data were fitted using Graph Pad Prim 9.0 to calculate the half-maximal inhibitory concentration (IC) of the test drug. 50 The data are shown in Table 3.

[0602] The test results show that the compound of the present invention can selectively inhibit PGK1, but has no obvious inhibitory activity on different subtypes of the CDK family.

[0603] Table 3. In vitro inhibitory activity (enzyme activity) test results of CDKs proteins

[0604] Example 186: Effects of Compounds on the Secretion of Inflammatory Factors in Mouse Mononuclear Macrophage Leukemia Cells RAW264.7

[0605] Three compounds were selected and their effects on the inflammatory factors IL-6 and IL-1β in mouse monocytic leukemia cells RAW264.7 (purchased from ATCC, USA) induced by LPS (Lipopolysaccharide, purchased from Sigma) were examined by western blot. The specific steps are as follows.

[0606] 106 cells were plated in a 6-well plate, one well was not added with LPS, and the rest were added with LPS. At the same time, 0.01, 0.03, 0.1, 0.3, 1, and 3 μM compounds were added. After incubation for 24 hours, the cells were collected (800 rpm / min, 4 min) in a 1.5 mL centrifuge tube. 50 μL of cell lysis buffer RIPA (purchased from Biyuntian, China) was added to each tube and lysed on ice for 10 minutes. 5× protein loading buffer (purchased from Biyuntian, China) was added and the sample was boiled at 95°C for 10 minutes. Separated by gel electrophoresis and transferred to the membrane. Incubated overnight in a 4°C refrigerator with IL-6 (Cat. No.: 12153S, purchased from CST, USA), IL-1β (Cat. No.: 12703S, purchased from CST, USA) and internal reference GAPDH (Cat. No.: 5174S, purchased from CST) antibodies. Quantified by ImageJ, analyzed by Graphad 9.0, and calculated IC 50 The results are shown in Table 4.

[0607] The test results showed that under LPS stimulation, the compound of the present invention can inhibit the secretion of inflammatory factors IL-6 and IL-1β in mouse mononuclear macrophage leukemia cells RAW264.7.

[0608] Table 4. IC values ​​of compounds for the secretion of inflammatory factors IL-6 and IL-1β in mouse mononuclear macrophage leukemia cells RAW264.7 under LPS induction 50 .

[0609] Example 187: Therapeutic effect of compound 94 on enema-induced enteritis in rats

[0610] A total of 33 male Wistar rats (purchased from Beijing Weitonglihua Laboratory Animal Technology Co., Ltd.) were randomly divided into four groups of 5-10 rats each: a normal control group (a blank solvent (citrate solution)) and a rat enteritis model induced by enema administration of the model solvent (citrate solution), aminosalicylic acid (5-ASA, purchased from Shanghai MCE), or compound 94 (50 mg / mL DNBS solution (Tokyo Chemical Industry Co., Ltd., 30% ethanol)). Dosing was initiated two days prior to DNBS induction and continued once daily until day 6 after modeling. The specific dosing schedule is described in Table 5.

[0611] The induction method of colitis is as follows. Rats fasted for 40 hours before administration, and were subcutaneously injected with 5% glucose saline (10 mL / kg, once a day) during the fasting period. On day 0, fasting rats were anesthetized using Shutai (intraperitoneal injection, 25 mg / kg, purchased from a pharmacy) and xylazine (intraperitoneal injection, 5 mg / kg, purchased from Sigma-Aldrich). In the vehicle model group, aminosalicylic acid model group, and compound 94 model group, a hose was inserted from the anus into the left flexure of the colon (about 8 cm from the anus) and DNBS enema (0.5 mL / only) was used to induce colitis in rats. The blank control group was enemaed using 30% ethanol in the same manner. The enema animals were kept in a head-down position for 15 minutes, and then kept in a Trendelenburg position until the animals woke up to avoid reflux of the enema solution.

[0612] Table 5. Grouping and dosing regimen

[0613] After modeling, the body weights of rats in all groups were recorded every day, as shown in Figure 1.

[0614] Six days after modeling, the animals were euthanized, and colorectal tissues were obtained to measure the length of the colorectum. The colon length is shown in FIG2 .

[0615] The disease activity index (DAI) on days 3-5 of modeling was recorded according to the scoring criteria in Table 6, and the results are shown in Figure 3.

