Novel inhibitors of ubiquitin-specific peptidase 1

Abstract

Provided are: a compound defined by chemical formula 1; a stereoisomer thereof; a tautomer thereof; and pharmaceutically acceptable salts of the compound, the stereoisomer, and the tautomer. The compound according to the present invention can inhibit the activity of the USP1 enzyme. In chemical formula 1, R1 to R4 and [the symbol A in chemical formula 1] are as defined in the present specification.

Description

Novel ubiquitin-specific peptidase 1 inhibitors

[0001] The present invention relates to small organic molecule inhibitors of enzymes. More specifically, the present invention relates to triazine compounds that are effective in inhibiting the activity of USP1 deubiquitinating enzyme.

[0002] Ubiquitin, a small protein consisting of 76 amino acids, plays a crucial role in regulating intracellular protein function. Ubiquitination and deubiquitination are enzyme-mediated processes in which ubiquitin is covalently linked to target proteins or its covalent bonds are broken. Ubiquitination and deubiquitination are involved in important functions such as cell cycle regulation, apoptosis, marking transmembrane proteins such as receptors for removal, and regulating DNA transcription and repair. Within cells, proteins are targeted for destruction by the proteasome by the attachment of three or more ubiquitin tags. Deubiquitination promotes ubiquitin recycling and restores the function of proteins from which ubiquitin has been removed. Deubiquitination is mediated by enzymes, and approximately 95 different deubiquitination enzymes exist in human cells. Among these, ubiquitin-specific protease 1 (USP1) is known to control the repair of DNA damage caused by DNA cross-linking agents such as ionizing radiation, ultraviolet light, and cisplatin. USP1 forms a complex with USP1 associated factor 1 (UAF1) and is activated by UAF1 (Cohn et al., 2007, Mol Cell 28:786-797).

[0003] USP1 is known to be overexpressed in various cancer cells. Therefore, selective inhibition of USP1 can lead to cancer cell death by inhibiting DNA damage repair. Recently, USP1 was identified as a novel synthetic lethality target for BRCA1-mutant cancers through CRISPR-Cas9 screening, and USP1 was also found to function as a synthetic lethality target in BRCA2-mutant cancers. USP1 inhibitors have been reported to exhibit excellent anticancer activity against BRCA-mutant cancers when used in combination with PARP inhibitors. Furthermore, recent studies have shown that USP1 inhibitors have potential as diabetes treatments by suppressing pancreatic beta cell apoptosis. USP1 plays a crucial role in adipogenesis by regulating the ubiquitination of the transcription factor C / EBPβ, and selective USP1 inhibitors show potential for treating metabolic disorders, including obesity. Therefore, USP1 inhibitors may be developed as therapeutic drugs for cancers, including BRCA-mutated cancers, and metabolic diseases, including diabetes and obesity.

[0004] The technical task of the present invention is to provide a novel small organic molecule compound capable of inhibiting the activity of USP1, a deubiquitinating enzyme.

[0005] In one aspect of the present invention, a compound defined by chemical formula 1 or a totoisomer thereof, a stereoisomer thereof, and a pharmaceutically acceptable salt thereof are provided.

[0006] [Chemical Formula 1]

[0007]

[0008] In chemical formula 1 is phenylene, 5-6 membered heteroarylene, 5-6 membered saturated or unsaturated heterocycloalkylene, C 7~10Bridged bicycloalkylene or cubaylene, wherein the phenylene, 5-6 membered heteroarylene, 5-6 membered saturated or unsaturated heterocycloalkylene, C 7~10 Bridged bicycloalkylene or cubaylene optionally comprises one or more hydrogens independently of one another, halogen, C 1~4 Alkoxy, C 1~4 Alkyl, C 1~4 Haloalkyl and C 3~6 which may be substituted with a substituent selected from the group consisting of cycloalkyl;

[0009] R 1 is a 5-6 membered substituted or unsubstituted heteroaryl, and the substituent of the substituted heteroaryl is halogen, C 1~4 Alkyl, C 1~4 Haloalkyl, alkoxy and C 3~6 At least one independently selected from the group consisting of cycloalkyl;

[0010] R 2 is hydrogen, C 1~4 Alkyl, C 1~4 Haloalkyl, deuterium substituted C 1~4 Alkyl, C 2~4 Alkynyl, cyano, C 3~6 Cycloalkyl, saturated or unsaturated 5-6 membered substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted phenyl or 5-6 membered substituted or unsubstituted heteroaryl, wherein the substituted heterocycloalkyl, substituted phenyl or substituted heteroaryl is halogen, C 1~3 Alkyl, C 1~3 Haloalkyl and C 3~6 which may be substituted with one or more substituents independently selected from the group consisting of cycloalkyl;

[0011] R 3 and R'

[0012] R' is absent and R 3 Silver hydrogen, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, cyano or C3~6 Cycloalkyl or,

[0013] R 3 When R and R' are connected to each other, R 3 The six-membered ring carbon and the six-membered ring nitrogen bonded to R' form a pyrazolotriazine fused ring;

[0014] R 4 is selected from substituted or unsubstituted phenyl and 5-6 membered substituted or unsubstituted heteroaryl, wherein the substituent of the substituted phenyl or substituted heteroaryl is C 1~4 Alkoxy, C 1~4 Alkyl, C 1~4 Haloalkyl, C 3~6 At least one independently selected from the group consisting of cycloalkyl and 3-6 membered saturated or unsaturated heterocycloalkyl.

[0015] In one embodiment of the present invention, the compound described above can be represented in a partial form of the following chemical formula 1a.

[0016] [Chemical Formula 1a]

[0017]

[0018] Here R 3a is hydrogen, alkyl or cycloalkyl, , R 1 , R 2 Wow R 4 The definition is as defined above in Chemical Formula 1.

[0019] In another embodiment of the present invention, the compound described above can be represented in a partial form of the following chemical formula 1b.

[0020] [Chemical Formula 1b]

[0021]

[0022] Here , R 1 , R 2 Wow R 4 The definition is as defined above in Chemical Formula 1.

[0023] In one specific embodiment, the compound of the present invention has a structure represented by chemical formula 2.

[0024] [Chemical Formula 2]

[0025]

[0026] R in chemical formula 2 2 is hydrogen, C 1~4 Alkyl, C 1~4 Haloalkyl, deuterium substituted C 1~4 Alkyl, C 2~4 Alkynyl, cyano, C 3~6 Cycloalkyl, saturated or unsaturated 5-6 membered substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted phenyl or 5-6 membered substituted or unsubstituted heteroaryl, wherein the substituted heterocycloalkyl, substituted phenyl or substituted heteroaryl is halogen, C 1~3 Alkyl, C 1~3 Haloalkyl and C 3~6 may be substituted with one or more substituents independently selected from the group consisting of cycloalkyl;

[0027] R 5 Inland R 7 are hydrogen, C respectively 1~4 Alkoxy, C 1~4 Alkyl, C 1~4 Haloalkyl and C 3~6 Independently selected from the group consisting of cycloalkyl;

[0028] R 8 Silver hydrogen, C 1~4 Alkoxy or C 1~4 It is alkyl;

[0029] R 9 is hydrogen, C 1~4 Alkoxy, C 1~4 Alkyl or C 1~4 It is haloalkyl,

[0030] R 10 is a halogen, and when n is 2 or more, each case is independently selected from among the halogens,

[0031] n is an integer from 0 to 4,

[0032] X 1 and X 2 are different elements to choose from among N and C.

[0033] That is X 1 If this N then X 2 is C, and X 1 and X 2 forms a five-membered imidazole ring. On the other hand, X 1 If this is C then X 2 is N, and X 1 and X 2 forms a pyrazole ring

[0034] In another aspect of the present invention, a pharmaceutical composition for the treatment of cancer is provided, comprising a therapeutically effective amount of the compound described above, a stereoisomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0035] In another aspect of the present invention, a method for treating cancer is provided. The method comprises administering to a patient a therapeutically effective amount of a compound of the present invention, such as a compound defined by Formula 1, or a pharmaceutical composition comprising such a compound of the present invention.

[0036] The compound of the present invention can inhibit the activity of ubiquitin-specific peptidase 1.

[0037] Hereinafter, embodiments of the present invention will be described in detail. Prior to this, it should be noted that the terms and words used in this specification and claims should not be construed as limited to their conventional or dictionary meanings. Based on the principle that the inventor can appropriately define the concept of a term to best explain his or her invention, they should be interpreted in a way that aligns with the technical spirit of the present invention.

[0038] Therefore, the embodiments described in this specification are merely examples presented for the purpose of helping to understand the present invention and do not represent all of the technical ideas of the present invention. Therefore, it should be understood that there may be various equivalents and modified examples that can replace them at the time of filing this application.

[0039] Unless otherwise defined, all technical terms used herein have the same meaning as commonly understood by those skilled in the art. While preferred methods and samples are described herein, similar or equivalent methods are also included within the scope of the present invention. Numerical values ​​described herein are considered to include the meaning of "about" even if not explicitly stated. The numerical range indicated using the term "to" herein includes the ranges that include the values ​​described before and after the term "to" as the lower and upper limits, respectively.

[0040] Definition of terms

[0041] In this specification, the prefix "C x~y " or "C x ~C y "(where x and y are natural numbers) is used in front of a functional group to indicate the number of carbon atoms that the functional group has in its backbone. For example, C 1~4 An alkyl group has 1 to 4 carbon atoms, C 1~3An alkyl group refers to an alkyl group having 1 to 3 carbon atoms. For example, C1~C4 alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, sec-butoxy (secondary butoxy), and t-butoxy (tertiary butoxy). For example, C3~C6 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups. In addition, when the number of elements constituting the ring is indicated in front of a ring functional group or compound (including both a carbon ring and a heterocycle) in the present specification, the ring is a ring composed of that number of elements, that is, carbon and / or heteroatoms. For example, a six-membered ring heteroaryl refers to a heteroaryl group that contains one or more heteroatoms and is formed together with carbon, and the number of elements constituting the ring is 6.

[0042] Unless otherwise specified herein, when a functional group is linked to another part of a compound by a bond, the linkage may be via any atom of that functional group, provided that it is a suitable atom. For example, when referring to a propyl group, both prop-1-yl and prop-2-yl are included.

[0043] As used herein, the term "halogen" refers to an atom selected from fluorine, chlorine, bromine and iodine.

[0044] In this specification, "C 1~6 The term "alkyl" refers to a group whose chemical formula is C when n is a natural number from 1 to 6. n H 2n+1 It refers to a saturated hydrocarbon group of 1-valent. C 1~6 Alkyl groups include all leading or branched saturated hydrocarbons having 1 to 6 carbon atoms, such as n-propyl, i-propyl, 2-methyl-ethyl, sec-butyl, tert-butyl, etc.

[0045] In this specification, "C 1~6 The term "alkylene" refers to a group whose chemical formula is C when n is a natural number from 1 to 6.n H 2n It refers to a saturated hydrocarbon group of two atoms.

[0046] The term "cycloalkyl" as used herein refers to a saturated hydrocarbon having a ring structure and the chemical formula C n H 2n-1 It refers to a group of atoms of the first group. C 3~6 Examples of cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0047] The term "cycloalkylene" as used herein refers to a saturated hydrocarbon having a ring structure and the chemical formula C n H 2n-2 It refers to a two-valent atomic group. C 3~6 Examples of cycloalkylenyl include cyclopropylenyl, cyclobutylenyl, cyclopentylenyl, and cyclohexylenyl.

[0048] The term "heterocycloalkyl" as used herein refers to a monovalent atomic group in which at least one carbon atom forming a ring in a cycloalkyl group is independently replaced in each instance by a heteroatom selected from nitrogen, oxygen, and sulfur. Examples of heterocycloalkyl groups include pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolyl, piperazinyl, morpholinyl, and thiazolidinyl.

[0049] The term "heterocycloalkylene" as used herein refers to a divalent atomic group in which at least one carbon atom forming a ring in a cycloalkyl is independently replaced in each instance with a heteroatom selected from nitrogen, oxygen, and sulfur. Examples of heterocycloalkyl include piperazine ylene and morpholinylene.

[0050] As used herein, the term "bicyclic" refers to a carbon ring compound or heterocyclic compound composed of two rings, which is formed by sharing one or more ring atoms between the two constituent rings. In a bicyclic compound, the atom shared between the two rings is called a bridgehead atom. Bicyclic compounds are divided into three types depending on the number of bridgehead atoms and whether or not there is a direct connection between the bridgehead atoms. A fused bicyclic compound has two bridgehead atoms, which are directly connected to each other by a bond. Examples of fused bicyclic compounds include decalin, naphthalene, anthracene, phenanthrene, indole, benzofuran, purine, and quinoline. A ring compound with only one bridgehead atom is a spirocyclic compound. A bridged ring compound has two bridgehead atoms that are not directly connected to each other by a bond, but rather have one or more ring atoms interposed between the two bridgehead atoms. Examples of bridged ring compounds include norbornane, 7-oxabicyclo[2.2.1]heptane, and adamantane.

[0051] The term "bridged bicycloalkylene" in this specification refers to a divalent atomic group in which any two hydrogens in a bridged bicycloalkane are replaced by bonding water. For example, exemplary C 3~10 Some examples of bridged bicycloalkylenes include bicyclo[2.2.1]heptylene (C7) and bicyclo[2.2.2]octylene (C8).

[0052] As used herein, "alkynyl" refers to a monovalent hydrocarbon atom group containing one carbon-carbon triple bond functional group and, if it contains additional carbons other than the triple bond functional group, those carbons are saturated carbons. For example, C 2~4Alkynyl refers to -C≡CH, -CH2C≡CH, -C≡CCH3, -C≡CCH2CH3, -CH2C≡CCH3, or -CH2CH2C≡CH.

[0053] In this specification, fused bicyclic compounds can be expressed by specifying the number of ring atoms in each of the two rings that make up the compound. For example, thienopyridine, benzofuran, indole, etc. can be referred to as five- or six-membered fused bicyclic compounds. Similarly, purine, naphthalene, chromane, tetrahydroquinoline, quinoline, quinoxaline, pteridine, etc. can be referred to as six- or six-membered fused bicyclic compounds.

[0054] The term "aryl" as used herein refers to an aromatic C6~C 14 It refers to a monovalent hydrocarbon functional group that can have one to three aromatic rings as a functional group. For example, aryl has C6, C 10 , C 13 and C 14 Aromatic hydrocarbon ring atoms are included, such as phenyl, naphthyl, anthracenyl, and fluorenyl.

[0055] The term "arylene" as used herein refers to an aromatic C6~C 14 It refers to a divalent hydrocarbon functional group that can have one to three aromatic rings as a functional group. For example, arylenyl has C6, C 10 , C 13 and C 14 Aromatic hydrocarbon ring atoms are included, such as phenylene, naphthalenylene, and anthracenylene.

[0056] The term "heteroaryl" as used herein refers to a monovalent aromatic ring composed of an unsaturated ring and one or more heteroatoms selected from nitrogen, oxygen, and sulfur. The ring system of a heteroaryl can be a single ring, a double ring in the form of a fused ring, or a tricyclic ring. The term heteroaryl excludes rings that contain a direct linkage between oxygen and sulfur atoms, such as -OO-, -OS-, or -SS-. Some examples of heteroaryl include pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, triazolyl, quinazolinyl, 2-furyl, 3-furyl, benzofuryl, 2-thienyl, oxazolyl, isothiazolyl, and thiadiazolyl. Heteroaryl can also be defined by specifying the heteroatom. For example, heteroaryl in which the heteroatom is nitrogen includes pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, etc., but excludes furyl, oxazolyl, thienyl, etc.

[0057] The term "heteroarylenyl" as used herein refers to a divalent aromatic ring comprising an unsaturated ring and one or more heteroatoms selected from the group consisting of carbon atoms and nitrogen, oxygen, and sulfur.

[0058] Fused bicyclic heteroaryl groups include six- and five-membered fused bicyclic heteroaryl groups such as benzimidazolyl, benzofuranyl, benzothiophenyl, isoindolyl, indazolyl, imidazopyridinyl, imidazopyrimidinyl, imidazopyridazinyl, indazolyl, pyrazolopyridinyl, pyrrolopyrimidinyl, pyrrolopyridinyl, pyrrolopyrazinyl, triazolopyrimidinyl, triazolopyrimidinyl, purinyl, benzoxazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, anthranilyl, benzoazoxazolyl, benzopyrazolyl, benzothiadiazolyl, etc., and six- and five-membered fused bicyclic heteroaryl compounds such as benzopyridinyl, benzopyrimidinyl, These include quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, quinolinzinyl, and cinnolinyl.

[0059] The term "heterocycloalkyl" as used herein refers to a monovalent atomic group in which at least one carbon atom forming a ring in a cycloalkyl group is independently replaced in each instance by a heteroatom selected from nitrogen, oxygen, and sulfur. Examples of heterocycloalkyl groups include pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolyl, piperazinyl, morpholinyl, and thiazolidinyl.

[0060] The term "unsaturated heterocycloalkyl" as used herein refers to a monovalent hydrocarbon atom group containing heteroatoms in which at least a double bond exists between adjacent atoms forming the ring of the heterocycloalkyl, but the ring as a whole cannot be designated as aromatic heteroaryl.

[0061] The term "unsaturated heterocycloalkylene" in this specification refers to a divalent hydrocarbon atom group containing a heteroatom, in which one more hydrogen atom is changed to a bonding number in the aforementioned unsaturated heterocycloalkyl.

[0062] In this specification, the term "substituted" or "substituted" in front of a functional group refers to a structure in which at least one of the hydrogens of the functional group is replaced with a functional group other than the designated hydrogen, unless otherwise stated in the specification, provided that the substituted functional group maintains its normal valence and yields a chemically stable functional group. In typical cases, the substituent is a halogen, CN, OH, C 1~6 Alkyl, C 3~6 Cycloalkyl, C 3~14 Heteroaryl, C 1~6 Choose between alkoxy and CF3.

