Purine ring-containing compound and use thereof

Abstract

The invention relates to a compound for treating or preventing hypersensitivity or autoimmune inflammatory related diseases, and application and a method of treating or preventing hypersensitivity or autoimmune inflammatory related diseases in a subject. The compound is a compound of a formula (I) or a pharmaceutically acceptable salt, a solvate, an isomer, an ester, an acid, a metabolite or a prodrug thereof. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of drugs, and particularly to compounds for treating hypersensitivity or autoimmune inflammatory-related diseases, their uses and treatment methods. Technical Background

[0002] Inflammatory bowel disease (IBD) is a chronic and recurrent inflammatory disease, commonly including ulcerative colitis (UC) and Crohn disease (CD). Statistical data from the Chinese Center for Disease Control and Prevention in 2014 showed that the number of patients with inflammatory bowel disease in China between 2005 and 2014 was approximately 350,000, and by 2025, the number of patients with inflammatory bowel disease in China is expected to reach 1.5 million cases.

[0003] Macrophages are the first line of defense for the body to resist foreign antigens and play an important role in maintaining body homeostasis and inflammatory regulation. In a healthy intestine, M2 macrophages or circulating monocytes are recruited to the intestine and clear apoptotic epithelial cells and invading bacteria, etc., to maintain the homeostatic balance of the intestine. In an inflammatory bowel disease model, peripheral circulating monocytes infiltrate and differentiate into M1 macrophages under inflammatory intestinal mucosal conditions, and at the same time secrete inflammatory cytokines to enhance the immune response and exacerbate the inflammatory symptoms of the colitis model. Phosphoglycerate kinase 1 (PGK1) is a key reaction enzyme in the glycolysis process. It catalyzes the transfer of the 1-phosphate of 1,3-bisphosphoglycerate (1,3-BPG) to adenosine diphosphate (ADP) to generate adenosine triphosphate (ATP), which is the first step reaction for generating ATP. PGK1 plays an important role in maintaining normal intracellular metabolism, redox balance, and DNA repair and replication. Research shows 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, and NRF2 translocates to the nucleus and binds to the proximal region of the IL-1β and IL-6 genes, thereby inhibiting the secretion of the inflammatory factors IL-1β and IL-6 (A potent PGK1 antagonist reveals PGK1 regulates the production of IL-1β and 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 treatments (such as aminosalicylic acid, glucocorticoids, and immunomodulators) and targeted treatments (such as anti-TNF, anti-IL-12 / IL-23, and anti-α4β7 integrin). Although biologic targeted therapies are effective for many patients, there are still up to 30% of patients who do not respond to the initial treatment, and up to 50% of patients lose their response over time. Currently, the latest advances in the field of molecular biology and the understanding of the IBD immune pathway have opened up new possibilities for innovative drug therapies. Therefore, finding new targets and effective drugs is expected to break through the bottleneck of IBD treatment and bring good news for the improvement of the disease in IBD patients. Summary of the Invention

[0005] The object of the present disclosure is to provide a novel PGK1 protein inhibitor and its use in treating and / or preventing diseases regulated by or affected by PGK1 protein activity or involving PGK1 protein activity or overexpression. A series of compounds provided by the present disclosure have good therapeutic effects and application prospects for hypersensitivity or autoimmune inflammatory related 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]

[0008] wherein,

[0009] X is carbon or nitrogen,

[0010] 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;

[0011] R 2 is 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;

[0012] 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;

[0013] 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 alkoxy C1-4 alkylamino, C1-4 hydroxyalkoxy C1-4 alkylamino, C1-6 alkylsulfonylamino, phenyl C1-4 alkylamino, and 4- to 6-membered heterocyclic group, where m is 0, 1, 2 or 3;

[0014] wherein the 4- to 6-membered heterocyclic groups are each independently selected from piperidinyl, morpholinyl, piperazinyl, tetrahydrofuranyl, oxetanyl, and imidazolidinyl.

[0015] In a preferred embodiment, X is carbon, and relative to the amino linking group of the benzene ring, R 1 is in the meta and / or para positions on the benzene ring.

[0016] Further preferably, relative to the amino linking group of the benzene ring, the para position of the benzene ring has no substituent or R at the para position 1 is selected from halogen and C1-3 alkoxy. Additionally preferably, 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.

[0017] In yet another preferred embodiment, 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. Particularly preferably, R 2 is selected from isopropyl and cyclopropyl.

[0018] In a further embodiment, Y is C2-5 alkyl, and R 3 are each independently selected from hydroxy, amino, carboxy, halogen, C1-3 alkyl, and C1-3 alkylaminoacyl, and m is 1 or 2.

[0019] In another embodiment, the compound of the present invention has the structure of formula (II):

[0020]

[0021] wherein, R 1 , R 2 , R 3 , m and n are as defined above.

[0022] Preferably, m is 1 or 2, more preferably 1.

[0023] Additionally preferably, R 3 are each independently selected from hydroxy, amino, cyano, oxo, carboxy, C1-3 alkyl, C1-3 hydroxyalkyl, C1-3 hydroxyalkylamino, C1-3 alkylamido, C1-3 alkoxy C1-3 alkylamino, C1-3 hydroxyalkoxy C1-3 alkylamino, C1-3 alkylsulfonamido, phenyl C1-3 alkylamino, morpholino, and piperidino. Further preferably, R 3 are each independently selected from hydroxy, amino, C1-3 alkyl, C1-3 hydroxyalkyl, C1-3 hydroxyalkylamino, and C1-3 alkoxy C1-3 alkylamino.

[0024] 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.

[0025] In other aspects, the present disclosure relates to the use of the aforementioned PGK1 protein inhibitor in the preparation of a medicament for treating or preventing hypersensitivity or autoimmune inflammatory-related diseases, particularly diseases regulated or affected by PGK1 protein activity or in which PGK1 protein activity or overexpression is involved, more preferably diseases related to high expression and / or overactivation of PGK1. Preferably, the hypersensitivity or autoimmune inflammatory-related 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, Sjogren's syndrome, pemphigus vulgaris, idiopathic plasmacytic lymphadenopathy, atherosclerosis, myocardial infarction and thrombosis, and combinations thereof.

[0026] In yet another aspect, the present disclosure relates to a method for treating or preventing hypersensitivity 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

[0027] Figure 1 Shows the body weight changes of mice in the blank group, solvent group, and medicated group during the administration period in the enteritis model.

[0028] Figure 2 Shows the results of measuring the colon length of mice in the blank group, solvent group, and medicated group after the administration in the enteritis model.

[0029] Figure 3 Shows the results of the colon DAI score of mice in the blank group, solvent group, and medicated group after the administration in the enteritis model.

[0030] Figure 4 Shows the results of testing the content of inflammatory factor IL-1β in the serum of mice in the blank group, solvent group, and medicated group after the administration in the enteritis model.

[0031] Figure 5 Shows the results of testing the content of inflammatory factor IL-6 in the serum of mice in the blank group, solvent group, and medicated group after the administration in the enteritis model. DETAILED DESCRIPTION OF THE INVENTION

[0032] Term

[0033] Unless otherwise defined, all technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter pertains.

[0034] The term "alkyl" refers to an aliphatic hydrocarbon group, which can be a branched or straight-chain alkyl. Depending on the structure, an alkyl can be a monovalent group or a divalent group (i.e., an alkylene). In the present invention, the alkyl is preferably an alkyl having 1 - 8 carbon atoms, more preferably a "lower alkyl" having 1 - 6 carbon atoms, and even more preferably an alkyl having 1 - 4 carbon atoms. Typical alkyls include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, etc. It should be understood that the "alkyl" mentioned herein includes all possible configurations and conformations of the alkyl, for example, the "propyl" mentioned herein includes n-propyl and isopropyl, the "butyl" includes n-butyl, isobutyl, and tert-butyl, and the "pentyl" includes n-pentyl, isopentyl, neopentyl, tert-pentyl, and pent-3-yl, etc.

[0035] The term "alkoxy" refers to -O-alkyl, where the alkyl is as defined herein. Typical alkoxys include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, etc.

[0036] The term "alkoxyalkyl" refers to an alkyl as defined herein substituted by an alkoxy as defined herein.

[0037] The term "cycloalkyl" refers to a monocyclic or polycyclic group that contains only carbon and hydrogen. Cycloalkyls include groups having 3 - 12 ring atoms. Depending on the structure, a cycloalkyl can be a monovalent group or a divalent group (such as a cycloalkylene). In the present invention, the cycloalkyl is preferably a cycloalkyl having 3 - 8 carbon atoms, more preferably a "lower cycloalkyl" having 3 - 6 carbon atoms. Examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and adamantyl.

[0038] The term "alkyl(cycloalkyl)" or "cycloalkylalkyl" refers to an alkyl as defined herein substituted by a cycloalkyl as defined herein. Non-limiting examples of cycloalkylalkyls include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, etc.

[0039] The term "aryl" refers to a planar ring having a delocalized π - electron system and containing 4n + 2 π - electrons, where n is an integer. The aryl ring can be composed of five, six, seven, eight, nine, or more than nine atoms. The aryl can be optionally substituted. The term "aryl" includes carbocyclic aryls (such as phenyl) and heteroaryl (or "heteroaromatic") groups (such as pyridine). This term includes monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) groups.

[0040] As used herein, the term "aryl" means that each ring-forming atom in an aromatic ring is a carbon atom. The aryl ring can be composed of five, six, seven, eight, nine or more than nine atoms. The aryl can be optionally substituted. Examples of aryl include, but are not limited to, phenyl, naphthyl, phenanthryl, anthryl, fluorenyl and indenyl. Depending on the structure, the aryl can be a monovalent group or a divalent group (i.e., arylene).

[0041] The term "aryloxy" means -O-aryl, wherein aryl is as defined herein.

[0042] The term "heteroaryl" means that the aryl includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur. The N-containing "heteroaryl" moiety means that at least one backbone atom in the aromatic ring is a nitrogen atom. Depending on the structure, the heteroaryl can be a monovalent group or a divalent group (i.e., heteroarylene). Examples of heteroaryl include, but are not limited to, pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuryl, indazolyl, indazinyl, phthalazinyl, pyridazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl, naphthyridinyl and furanopyridyl, etc.

[0043] The term "alkyl(aryl)" or "aralkyl" means that the alkyl as defined herein is substituted by the aryl as defined herein. Non-limiting alkyl(aryl) includes benzyl, phenethyl, etc.

[0044] The term "alkyl(heteroaryl)" or "heteroarylalkyl" means that the alkyl as defined herein is substituted by the heteroaryl as defined herein.

[0045] The term "heteroalkyl" as used herein means that one or more backbone chain atoms in the alkyl as defined herein are heteroatoms, such as oxygen, nitrogen, sulfur, silicon, phosphorus or a combination thereof. The heteroatom(s) can be located at any position within the heteroalkyl or at the position where the heteroalkyl is connected to the rest of the molecule.

[0046] As used herein, the term "heterocycloalkyl" or "heterocyclic group" refers to a non-aromatic ring in which one or more of the atoms constituting the ring are heteroatoms selected from nitrogen, oxygen, and sulfur. The heterocycloalkyl ring can be a monocyclic or polycyclic ring composed of three, four, five, six, seven, eight, nine, or more than nine atoms. The heterocycloalkyl ring can be optionally substituted. Examples of heterocycloalkyl include, but are not limited to, lactam, lactone, cyclic imine, cyclic thioimine, cyclic carbamate, tetrahydrothiopyran, 4H-pyran, tetrahydropyran, piperidine, 1,3-dioxin, 1,3-dioxane, 1,4-dioxin, 1,4-dioxane, piperazine, 1,3-oxathiane, 1,4-oxathiane-2,6-diene, 1,4-oxathiane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, morpholine, trioxane, hexahydro-1,3,5-triazine, tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine, imidazolidine, pyrrolidone, pyrazoline, pyrazolidine, imidazoline, imidazolidine, 1,3-dioxolene, 1,3-dioxolane, 1,3-dithiolene, 1,3-dithiolane, isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine, and 1,3-oxathiolane. Depending on the structure, heterocycloalkyl can be a monovalent group or a divalent group (i.e., heterocycloalkylene).

[0047] The term "alkyl(heterocycloalkyl)" or "heterocycloalkylalkyl" refers to an alkyl as defined herein substituted by a heterocycloalkyl as defined herein.

[0048] The term "alkoxy(heterocycloalkyl)" or "heterocycloalkylalkoxy" refers to an alkoxy as defined herein substituted by a heterocycloalkyl as defined herein.

[0049] The term "halo" or "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0050] The terms "haloalkyl", "haloalkoxy", and "haloheteroalkyl" include structures of an alkyl, alkoxy, or heteroalkyl in which at least one hydrogen is replaced by a halogen atom. In certain embodiments, if two or more hydrogen atoms are replaced by halogen atoms, the halogen atoms are the same or different from each other.

[0051] The term "hydroxy" refers to the -OH group.

[0052] The term "cyano" refers to the -CN group.

[0053] The term "ester group" refers to a chemical moiety having the formula -COOR, where R is selected from alkyl, cycloalkyl, aryl, heteroaryl (connected through a ring carbon), and heterocyclic group (connected through a ring carbon).

[0054] The term "amino" refers to the -NH2 group.

[0055] The term "aminoacyl" refers to the -CO-NH2 group.

[0056] The term "alkylaminoacyl" refers to the -CO-NH-R group, where R is an alkyl group as defined herein.

[0057] The term "amido" or "acylamino" refers to -NR-CO-R', where R and R' are each independently hydrogen or an alkyl group.

[0058] The term "alkylamino" refers to an amino substituent further substituted by one or two alkyl groups, specifically the group -NRR', where R and R' are each independently selected from hydrogen or a lower alkyl group, provided that -NRR' is not -NH2. "Alkylamino" includes the group of compounds in which the nitrogen of -NH2 is linked to at least one alkyl group. Examples of alkylamino groups include, but are not limited to, methylamino, ethylamino, etc. "Dialkylamino" includes the group in which the nitrogen of -NH2 is linked to at least two other alkyl groups. Examples of dialkylamino groups include, but are not limited to, dimethylamino, diethylamino, etc.

[0059] The terms "arylamino" and "diarylamino" refer to an amino substituent further substituted by one or two aryl groups, specifically the group -NRR', where R and R' are each independently selected from hydrogen, a lower alkyl group, or an aryl group, where N is linked to at least one or two aryl groups, respectively.

[0060] The term "cycloalkylamino" refers to an amino substituent further substituted by one or two cycloalkyl groups as defined herein.

[0061] The term "heteroalkylamino" refers to an amino substituent further substituted by one or two heteroalkyl groups as defined herein.

[0062] The term "aralkylamino" as used herein refers to the group -NRR' where R is a lower aralkyl and R' is hydrogen, a lower alkyl group, an aryl group, or a lower aralkyl group.

[0063] The term "heteroarylamino" refers to an amino substituent further substituted by one or two heteroaryl groups as defined herein.

[0064] The term "heterocycloalkylamino" refers to an amino group as defined herein substituted by a heterocycloalkyl group as defined herein.

[0065] The term "alkylaminoalkyl" refers to an alkyl group as defined herein substituted by an alkylamino group as defined herein.

[0066] The term "aminoalkyl" refers to an alkyl substituent further substituted by one or more amino groups.

[0067] The term "aminoalkoxy" refers to an alkoxy substituent further substituted by one or more amino groups.

[0068] The term "hydroxyalkyl" or "hydroxyalkyl group" refers to an alkyl substituent further substituted by one or more hydroxy groups.

[0069] The term "cyanoalkyl" refers to an alkyl substituent further substituted by one or more cyano groups.

[0070] The term "acyl" refers to a monovalent radical remaining after removal of a hydroxy group from an organic or inorganic oxyacid, with the general formula R-M(O)-, where M is usually C.

[0071] The term "carbonyl" is an organic functional group formed by a double bond between a carbon atom and an oxygen atom (C=O).

[0072] The term "alkanoyl" or "alkylcarbonyl" refers to a carbonyl group further substituted by an alkyl group. Typical alkanoyls include, but are not limited to, acetyl, propionyl, butyryl, valeryl, hexanoyl, etc.

[0073] The term "arylcarbonyl" refers to a carbonyl group as defined herein substituted by an aryl group as defined herein.

[0074] The term "alkoxycarbonyl" refers to a carbonyl group further substituted by an alkoxy group.

[0075] The term "heterocycloalkylcarbonyl" refers to a carbonyl group further substituted by a heterocycloalkyl group.

[0076] The terms "alkylaminocarbonyl", "cycloalkylaminocarbonyl", "arylaminocarbonyl", "aralkylaminocarbonyl", "heteroarylaminocarbonyl" refer to a carbonyl group as defined herein substituted by an alkylamino, cycloalkylamino, arylamino, aralkylamino, or heteroarylamino group as defined herein, respectively.

[0077] The term "alkylcarbonylalkyl" or "alkanoylalkyl" refers to an alkyl group further substituted by an alkylcarbonyl group.

[0078] The term "alkylcarbonylalkoxy" or "alkanoylalkoxy" refers to an alkoxy group further substituted by an alkylcarbonyl group.

[0079] The term "heterocycloalkylcarbonylalkyl" refers to an alkyl group further substituted by a heterocycloalkylcarbonyl group.

[0080] The term "mercapto" refers to the -SH group. The term "alkylthio" refers to a mercapto group as defined herein substituted by an alkyl group as defined herein.

[0081] The term "sulfonyl" or "sulfonyl group" refers to the functional group remaining after removal of a hydroxy group from sulfuric acid, specifically the -S(=O)2- group.

[0082] The term "sulfinyl" or "sulfinyl group" refers to -S(=O)-.

[0083] The term "sulfamoyl" or "sulfamoyl group" refers to the -S(=O)2-NH2 group.

[0084] The term "alkylsulfinyl" or "alkylsulfinyl group" refers to alkyl-S(=O)-.

[0085] The term "alkylsulfonyl" or "alkylsulfonyl group" refers to -S(=O)2-R, where R is an alkyl group.

[0086] The term "alkylaminosulfonyl" means that the sulfonyl group defined herein is substituted by an alkylamino group defined herein.

[0087] The terms "alkylsulfonamido" or "alkylsulfonamino", and "cycloalkylsulfonamido" or "cycloalkylsulfonamino" refer to the amino group defined herein being substituted by an alkylsulfonyl or cycloalkylsulfonyl group defined herein, i.e., -NH-S(=O)2-R, where R is an alkyl group and a cycloalkyl group respectively.

[0088] The terms "cycloalkylsulfonyl" and "cycloalkylsulfonyl group" refer to -S(=O)2-R, where R is a cycloalkyl group.

[0089] The term "quaternary ammonium group" refers to -N + RR’R”, where R, R’ and R” are each independently selected from alkyl groups having 1-8 carbon atoms.

[0090] The term "optionally" means that one or more of the events described later may or may not occur, and includes both the events that occur and the events that do not occur. The terms "optionally substituted" or "substituted" mean that the group mentioned can be substituted by one or more additional groups, and the additional groups are each independently selected from alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic, hydroxy, alkoxy, cyano, halogen, amido, nitro, haloalkyl, amino, methanesulfonyl, alkylcarbonyl, alkoxycarbonyl, heteroarylalkyl, heterocycloalkylalkyl, aminoacyl, amino protecting group, etc. Among them, the amino protecting group is preferably selected from pivaloyl, tert-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyl, p-methoxybenzyl, allyloxycarbonyl, and trifluoroacetyl, etc.

[0091] As used herein, the "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.

[0092] 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 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 separation 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.

[0093] "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 the crystalline solid state, thereby forming a solvate. 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 combination of one or more water molecules with one molecule of the substance, wherein the water remains in its molecular state as HO.

[0094] A "metabolite" of a compound disclosed herein is a derivative of a compound formed when the compound is metabolized. The term "active metabolite" refers to a bioactive derivative of a compound formed when the compound is metabolized. As used herein, the term "being metabolized" refers to the sum total of processes by which a particular substance is altered by an organism (including but not limited to hydrolysis reactions and enzyme-catalyzed reactions such as oxidation reactions). Thus, enzymes can effect specific structural transformations to compounds. For example, cytochrome P450 catalyzes various oxidation and reduction reactions, while uridine diphosphate glucuronosyltransferase 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》, Ninth 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 of these methods are known in the art. In some embodiments, the metabolite of a compound is formed by an oxidation process and corresponds to the corresponding hydroxy-containing compound. In some embodiments, the compound is metabolized to a pharmaceutically active metabolite.

[0095] As used herein, the term "modulate" means to interact directly or indirectly with a target to alter the activity of the target, including, by way of example only, enhancing the activity of the target, inhibiting the activity of the target, restricting the activity of the target, or prolonging the activity of the target.

[0096] The term "prodrug" or "precursor drug" refers to derivatives which may not have pharmacological activity but, in some cases, can be administered orally or parenterally and are thereafter metabolized in vivo to form the compounds of the present invention which have pharmacological activity. Non-limiting examples of prodrugs include: esters, carbonates, hemiesters, phosphates, nitroesters, sulfates, sulfoxides, amides, carbamates, nitrogen-containing compounds, phosphoramides, glycosides, ethers, acetals, and ketals, etc.

[0097] "Effective amount" means the amount of a drug or pharmaceutical preparation that will elicit a biological or medical response in a tissue, system, animal, or human being under investigation, for example, by a researcher or a physician. Additionally, the term "therapeutically effective amount" means any amount that causes an improvement in a disease, disorder, or side effect, a cure, prevention, or alleviation thereof, or a decrease in the rate of development of a disease or disorder, compared to the corresponding subject who has not received that amount. The term also encompasses amounts that effectively enhance normal physiological functions.

[0098] As used herein, the term "treatment" refers to alleviating at least one symptom of a disease, disorder or condition. The term includes administering and / or applying to a subject one or more compounds described herein to provide management or treatment of the condition. "Treatment" for the purposes of the present disclosure may or may not provide a cure; rather, "treatment" can be a form of management of the condition. When the compounds described herein are used to address harmful proliferating cells (including cancer), "treatment" includes partial or complete destruction of the harmful proliferating cells with minimal disruption to normal cells. The desired mechanism of action for harmful rapidly proliferating cells (including cancer cells) is apoptosis at the cellular level.

[0099] As used herein, the term "prevention" includes jointly preventing or retarding the onset of clinically significant disease development or preventing or retarding the onset of a pre-clinically significant disease stage in at-risk individuals. This includes prophylactic treatment of individuals at risk of disease development.

[0100] The terms "subject" or "patient" include organisms that can have a condition or a condition associated with reduced or insufficient programmed cell death (apoptosis) or organisms that can otherwise benefit from administration of the compounds of the invention, such as humans and non-human animals. Preferred humans include human patients suffering from or predisposed to a condition 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, and non-mammals, such as chickens, amphibians, reptiles, etc.

[0101] GI as used herein 50 is the drug concentration required to inhibit 50% of cell growth, i.e., the drug concentration at which the growth of 50% of the cells (such as cancer cells) is inhibited or controlled.

[0102] IC as used herein 50 is the amount, concentration or dose of a particular test compound that achieves 50% inhibition of the maximum effect in an assay measuring an effect.

[0103] EC as used herein 50 is the dose, concentration or amount of a compound that elicits a dose-dependent response that is 50% of the maximum expression of a particular response induced, stimulated or potentiated by the particular compound being assayed.

[0104] 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 scope of those skilled in the art. Unless specific definitions are provided, chemical nomenclature and laboratory operations and techniques related to analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are known to those skilled in the art. Generally, the foregoing techniques and procedures can be implemented by conventional methods well known in the art and described in various general and more specific documents, which are cited and discussed in this specification.

[0105] Active compound

[0106] 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,

[0107]

[0108] wherein,

[0109] X is carbon or nitrogen,

[0110] 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;

[0111] R 2 is 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 alkylaminoC1-C4 alkyl, and C2-6 dialkylaminoC1-C4 alkyl;

[0112] Y is selected from C1-6 alkyl, C3-6 cycloalkyl, C3-6 cycloalkylC1-4 alkyl, C3-6 cycloalkenyl, phenyl, a four- to six-membered heterocyclic group, and a four- to six-membered heterocyclic groupC1-4 alkyl;

[0113] R 3 each independently selected from hydroxy, amino, cyano, oxo, carboxy, 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;

[0114] Wherein the four- to six-membered heterocyclic group is 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.

[0115] In a preferred embodiment, X is carbon, and relative to the amino linking group of the benzene ring, R 1 is at the meta and / or para positions on the benzene ring.

[0116] Further preferably, 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. Additionally preferably, relative to the amino linking group of the benzene ring, R at the meta position of the benzene ring 1 are independently selected from cyano, halogen, C1-3 alkoxy, C1-3 haloalkyl, and C1-3 haloalkoxy.

[0117] In yet another preferred embodiment, 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. Particularly preferably, R 2 is selected from isopropyl and cyclopropyl.

[0118] In a further embodiment, Y is C2-5 alkyl, and R 3 are independently selected from hydroxyl, amino, carboxyl, halogen, C1-3 alkyl, and C1-3 alkylaminoacyl, and m is 1 or 2.

[0119] In another embodiment, the compound of the present invention has the structure of formula (II):

[0120]

[0121] Wherein, R 1 、R 2 、R 3 、m and n are as defined above.

[0122] Preferably, m is 1 or 2, more preferably 1.

[0123] Additionally preferably, R 3Each independently selected from hydroxyl, amino, nitrile, 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. Further preferably, R 3 Each independently selected from hydroxyl, amino, C1-3 alkyl, C1-3 hydroxyalkyl, C1-3 hydroxyalkylamino, and C1-3 alkoxyC1-3 alkylamino.

[0124] In a preferred embodiment, the PGK1 protein inhibitor of the present invention is selected from the following compounds or their pharmaceutically acceptable salts, solvates, isomers, esters, acids, metabolites or prodrugs:

[0125]

[0126]

[0127]

[0128]

[0129]

[0130]

[0131]

[0132]

[0133]

[0134]

[0135] For each variable, any combination of the above groups is also contemplated herein. It is understood that: the substituents and substitution patterns on the compounds provided herein can be selected by those skilled in the art so as to provide compounds that are chemically stable and can be synthesized using techniques known in the art as well as the techniques described herein.

[0136] The pharmaceutically acceptable salts, solvates, isomers, esters, acids, metabolites or prodrugs of this compound are also described herein.

[0137] 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, etc.; 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-carboxylic 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, hydroxy-naphthoic acid, stearic acid, muconic acid, etc.; (2) base addition salts, formed when the acidic proton in the parent compound is replaced by a metal ion such as an alkali metal ion (e.g., lithium, sodium, potassium), an alkaline earth metal ion (e.g., magnesium or calcium), or an aluminum ion; or coordinated with an organic or inorganic base, 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.

[0138] The corresponding counterions of pharmaceutically acceptable salts 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.

[0139] 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 freeze-drying in the case of an aqueous solution.

[0140] Screening and characterization of 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, microscopic methods, elemental analysis. The various spectroscopic techniques used include, but are not limited to, Raman, FTIR, UVIS, and NMR (liquid and solid states). The various microscopic techniques include, but are not limited to, IR microscopy and Raman microscopy.

[0141] Pharmaceutical use

[0142] The PGK1 protein inhibitor of the present disclosure can be used for treating and preventing hypersensitivity or autoimmune inflammatory-related diseases, particularly diseases regulated by or affected by PGK1 protein activity or in which PGK1 protein activity or overexpression is involved, more preferably diseases related to high expression and / or overactivation of PGK1. Preferably, the hypersensitivity or autoimmune inflammatory-related 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, Sjogren's syndrome, pemphigus vulgaris, idiopathic plasmacytic lymphadenopathy, atherosclerosis, myocardial infarction and thrombosis, and combinations thereof.

[0143] In an embodiment of the present invention, the medicament comprising the compound of the present invention can be administered to a patient by at least one of injection, oral administration, inhalation, rectal and percutaneous administration. When treating a patient according to the present invention, the amount of the given medicament depends on many factors, such as the specific dosing regimen, the type and severity of the disease or disorder, the uniqueness of the subject or host to be treated (e.g., body weight), however, depending on the specific circumstances, including for example the specific medicament employed, the route of administration, the disorder being treated, and the subject or host being treated, the dosage can be routinely determined by methods known in the art. Generally, for the dosage used in adult treatment, the dosage typically ranges from 0.02 - 5000 mg / day, for example about 1 - 1500 mg / day. The required dosage can be conveniently presented as a single dose, or as co-administered (or within a short period of time) or divided doses at appropriate intervals, such as two, three, four or more divided doses per day. Those skilled in the art can understand that although the above dosage ranges are given, the specific effective amount can be appropriately adjusted according to the situation of the patient and in combination with the diagnosis of the physician.

[0144] In some embodiments of the methods or uses disclosed herein, a compound of any of the compounds described herein is administered to a subject at a dose of about 2 mg, 1 - 3 mg, 1 - 5 mg, 1 - 10 mg, 0.5 - 20 mg or 0.1 - 50 mg (e.g., a therapeutically effective dose). In some embodiments, the dose (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 dose is about 1 - 10 mg. In some embodiments, the dose is about 1 - 50 mg. In some embodiments, the dose is about 1 - 100 mg.

[0145] Preparation of the compound

[0146] The compounds of formulas (I) and (II) can be synthesized using standard synthetic techniques known to those skilled in the art or by combining methods known in the art with the methods described herein. Additionally, the solvents, temperatures, and other reaction conditions given herein can be varied according to the art.

[0147] In certain embodiments, provided herein are methods for preparing the kinase inhibitor compounds described herein and methods of 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, by using appropriate alternative starting materials.

[0148] The starting materials for synthesizing the compounds described herein can be synthesized or can be obtained from commercial sources. The compounds described herein and other related compounds having different substituents can be synthesized using techniques and starting materials known to those skilled in the art. The reactions for preparing the compounds disclosed herein can be modified by reagents and conditions considered appropriate by those skilled in the art to introduce the various moieties into the molecules provided herein.

[0149] If desired, the reaction products can be separated and purified using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography, and the like. These products can be characterized using conventional methods, including physical constants and spectral data.

[0150] Example

[0151] The following specific non-limiting examples are to be construed as illustrative only and in no way limiting of the disclosure. Although no further detailed description is required, it is believed that those skilled in the art can fully utilize the disclosure based on the description herein.

[0152] Example 1: 3-Bromo-5-((2-((4-hydroxycyclohexyl)amino)-9-isopropyl-9H-purin-6-yl)amino)benzonitrile

[0153]

[0154] 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 the mixture was heated at 110 °C for 12 h. 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 3-bromo-5-((2-chloro-9-isopropyl-9H-purin-6-yl)amino)benzonitrile, 87 mg (yield 45%). MS m / z (ESI): 391.01 [M+H] + 。

[0155] 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 h, the mixture was cooled to room temperature and quenched by adding 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 the product, 13 mg (yield 55%). 1 H NMR (500 MHz, DMSO) δ 10.12 (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 = 5.0 Hz, 6H), 1.34 - 1.28 (m, 4H). MS m / z (ESI): 470.13 [M+H] + 。

[0156] Example 2: 3-Bromo-5-((9-cyclopentyl-2-((4-hydroxycyclohexyl)amino)-9H-purin-6-yl)amino)benzonitrile

[0157]

[0158] 2,6-Dichloropurine (187 mg, 1 mmol), triphenylphosphine (341 mg, 1.3 mmol) and cyclopentanol were dissolved in dry tetrahydrofuran (5 mL). The solution was cooled to 0 °C, and then diisopropyl azodicarboxylate (263 mg, 1.3 mmol) was added. The mixture was warmed to room temperature and stirred for 12 h. 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 give 155 mg (yield 60%) of 2,6-dichloro-9-cyclopentyl-9H-purine. MS m / z (ESI): 257.04 [M+H] + .

[0159] 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). The mixture was heated at 110 °C for 12 h. 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 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] + .

[0160] 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) were 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 h and then cooled to room temperature. The reaction was quenched by adding 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 (yield 55%) of the product. 1 1H NMR (500 MHz, DMSO) δ 10.56 (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] + .

