WO2023040998A1

WO2023040998A1 - A cyclin-dependent kinase inhibitor

Info

Publication number: WO2023040998A1
Application number: PCT/CN2022/119183
Authority: WO
Inventors: Lei MO; Junkai Huang; Kai Li; Jian Qiao; Tingyu YUAN; Yongping Xie; Xiaohui Hu; Li Zhou; Tao CUI; Dongqiang CHEN; Siwen TANG; Yao Yao; Heting LI; Deepak Hegde; Xiaoming ZOU
Original assignee: Taizhou Eoc Pharma Co., Ltd.
Priority date: 2021-09-17
Filing date: 2022-09-16
Publication date: 2023-03-23

Abstract

Provided herein are 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

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

The present disclosure provides a compound having the structure of formula (A-I) ,

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

wherein, each R ₁, R ₂, R ₃, R ₄, R ₅, R ₆, R ₇, R ₈, and R ₉ is independently absent or is independently selected from optional substituents,

wherein, A is optionally substituted optional substituents, B is optionally substituted carbocycle, m is 0 or more, and n is 0 or more.

The present disclosure provides a compound having the structure of formula (A-II-a) ,

wherein, each R ₁, R ₂, R ₃, R ₄, R ₅, and R ₆ is independently absent or is independently selected from optional substituents, each X ₁, X ₂, X ₃, X ₄, X ₅, X ₆, X ₇, X ₈ and X ₉ is independently absent or is independently selected from optionally substituted atom,

wherein, A is optionally substituted 7 or more-ring-membered ring, m is 0 or more, and n is 0 or more.

The present disclosure provides a compound having the structure of formula (A-II-b) ,

wherein, each R ₁, R ₂, R ₃, R ₄, and R ₅ is independently absent or is independently selected from optional substituents, each X ₁, X ₂, X ₃, X ₄, X ₅, X ₆, X ₇, and X ₈ is independently selected from optionally substituted atom, and at least one of X ₁, X ₂, X ₃, X ₄, and X ₅ is not C,

wherein, A is absent or is optionally substituted optional substituents, B is optionally substituted 7 or more-ring-membered ring, m is 0 or more, and n is 0 or more.

A compound having the structure of formula (A-II-c) ,

wherein, each R ₁, R ₂, and R ₃ is independently absent or is independently selected from optional substituents, each X ₁, X ₂, X ₃, X ₄, and X ₅ is independently absent or is independently selected from optionally substituted atom,

wherein, A is absent or is optionally substituted ring, B is optionally substituted 7 or more-ring-membered carbocycle, m is 0 or more, and n is 0 or more.

The present disclosure provides a compound having the structure of formula (A-III-a) ,

wherein, each R ₁, R ₂, R ₃, R ₄, R ₅, R ₆, and R ₇ is independently absent or is independently selected from optional substituents, and at least one of R ₁, R ₂ and R ₃ is halogen, each X ₁, X ₂, X ₃, and X ₄ is independently absent or is independently selected from optionally substituted atom,

wherein, A is optionally substituted heteroaryl, B is optionally substituted heterocycle, m is 0 or more, and n is 0 or more.

The present disclosure provides a compound having the structure of formula (A-III-b) ,

wherein, each R ₁, R ₂, R ₃, R ₄, R ₅, and R ₆ is independently absent or is independently selected from optional substituents, each X ₁, X ₂, X ₃, X ₄, X ₅, X ₆, X ₇, and X ₈ is independently selected from optionally substituted atom,

wherein, A is optionally substituted fused aryl, and n is 0 or more.

The present disclosure provides a compound having the structure of formula (A-III-c) ,

wherein, each R ₁, R ₂, R ₃, R ₄, R ₅, R ₆, and R ₇ is independently absent or is independently selected from optional substituents, each X ₁, X ₂, X ₃, and X ₄ is independently absent or is independently selected from optionally substituted atom,

wherein, A is optionally substituted heterocycle, B is optionally substituted aryl or optionally substituted heteroaryl, m is 0 or more, and n is 0 or more.

The present disclosure provides a compound having the structure of formula (B-I) ,

wherein, A is optionally substituted ring, B is optionally substituted 7 or more-ring-membered heterocycle,

each X ₁, X ₂, X ₃, X ₄, and X ₅ is independently selected from optionally substituted atom,

each R ₁, R ₂ and R ₃ is independently absent or is independently selected from optional substituents, m is 0 or more, n is 0 or more.

The present disclosure provides a compound having the structure of formula (B-II) ,

wherein, A is optionally substituted ring,

each X ₁, X ₂, X ₃, X ₄, X ₅, X ₆, X ₇, X ₈, X ₉, X ₁₀, X ₁₁, X ₁₂, and X ₁₃ is independently selected from optionally substituted atom,

R ₁ is optionally substituted alkyl, each R ₂, R ₃ and R ₄ is independently absent or is independently selected from optional substituents, wherein R ₂ is not hydrogen.

The present disclosure provides a compound having the structure of formula (B-III) ,

wherein, A is optionally substituted heteroaryl,

each X ₁, X ₂, X ₃, X ₄, X ₅, X ₆, and X ₇ is independently selected from optionally substituted atom,

each R ₁, R ₂, R ₃, R ₄ and R ₅ is independently absent or is independently selected from optional substituents.

The present disclosure provides a compound having the structure of formula (C-I) ,

each X ₁, X ₂, X ₃, X ₄, X ₅, X ₆, X ₇, X ₈, X ₉, X ₁₀, X ₁₁, and X ₁₂ is independently absent or is independently selected from optionally substituted atom,

each R ₁, R ₂, R ₃ and R ₄ is independently absent or is independently selected from optional substituents.

The present disclosure provides a compound having the structure of formula (D-I) ,

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.

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, “C ₁-C ₆ 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 term “alkenyl” contains 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 -NH ₂ 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 C ₄-C ₁₀ carbocyclic ring, such as a C ₅ or a C ₆ 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 C ₄-C ₁₀ 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 -NO ₂ 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-PH ₂, -P- (OH) ₂, -PH- (OH) , -PH ₄, -PH ₂=CH ₂, -CH=PH ₃, -O-P (=O) ₂, -O-P (=O) - (OH) ₂, -O-PH (=O) -OH, -P (=O) - (OH) ₂, -O-PH ₂ (=O) , -PH (=O) -OH, -PH ₂ (=O) , -O-P (=O) (OH) -P (=O) (OH) ₂, -O-P (=O) (OH) -O- P (=O) (OH) ₂, -PH-PH ₂, 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 -SiH ₃. 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, N ₃, trifluoromethyl, hydroxy, phosphorous-containing group, silicon-containing group, thio, amino, carboxyl, sulfonyl, sulfinyl, (C ₁-C ₆) acyl, (C ₁-C ₆) thioacyl, (C ₁-C ₆) alkyl, (C ₂-C ₆) alkenyl, (C ₂-C ₆) alkynyl, (C ₃-C ₁₀) carbocycle, (C ₂-C ₉) heterocycle, (C ₆-C ₁₀) aryl, (C ₁-C ₉) heteroaryl, trifluoromethyl (C ₁-C ₆) alkyl, cyano (C ₁-C ₆) alkyl, halo (C ₁-C ₆) alkyl, nitro (C ₁-C ₆) alkyl, hydroxy (C ₁-C ₆) alkyl, (C ₁-C ₆) alkoxy, (C ₁-C ₆) alkylthio, thio (C ₁-C ₆) alkyl, amino (C ₁-C ₆) alkyl, (C ₁-C ₆) alkylamino, ( (C ₁-C ₆) alkyl) ₂amino, (C ₁-C ₆) acyl (C ₁-C ₆) alkyl, (C ₁-C ₆) alkylsulfonyl, (C ₁-C ₆) alkylsulfinyl, hydroxysulfonyl, hydroxysulfinyl, (C ₃-C ₁₀) carbocycle (C ₁-C ₆) alkyl, (C ₂-C ₉) heterocycle (C ₁-C ₆) alkyl, (C ₆-C ₁₀) aryl (C ₁-C ₆) alkyl, and (C ₁-C ₉) heteroaryl (C ₁-C ₆) 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, N ₃, trifluoromethyl, hydroxy, phosphorous-containing group, silicon-containing group, thio, amino, carboxyl, sulfonyl, sulfinyl, (C ₁-C ₆) acyl, (C ₁-C ₆) thioacyl, (C ₁-C ₆) alkyl, (C ₂-C ₆) alkenyl, (C ₂-C ₆) alkynyl, (C ₃-C ₁₀) carbocycle, (C ₂-C ₉) heterocycle, (C ₆-C ₁₀) aryl, (C ₁-C ₉) heteroaryl, trifluoromethyl (C ₁-C ₆) alkyl, cyano (C ₁-C ₆) alkyl, halo (C ₁-C ₆) alkyl, nitro (C ₁-C ₆) alkyl, hydroxy (C ₁-C ₆) alkyl, (C ₁-C ₆) alkoxy, (C ₁-C ₆) alkylthio, thio (C ₁-C ₆) alkyl, amino (C ₁-C ₆) alkyl, (C ₁-C ₆) alkylamino, ( (C ₁-C ₆) alkyl) ₂amino, (C ₁-C ₆) acyl (C ₁-C ₆) alkyl, (C ₁-C ₆) alkylsulfonyl, (C ₁-C ₆) alkylsulfinyl, hydroxysulfonyl, hydroxysulfinyl, (C ₃- C ₁₀) carbocycle (C ₁-C ₆) alkyl, (C ₂-C ₉) heterocycle (C ₁-C ₆) alkyl, (C ₆-C ₁₀) aryl (C ₁-C ₆) alkyl, and (C ₁-C ₉) heteroaryl (C ₁-C ₆) 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

Compound Set A

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

wherein, each R ₁, R ₂, R ₃, R ₄, R ₅, R ₆, R ₇, R ₈, and R ₉ may be independently absent or may be independently selected from optional substituents,

wherein, A may be optionally substituted optional substituents, B may be optionally substituted carbocycle, m may be 0 or more, and n may be 0 or more.

For example, as a compound having the structure of formula (A-I) , said R ₁ may be optionally substituted alkyl. For example, said R ₁ may be optionally substituted methyl.

For example, as a compound having the structure of formula (A-I) , said R ₁ may be substituted with one, two, or three R _1-1, each said R _1-1 may be independently absent or may be independently selected from optional substituents.

For example, as a compound having the structure of formula (A-I) , said R ₁ may be substituted with three said R _1-1. For example, said R ₁ may be substituted with one, two, or three said R _1-1.

For example, as a compound having the structure of formula (A-I) , said R _1-1 may be halogen. For example, said R _1-1 may be F (fluorine) . For example, said R ₁ may be substituted with one, two, or three F.

For example, as a compound having the structure of formula (A-I) , said R ₂ may be H(hydrogen) . For example, as a compound having the structure of formula (A-I) , said R ₃ may be H.

For example, as a compound having the structure of formula (A-I) , said B may be optionally substituted 6-ring-membered carbocycle. For example, said B may be optionally substituted cyclohexyl.

For example, as a compound having the structure of formula (A-I) , said R ₄ may be H. For example, said m may be 0, 1, 2, or 3.

For example, as a compound having the structure of formula (A-I) , said A may be optionally substituted ring. For example, said A may be optionally substituted heteroaryl.

For example, as a compound having the structure of formula (A-I) , said A may be optionally substituted 9-ring-membered heteroaryl.

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

For example, as a compound having the structure of formula (A-I) , said A may be optionally substituted ring containing one N. For example, said A may be optionally substituted 9-ring-membered heteroaryl containing one N.

For example, as a compound having the structure of formula (A-I) , said A may be optionally substituted indolyl.

For example, as a compound having the structure of formula (A-I) , said R ₅ may be H. For example, as a compound having the structure of formula (A-I) , said R ₆ may be H. For example, as a compound having the structure of formula (A-I) , said R ₇ may be H. For example, as a compound having the structure of formula (A-I) , said R ₈ may be H. For example, as a compound having the structure of formula (A-I) , said R ₉ may be H.

said R ₁ may be optionally substituted methyl, said R ₁ may be substituted with one, two, or three F, said R ₂ may be H (hydrogen) , said R ₃ may be H,

said B may be optionally substituted cyclohexyl, said R ₄ may be H,

said A may be optionally substituted 9-ring-membered heteroaryl containing one N or optionally substituted indolyl,

said R ₅, R ₆, R ₇, R ₈, and R ₉ may be H.

m may be 0, 1, 2 or 3, and n may be 0, 1, 2 or 3.

In some cases, 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 may be selected from the group consisting of:

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

wherein, each R ₁, R ₂, R ₃, R ₄, R ₅, and R ₆ may be independently absent or may be independently selected from optional substituents, each X ₁, X ₂, X ₃, X ₄, X ₅, X ₆, X ₇, X ₈ and X ₉ may be independently absent or may be independently selected from optionally substituted atom,

wherein, A may be optionally substituted 7 or more-ring-membered ring, m may be 0 or more, and n may be 0 or more.

For example, as a compound having the structure of formula (A-II-a) , said R ₁ may be halogen. For example, said R ₁ may be F.

For example, as a compound having the structure of formula (A-II-a) , said R ₂ may be halogen. For example, said R ₂ may be F.

For example, as a compound having the structure of formula (A-II-a) , said R ₃ may be halogen. For example, said R ₃ may be F.

For example, as a compound having the structure of formula (A-II-a) , said R ₄ may be H.

For example, as a compound having the structure of formula (A-II-a) , said R ₅ may be selected from the group consisting of hydrogen, protium, deuterium, tritium, cyano and optionally substituted hydroxy. For example, said R ₅ may be hydrogen, protium, deuterium, tritium, cyano or optionally substituted hydroxy.

For example, as a compound having the structure of formula (A-II-a) , said R ₅ may be substituted with one, two, or three R _5-1, each said R _5-1 may be independently absent or may be independently selected from optional substituents.

For example, as a compound having the structure of formula (A-II-a) , said R ₅ may be substituted with one said R _5-1. For example, said R _5-1 may be optionally substituted alkyl. For example, said R _5-1 may be optionally substituted methyl. For example, said R ₅ may be optionally substituted hydroxy, said R ₅ may be substituted with optionally substituted methyl.

For example, as a compound having the structure of formula (A-II-a) , said A may be optionally substituted 7-ring-membered ring. For example, as a compound having the structure of formula (A-II-a) , said A may be optionally substituted heterocycle.

For example, as a compound having the structure of formula (A-II-a) , said A may be optionally substituted ring containing one, two, or three N. For example, as a compound having the structure of formula (A-II-a) , said A may be optionally substituted ring containing one N. For example, as a compound having the structure of formula (A-II-a) , said A may be optionally substituted ring containing one, two, or three N. For example, as a compound having the structure of formula (A-II-a) , said A may be optionally substituted 7-ring-membered ring containing one N.

For example, as a compound having the structure of formula (A-II-a) , said A may be optionally substituted azepaneyl.

For example, as a compound having the structure of formula (A-II-a) , said R ₆ may be H.

For example, as a compound having the structure of formula (A-II-a) , each X ₁, X ₂, and X ₃ may be independently absent or may be independently selected from optionally substituted -CH=, and -N=.

For example, as a compound having the structure of formula (A-II-a) , said X ₁ may be optionally substituted -CH=. For example, as a compound having the structure of formula (A-II-a) , said X ₂ may be optionally substituted -CH=. For example, as a compound having the structure of formula (A-II-a) , said X ₃ may be optionally substituted -CH=.

For example, as a compound having the structure of formula (A-II-a) , said X ₃ may be one, two, or three R ₅. For example, as a compound having the structure of formula (A-II-a) , said m may be 0, 1, 2, or 3.

For example, as a compound having the structure of formula (A-II-a) , each X ₄ and X ₅ may be independently absent or may be independently selected from optionally substituted -CH ₂, optionally substituted -CH=, optionally substituted -NH-and -N=.

For example, as a compound having the structure of formula (A-II-a) , said X ₄ may be optionally substituted -NH-. For example, as a compound having the structure of formula (A-II-a) , said X ₅ may be optionally substituted -CH=.

For example, as a compound having the structure of formula (A-II-a) , each X ₆, X ₇, X ₈, and X ₉ may be independently selected from optionally substituted -CH=, and -N=.

For example, as a compound having the structure of formula (A-II-a) , said X ₆ may be -N=. For example, as a compound having the structure of formula (A-II-a) , said X ₇ may be -N=. For example, as a compound having the structure of formula (A-II-a) , said X ₈ may be optionally substituted -CH=. For example, as a compound having the structure of formula (A-II-a) , said X ₉ may be optionally substituted -CH=.

For example, as a compound having the structure of formula (A-II-a) , said X ₉ may be substituted with one, two, or three R _x9-1, each said R _x9-1 may be independently absent or may be independently selected from optional substituents.

For example, as a compound having the structure of formula (A-II-a) , said X ₉ may be substituted with one R _x9-1. For example, as a compound having the structure of formula (A-II-a) , said R _x9-1 may be optionally substituted alkyl. For example, as a compound having the structure of formula (A-II-a) , said R _x9-1 may be optionally substituted methyl.

For example, as a compound having the structure of formula (A-II-a) , said R _x9-1 may be substituted with one, two, or three R _x9-2, each said R _x9-2 may be independently absent or may be independently selected from optional substituents.

For example, as a compound having the structure of formula (A-II-a) , said R _x9-1 may be substituted with one, two, or three said R _x9-2. For example, as a compound having the structure of formula (A-II-a) , said R _x9-2 may be halogen. For example, as a compound having the structure of formula (A-II-a) , said R _x9-2 may be F. For example, as a compound having the structure of formula (A-II-a) , said R _x9-2 may be F or Cl.

said R ₁ may be F, said R ₂ may be F, said R ₃ may be F, said R ₄ may be H,

said R ₅ may be hydrogen, protium, deuterium, tritium, cyano, optionally substituted hydroxy or said R ₅ may be optionally substituted hydroxy, said R ₅ may be substituted with optionally substituted methyl,

said A may be optionally substituted 7-ring-membered ring containing one N, or said A may be optionally substituted azepaneyl,

said R ₆ may be H, said X ₁ may be optionally substituted -CH=, said X ₂ may be optionally substituted -CH=, said X ₃ may be optionally substituted -CH=, said X ₃ may be one, two, or three said R _5, said X ₄ may be optionally substituted -NH-, said X ₅ may be optionally substituted -CH=, said X ₆ may be -N=, said X ₇ may be -N=, said X ₈ may be optionally substituted -CH=, said X ₉ may be optionally substituted -CH=, said X ₉ may be substituted with one, two, or three R _x9-1, said R _x9-1 may be optionally substituted methyl, said R _x9-1 may be substituted with three said R _x9-2, said R _x9- ₂ may be F.

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

wherein, each R ₁, R ₂, R ₃, R ₄, and R ₅ may be independently absent or may be independently selected from optional substituents, each X ₁, X ₂, X ₃, X ₄, X ₅, X ₆, X ₇, and X ₈ may be independently selected from optionally substituted atom, and at least one of X ₁, X ₂, X ₃, X ₄, and X ₅ may be not C,

wherein, A may be absent or may be optionally substituted optional substituents, B may be optionally substituted 7 or more-ring-membered ring, m may be 0 or more, and n may be 0 or more.

For example, as a compound having the structure of formula (A-II-b) , said B may be optionally substituted 7-ring-membered ring.

For example, as a compound having the structure of formula (A-II-b) , said B may be optionally substituted heterocycle. For example, as a compound having the structure of formula (A-II-b) , said B may be optionally substituted ring containing one, two or three N. For example, as a compound having the structure of formula (A-II-b) , said B may be optionally substituted ring containing one N. For example, as a compound having the structure of formula (A-II-b) , said B may be optionally substituted 7-ring-membered ring containing one N.

For example, as a compound having the structure of formula (A-II-b) , said B may be optionally substituted azepaneyl.

For example, as a compound having the structure of formula (A-II-b) , said R ₁ may be H. For example, said m may be 0, 1, 2, or 3. For example, as a compound having the structure of formula (A-II-b) , said R ₂ may be H.

For example, as a compound having the structure of formula (A-II-b) , said R ₃ may be optionally substituted alkyl. For example, as a compound having the structure of formula (A-II-b) , said R ₃ may be optionally substituted methyl.

For example, as a compound having the structure of formula (A-II-b) , said R ₃ may be substituted with one, two or three R _3-1, each said R _3-1 may be independently absent or may be independently selected from optional substituents.

For example, as a compound having the structure of formula (A-II-b) , said R ₃ may be substituted with three said R _3-1. For example, as a compound having the structure of formula (A-II-b) , said R _3-1 may be halogen. For example, as a compound having the structure of formula (A-II-b) , said R _3-1 may be F (fluorine) or Cl.

For example, as a compound having the structure of formula (A-II-b) , said R ₄ may be H.

For example, as a compound having the structure of formula (A-II-b) , said A may be optionally substituted ring. For example, as a compound having the structure of formula (A-II-b) , said A may be optionally substituted aryl. For example, as a compound having the structure of formula (A-II-b) , said A may be optionally substituted phenyl.

For example, as a compound having the structure of formula (A-II-b) , said R ₅ may be H. For example, said n may be 0, 1, 2, or 3.

For example, as a compound having the structure of formula (A-II-b) , each X ₁, X ₂, X ₃, X ₄, X ₅, X ₆, X ₇, and X ₈ may be independently selected from optionally substituted -CH=, C, and -N=.

For example, as a compound having the structure of formula (A-II-b) , at least one of X ₁, X ₂, X ₃, X ₄, and X ₅ may be -N=.

For example, as a compound having the structure of formula (A-II-b) , said X ₁ may be -N=. For example, as a compound having the structure of formula (A-II-b) , said X ₂ may be C. For example, as a compound having the structure of formula (A-II-b) , said X ₃ may be C. For example, as a compound having the structure of formula (A-II-b) , said X ₄ may be optionally substituted -CH=. For example, as a compound having the structure of formula (A-II-b) , said X ₅ may be optionally substituted -CH=. For example, as a compound having the structure of formula (A-II-b) , said X ₆ may be -N=. For example, as a compound having the structure of formula (A-II-b) , said X ₇ may be -N=. For example, as a compound having the structure of formula (A-II-b) , said X ₈ may be optionally substituted -CH=.

said B may be optionally substituted 7-ring-membered ring containing one N, or said B may be optionally substituted azepaneyl,

said R ₁ may be H, said R ₂ may be H, said R ₃ may be optionally substituted methyl, said R ₃ may be substituted with three F,

said R ₄ may be H, said A may be optionally substituted phenyl, said R ₅ may be H,

said X ₁ may be -N=, said X ₂ may be C, said X ₃ may be C, said X ₄ may be optionally substituted -CH=, said X ₅ may be optionally substituted -CH=, said X ₆ may be -N=, said X ₇ may be -N=, and said X ₈ may be optionally substituted -CH=, said m may be 0, 1, 2, or 3, said n may be 0, 1, 2, or 3.

In some cases, 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 may be

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

wherein, each R ₁, R ₂, and R ₃ may be independently absent or may be independently selected from optional substituents, each X ₁, X ₂, X ₃, X ₄, and X ₅ may be independently absent or may be independently selected from optionally substituted atom,

wherein, A may be absent or may be optionally substituted ring, B may be optionally substituted 7 or more-ring-membered carbocycle, m may be 0 or more, and n may be 0 or more.

For example, as a compound having the structure of formula (A-II-c) , said B may be optionally substituted 7-ring-membered ring. For example, as a compound having the structure of formula (A-II-c) , said B may be optionally substituted heterocycle. For example, as a compound having the structure of formula (A-II-c) , said B may be optionally substituted ring containing one, two or three N. For example, as a compound having the structure of formula (A-II-c) , said B may be optionally substituted ring containing one N. For example, as a compound having the structure of formula (A-II-c) , said B may be optionally substituted 7-ring-membered ring containing one N.

For example, as a compound having the structure of formula (A-II-c) , said B may be optionally substituted azepaneyl.

For example, as a compound having the structure of formula (A-II-c) , said R ₁ may be H. For example, said n may be 0, 1, 2 or 3. For example, as a compound having the structure of formula (A-II-c) , said R ₂ may be H.

For example, as a compound having the structure of formula (A-II-c) , said A may be optionally substituted aryl. For example, as a compound having the structure of formula (A-II-c) , said A may be optionally substituted phenyl.

For example, as a compound having the structure of formula (A-II-c) , said R ₃ may be selected from the group consisting of hydrogen, protium, deuterium, tritium, cyano and optionally substituted hydroxy. For example, as a compound having the structure of formula (A-II-c) , said R ₃ may be hydrogen, protium, deuterium, tritium, cyano or optionally substituted hydroxy.

For example, as a compound having the structure of formula (A-II-c) , said A may be substituted with one, two or three R ₃.

For example, as a compound having the structure of formula (A-II-c) , said R ₃ may be substituted with one, two or three R _3-1, each said R _3-1 may be independently absent or may be independently selected from optional substituents.

For example, as a compound having the structure of formula (A-II-c) , said R ₃ may be substituted with one said R _3-1. For example, as a compound having the structure of formula (A-II-c) , said m may be 1, 2 or 3.

For example, as a compound having the structure of formula (A-II-c) , said R _3-1 may be optionally substituted alkyl. For example, as a compound having the structure of formula (A-II-c) , said R _3-1 may be optionally substituted methyl.

For example, as a compound having the structure of formula (A-II-c) , each X ₁ and X ₂ may be independently absent or may be independently selected from optionally substituted -CH ₂, optionally substituted -CH=, optionally substituted -NH-and -N=. For example, as a compound having the structure of formula (A-II-c) , said X ₁ may be optionally substituted -CH=. For example, as a compound having the structure of formula (A-II-c) , said X ₂ may be optionally substituted -NH-. For example, as a compound having the structure of formula (A-II-c) , each X ₃, X ₄ and X ₅ may be independently selected from optionally substituted -CH=, and -N=. For example, as a compound having the structure of formula (A-II-c) , said X ₃ may be -N=.

For example, as a compound having the structure of formula (A-II-c) , said X ₄ may be optionally substituted -CH=. For example, as a compound having the structure of formula (A-II-c) , said X ₅ may be optionally substituted -CH=.

For example, as a compound having the structure of formula (A-II-c) , said X ₅ may be substituted with one, two or three R _x5-1, each said R _x5-1 may be independently absent or may be independently selected from optional substituents.

For example, as a compound having the structure of formula (A-II-c) , said X ₅ may be substituted with one R _x5-1. For example, as a compound having the structure of formula (A-II-c) , said R _x5-1 may be optionally substituted alkyl. For example, as a compound having the structure of formula (A-II-c) , said R _x5-1 may be optionally substituted methyl.

For example, as a compound having the structure of formula (A-II-c) , said R _x5-1 may be substituted with one, two or three R _x5-2, each said R _x5-2 may be independently absent or may be independently selected from optional substituents.

For example, as a compound having the structure of formula (A-II-c) , said R _x5-1 may be substituted with three said R _x5-2. For example, as a compound having the structure of formula (A- II-c) , said R _x5-2 may be halogen. For example, as a compound having the structure of formula (A-II-c) , said R _x5-2 may be F or Cl.

said R ₁ may be H, said R ₂ may be H, said A may be optionally substituted phenyl,

said R ₃ may be hydrogen, protium, deuterium, tritium, cyano, optionally substituted hydroxy, or optionally substituted hydroxy substituted with optionally substituted methyl,

said X ₁ may be optionally substituted -CH=, said X ₂ may be optionally substituted -NH-, said X ₃ may be -N=, said X ₄ may be optionally substituted -CH=, said X ₅ may be optionally substituted -CH=, said X ₅ may be substituted with optionally substituted methyl substituted with three F, said m may be 1, 2 or 3, said n may be 0, 1, 2 or 3.

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

wherein, each R ₁, R ₂, R ₃, R ₄, R ₅, R ₆, and R ₇ may be independently absent or may be independently selected from optional substituents, and at least one of R ₁, R ₂ and R ₃ may be halogen, each X ₁, X ₂, X ₃, and X ₄ may be independently absent or may be independently selected from optionally substituted atom,

wherein, A may be optionally substituted heteroaryl, B may be optionally substituted heterocycle, m may be 0 or more, and n may be 0 or more.

For example, as a compound having the structure of formula (A-III-a) , said R ₁ may be halogen. For example, as a compound having the structure of formula (A-III-a) , said R ₁ may be F.

For example, as a compound having the structure of formula (A-III-a) , said R ₂ may be halogen. For example, as a compound having the structure of formula (A-III-a) , said R ₂ may be F.

For example, as a compound having the structure of formula (A-III-a) , said R ₃ may be halogen. For example, as a compound having the structure of formula (A-III-a) , said R ₃ may be F.

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

For example, as a compound having the structure of formula (A-III-a) , said B may be optionally substituted piperidinyl.

For example, as a compound having the structure of formula (A-III-a) , said R ₄ may be H. For example, said n may be 0, 1, 2 or 3. For example, as a compound having the structure of formula (A-III-a) , said R ₅ may be H. For example, as a compound having the structure of formula (A-III-a) , said R ₆ may be H.

For example, as a compound having the structure of formula (A-III-a) , said A may be optionally substituted 6 or more-ring-membered heteroaryl. For example, as a compound having the structure of formula (A-III-a) , said A may be optionally substituted 6-ring-membered heteroaryl, optionally substituted 9-ring-membered heteroaryl or optionally substituted 10-ring-membered heteroaryl. For example, as a compound having the structure of formula (A-III-a) , said A may be optionally substituted heteroaryl containing one, two, or three N. For example, as a compound having the structure of formula (A-III-a) , said A may be optionally substituted heteroaryl containing one or two N. For example, as a compound having the structure of formula (A-III-a) , said A may be optionally substituted 6-ring-membered heteroaryl containing one or two N. For example, as a compound having the structure of formula (A-III-a) , said A may be optionally substituted 9-ring-membered heteroaryl containing one or two N. For example, as a compound having the structure of formula (A-III-a) , said A may be optionally substituted 10-ring-membered heteroaryl containing one or two N.

For example, as a compound having the structure of formula (A-III-a) , said A may be optionally substituted pyridinyl, optionally substituted indolyl, optionally substituted quinolinyl, optionally substituted isoquinolinyl, or optionally substituted quinazolinyl.

For example, as a compound having the structure of formula (A-III-a) , said A may be substituted with one, two, or three R _7. For example, said m may be 0, 1, 2 or 3.

For example, as a compound having the structure of formula (A-III-a) , m may be 1 _.

For example, as a compound having the structure of formula (A-III-a) , said R ₇ may be H or optionally substituted aryl. For example, as a compound having the structure of formula (A-III-a) , said R ₇ may be optionally substituted phenyl.

For example, as a compound having the structure of formula (A-III-a) , each X ₁, X ₂, X ₃, and X ₄ may be independently selected from optionally substituted -CH=, and -N=. For example, as a compound having the structure of formula (A-III-a) , said X ₁ may be -N=. For example, as a compound having the structure of formula (A-III-a) , said X ₂ may be -N=. For example, as a compound having the structure of formula (A-III-a) , said X ₃ may be optionally substituted -CH=. For example, as a compound having the structure of formula (A-III-a) , said X ₄ may be optionally substituted -CH=.

For example, as a compound having the structure of formula (A-III-a) , said X ₄ may be substituted with one, two, or three R _x4-1, each said R _x4-1 may be independently absent or may be independently selected from optional substituents.

For example, as a compound having the structure of formula (A-III-a) , said X ₄ may be substituted with one, two or three R _x4-1. For example, as a compound having the structure of formula (A-III-a) , said R _x4-1 may be optionally substituted alkyl. For example, as a compound having the structure of formula (A-III-a) , said R _x4-1 may be optionally substituted methyl.

For example, as a compound having the structure of formula (A-III-a) , said R _x4-1 may be substituted with one, two or three R _x4-2, each said R _x4-2 may be independently absent or may be independently selected from optional substituents. For example, as a compound having the structure of formula (A-III-a) , said R _x4-1 may be substituted with three said R _x4-2.

For example, as a compound having the structure of formula (A-III-a) , said R _x4-2 may be halogen. For example, as a compound having the structure of formula (A-III-a) , said R _x4-2 may be F or Cl.

said R ₁ may be F, said R ₂ may be F, said R ₃ may be F,

said B may be optionally substituted 6-ring-membered heterocycle containing one N, said R ₄ may be H, said n may be 0, 1, 2 or 3, said R ₅ may be H, said R ₆ may be H,

said A may be optionally substituted pyridinyl, optionally substituted indolyl, optionally substituted quinolinyl, optionally substituted isoquinolinyl, or optionally substituted quinazolinyl, said R ₇ may be H or optionally substituted aryl, said m may be 0, 1, 2 or 3,

said X ₁ may be -N=, said X ₂ may be -N=, said X ₃ may be optionally substituted -CH=, said X ₄ may be optionally substituted -CH=, said X ₄ may be substituted with one, two or three R _x4-1, said R _x4-1 may be optionally substituted methyl, said R _x4-1 may be substituted with one, two or three R _x4-2, said R _x4-2 may be F.

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

wherein, each R ₁, R ₂, R ₃, R ₄, R ₅, and R ₆ may be independently absent or may be independently selected from optional substituents, each X ₁, X ₂, X ₃, X ₄, X ₅, X ₆, X ₇, and X ₈ may be independently selected from optionally substituted atom,

wherein, A may be optionally substituted fused aryl, and n may be 0 or more.

For example, as a compound having the structure of formula (A-III-b) , said R ₁ may be H or optionally substituted alkyl. For example, as a compound having the structure of formula (A-III-b) , said R ₁ may be optionally substituted methyl.

For example, as a compound having the structure of formula (A-III-b) , said R ₁ may be substituted with one, two, or three R _1-1, each said R _1-1 may be independently absent or may be independently selected from optional substituents. For example, as a compound having the structure of formula (A-III-b) , said R _1-1 may be =O.

For example, as a compound having the structure of formula (A-III-b) , said R _1-1 may be optionally substituted alkenyl. For example, as a compound having the structure of formula (A-III-b) , said R _1-1 may be optionally substituted propenyl.

For example, as a compound having the structure of formula (A-III-b) , said R _1-1 may be substituted with one, two, or three R _1-2, each said R _1-2 may be independently absent or may be independently selected from optional substituents.

For example, as a compound having the structure of formula (A-III-b) , said R _1-2 may be optionally substituted amino. For example, as a compound having the structure of formula (A-III-b) , said R _1-2 may be substituted with one, two, or three R _1-3, each said R _1-3 may be independently absent or may be independently selected from optional substituents.

For example, as a compound having the structure of formula (A-III-b) , said R _1-3 may be optionally substituted alkyl. For example, as a compound having the structure of formula (A-III-b) , said R _1-3 may be optionally substituted methyl.

For example, as a compound having the structure of formula (A-III-b) , said R ₂ may be H. For example, as a compound having the structure of formula (A-III-b) , said R ₃ may be H. For example, as a compound having the structure of formula (A-III-b) , said R ₄ may be H. For example, as a compound having the structure of formula (A-III-b) , said R ₅ may be H.

For example, as a compound having the structure of formula (A-III-b) , said A may be optionally substituted naphthyl.

For example, as a compound having the structure of formula (A-III-b) , said R ₆ may be H. For example, n may be 0, 1, 2, or 3.

For example, as a compound having the structure of formula (A-III-b) , each X ₁, X ₂, and X ₄ may be independently absent or may be independently selected from optionally substituted -CH ₂-, and optionally substituted -NH-. For example, as a compound having the structure of formula (A-III-b) , said X ₁ may be optionally substituted -CH ₂-. For example, as a compound having the structure of formula (A-III-b) , said X ₂ may be optionally substituted -CH ₂-. For example, as a compound having the structure of formula (A-III-b) , said X ₄ may be optionally substituted -CH ₂-. For example, as a compound having the structure of formula (A-III-b) , X ₃ may be independently absent or may be independently selected from optionally substituted CH, and N. For example, as a compound having the structure of formula (A-III-b) , said X ₃ may be optionally substituted CH.

For example, as a compound having the structure of formula (A-III-b) , each X ₅, X ₆, X ₇, and X ₈ may be independently selected from optionally substituted -CH=, and -N=.

For example, as a compound having the structure of formula (A-III-b) , said X ₅ may be -N=. For example, as a compound having the structure of formula (A-III-b) , said X ₆ may be -N=. For example, as a compound having the structure of formula (A-III-b) , said X ₇ may be optionally substituted -CH=. For example, as a compound having the structure of formula (A-III-b) , said X ₈ may be optionally substituted -CH=.

For example, as a compound having the structure of formula (A-III-b) , said X ₈ may be substituted with one, two, or three R _x8-1, each said R _x8-1 may be independently absent or may be independently selected from optional substituents. For example, as a compound having the structure of formula (A-III-b) , said X ₈ may be substituted with one R _x8-1.

For example, as a compound having the structure of formula (A-III-b) , said R _x8-1 may be optionally substituted alkyl. For example, as a compound having the structure of formula (A-III-b) , said R _x8-1 may be optionally substituted methyl.

For example, as a compound having the structure of formula (A-III-b) , said R _x8-1 may be substituted with one, two, or three R _x8-2, each said R _x8-2 may be independently absent or may be independently selected from optional substituents.

For example, as a compound having the structure of formula (A-III-b) , said R _x8-1 may be substituted with three said R _x8-2. For example, as a compound having the structure of formula (A-III-b) , said R _x8-2 may be halogen. For example, as a compound having the structure of formula (A-III-b) , said R _x8-2 may be F or Cl.

said R ₁ may be H or optionally substituted methyl, said R ₁ may be substituted with one, two, or three R _1-1, one of said R _1-1 may be =O, one of said R _1-1 may be optionally substituted propenyl, said R _1-1 may be substituted with one, two, or three R _1-2, said R _1-2 may be optionally substituted amino, said R _1-2 may be substituted with one, two, or three R _1-3, said R _1-3 may be optionally substituted methyl,

said R ₂ may be H, said R ₃ may be H, said R ₄ may be H, said R ₅ may be H,

said A may be optionally substituted naphthyl, said R ₆ may be H, n may be 0, 1, 2, or 3,

said X ₁ may be optionally substituted -CH ₂-, said X ₂ may be optionally substituted -CH ₂-, said X ₄ may be optionally substituted -CH ₂-, said X ₃ may be optionally substituted CH, said X ₅ may be -N=, said X ₆ may be -N=, said X ₇ may be optionally substituted -CH=, said X ₈ may be optionally substituted -CH=,

said X ₈ may be substituted with one, two, or three R _x8-1, said R _x8-1 may be optionally substituted methyl substituted with three F.

