WO2023186065A1

WO2023186065A1 - A cyclin-dependent kinase inhibitor

Info

Publication number: WO2023186065A1
Application number: PCT/CN2023/085372
Authority: WO
Inventors: Lei MO; Junkai Huang; Kai Li; Xiaohui Hu; Li Zhou; Tao CUI; Dongqiang CHEN
Original assignee: Taizhou Eoc Pharma Co Ltd
Current assignee: Taizhou Eoc Pharma Co Ltd
Priority date: 2022-04-02
Filing date: 2023-03-31
Publication date: 2023-10-05
Anticipated expiration: 2024-10-02

Abstract

The present disclosure provides a series of compounds as potent inhibitors of cyclin-dependent kinase (CDK), or pharmaceutically acceptable salts thereof. Corresponding compositions are also provided.

Description

A CYCLIN-DEPENDENT KINASE INHIBITOR

CROSS REFERENCE TO RELATED APPLICATIONS

The present application claims priority to PCT International Application PCT/CN2022/085014, entitled "A CYCLIN-DEPENDENT KINASE INHIBITOR" , and filed to the China National Intellectural Property Administration on April 02, 2022, the entire contents of which are incorporated herein by reference. The present application also claims priority to PCT International Application PCT/CN2022/122533, entitled "A CYCLIN-DEPENDENT KINASE INHIBITOR" , and filed to the China National Intellectural Property Administration on September 29, 2022, the entire contents of which are incorporated herein by reference.

BACKGROUND OF THE INVENTION

Cyclin-dependent kinase (CDK) family members that trigger passage through the cell cycle are being considered as attractive therapeutic targets, especially for cancer. There is a continuing need for CDK inhibitors.

SUMMARY OF THE INVENTION

In a fitst aspect, the present disclosure provides a compound having the structure of formula (I) ,

or a pharmaceutically acceptable salt, or prodrug thereof, or a solvate or hydrate of any of the forgoing,

wherein, A is optionally substituted ring, B is optionally substituted ring,

each R₁, R₂, R₃, R₄, and R₅ is independently absent or is independently selected from optional substituents,

each X₁, X₂, X₃, X₄, X₅, X₆, X₇, X₈, X₉ and X₁₀ is independently absent or is independently selected from optionally substituted atom, wherein, m is 0 or more, and n is 0 or more.

In a second aspect, the present disclosure provides a compound having the structure of formula (II) ,

wherein, A is optionally substituted heterocycle, B is optionally substituted ring with one or more ortho-position substituent group,

each X₁ and X₂ is independently absent or is independently selected from optionally substituted atom,

each R₁, R₂ and R₃ is independently absent or is independently selected from optional substituents.

In a third aspect, the present disclosure provides a compound having the structure of formula (III) ,

wherein, X₁ is independently selected from optionally substituted atom,

each R₁, R₂, R₃ and R₄ is independently absent or is independently selected from optional substituents, n is 0 or more.

In a further aspect, the present disclosure provides a composition comprising a compound of the present disclosure, or a pharmaceutically acceptable salt, prodrug, or metabolite thereof, or a solvate or hydrate of any of the foregoing, and optionally a pharmaceutically acceptable carrier.

In a further aspect, the present disclosure provides a method for inhibiting cyclin-dependent kinase (CDK) activity, said method comprising administering to a subject in need thereof an effective amount of the compound of the present disclosure, or a pharmaceutically acceptable salt, prodrug, or metabolite thereof, or a solvate or hydrate of any of the foregoing.

Additional aspects and advantages of the present disclosure will become readily apparent to those skilled in this art from the following detailed description, wherein only illustrative embodiments of the present disclosure are shown and described. As will be realized, the present disclosure is capable of other and different embodiments, and its several details are capable of modifications in various obvious respects, all without departing from the disclosure. Accordingly, the drawings and description are to be regarded as illustrative in nature, and not as restrictive.

INCORPORATION BY REFERENCES

All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

DETAILED DESCRIPTION

While various embodiments of the invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions may occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed.

As used herein, the term “alkyl” , either alone or within other terms, generally refers to a linear or branched-chain saturated hydrocarbyl substituent (i.e., a substituent obtained from a hydrocarbon by removal of a hydrogen) containing from one to twenty carbon atoms; for example, from one to twelve carbon atoms; in another example, from one to ten carbon atoms; in another embodiment, from one to six carbon atoms; and in another embodiment, from one to four carbon atoms (such as 1, 2, 3 or more carbon atoms) . Examples of such substituents may include e.g., methyl, ethyl, propyl (including n-propyl and isopropyl) , butyl (including n-butyl, isobutyl, sec-butyl and terf-butyl) , pentyl, isoamyl, hexyl and the like. In some instances, the number of carbon atoms in a hydrocarbyl substituent (i.e., alkyl, alkenyl, cycloalkyl, aryl, etc. ) may be indicated by the prefix “C_a-C_b” wherein a is the minimum and b is the maximum number of carbon atoms in the substituent. Thus, for example, “C₁-C₆ alkyl” may refer to an alkyl substituent containing from 1 to 6 carbon atoms. The “alkyl” groups may be optionally substituted with one or more substitutions.

As used herein, the term “alkenyl” , either alone or within other terms, generally refers to a linear or branched-carbon radicals having at least one carbon-carbon double bond. The term “alkenyl” may contain conjugated and non-conjugated carbon-carbon double bonds or combinations thereof. An alkenyl group, for example and without being limited thereto, may contain two to about twenty carbon atoms or, in a particular embodiment, two to about twelve carbon atoms. In embodiments, alkenyl groups may contain two to about four carbon atoms (such as 2, 3 or more carbon atoms) . Examples of alkenyl groups include, but are not limited thereto, ethenyl, propenyl, allyl, propenyl, butenyl and 4-methylbutenyl. The terms “alkenyl” contain groups having “cis” and “trans” orientations, or alternatively, “E” and “Z” orientations. In some instances, the number of carbon atoms may be indicated by the prefix “C_a-C_b” wherein a is the minimum and b is the maximum number of carbon atoms in the substituent. The “alkenyl” groups may be optionally substituted with one or more substitutions.

As used herein, the term “alkynyl” , either alone or within other terms, generally refers to linear or branched carbon radicals having at least one carbon-carbon triple bond. The term “alkynyl” may contain conjugated and non-conjugated carbon-carbon triple bonds or combinations thereof. Alkynyl group, for example and without being limited thereto, may contain two to about twenty carbon atoms or, in a particular embodiment, two to about twelve carbon atoms. In embodiments, alkynyl groups may contain two to about ten carbon atoms. Some examples may be alkynyl having two to about four carbon atoms (such as 2, 3 or more carbon atoms) . In some instances, the number of carbon atoms may be indicated by the prefix “C_a-C_b” wherein a is the minimum and b is the maximum number of carbon atoms in the substituent. Examples of such groups include propargyl, butynyl, and the like. The “alkynyl” groups may be optionally substituted with one or more substitutions.

As used herein, the term “amino” , either alone or within other terms, generally refers to formula -NH₂ group. The “amino” groups may be optionally substituted with one or more substitutions.

As used herein, the term “ring” generally refers to a ring system or a ring structure. For example, ring may comprise carbocycle, heterocycle, aryl, or heteroaryl.

As used herein, the term “ring membered” , or “membered ring” generally refers to a ring system having ring atoms. For example, “n ring membered” or “n-membered ring” generally refers to a ring system having n ring atoms. For example, “5 ring membered” or “5-membered ring” generally refers to a ring system having 5 ring atoms which optionally contains one or more further heteroatom (s) selected from O, S or N.

As used herein, the term “carbocycle” , either alone or within other terms, generally refers to a saturated or unsaturated non-aromatic monocyclic, bicyclic, or polycyclic ring system having from 3 to 14 ring atoms (and all combinations and subcombinations of ranges and specific numbers of carbon atoms therein) wherein all of the ring atoms are carbon atoms. Monocyclic carbocycles may have 3 to 6 ring atoms, or 5 to 6 ring atoms. Bicyclic carbocycles may have 7 to 12 ring atoms, e.g., arranged as a bicyclo [4, 5] , [5, 5] , [5, 6] or [6, 6] system, or 9 or 10 ring atoms arranged as a bicyclo [5, 6] or [6, 6] system. The term “carbocycle” may contain, for example, a monocyclic carbocycle ring fused to an aryl ring (e.g., a monocyclic carbocycle ring fused to a benzene ring) . Carbocyles may have 3 to 8 carbon ring atoms. In some instances, the number of carbon atoms may be indicated by the prefix “C_a-C_b” wherein a is the minimum and b is the maximum number of carbon atoms in the substituent. The “carbocycle” groups may be optionally substituted with one or more substitutions.

As used herein, the term “heterocycle” , either alone or within other terms, generally refers to a monocyclic, bicyclic, or polycyclic ring system having from 3 to 14 ring atoms (also referred to as ring members) wherein at least one ring atom in at least one ring may be a heteroatom selected from N, O, P, or S (and all combinations and subcombinations of ranges and specific numbers of carbon atoms and heteroatoms therein) . The heterocycle may have from 1 to 4 ring heteroatoms independently selected from N, O, P, or S. One or more N, C, or S atoms in a heterocycle may be oxidized. A monocylic heterocycle may have 3 to 7 ring members (e.g., 2 to 6 carbon atoms and 1 to 3 heteroatoms independently selected from N, O, P, or S) , and a bicyclic heterocycle may have 5 to 10 ring members (e.g., 4 to 9 carbon atoms and 1 to 3 heteroatoms independently selected from N, O, P, or S) . The heterocycle that contains the heteroatom may be non-aromatic. Unless otherwise noted, the heterocycle is attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. In some instances, the number of carbon atoms may be indicated by the prefix “C_a-C_b” wherein a is the minimum and b is the maximum number of carbon atoms in the substituent. The “heterocycle” groups may be optionally substituted with one or more substitutions.

As used herein, the term “aryl” , either alone or within other terms, generally refers to an aromatic substituent containing one ring or two or three fused rings. The aryl substituent may have six to eighteen carbon atoms. As an example, the aryl substituent may have six to fourteen carbon atoms. The term “aryl” may refer to substituents such as phenyl, naphthyl and anthracenyl. The term “aryl” may also contain substituents such as phenyl, naphthyl and anthracenyl that are fused to a C₄-C₁₀ carbocyclic ring, such as a C₅ or a C₆ carbocyclic ring, or to a 4-to 10-membered heterocyclic ring, wherein a group having such a fused aryl group as a substituent is bound to an aromatic carbon of the aryl group. When such a fused aryl group is substituted with one more substituent, the one or more substituents, unless otherwise specified, may be each bound to an aromatic carbon of the fused aryl group. The fused C₄-C₁₀ carbocyclic or 4-to 10-membered heterocyclic ring may optionally be optionally substituted. Examples of aryl groups may include accordingly phenyl, naphthalenyl, tetrahydronaphthalenyl (also known as “tetralinyl” ) , indenyl, isoindenyl, indanyl, anthracenyl, phenanthrenyl, benzonaphthenyl (also known as “phenalenyl” ) , and fluorenyl. In some instances, the number of carbon atoms may be indicated by the prefix “C_a-C_b” wherein a is the minimum and b is the maximum number of carbon atoms in the substituent. The “aryl” groups may be optionally substituted with one or more substitutions.

As used herein, the term “heteroaryl” , either alone or within other terms, generally refers to an aromatic ring structure containing from 5 to 14 ring atoms in which at least one of the ring atoms is a heteroatom (for example, oxygen, nitrogen, or sulfur) , with the remaining ring atoms being independently selected from the group consisting of carbon, oxygen, nitrogen, and sulfur. A heteroaryl may be a single ring or 2 or 3 fused rings. Examples of heteroaryl substituents may include but not limited to: 6-membered ring substituents such as pyridyl, pyrazyl, pyrimidinyl, and pyridazinyl; 5-membered ring substituents such as triazolyl, imidazolyl, furanyl, thiophenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, 1, 2, 3-, 1, 2, 4-, 1, 2, 5-, or 1, 3, 4-oxadiazolyl and isothiazolyl; 6/5-membered fused ring substituents such as benzothiofuranyl, isobenzothiofuranyl, benzisoxazolyl, benzoxazolyl, purinyl, and anthranilyl; and 6/6-membered fused ring substituents such as quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, and 1, 4-benzoxazinyl. In a group that has a heteroaryl substituent, the ring atom of the heteroaryl substituent that is bound to the group may be the at least one heteroatom, or it may be a ring carbon atom, where the ring carbon atom may be in the same ring as the at least one heteroatom or where the ring carbon atom may be in a different ring from the at least one heteroatom. Similarly, if the heteroaryl substituent is in turn substituted with a group or substituent, the group or substituent may be bound to the at least one heteroatom, or it may be bound to a ring carbon atom, where the ring carbon atom may be in the same ring as the at least one heteroatom or where the ring carbon atom may be in a different ring from the at least one heteroatom. In some instances, the number of carbon atoms may be indicated by the prefix “C_a-C_b” wherein a is the minimum and b is the maximum number of carbon atoms in the substituent. The “heteroaryl” groups may be optionally substituted with one or more substitutions.

As used herein, the term “halogen” , either alone or within other terms, generally refers to fluorine (which may be depicted as -F) , chlorine (which may be depicted as -Cl) , bromine (which may be depicted as -Br) , or iodine (which may be depicted as -I) . In one embodiment, the halogen may be chlorine. In another embodiment, the halogen may be fluorine. In another embodiment, the halogen may be bromine.

As used herein, the term “cyano” , either alone or within other terms, generally refers to formula -CN group.

As used herein, the term “nitro” , either alone or within other terms, generally refers to formula -NO₂ group.

As used herein, the term “hydroxy” , either alone or within other terms, generally refers to formula -OH group. The “hydroxy” groups may be optionally substituted with one or more substitutions.

As used herein, the term “phosphorous-containing group” , either alone or within other terms, generally refers to functional group containing on or more phosphorous atoms. The phosphorous-containing group may refer to -O-P- (OH) ₂, -O-PH- (OH) , -O-PH₂, -P- (OH) ₂, -PH- (OH) , -PH₄, -PH₂=CH₂, -CH=PH₃, -O-P (=O) ₂, -O-P (=O) - (OH) ₂, -O-PH (=O) -OH, -P (=O) - (OH) ₂, -O-PH₂ (=O) , -PH (=O) -OH, -PH₂ (=O) , -O-P (=O) (OH) -P (=O) (OH) ₂, -O-P (=O) (OH) -O-P (=O) (OH) ₂, -PH-PH₂, or -P=PH. The “phosphorous-containing group” may be optionally substituted with one or more substitutions.

As used herein, the term “silicon-containing group” , either alone or within other terms, generally refers to functional group containing on or more silicon atoms. The silicon -containing group may refer to -SiH₃. The “silicon-containing group” may be optionally substituted with one or more substitutions.

As used herein, the term “thio” , either alone or within other terms, generally refers to formula -SH group. The “thio” groups may be optionally substituted with one or more substitutions.

As used herein, the term “carboxyl” , either alone or within other terms, generally refers to formula -C (=O) OH group. The “carboxyl” groups may be optionally substituted with one or more substitutions.

As used herein, the term “sulfonyl” , either alone or within other terms, generally refers to formula -S (=O) ₂-H, group. The “sulfonyl” groups may be optionally substituted with one or more substitutions.

As used herein, the term “sulfinyl” , either alone or within other terms, generally refers to formula -S (=O) -H group. The “sulfinyl” groups may be optionally substituted with one or more substitutions.

As used herein, the term “acyl” , either alone or within other terms, generally refers to a carboxylic acid ester of the formula -C (O) R in which the non-carbonyl moiety of the ester group (i.e., R) may be selected from straight, branched, or cyclic alkyl. The term acyl may include but not limited to acetyl, propionyl, butyryl and pentanoyl. In some instances, the number of carbon atoms may be indicated by the prefix “C_a-C_b” wherein a is the minimum and b is the maximum number of carbon atoms in the substituent. The “acyl” groups may be optionally substituted with one or more substitutions.

As used herein, the term “thioacyl” , either alone or within other terms, generally refers to the formula -C (S) R in which the moiety of the ester group (i.e., R) may be selected from straight, branched, or cyclic alkyl. In some instances, the number of carbon atoms may be indicated by the prefix “C_a-C_b” wherein a is the minimum and b is the maximum number of carbon atoms in the substituent. The “thioacyl” groups may be optionally substituted with one or more substitutions.

As used herein, the term “ring” , either alone or within other terms, generally refers to any covalently closed structure. Rings may include, for example, carbocycles, heterocycles, aryls and heteroaryls. Rings may be monocyclic or polycyclic. The “ring” groups may be optionally substituted with one or more substitutions.

As used herein, the term “pharmaceutically acceptable salt” generally refers to a salt that may be pharmaceutically acceptable and that may possess the desired pharmacological activity of the parent compound. Such salts may include: acid addition salts, formed with inorganic acids or formed with organic acids or basic addition salts formed with the conjugate bases of any of the inorganic acids wherein the conjugate bases comprise a cationic component.

As used herein, the term “pharmaceutically acceptable carrier” generally refers to aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles may include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like) , carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity may be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants. These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents such as paraben, chlorobutanol, phenol, sorbic acid and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents, such as aluminum monostearate and gelatin, which delay absorption. Injectable depot forms may be made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide, poly (orthoesters) and poly (anhydrides) . Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release may be controlled. Depot injectable formulations may be also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues. The injectable formulations may be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable media just prior to use. Suitable inert carriers may include sugars such as lactose. Desirably, at least 95%by weight of the particles of the active ingredient may have an effective particle size in the range of 0.01 to 10 micrometers.

As used herein, the term “prodrug” generally refers to a compound that is metabolized, for example hydrolyzed or oxidized, in the host to form the compound of the present invention. Typical examples of prodrugs may include compounds that have biologically labile protecting groups on a functional moiety of the active compound. Prodrugs may include compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, dedcylated, phosphorylated, dephosphorylated to produce the active compound.

As used herein, the term “cyclin-dependent kinase” or “CDK” generally refers to a protein having an activity of regulating the cell cycle. For example, inhibiting cyclin-dependent kinase (CDK) activity may comprise interacting with a cyclin-CDK complex to block kinase activity. For example, CDK may comprise CDK7. The UniProt ID for CDK7 may be P50613.

As used herein, a substituent is “substitutable” or can be “substituted” if it comprises at least one atom that is bonded to one or more hydrogen atoms. If a substituent is described as being “substituted, ” hydrogen or a non-hydrogen substituent is in the place of a hydrogen substituent on a atom of the substituent. Thus, for example, a substituted alkyl substituent is an alkyl substituent wherein at least one hydrogen or a non-hydrogen substituent is in the place of a hydrogen substituent on the alkyl substituent. To illustrate, monofluoroalkyl is alkyl substituted with a fluoro substituent, and difluoroalkyl is alkyl substituted with two fluoro substituents. It should be recognized that if there is more than one substitution on a substituent, each substituent may be identical or different (unless otherwise stated) .

If substituents are described as being “independently selected” from a group, each substituent may be selected independent of the other (s) . Each substituent therefore may be identical to or different from the other substituent (s) .

As used herein, the term “optionally substituted” or “optional substituent (s) ” generally refers to a given moiety may consist of only hydrogen substituents through available valencies (unsubstituted) or may further comprise one or more non-hydrogen substituents through available valencies (substituted) that are not otherwise specified by the name of the given moiety. For example, “R^x is optionally substituted” or R^x is optionally substituted with R^y” may mean that R^x may be substituted with 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9 R^y, for example, R^x may be substituted with 0, 1, 2, 3, 4, or 5 R^y, for example, R^x may be substituted with 1, 2, or 3 R^y, for example, R^x may be substituted with one R^y, for example, R^x may be substituted with 2 R^y, for example, R^x may be substituted with 3 R^y, for example, R^x may be substituted with 4 R^y, for example, R^x may be substituted with 5 R^y, for example, R^x may be substituted with 6 R^y, for example, R^x may be substituted with 7 R^y, for example, R^x may be substituted with 8 R^y, for example, R^x may be substituted with 9 R^y. In general, a non-hydrogen substituent may be any substituent that may be bound to an atom of the given moiety that is specified to be substituted. Examples of substituents include, but are not limited to, hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =S, =O, N₃, trifluoromethyl, hydroxy, phosphorous-containing group, silicon-containing group, thio, amino, carboxyl, sulfonyl, sulfinyl, (C₁-C₆) acyl, (C₁-C₆) thioacyl, (C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₃-C₁₀) carbocycle, (C₂-C₉) heterocycle, (C₆-C₁₀) aryl, (C₁-C₉) heteroaryl, trifluoromethyl (C₁-C₆) alkyl, cyano (C₁-C₆) alkyl, halo (C₁-C₆) alkyl, nitro (C₁-C₆) alkyl, hydroxy (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) alkylthio, thio (C₁-C₆) alkyl, amino (C₁-C₆) alkyl, (C₁-C₆) alkylamino, ( (C₁-C₆) alkyl) ₂amino, (C₁-C₆) acyl (C₁-C₆) alkyl, (C₁-C₆) alkylsulfonyl, (C₁-C₆) alkylsulfinyl, hydroxysulfonyl, hydroxysulfinyl, (C₃-C₁₀) carbocycle (C₁-C₆) alkyl, (C₂-C₉) heterocycle (C₁-C₆) alkyl, (C₆-C₁₀) aryl (C₁-C₆) alkyl, and (C₁-C₉) heteroaryl (C₁-C₆) alkyl. In addition, the substituent is itself optionally substituted by a further substituent. In one particular embodiment, examples of the further substituent include, but are not limited to, hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =S, =O, N₃, trifluoromethyl, hydroxy, phosphorous-containing group, silicon-containing group, thio, amino, carboxyl, sulfonyl, sulfinyl, (C₁-C₆) acyl, (C₁-C₆) thioacyl, (C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₃-C₁₀) carbocycle, (C₂-C₉) heterocycle, (C₆-C₁₀) aryl, (C₁-C₉) heteroaryl, trifluoromethyl (C₁-C₆) alkyl, cyano (C₁-C₆) alkyl, halo (C₁-C₆) alkyl, nitro (C₁-C₆) alkyl, hydroxy (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) alkylthio, thio (C₁-C₆) alkyl, amino (C₁-C₆) alkyl, (C₁-C₆) alkylamino, ( (C₁-C₆) alkyl) ₂amino, (C₁-C₆) acyl (C₁-C₆) alkyl, (C₁-C₆) alkylsulfonyl, (C₁-C₆) alkylsulfinyl, hydroxysulfonyl, hydroxysulfinyl, (C₃-C₁₀) carbocycle (C₁-C₆) alkyl, (C₂-C₉) heterocycle (C₁-C₆) alkyl, (C₆-C₁₀) aryl (C₁-C₆) alkyl, and (C₁-C₉) heteroaryl (C₁-C₆) alkyl.

As used herein, the term “formula” may be hereinafter referred to as a “compound (s) of the invention” . Such terms are also defined to include all forms of the compound of formula, including hydrates, solvates, isomers, crystalline and non-crystalline forms, isomorphs, polymorphs, and metabolites thereof. For example, the compounds of formula, or pharmaceutically acceptable salts thereof, may exist in unsolvated and solvated forms. When the solvent or water is tightly bound, the complex may have a well-defined stoichiometry independent of humidity. When, however, the solvent or water is weakly bound, as in channel solvates and hygroscopic compounds, the water/solvent content may be dependent on humidity and drying conditions. In such cases, non-stoichiometry will be the norm.

The compounds of “formula” may have asymmetric carbon atoms. The carbon-carbon bonds of the compounds of formula may be depicted herein using a solid line, a solid wedge, or a dotted wedge. The use of a solid line to depict bonds to asymmetric carbon atoms may be meant to indicate that all possible stereoisomers (e.g. specific enantiomers, racemic mixtures, etc. ) at that carbon atom are included. The use of either a solid or dotted wedge to depict bonds to asymmetric carbon atoms may be meant to indicate that only the stereoisomer shown is meant to be included. It is possible that compounds of the present application may contain more than one asymmetric carbon atom. In those compounds, the use of a solid line to depict bonds to asymmetric carbon atoms may be meant to indicate that all possible stereoisomers are meant to be included. For example, unless stated otherwise, it may be intended that the compounds of formula can exist as enantiomers and diastereomers or as racemates and mixtures thereof. The use of a solid line to depict bonds to one or more asymmetric carbon atoms in a compound of formula and the use of a solid or dotted wedge to depict bonds to other asymmetric carbon atoms in the same compound may be meant to indicate that a mixture of diastereomers is present.

The compounds of the present application (e.g., the compounds of formula) may exist as clathrates or other complexes. Included within the scope of the invention are complexes such as clathrates, drug-host inclusion complexes wherein, in contrast to the aforementioned solvates, the drug and host may be present in stoichiometric or non-stoichiometric amounts. Also included may be complexes of formula containing two or more organic and/or inorganic components which may be in stoichiometric or non-stoichiometric amounts. The resulting complexes may be ionized, partially ionized, or non-ionized.

Stereoisomers of formula may include cis and trans isomers, optical isomers such as R and S enantiomers, diastereomers, geometric isomers, rotational isomers, conformational isomers, and tautomers of the compounds of formula, including compounds exhibiting more than one type of isomerism; and mixtures thereof (such as racemates and diastereomeric pairs) . Also included may be acid addition or base addition salts wherein the counterion is optically active, for example, D-lactate or L-lysine, or racemic, for example, DL-tartrate or DL-arginine.

When any racemate crystallizes, crystals of two different types are possible. The first type is the racemic compound (true racemate) referred to above wherein one homogeneous form of crystal is produced containing both enantiomers in equimolar amounts. The second type is the racemic mixture or conglomerate wherein two forms of crystal are produced in equimolar amounts each comprising a single enantiomer.

The compounds of formula may exhibit the phenomena of tautomerism and structural isomerism. For example, the compounds of formula may exist in several tautomeric forms, including the enol and imine forms, and the keto and enamine forms, and geometric isomers and mixtures thereof. All such tautomeric forms may be included within the scope of compounds of formula. Tautomers may exist as mixtures of a tautomeric set in solution. In solid form, usually one tautomer predominates. Even though one tautomer may be described, the present invention includes all tautomers of the compounds of formula.

The present invention also includes isotopically-labeled compounds, which are identical to those recited in formula above, but for the fact that one or more atoms may be replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that may be incorporated into compounds of formula include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as, but not limited to, ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl. Certain isotopically-labeled compounds of formula, for example those into which radioactive isotopes such as ³H and ¹⁴C are incorporated, may be useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C, isotopes may be particularly used for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., ²H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be used in some circumstances. Isotopically-labeled compounds of formula may generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below, by substituting an isotopically-labeled reagent for a non-isotopically-labeled reagent.

The compounds of the present application may be used in the form of salts derived from inorganic or organic acids. Depending on the particular compound, a salt of the compound may be advantageous due to one or more of the salt's physical properties, such as enhanced pharmaceutical stability in differing temperatures and humidity, or a desirable solubility in water or oil. In some instances, a salt of a compound also may be used as an aid in the isolation, purification, and/or resolution of the compound.

Compounds

In one aspect, the present application provides a compound having the structure of formula (I) ,

wherein, A is optionally substituted ring, B is optionally substituted ring,

For example, as a compound having the structure of formula (I) , said R₁ is H.

For example, as a compound having the structure of formula (I) , said R₂ is H.

For example, as a compound having the structure of formula (I) , said R₃ is H.

For example, as a compound having the structure of formula (I) , said A is optionally substituted 5-ring-membered ring, optionally substituted 6-ring-membered ring, or optionally substituted 11-ring-membered ring.

For example, as a compound having the structure of formula (I) , said A is optionally substituted heteroaryl or optionally substituted heterocycle.

For example, as a compound having the structure of formula (I) , said A is optionally substituted ring containing one or more N, one or more S and/or one or more O.

For example, as a compound having the structure of formula (I) , said A is optionally substituted ring containing one, two or three N.

For example, as a compound having the structure of formula (I) , said A is optionally substituted ring containing one O.

For example, as a compound having the structure of formula (I) , said A is optionally substituted ring containing one S.

For example, as a compound having the structure of formula (I) , said A is selected from the group consisting of optionally substituted pyrrolyl, optionally substitutedpiperidinyl, optionally substitutedpyridinyl, optionally substitutedpiperazinyl, optionally substitutedpiperidinyl , optionally substitutedpyrrolidinyl, optionally substitutedthiazolyl, optionally substituteddiazaspiro [5.5] undecanyl, optionally substitutedpyrazolyl, optionally substitutedazaspiro [5.5] undecanyl, and optionally substitutedimidazolyl.

For example, as a compound having the structure of formula (I) , said A is substituted with one or more R_4. For example, each said R₄ is independently selected from the group consisting of hydrogen, halogen, =O, CN, optionally substituted alkyl, optionally substituted acyl, optionally substituted amino, optionally substituted hydroxyl, optionally substituted phosphorous-containing group, optionally substituted sulfonyl, and optionally substituted ring.

For example, as a compound having the structure of formula (I) , said m is 1_.

For example, as a compound having the structure of formula (I) , said R₄ is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted hydroxyl, and optionally substituted ring.

For example, as a compound having the structure of formula (I) , said R₄ is selected from the group consisting of optionally substituted methyl, optionally substituted ethyl, and optionally substituted propyl.

For example, as a compound having the structure of formula (I) , said R₄ is optionally substituted 4-ring-membered ring, 5-ring-membered ring or optionally substituted 6-ring-membered ring.

For example, as a compound having the structure of formula (I) , said R₄ is optionally substituted heterocycle.

For example, as a compound having the structure of formula (I) , said R₄ is optionally substituted ring containing one or more N.

For example, as a compound having the structure of formula (I) , said R₄ is optionally substituted ring containing one or two N.

For example, as a compound having the structure of formula (I) , said R₄ is optionally substituted azetidinyl.

For example, as a compound having the structure of formula (I) , said R₄ is substituted with one or more R_4-1, each said R_4-1 is independently absent or is independently selected from optional substituents. For example, each said R_4-1 is independently selected from the group consisting of hydrogen, halogen, =O, CN, optionally substituted alkyl, optionally substituted acyl, optionally substituted amino, optionally substituted hydroxyl, optionally substituted phosphorous-containing group, optionally substituted sulfonyl, and optionally substituted ring.

For example, as a compound having the structure of formula (I) , said R₄ is substituted with one or two said R_4-1.

For example, as a compound having the structure of formula (I) , each said R_4-1 is independently selected from the group consisting of hydrogen, halogen, and optionally substituted hydroxyl.

For example, as a compound having the structure of formula (I) , each said R_4-1 is independently selected from the group consisting of hydrogen, optionally substituted hydroxyl, optionally substituted amino, and optionally substituted methyl.

For example, as a compound having the structure of formula (I) , said R_4-1 is substituted with one or more R_4-2, each said R_4-2 is independently absent or is independently selected from optional substituents. For example, each said R_4-2 is independently selected from the group consisting of hydrogen, halogen, =O, CN, optionally substituted alkyl, optionally substituted acyl, optionally substituted amino, optionally substituted hydroxyl, optionally substituted phosphorous-containing group, optionally substituted sulfonyl, and optionally substituted ring.

For example, as a compound having the structure of formula (I) , said R_4-1 is substituted with one said R_4-2.

For example, as a compound having the structure of formula (I) , each said R_4-2 is independently selected from the group consisting of hydrogen, and halogen.

For example, as a compound having the structure of formula (I) , each said R_4-2 is independently selected from the group consisting of hydrogen, and F.

For example, as a compound having the structure of formula (I) , said B is optionally substituted 4-ring-membered ring or 6-ring-membered ring.

For example, as a compound having the structure of formula (I) , said B is optionally substituted ring containing one or more N and/or one or more O.

For example, as a compound having the structure of formula (I) , said B is optionally substituted ring containing one, or two N.

For example, as a compound having the structure of formula (I) , said B is optionally substituted ring containing one O.

For example, as a compound having the structure of formula (I) , said B is selected from the group consisting of optionally substituted piperidinyl, optionally substituted piperazinyl, and optionally substituted azetidinyl.

For example, as a compound having the structure of formula (I) , said B is substituted with one or more R_5. For example, each said R₅ is independently selected from the group consisting of hydrogen, halogen, =O, CN, optionally substituted alkyl, optionally substituted acyl, optionally substituted amino, optionally substituted hydroxyl, optionally substituted phosphorous-containing group, optionally substituted sulfonyl, and optionally substituted ring.

For example, as a compound having the structure of formula (I) , said n is 1.

For example, as a compound having the structure of formula (I) , each said R₅ is independently selected from the group consisting of hydrogen, optionally substituted hydroxyl, optionally substituted amino, and optionally substituted alkyl.

For example, as a compound having the structure of formula (I) , each said R₅ is independently selected from the group consisting of hydrogen, optionally substituted hydroxyl, optionally substituted amino, optionally substituted methyl, optionally substituted ethyl, optionally substituted propyl and optionally substituted butyl.

For example, as a compound having the structure of formula (I) , said R₅ is substituted with one or more R_5-1, each said R_5-1 is independently absent or is independently selected from optional substituents. For example, each said R_5-1 is independently selected from the group consisting of hydrogen, halogen, =O, CN, optionally substituted alkyl, optionally substituted acyl, optionally substituted amino, optionally substituted hydroxyl, optionally substituted phosphorous-containing group, optionally substituted sulfonyl, and optionally substituted ring.

For example, as a compound having the structure of formula (I) , said R₅ is substituted with one said R_5-1.

For example, as a compound having the structure of formula (I) , each said R_5-1 is independently selected from the group consisting of hydrogen, optionally substituted hydroxyl, and optionally substituted alkyl.

For example, as a compound having the structure of formula (I) , each said R_5-1 is independently selected from the group consisting of optionally substituted hydroxyl, optionally substituted methyl, optionally substituted ethyl, and optionally substituted propyl.

For example, as a compound having the structure of formula (I) , said X₁ is independently absent or is independently selected from optionally substituted -CH=, and -N=.

For example, as a compound having the structure of formula (I) , said X₂ is independently absent or is independently selected from optionally substituted -CH=, and -N=.

For example, as a compound having the structure of formula (I) , said X₃ is independently absent or is independently selected from optionally substituted -CH=, and -N=.

For example, as a compound having the structure of formula (I) , said X₄ is independently absent or is independently selected from optionally substituted -CH=, and -N=.

For example, as a compound having the structure of formula (I) , said X₅ is independently absent or is -N=.

For example, as a compound having the structure of formula (I) , said X₆ is optionally substituted -NH-or is optionally substituted -CH=.

For example, as a compound having the structure of formula (I) , said X₇ is optionally substituted -NH-or is optionally substituted -CH=.

For example, as a compound having the structure of formula (I) , said X₇ is substituted with one R_x7-1, each said R_x7-1 is independently absent or is independently selected from optional substituents. For example, each said R_x7-1 is independently selected from the group consisting of hydrogen, halogen, =O, CN, optionally substituted alkyl, optionally substituted acyl, optionally substituted amino, optionally substituted hydroxyl, optionally substituted phosphorous-containing group, optionally substituted sulfonyl, and optionally substituted ring.

For example, as a compound having the structure of formula (I) , said X₇ is substituted with one said R_x7-1.

For example, as a compound having the structure of formula (I) , said R_x7-1 is optionally substituted alkyl or optionally substituted ring.

For example, as a compound having the structure of formula (I) , said R_x7-1 is selected from the group consisting of optionally substituted methyl, optionally substituted ethyl, optionally substituted propyl, optionally substituted butyl, optionally substituted cyclopropyl, and optionally substituted cyclopentyl.

For example, as a compound having the structure of formula (I) , said X₈ is independently absent or is -N=.

For example, as a compound having the structure of formula (I) , said X₉ is independently absent or is optionally substituted -CH=.

For example, as a compound having the structure of formula (I) , said X₉ is substituted with one or more said B.

For example, as a compound having the structure of formula (I) , said X₁₀ is independently absent or is -N=.

In one aspect, the present application provides a compound or a pharmaceutically acceptable salt, prodrug, or metabolite thereof, or a solvate or hydrate of any of the foregoing, wherein, said compound is selected from the group consisting of:

In one aspect, the present application provides a compound having the structure of formula (II) ,

For example, as a compound having the structure of formula (II) , said A is optionally substituted 6-ring-membered ring.

For example, as a compound having the structure of formula (II) , said A is optionally substituted heterocycle.

For example, as a compound having the structure of formula (II) , said A is optionally substituted ring containing one or more N.

For example, as a compound having the structure of formula (II) , said A is optionally substituted ring containing one, two or three N.

For example, as a compound having the structure of formula (II) , said A is optionally substituted piperidinyl

For example, as a compound having the structure of formula (II) , said A is substituted with one or more R_A-1, each said R_A-1 is independently absent or is independently selected from optional substituents_. For example, each said R_A-1 is independently selected from the group consisting of hydrogen, halogen, =O, CN, optionally substituted alkyl, optionally substituted acyl, optionally substituted amino, optionally substituted hydroxyl, optionally substituted phosphorous-containing group, optionally substituted sulfonyl, and optionally substituted ring.

For example, as a compound having the structure of formula (II) , said R_A-1 is selected from the group consisting of hydrogen, and optionally substituted amino.

For example, as a compound having the structure of formula (II) , said B is optionally substituted 5 or 6-ring-membered ring.

For example, as a compound having the structure of formula (II) , said B is optionally substituted aryl or optionally substituted heteroaryl.

For example, as a compound having the structure of formula (II) , said B is optionally substituted ring containing no N or one or more N.

For example, as a compound having the structure of formula (II) , said B is selected from the group consisting of optionally substituted phenyl and optionally substituted pyridinyl.

For example, as a compound having the structure of formula (II) , said B is substituted with one or more R_B-1, each said R_B-1 is independently absent or is independently selected from optional substituents. For example, each said R_B-1 is independently selected from the group consisting of hydrogen, halogen, =O, CN, optionally substituted alkyl, optionally substituted acyl, optionally substituted amino, optionally substituted hydroxyl, optionally substituted phosphorous-containing group, optionally substituted sulfonyl, and optionally substituted ring.

For example, as a compound having the structure of formula (II) , said R_B-1 is on the ortho-position of said B.

For example, as a compound having the structure of formula (II) , said B is substituted with one or two R_B-1.

For example, as a compound having the structure of formula (II) , said R_B-1 is optionally substituted heterocycle or optionally substituted heteroaryl.

For example, as a compound having the structure of formula (II) , said R_B-1 is optionally substituted ring containing one or more N.

For example, as a compound having the structure of formula (II) , said R_B-1 is optionally substituted ring containing one, or two N.

For example, as a compound having the structure of formula (II) , said R_B-1 is selected from the group consisting of optionally substituted pyrazolyl, optionally substituted pyridinyl, and optionally substituted piperazinyl.

For example, as a compound having the structure of formula (II) , said R_B-1 is substituted with one or more R_B-2, each said R_B-2 is independently absent or is independently selected from optional substituents_. For example, each said R_B-2 is independently selected from the group consisting of hydrogen, halogen, =O, CN, optionally substituted alkyl, optionally substituted acyl, optionally substituted amino, optionally substituted hydroxyl, optionally substituted phosphorous-containing group, optionally substituted sulfonyl, and optionally substituted ring.

For example, as a compound having the structure of formula (II) , each said R_B-2 is independently selected from the group consisting of hydrogen, optionally substituted amino, optionally substituted alkyl, and optionally substituted heterocycle.

For example, as a compound having the structure of formula (II) , said R_B-2 is independently selected from the group consisting of hydrogen, optionally substituted amino, optionally substituted methyl, and optionally substituted piperazinyl.

For example, as a compound having the structure of formula (II) , said R_B-2 is substituted with one or more R_B-3, each said R_B-3 is independently absent or is independently selected from optional substituents. For example, each said R_B-3 is independently selected from the group consisting of hydrogen, halogen, =O, CN, optionally substituted alkyl, optionally substituted acyl, optionally substituted amino, optionally substituted hydroxyl, optionally substituted phosphorous-containing group, optionally substituted sulfonyl, and optionally substituted ring.

For example, as a compound having the structure of formula (II) , said R_B-3 is optionally substituted alkyl.

For example, as a compound having the structure of formula (II) , said R_B-3 is optionally substituted methyl.

For example, as a compound having the structure of formula (II) , said X₁ is independently absent or is optionally substituted -CH=.

For example, as a compound having the structure of formula (II) , said X₁ is substituted with R_X1-1, said R_X1-1 is selected from optional substituents. For example, each said R_x1-1 is independently selected from the group consisting of hydrogen, halogen, =O, CN, optionally substituted alkyl, optionally substituted acyl, optionally substituted amino, optionally substituted hydroxyl, optionally substituted phosphorous-containing group, optionally substituted sulfonyl, and optionally substituted ring.

For example, as a compound having the structure of formula (II) , said R_X1-1 is selected from the group consisting of hydrogen, and optionally substituted alkyl.

For example, as a compound having the structure of formula (II) , said R_X1-1 is optionally substituted propyl.

For example, as a compound having the structure of formula (II) , said R_X1-1 is optionally substituted isopropyl.

For example, as a compound having the structure of formula (II) , said X₂ is independently absent or is optionally substituted -CH=.

For example, as a compound having the structure of formula (II) , said R₁ is H.

For example, as a compound having the structure of formula (II) , said R₂ is H.

For example, as a compound having the structure of formula (II) , said R₃ is H.

In one aspect, the present application provides a compound having the structure of formula (III) ,

or a pharmaceutically acceptable salt, or prodrug thereof, or a solvate or hydrate of any of the forgoing, wherein, X₁ is independently selected from optionally substituted atom, each R₁, R₂, R₃ and R₄ is independently absent or is independently selected from optional substituents, n is 0 or more.

For example, as a compound having the structure of formula (III) , said R₁ is selected from the group consisting of halogen, CN, optionally substituted alkyl, optionally substituted acyl, optionally substituted amino, optionally substituted hydroxyl, optionally substituted phosphorous-containing group, optionally substituted sulfonyl, and optionally substituted ring.

For example, as a compound having the structure of formula (III) , said R₁ is selected from the group consisting of optionally substituted alkyl, optionally substituted amino, optionally substituted hydroxyl, and optionally substituted ring.

For example, as a compound having the structure of formula (III) , said R₁ is selected from the group consisting of optionally substituted methyl, and optionally substituted ethyl.

For example, as a compound having the structure of formula (III) , said R₁ is selected from the group consisting of optionally substituted carbocycle, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl.

For example, as a compound having the structure of formula (III) , said R₁ is optionally substituted 6-ring-membered ring.

For example, as a compound having the structure of formula (III) , said R₁ is optionally substituted cyclohexanyl.

For example, as a compound having the structure of formula (III) , said R₁ is optionally substituted 6 to 8-ring-membered ring.

For example, as a compound having the structure of formula (III) , said R₁ is optionally substituted ring containing one or more N and/or one or more O. For example, said R₁ is optionally substituted ring containing one, two or three N and/or one, two or three O.

For example, as a compound having the structure of formula (III) , said R₁ is optionally substituted ring containing one or two N.

For example, as a compound having the structure of formula (III) , said R₁ is optionally substituted piperazinyl, optionally substituted piperidinyl, or optionally substituted diazepanyl.

For example, as a compound having the structure of formula (III) , said R₁ is optionally substituted bicyclic ring.

For example, as a compound having the structure of formula (III) , said R₁ is optionally substituted diazabicycloheptanyl, or optionally substituted diazabicyclooctanyl.

For example, as a compound having the structure of formula (III) , said R₁ is optionally substituted benzenyl.

For example, as a compound having the structure of formula (III) , said R₁ is optionally substituted 5 to 12-ring-membered ring.

For example, as a compound having the structure of formula (III) , said R₁ is optionally substituted ring containing one, two or five N.

For example, as a compound having the structure of formula (III) , said R₁ is optionally substituted ring containing one O.

For example, as a compound having the structure of formula (III) , said R₁ is optionally substituted pyrrolyl, optionally substituted oxazolyl, optionally substituted pyrazolyl, optionally substituted oxadiazolyl, optionally substituted pyridinyl, or optionally substituted pyrazinyl.

For example, as a compound having the structure of formula (III) , said R₁ is optionally substituted fused ring.

For example, as a compound having the structure of formula (III) , said R₁ is optionally substituted pyrazolopyridinyl or optionally substituted quinolinyl.

For example, as a compound having the structure of formula (III) , said R₁ is substituted with one or more R_1-1, each said R_1-1 is independently absent or is independently selected from optional substituents. For example, as a compound having the structure of formula (III) , said R₁ is substituted with one, two or three R_1-1.

For example, as a compound having the structure of formula (III) , said R₁ is substituted with one or two said R_1-1.

For example, as a compound having the structure of formula (III) , each said R_1-1 is independently selected from the group consisting of hydrogen, halogen, =O, CN, optionally substituted alkyl, optionally substituted acyl, optionally substituted amino, optionally substituted hydroxyl, optionally substituted phosphorous-containing group, optionally substituted sulfonyl, and optionally substituted ring.

For example, as a compound having the structure of formula (III) , each said R_1-1 is independently selected from the group consisting of hydrogen, =O, optionally substituted alkyl, optionally substituted amino, optionally substituted hydroxyl, and optionally substituted ring.

For example, as a compound having the structure of formula (III) , each said R_1-1 is independently selected from the group consisting of optionally substituted methyl, optionally substituted ethyl and optionally substituted propyl.

For example, as a compound having the structure of formula (III) , each said R_1-1 is independently selected from the group consisting of optionally substituted methyl, optionally substituted ethyl and optionally substituted isopropyl.

For example, as a compound having the structure of formula (III) , each said R_1-1 is independently selected from the group consisting of optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl.

For example, as a compound having the structure of formula (III) , said R_1-1 is optionally substituted 4 to 5-ring-membered ring.

For example, as a compound having the structure of formula (III) , said R_1-1 is optionally substituted ring containing one or more N and/or one or more O. For example, said R_1-1 is optionally substituted ring containing one, two or three N and/or one, two or three O.

For example, as a compound having the structure of formula (III) , said R_1-1 is optionally substituted ring containing one N.

For example, as a compound having the structure of formula (III) , said R_1-1 is optionally substituted azetidinyl, or optionally substituted pyrrolidinyl.

For example, as a compound having the structure of formula (III) , said R_1-1 is optionally substituted benzenyl.

For example, as a compound having the structure of formula (III) , said R_1-1 is optionally substituted 6-ring-membered ring.

For example, as a compound having the structure of formula (III) , said R_1-1 is optionally substituted pyridinyl.

For example, as a compound having the structure of formula (III) , each said R_1-1 is independently substituted with one or more R_1-2, each said R_1-2 is independently absent or is independently selected from optional substituents. For example, as a compound having the structure of formula (III) , each said R_1-1 is independently substituted with one, two or three R_1-2.

For example, as a compound having the structure of formula (III) , each said R_1-1 is independently substituted with one, two or three said R_1-2.

For example, as a compound having the structure of formula (III) , each said R_1-2 is independently selected from the group consisting of hydrogen, halogen, =O, CN, optionally substituted alkyl, optionally substituted acyl, optionally substituted amino, optionally substituted hydroxyl, optionally substituted phosphorous-containing group, optionally substituted sulfonyl, and optionally substituted ring.

For example, as a compound having the structure of formula (III) , each said R_1-2 is independently selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted amino, optionally substituted hydroxyl, and optionally substituted ring.

For example, as a compound having the structure of formula (III) , each said R_1-2 is F.

For example, as a compound having the structure of formula (III) , each said R_1-2 is independently selected from the group consisting of optionally substituted methyl, and optionally substituted ethyl.

For example, as a compound having the structure of formula (III) , each said R_1-2 is independently selected from the group consisting of optionally substituted carbocycle, and optionally substituted heteroaryl.

For example, as a compound having the structure of formula (III) , said R_1-2 is optionally substituted 5-ring-membered ring.

For example, as a compound having the structure of formula (III) , said R_1-2 is optionally substituted cyclopropyl.

For example, as a compound having the structure of formula (III) , said R_1-2 is optionally substituted ring containing one or more N and/or one or more O. For example, said R_1-2 is optionally substituted ring containing one, two or three N and/or one, two or three O.

For example, as a compound having the structure of formula (III) , said R_1-2 is optionally substituted ring containing one N.

For example, as a compound having the structure of formula (III) , said R_1-2 is optionally substituted furanyl.

For example, as a compound having the structure of formula (III) , each said R_1-2 is independently substituted with one or more R_1-3, each said R_1-3 is independently absent or is independently selected from optional substituents. For example, as a compound having the structure of formula (III) , each said R_1-2 is independently substituted with one, two or three R_1-3.

For example, as a compound having the structure of formula (III) , each said R_1-2 is independently substituted with one, two or three said R_1-3.

For example, as a compound having the structure of formula (III) , each said R_1-3 is independently selected from the group consisting of hydrogen, halogen, =O, CN, optionally substituted alkyl, optionally substituted acyl, optionally substituted amino, optionally substituted hydroxyl, optionally substituted phosphorous-containing group, optionally substituted sulfonyl, and optionally substituted ring.

For example, as a compound having the structure of formula (III) , each said R_1-3 is independently selected from the group consisting of hydrogen, optionally substituted methyl, and optionally substituted hydroxyl.

For example, as a compound having the structure of formula (III) , said R₂ is selected from the group consisting of hydrogen, halogen, CN, optionally substituted alkyl, optionally substituted acyl, optionally substituted amino, optionally substituted hydroxyl, optionally substituted phosphorous-containing group, optionally substituted sulfonyl, and optionally substituted ring.

For example, as a compound having the structure of formula (III) , said R₂ is optionally substituted carbocycle.

For example, as a compound having the structure of formula (III) , said R₂ is optionally substituted 6-ring-membered ring.

For example, as a compound having the structure of formula (III) , said R₂ is optionally substituted ring containing one or more N and/or one or more O. For example, said R₂ is optionally substituted ring containing one, two or three N and/or one, two or three O.

For example, as a compound having the structure of formula (III) , said R₂ is optionally substituted ring containing one N.

For example, as a compound having the structure of formula (III) , said R₂ is optionally substituted piperidinyl.

For example, as a compound having the structure of formula (III) , said R₂ is substituted with one or more R_2-1, each said R_2-1 is independently absent or is independently selected from optional substituents. For example, as a compound having the structure of formula (III) , said R₂ is substituted with one, two or three R_2-1.

For example, as a compound having the structure of formula (III) , said R₂ is substituted with one said R_2-1.

For example, as a compound having the structure of formula (III) , each said R_2-1 is independently selected from the group consisting of hydrogen, halogen, =O, CN, optionally substituted alkyl, optionally substituted acyl, optionally substituted amino, optionally substituted hydroxyl, optionally substituted phosphorous-containing group, optionally substituted sulfonyl, and optionally substituted ring.

For example, as a compound having the structure of formula (III) , said R_2-1 is optionally substituted amino.

For example, as a compound having the structure of formula (III) , said R₃ is selected from the group consisting of hydrogen, halogen, CN, optionally substituted alkyl, optionally substituted acyl, optionally substituted amino, optionally substituted hydroxyl, optionally substituted phosphorous-containing group, optionally substituted sulfonyl, and optionally substituted ring.

For example, as a compound having the structure of formula (III) , said R₃ is optionally substituted propyl.

For example, as a compound having the structure of formula (III) , said R₃ is optionally substituted isopropyl.

For example, as a compound having the structure of formula (III) , said R₄ is selected from the group consisting of hydrogen, halogen, CN, optionally substituted alkyl, optionally substituted acyl, optionally substituted amino, optionally substituted hydroxyl, optionally substituted phosphorous-containing group, optionally substituted sulfonyl, and optionally substituted ring.

For example, as a compound having the structure of formula (III) , said R₄ is hydrogen.

For example, as a compound having the structure of formula (III) , said R₁ is optionally substituted heterocycle.

For example, as a compound having the structure of formula (III) , said R₁ is optionally substituted 6-ring-membered heterocycle.

For example, as a compound having the structure of formula (III) , said R₁ is optionally substituted 6-ring-membered heterocycle containing one or two N.

For example, as a compound having the structure of formula (III) , said R₁ is optionally substituted heteroaryl.

For example, as a compound having the structure of formula (III) , said R₁ is optionally substituted 5-ring-membered heteroaryl.

For example, as a compound having the structure of formula (III) , said R₁ is optionally substituted 5-ring-membered heteroaryl containing two N.

For example, as a compound having the structure of formula (III) , said R₁ is optionally substituted 6-ring-membered heteroaryl.

For example, as a compound having the structure of formula (III) , said R₁ is optionally substituted 6-ring-membered heteroaryl containing two N.

For example, as a compound having the structure of formula (III) , said R₁ is substituted with one or more R_1-1, each said R_1-1 is independently absent or is independently selected from optional substituents.

For example, as a compound having the structure of formula (III) , each said R_1-1 is optionally substituted methyl or two methyl substituted amino.

In one aspect, the present application provides a method for inhibiting cyclin-dependent kinase (CDK) activity, said method comprising administering to a subject in need thereof an effective amount of the present application, or a pharmaceutically acceptable salt, prodrug, or metabolite thereof, or a solvate or hydrate of any of the foregoing. For example, said cyclin-dependent kinase (CDK) may be CDK 7. For example, said method may be selected from the group consisting of an in vitro method, an ex vivo method, and an in vivo method.

In another embodiment, the present application provides use the compound of the present application, or a pharmaceutically acceptable salt, prodrug, or metabolite thereof, or a solvate or hydrate of any of the foregoing of the present application in the preparation of a drug and/or a kit for use in inhibiting cyclin-dependent kinase (CDK) activity. For example, said cyclin-dependent kinase (CDK) may be CDK 7. For example, said method of using said drug and/or said kit may be selected from the group consisting of an in vitro method, an ex vivo method, and an in vivo method.

In another embodiment, the present application provides the compound of the present application, or a pharmaceutically acceptable salt, prodrug, or metabolite thereof, or a solvate or hydrate of any of the foregoing of the present application for use in inhibiting cyclin-dependent kinase (CDK) activity. For example, said cyclin-dependent kinase (CDK) may be CDK 7. For example, said method or said use may be selected from the group consisting of an in vitro method, an ex vivo method, and an in vivo method.

In one aspect, the present application provides a composition comprising a compound of the present application, or a pharmaceutically acceptable salt, prodrug, or metabolite thereof, or a solvate or hydrate of any of the foregoing, and optionally a pharmaceutically acceptable carrier.

The compounds of the application may be administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the blood stream directly from the mouth.

In some cases, the compounds of the present application may also be administered directly into the blood stream, into muscle, or into an internal organ. Suitable means for parenteral administration may include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous. Suitable devices for parenteral administration may include needle (including microneedle) injectors, needle-free injectors and infusion techniques.

The compounds of the present application may also be administered topically to the skin or mucosa, that is, dermally or transdermally. In some cases, the compounds of the present application may also be administered intranasally or by inhalation. In some cases, the compounds of the present application may be administered rectally or vaginally. In another embodiment, the compounds of the present application may also be administered directly to the eye or ear.

The dosage regimen for the compounds and/or compositions containing the compounds is based on a variety of factors, including the type, age, weight, sex and condition of the patient; the severity of the condition; the route of administration; and the activity of the particular compound employed. Thus, the dosage regimen may vary widely. Dosage levels of body weight per day may be useful.

Suitable subjects according to the present invention include mammalian subjects. Mammals according to the present invention may include, but are not limited to, canine, feline, bovine, caprine, equine, ovine, porcine, rodents, lagomorphs, primates, and the like, and encompass mammals in utero. In one embodiment, humans are suitable subjects. Human subjects may be of either gender and at any stage of development.

In another embodiment, the present application provides use of one or more compounds of the present application for the preparation of a medicament.

For example, the compounds of the present application may be administered as compound per se. Alternatively, pharmaceutically acceptable salts may be suitable for medical applications because of their greater aqueous solubility relative to the parent compound.

In another embodiment, the present application provides compositions. Such compositions may comprise a compound of the present application presented with a pharmaceutically acceptable carrier. The carrier may be a solid product, a liquid, or both, and may be formulated with the compound as a unit-dose composition, for example, a tablet, which may contain the active compounds. A compound of the present application may be coupled with suitable polymers as targetable drug carriers. Other pharmacologically active substances may also be present.

The compounds of the present invention may be administered by any suitable route, maybe in the form of a pharmaceutical composition adapted to such a route. The active compounds and compositions, for example, may be administered orally, rectally, parenterally, or topically.

The compounds of the present application may be used, alone or in combination with other therapeutic agents. The compound (s) of the present application and other therapeutic agent (s) may be administered simultaneously (either in the same dosage form or in separate dosage forms) or sequentially.

The administration of two or more compounds “in combination” may mean that the two compounds are administered closely enough in time that the presence of one alters the biological effects of the other. The two or more compounds may be administered simultaneously, concurrently or sequentially. Additionally, simultaneous administration may be carried out by mixing the compounds prior to administration or by administering the compounds at the same point in time but at different anatomic sites or using different routes of administration.

The phrases “concurrent administration, ” “co-administration, ” “simultaneous administration, ” and “administered simultaneously” may mean that the compounds are administered in combination.

Examples

The following examples are set forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the present invention, and are not intended to limit the scope of what the inventors regard as their invention nor are they intended to represent that the experiments below are all or the only experiments performed. Efforts have been made to ensure accuracy with respect to numbers used (e.g. amounts, temperature, etc. ) but some experimental errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, molecular weight is weight average molecular weight, temperature is in degrees Celsius, and pressure is at or near atmospheric. Standard abbreviations may be used, e.g., bp, base pair (s) ; kb, kilobase (s) ; pl, picoliter (s) ; s or sec, second (s) ; min, minute (s) ; h or hr, hour (s) ; aa, amino acid (s) ; nt, nucleotide (s) ; i. m., intramuscular (ly) ; i.p., intraperitoneal (ly) ; s.c., subcutaneous (ly) ; and the like.

Example 1 Preparation of Compounds

2- (4-aminopiperidin-1-yl) -9-isopropyl-N- (2- (3- (prop-1-en-2-yl) -1H-pyrrol-1-yl) benzyl) -9H-purin-6-amine

Synthesis of 2- (4-aminopiperidin-1-yl) -9-isopropyl-N- (2- (3- (prop-1-en-2-yl) -1H-pyrrol-1-yl) benzyl) -9H-purin-6-amine

Synthesis of methyl 1- (2-cyanophenyl) pyrrole-3-carboxylate

A mixture of methyl 1H-pyrrole-3-carboxylate (500 mg, 4.00 mmol, 1.00 equiv) , 2-fluorobenzonitrile (581 mg, 4.80 mmol, 1.20 equiv) and potassium carbonate (1.10 g, 8.00 mmol, 2.00 equiv) in DMF (10 mL) was stirred for overnight at 60 ℃ under nitrogen atmosphere. The reaction was quenched with ice/water (50 mL) at room temperature. The resulting mixture was extracted with ethyl acetate (300 mL) . The combined organic layers were washed with water (3 x 50 mL) , dried over anhydrous sodium sulfate, and filtrated, concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether /ethyl acetate (1: 1) to afford methyl 1- (2-cyanophenyl) pyrrole-3-carboxylate (710 mg, 79%yield) as a yellow solid. ESI-MS (ESI, m/z) : 227 [M+H] ⁺.

Synthesis of 2- [3- (2-hydroxypropan-2-yl) pyrrol-1-yl] benzonitrile

To a stirred mixture of methyl 1- (2-cyanophenyl) pyrrole-3-carboxylate (300 mg, 1.33 mmol, 1.00 equiv) and tetrahydrofuran (6 mL) was added methyl-magnesiubromide (1.77 mL, 5.31 mmol, 4.00 equiv, 3M in THF) dropwise at 0℃ under nitrogen atmosphere. Then the resulting mixture was stirred for 2 h at 60 ℃ under nitrogen atmosphere and quenched with saturated ammonium chloride solution (40 mL) at room temperature. The resulting mixture was extracted with ethyl acetate (3 x 50 mL) . The combined organic layers were washed with brine (2 x 50 mL) , dried over anhydrous sodium sulfate, filtrated and concentrated under reduced pressure to afford 2- [3- (2-hydroxypropan-2-yl) pyrrol-1-yl] benzonitrile (330 mg, crude) as yellow oil. ESI-MS (ESI, m/z) : 209 [M+H-H₂O] ⁺.

Synthesis of 2- {1- [2- (aminomethyl) phenyl] pyrrol-3-yl} propan-2-ol

To a stirred solution of 2- [3- (2-hydroxypropan-2-yl) pyrrol-1-yl] benzonitrile (300 mg, 1.33 mmol, 1.00 equiv) and tetrahydrofuran (6 mL) were added lithium aluminum hydride (0.8 mL, 2.00 mmol, 1.50 equiv, 2.5 M in tetrahydrofuran) dropwise at 0℃. Then the resulting mixture was stirred for 2 h at room temperature and quenched with ice/water (3 mL) at room temperature. The solids were filtered off, the filter cake was washed with tetrahydrofuran (3 x 10 mL) . The filtrate was concentrated under reduced pressure to afford 2- {1- [2- (aminomethyl) phenyl] pyrrol-3-yl} propan-2-ol (320 mg, crude) as yellow oil. ESI-MS (ESI, m/z) : 213 [M+H-H₂O] ⁺.

Synthesis of 2- [1- (2- { [ (2-chloro-9-isopropylpurin-6-yl) amino] methyl} phenyl) pyrrol-3-yl] propan-2-ol

A mixture of 2- {1- [2- (aminomethyl) phenyl] pyrrol-3-yl} propan-2-ol (310 mg, 1.35 mmol, 1.00 equiv) , 2, 6-dichloro-9-isopropylpurine (311 mg, 1.35 mmol, 1.00 equiv) and N, N-diisopropylethylamine (522 mg, 4.04 mmol, 3.00 equiv) in n-butanol (6 mL) was stirred for overnight at 80 ℃ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with ethyl acetate to afford 2- [1- (2- { [ (2-chloro-9-isopropylpurin-6-yl) amino] methyl} phenyl) pyrrol-3-yl] propan-2-ol (110 mg, 19%yield) as a yellow solid. ESI-MS (ESI, m/z) : 407 [M+H-H₂O] ⁺.

Synthesis of 2- (4-aminopiperidin-1-yl) -9-isopropyl-N- ( {2- [3- (prop-1-en-2-yl) pyrrol-1-yl] phenyl} methyl) purin-6-amine

A mixture of 2- [1- (2- { [ (2-chloro-9-isopropylpurin-6-yl) amino] methyl} phenyl) pyrrol-3-yl] propan-2-ol (100 mg, 0.236 mmol, 1.00 equiv) , piperidin-4-amine (70.7 mg, 0.708 mmol, 3.00 equiv) and N, N-diisopropylethylamine (91.24 mg, 0.708 mmol, 3.00 equiv) in n-butanol (4 mL) was irradiated with microwave radiation for 3 h at 100℃. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C₁₈ Column, 30*150 mm, 5 μm; Mobile Phase A: Water (10 mmol/L NH₄HCO₃+0.1%NH₃·H₂O) , Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 43%B to 63%B in 7 min; Wave Length: 254 nm to afford 2- (4-aminopiperidin-1-yl) -9-isopropyl- N- ( {2- [3- (prop-1-en-2-yl) pyrrol-1-yl] phenyl} methyl) purin-6-amine (12.6 mg, 11%yield) as a white solid. LC-MS (ESI, m/z) : 471 [M+H] ⁺. ¹H NMR (300 MHz, Methanol-d₄) δ 7.80 (s, 1H) , 7.63 -7.50 (m, 1H) , 7.43 -7.24 (m, 3H) , 6.90 -6.89 (m, 1H) , 6.82 -6.80 (m, 1H) , 6.46 -6.45 (m, 1H) , 5.19 (s, 1H) , 4.74 -4.71 (m, 1H) , 4.68 -4.55 (m, 5H) , 3.01 -2.72 (m, 3H) , 2.08 -1.94 (m, 3H) , 1.89 -1.73 (m, 2H) , 1.57 (d, J = 6.0 Hz, 6H) , 1.28 -1.16 (m, 2H) .

2- (4-aminopiperidin-1-yl) -N- ( (2- (4- (difluoromethyl) piperidin-1-yl) pyridin-3-yl) methyl) -9-isopropyl-9H-purin-6-amine

Synthesis of 2- (4-aminopiperidin-1-yl) -N- ( (2- (4- (difluoromethyl) piperidin-1-yl) pyridin-3-yl) methyl) -9-isopropyl-9H-purin-6-amine

Synthesis of 2- [4- (difluoromethyl) piperidin-1-yl] pyridine-3-carbonitrile

A mixture of 2-chloropyridine-3-carbonitrile (200 mg, 1.44 mmol, 1.00 equiv) , 4- (difluoromethyl) piperidine (195 mg, 1.44 mmol, 1.00 equiv) and potassium carbonate (599 mg, 4.33 mmol, 3.00 equiv) in DMF (5 mL) was stirred for overnight at 60℃ and quenched with water (30 mL) . The resulting mixture was extracted with ethyl acetate (3 x 30 mL) . The combined organic layers were washed with water (3 x 20 mL) , dried over anhydrous sodium sulfate, and filtrated, concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether /ethyl acetate (1: 1) to afford 2- [4- (difluoromethyl) piperidin-1-yl] pyridine-3-carbonitrile (220 mg, 64%yield) as yellow oil. LC-MS (ESI, m/z) : 238 [M+H] ⁺.

Synthesis of 1- {2- [4- (difluoromethyl) piperidin-1-yl] pyridin-3-yl} methanamine

A mixture of 2- [4- (difluoromethyl) piperidin-1-yl] pyridine-3-carbonitrile (200 mg, 0.843 mmol, 1.00 equiv) and Raney Nickel (20 mg) in NH₃ (5 mL, 7M in methanol) was stirred for overnight at room temperature under hydrogen atmosphere (2 -3 atm) . The solids were filtered off, the filter cake was washed with methanol (3 x 10 mL) . The filtrate was concentrated under reduced pressure to afford 1- {2- [4- (difluoromethyl) piperidin-1-yl] pyridin-3-yl} methanamine (190 mg, crude) as a yellow oil. LC-MS (ESI, m/z) : 242 [M+H] ⁺.

Synthesis of 2-chloro-N- ( {2- [4- (difluoromethyl) piperidin-1-yl] pyridin-3-yl} methyl) -9-isopropylpurin-6-amine

A mixture of 1- {2- [4- (difluoromethyl) piperidin-1-yl] pyridin-3-yl} methanamine (190 mg, 0.787 mmol, 1.00 equiv) , 2, 6-dichloro-9-isopropylpurine (182 mg, 0.787 mmol, 1.00 equiv) and N, N-diisopropylethylamine (305 mg, 2.36 mmol, 3.00 equiv) in n-butanol (6 mL) was stirred for overnight at 80℃ and concentrated under reduce pressure. The residue was purified by silica gel column chromatography, eluted with ethyl acetate to afford 2-chloro-N- ( {2- [4- (difluoromethyl) piperidin-1-yl] pyridin-3-yl} methyl) -9-isopropylpurin-6-amine (240 mg, 70%yield) as a yellow solid. LC-MS (ESI, m/z) : 436 [M+H] ⁺.