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

[0162]

[0163] Dissolve 2,6-dichloropurine (187 mg, 1 mmol), triphenylphosphine (341 mg, 1.3 mmol) and cyclobutanol in dry tetrahydrofuran (5 mL), cool to 0 °C, then add diisopropyl azodicarboxylate (263 mg, 1.3 mmol), warm to room temperature and stir for 12 hours. Remove the solvent under reduced pressure, add water, extract with ethyl acetate, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography to obtain 97 mg of 2,6-dichloro-9-cyclobutyl-9H-purine (yield 40%), MS m / z (ESI): 243.02 [M+H] + 。

[0164] Dissolve 2,6-dichloro-9-cyclobutyl-9H-purine (72 mg, 0.3 mmol) and 3-amino-5-bromobenzonitrile (77 mg, 0.39 mmol) in dry sec-butanol (3 mL), and heat at 110 °C for 12 hours. Cool to room temperature, add saturated sodium bicarbonate solution to quench the reaction. Extract three times with dichloromethane, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (eluent CH2Cl2 / MeOH = 100 / 1) to obtain 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] + 。

[0165] Add trans-4-aminocyclohexan-1-ol (57 mg, 0.5 mmol) and triethylamine (0.14 mL, 1 mmol) 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), and heat at 130 °C for 24 hours. Cool to room temperature, add water to quench, extract three times with dichloromethane, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (eluent CH2Cl2 / MeOH = 50 / 1) to obtain 14 mg of the product (yield 60%). 11H NMR (500 MHz, DMSO) δ 10.01 (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 = 5.0 Hz, 1H), 3.87 (d, J = 10.0 Hz, 1H), 3.69 (d, J = 5.0 Hz, 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] + 。

[0166] Example 4: 3-Chloro-5-((9-cyclobutyl-2-((4-hydroxycyclohexyl)amino)-9H-purin-6-yl)amino)benzonitrile

[0167]

[0168] 2,6-Dichloro-9-cyclobutyl-9H-purine (72 mg, 0.3 mmol) (refer to 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 h. After cooling to room temperature, 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 purified by column chromatography (eluent CH2Cl2 / MeOH = 100 / 1) to obtain 3-chloro-5-((2-chloro-9-cyclobutyl-9H-purin-6-yl)amino)benzonitrile, 64 mg (yield 60%). MS m / z (ESI): 359.06 [M + H] + 。

[0169] 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) 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 h, it was cooled to room temperature. The reaction was quenched by adding water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent CH2Cl2 / MeOH = 50 / 1) to obtain the product, 13 mg (yield 65%). 11H NMR (500 MHz, DMSO) δ 10.04 (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 = 5.0 Hz, 1H), 3.87 (d, J = 10.0 Hz, 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] + 。

[0170] Example 5: 3 - ((2 - ((4 - Aminocyclohexyl)amino)-9 - isopropyl - 9H - purin - 6 - yl)amino)-5 - bromobenzonitrile

[0171]

[0172] To a solution of 3 - bromo - 5 - ((2 - chloro - 9 - isopropyl - 9H - purin - 6 - yl)amino)benzonitrile (19 mg, 0.05 mmol) (refer to 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). After heating at 130 °C for 24 hours, it was cooled to room temperature. The reaction was quenched by adding water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent CH2Cl2 / MeOH = 10 / 1) to obtain 10 mg of the product (yield 45%). 1 1H NMR (500 MHz, DMSO) δ 10.31 (s, 1H), 8.30 (s, 1H), 8.06 - 7.96 m, 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] + 。

[0173] Example 6: 3 - bromo - 5 - ((2 - ((4 - hydroxycyclohexyl)amino)-9 - methyl - 9H - purin - 6 - yl)amino)benzonitrile

[0174]

[0175] 2,6-Dichloro-9-methyl-9H-purine (110 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 h. After cooling to room temperature, the reaction was quenched with saturated sodium bicarbonate solution, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent CH2Cl2 / MeOH = 100 / 1) to give 3-bromo-5-((2-chloro-9-methyl-9H-purin-6-yl)amino)benzonitrile 126 mg (yield 65%). MS m / z (ESI): 362.98 [M+H] + 。

[0176] 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) 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 h, the mixture was cooled to room temperature. The reaction 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 the product 11 mg (yield 50%). 1 1H NMR (500 MHz, DMSO) δ 10.00 (s, 1H), 8.71 (s, 1H), 8.40 (s, 1H), 7.88 (s, 1H), 7.67 (s, 1H), 6.74 (d, J = 10.0 Hz, 1H), 4.52 (d, J = 5.0 Hz, 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] + 。

[0177] Example 7: 3-Bromo-5-((9-(cyclopropylmethyl)-2-((4-hydroxycyclohexyl)amino)-9H-purin-6-yl)amino)benzonitrile

[0178]

[0179] Dissolve 2,6-dichloropurine (187 mg, 1 mmol) in dry N,N-dimethylformamide (5 mL), add bromomethylcyclopropane (268 g, 2 mmol) and potassium carbonate (690 mg, 5 mmol), and react at room temperature for 24 hours. Quench the reaction by adding saturated sodium bicarbonate solution, extract three times with dichloromethane, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (eluent petroleum ether / ethyl acetate = 4 / 1) to obtain 121 mg of 2,6-dichloro-9-(cyclopropylmethyl)-9H-purine (yield 50%), MS m / z (ESI): 243.02 [M+H] + 。

[0180] Dissolve 2,6-dichloro-9-(cyclopropylmethyl)-9H-purine (130 mg, 0.5 mmol) in dry sec-butanol (5 mL), add 3-amino-5-bromobenzonitrile (129 mg, 0.65 mmol), and heat at 110 °C for 12 hours. Cool to room temperature, quench the reaction by adding saturated sodium bicarbonate solution. Extract three times with dichloromethane, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (eluent CH2Cl2 / MeOH = 100 / 1) to obtain 110 mg of 3-bromo-5-((2-chloro-9-(cyclopropylmethyl)-9H-purin-6-yl)amino)benzonitrile (yield 55%), MS m / z (ESI): 403.01 [M+H] + 。

[0181] 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), add trans-4-aminocyclohexan-1-ol (57 mg, 0.5 mmol) and triethylamine (0.14 mL, 1 mmol), heat at 130 °C for 24 hours, and then cool to room temperature. Quench with water, extract three times with dichloromethane, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (eluent CH2Cl2 / MeOH = 50 / 1) to obtain 12 mg of the product (yield 50%). 1 H NMR (500 MHz, DMSO) δ 10.01 (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 = 5.0 Hz, 1H), 3.87 (d, J = 10.0 Hz, 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] + 。

[0182] Example 8: 3-Bromo-5-((9-ethyl-2-((4-hydroxycyclohexyl)amino)-9H-purin-6-yl)amino)benzonitrile

[0183]

[0184] Dissolve 2,6-dichloro-9-ethyl-9H-purine (107 mg, 0.5 mmol) in dry sec-butyl alcohol (5 mL), add 3-amino-5-bromobenzonitrile (129 mg, 0.65 mmol), and heat at 110 °C for 12 hours. Cool to room temperature, and quench the reaction with saturated sodium bicarbonate solution. Extract three times with dichloromethane, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (eluent CH2Cl2 / MeOH = 100 / 1) to obtain 3-bromo-5-((2-chloro-9-ethyl-9H-purin-6-yl)amino)benzonitrile 112 mg (yield 60%), MS m / z (ESI): 376.99 [M+H] + 。

[0185] 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), add trans-4-aminocyclohexan-1-ol (57 mg, 0.5 mmol) and triethylamine (0.14 mL, 1 mmol), heat at 130 °C for 24 hours, and then cool to room temperature. Quench with water, extract three times with dichloromethane, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (eluent CH2Cl2 / MeOH = 50 / 1) to obtain the product 12 mg (yield 53%). 1 H NMR (500 MHz, DMSO) δ 10.01 (s, 1H), 8.71 (s, 1H), 8.41 (s, 1H), 7.95 (s, 1H), 7.67 (s, 1H), 6.73 (d, J = 10.0 Hz, 1H), 4.52 (d, J = 5.0 Hz, 1H), 4.04 (q, J = 10.0 Hz, 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] + 。

[0186] Example 9: 3-Bromo-5-((9-(tert-butyl)-2-((4-hydroxycyclohexyl)amino)-9H-purin-6-yl)amino)benzonitrile

[0187]

[0188] 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 then concentrated sulfuric acid (1.47 g, 15 mmol) was added dropwise. The reaction mixture was heated at 120 °C for 12 h. After cooling to room temperature, the reaction was quenched by adding saturated sodium bicarbonate solution. The mixture was extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 4 / 1) to obtain 121 mg of 2,6-dichloro-9-tert-butyl-9H-purine (yield 50%), MS m / z (ESI): 245.04 [M+H] + 。

[0189] 2,6-Dichloro-9-tert-butyl-9H-purine (122 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 h. 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 obtain 127 mg of 3-bromo-5-((2-chloro-9-tert-butyl-9H-purin-6-yl)amino)benzonitrile (yield 63%), MS m / z (ESI): 405.02 [M+H] + 。

[0190] 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) 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 h, the mixture was cooled to room temperature. The reaction was quenched by adding water, and 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 obtain 12 mg of the product (yield 50%). 1 1H NMR (500 MHz, DMSO) δ 9.94 (s, 1H), 8.57 (br, 2H), 7.92 (s, 1H), 7.66 (s, 1H), 6.67 (s, 1H), 4.53 (d, J = 5.0 Hz, 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] + 。Example 10: 3-bromo-5-((9-cyclopropyl-2-((4-hydroxycyclohexyl)amino)-9H-purin-6-yl)amino)benzonitrile

[0191]

[0192] Dissolve 2,6-dichloropurine (935 mg, 5 mmol) and cyclopropylboronic acid (860 mg, 10 mmol) in dry 1,2-dichloroethane (50 mL), then add copper acetate (1.0 g, 5 mmol), 2,2'-bipyridine (780 mg, 5 mmol), and anhydrous sodium carbonate (1.06 g, 10 mmol), and reflux for 12 hours. Cool to room temperature, and quench the reaction by adding saturated sodium bicarbonate solution. Extract with dichloromethane three times, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (eluent: petroleum ether / ethyl acetate = 4 / 1) to obtain 228 mg of 2,6-dichloro-9-cyclopropyl-9H-purine (yield 20%), MS m / z (ESI): 229.00 [M+H] + 。

[0193] Dissolve 2,6-dichloro-9-cyclopropyl-9H-purine (115 mg, 0.5 mmol) in dry sec-butanol (5 mL), add 3-amino-5-bromobenzonitrile (129 mg, 0.65 mmol), and heat at 110 °C for 12 hours. Cool to room temperature, and quench the reaction by adding saturated sodium bicarbonate solution. Extract with dichloromethane three times, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (eluent: CH2Cl2 / MeOH = 100 / 1) to obtain 123 mg of 3-bromo-5-((2-chloro-9-cyclopropyl-9H-purin-6-yl)amino)benzonitrile (yield 64%), MS m / z (ESI): 388.99 [M+H] + 。

[0194] Add trans-4-aminocyclohexan-1-ol (57 mg, 0.5 mmol) and triethylamine (0.14 mL, 1 mmol) 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), heat at 130 °C for 24 hours, and then cool to room temperature. Quench with water, extract with dichloromethane three times, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (eluent: CH2Cl2 / MeOH = 50 / 1) to obtain 10 mg of the product (yield 45%). 11H NMR (500 MHz, DMSO) δ 9.97 (s, 1H), 8.70 (s, 1H), 8.40 (s, 1H), 7.87 (s, 1H), 7.66 (s, 1H), 6.78 (d, J = 10.0 Hz, 1H), 4.49 (d, J = 5.0 Hz, 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] + 。

[0195] Example 11: 3 - ((2 - ((4 - Aminocyclohexyl)amino)-9 - cyclopropyl - 9H - purin - 6 - yl)amino)-5 - bromobenzonitrile

[0196]

[0197] 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). After heating at 130 °C for 24 hours, it was cooled to room temperature. The reaction 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 obtain 16 mg of the product (yield 70%). 1 1H NMR (500 MHz, DMSO) δ 9.99 (s, 1H), 8.85 (s, 1H), 8.25 (s, 1H), 7.89 (s, 1H), 7.67 (s, 1H), 6.88 (d, J = 5.0 Hz, 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] + 。

[0198] Example 12: 3 - ((2 - ((4 - Aminocyclohexyl)amino)-9 - cyclopropyl - 9H - purin - 6 - yl)amino)-5 - chlorobenzonitrile

[0199]

[0200] 2,6-Dichloro-9-cyclopropyl-9H-purine (115 mg, 0.5 mmol) was dissolved in dry sec-butanol (5 mL), 3-amino-5-chlorobenzonitrile (129 mg, 0.65 mmol) was added, and the mixture was heated at 110 °C for 12 h. After cooling to room temperature, the reaction was quenched with 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 3-chloro-5-((2-chloro-9-cyclopropyl-9H-purin-6-yl)amino)benzonitrile 115 mg (yield 67%). MS m / z (ESI): 345.04 [M+H] + 。

[0201] 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) were added trans-cyclohexane-1,4-diamine (57 mg, 0.5 mmol) and triethylamine (0.14 mL, 1 mmol). After heating at 130 °C for 24 h, the mixture was cooled to room temperature. The reaction 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 the product 14 mg (yield 65%). 1 1H NMR (500 MHz, DMSO) δ 10.03 (s, 1H), 8.70 - 7.84 (m, 3H), 7.56 (s, 1H), 6.91 (d, J = 5.0 Hz, 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] + 。

[0202] Example 13: 3-((2-((4-Aminocyclohexyl)amino)-9-cyclobutyl-9H-purin-6-yl)amino)-5-chlorobenzonitrile

[0203]

[0204] Dissolve 2,6-dichloropurine (187 mg, 1 mmol), triphenylphosphine (341 mg, 1.3 mmol) and cyclobutanol in dry tetrahydrofuran (5 mL), cool to 0 °C, then add diisopropyl azodicarboxylate (263 mg, 1.3 mmol), warm to room temperature and stir for 12 hours. Remove the solvent under reduced pressure, add water, extract with ethyl acetate, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography to obtain 97 mg (yield 40%) of 2,6-dichloro-9-cyclobutyl-9H-purine. MS m / z (ESI): 243.02 [M+H] + .

[0205] Dissolve 2,6-dichloro-9-cyclobutyl-9H-purine (72 mg, 0.3 mmol) and 3-amino-5-chlorobenzonitrile (59 mg, 0.39 mmol) in dry sec-butanol (3 mL), and heat at 110 °C for 12 hours. Cool to room temperature, add saturated sodium bicarbonate solution to quench the reaction. Extract three times with dichloromethane, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (eluent CH2Cl2 / MeOH = 100 / 1) to obtain 64 mg (yield 60%) of 3-chloro-5-((2-chloro-9-cyclobutyl-9H-purin-6-yl)amino)benzonitrile. MS m / z (ESI): 359.06 [M+H] + .

[0206] 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), add trans-cyclohexane-1,4-diamine (57 mg, 0.5 mmol) and triethylamine (0.14 mL, 1 mmol), heat at 130 °C for 24 hours, and then cool to room temperature. Quench with water, extract three times with dichloromethane, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (eluent CH2Cl2 / MeOH = 10 / 1) to obtain 13 mg (yield 60%) of the product. 1 H NMR (500 MHz, DMSO) δ 10.03 (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 = 10.0 Hz, 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] + .

[0207] Example 14: 3-((2-((4-Aminocyclohexyl)amino)-9-cyclobutyl-9H-purin-6-yl)amino)-5-bromobenzonitrile

[0208]

[0209] Dissolve 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) in dry sec-butanol (3 mL), and heat at 110 °C for 12 hours. Cool to room temperature, and quench the reaction by adding saturated sodium bicarbonate solution. Extract three times with dichloromethane, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (eluent CH2Cl2 / MeOH = 100 / 1) to obtain 3-bromo-5-((2-chloro-9-cyclobutyl-9H-purin-6-yl)amino)benzonitrile 78 mg (yield 65%). MS m / z (ESI): 403.01 [M+H] + 。

[0210] 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), add trans-cyclohexane-1,4-diamine (57 mg, 0.5 mmol) and triethylamine (0.14 mL, 1 mmol), heat at 130 °C for 24 hours, and then cool to room temperature. Quench with water, extract three times with dichloromethane, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (eluent CH2Cl2 / MeOH = 10 / 1) to obtain the product 13 mg (yield 55%). 1 H NMR (500 MHz, DMSO) δ 10.01 (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 = 10.0 Hz, 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] + 。

[0211] Example 15: 3-((2-((2-Aminoethyl)amino)-9-cyclobutyl-9H-purin-6-yl)amino)-5-bromobenzonitrile

[0212]

[0213] 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). After heating at 130 °C for 24 hours, the reaction mixture was cooled to room temperature. The reaction was quenched by adding water, and 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 obtain 13 mg of the product (yield 60%). 1 H NMR (500 MHz, DMSO) δ 10.07 (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 = 10.0 Hz, 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] + 。

[0214] Example 16: 3-Bromo-5-((9-isopropyl-2-((1-methylpiperidin-4-yl)amino)-9H-purin-6-yl)amino)benzonitrile

[0215]

[0216] 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). After heating at 130 °C for 24 hours, the reaction mixture was cooled to room temperature. The reaction was quenched by adding water, and 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 obtain 27 mg of the product (yield 22%). 11H NMR (500 MHz, DMSO-d6) δ 10.05 (s, 1H), 8.54 (s, 2H), 8.07 (s, 1H), 7.69 (s, 1H), 7.03 (d, J = 6.0 Hz, 1H), 4.61 (p, J = 6.6 Hz, 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] + 。

[0217] Example 17: 3-Bromo-5-((2-((4-(hydroxymethyl)cyclohexyl)amino)-9-isopropyl-9H-purin-6-yl)amino)benzonitrile

[0218]

[0219] 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). After heating at 130 °C for 24 hours, the reaction mixture was cooled to room temperature. The reaction was quenched with water and extracted three times with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 10 / 1) to obtain 24 mg of the product (yield 19%). 1 1H NMR (500 MHz, DMSO-d6) δ 9.99 (s, 1H), 8.67 - 8.47 (m, 2H), 8.02 (s, 1H), 7.66 (s, 1H), 6.71 (d, J = 6.3 Hz, 1H), 4.58 (p, J = 6.7 Hz, 1H), 4.36 (t, J = 5.3 Hz, 1H), 3.69 (ddt, J = 14.6, 11.1, 5.5 Hz, 1H), 3.23 (t, J = 5.8 Hz, 2H), 2.03 - 1.95 (m, 2H), 1.80 (d, J = 11.6 Hz, 2H), 1.50 (s, 3H), 1.49 (s, 3H), 1.24 (d, J = 9.9 Hz, 2H), 1.18 (d, J = 6.2 Hz, 1H), 1.12 - 1.00 (m, 2H). MS m / z (ESI): 484.14 [M+H] + 。

[0220] Example 18: 3-Bromo-5-((9-isopropyl-2-((4-oxocyclohexyl)amino)-9H-purin-6-yl)amino)benzonitrile

[0221]

[0222] 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-aminocyclohexan-1-one (30 mg, 0.5 mmol) and triethylamine (0.14 mL, 1 mmol). After heating at 130 °C for 24 hours, the reaction mixture was cooled to room temperature. The reaction 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 (yield 60%). 1 H NMR (500 MHz, DMSO-d6) δ 10.05 (s, 1H), 8.62 (s, 1H), 8.56 (s, 1H), 8.06 (s, 1H), 7.68 (s, 1H), 6.96 (d, J = 5.0 Hz, 1H), 4.65 - 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 = 5.0 Hz, 6H). MS m / z (ESI): 468.11 [M+H] + 。

[0223] Example 19: N-(4-((6-((3-bromo-5-cyanophenyl)amino)-9-isopropyl-9H-purin-2-yl)amino)cyclohexyl)acetamide

[0224]

[0225] 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). After heating at 130 °C for 24 hours, the reaction mixture was cooled to room temperature. The reaction 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 (yield 49%). 11H NMR (500 MHz, DMSO-d6) δ 10.02 (s, 1H), 8.91 (s, 1H), 8.27 (s, 1H), 8.03 (s, 1H), 7.72 (d, J = 5.0 Hz, 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 = 5.0 Hz, 6H); 1.45 - 1.31 (m, 4H). MS m / z (ESI): 511.16 [M + H] + 。

[0226] Example 20: 3 - ((2 - ((5 - Aminopentyl)amino)-9 - isopropyl - 9H - purin - 6 - yl)amino)-5 - bromobenzonitrile

[0227]

[0228] 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). After heating at 130 °C for 24 hours, it was cooled to room temperature. The reaction 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 obtain 16 mg of the product (yield 27%). 1 1H NMR (500 MHz, DMSO-d6) δ 9.94 (s, 1H), 8.60 (d, J = 44.5 Hz, 2H), 8.03 (s, 1H), 7.66 (t, J = 1.6 Hz, 1H), 6.98 (d, J = 6.4 Hz, 1H), 4.60 (p, J = 6.8 Hz, 1H), 3.35 (s, 4H), 2.76 (t, J = 7.0 Hz, 2H), 1.67 - 1.57 (m, 4H), 1.51 (s, 3H), 1.50 (s, 3H). MS m / z (ESI): 457.14 [M + H] + 。

[0229] Example 21: 3 - bromo - 5 - ((2 - ((((1R,3S)-3 - hydroxycyclohexyl)amino)-9 - isopropyl - 9H - purin - 6 - yl)amino)benzonitrile

[0230]

[0231] 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). After heating at 130 °C for 24 hours, the mixture was cooled to room temperature. The reaction was quenched by adding water, and 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 obtain 20 mg of the product (yield 17%). 1 1H NMR (500 MHz, DMSO-d6) δ 9.99 (s, 1H), 8.58 (d, J = 34.7 Hz, 2H), 8.03 (s, 1H), 7.66 (d, J = 1.7 Hz, 1H), 6.78 (d, J = 8.3 Hz, 1H), 4.59 (p, J = 7.1 Hz, 2H), 3.77 (dtd, J = 11.4, 7.8, 4.2 Hz, 1H), 3.56 (s, 1H), 3.17 (d, J = 3.5 Hz, 1H), 2.10 (d, J = 11.5 Hz, 1H), 1.89 (d, J = 11.7 Hz, 1H), 1.85 - 1.77 (m, 1H), 1.70 (dt, J = 13.7, 3.7 Hz, 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] + 。

[0232] Example 22: 3-bromo-5-((2-((((1R,3R)-3-hydroxycyclohexyl)amino)-9-isopropyl-9H-purin-6-yl)amino)benzonitrile

[0233]

[0234] 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). After heating at 130 °C for 24 hours, the mixture was cooled to room temperature. The reaction was quenched by adding water, and 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 obtain 12 mg of the product (yield 10%). 11H NMR (500 MHz, DMSO-d6) δ 9.93 (s, 1H), 8.57 (s, 2H), 8.01 (s, 1H), 7.65 (t, J = 1.6 Hz, 1H), 6.62 (d, J = 7.9 Hz, 1H), 4.60 (h, J = 7.7, 7.3 Hz, 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] + 。

[0235] Example 23: 3-Bromo-5-((2-((3-hydroxypropyl)amino)-9-isopropyl-9H-purin-6-yl)amino)benzonitrile

[0236]

[0237] 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). After heating at 130 °C for 24 hours, the reaction mixture was cooled to room temperature. The reaction 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 = 50 / 1) to give 18 mg of the product (yield 33%). 1 1H NMR (500 MHz, DMSO-d6) δ 9.97 (s, 1H), 8.60 (d, J = 30.1 Hz, 2H), 8.02 (s, 1H), 7.65 (t, J = 1.6 Hz, 1H), 6.88 (s, 1H), 4.60 (h, J = 6.7 Hz, 1H), 4.43 (t, J = 5.2 Hz, 1H), 3.52 (td, J = 6.4, 5.1 Hz, 2H), 3.37 (q, J = 6.6 Hz, 2H), 1.76 (p, J = 6.6 Hz, 2H), 1.51 (s, 3H), 1.50 (s, 3H). MS m / z (ESI): 430.09 [M+H] + 。

[0238] Example 24: 3-Bromo-5-((2-((4-hydroxybutyl)amino)-9-isopropyl-9H-purin-6-yl)amino)benzonitrile

[0239]

[0240] 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). After heating at 130 °C for 24 hours, the reaction mixture was cooled to room temperature. The reaction was quenched by adding water, and 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 obtain 32 mg of the product (yield 56%). 1 H NMR (500 MHz, DMSO-d6) δ 9.97 (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 = 6.8 Hz, 1H), 4.33 (t, J = 5.1 Hz, 1H), 3.42 (td, J = 6.5, 5.0 Hz, 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] + 。

[0241] Example 25: 3-bromo-5-((9-cyclopropyl-2-((4-(hydroxymethyl)cyclohexyl)amino)-9H-purin-6-yl)amino)benzonitrile

[0242]

[0243] 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). After heating at 130 °C for 24 hours, the reaction mixture was cooled to room temperature. The reaction was quenched by adding water, and 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 obtain 12 mg of the product (yield 19%). 11H NMR (500 MHz, DMSO-d6) δ 9.97 (s, 1H), 8.60 (s, 1H), 8.54 (s, 1H), 8.02 (d, J = 8.2 Hz, 1H), 7.87 (s, 1H), 7.66 (t, J = 1.6 Hz, 1H), 6.82 (d, J = 8.2 Hz, 1H), 4.36 (dt, J = 12.2, 5.3 Hz, 2H), 3.75 - 3.65 (m, 1H), 3.39 (d, J = 50.0 Hz, 1H), 3.22 (d, J = 4.9 Hz, 2H), 1.97 (s, 3H), 1.90 - 1.72 (m, 4H), 1.30 (d, J = 3.5 Hz, 2H), 1.29 - 1.21 (m, 5H). MS m / z (ESI): 482.12 [M + H] + 。

[0244] Example 26: 3-Bromo-5-((2-((5-hydroxypentyl)amino)-9-isopropyl-9H-purin-6-yl)amino)benzonitrile

[0245]

[0246] 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). After heating at 130 °C for 24 hours, it was cooled to room temperature. 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 obtain 27 mg of the product (yield 48%). 1 1H NMR (500 MHz, DMSO-d6) δ 9.96 (s, 1H), 8.60 (d, J = 40.1 Hz, 2H), 8.01 (s, 1H), 6.91 (s, 1H), 4.59 (h, J = 6.8 Hz, 1H), 4.30 (t, J = 5.1 Hz, 1H), 3.38 (td, J = 6.4, 5.0 Hz, 2H), 3.33 - 3.31 (m, 2H), 1.59 (p, J = 7.4 Hz, 2H), 1.51 (s, 3H), 1.50 (s, 3H), 1.48 - 1.42 (m, 2H), 1.38 (ddt, J = 14.0, 8.8, 5.0 Hz, 2H). MS m / z (ESI): 458.12 [M + H] + 。

[0247] Example 27: 3-Bromo-5-((9-isopropyl-2-((trans-4-((3-methoxypropyl)amino)cyclohexyl)amino)-9H-purin-6-yl)amino)benzonitrile

[0248]

[0249] 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). After heating at 130 °C for 24 hours, the reaction mixture was cooled to room temperature. The reaction was quenched with water and extracted three times with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 50 / 1) to give 8 mg of the product (yield 4%). 1 H NMR (500 MHz, DMSO-d6) δ 10.00 (s, 1H), 8.93 (s, 1H), 8.03 (s, 1H), 7.66 (t, J = 1.6 Hz, 1H), 6.79 (s, 1H), 4.67 - 4.54 (m, 1H), 3.40 (s, 3H), 3.25 (s, 3H), 2.92 (t, J = 7.9 Hz, 3H), 2.16 - 2.04 (m, 4H), 1.88 (dq, J = 12.6, 6.3 Hz, 2H), 1.55 (s, 2H), 1.51 (s, 3H), 1.50 (s, 3H), 1.35 (d, J = 12.9 Hz, 2H); MS m / z (ESI): 541.85 [M+H] + 。

[0250] Example 28: 3-Bromo-5-((9-isopropyl-2-(((tetrahydrofuran-2-yl)methyl)amino)-9H-purin-6-yl)amino)benzonitrile

[0251]

[0252] 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)methylamine (39 mg, 0.39 mmol) and triethylamine (0.088 mL, 0.64 mmol). After heating at 130 °C for 24 hours, the reaction mixture was cooled to room temperature. The reaction was quenched with water and extracted three times with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 50 / 1) to give 39 mg of the product (yield 67%). 11H NMR (500 MHz, DMSO-d6) δ 10.04 - 9.91 (m, 1H), 8.58 (s, 2H), 8.02 (s, 1H), 7.66 (t, J = 1.6 Hz, 1H), 6.90 (s, 1H), 4.61 (hept, J = 6.8 Hz, 1H), 4.06 (p, J = 6.4 Hz, 1H), 3.79 (td, J = 7.6, 5.9 Hz, 1H), 3.62 (td, J = 7.7, 6.3 Hz, 1H), 3.38 (td, J = 6.1, 1.8 Hz, 2H), 1.93 (ddt, J = 16.4, 9.9, 3.6 Hz, 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] + 。

[0253] Example 29: 3-Bromo-5-((9-cyclopropyl-2-((4-((2-hydroxyethyl)amino)cyclohexyl)amino)-9H-purin-6-yl)amino)benzonitrile

[0254]

[0255] Dissolve 3-((2-(((trans-4-aminocyclohexyl)amino)-9-cyclopropyl-9H-purin-6-yl)amino)-5-bromobenzonitrile (23 mg, 0.10 mmol) (Reference Example 11) in dry DMF (3 mL), then successively add triethylamine (20 mg, 0.20 mmol) and 2-bromoethan-1-ol (12 mg, 0.1 mmol), and react at room temperature for 12 hours. Quench with water, extract three times with dichloromethane, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (eluent CH2Cl2 / MeOH = 10 / 1) to obtain the product 5 mg (yield 20%). 1 1H NMR (500 MHz, DMSO) δ 9.97 (s, H), 8.76 (s, 1H), 8.34 (s, 1H), 7.88 (s, 1H), 6.84 (d, J = 5.0 Hz, 1H), 4.79 (s, 1H), 3.70 (s, 2H), 3.54 (t, J = 5.0 Hz, 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] + 。

[0256] Example 30: 3-Bromo-5-((2-((4-((2-hydroxyethyl)amino)cyclohexyl)amino)-9-isopropyl-9H-purin-6-yl)amino)benzonitrile

[0257]

[0258] 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). After heating at 130 °C for 24 hours, it was 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 purified by column chromatography (eluent: CH2Cl2 / MeOH = 10 / 1) to obtain 16 mg (yield 34%) of 3-((2-(((trans-4-aminocyclohexyl)amino)-9-isopropyl-9H-purin-6-yl)amino)-5-bromobenzonitrile. MS m / z (ESI): 469.15 [M+H] + 。

[0259] 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), then triethylamine (20 mg, 0.20 mmol) and 2-bromoethanol (12 mg, 0.1 mmol) were added successively. The reaction was carried out at room temperature for 12 hours. The reaction was quenched by adding water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 10 / 1) to obtain 6 mg (yield 23%) of the product. 1 H NMR (500 MHz, DMSO) δ 9.97 (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 = 5.0 Hz, 2H), 2.70 (t, J = 5.0 Hz, 2H), 2.01 - 1.94 (m, 4H), 1.50 (d, J = 5.0 Hz, 6H), 1.36 - 1.29 (m, 4H). MS m / z (ESI): 513.17 [M+H] + 。

[0260] Example 31: N-(4-((6-((3-bromo-5-cyanophenyl)amino)-9-isopropyl-9H-purin-2-yl)amino)cyclohexyl)methanesulfonamide

[0261]

[0262] Under an 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 successively. After reacting for 12 hours, the reaction was quenched with water. It was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent CH2Cl2 / MeOH = 10 / 1) to obtain 6 mg of the product (yield 23%). 1 H NMR (500 MHz, DMSO) δ 10.00 (s, 1H), 8.03 (s, 1H), 7.66 (s, 1H), 7.03 (s, 1H), 6.74 (s, 1H), 5.68 (d, J = 10.0 Hz, 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] + 。

[0263] Example 32: 2-(6-((3-bromo-5-cyanophenyl)amino)-2-((trans-4-hydroxycyclohexyl)amino)-9H-purin-9-yl)-N,N-dimethylacetamide

[0264]

[0265] 2,6-Dichloropurine (1.89 g, 10 mmol) was dissolved in dry N,N-dimethylformamide (50 mL), 2-bromo-N,N-dimethylacetamide (2.00 g, 12 mmol) and N,N-diisopropylethylamine (1.94 g, 15 mmol) were added, and the reaction was carried out at room temperature for 24 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 purified by column chromatography to obtain 1.47 g of 2-(2,6-dichloro-9H-purin-9-yl)-N,N-dimethylacetamide (yield 54%), MS m / z (ESI): 274.03 [M + H] + 。

[0266] Dissolve 2-(2,6-dichloro-9H-purin-9-yl)-N,N-dimethylacetamide (1.47 g, 5.4 mmol) in dry sec-butanol (50 mL), add 3-amino-5-bromobenzonitrile (1.4 g, 7.0 mmol), and heat at 110 °C for 12 h. Cool to room temperature, and quench the reaction by adding saturated sodium bicarbonate solution. Extract three times with dichloromethane, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (eluent CH2Cl2 / MeOH = 100 / 1) to obtain 550 mg of 2-(6-((3-bromo-5-cyanophenyl)amino)-2-chloro-9H-purin-9-yl)-N,N-dimethylacetamide (yield 32%), MS m / z (ESI): 434.01 [M+H] + .

[0267] 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), add trans-4-aminocyclohexan-1-ol (58 mg, 0.5 mmol) and triethylamine (0.14 mL, 1 mmol), heat at 130 °C for 24 h, and then cool to room temperature. Quench with water, extract three times with dichloromethane, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (eluent CH2Cl2 / MeOH = 50 / 1) to obtain 20 mg of the product (yield 39%). 1 1H NMR (500 MHz, DMSO-d6) δ 10.00 (s, 1H), 8.71 (s, 1H), 8.41 (s, 1H), 7.79 (s, 1H), 7.67 (d, J = 1.6 Hz, 1H), 6.69 (d, J = 8.2 Hz, 1H), 4.96 (s, 2H), 4.48 (d, J = 4.3 Hz, 1H), 3.74 - 3.61 (m, 1H), 3.39 (d, J = 4.1 Hz, 1H), 3.09 (s, 3H), 2.86 (s, 3H), 1.92 (d, J = 11.7 Hz, 2H), 1.83 (d, J = 11.1 Hz, 2H), 1.32 (q, J = 12.1, 10.9 Hz, 4H). MS m / z (ESI): 513.13 [M+H] + .