[0063] In this specification, a specific atom of a substituent forming part of a compound is " " indicates that the substituent is chemically bonded to the rest of the compound through that atom.

[0064] In this specification, if a dotted line such as "---" is displayed on a bond line, it indicates that the bond line is an optional element that may or may not be present. For example, A notation like this indicates that this structural formula encompasses benzene and 1,3-cyclohexadiene.

[0065] As used herein, the term "pharmaceutically acceptable salt" for a compound refers to a salt that does not impair the desired biological activity of the compound and does not cause inappropriate toxicity, irritation, or allergic reactions when used in contact with human or animal tissues. Pharmaceutically acceptable salts are well known in the art. For example, reference may be made to prior literature, such as the paper by Berge et al., J. Pharmaceutical Sciences (1977), Vol. 66, pp. 1-19. Some examples of pharmaceutically acceptable salts include acid addition salts such as hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, and hydrosulfide, and base addition salts such as alkali metal salts, alkaline earth metal salts, ammonium salts, and quaternary ammonium (N + (C 1~4 There are alkyl)4), and examples of alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium.

[0066] Those skilled in the art will appreciate that some of the compounds of the present invention may exist in more than one isomeric form. Since a chemical structural formula can only represent one isomeric form, it is well understood that when a compound is referred to by a single structural formula for convenience, the structural formula also encompasses the isomeric variations of that compound. Depending on the compound, one of several isomeric forms may exist primarily, a mixture of multiple isomeric forms may exist at room temperature, or only one isomeric form may be isolated. Examples of isomeric forms include those between the pyridone and hydroxypyridine forms, and those between the keto and enol forms.

[0067] compound

[0068] In one aspect of the present invention, a compound defined by chemical formula 1, its isomers, its stereoisomers, and pharmaceutically acceptable salts thereof are provided.

[0069] In one aspect of the present invention, a compound defined by Chemical Formula 1 or a totoisomer thereof, a stereoisomer thereof, and a pharmaceutically acceptable salt thereof are provided.

[0070]

[0071] In chemical formula 1 is phenylene, 5-6 membered heteroarylene, 5-6 membered saturated or unsaturated heterocycloalkylene, C 7~10 Bridged bicycloalkylene or cubaylene, wherein said phenylene, heteroarylene, saturated or unsaturated heterocycloalkylene, C 7~10 Bridged bicycloalkylene or cubaylene optionally comprises one or more hydrogens independently of one another, halogen, C 1~4 Alkoxy, C 1~4 Alkyl, C 1~4 Haloalkyl and C 3~6 which may be substituted with a substituent selected from the group consisting of cycloalkyl;

[0072] R 1 is a 5-6 membered substituted or unsubstituted heteroaryl, and the substituent of the substituted heteroaryl is halogen, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy and C 3~6 At least one independently selected from the group consisting of cycloalkyl;

[0073] R 2 is hydrogen, C 1~4 Alkyl, C 1~4 Haloalkyl, deuterium substituted C 1~4 Alkyl, C 2~4 Alkynyl, cyano, C 3~6Cycloalkyl, saturated or unsaturated 5-6 membered substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted phenyl or heteroaryl, wherein the substituted heterocycloalkyl, substituted phenyl or substituted heteroaryl is halogen, C 1~3 Alkyl, C 1~3 Haloalkyl and C 3~6 which may be substituted with one or more substituents independently selected from the group consisting of cycloalkyl;

[0074] R 3 and R'

[0075] R' is absent and R 3 Silver hydrogen, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, cyano or C 3~6 Cycloalkyl or,

[0076] R 3 When R and R' are connected to each other, R 3 Forming a pyrazolotriazine fused ring together with the six-membered ring carbon bonded to and the six-membered ring nitrogen bonded to R';

[0077] R 4 is selected from substituted or unsubstituted phenyl and 5-6 membered substituted or unsubstituted heteroaryl, wherein the substituent of the substituted phenyl or substituted heteroaryl is C 1~4 Alkoxy, C 1~4 Alkyl, C 1~4 Haloalkyl, C 3~6 At least one independently selected from the group consisting of cycloalkyl and 3-6 membered saturated or unsaturated heterocycloalkyl.

[0078] In chemical formula 1 The dotted line connection mark in the part ---- is these R' and R 3 According to the definition of , a pyrazolotriazine fused ring or a 1,3,5-triazine single ring is determined, and accordingly, the nitrogen bonded to R' in the 1,3,5-triazine ring and R 3This is an indication that the bond between the carbons bonded to each other can be appropriately changed to a single bond or a double bond. In either case, it will be obvious to those skilled in the art that the structural formula must be understood so that the four atoms of carbon and the three atoms of nitrogen satisfy the coordination.

[0079] In one embodiment of the present invention, the compound described above can be represented in a partial form of the following chemical formula 1a.

[0080] [Chemical Formula 1a]

[0081]

[0082] Here R 3a is hydrogen, alkyl or cycloalkyl, , R 1 , R 2 Wow R 4 The definition is as defined above in Chemical Formula 1.

[0083] In another embodiment of the present invention, the compound described above can be represented in a partial form of the following chemical formula 1b.

[0084] [Chemical Formula 1b]

[0085]

[0086] Here , R 1 , R 2 Wow R 4 The definition is as defined above in Chemical Formula 1.

[0087] In one specific embodiment, the compound of the present invention has a structure represented by chemical formula 2.

[0088]

[0089] R in chemical formula 2 2 is hydrogen, C 1~4 Alkyl, C 1~4 Haloalkyl, deuterium substituted C 1~4 Alkyl, C 2~4 Alkynyl, cyano, C 3~6Cycloalkyl, saturated or unsaturated 5-6 membered substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted phenyl or 5-6 membered substituted or unsubstituted heteroaryl, wherein the substituted heterocycloalkyl, substituted phenyl or substituted heteroaryl is halogen, C 1~3 Alkyl, C 1~3 Haloalkyl and C 3~6 may be substituted with one or more substituents independently selected from the group consisting of cycloalkyl;

[0090] R 5 Inland R 7 are hydrogen, C respectively 1~4 Alkoxy, C 1~4 Alkyl, C 1~4 Haloalkyl and C 3~6 Independently selected from the group consisting of cycloalkyl;

[0091] R 8 Silver hydrogen, C 1~4 Alkoxy or C 1~4 It is alkyl;

[0092] R 9 is hydrogen, C 1~4 Alkoxy, C 1~4 Alkyl or C 1~4 It is haloalkyl,

[0093] R 10 is a halogen, and when n is 2 or more, each case is independently selected from among the halogens,

[0094] n is an integer from 0 to 4,

[0095] X 1 and X 2 are different elements to choose from among N and C.

[0096] That is, in chemical formula 2, X 1 If this N then X 2 is C, and X 1 and X 2 forms a five-membered imidazole ring. On the other hand, X 1 If this is C then X 2 is N, and X 1and X 2 forms a pyrazole ring.

[0097] In chemical formula 2 The dotted line joining marks in the part ---- are these X 1 and X 2 It is an indication that the imidazole ring or pyrazole ring is determined according to the relationship, and the positions of the single bond and double bond can be changed accordingly, and it will be obvious to those skilled in the art that in any case, the structural formula must be understood so that the four atoms of carbon satisfy the coordination and the three atoms of nitrogen satisfy the coordination.

[0098] In a more specific embodiment, the compound of the present invention is a compound selected from the following: am.

[0099] The compound of the present invention described above can inhibit the enzymatic activity of USP1 / UAF1.

[0100] pharmaceutical composition

[0101] In another aspect, the present invention discloses a pharmaceutical composition comprising the aforementioned compound and a pharmaceutically acceptable excipient. The pharmaceutical composition of the present invention can be used to inhibit the activity of USP1 / UAF1 in the body, for example, for the treatment of cancer.

[0102] In the pharmaceutical composition of the present invention, the aforementioned compounds may be present as pharmaceutically acceptable salts. Pharmaceutically acceptable salts include, for example, base addition salts and acid addition salts. Pharmaceutically acceptable base addition salts may be formed with addition salts of metals or amines, such as alkali metal bases, alkaline earth metal bases, or organic amines. Pharmaceutically acceptable salts of the compounds may also be prepared using pharmaceutically acceptable cations. Pharmaceutically acceptable acid addition salts include salts of inorganic or organic acids.

[0103] In the present invention, a pharmaceutically acceptable excipient refers to an inactive ingredient approved by a relevant administrative agency (e.g., the Ministry of Food and Drug Safety of the Republic of Korea, the Federal Food and Drug Administration (FDA) of the United States) as being suitable for use together with an active pharmaceutical ingredient for the purpose of manufacturing a medicine for treating a disease in humans or livestock. Such pharmaceutically acceptable excipients include, but are not limited to, carriers, lubricants, fluidizing agents, disintegrating agents, sweeteners, diluents, preservatives, coloring agents, flavoring agents, surfactants, wetting agents, dispersing agents, suspending agents, stabilizers, isotonic agents, solvent emulsifiers, and adjuvants.

[0104] The pharmaceutical composition of the present invention may be in a form suitable for oral administration, such as a tablet, capsule, pill, powder, sustained-release preparation, solution, or suspension; in a form suitable for parenteral injection, such as a sterile solution, suspension, or emulsion; in a form suitable for topical administration, such as an ointment or cream; or in a form suitable for rectal administration, such as a suppository.

[0105] The pharmaceutical composition according to the present invention can be prepared in a conventional manner, for example, by conventional mixing, dissolving, granulating, sugar-coated tablet preparation, powdering, emulsifying, encapsulating, encapsulating, or lyophilizing processes. The appropriate formulation will vary depending on the chosen route of administration.

[0106] Pharmaceutical compositions suitable for oral administration can be readily formulated by combining the compounds disclosed herein with pharmaceutically acceptable excipients, such as carriers well known in the art. Using such excipients and carriers, the compounds disclosed herein can be formulated as tablets, pills, dragees, capsules, solutions, gels, syrups, slurries, suspensions, and the like for oral ingestion by patients to be treated. Oral pharmaceutical preparations can be obtained by adding the compounds of the present invention together with solid excipients, grinding the resulting mixture if necessary, adding suitable auxiliaries if necessary, and then processing the granulated mixture to form tablets or dragee cores. Suitable excipients include, for example, fillers and cellulose preparations. If desired, a disintegrant may be added.

[0107] For pharmaceutical compositions for oral administration of a therapeutically effective amount of a compound of the present disclosure, the compositions are generally in the form of solid (e.g., tablets, capsules, pills, powders, or troches) or liquid formulations (e.g., aqueous suspensions, solutions, elixirs, or syrups).

[0108] When administered in tablet form, the composition may additionally contain functional solids and / or solid carriers such as gelatin or adjuvants. Compositions in the form of tablets, capsules, and powders may contain from about 1 to about 95 wt% of the compound of the present invention, preferably from about 15 to about 90 wt% of the compound of the present invention, based on the total weight of the composition. An example of a tablet composition may contain, for example, up to about 80 wt% of the active pharmaceutical ingredient, from about 10 wt% to about 90 wt% of a binder, from about 0 wt% to about 85 wt% of a diluent, from about 2 wt% to about 10 wt% of a disintegrant, and from about 0.25 wt% to about 10 wt% of a lubricant.

[0109] When administered in liquid or suspension form, a functional liquid and / or liquid carrier such as water, petroleum, or animal or vegetable oil may be added. Liquid compositions may further contain saline, sugar alcohol solutions, dextrose or other sugar solutions, or glycols. When administered in liquid or suspension form, the composition may contain from about 0.5% to about 90% by weight of the compound of the present invention, preferably from about 1% to about 50% by weight of the compound of the present invention. In one contemplated embodiment, the liquid carrier is non-aqueous or substantially non-aqueous. For administration in liquid form, the composition may be supplied as a rapidly dissolving solid formulation for dissolution or suspension immediately prior to administration.

[0110] When the pharmaceutical composition of the present invention is administered intravenously, transdermally, or subcutaneously, it is in the form of a parenteral aqueous solution that does not contain a pyrogen. The preparation of such parenteral solutions, taking into account pH, isotonicity, stability, etc., is within the skill of the art. Preferred compositions for intravenous, transdermal, or subcutaneous injection generally contain an isotonic vehicle. Such compositions can be prepared for administration as a solution of the free base or a pharmacologically acceptable salt in water suitably mixed with a surfactant such as hydroxypropyl cellulose. Dispersions in glycerol, liquid polyethylene glycol, and mixtures thereof, as well as dispersions in oils, can also be prepared. Under normal storage and use conditions, such preparations may optionally contain a preservative to prevent the growth of microorganisms.

[0111] Injectable compositions may include sterile aqueous solutions, suspensions, or dispersions, and sterile powders for the extemporaneous preparation of sterile injectable solutions, suspensions, or dispersions. Sterile injectable solutions are prepared by incorporating the active compound in the required amount in an appropriate solvent with various other ingredients, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterile active ingredients into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above. In embodiments of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying techniques, which produce a powder of the active ingredient and any additional required ingredients from a previously sterile-filtered solution thereof.

[0112] To achieve controlled release of the active compound upon contact with body fluids in the gastrointestinal tract and to provide substantially constant and effective levels of the active compound in the plasma, sustained-release or sustained-release formulations may be prepared. For example, release may be controlled by one or more of dissolution, diffusion, and ion exchange. Furthermore, sustained-release approaches may enhance absorption through saturation or restriction pathways within the gastrointestinal tract. For example, for this purpose, the compound may be embedded in a polymer matrix comprising a biodegradable polymer, a water-soluble polymer, or a mixture thereof, and optionally a suitable surfactant. Embedding in this context may mean incorporating microparticles into the polymer matrix. Controlled-release formulations may also be obtained by encapsulating dispersed microparticles or emulsified microdroplets using known dispersion or emulsion coating techniques.

[0113] The pharmaceutical composition of the present invention may be formulated for parenteral administration by injection (e.g., bolus injection or continuous infusion). The injectable formulation may be presented in unit dosage form (e.g., ampoules or multi-dose containers) with an added preservative. The composition may take the form of a suspension, solution, or emulsion in an oily or aqueous vehicle, and may contain formulatory agents such as suspending, stabilizing, and / or dispersing agents.

[0114] The pharmaceutical composition may be presented in unit dosage form suitable for single administration of precise dosages.

[0115] A pharmaceutical composition containing the compound of the present invention can be used according to the method described below.

[0116] Treatment methods

[0117] In another aspect, the present invention provides a method for treating cancer. The method comprises administering to a patient in need of treatment a therapeutically effective amount of a compound of the present invention, such as a compound defined by Formula 1. Alternatively, the present invention comprises administering to the patient a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention and a pharmaceutically acceptable excipient.

[0118] In a method for treating cancer, the compound of the present invention may be administered alone or in combination with at least one other drug. These other drugs and the compound of the present invention may be administered simultaneously or sequentially.

[0119] As used herein, unless specifically stated otherwise, a “therapeutically effective amount” of a compound refers to an amount of the compound sufficient to delay or minimize one or more symptoms associated with a disease, disorder, or condition, or to provide a therapeutic effect for a disease, disorder, or condition. The term “therapeutically effective amount” encompasses an amount that improves overall healing, an amount that alleviates or avoids a symptom or cause of a disease or condition, and an amount that enhances the therapeutic effectiveness of another therapeutic agent.

[0120] The amount of compound administered may vary depending on the subject being treated, the subject's age, health, sex, and body weight, the type (if any) of concurrent treatment, the severity of the pain, the nature of the desired effect, the treatment regimen and frequency, and the prescribing physician's judgment. The frequency of administration may also vary depending on the pharmacodynamic effects on arterial oxygen pressure. However, the most desirable dosage can be tailored to the individual subject, as understood and determined by those skilled in the art without undue experimentation. This typically involves adjusting the standard dose (e.g., reducing the dose if the patient is underweight).

[0121] Although individual case needs may vary, determining the optimal range of therapeutically effective doses of a compound is common sense in this field. When administered to humans in the therapeutic or prophylactic treatment of conditions and disorders using the compounds of the present invention, for example, a typical dosage of the compounds of the present invention may be from about 0.05 mg / kg / day to about 50 mg / kg / day, for example, at least 0.05 mg / kg, at least 0.08 mg / kg, at least 0.1 mg / kg, at least 0.2 mg / kg, at least 0.3 mg / kg, at least 0.4 mg / kg, or at least 0.5 mg / kg, preferably not more than 50 mg / kg, not more than 40 mg / kg, not more than 30 mg / kg, not more than 20 mg / kg, or not more than 10 mg / kg, which may be, for example, from about 2.5 mg / day (0.5 mg / kg 5 kg) to about 5000 mg / day (50 mg / kg 100 kg). For example, the dosage of the compound may be from about 0.1 mg / kg / day to about 50 mg / kg / day, from about 0.05 mg / kg / day to about 10 mg / kg / day, from about 0.05 mg / kg / day to about 5 mg / kg / day, from about 0.05 mg / kg / day to about 3 mg / kg / day, from about 0.07 mg / kg / day to about 3 mg / kg / day, from about 0.09 mg / kg / day to about 3 mg / kg / day, from about 0.05 mg / kg / day to about 0.1 mg / kg / day, from about 0.1 mg / kg / day to about 1 mg / kg / day, from about 1 mg / kg / day to about 10 mg / kg / day, from about 1 mg / kg / day to about 5 mg / kg / day, from about 1 mg / kg / day to about 3 mg / kg / day, from about 3 mg / day to about The dose may be 500 mg / day, about 5 mg / day to about 250 mg / day, about 10 mg / day to about 100 mg / day, about 3 mg / day to about 10 mg / day, or about 100 mg / day to about 250 mg / day. This dose may be administered as a single dose or divided into multiple doses.

[0122] In another aspect of the present invention, a method for inhibiting the activity of an intracellular USP1 enzyme is provided. The method comprises the step of contacting a cell in which USP1 activity is to be inhibited with an effective amount of a compound of the present invention, e.g., a compound defined by Formula 1.