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

wherein, each R ₁, R ₂, R ₃, R ₄, R ₅, R ₆, and R ₇ may be independently absent or may be independently selected from optional substituents, each X ₁, X ₂, X ₃, and X ₄ may be independently absent or may be independently selected from optionally substituted atom,

wherein, A may be optionally substituted heterocycle, B may be optionally substituted aryl or optionally substituted heteroaryl, m may be 0 or more, and n may be 0 or more.

For example, as a compound having the structure of formula (A-III-c) , said R ₁ may be halogen. For example, as a compound having the structure of formula (A-III-c) , said R ₁ may be F.

For example, as a compound having the structure of formula (A-III-c) , said R ₂ may be halogen. For example, as a compound having the structure of formula (A-III-c) , said R ₂ may be F.

For example, as a compound having the structure of formula (A-III-c) , said R ₃ may be halogen. For example, as a compound having the structure of formula (A-III-c) , said R ₃ may be F.

For example, as a compound having the structure of formula (A-III-c) , said R ₄ may be H.

For example, as a compound having the structure of formula (A-III-c) , said B may be optionally substituted aryl. For example, as a compound having the structure of formula (A-III-c) , said B may be optionally substituted phenyl.

For example, as a compound having the structure of formula (A-III-c) , said R ₅ may be H. For example, n may be 0, 1, 2, or 3.

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

For example, as a compound having the structure of formula (A-III-c) , said A may be optionally substituted piperidinyl.

For example, as a compound having the structure of formula (A-III-c) , said R ₆ may be H. For example, m may be 0, 1, 2, or 3. For example, as a compound having the structure of formula (A-III-c) , said R ₇ may be H.

For example, as a compound having the structure of formula (A-III-c) , X ₁ may be independently absent or may be independently selected from optionally substituted -CH ₂, optionally substituted -CH=, optionally substituted -NH-and -N=. For example, as a compound having the structure of formula (A-III-c) , said X ₁ may be optionally substituted -CH=.

For example, as a compound having the structure of formula (A-III-c) , each X ₂, X ₃ and X ₄ may be independently selected from optionally substituted -CH=, and -N=. For example, as a compound having the structure of formula (A-III-c) , said X ₂ may be -N=. For example, as a compound having the structure of formula (A-III-c) , said X ₃ may be optionally substituted -CH=. For example, as a compound having the structure of formula (A-III-c) , said X ₄ may be optionally substituted -CH=.

For example, as a compound having the structure of formula (A-III-c) , said X ₄ may be substituted with one, two, or three R _x4-1, each said R _x4-1 may be independently absent or may be independently selected from optional substituents.

For example, as a compound having the structure of formula (A-III-c) , said X ₄ may be substituted with one R _x4-1. For example, as a compound having the structure of formula (A-III-c) , said R _x4-1 may be optionally substituted alkyl. For example, as a compound having the structure of formula (A-III-c) , said R _x4-1 may be optionally substituted methyl.

For example, as a compound having the structure of formula (A-III-c) , said R _x4-1 may be substituted with one, two, or three R _x4-2, each said R _x4-2 may be independently absent or may be independently selected from optional substituents.

For example, as a compound having the structure of formula (A-III-c) , said R _x4-1 may be substituted with three said R _x4-2. For example, as a compound having the structure of formula (A-III-c) , said R _x4-2 may be halogen. For example, as a compound having the structure of formula (A-III-c) , said R _x4-2 may be F or Cl.

said R ₁ may be F, said R ₂ may be F, said R ₃ may be F, said R ₄ may be H, said B may be optionally substituted phenyl, said R ₅ may be H, n may be 0, 1, 2, or 3,

said A may be optionally substituted 6-ring-membered heterocycle containing one N, or said A may be optionally substituted piperidinyl,

said R ₆ may be H, m may be 0, 1, 2, or 3, said R ₇ may be H, said X ₁ may be optionally substituted -CH=, said X ₂ may be -N=, said X ₃ may be optionally substituted -CH=, said X ₄ may be optionally substituted -CH=, said X ₄ may be substituted with one R _x4-1, said R _x4-1 may be optionally substituted methyl substituted with three F.

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.

Compound Set B

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

wherein, A may be optionally substituted ring, B may be optionally substituted 7 or more-ring-membered heterocycle,

each X ₁, X ₂, X ₃, X ₄, and X ₅ may be independently selected from optionally substituted atom,

each R ₁, R ₂ and R ₃ may be independently absent or may be independently selected from optional substituents, m may be 0 or more, n may be 0 or more.

For example, as a compound having the structure of formula (B-I) , said A may be optionally substituted 6-ring-membered ring.

For example, as a compound having the structure of formula (B-I) , said A may be optionally substituted aryl.

For example, as a compound having the structure of formula (B-I) , said A may be optionally substituted phenyl.

For example, as a compound having the structure of formula (B-I) , said A may be substituted with one or more, for example, one, two or three, R ₃, each said R ₃ may be independently absent or may be independently selected from optional substituents.

For example, as a compound having the structure of formula (B-I) , said m may be 1.

For example, as a compound having the structure of formula (B-I) , each said R ₃ may be independently selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, optionally substituted alkyl, and optionally substituted acyl.

For example, as a compound having the structure of formula (B-I) , each said R ₃ may be independently selected from the group consisting of hydrogen, Br, optionally substituted methyl, optionally substituted formyl.

For example, as a compound having the structure of formula (B-I) , said R ₃ may be substituted with one or more, for example, one, two or three, R _3-1, each said R _3-1 may be independently absent or may be independently selected from optional substituents.

For example, as a compound having the structure of formula (B-I) , each said R _3-1 may be independently selected from the group consisting of hydrogen, protium, deuterium, tritium, optionally substituted hydroxyl, and optionally substituted amino.

For example, as a compound having the structure of formula (B-I) , said R _3-1 may be substituted with one or more, for example, one, two or three, R _3-2, each said R _3-2 may be independently absent or may be independently selected from optional substituents.

For example, as a compound having the structure of formula (B-I) , each said R _3-2 may be independently selected from the group consisting of hydrogen, protium, deuterium, tritium, optionally substituted hydroxyl, and optionally substituted alkyl.

For example, as a compound having the structure of formula (B-I) , each said R _3-2 may be independently selected from the group consisting of hydrogen, optionally substituted hydroxyl, and optionally substituted methyl.

For example, as a compound having the structure of formula (B-I) , said X ₁ may be optionally substituted -CH=.

For example, as a compound having the structure of formula (B-I) , said X ₂ may be optionally substituted -NH-.

For example, as a compound having the structure of formula (B-I) , said B may be optionally substituted 7-ring-membered ring.

For example, as a compound having the structure of formula (B-I) , said B may be optionally substituted ring containing no N or one or more, for example, one, two or three, N.

For example, as a compound having the structure of formula (B-I) , said B may be optionally substituted ring containing one N.

For example, as a compound having the structure of formula (B-I) , said B may be optionally substituted azepanyl.

For example, as a compound having the structure of formula (B-I) , said B may be substituted with one or more R ₁, each said R ₁ may be independently absent or may be independently selected from optional substituents.

For example, as a compound having the structure of formula (B-I) , said n may be 1.

For example, as a compound having the structure of formula (B-I) , each said R ₁ may be independently selected from the group consisting of hydrogen, protium, deuterium, and tritium.

For example, as a compound having the structure of formula (B-I) , said R ₂ may be independently selected from the group consisting of hydrogen, protium, deuterium, and tritium.

For example, as a compound having the structure of formula (B-I) , said X ₃ may be -N= or optionally substituted -CH=.

For example, as a compound having the structure of formula (B-I) , said X ₄ may be optionally substituted -CH=.

For example, as a compound having the structure of formula (B-I) , said X ₅ may be optionally substituted -CH=.

For example, as a compound having the structure of formula (B-I) , said X ₅ may be substituted with R _X5-1, said R _X5-1 may be selected from optional substituents.

For example, as a compound having the structure of formula (B-I) , said R _X5-1 may be selected from the group consisting of hydrogen, protium, deuterium, tritium, CN, and optionally substituted alkyl.

For example, as a compound having the structure of formula (B-I) , said R _X5-1 may be selected from the group consisting of hydrogen, CN, and optionally substituted methyl.

For example, as a compound having the structure of formula (B-I) , said R _X5-1 may be substituted with one or more, for example, one, two or three, R _X5-2, each said R _X5-2 may be selected from optional substituents.

For example, as a compound having the structure of formula (B-I) , said R _X5-1 may be substituted with three R _X5-2.

For example, as a compound having the structure of formula (B-I) , each said R _X5-2 may be selected from the group consisting of hydrogen, protium, deuterium, tritium, and halogen.

For example, as a compound having the structure of formula (B-I) , each said R _X5-2 may be selected from the group consisting of hydrogen, and F.

wherein, A may be optionally substituted phenyl, said A may be substituted with one R ₃, said R ₃ may be independently absent or may be independently selected from the group consisting of hydrogen, Br, optionally substituted methyl, optionally substituted formyl, R ₃ may be substituted with R _3-1, each said R _3-1 may be independently absent or may be independently selected from the group consisting of hydrogen, protium, deuterium, tritium, optionally substituted hydroxyl, and optionally substituted amino, said R _3-1 may be substituted with R _3-2, each said R _3-2 may be independently absent or may be independently selected from the group consisting of hydrogen, optionally substituted hydroxyl, and optionally substituted methyl

said X ₁ may be optionally substituted -CH=, said X ₂ may be optionally substituted -NH-,

said B may be optionally substituted azepany, each said R ₁ may be independently selected from the group consisting of hydrogen, protium, deuterium, and tritium, said R ₂ may be independently selected from the group consisting of hydrogen, protium, deuterium, and tritium,

said X ₃ may be -N= or optionally substituted -CH=, said X ₄ may be optionally substituted -CH=, said X ₅ may be optionally substituted -CH=,

said X ₅ may be substituted with R _X5-1, said R _X5-1 may be selected from the group consisting of hydrogen, CN, and optionally substituted methyl, said R _X5-1 may be substituted with three R _X5- ₂, each said R _X5-2 may be selected from the group consisting of hydrogen, and F.

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 may be selected from the group consisting of:

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

wherein, A may be optionally substituted ring,

each X ₁, X ₂, X ₃, X ₄, X ₅, X ₆, X ₇, X ₈, X ₉, X ₁₀, X ₁₁, X ₁₂, and X ₁₃ may be independently selected from optionally substituted atom,

R ₁ may be optionally substituted alkyl, each R ₂, R ₃ and R ₄ may be independently absent or may be independently selected from optional substituents, wherein R ₂ may be not hydrogen.

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

For example, as a compound having the structure of formula (B-II) , said A may be optionally substituted ring containing one or more, for example, one, two or three, N.

For example, as a compound having the structure of formula (B-II) , said A may be optionally substituted ring containing one N.

For example, as a compound having the structure of formula (B-II) , said A may be optionally substituted piperidinyl.

For example, as a compound having the structure of formula (B-II) , said A may be substituted with one or more, for example, one, two or three, R ₂, each said R ₂ may be independently absent or may be independently selected from optional substituents.

For example, as a compound having the structure of formula (B-II) , each said R ₂ may be independently selected from the group consisting of hydrogen, protium, deuterium, tritium, and optionally substituted alkyl.

For example, as a compound having the structure of formula (B-II) , each said R ₂ may be independently selected from the group consisting of hydrogen, and optionally substituted methyl.

For example, as a compound having the structure of formula (B-II) , each said R ₃ may be independently selected from the group consisting of hydrogen, protium, deuterium, and tritium.

For example, as a compound having the structure of formula (B-II) , said X ₁₀ may be optionally substituted -CH ₂-.

For example, as a compound having the structure of formula (B-II) , said X ₁₁ may be optionally substituted CH.

For example, as a compound having the structure of formula (B-II) , said X ₁₂ may be optionally substituted -CH ₂-.

For example, as a compound having the structure of formula (B-II) , said X ₁₃ may be optionally substituted -CH ₂-.

For example, as a compound having the structure of formula (B-II) , said X ₁₃ may be substituted with said R ₂.

For example, as a compound having the structure of formula (B-II) , each said R ₄ may be independently selected from the group consisting of hydrogen, protium, deuterium, and tritium.

For example, as a compound having the structure of formula (B-II) , said R ₁ may be selected from the group consisting of hydrogen, protium, deuterium, tritium, and optionally substituted alkyl.

For example, as a compound having the structure of formula (B-II) , said R ₁ may be selected from the group consisting of hydrogen, and optionally substituted methyl.

For example, as a compound having the structure of formula (B-II) , said R ₁ may be substituted with one or more, for example, one, two or three, R _1-1, each said R _1-1 may be selected from optional substituents.

For example, as a compound having the structure of formula (B-II) , said R ₁ may be substituted with three R _1-1.

For example, as a compound having the structure of formula (B-II) , each said R _1-1 may be selected from the group consisting of hydrogen, protium, deuterium, tritium, and halogen.

For example, as a compound having the structure of formula (B-II) , each said R _1-1 may be selected from the group consisting of hydrogen, and F.

For example, as a compound having the structure of formula (B-II) , said X ₆ may be -N=.

For example, as a compound having the structure of formula (B-II) , said X ₇ may be -N=.

For example, as a compound having the structure of formula (B-II) , said X ₈ may be optionally substituted -CH=.

For example, as a compound having the structure of formula (B-II) , said X ₉ may be optionally substituted -CH=.

For example, as a compound having the structure of formula (B-II) , said X ₉ may be substituted with said R ₁.

For example, as a compound having the structure of formula (B-II) , said X ₁ may be optionally substituted -CH=.

For example, as a compound having the structure of formula (B-II) , said X ₂ may be optionally substituted -CH=.

For example, as a compound having the structure of formula (B-II) , said X ₃ may be optionally substituted -CH=.

For example, as a compound having the structure of formula (B-II) , said X ₃ may be substituted with R _x3-1.

For example, as a compound having the structure of formula (B-II) , said R _x3-1 may be selected from the group consisting of hydrogen, protium, deuterium, tritium, and halogen.

For example, as a compound having the structure of formula (B-II) , said R _x3-1 may be selected from the group consisting of hydrogen, and F.

For example, as a compound having the structure of formula (B-II) , said X ₄ may be optionally substituted -NH-.

For example, as a compound having the structure of formula (B-II) , said X ₅ may be optionally substituted -CH=.

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 may be

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

wherein, A may be optionally substituted heteroaryl,

each X ₁, X ₂, X ₃, X ₄, X ₅, X ₆, and X ₇ may be independently selected from optionally substituted atom,

each R ₁, R ₂, R ₃, R ₄ and R ₅ may be independently absent or may be independently selected from optional substituents.

For example, as a compound having the structure of formula (B-III) , said A may be optionally substituted 6 to 13-ring-membered ring.

For example, as a compound having the structure of formula (B-III) , said A may be optionally substituted ring containing one or more, for example, one, two or three, N.

For example, as a compound having the structure of formula (B-III) , said A may be optionally substituted ring containing one to three N.

For example, as a compound having the structure of formula (B-III) , said A may be selected from the group consisting of optionally substituted pyridinyl, optionally substituted quinolinyl, optionally substituted imidazopyrazinyl, optionally substituted indazolyl, and optionally substituted imidazoquinolinyl.

For example, as a compound having the structure of formula (B-III) , said A may be substituted with one or more, for example, one, two or three, R _A-1, each said R _A-1 may be independently absent or may be independently selected from optional substituents.

For example, as a compound having the structure of formula (B-III) , each said R _A-1 may be independently selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, CN, optionally substituted alkyl, optionally substituted aryl, and optionally substituted heteroaryl.

For example, as a compound having the structure of formula (B-III) , each said R _A-1 may be independently selected from the group consisting of hydrogen, Br, CN, optionally substituted methyl, optionally substituted butyl, optionally substituted phenyl, optionally substituted piperazinyl, and optionally substituted pyridinyl.

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

For example, as a compound having the structure of formula (B-III) , said R _A-1 may be substituted with one or three R _A-2.

For example, as a compound having the structure of formula (B-III) , each said R _A-2 may be independently selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen and optionally substituted alkyl.

For example, as a compound having the structure of formula (B-III) , each said R _A-2 may be independently selected from the group consisting of hydrogen, F and optionally substituted methyl.

For example, as a compound having the structure of formula (B-III) , said R ₅ may be absent or may be independently selected from the group consisting of hydrogen, protium, deuterium, tritium, and CN.

For example, as a compound having the structure of formula (B-III) , said R ₄ may be independently selected from the group consisting of hydrogen, protium, deuterium, and tritium.

For example, as a compound having the structure of formula (B-III) , said R ₃ may be selected from the group consisting of hydrogen, protium, deuterium, tritium, CN, and optionally substituted alkyl.

For example, as a compound having the structure of formula (B-III) , said R ₃ may be selected from the group consisting of hydrogen, CN and optionally substituted methyl.

For example, as a compound having the structure of formula (B-III) , said R ₃ may be substituted with one or more, for example, one, two or three, R _3-1, each said R _3-1 may be selected from optional substituents.

For example, as a compound having the structure of formula (B-III) , said R ₃ may be substituted with three R _3-1.

For example, as a compound having the structure of formula (B-III) , each said R _3-1 may be selected from the group consisting of hydrogen, protium, deuterium, tritium, and halogen.

For example, as a compound having the structure of formula (B-III) , each said R _3-1 may be selected from the group consisting of hydrogen, and F.

For example, as a compound having the structure of formula (B-III) , said X ₆ may be optionally substituted -CH=.

For example, as a compound having the structure of formula (B-III) , said X ₆ may be substituted with said R ₃.

For example, as a compound having the structure of formula (B-III) , said X ₇ may be optionally substituted -CH=.

For example, as a compound having the structure of formula (B-III) , said R ₂ may be independently selected from the group consisting of hydrogen, protium, deuterium, and tritium.

For example, as a compound having the structure of formula (B-III) , said R ₁ may be independently selected from the group consisting of hydrogen, protium, deuterium, and tritium.

For example, as a compound having the structure of formula (B-III) , said X ₁ may be optionally substituted -CH ₂-.

For example, as a compound having the structure of formula (B-III) , said X ₂ may be optionally substituted CH.

For example, as a compound having the structure of formula (B-III) , said X ₃ may be optionally substituted -CH ₂-.

For example, as a compound having the structure of formula (B-III) , said X ₄ may be optionally substituted -CH ₂-.

For example, as a compound having the structure of formula (B-III) , said X ₅ may be optionally substituted -CH ₂-.

said A may be selected from the group consisting of optionally substituted pyridinyl, and optionally substituted quinolinyl, said A may be substituted with R _A-1, each said R _A-1 may be independently absent or may be independently selected from the group consisting of hydrogen, Br, optionally substituted methyl, and optionally substituted pyridinyl, said R _A-1 may be substituted with R _A-2, each said R _A-2 may be independently absent or may be independently selected from hydrogen, and F,

said R ₅ may be absent or may be independently selected from the group consisting of hydrogen, protium, deuterium, and tritium, said R ₄ may be independently selected from the group consisting of hydrogen, protium, deuterium, and tritium, said R ₃ may be selected from the group consisting of hydrogen, CN and optionally substituted methyl, said R ₃ may be substituted with R _3- ₁, each said R _3-1 may be selected from the group consisting of hydrogen, and F, said X ₆ may be optionally substituted -CH=, said X ₆ may be substituted with said R ₃, said X ₇ may be optionally substituted -CH=, said R ₂ may be independently selected from the group consisting of hydrogen, protium, deuterium, and tritium, said R ₁ may be independently selected from the group consisting of hydrogen, protium, deuterium, and tritium, said X ₁ may be optionally substituted -CH ₂-, said X ₂ may be optionally substituted CH, said X ₃ may be optionally substituted -CH ₂-, said X ₄ may be optionally substituted -CH ₂-, said X ₅ may be optionally substituted -CH ₂-.

Compound Set C

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

each X ₁, X ₂, X ₃, X ₄, X ₅, X ₆, X ₇, X ₈, X ₉, X ₁₀, X ₁₁, and X ₁₂ may be independently absent or may be independently selected from optionally substituted atom,

each R ₁, R ₂, R ₃ and R ₄ may be independently absent or may be independently selected from optional substituents.

For example, as a compound having the structure of formula (C-I) , said R ₄ may be independently selected from the group consisting of hydrogen, protium, deuterium, and tritium.

For example, as a compound having the structure of formula (C-I) , said X ₉ may be -O-or -S-.

For example, as a compound having the structure of formula (C-I) , said X ₁₀ may be optionally substituted -CH=.

For example, as a compound having the structure of formula (C-I) , said X ₁₀ may be substituted with R _X10-1, said R _X10-1 may be selected from optional substituents.

For example, as a compound having the structure of formula (C-I) , said R _X10-1 may be selected from the group consisting of hydrogen, protium, deuterium, tritium, and optionally substituted hydroxyl.

For example, as a compound having the structure of formula (C-I) , said R _X10-1 may be substituted with one or more, for example, one, two or three, R _X10-2, each said R _X10-2 may be selected from optional substituents.

For example, as a compound having the structure of formula (C-I) , said R _X10-2 may be selected from the group consisting of hydrogen, protium, deuterium, tritium, and optionally substituted alkyl.

For example, as a compound having the structure of formula (C-I) , said R _X10-2 may be selected from the group consisting of hydrogen, protium, deuterium, tritium, and optionally substituted methyl.

For example, as a compound having the structure of formula (C-I) , said X ₁₁ may be optionally substituted -CH=.

For example, as a compound having the structure of formula (C-I) , said X ₁₁ may be substituted with R _X11-1, said R _X11-1 may be selected from optional substituents.

For example, as a compound having the structure of formula (C-I) , said R _X11-1 may be selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, optionally substituted alkyl and optionally substituted hydroxyl.

For example, as a compound having the structure of formula (C-I) , said R _X11-1 may be selected from the group consisting of hydrogen, Cl, optionally substituted methyl and optionally substituted hydroxyl.

For example, as a compound having the structure of formula (C-I) , said R _X11-1 may be substituted with one or more, for example, one, two or three, R _X11-2, each said R _X11-2 may be selected from optional substituents.

For example, as a compound having the structure of formula (C-I) , said R _X11-2 may be selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen and optionally substituted alkyl.

For example, as a compound having the structure of formula (C-I) , said R _X11-2 may be selected from the group consisting of hydrogen, protium, deuterium, tritium, F and optionally substituted methyl.

For example, as a compound having the structure of formula (C-I) , said X ₁₂ may be optionally substituted -CH=.

For example, as a compound having the structure of formula (C-I) , said X ₁₂ may be substituted with R _X12-1, said R _X12-1 may be selected from optional substituents.

For example, as a compound having the structure of formula (C-I) , said R _X12-1 may be selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, and optionally substituted hydroxyl.

For example, as a compound having the structure of formula (C-I) , said R _X12-1 may be selected from the group consisting of hydrogen, Cl, and optionally substituted hydroxyl.

For example, as a compound having the structure of formula (C-I) , said R _X12-1 may be substituted with one or more, for example, one, two or three, R _X12-2, each said R _X12-2 may be selected from optional substituents.

For example, as a compound having the structure of formula (C-I) , said R _X12-2 may be selected from the group consisting of hydrogen, protium, deuterium, tritium, and optionally substituted alkyl.

For example, as a compound having the structure of formula (C-I) , said R _X12-2 may be selected from the group consisting of hydrogen, protium, deuterium, tritium, and optionally substituted methyl.

For example, as a compound having the structure of formula (C-I) , said R ₃ may be independently selected from the group consisting of hydrogen, protium, deuterium, and tritium.

For example, as a compound having the structure of formula (C-I) , said X ₆ may be optionally substituted -CH=.

For example, as a compound having the structure of formula (C-I) , said X ₆ may be substituted with R _X6-1, said R _X6-1 may be selected from optional substituents.

For example, as a compound having the structure of formula (C-I) , said R _X6-1 may be selected from the group consisting of hydrogen, protium, deuterium, tritium, and optionally substituted alkyl.

For example, as a compound having the structure of formula (C-I) , said R _X6-1 may be selected from the group consisting of hydrogen, and optionally substituted methyl.

For example, as a compound having the structure of formula (C-I) , said R _X6-1 may be substituted with one or more, for example, one, two or three, R _X6-2, each said R _X6-2 may be selected from optional substituents.

For example, as a compound having the structure of formula (C-I) , said R _X6-2 may be selected from the group consisting of hydrogen, protium, deuterium, tritium, and halogen.

For example, as a compound having the structure of formula (C-I) , said R _X6-2 may be selected from the group consisting of hydrogen, protium, deuterium, tritium, and F.

For example, as a compound having the structure of formula (C-I) , said X ₇ may be optionally substituted -CH=.

For example, as a compound having the structure of formula (C-I) , said X ₈ may be -N=.

For example, as a compound having the structure of formula (C-I) , said R ₂ may be independently selected from the group consisting of hydrogen, protium, deuterium, and tritium.

For example, as a compound having the structure of formula (C-I) , said R ₁ may be independently selected from the group consisting of hydrogen, protium, deuterium, and tritium.

For example, as a compound having the structure of formula (C-I) , said X ₁ may be optionally substituted -CH ₂-.

For example, as a compound having the structure of formula (C-I) , said X ₂ may be optionally substituted CH.

For example, as a compound having the structure of formula (C-I) , said X ₃ may be optionally substituted -CH ₂-.

For example, as a compound having the structure of formula (C-I) , said X ₄ may be optionally substituted -CH ₂-.

For example, as a compound having the structure of formula (C-I) , said X ₅ may be optionally substituted -CH ₂-.

For example, as a compound having the structure of formula (C-I) , said X ₅ may be substituted with one or more, for example, one, two or three, R _X5-1, each said R _X5-1 may be selected from optional substituents.

For example, as a compound having the structure of formula (C-I) , said R _X5-1 may be selected from the group consisting of hydrogen, protium, deuterium, tritium, and optionally substituted alkyl.

For example, as a compound having the structure of formula (C-I) , said R _X5-1 may be selected from the group consisting of hydrogen, and optionally substituted methyl.

said R ₄ may be independently selected from the group consisting of hydrogen, protium, deuterium, and tritium, said X ₉ may be -O-or -S-, said X ₁₀ may be optionally substituted -CH=, said X ₁₀ may be substituted with R _X10-1, said R _X10-1 may be selected from the group consisting of hydrogen, protium, deuterium, tritium, and optionally substituted hydroxyl, said R _X10-1 may be substituted with R _X10-2, each said R _X10-2 may be selected from the group consisting of hydrogen, protium, deuterium, tritium, and optionally substituted methyl,

said X ₁₁ may be optionally substituted -CH=, said X ₁₁ may be substituted with R _X11-1, said R _X11-1 may be selected from the group consisting of hydrogen, Cl, optionally substituted methyl and optionally substituted hydroxyl, said R _X11-1 may be substituted with R _X11-2, each said R _X11-2 may be selected from the group consisting of hydrogen, protium, deuterium, tritium, F and optionally substituted methyl,

said X ₁₂ may be optionally substituted -CH=, said X ₁₂ may be substituted with R _X12-1, said R _X12-1 may be selected from the group consisting of hydrogen, Cl, and optionally substituted hydroxyl, said R _X12-1 may be substituted with R _X12-2, each said R _X12-2 may be selected from the group consisting of hydrogen, protium, deuterium, tritium, and optionally substituted methyl,

said R ₃ may be independently selected from the group consisting of hydrogen, protium, deuterium, and tritium, said X ₆ may be optionally substituted -CH=, said X ₆ may be substituted with R _X6-1, said R _X6-1 may be selected from the group consisting of hydrogen, and optionally substituted methyl, said R _X6-1 may be substituted with R _X6-2, each said R _X6-2 may be selected from the group consisting of hydrogen, protium, deuterium, tritium, and F,

said X ₇ may be optionally substituted -CH=, said X ₈ may be -N=,

said R ₂ may be independently selected from the group consisting of hydrogen, protium, deuterium, and tritium, said R ₁ may be independently selected from the group consisting of hydrogen, protium, deuterium, and tritium,

said X ₁ may be optionally substituted -CH ₂-, said X ₂ may be optionally substituted CH, said X ₃ may be optionally substituted -CH ₂-, said X ₄ may be optionally substituted -CH ₂-, said X ₅ may be optionally substituted -CH ₂-, said X ₅ may be substituted with two R _X5-1, each said R _X5-1 may be selected from the group consisting of hydrogen, and optionally substituted methyl.

Compound Set D

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

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

For example, as a compound having the structure of formula (D-I) , said A is optionally substituted aryl.

For example, as a compound having the structure of formula (D-I) , said A is optionally substituted phenyl.

For example, as a compound having the structure of formula (D-I) , said A is substituted with one or more R ₃, each said R ₃ is independently absent or is independently selected from optional substituents.

For example, as a compound having the structure of formula (D-I) , said m is 1 or 2.

For example, as a compound having the structure of formula (D-I) , each said R ₃ is independently 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 (D-I) , each said R ₃ is independently selected from the group consisting of hydrogen, F, Cl, Br, CN, optionally substituted formyl, optionally substituted amino, optionally substituted hydroxyl, optionally substituted P (=O) H ₂, and optionally substituted sulfonyl.

For example, as a compound having the structure of formula (D-I) , each said R ₃ is independently optionally substituted 6-ring-membered ring.

For example, as a compound having the structure of formula (D-I) , each said R ₃ is independently optionally substituted ring containing one or more N and/or one or more O.

For example, as a compound having the structure of formula (D-I) , each said R ₃ is independently optionally substituted ring containing one or two N.

For example, as a compound having the structure of formula (D-I) , each said R ₃ is independently optionally substituted ring containing one O.

For example, as a compound having the structure of formula (D-I) , each said R ₃ is independently optionally substituted heterocycle, or optionally substituted heteroaryl.

For example, as a compound having the structure of formula (D-I) , each said R ₃ is independently selected from the group consisting of optionally substituted piperidinyl, optionally substituted isoxazolyl, and optionally substituted pyrazolyl.

For example, as a compound having the structure of formula (D-I) , said R ₃ is substituted with one or more R _3-1, each said R _3-1 is independently absent or is independently selected from optional substituents.

For example, as a compound having the structure of formula (D-I) , said R ₃ is substituted with one or two said R _3-1.

For example, as a compound having the structure of formula (D-I) , each said R _3-1 is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted amino, optionally substituted hydroxyl, and optionally substituted ring.

For example, as a compound having the structure of formula (D-I) , each said R _3-1 is independently selected from the group consisting of hydrogen, optionally substituted methyl, optionally substituted ethyl, optionally substituted formyl, optionally substituted amino, and optionally substituted hydroxyl.

For example, as a compound having the structure of formula (D-I) , each said R _3-1 is independently optionally substituted 6-ring-membered ring.

For example, as a compound having the structure of formula (D-I) , each said R _3-1 is independently optionally substituted ring containing one or more N.

For example, as a compound having the structure of formula (D-I) , each said R _3-1 is independently optionally substituted ring containing one or two N.

For example, as a compound having the structure of formula (D-I) , each said R _3-1 is independently optionally substituted heterocycle.

For example, as a compound having the structure of formula (D-I) , each said R _3-1 is independently selected from the group consisting of optionally substituted piperidinyl, and optionally substituted piperazinyl.

For example, as a compound having the structure of formula (D-I) , said R _3-1 is substituted with one or more R _3-2, each said R _3-2 is independently absent or is independently selected from optional substituents.

For example, as a compound having the structure of formula (D-I) , said R _3-1 is substituted with one or two said R _3-2.

For example, as a compound having the structure of formula (D-I) , each said R _3-2 is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted amino, and optionally substituted hydroxyl.

For example, as a compound having the structure of formula (D-I) , said R _3-2 is substituted with one or more R _3-3, each said R _3-3 is independently absent or is independently selected from optional substituents.

For example, as a compound having the structure of formula (D-I) , said R _3-2 is substituted with one or two said R _3-3.

For example, as a compound having the structure of formula (D-I) , each said R _3-3 is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted amino, and optionally substituted hydroxyl.

For example, as a compound having the structure of formula (D-I) , said X ₁ is optionally substituted -CH=.

For example, as a compound having the structure of formula (D-I) , said X ₂ is optionally substituted -NH-.

For example, as a compound having the structure of formula (D-I) , said B is optionally substituted 7-ring-membered ring.

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

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

For example, as a compound having the structure of formula (D-I) , said B is optionally substituted azepanyl.

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

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

For example, as a compound having the structure of formula (D-I) , said R ₁ is hydrogen.

For example, as a compound having the structure of formula (D-I) , said R ₂ is hydrogen.

For example, as a compound having the structure of formula (D-I) , said X ₃ is -N=.

For example, as a compound having the structure of formula (D-I) , said X ₄ is optionally substituted -CH=.

For example, as a compound having the structure of formula (D-I) , said X ₅ is optionally substituted -CH=.

For example, as a compound having the structure of formula (D-I) , said X ₅ is substituted with one or more R _X5-1, said R _X5-1 is selected from optional substituents.

For example, as a compound having the structure of formula (D-I) , said X ₅ is substituted with one said R _X5-1.

For example, as a compound having the structure of formula (D-I) , said R _X5-1 is selected from the group consisting of hydrogen, and optionally substituted alkyl.

For example, as a compound having the structure of formula (D-I) , said R _X5-1 is selected from the group consisting of hydrogen, and optionally substituted methyl.

For example, as a compound having the structure of formula (D-I) , said R _X5-1 is substituted with one or more R _X5-2, each said R _X5-2 is selected from optional substituents.

For example, as a compound having the structure of formula (D-I) , said R _X5-1 is substituted with three R _X5-2.

For example, as a compound having the structure of formula (D-I) , each said R _X5-2 is selected from the group consisting of hydrogen and halogen.

For example, as a compound having the structure of formula (D-I) , each said R _X5-2 is selected from the group consisting of hydrogen and F.

said A is optionally substituted phenyl, said m is 1 or 2, each said R ₃ is independently selected from the group consisting of hydrogen, F, Cl, Br, CN, optionally substituted formyl, optionally substituted amino, optionally substituted hydroxyl, optionally substituted P (=O) H ₂, and optionally substituted sulfonyl, or each said R ₃ is independently selected from the group consisting of optionally substituted piperidinyl, optionally substituted isoxazolyl, and optionally substituted pyrazolyl, said R ₃ is substituted with one or more R _3-1, each said R _3-1 is independently selected from the group consisting of hydrogen, optionally substituted methyl, optionally substituted ethyl, optionally substituted formyl, optionally substituted amino, and optionally substituted hydroxyl, said X ₁ is optionally substituted -CH=, said X ₂ is optionally substituted -NH-, said B is optionally substituted azepanyl, said n is 1, said R ₁ is hydrogen, said R ₂ is hydrogen, said X ₃ is -N=, said X ₄ is optionally substituted -CH=, said X ₅ is optionally substituted -CH=, said X ₅ is substituted with one or more R _X5-1, said R _X5-1 is selected from optional substituents, said X ₅ is substituted with one said R _X5-1, said R _X5-1 is selected from the group consisting of hydrogen, and three-F substituted alkyl.

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

wherein, A is optionally substituted heteroaryl,

For example, as a compound having the structure of formula (D-II) , said A is optionally substituted 6 to 13-ring-membered ring.

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

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

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

For example, as a compound having the structure of formula (D-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, as a compound having the structure of formula (D-II) , said A is substituted with one said R _A-1.

For example, as a compound having the structure of formula (D-II) , each said R _A-1 is independently selected from the group consisting of hydrogen and optionally substituted heteroaryl.

For example, as a compound having the structure of formula (D-II) , each said R _A-1 is independently optionally substituted 5-ring-membered ring.

For example, as a compound having the structure of formula (D-II) , each said R _A-1 is independently optionally substituted ring containing two N.

For example, as a compound having the structure of formula (D-II) , each said R _A-1 is independently optionally substituted pyrazolyl.

For example, as a compound having the structure of formula (D-II) , said R ₅ is hydrogen.

For example, as a compound having the structure of formula (D-II) , said R ₄ is hydrogen.

For example, as a compound having the structure of formula (D-II) , said R ₃ is selected from the group consisting of hydrogen and optionally substituted alkyl.

For example, as a compound having the structure of formula (D-II) , said R ₃ is selected from the group consisting of hydrogen and optionally substituted methyl.

For example, as a compound having the structure of formula (D-II) , said R ₃ is substituted with one or more R _3-1, each said R _3-1 is selected from optional substituents.

For example, as a compound having the structure of formula (D-II) , said R ₃ is substituted with three R _3-1.

For example, as a compound having the structure of formula (D-II) , each said R _3-1 is selected from the group consisting of hydrogen and halogen.

For example, as a compound having the structure of formula (D-II) , each said R _3-1 is selected from the group consisting of hydrogen and F.

For example, as a compound having the structure of formula (D-II) , said X ₆ is optionally substituted -CH=.

For example, as a compound having the structure of formula (D-II) , said X ₆ is substituted with said R ₃.

For example, as a compound having the structure of formula (D-II) , said X ₇ is optionally substituted -CH=.

For example, as a compound having the structure of formula (D-II) , said R ₂ is hydrogen.

For example, as a compound having the structure of formula (D-II) , said R ₁ is hydrogen.

For example, as a compound having the structure of formula (D-II) , said X ₁ is optionally substituted -CH ₂-.

For example, as a compound having the structure of formula (D-II) , said X ₂ is optionally substituted CH.

For example, as a compound having the structure of formula (D-II) , said X ₃ is optionally substituted -CH ₂-.

For example, as a compound having the structure of formula (D-II) , said X ₄ is optionally substituted -CH ₂-.

For example, as a compound having the structure of formula (D-II) , said X ₅ is optionally substituted -CH ₂-.

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 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

Compound Set A

Compound A-I-1: 3- (2- ( ( (1R, 3S) -3-aminocyclohexyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-7-carbonitrile

Synthesis of 3- (2- ( ( (1R, 3S) -3-aminocyclohexyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-7-carbonitrile

Synthesis of 3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-7-carbonitrile

To a mixture of 2, 4-dichloro-5- (trifluoromethyl) pyrimidine (1 g, 4.63 mmol) in DCE (30 mL) was added AlCl ₃ (672 mg, 5.09 mmol) . The mixture was stirred at 90 ℃ for 0.5 h under N ₂. Then 1H-indole-7-carbonitrile (313 mg, 2.21 mmol) was added. The reaction mixture was stirred at 90℃ for another 3 h. The reaction was quenched with MeOH (20 mL) and water (15 mL) . The mixture was filtered. The filter cake was washed with MeOH (10 mL) and dried to give the product 3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-7-carbonitrile (200 mg, yield: 28%) as a yellow solid, which was used in the next step without further purification. ESI-MS [M +H] ⁺: 323.2.