[0268] Example 33: 2-(2-((((trans)-4-aminocyclohexyl)amino)-6-((3-bromo-5-cyanophenyl)amino)-9H-purin-9-yl)-N,N-dimethylacetamide

[0269]

[0270] 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-cyclohexanediamine (58 mg, 0.5 mmol) and triethylamine (0.14 mL, 1 mmol). After heating at 130 °C for 24 hours, the reaction mixture was cooled to room temperature. The reaction 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 (500 MHz, DMSO-d6) δ 8.73 (s, 1H), 8.41 (s, 1H), 7.79 (s, 1H), 7.67 (s, 1H), 6.73 (d, J = 8.1 Hz, 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 = 6.9 Hz, 2H), 1.84 (d, J = 8.9 Hz, 2H), 1.42 - 1.16 (m, 4H). MS m / z (ESI): 512.15 [M + H] + 。

[0271] Example 34: 2-(6-((3-bromo-5-cyanophenyl)amino)-2-((4-hydroxybutyl)amino)-9H-purin-9-yl)-N,N-dimethylacetamide

[0272]

[0273] 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). After heating at 130 °C for 24 hours, the reaction mixture was cooled to room temperature. The reaction 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 (yield 47%). 11H NMR (500 MHz, DMSO-d6) δ 10.01 (s, 1H), 8.69 (s, 1H), 8.54 (s, 1H), 7.79 (s, 1H), 7.66 (d, J = 1.5 Hz, 1H), 6.93 (t, J = 5.8 Hz, 1H), 4.97 (s, 2H), 4.33 (t, J = 5.0 Hz, 1H), 3.41 (d, J = 5.0 Hz, 2H), 3.33 (s, 2H), 3.10 (s, 3H), 2.86 (s, 3H), 1.66 - 1.55 (m, 2H), 1.50 (p, J = 6.6 Hz, 2H). MS m / z (ESI): 487.12 [M+H] + 。

[0274] Example 35: 2-(6-((3-Bromo-5-cyanophenyl)amino)-2-((5-hydroxypentyl)amino)-9H-purin-9-yl)-N,N-dimethylacetamide

[0275]

[0276] 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). After heating at 130 °C for 24 hours, the reaction mixture was cooled to room temperature. The reaction was quenched with water and extracted three times with dichloromethane. The organic layer was 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%). 1 1H NMR (500 MHz, DMSO-d6) δ 10.05 (s, 1H), 8.66 (s, 1H), 8.53 (s, 1H), 7.83 (s, 1H), 7.67 (d, J = 1.7 Hz, 1H), 6.96 (s, 1H), 4.98 (s, 2H), 3.30 (t, J = 7.1 Hz, 4H), 3.10 (s, 3H), 2.86 (s, 3H), 1.57 (p, J = 7.3 Hz, 2H), 1.45 (p, J = 6.6 Hz, 2H), 1.37 (dq, J = 10.8, 7.1, 5.3 Hz, 2H), 1.24 (d, J = 5.8 Hz, 1H). MS m / z (ESI): 501.13 [M+H] + 。

[0277] Example 36: 3-Bromo-5-((9-cyclopropyl-2-((trans-4-((2-(2-hydroxyethoxy)ethyl)amino)cyclohexyl)amino)-9H-purin-6-yl)amino)benzonitrile

[0278]

[0279] Dissolve 3-((2-(((trans-4-aminocyclohexyl)amino)-9-cyclopropyl-9H-purin-6-yl)amino)-5-bromobenzonitrile (23 mg, 0.10 mmol) (Reference Example 11) in dry DMF (3 mL), then successively add triethylamine (20 mg, 0.20 mmol) and 2-(2-bromoethoxy)ethan-1-ol (17 mg, 0.1 mmol), and react at room temperature for 12 hours. Quench with water, extract three times with dichloromethane, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (eluent CH2Cl2 / MeOH = 10 / 1) to obtain 9 mg of the product (yield 40%). 1 H NMR (500 MHz, DMSO) δ 9.99 (s, 1H), 8.79 (s, 1H), 8.23 (s, 1H), 7.88 (s, 1H), 7.66 (s, 1H), 6.87 (d, J = 10.0 Hz, 1H), 3.71 - 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

[0280]

[0281] Dissolve 3-((2-(((trans-4-aminocyclohexyl)amino)-9-isopropyl-9H-purin-6-yl)amino)-5-bromobenzonitrile (23 mg, 0.10 mmol) (Reference Example 30) in dry DMF (3 mL), then successively add triethylamine (20 mg, 0.20 mmol) and 2-(2-bromoethoxy)ethan-1-ol (17 mg, 0.1 mmol), and react at room temperature for 12 hours. Quench with water, extract three times with dichloromethane, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (eluent CH2Cl2 / MeOH = 10 / 1) to obtain 4 mg of the product (yield 20%). 11H NMR (500 MHz, DMSO) δ 10.03 (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] + 。

[0282] Example 38: 2-(6-((3-Bromo-5-cyanophenyl)amino)-2-((trans-4-hydroxycyclohexyl)amino)-9H-purin-9-yl)-N-methylacetamide

[0283]

[0284] Dissolve 2,6-dichloropurine (1.89 g, 10 mmol) in dry N,N-dimethylformamide (50 mL), add 2-bromo-N-methylacetamide (1.8 g, 12 mmol) and N,N-diisopropylethylamine (1.94 g, 15 mmol), and react at room temperature for 24 hours. Quench the reaction by adding saturated sodium bicarbonate solution, extract with dichloromethane three times, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography to obtain 2-(2,6-dichloro-9H-purin-9-yl)-N-methylacetamide 1.5 g (yield 58%), MS m / z (ESI): 260.01 [M + H] + 。

[0285] Dissolve 2-(2,6-dichloro-9H-purin-9-yl)-N-methylacetamide (1.5 g, 5.8 mmol) in dry sec-butanol (50 mL), add 3-amino-5-bromobenzonitrile (1.4 g, 7.0 mmol), and heat at 110 °C for 12 hours. Cool to room temperature, quench the reaction by adding saturated sodium bicarbonate solution. Extract with dichloromethane three times, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography to obtain 2-(6-((3-bromo-5-cyanophenyl)amino)-2-chloro-9H-purin-9-yl)-N-methylacetamide 700 mg (yield 35%), MS m / z (ESI): 420.00 [M + H] + 。

[0286] 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) was added trans-4-aminocyclohexan-1-ol (58 mg, 0.5 mmol) and triethylamine (0.14 mL, 1 mmol). After heating at 130 °C for 24 h, it was cooled to room temperature. The reaction 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 (yield 30%). 1 H NMR (500 MHz, DMSO-d6) δ 10.03 (s, 1H), 8.72 (s, 1H), 8.40 (s, 1H), 8.08 (s, 1H), 7.85 (s, 1H), 7.67 (t, J = 1.6 Hz, 1H), 6.77 - 6.66 (m, 1H), 4.67 (s, 2H), 4.50 (d, J = 4.2 Hz, 1H), 3.69 - 3.62 (m, 1H), 3.41 - 3.37 (m, 1H), 2.62 (d, J = 4.6 Hz, 3H), 1.92 (d, J = 11.3 Hz, 2H), 1.84 (d, J = 10.8 Hz, 2H), 1.39 - 1.25 (m, 4H). MS m / z (ESI): 499.13 [M+H] + 。

[0287] Example 39: 2-(2-(((trans-4-aminocyclohexyl)amino)-6-((3-bromo-5-cyanophenyl)amino)-9H-purin-9-yl)-N-methylacetamide

[0288]

[0289] 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) was added trans-1,4-cyclohexanediamine (58 mg, 0.5 mmol) and triethylamine (0.14 mL, 1 mmol). After heating at 130 °C for 24 h, it was cooled to room temperature. The reaction 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%). 11H NMR (500 MHz, DMSO-d6) δ 8.78 (s, 1H), 8.36 (s, 1H), 8.10 (s, 1H), 7.86 (s, 1H), 7.67 (d, J = 1.6 Hz, 1H), 6.77 (d, J = 8.1 Hz, 1H), 4.68 (s, 2H), 3.67 (s, 1H), 2.69 (s, 1H), 2.62 (d, J = 4.5 Hz, 3H), 1.96 (d, J = 10.0 Hz, 2H), 1.86 (d, J = 9.5 Hz, 2H), 1.32 (dd, J = 14.7, 5.5 Hz, 4H). MS m / z (ESI): 498.14 [M+H] + 。

[0290] Example 40: (R)-3-Bromo-5-((2-((1-hydroxybutan-2-yl)amino)-9-isopropyl-9H-purin-6-yl)amino)benzonitrile

[0291]

[0292] 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). After heating at 130 °C for 24 hours, the reaction mixture was cooled to room temperature. The reaction was quenched by adding water, and 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 (yield 57%). 1 1H NMR (500 MHz, DMSO) δ 9.97 (s, 1H), 8.57 (s, 1H), 8.02 (s, 1H), 7.66 (s, 1H), 6.46 (d, J = 10.0 Hz, 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, 5.0 Hz, 3H). MS m / z (ESI): 444.11 [M+H] + 。

[0293] Example 41: (R)-3-Bromo-5-((9-cyclopropyl-2-((1-hydroxybutan-2-yl)amino)-9H-purin-6-yl)amino)benzonitrile

[0294]

[0295] 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). After heating at 110 °C for 12 hours, the reaction mixture was cooled to room temperature. The reaction was quenched with water and extracted three times with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 50 / 1) to give 8 mg of the product (yield 40%). 1 1H NMR (500 MHz, DMSO) δ 9.97 (s, 1H), 8.59 (s, 1H), 8.50 (s, 1H), 7.88 (s, 1H), 7.66 (s, 1H), 6.56 (d, J = 10.0 Hz, 1H), 4.58 (s, 1H), 3.92 - 3.83 (m, 1H), 3.51 (d, J = 10.0, 5.0 Hz, 2H), 3.36 (s, 1H), 1.70 - 1.48 (m, 2H), 1.07 - 0.98 (m, 4H), 0.85 (dd, J = 10.0, 5.0 Hz, 3H). MS m / z (ESI): 442.10 [M+H] + Example 42: 3-bromo-5-((2-((cis-4-hydroxycyclohexyl)amino)-9-isopropyl-9H-purin-6-yl)amino)benzonitrile

[0296]

[0297] 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). After heating at 130 °C for 24 hours, the reaction mixture was cooled to room temperature. The reaction was quenched with water and extracted three times with dichloromethane. The organic layer was 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 40%). 1 1H NMR (500 MHz, DMSO) δ 9.98 (s, 1H), 8.59 (s, 2H), 8.02 (s, 1H), 7.65 (s, 1H), 6.71 (d, J = 10.0 Hz, 1H), 4.62 - 4.32 (m, 2H), 3.76 (s, 2H), 1.77 - 1.58 (m, 8H), 1.50 (d, J = 5.0 Hz, 3H). MS m / z (ESI): 470.13 [M+H] + 。

[0298] Example 43: 3-Bromo-5-((9-cyclopropyl-2-((cis-4-hydroxycyclohexyl)amino)-9H-purin-6-yl)amino)benzonitrile

[0299]

[0300] 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). After heating at 130 °C for 24 hours, the reaction mixture was cooled to room temperature. The reaction was quenched by adding water, and 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 5 mg of the product (yield 20%). 1 1H NMR (500 MHz, DMSO) δ 9.97 (s, 1H), 8.60 (s, 1H), 8.55 (s, 1H), 7.87 (s, 1H), 7.66 (s, 1H), 6.83 (d, J = 10.0 Hz, 1H), 4.32 (d, J = 5.0 Hz, 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] + 。

[0301] Example 44: 3-((2-(((trans-4-(benzylamino)cyclohexyl)amino)-9-isopropyl-9H-purin-6-yl)amino)-5-bromobenzonitrile

[0302]

[0303] 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). After heating at 130 °C for 24 hours, the reaction mixture was cooled to room temperature. The reaction was quenched by adding water, and 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 10 mg of the product (yield 18%). 11H NMR (500 MHz, DMSO-d6) δ 10.02 (s, 1H), 8.90 (s, 1H), 8.25 (s, 1H), 8.04 (s, 1H), 7.67 (d, J = 1.6 Hz, 1H), 7.54 (d, J = 7.3 Hz, 2H), 7.42 (dt, J = 14.4, 7.2 Hz, 2H), 6.77 (s, 1H), 4.65 - 4.53 (m, 1H), 4.11 (s, 2H), 3.72 (dtd, J = 11.6, 7.8, 4.1 Hz, 1H), 2.91 (s, 1H), 2.17 (d, J = 11.8 Hz, 2H), 2.09 (d, J = 10.8 Hz, 2H), 1.50 (d, J = 6.8 Hz, 8H), 1.39 - 1.27 (m, 2H). MS m / z (ESI): 559.20 [M + H] + 。

[0304] Example 45: (R)-3-Bromo-5-((2-((2,3-dihydroxypropyl)amino)-9-isopropyl-9H-purin-6-yl)amino)benzonitrile

[0305]

[0306] 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-aminopropane-1,2-diol (46 mg, 0.5 mmol) and triethylamine (0.140 mL, 1 mmol). After heating at 130 °C for 24 h, it was cooled to room temperature. The reaction 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 = 50 / 1) to give 15 mg of the product (yield 34%). 1 1H NMR (500 MHz, DMSO-d6) δ 9.99 (s, 1H), 8.58 (s, 2H), 8.03 (s, 1H), 7.66 (t, J = 1.6 Hz, 1H), 6.75 (s, 1H), 4.80 (s, 1H), 4.60 (td, J = 17.6, 15.5, 8.8 Hz, 1H), 3.71 (q, J = 5.5 Hz, 1H), 3.52 - 3.37 (m, 4H), 3.26 (dt, J = 12.9, 6.0 Hz, 1H), 1.51 (d, J = 6.7 Hz, 6H). MS m / z (ESI): 446.10 [M + H] + 。

[0307] Example 46: 3-Bromo-5-((9-cyclopropyl-2-(((cis-3-hydroxycyclobutyl)methyl)amino)-9H-purin-6-yl)amino)benzonitrile

[0308]

[0309] 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). After heating at 110 °C for 12 hours, the reaction mixture was cooled to room temperature. The reaction was quenched with water and extracted three times with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 50 / 1) to give 13 mg of the product (yield 6%). 1 1H NMR (500 MHz, DMSO-d6) δ 9.99 (s, 1H), 8.60 (d, J = 66.6 Hz, 2H), 7.88 (s, 1H), 7.66 (t, J = 1.6 Hz, 1H), 7.06 (t, J = 5.8 Hz, 1H), 4.88 (d, J = 6.3 Hz, 1H), 3.90 (d, J = 7.3 Hz, 1H), 3.51 (s, 1H), 2.33 - 2.21 (m, 2H), 2.09 - 1.95 (m, 1H), 1.56 (qd, J = 8.7, 2.9 Hz, 2H), 1.06 (d, J = 4.2 Hz, 2H), 1.01 (dd, J = 7.3, 4.9 Hz, 2H). MS m / z (ESI): 454.10 [M + H] + 。

[0310] Example 47: (S)-3-Bromo-5-((2-((2,3-dihydroxypropyl)amino)-9-isopropyl-9H-purin-6-yl)amino)benzonitrile

[0311]

[0312] 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 (S)-3-aminopropane-1,2-diol (46 mg, 0.5 mmol) and triethylamine (0.140 mL, 1 mmol). After heating at 130 °C for 24 hours, the reaction mixture was cooled to room temperature. The reaction was quenched with water and extracted three times with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 50 / 1) to give 7 mg of the product (yield 16%). 1HNMR (500 MHz, DMSO-d6) δ 9.99 (s, 1H), 8.58 (s, 2H), 8.03 (s, 1H), 7.66 (t, J = 1.6 Hz, 1H), 6.74 (s, 1H), 4.79 (s, 1H), 4.61 (p, J = 6.8 Hz, 1H), 4.55 (s, 1H), 3.71 (h, J = 5.3 Hz, 1H), 3.43 (ddq, J = 33.6, 11.0, 5.5 Hz, 4H), 3.26 (dt, J = 12.9, 6.1 Hz, 1H), 1.51 (d, J = 6.7 Hz, 6H). MS m / z (ESI): 446.09 [M+H] + 。

[0313] Example 48: (S)-3-Bromo-5-((9-cyclopropyl-2-((2,3-dihydroxypropyl)amino)-9H-purin-6-yl)amino)benzonitrile

[0314]

[0315] 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-aminopropane-1,2-diol (46 mg, 0.5 mmol) and triethylamine (0.140 mL, 1 mmol). After heating at 130 °C for 24 hours, it was cooled to room temperature. The reaction 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 20%). 1 HNMR (500 MHz, DMSO-d6) δ 9.99 (s, 1H), 8.57 (s, 2H), 7.89 (s, 1H), 7.66 (t, J = 1.6 Hz, 1H), 6.81 (s, 1H), 4.84 (s, 1H), 4.59 (s, 1H), 3.70 (dt, J = 6.8, 5.0 Hz, 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, 2.9 Hz, 2H), 1.04 - 0.97 (m, 2H). MS m / z (ESI): 444.08 [M+H] + 。

[0316] Example 49: 3-Bromo-5-((9-cyclopropyl-2-((3,4-dihydroxybutyl)amino)-9H-purin-6-yl)amino)benzonitrile

[0317]

[0318] 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). After heating at 130 °C for 24 hours, the reaction mixture was cooled to room temperature. The reaction was quenched with water and extracted three times with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 50 / 1) to obtain 10 mg of the product (yield 22%). 1 H NMR (500 MHz, DMSO-d6) δ 9.97 (s, 1H), 8.59 (d, J = 50.9 Hz, 2H), 7.88 (s, 1H), 7.65 (t, J = 1.7 Hz, 1H), 6.93 (s, 1H), 4.52 (s, 1H), 4.44 (t, J = 5.7 Hz, 1H), 3.58 (d, J = 7.1 Hz, 2H), 3.43 (q, J = 6.5 Hz, 3H), 3.39 - 3.33 (m, 2H), 3.29 (d, J = 5.3 Hz, 1H), 1.82 (ddq, J = 11.4, 7.5, 3.8 Hz, 1H), 1.55 - 1.46 (m, 1H), 1.07 (d, J = 4.1 Hz, 2H), 1.01 (dd, J = 7.5, 5.1 Hz, 2H). MS m / z (ESI): 458.10 [M+H] + 。

[0319] Example 50: 3-bromo-5-((9-isopropyl-2-((trans-4-morpholinocyclohexyl)amino)-9H-purin-6-yl)amino)benzonitrile

[0320]

[0321] 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). After heating at 110 °C for 12 hours, the reaction mixture was cooled to room temperature. The reaction was quenched with water and extracted three times with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 50 / 1) to obtain 14 mg of the product (yield 26%). 11H NMR (500 MHz, DMSO-d6) δ 9.99 (s, 1H), 8.78 - 8.43 (m, 2H), 8.03 (s, 1H), 7.66 (d, J = 1.7 Hz, 1H), 6.75 (s, 1H), 4.59 (p, J = 6.7 Hz, 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 = 6.8 Hz, 6H), 1.34 (d, J = 12.8 Hz, 2H). MS m / z (ESI): 539.18 [M + H] + 。

[0322] Example 51: 4 - ((6 - ((3 - Bromo - 5 - cyanophenyl)amino)-9 - isopropyl - 9H - purin - 2 - yl)amino)butyric acid

[0323]

[0324] 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). After heating at 130 °C for 24 hours, it was cooled to room temperature. The reaction 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 obtain 4 mg of the product (yield 5%). 1 1H NMR (500 MHz, DMSO-d6) δ 9.97 (s, 1H), 8.60 (d, J = 45.6 Hz, 2H), 8.01 (s, 1H), 7.64 (s, 1H), 6.97 (t, J = 5.8 Hz, 1H), 4.60 (p, J = 6.8 Hz, 1H), 2.24 (t, J = 7.6 Hz, 2H), 1.83 (q, J = 7.2 Hz, 2H), 1.50 (d, J = 6.8 Hz, 6H), 1.23 (s, 2H). MS m / z (ESI): 458.08 [M + H] + 。

[0325] Example 52: N6 - (3 - Amino - 5 - bromophenyl)-N2 - (trans - 4 - aminocyclohexyl)-9 - isopropyl - 9H - purine - 2,6 - diamine

[0326]

[0327] Dissolve 2,6-dichloro-9-isopropyl-9H-purine (115 mg, 0.5 mmol) in dry sec-butyl alcohol (5 mL), add 5-bromo-benzene-1,3-diamine (94 mg, 0.5 mmol), and heat at 110 °C for 12 hours. Cool to room temperature, and quench the reaction by adding saturated sodium bicarbonate solution. Extract with dichloromethane three times, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography to obtain 5-bromo-N1-(2-chloro-9-isopropyl-9H-purin-6-yl)benzene-1,3-diamine 70 mg (yield 30%), MS m / z (ESI): 381.02 [M+H] + .

[0328] 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-butyl alcohol (1 mL), add trans-1,4-cyclohexanediamine (58 mg, 0.5 mmol) and triethylamine (0.140 mL, 1 mmol), heat at 130 °C for 24 hours, and then cool to room temperature. Quench with water, extract with dichloromethane three times, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (eluent CH2Cl2 / MeOH = 50 / 1) to obtain the product 5 mg (yield 25%). 1 H NMR (500 MHz, DMSO) δ 9.33 (s, 1H), 8.05 (s, 4H), 6.42 (s, 1H), 4.61 - 4.55 (m, 1H), 4.48 (d, J = 5.0 Hz, 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] + .

[0329] Example 53: trans-3-((6-((3-bromo-5-cyanophenyl)amino)-9-cyclopropyl-9H-purin-2-yl)amino)cyclohexane-1-carboxamide

[0330]

[0331] 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). After heating at 110 °C for 12 hours, the reaction mixture was cooled to room temperature. The reaction was quenched by adding water, and the mixture was extracted with dichloromethane three times, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to obtain 20 mg of the product (yield 16%). 1 H NMR (500 MHz, DMSO-d6) δ 9.98 (s, 1H), 8.68 (s, 1H), 8.45 (s, 1H), 7.87 (s, 1H), 7.66 (t, J = 1.5 Hz, 1H), 7.14 (s, 1H), 6.91 (d, J = 8.4 Hz, 1H), 6.68 - 6.63 (m, 1H), 3.86 - 3.74 (m, 1H), 2.29 (d, J = 12.6 Hz, 1H), 2.01 - 1.94 (m, 2H), 1.76 (dd, J = 25.4, 13.1 Hz, 2H), 1.45 - 1.32 (m, 2H), 1.17 (d, J = 10.6 Hz, 2H), 1.06 (s, 2H), 1.02 - 0.98 (m, 2H). MS m / z (ESI): 495.13 [M + H] + 。

[0332] Example 54: trans-3-((6-((3-Bromo-5-cyanophenyl)amino)-9-isopropyl-9H-purin-2-yl)amino)cyclohexane-1-carboxamide

[0333]

[0334] 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). After heating at 130 °C for 24 hours, the reaction mixture was cooled to room temperature. The reaction was quenched by adding water, and the mixture was extracted with dichloromethane three times, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to obtain 22 mg of the product (yield 17%). 11H NMR (500 MHz, DMSO-d6) δ 9.98 (s, 1H), 8.66 (s, 1H), 8.48 (s, 1H), 8.02 (s, 1H), 7.66 (t, J = 1.6 Hz, 1H), 7.15 (s, 1H), 6.78 (d, J = 8.1 Hz, 1H), 6.65 (s, 1H), 4.59 (p, J = 6.8 Hz, 1H), 3.79 (dt, J = 7.7, 3.6 Hz, 1H), 2.29 (s, 1H), 1.99 (d, J = 11.7 Hz, 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, 10.5 Hz, 2H); MS m / z (ESI): 497.15 [M+H] + 。

[0335] Example 55: N2-(trans-4-Aminocyclohexyl)-N6-(3-bromo-5-methoxyphenyl)-9-cyclopropyl-9H-purine-2,6-diamine

[0336]

[0337] Dissolve 2,6-dichloro-9-cyclopropyl-9H-purine (50 mg, 0.22 mmol) (Reference Example 10) in dry sec-butanol (2 mL), add 3-bromo-5-methoxyaniline (132 m, 0.66 mmol), and heat at 110 °C for 12 hours. Cool to room temperature, quench the reaction with saturated sodium bicarbonate solution, extract three times with dichloromethane, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (eluent CH2Cl2 / MeOH = 100 / 1) to obtain 56 mg (yield 65%) of N-(3-bromo-5-methoxyphenyl)-2-chloro-9-cyclopropyl-9H-purine-6-amine, MS m / z (ESI): 394.01 [M+H] + 。

[0338] Add trans-1,4-cyclohexanediamine (44 mg, 0.38 mmol) and triethylamine (64 mg, 0.64 mmol) to a solution of N-(3-bromo-5-methoxyphenyl)-2-chloro-9-cyclopropyl-9H-purine-6-amine (50 mg, 0.13 mmol) in sec-butanol (1 mL), heat at 130 °C for 24 hours, and then cool to room temperature. Quench with water, extract three times with dichloromethane, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (eluent CH2Cl2 / MeOH = 20 / 1) to obtain 12 mg (yield 20%) of the product. 11H NMR (500 MHz, DMSO-d6) δ 9.53 (s, 1H), 8.15 (s, 1H), 7.83 (s, 1H), 7.53 (s, 1H), 6.74 (t, J = 2.0 Hz, 1H), 6.68 (s, 1H), 3.76 (s, 3H), 3.70 (ddd, J = 11.5, 7.9, 4.1 Hz, 1H), 2.86 (td, J = 10.6, 9.2, 5.4 Hz, 1H), 2.02 (d, J = 12.3 Hz, 2H), 1.94 (d, J = 11.7 Hz, 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, 5.0 Hz, 2H); MS m / z (ESI): 472.15 [M + H] + 。

[0339] Example 56: N2-(trans-4-Aminocyclohexyl)-N6-(3-bromo-5-methoxyphenyl)-9-isopropyl-9H-purine-2,6-diamine

[0340]

[0341] Dissolve 2,6-dichloro-9-isopropyl-9H-purine (80 mg, 0.28 mmol) in dry sec-butanol (2 mL), add 3-bromo-5-methoxyaniline (167 mg, 0.83 mmol), and heat at 110 °C for 12 h. Cool to room temperature, and quench the reaction with saturated sodium bicarbonate solution. Extract three times with dichloromethane, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (eluent CH2Cl2 / MeOH = 100 / 1) to obtain N-(3-bromo-5-methoxyphenyl)-2-chloro-9-isopropyl-9H-purine-6-amine 82 mg (yield 73%), MS m / z (ESI): 396.02 [M + H] + 。

[0342] To a solution of N-(3-bromo-5-methoxyphenyl)-2-chloro-9-isopropyl-9H-purine-6-amine (40 mg, 0.10 mmol) in sec-butanol (1 mL), add trans-1,4-cyclohexanediamine (35 mg, 0.30 mmol) and triethylamine (51 mg, 0.50 mmol), heat at 130 °C for 24 h, and then cool to room temperature. Quench with water, extract three times with dichloromethane, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (eluent CH2Cl2 / MeOH = 20 / 1) to obtain the product 12 mg (yield 25%). 11H NMR (500 MHz, DMSO-d6) δ 9.54 (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 = 7.9 Hz, 1H), 4.57 (p, J = 6.8 Hz, 1H), 3.77 (s, 3H), 3.70 (ddd, J = 11.4, 7.6, 3.9 Hz, 1H), 2.97 (tt, J = 11.4, 3.7 Hz, 1H), 2.10 - 2.03 (m, 2H), 2.00 (d, J = 12.3 Hz, 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] + 。

[0343] Example 57: trans-4-((6-((3-Bromo-5-methoxyphenyl)amino)-9-isopropyl-9H-purin-2-yl)amino)cyclohexan-1-ol

[0344]

[0345] 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). After heating at 130 °C for 24 hours, it was cooled to room temperature. The reaction 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 obtain 10 mg of the product (yield 21%). 1 1H NMR (500 MHz, DMSO-d6) δ 9.50 (s, 1H), 7.96 (s, 1H), 7.58 (s, 1H), 6.74 (t, J = 2.0 Hz, 1H), 6.45 (d, J = 8.1 Hz, 1H), 4.57 (p, J = 6.8 Hz, 1H), 4.48 (d, J = 4.4 Hz, 1H), 3.76 (s, 3H), 1.94 (d, J = 11.0 Hz, 2H), 1.84 (d, J = 10.3 Hz, 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] + 。

[0346] Example 58: 3-((2-(((trans-4-Aminocyclohexyl)amino)-9-cyclopropyl-9H-purin-6-yl)amino)-5-(trifluoromethyl)benzonitrile

[0347]

[0348] Dissolve 2,6-dichloro-9-cyclopropyl-9H-purine (100 mg, 0.44 mmol) (Reference Example 10) in dry sec-butanol (2 mL), add 3-amino-5-(trifluoromethyl)benzonitrile (244 mg, 1.32 mmol), and heat at 110 °C for 12 hours. Cool to room temperature, and quench the reaction with saturated sodium bicarbonate solution. Extract three times with dichloromethane, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (eluent CH2Cl2 / MeOH = 100 / 1) to obtain 3-((2-chloro-9-cyclopropyl-9H-purin-6-yl)amino)-5-(trifluoromethyl)benzonitrile 100 mg (yield 60%), MS m / z (ESI): 379.07 [M+H] + 。

[0349] Add trans-1,4-cyclohexanediamine (45 mg, 0.40 mmol) and triethylamine (67 mg, 0.66 mmol) 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), heat at 130 °C for 24 hours, and then cool to room temperature. Quench with water, extract three times with dichloromethane, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (eluent CH2Cl2 / MeOH = 20 / 1) to obtain the product 8 mg (yield 13%). 1 HNMR (500 MHz, DMSO-d6) δ 10.12 (s, 1H), 8.67 (s, 2H), 7.90 (s, 1H), 7.84 (s, 1H), 6.83 (d, J = 8.0 Hz, 1H), 3.69 (s, 1H), 2.86 (s, 1H), 2.02 (d, J = 8.4 Hz, 2H), 1.95 (s, 2H), 1.36 (q, J = 7.5, 5.0 Hz, 4H), 1.27 - 1.21 (m, 2H), 1.10 - 1.04 (m, 2H), 1.01 (dd, J = 7.5, 5.1 Hz, 2H); MS m / z (ESI): 457.20 [M+H] + 。

[0350] Example 59: 3-((9-Cyclopropyl-2-((trans-4-hydroxycyclohexyl)amino)-9H-purin-6-yl)amino)-5-(trifluoromethyl)benzonitrile

[0351]

[0352] 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). After heating at 110 °C for 12 h, the reaction mixture was cooled to room temperature. The reaction was quenched with water and extracted three times with dichloromethane. The organic layer was 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 1H NMR (500 MHz, DMSO-d6) δ 10.13 (s, 1H), 8.73 (s, 2H), 7.89 (s, 1H), 7.84 (s, 1H), 6.76 (d, J = 8.2 Hz, 1H), 4.50 (d, J = 3.8 Hz, 1H), 3.69 (d, J = 10.2 Hz, 1H), 3.35 (s, 1H), 1.92 (s, 2H), 1.83 (d, J = 10.4 Hz, 2H), 1.30 (q, J = 13.8 Hz, 4H), 1.07 (s, 2H), 1.00 (dd, J = 7.3, 5.0 Hz, 2H); MS m / z (ESI): 458.20 [M+H] + 。

[0353] Example 60: 3-Bromo-5-((9-isopropyl-2-((trans-4-(piperidin-1-yl)cyclohexyl)amino)-9H-purin-6-yl)amino)benzonitrile

[0354]

[0355] 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)cyclohexan-1-amine hydrochloride (109 mg, 0.50 mmol) and triethylamine (101 mg, 1 mmol). After heating at 130 °C for 24 h, the reaction mixture was cooled to room temperature. The reaction was quenched with water and extracted three times with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 10 / 1) to give 14 mg of the product (yield 26%). 11H NMR (500 MHz, DMSO-d6) δ 10.03 (s, 1H), 9.81 (s, 1H), 8.57 (s, 2H), 8.04 (s, 1H), 7.67 (s, 1H), 6.83 (d, J = 7.8 Hz, 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 = 12.0 Hz, 4H), 1.79 (s, 3H), 1.66 (s, 3H), 1.50 (d, J = 6.8 Hz, 6H), 1.38 (q, J = 12.3 Hz, 3H). MS m / z (ESI): 537.22 [M+H] + 。

[0356] Example 61: 3-Bromo-5-((9-cyclopropyl-2-((trans-4-(piperidin-1-yl)cyclohexyl)amino)-9H-purin-6-yl)amino)benzonitrile

[0357]

[0358] 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). After heating at 130 °C for 24 hours, the reaction mixture was cooled to room temperature. The reaction was quenched with water and extracted three times with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 10 / 1) to give 11 mg of the product (yield: 21%). 1 1H NMR (500 MHz, DMSO-d6) δ 10.03 (s, 1H), 9.80 (s, 1H), 8.57 (d, J = 16.4 Hz, 2H), 7.89 (s, 1H), 7.68 (d, J = 1.6 Hz, 1H), 6.97 (s, 1H), 3.71 (d, J = 8.5 Hz, 1H), 3.15 (s, 1H), 2.92 (s, 2H), 2.13 (d, J = 11.8 Hz, 4H), 1.79 (s, 4H), 1.66 (d, J = 12.9 Hz, 3H), 1.38 (q, J = 12.1 Hz, 3H), 1.06 (s, 2H), 1.03 - 0.93 (m, 2H). MS m / z (ESI): 535.20 [M+H] + 。

[0359] Example 62: 3-Bromo-5-((2-(((3-hydroxyoxetan-3-yl)methyl)amino)-9-isopropyl-9H-purin-6-yl)amino)benzonitrile

[0360]

[0361] 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). After heating at 130 °C for 24 hours, the reaction mixture was cooled to room temperature. The reaction was quenched by adding water, and the mixture was 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 22%). 1 1H NMR (500 MHz, DMSO-d6) δ 10.03 (s, 1H), 8.58 (d, J = 18.9 Hz, 2H), 8.04 (s, 1H), 7.66 (t, J = 1.6 Hz, 1H), 6.93 (s, 1H), 5.95 (s, 1H), 4.61 (p, J = 6.8 Hz, 1H), 4.51 (d, J = 6.2 Hz, 2H), 4.41 (d, J = 6.2 Hz, 2H), 3.70 (d, J = 6.1 Hz, 2H), 1.51 (d, J = 6.8 Hz, 6H). MS m / z (ESI): 458.09 [M+H] + 。

[0362] Example 63: 3-Bromo-5-((9-cyclopropyl-2-(((3-hydroxyoxetan-3-yl)methyl)amino)-9H-purin-6-yl)amino)benzonitrile

[0363]