[0123] Hereinafter, the present invention will be described in more detail through the following examples and experimental examples. However, these examples and experimental examples are intended only to aid understanding of the present invention and are not intended to limit the scope of the present invention in any way. Various changes and modifications may be made to the examples, and such changes and modifications also fall within the scope of the appended claims.

[0124] Dioxane: Dioxane

[0125] BrettPhos Pd G4: Methanesulfonato(2-dicyclohexylphosphino-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-methylamino-1,1-biphenyl-2-yl)palladium(II)

[0126] Pd(dppf)Cl2 . CH2Cl2: [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)

[0127] Pd(dpcy)Cl2: Dichlorobis(tricyclophosphine)palladium(II)

[0128] B2Pin2: Bis(Pinacolato) Diboron

[0129] <Example 1>

[0130] Preparation of N-(4-(1-cyclopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-4-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(pyridin-2-yl)-1,3,5-triazin-2-amine

[0131]

[0132] 4-(1-cyclopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanamine was used as a starting material and synthesized in the manner shown in Chemical Formula 3 below.

[0133]

[0134] <Example 2>

[0135] Preparation of N-(4-(1-cyclopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-4-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1,3,5-triazin-2-amine

[0136]

[0137] It was synthesized in the same manner as or similar to the method of Example 1 above, as shown in Chemical Formula 4 below.

[0138]

[0139] <Example 3>

[0140] Preparation of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrazolo[1,5-a][1,3,5]-triazin-4-amine

[0141]

[0142] 4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanamine was used as a starting material and synthesized in the manner shown in Chemical Formula 5 below.

[0143]

[0144] <Example 4>

[0145] Preparation of 4-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-N-(pyrimidin-2-yl)-1,3,5-triazin-2-amine

[0146]

[0147] To a solution of 4-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1,3,5-triazin-2-amine (200 mg, 392 μmol, 1.00 equiv) and 2-bromopyrimidine (125 mg, 784 μmol, 2.00 equiv) in dioxane (2.00 mL) was added methanesulfonato(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (33.7 mg, 39.2 μmol, 0.100 equiv) and cesium carbonate (255 mg, 784 μmol, 2.00 equivalents) was added. The mixture was stirred at 120°C for 12 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to obtain a crude product, which was then purified by Prep-HPLC (column: Phenomenex luna C18 150×25 mm×10 μm; mobile phase: [water (formic acid) - acetonitrile]; gradient: 45%-75% B, for 9 min) and lyophilized to obtain 4-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-N-(pyrimidin-2-yl)-1,3,5-triazin-2-amine (38.14 mg, 64.35 μmol, yield 16.42%, purity 99.3%) was obtained as a faded white solid.

[0148]

[0149] 1H-NMR (400 MHz, DMSO-d6)δ= 8.99 (s, 1H), 8.84 (d,J= 4.8 Hz, 2H), 8.66 (s, 1H), 8.15 (d,J= 1.2 Hz, 1H), 7.51 - 7.45 (m, 4H), 7.40 (t,J= 4.8 Hz, 1H), 5.52 (s, 2H), 4.43 (td,J= 6.4, 13.2 Hz, 1H), 3.85 (s, 3H), 2.05 - 1.88 (m, 1H), 1.38 (d,J= 6.4 Hz, 6H), 1.05 - 0.98 (m, 2H), 0.92 - 0.85 (m, 2H).

[0150] <Example 5>

[0151] Preparation of 4-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-N-(pyridin-2-yl)-1,3,5-triazin-2-amine

[0152]

[0153] Similar to the method of Example 4, 4-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1,3,5-triazin-2-amine was used as a starting material and synthesized according to the reaction route shown in Chemical Formula 7 below.

[0154]

[0155] 1H-NMR (400 MHz, DMSO-d6)δ= 8.92 (s, 1H), 8.66 (s, 1H), 8.49 (dd,J= 1.2, 4.8 Hz, 1H), 8.16 (d,J= 1.2 Hz, 1H), 7.89 - 7.83 (m, 1H), 7.80 - 7.74 (m, 1H), 7.47 (s, 4H), 7.27 (dd,J= 5.2, 6.8 Hz, 1H), 5.54 (s, 2H), 4.43 (td,J= 6.4, 13.2 Hz, 1H), 3.87 (s, 3H), 2.08 - 1.90 (m, 1H), 1.38 (d,J= 6.4 Hz, 6H), 1.04 - 0.98 (m, 2H), 0.93 - 0.83 (m, 2H).

[0156] <Example 6>

[0157] Preparation of 4-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1,3,5-triazin-2-amine

[0158]

[0159] It was synthesized by the route of chemical formula 8.

[0160]

[0161] (Step 1) Sodium acetate (24.5 g, 298 mmol) was added to an aqueous solution (100 mL) of 4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzonitrile (80 g, 298 mmol) at room temperature. The mixture was stirred at 100°C for 45 minutes. The solution was cooled to 30°C. The reaction mixture was added to a solution of 4-formylbenzonitrile (39.04 g, 298 mmol) in methanol (600 mL), followed by the addition of 130 mL of a 35% aqueous ammonium hydroxide solution. The reaction mixture was stirred at room temperature for 45 minutes, heated at 100°C for 1 hour, and concentrated. The residue was diluted with water and extracted with ethyl acetate (three times 500 mL each). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 1) to obtain compound 1 (35 g, 147.68 mmol, yield 49.55%) as a yellow solid.

[0162] MS m / z (ESI): 238.0 (M+H) + .

[0163] (Step 2) Potassium carbonate (21.8 g, 153.23 mmol), cesium carbonate (10.3 g, 31.64 mmol), and 2-iodopropane (19 mL, 190 mmol) were added to a solution of compound 1 (15 g, 63.29 mmol) in dimethylformamide (200 mL). The reaction mixture was stirred at 110°C for 5 h. The solution was cooled to room temperature and then filtered. The filtrate was diluted with water and extracted with ethyl acetate (200 mL each three times). The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 1) to give compound 2 (12 g, 42.99 mmol, yield 67.92%) as a yellow solid.

[0164] MS m / z (ESI): 280.1 (M+H) + .

[0165] (Step 3) Raney nickel was added to a solution of compound 2 (12 g, 42.99 mmol) in methanol (200 mL), and the mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. The reaction mixture was filtered, and the filtrate was concentrated to obtain intermediate A (11 g, 38.87 mmol, yield 90.42%) as a yellow oil.

[0166] MS m / z (ESI): 284.1 (M+H) + .

[0167] (Step 4) Intermediate A (1 g, 3.53 mmol) in dichloromethane (5 mL) was added dropwise to a solution of 2,4-dichloro-1,3,5-triazine (0.79 g, 5.29 mmol) in dichloromethane (5 mL) at -70°C. The mixture was stirred for 3 h under nitrogen at 20°C. The production of the target mass was confirmed by LC-MS, as evidenced by the observation of a spot on TLC (petroleum ether: ethyl acetate = 2:1, retardation factor 0.25). The solution was diluted with water (30 mL), extracted with ethyl acetate (three times 10 mL each), and washed with water (5 mL) and brine (10 mL). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 1) to obtain compound 4 (392 g, 0.99 mmol, yield 27.99%) as a colorless solid.

[0168] MS m / z (ESI): 397.2 (M+H) + .

[0169] 1H-NMR (400 MHz, DMSO-d6) δ 9.24 (q,J= 6.4 Hz, 1H), 8.46 (d,J= 20.8 Hz, 1H), 8.17 (s, 1H), 7.52-7.55 (m, 2H), 7.43-7.46 (m, 2H), 4.61 (dd,J= 17.2, 6.4 Hz, 2H), 4.46 (m, 1H), 1.40 (d,J= 6.8, 1.2 Hz, 6H).

[0170] (Step 5) To a solution of compound 5 (10 g, 69.18 mmol) in dichloromethane (50 mL) were added cyclopropylboronic acid (11.9 g, 138.35 mmol), potassium carbonate (19.1 mg, 138.35 mmol), and Pd(dpcy)Cl2 (5.23 g, 6.92 mmol). The mixture was stirred at 100°C under nitrogen for 18 h. The reaction mixture was poured into water (40 mL) and extracted with ethyl acetate (three times 80 mL each). The organic layers were combined, washed with brine (three times 20 mL each), and dried over sodium sulfate. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10:1) to give compound 6 (4.2 g, 27.97 mmol, yield 40.43%) as a brown solid.

[0171] MS m / z (ESI): 151.2 (M+H) + .

[0172] (Step 6) Br2 (1.5 mL, 30.0 mmol) was added dropwise to a solution of compound 6 (4.1 g, 27.30 mmol) in ethanol (5 mL) at -20°C. The mixture was stirred for 14 h under nitrogen at 20°C. LC-MS confirmed that half of the reactant remained, and Br2 (1.5 mL, 30.0 mmol) was added dropwise at -20°C. LC-MS confirmed that the reactant was completely consumed and the target mass of material was produced. The mixture was concentrated and diluted with ice water (40 mL). Saturated aqueous sodium carbonate solution (30 mL) was added and stirred for 30 min. The resulting white solid was filtered, washed with water (10 mL), and dried in vacuo to obtain compound 7 (5.65 g, 24.66 mmol, yield 90.40%) as a white solid.

[0173] MS m / z (ESI): 229.0 (M+H) + .

[0174] 1 H-NMR (400 MHz, DMSO-d6) δ 8.43 (s, 1H), 4.04 (s, 3H), 2.49 -2.55 (m, 1H), 1.14 - 1.19 (m, 2H), 1.06- 1.11 (m, 2H).

[0175] (Step 7) To a solution of compound 7 (2 g, 8.73 mmol) in dioxane (24 mL) were added B2Pin2 (2.66 g, 10.48 mmol), potassium acetate (2.57 g, 26.19 mmol), and Pd(dppf)Cl2CH2Cl2 (178 mg, 0.22 mmol). The mixture was stirred at 95°C under nitrogen for 6 h. The production of the target mass was confirmed by LC-MS, as evidenced by the observation of a spot on TLC (petroleum ether: ethyl acetate = 10:1, retardation factor 0.25). The reaction mixture was concentrated, diluted with water (40 mL), and extracted with ethyl acetate (three times, 20 mL each). The organic layers were combined, washed with water (10 mL) and brine (10 mL), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10:1) to obtain intermediate B (1.74 g, 6.30 mmol, yield 72.20%) as a white solid.

[0176] MS m / z (ESI): 277.1 (M+H) + .

[0177] 1 H-NMR (400 MHz, CDCl3) δ 8.56 (s, 1H), 3.93 (s, 3H), 2.03 - 2.11 (m, 1H), 1.39 (s, 12H), 1.15 - 1.19 (m, 2H), 0.96 - 1.00 (m, 2H).

[0178] (Step 8) Intermediate B (83 mg, 0.30 mmol), potassium carbonate (21 mg, 0.15 mmol), and Pd(dppf)Cl2CH2Cl2 (21 mg, 0.03 mmol) were added to a solution of compound 4 (100 mg, 0.25 mmol) in dioxane (1.2 mL) and water (0.12 mL). The mixture was stirred at 100°C under nitrogen for 3 h. LC-MS confirmed the production of the target mass of a substance, as evidenced by the observation of a spot on TLC (dichloromethane: methanol = 15:1, retardation factor 0.6). The reaction mixture was concentrated, diluted with water (10 mL), extracted with ethyl acetate (2×10 mL each), and washed with water (5 mL) and brine (2×5 mL). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The organic layers were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude mixture was purified by preparative TLC (dichloromethane: methanol = 15:1), and the residue was further purified by preparative HPLC (Waters-SunFire C18 10 μm- 19 × 250 mm, A: water (0.1% formic acid) B: acetonitrile]; gradient: 75%) to afford 4-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1,3,5-triazin-2-amine (41 mg, 0.08 mmol, yield 31.87%) as a white solid.

[0179] MS m / z (ESI): 397.2 (M+H) + .

[0180] HPLC: Purity 97.6%

[0181] 1H-NMR (400 MHz, DMSO-d6) δ8.73 (d, J= 42.4 Hz, 1H), 8.62 (s, 1H), 7.42- 7.56 (m, 5H), 6.04- 6.08 (m, 1H), 4.77 (dd, J= 15.2, 6.0 Hz, 2H), 4.51-4.59 (m, 1H), 3.95 (d,J= 2.8 Hz, 3H), 1.83 - 1.87 (m, 1H), 1.44-1.47 (m, 6H), 1.19 - 1.30 (m, 2H), 0.86-0.99 (m, 2H).

[0182] 19 F NMR (400 MHz, DMSO-d6) δ -62.6 ppm.

[0183] <Example 7>

[0184] Preparation of 4-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-N-methyl-1,3,5-triazin-2-amine

[0185]

[0186] It was synthesized by the route of chemical formula 9.

[0187]

[0188] (Step 1) To a solution of (4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanamine (5.67 g, 20.0 mmol, 1.00 equiv) in tetrahydrofuran (60.0 mL) were added triethylamine (4.05 g, 40.0 mmol, 5.57 mL, 2.00 equiv) and 2,4-dichloro-1,3,5-triazine (3.00 g, 20.0 mmol, 1.00 equiv). The reaction mixture was stirred at 20°C for 10 h. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to obtain 4-chloro-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1,3,5-triazin-2-amine (2.49 g, 6.28 mmol, yield 31.0%) as a yellow oil.

[0189] 1 H-NMR (400 MHz, DMSO-d6)δ= 9.28 (q,J= 6.4 Hz, 1H), 8.56 - 8.46 (m, 1H), 8.21 (d,J= 1.2 Hz, 1H), 7.61 - 7.55 (m, 2H), 7.49 (dd,J= 2.4, 8.2Hz, 2H), 4.66 (dd,J= 6.4, 17.2 Hz, 2H), 4.54 - 4.47 (m, 1H), 1.43 (br d,J= 1.6 Hz, 6H).

[0190] (Step 2) To a solution of 4-chloro-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1,3,5-triazin-2-amine (590 mg, 1.49 mmol, 1.00 equiv) and (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (433 mg, 2.23 mmol, 1.50 equiv) in dioxane (5.00 mL) and water (1.00 mL) were added [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (109 mg, 149 μmol, 0.100 equiv) and potassium phosphate (631 mg, 2.97 mmol, 2.00 equiv). The mixture was stirred at 100°C under a nitrogen atmosphere for 12 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to obtain 4-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1,3,5-triazin-2-amine (260 mg, 509 μmol, yield 34.0%) as a yellow solid.

[0191] 1 H-NMR (400 MHz, DMSO-d6)δ= 9.00 - 8.88 (m, 1H), 8.66 (d,J= 2.4Hz, 1H), 8.16 (s, 1H), 7.60 - 7.47 (m, 4H), 7.45 - 7.39 (m, 1H), 4.67 - 4.58 (m, 2H), 4.51 - 4.40 (m, 1H), 3.84 (s, 3H), 1.82 (tdd,J= 4.0 8.4 12.4 Hz, 1H), 1.40 (t,J= 6.0 Hz, 6H), 1.01 - 0.94 (m, 4H).

[0192] (Step 3) To a solution of 4-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-[[4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl]-1,3,5-triazin-2-amine (100 mg, 196 μmol, 1.00 equiv) in dimethylformamide (1.00 mL) at 0 °C was added sodium hydride (15.7 mg, 392 μmol, purity 60%, 2.00 equiv), and the reaction mixture was stirred at 0 °C for 30 min, followed by the addition of iodomethane (83.4 mg, 588 μmol, 36.6 μL, 3.00 equiv). The reaction mixture was stirred at 20 °C for 2 h. The reaction was stopped by adding 5.00 mL of saturated ammonium chloride solution at 20°C, and the mixture was extracted with ethyl acetate (10 mL each three times). The organic layers were combined, washed with 20.0 mL of brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (column Phenomenex luna C18 150×25 mm×10 μm; mobile phase: [water (formic acid)-acetonitrile]; gradient: 48-78% B, for 15 min) to give 4-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-N-methyl-1,3,5-triazin-2-amine (20.8 mg, 39.2 μmol, yield 20.0%, purity 99.0%) as a pink solid.

[0193] 1H-NMR (400 MHz, DMSO-d6)δ= 8.77 (d,J= 16.0 Hz, 1H), 8.66 (d,J= 11.6 Hz, 1H), 8.18 (s, 1H), 7.59 - 7.51 (m, 2H), 7.47 (d,J= 8.0 Hz, 1H), 7.40 (d,J= 8.0 Hz, 1H), 5.09 - 4.85 (m, 2H), 4.47 (td,J= 6.4, 17.8 Hz, 1H), 3.88 (d,J= 9.2 Hz, 3H), 3.24 - 3.12 (m, 3H), 1.96 - 1.77 (m, 1H), 1.40 (t,J= 6.4 Hz, 6H), 1.07 (td,J= 3.6, 7.1 Hz, 1H), 1.03 - 0.93 (m, 2H), 0.87 - 0.78 (m, 1H).

[0194] <Example 8>

[0195] Preparation of 4-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-N-(methyl-d3)-1,3,5-triazin-2-amine

[0196]

[0197] To a solution of Example 6 compound (100 mg, 196 μmol, 1.00 equiv) in dimethylformamide (1.00 mL) was added sodium hydride (15.7 mg, 392 μmol, purity 60%, 2.00 equiv), and the reaction mixture was stirred at 0°C for 30 minutes, followed by the addition of iodomethane-d3 (85.2 mg, 588 μmol, 36.6 μL, 3.00 equiv). The reaction mixture was stirred at 20°C for 2 hours. The reaction was stopped by the addition of 2 mL of saturated ammonium chloride solution, and the mixture was filtered. The filtrate was purified by preparative HPLC (column Phenomenex luna C18 150×25 mm×10 μm; mobile phase: [water (formic acid)-acetonitrile]; gradient: 48-78% B, for 15 min) and lyophilized to obtain 4-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-N-(methyl-d3)-1,3,5-triazin-2-amine (30.98 mg, 58.61 μmol, yield 29.92%, purity 99.8%) as a yellow solid.