Synthesis of tert-butyl ( (1S, 3R) -3- ( (4- (7-cyano-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) cyclohexyl) carbamate

A mixture of 3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-7-carbonitrile (60 mg, 0.19 mmol) , tert-butyl ( (1S, 3R) -3-aminocyclohexyl) carbamate (61 mg, 0.29 mmol) and DIPEA (74 mg, 0.57 mmol) in i-PrOH (3 mL) was irradiated in microwave at 140 ℃ for 1 h. The reaction mixture was concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 15/1) to give tert-butyl ( (1S, 3R) -3- ( (4- (7-cyano-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) cyclohexyl) carbamate (50 mg, yield: 53%) as a white solid. ESI-MS [M + H] ⁺: 501.2.

To a mixture of tert-butyl ( (1S, 3R) -3- ( (4- (7-cyano-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) cyclohexyl) carbamate (50 mg, 0.10 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 NH ₃ (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 3- (2- ( ( (1R, 3S) -3-aminocyclohexyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-7-carbonitrile (25 mg, yield: 63%) as a white solid.

ESI-MS [M +H] ⁺: 401.2.

¹H NMR (400 MHz, cd3od) δ 8.63 (s, 1H) , 8.51 (d, J = 14.4 Hz, 1H) , 7.93 (s, 1H) , 7.62 (d, J = 7.3 Hz, 1H) , 7.29 (t, J = 7.8 Hz, 1H) , 4.04-3.98 (m, 1H) , 2.76 (s, 1H) , 2.25 (s, 1H) , 2.05 (s, 1H) , 1.87 (t, J = 14.0 Hz, 2H) , 1.49-1.38 (m, 1H) , 1.33 –1.01 (m, 3H) .

Compound A-I-2: 3- (2- ( ( (1S, 3R) -3-aminocyclohexyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carbonitrile

Synthesis of 3- (2- ( ( (1S, 3R) -3-aminocyclohexyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carbonitrile

Synthesis of 3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carbonitrile

To a mixture of 2, 4-dichloro-5- (trifluoromethyl) pyrimidine (1 g, 4.63 mmol) in DCE (30 mL) was added AlCl ₃ (672 mg, 5.09 mmol) . The mixture was stirred at 90℃ for 0.5 h under N ₂. Then 1H-indole-6-carbonitrile (313 mg, 2.21 mmol) was added. The reaction mixture was stirred at 90℃ for another 3 h. The reaction was quenched with MeOH (20 mL) and water (15 mL) . The mixture was filtered. The filter cake was washed with MeOH (10 mL) and dried to give the product 3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carbonitrile (130 mg, yield: 18%) as a yellow solid, which was used in the next step without further purification. ESI-MS [M +H] ⁺: 323.2.

Synthesis of tert-butyl ( (1R, 3S) -3- ( (4- (6-cyano-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) cyclohexyl) carbamate

A mixture of 3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carbonitrile (100 mg, 0.31 mmol) , tert-butyl ( (1S, 3R) -3-aminocyclohexyl) carbamate (101 mg, 0.47 mmol) and DIPEA (120 mg, 0.93 mmol) in i-PrOH (3 mL) was irradiated in microwave at 140 ℃ for 1 h. The reaction mixture was concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 15/1) to give tert-butyl ( (1R, 3S) -3- ( (4- (6-cyano-1H-indol-3-yl) -5-(trifluoromethyl) pyrimidin-2-yl) amino) cyclohexyl) carbamate (100 mg, yield: 65%) as a white solid. ESI-MS [M + H] ⁺: 501.2.

To a mixture of tert-butyl ( (1R, 3S) -3- ( (4- (6-cyano-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) cyclohexyl) carbamate (100 mg, 0.20 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 NH ₃ (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 3- (2- ( ( (1S, 3R) -3-aminocyclohexyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carbonitrile (40 mg, yield: 50%) as a white solid.

ESI-MS [M +H] ⁺: 401.2.

1H NMR (400 MHz, cd3od) δ 8.52-8.46 (m, 2H) , 7.96 (d, J = 67.3 Hz, 1H) , 7.43 (d, J = 7.2 Hz, 1H) , 4.15-3.96 (m, 1H) , 2.80-2.73 (m, 1H) , 2.25 (s, 1H) , 2.03 (s, 1H) , 1.88 (t, J = 14.2 Hz, 2H) , 1.56 –1.37 (m, 1H) , 1.36 –0.98 (m, 3H) .

Compound A-II-a-1: (S) -3- (2- (azepan-3-ylamino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carbonitrile

Synthesis of (S) -3- (2- (azepan-3-ylamino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carbonitrile

To a mixture of 2, 4-dichloro-5- (trifluoromethyl) pyrimidine (608 mg, 2.81 mmol) in DCE (10 mL) was added AlCl ₃ (393 mg, 2.95 mmol) . The mixture was stirred at 90 ℃ for 0.5 h under N ₂. Then 1H-indole-6-carbonitrile (200 mg, 1.41 mmol) was added. The reaction mixture was stirred at 90 ℃ for another 3 h. The reaction was quenched with MeOH (10 mL) and water (10 mL) . The mixture was filtered. The filter cake was washed with MeOH (10 mL) and dried to give the product 3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carbonitrile (60 mg, yield: 13.2%) as a yellow solid, which was used in the next step without further purification. ESI-MS [M +H] ⁺: 323.0.

Synthesis of tert-butyl (S) -3- ( (4- (6-cyano-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) azepane-1-carboxylate

A mixture of 3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carbonitrile (60 mg, 0.19 mmol) , tert-butyl (S) -3-aminoazepane-1-carboxylate (40 mg, 0.19 mmol) and DIPEA (74 mg, 0.57 mmol) in i-PrOH (3 mL) was irradiated in microwave at 140 ℃ for 1 h. The reaction mixture was concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 15/1) to give tert-butyl (S) -3- ( (4- (6-cyano-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) azepane-1-carboxylate (60 mg, yield: 63.2%) as a white solid. ESI-MS [M + H] ⁺: 501.2.

To a mixture of tert-butyl (S) -3- ( (4- (6-cyano-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) azepane-1-carboxylate (60 mg, 0.12 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 NH ₃ (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 (S) -3- (2- (azepan-3-ylamino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carbonitrile (23 mg, yield: 47.9%) as a white solid.

ESI-MS [M +H] ⁺: 401.2.

¹H NMR (400 MHz, MeOD) δ 8.63 –8.49 (m, 1H) , 8.46 –8.27 (m, 1H) , 8.03 (s, 1H) , 7.88 (s, 1H) , 7.45 (s, 1H) , 4.39 –4.16 (m, 1H) , 3.25 (dd, J = 13.7, 4.3 Hz, 1H) , 3.08 –2.87 (m, 3H) , 2.23 –2.02 (m, 1H) , 1.90 –1.59 (m, 5H) .

Compound A-II-a-2: (S) -N- (4- (1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) azepan-3-amine

Synthesis of (S) -N- (4- (1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) azepan-3-amine

Synthesis of 3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole

To a mixture of 1H-indole (300 mg, 2.56 mmol) in DCE (10 mL) was added MeMgBr (3M solution in THF, 3.84 mmol, 1.28 mL) at 0 ℃ and the mixture was stirred at 0 ℃ for 0.5 h under N ₂. Then a solution of 2, 4-dichloro-5- (trifluoromethyl) pyrimidine (555 mg, 2.56 mmol) in DCE (10 mL) was added. The reaction mixture was stirred at room temperature for another 2h. The mixture was quenched with H ₂O (30 mL) and extracted with DCM (30 mL x 2) . The combined organic layers were washed with brine (50 mL) , dried over anhydrous Na ₂SO ₄, and concentrated in vacuo to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 15/1) to give 3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole (250 mg, yield: 32.9%) as a white solid. ESI-MS [M + H] ⁺: 298.2.

Synthesis of tert-butyl (S) -3- ( (4- (1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) azepane-1-carboxylate

A mixture of 3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole (80 mg, 0.27 mmol) , tert-butyl (S) -3-aminoazepane-1-carboxylate (87 mg, 0.41 mmol) and DIPEA (104 mg, 0.81 mmol) in i-PrOH (5 mL) was irradiated in microwave at 140 ℃ for 1 h. The reaction mixture was concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 15/1) to give tert-butyl (S) -3- ( (4- (1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) azepane-1-carboxylate (80 mg, yield: 62.4%) as a white solid. ESI-MS [M + H] ⁺: 476.2.

To a mixture of tert-butyl (S) -3- ( (4- (1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) azepane-1-carboxylate (80 mg, 0.17 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 NH ₃ (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 (S) -N- (4- (1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) azepan-3-amine (40 mg, yield: 62.7%) as a white solid.

ESI-MS [M +H] ⁺: 376.2.

¹H NMR (400 MHz, MeOD) δ 8.57 –8.44 (m, 1H) , 8.37 –8.22 (m, 1H) , 7.81 (s, 1H) , 7.45 (d, J = 7.8 Hz, 1H) , 7.28 –7.11 (m, 2H) , 4.48 –4.11 (m, 1H) , 3.28 –3.19 (m, 1H) , 3.05 –2.87 (m, 3H) , 2.20 –2.06 (m, 1H) , 1.92 –1.58 (m, 5H) .

Compound A-II-a-3: (S) -3- (2- (azepan-3-ylamino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-7-carbonitrile

Synthesis of (S) -3- (2- (azepan-3-ylamino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-7-carbonitrile

Synthesis of tert-butyl (S) -3- ( (4- (7-cyano-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) azepane-1-carboxylate

A mixture of 3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-7-carbonitrile (67 mg, 0.21 mmol) , tert-butyl (S) -3-aminoazepane-1-carboxylate (68 mg, 0.32 mmol) and DIPEA (81 mg, 0.63 mmol) in i-PrOH (3 mL) was irradiated in microwave at 140 ℃ for 1 h. The reaction mixture was concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 30/1) to give tert-butyl (S) -3- ( (4- (7-cyano-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) azepane-1-carboxylate (73 mg, yield: 70%) as a white solid. ESI-MS [M + H] ⁺: 501.2.

To a mixture of tert-butyl (S) -3- ( (4- (7-cyano-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) azepane-1-carboxylate (73 mg, 0.15 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 NH ₃ (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 (S) -3- (2- (azepan-3-ylamino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-7-carbonitrile (23 mg, yield: 38%) as a white solid.

ESI-MS [M +H] ⁺: 401.2.

1H NMR (400 MHz, MeOD) δ 8.74 –8.46 (m, 2H) , 7.91 (s, 1H) , 7.63 (d, J = 7.4 Hz, 1H) , 7.38 –7.21 (m, 1H) , 4.30 (s, 1H) , 3.28 –3.16 (m, 1H) , 3.09 –2.86 (m, 3H) , 2.22 –2.00 (m, 1H) , 1.92 –1.70 (m, 4H) , 1.70 –1.52 (m, 1H) .

Compound A-II-a-4: (S) -N- (4- (6-methoxy-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) azepan-3-amine

Synthesis of (S) -N- (4- (6-methoxy-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) azepan-3-amine

Synthesis of 3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -6-methoxy-1H-indole

To a mixture of 2, 4-dichloro-5- (trifluoromethyl) pyrimidine (1.0 g, 4.64 mmol) in DCE (20 mL) was added AlCl ₃ (648 mg, 4.87 mmol) . The mixture was stirred at 90 ℃ for 0.5 h under N ₂. Then 6-methoxy-1H-indole (341 mg, 2.32 mmol) was added. The reaction mixture was stirred at 90 ℃ for another 3 h. The reaction was quenched with MeOH (20 mL) and water (20 mL) . The mixture was filtered. The filter cake was washed with MeOH (10 mL) and dried to give the product 3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -6-methoxy-1H-indole (120 mg, yield: 15.8%) as a yellow solid, which was used in the next step without further purification. ESI-MS [M +H] ⁺: 328.2.

Synthesis of tert-butyl (S) -3- ( (4- (6-methoxy-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) azepane-1-carboxylate

A mixture of 3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -6-methoxy-1H-indole (120 mg, 0.37 mmol) , tert-butyl (S) -3-aminoazepane-1-carboxylate (120 mg, 0.56 mmol) and DIPEA (95 mg, 0.74 mmol) in i-PrOH (5 mL) was irradiated in microwave at 140 ℃ for 1 h. The reaction mixture was concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 20/1) to give tert-butyl (S) -3- ( (4- (6-methoxy-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) azepane-1-carboxylate (100 mg, yield: 53.5%) as a white solid. ESI-MS [M + H] ⁺: 506.2.

To a mixture of tert-butyl (S) -3- ( (4- (6-cyano-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) azepane-1-carboxylate (100 mg, 0.20 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 NH ₃ (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 (S) -N- (4- (6-methoxy-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) azepan-3-amine (48.7 mg, yield: 60%) as a white solid.

ESI-MS [M +H] ⁺: 406.2.

1H NMR (400 MHz, MeOD) δ 8.43 –8.25 (m, 1H) , 8.18 –8.03 (m, 1H) , 7.69 –7.56 (m, 1H) , 6.90 –6.82 (m, 1H) , 6.79 –6.66 (m, 1H) , 4.33 –4.03 (m, 1H) , 3.75 (s, 3H) , 3.16 –2.99 (m, 1H) , 2.89–2.68 (m, 3H) , 2.11 –1.91 (m, 1H) , 1.79 –1.47 (m, 5H) .

Compound A-II-b-1: (S) -N2- (azepan-3-yl) -N4- (quinolin-2-yl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine

Synthesis of (S) -N2- (azepan-3-yl) -N4- (quinolin-2-yl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine

Synthesis of N- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) quinolin-2-amine

A mixture of 2, 4-dichloro-5- (trifluoromethyl) pyrimidine (500 mg, 2.31 mmol) , quinolin-2-amine (333 mg, 2.31 mmol) and Na ₂CO ₃ (735 mg, 6.93 mmol) in i-PrOH (8 mL) was irradiated in microwave at 100 ℃ for 2 h. The reaction mixture was diluted with H ₂O (30 mL) and extracted with EtOAc (30 mL x 2) . The combined organic layers were washed with brine (50 mL) , dried over anhydrous Na ₂SO ₄, and concentrated in vacuo to give the crude, which was purified by Prep- TLC (eluent: PE/EtOAc = 10/1) to give N- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) quinolin-2-amine (120 mg, yield: 16%) as a white solid. ESI-MS [M + H] ⁺: 325.2.

Synthesis of tert-butyl (S) -3- ( (4- (quinolin-2-ylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) azepane-1-carboxylate

A mixture of N- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) quinolin-2-amine (120 mg, 0.37 mmol) , tert-butyl (S) -3-aminoazepane-1-carboxylate (120 mg, 0.56 mmol) and DIPEA (143 mg, 1.11 mmol) in i-PrOH (5 mL) was irradiated in microwave at 140 ℃ for 1 h. The reaction mixture was concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 20/1) to give tert-butyl (S) -3- ( (4- (quinolin-2-ylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) azepane-1-carboxylate (90 mg, yield: 48%) as a white solid. ESI-MS [M + H] ⁺: 503.2.

To a mixture of tert-butyl (S) -3- ( (4- (quinolin-2-ylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) azepane-1-carboxylate (90 mg, 0.18 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 NH ₃ (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 (S) -N2- (azepan-3-yl) -N4- (quinolin-2-yl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine (58.4 mg, yield: 80.7%) as a white solid.

ESI-MS [M +H] ⁺: 403.2.

¹H NMR (400 MHz, MeOD) δ = 8.58 –8.30 (m, 1H) , 8.29 –8.11 (m, 2H) , 7.78 (d, J = 7.9, 1H) , 7.74 (d, J = 8.5, 1H) , 7.66 –7.55 (m, 1H) , 7.47 –7.33 (m, 1H) , 4.16 –3.93 (m, 1H) , 3.15 –2.99 (m, 1H) , 2.94 –2.64 (m, 3H) , 2.09 –1.85 (m, 1H) , 1.82 –1.57 (m, 4H) , 1.57 –1.40 (m, 1H) .

Compound A-III-b-1: (S, E) -4- (dimethylamino) -1- (3- ( (4- (naphthalen-2-ylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidin-1-yl) but-2-en-1-one

Synthesis of (S, E) -4- (dimethylamino) -1- (3- ( (4- (naphthalen-2-ylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidin-1-yl) but-2-en-1-one

A mixture of (S) -N4- (naphthalen-2-yl) -N2- (piperidin-3-yl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine (55 mg, 0.14 mmol) , (E) -4- (dimethylamino) but-2-enoic acid (18 mg, 0.14 mmol) , HATU (79.8 mg, 0.21 mmol) and DIPEA (54 mg, 0.42 mmol) in DMF (5 mL) was stirred at room temperature for 3h. 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 Na ₂SO ₄, and concentrated to give the crude product, which was purified by Prep-TLC (eluent: DCM/MeOH = 10/1) to give (S, E) -4- (dimethylamino) -1- (3- ( (4- (naphthalen-2-ylamino) -5- (trifluoromethyl) pyrimidin-2yl) amino) piperidin-1-yl) but-2-en-1-one (48 mg, yield: 69%) as a white solid.

ESI-MS [M +H] ⁺: 499.2.

1H NMR (400 MHz, MeOD) δ 8.17 –8.05 (m, 2H) , 7.83 –7.62 (m, 4H) , 7.49 –7.41 (m, 2H) , 6.71 –6.62 (m, 1H) , 6.29 –5.95 (m, 1H) , 3.90 –3.67 (m, 3H) , 3.23 –3.13 (m, 3H) , 2.64 (d, J = 12.0 Hz, 1H) , 2.34 –2.25 (m, 3H) , 2.06 –1.95 (m, 4H) , 1.81 –1.56 (m, 3H) .

Compound A-III-a-1: (S) -N4- (1H-indol-3-yl) -N2- (piperidin-3-yl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine

Synthesis of (S) -N4- (1H-indol-3-yl) -N2- (piperidin-3-yl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine

Synthesis of N- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -1H-indol-3-amine

A mixture of 2, 4-dichloro-5- (trifluoromethyl) pyrimidine (100 mg, 0.46 mmol) , 1H-indol-3-amine (61 mg, 0.46 mmol) and DIPEA (89 mg, 0.69 mmol) in i-PrOH (8 mL) was stirred at room temperature for 3 h. The reaction mixture was concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 15/1) to give N- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -1H-indol-3-amine (60 mg, yield: 42%) as a white solid. ESI-MS [M + H] ⁺: 313.0.

Synthesis of tert-butyl (S) -3- ( (4- ( (1H-indol-3-yl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylate

A mixture of N- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -1H-indol-3-amine (60 mg, 0.19 mmol) , tert-butyl (S) -3-aminopiperidine-1-carboxylate (58 mg, 0.29 mmol) and DIPEA (74 mg, 0.57 mmol) in i-PrOH (8 mL) was irradiated in microwave at 140 ℃ for 1 h. The reaction mixture was concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 20/1) to give tert-butyl (S) -3- ( (4- ( (1H-indol-3-yl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (60 mg, yield: 66%) as a white solid. ESI-MS [M + H] ⁺: 477.2.

To a mixture of tert-butyl (S) -3- ( (4- ( (1H-indol-3-yl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (60 mg, 0.13 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 NH ₃ (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 (S) -N4- (1H-indol-3-yl) -N2- (piperidin-3-yl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine (45 mg, yield: 92.1%) as a white solid.

ESI-MS [M +H] ⁺: 377.2.

¹H NMR (400 MHz, MeOD) δ 8.09 (s, 1H) , 7.50 –7.40 (m, 1H) , 7.40 –7.28 (m, 2H) , 7.14 (t, J = 7.5 Hz, 1H) , 7.03 (t, J = 7.7 Hz, 1H) , 4.07 –3.71 (m, 1H) , 3.02 –2.67 (m, 2H) , 2.55 –2.26 (m, 2H) , 1.98 –1.77 (m, 1H) , 1.74 –1.51 (m, 1H) , 1.48 –1.15 (m, 2H) .

Compound A-III-a-2: (S) -N2- (piperidin-3-yl) -N4- (quinazolin-2-yl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine

Synthesis of (S) -N2- (piperidin-3-yl) -N4- (quinazolin-2-yl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine

Synthesis of N- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) quinazolin-2-amine

To a mixture of 2, 4-dichloro-5- (trifluoromethyl) pyrimidine (400 mg, 1.84 mmol) in THF (10 mL) was added NaH (60 %in mineral oil, 77 mg, 1.84 mmol) at 0 ℃. The mixture was stirred at 0 ℃ for 0.5 h under N ₂. Then quinazolin-2-amine (133 mg, 0.92 mmol) was added. The reaction mixture was stirred at room temperature for another 3 h. The reaction mixture was quenched with H ₂O (30 mL) and extracted with EtOAc (30 mL x 2) . The combined organic layers were washed with brine (50 mL) , dried over anhydrous Na ₂SO ₄, and concentrated in vacuo to give the crude, which was purified by Prep-TLC (eluent: PE/EtOAc = 20/1) to give N- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) quinazolin-2-amine (40 mg, yield: 13.4%) as a white solid. ESI-MS [M + H] ⁺: 326.2.

Synthesis of tert-butyl (S) -3- ( (4- (quinazolin-2-ylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylate

A mixture of N- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) quinazolin-2-amine (40 mg, 0.12 mmol) , tert-butyl (S) -3-aminopiperidine-1-carboxylate (36 mg, 0.18 mmol) and DIPEA (77 mg, 0.6 mmol) in i-PrOH (5 mL) was irradiated in microwave at 140 ℃ for 1 h. The reaction mixture was concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 20/1) to give tert-butyl (S) -3- ( (4- (quinazolin-2-ylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (30 mg, yield: 51.1%) as a white solid. ESI-MS [M + H] ⁺: 490.2.

To a mixture of tert-butyl (S) -3- ( (4- (quinazolin-2-ylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (30 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 1 h. The reaction mixture was quenched with NH ₃ (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 (S) -N2- (piperidin-3-yl) -N4- (quinazolin-2-yl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine (11.8 mg, yield: 50.5%) as a white solid.

ESI-MS [M +H] ⁺: 390.2.

¹H NMR (400 MHz, CDCl ₃) δ 9.39 –9.23 (m, 1H) , 8.45 –8.28 (m, 1H) , 8.03 –7.94 (m, 1H) , 7.93 –7.84 (m, 2H) , 7.83 –7.72 (m, 1H) , 7.61 –7.44 (m, 1H) , 6.28 –5.85 (m, 1H) , 4.19 –3.85 (m, 1 H) , 3.35 –3.01 (m, 1H) , 3.00 –2.69 (m, 2H) , 2.29 –1.73 (m, 6H) .

Compound A-III-b-2: (S) -N4- (naphthalen-2-yl) -N2- (piperidin-3-yl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine

Synthesis of (S) -N4- (naphthalen-2-yl) -N2- (piperidin-3-yl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine

Synthesis of N- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) quinolin-2-amine

To a mixture of naphthalen-2-amine (157 mg, 1.1 mmol) and Na ₂CO ₃ (212 mg, 2.0 mmol) in i-PrOH (5 mL) was added a solution of 2, 4-dichloro-5- (trifluoromethyl) pyrimidine (216 mg, 1.0 mmol) in i-PrOH (3 mL) at 0 ℃. The mixture was stirred at room temperature for 2 h. 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 Na ₂SO ₄, and concentrated to give the crude product, which was purified by Prep-TLC (eluent: PE/EtOAc = 10/1) to give 2-chloro-N- (naphthalen-2-yl) -5- (trifluoromethyl) pyrimidin-4-amine (260 mg, yield: 80.5%) as a light yellow solid. ESI-MS [M + H] ⁺: 324.2.

Synthesis of tert-butyl (S) -3- ( (4- (naphthalen-2-ylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylate

A mixture of 2-chloro-N- (naphthalen-2-yl) -5- (trifluoromethyl) pyrimidin-4-amine (100 mg, 0.31 mmol) , tert-butyl (S) -3-aminopiperidine-1-carboxylate (74 mg, 0.37 mmol) and DIPEA (200 mg, 1.55 mmol) in i-PrOH (5 mL) was irradiated in microwave at 150 ℃ for 1 h. The reaction mixture was concentrated to give the crude, which was purified by Prep-TLC (eluent: PE/EtOAc = 2/1) to give tert-butyl (S) -3- ( (4- (naphthalen-2-ylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (100 mg, yield: 66.2%) as a colourless oil. ESI-MS [M + H] ⁺: 488.2.

To a mixture of tert-butyl (S) -3- ( (4- (naphthalen-2-ylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (100 mg, 0.21 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 NH ₃ (7M solution in MeOH, 2 mL) and concentrated in vacuo to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 8/1) to give (S) -N4-(naphthalen-2-yl) -N2- (piperidin-3-yl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine (42 mg, yield: 51.7%) as a white solid.

ESI-MS [M +H] ⁺: 388.2.

1H NMR (400 MHz, MeOD) δ 8.16 (s, 1H) , 7.99 (s, 1H) , 7.85 –7.83 (m, 3H) , 7.62 (d, J =7.9 Hz, 1H) , 7.53 –7.34 (m, 2H) , 4.02 –3.66 (m, 1H) , 3.14 –2.96 (m, 1H) , 2.88 –2.83 (m, 1H) , 2.55 –2.50 (m, 2H) , 2.10 –1.89 (m, 1H) , 1.81 –1.61 (m, 1H) , 1.54 –1.30 (m, 2H) .

Compound A-III-a-3: (S) -N2- (piperidin-3-yl) -N4- (quinolin-3-yl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine

Synthesis of (S) -N2- (piperidin-3-yl) -N4- (quinolin-3-yl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine

Synthesis of N- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) quinolin-3-amine

To a mixture of quinolin-3-amine (144 mg, 1.0 mmol) and Na ₂CO ₃ (212 mg, 2.0 mmol) in i-PrOH (5 mL) was added a solution of 2, 4-dichloro-5- (trifluoromethyl) pyrimidine (216 mg, 1.0 mmol) in i-PrOH (5 mL) at 0 ℃. The mixture was stirred at room temperature for 16 h. The reaction was quenched with water (30 mL) and extracted with EtOAc (10 mL x 3) . The combined organic layers were washed with brine (30 mL) , dried over anhydrous Na ₂SO ₄, and concentrated to give the crude product, which was purified by Prep-TLC (eluent: DCM/MeOH = 30/1) to give N- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) quinolin-3-amine (120 mg, yield: 37%) as a white solid. ESI-MS [M + H] ⁺: 325.2.

Synthesis of tert-butyl (S) -3- ( (4- (quinolin-3-ylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylate

A mixture of N- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) quinolin-3-amine (120 mg, 0.37 mmol) , tert-butyl (S) -3-aminopiperidine-1-carboxylate (88 mg, 0.44 mmol) and DIPEA (143 mg, 1.11 mmol) in i-PrOH (5 mL) was irradiated in microwave at 140 ℃ for 1 h. The reaction mixture was concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 25/1) to give tert-butyl (S) -3- ( (4- (quinolin-3-ylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (140 mg, yield: 77.5%) as a white solid. ESI-MS [M + H] ⁺: 489.2.

To a mixture of tert-butyl (S) -3- ( (4- (quinolin-3-ylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (100 mg, 0.20 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 NH ₃ (7M solution in MeOH, 2 mL) and concentrated in vacuo to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 8/1) to give (S) -N2- (piperidin-3-yl) -N4- (quinolin-3-yl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine (54 mg, yield: 69.6%) as a white solid.

ESI-MS [M +H] ⁺: 389.2.

1H NMR (400 MHz, MeOD) δ 9.05 (d, J = 36.8 Hz, 1H) , 8.54 –8.38 (m, 1H) , 8.22 (s, 1H) , 8.02 -7.94 (m, 2H) , 7.75 –7.60 (m, 2H) , 4.25 –3.62 (m, 1H) , 3.18 –2.85 (m, 2H) , 2.63 –2.60 (m, 2H) , 2.03 –1.99 (m, 1H) , 1.81 –1.71 (m, 1H) , 1.54 –1.40 (m, 2H) .

Compound A-III-a-4: (S) -N4- (isoquinolin-3-yl) -N2- (piperidin-3-yl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine

Synthesis of (S) -N4- (isoquinolin-3-yl) -N2- (piperidin-3-yl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine

Synthesis of N- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) isoquinolin-3-amine

A mixture of 2, 4-dichloro-5- (trifluoromethyl) pyrimidine (217 mg, 1.0 mmol) , isoquinolin-3-amine (144 mg, 1.0 mmol) and Na ₂CO ₃ (212 mg, 2.0 mmol) in EtOH (10 mL) was stirred at room temperature for 16 h. The reaction mixture was diluted with H ₂O (30 mL) and extracted with EtOAc (30 mL x 2) . The combined organic layers were washed with brine (50 mL) , dried over anhydrous Na ₂SO ₄, and concentrated in vacuo to give the crude, which was purified by Prep-TLC (eluent: PE/EtOAc = 20/1) to give N- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) isoquinolin-3-amine (100 mg, yield: 30.8%) as a white solid. ESI-MS [M + H] ⁺: 325.0.

Synthesis of tert-butyl (S) -3- ( (4- (isoquinolin-3-ylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylate

A mixture of N- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) isoquinolin-3-amine (100 mg, 0.31 mmol) , tert-butyl (S) -3-aminopiperidine-1-carboxylate (94 mg, 0.47 mmol) and DIPEA (160 mg, 1.24 mmol) in i-PrOH (8 mL) was irradiated in microwave at 140 ℃ for 1 h. The reaction mixture was concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 20/1) to give tert-butyl (S) -3- ( (4- (isoquinolin-3-ylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (80 mg, yield: 53.0%) as a white solid. ESI-MS [M + H] ⁺: 489.2.

To a mixture of tert-butyl (S) -3- ( (4- (isoquinolin-3-ylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (80 mg, 0.16 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 NH ₃ (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 (S) -N4- (isoquinolin-3-yl) -N2- (piperidin-3-yl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine (50 mg, yield: 80.6%) as a white solid.

ESI-MS [M +H] ⁺: 389.2.

¹H NMR (400 MHz, MeOD) δ 9.10 –8.99 (m, 1H) , 8.93 –8.54 (m, 1H) , 8.35 –8.20 (m, 1H) , 8.09 –7.89 (m, 2H) , 7.80 –7.67 (m, 1H) , 7.62 –7.48 (m, 1H) , 4.18 –3.92 (m, 1H) , 3.28 –3.16 (m, 1H) , 3.09 –2.90 (m, 1H) , 2.83 –2.58 (m, 2H) , 2.26 –2.04 (m, 1H) , 1.95 –1.76 (m, 1H) , 1.75 –1.51 (m, 2H) .

Compound A-III-c-1: (S) -4- (1H-indol-2-yl) -N- (piperidin-3-yl) -5- (trifluoromethyl) pyrimidin-2-aminee

Synthesis of (S) -4- (1H-indol-2-yl) -N- (piperidin-3-yl) -5- (trifluoromethyl) pyrimidin-2-amine

Synthesis of tert-butyl 2- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-1-carboxylate

A mixture of 2, 4-dichloro-5- (trifluoromethyl) pyrimidine (108 mg, 0.5 mmol) , (1- (tert-butoxycarbonyl) -1H-indol-2-yl) boronic acid (131 mg, 0.5 mmol) , Pd (dppf) Cl ₂ (18 mg, 0.025 mmol) and K ₃PO ₄ (318 mg, 1.5 mmol) in dioxane/water (5 mL/0.5 mL) was stirred at 30 ℃ under N ₂ for 6 h. 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: PE/EtOAc = 10/1) to give tert-butyl 2- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-1-carboxylate (90 mg, yield: 45%) as a colourless oil. ESI-MS [M + H] ⁺: 398.2.

Synthesis of tert-butyl (S) -2- (2- ( (1- (tert-butoxycarbonyl) piperidin-3-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-1-carboxylate

A mixture of tert-butyl 2- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-1-carboxylate (90 mg, 0.23 mmol) , tert-butyl (S) -3-aminopiperidine-1-carboxylate (56 mg, 0.28 mmol) and DIPEA (148 mg, 1.15 mmol) in i-PrOH (5 mL) was irradiated in microwave at 140 ℃ for 1 h. The reaction mixture was concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM) to give tert-butyl (S) -2- (2- ( (1- (tert-butoxycarbonyl) piperidin-3-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-1-carboxylate (90 mg, yield: 70%) as a white solid. ESI-MS [M + H] ⁺: 562.2.

To a mixture of tert-butyl (S) -2- (2- ( (1- (tert-butoxycarbonyl) piperidin-3-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-1-carboxylate (90 mg, 0.16 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 NH ₃ (7M solution in MeOH, 2 mL) and concentrated in vacuo to give the crude, which was purified by Prep-HPLC (FA) to give (S) -4- (1H-indol-2-yl) -N- (piperidin-3-yl) -5- (trifluoromethyl) pyrimidin-2-amine (15 mg, yield: 26%) as a white solid.

ESI-MS [M +H] ⁺: 362.2.

1H NMR (400 MHz, MeOD) δ 8.60 –8.53 (m, 2H) , 7.64 (d, J = 8.0 Hz, 1H) , 7.49 (s, 1H) , 7.29 –7.24 (m, 2H) , 7.07 (t, J = 7.5 Hz, 1H) , 3.57 (d, J = 11.5 Hz, 1H) , 3.38 –3.31 (m, 2H) , 3.02 –2.91 (m, 2H) , 2.27 –2.03 (m, 2H) , 1.91 –1.75 (m, 2H) .

Compound A-III-a-5: (S) -N2- (piperidin-3-yl) -N4- (quinolin-2-yl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine

Synthesis of (S) -N2- (piperidin-3-yl) -N4- (quinolin-2-yl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine

Synthesis of N- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) quinolin-2-amine

A mixture of 2, 4-dichloro-5- (trifluoromethyl) pyrimidine (500 mg, 2.31 mmol) , quinolin-2-amine (333 mg, 2.31 mmol) and Na ₂CO ₃ (735 mg, 6.93 mmol) in i-PrOH (8 mL) was irradiated in microwave at 100 ℃ for 2 h. The reaction mixture was concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 15/1) to give N- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) quinolin-2-amine (80 mg, yield: 10.7%) as a white solid. ESI-MS [M + H] ⁺: 325.2.

Synthesis of tert-butyl (S) -3- ( (4- (quinolin-2-ylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylate

A mixture of N- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) quinolin-2-amine (80 mg, 0.25 mmol) , tert-butyl (S) -3-aminopiperidine-1-carboxylate (76 mg, 0.38 mmol) and DIPEA (161 mg, 1.25 mmol) in i-PrOH (5 mL) was irradiated in microwave at 140 ℃ for 1 h. The reaction mixture was concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 20/1) to give tert-butyl (S) -3- ( (4- (quinolin-2-ylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (80 mg, yield: 65.6%) as a white solid. ESI-MS [M + H] ⁺: 489.2.

To a mixture of tert-butyl (S) -3- ( (4- (quinolin-2-ylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (80 mg, 0.16 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 NH ₃ (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 (S) -N2- (piperidin-3-yl) -N4- (quinolin-2-yl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine (47 mg, yield: 75.8%) as a white solid.

ESI-MS [M +H] ⁺: 389.2.

1H NMR (400 MHz, MeOD) δ 8.79 –8.50 (m, 1H) , 8.49 –8.34 (m, 1H) , 8.35 –8.21 (m, 1H) , 7.88 (d, J = 7.8 Hz, 1H) , 7.83 (d, J = 8.5 Hz, 1H) , 7.76 –7.65 (m, 1H) , 7.57 –7.40 (m, 1H) , 4.05 –3.86 (m, 1H ) , 3.28 –3.15 (m, 1H) , 3.02 –2.84 (m, 1H) , 2.70 –2.47 (m, 2H) , 2.16 –1.99 (m, 1H) , 1.87 –1.71 (m, 1H) , 1.69 –1.46 (m, 2H) .

Compound A-III-a-6: (S) -N4- (6-phenylpyridin-2-yl) -N2- (piperidin-3-yl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine

Synthesis of (S) -N4- (6-phenylpyridin-2-yl) -N2- (piperidin-3-yl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine

Synthesis of 2-chloro-N- (6-phenylpyridin-2-yl) -5- (trifluoromethyl) pyrimidin-4-amine

To a mixture of 2, 4-dichloro-5- (trifluoromethyl) pyrimidine (216 mg, 1.0 mmol) in i-PrOH (5 mL) was added 6-phenylpyridin-2-amine (170 mg, 1.0 mmol) and DIPEA (387mg, 3.0 mmol) . The mixture was stirred at 100 ℃ for 1h under microwave. The reaction mixture was concentrated to give the crude, which was purified by Prep-TLC (eluent: PE/EtOAc = 15/1) to give 2-chloro-N-(6-phenylpyridin-2-yl) -5- (trifluoromethyl) pyrimidin-4-amine (100 mg, yield: 28.6%) as a yellow solid. ESI-MS [M + H] ⁺: 351.1.

Synthesis of tert-butyl (S) -3- ( (4- ( (6-phenylpyridin-2-yl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylate

A mixture of 2-chloro-N- (6-phenylpyridin-2-yl) -5- (trifluoromethyl) pyrimidin-4-amine (100 mg, 0.29 mmol) , tert-butyl (S) -3-aminopiperidine-1-carboxylate (88 mg, 0.44 mmol) and DIPEA (187 mg, 1.45 mmol) in i-PrOH (5 mL) was irradiated in microwave at 140 ℃ for 1 h. The reaction mixture was concentrated to give the crude, which was purified by Prep-TLC (eluent: PE/EtOAc = 4/1) to give tert-butyl (S) -3- ( (4- ( (6-phenylpyridin-2-yl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (100 mg, yield: 67.1%) as a white solid. ESI-MS [M + H] ⁺: 515.2.

To a mixture of tert-butyl (S) -3- ( (4- ( (6-phenylpyridin-2-yl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (100 mg, 0.19 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 NH ₃ (7M solution in MeOH, 2.0 mL) and concentrated in vacuo to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 15/1) to give (S) -N4- (6-phenylpyridin-2-yl) -N2- (piperidin-3-yl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine (39 mg, yield: 49.6%) as a white solid.

ESI-MS [M +H] ⁺: 415.2.