[0364] 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). After heating at 130 °C for 24 hours, the reaction mixture was cooled to room temperature. The reaction was quenched by adding water, and the mixture was 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 22%). 11H NMR (500 MHz, DMSO-d6) δ 10.03 (s, 1H), 8.57 (s, 2H), 7.91 (s, 1H), 7.66 (t, J = 1.5 Hz, 1H), 7.02 (s, 1H), 6.04 (s, 1H), 4.51 (d, J = 6.2 Hz, 2H), 4.42 (d, J = 6.3 Hz, 2H), 3.71 (d, J = 6.0 Hz, 2H), 3.37 (tt, J = 7.3, 3.9 Hz, 1H), 1.09 - 1.04 (m, 2H), 1.01 (dddd, J = 8.1, 6.8, 5.2, 2.2 Hz, 2H). MS m / z (ESI): 456.08 [M+H] + 。

[0365] Example 64: 3-Bromo-5-((9-isopropyl-2-((2-(4-methylpiperazin-1-yl)ethyl)amino)-9H-purin-6-yl)amino)benzonitrile

[0366]

[0367] To a solution of 3-bromo-5-((2-chloro-9-isopropyl-9H-purin-6-yl)amino)benzonitrile (39 mg, 0.10 mmol) in sec-butanol (1 mL) of Reference Example 1), 2-(4-methylpiperazin-1-yl)ethan-1-amine (72 mg, 0.50 mmol) and triethylamine (101 mg, 1 mmol) were added. After heating at 130 °C for 24 hours, it was cooled to room temperature. 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 obtain 5 mg of the product (yield 21%). 1 1H NMR (500 MHz, DMSO-d6) δ 9.97 (s, 1H), 8.56 (d, J = 23.2 Hz, 2H), 8.02 (s, 1H), 7.66 (s, 1H), 6.71 (s, 1H), 4.61 (p, J = 6.8 Hz, 1H), 3.44 (q, J = 6.5 Hz, 2H), 2.61 - 2.54 (m, 4H), 2.44 (s, 4H), 2.22 (s, 3H), 1.51 (d, J = 6.7 Hz, 6H). MS m / z (ESI): 498.15 [M+H] + 。

[0368] Example 65: 3-Bromo-5-((9-cyclopropyl-2-((2-(4-methylpiperazin-1-yl)ethyl)amino)-9H-purin-6-yl)amino)benzonitrile

[0369]

[0370] To a solution of 3-bromo-5-((2-chloro-9-cyclopropyl-9H-purin-6-yl)amino)benzonitrile (39 mg, 0.10 mmol) in sec-butanol (1 mL) of Reference Example 10), 2-(4-methylpiperazin-1-yl)ethan-1-amine (72 mg, 0.50 mmol) and triethylamine (101 mg, 1 mmol) were added. After heating at 130 °C for 24 hours, it was cooled to room temperature. The reaction 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 obtain 3 mg of the product (yield 13%). 1 HNMR (500 MHz, DMSO-d6) δ 9.97 (s, 1H), 8.55 (d, J = 36.3 Hz, 2H), 7.89 (s, 1H), 7.66 (t, J = 1.6 Hz, 1H), 6.80 (s, 1H), 3.45 (q, J = 6.5 Hz, 2H), 3.36 (q, J = 3.4 Hz, 1H), 2.56 (s, 4H), 2.45 (s, 4H), 2.25 (s, 3H), 1.07 (q, J = 4.3 Hz, 2H), 1.01 (dd, J = 7.4, 5.0 Hz, 2H). MS m / z (ESI): 496.15 [M+H] + 。

[0371] Example 66: 3-bromo-5-((9-isopropyl-2-((2-(2-oxoimidazolidin-1-yl)ethyl)amino)-9H-purin-6-yl)amino)benzonitrile

[0372]

[0373] To a solution of 3-bromo-5-((2-chloro-9-isopropyl-9H-purin-6-yl)amino)benzonitrile (39 mg, 0.10 mmol) in sec-butanol (1 mL) of Reference Example 1), 1-(2-aminoethyl)imidazolidin-2-one (66 mg, 0.50 mmol) and triethylamine (101 mg, 1 mmol) were added. After heating at 130 °C for 24 hours, it was cooled to room temperature. The reaction 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 obtain 11 mg of the product (yield 23%). 1HNMR (500 MHz, DMSO-d6) δ 9.98 (s, 1H), 8.57 (d, J = 28.5 Hz, 2H), 8.03 (s, 1H), 7.65 (t, J = 1.7 Hz, 1H), 6.94 (s, 1H), 6.23 (s, 1H), 4.62 (p, J = 6.7 Hz, 1H), 3.47 - 3.39 (m, 4H), 3.28 (s, 1H), 3.24 - 3.17 (m, 2H), 1.51 (d, J = 6.8 Hz, 6H). MS m / z (ESI): 484.13 [M+H] + 。

[0374] Example 67: 3 - ((2 - (((trans - 4 - aminocyclohexyl)amino)-9 - isopropyl - 9H - purin - 6 - yl)amino)-5 - (trifluoromethyl)benzonitrile

[0375]

[0376] Dissolve 2,6 - dichloro - 9 - isopropyl - 9H - purine (100 mg, 0.44 mmol) in dry sec - butanol (2 mL), add 3 - amino - 5 - (trifluoromethyl)benzonitrile (244 mg, 1.32 mmol), and heat at 110 °C for 12 h. Cool to room temperature, and quench the reaction with saturated sodium bicarbonate solution. Extract three times with dichloromethane, dry over anhydrous sodium sulfate, filter, concentrate, and purify by column chromatography (eluent CH2Cl2 / MeOH = 100 / 1) to obtain 3 - ((2 - chloro - 9 - isopropyl - 9H - purin - 6 - yl)amino)-5 - (trifluoromethyl)benzonitrile 110 mg (yield 63%), MS m / z (ESI): 381.08 [M+H] + 。

[0377] Add trans - 1,4 - cyclohexanediamine (45 mg, 0.40 mmol) and triethylamine (66 mg, 0.65 mmol) 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), heat at 130 °C for 24 h, and then cool to room temperature. Quench with water, extract three times with dichloromethane, dry over anhydrous sodium sulfate, filter, concentrate, and purify by column chromatography (eluent CH2Cl2 / MeOH = 10 / 1) to obtain the product 10 mg (yield 17%). 11H NMR (500 MHz, DMSO-d6) δ 10.14 (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 = 6.8 Hz, 1H), 3.73 - 3.59 (m, 1H), 2.97 (s, 1H), 2.03 (dd, J = 23.7, 11.2 Hz, 4H), 1.52 (s, 3H), 1.51 (s, 3H), 1.40 (pd, J = 12.7, 6.2 Hz, 4H); MS m / z (ESI): 459.23 [M+H] + 。

[0378] Example 68: 3-Bromo-5-((2-((((trans)-4-cyanohexyl)amino)-9-cyclopropyl-9H-purin-6-yl)amino)benzonitrile

[0379]

[0380] 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). After heating at 130 °C for 24 hours, the reaction mixture was cooled to room temperature. The reaction 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 17%). 1 1H NMR (500 MHz, DMSO-d6) δ 9.98 (s, 1H), 8.54 (d, J = 15.3 Hz, 2H), 7.88 (s, 1H), 7.68 (d, J = 1.6 Hz, 1H), 6.92 (d, J = 7.8 Hz, 1H), 3.74 (dt, J = 14.7, 5.5 Hz, 2H), 2.68 (tt, J = 11.7, 3.7 Hz, 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, 4.4 Hz, 2H), 1.00 (dd, J = 7.3, 5.0 Hz, 2H). MS m / z (ESI): 477.11 [M+H] + 。

[0381] Example 69: 3-((2-(((trans-4-aminocyclohexyl)amino)-9-isopropyl-9H-purin-6-yl)amino)-5-methoxybenzonitrile

[0382]

[0383] Dissolve 2,6-dichloro-9-isopropyl-9H-purine (100 mg, 0.44 mmol) in dry sec-butanol (2 mL), add 3-amino-5-methoxybenzonitrile (153 mg, 1.03 mmol), and heat at 110 °C for 12 h. Cool to room temperature, and quench the reaction by adding saturated sodium bicarbonate solution. Extract three times with dichloromethane, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (eluent CH2Cl2 / MeOH = 100 / 1) to obtain 3-((2-chloro-9-isopropyl-9H-purin-6-yl)amino)-5-methoxybenzonitrile 120 mg (yield 81%), MS m / z (ESI): 343.11 [M+H] + 。

[0384] 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), add trans-1,4-cyclohexanediamine (50 mg, 0.45 mmol) and triethylamine (73 mg, 0.73 mmol), heat at 130 °C for 24 h, and then cool to room temperature. Quench with water, extract three times with dichloromethane, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (eluent CH2Cl2 / MeOH = 10 / 1) to obtain the product 11 mg (yield 18%). 1 H NMR (500 MHz, DMSO-d6) δ 9.72 (s, 1H), 8.12 (s, 1H), 7.98 (s, 1H), 7.94 (t, J = 2.2 Hz, 1H), 7.01 (t, J = 1.8 Hz, 1H), 6.63 (d, J = 7.7 Hz, 1H), 4.58 (p, J = 6.7 Hz, 1H), 3.82 (s, 3H), 3.66 (d, J = 8.9 Hz, 1H), 2.82 (s, 1H), 2.03 (d, J = 9.7 Hz, 2H), 1.93 (d, J = 9.6 Hz, 2H), 1.51 (s, 3H), 1.50 (s, 3H), 1.36 (q, J = 10.4, 9.6 Hz, 4H); MS m / z (ESI): 421.25 [M+H] + 。

[0385] Example 70: 3-((2-(((trans-4-hydroxycyclohexyl)amino)-9-isopropyl-9H-purin-6-yl)amino)-5-methoxybenzonitrile

[0386]

[0387] 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). After heating at 130 °C for 24 hours, the reaction mixture was cooled to room temperature. The reaction was quenched by adding water, and 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 12 mg of the product (yield 20%). 1 H NMR (500 MHz, DMSO-d6) δ 10.13 (s, 1H), 8.71 (s, 2H), 8.03 (s, 1H), 7.83 (s, 1H), 6.63 (d, J = 8.2 Hz, 1H), 4.59 (p, J = 6.7 Hz, 1H), 4.50 (d, J = 3.9 Hz, 1H), 3.69 (s, 1H), 3.41 (s, 1H), 1.93 (d, J = 11.1 Hz, 2H), 1.84 (d, J = 10.5 Hz, 2H), 1.51 (s, 3H), 1.50 (s, 3H), 1.35 - 1.28 (m, 4H); MS m / z (ESI): 460.22 [M + H] + 。

[0388] Example 71: 3-((2-((trans-4-aminocyclohexyl)amino)-9-cyclopropyl-9H-purin-6-yl)amino)-5-methoxybenzonitrile

[0389]

[0390] 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. 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 125 mg of 3-((2-chloro-9-cyclopropyl-9H-purin-6-yl)amino)-5-methoxybenzonitrile (yield 84%), MS m / z (ESI): 341.09 [M + H] + 。

[0391] 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) were added trans-1,4-cyclohexanediamine (50 mg, 0.45 mmol) and triethylamine (74 mg, 0.73 mmol). After heating at 130 °C for 24 h, the reaction mixture was cooled to room temperature. The reaction was quenched with water and extracted with dichloromethane three times. The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 10 / 1) to give 15 mg of the product (yield 24%). 1 H NMR (500 MHz, DMSO-d6) δ 9.72 (s, 1H), 8.09 (s, 1H), 7.94 (s, 1H), 7.85 (s, 1H), 7.01 (t, J = 1.8 Hz, 1H), 6.75 (d, J = 7.6 Hz, 1H), 3.82 (s, 3H), 3.67 (s, 1H), 2.83 (s, 1H), 2.02 (d, J = 10.8 Hz, 2H), 1.94 (d, J = 10.3 Hz, 2H), 1.44 - 1.29 (m, 5H), 1.07 (s, 2H), 1.00 (dd, J = 7.4, 5.0 Hz, 2H); MS m / z (ESI): 419.23 [M + H] + 。

[0392] Example 72: 3-((9-Cyclopropyl-2-((trans-4-hydroxycyclohexyl)amino)-9H-purin-6-yl)amino)-5-methoxybenzonitrile

[0393]

[0394] 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). After heating at 110 °C for 24 h, the reaction mixture was cooled to room temperature. The reaction was quenched with water and extracted with dichloromethane three times. The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 10 / 1) to give 12 mg of the product (yield 20%). 11H NMR (500 MHz, DMSO-d6) δ 9.70 (s, 1H), 8.16 (t, J = 1.6 Hz, 1H), 7.97 (s, 1H), 7.92 (t, J = 2.2 Hz, 1H), 7.01 (dd, J = 2.4, 1.2 Hz, 1H), 6.55 (d, J = 7.8 Hz, 1H), 4.58 (p, J = 6.7 Hz, 1H), 4.49 (d, J = 4.1 Hz, 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] + 。

[0395] Example 73: 3 - ((9 - Cyclopropyl - 2 - ((2 - (4 - methylpiperazin - 1 - yl)ethyl)amino)-9H - purin - 6 - yl)amino)-5 - (trifluoromethyl)benzonitrile

[0396]

[0397] 2,6 - Dichloro - 9 - cyclopropyl - 9H - purine (100 mg, 0.44 mmol) 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 h. After cooling to room temperature, the reaction was quenched with saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane three times, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent CH2Cl2 / MeOH = 100 / 1) to obtain 100 mg of 3 - ((2 - chloro - 9 - cyclopropyl - 9H - purin - 6 - yl)amino)-5 - (trifluoromethyl)benzonitrile (yield 60%), MS m / z (ESI): 379.07 [M+H] + 。

[0398] 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). After heating at 130 °C for 24 h, the mixture was cooled to room temperature. The reaction was quenched with water, extracted with dichloromethane three times, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent CH2Cl2 / MeOH = 20 / 1) to obtain 16 mg of the product (yield 25%). 11H NMR (500 MHz, DMSO-d6) δ 10.17 (s, 1H), 8.77 (d, J = 28.7 Hz, 2H), 7.91 (s, 1H), 7.83 (s, 1H), 6.78 (t, J = 5.7 Hz, 1H), 3.45 (q, J = 6.4 Hz, 3H), 2.59 - 2.52 (m, 3H), 2.44 (s, 5H), 2.22 (s, 3H), 1.07 (q, J = 4.3 Hz, 2H), 1.04 - 0.98 (m, 2H). MS m / z (ESI): 486.24 [M+H] + 。

[0399] Example 74: 3 - ((6 - ((3 - Bromo - 5 - cyanophenyl)amino)-9 - isopropyl - 9H - purin - 2 - yl)amino)-N - methylpropanamide

[0400]

[0401] 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 - aminopropyl - N - methylamide (51 mg, 0.50 mmol) and triethylamine (101 mg, 1 mmol). After heating at 130 °C for 24 h, the reaction mixture was cooled to room temperature. The reaction 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 give 7 mg of the product (yield 31%). 1 1H NMR (500 MHz, DMSO) δ 9.97 (s, 1H), 8.60 (s, 1H), 8.55 (s, 1H), 8.03 (s, 1H), 7.73 (d, J = 5.0 Hz, 1H), 7.65 (s, 1H), 4.65 - 4.59 (m, 1H), 3.55 - 3.51 (m, 2H), 2.57 (d, J = 5.0 Hz, 3H), 2.42 (dd, J = 10.0, 5.0 Hz, 2H), 1.51 (d, J = 10.0 Hz, 1H). MS m / z (ESI): 457.11 [M+H] + 。

[0402] Example 75: 3 - ((6 - ((3 - Bromo - 5 - cyanophenyl)amino)-9 - cyclopropyl - 9H - purin - 2 - yl)amino)-N - methylpropanamide

[0403]

[0404] 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-methylpropanamide (51 mg, 0.50 mmol) and triethylamine (101 mg, 1 mmol). After heating at 130 °C for 24 hours, it was cooled to room temperature. The reaction 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 obtain 3 mg of the product (yield 13%). 1 H NMR (500 MHz, DMSO) δ 9.97 (s, 1H), 8.62 (s, 1H), 8.52 (s, 1H), 7.89 (s, 1H), 7.73 (d, J = 5.0 Hz, 1H), 7.65 (s, 1H), 3.56 - 3.51 (m, 2H), 3.39 (s, 1H), 2.58 (d, J = 5.0 Hz, 3H), 2.43 (dd, J = 10.0, 5.0 Hz, 2H), 1.08 - 0.99 (m, 4H). MS m / z (ESI): 455.09 [M + H] + 。

[0405] Example 76: 4-((6-((3-Bromo-5-cyanophenyl)amino)-9-isopropyl-9H-purin-2-yl)amino)cyclohexane-1-carboxylic acid

[0406]

[0407] 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). After heating at 130 °C for 24 hours, it was cooled to room temperature. The reaction 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 obtain 5 mg of the product (yield 20%). 1 H NMR (500 MHz, DMSO) δ 11.94 (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] + 。

[0408] Example 77: 3-Bromo-5-((9-cyclopropyl-2-((2-(4-hydroxypiperidin-1-yl)ethyl)amino)-9H-purin-6-yl)amino)benzonitrile

[0409]

[0410] 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). After heating at 110 °C for 12 hours, the reaction mixture was cooled to room temperature. The reaction was quenched by adding water, and the mixture was 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 HNMR (500 MHz, DMSO-d6) δ 9.99 (s, 1H), 8.56 (d, J = 42.9 Hz, 2H), 7.89 (s, 1H), 7.66 (t, J = 1.6 Hz, 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, 5.1 Hz, 2H), 1.04 - 0.93 (m, 2H). MS m / z (ESI): 497.14 [M+H] + 。

[0411] Example 78: 3-Bromo-5-((9-cyclopropyl-2-((2-(piperidin-2-yl)ethyl)amino)-9H-purin-6-yl)amino)benzonitrile

[0412]

[0413] 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-aminoethyl)piperidine-1-carboxylate (144 mg, 1 mmol) and triethylamine (202 mg, 2 mmol). After heating at 130 °C for 24 hours, the reaction mixture was cooled to room temperature. The reaction 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 = 50 / 1) to give 63 mg (yield 54%) of intermediate tert-butyl 2-(2-((6-((3-bromo-5-cyanophenyl)amino)-9-cyclopropyl-9H-purin-2-yl)amino)ethyl)piperidine-1-carboxylate.

[0414] To a solution of 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) in ethyl acetate solution of 6N HCl (2 mL) was added and stirred at room temperature for 12 hours. The solvent was removed under reduced pressure, and saturated sodium bicarbonate solution was added to neutralize the 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 give 23 mg (yield 68%) of the product. 1 1H NMR (500 MHz, DMSO-d6) δ 9.98 (s, 1H), 8.58 (d, J = 43.3 Hz, 2H), 7.88 (s, 1H), 7.66 (t, J = 1.6 Hz, 1H), 7.03 (s, 1H), 3.46 - 3.34 (m, 5H), 2.88 (d, J = 11.8 Hz, 1H), 2.45 (td, J = 11.6, 2.8 Hz, 1H), 1.73 - 1.67 (m, 1H), 1.59 (td, J = 13.4, 7.0 Hz, 3H), 1.48 - 1.42 (m, 1H), 1.30 - 1.22 (m, 2H), 1.06 (q, J = 4.4 Hz, 2H), 1.04 - 0.96 (m, 2H). MS m / z (ESI): 481.15 [M+H] + 。

[0415] Example 79: 3-Bromo-5-((9-isopropyl-2-((2-oxopiperidin-3-yl)amino)-9H-purin-6-yl)amino)benzonitrile

[0416]

[0417] 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). After heating at 130 °C for 24 hours, the reaction mixture was cooled to room temperature. The reaction was quenched by adding water, and the mixture was extracted with dichloromethane three times, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to obtain 6 mg of the product (yield 13%). 1 H NMR (500 MHz, DMSO-d6) δ 10.02 (s, 1H), 8.55 (t, J = 1.9 Hz, 2H), 8.04 (s, 1H), 7.67 (s, 1H), 7.58 (s, 1H), 6.89 (s, 1H), 4.61 (p, J = 6.7 Hz, 1H), 4.30 (s, 1H), 3.20 (s, 2H), 2.17 (s, 1H), 1.87 (s, 3H), 1.51 (d, J = 6.7 Hz, 6H). MS m / z (ESI): 469.11 [M+H] + 。

[0418] Example 80: 3-bromo-5-(((2-cis-4-hydroxytetrahydrofuran-3-yl)methyl)amino)-9-isopropyl-9H-purin-6-yl)amino)benzonitrile

[0419]

[0420] 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). After heating at 130 °C for 24 hours, the reaction mixture was cooled to room temperature. The reaction was quenched by adding water, and the mixture was extracted with dichloromethane three times, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to obtain 13 mg of the product (yield 28%). 11H NMR (500 MHz, DMSO-d6) δ 10.01 (s, 1H), 8.57 (s, 2H), 8.04 (s, 1H), 7.67 (t, J = 1.6 Hz, 1H), 6.90 (s, 1H), 5.02 (s, 1H), 4.60 (p, J = 6.8 Hz, 1H), 4.26 (s, 1H), 3.85 (t, J = 7.8 Hz, 1H), 3.79 (dd, J = 9.2, 3.9 Hz, 1H), 3.61 (dd, J = 9.3, 1.3 Hz, 1H), 3.49 (ddd, J = 11.7, 9.1, 6.6 Hz, 2H), 3.45 - 3.38 (m, 1H), 2.48 - 2.39 (m, 1H), 1.51 (d, J = 6.8 Hz, 6H). MS m / z (ESI): 472.12 [M+H] + 。

[0421] Example 81: 3-Bromo-5-((9-cyclopropyl-2-(((cis-4-hydroxytetrahydrofuran-3-yl)methyl)amino)-9H-purin-6-yl)amino)benzonitrile

[0422]

[0423] 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). After heating at 130 °C for 24 hours, the reaction mixture was cooled to room temperature. The reaction 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 give 11 mg of the product (yield 23%). 1 1H NMR (500 MHz, DMSO-d6) δ 10.01 (s, 1H), 8.56 (s, 2H), 7.90 (s, 1H), 7.67 (t, J = 1.6 Hz, 1H), 7.02 (s, 1H), 4.26 (s, 1H), 3.86 (t, J = 7.8 Hz, 1H), 3.79 (dd, J = 9.2, 3.9 Hz, 1H), 3.62 (dd, J = 9.2, 1.1 Hz, 1H), 3.54 - 3.46 (m, 2H), 3.43 - 3.34 (m, 3H), 2.44 (s, 1H), 1.06 (t, J = 3.0 Hz, 2H), 1.04 - 0.98 (m, 2H). MS m / z (ESI): 470.10 [M+H] + 。

[0424] Example 82: 3-Bromo-5-((2-((cis-4-(hydroxymethyl)cyclopent-2-en-1-yl)amino)-9-isopropyl-9H-purin-6-yl)amino)benzonitrile

[0425]

[0426] 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). After heating at 110 °C for 12 hours, the reaction mixture was cooled to room temperature. The reaction was quenched with water and extracted three times with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to obtain 10 mg of the product (yield 21%). 1 1H NMR (500 MHz, DMSO-d6) δ 10.01 (s, 1H), 8.57 (s, 2H), 8.04 (s, 1H), 7.65 (t, J = 1.6 Hz, 1H), 6.88 (s, 1H), 5.86 (s, 2H), 4.94 (q, J = 7.2 Hz, 1H), 4.61 (t, J = 5.3 Hz, 2H), 3.39 (t, J = 5.9 Hz, 2H), 2.76 (h, J = 7.1, 6.6 Hz, 1H), 2.49 - 2.42 (m, 1H), 1.51 (d, J = 6.7 Hz, 6H), 1.38 (dt, J = 13.1, 6.6 Hz, 1H). MS m / z (ESI): 468.12 [M+H] + 。

[0427] Example 83: 3-((2-((4-aminophenyl)amino)-9-cyclopropyl-9H-purin-6-yl)amino)-5-(trifluoromethyl)benzonitrile

[0428]

[0429] Dissolve 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) in dry 1,4-dioxane (1 mL), then successively add palladium acetate (6 mg, 0.026 mmol), Xanphos (16 mg, 0.026 mmol) and cesium carbonate (258 mg, 0.80 mmol), heat at 120 °C for 4 hours, and then cool to room temperature. Quench with water, extract three times with dichloromethane, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (eluent petroleum ether / ethyl acetate = 1 / 1) to obtain 5 mg of the product (yield 4%). 1 HNMR(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] + 。

[0430] Example 84: 3-((2-(((3-(benzylamino)oxetan-3-yl)methyl)amino)-9-isopropyl-9H-purin-6-yl)amino)-5-bromobenzonitrile

[0431]

[0432] Add 3-(aminomethyl)-N-benzyloxetan-3-amine (96 mg, 0.50 mmol) and triethylamine (101 mg, 1 mmol) 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), heat at 130 °C for 24 hours, and then cool to room temperature. Quench with water, extract three times with dichloromethane, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (eluent CH2Cl2 / MeOH = 20 / 1) to obtain 13 mg of the product (yield 28%). 11H NMR (500 MHz, DMSO-d6) δ 10.05 (s, 1H), 8.60 (d, J = 28.5 Hz, 2H), 8.05 (s, 1H), 7.67 (t, J = 1.6 Hz, 1H), 7.32 (d, J = 7.5 Hz, 2H), 7.26 (t, J = 7.5 Hz, 2H), 7.21 - 7.14 (m, 1H), 6.79 (s, 1H), 4.59 (q, J = 6.8 Hz, 1H), 4.51 (d, J = 6.1 Hz, 2H), 4.39 (d, J = 6.1 Hz, 2H), 3.87 - 3.77 (m, 4H), 2.78 (s, 1H), 1.48 (d, J = 6.8 Hz, 6H). MS m / z (ESI): 547.16 [M+H] + 。

[0433] Example 85: (S)-3-Bromo-5-((9-cyclopropyl-2-((2-fluoro-3-hydroxypropyl)amino)-9H-purin-6-yl)amino)benzonitrile

[0434]

[0435] 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). After heating at 130 °C for 24 hours, it was cooled to room temperature. The reaction 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 16%). 1 1H NMR (500 MHz, DMSO-d6) δ 10.02 (s, 1H), 8.55 (s, 2H), 7.92 (s, 1H), 7.67 (t, J = 1.6 Hz, 1H), 7.19 (s, 1H), 4.96 (s, 1H), 4.70 (d, J = 49.3 Hz, 1H), 3.74 - 3.60 (m, 2H), 3.60 - 3.51 (m, 2H), 3.38 (s, 1H), 1.08 (t, J = 4.2 Hz, 2H), 1.05 - 0.98 (m, 2H). MS m / z (ESI): 446.07 [M+H] + 。

[0436] Example 86: (R)-3-Bromo-5-((2-((2-fluoro-3-hydroxypropyl)amino)-9-isopropyl-9H-purin-6-yl)amino)benzonitrile

[0437]

[0438] 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). After heating at 130 °C for 24 hours, the reaction mixture was cooled to room temperature. The reaction was quenched by adding water, and the mixture was 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 HNMR(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] + 。

[0439] Example 87: (R)-3-bromo-5-((9-cyclopropyl-2-((2-fluoro-3-hydroxypropyl)amino)-9H-purin-6-yl)amino)benzonitrile

[0440]

[0441] 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). After heating at 130 °C for 24 hours, the reaction mixture was cooled to room temperature. The reaction was quenched by adding water, and the mixture was 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%). 1HNMR(500MHz, DMSO-d6) δ 10.01 (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 = 49.1 Hz, 1H), 3.74 - 3.59 (m, 2H), 3.59 - 3.52 (m, 2H), 3.38 (s, 1H), 1.08 (q, J = 4.2 Hz, 2H), 1.04 - 0.99 (m, 2H). MS m / z(ESI): 446.07 [M + H] + 。

[0442] Example 88: 3-Bromo-5-((2-(((3-(hydroxymethyl)oxetan-3-yl)methyl)amino)-9-isopropyl-9H-purin-6-yl)amino)benzonitrile

[0443]

[0444] 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). After heating at 130 °C for 24 hours, it was cooled to room temperature. The reaction was quenched by adding water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent CH2Cl2 / MeOH = 20 / 1) to obtain 10 mg of the product (yield 21%). 1 H NMR(500MHz, DMSO-d6) δ 10.03 (s, 1H), 8.57 (s, 2H), 8.05 (s, 1H), 7.67 (q, J = 1.5 Hz, 1H), 7.08 (s, 1H), 4.94 (s, 1H), 4.64 - 4.56 (m, 1H), 4.43 (d, J = 5.8 Hz, 2H), 4.33 (d, J = 5.8 Hz, 2H), 3.68 - 3.61 (m, 4H), 1.50 (d, J = 6.5 Hz, 6H). MS m / z(ESI): 472.11 [M + H] + 。

[0445] Example 89: 3-Bromo-5-((9-cyclopropyl-2-(((3-(hydroxymethyl)oxetan-3-yl)methyl)amino)-9H-purin-6-yl)amino)benzonitrile

[0446]

[0447] 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). After heating at 130 °C for 24 hours, the reaction mixture was cooled to room temperature. The reaction was quenched by adding water, and the mixture was 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 30%). 1 H NMR (500 MHz, DMSO-d6) δ 10.03 (s, 1H), 8.56 (s, 2H), 7.90 (s, 1H), 7.67 (t, J = 1.6 Hz, 1H), 7.18 (s, 1H), 4.97 (s, 1H), 4.43 (d, J = 5.8 Hz, 2H), 4.33 (d, J = 5.8 Hz, 2H), 3.65 (t, J = 6.1 Hz, 4H), 3.38 - 3.34 (m, 1H), 1.06 (dq, J = 6.7, 4.0 Hz, 2H), 1.04 - 0.98 (m, 2H). MS m / z (ESI): 470.10 [M+H] + 。

[0448] Example 90: 3-Bromo-5-((9-cyclopropyl-2-(((3,3-difluoro-1-(hydroxymethyl)cyclobutyl)methyl)amino)-9H-purin-6-yl)amino)benzonitrile

[0449]

[0450] 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). After heating at 130 °C for 24 hours, the reaction mixture was cooled to room temperature. The reaction was quenched by adding water, and the mixture was 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 24%). 11H NMR (500 MHz, DMSO-d6) δ 10.02 (s, 1H), 8.55 (s, 2H), 7.91 (s, 1H), 7.67 (t, J = 1.6 Hz, 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, 3.9 Hz, 2H), 2.52 (s, 1H), 2.41 (q, J = 13.5 Hz, 2H), 1.10 - 1.04 (m, 2H), 1.04 - 0.97 (m, 2H). MS m / z (ESI): 504.09 [M + H] + 。

[0451] Example 91: trans-4-((6-((3,5-Dimethoxyphenyl)amino)-9-isopropyl-9H-purin-2-yl)amino)cyclohexan-1-ol

[0452]

[0453] Dissolve 2,6-dichloro-9-isopropyl-9H-purine (1.4 g, 6 mmol) in dry sec-butanol (10 mL), add 3,5-dimethoxyaniline (1.2 g, 7.8 mmol), and heat at 110 °C for 12 h. Cool to room temperature, and quench the reaction by adding saturated sodium bicarbonate solution. Extract three times with dichloromethane, dry over anhydrous sodium sulfate, filter, concentrate, and purify by column chromatography (eluent CH2Cl2 / MeOH = 100 / 1) to obtain 1.1 g of 2-chloro-N-(3,5-dimethoxyphenyl)-9-isopropyl-9H-purin-6-amine (yield 52%). MS m / z (ESI): 348.12 [M + H] + 。

[0454] 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), add trans-4-aminocyclohexan-1-ol (58 mg, 0.50 mmol) and triethylamine (101 mg, 1 mmol), heat at 130 °C for 24 h, and then cool to room temperature. Quench with water, extract three times with dichloromethane, dry over anhydrous sodium sulfate, filter, concentrate, and purify by column chromatography (eluent CH2Cl2 / MeOH = 20 / 1) to obtain 5 mg of the product (yield 12%). 11H NMR (500 MHz, DMSO-d6) δ 9.20 (s, 1H), 7.93 (s, 1H), 7.30 (d, J = 2.2 Hz, 2H), 6.36 (d, J = 7.9 Hz, 1H), 6.14 (t, J = 2.3 Hz, 1H), 4.57 (p, J = 6.7 Hz, 1H), 4.50 (d, J = 4.4 Hz, 1H), 3.74 (s, 6H), 3.43 - 3.36 (m, 1H), 1.94 (d, J = 9.7 Hz, 2H), 1.83 (d, J = 9.4 Hz, 2H), 1.49 (d, J = 6.7 Hz, 6H), 1.35 - 1.20 (m, 5H). MS m / z (ESI): 427.22 [M + H] + 。

[0455] Example 92: N2-((trans)-4-Aminocyclohexyl)-N6-(3,5-dimethoxyphenyl)-9-isopropyl-9H-purine-2,6-diamine

[0456]

[0457] To a solution of 2-chloro-N-(3,5-dimethoxyphenyl)-9-isopropyl-9H-purine-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). After heating at 130 °C for 24 hours, the mixture was cooled to room temperature. The reaction 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 8 mg of the product (yield 19%). 1 1H NMR (500 MHz, DMSO-d6) δ 9.21 (s, 1H), 7.93 (s, 1H), 7.30 (d, J = 2.3 Hz, 2H), 6.38 (d, J = 7.9 Hz, 1H), 6.14 (t, J = 2.3 Hz, 1H), 4.57 (p, J = 6.8 Hz, 1H), 3.74 (s, 6H), 2.62 (tt, J = 10.7, 3.9 Hz, 1H), 2.02 - 1.94 (m, 2H), 1.88 - 1.77 (m, 2H), 1.49 (d, J = 6.8 Hz, 6H), 1.37 - 1.10 (m, 5H). MS m / z (ESI): 426.24 [M + H] + 。

[0458] Example 93: 4-((6-((3,5-Dimethoxyphenyl)amino)-9-isopropyl-9H-purin-2-yl)amino)butan-1-ol

[0459]