[0198] 1 H-NMR (400 MHz, DMSO-d6)δ= 8.78 (d,J= 15.6 Hz, 1H), 8.67 (d,J= 11.2 Hz, 1H), 8.21 - 8.13 (m, 1H), 7.61 - 7.51 (m, 2H), 7.48 (d,J= 8.4 Hz, 1H), 7.41 (d,J= 8.0 Hz, 1H), 5.05 - 4.88 (m, 2H), 4.58 - 4.32 (m, 1H), 3.88 (d,J= 9.2 Hz, 3H), 1.98 - 1.75 (m, 1H), 1.48 - 1.32 (m, 6H), 1.13 - 0.78 (m, 4H).

[0199] <Example 9>

[0200] Preparation of N-(4-(1-cyclopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)pyrazolo[1,5-a][1,3,5]triazin-4-amine

[0201]

[0202] (Step 1) To a solution of (4-(1-cyclopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanamine (1.00 g, 3.15 mmol, 1.00 equiv, hydrochloride) in dichloromethane (15.0 mL) was added N,N-diisopropylethylamine (1.22 g, 9.44 mmol, 1.64 mL, 3.00 equiv), the mixture was cooled to 0°C, and 4-chloro-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazine (758 mg, 3.78 mmol, 1.20 equiv) was added. The reaction mixture was stirred at 25°C for 2 h. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to obtain N-(4-(1-cyclopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(methylthio)pyrazolo[1,5-a]triazin-4-amine (1.20 g, 2.69 mmol, yield 85.6%) as a yellow solid.

[0203] 1 H-NMR (400 MHz, DMSO-d6)δ= 9.50 (t,J= 6.4 Hz, 1H), 8.10 (d,J= 2.0 Hz, 1H), 7.92 (d,J= 1.2 Hz, 1H), 7.86 (d,J= 8.4 Hz, 2H), 7.49 (d,J= 8.4 Hz, 2H), 6.30 (d,J= 2.0 Hz, 1H), 4.75 (d,J= 6.4 Hz, 2H), 3.72 (tt,J= 3.6, 7.2 Hz, 1H), 2.46 (s, 3H), 1.02 - 0.95 (m, 2H), 0.93 - 0.86 (m, 2H).

[0204] (Step 2) To a solution of N-(4-(1-cyclopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(methylthio)-pyrazolo[1,5-a][1,3,5]triazin-4-amine (1.00 g, 2.24 mmol, 1.00 equiv) in acetic acid (10.0 mL) was added hydrogen peroxide (2.04 g, 17.9 mmol, 1.73 mL, 30% purity, 8.00 equiv) at 0°C, and the mixture was stirred at 25°C for 12 h. To this, 50 mL of sodium sulfite was added at 0°C to stop the reaction, and the pH was adjusted to 7 by adding saturated sodium bicarbonate solution, followed by extraction with dichloromethane (three times 20 mL each). The organic layers were combined, washed with brine (2 times 40 mL each), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 4-((4-(1-cyclopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a][1,3,5]triazin-2-ol (1.10 g, crude) as a yellow solid.

[0205] MS (ESI) m / z 416.1 [M+H] +

[0206] (Step 3) A solution of 4-((4-(1-cyclopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a][1,3,5]triazin-2-ol (1.00 g, 2.41 mmol, 1.00 equiv) in phosphoryl chloride (10.0 mL) was stirred at 100°C for 1 h. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was diluted with 30 mL of a 3:1 mixture of dichloromethane:isopropanol, and 50 mL of ice water was added to stop the reaction. The mixture was adjusted to pH 8 with saturated sodium bicarbonate solution, and then extracted with a 3:1 mixture of dichloromethane:isopropanol (three times with 30 mL each). The organic layers were combined and washed with saturated sodium bicarbonate solution (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to obtain 2-chloro-N-(4-(1-cyclopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrazolo[1,5-a][1,3,5]triazin-4-amine (390 mg, 899.00 μmol, yield 37.34%) as a yellow oil.

[0207] 1 H-NMR (400 MHz, DMSO-d6)δ= 10.00 - 9.82 (m, 1H), 8.22 (br s, 1H), 7.92 (br s, 1H), 7.87 (br d,J= 8.0 Hz, 2H), 7.51 (br d,J= 7.2 Hz, 2H), 6.46 (br s, 1H), 4.78 (br d,J= 5.6 Hz, 2H), 3.73 (br s, 1H), 1.01 - 0.87 (m, 4H).

[0208] (Step 4) To a solution of 2-chloro-N-(4-(1-cyclopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrazolo[1,5-a][1,3,5]triazin-4-amine (250 mg, 576 μmol, 1.00 equiv) in dioxane (3.00 mL) and water (0.300 mL) was added (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (223 mg, 1.15 mmol, 2.00 equiv), methanesulfonato(2-dicyclohexylphosphino-2,6-diisopropoxy-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium(II) (144 mg, 172 μmol, 0.300 equiv) and Potassium fluoride (334 mg, 5.76 mmol, 10.0 equiv) was added. The mixture was stirred in a microwave at 130°C for 1 h under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) and concentrated under reduced pressure to obtain a crude product. This was further purified by preparative HPLC (column Phenomenex luna C18 150×25 mm×10 μm; mobile phase: [water (formic acid)-acetonitrile]; gradient: 42-72% B, for 9 min) and lyophilized to obtain N-(4-(1-cyclopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)pyrazolo[1,5-a][1,3,5]triazin-4-amine (11.02 mg, 19.70 μmol, yield 3.42%, purity 97.9%) as a white solid.

[0209] 1H-NMR (400 MHz, DMSO-d6)δ= 9.64 (t,J= 6.4 Hz, 1H), 8.64 (s, 1H), 8.26 (d,J= 2.0 Hz, 1H), 7.91 (d,J= 1.2 Hz, 1H), 7.84 (d,J= 8.4 Hz, 2H), 7.49 (d,J= 8.4 Hz, 2H), 6.56 (d,J= 2.0 Hz, 1H), 4.79 (d,J= 6.0 Hz, 2H), 3.85 (s, 3H), 3.71 (tt,J= 3.6, 7.2 Hz, 1H), 1.98 - 1.86 (m, 1H), 1.03 - 0.92 (m, 4H), 0.92 - 0.77 (m, 4H).

[0210] <Example 10>

[0211] Preparation of N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-4-(1-isopropyl-4-methyl-1H-pyrazol-5yl)-N-methyl-1,3,5-triazin-2-amine

[0212]

[0213] It was synthesized by the route of chemical formula 10.

[0214]

[0215] (Step 1) To a solution of intermediate A (2.6 g, 9.18 mmol) prepared in Example 6 in dichloromethane (30 mL) were added N,N-diisopropylethylamine (4.80 mL, 27.54 mmol) and 2,4-dichloro-1,3,5-triazine (1.38 g, 9.18 mmol) at -78°C under a nitrogen atmosphere. The mixture was stirred at 0°C for 1 hour, then 100 mL of water was added to the reaction mixture, the aqueous layer was separated, and washed with dichloromethane (2 times 30 mL each). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 1) to obtain intermediate C (1.4 g, 3.53 mmol, yield 38.44%) as a brown solid.

[0216] MS: m / z (ESI): 397.2 (M+H) + .

[0217] (Step 2) To a solution of intermediate C (400 mg, 1.01 mmol, 1.01 equiv) in dioxane (10 mL) and water (1 mL) were added 1-isopropyl-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (277 mg, 1.11 mmol), cesium carbonate (985 mg, 3.02 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (150 mg, 0.02 mmol) at room temperature. The mixture was stirred at 100°C under a nitrogen atmosphere for 18 h, then poured into water and extracted with ethyl acetate (three times, 10 mL each). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude product. This crude product was purified by preparative-HPLC (Waters Xbridge C18 column, 10 μm 19×250 mm; A: 0.1% formic acid aqueous solution, B: acetonitrile, delay time 1.27 min) to obtain the title compound of Example 14 (N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-4-(1-isopropyl-4-methyl-1H-pyrazol-5yl)-1,3,5-triazin-2-amine) (120 mg, 0.25 mmol, yield 24.57%) as a white solid.

[0218] MS: m / z (ESI): 485.2 (M+H) + .

[0219] 1 H-NMR (400 MHz, DMSO-d6)δ= 8.88 - 8.63 (m, 2H), 8.16 (dd,J= 3.55, 1.57 Hz, 1H), 7.58 - 7.34 (m, 5H), 5.55 (dt,J= 70.65, 6.56 Hz, 1H), 4.73 - 4.39 (m, 3H), 2.22 (d,J= 44.07 Hz, 3H), 1.42 - 1.21 (m, 12H).

[0220] (Step 3) To a solution of N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-4-(1-isopropyl-4-methyl-1H-pyrazol-5yl)-1,3,5-triazin-2-amine (100 mg, 0.62 mmol) in dimethylformamide (2 mL) was added sodium hydride (15 mg, 0.62 mmol) at 0°C. The mixture was stirred at 0°C for 1 h, then iodomethane (35 mg, 0.25 mmol) was added, and the mixture was stirred at room temperature for 18 h. The mixture was then poured into water, and extracted with ethyl acetate (three times 10 mL each). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. This crude product was purified by preparative HPLC (Waters Xbridge C18 column, 10 μm 19×250 mm; A: 0.1% formic acid aqueous solution, B: acetonitrile, delay time 1.827 min) to afford N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-4-(1-isopropyl-4-methyl-1H-pyrazol-5yl)-N-methyl-1,3,5-triazin-2-amine (35.77 mg, 0.07 mmol, yield 34.76%) as a white solid.

[0221] MS: m / z (ESI): 499.2 (M+H) + .

[0222] 1 H-NMR (400 MHz, DMSO-d6)δ= 8.76 (d,J= 25.04 Hz, 1H), 8.17 (dt,J= 3.33, 1.36 Hz, 1H), 7.58 - 7.36 (m, 5H), 5.58 (dt,J= 96.29, 6.52 Hz, 1H), 5.01 (s, 2H), 4.47 (dt,J= 9.97, 6.65 Hz, 1H), 3.23 (d,J= 15.74 Hz, 3H), 2.24 (d,J= 56.25 Hz, 3H), 1.43 - 1.22 (m, 12H).

[0223] <Example 11>

[0224] Preparation of 4-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6-methyl)-1,3,5-triazin-2-amine

[0225]

[0226] It was synthesized by the route of chemical formula 11.

[0227]

[0228] (Step 1) To a solution of 2,4,6-trichloro-1,3,5-triazine (1.0 g, 5.42 mmol) in tetrahydrofuran (10 mL) was added methylmagnesium bromide (1.81 mL, 3.0 M, 5.42 mmol) at 0 °C. After stirring at 0 °C for 2 h, the reaction mixture was quenched by adding 20 mL of saturated aqueous ammonium chloride solution, and extracted with ethyl acetate (50 mL each three times). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude 2,4-dichloro-6-methyl-1,3,5-triazine (600.0 mg, 3.66 mmol, yield 67.47%), which was used directly in the next step.

[0229] (Step 2) Intermediate A of Example 6 (1.04 g, 3.66 mmol) was added to a solution of 2,4-dichloro-6-methyl-1,3,5-triazine (600.0 mg, 3.66 mmol) and N,N-diisopropylethylamine (1.27 mL, 7.32 mmol) in dichloromethane (15 mL) at 0°C. After stirring at room temperature for 1 hour, the reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=4 / 1) to obtain 4-chloro-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6-methyl-1,3,5-triazin-2-amine (1.2 g, 2.92 mmol, yield 79.83%) as a white solid.

[0230] MS: m / z (ESI): 411.2 (M+H) + .

[0231] (Step 3) To a solution of 4-chloro-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6-methyl-1,3,5-triazin-2-amine (200.0 mg, 0.49 mmol), sodium carbonate (103 mg, 0.97 mmol), and 4-cyclopropyl-6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyrimidine (134 mg, 0.49 mmol) in dioxane (5 mL) and water (1 mL) was added Pd(dppf)Cl2·CH2Cl2 (56 mg, 0.07 mmol) at 25°C under a nitrogen atmosphere. The mixture was stirred at 100°C for 10 hours, poured into 20 mL of water, and extracted with ethyl acetate (30 mL each time). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. This crude product was purified by preparative HPLC (Waters Xbridge C18 column, 10 μm 19×250 mm; flow rate 25 mL / min, mobile phase A: 10 mM NH4HCO3 / H2O, B: acetonitrile, gradient 40% B to 60% B, delay time 8 min) to afford 4-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6-methyl)-1,3,5-triazin-2-amine (67.34 mg, 0.11 mmol, yield 23.50%) as a sandy yellow solid.

[0232] MS: m / z (ESI): 525.2 (M+H) + .

[0233] 1H-NMR (400 MHz, DMSO-d6) δ= 8.78 (d, J = 7.4 Hz, 1H), 8.64 (d, J = 10.6 Hz, 1H), 8.17 (s, 1H), 7.59 - 7.47 (m, 3H), 7.41 (d, J = 8.0 Hz, 1H), 4.71 - 4.55 (m, 2H), 4.46 (s, 1H), 3.85 (d, J = 10.1 Hz, 3H), 2.39 (s, 3H), 1.77 (s, 1H), 1.38 - 1.41 (m, 6H), 1.01 (d, J = 29.6 Hz, 3H), 0.81 (s, 1H).

[0234] <Example 12>

[0235] Preparation of 4-cyclopropyl-6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1,3,5-triazin-2-amine

[0236]

[0237] Except that 2,4-dichloro-6-cyclopropyl-1,3,5-triazine was used as a starting material, the synthesis was carried out according to the route of chemical formula 12 in the same manner as in Example 11.

[0238]

[0239] MS: m / z (ESI): 551.2 (M+H) + .

[0240] 1H-NMR (400 MHz, DMSO-d6)δ= 8.77 - 8.61 (m, 2H), 8.16 - 8.18 (m, 1H), 7.56 (d, J = 8.2 Hz, 1H), 7.52 - 7.46 (m, 2H), 7.41 (d, J = 8.2 Hz, 1H), 4.59 - 4.55 (m, 2H), 4.53 - 4.39 (m, 1H), 3.85 (d, J = 9.6 Hz, 3H), 1.95 - 1.91 (m, 1H), 1.79 - 1.74 (m, 1H), 1.41 - 1.38 (m, 6H), 1.07 - 1.00 (m, 5H), 0.97 - 0.94 (m, 2H), 0.83 - 0.80 (m, 1H).

[0241] <Example 13>

[0242] Preparation of 4-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-N-(prop-2-yn-1-yl)-1,3,5-triazin-2-amine

[0243]

[0244] To a solution of Example 6 compound (4-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1,3,5-triazin-2-amine (100 mg, 196 μmol, 1.00 equiv) in dimethylformamide (1.00 mL) at 0 °C was added sodium hydride (15.7 mg, 392 μmol, purity 60%, 2.00 equiv), and the reaction mixture was stirred at 0 °C for 30 min, followed by the addition of 3-bromoprop-1-yne (69.9 mg, 588 μmol, 50.7 μL, 3.00 equiv). The reaction mixture was stirred at 20 °C for 2 h. 2.00 mL of water was added. The reaction was stopped by adding ethanol at 20°C, and filtered. The filtrate was purified by preparative HPLC (column Phenomenex luna C18 150×25 mm×10 μm; mobile phase: [water (formic acid)-acetonitrile]; gradient: 45-75% B, for 15 min) to obtain 4-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-N-(prop-2-yn-1-yl)-1,3,5-triazin-2-amine (34.67 mg, 62.57 μmol, yield 31.94%, purity 99%) as a yellow solid.

[0245] 1H-NMR (400 MHz, DMSO-d6)δ= 8.86 (d,J= 18.8 Hz, 1H), 8.67 (d,J= 16.0 Hz, 1H), 8.17 (s, 1H), 7.62 - 7.47 (m, 3H), 7.46 - 7.40 (m, 1H), 5.08 - 4.91 (m, 2H), 4.54 (br d,J= 1.6 Hz, 1H), 4.52 - 4.39 (m, 2H), 3.87 (d,J= 13.6 Hz, 3H), 3.27 - 3.20 (m, 1H), 2.11 - 1.76 (m, 1H), 1.40 (t,J= 6.4 Hz, 6H), 1.08 (br s, 1H), 1.03 - 0.93 (m, 2H), 0.82 (br dd,J= 3.2, 7.8 Hz, 1H).

[0246] <Example 14>

[0247] Preparation of N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-4-(1-isopropyl-4-methyl-1H-pyrazol-5yl)-1,3,5-triazin-2-amine

[0248]

[0249] See Example 10.

[0250] <Example 15>

[0251] Preparation of 4-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)bicyclo[2.2.2]octan-1-yl)methyl)-1,3,5-triazin-2-amine

[0252]

[0253] It was synthesized by the route of chemical formula 13.

[0254]

[0255] (Step 1) To a solution of 4-(methoxycarbonyl)bicyclo[2.2.2]octane-1-carboxylic acid (5.00 g, 23.6 mmol, 1.00 equiv) in tetrahydrofuran (50.0 mL) was added a complex of dimethyl sulfide and borane ((CH3)2S·BH3) (10 M, 4.71 mL, 2.00 equiv) at 0°C, and the mixture was stirred at 20°C for 2 h. To the reaction mixture, 50 mL of methanol was added at 0°C to stop the reaction, and the mixture was concentrated under reduced pressure to obtain 4-(hydroxymethyl)bicyclo[2.2.2]octane-1-carboxylic acid (4.58 g, 23.1 mmol, yield 98.1%) as a yellow oil.