Synthesis of 2- (4-aminopiperidin-1-yl) -N- ( {2- [4- (difluoromethyl) piperidin-1-yl] pyridin-3-yl} methyl) -9-isopropylpurin-6-amine

A 5 mL vial was charged with 2-chloro-N- ( {2- [4- (difluoromethyl) piperidin-1-yl] pyridin-3-yl} methyl) -9-isopropylpurin-6-amine (100 mg, 0.229 mmol, 1.00 equiv) , piperidin-4-amine (68.9 mg, 0.687 mmol, 3.00 equiv) and N, N-diisopropylethylamine (89.0mg, 0.687 mmol, 3.00 equiv) and n-butanol (1.5 mL) . The final reaction mixture was irradiated with microwave radiation for 5 h at 130℃. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C₁₈ Column, 30*150 mm, 5 μm; Mobile Phase A: Water (10 mmol/L NH₄HCO₃) , Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 26%B to 46%B in 7 min; Wave Length: 254 nm to afford 2- (4-aminopiperidin-1-yl) -N- ( {2- [4- (difluoromethyl) piperidin-1-yl] pyridin-3-yl} methyl) -9-iso propylpurin-6-amine (67.4 mg, 59%yield) as a white solid. LC-MS (ESI, m/z) : 500 [M+H] ⁺. ¹H NMR (300 MHz, Methanol-d₄) δ 8.11 (d, J = 2.0 Hz, 1H) , 7.80 (s, 1H) , 7.75 -7.72 (m, 1H) , 6.98 (d, J = 2.0 Hz, 1H) , 5.95 -5.56 (m, 1H) , 4.77 -4.61 (m, 5H) , 3.45 (d, J = 6.0 Hz, 2H) , 2.91 -2.73 (m, 5H) , 2.02 -1.86 (m, 3H) , 1.77 -1.69 (m, 4H) , 1.66 (d, J = 2.0 Hz, 6H) , 1.23 -1.05 (m, 2H) .

2- (4-aminopiperidin-1-yl) -N- ( (6'- (difluoromethoxy) - [2, 3'-bipyridin] -3-yl) methyl) -9-isopropyl-9H-purin-6-amine

Synthesis of 2- (4-aminopiperidin-1-yl) -N- ( (6'- (difluoromethoxy) - [2, 3'-bipyridin] -3-yl) methyl) -9-isopropyl-9H-purin-6-amine

Synthesis of 2- (difluoromethoxy) -5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine

A mixture of 5-bromo-2- (difluoromethoxy) pyridine (500 mg, 2.23 mmol, 1.00 equiv) , bis(pinacolato) diboron (1.13 g, 4.46 mmol, 2.00 equiv) , potassium acetate (657 mg, 6.70 mmol, 3.00 equiv) and [1, 1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) (163 mg, 0.223 mmol, 0.10 equiv) in 1, 4-dioxane (5 mL) was stirred for overnight at 100 ℃ under nitrogen atmosphere. The mixture was allowed to cool down to room temperature and filtered, the filter cake was washed with ethyl acetate (2 x 20 mL) . The filtrate was concentrated under reduced pressure to afford 2- (difluoromethoxy) -5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine (650 mg, crude) as a black oil. LC-MS (ESI, m/z) : 272 [M+H] ⁺.

Synthesis of 6'- (difluoromethoxy) - [2, 3'-bipyridine] -3-carbonitrile

A mixture of 2- (difluoromethoxy) -5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine (640 mg, 2.36 mmol, 1.00 equiv) , 2-chloropyridine-3-carbonitrile (327 mg, 2.36 mmol, 1.00 equiv) , potassium carbonate (979 mg, 7.08 mmol, 3.00 equiv) and tetrakis (triphenylphosphine) palladium (273 mg, 0.236 mmol, 0.10 equiv) in 1, 4-dioxane (6 mL) and water (1.2 mL) was stirred for overnight at 100 ℃ under nitrogen atmosphere. The mixture was allowed to cool down to room temperature and filtered, the filter cake was washed with ethyl acetate (2 x 20 mL) . The filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions: column, C₁₈ silica gel; mobile phase, acetonitrile in water, 0%to 100%gradient in 10 min; detector, UV 254 nm to afford 6'- (difluoromethoxy) - [2, 3'-bipyridine] -3-carbonitrile (570 mg, crude) as a light yellow solid. LC-MS (ESI, m/z) : 248 [M+H] ⁺.

Synthesis of 1- [6'- (difluoromethoxy) - [2, 3'-bipyridin] -3-yl] methanamine

A mixture of 6'- (difluoromethoxy) - [2, 3'-bipyridine] -3-carbonitrile (560 mg, 2.27 mmol, 1.00 equiv) and Raney Ni (20 mg) in ammonia (gas) (5 mL, 7.0 M in methanol) was stirred for overnight at room temperature under hydrogen atmosphere (2 -3 atm) . The solids were filtered off, the filter cake was washed with methanol (2 x 30 mL) . The filtrate was concentrated under reduced pressure to afford 1- [6'- (difluoromethoxy) - [2, 3'-bipyridin] -3-yl] methanamine (200 mg, crude) as a pink oil. LC-MS (ESI, m/z) : 252 [M+H] ⁺.

Synthesis of 2-chloro-N- { [6'- (difluoromethoxy) - [2, 3'-bipyridin] -3-yl] methyl} -9-isopropylpurin-6-amine

A mixture of 1- [6'- (difluoromethoxy) - [2, 3'-bipyridin] -3-yl] methanamine (200 mg, 0.796 mmol, 1.00 equiv) , 2, 6-dichloro-9-isopropylpurine (184 mg, 0.796 mmol, 1.00 equiv) and N, N-diisopropylethylamine (308 mg, 2.38 mmol, 3.00 equiv) in n-buthanol (2 mL) was stirred for overnight at 80 ℃. The mixture was allowed to cool down to room temperature and concentrated under reduced pressure. The residue was purified by Prep-TLC with petroleum ether /ethyl acetate (1: 1) to afford 2-chloro-N- { [6'- (difluoromethoxy) - [2, 3'-bipyridin] -3-yl] methyl} -9-isopropylpurin-6-amine (270 mg, 76%yield) as a yellow solid. LC-MS (ESI, m/z) : 446 [M+H] ⁺.

Synthesis of 2- (4-aminopiperidin-1-yl) -N- { [6'- (difluoromethoxy) - [2, 3'-bipyridin] -3-yl] methyl} -9-isopropylpurin-6-amine

A mixture of 2-chloro-N- { [6'- (difluoromethoxy) - [2, 3'-bipyridin] -3-yl] methyl} -9-isopropylpurin-6-amine (100 mg, 0.224 mmol, 1.00 equiv) and N, N-diisopropylethylamine (86.9 mg, 0.672 mmol, 3.00 equiv) in n-buthanol (2 mL) was irradiated with microwave radiation for 5 h at 130 ℃. The mixture was allowed to cool down to room temperature and concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions: Column: XBridge Shield RP₁₈ OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH₄HCO₃) , Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 30%B to 45%B in 10 min; Wave Length: 254 nm to afford 2- (4-aminopiperidin-1-yl) -N- { [6'- (difluoromethoxy) - [2, 3'-bipyridin] -3-yl] methyl} -9-isopropylpurin-6-amine (59.7 mg, 52%yield) as a white solid. LC-MS (ESI, m/z) : 510 [M+H] ⁺. ¹H NMR (400 MHz, Chloroform-d) δ 8.60 -8.58 (m, 1H) , 8.39 (d, J = 2.0 Hz, 1H) , 7.97 -7.76 (m, 1H) , 7.89 -7.85 (m, 1H) , 7.70 -7.32 (m, 2H) , 7.28 (d, J = 6.0 Hz, 1H) , 6.98 -6.70 (m, 1H) , 5.86 (s, 1H) , 4.81 (d, J = 6.0 Hz, 2H) , 4.65 -4.62 (m, 1H) , 4.55 (d, J = 10.0 Hz, 2H) , 2.90 -2.77 (m, 3H) , 1.84 -1.76 (m, 2H) , 1.54 (d, J = 6.0 Hz, 6H) , 1.22 -1.19 (m, 2H) .

2- (4-aminopiperidin-1-yl) -N- ( (6'- (azetidin-1-yl) - [2, 3'-bipyridin] -3-yl) methyl) -9-isopropyl-9H-purin-6-amine

Synthesis of 2- (4-aminopiperidin-1-yl) -N- ( (6'- (azetidin-1-yl) - [2, 3'-bipyridin] -3-yl) methyl) -9 -isopropyl-9H-purin-6-amine

Synthesis of 2- (azetidin-1-yl) -5-bromopyridine

A mixture of 5-bromo-2-fluoropyridine (1.00 g, 5.68 mmol, 1.00 equiv) , azetidine hydrochloride (0.530 g, 5.68 mmol, 1.00 equiv) and dicesium carbonate (5.55 g, 17.0 mmol, 3.00 equiv) in DMSO (12 mL) was stirred for overnight at 60℃. The residue was purified by reverse flash chromatography with the following conditions: column, C₁₈ silica gel; mobile phase, MeCN in Water, 0%to 100%gradient in 40 min; detector, UV 254 nm to afford 2- (azetidin-1-yl) -5-bromopyridine (391 mg, 32%yield) as a yellow solid. LC-MS (ESI, m/z) : 213 [M+H] ⁺.

Synthesis of 2- (azetidin-1-yl) -5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine

A mixture of 2- (azetidin-1-yl) -5-bromopyridine (380 mg, 1.78 mmol, 1.00 equiv) , bis (pinacolato) diboron (543 mg, 2.14 mmol, 1.20 equiv) , potassium acetate (350 mg, 3.57 mmol, 2.00 equiv) and [1, 1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) (261 mg, 0.357 mmol, 0.20 equiv) in 1, 4-dioxane (6 mL) was stirred for overnight at 100℃ under nitrogen atmosphere. The solids were filtered off, the filter cake was washed with ethyl acetate (3 x 20 mL) . The filtrate was concentrated under reduced pressure to afford 2- (azetidin-1-yl) -5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine (1.2 g, crude) as yellow oil. LC-MS (ESI, m/z) : 261 [M+H] ⁺.

Synthesis of 6'- (azetidin-1-yl) - [2, 3'-bipyridine] -3-carbonitrile

A mixture of 2- (azetidin-1-yl) -5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine (1.20 g, crude) , 2-chloropyridine-3-carbonitrile (360 mg, 2.60 mmol, 1.00 equiv) , potassium carbonate (478 mg, 3.46 mmol, 1.33 equiv) , tetrakis (triphenylphosphine) palladium (200 mg, 0.173 mmol, 0.07 equiv) and water (2 mL) in 1, 4-dioxane (10 mL) was stirred for overnight at 100℃ under nitrogen atmosphere and quenched with water (50 mL) at room temperature. The resulting mixture was extracted with ethyl acetate (3 x 150 mL) . The combined organic layers were dried over anhydrous sodium sulfate, filtrated and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with ethyl acetate to afford 6'- (azetidin-1-yl) - [2, 3'-bipyridine] -3-carbonitrile (465 mg, crude) as yellow oil. LC-MS (ESI, m/z) : 237 [M+H] ⁺.

Synthesis of 1- [6'- (azetidin-1-yl) - [2, 3'-bipyridin] -3-yl] methanamine

A mixture of 2- [4- (difluoromethyl) piperidin-1-yl] pyridine-3-carbonitrile (200 mg, 0.843 mmol, 1.00 equiv) and Raney Ni (20 mg) in NH₃ (5 mL, 7M in methanol) was stirred for overnight at room temperature under hydrogen atmosphere (2 -3 atm) . The solids were filtered off, the filter cake was washed with methanol (3 x 10 mL) . The filtrate was concentrated under reduced pressure to afford 1- [6'- (azetidin-1-yl) - [2, 3'-bipyridin] -3-yl] methanamine (169 mg, crude) as yellow oil. LC-MS (ESI, m/z) : 241 [M+H] ⁺.

Synthesis of N- { [6'- (azetidin-1-yl) - [2, 3'-bipyridin] -3-yl] methyl} -2-chloro-9-isopropylpurin-6-amine

A mixture of 1- [6'- (azetidin-1-yl) - [2, 3'-bipyridin] -3-yl] methanamine (160 mg, 0.666 mmol, 1.00 equiv) , 2, 6-dichloro-9-isopropylpurine (154 mg, 0.666 mmol, 1.00 equiv) and N, N-diisopropylethylamine (258 mg, 2.00 mmol, 3.00 equiv) in n-butanol (6 mL) was stirred for overnight at 80℃. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with ethyl acetate to afford N- { [6'- (azetidin-1-yl) - [2, 3'-bipyridin] -3-yl] methyl} -2-chloro-9-isopropylpurin-6-amine (180 mg, 62%yield) as a white solid. LC-MS (ESI, m/z) : 435 [M+H] ⁺.

Synthesis of 2- (4-aminopiperidin-1-yl) -N- { [6'- (azetidin-1-yl) - [2, 3'-bipyridin] -3-yl] methyl} -9-isopropylpurin-6-amine

A 5 mL vial was charged with N- { [6'- (azetidin-1-yl) - [2, 3'-bipyridin] -3-yl] methyl} -2-chloro-9-isopropylpurin-6-amine (110 mg, 0.253 mmol, 1.00 equiv) , piperidin-4-amine (69.1 mg, 0.690 mmol, 3.00 equiv) , N, N-diisopropylethylamine (89.2 mg, 0.690 mmol, 3.00 equiv) and n-butanol (1.5 mL) at room temperature. The final reaction mixture was irradiated with microwave radiation for 5 h at 130℃. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions: Column: XBridge Shield RP₁₈ OBD Column, 30*150 mm, 5 μm; Mobile Phase A: water (10 mmol/L NH₄HCO₃) , Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 25%B to 55%B in 7 min; Wave Length: 254 nm to afford 2- (4-aminopiperidin-1-yl) -N- { [6'- (azetidin-1-yl) - [2, 3'-bipyridin] -3-yl] methyl} -9-isopropylpurin-6-amine (35.3 mg, 28%yield) as an off-white solid. LC-MS (ESI, m/z) : 499 [M+H] ⁺. ¹H NMR (300 MHz, Methanol-d₄) δ 8.46 -8.44 (m, 1H) , 8.17 (d, J = 2.0 Hz, 1H) , 7.95 -7.92 (m, 1H) , 7.78 (s, 1H) , 7.75 -7.70 (m, 1H) , 7.35 -7.31 (m, 1H) , 6.45 (d, J = 4.0 Hz, 1H) , 4.75 (s, 2H) , 4.70 -4.61 (m, 1H) , 4.52 (d, J = 9.0 Hz, 2H) , 4.12 -4.07 (m, 4H) , 2.87 -2.69 (m, 3H) , 2.49 -2.39 (m, 2H) , 1.75 (d, J = 9.0 Hz, 2H) , 1.53 (d, J = 2.0 Hz, 6H) , 1.18 -1.06 (m, 2H) .

(S) -2- (4-aminopiperidin-1-yl) -N- ( (2- (3, 4-dimethylpiperazin-1-yl) pyridin-3-yl) methyl) -9-is opropyl-9H-purin-6-amine

Synthesis of (S) -2- (4-aminopiperidin-1-yl) -N- ( (2- (3, 4-dimethylpiperazin-1-yl) pyridin-3-yl) methyl) -9-isopropyl-9H-purin-6-amine

Synthesis of (S) -2- (3, 4-dimethylpiperazin-1-yl) nicotinonitrile

To a solution of 2-fluoronicotinonitrile (150 mg, 1.23 mmol) in DMF (2 mL) were added (S) -1, 2-dimethylpiperazine (140.28 mg, 1.23 mmol) and Cs₂CO₃ (600.40 mg, 1.84 mmol) , the mixture was stirred at 100℃ for 7h. The reaction mixture was filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO₂, MeOH: DCM=0%to 7%) to give (S) -2- (3, 4-dimethylpiperazin-1-yl) nicotinonitrile (261 mg, 1.21 mmol, 98.19%yield, 99.96%purity) as an oil.

ESI-MS [M+H] ⁺ : 217.28.

Synthesis of (S) - (2- (3, 4-dimethylpiperazin-1-yl) pyridin-3-yl) methanamine

To a solution of (S) -2- (3, 4-dimethylpiperazin-1-yl) nicotinonitrile (261 mg, 1.21 mmol) were added NH₃ (7M in MeOH, 1 mL) and Ni (100 mg, 1.70 mmol) , replaced with H₂ three times and the mixture was stirred at RT for 5h. LCMS show the reaction was completed. The reaction mixture was filtered and concentrated to give (S) - (2- (3, 4-dimethylpiperazin-1-yl) pyridin-3-yl) methanamine (265 mg, crude) as an oil.

ESI-MS [M+H] ⁺ : 221.30.

Synthesis of 2, 6-dichloro-9-isopropyl-9H-purine

To a solution of 2, 6-dichloro-9H-purine (20 g, 105.82 mmol) in DMSO (100 mL) were added 2-bromopropane (65.07 g, 529.09 mmol) and potassium carbonate (43.88 g, 317.46 mmol) , the mixture was stirred at room temperature for 65h. The reaction was poured into water (400ml) , extracted with EA (300ml*2) , the organic layer was washed with brine (300ml*2) , dried over Na₂SO₄, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO₂, EA: PE=0%to 70%) to give 2, 6-dichloro-9-isopropyl-9H-purine (5.72 g, 24.58 mmol, 23.23%yield, 99.30%purity) as an off-white solid.

ESI-MS [M+H] ⁺: 231.16.

Synthesis of (S) -2-chloro-N- ( (2- (3, 4-dimethylpiperazin-1-yl) pyridin-3-yl) methyl) -9-isopropyl-9H-purin-6-amine

To a solution of N- (2- (1H-pyrazol-1-yl) benzyl) -2-chloro-9-isopropyl-9H-purin-6-amine (200 mg, 865.50 μmol) in EtOH (2 mL) were added (S) - (2- (3, 4-dimethylpiperazin-1-yl) pyridin-3-yl) methanamine (228.82 mg, 1.04 mmol) and TEA (175.16 mg, 1.73 mmol, 241.43 μL) , the mixture was stirred at 80℃ for 5h. The reaction mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO₂, 0.5M ammonia methanol solution: DCM=0%to 10%) to give (S) -2-chloro-N- ( (2- (3, 4-dimethylpiperazin-1-yl) pyridin-3-yl) methyl) -9-isopropyl-9H-purin-6-amine (351 mg, 842.62 μmol, 97.36%yield, 99.61%purity) as a white solid.

ESI-MS [M+H] ⁺ : 415.33.

To a solution of (S) -2-chloro-N- ( (2- (3, 4-dimethylpiperazin-1-yl) pyridin-3-yl) methyl) -9-isopropyl- 9H-purin-6-amine (200 mg, 482.00 μmol) in NMP (2 mL) were added piperidin-4-amine (57.93 mg, 578.41 μmol) and DIPEA (124.59 mg, 964.01 μmol, 167.91 μL) , the mixture was stirred at 160℃ for 7h. The reaction mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO₂, 0.5M ammonia methanol solution: DCM=0%to 20%) to give (S) -2- (4-aminopiperidin-1-yl) -N- ( (2- (3, 4-dimethylpiperazin-1-yl) pyridin-3-yl) methyl) -9-isopropyl-9H-purin-6-amine (25 mg, 52.00 μmol, 10.79%yield, 99.55%purity) as a white solid.

ESI-MS [M+H] ⁺ : 479.47.

¹H NMR (400 MHz, Methanol-d₄) δ 8.11 (dd, J = 4.9, 1.9 Hz, 1H) , 7.81 (s, 1H) , 7.73 (dd, J =7.6, 1.9 Hz, 1H) , 6.97 (dd, J = 7.5, 4.9 Hz, 1H) , 4.79 –4.60 (m, 5H) , 3.30 –3.21 (m, 2H) , 3.11 (td, J = 11.9, 2.7 Hz, 1H) , 2.94 (dq, J = 11.7, 3.5 Hz, 2H) , 2.85 –2.68 (m, 3H) , 2.53 (td, J =11.5, 3.1 Hz, 1H) , 2.41 (ddd, J = 9.6, 6.3, 3.0 Hz, 1H) , 2.36 (s, 3H) , 1.79 (dd, J = 12.9, 3.9 Hz, 2H) , 1.55 (d, J = 6.8 Hz, 6H) , 1.32 –1.16 (m, 2H) , 1.12 (d, J = 6.3 Hz, 3H) .

2- (4-aminopiperidin-1-yl) -9-isopropyl-N- ( (2- ( (3R, 5S) -3, 4, 5-trimethylpiperazin-1-yl) pyridin-3-yl) methyl) -9H-purin-6-amine

Synthesis of 2- (4-aminopiperidin-1-yl) -9-isopropyl-N- ( (2- ( (3R, 5S) -3, 4, 5-trimethylpiperazin -1-yl) pyridin-3-yl) methyl) -9H-purin-6-amine

Synthesis of 2- ( (3R, 5S) -3, 4, 5-trimethylpiperazin-1-yl) nicotinonitrile

To a solution of 2-fluoronicotinonitrile (150 mg, 1.23 mmol) in DMF (2 mL) were added (2R, 6S) -1, 2, 6-trimethylpiperazine (157.51 mg, 1.23 mmol) anS (600.40 mg, 1.84 mmol) , the mixture was stirred at 100℃ for 7h. The reaction mixture was filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO₂, MeOH: DCM=0%to 8%) to give 2- ( (3R, 5S) -3, 4, 5-trimethylpiperazin-1-yl) nicotinonitrile (281 mg, 1.22 mmol, 99.24%yield, 99.92%purity) as a yellow solid.

ESI-MS [M+H] ⁺ : 231.31.

Synthesis of (2- ( (3R, 5S) -3, 4, 5-trimethylpiperazin-1-yl) pyridin-3-yl) methanamine

To a solution of 2- ( (3R, 5S) -3, 4, 5-trimethylpiperazin-1-yl) nicotinonitrile (281 mg, 1.22 mmol) were added NH₃ (7M in MeOH, 1 mL) and Ni (100 mg, 1.70 mmol) , replaced with H₂ three times and the mixture was stirred at RT for 5h. LCMS show the reaction was completed. The reaction mixture was filtered and concentrated to give (2- ( (3R, 5S) -3, 4, 5-trimethylpiperazin-1-yl) pyridin-3-yl) methanamine (284 mg, crude) as an oil.

ESI-MS [M+H] ⁺ : 235.34.

Synthesis of 2, 6-dichloro-9-isopropyl-9H-purine

ESI-MS [M+H] ⁺: 231.16.

Synthesis of 2-chloro-9-isopropyl-N- ( (2- ( (3R, 5S) -3, 4, 5-trimethylpiperazin-1-yl) pyridin-3-yl) methyl) -9H-purin-6-amine

To a solution of N- (2- (1H-pyrazol-1-yl) benzyl) -2-chloro-9-isopropyl-9H-purin-6-amine (200 mg, 865.50 μmol) in EtOH (2 mL) were added (2- ( (3R, 5S) -3, 4, 5-trimethylpiperazin-1-yl) pyridin-3-yl) methanamine (243.38 mg, 1.04 mmol) and TEA (175.16 mg, 1.73 mmol, 241.43 μL) , the mixture was stirred at 80℃ for 5h. The reaction mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO₂, 0.5M ammonia methanol solution: DCM=0%to 12%) to give 2-chloro-9-isopropyl-N- ( (2- ( (3R, 5S) -3, 4, 5-trimethylpiperazin-1-yl) pyridin-3-yl) methyl) -9H-p urin-6-amine (348 mg, 810.29 μmol, 93.62%yield, 99.88%purity) as a white solid.

ESI-MS [M+H] ⁺ : 429.37.

Synthesis of 2- (4-aminopiperidin-1-yl) -9-isopropyl-N- ( (2- ( (3R, 5S) -3, 4, 5-trimethylpiperazin-1-yl) pyridin-3-yl) methyl) -9H-purin-6-amine

To a solution of 2-chloro-9-isopropyl-N- ( (2- ( (3R, 5S) -3, 4, 5-trimethylpiperazin-1-yl) pyridin-3-yl) methyl) -9H-purin-6-amine (200 mg, 466.24 μmol) in NMP (2 mL) were added piperidin-4-amine (56.04 mg, 559.49 μmol) and DIPEA (120.51 mg, 932.49 μmol, 162.42 μL) , the mixture was stirred at 160℃ for 7h. The reaction mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO₂, 0.5M ammonia methanol solution: DCM=0%to 25%) to give 2- (4-aminopiperidin-1-yl) -9-isopropyl-N- ( (2- ( (3R, 5S) -3, 4, 5-trimethylpiperazin-1-yl) pyridin-3-yl) methyl) -9H-purin-6-amine (149 mg, 298.36 μmol, 63.99%yield, 98.65%purity) as a white solid.

ESI-MS [M+H] ⁺ : 493.41.

¹H NMR (400 MHz, Methanol-d₄) δ 8.11 (dd, J = 5.0, 1.9 Hz, 1H) , 7.80 (s, 1H) , 7.73 (dd, J =7.6, 1.9 Hz, 1H) , 6.97 (dd, J = 7.5, 4.9 Hz, 1H) , 4.74 –4.60 (m, 5H) , 3.29 –3.24 (m, 2H) , 2.92 (tt, J = 11.1, 4.2 Hz, 1H) , 2.85 –2.69 (m, 4H) , 2.50 (dqd, J = 12.5, 6.1, 2.6 Hz, 2H) , 2.34 (s, 3H) , 1.84 –1.75 (m, 2H) , 1.55 (d, J = 6.8 Hz, 6H) , 1.22 (tt, J = 12.1, 6.1 Hz, 2H) , 1.15 (d, J =6.3 Hz, 6H) .

2- (4-aminopiperidin-1-yl) -9-isopropyl-N- ( (2- (4-methoxypiperidin-1-yl) pyridin-3-yl) methyl) -9H-purin-6-amine

Synthesis of 2- (4-aminopiperidin-1-yl) -9-isopropyl-N- ( (2- (4-methoxypiperidin-1-yl) pyridin-3-yl) methyl) -9H-purin-6-amine

Synthesis of 2- (4-methoxypiperidin-1-yl) nicotinonitrile

To a solution of 2-fluoronicotinonitrile (150 mg, 1.23 mmol) in DMF (2 mL) were added 4-methoxypiperidine (155.64 mg, 1.35 mmol) and Cs₂CO₃ (600.40 mg, 1.84 mmol) , the mixture was stirred at 100℃ for 7h. The reaction mixture was filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO₂, EA: PE=0%to 30%) to give 2- (4-methoxypiperidin-1-yl) nicotinonitrile (251 mg, 1.15 mmol, 93.91%yield, 99.86%purity) as a yellow solid.

ESI-MS [M+H] ⁺ : 218.24.

Synthesis of (2- (4-methoxypiperidin-1-yl) pyridin-3-yl) methanamine

To a solution of 2- (4-methoxypiperidin-1-yl) nicotinonitrile (251 mg, 1.16 mmol) were added NH₃ (7M in MeOH, 1 mL) and Ni (100 mg, 1.70 mmol) , replaced with H₂ three times and the mixture was stirred at RT for 5h. LCMS show the reaction was completed. The reaction mixture was filtered and concentrated to give (2- (4-methoxypiperidin-1-yl) pyridin-3-yl) methanamine (250 mg, crude) as an oil.

ESI-MS [M+H] ⁺ : 222.31.

Synthesis of 2, 6-dichloro-9-isopropyl-9H-purine

ESI-MS [M+H] ⁺: 231.16.

Synthesis of 2-chloro-9-isopropyl-N- ( (2- (4-methoxypiperidin-1-yl) pyridin-3-yl) methyl) -9H-purin-6-amine

To a solution of N- (2- (1H-pyrazol-1-yl) benzyl) -2-chloro-9-isopropyl-9H-purin-6-amine (200 mg, 865.50 μmol) in EtOH (2 mL) were added (2- (4-methoxypiperidin-1-yl) pyridin-3-yl) methanamine (229.84 mg, 1.04 mmol) and TEA (175.16 mg, 1.73 mmol, 241.43 μL) , the mixture was stirred at 85℃ for 5h. The reaction mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO₂, 0.5M ammonia methanol solution: DCM=0%to 7%) to give 2-chloro-9-isopropyl-N- ( (2- (4-methoxypiperidin-1-yl) pyridin-3-yl) methyl) -9H-purin-6-amine (300 mg, 721.01 μmol, 83.31%yield, 99.96%purity) as a white solid.

ESI-MS [M+H] ⁺ : 416.32.

Synthesis of 2- (4-aminopiperidin-1-yl) -9-isopropyl-N- ( (2- (4-methoxypiperidin-1-yl) pyridine -3-yl) methyl) -9H-purin-6-amine

To a solution of 2-chloro-9-isopropyl-N- ( (2- (4-methoxypiperidin-1-yl) pyridin-3-yl) methyl) -9H-purin-6-amine (200 mg, 480.86 μmol) in NMP (2 mL) were added piperidin-4-amine (57.80 mg, 577.04 μmol) and DIPEA (124.29 mg, 961.73 μmol, 167.51 μL) , the mixture was stirred at 85℃ for 5h. The reaction mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO₂, 0.5M ammonia methanol solution: DCM=0%to 10%) to give 2- (4-aminocyclohexyl) -9-isopropyl-N- ( (2- (4-methoxypiperidin-1-yl) pyridin-3-yl) methyl) -9H-purin-6-amine (166 mg, 345.35 μmol, 71.82%yield, 99.78%purity) as a white solid.

ESI-MS [M+H] ⁺ : 480.40.

¹H NMR (400 MHz, Methanol-d₄) δ 8.08 (dd, J = 4.9, 1.8 Hz, 1H) , 7.79 (s, 1H) , 7.72 (dd, J =7.6, 1.8 Hz, 1H) , 6.99 –6.91 (m, 1H) , 4.71 (s, 2H) , 4.68 –4.58 (m, 3H) , 3.47 –3.40 (m, 1H) , 3.39 (d, J = 1.1 Hz, 3H) , 3.35 (dd, J = 12.1, 5.2 Hz, 2H) , 2.94 (ddd, J = 12.7, 9.7, 2.9 Hz, 2H) , 2.87 –2.71 (m, 3H) , 2.13 –2.02 (m, 2H) , 1.80 –1.67 (m, 4H) , 1.54 (dd, J = 6.7, 1.0 Hz, 6H) , 1.17 (qd, J = 12.2, 4.2 Hz, 2H) .

(S) -2- (4-aminopiperidin-1-yl) -N- ( (2- (3- (dimethylamino) pyrrolidin-1-yl) pyridin-3-yl) methyl) -9-isopropyl-9H-purin-6-amine

Synthesis of (S) -2- (4-aminopiperidin-1-yl) -N- ( (2- (3- (dimethylamino) pyrrolidin-1-yl) pyridin-3-yl) methyl) -9-isopropyl-9H-purin-6-amine

Synthesis of (S) -2- (3- (dimethylamino) pyrrolidin-1-yl) nicotinonitrile

To a solution of 2-fluoronicotinonitrile (150 mg, 1.23 mmol) in DMF (2 mL) were added (S) -N, N-dimethylpyrrolidin-3-amine (140.28 mg, 1.23 mmol) and Cs₂CO₃ (600.40 mg, 1.84 mmol) , the mixture was stirred at 100℃ for 7h. The reaction mixture was filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO₂, MeOH: DCM=0%to 8%) to give (S) -2- (3- (dimethylamino) pyrrolidin-1-yl) nicotinonitrile (226 mg, 1.04 mmol, 84.84%yield, 99.75%purity) as a yellow solid.

ESI-MS [M+H] ⁺ : 217.29.

Synthesis of (S) -1- (3- (aminomethyl) pyridin-2-yl) -N, N-dimethylpyrrolidin-3-amine

To a solution of (S) -2- (3- (dimethylamino) pyrrolidin-1-yl) nicotinonitrile (226 mg, 1.04 mmol) in MeOH (20 mL) were added NH₃ (7M in MeOH, 1 mL) and Ni (100 mg, 1.70 mmol) , replaced with H₂ three times and the mixture was stirred at RT for 5h. LCMS show the reaction was completed. The reaction mixture was filtered and concentrated to give (S) -1- (3- (aminomethyl) pyridin-2-yl) -N, N-dimethylpyrrolidin-3-amine (230 mg, crude) as an oil.

ESI-MS [M+H] ⁺ : 221.33.

Synthesis of 2, 6-dichloro-9-isopropyl-9H-purine

ESI-MS [M+H] ⁺: 231.16.

Synthesis of (S) -2-chloro-N- ( (2- (3- (dimethylamino) pyrrolidin-1-yl) pyridin-3-yl) methyl) -9-isopropyl-9H-purin-6-amine

To a solution of N- (2- (1H-pyrazol-1-yl) benzyl) -2-chloro-9-isopropyl-9H-purin-6-amine (200 mg, 865.50 μmol) in EtOH (20 mL) were added (S) -1- (3- (aminomethyl) pyridin-2-yl) -N, N-dimethylpyrrolidin-3-amine (228.82 mg, 1.04 mmol) and TEA (175.16 mg, 1.73 mmol, 241.43 μL) , the mixture was stirred at 85℃ for 5h. The reaction mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO₂, 0.5M ammonia methanol solution: DCM=0%to 10%) to give (S) -2-chloro-N- ( (2- (3- (dimethylamino) pyrrolidin-1-yl) pyridin-3-yl) methyl) -9-isopropyl-9H-purin-6-amine (314 mg, 754.63 μmol, 87.19%yield, 99.72%purity) as a white solid.

ESI-MS [M+H] ⁺ : 415.31.

To a solution of (S) -2-chloro-N- ( (2- (3- (dimethylamino) pyrrolidin-1-yl) pyridin-3-yl) methyl) -9-isopropyl-9H-purin-6-amine (100 mg, 241.00 μmol) in NMP (2 mL) were added piperidin-4-amine (28.97 mg, 289.20 μmol) and DIPEA (62.29 mg, 482.00 μmol, 83.95 μL) , the mixture was stirred at 160℃ for 7h. The reaction mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO₂, 0.5M ammonia methanol solution: DCM=0%to 20%) to give (S) -2- (4-aminopiperidin-1-yl) -N- ( (2- (3- (dimethylamino) pyrrolidin-1-yl) pyridin-3-yl) methyl) -9-isopropyl-9H-purin-6-amine (57 mg, 118.90 μmol, 49.33%yield, 99.84%purity) as a white solid.

ESI-MS [M+H] ⁺ : 479.38.

¹H NMR (400 MHz, Methanol-d₄) δ 7.99 (dd, J = 5.0, 1.8 Hz, 1H) , 7.78 (s, 1H) , 7.60 (dd, J =7.4, 1.8 Hz, 1H) , 6.73 (dd, J = 7.4, 5.0 Hz, 1H) , 4.75 –4.66 (m, 4H) , 3.68 (ddt, J = 10.0, 7.1, 3.5 Hz, 2H) , 3.61 –3.44 (m, 2H) , 2.91 –2.77 (m, 4H) , 2.27 (s, 6H) , 2.21 (dtt, J = 11.0, 6.8, 3.4 Hz, 1H) , 1.91 –1.75 (m, 3H) , 1.54 (d, J = 6.8 Hz, 6H) , 1.38 –1.15 (m, 3H) .

2- (4-aminopiperidin-1-yl) -N- ( (5'- (dimethylamino) - [2, 3'-bipyridin] -3-yl) methyl) -9-isopropyl-9H-purin-6-amine

Synthesis of 2- (4-aminopiperidin-1-yl) -N- ( (5'- (dimethylamino) - [2, 3'-bipyridin] -3-yl) methyl) -9-isopropyl-9H-purin-6-amine

Synthesis of 5-bromo-N, N-dimethylpyridin-3-amine

To a mixture of 3, 5-dibromopyridine (50 mg, 0.211 mmol) and Cs₂CO₃ (227 mg, 0.696 mmol) in NMP (3 mL) was added Me₂NHHCl (38 mg, 0.464 mmol) . The mixture was stirred at 180℃ for 16h in a sealed tube. The reaction mixture was cooled to room temperature. The reaction was quenched with water (30 mL) and extracted with EtOAc (20 mL x 3) . The combined organic layers were washed with brine (30 mL) , dried over anhydrous Na₂SO₄, and concentrated to give the crude product, which was purified by Prep-TLC (eluent: DCM/MeOH = 20/1) to give 5-bromo-N, N-dimethylpyridin-3-amine (10 mg, yield: 23.5%) as a colorless oil.

ESI-MS [M +H] ⁺: 201.1.

Synthesis of (5- (dimethylamino) pyridin-3-yl) boronic acid

To a mixture of 5-bromo-N, N-dimethylpyridin-3-amine (35 mg, 0.175 mmol) , 4, 4, 4', 4', 5, 5, 5', 5'-octamethyl-2, 2'-bi (1, 3, 2-dioxaborolane) (111 mg, 0.438 mmol) and AcOK (51 mg, 0.525 mmol) in dioxane (3 mL) was added Pd (dppf) Cl₂ (13 mg, 0.018 mmol) . The mixture was stirred at 85℃ for 16h under N₂. The reaction mixture was cooled to room temperature. The mixture was filtered throughand the filter cake was washed with DCM/MeOH (10/1, 30 mL) . The filtrate was concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 20/1) to give (5- (dimethylamino) pyridin-3-yl) boronic acid (20 mg, yield: 68.4%) as a colorless oil. ESI-MS [M +H] +: 167.1.

Synthesis of 5'- (dimethylamino) - [2, 3'-bipyridine] -3-carbonitrile

To a mixture of 5-bromo-N, N-dimethylpyridin-3-amine (120 mg, 0.723 mmol) , 2-bromonicotinonitrile (26 mg, 0.145 mmol) and Na₂CO₃ (46 mg, 0.434 mmol) in DME (5 mL) and water (0.5 mL) was added Pd (dppf) Cl₂ (21 mg, 0.029 mmol) . The mixture was stirred at 85℃ for 16h under N₂. The reaction mixture was cooled to room temperature. The mixture was filtered throughand the filter cake was washed with DCM/MeOH (10/1, 30 mL) . The filtrate was concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 20/1) to give 5'- (dimethylamino) - [2, 3'-bipyridine] -3-carbonitrile (28 mg, yield: 17.3%) as a colorless oil. ESI-MS [M +H] +: 225.1.

Synthesis of 3- (aminomethyl) -N, N-dimethyl- [2, 3'-bipyridin] -5'-amine

To a mixture of 5'- (dimethylamino) - [2, 3'-bipyridine] -3-carbonitrile (28 mg, 1.25 mmol) in NH₃ (7M solution in MeOH, 1 mL) was added Raney Ni (10 mg) . The reaction mixture was stirred at room temperature for 3h under H₂. The reaction mixture was filtered throughand the filter cake was washed with DCM/MeOH (10/1, 20 mL) . The filtrate was concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 10/1) to give 3- (aminomethyl) -N, N-dimethyl- [2, 3'-bipyridin] -5'-amine (28 mg, yield: 98.2%) as a yellow oil. ESI-MS [M +H] +: 229.1.

Synthesis of 2-chloro-N- ( (5'- (dimethylamino) - [2, 3'-bipyridin] -3-yl) methyl) -9-isopropyl-9H-purin-6-amine

A mixture of 2, 6-dichloro-9-isopropyl-9H-purine (38 mg, 0.167 mmol) , 3- (aminomethyl) -N, N-dimethyl- [2, 3'-bipyridin] -5'-amine (38 mg, 0.167 mmol) and DIPEA (65 mg, 0.504 mmol) in i-PrOH (5 mL) was stirred at 90℃ for 3h. The reaction mixture was concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 20/1) to give 2-chloro-N- ( (5'- (dimethylamino) - [2, 3'-bipyridin] -3-yl) methyl) -9-isopropyl-9H-purin-6-amine (10 mg, yield: 14.1%) as a white solid. ESI-MS [M + H] ⁺: 423.1.

Synthesis of tert-butyl (1- (6- ( ( (5'- (dimethylamino) - [2, 3'-bipyridin] -3-yl) methyl) amino) -9-isopropyl-9H-purin-2-yl) piperidin-4-yl) carbamate

A mixture of 2-chloro-N- ( (5'- (dimethylamino) - [2, 3'-bipyridin] -3-yl) methyl) -9-isopropyl-9H-purin-6-amine (10 mg, 0.024 mmol) , tert-butyl piperidin-4-ylcarbamate (7.2 mg, 0.036 mmol) and DIPEA (93 mg, 0.72 mmol) in i-PrOH (8 mL) was irradiated in microwave at 140℃for 4h. The reaction mixture was concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 15/1) to give tert-butyl (1- (6- ( ( (5'- (dimethylamino) - [2, 3'-bipyridin] -3-yl) methyl) amino) -9-isopropyl-9H-purin-2-yl) piperidin-4-yl) carbamate (10 mg, yield: 71.1%) as a white solid. ESI-MS [M + H] ⁺: 587.3

To a mixture of tert-butyl (1- (6- ( ( (5'- (dimethylamino) - [2, 3'-bipyridin] -3-yl) methyl) amino) -9 -isopropyl-9H-purin-2-yl) piperidin-4-yl) carbamate (80 mg, 0.075 mmol) in MeOH (2 mL) was added HCl (4M solution in 1, 4-dioxane, 2 mL) . The reaction mixture was stirred at room temperature for 1h. The reaction mixture was quenched with NH₃ (7M solution in MeOH, 2 mL) and concentrated in vacuo to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 10/1) to give 2- (4-aminopiperidin-1-yl) -N- ( (5'- (dimethylamino) - [2, 3'-bipyridin] -3-yl) methyl) -9-isopropyl-9 H-purin-6-amine (13 mg, yield: 40.1%) as a white solid.

ESI-MS [M +H] ⁺: 487.3.

¹H NMR (400 MHz, Methanol-d₄) δ 8.41 (m, 1H) , 7.95 (d, J = 2.9 Hz, 1H) , 7.90 (m, 1H) , 7.86 (d, J = 1.6 Hz, 1H) , 7.69 (s, 1H) , 7.35 (m, 1H) , 7.13 –7.05 (m, 1H) , 4.66 (s, 2H) , 4.56 (m, 1H) , 4.46 (d, J = 13.3 Hz, 2H) , 3.01 –2.79 (m, 7H) , 2.67 (m, 2H) , 1.70 (d, J = 9.9 Hz, 2H) , 1.45 (d, J = 6.8 Hz, 6H) , 1.19 –1.10 (m, 2H) .

2- (2- (2- ( ( (2- (4-aminopiperidin-1-yl) -9-isopropyl-9H-purin-6-yl) amino) methyl) phenyl) thiazol-5-yl) propan-2-ol

Synthesis of 2- (2- (2- ( ( (2- (4-aminopiperidin-1-yl) -9-isopropyl-9H-purin-6-yl) amino) methyl) phenyl) thiazol-5-yl) propan-2-ol

Synthesis of methyl 2- (2- ( ( (tert-butoxycarbonyl) amino) methyl) phenyl) thiazole-5-carboxylate

A mixture of methyl 2-bromothiazole-5-carboxylate (250 mg, 1.1 mmol) , tert-butyl (2- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzyl) carbamate (566 mg, 1.7 mmol) , Pd(dppf) Cl₂ (73 mg, 0.1 mmol) and Na₂CO₃ (350 mg, 3.3 mmol) in dioxane/H₂O (10 mL/1 mL) was stirred at 90℃ for 16h under N₂. The reaction mixture was cooled to room temperature. The mixture was filtered through and the filter cake was washed with DCM/MeOH (10/1, 30 mL) . The filtrate was concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 30/1) to give methyl 2- (2- ( ( (tert-butoxycarbonyl) amino) methyl) phenyl) thiazole-5-carboxylate (150 mg, yield: 39%) as a yellow oil. ESI-MS [M +H] ⁺: 349.2.

Synthesis of methyl 2- (2- (aminomethyl) phenyl) thiazole-5-carboxylate

To a mixture of methyl 2- (2- ( ( (tert-butoxycarbonyl) amino) methyl) phenyl) thiazole-5-carboxylate (150 mg, 0.4 mmol) in MeOH (4 mL) was added HCl (4M solution in 1, 4-dioxane, 4 mL) . The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with NH₃ (7M solution in MeOH, 4 mL) and concentrated in vacuo to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 10/1) to give the product methyl 2- (2- (aminomethyl) phenyl) thiazole-5-carboxylate (100 mg, yield: 93%) as a white solid.

ESI-MS [M +H] ⁺: 249.2.

Synthesis of methyl 2- (2- ( ( (2-chloro-9-isopropyl-9H-purin-6-yl) amino) methyl) phenyl) thiazole-5-carboxylate

A mixture of methyl 2- (2- (aminomethyl) phenyl) thiazole-5-carboxylate (100 mg, 0.4 mmol) , DIPEA (155 mg, 1.2 mmol) and 2, 6-dichloro-9-isopropyl-9H-purine (92 mg, 0.4 mmol ) in IPA (10 mL) was stirred at 90℃ for 3 h. The reaction mixture was concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 20/1) to give the product methyl 2- (2- ( ( (2-chloro-9-isopropyl-9H-purin-6-yl) amino) methyl) phenyl) thiazole-5-carboxylate (120 mg, yield: 68%) as a yellow solid. ESI-MS [M + H] ⁺: 443.2.

Synthesis of methyl 2- (2- ( ( (2- (4- ( (tert-butoxycarbonyl) amino) piperidin-1-yl) -9-isopropyl-9H-purin-6-yl) amino) methyl) phenyl) thiazole-5-carboxylate

A mixture of methyl 2- (2- ( ( (2-chloro-9-isopropyl-9H-purin-6-yl) amino) methyl) phenyl) thiazole-5-carboxylate (120 mg, 0.3 mmol) , tert-butyl piperidin-4-ylcarbamate (120 mg, 0.6 mmol) and DIPEA (77 mg, 0.6 mmol) in i-PrOH (2 mL) was irradiated in microwave at 140℃ for 6h. The reaction mixture was concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 20/1) to give the product methyl 2- (2- ( ( (2- (4- ( (tert-butoxycarbonyl) amino) piperidin-1-yl) -9-isopropyl-9H-purin-6-yl) amino) methyl) phenyl) thiazole-5-carboxylate (50 mg, yield: 28%) as a yellow solid. ESI-MS [M + H] +: 607.2.

Synthesis of tert-butyl (1- (6- ( (2- (5- (2-hydroxypropan-2-yl) thiazol-2-yl) benzyl) amino) -9-isopropyl-9H-purin-2-yl) piperidin-4-yl) carbamate

To a mixture of methyl 2- (2- ( ( (2- (4- ( (tert-butoxycarbonyl) amino) piperidin-1-yl) -9-isopropyl-9H-purin-6-yl) amino) methyl) phenyl) thiazole-5-carboxylate (50 mg, 0.08 mmol) in THF (5 mL) was added MeMgBr (0.08 mL, 0.24 mmol) at 0℃ under nitrogen. The mixture was stirred at 0℃ for 3 h under N₂. The reaction was quenched with NH₄Cl (10 mL) and extracted with EtOAc (10 mL x 3) . The combined organic layers were washed with brine, dried over Na₂SO₄, filtered and concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 20/1) to give the product tert-butyl (1- (6- ( (2- (5- (2-hydroxypropan-2-yl) thiazol-2-yl) benzyl) amino) -9- isopropyl-9H-purin-2-yl) piperidin-4-yl) carbamate (30 mg, yield: 60%) as a yellow solid. ESI-MS [M +H] ⁺: 607.2.

To a mixture of 2- (1- (2- ( ( (2- (4-aminopiperidin-1-yl) -7- (prop-1-en-2-yl) imidazo [2, 1-f] [1, 2, 4] triazin -4-yl) amino) methyl) -3-chlorophenyl) -1H-pyrazol-3-yl) propan-2-ol (30 mg, 0.05 mmol) in HFIP (3 mL) was irradiated in microwave at 110℃ for 2h. . The reaction mixture was concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 20/1) to give the product 2- (2- (2- ( ( (2- (4-aminopiperidin-1-yl) -9-isopropyl-9H-purin-6-yl) amino) methyl) phenyl) thiazol-5-yl) propan-2-ol (10 mg, yield: 40%) as a white solid.

ESI-MS [M +H] ⁺: 507.2.

¹H NMR (400 MHz, Methanol-d₄) δ 7.68 (d, J = 8.0 Hz, 2H) , 7.56 –7.53 (m, 2H) , 7.32 –7.24 (m, 2H) , 4.83 (s, 2H) , 4.70 (d, J = 13.4 Hz, 2H) , 4.61 –4.51 (m, 2H) , 3.04 –2.96 (m, 1H) , 2.82 –2.76 (m, 2H) , 1.80 (d, J = 9.7 Hz, 2H) , 1.57 (s, 6H) , 1.44 (d, J = 6.8 Hz, 6H) , 1.30 –1.19 (m, 2H) .

2- (4-aminopiperidin-1-yl) -9-isopropyl-N- ( (2- (9-methyl-3, 9-diazaspiro [5.5] undecan-3-yl) pyridin-3-yl) methyl) -9H-purin-6-amine

Synthesis of 2- (4-aminopiperidin-1-yl) -9-isopropyl-N- ( (2- (9-methyl-3, 9-diazaspiro [5.5] undecan-3-yl) pyridin-3-yl) methyl) -9H-purin-6-amine

Synthesis of 2- (9-methyl-3, 9-diazaspiro [5.5] undecan-3-yl) nicotinonitrile

To a solution of 2-fluoronicotinonitrile (150 mg, 1.23 mmol) in DMF (2 mL) were added 3-methyl-3, 9-diazaspiro [5.5] undecane (206.73 mg, 1.23 mmol) and Cs₂CO₃ (600.40 mg, 1.84 mmol) , the mixture was stirred at 100℃ for 7h. The reaction mixture was filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO₂, MeOH: DCM= 0%to 15%) to give 2- (9-methyl-3, 9-diazaspiro [5.5] undecan-3-yl) nicotinonitrile (315 mg, 1.16 mmol, 94.36%yield, 99.50%purity) as a white solid.

ESI-MS [M+H] ⁺ : 271.35.

Synthesis of (2- (9-methyl-3, 9-diazaspiro [5.5] undecan-3-yl) pyridin-3-yl) methanamine

To a solution of 2- (9-methyl-3, 9-diazaspiro [5.5] undecan-3-yl) nicotinonitrile (315 mg, 1.17 mmol) were added NH₃ (7M in MeOH, 1 mL) and Ni (100 mg, 1.70 mmol) , replaced with H₂ three times and the mixture was stirred at RT for 5h. LCMS show the reaction was completed. The reaction mixture was filtered and concentrated to give (2- (9-methyl-3, 9-diazaspiro [5.5] undecan-3-yl) pyridin-3-yl) methanamine (311 mg, crude) as an oil.

ESI-MS [M+H] ⁺ : 275.39.

Synthesis of 2, 6-dichloro-9-isopropyl-9H-purine

ESI-MS [M+H] ⁺: 231.16.

Synthesis of 2-chloro-9-isopropyl-N- ( (2- (9-methyl-3, 9-diazaspiro [5.5] undecan-3-yl) pyridin-3-yl) methyl) -9H-purin-6-amine

To a solution of N- (2- (1H-pyrazol-1-yl) benzyl) -2-chloro-9-isopropyl-9H-purin-6-amine (200 mg, 865.50 μmol) in EtOH (19.88 mL) were added (2- (9-methyl-3, 9-diazaspiro [5.5] undecan-3-yl) pyridin-3-yl) methanamine (284.99 mg, 1.04 mmol) and TEA (175.16 mg, 1.73 mmol, 241.43 μL) , the mixture was stirred at 85℃ for 5h. The reaction mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO₂, 0.5M ammonia methanol solution: DCM=0%to 15%) to give 2-chloro-9-isopropyl-N- ( (2- (9-methyl-3, 9-diazaspiro [5.5] undecan-3-yl) pyridin-3-yl) methyl) -9 H-purin-6-amine (277 mg, 578.01 μmol, 66.78%yield, 97.87%purity) as a white solid.

ESI-MS [M+H] ⁺ : 469.37.

To a solution of 2-chloro-9-isopropyl-N- ( (2- (9-methyl-3, 9-diazaspiro [5.5] undecan-3-yl) pyridin-3-yl) methyl) -9 H-purin-6-amine (277 mg, 590.59 μmol) in NMP (2 mL) were added piperidin-4-amine (70.99 mg, 708.71 μmol) and DIPEA (152.66 mg, 1.18 mmol, 205.73 μL) , the mixture was stirred at 160℃ for 7h. The reaction mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO₂, 0.5M ammonia methanol solution: DCM=0%to 35%) to give 2- (4-aminopiperidin-1-yl) -9-isopropyl-N- ( (2- (9-methyl-3, 9-diazaspiro [5.5] undecan-3-yl) pyridin-3-yl) methyl) -9H-purin-6-amine (33 mg, 58.12 μmol, 9.84%yield, 93.82%purity) as a white solid.

ESI-MS [M+H] ⁺ : 533.45.

1H NMR (400 MHz, Methanol-d₄) δ 8.09 (dd, J = 5.0, 1.9 Hz, 1H) , 7.80 (s, 1H) , 7.72 (dd, J =7.6, 1.8 Hz, 1H) , 6.95 (dd, J = 7.5, 4.9 Hz, 1H) , 4.72 –4.60 (m, 5H) , 3.09 (t, J = 5.6 Hz, 4H) , 2.86 (tt, J = 10.8, 4.0 Hz, 1H) , 2.82 –2.72 (m, 2H) , 2.47 (s, 4H) , 2.29 (s, 3H) , 1.81 –1.73 (m, 2H) , 1.72 –1.62 (m, 8H) , 1.55 (d, J = 6.8 Hz, 6H) , 1.19 (qd, J = 12.0, 4.0 Hz, 2H) .

2- (4-aminopiperidin-1-yl) -9-isopropyl-N- (2- (3-isopropyl-1H-pyrazol-1-yl) benzyl) -9H-purin-6-amine

Synthesis of 2- (4-aminopiperidin-1-yl) -9-isopropyl-N- (2- (3-isopropyl-1H-pyrazol-1-yl) benzyl) -9H-purin-6-amine

Synthesis of 2- (3-isopropyl-1H-pyrazol-1-yl) benzonitrile

To a solution of 2-fluorobenzonitrile (200 mg, 1.65 mmol) in DMF (2 mL) were added 3-isopropyl-1H-pyrazole (218.29 mg, 1.98 mmol) and Cs₂CO₃ (807.07 mg, 2.48 mmol) , the mixture was stirred at 100℃ for 7h. The reaction mixture was filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO₂, EA: PE=0%to 20%) to give 2- (3-isopropyl-1H-pyrazol-1-yl) benzonitrile (304 mg, 1.44 mmol, 86.97%yield, 99.81%purity) as an oil.

ESI-MS [M+H] ⁺ : 212.25.

Synthesis of (2- (3-isopropyl-1H-pyrazol-1-yl) phenyl) methanamine

To a solution of 2- (3-isopropyl-1H-pyrazol-1-yl) benzonitrile (304 mg, 1.44 mmol) in MeOH (10 mL) were added NH₃ (7M in MeOH, 1 mL) and Ni (100 mg, 1.70 mmol) , replaced with H₂ three times and the mixture was stirred at RT for 5h. LCMS show the reaction was completed. The reaction mixture was filtered and concentrated to give (2- (3-isopropyl-1H-pyrazol-1-yl) phenyl) methanamine (288 mg, crude) as an oil.

ESI-MS [M+H] ⁺ : 216.27.

Synthesis of 2, 6-dichloro-9-isopropyl-9H-purine

ESI-MS [M+H] ⁺: 231.16.

Synthesis of 2-chloro-9-isopropyl-N- (2- (3-isopropyl-1H-pyrazol-1-yl) benzyl) -9H-purin-6-amine

To a solution of N- (2- (1H-pyrazol-1-yl) benzyl) -2-chloro-9-isopropyl-9H-purin-6-amine (250 mg, 1.08 mmol) in EtOH (15 mL) were added (2- (3-isopropyl-1H-pyrazol-1-yl) phenyl) methanamine (279.50 mg, 1.30 mmol) and TEA (218.95 mg, 2.16 mmol, 301.79 μL) , the mixture was stirred at 85℃ for 5h. The reaction mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO₂, 0.5M ammonia methanol solution: DCM=0%to 10%) to give 2-chloro-9-isopropyl-N- (2- (3-isopropyl-1H-pyrazol-1-yl) benzyl) -9H-purin-6-amine (389 mg, 920.60 μmol, 85.09%yield, 97.01%purity) as a white solid.

ESI-MS [M+H] ⁺ : 410.29.

To a solution of 2-chloro-9-isopropyl-N- (2- (3-isopropyl-1H-pyrazol-1-yl) benzyl) -9H-purin-6-amine (200 mg, 487.91 μmol) in NMP (3 mL) were added piperidin-4-amine (58.64 mg, 585.49 μmol) and DIPEA (126.11 mg, 975.81 μmol, 169.97 μL) , the mixture was stirred at 160℃ for 7h. The reaction mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO₂, 0.5M ammonia methanol solution: DCM=0%to 10%) to give 2- (4-aminopiperidin-1-yl) -9-isopropyl-N- (2- (3-isopropyl-1H-pyrazol-1-yl) benzyl) -9H-purin-6 -amine (161 mg, 327.73 μmol, 67.17%yield, 96.41%purity) as a white solid.

ESI-MS [M+H] ⁺ : 474.33.

¹H NMR (400 MHz, Methanol-d₄) δ 7.79 –7.72 (m, 2H) , 7.63 –7.54 (m, 1H) , 7.44 –7.32 (m, 3H) , 6.34 (d, J = 2.4 Hz, 1H) , 4.75 –4.59 (m, 5H) , 3.05 (hept, J = 6.9 Hz, 1H) , 2.94 (tt, J =11.0, 4.1 Hz, 1H) , 2.87 –2.77 (m, 2H) , 1.88 –1.79 (m, 2H) , 1.54 (d, J = 6.8 Hz, 6H) , 1.30 (d, J = 7.0 Hz, 6H) , 1.29 –1.21 (m, 2H) .

2- (4-aminopiperidin-1-yl) -9-isopropyl-N- ( (6'-methoxy- [2, 3'-bipyridin] -3-yl) methyl) -9H-purin-6-amine

Synthesis of 2- (4-aminopiperidin-1-yl) -9-isopropyl-N- ( (6'-methoxy- [2, 3'-bipyridin] -3-yl) methyl) -9H-purin-6-amine

Synthesis of 6'-methoxy- [2, 3'-bipyridine] -3-carbonitrile

To a solution of 2-bromonicotinonitrile (300 mg, 1.64 mmol) in DME (5 mL) and H₂O (0.5 mL) were added Pd (PPh₃) ₄ (189.43 mg, 163.93 μmol) and Na₂CO₃ (347.49 mg, 3.28 mmol) , replaced with N₂ three times, then added (6-methoxypyridin-3-yl) boronic acid (250.72 mg, 1.64 mmol) and (6-methoxypyridin-3-yl) boronic acid (250.72 mg, 1.64 mmol) , the mixture was stirred at 90℃ for 6h. The reaction mixture was filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO₂, EA: PE=0%to 50%) to give 6'-methoxy- [2, 3'-bipyridine] -3-carbonitrile (70 mg, 325.08 μmol, 19.83%yield, 98.09%purity) as a yellow solid.

ESI-MS [M+H] ⁺ : 212.21.

Synthesis of (6'-methoxy- [2, 3'-bipyridin] -3-yl) methanamine

To a solution of 6'-methoxy- [2, 3'-bipyridine] -3-carbonitrile (70 mg, 331.41 μmol) in MeOH (10.58 mL) were added NH₃ (7M, 428.57 μL) and Ni (100 mg, 1.70 mmol) , replaced with H₂ three times and the mixture was stirred at RT for 5h. LCMS show the reaction was completed. The reaction mixture was filtered and concentrated to give (6'-methoxy- [2, 3'-bipyridin] -3-yl) methanamine (70 mg, crude) as an oil.

ESI-MS [M+H] ⁺ : 216.22.

Synthesis of 2, 6-dichloro-9-isopropyl-9H-purine

ESI-MS [M+H] ⁺: 231.16.

Synthesis of 2-chloro-9-isopropyl-N- ( (6'-methoxy- [2, 3'-bipyridin] -3-yl) methyl) -9H-purin-6-amine

To a solution of N- (2- (1H-pyrazol-1-yl) benzyl) -2-chloro-9-isopropyl-9H-purin-6-amine (70 mg, 302.92 μmol) in EtOH (9.96 mL) were added (6'-methoxy- [2, 3'-bipyridin] -3-yl) methanamine (68.46 mg, 318.07 μmol) and TEA (61.31 mg, 605.85 μmol, 84.50 μL) , the mixture was stirred at 85℃ for 5h. The reaction mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO₂, 0.5M ammonia methanol solution: DCM=0%to 10%) to give 2-chloro-9-isopropyl-N- ( (6'-methoxy- [2, 3'-bipyridin] -3-yl) methyl) -9H-purin-6-amine (104 mg, 252.39 μmol, 83.32%yield, 99.47%purity) as a white solid.

ESI-MS [M+H] ⁺ : 410.21.

To a solution of 2-chloro-9-isopropyl-N- ( (6'-methoxy- [2, 3'-bipyridin] -3-yl) methyl) -9H-purin-6-amine (104 mg, 253.74 μmol) in NMP (3 mL) were added piperidin-4-amine (30.50 mg, 304.49 μmol) and DIPEA (65.59 mg, 507.48 μmol, 88.39 μL) , the mixture was stirred at 160℃ for 7h. The reaction mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO₂, 0.5M ammonia methanol solution: DCM=0%to 20%) to give 2- (4-aminopiperidin-1-yl) -9-isopropyl-N- ( (6'-methoxy- [2, 3'-bipyridin] -3-yl) methyl) -9H-purin -6-amine (43 mg, 90.24 μmol, 35.56%yield, 99.38%purity) as a white solid.

ESI-MS [M+H] ⁺ : 474.34.

¹H NMR (400 MHz, Methanol-d₄) δ 8.48 (dd, J = 4.9, 1.7 Hz, 1H) , 8.30 (dd, J = 2.4, 0.8 Hz, 1H) , 7.98 (dd, J = 7.9, 1.6 Hz, 1H) , 7.85 (dd, J = 8.5, 2.5 Hz, 1H) , 7.79 (s, 1H) , 7.39 (dd, J =7.9, 4.9 Hz, 1H) , 6.89 (dd, J = 8.6, 0.8 Hz, 1H) , 4.76 (s, 2H) , 4.65 (hept, J = 6.8 Hz, 1H) , 4.53 (d, J = 13.4 Hz, 2H) , 3.96 (s, 3H) , 2.91 (tt, J = 11.0, 4.1 Hz, 1H) , 2.74 (ddd, J = 13.7, 12.2, 2.5 Hz, 2H) , 1.82 –1.74 (m, 2H) , 1.54 (d, J = 6.9 Hz, 6H) , 1.19 (qd, J = 12.1, 4.2 Hz, 2H) .

2- (4-aminopiperidin-1-yl) -N- (2- (4- (dimethylamino) -1H-pyrazol-1-yl) benzyl) -9-isopropyl-9H-purin-6-amine

Synthesis of 2- (4-aminopiperidin-1-yl) -N- (2- (4- (dimethylamino) -1H-pyrazol-1-yl) benzyl) -9-isopropyl-9H-purin-6-amine

Synthesis of 2- (4-nitro-1H-pyrazol-1-yl) benzonitrile

To a solution of 2-fluorobenzonitrile (5.00 g, 41.28 mmol) in DMF (100 mL) were added 4-nitro-1H-pyrazole (4.67 g, 41.28 mmol) and K₂CO₃ (11.41 g, 82.57 mmol) , the mixture was stirred at 80℃ for 6hrs, The reaction was quenched with water (100ml) , The mixture was filtered. The filter cake was washed with water (50 mL) and dried to give the product 2- (4-nitro-1H-pyrazol-1-yl) benzonitrile (5.10 g, 23.81 mmol, 57.68%yield) as a white solid, which was used in the next step without further purification. ESI-MS [M +H] ⁺: 215.2

Synthesis of 2- (4- (dimethylamino) -1H-pyrazol-1-yl) benzonitrile

To a solution of 2- (3-nitro-1H-pyrazol-1-yl) benzonitrile (2.14 g, 10.00 mmol) in MeOH (100 mL) and H₂O (10 mL) were added Fe (2.79 g, 50.00 mmol) and NH₄Cl (5.34 g, 100.00 mmol) , the mixture was stirred at 70℃ for 4hrs, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO₂, DCM: MeOH=100%to 90%) to give the product 2- (3-amino-1H-pyrazol-1-yl) benzonitrile (0.99 g, 28.23 mmol, 53.75%yield) as a light yellow solid. ESI-MS [M+H] ⁺ : 185.2

Synthesis of 2- (4- (dimethylamino) -1H-pyrazol-1-yl) benzonitrile

To a solution of 2- (4-amino-1H-pyrazol-1-yl) benzonitrile (0.99 g, 5.37 mmol) in MeOH (50 mL) were added Paraformaldehyde (1.61 g, 53.75 mmol) , the mixture was stirred at 40℃ for 1h, cooled to 0℃ and NaCNBH₃ (1.69 g, 26.87 mmol) was added, the mixture was stirred at 70℃ for 3hrs, concentrated to give a residue, add water (50ml) and extracted with EA (50ml*2) , the organic layer was washed with brine (50ml) , dried over Na₂SO₄, filtered and concentrated to give a residue, The residue was purified by column chromatography (SiO₂, EA: PE=0%to 40%) to give 2- (4- (dimethylamino) -1H-pyrazol-1-yl) benzonitrile (0.90 g, 4.24 mmol, 78.89%yield) as a light yellow solid. ESI-MS [M+H] ⁺ : 213.3

Synthesis of 1- (2- (aminomethyl) phenyl) -N, N-dimethyl-1H-pyrazol-4-amine

To a solution of 2- (3- (dimethylamino) -1H-pyrazol-1-yl) benzonitrile (0.89 g, 4.19 mmol) in MeOH (50 mL) were added Raney Ni (1.00 g ) , keep on Hydrogen environment and stirred at room temperature for 15hrs, filtered and concentrated to give 1- (2- (aminomethyl) phenyl) -N, N-dimethyl-1H-pyrazol-4-amine (0.85 g, 3.93 mmol, 93.73%yield) as a light brown liquid. ESI-MS [M+H] ⁺ : 217.3

Synthesis of 2-chloro-N- (2- (4- (dimethylamino) -1H-pyrazol-1-yl) benzyl) -9-isopropyl-9H-purin-6-amine

To a solution of 1- (2- (aminomethyl) phenyl) -N, N-dimethyl-1H-pyrazol-4-amine (0.46 g, 2.00 mmol) in EtOH (50 mL) were added 2, 6-dichloro-9-isopropyl-9H-purine (0.44 g, 2.00 mmol) and TEA (0.61 g, 6.00 mmol) , the mixture was stirred at 80℃ for 6hrs. The reaction was concentrated to give a residue, and poured into water (50ml) , extracted with EA (50ml*2) , the organic layer was washed with brine (50ml) , dried over Na₂SO₄, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO₂, EA: PE=10%to 100%) to give 2-chloro-N- (2- (4- (dimethylamino) -1H-pyrazol-1-yl) benzyl) -9-isopropyl-9H-purin-6-amine (0.45 g, 1.10 mmol, 54.83%yield) as a light yellow solid. ESI-MS [M+H] ⁺ : 411.9

To a solution of 2-chloro-N- (2- (4- (dimethylamino) -1H-pyrazol-1-yl) benzyl) -9-isopropyl-9H-purin-6-amine (0.20 g, 0.49 mmol) in DMSO (3 mL) were added piperidin-4-amine (53.63 mg, 0.54mmol) and DIEA (188.72 mg, 1.46 mmol) , the mixture was stirred at 160℃ for 6hrs. The reaction was poured into water (5ml) , extracted with DCM and MeOH (10: 1 30ml*5) , the organic layer was washed with water and brine (30ml) , dried over Na₂SO₄, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO₂, MeOH: DCM=0%to 10%) to give 2- (4-aminopiperidin-1-yl) -N- (2- (4- (dimethylamino) -1H-pyrazol-1-yl) benzyl) -9-isopropyl-9H-purin-6-amine (0.13 g, 0.27 mmol, 56.28%yield) as a white solid.