1H NMR (400 MHz, MeOD) δ 8.35 –8.19 (m, 2H) , 8.07 –7.91 (m, 3H) , 7.67 –7.54 (m, 1H) , 7.48 (t, J = 7.3 Hz, 2H) , 7.45 –7.39 (m, 1H) , 3.97 (s, 1H) , 3.26 –3.17 (m, 1H) , 3.01 –2.91 (m, 2H) , 2.69 –2.49 (m, 1H) , 2.22 –2.00 (m, 1H) , 1.86 –1.74 (m, 1H) , 1.69 –1.47 (m, 2H) .

Compound A-III-a-7: (S) -N4- (5-phenylpyridin-2-yl) -N2- (piperidin-3-yl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine

Synthesis of (S) -N4- (5-phenylpyridin-2-yl) -N2- (piperidin-3-yl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine

Synthesis of 2-chloro-N- (5-phenylpyridin-2-yl) -5- (trifluoromethyl) pyrimidin-4-amine

To a mixture of 2, 4-dichloro-5- (trifluoromethyl) pyrimidine (216 mg, 1.0 mmol) in THF (5 mL) was added NaH (60 %in mineral oil, 80 mg, 2.0 mmol) at 0 ℃. The mixture was stirred at 0 ℃ for 0.5h under N ₂. Then 5-phenylpyridin-2-amine (340 mg, 2.0 mmol) was added. The reaction was stirred at room temperature for another 4 h. The mixture 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 Na ₂SO ₄, and concentrated to give the crude product, which was purified by Prep-TLC (eluent: PE/EtOAc = 10/1) to give 2-chloro-N- (5-phenylpyridin-2-yl) -5- (trifluoromethyl) pyrimidin-4-amine (75 mg, yield: 21.4%) as a white solid. ESI-MS [M + H] ⁺: 351.1.

Synthesis of tert-butyl (S) -3- ( (4- ( (5-phenylpyridin-2-yl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylate

A mixture of 2-chloro-N- (5-phenylpyridin-2-yl) -5- (trifluoromethyl) pyrimidin-4-amine (75 mg, 0.21 mmol) , tert-butyl (S) -3-aminopiperidine-1-carboxylate (64 mg, 0.32 mmol) and DIPEA (81 mg, 0.63 mmol) in i-PrOH (3 mL) was irradiated in microwave at 140 ℃ for 1 h. The reaction mixture was concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 20/1) to give tert-butyl (S) -3- ( (4- ( (5-phenylpyridin-2-yl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (95 mg, yield: 88%) as a white solid. ESI-MS [M + H] ⁺: 515.2.

To a mixture of tert-butyl (S) -3- ( (4- ( (5-phenylpyridin-2-yl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (95 mg, 0.19 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 NH ₃ (7M solution in MeOH, 2.0 mL) and concentrated in vacuo to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 10/1) to give (S) -N4- (5-phenylpyridin-2-yl) -N2- (piperidin-3-yl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine (50 mg, yield: 65.6%) as a white solid.

ESI-MS [M +H] ⁺: 415.2.

1H NMR (400 MHz, MeOD) δ 8.67 –8.34 (m, 2H) , 8.33 –8.02 (m, 2H) , 7.73 –7.59 (m, 2H) , 7.48 (t, J = 7.6 Hz, 2H) , 7.42 –7.35 (m, 1H) , 4.07 –3.89 (m, 1H) , 3.28 –3.18 (m, 1H) , 3.02 –2.91 (m, 1H) , 2.68 –2.51 (m, 2H) , 2.17 –2.02 (m, 1H) , 1.86 –1.75 (m, 1H) , 1.71 –1.48 (m, 2H) .

Compound Set B

(S) -2- (azepan-3-ylamino) -4- (1H-indol-3-yl) pyrimidine-5-carbonitrile

Synthesis of (S) -2- (azepan-3-ylamino) -4- (1H-indol-3-yl) pyrimidine-5-carbonitrile

Synthesis of 2-chloro-4- (1H-indol-3-yl) pyrimidine-5-carbonitrile

To a mixture of 2, 4-dichloropyrimidine-5-carbonitrile (149 mg, 0.85 mmol) in DCE (10 mL) was added AlCl ₃ (119 mg, 0.89 mmol) . The mixture was stirred at 90 ℃ for 0.5 h under N ₂. Then 1H-indole (50 mg, 0.43 mmol) was added. The reaction mixture was stirred at 90℃ for another 16 h. The reaction was quenched with MeOH (10 mL) and water (5 mL) . The mixture was filtered. The filter cake was washed with MeOH (10 mL) and dried to give the product 2-chloro-4- (1H-indol-3-yl) pyrimidine-5-carbonitrile (74 mg, yield: 68%) as a brown solid, which was used in the next step without further purification. ESI-MS [M +H] ⁺: 255.1.

Synthesis of tert-butyl (S) -3- ( (5-cyano-4- (1H-indol-3-yl) pyrimidin-2-yl) amino) azepane-1-carboxylate

A mixture of 2-chloro-4- (1H-indol-3-yl) pyrimidine-5-carbonitrile (74 mg, 0.29 mmol) , tert-butyl (S) -3-aminoazepane-1-carboxylate (94 mg, 0.44 mmol) and DIPEA (113 mg, 0.87 mmol) in i-PrOH (5 mL) was irradiated in microwave at 140 ℃ for 1 h. The reaction mixture was concentrated to give the crude, which was purified by Prep-TLC (eluent: PE/EtOAc = 10/1) to give tert-butyl (S) -3- ( (5-cyano-4- (1H-indol-3-yl) pyrimidin-2-yl) amino) azepane-1-carboxylate (66 mg, yield: 52%) as a yellow solid. ESI-MS [M + H] ⁺: 433.2.

To a mixture of tert-butyl (S) -3- ( (5-cyano-4- (1H-indol-3-yl) pyrimidin-2-yl) amino) azepane-1-carboxylate (66 mg, 0.15 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 NH ₃ (7M solution in MeOH, 2.0 mL) and concentrated in vacuo to give the crude, which was purified by Prep-TLC (eluent: DCM/NH ₃-MeOH = 15/1) to give (S) -2- (azepan-3-ylamino) -4- (1H-indol-3-yl) pyrimidine-5-carbonitrile (36 mg, yield: 71%) as a white solid.

ESI-MS [M +H] ⁺: 333.2.

1H NMR (400 MHz, MeOD) δ 8.70 –8.43 (m, 3H) , 7.48 (s, 1H) , 7.46 (s, 2H) , 4.48 –4.21 (m, 1H) , 3.31 –3.13 (m, 1H) , 2.94 –2.87 (m, 3H) , 2.22 –2.05 (m, 1H) , 1.88 –1.63 (m, 5H) .

Methyl (S) -3- (2- (azepan-3-ylamino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carboxylate hydrochloride

Synthesis of Methyl (S) -3- (2- (azepan-3-ylamino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carboxylate hydrochloride

Synthesis of methyl 3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carboxylate

To a solution of 2, 4-dichloro-5- (trifluoromethyl) pyrimidine (384.75 mg, 1.77 mmol) in DCE (10 mL) under nitrogen, was added AlCl ₃ (1.71 g, 12.80 mmol) , and the resulting mixture was stirred at 80℃ for 30 min. After this time, the reaction mixture was cooled to RT, and methyl 1H-indole-6-carboxylate (207.10 mg, 1.18 mmol) was added. The resulting mixture was stirred at 80℃ for 10 h, when the solution became reddish overtime. The mixture was then poured into crushed ice and EtOAc. Layers were separated, and organic layer was then dried over Na ₂SO ₄, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase chromatography to afford the methyl 3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carboxylate (87.3 mg, 236.73 μmol, 20.03%yield, 97%purity) as a beige solid. ESI-MS [M +H] +: 356.46.

To a solution of methyl 3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carboxylate (100 mg, 281.14 μmol) in NMP (2.5 mL) was added methyl 3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carboxylate (100 mg, 281.14 μmol) and DIPEA (72.67 mg, 562.27 μmol, 97.94 μL) , then stirred at 130 ℃ for 6 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 Na ₂SO ₄, filtered, and concentrated to give a residue. The residue purified by column chromatography to give yellow solid. The residue in MeOH (2 mL) was added HCl (4M solution in MeOH, 2 mL) . The reaction mixture was stirred at room temperature for 4 h. Then concentrated to give methyl (S) -3- (2- (azepan-3-ylamino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carboxylate hydrochloride (56.3 mg, 128.60 μmol, 45.74%yield, 99%purity) as a white solid. ESI-MS [M +H] +: 434.43.

¹H-NMR (400 MHz, MeOD) δ 8.62 (dd, J = 16.9, 8.3 Hz, 1H) , 8.52 –8.26 (m, 1H) , 8.16 (s, 1H) , 8.06 (t, J = 4.7 Hz, 1H) , 7.97 –7.69 (m, 1H) , 3.90 (s, 3H) , 3.78 –3.47 (m, 2H) , 3.20 (dq, J = 19.2, 13.3, 10.1 Hz, 1H) , 1.98 –1.72 (m, 3H) , 1.64 (dq, J = 15.0, 9.4, 6.0 Hz, 2H) , 1.31 (m, 3H) .

(S) -N- (4- (6-bromo-7-methyl-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) azepan-3-amine

Synthesis of (S) -N- (4- (6-bromo-7-methyl-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) azepan-3-amine

Synthesis of 6-bromo-3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -7-methyl-1H-indole

To a mixture of 2, 4-dichloro-5- (trifluoromethyl) pyrimidine (1028 mg, 4.76 mmol) in DCE (30 mL) was added AlCl ₃ (665 mg, 5.0 mmol) . The mixture was stirred at 90 ℃ for 0.5 h under N ₂. Then 6-bromo-7-methyl-1H-indole (500 mg, 2.38 mmol) was added. The reaction mixture was stirred at 90℃ for another 3 h. The reaction was quenched with MeOH (20 mL) and water (15 mL) . The mixture was filtered. The filter cake was washed with MeOH (10 mL) and dried to give the product 6-bromo-3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -7-methyl-1H-indole (50 mg, yield: 5.4%) as a yellow solid, which was used in the next step without further purification. ESI-MS [M +H] ⁺: 390.1.

Synthesis of tert-butyl (S) -3- ( (4- (6-bromo-7-methyl-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) azepane-1-carboxylate

A mixture of 6-bromo-3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -7-methyl-1H-indole (50 mg, 0.13 mmol) , tert-butyl (S) -3-aminoazepane-1-carboxylate (34 mg, 0.1 mmol) and DIPEA (50 mg, 0.39 mmol) in i-PrOH (5 mL) was irradiated in microwave at 100 ℃ for 1 h. The reaction mixture was concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 20/1) to give tert-butyl (S) -3- ( (4- (6-bromo-7-methyl-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) azepane-1-carboxylate (20 mg, yield: 27.1%) as a white solid. ESI-MS [M + H] ⁺: 568.2.

To a mixture of tert-butyl (S) -3- ( (4- (6-bromo-7-methyl-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) azepane-1-carboxylate (20 mg, 0.04 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 NH ₃ (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 (S) -N- (4- (6-bromo-7-methyl-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) azepan-3-amine (7.8 mg, yield: 41.7%) as a white solid.

ESI-MS [M +H] ⁺: 468.2. Purity: 99.78 (214 nm) , 99.81 (254 nm) .

1H NMR (400 MHz, MeOD) δ 8.49 –8.32 (m, 1H) , 8.04 –7.86 (m, 1H) , 7.70 (s, 1H) , 7.29 –7.15 (m, 1H) , 4.32 –4.02 (m, 1H) , 3.18 –3.06 (m, 1H) , 2.96 –2.70 (m, 3H) , 2.49 (s, 3H) , 2.11 –1.91 (m, 1H) , 1.82 –1.45 (m, 5H) .

(S) -3- (2- (azepan-3-ylamino) -5- (trifluoromethyl) pyrimidin-4-yl) -N-hydroxy-1H-indole-6-carboxamide hydrochloride

Synthesis of (S) -3- (2- (azepan-3-ylamino) -5- (trifluoromethyl) pyrimidin-4-yl) -N-hydroxy-1H-indole-6-carboxamide hydrochloride

Synthesis of methyl (S) -3- (2- ( (1- (tert-butoxycarbonyl) azepan-3-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carboxylate

To a solution of methyl 3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carboxylate (100 mg, 281.14 μmol) in NMP (2.5 mL) was added methyl 3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carboxylate (100 mg, 281.14 μmol) and DIPEA (72.67 mg, 562.27 μmol, 97.94 μL) , then stirred at 130 ℃ for 6 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 Na ₂SO ₄, filtered, and concentrated to give a residue. The residue purified by column chromatography to give yellow solid. ESI-MS [M +H] +: 534.23.

A solution of hydroxylamine hydrochloride (12.98 mg, 186.72 μmol) in anhydrous methanol (20 ml) was added to a solution of KOH (10.48 mg, 186.72 μmol) in anhydrous methanol (20 ml) at 0℃, and stirred for 5 min and the white precipitate formed was filtered. The resultant filtrate (8 ml) was added to a solution of methyl (S) -3- (2- ( (1- (tert-butoxycarbonyl) azepan-3-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carboxylate (50 mg, 93.36 μmol) in anhydrous DCM (10.00 mL) and the mixture was stirred at room temperature for 1 h. The reaction mixture was evaporated under vacuum. The residue was acidified with 1 N HCl to a pH 5-6 and then the resultant precipitate was filtered, washed with water, dried to afford the crude product, which was purified to afford (S) -3- (2- (azepan-3-ylamino) -5- (trifluoromethyl) pyrimidin-4-yl) -N-hydroxy-1H-indole-6-carboxamide hydrochloride (10.9 mg, 24.98 μmol, 26.75%yield) .

ESI-MS [M +H] +: 435.23. ¹H-NMR (400 MHz, DMSO) δ 12.67 (s, 1H) , 12.25 –11.92 (m, 1H) , 8.62 (dd, J = 16.9, 8.3 Hz, 1H) , 8.52 –8.26 (m, 1H) , 8.16 (s, 1H) , 8.06 (t, J = 4.7 Hz, 1H) , 7.97 –7.69 (m, 2H) , 4.36 (d, J = 43.7 Hz, 1H) , 3.94 –3.47 (m, 2H) , 3.20 (dq, J = 19.2, 13.3, 10.1 Hz, 1H) , 1.98 –1.72 (m, 3H) , 1.64 (dq, J = 15.0, 9.4, 6.0 Hz, 2H) , 1.31 (m, 4H) .

(S) -N- (4- (1H-indol-3-yl) -5- (trifluoromethyl) pyridin-2-yl) azepan-3-amine

Synthesis of (S) -N- (4- (1H-indol-3-yl) -5- (trifluoromethyl) pyridin-2-yl) azepan-3-amine

Synthesis of 3- (2-chloro-5- (trifluoromethyl) pyridin-4-yl) -1- (phenylsulfonyl) -1H-indole

To a solution of 2-chloro-4-iodo-5- (trifluoromethyl) pyridine (400 mg, 1.30 mmol) in 1, 4-dioxane (10 mL) and H ₂O (2 mL) were added Na ₂CO ₃ (165.48 mg, 1.56 mmol) , 3- (2-chloro-5- (trifluoromethyl) pyridin-4-yl) -1- (phenylsulfonyl) -1H-indole (498.66 mg, 1.30 mmol) and Pd (PPh ₃) ₄ (150.35 mg, 130.11 μmol) under N2. The mixture was replaced with N ₂ six times and stirred at 90℃ for 4h. The reaction mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO ₂, EA: PE=0%to 25%) to give 3- (2-chloro-5- (trifluoromethyl) pyridin-4-yl) -1- (phenylsulfonyl) -1H-indole (255 mg, 555.38 μmol, 42.69%yield, 95.14%purity) as a yellow solid.

ESI-MS [M+H] ⁺: 437.22.

Synthesis of tert-butyl (S) -3- ( (4- (1- (phenylsulfonyl) -1H-indol-3-yl) -5- (trifluoromethyl) pyridin-2-yl) amino) azepane-1-carboxylate

To a solution of 3- (2-chloro-5- (trifluoromethyl) pyridin-4-yl) -1- (phenylsulfonyl) -1H-indole (255 mg, 583.75 μmol) in NMP (5 mL) were added tert-butyl (S) -3-aminoazepane-1- carboxylate (187.65 mg, 875.62 μmol) and DIPEA (150.89 mg, 1.17 mmol, 203.35 μL) , the mixture was stirred at 120℃ for 2hrs. The reaction was poured into water (30ml) , extracted with EA (30ml*2) , the organic layer was washed with brine (30ml*2) , dried over Na ₂SO ₄, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO ₂, EA:PE=0%to 40%) to give tert-butyl (S) -3- ( (4- (1- (phenylsulfonyl) -1H-indol-3-yl) -5- (trifluoromethyl) pyridin-2-yl) amino) azepane-1-carboxylate (245 mg, 376.30 μmol, 64.46%yield, 94.41%purity) as a light yellow solid.

ESI-MS [M+H] ⁺: 615.45

To a solution of tert-butyl (S) -3- ( (4- (1- (phenylsulfonyl) -1H-indol-3-yl) -5- (trifluoromethyl) pyridin-2-yl) amino) azepane-1-carboxylate (245 mg, 398.58 μmol) in 1, 4-dioxane (5 mL) was added NaOH (5 M in water, 5 mL) , the mixture was stirred at 90℃ for 4h. The reaction mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO2, EA: PE=0%to 50%) to give tert-butyl (S) -3- ( (4- (1H-indol-3-yl) -5- (trifluoromethyl) pyridin-2-yl) amino) azepane-1-carboxylate (154 mg, 316.91 μmol, 79.51%yield, 97.65%purity) as a yellow solid.

ESI-MS [M+H] ⁺: 475.40.

To a solution of tert-butyl (S) -3- ( (4- (1H-indol-3-yl) -5- (trifluoromethyl) pyridin-2-yl) amino) azepane-1-carboxylate (154 mg, 324.54 μmol) in MeOH (5 mL) was added HCl (3 M in EA, 5 mL) , the mixture was stirred at RT for 4h. The reaction mixture was concentrated in vacuo to give a crude, which was dissolved in MeOH and quenched with NH ₃ (7M in MeOH, 5 mL) and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO ₂, 0.5M ammonia methanol solution: DCM=0%to 15%) to give (S) -N- (4- (1H-indol-3-yl) -5- (trifluoromethyl) pyridin-2-yl) azepan-3-amine (89 mg, 231.56 μmol, 71.35%yield, 97.41%purity) as an off-white solid.

ESI-MS [M+H] ⁺: 375.33.

¹H NMR (400 MHz, DMSO) δ11.56-11.55 (d, 1H) , 8.39 (s, 1H) , 7.55-7.53 (d, 1H) , 7.49-7.47 (d, 1H) , 7.45-7.44 (d, 1H) , 7.36-7.34 (d, 1H) , 7.19-7.15 (m, 1H) , 7.10-7.06 (m, 1H) , 6.75 (s, 1H) , 4.22 (s, 1H) , 3.21-3.16 (m, 1H) , 2.99-2.86 (m, 3H) , 2.00-1.93 (m, 1H) , 1.78-1.64 (m, 4H) , 1.59-1.51 (m, 1H)

4- (6, 7-difluoro-1H-indol-3-yl) -N- ( (3S, 5R) -5-methylpiperidin-3-yl) -5- (trifluoromethyl) pyrimidin-2-amine hydrochloride

Synthesis of 4- (6, 7-difluoro-1H-indol-3-yl) -N- ( (3S, 5R) -5-methylpiperidin-3-yl) -5- (trifluoromethyl) pyrimidin-2-amine hydrochloride

Synthesis of 3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -6, 7-difluoro-1H-indole

To a solution of 6, 7-difluoro-1H-indole (200 mg, 1.31 mmol) in DCE (10 mL) under nitrogen, was added AlCl3 (522.46 mg, 3.92 mmol) , and the resulting mixture was stirred at 80℃ for 30 min. After this time, the reaction mixture was cooled to RT, and 2-chloro-5- (trifluoromethyl) pyrimidine (850.17 mg, 3.92 mmol) was added. The resulting mixture was stirred at 80℃ for 10 h, when the solution became reddish overtime. The mixture was then poured into crushed ice and EtOAc. Layers were separated, and organic layer was then dried over Na ₂SO ₄, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase chromatography to afford the 3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -6, 7-difluoro-1H-indole (58.5 mg, 168.32 μmol, 12.89%yield, 96%purity) as a yellow solid. ESI-MS [M +H] +: 334.13.

To a solution of 3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -6, 7-difluoro-1H-indole (100 mg, 299.72 μmol) in NMP (2.5 mL) was added (3S, 5R) -5-methylpiperidin-3-amine (96.35 mg, 449.58 μmol) and DIPEA (77.47 mg, 599.44 μmol, 104.41 μL) , 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 Na ₂SO ₄, filtered, and concentrated to give a residue. The residue purified by column chromatography to give a white solid. Then added MeOH/HCl, stirred at rt. for 5h, concentrated to get 4- (6, 7-difluoro-1H-indol-3-yl) -N- ( (3S, 5R) -5-methylpiperidin-3-yl) -5- (trifluoromethyl) pyrimidin-2-amine hydrochloride (56.6 mg, 133.46 μmol, 44.53%yield, 97%purity) as a yellow solid. ESI-MS [M +H] +: 412.43. ¹H-NMR (400 MHz, MeOD) δ 8.64 (s, 1H) , 8.08 (d, J = 47.9 Hz, 2H) , 7.19 (d, J = 80.3 Hz, 1H) , 3.96 –3.54 (m, 1H) , 2.98 (d, J = 50.6 Hz, 1H) , 2.70 (s, 1H) , 2.48 –2.03 (m, 2H) , 1.74 –1.40 (m, 1H) , 1.37 –0.78 (m, 5H) .

(S) -2- (piperidin-3-ylamino) -4- (quinolin-2-ylamino) pyrimidine-5-carbonitrile

Synthesis of (S) -2- (piperidin-3-ylamino) -4- (quinolin-2-ylamino) pyrimidine-5-carbonitrile

Synthesis of 2-chloro-4- (quinolin-2-ylamino) pyrimidine-5-carbonitrile

A mixture of 2, 4-dichloropyrimidine-5-carbonitrile (300 mg, 1.73 mmol) , quinolin-2-amine (250 mg, 1.73 mmol) and Na ₂CO ₃ (550 mg, 5.19 mmol) in i-PrOH (15 mL) was irradiated in microwave at 100 ℃ for 2 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-4- (quinolin-2-ylamino) pyrimidine-5-carbonitrile (50 mg, yield: 10.3%) as a white solid. ESI-MS [M + H] ⁺: 282.1.

Synthesis of tert-butyl (S) -3- ( (5-cyano-4- (quinolin-2-ylamino) pyrimidin-2-yl) amino) piperidine-1-carboxylate

A mixture of 2-chloro-4- (quinolin-2-ylamino) pyrimidine-5-carbonitrile (50 mg, 0.18 mmol) , tert-butyl (S) -3-aminopiperidine-1-carboxylate (43 mg, 0.22 mmol) and DIPEA (70 mg, 0.54 mmol) in i-PrOH (5 mL) was irradiated in microwave at 140 ℃ for 1 h. The reaction mixture was concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 20/1) to give tert-butyl (S) -3- ( (5-cyano-4- (quinolin-2-ylamino) pyrimidin-2-yl) amino) piperidine-1-carboxylate (30 mg, yield: 37.5%) as a white solid. ESI-MS [M + H] ⁺: 446.2.

To a mixture of tert-butyl (S) -3- ( (5-cyano-4- (quinolin-2-ylamino) pyrimidin-2-yl) amino) piperidine-1-carboxylate (30 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 1 h. The reaction mixture was quenched with NH ₃ (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 (S) -2- (piperidin-3-ylamino) -4- (quinolin-2-ylamino) pyrimidine-5-carbonitrile (8.8 mg, yield: 36.7%) as a white solid.

ESI-MS [M +H] ⁺: 346.2.

1H NMR (400 MHz, MeOD) δ 8.46 –8.30 (m, 1H) , 8.30 –8.18 (m, 1H) , 8.02 –7.90 (m, 1H) , 7.88 –7.73 (m, 2H) , 7.69 –7.57 (m, 1H) , 7.49 –7.37 (m, 1H) , 4.30 –4.09 (m, 1H) , 3.58 –3.39 (m, 1H) , 3.15 –2.99 (m, 1H) , 2.98 –2.76 (m, 2H) , 2.15 –1.88 (m, 2H) , 1.82 –1.52 (m, 2H) .

(S) -N4- (6-methyl-5-phenylpyridin-2-yl) -N2- (piperidin-3-yl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine

Synthesis of (S) -N4- (6-methyl-5-phenylpyridin-2-yl) -N2- (piperidin-3-yl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine

Synthesis of 6-methyl-5-phenylpyridin-2-amine

To a mixture of 5-bromo-6-methylpyridin-2-amine (1 g, 5.38 mmol) , phenylboronic acid (1.31 g, 10.76 mmol) and K ₂CO ₃ (2.23 g, 16.14 mmol) in DME (40 mL) and water (4.0 mL) was added Pd (PPh ₃) ₄ (1.25 g, 1.08 mmol) . The mixture was stirred at 80℃ for 16 h under N ₂. 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 6-methyl-5-phenylpyridin-2-amine (500 mg, yield: 51%) as a yellow solid. ESI-MS [M +H] +: 185.2.

Synthesis of 2-chloro-N- (6-methyl-5-phenylpyridin-2-yl) -5- (trifluoromethyl) pyrimidin-4-amine

To a mixture of 6-methyl-5-phenylpyridin-2-amine (500 mg, 2.72 mmol) in THF (20 mL) was added NaH (60 %in mineral oil, 218 mg, 5.44 mmol) at 0℃. The mixture was stirred at 0℃ for 0.5 h under N ₂. Then 2, 4-dichloro-5- (trifluoromethyl) pyrimidine (881 mg, 4.08 mmol) was added. The reaction was stirred at room temperature for another 16 h. The mixture 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 Na ₂SO ₄, and concentrated to give the crude product, which was purified by Prep-TLC (eluent: PE/EtOAc = 5/1) to give 2-chloro-N- (6-methyl-5-phenylpyridin-2-yl) -5- (trifluoromethyl) pyrimidin-4-amine (210 mg, yield: 21%) as a white solid. ESI-MS [M + H] ⁺: 365.2.

Synthesis of tert-butyl (S) -3- ( (4- ( (6-methyl-5-phenylpyridin-2-yl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylate

A mixture of 2-chloro-N- (6-methyl-5-phenylpyridin-2-yl) -5- (trifluoromethyl) pyrimidin-4-amine (100 mg, 0.27 mmol) , tert-butyl (S) -3-aminopiperidine-1-carboxylate (82 mg, 0.41 mmol) and DIPEA (104 mg, 0.81 mmol) in i-PrOH (8 mL) was irradiated in microwave at 100℃ for 2 h. The reaction mixture was concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 20/1) to give tert-butyl (S) -3- ( (4- ( (6-methyl-5-phenylpyridin-2-yl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (80 mg, yield: 56%) as a white solid. ESI-MS [M + H] ⁺: 529.2.

To a mixture of tert-butyl (S) -3- ( (4- ( (6-methyl-5-phenylpyridin-2-yl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (80 mg, 0.15 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 NH ₃ (7M solution in MeOH, 2.0 mL) and concentrated in vacuo to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 10/1) to give (S) -N4- (6-methyl-5-phenylpyridin-2-yl) -N2- (piperidin-3-yl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine (23 mg, yield: 36%) as a white solid.

ESI-MS [M +H] ⁺: 429.2.

¹H NMR (400 MHz, MeOD) δ 8.53 –8.18 (m, 2H) , 7.84 –7.58 (m, 1H) , 7.48 –7.28 (m, 5H) , 4.02 –3.94 (m, 1H) , 3.21 (d, J = 11.0 Hz, 1H) , 2.93 (d, J = 12.7 Hz, 1H) , 2.66 –2.49 (m, 2H) , 2.42 (s, 3H) , 2.15 –2.11 (m, 1H) , 1.76 (s, 1H) , 1.66 –1.49 (m, 2H) .

(S) -N4- (5-methyl-6-phenylpyridin-2-yl) -N2- (piperidin-3-yl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine

Synthesis of (S) -N4- (5-methyl-6-phenylpyridin-2-yl) -N2- (piperidin-3-yl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine

Synthesis of 5-methyl-6-phenylpyridin-2-amine

To a mixture of 6-bromo-5-methylpyridin-2-amine (400 mg, 2.15 mmol) , phenylboronic acid (400 mg, 4.3 mmol) and K ₂CO ₃ (890 mg, 6.45 mmol) in DME (20 mL) and water (2.0 mL) was added Pd (PPh ₃) ₄ (254 mg, 0.22 mmol) . The mixture was stirred at 80℃ for 16 h under N ₂. 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 5-methyl-6-phenylpyridin-2-amine (240 mg, yield: 61%) as a yellow solid. ESI-MS [M +H] +: 185.2.

Synthesis of 2-chloro-N- (5-methyl-6-phenylpyridin-2-yl) -5- (trifluoromethyl) pyrimidin-4-amine

To a mixture of 5-methyl-6-phenylpyridin-2-amine (240 mg, 1.3 mmol) in THF (10 mL) was added NaH (60 %in mineral oil, 104 mg, 2.6 mmol) at 0℃℃. The mixture was stirred at 0℃ for 0.5 h under N ₂. Then 2, 4-dichloro-5- (trifluoromethyl) pyrimidine (516 mg, 2.6 mmol) was added. The reaction was stirred at room temperature for another 16 h. The mixture 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 Na ₂SO ₄, and concentrated to give the crude product, which was purified by Prep-TLC (eluent: PE/EtOAc = 5/1) to give 2-chloro-N- (5-methyl- 6-phenylpyridin-2-yl) -5- (trifluoromethyl) pyrimidin-4-amine (100 mg, yield: 21%) as a white solid. ESI-MS [M + H] ⁺: 365.2.

Synthesis of tert-butyl (S) -3- ( (4- ( (5-methyl-6-phenylpyridin-2-yl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylate

A mixture of 2-chloro-N- (5-methyl-6-phenylpyridin-2-yl) -5- (trifluoromethyl) pyrimidin-4-amine (100 mg, 0.27 mmol) , tert-butyl (S) -3-aminopiperidine-1-carboxylate (82 mg, 0.41 mmol) and DIPEA (104 mg, 0.81 mmol) in i-PrOH (8 mL) was irradiated in microwave at 100℃ for 2 h. The reaction mixture was concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 20/1) to give tert-butyl (S) -3- ( (4- ( (5-methyl-6-phenylpyridin-2-yl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (70 mg, yield: 49%) as a white solid. ESI-MS [M + H] ⁺: 529.2.

To a mixture of tert-butyl (S) -3- ( (4- ( (5-methyl-6-phenylpyridin-2-yl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (70 mg, 0.13 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 NH ₃ (7M solution in MeOH, 2.0 mL) and concentrated in vacuo to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 10/1) to give (S) -N4- (5-methyl-6-phenylpyridin-2-yl) -N2- (piperidin-3-yl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine (31 mg, yield: 56%) as a white solid.

ESI-MS [M +H] ⁺: 429.2.

¹H NMR (400 MHz, MeOD) δ 8.47 –8.24 (m, 2H) , 7.83 –7.72 (m, 1H) , 7.55 –7.26 (m, 5H) , 3.95 (s, 1H) , 3.25 –3.18 (m, 1H) , 2.96 (d, J = 12.7 Hz, 1H) , 2.67 –2.48 (m, 2H) , 2.30 (s, 3H) , 2.14 –2.08 (m, 1H) , 1.82 –1.78 (m, 1H) , 1.60 –1.52 (m, 2H) .

(S) -N4- (5-bromo-6- (trifluoromethyl) pyridin-2-yl) -N2- (piperidin-3-yl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine

Synthesis of (S) -N4- (5-bromo-6- (trifluoromethyl) pyridin-2-yl) -N2- (piperidin-3-yl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine

Synthesis of N- (5-bromo-6- (trifluoromethyl) pyridin-2-yl) -2-chloro-5- (trifluoromethyl) pyrimidin-4-amine

To a mixture of 5-bromo-6- (trifluoromethyl) pyridin-2-amine (300 mg, 1.25 mmol) in THF (10 mL) was added NaH (60 %in mineral oil, 100 mg, 2.5 mmol) at 0 ℃. The mixture was stirred at 0 ℃ for 0.5h under N ₂. Then 2, 4-dichloro-5- (trifluoromethyl) pyrimidine (810 mg, 3.75 mmol) was added. The reaction was stirred at room temperature for another 4 h. The mixture 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 Na ₂SO ₄, and concentrated to give the crude product, which was purified by Prep-TLC (eluent: PE/EtOAc = 15/1) to give N- (5-bromo-6- (trifluoromethyl) pyridin-2-yl) -2-chloro-5- (trifluoromethyl) pyrimidin-4-amine (88 mg, yield: 16.8%) as a white solid. ESI-MS [M + H] ⁺: 421.2.

Synthesis of tert-butyl (S) -3- ( (4- ( (5-bromo-6- (trifluoromethyl) pyridin-2-yl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylate

A mixture of N- (5-bromo-6- (trifluoromethyl) pyridin-2-yl) -2-chloro-5- (trifluoromethyl) pyrimidin-4-amine (88 mg, 0.21 mmol) , tert-butyl (S) -3-aminopiperidine-1-carboxylate (63 mg, 0.32 mmol) and DIPEA (81 mg, 0.63 mmol) in i-PrOH (8 mL) was irradiated in microwave at 130 ℃ for 2 h. The reaction mixture was concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM) to give tert-butyl (S) -3- ( (4- ( (5-bromo-6- (trifluoromethyl) pyridin-2-yl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (110 mg, yield: 97.9%) as a white solid. ESI-MS [M + H] ⁺: 585.1.

To a mixture of tert-butyl (S) -3- ( (4- ( (5-bromo-6- (trifluoromethyl) pyridin-2-yl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (110 mg, 0.19 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 NH ₃ (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 (S) -N4- (5-bromo-6- (trifluoromethyl) pyridin-2-yl) -N2- (piperidin-3-yl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine (67 mg, yield: 73.5%) as a white solid.

ESI-MS [M +H] +: 485.1.

1H NMR (400 MHz, MeOD) δ 8.69 –7.97 (m, 3H) , 4.00 –3.77 (m, 1H) , 3.18 –3.05 (m, 1H) , 3.01 –2.84 (m, 1H) , 2.69 –2.38 (m, 2H) , 2.06 –1.90 (m, 1H) , 1.82 –1.65 (m, 1H) , 1.64 –1.34 (m, 2H) .

N4- { [3, 3'-bipyridin] -6-yl} -N2- [ (3S) -piperidin-3-yl] -5- (trifluoromethyl) pyrimidine-2, 4-diamine

Synthesis of N4- { [3, 3'-bipyridin] -6-yl} -N2- [ (3S) -piperidin-3-yl] -5- (trifluoromethyl) pyrimidine-2, 4-diamine

Synthesis of tert-butyl (3S) -3- { [4-chloro-5- (trifluoromethyl) pyrimidin-2-yl] amino} piperidine-1-carboxylate

A 100 mL round-bottom flask was charged with 2, 4-dichloro-5- (trifluoromethyl) pyrimidine (800 mg, 3.69 mmol, 1.00 equiv) , 1, 2-dichloroethane (5 mL) , tert butanol (5 mL) and zinc chloride (5.53 mL, 5.53 mmol, 1.50 equiv, 1M in diethyl ether ) at 0 ℃. The resulting mixture was stirred for 1 h at 0 ℃ under nitrogen atmosphere. Tert-butyl (3S) -3-aminopiperidine-1-carboxylate (738 mg, 3.69 mmol, 1.00 equiv) and triethylamine (448 mg, 4.43 mmol, 1.20 equiv) were added to above mixture at 0 ℃. The mixture was allowed to warm to 60 ℃ and stirred for overnight at 60 ℃. The reaction mixture was quenched with water (50 mL) and extracted with DCM (3 x 50 mL) . The combined organic layers were washed with water (3 x 20 mL) , dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE/EA = 1/1) to afford tert-butyl (3S) - 3- { [4-chloro-5- (trifluoromethyl) pyrimidin-2-yl] amino} piperidine-1-carboxylate (520 mg, 37%yield) as a white solid. LCMS (ESI, m/z) : 381 [M+H] ⁺.

Synthesis of tert-butyl (3S) -3- [ (4- { [3, 3'-bipyridin] -6-ylamino} -5- (trifluoromethyl) pyrimidin-2-yl) amino] piperidine-1-carboxylate

A mixture of tert-butyl (3S) -3- { [4-chloro-5- (trifluoromethyl) pyrimidin-2-yl] amino} piperidine-1-carboxylate (160 mg, 0.420 mmol, 1.00 equiv) , [3, 3'-bipyridin] -6-amine (71.9 mg, 0.420 mmol, 1.00 equiv) , tris (dibenzylideneacetone) dipalladium (76.9 mg, 0.0840 mmol, 0.200 equiv) and 2- (dicyclohexylphosphino) -2', 4', 6'-triisopropylbiphenyl (40.1 mg, 0.0840 mmol, 0.200 equiv) in DMF (5 mL) was stirred for overnight at 100 ℃ under nitrogen atmosphere 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 (1 x 50 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 CH ₂Cl ₂/MeOH (10/1) to afford tert-butyl (3S) -3- [ (4- { [3, 3'-bipyridin] -6-ylamino} -5- (trifluoromethyl) pyrimidin-2-yl) amino] piperidine-1-carboxylate (150 mg, 69%yield) as a yellow solid. LCMS (ESI, m/z) : 516 [M+H] ⁺.

A mixture of tert-butyl (3S) -3- [ (4- { [3, 3'-bipyridin] -6-ylamino} -5- (trifluoromethyl) pyrimidin-2-yl) amino] piperidine-1-carboxylate (150 mg, 0.291 mmol, 1.00 equiv) and TFA (2 mL) in dichloromethane (5 mL) was stirred for 2 h at room temperature and concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions: Column: XBridge Shield RP ₁₈ OBD Column, 30*150 mm, 5 μm; Mobile Phase A: water (10 mmol/L NH ₄HCO ₃) , Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 35%B to 55%B in 7 min, Wave Length: 254 nm to afford N4- { [3, 3'-bipyridin] -6-yl} -N2- [ (3S) -piperidin-3-yl] -5- (trifluoromethyl) pyrimidine-2, 4-diamine (53.4 mg, 44%yield) as a white solid. LCMS (ESI, m/z) : 416 [M+H] ⁺. ¹H-NMR (300 MHz, DMSO-d ₆) δ 8.98 (q, J = 2.4 Hz, 1H) , 8.73 (dd, J = 8.9, 2.3 Hz, 1H) , 8.65 -8.52 (m, 1H) , 8.42 -8.26 (m, 2H) , 8.19 -8.12 (m, 1H) , 7.77 (m, 1H) , 7.53 (dd, J = 8.0, 4.8 Hz, 1H) , 3.78 (m, 1H) , 3.06 (t, J = 12.1 Hz, 1H) , 2.81 (d, J = 12.3 Hz, 1H) , 2.41 (q, J = 10.2 Hz, 2H) , 1.93 (d, J = 18.3 Hz, 1H) , 1.64 (s, 1H) , 1.45 (t, J = 9.4 Hz, 2H) .