[0256] 1 H-NMR (400 MHz, DMSO-d6)δ= 4.36 (t,J= 5.4 Hz, 1H), 3.55 (s, 3H), 3.03 (d,J= 5.4 Hz, 2H), 1.71 - 1.61 (m, 6H), 1.38 - 1.30 (m, 6H).

[0257] (Step 2) 2-Iodooxybenzoic acid (6.80 g, 24.3 mmol, 1.10 equiv) was added to a solution of 4-(hydroxymethyl)bicyclo[2.2.2]octane-1-carboxylic acid (4.38 g, 22.1 mmol, 1.00 equiv) in dimethyl sulfoxide (43.0 mL). The mixture was stirred at 25°C for 1 h. The reaction mixture was stopped by adding 300 mL of water at 25°C, filtered, and the filtrate was extracted with ethyl acetate (three times 200 mL each). The combined organic layers were washed with brine (300 mL each twice), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain methyl 4-formylbicyclo[2.2.2]octane-1-carboxylate (3.90 g, 19.9 mmol, yield 90.0%) as a yellow oil.

[0258] 1H-NMR (400 MHz, DMSO-d6)δ=9.41 (s, 1H), 3.58 (s, 3H), 1.77 - 1.69 (m, 6H), 1.62 - 1.56 (m, 6H).

[0259] (Step 3) A mixture of 3,3-dibromo-1,1,1-trifluoropropan-2-one (8.25 g, 30.6 mmol, 1.50 equiv) and sodium acetate (2.51 g, 30.6 mmol, 1.50 equiv) in water (6.00 mL) was stirred at 100°C for 1 h. The mixture was cooled to 20°C. Then, a mixture of methyl 4-formylbicyclo[2.2.2]octane-1-carboxylate (4.00 g, 20.4 mmol, 1.00 equiv) and ammonium hydroxide (5.46 g, 39.0 mmol, 6.00 mL, purity 25%, 1.91 equiv) in methanol (30.0 mL) was added. The reaction mixture was stirred at 20°C for 30 minutes, then heated to 100°C and stirred for 2 hours. The mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to obtain methyl 4-(4-(trifluoromethyl)-1H-imidazol-2-yl)bicyclo[2.2.2]octane-1-carboxylate (3.20 g, 10.6 mmol, yield 51.9%) as a white solid.

[0260] 1 H-NMR (400 MHz, DMSO-d6) δ= 12.28 (br s, 1H), 7.62 (s, 1H), 3.59 (s, 3H), 1.86 - 1.76 (m, 12H).

[0261] (Step 4) To a solution of methyl 4-(4-(trifluoromethyl)-1H-imidazol-2-yl)bicyclo[2.2.2]octane-1-carboxylate (3.20 g, 10.6 mmol, 1.00 equiv) in dimethylformamide (30.0 mL) at 0 °C was added sodium hydride (635 mg, 15.9 mmol, purity 60%, 1.50 equiv), and the reaction mixture was stirred at 25 °C for 0.5 h. Then, iodomethane (2.25 g, 15.9 mmol, 989 μL, 1.50 equiv) was added, and the mixture was stirred at 25 °C for 1.5 h. The reaction was stopped by adding 100 mL of saturated ammonium chloride solution, and extraction was performed with ethyl acetate (three times 100 mL each). The organic layers were combined and washed with brine (200 mL each twice), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain methyl 4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)bicyclo[2.2.2]octane-1-carboxylate (4.00 g, crude) as a yellow solid.

[0262] 1 H-NMR (400 MHz, DMSO-d6) δ= 7.65 (s, 1H), 3.77 (s, 3H), 3.59 (s, 3H), 1.99 - 1.89 (m, 6H), 1.85 - 1.73 (m, 6H).

[0263] (Step 5) To a solution of methyl 4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)bicyclo[2.2.2]octane-1-carboxylate (3.50 g, 11.1 mmol, 1.00 equiv) in methanol (30.0 mL) and water (10.0 mL) was added sodium hydroxide (885 mg, 22.1 mmol, 2.00 equiv). The reaction mixture was stirred at 25°C for 1 h. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was diluted with 15 mL of water, the pH was adjusted to 3 by adding hydrochloric acid, filtered, and the filter cake was concentrated under reduced pressure to obtain 4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)bicyclo[2.2.2]octane-1-carboxylic acid (2.30 g, 7.61 mmol, yield 68.8%) as a white solid.

[0264] 1 H-NMR (400 MHz, DMSO-d6) δ= 7.64 (br d,J= 0.8 Hz, 1H), 3.76 (s, 3H), 1.99 - 1.87 (m, 6H), 1.83 - 1.69 (m, 6H).

[0265] (Step 6) To a solution of 4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)bicyclo[2.2.2]octane-1-carboxylic acid (2.30 g, 7.61 mmol, 1.00 equiv) in dichloromethane (20.0 mL) was added ammonium chloride (488 mg, 9.13 mmol, 1.20 equiv), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.75 g, 9.13 mmol, 1.20 equiv), 1H-benzo[d][1,2,3]triazol-1-ol (1.54 g, 11.4 mmol, 1.50 equiv) and N,N-diisopropylethylamine (3.93 g, 30.4 mmol, 5.30 mL, 4.00 eq.) was added. The reaction mixture was stirred at 25°C for 12 h. The reaction mixture was diluted with dichloromethane (20 mL), washed with water (2 times 20 mL each), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)bicyclo[2.2.2]octane-1-carboxamide (2.00 g, 6.64 mmol, yield 87.2%) as a yellow solid.

[0266] 1 H-NMR (400 MHz, DMSO-d6)δ= 7.65 (br d,J= 1.2 Hz, 1H), 6.98 (br s, 1H), 6.73 (br s, 1H), 3.76 (s, 3H), 1.91 (br d,J= 4.0 Hz, 6H), 1.77 - 1.68 (m, 6H).

[0267] (Step 7) To a solution of 4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)bicyclo[2.2.2]octane-1-carboxamide (2.20 g, 7.30 mmol, 1.00 equiv) in tetrahydrofuran (20.0 mL) at 0 °C was added lithium aluminum hydride (2.5 M, 8.76 mL, 3.00 equiv). The reaction mixture was stirred at 20 °C for 2 h. The reaction was stopped by adding 0.8 mL of water, 15% sodium hydroxide solution (0.8 mL), and water (2.4 mL), filtered, and the filtrate concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (column Phenomenex luna C18 150×40 mm×15 μm; mobile phase: [water (formic acid)-acetonitrile]; gradient: 2%-32% B, for 15 min) to give (4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)bicyclo[2.2.2]octan-1-yl)methanamine (750 mg, 2.61 mmol, yield 35.8%) as a yellow solid.

[0268] 1 H-NMR (400 MHz, DMSO-d6)δ= 8.40 (s, 1H), 7.65 (d,J= 1.2 Hz, 1H), 3.76 (s, 3H), 2.49 (br s, 2H), 1.96 - 1.84 (m, 6H), 1.54 - 1.43 (m, 6H).

[0269] (Step 8) To a solution of (4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)bicyclo[2.2.2]octan-1-yl)methanamine (750 mg, 2.61 mmol, 1.00 equiv) in dichloromethane (7.00 mL) were added 2,4-dichloro-1,3,5-triazine (392 mg, 2.61 mmol, 1.00 equiv) and triethylamine (528 mg, 5.22 mmol, 727 μL, 2.00 equiv). The reaction mixture was stirred at 20°C for 2 h. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to obtain 4-chloro-N-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)bicyclo[2.2.2]octan-1-yl)methyl)-1,3,5-triazin-2-amine (160 mg, 399 μmol, yield 15.3%) as a yellow solid.

[0270] 1 H-NMR (400 MHz, DMSO-d6)δ= 8.67 (br d,J= 2.8 Hz, 1H), 8.46 - 8.32 (m, 1H), 7.63 (d,J= 1.2 Hz, 1H), 3.76 - 3.73 (m, 3H), 3.22 - 3.08 (m, 2H), 1.94 - 1.86 (m, 6H), 1.52 - 1.41 (m, 6H).

[0271] (Step 9) A mixture of 4-chloro-N-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)bicyclo[2.2.2]octan-1-yl)methyl)-1,3,5-triazin-2-amine (160 mg, 399 μmol, 1.00 equiv), (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (116 mg, 599 μmol, 1.50 equiv), potassium phosphate (170 mg, 798 μmol, 2.00 equiv) and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (29.2 mg, 39.9 μmol, 0.100 equiv) in dioxane (1.50 mL) and water (0.500 mL) was degassed. After purging with nitrogen three times, the mixture was stirred under a nitrogen atmosphere at 100°C for 12 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) and concentrated under reduced pressure to obtain the crude product. This crude product was purified by preparative HPLC (column Phenomenex luna C18 150×25 mm×10 μm; mobile phase: [water (formic acid)-acetonitrile]; gradient: 40%-70% B for 15 min) and lyophilized to give 4-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)bicyclo[2.2.2]octan-1-yl)methyl)-1,3,5-triazin-2-amine (25.63 mg, 47.87 μmol, yield 12.0%, purity 96.1%) as a yellow solid.

[0272] 1H-NMR (400 MHz, DMSO-d6)δ= 8.66 (s, 1H), 8.65 - 8.56 (m, 1H), 8.38 (q,J= 7.2 Hz, 1H), 7.63 (dd,J= 1.2, 3.6 Hz, 1H), 3.87 (d,J= 3.2 Hz, 3H), 3.75 (d,J= 4.4 Hz, 3H), 3.23 - 3.12 (m, 2H), 1.97 - 1.85 (m, 6H), 1.84 - 1.76 (m, 1H), 1.54 - 1.41 (m, 6H), 1.11 - 1.02 (m, 2H), 1.00 - 0.89 (m, 2H).

[0273] <Example 16>

[0274] Preparation of 4-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(((1s,2R,3s,4r,5S,6r,7R,8S)-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cubain-1-yl)methyl)-1,3,5-triazin-2-amine

[0275]

[0276] It was synthesized according to the route of chemical formula 14.

[0277]

[0278] (Step 1) To a solution of ((1s,2R,3s,4r,5S,6r,7R,8S)-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cubein-1-yl)methanamine (450 mg, 1.60 mmol, 1.00 equiv) in tetrahydrofuran (5.00 mL) were added triethylamine (324 mg, 3.20 mmol, 445 μL, 2.00 equiv) and 2,4-dichloro-1,3,5-triazine (240 mg, 1.60 mmol, 1.00 equiv). The reaction mixture was stirred at 20°C for 2 h. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=1 / 0 to 0 / 1) to give 4-chloro-N-(((1s,2R,3s,4r,5S,6r,7R,8S)-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cubain-1-yl)methyl)-1,3,5-triazin-2-amine (130 mg, 329 μmol, yield 20.6%) as a yellow oil.

[0279] 1 H-NMR (400 MHz, DMSO-d6)δ= 8.52 - 8.32 (m, 1H), 6.63 (td,J= 6.0, 15.6 Hz, 1H), 4.37 (t,J= 4.8 Hz, 3H), 4.02 (q,J= 4.4 Hz, 3H), 3.88 (dd,J= 6.0, 9.6 Hz, 2H), 3.66 (s, 3H).

[0280] (Step 2) To a solution of 4-chloro-N-(((1s,2R,3s,4r,5S,6r,7R,8S)-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cubain-1-yl)methyl)-1,3,5-triazin-2-amine (130 mg, 329 μmol, 1.00 equiv) and (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (95.8 mg, 494 μmol, 1.50 equiv) in dioxane (0.500 mL) and water (0.100 mL) was added potassium phosphate (140 mg, 659 μmol, 2.00 equiv) and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II)(24.1 A mixture of (mg, 32.9 μmol, 0.100 equiv) was added. The mixture was stirred at 100°C under a nitrogen atmosphere for 12 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to obtain the crude product. This crude product was purified by preparative HPLC (column Phenomenex luna C18 150×25 mm×10 μm; mobile phase: [water (formic acid)-acetonitrile]; gradient: 35%-65% B for 9 min) and lyophilized to give 4-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(((1s,2R,3s,4r,5S,6r,7R,8S)-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cubain-1-yl)methyl)-1,3,5-triazin-2-amine (7.91 mg, 15.5 μmol, yield 4.72%, purity 99.9%) as a white solid.

[0281] 1H-NMR (400 MHz, DMSO-d6)δ= 8.67 - 8.66 (m, 1H), 8.59 (s, 1H), 8.58 - 8.51 (m, 1H), 7.75 (s, 1H), 4.22 (td,J= 4.8, 12.0 Hz, 3H), 3.91 (td,J= 4.8, 11.6 Hz, 3H), 3.87 (d,J= 2.8 Hz, 3H), 3.68 (d,J= 5.6 Hz, 1H), 3.61 (d,J= 6.0 Hz, 1H), 3.56 (d,J= 5.6 Hz, 3H), 1.81 (dt,J=4.0, 8.0 Hz, 1H), 1.10 - 1.02 (m, 2H), 1.00 - 0.87 (m, 2H).

[0282] <Example 17>

[0283] Preparation of 4-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-methyl-N-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-1,3,5-triazin-2-amine

[0284]

[0285] To a solution of 4-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-1,3,5-triazin-2-amine (100 mg, 207 μmol, 1.00 equiv) in dimethylformamide (0.500 mL) was added sodium hydride (16.6 mg, 415 μmol, purity 60%, 2.00 equiv) at 0 °C, and the reaction mixture was stirred at 0 °C for 30 min, followed by the addition of iodomethane (88.3 mg, 622 μmol, 38.7 μL, 3.00 equiv). The reaction mixture was stirred at 20 °C for 2 h. The reaction was quenched by the addition of 2.00 mL of water, and the mixture was filtered. The filtrate was purified by preparative HPLC (column Phenomenex luna C18 250×50 mm×15 μm; mobile phase: [water (formic acid)-acetonitrile]; gradient: 58-88% B, over 15 min) and lyophilized to obtain 4-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-methyl-N-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-1,3,5-triazin-2-amine (6.31 mg, 12.7 μmol, yield 6.13%, purity 99.8%) as a yellow solid.

[0286] 1 H-NMR (400 MHz, DMSO-d6)δ= 8.78 (d,J= 15.2 Hz, 1H), 8.67 (d,J= 10.4 Hz, 1H), 7.61 - 7.48 (m, 3H), 7.44 (br d,J= 8.0 Hz, 1H), 6.76 (br s, 1H), 5.03 - 4.89 (m, 2H), 3.87 (d,J= 8.4 Hz, 3H), 3.24 - 3.09 (m, 3H), 2.34 (br d,J= 9.6 Hz, 3H), 1.95 - 1.77 (m, 1H), 1.09 - 0.82 (m, 4H).

[0287] <Example 18>

[0288] Preparation of N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-4-(2-isopropylphenyl)-1,3,5-triazin-2-amine

[0289]

[0290] To a solution of 4-chloro-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1,3,5-triazin-2-amine (200 mg, 504 μmol, 1.00 equiv) and (2-isopropylphenyl)boronic acid (165 mg, 1.01 mmol, 2.00 equiv) in dioxane (2.00 mL) and water (0.400 mL) were added potassium phosphate (214 mg, 1.01 mmol, 2.00 equiv) and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (36.9 mg, 50.4 μmol, 0.100 equiv). The mixture was stirred at 100 °C under a nitrogen atmosphere for 12 h. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to obtain a crude product. The crude product was purified by preparative HPLC (column Phenomenex luna C18 150×25 mm×10 μm; mobile phase: [water (formic acid)-acetonitrile]; gradient: 55%-85% B, for 15 min) and lyophilized to obtain N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-4-(2-isopropylphenyl)-1,3,5-triazin-2-amine (24.91 mg, 50.75 μmol, yield 10.07%, purity 97.9%) as a white solid.

[0291] 1H-NMR (400 MHz, DMSO-d6)δ= 8.74 (td,J= 6.4, 16.0 Hz, 1H), 8.69 - 8.61 (m, 1H), 8.16 (s, 1H), 7.61 - 7.39 (m, 7H), 7.30 - 7.19 (m, 1H), 4.66 (br d,J= 6.0 Hz, 2H), 4.53 - 4.38 (m, 1H), 3.68 - 3.49 (m, 1H), 1.44 - 1.34 (m, 6H), 1.21 - 1.02 (m, 6H).

[0292] <Example 19>

[0293] Preparation of 4-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-1,3,5-triazin-2-amine

[0294]

[0295] (Step 1) To a solution of (4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methanamine (1.20 g, 4.70 mmol, 1.00 equiv) in tetrahydrofuran (12.0 mL) were added triethylamine (952 mg, 9.40 mmol, 1.31 mL, 2.00 equiv) and 2,4-dichloro-1,3,5-triazine (705 mg, 4.70 mmol, 1.00 equiv). The reaction mixture was stirred at 20°C for 2 h. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = from 1 / 0 to 1 / 1) to give 4-chloro-N-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-1,3,5-triazin-2-amine (356 mg, 965 μmol, yield 20.0%) as a yellow oil.

[0296] 1H-NMR (400 MHz, DMSO-d6)δ= 9.24 (q,J= 6.4 Hz, 1H), 8.51 - 8.38 (m, 1H), 7.57 - 7.51 (m, 2H), 7.51 - 7.43 (m, 2H), 6.75 (s, 1H), 4.62 (dd,J= 6.4, 17.6 Hz, 2H), 2.33 (d,J= 3.2 Hz, 3H).

[0297] (Step 2) To a solution of 4-chloro-N-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-1,3,5-triazin-2-amine (330 mg, 895 μmol, 1.00 equiv) and (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (260 mg, 1.34 mmol, 1.50 equiv) in dioxane (5.00 mL) and water (1.00 mL) were added potassium phosphate (380 mg, 1.79 mmol, 895 μL, 2.00 equiv) and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (65.5 mg, 89.5 μmol, 0.100 equiv). The mixture was stirred at 100°C under a nitrogen atmosphere for 12 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to obtain the crude product. This crude product was purified by preparative HPLC (column YMC-Actus Triart C18 150×30 mm×7 μm; mobile phase: [water (formic acid)-acetonitrile]; gradient: 50%-80% B, for 10 min) to give 4-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-1,3,5-triazin-2-amine (44.8 mg, 89.9 μmol, yield 10.0%, purity 96.7%) as a pale white solid.