ESI-MS [M+H] ⁺ : 475.6

1H NMR (400 MHz, Methanol-d₄) δ 7.71 (s, 1H) , 7.61-7.58 (m, 1H) , 7.50-7.49 (m, 1H) , 7.41-7.40 (m, 1H) , 7.38-7.35 (m, 3H) , 5.96-5.95 (m, 1H) , 4.73 –4.64 (m, 5H) , 2.99 –2.92 (m, 1H) , 2.87 –2.81 (m, 2H) , 2.69 (s, 6H) , 1.87 –1.83 (m, 2H) , 1.55-1.53 (m, 6H) , 1.31 –1.27 (m, 2H) .

2- (4-aminopiperidin-1-yl) -N- (2- (3- (dimethylamino) -1H-pyrazol-1-yl) benzyl) -9-ethyl-9H-purin-6-amine

Synthesis of 2- (4-aminopiperidin-1-yl) -N- (2- (3- (dimethylamino) -1H-pyrazol-1-yl) benzyl) -9 -ethyl-9H-purin-6-amine

Synthesis of 2- (3-nitro-1H-pyrazol-1-yl) benzonitrile

To a solution of 2-fluorobenzonitrile (5.00 g, 41.28 mmol) in DMF (100 mL) were added 3-nitro-1H-pyrazole (4.67 g, 41.28 mmol) and K₂CO₃ (11.41 g, 82.57 mmol) , the mixture was stirred at 80℃ for 6hrs, The reaction was quenched with water (100ml) , The mixture was filtered. The filter cake was washed with water (50 mL) and dried to give the product 2- (3-nitro-1H-pyrazol-1-yl) benzonitrile (6.84 g, 31.94 mmol, 77.36%yield) as a white solid, which was used in the next step without further purification. ESI-MS [M +H] ⁺: 215.2

Synthesis of 2- (3-amino-1H-pyrazol-1-yl) benzonitrile

To a solution of 2- (3-nitro-1H-pyrazol-1-yl) benzonitrile (6.80 g, 31.75 mmol) in MeOH (100 mL) and H₂O (10 mL) were added Fe (8.87 g, 158.74 mmol) and NH₄Cl (16.98 g, 317.48 mmol) , the mixture was stirred at 70℃ for 4hrs, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO₂, DCM: MeOH=100%to 90%) to give the product 2- (3-amino-1H-pyrazol-1-yl) benzonitrile (5.20 g, 28.23 mmol, 88.92%yield) as a light yellow solid. ESI-MS [M+H] ⁺ : 185.2

Synthesis of 2- (3- (dimethylamino) -1H-pyrazol-1-yl) benzonitrile

To a solution of 2- (3-amino-1H-pyrazol-1-yl) benzonitrile (1.5 g, 8.14 mmol) in MeOH (50 mL) were added Paraformaldehyde (2.45 g, 81.43 mmol) , the mixture was stirred at 40℃ for 1h, cooled to 0℃ and NaCNBH₃ (2.56 g, 40.72 mmol) was added, the mixture was stirred at 70℃ for 3hrs, concentrated to give a residue, add water (50mL) and extracted with EA(50mL*2) , the organic layer was washed with brine (50mL) , dried over Na₂SO₄, filtered and concentrated to give a residue, The residue was purified by column chromatography (SiO₂, EA: PE=0%to 40%) to give 2- (3- (dimethylamino) -1H-pyrazol-1-yl) benzonitrile (0.72 g, 3.39 mmol, 41.66%yield) as a light yellow solid. ESI-MS [M+H] ⁺ : 213.3

Synthesis of 1- (2- (aminomethyl) phenyl) -N, N-dimethyl-1H-pyrazol-3-amine

To a solution of 2- (3- (dimethylamino) -1H-pyrazol-1-yl) benzonitrile (500 mg, 2.36 mmol) in MeOH (50 mL) were added Raney-Ni (100 mg, 2.36 mmol) under hydrogen environment and stirred at room temperature for 15hrs, filtered and concentrated to give 1- (2- (aminomethyl) phenyl) -N, N-dimethyl-1H-pyrazol-3-amine (490.42 mg, 2.27 mmol, 96.26%yield) as a light brown liquid. ESI-MS [M+H] ⁺ : 217.3

Synthesis of 2-chloro-N- (2- (3- (dimethylamino) -1H-pyrazol-1-yl) benzyl) -9-ethyl-9H-purin-6-amine

To a solution of 2, 6-dichloro-9-ethyl-9H-purine (200 mg, 921.43 μmol) in EtOH (15 mL) was added 1- (2- (aminomethyl) phenyl) -N, N-dimethyl-1H-pyrazol-3-amine (219.22 mg, 1.01 mmol) and TEA (279.72 mg, 2.76 mmol, 385.55 μL) , then stirred at 80 ℃ for 6 hrs. The reaction was concentrated to give a residue. The residue was purified by column chromatography to give 2-chloro-N- (2- (3- (dimethylamino) -1H-pyrazol-1-yl) benzyl) -9-ethyl-9H-purin-6-amine (289.4 mg, 714.61 μmol, 77.56%yield, 98%purity) as a yellow solid. ESI-MS [M+H] ⁺ : 397.12.

Synthesis of 2- (4-aminopiperidin-1-yl) -N- (2- (3- (dimethylamino) -1H-pyrazol-1-yl) benzyl) -9-ethyl-9H-purin-6-amine

To a solution of 2-chloro-N- (2- (3- (dimethylamino) -1H-pyrazol-1-yl) benzyl) -9-ethyl-9H -purin-6-amine (100 mg, 251.97 μmol) in DMSO (2.5 mL) were added piperidin-4-amine (50.48 mg, 503.94 μmol) and TEA (76.49 mg, 755.90 μmol, 105.43 μL) , the mixture was stirred at 160℃ for 6hrs. The reaction was poured into water (5ml) , extracted with DCM and MeOH (10: 1 30ml*5) , the organic layer was washed with water and brine, dried over Na₂SO₄, and filtered, concentrated to give a residue. The residue was purified by column chromatography to give 2- (4-aminopiperidin-1-yl) -N- (2- (3- (dimethylamino) -1H-pyrazol-1-yl) benzyl) -9-ethyl-9H -purin-6-amine (58.9 mg, 124.05 μmol, 49.23%yield, 97%purity) as a white solid. ESI-MS [M+H] ⁺ : 461.23.¹H NMR (400 MHz, Methanol-d₄) δ 7.72 (s, 1H) , 7.65 (d, J = 2.5 Hz, 1H) , 7.55 (d, J = 6.1 Hz, 1H) , 7.38 –7.28 (m, 3H) , 5.94 (d, J = 2.5 Hz, 1H) , 4.85 –4.68 (m, 4H) , 4.10 (q, J = 7.3 Hz, 2H) , 3.35 –3.24 (m, 2H) , 2.89 (s, 6H) , 2.88 –2.82 (m, 2H) , 1.95 (dt, J =16.6, 8.3 Hz, 2H) , 1.48 –1.38 (m, 4H) .

2- (4-aminopiperidin-1-yl) -9-cyclopentyl-N- (2- (3- (dimethylamino) -1H-pyrazol-1-yl) benzyl) -9H-purin-6-amine

Synthesis of 2- (4-aminopiperidin-1-yl) -9-cyclopentyl-N- (2- (3- (dimethylamino) -1H-pyrazol-1-yl) benzyl) -9H-purin-6-amine

Synthesis of 2- (3-nitro-1H-pyrazol-1-yl) benzonitrile

Synthesis of 2- (3-amino-1H-pyrazol-1-yl) benzonitrile

To a solution of 2- (3-nitro-1H-pyrazol-1-yl) benzonitrile (6.80 g, 31.75 mmol) in MeOH (100 mL) and H₂O (10 mL) were added Fe (8.87 g, 158.74 mmol) and NH₄Cl (16.98 g, 317.48 mmol) , the mixture was stirred at 70℃ for 4hrs, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO₂, DCM: MeOH=100%to 90%) give the product 2- (3-amino-1H-pyrazol-1-yl) benzonitrile (5.20 g, 28.23 mmol, 88.92%yield) as a light yellow solid. ESI-MS [M+H] ⁺ : 185.2

Synthesis of 2- (3- (dimethylamino) -1H-pyrazol-1-yl) benzonitrile

To a solution of 2- (3-amino-1H-pyrazol-1-yl) benzonitrile (1.5 g, 8.14 mmol) in MeOH (50 mL) were added Paraformaldehyde (2.45 g, 81.43 mmol) , the mixture was stirred at 40℃ for 1h, cooled to 0℃ and NaCNBH₃ (2.56 g, 40.72 mmol) was added, the mixture was stirred at 70℃ for 3hrs, concentrated to give a residue, add water (50ml) and extracted with EA (50ml*2) , the organic layer was washed with brine (50ml) , dried over Na₂SO₄, filtered and concentrated to give a residue, The residue was purified by column chromatography (SiO₂, EA: PE=0%to 40%) to give 2- (3- (dimethylamino) -1H-pyrazol-1-yl) benzonitrile (0.72 g, 3.39 mmol, 41.66%yield) as a light yellow solid. ESI-MS [M+H] ⁺ : 213.3

Synthesis of 1- (2- (aminomethyl) phenyl) -N, N-dimethyl-1H-pyrazol-3-amine

To a solution of 2- (3- (dimethylamino) -1H-pyrazol-1-yl) benzonitrile (500 mg, 2.36 mmol) in MeOH (50 mL) were added Raney Ni (100 mg, 2.36 mmol) , keep on Hydrogen environment and stirred at room temperature for 15hrs, filtered and concentrated to give 1- (2- (aminomethyl) phenyl) -N, N-dimethyl-1H-pyrazol-3-amine (490.42 mg, 2.27 mmol, 96.26%yield) as a light brown liquid. ESI-MS [M+H] ⁺ : 217.3

Synthesis of 2-chloro-9-cyclopentyl-N- (2- (3- (dimethylamino) -1H-pyrazol-1-yl) benzyl) -9H-purin-6-amine

To a solution of 2, 6-dichloro-9-cyclopentyl-9H-purine (200 mg, 777.85 μmol) in EtOH (20 mL) was added 1- (2- (aminomethyl) phenyl) -N, N-dimethyl-1H-pyrazol-3-amine (185.06 mg, 855.64 μmol) and TEA (236.13 mg, 2.33 mmol, 325.47 μL) , then stirred at 80 ℃ for 10 hrs. The reaction was concentrated to give a residue. The residue was purified by column chromatography to give 2-chloro-9-cyclopentyl-N- (2- (3- (dimethylamino) -1H-pyrazol-1-yl) benzyl) -9H-purin-6-amine (267.8 mg, 600.64 μmol, 77.22%yield, 98%purity) as a yellow solid. ESI-MS [M+H] ⁺ : 437.12.

To a solution of 2-chloro-9-cyclopentyl-N- (2- (3- (dimethylamino) -1H-pyrazol-1-yl) benzyl) -9H-purin-6-amine (100 mg, 228.86 μmol) in EtOH (20 mL) were added piperidin-4-amine (45.85 mg, 457.73 μmol) and TEA (23.16 mg, 228.86 μmol, 31.92 μL) , the mixture was stirred at 160℃ for 6hrs. The reaction was poured into water (5ml) , extracted with DCM and MeOH (10: 1 30ml*5) , the organic layer was washed with water and brine, dried over Na₂SO₄, and filtered, concentrated to give a residue. The residue was purified by column chromatography to give 2- (4-aminopiperidin-1-yl) -9-cyclopentyl-N- (2- (3- (dimethylamino) -1H-pyrazol-1-yl) benz yl) -9H-purin-6-amine (79.6 mg, 155.82 μmol, 68.08%yield, 98%purity) as a white solid. ESI-MS [M+H] ⁺ : 501.24.¹H NMR (400 MHz, Methanol-d₄) δ 7.75 –7.71 (m, 1H) , 7.64 (t, J = 2.5 Hz, 1H) , 7.59 –7.53 (m, 1H) , 7.36 –7.30 (m, 3H) , 5.93 (t, J = 2.2 Hz, 1H) , 4.80 –4.68 (m, 4H) , 2.92 –2.78 (m, 8H) , 2.26 –2.11 (m, 2H) , 2.10 –1.67 (m, 8H) , 1.43 –1.19 (m, 4H) .

2- (4-aminopiperidin-1-yl) -N- (2- (3- (3, 3-difluoropyrrolidin-1-yl) -1H-pyrazol-1-yl) benzyl) -9-isopropyl-9H-purin-6-amine

Synthesis of 2- (4-aminopiperidin-1-yl) -N- (2- (3- (3, 3-difluoropyrrolidin-1-yl) -1H-pyrazol-1-yl) benzyl) -9-isopropyl-9H-purin-6-amine

Synthesis of 2- (3-bromo-1H-pyrazol-1-yl) benzonitrile

To a mixture of 2-fluorobenzonitrile (1 g, 8.26 mmol) ) and 3-bromo-1H-pyrazole (2.43 g, 16.51 mmol) ) in DMF (20 mL) was Cs₂CO₃ (5.38 g, 16.51 mmol) . The mixture was stirred at 15 ℃ for 15 hours to form a white suspension. TLC showed the reaction was completed. The mixture was partitioned between EtOAc (150 mL) and H₂O (150 mL) . The aqueous phase was extracted with EtOAc (150 mL x 2) . The combined organic extracts were washed with brine (100 mL x 3) , dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give the crude product, which was purified by combi flash to give 2- (3-bromo-1H-pyrazol-1-yl) benzonitrile (1.23 g, 4.71 mmol, 57.05%yield, 95%purity) as a yellow solid. LCMS [M+H] ⁺: 249.33.

Synthesis of 2- (3- (3, 3-difluoropyrrolidin-1-yl) -1H-pyrazol-1-yl) benzonitrile

To a solution of 2- (3-bromo-1H-pyrazol-1-yl) benzonitrile (100 mg, 403.10 μmol) in toluene (10 mL) was added 3, 3-difluoropyrrolidine (86.35 mg, 806.20 μmol) , BINAP (75.30 mg, 120.93 μmol) , Pd₂ (dba) ₃ (36.91 mg, 40.31 μmol) and NaOBu (116.21 mg, 1.21 mmol) under N₂, then stirred at 120 ℃ for 6 hrs. The reaction was poured into water (30 mL) , extracted with EtOAc (10 mL*2) , the organic layer was washed with water (10 mL*2) , dried over Na₂SO₄, filtered, and concentrated to give a residue. The residue was purified by column chromatography to give 2- (3- (3, 3-difluoropyrrolidin-1-yl) -1H-pyrazol-1-yl) benzonitrile (51.2 mg, 179.21 μmol, 44.46%yield, 96%purity) as a yellow solid. LC-MS [M+H] ⁺: 275.22.

Synthesis of (2- (3- (3, 3-difluoropyrrolidin-1-yl) -1H-pyrazol-1-yl) phenyl) methanamine

To a solution of 2- (3- (3, 3-difluoropyrrolidin-1-yl) -1H-pyrazol-1-yl) benzonitrile (100 mg, 364.61 μmol) in THF (15 mL) was added LiAlH₄ (27.67 mg, 729.21 μmol) . After being stirred for 1 h, diluted with THF and quenched with water (100 μL) , NaOH (15%in water, 100μL) . The reaction mixture was stirred at room temperature for 1 h, then dried over Na₂SO₄. After filtration and evaporation of the solvent, the crude mixture was purified by column chromatography on silica gel. The product obtained is a thick oil (2- (3- (3, 3-difluoropyrrolidin-1-yl) -1H-pyrazol-1-yl) phenyl) methanamine. LC-MS [M+H] ⁺: 279.34.

Synthesis of 2-chloro-N- (2- (3- (3, 3-difluoropyrrolidin-1-yl) -1H-pyrazol-1-yl) benzyl) -9-isopropyl -9H-purin-6-amine

To a mixture of 2, 6-dichloro-9-isopropyl-9H-purine (200 mg, 865.50 μmol) , (2- (3- (3, 3-difluoropyrrolidin-1-yl) -1H-pyrazol-1-yl) phenyl) methanamine (481.73 mg, 1.73 mmol) in EtOH (20 mL) was added TEA (262.74 mg, 2.60 mmol, 362.15 μL) . The mixture was stirred at 78℃ for 6 hours to give a suspension. TLC showed the reaction was completed. The mixture was partitioned between EtOAc (100 mL) and water (100 mL) , the aqueous phase was extracted with EtOAc (80 mL x 2) , the combined extracted phase was washed with water (80 mL) , dried over Na₂SO₄, filtered, concentrated under reduced pressure to give a green oil, which was purified by Combi flash to give 2-chloro-N- (2- (3- (3, 3-difluoropyrrolidin-1-yl) -1H-pyrazol-1-yl) benzyl) -9-isopropyl-9H-p urin-6-amine (327.8 mg, 665.41 μmol, 76.88%yield, 96%purity) as a white solid. LC-MS [M+H] ⁺: 473.31.

Synthesis of 2- (1- (2- ( ( (2- (4- (dimethylamino) piperidin-1-yl) -9-isopropyl-9H-purin-6-yl) amino) methyl) phenyl) -1H-pyrazol-3-yl) propan-2-ol

To a solution of 2-chloro-N- (2- (3- (3, 3-difluoropyrrolidin-1-yl) -1H-pyrazol-1-yl) benzyl) -9-isopropyl -9H-purin-6-amine (100 mg, 211.45 μmol) in DMSO (10 mL) was addedpiperidin-4-amine (42.36 mg, 422.90 μmol) and TEA (64.19 mg, 634.36 μmol, 88.48 μL) , then stirred at 160 ℃ for 10 hrs. The reaction was poured into water (30 mL) , extracted with EtOAc (10 mL*2) , the organic layer was washed with water (10 mL*2) , dried over Na₂SO₄, filtered, and concentrated to give a residue. The residue was purified by column chromatography to give 2- (4-aminopiperidin-1-yl) -N- (2- (3- (3, 3-difluoropyrrolidin-1-yl) -1H-pyrazol-1-yl) benzyl) -9-isopropyl-9H-purin-6-amine (67.4 mg, 123.09 μmol, 58.21%yield, 98%purity) as a yellow solid. LC-MS (ESI, m/z) : 537.23. [M+H] ⁺. ¹H NMR (400 MHz, Methanol-d₄) δ 7.76 (d, J =12.4 Hz, 1H) , 7.67 (dd, J = 3.7, 2.5 Hz, 1H) , 7.57 (dt, J = 7.8, 3.2 Hz, 1H) , 7.38 –7.31 (m, 3H) , 5.88 (t, J = 2.3 Hz, 1H) , 4.76 (d, J = 8.8 Hz, 3H) , 3.64 (td, J = 13.4, 2.3 Hz, 2H) , 3.51 (t, J = 7.2 Hz, 2H) , 3.24 –3.09 (m, 1H) , 2.93 –2.79 (m, 2H) , 2.44 (tq, J = 14.0, 7.1 Hz, 2H) , 1.97 –1.80 (m, 2H) , 1.54 (dd, J = 6.8, 2.2 Hz, 6H) , 1.46 –1.33 (m, 2H) , 1.32 –1.23 (m, 2H) .

3- (3- ( ( (2- (4-aminopiperidin-1-yl) -9-isopropyl-9H-purin-6-yl) amino) methyl) pyridin-2-yl) -N, N-dimethyl-3-azaspiro [5.5] undecan-9-amine

Synthesis of 3- (3- ( ( (2- (4-aminopiperidin-1-yl) -9-isopropyl-9H-purin-6-yl) amino) methyl) pyridine-2-yl) -N, N-dimethyl-3-azaspiro [5.5] undecan-9-amine

Synthesis of 2- (9- (dimethylamino) -3-azaspiro [5.5] undecan-3-yl) nicotinonitrile

To a solution of 2-fluoronicotinonitrile (200 mg, 1.64 mmol) in DMF (10 mL) were added N, N-dimethyl-3-azaspiro [5.5] undecan-9-amine dihydrochloride (485.14 mg, 1.80 mmol, 2HCl) and Cs₂CO₃ (2.13 g, 6.55 mmol) , the mixture was stirred at RT for 17h. The reaction mixture was filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO₂, 0.5M ammonia methanol solution: DCM=0%to 10%) to give 2- (9- (dimethylamino) -3-azaspiro [5.5] undecan-3-yl) nicotinonitrile (325 mg, 1.09 mmol, 66.41%yield, 99.88%purity) as a yellow solid.

ESI-MS [M+H] ⁺ : 299.32.

Synthesis of 3- (3- (aminomethyl) pyridin-2-yl) -N, N-dimethyl-3-azaspiro [5.5] undecan-9-amine

To a solution of 2- (9- (dimethylamino) -3-azaspiro [5.5] undecan-3-yl) nicotinonitrile (325 mg, 1.09 mmol) in MeOH (8.23 mL) were added NH₃ (7M in MeOH, 155.58 μL) and Ni (100 mg, 1.70 mmol) , replaced with H₂ three times and the mixture was stirred at RT for 5h. LCMS show the reaction was completed. The reaction mixture was filtered and concentrated to give 3- (3- (aminomethyl) pyridin-2-yl) -N, N-dimethyl-3-azaspiro [5.5] undecan-9-amine (321 mg, crude) as an oil.

ESI-MS [M+H] ⁺ : 303.36.

Synthesis of 2, 6-dichloro-9-isopropyl-9H-purine

ESI-MS [M+H] ⁺: 231.16.

Synthesis of 3- (3- ( ( (2-chloro-9-isopropyl-9H-purin-6-yl) amino) methyl) pyridin-2-yl) -N, N-dimethyl-3-azaspiro [5.5] undecan-9-amine

To a solution of N- (2- (1H-pyrazol-1-yl) benzyl) -2-chloro-9-isopropyl-9H-purin-6-amine (200 mg, 865.50 μmol) in EtOH (20 mL) were added 3- (3- (aminomethyl) pyridin-2-yl) -N, N-dimethyl-3-azaspiro [5.5] undecan-9-amine (314.13 mg, 1.04 mmol) and TEA (175.16 mg, 1.73 mmol, 241.43 μL) , the mixture was stirred at 85℃ for 5h. The reaction mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO₂, 0.5M ammonia methanol solution: DCM=0%to 15%) to give 3- (3- ( ( (2-chloro-9-isopropyl-9H-purin-6-yl) amino) methyl) pyridin-2-yl) -N, N-dimethyl-3-azaspiro [5.5] undecan-9-amine (306 mg, 615.11 μmol, 71.07%yield, 99.92%purity) as a white solid.

ESI-MS [M+H] ⁺ : 497.35.

Synthesis of 3- (3- ( ( (2- (4-aminopiperidin-1-yl) -9-isopropyl-9H-purin-6-yl) amino) methyl) pyridin-2-yl) -N, N-dimethyl-3-azaspiro [5.5] undecan-9-amine

To a solution of 3- (3- ( ( (2-chloro-9-isopropyl-9H-purin-6-yl) amino) methyl) pyridin-2-yl) -N, N-dimethyl-3-azaspiro [5.5] undecan-9-amine (200 mg, 402.35 μmol) in NMP (2 mL) were added piperidin-4-amine (60.45 mg, 603.53 μmol) and DIPEA (104.00 mg, 804.70 μmol, 140.16 μL) , the mixture was stirred at 160℃ for 7h. The reaction mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO₂, 0.5M ammonia methanol solution: DCM=0%to 35%) to give 3- (3- ( ( (2- (4-aminopiperidin-1-yl) -9-isopropyl-9H-purin-6-yl) amino) methyl) pyridin-2-yl) -N, N-dimethyl-3-azaspiro [5.5] undecan-9-amine (54 mg, 92.33 μmol, 22.95%yield, 95.88%purity) as a white solid.

ESI-MS [M+H] ⁺ : 561.49.

¹H NMR (400 MHz, Methanol-d₄) δ 8.09 (dd, J = 4.9, 1.9 Hz, 1H) , 7.80 (s, 1H) , 7.72 (dd, J =7.5, 1.9 Hz, 1H) , 6.95 (dd, J = 7.5, 5.0 Hz, 1H) , 4.74 –4.60 (m, 5H) , 3.09 (dt, J = 7.8, 4.1 Hz, 4H) , 2.88 (tt, J = 11.0, 4.1 Hz, 1H) , 2.83 –2.72 (m, 2H) , 2.31 (s, 6H) , 2.29 –2.17 (m, 1H) , 1.94 –1.85 (m, 2H) , 1.76 (dt, J = 14.0, 5.0 Hz, 6H) , 1.55 (d, J = 6.8 Hz, 8H) , 1.52 –1.38 (m, 2H) , 1.26 –1.10 (m, 4H) .

2- (1- (2- ( ( (9-isopropyl-2- (4-methoxypiperidin-1-yl) -9H-purin-6-yl) amino) methyl) phenyl) -1H-pyrazol-3-yl) propan-2-ol

2- (1- (2- ( ( (9-isopropyl-2- (4-methoxypiperidin-1-yl) -9H-purin-6-yl) amino) methyl) phenyl) -1H -pyrazol-3-yl) propan-2-ol

Synthesis of 2- (1H-pyrazol-3-yl) propan-2-ol

To a solution of compound ethyl 1H-pyrazole-3-carboxylate (5 g, 35.68 mmol) in THF (50 mL) was added MeMgBr (124.88 mmol, 5 mL) dropwise at 0-5 ℃ under N₂ atmosphere. The resulting mixture was stirred at 10 ℃ for 15 hours to form a white suspension. TLC showed the reaction was completed. The mixture was poured into saturated aqueous NH4CI (50 mL) . The mixture was extracted with EtOAc (50 mL x 3) . The combined organic extract was washed with brine (80 mL x 2) , dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to give compound 2- (1H-pyrazol-3-yl) propan-2-ol (4.33 g, 33.64 mmol, 94.28%yield, 98%purity) as a white solid. LCMS [M+H] ⁺: 127.23

Synthesis of 2- (3- (2-hydroxypropan-2-yl) -1H-pyrazol-1-yl) benzonitrile

To a mixture of compound 2- (1H-pyrazol-3-yl) propan-2-ol (1.3 g, 10.30 mmol) and 2-fluorobenzonitrile (1.50 g, 12.37 mmol) in DMF (15 mL) was added Cs₂CO₃ (6.7 g, 20.61 mmol) . The mixture was stirred at 15 ℃ for 15 hours to form a white suspension. TLC showed the reaction was completed. The mixture was partitioned between EtOAc (150 mL) and H₂O (150 mL) . The aqueous phase was extracted with EtOAc (150 mL x 2) . The combined organic extracts were washed with brine (100 mL x 3) , dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give the crude product, which was purified by combi flash to give compound 2- (3- (2-hydroxypropan-2-yl) -1H-pyrazol-1-yl) benzonitrile (1.3 g, 5.43 mmol, 52.74%yield, 95%purity) as a yellow solid. LCMS [M+H] ⁺: 228.43.

Synthesis of 2- (1- (2- (aminomethyl) phenyl) -1H-pyrazol-3-yl) propan-2-ol

To a solution of 2- (3- (2-hydroxypropan-2-yl) -1H-pyrazol-1-yl) benzonitrile (200 mg, 880.04 μmol) in THF (10 mL) was added LiAlH₄ (36.74 mg, 968.05 μmol) . After being stirred for 1 h, diluted with THF and quenched with water (100 μL) , NaOH (15%in water, 100μL) . The reaction mixture was stirred at room temperature for 1 h, then dried over Na₂SO₄. After filtration and evaporation of the solvent, the crude mixture was purified by column chromatography on silica gel to get a thick oil 2- (1- (2- (aminomethyl) phenyl) -1H-pyrazol-3-yl) propan-2-ol (168 mg, 726.35 μmol, 82.54%yield) . LCMS [M+H] ⁺: 231.29.

Synthesis of 2, 6-dichloro-9-isopropyl-9H-purine

2,6-dichloro-9H-purine (10.0g, 52.91mmol) , isopropyl bromide (32.5g, 264.55mmol) , potassium carbonate (21.9g, 158.73mmol) and dimethyl sulfoxide (50ml) were added to a 250 ml two-necked flask, and the mixture was stirred at room temperature for 96 hours. The reaction solution was added dropwise to water, ethyl acetate was added for extraction three times, the organic phases were combined, washed twice with saturated brine, dried over sodium sulfate, and filtered, concentrated in vacuo to obtain 9.8 g of a yellow solid. The crude product was passed through a silica gel column (ethyl acetate/n-heptane=0～60%) to obtain 4.94g of white solid.

Synthesis of 2- (1- (2- ( ( (2-chloro-9-isopropyl-9H-purin-6-yl) amino) methyl) phenyl) -1H-pyrazol-3-yl) propan-2-ol

To a mixture of 2, 6-dichloro-9-isopropyl-9H-purine (610 mg, 2.64 mmol) , 2- (1- (2- (aminomethyl) phenyl) -1H-pyrazol-3-yl) propan-2-ol (641.09 mg, 2.77 mmol) in EtOH (20 mL) was added TEA (801.35 mg, 7.92 mmol, 1.10 mL) . The mixture was stirred at 78℃ for 6 hours to give a green suspension. TLC showed the reaction was completed. The mixture was partitioned between EtOAc (100 mL) and water (100 mL) , the aqueous phase was extracted with EtOAc (80 mL x 2) , the combined extracted phase was washed with water (80 mL) , dried over Na2S04, filtered, concentrated under reduced pressure to give a green oil, which was purified by Combi flash to give 2- (1- (2- ( ( (2-chloro-9-isopropyl-9H-purin-6-yl) amino) methyl) phenyl) -1H-pyrazol-3-yl) pr opan-2-ol (908 mg, 2.05 mmol, 77.53%yield, 96%purity) as a white solid. LCMS [M+H] ⁺: 426.41.

Synthesis of 2- (1- (2- ( ( (9-isopropyl-2- (4-methoxypiperidin-1-yl) -9H-purin-6-yl) amino) methyl) phenyl) -1H-pyrazol-3-yl) propan-2-ol

To a solution of2- (1- (2- ( ( (2-chloro-9-isopropyl-9H-purin-6-yl) amino) methyl) phenyl) -1H-pyrazol-3-yl) propan-2-ol (100 mg, 234.79 μmol) in DMSO (2.5 mL) was added4-methoxypiperidine (32.45 mg, 281.75 μmol) and TEA (71.28 mg, 704.37 μmol, 98.24 μL) , then stirred at 160 ℃ for 10 hrs. The reaction was poured into water (30 mL) , extracted with EtOAc (10 mL*2) , the organic layer was washed with water (10 mL*2) , dried over Na₂SO₄, and filtered and concentrated to give a residue. The residue was purified by column chromatography to give 2- (1- (2- ( ( (9-isopropyl-2- (4-methoxypiperidin-1-yl) -9H-purin-6-yl) amino) methyl) phenyl) -1H-pyrazol-3-yl) propan-2-ol (54.3 mg, 103.30 μmol, 44.00%yield, 96%purity) as a white solid. ESI-MS [M+H] ⁺: 505.12.¹H NMR (400 MHz, DMSO-d₆) δ 8.03 (t, J = 6.5 Hz, 1H) , 7.90 (d, J = 6.2 Hz, 1H) , 7.80 (s, 1H) , 7.66 –7.52 (m, 1H) , 7.49 –7.33 (m, 3H) , 6.56 (d, J = 2.4 Hz, 1H) , 5.11 (s, 1H) , 4.77 –4.49 (m, 3H) , 4.18 (d, J = 13.1 Hz, 2H) , 3.42 (dd, J = 13.3, 8.5 Hz, 1H) , 3.38 (s, 3H) , 3.25 –3.06 (m, 3H) , 1.93 –1.75 (m, 3H) , 1.58 (s, 6H) , 1.51 (d, J = 6.8 Hz, 6H) .

2- (1- (2- ( ( (2- (4- (tert-butyl) piperazin-1-yl) -9-isopropyl-9H-purin-6-yl) amino) methyl) phenyl) -1H-pyrazol-3-yl) propan-2-ol

Synthesis of 2- (1- (2- ( ( (2- (4- (tert-butyl) piperazin-1-yl) -9-isopropyl-9H-purin-6-yl) amino) methyl) phenyl) -1H-pyrazol-3-yl) propan-2-ol

Synthesis of 2- (1H-pyrazol-3-yl) propan-2-ol

To a solution of compound ethyl 1H-pyrazole-3-carboxylate (5 g, 35.68 mmol) in THF (50 mL) was added MeMgBr (124.88 mmol, 5 mL) dropwise at 0-5 ℃ under N₂ atmosphere. The resulting mixture was stirred at 10 ℃ for 15 hours to form a white suspension. TLC showed the reaction was completed. The mixture was poured into saturated aqueous NH₄CI (50 mL) . The mixture was extracted with EtOAc (50 mL x 3) . The combined organic extract was washed with brine (80 mL x 2) , dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to give compound 2- (1H-pyrazol-3-yl) propan-2-ol (4.33 g, 33.64 mmol, 94.28%yield, 98%purity) as a white solid. LCMS [M+H] ⁺: 127.23

Synthesis of 2- (3- (2-hydroxypropan-2-yl) -1H-pyrazol-1-yl) benzonitrile

Synthesis of 2- (1- (2- (aminomethyl) phenyl) -1H-pyrazol-3-yl) propan-2-ol

Synthesis of 2, 6-dichloro-9-isopropyl-9H-purine

2,6-dichloro-9H-purine (10.0g, 52.91mmol) , isopropyl bromide (32.5g, 264.55mmol) , potassium carbonate (21.9g, 158.73mmol) and dimethyl sulfoxide (50ml) were added to a 250 ml two-necked flask, and the mixture was stirred at room temperature for 96hours. The reaction solution was added dropwise to water, ethyl acetate was added for extraction three times, the organic phases were combined, washed twice with saturated brine, dried over sodium sulfate, and filtered, concentrated in vacuo to obtain 9.8 g of a yellow solid. The crude product was passed through a silica gel column (ethyl acetate/n-heptane=0～60%) to obtain 4.941g of white solid.

To a mixture of 2, 6-dichloro-9-isopropyl-9H-purine (610 mg, 2.64 mmol) , 2- (1- (2- (aminomethyl) phenyl) -1H-pyrazol-3-yl) propan-2-ol (641.09 mg, 2.77 mmol) in EtOH (20 mL) was added TEA (801.35 mg, 7.92 mmol, 1.10 mL) . The mixture was stirred at 78℃ for 6 hours to give a green suspension. TLC showed the reaction was completed. The mixture was partitioned between EtOAc (100 mL) and water (100 mL) , the aqueous phase was extracted with EtOAc (80 mL x 2) , the combined extracted phase was washed with water (80 mL) , dried over Na2S04, filtered, concentrated under reduced pressure to give a green oil, which was purified by Combi flash to give 2- (1- (2- ( ( (2-chloro-9-isopropyl-9H-purin-6-yl) amino) methyl) phenyl) -1H-pyrazol-3-yl) propan-2-ol (908 mg, 2.05 mmol, 77.53%yield, 96%purity) as a white solid. LCMS [M+H] ⁺: 426.41.

To a solution of2- (1- (2- ( ( (2-chloro-9-isopropyl-9H-purin-6-yl) amino) methyl) phenyl) -1H-pyrazol-3-yl) propan-2-ol (100 mg, 234.79 μmol) in DMSO (2.5 mL) was added1- (tert-butyl) piperazine (40.08 mg, 281.75 μmol) and TEA (71.28 mg, 704.37 μmol, 98.24 μL) , then stirred at 160 ℃ for 10 hrs. The reaction was poured into water (30 mL) , extracted with EtOAc (10 mL*2) , the organic layer was washed with water (10 mL*2) , dried over Na₂SO₄, and filtered and concentrated to give a residue. The residue was purified by column chromatography to give2- (1- (2- ( ( (2- (4- (tert-butyl) piperazin-1-yl) -9-isopropyl-9H-purin-6-yl) amino) methyl) phenyl) -1H-pyrazol-3-yl) propan-2-ol (89.5 mg, 163.28 μmol, 69.54%yield, 97%purity) as a white solid. LC-MS [M+H] ⁺: 532.42.¹H NMR (400 MHz, DMSO-d₆) δ 8.01 (d, J = 2.4 Hz, 1H) , 7.85 (s, 1H) , 7.59 –7.48 (m, 1H) , 7.46 –7.29 (m, 3H) , 6.52 (d, J = 2.4 Hz, 1H) , 5.06 (s, 1H) , 4.73 –4.37 (m, 3H) , 3.56 (s, 3H) , 2.47 (s, 3H) , 1.53 (s, 6H) , 1.46 (d, J = 6.7 Hz, 6H) , 1.28 –1.20 (m, 2H) , 1.02 (d, J = 4.4 Hz, 9H) .

2- (1- (2- ( ( (2- (4- (2-hydroxyethyl) piperazin-1-yl) -9-isopropyl-9H-purin-6-yl) amino) methyl) phenyl) -1H-pyrazol-3-yl) propan-2-ol

Synthesis of 2- (1- (2- ( ( (2- (4- (2-hydroxyethyl) piperazin-1-yl) -9-isopropyl-9H-purin-6-yl) amino) methyl) phenyl) -1H-pyrazol-3-yl) propan-2-ol

Synthesis of 2- (1H-pyrazol-3-yl) propan-2-ol

To a solution of compound ethyl 1H-pyrazole-3-carboxylate (5 g, 35.68 mmol) in THF (50 mL) was added MeMgBr (124.88 mmol, 5 mL) dropwise at 0-5 ℃ under N₂ atmosphere. The resulting mixture was stirred at 10 ℃ for 15 hours to form a white suspension. TLC showed the reaction was completed. The mixture was poured into saturated aqueous NH4CI (50 mL) . The mixture was extracted with EtOAc (50 mL x 3) . The combined organic extract was washed with brine (80 mL x 2) , dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give compound 2- (1H-pyrazol-3-yl) propan-2-ol (4.33 g, 33.64 mmol, 94.28%yield, 98%purity) as a white solid. ESI-MS [M+H] ⁺: 127.23

Synthesis of 2- (3- (2-hydroxypropan-2-yl) -1H-pyrazol-1-yl) benzonitrile

To a mixture of compound 2- (1H-pyrazol-3-yl) propan-2-ol (1.3 g, 10.30 mmol) and 2-fluorobenzonitrile (1.50 g, 12.37 mmol) in DMF (15 mL) was added Cs₂CO₃ (6.7 g, 20.61 mmol) . The mixture was stirred at 15 ℃ for 15 hours to form a white suspension. TLC showed the reaction was completed. The mixture was partitioned between EtOAc (150 mL) and H₂O (150 mL) . The aqueous phase was extracted with EtOAc (150 mL x 2) . The combined organic extracts were washed with brine (100 mL x 3) , dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give the crude product, which was purified by combi flash to give compound 2- (3- (2-hydroxypropan-2-yl) -1H-pyrazol-1-yl) benzonitrile (1.3 g, 5.43 mmol, 52.74%yield, 95%purity) as a yellow solid. ESI-MS [M+H] ⁺: 228.43.

Synthesis of 2- (1- (2- (aminomethyl) phenyl) -1H-pyrazol-3-yl) propan-2-ol

To a solution of 2- (3- (2-hydroxypropan-2-yl) -1H-pyrazol-1-yl) benzonitrile (200 mg, 880.04 μmol) in THF (10 mL) was added LiAlH₄ (36.74 mg, 968.05 μmol) . After being stirred for 1 h, diluted with THF and quenched with water (100 μL) , NaOH (15%in water, 100μL) . The reaction mixture was stirred at room temperature for 1 h, then dried over Na₂SO₄. After filtration and evaporation of the solvent, the crude mixture was purified by column chromatography on silica gel to get a thick oil 2- (1- (2- (aminomethyl) phenyl) -1H-pyrazol-3-yl) propan-2-ol (168 mg, 726.35 μmol, 82.54%yield) . ESI-MS [M+H] ⁺: 231.29.

Synthesis of 2, 6-dichloro-9-isopropyl-9H-purine

2,6-dichloro-9H-purine (10.0g, 52.91mmol) , isopropyl bromide (32.5g, 264.55mmol) , potassium carbonate (21.9g, 158.73mmol) and dimethyl sulfoxide (50ml) were added to a 250 ml two-necked flask, and the mixture was stirred at room temperature for 96 hours. The reaction solution was added dropwise to water, ethyl acetate was added for extraction three times, the organic phases were combined, washed twice with saturated brine, dried over sodium sulfate, and filtered, concentrated in vacuo to obtain 9.8 g of a yellow solid. The crude product was passed through a silica gel column (ethyl acetate/n-heptane=0～60%) to obtain 4.941g of white solid.

To a mixture of 2, 6-dichloro-9-isopropyl-9H-purine (610 mg, 2.64 mmol) , 2- (1- (2- (aminomethyl) phenyl) -1H-pyrazol-3-yl) propan-2-ol (641.09 mg, 2.77 mmol) in EtOH (20 mL) was added TEA (801.35 mg, 7.92 mmol, 1.10 mL) . The mixture was stirred at 78℃ for 6 hours to give a green suspension. TLC showed the reaction was completed. The mixture was partitioned between EtOAc (100 mL) and water (100 mL) , the aqueous phase was extracted with EtOAc (80 mL x 2) , the combined extracted phase was washed with water (80 mL) , dried over Na₂SO₄, filtered, concentrated under reduced pressure to give a green oil, which was purified by Combi flash to give 2- (1- (2- ( ( (2-chloro-9-isopropyl-9H-purin-6-yl) amino) methyl) phenyl) -1H-pyrazol-3-yl) pr opan-2-ol (908 mg, 2.05 mmol, 77.53%yield, 96%purity) as a white solid. ESI-MS [M+H] ⁺: 426.41.

To a solution of2- (1- (2- ( ( (2-chloro-9-isopropyl-9H-purin-6-yl) amino) methyl) phenyl) -1H-pyrazol -3-yl) propan-2-ol (100 mg, 234.79 μmol) in DMSO (2.5 mL) was added2- (piperazin-1-yl) ethan-1-ol (36.68 mg, 281.75 μmol) and TEA (71.28 mg, 704.37 μmol, 98.24 μL) , then stirred at 160 ℃ for 10 hrs. The reaction was poured into water (30 mL) , extracted with EtOAc (10 mL*2) , the organic layer was washed with water (10 mL*2) , dried over Na₂SO₄, and filtered and concentrated to give a residue. The residue was purified by column chromatography to give 2- (1- (2- ( ( (2- (4- (2-hydroxyethyl) piperazin-1-yl) -9-isopropyl-9H-purin-6-yl) amino) methyl) phenyl) -1H-pyrazol-3-yl) propan-2-ol (76.8 mg, 144.84 μmol, 61.69%yield, 98%purity) as a white solid. ESI-MS [M+H] ⁺: 520.12.¹H NMR (400 MHz, DMSO-d₆) δ 8.05 –7.94 (m, 1H) , 7.86 (s, 1H) , 7.54 (dd, J = 6.6, 2.5 Hz, 1H) , 7.47 –7.27 (m, 3H) , 6.51 (d, J =2.4 Hz, 1H) , 5.06 (s, 1H) , 4.56 (dt, J = 13.5, 6.7 Hz, 3H) , 3.68 –3.47 (m, 6H) , 2.55 (s, 1H) , 2.48 –2.32 (m, 7H) , 1.53 (s, 6H) , 1.46 (d, J = 6.8 Hz, 6H) .

2- (1- (2- ( ( (2- (4-aminopiperidin-1-yl) -9-isopropyl-9H-purin-6-yl) amino) methyl) -3-fluorophenyl) -1H-pyrazol-3-yl) propan-2-ol

Synthesis of 2- (1- (2- ( ( (2- (4-aminopiperidin-1-yl) -9-isopropyl-9H-purin-6-yl) amino) methyl) -3-fluorophenyl) -1H-pyrazol-3-yl) propan-2-ol

Synthesis of 2- (1H-pyrazol-3-yl) propan-2-ol

To a stirred mixture of ethyl 1H-pyrazole-3-carboxylate (5.00 g, 35.7 mmol, 1.00 equiv) and tetrahydrofuran (50 mL) was added methyl-magnesiubromide (47.6 mL, 143 mmol, 4.00 equiv, 3M in Et₂O) at 0-5℃ under nitrogen atmosphere. The resulting mixture was stirred for overnight at room temperature and quenched with saturated ammonium chloride solution (40 mL) at room temperature. The resulting mixture was extracted with ethyl acetate (3 × 100 mL) . The combined organic layers were washed with brine (2 × 50 mL) , dried over anhydrous sodium sulfate, filtrated, and concentrated under reduced pressure to afford 2- (1H-pyrazol-3-yl) propan-2-ol (3.90 g, 86%yield) as a white solid. ESI-MS [M +H] ⁺: 127.23 .

Synthesis of 2-fluoro-6- (3- (2-hydroxypropan-2-yl) -1H-pyrazol-1-yl) benzonitrile

To a mixture of compound 2- (1H-pyrazol-3-yl) propan-2-ol (0.56 g, 4.00 mmol) and 2,6-difluorobenzonitrile (0.50 g, 4.00 mmol) in DMF (100 mL) was added Cs₂CO₃ (2.62 g, 8.00 mmol) . The mixture was stirred at 20 ℃ for 6 hours to form a white suspension. TLC showed the reaction was completed. The mixture was partitioned between EtOAc (150 mL) and H2O (150 mL) . The aqueous phase was extracted with EtOAc (150 mL x 2) . The combined organic extracts were washed with brine (100 mL x 3) , dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give the crude product, which was purified by column chromatography (SiO₂, EA: PE=0%to 40%) to give compound 2-fluoro-6- (3- (2-hydroxypropan-2-yl) -1H-pyrazol-1-yl) benzonitrile (0.64 g, 2.61 mmol, 65.24%yield) as a yellow solid. ESI-MS [M +H] ⁺: 246.4.

Synthesis of 2- (1- (2- (aminomethyl) -3-fluorophenyl) -1H-pyrazol-3-yl) propan-2-ol

To a solution of 2-fluoro-6- (3- (2-hydroxypropan-2-yl) -1H-pyrazol-1-yl) benzonitrile (0.49 g, 2.00 mmol) in MeOH (50 mL) and Raney-Ni (1g) under H₂, then stirred at 20 ℃ for 18 hrs. The reaction was filtered and concentrated to give 2- (1- (2- (aminomethyl) -3-fluorophenyl) -1H-pyrazol-3-yl) propan-2-ol (0.44 g, 1.77m mol, 88.25%yield) . ESI-MS [M +H] ⁺: 250.3.

Synthesis of 2- (1- (2- ( ( (2-chloro-9-isopropyl-9H-purin-6-yl) amino) methyl) -3-fluorophenyl) -1H-pyrazol-3-yl) propan-2-ol

To a mixture of 2, 6-dichloro-9-isopropyl-9H-purine (0.41 g, 1.77 mmol) , 2- (1- (2- (aminomethyl) -3-fluorophenyl) -1H-pyrazol-3-yl) propan-2-ol (0.44 g, 1.77 mmol) in EtOH (50 mL) was added TEA (0.54 g, 5.30 mmol, 0.74 mL) . The mixture was stirred at 80℃ for 6 hours. TLC showed the reaction was completed. The mixture was partitioned between EtOAc (100 mL) and water (100 mL) , the aqueous phase was extracted with EtOAc (80 mL x 2) , the combined extracted phase was washed with water (80 mL) , dried over Na₂SO₄, filtered, concentrated under reduced pressure to give an oil, which was purified by column chromatography (SiO₂, EA: PE=0%to 50%) to give 2- (1- (2- ( ( (2-chloro-9-isopropyl-9H-purin-6-yl) amino) methyl) -3-fluorophenyl) -1H-pyrazo l-3-yl) propan-2-ol (0.35 g, 0.79 mmol, 44.67%yield) as a white solid. ESI-MS [M +H] +: 444.4.

To a solution of 2- (1- (2- ( ( (2-chloro-9-isopropyl-9H-purin-6-yl) amino) methyl) -3-fluorophenyl) -1H-pyrazol-3-yl) propan-2-ol (0.12 g, 0.27 mmol) in DMSO (3 mL) was added piperidin-4-amine (29.78 mg, 0.30 mmol) and DIPEA (0.11 g, 0.81 mmol, 0.14 mL) , then stirred at 160 ℃ for 8 hrs. The reaction was poured into water (5ml) , extracted with DCM and MeOH (10: 1 30ml*5) , the organic layer was washed with water and brine (30ml) , dried over Na₂SO₄, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO₂, MeOH: DCM=0%to 10%) to give 2- (1- (2- ( ( (2- (4-aminopiperidin-1-yl) -9-isopropyl-9H-purin-6-yl) amino) methyl) -3-fluorophenyl) -1H-pyrazol-3-yl) propan-2-ol (0.05 g, 0.098 mmol, 36.44%yield) as a white solid.

ESI-MS [M +H] +: 508.6.

¹H NMR (400 MHz, Methanol-d₄) δ 7.79-7.77 (m, 1H) , 7.73 (s, 1H) , 7.46-7.38 (m, 1H) , 7.25-7.19 (m, 2H) , 6.51-6.50 (m, 1H) , 4.82-4.75 (m, 4H) , 4.66-4.63 (m, 1H) , 2.97-2.92 (m, 1H) , 2.89-2.82 (m, 2H) , 1.87-1.85 (m, 2H) , 1.57 (s, 6H) , 1.54-1.52 (m, 6H) , 1.35-1.28 (m, 2H) .

2- (1- (3- ( ( (2- (4-aminopiperidin-1-yl) -9-cyclopropyl-9H-purin-6-yl) amino) methyl) pyridin-2-yl) -1H-pyrazol-3-yl) propan-2-ol

Synthesis of 2- (1- (3- ( ( (2- (4-aminopiperidin-1-yl) -9-cyclopropyl-9H-purin-6-yl) amino) methyl) pyridin-2-yl) -1H-pyrazol-3-yl) propan-2-ol

Synthesis of 2- (3- (2-hydroxypropan-2-yl) -1H-pyrazol-1-yl) nicotinonitrile

To a solution of 2-fluoronicotinonitrile (1.06 g, 8.72 mmol) in DMF (15 mL) was added 2- (1H-pyrazol-3-yl) propan-2-ol (1 g, 7.93 mmol) and Cs₂CO₃ (5.17 g, 15.85 mmol) , then stirred at 20 ℃ for 16 hrs. The reaction was poured into water (300 mL) , extracted with EtOAc (100 mL*2) , the organic layer was washed with water (100 mL*2) , dried over Na₂SO₄, and filtered, concentrated to give a residue. The residue was purified by column chromatography to give 2- (3- (2-hydroxypropan-2-yl) -1H-pyrazol-1-yl) nicotinonitrile (1.56 g, 6.42 mmol, 81.05%yield, 94%purity) as a yellow solid. ESI-MS [M+H] ⁺: 229.45.

Synthesis of 2- (1- (3- (aminomethyl) pyridin-2-yl) -1H-pyrazol-3-yl) propan-2-ol

To a solution of 2- (3- (2-hydroxypropan-2-yl) -1H-pyrazol-1-yl) nicotinonitrile (500 mg, 2.19 mmol) in MeOH (10 mL) was added NH₃·H₂O (2.19 mmol) and Raney-Ni (2.19 mmol) then stirred at 20 ℃ for 6 hrs. The reaction was filtered and concentrated to give a residue. The residue was purified by column chromatography to give 2- (1- (3- (aminomethyl) pyridin-2-yl) -1H-pyrazol-3-yl) propan-2-ol (489.33 mg, 1.96 mmol, 89.44%yield, 93%purity) as a colorless oil. ESI-MS [M+H] ⁺: 233.41.

Synthesis of 2- (1- (3- ( ( (2-chloro-9-isopropyl-9H-purin-6-yl) amino) methyl) pyridin-2-yl) -1H-pyrazol-3-yl) propan-2-ol

To a solution of2, 6-dichloro-9-cyclopropyl-9H-purine (100 mg, 436.56 μmol) in EtOH (10 mL) was added2- (1- (3- (aminomethyl) pyridin-2-yl) -1H-pyrazol-3-yl) propan-2-ol (121.68 mg, 523.87 μmol) and TEA (132.53 mg, 1.31 mmol, 182.67 μL) , then stirred at 80 ℃ for 6 hrs. The reaction was concentrated to give a residue. The residue was purified by column chromatography to give2- (1- (3- ( ( (2-chloro-9-cyclopropyl-9H-purin-6-yl) amino) methyl) pyridin-2-yl) -1H-pyrazol-3-yl) propan-2-ol (153.4 mg, 342.99 μmol, 78.57%yield, 95%purity) as a white solid. ESI-MS [M+H] ⁺: 425.32.

To a solution of2- (1- (3- ( ( (2-chloro-9-cyclopropyl-9H-purin-6-yl) amino) methyl) pyridin-2-yl) -1H-pyrazol-3-yl) propan-2-ol (50 mg, 117.68 μmol) in DMSO (2.5 mL) was addedpiperidin-4-amine (23.57 mg, 235.36 μmol) and TEA (35.72 mg, 353.04 μmol, 49.24 μL) , then stirred at 160 ℃ for 10 hrs. The reaction was poured into water (30 mL) , extracted with EtOAc (10 mL*2) , the organic layer was washed with water (10 mL*2) , dried over Na₂SO₄, and filtered, concentrated to give a residue. The residue was purified by column chromatography to give2- (1- (3- ( ( (2- (4-aminopiperidin-1-yl) -9-cyclopropyl-9H-purin-6-yl) amino) methyl) pyridin-2-yl) -1H-pyrazol-3-yl) propan-2-ol (25.4 mg, 50.95 μmol, 43.29%yield, 98%purity) as a yellow solid. ESI-MS [M+H] ⁺: 489.22.¹H NMR (400 MHz, DMSO-d₆) δ 8.40 –8.31 (m, 2H) , 7.95 (dd, J = 7.8, 1.8 Hz, 1H) , 7.84 (s, 1H) , 7.73 (s, 1H) , 7.33 (dd, J = 7.7, 4.7 Hz, 1H) , 6.57 (d, J = 2.5 Hz, 1H) , 5.15 (s, 1H) , 4.87 (s, 2H) , 4.46 (d, J = 13.2 Hz, 2H) , 3.08 –2.87 (m, 2H) , 2.79 (t, J = 12.3 Hz, 2H) , 1.83 –1.67 (m, 2H) , 1.55 (s, 6H) , 1.35 –1.11 (m, 4H) , 0.99 (dddd, J = 12.3, 5.2, 2.7, 1.5 Hz, 4H) .

2- (1- (3- ( ( (2- (4-aminopiperidin-1-yl) -9-ethyl-9H-purin-6-yl) amino) methyl) pyridin-2-yl) -1H-pyrazol-3-yl) propan-2-ol

Synthesis of 2- (1- (3- ( ( (2- (4-aminopiperidin-1-yl) -9-ethyl-9H-purin-6-yl) amino) methyl) pyridin-2-yl) -1H-pyrazol-3-yl) propan-2-ol

Synthesis of 2- (3- (2-hydroxypropan-2-yl) -1H-pyrazol-1-yl) nicotinonitrile

Synthesis of 2- (1- (3- ( ( (2-chloro-9-ethyl-9H-purin-6-yl) amino) methyl) pyridin-2-yl) -1H-pyrazol-3-yl) propan-2-ol

To a solution of 2, 6-dichloro-9-ethyl-9H-purine (100 mg, 460.71 μmol) in EtOH (10 mL) was added 2- (1- (3- (aminomethyl) pyridin-2-yl) -1H-pyrazol-3-yl) propan-2-ol (128.42 mg, 552.86 μmol) and TEA (139.86 mg, 1.38 mmol, 192.78 μL) , then stirred at 80 ℃ for 6 hrs. The reaction was concentrated to give a residue. The residue was purified by column chromatography to give 2- (1- (3- ( ( (2-chloro-9-ethyl-9H-purin-6-yl) amino) methyl) pyridin-2-yl) -1H-pyrazol-3-yl) propa n-2-ol (157.4 mg, 365.98 μmol, 79.44%yield, 96%purity) as a white solid. ESI-MS [M+H] ⁺: 413.33.

To a solution of 2- (1- (3- ( ( (2-chloro-9-ethyl-9H-purin-6-yl) amino) methyl) pyridin-2-yl) -1H-pyrazol-3-yl) propan-2-ol (50 mg, 121.10 μmol) in DMSO (2.5 mL) was added piperidin-4-amine (12.13 mg, 121.10 μmol) and TEA (36.76 mg, 363.31 μmol, 50.67 μL) , then stirred at 160℃ for 10 hrs. The reaction was poured into water (30 mL) , extracted with EtOAc (10 mL*2) , the organic layer was washed with water (10 mL*2) , dried over Na₂SO₄, and filtered, concentrated to give a residue. The residue was purified by column chromatography to give 2- (1- (3- ( ( (2- (4-aminopiperidin-1-yl) -9-ethyl-9H-purin-6-yl) amino) methyl) pyridin-2-yl) -1H-pyrazol-3-yl) propan-2-ol (35.4 mg, 72.79 μmol, 60.11%yield, 98%purity) as a yellow solid. ESI-MS [M+H] ⁺: 477.52.¹H NMR (400 MHz, DMSO-d₆) δ 8.37 (dd, J = 4.5, 1.9 Hz, 2H) , 7.96 (d, J = 8.9 Hz, 1H) , 7.89 (s, 1H) , 7.81 (s, 1H) , 7.34 (dd, J = 7.7, 4.7 Hz, 1H) , 6.57 (d, J = 2.6 Hz, 1H) , 5.16 (s, 1H) , 4.89 (s, 2H) , 4.51 (d, J = 13.2 Hz, 2H) , 4.01 (q, J = 7.2 Hz, 2H) , 3.57 –3.25 (m, 2H) , 3.21 –3.08 (m, 2H) , 2.79 (t, J = 12.6 Hz, 2H) , 1.85 (t, J = 13.5 Hz, 2H) , 1.56 (s, 6H) , 1.35 (d, J = 7.2 Hz, 4H) .

2- (1- (3- ( ( (2- (4- (dimethylamino) piperidin-1-yl) -9-ethyl-9H-purin-6-yl) amino) methyl) pyridin-2-yl) -1H-pyrazol-3-yl) propan-2-ol

Synthesis of 2- (1- (3- ( ( (2- (4- (dimethylamino) piperidin-1-yl) -9-ethyl-9H-purin-6-yl) amino) methyl) pyridin-2-yl) -1H-pyrazol-3-yl) propan-2-ol

Synthesis of 2- (3- (2-hydroxypropan-2-yl) -1H-pyrazol-1-yl) nicotinonitrile

To a solution of2, 6-dichloro-9-ethyl-9H-purine (100 mg, 460.71 μmol) in EtOH (10 mL) was added2- (1- (3- (aminomethyl) pyridin-2-yl) -1H-pyrazol-3-yl) propan-2-ol (128.42 mg, 552.86 μmol) and TEA (139.86 mg, 1.38 mmol, 192.78 μL) , then stirred at 80 ℃ for 6 hrs. The reaction was concentrated to give a residue. The residue was purified by column chromatography to give 2- (1- (3- ( ( (2-chloro-9-ethyl-9H-purin-6-yl) amino) methyl) pyridin-2-yl) -1H-pyrazol-3-yl) propa n-2-ol (157.4 mg, 365.98 μmol, 79.44%yield, 96%purity) as a white solid. ESI-MS [M+H] ⁺ : 413.33.

To a solution of2- (1- (3- ( ( (2-chloro-9-isopropyl-9H-purin-6-yl) amino) methyl) pyridin-2-yl) -1H-pyrazol-3-yl) propan-2-ol (100 mg, 242.20 μmol) in DMSO (2.5 mL) was added N, N-dimethylpiperidin-4-amine (37.27 mg, 290.64 μmol) and TEA (73.53 mg, 726.61 μmol, 101.35 μL) , then stirred at 160 ℃ for 10 hrs. The reaction was poured into water (30 mL) , extracted with EtOAc (10 mL*2) , the organic layer was washed with water (10 mL*2) , dried over Na₂SO₄, and filtered, concentrated to give a residue. The residue was purified by column chromatography to give 2- (1- (3- ( ( (2- (4- (dimethylamino) piperidin-1-yl) -9-ethyl-9H-purin-6-yl) amino) methyl) pyridin-2-yl) -1H-pyrazol-3-yl) propan-2-ol (87.4 mg, 169.73 μmol, 70.08%yield, 98%purity) as a yellow solid. ESI-MS [M+H] ⁺: 505.34.¹H NMR (400 MHz, DMSO-d₆) δ 8.41 –8.33 (m, 2H) , 7.95 (d, J = 6.8 Hz, 1H) , 7.86 (s, 1H) , 7.79 (s, 1H) , 7.34 (dd, J = 7.7, 4.7 Hz, 1H) , 6.57 (d, J = 2.6 Hz, 1H) , 5.15 (s, 1H) , 4.88 (s, 2H) , 4.56 (d, J = 13.0 Hz, 2H) , 4.00 (q, J = 7.2 Hz, 2H) , 2.76 –2.63 (m, 2H) , 2.32 (s, 6H) , 2.24 (s, 2H) , 1.86 –1.69 (m, 3H) , 1.55 (s, 6H) , 1.34 (t, J = 7.2 Hz, 3H) .

2- (1- (3- ( ( (2- (4-aminopiperidin-1-yl) -9-cyclopentyl-9H-purin-6-yl) amino) methyl) pyridin-2 -yl) -1H-pyrazol-3-yl) propan-2-ol

Synthesis of 2- (1- (3- ( ( (2- (4-aminopiperidin-1-yl) -9-cyclopentyl-9H-purin-6-yl) amino) methyl) pyridin-2-yl) -1H-pyrazol-3-yl) propan-2-ol

Synthesis of 2- (3- (2-hydroxypropan-2-yl) -1H-pyrazol-1-yl) nicotinonitrile

To a solution of 2-fluoronicotinonitrile (1.06 g, 8.72 mmol) in DMF (15 mL) was added 2- (1H-pyrazol-3-yl) propan-2-ol (1 g, 7.93 mmol) and Cs₂CO₃ (5.17 g, 15.85 mmol) , then stirred at 20 ℃ for 16 hrs. The reaction was poured into water (300 mL) , extracted with EtOAc (100 mL*2) , the organic layer was washed with water (100 mL*2) , dried over Na₂SO₄, and filtered and concentrated to give a residue. The residue was purified by column chromatography to give 2- (3- (2-hydroxypropan-2-yl) -1H-pyrazol-1-yl) nicotinonitrile (1.56 g, 6.42 mmol, 81.05%yield, 94%purity) as a yellow solid. ESI-MS [M+H] ⁺: 229.45.

Synthesis of 2, 6-dichloro-9-cyclopentyl-9H-purine

cyclopentanol (2.5 g, 29.03 mmol) , 2, 6-dichloro-9H-purine (6.58 g, 34.83 mmol) and triphenyl phosphine (9.14 g, 34.83 mmol) in dry THF (30 mL) and cool to 0℃. Add diethyl azodicarboxylate (6.07 g, 34.83 mmol, 5.46 mL) dropwise over a period of 15 minutes under a nitrogen atmosphere. Stir the resulting solution for 60 hours at room temperature. Evaporate the solvent in vacuo, charge directly onto a silica gel column, and elute with methylene chloride to give 2, 6-dichloro-9-cyclopentyl-9H-purine (5.32 g, 19.86 mmol, 68.43%yield, 96%purity) as a white solid.

Synthesis of 2- (1- (3- ( ( (2-chloro-9-cyclopentyl-9H-purin-6-yl) amino) methyl) pyridin-2-yl) -1H-pyrazol-3-yl) propan-2-ol

To a solution of2, 6-dichloro-9-cyclopentyl-9H-purine (100 mg, 388.93 μmol) in EtOH (15 mL) was added2- (1- (3- (aminomethyl) pyridin-2-yl) -1H-pyrazol-3-yl) propan-2-ol (90.34 mg, 388.93 μmol) and TEA (118.07 mg, 1.17 mmol, 162.74 μL) , then stirred at 80 ℃ for 6 hrs. The reaction was concentrated to give a residue. The residue was purified by column chromatography to give2- (1- (3- ( ( (2-chloro-9-cyclopentyl-9H-purin-6-yl) amino) methyl) pyridin-2-yl) -1H-pyrazol-3-yl) propan-2-ol (165.4 mg, 354.22 μmol, 91.08%yield, 97%purity) as a white solid. ESI-MS [M+H] ⁺: 453.24.

To a solution of 2- (1- (3- ( ( (2-chloro-9-cyclopentyl-9H-purin-6-yl) amino) methyl) pyridin-2-yl) -1H-pyrazol-3-yl) propan-2-ol (50 mg, 110.39 μmol) in DMSO (2.5 mL) was addedN, N-dimethylpiperidin-4-amine (28.31 mg, 220.78 μmol) and TEA (33.51 mg, 331.17 μmol, 46.19 μL) , then stirred at 160 ℃ for 10 hrs. The reaction was poured into water (30 mL) , extracted with EtOAc (10 mL*2) , the organic layer was washed with water (10 mL*2) , dried over Na₂SO₄, filtered, and concentrated to give a residue. The residue was purified by column chromatography to give2- (1- (3- ( ( (9-cyclopentyl-2- (4- (dimethylamino) piperidin-1-yl) -9H-purin-6-yl) amino) methyl) pyridin-2-yl) -1H-pyrazol-3-yl) propan-2-ol (40.3 mg, 71.77 μmol, 65.01%yield, 97%purity) as a white solid. ESI-MS [M+H] ⁺: 545.21.¹H NMR (400 MHz, DMSO-d₆) δ 8.45 –8.31 (m, 2H) , 8.08 –7.93 (m, 1H) , 7.89 (s, 1H) , 7.84 (s, 1H) , 6.58 (d, J = 2.6 Hz, 1H) , 5.16 (s, 1H) , 4.88 (s, 1H) , 4.75 –4.50 (m, 2H) , 3.34 (s, 6H) , 2.79 –2.61 (m, 2H) , 2.08 (qdd, J = 7.5, 5.1, 1.9 Hz, 2H) , 2.01 –1.78 (m, 6H) , 1.66 (qd, J = 6.9, 5.5, 2.9 Hz, 2H) , 1.55 (s, 6H) , 1.28 –1.21 (m, 2H) .