[0616] At the end of dosing on day 6, blood was collected from the eye sockets, and serum levels of IL-6 (Mouse IL-6 ELISA Kit purchased from Lianke, Cat. No. EK206) and IL-1β (Mouse IL-1B ELISA Kit purchased from Lianke, Cat. No. EK201B) were measured using ELISA. Specific experimental procedures were performed according to the manufacturer's instructions. The serum levels of the inflammatory factors IL-1β and IL-6 in each model group are shown in Figures 4 and 5, respectively.

[0617] Test results showed that in the DNBS-induced enteritis model, the colorectal lengths of the animals in the compound group and the normal group were similar, indicating that Compound 94 has a strong protective effect on the colorectum. Furthermore, compared with the aminosalicylic acid group, Compound 94 significantly reduced the secretion of the inflammatory factors IL-1β and IL-6 in the serum. These results demonstrate that Compound 94 can demonstrate a therapeutic effect in the inflammatory bowel disease model by inhibiting the secretion of the inflammatory factors IL-1β and IL-6 in the serum of enteritis model mice.

[0618] Table 6. Macroscopic evaluation of colon ulcer scores in rats

[0619] *Normal stool: formed stool; loose stool: mushy, semi-formed stool that does not stick to the anus; loose stool: loose, watery stool that can stick to the anus.

[0620] As demonstrated in the Examples, the purine ring-containing compounds of the present invention can inhibit PGK1 activity. In LPS-induced cell models, the compounds of the present invention can suppress the mRNA levels of inflammatory factors such as IL-1β and IL-6. In a DNBS-induced inflammatory bowel disease animal model, they can also inhibit the secretion of inflammatory factors such as IL-1β and IL-6. These results suggest that the compounds of the present invention have potential therapeutic effects for inflammatory bowel disease.

[0621] Industrial Applicability

[0622] The present invention provides a purine ring-containing compound that can be used to reduce or inhibit PGK1 protein activity in cells or subjects, and / or to prevent or treat PGK1-related conditions in subjects, such as hypersensitivity reactions or autoimmune inflammatory conditions. The compound can be formulated into a corresponding pharmaceutical suitable for industrial applications.

[0623] Although the present invention is described in detail herein, the present invention is not limited thereto. Those skilled in the art may make modifications based on the principles of the present invention. Therefore, all modifications made in accordance with the principles of the present invention should be understood to fall within the scope of protection of the present invention.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt, solvate, isomer, ester, acid, metabolite or prodrug thereof, Among them, X is carbon or nitrogen, R 1 each independently selected from amino, hydroxy, cyano, halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, and C1-6 alkylsulfonyl, where n is 2 or 3; R 2 selected from C1-6 alkyl, C3-6 cycloalkyl, C3-6 cycloalkyl C1-4 alkyl, C1-4 alkoxy C1-4 alkyl, C1-6 haloalkyl, C3-6 halocycloalkyl C1-4 alkyl, C1-4 alkylaminoacyl C1-C4 alkyl, and C2-6 dialkylaminoacyl C1-C4 alkyl; Y is selected from C1-6 alkyl, C3-6 cycloalkyl, C3-6 cycloalkyl C1-4 alkyl, C3-6 cycloalkenyl, phenyl, 4- to 6-membered heterocyclic group, and 4- to 6-membered heterocyclic group C1-4 alkyl; R 3 each independently selected from hydroxy, amino, cyano, oxo, carboxyl, aminoacyl, halogen, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 hydroxyalkylamino, C1-6 alkylamido, C1-6 alkylaminoacyl, C1-4 alkoxyC1-4 alkylamino, C1-4 hydroxyalkoxyC1-4 alkylamino, C1-6 alkylsulfonylamino, phenylC1-4 alkylamino, and a four- to six-membered heterocyclic group, where m is 0, 1, 2 or 3; wherein the 4- to 6-membered heterocyclic groups are each independently selected from piperidinyl, morpholinyl, piperazinyl, tetrahydrofuranyl, oxetanyl, and imidazolidinyl.

2. The compound according to claim 1 or a pharmaceutically acceptable salt, solvate, isomer, ester, acid, metabolite or prodrug thereof, wherein X is carbon and the position of R relative to the amino linking group of the benzene ring is meta and / or para on the benzene ring. 1 is meta and / or para on the benzene ring.