[0298] 1H-NMR (400 MHz, DMSO-d6)δ= 9.02 - 8.88 (m, 1H), 8.73 - 8.63 (m, 2H), 7.59 - 7.50 (m, 3H), 7.48 - 7.43 (m, 1H), 6.75 (d,J= 3.6 Hz, 1H), 4.72 - 4.56 (m, 2H), 3.86 (d,J= 11.6 Hz, 3H), 2.33 (d,J= 9.6 Hz, 3H), 1.89 - 1.76 (m, 1H), 1.09 - 1.03 (m, 1H), 1.02 - 0.94 (m, 2H), 0.87 - 0.79 (m, 1H).

[0299] <Example 20>

[0300] Preparation of 4-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(3-fluoro-4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1,3,5-triazin-2-amine

[0301]

[0302] (Step 1) To a solution of (3-fluoro-4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanamine (1.00 g, 2.88 mmol, 1.00 equiv, formate) in tetrahydrofuran (5.00 mL) were added triethylamine (583 mg, 5.76 mmol, 802 μL, 2.00 equiv) and 2,4-dichloro-1,3,5-triazine (432 mg, 2.88 mmol, 1.00 equiv). The reaction mixture was stirred at 20°C for 2 h. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to give 4-chloro-N-(3-fluoro-4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1,3,5-triazin-2-amine (285 mg, 687 μmol, yield 23.8%) as a yellow oil.

[0303] 1H-NMR (400 MHz, DMSO-d6)δ= 9.24 (q,J= 6.4 Hz, 1H), 8.47 (d,J= 17.6 Hz, 1H), 8.24 (s, 1H), 7.52 (q,J= 7.2 Hz, 1H), 7.38 - 7.26 (m, 2H), 4.63 (dd,J= 6.4, 16.0 Hz, 2H), 4.14 (qd,J= 6.4, 12.0 Hz, 1H), 1.35 (d,J= 6.8 Hz, 6H).

[0304] (Step 2) To a solution of 4-chloro-N-(3-fluoro-4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1,3,5-triazin-2-amine (285 mg, 687 μmol, 1.00 equiv) and (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (200 mg, 1.03 mmol, 1.50 equiv) in dioxane (5.00 mL) and water (1.00 mL) were added potassium phosphate (292 mg, 1.37 mmol, 2.00 equiv) and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (50.3 mg, 68.7 μmol, 0.100 equiv). The mixture was stirred at 100°C under a nitrogen atmosphere for 12 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to obtain the crude product. This crude product was purified by preparative HPLC (column Phenomenex luna C18 150×25 mm×10 μm; mobile phase: [water (formic acid)-acetonitrile]; gradient: 40%-70% B for 15 min) and lyophilized to give 4-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(3-fluoro-4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1,3,5-triazin-2-amine (7.91 mg, 15.5 μmol, yield 4.72%, purity 99.9%) as a pale white solid.

[0305] 1H-NMR (400 MHz, DMSO-d6)δ= 8.96 (td,J= 6.4, 18.0 Hz, 1H), 8.74 - 8.63 (m, 2H), 8.25 (s, 1H), 7.53 (td,J= 7.6, 12.8 Hz, 1H), 7.42 - 7.22 (m, 2H), 4.73 - 4.56 (m, 2H), 4.22 - 4.06 (m, 1H), 3.86 (d,J= 14.8 Hz, 3H), 1.92 - 1.74 (m, 1H), 1.36 (dd,J= 5.2, 6.4 Hz, 6H), 1.11 - 1.04 (m, 1H), 1.03 - 0.93 (m, 2H), 0.88 - 0.80 (m, 1H).

[0306] <Example 21>

[0307] Preparation of N-(4-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1,3,5-triazin-2-yl)-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)cyanamide

[0308]

[0309] To a solution of 4-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1,3,5-triazin-2-amine (100 mg, 196 μmol, 1.00 equiv) in dimethylformamide (1.00 mL) at 0 °C was added sodium hydride (15.7 mg, 392 μmol, purity 60%, 2.00 equiv). The reaction mixture was stirred at 0 °C for 30 min, followed by the addition of cyanogen bromide (62.2 mg, 588 μmol, 43.1 μL, 3.00 equiv). The reaction mixture was stirred at 20 °C for 2 h. The reaction was stopped by adding 2 mL of water at 20°C, diluted with 5.00 mL of water, and extracted with ethyl acetate (5 mL each three times). The combined organic layers were washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (column Phenomenex luna C18 150×25 mm×10 μm; mobile phase: [water (formic acid)-acetonitrile]; gradient: 48-78% B, for 15 min) and lyophilized to give N-(4-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1,3,5-triazin-2-yl)-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)cyanamide (31.0 mg, 57.60 μmol, yield 29.40%, purity 99.5%) as a white solid.

[0310] 1H-NMR (400 MHz, DMSO-d6)δ= 9.29 (s, 1H), 8.73 (s, 1H), 8.20 (d,J= 1.2 Hz, 1H), 7.69 - 7.53 (m, 4H), 5.23 (s, 2H), 4.55 - 4.40 (m, 1H), 3.89 (s, 3H), 2.05 - 1.93 (m, 1H), 1.41 (d,J= 6.8 Hz, 6H), 1.17 - 1.02 (m, 2H), 0.92 (br d,J= 3.6 Hz, 2H).

[0311] <Example 22>

[0312] Preparation of 4-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(2-methoxy-4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-1,3,5-triazin-2-amine

[0313]

[0314] (Step 1) To a solution of 4-fluoro-2-methoxybenzonitrile (1.00 g, 6.62 mmol, 1.00 equiv) in dimethylformamide (10.0 mL) were added 5-methyl-3-(trifluoromethyl)-1H-pyrazole (1.19 g, 7.94 mmol, 1.20 equiv) and potassium carbonate (1.83 g, 13.2 mmol, 2.00 equiv). The reaction mixture was stirred at 100°C for 12 h. The mixture was diluted with 100 mL of water and extracted with ethyl acetate (60 mL each three times). The organic layers were combined, washed with brine (100 mL each twice), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to obtain 2-methoxy-4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzonitrile (1.36 g, 4.84 mmol, yield 73.1%) as a white solid.

[0315] 1H-NMR (400 MHz, DMSO-d6)δ= 7.95 (d,J= 8.4 Hz, 1H), 7.44 (d,J= 2.0 Hz, 1H), 7.34 (dd,J= 2.0, 8.4 Hz, 1H), 6.85 (s, 1H), 3.99 (s, 3H), 2.43 (s, 3H).

[0316] (Step 2) To a solution of 2-methoxy-4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzonitrile (1.36 g, 4.84 mmol, 1.00 equiv) in ammonia / methanol (15.0 mL) was added Raney nickel (41.4 mg, 483 μmol, 0.100 equiv). The mixture was degassed and purged with hydrogen three times, then stirred at 25 °C for 2 h under a hydrogen atmosphere of 50 psi. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give 2-methoxy-4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methanamine (1.16 g, 4.07 mmol, yield 84.1%) as a green oil.

[0317] 1 H-NMR (400 MHz, DMSO-d6)δ= 7.50 (br d,J= 8.0 Hz, 1H), 7.15 - 7.03 (m, 2H), 6.74 (s, 1H), 3.84 (s, 3H), 3.78 - 3.62 (m, 2H), 2.34 (s, 3H).

[0318] (Step 3) To a solution of 2-methoxy-4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methanamine (1.16 g, 4.07 mmol, 1.00 equiv) in tetrahydrofuran (10.0 mL) were added triethylamine (823 mg, 8.13 mmol, 1.13 mL, 2.00 equiv) and 2,4-dichloro-1,3,5-triazine (609 mg, 4.07 mmol, 1.00 equiv). The reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=1 / 0 to 1 / 1) to obtain 4-chloro-N-(2-methoxy-4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-1,3,5-triazin-2-amine (560 mg, 1.40 mmol, yield 34.5%) as a white oil.

[0319] 1 H-NMR (400 MHz, DMSO-d6)δ= 9.16 - 9.05 (m, 1H), 8.45 (d,J= 13.6 Hz, 1H), 7.31 (d,J= 8.0 Hz, 1H), 7.17 (dd,J= 2.0, 5.6 Hz, 1H), 7.10 (dt,J= 2.0, 8.4 Hz, 1H), 6.75 (s, 1H), 4.54 (dd,J= 6.0, 17.2 Hz, 2H), 3.88 (d,J= 3.2 Hz, 3H), 2.34 (d,J= 3.6 Hz, 3H).

[0320] (Step 4) A mixture of 4-chloro-N-(2-methoxy-4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-1,3,5-triazin-2-amine (200 mg, 501 μmol, 1.00 equiv), (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (389 mg, 2.01 mmol, 4.00 equiv), potassium phosphate (212 mg, 1.00 mmol, 2.00 equiv) and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (36.7 mg, 50.1 μmol, 0.100 equiv) in dioxane (2.00 mL) and water (0.400 mL) was degassed and purged with nitrogen three times, and the mixture was The mixture was stirred for 12 hours under a nitrogen atmosphere at 100°C. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) and concentrated under reduced pressure to obtain the crude product. This crude product was purified by preparative HPLC (column Phenomenex luna C18 150×25 mm×10 μm; mobile phase: [water (formic acid)-acetonitrile]; gradient: 48%-78% B, for 15 min) and lyophilized to give 4-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(2-methoxy-4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-1,3,5-triazin-2-amine (55.84 mg, 108.96 μmol, yield 21.72%, purity 99.9%) as a white solid.

[0321] 1H-NMR (400 MHz, DMSO-d6)δ= 8.86 - 8.73 (m, 1H), 8.71 - 8.60 (m, 2H), 7.39 - 7.24 (m, 1H), 7.20 - 7.04 (m, 2H), 6.75 (d,J= 3.2 Hz, 1H), 4.66 - 4.46 (m, 2H), 3.86 (dd,J= 4.0, 19.2 Hz, 6H), 2.34 (d,J= 8.8 Hz, 3H), 1.91 - 1.72 (m, 1H), 1.10 - 1.03 (m, 1H), 0.97 (td,J= 3.2, 7.6 Hz, 2H), 0.86 - 0.73 (m, 1H).

[0322] <Example 23>

[0323] Preparation of 4-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-((1-(1-methyl-4-(lifluoromethyl)-1H-imidazol-2-yl)piperidin-4-yl)methyl)-1,3,5-triazin-2-amine

[0324]

[0325] It was synthesized according to the route of chemical formula 15.

[0326]

[0327] (Step 1) To a solution of 4-(trifluoromethyl)-1H-imidazole (20.0 g, 147 mmol, 1.00 equiv) and methyl iodide (41.7 g, 294 mmol, 18.3 mL, 2.00 equiv) in dimethylformamide (200 mL) was added sodium hydride (7.06 g, 147 mmol, purity 60%, 2.00 equiv) in dichloromethane (100 mL) dropwise at 0°C. The reaction mixture was stirred under a nitrogen atmosphere at 25°C for 20 minutes using flow chemistry. The reaction was quenched by adding 200 mL of saturated ammonium chloride solution, and the mixture was extracted with ethyl acetate (three times 100 mL each). The combined organic layers were washed with brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to obtain 1-methyl-4-(trifluoromethyl)-1H-imidazole (6.00 g, 40.0 mmol, yield 67%) as a yellow solid.

[0328] 1 H-NMR (400 MHz, DMSO-d6)δ87.77 (d,J=7.6 Hz, 2H), 3.70 (s, 3H).

[0329] (Step 2) To a solution of 1-methyl-4-(trifluoromethyl)-1H-imidazole (5.00 g, 33.3 mmol, 1.00 equiv) in tetrahydrofuran (80.0 mL) at -78 °C was added n-Butyllithium (2.5 M, 13.3 mL, 1.00 equiv), and the mixture was stirred at -78 °C for 30 minutes, followed by the addition of carbon tetrabromide (16.5 g, 50.0 mmol, 1.50 equiv). The reaction mixture was stirred for 2 hours under a nitrogen atmosphere at -78 °C. The reaction was stopped by adding 200 mL of a saturated aqueous ammonium chloride solution at 20 °C, and the mixture was extracted with ethyl acetate (three times 200 mL each). The combined organic layers were washed with brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to obtain 2-bromo-1-methyl-4-(trifluoromethyl)-1H-imidazole (1.00 g, 4.37 mmol, yield 13%) as a yellow oil.

[0330] 1 H-NMR (400 MHz, CDCl3)δ7.31 (d,J=1.2 Hz, 1H), 3.69 (s, 3H).

[0331] (Step 3) To a solution of 2-bromo-1-methyl-4-(trifluoromethyl)-1H-imidazole (840 mg, 3.67 mmol, 1.00 equiv) and tert-butyl (piperidin-4-ylmethyl)carbamate (943 mg, 4.40 mmol, 1.20 equiv) in dioxane (9.00 mL) were added cesium carbonate (2.39 g, 7.34 mmol, 2.00 equiv) and 1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-2H-imidazol-1-ium-2-ide;3-chloropyridine;dichloropalladium (357 mg, 367 μmol, 0.100 equiv). The mixture was stirred at 100°C under a nitrogen atmosphere for 12 h. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to obtain tert-butyl ((1-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)piperidin-4-yl)methyl)carbamate (750 mg, 2.07 mmol, yield 56%) as a yellow oil.

[0332] 1 H-NMR (400 MHz, DMSO-d6)δ= 7.51 (d,J= 1.2 Hz, 1H), 6.88 (br s, 1H), 3.47 (s, 3H), 3.23 (br d,J= 12.0 Hz, 2H), 2.86 (br t,J= 6.4 Hz, 2H), 2.67 (br t,J= 11.2 Hz, 2H), 1.67 (br d,J= 11.2 Hz, 2H), 1.55 - 1.45 (m, 1H), 1.38 (s, 9H), 1.31 - 1.21 (m, 2H).

[0333] (Step 4) To tert-butyl ((1-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)piperidin-4-yl)methyl)carbamate (750 mg, 2.07 mmol, 1.00 equiv) in dioxane was added 2 M hydrochloric acid in methanol (7.00 mL, 6.76 equiv) and stirred at 20 °C for 5 h. The reaction mixture was concentrated under reduced pressure to give (1-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)piperidin-4-yl)methanamine (750 mg, crude) as a yellow oil.

[0334] MS (ESI) m / z 263.3 [M+H] +

[0335] (Step 5) To a solution of (1-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)piperidin-4-yl)methanamine (750 mg, 2.86 mmol, 1.00 equiv) in dichloromethane (10.0 mL) were added triethylamine (579 mg, 5.72 mmol, 796 μL, 2.00 equiv) and 2,4-dichloro-1,3,5-triazine (428.8 mg, 2.86 mmol, 1.00 equiv). The reaction mixture was stirred at 20 °C for 2 h. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to obtain 4-chloro-N-((1-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)piperidin-4-yl)methyl)-1,3,5-triazin-2-amine (210 mg, 559 μmol, yield 19%) as a white solid.

[0336] 1H-NMR (400 MHz, DMSO-d6)δ= 8.79 (br t,J= 5.6 Hz, 1H), 8.52 - 8.35 (m, 1H), 7.53 (s, 1H), 3.49 (s, 3H), 3.33 - 3.23 (m, 4H), 2.77 - 2.65 (m, 2H), 1.80 - 1.65 (m, 3H), 1.34 (q,J= 12.4 Hz, 2H).

[0337] (Step 6) To a solution of 4-chloro-N-((1-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)piperidin-4-yl)methyl)-1,3,5-triazin-2-amine (180 mg, 479 μmol, 1.00 equiv) and (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (139 mg, 719 μmol, 1.50 equiv) in dioxane (2.00 mL) and water (0.400 mL) were added potassium phosphate (203 mg, 958 μmol, 2.00 equiv) and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (35.1 mg, 47.9 μmol, 0.100 equiv). This mixture was stirred at 100°C under a nitrogen atmosphere for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue. This residue was subjected to column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to obtain the crude product. This crude product was purified by preparative HPLC (column Phenomenex luna C18 150×25 mm×10 μm; mobile phase: [water (formic acid)-acetonitrile]; gradient: 35%-65% B for 15 min) and lyophilized to give 4-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-((1-(1-methyl-4-(lifluoromethyl)-1H-imidazol-2-yl)piperidin-4-yl)methyl)-1,3,5-triazin-2-amine (70.51 mg, 143.61 μmol, yield 29.98%, purity 99.7%) as a white solid.

[0338] 1H-NMR (400 MHz, DMSO-d6)δ= 8.69 - 8.52 (m, 2H), 8.47 - 8.32 (m, 1H), 7.52 - 7.45 (m, 1H), 3.85 (d,J= 1.2 Hz, 3H), 3.46 (d,J= 7.2 Hz, 3H), 3.32 - 3.19 (m, 4H), 2.68 (q,J= 12.8 Hz, 2H), 1.88 - 1.62 (m, 4H), 1.32 (br t,J= 12.0 Hz, 2H), 1.08 - 1.00 (m, 2H), 0.95 (dt,J= 2.8, 5.2 Hz, 2H).

[0339] <Example 24>

[0340] Preparation of 4-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-N-(tetrahydrofuran-3-yl)-1,3,5-triazin-2-amine

[0341]

[0342] To a solution of Example 6 compound (30 mg, 0.06 mmol) in dimethylformamide (0.1 mL) was added NaH (23 mg, 0.59 mmol) at 0°C. The mixture was stirred at 0°C for 30 min, and then a solution of 3-iodotetrahydrofuran (175 mg, 0.88 mmol) in dimethylformamide (0.1 mL) was added dropwise. The mixture was stirred at 50°C under nitrogen for 16 h. LC-MS confirmed that the target mass of the product had been produced. The reaction mixture was diluted with water (10 mL), extracted with ethyl acetate (three times 10 mL each), and washed with water (5 mL) and brine (5 mL). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters-SunFire C18 10 μm - 19×250 mm, A: water (0.1% formic acid) B: acetonitrile]; gradient: 75%) to give 4-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-N-(tetrahydrofuran-3-yl)-1,3,5-triazin-2-amine (3 mg, 0.01 mmol, yield 8.79%) as a white solid.