(S) -N4- (4-methylquinolin-2-yl) -N2- (piperidin-3-yl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine

Synthesis of (S) -N4- (4-methylquinolin-2-yl) -N2- (piperidin-3-yl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine

Synthesis of N- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -4-methylquinolin-2-amine

To a mixture of 4-methylquinolin-2-amine (200 mg, 1.27 mmol) in THF (10 mL) was added NaH (60 %in mineral oil, 106 mg, 4.42 mmol) at 0 ℃. The mixture was stirred at 0 ℃ for 0.5 h under N ₂. Then 2, 4-dichloro-5- (trifluoromethyl) pyrimidine (550 mg, 2.55 mmol) was added. The reaction mixture was stirred at room temperature for another 16 h. The reaction mixture was quenched with H ₂O (30 mL) and extracted with EtOAc (30 mL x 2) . The combined organic layers were washed with brine (50 mL) , dried over anhydrous Na ₂SO ₄, and concentrated in vacuo to give the crude, which was purified by Prep-TLC (eluent: PE/EtOAc = 20/1) to give N- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -4-methylquinolin-2-amine (40 mg, yield: 9.3%) as a white solid. ESI-MS [M + H] ⁺: 339.1.

Synthesis of tert-butyl (S) -3- ( (4- ( (4-methylquinolin-2-yl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylate

A mixture of N- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -4-methylquinolin-2-amine (40 mg, 0.12 mmol) , tert-butyl (S) -3-aminopiperidine-1-carboxylate (28 mg, 0.14 mmol) and DIPEA (46 mg, 0.36 mmol) in i-PrOH (5 mL) was irradiated in microwave at 130 ℃ for 2 h. The reaction mixture was concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 20/1) to give tert-butyl (S) -3- ( (4- ( (4-methylquinolin-2-yl) amino) -5-(trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (40 mg, yield: 66.7%) as a white solid. ESI-MS [M + H] ⁺: 503.2.

To a mixture of tert-butyl (S) -3- ( (4- ( (4-methylquinolin-2-yl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (40 mg, 0.08 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 NH ₃ (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 (S) -N4- (4-methylquinolin-2-yl) -N2- (piperidin-3-yl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine (18.2 mg, yield: 56.7%) as a white solid.

ESI-MS [M +H] ⁺: 403.2.

1H NMR (400 MHz, MeOD) δ 8.59 –8.29 (m, 1H) , 8.28 –8.13 (m, 1H) , 8.00 –7.88 (m, 1H) , 7.78 –7.67 (m, 1H) , 7.65 –7.54 (m, 1H) , 7.48 –7.36 (m, 1H) , 3.99 –3.74 (m, 1H) , 3.18 –2.98 (m, 1H) , 2.94 –2.76 (m, 1H) , 2.69 (s, 3H) , 2.61 –2.38 (m, 2H) , 2.10 –1.89 (m, 1H) , 1.78 –1.63 (m, 1H) , 1.58 –1.38 (m, 2H) .

(S) -N4- (6-bromoquinolin-2-yl) -N2- (piperidin-3-yl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine

Synthesis of (S) -N4- (6-bromoquinolin-2-yl) -N2- (piperidin-3-yl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine

Synthesis of 6-bromo-N- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) quinolin-2-amine

To a mixture of 6-bromoquinolin-2-amine (200 mg, 0.90 mmol) in THF (10 mL) was added NaH (60 %in mineral oil, 80 mg, 3.34 mmol) at 0 ℃. The mixture was stirred at 0 ℃℃ for 0.5 h under N ₂. Then 2, 4-dichloro-5- (trifluoromethyl) pyrimidine (390 mg, 1.81 mmol) was added. The reaction mixture was stirred at room temperature for another 16 h. The reaction mixture was quenched with H ₂O (30 mL) and extracted with EtOAc (30 mL x 2) . The combined organic layers were washed with brine (30 mL) , dried over anhydrous Na ₂SO ₄, and concentrated in vacuo to give the crude, which was purified by Prep-TLC (eluent: PE/EtOAc = 20/1) to give 6-bromo-N- (2- chloro-5- (trifluoromethyl) pyrimidin-4-yl) quinolin-2-amine (60 mg, yield: 16.6%) as a white solid. ESI-MS [M + H] ⁺: 403.0.

Synthesis of tert-butyl (S) -3- ( (4- ( (6-bromoquinolin-2-yl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylate

A mixture of 6-bromo-N- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) quinolin-2-amine (60 mg, 0.15 mmol) , tert-butyl (S) -3-aminopiperidine-1-carboxylate (36 mg, 0.18 mmol) and DIPEA (58 mg, 0.45 mmol) in i-PrOH (5 mL) was irradiated in microwave at 130 ℃ for 2 h. The reaction mixture was concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 20/1) to give tert-butyl (S) -3- ( (4- ( (6-bromoquinolin-2-yl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (50 mg, yield: 58.8%) as a white solid. ESI-MS [M + H] ⁺: 567.1.

To a mixture of tert-butyl (S) -3- ( (4- ( (6-bromoquinolin-2-yl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (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 1 h. The reaction mixture was quenched with NH ₃ (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 (S) -N4- (6-bromoquinolin-2-yl) -N2- (piperidin-3-yl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine (29.1 mg, yield: 69.3%) as a white solid.

ESI-MS [M +H] ⁺: 467.1.

1H NMR (400 MHz, MeOD) δ 8.61 –8.30 (m, 1H) , 8.28 –8.09 (m, 2H) , 7.98 (s, 1H) , 7.76 –7.57 (m, 2H) , 3.95 –3.74 (m, 1H) , 3.16 –3.02 (m, 1H) , 2.90 –2.77 (m, 1H) , 2.56 –2.37 (m, 2H) , 2.07 –1.90 (m, 1H) , 1.75 –1.63 (m, 1H) , 1.57 –1.36 (m, 2H) .

(S) -N4- (5- (piperazin-1-yl) pyridin-2-yl) -N2- (piperidin-3-yl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine

Synthesis of (S) -N4- (5- (piperazin-1-yl) pyridin-2-yl) -N2- (piperidin-3-yl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine

Synthesis of tert-butyl 4- (6- ( (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) amino) pyridin-3-yl) piperazine-1-carboxylate

To a solution of 2, 4-dichloro-5- (trifluoromethyl) pyrimidine (2 g, 9.22 mmol) in EtOH (20 mL) were added tert-butyl 4- (6-aminopyridin-3-yl) piperazine-1-carboxylate (2.31 g, 8.30 mmol) and DIPEA (2.38 g, 18.44 mmol, 3.21 mL) , the mixture was stirred at 78℃ for 4h. The reaction mixture was concentrated to give a residue, the residue was purified by column chromatography (SiO2, EA: PE=0%to 30%) to give tert-butyl 4- (6- ( (2-chloro-5-(trifluoromethyl) pyrimidin-4-yl) amino) pyridin-3-yl) piperazine-1-carboxylate (401 mg, 841.39 μmol, 9.13%yield, 96.28%purity) as a yellow solid.

ESI-MS [M+H] ⁺: 459.35

Synthesis of tert-butyl (S) -4- (6- ( (2- ( (1- (tert-butoxycarbonyl) piperidin-3-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) pyridin-3-yl) piperazine-1-carboxylate

To a solution of tert-butyl 4- (6- ( (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) amino) pyridin-3-yl) piperazine-1-carboxylate (100 mg, 217.93 μmol) in NMP (2 mL) were added tert-butyl (S) -3-aminopiperidine-1-carboxylate (65.47 mg, 326.89 μmol) and DIPEA (56.33 mg, 435.86 μmol) , the mixture was stirred at 120℃ for 2hrs. The reaction was poured into water (12ml) , extracted with EA (12ml*2) , the organic layer was washed with brine (12ml*2) , dried over Na ₂SO ₄, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, EA: PE=0%to 50%) to give tert-butyl (S) -4- (6- ( (2- ( (1- (tert-butoxycarbonyl) piperidin-3-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) pyridin-3-yl) piperazine-1-carboxylate (131 mg, 208.89 μmol, 95.85%yield, 99.29%purity) as a light yellow solid.

ESI-MS [M+H] ⁺: 623.50

To a solution of tert-butyl (S) -4- (6- ( (2- ( (1- (tert-butoxycarbonyl) piperidin-3-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) pyridin-3-yl) piperazine-1-carboxylate (130.21 mg, 209.11 μmol) in EA (3 mL) was added HCl (3 M in EA, 3 mL) , the mixture was stirred at RT for 4h. The reaction mixture was concentrated in vacuo to give a crude, which was dissolved in MeOH and quenched with NH3 (7M in MeOH, 5 mL) and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO2, 0.5M ammonia methanol solution: DCM=0%to 20%) to give (S) -N4- (5- (piperazin-1-yl) pyridin-2-yl) -N2- (piperidin-3-yl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine (66 mg, 155.00 μmol, 74.12%yield, 99.21%purity) as an off-white solid.

ESI-MS [M+H] ⁺: 423.38.

¹H NMR (400 MHz, MeOD) δ8.21-8.10 (m, 2H) , 8.01-8.01 (d, 1H) , 7.59-7.48 (m, 1H) , 3.99-3.88 (m, 1H) , 3.25-3.19 (m, 5H) , 3.04-2.97 (m, 5H) , 2.67-2.57 (m, 2H) , 2.07-2.05 (m, 1H) , 1.83- 1.80 (m, 1H) , 1.65-1.54 (m, 2H)

(S) -N4- (6-bromoimidazo [1, 2-a] pyrazin-2-yl) -N2- (piperidin-3-yl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine

Synthesis of (S) -N4- (6-bromoimidazo [1, 2-a] pyrazin-2-yl) -N2- (piperidin-3-yl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine

Synthesis of 6-bromo-N- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) imidazo [1, 2-a] pyrazin-2-amine

To a mixture of 6-bromoimidazo [1, 2-a] pyrazin-2-amine (200 mg, 0.94 mmol) in THF (10 mL) was added NaH (60 %in mineral oil, 100 mg, 4.17 mmol) at 0 ℃. The mixture was stirred at 0 ℃ for 0.5 h under N ₂. Then 2, 4-dichloro-5- (trifluoromethyl) pyrimidine (408 mg, 1.89 mmol) was added. The reaction mixture was stirred at room temperature for another 2 h. The reaction mixture was quenched with H ₂O (30 mL) and extracted with EtOAc (30 mL x 2) . The combined organic layers were washed with brine (50 mL) , dried over anhydrous Na ₂SO ₄, and concentrated in vacuo to give the crude, which was purified by Prep-TLC (eluent: PE/EtOAc = 20/1) to give 6-bromo-N- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) imidazo [1, 2-a] pyrazin-2-amine (70 mg, yield: 19.0%) as a white solid. ESI-MS [M + H] ⁺: 393.1.

Synthesis of tert-butyl (S) -3- ( (4- ( (6-bromoimidazo [1, 2-a] pyrazin-2-yl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylate

A mixture of 6-bromo-N- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) imidazo [1, 2-a] pyrazin-2-amine (70 mg, 0.18 mmol) , tert-butyl (S) -3-aminopiperidine-1-carboxylate (43 mg, 0.22 mmol) and DIPEA (70 mg, 0.54 mmol) in i-PrOH (6 mL) was irradiated in microwave at 140 ℃ for 1 h. The reaction mixture was concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 20/1) to give tert-butyl (S) -3- ( (4- ( (6-bromoimidazo [1, 2-a] pyrazin-2-yl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (50 mg, yield: 50.0%) as a white solid. ESI-MS [M + H] ⁺: 557.1.

To a mixture of tert-butyl (S) -3- ( (4- ( (6-bromoimidazo [1, 2-a] pyrazin-2-yl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (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 1 h. The reaction mixture was quenched with NH ₃ (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 (S) -N4- (6-bromoimidazo [1, 2-a] pyrazin-2-yl) -N2- (piperidin-3-yl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine (9.2 mg, yield: 22.4%) as a white solid.

ESI-MS [M +H] ⁺: 457.1.

1H NMR (400 MHz, DMSO) δ 9.11 –8.69 (m, 1H) , 8.50 –8.21 (m, 1H) , 7.93 –7.72 (m, 0H) , 4.05 –3.89 (m, 1H) , 3.18 –3.07 (m, 1H) , 3.00 –2.83 (m, 1H) , 2.69 –2.54 (m, 1H) , 2.02 –1.86 (m, 1H) , 1.81 –1.40 (m, 1H) .

N4- [6-methyl-5- (4-methylpiperazin-1-yl) pyridin-2-yl] -N2- [ (3S) -piperidin-3-yl] -5- (trifluoromethyl) pyrimidine-2, 4-diamine trifluoroacetic acid salt

Synthesis of N4- [6-methyl-5- (4-methylpiperazin-1-yl) pyridin-2-yl] -N2- [ (3S) -piperidin-3-yl] -5- (trifluoromethyl) pyrimidine-2, 4-diamine trifluoroacetic acid salt

Synthesis of tert-butyl 4- (2-methyl-6-nitropyridin-3-yl) piperazine-1-carboxylate

A 100 mL round-bottom flask was charged with 3-bromo-2-methyl-6-nitropyridine (100 mg, 0.461 mmol, 1.00 equiv) , tert-butyl piperazine-1-carboxylate (343 mg, 1.84 mmol, 4.00 equiv) , cesium carbonate (450 mg, 1.38 mmol, 3.00 equiv) , XPhos (43.9 mg, 0.092 mmol, 0.20 equiv) , Pd ₂ (dba) ₃ (42.2 mg, 0.046 mmol, 0.10 equiv) and DMF (15 mL) . The resulting mixture was stirred for 16 h at 100 ℃ under nitrogen atmosphere and quenched with water (80 mL) . The mixture was extracted with ethyl acetate (3 x 100 mL) . The organic layers were combined, washed with saturated sodium chloride solution (3 x 50 mL) , dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by Prep-TLC (ethyl acetate/petroleum ether = 3/2) to afford tert-butyl 4- (2-methyl-6-nitropyridin-3-yl) piperazine-1-carboxylate (85.1 mg, 57%yield) as a brown semi-solid. LCMS (ESI, m/z) : 323 [M+H] ⁺.

Synthesis of 6-methyl-5- (4-methylpiperazin-1-yl) pyridin-2-amine

A 100 mL round-bottom flask was charged with tert-butyl 4- (2-methyl-6-nitropyridin-3-yl) piperazine-1-carboxylate (85.0 mg, 0.264 mmol, 1.00 equiv) and THF (15 mL) . Then lithium aluminum hydride (0.6 mL, 1 mol/L in THF) was added dropwise to above mixture at room temperature. The resulting solution was stirred for overnight at 60 ℃ and quenched with water (2 mL) . The solid was filtered out and the filter cake was washed with THF (3 x 50 mL) . The filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (ethyl acetate/ petroleum 2/1) to afford 6-methyl-5- (4-methylpiperazin-1-yl) pyridin-2-amine (30.1 mg, 55%yield) as an orange solid. LCMS (ESI, m/z) : 207 [M+H] ⁺.

Synthesis of tert-butyl (3S) -3- [ (4- { [6-methyl-5- (4-methylpiperazin-1-yl) pyridin-2-yl] amino} -5- (trifluoromethyl) pyrimidin-2-yl) amino] piperidine-1-carboxylate

A 100 mL round bottom flask was charged with 6-methyl-5- (4-methylpiperazin-1-yl) pyridin-2-amine (30.0 mg, 0.145 mmol, 1.00 equiv) , tert-butyl (3S) -3- { [4-chloro-5- (trifluoromethyl) pyrimidin-2-yl] amino} piperidine-1-carboxylate (66.5 mg, 0.183 mmol, 1.20 equiv) , cesium carbonate (142 mg, 0.435 mmol, 3.00 equiv) , XPhos (13.9 mg, 0.03 mmol, 0.20 equiv) , Pd ₂ (dba) ₃ (13.3 mg, 0.014 mmol, 0.10 equiv) and DMF (15 mL) . The resulting mixture was stirred for 16 h at 100 ℃ under nitrogen atmosphere and quenched with water (80 mL) . The mixture was extracted with ethyl acetate (3 x 100 mL) . The organic layers were combined, washed with saturated sodium chloride solution (3 x 50 mL) , dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by Prep-TLC (dichloromethane /methyl alcohol = 9/1) to afford tert-butyl (3S) -3- [ (4- { [6-methyl-5- (4-methylpiperazin-1-yl) pyridin-2-yl] amino} -5- (trifluoromethyl) pyrimidin-2-yl) amino] piperidine-1-carboxylate (31.4 mg, 39%yield) as a yellow solid. LCMS (ESI, m/z) : 551 [M+H] ⁺.

A 100 mL round bottom flask was charged with tert-butyl (3S) -3- [ (4- { [6-methyl-5- (4-methylpiperazin-1-yl) pyridin-2-yl] amino} -5- (trifluoromethyl) pyrimidin-2-yl) amino] piperidine-1-carboxylate (30.0 mg, 0.05 mmol, 1.00 equiv) , dichloromethane (30 mL) and trifluoroacetic acid (6 mL) . The resulting solution was stirred for 2 h at room temperature and concentrated under reduced pressure to afford the crude product. The crude product was purified by Prep-HPLC with the following conditions: Column: Xselect CSH C ₁₈ OBD Column 30 x 150 mm 5 μm; Mobile Phase A: Water (0.05%TFA ) , Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 3%B to 3%B in 2 min, 3%B to 20%B in 9 min, Wave Length: 220 nm to afford N4- [6-methyl-5- (4-methylpiperazin-1-yl) pyridin-2-yl] -N2- [ (3S) -piperidin-3-yl] -5- (trifluoromethyl) pyrimidine-2, 4-diamine trifluoroacetic acid salt (10.4 mg, 34%yield) as a colorless semi-solid. LCMS (ESI, m/z) : 451 [M+H-TFA] ⁺. ¹H NMR (300 MHz, Methanol-d ₄) δ 8.37 (s, 1H) , 8.19 (s, 1H) , 7.83 (s, 1H) , 4.21 (m, 1H) , 3.64 (d, J = 9.7 Hz, 2H) , 3.58 -3.37 (m, 4H) , 3.32 -3.10 (m, 4H) , 3.08 -3.01 (m, 5H) , 2.58 (s, 3H) , 2.15 -2.03 (m, 2H) , 1.91 -1.58 (m, 2H) .

N4- (1H-indazol-3-yl) -N2- [ (3S) -piperidin-3-yl] -5- (trifluoromethyl) pyrimidine-2, 4-diamine

Synthesis of N4- (1H-indazol-3-yl) -N2- [ (3S) -piperidin-3-yl] -5- (trifluoromethyl) pyrimidine-2, 4-diamine

Synthesis of (Z) -N'- (1H-indazol-3-yl) -N, N-dimethylformimidamide

A 100 mL round-bottom flask was charged with 3-aminoindazole (800 mg, 6.01 mmol, 1.00 equiv) and DMF-DMA (20 mL) at room temperature. The resulting mixture was stirred for 16 h at room temperature and quenched with water (80 mL) . The mixture was extracted with ethyl acetate (3 x 100 mL) . The organic layers were combined, washed with saturated sodium chloride solution (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 ethyl acetate/petroleum ether (5/3) to afford (Z) -N'- (1H-indazol-3-yl) -N, N-dimethylmethanimidamide (536 mg, 47%yield) as a brown oil. LCMS (ESI, m/z) : 189 [M+H] +.

Synthesis of (Z) -N'- {1- [ (4-methoxyphenyl) methyl] indazol-3-yl} -N, N-dimethylmethanimidamide

A 100 mL round-bottom flask was charged with (Z) -N'- (1H-indazol-3-yl) -N, N-dimethylmethanimidamide (536 mg, 2.85 mmol, 1.00 equiv) , t-BuOK (479 mg, 4.27 mmol, 1.50 equiv) , PMB-Cl (669 mg, 4.27 mmol, 1.50 equiv) and THF (30 mL) . The resulting solution was stirred for overnight at room temperature and quenched with water (80 mL) . The mixture was extracted with ethyl acetate (3 x 100 mL) . The organic layers were combined, washed with saturated sodium chloride solution (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 ethyl acetate/petroleum ether (1/1) to afford (Z) -N'- {1- [ (4-methoxyphenyl) methyl] indazol-3-yl} -N, N-dimethylmethanimidamide (409 mg, 46%yield) as a brown oil. LCMS (ESI, m/z) : 309 [M+H] +.

Synthesis of 1- [ (4-methoxyphenyl) methyl] indazol-3-amine

A 100 mL round bottom flask was charged with (Z) -N'- {1- [ (4-methoxyphenyl) methyl] indazol-3-yl} -N, N-dimethylmethanimidamide (409 mg, 1.331 mmol, 1.00 equiv) , hydrazine monohydrate (666 mg, 13.3 mmol, 10.0 equiv) and methyl alcohol (20 mL) . The resulting solution was stirred for overnight at 60 ℃ and quenched with water (100 mL) . The mixture was extracted with ethyl acetate (3 x 200 mL) . The organic layers were combined, washed with saturated sodium chloride solution (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 ethyl acetate/petroleum ether (2/1) to afford 1- [ (4-methoxyphenyl) methyl] indazol-3-amine (213 mg, 63%yield) as a brown solid. LCMS (ESI, m/z) : 254 [M+H] ⁺.

Synthesis of tert-butyl (3S) -3- { [4- ( {1- [ (4-methoxyphenyl) methyl] indazol-3-yl} amino) -5- (trifluoromethyl) pyrimidin-2-yl] amino} piperidine-1-carboxylate

A 100 mL round bottom flask was charged with tert-butyl (3S) -3- { [4-chloro-5- (trifluoromethyl) pyrimidin-2-yl] amino} piperidine-1-carboxylate (100 mg, 0.263 mmol, 1.00 equiv) , 1- [ (4-methoxyphenyl) methyl] indazol-3-amine (79.8 mg, 0.316 mmol, 1.20 equiv) , cesium carbonate (257 mg, 0.789 mmol, 3.00 equiv) , XPhos (25.0 mg, 0.053 mmol, 0.20 equiv) , Pd ₂ (dba) ₃ (24.1 mg, 0.026 mmol, 0.10 equiv) and DMF (15 mL) . The resulting mixture was stirred for overnight at room temperature and quenched with water (80 ml) . The resulting mixture was extracted with ethyl acetate (3 x 100 mL) . The combined organic layers were washed with saturated sodium chloride solution (3 x 50 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 ethyl acetate/petroleum ether (3/2) to afford tert-butyl (3S) -3- { [4- ( {1- [ (4-methoxyphenyl) methyl] indazol-3-yl} amino) -5- (trifluoromethyl) pyrimidin-2-yl] amino} piperidine-1-carboxylate (102 mg, 65%yield) as a yellow solid. LCMS (ESI, m/z) : 598 [M+H] ⁺.

A 100 mL round bottom flask was charged with tert-butyl (3S) -3- { [4- ( {1- [ (4-methoxyphenyl) methyl] indazol-3-yl} amino) -5- (trifluoromethyl) pyrimidin-2-yl] amino} piperidine-1-carboxylate (90.0 mg, 0.151 mmol, 1.00 equiv) and TFA (30 mL) at room temperature. The resulting mixture was stirred for 2 days at 60 ℃ and concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions: Column: XBridge Shield RP ₁₈ OBD Column, 30*150 mm, 5 μm; Mobile Phase A: Water (10 mmol/L NH4HCO ₃+0.1%NH ₃. H ₂O) , Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 38%B to 58%B in 7 min; Wave Length: 254 nm to afford N4- (1H-indazol-3-yl) -N2- [ (3S) -piperidin-3-yl] -5- (trifluoromethyl) pyrimidine-2, 4-diamine (26.1 mg, 45%yield) as a yellow solid. LCMS (ESI, m/z) : 378 [M+H] ⁺. ¹H-NMR (300 MHz, Methanol-d ₄) δ 8.16 (s, 1H) , 7.58 -7.49 (m, 2H) , 7.42 -7.38 (m, 1H) , 7.16 -7.11 (m, 1H) , 3.83 (s, 1H) , 3.27 -2.79 (m, 1H) , 2.78 -2.60 (m, 1H) , 2.49 -2.19 (m, 2H) , 1.89 -0.95 (m, 4H) .

(S) -2- ( (2- (piperidin-3-ylamino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) quinoline-3-carbonitrile

Synthesis of (S) -2- ( (2- (piperidin-3-ylamino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) quinoline-3-carbonitrile

Synthesis of 2- ( (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) amino) quinoline-3-carbonitrile

To a mixture of 2-aminoquinoline-3-carbonitrile (150 mg, 0.89 mmol) in THF (5 mL) was added NaH (60 %in mineral oil, 71 mg, 1.78 mmol) at 0 ℃. The mixture was stirred at 0 ℃ for 0.5h under N ₂. Then 2, 4-dichloro-5- (trifluoromethyl) pyrimidine (288 mg, 1.33 mmol) was added. The reaction was stirred at room temperature for another 4 h. The mixture was quenched with water (30 mL) and extracted with EtOAc (30 mL x 3) . The combined organic layers were washed with brine (30 mL) , dried over anhydrous Na ₂SO ₄, and concentrated to give the crude product, which was purified by Prep-TLC (eluent: PE/EtOAc = 10/1) to give 2- ( (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) amino) quinoline-3-carbonitrile (70 mg, yield: 23%) as a yellow solid. ESI-MS [M + H] ⁺: 350.2.

Synthesis of tert-butyl (S) -3- ( (4- ( (3-cyanoquinolin-2-yl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylate

A mixture of 2- ( (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) amino) quinoline-3-carbonitrile (70 mg, 0.20 mmol) , tert-butyl (S) -3-aminopiperidine-1-carboxylate (60 mg, 0.30 mmol) and DIPEA (78mg, 0.60 mmol) in i-PrOH (5 mL) was irradiated in microwave at 140 ℃ for 1 h. The reaction mixture was concentrated to give the crude, which was purified by Prep-TLC (eluent: PE/EtOAc = 2/1) to give tert-butyl (S) -3- ( (4- ( (3-cyanoquinolin-2-yl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (24 mg, yield: 23%) as a yellow solid. ESI-MS [M + H] ⁺: 514.2.

To a mixture of tert-butyl (S) -3- ( (4- ( (3-cyanoquinolin-2-yl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (24 mg, 0.05 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 NH ₃ (7M solution in MeOH, 2.0 mL) and concentrated in vacuo to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 10/1) to give (S) -2- ( (2- (piperidin-3-ylamino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) quinoline-3-carbonitrile (12 mg, yield: 62%) as a white solid.

ESI-MS [M +H] ⁺: 414.2.

1H NMR (400 MHz, MeOD) δ 8.84 –8.68 (m, 1H) , 8.23 (s, 1H) , 7.97 –7.85 (m, 2H) , 7.82 –7.76 (m, 1H) , 7.56 (s, 1H) , 4.11 –3.86 (m, 1H) , 3.09 –2.93 (m, 1H) , 2.69 –2.53 (m, 2H) , 1.99 –1.31 (m, 5H) .

(S) -N4- (1-isobutyl-1H-imidazo [4, 5-c] quinolin-4-yl) -N2- (piperidin-3-yl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine

Synthesis of (S) -N4- (1-isobutyl-1H-imidazo [4, 5-c] quinolin-4-yl) -N2- (piperidin-3-yl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine

Synthesis of N- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -1-isobutyl-1H-imidazo [4, 5-c] quinolin-4-amine

A mixture of 2, 4-dichloro-5- (trifluoromethyl) pyrimidine (405 mg, 1.88 mmol) , 1-isobutyl-1H-imidazo [4, 5-c] quinolin-4-amine (150 mg, 0.62 mmol) and DIPEA (403 mg, 3.12 mmol) in i-PrOH (15 mL) was stirred at 80 ℃ for 16 h. The reaction mixture was concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 15/1) to give N- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -1-isobutyl-1H-imidazo [4, 5-c] quinolin-4-amine (isomer A, 60 mg, yield: 22.9%) as a white solid (ESI-MS [M + H] ⁺: 421.1) and N- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -1-isobutyl-1H-imidazo [4, 5-c] quinolin-4-amine (isomer B, 60 mg, yield: 22.9%) as a white solid (ESI-MS [M + H] ⁺: 421.1) .

Synthesis of tert-butyl (S) -3- ( (4- ( (1-isobutyl-1H-imidazo [4, 5-c] quinolin-4-yl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylate

A mixture N- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -1-isobutyl-1H-imidazo [4, 5-c] quinolin-4-amine (60 mg, 0.14 mmol) , tert-butyl (S) -3-aminopiperidine-1-carboxylate (43 mg, 0.21 mmol) and DIPEA (55 mg, 0.43 mmol) in i-PrOH (5 mL) was irradiated in microwave at 130 ℃ for 1 h. The reaction mixture was concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 15/1) to give tert-butyl (S) -3- ( (4- ( (1-isobutyl-1H-imidazo [4, 5-c] quinolin-4-yl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (49 mg, yield: 58.7%) as a white solid. ESI-MS [M + H] ⁺: 585.3.

To a mixture of tert-butyl (S) -3- ( (4- ( (1-isobutyl-1H-imidazo [4, 5-c] quinolin-4-yl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (49 mg, 0.08 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 NH ₃ (7M solution in MeOH, 2 mL) and concentrated in vacuo to give the crude, which was purified by Prep-TLC (eluent: DCM/NH ₃-MeOH = 15/1) to give (S) -N4- (1-isobutyl-1H-imidazo [4, 5-c] quinolin-4-yl) -N2- (piperidin-3-yl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine (32 mg, yield: 78.8%) as a white solid.

ESI-MS [M +H] ⁺: 485.2.

1H NMR (400 MHz, MeOD) δ 8.34 –8.05 (m, 3H) , 8.04 –7.86 (m, 1H) , 7.69 –7.40 (m, 2H) , 4.42 (d, J = 6.3 Hz, 2H) , 3.08 –2.75 (m, 2H) , 2.61 –2.34 (m, 2H) , 2.32 –2.13 (m, 1H) , 2.02 –1.83 (m, 1H) , 1.82 –1.27 (m, 4H) , 0.94 (d, J = 6.6 Hz, 6H) .

Compound Set C

(S) -N4- (benzo [d] thiazol-2-yl) -N2- (piperidin-3-yl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine

Synthesis of (S) -N4- (benzo [d] thiazol-2-yl) -N2- (piperidin-3-yl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine

Synthesis of N- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) benzo [d] thiazol-2-amine

To a mixture of 2, 4-dichloro-5- (trifluoromethyl) pyrimidine (100 mg, 0.46 mmol) and benzo [d] thiazol-2-amine (68 mg, 0.46 mmol) in DMF (3 mL) was added NaOH (18 mg, 0.46 mmol) at 0 ℃. The reaction mixture was stirred at room temperature for 5 h. 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 Na ₂SO ₄, and concentrated to give the crude product, which was purified by Prep-TLC (eluent: DCM/MeOH = 20/1) to give N- (2-chloro-5-(trifluoromethyl) pyrimidin-4-yl) benzo [d] thiazol-2-amine (70 mg, yield: 46.1%) as a yellow solid. ESI-MS [M +H] ⁺: 331.0.

Synthesis of tert-butyl (S) -3- ( (4- (benzo [d] thiazol-2-ylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylate

A mixture of N- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) benzo [d] thiazol-2-amine (70 mg, 0.21 mmol) , tert-butyl (S) -3-aminopiperidine-1-carboxylate (50 mg, 0.25 mmol) and DIPEA (81 mg, 0.63 mmol) in i-PrOH (6 mL) was irradiated in microwave at 140 ℃ for 1 h. The reaction mixture was concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 20/1) to give tert-butyl (S) -3- ( (4- (benzo [d] thiazol-2-ylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (60 mg, yield: 57.7%) as a white solid. ESI-MS [M + H] ⁺: 495.2.

To a mixture of tert-butyl (S) -3- ( (4- (benzo [d] thiazol-2-ylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (60 mg, 0.12 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 NH ₃ (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 (S) -N4- (benzo [d] thiazol-2-yl) -N2- (piperidin-3-yl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine (27 mg, yield: 45.8%) as a white solid.

ESI-MS [M +H] ⁺: 494.2. Purity: 99.16 (214 nm) , 98.31 (254 nm) .

1H NMR (400 MHz, MeOD) δ 8.22 (s, 1H) , 7.75 –7.65 (m, 1H) , 7.44 –7.37 (m, 1H) , 7.32 (t, J = 7.3 Hz, 1H) , 7.18 (t, J = 7.6 Hz, 1H) , 4.51 –4.27 (m, 1H) , 3.58 –3.42 (m, 1H) , 3.30 –3.23 (m, 1H) , 3.05 –2.86 (m, 2H) , 2.26 –2.12 (m, 1H) , 2.07 –1.95 (m, 1H) , 1.91 –1.78 (m, 1H) , 1.74 –1.58 (m, 1H) .

(S) -N4- (4-methoxybenzo [d] thiazol-2-yl) -N2- (piperidin-3-yl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine

Synthesis of (S) -N4- (4-methoxybenzo [d] thiazol-2-yl) -N2- (piperidin-3-yl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine

Synthesis of N- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -4-methoxybenzo [d] thiazol-2-amine

To a solution of 1H-indole-6-carbonitrile (500 mg, 2.30 mmol) in IPA (4 mL) were added 4-methoxybenzo [d] thiazol-2-amine (415.32 mg, 2.30 mmol) and NaOH (138.26 mg, 3.46 mmol) , the mixture was stirred at RT for 17h. The reaction mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO ₂, EA: PE=0%to 50%) to give N- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -4-methoxybenzo [d] thiazol-2-amine (138 mg, 334.61 μmol, 14.52%yield, 87.47%purity) as a yellow solid.

ESI-MS [M+H] ⁺: 361.20.

Synthesis of tert-butyl (S) -3- ( (4- ( (4-methoxybenzo [d] thiazol-2-yl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylate

To a solution of N- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -4-methoxybenzo [d] thiazol-2-amine (110 mg, 304.93 μmol) in IPA (2 mL) were added tert-butyl (S) -3-aminopiperidine-1-carboxylate (91.60 mg, 457.39 μmol) and DIPEA (78.82 mg, 609.85 μmol, 106.22 μL) , the mixture was stirred at 85℃ for 8h. The reaction mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO ₂, EA: PE=0%to 60%) to give tert-butyl (S) -3- ( (4- ( (4-methoxybenzo [d] thiazol-2-yl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (122 mg, 231.58 μmol, 75.94%yield, 99.57%purity) as a yellow solid.

ESI-MS [M+H] ⁺: 525.36.

To a solution of tert-butyl (S) -3- ( (4- ( (4-methoxybenzo [d] thiazol-2-yl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (122 mg, 232.58 μmol) in MeOH (5 mL) was added HCl (3 M in EA, 5 mL) , the mixture was stirred at RT for 4h. The reaction mixture was concentrated in vacuo to give a crude, which was dissolved in MeOH and quenched with NH ₃ (7M in MeOH, 5 mL) and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO ₂, 0.5M ammonia methanol solution: DCM=0%to 15%) to give (S) -N4- (4-methoxybenzo [d] thiazol-2-yl) -N2- (piperidin-3-yl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine (97 mg, 226.75 μmol, 97.50%yield, 99.22%purity) as an off-white solid.

ESI-MS [M+H] ⁺: 425.33.

¹H NMR ( (400 MHz, DMSO) δ8.26 (s, 1H) , 7.66 (s, 1H) , 7.42-7.27 (m, 2H) , 7.20-7.16 (t, 1H) , 7.02-6.98 (t, 1H) , 4.46 (s, 1H) , 4.27 (s, 1H) , 3.39 (s, 3H) , 3.20 (s, 1H) , 2.89 (s, 2H) , 2.19-2.17 (m, 1H) 2.03-1.98 (m, 1H) , 1.91-1.88 (m, 3H)

(S) -N4- (5, 6-dichlorobenzo [d] thiazol-2-yl) -N2- (piperidin-3-yl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine

Synthesis of (S) -N4- (5, 6-dichlorobenzo [d] thiazol-2-yl) -N2- (piperidin-3-yl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine

Synthesis of 5, 6-dichloro-N- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) benzo [d] thiazol-2-amine

To a mixture of 2, 4-dichloro-5- (trifluoromethyl) pyrimidine (447 mg, 2.07 mmol) and 5, 6-dichlorobenzo [d] thiazol-2-amine (300 mg, 1.38 mmol) in DMF (10 mL) was added NaOH (55 mg, 1.38 mmol) at 0 ℃. The reaction mixture was stirred at room temperature for 5 h. 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 Na ₂SO ₄, and concentrated to give the crude product, which was Prep-TLC (eluent: DCM/MeOH = 20/1) to give 5, 6-dichloro-N- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) benzo [d] thiazol-2-amine (180 mg, yield: 32.8%) as a yellow solid. ESI-MS [M +H] ⁺: 399.1.

Synthesis of tert-butyl (S) -3- ( (4- ( (5, 6-dichlorobenzo [d] thiazol-2-yl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylate

A mixture of 5, 6-dichloro-N- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) benzo [d] thiazol-2-amine (180 mg, 0.45 mmol) , tert-butyl (S) -3-aminopiperidine-1-carboxylate (108 mg, 0.54 mmol) and DIPEA (174 mg, 1.35 mmol) in i-PrOH (8 mL) was irradiated in microwave at 130 ℃ for 2 h. The reaction mixture was concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 20/1) to give tert-butyl (S) -3- ( (4- ( (5, 6-dichlorobenzo [d] thiazol-2-yl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (80 mg, yield: 31.6%) as a white solid. ESI-MS [M + H] ⁺: 563.1.