2- (1- (2- ( ( (2- (4-aminopiperidin-1-yl) -9-ethyl-9H-purin-6-yl) amino) methyl) phenyl) -5-propyl-1H-pyrazol-3-yl) propan-2-ol

Synthesis of 2- (1- (2- ( ( (2- (4-aminopiperidin-1-yl) -9-ethyl-9H-purin-6-yl) amino) methyl) phenyl) -5-propyl-1H-pyrazol-3-yl) propan-2-ol

Synthesis of 2- (5-propyl-1H-pyrazol-3-yl) propan-2-ol

To a solution of methyl 5-propyl-1H-pyrazole-3-carboxylate (500 mg, 2.97 mmol) in THF (20 mL) was added MeMgBr (1.06 g, 8.92 mmol) dropwise at 0-5 ℃ under N₂ atmosphere. The resulting mixture was stirred at 10 ℃ for 15 hours to form a white suspension. TLC showed the reaction was completed. The mixture was poured into saturated aqueous NH₄Cl (50 mL) . The mixture was extracted with EtOAc (50 mL x 3) . The combined organic extract was washed with brine (80 mL x 2) , dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give 2- (5-propyl-1H-pyrazol-3-yl) propan-2-ol (468.2 mg, 2.56 mmol, 86.13%yield, 92%purity) as a colorless oil.

Synthesis of 2- (3- (2-hydroxypropan-2-yl) -5-methyl-1H-pyrazol-1-yl) benzonitrile

To a mixture of 2-fluorobenzonitrile (172.77 mg, 1.43 mmol) and 2- (5-propyl-1H-pyrazol-3-yl) propan-2-ol (200 mg, 1.19 mmol) in DMF (10 mL) was added Cs₂CO₃ (1.16 g, 3.57 mmol) . The mixture was stirred at 15 ℃ for 15 hours to form a white suspension. TLC showed the reaction was completed. The mixture was partitioned between EtOAc (150 mL) and H₂O (150 mL) . The aqueous phase was extracted with EtOAc (150 mL x 2) . The combined organic extracts were washed with brine (100 mL x 3) , dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give the crude product, which was purified by combi flash to give 2- (3- (2-hydroxypropan-2-yl) -5-propyl-1H-pyrazol-1-yl) benzonitrile (234.5 mg, 835.82 μmol, 70.31%yield, 96%purity) as a yellow solid. ESI-MS [M+H] ⁺: 270.32.

Synthesis of 2- (1- (2- (aminomethyl) phenyl) -5-propyl-1H-pyrazol-3-yl) propan-2-ol

To a solution of2- (3- (2-hydroxypropan-2-yl) -5-propyl-1H-pyrazol-1-yl) benzonitrile (500 mg, 1.86 mmol) in THF (15 mL) was added LiAlH₄ (211.35 mg, 5.57 mmol) . After being stirred for 1 h, diluted with THF and quenched with water (100 μL) , NaOH (15%in water, 100μL) . The reaction mixture was stirred at room temperature for 1 h, then dried over Na₂SO₄. After filtration and evaporation of the solvent, the crude mixture was purified by column chromatography on silica gel to get a thick oil 2- (1- (2- (aminomethyl) phenyl) -5-propyl-1H-pyrazol-3-yl) propan-2-ol (302.4 mg, 1.06 mmol, 57.20%yield, 96%purity) . ESI-MS [M+H] ⁺: 274.45.

Synthesis of 2- (1- (2- ( ( (2-chloro-9-ethyl-9H-purin-6-yl) amino) methyl) phenyl) -5-propyl-1H -pyrazol-3-yl) propan-2-ol

To a mixture of 2, 6-dichloro-9-ethyl-9H-purine (100 mg, 460.71 μmol) , 2- (1- (2- (aminomethyl) phenyl) -5-propyl-1H-pyrazol-3-yl) propan-2-ol (132.24 mg, 483.75 μmol) in EtOH (14.90 mL) was added TEA (139.86 mg, 1.38 mmol, 192.78 μL) . The mixture was stirred at 78℃ for 6 hours to give a green suspension. TLC showed the reaction was completed. The mixture was partitioned between EtOAc (100 mL) and water (100 mL) , the aqueous phase was extracted with EtOAc (80 mL x 2) , the combined extracted phase was washed with water (80 mL) , dried over Na₂SO₄, filtered, concentrated under reduced pressure to give an oil, which was purified by Combi flash to give 2- (1- (2- ( ( (2-chloro-9-ethyl-9H-purin-6-yl) amino) methyl) phenyl) -5-propyl-1H-pyrazol-3-yl) propan-2-ol (185.2 mg, 391.64 μmol, 85.01%yield, 96%purity) as a white solid. ESI-MS [M+H] ⁺: 454.23.

To a solution of 2- (1- (2- ( ( (2-chloro-9-ethyl-9H-purin-6-yl) amino) methyl) phenyl) -5-propyl -1H-pyrazol-3-yl) propan-2-ol (50 mg, 110.14 μmol) in DMSO (2.5 mL) was adde piperidin-4-amine (13.24 mg, 132.17 μmol) and TEA (33.44 mg, 330.42 μmol, 46.09 μL) , then stirred at 160 ℃ for 10 hrs. The reaction was poured into water (30 mL) , extracted with EtOAc (10 mL*2) , the organic layer was washed with water (10 mL*2) , dried over Na₂SO₄, and filtered and concentrated to give a residue. The residue was purified by column chromatography to give 2- (1- (2- ( ( (2- (4-aminopiperidin-1-yl) -9-ethyl-9H-purin-6-yl) amino) me thyl) phenyl) -5-propyl-1H-pyrazol-3-yl) propan-2-ol (43.3 mg, 81.14 μmol, 73.67%yield, 97%purity) as a white solid. ESI-MS [M+H] ⁺: 518.12.¹H NMR (400 MHz, DMSO-d₆) δ 7.84 (s, 1H) , 7.67 (s, 1H) , 7.46 –7.33 (m, 3H) , 7.27 (d, J = 7.4 Hz, 1H) , 6.39 (s, 1H) , 4.57 (dt, J =13.5, 6.8 Hz, 1H) , 4.47 –4.22 (m, 3H) , 2.89 (d, J = 12.2 Hz, 2H) , 2.74 (t, J = 11.0 Hz, 2H) , 2.61 (ddd, J = 14.3, 10.3, 3.9 Hz, 2H) , 2.47 –2.30 (m, 4H) , 1.66 (dd, J = 8.6, 3.5 Hz, 3H) , 1.49 (dd, J = 17.5, 7.1 Hz, 6H) , 1.12 (ddd, J = 15.4, 12.1, 3.9 Hz, 6H) , 0.84 (t, J = 7.2 Hz, 3H) .

2- (1- (2- ( ( (2- (4-aminopiperidin-1-yl) -9-isopropyl-9H-purin-6-yl) amino) methyl) -3- (trifluoromethyl) phenyl) -1H-pyrazol-3-yl) propan-2-ol

Synthesis of 2- (1- (2- ( ( (2- (4-aminopiperidin-1-yl) -9-isopropyl-9H-purin-6-yl) amino) methyl) -3- (trifluoromethyl) phenyl) -1H-pyrazol-3-yl) propan-2-ol

Synthesis of 2- (1H-pyrazol-3-yl) propan-2-ol

To a stirred mixture of ethyl 1H-pyrazole-3-carboxylate (5.00 g, 35.7 mmol, 1.00 equiv) and tetrahydrofuran (50 mL) was added methyl-magnesiubromide (47.6 mL, 143 mmol, 4.00 equiv, 3M in Et₂O) at 0-5℃ under nitrogen atmosphere. The resulting mixture was stirred for overnight at room temperature and quenched with saturated ammonium chloride solution (40 mL) at room temperature. The resulting mixture was extracted with ethyl acetate (3 x 100 mL) . The combined organic layers were washed with brine (2 x 50 mL) , dried over anhydrous sodium sulfate, filtrated, and concentrated under reduced pressure to afford 2- (1H-pyrazol-3-yl) propan-2-ol (3.90 g, 86%yield) as a white solid. ESI-MS [M +H] +: 127.23 .

Synthesis of2- (3- (2-hydroxypropan-2-yl) -1H-pyrazol-1-yl) -6- (trifluoromethyl) benzonitrile

To a mixture of compound 2- (1H-pyrazol-3-yl) propan-2-ol (0.38 g, 3.00 mmol) and 2-fluoro-6- (trifluoromethyl) benzonitrile (0.57 g, 3.00 mmol) in DMF (100 mL) was added Cs₂CO₃ (1.95 g, 6.00 mmol) . The mixture was stirred at 20 ℃ for 6 hours to form a white suspension. TLC showed the reaction was completed. The mixture was partitioned between EtOAc (150 mL) and H2O (150 mL) . The aqueous phase was extracted with EtOAc (150 mL x 2) . The combined organic extracts were washed with brine (100 mL x 3) , dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give the crude product, which was purified by column chromatography (SiO₂, EA: PE=0%to 40%) to give compound 2- (3- (2-hydroxypropan-2-yl) -1H-pyrazol-1-yl) -6- (trifluoromethyl) benzonitrile

(0.70 g, 2.37 mmol, 79.03%yield) as a yellow solid. ESI-MS [M +H] ⁺: 296.4.

Synthesis of 2- (1- (2- (aminomethyl) -3- (trifluoromethyl) phenyl) -1H-pyrazol-3-yl) propan-2-ol

To a solution of 2- (3- (2-hydroxypropan-2-yl) -1H-pyrazol-1-yl) -6- (trifluoromethyl) benzonitrile (0.70 g, 2.37 mmol) in MeOH (50 mL) and Raney-Ni (1g) under H₂, then stirred at 20 ℃ for 18 hrs. The reaction was filtered and concentrated to give 2- (1- (2- (aminomethyl) -3- (trifluoromethyl) phenyl) -1H-pyrazol-3-yl) propan-2-ol (0.65 g, 2.17 mmol, 91.61%yield) . ESI-MS [M +H] ⁺: 300.3.

Synthesis of 2- (1- (2- ( ( (2-chloro-9-isopropyl-9H-purin-6-yl) amino) methyl) -3- (trifluoromethyl) phenyl) -1H-pyrazol-3-yl) propan-2-ol

To a mixture of 2, 6-dichloro-9-isopropyl-9H-purine (0.69 g, 3.00 mmol) , 2- (1- (2- (aminomethyl) -3-fluorophenyl) -1H-pyrazol-3-yl) propan-2-ol (0.90 g, 3.00 mmol) in EtOH (50 mL) was added TEA (0.91 g, 9.00 mmol, 1.26 mL) . The mixture was stirred at 80℃ for 6 hours. TLC showed the reaction was completed. The mixture was partitioned between EtOAc (100 mL) and water (100 mL) , the aqueous phase was extracted with EtOAc (80 mL x 2) , the combined extracted phase was washed with water (80 mL) , dried over Na₂SO₄, filtered, concentrated under reduced pressure to give an oil, which was purified by column chromatography (SiO₂, EA: PE=0%to 50%) to give 2- (1- (2- ( ( (2-chloro-9-isopropyl-9H-purin-6-yl) amino) methyl) -3- (trifluoromethyl) phenyl) -1H-pyrazol-3-yl) propan-2-ol (1.00 g, 2.02 mmol, 67.49%yield) as a white solid. ESI-MS [M +H] ⁺: 494.9.

To a solution of 2- (1- (2- ( ( (2-chloro-9-isopropyl-9H-purin-6-yl) amino) methyl) -3- (trifluoromethyl) phenyl) -1H-pyrazol-3-yl) propan-2-ol (0.15 g, 0.30 mmol) in DMSO (3 mL) was added piperidin-4-amine (33.05 mg, 0.33 mmol) and DIPEA (0.12 g, 0.90 mmol, 0.16 mL) , then stirred at 160 ℃ for 8 hrs. The reaction was poured into water (5ml) , extracted with DCM and MeOH (10: 1 30ml*5) , the organic layer was washed with water and brine (30ml) , dried over Na₂SO₄, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO₂, MeOH: DCM=0%to 10%) to give 2- (1- (2- ( ( (2- (4-aminopiperidin-1-yl) -9-isopropyl-9H-purin-6-yl) amino) methyl) -3- (trifluorome thyl) phenyl) -1H-pyrazol-3-yl) propan-2-ol (0.11 g, 0.20 mmol, 65.76%yield) as a white solid. ESI-MS [M +H] ⁺: 558.6.

¹H NMR (400 MHz, Methanol-d₄) δ 7.90-7.88 (m, 1H) , 7.82-7.81 (m, 1H) , 7.76 (s, 1H) , 7.70-7.66 (m, 2H) , 6.46-6.45 (m, 1H) , 4.83-4.77 (m, 4H) , 4.70-4.63 (m, 1H) , 3.19-3.12 (m, 1H) , 2.93-2.86 (m, 2H) , 1.95-1.91 (m, 2H) , 1.55-1.54 (m, 6H) , 1.47 (s, 6H) , 1.46-1.42 (m, 2H) .

2- (1- (4- ( ( (2- (4-aminopiperidin-1-yl) -9-isopropyl-9H-purin-6-yl) amino) methyl) pyridin-3-yl) -1H-pyrazol-3-yl) propan-2-ol

Synthesis of 2- (1- (4- ( ( (2- (4-aminopiperidin-1-yl) -9-isopropyl-9H-purin-6-yl) amino) methyl) pyridin-3-yl) -1H-pyrazol-3-yl) propan-2-ol

Synthesis of 2- (1H-pyrazol-3-yl) propan-2-ol

To a stirred mixture of ethyl 1H-pyrazole-3-carboxylate (5.00 g, 35.7 mmol, 1.00 equiv) and tetrahydrofuran (50 mL) was added methyl-magnesiubromide (47.6 mL, 143 mmol, 4.00 equiv, 3M in Et₂O) at 0-5℃ under nitrogen atmosphere. The resulting mixture was stirred for overnight at room temperature and quenched with saturated ammonium chloride solution (40 mL) at room temperature. The resulting mixture was extracted with ethyl acetate (3 x 100 mL) . The combined organic layers were washed with brine (2 x 50 mL) , dried over anhydrous sodium sulfate, filtrated, and concentrated under reduced pressure to afford 2- (1H-pyrazol-3-yl) propan-2-ol (3.90 g, 86%yield) as a white solid. ESI-MS [M +H] ⁺: 127.23.

Synthesis of 3- (3- (2-hydroxypropan-2-yl) -1H-pyrazol-1-yl) isonicotinonitrile

To a mixture of compound 2- (1H-pyrazol-3-yl) propan-2-ol (0.25 g, 2.00 mmol) and 3-fluoroisonicotinonitrile (0.24 g, 2.00 mmol) in DMF (50 mL) was added Cs₂CO₃ (1.31 g, 4.00 mmol) . The mixture was stirred at 20 ℃ for 6 hours to form a white suspension. TLC showed the reaction was completed. The mixture was partitioned between EtOAc (150 mL) and H2O (150 mL) . The aqueous phase was extracted with EtOAc (150 mL x 2) . The combined organic extracts were washed with brine (100 mL x 3) , dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give the crude product, which was purified by column chromatography (SiO₂, EA: PE=0%to 40%) to give compound 3- (3- (2-hydroxypropan-2-yl) -1H-pyrazol-1-yl) isonicotinonitrile (0.32 g, 1.40 mmol, 70.10%yield) as a yellow solid. ESI-MS [M +H] ⁺: 229.4.

Synthesis of 2- (1- (4- (aminomethyl) pyridin-3-yl) -1H-pyrazol-3-yl) propan-2-ol

To a solution of 3- (3- (2-hydroxypropan-2-yl) -1H-pyrazol-1-yl) isonicotinonitrile (0.32 g, 1.40 mmol) in MeOH (50 mL) and Raney-Ni (1g) under H₂, then stirred at 20 ℃ for 18 hrs. The reaction was filtered and concentrated to give 2- (1- (4- (aminomethyl) pyridin-3-yl) -1H-pyrazol-3-yl) propan-2-ol (0.30 g, 1.29 mmol, 92.12%yield) . ESI-MS [M +H] ⁺: 233.3.

Synthesis of 2- (1- (4- ( ( (2-chloro-9-isopropyl-9H-purin-6-yl) amino) methyl) pyridin-3-yl) -1H-pyrazol-3-yl) propan-2-ol

To a mixture of 2, 6-dichloro-9-isopropyl-9H-purine (0.3 g, 1.29 mmol) , 2- (1- (4- (aminomethyl) pyridin-3-yl) -1H-pyrazol-3-yl) propan-2-ol (0.3 g, 1.29 mmol) in EtOH (50 mL) was added TEA (0.39 g, 3.87 mmol, 0.54 mL) . The mixture was stirred at 80℃ for 6 hours. TLC showed the reaction was completed. The mixture was partitioned between EtOAc (100 mL) and water (100 mL) , the aqueous phase was extracted with EtOAc (80 mL x 2) , the combined extracted phase was washed with water (80 mL) , dried over Na₂SO₄, filtered, concentrated under reduced pressure to give an oil, which was purified by column chromatography (SiO₂, EA: PE=0%to 50%) to give 2- (1- (4- ( ( (2-chloro-9-isopropyl-9H-purin-6-yl) amino) methyl) pyridin-3-yl) -1H-pyrazol-3-yl) propan-2-ol (0.42 g, 0.98 mmol, 76.18%yield) as a white solid. ESI-MS [M +H] ⁺: 427.9.

To a solution of 2- (1- (4- ( ( (2-chloro-9-isopropyl-9H-purin-6-yl) amino) methyl) pyridin-3-yl) -1H-pyrazol-3-yl) propan-2-ol (0.21 g, 0.50 mmol) in DMSO (3 mL) was added piperidin-4-amine (55.09 mg, 0.55 mmol) and DIPEA (0.19 g, 1.50 mmol, 0.26 mL) , then stirred at 160 ℃ for 8 hrs. The reaction was poured into water (5ml) , extracted with DCM and MeOH (10: 1 30ml*5) , the organic layer was washed with water and brine (30ml) , dried over Na₂SO₄, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO₂, MeOH: DCM=0%to 10%) to give 2- (1- (4- ( ( (2- (4-aminopiperidin-1-yl) -9-isopropyl-9H-purin-6-yl) amino) methyl) pyridin-3-yl) -1H-pyrazol-3-yl) propan-2-ol (0.14 g, 0.29 mmol, 57.07%yield) as a white solid.

ESI-MS [M +H] ⁺: 491.4.

¹H NMR (400 MHz, Methanol-d₄) δ 8.57 (s, 1H) , 8.47-8.46 (m, 1H) , 7.92-7.91 (m, 1H) , 7.80 (s, 1H) , 7.61-7.59 (m, 1H) , 6.59-6.58 (m, 1H) , 4.80 (s, 2H) , 4.67-4.55 (m, 3H) , 2.85-2.73 (m, 3H) , 1.78-1.75 (m, 2H) , 1.62 (s, 6H) , 1.55-1.53 (m, 6H) , 1.20-1.10 (m, 2H) .

2- (1- (3- ( ( (2- (4-aminopiperidin-1-yl) -9-isopropyl-9H-purin-6-yl) amino) methyl) phenyl) -1H -pyrazol-3-yl) propan-2-ol

Synthesis of 2- (1- (3- ( ( (2- (4-aminopiperidin-1-yl) -9-isopropyl-9H-purin-6 -yl) amino) methyl) phenyl) -1H-pyrazol-3-yl) propan-2-ol

Synthesis of 2- (1H-pyrazol-3-yl) propan-2-ol

Synthesis of 3- (3- (2-hydroxypropan-2-yl) -1H-pyrazol-1-yl) benzonitrile

To a mixture of compound 2- (1H-pyrazol-3-yl) propan-2-ol (0.25 g, 2.00 mmol) and 3-fluorobenzonitrile (0.24 g, 2.00 mmol) in DMF (50 mL) was added Cs₂CO₃ (1.31 g, 4.00 mmol) . The mixture was stirred at 20 ℃ for 6 hours to form a white suspension. TLC showed the reaction was completed. The mixture was partitioned between EtOAc (150 mL) and H₂O (150 mL) . The aqueous phase was extracted with EtOAc (150 mL x 2) . The combined organic extracts were washed with brine (100 mL x 3) , dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give the crude product, which was purified by column chromatography (SiO₂, EA: PE=0%to 40%) to give compound 3- (3- (2-hydroxypropan-2-yl) -1H-pyrazol-1-yl) benzonitrile (0.13 g, 0.57 mmol, 28.60%yield) as a yellow solid. ESI-MS [M +H] ⁺: 228.4.

Synthesis of 2- (1- (3- (aminomethyl) phenyl) -1H-pyrazol-3-yl) propan-2-ol

To a solution of 3- (3- (2-hydroxypropan-2-yl) -1H-pyrazol-1-yl) benzonitrile (0.13 g, 0.57 mmol) in MeOH (50 mL) and Raney-Ni (1g) under H₂, then stirred at 20 ℃ for 18 hrs. The reaction was filtered and concentrated to give 2- (1- (3- (aminomethyl) phenyl) -1H-pyrazol-3-yl) propan-2-ol (0.08 g, 0.34 mmol, 60.47%yield) . ESI-MS [M +H] ⁺: 232.3.

Synthesis of 2- (1- (3- ( ( (2-chloro-9-isopropyl-9H-purin-6-yl) amino) methyl) phenyl) -1H-pyrazol-3-yl) propan-2-ol

To a mixture of 2, 6-dichloro-9-isopropyl-9H-purine (0.08 g, 0.35 mmol) , 2- (1- (3- (aminomethyl) phenyl) -1H-pyrazol-3-yl) propan-2-ol (0.08 g, 0.35 mmol) in EtOH (50 mL) was added TEA (0.11 g, 1.04 mmol, 0.14 mL) . The mixture was stirred at 80℃ for 6 hours. TLC showed the reaction was completed. The mixture was partitioned between EtOAc (100 mL) and water (100 mL) , the aqueous phase was extracted with EtOAc (80 mL x 2) , the combined extracted phase was washed with water (80 mL) , dried over Na₂SO₄, filtered, concentrated under reduced pressure to give an oil, which was purified by column chromatography (SiO₂, EA: PE=0%to 50%) to give 2- (1- (3- ( ( (2-chloro-9-isopropyl-9H-purin-6-yl) amino) methyl) phenyl) -1H-pyrazol-3-yl) propan-2-ol (0.12 g, 0.28 mmol, 81.46%yield) as a white solid. ESI-MS [M +H] ⁺: 426.9.

Synthesis of 2- (1- (3- ( ( (2- (4-aminopiperidin-1-yl) -9-isopropyl-9H-purin-6-yl) amino) methyl) phenyl) -1H-pyrazol-3-yl) propan-2-ol

To a solution of 2- (1- (4- ( ( (2-chloro-9-isopropyl-9H-purin-6-yl) amino) methyl) pyridin-3-yl) -1H-pyrazol-3-yl) propan-2-ol (0.12 g, 0.29 mmol) in DMSO (3 mL) was added piperidin-4-amine (32.34 mg, 0.32 mmol) and DIPEA (0.11 g, 0.88 mmol, 0.15 mL) , then stirred at 160 ℃ for 8 hrs. The reaction was poured into water (5ml) , extracted with DCM and MeOH (10: 1 30ml*5) , the organic layer was washed with water and brine (30ml) , dried over Na₂SO₄, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO₂, MeOH: DCM=0%to 10%) to give 2- (1- (3- ( ( (2- (4-aminopiperidin-1-yl) -9-isopropyl-9H-purin-6-yl) amino) methyl) phenyl) -1H-pyrazol-3-yl) propan-2-ol (0.097 g, 0.20 mmol, 67.50%yield) as a white solid.

ESI-MS [M +H] ⁺: 490.5.

¹H NMR (400 MHz, Methanol-d₄) δ 8.05-8.04 (m, 1H) , 7.80-7.79 (m, 2H) , 7.59-7.57 (m, 1H) , 7.41-7.37 (m, 1H) , 7.32-7.30 (m, 1H) , 6.48-6.47 (m, 1H) , 4.78-4.76 (m, 4H) , 4.69-4.66 (m, 1H) , 3.06-3.01 (m, 1H) , 2.89-2.82 (m, 2H) , 1.83-1.80 (m, 2H) , 1.58 (s, 6H) , 1.56-1.54 (m, 6H) , 1.35-1.25 (m, 2H) .

2- (1- (2- ( ( (2- (4-aminopiperidin-1-yl) -9-isopropyl-9H-purin-6-yl) amino) methyl) pyridin-3-yl) -1H-pyrazol-3-yl) propan-2-ol

Synthesis of 2- (1- (2- ( ( (2- (4-aminopiperidin-1-yl) -9-isopropyl-9H-purin-6-yl) amino) methyl) pyridin-3-yl) -1H-pyrazol-3-yl) propan-2-ol

Synthesis of 2- (1H-pyrazol-3-yl) propan-2-ol

Synthesis of 3- (3- (2-hydroxypropan-2-yl) -1H-pyrazol-1-yl) picolinonitrile

To a mixture of compound 2- (1H-pyrazol-3-yl) propan-2-ol (0.25 g, 2.00 mmol) and 3-fluoropicolinonitrile (0.24 g, 2.00 mmol) in DMF (50 mL) was added Cs₂CO₃ (1.31 g, 4.00 mmol) . The mixture was stirred at 20 ℃ for 6 hours to form a white suspension. TLC showed the reaction was completed. The mixture was partitioned between EtOAc (150 mL) and H₂O (150 mL) . The aqueous phase was extracted with EtOAc (150 mL x 2) . The combined organic extracts were washed with brine (100 mL x 3) , dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give the crude product, which was purified by column chromatography (SiO₂, EA: PE=0%to 40%) to give compound 3- (3- (2-hydroxypropan-2-yl) -1H-pyrazol-1-yl) picolinonitrile (0.38 g, 1.66 mmol, 83.24%yield) as a yellow solid. ESI-MS [M +H] ⁺: 229.4.

Synthesis of 2- (1- (2- (aminomethyl) pyridin-3-yl) -1H-pyrazol-3-yl) propan-2-ol

To a solution of 3- (3- (2-hydroxypropan-2-yl) -1H-pyrazol-1-yl) isonicotinonitrile (0.38 g, 1.66 mmol) in MeOH (50 mL) and Raney-Ni (1g) under H₂, then stirred at 20 ℃ for 18 hrs. The reaction was filtered and concentrated to give 2- (1- (2- (aminomethyl) pyridin-3-yl) -1H-pyrazol-3-yl) propan-2-ol (0.34 g, 1.46 mmol, 87.92%yield) . ESI-MS [M +H] ⁺: 233.3.

Synthesis of 2- (1- (2- ( ( (2-chloro-9-isopropyl-9H-purin-6-yl) amino) methyl) pyridin-3-yl) -1H-pyrazol-3-yl) propan-2-ol

To a mixture of 2, 6-dichloro-9-isopropyl-9H-purine (0.34 g, 1.46 mmol) , 2- (1- (4- (aminomethyl) pyridin-3-yl) -1H-pyrazol-3-yl) propan-2-ol (0.34 g, 1.46 mmol) in EtOH (50 mL) was added TEA (0.44 g, 4.39 mmol, 0.61 mL) . The mixture was stirred at 80℃ for 6 hours. TLC showed the reaction was completed. The mixture was partitioned between EtOAc (100 mL) and water (100 mL) , the aqueous phase was extracted with EtOAc (80 mL x 2) , the combined extracted phase was washed with water (80 mL) , dried over Na₂SO₄, filtered, concentrated under reduced pressure to give an oil, which was purified by column chromatography (SiO₂, EA: PE=0%to 50%) to give 2- (1- (2- ( ( (2-chloro-9-isopropyl-9H-purin-6-yl) amino) methyl) pyridin-3-yl) -1H-pyrazol-3-yl) propan-2-ol (0.38 g, 0.89 mmol, 60.81%yield) as a white solid. ESI-MS [M +H] ⁺: 427.9.

To a solution of 2- (1- (4- ( ( (2-chloro-9-isopropyl-9H-purin-6-yl) amino) methyl) pyridin-3-yl) -1H-pyrazol-3-yl) propan-2-ol (0.21 g, 0.50 mmol) in DMSO (3 mL) was added piperidin-4-amine (55.09 mg, 0.55 mmol) and DIPEA (0.19 g, 1.50 mmol, 0.26 mL) , then stirred at 160 ℃ for 8 hrs. The reaction was poured into water (5ml) , extracted with DCM and MeOH (10: 1 30ml*5) , the organic layer was washed with water and brine (30ml) , dried over Na₂SO₄, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO₂, MeOH: DCM=0%to 10%) to give 2- (1- (2- ( ( (2- (4-aminopiperidin-1-yl) -9-isopropyl-9H-purin-6-yl) amino) methyl) pyridin-3-yl) -1H-pyrazol-3-yl) propan-2-ol (0.14 g, 0.29 mmol, 57.07%yield) as a white solid.

ESI-MS [M +H] ⁺: 491.4.

¹H NMR (400 MHz, Methanol-d₄) δ 8.60-8.58 (m, 1H) , 7.86-7.83 (m, 2H) , 7.76 (s, 1H) , 7.47-7.44 (m, 1H) , 6.56-6.55 (m, 1H) , 4.89 (s, 2H) , 4.66-4.61 (m, 3H) , 2.83-2.73 (m, 3H) , 1.81-1.77 (m, 2H) , 1.60 (s, 6H) , 1.54-1.52 (m, 6H) , 1.22-1.13 (m, 2H) .

2- (1- (2- ( ( (2- (4-aminopiperidin-1-yl) -9-isopropyl-9H-purin-6-yl) amino) methyl) phenyl) -1H -imidazol-2-yl) propan-2-ol

Synthesis of 2- (1- (2- ( ( (2- (4-aminopiperidin-1-yl) -9-isopropyl-9H-purin-6-yl) amino) methyl) phenyl) -1H-imidazol-2-yl) propan-2-ol

Synthesis of ethyl 1- (2-cyanophenyl) -1H-imidazole-2-carboxylate

To a solution of 2-fluorobenzonitrile (1 g, 8.26 mmol) in DMF (20 mL) were added ethyl 1H-imidazole-2-carboxylate (1.21 g, 8.67 mmol) and Cs₂CO₃ (4.04 g, 12.39 mmol) , the mixture was stirred at RT for 7h. The reaction mixture was filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO₂, EA: PE =0%to 73%) to give ethyl 1- (2-cyanophenyl) -1H-imidazole-2-carboxylate (535 mg, 2.22 mmol, 26.85%yield, 99.96%purity) as a yellow solid.

ESI-MS [M+H] ⁺ : 242.22.

Synthesis of 2- (2- (2-hydroxypropan-2-yl) -1H-imidazol-1-yl) benzonitrile

To a solution of ethyl 1- (2-cyanophenyl) -1H-imidazole-2-carboxylate (535 mg, 2.22 mmol) in THF (17.02 mL) was added MeMgBr (3 M in 2-MeTHF, 5.91 mL) at 0℃ under N2, the mixture was stirred at RT for 17h. The reaction mixture was poured into NH₄Cl solution (35%, 100mL) , extracted with EA (50ml*2) , the organic layer was washed with brine (50mL*2) , dried over Na₂SO₄, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO₂, MeOH: DCM=0%to 7%) to give 2- (2- (2-hydroxypropan-2-yl) -1H-imidazol-1-yl) benzonitrile (501 mg, 2.18 mmol, 98.47%yield, 99.06%purity) as an oil.

ESI-MS [M+H] ⁺ : 228.21.

Synthesis of 2- (1- (2- (aminomethyl) phenyl) -1H-imidazol-2-yl) propan-2-ol

To a solution of 2- (2- (2-hydroxypropan-2-yl) -1H-imidazol-1-yl) benzonitrile (501 mg, 2.20 mmol) in MeOH (10 mL) were added NH₃ (7M in MeOH, 1 mL) and Ni (100 mg, 1.70 mmol) , replaced with H₂ three times and the mixture was stirred at RT for 5h. LC-MS show the reaction was completed. The reaction mixture was filtered and concentrated to give 2- (1- (2- (aminomethyl) phenyl) -1H-imidazol-2-yl) propan-2-ol (508 mg, crude) as an oil.

ESI-MS [M+H] ⁺ : 232.28.

Synthesis of 2, 6-dichloro-9-isopropyl-9H-purine

ESI-MS [M+H] ⁺: 231.16.

Synthesis of 2- (1- (2- ( ( (2-chloro-9-isopropyl-9H-purin-6-yl) amino) methyl) phenyl) -1H-imidazol-2-yl) propan-2-ol

To a solution of N- (2- (1H-pyrazol-1-yl) benzyl) -2-chloro-9-isopropyl-9H-purin-6-amine (400 mg, 1.73 mmol) in EtOH (20 mL) were added 2- (1- (2- (aminomethyl) phenyl) -1H-imidazol-2-yl) propan-2-ol (480.44 mg, 2.08 mmol) and TEA (350.32 mg, 3.46 mmol, 482.86 μL) , the mixture was stirred at 85℃ for 5h. The reaction mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO₂, 0.5M ammonia methanol solution: DCM=0%to 10%) to give 2- (1- (2- ( ( (2-chloro-9-isopropyl-9H-purin-6-yl) amino) methyl) phenyl) -1H-imidazol-2-yl) propan-2-ol (436 mg, 995.53 μmol, 57.51%yield, 97.25%purity) as a white solid.

ESI-MS [M+H] ⁺ : 426.23.

To a solution of 2- (1- (2- ( ( (2-chloro-9-isopropyl-9H-purin-6-yl) amino) methyl) phenyl) -1H-imidazol-2-yl) propan-2-ol (200 mg, 469.58 μmol) in NMP (2 mL) were added piperidin-4-amine (70.55 mg, 704.37 μmol) and DIPEA (121.38 mg, 939.16 μmol, 163.58 μL) , the mixture was stirred at 160℃ for 7h. The reaction mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO₂, 0.5M ammonia methanol solution: DCM=0%to 20%) to give 2- (1- (2- ( ( (2- (4-aminopiperidin-1-yl) -9-isopropyl-9H-purin-6-yl) amino) methyl) phenyl) -1H-imidazol-2-yl) propan-2-ol (40 mg, 79.39 μmol, 16.91%yield, 97.18%purity) as a white solid.

ESI-MS [M+H] ⁺ : 490.41.

¹H NMR (400 MHz, Methanol-d₄) δ 7.81 (s, 1H) , 7.54 (d, J = 7.5 Hz, 1H) , 7.45 (dt, J = 7.8, 4.4 Hz, 1H) , 7.39 (d, J = 4.4 Hz, 2H) , 6.98 (d, J = 25.2 Hz, 2H) , 4.80 (s, 2H) , 4.68 (hept, J =6.9 Hz, 1H) , 4.57 (d, J = 15.4 Hz, 1H) , 4.48 (d, J = 15.5 Hz, 1H) , 3.34 (d, J = 4.8 Hz, 1H) , 2.90 (t, J = 12.5 Hz, 2H) , 1.97 (s, 2H) , 1.55 (d, J = 6.8 Hz, 6H) , 1.51 (d, J = 6.0 Hz, 8H) .

2- (4-aminopiperidin-1-yl) -9-isopropyl-N- (2- (2-methyl-1H-imidazol-1-yl) benzyl) -9H-purin-6-amine

Synthesis of 2- (4-aminopiperidin-1-yl) -9-isopropyl-N- (2- (2-methyl-1H-imidazol-1-yl) benzyl) -9H-purin-6-amine

Synthesis of 2- (2-methyl-1H-imidazol-1-yl) benzonitrile

To a solution of 2-fluorobenzonitrile (500 mg, 4.13 mmol) in DMF (20 mL) were added 2-methyl-1H-imidazole (406.75 mg, 4.95 mmol) and Cs₂CO₃ (2.69 g, 8.26 mmol) , the mixture was stirred at 90℃ for 7h. The reaction mixture was filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO₂, MeOH: DCM =0%to 10%) to give 2- (2-methyl-1H-imidazol-1-yl) benzonitrile (296 mg, 1.54 mmol, 37.32%yield, 95.37%purity) as a yellow solid.

ESI-MS [M+H] ⁺: 184.17.

Synthesis of (2- (2-methyl-1H-imidazol-1-yl) phenyl) methanamine

To a solution of 2- (2-methyl-1H-imidazol-1-yl) benzonitrile (296 mg, 1.62 mmol) in MeOH (30 mL) were added NH₃ (7 M in MeOH, 1 mL) and Ni (100 mg, 1.70 mmol) , replaced with H₂ three times and the mixture was stirred at RT for 17h. LCMS show the reaction was completed. The reaction mixture was filtered and concentrated to give (2- (2-methyl-1H-imidazol-1-yl) phenyl) methanamine (300 mg, crude) as an oil.

ESI-MS [M+H] ⁺ : 188.16.

Synthesis of 2, 6-dichloro-9-isopropyl-9H-purine

ESI-MS [M+H] ⁺: 231.16.

Synthesis of 2-chloro-9-isopropyl-N- (2- (2-methyl-1H-imidazol-1-yl) benzyl) -9H-purin-6-amine

To a solution of N- (2- (1H-pyrazol-1-yl) benzyl) -2-chloro-9-isopropyl-9H-purin-6-amine (300 mg, 1.30 mmol) in EtOH (20 mL) were added (2- (2-methyl-1H-imidazol-1-yl) phenyl) methanamine (291.70 mg, 1.56 mmol) and TEA (262.74 mg, 2.60 mmol, 362.15 μL) , the mixture was stirred at 85℃ for 5h. The reaction mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO₂, MeOH: DCM=0%to 7%) to give 2-chloro-9-isopropyl-N- (2- (2-methyl-1H-imidazol-1-yl) benzyl) -9H-purin-6-amine (424 mg, 1.11 mmol, 85.42%yield, 99.87%purity) as a white solid.

ESI-MS [M+H] ⁺ : 382.26.

To a solution of 6-chloro-1-isopropyl-N- (2- (2-methyl-1H-imidazol-1-yl) benzyl) -1H-benzo [d] imidazol-4-amine (200 mg, 523.75 μmol) in NMP (2 mL) were added piperidin-4-amine (78.69 mg, 785.63 μmol) and DIPEA (135.38 mg, 1.05 mmol, 182.45 μL) , the mixture was stirred at 160℃ for 7h. The reaction mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO₂, 0.5M ammonia methanol solution: DCM=0%to 22%) to give 2- (4-aminopiperidin-1-yl) -9-isopropyl-N- (2- (2-methyl-1H-imidazol-1-yl) benzyl) -9H-purin-6-amine (101 mg, 226.48 μmol, 43.24%yield, 99.91%purity) as a white solid.

ESI-MS [M+H] ⁺ : 446.39.

¹H NMR (400 MHz, Methanol-d₄) δ 7.78 (s, 1H) , 7.61 (dd, J = 7.6, 1.6 Hz, 1H) , 7.50 (td, J =7.6, 1.4 Hz, 1H) , 7.44 (td, J = 7.6, 1.7 Hz, 1H) , 7.28 (dd, J = 7.6, 1.5 Hz, 1H) , 7.10 (d, J = 1.5 Hz, 1H) , 6.95 (d, J = 1.5 Hz, 1H) , 4.74 –4.59 (m, 3H) , 4.50 (d, J = 33.9 Hz, 2H) , 2.98 (tt, J =11.1, 4.1 Hz, 1H) , 2.89 –2.77 (m, 2H) , 2.14 (s, 3H) , 1.87 –1.79 (m, 2H) , 1.55 (d, J = 6.8 Hz, 6H) , 1.34 –1.26 (m, 2H) .

2- (1- (2- ( ( (9-isopropyl-2- (propyl (2- (4-propylpiperazin-1-yl) ethyl) amino) -9H-purin-6-yl) amino) methyl) phenyl) -1H-pyrazol-3-yl) propan-2-ol

Synthesis of 2- (1- (2- ( ( (9-isopropyl-2- (propyl (2- (4-propylpiperazin-1-yl) ethyl) amino) -9H-purin-6-yl) amino) methyl) phenyl) -1H-pyrazol-3-yl) propan-2-ol

Synthesis of 2- (1H-pyrazol-3-yl) propan-2-ol

To a solution of compound ethyl 1H-pyrazole-3-carboxylate (5 g, 35.68 mmol) in THF (50 mL) was added MeMgBr (124.88 mmol, 5 mL) dropwise at 0-5 ℃ under N₂ atmosphere. The resulting mixture was stirred at 10 ℃ for 15 hours to form a white suspension. TLC showed the reaction was completed. The mixture was poured into saturated aqueous NH₄Cl (50 mL) . The mixture was extracted with EtOAc (50 mL x 3) . The combined organic extract was washed with brine (80 mL x 2) , dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give compound 2- (1H-pyrazol-3-yl) propan-2-ol (4.33 g, 33.64 mmol, 94.28%yield, 98%purity) as a white solid. ESI-MS [M+H] ⁺: 127.23

Synthesis of 2- (3- (2-hydroxypropan-2-yl) -1H-pyrazol-1-yl) benzonitrile

Synthesis of 2- (1- (2- (aminomethyl) phenyl) -1H-pyrazol-3-yl) propan-2-ol

Synthesis of 2, 6-dichloro-9-isopropyl-9H-purine

2,6-dichloro-9H-purine (10.0g, 52.91mmol) , isopropyl bromide (32.5g, 264.55mmol) , potassium carbonate (21.9g, 158.73mmol) and dimethyl sulfoxide (50ml) were added to a 250 ml two-necked flask, and the mixture was stirred at room temperature for 96 hours. The reaction solution was added dropwise to water, ethyl acetate was added for extraction three times, the organic phases were combined, washed twice with saturated brine, dried over sodium sulfate, and filtered and concentrated in vacuo to obtain 9.8 g of a yellow solid. The crude product was passed through a silica gel column (ethyl acetate/n-heptane=0～60%) to obtain 4.941g of white solid.

To a mixture of 2, 6-dichloro-9-isopropyl-9H-purine (610 mg, 2.64 mmol) , 2- (1- (2- (aminomethyl) phenyl) -1H-pyrazol-3-yl) propan-2-ol (641.09 mg, 2.77 mmol) in EtOH (20 mL) was added TEA (801.35 mg, 7.92 mmol, 1.10 mL) . The mixture was stirred at 78℃ for 6 hours to give a green suspension. TLC showed the reaction was completed. The mixture was partitioned between EtOAc (100 mL) and water (100 mL) , the aqueous phase was extracted with EtOAc (80 mL x 2) , the combined extracted phase was washed with water (80 mL) , dried over Na2S04, filtered, concentrated under reduced pressure to give a green oil, which was purified by Combi flash to give 2- (1- (2- ( ( (2-chloro-9-isopropyl-9H-purin-6-yl) amino) methyl) phenyl) -1H-pyrazol-3-yl) pr opan-2-ol (908 mg, 2.05 mmol, 77.53%yield, 96%purity) as a white solid. ESI-MS [M+H] ⁺: 426.41.

To a solution of2- (1- (2- ( ( (2-chloro-9-isopropyl-9H-purin-6-yl) amino) methyl) phenyl) -1H-pyrazol-3-yl) propan-2-ol (60 mg, 140.87 μmol) in DMSO (2.5 mL) was added TEA (42.77 mg, 422.62 μmol, 58.95 μL) and N- (2- (4-propylpiperazin-1-yl) ethyl) propan-1-amine (36.07 mg, 169.05 μmol) , then stirred at 160 ℃ for 10 hrs. The reaction was poured into water (30 mL) , extracted with EtOAc (10 mL*2) , the organic layer was washed with water (10 mL*2) , dried over Na₂SO₄, and filtered and concentrated to give a residue. The residue was purified by column chromatography to give 2- (1- (2- ( ( (9-isopropyl-2- (propyl (2- (4-propylpiperazin-1-yl) ethyl) amino) -9H-purin-6-yl) amino) methyl) phenyl) -1H-pyrazol-3-yl) propan-2-ol (56.4 mg, 90.75 μmol, 64.42%yield, 97%purity) as a white solid. ESI-MS [M+H] ⁺: 603.21.¹H NMR (400 MHz, DMSO-d₆) δ 8.00 (d, J = 2.4 Hz, 1H) , 7.87 (s, 1H) , 7.80 (s, 1H) , 7.53 (dd, J = 6.8, 2.4 Hz, 1H) , 7.45 –7.30 (m, 3H) , 6.51 (d, J = 2.4 Hz, 1H) , 5.06 (s, 1H) , 4.57 (dd, J = 13.6, 6.9 Hz, 3H) , 3.58 (m, 5H) , 3.42 (m, 3H) , 2.45 –2.23 (m, 8H) , 1.53 (m, 6H) , 1.46 (d, J = 6.8 Hz, 8H) , 1.25 (d, J = 9.5 Hz, 2H) , 0.87 (t, J = 7.3 Hz, 6H) .

2- (1- (2- ( ( (9-isopropyl-2- (4-propylpiperazin-1-yl) -9H-purin-6-yl) amino) methyl) phenyl) -1H-pyrazol-3-yl) propan-2-ol

Synthesis of 2- (1- (2- ( ( (9-isopropyl-2- (4-propylpiperazin-1-yl) -9H-purin-6-yl) amino) methyl) phenyl) -1H-pyrazol-3-yl) propan-2-ol

Synthesis of 2- (1H-pyrazol-3-yl) propan-2-ol

To a solution of compound ethyl 1H-pyrazole-3-carboxylate (5 g, 35.68 mmol) in THF (50 mL) was added MeMgBr (124.88 mmol, 5 mL) dropwise at 0-5 ℃ under N₂ atmosphere. The resulting mixture was stirred at 10 ℃ for 15 hours to form a white suspension. TLC showed the reaction was completed. The mixture was poured into saturated aqueous NH₄Cl (50 mL) . The mixture was extracted with EtOAc (50 mL x 3) . The combined organic extract was washed with brine (80 mL x 2) , dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to give compound 2- (1H-pyrazol-3-yl) propan-2-ol (4.33 g, 33.64 mmol, 94.28%yield, 98%purity) as a white solid. ESI-MS [M+H] ⁺: 127.23

Synthesis of 2- (3- (2-hydroxypropan-2-yl) -1H-pyrazol-1-yl) benzonitrile

Synthesis of 2- (1- (2- (aminomethyl) phenyl) -1H-pyrazol-3-yl) propan-2-ol

Synthesis of 2, 6-dichloro-9-isopropyl-9H-purine

2, 6-dichloro-9H-purine (10.0g, 52.91mmol) , isopropyl bromide (32.5g, 264.55mmol) , potassium carbonate (21.9g, 158.73mmol) and dimethyl sulfoxide (50ml) were added to a 250 ml two-necked flask, and the mixture was stirred at room temperature for 96 hours. The reaction solution was added dropwise to water, ethyl acetate was added for extraction three times, the organic phases were combined, washed twice with saturated brine, dried over sodium sulfate, and filtered and concentrated in vacuo to obtain 9.8 g of a yellow solid. The crude product was passed through a silica gel column (ethyl acetate/n-heptane=0～60%) to obtain 4.941g of white solid.

To a mixture of 2, 6-dichloro-9-isopropyl-9H-purine (610 mg, 2.64 mmol) , 2- (1- (2- (aminomethyl) phenyl) -1H-pyrazol-3-yl) propan-2-ol (641.09 mg, 2.77 mmol) in EtOH (20 mL) was added TEA (801.35 mg, 7.92 mmol, 1.10 mL) . The mixture was stirred at 78℃ for 6 hours to give a green suspension. TLC showed the reaction was completed. The mixture was partitioned between EtOAc (100 mL) and water (100 mL) , the aqueous phase was extracted with EtOAc (80 mL x 2) , the combined extracted phase was washed with water (80 mL) , dried over Na₂SO₄, filtered, concentrated under reduced pressure to give a green oil, which was purified by Combi flash to give 2- (1- (2- ( ( (2-chloro-9-isopropyl-9H-purin-6-yl) amino) methyl) phenyl) -1H-pyrazol-3-yl) propan-2-ol (908 mg, 2.05 mmol, 77.53%yield, 96%purity) as a white solid. ESI-MS [M+H] ⁺: 426.41.

To a solution of2- (1- (2- ( ( (2-chloro-9-isopropyl-9H-purin-6-yl) amino) methyl) phenyl) -1H-pyrazol-3-yl) propan-2-ol (60 mg, 140.87 μmol) in DMSO (2.5 mL) was added1-propylpiperazine (21.67 mg, 169.05 μmol) and TEA (42.77 mg, 422.62 μmol, 58.95 μL) ) , then stirred at 160 ℃ for 10 hrs. The reaction was poured into water (30 mL) , extracted with EtOAc (10 mL*2) , the organic layer was washed with water (10 mL*2) , dried over Na₂SO₄, and filtered and concentrated to give a residue. The residue was purified by column chromatography to give2- (1- (2- ( ( (9-isopropyl-2- (4-propylpiperazin-1-yl) -9H-purin-6-yl) amino) methyl) phenyl) -1 H-pyrazol-3-yl) propan-2-ol (46.9 mg, 88.79 μmol, 63.03%yield, 98%purity) as a white solid. ESI-MS [M+H] ⁺: 518.11.¹H NMR (400 MHz, DMSO-d₆) δ 8.00 (d, J = 2.4 Hz, 1H) , 7.85 (s, 1H) , 7.57 –7.50 (m, 1H) , 7.45 –7.30 (m, 3H) , 6.51 (d, J = 2.4 Hz, 1H) , 5.05 (s, 1H) , 4.57 (dd, J = 14.2, 7.4 Hz, 3H) , 3.57 (d, J = 5.3 Hz, 4H) , 2.40 –2.28 (m, 4H) , 2.24 (t, J = 7.4 Hz, 2H) , 1.53 (s, 6H) , 1.46 (dd, J = 7.1, 4.4 Hz, 8H) , 0.88 (t, J = 7.3 Hz, 4H) .

2- (1- (2- ( ( (2- (4-aminopiperidin-1-yl) -9-isopropyl-9H-purin-6-yl) amino) methyl) phenyl) -5-methyl-1H-pyrazol-3-yl) propan-2-ol

Synthesis of 2- (1- (2- ( ( (2- (4-aminopiperidin-1-yl) -9-isopropyl-9H-purin-6-yl) amino) methyl) phenyl) -5-methyl-1H-pyrazol-3-yl) propan-2-ol

Synthesis of 2- (5-methyl-1H-pyrazol-3-yl) propan-2-ol

To a solution of methyl 5-methyl-1H-pyrazole-3-carboxylate (1 g, 6.49 mmol) in THF (30 mL) was added MeMgBr (3.09 g, 25.95 mmol) dropwise at 0-5 ℃ under N₂ atmosphere. The resulting mixture was stirred at 10 ℃ for 15 hours to form a white suspension. TLC showed the reaction was completed. The mixture was poured into saturated aqueous NH₄Cl (50 mL) . The mixture was extracted with EtOAc (50 mL x 3) . The combined organic extract was washed with brine (80 mL x 2) , dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give 2- (5-methyl-1H-pyrazol-3-yl) propan-2-ol (878.5 mg, 6.27 mmol, 96.61%yield) as a colorless oil.

To a mixture of 2- (5-methyl-1H-pyrazol-3-yl) propan-2-ol (500 mg, 3.57 mmol) and2-fluorobenzonitrile (518.37 mg, 4.28 mmol) in DMF (20 mL) was added Cs₂CO₃ (3.49 g, 10.70 mmol) . The mixture was stirred at 15 ℃ for 15 hours to form a white suspension. TLC showed the reaction was completed. The mixture was partitioned between EtOAc (150 mL) and H₂O (150 mL) . The aqueous phase was extracted with EtOAc (150 mL x 2) . The combined organic extracts were washed with brine (100 mL x 3) , dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give the crude product, which was purified by combi flash to give 2- (3- (2-hydroxypropan-2-yl) -5-methyl-1H-pyrazol-1-yl) benzonitrile (804.4 mg, 3.20 mmol, 89.73%yield, 96%purity) as a yellow solid. ESI-MS [M+H] ⁺: 242.21.

Synthesis of 2- (1- (2- (aminomethyl) phenyl) -5-methyl-1H-pyrazol-3-yl) propan-2-ol

To a solution of2- (3- (2-hydroxypropan-2-yl) -5-methyl-1H-pyrazol-1-yl) benzonitrile (800 mg, 3.32 mmol) in THF (15 mL) was added LiAlH₄ (377.47 mg, 9.95 mmol) . After being stirred for 1 h, diluted with THF and quenched with water (100 μL) , NaOH (15%in water, 100μL) . The reaction mixture was stirred at room temperature for 1 h, then dried over Na₂SO₄. After filtration and evaporation of the solvent, the crude mixture was purified by column chromatography on silica gel to get a thick oil 2- (1- (2- (aminomethyl) phenyl) -5-methyl-1H-pyrazol-3-yl) propan-2-ol (786.5 mg, 3.21 mmol, 96.70%yield) . ESI-MS [M+H] ⁺: 246.21.

Synthesis of 2, 6-dichloro-9-isopropyl-9H-purine

Synthesis of 2- (1- (2- ( ( (2-chloro-9-isopropyl-9H-purin-6-yl) amino) methyl) phenyl) -5-methyl-1H -pyrazol-3-yl) propan-2-ol

To a mixture of2, 6-dichloro-9-isopropyl-9H-purine (500 mg, 2.16 mmol) , 2- (1- (2- (aminomethyl) phenyl) -5-methyl-1H-pyrazol-3-yl) propan-2-ol (636.97 mg, 2.60 mmol) in EtOH (15 mL) was added TEA (656.85 mg, 6.49 mmol, 905.37 μL) . The mixture was stirred at 78℃ for 6 hours to give a green suspension. TLC showed the reaction was completed. The mixture was partitioned between EtOAc (100 mL) and water (100 mL) , the aqueous phase was extracted with EtOAc (80 mL x 2) , the combined extracted phase was washed with water (80 mL) , dried over Na₂SO₄, filtered, concentrated under reduced pressure to give an oil, which was purified by Combi flash to give2- (1- (2- ( ( (2-chloro-9-isopropyl-9H-purin-6-yl) amino) methyl) phenyl) -5-methyl-1H-pyrazol-3-yl) propan-2-ol (754.3 mg, 1.63 mmol, 75.28%yield, 95%purity) as a white solid. ESI-MS [M+H] ⁺: 440.23.

To a solution of2- (1- (2- ( ( (2-chloro-9-isopropyl-9H-purin-6-yl) amino) methyl) phenyl) -5-methyl-1H -pyrazol-3-yl) propan-2-ol (100 mg, 227.30 μmol) in DMSO (2.5 mL) was addedpiperidin-4-amine (27.32 mg, 272.76 μmol) and TEA (69.00 mg, 681.91 μmol, 95.11 μL) , then stirred at 160 ℃ for 10 hrs. The reaction was poured into water (30 mL) , extracted with EtOAc (10 mL*2) , the organic layer was washed with water (10 mL*2) , dried over Na₂SO₄, and filtered and concentrated to give a residue. The residue was purified by column chromatography to give2- (1- (2- ( ( (2- (4-aminopiperidin-1-yl) -9-isopropyl-9H-purin-6-yl) amino) methyl) phenyl) -5-methyl-1H-pyrazol-3-yl) propan-2-ol (78.9 mg, 153.53 μmol, 67.54%yield, 98%purity) as a white solid. ESI-MS [M+H] ⁺: 504.22.¹H NMR (400 MHz, Methanol-d₄) δ 7.81 –7.73 (m, 1H) , 7.60 (dd, J = 7.6, 1.3 Hz, 1H) , 7.44 (dtd, J = 20.1, 7.4, 1.5 Hz, 2H) , 7.30 (dd, J = 7.6, 1.4 Hz, 1H) , 6.26 (d, J = 0.7 Hz, 1H) , 4.76 –4.60 (m, 3H) , 4.51 (s, 2H) , 3.08 –2.96 (m, 1H) , 2.90 –2.77 (m, 2H) , 2.06 (s, 3H) , 1.89 (ddd, J = 14.6, 12.3, 2.2 Hz, 3H) , 1.54 (d, J = 6.0 Hz, 13H) .

2- (1- (2- ( ( (9-isopropyl-2- (4- (isopropylamino) piperidin-1-yl) -9H-purin-6-yl) amino) methyl) phenyl) -1H-pyrazol-3-yl) propan-2-ol

Synthesis of 2- (1- (2- ( ( (9-isopropyl-2- (4- (isopropylamino) piperidin-1-yl) -9H-purin-6-yl) amino) methyl) phenyl) -1H-pyrazol-3-yl) propan-2-ol

Synthesis of 2- (1H-pyrazol-3-yl) propan-2-ol

Synthesis of 2- (3- (2-hydroxypropan-2-yl) -1H-pyrazol-1-yl) benzonitrile

Synthesis of 2- (1- (2- (aminomethyl) phenyl) -1H-pyrazol-3-yl) propan-2-ol

Synthesis of 2, 6-dichloro-9-isopropyl-9H-purine

To a solution of 2- (1- (2- ( ( (2-chloro-9-isopropyl-9H-purin-6-yl) amino) methyl) phenyl) -1H-pyrazol-3-yl) propan-2-ol (50 mg, 117.39 μmol) in DMSO (2.5 mL) was addedN-isopropylpiperidin-4-amine (33.40 mg, 234.79 μmol) and TEA (35.64 mg, 352.18 μmol, 49.12 μL) , then stirred at 160 ℃ for 10 hrs. The reaction was poured into water (30 mL) , extracted with EtOAc (10 mL*2) , the organic layer was washed with water (10 mL*2) , dried over Na₂SO₄, and filtered and concentrated to give a residue. The residue was purified by column chromatography to give 2- (1- (2- ( ( (9-isopropyl-2- (4- (isopropylamino) piperidin-1-yl) -9H-purin-6-yl) amino) methyl) phenyl) -1H-pyrazol-3-yl) propan-2-ol (35.4 mg, 64.58 μmol, 55.01%yield, 97%purity) as a white solid. ESI-MS [M+H] ⁺: 532.45.¹H NMR (400 MHz, Methanol-d₄) δ 7.79 (d, J = 2.6 Hz, 2H) , 7.64 –7.57 (m, 1H) , 7.44 –7.36 (m, 3H) , 6.52 (t, J =3.2 Hz, 1H) , 4.78 –4.59 (m, 4H) , 3.43 (tt, J = 9.8, 5.0 Hz, 1H) , 2.96 –2.80 (m, 2H) , 2.08 –1.96 (m, 3H) , 1.60 (s, 6H) , 1.54 (dd, J = 6.8, 2.9 Hz, 6H) , 1.29 (t, J = 4.4 Hz, 9H) .

(R) -2- (1- (2- ( ( (2- (3-aminopiperidin-1-yl) -9-isopropyl-9H-purin-6-yl) amino) methyl) phenyl) -1H-pyrazol-3-yl) propan-2-ol

Synthesis of (R) -2- (1- (2- ( ( (2- (3-aminopiperidin-1-yl) -9-isopropyl-9H-purin-6-yl) amino) methyl) phenyl) -1H-pyrazol-3-yl) propan-2-ol

Synthesis of 2- (1H-pyrazol-3-yl) propan-2-ol

Synthesis of 2- (3- (2-hydroxypropan-2-yl) -1H-pyrazol-1-yl) benzonitrile

Synthesis of 2- (1- (2- (aminomethyl) phenyl) -1H-pyrazol-3-yl) propan-2-ol

Synthesis of 2, 6-dichloro-9-isopropyl-9H-purine

To a solution of 2- (1- (2- ( ( (2-chloro-9-isopropyl-9H-purin-6-yl) amino) methyl) phenyl) -1H-pyrazol-3-yl) propan-2-ol (60 mg, 140.87 μmol) in DMSO (2.5 mL) was added (R) -piperidin-3-amine (16.93 mg, 169.05 μmol) and TEA (42.76 mg, 422.62 μmol, 58.95 μL) , then stirred at 160 ℃ for 10 hrs. The reaction was poured into water (30 mL) , extracted with EtOAc (10 mL*2) , the organic layer was washed with water (10 mL*2) , dried over Na₂SO₄, and filtered and concentrated to give a residue. The residue was purified by column chromatography to give (R) -2- (1- (2- ( ( (2- (3-aminopiperidin-1-yl) -9-isopropyl-9H-purin-6-yl) amino) methyl) phenyl) -1H -pyrazol-3-yl) propan-2-ol (47.7 mg, 94.50 μmol, 67.08%yield, 97%purity) as a white solid. ESI-MS [M+H] ⁺: 490.34.¹H NMR (400 MHz, Methanol-d₄) δ 7.81 (dd, J = 13.3, 10.9 Hz, 2H) , 7.61 –7.50 (m, 1H) , 7.45 –7.33 (m, 3H) , 6.51 (d, J = 2.4 Hz, 1H) , 4.67 (dq, J = 13.7, 6.8 Hz, 3H) , 4.50 (dd, J = 12.8, 3.4 Hz, 1H) , 4.26 (d, J = 13.4 Hz, 1H) , 3.23 –3.10 (m, 2H) , 2.98 (dt, J = 29.9, 12.8 Hz, 1H) , 2.04 (dt, J = 18.5, 9.4 Hz, 1H) , 1.82 –1.69 (m, 1H) , 1.60 (s, 6H) , 1.54 (d, J = 6.8 Hz, 6H) , 1.32 –1.25 (m, 2H) .

2- (1- (2- ( ( (2- (4- (ethylamino) piperidin-1-yl) -9-isopropyl-9H-purin-6-yl) amino) methyl) phenyl) -1H-pyrazol-3-yl) propan-2-ol

Synthesis of 2- (1- (2- ( ( (2- (4- (ethylamino) piperidin-1-yl) -9-isopropyl-9H-purin-6-yl) amino) methyl) phenyl) -1H-pyrazol-3-yl) propan-2-ol

Synthesis of 2- (1H-pyrazol-3-yl) propan-2-ol

Synthesis of 2- (3- (2-hydroxypropan-2-yl) -1H-pyrazol-1-yl) benzonitrile

Synthesis of 2- (1- (2- (aminomethyl) phenyl) -1H-pyrazol-3-yl) propan-2-ol

Synthesis of 2, 6-dichloro-9-isopropyl-9H-purine

To a solution of2- (1- (2- ( ( (2-chloro-9-isopropyl-9H-purin-6-yl) amino) methyl) phenyl) -1H-pyrazol-3-yl) propan-2-ol (60 mg, 140.87 μmol) in DMSO (2.5 mL) was added TEA (42.76 mg, 422.62 μmol, 58.95 μL) and N-ethylpiperidin-4-amine (36.12 mg, 281.75 μmol) , then stirred at 160 ℃ for 10 hrs. The reaction was poured into water (30 mL) , extracted with EtOAc (10 mL*2) , the organic layer was washed with water (10 mL*2) , dried over Na₂SO₄, and filtered and concentrated to give a residue. The residue was purified by column chromatography to give2- (1- (2- ( ( (2- (4- (ethylamino) piperidin-1-yl) -9-isopropyl-9H-purin-6-yl) amino) methyl) phenyl) -1H-pyrazol-3-yl) propan-2-ol (47.8 mg, 90.49 μmol, 64.24%yield, 98%purity) as a white solid. ESI-MS [M+H] ⁺: 518.22.¹H NMR (400 MHz, Methanol-d₄) δ 7.79 (d, J = 2.4 Hz, 2H) , 7.64 –7.56 (m, 1H) , 7.41 –7.35 (m, 3H) , 6.52 (d, J = 2.4 Hz, 1H) , 4.77 –4.58 (m, 3H) , 3.20 –3.08 (m, 1H) , 3.04 –2.94 (m, 2H) , 2.90 –2.72 (m, 3H) , 2.09 –1.93 (m, 3H) , 1.60 (s, 6H) , 1.55 –1.53 (m, 6H) , 1.30 –1.22 (m, 5H) .

2- (1- (3- ( ( (9-isopropyl-2-morpholino-9H-purin-6-yl) amino) methyl) pyridin-2-yl) -1H-pyrazol-3-yl) propan-2-ol

Synthesis of 2- (1- (3- ( ( (9-isopropyl-2-morpholino-9H-purin-6-yl) amino) methyl) pyridin-2-yl) -1H-pyrazol-3-yl) propan-2-ol

Synthesis of 2- (3- (2-hydroxypropan-2-yl) -1H-pyrazol-1-yl) nicotinonitrile

To a solution of 2- (3- (2-hydroxypropan-2-yl) -1H-pyrazol-1-yl) nicotinonitrile (500 mg, 2.19 mmol) in MeOH (10 mL) was added NH₃·H₂O (2.19 mmol) and Raney-Ni (2.19 mmol) then stirred at 20 ℃ for 6 hrs. The reaction was filtered and concentrated to give a residue. The residue was purified by column chromatography to give 2- (1- (3- (aminomethyl) pyridin-2-yl) -1H -pyrazol-3-yl) propan-2-ol (489.33 mg, 1.96 mmol, 89.44%yield, 93%purity) as a colorless oil. ESI-MS [M+H] ⁺: 233.41.

Synthesis of 2, 6-dichloro-9-isopropyl-9H-purine

To a solution of 2, 6-dichloro-9-isopropyl-9H-purine (100 mg, 432.75 μmol) in EtOH (9.82 mL) was added (2- (3- (tert-butyl) -1H-pyrazol-1-yl) pyridin-3-yl) methanamine (105.54 mg, 454.38 μmol) and TEA (131.37 mg, 1.30 mmol, 181.07 μL) , then stirred at 80 ℃ for 6 hrs. The reaction was concentrated to give a residue. The residue was purified by column chromatography to give N- ( (2- (3- (tert-butyl) -1H-pyrazol-1-yl) pyridin-3-yl) methyl) -2-chloro-9-isopropyl-9H-puri n-6-amine (177.32 mg, 415.36 μmol, 95.98%yield) as a white solid. ESI-MS [M+H] ⁺: 427.33.