[0343] MS m / z (ESI): 581.2 (M+H) + .

[0344] HPLC: 100% purity

[0345] 1H-NMR (400 MHz, CDCl3) δ8.75 (d,J= 31.6 Hz, 1H), 8.61 (d,J= 31.1 Hz, 1H), 7.53 (d,J= 7.9 Hz, 1H), 7.46 (d,J= 8.0 Hz, 1H), 7.41 (s, 1H), 7.36 (d,J= 8.1 Hz, 1H), 7.30 (d,J= 8.1 Hz, 1H), 5.42 (d,J= 64.2 Hz, 1H), 5.09 - 4.87 (m, 2H), 4.54 (m, 1H), 4.08 - 3.87 (m, 4H), 3.78 (m, 3H), 2.36 - 2.23 (m, 1H), 1.97 (m, 2H), 1.48 - 1.43 (m, 6H), 1.10 (s, 1H), 1.04 - 0.95 (m, 1H), 0.88 (t,J= 6.8 Hz, 1H), 0.77 - 0.65 (m, 1H).

[0346] <Example 25>

[0347] Preparation of 4-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-N,6-dimethyl-1,3,5-triazin-2-amine

[0348]

[0349] (Step 1) To a solution of (4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanamine (2.00 g, 7.06 mmol, 1.00 equiv) in dimethylformamide (1.00 mL) were added triethylamine (1.43 g, 14.1 mmol, 1.97 mL, 2.00 equiv) and 2,4-dichloro-6-methyl-1,3,5-triazine (1.16 g, 7.06 mmol, 1.00 equiv). The reaction mixture was stirred at 20°C for 2 h. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=1 / 0 to 1 / 1) to give 4-chloro-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6-methyl-1,3,5-triazin-2-amine (1.44 g, 3.51 mmol, yield 49.7%) as a yellow oil.

[0350] 1 H-NMR (400 MHz, CDCl3)δ= 7.53 (d,J= 8.0 Hz, 2H), 7.46 - 7.37 (m, 3H), 6.50 - 6.16 (m, 1H), 4.74 (dd,J= 6.0, 13.2 Hz, 2H), 4.55 (spt,J= 6.8 Hz, 1H), 2.50 - 2.38 (m, 3H), 1.46 (d,J= 6.8 Hz, 6H).

[0351] (Step 2) To a solution of 4-chloro-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6-methyl-1,3,5-triazin-2-amine (1.44 g, 3.51 mmol, 1.00 equiv) in dioxane (15.0 mL) and water (3.00 mL) were added (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (884 mg, 4.56 mmol, 1.30 equiv), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (257 mg, 351 μmol, 0.100 equiv) and potassium phosphate (1.49 g, 7.01 mmol, 2.00 equiv). The mixture was stirred under a nitrogen atmosphere at 100°C for 12 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to obtain 4-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6-methyl-1,3,5-triazin-2-amine (1.16 g, 2.21 mmol, yield 63.1%) as a green solid.

[0352] 1 H-NMR (400 MHz, DMSO-d6)δ= 8.77 (q,J= 6.4 Hz, 1H), 8.64 (d,J= 10.8 Hz, 1H), 8.16 (d,J= 2.4 Hz, 1H), 7.58 - 7.53 (m, 1H), 7.50 (d,J= 7.6 Hz, 2H), 7.45 - 7.38 (m, 1H), 4.72 - 4.54 (m, 2H), 4.54 - 4.38 (m, 1H), 3.85 (d,J= 10.0 Hz, 3H), 2.38 (d,J= 3.6 Hz, 3H), 1.85 - 1.70 (m, 1H), 1.40 (t,J= 6.8 Hz, 6H), 1.09 - 0.91 (m, 3H), 0.87 - 0.75 (m, 1H).

[0353] (Step 3) To a solution of 4-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6-methyl-1,3,5-triazin-2-amine (100 mg, 191 μmol, 1.00 equiv) in dimethylformamide (1.00 mL) at 0 °C was added sodium hydride (15.3 mg, 381 μmol, purity 60%, 2.00 equiv), and the reaction mixture was stirred at 20 °C for 30 min. Then, iodomethane (81.2 mg, 572 μmol, 35.6 μL, 3.00 equiv) was added at 0 °C. The reaction mixture was stirred at 20 °C for 1 h. Here, 0.5 mL of formic acid was added at 0 °C to stop the reaction, followed by filtration. The filtrate was purified by preparative HPLC (column Phenomenex luna C18 150 × 25 mm × 10 μm; mobile phase: [water (formic acid)-acetonitrile]; gradient: 48-78% B, for 15 min) and lyophilized to obtain 4-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-N,6-dimethyl-1,3,5-triazin-2-amine (42.91 mg, 79.59 μmol, yield 41.8%, purity 99.9%) as a yellow solid.

[0354] 1 H-NMR (400 MHz, DMSO-d6)δ= 8.63 (s, 1H), 8.02 (d,J= 1.2 Hz, 1H), 7.53 (br s, 2H), 7.43 (br d,J= 2.4 Hz, 2H), 5.08 - 4.87 (m, 2H), 4.58 - 4.40 (m, 1H), 3.89 (s, 3H), 3.20 (br s, 3H), 2.45 (s, 3H), 1.96 - 1.81 (m, 1H), 1.41 (d,J= 6.4 Hz, 6H), 1.05 (br s, 2H), 0.97 - 0.78 (m, 2H).

[0355] <Example 26>

[0356] Preparation of 4-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6-methyl-N-(prop-2-yn-1-yl)-1,3,5-triazin-2-amine

[0357]

[0358] To a solution of 4-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6-methyl-1,3,5-triazin-2-amine (100 mg, 191 μmol, 1.00 equiv) in dimethylformamide (1.00 mL) at 0 °C was added sodium hydride (15.3 mg, 381 μmol, purity 60%, 2.00 equiv), and the reaction mixture was stirred at 20 °C for 30 min. Then, 3-bromoprop-1-yne (85.1 mg, 572 μmol, 61.6 μL, 3.00 equiv) was added at 0 °C. The reaction mixture was stirred at 20 °C for 1 h. Here, 0.50 mL of formic acid was added at 0 °C to stop the reaction, and it was filtered. The filtrate was purified by preparative HPLC (column Phenomenex luna C18 150×25 mm×10 μm; mobile phase: [water (formic acid)-acetonitrile]; gradient: 50-80% B, for 15 min) and lyophilized to obtain 4-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6-methyl-N-(prop-2-yn-1-yl)-1,3,5-triazin-2-amine (29.59 mg, 51.70 μmol, yield 27.1%, purity 98.3%) as a yellow solid.

[0359] 1H-NMR (400 MHz, DMSO-d6)δ= 8.63 (s, 1H), 8.02 (d,J= 1.2 Hz, 1H), 7.61 - 7.38 (m, 4H), 5.02 (br s, 2H), 4.64 - 4.34 (m, 3H), 3.89 (s, 3H), 3.07 (s, 1H), 2.48 (br s, 3H), 2.08 - 1.74 (m, 1H), 1.41 (d,J= 6.8 Hz, 6H), 1.05 (br s, 2H), 0.98 - 0.77 (m, 2H).

[0360] <Example 27>

[0361] Preparation of 4-cyclopropyl-6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-N-methyl-1,3,5-triazin-2-amine

[0362]

[0363] (Step 1) Bromo(cyclopropyl)magnesium (0.5 M, 5.96 mL, 1.10 eq) was added to a solution of 2,4,6-trichloro-1,3,5-triazine (0.500 g, 2.71 mmol, 1.00 eq) in tetrahydrofuran (5.00 mL) at -10 °C. The mixture was stirred for 3 h under a nitrogen atmosphere at 0 °C. The reaction mixture was quenched by adding 100 mL of saturated aqueous ammonium chloride solution, and extracted with ethyl acetate (50 mL each three times). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = from 1 / 0 to 1 / 1) to obtain 2,4-dichloro-6-cyclopropyl-1,3,5-triazine (280 mg, 1.47 mmol, yield 54.34%) as a yellow oil.

[0364] 1H-NMR (400 MHz, CDCl3)δ= 2.19 - 2.07 (m, 1H), 1.30 (td,J= 2.8, 4.4 Hz, 2H), 1.26 (td,J= 2.8, 7.6 Hz, 2H).

[0365] (Step 2) To a solution of (4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanamine (417 mg, 1.47 mmol, 1.00 equiv) in dichloromethane (3.00 mL) were added triethylamine (298 mg, 2.95 mmol, 410 μL, 2.00 equiv) and 2,4-dichloro-6-cyclopropyl-1,3,5-triazine (280 mg, 1.47 mmol, 1.00 equiv). The mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to give 4-chloro-6-cyclopropyl-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1,3,5-triazin-2-amine (220 mg, 504 μmol, yield 34%) as a yellow oil.

[0366] 1 H-NMR (400 MHz, CDCl3)δ= 7.52 (d,J= 7.6 Hz, 2H), 7.44 - 7.35 (m, 3H), 6.68 - 5.89 (m, 1H), 4.70 (d,J= 6.0 Hz, 2H), 4.60 - 4.47 (m, 1H), 2.03 - 1.87 (m, 1H), 1.46 (d,J= 6.4 Hz, 6H), 1.21 - 1.12 (m, 2H), 1.07 (td,J= 3.6, 7.2 Hz, 2H).

[0367] (Step 3) To a solution of 4-chloro-6-cyclopropyl-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1,3,5-triazin-2-amine (220 mg, 504 μmol, 1.00 equiv) and (4-cyclopropyl-6-methoxy-pyrimidin-5-yl)boronic acid (147 mg, 755 μmol, 1.50 equiv) in dioxane (2.00 mL) and water (0.400 mL) were added potassium phosphate (214 mg, 1.01 mmol, 2.00 equiv) and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (36.9 mg, 50.4 μmol, 0.100 equiv). The mixture was stirred under a nitrogen atmosphere at 100°C for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to obtain 4-cyclopropyl-6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1,3,5-triazin-2-amine (150 mg, 272 μmol, yield 54%) as a yellow oil.

[0368] 1 H-NMR (400 MHz, DMSO-d6)δ= 8.74 (br t,J= 6.4 Hz, 1H), 8.64 (d,J= 10.0 Hz, 1H), 8.18 (br d,J= 2.4 Hz, 1H), 7.59 - 7.47 (m, 3H), 7.41 (br d,J= 8.0 Hz, 1H), 4.66 - 4.52 (m, 2H), 4.47 (dt,J= 6.4, 13.6 Hz, 1H), 3.86 (d,J= 9.6 Hz, 3H), 1.94 (br dd,J= 6.0, 10.8 Hz, 1H), 1.84 - 1.70 (m, 1H), 1.44 - 1.36 (m, 6H), 1.09 - 0.95 (m, 7H), 0.87 - 0.78 (m, 1H).

[0369] (Step 4) To a solution of 4-cyclopropyl-6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1,3,5-triazin-2-amine (90.0 mg, 164 μmol, 1.00 equiv) in dimethylformamide (1.00 mL) at 0 °C was added sodium hydride (13.1 mg, 327 μmol, purity 60%, 2.00 equiv), and the reaction mixture was stirred at 0 °C for 30 min. Then, iodomethane (69.6 mg, 490 μmol, 30.5 μL, 3.00 equiv) was added. The reaction mixture was stirred at 20 °C for 1 h. Here, 0.5 mL of formic acid was added at 0 °C to stop the reaction, followed by filtration. The filtrate was purified by preparative HPLC (column Phenomenex luna C18 150 × 25 mm × 10 μm; mobile phase: [water (formic acid)-acetonitrile]; gradient: 60-90% B, for 15 min) and lyophilized to obtain 4-cyclopropyl-6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-N-methyl-1,3,5-triazin-2-amine (70.51 mg, 143.61 μmol, yield 29.98%, purity 99.7%) as a yellow solid.

[0370] 1 H-NMR (400 MHz, DMSO-d6)δ= 8.62 (s, 1H), 8.02 (d,J= 1.2 Hz, 1H), 7.61 - 7.32 (m, 4H), 4.93 (br s, 2H), 4.59 - 4.36 (m, 1H), 3.89 (s, 3H), 3.18 (br s, 3H), 2.07 - 1.95 (m, 1H), 1.89 (br dd,J= 3.6, 4.8 Hz, 1H), 1.41 (d,J= 6.4 Hz, 6H), 1.18 - 0.98 (m, 6H), 0.96 - 0.76 (m, 2H).

[0371] <Example 28>

[0372] Preparation of 4-cyclopropyl-6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-N-(prop-2-yn-1-yl)-1,3,5-triazin-2-amine

[0373]

[0374] To a solution of 4-cyclopropyl-6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)- 1,3,5-triazin-2-amine (90.0 mg, 164 μmol, 1.00 equiv) in dimethylformamide (1.00 mL) at 0 °C was added sodium hydride (13.1 mg, 327 μmol, purity 60%, 2.00 equiv), and the reaction mixture was stirred at 0 °C for 30 min. 3-Bromoprop-1-yne (58.3 mg, 490 μmol, 42.3 μL, 3.00 equiv) was then added. The reaction mixture was stirred at 25 °C for 1 h. Here, 0.500 mL of formic acid was added at 0 °C to stop the reaction, and it was filtered. The filtrate was purified by preparative HPLC (column Phenomenex luna C18 150×25 mm×10 μm; mobile phase: [water (formic acid)-acetonitrile]; gradient: 45-75% B, for 15 min) and lyophilized to obtain 4-cyclopropyl-6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-N-(prop-2-yn-1-yl)-1,3,5-triazin-2-amine (41.04 mg, 68.26 μmol, yield 41.76%, purity 97.9%) as a yellow solid.

[0375] 1H-NMR (400 MHz, DMSO-d6)δ= 8.62 (s, 1H), 8.02 (s, 1H), 7.65 - 7.37 (m, 4H), 4.98 (s, 2H), 4.49 (br s, 3H), 3.89 (s, 3H), 3.05 (br s, 1H), 2.12 - 1.75 (m, 2H), 1.41 (d,J= 6.4 Hz, 6H), 1.22 - 0.97 (m, 6H), 0.96 - 0.80 (m, 2H).

[0376] <Example 29>

[0377] Preparation of N-(4-(1-cyclopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-4-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-6-methyl-1,3,5-triazin-2-amine

[0378]

[0379] The synthesis was performed in the same manner as in Example 11, except that (4-(1-cyclopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanamine was used instead of intermediate A of Example 6.

[0380] <Example 30>

[0381] Preparation of 4-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-6-ethyl-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1,3,5-triazin-2-amine

[0382]

[0383] (Step 1) To a solution of (4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanamine (0.200 g, 706 μmol, 1.00 equiv) in dichloromethane (2.00 mL) were added 2,4-dichloro-6-ethyl-1,3,5-triazine (126 mg, 706 μmol, 1.00 equiv) and triethylamine (143 mg, 1.41 mmol, 197 μL, 2.00 equiv) at 0 °C. The mixture was stirred at 20 °C for 2 h. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to obtain 4-chloro-6-ethyl-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1,3,5-triazin-2-amine (250 mg, 588 μmol, yield 83%) as a white solid.

[0384] 1 H-NMR (400 MHz, DMSO-d6)δ= 9.09 (td,J= 6.4, 17.2 Hz, 1H), 8.16 (s, 1H), 7.57 - 7.49 (m, 2H), 7.48 - 7.40 (m, 2H), 4.69 - 4.53 (m, 2H), 4.46 (dt,J= 4.4, 6.4 Hz, 1H), 2.59 (q,J= 7.6 Hz, 2H), 1.39 (dd,J= 1.6, 6.4 Hz, 6H), 1.18 - 1.15 (m, 3H).

[0385] (Step 2) A mixture of 4-chloro-6-ethyl-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1,3,5-triazin-2-amine (0.100 g, 235 μmol, 1.00 equiv), (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (91.3 mg, 471 μmol, 2.00 equiv), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (17.2 mg, 23.5 μmol, 0.100 equiv) and potassium phosphate (99.9 mg, 471 μmol, 2.00 equiv) in dioxane (1.00 mL) and water (0.200 mL) was degassed and purged with nitrogen three times. The mixture was stirred at 100°C under a nitrogen atmosphere for 12 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to obtain a yellow solid. This yellow solid was purified by preparative HPLC (column Phenomenex luna C18 150×25 mm×10 μm; mobile phase: [water (formic acid)-acetonitrile]; gradient: 45%-75% B, for 9 min) and lyophilized to obtain 4-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-6-ethyl-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1,3,5-triazin-2-amine (46.07 mg, 85.11 μmol, yield 36.1%, purity 99.5%) as a white solid.

[0386] 1H-NMR (400 MHz, DMSO-d6)δ= 8.84 - 8.74 (m, 1H), 8.64 (d,J= 9.2 Hz, 1H), 8.16 (d,J= 1.2 Hz, 1H), 7.58 - 7.48 (m, 3H), 7.46 - 7.37 (m, 1H), 4.65 (d,J= 6.0 Hz, 1H), 4.58 (br d,J= 6.4 Hz, 1H), 4.53 - 4.39 (m, 1H), 3.85 (d,J= 9.2 Hz, 3H), 2.70 - 2.61 (m, 2H), 1.84 - 1.72 (m, 1H), 1.40 (t,J= 6.0 Hz, 6H), 1.21 (q,J= 7.6 Hz, 3H), 1.07 - 1.02 (m, 1H), 1.01 - 0.91 (m, 2H), 0.86 - 0.77 (m, 1H).