To a mixture of tert-butyl (S) -3- ( (4- ( (5, 6-dichlorobenzo [d] thiazol-2-yl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (80 mg, 0.14 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 NH ₃ (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 (S) -N4- (5, 6-dichlorobenzo [d] thiazol-2-yl) -N2- (piperidin-3-yl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine (51.4 mg, yield: 79.5%) as a white solid.

ESI-MS [M +H] ⁺: 463.1. Purity: 96.88 (214 nm) , 96.73 (254 nm) .

1H NMR (400 MHz, MeOD) δ 8.34 (s, 1H) , 8.02 (s, 1H) , 7.74 (s, 1H) , 4.51 –4.30 (m, 1H) , 3.62 –3.46 (m, 1H) , 3.31 –3.23 (m, 1H) , 3.00 –2.84 (m, 2H) , 2.34 –2.17 (m, 1H) , 2.10 –1.99 (m, 1H) , 1.99 –1.82 (m, 1H) , 1.80 –1.62 (m, 1H) .

(S) -N2- (piperidin-3-yl) -5- (trifluoromethyl) -N4- (5- (trifluoromethyl) benzo [d] thiazol-2-yl) pyrimidine-2, 4-diamine

Synthesis of (S) -N2- (piperidin-3-yl) -5- (trifluoromethyl) -N4- (5- (trifluoromethyl) benzo [d] thiazol-2-yl) pyrimidine-2, 4-diamine

Synthesis of N- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -5- (trifluoromethyl) benzo [d] thiazol-2-amine

A mixture of 2, 4-dichloro-5- (trifluoromethyl) pyrimidine (300 mg, 1.39 mmol) , 5- (trifluoromethyl) benzo [d] thiazol-2-amine (240 mg, 1.1 mmol) and NaOH (44 mg, 1.1 mmol) in DMF (5 mL) was stirred at room temperature for 6 h. The reaction mixture was diluted with H ₂O (50 mL) and extracted with EtOAc (30 mL x 3) . The combined organic layers were washed with brine (50 mL) , dried over anhydrous Na ₂SO ₄, and concentrated in vacuo to give the crude, which was purified by Prep-TLC (eluent: PE/EtOAc = 3/1) to give N- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -5- (trifluoromethyl) benzo [d] thiazol-2-amine (200 mg, yield: 36%) as a white solid. ESI-MS [M + H] ⁺: 399.2.

Synthesis of tert-butyl (S) -3- ( (5- (trifluoromethyl) -4- ( (5- (trifluoromethyl) benzo [d] thiazol-2-yl) amino) pyrimidin-2-yl) amino) piperidine-1-carboxylate

A mixture of N- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -5- (trifluoromethyl) benzo [d] thiazol-2-amine (80 mg, 0.2 mmol) , tert-butyl (S) -3-aminopiperidine-1-carboxylate (60 mg, 0.3 mmol) and DIPEA (77 mg, 0.6 mmol) in i-PrOH (6 mL) was irradiated in microwave at 100 ℃℃ for 1 h. The reaction mixture was concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 20/1) to give tert-butyl (S) -3- ( (5- (trifluoromethyl) -4- ( (5- (trifluoromethyl) benzo [d] thiazol-2-yl) amino) pyrimidin-2-yl) amino) piperidine-1-carboxylate (70 mg, yield: 62%) as a white solid. ESI-MS [M + H] ⁺: 563.2.

To a mixture of tert-butyl (S) -3- ( (5- (trifluoromethyl) -4- ( (5- (trifluoromethyl) benzo [d] thiazol-2-yl) amino) pyrimidin-2-yl) amino) piperidine-1-carboxylate (70 mg, 0.12 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 NH ₃ (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 (S) -N2- (piperidin-3-yl) -5- (trifluoromethyl) -N4- (5- (trifluoromethyl) benzo [d] thiazol-2-yl) pyrimidine-2, 4-diamine (40 mg, yield: 72%) as a white solid.

ESI-MS [M +H] ⁺: 463.1. Purity: 100.00 (214 nm) , 99.6 (254 nm) .

¹H NMR (400 MHz, MeOD) δ 8.24 (s, 1H) , 7.98 (d, J = 8.1 Hz, 1H) , 7.83 (s, 1H) , 7.47 (d, J = 8.1 Hz, 1H) , 4.32 (s, 1H) , 3.39 –3.36 (m, 1H) , 3.08 (d, J = 12.0 Hz, 1H) , 2.76 –2.66 (m, 2H) , 2.24 –2.21 (m, 1H) , 1.94 –1.72 (m, 2H) , 1.62 –1.56 (m, 1H) .

(S) -N4- (benzo [d] thiazol-2-yl) -N2- (6, 6-dimethylpiperidin-3-yl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine

Synthesis of (S) -N4- (benzo [d] thiazol-2-yl) -N2- (6, 6-dimethylpiperidin-3-yl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine

To an ice-cooled solution of benzo [d] thiazol-2-amine (449.96 mg, 3.00 mmol) in DMF (10ml) under nitrogen was added sodium hydride and the mixture was stirred for 15 minutes. A solution of 2, 4-dichloro-5- (trifluoromethyl) pyrimidine (500 mg, 2.30 mmol) in DMF was added and the mixture allowed to stir and slowly warm to rt. After 3 hours the mixture was treated with saturated aqueous ammonium chloride and EA. The organic phase was dried over magnesium sulfate, filtered, and evaporated to dryness. Purification by flash chromatography to afford the N- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) benzo [d] thiazol-2-amine (250.32 mg, 726.63 μmol, 31.53%yield, 96%purity) as a white solid. ESI-MS [M +H] +: 331.23.

To a solution of N- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) benzo [d] thiazol-2-amine (100 mg, 300.54 μmol) in NMP (2.40 mL) was added (S) -6, 6-dimethylpiperidin-3-amine (42.39 mg, 330.60 μmol) and DIPEA (77.68 mg, 601.09 μmol, 104.70 μL) , then stirred at 130 ℃ for 8 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 (S) - N4- (benzo [d] thiazol-2-yl) -N2- (6, 6-dimethylpiperidin-3-yl) -5- (trifluoromethyl) pyrimidine- 2, 4-diamine (58.6 mg, 132.53 μmol, 44.10%yield, 96%purity) as a white solid. ESI-MS [M+H] +: 423.36. ¹H-NMR (400 MHz, MeOD) δ 8.21 (s, 1H) , 7.75 –7.61 (m, 1H) , 7.40 (d, J = 8.1 Hz, 1H) , 7.31 (ddd, J = 8.2, 7.3, 1.2 Hz, 1H) , 7.17 (td, J = 7.6, 1.2 Hz, 1H) , 4.54 –4.15 (m, 1H) , 3.36 (ddd, J = 13.8, 7.5, 5.3 Hz, 1H) , 1.83 (m, 1H) , 1.39 (d, J = 6.8 Hz, 6H) , 1.24 (m, 1H) , 1.20 (m, 1H) , 1.18 (m, 2H) .

(S) -N4- (5-methoxybenzo [d] thiazol-2-yl) -N2- (piperidin-3-yl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine

Synthesis of (S) -N4- (5-methoxybenzo [d] thiazol-2-yl) -N2- (piperidin-3-yl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine

Synthesis of N- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -5-methoxybenzo [d] thiazol-2-amine

To a solution of 1H-indole-6-carbonitrile (500 mg, 2.30 mmol) in DMF (5 mL) were added 5-methoxybenzo [d] thiazol-2-amine (415.32 mg, 2.30 mmol) and NaOH (138.26 mg, 3.46 mmol) , the mixture was stirred at RT for 17h. The reaction was poured into water (30ml) , extracted with EA (30ml*2) , the organic layer was washed with brine (30ml*2) , dried over Na ₂SO ₄, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO ₂, EA: PE=0%to 35%) to give N- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -5-methoxybenzo [d] thiazol-2-amine (127 mg, 314.42 μmol, 13.64%yield, 89.31%purity) as a yellow solid.

ESI-MS [M+H] ⁺: 361.16.

Synthesis of tert-butyl (S) -3- ( (4- ( (5-methoxybenzo [d] thiazol-2-yl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylate

To a solution of N- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -5-methoxybenzo [d] thiazol-2-amine (127 mg, 352.05 μmol) in IPA (2 mL) were added tert-butyl (S) -3-aminopiperidine-1-carboxylate (105.76 mg, 528.08 μmol) and DIPEA (91.00 mg, 704.10 μmol, 122.64 μL) , the mixture was stirred at 85℃ for 8h. The reaction mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO ₂, EA: PE=0%to 50%) to give tert-butyl (S) -3- ( (4- ( (5-methoxybenzo [d] thiazol-2-yl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (86 mg, 163.26 μmol, 46.37%yield, 99.58%purity) as a yellow solid.

ESI-MS [M+H] ⁺: 525.41.

To a solution of tert-butyl (S) -3- ( (4- ( (5-methoxybenzo [d] thiazol-2-yl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (86 mg, 163.95 μmol) in MeOH (5 mL) was added HCl (3 M in EA, 5 mL) , the mixture was stirred at RT for 4h. The reaction mixture was concentrated in vacuo to give a crude, which was dissolved in MeOH and quenched with NH ₃ (7M in MeOH, 5 mL) and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO2, 0.5M ammonia methanol solution: DCM=0%to 15%) to give (S) -N4- (5-methoxybenzo [d] thiazol-2-yl) -N2- (piperidin-3-yl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine (46 mg, 107.69 μmol, 65.69%yield, 99.37%purity) as an off-white solid.

ESI-MS [M+H] ⁺: 425.30.

¹H NMR (400 MHz, MeOD) δ8.14 (s, 1H) , 7.57 (s, 1H) , 6.97-6.96 (d, 1H) , 6.80-6.77 (dd, 1H) , 4.20 (s, 1H) , 3.75 (s, 3H) , 3.25-3.21 (m, 1H) , 2.95-2.92 (d, 1H) , 2.61-2.52 (m, 2H) , 2.11-2.07 (m, 1H) , 1.79-1.73 (m, 1H) , 1.66 (s, 1H) , 1.48 (m, 1H)

(S) -N4- (6-methoxybenzo [d] thiazol-2-yl) -N2- (piperidin-3-yl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine

Synthesis of (S) -N4- (6-methoxybenzo [d] thiazol-2-yl) -N2- (piperidin-3-yl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine

Synthesis of N- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -6-methoxybenzo [d] thiazol-2-amine

To a solution of 1H-indole-6-carbonitrile (500 mg, 2.30 mmol) in IPA (10 mL) were added 6-methoxybenzo [d] thiazol-2-amine (415.31 mg, 2.30 mmol) and NaOH (138.26 mg, 3.46 mmol) , the mixture was stirred at RT for 17h. The reaction mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO ₂, EA: PE=0%to 35%) to give N- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -6-methoxybenzo [d] thiazol-2-amine (145 mg, 320.55 μmol, 13.91%yield, 79.75%purity) as a yellow solid.

ESI-MS [M+H] ⁺: 361.20.

To a solution of N- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -6-methoxybenzo [d] thiazol-2-amine (145 mg, 401.95 μmol) in IPA (2 mL) were added tert-butyl (S) -3-aminopiperidine-1-carboxylate (120.75 mg, 602.92 μmol) and DIPEA (103.90 mg, 803.90 μmol, 140.02 μL) , the mixture was stirred at 85℃ for 8h. The reaction mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO ₂, EA: PE=0%to 50%) to give (S) -N4- (6-methoxybenzo [d] thiazol-2-yl) -N2- (piperidin-3-yl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine (80 mg, 152.40 μmol, 37.92%yield, 99.93%purity) as a yellow solid.

ESI-MS [M+H] ⁺: 525.38.

To a solution of tert-butyl (S) -3- ( (4- ( (6-methoxybenzo [d] thiazol-2-yl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (80 mg, 152.51 μmol) in MeOH (10 mL) was added HCl (3 M in EA, 5 mL) , the mixture was stirred at RT for 4h. The reaction mixture was concentrated in vacuo to give a crude, which was dissolved in MeOH and quenched with NH ₃ (7M in MeOH, 5 mL) and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO2, 0.5M ammonia methanol solution: DCM=0%to 15%) to give (S) -N4- (6-methoxybenzo [d] thiazol-2-yl) -N2- (piperidin-3-yl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine (31 mg, 58.90 μmol, 38.62%yield, 99.66%purity) as an off-white solid.

ESI-MS [M+H] ⁺: 425.32.

¹H NMR (400 MHz, MeOD) δ8.15 (s, 1H) , 7.38-7.36 (d, 2H) , 6.93-6.91 (dd, 1H) , 4.21 (s, 1H) , 3.76 (s, 3H) , 3.27 (s, 1H) , 2.97-2.94 (d, 1H) , 2.62-2.53 (m, 2H) , 2.11-2.07 (m, 1H) , 1.80-1.74 (m, 1H) , 1.68 (s, 1H) , 1.49 (s, 1H)

N4- (1, 3-benzoxazol-2-yl) -N2- [ (3S) -piperidin-3-yl] -5- (trifluoromethyl) pyrimidine-2, 4-diamine trifluoroacetic acid salt

Synthesis of N4- (1, 3-benzoxazol-2-yl) -N2- [ (3S) -piperidin-3-yl] -5- (trifluoromethyl) pyrimidine-2, 4-diamine trifluoroacetic acid salt

Synthesis of tert-butyl (3S) -3- { [4- (1, 3-benzoxazol-2-ylamino) -5- (trifluoromethyl) pyrimidin-2-yl] amino} piperidine-1-carboxylate

A 100 mL round bottom flask was charged with tert-butyl (3S) -3- { [4-chloro-5- (trifluoromethyl) pyrimidin-2-yl] amino} piperidine-1-carboxylate (100 mg, 0.263 mmol, 1.00 equiv) , benzo [d] oxazol-2-amine (42.3 mg, 0.316 mmol, 1.20 equiv) , cesium carbonate (257 mg, 0.789 mmol, 3.00 equiv) , XPhos (25.0 mg, 0.053 mmol, 0.20 equiv) , Pd ₂ (dba) ₃ (24.1 mg, 0.026 mmol, 0.10 equiv) and DMF (25 mL) . The resulting mixture was stirred for 16 h at 100 ℃ under nitrogen atmosphere and quenched with water (80 mL) . The mixture was extracted with ethyl acetate (3 x 100 mL) . The organic layers were combined, washed with saturated sodium chloride solution (3 x 50 mL) , dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by Prep-TLC (ethyl acetate /petroleum = 3/2) to afford tert-butyl (3S) -3- { [4- (1, 3-benzoxazol-2-ylamino) -5- (trifluoromethyl) pyrimidin-2-yl] amino} piperidine-1-carboxylate (103 mg, 82%yield) as a yellow solid. LCMS (ESI, m/z) : 479 [M+H] ⁺.

A 100 mL round bottom flask was charged with tert-butyl (3S) -3- { [4- (1, 3-benzoxazol-2-ylamino) -5- (trifluoromethyl) pyrimidin-2-yl] amino} piperidine-1-carboxylate (90.0 mg, 0.188 mmol, 1.00 equiv) , dichloromethane (30 mL) and trifluoroacetic acid (6 mL) . The resulting solution was stirred for 2 h at room temperature and concentrated under reduced pressure to the crude product. The crude product was purified by Prep-HPLC with the following conditions: Column: Xselect CSH C ₁₈ OBD Column 30*150mm 5μm; Mobile Phase A: Water (0.05%TFA ) , Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 12%B to 42%B in 7 min; Wave Length: 220 nm to afford N4- (1, 3-benzoxazol-2-yl) -N2- [ (3S) -piperidin-3-yl] -5- (trifluoromethyl) pyrimidine-2, 4-diamine trifluoroacetic acid salt (17.9 mg, 19%yield) as a white solid. LCMS (ESI, m/z) : 379 [M+H-TFA] ⁺. ¹H NMR (300 MHz, DMSO-d ₆) δ 12.55 (s, 1H) , 8.71 (s, 2H) , 8.38 (s, 1H) , 7.74 (d, J = 6.2 Hz, 1H) , 7.53 (d, J = 7.8 Hz, 1H) , 7.44 (d, J = 7.7 Hz, 1H) , 7.36 -7.24 (m, 2H) , 4.24 -4.10 (m, 2H) , 3.44 (d, J = 9.9 Hz, 1H) , 3.17 (d, J = 10.2 Hz, 1H) , 3.04 -2.72 (m, 2H) , 2.09 (d, J = 8.2 Hz, 1H) , 1.94 (d, J = 8.8 Hz, 1H) , 1.83 -1.51 (m, 2H) .

Compound Set D

(S) -N- (4- (7-methoxy-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) azepan-3-amine

Synthesis of (S) -N- (4- (7-methoxy-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) azepan-3-amine

Synthesis of 3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -7-methoxy-1H-indole

To a mixture of 2, 4-dichloro-5- (trifluoromethyl) pyrimidine (500 mg, 2.31 mmol) in DCE (20 mL) was added AlCl ₃ (305 mg, 2.54 mmol) . The mixture was stirred at 90 ℃ for 0.5 h under N ₂. Then 7-methoxy-1H-indole (171 mg, 1.16 mmol) was added. The reaction mixture was stirred at 90 ℃ for another 3 h. The reaction was quenched with MeOH (20 mL) and water (10 mL) . The mixture was filtered. The filter cake was washed with MeOH (10 mL) and dried to give the product 3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -7-methoxy-1H-indole (100 mg, yield: 13.2%) as a yellow solid, which was used in the next step without further purification. ESI-MS [M +H] ⁺: 328.1.

Synthesis of tert-butyl (S) -3- ( (4- (7-methoxy-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) azepane-1-carboxylate

A mixture of 3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -7-methoxy-1H-indole (70 mg, 0.21 mmol) , tert-butyl (S) -3-aminoazepane-1-carboxylate (68 mg, 0.32 mmol) and DIPEA (81 mg, 0.63 mmol) in i-PrOH (8 mL) was irradiated in microwave at 140 ℃ for 1 h. The reaction mixture was concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 15/1) to give tert-butyl (S) -3- ( (4- (7-methoxy-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) azepane-1-carboxylate (40 mg, yield: 38%) as a white solid. ESI-MS [M + H] ⁺: 506.2.

To a mixture of tert-butyl (S) -3- ( (4- (7-methoxy-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) azepane-1-carboxylate (40 mg, 0.079 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 NH ₃ (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 (S) -N- (4- (7-methoxy-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) azepan-3-amine (25 mg, yield: 78%) as a white solid.

ESI-MS [M +H] ⁺: 406.2.

¹H NMR (400 MHz, MeOD) δ 8.52 (s, 1H) , 7.88 (s, 1H) , 7.77 (s, 1H) , 7.12 (t, J = 7.9 Hz, 1H) , 6.77 (d, J = 7.7 Hz, 1H) , 4.38 –4.22 (m, 1H) , 4.01 (s, 3H) , 3.31 –3.22 (m, 1H) , 3.06 –2.95 (m, 3H) , 2.15 –2.13 (m, 1H) , 1.95 –1.59 (m, 5H) .

(S) -N- (4- (6, 7-dichloro-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) azepan-3-amine

Synthesis of (S) -N- (4- (6, 7-dichloro-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) azepan-3-amine

Synthesis of 6, 7-dichloro-3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole

To a mixture of 2, 4-dichloro-5- (trifluoromethyl) pyrimidine (933 mg, 4.32 mmol) in DCE (30 mL) was added AlCl ₃ (604 mg, 4.54 mmol) . The mixture was stirred at 90 ℃ for 0.5 h under N ₂. Then 6, 7-dichloro-1H-indole (400 mg, 2.16 mmol) was added. The reaction mixture was stirred at 90℃ for another 3 h. The reaction was quenched with MeOH (20 mL) and water (15 mL) . The mixture was filtered. The filter cake was washed with MeOH (10 mL) and dried to give the product 6, 7-dichloro-3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole (200 mg, yield: 25.4%) as a yellow solid, which was used in the next step without further purification. ESI-MS [M +H] ⁺: 366.2.

Synthesis of tert-butyl (S) -3- ( (4- (6, 7-dichloro-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) azepane-1-carboxylate

A mixture of 6, 7-dichloro-3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole (200 mg, 0.55 mmol) , tert-butyl (S) -3-aminoazepane-1-carboxylate (141 mg, 0.66 mmol) and DIPEA (213 mg, 1.65 mmol) in i-PrOH (12 mL) was irradiated in microwave at 100 ℃ for 1 h. The reaction mixture was concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 20/1) to give tert-butyl (S) -3- ( (4- (6, 7-dichloro-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) azepane-1-carboxylate (50 mg, yield: 16.7%) as a white solid. ESI-MS [M + H] ⁺: 544.1.

To a mixture of tert-butyl (S) -3- ( (4- (6, 7-dichloro-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) azepane-1-carboxylate (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 1 h. The reaction mixture was quenched with NH ₃ (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 (S) -N- (4- (6, 7-dichloro-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) azepan-3-amine (16.4 mg, yield: 41%) as a white solid.

ESI-MS [M +H] ⁺: 444.1.

1H NMR (400 MHz, MeOD) δ 8.47 (s, 1H) , 8.29 –7.97 (m, 1H) , 7.77 (s, 1H) , 7.30 –7.08 (m, 1H) , 4.32 –4.10 (m, 1H) , 3.28 –3.23 (m, 1H) , 3.08 –2.80 (m, 3H) , 2.15 –1.97 (m, 1H) , 1.88 –1.63 (m, 3H) , 1.63 –1.48 (m, 1H) , 1.28 –1.14 (m, 1H) .

(S) -3- (2- (azepan-3-ylamino) -5- (trifluoromethyl) pyrimidin-4-yl) -7- (dimethylphosphoryl) -1H-indole-6-carbonitrile

Synthesis of (S) -3- (2- (azepan-3-ylamino) -5- (trifluoromethyl) pyrimidin-4-yl) -7- (dimethylphosphoryl) -1H-indole-6-carbonitrile

Synthesis of 7-chloro-1H-indole-6-carbonitrile

To a mixture of 2-chloro-3-nitrobenzonitrile (400 mg, 2.2 mmol) in THF (10 mL) was added vinylmagnesium bromide (11 mL, 11.0 mmol) at -78℃ under nitrogen. The mixture was stirred at -78℃ for 2 h under N ₂. The reaction was quenched with water (30 mL) and extracted with EtOAc (30 mL x 3) . The combined organic layers were washed with brine, dried with Na ₂SO ₄, concentrated in vacuo to give the crude, which was purified by column chromatography (eluent: DCM/MeOH = 30/1) to give 7-chloro-1H-indole-6-carbonitrile (120 mg, yield: 31%) as a yellow solid. ESI-MS [M +H] ⁺: 177.2.

Synthesis of 7-chloro-3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carbonitrile

To a mixture of 2, 4-dichloro-5- (trifluoromethyl) pyrimidine (247 mg, 1.14 mmol) in DCE (10 mL) was added AlCl ₃ (158 mg, 1.2 mmol) . The mixture was stirred at 85℃ for 0.5 h under N ₂. Then 7-chloro-1H-indole-6-carbonitrile (100 mg, 0.57 mmol) was added. The reaction mixture was stirred at 85℃ for another 12 h. The reaction was quenched with MeOH (10 mL) and water (10 mL) . The mixture was filtered. The filter cake was washed with MeOH (10 mL) and dried to give the product 7-chloro-3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carbonitrile (30 mg, crude) as a yellow solid, which was used in the next step without further purification. ESI-MS [M +H] ⁺: 357.2.

Synthesis of tert-butyl (S) -3- ( (4- (7-chloro-6-cyano-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) azepane-1-carboxylate

A mixture of 7-chloro-3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carbonitrile (80 mg, 0.22 mmol) , tert-butyl (S) -3-aminoazepane-1-carboxylate (94 mg, 0.44 mmol) and DIPEA (85 mg, 0.66 mmol) in i-PrOH (8 mL) was irradiated in microwave at 90℃ for 1 h. The reaction mixture was concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 15/1) to give tert-butyl (S) -3- ( (4- (7-chloro-6-cyano-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) azepane-1-carboxylate (60 mg, yield: 51%) as a white solid. ESI-MS [M + H] ⁺: 535.2.

Synthesis of tert-butyl (S) -3- ( (4- (6-cyano-7- (dimethylphosphoryl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) azepane-1-carboxylate

A mixture of tert-butyl (S) -3- ( (4- (7-chloro-6-cyano-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) azepane-1-carboxylate (80 mg, 0.16 mmol) , dimethylphosphine oxide (64 mg, 0.8 mmol) , Pd (OAc) ₂ (1.6 mg, 0.016 mmol) , Xantphos (8 mg, 0.016 mmol) and K ₃PO ₄ (64 mg, 0.32 mmol) in DMF (3 mL) was irradiated in microwave at 120℃ for 2h under nitrogen. The reaction was quenched with water (50 mL) and extracted with EtOAc (30 mL x 3) . The combined organic layers were washed with brine, dried with Na ₂SO ₄, and concentrated in vacuo to give the crude, which was purified by column chromatography (eluent: DCM/MeOH = 30/1) to give tert-butyl (S) -3- ( (4- (6-cyano-7- (dimethylphosphoryl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) azepane-1-carboxylate (40 mg, crude) as a yellow solid. ESI-MS [M + H] ⁺: 577.2.

To a mixture of tert-butyl (S) -3- ( (4- (6-cyano-7- (dimethylphosphoryl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) azepane-1-carboxylate (25 mg, 0.043 mmol) in DCM (5 mL) was added TFA (0.5 mL) . The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was quenched with NaHCO ₃ (Sat. aq., 20 mL) and extracted with DCM (20 mL x 3) . The combined organic layers were washed with brine, dried with Na ₂SO ₄, and concentrated in vacuo to give the crude, which was purified with combi flash chromatography (eluent: DCM/MeOH = 10/1) to give (S) -3- (2- (azepan-3-ylamino) -5- (trifluoromethyl) pyrimidin-4-yl) -7- (dimethylphosphoryl) -1H-indole-6-carbonitrile (15 mg, yield: 73%) as a white solid.

ESI-MS [M +H] ⁺: 477.2.

¹H NMR (400 MHz, MeOD) δ 8.76 –8.56 (m, 2H) , 8.20 (s, 1H) , 7.68 (s, 1H) , 4.30 (s, 1H) , 3.28 –3.25 (m, 1H) , 2.98 (s, 3H) , 2.15 (d, J = 13.7 Hz, 7H) , 1.82 –1.54 (m, 5H) .

(S) -N- (4- (7-bromo-6-methoxy-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) azepan-3-amine

Synthesis of (S) -N- (4- (7-bromo-6-methoxy-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) azepan-3-amine

Synthesis of 7-bromo-6-methoxy-1H-indole

To a mixture of 2-bromo-1-methoxy-3-nitrobenzene (1.5 g, 6.49 mmol) in THF (30 mL) was added vinylmagnesium bromide (1M solution in THF, 32.5 mL, 32.5 mmol) at -78 ℃. The mixture was stirred at -78 ℃ for 2 h under N ₂. The reaction was quenched with NH ₄Cl solution (50 mL) and extracted with EtOAc (30 mL x 3) . The combined organic layers were washed with brine (50 mL) , dried over anhydrous Na ₂SO ₄, and concentrated in vacuo to give the crude, which was purified by Prep-TLC (eluent: PE/EtOAc = 20/1) to give the product 7-bromo-6-methoxy-1H-indole (480 mg, yield: 32.9%) as a yellow solid. ESI-MS [M +H] ⁺: 226.1.

Synthesis of 7-bromo-3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -6-methoxy-1H-indole

To a mixture of 2, 4-dichloro-5- (trifluoromethyl) pyrimidine (480 mg, 2.22 mmol) in DCE (20 mL) was added AlCl ₃ (310 mg, 2.33 mmol) . The mixture was stirred at 90 ℃ for 0.5 h under N ₂. Then 7-bromo-6-methoxy-1H-indole (250 mg, 1.11 mmol) was added. The reaction mixture was stirred at 90℃ for another 3 h. The reaction was quenched with MeOH (20 mL) and water (15 mL) . The mixture was filtered. The filter cake was washed with MeOH (10 mL) and dried to give the product 7-bromo-3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -6-methoxy-1H-indole (70 mg, yield: 15.6%) as a yellow solid. ESI-MS [M +H] ⁺: 406.1.

Synthesis of tert-butyl (S) -3- ( (4- (7-bromo-6-methoxy-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) azepane-1-carboxylate

A mixture of 7-bromo-3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -6-methoxy-1H-indole (70 mg, 0.17 mmol) , tert-butyl (S) -3-aminoazepane-1-carboxylate (43 mg, 0.20 mmol) and DIPEA (66 mg, 0.51 mmol) in i-PrOH (6 mL) was irradiated in microwave at 100 ℃ for 1 h. The reaction mixture was concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 20/1) to give tert-butyl (S) -3- ( (4- (7-bromo-6-methoxy-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) azepane-1-carboxylate (50 mg, yield: 50.5%) as a white solid. ESI-MS [M + H] ⁺: 584.1.

To a mixture of tert-butyl (S) -3- ( (4- (7-bromo-6-methoxy-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) azepane-1-carboxylate (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 1 h. The reaction mixture was quenched with NH ₃ (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 (S) -N- (4- (7-bromo-6-methoxy-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) azepan-3-amine (26.7 mg, yield: 61.4%) as a white solid.

ESI-MS [M +H] ⁺: 484.1.

1H NMR (400 MHz, MeOD) δ 8.46 –8.34 (m, 1H) , 8.23 –8.07 (m, 1H) , 7.73 –7.62 (m, 1H) , 7.00 –6.81 (m, 1H) , 4.31 –4.07 (m, 1H) , 3.84 (s, 3H) , 3.16 –2.98 (m, 1H) , 2.92 –2.66 (m, 3H) , 2.11 –1.89 (m, 1H) , 1.82 –1.44 (m, 5H) .

(S) -N- (4- (6, 7-dimethoxy-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) azepan-3-amine

Synthesis of (S) -N- (4- (6, 7-dimethoxy-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) azepan-3-amine

Synthesis of 3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -6, 7-dimethoxy-1H-indole

To a mixture of 2, 4-dichloro-5- (trifluoromethyl) pyrimidine (386 mg, 1.79 mmol) in DCE (10 mL) was added AlCl ₃ (247 mg, 1.87 mmol) . The mixture was stirred at 90 ℃ for 0.5 h under N ₂.Then 6, 7-dimethoxy-1H-indole (150 mg, 0.85 mmol) was added. The reaction mixture was stirred at 90℃ for another 16 h. The reaction was quenched with MeOH (10 mL) and water (10 mL) . The mixture was filtered. The filter cake was washed with MeOH (10 mL) and dried to give the product 3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -6, 7-dimethoxy-1H-indole (30 mg, crude) as a yellow solid, which was used in the next step without further purification. ESI-MS [M +H] ⁺: 358.2.

Synthesis of tert-butyl (S) -3- ( (4- (6, 7-dimethoxy-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) azepane-1-carboxylate

A mixture of 3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -6, 7-dimethoxy-1H-indole (30 mg, 0.084 mmol) , tert-butyl (S) -3-aminoazepane-1-carboxylate (135 mg, 0.25 mmol) and DIPEA (32 mg, 0.25 mmol) in i-PrOH (4 mL) was irradiated in microwave at 80 ℃ for 1 h. The reaction mixture was concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 20/1) to give tert-butyl (S) -3- ( (4- (6, 7-dimethoxy-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) azepane-1-carboxylate (25 mg, yield: 56%) as a yellow solid. ESI-MS [M + H] ⁺: 536.2.

To a mixture of tert-butyl (S) -3- ( (4- (6, 7-dimethoxy-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) azepane-1-carboxylate (25 mg, 0.047 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 NH ₃ (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 (S) -N- (4- (6, 7-dimethoxy-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) azepan-3-amine (15 mg, yield: 73%) as a white solid.

ESI-MS [M +H] ⁺: 436.2

1H NMR (400 MHz, MeOD) δ 8.48 (s, 1H) , 8.03 (s, 1H) , 7.77 (s, 1H) , 7.00 (d, J = 8.5 Hz, 1H) , 4.36 –4.24 (m, 1H) , 4.00 (s, 3H) , 3.95 (s, 3H) , 3.22 (d, J = 12.6 Hz, 1H) , 2.96 –2.88 (m, 3H) , 2.18 –2.08 (m, 1H) , 1.89 –1.64 (m, 5H) .

(3S) -N- {4- [6- (1H-pyrazol-4-yl) -1H-indol-3-yl] -5- (trifluoromethyl) pyrimidin-2-yl} azepan-3-amine

Synthesis of (3S) -N- {4- [6- (1H-pyrazol-4-yl) -1H-indol-3-yl] -5- (trifluoromethyl) pyrimidin-2-yl} azepan-3-amine

Synthesis of 6-bromo-3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole

A solution of 2, 4-dichloro-5- (trifluoromethyl) pyrimidine (8.30 g, 38.3 mmol, 1.50 equiv) in dichloroethane (30 mL) was treated with aluminnium chlorolide (5.10 g, 38.3 mmol, 1.50 equiv) for 0.5 h at 80 ℃ under nitrogen atmosphere. Then 6-bromo-1H-indole (5.00 g, 25.5 mmol, 1.00 equiv) in dichloroethane (20 mL) was added dropwise to above mixture at 80 ℃. The final reaction mixture was stirred for overnight at 80 ℃ and quenched with water (50 mL) . The resulting mixture was extracted with ethyl acetate (2 x 100 mL) . The combined organic layers were washed with water (2 x 50 mL) , dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions: column, C ₁₈ column; mobile phase, Acetonitrile in Water (0.1% TFA) , 10%to 50%gradient in 20 min; detector, UV 254 nm to afford 6-bromo-3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole (4.20 g, 44%yield) as a yellow solid. LCMS (ESI, m/z) : 376 [M+H] ⁺.

Synthesis of tert-butyl (S) -3- ( (4- (6-bromo-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) azepane-1-carboxylate

To a solution of 6-bromo-3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole (1 g, 2.66 mmol) in NMP (10 mL) was added tert-butyl (S) -3-aminoazepane-1-carboxylate (597.57 mg, 2.79 mmol) and DIPEA (686.43 mg, 5.31 mmol, 925.10 μL) , then stirred at 70 ℃ 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, filtered, and concentrated to give a residue. The residue purified by column chromatography to give tert-butyl (S) -3- ( (4- (6-bromo-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) azepane-1-carboxylate (756.3 mg, 1.31 mmol, 49.31%yield, 96%purity) as a yellow solid. LCMS (ESI, m/z) : 694 [M+H] ⁺.

Synthesis of tert-butyl (S) -3- ( (4- (6- (1- (tert-butoxycarbonyl) -1H-pyrazol-4-yl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) azepane-1-carboxylate

A mixture of tert-butyl 4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole-1-carboxylate (300 mg, 1.02 mmol) , tert-butyl (S) -3- ( (4- (6-bromo-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) azepane-1-carboxylate (384.04 mg, 1.02 mmol) , Pd (PPh ₃) ₄ (12.02 g, 10.40 mmol) and NaHCO ₃ (257.04 mg, 3.06 mmol) , 1, 4-dioxane (5 mL) and H ₂O (1 mL) was stirred for overnight at 100 ℃ under nitrogen atmosphere. The mixture was quenched with water (30 mL) . The resulting mixture was extracted with ethyl acetate (2 x 30 mL) . The combined organic layers were washed with water (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 (1: 1) to afford tert-butyl (S) -3- ( (4- (6- (1H-pyrazol-4-yl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) azepane-1-carboxylate (254.23 mg, 515.21 μmol, 50.52%yield, 94%purity) as a yellow solid. LCMS (ESI, m/z) : 464.23 [M+H] ⁺.

A mixture of tert-butyl (S) -3- ( (4- (6- (1- (tert-butoxycarbonyl) -1H-pyrazol-4-yl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) azepane-1-carboxylate (55.0 mg, 0.102 mmol, 1.00 equiv) and TFA (2 mL) in DCM (5 mL) was stirred for 2 h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C ₁₈ Column, 30*150 mm, 5 μm; Mobile Phase A: water (10 mmol/L NH ₄HCO ₃) , Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 22%B to 44%B in 7 min; Wave Length: 254 nm to afford (3S) -N- {4- [6- (1H-pyrazol-4-yl) -1H-indol-3-yl] -5- (trifluoromethyl) pyrimidin-2-yl} azepan-3-amine (32.8 mg, 73%yield) as a yellow solid. LCMS (ESI, m/z) : 442 [M+H] ⁺. ¹H-NMR (400 MHz, Methanol-d ₄) δ 8.57 (s, 1H) , 8.30 (s, 1H) , 7.97 (s, 2H) , 7.82 (s, 1H) , 7.65 (s, 1H) , 7.43 (d, J = 8.5 Hz, 1H) , 4.42 (s, 1H) , 3.48 (dd, J = 13.6, 4.0 Hz, 1H) , 3.35 (s, 1H) , 3.24 -3.13 (m, 2H) , 2.26 -2.18 (m, 1H) , 2.12 -1.80 (m, 4H) , 1.79 -1.66 (m, 1H) .

(S) - (3- (2- (azepan-3-ylamino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indol-6-yl) (4- (2-hydroxypropan-2-yl) piperidin-1-yl) methanone

Synthesis of (S) - (3- (2- (azepan-3-ylamino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indol-6-yl) (4- (2-hydroxypropan-2-yl) piperidin-1-yl) methanone

To a solution of 2, 4-dichloro-5- (trifluoromethyl) pyrimidine (5.56 g, 25.61 mmol) in anh. (anhydrous) DCE (10 mL) under nitrogen, was added AlCl ₃ (1.71 g, 12.80 mmol) , and the resulting mixture was stirred at 80℃ for 30 min. After this time, the reaction mixture was cooled to RT, and methyl 1H-indole-6-carboxylate (1.50 g, 8.54 mmol) was added. The resulting mixture was stirred at 80℃ for 3 h, when the solution became reddish overtime. The mixture was then poured into crushed ice and EtOAc. Layers were separated, and organic layer was then dried over Na ₂SO ₄, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase chromatography to afford the methyl 3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -1H- indole-6-carboxylate (612.34 mg, 1.60 mmol, 18.76%yield, 93%purity) as a beige solid. LCMS (ESI, m/z) : 356.23 [M+H] ⁺.

To a solution of 3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -6-ethoxy-1H-indole (2 g, 5.62 mmol) in NMP (20 mL) was added DIPEA (2.18 g, 16.87 mmol, 2.94 mL) and tert-butyl (S) -3-aminoazepane-1-carboxylate (1.33 g, 6.19 mmol) , then stirred at 130 ℃ for 6 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 Na ₂SO ₄, filtered, and concentrated to give a residue. The residue purified by column chromatography to give tert-butyl (S) -3- ( (4- (6-ethoxy-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) azepane-1-carboxylate (2.03 g, 3.65 mmol, 64.96%yield, 96%purity) as a yellow solid. LCMS (ESI, m/z) : 534.12 [M+H] ⁺.