To a solution of 2- (1- (3- ( ( (2-chloro-9-isopropyl-9H-purin-6-yl) amino) methyl) pyridin-2-yl) -1H -pyrazol-3-yl) propan-2-ol (50 mg, 117.12 μmol) in DMSO (2.5 mL) was added morpholine (20.41 mg, 234.25 μmol) and TEA (35.56 mg, 351.37 μmol, 49.01 μL) , then stirred at 160 ℃ for 10 hrs. The reaction was poured into water (30 mL) , extracted with EtOAc (10 mL*2) , the organic layer was washed with water (10 mL*2) , dried over Na₂SO₄, filtered, and concentrated to give a residue. The residue was purified by column chromatography to give 2- (1- (3- ( ( (9-isopropyl-2-morpholino-9H-purin-6-yl) amino) methyl) pyridin-2-yl) -1H-pyra zol-3-yl) propan-2-ol (23.5 mg, 47.73 μmol, 40.75%yield, 97%purity) as a white solid. ESI-MS [M+H] ⁺: 478.22.¹H NMR (400 MHz, Methanol-d₄) δ 8.42 –8.25 (m, 2H) , 8.06 (dd, J = 7.7, 1.7 Hz, 1H) , 7.79 (s, 1H) , 7.37 –7.22 (m, 1H) , 6.56 (t, J = 2.5 Hz, 1H) , 5.03 (d, J = 8.5 Hz, 2H) , 4.76 –4.58 (m, 1H) , 3.75 –3.60 (m, 8H) , 1.74 –1.61 (m, 6H) , 1.54 (t, J =7.7 Hz, 6H) .

2- (1- (3- ( ( (2- (3- (dimethylamino) azetidin-1-yl) -9-isopropyl-9H-purin-6-yl) amino) methyl) pyridin-2-yl) -1H-pyrazol-3-yl) propan-2-ol

Synthesis of 2- (1- (3- ( ( (2- (3- (dimethylamino) azetidin-1-yl) -9-isopropyl-9H-purin-6-yl) amino) methyl) pyridin-2-yl) -1H-pyrazol-3-yl) propan-2-ol

Synthesis of 2- (3- (2-hydroxypropan-2-yl) -1H-pyrazol-1-yl) nicotinonitrile

Synthesis of 2, 6-dichloro-9-isopropyl-9H-purine

2,6-dichloro-9H-purine (10.0g, 52.91mmol) , isopropyl bromide (32.5g, 264.55mmol) , potassium carbonate (21.9g, 158.73mmol) and dimethyl sulfoxide (50ml) were added to a 250 ml two-necked flask, and the mixture was stirred at room temperature for 96 hours. The reaction solution was added dropwise to water, ethyl acetate was added for extraction three times, the organic phases were combined, washed twice with saturated brine, dried over sodium sulfate, filtered and concentrated in vacuo to obtain 9.8 g of light yellow solid. The crude product was passed through a silica gel column (ethyl acetate/n-heptane=0～60%) to obtain 4.941g of white solid.

To a solution of 2, 6-dichloro-9-isopropyl-9H-purine (100 mg, 432.75 μmol) in EtOH (9.82 mL) was added (2- (3- (tert-butyl) -1H-pyrazol-1-yl) pyridin-3-yl) methanamine (105.54 mg, 454.38 μmol) and TEA (131.37 mg, 1.30 mmol, 181.07 μL) , then stirred at 80 ℃ for 6 hrs. The reaction was concentrated to give a residue. The residue was purified by column chromatography to give N- ( (2- (3- (tert-butyl) -1H-pyrazol-1-yl) pyridin-3-yl) methyl) -2-chloro-9-isopropyl-9H-purin-6-amine (177.32 mg, 415.36 μmol, 95.98%yield) as a white solid. ESI-MS [M+H] ⁺: 427.33.

To a solution of2- (1- (3- ( ( (2-chloro-9-isopropyl-9H-purin-6-yl) amino) methyl) pyridin-2-yl) -1H-pyrazol-3-yl) propan-2-ol (50.12 mg, 117.39 μmol) in DMSO (2.5 mL) was addedN, N-dimethylazetidin-3-amine (14.11 mg, 140.87 μmol) and TEA (35.64 mg, 352.18 μmol, 49.12 μL) , then stirred at 160 ℃ for 10 hrs. The reaction was poured into water (30 mL) , extracted with EtOAc (10 mL*2) , the organic layer was washed with water (10 mL*2) , dried over Na₂SO₄, and filtered and concentrated to give a residue. The residue was purified by column chromatography to give 2- (1- (3- ( ( (2- (3- (dimethylamino) azetidin-1-yl) -9-isopropyl-9H-purin-6-yl) amino) methyl) pyridin-2-yl) -1H-pyrazol-3-yl) propan-2-ol (48.4 mg, 96.68 μmol, 82.36%yield, 98%purity) as a white solid. ESI-MS [M+H] ⁺: 491.12.¹H NMR (400 MHz, Methanol-d₄) δ 8.48 –8.25 (m, 2H) , 8.11 (dd, J = 7.6, 1.6 Hz, 1H) , 7.77 (d, J = 32.2 Hz, 1H) , 7.29 (dt, J = 22.9, 11.4 Hz, 1H) , 6.57 (dd, J = 4.9, 2.6 Hz, 1H) , 5.04 (s, 2H) , 4.74 –4.57 (m, 1H) , 4.12 (dd, J = 8.9, 7.1 Hz, 2H) , 3.86 (dd, J = 9.1, 5.4 Hz, 2H) , 3.26 –3.15 (m, 1H) , 2.25 (s, 6H) , 1.65 (s, 6H) , 1.52 (d, J = 6.8 Hz, 6H) .

2- (1- (2- ( ( (2- (3- (dimethylamino) azetidin-1-yl) -9-isopropyl-9H-purin-6-yl) amino) methyl) phenyl) -1H-pyrazol-3-yl) propan-2-ol

Synthesis of 2- (1- (2- ( ( (2- (3- (dimethylamino) azetidin-1-yl) -9-isopropyl-9H-purin-6-yl) amino) methyl) phenyl) -1H-pyrazol-3-yl) propan-2-ol

Synthesis of 2- (1H-pyrazol-3-yl) propan-2-ol

Synthesis of 2- (3- (2-hydroxypropan-2-yl) -1H-pyrazol-1-yl) benzonitrile

Synthesis of 2- (1- (2- (aminomethyl) phenyl) -1H-pyrazol-3-yl) propan-2-ol

Synthesis of 2, 6-dichloro-9-isopropyl-9H-purine

To a solution of2- (1- (2- ( ( (2-chloro-9-isopropyl-9H-purin-6-yl) amino) methyl) phenyl) -1H-pyrazol -3-yl) propan-2-ol (100 mg, 234.79 μmol) in DMSO (2.5 mL) was added N, N-dimethylazetidin-3-amine (28.22 mg, 281.75 μmol) and TEA (71.27 mg, 704.37 μmol, 98.24 μL) , then stirred at 160 ℃ for 10 hrs. The reaction was poured into water (30 mL) , extracted with EtOAc (10 mL*2) , the organic layer was washed with water (10 mL*2) , dried over Na₂SO₄, and filtered and concentrated to give a residue. The residue was purified by column chromatography to give 2- (1- (2- ( ( (2- (3- (dimethylamino) azetidin-1-yl) -9-isopropyl-9H-purin-6-yl) amino) methyl) phenyl) -1H-pyrazol-3-yl) propan-2-ol (89.7 mg, 179.54 μmol, 76.47%yield, 98%purity) as a white solid. ESI-MS [M+H] ⁺: 490.32.¹H NMR (400 MHz, Methanol-d₄) δ 7.80 (d, J = 2.7 Hz, 2H) , 7.64 (d, J = 3.2 Hz, 1H) , 7.39 (t, J = 4.4 Hz, 3H) , 6.51 (d, J = 2.2 Hz, 1H) , 4.80 –4.60 (m, 3H) , 4.19 –4.02 (m, 2H) , 3.85 (dd, J = 8.9, 5.4 Hz, 2H) , 3.25 –3.12 (m, 1H) , 2.23 (s, 6H) , 1.60 (s, 6H) , 1.52 (d, J = 6.8 Hz, 6H) .

2- (1- (3- ( ( (2- (4-aminopiperidin-1-yl) -9-isopropyl-9H-purin-6-yl) amino) methyl) pyridin-4-yl) -1H-pyrazol-3-yl) propan-2-ol

Synthesis of 2- (1- (3- ( ( (2- (4-aminopiperidin-1-yl) -9-isopropyl-9H-purin-6-yl) amino) methyl) pyridin-4-yl) -1H-pyrazol-3-yl) propan-2-ol

Synthesis of 2- (1H-pyrazol-3-yl) propan-2-ol

Synthesis of 4- (3- (2-hydroxypropan-2-yl) -1H-pyrazol-1-yl) nicotinonitrile

To a mixture of compound 2- (1H-pyrazol-3-yl) propan-2-ol (0.25 g, 2.00 mmol) and 4-fluoronicotinonitrile (0.24 g, 2.00 mmol) in DMF (50 mL) was added Cs₂CO₃ (1.31 g, 4.00 mmol) . The mixture was stirred at 20 ℃ for 6 hours to form a white suspension. TLC showed the reaction was completed. The mixture was partitioned between EtOAc (150 mL) and H₂O (150 mL) . The aqueous phase was extracted with EtOAc (150 mL x 2) . The combined organic extracts were washed with brine (100 mL x 3) , dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give the crude product, which was purified by column chromatography (SiO₂, EA: PE=0%to 40%) to give compound 4- (3- (2-hydroxypropan-2-yl) -1H-pyrazol-1-yl) nicotinonitrile (0.14 g, 0.61 mmol, 30.67%yield) as a yellow solid. ESI-MS [M +H] ⁺: 229.4.

Synthesis of 2- (1- (3- (aminomethyl) pyridin-4-yl) -1H-pyrazol-3-yl) propan-2-ol

To a solution of 4- (3- (2-hydroxypropan-2-yl) -1H-pyrazol-1-yl) nicotinonitrile (0.14 g, 0.61 mmol) in MeOH (50 mL) and Raney-Ni (1g) under H₂, then stirred at 20 ℃ for 18 hrs. The reaction was filtered and concentrated to give 2- (1- (3- (aminomethyl) pyridin-4-yl) -1H-pyrazol-3-yl) propan-2-ol (0.12 g, 0.52 mmol, 84.23%yield) . ESI-MS [M +H] ⁺: 233.3.

Synthesis of 2- (1- (3- ( ( (2-chloro-9-isopropyl-9H-purin-6-yl) amino) methyl) pyridin-4-yl) -1H -pyrazol-3-yl) propan-2-ol

To a mixture of 2, 6-dichloro-9-isopropyl-9H-purine (0.12 g, 0.52 mmol) , 2- (1- (3-(aminomethyl) pyridin-4-yl) -1H-pyrazol-3-yl) propan-2-ol (0.12 g, 0.52 mmol) in EtOH (50 mL) was added TEA (0.16 g, 1.55 mmol, 0.22 mL) . The mixture was stirred at 80℃ for 6 hours. TLC showed the reaction was completed. The mixture was partitioned between EtOAc (100 mL) and water (100 mL) , the aqueous phase was extracted with EtOAc (80 mL x 2) , the combined extracted phase was washed with water (80 mL) , dried over Na₂SO₄, filtered, concentrated under reduced pressure to give an oil, which was purified by column chromatography (SiO₂, EA: PE=0%to 50%) to give 2- (1- (3- ( ( (2-chloro-9-isopropyl-9H-purin-6-yl) amino) methyl) pyridin-4-yl) -1H-pyrazol-3-yl) propan-2-ol (0.14 g, 0.33 mmol, 63.48%yield) as a white solid. ESI-MS [M +H] ⁺: 427.9.

To a solution of 2- (1- (3- ( ( (2-chloro-9-isopropyl-9H-purin-6-yl) amino) methyl) pyridin-4-yl) -1H-pyrazol-3-yl) propan-2-ol (0.14 g, 0.33 mmol) in DMSO (3 mL) was added piperidin-4-amine (36.13 mg, 0.36 mmol) and DIPEA (0.13 g, 0.098 mmol, 0.17 mL) , then stirred at 160 ℃ for 8 hrs. The reaction was poured into water (5ml) , extracted with DCM and MeOH (10: 1 30ml*5) , the organic layer was washed with water and brine (30ml) , dried over Na₂SO₄, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO₂, MeOH: DCM=0%to 10%) to give 2- (1- (3- ( ( (2- (4-aminopiperidin-1-yl) -9-isopropyl-9H-purin-6-yl) amino) methyl) pyridin-4-yl) -1H-pyrazol-3-yl) propan-2-ol (0.11 g, 0.22 mmol, 68.37%yield) as a white solid.

ESI-MS [M +H] ⁺: 491.4.

¹H NMR (400 MHz, Methanol-d₄) δ 8.79 (s, 1H) , 8.49-8.48 (m, 1H) , 8.14-8.13 (m, 1H) , 7.76 (s, 1H) , 7.56-7.54 (m, 1H) , 6.63-6.62 (m, 1H) , 5.01 (s, 2H) , 4.72-4.63 (m, 3H) , 2.89-2.82 (m, 3H) , 1.85-1.82 (m, 2H) , 1.64 (s, 6H) , 1.54-1.52 (m, 6H) , 1.27-1.23 (m, 2H) .

2- (4-aminopiperidin-1-yl) -7-isopropyl-N- (2- (3- (4-methylpiperazin-1-yl) -1H-pyrazol-1-yl) benzyl) imidazo [2, 1-f] [1, 2, 4] triazin-4-amine

Synthesis of 2- (4-aminopiperidin-1-yl) -7-isopropyl-N- (2- (3- (4-methylpiperazin-1-yl) -1H-pyrazol -1-yl) benzyl) imidazo [2, 1-f] [1, 2, 4] triazin-4-amine

Synthesis of 2- (3-nitro-1H-pyrazol-1-yl) benzonitrile

To a mixture of 2-fluorobenzonitrile (1.5 g, 12.4 mmol) in DMF (40 mL) was added 3-nitro-1H-pyrazole (1.7 g, 14.9 mmol) and Cs₂CO₃ (8.1 g, 24.8 mmol) at room temperature. The mixture was stirred at room temperature for 16h under N₂. The reaction was quenched with H₂O (200 mL) and extracted with EtOAc (100 mL x 3) . The combined organic layers were washed with brine, dried over Na₂SO₄, filtered and concentrated to give the product 2- (3-nitro-1H-pyrazol-1-yl) benzonitrile (800 mg, crude) as a yellow solid, which was used in the next step without further purification. ESI-MS [M +H] ⁺: 215.2.

Synthesis of 2- (3-amino-1H-pyrazol-1-yl) benzonitrile

To a mixture of 2-chloro-6- (3- (2-hydroxypropan-2-yl) -1H-pyrazol-1-yl) benzonitrile (800 mg, 3.7 mmol) in EtOH/H₂O (25 mL/12.5 mL) was added Fe (1.0 g, 18.5 mmol ) and NH₄Cl (2.1 g, 37.0 mmol) at room temperature. The reaction mixture was stirred at 90℃ for 3h. The reaction mixture was filtered throughand the filter cake was washed with DCM/MeOH (10/1, 30 mL) . The filtrate was concentrated to give the crude, which was purified by column chromatography (eluent: DCM/MeOH = 10/1) to give the product 2- (3-amino-1H-pyrazol-1-yl) benzonitrile (450 mg, yield: 66%) as a yellow oil. ESI-MS [M +H] ⁺: 185.2.

Synthesis of 2- (3- (4-methylpiperazin-1-yl) -1H-pyrazol-1-yl) benzonitrile

A mixture of 2- (3-amino-1H-pyrazol-1-yl) benzonitrile (450 mg, 2.4 mmol) , 2-chloro-N- (2-chloroethyl) -N-methylethan-1-amine hydrochloride (916 mg, 4.8 mmol) and DIPEA (929 mg, 7.2 mmol) in DMA (10 mL) was irradiated in microwave at 140℃ for 3h. The reaction mixture was concentrated to give the crude, which was purified by column chromatography (eluent: DCM/MeOH = 20/1) to give the product 2- (3- (4-methylpiperazin-1-yl) -1H-pyrazol-1-yl) benzonitrile (200 mg, yield: 31%) as a yellow solid. ESI-MS [M + H] ⁺: 268.2.

Synthesis of (2- (3- (4-methylpiperazin-1-yl) -1H-pyrazol-1-yl) phenyl) methanamine

To a mixture of 2- (3- (4-methylpiperazin-1-yl) -1H-pyrazol-1-yl) benzonitrile (200 mg, 0.7 mmol) in NH₃ (7M solution in MeOH, 5 mL) was added Raney Ni (50 mg) . The reaction mixture was stirred at room temperature for 3h under H₂. The reaction mixture was filtered through and the filter cake was washed with DCM/MeOH (10/1, 30 mL) . The filtrate was concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH =10/1) to give the product (2- (3- (4-methylpiperazin-1-yl) -1H-pyrazol-1-yl) phenyl) methanamine (140 mg, yield: 74%) as a yellow oil. ESI-MS [M +H] ⁺: 272.2.

Synthesis of 7-bromo-2-chloro-N- (2- (3- (4-methylpiperazin-1-yl) -1H-pyrazol-1-yl) benzyl) imidazo [2, 1-f] [1, 2, 4] triazin-4-amine

A mixture of 7-bromo-2, 4-dichloroimidazo [2, 1-f] [1, 2, 4] triazine (106 mg, 0.4 mmol) , (2- (3- (4-methylpiperazin-1-yl) -1H-pyrazol-1-yl) phenyl) methanamine (140 mg, 0.5 mmol) and DIPEA (155 mg, 1.2 mmol) in IPA (10 mL) was stirred at room temperature for 3h. The reaction mixture was concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 20/1) to give the product 7-bromo-2-chloro-N- (2- (3- (4-methylpiperazin-1-yl) -1H-pyrazol-1-yl) benzyl) imidazo [2, 1-f] [1, 2, 4] triazin-4-amine (130 mg, yield: 65%) as a yellow solid.

ESI-MS [M + H] ⁺: 502.2.

Synthesis of 2-chloro-N- (2- (3- (4-methylpiperazin-1-yl) -1H-pyrazol-1-yl) benzyl) -7- (prop-1-en-2-yl) imidazo [2, 1-f] [1, 2, 4] triazin-4-amine

A mixture of 7-bromo-2-chloro-N- (2- (3- (4-methylpiperazin-1-yl) -1H-pyrazol-1-yl) benzyl) imidazo [2, 1-f] [1, 2, 4] triazin-4-amine (130 mg, 0.3 mmol) , 4, 4, 5, 5-tetramethyl-2- (prop-1-en-2-yl) -1, 3, 2-dioxaborolane (201 mg, 1.2 mmol) , Pd (dppf) Cl₂ (44 mg, 0.06 mmol) and Cs₂CO₃ (391 mg, 1.2 mmol) in dioxane/H₂O (10 mL/1 mL) was stirred at 100℃ for 16h under N₂. The reaction mixture was cooled to room temperature. The mixture was filtered throughand the filter cake was washed with DCM/MeOH (10/1, 30 mL) . The filtrate was concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 30/1) to give the product 2-chloro-N- (2- (3- (4-methylpiperazin-1-yl) -1H-pyrazol-1-yl) benzyl) -7- (prop-1-en-2-yl) imidazo [2, 1-f] [1, 2, 4] triazin-4-amine (100 mg, yield: 72%) as a yellow oil. ESI-MS [M +H] ⁺: 464.2.

Synthesis of tert-butyl (1- (4- ( (2- (3- (4-methylpiperazin-1-yl) -1H-pyrazol-1-yl) benzyl) amino) -7- (prop-1-en-2-yl) imidazo [2, 1-f] [1, 2, 4] triazin-2-yl) piperidin-4-yl) carbamate

A mixture of 2-chloro-N- (2- (3- (4-methylpiperazin-1-yl) -1H-pyrazol-1-yl) benzyl) -7- (prop-1-en-2-yl) imidazo [2, 1-f] [1, 2, 4] triazin-4-amine (100 mg, 0.2 mmol) , piperidin-4-amine (40 mg, 0.4 mmol) and DIPEA (77 mg, 0.6 mmol) in i-PrOH (5 mL) was irradiated in microwave at 140℃ for 3h. The reaction mixture was concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 20/1) to give the product tert-butyl (1- (4- ( (2- (3- (4-methylpiperazin-1-yl) -1H-pyrazol-1-yl) benzyl) amino) -7- (prop-1-en-2-yl) imida zo[2, 1-f] [1, 2, 4] triazin-2-yl) piperidin-4-yl) carbamate (60 mg, yield: 48%) as a yellow solid. ESI-MS [M + H] ⁺: 628.2.

Synthesis of tert-butyl (1- (7-isopropyl-4- ( (2- (3- (4-methylpiperazin-1-yl) -1H-pyrazol-1-yl) benzyl) amino) imidazo [2, 1-f] [1, 2, 4] triazin-2-yl) piperidin-4-yl) carbamate

A mixture of tert-butyl (1- (4- ( (2- (3- (4-methylpiperazin-1-yl) -1H-pyrazol-1-yl) benzyl) amino) -7- (prop-1-en-2-yl) imidazo [2, 1-f] [1, 2, 4] triazin-2-yl) piperidin-4-yl) carbamate (60 mg, 0.1 mmol) and 10 %Pd/C (20 mg) in MeOH (10 mL) was stirred at room temperature for 0.5h under H₂. The reaction mixture was filtered and the filtrate was concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 20/1) to give the product tert-butyl (1- (7-isopropyl-4- ( (2- (3- (4-methylpiperazin-1-yl) -1H-pyrazol-1-yl) benzyl) amino) imidazo [2, 1 -f][1, 2, 4] triazin-2-yl) piperidin-4-yl) carbamate (40 mg, yield: 64%) as a white solid. ESI-MS [M + H] ⁺: 630.2.

Synthesis of 2- (4-aminopiperidin-1-yl) -7-isopropyl-N- (2- (3- (4-methylpiperazin-1-yl) -1H-pyrazol-1-yl) benzyl) imidazo [2, 1-f] [1, 2, 4] triazin-4-amine

To a mixture of tert-butyl (1- (7-isopropyl-4- ( (2- (3- (4-methylpiperazin-1-yl) -1H-pyrazol-1-yl) benzyl) amino) imidazo [2, 1-f] [1, 2, 4] triazin-2-yl) piperidin-4-yl) carbamate (40 mg, 0.06 mmol) in MeOH (2 mL) was added HCl (4M solution in 1, 4-dioxane, 2 mL) . The reaction mixture was stirred at room temperature for 1h. The reaction mixture was quenched with NH₃ (7M solution in MeOH, 2 mL) and concentrated in vacuo to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 10/1) to give the product 2- (4-aminopiperidin-1-yl) -7-isopropyl-N- (2- (3- (4-methylpiperazin-1-yl) -1H-pyrazol-1-yl) ben zyl) imidazo [2, 1-f] [1, 2, 4] triazin-4-amine (20 mg, yield: 63%) as a white solid.

ESI-MS [M +H] ⁺: 530.2.

¹H NMR (400 MHz, Methanol-d₄) δ 7.74 (d, J = 2.6 Hz, 1H) , 7.62 –7.55 (m, 1H) , 7.45 –7.33 (m, 3H) , 7.11 (s, 1H) , 6.05 (d, J = 2.6 Hz, 1H) , 4.78 (s, 2H) , 4.53 (d, J = 13.3 Hz, 2H) , 3.31 –3.22 (m, 5H) , 2.94 –2.82 (m, 3H) , 2.61 –2.51 (m, 4H) , 2.34 (s, 3H) , 1.86 (d, J = 9.8 Hz, 2H) , 1.44 –1.20 (m, 8H) .

2- (4-aminopiperidin-1-yl) -7-isopropyl-N- (2- (1-methyl-1H-pyrazol-5-yl) benzyl) imidazo [2, 1-f] [1, 2, 4] triazin-4-amine

Synthesis of 2- (4-aminopiperidin-1-yl) -7-isopropyl-N- (2- (1-methyl-1H-pyrazol-5-yl) benzyl) imidazo [2, 1-f] [1, 2, 4] triazin-4-amine

Synthesis of 2- (1-methyl-1H-pyrazol-5-yl) benzonitrile

To a mixture of 2-bromobenzonitrile (1.10 g, 6.08 mmol) , (1-methyl-1H-pyrazol-5-yl) boronic acid (1.53 mg, 12.16 mmol) and Na₂CO₃ (1.93 g, 18.24 mmol) in DME (25 mL) and water (2.5 mL) was added Pd (PPh₃) ₄ (381 mg, 0.33 mmol) . The reaction mixture was stirred at 90℃for 16h under N₂. The reaction was cooled to room temperature. The mixture was filtered throughand the filter cake was washed with DCM/MeOH (10/1, 30 mL) . The filtrate was concentrated to give the crude, which was purified by column chromatography (eluent: DCM/MeOH = 30/1) to give 2- (1-methyl-1H-pyrazol-5-yl) benzonitrile (450 mg, yield: 40.4%) as a yellow oil. ESI-MS [M +H] ⁺: 184.1.

Synthesis of (2- (1-methyl-1H-pyrazol-5-yl) phenyl) methanamine

To a mixture of 2- (1-methyl-1H-pyrazol-5-yl) nicotinonitrile (450 mg, 2.46 mmol) in NH₃ (7M solution in MeOH, 5 mL) was added Raney Ni (50 mg) . The reaction mixture was stirred at room temperature for 3h under H₂. The reaction mixture was filtered throughand the filter cake was washed with DCM/MeOH (10/1, 30 mL) . The filtrate was concentrated to give the crude, which was purified by column chromatography (eluent: DCM/MeOH = 10/1) to give (2- (1-methyl-1H-pyrazol-5-yl) phenyl) methanamine (320 mg, yield: 69.6%) as a yellow oil. ESI-MS [M +H] ⁺: 188.1.

Synthesis of 7-bromo-2-chloro-N- (2- (1-methyl-1H-pyrazol-5-yl) benzyl) imidazo [2, 1-f] [1,2, 4] triazin-4-amine

A mixture of 7-bromo-2, 4-dichloroimidazo [2, 1-f] [1, 2, 4] triazine (242 mg, 0.91 mmol) , (2- (1-methyl-1H-pyrazol-5-yl) phenyl) methanamine (170 mg, 0.91 mmol ) and DIPEA (587 mg, 4.55 mmol) in IPA (10 mL) was stirred at room temperature for 3h. The reaction mixture was concentrated to give the crude, which was purified by column chromatography (eluent: DCM/MeOH = 20/1) to give 7-bromo-2-chloro-N- (2- (1-methyl-1H-pyrazol-5-yl) benzyl) imidazo [2, 1-f] [1, 2, 4] triazin-4-amine (170 mg, yield: 60%) as a yellow solid. ESI-MS [M + H] ⁺: 418.2.

Synthesis of 2-chloro-N- (2- (1-methyl-1H-pyrazol-5-yl) benzyl) -7- (prop-1-en-2-yl) imidazo [2, 1-f] [1, 2, 4] triazin-4-amine

A mixture of 7-bromo-2-chloro-N- (2- (1-methyl-1H-pyrazol-5-yl) benzyl) imidazo [2, 1-f] [1, 2, 4] triazin-4-amine (170 mg, 0.41 mmol) , 4, 4, 5, 5-tetramethyl-2- (prop-1-en-2-yl) -1,3, 2-dioxaborolane (344 mg, 2.05 mmol) , Pd (dppf) Cl₂ (30 mg, 0.041 mmol) and Cs₂CO₃ (401 mg, 1.2 mmol) in dioxane/H₂O (10 mL/1 mL) was stirred at 100℃ for 16h under N₂. The reaction mixture was cooled to room temperature. The mixture was filtered throughand the filter cake was washed with DCM/MeOH (10/1, 20 mL) . The filtrate was concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 30/1) to give 2-chloro-N- (2- (1-methyl-1H-pyrazol-5-yl) benzyl) -7- (prop-1-en-2-yl) imidazo [2, 1-f] [1, 2, 4] tria zin-4-amine (80 mg, yield: 51.6%) as a yellow oil. ESI-MS [M +H] ⁺: 380.1.

Synthesis of tert-butyl (1- (4- ( (2- (1-methyl-1H-pyrazol-5-yl) benzyl) amino) -7- (prop-1-en-2-yl) imidazo [2, 1-f] [1, 2, 4] triazin-2-yl) piperidin-4-yl) carbamate

A mixture of 2-chloro-N- ( (2- (1-methyl-1H-pyrazol-5-yl) pyridin-3-yl) methyl) -7- (prop-1-en-2-yl) imidazo [2, 1-f] [1, 2, 4] triazin-4-amine (80 mg, 0.21 mmol) , tert-butyl piperidin-4-ylcarbamate (50 mg, 0.25 mmol) and DIPEA (81 mg, 0.63 mmol) in i-PrOH (4 mL) was irradiated in microwave at 140℃ for 10h. The reaction mixture was concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 20/1) to give tert-butyl (1- (4- ( (2- (1-methyl-1H-pyrazol-5-yl) benzyl) amino) -7- (prop-1-en-2-yl) imidazo [2, 1-f] [1, 2, 4] triazin-2-yl) piperidin-4-yl) carbamate (50 mg, yield: 43.9%) as a yellow solid. ESI-MS [M +H] ⁺: 544.3.

Synthesis of tert-butyl (1- (7-isopropyl-4- ( (2- (1-methyl-1H-pyrazol-5-yl) benzyl) amino) imidazo [2, 1-f] [1, 2, 4] triazin-2-yl) piperidin-4-yl) carbamate

A mixture of tert-butyl (1- (4- ( (2- (1-methyl-1H-pyrazol-5-yl) benzyl) amino) -7- (prop-1-en-2-yl) imidazo [2, 1-f] [1, 2, 4] triazin-2-yl) piperidin-4-yl) carbamate (50 mg, 0.092 mmol) and 10 %Pd/C (10 mg) in MeOH (10 mL) was stirred at room temperature for 0.5h under H₂. The reaction mixture was filtered and the filtrate was concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 20/1) to give the product tert-butyl (1- (7-isopropyl-4- ( (2- (1-methyl-1H-pyrazol-5-yl) benzyl) amino) imidazo [2, 1-f] [1, 2, 4] triazin-2-yl) piperidin-4-yl) carbamate (25 mg, yield: 56%) as a white solid. ESI-MS [M + H] ⁺: 546.2.

To a mixture of tert-butyl (1- (7-isopropyl-4- ( (2- (1-methyl-1H-pyrazol-5-yl) benzyl) amino) imidazo [2, 1-f] [1, 2, 4] triazin-2-yl) piperidin-4-yl) carbamate (25 mg, 0.046 mmol) in MeOH (2 mL) was added HCl (4M solution in 1, 4-dioxane, 2 mL) . The reaction mixture was stirred at room temperature for 1h. The reaction mixture was quenched with NH₃ (7M solution in MeOH, 2 mL) and concentrated in vacuo to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 10/1) to give 2- (4-aminopiperidin-1-yl) -7-isopropyl-N- (2- (1-methyl-1H-pyrazol-5-yl) benzyl) imidazo [2, 1-f] [1, 2, 4] triazin-4-amine (4.6 mg, yield: 22.5%) as a white solid.

ESI-MS [M +H] ⁺: 446.2.

¹H NMR (400 MHz, Methanol-d₄) δ 7.63 –7.58 (m, 1H) , 7.54 –7.48 (m, 2H) , 7.47 –7.41 (m, 1H) , 7.35 –7.30 (m, 1H) , 7.15 –7.12 (m, 1H) , 6.35 –6.31 (m, 1H) , 4.68 –4.61 (m, 2H) , 4.52 –4.44 (m, 2H) , 3.64 (s, 3H) , 3.30 –3.26 (m, 1H) , 3.02 –2.94 (m, 1H) , 2.91 –2.82 (m, 2H) , 1.91 –1.83 (m, 2H) , 1.47 –1.28 (m, 8H) ..

N- ( [2, 3'-bipyridin] -3-ylmethyl) -2- (4-aminopiperidin-1-yl) -7-isopropylimidazo [2, 1-f] [1, 2, 4] triazin-4-amine

Synthesis of N- ( [2, 3'-bipyridin] -3-ylmethyl) -2- (4-aminopiperidin-1-yl) -7-isopropylimidazo [2, 1-f] [1, 2, 4] triazin-4-amine

Synthesis of [2, 3'-bipyridine] -3-carbonitrile

To a mixture of 2-bromonicotinonitrile (400 mg, 2.2 mmol) in DME/H₂O (10 mL/1 mL) was added pyridin-3-ylboronic acid (406 mg, 3.3 mmol) , Pd (PPh₃) ₄ (254 mg, 0.22 mmol) and Na₂CO₃ (466 mg, 4.4 mmol) . The reaction mixture was stirred at 90℃ for 16h under N₂. The reaction was quenched with water (30 mL) and extracted with EtOAc (20 mL x 3) . The combined organic layers were washed with brine (50 mL) , dried over anhydrous Na₂SO₄, and concentrated to give the crude product [2, 3'-bipyridine] -3-carbonitrile (300 mg, crude) as a yellow solid, which was used in the next step without further purification. ESI-MS [M +H] ⁺: 182.2.

Synthesis of [2, 3'-bipyridin] -3-ylmethanamine

To a mixture of [2, 3'-bipyridine] -3-carbonitrile (300 mg, 1.6 mmol) in NH₃ (7M solution in MeOH, 5 mL) was added Raney Ni (50 mg) . The reaction mixture was stirred at room temperature for 3h under H₂. The reaction mixture was filtered throughand the filter cake was washed with DCM/MeOH (10/1, 20 mL) . The filtrate was concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 10/1) to give the product [2, 3'-bipyridin] -3-ylmethanamine (170 mg, yield: 57%) as a yellow oil. ESI-MS [M +H] ⁺: 186.2.

Synthesis of N- ( [2, 3'-bipyridin] -3-ylmethyl) -7-bromo-2-chloroimidazo [2, 1-f] [1, 2, 4] triazin-4-amine

A mixture of [2, 3'-bipyridin] -3-ylmethanamine (170 mg, 0.92 mmol) , DIPEA (348 mg, 2.7 mmol) and 7-bromo-2, 4-dichloroimidazo [2, 1-f] [1, 2, 4] triazine (160 mg, 0.60 mmol) in IPA (10 mL) was stirred at room temperature for 3h. The reaction mixture was concentrated to give the crude, which was purified by column chromatography (eluent: DCM/MeOH = 20/1) to give the product N- ( [2, 3'-bipyridin] -3-ylmethyl) -7-bromo-2-chloroimidazo [2, 1-f] [1, 2, 4] triazin-4-amine (200 mg, yield: 80%) as a yellow solid. ESI-MS [M + H] ⁺: 416.2.

Synthesis of N- ( [2, 3'-bipyridin] -3-ylmethyl) -2-chloro-7- (prop-1-en-2-yl) imidazo [2, 1-f] [1, 2, 4] triazin-4-amine

A mixture of N- ( [2, 3'-bipyridin] -3-ylmethyl) -7-bromo-2-chloroimidazo [2, 1-f] [1, 2, 4] triazin-4-amine (200 mg, 0.5 mmol) , 4, 4, 5, 5-tetramethyl-2- (prop-1-en-2-yl) -1, 3, 2-dioxaborolane (252 mg, 1.5 mmol) , Pd (dppf) Cl₂ (37 mg, 0.05 mmol) and Cs₂CO₃ (489 mg, 1.5 mmol) in dioxane/H₂O (10 mL/1 mL) was stirred at 100℃ for 16h under N₂. The reaction mixture was cooled to room temperature. The mixture was filtered throughand the filter cake was washed with DCM/MeOH (10/1, 30 mL) . The filtrate was concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 30/1) to give the product N- ( [2, 3'-bipyridin] -3-ylmethyl) -2-chloro-7- (prop-1-en-2-yl) imidazo [2, 1-f] [1, 2, 4] triazin-4-amine (140 mg, yield: 74%) as a yellow oil. ESI-MS [M +H] ⁺: 378.2.

Synthesis of tert-butyl (1- (4- ( ( [2, 3'-bipyridin] -3-ylmethyl) amino) -7- (prop-1-en-2-yl) imidazo [2, 1-f] [1, 2, 4] triazin-2-yl) piperidin-4-yl) carbamate

A mixture of N- ( [2, 3'-bipyridin] -3-ylmethyl) -2-chloro-7- (prop-1-en-2-yl) imidazo [2, 1-f] [1, 2, 4] triazin-4-amine (140 mg, 0.4 mmol) , tert-butyl piperidin-4-ylcarbamate (160 mg, 0.8 mmol) and DIPEA (155 mg, 1.2 mmol) in i-PrOH (5 mL) was irradiated in microwave at 140℃for 6h. The reaction mixture was concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 20/1) to give the product tert-butyl (1- (4- ( ( [2, 3'-bipyridin] -3-ylmethyl) amino) -7- (prop-1-en-2-yl) imidazo [2, 1-f] [1, 2, 4] triazin-2-yl) piperidin-4-yl) carbamate (60 mg, yield: 28%) as a yellow solid. ESI-MS [M + H] +: 542.2.

Synthesis of tert-butyl (1- (4- ( ( [2, 3'-bipyridin] -3-ylmethyl) amino) -7-isopropylimidazo [2, 1-f] [1, 2, 4] triazin-2-yl) piperidin-4-yl) carbamate

A mixture of tert-butyl (1- (4- ( ( [2, 3'-bipyridin] -3-ylmethyl) amino) -7- (prop-1-en-2-yl) imidazo [2, 1-f] [1, 2, 4] triazin-2-yl) piperidin-4-yl) carbamate (60 mg, 0.1 mmol) and 10 %Pd/C (10 mg) in MeOH (10 mL) was stirred at room temperature for 1h under H₂. The reaction mixture was filtered and the filtrate was concentrated to give the crude product tert-butyl (1- (4- ( ( [2, 3'-bipyridin] -3-ylmethyl) amino) -7-isopropylimidazo [2, 1-f] [1, 2, 4] triazin-2-yl) piperidin-4-yl) carbamate (40 mg, crude) as a yellow solid. ESI-MS [M + H] ⁺: 544.2.

To a mixture of tert-butyl (1- (4- ( ( [2, 3'-bipyridin] -3-ylmethyl) amino) -7-isopropylimidazo [2, 1-f] [1, 2, 4] triazin-2-yl) piperidin-4-yl) carbamate (40 mg, 0.07 mmol) in MeOH (2 mL) was added HCl (4M solution in 1, 4-dioxane, 2 mL) . The reaction mixture was stirred at room temperature for 1h. The reaction mixture was quenched with NH₃ (7M solution in MeOH, 2 mL) and concentrated in vacuo to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 10/1) to give the product N- ( [2, 3'-bipyridin] -3-ylmethyl) -2- (4-aminopiperidin-1-yl) -7-isopropylimidazo [2, 1-f] [1, 2, 4] triazin-4-amine (15 mg, yield: 48%) as a white solid.

ESI-MS [M +H] ⁺: 444.2.

¹H NMR (400 MHz, Methanol-d₄) δ 8.75 (s, 1H) , 8.67 –8.43 (m, 4H) , 8.05 (t, J = 7.2 Hz, 2H) , 7.56 –7.49 (m, 2H) , 7.17 (s, 1H) , 4.83 (s, 2H) , 4.40 (d, J = 13.4 Hz, 2H) , 3.28 –3.22 (m, 2H) , 2.82 (t, J = 12.2 Hz, 2H) , 1.93 (d, J = 10.9 Hz, 2H) , 1.53 –1.40 (m, 2H) , 1.37 (d, J = 6.9 Hz, 6H) .

2- (4-aminopiperidin-1-yl) -7-isopropyl-N- (2- (4-methylpiperazin-1-yl) benzyl) imidazo [2, 1-f] [1, 2, 4] triazin-4-amine

Synthesis of 2- (4-aminopiperidin-1-yl) -7-isopropyl-N- (2- (4-methylpiperazin-1-yl) benzyl) imidazo [2, 1-f] [1, 2, 4] triazin-4-amine

Synthesis of 2- (4-methylpiperazin-1-yl) benzonitrile

A mixture of 2-fluorobenzonitrile (500 mg, 4.1 mmol) , 1-methylpiperazine (1.6 g, 8.2 mmol) and K₂CO₃ (1.1 g, 8.2 mmol) in DMSO (15 mL) was stirred at 100℃ for 16h under N₂. The reaction was quenched with H₂O (100 mL) and extracted with EtOAc (50 mL x 3) . The combined organic layers were washed with brine, dried over Na₂SO₄, filtered and concentrated to give the product 2- (4-methylpiperazin-1-yl) benzonitrile (350 mg, crude) as a yellow solid, which was used in the next step without further purification. ESI-MS [M +H] ⁺: 202.2.

Synthesis of (2- (4-methylpiperazin-1-yl) phenyl) methanamine

To a mixture of 2- (4-methylpiperazin-1-yl) benzonitrile (350 mg, 1.7 mmol) in NH₃ (7M solution in MeOH, 10 mL) was added Raney Ni (50 mg) . The reaction mixture was stirred at room temperature for 3h under H₂. The reaction mixture was filtered throughand the filter cake was washed with DCM/MeOH (10/1, 20 mL) . The filtrate was concentrated to give the crude, which was purified by column chromatography (eluent: DCM/MeOH = 10/1) to give the product (2- (4-methylpiperazin-1-yl) phenyl) methanamine (300 mg, yield: 86%) as a yellow oil. ESI-MS [M +H] ⁺: 206.2.

Synthesis of 7-bromo-2-chloro-N- (2- (4-methylpiperazin-1-yl) benzyl) imidazo [2, 1-f] [1, 2, 4] triazin-4-amine

A mixture of (2- (4-methylpiperazin-1-yl) phenyl) methanamine (150 mg, 0.7 mmol) , DIPEA (271 mg, 2.1 mmol) and 7-bromo-2, 4-dichloroimidazo [2, 1-f] [1, 2, 4] triazine (133 mg, 0.5 mmol ) in IPA (10 mL) was stirred at room temperature for 3h. The reaction mixture was concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 20/1) to give the product 7-bromo-2-chloro-N- (2- (4-methylpiperazin-1-yl) benzyl) imidazo [2, 1-f] [1, 2, 4] triazin-4-amine (130 mg, yield: 60%) as a yellow solid. ESI-MS [M + H] ⁺: 436.2.

Synthesis of 2-chloro-N- (2- (4-methylpiperazin-1-yl) benzyl) -7- (prop-1-en-2-yl) imidazo [2, 1-f] [1, 2, 4] triazin-4-amine

A mixture of 7-bromo-2-chloro-N- (2- (4-methylpiperazin-1-yl) benzyl) imidazo [2, 1-f] [1, 2, 4] triazin-4-amine (130 mg, 0.3 mmol) , 4, 4, 5, 5-tetramethyl-2- (prop-1-en-2-yl) -1, 3, 2-dioxaborolane (151 mg, 0.9 mmol) , Pd (dppf) Cl₂ (22 mg, 0.03 mmol) and Cs₂CO₃ (293 mg, 0.9 mmol) in dioxane/H₂O (10 mL/1 mL) was stirred at 100℃ for 16h under N₂. The reaction mixture was cooled to room temperature. The mixture was filtered throughand the filter cake was washed with DCM/MeOH (10/1, 30 mL) . The filtrate was concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 30/1) to give the product

2-chloro-N- (2- (4-methylpiperazin-1-yl) benzyl) -7- (prop-1-en-2-yl) imidazo [2, 1-f] [1, 2, 4] triazin-4-amine (100 mg, yield: 25%) as a yellow oil. ESI-MS [M +H] ⁺: 398.2.

Synthesis of tert-butyl (1- (4- ( (2- (4-methylpiperazin-1-yl) benzyl) amino) -7- (prop-1-en-2-yl) imidazo [2, 1-f] [1, 2, 4] triazin-2-yl) piperidin-4-yl) carbamate

A mixture of 2-chloro-N- (2- (4-methylpiperazin-1-yl) benzyl) -7- (prop-1-en-2-yl) imidazo [2, 1-f] [1, 2, 4] triazin-4-amine (100 mg, 0.3 mmol) , tert-butyl piperidin-4-ylcarbamate (120 mg, 0.6 mmol) and DIPEA (77 mg, 0.6 mmol) in i-PrOH (5 mL) was irradiated in microwave at 140℃ for 6h. The reaction mixture was concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 20/1) to give the product tert-butyl (1- (4- ( (2- (4-methylpiperazin-1-yl) benzyl) amino) -7- (prop-1-en-2-yl) imidazo [2, 1-f] [1, 2, 4] triazi n-2-yl) piperidin-4-yl) carbamate (50 mg, yield: 30%) as a yellow solid. ESI-MS [M + H] ⁺: 562.2.

Synthesis of tert-butyl (1- (7-isopropyl-4- ( (2- (4-methylpiperazin-1-yl) benzyl) amino) imidazo [2, 1-f] [1, 2, 4] triazin-2-yl) piperidin-4-yl) carbamate

A mixture of tert-butyl (1- (4- ( (2- (4-methylpiperazin-1-yl) benzyl) amino) -7- (prop-1-en-2-yl) imidazo [2, 1-f] [1, 2, 4] triazin-2-yl) piperidin-4-yl) carbamate (50 mg, 0.09 mmol) and 10 %Pd/C (10 mg) in MeOH (5 mL) was stirred at room temperature for 1h under H₂. The reaction mixture was filtered and the filtrate was concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 20/1) to give the product tert-butyl (1- (7-isopropyl-4- ( (2- (4-methylpiperazin-1-yl) benzyl) amino) imidazo [2, 1-f] [1, 2, 4] triazin-2-yl) piperidin-4-yl) carbamate (35 mg, yield: 51%) as a white solid. ESI-MS [M +H] ⁺: 564.2

To a mixture of tert-butyl (1- (7-isopropyl-4- ( (2- (4-methylpiperazin-1-yl) benzyl) amino) imidazo [2, 1-f] [1, 2, 4] triazin-2-yl) piperidin-4-yl) carbamate (35 mg, 0.06 mmol) in MeOH (2 mL) was added HCl (4M solution in 1, 4-dioxane, 2 mL) . The reaction mixture was stirred at room temperature for 1h. The reaction mixture was quenched with NH₃ (7M solution in MeOH, 2 mL) and concentrated in vacuo to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 10/1) to give the product 2- (4-aminopiperidin-1-yl) -7-isopropyl-N- (2- (4-methylpiperazin-1-yl) benzyl) imidazo [2, 1-f] [1, 2, 4] triazin-4-amine (20 mg, yield: 72%) as a white solid.

ESI-MS [M +H] ⁺: 464.2.

¹H NMR (400 MHz, Methanol-d₄) δ 7.36 (d, J = 7.6 Hz, 1H) , 7.29 –7.16 (m, 2H) , 7.13 (s, 1H) , 7.08 –7.04 (m, 1H) , 4.82 (d, J = 5.0 Hz, 2H) , 4.62 (d, J = 13.6 Hz, 2H) , 3.28 –3.18 (m, 2H) , 2.97 (t, J = 4.8 Hz, 4H) , 2.94 –2.84 (m, 2H) , 2.64 (s, 4H) , 2.35 (s, 3H) , 1.93 (d, J = 9.7 Hz, 2H) , 1.54 –1.40 (m, 2H) , 1.35 (d, J = 6.9 Hz, 6H) .

2- (4-aminopiperidin-1-yl) -N- (2- (3- (dimethylamino) -1H-pyrazol-1-yl) benzyl) -7-isopropylimidazo [2, 1-f] [1, 2, 4] triazin-4-amine

Synthesis of 2- (4-aminopiperidin-1-yl) -N- (2- (3- (dimethylamino) -1H-pyrazol-1-yl) benzyl) -7-isopropylimidazo [2, 1-f] [1, 2, 4] triazin-4-amine

Synthesis of N, N-dimethyl-1H-pyrazol-3-amine

To a mixture of 1H-pyrazol-3-amine (500 mg, 6.0 mmol) in MeOH (20 mL) was added polyformaldehyde (900 mg, 30.0 mmol) at room temperature. The mixture was stirred at room temperature for 0.5h under N₂. Then NaBH₃CN (756 mg, 12.0 mmol) was added at 0℃. The reaction mixture was stirred at room temperature for 16h. The reaction was quenched with saturated aqueous NH₄Cl (30 mL) and extracted with EtOAc (30 mL x 3) . The combined organic layers were washed with brine, dried over Na₂SO₄, filtered and concentrated to give the product N, N-dimethyl-1H-pyrazol-3-amine (200 mg, crude) as a yellow solid, which was used in the next step without further purification. ESI-MS [M +H] ⁺: 112.2.

Synthesis of 2- (3- (dimethylamino) -1H-pyrazol-1-yl) benzonitrile

To a mixture of N, N-dimethyl-1H-pyrazol-3-amine (200 mg, 1.8 mmol) in DMF (10 mL) was added 2-fluorobenzonitrile (436 mg, 3.6 mmol) and Cs₂CO₃ (1.8 g, 5.4 mmol) at room temperature. The mixture was stirred at 80℃ for 2h under N₂. The reaction was quenched with H₂O (50 mL) and extracted with EtOAc (30 mL x 3) . The combined organic layers were washed with brine, dried over Na₂SO₄, filtered and concentrated to give the product 2- (3- (dimethylamino) -1H-pyrazol-1-yl) benzonitrile (200 mg, crude) as a yellow solid, which was used in the next step without further purification. ESI-MS [M +H] ⁺: 213.2.

Synthesis of 1- (2- (aminomethyl) phenyl) -N, N-dimethyl-1H-pyrazol-3-amine

To a mixture of 2- (3- (dimethylamino) -1H-pyrazol-1-yl) benzonitrile (200 mg, 0.9 mmol) in NH₃ (7M solution in MeOH, 5 mL) was added Raney Ni (50 mg) . The reaction mixture was stirred at room temperature for 2h under H₂. The reaction mixture was filtered throughand the filter cake was washed with DCM/MeOH (10/1, 20 mL) . The filtrate was concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 10/1) to give the product 1- (2- (aminomethyl) phenyl) -N, N-dimethyl-1H-pyrazol-3-amine (180 mg, yield: 93%) as a yellow oil. ESI-MS [M +H] ⁺: 217.2.

Synthesis of 7-bromo-2-chloro-N- (2- (3- (dimethylamino) -1H-pyrazol-1-yl) benzyl) imidazo [2, 1-f] [1, 2, 4] triazin-4-amine

A mixture of 1- (2- (aminomethyl) phenyl) -N, N-dimethyl-1H-pyrazol-3-amine (180 mg, 0.8 mmol) , DIPEA (310 mg, 2.4 mmol) and 7-bromo-2, 4-dichloroimidazo [2, 1-f] [1, 2, 4] triazine (133 mg, 0.5 mmol ) in IPA (10 mL) was stirred at room temperature for 3h. The reaction mixture was concentrated to give the crude, which was purified by column chromatography (eluent: DCM/MeOH = 20/1) to give the product 7-bromo-2-chloro-N- (2- (3- (dimethylamino) -1H-pyrazol-1-yl) benzyl) imidazo [2, 1-f] [1, 2, 4] triazin-4-amine (200 mg, yield: 90%) as a yellow solid. ESI-MS [M + H] +: 447.2.

Synthesis of 2-chloro-N- (2- (3- (dimethylamino) -1H-pyrazol-1-yl) benzyl) -7- (prop-1-en-2-yl) imidazo [2, 1-f] [1, 2, 4] triazin-4-amine

A mixture of 7-bromo-2-chloro-N- (2- (3- (dimethylamino) -1H-pyrazol-1-yl) benzyl) imidazo [2, 1-f] [1, 2, 4] triazin-4-amine (200 mg, 0.4 mmol) , 4, 4, 5, 5-tetramethyl-2- (prop-1-en-2-yl) -1, 3, 2-dioxaborolane (202 mg, 1.2 mmol) , Pd (dppf) Cl₂ (29 mg, 0.04 mmol) and Cs₂CO₃ (391 mg, 1.2 mmol) in dioxane/H₂O (10 mL/1 mL) was stirred at 100℃ for 16h under N₂. The reaction mixture was cooled to room temperature. The mixture was filtered throughand the filter cake was washed with DCM/MeOH (10/1, 30 mL) . The filtrate was concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 30/1) to give the product 2-chloro-N- (2- (3- (dimethylamino) -1H-pyrazol-1-yl) benzyl) -7- (prop-1-en-2-yl) imidazo [2, 1-f] [1, 2, 4] triazin-4-amine (100 mg, yield: 61%) as a yellow oil. ESI-MS [M +H] ⁺: 409.2.

Synthesis of tert-butyl (1- (4- ( (2- (3- (dimethylamino) -1H-pyrazol-1-yl) benzyl) amino) -7- (prop-1-en-2-yl) imidazo [2, 1-f] [1, 2, 4] triazin-2-yl) piperidin-4-yl) carbamate

A mixture of 2-chloro-N- (2- (3- (dimethylamino) -1H-pyrazol-1-yl) benzyl) -7- (prop-1-en-2-yl) imidazo [2, 1-f] [1, 2, 4] triazin-4-amine (100 mg, 0.2 mmol) , tert-butyl piperidin-4-ylcarbamate (80 mg, 0.4 mmol) and DIPEA (77 mg, 0.6 mmol) in i-PrOH (5 mL) was irradiated in microwave at 140℃ for 3h. The reaction mixture was concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 20/1) to give the product tert-butyl (1- (4- ( (2- (3- (dimethylamino) -1H-pyrazol-1-yl) benzyl) amino) -7- (prop-1-en-2-yl) imidazo [2, 1-f ] [1, 2, 4] triazin-2-yl) piperidin-4-yl) carbamate (60 mg, yield: 43%) as a yellow solid. ESI-MS [M + H] ⁺: 573.2.

Synthesis of tert-butyl (1- (4- ( (2- (3- (dimethylamino) -1H-pyrazol-1-yl) benzyl) amino) -7-isopropylimidazo [2, 1-f] [1, 2, 4] triazin-2-yl) piperidin-4-yl) carbamate

A mixture of tert-butyl (1- (4- ( (2- (3- (dimethylamino) -1H-pyrazol-1-yl) benzyl) amino) -7-(prop-1-en-2-yl) imidazo [2, 1-f] [1, 2, 4] triazin-2-yl) piperidin-4-yl) carbamate (60 mg, 0.1 mmol) and 10 %Pd/C (10 mg) in MeOH (5 mL) was stirred at room temperature for 1h under H₂. The reaction mixture was filtered and the filtrate was concentrated to give the crude product tert-butyl (1- (4- ( (2- (3- (dimethylamino) -1H-pyrazol-1-yl) benzyl) amino) -7-isopropylimidazo [2, 1-f] [1, 2, 4 ]triazin-2-yl) piperidin-4-yl) carbamate (40 mg, crude) as a yellow solid. ESI-MS [M + H] ⁺: 575.2.

To a mixture of tert-butyl (1- (4- ( (2- (3- (dimethylamino) -1H-pyrazol-1-yl) benzyl) amino) -7-isopropylimidazo [2, 1-f] [1, 2, 4] triazin-2-yl) piperidin-4-yl) carbamate (40 mg, 0.07 mmol) in MeOH (2 mL) was added HCl (4M solution in 1, 4-dioxane, 2 mL) . The reaction mixture was stirred at room temperature for 1h. The reaction mixture was quenched with NH₃ (7M solution in MeOH, 2 mL) and concentrated in vacuo to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 10/1) to give the product 2- (4-aminopiperidin-1-yl) -N- (2- (3- (dimethylamino) -1H-pyrazol-1-yl) benzyl) -7-isopropylimidazo [2, 1-f] [1, 2, 4] triazin-4-amine (22 mg, yield: 66%) as a white solid.

ESI-MS [M +H] ⁺: 475.4.

¹H NMR (400 MHz, Methanol-d₄) δ 7.63 (d, J = 2.6 Hz, 1H) , 7.51 (d, J = 6.8 Hz, 1H) , 7.39 –7.25 (m, 3H) , 7.07 (s, 1H) , 5.89 (d, J = 2.6 Hz, 1H) , 4.77 (d, J = 3.7 Hz, 2H) , 4.56 (d, J = 13.8 Hz, 2H) , 3.23 –3.15 (m, 2H) , 2.90 –2.77 (m, 8H) , 1.92 (d, J = 9.7 Hz, 2H) , 1.48 –1.35 (m, 2H) , 1.31 (d, J = 6.9 Hz, 6H) .

2- (4-aminopiperidin-1-yl) -N- ( (6'- (dimethylamino) - [2, 3'-bipyridin] -3-yl) methyl) -7-isopropylimidazo [2, 1-f] [1, 2, 4] triazin-4-amine

Synthesis of 2- (4-aminopiperidin-1-yl) -N- ( (6'- (dimethylamino) - [2, 3'-bipyridin] -3-yl) methyl) -7-isopropylimidazo [2, 1-f] [1, 2, 4] triazin-4-amine

Synthesis of 7-bromo-2-chloro-N- ( (6'- (dimethylamino) - [2, 3'-bipyridin] -3-yl) methyl) imidazo [2, 1-f] [1, 2, 4] triazin-4-amine

A mixture of 7-bromo-2, 4-dichloroimidazo [2, 1-f] [1, 2, 4] triazine (200 mg, 0.8 mmol) , DIPEA (310 mg, 2.4 mmol) and 3- (aminomethyl) -N, N-dimethyl- [2, 3'-bipyridin] -6'-amine (228 mg, 1.0 mmol ) in IPA (10 mL) was stirred at room temperature for 3h. The reaction mixture was concentrated to give the crude, which was purified by column chromatography (eluent: DCM/MeOH = 20/1) to give the product 7-bromo-2-chloro-N- ( (6'- (dimethylamino) - [2, 3'-bipyridin] -3-yl) methyl) imidazo [2, 1-f] [1, 2, 4] tr iazin-4-amine (200 mg, yield: 55%) as a yellow solid. ESI-MS [M + H] ⁺: 459.2.

Synthesis of 2-chloro-N- ( (6'- (dimethylamino) - [2, 3'-bipyridin] -3-yl) methyl) -7- (prop-1-en-2-yl) imidazo [2, 1-f] [1, 2, 4] triazin-4-amine

A mixture of 7-bromo-2-chloro-N- ( (6'- (dimethylamino) - [2, 3'-bipyridin] -3-yl) methyl) imidazo [2, 1-f] [1, 2, 4] triazin-4-amine (200 mg, 0.4 mmol) , 4, 4, 5, 5-tetramethyl-2- (prop-1-en-2-yl) -1, 3, 2-dioxaborolane (201 mg, 1.2 mmol) , Pd (dppf) Cl₂ (29 mg, 0.04 mmol) and Cs₂CO₃ (391 mg, 1.2 mmol) in dioxane/H₂O (10 mL/1 mL) was stirred at 100℃ for 16h under N₂. The reaction mixture was cooled to room temperature. The mixture was filtered throughand the filter cake was washed with DCM/MeOH (10/1, 20 mL) . The filtrate was concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 30/1) to give the product 2-chloro-N- ( (6'- (dimethylamino) - [2, 3'-bipyridin] -3-yl) methyl) -7- (prop-1-en-2-yl) imidazo [2, 1-f] [1, 2, 4] triazin-4-amine (120 mg, yield: 71%) as a yellow oil.

ESI-MS [M +H] ⁺: 421.2.

Synthesis of tert-butyl (1- (4- ( ( (6'- (dimethylamino) - [2, 3'-bipyridin] -3-yl) methyl) amino) -7- (prop-1-en-2-yl) imidazo [2, 1-f] [1, 2, 4] triazin-2-yl) piperidin-4-yl) carbamate

A mixture of 2-chloro-N- ( (6'- (dimethylamino) - [2, 3'-bipyridin] -3-yl) methyl) -7- (prop-1-en-2-yl) imidazo [2, 1-f] [1, 2, 4] triazin-4-amine (120 mg, 0.3 mmol) , piperidin-4-amine (120 mg, 0.6 mmol) and DIPEA (116 mg, 0.9 mmol) in i-PrOH (5 mL) was irradiated in microwave at 140℃ for 3h. The reaction mixture was concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 20/1) to give the product tert-butyl

(1- (4- ( ( (6'- (dimethylamino) - [2, 3'-bipyridin] -3-yl) methyl) amino) -7- (prop-1-en-2-yl) imidazo [2, 1-f] [1, 2, 4] triazin-2-yl) piperidin-4-yl) carbamate (70 mg, yield: 40%) as a yellow solid. ESI-MS [M + H] ⁺: 585.2.

Synthesis of tert-butyl (1- (4- ( ( (6'- (dimethylamino) - [2, 3'-bipyridin] -3-yl) methyl) amino) -7-isopropylimidazo [2, 1-f] [1, 2, 4] triazin-2-yl) piperidin-4-yl) carbamate

A mixture of tert-butyl (1- (4- ( ( (6'- (dimethylamino) - [2, 3'-bipyridin] -3-yl) methyl) amino) -7- (prop-1-en-2-yl) imidazo [2, 1-f] [1, 2, 4] triazin-2-yl) piperidin-4-yl) carbamate (70 mg, 0.1 mmol) and 10%Pd/C (10 mg) in MeOH (5 mL) was stirred at room temperature for 0.5h under H₂. The reaction mixture was filtered and the filtrate was concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 20/1) to give the product tert-butyl (1- (4- ( ( (6'- (dimethylamino) - [2, 3'-bipyridin] -3-yl) methyl) amino) -7-isopropylimidazo [2, 1-f] [1, 2, 4] triazin-2-yl) piperidin-4-yl) car bamate (50 mg, yield: 85%) as a white solid. ESI-MS [M + H] ⁺: 587.2.

To a mixture of tert-butyl (1- (4- ( ( (6'- (dimethylamino) - [2, 3'-bipyridin] -3-yl) methyl) amino) -7 -isopropylimidazo [2, 1-f] [1, 2, 4] triazin-2-yl) piperidin-4-yl) carbamate (50 mg, 0.09 mmol) in MeOH (2 mL) was added HCl (4M solution in 1, 4-dioxane, 2 mL) . The reaction mixture was stirred at room temperature for 1h. The reaction mixture was quenched with NH₃ (7M solution in MeOH, 2 mL) and concentrated in vacuo to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 10/1) to give the product 2- (4-aminopiperidin-1-yl) -N- ( (6'- (dimethylamino) - [2, 3'-bipyridin] -3-yl) methyl) -7-isopropylimidazo [2, 1-f] [1, 2, 4] triazin-4-amine (21 mg, yield: 48%) as a white solid.

ESI-MS [M +H] ⁺: 487.2.

¹H NMR (400 MHz, Methanol-d₄) δ 8.66 (d, J = 4.3 Hz, 1H) , 8.22 –8.14 (m, 3H) , 7.60 (t, J =6.3 Hz, 2H) , 7.27 (d, J = 9.5 Hz, 1H) , 4.95 (s, 2H) , 4.58 (d, J = 13.5 Hz, 2H) , 3.50 –3.33 (m, 8H) , 3.00 (t, J = 12.3 Hz, 2H) , 2.05 (d, J = 10.2 Hz, 2H) , 1.58 –1.52 (m, 2H) , 1.40 (d, J = 6.9 Hz, 6H) .

Example 2 Biological activity

Materials

Human CDKs, cyclins and other partner proteins were expressed in insect cell, purified individually, reconstituted and then purified to homogeneity before being used for kinase activity assay. Fluorescence-labelled substrate peptides used in the assays are listed in Table 1.

Table 1. List of CDKs peptides used in kinase assay

Methods

Kinase activity of CDKs were determined by mobility shift assay (MSA) , in which the formation of a phosphorylated fluorescence-labelled peptide in reaction mixture was monitored through capillary electrophoresis in a microfluidic environment. Kinase reaction was carried out in a 384-well plate with a total volume of 12 μl, containing 20 mM MES, pH 6.75, 0.01%Tween20, 0.05 mg/ml BSA, 6 mM MgCl₂, 2 μM substrate peptide, 2 mM ATP, 3 nM CDK/Cyclin, 2%DMSO and compound of 10-dose 3x serial dilution starting from 10 μM. The mixtures were incubated at 27℃ for 40 min before being quenched with 4 μl 80 mM EDTA, then read on a LabChip EZ Reader Ⅱ (Caliper Life Science) .

IC₅₀ of compound for CDKs was calculated by Prism (GraphPad) using a four-parameter nonlinear curve fit.

The CDK inhibition results (IC₅₀) without or with pre-incubation are summarized in Table 2. The CDK may be CDK7.

Table 2. List of CDK inhibition

For evaluating the CDK inhibitory activity of the present application, the following ranges for the IC50 [nM] were applied:

A: IC50 ≤ 100 nM;

B:100 nM < IC50 ≤ 500 nM;

C: 500 nM < IC50 ≤ 1000 nM;

D: 1000 nM < IC50 ≤ 6000 nM;

E: 6000 nM < IC50.

Example 3 Preparation of Compounds

N- (2- (2H-pyrazolo [3, 4-c] pyridin-2-yl) benzyl) -2- (4-aminopiperidin-1-yl) -9-isopropyl-9H-purin-6-amine

Synthesis of N- (2- (2H-pyrazolo [3, 4-c] pyridin-2-yl) benzyl) -2- (4-aminopiperidin-1-yl) -9 -isopropyl-9H-purin-6-amine

Synthesis of 2- (2H-pyrazolo [3, 4-c] pyridin-2-yl) benzonitrile

To a solution of 2-fluorobenzonitrile (1.21 g, 10.00 mmol) in DMF (150 mL) were added 2H-pyrazolo [3, 4-c] pyridine (1.19 g, 10.00 mmol) and K₂CO₃ (2.76 g, 20.00 mmol) , the mixture was stirred at 80℃ for 6hrs, The reaction was poured into water (100ml) , solid precipitation and filtered, give 2- (2H-pyrazolo [3, 4-c] pyridin-2-yl) benzonitrile (0.82 g, 3.72 mmol, 37.23%yield) and 2- (1H-pyrazolo [3, 4-c] pyridin-1-yl) benzonitrile (0.42 g, 1.91 mmol, 19.07%yield) as a white solid .

ESI-MS [M+H] + : 221.2

Synthesis of (2- (2H-pyrazolo [3, 4-c] pyridin-2-yl) phenyl) methanamine

To a solution of 2- (3- (methylamino) -1H-pyrazol-1-yl) benzonitrile (660.69 mg, 3.0 mmol) in MeOH (50 mL) were added Raney Ni (100 mg) , keep on Hydrogen environment and stirred at room temperature for 4hrs, filtered and concentrated to give (2- (2H-pyrazolo [3, 4-c] pyridin-2-yl) phenyl) methanamine (395 mg, 1.76mmol, 58.71%yield) as a light brown liquid.