[0460] 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). After heating at 130 °C for 24 hours, the reaction mixture was cooled to room temperature. The reaction was quenched by adding water, and the mixture was 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 1H NMR (500 MHz, DMSO-d6) δ 9.21 (s, 1H), 7.93 (s, 1H), 7.35 (d, J = 2.3 Hz, 2H), 6.60 (t, J = 5.8 Hz, 1H), 6.12 (t, J = 2.3 Hz, 1H), 4.58 (p, J = 6.8 Hz, 1H), 4.34 (t, J = 5.1 Hz, 1H), 3.73 (s, 6H), 3.41 (td, J = 6.5, 5.1 Hz, 2H), 1.67 - 1.54 (m, 2H), 1.50 (d, J = 6.8 Hz, 6H), 1.46 (d, J = 6.6 Hz, 2H). MS m / z (ESI): 401.22 [M+H] + 。

[0461] Example 94: trans-4-((9-Cyclopropyl-6-((3,5-dimethoxyphenyl)amino)-9H-purin-2-yl)amino)cyclohexan-1-ol

[0462]

[0463] 2,6-Dichloro-9-cyclopropyl-9H-purine (500 mg, 2.2 mmol) was dissolved in dry sec-butanol (10 mL), and 3,5-dimethoxyaniline (478 mg, 2.86 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 300 mg of 2-chloro-N-(3,5-dimethoxyphenyl)-9-cyclopropyl-9H-purin-6-amine (yield 40%), MS m / z (ESI): 346.11 [M+H] + 。

[0464] 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) were added trans-4-aminocyclohexan-1-ol (58 mg, 0.50 mmol) and triethylamine (101 mg, 1 mmol). After heating at 130 °C for 24 h, the reaction mixture was cooled to room temperature. The reaction was quenched by adding water, and then extracted with dichloromethane three times. The organic layer was 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 17%). 1 H NMR (500 MHz, DMSO-d6) δ 9.20 (s, 1H), 7.79 (s, 1H), 7.30 (d, J = 2.2 Hz, 2H), 6.51 (s, 1H), 6.15 (t, J = 2.2 Hz, 1H), 4.50 (d, J = 4.4 Hz, 1H), 3.73 (s, 6H), 3.38 (dd, J = 9.9, 4.6 Hz, 2H), 1.93 (d, J = 8.8 Hz, 2H), 1.83 (s, 2H), 1.27 (p, J = 10.3 Hz, 5H), 1.09 - 1.03 (m, 2H), 1.02 - 0.95 (m, 2H). MS m / z (ESI): 425.22 [M+H] + 。

[0465] Example 95: trans-4-((6-((3-Bromo-5-(difluoromethoxy)phenyl)amino)-9-isopropyl-9H-purin-2-yl)amino)cyclohexan-1-ol

[0466]

[0467] 2,6-Dichloro-9-isopropyl-9H-purine (100 mg, 0.44 mmol) was dissolved in dry sec-butanol (2 mL), and 3-bromo-5-(difluoromethoxy)aniline (312 mg, 1.32 mmol) was added. The mixture was heated at 110 °C for 12 h. After cooling to room temperature, the reaction was quenched by adding saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane three times, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 100 / 1) to give 130 mg of N-(3-bromo-5-(difluoromethoxy)phenyl)-2-chloro-9-isopropyl-9H-purin-6-amine (yield 69%), MS m / z (ESI): 432.00 [M+H] + 。

[0468] 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-aminocyclohexan-1-ol (80 mg, 0.70 mmol) and triethylamine (117 mg, 1.16 mmol). After heating at 130 °C for 24 h, the reaction mixture was cooled to room temperature. The reaction was quenched by adding water, and the mixture was extracted with dichloromethane three times, 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 1H NMR (500 MHz, DMSO-d6) δ 9.81 (s, 1H), 8.34 (s, 1H), 7.99 (s, 1H), 7.87 (s, 1H), 7.26 (s, 1H), 6.99 (t, J = 2.0 Hz, 1H), 6.55 (d, J = 8.1 Hz, 1H), 4.58 (p, J = 6.8 Hz, 1H), 4.49 (d, J = 4.3 Hz, 1H), 3.75 - 3.65 (m, 1H), 1.94 (d, J = 11.0 Hz, 2H), 1.84 (d, J = 10.2 Hz, 2H), 1.50 (s, 3H), 1.49 (s, 3H), 1.31 (dd, J = 16.7, 6.5 Hz, 4H). MS m / z (ESI): 511.15 [M + H] + 。

[0469] Example 96: trans-4-((6-((3-bromo-5-(difluoromethoxy)phenyl)amino)-9-cyclopropyl-9H-purin-2-yl)amino)cyclohexan-1-ol

[0470]

[0471] 2,6-Dichloro-9-cyclopropyl-9H-purine (100 mg, 0.44 mmol) was dissolved in dry sec-butanol (2 mL), and 3-bromo-5-(difluoromethoxy)aniline (312 mg, 1.32 mmol) was added. The mixture was heated at 110 °C for 12 h. After cooling to room temperature, the reaction was quenched by adding saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane three times, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 100 / 1) to give 140 mg of N-(3-bromo-5-(difluoromethoxy)phenyl)-2-chloro-9-cyclopropyl-9H-purin-6-amine (yield 75%), MS m / z (ESI): 429.99 [M + H] + 。

[0472] 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-aminocyclohexan-1-ol (40 mg, 0.35 mmol) and triethylamine (59 mg, 0.58 mmol). After heating at 130 °C for 24 h, the reaction mixture was cooled to room temperature. The reaction was quenched with water and extracted three times with dichloromethane. The organic layer was 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 20%). 1 H NMR (500 MHz, DMSO-d6) δ 9.80 (s, 1H), 8.36 (s, 1H), 7.85 (s, 2H), 7.25 (t, J = 73.7 Hz, 1H), 7.00 (t, J = 1.9 Hz, 1H), 6.69 (s, 1H), 4.50 (d, J = 4.3 Hz, 1H), 3.39 (q, J = 8.4, 7.0 Hz, 1H), 1.93 (d, J = 11.4 Hz, 2H), 1.84 (d, J = 10.7 Hz, 2H), 1.42 - 1.29 (m, 4H), 1.05 (d, J = 4.2 Hz, 2H), 0.99 (dd, J = 7.3, 5.1 Hz, 2H). MS m / z (ESI): 509.11 [M+H] + 。

[0473] Example 97: N2-(trans-4-Aminocyclohexyl)-9-cyclopropyl-N6-(3,5-dimethoxyphenyl)-9H-purine-2,6-diamine

[0474]

[0475] 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). After heating at 110 °C for 12 h, the reaction mixture was cooled to room temperature. The reaction was quenched with water and extracted three times with dichloromethane. The organic layer was 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 33%). 11H NMR (500 MHz, DMSO-d6) δ 9.21 (s, 1H), 7.79 (s, 1H), 7.30 (d, J = 2.2 Hz, 2H), 6.53 (s, 1H), 6.14 (t, J = 2.3 Hz, 1H), 3.74 (s, 6H), 3.70 (td, J = 7.7, 4.0 Hz, 1H), 2.61 (tt, J = 10.6, 3.5 Hz, 1H), 1.99 - 1.93 (m, 2H), 1.81 (d, J = 12.2 Hz, 2H), 1.36 - 1.13 (m, 5H), 1.05 (t, J = 3.8 Hz, 2H), 0.98 (dd, J = 7.4, 5.1 Hz, 2H). MS m / z (ESI): 424.24 [M + H] + 。

[0476] Example 98: N2-(trans-4-Aminocyclohexyl)-N6-(3-bromo-5-(trifluoromethoxy)phenyl)-9-isopropyl-9H-purine-2,6-diamine

[0477]

[0478] Dissolve 2,6-dichloro-9-isopropyl-9H-purine (462 mg, 2 mmol) in dry sec-butanol (5 mL), add 3-bromo-5-(trifluoromethoxy)aniline (660 mg, 2.6 mmol), and heat at 110 °C for 12 h. Cool to room temperature, and quench the reaction with saturated sodium bicarbonate solution. Extract with dichloromethane three times, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (eluent CH2Cl2 / MeOH = 100 / 1) to obtain 600 mg (yield 67%) of N-(3-bromo-5-(trifluoromethoxy)phenyl)-2-chloro-9-isopropyl-9H-purine-6-amine, MS m / z (ESI): 449.99 [M + H] + 。

[0479] To a solution of N-(3-bromo-5-(trifluoromethoxy)phenyl)-2-chloro-9-isopropyl-9H-purine-6-amine (45 mg, 0.1 mmol) in sec-butanol (1 mL), add trans-1,4-cyclohexanediamine (58 mg, 0.50 mmol) and triethylamine (101 mg, 1 mmol), heat at 110 °C for 12 h, and then cool to room temperature. Quench with water, extract with dichloromethane three times, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (eluent CH2Cl2 / MeOH = 10 / 1) to obtain 8 mg (yield 15%) of the product. 1HNMR(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] + 。

[0480] Example 99: N2-(trans-4-Aminocyclohexyl)-N6-(3-bromo-5-(trifluoromethoxy)phenyl)-9-cyclopropyl-9H-purine-2,6-diamine

[0481]

[0482] Dissolve 2,6-dichloro-9-cyclopropyl-9H-purine (229 mg, 1 mmol) (Reference Example 10) in dry sec-butanol (2 mL), add 3-bromo-5-(trifluoromethoxy)aniline (330 mg, 1.3 mmol), and heat at 110 °C for 12 hours. Cool to room temperature, and quench the reaction by adding saturated sodium bicarbonate solution. Extract three times with dichloromethane, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (eluent CH2Cl2 / MeOH = 100 / 1) to obtain 160 mg (yield 32%) of N-(3-bromo-5-(trifluoromethoxy)phenyl)-2-chloro-9-cyclopropyl-9H-purine-6-amine, MS m / z (ESI): 447.98 [M+H] + 。

[0483] Add trans-1,4-cyclohexanediamine (58 mg, 0.50 mmol) and triethylamine (101 mg, 1 mmol) to a solution of N-(3-bromo-5-(trifluoromethoxy)phenyl)-2-chloro-9-cyclopropyl-9H-purine-6-amine (45 mg, 0.1 mmol) in sec-butanol (1 mL), heat at 110 °C for 12 hours, and then cool to room temperature. Quench with water, extract three times with dichloromethane, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (eluent CH2Cl2 / MeOH = 10 / 1) to obtain 10 mg (yield 19%) of the product. 1HNMR(500MHz, DMSO-d6) δ 9.93 (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, 4.0 Hz, 1H), 3.51 (s, 1H), 2.55 (dt, J=10.9, 3.9 Hz, 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=4.2 Hz, 2H), 1.03 - 0.95 (m, 2H). MS m / z(ESI): 526.12 [M + H] + 。

[0484] Example 100: trans-N2-(4-Aminocyclohexyl)-N6-(3-bromo-5-(difluoromethoxy)phenyl)-9-isopropyl-9H-purine-2,6-diamine

[0485]

[0486] To a solution of N-(3-bromo-5-(difluoromethoxy)phenyl)-2-chloro-9-isopropyl-9H-purine-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). After heating at 110 °C for 12 hours, the mixture was cooled to room temperature. It 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 obtain 11 mg of the product (yield 19%). 1 H NMR(500MHz, DMSO-d6) δ 9.83 (s, 1H), 8.45 (s, 1H), 8.01 (s, 1H), 7.80 (s, 1H), 6.99 (d, J=1.9 Hz, 1H), 6.63 (d, J=8.0 Hz, 1H), 4.58 (p, J=6.7 Hz, 1H), 3.70 (dtt, J=11.6, 8.0, 4.2 Hz, 1H), 2.83 (ddt, J=11.4, 8.0, 3.8 Hz, 1H), 2.02 (d, J=12.2 Hz, 2H), 1.94 (d, J=12.0 Hz, 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] + 。

[0487] Example 101: trans-4-((6-((3-chloro-5-methoxyphenyl)amino)-9-isopropyl-9H-purin-2-yl)amino)cyclohexan-1-ol

[0488]

[0489] Dissolve 2,6-dichloro-9-isopropyl-9H-purine (230 mg, 1 mmol) in dry sec-butanol (5 mL), add 3-chloro-5-methoxyaniline (204 mg, 1.3 mmol), and heat at 110 °C for 12 h. Cool to room temperature, and quench the reaction with saturated sodium bicarbonate solution. Extract with dichloromethane three times, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (eluent CH2Cl2 / MeOH = 100 / 1) to obtain 2-chloro-N-(3-chloro-5-methoxyphenyl)-9-isopropyl-9H-purin-6-amine 226 mg (yield 64%), MS m / z (ESI): 352.07 [M+H] + 。

[0490] 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), add trans-4-aminocyclohexan-1-ol (58 mg, 0.50 mmol) and triethylamine (101 mg, 1 mmol), heat at 130 °C for 24 h, and then cool to room temperature. Quench with water, extract with dichloromethane three times, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (eluent CH2Cl2 / MeOH = 20 / 1) to obtain the product 13 mg (yield 30%). 1 1H NMR (500 MHz, DMSO) δ 9.53 (s, 1H), 7.96 (s, 2H), 7.53 (s, 1H), 6.62 (d, J = 5.0 Hz, 1H), 6.48 (d, J = 10.0 Hz, 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] + 。

[0491] Example 102: trans-4-((6-((3-chloro-5-methoxyphenyl)amino)-9-cyclopropyl-9H-purin-2-yl)amino)cyclohexan-1-ol

[0492]

[0493] Dissolve 2,6-dichloro-9-cyclopropyl-9H-purine (230 mg, 1 mmol) in dry sec-butanol (5 mL), add 3-chloro-5-methoxyaniline (204 mg, 1.3 mmol), and heat at 110 °C for 12 hours. Cool to room temperature, and quench the reaction by adding saturated sodium bicarbonate solution. Extract three times with dichloromethane, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (eluent CH2Cl2 / MeOH = 100 / 1) to obtain 2-chloro-N-(3-chloro-5-methoxyphenyl)-9-cyclopropyl-9H-purin-6-amine 176 mg (yield 51%), MS m / z (ESI): 350.06 [M+H] + 。

[0494] Add trans-4-aminocyclohexan-1-ol (58 mg, 0.50 mmol) and triethylamine (101 mg, 1 mmol) 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), heat at 130 °C for 24 hours, and then cool to room temperature. Quench with water, extract three times with dichloromethane, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (eluent CH2Cl2 / MeOH = 20 / 1) to obtain the product 14 mg (yield 32%). 1 H NMR (500 MHz, DMSO) δ 9.53 (s, 1H), 7.98 (s, 2H), 7.82 (s, 1H), 7.50 (s, 1H), 6.62 (s, 1H), 4.51 (d, J = 5.0 Hz,, 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] + 。

[0495] Example 103: trans-4-((6-((3-bromo-4-chloro-5-methoxyphenyl)amino)-9-isopropyl-9H-purin-2-yl)amino)cyclohexan-1-ol

[0496]

[0497] Dissolve 2,6-dichloro-9-isopropyl-9H-purine (230 mg, 1 mmol) in dry sec-butanol (5 mL), add 3-bromo-4-chloro-5-methoxyaniline (306 mg, 1.3 mmol), and heat at 110 °C for 12 h. Cool to room temperature, and quench the reaction by adding saturated sodium bicarbonate solution. Extract three times with dichloromethane, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (eluent CH2Cl2 / MeOH = 100 / 1) to obtain 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] + 。

[0498] 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), add trans-4-aminocyclohexan-1-ol (58 mg, 0.50 mmol) and triethylamine (101 mg, 1 mmol), heat at 130 °C for 24 h, and then cool to room temperature. Quench with water, extract three times with dichloromethane, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (eluent CH2Cl2 / MeOH = 20 / 1) to obtain 15 mg (yield 30%) of the product. 1 HNMR (500 MHz, DMSO) δ 9.63 (s, 1H), 8.41 (s, 1H), 7.98 (s, 1H), 7.70 (s, 1H), 6.49 (d, J = 10.0 Hz, 1H), 4.60 - 4.55 (m, 1H), 4.49 (d, J = 5.0 Hz, 1H), 3.76 - 3.68 (m, 1H), 3.44 - 3.37 (m, 1H), 1.99 - 1.84 (m, 4H), 1.50 (d, J = 5.0 Hz, 6H), 1.34 - 1.27 (m, 4H), 1.05 - 0.96 (m, 4H). MS m / z (ESI): 509.11 [M+H] + 。

[0499] Example 104: trans-4-((6-((3-bromo-4-chloro-5-methoxyphenyl)amino)-9-cyclopropyl-9H-purin-2-yl)amino)cyclohexan-1-ol

[0500]

[0501] Dissolve 2,6-dichloro-9-cyclopropyl-9H-purine (230 mg, 1 mmol) in dry sec-butanol (5 mL), add 3-bromo-4-chloro-5-methoxyaniline (306 mg, 1.3 mmol), and heat at 110 °C for 12 hours. Cool to room temperature, and quench the reaction by adding saturated sodium bicarbonate solution. Extract three times with dichloromethane, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (eluent CH2Cl2 / MeOH = 100 / 1) to obtain N-(3-bromo-4-chloro-5-methoxyphenyl)-2-chloro-9-cyclopropyl-9H-purin-6-amine 256 mg (yield 60%), MS m / z (ESI): 427.97 [M+H] + .

[0502] 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), add trans-4-aminocyclohexan-1-ol (58 mg, 0.50 mmol) and triethylamine (101 mg, 1 mmol), heat at 130 °C for 24 hours, and then cool to room temperature. Quench with water, extract three times with dichloromethane, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (eluent CH2Cl2 / MeOH = 20 / 1) to obtain the product 17 mg (yield 34%). 1 1H NMR (500 MHz, DMSO) δ 9.62 (s, 1H), 8.46 (s, 1H), 7.84 (s, 1H), 7.66 (s, 1H), 6.64 (s, 1H), 4.48 (d, J = 10.0 Hz, 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] + .

[0503] Example 105: trans-4-((6-((3,5-dimethoxyphenyl)amino)-9-isopropyl-9H-purin-2-yl)amino)-1-methylcyclohexan-1-ol

[0504]

[0505] 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-methylcyclohexan-1-ol (65 mg, 0.50 mmol) and triethylamine (101 mg, 1 mmol). After heating at 130 °C for 24 hours, the reaction mixture was cooled to room temperature. The reaction was quenched by adding water, and the mixture was extracted with dichloromethane three times, 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 (500 MHz, DMSO-d6) δ 9.19 (s, 1H), 7.93 (s, 1H), 7.31 (d, J = 2.3 Hz, 2H), 6.35 (d, J = 8.0 Hz, 1H), 6.14 (s, 1H), 4.57 (p, J = 6.8 Hz, 1H), 4.19 (s, 1H), 3.82 (s, 1H), 3.74 (s, 6H), 1.85 (d, J = 10.6 Hz, 2H), 1.58 (q, J = 5.6, 5.2 Hz, 2H), 1.49 (d, J = 6.8 Hz, 6H), 1.45 (d, J = 8.4 Hz, 4H), 1.15 (s, 3H). MS m / z (ESI): 441.23 [M+H] + 。

[0506] Example 106: trans-4-((9-Cyclopropyl-6-((3,5-dimethoxyphenyl)amino)-9H-purin-2-yl)amino)-1-methylcyclohexan-1-ol

[0507]

[0508] 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-methylcyclohexan-1-ol (65 mg, 0.50 mmol) and triethylamine (101 mg, 1 mmol). After heating at 130 °C for 24 hours, the reaction mixture was cooled to room temperature. The reaction was quenched by adding water, and the mixture was extracted with dichloromethane three times, 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%). 11H NMR (500 MHz, DMSO-d6) δ 9.19 (s, 1H), 7.79 (s, 1H), 7.30 (d, J = 2.2 Hz, 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, 6.0 Hz, 2H), 1.59 (dd, J = 8.7, 5.4 Hz, 2H), 1.45 (q, J = 8.0, 5.2 Hz, 4H), 1.15 (s, 3H), 1.05 (p, J = 4.0 Hz, 2H), 1.02 - 0.94 (m, 2H). MS m / z (ESI): 439.24 [M+H] + 。

[0509] Example 107: trans-4-((6-((3-Bromo-5-(methylsulfonyl)phenyl)amino)-9-isopropyl-9H-purin-2-yl)amino)cyclohexan-1-ol

[0510]

[0511] Dissolve 2,6-dichloro-9-isopropyl-9H-purine (100 mg, 0.44 mmol) in dry sec-butanol (2 mL), add 3-bromo-5-(methylsulfonyl)aniline (196 mg, 0.44 mmol), and heat at 110 °C for 12 h. Cool to room temperature, and quench the reaction with saturated sodium bicarbonate solution. Extract three times with dichloromethane, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (eluent CH2Cl2 / MeOH = 100 / 1) to obtain 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] + 。

[0512] Add trans-4-aminocyclohexan-1-ol (39 mg, 0.34 mmol) and triethylamine (57 mg, 0.57 mmol) 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), heat at 130 °C for 24 h, and then cool to room temperature. Quench with water, extract three times with dichloromethane, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (eluent CH2Cl2 / MeOH = 20 / 1) to obtain 13 mg (yield 22%) of the product. 11H NMR (500 MHz, DMSO-d6) δ 10.05 (s, 1H), 8.82 (s, 1H), 8.46 (s, 1H), 8.01 (s, 1H), 7.64 (t, J = 1.7 Hz, 1H), 6.51 (d, J = 8.1 Hz, 1H), 4.58 (h, J = 6.8 Hz, 1H), 4.46 (d, J = 4.4 Hz, 1H), 3.76 (s, 1H), 3.40 (s, 1H), 3.27 (s, 3H), 1.93 (d, J = 11.9 Hz, 2H), 1.82 (d, J = 11.5 Hz, 2H), 1.50 (s, 3H), 1.49 (s, 3H), 1.40 (d, J = 11.6 Hz, 2H), 1.32 (t, J = 12.2 Hz, 2H); MS m / z (ESI): 523.10 [M+H] + 。

[0513] Example 108: trans-4-((6-((3-Bromo-5-(methylsulfonyl)phenyl)amino)-9-cyclopropyl-9H-purin-2-yl)amino)cyclohexan-1-ol

[0514]

[0515] 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. After cooling to room temperature, the reaction was quenched with saturated sodium bicarbonate solution. Extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent CH2Cl2 / MeOH = 100 / 1) to obtain 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] + 。

[0516] 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-aminocyclohexan-1-ol (39 mg, 0.34 mmol) and triethylamine (57 mg, 0.57 mmol). After heating at 130 °C for 24 hours, the mixture was cooled to room temperature. 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 obtain 12 mg (yield 20%) of the product. 11H NMR (500 MHz, DMSO-d6) δ 10.04 (s, 1H), 8.82 (s, 1H), 8.46 (t, J = 1.9 Hz, 1H), 7.87 (s, 1H), 7.64 (t, J = 1.6 Hz, 1H), 6.66 (s, 1H), 4.47 (d, J = 4.4 Hz, 1H), 3.42 - 3.37 (m, 1H), 3.26 (s, 3H), 1.92 (d, J = 11.9 Hz, 2H), 1.85 - 1.77 (m, 2H), 1.46 - 1.36 (m, 2H), 1.36 - 1.29 (m, 2H), 1.05 (q, J = 5.5, 4.8 Hz, 2H), 1.02 - 0.97 (m, 2H); MS m / z (ESI): 521.08 [M+H] + 。

[0517] Example 109: trans-4-((9-Cyclopentyl-6-((3,5-dimethoxyphenyl)amino)-9H-purin-2-yl)amino)cyclohexan-1-ol

[0518]

[0519] Dissolve 2,6-dichloro-9-cyclopentyl-9H-purine (300 mg, 1.17 mmol) (Reference Example 2) in dry sec-butanol (5 mL), add 3,5-dimethoxyaniline (233 mg, 1.52 mmol), and heat at 110 °C for 12 hours. Cool to room temperature, and quench the reaction by adding saturated sodium bicarbonate solution. Extract three times with dichloromethane, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (eluent CH2Cl2 / MeOH = 100 / 1) to obtain 160 mg (yield 36%) of 2-chloro-9-cyclopentyl-N-(3,5-dimethoxyphenyl)-9H-purin-6-amine, MS m / z (ESI): 374.14 [M+H] + 。

[0520] Add trans-4-aminocyclohexan-1-ol (58 mg, 0.50 mmol) and triethylamine (101 mg, 1.0 mmol) 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), heat at 130 °C for 24 hours, and then cool to room temperature. Quench with water, extract three times with dichloromethane, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (eluent CH2Cl2 / MeOH = 20 / 1) to obtain 9 mg (yield 20%) of the product. 11H NMR (500 MHz, DMSO-d6) δ 9.18 (s, 1H), 7.88 (s, 1H), 7.30 (d, J = 2.3 Hz, 2H), 6.35 (d, J = 7.9 Hz, 1H), 6.14 (t, J = 2.3 Hz, 1H), 4.69 (p, J = 7.6 Hz, 1H), 4.49 (d, J = 4.3 Hz, 1H), 3.73 (s, 6H), 3.69 (s, 1H), 3.40 (dt, J = 9.9, 5.4 Hz, 1H), 2.09 (p, J = 5.8 Hz, 2H), 2.03 - 1.79 (m, 8H), 1.69 (ddd, J = 16.9, 8.9, 4.6 Hz, 2H), 1.28 (q, J = 10.9, 10.1 Hz, 4H). MS m / z (ESI): 453.26 [M+H] + 。

[0521] Example 110: cis-3-(((9-Cyclopentyl-6-((3,5-dimethoxyphenyl)amino)-9H-purin-2-yl)amino)methyl)cyclobutan-1-ol

[0522]

[0523] 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)cyclobutan-1-ol (50 mg, 0.50 mmol) and triethylamine (101 mg, 1.0 mmol). After heating at 130 °C for 24 hours, the reaction mixture was cooled to room temperature. The reaction was quenched with water and extracted three times with dichloromethane. The organic layer was 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%). 11H NMR (500 MHz, DMSO-d6) δ 9.19 (s, 1H), 7.89 (s, 1H), 7.35 (d, J = 2.3 Hz, 2H), 6.60 (t, J = 5.7 Hz, 1H), 6.12 (t, J = 2.2 Hz, 1H), 4.86 (d, J = 6.5 Hz, 1H), 4.69 (p, J = 7.5 Hz, 1H), 3.88 (h, J = 7.4 Hz, 1H), 3.73 (s, 6H), 3.33 (d, J = 6.3 Hz, 1H), 2.29 - 2.20 (m, 2H), 2.10 (dt, J = 11.7, 6.7 Hz, 2H), 1.99 (dtd, J = 14.3, 7.1, 4.7 Hz, 3H), 1.89 (d, J = 8.4 Hz, 2H), 1.69 (qt, J = 6.5, 2.8 Hz, 2H), 1.56 - 1.48 (m, 2H). MS m / z (ESI): 439.24 [M + H] + 。

[0524] Example 111: trans-4-((9-Cyclohexyl-6-((3,5-dimethoxyphenyl)amino)-9H-purin-2-yl)amino)cyclohexan-1-ol

[0525]

[0526] 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. After cooling to room temperature, the reaction was quenched with saturated sodium bicarbonate solution. Extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent CH2Cl2 / MeOH = 100 / 1) to obtain 2-chloro-9-cyclohexyl-N-(3,5-dimethoxyphenyl)-9H-purin-6-amine 80 mg (yield 19%), MS m / z (ESI): 388.15 [M + H] + 。

[0527] 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) were added trans-4-aminocyclohexan-1-ol (58 mg, 0.50 mmol) and triethylamine (101 mg, 1.0 mmol). After heating at 130 °C for 24 hours, the mixture was cooled to room temperature. 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 obtain the product 11 mg (yield 24%).1 1H NMR (500 MHz, DMSO-d6) δ 9.20 (s, 1H), 7.91 (s, 1H), 7.30 (d, J = 2.2 Hz, 2H), 6.40 (d, J = 7.9 Hz, 1H), 6.14 (t, J = 2.2 Hz, 1H), 4.49 (d, J = 4.4 Hz, 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 = 12.9 Hz, 1H), 1.44 - 1.18 (m, 8H). MS m / z (ESI): 467.27 [M+H] + 。

[0528] Example 112: cis-4-((6-((3,5-Dimethoxyphenyl)amino)-9-isopropyl-9H-purin-2-yl)amino)cyclohexan-1-ol

[0529]

[0530] 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-aminocyclohexan-1-ol (58 mg, 0.50 mmol) and triethylamine (101 mg, 1.0 mmol). After heating at 130 °C for 24 h, the reaction mixture was cooled to room temperature. The reaction 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 give the product 9 mg (yield 21%). 1 1H NMR (500 MHz, DMSO-d6) δ 9.19 (s, 1H), 7.93 (s, 1H), 7.32 (d, J = 2.2 Hz, 2H), 6.35 (d, J = 7.5 Hz, 1H), 6.14 (t, J = 2.3 Hz, 1H), 4.58 (hept, J = 6.8 Hz, 1H), 4.30 (d, J = 3.1 Hz, 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 = 6.7 Hz, 6H). MS m / z (ESI): 427.25 [M+H] + 。

[0531] Example 113: trans-4-((6-((4-Chloro-3,5-dimethoxyphenyl)amino)-9-isopropyl-9H-purin-2-yl)amino)cyclohexan-1-ol

[0532]

[0533] Dissolve 2,6-dichloro-9-isopropyl-9H-purine (115 mg, 0.5 mmol) in dry sec-butanol (5 mL), add 4-chloro-3,5-dimethoxyaniline (122 mg, 0.65 mmol), and heat at 110 °C for 12 h. Cool to room temperature, and quench the reaction by adding saturated sodium bicarbonate solution. Extract three times with dichloromethane, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (eluent CH2Cl2 / MeOH = 100 / 1) to obtain 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] + 。

[0534] 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), add trans-4-aminocyclohexan-1-ol (58 mg, 0.50 mmol) and triethylamine (101 mg, 1 mmol), heat at 130 °C for 24 h, and then cool to room temperature. Quench with water, extract three times with dichloromethane, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (eluent CH2Cl2 / MeOH = 20 / 1) to obtain 16 mg (yield 35%) of the product. 1 H NMR (500 MHz, DMSO) δ 9.79 (s, 1H), 8.36 (s, 2H), 8.00 (s, 1H), 7.35 (d, J = 5.0 Hz, 1H), 6.56 (d, J = 5.0 Hz, 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 = 10.0 Hz, 1H), 1.40 - 1.25 (m, 4H). MS m / z (ESI): 461.21 [M+H] + 。

[0535] Example 114: trans-4-((6-((4-chloro-3,5-dimethoxyphenyl)amino)-9-cyclopropyl-9H-purin-2-yl)amino)cyclohexan-1-ol

[0536]

[0537] 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 h. After cooling to room temperature, the reaction was quenched by adding saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane three times, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent CH2Cl2 / MeOH = 100 / 1) to give 2-chloro-N-(4-chloro-3,5-dimethoxyphenyl)-9-cyclopropyl-9H-purin-6-amine 102 mg (yield 54%), MS m / z (ESI): 380.07 [M+H] + 。

[0538] 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) were added trans-4-aminocyclohexan-1-ol (58 mg, 0.50 mmol) and triethylamine (101 mg, 1 mmol), and the mixture was heated at 130 °C for 24 h. After cooling to room temperature, the reaction was quenched by adding water. The mixture was extracted with dichloromethane three times, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent CH2Cl2 / MeOH = 20 / 1) to give the product 14 mg (yield 31%). 1 H NMR (500 MHz, DMSO) δ 9.36 (s, 1H), 7.82 (s, 1H), 7.53 (s, 2H), 6.49 (d, J = 10.0 Hz, 1H), 4.51 (d, J = 5.0 Hz, 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] + 。

[0539] Example 115: trans-4-((6-((3,5-dibromophenyl)amino)-9-isopropyl-9H-purin-2-yl)amino)cyclohexan-1-ol

[0540]

[0541] Dissolve 2,6-dichloro-9-isopropyl-9H-purine (115 mg, 0.5 mmol) in dry sec-butanol (5 mL), add 3,5-dibromoaniline (160 mg, 0.65 mmol), and heat at 110 °C for 12 h. Cool to room temperature, and quench the reaction by adding saturated sodium bicarbonate solution. Extract three times with dichloromethane, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (eluent CH2Cl2 / MeOH = 100 / 1) to obtain 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] + 。

[0542] Add trans-4-aminocyclohexan-1-ol (58 mg, 0.50 mmol) and triethylamine (101 mg, 1 mmol) 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), heat at 130 °C for 24 h, and then cool to room temperature. Quench with water, extract three times with dichloromethane, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (eluent CH2Cl2 / MeOH = 20 / 1) to obtain 17 mg (yield 33%) of the product. 1 H NMR (500 MHz, DMSO) δ 9.79 (s, 1H), 8.36 (s, 2H), 8.00 (s, 1H), 7.36 (d, J = 5.0 Hz, 1H), 6.56 (d, J = 5.0 Hz, 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 = 10.0 Hz, 1H), 1.40 - 1.25 (m, 4H). MS m / z (ESI): 523.05 [M+H] + 。

[0543] Example 116: trans-4-((9-cyclopropyl-6-((3,5-dibromophenyl)amino)-9H-purin-2-yl)amino)cyclohexan-1-ol

[0544]

[0545] Dissolve 2,6-dichloro-9-cyclopropyl-9H-purine (115 mg, 0.5 mmol) (Reference Example 10) in dry sec-butyl alcohol (5 mL), add 3,5-dibromoaniline (160 mg, 0.65 mmol), and heat at 110 °C for 12 h. Cool to room temperature, and quench the reaction by adding saturated sodium bicarbonate solution. Extract three times with dichloromethane, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (eluent CH2Cl2 / MeOH = 100 / 1) to obtain 110 mg (yield 50%) of 2-chloro-N-(3,5-dibromophenyl)-9-cyclopropyl-9H-purin-6-amine, MS m / z (ESI): 441.91 [M+H] + 。