[0387] <Example 31>

[0388] Preparation of N-(4-(1-cyclopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-4-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-6-ethyl-1,3,5-triazin-2-amine

[0389]

[0390] A synthesis was performed in the same manner as in Example 31, except that (4-(1-cyclopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanamine was used instead of (4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanamine.

[0391] <Example 32>

[0392] Preparation of 4-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-6-isopropyl-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1,3,5-triazin-2-amine

[0393]

[0394] (Step 1) To a solution of 2,4,6-trichloro-1,3,5-triazine (1.00 g, 5.42 mmol, 1.00 equiv) in tetrahydrofuran (10.0 mL) was added isopropylmagnesium chloride·lithium chloride (2.00 M, 3.25 mL, 1.20 equiv) at -10 °C. The mixture was stirred for 2 h under a nitrogen atmosphere at 0 °C. The reaction mixture was stopped by adding 100 mL of aqueous ammonium bicarbonate solution, and extracted with ethyl acetate (50 mL each three times). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to obtain 2,4-dichloro-6-isopropyl-1,3,5-triazine (500 mg, 2.60 mmol, yield 48%) as a yellow oil.

[0395] 1 H-NMR (400 MHz, CDCl3)δ= 3.20 - 3.08 (m, 1H), 1.40 - 1.31 (m, 6H).

[0396] (Step 2) To a solution of (4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanamine (295 mg, 1.04 mmol, 1.00 equiv) in dichloromethane (2.00 mL) were added 2,4-dichloro-6-isopropyl-1,3,5-triazine (200 mg, 1.04 mmol, 1.00 equiv) and triethylamine (211 mg, 2.08 mmol, 290 μL, 2.00 equiv). The mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to give 4-chloro-6-isopropyl-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1,3,5-triazin-2-amine (220 mg, 501 μmol, yield 48%) as a yellow oil.

[0397] 1 H-NMR (400 MHz, DMSO-d6)δ= 9.18 - 9.05 (m, 1H), 8.16 (s, 1H), 7.56 - 7.50 (m, 2H), 7.48 - 7.41 (m, 2H), 4.59 (dd,J= 6.4, 17.4 Hz, 2H), 4.46 (br dd,J= 6.8, 14.2 Hz, 1H), 2.78 (dt,J= 4.4, 6.8 Hz, 1H), 1.39 (dd,J= 4.4, 6.4 Hz, 6H), 1.20 - 1.14 (m, 6H).

[0398] (Step 3) A mixture of 4-chloro-6-isopropyl-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1,3,5-triazin-2-amine (220 mg, 501 μmol, 1.00 equiv), (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (146 mg, 752 μmol, 1.50 equiv), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (36.7 mg, 50.1 μmol, 0.100 equiv) and potassium phosphate (213 mg, 1.00 mmol, 2.00 equiv) in dioxane (2.00 mL) and water (0.400 mL) was degassed and purged with nitrogen three times, and the mixture was then The mixture was stirred for 2 hours under a nitrogen atmosphere at 100°C. The reaction mixture was concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to obtain the crude product. This crude product was purified by preparative HPLC (column Phenomenex luna C18 150×25 mm×10 μm; mobile phase: [water (formic acid)-acetonitrile]; gradient: 55%-85% B for 15 min) and lyophilized to give 4-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-6-isopropyl-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1,3,5-triazin-2-amine (53.64 mg, 95.52 μmol, yield 19.05%, purity 98.4%) as a white solid.

[0399] 1H-NMR (400 MHz, DMSO-d6)δ= 8.62 (s, 1H), 8.47 (br d,J= 2.8 Hz, 1H), 8.01 (s, 1H), 7.52 (br s, 4H), 4.64 (br s, 2H), 4.55 - 4.40 (m, 1H), 3.88 (s, 3H), 2.87 (td,J= 6.8, 13.6 Hz, 1H), 1.93 - 1.76 (m, 1H), 1.41 (d,J= 6.8 Hz, 6H), 1.24 (br d,J= 6.8 Hz, 6H), 1.05 (br s, 2H), 0.97 - 0.77 (m, 2H).

[0400] <Example 33>

[0401] Preparation of N-(4-(1-cyclopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-4-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-6-isopropyl-1,3,5-triazin-2-amine

[0402]

[0403] A synthesis was performed in the same manner as in Example 32, except that (4-(1-cyclopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanamine was used as the starting material instead of (4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanamine.

[0404] 1 H-NMR (400 MHz, DMSO-d6)δ= 8.63 (br s, 1H), 8.49 (br d,J= 2.4 Hz, 1H), 7.83 (br d,J= 16.4 Hz, 3H), 7.60 - 7.29 (m, 2H), 4.65 (br s, 2H), 3.89 (br s, 3H), 3.70 (br s, 1H), 2.93 - 2.74 (m, 1H), 1.86 (br s, 1H), 1.25 (br d,J= 5.2 Hz, 6H), 1.12 - 0.98 (m, 4H), 0.97 - 0.78 (m, 4H).

[0405] <Example 34>

[0406] Preparation of N-(4-(1-cyclopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-4-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-6-(trifluoromethyl)-1,3,5-triazin-2-amine

[0407]

[0408] (Step 1) To a solution of (4-(1-cyclopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanamine (1.00 g, 3.15 mmol, 1.00 equiv, hydrochloride) in toluene (10.0 mL) was added dicyandiamide (529 mg, 6.29 mmol, 2.00 equiv). The mixture was stirred at 120 °C for 12 h. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was triturated with ethyl acetate at 25 °C for 30 min, filtered, and the filtrate was concentrated under reduced pressure to obtain 1-carbamimidoyl-3-((4-[1-cyclopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl)methyl)guanidine (820 mg, crude) as a yellow oil.

[0409] 1 H-NMR (400 MHz, DMSO-d6)δ= 8.60 (br s, 1H), 8.03 - 7.90 (m, 3H), 7.51 (br d,J= 8.0 Hz, 1H), 7.16 (br s, 3H), 6.71 (br s, 2H), 4.52 (br d,J= 5.6 Hz, 1H), 3.81 (td,J= 3.2, 6.8 Hz, 1H), 1.12 - 1.00 (m, 2H), 0.96 (br d,J= 3.2 Hz, 2H).

[0410] (Step 2) To a solution of 1-carbamimidoyl-3-((4-[1-cyclopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl)methyl)guanidine (760 mg, 2.08 mmol, 1.00 equiv) in methanol (8.00 mL) were added ethyl trifluoroacetate (591 mg, 4.16 mmol, 571 μL, 2.00 equiv) and sodium methoxide (225 mg, 4.16 mmol, 2.00 equiv). The reaction mixture was stirred at 20°C for 12 h. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by reverse phase chromatography (C18, 80 g; conditions: water / acetonitrile = 100:0 to 0:100, 0.1% formic acid) and lyophilized to N 2 -(4-(1-Cyclopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6-(trifluoromethyl)-1,3,5-triazine-2,4-diamine (280 mg, 632 μmol, yield 30%) was obtained as a white solid.

[0411] 1 H-NMR (400 MHz, DMSO-d6) δ10.24 - 8.20 (m, 1H), 7.98 - 7.81 (m, 3H), 7.66 - 7.19 (m, 4H), 4.63 - 4.45 (m, 2H), 3.78 - 3.69 (m, 1H), 1.04 - 0.96 (m, 2H), 0.91 (br s, 2H).

[0412] (Step 3) N in acetonitrile (3.00 mL) 2To a solution of -(4-(1-cyclopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6-(trifluoromethyl)-1,3,5-triazine-2,4-diamine (270 mg, 609 μmol, 1.00 equiv) were added cuprous bromide (131 mg, 914 μmol, 27.9 μL, 1.50 equiv) and tert-butyl nitrite (94.2 mg, 914 μmol, 109 μL, 1.50 equiv). The reaction mixture was stirred at 60°C for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by reverse phase chromatography (C18, 120 g; conditions: water / acetonitrile = 100:0 to 0:100, 0.1% formic acid) and lyophilized to give 4-bromo-N-(4-(1-cyclopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6-(trifluoromethyl)-1,3,5-triazin-2-amine (50.0 mg, 98.6 μmol, yield 16%) as a white solid.

[0413] 1 H-NMR (400 MHz, CDCl3)δ= 7.98 - 7.73 (m, 2H), 7.45 - 7.39 (m, 2H), 7.37 (s, 1H), 6.57 - 6.27 (m, 1H), 4.77 (t,J= 6.0 Hz, 2H), 3.51 (dt,J= 2.8, 6.8 Hz, 1H), 1.15 - 1.01 (m, 2H), 0.90 (br s, 2H).

[0414] (Step 4) To a solution of 4-bromo-N-(4-(1-cyclopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6-(trifluoromethyl)-1,3,5-triazin-2-amine (40 mg, 78.9 μmol, 1.00 equiv) and (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (23.0 mg, 118 μmol, 1.50 equiv) in dioxane (0.500 mL) and water (0.100 mL) were added [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (5.77 mg, 7.89 μmol, 0.100 equiv) and potassium phosphate (33.5 mg, 158 μmol, 2.00 equiv). This mixture was stirred at 100°C under a nitrogen atmosphere for 1 hour. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to obtain the crude product. This crude product was purified by preparative HPLC (column Phenomenex luna C18 150×25 mm×10 μm; mobile phase: [water (formic acid)-acetonitrile]; gradient: 55%-85% B for 15 min) and lyophilized to give N-(4-(1-cyclopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-4-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-6-(trifluoromethyl)-1,3,5-triazin-2-amine (21.66 mg, 37.46 μmol, yield 47.50%, purity 99.7%) as a yellow solid.

[0415] 1H-NMR (400 MHz, DMSO-d6)δ= 9.51 - 9.37 (m, 1H), 8.67 (d,J= 7.2 Hz, 1H), 7.86 (dd,J= 8.0, 14.4 Hz, 2H), 7.80 (s, 1H), 7.52 (br d,J= 8.0 Hz, 1H), 7.45 (br d,J= 8.0 Hz, 1H), 4.84 - 4.57 (m, 2H), 3.90 (d,J= 10.0 Hz, 3H), 3.78 - 3.58 (m, 1H), 1.97 - 1.85 (m, 1H), 1.15 - 1.04 (m, 2H), 1.04 - 0.89 (m, 5H), 0.89 - 0.82 (m, 1H).

[0416] [Experimental Example 1] Inhibition test of deubiquitination activity

[0417] In this experimental example, the inhibitory effect of the compound obtained in the above example on the activity of ubiquitin-specific peptidase 1 was examined. To this end, the degree of fluorescence quenching that occurs when the deubiquitinating enzyme action breaks down the heterocyclic amide bond of the rhodamine substrate bound to the C-terminal glycine residue of ubiquitin was measured.

[0418] Specifically, the deubiquitination reaction was initiated by adding 250 nM ubiquitin-rhodamine 110 (Boston Biochem, USA) substrate to 0.03125 nM USP1 / UAF1 enzyme dispersed in an enzyme reaction buffer solution (50 mM HEPES, 100 mM NaCl, 0.1 mg / mL BSA, 2 mM TCEP) at pH 7.4. The test substances, the example compounds, were each added in the form of a solution in dimethyl sulfoxide (DMSO) to examine the dose-response relationship by increasing the concentration, and the lowest concentration of the compound was started at 10 μM. Fluorescence was measured under 480 nm excitation light and 540 nm emission light in kinetic mode for 30 minutes for the reaction mixture to which the DMSO solution of the test substance and the mixture of the substrate were added. Based on the measured value, the half-maximal inhibition concentration (IC), which is the concentration of the test substance corresponding to half the fluorescence intensity observed when the test substance was not treated, was determined. 50 The values ​​were calculated. IC of each compound 50 The values ​​are as shown in Table 1 below.

[0419]

[0420] [Experimental Example 2] Cell Survival Assay Experiment

[0421] In this experimental example, the cell growth inhibitory effect of compounds according to the present invention and positive control compounds in tumor cell lines was examined.

[0422] MDA-MB-436 (ATCC, #HTB-130) cell line was cultured in cell culture medium (Leibovitz's L-15 (GIBCO catalog no. 11415064) + 10 μg / mL insulin (Yeasen catalog no. 40112ES25) + 16 μg / mL glutathione (GIBCO catalog no. 25030-081) + 10% fetal bovine serum (FBS) (Excell Bio catalog no. FSP500)). 3,000 MDA-MB-436 cells were plated per well in a 96-well plate and cultured for 1 day at 37°C in 5% CO2. Using a 10-fold concentrated stock solution of the compound in dimethyl sulfoxide (DMSO) solvent, the compound, the control compound (ML323), or a blank sample of DMSO without the compound was added to each well to adjust the concentration of the compound in the culture medium to the final test concentration (0.25%). The cells were then cultured in a cell incubator for 10 days, and the cell culture medium containing the compound was replaced on the 5th day of culture. Cell viability was analyzed for luminescence using the Promega CellTiter-Glo Luminescent Cell Viability Assay Kit (Promega catalog number G7573), and the luminescence was measured using a PerkinElmer EnVision instrument. The percent cell growth inhibition rate was calculated from the measured relative luminescence unit (RLU) as follows.

[0423]

[0424] From this cell growth inhibition rate, the half maximal inhibitory concentration (IC), which is the concentration at which each compound inhibits cell growth by 50%, was calculated using the GraphPad Prism program. 50 ) were calculated and summarized in Table 2 below.

[0425]

[0426] From these results, it was found that the compound of the present invention can inhibit USP1 enzyme activity and has selectivity to exhibit synthetic lethal efficacy together with BRCA1.

[0427] Although the present invention has been described through limited embodiments as described above, the technical idea and scope of the present invention are not limited to these embodiments, and the invention of the patent claims described below, as well as various modifications or variations of the invention described in the patent claims that are obvious to a person having ordinary skill in the art to which the present invention pertains, are also included in the scope of the present invention within the equivalent scope of the invention described in the patent claims.

Claims

1. A compound of chemical formula 1 or a stereoisomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: [Chemical Formula 1] In chemical formula 1 is phenylene, 5-6 membered heteroarylene, 5-6 membered saturated or unsaturated heterocycloalkylene, C 7~10 Bridged bicycloalkylene or cubaylene, wherein said phenylene, 5-6 membered heteroarylene, 5-6 membered saturated or unsaturated heterocycloalkylene, C 7~10 Bridged bicycloalkylene or cubaylene optionally comprises one or more hydrogens independently of one another, halogen, C 1~4 Alkoxy, C 1~4 Alkyl, C 1~4 Haloalkyl and C 3~6 may be substituted with a substituent selected from the group consisting of cycloalkyl; R 1 is a 5-6 membered substituted or unsubstituted heteroaryl, and the substituent of the substituted heteroaryl is halogen, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy and C 3~6 At least one independently selected from the group consisting of cycloalkyl; R 2 is hydrogen, C 1~4 Alkyl, C 1~4 Haloalkyl, deuterium substituted C 1~4 Alkyl, C 2~4 Alkynyl, Cyano, C 3~6 Cycloalkyl, saturated or unsaturated 5-6 membered substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted phenyl or 5-6 membered substituted or unsubstituted heteroaryl, wherein the substituted heterocycloalkyl, substituted phenyl or substituted heteroaryl is halogen, C 1~3 Alkyl, C 1~3 Haloalkyl and C 3~6 may be substituted with one or more substituents independently selected from the group consisting of cycloalkyl; R 3 And R' is R in the absence of R' 3 Silver hydrogen, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, cyano or C 3~6 Cycloalkyl or, R 3 R and R' are connected to each other 3 Forming a pyrazolotriazine fused ring together with the six-membered ring carbon bonded to and the six-membered ring nitrogen bonded to R'; R 4 is selected from substituted or unsubstituted phenyl and 5-6 membered substituted or unsubstituted heteroaryl, wherein the substituent of the substituted phenyl or substituted heteroaryl is C 1~4 Alkoxy, C 1~4 Alkyl, C 1~4 Haloalkyl, C 3~6 At least one independently selected from the group consisting of cycloalkyl and 3-6 membered saturated or unsaturated heterocycloalkyl.

2. In the first paragraph, the compound is characterized by having a structure of chemical formula 2: [Chemical formula 2] R in chemical formula 2 2 is hydrogen, C 1~4 Alkyl, C 1~4 Haloalkyl, deuterium substituted C 1~4 Alkyl, C 2~4 Alkynyl, Cyano, C 3~6 Cycloalkyl, saturated or unsaturated 5-6 membered substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted phenyl or 5-6 membered substituted or unsubstituted heteroaryl, wherein the substituted heterocycloalkyl, substituted phenyl or substituted heteroaryl is halogen, C 1~3 Alkyl, C 1~3 Haloalkyl and C 3~6 may be substituted with one or more substituents independently selected from the group consisting of cycloalkyl; R 5 Inland R 7 are hydrogen and C respectively 1~4 Alkoxy, C 1~4 Alkyl, C 1~4 Haloalkyl and C 3~6 Independently selected from the group consisting of cycloalkyl; R 8 Silver hydrogen, C 1~4 Alkoxy or C 1~4 It is alkyl; R 9 is hydrogen, C 1~4 Alkoxy, C 1~4 Alkyl or C 1~4 It is haloalkyl, R 10 is a halogen, and when n is 2 or more, each case is independently selected from among the halogens, n is an integer from 0 to 4, X 1 And X 2 are different elements to choose from among N and C.

3. In paragraph 1, the compound A compound characterized by:

4. A pharmaceutical composition for the treatment of cancer comprising a therapeutically effective amount of a compound according to claim 1 and a pharmaceutically acceptable excipient.

5. A pharmaceutical composition for the treatment of a disease that can be treated by inhibiting the activity of a deubiquitinating enzyme, comprising a therapeutically effective amount of a compound according to claim 1 and a pharmaceutically acceptable excipient.

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