3. The compound according to claim 2, or a pharmaceutically acceptable salt, solvate, isomer, ester, acid, metabolite or prodrug thereof, wherein relative to the amino linking group of the benzene ring, the para position of the benzene ring is unsubstituted or R at the para position 1 is selected from halogen and C1-3 alkoxy; and / or, relative to the amino linking group of the benzene ring, R at the meta position of the benzene ring 1 are each independently selected from cyano, halogen, C1-3 alkoxy, C1-3 haloalkyl, and C1-3 haloalkoxy.

4. The compound according to any one of claims 1-3 or a pharmaceutically acceptable salt, solvate, isomer, ester, acid, metabolite or prodrug thereof, wherein R 2 is selected from C3-6 alkyl, C3-6 cycloalkyl, C3-6 cycloalkyl C1-3 alkyl, C1-3 alkoxy C1-3 alkyl, C1-3 haloalkyl, C1-3 alkylaminoacyl C1-C3 alkyl, and C2-4 dialkylaminoacyl C1-C3 alkyl; R 2 is more preferably selected from isopropyl and cyclopropyl.

5. The compound according to any one of claims 1-4 or a pharmaceutically acceptable salt, solvate, isomer, ester, acid, metabolite or prodrug thereof, wherein Y is C2-5 alkyl.

6. The compound according to claim 5 or a pharmaceutically acceptable salt, solvate, isomer, ester, acid, metabolite or prodrug thereof, wherein R 3 are each independently selected from hydroxy, amino, carboxy, halogen, C1-3 alkyl, and C1-3 alkylaminoacyl, and m is 1 or 2.

7. A compound according to any one of claims 1-4, or a pharmaceutically acceptable salt, solvate, isomer, ester, acid, metabolite or prodrug thereof, wherein the compound has the structure of formula (II):

8. The compound according to claim 7 or a pharmaceutically acceptable salt, solvate, isomer, ester, acid, metabolite or prodrug thereof, wherein, m is 1 or 2, preferably 1; and / or, R 3 each independently selected from hydroxy, amino, cyano, oxo, carboxyl, C1-3 alkyl, C1-3 hydroxyalkyl, C1-3 hydroxyalkylamino, C1-3 alkylamido, C1-3 alkoxyC1-3 alkylamino, C1-3 hydroxyalkoxyC1-3 alkylamino, C1-3 alkylsulfonamido, phenylC1-3 alkylamino, morpholino, and piperidino; R 3 more preferably each independently selected from hydroxy, amino, C1-3 alkyl, C1-3 hydroxyalkyl, C1-3 hydroxyalkylamino, and C1-3 alkoxyC1-3 alkylamino.

9. The compound or a pharmaceutically acceptable salt, solvate, isomer, ester, acid, metabolite or prodrug thereof according to claim 1, wherein the compound is selected from the following compounds:

10. A pharmaceutical composition comprising the compound according to any one of claims 1-9 or a pharmaceutically acceptable salt, solvate, isomer, ester, acid, metabolite or prodrug thereof, and a pharmaceutically acceptable carrier or excipient, and optionally other therapeutic agents.

11. Use of the compound according to any one of claims 1-9 or a pharmaceutically acceptable salt, solvate, isomer, ester, acid, metabolite or prodrug thereof for the treatment or prevention of hypersensitivity or autoimmune inflammatory-related diseases.

12. Use of the compound according to claim 11 or a pharmaceutically acceptable salt, solvate, isomer, ester, acid, metabolite or prodrug thereof, wherein the hypersensitivity or autoimmune inflammatory-related disease is a disease regulated by or affected by PGK1 protein activity or wherein PGK1 protein activity or overexpression is involved, more preferably a disease related to high expression and / or overactivation of PGK1.

13. Use of the compound according to claim 11 or 12 or a pharmaceutically acceptable salt, solvate, isomer, ester, acid, metabolite or prodrug thereof, wherein the hypersensitivity or autoimmune inflammatory-related diseases are selected from: allergic rhinitis, asthma, atopic dermatitis, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, psoriasis, immune thrombocytopenic purpura, inflammatory bowel disease, chronic obstructive pulmonary disease, Sjogren's syndrome, pemphigus vulgaris, idiopathic plasmacytic lymphadenopathy, atherosclerosis, myocardial infarction and thrombosis, and combinations thereof.

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