[0546] To a solution of 2-chloro-N-(3,5-dibromophenyl)-9-cyclopropyl-9H-purin-6-amine (44 mg, 0.10 mmol) in sec-butyl alcohol (1 mL), add trans-4-aminocyclohexan-1-ol (58 mg, 0.50 mmol) and triethylamine (101 mg, 1 mmol), heat at 130 °C for 24 h, and then cool to room temperature. Quench with water, extract three times with dichloromethane, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (eluent CH2Cl2 / MeOH = 20 / 1) to obtain 20 mg (yield 37%) of the product. 1 1H NMR (500 MHz, DMSO) δ 9.78 (s, 1H), 8.35 (s, 2H), 7.85 (s, 1H), 7.36 (d, J = 5.0 Hz, 1H), 6.71 (d, J = 5.0 Hz, 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] + 。

[0547] Example 117: cis-4-((9-Cyclopentyl-6-((3,5-dimethoxyphenyl)amino)-9H-purin-2-yl)amino)-1-methylcyclohexan-1-ol

[0548]

[0549] 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-methylcyclohexan-1-ol (65 mg, 0.50 mmol) and triethylamine (101 mg, 1.0 mmol). After heating at 130 °C for 24 hours, the reaction mixture was cooled to room temperature. The reaction was quenched with water and extracted three times with dichloromethane. The organic layer was 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 (500 MHz, DMSO-d6) δ 9.18 (s, 1H), 7.88 (s, 1H), 7.32 (d, J = 2.3 Hz, 2H), 6.37 (d, J = 7.6 Hz, 1H), 6.14 (t, J = 2.3 Hz, 1H), 4.69 (p, J = 7.6 Hz, 1H), 3.95 (s, 1H), 3.73 (s, 6H), 3.68 (s, 1H), 2.09 (dt, J = 12.2, 6.4 Hz, 2H), 1.98 (d, J = 6.5 Hz, 2H), 1.88 (s, 2H), 1.74 - 1.61 (m, 6H), 1.61 - 1.55 (m, 2H), 1.40 (t, J = 12.7 Hz, 2H), 1.13 (s, 3H). MS m / z (ESI): 467.27 [M + H] + 。

[0550] Example 118: trans-4-((9-Cyclopentyl-6-((3,5-dimethoxyphenyl)amino)-9H-purin-2-yl)amino)-1-methylcyclohexan-1-ol

[0551]

[0552] 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-methylcyclohexan-1-ol (65 mg, 0.50 mmol) and triethylamine (101 mg, 1.0 mmol). After heating at 130 °C for 24 hours, the reaction mixture was cooled to room temperature. The reaction was quenched with water and extracted three times with dichloromethane. The organic layer was 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%). 11H NMR (500 MHz, DMSO-d6) δ 9.18 (s, 1H), 7.88 (s, 1H), 7.30 (d, J = 2.3 Hz, 2H), 6.34 (d, J = 7.9 Hz, 1H), 6.14 (t, J = 2.3 Hz, 1H), 4.69 (p, J = 7.6 Hz, 1H), 4.20 (s, 1H), 3.80 (s, 1H), 3.74 (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, 4.5 Hz, 2H), 1.58 (t, J = 7.1 Hz, 2H), 1.45 (dd, J = 11.4, 8.5 Hz, 4H), 1.15 (s, 3H). MS m / z (ESI): 467.27 [M+H] + 。

[0553] Example 119: cis-4-((9-Cyclopentyl-6-((3,5-dimethoxyphenyl)amino)-9H-purin-2-yl)amino)cyclohexan-1-ol

[0554]

[0555] 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). After heating at 130 °C for 24 hours, the reaction mixture was cooled to room temperature. The reaction 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 give the product 6 mg (yield 13%). 1 1H NMR (500 MHz, DMSO-d6) δ 9.18 (s, 1H), 7.89 (d, J = 2.9 Hz, 1H), 7.32 (t, J = 2.7 Hz, 2H), 6.36 (d, J = 7.5 Hz, 1H), 6.14 (q, J = 2.6 Hz, 1H), 4.69 (tt, J = 9.3, 4.6 Hz, 1H), 4.30 (s, 1H), 3.75 (s, 2H), 3.73 (d, J = 2.8 Hz, 6H), 2.15 - 2.03 (m, 2H), 2.00 (d, J = 9.9 Hz, 2H), 1.89 (s, 2H), 1.77 - 1.61 (m, 8H), 1.53 (d, J = 14.8 Hz, 2H). MS m / z (ESI): 453.26 [M+H] + 。

[0556] Example 120: trans-4-((6-((4-bromo-3-methoxyphenyl)amino)-9-cyclopropyl-9H-purin-2-yl)amino)cyclohexan-1-ol

[0557]

[0558] 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 h. After cooling to room temperature, the reaction was quenched with saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane three times, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent CH2Cl2 / MeOH = 100 / 1) to obtain 61 mg (yield 31%) of N-(4-bromo-3-methoxyphenyl)-2-chloro-9-cyclopropyl-9H-purin-6-amine. MS m / z (ESI): 394.01 [M+H] + 。

[0559] 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-aminocyclohexan-1-ol (58 mg, 0.50 mmol) and triethylamine (101 mg, 1 mmol). After heating at 130 °C for 24 h, the mixture was cooled to room temperature. The reaction was quenched with water, extracted with dichloromethane three times, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent CH2Cl2 / MeOH = 20 / 1) to obtain 16 mg (yield 34%) of the product. 1 H NMR (500 MHz, DMSO) δ 9.47 (s, 1H), 7.82 (d, J = 5.0 Hz, 1H), 7.81 (s, 1H), 7.70 (s, 1H), 7.39 (d, J = 5.0 Hz, 1H), 6.51 (s, 1H), 4.41 (d, J = 5.0 Hz, 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] + 。

[0560] Example 121: trans-4-((6-((3-bromo-4-methoxyphenyl)amino)-9-isopropyl-9H-purin-2-yl)amino)cyclohexan-1-ol

[0561]

[0562] Dissolve 2,6-dichloro-9-isopropyl-9H-purine (115 mg, 0.5 mmol) in dry sec-butanol (5 mL), add 3-bromo-4-methoxyaniline (132 mg, 0.65 mmol), and heat at 110 °C for 12 hours. Cool to room temperature, and quench the reaction by adding saturated sodium bicarbonate solution. Extract three times with dichloromethane, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (eluent CH2Cl2 / MeOH = 100 / 1) to obtain 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] + 。

[0563] Add trans-4-aminocyclohexan-1-ol (58 mg, 0.50 mmol) and triethylamine (101 mg, 1 mmol) 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), heat at 130 °C for 24 hours, and then cool to room temperature. Quench with water, extract three times with dichloromethane, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (eluent CH2Cl2 / MeOH = 20 / 1) to obtain 19 mg (yield 40%) of the product. 1 H NMR (500 MHz, DMSO) δ 9.39 (s, 1H), 8.44 (s, 1H), 7.92 (s, 1H), 7.83 (s, 1H), 7.03 (d, J = 10.0 Hz, 1H), 6.36 (d, J = 10.0 Hz, 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 = 5.0 Hz, 6H), 1.35 - 1.27 (m, 4H). MS m / z (ESI): 475.15 [M+H] + 。

[0564] Example 122: trans-4-((6-((3-bromo-4-methoxyphenyl)amino)-9-cyclopropyl-9H-purin-2-yl)amino)cyclohexan-1-ol

[0565]

[0566] 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 h. After cooling to room temperature, the reaction was quenched by adding saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane three times, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 100 / 1) to give 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] + .

[0567] 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-aminocyclohexan-1-ol (58 mg, 0.50 mmol) and triethylamine (101 mg, 1 mmol). After heating at 130 °C for 24 h, the mixture was cooled to room temperature. The reaction was quenched by adding water, and the mixture was extracted with dichloromethane three times, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to give 14 mg (yield 30%) of the product. 1 H NMR (500 MHz, DMSO) δ 9.38 (s, 1H), 8.46 (s, 1H), 7.78 (s, 2H), 7.03 (d, J = 10.0 Hz, 1H), 6.51 (s, 1H), 4.49 (d, J = 5.0 Hz, 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] + .

[0568] Example 123: trans-4-((6-((4-bromo-3-methoxyphenyl)amino)-9-isopropyl-9H-purin-2-yl)amino)cyclohexan-1-ol

[0569]

[0570] 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 h. After cooling to room temperature, the reaction was quenched with 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 obtain 105 mg of N-(4-bromo-3-methoxyphenyl)-2-chloro-9-isopropyl-9H-purin-6-amine (yield 53%), MS m / z (ESI): 396.02 [M+H] + 。

[0571] 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-aminocyclohexan-1-ol (58 mg, 0.50 mmol) and triethylamine (101 mg, 1 mmol). After heating at 130 °C for 24 h, the mixture was cooled to room temperature. The reaction 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 obtain 16 mg of the product (yield 34%). 1 1H NMR (500 MHz, DMSO) δ 9.47 (s, 1H), 7.95 (s, 1H), 7.82 (dd, J = 10.0, 5.0 Hz, 1H), 7.72 (s, 1H), 7.39 (d, J = 5.0 Hz, 1H), 6.45 (d, J = 5.0 Hz, 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 = 5.0 Hz, 6H), 1.33 - 1.23 (m, 4H). MS m / z (ESI): 475.15 [M+H] + 。

[0572] Example 124: trans-4-((6-((2-bromo-3-methoxyphenyl)amino)-9-isopropyl-9H-purin-2-yl)amino)cyclohexan-1-ol

[0573]

[0574] 2,6-Dichloro-9-isopropyl-9H-purine (115 mg, 0.5 mmol) was dissolved in dry sec-butyl alcohol (5 mL), 2-bromo-3-methoxyaniline (130 mg, 0.65 mmol) was added, and the mixture was heated at 110 °C for 12 h. 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 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] + 。

[0575] To a solution of N-(2-bromo-3-methoxyphenyl)-2-chloro-9-isopropyl-9H-purin-6-amine (40 mg, 0.10 mmol) in sec-butyl alcohol (1 mL) were added trans-4-aminocyclohexan-1-ol (58 mg, 0.50 mmol) and triethylamine (101 mg, 1 mmol). After heating at 130 °C for 24 h, the mixture was cooled to room temperature. The reaction was quenched by adding water, and the mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent CH2Cl2 / MeOH = 20 / 1) to give 19 mg (yield 40%) of the product. 1 H NMR (500 MHz, DMSO) δ 9.47 (s, 1H), 7.95 (s, 1H), 7.82 (dd, J = 10.0, 5.0 Hz, 1H), 7.72 (s, 1H), 7.39 (d, J = 5.0 Hz, 1H), 6.45 (d, J = 5.0 Hz, 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 = 5.0 Hz, 6H), 1.33 - 1.23 (m, 4H). MS m / z (ESI): 475.15 [M+H] + 。

[0576] Example 125: trans-4-((6-((2-bromo-5-methoxyphenyl)amino)-9-isopropyl-9H-purin-2-yl)amino)cyclohexan-1-ol

[0577]

[0578] 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 h. After cooling to room temperature, the reaction was quenched with 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 obtain 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] + .

[0579] 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-aminocyclohexan-1-ol (58 mg, 0.50 mmol) and triethylamine (101 mg, 1 mmol). After heating at 130 °C for 24 h, the mixture was cooled to room temperature. The reaction 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 obtain 12 mg (yield 25%) of the product. 1 H NMR (500 MHz, DMSO) δ 9.47 (s, 1H), 7.95 (s, 1H), 7.82 (dd, J = 10.0, 5.0 Hz, 1H), 7.72 (s, 1H), 7.39 (d, J = 5.0 Hz, 1H), 6.45 (d, J = 5.0 Hz, 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 = 5.0 Hz, 6H), 1.33 - 1.23 (m, 4H). MS m / z (ESI): 475.15 [M+H] + .

[0580] Example 126: trans-4-((9-Cyclopropyl-6-((2,6-dimethoxypyridin-4-yl)amino)-9H-purin-2-yl)amino)-1-methylcyclohexan-1-ol

[0581]

[0582] Dissolve 2,6-dichloro-9-cyclopropyl-9H-purine (1 g, 4.4 mmol) in dry sec-butanol (10 mL), add 2,6-dimethoxypyridin-4-amine (880 mg, 5.72 mmol), and heat at 110 °C for 12 h. Cool to room temperature, and quench the reaction by adding saturated sodium bicarbonate solution. Extract three times with dichloromethane, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (eluent CH2Cl2 / MeOH = 100 / 1) to obtain 150 mg of 2-chloro-9-cyclopropyl-N-(2,6-dimethoxypyridin-4-yl)-9H-purin-6-amine (yield 13%), MS m / z (ESI): 347.10 [M+H] + 。

[0583] 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), add trans-4-amino-1-methylcyclohexan-1-ol (65 mg, 0.50 mmol) and triethylamine (101 mg, 1.0 mmol), heat at 130 °C for 24 h, and then cool to room temperature. Quench with water, extract three times with dichloromethane, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (eluent CH2Cl2 / MeOH = 20 / 1) to obtain 11 mg of the product (yield 25%). 1 H NMR (500 MHz, DMSO-d6) δ 9.67 (s, 1H), 7.85 (s, 1H), 7.15 (s, 2H), 6.69 (d, J = 7.5 Hz, 1H), 4.22 (s, 1H), 3.82 (s, 6H), 3.78 (s, 1H), 3.35 (s, 1H), 1.88 (d, J = 10.5 Hz, 2H), 1.66 - 1.56 (m, 2H), 1.46 (t, J = 12.4 Hz, 4H), 1.16 (s, 3H), 1.06 (d, J = 3.8 Hz, 2H), 0.99 (td, J = 7.4, 5.3 Hz, 2H). MS m / z (ESI): 440.24 [M+H] + 。

[0584] Example 127: cis-4-((9-Cyclopropyl-6-((2,6-dimethoxypyridin-4-yl)amino)-9H-purin-2-yl)amino)-1-methylcyclohexan-1-ol

[0585]

[0586] 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-methylcyclohexan-1-ol (65 mg, 0.50 mmol) and triethylamine (101 mg, 1.0 mmol). After heating at 130 °C for 24 h, the reaction mixture was cooled to room temperature. The reaction was quenched by adding water, and the mixture was extracted with dichloromethane three times, 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 25%). 1 H NMR (500 MHz, DMSO-d6) δ 9.69 (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 = 6.8 Hz, 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, 3.1 Hz, 2H). MS m / z (ESI): 440.24 [M + H] + 。

[0587] Example 128: trans-4-((6-((3,5-Dimethoxyphenyl)amino)-9-(2-ethoxyethyl)-9H-purin-2-yl)amino)cyclohexan-1-ol

[0588]

[0589] 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 h. The reaction was quenched by adding saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane three times, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give 510 mg of 2,6-dichloro-9-(2-ethoxyethyl)-9H-purine (yield 39%), MS m / z (ESI): 261.03 [M + H] + 。

[0590] 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 h. After cooling to room temperature, the reaction was quenched by adding saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane three times, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent CH2Cl2 / MeOH = 100 / 1) to obtain 2 - chloro - N - (3,5 - dimethoxyphenyl) - 9 - (2 - ethoxyethyl) - 9H - purine - 6 - amine 390 mg (yield 54%), MS m / z (ESI): 378.13 [M + H] + 。

[0591] To a solution of 2 - chloro - N - (3,5 - dimethoxyphenyl) - 9 - (2 - ethoxyethyl) - 9H - purine - 6 - amine (40 mg, 0.10 mmol) in sec - butanol (1 mL) were added trans - 4 - aminocyclohexan - 1 - ol (58 mg, 0.50 mmol) and triethylamine (101 mg, 1 mmol). After heating at 130 °C for 24 h, the mixture was cooled to room temperature. The reaction was quenched by adding water, and the mixture was extracted with dichloromethane three times, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent CH2Cl2 / MeOH = 20 / 1) to obtain the product 15 mg (yield 33%). 1 HNMR (500 MHz, DMSO - d6) δ 9.24 (s, 1H), 7.79 (s, 1H), 7.30 (d, J = 2.2 Hz, 2H), 6.44 (s, 1H), 6.15 (t, J = 2.2 Hz, 1H), 4.51 (d, J = 4.3 Hz, 1H), 4.15 (t, J = 5.6 Hz, 2H), 3.74 (s, 6H), 3.73 - 3.66 (m, 2H), 3.44 (q, J = 7.0 Hz, 2H), 3.39 (d, J = 4.5 Hz, 1H), 1.93 (d, J = 9.2 Hz, 2H), 1.83 (s, 2H), 1.28 (q, J = 10.4 Hz, 4H), 1.06 (t, J = 7.0 Hz, 3H). MS m / z (ESI): 457.26 [M + H] + 。

[0592] Example 129: cis - 4 - ((6 - ((3,5 - dimethoxyphenyl)amino) - 9 - (2 - ethoxyethyl) - 9H - purin - 2 - yl)amino) - 1 - methylcyclohexan - 1 - ol

[0593]

[0594] 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-methylcyclohexan-1-ol (65 mg, 0.50 mmol) and triethylamine (101 mg, 1 mmol). After heating at 130 °C for 24 h, the reaction mixture was cooled to room temperature. The reaction was quenched by adding water, and the mixture was extracted with dichloromethane three times, 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 (500 MHz, DMSO-d6) δ 9.24 (s, 1H), 7.79 (s, 1H), 7.33 (d, J = 2.2 Hz, 2H), 6.47 (s, 1H), 6.14 (t, J = 2.2 Hz, 1H), 4.14 (t, J = 5.6 Hz, 2H), 3.97 (s, 1H), 3.73 (s, 6H), 3.70 (d, J = 5.2 Hz, 2H), 3.44 (q, J = 7.0 Hz, 2H), 1.72 - 1.54 (m, 6H), 1.41 (t, J = 12.7 Hz, 2H), 1.13 (s, 3H), 1.06 (t, J = 7.0 Hz, 3H). MS m / z (ESI): 471.27 [M + H] + 。

[0595] Example 130: trans-4-((9-(Cyclopropylmethyl)-6-((3,5-dimethoxyphenyl)amino)-9H-purin-2-yl)amino)cyclohexan-1-ol

[0596]

[0597] 2,6-Dichloro-9-(cyclopropylmethyl)-9H-purine (500 mg, 2.07 mmol) (Reference Example 7) was dissolved in dry sec-butanol (10 mL), and 3,5-dimethoxyaniline (412 mg, 2.69 mmol) was added. The mixture was heated at 95 °C for 12 h. After cooling to room temperature, the reaction was quenched by adding saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane three times, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 100 / 1) to give 223 mg of 2-chloro-9-(cyclopropylmethyl)-N-(3,5-dimethoxyphenyl)-9H-purin-6-amine (yield 29%), MS m / z (ESI): 360.12 [M + H] + 。

[0598] 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-aminocyclohexan-1-ol (58 mg, 0.50 mmol) and triethylamine (101 mg, 1 mmol). After heating at 130 °C for 24 h, the reaction mixture was cooled to room temperature. The reaction 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 give 7 mg of the product (yield 32%). 1 H NMR (500 MHz, DMSO-d6) δ 9.22 (s, 1H), 7.88 (s, 1H), 7.31 (d, J = 2.3 Hz, 2H), 6.39 (s, 1H), 6.15 (t, J = 2.3 Hz, 1H), 4.50 (d, J = 4.4 Hz, 1H), 3.85 (d, J = 7.1 Hz, 2H), 3.74 (s, 6H), 3.72 - 3.68 (m, 1H), 3.39 (q, J = 4.4 Hz, 1H), 1.93 (d, J = 8.9 Hz, 2H), 1.83 (d, J = 6.8 Hz, 2H), 1.28 (qd, J = 9.0, 7.0, 2.9 Hz, 5H), 0.57 - 0.49 (m, 2H), 0.42 (d, J = 4.9 Hz, 2H). MS m / z (ESI): 439.24 [M + H] + 。

[0599] Example 131: trans-4-((6-((3,5-Dimethoxyphenyl)amino)-9-propyl-9H-purin-2-yl)amino)cyclohexan-1-ol

[0600]

[0601] 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 h. The reaction was quenched with saturated sodium bicarbonate solution, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give 920 mg of 2,6-dichloro-9-propyl-9H-purine (yield 40%), MS m / z (ESI): 231.02 [M + H] + 。

[0602] 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 h. After cooling to room temperature, the reaction was quenched by adding saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane three times, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent CH2Cl2 / MeOH = 100 / 1) to obtain 2-chloro-N-(3,5-dimethoxyphenyl)-9-propyl-9H-purin-6-amine 243 mg (yield 41%), MS m / z (ESI): 348.12 [M+H] + 。

[0603] 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) were added trans-4-aminocyclohexan-1-ol (58 mg, 0.50 mmol) and triethylamine (101 mg, 1 mmol). After heating at 130 °C for 24 h, the mixture was cooled to room temperature. The reaction was quenched by adding water, and the mixture was extracted with dichloromethane three times, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent CH2Cl2 / MeOH = 20 / 1) to obtain the product 13 mg (yield 30%). 1 1H NMR (500 MHz, DMSO-d6) δ 9.22 (s, 1H), 7.84 (s, 1H), 7.30 (d, J = 2.2 Hz, 2H), 6.42 (s, 1H), 6.15 (t, J = 2.2 Hz, 1H), 4.50 (d, J = 4.3 Hz, 1H), 3.96 (t, J = 7.0 Hz, 2H), 3.74 (s, 6H), 3.71 - 3.66 (m, 1H), 3.39 (q, J = 5.2, 4.8 Hz, 1H), 1.93 (d, J = 8.5 Hz, 2H), 1.80 (dt, J = 21.7, 5.9 Hz, 4H), 1.28 (q, J = 9.3 Hz, 4H), 0.85 (t, J = 7.4 Hz, 3H). MS m / z (ESI): 427.24 [M+H] + 。

[0604] Example 132: (trans)-(4-((6-((3,5-Dimethoxyphenyl)amino)-9-isopropyl-9H-purin-2-yl)amino)cyclohexyl)methanol

[0605]

[0606] 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). After heating at 130 °C for 24 hours, the reaction mixture was cooled to room temperature. The reaction 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 (500 MHz, DMSO-d6) δ 9.21 (s, 1H), 7.93 (s, 1H), 7.32 (d, J = 2.3 Hz, 2H), 6.40 (s, 1H), 6.14 (t, J = 2.2 Hz, 1H), 4.57 (p, J = 6.7 Hz, 1H), 4.38 (t, J = 5.3 Hz, 1H), 3.73 (s, 6H), 3.71 - 3.67 (m, 1H), 3.24 (t, J = 5.8 Hz, 2H), 1.99 (d, J = 12.2 Hz, 2H), 1.81 - 1.70 (m, 2H), 1.49 (d, J = 6.7 Hz, 6H), 1.37 - 1.17 (m, 4H), 1.09 - 0.94 (m, 2H). MS m / z (ESI): 441.26 [M + H] + 。

[0607] Example 133: (cis)-4-((6-((3,5-Dimethoxyphenyl)amino)-9-isopropyl-9H-purin-2-yl)amino)cyclohexyl)methanol

[0608]

[0609] 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). After heating at 130 °C for 24 hours, the reaction mixture was cooled to room temperature. The reaction 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%). 11H NMR (500 MHz, DMSO-d6) δ 9.21 (s, 1H), 7.93 (s, 1H), 7.32 (d, J = 2.2 Hz, 2H), 6.40 (s, 1H), 6.14 (t, J = 2.2 Hz, 1H), 4.57 (p, J = 6.7 Hz, 1H), 4.38 (t, J = 5.3 Hz, 1H), 3.73 (s, 6H), 3.71 - 3.64 (m, 1H), 3.24 (t, J = 5.8 Hz, 2H), 2.02 - 1.96 (m, 2H), 1.77 (d, J = 12.8 Hz, 2H), 1.49 (d, J = 6.7 Hz, 6H), 1.37 - 1.19 (m, 4H), 1.07 - 0.95 (m, 2H). MS m / z (ESI): 441.26 [M+H] + 。

[0610] Example 134: ((trans)-4-((9-Cyclopropyl-6-((3,5-dimethoxyphenyl)amino)-9H-purin-2-yl)amino)cyclohexyl)methanol

[0611]

[0612] 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). After heating at 130 °C for 24 h, the reaction mixture was cooled to room temperature. The reaction 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 give 10 mg of the product (yield 25%). 1 1H NMR (500 MHz, DMSO-d6) δ 9.21 (s, 1H), 7.79 (s, 1H), 7.31 (d, J = 2.3 Hz, 2H), 6.54 (d, J = 15.6 Hz, 1H), 6.14 (t, J = 2.3 Hz, 1H), 4.38 (t, J = 5.3 Hz, 1H), 3.73 (s, 6H), 3.24 (t, J = 5.8 Hz, 2H), 2.03 - 1.94 (m, 2H), 1.77 (d, J = 12.9 Hz, 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] + 。

[0613] Example 135: (cis)-4-((9-Cyclopropyl-6-((3,5-dimethoxyphenyl)amino)-9H-purin-2-yl)amino)cyclohexyl)methanol

[0614]

[0615] 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). After heating at 130 °C for 24 hours, the reaction mixture was cooled to room temperature. The reaction was quenched with water and extracted three times with dichloromethane. The organic layer was 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 14%). 1 1H NMR (500 MHz, DMSO-d6) δ 9.21 (s, 1H), 7.79 (s, 1H), 7.31 (d, J = 2.3 Hz, 2H), 6.55 (s, 1H), 6.14 (t, J = 2.3 Hz, 1H), 4.38 (t, J = 5.3 Hz, 1H), 3.73 (s, 6H), 3.24 (t, J = 5.8 Hz, 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, 12.6 Hz, 2H), 1.09 - 0.94 (m, 6H). MS m / z (ESI): 439.24 [M+H] + 。

[0616] Example 136: ((trans)-4-((6-((3-Bromo-4-chloro-5-methoxyphenyl)amino)-9-isopropyl-9H-purin-2-yl)amino)cyclohexyl)methanol

[0617]

[0618] 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). After heating at 130 °C for 24 hours, the reaction mixture was cooled to room temperature. The reaction was quenched with water and extracted three times with dichloromethane. The organic layer was 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%). 11H NMR (500 MHz, DMSO-d6) δ 9.64 (s, 1H), 8.48 (s, 1H), 7.98 (s, 1H), 7.68 (s, 1H), 6.59 - 6.50 (m, 1H), 4.58 (p, J = 6.8 Hz, 1H), 4.38 (t, J = 5.3 Hz, 1H), 3.86 (s, 3H), 3.74 (d, J = 12.3 Hz, 1H), 3.24 (t, J = 5.8 Hz, 2H), 2.01 - 1.95 (m, 2H), 1.81 - 1.74 (m, 2H), 1.49 (d, J = 6.7 Hz, 6H), 1.29 - 1.21 (m, 4H), 1.07 (d, J = 13.1 Hz, 1H). MS m / z (ESI): 523.12 [M+H] + 。

[0619] Example 137: cis-4-((6-((3-Bromo-4-chloro-5-methoxyphenyl)amino)-9-isopropyl-9H-purin-2-yl)amino)cyclohexyl)methanol

[0620]

[0621] 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). After heating at 130 °C for 24 hours, the mixture was cooled to room temperature. The reaction was quenched with water and extracted three times with dichloromethane. The organic layer was 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 1H NMR (500 MHz, DMSO-d6) δ 9.64 (s, 1H), 8.49 (s, 1H), 7.98 (s, 1H), 7.68 (s, 1H), 6.69 - 6.32 (m, 1H), 4.58 (p, J = 6.8 Hz, 1H), 4.38 (t, J = 5.4 Hz, 1H), 3.86 (s, 3H), 3.73 (d, J = 10.6 Hz, 1H), 3.24 (t, J = 5.8 Hz, 2H), 2.03 - 1.93 (m, 2H), 1.77 (d, J = 12.7 Hz, 2H), 1.49 (d, J = 6.7 Hz, 6H), 1.29 - 1.20 (m, 4H), 1.09 (t, J = 12.9 Hz, 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

[0622]

[0623] 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). After heating at 130 °C for 24 hours, the mixture was cooled to room temperature. The reaction was quenched with water and extracted three times with dichloromethane. The organic layer was 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 1H NMR (500 MHz, DMSO-d6) δ 9.64 (s, 1H), 8.50 (s, 1H), 7.84 (s, 1H), 7.65 (s, 1H), 6.70 (s, 1H), 4.38 (t, J = 5.4 Hz, 1H), 3.86 (s, 3H), 3.79 - 3.68 (m, 1H), 3.23 (t, J = 5.8 Hz, 2H), 1.97 (d, J = 12.0 Hz, 2H), 1.77 (d, J = 12.7 Hz, 2H), 1.27 (dd, J = 24.4, 10.9 Hz, 5H), 1.11 (d, J = 12.9 Hz, 1H), 1.07 - 1.04 (m, 2H), 0.99 (ddd, J = 6.4, 3.7, 2.4 Hz, 2H). MS m / z (ESI): 521.11 [M+H] + 。

[0624] Example 139: cis-4-((6-((3-bromo-4-chloro-5-methoxyphenyl)amino)-9-cyclopropyl-9H-purin-2-yl)amino)cyclohexyl)methanol

[0625]

[0626] 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). After heating at 130 °C for 24 hours, the reaction mixture was cooled to room temperature. The reaction was quenched by adding water, and the mixture was 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 (500 MHz, DMSO-d6) δ 9.64 (s, 1H), 8.50 (s, 1H), 7.84 (s, 1H), 7.65 (s, 1H), 6.70 (s, 1H), 4.38 (t, J = 5.4 Hz, 1H), 3.86 (s, 3H), 3.74 (td, J = 11.0, 9.2, 5.6 Hz, 1H), 3.23 (t, J = 5.8 Hz, 2H), 1.98 (t, J = 7.5 Hz, 2H), 1.77 (d, J = 12.7 Hz, 2H), 1.36 - 1.20 (m, 5H), 1.11 (d, J = 12.9 Hz, 1H), 1.05 (d, J = 5.0 Hz, 2H), 0.99 (ddd, J = 6.6, 3.8, 2.5 Hz, 2H). MS m / z (ESI): 521.11 [M + H] + 。

[0627] Example 140: trans-4-((9-Cyclopropyl-6-((4-fluoro-3,5-dimethoxyphenyl)amino)-9H-purin-2-yl)amino)cyclohexan-1-ol

[0628]

[0629] 2,6-Dichloro-9-cyclopropyl-9H-purine (115 mg, 0.5 mmol) was dissolved in dry sec-butanol (5 mL), and 4-fluoro-3,5-dimethoxyaniline (111 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 109 mg of 2-chloro-N-(4-fluoro-3,5-dimethoxyphenyl)-9-cyclopropyl-9H-purin-6-amine (yield 60%), MS m / z (ESI): 364.10 [M + H] + 。

[0630] 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) were added trans-4-aminocyclohexan-1-ol (115 mg, 1.0 mmol) and triethylamine (202 mg, 2.0 mmol). After heating at 130 °C for 24 h, the reaction mixture was cooled to room temperature. The reaction was quenched by adding water, and the mixture was extracted with dichloromethane three times, 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 (500 MHz, DMSO) δ 9.30 (s, 1H), 7.82 (s, 1H), 7.49 (d, J = 5.0 Hz, 2H), 6.56 (s, 1H), 4.57 (d, J = 5.0 Hz, 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] + 。

[0631] Example 141: trans-4-((6-((4-Fluoro-3,5-dimethoxyphenyl)amino)-9-isopropyl-9H-purin-2-yl)amino)cyclohexan-1-ol

[0632]

[0633] 2,6-Dichloro-9-isopropyl-9H-purine (115 mg, 0.5 mmol) was dissolved in dry sec-butanol (5 mL), and 4-fluoro-3,5-dimethoxyaniline (111 mg, 0.65 mmol) was added. The mixture was heated at 110 °C for 12 h. After cooling to room temperature, the reaction was quenched by adding saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane three times, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 100 / 1) to give 111 mg of 2-chloro-N-(4-fluoro-3,5-dimethoxyphenyl)-9-isopropyl-9H-purin-6-amine (yield 61%), MS m / z (ESI): 366.11 [M + H] + 。

[0634] 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) were added trans-4-aminocyclohexan-1-ol (115 mg, 1.0 mmol) and triethylamine (202 mg, 2.0 mmol). After heating at 130 °C for 24 h, the reaction mixture was cooled to room temperature. The reaction was quenched by adding water, and the mixture was extracted with dichloromethane three times, 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 (500 MHz, DMSO) δ 9.31 (s, 1H), 7.96 (s, 1H), 7.50 (d, J = 5.0 Hz, 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 = 5.0 Hz, 1H), 1.34 - 1.15 (m, 4H). MS m / z (ESI): 445.24 [M + H] + 。

[0635] Example 142: ((trans)-4-((6-((3,5-Dimethoxyphenyl)amino)-9-propyl-9H-purin-2-yl)amino)cyclohexyl)methanol

[0636]

[0637] 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). After heating at 130 °C for 24 h, the reaction mixture was cooled to room temperature. The reaction was quenched by adding water, and the mixture was extracted with dichloromethane three times, 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 9%). 1HNMR (500 MHz, DMSO-d6) δ 9.29 (s, 1H), 7.85 (s, 1H), 7.33 (d, J = 2.2 Hz, 2H), 6.54 (s, 1H), 6.14 (t, J = 2.2 Hz, 1H), 4.43 (t, J = 5.3 Hz, 1H), 3.96 (t, J = 7.1 Hz, 2H), 3.73 (s, 6H), 3.23 (t, J = 5.8 Hz, 2H), 1.98 (d, J = 12.2 Hz, 2H), 1.77 (t, J = 11.6 Hz, 4H), 1.38 - 1.17 (m, 4H), 1.01 (q, J = 12.6 Hz, 2H), 0.85 (t, J = 7.4 Hz, 3H). MS m / z (ESI): 441.26 [M+H] + 。

[0638] Example 143: cis-4-((6-((3,5-Dibromophenyl)amino)-9-isopropyl-9H-purin-2-yl)amino)cyclohexyl)methanol

[0639]