Synthesis of (S) -7-bromo-3- (2- ( (1- (tert-butoxycarbonyl) azepan-3-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carboxylic acid

A mixture of methyl (S) -3- (2- ( (1- (tert-butoxycarbonyl) azepan-3-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carboxylate (300 mg, 562.28 μmol) , NaOH (44.98 mg, 1.12 mmol) and H ₂O (5 mL) in MeOH (20 mL) was stirred for overnight at 60 ℃. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with water (5 mL) . The residue was acidified to pH 6 with HCl (1M aq) . The resulting mixture was concentrated under reduced pressure to afford (S) -7-bromo-3- (2- ( (1- (tert-butoxycarbonyl) azepan-3-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carboxylic acid (223.4 mg, 395.62 μmol, 70.36%yield, 92%purity) as a yellow solid. LCMS (ESI, m/z) : 520 [M+H] ⁺.

Synthesis of tert-butyl (S) -3- ( (4- (6- (4- (2-hydroxypropan-2-yl) piperidine-1-carbonyl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) azepane-1-carboxylate

To a solution of (S) -7-bromo-3- (2- ( (1- (tert-butoxycarbonyl) azepan-3-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carboxylic acid (250 mg, 481.22 μmol) in DCM (15 mL) was added 2- (piperidin-4-yl) propan-2-ol (82.71 mg, 577.46 μmol) , HATU (217.86 mg, 577.46 μmol) and DIPEA (186.58 mg, 1.44 mmol, 251.45 μL) , then sitrred at 20 ℃ for 16 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 Na ₂SO ₄, filtered, and concentrated to give a residue. The residue purified by column chromatography to give tert-butyl (S) -3- ( (4- (6- (4- (2-hydroxypropan-2-yl) piperidine-1-carbonyl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) azepane-1-carboxylate as a yellow oil. LCMS [M+H] ⁺: 645.32.

Synthesis of 2- [1- (3- {2- [ (3S) -azepan-3-ylamino] -5- (trifluoromethyl) pyrimidin-4-yl} -1H-indole-6-carbonyl) piperidin-4-yl] propan-2-ol

A mixture of tert-butyl (3S) -3- [ (4- {6- [4- (2-hydroxypropan-2-yl) piperidine-1-carbonyl] -1H-indol-3-yl} -5- (trifluoromethyl) pyrimidin-2-yl) amino] azepane-1-carboxylate (80.0 mg, 0.124 mmol, 1.00 equiv) , N, N-diisopropylethylamine (48.1 mg, 0.372 mmol, 3.00 equiv) and trimethylsilyl trifluoromethanesulfonate (55.1 mg, 0.248 mmol, 2.00 equiv) in dichloromethane (2 mL) was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C ₁₈ Column, 30*150 mm, 5 μm; Mobile Phase A: Water (10 mmol/L NH ₄HCO ₃+0.1%NH ₃. H ₂O) , 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- (3- {2- [ (3S) -azepan-3-ylamino] -5- (trifluoromethyl) pyrimidin-4-yl} -1H-indole-6-carbonyl) piperidin-4-yl] propan-2-ol (18.2 mg, 27%yield) as a white solid. LCMS (ESI, m/z) : 545 [M+H] ⁺. ¹H-NMR (300 MHz, DMSO-d ₆) δ 8.57 (d, J = 10.0 Hz, 1H) , 8.44 -8.26 (m, 1H) , 7.93 -7.86 (m, 1H) , 7.71 (d, J = 4.0 Hz, 1H) , 7.51 (s, 1H) , 7.17 -7.13 (m, 1H) , 4.34 -4.01 (m, 2H) , 3.49 -3.22 (m, 4H) , 3.10 -2.94 (m, 1H) , 2.86 -2.69 (m, 4H) , 2.00 -1.42 (m, 10H) , 1.25 -1.14 (m, 2H) , 1.06 (s, 6H) .

Methyl (S) -3- (2- (azepan-3-ylamino) -5- (trifluoromethyl) pyrimidin-4-yl) -7-bromo-1H-indole-6-carboxylate

Synthesis of methyl (S) -3- (2- (azepan-3-ylamino) -5- (trifluoromethyl) pyrimidin-4-yl) -7-bromo-1H-indole-6-carboxylate

Synthesis of methyl 7-bromo-3- [2-chloro-5- (trifluoromethyl) pyrimidin-4-yl] -1H-indole-6-carboxylate

A solution of 2, 4-dichloro-5- (trifluoromethyl) pyrimidine (1.71 g, 7.872 mmol, 2.00 equiv) in 1, 2-dichloroethane (10 mL) was treated with aluminium chloride (1.10 g, 8.26 mmol, 2.10 equiv) for 30 min at 90 ℃. Then methyl 7-bromo-1H-indole-6-carboxylate (1.00 g, 3.94 mmol, 1.00 equiv) was added to above mixture in portions at 90℃. The resulting mixture was stirred for 3 h at 90 ℃and quenched with water (10 mL) . The resulting mixture was extracted with ethyl acetate (3 x 20 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 petroleum ether /ethyl acetate (3/1) to afford crude product as a yellow solid. The residue was purified by reverse flash chromatography with the following conditions: column, C ₁₈ column; mobile phase, acetonitrile in water, 10%to 100%gradient in 40 min; detector, UV 254 nm to afford methyl 7-bromo-3- [2-chloro-5- (trifluoromethyl) pyrimidin-4-yl] -1H-indole-6-carboxylate (420 mg, 24%yield) as a white solid. LCMS (ESI, m/z) : 434 [M+H] ⁺.

Synthesis of methyl 7-bromo-3- (2- { [ (3S) -1- (tert-butoxycarbonyl) azepan-3-yl] amino} -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carboxylate

A 5 mL vial was charged with methyl 7-bromo-3- [2-chloro-5- (trifluoromethyl) pyrimidin-4-yl] -1H-indole-6-carboxylate (420 mg, 0.966 mmol, 1.00 equiv) , tert-butyl (3S) -3-aminoazepane-1-carboxylate (207 mg, 0.966 mmol, 1.00 equiv) , NMP (4 mL) and DIEA (374 mg, 2.90 mmol, 3.00 equiv) at room temperature. The final reaction mixture was irradiated with microwave radiation for 1 h at 140 ℃. The residue was purified by reverse flash chromatography with the following conditions: column, C ₁₈ column; mobile phase, acetonitrile in water, 10%to 100%gradient in 40 min; detector, UV 254 nm to afford methyl 7-bromo-3- (2- { [ (3S) -1- (tert-butoxycarbonyl) azepan-3-yl] amino} -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carboxylate (420 mg, 71%yield) as a yellow solid. LCMS (ESI, m/z) : 612 [M+H] ⁺.

Synthesis of methyl 3- {2- [ (3S) -azepan-3-ylamino] -5- (trifluoromethyl) pyrimidin-4-yl} -7-bromo-1H-indole-6-carboxylate

A mixture of methyl 7-bromo-3- (2- { [ (3S) -1- (tert-butoxycarbonyl) azepan-3-yl] amino} -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carboxylate (50.0 mg, 0.098 mmol, 1.00 equiv) and TFA (1 mL) in dichloromethane (5 mL) was stirred for 3 h at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions Column: XBridge Prep OBD C ₁₈ Column, 30*150 mm, 5 μm; Mobile Phase A: Water (10 mmol/L NH ₄HCO ₃) , Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 40%B to 60%B in 7 min; Wave Length: 254 nm to afford methyl 3- {2- [ (3S) -azepan-3-ylamino] -5- (trifluoromethyl) pyrimidin-4-yl} -7-bromo-1H-indole-6-carboxylate (23.7 mg, 47%yield) as a white solid. LCMS (ESI, m/z) : 512 [M+H] ⁺. ¹H-NMR (300 MHz, Methanol-d ₄) δ 8.54 (d, J = 6.0 Hz, 1H) , 8.38 -8.26 (m, 1H) , 7.99 (s, 1H) , 7.72 -7.64 (m, 1H) , 4.30 (s, 1H) , 3.94 (s, 3H) , 3.25 (d, J = 4.0 Hz, 1H) , 2.99 (s, 3H) , 2.12 (d, J = 4.0 Hz, 1H) , 1.90 -1.64 (m, 5H) .

(S) -N- (4- (6-methoxy-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) azepan-3-amine

Synthesis of 6- (methylsulfonyl) -1H-indole

A mixture of 6-bromo-1H-indole (500 mg, 2.55 mmol) , CH ₃SOONa (338 mg, 3.32 mmol) , S-Proline (12 mg, 0.20 mmol) and CuI (10 mg, 0.10 mmol) in DMSO (10.0 mL) was stirred at 110℃ for 24 h. The mixture was filtered and the filter cake was washed with DCM/MeOH (v/v =3/1, 20 mL) . The filtrate was concentrated to give the crude, which was purified by purified by column chromatography (eluent: DCM/MeOH = 100/1 ～ 50/1) to give 6- (methylsulfonyl) -1H-indole (250 mg, 50.0%) as a white solid. ESI-MS [M +H] +: 196.2.

Synthesis of 3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -6- (methylsulfonyl) -1H-indole

To a mixture of 2, 4-dichloro-5- (trifluoromethyl) pyrimidine (694 mg, 3.20 mmol) in DCE (20 mL) was added AlCl ₃ (512 mg, 3.84 mmol) . The mixture was stirred at 90 ℃ for 0.5 h under N ₂. Then 6- (methylsulfonyl) -1H-indole (250 mg, 1.28 mmol) was added. The reaction mixture was stirred at 90 ℃ for another 16 h. The reaction was quenched with MeOH (20 mL) and water (10 mL) . The mixture was filtered. The filter cake was washed with MeOH (10 mL) and dried to give the product 3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -6- (methylsulfonyl) -1H-indole (20 mg, yield: 4.2%) as a yellow solid, which was used in the next step without further purification. ESI-MS [M +H] ⁺: 376.1.

Synthesis of tert-butyl (S) -3- ( (4- (6- (methylsulfonyl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) azepane-1-carboxylate

A mixture of 3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -6- (methylsulfonyl) -1H-indole (40 mg, 0.11 mmol) , tert-butyl (S) -3-aminoazepane-1-carboxylate (28 mg, 0.13 mmol) and DIPEA (43 mg, 0.33 mmol) in i-PrOH (4 mL) was irradiated in microwave at 90 ℃ for 1 h. The reaction mixture was concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 20/1) to give tert-butyl (S) -3- ( (4- (6- (methylsulfonyl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) azepane-1-carboxylate (20 mg, yield: 32.8%) as a white solid. ESI-MS [M + H] ⁺: 554.2.

Synthesis of (S) -N- (4- (6- (methylsulfonyl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) azepan-3-amine

To a mixture of tert-butyl (S) -3- ( (4- (6- (methylsulfonyl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) azepane-1-carboxylate (20 mg, 0.036 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 NH ₃ (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 (S) -N- (4- (6- (methylsulfonyl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) azepan-3-amine (4.67 mg, yield: 28.6 %) as a white solid.

ESI-MS [M +H] ⁺: 454.1.

1H NMR (400 MHz, MeOD) δ 8.66 (s, 1H) , 8.53 (s, 1H) , 8.13 (s, 1H) , 8.10 (s, 1H) , 7.75 (d, J = 7.0 Hz, 1H) , 4.43 (s, 1H) , 3.53 (dd, J = 13.6, 3.8 Hz, 1H) , 3.39 –3.36 (m, 2H) , 3.25 (s, 1H) , 3.18 (s, 3H) , 2.25 –2.21 (m, 1H) , 2.07 –1.89 (m, 4H) , 1.77 (t, J = 12.5 Hz, 1H) .

(S) -3- (2- (azepan-3-ylamino) -5- (trifluoromethyl) pyrimidin-4-yl) -7- (diethylphosphoryl) -1H-indole-6-carbonitrile

Synthesis of (S) -3- (2- (azepan-3-ylamino) -5- (trifluoromethyl) pyrimidin-4-yl) -7- (diethylphosphoryl) -1H-indole-6-carbonitrile

Synthesis of tert-butyl (S) -3- ( (4- (6-cyano-7- (diethylphosphoryl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) azepane-1-carboxylate

A mixture of tert-butyl (S) -3- ( (4- (7-chloro-6-cyano-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) azepane-1-carboxylate (50 mg, 0.094 mmol) , diethylphosphine oxide (50 mg, 0.47 mmol) , Pd (OAc) ₂ (2 mg, 0.0094 mmol) , Xantphos (5 mg, 0.0094 mmol) and K ₃PO ₄ (39 mg, 0.18 mmol) in DMF (3 mL) was irradiated in microwave at 120℃ for 2 h under nitrogen. The reaction was quenched with water (50 mL) and extracted with EtOAc (30 mL x 3) . The combined organic layers were washed with brine, dried with Na ₂SO ₄ and concentrated in vacuo to give the crude, which was purified by column chromatography (eluent: DCM/MeOH = 20/1) to give tert-butyl (S) -3- ( (4- (6-cyano-7- (diethylphosphoryl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) azepane-1-carboxylate (20 mg, crude) as a yellow solid. ESI-MS [M + H] ⁺: 605.2.

To a mixture of tert-butyl (S) -3- ( (4- (6-cyano-7- (diethylphosphoryl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) azepane-1-carboxylate (20 mg, 0.033 mmol) in DCM (5 mL) was added TFA (0.5 mL) . The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was quenched with NaHCO ₃ (Sat. aq., 20 mL) and extracted with DCM (20 mL x 3) . The combined organic layers were washed with brine, dried with Na ₂SO ₄, and concentrated in vacuo to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 10/1) to give (S) -3- (2- (azepan-3-ylamino) -5- (trifluoromethyl) pyrimidin-4-yl) -7- (diethylphosphoryl) -1H-indole-6-carbonitrile (15 mg, yield: 90%) as a white solid.

ESI-MS [M +H] ⁺: 505.3.

¹H NMR (400 MHz, MeOD) δ 8.71 –8.42 (m, 2H) , 8.09 (s, 1H) , 7.58 (s, 1H) , 4.23 (s, 1H) , 3.31 –3.24 (m, 1H) , 3.12 –2.95 (m, 3H) , 2.47 –2.16 (m, 4H) , 2.13 –1.99 (m, 1H) , 1.89 –1.50 (m, 5H) , 1.12 –1.02 (m, 6H) .

(S) -N- (4- (6- (3, 5-dimethylisoxazol-4-yl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) azepan-3-amine

Synthes of (S) -N- (4- (6- (3, 5-dimethylisoxazol-4-yl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) azepan-3-amine

To a mixture of 2, 4-dichloro-5- (trifluoromethyl) pyrimidine (2.22 g, 10.20 mmol) in DCE (30 mL) was added AlCl ₃ (1.36 g, 10.20 mmol) . The mixture was stirred at 90 ℃ for 0.5 h under N ₂. Then 6-bromo-1H-indole (1.0 g, 5.10 mmol) was added. The reaction mixture was stirred at 90℃ for another 12 h. The reaction was quenched with MeOH (20 mL) and water (20 mL) . The mixture was filtered. The filter cake was washed with MeOH (20 mL) and dried to give the product 6-bromo-3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole (350 mg, yield: 17.7%) as a yellow solid, which was used in the next step without further purification. ESI-MS [M +H] ⁺: 376.1.

A mixture of 6-bromo-3- [2-chloro-5- (trifluoromethyl) pyrimidin-4-yl] -1H-indole (50 mg, 0.13 mmol) , tert-butyl (3S) -3-aminoazepane-1-carboxylate (34 mg, 0.16 mmol) and DIPEA (51 mg, 0.40 mmol) in i-PrOH (4 mL) was irradiated in microwave at 100 ℃ for 1 h. The reaction mixture was concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 20/1) to give tert-butyl (S) -3- ( (4- (6-bromo-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) azepane-1-carboxylate (60 mg, yield: 81.5%) as a white solid. ESI-MS [M + H] ⁺: 554.2.

A mixture of tert-butyl (S) -3- ( (4- (6-bromo-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) azepane-1-carboxylate (50 mg, 0.090 mmol) , (3, 5-dimethylisoxazol-4-yl) boronic acid (38 mg, 0.27 mmol) , Pd (dppf) Cl ₂ (13 mg, 0.018 mmol) and NaHCO ₃ (13 mg, 0.27 mmol) in DME (4.5 mL) and H ₂O (0.5 mL) was stirred at 100 ℃ for 2 h. The mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by Prep-TLC (eluent: DCM/MeOH = 20/1) to give tert-butyl (S) -3- ( (4- (6- (3, 5-dimethylisoxazol-4-yl) -1H-indol-3-yl) - 5- (trifluoromethyl) pyrimidin-2-yl) amino) azepane-1-carboxylate (40 mg, yield: 77.7%) as a white solid. ESI-MS [M + H] ⁺: 571.2.

Synthesis of (S) -N- (4- (6- (3, 5-dimethylisoxazol-4-yl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) azepan-3-amine

To a mixture of tert-butyl (S) -3- ( (4- (6- (3, 5-dimethylisoxazol-4-yl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) azepane-1-carboxylate (30 mg, 0.053 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 NH ₃ (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 (S) -N- (4- (6- (3, 5-dimethylisoxazol-4-yl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) azepan-3-amine (13.47 mg, yield: 54.4%) as a white solid.

ESI-MS [M +H] ⁺: 471.2.

1H NMR (400 MHz, MeOD) δ 8.56 (s, 1H) , 8.39 (s, 1H) , 7.89 (s, 1H) , 7.41 (s, 1H) , 7.14 (d, J = 7.9 Hz, 1H) , 4.37 (s, 1H) , 3.38 (dd, J = 13.7, 4.1 Hz, 1H) , 3.18 –3.08 (m, 3H) , 2.44 (s, 3H) , 2.29 (s, 3H) , 2.18 (t, J = 12.2 Hz, 1H) , 1.88 (t, J = 22.3 Hz, 4H) , 1.70 (t, J = 12.6 Hz, 1H) .

(S) -3- (2- (azepan-3-ylamino) -5- (trifluoromethyl) pyrimidin-4-yl) -N-methyl-1H-indole-6-carboxamide

Synthesis of (S) -3- (2- (azepan-3-ylamino) -5- (trifluoromethyl) pyrimidin-4-yl) -N-methyl-1H-indole-6-carboxamide

To a mixture of 2, 4-dichloro-5- (trifluoromethyl) pyrimidine (4.9 g, 22.8 mmol) in DCE (30 mL) was added AlCl ₃ (3.2 g, 23.9 mmol) . The mixture was stirred at 90 ℃ for 0.5 h under N ₂. Then methyl 1H-indole-6-carboxylate (2.0 g, 11.4 mmol) was added. The reaction mixture was stirred at 90℃ for another 3 h. The reaction was quenched with MeOH (20 mL) and water (15 mL) . The mixture was filtered. The filter cake was washed with MeOH (10 mL) and dried to give the product methyl 3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carboxylate (1.0 g, yield: 24.7%) as a yellow solid. ESI-MS [M +H] ⁺: 356.1.

A mixture of methyl 3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carboxylate (200 mg, 0.56 mmol) , tert-butyl (S) -3-aminoazepane-1-carboxylate (144 mg, 0.67 mmol) and DIPEA (217 mg, 1.68 mmol) in i-PrOH (5 mL) was irradiated in microwave at 100 ℃ for 1 h. The reaction mixture was concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 20/1) to give methyl (S) -3- (2- ( (1- (tert-butoxycarbonyl) azepan-3-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carboxylate (180 mg, yield: 60.3%) as a white solid.

ESI-MS [M + H] +: 534.2.

Synthesis of (S) -3- (2- ( (1- (tert-butoxycarbonyl) azepan-3-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carboxylic acid

To a mixture of methyl (S) -3- (2- ( (1- (tert-butoxycarbonyl) azepan-3-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carboxylate (180 mg, 0.34 mmol) in THF/H ₂O (8 mL /8 mL) was added LiOHH ₂O (28.6 mg, 0.68 mmol) . The reaction mixture was stirred at 50 ℃ for 16 h. The reaction mixture was adjust to pH=7 with HCl (1M solution in H ₂O, 2 mL) and extracted with EtOAc (30 mL x 2) . The organic layer was concentrated in vacuo to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 10/1) to give (S) -3- (2- ( (1- (tert-butoxycarbonyl) azepan-3-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carboxylic acid (50 mg, yield: 28.3%) as a white solid. ESI-MS [M + H] +: 520.2

Synthesis of tert-butyl (S) -3- ( (4- (6- (methylcarbamoyl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) azepane-1-carboxylate

A mixture of (S) -3- (2- ( (1- (tert-butoxycarbonyl) azepan-3-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carboxylic acid (50 mg, 0.10 mmol) , CH ₃NH ₂HCl (20 mg, 0.30 mmol) , HATU (76 mg, 0.20 mmol) and DIPEA (65 mg, 0.50 mmol) in DMF (5 mL) was stirred at room temperature for 16 h. The mixture was diluted with H ₂O (50 mL) and extracted with EtOAc (30 mL x 2) . The combined organic layer was concentrated in vacuo to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 10/1) to give tert-butyl (S) -3- ( (4- (6- (methylcarbamoyl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) azepane-1-carboxylate (45 mg, yield: 84.6%) as a white solid. ESI-MS [M + H] +: 533.2

To a mixture of tert-butyl (S) -3- ( (4- (6- (methylcarbamoyl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) azepane-1-carboxylate (45 mg, 0.08 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 NH ₃ (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 (S) -3- (2- (azepan-3-ylamino) -5- (trifluoromethyl) pyrimidin-4-yl) -N-methyl-1H-indole-6-carboxamide (28 mg, yield: 81%) as a white solid.

ESI-MS [M +H] ⁺: 433.2.

1H NMR (400 MHz, MeOD) δ 8.60 –8.47 (m, 1H) , 8.44 –8.31 (m, 1H) , 8.05 –7.99 (m, 1H) , 7.98 –7.92 (m, 1H) , 7.70 –7.62 (m, 1H) , 4.48 –4.12 (m, 1H) , 3.29 –3.17 (m, 1H) , 2.98 (s, 3H) , 2.97 –2.75 (m, 3H) , 2.21 –2.08 (m, 1H) , 1.91 –1.62 (m, 5H) .

(S) -N- (4- (6, 7-difluoro-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) azepan-3-amine

Synthesis of (S) -N- (4- (6, 7-difluoro-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) azepan-3-amine

To a solution of 6, 7-difluoro-1H-indole (200 mg, 1.31 mmol) in DCE (10 mL) under nitrogen, was added AlCl ₃ (522.46 mg, 3.92 mmol) , and the resulting mixture was stirred at 80℃ for 30 min. After this time, the reaction mixture was cooled to RT, and 2-chloro-5-(trifluoromethyl) pyrimidine (850.17 mg, 3.92 mmol) was added. The resulting mixture was stirred at 80℃ for 10 h, when the solution became reddish overtime. The mixture was then poured into crushed ice and EtOAc. Layers were separated, and organic layer was then dried over Na ₂SO ₄, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase chromatography to afford the 3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -6, 7-difluoro-1H-indole (58.5 mg, 168.32 μmol, 12.89%yield, 96%purity) as a yellow solid. ESI-MS [M +H] +: 334.13.

Synthesis of tert-butyl (S) -3- ( (4- (6, 7-difluoro-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) azepane-1-carboxylate

To a solution of 3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -6, 7-difluoro-1H-indole (150 mg, 449.58 μmol) in NMP (2.5 mL) was added DIPEA (174.31 mg, 1.35 mmol, 234.92 μL) and tert-butyl (S) -3-aminoazepane-1-carboxylate (192.69 mg, 899.16 μmol) , then stirred at 130 ℃ for 6 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 Na ₂SO ₄, filtered, and concentrated to give a residue. The residue purified by column chromatography to give tert-butyl (S) -3- ( (4- (6, 7-difluoro-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) azepane-1-carboxylate as a yellow solid. LCMS (ESI, m/z) : 512.12 [M+H] ⁺.

Synthesis of (3S) -N- [4- (6, 7-difluoro-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl] azepan-3-amine

A mixture of tert-butyl (3S) -3- { [4- (6, 7-difluoro-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl] amino} azepane-1-carboxylate (89.0 mg, 0.174 mmol, 1.00 equiv) and trifluoroacetic acid (2 mL) in dichloromethane (5 mL) was stirred for 2 h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C ₁₈ Column, 30*150 mm, 5 μm; Mobile Phase A: water (10 mmol/L NH ₄HCO ₃) , Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 35%B to 55%B in 7 min, 55%B to 55%B in 10 min; Wave Length: 254 nm to afford (3S) -N- [4- (6, 7-difluoro-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl] azepan-3-amine (31.7 mg, 44%yield) as a white solid. LCMS (ESI, m/z) : 412 [M+H] ⁺. ¹H-NMR (300 MHz, DMSO-d ₆) δ 8.59 (d, J = 14.9 Hz, 1H) , 8.39 -8.13 (m, 1H) , 8.04 -7.88 (m, 1H) , 7.84 -7.75 (m, 2H) , 7.24 -7.10 (m, 1H) , 4.10 (s, 1H) , 3.05 (d, J =13.5 Hz, 1H) , 2.83 -2.71 (m, 3H) , 1.95 -1.87 (m, 1H) , 1.80 -1.45 (m, 5H) .

(S) -1- (3- (2- (azepan-3-ylamino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indol-6-yl) piperidine-4-carboxamide 2, 2, 2-trifluoroacetate

Synthesis of (S) -1- (3- (2- (azepan-3-ylamino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indol-6-yl) piperidine-4-carboxamide 2, 2, 2-trifluoroacetate

Synthesis of tert-butyl (S) -3- ( (4- (6- (4- (methoxycarbonyl) piperidin-1-yl) -1-(phenylsulfonyl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) azepane-1-carboxylate

A mixture of tert-butyl (3S) -3- ( {4- [1- (benzenesulfonyl) -6-bromoindol-3-yl] -5- (trifluoromethyl) pyrimidin-2-yl} amino) azepane-1-carboxylate (180 mg, 0.259 mmol, 1.00 equiv) , N-methylpiperidine-4-carboxamide (36.8 mg, 0.259 mmol, 1.00 equiv) , 2- (dicyclohexylphosphino) -2', 4', 6'-triisopropylbiphenyl (24.7 mg, 0.052 mmol, 0.20 equiv) , dicesium carbonate (338 mg, 1.04 mmol, 4.00 equiv) and palladium acetate (11.6 mg, 0.052 mmol, 0.20 equiv) in 1, 4-dioxane (4 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 Prep-TLC with petroleum ether/ethyl acetate = 5/1 to afford tert-butyl (3S) -3- ( {4- [1- (benzenesulfonyl) -6- [4- (methoxycarbonyl) piperidin-1-yl] indol-3-yl] -5- (trifluoromethyl) pyrimidin-2-yl} amino) azepane-1-carboxylate (90.0 mg, 46%yield) as a yellow solid. LCMS (ESI, m/z) : 757 [M+H] ⁺.

Synthesis of (S) -1- (3- (2- ( (1- (tert-butoxycarbonyl) azepan-3-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indol-6-yl) piperidine-4-carboxylic acid

A mixture of tert-butyl (3S) -3- ( {4- [1- (benzenesulfonyl) -6- [4- (methoxycarbonyl) piperidin-1-yl] indol-3-yl] -5- (trifluoromethyl) pyrimidin-2-yl} amino) azepane-1-carboxylate (80.0 mg, 0.106 mmol, 1.00 equiv) in ammonia (2 mL, 25%in water) was stirred for overnight at 80 ℃. The resulting mixture was concentrated under reduced pressure to afford 1- [3- (2- { [ (3S) -1- (tert-butoxycarbonyl) azepan-3-yl] amino} -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indol-6-yl]piperidine-4-carboxylic acid (80.0 mg, crude) as a yellow solid. LCMS (ESI, m/z) : 603 [M+H] ⁺.

Synthesis of tert-butyl (S) -3- ( (4- (6- (4-carbamoylpiperidin-1-yl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) azepane-1-carboxylate

A mixture of 1- [3- (2- { [ (3S) -1- (tert-butoxycarbonyl) azepan-3-yl] amino} -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indol-6-yl] piperidine-4-carboxylic acid (80.0 mg, 0.133 mmol, 1.00 equiv) , 1-hydroxybenzotrizole (26.9 mg, 0.200 mmol, 1.50 equiv) , N, N-diisopropylethylamine (34.3 mg, 0.266 mmol, 2.00 equiv) and N- (3-dimethylaminopropyl) -N’-ethylcarbodiimide hydrochloride (38.0 mg, 0.200 mmol, 1.50 equiv) in ammonia (4 mL, 0.5M in tetrahydrofuran) was stirred for overnight at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC with petroleum ether /ethyl acetate = 1/1 to afford tert-butyl (3S) -3- ( {4- [1- (benzenesulfonyl) -6- (4-carbamoylpiperidin- 1-yl) indol-3-yl] -5- (trifluoromethyl) pyrimidin-2-yl} amino) azepane-1-carboxylate (20 mg, 25%yield) as a yellow solid. LCMS (ESI, m/z) : 602 [M+H] ⁺.

Synthesis of (S) -1- (3- (2- (azepan-3-ylamino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indol-6-yl) piperidine-4-carboxamide trifluoroacetate

A mixture of tert-butyl (3S) -3- ( {4- [6- (4-carbamoylpiperidin-1-yl) -1H-indol-3-yl] -5- (trifluoromethyl) pyrimidin-2-yl} amino) azepane-1-carboxylate (20.0 mg, 0.033 mmol, 1.00 equiv) and trifluoroacetic acid (0.6 mL) in dichloromethane (3 mL) was stirred for 3 h at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions: Column: XSelect CSH Prep C ₁₈ OBD Column, 19*150 mm, 5μm; Mobile Phase A: Water (0.05%TFA) , Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 5%B to 30%B in 7 min; Wave Length: 254 nm to afford (S) -1- (3- (2- (azepan-3-ylamino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indol-6-yl) piperidine-4-carboxamide trifluoroacetate (2.7 mg, 13%yield) as a yellow solid. LCMS (ESI, m/z) : 502 [M+H-TFA] ⁺. ¹H-NMR (400 MHz, Methanol-d ₄) δ 8.63 (s, 1H) , 8.01 (s, 1H) , 7.85 -7.81 (d, J = 8.0 Hz, 1H) , 7.46 -7.42 (d, J = 8.0 Hz, 1H) , 4.43 (s, 1H) , 3.92 -3.86 (d, J = 12.0 Hz, 2H) , 3.79 -3.76 (m, 2H) , 3.57 -3.52 (m, 1H) , 3.24 -3.22 (d, J = 4.0 Hz, 1H) , 2.81 -2.78 (m, 1H) , 2.32 -2.25 (m, 5H) , 2.01 -1.94 (d, J = 14.0 Hz, 4H) , 1.78 -1.75 (m, 1H) .

(S) -N- (4- (6- (1H-pyrazol-3-yl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) azepan-3-amine 2, 2, 2-trifluoroacetate

Synthesis of (S) -N- (4- (6- (1H-pyrazol-3-yl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) azepan-3-amine 2, 2, 2-trifluoroacetate

A solution of 2, 4-dichloro-5- (trifluoromethyl) pyrimidine (8.30 g, 38.3 mmol, 1.50 equiv) in dichloroethane (30 mL) was treated with aluminnium chlorolide (5.10 g, 38.3 mmol, 1.50 equiv) for 0.5 h at 80 ℃ under nitrogen atmosphere. Then 6-bromo-1H-indole (5.00 g, 25.5 mmol, 1.00 equiv) in dichloroethane (20 mL) was added dropwise to above mixture at 80 ℃. The final reaction mixture was stirred for overnight at 80 ℃ and quenched with water (50 mL) . The resulting mixture was extracted with ethyl acetate (2 x 100 mL) . The combined organic layers were washed with water (2 x 50 mL) , dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions: column, C ₁₈ column; mobile phase, Acetonitrile in Water (0.1%TFA) , 10%to 50%gradient in 20 min; detector, UV 254 nm to afford 6-bromo-3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole (4.20 g, 44%yield) as a yellow solid. LCMS (ESI, m/z) : 376 [M+H] ⁺.

Synthesis of 6-bromo-3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -1- (phenylsulfonyl) -1H-indole

A solution of 6-bromo-3- [2-chloro-5- (trifluoromethyl) pyrimidin-4-yl] -1H-indole (1.00 g, 2.66 mmol, 1.00 equiv) in anhydrous tetrahydrofuran (10 mL) was added 60%sodium hydride (0.213 g, 5.32 mmol, 2.00 equiv) for 0.5 h at 0 ℃ under nitrogen atmosphere. Then benzenesulfonyl chloride (0.470 g, 0.266 mmol, 1.00 equiv) in tetrahydrofuran (10 mL) was added dropwise to above mixture at 0 ℃. The resulting mixture was stirred for additional 0.5 h at 0 ℃and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether /ethyl acetate (5: 1) to afford 1- (benzenesulfonyl) -6-bromo-3- [2-chloro-5- (trifluoromethyl) pyrimidin-4-yl] indole (1.14 g, 83%yield) as a brown solid. LCMS (ESI, m/z) : 516 [M+H] ⁺.

A solution of 1- (benzenesulfonyl) -6-bromo-3- [2-chloro-5- (trifluoromethyl) pyrimidin-4-yl] indole (500 mg, 0.968 mmol, 1.00 equiv) and tert-butyl (3S) -3-aminoazepane-1-carboxylate (207 mg, 0.968 mmol, 1.00 equiv) and N, N-diisopropylethylamine (250 mg, 1.94 mmol, 2.00 equiv) in NMP (4 mL) was stirred with microwave radiation for 3 h at 140 ℃. The residue was purified by reverse flash chromatography with the following conditions: column, C ₁₈ column; mobile phase, acetonitrile in water (0.1%TFA) , 0 to 100%gradient in 40 min; detector, UV 254 nm to afford 1- (benzenesulfonyl) -6-bromo-3- [2-chloro-5- (trifluoromethyl) pyrimidin-4-yl] indole (560 mg, 83%yield) as a yellow solid. LCMS (ESI, m/z) : 694 [M+H] ⁺.

Synthesis of tert-butyl (S) -3- ( (4- (1- (phenylsulfonyl) -6- (1H-pyrazol-3-yl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) azepane-1-carboxylate

A mixture of tert-butyl (3S) -3- ( {4- [1- (benzenesulfonyl) -6-bromoindol-3-yl] -5- (trifluoromethyl) pyrimidin-2-yl} amino) azepane-1-carboxylate (300 mg, 0.432 mmol, 1.00 equiv) , 3- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (83.8 mg, 0.432 mmol, 1.00 equiv) , sodium bicarbonate (109 mg, 1.30 mmol, 3.00 equiv) and Pd (PPh ₃) ₄ (99.4 mg, 0.0860 mmol, 0.20 equiv) , 1, 4-dioxane (5 mL) and water (1 mL) was stirred for overnight at 100 ℃ under nitrogen atmosphere. The mixture was quenched with water (30 mL) . The resulting mixture was extracted with ethyl acetate (2 x 30 mL) . The combined organic layers were washed with water (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 (1: 1) to afford tert-butyl (3S) -3- ( {4- [1- (benzenesulfonyl) -6- (1H-pyrazol-3-yl) indol-3-yl] -5- (trifluoromethyl) pyrimidin-2-yl} amino azepane-1-carboxylate) (180 mg, 61%yield) as a yellow solid. LCMS (ESI, m/z) : 682 [M+H] ⁺.

Synthesis of tert-butyl (S) -3- ( (4- (6- (1H-pyrazol-3-yl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) azepane-1-carboxylate

A 40 mL vial was charged with tert-butyl (3S) -3- ( {4- [1- (benzenesulfonyl) -6- (1H-pyrazol-3-yl) indol-3-yl] -5- (trifluoromethyl) pyrimidin-2-yl} amino) azepane-1-carboxylate (80.0 mg, 0.117 mmol, 1.00 equiv) , sodium hydroxide (4.7 mg, 0.117 mmol, 1.00 equiv) , 1, 4-dioxane (1 mL) and water (1 mL) at room temperature. The mixture was stirred for overnight at room temperature and diluted with water (10 mL) . The resulting mixture was extracted with ethyl acetate (2 x 10 mL) . The combined organic layers were washed with deionized water (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 (petroleum ether /ethyl acetate = 1: 1) to afford tert-butyl (3S) -3- ( {4- [6- (1H-pyrazol-3-yl) -1H-indol-3-yl] -5- (trifluoromethyl) pyrimidin-2-yl} amino) azepane-1-carboxylate as a yellow solid (40.0 mg, 63%yield) . LCMS (ESI, m/z) : 542 [M+H] ⁺.

Synthesis of (S) -N- (4- (6- (1H-pyrazol-3-yl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) azepan-3-amine trifluoroacetic acid salt

A 25 mL round-bottom flask was charged with tert-butyl (3S) -3- ( {4- [6- (1H-pyrazol-3-yl) -1H-indol-3-yl] -5- (trifluoromethyl) pyrimidin-2-yl} amino) azepane-1-carboxylate (35.0 mg, 0.0650 mmol, 1.00 equiv) , TFA (0.6 mL) and DCM (3 mL) at room temperature. The mixture was stirred for 2 h at room temperature and concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions: Column: Kinetex EVO C ₁₈ Column, 21.2*150, 5um; Mobile Phase A: Water (0.05%TFA) , Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 5%B to 42%B in 7 min; Wave Length: 220 nm; to afford (3S) -N- {4- [6- (1H-pyrazol-3-yl) -1H-indol-3-yl] -5- (trifluoromethyl) pyrimidin-2-yl} azepan-3-amine trifluoroacetic acid salt (20.5 mg, 56%yield) as a yellow solid. LCMS (ESI, m/z) : 442 [M+H-TFA] ⁺. ¹H-NMR (400 MHz, Methanol-d ₄) δ 8.61 (s, 1H) , 8.42 -8.32 (m, 1H) , 7.89 (d, J = 4.0 Hz, 2H) , 7.74 (d, J =2.0 Hz, 1H) , 7.64 (d, J = 6.0 Hz, 1H) , 6.74 (d, J = 2.0 Hz, 1H) , 4.46 -4.41 (m, 1H) , 3.55 (m, 1H) , 3.48 -3.30 (m, 2H) , 3.25 -3.20 (m, 1H) , 2.23 (d, J = 4.0 Hz, 1H) , 2.02 -1.79 (m, 4H) , 1.75 (d, J =6.0 Hz, 1H) .