ESI-MS [M+H] + : 224.3

Synthesis of N- (2- (2H-pyrazolo [3, 4-c] pyridin-2-yl) benzyl) -2-chloro-9-isopropyl-9H-purin-6-amine

To a solution of (2- (2H-pyrazolo [3, 4-c] pyridin-2-yl) phenyl) methanamine (412.17 mg, 1.78 mmol) in EtOH (50 mL) were added 2, 6-dichloro-9-isopropyl-9H-purine (400.00 mg, 1.78 mmol) and TEA (541.46 mg, 5.35 mmol) , the mixture was stirred at 80℃ for 6hrs. The reaction was concentrated to give a residue, and poured into water (50ml) , extracted with EA(50ml*2) , the organic layer was washed with brine (50ml) , dried over Na₂SO₄, filtered and concentrated to give a residue. The residue purified by column chromatography (SiO₂, EA: PE=10%to 100%) to give N- (2- (2H-pyrazolo [3, 4-c] pyridin-2-yl) benzyl) -2-chloro-9-isopropyl-9H-purin-6-amine (450.00 mg, 1.07mol, 60.23%yield) as a light yellow solid. ESI-MS [M+H] + : 419.9

Synthesis of N- (2- (2H-pyrazolo [3, 4-c] pyridin-2-yl) benzyl) -2- (4-aminopiperidin-1-yl) -9-isopropyl-9H-purin-6-amine

To a solution of N- (2- (2H-pyrazolo [3, 4-c] pyridin-2-yl) benzyl) -2-chloro-9-isopropyl -9H-purin-6-amine (209.44 mg, 0.5 mmol) in DMSO (3 mL) were added piperidin-4-amine (55.09 mg, 0.55 mol) and DIEA (193.86 mg, 1.50 mmol) , the mixture was stirred at 160℃ for 6hrs. The reaction was poured into water (5ml) , extracted with DCM and MeOH (10: 1 30ml*5) , the organic layer was washed with water and brine (30ml) , dried over Na₂SO₄, filtered and concentrated to give a residue. The residue purified by column chromatography (SiO₂, MeOH: DCM=0%to 10%) to give N- (2- (2H-pyrazolo [3, 4-c] pyridin-2-yl) benzyl) -2- (4-aminopiperidin-1-yl) -9-isopropyl-9H-puri n-6-amine (88 mg, 182.35 μmol, 36.47%yield) as a white solid.

ESI-MS [M+H] + : 483.5

1H NMR (400 MHz, MeOD) δ 8.66 (s, 1H) , 8.39 (s, 1H) , 8.19-8.18 (m, 1H) , 7.80-7.78 (m, 1H) , 7.73-7.71 (m, 1H) , 7.66 (s, 1H) , 7.55-7.49 (m, 3H) , 4.61-4.57 (m, 3H) , 4.53-4.50 (m, 2H) , 2.81 -2.69 (m, 3H) , 1.76-1.73 (m, 2H) , 1.52-1.50 (m, 6H) , 1.22-1.13 (m, 2H) .

N- (2- (1H-pyrazolo [3, 4-c] pyridin-1-yl) benzyl) -2- (4-aminopiperidin-1-yl) -9-isopropyl-9H-purin-6-amine

Synthesis of N- (2- (1H-pyrazolo [3, 4-c] pyridin-1-yl) benzyl) -2- (4-aminopiperidin-1-yl) -9-isopropyl-9H-purin-6-amine

Synthesis of 2- (1H-pyrazolo [3, 4-c] pyridin-1-yl) benzonitrile

ESI-MS [M+H] + : 221.2

Synthesis of (2- (1H-pyrazolo [3, 4-c] pyridin-1-yl) phenyl) methanamine

To a solution of 2- (1H-pyrazolo [3, 4-c] pyridin-1-yl) benzonitrile (330.34 mg, 1.5 mmol) in MeOH (50 mL) were added Raney Ni (100 mg) , keep on Hydrogen environment and stirred at room temperature for 4hrs, filtered and concentrated to give (2- (1H-pyrazolo [3, 4-c] pyridin-1-yl) phenyl) methanamine (395 mg, 1.76mmol, 58.71%yield) as a light brown liquid.

ESI-MS [M+H] + : 224.3

Synthesis of N- (2- (1H-pyrazolo [3, 4-c] pyridin-1-yl) benzyl) -2-chloro-9-isopropyl-9H-purin-6-amine

To a solution of (2- (1H-pyrazolo [3, 4-c] pyridin-1-yl) phenyl) methanamine (309.12 mg, 1.34 mmol) in EtOH (50 mL) were added 2, 6-dichloro-9-isopropyl-9H-purine (300.00 mg, 1.34 mmol) and TEA (406.09 mg, 4.01 mmol) , the mixture was stirred at 80℃ for 6hrs. The reaction was concentrated to give a residue, and poured into water (50ml) , extracted with EA (50ml*2) , the organic layer was washed with brine (50ml) , dried over Na₂SO₄, filtered and concentrated to give a residue. The residue purified by column chromatography (SiO₂, EA: PE=10%to 100%) to give N- (2- (1H-pyrazolo [3, 4-c] pyridin-1-yl) benzyl) -2-chloro-9-isopropyl-9H-purin-6-amine (280 mg, 668.45 μmol, 49.97%yield) as a light yellow solid. ESI-MS [M+H] + : 419.9

To a solution of N- (2- (1H-pyrazolo [3, 4-c] pyridin-1-yl) benzyl) -2-chloro-9-isopropyl-9H-purin-6-amine (209.44 mg, 0.5 mmol) in DMSO (3 mL) were added piperidin-4-amine (55.09 mg, 0.55 mol) and DIEA (193.86 mg, 1.50 mmol) , the mixture was stirred at 160℃ for 6hrs. The reaction was poured into water (5ml) , extracted with DCM and MeOH (10: 1 30ml*5) , the organic layer was washed with water and brine (30ml) , dried over Na₂SO₄, filtered and concentrated to give a residue. The residue purified by column chromatography (SiO₂, MeOH: DCM=0%to 10%) to give N- (2- (1H-pyrazolo [3, 4-c] pyridin-1-yl) benzyl) -2- (4-aminopiperidin-1-yl) -9-isopropyl-9H-purin-6-amine (88 mg, 182.35 μmol, 36.47%yield) as a white solid.

ESI-MS [M+H] + : 482.6

1H NMR (400 MHz, MeOD) δ 9.22 (s, 1H) , 8.58-8.56 (m, 1H) , 8.08-8.07 (m, 1H) , 7.73-7.69 (m, 3H) , 7.57-7.48 (m, 3H) , 4.71 (s, 2H) , 4.63-4.57 (m, 3H) , 2.84-2.72 (m, 3H) , 1.79-1.76 (m, 2H) , 1.53-1.51 (m, 6H) , 1.24-1.15 (m, 2H) .

2- (4-aminopiperidin-1-yl) -9-isopropyl-N- (2- (pyrrolidin-3-yloxy) benzyl) -9H-purin-6-amine

Synthesis of 2- (4-aminopiperidin-1-yl) -9-isopropyl-N- (2- (pyrrolidin-3-yloxy) benzyl) -9H-purin-6-amine

Synthesis of tert-butyl 3- (2-cyanophenoxy) pyrrolidine-1-carboxylate

To a solution of tert-butyl 3-hydroxypyrrolidine-1-carboxylate (1.0 g, 8.26 mmol) in DMF (10 mL) was added NaH (1.70 g 9.08 mmol) at 0 ℃. The mixture was stirred at RT for 30 mins under N₂.2-fluorobenzonitrile was added to the mixture at 0 ℃. The mixture was stirred at RT for 4 hours under N₂. TLC showed the reaction was completed. The mixture was partitioned between EtOAc (100 mL) and NH₄Cl aqueous solution (100 mL) , the aqueous phase was extracted with EtOAc (100 mL x 2) , the combined extracted phase was washed with water (100 mL) , dried over Na₂SO₄, filtered, concentrated under reduced pressure to give a yellow solid, which was purified by Combi flash to tert-butyl 3- (2-cyanophenoxy) pyrrolidine-1-carboxylate (1.2 g, yield: 50.40 %) as a off-white solid. ESI-MS [M + H] ⁺: 289.4.

Synthesis of tert-butyl 3- (2- (aminomethyl) phenoxy) pyrrolidine-1-carboxylate

To a solution of tert-butyl 3- (2-cyanophenoxy) pyrrolidine-1-carboxylate (1.2 g, 4.16 mmol) in MeOH (20 mL) was added Raney-Ni (0.24 g, 4.16 mmol) and NH₃-H₂O (4.16 mmol) stirred at RT for 15 hours under H₂ (15 Psi) . The reaction mixture was filtered and the filtrated to give tert-butyl 3- (2- (aminomethyl) phenoxy) pyrrolidine-1-carboxylate (0.96 g, yield: 78.90%) . ESI-MS [M + H] ⁺: 293.4.

Synthesis of tert-butyl 3- (2- ( ( (2-chloro-9-isopropyl-9H-purin-6-yl) amino) methyl) phenoxy) pyrrolidine-1-carboxylate

To a solution of 2, 6-dichloro-9-isopropyl-9H-purine (300 mg, 1.30 mmol) , tert-butyl 3- (2- (aminomethyl) phenoxy) pyrrolidine-1-carboxylate (417.53 mg, 1.43 mmol) in EtOH (3 mL) was added TEA (394.11 mg, 3.89 mmol) . The mixture was stirred at 80 ℃ for 8 hours to give a yellow suspension. TLC showed the reaction was completed. The mixture was partitioned between EtOAc (50 mL) and water (50 mL) , the aqueous phase was extracted with EtOAc (50 mL x 2) , the combined extracted phase was washed with water (50 mL) , dried over Na2SO4, filtered, concentrated under reduced pressure to give a off-white oil, which was purified by Combi flash to give tert-butyl 3- (2- ( ( (2-chloro-9-isopropyl-9H-purin-6-yl) amino) methyl) phenoxy) pyrrolidine-1-carboxylate (460.1 mg, yield: 72.76%) as a white solid. ESI-MS [M + H] ⁺: 488.0.

Synthesis of tert-butyl 3- (2- ( ( (2- (4-aminopiperidin-1-yl) -9-isopropyl-9H-purin-6-yl) amino) methyl) phenoxy) pyrrolidine-1-carboxylate

To a solution of 3- (2- ( ( (2-chloro-9-isopropyl-9H-purin-6-yl) amino) methyl) phenoxy) pyrrolidine -1-carboxylate (460 mg, 0.94 mmol) in DMSO (3 mL) was added piperidin-4-amine (100.16 mg, 1.04 mmol) and TEA (286.74 mg, 2.83 mmol) , then stirred at 160 ℃ for 8 hours. The reaction was poured into water (30 mL) , extracted with EtOAc (20 mL*2) , the organic layer was washed with water (20 mL*2) , dried over Na₂SO₄, filtered and concentrated to give a residue. The residue purified by column chromatography to give tert-butyl 3- (2- ( ( (2- (4-aminopiperidin-1-yl) -9-isopropyl-9H-purin-6-yl) amino) methyl) phenoxy) pyrrolidi ne-1-carboxylate (170 mg, yield: 32.68%) as a white solid. ESI-MS [M + H] ⁺: 551.7.

Synthesis of tert-butyl 2- (4-aminopiperidin-1-yl) -9-isopropyl-N- (2- (pyrrolidin-3-yloxy) benzyl) -9H-purin-6-amine

To a solution of tert-butyl 3- (2- ( ( (2- (4-aminopiperidin-1-yl) -9-isopropyl-9H-purin-6-yl) amino) methyl) phenoxy) pyrrolidine-1-carboxylate (170 mg, 0.309 mmol) in MeOH (3 mL) was added HCl in MeOH (3 mL) , then stirred at RT for 2 hours. The reaction was poured into aq. NaHCO₃ (30 mL) , extracted with EtOAc (20 mL*2) , the organic layer was washed with water (20 mL*2) , dried over Na₂SO₄, filtered and concentrated to give a residue. The residue purified by column chromatography to give 2- (4-aminopiperidin-1-yl) -9-isopropyl-N- (2- (pyrrolidin-3-yloxy) benzyl) -9H-purin-6-amine (78.26 mg, yield: 56.26%) as a white solid. ESI-MS [M + H] ⁺: 451.6.

¹H NMR (400 MHz, MeOD) δ 8.01 (s, 1H) , 7.40 (d, J = 7.5 Hz, 1H) , 7.27 (t, J = 7.4 Hz, 1H) , 7.01 (d, J = 8.2 Hz, 1H) , 6.95 (t, J = 7.3 Hz, 1H) , 5.28 (s, 1H) , 4.91 (d, J = 14.1 Hz, 2H) , 4.74 –4.69 (m, 3H) , 3.70 (d, J = 12.9 Hz, 1H) , 3.62 (dd, J = 13.0, 4.4 Hz, 1H) , 3.50 (t, J = 7.4 Hz, 2H) , 3.42 –3.36 (m, 1H) , 2.97 (t, J = 12.7 Hz, 2H) , 2.36 (dd, J = 7.3, 4.6 Hz, 2H) , 2.02 (d, J =11.3 Hz, 2H) , 1.57 (s, 3H) , 1.55 (s, 3H) , 1.52 (d, J = 12.2 Hz, 2H) .

2- (4-aminopiperidin-1-yl) -N- ( (6'- (dimethylamino) - [2, 3'-bipyridin] -3-yl) methyl) -9-isopropyl-9H-purin-6-amine

Synthesis of 2- (4-aminopiperidin-1-yl) -N- ( (6'- (dimethylamino) - [2, 3'-bipyridin] -3-yl) methyl) -9-isopropyl-9H-purin-6-amine

Synthesis of 6'- (dimethylamino) - [2, 3'-bipyridine] -3-carbonitrile

To a mixture of 2-bromopyridine-3-carbonitrile (600 mg, 3.279 mmol) , pyridin-2-ylboronic acid (1088 mg, 6.557 mmol) and Na₂CO₃ (1042 mg, 9.836 mmol) in DME (15 mL) and water (3 mL) was added Pd (PPh₃) ₄ (758 mg, 0.656 mmol) . The mixture was stirred at 90 ℃ for 16 h under N₂. The reaction mixture was cooled to room temperature. The mixture was filtered throughand the filter cake was washed with EA (30 mL) . The filtrate was concentrated to give the crude, which was purified by Prep-TLC (eluent: PE/EA = 3/1) to give 3- (aminomethyl) -N, N-dimethyl- [2, 3'-bipyridin] -6'-amine (480 mg, yield: 65%) as a light yellow solid. ESI-MS [M +H] ⁺: 225.1.

Synthesis of 3- (aminomethyl) -N, N-dimethyl- [2, 3'-bipyridin] -6'-amine

To a mixture of 6'- (dimethylamino) - [2, 3'-bipyridine] -3-carbonitrile (480 mg, 2.140 mmol) in NH₃ (7M solution in MeOH, 10 mL) was added Raney Ni (100 mg) . The reaction mixture was stirred at room temperature for 3h under H₂. The reaction mixture was filtered throughand the filter cake was washed with DCM/MeOH (10/1, 100 mL) . The filtrate was concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/NH₃ in MeOH = 15/1) to give 2-chloro-N- ( (6'- (dimethylamino) - [2, 3'-bipyridin] -3-yl) methyl) -9-isopropyl-9H-purin-6-amine (450 mg, yield: 92%) as a grey solid. ESI-MS [M +H] +: 229.2.

Synthesis of 2-chloro-N- ( (6'- (dimethylamino) - [2, 3'-bipyridin] -3-yl) methyl) -9-isopropyl-9H-purin-6-amine

A mixture of 2, 6-dichloro-9-isopropyl-9H-purine (337 mg, 1.460 mmol) , 3- (aminomethyl) -N, N-dimethyl- [2, 3'-bipyridin] -6'-amine (500 mg, 2.190 mmol) and DIPEA (849 mg, 6.571 mmol) in i-PrOH (10 mL) was stirred at 90 ℃ for 3h. The reaction mixture was concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH =20/1) to give 2-chloro-N- ( (6'- (dimethylamino) - [2, 3'-bipyridin] -3-yl) methyl) -9-isopropyl-9H-purin-6-amine (640 mg, yield: 70%) as a white solid. ESI-MS [M + H] ⁺: 423.2.

Synthesis of tert-butyl (1- (6- ( ( (6'- (dimethylamino) - [2, 3'-bipyridin] -3-yl) methyl) amino) -9-isopropyl -9H-purin-2-yl) piperidin-4-yl) carbamate

A mixture of 2-chloro-N- ( (6'- (dimethylamino) - [2, 3'-bipyridin] -3-yl) methyl) -9-isopropyl-9H-purin-6-amine (320 mg, 0.757 mmol) , tert-butyl piperidin-4-ylcarbamate (303 mg, 1.513 mmol) and DIPEA (293 mg, 2.270 mmol) in i-PrOH (10 mL) was irradiated in microwave at 140 ℃ for 8h. The reaction mixture was concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 16/1) to give tert-butyl (1- (6- ( ( (6'- (dimethylamino) - [2, 3'-bipyridin] -3-yl) methyl) amino) -9-isopropyl-9H-purin-2-yl) piperidin-4-yl) carbamate (350 mg, yield: 79%) as a white solid. ESI-MS [M + H] ⁺: 587.2.

To a mixture of tert-butyl (1- (6- ( ( (6'- (dimethylamino) - [2, 3'-bipyridin] -3-yl) methyl) amino) -9-isopropyl-9H-purin-2-yl) piperidin-4-yl) carbamate (650 mg, 1.108 mmol) in MeOH (5 mL) was added HCl (4M solution in 1, 4-dioxane, 5 mL) . The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with NH₃ (7M solution in MeOH, 5 mL) and concentrated in vacuo to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 10/1) to give 2- (4-aminopiperidin-1-yl) -N- ( (6'- (dimethylamino) - [2, 3'-bipyridin] -3-yl) methyl) -9-isopropyl-9H-purin-6-amine (385 mg, yield: 71%) as a white solid.

ESI-MS [M +H] ⁺: 487.2.

1H NMR (400 MHz, MeOD) δ 8.47 (d, J = 4.5 Hz, 1H) , 8.27 (d, J = 2.2 Hz, 1H) , 7.96 (d, J =7.8 Hz, 1H) , 7.82 (s, 1H) , 7.76 (dd, J = 8.9, 2.4 Hz, 1H) , 7.35 (dd, J = 7.8, 4.9 Hz, 1H) , 6.78 (d, J = 8.9 Hz, 1H) , 4.80 (s, 2H) , 4.68 (t, J = 13.5 Hz, 1H) , 4.55 (d, J = 13.2 Hz, 2H) , 3.17 (s, 6H) , 2.92 (s, 1H) , 2.75 (t, J = 12.8 Hz, 2H) , 1.79 (d, J = 12.1 Hz, 2H) , 1.56 (d, J = 6.8 Hz, 6H) , 1.20 (t, J = 19.6 Hz, 2H) .

2- (4-aminopiperidin-1-yl) -9-isopropyl-N- ( (2- (4-methylpiperazin-1-yl) pyridin-3-yl) methyl) -9H-purin-6-amine

Synthesis of 2- (4-aminopiperidin-1-yl) -9-isopropyl-N- ( (2- (4-methylpiperazin-1-yl) pyridin-3-yl) methyl) -9H-purin-6-amine

Synthesis of 2- (4-methylpiperazin-1-yl) nicotinonitrile

To a solution of 2-fluoronicotinonitrile (1000 mg, 8.19 mmol) in DMF (15 mL) were added 1-methylpiperazine (1.64 g, 16.38 mmol) and Cs₂CO₃ (5.34 g, 16.38 mmol) , the mixture was stirred at 90℃ for 7h. The reaction mixture was filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO₂, 0.5M ammonia methanol solution: DCM=0%to 15%) to give 2- (4-methylpiperazin-1-yl) nicotinonitrile (1.66 g, 8.19 mmol, 100.00%yield, 99.80%purity) as a yellow solid.

ESI-MS [M+H] ⁺: 203.24.

Synthesis of (2- (4-methylpiperazin-1-yl) pyridin-3-yl) methanamine

To a solution of 2- (4-methylpiperazin-1-yl) nicotinonitrile (1.66 g, 8.21 mmol) were added NH₃ (3M in MeOH, 1 mL) and Ni (202.44 mg, 3.45 mmol) , replaced with H₂ three times and the mixture was stirred at RT for 5h. LCMS show the reaction was completed. The reaction mixture was filtered and concentrated to give (2- (4-methylpiperazin-1-yl) pyridin-3-yl) methanamine (1.69 g, crude) as an oil.

ESI-MS [M+H] ⁺: 207.29.

Synthesis of 2, 6-dichloro-9-isopropyl-9H-purine

ESI-MS [M+H] ⁺: 231.16.

Synthesis of 2-chloro-9-isopropyl-N- ( (2- (4-methylpiperazin-1-yl) pyridin-3-yl) methyl) -9H-purin-6-amine

To a solution of 2, 6-dichloro-9-isopropyl-9H-purine (200 mg, 865.50 μmol) in EtOH (10 mL) were added (2- (4-methylpiperazin-1-yl) pyridin-3-yl) methanamine (214.25 mg, 1.04 mmol) and TEA (175.16 mg, 1.73 mmol, 241.43 μL) , the mixture was stirred at 85℃ for 5h. The reaction mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO₂, 0.5M ammonia methanol solution: DCM=0%to 10%) to give 2-chloro-9-isopropyl-N- ( (2- (4-methylpiperazin-1-yl) pyridin-3-yl) methyl) -9H-purin-6-am ine (234 mg, 571.71 μmol, 66.06%yield, 97.95%purity) as a white solid.

ESI-MS [M+H] ⁺: 401.31.

To a solution of 2-chloro-9-isopropyl-N- ( (2- (4-methylpiperazin-1-yl) pyridin-3-yl) methyl) -9H-purin-6-amine (243 mg, 606.13 μmol) in NMP (2 mL) were added piperidin-4-amine (91.07 mg, 909.19 μmol) and DIPEA (156.67 mg, 1.21 mmol, 211.15 μL) , the mixture was stirred at 160℃ for 7h. The reaction mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO₂, 0.5M ammonia methanol solution: DCM=0%to 25%) to give 2- (4-aminopiperidin-1-yl) -9-isopropyl-N- ( (2- (4-methylpiperazin-1-yl) pyridin-3-yl) methyl) -9H-purin-6-amine (123 mg, 264.47 μmol, 43.63%yield, 99.90%purity) as a white solid.

ESI-MS [M+H] ⁺: 465.43.

¹HNMR (400 MHz, MeOD) δ 8.11 (dd, J = 4.9, 1.9 Hz, 1H) , 7.80 (s, 1H) , 7.73 (dd, J = 7.6, 1.8 Hz, 1H) , 6.97 (dd, J = 7.5, 4.9 Hz, 1H) , 4.74 –4.58 (m, 5H) , 3.20 (t, J = 4.9 Hz, 4H) , 2.89 –2.72 (m, 3H) , 2.66 (s, 4H) , 2.36 (s, 3H) , 1.80 –1.71 (m, 2H) , 1.55 (d, J = 6.8 Hz, 6H) , 1.17 (qd, J = 12.2, 4.1 Hz, 2H) .

2- (4-aminopiperidin-1-yl) -N- (2- (3, 4-dimethylpiperazin-1-yl) benzyl) -9-isopropyl-9H-purin-6-amine

Synthesis of 2- (4-aminopiperidin-1-yl) -N- (2- (3, 4-dimethylpiperazin-1-yl) benzyl) -9-isopropyl-9H-purin-6-amine

Synthesis of 2- (3, 4-dimethylpiperazin-1-yl) benzonitrile

To a solution of 2-fluorobenzonitrile (1000 mg, 8.26 mmol) in DMF (15 mL) were added 1, 2-dimethylpiperazine (1.89 g, 16.51 mmol) and Cs₂CO₃ (5.38 g, 16.51 mmol) , the mixture was stirred at 90℃ for 7h. The reaction mixture was filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO₂, MeOH: DCM=0%to 10%) to give 2- (3, 4-dimethylpiperazin-1-yl) benzonitrile (637 mg, 2.72 mmol, 32.99%yield, 92.05%purity) as a yellow solid.

ESI-MS [M+H] ⁺: 216.21.

Synthesis of (2- (3, 4-dimethylpiperazin-1-yl) phenyl) methanamine

To a solution of 2- (3, 4-dimethylpiperazin-1-yl) benzonitrile (637 mg, 2.96 mmol) were added NH₃ (7M in MeOH, 1 mL) and Ni (100 mg, 1.70 mmol) , replaced with H₂ three times and the mixture was stirred at RT for 5h. LCMS show the reaction was completed. The reaction mixture was filtered and concentrated to give (2- (3, 4-dimethylpiperazin-1-yl) phenyl) methanamine (637 mg, crude) as an oil.

ESI-MS [M+H] ⁺: 220.29.

Synthesis of 2, 6-dichloro-9-isopropyl-9H-purine

ESI-MS [M+H] ⁺: 231.16.

Synthesis of 2-chloro-N- (2- (3, 4-dimethylpiperazin-1-yl) benzyl) -9-isopropyl-9H-purin-6-amine

To a solution of 2, 6-dichloro-9-isopropyl-9H-purine (450 mg, 1.95 mmol) in EtOH (20 mL) were added (2- (3, 4-dimethylpiperazin-1-yl) phenyl) methanamine (640.66 mg, 2.92 mmol) and TEA (394.11 mg, 3.89 mmol) , the mixture was stirred at 85℃ for 5h. The reaction mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO₂, 0.5M ammonia methanol solution: DCM=0%to 12%) to give 2-chloro-N- (2- (3, 4-dimethylpiperazin-1-yl) benzyl) -9-isopropyl-9H-purin-6-amine (653 mg, 1.56 mmol, 80.10%yield, 98.88%purity) as a white solid.

ESI-MS [M+H] ⁺: 414.31.

Synthesis of 2- (4-aminopiperidin-1-yl) -N- (2- (3, 4-dimethylpiperazin-1-yl) benzyl) -9-isopropyl -9H-purin-6-amine

To a solution of 2-chloro-N- (2- (3, 4-dimethylpiperazin-1-yl) benzyl) -9-isopropyl-9H-purin-6-amine (200 mg, 483.16 μmol) in NMP (2 mL) were added piperidin-4-amine (72.59 mg, 724.73 μmol) and DIPEA (124.89 mg, 966.31 μmol) , the mixture was stirred at 160℃ for 7h. The reaction mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO₂, 0.5M ammonia methanol solution: DCM=0%to 25%) to give 2- (4-aminopiperidin-1-yl) -N- (2- (3, 4-dimethylpiperazin-1-yl) benzyl) -9-isopropyl-9H-puri n-6-amine (98 mg, 204.70 μmol, 42.37%yield, 99.77%purity) as a white solid.

ESI-MS [M+H] ⁺: 478.44.

¹HNMR (400 MHz, MeOD) δ 7.77 (s, 1H) , 7.37 (dd, J = 7.6, 1.6 Hz, 1H) , 7.27 –7.18 (m, 1H) , 7.15 (dd, J = 8.1, 1.3 Hz, 1H) , 7.04 (td, J = 7.4, 1.3 Hz, 1H) , 4.85 (s, 1H) , 4.76 (d, J = 13.9 Hz, 3H) , 4.67 (h, J = 6.8 Hz, 1H) , 3.04 –2.80 (m, 7H) , 2.61 –2.45 (m, 2H) , 2.33 (s, 4H) , 1.87 –1.78 (m, 2H) , 1.55 (d, J = 6.8 Hz, 6H) , 1.38 –1.21 (m, 2H) , 1.05 (d, J = 6.3 Hz, 3H) .

2- (4-aminopiperidin-1-yl) -N- (2- ( (furan-3-ylmethyl) amino) benzyl) -9-isopropyl-9H-purin-6-amine trifluoroacetic acid salt

Synthesis of 2- (4-aminopiperidin-1-yl) -N- (2- ( (furan-3-ylmethyl) amino) benzyl) -9-isopropyl -9H-purin-6-amine trifluoroacetic acid salt

Synthesis of 2- [ (furan-3-ylmethyl) amino] benzonitrile

A mixture of 2-fluorobenzonitrile (400 mg, 3.30 mmol, 1.00 equiv) , 1- (furan-3-yl) methanamine (385 mg, 3.96 mmol, 1.20 equiv) and potassium carbonate (913 mg, 6.61 mmol, 2.00 equiv) in DMF (4 mL) was stirred for 24 h at 100 ℃. The mixture was allowed to cool down to room temperature and filtered, the filter cake was washed with ethyl acetate (2 x 10 mL) . The filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions: column, C₁₈ column; mobile phase, Acetonitrile in Water, 10%to 100%gradient in 20 min; detector, UV 254 nm to afford 2- [ (furan-3-ylmethyl) amino] benzonitrile (208 mg, 32%yield) as a yellow oil. LCMS (ESI, m/z) : 199 [M+H] ⁺.

Synthesis of 2- (aminomethyl) -N- (furan-3-ylmethyl) aniline

A mixture of 2- [ (furan-3-ylmethyl) amino] benzonitrile (100 mg, 0.504 mmol, 1.00 equiv) and Raney Nickel (4.50 mg) in ammonia (2 mL, 7.00 M in methanol) was stirred for overnight at room temperature under hydrogen atmosphere (2 –3 atm) . The solids were filtered off, the filter cake was washed with methanol (2 x 10 mL) . The filtrate was concentrated under reduced pressure to afford 2- (aminomethyl) -N- (furan-3-ylmethyl) aniline (73 mg, crude) as a yellow oil. LCMS (ESI, m/z) : 203 [M+H] ⁺.

Synthesis of 2-chloro-N- ( {2- [ (furan-3-ylmethyl) amino] phenyl} methyl) -9-isopropylpurin-6-amine

A mixture of 2- (aminomethyl) -N- (furan-3-ylmethyl) aniline (73.0 mg, 0.361 mmol, 1.00 equiv) , 2, 6-dichloro-9-isopropylpurine (83.4 mg, 0.361 mmol, 1.00 equiv) and N, N-diisopropylethylamine (140 mg, 1.08 mmol, 3.00 equiv) in n-buthanol (3 mL) was stirred for overnight at 80 ℃. The mixture was allowed to cool down to room temperature and concentrated under reduced pressure. The residue was purified by Prep-TLC with petroleum ether/ethyl acetate = 1/2 to afford 2-chloro-N- ( {2- [ (furan-3-ylmethyl) amino] phenyl} methyl) -9-isopropylpurin-6-amine (110 mg, 77%yield) as a yellow oil. LCMS (ESI, m/z) : 397 [M+H] ⁺.

Synthesis of 2- (4-aminopiperidin-1-yl) -N- (2- ( (furan-3-ylmethyl) amino) benzyl) -9 -isopropyl-9H-purin-6-amine trifluoroacetic acid salt

A mixture of 2-chloro-N- ( {2- [ (furan-3-ylmethyl) amino] phenyl} methyl) -9-isopropylpurin-6-amine (110 mg, 0.277 mmol, 1.00 equiv) , piperidin-4-amine (83.3 mg, 0.831 mmol, 3.00 equiv) and N, N-diisopropylethylamine (107 mg, 0.831 mmol, 3.00 equiv) in n-buthanol (3 mL) was irradiated with microwave radiation for 5 h at 130 ℃. The mixture was allowed to cool down to room temperature and concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C₁₈ Column, 30*150 mm, 5 μm; Mobile Phase A: Water (0.05%TFA) , Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 5%B to 35%B in 9 min; Wave Length: 254 nm to afford 2- (4-aminopiperidin-1-yl) -N- (2- ( (furan-3-ylmethyl) amino) benzyl) -9-isopropyl-9H-purin-6-am ine trifluoroacetic acid salt (77.5 mg, 49%yield) as an off-white solid. LCMS (ESI, m/z) : 461 [M+H-TFA] ⁺. ¹H-NMR (300 MHz, Methanol-d₄) δ 8.65 (s, 1H) , 7.39 -7.21 (m, 4H) , 6.82 -6.70 (m, 2H) , 6.16 (s, 1H) , 4.86 -4.81 (d, J = 10.0 Hz, 3H) , 4.77 (s, 2H) , 4.21 (s, 2H) , 3.40 - 3.36 (d, J = 8.0 Hz, 1H) , 3.01 -2.96 (m, 2H) , 2.05 -1.98 (d, J = 14.0 Hz, 2H) , 1.65 -1.62 (d, J = 6.0 Hz, 6H) , 1.59 -1.51 (m, 2H) .

2- (4-aminopiperidin-1-yl) -9-isopropyl-N- { [2- (quinolin-4-yl) phenyl] methyl} purin-6-amine trifluoroacetic acid salt

Synthesis of 2- (4-aminopiperidin-1-yl) -9-isopropyl-N- { [2- (quinolin-4-yl) phenyl] methyl} purin-6-amine trifluoroacetic acid salt

Synthesis of tert-butyl N- { [2- (quinolin-4-yl) phenyl] methyl} carbamate

A mixture of 2- { [ (tert-butoxycarbonyl) amino] methyl} phenylboronic acid (500 mg, 1.99 mmol, 1.00 equiv) , 4-bromoquinoline (621 mg, 2.99 mmol, 1.50 equiv) , potassium carbonate (550 mg, 3.98 mmol, 2.00 equiv) , tetrakis (triphenylphosphine) palladium (230 mg, 0.199 mmol, 0.10 equiv) and water (1 mL) in 1, 4-dioxane (5 mL) was stirred for overnight at 100 ℃ under nitrogen atmosphere. The solids were filtered off, the filter cake was washed with 1, 4-dioxane (3 x 5 mL) . The filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions: column, C₁₈ column; mobile phase, MeCN in Water, 10%to 100%gradient in 40 min; detector, UV 254 nm to afford tert-butyl N- { [2- (quinolin-4-yl) phenyl] methyl} carbamate (540 mg, 81%yield) as a white solid. LCMS (ESI, m/z) : 335 [M+H] ⁺.

Synthesis of 1- [2- (quinolin-4-yl) phenyl] methanamine

A mixture of tert-butyl N- { [2- (quinolin-4-yl) phenyl] methyl} carbamate (540 mg, 1.62 mmol, 1.00 equiv) and trifluoroacetic acid (1 mL) in dichloromethane (5 mL) was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure to afford 1- [2- (quinolin-4-yl) phenyl] methanamine (940 mg, crude) as yellow oil. LCMS (ESI, m/z) : 235 [M+H] ⁺.

Synthesis of 2-chloro-9-isopropyl-N- { [2- (quinolin-4-yl) phenyl] methyl} purin-6-amine

A mixture of 1- [2- (quinolin-4-yl) phenyl] methanamine (150 mg, 0.640 mmol, 1.00 equiv) , 2, 6-dichloro-9-isopropylpurine (148 mg, 0.640 mmol, 1.00 equiv) and N, N-diisopropylethylamine (248 mg, 1.92 mmol, 3.00 equiv) in n-butanol (3 mL) was stirred for overnight at 80℃ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with ethyl acetate to afford 2-chloro-9-isopropyl-N- { [2- (quinolin-4-yl) phenyl] methyl} purin-6-amine (190 mg, 69%yield) as a yellow solid. LCMS (ESI, m/z) : 429 [M+H] ⁺.

A 5 mL vial was charged with 2-chloro-9-isopropyl-N- { [2- (quinolin-4-yl) phenyl] methyl} purin-6-amine (180 mg, 0.420 mmol, 1.00 equiv) , piperidin-4-amine (126 mg, 1.26 mmol, 3.00 equiv) , N, N-diisopropylethylamine (163 mg, 1.26 mmol, 3.00 equiv) and n-butanol (2 mL) at room temperature. The final reaction mixture was irradiated with microwave radiation for 5 h at 130 ℃. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions: Column: XSelect CSH Prep C₁₈ OBD Column, 19*250 mm, 5 μm; Mobile Phase A: Water (0.05%TFA) , Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 6%B to 30%B in 7 min; Wave Length: 254 nm to afford 2- (4-aminopiperidin-1-yl) -9-isopropyl-N- { [2- (quinolin-4-yl) phenyl] methyl} purin-6-amine trifluoroacetic acid salt (151.5 mg, 60%yield) as a yellow solid. LCMS (ESI, m/z) : 493 [M+H-TFA] ⁺. ¹H-NMR (300 MHz, DMSO-d₆) δ 8.99 (d, J = 2.0 Hz, 1H) , 8.28 (s, 1H) , 8.06 (d, J = 6.0 Hz, 1H) , 7.94 -7.79 (m, 3H) , 7.75 (d, J = 6.0 Hz, 1H) , 7.60 -7.39 (m, 6H) , 7.28 (d, J =6.0 Hz, 1H) , 4.61 -4.54 (m, 2H) , 4.41 -4.28 (m, 3H) , 3.23 (d, J = 2.0 Hz, 1H) , 2.77 -2.69 (m, 2H) , 1.86 -1.78 (m, 2H) , 1.48 (d, J = 2.0 Hz, 6H) , 1.34 -1.14 (m, 2H) .

2- (4-aminopiperidin-1-yl) -N- ( (2'- ( (dimethylamino) methyl) - [1, 1'-biphenyl] -2-yl) methyl) -9 -isopropyl-9H-purin-6-amine

Synthesis of 2- (4-aminopiperidin-1-yl) -N- ( (2'- ( (dimethylamino) methyl) - [1, 1'-biphenyl] -2-yl) methyl) -9-isopropyl-9H-purin-6-amine

Synthesis of 2'- ( (dimethylamino) methyl) - [1, 1'-biphenyl] -2-carbonitrile

A mixture of 2-bromobenzonitrile (500 mg, 2.74 mmol, 1.00 equiv) , 2- [ (dimethylamino) methyl] phenylboronic acid (492 mg, 2.74 mmol, 1.00 equiv) , potassium carbonate (1.13 g, 8.24 mmol, 3.00 equiv) and tetrakis (triphenylphosphine) palladium (317 mg, 0.275 mmol, 0.100 equiv) in dioxane (5 mL) and water (1 mL) was stirred for overnight at 100 ℃ under nitrogen atmosphere. The mixture was allowed to cool down to room temperature and filtered, the filter cake was washed with ethyl acetate (2x20 mL) . The filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions: column, C₁₈ silica gel; mobile phase, Acetonitrile in Water, 0%to 100%gradient in 20 min; detector, UV 254 nm to afford 2'- [ (dimethylamino) methyl] - [1, 1'-biphenyl] -2-carbonitrile (400 mg, 62%yield) as a yellow oil.

LCMS (ESI, m/z) : 237 [M+H] ⁺.

Synthesis of 1- {2'- [ (dimethylamino) methyl] - [1, 1'-biphenyl] -2-yl} methanamine

A mixture of 2'- [ (dimethylamino) methyl] - [1, 1'-biphenyl] -2-carbonitrile (200 mg, 0.846 mmol, 1.00equiv) and Raney Nickel (14.5 mg, 0.169 mmol, 0.200 equiv) in ammonia (4 mL, 7.00 M in methanol) was stirred for overnight at room temperature under hydrogen atmosphere. The solids were filtered off, the filter cake was washed with methanol (2 x 10 mL) . The filtrate was concentrated under reduced pressure to afford 1- {2'- [ (dimethylamino) methyl] - [1, 1'-biphenyl] -2-yl} methanamine (201 mg, 99%yield) as a yellow oil. LCMS (ESI, m/z) : 241 [M+H] ⁺.

Synthesis of 2-chloro-N- ( {2'- [ (dimethylamino) methyl] - [1, 1'-biphenyl] -2-yl} methyl) -9-isopropylpurin-6-amine

A mixture of 1- {2'- [ (dimethylamino) methyl] - [1, 1'-biphenyl] -2-yl} methanamine (200 mg, 0.832 mmol, 1.00 equiv) , 2, 6-dichloro-9-isopropylpurine (192 mg, 0.832 mmol, 1.00 equiv) and N, N-diisopropylethylamine (323 mg, 2.49 mmol, 3.00 equiv) in n-buthanol (4 mL) was stirred for overnight at 80 ℃. The mixture was allowed to cool down to room temperature and concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions: column, C₁₈ silica gel; mobile phase, Acetonitrile in Water, 0%to 100%gradient in 20 min; detector, UV 254 nm to afford 2-chloro-N- ( {2'- [ (dimethylamino) methyl] - [1, 1'-biphenyl] -2-yl} methyl) -9-isopropylpurin-6-amine (176 mg, 49%yield) as a yellow oil. LCMS (ESI, m/z) : 435 [M+H] ⁺.

A mixture of 2-chloro-N- ( {2'- [ (dimethylamino) methyl] - [1, 1'-biphenyl] -2-yl} methyl) -9-isopropylpurin-6-amine (176 mg, 0.405 mmol, 1.00 equiv) , piperidin-4-amine (122 mg, 1.22 mmol, 3.00 equiv) and N, N-diisopropylethylamine (157 mg, 1.22 mmol, 3.00 equiv) in n-buthanol (3 mL) was irradiated with microwave radiation for 5 h at 130 ℃. The mixture was allowed to cool down to room temperature and concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH₄HCO₃+0.1%NH₃. H₂O) , Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 25%B to 55%B in 9 min, 55%B; Wave Length: 254 nm to afford 2- (4-aminopiperidin-1-yl) -N- ( {2'- [ (dimethylamino) methyl] - [1, 1'-biphenyl] -2-yl} methyl) -9-isopropylpurin-6-amine (94.2 mg, 46%yield, 98.7 %purity ) as an off-white solid. LCMS (ESI, m/z) : 499 [M+H] ⁺. ¹H-NMR (300 MHz, Chloroform-d) δ7.57 -7.54 (m, 1H) , 7.46 -7.40 (d, 2H) , 7.36 -7.29 (m, 3H) , 7.20 -7.15 (m, 1H) , 7.18 -7.12 (m, 1H) , 6.55 (s, 1H) , 4.78 -4.61 (m, 3H) , 4.23 -4.19 (d, J = 8.0 Hz, 1H) , 3.47 -3.41 (d, J =12.0 Hz, 1H) , 3.01 -2.82 (m, 4H) , 2.62 (s, 2H) , 2.15 (s, 6H) , 1.91 -1.85 (d, J = 12.0 Hz, 2H) , 1.62 -1.45 (m, 6H) , 1.45 –1.31 (m, 2H) .

{1- [2- ( { [2- (4-aminopiperidin-1-yl) -9-isopropylpurin-6-yl] amino} methyl) phenyl] piperidin -3-yl} methanol

Synthesis of {1- [2- ( { [2- (4-aminopiperidin-1-yl) -9-isopropylpurin-6-yl] amino} methyl) phenyl] piperidin-3-yl} methanol

Synthesis of 2- [3- (hydroxymethyl) piperidin-1-yl] benzonitrile

A mixture of piperidin-3-yl-methanol (500 mg, 4.34 mmol, 1.00 equiv) , 2-fluorobenzonitrile (631 mg, 5.21 mmol, 1.20 equiv) and dicesium carbonate (2.83 g, 8.68 mmol, 2.00 equiv) in DMF (10 mL) was stirred for overnight at 60 ℃ and quenched with water (50 mL) . The resulting mixture was extracted with ethyl acetate (3 x 50 mL) . The combined organic layers were washed with water (3 x 50 mL) , dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether /ethyl acetate (1/1) to afford 2- [3- (hydroxymethyl) piperidin-1-yl] benzonitrile (164 mg, 17%yield) as yellow oil. LCMS (ESI, m/z) : 217 [M+H] ⁺.

Synthesis of {1- [2- (aminomethyl) phenyl] piperidin-3-yl} methanol

A mixture of 2- [3- (hydroxymethyl) piperidin-1-yl] benzonitrile (160 mg, 0.740 mmol, 1.00 equiv) and Raney nickel (15 mg) in NH₃ (gas) (5 mL, 7 mol/L in MeOH) was stirred for overnight at room temperature under hydrogen atmosphere (2 -3 atm) . The solids were filtered off, the filter cake was washed with methanol (3 x 10 mL) . The filtrate was concentrated under reduced pressure to afford {1- [2- (aminomethyl) phenyl] piperidin-3-yl} methanol (122 mg, crude) as yellow oil. LCMS (ESI, m/z) : 221 [M+H] ⁺.

Synthesis of [1- (2- { [ (2-chloro-9-isopropylpurin-6-yl) amino] methyl} phenyl) piperidin-3-yl] methanol

A mixture of {1- [2- (aminomethyl) phenyl] piperidin-3-yl} methanol (120 mg, 0.545 mmol, 1.00 equiv) , 2, 6-dichloro-9-isopropylpurine (126 mg, 0.545 mmol, 1.00 equiv) and N, N-diisopropylethylamine (211 mg, 1.64 mmol, 3.00 equiv) in n-butanol (5 mL) was stirred for overnight at 80℃. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with ethyl acetate to afford [1- (2- { [ (2-chloro-9-isopropylpurin-6-yl) amino] methyl} phenyl) piperidin-3-yl] methanol (198 mg, 87%yield) as a yellow solid. LCMS (ESI, m/z) : 415 [M+H] ⁺.

A 5 mL vial was charged with [1- (2- { [ (2-chloro-9-isopropylpurin-6-yl) amino] methyl} phenyl) piperidin-3-yl] methanol (190 mg, 0.458 mmol, 1.00 equiv) , piperidin-4-amine (138 mg, 1.37 mmol, 3.00 equiv) , N, N-diisopropylethylamine (178 mg, 1.37 mmol, 3.00 equiv) and n-butanol (5 mL) at room temperature. The final reaction mixture was irradiated with microwave radiation for 5 h at 130℃. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C₁₈ Column, 30*150 mm, 5 μm; Mobile Phase A: Water (10 mmol/L NH₄HCO₃) , Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 23%B to 53%B in 7 min; Wave Length: 254 nm to afford {1- [2- ( { [2- (4-aminopiperidin-1-yl) -9-isopropylpurin-6-yl] amino} methyl) phenyl] piperidin-3-yl} methanol (93.6 mg, 43%yield) as a white solid. LCMS (ESI, m/z) : 479 [M+H] ⁺. ¹H-NMR (300 MHz, Methanol-d₄) δ 7.78 (s, 1H) , 7.34 (d, J = 4.0 Hz, 1H) , 7.22 -7.12 (m, 2H) , 7.02 -6.96 (m, 1H) , 4.81 -4.60 (m, 5H) , 3.54 -3.43 (m, 2H) , 3.19 (d, J = 8.0 Hz, 1H) , 3.03 (d, J = 8.0 Hz, 1H) , 2.88 -2.80 (m, 3H) , 2.73 -2.66 (m, 1H) , 2.52 -2.45 (m, 1H) , 1.96 (d, J = 2.0 Hz, 1H) , 1.89 -1.71 (m, 5H) , 1.56 -1.47 (m, 6H) , 1.32 -1.10 (m, 3H) .

(2- { [2- ( { [2- (4-aminopiperidin-1-yl) -9-isopropylpurin-6-yl] amino} methyl) phenyl] amino} phenyl) methanol

Synthesis of (2- { [2- ( { [2- (4-aminopiperidin-1-yl) -9-isopropylpurin-6-yl] amino} methyl) phenyl] amino} phenyl) methanol

Synthesis of 2- { [2- (hydroxymethyl) phenyl] amino} benzonitrile

A mixture of (2-aminophenyl) methanol (500 mg, 4.06 mmol, 1.00 equiv) , 2-fluorobenzonitrile (590 mg, 4.87 mmol, 1.20 equiv) and dicesium carbonate (2.65 g, 8.12 mmol, 2.00 equiv) in DMF (6 mL) was stirred for overnight at 60℃. The resulting mixture was extracted with ethyl acetate (3 x 50 mL) . The combined organic layers were washed with water (3 x 40 mL) , dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether /ethyl acetate (1/1) to afford a crude product. The crude product was purified by reverse flash chromatography with the following conditions: column, C₁₈ column; mobile phase, MeCN in Water, 10%to 100%gradient in 40 min; detector, UV 254 nm to afford 2- { [2- (hydroxymethyl) phenyl] amino} benzonitrile (272 mg, 30%yield) as yellow oil. LCMS (ESI, m/z) : 225 [M+H] ⁺.

Synthesis of (2- { [2- (aminomethyl) phenyl] amino} phenyl) methanol

A mixture of 2- { [2- (hydroxymethyl) phenyl] amino} benzonitrile (272 mg, 1.21 mmol, 1.00 equiv) and Raney nickel (20 mg) in NH₃ (gas) (8 mL, 7 mol/L in MeOH) was stirred for overnight at room temperature under hydrogen atmosphere (2 -3 atm) . The solids were filtered off and the filter cake was washed with methanol (3 x 10 mL) . The filtrate was concentrated under reduced pressure to afford (2- { [2- (aminomethyl) phenyl] amino} phenyl) methanol (206 mg, crude) as yellow oil. LCMS (ESI, m/z) : 229 [M+H] ⁺.

Synthesis of {2- [ (2- { [ (2-chloro-9-isopropylpurin-6-yl) amino] methyl} phenyl) amino] phenyl} methanol

A mixture of (2- { [2- (aminomethyl) phenyl] amino} phenyl) methanol (200 mg, 0.876 mmol, 1.00 equiv) , 2, 6-dichloro-9-isopropylpurine (202 mg, 0.876 mmol, 1.00 equiv) and N, N-diisopropylethylamine (340 mg, 2.63 mmol, 3.00 equiv) in n-butanol (6 mL) was stirred for overnight at 80℃ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether /ethyl acetate (1/1) to afford {2- [ (2- { [ (2-chloro-9-isopropylpurin-6-yl) amino] methyl} phenyl) amino] phenyl} methanol (320 mg, 86%yield) as yellow oil. LCMS (ESI, m/z) : 423 [M+H] ⁺.

A 5 mL vial was charged with {2- [ (2- { [ (2-chloro-9-isopropylpurin-6-yl) amino] methyl} phenyl) amino] phenyl} methanol (150 mg, 0.355 mmol, 1.00 equiv) , piperidin-4-amine (107 mg, 1.07 mmol, 3.00 equiv) , N, N-diisopropylethylamine (138 mg, 1.07 mmol, 3.00 equiv) and n-butanol (3 mL) at room temperature. The final reaction mixture was irradiated with microwave radiation for 5 h at 130 ℃. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C₁₈ Column, 30*150 mm, 5 μm; Mobile Phase A: Water (10 mmol/L NH₄HCO₃+0.1%NH₃. H₂O) , Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 27%B to 57%B in 7 min; Wave Length: 254 nm to afford (2- { [2- ( { [2- (4-aminopiperidin-1-yl) -9-isopropylpurin-6-yl] amino} methyl) phenyl] amino} phen yl) methanol (31.2 mg, 18%yield) as a white solid. LCMS (ESI, m/z) : 487 [M+H] ⁺. ¹H-NMR (300 MHz, Methanol-d₄) δ 7.78 -7.76 (m, 1H) , 7.34 -7.31 (m, 1H) , 7.24 -7.19 (m, 2H) , 7.11 -7.05 (m, 2H) , 6.91 -6.86 (m, 1H) , 6.76 -6.72 (m, 1H) , 6.68 -6.63 (m, 1H) , 5.09 (s, 2H) , 4.75 -4.62 (m, 5H) , 2.87 -2.80 (m, 3H) , 1.80 (d, J = 10.0 Hz, 2H) , 1.55 -1.46 (m, 6H) , 1.32 -1.27 (m, 2H) .

4- (2- ( ( (2- (4-aminopiperidin-1-yl) -9-isopropyl-9H-purin-6-yl) amino) methyl) phenyl) cyclohexan-1-ol

Synthesis of 4- (2- ( ( (2- (4-aminopiperidin-1-yl) -9-isopropyl-9H-purin-6-yl) amino) methyl) phenyl) cyclohexan-1-ol

Synthesis of 2- (1, 4-dioxaspiro [4.5] dec-7-en-8-yl) benzonitrile

A mixture of 2-bromobenzonitrile (500 mg, 2.74 mmol, 1.00 equiv) , 2- {1, 4-dioxaspiro [4.5] dec-7-en-8-yl} -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane (731 mg, 2.75 mmol, 1.00 equiv) , potassium carbonate (1.14 g, 8.24 mmol, 3.00 equiv) , tetrakis (triphenylphosphine) palladium (317 mg, 0.275 mmol, 0.100 equiv) in 1, 4-dioxane (2.5 mL) and water (0.5 mL) was stirred for overnight at 100 ℃ under nitrogen atmosphere. The solids were filtered off, the filter cake was washed with ethyl acetate (2 x 10 mL) . The filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions: column, C₁₈ column; mobile phase, Acetonitrile in Water, 0%to 100%gradient in 20 min; detector, UV 254 nm to afford 2- {1, 4-dioxaspiro [4.5] dec-7-en-8-yl} benzonitrile (884 mg, crude) as a light yellow solid. LCMS (ESI, m/z) : 242 [M+H] ⁺.

Synthesis of 2- (1, 4-dioxaspiro [4.5] decan-8-yl) benzonitrile

A mixture of 2- {1, 4-dioxaspiro [4.5] dec-7-en-8-yl} benzonitrile (880 mg, 3.65 mmol, 1.00 equiv) and 10%Pd/C (78 mg) in methanol (10 mL) was stirred for overnight at room temperature under hydrogen atmosphere (2 -3 atm) . The solids were filtered off, the filter cake was washed with methanol (2 x 10 mL) . The filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions: column, C₁₈ silica gel; mobile phase, Acetonitrile in Water, 0%to 100%gradient in 20 min; detector, UV 254 nm to afford 2- {1, 4-dioxaspiro [4.5] decan-8-yl} benzonitrile (658 mg, 74 %yield) as a brown oil. LCMS (ESI, m/z) : 244 [M+H] ⁺ .

Synthesis of 2- (4-oxocyclohexyl) benzonitrile

A mixture of 2- {1, 4-dioxaspiro [4.5] decan-8-yl} benzonitrile (300 mg, 1.23 mmol, 1.00 equiv) in water (0.50 mL) and hydrogen chloride (gas) (2.5 mL, 4.00 M in 1, 4-dioxane) was stirred for 4 h at room temperature and concentrated under reduced pressure to afford 2- (4-oxocyclohexyl) benzonitrile) (277 mg, crude) as a yellow oil. LCMS (ESI, m/z) : 200 [M+H] ⁺.

Synthesis of 4- (2- (aminomethyl) phenyl) cyclohexan-1-ol

A mixture of 2- (4-oxocyclohexyl) benzonitrile (277 mg, 1.39 mmol, 1.00 equiv) and lithium aluminum hydride (10 mL, 2.5 M in tetrahydrofuran) was refluxed for 2 h under nitrogen atmosphere. The mixture was allowed to cool down to -10 ℃ and quenched with water (1 mL) , sodium hydroxide aqueous solution (15%3 mL) and water (1 mL) . The solids were filtered off, the filter cake was washed with THF (2 x 30 mL) . The filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions: column, C₁₈ column; mobile phase, Acetonitrile in Water, 0%to 100%gradient in 20 min; detector, UV 254 nm to afford 4- [2- (aminomethyl) phenyl] cyclohexan-1-ol (52.0 mg, 18%yield) as an off-white solid. LCMS (ESI, m/z) : 206 [M+H] ⁺.

Synthesis of 4- (2- ( ( (2-chloro-9-isopropyl-9H-purin-6-yl) amino) methyl) phenyl) cyclohexan-1-ol

A mixture of 4- [2- (aminomethyl) phenyl] cyclohexan-1-ol (52.0 mg, 0.253 mmol, 1.00 equiv) , 2,6-dichloro-9-isopropylpurine (58.5 mg, 0.253 mmol, 1.00 equiv) and N, N-diisopropylethylamine (98.2 mg, 0.759 mmol, 3.00 equiv) in n-buthanol (3 mL) was stirred for overnight at 80 ℃ and concentrated under reduced pressure. The residue was purified by Prep-TLC (petroleum ether /ethyl acetate = 1/2) to afford 4- (2- { [ (2-chloro-9-isopropylpurin-6-yl) amino] methyl} phenyl) cyclohexan-1-ol (77.0 mg, 76%yield) as a light yellow solid. LCMS (ESI, m/z) : 400 [M+H] ⁺.

A mixture of 4- (2- { [ (2-chloro-9-isopropylpurin-6-yl) amino] methyl} phenyl) cyclohexan-1-ol (77.0 mg, 0.193 mmol, 1.00 equiv) , piperidin-4-amine (57.8 mg, 0.579 mmol, 3.00 equiv) and N, N-diisopropylethylamine (74.7 mg, 0.579 mmol, 3.00 equiv) in n-buthanol (3 mL) was irradiated with microwave radiation for 5 h at 130 ℃. The mixture was allowed to cool down to room temperature and concentrated under reduced pressure. The residue product was purified by Prep-HPLC with the following conditions: Column, XBridge Shield RP₁₈ OBD Column, 30*150 mm, 5 μm; Mobile Phase A: Water (10 mmol/L NH₄HCO₃+0.1%NH₃. H₂O) , Mobile Phase B: Acetonitrile; Flow rate: 60 mL/min; Gradient: 55%B to 85%B in 9 min; Wave Length: 254 nm to afford 4- [2- ( { [2- (4-aminopiperidin-1-yl) -9-isopropylpurin-6-yl] amino} methyl) phenyl] cyclohexan-1-ol (21.2 mg, 24%yield) as an off-white solid. LCMS (ESI, m/z) : 464 [M+H] ⁺. ¹H-NMR (300 MHz, Chloroform-d) δ 7.45 (s, 1H) , 7.40 -7.34 (d, J = 12.0 Hz, 1H) , 7.24 -7.21 (d, J =6.0 Hz, 2H) , 7.19 -7.11 (m, 1H) , 5.65 (s, 1H) , 4.89 -4.61 (m, 5H) , 3.62 -3.56 (m, 1H) , 2.92 -2.78 (m, 4H) , 2.01 -1.94 (d, J = 14.0 Hz, 2H) , 1.90 -1.78 (m, 4H) , 1.55 (s, 6H) , 1.50 -1.18 (m, 6H) .

N- (2- (2, 5-diazabicyclo [2.2.1] heptan-2-yl) benzyl) -2- (4-aminopiperidin-1-yl) -9-isopropyl-9H-purin-6-amine

Synthesis of N- (2- (2, 5-diazabicyclo [2.2.1] heptan-2-yl) benzyl) -2- (4-aminopiperidin-1-yl) -9-isopropyl-9H-purin-6-amine

Synthesis of tert-butyl 5- (2-cyanophenyl) -2, 5-diazabicyclo [2.2.1] heptane-2-carboxylate

To a solution of tert-butyl 2, 5-diazabicyclo [2.2.1] heptane-2-carboxylate (589.3 mg, 2.97 mmol) and 2-fluorobenzonitrile (300 mg, 2.48 mmol) in DMF (5 mL) was added K₂CO₃ (684.71 mg, 4.95 mmol) . The mixture was stirred at 110 ℃ for 18 hours to form a white suspension. TLC showed the reaction was completed. The mixture was partitioned between EtOAc (30 mL) and H₂O (30 mL) . The aqueous phase was extracted with EtOAc (30 mL x 2) . The combined organic extracts were washed with brine (30 mL x 3) , dried over anhydrous Na2SO₄, filtered and concentrated under reduced pressure to give the crude product, which was purified by combi flash to give tert-butyl 5- (2-cyanophenyl) -2, 5-diazabicyclo [2.2.1] heptane-2-carboxylate (270 mg, yield: 36.41%) as a off-white solid. ESI-MS [M + H] ⁺: 300.4.

Synthesis of tert-butyl 5- (2- (aminomethyl) phenyl) -2, 5-diazabicyclo [2.2.1] heptane-2-carboxylate

To a solution of tert-butyl 5- (2-cyanophenyl) -2, 5-diazabicyclo [2.2.1] heptane-2-carboxylate (270 mg, 0.902 mmol) in MeOH (5 mL) was added Raney-Ni (53.05 mg, 0.902 mmol) and NH₃-H₂O (0.902 mmol) . The mixture was stirred at RT for 15 hours under H₂ (15 Psi) . The reaction mixture was filtered and the filtrated to give tert-butyl 5- (2- (aminomethyl) phenyl) -2, 5-diazabicyclo [2.2.1] heptane-2-carboxylate (229 mg, yield: 83.69%) . ESI-MS [M + H] ⁺: 304.4.

Synthesis of tert-butyl 5- (2- ( ( (2-chloro-9-isopropyl-9H-purin-6-yl) amino) methyl) phenyl) -2, 5-diazabicyclo [2.2.1] heptane-2-carboxylate

To a solution of 2, 6-dichloro-9-isopropyl-9H-purine (158.56 mg, 0.686 mmol) , tert-butyl 5- (2- (aminomethyl) phenyl) -2, 5-diazabicyclo [2.2.1] heptane-2-carboxylate (229 mg, 0.755 mmol) in EtOH (3 mL) was added TEA (208.33 mg, 2.06 mmol) . The mixture was stirred at 80 ℃ for 8 hours to give a yellow suspension. TLC showed the reaction was completed. The mixture was partitioned between EtOAc (50 mL) and water (50 mL) , the aqueous phase was extracted with EtOAc (50 mL x 2) , the combined extracted phase was washed with water (50 mL) , dried over Na2SO4, filtered, concentrated under reduced pressure to give a off-white oil, which was purified by Combi flash to give tert-butyl 5- (2- ( ( (2-chloro-9-isopropyl-9H-purin-6-yl) amino) methyl) phenyl) -2, 5-diazabicyclo [2.2.1] heptane-2-carboxylate (277 mg, yield: 81.06%) as a white solid. ESI-MS [M + H] ⁺: 499.0.

Synthesis of tert-butyl 5- (2- ( ( (2- (4-aminopiperidin-1-yl) -9-isopropyl-9H-purin-6-yl) amino) methyl) phenyl) -2, 5-diazabicyclo [2.2.1] heptane-2-carboxylate

To a solution of tert-butyl 5- (2- ( ( (2-chloro-9-isopropyl-9H-purin-6-yl) amino) methyl) phenyl) -2, 5-diazabicyclo [2.2.1] heptane-2-carboxylate (277 mg, 0.56 mmol) in DMSO (3 mL) was added piperidin-4-amine (61, 28 mg, 0.61 mmol) and TEA (168.85 mg, 1.67 mmol) , then stirred at 160 ℃ for 8 hours. The reaction was poured into water (30 mL) , extracted with EtOAc (20 mL*2) , the organic layer was washed with water (20 mL*2) , dried over Na₂SO₄, filtered and concentrated to give a residue. The residue purified by column chromatography to give tert-butyl 5- (2- ( ( (2- (4-aminopiperidin-1-yl) -9-isopropyl-9H-purin-6-yl) amino) methyl) phenyl) -2, 5-diaza bicyclo [2.2.1] heptane-2-carboxylate (216 mg, yield: 69.14%) as a white solid. ESI-MS [M +H] ⁺: 562.7.

To a solution of tert-butyl 5- (2- ( ( (2- (4-aminopiperidin-1-yl) -9-isopropyl-9H-purin-6-yl) amino) methyl) phenyl) -2, 5-diazabicyclo [2.2.1] heptane-2-carboxylate (216 mg, 0.385 mmol) in MeOH (3 mL) was added HCl in MeOH (3 mL) , then stirred at RT for 2 hours. The reaction was poured into aq. NaHCO₃ (30 mL) , extracted with EtOAc (20 mL*2) , the organic layer was washed with water (20 mL*2) , dried over Na₂SO₄, filtered and concentrated to give a residue. The residue purified by column chromatography to give N- (2- (2, 5-diazabicyclo [2.2.1] heptan-2-yl) benzyl) -2- (4-aminopiperidin-1-yl) -9-isopropyl-9H-purin-6-amine (69.92 mg, yield: 39.39%) as a white solid. ESI-MS [M + H] ⁺: 462.6.

¹H NMR (400 MHz, MeOD) δ 7.80 (s, 1H) , 7.32 (dd, J = 7.6, 1.4 Hz, 1H) , 7.19 –7.14 (m, 1H) , 7.05 –7.01 (m, 1H) , 6.89 (td, J = 7.5, 1.0 Hz, 1H) , 4.84 –4.75 (m, 3H) , 4.68 (dt, J = 13.5, 6.8 Hz, 2H) , 4.20 (s, 1H) , 3.99 (s, 1H) , 3.50 –3.45 (m, 1H) , 3.35 (dd, J = 15.5, 5.4 Hz, 2H) , 3.20 –3.08 (m, 2H) , 2.92 –2.85 (m, 2H) , 2.10 (d, J = 10.2 Hz, 1H) , 1.93 –1.88 (m, 2H) , 1.84 (d, J = 10.2 Hz, 1H) , 1.55 (d, J = 6.8 Hz, 6H) , 1.40 (dt, J = 18.4, 6.8 Hz, 2H) .

2- (4-aminopiperidin-1-yl) -9-isopropyl-N- ( (6'- (trifluoromethyl) - [2, 3'-bipyridin] -3-yl) methyl) -9H-purin-6-amine

Synthesis of 2- (4-aminopiperidin-1-yl) -9-isopropyl-N- ( (6'- (trifluoromethyl) - [2, 3'-bipyridin] -3-yl) methyl) -9H-purin-6-amine

Synthesis of 6'- (trifluoromethyl) - [2, 3'-bipyridine] -3-carbonitrile

To a mixture of 2-bromonicotinonitrile (200 mg, 1.10 mmol) , (6- (trifluoromethyl) pyridin-3-yl) boronic acid (420 mg, 2.20 mmol) and Na₂CO₃ (350 mg, 3.30 mmol) in DME (10 mL) and water (1 mL) was added Pd (PPh₃) ₄ (127 mg, 0.11 mmol) . The mixture was stirred at 90 ℃ for 16 h under N₂. The reaction mixture was cooled to room temperature. The mixture was filtered through and the filter cake was washed with DCM/MeOH (10/1, 30 mL) . The filtrate was concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 50/1) to give 6'- (trifluoromethyl) - [2, 3'-bipyridine] -3-carbonitrile (150 mg, yield: 55%) as a colourless oil. ESI-MS [M +H] ⁺: 250.2.

Synthesis of (6'- (trifluoromethyl) - [2, 3'-bipyridin] -3-yl) methanamine

To a mixture of 6'- (trifluoromethyl) - [2, 3'-bipyridine] -3-carbonitrile (150 mg, 0.60 mmol) in NH₃ (7M solution in MeOH, 5 mL) was added Raney Ni (50 mg) . The reaction mixture was stirred at room temperature for 3h under H₂. The reaction mixture was filtered throughand the filter cake was washed with DCM/MeOH (10/1, 20 mL) . The filtrate was concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 10/1) to give (6'- (trifluoromethyl) - [2, 3'-bipyridin] -3-yl) methanamine (80 mg, yield: 53%) as a yellow oil. ESI-MS [M +H] +: 254.2.

Synthesis of 2-chloro-9-isopropyl-N- ( (6'- (trifluoromethyl) - [2, 3'-bipyridin] -3-yl) methyl) -9H-purin-6-amine

A mixture of 2, 6-dichloro-9-isopropyl-9H-purine (60 mg, 0.26 mmol) , (6'- (trifluoromethyl) - [2, 3'-bipyridin] -3-yl) methanamine (80 mg, 0.31 mmol) and DIPEA (101 mg, 0.78 mmol) in i-PrOH (5 mL) was stirred at 90 ℃ for 3 h. The reaction mixture was concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 20/1) to give 2-chloro-9-isopropyl-N- ( (6'- (trifluoromethyl) - [2, 3'-bipyridin] -3-yl) methyl) -9H-purin-6-amine (100 mg, yield: 86%) as a white solid. ESI-MS [M + H] ⁺: 448.2.