[0640] 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) was added cis-(4-aminocyclohexyl)methanol (65 mg, 0.50 mmol) and triethylamine (101 mg, 1.0 mmol). After heating at 130 °C for 24 hours, it was cooled to room temperature. 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 obtain 5 mg of the product (yield 19%). 1 HNMR (500 MHz, DMSO-d6) δ 9.87 (s, 1H), 8.37 (s, 2H), 8.02 (s, 1H), 7.36 (t, J = 1.7 Hz, 1H), 6.68 (d, J = 8.3 Hz, 1H), 4.62 - 4.53 (m, 1H), 4.42 (t, J = 5.3 Hz, 1H), 3.71 (s, 1H), 3.23 (t, J = 5.8 Hz, 2H), 1.97 (d, J = 10.9 Hz, 2H), 1.78 (d, J = 12.5 Hz, 2H), 1.49 (d, J = 6.8 Hz, 6H), 1.26 (dd, J = 24.4, 11.1 Hz, 4H), 1.13 (s, 1H). MS m / z (ESI): 537.06 [M+H] + 。

[0641] Example 144: ((trans)-4-((9-Cyclopropyl-6-((3,5-dibromophenyl)amino)-9H-purin-2-yl)amino)cyclohexyl)methanol

[0642]

[0643] 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). After heating at 130 °C for 24 hours, the reaction mixture was cooled to room temperature. The reaction 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 1H NMR (500 MHz, DMSO-d6) δ 9.86 (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 = 5.3 Hz, 1H), 3.79 - 3.58 (m, 1H), 3.33 (d, J = 9.9 Hz, 1H), 3.23 (t, J = 5.9 Hz, 2H), 1.96 (d, J = 11.8 Hz, 2H), 1.78 (d, J = 12.5 Hz, 2H), 1.27 (dt, J = 22.5, 11.7 Hz, 4H), 1.13 (s, 1H), 1.05 (s, 2H), 1.01 - 0.95 (m, 2H). MS m / z (ESI): 535.05 [M + H] + 。

[0644] Example 145: (cis)-4-((9-Cyclopropyl-6-((3,5-dibromophenyl)amino)-9H-purin-2-yl)amino)cyclohexyl)methanol

[0645]

[0646] 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). After heating at 130 °C for 24 hours, the reaction mixture was cooled to room temperature. The reaction 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 HNMR (500 MHz, DMSO-d6) δ 9.86 (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 = 5.3 Hz, 1H), 3.83 - 3.58 (m, 1H), 3.33 (d, J = 11.5 Hz, 1H), 3.23 (t, J = 5.9 Hz, 2H), 1.96 (d, J = 11.9 Hz, 2H), 1.78 (d, J = 12.5 Hz, 2H), 1.27 (dt, J = 22.1, 11.6 Hz, 4H), 1.13 (s, 1H), 1.05 (s, 2H), 1.01 - 0.97 (m, 2H). MS m / z (ESI): 535.04 [M + H] + 。

[0647] Example 146: cis-4-((6-((4-chloro-3,5-dimethoxyphenyl)amino)-9-cyclopropyl-9H-purin-2-yl)amino)cyclohexyl)methanol

[0648]

[0649] 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). After heating at 130 °C for 24 hours, it was cooled to room temperature. 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 obtain 4 mg of the product (yield 17%). 1 H NMR (500 MHz, DMSO-d6) δ 9.41 (s, 1H), 7.84 (s, 1H), 7.56 (s, 2H), 6.61 (s, 1H), 4.44 (t, J = 5.3 Hz, 1H), 3.85 (s, 6H), 3.78 (s, 1H), 3.23 (t, J = 5.8 Hz, 2H), 1.97 (s, 2H), 1.76 (d, J = 12.7 Hz, 2H), 1.30 (s, 1H), 1.28 (s, 1H), 1.26 (d, J = 4.2 Hz, 2H), 1.06 (s, 2H), 0.99 (q, J = 7.4, 6.5 Hz, 2H), 0.96 - 0.90 (m, 1H). MS m / z (ESI): 473.17 [M + H] + 。

[0650] Example 147: cis-4-((6-((4-chloro-3,5-dimethoxyphenyl)amino)-9-isopropyl-9H-purin-2-yl)amino)cyclohexyl)methanol

[0651]

[0652] 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). After heating at 130 °C for 24 hours, the mixture was cooled to room temperature. The reaction 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 obtain 4 mg of the product (yield 17%). 1 1H NMR (500 MHz, DMSO-d6) δ 9.42 (s, 1H), 7.97 (s, 1H), 7.57 (s, 2H), 6.46 (s, 1H), 4.61 - 4.53 (m, 1H), 4.43 (t, J = 5.3 Hz, 1H), 3.85 (s, 6H), 3.75 (s, 1H), 3.23 (t, J = 5.8 Hz, 2H), 1.98 (d, J = 11.6 Hz, 2H), 1.76 (d, J = 12.7 Hz, 2H), 1.50 (d, J = 6.8 Hz, 6H), 1.30 (s, 1H), 1.28 (s, 1H), 1.26 (d, J = 4.3 Hz, 1H), 0.94 (s, 1H). MS m / z (ESI): 475.22 [M+H] + 。

[0653] Example 148: cis-4-((6-((3,5-dimethoxyphenyl)amino)-9-(3-methoxypropyl)-9H-purin-2-yl)amino)cyclohexyl)methanol

[0654]

[0655] 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 h. The reaction was quenched by adding saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane three times, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain 1.12 g of 2,6-dichloro-9-(3-methoxypropyl)-9H-purine (yield 43%), MS m / z (ESI): 261.03 [M+H] + 。

[0656] 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 h. After cooling to room temperature, the reaction was quenched by adding saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane three times, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent CH2Cl2 / MeOH = 100 / 1) to obtain 100 mg of 2-chloro-N-(3,5-dimethoxyphenyl)-9-(3-methoxypropyl)-9H-purin-6-amine (yield 53%), MS m / z (ESI): 378.13 [M+H] + 。

[0657] 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) were added cis-(4-aminocyclohexyl)methanol (65 mg, 0.50 mmol) and triethylamine (101 mg, 1.0 mmol). After heating at 130 °C for 24 h, the mixture was cooled to room temperature. The reaction was quenched by adding water, and the mixture was extracted with dichloromethane three times, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent CH2Cl2 / MeOH = 20 / 1) to obtain 9 mg of the product (yield 28%). 11H NMR (500 MHz, DMSO-d6) δ 9.25 (s, 1H), 7.81 (s, 1H), 7.32 (d, J = 2.3 Hz, 2H), 6.50 (s, 1H), 6.14 (t, J = 2.3 Hz, 1H), 4.40 (t, J = 5.3 Hz, 1H), 4.05 (t, J = 7.1 Hz, 2H), 3.73 (s, 6H), 3.31 (t, J = 6.1 Hz, 2H), 3.23 (s, 4H), 2.00 (td, J = 15.5, 14.3, 8.1 Hz, 4H), 1.76 (d, J = 12.8 Hz, 2H), 1.40 - 1.18 (m, 5H), 1.01 (q, J = 12.8, 12.4 Hz, 2H). MS m / z (ESI): 471.27 [M+H] + 。

[0658] Example 149: cis-4-((9-(Cyclobutylmethyl)-6-((3,5-dimethoxyphenyl)amino)-9H-purin-2-yl)amino)cyclohexyl)methanol

[0659]

[0660] Dissolve 2,6-dichloropurine (1.89 g, 10 mmol) in dry N,N-dimethylformamide (50 mL), add (iodomethyl)cyclobutane (2.35 g, 12 mmol) and potassium carbonate (2.07 g, 15 mmol), and stir at room temperature for 12 hours. Quench the reaction by adding saturated sodium bicarbonate solution. Extract three times with dichloromethane, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography to obtain 1.02 g (yield 40%) of 2,6-dichloro-9-(cyclobutylmethyl)-9H-purine, MS m / z (ESI): 257.04 [M+H] + 。

[0661] Dissolve 2,6-dichloro-9-(cyclobutylmethyl)-9H-purine (300 mg, 1.17 mmol) in dry sec-butanol (10 mL), add 3,5-dimethoxyaniline (179 mg, 1.17 mmol), and heat at 100 °C for 12 hours. Cool to room temperature, quench the reaction by adding saturated sodium bicarbonate solution, extract three times with dichloromethane, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (eluent CH2Cl2 / MeOH = 100 / 1) to obtain 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] + 。

[0662] 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) were added cis-(4-aminocyclohexyl)methanol (65 mg, 0.50 mmol) and triethylamine (101 mg, 1.0 mmol). After heating at 130 °C for 24 h, the reaction mixture was cooled to room temperature. The reaction 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 19%). 1 H NMR (500 MHz, DMSO-d6) δ 9.25 (s, 1H), 7.83 (s, 1H), 7.32 (d, J = 2.2 Hz, 2H), 6.50 (s, 1H), 6.14 (t, J = 2.3 Hz, 1H), 4.40 (t, J = 5.3 Hz, 1H), 4.02 (d, J = 7.4 Hz, 2H), 3.73 (s, 6H), 3.23 (t, J = 5.8 Hz, 2H), 2.78 (p, J = 7.5 Hz, 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] + 。

[0663] Example 150: ((trans-4-((9-(cyclobutylmethyl)-6-((3,5-dimethoxyphenyl)amino)-9H-purin-2-yl)amino)cyclohexyl)methanol

[0664]

[0665] 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). After heating at 130 °C for 24 h, the reaction mixture was cooled to room temperature. The reaction 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 24%). 11H NMR (500 MHz, DMSO-d6) δ 9.25 (s, 1H), 7.83 (s, 1H), 7.32 (d, J = 2.3 Hz, 2H), 6.50 (s, 1H), 6.14 (t, J = 2.3 Hz, 1H), 4.40 (t, J = 5.3 Hz, 1H), 4.02 (d, J = 7.4 Hz, 2H), 3.73 (s, 6H), 3.23 (t, J = 5.8 Hz, 2H), 2.78 (hept, J = 7.7 Hz, 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, 10.7 Hz, 2H). MS m / z (ESI): 467.28 [M+H] + 。

[0666] Example 151: ((trans)-4-((6-((3,5-Dimethoxyphenyl)amino)-9-(3-methoxypropyl)-9H-purin-2-yl)amino)cyclohexyl)methanol

[0667]

[0668] 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). After heating at 130 °C for 24 h, it was cooled to room temperature. The reaction 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%). 1 1H NMR (500 MHz, DMSO-d6) δ 9.25 (s, 1H), 7.81 (s, 1H), 7.32 (d, J = 2.3 Hz, 2H), 6.50 (s, 1H), 6.14 (t, J = 2.2 Hz, 1H), 4.40 (t, J = 5.3 Hz, 1H), 4.05 (t, J = 7.1 Hz, 2H), 3.73 (s, 6H), 3.31 (t, J = 6.1 Hz, 2H), 3.23 (s, 5H), 2.00 (tt, J = 12.6, 5.2 Hz, 4H), 1.76 (d, J = 12.7 Hz, 2H), 1.39 - 1.17 (m, 4H), 1.07 - 0.95 (m, 2H). MS m / z (ESI): 471.27 [M+H] + 。

[0669] Example 152: trans-4-((6-((3-bromo-4-chloro-5-methoxyphenyl)amino)-9-(3-methoxypropyl)-9H-purin-2-yl)amino)cyclohexan-1-ol

[0670]

[0671] Dissolve 2,6-dichloro-9-(3-methoxypropyl)-9H-purine (188 mg, 0.72 mmol) (Reference Example 148) in dry sec-butanol (5 mL), add 3-bromo-4-chloro-5-methoxyaniline (170 mg, 0.72 mmol), and heat at 90 °C for 12 hours. Cool to room temperature, and quench the reaction with saturated sodium bicarbonate solution. Extract three times with dichloromethane, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (eluent CH2Cl2 / MeOH = 100 / 1) to obtain 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] + .

[0672] Add trans-4-aminocyclohexan-1-ol (58 mg, 0.5 mmol) and triethylamine (101 mg, 1.0 mmol) 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), heat at 130 °C for 24 hours, and then cool to room temperature. Quench with water, extract three times with dichloromethane, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (eluent CH2Cl2 / MeOH = 20 / 1) to obtain 15 mg (yield 28%) of the product. 1 H NMR (500 MHz, DMSO-d6) δ 9.67 (s, 1H), 8.47 (s, 1H), 7.86 (s, 1H), 7.68 (s, 1H), 6.59 (s, 1H), 4.51 (d, J = 4.7 Hz, 1H), 4.06 (t, J = 7.1 Hz, 2H), 3.87 (s, 3H), 3.73 (s, 1H), 3.45 - 3.36 (m, 1H), 3.31 (d, J = 6.1 Hz, 2H), 3.23 (s, 3H), 2.01 (p, J = 6.6 Hz, 2H), 1.92 (d, J = 9.9 Hz, 2H), 1.84 (d, J = 9.4 Hz, 2H), 1.40 - 1.27 (m, 4H). MS m / z (ESI): 539.11 [M+H] + .

[0673] Example 153: ((Trans)-4-((6-((3-bromo-4-chloro-5-methoxyphenyl)amino)-9-(3-methoxypropyl)-9H-purin-2-yl)amino)cyclohexyl)methanol

[0674]

[0675] 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). After heating at 130 °C for 24 hours, the mixture was cooled to room temperature. The reaction 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 1H NMR (500 MHz, DMSO-d6) δ 9.67 (s, 1H), 8.50 (s, 1H), 7.86 (s, 1H), 7.66 (s, 1H), 6.62 (s, 1H), 4.39 (t, J = 5.3 Hz, 1H), 4.06 (t, J = 7.2 Hz, 2H), 3.86 (s, 3H), 3.78 - 3.67 (m, 1H), 3.32 (t, J = 6.3 Hz, 2H), 3.23 (s, 5H), 2.05 - 1.93 (m, 4H), 1.77 (d, J = 12.6 Hz, 2H), 1.38 - 1.23 (m, 3H), 1.07 (d, J = 12.9 Hz, 2H). MS m / z (ESI): 553.13 [M + H] + 。

[0676] Example 154: Trans-4-((6-((4-chloro-3,5-dimethoxyphenyl)amino)-9-propyl-9H-purin-2-yl)amino)cyclohexan-1-ol

[0677]

[0678] Dissolve 2,6-dichloro-9-propyl-9H-purine (164 mg, 0.7 mmol) (Refer to Example 131) in dry sec-butanol (5 mL), add 4-chloro-3,5-dimethoxyaniline (131 mg, 0.7 mmol), and heat at 90 °C for 12 h. Cool to room temperature, and quench the reaction by adding saturated sodium bicarbonate solution. Extract with dichloromethane three times, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (eluent CH2Cl2 / MeOH = 100 / 1) to obtain 156 mg (yield 58%) of 2-chloro-N-(4-chloro-3,5-dimethoxyphenyl)-9-propyl-9H-purin-6-amine, MS m / z (ESI): 382.08 [M+H] + .

[0679] 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), add trans-4-aminocyclohexan-1-ol (58 mg, 0.5 mmol) and triethylamine (101 mg, 1.0 mmol), heat at 130 °C for 24 h, and then cool to room temperature. Quench with water, extract with dichloromethane three times, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (eluent CH2Cl2 / MeOH = 20 / 1) to obtain 12 mg (yield 26%) of the product. 1 H NMR (500 MHz, DMSO-d6) δ 9.38 (s, 1H), 7.87 (s, 1H), 7.54 (s, 2H), 6.40 (s, 1H), 4.51 (d, J = 4.6 Hz, 1H), 3.97 (t, J = 7.1 Hz, 2H), 3.85 (s, 6H), 3.76 (s, 1H), 3.39 (dq, J = 10.3, 5.2 Hz, 1H), 1.91 (d, J = 12.3 Hz, 2H), 1.82 (td, J = 14.5, 5.7 Hz, 4H), 1.37 - 1.19 (m, 4H), 0.86 (t, J = 7.3 Hz, 3H). MS m / z (ESI): 461.20 [M+H] + .

[0680] Example 155: (trans-4-((6-((3-bromo-4-chloro-5-methoxyphenyl)amino)-9-cyclopropyl-9H-purin-2-yl)amino)cyclohexyl)methanol

[0681]

[0682] 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). After heating at 130 °C for 24 hours, the reaction mixture was cooled to room temperature. The reaction was quenched by adding water, and the mixture was extracted with dichloromethane three times, 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 (500 MHz, DMSO-d6) δ 9.62 (s, 1H), 8.48 (s, 1H), 7.84 (s, 1H), 7.66 (s, 1H), 6.68 (s, 1H), 4.37 (t, J = 5.3 Hz, 1H), 3.86 (s, 3H), 3.74 (ddt, J = 15.6, 11.5, 5.9 Hz, 1H), 3.24 (t, J = 5.8 Hz, 2H), 1.98 (d, J = 12.1 Hz, 2H), 1.77 (d, J = 12.7 Hz, 2H), 1.29 (dd, J = 25.1, 11.8 Hz, 3H), 1.14 - 1.03 (m, 4H), 0.99 (dd, J = 7.3, 5.1 Hz, 2H). MS m / z (ESI): 521.11 [M + H] + Example 156: trans-4-((6-((4-chloro-3,5-dimethoxyphenyl)amino)-9-(cyclopropylmethyl)-9H-purin-2-yl)amino)cyclohexan-1-ol

[0683]

[0684] 2,6-Dichloro-9-(cyclopropylmethyl)-9H-purine (200 mg, 0.83 mmol) (Reference Example 7) was dissolved in dry sec-butanol (5 mL), and 4-chloro-3,5-dimethoxyaniline (155 mg, 0.83 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 with dichloromethane three times, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 100 / 1) to give 160 mg of 2-chloro-N-(4-chloro-3,5-dimethoxyphenyl)-9-(cyclopropylmethyl)-9H-purin-6-amine (yield 50%), MS m / z (ESI): 394.08 [M + H] + 。

[0685] 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) were added trans-4-aminocyclohexan-1-ol (58 mg, 0.5 mmol) and triethylamine (101 mg, 1.0 mmol). After heating at 130 °C for 24 h, the reaction mixture was cooled to room temperature. The reaction was quenched with water and extracted with dichloromethane three times. The organic layer was 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 (500 MHz, DMSO-d6) δ 9.38 (s, 1H), 7.91 (s, 1H), 7.55 (s, 2H), 6.38 (d, J = 8.3 Hz, 1H), 4.51 (d, J = 4.6 Hz, 1H), 3.88 (s, 1H), 3.86 (s, 6H), 3.77 (d, J = 10.1 Hz, 1H), 3.39 (td, J = 10.3, 4.7 Hz, 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, 2.9 Hz, 2H), 0.46 - 0.42 (m, 2H). MS m / z (ESI): 473.21 [M+H] + 。

[0686] Example 157: (trans-4-((6-((4-chloro-3,5-dimethoxyphenyl)amino)-9-(cyclopropylmethyl)-9H-purin-2-yl)amino)cyclohexyl)methanol

[0687]

[0688] 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). After heating at 130 °C for 24 h, the reaction mixture was cooled to room temperature. The reaction was quenched with water and extracted with dichloromethane three times. The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to give 16 mg of the product (yield 8%). 11H NMR (500 MHz, DMSO-d6) δ 9.37 (s, 1H), 7.91 (s, 1H), 7.57 (s, 2H), 6.40 (s, 1H), 4.38 (t, J = 5.3 Hz, 1H), 3.87 (s, 1H), 3.86 (d, J = 3.1 Hz, 6H), 3.80 - 3.72 (m, 1H), 3.24 (t, J = 5.8 Hz, 2H), 2.01 - 1.94 (m, 2H), 1.80 - 1.72 (m, 2H), 1.36 - 1.20 (m, 5H), 0.96 (t, J = 13.0 Hz, 2H), 0.55 - 0.50 (m, 2H), 0.46 - 0.41 (m, 2H). MS m / z (ESI): 487.22 [M+H] + 。

[0689] Example 158: trans-4-((6-((3-Bromo-4-chloro-5-methoxyphenyl)amino)-9-(cyclopropylmethyl)-9H-purin-2-yl)amino)cyclohexan-1-ol

[0690]

[0691] 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 h. After cooling to room temperature, the reaction was quenched with 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 obtain 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] + 。

[0692] 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-aminocyclohexan-1-ol (58 mg, 0.5 mmol) and triethylamine (101 mg, 1.0 mmol). After heating at 130 °C for 24 h, the mixture was cooled to room temperature. The reaction 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 obtain 11 mg (yield 21%) of the product. 11H NMR (500 MHz, DMSO-d6) δ 9.64 (s, 1H), 8.42 (s, 1H), 7.93 (s, 1H), 7.70 (s, 1H), 6.52 (d, J = 8.2 Hz, 1H), 4.48 (d, J = 4.7 Hz, 1H), 3.87 (s, 3H), 3.86 (s, 1H), 3.73 (s, 1H), 3.43 - 3.35 (m, 1H), 1.93 (d, J = 9.8 Hz, 2H), 1.84 (d, J = 9.3 Hz, 2H), 1.39 - 1.22 (m, 6H), 0.52 (dt, J = 8.0, 2.9 Hz, 2H), 0.42 (d, J = 5.0 Hz, 2H). MS m / z (ESI): 521.11 [M + H] + 。

[0693] Example 159: cis-4-((6-((4-Chloro-3,5-dimethoxyphenyl)amino)-9-propyl-9H-purin-2-yl)amino)cyclohexyl)methanol

[0694]

[0695] 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). After heating at 130 °C for 24 hours, it was cooled to room temperature. The reaction 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 obtain 9 mg of the product (yield 20%). 1 1H NMR (500 MHz, DMSO-d6) δ 9.36 (s, 1H), 7.86 (s, 1H), 7.56 (s, 2H), 6.42 (s, 1H), 4.38 (t, J = 5.4 Hz, 1H), 3.97 (t, J = 7.1 Hz, 2H), 3.85 (s, 6H), 3.76 (d, J = 10.2 Hz, 1H), 3.23 (t, J = 5.8 Hz, 2H), 1.97 (d, J = 12.4 Hz, 2H), 1.85 - 1.70 (m, 4H), 1.33 - 1.20 (m, 3H), 0.94 (q, J = 13.5 Hz, 2H), 0.86 (t, J = 7.3 Hz, 3H). MS m / z (ESI): 475.22 [M + H] + 。

[0696] Example 160: trans-4-((9-Cyclopropyl-6-((3,4-difluoro-5-methoxyphenyl)amino)-9H-purin-2-yl)amino)cyclohexan-1-ol

[0697]

[0698] Dissolve 2,6-dichloro-9-cyclopropyl-9H-purine (115 mg, 0.5 mmol) in dry sec-butanol (5 mL), add 3,4-difluoro-5-methoxyaniline (103 mg, 0.65 mmol), and heat at 110 °C for 12 hours. Cool to room temperature, and quench the reaction by adding saturated sodium bicarbonate solution. Extract three times with dichloromethane, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (eluent CH2Cl2 / MeOH = 100 / 1) to obtain 2-chloro-9-cyclopropyl-N-(3,4-difluoro-5-methoxyphenyl)-9H-purin-6-amine 58 mg (yield 33%), MS m / z (ESI): 352.08 [M+H] + .

[0699] Add trans-4-aminocyclohexan-1-ol (58 mg, 0.5 mmol) and triethylamine (101 mg, 1.0 mmol) 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), heat at 130 °C for 24 hours, and then cool to room temperature. Quench with water, extract three times with dichloromethane, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (eluent CH2Cl2 / MeOH = 20 / 1) to obtain the product 10 mg (yield 24%). 1 H NMR (500 MHz, DMSO) δ 9.55 (s, 1H), 8.10 - 8.06 (m, 1H), 7.82 (s, 1H), 7.48 (s, 1H), 6.70 (s, 1H), 4.45 (d, J = 5.0 Hz, 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] + .

[0700] Example 161: trans-4-((6-((3,5-dibromo-4-fluorophenyl)amino)-9-isopropyl-9H-purin-2-yl)amino)cyclohexan-1-ol

[0701]

[0702] 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 h. After cooling to room temperature, the reaction was quenched with saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane three times, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 100 / 1) to obtain 123 mg of 2-chloro-N-(3,5-dibromo-4-fluorophenyl)-9-isopropyl-9H-purin-6-amine (yield 53%), MS m / z (ESI): 459.90 [M+H] + .

[0703] 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) were added trans-4-aminocyclohexan-1-ol (58 mg, 0.5 mmol) and triethylamine (101 mg, 1.0 mmol). After heating at 130 °C for 24 h, the mixture was cooled to room temperature. The reaction was quenched by adding water, and the mixture was extracted with dichloromethane three times, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to obtain 11 mg of the product (yield 40%). 1 1H NMR (500 MHz, DMSO) δ 9.78 (s, 1H), 8.44 (d, J = 5.0 Hz, 2H)), 8.00 (s, 1H), 6.59 (d, J = 5.0 Hz, 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 = 5.0 Hz, 6H), 1.39 - 1.28 (m, 4H). MS m / z (ESI): 541.04 [M+H] + .

[0704] Example 162: trans-4-((9-Cyclopropyl-6-((3,5-dibromo-4-fluorophenyl)amino)-9H-purin-2-yl)amino)cyclohexan-1-ol

[0705]

[0706] Dissolve 2,6-dichloro-9-cyclopropyl-9H-purine (115 mg, 0.5 mmol) in dry sec-butanol (5 mL), add 3,5-dibromo-4-fluoroaniline (177 mg, 0.65 mmol), and heat at 110 °C for 12 h. Cool to room temperature, and quench the reaction by adding saturated sodium bicarbonate solution. Extract three times with dichloromethane, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (eluent CH2Cl2 / MeOH = 100 / 1) to obtain 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] + 。

[0707] 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), add trans-4-aminocyclohexan-1-ol (58 mg, 0.5 mmol) and triethylamine (101 mg, 1.0 mmol), heat at 130 °C for 24 h, and then cool to room temperature. Quench with water, extract three times with dichloromethane, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (eluent CH2Cl2 / MeOH = 20 / 1) to obtain 10 mg (yield 36%) of the product. 1 H NMR (500 MHz, DMSO) δ 9.78 (s, 1H), 8.44 (d, J = 5.0 Hz, 2H)), 7.85 (s, 1H), 6.73 (d, J = 5.0 Hz, 1H)), 4.49 (d, J = 5.0 Hz, 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] + 。

[0708] Example 163: trans-4-((6-((3,5-dimethoxyphenyl)amino)-9-isobutyl-9H-purin-2-yl)amino)cyclohexan-1-ol

[0709]

[0710] Dissolve 2,6-dichloropurine (1.89 g, 10 mmol) in dry N,N-dimethylformamide (50 mL), add 1-iodo-2-methylpropane (2.2 g, 12 mmol) and potassium carbonate (2.07 g, 15 mmol), and stir at room temperature for 12 h. Quench the reaction by adding saturated sodium bicarbonate solution. Extract with dichloromethane three times, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography to obtain 1.1 g of 2,6-dichloro-9-isobutyl-9H-purine (yield 45%), MS m / z (ESI): 245.04 [M+H] + 。

[0711] Dissolve 2,6-dichloro-9-isobutyl-9H-purine (168 mg, 0.7 mmol) in dry sec-butanol (10 mL), add 3,5-dimethoxyaniline (107 mg, 0.7 mmol), and heat at 90 °C for 12 h. Cool to room temperature, quench the reaction by adding saturated sodium bicarbonate solution. Extract with dichloromethane three times, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (eluent CH2Cl2 / MeOH = 100 / 1) to obtain 125 mg of 2-chloro-N-(3,5-dimethoxyphenyl)-9-isobutyl-9H-purin-6-amine (yield 51%), MS m / z (ESI): 362.14 [M+H] + 。

[0712] Add trans-4-aminocyclohexan-1-ol (58 mg, 0.5 mmol) and triethylamine (101 mg, 1.0 mmol) 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), heat at 130 °C for 24 h, and then cool to room temperature. Quench with water, extract with dichloromethane three times, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (eluent CH2Cl2 / MeOH = 20 / 1) to obtain 15 mg of the product (yield 34%). 11H NMR (500 MHz, DMSO-d6) δ 9.24 (s, 1H), 7.82 (s, 1H), 7.30 (d, J = 2.3 Hz, 2H), 6.44 (s, 1H), 6.15 (t, J = 2.3 Hz, 1H), 4.51 (d, J = 4.3 Hz, 1H), 3.81 (d, J = 7.2 Hz, 2H), 3.74 (s, 6H), 3.71 (s, 1H), 3.43 - 3.36 (m, 1H), 2.18 (hept, J = 6.8 Hz, 1H), 1.95 - 1.90 (m, 2H), 1.87 - 1.81 (m, 2H), 1.32 - 1.24 (m, 4H), 0.86 (d, J = 6.7 Hz, 6H). MS m / z (ESI): 441.26 [M+H] + 。

[0713] Example 164: ((trans)-4-((6-((3,5-Dimethoxyphenyl)amino)-9-isobutyl-9H-purin-2-yl)amino)cyclohexyl)methanol

[0714]

[0715] 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). After heating at 130 °C for 24 hours, the reaction mixture was cooled to room temperature. The reaction was quenched with water and extracted three times with dichloromethane. The organic layer was 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 34%). 1 1H NMR (500 MHz, DMSO-d6) δ 9.24 (s, 1H), 7.81 (s, 1H), 7.32 (d, J = 2.3 Hz, 2H), 6.47 (s, 1H), 6.14 (t, J = 2.3 Hz, 1H), 4.39 (t, J = 5.3 Hz, 1H), 3.81 (d, J = 7.3 Hz, 2H), 3.73 (s, 6H), 3.23 (t, J = 5.8 Hz, 2H), 2.18 (hept, J = 6.8 Hz, 1H), 2.01 - 1.94 (m, 2H), 1.76 (d, J = 12.9 Hz, 2H), 1.37 - 1.21 (m, 4H), 1.06 - 0.94 (m, 2H), 0.86 (d, J = 6.6 Hz, 6H). MS m / z (ESI): 455.28 [M+H] + 。

[0716] Example 165: trans-4-((6-((3-bromo-4-chloro-5-methoxyphenyl)amino)-9-isobutyl-9H-purin-2-yl)amino)cyclohexan-1-ol

[0717]

[0718] Dissolve 2,6-dichloro-9-isobutyl-9H-purine (168 mg, 0.7 mmol) (Reference Example 163) in dry sec-butanol (10 mL), add 3-bromo-4-chloro-5-methoxyaniline (165 mg, 0.7 mmol), and heat at 90 °C for 12 hours. Cool to room temperature, and quench the reaction by adding saturated sodium bicarbonate solution. Extract three times with dichloromethane, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (eluent CH2Cl2 / MeOH = 100 / 1) to obtain 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] + 。

[0719] Add trans-4-aminocyclohexan-1-ol (58 mg, 0.5 mmol) and triethylamine (101 mg, 1.0 mmol) 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), heat at 130 °C for 24 hours, and then cool to room temperature. Quench with water, extract three times with dichloromethane, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (eluent CH2Cl2 / MeOH = 20 / 1) to obtain 12 mg (yield 23%) of the product. 1 H NMR (500 MHz, DMSO-d6) δ 9.67 (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 = 7.3 Hz, 2H), 3.72 (s, 1H), 3.38 (s, 1H), 2.18 (hept, J = 6.8 Hz, 1H), 1.92 (d, J = 10.5 Hz, 2H), 1.84 (d, J = 9.7 Hz, 2H), 1.37 - 1.28 (m, 4H), 0.86 (d, J = 6.6 Hz, 6H). MS m / z (ESI): 523.12 [M+H] + 。

[0720] Example 166: ((trans)-4-((6-((3-bromo-4-chloro-5-methoxyphenyl)amino)-9-isobutyl-9H-purin-2-yl)amino)cyclohexyl)methanol

[0721]

[0722] 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). After heating at 130 °C for 24 hours, the reaction mixture was cooled to room temperature. The reaction was quenched with water and extracted three times with dichloromethane. The organic layer was 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 (500 MHz, DMSO-d6) δ 9.66 (s, 1H), 8.49 (s, 1H), 7.87 (s, 1H), 7.67 (s, 1H), 6.61 (s, 1H), 4.39 (t, J = 5.3 Hz, 1H), 3.86 (s, 3H), 3.82 (d, J = 7.3 Hz, 2H), 3.72 (d, J = 9.7 Hz, 1H), 3.23 (t, J = 5.8 Hz, 2H), 2.18 (hept, J = 6.9 Hz, 1H), 1.97 (d, J = 12.0 Hz, 2H), 1.77 (d, J = 12.6 Hz, 2H), 1.36 - 1.23 (m, 3H), 1.08 (t, J = 12.8 Hz, 2H), 0.86 (d, J = 6.7 Hz, 6H). MS m / z (ESI): 537.14 [M+H] + 。

[0723] Example 167: cis-4-((6-((3-bromo-4-chloro-5-methoxyphenyl)amino)-9-isobutyl-9H-purin-2-yl)amino)cyclohexyl)methanol

[0724]

[0725] 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). After heating at 130 °C for 24 hours, the reaction mixture was cooled to room temperature. The reaction was quenched with water and extracted three times with dichloromethane. The organic layer was 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%). 11H NMR (500 MHz, DMSO-d6) δ 9.66 (s, 1H), 8.49 (s, 1H), 7.87 (s, 1H), 7.67 (s, 1H), 6.61 (s, 1H), 4.39 (t, J = 5.3 Hz, 1H), 3.86 (s, 3H), 3.82 (d, J = 7.3 Hz, 2H), 3.72 (d, J = 8.1 Hz, 1H), 3.23 (t, J = 5.8 Hz, 2H), 2.18 (hept, J = 6.8 Hz, 1H), 1.97 (d, J = 12.1 Hz, 2H), 1.77 (d, J = 12.7 Hz, 2H), 1.34 - 1.22 (m, 3H), 1.07 (d, J = 12.9 Hz, 2H), 0.86 (d, J = 6.6 Hz, 6H). MS m / z (ESI): 537.14 [M+H] + 。

[0726] 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

[0727]

[0728] Dissolve 2,6-dichloropurine (1.89 g, 10 mmol) in dry N,N-dimethylformamide (50 mL), add 1,1,1-trifluoro-3-iodopropane (2.7 g, 12 mmol) and potassium carbonate (2.07 g, 15 mmol), and stir at room temperature for 12 hours. Quench the reaction by adding saturated sodium bicarbonate solution. Extract with dichloromethane three times, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography to obtain 1.14 g of 2,6-dichloro-9-(3,3,3-trifluoropropyl)-9H-purine (yield 40%), MS m / z (ESI): 284.99 [M+H] + 。

[0729] Dissolve 2,6-dichloro-9-(3,3,3-trifluoropropyl)-9H-purine (200 mg, 0.7 mmol) in dry sec-butanol (10 mL), add 3-bromo-4-chloro-5-methoxyaniline (165 mg, 0.7 mmol), and heat at 90 °C for 12 hours. Cool to room temperature, quench the reaction by adding saturated sodium bicarbonate solution. Extract with dichloromethane three times, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (eluent CH2Cl2 / MeOH = 100 / 1) to obtain 101 mg of N-(3-bromo-4-chloro-5-methoxyphenyl)-2-chloro-9-(3,3,3-trifluoropropyl)-9H-purin-6-amine (yield 36%), MS m / z (ESI): 483.96 [M+H]+ .