Methyl (S) - (3- (2- (azepan-3-ylamino) -5- (trifluoromethyl) pyrimidin-4-yl) -7-bromo-1H-indol-6-yl) carbamate 2, 2, 2-trifluoroacetate

Synthesis of methyl (S) - (3- (2- (azepan-3-ylamino) -5- (trifluoromethyl) pyrimidin-4-yl) -7-bromo-1H-indol-6-yl) carbamate 2, 2, 2-trifluoroacetate

Synthesis of tert-butyl (3S) -3- [ (4- {7-bromo-6- [ (methoxycarbonyl) amino] -1H-indol-3-yl} -5- (trifluoromethyl) pyrimidin-2-yl) amino] azepane-1-carboxylate

A mixture of 7-bromo-3- (2- { [ (3S) -1- (tert-butoxycarbonyl) azepan-3-yl] amino} -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carboxylic acid (From EP-A-031, 77.0 mg, 0.129 mmol, 1.00 equiv) , diphenylphosphoryl azide (70.8 mg, 0.258 mmol, 2.00 equiv) , triethylamine (26.0 mg, 0.258 mmol, 2.00 equiv) and toluene (4 mL) was stirred for overnight at 100 ℃. Then methanol (5 mL) was added to above mixture and stirred for additional 2 h at 100 ℃. The resulting mixture was concentrated under reduced pressure and quenched with water (30 mL) . The resulting mixture was extracted with ethyl acetate (3 x 100 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 petroleum ether /ethyl acetate (1/1) to afford tert-butyl (3S) -3- [ (4- {7-bromo-6- [ (methoxycarbonyl) amino] -1H-indol-3-yl} -5- (trifluoromethyl) pyrimidin-2-yl) amino] azepane-1-carboxylate (60.0 mg, 74%yield) as a yellow solid. LCMS (ESI, m/z) : 627 [M+H] ⁺.

Synthesis of tert-butyl (3S) -3- [ (4- {7-bromo-6- [ (methoxycarbonyl) amino] -1H-indol-3-yl} -5- (trifluoromethyl) pyrimidin-2-yl) amino] azepane-1-carboxylate trifluoroacetic acid salt

A mixture of tert-butyl (3S) -3- [ (4- {7-bromo-6- [ (methoxycarbonyl) amino] -1H-indol-3-yl} -5- (trifluoromethyl) pyrimidin-2-yl) amino] azepane-1-carboxylate (60.0 mg, 0.096 mmol, 1.00 equiv) and TFA (1 mL) in dichloromethane (4 mL) was stirred for 3 h at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions: Column: Kinetex EVO C ₁₈, 21.2*250mm, 5μm; Mobile Phase A: Water (0.05%TFA) , Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 25%B to 51%B in 7 min; Wave Length: 254 nm to afford tert-butyl (3S) -3- [ (4- {7-bromo-6- [ (methoxycarbonyl) amino] -1H-indol-3-yl} -5- (trifluoromethyl) pyrimidin-2-yl) amino] azepane-1-carboxylate trifluoroacetic acid salt (17.6 mg, 29%yield) as a yellow solid. LCMS (ESI, m/z) : 527 [M+H-TFA] ⁺. ¹H NMR (300 MHz, Methanol-d ₄) δ 8.61 (s, 1H) , 8.30 (s, 1H) , 7.85 (s, 1H) , 7.44 (d, J = 4.0 Hz, 1H) , 4.40 (d, J = 2.0 Hz, 1H) , 3.77 (s, 3H) , 3.56 -3.41 (m, 1H) , 3.39 -3.34 (m, 2H) , 3.24 -3.18 (m, 1H) , 2.24 -2.19 (m, 1H) , 2.01 -1.86 (m, 4H) , 1.74 -1.69 (m, 1H) .

(S) -3- (2- (azepan-3-ylamino) -5- (trifluoromethyl) pyrimidin-4-yl) -7-bromo-1H-indole-6-carboxylic acid

Synthesis of (S) -3- (2- (azepan-3-ylamino) -5- (trifluoromethyl) pyrimidin-4-yl) -7-bromo-1H-indole-6-carboxylic acid

A solution of 2, 4-dichloro-5- (trifluoromethyl) pyrimidine (1.71 g, 7.872 mmol, 2.00 equiv) in 1, 2-dichloroethane (10 mL) was treated with aluminium chloride (1.10 g, 8.26 mmol, 2.10 equiv) for 30 min at 90 ℃. Then methyl 7-bromo-1H-indole-6-carboxylate (1.00 g, 3.94 mmol, 1.00 equiv) was added to above mixture in portions at 90℃. The resulting mixture was stirred for 3 h at 90 ℃ and quenched with water (10 mL) . The resulting mixture was extracted with ethyl acetate (3 x 20 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 petroleum ether /ethyl acetate (3/1) to afford crude product as a yellow solid. The residue was purified by reverse flash chromatography with the following conditions: column, C ₁₈ column; mobile phase, acetonitrile in water, 10%to 100%gradient in 40 min; detector, UV 254 nm to afford methyl 7-bromo-3- [2-chloro-5- (trifluoromethyl) pyrimidin-4-yl]-1H-indole-6-carboxylate (420 mg, 24%yield) as a white solid. LCMS (ESI, m/z) : 434 [M+H] ⁺.

Synthesis of 7-bromo-3- (2- { [ (3S) -1- (tert-butoxycarbonyl) azepan-3-yl] amino} -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carboxylic acid

A mixture of methyl 7-bromo-3- (2- { [ (3S) -1- (tert-butoxycarbonyl) azepan-3-yl] amino} -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carboxylate (420 mg, 0.686 mmol, 1.00 equiv) , sodium hydroxide (54.8 mg, 1.37 mmol, 2.00 equiv) and water (5 mL) in methanol (20 mL) was stirred for overnight at 60 ℃. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with water (5 mL) . The residue was acidified to pH 6 with HCl (1M aq) . The resulting mixture was concentrated under reduced pressure to afford 7-bromo-3- (2- { [ (3S) -1- (tert-butoxycarbonyl) azepan-3-yl] amino} -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carboxylic acid (450 mg, crude) as a yellow solid. LCMS (ESI, m/z) : 598 [M+H] ⁺.

A mixture of 7-bromo-3- (2- { [ (3S) -1- (tert-butoxycarbonyl) azepan-3-yl] amino} -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carboxylic acid (20.0 mg, 0.0330 mmol, 1.00 equiv) and TFA (1 mL) in dichloromethane (5 mL) was stirred for 3 h at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions: Column: YMC-Actus Triart C ₁₈ ExRS, 20*250 mm, 5 μm; Mobile Phase A: Water (10 mmol/L NH ₄HCO ₃) , Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 17%B to 37%B in 7 min; Wave Length: 254 nm to afford 3- {2- [ (3S) -azepan-3-ylamino] -5- (trifluoromethyl) pyrimidin-4-yl} -7-bromo-1H-indole-6-carboxylic acid (3.20 mg, 19%yield) as an off-white solid. LCMS (ESI, m/z) : 499 [M+H] ⁺. 1H-NMR (300 MHz, Methanol-d ₄) δ 8.55 (s, 1H) , 8.51 -8.01 (m, 1H) , 7.87 (s, 1H) , 7.39 (d, J = 6.0 Hz, 1H) , 4.38 (s, 1H) , 3.45 -3.37 (s, 1H) , 3.16 -3.12 (m, 3H) , 2.25 (d, J = 8.0 Hz, 1H) , 1.91 (d, J = 4.0 Hz, 4H) , 1.72 (d, J = 4.0 Hz, 1H) .

(S) - (3- (2- (azepan-3-ylamino) -5- (trifluoromethyl) pyrimidin-4-yl) -6-methoxy-1H-indol-7-yl) dimethylphosphine oxide

Synthesis of (S) - (3- (2- (azepan-3-ylamino) -5- (trifluoromethyl) pyrimidin-4-yl) -6-methoxy-1H-indol-7-yl) dimethylphosphine oxide

Synthesis of 7-bromo-6-methoxy-1H-indole

To a mixture of 2-bromo-1-methoxy-3-nitrobenzene (1.5 g, 6.49 mmol) in THF (20 mL) at -78 ℃ was added vinylmagnesium bromide (1M solution in THF, 32.5 mL, 32.5 mmol) . The mixture was stirred at -78 ℃ for 2 h under N ₂. The reaction was quenched with NH ₄Cl solution (20 mL) and extracted with EtOAc (30 mL x 2) . The combined organic layers were washed with brine (50 mL) , dried over anhydrous Na ₂SO4, and concentrated in vacuo to give the crude, which was purified by Prep-TLC (eluent: PE/EtOAc = 20/1) to give the product 7-bromo-6-methoxy-1H-indole (300 mg, yield: 20.5%) as a yellow solid. ESI-MS [M +H] ⁺: 226.1.

To a mixture of 2, 4-dichloro-5- (trifluoromethyl) pyrimidine (575 mg, 2.66 mmol) in DCE (30 mL) was added AlCl ₃ (371 mg, 2.79 mmol) . The mixture was stirred at 90 ℃ for 0.5 h under N ₂. Then 7-bromo-6-methoxy-1H-indole (300 mg, 1.33 mmol) was added. The reaction mixture was stirred at 90℃ for another 3 h. The reaction was quenched with MeOH (20 mL) and water (15 mL) . The mixture was filtered. The filter cake was washed with MeOH (10 mL) and dried to give the product 7-bromo-3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -6-methoxy-1H-indole (50 mg, yield: 9.3%) as a yellow solid. ESI-MS [M +H] ⁺: 406.2.

A mixture of 7-bromo-3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -6-methoxy-1H-indole (50 mg, 0.12 mmol) , tert-butyl (S) -3-aminoazepane-1-carboxylate (31 mg, 0.14 mmol) and DIPEA (46 mg, 0.36 mmol) in i-PrOH (5 mL) was irradiated in microwave at 100 ℃ for 1 h. The reaction mixture was concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 20/1) to give tert-butyl (S) -3- ( (4- (7-bromo-6-methoxy-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) azepane-1-carboxylate (55 mg, yield: 78.6%) as a white solid. ESI-MS [M + H] ⁺: 584.1.

Synthesis of tert-butyl (S) -3- ( (4- (7- (dimethylphosphoryl) -6-methoxy-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) azepane-1-carboxylate

To a mixture of tert-butyl (S) -3- ( (4- (7-bromo-6-methoxy-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) azepane-1-carboxylate (55 mg, 0.094 mmol) , dimethylphosphine oxide (35 mg, 0.45 mmol) and Xantphos (5.2 mg, 0.0094 mmol) in DMF (10 mL) was added Pd (OAc) ₂ (2.1 mg, 0.0094 mmol) . The mixture was irradiated in microwave at 120 ℃ for 2 h under N ₂. 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 = 15/1) to give tert-butyl (S) -3- ( (4- (7- (dimethylphosphoryl) -6-methoxy-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) azepane-1-carboxylate (25 mg, yield: 39.6%) as a colourless oil. ESI-MS [M +H] +: 582.2.

To a mixture of tert-butyl (S) -3- ( (4- (7- (dimethylphosphoryl) -6-methoxy-1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) azepane-1-carboxylate (25 mg, 0.04 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 NH ₃ (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 ( (S) - (3- (2- (azepan-3-ylamino) -5- (trifluoromethyl) pyrimidin-4-yl) -6-methoxy-1H-indol-7-yl) dimethylphosphine oxide (12 mg, yield: 63.2%) as a white solid.

ESI-MS [M +H] ⁺: 482.2.

1H NMR (400 MHz, MeOD) δ 8.72 –8.45 (m, 2H) , 7.91 –7.83 (m, 1H) , 7.12 –7.03 (m, 1H) , 4.40 –4.32 (m, 1H) , 4.00 (s, 3H) , 3.41 –3.35 (m, 1H) , 3.22 –3.04 (m, 3H) , 2.22 –2.14 (m, 1H) , 2.01 –1.77 (m, 8H) , 1.76 –1.67 (m, 1H) , 1.40 –1.23 (m, 2H) .

(S) - (3- (2- (azepan-3-ylamino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indol-6-yl) (piperazin-1-yl) methanone

Synthesis of (S) - (3- (2- (azepan-3-ylamino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indol-6-yl) (piperazin-1-yl) methanone

Synthesis of tert-butyl (S) -3- ( (4- (6- (4- (tert-butoxycarbonyl) piperazine-1-carbonyl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) azepane-1-carboxylate

A mixture of (S) -3- (2- ( (1- (tert-butoxycarbonyl) azepan-3-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carboxylic acid (80 mg, 0.15 mmol) , tert-butyl piperazine-1-carboxylate (55.8 mg, 0.30 mmol) , HATU (114 mg, 0.30 mmol) and DIPEA (77.4 mg, 0.60 mmol) in DMF (5 mL) was stirred at room temperature for 3 h. The mixture was diluted with EA (50 mL) and washed with water (30 mL x 3) . The organic layer was concentrated in vacuo to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 10/1) to give tert-butyl (S) -3- ( (4- (6- (4- (tert-butoxycarbonyl) piperazine-1-carbonyl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) azepane-1-carboxylate (65 mg, yield: 63.1 %) as a white solid. ESI-MS [M + H] +: 688.2

To a mixture of tert-butyl (S) -3- ( (4- (6- (4- (tert-butoxycarbonyl) piperazine-1-carbonyl) -1H-indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) azepane-1-carboxylate (65 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 1 h. The reaction mixture was quenched with NH ₃ (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 (S) - (3- (2- (azepan-3-ylamino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indol-6-yl) (piperazin-1-yl) methanone (22.44 mg, yield: 51.2 %) as a white solid.

ESI-MS [M +H] ⁺: 488.2.

1H NMR (400 MHz, MeOD) δ 8.61 (s, 1H) , 8.39 (s, 1H) , 7.96 (s, 1H) , 7.59 (s, 1H) , 7.26 (d, J = 8.2 Hz, 1H) , 4.55 –4.27 (m, 1H) , 3.95 –3.43 (m, 4H) , 3.32 –3.14 (m, 3H) , 3.03 –2.67 (m, 6H) , 2.30 –2.11 (m, 1H) , 2.05 –1.72 (m, 3H) , 1.82 –1.63 (m, 1H) .

(S) -N4- (6- (1H-pyrazol-1-yl) pyridin-2-yl) -N2- (piperidin-3-yl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine

Synthesis of (S) -N4- (6- (1H-pyrazol-1-yl) pyridin-2-yl) -N2- (piperidin-3-yl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine

Synthesis of 2-bromo-6- (1H-pyrazol-1-yl) pyridine

A mixture of 2, 6-dibromopyridine (1 g, 4.26 mmol) , 1H-pyrazole (377 mg, 5.54 mmol) and t-BuOK (1.43 g, 12.78 mmol) in dioxane (30 mL) was stirred at 100℃ for 24h. H ₂O (100 mL) was added to the reaction and the mixture was extracted with EtOAc (30 mL x 3) . The combined organic layers were washed with brine, dried over Na ₂SO ₄, concentrate in vacuo to give the crude, which was purified with silica gel chromatography (EtOAc/PE = 1/3) to give the 2-bromo-6- (1H-pyrazol-1-yl) pyridine (600 mg, yield: 62%) as a yellow solid. ESI-MS [M +H] ⁺: 229.2.

Synthesis of tert-butyl (6- (1H-pyrazol-1-yl) pyridin-2-yl) carbamate

To a mixture of 2-bromo-6- (1H-pyrazol-1-yl) pyridine (600 mg, 2.63 mmol) , tert-butyl carbamate (923 mg, 7.89 mmol) , Pd ₂ (dba) ₃ (241 mg, 0.263 mmol) , Xantphos (152 mg, 0.263 mmol) and Cs ₂CO ₃ (2.57 g, 7.89 mmol) in toluene (30 mL) was stirred at 100℃ for 16 h under N ₂. 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: EtOAc/PE = 1/3) to give tert-butyl (6- (1H-pyrazol-1-yl) pyridin-2-yl) carbamate (360 mg, yield: 53%) as a yellow solid. ESI-MS [M +H]+: 261.2.

Synthesis of 6- (1H-pyrazol-1-yl) pyridin-2-amine

To a mixture of tert-butyl (6- (1H-pyrazol-1-yl) pyridin-2-yl) carbamate (360 mg, 1.38 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 NH ₃ (7M solution in MeOH, 10.0 mL) and concentrated in vacuo to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 10/1) to give 6- (1H-pyrazol-1-yl) pyridin-2-amine (180 mg, yield: 82%) as a white solid. ESI-MS [M +H] +: 161.2.

Synthesis of N- (6- (1H-pyrazol-1-yl) pyridin-2-yl) -2-chloro-5- (trifluoromethyl) pyrimidin-4-amine

To a mixture of 6- (1H-pyrazol-1-yl) pyridin-2-amine (100 mg, 0.63 mmol) , 2, 4-dichloro-5- (trifluoromethyl) pyrimidine (272 mg, 1.26 mmol) and DIPEA (244 mg, 1.89 mmol) in IPA (5 mL) was stirred at 95℃ for 8 h under N ₂. The mixture was concentrated to give the crude product, which was purified by Prep-TLC (eluent: DCM/MeOH = 15/1) to give N- (6- (1H-pyrazol-1-yl) pyridin-2-yl) -2-chloro-5- (trifluoromethyl) pyrimidin-4-amine (120 mg, yield: 56%) as a white solid. ESI-MS [M + H] +: 341.2.

Synthesis of tert-butyl (S) -3- ( (4- ( (6- (1H-pyrazol-1-yl) pyridin-2-yl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylate

To a mixture of N- (6- (1H-pyrazol-1-yl) pyridin-2-yl) -2-chloro-5- (trifluoromethyl) pyrimidin-4-amine (40 mg, 0.12 mmol) , tert-butyl (S) -3-aminopiperidine-1-carboxylate (24 mg, 0.24 mmol) and DIPEA (46 mg, 0.36 mmol) in i-PrOH (3 mL) was irradiated in microwave at 80℃ for 2 h. The reaction mixture was concentrated to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 20/1) to give tert-butyl (S) -3- ( (4- ( (6- (1H-pyrazol-1-yl) pyridin-2-yl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (30 mg, yield: 25%) as a yellow solid. ESI-MS [M + H] ⁺: 505.2.

To a mixture of tert-butyl (S) -3- ( (4- ( (6- (1H-pyrazol-1-yl) pyridin-2-yl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) piperidine-1-carboxylate (30 mg, 0.60 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 NH ₃ (7M solution in MeOH, 2.0 mL) and concentrated in vacuo to give the crude, which was purified by Prep-TLC (eluent: DCM/MeOH = 10/1) to give (S) -N4- (6- (1H-pyrazol-1-yl) pyridin-2-yl) -N2- (piperidin-3-yl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine (15 mg, yield: 62%) as a white solid.

ESI-MS [M +H] ⁺: 405.2.

1H NMR (400 MHz, MeOD) δ 8.48 (s, 1H) , 8.40 –8.06 (m, 2H) , 7.96 –7.82 (m, 1H) , 7.66 (s, 1H) , 7.56 –7.52 (m, 1H) , 6.48 –6.38 (m, 1H) , 3.96 –3.84 (m, 1H) , 3.11 (d, J = 9.9 Hz, 1H) , 2.84 (d, J = 12.4 Hz, 1H) , 2.56 –2.35 (m, 2H) , 2.06 –1.96 (m, 1H) , 1.78 –1.66 (m, 1H) , 1.55 –1.42 (m, 2H) .

Methyl (S) -7-bromo-3- (2- ( (6, 6-dimethylpiperidin-3-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carboxylate

Synthesis of methyl (S) -7-bromo-3- (2- ( (6, 6-dimethylpiperidin-3-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carboxylate

Synthesis of tert-butyl N- [ (3S) -6, 6-dimethylpiperidin-3-yl] carbamate

Tert-butyl N- [ (3S) -6-oxopiperidin-3-yl] carbamate (1.00 g, 4.67 mmol, 1.00 equiv) was dissolved in THF (100 mL) , the solution was cooled to -10℃. Zirconium (IV) chloride (2.61 g, 11.2 mmol, 2.40 equiv) was added and the mixture was stirred for 30 min at -10 ℃. Then bromo (methyl) magnesium (20.2 mL, 60.7 mmol, 13.0 equiv, 3M in Et ₂O) was added, the reaction mixture was allowed to slowly warm up to room temperature and then stirred for overnight at room temperature. The solution was quenched with 30%NaOH (20 mL) and concentrated under reduced pressure. The mixture was diluted with ethyl acetate (100 mL) . The organic layer was washed with water (3 x 50 mL) , dried over anhydrous sodium sulfate, filtrated, and concentrated under reduced pressure to afford crude product tert-butyl N- [ (3S) -6, 6-dimethylpiperidin-3-yl] carbamate (1.06 g, crude) as a yellow oil that was used without further purification. LCMS (ESI, m/z) : 229 [M+H] ⁺.

Synthesis of phenyl (3S) -6, 6-dimethylpiperidin-3-amine

A solution of tert-butyl N- [ (3S) -6, 6-dimethylpiperidin-3-yl] carbamate (1.06 g, 4.64 mmol, 1.00 equiv) and trifluoroacetic acid (5 mL) in dichloromethane (10 mL) was stirred for 2 h at room temperature and concentrated under reduced pressure to afford (3S) -6, 6-dimethylpiperidin-3-amine (500 mg, crude) as a brown oil. LCMS (ESI, m/z) : 129 [M+H] ⁺.

A solution of 2, 4-dichloro-5- (trifluoromethyl) pyrimidine (1.71 g, 7.87 mmol, 2.00 equiv) in 1, 2-dichloroethane (10 mL) was treated with aluminium chloride (1.10 g, 8.26 mmol, 2.10 equiv) for 30 min at 90 ℃. Then methyl 7-bromo-1H-indole-6-carboxylate (1.00 g, 3.94 mmol, 1.00 equiv) was added to above mixture in portions at 90℃. The resulting mixture was stirred for 3 h at 90 ℃and quenched with water (10 mL) . The resulting mixture was extracted with ethyl acetate (3 x 20 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 petroleum ether /ethyl acetate (3/1) to afford crude product as a yellow solid. The residue was purified by reverse flash chromatography with the following conditions: column, C ₁₈ column; mobile phase, acetonitrile in water, 10%to 100%gradient in 40 min; detector, UV 254 nm to afford methyl 7-bromo-3- [2-chloro-5- (trifluoromethyl) pyrimidin-4-yl] -1H-indole-6-carboxylate (420 mg, 24%yield) as a white solid. LCMS (ESI, m/z) : 434 [M+H] ⁺.

Synthesis of methyl 7-bromo-3- (2- { [ (3S) -6, 6-dimethylpiperidin-3-yl] amino} -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carboxylate

A mixture of methyl 7-bromo-3- [2-chloro-5- (trifluoromethyl) pyrimidin-4-yl] -1H-indole-6-carboxylate (90.0 mg, 0.207 mmol, 1.00 equiv) , (3S) -6, 6-dimethylpiperidin-3-amine (26.5 mg, 0.207 mmol, 1.00 equiv) and DIEA (80.3 mg, 0.621 mmol, 3.00 equiv) in NMP (1.5 mL) was irradiated with microwave radiation for 3 h at 130 ℃. The crude product was purified by prep-HPLC with the following conditions: Column: Kinetex EVO C ₁₈, 21.2*250mm, 5μm; Mobile Phase A: Water (10 mmol/L NH ₄HCO ₃) , Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 49%B to 69%B in 7 min; Wave Length: 254 nm to afford methyl 7-bromo-3- (2- { [ (3S) -6, 6-dimethylpiperidin-3-yl] amino} -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carboxylate (49 mg, 45%yield) as an off-white solid. LCMS (ESI, m/z) : 526 [M+H] ⁺. ¹H-NMR (300 MHz, Methanol-d ₄) δ 8.55 (s, 1H) , 8.32 (d, J = 18.0 Hz, 1H) , 7.98 (s, 1H) , 7.69 (d, J = 6.0 Hz, 1H) , 4.06 (s, 1H) , 3.94 (s, 3H) , 3.15 (d, J = 6.0 Hz, 1H) , 2.90 -2.83 (m, 1H) , 2.02 (d, J = 6.0 Hz, 1H) , 1.81 -1.68 (m, 2H) , 1.59 -1.52 (m, 1H) , 1.27 -1.21 (m, 6H) .

(S) -7-bromo-3- (2- ( (6, 6-dimethylpiperidin-3-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carboxylic acid

Synthesis of (S) -7-bromo-3- (2- ( (6, 6-dimethylpiperidin-3-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carboxylic acid

Synthesis of tert-butyl N- [ (3S) -6, 6-dimethylpiperidin-3-yl] carbamate

Synthesis of phenyl (3S) -6, 6-dimethylpiperidin-3-amine

A solution of 2, 4-dichloro-5- (trifluoromethyl) pyrimidine (1.71 g, 7.87 mmol, 2.00 equiv) in 1, 2-dichloroethane (10 mL) was treated with aluminium chloride (1.10 g, 8.26 mmol, 2.10 equiv) for 30 min at 90 ℃. Then methyl 7-bromo-1H-indole-6-carboxylate (1.00 g, 3.94 mmol, 1.00 equiv) was added to above mixture in portions at 90℃. The resulting mixture was stirred for 3 h at 90 ℃and quenched with water (10 mL) . The resulting mixture was extracted with ethyl acetate (3 x 20 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 petroleum ether /ethyl acetate (3/1) to afford crude product as a yellow solid. The residue was purified by reverse flash chromatography with the following conditions: column, C ₁₈ column; mobile phase, acetonitrile in water, 10%to 100%gradient in 40 min; detector, UV 254 nm to afford methyl 7-bromo-3- [2-chloro-5- (trifluoromethyl) pyrimidin-4-yl]-1H-indole-6-carboxylate (420 mg, 24%yield) as a white solid. LCMS (ESI, m/z) : 434 [M+H] ⁺.

A mixture of methyl 7-bromo-3- [2-chloro-5- (trifluoromethyl) pyrimidin-4-yl] -1H-indole-6-carboxylate (90.0 mg, 0.207 mmol, 1.00 equiv) , (3S) -6, 6-dimethylpiperidin-3-amine (26.5 mg, 0.207 mmol, 1.00 equiv) and DIEA (80.3 mg, 0.621 mmol, 3.00 equiv) in NMP (1.5 mL) was irradiated with microwave radiation for 3 h at 130 ℃. The crude product was purified by prep-HPLC with the following conditions: Column: Kinetex EVO C ₁₈, 21.2*250mm, 5μm; Mobile Phase A: Water (10 mmol/L NH ₄HCO ₃) , Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 49%B to 69%B in 7 min; Wave Length: 254 nm to afford methyl 7-bromo-3- (2- { [ (3S) -6, 6-dimethylpiperidin-3-yl] amino} -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carboxylate (49 mg, 45%yield) as an off-white solid.

Synthesis of 7-bromo-3- (2- { [ (3S) -6, 6-dimethylpiperidin-3-yl] amino} -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carboxylic acid

A mixture of methyl 7-bromo-3- (2- { [ (3S) -6, 6-dimethylpiperidin-3-yl] amino} -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carboxylate (30.0 mg, 0.0570 mmol, 1.00 equiv) , sodium hydroxide (4.56 mg, 0.114 mmol, 2.00 equiv) and water (0.5 mL) in ethanol (2 mL) was stirred for overnight at 60 ℃. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with water (5mL) . The residue was acidified to pH 6 with HCl (1M aq) . The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C ₁₈ Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH ₄HCO ₃+0.1%NH ₃. H ₂O) , Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 14%B to 44%B in 7 min; Wave Length: 254 nm to afford 7-bromo-3- (2- { [ (3S) -6, 6-dimethylpiperidin-3-yl] amino} -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carboxylic acid (13.8 mg, 47%yield) as a white solid. LCMS (ESI, m/z) : 512 [M+H] ⁺. ¹H-NMR (300 MHz, Methanol-d ₄) δ 8.53 (s, 1H) , 8.32 -8.04 (m, 1H) , 7.83 (s, 1H) , 7.33 (d, J = 6.0 Hz, 1H) , 4.28 -4.16 (m, 1H) , 3.22 -3.14 (m, 1H) , 2.93 (d, J = 26.0 Hz, 1H) , 2.04 (d, J = 6.0 Hz, 1H) , 1.91 -1.74 (m, 3H) , 1.39 (s, 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 MgCl ₂, 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) .

IC ₅₀ of compound for CDKs was calculated by Prism (GraphPad) using a four-parameter nonlinear curve fit.

The CDK inhibition results (IC ₅₀) without or with pre-incubation are summarized in Table 2. The CDK may be CDK7.

Table 2A. List of CDK inhibition; The CDK may be CDK7.

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.

Table 2B. List of CDK inhibition; The CDK may be CDK7.

For evaluating the CDK inhibitory activity of the present application, the following ranges for the IC ₅₀ [nM] were applied:

A: IC ₅₀ ≤ 100 nM;

B: 100 nM < IC ₅₀ ≤ 500 nM;

C: 500 nM < IC ₅₀ ≤ 1000 nM;

D: 1000 nM < IC ₅₀.

Table 2C. List of CDK inhibition; The CDK may be CDK7.

A: IC ₅₀ ≤ 100 nM;

B: 100 nM < IC ₅₀ ≤ 500 nM;

C: 500 nM < IC ₅₀ ≤ 1000 nM;

D: 1000 nM < IC ₅₀.

Table 2D. List of CDK inhibition; The CDK may be CDK7.

A: IC50 ≤ 100 nM;

B: 100 nM < IC50 ≤ 500 nM;

C: 500 nM < IC50 ≤ 1000 nM;

D: 1000 nM < IC50.

Example 3 Inhibition of cell proliferation

Exemplary compounds of the invention were tested at different concentrations (from 10 μΜ to 610 pM; 4 fold serial dilutions) for their ability to inhibit the proliferation of various cancer cell lines. Known kinase inhibitor staurosporine were used as positive controls. Cells were grown in the indicated media listed below. All cell lines were supplemented with FBS (Life Technologies) and 100 U-mL ^-1 penicillin, 100 μg·mL ^-1 streptomycin (Invitrogen) and cultured at 37 ℃ in a humidified chamber in the presence of 5%CO ₂. Proliferation assays were conducted over a 120 hour time period. CyQuant assay kit (ThermoFisher) was used to assess the anti-proliferative effects of the compounds following manufacturer's directions.

The following cancer cell lines may be tested with the exemplary media conditions indicated:

Breast cancer cell lines

-HCC70: RPMI1640 + 10%FBS + 1%Glutamax

Ovarian cancer cell line

-OVCAR3: RPMI 1640 + 0.01 mg/ml bovine insulin + 20%FBS + 1%Glutamax

Prostate cancer cell line

-DU145: EMEM+10%FBS + 1%Glutamax

Colon cancer cell line

-HCT-116: McCoy`5A+10%FBS + 1%Glutamax

Exemplary results of these assays are set forth in following Tables, wherein:

"A" represents an IC ₅₀ value of less than 0.1 μM;

"B" represents an IC ₅₀ value of between 0.1 μM and 0.2 μM, inclusive; and

"C" represents an IC ₅₀ value of greater than 0.2 μM.

Table 3. IC ₅₀ Value of Inhibition of cell proliferation

Example 4 Safety Assay

Exemplary compounds of the invention were tested for interfering of CYP2D6 activity. CYP2D6 is an important site of drug-drug interactions, leading to increased drug toxicity. Assays with human CYP2D6 determined the inhibitory potential (IC50) of each drug. These data showed inhibitory effects in CYP2D6 activity in each compound tested. Alterations in CYP2D6 activity may result in complex drug-drug interactions leading to elevated plasma levels of drugs and increased risk for toxicity. Wherein:

"A" represents an IC ₅₀ value of greater than 1 μM;

"B" represents an IC ₅₀ value of between 0.05 μM and 1 μM, inclusive; and

"C" represents an IC ₅₀ value of less than 0.05 μM.

Table 4. IC ₅₀ Value of CYP2D6

As SY-5609 is a current benchmark for CDK inhibitor, the compound in this application is much safer than SY-5609; And the compounds of the present application would have both better safety and superior tumor growth inhibitory effect.

While preferred embodiments of the present 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. It is not intended that the invention be limited by the specific examples provided within the specification. While the invention has been described with reference to the aforementioned specification, the descriptions and illustrations of the embodiments herein are not meant to be construed in a limiting sense. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. Furthermore, it shall be understood that all aspects of the invention are not limited to the specific depictions, configurations or relative proportions set forth herein which depend upon a variety of conditions and variables. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is therefore contemplated that the invention shall also cover any such alternatives, modifications, variations or equivalents. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

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 7 or more-ring-membered heterocycle,

each X ₁, X ₂, X ₃, X ₄, and X ₅ is independently selected from optionally substituted atom,

each R ₁, R ₂ and R ₃ is independently absent or is independently selected from optional substituents, m is 0 or more, n is 0 or more.
The compound of claim 1, said A is optionally substituted 6-ring-membered ring.
The compound of any one of claims 1-2, said A is optionally substituted aryl.
The compound of any one of claims 1-3, said A is optionally substituted phenyl.
The compound of any one of claims 1-4, said A is substituted with one or more R ₃, each said R ₃ is independently absent or is independently selected from optional substituents.
The compound of any one of claims 1-5, said m is 1 or 2.
The compound of any one of claims 1-6, each said R ₃ is independently 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 1-7, each said R ₃ is independently selected from the group consisting of hydrogen, F, Cl, Br, CN, optionally substituted formyl, optionally substituted amino, optionally substituted hydroxyl, optionally substituted P (=O) H ₂, and optionally substituted sulfonyl.
The compound of any one of claims 1-8, each said R ₃ is independently optionally substituted 6-ring-membered ring.
The compound of any one of claims 1-9, each said R ₃ is independently optionally substituted ring containing one or more N and/or one or more O.
The compound of any one of claims 1-10, each said R ₃ is independently optionally substituted ring containing one or two N.
The compound of any one of claims 1-11, each said R ₃ is independently optionally substituted ring containing one O.
The compound of any one of claims 1-12, each said R ₃ is independently optionally substituted heterocycle, or optionally substituted heteroaryl.
The compound of any one of claims 1-13, each said R ₃ is independently selected from the group consisting of optionally substituted piperidinyl, optionally substituted isoxazolyl, and optionally substituted pyrazolyl.
The compound of any one of claims 1-14, said R ₃ is substituted with one or more R _3-1, each said R _3-1 is independently absent or is independently selected from optional substituents.
The compound of claim 15, said R ₃ is substituted with one or two said R _3-1.
The compound of any one of claims 15-16, each said R _3-1 is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted amino, optionally substituted hydroxyl, and optionally substituted ring.
The compound of any one of claims 15-17, each said R _3-1 is independently selected from the group consisting of hydrogen, optionally substituted methyl, optionally substituted ethyl, optionally substituted formyl, optionally substituted amino, and optionally substituted hydroxyl.
The compound of any one of claims 15-18, each said R _3-1 is independently optionally substituted 6-ring-membered ring.
The compound of any one of claims 15-19, each said R _3-1 is independently optionally substituted ring containing one or more N.
The compound of any one of claims 15-20, each said R _3-1 is independently optionally substituted ring containing one or two N.
The compound of any one of claims 15-21, each said R _3-1 is independently optionally substituted heterocycle.
The compound of any one of claims 15-22, each said R _3-1 is independently selected from the group consisting of optionally substituted piperidinyl, and optionally substituted piperazinyl.
The compound of any one of claims 15-23, said R _3-1 is substituted with one or more R _3-2, each said R _3-2 is independently absent or is independently selected from optional substituents.
The compound of claim 24, said R _3-1 is substituted with one or two said R _3-2.
The compound of any one of claims 24-25, each said R _3-2 is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted amino, and optionally substituted hydroxyl.
The compound of any one of claims 24-26, said R _3-2 is substituted with one or more R _3-3, each said R _3-3 is independently absent or is independently selected from optional substituents.
The compound of claim 27, said R _3-2 is substituted with one or two said R _3-3.
The compound of any one of claims 27-28, each said R _3-3 is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted amino, and optionally substituted hydroxyl.
The compound of any one of claims 1-29, said X ₁ is optionally substituted -CH=.
The compound of any one of claims 1-30, said X ₂ is optionally substituted -NH-.
The compound of any one of claims 1-31, said B is optionally substituted 7-ring-membered ring.
The compound of any one of claims 1-32, said B is optionally substituted ring containing no N or one or more N.
The compound of any one of claims 1-33, said B is optionally substituted ring containing one N.
The compound of any one of claims 1-34, said B is optionally substituted azepanyl.
The compound of any one of claims 1-35, said B is substituted with one or more R ₁, each said R ₁ is independently absent or is independently selected from optional substituents.
The compound of any one of claims 1-36, said n is 1.
The compound of any one of claims 1-37, said R ₁ is hydrogen.
The compound of any one of claims 1-38, said R ₂ is hydrogen.
The compound of any one of claims 1-39, said X ₃ is -N=.
The compound of any one of claims 1-40, said X ₄ is optionally substituted -CH=.
The compound of any one of claims 1-41, said X ₅ is optionally substituted -CH=.
The compound of any one of claims 1-42, said X ₅ is substituted with one or more R _X5-1, said R _X5-1 is selected from optional substituents.
The compound of claim 43, said X ₅ is substituted with one said R _X5-1.
The compound of any one of claims 43-44, said R _X5-1 is selected from the group consisting of hydrogen, and optionally substituted alkyl.
The compound of any one of claims 43-45, said R _X5-1 is selected from the group consisting of hydrogen, and optionally substituted methyl.
The compound of any one of claims 43-46, said R _X5-1 is substituted with one or more R _X5-2, each said R _X5-2 is selected from optional substituents.
The compound of claim 47, said R _X5-1 is substituted with three said R _X5-2.
The compound of any one of claims 47-48, each said R _X5-2 is selected from the group consisting of hydrogen and halogen.
The compound of any one of claims 47-49, each said R _X5-2 is selected from the group consisting of hydrogen and F.
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 1-51 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 1-51, or a pharmaceutically acceptable salt, prodrug, or metabolite thereof, or a solvate or hydrate of any of the foregoing.
The method of claim 53, wherein said cyclin-dependent kinase (CDK) is CDK 7.
The method of any of claims 53-54, wherein said method is selected from the group consisting of an in vitro method, an ex vivo method, and an in vivo method.