Synthesis of tert-butyl (1- (9-isopropyl-6- ( ( (6'- (trifluoromethyl) - [2, 3'-bipyridin] -3-yl) methyl) amino) -9H-purin-2-yl) piperidin-4-yl) carbamate

A mixture of 2-chloro-9-isopropyl-N- ( (6'- (trifluoromethyl) - [2, 3'-bipyridin] -3-yl) methyl) -9H-purin-6-amine (60 mg, 0.13 mmol) , tert-butyl piperidin-4-ylcarbamate (52 mg, 0.26 mmol) and DIPEA (101 mg, 0.78 mmol) in i-PrOH (2 mL) was irradiated in microwave at 140 ℃ for 4 h. The reaction mixture was concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 16/1) to give tert-butyl (1- (9-isopropyl-6- ( ( (6'- (trifluoromethyl) - [2, 3'-bipyridin] -3-yl) methyl) amino) -9H-purin-2-yl) piperidin-4-yl) carbamate (40 mg, yield: 50%) as a white solid. ESI-MS [M + H] ⁺: 612.2.

To a mixture of tert-butyl (1- (9-isopropyl-6- ( ( (6'- (trifluoromethyl) - [2, 3'-bipyridin] -3-yl) methyl) amino) -9H-purin-2-yl) piperidin-4-yl) carbamate (40 mg, 0.065 mmol) in MeOH (2 mL) was added HCl (4M solution in 1, 4-dioxane, 2 mL) . The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with NH₃ (7M solution in MeOH, 5 mL) and concentrated in vacuo to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 10/1) to give 2- (4-aminopiperidin-1-yl) -9-isopropyl-N- ( (6'- (trifluoromethyl) -[2, 3'-bipyridin] -3-yl) methyl) -9H-purin-6-amine (25 mg, yield: 38%) as a white solid.

ESI-MS [M +H] +: 512.2. Purity: 99.43 (214 nm) , 100 (254 nm) .

1H NMR (400 MHz, MeOD) δ 8.88 (s, 1H) , 8.59 (d, J = 3.7 Hz, 1H) , 8.21 (d, J = 7.9 Hz, 1H) , 8.07 (d, J = 7.5 Hz, 1H) , 7.88 (d, J = 8.1 Hz, 1H) , 7.78 (s, 1H) , 7.52-7.48 (m, 1H) , 4.82 (s, 2H) , 4.70-4.63 (m, 1H) , 4.53 (d, J = 13.3 Hz, 2H) , 2.94 –2.66 (m, 3H) , 1.79 (d, J = 11.8 Hz, 2H) , 1.55 (d, J = 6.8 Hz, 6H) , 1.24-1.14 (m, 2H) .

1- (1- (2- ( ( (2- (4-aminopiperidin-1-yl) -9-isopropyl-9H-purin-6-yl) amino) methyl) phenyl) -1H -pyrazol-3-yl) azetidin-3-ol

Synthesis of 1- (1- (2- ( ( (2- (4-aminopiperidin-1-yl) -9-isopropyl-9H-purin-6-yl) amino) methyl) phenyl) -1H-pyrazol-3-yl) azetidin-3-ol

Synthesis of 2- (3- (3-hydroxyazetidin-1-yl) -1H-pyrazol-1-yl) benzonitrile

To a mixture of 2- (3-bromo-1H-pyrazol-1-yl) benzonitrile (150 mg, 604.65 μmol) , azetidin-3-ol (66.29 mg, 906.97 μmol) , L-Proline (104.42 mg, 906.97 μmol) and K₂CO₃ (167.13 mg, 1.21 mmol) in DMSO (10 mL) was added CuI (115.16 mg, 604.65 μmol) . The mixture was stirred at 120℃ for 6 h under N₂. The reaction mixture was cooled to room temperature. The mixture was filtered throughand the filter cake was washed with DCM/MeOH (10/1, 30 mL) . The filtrate was concentrated to give the crude, which was purified to give 2- (3- (3-hydroxyazetidin-1-yl) -1H-pyrazol-1-yl) benzonitrile (87.5 mg, 343.43 μmol, 56.80%yield, 94.3%purity) as a yellow solid. ESI-MS [M+H] ⁺: 241.25.

Synthesis of 1- (1- (2- (aminomethyl) phenyl) -1H-pyrazol-3-yl) azetidin-3-ol

To a mixture of 2- (3- (3-hydroxyazetidin-1-yl) -1H-pyrazol-1-yl) benzonitrile (300 mg, 1.25 mmol) in NH₃ (7M solution in MeOH, 5 mL) was added Raney-Ni (250 mg, 1.25 mmol) . The reaction mixture was stirred at room temperature for 3h under H₂. The reaction mixture was filtered through and the filter cake was washed with DCM/MeOH (10/1, 20 mL) . The filtrate was concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 10/1) to give1- (1- (2- (aminomethyl) phenyl) -1H-pyrazol-3-yl) azetidin-3-ol (264.8 mg, 1.02 mmol, 81.86%yield, 94.3%purity) . ESI-MS [M+H] ⁺: 245.23.

Synthesis of 1- (1- (2- ( ( (2-chloro-9-isopropyl-9H-purin-6-yl) amino) methyl) phenyl) -1H-pyrazol-3-yl) azetidin-3-ol

To a solution of 2, 6-dichloro-9-isopropyl-9H-purine (150 mg, 649.12 μmol) in EtOH (15 mL) was TEA (197.05 mg, 1.95 mmol, 271.61 μL) and 1- (1- (2- (aminomethyl) phenyl) -1H-pyrazol-3-yl) azetidin-3-ol (237.86 mg, 973.68 μmol) , then stirred at 80 ℃ for 6 hrs. The reaction was concentrated to give a residue. The residue purified by column chromatography to give1- (1- (2- ( ( (2-chloro-9-isopropyl-9H-purin-6-yl) amino) methyl) phenyl) -1H-pyrazol-3-yl) azetidin-3-ol (256.4 mg, 562.56 μmol, 86.66%yield, 96.3%purity) as a white solid. ESI-MS [M+H] ⁺: 439.12.

To a solution of 1- (1- (2- ( ( (2-chloro-9-isopropyl-9H-purin-6-yl) amino) methyl) phenyl) -1H-pyrazol-3-yl) azetidin-3-ol (100 mg, 227.84 μmol) in DMSO (10 mL) was added piperidin-4-amine (45.64 mg, 455.67 μmol) and TEA (69.16 mg, 683.51 μmol, 95.33 μL) , then stirred at 160 ℃ for 10 hrs. The reaction was poured into water (30 mL) , extracted with EtOAc (10 mL*2) , the organic layer was washed with water (10 mL*2) , dried over Na₂SO₄, filtered, and concentrated to give a residue. The residue purified by column chromatography to give 1- (1- (2- ( ( (2- (4-aminopiperidin-1-yl) -9-isopropyl-9H-purin-6-yl) amino) methyl) phenyl) -1 H-pyrazol-3-yl) azetidin-3-ol (65.3 mg, 124.72 μmol, 54.74%yield, 96%purity) as a yellow powder. ESI-MS [M+H] ⁺: 503.46.¹H-NMR (400 MHz, MeOD) δ 7.82 (s, 1H) , 7.64 (d, J = 2.5 Hz, 1H) , 7.58 –7.52 (m, 1H) , 7.39 –7.29 (m, 3H) , 5.81 (d, J = 2.5 Hz, 1H) , 4.80 (dt, J = 13.9, 2.4 Hz, 1H) , 4.75 –4.56 (m, 3H) , 4.14 (dd, J = 8.1, 6.3 Hz, 2H) , 3.70 (dd, J = 8.2, 5.2 Hz, 2H) , 3.21 (q, J = 7.3 Hz, 1H) , 2.88 (ddd, J = 13.9, 12.0, 2.5 Hz, 2H) , 2.65 (s, 3H) , 1.96 (ddd, J = 9.2, 4.7, 2.5 Hz, 2H) , 1.55 (d, J = 6.8 Hz, 6H) , 1.46 (dd, J = 12.1, 4.2 Hz, 1H)

2- (4-aminopiperidin-1-yl) -N- (2- (dimethylamino) benzyl) -9-isopropyl-9H-purin-6-amine

Synthesis of 2- (4-aminopiperidin-1-yl) -N- (2- (dimethylamino) benzyl) -9-isopropyl-9H-purin-6-amine

Synthesis of 2-chloro-N- (2- (dimethylamino) benzyl) -9-isopropyl-9H-purin-6-amine

To a solution of 2, 6-dichloro-9-isopropyl-9H-purine (300 mg, 1.29 mmol) in EtOH (10 mL) were added TEA (390.70 mg, 3.86 mmol, 538.52 μL) and2- (aminomethyl) -N, N-dimethylaniline (232.00 mg, 1.54 mmol) , the mixture was stirred at 80℃ for 6h. The reaction mixture was concentrated to give a residue. The residue was purified by column chromatography to give 2-chloro-N- (2- (dimethylamino) benzyl) -9-isopropyl-9H-purin-6-amine (389.6 mg, 1.08 mmol, 83.78%yield, 96%purity) as a yellow solid. ESI-MS [M+H] ⁺: 347.21.

To a solution of 2-chloro-N- (2- (dimethylamino) benzyl) -9-isopropyl-9H-purin-6-amine (100 mg, 289.99 μmol) in DMSO (2.5 mL) was addedpiperidin-4-amine (58.09 mg, 579.98 μmol) and TEA (88.03 mg, 869.97 μmol, 121.34 μL) , then stirred at 160 ℃ for 10 hrs. The reaction was poured into water (30 mL) , extracted with EtOAc (10 mL*2) , the organic layer was washed with water (10 mL*2) , dried over Na₂SO₄, filtered, and concentrated to give a residue. The residue purified by column chromatography to give 2- (4-aminopiperidin-1-yl) -N- (2- (dimethylamino) benzyl) -9-isopropyl-9H-purin-6-amine (79.4 mg, 186.58 μmol, 64.34%yield, 96%purity) as a yellow powder. ESI-MS [M+H] ⁺: 409.41.¹H-NMR (400 MHz, MeOD) δ 7.81 (s, 1H) , 7.36 –7.30 (m, 1H) , 7.23 –7.13 (m, 2H) , 6.98 (ddd, J = 7.6, 6.7, 1.9 Hz, 1H) , 4.86 (m, 3H) , 4.68 (p, J = 6.8 Hz, 1H) , 3.29 –3.19 (m, 1H) , 2.95 –2.83 (m, 2H) , 2.73 (s, 6H) , 1.93 (dd, J = 11.8, 3.6 Hz, 2H) , 1.55 (d, J =6.8 Hz, 6H) , 1.50 –1.36 (m, 3H) .

3- (2- ( ( (2- (4-aminopiperidin-1-yl) -9-isopropyl-9H-purin-6-yl) amino) methyl) phenyl) -1, 2, 4-oxadiazol-5 (4H) -one

Synthesis of 3- (2- ( ( (2- (4-aminopiperidin-1-yl) -9-isopropyl-9H-purin-6-yl) amino) methyl) phenyl) -1, 2, 4-oxadiazol-5 (4H) -one

Synthesis of tert-butyl N- [ (2-cyanophenyl) methyl] carbamate

A mixture of 2- (aminomethyl) benzonitrile (1.00 g, 7.57 mmol, 1.00 equiv) , ditertbutyl dicarbonate (4.95 g, 22.7 mmol, 3.00 equiv) , 4-dimethylaminopyridine (924 mg, 7.57 mmol, 1.00 equiv) and triethylamine (2.30 g, 22.7 mmol, 3.00 equiv) in acetonitrile (12 mL) was stirred for overnight at 60 ℃ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether /ethyl acetate (3/1) to afford tert-butyl N- [ (2-cyanophenyl) methyl] carbamate (240 mg, 14%yield) as a white solid. LCMS (ESI, m/z) : 233 [M+H] ⁺.

Synthesis of tert-butyl N- ( {2- [ (Z) -N'-hydroxycarbamimidoyl] phenyl} methyl) carbamate

A mixture of tert-butyl N- [ (2-cyanophenyl) methyl] carbamate (230 mg, 0.99 mmol, 1.00 equiv) , hydroxylamine hydrochloride (138 mg, 1.98 mmol, 2.00 equiv) and triethylamine (300 mg, 2.97 mmol, 3.00 equiv) in EtOH (4 mL) was stirred for overnight at 60 ℃. The resulting mixture was concentrated under reduced pressure and quenched with water (50 mL) . The mixture was extracted with ethyl acetate (3 x 50 mL) . The combined organic layers were washed with water (2 x 50 mL) , dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether /ethyl acetate (2/1) to afford tert-butyl N- ( {2- [ (Z) -N'-hydroxycarbamimidoyl] phenyl} methyl) carbamate (190 mg, 72%yield) as a white solid. LCMS (ESI, m/z) : 266 [M+H] ⁺.

Synthesis of tert-butyl N- { [2- (5-oxo-4H-1, 2, 4-oxadiazol-3-yl) phenyl] methyl} carbamate

A mixture of tert-butyl N- ( {2- [ (Z) -N'-hydroxycarbamimidoyl] phenyl} methyl) carbamate (180 mg, 0.678 mmol, 1.00 equiv) , CDI (165 mg, 1.02 mmol, 1.50 equiv) and DBU (114 mg, 0.746 mmol, 1.10 equiv) in 1, 4-dioxane (3 mL) was stirred for overnight at 110℃ under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and quenched with water (30 mL) . The mixture was extracted with ethyl acetate (3 x 50 mL) . The combined organic layers were washed with water (2 x 50 mL) , dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with ethyl acetate to afford a crude product. The residue was purified by reverse flash chromatography with the following conditions: column, C₁₈ silica gel; mobile phase, MeCN in Water, 10%to 50%gradient in 10 min; detector, UV 254 nm to afford tert-butyl N- { [2- (5-oxo-4H-1, 2, 4-oxadiazol-3-yl) phenyl] methyl} carbamate (160 mg, 81%yield) as a yellow solid. LCMS (ESI, m/z) : 292 [M+H] ⁺.

Synthesis of 3- [2- (aminomethyl) phenyl] -4H-1, 2, 4-oxadiazol-5-one

A mixture of tert-butyl N- { [2- (5-oxo-4H-1, 2, 4-oxadiazol-3-yl) phenyl] methyl} carbamate (150 mg, 0.515 mmol, 1.00 equiv) and TFA (1 mL) in dichloromethane (5 mL) was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure to afford 3- [2- (aminomethyl) phenyl] -4H-1, 2, 4-oxadiazol-5-one (95.0 mg, crude) as a yellow oil. LCMS (ESI, m/z) : 192 [M+H] ⁺.

Synthesis of 3- (2- { [ (2-chloro-9-isopropylpurin-6-yl) amino] methyl} phenyl) -4H -1, 2, 4-oxadiazol-5-one

A mixture of 3- [2- (aminomethyl) phenyl] -4H-1, 2, 4-oxadiazol-5-one (90.0 mg, 0.471 mmol, 1.00 equiv) , 2, 6-dichloro-9-isopropylpurine (109 mg, 0.471 mmol, 1.00 equiv) and N, N-diisopropylethylamine (183 mg, 1.42 mmol, 3.00 equiv) in n-butanol (2 mL) was stirred for overnight at 80℃. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with ethyl acetate to afford 3- (2- { [ (2-chloro-9-isopropylpurin-6-yl) amino] methyl} phenyl) -4H-1, 2, 4-oxadiazol-5-one (90.0 mg, 50%yield) as a white solid. LCMS (ESI, m/z) : 386 [M+H] ⁺.

Synthesis of 3- [2- ( { [2- (4-aminopiperidin-1-yl) -9-isopropylpurin-6-yl] amino} methyl) phenyl] -4H-1, 2, 4-oxadiazol-5-one

A 5 mL vial was charged with 3- (2- { [ (2-chloro-9-isopropylpurin-6-yl) amino] methyl} phenyl) -4H-1, 2, 4-oxadiazol-5-one (80.0 mg, 0.207 mmol, 1.00 equiv) , piperidin-4-amine (62.3 mg, 0.621 mmol, 3.00 equiv) , N, N-diisopropylethylamine (80.4 mg, 0.621 mmol, 3.00 equiv) and n-butanol (1.5 mL) at room temperature. The final reaction mixture was irradiated with microwave radiation for 5 h at 130 ℃. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C₁₈ Column, 30*150 mm, 5 μm; Mobile Phase A: Water (10 mmol/L NH₄HCO₃+0.1%NH₃. H₂O) , Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 5%B to 35%B in 7 min; Wave Length: 254 nm to afford 3- [2- ( { [2- (4-aminopiperidin-1-yl) -9-isopropylpurin-6-yl] amino} methyl) phenyl] -4H-1, 2, 4-oxa diazol-5-one (4.2 mg, 4%yield) as a white solid. LCMS (ESI, m/z) : 450 [M+H] ⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 7.96 (s, 1H) , 7.80 -7.77 (m, 2H) , 7.46 (s, 1H) , 7.27 -7.25 (m, 2H) , 4.81 (d, J = 2.0 Hz, 2H) , 4.69 -4.53 (m, 3H) , 3.21 (s, 2H) , 2.89 -2.83 (m, 2H) , 187 (d, J = 6.0 Hz, 2H) , 1.50 -1.39 (m, 8H) .

2- (4-aminopiperidin-1-yl) -9-isopropyl-N- (2- (oxazol-4-yl) benzyl) -9H-purin-6-amine

Synthesis of 2- (4-aminopiperidin-1-yl) -9-isopropyl-N- (2- (oxazol-4-yl) benzyl) -9H-purin-6-amine

Synthesis of 2- (1, 3-oxazol-4-yl) benzonitrile

A mixture of 2-formylbenzonitrile (1.00 g, 7.62 mmol, 1.00 equiv) , 1- (isocyanosulfonyl) -4-methylbenzene (2.98 g, 15.25 mmol, 2.00 equiv) and potassium carbonate (3.16 g, 22.87 mmol, 3.00 equiv) in methanol (10 mL) was refluxed for overnight. The mixture was allowed to cool down to room temperature. The solids were filtered off, the filter cake was washed with methanol (2 x 20 mL) . The filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions: column, C₁₈ silica gel; mobile phase, acetonitrile in water, 0%to 100%gradient in 20 min; detector, UV 254 nm to afford 2- (1, 3-oxazol-4-yl) benzonitrile (673 mg, 52%yield) as a blue solid. LCMS (ESI, m/z) : 171 [M+H] ⁺.

Synthesis of 1- [2- (1, 3-oxazol-4-yl) phenyl] methanamine

A mixture of 2- (1, 3-oxazol-4-yl) benzonitrile (473 mg, 2.78 mmol, 1.00 equiv) and Raney Nickel (23.8 mg, 0.278 mmol, 0.100 equiv) in ammonia (5 mL, 7.00 M in methanol) was stirred for overnight at room temperature under hydrogen atmosphere (2 -3 atm) . The solids were filtered off, the filter cake was washed with methanol (2 x 10 mL) . The filtrate was concentrated under reduced pressure to afford 1- [2- (1, 3-oxazol-4-yl) phenyl] methanamine (420 mg, crude) as a wine oil. LCMS (ESI, m/z) : 175 [M+H] ⁺.

Synthesis of 2-chloro-9-isopropyl-N- { [2- (1, 3-oxazol-4-yl) phenyl] methyl} purin-6-amine

A mixture of 1- [2- (1, 3-oxazol-4-yl) phenyl] methanamine (150 mg, 0.861 mmol, 1.00 equiv) , 2,6-dichloro-9-isopropylpurine (199 mg, 0.861 mmol, 1.00 equiv) and N, N-diisopropylethylamine (333 mg, 2.58 mmol, 3.00 equiv) in n-buthanol (4 mL) was stirred for overnight at 80 ℃. The mixture was allowed to cool down to room temperature and concentrated under reduced pressure. The residue was purified by Prep-TLC with petroleum ether /ethyl acetate 1: 2 to afford 2-chloro-9-isopropyl-N- { [2- (1, 3-oxazol-4-yl) phenyl] methyl} purin-6-amine (130 mg, 41%yield) as a brown solid. LCMS (ESI, m/z) : 369 [M+H] ⁺.

Synthesis of 2- (4-aminopiperidin-1-yl) -9-isopropyl-N- { [2- (1, 3-oxazol-4-yl) phenyl] methyl} purin-6-amine

A mixture of 2-chloro-9-isopropyl-N- { [2- (1, 3-oxazol-4-yl) phenyl] methyl} purin-6-amine (160 mg, 0.434 mmol, 1.00 equiv) and N, N-diisopropylethylamine (168 mg, 1.30 mmol, 3.00 equiv) in n-buthanol (2 mL) was stirred for 2 h at 130 ℃. The mixture was allowed to cool down to room temperature and concentrated under reduced pressure. The residue was purified by prep-TLC with DCM/MeOH = 4/1 to afford the crude product. The crude product was purified by Prep-HPLC with the following conditions: Column: XBridge BEH130 Prep C₁₈ OBD Column, 19*150 mm, 5 μm; Mobile Phase A: Water (10 mmol/L NH₄HCO₃+0.1%NH₃. H₂O) , Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 20%B to 50%B in 7 min; Wave Length: 254 nm to afford 2- (4-aminopiperidin-1-yl) -9-isopropyl-N- { [2- (1, 3-oxazol-4-yl) phenyl] methyl} purin-6-amine (10.6 mg, 6%yield) as a light yellow solid. LCMS (ESI, m/z) : 433 [M+H] ⁺. ¹H-NMR (300 MHz, Methanol-d₄) δ 8.34 (s, 1H) , 7.82 (s, 1H) , 7.75 -7.70 (m, 1H) , 7.59 (s, 1H) , 7.38 -7.32 (m, 3H) , 4.90 (s, 2H) , 4.72 -4.60 (m, 3H) , 2.84 -2.76 (m, 3H) , 1.80 (s, 2H) , 1.54 -1.52 (d, J =4.0 Hz, 6H) , 1.26 (s, 2H) .

1- (2- ( ( (2- (4-aminopiperidin-1-yl) -9-isopropyl-9H-purin-6-yl) amino) methyl) phenyl) ethan-1-ol

Synthesis of 1- (2- ( ( (2- (4-aminopiperidin-1-yl) -9-isopropyl-9H-purin-6-yl) amino) methyl ) phenyl) ethan-1-ol

Synthesis of 1- [2- (aminomethyl) phenyl] ethanol

A mixture of 2-acetylbenzonitrile (300 mg, 2.06 mmol, 1.00 equiv) and lithium aluminium hydride (5.0 mL, 12.5 mmol, 6.07 equiv, 2.5M in THF) was stirred for 2 h at room temperature under nitrogen atmosphere. The mixture was allowed to cool down to -10 ℃ and quenched with ice/water (1 mL) . The solids were filtered off, the filter cake was washed with tetrahydrofuran (3 x 10 mL) . The filtrate was concentrated under reduced pressure to afford 1- [2- (aminomethyl) phenyl] ethanol (251 mg, crude) as an off-white solid. LCMS (ESI, m/z) : 152 [M+H] ⁺.

Synthesis of 1- (2- { [ (2-chloro-9-isopropylpurin-6-yl) amino] methyl} phenyl) ethanol

A mixture of 1- [2- (aminomethyl) phenyl] ethanol (100 mg, 0.661 mmol, 1.00 equiv) , 2, 6-dichloro-9-isopropylpurine (153 mg, 0.661 mmol, 1.00 equiv) and N, N-diisopropylethylamine (256 mg, 1.98 mmol, 3.00 equiv) in n-buthanol (3 mL) was stirred for overnight at 80 ℃. The mixture was allowed to cool down to room temperature and concentrated under reduced pressure. The residue was purified by Prep-TLC with petroleum ether/ethyl acetate = 1/2 to afford 1- (2- { [ (2-chloro-9-isopropylpurin-6-yl) amino] methyl} phenyl) ethanol (151 mg, 66%yield) as a wine oil. LCMS (ESI, m/z) : 346 [M+H] ⁺.

Synthesis of 1- [2- ( { [2- (4-aminopiperidin-1-yl) -9-isopropylpurin-6-yl] amino} methyl) phenyl] ethanol

A mixture of 1- (2- { [ (2-chloro-9-isopropylpurin-6-yl) amino] methyl} phenyl) ethanol (151 mg, 0.437 mmol, 1.00 equiv) , piperidin-4-amine (131 mg, 1.31 mmol, 3.00 equiv) and N, N-diisopropylethylamine (169 mg, 1.31 mmol, 3.00 equiv) in n-buthanol (3 mL) was irradiated with microwave radiation for 5 h at 130 ℃. The mixture was allowed to cool down to room temperature and concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions : Column: XBridge Shield RP₁₈ OBD Column, 30*150 mm, 5 μm; Mobile Phase A: Water (10 mmol/L NH₄HCO₃+0.1%NH₃. H₂O) , Mobile Phase B: Acetonitrile; Flow rate: 60 mL/min; Gradient: 5%B to 35%B in 9 min; Wave Length: 254 nm to afford 1- [2- ( { [2- (4-aminopiperidin-1-yl) -9-isopropylpurin-6-yl] amino} methyl) phenyl] ethanol (68 mg, 38%yield as an off-white solid. LCMS (ESI, m/z) : 410 [M+H] ⁺. ¹H-NMR (300 MHz, Chloroform-d) δ 7.56 -7.52 (d, J = 7.6 Hz, 1H) , 7.44 (s, 1H) , 7.36 -7.33 (d, J = 6.0 Hz, 1H) , 7.31 -7.28 (d, J = 6.0 Hz, 1H) , 7.24 -7.14 (m, 1H) , 5.93 -5.87 (m, 1H) , 5.31 -5.21 (m, 1H) , 4.99 -4.56 (m, 5H) , 2.94 -2.86 (m, 3H) , 1.92 -1.84 (m, 2H) , 1.53 -1.52 (m, 9H) , 1.38 -1.24 (m, 2H) .

2- (4-aminopiperidin-1-yl) -9-isopropyl-N- (2- (pyrazin-2-yl) benzyl) -9H-purin-6-amine

Synthesis of 2- (4-aminopiperidin-1-yl) -9-isopropyl-N- (2- (pyrazin-2-yl) benzyl) -9H-purin-6-amine

Synthesis of tert-butyl N- { [2- (pyrazin-2-yl) phenyl] methyl} carbamate

A mixture of 2- { [ (tert-butoxycarbonyl) amino] methyl} phenylboronic acid (500 mg, 1.99 mmol, 1.00 equiv) , 2-chloropyrazine (228 mg, 1.99 mmol, 1.00 equiv) , potassium carbonate (826 mg, 5.97 mmol, 3.00 equiv) and tetrakis (triphenylphosphine) palladium (230 mg, 0.199 mmol, 0.100 equiv) in 1, 4-dioxane (5 mL) and water (1 mL) was stirred for overnight at 100 ℃under nitrogen atmosphere. The mixture was allowed to cool down to room temperature and filtered, the filter cake was washed with ethyl acetate (2 x 30 mL) . The filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions: column, C₁₈ silica gel; mobile phase, Acetonitrile in Water, 0%to 100%gradient in 20 min; detector, UV 254 nm to afford tert-butyl N- { [2- (pyrazin-2-yl) phenyl] methyl} carbamate (504 mg, 89%yield) as a yellow oil. LCMS (ESI, m/z) : 286 [M+H] ⁺.

Synthesis of (2- (pyrazin-2-yl) phenyl) methanamine trifluoroacetate

A mixture of tert-butyl N- { [2- (pyrazin-2-yl) phenyl] methyl} carbamate (200 mg, 0.701 mmol, 1.00 equiv) and trifluoroacetic acid (1 mL) in dichloromethane (5 mL) was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure to afford (2- (pyrazin-2-yl) phenyl) methanamine trifluoroacetate (220 mg, crude) as a yellow oil. LCMS (ESI, m/z) : 186 [M+H-TFA] ⁺.

Synthesis of 2-chloro-9-isopropyl-N- { [2- (pyrazin-2-yl) phenyl] methyl} purin-6-amine

A mixture of (2- (pyrazin-2-yl) phenyl) methanamine trifluoroacetate (100 mg, 0.334 mmol, 1.00 equiv) , 2, 6-dichloro-9-isopropylpurine (77.2 mg, 0.334 mmol, 1.00 equiv) and N, N-diisopropylethylamine (259 mg, 2.00 mmol, 6.00 equiv) in n-buthanol (2.00 mL) was stirred for overnight at 80 ℃. The mixture was allowed to cool down to room temperature and concentrated under reduced pressure. The residue was purified by Prep-TLC with petroleum ether/ethyl acetate = 1/2 to afford 2-chloro-9-isopropyl-N- { [2- (pyrazin-2-yl) phenyl] methyl} purin-6-amine (111 mg, 87%yield) as a yellow oil. LCMS (ESI, m/z) : 380 [M+H] ⁺.

Synthesis of 2- (4-aminopiperidin-1-yl) -9-isopropyl-N- { [2- (pyrazin-2-yl) phenyl] methyl} purin -6-amine

A mixture of 2-chloro-9-isopropyl-N- { [2- (pyrazin-2-yl) phenyl] methyl} purin-6-amine (111 mg, 0.292 mmol, 1.00 equiv) , piperidin-4-amine (87.8 mg, 0.876 mmol, 3.00 equiv) and N, N-diisopropylethylamine (113 mg, 0.876 mmol, 3.00 equiv) in n-buthanol (3.00 mL) was irradiated with microwave radiation for 5 h at 130 ℃. The mixture was allowed to cool down to room temperature and concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions: Column: XBridge Shield RP₁₈ OBD Column, 30*150 mm, 5 μm; Mobile Phase A: Water (10 mmol/L NH₄HCO₃+0.1%NH₃. H₂O) , Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 15%B to 45%B in 9 min; Wave Length: 254 nm to afford 2- (4-aminopiperidin-1-yl) -9-isopropyl-N- { [2- (pyrazin-2-yl) phenyl] methyl} purin-6-amine (18.6 mg, 14%yield) as an off-white solid. LCMS (ESI, m/z) : 444 [M+H] ⁺. ¹H-NMR (300 MHz, Chloroform-d) δ 8.85 -8.84 (d, J = 2.0 Hz, 1H) , 8.75 -8.72 (m, 1H) , 8.57 -8.55 (d, J =4.0 Hz, 1H) , 7.77 -7.71 (m, 1H) , 7.52 -7.48 (m, 2H) , 7.42 -7.33 (m, 2H) , 6.56 (s, 1H) , 4.90 -4.73 (m, 4H) , 4.71 -4.61 (m, 1H) , 3.00 -2.88 (m, 3H) , 1.93 -1.88 (d, J = 14.0 Hz, 4H) , 1.54 -1.51 (d, J = 6.0 Hz, 6H) , 1.41 -1.27 (m, 2H) .

2- (4-aminopiperidin-1-yl) -N- (2- (4- (dimethylamino) piperidin-1-yl) benzyl) -9-isopropyl-9H -purin-6-amine

Synthesis of 2- (4-aminopiperidin-1-yl) -N- (2- (4- (dimethylamino) piperidin-1-yl) benzyl) -9-isopropyl-9H-purin-6-amine

Synthesis of 2- (4- (dimethylamino) piperidin-1-yl) benzonitrile

To a solution of 2-fluorobenzonitrile (500 mg, 4.13 mmol) in DMF (5 mL) were added N, N-dimethylpiperidin-4-amine (1.06 g, 8.26 mmol) and Cs₂CO₃ (2.69 g, 8.26 mmol) , the mixture was stirred at 90℃ for 7h. The reaction mixture was filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO₂, MeOH: DCM=0%to 8%) to give 2- (4- (dimethylamino) piperidin-1-yl) benzonitrile (673 mg, 2.92 mmol, 70.83%yield, 99.64%purity) as a yellow solid.

ESI-MS [M+H] ⁺: 230.33.

Synthesis of 1- (2- (aminomethyl) phenyl) -N, N-dimethylpiperidin-4-amine

To a solution of 2- (4- (dimethylamino) piperidin-1-yl) benzonitrile (673 mg, 2.93 mmol) were added NH₃ (7M in MeOH, 1 mL) and Ni (100 mg, 1.70 mmol) , replaced with H₂ three times and the mixture was stirred at RT for 5h. LCMS show the reaction was completed. The reaction mixture was filtered and concentrated to give 1- (2- (aminomethyl) phenyl) -N, N-dimethylpiperidin-4-amine (670 mg, crude) as an oil.

ESI-MS [M+H] ⁺: 234.36.

Synthesis of 2, 6-dichloro-9-isopropyl-9H-purine

ESI-MS [M+H] ⁺: 231.16.

Synthesis of 2-chloro-N- (2- (4- (dimethylamino) piperidin-1-yl) benzyl) -9-isopropyl-9H-purin-6-amine

To a solution of N- (2- (1H-pyrazol-1-yl) benzyl) -2-chloro-9-isopropyl-9H-purin-6-amine (400 mg, 1.73 mmol) in EtOH (10 mL) were added 1- (2- (aminomethyl) phenyl) -N, N-dimethylpiperidin -4-amine (605.89 mg, 2.60 mmol) and TEA (350.32 mg, 3.46 mmol, 482.86 μL) , the mixture was stirred at 85℃ for 5h. The reaction mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO₂, 0.5M ammonia methanol solution: DCM=0%to 15%) to give 2-chloro-N- (2- (4- (dimethylamino) piperidin-1-yl) benzyl) -9-isopropyl-9H-purin-6-amine (646 mg, 1.50 mmol, 86.54%yield, 99.24%purity) as a white solid.

ESI-MS [M+H] ⁺: 428.37.

Synthesis of 2- (4-aminopiperidin-1-yl) -N- (2- (4- (dimethylamino) piperidin-1-yl) benzyl) -9 -isopropyl-9H-purin-6-amine

To a solution of 2-chloro-N- (2- (4- (dimethylamino) piperidin-1-yl) benzyl) -9-isopropyl -9H-purin-6-amine (200 mg, 467.32 μmol) in NMP (2 mL) were added piperidin-4-amine (93.62 mg, 934.64 μmol) and DIPEA (120.79 mg, 934.64 μmol, 162.79 μL) , the mixture was stirred at 85℃ for 5h. The reaction mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO₂, 0.5M ammonia methanol solution: DCM=0%to 21%) to give 2- (4-aminopiperidin-1-yl) -N- (2- (4- (dimethylamino) piperidin-1-yl) benzyl) -9-isopropyl-9 H-purin-6-amine (92 mg, 186.12 μmol, 39.83%yield, 99.47%purity) as a white solid.

ESI-MS [M+H] ⁺: 492.49.

¹H NMR (400 MHz, MeOD) δ 7.77 (d, J = 1.2 Hz, 1H) , 7.35 (dd, J = 7.6, 1.6 Hz, 1H) , 7.23 –7.17 (m, 1H) , 7.14 (dt, J = 8.0, 1.4 Hz, 1H) , 7.01 (td, J = 7.4, 1.4 Hz, 1H) , 4.80 (s, 2H) , 4.74 (d, J = 13.5 Hz, 2H) , 4.67 (p, J = 6.9 Hz, 1H) , 3.17 (d, J = 11.7 Hz, 2H) , 2.84 (t, J = 12.4 Hz, 3H) , 2.73 (t, J = 11.8 Hz, 2H) , 2.34 (m, 1H) , 2.29 (d, J = 1.3 Hz, 6H) , 1.91 (d, J = 12.2 Hz, 2H) , 1.81 (d, J = 12.6 Hz, 2H) , 1.67 (qd, J = 12.0, 3.8 Hz, 2H) , 1.55 (dd, J = 6.9, 0.9 Hz, 6H) , 1.27 (d, J = 12.3 Hz, 2H) .

2- (4-aminopiperidin-1-yl) -9-isopropyl-N- (2- (4-methyl-1, 4-diazepan-1-yl) benzyl) -9H-purin-6-amine

Synthesis of 2- (4-aminopiperidin-1-yl) -9-isopropyl-N- (2- (4-methyl-1, 4-diazepan-1-yl) benzyl) -9H-purin-6-amine

Synthesis of 2- (1, 4-diazepan-1-yl) benzonitrile

To a solution of 2-fluorobenzonitrile (1000 mg, 8.26 mmol) in DMF (15 mL) were added 1, 4-diazepane (992.43 mg, 9.91 mmol) and Cs₂CO₃ (5.38 g, 16.51 mmol) , the mixture was stirred at 90℃ for 10h. The reaction mixture was filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO₂, 0.5M ammonia methanol solution: DCM=0%to 10%) to give 2- (1, 4-diazepan-1-yl) benzonitrile (767 mg, 3.78 mmol, 45.78%yield, 99.18%purity) as a yellow solid.

ESI-MS [M+H] ⁺: 202.28.

Synthesis of 2- (4-methyl-1, 4-diazepan-1-yl) benzonitrile

To a solution of 2- (1, 4-diazepan-1-yl) benzonitrile (767 mg, 3.81 mmol) in MeOH (10 mL) were added Paraformaldehyde (686.55 mg, 7.62 mmol) and NaBH₃CN (1.20 g, 19.05 mmol) and AcOH (228.85 mg, 3.81 mmol) under N₂, the mixture was stirred at 50℃ for 3h. The reaction mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO₂, 0.5M ammonia methanol solution: DCM=0%to 20%) to give 2- (4-methyl-1, 4-diazepan-1-yl) benzonitrile (708 mg, 3.24 mmol, 84.98%yield, 98.48%purity) as a white solid.

ESI-MS [M+H] ⁺: 216.30.

Synthesis of (2- (4-methyl-1, 4-diazepan-1-yl) phenyl) methanamine

To a solution of 2- (4-methyl-1, 4-diazepan-1-yl) benzonitrile (708 mg, 3.29 mmol) were added NH₃ (3M in MeOH, 1 mL) and Ni (100 mg, 1.70 mmol) , replaced with H₂ three times and the mixture was stirred at RT for 5h. LCMS show the reaction was completed. The reaction mixture was filtered and concentrated to give (2- (4-methyl-1, 4-diazepan-1-yl) phenyl) methanamine (715 mg, crude) as an oil.

ESI-MS [M+H] ⁺: 220.31.

Synthesis of 2, 6-dichloro-9-isopropyl-9H-purine

ESI-MS [M+H] ⁺: 231.16.

Synthesis of 2-chloro-9-isopropyl-N- (2- (4-methyl-1, 4-diazepan-1-yl) benzyl) -9H-purin-6-amine

To a solution of N- (2- (1H-pyrazol-1-yl) benzyl) -2-chloro-9-isopropyl-9H-purin-6-amine (300 mg, 1.30 mmol) in EtOH (20 mL) were added (2- (4-methyl-1, 4-diazepan-1-yl) phenyl) methanamine (711.84 mg, 3.25 mmol) and TEA (262.74 mg, 2.60 mmol, 362.15 μL) , the mixture was stirred at 85℃ for 5h. The reaction mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO₂, 0.5M ammonia methanol solution: DCM=0%to 7%) to give 2-chloro-9-isopropyl-N- (2- (4-methyl-1, 4-diazepan-1-yl) benzyl) -9H-purin-6-amine (193 mg, 458.04 μmol, 35.28%yield, 98.24%purity) as a white solid.

ESI-MS [M+H] ⁺: 414.34.

To a solution of 2-chloro-9-isopropyl-N- (2- (4-methyl-1, 4-diazepan-1-yl) benzyl) -9H-purin-6-amine (193 mg, 466.24 μmol) in NMP (2 mL) were added piperidin-4-amine (93.40 mg, 932.49 μmol) and DIPEA (120.51 mg, 932.49 μmol, 162.42 μL) , the mixture was stirred at 160℃ for 7h. The reaction mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO₂, 0.5M ammonia methanol solution: DCM=0%to 22%) to give 2- (4-aminopiperidin-1-yl) -9-isopropyl-N- (2- (4-methyl-1, 4-diazepan-1-yl) benzyl) -9H-pur in-6-amine (66 mg, 138.18 μmol, 29.64%yield) as a white solid.

ESI-MS [M+H] ⁺: 478.48.

¹H NMR (400 MHz, MeOD) δ 7.78 (s, 1H) , 7.34 (dd, J = 7.4, 1.4 Hz, 1H) , 7.25 –7.15 (m, 2H) , 7.01 (ddd, J = 7.6, 5.9, 2.6 Hz, 1H) , 4.83 (s, 2H) , 4.80 –4.72 (m, 2H) , 4.68 (p, J = 6.8 Hz, 1H) , 3.26 –3.15 (m, 4H) , 2.98 –2.73 (m, 7H) , 2.37 (s, 3H) , 1.97 (p, J = 6.2 Hz, 2H) , 1.87 –1.79 (m, 2H) , 1.55 (d, J = 6.8 Hz, 6H) , 1.32 –1.28 (m, 2H) .

2- (4-aminopiperidin-1-yl) -N- (2- (1- (2-fluoropyridin-4-yl) -1H-pyrazol-4-yl) benzyl) -9-isopropyl-9H-purin-6-amine

Synthesis of 2- (4-aminopiperidin-1-yl) -N- (2- (1- (2-fluoropyridin-4-yl) -1H-pyrazol-4-yl) benzyl) -9-isopropyl-9H-purin-6-amine

Synthesis of 4- (4-bromo-1H-pyrazol-1-yl) -2-fluoropyridine

To a mixture of 4-bromo-1H-pyrazole (500 mg, 3.42 mmol) in DMF (10 mL) was added NaH (162 mg, 5.13 mmol) at 0 ℃. The mixture was stirred at 0 ℃ for 0.5 h, then 2, 4-difluoropyridine (590 mg, 5.13 mmol) was added. The mixture was stirred at room temperature for 3h under N₂. The reaction was quenched with water (50 mL) and extracted with EtOAc (30 mL x 3) . The combined organic layers were washed with brine (50 mL) , dried over anhydrous Na₂SO₄, and concentrated to give the crude product, which was purified by column chromatography (eluent: DCM/MeOH =5 0/1 ～ 30/1) to give 4- (4-bromo-1H-pyrazol-1-yl) -2-fluoropyridine (300 mg, yield: 36.4%) as a light yellow solid. ESI-MS [M +H] ⁺: 242.1.

Synthesis of 2- (1- (2-fluoropyridin-4-yl) -1H-pyrazol-4-yl) benzonitrile

To a mixture of 4- (4-bromo-1H-pyrazol-1-yl) -2-fluoropyridine (300 mg, 1.245 mmol) , (2-cyanophenyl) boronic acid (275 mg, 1.868 mmol) and Cs₂CO₃ (1218 mg, 3.735 mmol) in 1, 4-dioxane (15 mL) and water (1.5 mL) was added Pd (dppf) Cl₂ (91 mg, 0.125 mmol) . The mixture was stirred at 90 ℃ for 3h under N₂. The reaction mixture was cooled to room temperature. The mixture was filtered throughand the filter cake was washed with DCM (30 mL) . The filtrate was concentrated to give the crude, which was purified by Prep-TLC (eluent: PE/EA = 1/1) to give 2- (1- (2-fluoropyridin-4-yl) -1H-pyrazol-4-yl) benzonitrile (287 mg, yield: 87.3%) as a light yellow oil. ESI-MS [M +H] ⁺: 265.2.

Synthesis of (2- (1- (2-fluoropyridin-4-yl) -1H-pyrazol-4-yl) phenyl) methanamine

To a mixture of 2- (1- (2-fluoropyridin-4-yl) -1H-pyrazol-4-yl) benzonitrile (260 mg, 0.985 mmol) in NH₃ (7M solution in MeOH, 5 mL) was added Raney Ni (50 mg) . The reaction mixture was stirred at room temperature for 3h under H₂. The reaction mixture was filtered throughand the filter cake was washed with DCM/MeOH (10/1, 20 mL) . The filtrate was concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH =10/1) to give (2- (1- (2-fluoropyridin-4-yl) -1H-pyrazol-4-yl) phenyl) methanamine (260 mg, yield: 91.8%) as a yellow solid. ESI-MS [M +H] +: 269.2.

Synthesis of 2-chloro-N- (2- (1- (2-fluoropyridin-4-yl) -1H-pyrazol-4-yl) benzyl) -9-isopropyl-9H-purin-6-amine

A mixture of 2, 6-dichloro-9-isopropyl-9H-purine (179 mg, 0.777 mmol) , (2- (1- (2-fluoropyridin-4-yl) -1H-pyrazol-4-yl) phenyl) methanamine (250 mg, 0.933 mmol) and DIPEA (301 mg, 2.332 mmol) in i-PrOH (8 mL) was stirred at 90 ℃ for 3h. The reaction mixture was concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 20/1) to give 2-chloro-N- (2- (1- (2-fluoropyridin-4-yl) -1H-pyrazol-4-yl) benzyl) -9-isopropyl-9H-purin-6-ami ne (90 mg, yield: 72%) as a white solid. ESI-MS [M + H] ⁺: 463.2.

Synthesis of tert-butyl (1- (6- ( (2- (1- (2-fluoropyridin-4-yl) -1H-pyrazol-4-yl) benzyl) amino) -9-isopropyl-9H-purin-2-yl) piperidin-4-yl) carbamate

A mixture of 2-chloro-N- (2- (1- (2-fluoropyridin-4-yl) -1H-pyrazol-4-yl) benzyl) -9-isopropyl-9H-purin-6-amine (160 mg, 0.346 mmol) , tert-butyl piperidin-4-ylcarbamate (83 mg, 0.416 mmol) and DIPEA (134 mg, 1.039 mmol) in i-PrOH (6 mL) was irradiated in microwave at 140 ℃ for 12h. The reaction mixture was concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 15/1) to give tert-butyl (1- (6- ( (2- (1- (2-fluoropyridin-4-yl) -1H-pyrazol-4-yl) benzyl) amino) -9-isopropyl-9H-purin-2-yl) piperidin-4-yl) carbamate (62 mg, yield: 28.6%) as a white solid. ESI-MS [M + H] ⁺: 627.

To a mixture of tert-butyl (1- (6- ( (2- (1- (2-fluoropyridin-4-yl) -1H-pyrazol-4-yl) benzyl) amino) -9-isopropyl-9H-purin-2-yl) piperidin-4-yl) carbamate (50 mg, 0.080 mmol) in MeOH (2 mL) was added HCl (4M solution in 1, 4-dioxane, 2 mL) . The reaction mixture was stirred at room temperature for 1h. The reaction mixture was quenched with NH₃ (7M solution in MeOH, 2 mL) and concentrated in vacuo to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 10/1) to give 2- (4-aminopiperidin-1-yl) -N- (2- (1- (2-fluoropyridin-4-yl) -1H-pyrazol-4-yl) benzyl) -9-isopropyl-9H-purin-6-amine (25.23 mg, yield: 60%) as a white solid.

ESI-MS [M +H] ⁺: 527.3.

¹H NMR (400 MHz, MeOD) δ 8.78 (s, 1H) , 8.43 (s, 1H) , 8.15 (d, J = 5.7 Hz, 1H) , 7.83 (s, 1H) , 7.61 (d, J = 5.8 Hz, 1H) , 7.46 -7.44 (m, 1H) , 7.40 –7.35 (m, 1H) , 7.34 –7.28 (m, 3H) , 4.80 (s, 2H) , 4.66 (d, J = 13.7 Hz, 3H) , 3.28 -3.26 (m, 1H) , 2.77 (d, J = 12 Hz, 2H) , 1.88 (d, J = 15.6 Hz, 2H) , 1.51 (d, J = 6.8 Hz, H) , 1.42 –1.30 (m, 2H) .

2- (4-aminopiperidin-1-yl) -N- (2- (1- (2-fluoropyridin-4-yl) -1H-pyrazol-4-yl) benzyl) -9-isopropyl-9H-purin-6-amine0

Synthesis of 2- (6- (dimethylamino) pyridin-3-yl) benzonitrile

To a mixture of 2-bromobenzonitrile (300 mg, 1.638 mmol) , (6- (dimethylamino) pyridin-3-yl) boronic acid (327 mg, 1.965 mmol) and Na₂CO₃ (522 mg, 4.917 mmol) in DME (10 mL) and water (1 mL) was added Pd (PPh₃) ₄ (192 mg, 0.165 mmol) . The mixture was stirred at 90 ℃ for 16h under N₂. The reaction mixture was cooled to room temperature. The mixture was filtered throughand the filter cake was washed with DCM (30 mL) . The filtrate was concentrated to give the crude, which was purified by Prep-TLC (eluent: PE/EA = 1/1) to give 2- (6- (dimethylamino) pyridin-3-yl) benzonitrile (300 mg, yield: 82.1%) as a light yellow oil. ESI-MS [M +H] ⁺: 224.2.

Synthesis of 5- (2- (aminomethyl) phenyl) -N, N-dimethylpyridin-2-amine

To a mixture of 2- (6- (dimethylamino) pyridin-3-yl) benzonitrile (300 mg, 1.339 mmol) in NH₃ (7M solution in MeOH, 5 mL) was added Raney Ni (50 mg) . The reaction mixture was stirred at room temperature for 3h under H₂. The reaction mixture was filtered throughand the filter cake was washed with DCM/MeOH (10/1, 20 mL) . The filtrate was concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 10/1) to 5- (2- (aminomethyl) phenyl) -N, N-dimethylpyridin-2-amine (294 mg, yield: 96.7%) as a yellow solid. ESI-MS [M +H] +: 228.2.

Synthesis of 2-chloro-N- (2- (6- (dimethylamino) pyridin-3-yl) benzyl) -9-isopropyl-9H -purin-6-amine

A mixture of 2, 6-dichloro-9-isopropyl-9H-purine (230 mg, 1.0 mmol) , 5- (2- (aminomethyl) phenyl) -N, N-dimethylpyridin-2-amine (296 mg, 1.3 mmol) and DIPEA (387 mg, 3.0 mmol) in i-PrOH (8 mL) was stirred at 90 ℃ for 3h. The reaction mixture was concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 20/1) to give 2-chloro-N- (2- (6- (dimethylamino) pyridin-3-yl) benzyl) -9-isopropyl-9H-purin-6-amine (400 mg, yield: 95.0 %) as a white solid. ESI-MS [M + H] ⁺: 422.2.

Synthesis of tert-butyl (1- (6- ( (2- (6- (dimethylamino) pyridin-3-yl) benzyl) amino) -9-isopropyl-9H-purin-2-yl) piperidin-4-yl) carbamate

A mixture of 2-chloro-N- (2- (6- (dimethylamino) pyridin-3-yl) benzyl) -9-isopropyl-9H-purin-6-amine (210 mg, 0.5 mmol) , tert-butyl piperidin-4-ylcarbamate (150 mg, 0.75 mmol) and DIPEA (194 mg, 1.5 mmol) in i-PrOH (8 mL) was irradiated in microwave at 140 ℃ for 4h. The reaction mixture was concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 15/1) to give tert-butyl (1- (6- ( (2- (6- (dimethylamino) pyridin-3-yl) benzyl) amino) -9-isopropyl-9H-purin- 2-yl) piperidin-4-yl) carbamate (100 mg, yield: 34.2%) as a white solid. ESI-MS [M + H] ⁺: 586.2.

Synthesis of 2- (4-aminopiperidin-1-yl) -N- (2- (6- (dimethylamino) pyridin-3-yl) benzyl) -9-isopropyl-9H-purin-6-amine

To a mixture of tert-butyl (1- (6- ( (2- (6- (dimethylamino) pyridin-3-yl) benzyl) amino) -9-isopropyl-9H-purin-2-yl) piperidin-4-yl) carbamate (100 mg, 0.171 mmol) in MeOH (2 mL) was added HCl (4M solution in 1, 4-dioxane, 2 mL) . The reaction mixture was stirred at room temperature for 1h. The reaction mixture was quenched with NH₃ (7M solution in MeOH, 2 mL) and concentrated in vacuo to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 10/1) to give 2- (4-aminopiperidin-1-yl) -N- (2- (6- (dimethylamino) pyridin-3-yl) benzyl) -9-isopropyl-9H-purin-6-amine (46.14 mg, yield: 55.6%) as a white solid.

ESI-MS [M +H] ⁺: 486.2.

¹H NMR (400 MHz, MeOD) δ 8.03 (d, J = 2.1 Hz, 1H) , 7.77 (s, 1H) , 7.60 –7.48 (m, 2H) , 7.34 –7.31 (m, 2H) , 7.25 –7.23 (m, 1H) , 6.67 (d, J = 8.8 Hz, 1H) , 4.77 –4.58 (m, 4H) , 3.11 (s, 6H) , 2.87–2.77 (m, 2H) , 1.81 (d, J = 11.8 Hz, 2H) , 1.56 (d, J = 6.8 Hz, 6H) , 1.24 –1.19 (m, 2H) .

2- (4-aminopiperidin-1-yl) -N- (2- (4-ethylpiperazin-1-yl) benzyl) -9-isopropyl-9H-purin-6-amine

Synthesis of 2- (4-aminopiperidin-1-yl) -N- (2- (4-ethylpiperazin-1-yl) benzyl) -9-isopropyl -9H-purin-6-amine

Synthesis of 2- (4-ethylpiperazin-1-yl) benzonitrile

To a solution of 2-fluorobenzonitrile (1000 mg, 8.26 mmol) in DMF (15 mL) were added 1-ethylpiperazine (1.13 g, 9.91 mmol) and Cs₂CO₃ (5.38 g, 16.51 mmol) , the mixture was stirred at 100℃ for 7h. The reaction mixture was filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO₂, MeOH: DCM=0%to 7%) to give 2- (4-ethylpiperazin-1-yl) benzonitrile (1.45 g, 6.73 mmol, 81.57%yield) as a yellow solid.

ESI-MS [M+H] ⁺: 216.31.

Synthesis of (2- (4-ethylpiperazin-1-yl) phenyl) methanamine

To a solution of 2- (4-ethylpiperazin-1-yl) benzonitrile (1.45 g, 6.73 mmol) were added NH₃ (7M in MeOH, 1 mL) and Ni (200 mg, 3.41 mmol) , replaced with H₂ three times and the mixture was stirred at RT for 17h. LCMS show the reaction was completed. The reaction mixture was filtered and concentrated to give (2- (4-ethylpiperazin-1-yl) phenyl) methanamine (1.48 g, crude) as an oil.

ESI-MS [M+H] ⁺: 220.31.

Synthesis of 2, 6-dichloro-9-isopropyl-9H-purine

ESI-MS [M+H] ⁺: 231.16.

Synthesis of 2-chloro-N- (2- (4-ethylpiperazin-1-yl) benzyl) -9-isopropyl-9H-purin-6-amine

To a solution of N- (2- (1H-pyrazol-1-yl) benzyl) -2-chloro-9-isopropyl-9H-purin-6-amine (300 mg, 1.30 mmol) in EtOH (15 mL) were added (2- (4-ethylpiperazin-1-yl) phenyl) methanamine (427.11 mg, 1.95 mmol) and TEA (262.74 mg, 2.60 mmol, 362.15 μL) , the mixture was stirred at 85℃ for 5h. The reaction mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO₂, 0.5M ammonia methanol solution: DCM=0%to 10%) to give 2-chloro-N- (2- (4-ethylpiperazin-1-yl) benzyl) -9-isopropyl-9H-purin-6-amine (610 mg, 1.46 mmol, 112.43%yield, 99.05%purity) as a white solid.

ESI-MS [M+H] ⁺: 414.32.

Synthesis of 2- (4-aminopiperidin-1-yl) -N- (2- (4-ethylpiperazin-1-yl) benzyl) -9-isopropyl-9H-purin-6-amine

To a solution of 2-chloro-N- (2- (4-ethylpiperazin-1-yl) benzyl) -9-isopropyl-9H-purin-6-amine (200 mg, 483.16 μmol) in NMP (2 mL) were added piperidin-4-amine (96.79 mg, 966.31 μmol) and DIPEA (124.89 mg, 966.31 μmol, 168.31 μL) , the mixture was stirred at 160℃ for 7h. The reaction mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO₂, 0.5M ammonia methanol solution: DCM=0%to 15%) to give 2- (4-aminopiperidin-1-yl) -N- (2- (4-ethylpiperazin-1-yl) benzyl) -9-isopropyl-9H-purin-6-a mine (165 mg, 345.44 μmol, 71.50%yield) as a white solid.

ESI-MS [M+H] ⁺: 478.46.

¹HNMR (400 MHz, MeOD) δ 7.77 (s, 1H) , 7.37 (dd, J = 7.6, 1.6 Hz, 1H) , 7.27 –7.13 (m, 2H) , 7.04 (td, J = 7.3, 1.4 Hz, 1H) , 4.81 (s, 2H) , 4.75 (d, J = 13.3 Hz, 2H) , 4.68 (td, J = 14.1, 13.5, 7.3 Hz, 1H) , 2.98 (t, J = 4.8 Hz, 4H) , 2.95 –2.79 (m, 3H) , 2.65 (s, 4H) , 2.50 (q, J = 7.3 Hz, 2H) , 1.86 –1.77 (m, 2H) , 1.55 (d, J = 6.8 Hz, 6H) , 1.28 (qd, J = 12.1, 4.2 Hz, 2H) , 1.13 (t, J =7.2 Hz, 3H) .

2- (4-aminopiperidin-1-yl) -N- ( (2- (4- (dimethylamino) piperidin-1-yl) pyridin-3-yl) methyl) -9 -isopropyl-9H-purin-6-amine

Synthesis of 2- (4-aminopiperidin-1-yl) -N- ( (2- (4- (dimethylamino) piperidin-1-yl) pyridin-3-yl) methyl) -9-isopropyl-9H-purin-6-amine

Synthesis of 2- (4- (dimethylamino) piperidin-1-yl) nicotinonitrile

To a solution of 2-fluoronicotinonitrile (500 mg, 4.10 mmol) in DMF (10 mL) were added N, N-dimethylpiperidin-4-amine (630.05 mg, 4.91 mmol) and Cs₂CO₃ (2.67 g, 8.19 mmol) , the mixture was stirred at 100℃ for 7h. The reaction mixture was filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO₂, MeOH: DCM=0%to 7%) to give 2- (4- (dimethylamino) piperidin-1-yl) nicotinonitrile (797 mg, 3.45 mmol, 84.14%yield, 99.56%purity) as a yellow solid.

ESI-MS [M+H] ⁺: 231.31.

Synthesis of 1- (3- (aminomethyl) pyridin-2-yl) -N, N-dimethylpiperidin-4-amine

To a solution of 2- (4- (dimethylamino) piperidin-1-yl) nicotinonitrile (797 mg, 3.46 mmol) were added NH₃ (7M in MeOH, 1 mL) and Ni (100 mg, 1.70 mmol) , replaced with H₂ three times and the mixture was stirred at RT for 5h. LCMS show the reaction was completed. The reaction mixture was filtered and concentrated to give 1- (3- (aminomethyl) pyridin-2-yl) -N, N-dimethylpiperidin-4-amine (799 mg, crude) as a white solid.

ESI-MS [M+H] ⁺: 235.33.

Synthesis of 2, 6-dichloro-9-isopropyl-9H-purine

ESI-MS [M+H] ⁺: 231.16.

Synthesis of 2-chloro-N- ( (2- (4- (dimethylamino) piperidin-1-yl) pyridin-3-yl) methyl) -9-isopropyl-9H-purin-6-amine

To a solution of N- (2- (1H-pyrazol-1-yl) benzyl) -2-chloro-9-isopropyl-9H-purin-6-amine (200 mg, 865.50 μmol) in EtOH (2mL) were added 1- (3- (aminomethyl) pyridin-2-yl) -N, N-dimethylpiperidin-4-amine (243.38 mg, 1.04 mmol) and TEA (175.16 mg, 1.73 mmol, 241.43 μL) , the mixture was stirred at 85℃ for 5h. The reaction mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO₂, 0.5M ammonia methanol solution: DCM=0%to 11%) to give 2-chloro-N- ( (2- (4- (dimethylamino) piperidin-1-yl) pyridin-3-yl) methyl) -9-isopropyl-9H-purin-6-amine (352 mg, 818.37 μmol, 94.56%yield, 99.73%purity) as a white solid.

ESI-MS [M+H] ⁺: 429.36.

To a solution of 2-chloro-N- ( (2- (4- (dimethylamino) piperidin-1-yl) pyridin-3-yl) methyl) -9-isopropyl-9H-purin-6-amine (150 mg, 349.68 μmol) in NMP (2 mL) were added piperidin-4-amine (70.05 mg, 699.37 μmol) and DIPEA (90.39 mg, 699.37 μmol, 121.81 μL) , the mixture was stirred at 160℃ for 7h. The reaction mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO₂, 0.5M ammonia methanol solution: DCM=0%to 35%) to give 2- (4-aminopiperidin-1-yl) -N- ( (2- (4- (dimethylamino) piperidin -1-yl) pyridin-3-yl) methyl) -9-isopropyl-9H-purin-6-amine (97 mg, 194.94 μmol, 55.75%yield, 99.01%purity) as a white solid.

ESI-MS [M+H] ⁺: 493.48.

¹HNMR (400 MHz, MeOD) δ 8.09 (dd, J = 5.0, 1.9 Hz, 1H) , 7.79 (s, 1H) , 7.72 (dd, J = 7.5, 1.8 Hz, 1H) , 6.96 (dd, J = 7.5, 4.9 Hz, 1H) , 4.72 (s, 2H) , 4.70 –4.58 (m, 3H) , 3.50 –3.41 (m, 2H) , 2.92 –2.72 (m, 5H) , 2.39 (td, J = 7.8, 3.8 Hz, 1H) , 2.32 (s, 6H) , 2.03 –1.94 (m, 2H) , 1.76 (dt, J = 15.0, 2.4 Hz, 2H) , 1.68 (td, J = 12.1, 3.8 Hz, 2H) , 1.54 (d, J = 6.8 Hz, 6H) , 1.17 (qd, J = 12.3, 4.3 Hz, 2H) .

2- (4-aminopiperidin-1-yl) -N- ( (2- (3- (dimethylamino) -1H-pyrazol-1-yl) pyridin-3-yl) methyl) -9-isopropyl-9H-purin-6-amine

Synthesis of 2- (4-aminopiperidin-1-yl) -N- ( (2- (3- (dimethylamino) -1H-pyrazol-1-yl) pyridin-3-yl) methyl) -9-isopropyl-9H-purin-6-amine

Synthesis of N, N-dimethyl-1H-pyrazol-3-amine

To a solution of 1H-pyrazol-3-amine (2 g, 24.07 mmol) and Paraformaldehyde (3.61 g, 120.35 mmol) in MeOH (50 mL) was added NaCNBH₃ (7.56 g, 120.35 mmol) at RT. The mixture was stirred at 50 ℃ for 4 hours. TLC showed the reaction was completed. The mixture was partitioned between EtOAc (100 mL) and H₂O (100 mL) . The aqueous phase was extracted with EtOAc (100 mL x 2) . The combined organic extracts were washed with brine (100 mL x 3) , dried over anhydrous Na2SO₄, filtered and concentrated under reduced pressure to give the crude product, which was purified by combi flash to give N, N-dimethyl-1H-pyrazol-3-amine (659.14 mg, yield: 24.64%) as a white solid. ESI-MS [M + H] ⁺: 112.2.

Synthesis of 2- (3- (dimethylamino) -1H-pyrazol-1-yl) nicotinonitrile

To a solution of N, N-dimethyl-1H-pyrazol-3-amine (500 mg, 4.50 mmol) and 2-fluoronicotinonitrile (660 mg, 5.40 mmol) in DMF (10 mL) was added Cs₂CO₃ (2.93 g, 9.0 mmol) . The mixture was stirred at RT for 16 hours to form a white suspension. TLC showed the reaction was completed. The mixture was partitioned between EtOAc (30 mL) and H₂O (30 mL) . The aqueous phase was extracted with EtOAc (30 mL x 2) . The combined organic extracts were washed with brine (30 mL x 3) , dried over anhydrous Na2SO₄, filtered and concentrated under reduced pressure to give the crude product, which was purified by combi flash to give 2- (3- (dimethylamino) -1H-pyrazol-1-yl) nicotinonitrile (499.2 mg, yield: 52.04%) as a off-white solid. ESI-MS [M + H] ⁺: 214.2.

Synthesis of 1- (3- (aminomethyl) pyridin-2-yl) -N, N-dimethyl-1H-pyrazol-3-amine

To a solution of 2- (3- (dimethylamino) -1H-pyrazol-1-yl) nicotinonitrile (499.2 mg, 2.34 mmol) in MeOH (5 mL) was added Raney-Ni (138 mg, 2.34 mmol) and NH₃-H₂O (2.34 mmol) . The mixture was stirred at RT for 15 hours under H₂ (15 Psi) . The reaction mixture was filtered and the filtrated to give 1- (3- (aminomethyl) pyridin-2-yl) -N, N-dimethyl-1H-pyrazol-3-amine (310.28 mg, yield: 60.90%) . ESI-MS [M + H] ⁺: 217.3.

Synthesis of 2-chloro-N- ( (2- (3- (dimethylamino) -1H-pyrazol-1-yl) pyridin-3-yl) methyl) -9-isopropyl-9H-purin-6-amine

To a solution of 2, 6-dichloro-9-isopropyl-9H-purine (300 mg, 1.30 mmol) and 1- (3- (aminomethyl) pyridin-2-yl) -N, N-dimethyl-1H-pyrazol-3-amine (310 mg, 1.43 mmol) in EtOH (3 mL) was added TEA (394.11 mg, 3.89 mmol) . The mixture was stirred at 80 ℃ for 8 hours to give a yellow suspension. TLC showed the reaction was completed. The mixture was partitioned between EtOAc (50 mL) and water (50 mL) , the aqueous phase was extracted with EtOAc (50 mL x 2) , the combined extracted phase was washed with water (50 mL) , dried over Na2SO4, filtered, concentrated under reduced pressure to give a off-white oil, which was purified by Combi flash to give 2-chloro-N- ( (2- (3- (dimethylamino) -1H-pyrazol-1-yl) pyridin-3-yl) methyl) -9-isopropyl-9 H-purin-6-amine (241 mg, yield: 45.07%) as a white solid. ESI-MS [M + H] ⁺: 412.9.

Synthesis of 2- (4-aminopiperidin-1-yl) -N- ( (2- (3- (dimethylamino) -1H-pyrazol-1-yl) pyridine -3-yl) methyl) -9-isopropyl-9H-purin-6-amine

To a solution of 2-chloro-N- ( (2- (3- (dimethylamino) -1H-pyrazol-1-yl) pyridin-3-yl) methyl) -9-isopropyl-9H-purin-6-amine (241 mg, 0.59 mmol) in DMSO (3 mL) was added piperidin-4-amine (70.33 mg, 0.70 mmol) and TEA (177.62 mg, 1.76 mmol) , then stirred at 160 ℃ for 8 hours. The reaction was poured into water (30 mL) , extracted with EtOAc (20 mL*2) , the organic layer was washed with water (20 mL*2) , dried over Na₂SO₄, filtered and concentrated to give a residue. The residue purified by column chromatography to give 2- (4-aminopiperidin-1-yl) -N- ( (2- (3- (dimethylamino) -1H-pyrazol-1-yl) pyridin-3-yl) methy l) -9-isopropyl-9H-purin-6-amine (138.62 mg, yield: 49.81%) as a white solid. ESI-MS [M +H] ⁺: 476.6.