[0730] 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) were added trans-4-aminocyclohexan-1-ol (115 mg, 1.0 mmol) and triethylamine (202 mg, 2.0 mmol). After heating at 130 °C for 24 h, the reaction mixture was cooled to room temperature. The reaction was quenched with water and extracted three times with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to give 45 mg of the product (yield 40%). 1 1H NMR (500 MHz, DMSO-d6) δ 9.70 (s, 1H), 8.47 (s, 1H), 7.94 (s, 1H), 7.66 (s, 1H), 6.65 (d, J = 8.0 Hz, 1H), 4.51 (d, J = 4.7 Hz, 1H), 4.29 (t, J = 7.1 Hz, 2H), 3.87 (s, 3H), 3.73 (s, 1H), 3.39 (d, J = 4.6 Hz, 1H), 2.94 (td, J = 11.5, 5.7 Hz, 2H), 1.93 (s, 2H), 1.84 (d, J = 9.6 Hz, 2H), 1.39 - 1.29 (m, 4H). MS m / z (ESI): 563.08 [M+H] + .

[0731] Example 169: (trans-4-((6-((3-bromo-4-chloro-5-methoxyphenyl)amino)-9-(3,3,3-trifluoropropyl)-9H-purin-2-yl)amino)cyclohexyl)methanol

[0732]

[0733] 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). After heating at 130 °C for 24 h, the reaction mixture was cooled to room temperature. The reaction was quenched with water and extracted three times with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to give 17 mg of the product (yield 30%). 11H NMR (500 MHz, DMSO-d6) δ 9.70 (s, 1H), 8.51 (s, 1H), 7.94 (s, 1H), 7.64 (s, 1H), 6.68 (s, 1H), 4.39 (t, J = 5.4 Hz, 1H), 4.29 (t, J = 7.0 Hz, 2H), 3.86 (s, 3H), 3.73 (s, 1H), 3.23 (t, J = 5.8 Hz, 2H), 2.94 (dtd, J = 17.9, 11.1, 8.8 Hz, 2H), 1.98 (d, J = 12.0 Hz, 2H), 1.77 (d, J = 12.7 Hz, 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

[0734]

[0735] Dissolve 2,6-dichloro-9-(3,3,3-trifluoropropyl)-9H-purine (200 mg, 0.7 mmol) (Reference Example 168) in dry sec-butanol (10 mL), add 4-chloro-3,5-dimethoxyaniline (131 mg, 0.7 mmol), and heat at 90 °C for 12 hours. Cool to room temperature, and quench the reaction by adding saturated sodium bicarbonate solution. Extract three times with dichloromethane, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (eluent CH2Cl2 / MeOH = 100 / 1) to obtain 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] + 。

[0736] Add trans-4-aminocyclohexan-1-ol (58 mg, 0.5 mmol) and triethylamine (101 mg, 1.0 mmol) 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), heat at 130 °C for 24 hours, and then cool to room temperature. Quench with water, extract three times with dichloromethane, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (eluent CH2Cl2 / MeOH = 20 / 1) to obtain 14 mg (yield 27%) of the product. 11H NMR (500 MHz, DMSO-d6) δ 9.44 (s, 1H), 7.92 (s, 1H), 7.53 (s, 2H), 6.49 (s, 1H), 4.53 (d, J = 4.6 Hz, 1H), 4.30 (t, J = 7.0 Hz, 2H), 3.85 (s, 6H), 3.75 (s, 1H), 3.39 (h, J = 5.2 Hz, 1H), 2.94 (ddt, J = 18.2, 11.5, 6.8 Hz, 2H), 1.92 (d, J = 12.3 Hz, 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] + 。

[0737] Example 171: ((trans)-4-((6-((4-Chloro-3,5-dimethoxyphenyl)amino)-9-(3,3,3-trifluoropropyl)-9H-purin-2-yl)amino)cyclohexyl)methanol

[0738]

[0739] 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). After heating at 130 °C for 24 hours, the reaction mixture was cooled to room temperature. The reaction was quenched with water and extracted three times with dichloromethane. The organic layer was 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 1H NMR (500 MHz, DMSO-d6) δ 9.43 (s, 1H), 7.92 (s, 1H), 7.55 (s, 2H), 6.51 (s, 1H), 4.40 (t, J = 5.3 Hz, 1H), 4.30 (t, J = 6.9 Hz, 2H), 3.85 (s, 6H), 3.75 (s, 1H), 3.23 (t, J = 5.7 Hz, 2H), 2.95 (dtd, J = 18.2, 11.3, 7.0 Hz, 2H), 1.98 (d, J = 12.0 Hz, 2H), 1.76 (d, J = 12.9 Hz, 2H), 1.35 - 1.21 (m, 3H), 0.93 (d, J = 13.1 Hz, 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

[0740]

[0741] 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). After heating at 130 °C for 24 hours, the reaction mixture was cooled to room temperature. The reaction 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 1H NMR (500 MHz, DMSO-d6) δ 9.68 (s, 1H), 8.45 (d, J = 28.5 Hz, 1H), 7.93 (s, 1H), 7.66 (s, 1H), 6.65 (s, 1H), 4.38 (t, J = 5.4 Hz, 1H), 4.29 (t, J = 7.1 Hz, 2H), 3.87 (s, 3H), 3.73 (d, J = 11.3 Hz, 1H), 3.24 (t, J = 5.8 Hz, 2H), 2.99 - 2.88 (m, 2H), 1.98 (d, J = 12.0 Hz, 2H), 1.81 - 1.74 (m, 2H), 1.36 - 1.25 (m, 3H), 1.07 (d, J = 13.0 Hz, 2H). MS m / z (ESI): 577.10 [M+H] + 。

[0742] Example 173: trans-4-((6-((3-bromo-5-methoxyphenyl)amino)-9-(2-fluoroethyl)-9H-purin-2-yl)amino)cyclohexan-1-ol

[0743]

[0744] Dissolve 2,6-dichloropurine (1.89 g, 10 mmol) in dry N,N-dimethylformamide (50 mL), add 1-fluoro-2-iodoethane (2.09 g, 12 mmol) and potassium carbonate (2.07 g, 15 mmol), and stir at room temperature for 12 h. Quench the reaction by adding saturated sodium bicarbonate solution. Extract three times with dichloromethane, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography to obtain 1.0 g of 2,6-dichloro-9-(2-fluoroethyl)-9H-purine (yield 43%), MS m / z (ESI): 235.00 [M+H] + 。

[0745] Dissolve 2,6-dichloro-9-(2-fluoroethyl)-9H-purine (200 mg, 0.85 mmol) in dry sec-butanol (10 mL), add 3-bromo-5-methoxyaniline (172 mg, 0.85 mmol), and heat at 90 °C for 12 h. Cool to room temperature, quench the reaction by adding saturated sodium bicarbonate solution. Extract three times with dichloromethane, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (eluent CH2Cl2 / MeOH = 100 / 1) to obtain 210 mg of N-(3-bromo-5-methoxyphenyl)-2-chloro-9-(2-fluoroethyl)-9H-purin-6-amine (yield 62%), MS m / z (ESI): 400.00 [M+H] + 。

[0746] Add trans-4-aminocyclohexan-1-ol (58 mg, 0.5 mmol) and triethylamine (101 mg, 1.0 mmol) 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), heat at 130 °C for 24 h, and then cool to room temperature. Quench with water, extract three times with dichloromethane, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (eluent CH2Cl2 / MeOH = 20 / 1) to obtain 15 mg of the product (yield 38%). 11H NMR (500 MHz, DMSO-d6) δ 9.59 (s, 1H), 8.11 (s, 1H), 7.88 (s, 1H), 7.57 (s, 1H), 6.76 (t, J = 1.9 Hz, 1H), 6.56 (d, J = 8.1 Hz, 1H), 4.83 (t, J = 5.0 Hz, 1H), 4.74 (t, J = 4.9 Hz, 1H), 4.50 (d, J = 4.4 Hz, 1H), 4.36 (t, J = 4.8 Hz, 1H), 4.30 (t, J = 5.0 Hz, 1H), 3.76 (s, 3H), 3.74 - 3.67 (m, 1H), 3.44 - 3.35 (m, 1H), 1.93 (d, J = 11.3 Hz, 2H), 1.84 (d, J = 10.9 Hz, 2H), 1.30 (dd, J = 24.3, 11.9 Hz, 4H). MS m / z (ESI): 479.13 [M+H] + 。

[0747] Example 174: trans-4-((6-((3-Bromo-5-methoxyphenyl)amino)-9-(3-fluoropropyl)-9H-purin-2-yl)amino)cyclohexan-1-ol

[0748]

[0749] Dissolve 2,6-dichloropurine (1.89 g, 10 mmol) in dry N,N-dimethylformamide (50 mL), add 1-fluoro-3-iodopropane (2.26 g, 12 mmol) and potassium carbonate (2.07 g, 15 mmol), and stir at room temperature for 12 hours. Quench the reaction by adding saturated sodium bicarbonate solution. Extract with dichloromethane three times, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography to obtain 1.14 g of 2,6-dichloro-9-(3-fluoropropyl)-9H-purine (yield 46%), MS m / z (ESI): 249.01 [M+H] + 。

[0750] Dissolve 2,6-dichloro-9-(3-fluoropropyl)-9H-purine (200 mg, 0.8 mmol) in dry sec-butanol (10 mL), add 3-bromo-5-methoxyaniline (161 mg, 0.8 mmol), and heat at 90 °C for 12 hours. Cool to room temperature, quench the reaction by adding saturated sodium bicarbonate solution. Extract with dichloromethane three times, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (eluent CH2Cl2 / MeOH = 100 / 1) to obtain 211 mg of N-(3-bromo-5-methoxyphenyl)-2-chloro-9-(3-fluoropropyl)-9H-purin-6-amine (yield 62%), MS m / z (ESI): 414.01 [M+H] + 。

[0751] 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-aminocyclohexan-1-ol (58 mg, 0.5 mmol) and triethylamine (101 mg, 1.0 mmol). After heating at 130 °C for 24 h, the reaction mixture was cooled to room temperature. The reaction was quenched with water and extracted three times with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: CH2Cl2 / MeOH = 20 / 1) to give 17 mg of the product (yield 35%). 1 H NMR (500 MHz, DMSO-d6) δ 9.55 (s, 1H), 8.10 (s, 1H), 7.88 (s, 1H), 7.57 (s, 1H), 6.75 (t, J = 1.9 Hz, 1H), 6.54 (d, J = 8.0 Hz, 1H), 4.53 (t, J = 5.6 Hz, 1H), 4.49 (d, J = 4.4 Hz, 1H), 4.44 (t, J = 5.7 Hz, 1H), 4.12 (t, J = 7.1 Hz, 2H), 3.76 (s, 3H), 3.72 (d, J = 10.4 Hz, 1H), 3.43 - 3.35 (m, 1H), 2.19 (dp, J = 26.3, 6.3 Hz, 2H), 1.93 (d, J = 11.3 Hz, 2H), 1.83 (d, J = 10.7 Hz, 2H), 1.41 - 1.25 (m, 4H). MS m / z (ESI): 493.13 [M + H] + 。

[0752] Example 175: trans-4-((6-((3-bromo-5-(difluoromethoxy)phenyl)amino)-9-(2-fluoroethyl)-9H-purin-2-yl)amino)cyclohexan-1-ol

[0753]

[0754] Dissolve 2,6-dichloro-9-(2-fluoroethyl)-9H-purine (200 mg, 0.85 mmol) (refer to Example 173) in dry sec-butanol (10 mL), add 3-bromo-5-(difluoromethoxy)aniline (202 mg, 0.85 mmol), and heat at 95 °C for 12 h. Cool to room temperature, and quench the reaction by adding saturated sodium bicarbonate solution. Extract with dichloromethane three times, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (eluent CH2Cl2 / MeOH = 100 / 1) to obtain 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] + 。

[0755] 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), add trans-4-aminocyclohexan-1-ol (58 mg, 0.5 mmol) and triethylamine (101 mg, 1.0 mmol), heat at 130 °C for 24 h, and then cool to room temperature. Quench with water, extract with dichloromethane three times, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (eluent CH2Cl2 / MeOH = 20 / 1) to obtain 19 mg (yield 10%) of the product. 1 1H NMR (500 MHz, DMSO-d6) δ 9.89 - 9.79 (m, 1H), 8.35 (s, 1H), 7.90 (s, 1H), 7.86 (s, 1H), 7.26 (t, J = 73.7 Hz, 1H), 7.01 (d, J = 1.9 Hz, 1H), 6.62 (d, J = 8.1 Hz, 1H), 4.84 (t, J = 5.0 Hz, 1H), 4.74 (t, J = 4.8 Hz, 1H), 4.49 (d, J = 4.3 Hz, 1H), 4.37 (t, J = 4.9 Hz, 1H), 4.31 (t, J = 5.0 Hz, 1H), 3.71 (d, J = 11.3 Hz, 1H), 3.43 - 3.35 (m, 1H), 1.93 (d, J = 11.1 Hz, 2H), 1.84 (d, J = 10.4 Hz, 2H), 1.38 - 1.27 (m, 4H). MS m / z (ESI): 515.10 [M+H] + 。

[0756] Example 176: trans-4-((6-((4-bromo-3,5-dimethoxyphenyl)amino)-9-isopropyl-9H-purin-2-yl)amino)cyclohexan-1-ol

[0757]

[0758] Dissolve 2,6-dichloro-9-isopropyl-9H-purine (115 mg, 0.5 mmol) in dry sec-butyl alcohol (5 mL), add 4-bromo-3,5-dimethoxyaniline (151 mg, 0.65 mmol), and heat at 110 °C for 12 h. Cool to room temperature, and quench the reaction by adding saturated sodium bicarbonate solution. Extract with dichloromethane three times, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (eluent CH2Cl2 / MeOH = 100 / 1) to obtain 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] + 。

[0759] 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-butyl alcohol (1 mL), add trans-4-aminocyclohexan-1-ol (58 mg, 0.5 mmol) and triethylamine (101 mg, 1.0 mmol), heat at 130 °C for 24 h, and then cool to room temperature. Quench with water, extract with dichloromethane three times, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (eluent CH2Cl2 / MeOH = 20 / 1) to obtain 10 mg (yield 20%) of the product. 1 H NMR (500 MHz, DMSO) δ 9.38 (s, 1H), 7.96 (s, 1H), 7.53 (s, 2H), 6.57 (s, 1H), 6.36 (d, J = 5.0 Hz, 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 = 10.0 Hz, 6H), 1.33 - 1.19 (m, 4H). MS m / z (ESI): 505.16 [M+H] + 。

[0760] Example 177: trans-4-((6-((4-bromo-3,5-dimethoxyphenyl)amino)-9-cyclopropyl-9H-purin-2-yl)amino)cyclohexan-1-ol

[0761]

[0762] Dissolve 2,6-dichloro-9-cyclopropyl-9H-purine (115 mg, 0.5 mmol) in dry sec-butanol (5 mL), add 4-bromo-3,5-dimethoxyaniline (151 mg, 0.65 mmol), and heat at 110 °C for 12 h. Cool to room temperature, and quench the reaction by adding saturated sodium bicarbonate solution. Extract three times with dichloromethane, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (eluent CH2Cl2 / MeOH = 100 / 1) to obtain 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] + .

[0763] 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), add trans-4-aminocyclohexan-1-ol (58 mg, 0.5 mmol) and triethylamine (101 mg, 1.0 mmol), heat at 130 °C for 24 h, and then cool to room temperature. Quench with water, extract three times with dichloromethane, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (eluent CH2Cl2 / MeOH = 20 / 1) to obtain 12 mg (yield 25%) of the product. 1 1H NMR (500 MHz, DMSO) δ 9.38 (s, 1H), 7.82 (s, 1H), 7.52 (s, 2H), 6.48 (s, 1H), 4.51 (d, J = 5.0 Hz, 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] + .

[0764] Example 178: trans-4-((6-((4-chloro-3,5-dimethoxyphenyl)amino)-9-((3,3-difluorocyclobutyl)methyl)-9H-purin-2-yl)amino)cyclohexan-1-ol

[0765]

[0766] Dissolve 2,6-dichloropurine (1.89 g, 10 mmol) in dry N,N-dimethylformamide (50 mL), add 1,1-difluoro-3-(iodomethyl)cyclobutane (2.78 g, 12 mmol) and potassium carbonate (2.07 g, 15 mmol), and stir at room temperature for 12 hours. Quench the reaction by adding saturated sodium bicarbonate solution. Extract three times with dichloromethane, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography 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] + .

[0767] Dissolve 2,6-dichloro-9-((3,3-difluorocyclobutyl)methyl)-9H-purine (155 mg, 0.53 mmol) in dry sec-butanol (10 mL), add 4-chloro-3,5-dimethoxyaniline (99 mg, 0.53 mmol), and heat at 90 °C for 12 hours. Cool to room temperature, quench the reaction by adding saturated sodium bicarbonate solution. Extract three times with dichloromethane, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (eluent CH2Cl2 / MeOH = 100 / 1) to obtain 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] + .

[0768] Add trans-4-aminocyclohexan-1-ol (58 mg, 0.5 mmol) and triethylamine (101 mg, 1.0 mmol) 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), heat at 130 °C for 24 hours, and then cool to room temperature. Quench with water, extract three times with dichloromethane, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (eluent CH2Cl2 / MeOH = 20 / 1) to obtain 15 mg (yield 29%) of the product. 11H NMR (500 MHz, DMSO-d6) δ 9.39 (s, 1H), 7.91 (s, 1H), 7.55 (s, 2H), 6.45 (s, 1H), 4.39 (t, J = 5.3 Hz, 1H), 4.15 (d, J = 5.2 Hz, 2H), 3.85 (s, 6H), 3.78 - 3.73 (m, 1H), 3.23 (t, J = 5.7 Hz, 2H), 2.70 - 2.62 (m, 3H), 1.97 (d, J = 12.2 Hz, 2H), 1.77 (d, J = 12.9 Hz, 2H), 1.36 - 1.22 (m, 4H), 1.00 - 0.89 (m, 2H). MS m / z (ESI): 537.22 [M+H] + 。

[0769] Example 179: trans-4-((6-((4-Chloro-3,5-dimethoxyphenyl)amino)-9-isobutyl-9H-purin-2-yl)amino)cyclohexan-1-ol

[0770]

[0771] Dissolve 2,6-dichloro-9-isobutyl-9H-purine (200 mg, 0.82 mmol) (Reference Example 163) in dry sec-butanol (5 mL), add 4-chloro-3,5-dimethoxyaniline (153 mg, 0.82 mmol), and heat at 90 °C for 12 hours. Cool to room temperature, and quench the reaction by adding saturated sodium bicarbonate solution. Extract three times with dichloromethane, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (eluent CH2Cl2 / MeOH = 100 / 1) to obtain 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] + 。

[0772] Add trans-4-aminocyclohexan-1-ol (58 mg, 0.5 mmol) and triethylamine (101 mg, 1.0 mmol) 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), heat at 130 °C for 24 hours, and then cool to room temperature. Quench with water, extract three times with dichloromethane, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (eluent CH2Cl2 / MeOH = 20 / 1) to obtain 11 mg (yield 23%) of the product. 11H NMR (500 MHz, DMSO-d6) δ 9.38 (s, 1H), 7.84 (s, 1H), 7.53 (s, 2H), 6.40 (s, 1H), 4.51 (d, J = 4.6 Hz, 1H), 3.85 (s, 6H), 3.83 (d, J = 7.3 Hz, 2H), 3.75 (s, 1H), 3.43 - 3.36 (m, 1H), 2.19 (dp, J = 13.9, 7.0 Hz, 1H), 1.94 - 1.88 (m, 2H), 1.87 - 1.79 (m, 2H), 1.37 - 1.14 (m, 4H), 0.87 (d, J = 6.6 Hz, 6H). MS m / z (ESI): 475.22 [M+H] + 。

[0773] Example 180: ((trans)-4-((6-((4-Chloro-3,5-dimethoxyphenyl)amino)-9-isobutyl-9H-purin-2-yl)amino)cyclohexyl)methanol

[0774]

[0775] 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). After heating at 130 °C for 24 h, the reaction mixture was cooled to room temperature. The reaction 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%). 1 1H NMR (500 MHz, DMSO-d6) δ 9.37 (s, 1H), 7.84 (s, 1H), 7.55 (s, 2H), 6.42 (s, 1H), 4.38 (t, J = 5.3 Hz, 1H), 3.85 (s, 6H), 3.83 (d, J = 7.4 Hz, 2H), 3.75 (s, 1H), 3.23 (t, J = 5.7 Hz, 2H), 2.19 (dq, J = 13.5, 6.8 Hz, 1H), 1.97 (d, J = 12.3 Hz, 2H), 1.76 (d, J = 12.9 Hz, 2H), 1.28 (d, J = 13.9 Hz, 3H), 0.93 (q, J = 15.5, 14.2 Hz, 2H), 0.86 (d, J = 6.7 Hz, 6H). MS m / z (ESI): 489.23 [M+H] + 。

[0776] Example 181: trans-4-((6-((3-bromo-4-chloro-5-methoxyphenyl)amino)-9-(2-fluoroethyl)-9H-purin-2-yl)amino)cyclohexan-1-ol

[0777]

[0778] Dissolve 2,6-dichloro-9-(2-fluoroethyl)-9H-purine (200 mg, 0.85 mmol) (refer to Example 173) in dry sec-butanol (5 mL), add 3-bromo-4-chloro-5-methoxyaniline (201 mg, 0.85 mmol), and heat at 90 °C for 12 hours. Cool to room temperature, and quench the reaction by adding saturated sodium bicarbonate solution. Extract three times with dichloromethane, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (eluent CH2Cl2 / MeOH = 100 / 1) to obtain 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] + .

[0779] Add trans-4-aminocyclohexan-1-ol (58 mg, 0.5 mmol) and triethylamine (101 mg, 1.0 mmol) 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), heat at 130 °C for 24 hours, and then cool to room temperature. Quench with water, extract three times with dichloromethane, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (eluent CH2Cl2 / MeOH = 20 / 1) to obtain 14 mg (yield 27%) of the product. 1 H NMR (500 MHz, DMSO-d6) δ 9.69 (s, 1H), 8.44 (s, 1H), 7.89 (s, 1H), 7.68 (s, 1H), 6.58 (d, J = 7.9 Hz, 1H), 4.84 (t, J = 4.9 Hz, 1H), 4.74 (t, J = 4.8 Hz, 1H), 4.49 (d, J = 4.7 Hz, 1H), 4.37 (t, J = 4.6 Hz, 1H), 4.31 (t, J = 5.0 Hz, 1H), 3.87 (s, 3H), 3.74 (s, 1H), 3.39 (d, J = 4.6 Hz, 1H), 1.93 (d, J = 10.2 Hz, 2H), 1.84 (d, J = 9.9 Hz, 2H), 1.38 - 1.27 (m, 4H). MS m / z (ESI): 513.08 [M+H] + .

[0780] Example 182: trans-4-((6-((3-Bromo-4-chloro-5-methoxyphenyl)amino)-9-(3-fluoropropyl)-9H-purin-2-yl)amino)cyclohexan-1-ol

[0781]

[0782] Dissolve 2,6-dichloro-9-(3-fluoropropyl)-9H-purine (200 mg, 0.8 mmol) (refer to Example 174) in dry sec-butanol (5 mL), add 3-bromo-4-chloro-5-methoxyaniline (189 mg, 0.8 mmol), and heat at 90 °C for 12 h. Cool to room temperature, and quench the reaction by adding saturated sodium bicarbonate solution. Extract three times with dichloromethane, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (eluent CH2Cl2 / MeOH = 100 / 1) to obtain 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] + 。

[0783] Add trans-4-aminocyclohexan-1-ol (58 mg, 0.5 mmol) and triethylamine (101 mg, 1.0 mmol) 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), heat at 130 °C for 24 h, and then cool to room temperature. Quench with water, extract three times with dichloromethane, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (eluent CH2Cl2 / MeOH = 20 / 1) to obtain 11 mg (yield 21%) of the product. 1 H NMR (500 MHz, DMSO-d6) δ 9.66 (s, 1H), 8.43 (s, 1H), 7.90 (s, 1H), 7.68 (s, 1H), 6.57 (d, J = 8.1 Hz, 1H), 4.53 (t, J = 5.6 Hz, 1H), 4.49 (d, J = 4.7 Hz, 1H), 4.44 (t, J = 5.7 Hz, 1H), 4.13 (t, J = 7.0 Hz, 2H), 3.87 (s, 3H), 3.73 (s, 1H), 3.42 - 3.35 (m, 1H), 2.19 (dp, J = 26.2, 6.3 Hz, 2H), 1.93 (d, J = 9.9 Hz, 2H), 1.84 (d, J = 9.5 Hz, 2H), 1.38 - 1.28 (m, 4H). MS m / z (ESI): 527.10 [M+H] + 。

[0784] Example 183: trans-4-((6-((3-bromo-5-(difluoromethoxy)phenyl)amino)-9-(cyclopropylmethyl)-9H-purin-2-yl)amino)cyclohexan-1-ol

[0785]

[0786] Dissolve 2,6-dichloro-9-(cyclopropylmethyl)-9H-purine (200 mg, 0.87 mmol) (Reference Example 7) in dry sec-butanol (5 mL), add 3-bromo-5-(difluoromethoxy)aniline (207 mg, 0.87 mmol), and heat at 90 °C for 12 hours. Cool to room temperature, and quench the reaction by adding saturated sodium bicarbonate solution. Extract three times with dichloromethane, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (eluent CH2Cl2 / MeOH = 100 / 1) to obtain 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] + 。

[0787] Add trans-4-aminocyclohexan-1-ol (58 mg, 0.5 mmol) and triethylamine (101 mg, 1.0 mmol) 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), heat at 130 °C for 24 hours, and then cool to room temperature. Quench with water, extract three times with dichloromethane, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (eluent CH2Cl2 / MeOH = 20 / 1) to obtain 16 mg (yield 31%) of the product. 1 1H NMR (500 MHz, DMSO-d6) δ 9.82 (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 = 2.0 Hz, 1H), 6.57 (d, J = 8.2 Hz, 1H), 4.49 (d, J = 4.3 Hz, 1H), 3.86 (d, J = 7.1 Hz, 2H), 3.73 - 3.66 (m, 1H), 3.40 (q, J = 6.1, 4.8 Hz, 1H), 1.94 (d, J = 10.9 Hz, 2H), 1.84 (d, J = 10.3 Hz, 2H), 1.30 (dd, J = 23.5, 11.2 Hz, 5H), 0.52 (dt, J = 8.1, 3.0 Hz, 2H), 0.42 (d, J = 5.0 Hz, 2H). MS m / z (ESI): 523.13 [M+H] + 。

[0788] Example 184: Detection of the in vitro inhibitory activity (enzyme activity) of a compound against PGK1 protein

[0789] Dissolve the powders of the compounds of the present invention and the comparative compounds in DMSO to prepare a stock solution with a concentration of 1 mM. Next, perform gradient dilution with DMSO at a three-fold dilution factor to obtain 8 concentrations, and then dilute 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, add 5 μL of PGK1 protein (recombinant human PGK1 protein, purchased from abcom, USA, catalog number ab211320) solution diluted to 0.2 ng / μL with reaction buffer to each tube, and then add 5 μL of the diluted compound. Incubate for 10 minutes, and then add 10 μL of substrate 3-phosphoglycerate diluted to 0.4 μg / μL and 20 μM ATP (purchased from Promega, Madison, WI) with reaction buffer (20 mM Tris, 100 mM NaCl, 0.1 mM MgCl2, 2 mM DTT, pH 8.6), and react at room temperature for 30 minutes. Then, add 20 μL of ADP Glo TM reagent (purchased from Promega, Madison, WI) and incubate for 40 minutes to stop the reaction and deplete the remaining ATP. Then, add 40 uL of kinase detection reagent (purchased from Promega, Madison, WI) to convert ADP to ATP. Detect the newly synthesized ATP using the luciferase / luciferin system. Use a multi-functional microplate reader (Envision, PerkinElmer, MA, USA) to detect the luminescence value, and use Graph Pad Prim 9.0 for data fitting to calculate the half-maximal inhibitory concentration IC 50 value, and the data is shown in Table 2.

[0790] The detection results show that the compounds of the present invention have strong inhibitory activity against PGK1, and their IC 50 values are all below 100 nM (see Table 2). At the same time, the inventors synthesized Comparative Compound 1 and Comparative Compound 2, and purchased Compound NG52 from MedChem Express, China. Their structures are shown in Table 1. The results show that the inhibitory activity of the compounds of the present invention against PGK1 is significantly better than that of the comparative compounds, and the substituents on the five-membered ring of purine and the substituents and their numbers on the benzene ring may affect the inhibitory activity against PGK1.

[0791] Table 1. Structures of comparative compounds

[0792]

[0793]

[0794] Table 2. Test results of in vitro inhibitory activity (enzyme activity) against PGK1 protein

[0795]

[0796]

[0797]

[0798] Example 185: Detection of in vitro inhibitory activity (enzyme activity) of Compound 1 against CDKs proteins

[0799] 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.

[0800] The powder of Compound 1 of the present invention was dissolved in DMSO to prepare a stock solution with a concentration of 1 mM. Next, it was serially diluted into 8 concentrations with DMSO at a three-fold dilution factor, 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 CDKs protein solution diluted to 0.2 - 1 ng / μL (specific amount according to the protein instruction manual) with reaction buffer was added to each tube, and then 5 μL of the diluted Compound 1 was added. Incubate for 10 minutes, then add 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 react at room temperature for 30 minutes. Then, 20 μL of ADP Glo was added to each well TMThe reagent (purchased from Promega, Madison, WI) was added and incubated for 40 minutes to stop the reaction and deplete the remaining ATP. Then, 40 μL of kinase detection reagent (purchased from Promega, Madison, WI) was added to convert ADP into ATP. The newly synthesized ATP was detected using the luciferase / luciferin system. The luminescence value was detected using a multimode microplate reader (Envision, PerkinElmer, MA, USA), and data fitting was performed using Graph Pad Prism 9.0 to calculate the half inhibitory concentration IC 50 value, and the data are shown in Table 3.

[0801] The detection results showed that the compounds of the present invention could selectively inhibit PGK1, and had no obvious inhibitory activity against different subtypes of the CDK family.

[0802] Table 3. Test results of in vitro inhibitory activity (enzyme activity) against CDKs proteins

[0803] Protein <![CDATA[Compound 1 / IC 50 : nM]]> PGK1 63 CDK1 >1000 CDK2 390 CDK6 >1000 CDK7 839 CDK9 548

[0804] Example 186: Effect of compounds on the secretion of inflammatory factors in mouse monocyte macrophage leukemia cells RAW264.7

[0805] Three compounds of the invention were selected, and the effects of the compounds 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 detected by western blot. The specific steps are as follows.

[0806] 106 cells were seeded in a 6-well plate. LPS was not added to one well, and LPS was added to the remaining wells. At the same time, compounds at 0.01, 0.03, 0.1, 0.3, 1, and 3 μM were added. After incubation for 24 hours, the cells were collected (800 rpm / min, 4 min) into 1.5 mL centrifuge tubes. 50 μL of cell lysis buffer RIPA (purchased from Beyotime, China) was added to each tube, and the cells were lysed on ice for 10 minutes. 5× protein loading buffer (purchased from Beyotime, China) was added, and the samples were boiled at 95 °C for 10 minutes. Separated by gel electrophoresis and transferred to a membrane....

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt, solvate, isomer, ester, acid, metabolite or prodrug thereof, wherein, 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, wherein 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, a four- to six-membered heterocyclic group, and a four- to six-membered heterocyclic group C1-4 alkyl; R 3 each independently selected from hydroxy, amino, nitrile, oxo, carboxyl, amido, halogen, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 hydroxyalkylamino, C1-6 alkylamido, C1-6 alkylamido, 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 four- to six-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 relative to the amino linking group of the benzene ring, R 1 is in the meta and / or para positions 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 claim 1 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, and R 3 are each independently selected from hydroxy, amino, carboxyl, halogen, C1-3 alkyl, and C1-3 alkylaminoacyl, and m is 1 or 2.

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

7. 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:

8. A pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt, solvate, isomer, ester, acid, metabolite or prodrug thereof according to any one of claims 1-7, and a pharmaceutically acceptable carrier or excipient, and optionally other therapeutic agents.

9. Use of the compound or a pharmaceutically acceptable salt, solvate, isomer, ester, acid, metabolite or prodrug thereof according to any one of claims 1-7 in the preparation of a drug for the treatment or prevention of hypersensitivity or autoimmune inflammatory-related diseases.

10. The use according to claim 9, 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.

11. The use according to claim 9 or 10, wherein the hypersensitivity or autoimmune inflammatory-related disease is 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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