¹H NMR (400 MHz, MeOD) δ 8.25 (q, J = 1.8 Hz, 2H) , 7.97 (dd, J = 7.6, 1.6 Hz, 1H) , 7.74 (s, 1H) , 7.17 (dd, J = 7.6, 4.8 Hz, 1H) , 6.05 (d, J = 2.8 Hz, 1H) , 5.09 (s, 2H) , 4.71 (d, J = 13.4 Hz, 2H) , 4.64 (dd, J = 13.6, 6.8 Hz, 1H) , 2.96 (s, 6H) , 2.94 –2.90 (m, 1H) , 2.88 –2.81 (m, 2H) , 1.83 (dd, J = 12.1, 2.4 Hz, 2H) , 1.54 (s, 3H) , 1.52 (s, 3H) , 1.31 –1.22 (m, 2H) .

2- (4-aminopiperidin-1-yl) -N- (2- (5- (dimethylamino) pyrazin-2-yl) benzyl) -9-isopropyl-9H-purin-6-amine

Synthesis of 2- (4-aminopiperidin-1-yl) -N- (2- (5- (dimethylamino) pyrazin-2-yl) benzyl) -9-isopropyl-9H-purin-6-amine

Synthesis of tert-butyl N- ( {2- [5- (dimethylamino) pyrazin-2-yl] phenyl} methyl) carbamate

A mixture of 2- { [ (tert-butoxycarbonyl) amino] methyl} phenylboronic acid (130 mg, 0.518 mmol, 1.00 equiv) , 5-bromo-N, N-dimethylpyrazin-2-amine (100 mg, 0.495 mmol, 0.96 equiv) , potassium carbonate (214 mg, 1.55 mmol, 3.00 equiv) and tetrakis (triphenylphosphine) palladium (59.8 mg, 0.052 mmol, 0.10 equiv) in 1, 4-dioxane (3 mL) and water (0.6 mL) was stirred for overnight at 100 ℃ under nitrogen atmosphere. The mixture was allowed to cool down to room temperature and filtered, the filter cake was washed with methanol (2 x 10 mL) . The filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC with petroleum ether /ethyl acetate (5: 1) to afford tert-butyl N- ( {2- [5- (dimethylamino) pyrazin-2-yl] phenyl} methyl) carbamate (130 mg, 76%yield) as a light yellow solid. LCMS (ESI, m/z) : 329 [M+H] ⁺.

Synthesis of 5- (2- (aminomethyl) phenyl) -N, N-dimethylpyrazin-2-amine 2, 2, 2-trifluoroacetate

A mixture of tert-butyl N- ( {2- [5- (dimethylamino) pyrazin-2-yl] phenyl} methyl) carbamate (130 mg, 0.396 mmol, 1.00 equiv) and TFA (0.60 mL) in dichloromethane (3 mL) was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure to afford 5- (2- (aminomethyl) phenyl) -N, N-dimethylpyrazin-2-amine 2, 2, 2-trifluoroacetate (140 mg, crude) as a yellow oil. LCMS (ESI, m/z) : 229 [M+H-TFA] ⁺.

Synthesis of 2-chloro-N- ( {2- [5- (dimethylamino) pyrazin-2-yl] phenyl} methyl) -9-isopropylpurin-6-amine

A mixture of 5- (2- (aminomethyl) phenyl) -N, N-dimethylpyrazin-2-amine 2, 2, 2-trifluoroacetate (140 mg, 0.409 mmol, 1.00 equiv) , 2, 6-dichloro-9-isopropylpurine (94.5 mg, 0.409 mmol, 1.00 equiv) and N, N-diisopropylethylamine (317 mg, 2.45 mmol, 6.00 equiv) in n-buthanol (2 mL) was stirred for overnight at 80 ℃. The mixture was allowed to cool down to room temperature and concentrated under reduced pressure. The residue was purified by Prep-TLC with petroleum ether /ethyl acetate (5: 1) to afford 2-chloro-N- ( {2- [5- (dimethylamino) pyrazin-2-yl] phenyl} methyl) -9-isopropylpurin-6-amine (160 mg, 92%yield) as a light yellow solid. LCMS (ESI, m/z) : 423 [M+H] ⁺.

Synthesis of 2- (4-aminopiperidin-1-yl) -N- ( {2- [5- (dimethylamino) pyrazin-2-yl] phenyl} methyl) -9-isopropylpurin-6-amine

A mixture of 2-chloro-N- ( {2- [5- (dimethylamino) pyrazin-2-yl] phenyl} methyl) -9-isopropylpurin-6-amine (180 mg, 0.426 mmol, 1.00 equiv) , piperidin-4-amine (128 mg, 1.28 mmol, 3.00 equiv) and N, N-diisopropylethylamine (165 mg, 1.28 mmol, 3.00 equiv) in n-buthanol (3 mL) was irradiated with microwave radiation for 5 h at room temperature. The mixture was allowed to cool down to room temperature and concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C₁₈ Column, 30*150 mm, 5 μm; Mobile Phase A: Water (10 mmol/L NH₄HCO₃) , Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 20%B to 50%B in 7 min; Wave Length: 254 nm to afford 2- (4-aminopiperidin-1-yl) -N- ( {2- [5- (dimethylamino) pyrazin-2-yl] phenyl} methyl) -9-isopropyl purin-6-amine (54.0 mg, 26%yield) as an off-white solid. LCMS (ESI, m/z) : 487 [M+H] ⁺. ¹H-NMR (300 MHz, Chloroform-d) δ 8.31 (d, J = 2.0 Hz, 1H) , 8.23 (d, J = 2.0 Hz, 1H) , 7.69 (m, 1H) , 7.51 (s, 1H) , 7.43 (m, 1H) , 7.34 (m, 2H) , 4.82 -4.76 (m, 4H) , 4.69 -4.61 (m, 1H) , 3.21 (s, 6H) , 2.99 -2.93 (m, 3H) , 1.92 -1.88 (m, 2H) , 1.69 (s, 3H) , 1.53 (s, 6H) , 1.43 -1.32 (m, 2H) .

2- (4-aminopiperidin-1-yl) -9-isopropyl-N- (2- (8-methyl-3, 8-diazabicyclo [3.2.1] octan-3-yl) benzyl) -9H-purin-6-amine

Synthesis of 2- (4-aminopiperidin-1-yl) -9-isopropyl-N- (2- (8-methyl-3, 8-diazabicyclo [3.2.1] octan-3-yl) benzyl) -9H-purin-6-amine

Synthesis of tert-butyl 3- (2-cyanophenyl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate

A mixture of 2-iodobenzonitrile (777 mg, 3.39 mmol, 1.20 equiv) , tert-butyl 3,8-diazabicyclo [3.2.1] octane-8-carboxylate (600 mg, 2.83 mmol, 1.00 equiv) , dicesium carbonate (2.76 g, 8.48 mmol, 3.00 equiv) , palladium acetate (127 mg, 0.565 mmol, 0.20 equiv) and 2- (dicyclohexylphosphino) -2', 4', 6'-triisopropylbiphenyl (269 mg, 0.565 mmol, 0.20 equiv) in toluene (8 mL) was stirred for overnight at 110 ℃ under nitrogen atmosphere. The reaction was quenched with water (50 mL) at room temperature. The resulting mixture was extracted with ethyl acetate (3 x 50 mL) . The combined organic layers were washed with water (3 x 50 mL) , dried over anhydrous sodium sulfate, filtrated and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether /ethyl acetate (10/1) to afford tert-butyl 3- (2-cyanophenyl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (607 mg, 68%yield) as yellow oil. LCMS (ESI, m/z) : 314 [M+H] ⁺.

Synthesis of 1- (2- {8-methyl-3, 8-diazabicyclo [3.2.1] octan-3-yl} phenyl) methanamine

To a stirred mixture of tert-butyl 3- (2-cyanophenyl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (200 mg, 0.638 mmol, 1.00 equiv) and tetrahydrofuran (4 mL) was added lithium aluminum hydride (0.38 mL, 0.950 mmol, 1.49 equiv, 2.5 M in tetrahydrofuran) dropwise at 0 ℃ under nitrogen atmosphere. The final reaction mixture was stirred for 2 h at room temperature and quenched with ice/water (2 mL) at room temperature. The solids were filtered off, the filter cake was washed with tetrahydrofuran (3 x 10 mL) . The filtrate was concentrated under reduced pressure to afford 1- (2- {8-methyl-3, 8-diazabicyclo [3.2.1] octan-3-yl} phenyl) methanamine (169 mg, crude) as a yellow oil. LCMS (ESI, m/z) : 232 [M+H] ⁺.

Synthesis of 2-chloro-9-isopropyl-N- [ (2- {8-methyl-3, 8-diazabicyclo [3.2.1] octan-3-yl} phenyl) methyl] purin-6-amine

A mixture of 1- (2- {8-methyl-3, 8-diazabicyclo [3.2.1] octan-3-yl} phenyl) methanamine (160 mg, 0.692 mmol, 1.00 equiv) , 2, 6-dichloro-9-isopropylpurine (160 mg, 0.692 mmol, 1.00 equiv) and N, N-diisopropylethylamine (268 mg, 2.08 mmol, 3.00 equiv) in n-butanol (5 mL) was stirred for overnight at 80 ℃. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether /ethyl acetate (1/1) to afford 2-chloro-9-isopropyl-N- [ (2- {8-methyl-3, 8-diazabicyclo [3.2.1] octan-3-yl} phenyl) methyl] purin -6-amine (220 mg, 75%yield) as a yellow solid. LCMS (ESI, m/z) : 426 [M+H] ⁺.

Synthesis of 2- (4-aminopiperidin-1-yl) -9-isopropyl-N- [ (2- {8-methyl-3, 8-diazabicyclo [3.2.1] octan-3-yl} phenyl) methyl] purin-6-amine

A mixture of 2-chloro-9-isopropyl-N- [ (2- {8-methyl-3, 8-diazabicyclo [3.2.1] octan-3-yl} phenyl) methyl] purin-6-amine (100 mg, 0.235 mmol, 1.00 equiv) , piperidin-4-amine (70.5 mg, 0.705 mmol, 3.00 equiv) and N, N-diisopropylethylamine (91.0 mg, 0.705 mmol, 3.00 equiv) in n-butanol (1.5 mL) was irradiated with microwave radiation for 5 h at 130 ℃. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions: Column: XSelect CSH Prep C₁₈ OBD Column, 19*150 mm, 5 μm; Mobile Phase A: Water (10 mmol/L NH₄HCO₃) , Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 30%B to 50%B in 7 min; Wave Length: 254 nm to afford 2- (4-aminopiperidin-1-yl) -9-isopropyl-N- [ (2- {8-methyl-3, 8-diazabicyclo [3.2.1] octan-3-yl} phe nyl) methyl] purin-6-amine (52.4 mg, 46%yield) as a white solid. LCMS (ESI, m/z) : 490 [M+H] ⁺. ¹H-NMR (300 MHz, Methanol-d₄) δ 7.79 (s, 1H) , 7.36 (d, J = 4.0 Hz, 1H) , 7.27 -7.20 (m, 2H) , 7.15 -6.98 (m, 1H) , 4.89 -4.61 (m, 5H) , 3.26 (s, 2H) , 3.12 (d, J = 6.0 Hz, 2H) , 3.01 -2.70 (m, 5H) , 2.36 (s, 3H) , 2.10 (s, 4H) , 1.85 (d, J = 8.0 Hz, 2H) , 1.58 (d, J = 6.0 Hz, 6H) , 1.35 -1.31 (m, 2H) .

2- ( (1- (2- ( ( (2- (4-aminopiperidin-1-yl) -9-isopropyl-9H-purin-6-yl) amino) methyl) phenyl) -1H-pyrazol-3-yl) (methyl) amino) ethan-1-ol

Synthesis of 2- ( (1- (2- ( ( (2- (4-aminopiperidin-1-yl) -9-isopropyl-9H-purin-6-yl) amino) methyl) phenyl) -1H-pyrazol-3-yl) (methyl) amino) ethan-1-ol

Synthesis of 2- {3- [ (2-hydroxyethyl) (methyl) amino] pyrazol-1-yl} benzonitrile

A mixture of 2- (3-iodopyrazol-1-yl) benzonitrile (600 mg, 2.03 mmol, 1.00 equiv) methylethanolamine (458 mg, 6.09 mmol, 3.00 equiv) , L-proline (46.8 mg, 0.407 mmol, 0.20 equiv) , potassium phosphate (1.29 g, 6.10 mmol, 3.00 equiv) and cuprous iodide (77.4 mg, 0.407 mmol, 0.20 equiv) in DMSO (2 mL) was stirred for overnight at 100 ℃ under nitrogen atmosphere. The mixture was allowed to cool down to room temperature and concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions: column, C₁₈ silica gel; mobile phase, acetonitrile in water, 0%to 100% gradient in 20 min; detector, UV 254 nm to afford 2- {3- [ (2-hydroxyethyl) (methyl) amino] pyrazol-1-yl} benzonitrile (300 mg, 61%yield) as a light yellow solid. LCMS (ESI, m/z) : 243 [M+H] ⁺.

Synthesis of 2- ( {1- [2- (aminomethyl) phenyl] pyrazol-3-yl} (methyl) amino) ethanol

A mixture of 2- {3- [ (2-hydroxyethyl) (methyl) amino] pyrazol-1-yl} benzonitrile (300 mg, 1.24 mmol, 1.00 equiv) and Raney Nickel (10.6 mg) in ammonia (gas) (3.0 mL, 7.5 M in methanol) was stirred for overnight at room temperature under hydrogen atmosphere (2 ～ 3 atm) . The solids were filtered off, the filter cake was washed with methanol (2 x 10 mL) . The filtrate was concentrated under reduced pressure to afford 2- ( {1- [2- (aminomethyl) phenyl] pyrazol-3-yl} (methyl) amino) ethanol (230 mg, crude) as a yellow oil. LCMS (ESI, m/z) : 247 [M+H] ⁺.

Synthesis of 2- { [1- (2- { [ (2-chloro-9-isopropylpurin-6-yl) amino] methyl} phenyl) pyrazol-3-yl] (methyl) amino} ethanol

A mixture of 2- ( {1- [2- (aminomethyl) phenyl] pyrazol-3-yl} (methyl) amino) ethanol (115 mg, 0.467 mmol, 1.00 equiv) and N, N-diisopropylethylamine (181 mg, 1.40 mmol, 3.00 equiv) in n-buthanol (2 mL) was stirred for overnight at 80 ℃. The mixture was allowed to cool down to room temperature and concentrated under reduced pressure. The residue was purified by Prep-TLC with petroleum ether /ethyl acetate (1/1) to afford 2- { [1- (2- { [ (2-chloro-9-isopropylpurin-6-yl) amino] methyl} phenyl) pyrazol-3-yl] (methyl) amino} ethanol (120 mg, 58%yield) as a light yellow solid. LCMS (ESI, m/z) : 441 [M+H] ⁺.

Synthesis of 2- ( {1- [2- ( { [2- (4-aminopiperidin-1-yl) -9-isopropylpurin-6-yl] amino} methyl) phenyl] pyrazol-3-yl} (methyl) amino) ethanol

A mixture of 2- { [1- (2- { [ (2-chloro-9-isopropylpurin-6-yl) amino] methyl} phenyl) pyrazol-3-yl] (methyl) amino} ethanol (120 mg, 0.272 mmol, 1.00 equiv) , piperidin-4-amine (81.8 mg, 0.816 mmol, 3.00 equiv) and N, N-diisopropylethylamine (105 mg, 0.816 mmol, 3.00 equiv) in n-buthanol (1 mL) was irradiated with microwave radiation for 5 h at 130 ℃. The mixture was allowed to cool down to room temperature and concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C₁₈ Column, 30*150 mm, 5 μm; Mobile Phase A: Water (10 mmol/L NH₄HCO₃) , Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 20%B to 50%B in 7 min; Wave Length: 254 nm to afford 2- ( {1- [2- ( { [2- (4-aminopiperidin-1-yl) -9-isopropylpurin-6-yl] amino} methyl) phenyl] pyrazol-3-yl} (methyl) amino) ethanol (62.8 mg, 46%yield) as an off-white solid. LCMS (ESI, m/z) : 505 [M+H] ⁺. ¹H-NMR (300 MHz, Chloroform-d) δ 7.76 (d, J = 2.0 Hz, 1H) , 7.66 -7.55 (m, 2H) , 7.51 (s, 1H) , 7.28 (d, J = 2.0 Hz, 1H) , 7.28 -7.18 (m, 2H) , 5.85 (d, J = 2.0 Hz, 1H) , 4.89 (d, J = 2.0 Hz, 2H) , 4.79 (d, J = 6.0 Hz, 2H) , 4.64 -4.52 (m, 1H) , 3.95 -3.89 (m, 2H) , 3.65 -3.60 (m, 2H) , 3.02 (s, 6H) , 1.98 -1.91 (m, 2H) , 1.50 (s, 6H) , 1.42 -1.39 (m, 2H) .

2- (1- (2- ( ( (2- (4-aminopiperidin-1-yl) -9-isopropyl-9H-purin-6-yl) amino) methyl) phenyl) -1H -pyrrol-3-yl) propan-2-ol

Synthesis of 2- (1- (2- ( ( (2- (4-aminopiperidin-1-yl) -9-isopropyl-9H-purin-6-yl) amino) methyl) phenyl) -1H-pyrrol-3-yl) propan-2-ol

Synthesis of methyl 1- (2-cyanophenyl) pyrrole-3-carboxylate

A mixture of methyl 1H-pyrrole-3-carboxylate (500 mg, 4.00 mmol, 1.00 equiv) , 2-fluorobenzonitrile (581 mg, 4.80 mmol, 1.20 equiv) and potassium carbonate (1.10 g, 8.00 mmol, 2.00 equiv) in DMF (10 mL) was stirred for overnight at 60 ℃ under nitrogen atmosphere. The reaction was quenched with ice/water (50 mL) at room temperature. The resulting mixture was extracted with ethyl acetate (300 mL) . The combined organic layers were washed with water (3 x 50 mL) , dried over anhydrous sodium sulfate, filtrated and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether /ethyl acetate (1: 1) to afford methyl 1- (2-cyanophenyl) pyrrole-3-carboxylate (710 mg, 79%yield) as a yellow solid. LCMS (ESI, m/z) : 227 [M+H] ⁺.

Synthesis of 2- [3- (2-hydroxypropan-2-yl) pyrrol-1-yl] benzonitrile

To a stirred mixture of methyl 1- (2-cyanophenyl) pyrrole-3-carboxylate (300 mg, 1.33 mmol, 1.00 equiv) and tetrahydrofuran (6 mL) was added methyl-magnesiubromide (1.77 mL, 5.31 mmol, 4.00 equiv, 3M in THF) dropwise at 0℃ under nitrogen atmosphere. Then the resulting mixture was stirred for 2 h at 60 ℃ under nitrogen atmosphere and quenched with saturated ammonium chloride solution (40 mL) at room temperature. The resulting mixture was extracted with ethyl acetate (3 x 50 mL) . The combined organic layers were washed with brine (2 x 50 mL) , dried over anhydrous sodium sulfate, filtrated and concentrated under reduced pressure to afford 2- [3- (2-hydroxypropan-2-yl) pyrrol-1-yl] benzonitrile (330 mg, crude) as yellow oil. LCMS (ESI, m/z) : 209 [M+H-H₂O] ⁺.

Synthesis of 2- {1- [2- (aminomethyl) phenyl] pyrrol-3-yl} propan-2-ol

To a stirred solution of 2- [3- (2-hydroxypropan-2-yl) pyrrol-1-yl] benzonitrile (300 mg, 1.33 mmol, 1.00 equiv) and tetrahydrofuran (6 mL) were added lithium aluminum hydride (0.8 mL, 2.00 mmol, 1.50 equiv, 2.5 M in tetrahydrofuran) dropwise at 0℃. Then the resulting mixture was stirred for 2 h at room temperature and quenched with ice/water (3 mL) at room temperature. The solids were filtered off, the filter cake was washed with tetrahydrofuran (3 x 10 mL) . The filtrate was concentrated under reduced pressure to afford 2- {1- [2- (aminomethyl) phenyl] pyrrol-3-yl} propan-2-ol (320 mg, crude) as yellow oil. LCMS (ESI, m/z) : 213 [M+H-H₂O] ⁺.

A mixture of 2- {1- [2- (aminomethyl) phenyl] pyrrol-3-yl} propan-2-ol (310 mg, 1.35 mmol, 1.00 equiv) , 2, 6-dichloro-9-isopropylpurine (311 mg, 1.35 mmol, 1.00 equiv) and N, N-diisopropylethylamine (522 mg, 4.04 mmol, 3.00 equiv) in n-butanol (6 mL) was stirred for overnight at 80 ℃ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with ethyl acetate to afford 2- [1- (2- { [ (2-chloro-9-isopropylpurin-6-yl) amino] methyl} phenyl) pyrrol-3-yl] propan-2-ol (110 mg, 19%yield) as a yellow solid. LCMS (ESI, m/z) : 407 [M+H-H₂O] ⁺.

Synthesis of 2- {1- [2- ( { [2- (4-aminopiperidin-1-yl) -9-isopropylpurin-6-yl] amino} methyl) phenyl] pyrrol-3-yl} propan-2-ol

A mixture of 2- [1- (2- { [ (2-chloro-9-isopropylpurin-6-yl) amino] methyl} phenyl) pyrrol-3-yl] propan-2-ol (100 mg, 0.236 mmol, 1.00 equiv) piperidin-4-amine (70.7 mg, 0.708 mmol, 3.00 equiv) and N, N-diisopropylethylamine (91.24 mg, 0.708 mmol, 3.00 equiv) in n-butanol (4 mL) was irradiated with microwave radiation for 3 h at 100 ℃ and concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C₁₈ Column, 30*150 mm, 5 μm; Mobile Phase A: Water (10 mmol/L NH₄HCO₃+0.1%NH₃. H₂O) , Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 43%B to 63%B in 7 min; Wave Length: 254 nm to afford 2- {1- [2- ( { [2- (4-aminopiperidin-1-yl) -9-isopropylpurin-6-yl] amino} methyl) phenyl] pyrrol-3-yl } propan-2-ol (3.5 mg, 3%yield) as a white solid. LCMS (ESI, m/z) : 489 [M+H] ⁺. ¹H-NMR (300 MHz, Methanol-d₄) δ 7.80 (s, 1H) , 7.60 -7.47 (m, 1H) , 7.41 -7.25 (m, 3H) , 6.80 -6.76 (m, 2H) , 6.32 -6.31 (m, 1H) , 4.77 -4.54 (m, 5H) , 2.98 -2.68 (m, 3H) , 1.83 (d, J = 6.0 Hz, 2H) , 1.64 -1.41 (m, 12H) , 1.28 -1.19 (m, 2H) .

2- (3- ( ( (2- (4-aminopiperidin-1-yl) -9-isopropyl-9H-purin-6-yl) amino) methyl) - [2, 3'-bipyridin] -6'-yl) propan-2-ol

Synthesis of 2- (3- ( ( (2- (4-aminopiperidin-1-yl) -9-isopropyl-9H-purin-6-yl) amino) methyl) - [2, 3'-bipyridin] -6'-yl) propan-2-ol

Synthesis of 2- (5-bromopyridin-2-yl) propan-2-ol

To a stirred mixture of methyl 5-bromopyridine-2-carboxylate (2.00 g, 9.26 mmol, 1.00 equiv) and tetrahydrofuran (20 mL) was added methyl-magnesiubromide (37.0 mL, 37.0 mmol, 4.00 equiv, 1M in THF) in dropwise at 0℃ under nitrogen atmosphere. The resulting mixture was stirred for overnight at room temperature and quenched with saturated NH₄Cl (100 mL, aq. ) at room temperature. The resulting mixture was extracted with ethyl acetate (3 x 100 mL) . The combined organic layers were washed with brine (2 x 50 mL) , dried over anhydrous sodium sulfate, filtrated and concentrated under reduced pressure to afford 2- (5-bromopyridin-2-yl) propan-2-ol (565 mg, 28%yield) as yellow oil. LCMS (ESI, m/z) : 216 [M+H] ⁺.

Synthesis of 2- [5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-yl] propan-2-ol

A mixture of 2- (5-bromopyridin-2-yl) propan-2-ol (560 mg, 2.59 mmol, 1.00 equiv) , bis (pinacolato) diboron (658 mg, 2.59 mmol, 1.00 equiv) , potassium acetate (508 mg, 5.18 mmol, 2.00 equiv) and [1, 1'-bis (diphenylphosphino) ferrocene] dichloropalladium (379 mg, 0.518 mmol, 0.20 equiv) in 1, 4-dioxane (6 mL) was stirred for overnight at 100℃ under nitrogen atmosphere. The solids were filtered off, the filter cake was washed with ethyl acetate (3 x 10 mL) . The filtrate was concentrated under reduced pressure to afford 2- [5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-yl] propan-2-ol (1.60 g, crude) as brown oil. LCMS (ESI, m/z) : 264 [M+H] ⁺.

Synthesis of 6'- (2-hydroxypropan-2-yl) - [2, 3'-bipyridine] -3-carbonitrile

A mixture of 2- [5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-yl] propan-2-ol (230 mg, 0.874 mmol, 1.00 equiv) , 2-chloropyridine-3-carbonitrile (182 mg, 1.31 mmol, 1.50 equiv) , potassium carbonate (242 mg, 1.75 mmol, 2.00 equiv) , tetrakis (triphenylphosphine) palladium (101 mg, 0.087 mmol, 0.10 equiv) and water (2 mL) in 1, 4-dioxane (10 mL) was stirred for overnight at 100℃ under nitrogen atmosphere and quenched with water (20 mL) at room temperature. The resulting mixture was extracted with ethyl acetate (3 x 150 mL) . The combined organic layers were dried over anhydrous sodium sulfate, filtrated and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with ethyl acetate to afford 6'- (2-hydroxypropan-2-yl) - [2, 3'-bipyridine] -3-carbonitrile (180 mg, 86%yield) as yellow oil. LCMS (ESI, m/z) : 240 [M+H] ⁺.

Synthesis of 2- [3- (aminomethyl) - [2, 3'-bipyridin] -6'-yl] propan-2-ol

A mixture of 6'- (2-hydroxypropan-2-yl) - [2, 3'-bipyridine] -3-carbonitrile (180 mg, 0.752 mmol, 1.00 equiv) and Raney Nickel (20 mg) in NH₃ (g) (5 mL, 7M in methanol) was stirred for overnight at room temperature under hydrogen atmosphere (2 -3 atm) . The solids were filtered off, the filter cake was washed with methanol (3 x 10 mL) . The filtrate was concentrated under reduced pressure to afford 2- [3- (aminomethyl) - [2, 3'-bipyridin] -6'-yl] propan-2-ol (140 mg, crude) as a red oil. LCMS (ESI, m/z) : 244 [M+H] ⁺.

Synthesis of 2- (3- { [ (2-chloro-9-isopropylpurin-6-yl) amino] methyl} - [2, 3'-bipyridin] -6'-yl) propan-2-ol

A mixture of 2- [3- (aminomethyl) - [2, 3'-bipyridin] -6'-yl] propan-2-ol (140 mg, 0.575 mmol, 1.00 equiv) , 2, 6-dichloro-9-isopropylpurine (133 mg, 0.575 mmol, 1.00 equiv) and N, N-diisopropylethylamine (223 mg, 1.73 mmol, 3.00 equiv) in n-butanol (6 mL) was stirred for overnight at 80℃. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with ethyl acetate to afford 2- (3- { [ (2-chloro-9-isopropylpurin-6-yl) amino] methyl} - [2, 3'-bipyridin] -6'-yl) propan-2-ol (170 mg, 67%yield) as yellow oil. LCMS (ESI, m/z) : 438 [M+H] ⁺.

Synthesis of 2- [3- ( { [2- (4-aminopiperidin-1-yl) -9-isopropylpurin-6-yl] amino} methyl) - [2, 3'-bipyridin] -6'-yl] propan-2-ol

A mixture of 2- (3- { [ (2-chloro-9-isopropylpurin-6-yl) amino] methyl} - [2, 3'-bipyridin] -6'-yl) propan-2-ol (100 mg, 0.228 mmol, 1.00 equiv) , piperidin-4-amine (68.6 mg, 0.684 mmol, 3.00 equiv) and N, N-diisopropylethylamine (88.5 mg, 0.684 mmol, 3.00 equiv) in n-butanol (1.5 mL) was irradiated with microwave radiation for 5 h at 130℃. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions: Column: XSelect CSH Prep C₁₈ OBD Column, 19*150 mm, 5 μm; Mobile Phase A: Water (10 mmol/L NH₄HCO₃) , Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 16%B to 39%B in 7 min; Wave Length: 254 nm to afford 2- [3- ( { [2- (4-aminopiperidin-1-yl) -9-isopropylpurin-6-yl] amino} methyl) - [2, 3'-bipyridin] -6'-yl] propan-2-ol (67.0 mg, 58%yield) as a white solid. LCMS (ESI, m/z) : 502 [M+H] ⁺. ¹H-NMR (300 MHz, Methanol-d₄) δ 8.65 (d, J = 2.0 Hz, 1H) , 8.52 (d, J = 4.0 Hz, 1H) , 8.02 -7.97 (m, 2H) , 7.79 (d, J = 6.0 Hz, 2H) , 7.45 -7.41 (m, 1H) , 4.76 (s, 2H) , 4.69 -4.60 (m, 1H) , 4.50 (d, J = 8.0 Hz, 2H) , 2.85 -2.70 (m, 3H) , 1.76 (d, J = 8.0 Hz, 2H) , 1.57 -1.45 (m, 12H) , 1.21 -1.08 (m, 2H) .

2- (4-aminopiperidin-1-yl) -N- (2- (3- (cyclopropylamino) -1H-pyrazol-1-yl) benzyl) -9-isopropyl-9H-purin-6-amine

Synthesis of 2- (4-aminopiperidin-1-yl) -N- (2- (3- (cyclopropylamino) -1H-pyrazol-1-yl) benzyl) -9-isopropyl-9H-purin-6-amine

Synthesis of 2- (3-iodopyrazol-1-yl) benzonitrile

A mixture of 2-fluorobenzonitrile (200 mg, 1.65 mmol, 1.00 equiv) , 3-iodo-1H-pyrazole (384 mg, 1.98 mmol, 1.20 equiv) and dicesium carbonate (1.07 g, 3.30 mmol, 2.00 equiv) in DMF (2 mL) was stirred for overnight at room temperature. The solids were filtered off, the filter cake was washed with ethyl acetate (2 x 10 mL) . The filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions: column, C₁₈ silica gel; mobile phase, acetonitrile in water, 0%to 100%gradient in 20 min; detector, UV 254 nm to afford 2- (3-iodopyrazol-1-yl) benzonitrile (568 mg, crude) as a white solid. LCMS (ESI, m/z) : 296 [M+H] ⁺.

Synthesis of 2- [3- (cyclopropylamino) pyrazol-1-yl] benzonitrile

A mixture of 2- (3-iodopyrazol-1-yl) benzonitrile (568 mg, 1.92 mmol, 1.00 equiv) , aminocyclopropane (549 mg, 9.62 mmol, 5.00 equiv) , L-proline (44.3 mg, 0.380 mmol, 0.20 equiv) , potassium phosphate (817 mg, 3.85 mmol, 2.00 equiv) and cuprous iodide (73.3 mg, 0.385 mmol, 0.20 equiv) in DMSO (3 mL) was stirred for overnight at 100 ℃ under nitrogen atmosphere. The mixture was allowed to cool down to room temperature and filtered, the filter cake was washed with ethyl acetate (2 x 10 mL) . The filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions: column, C₁₈ silica gel; mobile phase, MeCN in water, 0%to 100%gradient in 20 min; detector, UV 254 nm to afford 2- [3- (cyclopropylamino) pyrazol-1-yl] benzonitrile (110 mg, 26%yield) as an off-white solid. LCMS (ESI, m/z) : 225 [M+H] ⁺.

Synthesis of 1- [2- (aminomethyl) phenyl] -N-cyclopropylpyrazol-3-amine

A mixture of 2- [3- (cyclopropylamino) pyrazol-1-yl] benzonitrile (110 mg, 0.490 mmol, 1.00 equiv) , lithium aluminium hydride (1 mL, 2.5 mmol, 5.1 equiv, 2.5 M in tetrahydrofuran) and THF (5 mL) was stirred for overnight at room temperature under nitrogen atmosphere. The reaction was quenched with water (0.2 mL) , 15%sodium hydroxide (0.6 mL) and water (0.2 mL) at 0 ℃. The resulting mixture was diluted with ethyl acetate (10 mL) , filtered, the filter cake was washed with ethyl acetate (2 x 10 mL) . The filtrate was concentrated under reduced pressure to afford 1- [2- (aminomethyl) phenyl] -N-cyclopropylpyrazol-3-amine (130 mg, crude) as an off-white solid. LCMS (ESI, m/z) : 229 [M+H] ⁺.

Synthesis of 2-chloro-N- ( {2- [3- (cyclopropylamino) pyrazol-1-yl] phenyl} methyl) -9-isopropylpurin-6-amine

A mixture of 1- [2- (aminomethyl) phenyl] -N-cyclopropylpyrazol-3-amine (130 mg, 0.569 mmol, 1.00 equiv) and N, N-diisopropylethylamine (221 mg, 1.71 mmol, 3.00 equiv) in n-buthanol (2 mL) was stirred for overnight at 80 ℃. The mixture was allowed to cool down to room temperature and concentrated under reduced pressure. The residue was purified by Prep-TLC with petroleum ether /ethyl acetate (1: 1) to afford 2-chloro-N- ( {2- [3- (cyclopropylamino) pyrazol-1-yl] phenyl} methyl) -9-isopropylpurin-6-amine (40.0 mg, 17%yield) as a light yellow solid. LCMS (ESI, m/z) : 423 [M+H] ⁺.

Synthesis of 2- (4-aminopiperidin-1-yl) -N- ( {2- [3- (cyclopropylamino) pyrazol-1-yl] phenyl} methyl) -9-isopropylpurin-6-amine

A mixture of 2-chloro-N- ( {2- [3- (cyclopropylamino) pyrazol-1-yl] phenyl} methyl) -9-isopropylpurin-6-amine (40.0 mg, 0.095 mmol, 1.00 equiv) , piperidin-4-amine (9.47 mg, 0.095 mmol, 1.00 equiv) and N, N-diisopropylethylamine (36.6 mg, 0.285 mmol, 3.00 equiv) in n-buthanol (2 mL) was irradiated with microwave radiation for 5 h at 130 ℃. The mixture was allowed to cool down to room temperature and concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions: Column: XSelect CSH Prep C₁₈ OBD Column, 19*250 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH₄HCO₃) , Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 46%B to 66%B in 7 min; Wave Length: 254 nm to afford 2- (4-aminopiperidin-1-yl) -N- ( {2- [3- (cyclopropylamino) pyrazol-1-yl] phenyl} methyl) -9-isopro pylpurin-6-amine (4.4 mg, 10%yield) as an off-white solid. LCMS (ESI, m/z) : 487 [M+H] ⁺. ¹H-NMR (300 MHz, Chloroform-d) δ 7.64 (s, 1H) , 7.55 -7.42 (m, 2H) , 7.24 -7.42 (d, J = 4.0 Hz, 1H) , 7.21 (s, 1H) , 6.79 (s, 1H) , 5.97 -5.95 (d, J = 4.0 Hz, 1H) , 4.77 -4.70 (d, J = 14.0 Hz, 4H) , 4.63 (s, 2H) , 2.95 -2.89 (d, J = 12.0 Hz, 3H) , 2.63 (s, 1H) , 1.88 –1.82 (d, J = 12.0 Hz, 2H) , 1.54 -1.48 (m, 6H) , 1.33 -1.27 (d, J = 12.0 Hz, 2H) , 0.74 –0.71 (d, J = 6.0 Hz, 2H) , 0.59 (s, 2H) .

4- (2- ( ( (2- (4-aminopiperidin-1-yl) -9-isopropyl-9H-purin-6-yl) amino) methyl) phenyl) -N, N-dimethyloxazol-2-amine 2, 2, 2-trifluoroacetate

Synthesis of 4- (2- ( ( (2- (4-aminopiperidin-1-yl) -9-isopropyl-9H-purin-6-yl) amino) methyl) phenyl) -N, N-dimethyloxazol-2-amine 2, 2, 2-trifluoroacetate

Synthesis of 4- (2-bromophenyl) -1, 3-oxazole

2-bromo-1- (2-bromophenyl) ethanone (2.00 g, 7.19 mmol, 1.0 equiv) in ammonium formate (20 mL) was irradiated with microwave radiation for 2 h at 110 ℃ under nitrogen atmosphere. The mixture was allowed to cool down to room temperature and quenched with water (50 mL) . The mixture was extracted with ethyl acetate (2 x 30 mL) . The combined organic layers were washed with brine (2 x 30 mL) , dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether /ethyl acetate (10: 1) to afford 4- (2-bromophenyl) -1, 3-oxazole (820 mg, 51%yield) as a yellow oil. LCMS (ESI, m/z) : 224 [M+H] ⁺.

Synthesis of 4- (2-bromophenyl) -2-chloro-1, 3-oxazole

A solution of 4- (2-bromophenyl) -1, 3-oxazole (400 mg, 1.79 mmol, 1.0 equiv) in tetrahydrofuran (4 mL) was stirred for 10 min at -78 ℃ under nitrogen atmosphere then followed by the addition of lithium hexamethyldisiliazide (2.68 mL, 2.68 mmol, 1.50 equiv, 1.0 M in tetrahydrofuran) dropwise at -78 ℃. The mixture was stirred for 30 min at -78 ℃, then perchloroethane (1.26 g, 5.35 mmol, 3.00 equiv, in 4 mL tetrahydrofuran) was added dropwise to above mixture at -78 ℃. The mixture of was stirred for overnight at room temperature under nitrogen atmosphere and concentrated under reduced pressure to afford 4- (2-bromophenyl) -2-chloro-1, 3-oxazole (420 mg, crude) as a yellow oil. LCMS (ESI, m/z) : 258 [M+H] ⁺.

Synthesis of 4- (2-bromophenyl) -N, N-dimethyl-1, 3-oxazol-2-amine

4- (2-bromophenyl) -2-chloro-1, 3-oxazole (420 mg, 1.63 mmol, 1.00 equiv) in dimethylamine (5 mL, 2 M in THF) was stirred for overnight at room temperature and concentrated under reduced pressure. The residue was purified by Prep-TLC with petroleum ether /ethyl acetate (5: 1) to afford 4- (2-bromophenyl) -N, N-dimethyl-1, 3-oxazol-2-amine (225 mg, 52%yield) as a yellow oil. LCMS (ESI, m/z) : 267 [M+H] ⁺.

Synthesis of 2- [2- (dimethylamino) -1, 3-oxazol-4-yl] benzonitrile

A mixture of 4- (2-bromophenyl) -N, N-dimethyl-1, 3-oxazol-2-amine (105 mg, 0.393 mmol, 1.00 equiv) , zinc cyanide (185 mg, 1.57 mmol, 4.00 equiv) , potassium carbonate (163 mg, 1.18 mmol, 3.00 equiv) and tetrakis (triphenylphosphine) palladium (45.4 mg, 0.0390 mmol, 0.10 equiv) in DMF (2 mL) was stirred for overnight at 80 ℃ under nitrogen atmosphere. The mixture was allowed to cool down to room temperature and quenched with water (20 mL) . The mixture was extracted with ethyl acetate (2 x 10 mL) . The combined organic layers were washed with brine (2 x 10 mL) , dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC with petroleum ether /ethyl acetate (5: 1) to afford 2- [2- (dimethylamino) -1, 3-oxazol-4-yl] benzonitrile (70.0 mg, 84%yield) as a yellow oil. LCMS (ESI, m/z) : 214 [M+H] ⁺.

Synthesis of 4- [2- (aminomethyl) phenyl] -N, N-dimethyl-1, 3-oxazol-2-amine

A mixture of 2- [2- (dimethylamino) -1, 3-oxazol-4-yl] benzonitrile (105 mg, 0.492 mmol, 1.0 equiv) and lithium aluminium hydride (1.0 mL, 2.50 mmol, 5.08 equiv, 2.5 M in tetrahydrofuran) in tetrahydrofuran (1 mL) was stirred for 2 h at room temperature under nitrogen atmosphere. The reaction was quenched by the addition of water (0.1 mL) , 15%sodium hydroxide (0.3 mL) and water (0.1 mL) at 0 ℃. The solids were filtered off, the filter cake was washed with tetrahydrofuran (3 x 10 mL) . The filtrate was concentrated under reduced pressure to afford 4- [2- (aminomethyl) phenyl] -N, N-dimethyl-1, 3-oxazol-2-amine (70.0 mg, crude) as a pink oil. LCMS (ESI, m/z) : 218 [M+H] ⁺.

Synthesis of 2-chloro-N- ( {2- [2- (dimethylamino) -1, 3-oxazol-4-yl] phenyl} methyl) -9-isopropylpurin-6-amine

A mixture of 4- [2- (aminomethyl) phenyl] -N, N-dimethyl-1, 3-oxazol-2-amine (70.0 mg, 0.322 mmol, 1.00 equiv) , 2, 6-dichloro-9-isopropylpurine (74.5 mg, 0.322 mmol, 1.00 equiv) and N, N-diisopropylethylamine (125 mg, 0.966 mmol, 3.00 equiv) in n-buthanol (1 mL) was stirred for overnight at 80 ℃. The mixture was allowed to cool down to room temperature and concentrated under reduced pressure. The residue was purified by Prep-TLC with petroleum ether /ethyl acetate (1: 1) to afford 2-chloro-N- ( {2- [2- (dimethylamino) -1, 3-oxazol-4-yl] phenyl} methyl) -9-isopropylpurin-6-amine (20 mg, 15%yield) as an off-white solid. LCMS (ESI, m/z) : 412 [M+H] +.

A mixture of 2-chloro-N- ( {2- [2- (dimethylamino) -1, 3-oxazol-4-yl] phenyl} methyl) -9-isopropylpurin-6-amine (20.0 mg, 0.0490 mmol, 1.00 equiv) and N, N-diisopropylethylamine (18.8 mg, 0.147 mmol, 3.00 equiv) in n-buthanol (2 mL) was irradiated with microwave radiation for 5 h at 130℃. The mixture was allowed to cool down to room temperature and concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C₁₈ Column, 19*250 mm, 5 μm; Mobile Phase A: Water (0.05%TFA ) , Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 13%B to 35%B in 10 min; Wave Length: 254 nm to afford 4- (2- ( ( (2- (4-aminopiperidin-1-yl) -9-isopropyl-9H-purin-6-yl) amino) methyl) phenyl) -N, N-dimethyloxazol-2-amine 2, 2, 2-trifluoroacetate (4.1 mg, 14%yield) as a yellow solid. LCMS (ESI, m/z) : 476 [M+H-TFA] ⁺. ¹H-NMR (400 MHz, Methanol-d₄) δ8.05 (d, J = 2.0 Hz, 1H) , 7.81 -7.76 (m, 1H) , 7.62 -7.54 (m, 3H) , 5.75 -5.70 (m, 1H) , 5.60 -5.44 (m, 2H) , 5.15 (d, J = 10.0 Hz, 1H) , 3.44 -3.39 (m, 1H) , 3.58 -3.41 (m, 5H) , 3.33 (d, J =2.0 Hz, 3H) , 3.07 -2.98 (m, 5H) , 2.10 (d, J = 10.0 Hz, 2H) , 1.61 -1.58 (m, 8H) .

Example 4 Biological activity

Materials

Human CDKs, cyclins and other partner proteins were expressed in insect cell, purified individually, reconstituted and then purified to homogeneity before being used for kinase activity assay. Fluorescence-labelled substrate peptides used in the assays are listed in Table 3.

Table 3. List of CDKs peptides used in kinase assay

Methods

The CDK inhibition results (IC₅₀) without or with pre-incubation are summarized in Table 4. The CDK may be CDK7.

Table 4. List of CDK inhibition

A: IC50 ≤ 100 nM;

B: 100 nM < IC50 ≤ 500 nM;

C: 500 nM < IC50 ≤ 1000 nM;

D: 1000 nM < IC50.

Cancer cell proliferation assay

Materials

All cancer cell were purchased from ATCC and STR-certified.

Methods

Testing cancer cells were seeded in 96-well plate with certain amount so that the untreated cell will reach 80-90%confluence at the end of experiment and treated with serial-diluted compounds 24 hours after seeding. Cells were kept culturing for another 120 hours before being incubated with 100 μl CyQuant reagent (ThermoFisher) for another 1 hour. Total flouresnce was then recorder on an Acuman Cellista cytometer (Sptlabtech) . The data was processed with XLfit software by fitting to one site dose response model.

Claims

A compound having the structure of formula (I) ,

or a pharmaceutically acceptable salt, or prodrug thereof, or a solvate or hydrate of any of the forgoing,

wherein, A is optionally substituted ring, B is optionally substituted ring,

each R₁, R₂, R₃, R₄, and R₅ is independently absent or is independently selected from optional substituents,

each X₁, X₂, X₃, X₄, X₅, X₆, X₇, X₈, X₉ and X₁₀ is independently absent or is independently selected from optionally substituted atom, wherein, m is 0 or more, and n is 0 or more.
The compound of claim 1, said R₁ is H.
The compound of any one of claims 1-2, said R₂ is H.
The compound of any one of claims 1-3, said R₃ is H.
The compound of any one of claims 1-4, said A is optionally substituted 5-ring-membered ring, optionally substituted 6-ring-membered ring, or optionally substituted 11-ring-membered ring.
The compound of any one of claims 1-5, said A is optionally substituted heteroaryl or optionally substituted heterocycle.
The compound of any one of claims 1-6, said A is optionally substituted ring containing one or more N, one or more S and/or one or more O.
The compound of any one of claims 1-7, said A is optionally substituted ring containing one, two or three N.
The compound of any one of claims 1-8, said A is optionally substituted ring containing one O.
The compound of any one of claims 1-9, said A is optionally substituted ring containing one S.
The compound of any one of claims 1-10, said A is selected from the group consisting of optionally substituted pyrrolyl, optionally substitutedpiperidinyl, optionally substitutedpyridinyl, optionally substitutedpiperazinyl, optionally substitutedpiperidinyl , optionally substitutedpyrrolidinyl, optionally substitutedthiazolyl, optionally substituteddiazaspiro [5.5] undecanyl, optionally substitutedpyrazolyl, optionally substitutedazaspiro [5.5] undecanyl, and optionally substitutedimidazolyl.
The compound of any one of claims 1-11, said A is substituted with one or more R₄.
The compound of any one of claims 1-12, said m is 1.
The compound of any one of claims 1-13, said R₄ is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted hydroxyl, and optionally substituted ring.
The compound of any one of claims 1-14, said R₄ is selected from the group consisting of optionally substituted methyl, optionally substituted ethyl, and optionally substituted propyl.
The compound of any one of claims 1-15, said R₄ is optionally substituted 4-ring-membered ring, 5-ring-membered ring or optionally substituted 6-ring-membered ring.
The compound of any one of claims 1-16, said R₄ is optionally substituted heterocycle.
The compound of any one of claims 1-17, said R₄ is optionally substituted ring containing one or more N.
The compound of any one of claims 1-18, said R₄ is optionally substituted ring containing one or two N.
The compound of any one of claims 1-19, said R₄ is optionally substituted azetidinyl.
The compound of any one of claims 1-20, said R₄ is substituted with one or more R_4-1, each said R_4-1 is independently absent or is independently selected from optional substituents.
The compound of claim 21, said R₄ is substituted with one or two said R_4-1.
The compound of any one of claims 21-22, each said R_4-1 is independently selected from the group consisting of hydrogen, halogen, and optionally substituted hydroxyl.
The compound of any one of claims 21-23, each said R_4-1 is independently selected from the group consisting of hydrogen, optionally substituted hydroxyl, optionally substituted amino, and optionally substituted methyl.
The compound of any one of claims 21-24, said R_4-1 is substituted with one or more R_4-2, each said R_4-2 is independently absent or is independently selected from optional substituents.
The compound of claim 25, said R_4-1 is substituted with one said R_4-2.
The compound of any one of claims 25-26, each said R_4-2 is independently selected from the group consisting of hydrogen, and halogen.
The compound of any one of claims 25-27, each said R_4-2 is independently selected from the group consisting of hydrogen, and F.
The compound of any one of claims 1-28, said B is optionally substituted 4-ring-membered ring or 6-ring-membered ring.
The compound of any one of claims 1-29, said B is optionally substituted ring containing one or more N and/or one or more O.
The compound of any one of claims 1-30, said B is optionally substituted ring containing one, or two N.
The compound of any one of claims 1-31, said B is optionally substituted ring containing one O.
The compound of any one of claims 1-32, said B is selected from the group consisting of optionally substituted piperidinyl, optionally substituted piperazinyl, and optionally substituted azetidinyl.
The compound of any one of claims 1-33, said B is substituted with one or more R_5.
The compound of any one of claims 1-34, said n is 1_.
The compound of any one of claims 1-35, each said R₅ is independently selected from the group consisting of hydrogen, optionally substituted hydroxyl, optionally substituted amino, and optionally substituted alkyl.
The compound of any one of claims 1-36, each said R₅ is independently selected from the group consisting of hydrogen, optionally substituted hydroxyl, optionally substituted amino, optionally substituted methyl, optionally substituted ethyl, optionally substituted propyl and optionally substituted butyl.
The compound of any one of claims 1-37, said R₅ is substituted with one or more R_5-1, each said R_5-1 is independently absent or is independently selected from optional substituents.
The compound of claim 38, said R₅ is substituted with one said R_5-1.
The compound of any one of claims 38-39, each said R_5-1 is independently selected from the group consisting of hydrogen, optionally substituted hydroxyl, and optionally substituted alkyl.
The compound of any one of claims 38-40, each said R_5-1 is independently selected from the group consisting of optionally substituted hydroxyl, optionally substituted methyl, optionally substituted ethyl, and optionally substituted propyl.
The compound of any one of claims 1-41, said X₁ is independently absent or is independently selected from optionally substituted -CH=, and -N=.
The compound of any one of claims 1-42, said X₂ is independently absent or is independently selected from optionally substituted -CH=, and -N=.
The compound of any one of claims 1-43, said X₃ is independently absent or is independently selected from optionally substituted -CH=, and -N=.
The compound of any one of claims 1-44, said X₄ is independently absent or is independently selected from optionally substituted -CH=, and -N=.
The compound of any one of claims 1-45, said X₅ is independently absent or is -N=.
The compound of any one of claims 1-46, said X₆ is optionally substituted -NH-or is optionally substituted -CH=.
The compound of any one of claims 1-47, said X₇ is optionally substituted -NH-or is optionally substituted -CH=.
The compound of any one of claims 1-48, said X₇ is substituted with one R_x7-1, each said R_x7-1 is independently absent or is independently selected from optional substituents.
The compound of claim 49, said X₇ is substituted with one said R_x7-1.
The compound of any one of claims 49-50, said R_x7-1 is optionally substituted alkyl or optionally substituted ring.
The compound of any one of claims 49-51, said R_x7-1 is selected from the group consisting of optionally substituted methyl, optionally substituted ethyl, optionally substituted propyl, optionally substituted butyl, optionally substituted cyclopropyl, and optionally substituted cyclopentyl.
The compound of any one of claims 1-52, said X₈ is independently absent or is -N=.
The compound of any one of claims 1-53, said X₉ is independently absent or is optionally substituted -CH=.
The compound of any one of claims 1-54, said X₉ is substituted with one or more said B.
The compound of any one of claims 1-55, said X₁₀ is independently absent or is -N=.
A compound or a pharmaceutically acceptable salt, prodrug, or metabolite thereof, or a solvate or hydrate of any of the foregoing, wherein, said compound is selected from the group consisting of:
A compound having the structure of formula (II) ,

or a pharmaceutically acceptable salt, or prodrug thereof, or a solvate or hydrate of any of the forgoing,

wherein, A is optionally substituted heterocycle, B is optionally substituted ring with one or more ortho-position substituent group,

each X₁ and X₂ is independently absent or is independently selected from optionally substituted atom,

each R₁, R₂ and R₃ is independently absent or is independently selected from optional substituents.
The compound of claim 58, said A is optionally substituted 6-ring-membered ring.
The compound of any one of claims 58-59, said A is optionally substituted heterocycle.
The compound of any one of claims 58-60, said A is optionally substituted ring containing one or more N.
The compound of any one of claims 58-61, said A is optionally substituted ring containing one, two or three N.
The compound of any one of claims 58-62, said A is optionally substituted piperidinyl
The compound of any one of claims 58-63, said A is substituted with one or more R_A-1, each said R_A-1 is independently absent or is independently selected from optional substituents.
The compound of claim 64, said R_A-1 is selected from the group consisting of hydrogen, and optionally substituted amino.
The compound of any one of claims 58-65, said B is optionally substituted 5 or 6-ring-membered ring.
The compound of any one of claims 58-66, said B is optionally substituted aryl or optionally substituted heteroaryl.
The compound of any one of claims 58-67, said B is optionally substituted ring containing no N or one or more N.
The compound of any one of claims 58-68, said B is selected from the group consisting of optionally substituted phenyl and optionally substituted pyridinyl.
The compound of any one of claims 58-69, said B is substituted with one or more R_B-1, each said R_B-1 is independently absent or is independently selected from optional substituents.
The compound of claim 70, said R_B-1 is on the ortho-position of said B.
The compound of any one of claims 70-71, said B is substituted with one or two R_B-1.
The compound of any one of claims 70-72, said R_B-1 is optionally substituted heterocycle or optionally substituted heteroaryl.
The compound of any one of claims 70-73, said R_B-1 is optionally substituted ring containing one or more N.
The compound of any one of claims 70-74, said R_B-1 is optionally substituted ring containing one, or two N.
The compound of any one of claims 70-75, said R_B-1 is selected from the group consisting of optionally substituted pyrazolyl, optionally substituted pyridinyl, and optionally substituted piperazinyl.
The compound of any one of claims 70-76, said R_B-1 is substituted with one or more R_B-2, each said R_B-2 is independently absent or is independently selected from optional substituents.
The compound of claim 77, each said R_B-2 is independently selected from the group consisting of hydrogen, optionally substituted amino, optionally substituted alkyl, and optionally substituted heterocycle.
The compound of any one of claims 77-78, said R_B-2 is independently selected from the group consisting of hydrogen, optionally substituted amino, optionally substituted methyl, and optionally substituted piperazinyl.
The compound of any one of claims 77-79, said R_B-2 is substituted with one or more R_B-3, each said R_B-3 is independently absent or is independently selected from optional substituents.
The compound of claim 80, said R_B-3 is optionally substituted alkyl.
The compound of any one of claims 80-81, said R_B-3 is optionally substituted methyl.
The compound of any one of claims 58-82, said X₁ is independently absent or is optionally substituted -CH=.
The compound of any one of claims 58-83, said X₁ is substituted with R_X1-1, said R_X1-1 is selected from optional substituents.
The compound of claim 84, said R_X1-1 is selected from the group consisting of hydrogen, and optionally substituted alkyl.
The compound of any one of claims 84-85, said R_X1-1 is optionally substituted propyl.
The compound of any one of claims 84-86, said R_X1-1 is optionally substituted isopropyl.
The compound of any one of claims 58-87, said X₂ is independently absent or is optionally substituted -CH=.
The compound of any one of claims 58-88, said R₁ is H.
The compound of any one of claims 58-89, said R₂ is H.
The compound of any one of claims 58-90, said R₃ is H.
A compound or a pharmaceutically acceptable salt, prodrug, or metabolite thereof, or a solvate or hydrate of any of the foregoing, wherein, said compound is selected from the group consisting of:
A composition comprising a compound of any one of claims 1-92, or a pharmaceutically acceptable salt, prodrug, or metabolite thereof, or a solvate or hydrate of any of the foregoing, and optionally a pharmaceutically acceptable carrier.
A method for inhibiting cyclin-dependent kinase (CDK) activity, said method comprising administering to a subject in need thereof an effective amount of the compound of any of claims 1-92, or a pharmaceutically acceptable salt, prodrug, or metabolite thereof, or a solvate or hydrate of any of the foregoing.
The method of claim 94, wherein said cyclin-dependent kinase (CDK) is CDK 7.
The method of any of claims 94-95, wherein said method is selected from the group consisting of an in vitro method, an ex vivo method, and an in vivo method.
A compound having the structure of formula (III) ,

or a pharmaceutically acceptable salt, or prodrug thereof, or a solvate or hydrate of any of the forgoing,

wherein,

X₁ is independently selected from optionally substituted atom, each R₁, R₂, R₃ and R₄ is independently absent or is independently selected from optional substituents, n is 0 or more.
The compound of claim 97, said R₁ is selected from the group consisting of halogen, CN, optionally substituted alkyl, optionally substituted acyl, optionally substituted amino, optionally substituted hydroxyl, optionally substituted phosphorous-containing group, optionally substituted sulfonyl, and optionally substituted ring.
The compound of any one of claims 97-98, said R₁ is selected from the group consisting of optionally substituted alkyl, optionally substituted amino, optionally substituted hydroxyl, and optionally substituted ring.
The compound of any one of claims 97-99, said R₁ is selected from the group consisting of optionally substituted methyl, and optionally substituted ethyl.
The compound of any one of claims 97-100, said R₁ is selected from the group consisting of optionally substituted carbocycle, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl.
The compound of any one of claims 97-101, said R₁ is optionally substituted 6-ring-membered ring.
The compound of any one of claims 97-102, said R₁ is optionally substituted cyclohexanyl.
The compound of any one of claims 97-103, said R₁ is optionally substituted 6 to 8-ring-membered ring.
The compound of any one of claims 97-104, said R₁ is optionally substituted ring containing one or more N and/or one or more O.
The compound of any one of claims 97-105, said R₁ is optionally substituted ring containing one or two N.
The compound of any one of claims 97-106, said R₁ is optionally substituted piperazinyl, optionally substituted piperidinyl, or optionally substituted diazepanyl.
The compound of any one of claims 97-107, said R₁ is optionally substituted bicyclic ring.
The compound of any one of claims 97-108, said R₁ is optionally substituted diazabicycloheptanyl, or optionally substituted diazabicyclooctanyl.
The compound of any one of claims 97-109, said R₁ is optionally substituted benzenyl.
The compound of any one of claims 97-110, said R₁ is optionally substituted 5 to 12-ring-membered ring.
The compound of any one of claims 97-111, said R₁ is optionally substituted ring containing one or more N and/or one or more O.
The compound of any one of claims 97-112, said R₁ is optionally substituted ring containing one, two or five N.
The compound of any one of claims 97-113, said R₁ is optionally substituted ring containing one O.
The compound of any one of claims 97-114, said R₁ is optionally substituted pyrrolyl, optionally substituted oxazolyl, optionally substituted pyrazolyl, optionally substituted oxadiazolyl, optionally substituted pyridinyl, or optionally substituted pyrazinyl.
The compound of any one of claims 97-115, said R₁ is optionally substituted fused ring.
The compound of any one of claims 97-116, said R₁ is optionally substituted pyrazolopyridinyl or optionally substituted quinolinyl.
The compound of any one of claims 97-117, said R₁ is substituted with one or more R_1-1, each said R_1-1 is independently absent or is independently selected from optional substituents.
The compound of claim 118, said R₁ is substituted with one or two said R_1-1.
The compound of any one of claims 118-119, each said R_1-1 is independently selected from the group consisting of hydrogen, halogen, =O, CN, optionally substituted alkyl, optionally substituted acyl, optionally substituted amino, optionally substituted hydroxyl, optionally substituted phosphorous-containing group, optionally substituted sulfonyl, and optionally substituted ring.
The compound of any one of claims 118-120, each said R_1-1 is independently selected from the group consisting of hydrogen, =O, optionally substituted alkyl, optionally substituted amino, optionally substituted hydroxyl, and optionally substituted ring.
The compound of any one of claims 118-121, each said R_1-1 is independently selected from the group consisting of optionally substituted methyl, optionally substituted ethyl and optionally substituted propyl.
The compound of any one of claims 118-122, each said R_1-1 is independently selected from the group consisting of optionally substituted methyl, optionally substituted ethyl and optionally substituted isopropyl.
The compound of any one of claims 118-123, each said R_1-1 is independently selected from the group consisting of optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl.
The compound of any one of claims 118-124, said R_1-1 is optionally substituted 4 to 5-ring-membered ring.
The compound of any one of claims 118-125, said R_1-1 is optionally substituted ring containing one or more N and/or one or more O.
The compound of any one of claims 118-126, said R_1-1 is optionally substituted ring containing one N.
The compound of any one of claims 118-127, said R_1-1 is optionally substituted azetidinyl, or optionally substituted pyrrolidinyl.
The compound of any one of claims 118-128, said R_1-1 is optionally substituted benzenyl.
The compound of any one of claims 118-129, said R_1-1 is optionally substituted 6-ring-membered ring.
The compound of any one of claims 118-130, said R_1-1 is optionally substituted ring containing one or more N and/or one or more O.
The compound of any one of claims 118-131, said R_1-1 is optionally substituted ring containing one N.
The compound of any one of claims 118-132, said R_1-1 is optionally substituted pyridinyl.
The compound of any one of claims 118-133, each said R_1-1 is independently substituted with one or more R_1-2, each said R_1-2 is independently absent or is independently selected from optional substituents.
The compound of claim 134, each said R_1-1 is independently substituted with one, two or three said R_1-2.
The compound of any one of claims 134-135, each said R_1-2 is independently selected from the group consisting of hydrogen, halogen, =O, CN, optionally substituted alkyl, optionally substituted acyl, optionally substituted amino, optionally substituted hydroxyl, optionally substituted phosphorous-containing group, optionally substituted sulfonyl, and optionally substituted ring.
The compound of any one of claims 134-136, each said R_1-2 is independently selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted amino, optionally substituted hydroxyl, and optionally substituted ring.
The compound of any one of claims 134-137, each said R_1-2 is F.
The compound of any one of claims 134-138, each said R_1-2 is independently selected from the group consisting of optionally substituted methyl, and optionally substituted ethyl.
The compound of any one of claims 134-139, each said R_1-2 is independently selected from the group consisting of optionally substituted carbocycle, and optionally substituted heteroaryl.
The compound of any one of claims 134-140, said R_1-2 is optionally substituted 5-ring-membered ring.
The compound of any one of claims 134-141, said R_1-2 is optionally substituted cyclopropyl.
The compound of any one of claims 134-142, said R_1-2 is optionally substituted 5-ring-membered ring.
The compound of any one of claims 134-143, said R_1-2 is optionally substituted ring containing one or more N and/or one or more O.
The compound of any one of claims 134-144, said R_1-2 is optionally substituted ring containing one N.
The compound of any one of claims 134-145, said R_1-2 is optionally substituted furanyl.
The compound of any one of claims 134-146, each said R_1-2 is independently substituted with one or more R_1-3, each said R_1-3 is independently absent or is independently selected from optional substituents.
The compound of claim 147, each said R_1-2 is independently substituted with one, two or three said R_1-3.
The compound of any one of claims 147-148, each said R_1-3 is independently selected from the group consisting of hydrogen, halogen, =O, CN, optionally substituted alkyl, optionally substituted acyl, optionally substituted amino, optionally substituted hydroxyl, optionally substituted phosphorous-containing group, optionally substituted sulfonyl, and optionally substituted ring.
The compound of any one of claims 147-149, each said R_1-3 is independently selected from the group consisting of hydrogen, optionally substituted methyl, and optionally substituted hydroxyl.
The compound of any one of claims 97-150, said R₂ is selected from the group consisting of hydrogen, halogen, CN, optionally substituted alkyl, optionally substituted acyl, optionally substituted amino, optionally substituted hydroxyl, optionally substituted phosphorous-containing group, optionally substituted sulfonyl, and optionally substituted ring.
The compound of any one of claims 97-151, said R₂ is optionally substituted carbocycle.
The compound of any one of claims 97-152, said R₂ is optionally substituted 6-ring-membered ring.
The compound of any one of claims 97-153, said R₂ is optionally substituted ring containing one or more N and/or one or more O.
The compound of any one of claims 97-154, said R₂ is optionally substituted ring containing one N.
The compound of any one of claims 97-155, said R₂ is optionally substituted piperidinyl.
The compound of any one of claims 97-156, said R₂ is substituted with one or more R_2-1, each said R_2-1 is independently absent or is independently selected from optional substituents.
The compound of claim 157, said R₂ is substituted with one said R_2-1.
The compound of any one of claims 157-158, each said R_2-1 is independently selected from the group consisting of hydrogen, halogen, =O, CN, optionally substituted alkyl, optionally substituted acyl, optionally substituted amino, optionally substituted hydroxyl, optionally substituted phosphorous-containing group, optionally substituted sulfonyl, and optionally substituted ring.
The compound of any one of claims 157-159, said R_2-1 is optionally substituted amino.
The compound of any one of claims 97-160, said R₃ is selected from the group consisting of hydrogen, halogen, CN, optionally substituted alkyl, optionally substituted acyl, optionally substituted amino, optionally substituted hydroxyl, optionally substituted phosphorous-containing group, optionally substituted sulfonyl, and optionally substituted ring.
The compound of any one of claims 97-161, said R₃ is optionally substituted propyl.
The compound of any one of claims 97-162, said R₃ is optionally substituted isopropyl.
The compound of any one of claims 97-163, said R₄ is selected from the group consisting of hydrogen, halogen, CN, optionally substituted alkyl, optionally substituted acyl, optionally substituted amino, optionally substituted hydroxyl, optionally substituted phosphorous-containing group, optionally substituted sulfonyl, and optionally substituted ring.
The compound of any one of claims 97-164, said R₄ is hydrogen.
A compound or a pharmaceutically acceptable salt, prodrug, or metabolite thereof, or a solvate or hydrate of any of the foregoing, wherein, said compound is selected from the group consisting of:
A composition comprising a compound of any one of claims 97-166, or a pharmaceutically acceptable salt, prodrug, or metabolite thereof, or a solvate or hydrate of any of the foregoing, and optionally a pharmaceutically acceptable carrier.
A method for inhibiting cyclin-dependent kinase (CDK) activity, said method comprising administering to a subject in need thereof an effective amount of the compound of any of claims 97-166, or a pharmaceutically acceptable salt, prodrug, or metabolite thereof, or a solvate or hydrate of any of the foregoing.
The method of claim 168, wherein said cyclin-dependent kinase (CDK) is CDK 7.
The method of any of claims 168-169, wherein said method is selected from the group consisting of an in vitro method, an ex vivo method, and an in vivo method.